👤 J Gustav Smith

The preoptic area (POA) is a well-established regulator of body temperature, but its role in feeding behavior remains underexplored. Our study identifies leptin receptor (Lepr)-expressing neurons in the POA (POA Show less

Following their domestication, chickens were translocated around the world to novel environments. Through a combination of natural and artificial selection, chickens adapted to these local conditions, creating significant genetic diversity across populations worldwide. Studying this diversity in the context of local environmental conditions may offer insights into mechanisms of adaptation to environmental stressors. In this study, we analyzed genomic data from the Chicken Genomic Diversity Consortium, applying multiple statistical approaches, including fixation index (F The online version contains supplementary material available at 10.1038/s41598-026-41813-8. Show less

Overactive bladder (OAB) syndrome, characterised by urinary urgency, frequency, and nocturia can significantly impacts patients' quality of life. Current diagnosis is clinical, but complex cases often require invasive urodynamic studies (UDS), which are costly, subjective, and carry risks like discomfort and infection. Therefore, we hypothesise that urinary biomarkers could serve as noninvasive diagnostic tools for OAB. Establishing a reliable biomarker profile could ultimately lessen the reliance on invasive US, provided clinical validity is confirmed. Following PRISMA guidelines and registered under PROSPERO (ID: CRD420251026279), a comprehensive search across six major databases was conducted from their inception until September 2025, yielding 39 studies for qualitative analysis. This qualitative review identified several promising biomarkers for OAB diagnosis. Notably, NGF and BDNF consistently emerged as elevated in OAB patients and were responsive to treatment. Additionally, TNF-α, MIP-1β, Tie2, and CCL2 showed diagnostic potential, with TNF-α and MIP-1β particularly useful for differentiating OAB from interstitial cystitis/bladder pain syndrome (IC/BPS) and urinary tract infections (UTIs). However, limitations such as variability in measurement protocols and a lack of specificity for certain biomarkers (e.g. MMP-1, 8-OHdG) were noted. Urinary biomarkers offer a promising noninvasive approach to diagnosing OAB. Further validation of promising markers, particularly NGF, BDNF, TNF-α, MIP-1β, and CCL2, could lead to individualised therapies. While promising, the routine replacement of UDS remains an aspirational goal dependent on future large-scale validation. Show less

Annotation of regulatory elements is essential for understanding mechanisms underlying gene regulation, particularly tissue-specific regulation in human and animals. Here, we characterize 274,682 enhancers and 25,975 promoters across 24 tissues from an adult female sheep using ChIP-seq, ATAC-seq, CAGE-seq, RRBS, WGBS, and RNA-seq. We identify seven neural development-related genes with over 10 enhancers in brain tissues, highlighting the role of tissue-specific regulation. Cis-regulatory enhancer-promoter combinations provide insights into tissue-specific enhancers, such as the cerebellum-specific enhancer (chr15: 57390520-57390685) regulating BDNF, which is expressed in both the cerebellum and cerebral cortex. Comparative analysis of enhancer-promoter combinations in human, mouse, pig, cattle, and sheep reveals ruminant-specific pathways, including pentose catabolism and long-chain fatty acid import regulation. A milk fat yield quantitative trait locus (QTL) identified within an enhancer interacts with the fat metabolism-related gene COMMD1, and a birth weight-associated QTL detected within a cerebellum-specific enhancer regulates XKR4. This study provides a robust framework for exploring cis-regulatory mechanisms and tissue-specific regulation, advancing the functional annotation of the sheep reference genome. Show less

Pain is common among adults with heart failure (HF), but pain subtypes and associated biomarkers are understudied. The aims were to: 1) characterize chronic pain severity, neuropathic pain quality, locations, and subtypes; and 2) compare pain severity and levels of biomarkers among pain subtypes. An exploratory aim was to correlate levels of biomarkers with pain severity. This pilot descriptive study included cross-sectional data from 60 adults with HF and chronic pain. Pain was evaluated using the PainDETECT questionnaire. Blood biomarkers included interleukin (IL)-10, IL-18, IL-1β, IL-33, IL-6, IL-8, tumor necrosis factor (TNF)-α, brain-derived neurotrophic factor, leptin, adiponectin, and C-reactive protein. Descriptive statistics, Chi-square test of homogeneity, one-way analysis of variance, and Spearman correlation were used for analyses. The mean age was 70.45 (SD 7.92) years. The sample consisted of 63.3% women and 65.0% White race. Participants primarily reported nociceptive pain only (73.3%) with fewer reporting neuropathic pain only (6.7%) and mixed pain (20.0%). Current and 4-week mean pain severity scores were highest in the mixed pain subtype (p both <.05). No biomarkers were significantly different across the pain subtypes, but lower lL-10 (p=.049), and IL-33 (p=.014), were associated with higher pain severity. In this study, chronic pain and its association with underlying biomarkers were characterized. Future research with a larger sample is needed to understand the unique contributions of biomarkers with targeted pain phenotypes. Show less

Advanced prostate cancer remains challenging, driven in part by Epidermal Growth Factor (EGF) signaling that promotes migration, invasion, and angiogenesis. We evaluated LA3IK ( The online version contains supplementary material available at 10.1038/s41598-026-41933-1. Show less

GLP-1 RAs are effective in treating obesity; however, they typically result in significant loss of skeletal muscle mass. Real-world evidence to inform systematic guidelines and clinical implementation for preserving skeletal muscle mass and reducing cardiometabolic risk with lifestyle modifications on GLP-1 RAs remains limited. This study evaluated the effectiveness of the TouchCare Method, a lifestyle intervention incorporating nutrition and exercise with GLP-1 RAs, for improving body composition and cardiometabolic risk. A retrospective chart review included patients enrolled in Bucks Health and Wellness between February 2024 and September 2025, for at least 12 month ( Patients adherent to the TouchCare Method for 12 months were included in the final analysis ( The TouchCare Method may improve GLP-1 RA treatment outcomes by providing comprehensive structured lifestyle interventions supporting clinically significant weight loss while preserving skeletal muscle mass and improving cardiometabolic risk factors. Show less

Oxidized phospholipids (OxPL) are bioactive lipid species that circulate bound to apolipoprotein B-100 [apoB] and apolipoprotein(a) [apo(a)] and have been widely studied as biomarkers of oxidative lipid burden. When bound to apolipoprotein B-100 [OxPL-apoB] and apolipoprotein(a) [OxPL-apo(a)], they serve as informative biomarkers for CVD risk prediction, risk reclassification, and therapeutic monitoring, particularly in studies involving RNA-targeted therapies against lipoprotein(a). To date, measurement of OxPL-apoB and OxPL-apo(a) has been limited to research-use assays performed in an academic laboratory without formal clinical laboratory validation. Here we report the first full CLIA-compliant analytical validation of chemiluminescent ELISA methods for OxPL-apoB and OxPL-apo(a), enabling their implementation in a regulated clinical reference laboratory setting. The OxPL-apoB ELISA employs murine monoclonal IgG antibody MB47 to capture apoB-100-containing lipoproteins, while the OxPL-apo(a) employs murine monoclonal IgG antibody LPA4 to capture apo(a)-containing particles. In both assays, OxPL is detected by murine monoclonal IgM antibody biotin-E06. The concentration of OxPL is determined against a standard curve of phosphocholine (PC) equivalents using PC-modified bovine serum albumin. The analytical measuring range of both assays is 1.48-148.48 nmol/L PC-OxPL. Serum and plasma matrices showed minimal bias and were analytically equivalent. In healthy donors, OxPL-apoB levels ranged from <1.48 to 25.23 nmol/L PC-OxPL (mean 4.18, median 1.79 nmol/L), while OxPL-apo(a) levels ranged from <1.48 to 126.94 nmol/L PC-OxPL (mean 31.04, median 6.90 nmol/L), with strong correlation to Lp(a) concentrations (R Show less

This study determines the phenotypic and functional characteristics that define distinct fibroblast-like synoviocyte (FLS) populations in rheumatoid arthritis (RA) vs psoriatic arthritis (PsA). Single-cell RNA sequencing and multiparametric flow cytometry analysis (21 markers) were performed on RA and PsA synovial cell suspensions to determine FLS phenotype/function. Podoplanin (PDPN) Flow analysis of PDPN RA and PsA possess distinct FLS populations with unique functional and metabolic properties, which may facilitate improved understanding of disease pathogenesis and therapeutic response. Show less

The apolipoprotein E (APOE) gene ε4 allele leads to increased Alzheimer disease risk and neuroinflammation and is also believed to play a role in postoperative delirium. However, the safety and feasibility of modulating apoE protein signaling to reduce postoperative neuroinflammation and delirium in older adults are unclear. To assess the safety and feasibility of the apoE mimetic peptide CN-105 for reducing delirium incidence and severity and neuroinflammation after noncardiac or nonintracranial surgery in older adults. This triple-blind, escalating dose, phase 2 randomized clinical trial enrolled patients from April 17, 2019, to December 28, 2022, at a tertiary academic medical center. Included patients were 60 years or older and scheduled for a noncardiac or nonintracranial surgery. Exclusion criteria were incarceration, planned chemotherapy within 6 weeks after surgery, or inability to undergo lumbar punctures. Data analyses were based on a modified intention-to-treat approach and were performed from August 14, 2023, to August 22, 2025. Patients were randomly assigned 3:1 to the CN-105 group or placebo group. The CN-105 group received intravenous CN-105 doses of 0.1, 0.5, or 1 mg/kg starting within 1 hour before surgery and administered every 6 hours afterward until hospital discharge or 13 doses were received. Patients in the placebo group followed the same administration schedule. The primary outcome was safety-the incidence and number of postoperative adverse events (AEs). Secondary outcomes included feasibility (rate of drug doses administered within 90 minutes of schedule), postoperative delirium incidence and severity, and postoperative changes in cerebrospinal fluid (CSF) cytokine levels (interleukin [IL] 6, granulocyte-colony stimulating factor [G-CSF], monocyte chemoattractant protein-1 [MCP-1], and IL-8). Among 203 enrolled patients, 186 (mean [SD] age, 68.7 [5.2] years; 119 males [64.0%]) were randomized (137 to the CN-105 group, 49 to the placebo group) and underwent surgery. The rates of grade 2 or higher AEs among patients in the CN-105 and placebo groups were 76.6% and 87.8% (relative risk [RR], 0.87; 95% CI, 0.76-1.00; P = .10). The CN-105 vs placebo group had fewer grade 2 or higher AEs per patient (median [IQR], 1 [1-3] vs 2 [1-5]; P = .03). The percentage of CN-105 doses administered within the time window was 94.6% (860 of 909; 95% CI, 92.9%-96.0%) in the CN-105 group and 93.8% (346 of 369; 95% CI, 90.8%-96.0%) in the placebo group. Among patients in the CN-105 vs placebo group, the postoperative delirium incidence was 19.3% vs 26.5% (odds ratio [OR], 0.66; 95% CI, 0.31-1.42; P = .29); the median (IQR) postoperative delirium severity scores were 1 (1-2) vs 2 (1-2) (P = .19); and the median difference in preoperative to 24-hour postoperative CSF cytokine-level changes were as follows: -0.39 pg/mL (95% CI, -0.93 to 0.14 pg/mL, P = .12) for IL-6, -0.84 pg/mL (95% CI, -3.06 to 1.40 pg/mL; P = .18) for G-CSF,-23.32 pg/mL (95% CI, -94.36 to 44.93 pg/mL; P = .57) for IL-8, and -2.36 pg/mL (95% CI, -58.57 to 58.62 pg/mL; P = .50) for MCP-1. In this phase 2 randomized clinical trial of older surgical patients, CN-105 (vs placebo) administration was feasible and did not increase AEs. A phase 3 trial is warranted to further evaluate the efficacy of CN-105 for reducing postoperative AEs and to more precisely determine its effects on postoperative delirium incidence and severity. ClinicalTrials.gov Identifier: NCT03802396. Show less

CNS diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors, including genetic risk. Here, we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered into 15 broad categories by International Classification of Diseases-10 (ICD-10) coding. These donors were collected by six repositories comprising the National Institutes of Health NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants were detected in whole-genome sequencing (WGS), normalized and annotated to describe their functional impact, resulting in 171,121,209 unique variants and 1,078,774 non-silent variants. These raw and normalized data have been made available as a neurogenomics resource in the National Institute of Mental Health Data Archive (NIMH NDA) (nda.nih.gov), combined with donor-matched deep demographic and phenotypic data from the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate applications, we replicated the strong association observed in previous studies between pathogenic CAG nucleotide repeat expansions in the HTT gene with the clinical diagnosis of Huntington's disease, as well as associations of the APOE gene with Alzheimer's disease, and examined the association of polygenic risk scores with the three most common disease diagnoses in the cohort. Show less

Untargeted mass spectrometry remains underutilised for blood-based biomarker discovery in dementia research from large cohorts, where affinity-based approaches dominate. To address this, we examined mass-spectrometry-derived proteomic correlates of cognitive function, genetic predisposition to cognitive health, Show less

Lobar intracerebral haemorrhage (ICH) is associated with cerebral amyloid angiopathy (CAA) pathology. Uncertainty remains about the mechanisms leading from CAA to ICH. We investigated the distribution and characteristics of CAA, and its clinical and neuropathological associations. Participants underwent research autopsy in the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study. Neuropathologists rated tissue for CAA using standardised consensus criteria, as well as non-amyloid small vessel disease, Thal phase, and Braak stage. We compared the presence, distribution, and severity of CAA among different brain regions, and in the lobe or hemisphere affected by lobar ICH to corresponding contralateral regions. We evaluated the diagnostic accuracy of Vonsattel CAA grade on a post-mortem cortical specimen (simulating surgical biopsy) versus the reference standard of moderate-to-severe parenchymal CAA at autopsy. Among 162 participants, parenchymal CAA, meningeal CAA, and CAA-associated vasculopathy were diffusely distributed among all cerebral lobes irrespective of the ICH location, but capillary CAA showed an occipital predominance. In lobar ICH, all CAA measures did not differ between the ICH lobe or hemisphere and the contralateral unaffected region. CAA measures did not increase with age, but they were higher in carriers of APOE ε2 or ε4 alleles and in individuals with higher Thal phase or Braak stage. Using a rule-out category of Vonsattel grade ≥ 1 to diagnose CAA on a simulated cortical biopsy achieved 100% sensitivity (95%CI 93.4-100), and a rule-in category of Vonsattel grade ≥ 2 had 79.5% specificity (95%CI 63.5-90.7) versus the reference standard. The distribution and severity of parenchymal CAA, meningeal CAA, and CAA-associated vasculopathy are diffuse regardless of ICH location, indicating the need to better understand the factors underlying bleeding in CAA-affected vessels. Show less

Factors underlying discordant visual and quantitative amyloid beta-positron emission tomography (Aβ-PET) results and their clinical implications are not well understood. Participants from the 1Florida Alzheimer's Disease Research Center (1FLADRC) underwent Aβ-PET, blood draw, brain magnetic resonance imaging (MRI), and neuropsychological testing. We evaluated differences in demographics, apolipoprotein E ( We studied 386 participants (mean age ± SD: 70.7 ± 7.8, 55.2% female, 44.6% Hispanic White). Compared to V+/Q-, V-/Q+ had a higher frequency of Discordant Aβ-PET findings likely hold clinical significance and may reflect early stages of neuropathological progression. Groups with concordant/discordant visual-quantitative amyloid beta-positron emission tomography (Aβ-PET) results were compared.Visual-/quant+ were more likely than visual+/quant- to be apolipoprotein E ( Show less

BackgroundFunctional independence is crucial for healthy aging, and its loss is a diagnostic criterion for dementia, including Alzheimer's disease. However, functional impairment (FI) can emerge before dementia diagnosis. Early and accurate characterization of FI may help identify individuals at elevated risk of cognitive decline and dementia.ObjectiveExploring the utility of capturing persistent versus impersistent FI, to identify a higher-risk group for incident cognitive decline and dementia.MethodData from 11,793 cognitively normal (CN) older adults from the National Alzheimer's Coordinating Center were analyzed. Exploratory factor analysis identified four Functional Activities Questionnaire items-preparing hot drinks, preparing balanced meals, shopping, and traveling-representing primarily functional abilities. An FI composite score was calculated as the sum of these items. Persistent FI was operationalized as FI present (composite score ≥ 2) at more than two-thirds of all visits prior to cognitive decline and dementia. Comparator groups were impersistent/transient FI and no FI. Time-dependent covariate Cox models compared incidence of cognitive decline and dementia across time-dependent FI groups, adjusted for demographics, Show less

Functional impairment (FI) is a key criterion for diagnosing dementia. However, subtle functional changes may occur during preclinical and prodromal phases but may not be accurately characterized. Furthermore, research linking FI to Alzheimer disease (AD) biofluid biomarkers is limited. Here we examined cross-sectional associations between cerebrospinal fluid (CSF) AD biomarkers and persistent versus transient FI in dementia-free older adults, and the longitudinal association of FI with incident dementia. Data from 1000 participants (age 72.9 ± 7.0; 45.2% female; 62.8% MCI) from the Alzheimer's Disease Neuroimaging Initiative were analyzed. CSF biomarkers included p-tau181, Aβ42, and ptau-181/Aβ42 ratio. Three Functional Activities Questionnaire items of "preparing a hot beverage," "preparing a balanced meal," and "shopping alone" were identified by factor analysis as assessing function rather than cognition directly. Persistent-FI was operationalized as FI present at> two-thirds of pre-dementia visits. Comparator groups included Transient-FI and No-FI. Linear regression modeled the association between FI status and baseline biomarker levels, while Cox regression assessed the association between FI and incident dementia. Models adjusted for age, sex, education, APOE-ε4 status, and MMSE. Compared to No-FI, Persistent-FI was associated with lower Aβ42 (Beta = -8.93; 95% CI: -13.56 to -4.03; p < 0.001), higher p-tau181 (Beta = 10.81; 95% CI: 0.44-22.26; p = 0.041), and ptau181/Aβ42 ratio (Beta = 21.66; 95% CI: 7.02-38.31; p = 0.003). In contrast, Transient-FI showed no significant associations. APOE-ε4 carrier status was more prevalent in the Persistent-FI group compared to No-FI (p = 0.009), but not in Transient-FI (p = 0.931). Compared to No-FI, Persistent-FI had a 6.66-fold greater dementia incidence rate (95% CI: 4.98-8.91, p < 0.001), while Transient-FI had a 1.72-fold greater incidence rate (95% CI: 1.09-2.72, p = 0.021). Findings extend the limited research on the association of FI with CSF AD biomarkers in dementia-free populations. Operationalizing FI-related risk by persistence enhances prognostication, identifying individuals with greater AD pathology and progression risk. This approach could enhance screening, early detection, and risk stratification, informing timely interventions before dementia onset. Show less

Innate lymphoid cells (ILCs) are rare, tissue-resident innate lymphocytes that functionally mirror CD4+ T helper cell lineages but lack antigen receptors. Type 3 ILCs (ILC3s) are enriched in the gut, airways, and mucosal lymphoid tissues, where they regulate inflammation and promote barrier integrity. To define the regulatory architecture of primary human ILC3s, we map promoter-anchored chromosomal contacts using high-resolution, low-input Promoter Capture Hi-C (PCHi-C) in these cells alongside CD4+ T cells. By combining statistical detection with a PCHi-C-adapted Activity-by-Contact approach, we link promoters to distal regulatory elements, identifying hundreds of ILC3-specific contacts. We use these maps to connect genome-wide association study (GWAS) risk variants for Crohn's disease to target genes using multiCOGS, a Bayesian framework that integrates PCHi-C with summary-statistic imputation and multivariate fine-mapping. This analysis highlights both known and unanticipated candidates, including Show less

To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Twenty-four patients with concern for NS underwent clinical and central radiological review in this multi-institutional study. Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and/or tumor specimens were performed. Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline The online version contains supplementary material available at 10.1007/s11060-026-05478-7. Show less

Fibroblast growth factor 21 (FGF21) analogs are in development for metabolic dysfunction-associated steatotic liver disease (MASLD), but their impact on problematic alcohol use (PAU), alcohol use disorder, binge drinking, and alcohol-related liver disease (ALD) is unknown. We leveraged genome-wide association study data from the UK Biobank, FinnGen, Million Veterans Program, and GenomALC for PAU, alcohol use disorder, binge drinking, weekly drinks, and ALD. Our four-tier evaluation included: (1) multivariable Mendelian randomization (MR) and mediation with circulating FGF21 levels; (2) comparative MR of MASLD and ALD targets (PNPLA3, TM6SF2, HSD17B13) using liver fat and expression instruments; (3) receptor-focused MR of β-Klotho (KLB) and FGFR1/2/3 incorporating brain-region expression; and (4) a phenome-wide MR across 1,022 traits to assess safety. Genetically higher FGF21 protein levels were associated with lower PAU (β = -0.097, 95% CI -0.135 to -0.059, p = 6.13 × 10 Human genetic evidence indicates that FGF21 analogs mitigate hazardous drinking and ALD via both behavioral and metabolic pathways. These findings distinguish FGF21 from other MASLD targets and highlight its potential for precision treatment of alcohol-related disorders. This study leverages human genetic evidence to validate FGF21 - a liver-derived hormone currently in clinical trials for fatty liver disease - as a dual-action therapeutic that both curbs harmful drinking behaviors and protects against alcohol-related liver injury, addressing a critical therapeutic gap with limited existing pharmacotherapies. The results are important for clinicians and researchers seeking precision medicine strategies for alcohol use disorder and liver disease, as well as for patients who currently face limited treatment options. By pinpointing FGF21's behavioral and metabolic pathways and demonstrating a favorable safety profile, our findings support the repurposing of FGF21 analogs in clinical trials of alcohol use disorder and alcohol-related liver disease and suggest that genetic stratification could optimize patient selection for therapy. While these conclusions rely on European-ancestry genetic data and Mendelian randomization assumptions, they help inform future clinical studies, biomarker development, and policy efforts aimed at expanding treatment options for alcohol-related conditions. Show less

Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in men. Androgen deprivation therapy (ADT) has been widely used as the first-line treatment for PCa. However, most PCa will progress to castration-resistant PCa (CRPC) that resists ADT 1 to 3 years after the treatment. Steroidogenesis from cholesterol is one of the mechanisms leading to ADT resistance. In PCa cells, low-density lipoprotein (LDL) mediated uptake is the major venue to acquire cholesterol. However, the mechanism of regulating this process is not fully understood. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that is ectopically expressed in PCa cells and promotes PCa progression by activating downstream signaling pathways. To comprehensively determine the roles of FGFR1 in PCa, we generated FGFR1-null DU145 cells and compared the transcriptomes of FGFR1-null and wild-type cells. We found that ablation of FGFR1 reduced the expression of genes promoting LDL uptake and de novo synthesis of cholesterol, thereby reducing the overall cholesterol pool in PCa cells. Detailed mechanistic studies further revealed that FGFR1 boosted the activation of sterol regulatory element-binding protein 2 (SREBP2) through ERK-dependent phosphorylation and cleavage, which, in turn, increased the expression of low-density lipoprotein receptor (LDLR) and enzymes involved in de novo cholesterol synthesis. Furthermore, in silico analyses demonstrated that high expression of FGFR1 was associated with high LDLR expression and clinicopathological features in PCa. Collectively, our data unveiled a previously unrecognized therapeutic avenue for CRPC by targeting FGFR1-driven cholesterol uptake and de novo synthesis. Show less

To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Twenty-four patients with concern for NS underwent clinical and central radiological review in this multi-institutional study. Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and/or tumor specimens were performed. Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline Show less

Gynecologic carcinosarcoma is an uncommon but aggressive malignancy that frequently requires systemic therapy but therapeutic options are limited. Development of preclinical models is therefore important for therapeutic advancement. Carcinosarcoma tumor (6 uterine and 1 tubo-ovarian) from 7 surgical samples were implanted into immunocompromised mice for patient-derived xenograft (PDX) and/or cell line development. The histologic, immunophenotypic and genetic features were characterized. Based on the observed molecular profiles and targetable molecular alterations, in vivo studies were conducted to evaluate the efficacy of targeted therapy on tumor growth. We established 1 cell line and 6 PDX models which recapitulated the dominant phenotype of the respective parental tumors with preserved mesenchymal differentiation lineage in the sarcomatous component. Genomically, the PDX/cell line models preserved similar complex pattern of copy number alterations and similar mutation landscape when compared to the respective parental tumors. All 7 parental carcinosarcoma tumors and PDX/cell line models harbored pathogenic TP53 mutations. Moreover, we identified recurrent copy number gain/amplification involving several receptor tyrosine kinases (RTK), including amplification and protein over-expression of FGFR1. In vivo drug evaluation using a small molecule inhibitor (AZD4547) of FGFRs showed significant growth inhibition in the carcinosarcoma PDX tumor with the highest FGFR1 amplification and protein expression whereas AZD4547 showed no significant growth effects on carcinosarcoma lacking high level FGFR1 amplification, indicating oncogenic dependency on the amplified RTK pathway. These findings demonstrate the utility of patient-derived tumor models in the identification and the functional validation of potentially targetable molecular alterations in preclinical setting. Show less

Accurate measurement of lipoprotein(a)-cholesterol [Lp(a)-C] may be useful in interpreting the traditional lipid panel, particularly in patients with high Lp(a). We developed and analytically validated a direct immunocapture ELISA in a Clinical Laboratory Improvement Amendments-certified laboratory for quantifying Lp(a)-C in human plasma using an apolipoprotein(a)-specific monoclonal antibody (LPA4) coupled to magnetic beads. The linearity of the assay was found to be excellent (R Show less

Individuals with chronic conditions have persistent, co-occurring symptoms affecting quality of life. Understanding symptom severity susceptibilities is critical for early risk identification, but gaps remain among racial and ethnic minority men with chronic conditions. As such, this study identifies symptom severity profiles in non-Hispanic Black and Hispanic men based on five common symptoms (fatigue, pain, shortness of breath, sleep disturbance, depression) and its associated demographic, clinical, and modifiable sociobehavioral risk factors. Online survey data from 1,982 men aged 40 and older with chronic conditions was analyzed using latent profile analysis (LPA) to identify symptom severity profiles. LPA revealed three symptom severity profiles: lowest (63.4%); moderate (13.9%); and highest (22.7%). Multinomial and binary logistic regressions were used to analyze demographic, clinical, social, and behavioral factors associated with symptom severity profiles. Compared to men in the lowest symptom severity profile, men in the highest symptom severity profile were younger (OR = 0.98, p < 0.001), had lower incomes (OR = 0.95, p = 0.028), had more comorbidities (OR = 1.92, P = 0.001), had more medications (OR = 1.09, P = 0.012), reported current tobacco (OR = 1.55, P < 0.001) or cannabis (OR = 1.45, P = 0.011) use, experienced more social disconnectedness (OR = 1.34, P < 0.001), and had poorer self-management efficacy (OR = 0.93, P < 0.001). Compared to men in the moderate profile, men in the highest profile had lower education (OR = 0.53, P = 0.002), more comorbidities (OR = 1.77, P = 0.018), higher medication use (OR = 1.11 P = 0.009), and increased cannabis use (OR = 1.56, P = 0.017). Findings highlight diverse symptom experiences and key factors that can be targeted in prevention and treatment strategies to reduce symptom severity within these subpopulations. Show less

To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D). Bayesian network analyses and complementary two-sample Mendelian randomization were used to quantify causal pathways linking adipose distribution, glycemia, and insulin dynamics with liver fat in the IMI-DIRECT prospective cohort study. Data included frequently sampled metabolic challenge tests, MRI-derived abdominal and hepatic fat content, serological biomarkers, and Olink plasma proteomics from 331 adults with new-onset T2D and 964 adults without diabetes, with harmonized protocols enabling replication. High basal insulin secretion rate (BasalISR), estimated via C-peptide deconvolution, emerged as the primary potential causal driver of liver fat accumulation in both cohorts. BasalISR, a clearance-independent measure of β-cell insulin output distinct from peripheral insulin levels, was independently linked to hepatic steatosis. Visceral adipose tissue exhibited bidirectional associations with liver fat, suggesting a self-reinforcing metabolic loop. Of 446 analyzed proteins, 34 mapped to these metabolic networks (27 in the non-diabetes network, 18 in the T2D network, and 11 shared). Key proteins directly associated with liver fat included GUSB, ALDH1A1, LPL, IGFBP1/2, CTSD, HMOX1, FGF21, AGRP, and ACE2. Sex-stratified analyses identified GUSB in females and LEP in males as the strongest protein predictors of liver fat. BasalISR may better capture early β-cell-driven disturbances contributing to MASLD. These findings outline a multifactorial, sex- and disease stage-specific proteo-metabolic architecture of hepatic steatosis and identify potential biomarkers or therapeutic targets. Show less

White adipose tissue (WAT) expansion occurs through generation of new adipocytes from adipose progenitor cells (APC). The objective of this study was to characterize and validate a new transcriptional profile of APC. Single-cell (sc)/nuclei (sn) RNA-Seq was performed on nuclei from whole WAT (n = 20), cells from WAT stromal vascular fraction (n = 5), and cultured APC in vitro (n = 8) using ICELL8 smart-Seq technology. Additional snRNA-Seq was performed on WAT using 10x genomic platform. Pseudotime analyses and differentiation of hiPSCs was used to track the temporal patterns of novel gene signatures. Immunohistochemistry was performed to validate a new marker. A pre-adipocyte population was found across the four independent datasets that expressed known pre-adipocyte markers (ZNF423 and DLK1) in addition to genes typically associated with neurogenes (DPP10, PTRPT, CTNNA2, NRXN3, CTNNA2, PTPRD, CNTNAP2 and RBFOX1). The expression of these genes were temporally regulated with adipocyte differentiation. Immunohistochemistry analyses confirmed these pre-adipocytes are located in the neurovascular niche of WAT but are not neurons or endothelial cells. This work has defined a new transcriptional signature of pre-adipocytes in human subcutaneuous WAT that are distinct from mesencyhmal stem cell populations and represent novel targets for WAT expansion. Show less

Low-intensity extracorporeal shockwave therapy (Li-ESWT) is thought to treat erectile dysfunction (ED) by stimulating neovascularization and nerve regeneration as demonstrated in animal models by histologically increased angiogenesis and neuronal-related growth factors, though corresponding human studies are limited. We hypothesized that Li-ESWT results in appreciable increases in growth factors in human tissues, and in this proof-of-concept study we aimed to determine whether markers for neovascularization and nerve regeneration can be detected in the corporal blood of men following Li-ESWT treatment. Patients were prospectively enrolled in a clinical trial of Li-ESWT for ED. Patients received 12 bi-weekly Li-ESWT treatments of 0.2 mJ/mm eNOS, nNOS, VEGF, and BDNF were detectable and demonstrated changes in cavernosal plasma samples following Li-ESWT treatment. Twenty-five patients completed all five study visits. Mean patient age was 63. Mean baseline International Index of Erectile Function-Erectile Function score prior to treatment was 14.24 (±1.21). Corporal plasma samples were analyzed for eNOS, nNOS, VEGF, and BDNF using the enzyme-linked immunosorbent assay. Levels of eNOS, nNOS, and VEGF showed an upward trend following treatment but did not reach significance. BDNF levels were noted to decrease. Corporal blood aspirates may function as surrogates for histological studies to understand effects of Li-ESWT at the tissue level in humans. To our knowledge, this is first the molecular study in human tissues to attempt to quantify neurogenesis and neovascularization in penile tissue following Li-ESWT for ED. Although our sample size is small, we believe this represents a promising first step in understanding the effect of Li-ESWT at a tissue level in men. The clinical significance of our findings is currently unknown, but markers of neovascularization and neurogenesis are detectable in corporal plasma and may change following Li-ESWT. ClinicalTrials.gov Show less