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PubMed2026

Proteomic insights into hepatic responses to high soybean meal inclusion with citric acid supplementation in hybrid grouper (Epinephelus fuscoguttatus × Epinephelus lanceolatus) juveniles.

This study evaluated the growth performance and hepatic proteomic responses of juvenile hybrid grouper (Epinephelus fuscoguttatus × Epinephelus lanceolatus) juveniles fed diets containing 30% or 40% soybean meal (SBM), with or without 3% citric acid supplementation, and compared with a fishmeal (FM) control diet over a 10-week feeding trial. Fish fed 30% SBM (LSBM) showed a final body weight comparable to the FM group, whereas fish fed 40% SBM (HSBM) recorded significantly reduced growth and net protein utilization (NPU) (p < 0.05). Supplementation of citric acid in the 40% SBM diet (HSBM + CA) significantly improved NPU and partially restored growth relative to HSBM. LC-MS/MS based quantitative proteomics identified 1544 hepatic proteins and showed clear dietary segregation. Differentially expressed proteins were predominantly associated with reduced abundance of proteins involved in lipid metabolism, amino acid metabolism, pyruvate metabolism, and the tricarboxylic cycle across all SBM diets, suggesting a shift in oxidative metabolic capacity. In contrast, LSBM induced upregulation of spliceosome-associated proteins and RNA processing components, suggesting adaptive post-transcriptional regulation under moderate SBM inclusion. In contrast, HSBM exhibited greater reduction in metabolic protein abundance without comparable upregulation of adaptive regulatory components, coinciding with reduced nutrient retention. Protein-protein interaction analysis further confirms the correlation between the regulation of spliceosomal clusters and mitochondrial lipid-catabolic modules. Citric acid supplementation did not markedly reverse hepatic metabolic protein changes but improved protein retention. Data are available via ProteomeXchange with identifier PXD081994. These findings suggest a tolerance limit between 30% and 40% SBM inclusion, with 30% inducing adaptive hepatic proteomic responses compatible with maintained growth performance.

Animals↗

PubMed2026

Peripheral pain threshold, glycaemic status, and LAMP3 genetic variation: A community-based analysis.

Diabetic polyneuropathy is a common complication of diabetes, yet substantial inter-individual variation in peripheral pain perception suggests underlying genetic influences. This population-based study investigated clinical, metabolic, and genetic determinants of pain threshold using intraepidermal electrical stimulation in 906 participants from the Iwaki Health Promotion Project 2017. Genome-wide association analysis identified 12 loci showing suggestive associations, among which a missense variant in LAMP3 (rs482912) was prioritized as a biologically plausible candidate. Phenotype-stratified analyses showed that individuals carrying the CT or CC genotypes had lower PINT indices than those with the TT genotype, indicating reduced pain thresholds. Notably, the CC genotype retained an association with lower pain threshold using intraepidermal electrical stimulation under conditions of metabolic stress, including impaired glucose tolerance, elevated HbA1c, and obesity, whereas this association was attenuated in the presence of hypertension. Single-cell RNA sequencing analysis of human skin revealed that LAMP3-positive mature dendritic cells, enriched in immunoregulatory molecules, exhibited transcriptional enrichment of inflammatory, antigen-presenting, and nociception-related pathways, including NF-κB, JAK-STAT, cytokine signaling, and neuroimmune sensitization cascades. Autopsy-based skin analysis further demonstrated genotype-associated differences in dermal LAMP3-positive cell infiltration and CD8-positive T-cell abundance, while CD4-positive T-cell abundance and intraepidermal nerve fiber density remained unchanged across genotypes. Taken together, these findings suggest a potential association between LAMP3 variation and individual differences in peripheral pain threshold and provide biological context supporting a role for neuroimmune interactions in early sensory modulation under metabolic stress. Given the suggestive genetic evidence and indirect mechanistic data, these observations should be interpreted as exploratory and hypothesis-generating.

Humans↗

PubMed2026

In Vivo Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the HAO1 gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and Agxt-/- mice, a mouse model of PH1. We observed >30% editing of HAO1 in Agxt-/- mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated in vivo targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target HAO1 in mice and nonhuman primates to achieve high levels of HAO1 gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.

Hyperoxaluria, Primary↗

PubMed2026

Genomic diversity and thermal niches of Aspergillus molds disrupting rind formation of surface-ripened cheeses.

Filamentous fungi play important roles in the development of surface-ripened cheese microbial communities and contribute to the aesthetics and flavors of these products. Much is known about the diversity and ecology of desirable cheese fungi, but our understanding of the natural history of cheese spoilage molds is limited. The goal of this work was to characterize the genomic diversity of Aspergillus species contaminating artisan cheeses and to identify how the abiotic environment of cheese (the substrate itself and temperature) may constrain the growth of Aspergillus. Comparative genomics identified two main species of Aspergillus, A. westerdijkiae and A. ostianus, as the spoilage molds across three different facilities in the Northeastern United States that experienced contamination events. Multiple genomic types of A. westerdijkiae were found across the different cheese production facilities, indicating that these contamination events are not caused by a single clonal strain. All A. westerdijkiae isolates produced ochratoxin A, but concentrations varied greatly across strains. RNA-sequencing of A. westerdijkiae on nutrient-rich lab media (malt extract agar) versus cheese curd agar identified a suite of pathways enriched in expression on cheese, including degradation of amino and fatty acids. Experiments measuring growth over a range of temperatures identified that spoilage Aspergillus species have a higher optimal growth temperature compared to desirable fungal species in cheese rinds and are outcompeted by Penicillium species at temperatures lower than 15°C. Global fungal metabarcoding databases suggest that A. westerdijkiae is not normally found in natural habitats of the Northeastern United States, and it may be introduced to this region.IMPORTANCEOver the past decade, disruptive contamination events of Aspergillus spoilage molds have occurred at cheese production facilities in Massachusetts, Connecticut, and Vermont in the United States, causing aesthetic, flavor, and potential safety issues. Our work highlights independent introductions of different strains of A. westerdijkiae into multiple cheese facilities and suggests that temperature could be used to control the abundance of Aspergillus spoilage molds. Based on our analysis of the global distribution of A. westerdijkiae, it is not invading cheese facilities from local fungal populations and may be a contaminant in materials used for cheese production.

Aspergillus↗

PubMed2026

Integrated bioinformatics analysis reveals cross-talking hub genes and therapeutic agents between sepsis and acute myocardial infarction.

BACKGROUND: Sepsis and acute myocardial infarction (AMI) are two significant diseases that may share overlapping etiological mechanisms. This study aims to systematically identify core genes common to both conditions and to explore their potential as therapeutic targets and drug candidates through an integrative analysis of clinical data and bioinformatics. METHODS: The AMI dataset was obtained from the GEO database, and RNA sequencing data were collected from blood samples of patients with sepsis at our hospital. Common genes were identified using differential expression gene analysis (DEG) and weighted gene co-expression network analysis (WGCNA). Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, were performed. A protein-protein interaction (PPI) network was constructed, and hub genes were identified using the MCC/Degree algorithm. Diagnostic value was assessed via receiver operating characteristic curve analysis. Immune infiltration patterns, single-cell sequencing data, and molecular docking simulations were employed to evaluate immune relevance and identify potential therapeutic compounds. RESULTS: A total of 417 genes were identified between sepsis and AMI, with enrichment analysis revealing significant involvement in inflammatory responses. Three hub genes-JAK2, MYD88, and TIMP1-were selected for further investigation. ROC curves confirmed their strong diagnostic performance for both diseases. Immune infiltration analysis showed that these core genes were significantly correlated with the infiltration levels of various immune cell types. Molecular docking indicated that quercetin exhibited stable binding affinity with the proteins encoded by these genes. qPCR validation further confirmed the upregulation of these three genes, supporting the anti-inflammatory effects of quercetin as a potential targeted therapy. CONCLUSION: JAK2, MYD88, and TIMP1 were identified as shared core genes in sepsis and AMI. These genes not only serve as potential diagnostic biomarkers but also offer novel targets for developing common therapeutic strategies for both conditions. Furthermore, quercetin emerges as a promising candidate for targeted treatment.

Humans↗

PubMed2026

Intravesical mitomycin-C administered immediately before transurethral resection of bladder tumor in non-muscle-invasive bladder cancer: Clinical outcomes and molecular predictors from over 3 years of extended follow-up in a phase II trial.

PURPOSE: To evaluate the long-term outcomes and molecular correlates of response after immediate preoperative intravesical chemotherapy (IPeIC) with mitomycin-C (MMC) in patients with non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: In this single-center, open-label, randomized phase II trial, 33 patients received two split doses of IPeIC/MMC (40 mg/20 mL), whereas 38 patients underwent transurethral resection of bladder tumor (TURBT) alone. The primary endpoint was 3-year recurrence-free survival (RFS), and secondary endpoints included progression-free survival (PFS). Exploratory RNA sequencing was performed on IPeIC-treated patients (three with recurrence, 25 without) using a Monte Carlo-based resampling strategy. RESULTS: The median follow-up durations were comparable between the intervention (60.0 months) and control arms (60.4 months). IPeIC/MMC reduced recurrence risk by 76.8% versus TURBT alone (p=0.024), yielding a 3-year RFS rate of 90.7% versus 78.6%. On multivariable analysis, IPeIC/MMC independently improved RFS (hazard ratio [HR] 0.266, p=0.044). IPeIC was associated with superior PFS, with 3-year and 5-year rates of 100% versus 92.1% and 85.8%, respectively, in the controls (HR 0.078, p=0.014). Exploratory transcriptomics identified low Glutathione S-transferase Mu 1 (GSTM1) expression as the factor most strongly associated with recurrence. CONCLUSIONS: IPeIC/MMC is associated with improved long-term oncological outcomes compared with TURBT alone and represents a safe prophylactic option for patients with NMIBC who are unable to receive standard immediate postoperative intravesical chemotherapy because of safety concerns or practical constraints. The GSTM1 findings are hypothesis-generating and support future biomarker-driven validation studies.

Aged↗

PubMed2026

Characteristics of p53 and Smad4 immunohistochemistry in pancreatic ductal adenocarcinoma and validation by next-generation sequencing.

BACKGROUND: Mutations in four major driver genes -KRAS, CDKN2A, TP53, and SMAD4- are central to the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) and critically inform diagnosis, therapeutic decision-making, and prognostic assessment. Although next-generation sequencing (NGS) is widely regarded as the gold standard for detecting these mutations, its clinical application is often limited by suboptimal analytical efficiency and substantial economic cost. Among these genes, immunohistochemical (IHC) staining for the proteins encoded by TP53 and SMAD4 has been extensively adopted in routine pathology practice. However, standardized IHC pattern classification schemes and rigorous validation of their predictive accuracy for underlying genomic alterations remain lacking in PDAC. METHODS: We retrospectively enrolled 63 PDAC patients and systematically characterized the typical IHC expression patterns of p53 and Smad4. Targeted NGS was subsequently performed on all available tumor specimens, and the resulting mutational profiles were correlated with corresponding IHC findings. Diagnostic performance including sensitivity, specificity and accuracy of p53 IHC for predicting TP53 mutations and of Smad4 IHC for predicting SMAD4 mutations was rigorously evaluated. RESULTS: Among the four canonical driver genes, co-occurring double- or triple-gene mutations were prevalent; within TP53 and SMAD4, missense mutations constituted the most frequent variant type. Using NGS as the reference standard, we validated the diagnostic utility of a three-tiered p53 IHC classification system, particularly in fine-needle biopsy (FNB) specimens. Furthermore, we proposed a novel, refined Smad4 IHC pattern classification that incorporates an "intermediate" category, thereby expanding upon conventional binary interpretation. This new scheme achieved markedly improved mutation prediction accuracy (0.76) compared with traditional approaches (0.57). CONCLUSION: Our study highlights the complementary diagnostic value of p53 and Smad4 IHC relative to molecular testing in PDAC, especially when tissue is limited, as commonly encountered in FNB specimens. The newly established Smad4 IHC classification system, which integrates an intermediate expression category into the conventional two-tier framework, demonstrates superior clinical utility and enhances predictive accuracy for SMAD4 genomic alterations.

Humans↗

PubMed2026

Social support and cognitive function in postmenopausal women.

OBJECTIVE: An active social lifestyle may protect against cognitive decline in older adults, but few studies have examined specific social support dimensions in relation to specific cognitive domains. This study examines associations between social support dimensions and cognitive function in older women. METHODS: The Early versus Late Intervention Trial with Estradiol (ELITE) was a randomized, double-blinded, placebo-controlled trial of oral 17β-estradiol versus placebo in postmenopausal women, designed primarily to evaluate the timing hypothesis on atherosclerosis progression and cognitive decline; the present analysis is a secondary, hypothesis-generating examination of the psychosocial substudy data (2009-2012). A total of 448 women completed psychosocial assessments every 6 months. Cognitive function was assessed at baseline, 2.5, and 5 years using composite scores for executive function, verbal memory, visual memory, and global cognition derived from 14 standardized tests. Perceived social support was assessed using the Medical Outcomes Study-Social Support Survey (MOS-SSS; 0-100 scale). Paired cognitive-psychosocial assessments were analyzed using linear mixed-effects models adjusted for age, marital status, blood pressure medication, BMI, education, income, race, and randomized treatment (hormone therapy or placebo). RESULTS: A total of 298 women (mean age 60.3 y) provided 322 paired visits. Positive associations were observed between instrumental social support and visual memory (β(SE)=0.0044(0.0022), 95% CI: -0.00002 to 0.0088, P=0.051) and between positive social interaction and global cognition (β(SE)=0.0092(0.0046), 95% CI: 0.0001-0.0182, P=0.047). In age-stratified analyses, the positive social interaction-global cognition association was significant among women <65 years (P=0.042) but not women ≥65 years (P=0.34). No association survived false discovery rate (FDR) correction for multiple comparisons. CONCLUSIONS: In this sample of healthy middle- to older-aged women, no association between specific dimensions of social support and cognitive domains was statistically significant after correction for multiple comparisons. These hypothesis-generating findings suggest any association is modest at best and warrant confirmation in studies designed specifically for this question.

Cognitive function↗

PubMed2026

Adaptive proteomic remodeling and eNOS upregulation in luminal endothelium and perivascular adipose tissue of patent saphenous vein grafts after CABG.

OBJECTIVE: Long-term patency of saphenous vein grafts (SVGs) remains a significant challenge in coronary artery bypass grafting (CABG). The biological factors underlying successful human grafts are poorly understood. We aimed to characterize the structural and molecular features associated with successful graft function. METHODS: Patent and occluded SVG and internal thoracic artery (ITA) grafts were obtained from explanted hearts of CABG patients undergoing heart transplantation for end-stage heart failure not attributable to graft failure, along with freshly harvested ITA and SVG controls. Samples underwent histomorphological analysis, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics. RESULTS: Patent ITA (ITA-P) showed minimal intimal hyperplasia with medial reinforcement, whereas patent SVGs (SVG-P) had organized, α-smooth muscle actin (αSMA)-positive myofibroblast-rich neointima. Endothelial nitric oxide synthase (eNOS) was markedly upregulated in patent grafts at two sites-the luminal endothelium and adventitial microvessels within perivascular adipose tissue (PVAT)-and lost at both sites in occluded SVG (SVG-O). Adventitial CD31-positive microvessels were significantly increased in patent grafts. Proteomically, ITA-P and SVG-P shared a largely common adaptive proteome enriched in translation, RNA processing, and extracellular matrix (ECM) organization, with shared upstream activation of NR4A3, EGFR, and STAT1, and conduit-specific signatures (IGF-1/RUNX2 in ITA-P; RETN/SRC/PTGES in SVG-P). PTGES was strongly expressed in the adventitia of SVG-P. CONCLUSIONS: Patent arterial and venous bypass grafts exhibited a shared adaptive phenotype characterized by dual-site upregulation of eNOS in both the luminal endothelium and the perivascular microvessels/PVAT. In SVG-P, PTGES was co-upregulated alongside eNOS, indicating a mechanistic link between the proteomic and IHC findings. These findings highlight the perivascular compartment as a site of adaptive, eNOS-associated changes in patent vein grafts.

Humans↗

PubMed2026

Amino acid reprogramming and biofilm-specific tricarboxylate transporters in PET-degrading Piscinibacter sakaiensis.

Plastic-degrading bacteria predominantly colonize polymer surfaces as biofilms, yet it remains unclear whether the biofilm phenotype contributes to metabolism beyond retaining extracellular enzymes. Here, we combine population-level RNA-sequencing across three conditions-biofilm cells on polyethylene terephthalate (PET), planktonic cells incubated with PET, and planktonic cells on maltose-with single-cell Raman spectroscopy to characterize the PET response of Piscinibacter sakaiensis (formerly Ideonella sakaiensis). This integrated approach reveals two metabolically distinct response layers. A carbon-source-driven response shared by all PET-exposed cells is dominated by a broad amino acid reprogramming, led by upregulation of branched-chain amino acid transport genes, enhanced serine biosynthesis, and reduced chemotaxis. A biofilm-specific layer selectively induces tripartite tricarboxylate transporter genes from three distinct genomic loci. This transcriptional feature is accompanied by a single-cell phenotype consistent with a protein-rich and saturated membrane. These results suggest that biofilm formation is not limited to enzyme retention but is associated with selective activation of transport systems, consistent with a putative role in capturing PET-derived intermediates at the polymer interface. This two-layer model separates general metabolic adaptation to PET from biofilm-specific functions and provides a framework for understanding how surface-associated bacterial physiology contributes to plastic degradation.IMPORTANCEPolyethylene terephthalate (PET) degradation in natural and engineered environments is largely mediated by surface-attached microbial communities, yet the physiological role of biofilm state during plastic degradation remains poorly understood. Using the model PET degrader Piscinibacter sakaiensis, we show that biofilm-associated cells are not simply retained near the polymer surface but exhibit a distinct metabolic program characterized by selective induction of tripartite tricarboxylate transporters. In contrast, extensive amino acid reprogramming occurs in both biofilm and planktonic PET-exposed cells, indicating that it is driven by carbon source rather than surface attachment. These findings reveal that PET degradation involves two separable physiological layers: a general metabolic response to PET-derived carbon shared across cell phenotypes, and a biofilm-specific transport response potentially linked to substrate capture at the plastic interface. This work advances our understanding of how microbial physiology is organized during plastic biodegradation and identifies transport processes as previously unrecognized components of PET-degrading biofilms.

PET biodegradation↗

PubMed2026

Omics in hereditary optic neuropathies: A systematic review of clinical studies with an integrated point of view.

Hereditary optic neuropathies are characterized by bilateral visual loss due to the degeneration of retinal ganglion cells, resulting in optic nerve degeneration and atrophy. Although the genetic origin of the main isolated and syndromic hereditary optic neuropathies has been characterized, the clinical phenotypes exhibit significant and poorly understood variability in both penetrance and expressivity. Additionally, the genetic and environmental factors that influence the onset of these optic neuropathies remain poorly understood, with limited biomarkers to predict disease progression or as readouts for therapeutic trials. Data-driven omics strategies allow deep phenotyping to improve our understanding of pathophysiological mechanisms and to search for new biomarkers and therapeutic targets. We explore whether the omics strategies applied to patients with hereditary optic neuropathies have provided such new insights. MEDLINE, Web of Science and EMBASE databases were screened for studies with terms relating to hereditary optic neuropathies, transcriptomics, epigenomics, proteomics, metabolomics and lipidomics in clinical studies exploring patients' samples. Out of 1244 references identified, 22 articles were included after double-masked data curation. These articles focused only on the 3 main forms of hereditary optic neuropathies, namely, OPA1-related dominant optic atrophy (n = 4), Leber hereditary optic neuropathy (n = 13), and Wolfram syndrome (n = 5). While the methodological designs and results of these studies were highly heterogeneous, they revealed molecular alterations that we have attempted to discuss at the integrated multi-omics level. This data integration highlighted several common pathophysiological mechanisms such as energetic impairment, endoplasmic reticulum stress, proteotoxic and oxidative stresses, lipid remodeling and altered amino acid and purine metabolisms, while suggesting potential new biomarkers and therapeutic targets. These findings underscore the potential of integrated multi-omics approaches to deepen our understanding of the phenotypic complexity of hereditary optic neuropathies and to support the development of innovative diagnostic and therapeutic strategies.

Humans↗

PubMed2026

Proteomic and phosphoproteomic profiles of time-dependent dynamic changes in LPS-induced macrophage polarization.

The temporal proteomic and phosphoproteomic reprogramming during early M1 macrophage polarization (0-6 h) remains poorly understood. We performed time-resolved proteomic and phosphoproteomic analyses of LPS-stimulated RAW264.7 macrophages at seven time points within 6 h. Time-clustering of differentially expressed molecules revealed two patterns: initial change with partial recovery, and sustained dysregulation. Upregulated proteins and phosphorylation sites were enriched in the Rho GTPase signaling pathway, T-cell receptor signaling pathway, NF-κB cascade, osteoclast differentiation pathway, and antiviral immune pathway. Downregulated pathways were associated with cell cycle regulation, chromatin remodeling, RNA metabolism, and mRNA processing, indicating resource reallocation to prioritize acute inflammatory responses. Kinase-substrate network analysis confirmed the mitogen-activated protein kinase (MAPK), cyclin-dependent kinase (CDK), protein kinase B (AKT), and ribosomal S6 kinase (RSK) families as core upstream phosphorylation regulators. Integrated analysis revealed synergistic and antagonistic relationships between proteomic and phosphoproteomic changes. This study provides a temporal molecular atlas of M1 polarization, delineating inflammatory signaling dynamics and offering a basis for therapeutic target discovery in inflammatory diseases. SIGNIFICANCE: Macrophage M1 polarization is a central event in innate immune defense against pathogenic invasion, yet its dysregulation is a pivotal driver of the onset and progression of a broad spectrum of inflammation-associated disorders, spanning autoimmune diseases, infectious conditions and inflammatory bone diseases, making the dissection of its molecular regulatory mechanisms an urgent research priority in immunology and translational medicine. Dynamic molecular events within 0-6 h after LPS stimulation are critical for initiating and shaping M1 inflammatory activation, yet systematic time-resolved proteomic and phosphoproteomic profiling remains insufficient.In this study, we comprehensively characterized temporal proteome and phosphoproteome changes at seven consecutive time points during macrophage polarization, clarified two distinct dynamic molecular patterns, identified core signaling pathways and key kinase regulators involved in inflammatory reprogramming, and uncovered the leading role of post-translational phosphorylation modifications in initiating polarization. This work delineates the time-series molecular atlas of early macrophage activation, provides novel insights into the temporal regulatory mechanism of inflammatory signaling networks, and lays a solid experimental foundation for exploring new intervention targets and regulatory nodes in clinical translational research.

Lipopolysaccharides↗

PubMed2026

Human iPSC-EV-loaded nanofiber stent coatings accelerate vascular repair by enhancing EGFR/HIF-1α signaling and suppressing ROCK1-mediated remodeling.

Arterial disease management is shifting from antiproliferative drug-eluting stents toward approaches that restore endothelial function and modulate smooth muscle cell (SMC) behavior. Stem cell-derived extracellular vesicles (EVs) carry miRNAs that promote endothelial proliferation and migration while restraining aberrant SMC growth and inflammation. Here, human induced pluripotent stem cell (iPSC)-derived EVs were collected by ultracentrifugation and incorporated into 50:50 poly (lactic-co-glycolic acid) (PLGA 503) core-shell nanofibrous membranes, which were fabricated as stent coatings for sustained release to overcome rapid clearance and poor tissue retention. EVs derived from three independent iPSC lines all enhanced tube formation in human umbilical vein endothelial cells (HUVECs) under hypoxic and serum-starved conditions and revealed a trend toward reduced platelet-derived growth factor-BB (PDGF-BB)-induced smooth muscle cell (SMC) migration. The fabricated core-shell nanofibers enabled sustained EV release, maintaining therapeutic efficacy for 28 days. Small RNA sequencing (NGS) analysis demonstrated that EVs from these independent iPSC lines shared miR-148a-3p and members of the miR-92 family, which collectively accounted for more than 75% of the reads within the 25 top-expressed miRNA set. In vitro, iPSC-EVs enhanced HUVEC proliferation and survival signaling by downregulating the negative regulators ERRFI1 and VHL, which are specific targets of miR-148a-3p and the miR-92 family, thereby activating the EGFR and HIF-1α axes and driving downstream ERK1/2 and VEGF expression under hypoxic and serum starvation stress conditions. Concurrently, iPSC-EVs prevented PDGF-BB-induced SMC phenotypic switching by downregulating ROCK1, a target of miR-148a-3p, thereby inhibiting downstream AKT and ERK signaling and preserving contractile markers while suppressing the synthetic phenotype. In vivo, the iPSC-EV-functionalized scaffolds significantly accelerated re-endothelialization and inhibited neointimal hyperplasia, evidenced by the upregulation of angiogenic factors (VEGF, CD31) and the concurrent suppression of pathological remodeling markers (α-SMA, MMPs) and inflammatory cytokines (IL-6, TGF-β1). Therefore, iPSC-EVs enriched with specific miRNAs and delivered via PLGA 503 core-shell nanofibers promote endothelial repair while suppressing SMC overgrowth, providing a promising strategy for vascular healing.

Core-shell nanofibers↗

PubMed2026

Biomarker Analysis from Patients with Metastatic PDAC Treated with TGFβ Antibody NIS793 plus Abraxane + Gemcitabine versus Abraxane + Gemcitabine Alone in a Phase II, Open-Label, Randomized Study.

PURPOSE: Transforming growth factor β (TGFβ) plays a dual role in cancer, acting as a tumor suppressor early in the disease but promoting progression and immune evasion when dysregulated. In pancreatic ductal adenocarcinoma (PDAC), TGFβ-driven desmoplasia fosters chemoresistance and immunosuppression, limiting therapeutic efficacy. NIS793, a fully human mAb targeting TGFβ, demonstrated antifibrotic and immunomodulatory activity in preclinical models and early-phase trials. PATIENTS AND METHODS: We conducted a randomized, open-label, phase II study in treatment-naïve patients with metastatic PDAC (mPDAC) to evaluate NIS793 ± spartalizumab (anti-PD-1) combined with nab-paclitaxel (or Abraxane)/gemcitabine (ABRA/GEM) versus ABRA/GEM alone. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), safety, pharmacokinetics, and biomarker analyses. Exploratory assessments included paired tumor RNA sequencing, cell-free DNA profiling, and plasma proteomics. RESULTS: NIS793 demonstrated target engagement and suppression of TGFβ signaling, confirmed by transcriptomic and proteomic analyses. Stromal remodeling was evident, with significant downregulation of cancer-associated fibroblast markers (Acta2, Fap) and collagen-related signatures. Despite proof of mechanism, clinical efficacy was not observed: Median PFS and OS were comparable or numerically worse in the NIS793 arm versus control (HR for OS in NIS793 + ABRA/GEM vs. ABRA/GEM: 1.32; 95% confidence interval, 0.84-2.07). The safety profile was manageable, with no unexpected toxicities. Biomarker data revealed increased expression of neutrophil-related genes after treatment, suggesting potential induction of tumor-promoting inflammation. CONCLUSIONS: NIS793 effectively inhibited TGFβ signaling and led to stromal remodeling but failed to improve outcomes in mPDAC. These findings highlight the complexity of TGFβ biology and caution against its blockade in combination with chemotherapy for PDAC. Future strategies should consider context-dependent effects of TGFβ inhibition.

Humans↗

PubMed2026

Risk Factors for Long-Term Health-Related Quality-of-Life and Mental Health Outcomes in Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Traumatic brain injury (TBI) often leads to long-term disability, including persistent mental health issues and lower health-related quality of life (HRQoL). Early interventions can improve recovery, but because resources limit routine monitoring of all patients, trauma care remains largely symptom-driven. The combination of long-term disability and limited capacity for routine follow-up highlights the need for risk-stratified follow-up care and reliable evidence on early prognostic factors. However, the existing literature is sparse and methodologically heterogeneous, limiting the clinical applicability of findings. We therefore conducted a systematic review and meta-analysis to identify early risk factors for poorer long-term mental health and HRQoL outcomes. A systematic search of seven electronic databases identified studies of adult patients with TBI, with outcomes assessed at least 6 months postdischarge. Two authors independently screened the studies, assessed the risk of bias, and extracted the data. We pooled effect estimates using a random-effects meta-analysis and calculated 95% prediction intervals. A narrative synthesis was applied when meta-analysis was not feasible. The review was registered with PROSPERO (CRD42024576912) and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of the 8,104 articles screened, 64 studies met the inclusion criteria (n = 334,672). Most studies (58%) had a low risk of bias. Female sex, socioeconomic disadvantage, psychiatric history, assaultive-related injuries, and previous TBI were consistently associated with worse long-term outcomes. Across meta-analyses, assault-related injuries more than doubled the odds of post-traumatic stress disorder (odds ratio [OR] = 2.72; 95% confidence interval [CI]: 2.01-3.66, I2 = 0%). Higher odds were also observed among females (OR = 1.33; 95% CI: 1.11-1.59, I2 = 0%), individuals with prior TBI (OR = 1.56; 95% CI: 1.07-2.27, I2 = 0%), and those with psychiatric history (OR = 2.38; 95% CI: 1.83-3.10, I2 = 48%). We found that female sex (OR = 1.72; 95% CI: 1.38-2.16, I2 = 58%), prior TBI (OR = 1.52; 95% CI: 1.25-1.85, I2 = 0%), and psychiatric history (OR = 3.25; 95%CI: 1.86-5.69, I2 = 98%) were associated with higher odds of depression. Furthermore, higher pooled anxiety scores were observed in females and in individuals with a psychiatric history. The study identified several readily available factors present before or at discharge that are associated with poor long-term HRQoL and mental health outcomes. Leveraging these factors in follow-up protocols, prediction modeling, and clinical decision support systems may facilitate risk-stratified postdischarge care for TBI patients.

Humans↗

PubMed2026

Diagnostic performance of panfungal PCR on tissue specimens for the diagnosis of invasive fungal diseases: a systematic review and meta-analysis of the Fungal PCR Initiative (FPCRI).

UNLABELLED: Invasive fungal diseases are difficult to diagnose because of the limited sensitivity of culture. Panfungal PCR amplicon sequencing assays (targeting ribosomal RNA, such as 18S, 28S, ITS) are recommended for fungal identification in histopathology samples showing fungal elements. However, data describing its overall performance and consistency are lacking. This systematic literature review and meta-analysis assessed the performance of panfungal PCR on formalin-fixed paraffin-embedded (FFPE) and non-fixed (fresh or frozen) tissue samples. A systematic literature search was performed to include studies reporting the use of panfungal PCR for fungal identification in FFPE or non-fixed tissue samples. PCR sensitivity and specificity were assessed using the reference standard of histopathology showing fungal elements. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Pooled estimates were obtained using random-effects meta-analysis. Twenty-eight studies were included. In FFPE samples (18 studies, 852 samples), sensitivity and specificity were 75.4% (95% confidence interval [CI], 59.2-86.6) and 93.5% (70.2-98.9), respectively. Sensitivity in non-fixed samples (13 studies, 207 samples) was 86.5% (74.7-93.3), while specificity could not be assessed (insufficient data). Comparative analyses showed a significantly higher sensitivity of panfungal PCR over culture (88.2%; 76-94.7 vs 52.2%; 39-65, P = 0.001). Sub-analyses could not demonstrate the superiority of one PCR target over another due to limited data. Panfungal PCR exhibited adequate sensitivity and good specificity in FFPE samples. Sensitivity was even higher in non-fixed samples and largely superior to culture. Nevertheless, large interstudy variability was observed, warranting interlaboratory studies to define the optimal PCR target and standardized protocols. IMPORTANCE: Invasive fungal diseases are difficult to diagnose because of the low sensitivity of culture. Panfungal PCRs are widely used for fungal identification in tissue specimens but suffer from heterogeneous procedures and performance. This meta-analysis shows an acceptable sensitivity (75.4% and 86.5% in fixed and non-fixed samples, respectively) and good specificity (93.5%) of panfungal PCR, supporting its use, not only on histopathology-positive fixed samples but also in non-fixed samples concomitantly with other diagnostic tools (cultures and fungal-specific PCRs if available). These results provide a strong basis for further standardization of panfungal PCR techniques via interlaboratory assays to assess reproducibility and optimize analytical protocols. CLINICAL TRIALS: This study is registered with PROSPERO as CRD42023461148.

Humans↗

PubMed2026

Multi-omics integrative analysis provides insight into potential molecular responses to sustained high water flow in common carp (Cyprinus carpio) cultured in recirculating aquaculture.

To investigate the potential molecular responses by which water flow intensity affects the growth of common carp (Cyprinus carpio) in a recirculating aquaculture system (RAS), a control group (CG, actual water velocity 0.3 cm/s) and three sustained flow treatment groups were established, including a low-flow group (LF, 1 body length per second, bl/s), a medium-flow group (MF, 2 bl/s), and a high-flow group (HF, 3 bl/s). After 12 weeks of culture in the RAS, growth performance was compared among groups under different flow intensities. The best-performing group and the control group were then selected for the determination of intestinal digestive enzyme activities, as well as transcriptomic and whole-genome bisulfite sequencing analyses of muscle tissue. The results showed that the specific growth rate and feed intake of the HF group were significantly higher than those of the other groups (P < 0.05), whereas no significant difference in feed conversion ratio was observed among groups. Compared with the CG group, lipase activity was significantly higher in the HF group (P < 0.05), while α-amylase and trypsin activities showed increasing trends without significant differences. RNA-seq identified a total of 273 differentially expressed genes, including 72 upregulated genes and 201 downregulated genes in the HF group relative to the CG group. These genes were mainly enriched in glycolysis, pyruvate metabolism, ATP metabolism, the pentose phosphate pathway, the insulin signaling pathway, the PPAR signaling pathway, and the adipocytokine signaling pathway, indicating that sustained high water flow induced a muscle transcriptional response characterized by remodeling of energy metabolism and substrate utilization. Whole-genome bisulfite sequencing analysis showed that DNA methylation in common carp muscle occurred predominantly in the CpG context. Differentially methylated regions between the HF and CG groups were mainly distributed in transcription-related regulatory regions, including promoters, CpG islands, and CpG island shores. In promoter regions, the number of hypermethylated regions in the HF group relative to the CG group was markedly higher than that of hypomethylated regions. Integrated analysis further identified two candidate genes showing both promoter differential methylation and differential expression, namely LOC109094644 and bcorl1, suggesting that adaptation to high water flow may involve IGF-related growth regulation and remodeling of upstream transcriptional programs. The qPCR results were consistent with the transcriptomic data. Taken together, within the tested range, a sustained water flow of 3 bl/s was more conducive to the growth of common carp in the RAS, which may be associated with enhanced lipid digestion and utilization, remodeling of the muscle energy metabolic network, changes in promoter methylation, and the coordinated regulation of key candidate genes. This study provides a theoretical basis for clarifying the exercise adaptation mechanism of common carp in recirculating aquaculture and for optimizing flow velocity parameters.

Animals↗

PubMed2026

Long-term hormone therapy for perimenopausal and postmenopausal women.

BACKGROUND: Hormone therapy is widely provided to control menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005. OBJECTIVES: To assess the long-term effects of prolonged use (at least one year) of hormone therapy on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures and cognition in perimenopausal and postmenopausal women. SEARCH METHODS: We used the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, three other databases and two trial registers, together with reference checking, citation searching and contact with study authors to identify the studies included in the review. The latest search date was 26 September 2024. SELECTION CRITERIA: We included randomised, double-blind trials in which peri- or postmenopausal women took hormone therapy or placebo for at least one year. We included various oestrogen formulations, with or without progestogens. We focused on studies assessing hormone therapy's effects on long-term clinical outcomes, including death, coronary events and cancer. Hormone therapy's efficacy in managing menopausal symptoms was beyond the scope of this review, and is assessed in other Cochrane reviews. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 24 studies - with two newly added in this update - involving 45,660 participants. We derived nearly 70% of the data from two well-conducted studies: the Heart and Estrogen/progestin Replacement Study (HERS 1998) and the large, multi-component Women's Health Initiative research programme, which included two hormone therapy arms (WHI 1998). Across all the studies, most participants were postmenopausal American women with one or more comorbidities. The mean participant age in most studies was over 60 years. Only one included study focused on perimenopausal women. We present full results for all included studies with available data in the main review. The results presented below are drawn from WHI 1998, in which the combined hormone therapy arm and the oestrogen-only arm were run concurrently, with women assigned to the appropriate trial based on their uterus status. One study with 16,608 postmenopausal women with an intact uterus compared combined continuous hormone therapy (conjugated equine oestrogen and medroxyprogesterone acetate) to placebo, and measured outcomes at an average of 5.6 years of follow-up. Based on this study, combined continuous hormone therapy probably makes little to no difference to the risk of a coronary event (RR 1.17, 95% CI 0.95 to 1.44; moderate-certainty evidence). It may increase the risk of stroke (RR 1.39, 95% CI 1.09 to 2.09; low-certainty evidence) and venous thromboembolism (RR 2.03, 95% CI 1.55 to 6.64; low-certainty evidence). Compared to placebo, combined continuous hormone therapy probably increases the risk of breast cancer (RR 1.27, 95% CI 1.03 to 1.56; moderate-certainty evidence) and probably makes little to no difference to the risk of lung cancer (RR 1.06, 95% CI 0.77 to 1.46; moderate-certainty evidence). It may increase gallbladder disease requiring surgery (RR 1.64, 95% CI 1.30 to 2.06; 14,203 participants; low-certainty evidence), and probably reduces the risk of all clinical fractures (RR 0.78, 95% CI 0.71 to 0.86; moderate-certainty evidence). One study including 10,739 postmenopausal women who had undergone a hysterectomy compared oestrogen-only (conjugated equine oestrogen) hormone therapy to placebo, and measured outcomes at an average of seven years' follow-up. Based on this study, oestrogen-only hormone therapy probably makes little to no difference to the risk of coronary events (RR 0.94, 95% CI 0.78 to 1.13), venous thromboembolism (RR 1.32, 95% CI 1.00 to 1.74) and breast cancer (RR 0.79, 95% CI 0.61 to 1.01), all with moderate-certainty evidence. It may make little to no difference to the risk of lung cancer (RR 1.04, 95% CI 0.73 to 1.48; low-certainty evidence). Oestrogen-only hormone therapy probably increases the risk of stroke (RR 1.33, 95% CI 1.06 to 1.67) and gallbladder disease requiring surgery (RR 1.78, 95% CI 1.42 to 2.24), and probably reduces the risk of all clinical fractures (RR 0.73, 95% CI 0.65 to 0.80), all with moderate-certainty evidence. We judged most included studies to have a low risk of bias for most domains. The overall certainty of evidence for the main comparisons was moderate. The main limitation was that only about 30% of women were 50 to 59 years old at baseline, the age group most likely to consider hormone therapy for vasomotor symptoms. AUTHORS' CONCLUSIONS: Long-term follow-up of women using hormone therapy suggests that the risk profiles vary between combined hormone therapy and oestrogen-only therapy. Oestrogen-only hormone therapy probably makes little to no difference to coronary events, and probably increases the risk of stroke and gallbladder disease. It probably makes little to no difference in the risk of breast cancer, and probably reduces the risk of all fractures. Combined hormone therapy may increase the risk of thromboembolism and probably increases the risk of breast cancer. These results should be interpreted with caution as they are based on one study using oral hormone therapy, which may not represent the risks of the hormone therapy currently used in clinical practice.

Humans↗