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PubMed2026

The Inflammation-Thrombosis Genetic Axis in Abdominal Aortic Aneurysm: A Shared Roadmap to Precision Medicine.

Abdominal Aortic Aneurysm (AAA) is characterized by persistent inflammation, extracellular matrix loss, and intraluminal thrombus formation, yet the genetic links among these processes remain incompletely defined. Here, we examine evidence that genetic variation can influence inflammatory and thrombotic responses at the same time. Findings from genome-wide association studies are considered alongside transcriptomic, proteomic, single-cell, epigenetic, and experimental data. Particular attention is given to candidate genes and signaling networks relevant to AAA susceptibility, enlargement, and rupture. The available evidence supports a model in which inherited susceptibility alters the balance between vascular inflammation, coagulation, fibrinolysis, and wall repair. However, many reported loci still lack functional confirmation, and most genetic data come from populations of European ancestry. Defining the causal variants and the cells in which they act will be necessary before these findings can be used for individualized screening or treatment.

abdominal aortic aneurysm↗

PubMed2026

Mechanotransduction in musculoskeletal mesenchymal tissues: implications for bone, tendon, and cartilage regenerative engineering-a narrative review.

PURPOSE/AIM OF THE STUDY: To integrate evidence on how mechanical signals regulate musculoskeletal connective-tissue biology and how cellular context and loading history shape mechanotransduction and mechanical memory. MATERIALS AND METHODS: This narrative review synthesized PubMed-indexed evidence on extracellular matrix mechanics, adhesion complexes, the cytoskeleton, nucleus, primary cilia, mechanosensitive ion channels, cell state, and loading history in bone, tendon, ligament, and cartilage. RESULTS: Mechanotransduction is best understood as a coupled extracellular matrix-integrin-cytoskeleton-nucleus continuum rather than as independent cytoskeletal or nuclear drivers. Responses are conditioned by lineage stage, anatomic niche, inflammation, cellular subpopulation, and prior mechanical exposure. Mechanical memory may be encoded through persistent YAP/TAZ activity, microRNA programs, DNA methylation, histone modifications, chromatin architecture, and metabolic remodeling. Evidence is strongest for bone, including Piezo-dependent osteogenesis, TRPV4-mediated shear sensing, viscoelastic compression, osteocyte-stromal extracellular-vesicle signaling, and osteogenesis-angiogenesis coupling. Tendon and ligament require anisotropic architecture and strain-window control, whereas cartilage shows a narrow distinction between physiologic TRPV4-associated anabolism and high-strain or inflammation-sensitized Piezo/YAP-mediated maladaptation. CONCLUSIONS: Translational implications include mechanically defined cell expansion, biomaterial preconditioning, stage-specific rehabilitation, and potency assays incorporating loading history. Direct clinical validation of stable perioperative cellular mechanical memory remains limited. Future studies should combine controlled mechanical perturbation with bulk and single-cell RNA sequencing, chromatin-accessibility profiling, spatial methods, and perturbational genomics.

Mechanotransduction↗

PubMed2026

A system-level metastable model of cancer evolution: integrating replication stress, cell cycle deregulation and chromosomal instability.

INTRODUCTION: Cancer cell proliferation occurs within the context of persistent genomic instability. In this review, we propose the RS-CCD-CIN axis as a systems-level framework in which replication stress (RS), cell cycle deregulation (CCD) and chromosomal instability (CIN) form an interdependent triad that shapes tumour evolution. This axis represents a constrained metastable state in which genomic instability is tolerated and buffered. The objective of this review is to synthesize the current understanding of how the RS-CCD-CIN axis contributes to tumour heterogeneity, adaptability and therapy response. DISCUSSION: Evidence indicates that RS, CCD and CIN operate as a dynamic, interconnected network rather than as independent processes. Replication stress induces DNA damage and mutagenesis, while partial checkpoint disruption permits cells with unresolved lesions to proliferate. Chromosomal instability generates both structural and numerical alterations, contributing to intratumoural heterogeneity. Together, these processes facilitate adaptation to environmental and therapeutic pressures. Extrachromosomal DNA, micronuclei formation and cytosolic DNA signalling, including the cGAS-STING pathway, connect genomic instability to adaptive responses and immune modulation. Single-cell and spatial profiling reveal temporal and spatial variability in RS, CCD and CIN states, highlighting the limitations of static biomarkers. Therapeutically, targeting individual components often yields limited durability, whereas approaches that simultaneously perturb multiple aspects of the RS-CCD-CIN axis may improve clinical outcomes. CONCLUSIONS: This review highlights the RS-CCD-CIN axis as a fragile and metastable architecture that supports cancer evolution, while also being susceptible to collapse. A deeper understanding of this interconnected framework may inform the development of therapeutic strategies and enhance the management of resistance.

Humans↗

PubMed2026

PPRC1 is a prognostic biomarker and key regulator of mitochondrial oxidative phosphorylation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) remains an incurable haematological malignancy, underscoring the need for novel prognostic biomarkers and therapeutic targets. This study aimed to investigate the clinical and biological significance of peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) in MM. METHODS: Expression and clinical data were obtained from public databases and an independent local cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate prognostic value. Differential expression analysis, pathway enrichment analysis and single-cell RNA-seq data analysis were used to explore biological functions. PPRC1 was silenced in MM cell lines using siRNA to assess its effects on cell survival and oxidative phosphorylation. RESULTS: PPRC1 was significantly upregulated in MM and was associated with advanced disease stage and poor overall survival. Multivariate Cox analysis identified PPRC1 as an independent prognostic factor. A nomogram incorporating PPRC1 and revised-ISS improved survival prediction. Functional analyses revealed that PPRC1 was positively correlated with oxidative phosphorylation and oncogenic signalling pathways. A potential connection between PPRC1 expression and immune cell infiltration was observed. PPRC1 knockdown inhibited cell proliferation, induced cell cycle arrest and apoptosis and impaired oxidative phosphorylation in MM. CONCLUSIONS: PPRC1 acts as a prognostic biomarker and metabolic regulator in MM by sustaining mitochondrial oxidative phosphorylation. These findings highlight PPRC1 as a potential therapeutic target in MM.

Humans↗

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

Bacteroides cellulosilyticus-derived 2-hydroxyphenylacetic acid rectifies hepatic lipid homeostasis in MASLD by targeting the PPARγ-CD36 axis.

The gut microbiota plays an important role in the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD), but the specific molecular mechanisms involved have not been fully elucidated. In this study, human cohort studies were performed to identify that the relative abundance of Bacteroides cellulosilyticus (B. cellulosilyticus) was significantly decreased in patients with MASLD. Through the integration of metagenomic and metabolomic analyses, it was confirmed that B. cellulosilyticus and its metabolite 2-hydroxyphenylacetic acid (2HPAA) are key factors regulating the occurrence and development of MASLD. Single-cell sequencing and lipidomic analyses revealed that 2HPAA can enter the liver through the enterohepatic circulation to exert regulatory effects. Specifically, 2HPAA inhibits the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, thereby suppressing the expression of the fatty acid transporter CD36. Meanwhile, 2HPAA regulates lipid metabolism in hepatocytes by significantly enhancing palmitate conversion efficiency and inhibiting CD36 palmitoylation. This dual regulatory effect on CD36 expression and palmitoylation can reduce lipid accumulation in hepatocytes and ultimately alleviate MASLD progression. These findings reveal the mechanism by which B. cellulosilyticus and 2HPAA alleviate MASLD by targeting the PPARγ-CD36 pathway. This work provides a new perspective for the study of gut microbiota-host interactions in regulating liver diseases.

PPAR gamma↗

PubMed2026

ARX mutation-associated interneuron defects provide insights into mechanisms underlying developmental epilepsies.

Cortical interneuron (cIN) dysfunction is associated with various neurodevelopmental and neurological disorders, including developmental epilepsies, autism spectrum disorders and intellectual disabilities. Mutations in ARX (aristaless-related homeobox) are linked to these conditions, with or without accompanying structural brain anomalies. We previously demonstrated that the loss of Arx in the mouse ganglionic eminence, the birthplace of cINs, is associated with seizures, whereas its loss in cortical excitatory neuron progenitor cells results in structural anomalies but no seizures. To elucidate the pathophysiological role of ARX in cINs and its relationship to seizure phenotype, Arx conditional mutant mouse lines were investigated using Gad2- and Nkx2.1-Cre drivers to target distinct populations in the cIN lineage. Our data demonstrate that ARX abrogation results in defects in cIN density and distribution, as well as perinatal lethality. In these mice, we observed defects in cell cycle exit, a biased loss of the marginal zone migration stream of cINs, shifts in cell fate from caudal ganglionic eminence to medial ganglionic eminence identity, and a reduced number of parvalbumin⁺ and somatostatin⁺ cINs, with parvalbumin⁺ cINs being more severely affected. Single-cell RNA sequencing combined with chromatin immunoprecipitation and sequencing revealed that ARX regulates key processes involved in cell cycle progression, cIN subtype differentiation and cIN migration. Investigation of one downregulated target gene, Lmo1, uncovered a potential mechanism by which ARX regulates the number and distribution of cINs in the cortex. Cortical slice cultures demonstrate that LMO1 inhibits cIN migration by repressing Cxcr4 expression, which encodes a key receptor involved in cortical guidance. These data indicate that ARX positively regulates cIN migration by derepressing LMO1's repressive role. Consistent with our mouse model, we observed a significant loss of parvalbumin+ and somatostatin+ cINs in the brain of a patient carrying a pathogenic variant of ARX, who was diagnosed with developmental epileptic encephalopathy. Together, our data provide novel insights into how ARX and its target genes regulate cIN development and migration and into the pathogenic mechanisms underlying a spectrum of neurodevelopmental disorders linked to loss of ARX.

Animals↗

PubMed2026

Genetic architecture of endometriosis: risk factors, comorbidities and clinical implications.

BACKGROUND: In 1999, Dr Susan Treloar and colleagues conducted a landmark twin study in Australia and reported their estimate of 51% for the heritability of endometriosis. This important result led several groups to begin mapping genetic factors contributing to increased endometriosis risk. Despite early challenges, advances in genome-wide association studies (GWAS) have identified multiple genetic risk factors and some target genes implicated in follow-up studies on genetic regulation of transcription. Access to large publicly available genetic datasets and analysis with endometriosis GWAS results is also providing new opportunities to answer important questions about comorbid conditions associated with endometriosis and their implications for clinical practice. OBJECTIVE AND RATIONALE: The objective of the review is to summarize the last 25 years of genetic studies in endometriosis, outline contributions to our understanding of the disease, and suggest future directions to accelerate biological insights from genetic studies to improve clinical outcomes. SEARCH METHODS: A comprehensive review of scientific literature on the genetics of endometriosis was conducted through searches in PubMed and Google Scholar up to June 2026. Search terms included "endometriosis AND (genetics OR GWAS OR genetic risk factors)", For studies addressing the functional characterization of genetic risk loci, additional searches employed the terms "endometriosis AND (genotype-phenotype associations OR colocalization OR eQTL OR mQTL OR multi omics methods)". To identify studies examining shared genetic risk between endometriosis and comorbid conditions, the search strategy included "endometriosis AND (genetic correlation OR colocalization OR Mendelian randomisation)". Publications reporting discoveries related to genetic risk factors for endometriosis and studies interpreting their biological and clinical significance were critically evaluated, and 144 publications were discussed in the review. OUTCOMES: Discovery of genetic risk factors started slowly and has accelerated in recent years with developments in technology and international collaborations to combine data and increase statistical power. GWAS have mapped 80 genetic risk factors that implicate gene regulation of hormonal targets, development of the reproductive tract, regulation of cell proliferation, and regulation of epithelial cell differentiation. In common with most other complex diseases, effects of individual common genetic risk factors are small. However, several examples demonstrate that small effect sizes are not a good predictor for the impact of drugs developed against genetically validated targets. Genetic risk factors implicate five genes regulating gonadotrophin release and oestrogen action, the major target pathway of current drugs for treatment of endometriosis demonstrating proof-of-principal for biologically meaningful results. Genetic correlation and Mendelian Randomization studies highlight important causal relationships between endometriosis and comorbid conditions including a possible role for testosterone during development and shared genetic risk factors for gynaecological, gastrointestinal, pain, psychiatric, and inflammatory conditions. Understanding causal relationships between endometriosis and related conditions will aid clinical management and more personalized treatments. WIDER IMPLICATIONS: Genetic studies provide novel insights into endometriosis pathogenesis and associations with related comorbid conditions. Genetic factors modifying gene regulation and disease risk likely act in specific cell types, and access to datasets from genetically informed cell-based models, single-cell and spatial omics data are needed to accelerate progress. Future studies should address critical questions of heterogeneity and disease subtypes, expand the search for genetic risk factors to non-European populations, evaluate the role of rare and structural variants, and better integrate data from functional, genomics, genetics, and clinical studies to reduce diagnostic delay, develop novel treatment strategies, and translate discoveries into personalized management strategies for affected individuals. REGISTRATION NUMBER: N/A.

comorbid conditions↗

PubMed2026

Generation of spCAS9 expressing human mesenchymal stem cell line to study gene function during osteoblast differentiation.

Human bone marrow-derived stromal cells (hMSCs) are a great resource for studying how genes influence cell fate and differentiation into various cell types like osteoblasts, adipocytes, and chondrocytes, among other cell types. However, genetic manipulation of primary hMSCs has been challenging due to their short lifespan and cellular senescence after limited passaging. Their low and unstable transfection efficiency also complicates gene delivery or inactivation, hindering long-term functional studies. The limited lifespan has been effectively solved by immortalizing hMSCs with telomerase reverse transcriptase (hMSCs-TERT). The use of these cells is ideal for functional studies of osteoblast and adipocyte differentiation through genetic manipulation, providing a stable and reliable model. Here, we have engineered a stable CAS9 expressing hMSC-TERT cell line (hMSC-TERTCAS9) via lentiviral transduction. The constitutive expression of spCas9 enables efficient and reproducible gene editing. We demonstrate the potential of these hMSC-TERTCAS9 cells for generating gene disruptions using plasmid delivery of guide RNAs as a fast and efficient strategy for targeted genome editing. The edited cells can be sorted and expanded as single cells to obtain homogenous clonal cell lines with mono- as well as bi-allelic gene deletions, a crucial step for producing reliable experimental results. We further validate this cell line as a powerful tool for studying gene function during hMSC proliferation and differentiation, providing 3 distinct examples of its utility. Through the generation of indels, single-cell sorting, and clonal selection, we have efficiently inactivated the vitamin D receptor and created both larger (256 nucleotides) gene disruptions in Forkhead box protein O1 and precise removals of a small genomic sequence (73 nucleotides) coding for microRNA MIR675. This novel hMSC-TERTCAS9 cell line represents a significant advancement, offering a stable, efficient, and versatile platform for advanced genetic studies, high-throughput screening, and the creation of reliable cellular disease models.

CRISPR-Cas9↗

PubMed2026

Genome-Wide Association Analyses Identify Distinct Genetic Architectures for Extreme Early-Onset and Late-Onset T2D.

AIMS: Type 2 diabetes (T2D) is a heterogeneous disorder with substantial variation in age at onset (AAO). This study aimed to characterize the distinct genetic architectures and biological mechanisms underlying extreme AAO-defined T2D subtypes. MATERIALS AND METHODS: Using 74 795 European-ancestry participants from the UK Biobank, we performed genome-wide association studies (GWAS) of relatively early-onset T2D (eoT2D; AAO < 55 years) and late-onset T2D (loT2D; AAO ≥ 70 years). We investigated subtype-specific genetic loci, SNP-based heritability, genetic correlations, Mendelian randomization (MR)-based relationships, polygenic risk scores (PRS) and phenome-wide association studies (PheWAS). Single-cell transcriptomic data from human pancreatic tissues were further used to evaluate cell-type-specific expression patterns of candidate genes. RESULTS: SNP-based heritability was substantially higher for eoT2D than loT2D (11.2% vs. 6.4%), with eoT2D displaying distinct genetic loci related to β-cell function and insulin regulation, including SLC30A8 and IRS1. By contrast, loT2D showed a comparatively lipid-related genetic profile, featuring APOE-associated signals and expression patterns in immune-related cell populations. Linkage disequilibrium score regression (LDSC) and MR analyses further underscored this divergence: eoT2D exhibited broader genetic overlap with cardiometabolic traits, whereas loT2D showed stronger relationships with traditional metabolic risk factors. Finally, subtype-specific PRSs improved risk discrimination beyond conventional covariates, although their clinical utility warrants further evaluation. CONCLUSIONS: Extreme AAO-defined T2D subtypes exhibit partially distinct genetic architectures, highlighting AAO as an important dimension of T2D heterogeneity and providing a framework for future age-stratified genetic risk assessment.

Type 2 diabetes↗

PubMed2026

Intestinal blood vessel-associated macrophages and gut-vascular barrier dysfunction in cirrhosis.

BACKGROUND: Bacterial translocation in cirrhosis can trigger infection and hepatic decompensation, leading to systemic inflammation, organ failure and increased mortality. These infections often originate from the gastrointestinal tract after bacteria breach the intestinal barrier and disseminate to systemic sites. OBJECTIVE: In this study, we explore the mechanisms underlying intestinal barrier dysfunction in cirrhosis using an experimental cirrhosis model and patient-derived intestinal biopsies. DESIGN: We developed a murine model of cirrhosis through chronic administration of carbon tetrachloride for up to 20 weeks. We investigated both the intestinal epithelial and vascular compartments and performed single-cell transcriptomic profiling of myeloid cells isolated from cirrhotic mice and from individuals with compensated and decompensated cirrhosis. RESULTS: Our findings indicate that bacterial translocation in cirrhosis is the result of failure at multiple checkpoints, including aberrant epithelial cell death, vascular barrier damage and dysfunction of gut-vascular macrophages. In a preclinical model of cirrhosis, macrophages exhibited increased levels of monocyte-attracting chemokines, reduced bacterial clearance and impaired interactions with blood vessels. Importantly, depleting vascular-lining macrophages resulted in bacterial translocation to systemic sites, even in the absence of experimental liver disease. Transcriptional profiling of macrophages from duodenal biopsies of patients with cirrhosis indicated similar dysregulation of pathways supporting blood vessels and elevated expression of chemokines. CONCLUSIONS: This study emphasises the critical role of intestinal macrophages in preventing the dissemination of luminal bacteria and highlights the multifaceted breakdown of the intestinal barrier in cirrhosis and the importance of the gut-vascular barrier.

Animals↗

PubMed2026

SDC1+ CAFs secreting CTGF drive tumour metastasis via FGFR3 signalling in cancers.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are key stromal components of the tumour microenvironment (TME) that profoundly influence tumour progression. However, CAFs exhibit pronounced phenotypic and functional heterogeneity, and whether conserved CAF subtypes with shared functional hallmarks exist across different cancer types remains unclear. OBJECTIVE: We sought to uncover universal CAF subtypes that transcend tumour origins, defining their core molecular signatures and pro-tumorigenic functions within the TME. DESIGN: We constructed a pan-cancer CAF atlas through single-cell transcriptomic analysis of 554 specimens across 14 cancer types. To validate the findings, we performed further functional analyses, including in vitro migration and invasion assays, in vivo lymphatic metastasis models and mechanistic studies focusing on candidate signalling pathways. RESULTS: We identified a conserved syndecan 1 (SDC1) + CAF subset associated with advanced tumour stage and poor outcomes. These CAFs enhanced tumour cell migration and invasion in vitro and promoted lymphatic metastasis in vivo. This effect is mediated through connective tissue growth factor (CTGF) secretion, which activates fibroblast growth factor receptor 3 (FGFR3) signalling in tumour cells to induce epithelial-mesenchymal transition (EMT). Blocking CTGF or FGFR3 signalling abrogated these effects. We also found that kruppel like factor 6 (KLF6) directly regulates CTGF in SDC1+ CAFs, establishing a complete KLF6-CTGF-FGFR3 metastatic axis. CONCLUSIONS: Our study establishes SDC1+ CAFs as a universal, metastasis-promoting CAF subset across multiple cancer types and uncovers a novel KLF6-CTGF-FGFR3 axis that drives EMT and tumour dissemination. These findings provide mechanistic insight into CAF-tumour cell crosstalk and highlight actionable stromal targets for anti-metastatic therapies across diverse malignancies.

Humans↗

PubMed2026

The Pathogenesis of Epithelial Ovarian Cancer.

Epithelial ovarian cancer is not a single disease but a group of biologically distinct malignancies that include serous (high-grade and low-grade), endometrioid, clear cell, and mucinous carcinomas, along with other rare subtypes. Integrating clinicopathological analyses, genomic and multiomic data, and experimental investigations in model systems has revealed the pathogenesis of the various histologic subtypes. A unique feature of epithelial ovarian cancer is that most of these tumors are now recognized to arise not from ovarian tissue but from the fallopian tube or endometrium, the latter in the context of ovarian endometriosis. Studies of precursor lesions have revealed complex evolutionary trajectories and the earliest molecular events in their development. Recent single-cell and spatial technologies further elucidate the roles of intratumoral heterogeneity and the tumor microenvironment in disease progression. This review summarizes these advances from the perspective of tissue of origin and highlights their implications for prevention, early detection, and therapeutic development.

Journal Article↗

PubMed2026

Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in Tet2 Clonal Hematopoiesis.

BACKGROUND: Clonal hematopoiesis (CH) arising from mutations in hematopoietic genes has been identified as an important risk factor for atherosclerotic cardiovascular disease. Despite the established role of some CH mutations in promoting atherosclerosis progression, their role in clinically relevant LDL (low-density lipoprotein) lowering-induced plaque remodeling or regression has not been extensively studied. METHODS: To assess the effects of TET2 (tet methylcytosine dioxygenase 2) CH on plaque resolution, we prepared control or chimeric Tet2+/- CH mice with conditional deletion of Tet2 in hematopoietic stem cells during LDL lowering-induced plaque remodeling. After establishing atherosclerosis by Western diet feeding for 12 weeks in Ldlr-/- mice, Tet2 was deleted by tamoxifen injection, and hypercholesterolemia was either normalized to simulate clinical lipid management, or mice were continued on the Western diet. RESULTS: Unlike control mice, Tet2+/- CH mice failed to significantly reduce necrotic core area or increase fibrous cap thickness and showed impaired macrophage efferocytosis during LDL lowering. Single-cell RNA sequencing and gene set enrichment analysis of aortic cell populations revealed that Tet2 deficient monocyte/macrophage populations were defective in glycolysis, phagocytosis, and actin polymerization. Tet2-deficient bone marrow-derived macrophages and Tet2+/- induced pluripotent stem cell-derived human macrophages showed defective ability to sustain continuing rounds of efferocytosis. Bone marrow-derived macrophages displayed reduced apoptotic cell binding and internalization and impaired activity of Wiskott-Aldrich syndrome protein and SCAR (suppressor of cyclic AMP receptor) homolog complex mediated actin polymerization. We linked these defects to reduced anaerobic glycolysis and lactate levels and rescued them by lactate supplementation or by treatment with the HIF-1α (hypoxia-inducible factor 1α) activator molidustat. Molidustat treatment reversed the defects in necrotic core and fibrous cap formation during LDL lowering-induced plaque remodeling in Tet2+/- CH mice. Reduced plasma lactate levels were also shown in TET2 clonal hematopoiesis of indeterminate potential carriers in the UK Biobank. CONCLUSIONS: Our data identify impaired efferocytosis and glycolysis-lactate-actin polymerization pathways in advanced atherosclerosis as potential therapeutic targets to induce proresolving restructuring of the plaque immune cells and to promote beneficial atherosclerosis remodeling in subjects with TET2 CH.

LDL lowering↗

PubMed2026

Tracking GAD-specific T-cell expansions in Type 1 diabetes by intradermal GAD-Alum challenge.

Identifying and monitoring autoreactive T cells that drive beta cell destruction remains a major obstacle to developing effective immunotherapies for type 1 diabetes (T1D). These cells are extremely rare in peripheral blood and cannot be accessed directly from the pancreas. We used intradermal injection of Glutamic Acid Decarboxylase (GAD)-Alum to recruit GAD-specific T cells to accessible sites in the skin and skin-draining lymph nodes (LNs), sampled by skin suction blisters and ultrasound-guided LN aspiration. Peripheral blood samples obtained before GAD injection were restimulated with GAD in vitro to detect reactive CD4+ T cells. Single-cell RNA sequencing (scRNAseq) followed by re-expression of selected T cell receptors (TCRs) confirmed antigen specificity. Up to 70% of T cells at the skin injection site were clonally-expanded and 4 of 14 (28%) re-expressed TCRs were GAD-reactive. In LNs 1 of 14 (4%) clonally-expanded TCRs was GAD-reactive, representing ~0.08% of all T-cells. GAD-reactive cells across compartments displayed Th1 and Th17-associated transcription signatures. These results demonstrate the intradermal autoantigen challenge and scRNAseq, enable direct identification and molecular profiling of autoreactive T cells in vivo. This minimally invasive approach provides a powerful platform for tracking antigen-specific T cells to monitor disease activity and evaluate immune interventions in T1D.

Autoimmunity↗

PubMed2026

Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature.

Dysfunctional tumor vessels promote disease progression, whereas improved function enhances therapeutic delivery. However, current approaches to normalize tumor vasculature have limited efficacy. In vascular malformations, vessels are similarly dysfunctional, with endothelial cell (EC) hyperproliferation impairing arterial-venous specification. These defects are corrected with palbociclib, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) that has beneficial effects on tumor and immune cells, but the effects on tumor vasculature are not well characterized. In our studies, murine mammary tumor ECs (TECs) exhibited disrupted cell cycle and specification, and CDK4/6i promoted TEC cycle control, enabling improved tumor vascular function. To investigate transcriptomic changes, we performed single-cell RNA sequencing (scRNAseq) of treated and untreated tumors, and healthy tissues. CDK4/6i-mediated TEC cycle arrest promoted arterial-venous specification, cellular junctions, and pericyte association, and suppressed glycolytic and immunosuppressive gene expression. These effects were associated with increased vessel perfusion, decreased tumor hypoxia, and a more favorable immune landscape with immunotherapy. In scRNAseq datasets from patients treated long-term with CDK4/6i, TECs exhibited similar transcriptomic changes associated with arterial-venous specification, pericyte recruitment, and immune signaling. Thus, in contrast to current strategies, CDK4/6i-mediated vascular changes may be maintained with continued treatment, highlighting the relevance of modulating TEC cycle to improve vessel maturation/function.

Angiogenesis↗

PubMed2026

CDC20B Dysregulation: Links to Tumor Prognosis and Immunity.

OBJECTIVE: This study aimed to clarify the pan-cancer expression pattern, upstream regulatory mechanisms, prognostic relevance, and immune associations of CDC20B. METHOD: Using public databases (GTEx, GEO, and TCGA), we examined CDC20B expression and its associations with prognosis and tumor immunity across multiple cancers. Immunohistochemistry (IHC) on an independent clinical cohort was performed to validate CDC20B upregulation in tumor tissues. Promoter methylation, genetic alterations, and immune infiltration were analyzed using bioinformatics tools (cBioPortal, UALCAN, TIMER2.0, ESTIMATE). Functional enrichment was assessed by GSEA and single-cell state analysis (CancerSEA). RESULTS: CDC20B was markedly upregulated in most tumor types (p < 0.001), with strong diagnostic efficiency (AUC > 0.7 in 15 cancers) and potential regulation by promoter hypomethylation. IHC confirmed its overexpression in clinical tumor tissues. However, the prognostic impact of CDC20B was cancer-type-specific: high expression correlated with poor overall survival in UCS, LGG, KIRC, and OV, but with favorable survival in BRCA, LUAD, and PAAD. CDC20B expression was associated with immune infiltration patterns, showing negative correlations with ImmuneScore in most cancers but positive correlations with CD8+ T cells in PAAD. Functional analyses indicated involvement in EMT, KRAS/NF-κB signaling, and DNA damage response pathways. DISCUSSION: The dual prognostic role of CDC20B suggests context-dependent functions, likely influenced by tumor microenvironment composition and underlying oncogenic programs. Promoter hypomethylation emerges as a potential epigenetic driver of overexpression. The associations with immune modulation and genomic instability suggest that CDC20B is a candidate biomarker, though causal relationships require experimental validation. CONCLUSION: CDC20B may contribute to tumor progression in a context-dependent manner, with its prognostic impact varying across cancer types. Its role in tumor immunity and oncogenic pathways warrants further investigation, particularly in stratified patient populations.

CDC20B↗

PubMed2026

Tumor-Intrinsic Blood and Imaging Correlatives in Advanced Prostate Cancer Treated with Combination Radiopharmaceutical Therapy and Immunotherapy.

The PRINCE trial showed the clinical activity for 177Lu-PSMA-617 in combination with pembrolizumab for metastatic castration-resistant prostate cancer. To refine patient selection and improve response monitoring strategies to this combination, we investigated candidate tumor-intrinsic biomarkers of treatment response and resistance. Methods: We performed circulating tumor DNA (ctDNA), circulating tumor cell (CTC), and PET imaging analyses at baseline, 12 wk on-treatment, and disease progression in participants enrolled in PRINCE (n = 37). We performed targeted sequencing for ctDNA quantification and genomic analysis of more than 70 prostate cancer genes. CTC enumeration was performed on the EpicSciences platform and was combined with selective single-cell whole-genome sequencing. PET imaging included serial PSMA PET as well as 18F-FDG PET imaging at baseline. Results: A low baseline ctDNA fraction and high PSMA avidity in metastatic lesions were linked to superior treatment responses and may have composite biomarker value. Genomic alterations in tumor suppressor genes TP53, RB1, or PTEN were associated with higher 18F-FDG avidity and metabolic tumor volume on 18F-FDG PET imaging and worse prognosis. At 12-wk on-treatment, both ctDNA detection and PSMA PET imaging were strong indicators of response depth and durability. At disease progression, PSMA expression on PET imaging was lower compared with baseline and supported by subclonal remodeling of ctDNA and CTC copy number profiles and by clonal expansions of tumor suppressor gene mutations. Conclusion: We provide the first integrated molecular and imaging insights into determinants of response and resistance to combined radiopharmaceutical therapy and immunotherapy in prostate cancer and propose biomarker strategies to inform future clinical development.

177Lu-PSMA-617↗