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Results for “Extracellular Traps”

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PubMed1979

Transmembrane potential and ionic content of rat alveolar macrophages.

The cell volume, cell water, intracellular ionic concentrations, and transmembrane potential of rat alveolar macrophages were determined. The measurements were made on cells which had been separated from the medium by centrifugation through dibutyl phthalate in order to greatly reduce the trapped extracellular space. The mean cell volume of the alveolar macrophages is 1,525 cubic microns and 72% of this volume is water. The intracellular fluid is high in Na+ (97 mM) and lower in K+ (50 mM) and the intracellular Cl- concentration in 64 mM. The transmembrane potential, as measured from the equilibrium distribution of tritiated triphenylmethyl phosphonium and by using the fluorescent probe, Di-S-C3(5), is approximately -37 millivolts. Neither Na+, K+, nor Cl- is distributed at equilibrium. However, the K+ permeability of alveolar macrophage membranes appears to be greater than Na+ permeability.

Animals↗

PubMed2006

Disturbances in placental immunology: ready for therapeutic interventions?

Recent studies have provided new insight into aberrations in the immunological interplay between mother and fetus and their potential role in the development of recurrent fetal loss and preeclampsia. The action of anti-phospholipid antibodies in recurrent fetal loss is now proposed to involve the complement system, neutrophil activation and the production of TNFalpha by immune bystander cells. A clear involvement of the immune system is emerging in preeclampsia, involving mainly the innate arm, especially neutrophils. The activation of peripheral neutrophils by placentally released inflammatory debris triggers the induction of neutrophil extracellular traps (NETs), which may lead to an occlusion of the intervillous space, thereby further promoting a condition of placental hypoxia. It has, hence, been suggested that new therapeutic strategies be developed, including the possible use of TNFalpha antagonists in cases of recurrent miscarriage. These strategies need to be addressed with caution due to the possible induction of fetal congenital abnormalities.

Abortion, Habitual↗

PubMed2005

Plasma bikunin: half-life and tissue uptake.

Bikunin is a chondroitin sulfate-containing plasma protein synthesized in the liver. In vitro, it has been shown to inhibit proteases and to have additional activities, but its biological function is still unclear. Here we have studied the dynamics of plasma bikunin in rats and mice. A half-life of 7 +/- 2 min was obtained from the time course of the decrease of the plasma level of bikunin following hepatectomy. Clearance experiments with intravenously injected radiolabeled bikunin with or without the chondroitin sulfate chain showed that the polysaccharide had little influence on the elimination rate of the protein. The uptake of bikunin by different tissues was studied using bikunin labeled with the residualizing agent 125I-tyramine cellobiose; 60 min after intravenous injection, 49% of the radioactivity was recovered in the kidneys and 6-11% in the liver, bones, skin, intestine and skeletal muscle. The uptake in the liver was analyzed by intravenous injection of radiolabeled bikunin followed by collagenase perfusion and dispersion of the liver cells. These experiments indicated that bikunin is first trapped extracellularly within the liver before being internalized by the cells.

Animals↗

PubMed1982

Consequences of 125I-labeled insulin degradation by hepatocytes on the interpretation of receptor binding studies.

The association of 125I-labeled insulin with hepatocytes was assayed by filtration or microcentrifugation. Assay by centrifugation resulted in a greater amount of retained radioactive label throughout the course of association of 125I-labeled insulin with hepatocytes. Similarly, saturation experiments assayed by microcentrifugation suggested greater binding than filtration. During dissociation, cells isolated by centrifugation release a greater amount of rapid-dissociating radioactive label. Control experiments of [3H]-inulin exclusion with cell pellets, which were isolated during microcentrifugation, demonstrated that the difference between the methods was not due to extracellular trapping of radioactivity. Therefore, the data suggested that there was more low-affinity retention when binding was assayed by centrifugation than filtration. The integrity of the 125I-labeled insulin extracted from hepatocytes was determined by column chromatography. A substantially greater proportion of the extracted radioactivity was fragments of 125I-labeled insulin in cells isolated by centrifugation. It is suggested that the extensive washing of the cells during filtration removes more fragments than does centrifugation. During dissociation, the low-affinity component of radioactivity, which was observed in the centrifugal assay, resulted from the transient retention of insulin fragments. The extensive degradation of insulin, which was assayed by either method, and the differences observed between these methods, should be considered in the interpretation of binding experiments with cells.

Animals↗

PubMed2026

Toxicological effects of propyl 4-hydroxybenzoate on gallstone pathogenesis: An integrated mendelian randomization, network toxicology, and experimental study.

BACKGROUND: Gallstone disease is a prevalent digestive disorder with substantial global socioeconomic burden. Propyl 4-hydroxybenzoate (PP), a widely used paraben preservative, exhibits potential metabolic and hepatic toxicity, yet its role in gallstone pathogenesis remains unclear. This study aimed to explore the causal association between PP exposure and gallstone formation and the underlying mechanism. METHODS: Two-sample Mendelian randomization (MR) was performed using genome-wide association study (GWAS) data. Network toxicology, molecular docking, and molecular dynamics simulation were applied to screen for core targets. In vivo experiments, transcriptome sequencing, Western blot (WB), and ELISA were conducted for mechanistic validation. RESULTS: MR confirmed a causal link between circulating PP levels and an elevated risk of gallstones (P < 0.05), with AKT1 identified as the key target. In mice, PP aggravated gallstone formation by activating the AKT1-NF-κB-CXCL1 pathway, enhancing hepatic inflammation and neutrophil extracellular traps (NETs) formation; these effects were reversed by AKT inhibition. CONCLUSION: PP promotes gallstone formation via the AKT1-NF-κB-CXCL1-NETs axis. Our findings highlight PP as an environmental risk factor for gallstones, providing novel insights into their prevention and targeted therapy.

Animals↗

PubMed1998

Human monocyte-derived macrophages secrete two forms of proteoglycan-macrophage colony-stimulating factor that differ in their ability to bind low density lipoproteins.

This study evaluated whether human monocyte-derived macrophages synthesize specific types of proteoglycans with lipoprotein-binding capability that could contribute to lipid retention in the arterial wall. After labeling with either [35S]SO4 or [35S]methionine, macrophages secreted a high molecular mass proteoglycan, with glycosaminoglycan chains of approximately 18 kDa and core protein bands of approximately 100 and 55 kDa. Both core protein bands were recognized by an antibody to PG-100, an antibody that recognizes the proteoglycan form of macrophage colony-stimulating factor (PG-100/PG-MCSF). The interaction between PG-100/PG-MCSF and low density lipoproteins (LDL) was examined by gel mobility shift. In this system, PG-100/PG-MCSF was resolved further into two forms. The two forms had the same core proteins but differed in their overall size and glycosaminoglycan content. The larger form contained glycosaminoglycan chains that were entirely chondroitin ABC lyase-sensitive, whereas the smaller form contained chains that were sensitive to both chondroitin ABC lyase and heparinase. Both forms bound native LDL with high affinity, but the larger form bound LDL with higher affinity than the smaller form. The glycosaminoglycan chains of PG-100/PG-MCSF, but not the core proteins, were responsible for binding to native LDL. Mildly oxidized LDL and methyl-LDL, which have an electrophoretic charge similar to that of native LDL, also bound PG-100/PG-MCSF. In contrast, extensively oxidized LDL and acetyl-LDL, which are more electronegative than native LDL, did not bind to either form of PG-100/PG-MCSF. The demonstration of two forms of human monocyte-derived macrophage PG-100/PG-MCSF which bind LDL may represent an additional role for macrophages in the extracellular trapping of lipoproteins in atherosclerosis.

Cells, Cultured↗

PubMed2005

Modulation of the metabolism and adverse effects of benzo[a]pyrene by a specific antibody: a novel host factor in environmental carcinogenesis?

The influence of specific antibodies on molecular and cellular mechanisms of activation, detoxification and biological activity of the ubiquitous carcinogen benzo[a]pyrene (B[a]P) was investigated using a monoclonal antibody. The antibody was shown to decrease cellular uptake and metabolic activation of B[a]P as demonstrated by higher recovery of unmetabolized B[a]P and decreased formation of end-point phenol metabolites in two types of target cells. Furthermore, strong antibody reactivity with 7,8-diol-B[a]P provided a second chance for interrupting metabolic activation by sequestration of this intermediate metabolite in the extracellular space. The biological relevance of B[a]P and 7,8-diol-B[a]P redistribution by antibody was demonstrated by reversion of B[a]P-induced inhibition of proliferation of human peripheral blood lymphocytes and by inhibition of CYP 1A1 induction in HepG2 cells. Remarkably, the antibody was still protective against B[a]P-induced immunotoxicity even after delayed addition, suggesting a more important role of metabolites in immunotoxicity than has been appreciated so far. Although B[a]P is activated to 7,8-diol-B[a]P in the same cells that are inhibited by this metabolite, the antibody completely restored lymphocyte proliferation indicating that extracellular trapping of the 7,8-diol-B[a]P is biologically highly effective. Thus, repartitioning of both B[a]P and its metabolites by the antibody may reduce their effective concentration in susceptible target organs and therefore relieve overloaded DNA repair mechanisms and inhibit carcinogen-induced P450 induction. These in vitro data also suggest that a natural or prophylactic antibody response against carcinogens may be associated with a reduced risk of cancer.

Alkylation↗

PubMed2025

Exploring prognostic genes in the immune microenvironment of acute myeloid leukemia via weighted gene co-expression network analysis.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous blood cancer that arises from transformed myeloid precursor cells in a compromised bone marrow microenvironment. This environment is essential for AML initiation, progression, and relapse. Alongside oncogenic changes in hematopoietic cells, immunological dysregulation also contributes to leukemogenesis. The present study is aimed to identify prognostic genes in stromal and immune cells associated with AML using the weighted gene co-expression network analysis (WGCNA). METHODS: Gene expression profiles were retrieved from The Cancer Genome Atlas database, and immune and stromal cell scores were calculated using the ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) method. These scores helped identify differentially expressed genes (DEGs), which were then used to create gene clusters through WGCNA. To explore the functions of genes linked to AML subtypes, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. A protein-protein interaction network was developed to identify hub genes. The top 18 hub genes were identified using the cytoHubba plug-in in Cytoscape software, and survival analysis was conducted with the Gene Expression Profiling Interactive Analysis 2 online tool. RESULTS: A total of 1097 DEGs were identified, with 601 being upregulated and 496 downregulated. WGCNA analysis indicated that the gray module, comprising 165 genes, had the strongest association with AML subtypes (Cor > 0.3; P < .05). Gene Ontology enrichment analysis demonstrated that the 18 identified hub genes were predominantly associated with neutrophil activation, immune response, secretory granule membrane, and pattern recognition receptor activity. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the DEGs were mainly involved in pathways related to phagosome, lysosome, tuberculosis, leishmaniasis, and neutrophil extracellular trap formation. Kaplan-Meier survival analysis of the top 18 hub genes indicated that ITGAM, IL10, and CD163 were significantly correlated with survival outcomes in AML. CONCLUSION: Key stromal and immune-related genes influencing AML patient outcomes were identified, highlighting their potential as therapeutic targets. These discoveries provide deeper insights into the molecular mechanisms driving AML pathogenesis and subtype differentiation.

Leukemia, Myeloid, Acute↗

PubMed2026

Admission whole-blood transcriptomic characterization of a neutrophil-predominant systemic immune response in patients with acute traumatic brain injury.

BACKGROUND: Acute traumatic brain injury (TBI) is accompanied by systemic immune responses, but their whole-blood transcriptomic features at hospital arrival remain incompletely characterized. We aimed to characterize these features in patients with acute TBI compared with healthy controls. METHODS: In this single-center prospective observational study, we performed whole-blood RNA sequencing on hospital-arrival samples from 42 patients with acute TBI and 21 healthy controls. Analyses included differential expression (limma-voom; FDR < 0.05, |log2FC| > 0.7), functional enrichment, Ingenuity Pathway Analysis, CIBERSORTx LM22 deconvolution, and per-sample neutrophil degranulation signature scoring. RESULTS: Differential expression analysis identified 996 upregulated and 863 downregulated genes, with marked upregulation of inflammation-, innate immunity-, and neutrophil-related genes including DUSP1, HMGB2, MMP9, and S100A8. Canonical pathways with positive IPA z-scores included Neutrophil degranulation, Neutrophil Extracellular Trap Signaling Pathway, and Toll-like Receptor Signaling; upstream regulators included TNF, IL1B, IFNG, and STAT3. Deconvolution identified 7 of 22 differing subsets (q < 0.05), with relatively higher myeloid and lower lymphoid fractions in TBI. The Neutrophil degranulation signature score correlated with Injury Severity Score within TBI (Spearman ρ = +0.55; q < 0.001). CONCLUSIONS: Admission whole-blood transcriptomics characterized a neutrophil-predominant systemic transcriptional response in patients with acute TBI. This response was also evident among patients without major extracranial injury and was associated with total ISS. However, because the study lacked an appropriately matched non-TBI trauma comparator, the findings should be interpreted as a descriptive characterization of a systemic injury response accompanying TBI and do not establish a TBI-specific molecular signature or mechanism.

gene expression↗

PubMed2025

CRISPR/Cas9 screenings reveal the role of STX1A and CDK1 in Cathepsin G entering and killing colorectal cancer cells.

Neutrophils are the major populations of white blood cells and have been reported to facilitate cancer metastasis. Meanwhile, emerging evidence has recently suggested the anti-cancer role of neutrophils. Our previous study revealed that CB-839 and 5-FU-treated colorectal cancer (CRC) tumors recruited neutrophils and induced neutrophil extracellular traps (NETs). Cathepsin G (CTSG), which is released during NET formation, enters CRC cells through the receptor for advanced glycation end products (RAGE) and cleaves 14-3-3ε to promote apoptosis. However, the detailed mechanism underlying CTSG's anti-tumor function remains less studied. In this study, we report that CTSG enters CRC cells through RAGE-mediated endocytosis. Knocking out RAGE or inhibiting endocytosis blocks CTSG from entering CRC cells and attenuates CTSG-induced apoptosis. Furthermore, the clathrin coat assembly complex and SNARE proteins were enriched in an arrayed CRISPR/Cas9 screening targeting human membrane trafficking genes. Knocking out SNARE protein STX1A prevents the spread of CTSG in CRC cells and the induction of cleaved PARP. A pooled genome-wide CRISPR/Cas9 screening further identifies the role of CDK1 in the NET-induced killing of CRC cells. Inhibiting CDK1 protected CRC cells from killing by CTSG. Our study reveals novel mechanisms by which CTSG enters and kills CRC cells.

CDK1↗

PubMed2006

How do microbes evade neutrophil killing?

Many microbial pathogens evolved to circumvent the attack of neutrophils, which are essential effector cells of the innate immune system. Here we review six major strategies that pathogenic bacteria and fungi use to evade neutrophil defences: (i) turning on survival and stress responses, (ii) avoiding contact, (iii) preventing phagocytosis, (iv) surviving intracellularly, (v) inducing cell death and (vi) evading killing by neutrophil extracellular traps. For each category we give examples and further focus on one particular pathogenic microbe in more detail. Pathogens include Candida albicans, Cryptococcus neoformans, Yersinia ssp., Helicobacter pylori, Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae.

Animals↗

PubMed1998

In vivo distribution of the human immunodeficiency virus/simian immunodeficiency virus coreceptors: CXCR4, CCR3, and CCR5.

We have evaluated the in vivo distribution of the major human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) coreceptors, CXCR4, CCR3, and CCR5, in both rhesus macaques and humans. T lymphocytes and macrophages in both lymphoid and nonlymphoid tissues are the major cell populations expressing HIV/SIV coreceptors, reaffirming that these cells are the major targets of HIV/SIV infection in vivo. In lymphoid tissues such as the lymph node and the thymus, approximately 1 to 10% of the T lymphocytes and macrophages are coreceptor positive. However, coreceptor expression was not detected on follicular dendritic cells (FDC) in lymph nodes, suggesting that the ability of FDC to trap extracellular virions is unlikely to be mediated by a coreceptor-specific mechanism. In the thymus, a large number of immature and mature T lymphocytes express CXCR4, which may render these cells susceptible to infection by syncytium-inducing viral variants that use this coreceptor for entry. In addition, various degrees of coreceptor expression are found among different tissues and also among different cells within the same tissues. Coreceptor-positive cells are more frequently identified in the colon than in the rectum and more frequently identified in the cervix than in the vagina, suggesting that the expression levels of coreceptors are differentially regulated at different anatomic sites. Furthermore, extremely high levels of CXCR4 and CCR3 expression are found on the neurons from both the central and peripheral nervous systems. These findings may be helpful in understanding certain aspects of HIV and SIV pathogenesis and transmission.

Animals↗

PubMed1979

A rapid technique for measuring calcium uptake in mitogen-induced T and B lymphocytes.

The procedures for lymphocyte activation and for removing the cells from the radioactive loading solution in incubation medium were modified to routinely obtain significant and reproducible 45Ca2+ uptakes in mitogen-induced mouse T and B lymphocytes. Factors such as mouse strain, lymphocyte origin, and media pH were not critical to the 45Ca2+ uptake measurements. In contrast, factors such as lymphocyte cell concentration during mitogenic activation, filtering the 45Ca2+:3H2O mixtures, and the nature and purity of the B-cell mitogens were critical for obtaining maximal and reproducible 45Ca2+ uptakes. Centrifugation through silicone oil into sucrose was an efficient and rapid procedure for separating the cells from the radioactive loading solution in the incubation medium. Using optimal conditions, an approximate twofold increase in 45Ca2+ uptake (representing an influx of approximately 97 amol per lymphocyte and an increase in average cellular Ca2+ of approximately 0.72 mM) was routinely obtained with purified mouse lymphocytes activated with a variety of T- and B-cell mitogens (using concentrations resulting in maximal [3H]thymidine incorporation). A larger 45Ca2+ uptake was routinely obtained with mitogenic concentrations of A23187, a divalent cation ionophore stimulating T cells. Experiments employing [14C]sucrose and [14C]inulin with control and mitogen-induced lymphocytes showed that the trapped extracellular fluid measurements in the cell pellets should be used to correct the magnitude of the 45Ca2+ uptake measurements.

Animals↗

PubMed2026

Pathogenic role of serpin B3-positive neutrophils in reinforcing thrombus stiffening during ischemic stroke.

The contribution of immune cells to thrombus architecture and mechanical properties in acute ischemic stroke (AIS) remains poorly understood. Using 3-dimensional imaging and multiplex staining, we mapped immune cells in human stroke thrombi and identified neutrophils as the dominant population. Analysis of 19 thrombi confirmed their positive correlation with collagen, increased stiffness, and poorer clinical outcomes. To preserve spatial context, we developed a laser capture-based proteomic workflow and analyzed thrombus neutrophils from 34 patients with AIS stratified by 90-day outcomes, followed by validation in an independent cohort of 22 patients. Proteomic analysis revealed serpin B3 as a neutrophil-enriched protein strongly correlated with poor prognosis. In murine models of ferric chloride-induced carotid artery thrombosis and middle cerebral artery occlusion, experiments using wild-type, neutrophil-depleted, and Serpinb3a knockout mice demonstrated that neutrophil-derived serpin B3 promotes early thrombus formation, enhances collagen deposition, and contributes to progressive thrombus stiffening. Mechanistically, serpin B3 secreted by neutrophils amplifies thrombus stiffness through upregulation of transforming growth factor β1, neutrophil extracellular traps, and COL1A1. Targeted Serpinb3a knockdown delayed vascular occlusion, improved thrombolysis efficiency, and resulted in better neurological recovery. Collectively, these findings identify a neutrophil-driven mechanism underlying thrombus stiffening and establish SERPINB3 as both a prognostic biomarker and a promising therapeutic target in AIS. This project has been registered with the Chinese Clinical Trial Registration Platform (https://www.chictr.org.cn/index.html) and has successfully passed the review process (registration number: ChiCTR2300077911).

Animals↗

PubMed2026

A weakly supervised deep learning-based recurrence prediction and risk stratification of lung adenocarcinoma from pathology whole-slide images.

BACKGROUND: Accurate prediction of postoperative recurrence in lung adenocarcinoma (LUAD) is essential for guiding clinical decision-making and improving patient outcomes. Although various predictive models have been developed, most rely on complex genomic analyses and high-dimensional clinical data. The complexity of these approaches substantially limits their feasibility for routine clinical use. To address this clinical challenge, this study aims to predict postoperative recurrence using routinely available hematoxylin and eosin (H&E)-stained images and characterize the associated biological features. METHODS: A total of 329 patients who underwent curative resection at the First Affiliated Hospital of Wenzhou Medical University (FHWMU) were retrospectively enrolled and randomly assigned to training and internal validation cohorts in a 7:3 ratio. An independent external validation cohort comprising 70 patients from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) was included. Three patch-level feature extractors (Inception_V3, ResNet18, and DenseNet121) were evaluated within a weakly supervised multiple-instance learning (MIL) framework incorporating automated region-of-interest (ROI) detection on segmented whole-slide images (WSIs). Model performance was assessed using the area under the receiver operating characteristic curve (AUC), Kaplan-Meier (KM) survival analysis, and multivariable Cox proportional hazards regression. Transcriptomic profiling and gene set enrichment analysis (GSEA) were conducted to investigate biological differences between risk groups. RESULTS: The model achieved AUCs of 0.923 in the training cohort, 0.891 in the internal validation cohort, and 0.847 in the external validation cohort. The model effectively stratified patients into high- and low-risk groups with significantly different recurrence-free survival (RFS) across all cohorts (all P < 0.001) and retained prognostic value within AJCC stages I-III. Transcriptomic analyses revealed consistent enrichment of cell cycle-related pathways and neutrophil extracellular trap (NET) formation in high-risk patients across both institutional and CPTAC cohorts, aligning with distinct biological profiles of the model-derived risk stratification. CONCLUSIONS: This weakly supervised deep learning framework enables accurate and externally validated prediction of postoperative recurrence in LUAD using routinely available histopathological images, and integration of histopathological features with molecular analyses enhances biological interpretability. This work provides a clinically accessible and cost-effective tool for postoperative risk assessment in LUAD patients.

Humans↗

PubMed2026

Spatial proteomics reveals four-stage molecular evolution in cancer immunotherapy-related gastritis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet immune-related adverse events (irAEs) including immunotherapy-related gastritis (IRAEG) pose significant clinical challenges-often necessitating treatment interruption that may compromise antitumor efficacy. IRAEG presents with atypical symptoms, lacks specific biomarkers, and shows histopathological overlap with other forms of gastritis, complicating diagnosis and management. Despite increasing clinical recognition, a systematic understanding of spatial molecular alterations across the full disease course remains limited. Here, we used spatial proteomics to map the molecular landscape of IRAEG during disease progression and to define stage-specific patterns of molecular evolution relevant to cancer immunotherapy management. METHODS: We analyzed tissue samples from seven patients, including four non-immunotherapy-related gastritis controls and three cancer patients who developed IRAEG following ICI therapy for solid tumors, sampled longitudinally across four disease stages: baseline (G1), acute severe inflammation (G2), early recovery (G3), and complete recovery (G4). Using laser capture microdissection coupled with data-independent acquisition mass spectrometry, we profiled 177 spatially resolved gastric tissue regions. Multiplex immunohistochemistry and immunofluorescence characterized features of the immune microenvironment, while Gene Ontology, KEGG pathway analysis, Gene Set Variation Analysis, and xCell inference enabled functional, metabolic, and immune profiling. Key immune and NET-related findings were further validated by multiplex immunofluorescence in an independent, expanded cohort of IRAEG and non-immunotherapy-related gastritis samples. RESULTS: IRAEG was characterized by widespread HLA molecule activation and enhanced antigen processing, resembling the immune phenotype observed in organ transplant rejection. The acute G2 stage exhibited excessive neutrophil extracellular trap formation, profound metabolic suppression, and collapse of immune homeostasis-features that may inform early intervention strategies to preserve ICI treatment continuity. During early recovery (G3), inflammatory injury transitioned toward repair, marked by activation of fatty acid metabolism and PPAR signaling. Notably, even at complete clinical recovery (G4), more than 1,000 proteins remained differentially expressed, reflecting sustained enhancement of metabolic and immune functions and establishing a distinct molecular "memory" state with implications for ICI rechallenge decisions. CONCLUSIONS: These findings define four molecularly distinct stages of IRAEG progression and recovery. The stage-specific signatures identified here serve as candidate biomarkers for diagnosis, disease staging, and therapeutic response assessment, and may guide clinical decisions regarding irAE management, treatment modification, and safe ICI rechallenge to support continued antitumor therapy.

Humans↗

PubMed2025

Multi-omics reveals cross-tissue regulatory mechanisms of autism risk loci via gut microbiota-immunity-brain axis.

Autism Spectrum Disorder (ASD) involves a multi-system interaction mechanism among genetics, immunity, and gut microbiota, yet its regulatory network remains undefined. This study conducted a meta-analysis on Genome-Wide Association Study data from four independent ASD cohorts to identify potential genetic loci. By integrating Polygenic Priority Score, brain region, and brain cell eQTL enrichment analyses, and combining summary-data-based Mendelian Randomisation (SMR) analyses of brain cis-eQTL and mQTL, bidirectional Mendelian Randomisation analyses of 473 gut microbiota, and SMR analysis of blood eQTL, SNPs such as rs2735307 and rs989134 with significant multi-dimensional associations were identified. These loci exert cross-tissue regulatory effects by participating in gut microbiota regulation, involving immune pathways such as T cell receptor signal activation and neutrophil extracellular trap formation, as well as cis-regulating neurodevelopmental genes (HMGN1 and H3C9P), or synergistically influencing epigenetic methylation modifications to regulate the expression of BRWD1 and ABT1. The cross-scale evidence chain constructed in this study provides a theoretical foundation for precision medicine research in ASD, holding promise to advance the development of innovative therapeutic strategies.

Autism spectrum disorder↗

PubMed2024

Serum proteomic profiling of patients with compensated advanced chronic liver disease with and without clinically significant portal hypertension.

INTRODUCTION: Portal hypertension (PH) drives the progression of liver cirrhosis to decompensation and death. Hepatic venous pressure gradient (HVPG) measurement is the standard of PH quantification, and HVPG≥10 mmHg defines clinically significant PH (CSPH). We performed proteomics-based serum profiling to search for a proteomic signature of CSPH in patients with compensated advanced chronic liver disease (cACLD). MATERIALS AND METHODS: Consecutive patients with histologically confirmed cACLD and results of HVPG measurements were prospectively included. Serum samples were pooled according to the presence/absence of CSPH and analysed by liquid chromatography-mass spectrometry. Gene set enrichment analysis was performed, followed by comprehensive literature review for proteins identified with the most striking difference between the groups. RESULTS: We included 48 patients (30 with, and 18 without CSPH). Protein CD44, involved in the inflammatory response, vascular endothelial growth factor C (VEGF-C) and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), both involved in lymphangiogenesis were found solely in the CSPH group. Although identified in both groups, proteins involved in neutrophil extracellular traps (NET) formation, as well as tenascin C, autotaxin and nephronectin which mediate vascular contractility and lymphangiogenesis were more abundant in CSPH. DISCUSSION AND CONCLUSION: We propose that altered inflammatory response, including NET formation, vascular contractility and formation of new lymph vessels are key steps in PH development. Proteins such as CD44, VEGF-C, LYVE-1, tenascin C, Plasminogen activator inhibitor 1, Nephronectin, Bactericidal permeability-increasing protein, Autotaxin, Myeloperoxidase and a disintegrin and metalloproteinase with thrombospondin motifs-like protein 4 might be considered for further validation as potential therapeutic targets and candidate biomarkers of CSPH in cACLD.

Humans↗