OBJECTIVES:Sepsis-induced coagulopathy (SIC) is a critical complication of sepsis that profoundly affects the severity of organ dysfunction and clinical prognosis. The current study aimed to construct and compare multiple individualized machine learning (ML) prediction models for predicting severe acute kidney injury (AKI) in patients with SIC, with the goal of identifying the most robust model to improve the accuracy of clinical decision-making. METHODS:The retrospective analysis was conducted based on the MIMIC‑IV database and a Chinese cohort. Eligible patients with sepsis and SIC were included. Both LASSO regression and the Boruta algorithm were used to select predictive variables. Eight ML models were constructed to predict the individual probability for severe AKI development. The receiver operating characteristic (ROC) curve, area under the precision-recall curve (PR-AUC) value, calibration indicators, and net benefit were used to assess the predictive model performance. Subgroup analyses were performed to evaluate the stability of model performance. Model predictions and feature importance were estimated using SHapley additive explanations (SHAP). RESULTS:Among the 14,155 patients with sepsis, 5,207 developed SIC and were randomly divided into training and internal validation cohorts. The severe AKI incidence rate was 24.7% (1288/5207). The Chinese external validation cohort enrolled 525 patients with SIC, with a severe AKI incidence rate of 28.1% (148/525). Six key predictive variables were identified to construct the ML models. The XGBoost prediction model demonstrated the most robust performance and best discrimination, achieving an area under the ROC curve of 0.875 (0.862-0.888) in the training cohort, 0.831 (0.807-0.854) in the internal cohort, and 0.843 (0.806-0.879) in the external validation cohort. Serum creatinine on the day of SIC diagnosis was identified as the most influential feature in the SHAP analysis. Subgroup analyses demonstrated that the model maintained predictive efficacy when stratified by age, sex, chronic kidney disease, and liver disease. CONCLUSIONS:The XGBoost machine learning model performed well in predicting the risk of severe AKI in patients with SIC, exhibiting satisfactory generalizability and interpretability. This prediction model provides a valuable and evidence-based tool for early identification and facilitates personalized targeted management in critical care settings.

Severe acute pancreatitis (SAP) is a life-threatening acute inflammatory disorder characterized by systemic inflammation and high mortality, for which specific targeted therapeutic strategies are still severely lacking in clinical practice. Mitochondrial dysfunction and impaired mitophagy have been validated as critical pathological drivers of SAP; nevertheless, the precise molecular targets governing the dysregulation of mitochondrial quality control remain poorly defined. Herein, we identify p38α (MAPK14) as a central regulator of mitophagy during SAP progression. Combining bioinformatic screening with an experimental SAP model, we demonstrate aberrantly hyperactivated p38α in pancreatic acinar cells. Mechanistically, activated p38α phosphorylates the S131 site of the E3 ubiquitin ligase Parkin. This site-specific phosphorylation triggers a “ubiquitination switch”, which selectively accelerates K48-linked polyubiquitination-dependent degradation of Parkin while impairing its K63-linked autoubiquitination and functional activity. Consequently, blockade of Parkin-dependent mitophagy results in accumulation of damaged mitochondria and massive leakage of mitochondrial DNA (mtDNA) into the cytoplasm, which further activates the cGAS-STING signaling cascade and exacerbates the sterile inflammatory storm. Pharmacological inhibition of p38α or genetic overexpression of the phosphorylation-deficient Parkin mutant (S131A) effectively restores mitophagic flux, eliminates cytoplasmic mtDNA accumulation, and suppresses cGAS-STING-mediated pro-inflammatory cytokine release, thereby markedly alleviating pathological injury in SAP. Our study illuminates a novel role of the p38α/Parkin/mtDNA/cGAS-STING signaling axis in the pathogenesis of SAP, and highlights targeting the p38α-mediated Parkin S131 phosphorylation switch as a promising therapeutic strategy for clinical intervention against SAP.

PURPOSE:In this study, various informatics analyses were employed to identify the hub genes associated with septic cardiomyopathy (SCM) onset and investigate their immune infiltration status. METHODS:High-throughput sequencing data of myocardial tissue samples from mice with SCM were obtained from the GEO database and our previously published articles. The Limma and weighted gene co-expression network analysis (WGCNA) packages were used to identify the hub genes associated with SCM onset. GSEA and the DAVID database were employed for gene enrichment analysis. Additionally, the CIBERSORT database was used to analyze the immune infiltration in SCM. Finally, the multiMiR package was used to analyze the microRNAs acting as ceRNAs for the hub genes. Receiver operating characteristic (ROC) curves and Mendelian randomization analysis were used to evaluate the predictive value of hub genes for SCM. RESULTS:The SCM group included nine samples, while the control group included ten samples. SCM upregulated 15 genes and downregulated 7. Mt1 and Actc1 were the most significantly upregulated and downregulated, respectively. GO analysis indicated that the most significantly enriched biological process was "response to bacterium," and the most enriched signaling pathway was "mineral absorption." Immunoinfiltration analysis revealed decreased T cells CD4 naive, B cells naive, resting mast cells, and M2 macrophage infiltration in the hearts of SCM mice. WGCNA and Limma package analyses identified Clu, Igf1, and Trp53 as hub genes associated with SCM onset. The ROC curves demonstrated a strong correlation and predictive value for Trp53, Igf1, and Clu in the SCM. Moreover, Clu and Igf1 demonstrated predictive values for SCM using Mendelian randomization analysis from the IEU database. Eleven miRNAs formed a ceRNA network with these hub genes. CONCLUSION:In summary, our results implicated Igf1 and Clu as the potential candidates involved in SCM pathogenesis.

Infected pancreatic necrosis (IPN) is a life-threatening complication of acute pancreatitis (AP), and its early prediction remains challenging. This study aimed to develop and externally validate interpretable machine learning models for individualized IPN risk prediction. A total of 728 patients with AP admitted to Xuanwu Hospital, Capital Medical University, between 2017 and 2023 were retrospectively analyzed. Embedded feature selection was incorporated within model training using regularized linear and tree-based algorithms to enhance interpretability and prevent overfitting. Five machine learning algorithms and one neural network model were evaluated through nested cross-validation and an independent temporal external cohort consisting of 166 AP patients admitted to Xuanwu Hospital, Capital Medical University, between 2022 and 2023. Model discrimination, precision-recall, and probability calibration were assessed, and model explainability was analyzed using Shapley Additive Explanations (SHAP). The Random Forest model achieved the best overall performance, achieving an external AUC of 0.764 (95% CI 0.696-0.830, [Formula: see text]), precision of 0.893, recall of 0.604, and the lowest Brier score, indicating reliable probability calibration. SHAP analysis identified Fibrinogen, APACHE II score, D-dimer, IL-6, and C-reactive protein as key predictors associated with increased IPN risk, while higher Lymphocyte count, and Hematocrit were protective. These findings are consistent clinical pathophysiology. The interpretable Random Forest model demonstrated robust discrimination and calibration for IPN prediction, providing a transparent and data-driven framework for early risk stratification in acute pancreatitis. Prospective multicenter validation is warranted before clinical implementation.

Acute pancreatitis (AP) lacks effective therapies, and excessive programmed cell death (PCD) drives its pathogenesis. This study identified cathepsin B (CTSB) as a core PCD regulator in AP via bioinformatics and animal experiments. Gene Expression Omnibus (GEO) datasets were analyzed with differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning algorithms, screening CTSB as a hub gene with high diagnostic value and enrichment in PCD/inflammatory pathways. Cerulein-induced AP mice showed activated multiple PCD pathways and elevated cytoplasmic CTSB. CTSB inhibition by CA-074 Me alleviated pancreatic inflammation and injury, reduced inflammatory cytokines, and mitigated apoptosis, restored autophagic flux, and suppressed necroptosis, ferroptosis, pyroptosis in AP tissues. CTSB is a central regulator of PCD in AP, serving as a promising therapeutic target for AP by modulating diverse PCD modalities.

Locally advanced pancreatic cancer (LAPC) is associated with a poor prognosis and limited therapeutic options. This study aimed to evaluate the efficacy and safety of nab-paclitaxel plus S-1 (SnP) as a first-line treatment in patients with previously untreated LAPC. In this multicenter, single-arm phase 2 trial conducted across four centers in China, eligible patients received up to eight cycles of nab-paclitaxel combined with S-1, followed by investigator-selected continuation strategies in the absence of disease progression or intolerable toxicity. The primary endpoint was the 6-month progression-free survival (PFS). Between April 2019 and March 2023, 60 patients were enrolled, of whom 48.3% completed induction therapy and 18.3% subsequently underwent surgical resection, with 10 achieving R0/R1 status. The 6-month PFS rate was 71.0% (95% CI: 57.6%-80.9%), while the median PFS and overall survival (OS) were 11.1 months and 20.2 months, respectively. The 12-month OS rate reached 83.3%. The objective response rate was 26.7%, and the disease control rate was 90.0%. Grade ≥3 treatment-related adverse events occurred in 53.3% of patients, most commonly neutropenia and leukopenia, with no treatment-related deaths observed. These findings suggest that SnP demonstrates promising antitumor activity with manageable toxicity in LAPC and may facilitate conversion to surgical resectability in a subset of patients. This clinical study was registered at ClinicalTrials.gov (NCT03885219).

This study aimed to explore the associations between various lipid parameters and the risk of gallstone disease (GSD). A multicenter cross-sectional study was conducted to explore the associations between nine lipid parameters and the risk of GSD. Multivariable logistic regression models, adjusted for covariates, were employed to evaluate these associations. Stratified analyses by age and sex were performed to assess population-specific effects. Data from multiple centers were integrated using meta-analysis to generate pooled odds ratios with 95% confidence intervals. Trial Sequential Analysis (TSA) was implemented to determine the sufficiency of the sample size and the robustness of the associations under cumulative evidence conditions. This multicenter study included 580,935 participants, with a GSD prevalence of 7.43%. After adjusting for covariables, the combined multi-center results showed that total cholesterol, high-density and low-density lipoprotein cholesterol, and non-HDL cholesterol were negatively associated with GSD risk. In contrast, the Castelli risk index I and II, atherogenic coefficient, and atherogenic index of plasma were positively associated with the risk of GSD. Subgroup analyses and sensitivity analyses yielded consistent results. Stratified analysis revealed distinct lipid-gallstone associations between people with cholecystectomy and gallbladder stones. TSA revealed that the required amount of information has been achieved, and the results are conclusive. This study suggests significant associations between lipid metabolism and the risk of GSD. There are differences in the relationship between blood lipid indexes and cholecystectomy and gallstones. These findings not only enhance our understanding of the relationship between lipid metabolism and GSD but also provide a novel perspective for risk assessment and prevention strategies.

Journal Article Corrected proof Cardiac neuroendocrine tumour with cystic changes: comprehensive imaging and surgical approach Get access Xia Gu , Xia Gu Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, 246 Xuefu Road, Harbin, Heilongjiang 150086, China https://orcid.org/0000-0001-8030-3631 Search for other works by this author on: Oxford Academic PubMed Google Scholar Zhenhua Li , Zhenhua Li Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, 246 Xuefu Road, Harbin, Heilongjiang 150086, China Search for other works by this author on: Oxford Academic PubMed Google Scholar Ruiqi Wang , Ruiqi Wang Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, 246 Xuefu Road, Harbin, Heilongjiang 150086, China Search for other works by this author on: Oxford Academic PubMed Google Scholar Fei Li , Fei Li Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, 2 Anzhen Road, Chaoyang District, Beijing 100029, China Corresponding authors. E-mail: [email protected] (B.Y.); E-mail: [email protected] (F.L.) Search for other works by this author on: Oxford Academic PubMed Google Scholar Bo Yu Bo Yu Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, 246 Xuefu Road, Harbin, Heilongjiang 150086, China Corresponding authors. E-mail: [email protected] (B.Y.); E-mail: [email protected] (F.L.) https://orcid.org/0000-0002-5955-6332 Search for other works by this author on: Oxford Academic PubMed Google Scholar European Heart Journal - Cardiovascular Imaging, jeaf222, https://doi.org/10.1093/ehjci/jeaf222 Published: 07 August 2025 Article history Published: 07 August 2025 Corrected and typeset: 13 August 2025

Severe acute pancreatitis (SAP) involves dynamic interactions between immune dysregulation and inflammatory infiltration. Although elevated levels of neutrophil extracellular traps (NETs) are associated with SAP, the downstream mechanisms by which NETs exacerbate the inflammatory injury remain unclear. In this study, we demonstrate that NETs levels positively correlate with SAP severity, and pharmacological inhibition of NETs reduces pancreatic injury, and acinar cell death. Mechanistically, NETs activate the ZBP1-cGAS complex via mitochondrial DNA (mtDNA), triggering downstream necroptosis and inflammatory pathways, thereby driving pancreatic inflammatory injury. Specifically, NETs induce mitochondrial damage in acinar cells, leading to cytosolic accumulation of mtDNA. This recruits ZBP1 to form a complex with cGAS dependent on the RHIM domain, wherein ZBP1 stabilizes Z-form mtDNA and potentiates cGAS recognition of Z-mtDNA, thereby cooperatively promoting necroptosis and inflammation. Furthermore, cyclosporine A inhibits mtDNA release, thereby suppressing NETs-induced ZBP1-cGAS complex formation and mitigating pancreatic injury. Our findings establish the mtDNA- ZBP1-cGAS axis as a pivotal mechanism by which NETs exacerbate pancreatic inflammation, revealing new therapeutic targets for SAP.

Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide, with a dismal 5-year survival rate. New drugs targeting pancreatic ductal adenocarcinoma (PDAC), the primary pathological subtype, are urgently needed. LAQ824, a novel pan-histone deacetylase inhibitor (HDACi), has shown anti-tumor activity in various cancers, but its effects on PDAC remain unexplored. This study investigates the therapeutic potential of LAQ824 in PDAC and its role in modulating immune escape mechanisms. Using a subcutaneous tumor model in C57BL/6 J mice, LAQ824's anti-tumor effects were evaluated. In vitro and in vivo experiments-including IHC, flow cytometry, RNA sequencing, and single-cell RNA sequencing-demonstrated that LAQ824 inhibits tumor proliferation, suppresses the epithelial-mesenchymal transition (EMT), and induces apoptosis. LAQ824 also enhances immunogenicity by upregulating MHC-I-mediated antigen presentation, increasing immune cell infiltration, and promoting CD8+ T cell maturation and differentiation. Mechanistically, LAQ824 upregulated MHC-I expression by enhancing chromatin accessibility of related genes, with HDAC1 identified as a key repressor of MHC-I in PDAC cells. In conclusion, we found that LAQ824 has a significant anti-tumor effect in PDAC. LAQ824 not only directly affects general biological behaviors such as proliferation, apoptosis, and EMT, but also increases the immunogenicity of tumor cells by upregulating the expression of MHC-I in PDAC, which promotes the antigen presentation process and enhances anti-tumor immunity. By showcasing LAQ824's potential as a therapeutic target against PDAC, the present study provides novel insights into the link between epigenetic regulation and immunogenicity in PDAC.

Purpose:Immune checkpoint inhibitors (ICIs) have significantly changed cancer therapy, improving patient survival rates and clinical outcomes. Nevertheless, the use of PD-1/PD-L1 inhibitors can result in immune-related adverse events (irAEs). This study aims to investigate the prevalence and associated risk factors of irAEs in a real-world setting, as well as to assess their effects on optimal therapeutic outcomes. Methods:A retrospective analysis involved 2523 patients with cancer who received inpatient PD-1/PD-L1 inhibitors treatment between January 2018 and December 2022. We documented patients' demographic and clinical characteristics, PD-1 or PD-L1 inhibitors, treatment modalities, incidences, timing, and severity of irAEs, and efficacy outcomes by reviewing inpatient records. Patients were categorized into an irAEs group and a non-irAEs group, with the former further subdivided into a multiple irAEs group and a single irAE group. Chi-square tests were employed to evaluate differences in baseline characteristics and efficacy outcomes between the irAEs and non-irAEs groups, as well as between the multiple and single irAE groups. Additionally, logistic regression analysis was utilized to identify risk factors linked to irAEs. Results:Among 2523 eligible patients, 1096 reported 1802 irAEs, with an incidence incidence of 43.4%. Among 1096 individuals, 92.1% were classified as grade 1-2, while 7.9% were grade 3 or higher. IrAEs affected various organ systems, with endocrine toxicity (17.7%), hepatic toxicity (17.2%), and hematologic toxicity (11.4%) being the most common. 20.5% patients experienced multi-system irAEs. The average time for patients to develop irAEs was within four treatment cycles. Significant differences in patient gender, age, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), comorbidities, PD-1 or PD-L1 inhibitors, and treatment modalities were observed between the irAEs and non-irAEs groups, but not between the multiple irAEs and single irAE groups. Compared to the non-irAEs group, the irAEs group exhibited a higher objective response rate (ORR) and disease control rate (DCR), and the multiple irAEs group also showed a higher ORR than the single irAE group. Conclusion:This real-world study indicated that the occurrence of irAEs is related to patient gender, age, ECOG PS, comorbidities, PD-1/PD-L1 inhibitors, and treatment modalities. The occurrence of irAEs may be associated with better treatment benefits.

Polycystic ovary syndrome (PCOS) is a multifactorial reproductive endocrine metabolism disorder, which is closely related to granulosa cell dysfunction, high androgen, insulin resistance, oxidative stress and cellular autophagy. Phosphatidylinositol 3-kinase/protein kinase B (phosphatidylinositol3-kinase/proteinkinaseB, PI3K/AKT) is the main pathway of intracellular signaling. In recent years, studies have confirmed that PI3K/AKT pathway participates in the repair of ovarian tissue damage and the regulation of glucose and lipid metabolism by regulating granulosa cell function, insulin resistance state, oxidative stress and autophagy. TCM has obvious advantages in the treatment of PCOS. One of the mechanisms of PCOS is the regulation of PI3K/AKT signaling pathway, but there are few systematic reviews and reviews of this field at home and abroad. Based on this, this paper summarizes the regulation mechanism of PI3K/AKT signaling pathway in PCOS in recent years and the role of TCM monomer and compound intervention in diseases, in order to provide theoretical basis for the basic and clinical research of PCOS.

The positive feedback of acinar cell death, immune infiltration and inflammation aggravated the severity of the severe acute pancreatitis (SAP). Neutrophil extracellular traps (NETs) were demonstrated to trigger trypsin activation and organ damage. Exploration of the underlying mechanism of the damage effect of NETs on pancreas and potential to block the process was needed. The aim of this study was to explore the genes involved in the effect of NETs on pancreas in SAP and potential mechanism of inhibition of matrix metallopeptidase 9 (MMP9) in alleviating pancreatitis. RNA sequencing analysis was performed using human blood and mouse pancreatic tissues, and the mice AP models were established. The result showed that differentially expressed genes between clinical SAP and healthy patients enriched significantly in NETs formation. MMP9 was considered the hub gene in NETs and its expression increased accompanied with the aggravated organ damage and extensive NETs formation. The administration of MMP9-IN-1 alleviated pancreatic damage and necroptosis after the presence of NETs in vivo. KEGG enrichment analyses of acinar cells showed that autophagy was a vital process in pancreatic inflammatory injury, and the inhibition of MMP9 alleviated impaired autophagy. The effect of NETs on pancreatic necroptosis was further demonstrated to be associated with the regulation of impaired autophagy by MMP9. MMP9-IN-1 regulated SIRT2/NRF2 signaling pathway and alleviated pancreatic impaired autophagy and necroptosis. In conclusion, NETs formation is a key and predictive biological behavior of clinical SAP patients. MMP9 might be involved in NETs-mediated pancreatic damage and necroptosis by regulation of impaired autophagy during SAP.

N(6)-methyladenosine (m6A) modification is the most abundant and prevalent internal modification in eukaryotic mRNAs. The role of m6A modification in cancer has become a hot research topic in recent years and has been widely explored. m6A modifications have been shown to regulate cancer occurrence and progression by modulating different target molecules. This paper reviews the recent research progress of m6A modifications in cancer and provides an outlook on future research directions, especially the development of molecularly targeted drugs.

Radiotherapy displays unique antitumor synergism with immune checkpoint inhibitors, which is indicated by high pathological complete response (pCR) rates from single-arm trials of locally advanced rectal cancer (LARC). Here we test the efficacy and safety of the radiation–immune checkpoint inhibitor combination in patients with LARC in a phase 2, randomized trial conducted in eight major colorectal cancer centers in Beijing. In total, 186 eligible all-comer (proficient mismatch repair and deficient mismatch repair) participants were enrolled. The patients were randomly assigned to receive neoadjuvant chemoradiation + concurrent/sequential PD-1 blockade (experiment groups A/B) or neoadjuvant chemoradiation alone (control group). Radical surgeries were scheduled after neoadjuvant treatments. The primary endpoint was the pCR rate. The pCR rates were 27.1 NCT05245474 ). In a multicenter, open-label, randomized phase 2 trial, neoadjuvant chemoradiation with PD-1 blockade elicited a pathological complete response rate superior to that with neoadjuvant chemoradiation alone in patients with locally advanced rectal cancer.

Early acute pancreatitis is an acute inflammatory disease that involves multiple modes of cell death, including apoptosis, necrotic apoptosis, and pyroptosis in its disease process. PANoptosis, a type of cell death that includes pyroptosis, apoptosis, and necroptosis, has had an important role in a variety of infectious and inflammatory diseases in recent years. To judge the relationship between PANoptosis and AP, we first analyzed the data from pancreatic transcriptome data by bioinformatics techniques, and we found the enrichment of PANoptosis pathway in AP. Next, we screened the genes and identified differentially expressed genes (DEGs) associated with AP and PANoptosis. Finally, we found that Zbp1 may have a major role in the process of PANoptosis. For this purpose, we constructed AP models in mice and in vitro cell line 266-6 and intervened by inhibiting Zbp1. The final results showed that the PANoptosis in mice was significantly suppressed after inhibition of Zbp1. In conclusion, inflammatory injury in AP can be significantly improved by inhibiting Zbp1- PANoptosome-mediated PANoptosis.

N(6)-methyladenosine (m6A) modification is the most abundant and prevalent internal modification in eukaryotic mRNAs. The role of m6A modification in cancer has become a hot research topic in recent years and has been widely explored. m6A modifications have been shown to regulate cancer occurrence and progression by modulating different target molecules. This paper reviews the recent research progress of m6A modifications in cancer and provides an outlook on future research directions, especially the development of molecularly targeted drugs. See also the graphical abstract(Fig. 1).

Forced vital capacity (FVC) has been utilized as a surrogate for vital capacity (VC) in monitoring the progression of restrictive pulmonary disorders, particularly in clinical trials of idiopathic pulmonary fibrosis (IPF). A dose-response relationship between decreased FVC and mortality in IPF has also been established. Since 2005, total lung capacity (TLC) has been routinely required to differentiate and diagnose restrictive pulmonary disorders. However, the relationship between changes in TLC change and the risk of mortality remains unclear. To investigate and quantify the relationship between changes in TLC and the risk of mortality in patients with restrictive pulmonary disorders. This study employed a systematic review and meta-analysis following the PRISMA 2020 guidelines. A total of 26 studies were included in the meta-analysis, comprising a combined sample of 16,579 subjects, which included 7,961 females, 4,460 subjects in the relative low TLC group, and 12,119 subjects in the high TLC group. A reduced TLC was associated with an increased risk of all-cause mortality, as indicated by both unadjusted and adjusted hazard ratios. The unadjusted hazard ratio (95