Chinese Medical Journal最新文献

Background: The cardiovascular-kidney-metabolic (CKM) syndrome is highly prevalent globally. However, the associations between the CKM syndrome and its various components and all-cause and cause-specific mortality are not well understood. This study aims to clarify these mortality associations and inform preventive strategies.

Methods: The China Health Evaluation and Risk Reduction through Nationwide Teamwork was a nationwide and population-based project, which was performed in 353 counties/districts across 31 provincial-level administrative divisions in Chinese mainland. A total of 764,856 eligible residents aged ≥35 years from this cohort were included in the study. CKM was classified into stages 0-4 and further sub-grouped stages 2-4 by the presence of chronic kidney disease (CKD) and CKD risk stratification. CKM stage 2 was further divided into six groups in descending order of clinical risk priority. The main outcomes were all-cause and cause-specific mortality. Cox proportional hazards models were performed to evaluate the associations of CKM stages and components with mortality, incorporating competing risks models to account for competing events.

Results: We found significant positive associations between CKM stages and mortality risk, particularly for cardiovascular mortality with adjusted hazard ratios and 95% confidence intervals of 2.62 (2.10-3.27), 4.04 (3.22-5.07), and 5.64 (4.51-7.05) for stages 2, 3, and 4, respectively. In comparison of participants with CKD with those without CKD at each CKM stage, CKD was associated with an increased risk of all-cause mortality by 64.29%, 68.62%, and 74.89%, and an increased risk of cardiovascular mortality by 72.58%, 71.55%, and 71.95% for CKM stages 2, 3, and 4, respectively. Notably, even moderate-risk CKD was associated with an increased risk of mortality. Among the various components at CKM stage 2, CKD (both high- and moderate-risk) was the most significant risk factor for mortality, with high-risk CKD showing a higher risk (hazard ratio [95% confidence interval]: 2.83 [2.36-3.39]) than moderate-risk CKD (hazard ratio [95% confidence interval]: 2.16 [1.89-2.47]), followed by the coexistence of diabetes and hypertension (hazard ratio [95% confidence interval]: 1.87 [1.65-2.12]) (all P <0.05).

Conclusions: The risk of mortality, primarily by cardiovascular disease, increases with advancing stages of CKM. Sub-staging CKM syndrome by stratifying patients according to the presence and severity of CKD and metabolic risk factors can improve the accuracy of evaluating the mortality risk. Consistent monitoring and early interventions aimed at maintaining renal function may considerably reduce the risk of mortality.

Background: Glioma is a common malignant brain tumor with poor prognosis. Choline kinase α (CHKA) has been implicated in glioma progression, but its regulatory mechanisms remain unclear.

Methods: Single-cell ribonucleic acid (RNA) sequencing was performed to assess the coexpression of CHKA and epidermal growth factor receptor (EGFR) in glioma subpopulations. Public datasets were analyzed to evaluate their clinical relevance, which was verified in a cohort from Ningxia Medical Hospital (November 2019-October 2024). Immunohistochemical staining confirmed their expression and subcellular localization. The interaction between CHKA and EGFR was examined using mass spectrometry, coimmunoprecipitation, polymerase chain reaction, and Western blotting. The effects of the CHKA/EGFR axis on the mitogen-activated protein kinase (MAPK) pathway were explored using polymerase chain reaction and Western blotting. Cell Counting Kit-8 (CCK-8), transwell, and wound-healing assays were conducted in glioma cell lines following CHKA knockdown and EGFR rescue. Finally, a nude mouse xenograft model was established to validate in vivo tumorigenicity and MAPK pathway activation.

Results: CHKA was highly coexpressed with EGFR in specific glioma subpopulations, and their expression levels were positively correlated. Both genes were associated with advanced tumor grade and poor prognosis. CHKA interacted with EGFR and promoted its expression and phosphorylation. Silencing CHKA reduced EGFR levels and suppressed MAPK signaling. Functionally, CHKA enhanced glioma cell proliferation, migration, and invasion through EGFR upregulation. Moreover, CHKA knockdown inhibited tumor growth and MAPK activation in vivo, while EGFR overexpression restored tumorigenesis.

Conclusions: CHKA drives glioma malignancy by regulating EGFR and activating the MAPK pathway. The CHKA/EGFR/MAPK axis represents a potential therapeutic target for glioma treatment.

Background: The development of gemcitabine resistance significantly diminishes treatment efficacy and worsens prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). A comprehensive understanding of the molecular and cellular mechanisms driving gemcitabine resistance is thus essential for optimizing treatment strategies and improving survival outcomes in PDAC.

Methods: An integrated analysis of bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics was performed to elucidate the molecular mechanisms of gemcitabine resistance. Tumor-associated epithelial and myeloid cell subsets were identified, and their interactions were characterized using clustering, pseudotime analysis, and cell-to-cell communication networks. Findings were validated through molecular and cellular experiments in PDAC cell lines, as well as multicolor immunofluorescence staining in clinical cohort samples.

Results: The findings revealed that PRRX2+ epithelial cells (EC) and SPP1+ tumor-associated macrophages (TAM) were enriched in gemcitabine-resistant samples, with robust cell-to-cell communication observed between these two populations. PRRX2+ EC cells and SPP1+ TAM cells interacted through the TGFB1/TGFBR2 axis, promoting epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) remodeling, thereby contributing to drug resistance. The transcription factor PRRX2 was identified as a central regulator of this resistance mechanism, amplifying TGF-β signaling through TGFB1 to induce EMT and activating Fibronectin 1 to remodel the ECM, thereby enhancing an immunosuppressive tumor microenvironment. Furthermore, experimental downregulation of PRRX2 in pancreatic cancer cell lines resulted in reduced tumor cell migration. High expression levels of PRRX2+EC/SPP1+TAM were associated with poor prognosis and may indicate susceptibility to Dasatinib and antibody-drug conjugates (ADCs) targeting TROP2, MUC1, and CEACAM5.

Conclusions: The results revealed the critical role of PRRX2+EC/SPP1+TAM cell communication in mediating gemcitabine resistance in PDAC. These findings provide new insights into potential therapeutic strategies, highlighting the importance of targeting the PRRX2+EC/SPP1+TAM axis and supporting the use of multidrug regimens to overcome resistance and improve patient outcomes in PDAC.

Background: Endometrial cancer (EC) is one of the most common gynecological cancers worldwide. High-order chromatin structure plays a critical role in regulating gene expression. Our previous study identified frequent mutations in the chromatin remodeling-related gene adenomatous polyposis coli (APC) in EC. Here, we investigated the role of APC in chromatin remodeling and EC progression.

Methods: The efforts of APC against EC cells in vitro and in vivo were characterized by gene expression and overall survival analysis with The Cancer Genome Atlas (TCGA) database, Western blotting, RNA isolation and quantitative real-time polymerase chain reaction (RT-PCR), the integrated multiomics analysis, lentivirus transfection, nude mice tumorigenesis experiment and immunohistochemistry.

Results: APC expression was reduced in EC tissues, and APC-knockdown KLE cells exhibited enhanced cell migration. Integrated multi-omics analyses, including RNA sequencing (RNA-seq), assay for transposase-accessible chromatin by high-throughput sequencing (ATAC-seq), and high-through chromosome conformation capture (Hi-C), compared control and APC-knockdown KLE cells. These analyses identified fibroblast growth factor 12 (FGF12) as a differentially expressed gene (DEG) localized to switched chromatin compartments, cell-specific boundaries, and loops, with elevated expression in APC-knockdown cells. High FGF12 expression correlated with poor prognosis in EC patients. Knockdown of FGF12 in APC-deficient KLE cells reversed the enhanced migratory phenotype.

Conclusions: Loss of APC promotes EC cell migration and reprograms chromatin architecture to upregulate FGF12, activating tumorigenesis-related protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) signaling pathways and driving EC progression. Elevated FGF12 levels are associated with poor prognosis, highlighting its potential as a therapeutic target for EC patients with low APC expression.