Yang Ge

Breast cancer remains a major global health burden, underscoring the urgent need for reliable early detection strategies. Exosomes, as mediators of intercellular communication, have shown promise in early tumor screening through Raman spectroscopy and gene expression profiling in pancreatic and colorectal cancers. However, the application of exosomal gene expression profiles for breast cancer prediction remains largely unexplored. Exosomal mRNA profiles were obtained from exoRBase 3.0 (242 breast cancer, 244 healthy controls). Sample sex was inferred using XIST and UTY expression, yielding 337 female samples for analysis. A nested cross-validation framework (20 repetitions, fivefold) was implemented, with differential expression analysis and feature selection performed exclusively within each training fold to prevent information leakage. Ten machine learning classifiers were evaluated on an independent held-out test set. Model performance was assessed using accuracy, precision, recall, and F1-score. Feature selection demonstrated high stability (average Jaccard score 0.5912), with 9 genes consistently selected across all 100 iterations and a set of robust feature genes was identified. Among classifiers, xgbTree achieved the best performance (AUC 0.992, accuracy 0.970, F1 0.979) on the independent test set, supporting exosomal mRNA profiles as a promising non-invasive approach for the early breast cancer detection.

We aimed to examine the panoramic cellular composition and spatial structure of clinical samples from nonalcoholic fatty liver disease-associated hepatocel

Studies regarding the prevalence of early childhood development (ECD) delays and comprehensive evidence of family ecological influences in urban regions of

Background Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to limited treatment options and frequent resistance to targeted therapies. MET amplification is a promising therapeutic target in a subset of HCC. However, mechanisms of resistance to MET inhibitors are not fully understood, impeding the efficacy of treatments. Methods We performed a genome-wide CRISPR-Cas9 screen to identify genetic determinants of resistance to MET inhibitors. The efficacy of selective MET inhibitors, including capmatinib and tepotinib, was evaluated in MET-amplified HCC models. Mechanistic studies were conducted to characterize AKT signaling dynamics and tumour cell responses under various treatment conditions. Results MET inhibitors selectively suppressed tumour growth in MET-amplified HCC. However, PTEN deficiency sustained AKT activation despite MET blockade, facilitating tumour survival. Moreover, MET inhibitor treatment triggered adaptive upregulation of ERBB2/ERBB3, leading to AKT reactivation and resistance. Combined inhibition of MET and AKT or ERBB kinases synergistically restored therapeutic response and induced apoptosis. These resistance mechanisms also reduced the efficacy of cabozantinib. Notably, neither combination was effective in MET-high non-amplified HCC. Conclusion Our study identifies PTEN deficiency and ERBB2/ERBB3-mediated reactivation as key resistance mechanisms to MET inhibition in MET-amplified HCC. The findings support biomarker-informed combination strategies and underscore the importance of stratifying patients based on MET amplification status.

The progression of hepatocellular carcinoma (HCC) is partly driven by reactive oxygen species (ROS)-induced tissue damage and inflammation. Nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are key regulators of ROS production, yet the specific role of NOX1 in HCC progression and therapeutic response remain incompletely understood. In this study we investigated the critical role of NOX1 in progression, metastasis and therapeutic sensitivity of HCC, and explored its potential as a therapeutic target. By comprehensive analysis of public databases and validation with in-house clinical specimens, we showed that NOX1 expression was significantly elevated in metastatic HCC that was correlated to poor patient prognosis. Knockdown of NOX1 or pharmacological inhibition with a selective NOX1 inhibitor ML171 significantly reduced ROS production and suppressed HCC cell motility and invasion in vitro. NOX1 inhibition also attenuated HCC metastasis in experimental metastasis mouse model using direct injection of HCC cells, and mitigated CCl₄-induced liver injury and pro-tumorigenic microenvironment in CCl₄-induced chronic liver injury and spontaneous tumor development mouse model. Importantly, we demonstrated that combined sorafenib or radiotherapy with NOX1 inhibition synergistically reduced the metastatic potential of HCC cells and enhanced the therapeutic efficacy. Bioinformatics analysis revealed that NOX1 contributed to HCC metastasis and therapy resistance by modulating ROS homeostasis, cellular antioxidant systems and inflammatory pathways. Taken together, this study elucidates the critical role of NOX1 in HCC pathogenesis, suggesting that NOX1 inhibition represents a promising strategy to overcome resistance and enhance HCC sensitivity to sorafenib and radiotherapy.

Ferroptosis is a programmed cell death mode associated with iron metabolism, with accumulation of intracellular lipid peroxides, which is closely related to the occurrence and development of multiple diseases, including type 2 diabetes mellitus (T2DM) and hepatocellular carcinoma (HCC). T2DM is a chronic metabolic disorder characterized by a combination of impaired insulin sensitivity and insufficient insulin production, frequently accompanied by obesity and fatty liver, which increases the risk of developing HCC. To explore the complex interactions between ferritin deposition, T2DM, and HCC, we performed bioinformatics analysis on publicly available gene expression data and identified 23 differentially expressed genes (DEGs) that are commonly expressed in both T2DM and HCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that these DEGs are primarily enriched in fatty acid metabolism and ferroptosis pathways. The weighted gene co-expression network analysis (WGCNA) identified 6 key genes associated with the pathogenesis of both diseases. Taking the intersection of DEGs and iron deposition-related genes, we identified ACSL4 as a key ferroptosis gene involved in the co-morbidity of T2DM and HCC. To validate the bioinformatics findings, we assessed the expression of ACSL4 using Receiver operating characteristic (ROC) curve analysis, which revealed an Area Under the Curve (AUC) of 0.886 for HCC and 0.745 for T2DM. Additionally, an insulin resistance model was established in HepG2 cells by treatment with 350 µM palmitic acid (PA), resulting in significant changes in cell morphology. Oil Red O staining showed a marked increase in lipid accumulation. RT-PCR analysis further confirmed the significant alteration in ACSL4 gene expression. In conclusion, this study is the first to integrate bioinformatics tools to investigate the potential mechanistic links between iron metabolism and the comorbidity of T2DM and HCC, uncovering a novel pathogenic pathway. These findings provide new directions for drug development and therapeutic strategies in the future.

Benzo[a]pyrene (B[a]P) is a widespread and persistent organic pollutant that poses serious threats to human health. Although its carcinogenic properties have been extensively studied, its developmental toxicity and underlying mechanisms remain poorly understood. In this study, we employed Caenorhabditis elegans (C. elegans) as a model organism to investigate the effects of B[a]P exposure during early developmental stages. To comprehensively assess B[a]P-induced developmental toxicity, we employed high-throughput sequencing along with transgenic and mutant C. elegans strains. Exposure to B[a]P at concentrations exceeding 1 mg/L significantly reduced larval body size, decreased the number of adult worms, and delayed larval-to-adult development. Furthermore, we analyzed the expression of genes involved in cuticle collagen synthesis and key components of the insulin/insulin-like growth factor signaling (IIS) pathway, including daf-2 and daf-16. These findings suggest that B[a]P-induced developmental toxicity may be associated with dysregulation of the IIS pathway. Specifically, B[a]P appears to influence the activity of the downstream transcription factor daf-16, thereby altering the expression of collagen-related genes. This disruption in collagen synthesis may contribute to delayed larval development and impaired maturation. Our study provides new insights into the environmental hazards associated with B[a]P exposure and reveals a potential mechanism underlying its developmental toxicity. Moreover, our findings highlight the critical role of collagen gene regulation during early developmental stages. These genes may serve as potential biomarkers for environmental toxicant exposure, particularly in vulnerable populations such as children undergoing critical periods of development.

Gender differences in the health workforce matter for women's health and healthcare, and is also crucial for both health and economic development. Drawing on limited national gender data from China over the last 10 years, during which the country was undergoing a healthcare reform, this study dissects gender-related issues to identify existing problems, monitor progress, and develop strategies to promote change. Although women constituted the majority of health workers, they are predominantly engaged in service-oriented occupations. The gender distribution substantially differed between urban and rural primary health institutions. Moreover, significant differences in gender distribution among professional public health institutions were observed. The gender distribution of administrators varied in different types of health institutions. Women had lighter workloads because of the imbalanced distribution of specialties. Academicians comprised very few female scientists. To promote a more balanced gender distribution, policies should be developed to encourage a more reasonable division of family responsibilities. Further, equal higher education opportunities should be ensured for girls, especially in rural areas. Solutions to free more women from work–marriage–childcare conflicts and to decrease turnover rates deserve further discussion. Gender data should be highlighted and optimized to further advance gender differences among the health workforce and for women's health in China.

Objective Nonalcoholic fatty liver disease (NAFLD) is increasingly implicated in hepatocellular carcinoma (HCC) pathogenesis. We aimed to examine panoramic cellular composition and spatial structure of NAFLD-HCC clinical samples, assess the role of tumor micro-environment (TME) in the process of liver fibrosis and oncogenesis, and find potential clinical intervention measures. Methods Imaging mass cytometry (IMC) technology was used to reveal the expression and spatial distribution of biomarkers in samples from 56 patients with NAFLD-HCC and 6 patients with focal nodular hyperplasia as control. 37 different metal coupling biomarkers were designed to label the tumor, border and adjacent regions of the tissues to generate 367 highly multiplexed histology images at single-cell resolution. By integrating the expression levels of biomarkers with the relative positional relationships between cells, we defined functional units as tightly interacting cellular neighborhoods (CNs). The relationship between CNs and patients’ prognosis was then accessed to identify potential clinical targets of NAFLD-HCC. Results Cells were dimensionally reduced to access the cellular phenotype and 18 clusters of cells and 9 CNs were defined. Heterogeneity in TME and CN composition was observed not only across various regions within the same individual but also among comparable regions in different patients. The combined analysis of the overall survival data revealed that patients with a high enrichment of T & NK cell associated CN exhibited a more favorable clinical prognosis. In contrast, those with a high enrichment of myofibroblast associated CN and a YAP+ cancer cell associated CN exhibited a poor clinical prognosis. Conclusion Our study provided a landscape of NAFLD-HCC and its TME characteristics from the topological perspective. The findings indicated that changing the low immune cell infiltration status of NAFLD-HCC through the augmentation of active T and NK cells and hepatic antifibrotic therapy may benefit the long-term prognosis of patients with NAFLD-HCC. Key words: imaging mass cytometry, NAFLD-HCC, cellular neighborhoods, prognosis, tumor micro-environment