Gastrointestinal cancers (GICs), including gastric cancer (GC) and pancreatic cancer (PC), have high mortality rates and limited therapeutic options. The treatment of these two cancers still faces many challenges, especially due to their high genetic heterogeneity and genomic instability. Claudin 18.2 (CLDN18.2) is highly restricted in normal tissues but is frequently upregulated in gastrointestinal cancers, making it an attractive target for chimeric antigen receptor-T (CAR-T) cell therapy against GICs, with encouraging results in phase I trials. However, enhancing CAR-T cell efficacy requires overcoming several challenges, including T cells expansion, persistence, exhaustion, and the suppressive tumor microenvironment (TME). We developed a novel CAR-T construct combining a CLDN18.2-specific CAR with the human p40 subunit (CLDN18.2-p40 CAR) to improve antitumor efficacy. Our finding demonstrated that CLDN18.2-p40 CAR-T cells exhibited greater persistence, reduced differentiation, enhanced cytotoxicity, and improved long-term survival in vitro compared with conventional CAR-T cells. In vivo, treatment with CLDN18.2-p40 CAR-T cells led to enhanced tumor cell lysis, sustained cytotoxicity, and increased tumor infiltration, resulting in significant tumor regression in both xenograft and syngeneic mice models. RNA-sequencing revealed an enrichment of pro-inflammatory pathways related to leukocyte migration and chemotaxis in the tumor tissue, aligning with the observed increase in T cell infiltration. This study underscored the pivotal role of the p40 subunit in enhancing the phenotype, persistence, and migration of CAR-T cells, and ameliorating the TME, identifying CLDN18.2-p40 CAR-T as a potentially more effective therapy for improving the clinical outcomes of patients with GIC.
Traditional Chinese medicine has long been valued for its diverse bioactive properties, with chrysin emerging as a potential agent for preventing H1N1 infection. However, its specific targets and underlying mechanisms of chrysin remain to be elucidated.
In this study, we employed predictive algorithms from the SEA, Swiss, and PharmMapper databases to identify targets of chrysin, while H1N1 infection-related genes were sourced from the OMIM and GeneCards databases. We then constructed a protein–protein interaction network using Cytoscape 3.9.1, and then performed Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Finally, we performed molecular docking with AutoDock Vina algorithm to predict interaction sites.
We identified 30 target genes of chrysin, with VEGFA, SRC, PTGS2, EGFR, HIF1A, MMP9, APP, IL2, MMP2, and PLG ranking as the top candidates. Enrichment analysis revealed involvement of multiple signaling pathways (including ROS, relaxin, and EGFR pathways) associated with inflammation, infection, and cell apoptosis. Molecular docking studies further supported the strong affinity of chrysin for its target proteins.
We have identified diverse signalling pathways and targets by which chrysin prevents H1N1 infection. This work highlights several molecular targets for further investigation and supports the potential of chrysin as a basis for antiviral development.
Epigenetic signatures, particularly DNA methylation, have emerged as potential biomarkers in various cancers, including adult B-ALL. In particular, DNA methylation increases with age and significantly affects overall survival. As a result, it holds promise as a diagnostic tool for B-ALL, providing insights into disease progression and prognosis. By integrating epigenetic and transcriptomic analyses, we identified potential biomarkers associated with B-ALL. Notably, our findings suggest that the methylation status of brain abundant membrane attached signal protein 1 (BASP1) is linked to relapse in B-ALL and may serve as a valuable diagnostic marker.
Cervical cancer is one of the most prevalent malignant tumors of the female reproductive system. While its occurrence and progression is influenced by various factors, recent research has highlighted roles for histone deacetylase 6 (HDAC6) and the human papillomavirus E7 (HPV E7) protein in cervical cancer pathogenesis. HPV E7 promotes cancer cell survival and proliferation by regulating the cell cycle, inhibiting apoptosis, and integrating into the genome. Meanwhile, HDACs mediate cancer development and invasiveness by regulating key physiological processes, including cell proliferation, apoptosis, motility, epithelial–mesenchymal transition, and angiogenesis. HDAC6, specifically, contributes to cellular stress responses by deacetylating various substrate proteins and interacting with other proteins that together enhance tumor cell survival. In this review, we summarize recent advances in understanding the role of HDACs in HPV E7-induced cervical cancer, including HDAC structure and function, and HDAC6 involvement in tumor initiation and progression. We then explore the potential of HDAC6 as a therapeutic target for cervical cancer.
Embryonic development is a complex process involving the rapid and precise proliferation of cells. Maintaining genome integrity is critical for normal development. Research on the mechanisms by which the tissue microenvironment preserves genomic stability during development, however, is scarce. Now, a study by Dengli Hong et al., published in Nature journal provides a novel perspective for understanding the mechanisms of genomic protection in embryonic liver development. Here, we discuss the data that explains how embryonic liver cells can regulate the genomic stability of hematopoietic stem cells through fetuin-A.