A novel focal adhesion-related risk model predicts prognosis of bladder cancer -- a bioinformatic study based on TCGA and GEO database.

BACKGROUND: Bladder cancer (BLCA) is the ninth most common cancer globally, as well as the fourth most common cancer in men, with an incidence of 7%. However, few effective prognostic biomarkers or models of BLCA are available at present. METHODS: The prognostic genes of BLCA were screened from one cohort of The Cancer Genome Atlas (TCGA) database through univariate Cox regression analysis and functionally annotated by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The intersecting genes of the BLCA gene set and focal adhesion-related gene were obtained and subjected to the least absolute shrinkage and selection operator regression (LASSO) to construct a prognostic model. Gene set enrichment analysis (GSEA) of high- and low-risk patients was performed to explore further the biological process related to focal adhesion genes. Univariate and multivariate Cox analysis, receiver operating characteristic (ROC) curve analysis, and Kaplan-Meier survival analysis (KM) were used to evaluate the prognostic model. DNA methylation analysis was presented to explore the relationship between prognosis and gene methylation. Furthermore, immune cell infiltration was assessed by CIBERSORT, ESTIMATE, and TIMER. The model was verified in an external GSE32894 cohort of the Gene Expression Omnibus (GEO) database, and the Prognoscan database presented further validation of genes. The HPA database validated the related protein level, and functional experiments verified significant risk factors in the model. RESULTS: VCL, COL6A1, RAC3, PDGFD, JUN, LAMA2, and ITGB6 were used to construct a prognostic model in the TCGA-BLCA cohort and validated in the GSE32894 cohort. The 7-gene model successfully stratified the patients into both cohorts' high- and low-risk groups. The higher risk score was associated with a worse prognosis. CONCLUSIONS: The 7-gene prognostic model can classify BLCA patients into high- and low-risk groups based on the risk score and predict the overall survival, which may aid clinical decision-making.

Hypoxia-related prognostic model in bladder urothelial reflects immune cell infiltration.

Hypoxia is a common feature of tumor microenvironment (TME). This study aims to establish the genetic features related to hypoxia in Bladder urothelial carcinoma (BLCA) and investigate the potential correlation with hypoxia in the TME and immune cells. We established a BLCA outcome model using the hypoxia-related genes from The Cancer Genome Atlas using regression analysis and verified the model using the Gene Expression Omnibus GSE32894 cohort. We measured the effect of each gene in the hypoxia-related risk model using the Human Protein Atlas website. The predictive abilities were compared using the area under the receiver operating characteristic curves. Gene Set Enrichment Analysis was utilized for indicating enrichment pathways. We analyzed immune cell infiltration between risk groups using the CIBERSORT method. The indicators related to immune status between the two groups were also analyzed. The findings indicated that the high-risk group had better outcomes than the low-risk group in the training and validation sets. Each gene in the model affected the survival of BLCA patients. Our hypoxia-related risk model had better performance compared to other hypoxia-related markers (HIF-1α and GLUT-1). The high-risk group was enriched in immune-related pathways. The expression of chemokines and immune cell markers differed significantly between risk groups. Immune checkpoints were more highly expressed in the high-risk group. These findings suggest that the hypoxia-related risk model predicts patients' outcomes and immune status in BLCA risk groups. Our findings may contribute to the treatment of BLCA.

Identification of a Prognosis-Related Risk Signature for Bladder Cancer to Predict Survival and Immune Landscapes.

BACKGROUND: Bladder cancer is the tenth most common cancer worldwide. Valuable biomarkers in the field of diagnostic bladder cancer are urgently required. METHOD: Here, the gene expression matrix and clinical data were obtained from The Cancer Genome Atlas (TCGA), GSE13507, GSE32894, and Mariathasan et al. Five prognostic genes were identified by the univariate, robust, and multivariate Cox's regression and were used to develop a prognosis-related model. The Kaplan-Meier survival curves and receiver operating characteristics were used to evaluate the model's effectiveness. The potential biological functions of the selected genes were analyzed using CIBERSORT and ESTIMATE algorithms. Cancer Therapeutics Response Portal (CTRP) and PRISM datasets were used to identify drugs with high sensitivity. Subsequently, using the bladder cancer (BLCA) cell lines, the role of TNFRSF14 was determined by Western blotting, cell proliferation assay, and 5-ethynyl-20-deoxyuridine assay. RESULTS: GSDMB, CLEC2D, APOL2, TNFRSF14, and GBP2 were selected as prognostic genes in bladder cancer patients. The model's irreplaceable reliability was validated by the training and validation cohorts. CD8+ T cells were highly infiltrated in the high-TNFRSF14-expression group, and M2 macrophages were the opposite. Higher expression of TNFRSF14 was associated with higher expression levels of LCK, interferon, MHC-I, and MHC-II, while risk score was the opposite. Many compounds with higher sensitivity for treating bladder cancer patients in the low-TNFRSF14-expression group were identified, with obatoclax being a potential drug most likely to treat patients in the low-TNFRSF14-expression group. Finally, the proliferation of BLCA cell lines was increased in the TNFRSF14-reduced group, and the differential expression was identified. TNFRSF14 plays a role in bladder cancer progression through the Wnt/ß-catenin-dependent pathway. TNFRSF14 is a potential protective biomarker involved in cell proliferation in BLCA. CONCLUSION: We conducted a study to establish a 5-gene score model, providing reliable prediction for the outcome of bladder cancer patients and therapeutic drugs to individualize therapy. Our findings provide a signature that might help determine the optimal treatment for individual patients with bladder cancer.

Peptide-based therapeutic cancer vaccine: Current trends in clinical application.

The peptide-based therapeutic cancer vaccines have attracted enormous attention in recent years as one of the effective treatments of tumour immunotherapy. Most of peptide-based vaccines are based on epitope peptides stimulating CD8+ T cells or CD4+ T helper cells to target tumour-associated antigens (TAAs) or tumour-specific antigens (TSAs). Some adjuvants and nanomaterials have been exploited to optimize the efficiency of immune response of the epitope peptide to improve its clinical application. At present, numerous peptide-based therapeutic cancer vaccines have been developed and achieved significant clinical benefits. Similarly, the combination of peptide-based vaccines and other therapies has demonstrated a superior efficacy in improving anti-cancer activity. We delve deeper into the choices of targets, design and screening of epitope peptides, clinical efficacy and adverse events of peptide-based vaccines, and strategies combination of peptide-based therapeutic cancer vaccines and other therapies. The review will provide a detailed overview and basis for future clinical application of peptide-based therapeutic cancer vaccines.

Design, synthesis of 1,3-dimethylpyrimidine-2,4-diones as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity.

LDH1A1, one of 19 NAD(P)+-dependent aldehyde dehydrogenases, participates in multiple metabolic pathways and has been indicated to play an important role in obesity and diabetes. In this study, a series of 1,3-dimethylpyrimidine-2,4-diones were designed, synthesized and evaluated as novel selective aldehyde dehydrogenase 1A1 inhibitors. Among them, compounds 46, 50, 53, 56 and 57 exhibited excellent inhibitory activity against ALDH1A1 with IC50 values in the low nanomolar range and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Furthermore, in vitro study demonstrated that compound 57 effectively improved glucose consumption in HepG2 cells compared to compound 1 (CM026).

A "GC-rich" method for mammalian gene expression: a dominant role of non-coding DNA GC content in regulation of mammalian gene expression.

High mammalian gene expression was obtained for more than twenty different proteins in different cell types by just a few laboratory scale stable gene transfections for each protein. The stable expression vectors were constructed by inserting a naturally-occurring 1.006 kb or a synthetic 0.733 kb DNA fragment (including intron) of extremely GC-rich at the 5' or/and 3' flanking regions of these protein genes or their gene promoters. This experiment is the first experimental evidence showing that a non-coding extremely GC-rich DNA fragment is a super "chromatin opening element" and plays an important role in mammalian gene expression. This experiment has further indicated that chromatin-based regulation of mammalian gene expression is at least partially embedded in DNA primary structure, namely DNA GC-content.