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Objective: To explore genes related to costimulatory molecule related to the prognosis of bladder cancer, and to construct and evaluate prognosis model based on costimulatory molecule-based signature (CMS). Methods: Gene expression matrix and clinical information of bladder cancer patients were downloaded from TCGA database and GEO database (GSE31684), and costimulatory molecule-related genes were retrieved from the literature. The univariate and multivariate Cox analysis were used to screened prognostic-related genes and constructed prognostic model. Forecast accuracy of model was verified in TCGA training group, TCGA validation data group and GEO group by Kaplan-Meier survival analysis and receiver operating characteristic curve (ROC). Considering risk score and clinical characteristics, we constructed a nomogram and evaluated its performance by consistency analysis and ROC. CIBERSORT algorithm was used to analyze immune cell composition of tumor microenvironment infiltration, and gene set enrichment analysis (GSEA) was performed to explore the potential mechanism. Results: Four prognostic-related CMSs were found: TNFRSF14, CD276, ICOS and TMIGD2, of which three were included in the risk score construction. Multivariate Cox regression results showed that the risk score based on CMS was an independent prognostic factor for bladder cancer patients. Consistency analysis and ROC results showed that the nomogram had ideal prognosis prediction accuracy. Immune infiltration analysis showed that the high risk group was likely to be in immunosuppressive state. GSEA results suggested that genes in high risk group were enriched in extracellular matrix (ECM) receptors interaction, cell cycle and other pathways. Conclusion:TNFRSF14, CD276 and ICOS may be potential prognostic biomarkers for bladder cancer patients. CMS-based risk score and nomogram could contribute to early prognosis and choice of personalized treatment. [ABSTRACT FROM AUTHOR]

Aims: N6‐methyladenosine (m6A) modification is a critical posttranscriptional event in gene regulation. Thus, identifying methyltransferase, demethylase, or m6A binding protein‐mediated m6A modifications in cancer or noncancer transcriptomes has become a promising novel strategy for disease therapy development. However, novel insights into m6A modification in partial bladder outlet obstruction (pBOO) and detailed information about the drivers of bladder remodeling remain to be elucidated. Here, we first characterized the m6A modification landscape in pBOO and investigated potential actionable pharmaceutical targets for future therapies. Methods: We generated an improved animal model of pBOO in SD rats with urethral meatus stricture induced by suturing. Urodynamic investigations and cystometry were carried out to evaluate the physiologic changes elicited by pBOO. Whole‐transcriptome sequencing (RNA‐seq) and m6A‐modified RNA immunoprecipitation sequencing (MeRIP‐seq) were subsequently performed to analyze the expression pattern associated with bladder remodeling in pBOO. Results: The cystometric evaluation of bladder function demonstrated obvious increases in pressure‐related parameters in the pBOO group. Hematoxylin and eosin staining and Masson's trichrome staining validated the occurrence of bladder remodeling. A global elevation in m6A RNA methylation levels was observed in parallel to a increased expression of METTL3 in the pBOO group. High‐throughput sequencing revealed the differences in expression patterns between the pBOO and sham‐operated groups. Furthermore, potential m6A‐modified genes, including CCN2, may serve as new pharmaceutical targets to reverse bladder remodeling. Conclusions: Exploring the roles of m6A‐modified genes identified as associated with bladder remodeling by integrating RNA‐seq and MeRIP‐seq data can offer new insights for developing promising treatments for pBOO patients. [ABSTRACT FROM AUTHOR]

Bladder cancer (BLCA) is a common and difficult‐to‐manage disease worldwide. Most common type of BLCA is urothelial carcinoma (UC). Fibrillin 2 (FBN2) was first discovered while studying Marfan syndrome, and its encoded products are associated with elastin fibres. To date, the role of FBN2 in BLCA remains unclear. The authors first downloaded data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The patients were divided into high FBN2 expression and low FBN2 expression groups, and the survival curve, clinical characteristics, tumour microenvironment (TME), and immune cell differences were analysed between the two groups. Then, the differentially expressed genes (DEGs) were filtered, and functional enrichment for DEGs was performed. Finally, chemotherapy drug susceptibility analysis based on the high and low FBN2 groups was conducted. The authors found upregulated expression of FBN2 in BLCA and proved that FBN2 could be an independent prognostic factor for BLCA. TME analysis showed that the expression of FBN2 affects several aspects of the TME. The upregulated expression of FBN2 was associated with a high stromal score, which may lead to immunosuppression and be detrimental to immunotherapy. In addition, the authors found that NK cells resting, macrophage M0 infiltration, and other phenomena of immune cell infiltration appeared in the high expression group of FBN2. The high expression of FBN2 was related to the high sensitivity of some chemotherapy drugs. The authors systematically investigated the effects and mechanisms of FBN2 on BLCA and provided a new understanding of the role of FBN2 as a risk factor and TME influencer in BLCA. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is one of the most common tumours of the urinary system, and is insidious and not susceptible to chemoradiotherapy. As the most common subtype of RCC (70–80% of cases), clear cell renal cell carcinoma (ccRCC) is characterized by the loss of von Hippel–Lindau and the accumulation of robust lipid and glycogen. For advanced RCC, molecular‐targeted drugs, tyrosine kinase inhibitors (TKIs) and the immune checkpoint inhibitors (ICIs) have been increasingly recommended and investigated. Due to the existence of a highly dynamic, adaptive and heterogeneous tumour microenvironment (TME), and due to the glucose and lipid metabolism in RCC, this cancer may be accompanied by various types of resistance to TKIs and ICIs. With the increased production of lactate, nitric oxide, and other new by‐products of metabolism, novel findings of the TME and key metabolic enzymes drived by HIF and other factors have been increasingly clarified in RCC carcinogenesis and therapy. However, there are few summaries of the TME and tumour metabolism for RCC progression and therapy. Here, we summarize and discuss the relationship of the important implicated characteristics of the TME as well as metabolic molecules and RCC carcinogenesis to provide prospects for future treatment strategies to overcome TME‐related resistance in RCC. [ABSTRACT FROM AUTHOR]

Renal calculus is a global common urological disease that is closely related to crystal adhesion and renal tubular epithelial cell impairment. Gap junctions (GJs) and their components (connexins and Cxs) are involved in various pathophysiology processes, but their roles in renal calculi progression are not well defined. Our previous RNA microarray analysis suggests that GJs are one of the key predicted pathways involved in the renal calcium oxalate (CaOx) crystal rat model. In the current study, we found that the Cx43 and Cx32 expression and the GJ function decreased significantly after stimulation with CaOx or sodium oxalate (NaOx) in NRK‐52E, MDCK, and HK‐2 cells, and Cx43 expression also decreased in renal tissues in renal CaOx crystal model rats. Inhibition of Cx43 in NRK‐52E cells by small interference RNA significantly increased the CD44 and androgen receptor expression, and the adhesion between CaOx crystals and cells, which were consistent with the function of GJ inhibitors. On the other hand, after GJ function and Cx43 expression were increased by allicin, diallyl disulfide, or diallyl trisulfide, the impairment of NRK‐52E cells by NaOx or other GJ inhibitors and the adhesion between CaOx crystals and renal cells decreased significantly. Furthermore, allicin also increased Cx43 expression and inhibited crystal deposition in rat kidneys. Taken together, our results provide a basis that GJs and Cx43 may participate in renal CaOx stone progression and that allicin, together with its analogues, could be potential drugs for renal calculus precaution. Gap junctions (GJs) and their components (connexins, Cxs) are involved in various pathophysiology processes, but their roles in renal calculi progression are not well defined. In the current study, we found that the Cx43 and Cx32 expression and the GJ function decreased significantly after stimulation with CaOx or sodium oxalate (NaOx) in NRK‐52E, MDCK, and HK‐2 cells, and Cx43 expression also decreased in renal tissues in renal CaOx crystal model rats. Taken together, our results provide a basis that GJs and Cx43 may participate in renal CaOx stone progression and that allicin, together with its analogues, could be potential drugs for renal calculus precaution. [ABSTRACT FROM AUTHOR]

Melanoma is one of the most aggressive forms of skin tumour with poor prognosis; no effective therapy has been established for melanoma at the metastatic stage. The present study aimed to investigate the role of poly (ADP ribose) polymerase (PARP) inhibitors (PARPis) and PARP1 expression in melanoma progression. In addition, whether high PARP1 expression was associated with poor overall survival in melanoma, and whether a combination effect existed between PARPis and other anti-tumour compounds (e.g., sunitinib) was analysed. The PARP1 expression was detected using western blot analysis and the proliferation of cells was detected with a colony formation assay. In addition, cell viability assays and xenograft tumor experiments were conducted. The results of the present study demonstrated that sunitinib reduced PARP1 expression and proliferation of melanoma cells. Notably, one of the PARPis, veliparib, reversed the inhibitory effect of sunitinib on PARP1 expression and proliferation, indicating that inhibition of PARP1 enzyme activity by PARPi may be different from the inhibition of PARP1 expression in melanoma cell biological function. To further confirm the relationship between PARP1 expression and tumour cell proliferation, seven compounds, including common approved drugs and natural Chinese medicine monomers, were screened, and the results demonstrated that simvastatin and tanshinone I exerted an inhibitory effect on PARP1 expression and melanoma cell proliferation, and their combination was more effective than simvastatin alone in vivo. The results indicated that simvastatin and tanshinone I inhibited melanoma and renal tumour cells by regulating PARP1 expression, and in addition to the enzyme activity of PARP1, the expression of PARP1 protein may serve a role in tumour progression. [ABSTRACT FROM AUTHOR]

Purpose: Targeted ferroptosis is a reliable therapy to inhibit tumor growth and enhance immunotherapy. This study generated a novel prognostic risk signature based on ferroptosis-related genes (FRGs), and explored the ability in clinic for clear cell renal cell carcinoma (ccRCC).Materials and Methods: The expression profile of mRNA and FRGs for ccRCC patients were exacted from The Cancer Genome Atlas (TCGA) database. A ferroptosis-related prognostic risk signature was constructed based on univariable and multivariable Cox-regression analysis. Kaplan-Meier (KM) survival curves and receiver operating characteristic (ROC) curves were performed to access prognostic value of riskscore. A nomogram integrating riskscore and clinical features was established to predict overall survival (OS). Based on differentially expressed genes between high- and low-OS groups with 5-year OS, function enrichment analyses and single-sample gene set enrichment analysis (ssGSEA) were investigated to immune status.Results: A 9-FRGs prognostic risk signature was constructed based on 37 differentially expressed FRGs. ROC and KM curves showed that riskscore has excellent reliability and predictive ability; Cox regression disclosed the riskscore as an independent prognosis for ccRCC patients. Then, the C-index and calibration curve demonstrated the good performance of nomogram in training and validation cohort, and its predictive ability better than other features. Immune-related biological processes were enriched by function enrichment analysis, and the immune-related cells and functions were differential by ssGSEA between high- and low-OS groups.Conclusion: Our study identified and verified a novel 9-FRGs prognostic signature and nomogram to predict OS, providing a novel sight to explore targeted therapy of ferroptosis for ccRCC. [ABSTRACT FROM AUTHOR]

As the main type of renal cell carcinoma (RCC), clear cell RCC (ccRCC) is often associated with the deletion or mutation of the von Hippel Lindau (VHL) gene, enhancement of glucose and lipid metabolism, and heterogeneity of the tumor microenvironment. VHL alterations in RCC cells lead to the activation of hypoxia-inducible factors and their downstream target vascular endothelial growth factor, and to the reprogramming of multiple cell death pathways and metabolic weakness, including ferroptosis, which are associated with targeted therapy or immunotherapy. The changes in biological metabolites (e.g., iron and lipids) support ferroptosis as a potential therapeutic strategy for RCC, while iron metabolism and ferroptosis regulation have been examined as anti-RCC agents in numerous studies, and various ferroptosis-related molecules have been shown to be related to the metastasis and prognosis of ccRCC. For example, glutathione peroxidase 4 and glutaminase inhibitors can inhibit pyrimidine synthesis and increase reactive oxygen species levels in VHL-deficient RCC cells. In addition, the release of damage-associated molecular patterns by tumor cells undergoing ferroptosis also mediates antitumor immunity, and immune therapy can synergize with targeted therapy or radiotherapy through ferroptosis. However, Inducing ferroptosis not only suppresses cancer, but also promotes cancer development due to its potential negative effects on anti-cancer immunity. Therefore, ferroptosis and various tumor microenviroment-related molecules may co-occur during the development and treatment of RCC, and further understanding of the interactions, core targets, and related drugs of ferroptosis may provide new combination drug strategies for RCC treatment. Here we summarize the key genes and compounds on ferroptosis and RCC in order to envision future treatment strategies and to provide sufficient information for overcoming RCC resistance through ferroptosis., Competing Interests: XL was employed by Tibet Future Biomedicine Company Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JX declared a shared parent affiliation, with no collaboration, with some of the authors, QL, HZ, WW, KL, CH, to the handling editor at the time of the review., (Copyright © 2024 He, Li, Wu, Liu, Li, Zheng and Lai.)

Purpose: Targeted ferroptosis is a reliable therapy to inhibit tumor growth and enhance immunotherapy. This study generated a novel prognostic risk signature based on ferroptosis-related genes (FRGs), and explored the ability in clinic for clear cell renal cell carcinoma (ccRCC)., Materials and Methods: The expression profile of mRNA and FRGs for ccRCC patients were exacted from The Cancer Genome Atlas (TCGA) database. A ferroptosis-related prognostic risk signature was constructed based on univariable and multivariable Cox-regression analysis. Kaplan-Meier (KM) survival curves and receiver operating characteristic (ROC) curves were performed to access prognostic value of riskscore. A nomogram integrating riskscore and clinical features was established to predict overall survival (OS). Based on differentially expressed genes between high- and low-OS groups with 5-year OS, function enrichment analyses and single-sample gene set enrichment analysis (ssGSEA) were investigated to immune status., Results: A 9-FRGs prognostic risk signature was constructed based on 37 differentially expressed FRGs. ROC and KM curves showed that riskscore has excellent reliability and predictive ability; Cox regression disclosed the riskscore as an independent prognosis for ccRCC patients. Then, the C-index and calibration curve demonstrated the good performance of nomogram in training and validation cohort, and its predictive ability better than other features. Immune-related biological processes were enriched by function enrichment analysis, and the immune-related cells and functions were differential by ssGSEA between high- and low-OS groups., Conclusion: Our study identified and verified a novel 9-FRGs prognostic signature and nomogram to predict OS, providing a novel sight to explore targeted therapy of ferroptosis for ccRCC.

Melanoma is one of the most aggressive forms of skin tumour with poor prognosis; no effective therapy has been established for melanoma at the metastatic stage. The present study aimed to investigate the role of poly (ADP ribose) polymerase (PARP) inhibitors (PARPis) and PARP1 expression in melanoma progression. In addition, whether high PARP1 expression was associated with poor overall survival in melanoma, and whether a combination effect existed between PARPis and other anti‑tumour compounds (e.g., sunitinib) was analysed. The PARP1 expression was detected using western blot analysis and the proliferation of cells was detected with a colony formation assay. In addition, cell viability assays and xenograft tumor experiments were conducted. The results of the present study demonstrated that sunitinib reduced PARP1 expression and proliferation of melanoma cells. Notably, one of the PARPis, veliparib, reversed the inhibitory effect of sunitinib on PARP1 expression and proliferation, indicating that inhibition of PARP1 enzyme activity by PARPi may be different from the inhibition of PARP1 expression in melanoma cell biological function. To further confirm the relationship between PARP1 expression and tumour cell proliferation, seven compounds, including common approved drugs and natural Chinese medicine monomers, were screened, and the results demonstrated that simvastatin and tanshinone I exerted an inhibitory effect on PARP1 expression and melanoma cell proliferation, and their combination was more effective than simvastatin alone in vivo. The results indicated that simvastatin and tanshinone I inhibited melanoma and renal tumour cells by regulating PARP1 expression, and in addition to the enzyme activity of PARP1, the expression of PARP1 protein may serve a role in tumour progression.

For pregnant women with high viral load, antiviral therapy has been administered in addition to active and passive immune prophylaxis as a crucial adjunctive therapy to interrupt mother-to-child hepatitis B virus (HBV) transmission (MTCT). However, the time of antiviral therapy onset remains controversial. A systematic review and meta-analysis was conducted to compare the efficacy of antiviral therapy during the second or the third trimester for prevention of HBV vertical transmission. We searched nine databases for observational studies and randomized controlled trials that enrolled pregnant women with positive HBsAg treated with antivirals. The outcomes of interest were maternal HBV-DNA levels prior to delivery and the rates of HBV MTCT. We included nine studies that enrolled 1,502 pregnant women. The average HBV-DNA level before treatment was approximately 8 log10 copies/mL. Compared to the onset of antiviral intervention in the third trimester, the beginning of treatment in the second trimester distinctly reduced maternal predelivery HBV-DNA levels. However, no significant difference in HBV MTCT was found between the second and third trimester groups. Furthermore, the subgroup analysis showed that there were no significant differences between groups beginning treatment at different times (second or third trimester) with regard to HBV MTCT or other evaluated endpoints. For pregnant women with HBV-DNA levels less than or equal to 8 log10 copies/mL, the beginning of antiviral treatment can be delayed until the third trimester.

Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib or rucaparib, have shown treatment efficacy in BRCA1/2-deficient tumors. However, since PARP inhibitors (PARPi) mainly modulate the activation of PARP but not its expression, whether small interfering RNA (siRNA) specific to PARP has the same function as PARPi has not been well defined. In the present study it was demonstrated that PARP1-siRNA could reduce prostate cancer (PCa) cell progression regardless of the BRCA1/2 mutation. PARP1 silencing could significantly inhibit PC3 cell migration and invasion. Additionally, PARP1-siRNA also inhibited the proliferation of PC3 and Du145 cells. After the induction of apoptosis by docetaxel, cleaved-caspase3 of DU145 and C4-2 cells increased significantly in the PARP1-siRNA group. In the xenograft nude mouse model, PARP1-siRNA could suppress xenograft tumor size of PC3 cells and produce a more regular morphology. In vitro and in vivo, PARP1 silencing significantly downregulated vimentin expression and upregulated E-cadherin expression, both of which are epithelial-mesenchymal transition (EMT) markers. It has been revealed that PI3K inhibition could sensitize the effect of PARPi. Notably, PARP1-siRNA could suppress the expression of EGFR and p-GSK3β (Ser9) in PCa cells, which was different from PARPi. Our results indicated that PARP1-siRNA can suppress the growth and invasion capacity of PCa cells, thereby suggesting that PARP1-siRNA, which is different from PARPi, may provide a potential treatment method for PCa.