Background: Tyrosine kinase inhibitors (TKIs) alone and in combination with immune checkpoint inhibitors (ICIs) have been shown to be beneficial for the survival of metastatic renal cell carcinoma (mRCC) patients, but resistance to targeted therapy and ICIs is common in the clinic. Understanding the underlying mechanism is critical for further prolonging the survival of renal cancer patients. Nuclear factor of activated T cell 1 (NFAT1) is expressed in immune and nonimmune cells, and the dysregulation of NFAT1 contributes to the progression of various type of malignant tumors. However, the specific role of NFAT1 in RCC is elusive. As a regulator of the immune response, we would like to systemically study the role of NFAT1 in RCC.Methods: TCGA-KIRC dataset analysis, Western blot analysis and RT-qPCR analysis was used to determine the clinic-pathological characteristic of NFAT1 in RCC. CCK-8 assays, colony formation assays and xenograft assays were performed to examine the biological role of NFAT1 in renal cancer cells. RNA-seq analysis was used to examine the pathways changed after NFAT1 silencing. ChIP-qPCR, coimmunoprecipitation analysis, Western blot analysis and RT-qPCR analysis were applied to explore the mechanism by NAFT1 was regulated in the renal cancer cells.Results: In our study, we found that NFAT1 was abnormally overexpressed in RCC and that NFAT1 overexpression was associated with an unfavorable prognosis. Then, we showed that NFAT1 enhanced tumor growth and regulated the immune response by increasing PD-L1 expression in RCC. In addition, we demonstrated that NFAT1 was stabilized in sunitinib-resistant RCC via hyperactivation of the PI3K/AKT/GSK-3β signaling pathway. Furthermore, our study indicated that downregulation of the expression of FBW7, which promotes NFAT1 degradation, was induced by FOXA1 and SETD2 in sunitinib-resistant RCC. Finally, FBW7 was found to contribute to modulating the immune response in RCC.Conclusions: Our data reveal a novel role for the FBW7/NFAT1 axis in the RCC response to TKIs and ICIs. NFAT1 and its associated signaling pathway might be therapeutic targets for RCC treatment, especially when combined with ICIs and/or TKIs.

Circular RNAs (circRNAs) are involved in the pathogenesis of certain renal diseases, however, the function and mechanism of them in renal fibrosis remains largely unknown. In the present study, RNA expression data in unilateral ureteral obstruction (UUO) kidneys was obtained from our previous circRNA Microarray and public Gene Expression Omnibus datasets to construct a ceRNA network. The effects of target circRNA as long as the homologous human circRNA on renal fibrosis was examined in vitro and in vivo. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was further performed among genes regulated by the human circRNA. We found that circRNA_37492, showing well connection degree in the ceRNA network, was abundant expression and high sequence conservation. We observed that the expression of circRNA_37492 was induced by the TGF-β1 or UUO in BUMPT cells and C57BL/6 mice, respectively. In vitro, cytoplasmic circRNA_37492 inhibited type I, III collagen and fibronectin deposition by sponging miR-7682-3p and then upregulated its downstream target Fgb. In vivo, overexpression of circRNA_37492 attenuated fibrotic lesions in the kidneys of UUO mice via targeting miR-7682-3p/Fgb axis. Furthermore, hsa_circ_0012138, homologous with circRNA_37492, may potentially target miR-651-5p/FGB axis in human renal fibrosis. Not only that, GO and KEGG enrichment revealed that hsa_circ_0012138-regulated genes were previously demonstrated to related to the fibrosis. In conclusion, we for the first time demonstrated that circRNA_37492 attenuated renal fibrosis via targeting miR-7682-3p/Fgb axis, and the homologous hsa_circRNA_0012138 was speculated as a possible ceRNA to regulate multiple gene expressions and involve in human renal fibrosis, suggesting that circRNA_37492/hsa_circ_0012138 may serve as potent therapy target for obstructive renal fibrosis disease.

Background: Single-port robot-assisted pyeloplasty (SP-RP) has been performed in recent years. However, the advantages and disadvantages of SP-RP compared with multiple-port robot-assisted pyeloplasty (MP-RP) remain unclear. The purpose of this meta-analysis was to compare the safety and feasibility of the two technologies. Materials and Methods: Through a literature search using MEDLINE, EMBASE, and the Cochrane Library, studies comparing SP-RP and MP-RP were identified for meta-analysis. Comparisons of perioperative and postoperative outcomes between the groups were analyzed using weighted mean difference (WMD) and risk ratio. Results: Five retrospective cohort studies with 179 patients were included in this meta-analysis. The results showed that SP-RP was associated with shorter hospital stay (WMD: −0.6 minutes, 95% confidence interval [CI]: −1.19 to −0.02, p = 0.04), less postoperative pain (pain score, WMD: −0.84, 95% CI: −1.62 to −0.07, p = 0.03), and superior cosmetic appearance compared with MP-RP. In addition, no differences were found between the SP-RP and MP-RP groups in terms of operative time, blood loss, rate of complications, and recovery of renal function. Conclusion: SP-RP provided comparable effectiveness, safety, and superior outcomes in terms of cosmetic appearance and pain compared with MP-RP, which gives surgeons the confidence to adopt and promote these ultraminimal invasive surgeries.

Background: Androgen deprivation therapy is the mainstay of medical treatment for prostate cancer (Pca); however, it is associated with an increased risk of adverse cardiovascular (CV) events and death. To date, CV death has been the leading noncancer cause of death in Pca patients. Both GnRH antagonists (an emerging class of drugs) and GnRH agonists (most frequently prescribed) are efficacious against Pca. However, the adverse effects, especially the adverse CV effect between them remain unclear.Methods: Through a literature search using MEDLINE, EMBASE and the Cochrane Library, all available studies comparing the safety of CV risk between GnRH antagonists and GnRH agonists in Pca patients were extracted. Comparisons of outcomes of interest between these two classes of drugs were calculated using the risk ratio (RR). Subgroup analyses were performed depending on the study design and preexisting CV disease at baseline.Results: Nine randomized controlled clinical trials (RCTs) and five real-world observational studies comprising 62160 Pca patients were included in our meta-analysis. Patients receiving GnRH antagonists experienced fewer CV events (RR: 0.66, 95% CI:0.53-0.82, P<0.001), CV death (RR:0.4, 95% CI: 0.24-0.67, P<0.001) and myocardial infarctions (RR: 0.71, 95% CI: 0.52-0.96, P=0.03). No difference was found in the incidence of stroke and heart failure. Moreover, GnRH antagonists were associated with fewer CV events in patients with preexisting CV disease but not in those without preexisting CV disease in the RCT series.Conclusion: GnRH antagonists appear to offer favorable safety in terms of adverse CV events and CV death compared with GnRH agonists among men diagnosed with Pca, especially those who had established CV disease at baseline.Systematic review registration: https://inplasy.com/inplasy-2023-2-0009/, identifier INPLASY202320009.

Objective: Radical cystectomy (RC) is the gold standard treatment for muscle-invasive bladder cancer (MIBC). As a bladder-preservation option recommended in guidelines, trimodal therapy (TMT) has become increasingly popular in recent years. However, it is still uncertain whether TMT can provide comparable oncologic outcomes to RC. Therefore, it is imperative to evaluate whether TMT yields comparable outcomes to RC. Methods: We conducted a systematic search of Web of Science, MEDLINE, the Cochrane Library, and EMBASE databases up to June 2023 to identify studies that met our inclusion criteria. The primary outcome measures evaluated in this study were overall survival (OS) and cancer-specific survival (CSS). The study quality was evaluated independently by two authors, and data were extracted accordingly. Results: After excluding duplicates and ineligible articles, our meta-analysis included seven studies involving 3,489 and 13,877 patients in the TMT and RC groups, respectively. Short-term overall survival rates were comparable between the groups, but beyond 5 and > 10-years, the RC group had significantly higher overall survival rates compared to the TMT group. In terms of cancer-specific survival, there was no significant difference between the groups at 1-year follow-up, but from the second year onwards, including the 5-year and > 10-year nodes, the RC group had significantly better outcomes compared to the TMT group. Conclusion: The treatment effect of RC is better than that of TMT. Unless the patient can’t tolerate RC or has a strong desire to preserve the bladder, RC should be chosen over TMT in treatment, and patients undergoing TMT should be closely followed up.