Background: Ferroptosis, a novel form of regulated cell death, has been implicated in the pathogenesis of cancers. Nevertheless, the potential function and prognostic values of ferroptosis in bladder urothelial carcinoma (BLCA) are complex and remain to be clarified. Therefore, we proposed to systematically examine the roles of ferroptosis-associated genes (FAGs) in BLCA. Methods: According to The Cancer Genome Atlas (TCGA) database, differently expressed FAGs (DEFAGs) and differently expressed transcription factors (DETFs) were identified in BLCA. Next, the network between DEFAGs and DETFs, GO annotations and KEGG pathway analyses were performed. Then, through univariate, LASSO and multivariate regression analyses, a novel signature based on FAGs was constructed. Moreover, survival analysis, PCA analysis, t-SNE analysis, ROC analysis, independent prognostic analysis, clinicopathological and immune correlation analysis, and experimental validation were utilized to evaluate the signature. Results: Twenty-eight DEFAGs were identified, and four FAGs (CRYAB, TFRC, SQLE and G6PD) were finally utilized to establish the FAGs based signature in the TCGA cohort, which was subsequently validated in the GEO database. Moreover, we found that immune cell infiltration, immunotherapy-related biomarkers and immune-related pathways were significantly different between two risk groups. Besides, nine molecule drugs with the potential to treat bladder cancer were identified by the connectivity map database analysis. Finally, the expression levels of crucial FAGs were verified by the experiment, which were consistent with our bioinformatics analysis, and knockdown of TFRC could inhibit cell proliferation and colony formation in BLCA cell lines in vitro. Conclusions: Our study identified prognostic ferroptosis-associated genes and established a novel FAGs signature, which could accurately predict prognosis in BLCA patients.

Background: Immune infiltration has an important impact on the development of clear cell renal cell carcinoma (ccRCC). This article aims to investigate the association between immune infiltration and the clinical features as well as prognosis of clear cell renal cell carcinoma. Methods: Analyze the immune infiltration in ccRCC by applying ESTIMATE and CIBERSORT methods on basic of dataset in TCGA and GEO. And identify the kind of immune cell and genes that may play the central role. Results: High Immune score and high property of T-regs are both significantly associated with the poor OS, high stage and more chances of metastases in ccRCC. CXCL-1, SAA1, PMCH, CCL-5 are all significantly negatively correlated to OS and positively correlated to stage and chance of metastases in ccRCC. High property of T-regs, CXCL-1 and SAA1 are also significantly associated with high Fuhrman grade while PMCH and CCL5 not. Conclusions: Immune infiltration in RCC has a negative influence on ccRCC and T-regs may play a vital role in this process mediated by CXCL-1 or SSA1.

Background: Although abnormal sympathetic nerve system (SNS) activity has been demonstrated in the pathogenesis of ejaculation disorders, few data are available on its underlying mechanism. Aim: To investigate whether differences in ejaculatory behavior of rats were associated with the state of SNS activity and gamma-aminobutyric (GABA) receptor expressions in the paraventricular nucleus (PVN) of the hypothalamus and the effects of GABA receptors in the PVN on ejaculatory behavior. Methods: Based on ejaculatory performance, Sprague-Dawley rats were divided into “sluggish,” “normal,” and “rapid” ejaculators. PVN microinjection was performed to evaluate the role of GABA receptors on sexual behavior. Outcomes: The outcomes include differences in expression and distribution of GABA receptors and norepinephrine level among the 3 groups and changes in copulation behavior parameters after PVN microinjection. Results: Compared with “normal” rats, the “rapid” group ejaculated more times with shorter latency (P < .001, P < .001) and had lower expression and distribution of both GABA-A and GABA-B receptors, while the opposed results appeared in the “sluggish” group. The norepinephrine level was successively increased among “sluggish,” “normal,” and “rapid” rats (P < .001) and correlated with ejaculation frequency (r = 0.896, P < .001) and ejaculation latency (r = −0.835, P < .001). In addition, bilateral microinjection of the GABA-A and GABA-B receptor agonist (isoguvacine and baclofen) into the PVN both significantly prolonged the intromission latency and inhibited ejaculation, which could be blocked by antagonist gabazine and CGP-35348, respectively. Vigabatrin, the GABA-transaminase inhibitor, caused a significantly reduced ejaculation frequency and extended ejaculation latency in rats, which could be offset by simultaneous injections of gabazine and CGP-35348. Clinical Implications: Our findings provide new understanding about GABA receptors in the PVN on sexual behavior and enhance the comprehension of neurobiological mechanisms involved in premature ejaculation. Strengths & Limitations: Our results have indicated that GABA receptors in the PVN may inhibit ejaculation through restraining the activity of SNS. However, our study did not analyze the changes of GABA receptors in other brain areas, which needs further study. Conclusion: Ejaculation behaviors in male rats are associated with SNS activity and could be regulated by GABA receptors in the PVN, which may be of assistance in the treatment of ejaculation disorders in the future.

Immune checkpoint blockade (ICB) therapies have significantly improved the prognosis and shown considerable promise for cancer therapy; however, differences in ICB treatment efficacy between the elderly and young are unknown. We analyzed the studies enrolled in the meta-analysis using the deft approach, and found no difference in efficacy except melanoma patients receiving anti–PD-1 therapy. Similarly, higher treatment response rate and more favorable prognosis were observed in elderly patients in some cancer types (e.g., melanoma) with data from published ICB treatment clinical trials. In addition, we comprehensively compared immunotherapy-related molecular profiles between elderly and young patients from public trials and The Cancer Genome Atlas (TCGA), and validated these findings in several independent datasets. We discovered a divergent age-biased immune profiling, including the properties of tumors (e.g., tumor mutation load) and immune features (e.g., immune cells), in a pancancer setting across 27 cancer types. We believe that ICB treatment efficacy might vary depending on specific cancer types and be determined by both the tumor internal features and external immune microenvironment. Considering the high mutational properties in elderly patients in many cancer types, modulating immune function could be beneficial to immunotherapy in the elderly, which requires further investigation.