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Objective and design: Post-traumatic urethral stricture is a clinical challenge for both patients and clinicians. Targeting glutamine metabolism to suppress excessive activation of urethral fibroblasts (UFBs) is assumed to be a potent and attractive strategy for preventing urethral scarring and stricture. Material or subjects: In cellular experiments, we explored whether glutaminolysis meets the bioenergetic and biosynthetic demands of quiescent UFBs converted into myofibroblasts. At the same time, we examined the specific effects of M2-polarized macrophages on glutaminolysis and activation of UFBs, as well as the mechanism of intercellular signaling. In addition, findings were further verified in vivo in New Zealand rabbits. Results: It revealed that glutamine deprivation or knockdown of glutaminase 1 (GLS1) significantly inhibited UFB activation, proliferation, biosynthesis, and energy metabolism; however, these effects were rescued by cell-permeable dimethyl α-ketoglutarate. Moreover, we found that exosomal miR-381 derived from M2-polarized macrophages could be ingested by UFBs and inhibited GLS1-dependent glutaminolysis, thereby preventing excessive activation of UFBs. Mechanistically, miR-381 directly targets the 3′UTR of Yes-associated protein (YAP) mRNA to reduce its stability at the transcriptional level, ultimately downregulating expression of YAP, and GLS1. In vivo experiments revealed that treatment with either verteporfin or exosomes derived from M2-polarized macrophages significantly reduced urethral stricture in New Zealand rabbits after urethral trauma. Conclusion: Collectively, this study demonstrates that exosomal miR-381 from M2-polarized macrophages reduces myofibroblast formation of UFBs and urethral scarring and stricture by inhibiting YAP/GLS1-dependent glutaminolysis. [ABSTRACT FROM AUTHOR]

In our study, 49 key genes significantly associated with renal cell carcinoma (RCC) stemness were obtained. Next, we developed a molecular prognostic signature associated with stemness features of pan-RCC. The difference in overall survival (OS) between the high- and low-risk groups was statistically significant (p <.05). The area under the receiver operating characteristic curve for 1-year OS, 5-year OS, and 10-year OS was 0.759, 0.712, and 0.918, respectively. The results of validation in The Cancer Genome Atlas cohort and International Cancer Genome Consortium cohort revealed the predictive capability of this signature. Furthermore, we selected three genes and further validation showed that these three hub genes were potential hub biomarkers for pan-RCC stemness features. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to identify potential biomarkers for prostate cancer (PCa) progression and metastasis, and to discern their biological functions. Methods: Bioinformatics methods were used to screen for hub genes. The expression level of key hub genes in PCa was determined and their prognostic significance was examined. A series of functional assays were performed to investigate the function of the highest-ranking hub gene. Results: Actin related protein 2/3 complex subunit 1A (ARPC1A) was identified as the hub gene. ARPC1A was highly expressed in PCa tissues and cell lines, and was an independent prognostic factor for predicting biochemical recurrence after radical prostatectomy and overall survival of PCa patients. Knockdown of ARPC1A inhibited PCa cell migration, invasion and cytoskeleton formation, but had no impact on cell proliferation and cell cycle progression. In vivo, ARPC1A overexpression promoted lung metastasis of PCa, but had no efffect on tumor growth. Additionally, glutamine metabolism was identified as an upstream regulator of ARPC1A, and promoted migration, invasion and cytoskeletal changes of PCa cell through ARPC1A. Conclusion: These findings suggested that ARPC1A, which correlates with poor prognosis in PCa, functions downstream of glutamine metabolism to regulate cytoskeletal changes, cellular migration and cellular invasion in this disease. [ABSTRACT FROM AUTHOR]

Testicular cancer is the most common solid malignancy among young men. We downloaded data of testicular cancer patients from The Cancer Genome Atlas database to find novel genes in the testicular cancer microenviroment based on ESTIMATE algorithm‐derived immune scores. A total of 156 cases of testicular cancer were included in this study and 165 cases of normal testicular tissues were used. We divided the testicular cancer patients into high‐ and low‐score groups based on their immune scores. We identified 1,226 differentially expressed genes (fold change > 2, false discovery rate < 0.05), including 688 downregulated genes and 538 upregulated genes, between these two groups. The top Gene Ontology terms were involved in the immune response‐regulating cell surface receptor signaling pathway, immune response‐activating cell surface receptor signaling pathway, external side of the plasma membrane, and receptor ligand activity. By performing the Kyoto Encyclopedia of Genes and Genomes analysis, we demonstrated that cAMP signaling pathway was highly enriched among these differentially expressed genes. High expression of LINC01564, LINC02208, ODAM, RNA5SP111, and RNU6‐196P were found to be associated with poor overall survival. The expression of genes was further validated by the Human Protein Atlas and only ALB and IFNG were demonstrated to be differentially expressed between testis tissue and testicular cancer tissue. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer (BCa) is one of the important tumors that have been proven to be treatable with immunotherapy. This study aims to identify and validate a molecular prognostic index of BCa based on immunogenomic landscape analysis. Methods: The cancer genome atlas (TCGA) database and immunology database and analysis portal (ImmPort) database were used to identified differentially expressed immune-related genes (IRGs). Prognostic IRGs were screened and protein–protein interaction (PPI) network was constructed. Multivariate Cox analysis was performed to develop a molecular prognostic index of BCa. Internal and external validation were then performed in TCGA cohort and GEO cohort, respectively. Besides, we also explore the relationship between this index and clinical characteristics, immune cell infiltration and tumor microenvironment. Results: A total of 61 prognostic IRGs were identified and a molecular prognostic index was developed. The top four hub genes included MMP9, IGF1, CXCL12 and PGF. The difference in overall survival between high-risk group and low-risk group was statistically significant. The area under curve of the receiver operating characteristic (ROC) curve was 0.757, suggesting the potential for this index. Besides, Internal validation using TCGA cohort and external validation using GEO cohort indicated that this index was of great performance in predicting outcome. T cells CD8, T cells CD4 memory activated, T cells follicular helper, macrophages M0, macrophages M2 and neutrophils were significantly associated with prognosis of BCa patients. Female, high grade, stage III&IV, N1-3 and T3-4 were associated significantly with higher risk score compared with male, low grade, stage I&II, N0 and T1-2, respectively. High risk score had a positive association with higher stromal score and ESTIMATE score while high risk score had a negative association with tumor purity. Conclusions: This study identified several prognostic immune-related genes of clinical value. Besides, we developed and validated a molecular index based on immunogenomic landscape analysis, which performed well in predicting prognosis of BCa. Further researches are needed to verify the effectiveness of this index and these vital genes. [ABSTRACT FROM AUTHOR]