Troglitazone is a synthetic ligand of peroxisome proliferators activated receptor-γ (PPARγ) and induces apoptosis in a variety of malignant cells. However, the underlying mechanism of its regulator...

While the somatic mutation profiles of renal cell carcinoma (RCC) have been revealed by several studies worldwide, the overwhelming majority of those were not derived from Chinese patients. The landscape of somatic alterations in RCC from Chinese patients still needs to be elucidated to determine whether discrepancies exist between Chinese patients and sufferers from other countries and regions. We collected specimens from 26 Chinese patients with primary RCC, including 15 clear cell renal cell carcinoma (ccRCC) samples, 5 papillary renal cell carcinoma (PRCC) samples and 6 chromophobe renal cell carcinoma (ChRCC) samples. Genomic DNAs were isolated from paired tumor-normal tissues and subjected to whole exome sequencing (WES). Immunohistochemistry analysis was performed to detect the programmed death ligand 1 (PD-L1) expression in tumor tissues. A total of 1920 nonsynonymous somatic variants in exons and 86 mutations at splice junctions were revealed. The tumor mutation burden of ccRCC was significantly higher than that of ChRCC (P < 0.05). For both ccRCC and PRCC, the most frequent substitution in somatic missense mutations was T:A > A:T, which was different from that recorded in the COSMIC database. Among eight significantly mutated genes in ccRCC in the TCGA database, six genes were verified in our study including VHL (67%), BAP1 (13%), SETD2 (13%), PBRM1 (7%), PTEN (7%) and MTOR (7%). All the mutations detected in those genes had not been reported in ccRCC before, except for alterations in VHL and PBRM1. Regarding the frequently mutated genes in PRCC in our study, DEPDC4 (p.E293A, p.T279A), PNLIP (p.N401Y, p.F342L) and SARDH (p.H554Q, p.M1T) were newly detected gene mutations predicted to be deleterious. As the most recurrently mutated gene in ChRCC in the TCGA dataset, TP53 (p.R81Q) was somatically altered only in one ChRCC case in this study. The HIF-1 signaling pathway was the most affected pathway in ccRCC, while the PI3K-Akt signaling pathway was altered in all of the three RCC types. Membranous PD-L1 expression was positive in tumor cells from 6/26 (23%) RCC specimens. The PD-L1-positive rate was higher in RCC samples with the somatically mutated genes CSPG4, DNAH11, INADL and TMPRSS13 than in specimens without those (P < 0.05). Using WES, we identified somatic mutations in 26 Chinese patients with RCC, which enriched the racial diversity of the somatic mutation profiles of RCC subjects, and revealed a few discrepancies in molecular characterizations between our study and published datasets. We also identified numerous newly detected somatic mutations, which further supplements the somatic mutation landscape of RCC. Moreover, 4 somatically mutated genes, including CSPG4, DNAH11, INADL and TMPRSS13, might be promising predictive factors of PD-L1-positive expression in RCC tumor cells.

The molecular mechanism underlying epidermal growth factor receptor (EGFR) localization in mitochondria remains largely unknown. Using immune electron microscopy, we validated that EGFR could be localized on either the outer or the inner membrane of mitochondria. Mutant receptor lacked amino acids 646–660 was flawed in migration onto the organelles, whereas the mutated receptor with a defective endocytosis showed a greater capability of moving onto mitochondria upon stimulation of epidermal growth factor (EGF). Gefitinib, an inhibitor of EGFR kinase, inhibited the receptor endocytosis after short time of treatment, yet, only reduced cell viability as well as the amount of mitochondrial EGFR after longer time of exposure. Moreover, the content of mitochondrial EGFR transfer was decreased when the cells were exposed to the apoptotic inducer etoposide. EGF-induced programmed cell death usually coincided with a decline in mitochondrial EGFR. These data indicated that the mitochondrial-localized EGFR is independent of its internalization and may be correlated with cell survival and participate in the ligand-induced programmed cell death.

Sunitinib (ST), a multitargeted receptor tyrosine kinase inhibitor, has been demonstrated to be effective for the treatment of renal carcinoma. It has been reported that ST is involved in the mediation of autophagy; however, its regulatory role in the autophagic process remains controversial. Furthermore, the mechanism by which activated AMP-activated protein kinase (AMPK) negatively regulates autophagy remains nearly unexplored. In the present study, we revealed that ST inhibited AMPK activity and regulated autophagy in a cell type- and dose-dependent manner. In a number of cell lines, ST was demonstrated to inhibit H₂O₂-induced autophagy and the phosphorylation of acetyl-CoA carboxylase (ACC), whereas alone it could block the autophagic flux concurrent with increased expression of p62. An immunoprecipitation assay revealed that LC3 directly interacted with p62, whereas ST increased punctate LC3 staining, which was well colocalized with p62. Taken together, we reveal a previously unnoticed pathway for ST to regulate the autophagic process, and p62, although often utilized as a substrate in autophagy, plays a critical role in regulating the inhibition of ST in both basal and induced autophagy.

Objectives: To compare perioperative and oncologic survival outcomes between laparoscopic radical cystectomy and open radical cystectomy.Methods: A total of 607 patients underwent open radical cystectomy (n = 412) or laparoscopic radical cystectomy (n = 195) at a single academic institution from January 2006 to April 2017. Their medical records were retrospectively analyzed. One‐to‐one propensity score matching was carried out to reduce selection bias. Estimated blood loss and complications were compared. Overall survival, cancer‐specific survival and progression‐free survival estimates for all patients and patients with locally advanced bladder cancer were analyzed using the Kaplan–Meier method.Results: Either before or after matching, the laparoscopic radical cystectomy group had less estimated blood loss (P < 0.001 and P < 0.001) and fewer complications (P < 0.001 and P = 0.008). There was no difference in the overall survival (P = 0.216 and P = 0.961) and progression‐free survival (P = 0.826 and P = 0.462) for all the patients having either laparoscopic radical cystectomy or open radical cystectomy. However, the 5‐year progression‐free survival of open radical cystectomy was higher than that of laparoscopic radical cystectomy (P = 0.019 and P = 0.021) for patients with locally advanced bladder cancer.Conclusions: Laparoscopic radical cystectomy is superior to open radical cystectomy in terms of perioperative outcomes, and similar to open radical cystectomy in terms of oncologic outcomes for patients with early stage bladder cancer. However, for patients with locally advanced bladder cancer, laparoscopic radical cystectomy seems to be associated with shorter progression‐free survival than open radical cystectomy.

There is no criterion for determining whether female patients operated with cystectomy would benefit from hysterectomy. This study compares the oncological outcomes between female patients receiving uterus preserving cystectomy (UPC) and uterus excision cystectomy (UEC). Retrospective review of 121 female patients with urothelial carcinoma of bladder undergoing UPC (n = 63) or UEC (n = 49) at a single institute between January 2006 and April 2017. Individual postoperative follow-up plans were performed for patients through outpatient visits. Overall survival (OS) and progression-free survival (PFS) estimates were analyzed using Kaplan-Meier method and multivariable Cox regression. The median follow-up time was 36 months (interquartile range 16–69). Among patients, 5 (4.1%) had uterus invasion. OS probability (p = 0.939) and PFS probability (p = 0.565) were similar in two groups. In multivariable Cox regression analysis, hysterectomy was not found to be a predictor of OS (hazard ratio 0.908, 95%CI 0.428–1.924, p = 0.801) and PFS (hazard ratio 1.109, 95%CI 0.439–2.805, p = 0.826) after adjusting for age, preoperative clinical stage, pathological stage, pathological nodal stage, neoadjuvant/adjuvant chemotherapy, location of the tumor, and surgical margin. No significant difference of overall survival probability was observed in the patients with organ-confined bladder cancer (p = 0.675) and in patients with no organ-confined bladder cancer (p = 0.695). The results showed that the rate of uterus invasion was low in patients analyzed in this cohort. It was also found that hysterectomy was not an independent predictor of OS and PFS after radical cystectomy in patients with bladder cancer.