Increasing evidence suggests that autophagy plays a major role during renal fibrosis. Transcription factor EB (TFEB) is a critical regulator of autophagy- and lysosome-related gene transcription. However, the pathophysiological roles of TFEB in renal fibrosis and fine-tuned mechanisms by which TFEB regulates fibrosis remain largely unknown. Here, we found that TFEB was downregulated in unilateral ureteral obstruction (UUO)-induced human and mouse fibrotic kidneys, and kidney-specific TFEB overexpression using recombinant AAV serotype 9 (rAAV9)-TFEB in UUO mice alleviated renal fibrosis pathogenesis. Mechanically, we found that TFEB's prevention of extracellular matrix (ECM) deposition depended on autophagic flux integrity and its subsequent blockade of G2/M arrest in tubular cells, rather than the autophagosome synthesis. In addition, we together RNA-seq with CUT&Tag analysis to determine the TFEB targeted gene ATP6V0C, and revealed that TFEB was directly bound to the ATP6V0C promoter only at specific site to promote its expression through CUT&Run-qPCR and luciferase reporter assay. Interestingly, TFEB induced autophagic flux integrity, mainly dependent on scaffold protein ATP6V0C-mediated autophagosome-lysosome fusion by bridging with STX17 and VAMP8 (major SNARE complex) by co-immunoprecipitation analysis, rather than its mediated lysosomal acidification and degradation function. Moreover, we further investigated the underlying mechanism behind the low expression of TEFB in UUO-induced renal fibrosis, and clearly revealed that TFEB suppression in fibrotic kidney was due to DNMT3a-associated TFEB promoter hypermethylation by utilizing methylation specific PCR (MSP) and bisulfite-sequencing PCR (BSP), which could be effectively recovered by 5-Aza-2'-deoxycytidine (5A-za) to alleviate renal fibrosis pathogenesis. These findings reveal for the first time that impaired TFEB-mediated autophagosome-lysosome fusion disorder, tubular cell G2/M arrest and renal fibrosis appear to be sequentially linked in UUO-induced renal fibrosis and suggest that DNMT3a/TFEB/ATP6V0C may serve as potential therapeutic targets to prevent renal fibrosis.

Background: Combining immune checkpoint inhibitors with chemotherapy can synergistically improve antitumor activity and are generally well tolerated. Recently, the efficacy and safety of combination therapy has been demonstrated for many cancers, including urothelial carcinomas. The aim of this retrospective pilot study was to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line adjuvant treatment for locally advanced or metastatic bladder cancer. Methods: We conducted a retrospective analysis of 31 patients with locally advanced or metastatic bladder cancer from December 2020 to January 2022 with an Eastern Cooperative Oncology Group performance status of 0/1. Of the 31 patients, 14 patients received tislelizumab (200 mg i.v. every 3 weeks, Q3W) plus 21 days cycles of chemotherapy (gemcitabine, 1000 mg/m² i.v. on days 1 and 8 of each cycle + cisplatin, 70 mg/m² i.v. on day 2 of each cycle) (TGC) treatment and 17 patients received gemcitabine plus cisplatin chemotherapy (GC) treatment. All patients treated with bladder cytoreductive surgery and were treated for four 21 days cycles until disease progression or intolerable treatment-related adverse events (TRAEs). The objective progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR) and TRAEs were recorded and reviewed. Results: As of the cut-off date (March 25, 2022), PFS, OS, ORR, DCR, CBR and TRAEs were evaluated in 14 patients receiving combination therapy and 17 patients in the chemotherapy alone group. The median PFS was 36.0 [95% confidence interval (CI) 33.1–38.9] weeks in the TGC group and 29.0 (95% CI 25.4–32.6) weeks in the GC group [hazard ratio (HR) 0.15 (95% CI 0.04–0.55)]. In the GC group, the median OS was 48.0 (95% CI 39.7–56.3) weeks; the median OS was not yet mature for the TGC group [HR 0.26 (95% CI 0.07–0.94)]. Treatment with TGC resulted in improved DCR (TGC 71.4%; GC 65.0%) and CBR (TGC 64.3%; GC 52.9%) compared with GC. However, although higher incidences of grade ≥ 3 TRAEs were observed with TGC compared with GC (35.7% vs 23.5%), the difference was not statistically significant (p = 0.47). Conclusion: This study suggested that TGC provided survivors of locally advanced or metastatic bladder cancer with encouraging antitumor activity and was generally well tolerated.

Prostate cancer (PCa) is one of the most common cancers among men globally. The authors aimed to evaluate the ability of the Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) to classify men with PCa, clinically significant PCa (CSPCa), or no PCa, especially among those with serum total prostate-specific antigen (tPSA) levels in the “gray zone” (4–10 ng ml⁻¹). A total of 308 patients (355 lesions) were enrolled in this study. Diagnostic efficiency was determined. Univariate and multivariate analyses, receiver operating characteristic curve analysis, and decision curve analysis were performed to determine and compare the predictors of PCa and CSPCa. The results suggested that PI-RADS v2, tPSA, and prostate-specific antigen density (PSAD) were independent predictors of PCa and CSPCa. A PI-RADS v2 score ≥4 provided high negative predictive values (91.39% for PCa and 95.69% for CSPCa). A model of PI-RADS combined with PSA and PSAD helped to define a high-risk group (PI-RADS score = 5 and PSAD ≥0.15 ng ml^-1 cm^-3, with tPSA in the gray zone, or PI-RADS score ≥4 with high tPSA level) with a detection rate of 96.1% for PCa and 93.0% for CSPCa while a low-risk group with a detection rate of 6.1% for PCa and 2.2% for CSPCa. It was concluded that the PI-RADS v2 could be used as a reliable and independent predictor of PCa and CSPCa. The combination of PI-RADS v2 score with PSA and PSAD could be helpful in the prediction and diagnosis of PCa and CSPCa and, thus, may help in preventing unnecessary invasive procedures.

Background: The kidney is a target organ that could be infected by SARS-CoV-2, and acute kidney injury (AKI) was associated with a higher risk of COVID-19 patients' in-hospital death. However, no published works discussed about the risk factors of COVID-19 related AKI. Methods: We conducted a retrospective cohort study, recruiting COVID-19 inpatients from the Sino-French branch of Tongji Hospital. Demographic, clinical, treatment, and laboratory data were collected and compared. We used univariable and multivariable logistic regression methods to identify the risk factors of COVID-19-related AKI. Results: Of the 116 patients in our study, 12 (10.3%) were recognized as AKI, including 5 (4.3%) in-hospital AKI. Multivariable regression showed increasing odds of COVID-19-related AKI associated with COVID-19 clinical classification (OR = 8.155, 95% CI = 1.848–35.983, ref = non-critical, p = 0.06), procalcitonin more than 0.1 ng/mL (OR = 4.822, 95% CI = 1.095–21.228, p = 0.037), and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² (OR = 13.451, 95% CI = 1.617–111.891, p = 0.016). Conclusions: COVID-19-related AKI was likely to be related to multiorgan failure rather than the kidney tropism of SARS-CoV-2. The potential risk factors of COVID-19 clinical classification, procalcitonin more than 0.1 ng/mL, and eGFR <60 mL/min/1.73 m² could help clinicians to identify patients with kidney injury at an early stage.

Ki-67 index and percentage of sarcomatoid differentiation were two independent prognostic predictors in sarcomatoid renal cell carcinoma Zhixian Wang,1 Xiaoyong Zeng,1,2 Ruibao Chen,1 Zhiqiang Chen1,2 1Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; 2Hubei Institute of Urology, Wuhan, China Purpose: To identify whether and which of pathological features of sarcomatoid differentiation (SD) in renal cell carcinoma (RCC) can be used as independent predictors associated with overall survival (OS).Materials and methods: After institutional review board approval, patients with a diagnosis of sarcomatoid RCC (sRCC), spindled RCC, or RCC with the presence of spindle cells between 2003 and 2017 were further selected and re-examined. The primary pathological features including histological subtypes, tumor necrosis, Ki-67 index of SD, and the percent of SD (%SD) were included into analysis. Histological subtypes were categorized into clear-cell RCC and nonclear-cell RCC. Ki-67 index of SD was confirmed by immunohistochemical staining. %SD was estimated through reviewing all of the tumor sections microscopically and then giving an approximate %SD within the entire tumor. The clinical relevant prognostic predictor’s association with OS was analyzed within Cox proportional hazards regression models. Survival curves were generated using the Kaplan–Meier method, and OS differences were compared using the log-rank test.Results: A total of 2,089 consecutive patients of RCC were referred to our department, of whom 62 (3.0%) patients were identified with histological element of SD after re-examining the available slides of suspicious cases. Finally, 53 patients were included into survival analysis after excluding 9 patients without adequate information. Thirty-eight (71.7%) patients died at last follow-up. The median OS for all patients was 11.0 months from the date of surgery. In patients with clinical distant metastasis (cM1), the median OS was only 3 compared with 21 months for patients with no clinical distant metastasis (cM0). Tumor stage, status of clinical distant metastasis, Ki-67 index, and %SD were independent predictors of multivariate analysis in overall 53 patients. However, in the cohort of cM0 patients, we found that only %SD and Ki-67 index were two independent predictors of OS in multivariate analysis.Conclusion: Patients with sRCC are associated with very poor prognosis. Ki-67 index of SD and %SD were identified as the two most important independent predictors particularly for nonmetastatic patients. The limitations of our study were also observed, and further studies are needed. Keywords: sarcomatoid renal cell carcinoma, nephrectomy, Ki-67, percentage, survival

Objective: More T1N0M0 renal cell carcinoma (RCC) is detected and the prognosis has improved, but, the current focus on non-RCC-related mortality is superficial. We investigated cause-specific mortality and its temporal patterns after an RCC diagnosis.Methods: In the Surveillance, Epidemiology, and End Results-18 database, patients with T1N0M0 RCC treated with partial nephrectomy (PN) or radical nephrectomy (RN) during 2000–15 were identified. Standardized mortality ratios (SMRs) for cause of death were calculated. Risk predictors for each cause-specific mortality were investigated using the Fine and Gray sub-distribution model.Results: In all, 68,612 eligible patients were pooled. A total of 14,047 (20.5%) patients had died (cardiovascular disease [CVD], 28.3%; other non-cancer-related diseases, 20.3%; RCC, 18.7%; other cancer types, 16.3%; non-disease events, 16.1%) during follow-up. Heart disease, diabetes mellitus, and cerebrovascular disease were the primary causes of non-RCC-related mortality within 1 year after the diagnosis. The greatest proportion of death (39.0%) occurred within 1–5 years after the diagnosis, mostly due to RCC itself, followed by heart disease. However, >5 years after the diagnosis, heart disease became the leading cause of death. Compared with the general US population, a 21% (SMR, 1.21; 95%CI 1.19–1.23) increased risk of all-mortality was observed; RCC patients had a higher risk of heart disease-related death within 5–10 years (SMR, 1.10; 95%CI 1.04–1.17) and >10 years (1.12; 1.02–1.22) after the diagnosis. Older age and RN increased the death risk of CVD and RCC-specific mortality. Although a larger tumor diameter increased the risk of RCC-specific death, this was not a significant predictor for CVD. Moreover, for T1N0M0 RCC tumors of diameter >4 cm, there was no significant difference in CVD incidence for RN vs. PN.Conclusions: RCC-specific mortality is a common challenge for the prognosis. Importantly, a large proportion and higher SMRs of other non-RCC-related diseases (especially CVD) should not be disregarded for the better holistic management of survivors of local RCC. Targeted prevention strategies for non-RCC-related death could lead to significant reductions in mortality for RCC survivors.