The clinicopathologic and molecular features, and treatment outcome of fumarate hydratase-deficient renal cell carcinoma: a retrospective comparison with type 2 papillary renal cell carcinoma.

BACKGROUND: To compare clinicopathologic, molecular features, and treatment outcome between fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) and type 2 papillary renal cell carcinoma (T2 pRCC). METHODS: Data of T2 pRCC patients and FH-dRCC patients with additional next-generation sequencing information were retrospectively analyzed. The cancer-specific survival (CSS) and disease-free survival (DFS) were primary endpoint. RESULTS: A combination of FH and 2-succino-cysteine (2-SC) increased the rate of negative predictive value of FH-dRCC. Compared with T2 pRCC cases, FH-dRCC cases displayed a greater prevalence in young patients, a higher frequency of radical nephrectomy. Seven FH-dRCC and two T2 pRCC cases received systemic therapy. The VEGF treatment was prescribed most frequently, with an objective response rate (ORR) of 22.2% and a disease control rate (DCR) of 30%. A combined therapy with VEGF and checkpoint inhibitor reported an ORR of 40% and a DCR of 100%. FH-dRCC cases showed a shortened CSS (P = 0.042) and DFS (P < 0.001). The genomic sequencing revealed 9 novel mutations. CONCLUSIONS: Coupled with genetic detection, immunohistochemical biomarkers (FH and 2-SC) can distinguish the aggressive FH-dRCC from T2 pRCC. Future research is awaited to illuminate the association between the novel mutations and the clinical phenotypes of FH-dRCC in the disease progression.

Development and validation of a nomogram for predicting the impact of tumor size on cancer-specific survival of locally advanced renal cell carcinoma: a SEER-based study.

This study was aimed to integrate tumor size with other prognostic factors into a prognostic nomogram to predict cancer-specific survival (CSS) in locally advanced (≥pT3a Nany M0) renal cell carcinoma (RCC) patients. Based on the Surveillance, Epidemiology, and End Results (SEER) database, 10,800 patients diagnosed with locally advanced RCC were collected. They were randomly divided into a training cohort (n = 7,056) and a validation cohort (n = 3,024). X-tile program was used to identify the optimal cut-off value of tumor size and age. The cut-off of age at diagnosis was 65 years old and 75 years old. The cut-off of tumor size was 54 mm and 119 mm. Univariate and multivariate Cox regression analyses were performed in the training cohort to identify independent prognostic factors for construction of nomogram. Then, the nomogram was used to predict the 1-, 3- and 5-year CSS. The performance of nomogram was evaluated by using concordance index (C-index), area under the Subject operating curve (AUC) and decision curve analysis (DCA). Moreover, the nomogram and tumor node metastasis (TNM) staging system (AJCC 8th edition) were compared. 10 variables were screened to develop the nomogram. The area under the receiver operating characteristic (ROC) curve (AUC) indicated satisfactory ability of the nomogram. Compared with the AJCC 8th edition of TNM stage, DCA showed that the nomogram had improved performance. We developed and validated a nomogram for predicting the CSS of patients with locally advanced RCC, which was more precise than the AJCC 8th edition of TNM staging system.

P2X2 receptors in pyramidal neurons are critical for regulating vulnerability to chronic stress.

Rationale: Stress is a major risk factor for the development of depression. However, the underlying molecular mechanisms of stress vulnerability in depression are largely uncharacterized. Methods: P2X2 receptors (a major receptor for gliotransmitter-ATP) in the medial prefrontal cortex (mPFC) were identified by real-time qPCR, western blots and RNAscope in situ hybridization in chronic social defeat stress model (CSDS). We generated P2X2 conditional knockout mice and overexpressed AAV-P2X2 in CamkIIα-Cre mice. The depression-like behaviors were assessed via CSDS, subthreshold social defeat stress (SSDS), social interaction test (SI), forced interaction test (FIT), forced swimming test (FST), sucrose preference test (SPT), novel stressed feeding (NSF) and open field test (OFT). The neuronal activity and synapse function of P2X2 receptors in the mPFC were detected by in vivo fiber-photometry, patch-clamp techniques and neuronal morphometric analysis. Results: We identified that P2X2 receptors were increased in the mPFC of susceptible mice in CSDS. Conditional knockout of P2X2 receptors in pyramidal neurons promoted resilience of chronic stress-induced depressive-like behaviors, whereas pyramidal neurons - specific gain of P2X2 in the mPFC increased vulnerability to depressive-like behaviors. In vivo fiber-photometry, electrophysiology and neuronal morphometric analysis showed P2X2 receptors regulated neuronal activity and synapse function in the mPFC. Conclusions: Overall, our studies reveal a critical role of P2X2 in mediating vulnerability to chronic stress and identify P2X2 as a potential therapeutic target for treatment of stress-related mood disorders.

OTUB1-mediated deubiquitination of FOXM1 up-regulates ECT-2 to promote tumor progression in renal cell carcinoma.

BACKGROUND: OTUB1 (ovarian tumor domain protease domain-containing ubiquitin aldehyde-binding proteins)-mediated deubiquitination of FOXM1 (Forkhead box M1) participates in carcinogenesis of various tumors. We aim to investigate the effect and mechanism of OTUB1/FOXM1 on RCC (renal cell carcinoma) progression. Expression levels of OTUB1 in RCC tissues and cell lines were examined by qRT-PCR (quantitative real-time polymerase chain reaction) and immunohistochemistry. Cell proliferation was measured with CCK8 (Cell Counting Kit-8) and colony formation assays. Wound healing and transwell assays were used to determine cell migration and invasion, respectively. The effect of OTUB1 on FOXM1 ubiquitination was examined by Immunoprecipitation. Western blot was used to uncover the underlying mechanism. In vivo subcutaneous xenotransplanted tumor model combined with immunohistochemistry and western blot were used to examine the tumorigenic function of OTUB1. RESULTS: OTUB1 was up-regulated in RCC tissues and cell lines, and was associated with poor prognosis of RCC patients. Knockdown of OTUB1 inhibited cell viability and proliferation, as well as migration and invasion of RCC cells. Mechanistically, knockdown of OTUB1 down-regulated FOXM1 expression by promoting its ubiquitination. Down-regulation of FOXM1 inhibited ECT2 (epithelial cell transforming 2)-mediated Rho signaling. Moreover, the inhibition of RCC progression caused by OTUB1 knockdown was reversed by FOXM1 over-expression. In vivo subcutaneous xenotransplanted tumor model also revealed that knockdown of OTUB1 could suppress in vivo RCC growth via down-regulation of FOXM1-mediated ECT2 expression. CONCLUSIONS: OTUB1-mediated deubiquitination of FOXM1 up-regulates ECT-2 to promote tumor progression in RCC, providing a new potential therapeutic target for RCC treatment.

MiR-193b inhibits the growth and metastasis of renal cell carcinoma by targeting IGF1R.

Objective: To explore the effects of miR-193b on cell proliferation, migration, invasion and tumourigenicity of renal cell carcinoma, and the underlying molecular mechanisms. Methods: The expression of miR-193b and IGF1R was detected by quantitative real-time polymerase chain reaction (qRT-PCR). MTT assay was used to detect cell viability. The migration and invasion abilities were measured by transwell assay. Western blot was used to detect the protein expression of IGF1R. Murine xenograft model was established using Caki-1cells transfected with miR193b. Results: The expression of miR-193b was significantly down-regulated in renal cell carcinoma tissues and cells while the expression of IGF1R was obvious increased in tissues. Overexpression miR-193b or knockdown of IGF1R significantly inhibited the abilities of cells proliferation, migration and invasion in renal cell carcinoma. MiR-193b directly targeted IGF1R and inhibited its expression in vitro and vivo. Up-regulation miR-193b inhibits cells proliferation, migration and invasion of renal cell carcinoma by targeting IGF1R. In addition, overexpression miR-193b significantly inhibited tumour growth in nude mice. Conclusion: miR-193b can inhibit the growth and metastasis of renal cell carcinoma by targeting decreasing IGF1R expression, which provides a new target for the prevention and treatment of renal cell carcinoma.

Real-Time Ultrasound-Guided Percutaneous Nephrolithotomy Using Newly Developed Wireless Portable Ultrasound: A Single-Center Experience.

OBJECTIVES: To assess the feasibility and utility of a newly developed wireless portable ultrasound "UProbe- 2" for puncture guidance in percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: The UProbe-2 consists of a probe with integrated ultrasound circuit boards inside, an intelligent terminal that installed specific ultrasound software, and a puncture trestle. The probe can connect to an intelligent terminal via WI-FI. It was used to guide puncture in PCNL in 31 patients who suffered kidney stones or large impacted proximal upper ureteral stones with hydronephrosis from June 2016 to July 2017. Patients' characteristics as well as parameters during operation were collected. RESULTS: PCNL was successfully performed in all patients with the guidance of the UProbe-2. The mean (standard deviation) puncture time was 3.6 (0.9) minutes, and the median operative duration was 50 (35-80) minutes. The primary stone clearance rate was 87% (27/31). No major intraoperative or postoperative complications occurred. CONCLUSION: The UProbe-2 ultrasound is safe and effective for puncture guidance during PCNL according to this initial study. It could provide a new and alternative choice for guidance of PCNL. However, more clinical trials especially randomized controlled trials should be performed.

Computer tomography urography assisted real-time ultrasound-guided percutaneous nephrolithotomy on renal calculus.

This study aimed to assess the role of pre-designed route on computer tomography urography (CTU) in the ultrasound-guided percutaneous nephrolithotomy (PCNL) for renal calculus.From August 2013 to May 2016, a total of 100 patients diagnosed with complex renal calculus in our hospital were randomly divided into CTU group and control group (without CTU assistance). CTU was used to design a rational route for puncturing in CTU group. Ultrasound was used in both groups to establish a working trace in the operation areas. Patients' perioperative parameters and postoperative complications were recorded.All operations were successfully performed, without transferring to open surgery. Time of channel establishment in CTU group (6.5 ±â€Š4.3 minutes) was shorter than the control group (10.0 ±â€Š6.7 minutes) (P = .002). In addition, there was shorter operation time, lower rates of blood transfusion, secondary operation, and less establishing channels. The incidence of postoperative complications including residual stones, sepsis, severe hemorrhage, and perirenal hematoma was lower in CTU group than in control group.Pre-designing puncture route on CTU images would improve the puncturing accuracy, lessen establishing channels as well as improve the security in the ultrasound-guided PCNL for complex renal calculus, but at the cost of increased radiation exposure.

Leporin B: a novel hexokinase II gene inducing agent from an unidentified fungus.

Leporin B (1), a novel demethylated analogue of leporin A (2), was isolated from a taxonomically unidentified fungal strain as part of an effort to discover compounds with the ability to increase expression levels of the enzyme hexokinase II. The structure was determined by spectral methods, including 1D and 2D NMR, and HRMS. The relative stereochemistry was assigned by NOESY experiments and coupling constants.

The hepatitis C virus (HCV)-Trimera mouse: a model for evaluation of agents against HCV.

The lack of small-animal models that are suitable for evaluation of agents used to treat infection with hepatitis C virus (HCV) severely hinders the assessment of potential new therapies for the disease. This study created such a model, termed the "HCV-Trimera" model. The HCV-Trimera model was developed by using lethally irradiated mice, reconstituted with SCID mouse bone marrow cells, in which human liver fragments infected ex vivo with HCV had been transplanted. Viremia (positive-strand HCV RNA levels) in HCV-Trimera mice peaked at approximately day 18 after liver transplantation, and an infection rate of 85% was reached. Viral replication in liver grafts was evidenced by the presence of specific negative-strand HCV RNA. The usefulness of this model for evaluation of anti-HCV agents was demonstrated by the ability of a small molecule (an HCV internal ribosomal entry site inhibitor) and an anti-HCV human monoclonal antibody (HCV AB(XTL)68) to reduce virus loads in HCV-Trimera mice in a dose-dependent manner.