Novel Flexible Vacuum-Assisted Ureteral Access Sheath Can Actively Control Intrarenal Pressure and Obtain a Complete Stone-Free Status.

Objectives: To compare the safety and effectiveness of a novel flexible vacuum-assisted ureteral access sheath (FV-UAS) and traditional ureteral access sheath (UAS) in simulating retrograde intrarenal surgery (RIRS). Materials and Methods: A manometric model was established in porcine kidneys to observe the change in intrarenal pressure (IRP) in the FV-UAS and traditional UAS groups at different irrigation fluid velocities of 30, 50, 80, and 100 mL/min. Establish a kidney stone model (with 0.2 g, dry, ≤5 mm stones) to simulate RIRS. A total of 20 porcine kidneys were randomly numbered from 1 to 20 (FV-UAS group, 1 - 10; traditional UAS group, 11 - 20). The stone volume clearance rate and operation time were compared between the two groups. ("Stonevolumeclearancerate=1-ResidualstonevolumePreoperativestonevolume×100%"). Stone volume was obtained by CT pre- and postoperatively. Results: FV-UAS can follow flexible ureteroscopy (f-URS) to cross the ureteropelvic junction (UPJ) and into the renal pelvis and calices. FV-UAS can actively make IRP <10 cmH2O by adjusting the negative values at different irrigation fluid velocities. The mean residual stone volume of the FV-UAS vs traditional UAS groups was 33.7 vs 92.5 mm3 (p = 0.017). The mean stone volume clearance rates of the FV-UAS vs traditional UAS groups were 98.5% and 95.9%, respectively (p = 0.017). Seven cases achieved complete stone-free status in the FV-UAS group. All patients had residual fragments postoperatively in the traditional UAS group. Conclusions: FV-UAS can follow f-URS to cross the UPJ and into the renal pelvis and calices, avoiding the interference of UPJ in controlling IRP. FV-UAS can actively control the IRP to be reduced to the desired range by adjusting the negative value under any irrigation fluid velocity. FV-UAS close to the stone can achieve complete stone-free status in RIRS.

Standard versus mini-percutaneous nephrolithotomy for renal stones: a meta-analysis.

OBJECTIVES: To compare the standard percutaneous nephrolithotomy and mini-percutaneous nephrolithotomy in order to determine the optimal tract size for patients with renal stones. METHODS: A systematic search of Web of Science, EMBASE, Cochrane Library, and PubMed databases was conducted for articles published through 20 August 2019, reporting on a comparison of the standard percutaneous nephrolithotomy and mini-percutaneous nephrolithotomy using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Of 763 studies, 14 were considered for the evidence synthesis. A total of 1980 cases were included. Of these patients, 897 cases underwent standard percutaneous nephrolithotomy, and 1083 cases underwent mini-percutaneous nephrolithotomy. Stone-free rates were 87.6% (786 of 897 patients) for standard percutaneous nephrolithotomy and 87.8% (951 of 1083 patients) for mini-percutaneous nephrolithotomy (p = 0.57). Tract sizes of 30F and 22-26F in standard percutaneous nephrolithotomy group shorten operation time compared with mini-percutaneous nephrolithotomy (p = 0.02; p = 0.004; respectively). Leakage (p = 0.04), bleeding (p = 0.01), blood transfusion (p < 0.00001), and renal pelvis perforation (p = 0.02) were more common in standard percutaneous nephrolithotomy group than in mini-percutaneous nephrolithotomy group. Subgroup analysis showed only blood transfusion for 30F and 22-26F standard percutaneous nephrolithotomy group was more common than mini-percutaneous nephrolithotomy (p < 0.0001, p = 0.005, respectively). CONCLUSIONS: Standard percutaneous nephrolithotomy was associated with higher leakage, bleeding, blood transfusion, and renal pelvis perforation, but had a shorter operation time. Tract size of 30F improved the stone-free rate compared with mini-percutaneous nephrolithotomy, but led to more complications. Tract size of 22-26F was no better than 30F or mini-percutaneous nephrolithotomy.

TMSB10 promotes migration and invasion of cancer cells and is a novel prognostic marker for renal cell carcinoma.

OBJECTIVE: The study aims to examine the effect of thymosin ß10 (TMSB10) on renal cell carcinoma (RCC) progression and metastasis. METHODS: Real-time PCR and immunohistochemistry analysis were used to evaluate TMSB10 expression in RCC tissue samples and renal cancer cells. Statistical analyses were applied to investigate the association between TMSB10 expression and the clinicopathological characteristics and prognosis of RCC patients. In vitro migration and invasion assays were performed in 786-O and ACHN cells. RESULTS: The expression of TMSB10 was significantly higher in renal cancer cells and tissues compared with normal kidney cells and tissues. TMSB10 expression was significantly related to tumor stage (P=0.002), lymph node metastasis (P=0.034), and distant metastasis (P=0.039). Kaplan-Meier analysis suggested that high TMSB10 expression was significantly associated with unfavorable overall (P=0.004) and recurrent-free survival (P=0.025) of RCC patients. Furthermore, TMSB10 knockdown inhibited the migration and invasion abilities of renal cancer cells in vitro. CONCLUSION: TMSB10 is overexpressed in RCC and regulates malignant cell metastasis by inducing epithelial-mesenchymal transition, which makes TMSB10 a candidate therapeutic target for RCC.

Musashi1 promotes tumor metastasis and is a prognostic marker for renal carcinoma.

BACKGROUND: Musashi1 (MSI1) has been reported to be involved in cancer development and progression. The biologic role of MSI1 in renal cell carcinoma (RCC), however, remains unknown. METHODS: Expression of MSI1 in normal kidney cells and kidney cancer cells were measured by real-time PCR. In addition, MSI1 expression in 20 paired kidney cancer and non-cancerous tissues were quantified using real-time PCR. Furthermore, the expression of MSI1 in 115 kidney cancer samples was detected to analyze the correlations between MSI1 expression and the clinicopathological features of RCC patients. The biological function of MSI1 on tumor cell invasion and migration were explored through wound healing and transwell migration assays. RESULTS: MSI1 was significantly upregulated in renal cancer cells and tissues compared with normal kidney cells and tissues. High levels of MSI1 were positively associated with tumor stage (P=0.002) and distant metastasis (P=0.013) of RCC patients. Patients with higher MSI1 expression had a significantly poorer overall and recurrence-free survival time (P=0.019 and P=0.012, respectively) than patients with low MSI1 expression. Multivariate analysis showed that MSI1 overexpression was an independent prognostic indicator (P=0.009 and P=0.015, respectively) for the survival of RCC patients. Ablation of MSI1 inhibited the invasion and metastasis of renal cancer cells. CONCLUSION: Our results suggest that MSI1 expression is upregulated in RCC, and that MSI1 plays an important role in promoting cell invasion and metastasis of RCC.

Pioglitazone Protects Against Renal Ischemia-Reperfusion Injury via the AMP-Activated Protein Kinase-Regulated Autophagy Pathway.

Renal ischemia-reperfusion injury (IRI) is a major cause of acute renal failure. Our previous studies have shown that pioglitazone, a peroxisome proliferators-activated receptor (PPAR)-γ agonist used in type 2 diabetes, protects against renal IRI; however, the molecular mechanism underlying the renoprotective effects of pioglitazone is still unclear. In this study, we investigated the role of AMP-activated protein kinase (AMPK)-regulated autophagy in renoprotection by pioglitazone in IRI. To investigate whether pioglitazone protects renal cells from IRI, an in vivo renal IRI model was used. Cell apoptosis in the kidneys was determined by TUNEL staining. Western blotting was used to determine the expression of AMPK, autophagy-related proteins, and caspase-3/8 proteins in the kidneys. In a rat model of IRI, pioglitazone decreased the increased serum creatinine and urea nitrogen, improved renal histological score, and decreased the cell injury. Pioglitazone also increased AMPK phosphorylation, inhibited p62 and cleaved caspase-3/8 proteins, and activated autophagy-related proteins LC3 II and Beclin-1 in the kidneys of IRI rats. Moreover, GW9662, as a selective inhibitor of PPAR-γ, inhibited the protective effects of pioglitazone. These results suggest that pioglitazone exerts its protective effects in renal IRI via activation of an AMPK-regulated autophagy signaling pathway.

Prognostic Implication of Urothelial Stem Cell Markers Differs According to Primary Tumour Location in Non-Muscle-Invasive Bladder Cancer.

BACKGROUND/AIMS: This study aimed to validate the value of urothelial stem cell (USC) markers ΔNp63, integrin ß4, CD47, and CD44v6 in predicting the prognosis of non-muscle invasive bladder cancer (NMIBC) located in different anatomic regions of bladder. METHODS: The study reviewed the clinicopathologic data of 169 patients with NMIBC. Using real-time PCR and immunohistochemistry, the expression of ΔNp63, integrin ß4, CD47, and CD44v6 in archived specimens of patients with NMIBC were validated. Kaplan-Meier analysis and Cox proportional hazards model were used to assess the prognostic impact of USC markers for recurrent-free survival (RFS). RESULTS: The Real-time PCR data showed that the expression of USC markers were higher in tumors located in the trigone and posterior wall than that in other regions of bladder (P< 0.05). Statistical analysis showed that high expression of ΔNp63 was correlated with tumor stage (P=0.023) and tumor size (P=0.001), that high expression of integrin ß4 was correlated with tumor stage (P=0.026), tumor grade (P=0.005) and tumor size (P=0.003), and that high integrin ß4, CD47, and CD44v6 expression were significantly associated with tumor recurrence (P=0.032, P=0.010, and P=0.043, respectively). Moreover, high expression of ΔNp63 and integrin ß4 was correlated with poor RFS in patients with tumors located in the trigone (P=0.025 and P=0.023, respectively). High expression of integrin ß4, CD47, and CD44v6 was correlated with poor RFS in patients with tumors in the posterior wall (P=0.017, P=0.033 and P=0.047, respectively). High expression of integrin ß4 and CD47 was correlated with poor RFS in patients with tumors in the trigone/posterior wall area (P=0.002 and P=0.005, respectively). CONCLUSION: Our results suggest that USC markers are linked with poor prognosis of NMIBC patients, especially in patients with tumors in the trigone and posterior wall.

Fibroblasts from pBOO promote tumorigenesis by secreting TGFbeta1 to induce EMT in bladder urothelial carcinoma cells.

Urinary bladder cancer (UBC) is one of the most common malignancies worldwide. UBC patients at muscle invasive stage have poor clinical outcome, due to high propensity for metastasis. Non-tumor activated fibroblasts, named α-SMA+Fs, is similar to carcinoma-associated fibroblasts (CAFs) which could express α-SMA. However, whether α-SMA+Fs patients could induce UBC cell invasion is unclear. Herein, we found that characterization of primary α-SMA+Fs separated from PBOO (partial bladder outlet obstruction) rats was fell in between normal fibroblasts (α-SMA-Fs) and CAFs. Additionally, the conditional medium from α-SMA+Fs enhanced the NBT-II cell invasion through inducing EMT, and the oncogenic function of mixed supernatant of α-SMA+Fs/CAFs was stronger than that of CAFs. Inhibition of TGF-ß1 by TGF-ß1 neutralizing antibody decreased the EMT-associated gene expression and NBT-II cell invasion, suggesting that α-SMA+Fs can induce tumor EMT through TGF-ß1. Xenograft experiments showed that the tumorigenic effect of α-SMA+Fs in mice was also between CAFs and α-SMA-Fs, and α-SMA+Fs/CAFs also had a strong tumorigenic effect. We preformed rats with PBOO and found that the incidence of invasive bladder cancer in PBOO+BBN group was higher than in BBN group, suggesting the PBOO treatment contributed to tumorigenesis. Thus, α-SMA+Fs promoted tumorigenesis by secreting TGF-ß1 to induce EMT.

Association of increased urine brain derived neurotrophic factor with lower urinary tract symptoms in men with benign prostatic hyperplasia.

Urinary brain-derived neurotrophic factor (BDNF), an ubiquitous neurotrophin, was found to rise in patients with benign prostatic hyperplasia (BPH). We hypothesized that the urinary level of BDNF could be a potential biomarker for lower urinary tract symptoms (LUTS) in patients with BPH. Totally, 76 patients with BPH-caused LUTS and 32 male control subjects without BPH were enrolled. International Prostate Symptom Score (IPSS) was applied to assess the symptom severity of LUTS. Urodynamic tests were performed for the diagnosis of underlying detrusor overactivity (DO) in the patients with BPH. Urine samples were collected from all subjects. Urinary BDNF levels were measured using enzyme-linked immunosorbent assays and normalized by urinary creatinine (Cr) levels. Seventy-six BPH patients were divided into moderate LUTS group (n=51, 720) according to the IPSS. Of the 76 BPH patients, DO was present in 34 (44.7%) according to the urodynamic test. The urinary BDNF/Cr levels were significantly higher in BPH patients with moderate LUTS (8.29±3.635, P<0.0001) and severe LUTS (11.8±6.44, P<0.0001) than normal controls (1.71±0.555). Patients with severe LUTS tended to have higher urinary BDNF/Cr levels than patients with moderate LUTS (11.8±6.44 vs. 8.29±3.635, P=0.000). The conditions of BPH with LUTS correlated with elevated urinary BDNF levels, and urinary BDNF levels were even higher in BPH-DO patients. The results of this study have provided evidence to suggest that urinary BDNF level test could evaluate the severity of LUTS in BPH patients, and BDNF level can be used as a biomarker for the diagnosis of DO in BPH patients.

Inhibition of NEDD4 inhibits cell growth and invasion and induces cell apoptosis in bladder cancer cells.

The neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) plays a pivotal oncogenic role in various types of human cancers. However, the function of NEDD4 in bladder cancer has not been fully investigated. In the present study, we aim to explore whether NEDD4 governs cell proliferation, apoptosis, migration, and invasion in bladder cancer cells. Our results showed that downregulation of NEDD4 suppressed cell proliferation in bladder cancer cells. Moreover, we found that inhibition of NEDD4 significantly induced cell apoptosis. Furthermore, downregulation of NEDD4 retarded cell migration and invasion. Notably, overexpression of NEDD4 enhanced cell growth and inhibited apoptosis. Consistently, upregulation of NEDD4 promoted cell migration and invasion in bladder cancer cells. Mechanically, our Western blotting results revealed that downregulation of NEDD4 activated PTEN and inhibited Notch-1 expression, whereas upregulation of NEDD4 reduced PTEN level and increased Notch-1 level in bladder cancer cells. Our findings indicated that NEDD4 exerts its oncogenic function partly due to regulation of PTEN and Notch-1 in bladder cancer cells. These results further revealed that targeting NEDD4 could be a useful approach for the treatment of bladder cancer.

Combining Protein and miRNA Quantification for Bladder Cancer Analysis.

We combine the telomerase extension reaction and microRNA (miRNA)-induced rolling circle amplification, followed by graphene oxide (GO) and nicking enzyme-assisted signal amplification as a method to analyze telomerase and miRNA-21 in urine samples with the following merits. First, it is a binary assay and can simultaneously output double signals that correspond to the quantities of telomerase and miRNA, respectively. Second, telomerase activity is enhanced by using a DNA molecular beacon probe to inhibit the formation of G-quadruplex. Third, background noise is decreased significantly via introduction of GO. Fourth, performance tests on about 258 urine samples demonstrate that this binary assay can distinguish between urine from bladder cancer patients, those with cystitis, and normal individuals. Finally, this strategy also shows great potential in distinguishing between muscle-invasive bladder cancers and non-muscle-invasive bladder cancers. The proposed strategy will greatly contribute to clinical decision-making and individualized treatments.

Association of Increased Urine Brain Derived Neurotrophic Factor with Lower Urinary Tract Symptoms in Men with Benign Prostatic Hyperplasia / 华中科技大学学报（医学）（英德文版）

Urinary brain-derived neurotrophic factor (BDNF),an ubiquitous neurotrophin,was found to rise in patients with benign prostatic hyperplasia (BPH).We hypothesized that the urinary level of BDNF could be a potential biomarker for lower urinary tract symptoms (LUTS) in patients with BPH.Totally,76 patients with BPH-caused LUTS and 32 male control subjects without BPH were enrolled.International Prostate Symptom Score (IPSS) was applied to assess the symptom severity of LUTS.Urodynamic tests were performed for the diagnosis of underlying detrusor overactivity (DO) in the patients with BPH.Urine samples were collected from all subjects.Urinary BDNF levels were measured using enzyme-linked immunosorbent assays and normalized by urinary creatinine (Cr) levels.Seventy-six BPH patients were divided into moderate LUTS group (n=51,7＜IPSS ≤ 20) and severe LUTS group (n=25,IPSS＞20) according to the IPSS.Of the 76 BPH patients,DO was present in 34 (44.7％)according to the urodynamic test.The urinary BDNF/Cr levels were significantly higher in BPH patients with moderate LUTS (8.29±3.635,P＜0.0001) and severe LUTS (11.8±6.44,P＜0.0001) than normal controls (1.71±0.555).Patients with severe LUTS tended to have higher urinary BDNF/Cr levels than patients with moderate LUTS (11.8±6.44 vs.8.29±3.635,P=0.000).The conditions of BPH with LUTS correlated with elevated urinary BDNF levels,and urinary BDNF levels were even higher in BPH-DO patients.The results of this study have provided evidence to suggest that urinary BDNF level test could evaluate the severity of LUTS in BPH patients,and BDNF level can be used as a biornarker for the diagnosis of DO in BPH patients.

High expression of constitutive photomorphogenic 1 (COP1) is associated with poor prognosis in bladder cancer.

The present study was to investigate the expression and prognostic value of constitutive photomorphogenic 1 (COP1) in bladder cancer. In our study, real-time quantitative PCR (RT-PCR) was performed to detect 10 pairs of fresh bladder cancer (BCa) and adjacent noncancerous tissues. In addition, immunohistochemistry was utilized to detect the expression of COP1 in 174 clinical bladder cancer samples. What is more, the correlation of COP1 expression and clinicopathological features and clinical outcomes were analyzed. The expression levels of COP1 in clinical bladder cancer were much higher than that in paired adjacent noncancerous tissues (p < 0.0001). High expression of COP1 was closely related with differentiation (p = 0.040) and recurrence (p = 0.001) of patients with bladder cancer. Kaplan-Meier analysis revealed that the expression of COP1 was closely correlated with overall survival (p = 0.048) of bladder cancer, while, recurrence-free survival (p = 0.201). Moreover, Cox multivariate regression analyses showed that COP1 expression was an independent predictor of overall survival (OS; p = 0.027, hazard ratio = 2.127, confidence interval 0.814 to 9.736). Based on our data, the present study suggests that high expression of COP1 may be a novel biological indicator for evaluation of poor prognosis in bladder cancer.