Zhenli Gao

Relevance and therapeutic possibility of PTEN-long in renal cell carcinoma.

PTEN-Long is a translational variant of PTEN (Phosphatase and Tensin Homolog). Like PTEN, PTEN-Long is able to antagonize the PI3K-Akt pathway and inhibits tumor growth. In this study, we investigated the role PTEN-Long plays in the development and progression of clear cell renal cell carcinoma (ccRCC) and explored the therapeutic possibility using proteinaceous PTEN-Long to treat ccRCC. We found that the protein levels of PTEN-Long were drastically reduced in ccRCC, which was correlated with increased levels of phosphorylated Akt (pAkt). Gain of function experiments showed overexpression of PTEN-Long in the ccRCC cell line 786-0 suppressed PI3K-Akt signaling, inhibited cell proliferation, migration and invasion, and eventually induced cell death. When purified PTEN-Long was added into cultured 786-0 cells, it entered cells, blocked Akt activation, and induced apoptosis involving Caspase 3 cleavage. Furthermore, PTEN-Long inhibited proliferation of 786-0 cells in xenograft mouse model. Our results implicated that understanding the roles of PTEN-Long in renal cell carcinogenesis has therapeutic significance.

Impact of age on the cancer-specific survival of patients with localized renal cell carcinoma: martingale residual and competing risks analysis.

Background Age at diagnosis has been shown to be an independent prognostic factor of localized renal cell carcinoma (RCC) in several studies. We used contemporary statistical methods to reevaluate the effect of age on the cancer-specific survival (CSS) of localized RCC. Methods and Findings 1,147 patients with localized RCC who underwent radical nephrectomy between 1993 and 2009 were identified in our four institutions. The association between age and CSS was estimated, and the potential threshold was identified by a univariate Cox model and by martingale residual analysis. Competing risks regression was used to identify the independent impact of age on CSS. The median age was 52 years (range, 19–84 years). The median follow-up was 61 months (range, 6–144 months) for survivors. A steep increasing smoothed martingale residual plot indicated an adverse prognostic effect of age on CSS. The age cut-off of 45 years was most predictive of CSS on univariate Cox analysis and martingale residual analysis (p = 0.005). Age ≤45 years was independently associated with a higher CSS rate in the multivariate Cox regression model (HR = 1.59, 95% CI = 1.05–2.40, p = 0.027) as well as in competing risks regression (HR = 3.60, 95% CI = 1.93–6.71, p = 0.001). Conclusions Increasing age was associated with a higher incidence of cancer-specific mortality of localized RCC. Age dichotomized at 45 years would maximize the predictive value of age on CSS, and independently predict the CSS of patients with localized RCC.

PUMA decreases the growth of prostate cancer PC-3 cells independent of p53

PUMA (p53 upregulated modulator of apoptosis), a member of the B-cell lymphoma 2 (Bcl-2) protein family, is a pro-apoptotic protein. PUMA expression is modulated by the tumor suppressor p53. PUMA has a role in rapid cell death via p53-dependent and -independent mechanisms. To evaluate whether p53 is required for PUMA-mediated apoptosis in prostate cancer cells, p53 protein was silenced in human prostate cancer PC-3 cells by using p53 small interfering RNA (siRNA). The interference efficiency of p53 on RNA and protein levels was detected by reverse transcription-quantitative polymerase chain reaction and western blotting. Cell proliferation and p21 expression were subsequently examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and western blot analysis, respectively. p53-silenced or control PC-3 cells were transfected with pCEP4-(hemagglutinin)-PUMA plasmid, or non-carrier plasmid. Enzyme-linked immunosorbent assay was used to determine cell apoptosis by measuring histone release and caspase-3 activation, and MTT assay was used to measure cell viability. In addition, the expression of pro-apoptosis protein Bax and anti-apoptosis protein Bcl-2 were evaluated. The results of the present study revealed that p53 siRNA significantly suppressed p53 RNA and protein expression in PC-3 cells. Deficiency of p53 increased the cell growth rate and decreased p21 expression. However, PUMA overexpression remained able to induce apoptosis in p53-silenced and control cells by increasing Bax expression and decreasing Bcl-2 expression, leading to the activation of caspase-3. These results suggest that PUMA may mediate apoptosis of prostate cancer PC-3 cells, potentially independently of p53. Furthermore, PUMA gene treatment to induce cancer cell apoptosis may be more efficient compared with p53-dependent apoptosis, where loss of p53 expression or function may lead to limited efficacy of PUMA expression. Therefore, the present study proposes the significant hypothesis that increasing PUMA expression may be an effective approach for the treatment of prostate cancer, regardless of p53 status.

Knockdown of Mediator Complex Subunit 19 Suppresses the Growth and Invasion of Prostate Cancer Cells

Prostate cancer (PCa) is one of the most common cancers in elderly men. Mediator Complex Subunit 19 (Med19) is overexpressed and plays promotional roles in many cancers. However, the roles of Med19 in PCa are still obscure. In this study, by using immunohistochemical staining, we found higher expression level of Med19 in PCa tissues than in adjacent benign prostate tissues. We then knocked down the Med19 expression in PCa cell lines LNCaP and PC3 by using lentivirus siRNA. Cell proliferation, anchor-independent growth, migration, and invasion were suppressed in Med19 knockdown PCa cells. In nude mice xenograft model, we found that Med19 knockdown PCa cells formed smaller tumors with lower proliferation index than did control cells. In the mechanism study, we found that Med19 could regulate genes involved in cell proliferation, cell cycle, and epithelial-mesenchymal transition, including P27, pAKT, pPI3K, IGF1R, E-Cadherin, N-Cadherin, Vimentin, ZEB2, Snail-1 and Snail-2. Targeting Med19 in PCa cells could inhibit the PCa growth and metastasis, and might be a therapeutic option for PCa in the future.

Meta-Analysis of the Efficacy and Safety of Mirabegron Add-On Therapy to Solifenacin for Overactive Bladder

Purpose We performed a meta-analysis to evaluate the efficacy and safety of mirabegron add-on therapy to solifenacin for patients with overactive bladder (OAB). Methods We conducted a systematic literature review to identify all randomized, double-blind, controlled trials (RCTs) of this combination (mirabegron and solifenacin) for OAB. Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched. A manual search was also performed to investigate relevant references from the retrieved studies. Results Four publications describing 5 RCTs that compared combination therapy with solifenacin, including a total of 3,309 patients, were analyzed. The mean number of micturitions per 24 hours (mean difference [MD], -0.45; 95% confidence interval [CI], -0.65 to -0.26; P<0.00001), number of episodes of incontinence per 24 hours (MD, -0.71; 95% CI, -0.14 to -0.02; P=0.04), volume voided per micturition, and number of urgency episodes per 24 hours demonstrated that combination therapy was more effective than solifenacin therapy alone. Safety assessments, including common treatment-emergent adverse events (odds ratio, 1.09; 95% CI, 0.95–1.27; P=0.23) and discontinuations due to adverse events (P=0.30), demonstrated that the combination therapy was well tolerated. Conclusions This meta-analysis suggests that mirabegron therapy as an add-on to solifenacin provides a satisfactory therapeutic effect for OAB symptoms with a low occurrence of side effects.

Clinical Significance of Peripheral Blood PCA3 Gene Expression in Early Diagnosis of Prostate Cancer

Prostate cancer antigen 3 (PCA3) is one of the most promising genes currently investigated as a specific tumor biomarker for the diagnosis of prostate cancer. The purpose of this study was to investigate PCA3 gene expression in peripheral blood of prostate cancer (PCa) and benign prostate hyperplasia (BPH), and further to assess its clinical significance. We determined the copies of PCA3 mRNA in peripheral blood of PCa and BPH from 115 samples (PCa, n = 78; BPH, n = 37) using a quantitative reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) with TaqMan assay. The sensitivity and specificity of PCA3 for the diagnosis of prostate cancer was compared with that of prostate-specific antigen (PSA) by receiver operating characteristic (ROC) curve analysis. To evaluate the association between PCA mRNA and disease progression, we analyzed PCA3 levels in connection with Gleason score and TNM stage of PCa. The clinical data revealed that expression of PCA3 gene was significantly higher in PCa than in BPH. Moreover, PCA3 mRNA was significantly higher in PCa patients with a Gleason score ≥8 than in those with a Gleason score ≤7 (P < .01). The results showed that the area under the curve (AUC) was 0.790, 0.606, and 0.620 for the copy number of PCA3, PSA level, and significantly free PSA (fPSA) level, respectively. Increased PCA3 in peripheral blood is correlated with PCa, and the detection of PCA3 may significantly reduce adverse screening outcomes. PCA3 gene expression in peripheral blood had a promising clinical application in the early diagnosis of PCa.

Effects of increased Kindlin-2 expression in bladder cancer stromal fibroblasts

Kindlin-2 is a focal adhesion protein highly expressed in bladder cancer stromal fibroblasts. We investigated the prognostic significance of Kindlin-2 in bladder cancer stromal fibroblasts and evaluated the effects of Kindlin-2 on the malignant behaviors of tumor cells. Immunohistochemical staining of 203 paraffin-embedded bladder cancer tissues showed that Kindlin-2 expression correlated with advanced stage, high grade, and relapse of bladder cancer. Kaplan-Meier survival analysis demonstrated that patients exhibiting high Kindlin-2 expression had shorter survival times than those with low Kindlin-2 expression (p < 0.01). Multivariate analysis revealed that high Kindlin-2 expression leads to poor prognosis in bladder cancer. Using cancer-associated fibroblasts (CAFs) isolated from human bladder cancer tissue, we observed that Kindlin-2 knockdown decreased CAFs activation, resulting in decreased expression of α-smooth muscle actin (α-SMA) and the extracellular matrix protein fibronectin. Kindlin-2 suppression also reduced CAF-induced bladder cancer cell migration and invasion. Moreover, we found that Kindlin-2 activates CAFs and promotes the invasiveness of bladder cancer cells by stimulating TGF-β-induced epithelial-mesenchymal transition. These results support targeting Kindlin-2 and the corresponding activated CAFs in bladder cancer therapy.Kindlin-2 is a focal adhesion protein highly expressed in bladder cancer stromal fibroblasts. We investigated the prognostic significance of Kindlin-2 in bladder cancer stromal fibroblasts and evaluated the effects of Kindlin-2 on the malignant behaviors of tumor cells. Immunohistochemical staining of 203 paraffin-embedded bladder cancer tissues showed that Kindlin-2 expression correlated with advanced stage, high grade, and relapse of bladder cancer. Kaplan-Meier survival analysis demonstrated that patients exhibiting high Kindlin-2 expression had shorter survival times than those with low Kindlin-2 expression (p < 0.01). Multivariate analysis revealed that high Kindlin-2 expression leads to poor prognosis in bladder cancer. Using cancer-associated fibroblasts (CAFs) isolated from human bladder cancer tissue, we observed that Kindlin-2 knockdown decreased CAFs activation, resulting in decreased expression of α-smooth muscle actin (α-SMA) and the extracellular matrix protein fibronectin. Kindlin-2 suppression also reduced CAF-induced bladder cancer cell migration and invasion. Moreover, we found that Kindlin-2 activates CAFs and promotes the invasiveness of bladder cancer cells by stimulating TGF-β-induced epithelial-mesenchymal transition. These results support targeting Kindlin-2 and the corresponding activated CAFs in bladder cancer therapy.

Inguinal incision as a successful route to extract the kidney during laparoscopic retroperitoneal live-donor nephrectomy.

OBJECTIVES We sought to evaluate the advantages of an inguinal incision in extracting the kidney during retroperitoneal laparoscopic live-donor nephrectomy. MATERIALS AND METHODS From May 2008 to June 2011, fifty-eight cases of retroperitoneal live-donor nephrectomy were performed at our hospital; all data were analyzed retrospectively. All donors were grouped in a test group (n=32, inguinal incision) or a control group (n=26, lumbar incision) according to the selected graft retrieval incision. Donors were compared with regard to operative time and warm ischemia time, operative blood loss, hospital stay, cosmetic satisfaction, and incision complications. RESULTS All 58 cases of retroperitoneal live-donor nephrectomy were successfully accomplished, without donor death, serious complications, and conversion to open surgery. There were no differences in mean operative time, mean blood loss, mean warm ischemic time, graft function, and 1-year graft survival rate between the groups. However, in a test group, the mean hospital stay was shorter (P < .01), and the satisfaction with cosmesis was higher (P < .01). The incidence rates of abdomen asymmetry (9/28), incision hernia (4/28), wound infection (5/28), and wound faulty union (6/28) were higher in the control group than they were in the test group. CONCLUSIONS Inguinal incision is a safe and practical graft retrieval incision in retroperitoneal laparoscopic donor nephrectomy and can be generally applied.

Meta-analysis of the efficacy and safety of mirabegron and solifenacin monotherapy for overactive bladder.

We conducted a meta‐analysis to evaluate the safety and efficacy of mirabegron (50 mg) and solifenacin (5 mg) monotherapy for overactive bladder (OAB) during a 12‐week cycle.

Application of enhanced recovery after surgery in patients undergoing radical cystectomy

Objective This study was performed to evaluate the application of enhanced recovery after surgery (ERAS) in patients undergoing radical cystectomy (RC). Methods The clinical data of 192 patients who underwent RC were collected in this retrospective cohort study. Among them, 91 patients who underwent ERAS were allocated to the ERAS group, and the remaining 101 patients who underwent traditional postoperative care procedures were allocated to the non-ERAS group. Perioperative indexes in the two groups were compared. The ERAS components included rehabilitation exercise, carbohydrate fluid loading, cessation of nasogastric tubes, omission of oral bowel preparation, regional local anesthesia, body-warming procedures, reduced drainage use, and early postoperative drinking and eating. Results The times from RC to first water intake, first ambulation, first anal exhaust, first defecation, and pelvic drainage tube removal were significantly shorter and the hospitalization costs were significantly lower in the ERAS than non-ERAS group. The intraoperative blood loss volume, blood transfusion rate, readmission rate, and incidence of postoperative complications were also significantly lower in the ERAS than non-ERAS group. Conclusion ERAS may effectively accelerate patient rehabilitation and reduce the length of stay, incidence of postoperative complications, readmission rates, and hospitalization costs for patients undergoing RC.