Qianyuan Zhuang

Rapamycin regulates Akt and ERK phosphorylation through mTORC1 and mTORC2 signaling pathways

Numerous studies have shown that mammalian target of rapamycin (mTOR) inhibitor activates Akt signaling pathway via a negative feedback loop while inhibiting mTORC1 signaling. In this report, we focused on studying the role of mTORC1 and mTORC2 in rapamycin‐mediated Akt and ERK phosphorylation, and the antitumor effect of rapamycin in cancer cells in combination with Akt and ERK inhibitors. Moreover, we analyzed the effect of mTORC1 and mTORC2 on regulating cell cycle progression. We found that low concentrations rapamycin increased Akt and ERK phosphorylation through a mTORC1‐dependent mechanism because knockdowned raptor induced the activation of Akt and ERK, but higher doses of rapamycin inhibited Akt and ERK phosphorylation mainly via the mTORC2 signaling pathway because that the silencing of rictor led to the inhibition of Akt and ERK phosphorylation. We further showed that mTORC2 was tightly associated with the development of cell cycle through an Akt‐dependent mechanism. Therefore, we combined PI3K and ERK inhibitors prevent rapamycin‐induced Akt activation and enhanced antitumor effects of rapamycin. Collectively, we conclude that mTORC2 plays a much more important role than mTORC1 in rapamycin‐mediated phosphorylation of Akt and ERK, and cotargeting AKT and ERK signaling may be a new strategy for enhancing the efficacy of rapamycin‐based therapeutic approaches in cancer cells.

Microwave ablation versus partial nephrectomy for small renal tumors: Intermediate-term results†

Prospective randomized comparison of intermediate‐term outcomes of patients with small renal tumors who were treated with partial nephrectomy (PN) or microwave ablation.

Laparoscopic versus Open Radical Cystectomy in Bladder Cancer: A Systematic Review and Meta-Analysis of Comparative Studies

Background and Objective More recently laparoscopic radical cystectomy (LRC) has increasingly been an attractive alternative to open radical cystectomy (ORC) and many centers have reported their early experiences in the treatment of bladder cancer. Evaluate the safety and efficacy of LRC compared with ORC in the treatment of bladder cancer. Methods A systematic search of Medline, Scopus, and the Cochrane Library was performed up to Mar 1, 2013. Outcomes of interest assessing the two techniques included demographic and clinical baseline characteristics, perioperative, pathologic and oncological variables, and post-op neobladder function and complications. Results Sixteen eligible trials evaluating LRC vs ORC were identified including seven prospective and nine retrospective studies. Although LRC was associated with longer operative time (p<0.001), patients might benefit from significantly fewer overall complications (p<0.001), less blood loss (p<0.001), shorter length of hospital stay (p<0.001), less need of blood transfusion (p<0.001), less narcotic analgesic requirement (p<0.001), shorter time to ambulation (p = 0.03), shorter time to regular diet (p<0.001), fewer positive surgical margins (p = 0.006), fewer positive lymph node (p = 0.05), lower distant metastasis rate (p = 0.05) and fewer death (p = 0.004). There was no significant difference in other demographic parameters except for a lower ASA score (p = 0.01) in LRC while post-op neobladder function were similar between the two groups. Conclusions Our data suggest that LRC appears to be a safe, feasible and minimally invasive alternative to ORC with reliable perioperative safety, pathologic & oncologic efficacy, comparable post-op neobladder function and fewer complications. Because of the inherent limitations of the included studies, further large sample prospective, multi-centric, long-term follow-up studies and randomized control trials should be undertaken to confirm our findings.

Costimulatory molecule B7-H1 on the immune escape of bladder cancer and its clinical significance

B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in tumor immune escape by inducing T-cell apoptosis. In order to investigate the relationship between B7-H1 and immune escape of bladder cancer, B7-H1 expression in 50 cases of bladder cancer was detected by using immunohistochemical method. Survival curves were constructed using the Kaplan-Meier method and independent prognostic factors were evaluated using the Cox regression model. Our results showed that the positive rate of B7-H1 immunostaining in normal bladder tissue and bladder cancer was 0 and 72% respectively. The expression of B7-H1 was strongly associated with the pathological grade, clinical stage and recurrence (P<0.05). The survival rate was significantly lower in patients with B7-H1 positive group than in those with B7-H1 negative group and multi-variable analysis revealed that B7-H1 could be regarded as an independent factor in evaluating the prognosis of bladder cancer. It is concluded that the expression of B7-H1 is strongly associated with neoplastic progression and prognosis of bladder cancer. The manipulation of B7-H1 may become a beneficial target for immunotherapy in human bladder cancer.SummaryB7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in tumor immune escape by inducing T-cell apoptosis. In order to investigate the relationship between B7-H1 and immune escape of bladder cancer, B7-H1 expression in 50 cases of bladder cancer was detected by using immunohistochemical method. Survival curves were constructed using the Kaplan-Meier method and independent prognostic factors were evaluated using the Cox regression model. Our results showed that the positive rate of B7-H1 immunostaining in normal bladder tissue and bladder cancer was 0 and 72% respectively. The expression of B7-H1 was strongly associated with the pathological grade, clinical stage and recurrence (P<0.05). The survival rate was significantly lower in patients with B7-H1 positive group than in those with B7-H1 negative group and multi-variable analysis revealed that B7-H1 could be regarded as an independent factor in evaluating the prognosis of bladder cancer. It is concluded that the expression of B7-H1 is strongly associated with neoplastic progression and prognosis of bladder cancer. The manipulation of B7-H1 may become a beneficial target for immunotherapy in human bladder cancer.

Initial Experience with Retroperitoneoscopic Microwave Ablation of Clinical T1a Renal Tumors

PURPOSE To evaluate the feasibility, safety, and efficacy of retroperitoneoscopic microwave ablation (MWA) for clinical stage T(1a) (cT(1a)) renal tumors. PATIENTS AND METHODS Consecutive renal cell carcinomas (RCCs) managed since April 2006 with a minimal follow-up of 12 months were included. A total of 23 tumors in 22 patients were managed with laparoscopic MWA. A cooled shaft needle antenna was inserted into the tumor under direct visual guidance. Microwaves were emitted at 50 W for 8 minutes and prolonged as necessary to ensure complete tumor kill. Short-term efficacy was assessed by contrast-enhanced CT at 1, 3, and 6 months, and every 6 months thereafter. RESULTS Pathologic analysis revealed low-grade clear-cell RCC in all patients. Mean tumor size was 2.8 cm (range 0.9-4.0 cm). Excluding 5 lost patients, the initial ablation was successful in 17 (94.4%) of 18 tumors. One patient with an incomplete ablation lesion under strict surveillance had no evidence of disease progression at 31 months of follow-up. No recurrence was observed at a median follow-up of 20 months (range 12-45 mos). All 17 remaining patients had no clinical or radiographic evidence of disease at last follow-up. In addition, complications were mild and tolerable (18.2%), and there was no significant deterioration of renal function. CONCLUSIONS Retroperitoneoscopic MWA appears to be a safe and effective technique for cT(1a) RCC in selected patients. Additional follow-up is needed to assess long-term effectiveness.

Comparison of the Proliferation, Viability, and Differentiation Capacity of Adipose-Derived Stem Cells from Different Anatomic Sites in Rabbits

Tissue engineering is clinically promising for missing and damaged tissues. Adipose-derived stem cells (ASCs), a type of mesenchymal stem cells, represent a reliable source of seed cells for tissue engineering with multiple merits such as minimal invasion, abundant yield, little immunity, low morbidity, easy isolation, and rapid expansion. However, because the properties of adipose tissue-derived cells differ depending on the fat depot from which they are derived, we compared the ASCs from three anatomic sites of New Zealand white rabbits: subcutaneous inguinal (SI), subcutaneous dorsocervical (SD), and retroperitoneal perinephric (RP) regions. We investigated cellular behaviors including proliferation, viability, and differentiation. The ASCs of the subcutaneous regions (SI and SD) had higher performances in all assessments compared to those of the RP region. Moreover, the SI and SD ASCs had significant differences, with SI ASCs having better properties than SD ASCs. We conclude that the different anatomic distributions of fat contribute to the different behaviors of ASCs. The SI region offers the most applicable cell source reservoir for ASC tissue engineering.

Restoration of LRIG1 suppresses bladder cancer cell growth by directly targeting EGFR activity

BackgroundRecently, leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), a negative regulator of EGFR, was discovered is a novel agent for suppressing bladder cancer. The aim of this study was to investigate the impact of LRIG1 on the biological features of aggressive bladder cancer cells and the possible mechanisms of enhanced apoptosis induced by upregulation of LRIG1.MethodsIn this study, we examined the mRNA and protein expression of LRIG1 and EGFR in bladder cancers and normal bladder. Meanwhile, we overexpressed LRIG1 with adenovirus vector in T24/5637 bladder cancer cell lines, and we used real time-PCR, western blot, and co-immunoprecipitation analysis in order to examine the effects of LRIG1 gene on EGFR. Furthermore, we evaluate the impact of LRIG1 gene on the function of human bladder cancer cells and EGFR signaling.ResultsThe expression of LRIG1 was decreased, while the expression of EGFR was increased in the majority of bladder cancer, and the ratio of EGFR/LRIG1 was increased in tumors versus normal tissue. We found that upregulation of LRIG1 induced cell apoptosis and cell growth inhibition, and further reversed invasion in bladder cancer cell lines in vitro by inhibiting phosphorylation of downstream MAPK and AKT signaling pathway.ConclusionTaken together, our findings provide us with an insight into LRIG1 function, and we conclude that LRIG1 evolved in bladder cancer as a rare feedback negative attenuator of EGFR, thus could offer a novel therapeutic target to treat patients with bladder cancer.

A Modified Ureteroileal Anastomosis Technique for Bricker Urinary Diversion

OBJECTIVE Up to 10% of patients who have undergone the Bricker ileal conduit urinary diversion may develop ureteroileal anastomotic complications that are more frequently associated with the left side ureter. We have therefore modified the standard Bricker ileal conduit technique to minimize the anastomotic complications associated with the left side ureter. MATERIALS AND METHODS In our modification, the proximate end of the ileal conduit was brought from the right side to the left under the mesosigmoid in an isoperistaltic fashion. The left ureter that remained in the natural extraperitoneal location was anastomosed to the ileal segment in the usual end-to-side fashion without the need of extensive ureteral dissection. RESULTS A series of 42 patients have undergone ileal conduit urinary diversion using this modified technique. During a median follow-up period of 18.6 months, this technique was found to have no associated major perioperative complications and early- and intermediate-term ureteroileal anastomotic complications from both sides of the ureters. CONCLUSION Our modified ileal conduit diversion technique was easy and safe to perform, and may serve as an alternative technique for the standard Bricker ileal conduit urinary diversion, especially when the left distal ureter was involved extensively with urothelial carcinoma.

VEGF pathway-targeted therapy for advanced renal cell carcinoma: A meta-analysis of randomized controlled trials

SummaryImmunotherapy which has been in practice for more than 20 years proves effective for the treatment of metastatic renal cell carcinoma (mRCC). Anti-angiogenesis-targeted therapy has recently been identified as a promising therapeutic strategy for mRCC. This study was aimed to evaluate the effectiveness of vascular endothelial growth factor (VEGF) pathway-targeted therapy for mRCC by comparing its effectiveness with that of immunotherapy. The electronic databases were searched. Randomized controlled trials (RCTs) on comparison of VEGF inhibiting drugs (sorafenib, sunitinib and bevacizumab) with interferon (IFN) or placebo for mRCC treatment were included. Data were pooled to meta-analyze. A total of 7 RCTs with 3451 patients were involved. The results showed that anti-VEGF agents improved progression-free survival (PFS) and offered substantial clinical benefits to patients with mRCC. Among them, sunitinib had a higher overall response rate (ORR) than IFN (47% versus 12%, P<0.000001). Bevacizumab plus IFN produced a superior PFS [risk ratio (RR): 0.86, 95% confidence interval (CI): 0.76–0.97; P=0.01] and ORR (RR: 2.19; 95% CI: 1.72–2.78; P<0.00001) in patients with mRCC over IFN, but it yielded an increase by 31% in the risk of serious toxic effects (RR: 1.31; 95% CI: 1.20–1.43; P<0.00001) as compared with IFN. The overall survival (OS) was extended by sorafenib (17.8 months) and sunitinib (26.4 months) as compared with IFN (13 months). It was concluded that compared with IFN therapy, VEGF pathway-targeted therapies improved PFS and achieved significant therapeutic benefits in mRCC. However, the risk to benefit ratio of these agents needs to be further evaluated.Immunotherapy which has been in practice for more than 20 years proves effective for the treatment of metastatic renal cell carcinoma (mRCC). Anti-angiogenesis-targeted therapy has recently been identified as a promising therapeutic strategy for mRCC. This study was aimed to evaluate the effectiveness of vascular endothelial growth factor (VEGF) pathway-targeted therapy for mRCC by comparing its effectiveness with that of immunotherapy. The electronic databases were searched. Randomized controlled trials (RCTs) on comparison of VEGF inhibiting drugs (sorafenib, sunitinib and bevacizumab) with interferon (IFN) or placebo for mRCC treatment were included. Data were pooled to meta-analyze. A total of 7 RCTs with 3451 patients were involved. The results showed that anti-VEGF agents improved progression-free survival (PFS) and offered substantial clinical benefits to patients with mRCC. Among them, sunitinib had a higher overall response rate (ORR) than IFN (47% versus 12%, P<0.000001). Bevacizumab plus IFN produced a superior PFS [risk ratio (RR): 0.86, 95% confidence interval (CI): 0.76–0.97; P=0.01] and ORR (RR: 2.19; 95% CI: 1.72–2.78; P<0.00001) in patients with mRCC over IFN, but it yielded an increase by 31% in the risk of serious toxic effects (RR: 1.31; 95% CI: 1.20–1.43; P<0.00001) as compared with IFN. The overall survival (OS) was extended by sorafenib (17.8 months) and sunitinib (26.4 months) as compared with IFN (13 months). It was concluded that compared with IFN therapy, VEGF pathway-targeted therapies improved PFS and achieved significant therapeutic benefits in mRCC. However, the risk to benefit ratio of these agents needs to be further evaluated.

Prognostic significance of lymphovascular invasion in bladder cancer after surgical resection: A meta-analysis.

Bladder cancer remains a commonly diagnosed malignancy worldwide, bringing huge economic burden and high morbidity for patients. Assessment of prognostic significance of lymphovascular invasion (LVI) is a critical issue in the surgical management of bladder cancer after transurethral resection or radical cystectomy. A systematic search of PubMed, Embase and Cochrane Library was performed up to Oct 10, 2014 to identify eligible studies. Outcomes of interest were collected from studies comparing overall survival (OS), cancer specific survival (CSS) and recurrence free survival (RFS) in patients with the LVI. Results of studies were pooled, and combined hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for survival were used as the effect size estimation. Funnel plots were done to show the publication bias, while the forest plots and subgroup analyses were used to limit the heterogeneity. A total of 20 studies (10 663 patients) met the eligibility criteria and were included for this meta-analysis. Our pooled results showed that there were significant differences in OS (pooled HR, 1.71; 95%CI, 1.52–1.92; P<0.00001), CSS (pooled HR, 2.25; 95% CI, 1.80–2.81; P<0.00001) and RFS (pooled HR, 1.91; 95% CI, 1.57–2.32; P<0.00001) between the patients with LVI and the patients without LVI. There were significant heterogeneities observed in the studies concerning the relationship between LVI and CSS, RFS. There was no clear evidence of publication bias. When tumor stage was beyond T3, LVI lost its predictive value for CSS and RFS. For the patients who had negative lymph nodes, LVI was still an adverse predictor. Our pooled results demonstrate that LVI indicates poor prognosis of patients with bladder cancer after surgical procedures, and it can be of particular importance in clinical practice. However, these results need to be further confirmed by more adequately designed prospective studies.SummaryBladder cancer remains a commonly diagnosed malignancy worldwide, bringing huge economic burden and high morbidity for patients. Assessment of prognostic significance of lymphovascular invasion (LVI) is a critical issue in the surgical management of bladder cancer after transurethral resection or radical cystectomy. A systematic search of PubMed, Embase and Cochrane Library was performed up to Oct 10, 2014 to identify eligible studies. Outcomes of interest were collected from studies comparing overall survival (OS), cancer specific survival (CSS) and recurrence free survival (RFS) in patients with the LVI. Results of studies were pooled, and combined hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for survival were used as the effect size estimation. Funnel plots were done to show the publication bias, while the forest plots and subgroup analyses were used to limit the heterogeneity. A total of 20 studies (10 663 patients) met the eligibility criteria and were included for this meta-analysis. Our pooled results showed that there were significant differences in OS (pooled HR, 1.71; 95%CI, 1.52–1.92; P<0.00001), CSS (pooled HR, 2.25; 95% CI, 1.80–2.81; P<0.00001) and RFS (pooled HR, 1.91; 95% CI, 1.57–2.32; P<0.00001) between the patients with LVI and the patients without LVI. There were significant heterogeneities observed in the studies concerning the relationship between LVI and CSS, RFS. There was no clear evidence of publication bias. When tumor stage was beyond T3, LVI lost its predictive value for CSS and RFS. For the patients who had negative lymph nodes, LVI was still an adverse predictor. Our pooled results demonstrate that LVI indicates poor prognosis of patients with bladder cancer after surgical procedures, and it can be of particular importance in clinical practice. However, these results need to be further confirmed by more adequately designed prospective studies.