Shimiao Zhu

Androgen Deprivation Therapy for Prostate Cancer Is Associated with Cardiovascular Morbidity and Mortality: A Meta-Analysis of Population-Based Observational Studies

Background There is no consensus regarding whether androgen deprivation therapy (ADT) is associated with cardiovascular disease (CVD) and cardiovascular mortality (CVM). The objective of this study was to determine the role of ADT for prostate cancer (PCa) in development of cardiovascular events (CVD and CVM). Methods and Findings We performed a meta-analysis from population-based observational studies comparing ADT vs control aimed at treating PCa in patients with PCa, reporting either CVD or CVM as outcome. Publications were searched using Medline, Embase, Cochrane Library Central Register of observational studies database up to May 31th 2014, and supplementary searches in publications from potentially relevant journals. 6 studies were identified with a total of 129,802 ADT users and 165,605 controls investigating the relationship between ADT and CVD. The incidence of CVD was 10% higher in ADT groups, although no significant association was observed (HR = 1.10, 95%CIs: 1.00–1.21; P = 0.06). For different types of ADT, CVD was related with gonadotropin-releasing hormone (GnRH) (HR = 1.19, 95%CIs: 1.04–1.36; P<0.001) and GnRH plus oral antiandrogen (AA) (HR = 1.46, 95%CIs: 1.03–2.08; P = 0.04), but not with AA alone or orchiectomy. For CVM, 119,625 ADT users and 150,974 controls from 6 eligible studies were included, pooled results suggested that ADT was associated with CVM (HR = 1.17, 95%CIs: 1.04–1.32; P = 0.01). Significantly increased CVM was also detected in GnRH and GnRH plus AA groups. When patients received other treatments (e.g. prostatectomy and radiotherapy) were ruled out of consideration, more increased CVD (HR = 1.19, 95%CIs: 1.08–1.30; P<0.001) and CVM (HR = 1.30, 95%CIs: 1.13–1.50; P<0.001) were found in men treated with ADT monotherapy. Conclusions ADT is associated with both CVD and CVM. Particularly, GnRH alone and GnRH plus AA can significantly increase the incidence of cardiovascular events in patients with PCa.

Risk Factors and Prevention of Inguinal Hernia After Radical Prostatectomy: A Systematic Review and Meta-Analysis

PURPOSE Inguinal hernia is widely recognized as a complication after radical prostatectomy. We systematically investigated the risk factors for inguinal hernia, compared the incidence after various surgical procedures and explored prophylactic surgical maneuvers. MATERIALS AND METHODS A systematic search of the literature was performed using Medline®, Web of Knowledge® and the Cochrane Library databases. All analyses and tests were conducted using STATA® software. RESULTS A total of 31 trials from 29 eligible studies were identified according to the predefined selection criteria. As integrated, postoperative inguinal hernia developed in 15.9% (13.1-18.7) of patients who underwent radical retropubic prostatectomy and 6.7% (4.8-8.6) of those who underwent laparoscopic radical prostatectomy. Most cases of inguinal hernia occurred within the first 2 years after surgery. Right side and indirect-type dominance was found in those inguinal hernias. Pooled results of comparative studies revealed that the incidence of inguinal hernia after radical retropubic prostatectomy was significantly higher than that after no operation, laparoscopic surgery, radical perineal prostatectomy, mini-laparotomy radical retropubic prostatectomy and pelvic lymph node dissection, but was not significantly higher than that after open prostatectomy and cystectomy. In addition, increasing age, low body mass index, subclinical inguinal hernia, previous inguinal hernia repair and anastomotic stricture can increase the risk for inguinal hernia after radical prostatectomy. CONCLUSIONS While some limitations cannot be overcome, this meta-analysis suggests that damage to the posterior layer of the rectus sheath may be involved in the development of inguinal hernia after radical prostatectomy. Prophylactic surgery for high risk subjects is advised at the time of radical prostatectomy to minimize the incidence of inguinal hernia.

Germline Homeobox B13 (HOXB13) G84E Mutation and Prostate Cancer Risk in European Descendants: A Meta-analysis of 24 213 Cases and 73 631 Controls

Next-generation sequencing technologies may provide new opportunities to discover disease-related variants through interrogating large genomic intervals in a rapid and comprehensive manner. Through scanning >200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with familial prostate cancer (PCa), Ewing et al. [1] identified a rare but recurrent mutation (G84E) in homeobox B13 (HOXB13) (rs138213197), a homeobox transcription factor gene that is important in prostate development. In an attempt to confirm and expand the findings by Ewing et al., we completed a meta-analysis of HOXB13 G84E mutation in men of European lineage across different geographic regions who had PCa. We undertook a systematic literature review with search terms (see Supplementary Table 1) and hand-searched online journals without language restriction. We restricted the search to Medline, Embase, Web of Science, and the Cochrane Library. The last quest was updated on January 3, 2013. Bibliographies of relevant retrieved studies and recent reviews were also scanned for additional publications. Studies were included if they fulfilled the following criteria: (1) Patients were pathologically verified to have adenocarcinoma of the prostate, (2) the control group consisted of subjects who were men and were free of PCa, (3) the studies were prospective or retrospective case– control studies, and (4) the studies were investigating the association of germline HOXB13 G84E mutation with PCa risk as the main outcome. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses [2] and Meta-analysis of Observational Studies in Epidemiology [3] guidelines. The effect estimates of choice were odds radio (OR) for dichotomous variables and the corresponding 95% confidence intervals (CIs). The random effects model of DerSimonian and Laird was prespecified for use in overall estimates because of the apriority that studies were from different populations and had different designs (eg, population-based, family-based compared with hospital-based case–control studies). The departure of frequencies from those expected under HardyWeinberg equilibrium was assessed by x goodness-of-fit

HoxB3 promotes prostate cancer cell progression by transactivating CDCA3

Homeobox (Hox) genes encode homeodomain-containing transcription factors critical to development, differentiation, and homeostasis. Their dysregulation has been implicated in various cancers. In the present study, we show that HoxB3 mRNA and protein are overexpressed in primary prostate cancer tissues compared to the adjacent normal prostate tissues. Moreover, HoxB3 overexpression is associated with higher Gleason grade (⩾7) (P=0.002), clinical stage (P<0.001) and PSA level (⩾10) (P=0.013). The Kaplan and Meier analysis showed that HoxB3 overexpression predicts poor survival outcome. Overexpression of HoxB3 promotes LNCaP cells proliferation and migration in vitro. Furthermore, depletion of HoxB3 in PC-3 cells decreased the capacity of proliferation in a cell division cycle associated 3 (CDCA3)-dependent manner both in vitro and in vivo. The ChIP analysis indicates that HoxB3 can bind to the CDCA3 promoter region and transactivate the CDCA3 expression. These data suggested that HoxB3 promote prostate cancer progression by upregulating CDCA3 expression and may serve as a potential therapeutic target for human prostate cancer.

Optimal schedule of bacillus calmette-guerin for non-muscle-invasive bladder cancer: a meta-analysis of comparative studies

BackgroundTo explore the necessity of maintenance, efficacy of low-dose and superiority of various combination therapies of Bacillus Calmette-Guérin (BCG) in treatment of superficial bladder cancer (BCa).MethodsComprehensive searches of electronic databases (PubMed, Embase, and the Cochrane Library) were performed, then a systematic review and cumulative meta-analysis of 21 randomized controlled trials (RCTs) and 9 retrospective comparative studies were carried out according to predefined inclusion criteria.ResultsSignificantly better recurrence-free survivals (RFS) were observed respectively in patients who received BCG maintenance, standard-dose and BCG plus epirubicin therapy comparing to those received induction, low-dose and BCG alone. BCG maintenance therapy was also associated with significantly better progression-free survival (PFS), but there were more incidences of adverse events. Pooled results showed no remarkable advantage of BCG combined with Mitomycin C or with interferon α-2b in improving oncologic outcomes. Sensitivity-analyses stratified by study-design and tumor stage led to very similar overall results and often to a decrease of the between-study heterogeneity. Our data confirmed that non-RCT only affected strength rather than direction of the overall results.ConclusionsAll patients with superficial BCa should be encouraged to accept BCG maintenance therapy with standard-dose if well tolerated. Patients can benefit from BCG combined with epirubicin but not from BCG combined with Mitomycin C or interferon α-2b.

Androgen receptor enhances entosis, a non‐apoptotic cell death, through modulation of Rho/ROCK pathway in prostate cancer cells

Cell‐in‐cell phenomenon has been found for more than a century. Entosis, which is a newly found homogeneous cell‐in‐cell phenomenon and a non‐apoptosis cell death progress, has unclear function in prostate cancer progression. Here, we dissected mechanism of AR signaling related to entosis incidence in PCa progression.

Catalase C-262T polymorphism and risk of prostate cancer: Evidence from meta-analysis

Catalase is an important endogenous antioxidant enzyme that detoxifies hydrogen peroxide to oxygen and water, thus limiting the deleterious effects of reactive oxygen species. Several studies investigated the role of the Catalase (CAT) C-262T gene polymorphism on the risk of prostate cancer (PCa), but get conflicting results. We performed a meta-analysis based on five studies, to determine whether Catalase C-262T polymorphism contributes to the risk of prostate cancer using odds ratios (OR) with 95% confidence intervals (CI). On the whole, our evidence indicates that CAT C-262T polymorphism significantly increases PCa risk in the allele comparison model (OR=1.094, 95% CI=1.015-1.178, P=0.018). In the stratified analysis by ethnicity, the same results are found among Caucasians (allele model, OR=1.090, 95% CI=1.009-1.177, P=0.028, dominant model, OR=1.108, 95% CI=1.023-1.201, P=0.012, recessive model, OR=1.379, 95% CI=1.158-1.641, P=0.000, homozygous model, OR=1.429, 95% CI=1.196-1.707, P=0.000, and heterozygote model, OR=1.224, 95% CI=1.020-1.469, P=0.030). In conclusion, this meta-analysis suggests a positive correlation between Catalase C-262T polymorphism and the development of PCa.

In vivo targeted imaging of early stage prostate cancer using a transferrin based near-infrared fluorescence probe

Transferrin (Tf) stabilized Au nanoclusters were successfully applied in the near-infrared targeted imaging of prostate cancer overexpressing Tf receptor in vivo. The prepared Tf-Au NCs owned the merits of low cytotoxicity, good biocompatibility, and natural metabolism, excellent optical properties in the NIR region and receptor specific cancer targeting ability. In our study, serial imaging in vivo has been performed sequently. The results showed that targeted fluorescence imaging with Tf-Au NCs possessed an amazing capability of detecting the early-stage small tumours, and giving as accurate and reproducible measures of tumour size in mice as external calliper measurements. To our knowledge, this was the first time to study the biomedical application of Tf-Au NCs in vivo via intravenous administration rather than cell experiments or orthotopic injection. These remarkable data could provide direct and factual evidence that Tf-Au NCs are very promising nanoprobes which could be harmlessly and efficiently used for the targeted diagnosis of human tumours in vivo, indicating that the further clinical translation of Tf-Au NCs could be expected.

Two-gene expression ratio as predictor for breast cancer treated with tamoxifen: evidence from meta-analysis

A HOXB13-to-IL17BR expression ratio was previously identified to predict a clinical outcome of breast cancer patients treated with adjuvant tamoxifen. A large number of studies were addressed to confirm its function as a predictor of breast cancer outcome treated with tamoxifen. However, conflicting results were got. In this study, a systematic search of databases was carried out, and other relevant papers were also identified. Then, the analyses were conducted according to the PRISMA and MOOSE guidelines. After full review, 11 studies with a total of 2,958 participants were deemed eligible and were included in the study. Pooled results revealed that women with higher HOXB13-to-IL17BR expression ratio had significantly worse outcomes in breast patients treated with tamoxifen, especially for those who are negative of node.

Sox5 contributes to prostate cancer metastasis and is a master regulator of TGF-β-induced epithelial mesenchymal transition through controlling Twist1 expression

Background:Metastatic castration-resistant prostate cancer (mCRPC) is one of the main contributors to the death of prostate cancer patients. To date, the detailed molecular mechanisms underlying mCRPC are unclear. Given the crucial role of epithelial–mesenchymal transition (EMT) in cancer metastasis, we aimed to analyse the expression and function of Transforming growth factor-beta (TGF-β) signal-associated protein named Sox5 in mCRPC.Methods:The protein expression levels were analysed by western blot, immunohistochemistry and immunofluorescence. Luciferase reporter assays and chromatin immunoprecipitation were employed to validate the target of Sox5. The effect of Smad3/Sox5/Twist1 on PCa progression was investigated in vitro and in vivo.Results:Here, we found that TGF-β-induced EMT was accompanied by increased Sox5 expression. Interestingly, knockdown of Sox5 expression attenuated EMT induced by TGF-β signalling. Furthermore, we demonstrated that Smad3 could bind to the promoter of Sox5 and regulate its expression. Mechanistically, Sox5 could bind to Twist1 promoter and active Twist1, which initiated EMT. Importantly, knockdown of Sox5 in prostate cancer cells resulted in less of the mesenchymal phenotype and cell migration ability. Furthermore, targeting Sox5 could inhibit prostate cancer progression in a xenograft mouse model. In clinic, patients with high Sox5 expression were more likely to suffer from metastases, and high Sox5 expression also has a lower progression-free survival and cancer specific-survival in clinic database.Conclusions:Therefore, we propose a new mechanism in which Smad3/Sox5/Twist1 promotes EMT and contributes to PCa progression.