CIP2A depletion potentiates the chemosensitivity of cisplatin by inducing increased apoptosis in bladder cancer cells.

Poor response and chemotherapy resistance to cisplatin (DDP)­based therapy frequently lead to treatment failure in advanced bladder cancer; however the underlying mechanism is extremely complex and unclear. Furthermore, cancerous inhibitor of protein phosphatase 2A (CIP2A), a recently identified human oncoprotein, has been shown to play important regulatory roles in cancer cell survival. The present study aimed to investigate the correlation of CIP2A with sensitivity to DDP in bladder cancer cells. In the present study, knockdown of CIP2A was performed using short hairpin­RNA. IC50 determination was used to estimate the chemosensitivity of cells to DDP. Apoptosis and DNA damage indicators were tested in vitro and in vivo to clarify the role of CIP2A in enhancing DDP sensitivity. We observed that CIP2A knockdown enhanced DDP sensitivity. CIP2A depletion accelerated the process of DNA damage caused by DDP treatment. Furthermore, DDP triggered inhibition of CIP2A by preventing AKT Ser473 phosphorylation. In vivo, CIP2A suppression increased the cytotoxicity of DDP, which resulted in a decrease in the subcutaneous tumor growth in a xenograft mouse model. Our findings revealed that the mechanism underlying the involvement of CIP2A in DDP sensitivity enhancement is that CIP2A mediates DDP­induced cell apoptosis and DNA damage. CIP2A is a potential target to improve the response to DDP­based therapy in bladder cancer patients.

Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis.

OBJECTIVES: To perform a systematic evaluation of whether germline DNA repair gene mutations in bladder cancer (BCa) are associated with increased risk of BCa and aggressive disease. MATERIALS AND METHODS: Germline DNA from 98 patients with BCa was analysed for 54 DNA repair genes using a customized targeted sequencing panel. Population control data were obtained from the public databases the Exome Aggregation Consortium database and the Genome Aggregation Database. Mutation pathogenicity was annotated based on American College of Medical Genetics criteria, mutation frequencies in the general population and the ClinVar database. Mutation frequencies were compared based on case-control and case-case designs for disease risks, disease aggressiveness and outcomes. RESULTS: The frequency of pathogenic/likely pathogenic germline DNA repair gene mutations was 10.2% among patients with BCa. Within the subset of patients with carcinoma invading the bladder muscle, the frequency was 15.8%, ~2.4-fold higher than in patients with non-muscle invasive BCa (6.67%). The mutation frequency among patients with early-onset disease (at age <45 years) was ~3-fold higher than among those diagnosed after age 45 years (28.57% vs 8.79%). Mutation carriers had a significantly higher frequency of unfavourable clinical outcomes (disease recurrence or progression to metastatic BCa) than non-carriers (50.0% vs 13.64%; P = 0.013). CONCLUSION: Pathogenic and likely pathogenic mutations in DNA repair genes were associated with unfavourable prognosis of BCa.

Nomograms to Predict Individual Prognosis of Patients with Primary Small Cell Carcinoma of the Bladder.

Objectives: To develop reliable nomograms to estimate individualized overall survival (OS) and cancer specific survival (CSS) for patients with primary small cell carcinoma of the bladder (SCCB) and compare the predictive value with the AJCC stages. Patients and Methods: 582 eligible SCCB patients identified in the Surveillance, Epidemiology, and End Results (SEER) dataset were randomly divided into training (n=482) and validation (n=100) cohorts. Akaike information criterion was used to select the clinically important variables in multivariate Cox models when establishing nomograms. The performance of nomograms was bootstrapped validated internally and externally using the concordance index (C-index) with 95% confidence interval (95% CI) and calibration curves and was compared with that of the AJCC stages using C-index, Kaplan-Meier curves and decision curve analysis (DCA). Results: Two nomograms shared common indicators including age, tumor size, T stage, lymph node ratio, metastases, chemotherapy, radiation and radical cystectomy, while marriage and gender were only incorporated in the OS nomogram. The C-indices of nomograms for OS and CSS were 0.736 (95%CI 0.711-0.761) and 0.731(95%CI 0.704-0.758), respectively, indicating considerable predictive accuracy. Calibration curves showed consistency between the nomograms and the actual observation. The results remained reproducible when nomograms were applied to the validation cohort. Additionally, comparisons between C-indices, Kaplan-Meier curves and DCA proved that the nomograms obtained obvious superiority over the AJCC stages with wide practical threshold probabilities. Conclusions: We proposed the first two nomograms for individualized prediction of OS and CSS in SCCB patients with satisfactory predictive accuracy, good robustness and wide applicability.

Effectiveness of urine fibronectin as a non-invasive diagnostic biomarker in bladder cancer patients: a systematic review and meta-analysis.

BACKGROUND: Previous researches pointed out that the measurement of urine fibronectin (Fn) could be a potential diagnostic test for bladder cancer (BCa). We conducted this meta-analysis to fully assess the diagnostic value of urine Fn for BCa detection. METHODS: A systematic literature search in PubMed, ISI Web of Science, EMBASE, Cochrane library, and CBM was carried out to identify eligible studies evaluating the urine Fn in diagnosing BCa. Pooled sensitivity, specificity, and diagnostic odds ratio (DOR) with their 95% confidence intervals (CIs) were calculated, and summary receiver operating characteristic (SROC) curves were established. We applied the STATA 13.0, Meta-Disc 1.4, and RevMan 5.3 software to the meta-analysis. RESULTS: Eight separate studies with 744 bladder cancer patients were enrolled in this meta-analysis. The pooled sensitivity, specificity, and DOR were 0.80 (95%CI = 0.77-0.83), 0.79 (95%CI = 0.73-0.84), and 15.18 (95%CI = 10.07-22.87), respectively, and the area under the curve (AUC) of SROC was 0.83 (95%CI = 0.79-0.86). The diagnostic power of a combined method (urine Fn combined with urine cytology) was also evaluated, and its sensitivity and AUC were significantly higher (0.86 (95%CI = 0.82-0.90) and 0.89 (95%CI = 0.86-0.92), respectively). Meta-regression along with subgroup analysis based on various covariates revealed the potential sources of the heterogeneity and the detailed diagnostic value of each subgroup. Sensitivity analysis supported that the result was robust. No threshold effect and publication bias were found in this meta-analysis. CONCLUSIONS: Urine Fn may become a promising non-invasive biomarker for bladder cancer with a relatively satisfactory diagnostic power. And the combination of urine Fn with cytology could be an alternative option for detecting BCa in clinical practice. The potential value of urine Fn still needs to be validated in large, multi-center, and prospective studies.

Enhanced recovery after surgery for radical cystectomy with ileal urinary diversion: a multi-institutional, randomized, controlled trial from the Chinese bladder cancer consortium.

PURPOSE: Enhanced recovery after surgery (ERAS) has played an important role in recovery management for radical cystectomy with ileal urinary diversion (RC-IUD). This study is to evaluate ERAS compared with the conventional recovery after surgery (CRAS) for RC-IUD. METHODS: From October 2014 and July 2016, bladder cancer patients scheduled for curative treatment from 25 centers of Chinese Bladder Cancer Consortium were randomly assigned to either ERAS or CRAS group. Primary endpoint was the 30-day complication rate. Secondary endpoints included recovery of fluid and regular diet, flatus, bowel movement, ambulation, and length of stay (LOS) postoperatively. Follow-up period was 30-day postoperatively. RESULTS: There were 144 ERAS and 145 CRAS patients. Postoperative complications occurred in 25.7 and 30.3% of the ERAS and CRAS patients with 55 complications in each group, respectively (p = 0.40). There was no significant difference between groups in major complications (p = 0.82), or type of complications (p = 0.99). The ERAS group had faster recovery of bowel movements (median 88 versus 100 h, p = 0.01), fluid diet tolerance (68 versus 96 h, p < 0.001), regular diet tolerance (125 versus 168 h, p = 0.004), and ambulation (64 versus 72 h, p = 0.047) than the CRAS group, but similar time to flatus and LOS. CONCLUSIONS: ERAS did not increase 30-day complications compared with CRAS after RC. ERAS may be better than CRAS in terms of bowel movement, tolerance of fluid and regular diet, and ambulation.

Prognostic value of site-specific metastases and therapeutic roles of surgery for patients with metastatic bladder cancer: a population-based study.

BACKGROUND: We aimed to evaluate the prognostic value of site-specific metastases in patients with metastatic bladder cancer and analyze the roles that surgeries play in the treatment of this malignancy. MATERIALS AND METHODS: A population-based retrospective study using Surveillance, Epidemiology and End Results dataset was performed and metastatic bladder cancer patients were classified according to the sites of metastases (bone, brain, liver, lung and distant lymph nodes). Kaplan-Meier analysis with log-rank test was used for survival comparisons. Multivariate Cox regression model was employed to analyze the effect of distant metastatic sites on overall survival (OS) and cancer-specific survival (CSS). RESULTS: A total of 1862 patients with metastatic bladder cancer from 2010 to 2014 were identified. Bone, lung and distant lymph nodes were the most common metastatic sites. Patients with bone, brain, liver and lung involvement had worse OS and CSS compared to patients without the corresponding sites of metastases. Multivariate analysis showed that bone, brain, liver and lung metastases were independent prognostic factors for both OS and CSS, while distant node metastasis was not. Moreover, patients with a single metastatic site had more favorable OS (p<0.001) and CSS (p<0.001) than patients with multisite metastases. Among single-site metastatic patients, distant nodes and liver metastases represented the best and the worst prognosis, respectively. Moreover, radical cystectomy was an independent predictor for better OS and CSS, while in patients with liver metastasis and multiple metastatic sites, RC did not bring benefits. Besides, in patients with a single metastatic site, metastasectomy seemed to be associated with favorable OS (p=0.042), especially for patients with age <65 years (p=0.006) and for muscle-invasive bladder cancer patients (p=0.031). CONCLUSION: Distant metastatic sites have differential impact on survival outcomes in patients with metastatic bladder cancer. Surgeries, including radical cystectomy and metastasectomy, might still lead to survival benefits for highly selected patients.

The Triglycerides and Glucose Index rather than HOMA-IR is more associated with Hypogonadism in Chinese men.

Previous studies have reported that insulin resistant and low testosterone are related. The triglyceride and glucose index (TyG) well mirrors insulin sensitivity. No study investigated the application of TyG in male hypogonadism. We aimed to explore whether TyG was associated with hypogonadism, and also evaluate the ability of TyG compared to HOMA-IR as a possible hypogonadism predictor. A total of 4299 male subjects were enrolled from 22 sites in East China. Hypogonadism was defined as total testosterone <11.3 nmol/L. 695 (16.2%) hypogonadal men had significantly higher TyG index. The prevalence of hypogonadism stepwise increased across increasing TyG quartiles (P < 0.01). TyG was negatively associated with sex hormones and hypogonadism after adjustment for age, current smoking status, hypertension and overweight/obesity (all P for trend <0.01). The full-adjusted odds ratio was 6.1 for the highest quartile compared with the lowest quartile of TyG (95% CI 4.51, 8.25, P < 0.001). On ROC curve analysis, a larger area under the curve was found for TyG (0.71, 95% CI 0.69,0.73) than for HOMA-IR (0.68, 95% CI 0.66,0.70). Thus, the TyG was significantly associated with a higher prevalence of hypogonadism in Chinese men. TyG had a better predictive power for hypogonadism than HOMA-IR.

Targeting of CCN2 suppresses tumor progression and improves chemo-sensitivity in urothelial bladder cancer.

Urothelial bladder cancer (UBC) is the most common urinary neoplasm in China. CCN family protein 2 (CCN2), a cysteine-rich matricellular protein, is abnormally expressed in several cancer types and involved in tumor progression or chemo-resistance. However, detailed expression patterns and effects of CCN2 in UBC still remain unknown. We found that down-regulation of CCN2 suppressed proliferation, migration and invasion of UBC cells in vitro and targeting of CCN2 decelerated xenograft growth in vivo. When treated with mitomycin C (MMC), CCN2-scilencing UBC cells showed lower survival and higher apoptotic rates and these effects were probably mediated via inactivation of Akt and Erk pathways. We also demonstrated the clinical significance of CCN2 expression, which was higher in UBC tissues and associated with advanced tumor stage and high pathologic grade. Taken together, our data suggest that CCN2 is an oncogene in UBC and might serve as a matricellular target for improving chemotherapeutic efficacy.

Are thyroid nodules associated with sex-related hormones? A cross-sectional SPECT-China study.

OBJECTIVE: Little is known about the association between thyroid nodules (TNs) and endogenous sex hormones. We aimed to investigate the relationship between TNs and sex-related hormones among men in China. SETTING: The data were obtained from a cross-sectional study Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China study, 2014-2015) based on the population. PARTICIPANTS: In total, 4024 men over 18 years of age who were not using hormone replacement therapy and who underwent complete assays of the serum total testosterone (T), oestradiol (E2), follicle-stimulating hormone (FSH), luteinising hormone (LH) and sex hormone-binding globulin (SHBG) levels as well as thyroid ultrasonography (US) enrolled in this study. RESULTS: Of the 4024 participants (54.15±13.08 years old), 1667 participants (41.4%) had TNs. Men with TN(s) (TN(+) group) had significantly lower levels of total T and SHBG and higher E2/T levels compared with the men without TN(s) (TN(-) group) (p<0.05). The TN prevalence decreased with the quartiles of the SHBG level (p<0.05). Binary logistic analysis showed that lower quartiles of SHBG had a greater risk of TN(s) (all p for trend <0.05). This association persisted in the fully adjusted model (p for trend=0.017), in which, for the lowest compared with the highest quartile of SHBG, the OR of TN(s) was 1.42 (95% CI 1.07 to 1.89). No statistically significant association was found between sex-related hormones and US characteristics associated with malignancy (nodule >10 mm, microcalcification and a 'taller' than 'wider' shape). CONCLUSIONS: TNs are highly prevalent in men in China. A lower SHBG level was significantly associated with TN among men. The potential role of SHBG in the pathogenesis of the TN remains to be elucidated.

Identifying unilateral disease in Chinese patients with primary aldosteronism by using a modified prediction score.

OBJECTIVE: The current study aimed to evaluate the role of Küpers' score in predicting unilateral aldosteronism, and develop a modified score in Chinese patients with primary aldosteronism. METHODS: The current retrospective study included 406 patients with primary aldosteronism who underwent successful adrenal venous sampling (AVS) and were divided into the unilateral (n = 211) and bilateral (n = 195) groups according to the AVS results. Normokalemia was noted in both the unilateral (n = 64) and bilateral groups (n = 84) when plasma and urinary aldosterone were measured. RESULTS: We evaluated Küpers' prediction score, which had the best cutoff value at four points [area under the curve, 0.601 (95% confidence interval 0.551-0.650); specificity, 53%; sensitivity, 62%]. Then, we modified this score by using urinary aldosterone level quartiles, history of hypokalemia, and typical adenoma more than 10 mm on computed tomography (CT) [area under the curve, 0.745 (95% confidence interval 0.667-0.813)]; sensitivity, 45.3%; specificity, 90.5%). The best cutoff value to discriminate unilateral from bilateral disease was a score of 5. This modified prediction score only applied to patients who were normokalemic when urinary aldosterone was measured. A specificity of 100% was achieved at a score of 6 for patients aged 40 years or less, and 5 when the adrenal lesion was on the right side on CT imaging. CONCLUSION: Küpers' prediction score is not suitable for our patients. Urinary aldosterone levels combined with a history of hypokalemia are useful to discriminate unilateral from bilateral aldosteronism in patients with typical adenoma on the right adrenal gland on CT or in patients 40 years old or less.

A Higher Ratio of Estradiol to Testosterone Is Associated with Autoimmune Thyroid Disease in Males.

BACKGROUND: Autoimmune thyroid disease (AITD) is highly prevalent. Although AITD is less common in males, it is unclear whether estradiol (E2) combined with total testosterone (T) contributes to the prevalence of AITD. This study evaluated the association between the E2/T ratio and the prevalence of AITD in males. METHODS: The data were obtained from a cross-sectional population-based study, the SPECT-China study, 2014-2015. A total of 4109 males ≥18 years of age were enrolled in this study. Participants underwent several checkups, which included assays of serum E2, T, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) levels, as well as thyroid ultrasonography (US). AITD was defined based on the presence of TPOAb and TgAb levels, and the presence of thyroid US findings. RESULTS: Overall, the prevalence of positivity for TPOAb and/or TgAb (TPO/TgAb[+]) was 11.02%, and the positivity for TPOAb and/or TgAb together with US (TPO/TgAb[+] and US[+]) was 4.58%. The E2/T ratio levels were significantly higher in the TPO/TgAb(+) group and the TPO/TgAb(+) and US(+) group (7.91 ± 8.03 vs. 7.19 ± 10.30, p = 0.003; 8.78 ± 11.26 vs. 7.19 ± 10.30, p = 0.001) compared to the TPO and TgAb(-) group. The prevalence of TPO/TgAb(+) and US(+) significantly increased with an increasing E2/T ratio (p = 0.013). Binary logistic analysis showed that increased E2/T ratio levels were associated with an increased risk of AITD (TPO/TgAb[+]: odds ratio = 1.35, p = 0.002; TPO/TgAb[+] and US[+]: odds ratio = 1.48, p = 0.006). CONCLUSIONS: AITD is highly prevalent in males in China. Higher E2/T ratios were significantly associated with AITD among males. Further studies will be needed to assess whether there is a causal relationship between E2/T ratios and AITD.

Serum Uric Acid Is Associated with Erectile Dysfunction: A Population-Based Cross-Sectional Study in Chinese Men.

The role that serum uric acid (UA) plays in the pathophysiological development of erectile dysfunction (ED) is controversial. We aimed to screen the factors related with ED, and to examine the association between serum UA and ED. Our data were derived from a cross-sectional Survey on Prevalence in East China for Metabolic Diseases and Risk Factors study in 2014-2015. Questionnaire of International Index of Erectile Dysfunction-5 was used for assessment of ED. Data were collected in three general communities respectively. A total of 1365 men were enrolled with an overall mean age 55.5 ± 10.8 years (range: 20-83 years). The prevalence of ED was 62.4% (51.4% standardized) in the population. Males with ED were older, and more prone to have a higher follicle-stimulating hormone, luteinizing hormone, sex hormone-binding globulin, glycated hemoglobin, fasting plasma glucose levels and lower free androgen index (FAI), UA levels, and more likely to have diabetes and elevated blood pressure compared with those without ED. Age and UA were independent influencing factors for ED. Besides, UA was positively correlated with FAI after adjustment for age. In conclusion, our study demonstrated the protective role that UA might play in development of ED.

CIP2A mediates fibronectin-induced bladder cancer cell proliferation by stabilizing ß-catenin.

BACKGROUND: Fibronectin (FN) is associated with tumorigenesis and progression in bladder cancer, however, the underlying mechanisms causing this remain largely unknown. Furthermore, cancerous inhibitor of protein phosphatase 2A (CIP2A) has been shown to play important regulatory roles in cancer proliferation. Here, we investigated whether FN regulates CIP2A expression to promote bladder cancer cell proliferation. METHODS: The correlations of stromal FN with CIP2A and proliferating cell nuclear antigen (PCNA) expression were analyzed in a cohort bladder cancer patients. The roles of FN and CIP2A in regulating bladder cancer cell proliferation were evaluated in cell and animal models. Cycloheximide treatment was used to determine the effects of CIP2A on ß-catenin stabilization. The CIP2A-ß-catenin interaction was confirmed by immunofluorescence staining and co-immunoprcipitation. RESULTS: In this study, we found that stromal FN expression correlated positively with the levels of CIP2A and PCNA in bladder cancer tissues. Meanwhile, in human bladder cancer cell lines (T24 and J82), exogenous FN significantly promoted cell proliferation, however, CIP2A depletion inhibited this process. Furthermore, the interaction between CIP2A and ß-catenin enhanced the stabilization of ß-catenin, which was involved in FN-induced cell proliferation. In vivo, CIP2A depletion repressed FN-accelerated subcutaneous xenograft growth rates. CONCLUSIONS: These data reveal that CIP2A is a crucial mediator of FN-induced bladder cancer cell proliferation via enhancing the stabilization of ß-catenin. Promisingly, FN and CIP2A could serve as potential therapeutic targets for bladder cancer treatment.

The preclinical assessment of XL388, a mTOR kinase inhibitor, as a promising anti-renal cell carcinoma agent.

XL388 is a mammalian target of rapamycin (mTOR) kinase inhibitor. We demonstrated that XL388 inhibited survival and proliferation of renal cell carcinoma (RCC) cell lines (786-0 and A549) and primary human RCC cells. XL388 activated caspase-dependent apoptosis in the RCC cells. XL388 blocked mTOR complex 1 (mTORC1) and mTORC2 activation, and depleted hypoxia-inducible factor 1α (HIF1α) and HIF-2α expression in RCC cells. Yet, XL388 was ineffective in RCC cells with mTOR shRNA knockdown or kinase-dead mutation. Notably, XL388 was more efficient than mTORC1 inhibitors (rapamycin, everolimus and temsirolimus) in killing RCC cells. Further studies showed that activation of MEK-ERK might be a key resistance factor of XL388. Pharmacological or shRNA-mediated inhibition of MEK-ERK pathway sensitized XL388-induced cytotoxicity in RCC cells. In vivo, oral administration of XL388 inhibited in nude mice 786-0 RCC tumor growth, and its anti-tumor activity was sensitized with co-administration of the MEK-ERK inhibitor MEK162. Together, these results suggest that concurrent inhibition of mTORC1/2 by XL388 may represent a fine strategy to inhibit RCC cells.

Segmental ureterectomy is not inferior to radical nephroureterectomy for either middle or distal ureter urothelial cell carcinomas within 3.5 cm.

OBJECTIVE: To evaluate oncologic outcomes of segmental ureterectomy (SU) compared with radical nephroureterectomy (RNU) for urothelial carcinoma of ureter. To evaluate whether tumor position is a factor to influence outcomes of different surgical procedures. METHODS: From November 2003 to June 2016, 131 patients with urothelial carcinoma of ureter underwent SU or RNU at our department. We used survival analysis and Cox regression models to compare oncologic outcomes after SU and RNU. Covariates included surgical type, tumor stage, cancer grade, lesion position, presence of preoperative hydronephrosis and histories of bladder cancer. Patients were divided according to lesion sites for further comparison. RESULTS: The mean length of follow-up was 55.3 and 50.9 months for the RNU and SU group, respectively. The bladder recurrences, local recurrences, distant metastasis, cancer-specific survival and overall survival rates showed no significant differences between RNU and SU (p = 0.596, p = 0.636, p = 0.740, p = 0.809, p = 0.553, respectively). For mid-ureter or distal ureter lesions, no significant difference of oncologic outcomes between SU and RUN was observed. CONCLUSIONS: Our study suggested SU is not inferior to RNU for either middle or distal ureter urothelial cell carcinomas.

Follicle stimulating hormone, its novel association with sex hormone binding globulin in men and postmenopausal women.

PURPOSE: Follicle stimulating hormone plays direct roles in a variety of nongonadal tissues and sex hormone binding globulin is becoming the convergence of the crosstalk among metabolic diseases. However, no studies have explored the association between follicle stimulating hormone and sex hormone binding globulin. We aimed to study this association among men and women. METHODS: SPECT-China is a population-based study conducted since 2014. This study included 4206 men and 2842 postmenopausal women. Collected serum was assayed for gonadotropins, sex hormone binding globulin, sex hormones etc. Regression analyses were performed to assess the relationship between sex hormone binding globulin and follicle stimulating hormone and other variables including metabolic factors, thyroid function and sex hormones. Treatment with follicle stimulating hormone at different concentrations of 0, 5, 50 and 100 IU/L for 24 h was performed in HepG2 cells. RESULTS: In Spearman correlation, sex hormone binding globulin was significantly correlated with FSH, triglycerides, thyroxins, body mass index and blood pressure in men and postmenopausal women (all P < 0.05). In regression analyses, follicle stimulating hormone was a significant predictor of sex hormone binding globulin in men and postmenopausal women (P < 0.05), independent of above variables. Follicle stimulating hormone induced sex hormone binding globulin expression in a dose-dependent fashion in HepG2 cells. CONCLUSION: Serum follicle stimulating hormone levels were positively associated with circulating sex hormone binding globulin levels in men and postmenopausal women. This association is independent of age, insulin resistance, hepatic function, lipid profile, thyroid function, adiposity, blood pressure, and endogenous sex hormones.

Dysregulation of miRNAs in bladder cancer: altered expression with aberrant biogenesis procedure.

Aberrant expression profiles of miRNAs are widely observed in the clinical tissue specimens and urine samples as well as the blood samples of bladder cancer patients. These profiles are closely related to the pathological features of bladder cancer, such as the tumour stage/grade, metastasis, recurrence and chemo-sensitivity. MiRNA biogenesis forms the basis of miRNA expression and function, and its dysregulation has been shown to be essential for variations in miRNA expression profiles as well as tumourigenesis and cancer progression. In this review, we summarize the up-to-date and widely reported miRNAs in bladder cancer that display significantly altered expression. We then compare the miRNA expression profiles among three different sample types (tissue, urine and blood) from patients with bladder cancer. Moreover, for the first time, we outline the dysregulated miRNA biogenesis network in bladder cancer from different levels and analyse its possible relationship with aberrant miRNA expression and the pathological characteristics of the disease.

Results of a randomized, double-blind, active-controlled clinical trial with propiverine extended release 30 mg in patients with overactive bladder.

OBJECTIVE: To compare the efficacy and safety of the 30 mg extended release (ER) formulation of propiverine hydrochloride with the 4 mg ER formulation of tolterodine tartrate in patients with overactive bladder (OAB) in a non-inferiority trial. PATIENTS AND METHODS: Eligible patients, aged 18-75 years and with symptoms of OAB, were enrolled in this multicentre, randomized, double-blind, parallel-group, active-controlled study. After a 2-week screening period, patients were randomized at a 1:1 ratio to receive either propiverine ER 30 mg or tolterodine ER 4 mg daily during the 8-week treatment period. Efficacy was assessed using a 3-day voiding diary and patient's self-reported assessment of treatment effect. Safety assessment included recording of adverse events, laboratory test results, measurement of post-void residual urine and electrocardiograms. RESULTS: A total of 324 patients (244 female and 80 male) were included in the study. Both active treatments improved the variables included in the voiding diary and in the patient's self-reported assessment. The change from baseline in the number of voidings per 24 h was significantly greater in the propiverine ER 30 mg group compared with the tolterodine ER 4 mg group after 8 weeks of treatment (full analysis set [FAS] -4.6 ± 4.1 vs -3.8 ± 5.1; P = 0.005). Significant improvements were also observed for the change of urgency incontinence episodes after 2 weeks (P = 0.026) and 8 weeks (P = 0.028) of treatment when comparing propiverine ER 30 mg with tolterodine ER 4 mg. Both treatments were well tolerated, with a similar frequency of adverse drug reactions in both the propiverine ER 30 mg and tolterodine ER 4 mg groups (FAS 40.7 vs 39.5%; P = 0.8). More patients treated with tolterodine ER 4 mg discontinued the treatment because of adverse drug reactions compared with propiverine ER 30 mg (7.4 vs 3.1%). CONCLUSIONS: Propiverine ER 30 mg was confirmed to be an effective and well-tolerated treatment option for patients with OAB symptoms. This first head-to-head study showed non-inferiority of propiverine ER 30 mg compared with tolterodine ER 4 mg.

Hypothalamic-Pituitary-Gonadal Axis in Aging Men and Women: Increasing Total Testosterone in Aging Men.

BACKGROUND: Aging is associated with variations in hypothalamic-pituitary-gonadal (HPG) axis hormones. However, it is not clear how aging changes these hormones. This study examined the natural alterations in the HPG axis in aging men and women in China. METHODS: Data were obtained from our cross-sectional study (SPECT-China) in 16 areas of three provinces in East China between February and June 2014. There were 6,825 subjects selected, including 2,908 men and 3,917 women aged 25-93 years who had no diseases affecting HPG hormones and did not take exogenous supplements. Total testosterone (TT), estradiol (E2), free testosterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured. RESULTS: In men, the ranges of the 10-90th percentiles for each hormone were as follows: TT, 9.9-23.4 nmol/l; SHBG, 20.6-79.54 nmol/l; E2, 34.84-187 pmol/l. TT values were higher in men aged 25-30 years than in those aged 31-35 years and began to increase progressively at the age of 41-50 years until men reached their eighties. The unadjusted annual age trend (ß) was 0.079 nmol/l/year (p < 0.001). A linear regression analysis, after full adjustment for demographic variables, metabolic factors, other hormones, lifestyle and co-morbidities, showed that higher TT levels were still associated with aging (p < 0.05). However, the ratio of TT to LH decreased with age (ß = -0.272/year, p < 0.001). E2 and SHBG increased with age (ß = 1.774 pmol/l/year and 1.118 nmol/l/year, respectively, p < 0.001). In women, the 10-90th percentile range of E2 was 32.79-565.8 pmol/l. E2 began to decrease at the age of 46-50 years, declined sharply at the age of 51-55 years (ß = -5.73 pmol/l/year, p < 0.001) and then stabilized at a low concentration after the age of 55 years. The 10-90th percentile ranges of LH and FSH in men were 2.4-9.2 and 3.4-15.5 IU/l, and in women they were 3-36.6 and 4-89.28 IU/l, respectively. FSH increased by 7.11% per annum in men and by 12.76% per annum in women, but LH increased by only approximately 4.00% per annum in both sexes. CONCLUSIONS: The influence of aging on the HPG axis is sex dependent. The pattern of age-related TT was different in Chinese Han men when compared with previous studies in Western populations. TT values increased in aging men, so it is not suitable to estimate the life quality of older Chinese men just based on TT.