Dysbiosis of urine microbiota in obstructive urinary retention patients revealed by next-generation sequencing.

BACKGROUND: Urinary retention (UR) is a common urinary system disease can be caused by urinary tract obstruction with numerous reasons, however, the role of urine microbes in these disorders is still poorly understood. The aim of this study was to identify the urine microbial features of two common types of obstructive UR, caused by urinary stones or urinary tract tumors, with comparison to healthy controls. METHODS: Urine samples were collected from a cohort of 32 individuals with stone UR, 25 subjects with tumor UR and 25 healthy controls. The urine microbiome of all samples was analyzed using high-throughput 16S rRNA (16S ribosomal RNA) gene sequencing. RESULTS: We observed dramatically increased urine microbial richness and diversity in both obstructive UR groups compared to healthy controls. Despite different origins of UR, bacteria such as Pseudomonas, Acinetobacter and Sphingomonas were enriched, while Lactobacillus, Streptococcus, Gardnerella, Prevotella and Atopobium were decreased in both UR groups in comparison with healthy controls, exhibited an approximate urine microbial community and functional characteristics of two types of obstructive UR. Furthermore, disease classifiers were constructed using specific enriched genera in UR, which can distinguish stone UR or tumor UR patients from healthy controls with an accuracy of 92.29% and 97.96%, respectively. CONCLUSION: We presented comprehensive microbial landscapes of two common types of obstructive urinary retention and demonstrated that urine microbial features of these patients are significantly different from that of healthy people. The urine microbial signatures would shed light on the pathogenesis of these types of urinary retention and might be used as potential classification tools in the future.

Androgen receptor regulates eIF5A2 expression and promotes prostate cancer metastasis via EMT.

Androgen receptor (AR) is an androgen-activated transcription factor of the nuclear receptor superfamily. AR plays a role in the development and progression of prostate cancer (PCa). However, the exact role of AR in PCa metastasis remains unclear. In the present study, we aimed to elucidate the function of AR in PCa. We found that eukaryotic translation initiation factor (EIF) 5A2, an elongation factor that induces epithelial-to-mesenchymal transition (EMT) in PCa cells, was significantly upregulated after 5α-dihydrotestosterone (DHT) stimulation and downregulated after anti-androgen bicalutamide treatment in PCa cells with high AR expression, but not in cells with low AR expression. Moreover, eIF5A2 knockdown could eliminate DHT-induced invasion and migration of AR-positive PCa cells. DHT treatment decreased epithelial expression of E-cadherin and ß-catenin but increased the expression of the mesenchymal marker proteins Vimentin and N-cadherin. DHT therefore induced EMT, and knockdown of eIF5A2 inhibited DHT-induced EMT. Moreover, in vivo study, Luciferase signals from the lungs of the eIF5A2 plasmid group indicated higher metastasis ability, and the eIF5A2 siRNA group had lower metastasis ability. Our results suggest that AR positively regulates eIF5A2 expression in androgen-dependent cells, and stimulation of AR expression and signaling in prostate tumors promotes PCa metastasis by EMT induction and upregulation of eIF5A2.

Significance of TP53 and immune-related genes to prostate cancer.

BACKGROUND: Prostate cancer (PCa) is one of most common male neoplasms. TP53 is the tumor suppressor gene with the highest correlation with human tumorigenesis discovered so far. Besides the TP53, immune-related genes attracted much attention since the clinical application of PD-1/PD-L1 (programmed death 1/programmed cell death-ligand 1) related drugs. There is currently a lack of studies that combine TP53 with immune-related genes to analyze the prognosis of prostate cancer patients. METHODS: Differentially expressed genes were filtered out by R package (edgeR) based on the TCGA-PRAD (The Cancer Genome Atlas-Prostate adenocarcinoma) data set. Using the R package (coxph), we distinguished which ones were related to survival prognosis. Constructing high and low risk groups, we used GEO (Gene Expression Omnibus) data set to verify the prediction performance. Subsequently, we explored the functional differences in gene expression between high and low risk groups. RESULTS: A total of six immune-related genes can be seen as prognostic factors in individuals with TP53 mutations. In the high-risk group, genes related to macrophage activation, epithelial cell apoptosis, and inflammation of the skin should be highly expressed. In the low-risk group, highly expressed genes are mainly involved in nucleotide phosphorylation, tRNA metabolism, and mitochondrial metabolism. CONCLUSIONS: Mutations in the TP53 gene can adversely affect the prognosis of prostate cancer and prostate cancer patients with mutations in some immune-related genes together have a worse prognosis. Compared with any other single clinical index, the prognostic score we proposed gave a more accurate forecast. In order to assist clinicians in making predictive assessments, we have also drawn a nomogram of the prognosis of prostate cancer patients.

Islet transplantation ameliorates diabetes-induced testicular interstitial fibrosis and is associated with inhibition of TGF-ß1/Smad2 pathway in a rat model of type 1 diabetes.

Islet transplantation (IT) is considered the most effective endocrine replacement therapy for diabetes mellitus (DM). Studies have demonstrated that IT can repair testicular structural injury caused by inflammatory and oxidative stress in a diabetic rat model. However, highly effective exogenous antioxidant and anti-inflammatory drugs can achieve this effect. Testicular interstitial fibrosis caused by long-term hyperglycemia is however difficult to reverse or recover. Thus far, there are no effective drugs that prevent or relieve testicular interstitial fibrosis. Therefore, it is necessary to explore the potential benefit of IT on testicular interstitial fibrosis induced by DM and its underlying molecular mechanisms. In the present study, Wistar rats were used to establish a DM model by intraperitoneal injection of streptozotocin. The diabetic models then underwent IT or received insulin treatment after 12 weeks. IT was more effective than insulin treatment in ameliorating diabetic-induced testicular interstitial fibrosis, Leydig cells apoptosis, testosterone deficiency and poor sperm motility. IT and insulin treatment both significantly inhibited the upregulation of TGF-ß1 and phosphorylated Smad2 in DM, with IT being more effective than insulin. The present study's findings proved that IT effectively protects diabetic-induced testicular interstitial fibrosis probably by inhibiting the TGF-ß1/Smad2 signaling pathway, which offers hope in male patients with DM complicating with testicular interstitial fibrosis.

The impact of marriage on the overall survival of prostate cancer patients: A Surveillance, Epidemiology, and End Results (SEER) analysis.

INTRODUCTION: Marital status has long been associated with positive patient outcomes in several malignances; however, little is known about its influence on prostate cancer. We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database to evaluate whether married patients with prostate cancer had a better prognosis than unmarried patients. METHODS: We identified 824 554 patients diagnosed with prostate cancer between 1973 and 2012 in the SEER database. Using the Cox proportional hazard models, we analyzed the impact of marital status (single, married, divorced/separated, and widowed) on survival after diagnosis with prostate cancer. Chi-square tests were used to analyze the association between marital status and other variables, and the Kaplan-Meier method was used to estimate survival curves. RESULTS: Married men were more likely to be diagnosed with a lower Gleason score and undergo surgery than patients in the other groups (p<0.001). The married group had a lower risk of mortality caused by prostate cancer than the other groups. The five-year survival rate for married patients was higher than that for patients in the other groups. CONCLUSIONS: Marital status is a prognostic factor for the survival of prostate cancer patients, as being married was associated with better outcomes.

The Effect of MGCD0103 on CYP450 Isoforms Activity of Rats by Cocktail Method.

MGCD0103, an isotype-selective histone deacetylase inhibitor (HDACi), has been clinically evaluated for the treatment of hematologic malignancies and advanced solid tumors, alone and in combination with standard-of-care agents. In order to investigate the effects of MGCD0103 on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the activities of human CYP2B1, CYP1A2, CYP2C11, CYP2D6, CYP3A4, and CYP2C9. The rats were randomly divided into MGCD0103 group (Low, Medium, and High) and control group. The MGCD0103 group rats were given 20, 40, and 80 mg/kg (Low, Medium, and High) MGCD0103 by continuous intragastric administration for 7 days. Six probe drugs, bupropion, phenacetin, tolbutamide, metoprolol, testosterone, and omeprazole, were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS. Statistical pharmacokinetics difference for tolbutamide in rats were observed by comparing MGCD0103 group with control group. Continuous 7-day intragastric administration of MGCD0103 slightly induces the activities of CYP2C11 of rats.

Effects of suberoylanilide hydroxamic acid on rat cytochrome P450 enzyme activities.

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is the first approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma after progressive disease following two systemic therapies. The rats were randomly divided into SAHA groups (low, medium and high dosage) and control group. The SAHA group rats were given 12.3, 24.5, and 49 mg/kg SAHA, respectively, by continuous intragastric administration for 7 days. The influence of SAHA on the activities of CYP450 isoforms CYP2B6, CYP1A2, CYP2C19, CYP2D6 and CYP2C9 were evaluated by cocktail method, they were responsed by the changes of pharmacokinetic parameters of bupropion, phenacetin, tolbutamide, metroprolol and omeprazole. The five probe drugs were given to rats through intragastric administration, and the plasma concentration were determined by UPLC-MS/MS. The result of SAHA group compared to control group, there were statistical pharmacokinetics difference for bupropion, phenacetin, tolbutamide and metroprolol. Continuous intragastric administration for 7 days may induce the activities of CYP2C19 of rats, inhibit CYP1A2 and slightly inhibit CYP2B6 and CYP2D6 of rats. This may give advising for reasonable drug use after co-used with SAHA. The results indicated that drug co-administrated with SAHA may need dose adjustment. Furthermore, continuous intragastric administration of SAHA for 7 days, liver cell damaged, causing liver cell edema, in liver metabolism process.

Effect of ademetionine on cytochrome P450 isoforms activity in rats.

Cocktail method was used to evaluate the influence of ademetionine on the activities of CYP450 isoforms CYP1A2, CYP2D6, CYP3A4, CYP2C19, CYP2C9 and CYP2B6, which were reflected by the changes of pharmacokinetic parameters of six specific probe drugs phenacetin, metroprolol, midazolam, omeprazole, tolbutamide and bupropion, respectively. The experimental rats were randomly divided into two group, control group and ademetionine group. The ademetionine group rats were given 50 mg/kg ademetionine by continuous oral administration for 7 days. The mixture of six probes was given to rats through oral administration and the blood samples were obtained at a series of time-points through the caudal vein. The concentrations of probe drugs in rat plasma were measured by UPLC-MS/MS. In the experiment for ademetionine and control group, there was statistical pharmacokinetics difference for phenacetin, metroprolol, midazolam, omeprazole, tolbutamide and bupropion. Continuous oral administration for 7 days could induce the activities of CYP450 isoforms CYP1A2 of rats, while it may inhibit the activities of CYP2D6, CYP3A4, CYP2C19 and CYP2C9.

Docetaxel with or without zoledronic acid for castration-resistant prostate cancer.

PURPOSE: The aim of this study was to evaluate the efficacy and safety of zoledronic acid (ZA) in the combination of docetaxel-based chemotherapy for castration-resistant prostate cancer with bone metastases. METHODS: We conducted a prospective study in recruiting 105 prostate cancer patients with bone metastases from 2008 to 2010. Patients were randomly divided into two groups, 53 in the docetaxel-based chemotherapy + ZA(Group A) and 52 in the docetaxel-based chemotherapy + placebo(Group B). The different outcome between patients treated with chemotherapy combined with ZA and those with chemotherapy alone was evaluated. The Cox multivariate analyses of clinical features and different treatment methods of the 105 patients were conducted. RESULTS: There was a response of prostate-specific antigen (PSA) in 33 (62.3 %) in Group A and 28 (53.8 %) in Group B (P = 0.20). The combined approach group had better bone progression-free survival (BPFS) (9.0 vs. 6.0 months, P < 0.05) and overall survival (OS) (19.0 vs. 15.0 months, P = 0.02), but no statistical evidence of benefit was observed in terms of PSA response. Cox multivariate analysis identified the following independent prognostic factors: received ZA, high Hb level and more than 6 cycles of chemotherapy. There were no clinical relevant differences in the frequencies of adverse events between these two groups. CONCLUSIONS: Zoledronic acid treatment combined with docetaxel-based chemotherapy could have a better bone pain control and improve BPFS and OS for prostate cancer patients with bone metastases. The PSA response and SREs rate are similar.