Artificial Neural Network Inference (ANNI): A Study on Gene-Gene Interaction for Biomarkers in Childhood Sarcomas

Objective: To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI). Method: To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs) dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross-validation to minimize the risk of over-fitting and to optimize generalization ability of the model. Results: Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS); FCGRT and OLFM1 in Ewing’s sarcoma (EWS)) suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen. Conclusions: The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas

Evaluation of a short RNA within Prostate Cancer Gene 3 in the predictive role for future cancer using non-malignant prostate biopsies.

BACKGROUND: Prostate Cancer 3 (PCA3) is a long non-coding RNA (ncRNA) upregulated in prostate cancer (PCa). We recently identified a short ncRNA expressed from intron 1 of PCA3. Here we test the ability of this ncRNA to predict the presence of cancer in men with a biopsy without PCa. METHODS: We selected men whose initial biopsy did not identify PCa and selected matched cohorts whose subsequent biopsies revealed PCa or benign tissue. We extracted RNA from the initial biopsy and measured PCA3-shRNA2, PCA3 and PSA (qRT-PCR). RESULTS: We identified 116 men with and 94 men without an eventual diagnosis of PCa in 2-5 biopsies (mean 26 months), collected from 2002-2008. The cohorts were similar for age, PSA and surveillance period. We detected PSA and PCA3-shRNA2 RNA in all samples, and PCA3 RNA in 90% of biopsies. The expression of PCA3 and PCA3-shRNA2 were correlated (Pearson's r = 0.37, p<0.01). There was upregulation of PCA3 (2.1-fold, t-test p = 0.02) and PCA3-shRNA2 (1.5-fold) in men with PCa on subsequent biopsy, although this was not significant for the latter RNA (p = 0.2). PCA3 was associated with the future detection of PCa (C-index 0.61, p = 0.01). This was not the case for PCA3-shRNA2 (C-index 0.55, p = 0.2). CONCLUSIONS: PCA3 and PCA3-shRNA2 expression are detectable in historic biopsies and their expression is correlated suggesting co-expression. PCA3 expression was upregulated in men with PCa diagnosed at a future date, the same did not hold for PCA3-shRNA2. Futures studies should explore expression in urine and look at a time course between biopsy and PCa detection

Red wine and components flavonoids inhibit UGT2B17 in vitro

Background The metabolism and excretion of the anabolic steroid testosterone occurs by glucuronidation to the conjugate testosterone glucuronide which is then excreted in urine. Alterations in UGT glucuronidation enzyme activity could alter the rate of testosterone excretion and thus its bioavailability. The aim of this study is to investigate if red wine, a common dietary substance, has an inhibitory effect on UGT2B17. Methods Testosterone glucuronidation was assayed using human UGT2B17 supersomes with quantification of unglucuronidated testosterone over time using HPLC with DAD detection. The selected red wine was analysed using HPLC and the inhibitory effects of the wine and phenolic components were tested independently in a screening assay. Further analyses were conducted for the strongest inhibitors at physiologically relevant concentrations. Control experiments were conducted to determine the effects of the ethanol on UGT2B17. Results Over the concentration range of 2 to 8% the red wine sample inhibited the glucuronidation of testosterone by up to 70% over 2 hours. The ethanol content had no significant effect. Three red wine phenolics, identified by HLPC analyses, also inhibited the enzyme by varying amounts in the order of quercetin (72%), caffeic acid (22%) and gallic acid (9%); using a ratio of phenolic:testosterone of 1:2.5. In contrast p-coumaric acid and chlorogenic acid had no effect on the UGT2B17. The most active phenolic was selected for a detailed study at physiologically relevant concentrations, and quercetin maintained inhibitory activity of 20% at 2 M despite a ten-fold excess of testosterone. Conclusion This study reports that in an in vitro supersome-based assay, the key steroid-metabolising enzyme UGT2B17 is inhibited by a number of phenolic dietary substances and therefore may reduce the rate of testosterone glucuronidation in vivo. These results highlight the potential interactions of a number of common dietary compounds on testosterone metabolism. Considering the variety of foodstuffs that contain flavonoids, it is feasible that diet can elevate levels of circulating testosterone through reduction in urinary excretion. These results warrant further investigation and extension to a human trial to delineate the healt

Development and validation of risk score for predicting positive repeat prostate biopsy in patients with a previous negative biopsy in a UK population

Background. Little evidence is available to determine which patients should undergo repeat biopsy after initial benign extended core biopsy (ECB). Attempts have been made to reduce the frequency of negative repeat biopsies using PSA kinetics, density, free-to-total ratios and Kattan's nomogram, to identify men more likely to harbour cancer but no single tool accurately predicts biopsy outcome. The objective of this study was to develop a predictive nomogram to identify men more likely to have a cancer diagnosed on repeat prostate biopsy. Methods. Patients with previous benign ECB undergoing repeat biopsy were identified from a database. Association between age, volume, stage, previous histology, PSA kinetics and positive repeat biopsy was analysed. Variables were entered stepwise into logistic regression models. A risk score giving the probability of positive repeat biopsy was estimated. The performance of this score was assessed using receiver characteristic (ROC) analysis. Results. 110 repeat biopsies were performed in this period. Cancer was detected in 31% of repeat biopsies at Hospital (1) and 30% at Hospital (2). The most accurate predictive model combined age, PSA, PSA velocity, free-to-total PSA ratio, prostate volume and digital rectal examination (DRE) findings. The risk model performed well in an independent sample, area under the curve (AUCROC) was 0.818 (95% CI 0.707 to 0.929) for the risk model and 0.696 (95% CI 0.472 to 0.921) for the validation model. It was calculated that using a threshold risk score of > 0.2 to identify high risk individuals would reduce repeat biopsies by 39% while identifying 90% of the men with prostate cancer. Conclusion. An accurate multi-variable predictive tool to determine the risk of positive repeat prostate biopsy is presented. This can be used by urologists in an outpatient setting to aid decision-making for men with prior benign histology for whom a repeat biopsy is being considered. © 2009 Rochester et al; licensee BioMed Central Ltd

Orgasm is preserved regardless of ejaculatory dysfunction with selective α1A-blocker administration

We evaluated whether ejaculatory dysfunction induced with a selective α1A-blocker influenced orgasm. Fifteen healthy male volunteers took silodosin or a placebo in a randomized, double-blind crossover design. We investigated the ejaculatory volume before and after administration of the agents. After each ejaculation, participants self-reported the answers to an original questionnaire, which was about discomfort on ejaculation, orgasm and satisfaction with the discomforting ejaculation. All participants on silodosin had a complete lack of seminal emission and expulsion. All participants felt orgasm in spite of a complete lack of seminal emission. Of the 15, 12 (80%) who had a somewhat uncomfortable feeling during orgasm were dissatisfied with this feeling, although 9 of the 12 reported that its degree was mild. Orgasm is preserved regardless of the loss of seminal emission with silodosin administration. Although most participants reported mild discomfort during orgasm, they were greatly dissatisfied with the loss of seminal emission

Primary mucinous adenocarcinoma in a defunctionalized urinary bladder: a case report

<p>Abstract</p> <p>Introduction</p> <p>Malignancies are rare in defunctionalized bladders and are thought to arise from metaplasia secondary to chronic inflammation. Transitional cell and squamous cell carcinomas are the most common but there are three reported cases of mucinous adenocarcinoma.</p> <p>Case presentation</p> <p>We report a 57-year-old Caucasian man presenting with penile discharge for 30 years following ileal conduit surgery for neurogenic bladder, and who was found to have primary mucinous adenocarcinoma of his defunctionalized bladder.</p> <p>Conclusion</p> <p>Although urinary diversion without cystectomy is less common in current urologic practice, there are many patients with longstanding defunctionalized bladders. While there are no established surveillance protocols, defunctionalized bladder patients with urethral discharge should be evaluated.</p

Characterization of prostate cancer detected at repeat biopsy

Research articl