Faculty Bibliography

Although formation of urothelial carcinoma of the bladder (UCB) requires multiple steps and proceeds along divergent pathways, the underlying genetic and molecular determinants for each step and pathway remain undefined. By developing transgenic mice expressing single or combinatorial genetic alterations in urothelium, we demonstrated here that overcoming oncogene-induced compensatory tumor barriers was critical for urothelial tumor initiation. Constitutively active Ha-ras (Ras*) elicited urothelial hyperplasia that was persistent and did not progress to tumors over a 10 months period. This resistance to tumorigenesis coincided with increased expression of p53 and all pRb family proteins. Expression of a Simian virus 40 T antigen (SV40T), which disables p53 and pRb family proteins, in urothelial cells expressing Ras* triggered early-onset, rapidly-growing and high-grade papillary UCB that strongly resembled the human counterpart (pTaG3). Urothelial cells expressing both Ras* and SV40T had defective G(1)/S checkpoint, elevated Ras-GTPase and hyperactivated AKT-mTOR signaling. Inhibition of the AKT-mTOR pathway with rapamycin significantly reduced the size of high-grade papillary UCB but hyperactivated mitogen-activated protein kinase (MAPK). Inhibition of AKT-mTOR, MAPK and STAT3 altogether resulted in much greater tumor reduction and longer survival than did inhibition of AKT-mTOR pathway alone. Our studies provide the first experimental evidence delineating the combinatorial genetic events required for initiating high-grade papillary UCB, a poorly defined and highly challenging clinical entity. Furthermore, they suggest that targeted therapy using a single agent such as rapamycin may not be highly effective in controlling high-grade UCB and that combination therapy employing inhibitors against multiple targets are more likely to achieve desirable therapeutic outcomes.

BACKGROUND: During normal development in human and other placental mammals, the embryonic cloacal cavity separates along the axial longitudinal plane to give rise to the urethral system, ventrally, and the rectum, dorsally. Defects in cloacal development are very common and present clinically as a rectourethral fistula in about 1 in 5,000 live human births. Yet, the cellular mechanisms of cloacal septation remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We previously detected Bone morphogenetic protein 7 (Bmp7) expression in the urorectal mesenchyme (URM), and have shown that loss of Bmp7 function results in the arrest of cloacal septation. Here, we present evidence that cloacal partitioning is driven by Bmp7 signaling in the cloacal endoderm. We performed TUNEL and immunofluorescent analysis on cloacal sections from Bmp7 null and control littermate embryos. We found that loss of Bmp7 results in a dramatic decrease in the endoderm survival and a delay in differentiation. We used immunological methods to show that Bmp7 functions by activating the c-Jun N-terminal kinase (JNK) pathway. We carried out confocal and 3D imaging analysis of mitotic chromosome bundles to show that during normal septation cells in the cloacal endoderm divide predominantly in the apical-basal direction. Loss of Bmp7/JNK signaling results in randomization of mitotic angles in the cloacal endoderm. We also conducted immunohistochemical analysis of human fetal sections to show that BMP/phospho-SMAD and JNK pathways function in the human cloacal region similar as in the mouse. CONCLUSION/SIGNIFICANCE: Our results strongly indicate that Bmp7/JNK signaling regulates remodeling of the cloacal endoderm resulting in a topological separation of the urinary and digestive systems. Our study points to the importance of Bmp and JNK signaling in cloacal development and rectourethral malformations

PURPOSE OF REVIEW: alpha1-Adrenoceptor blockers are the most frequently prescribed medical therapy in the treatment of lower urinary tract symptom suggestive of benign prostatic hyperplasia (LUTS/BPH). The purpose of this review is to highlight the evolution of adrenoceptor blockers with emphasis on newly approved drugs. RECENT FINDINGS: Over the past years new formulations of several alpha1-adrenoceptor blockers were introduced to the market. Five long-acting alpha1-blockers are currently approved by the Food and Drug Administration for treatment of symptomatic LUTS/BPH: terazosin, doxazosin, tamsulosin, alfuzosin and silodosin. Silodosin is the only adrenoceptor blocker that exhibits true selectivity for the alpha1-adrenoceptor subtypes. This unique adrenoceptor selectivity profile likely accounts for the very favorable cardiovascular safety profile. SUMMARY: Tamsulosin, alfuzosin slow release and silodosin do not require dose titration. Alfuzosin, terazosin, doxazosin and silodosin have all been shown to be effective in relieving LUTS/BPH independent of prostate size. Low incidence of orthostatic hypotension has been reported for silodosin, but abnormal ejaculation is the most commonly reported adverse effect

Study Type - Diagnostic (validating cohort) Level of Evidence 1b What's known on the subject? and What does the study add? Nadir Ultrasensitive PSA levels has some value for predicting BCR following RD. AccuPSA assays lower limit of PSA quantification of <0.01 pg/ml greatly enhances sensitivity and specificity of nadir PSA to predict BCR following RP. Our pilot study shows an AccuPSA of 3 pg/ml has a sensitory and specificity of 100% and 75% respectively for predicting 5 year BCR following RP. OBJECTIVES * To conduct a proof of concept study to evaluate a novel digital single molecule immunoassay (AccuPSA(TM) ) that detects prostate-specific antigen (PSA) a thousandfold more sensitively than current PSA detection methods. * To determine the ability of the AccuPSA(TM) assay to predict 5-year biochemical recurrence (BCR)-free survival after radical prostatectomy (RP). PATIENTS AND METHODS * A total of 31 frozen serum specimens were obtained from specimen logs maintained at New York University Langone Medical Center and the Johns Hopkins University School of Medicine on men who had undergone RP. Those men without evidence of BCR had a minimum of 5 years' PSA follow-up. * In all cases, preoperative and pathological information were available, as was a serum specimen 3-6 months after RP, with a PSA level of <0.1 ng/mL measured by conventional PSA methods at the time of serum collection. * Specimens were tested using the AccuPSA(TM) method. * A Cox proportional hazard model and Kaplan-Meier analysis were used to determine whether AccuPSA(TM) predicted the risk of BCR. RESULTS * Overall, 11/31 (35.5%) men developed BCR. * Mean AccuPSA(TM) nadir levels were significantly different (P < 0.001) between the non-BCR group (2.27 pg/mL) and the BCR group (46.99 pg/mL). * Using a multivariate Cox proportional hazard model, AccuPSA(TM) nadir level was a significant predictor of BCR-free survival (P < 0.01). * Kaplan-Meier analysis of up to 5 years follow-up showed that 100% of men with AccuPSA(TM) nadir values <3 pg/mL did not develop BCR, whereas 62.5% of men with values >3 pg/mL developed BCR (P= 0.00024). * The sensitivity, specificity, positive predictive value and negative predictive value of the AccuPSA(TM) method was 100%, 75%, 69% and 100%, respectively. CONCLUSIONS * AccuPSA(TM) assay predicts 5-year BCR- free survival after RP. * Identifying a reliable predictor of BCR soon after RP has important implications for frequency of PSA testing, selection of candidates for adjuvant therapy, and reassuring a large subset of men that they are not at risk of recurrence. * Larger studies are needed to validate these findings

Data from phase 3 studies (NCT00224107, NCT00224120) of silodosin for treatment of BPH symptoms were analyzed to examine the relationship between treatment efficacy and occurrence of abnormal ejaculation. Men aged >/=50 years with International Prostate Symptom Scores (IPSS) >/=13 and peak urinary flow rates (Qmax) of 4-15 ml s(-1) received placebo or silodosin 8 mg once daily for 12 weeks. Silodosin-treated patients were stratified by absence or presence of 'retrograde ejaculation' (RE). Groups were compared using analysis of covariance (for change from baseline) and responder analyses. Of the 466 patients receiving silodosin, 131 (28%) reported RE and 335 (72%) did not; 4 of the 457 patients receiving placebo (0.9%) reported RE. Most RE events in silodosin-treated patients (110/134; 82%) were reported as 'orgasm with absence of seminal emission.' Silodosin-treated patients with (+) and without (-) RE showed significant improvement in IPSS, Qmax and quality of life versus placebo (P<0.02). RE+ patients versus RE- patients experienced numerically greater improvement, but differences were not statistically significant (P>0.05). For RE+ patients, the odds of achieving improvement of >/=3 points in IPSS and >/=3 ml s(-1) in Qmax by study end were 1.75 times those for RE- patients (P=0.0127). Absence of seminal emission may predict superior treatment efficacy of silodosin in individual patients.