Prevalence of Peyronie's Disease-Like Symptoms in Men Presenting With Dupuytren Contractures.

INTRODUCTION: Peyronie's disease (PD) and Dupuytren contractures (DC) are often comorbid and are believed to have a similar underlying pathophysiologic mechanism. AIM: To investigate the prevalence of PD-like symptoms (PDLS) in men with DC. METHODS: From October 2013 to December 2016, men who were seen and evaluated for DC were offered the opportunity to participate in an anonymous survey. The survey assessed several basic demographic and sexual health factors and included items from the International Index of Erectile Function and the Erection Hardness Scale. Men who reported PDLS were asked a series of questions derived from the Peyronie's Disease Questionnaire and for their opinions on theoretical treatment modalities for sexual problems and penile deformity. MAIN OUTCOME MEASURE: Prevalence of PDLS in men with DC. RESULTS: One hundred forty men with DC were invited to participate; 85 surveys were returned (response rate = 61%). Twenty-two respondents (26%, 95% confidence interval = 17-35) reported PDLS. Approximately one fourth of all respondents had an Erection Hardness Scale score lower than 3. The most common specific PDLS concerns were penile curvature (91%), length loss (55%), narrowing (36%), and hinging (32%). In men with PDLS, 73% felt at least a little bothered by the symptoms when attempting sexual activity and 40% reported having sex less frequently because of the symptoms. Just 27% of men with PDLS had ever used a treatment for a sexual concern. In terms of treatments for penile deformities, 64% of men with PDLS expressed an interest in treatment administered in the form of an in-office procedure; 41% were potentially amenable to a surgical procedure. CONCLUSION: The prevalence of PDLS in men with DC is similar to the prevalence of DC in men diagnosed with PD. A substantial number of these men have distress and would consider standard-of-care treatments for PD. Shindel AW, Sweet G, Thieu W, et al. Prevalence of Peyronie's Disease-Like Symptoms in Men Presenting With Dupuytren Contractures. Sex Med 2017;5:e135-e141.

Impact of synchronous metastasis distribution on cancer specific survival in renal cell carcinoma after radical nephrectomy with tumor thrombectomy.

PURPOSE: Metastatic renal cell carcinoma can be clinically diverse in terms of the pattern of metastatic disease and response to treatment. We studied the impact of metastasis and location on cancer specific survival. MATERIALS AND METHODS: The records of 2,017 patients with renal cell cancer and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1971 to 2012 at 22 centers in the United States and Europe were analyzed. Number and location of synchronous metastases were compared with respect to patient cancer specific survival. Multivariable Cox regression models were used to quantify the impact of covariates. RESULTS: Lymph node metastasis (155) or distant metastasis (725) was present in 880 (44%) patients. Of the patients with distant disease 385 (53%) had an isolated metastasis. The 5-year cancer specific survival was 51.3% (95% CI 48.6-53.9) for the entire group. On univariable analysis patients with isolated lymph node metastasis had a significantly worse cancer specific survival than those with a solitary distant metastasis. The location of distant metastasis did not have any significant effect on cancer specific survival. On multivariable analysis the presence of lymph node metastasis, isolated distant metastasis and multiple distant metastases were independently associated with cancer specific survival. Moreover higher tumor thrombus level, papillary histology and the use of postoperative systemic therapy were independently associated with worse cancer specific survival. CONCLUSIONS: In our multi-institutional series of patients with renal cell cancer who underwent radical nephrectomy and tumor thrombectomy, almost half of the patients had synchronous lymph node or distant organ metastasis. Survival was superior in patients with solitary distant metastasis compared to isolated lymph node disease.

The role of microRNA in castration-resistant prostate cancer.

INTRODUCTION: Castration-resistant prostate cancer (CRPC) has a historically low median survival rate, but recent advances and discoveries in microRNAs (miRNAs) have opened the potential for new prognostication modalities to enhance therapeutic success. As new chemotherapies and immunotherapies are developed, there is an increasing need for precision and stratification of CRPC to allow for optimization and personalization of therapy. METHODS: A systematic literature review was conducted via electronic database resulting in the selection of 42 articles based on title, abstract, study format, and content by a consensus of all participating authors. Most selected articles were published between 2002 and 2013. In this review, we discuss the robustness of miRNAs as a biomarker platform, miRNAs associated with prostate cancer, and recent discoveries of miRNA associations with CRPC. RESULTS: The associations discovered have been of interest owing to the ability to differentiate between CRPC and localized prostate cancer. With the evaluation of multiple miRNAs, it is possible to provide a profile regarding tumor characteristics. Furthermore, actions of miRNAs on CRPC tumor cells have the ability to suppress metastatic phenotypes. CONCLUSION: miRNAs may have a growing role in CRPC prognostication and may potentially transform into a therapeutic potential.

Discovery and structure-activity relationship analysis of Staphylococcus aureus sortase A inhibitors.

Methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. Compounds that inhibit the S. aureus SrtA sortase may function as potent anti-infective agents as this enzyme attaches virulence factors to the cell wall. Using high-throughput screening, we have identified several compounds that inhibit the enzymatic activity of the SrtA. A structure-activity relationship (SAR) analysis led to the identification of several pyridazinone and pyrazolethione analogs that inhibit SrtA with IC(50) values in the sub-micromolar range. Many of these molecules also inhibit the sortase enzyme from Bacillus anthracis suggesting that they may be generalized sortase inhibitors.

The structure of the Staphylococcus aureus sortase-substrate complex reveals how the universally conserved LPXTG sorting signal is recognized.

In Gram-positive bacteria, sortase enzymes assemble surface proteins and pili in the cell wall envelope. Sortases catalyze a transpeptidation reaction that joins a highly conserved LPXTG sorting signal within their polypeptide substrate to the cell wall or to other pilin subunits. The molecular basis of transpeptidation and sorting signal recognition are not well understood, because the intermediates of catalysis are short lived. We have overcome this problem by synthesizing an analog of the LPXTG signal whose stable covalent complex with the enzyme mimics a key thioacyl catalytic intermediate. Here we report the solution structure and dynamics of its covalent complex with the Staphylococcus aureus SrtA sortase. In marked contrast to a previously reported crystal structure, we show that SrtA adaptively recognizes the LPXTG sorting signal by closing and immobilizing an active site loop. We have also used chemical shift mapping experiments to localize the binding site for the triglycine portion of lipid II, the second substrate to which surface proteins are attached. We propose a unified model of the transpeptidation reaction that explains the functions of key active site residues. Since the sortase-catalyzed anchoring reaction is required for the virulence of a number of bacterial pathogens, the results presented here may facilitate the development of new anti-infective agents.

Staphylococcus aureus Sortase A transpeptidase. Calcium promotes sorting signal binding by altering the mobility and structure of an active site loop.

Many virulence factors in gram-positive bacteria are covalently anchored to the cell-wall peptidoglycan by sortase enzymes, a group of widely distributed cysteine transpeptidases. The Staphylococcus aureus Sortase A protein (SrtA) is the archetypal member of the Sortase family and is activated by Ca2+, an adaptation that may facilitate host colonization as elevated concentrations of this ion are encountered in human tissue. Here we show that a single Ca2+ ion bound to an ordered pocket on SrtA allosterically activates catalysis by modulating both the structure and dynamics of a large active site loop. Detailed nitrogen-15 relaxation measurements indicate that Ca2+ may facilitate the adaptive recognition of the substrate by inducing slow micro- to millisecond time-scale dynamics in the active site. Interestingly, relaxation compensated Carr-Purcell-Meiboom-Gill experiments suggest that the time scale of these motions is directly correlated with ion binding. The results of site-directed mutagenesis indicate that this motional coupling is mediated by the side chain of Glu-171, which is positioned within the beta6/beta7 loop and shown to contribute to Ca2+ binding. The available structural and dynamics data are compatible with a loop closure model of Ca2+ activation, in which the beta6/beta7 loop fluctuates between a binding competent closed form that is stabilized by Ca2+, and an open, highly flexible state that removes key substrate contacting residues from the active site.