Design of drug-like hepsin inhibitors against prostate cancer and kidney stones

Hepsin, a transmembrane serine protease abundant in renal endothelial cells, is a promising therapeutic target against several cancers, particularly prostate cancer. It is involved in the release and polymerization of uromodulin in the urine, which plays a role in kidney stone formation. In this work, we design new potential hepsin inhibitors for high activity, improved specificity towards hepsin, and promising ADMET properties. The ligands were developed through a novel hierarchical pipeline. This pipeline explicitly accounts for off-target binding to the related serine proteases matriptase and HGFA (human hepatocyte growth factor activator). We completed the pipeline incorporating ADMET properties of the candidate inhibitors into custom multi-objective optimization functions. The ligands designed show excellent prospects for targeting hepsin the blood stream and the urine and thus enable key experimental studies. The computational pipeline proposed is remarkably cost-efficient and can be easily adapted for designing inhibitors against new drug targets.

Impact of time from biopsy to surgery on complications, functional and oncologic outcomes following radical prostatectomy

ABSTRACT Introduction: To determine the impact of time from biopsy to surgery on outcomes following radical prostatectomy (RP) as the optimal interval between prostate biopsy and RP is unknown. Material and methods: We identified 7, 350 men who underwent RP at our institution between 1994 and 2012 and had a prostate biopsy within one year of surgery. Patients were grouped into five time intervals for analysis: ≤ 3 weeks, 4-6 weeks, 7-12 weeks, 12-26 weeks, and > 26 weeks. Oncologic outcomes were stratified by NCCN disease risk for comparison. The associations of time interval with clinicopathologic features and survival were evaluated using multivariate logistic and Cox regression analyses. Results: Median time from biopsy to surgery was 61 days (IQR 37, 84). Median follow-up after RP was 7.1 years (IQR 4.2, 11.7) while the overall perioperative complication rate was 19.7% (1,448/7,350). Adjusting for pre-operative variables, men waiting 12-26 weeks until RP had the highest likelihood of nerve sparing (OR: 1.45, p = 0.02) while those in the 4-6 week group had higher overall complications (OR: 1.33, p = 0.01). High risk men waiting more than 6 months had higher rates of biochemical recurrence (HR: 3.38, p = 0.05). Limitations include the retrospective design. Conclusions: Surgery in the 4-6 week time period after biopsy is associated with higher complications. There appears to be increased biochemical recurrence rates in delaying RP after biopsy, for men with both low and high risk disease.

Oncological outcomes following radical prostatectomy for patients with pT4 prostate cancer

ABSTRACT Objectives: Radical prostatectomy (RP) for locally advanced prostate cancer may reduce the risk of metastasis and cancer-specific death. Herein, we evaluated the outcomes for patients with pT4 disease treated with RP. Materials and methods: Among 19,800 men treated with RP at Mayo Clinic from 1987 to 2010, 87 were found to have pT4 tumors. Biochemical recurrence (BCR)-free survival, systemic progression (SP) free survival and overall survival (OS) were estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards regression models were used to assess the association of clinic-pathological features with outcome. Results: Median follow-up was 9.8 years (IQR 3.6, 13.4). Of the 87 patients, 50 (57.5%) were diagnosed with BCR, 30 (34.5%) developed SP, and 38 (43.7%) died, with 11 (12.6%) dying of prostate cancer. Adjuvant androgen deprivation therapy was administered to 77 men, while 32 received adjuvant external beam radiation therapy. Ten-year BCR-free survival, SP-free survival, and OS was 37%, 64%, and 70% respectively. On multivariate analysis, the presence of positive lymph nodes was marginally significantly associated with patients' risk of BCR (HR: 1.94; p=0.05), while both positive lymph nodes (HR 2.96; p=0.02) and high pathologic Gleason score (HR 1.95; p=0.03) were associated with SP. Conclusions: Patients with pT4 disease may experience long-term survival following RP, and as such, when technically feasible, surgical resection should be considered in the multimodal treatment approach to these men.

Comparison of different indicators of iodine deficiency in school children

To compare different indicators of iodine deficiency disorders [IDD] in school children from study sites in Bangladesh Indonesia, Guatemala, and the United States. Cross-sectional surveys were performed in Savar, Bangladesh; Sukabumi, Indonesia; San Pedro Sacatepequez, Guatemala; and Atlanta, United States. In each study site, school children were assessed for thyroid size by palpation and thyroid volume by ultrasonography, urine specimens collected for iodine concentration, and finger stick blood specimens spotted onto filter paper for assessment of thyroid stimulating hormone [TSH] and thyroglobulin [Tg]. Weights and heights were collected in all sites except Guatemala. Between 305 to 518 school children were surveyed in each site. Indicators based on thyroid size tended to indicate more severe levels of iodine deficiency compared to urinary iodine based on WHO/UNICEF/ICCIDD criteria. TSH levels appeared to correlate well with other indicators of IDD whereas Tg did not. In these study sties, it appeared that urinary iodine, thyroid volume [based on body surface area], palpation, and TSH were consistent in identifying the Bangladesh site as having the highest prevalence of IDD, followed by sites in Indonesia, Guatemala, and the United States. The prevalence of goiter indicated more severe levels of IDD compared to urinary iodine levels. Tg was not significantly different between the study sites