Virtual Screening for Potential Phytobioactives as Therapeutic Leads to Inhibit NQO1 for Selective Anticancer Therapy.

NAD(P)H:quinone acceptor oxidoreductase-1 (NQO1) is a ubiquitous flavin adenine dinucleotide-dependent flavoprotein that promotes obligatory two-electron reductions of quinones, quinonimines, nitroaromatics, and azo dyes. NQO1 is a multifunctional antioxidant enzyme whose expression and deletion are linked to reduced and increased oxidative stress susceptibilities. NQO1 acts as both a tumor suppressor and tumor promoter; thus, the inhibition of NQO1 results in less tumor burden. In addition, the high expression of NQO1 is associated with a shorter survival time of cancer patients. Inhibiting NQO1 also enables certain anticancer agents to evade the detoxification process. In this study, a series of phytobioactives were screened based on their chemical classes such as coumarins, flavonoids, and triterpenoids for their action on NQO1. The in silico evaluations were conducted using PyRx virtual screening tools, where the flavone compound, Orientin showed a better binding affinity score of -8.18 when compared with standard inhibitor Dicumarol with favorable ADME properties. An MD simulation study found that the Orientin binding to NQO1 away from the substrate-binding site induces a potential conformational change in the substrate-binding site, thereby inhibiting substrate accessibility towards the FAD-binding domain. Furthermore, with this computational approach we are offering a scope for validation of the new therapeutic components for their in vitro and in vivo efficacy against NQO1.

Interobserver variability when employing the IUGA/ICS classification system for complications related to prostheses and grafts in female pelvic floor surgery.

INTRODUCTION AND HYPOTHESIS: To unify and organize reporting, an International Urogynecological Association (IUGA)/International Continence Society (ICS) expert consortium published terminology guidelines with a classification system for complications related to implants used in female pelvic surgery. We hypothesize that the complexity of the codification system may be a hindrance to precision, especially with decreasing levels of postgraduate expertise. METHODS: Residents, fellows, and attending physicians were asked to code seven test cases taken from published literature. Category, timing, and site components of the classification system were assessed independently and according to the level of training. Interobserver reliability was calculated as percent agreement and Fleiss' kappa statistic. RESULTS: A total of 24 participants (6 attending physicians, 3 fellows, and 15 residents) were tested. The percent agreement showed significant variation when classified by level of training. In all categories, attending physicians had the greatest percentage agreement and largest kappa. The most agreement was seen when attending physicians classified mesh complications by time, 71% agreement with kappa 0.73 [95% confidence interval (CI) 0.58-0.88]. For the same task, the percentage agreement for fellows was 57%, kappa 0.55 (95% CI 0.23-0.87) and with residents 57%, kappa 0.71([95% CI 0.64-0.78). Interestingly, the site component of the classification system had the least overall agreement and lowest kappa [0%, kappa 0.29 (95% CI 0.26-0.32)] followed by the category component [14%, kappa 0.48 (95% CI 0.46-0.5)]. CONCLUSIONS: The IUGA/ICS mesh complication classification system has poor interobserver reliability. This trended downward with decreasing postgraduate level; however, we did not have sufficient statistical power to show an association when stratifying by all training levels. This highlights the complex nature of the classification system in its current form and its limitation for widespread clinical and research application.

Clinical findings associated with bladder trabeculations in women.

INTRODUCTION AND HYPOTHESIS: This study evaluated whether bladder trabeculations are associated with advanced prolapse, urinary urgency, or detrusor overactivity among women undergoing office cystoscopy. It is well established that bladder trabeculations are associated with bladder outlet obstruction (BOO) in men; however, the clinical significance of trabeculations in women is unclear. Whereas an analogous relationship has been proposed between prostatic obstruction in men and advanced pelvic organ prolapse (POP) in women, little data in the medical literature supports this theory. METHODS: A retrospective cohort study was conducted using Current Procedural Terminology (CPT) codes (52000, 52204) to identify all women who underwent office cystoscopy at our urogynecology center between January 2008 and May 2011. The 551 women identified were grouped by the presence or absence of bladder trabeculations. Multivariable logistic regression was used to estimate the association between trabeculations and the primary aim, increasing stage of prolapse, and the secondary aims: bladder outlet obstruction, detrusor overactivity, or urge urinary incontinence (UUI). RESULTS: Of the 551 women meeting inclusion criteria, 86 had trabeculations. Controlling for age, the odds of bladder trabeculations were eightfold greater for women with stage IV POP when compared with women with stage 0 prolapse [odds ratio (OR) 8.2, 95% confidence interval (CI) 1.6-43.1]. The odds of bladder trabeculations were twofold greater for women with detrusor overactivity (OR 2.3, 95% CI 1.3-4.0) found on urodynamic study and also as reflected subjectively by answers to Pelvic Floor Distress Inventory (PFDI) item number 16 (OR 4.2, 95% CI 1.3-14.5). CONCLUSION: In this study, bladder trabeculations were associated with stage IV prolapse in the anterior compartment as well as with detrusor overactivity and UUI.

Bile acid ratio in diagnosis of intrahepatic cholestasis of pregnancy.

We sought to determine if the bile acid ratio of cholic acid to chenodeoxycholic acid (CA:CDCA) is an important component for diagnosis of intrahepatic cholestasis of pregnancy (ICP). We assessed the addition of bile acid CA:CDCA ratio information in diagnosing ICP in a database of patients evaluated for ICP by serum bile acids and hepatic transaminases. Patients were considered to test positive for ICP if there was elevation in total bile acid, CA:CDCA ratio, or transaminase. Of 231 specimens evaluated for ICP with bile acid and transaminases, 17.1% had elevated total bile acids, 29.4% had elevated transaminase, and 8.2% had an elevated bile acid ratio. Most specimens with elevated bile acid ratio also had elevated total bile acid; 35.5% of specimens tested positive by total bile acid and/or transaminases, increasing minimally to 35.9% with bile acid ratio information. Similar results were found using lower total bile acid and bile acid ratio thresholds. The bile acid CA:CDCA ratio contributed little to the diagnosis of ICP. The use of total bile acid and hepatic transaminases without bile acid ratios decreased positive tests by less than 2%.