Three-dimensional interactions analysis of the anticancer target c-src kinase with its inhibitors

Src family kinases (SFKs) constitute the biggest family of non-receptor tyrosine kinases considered as therapeutic targets for cancer therapy. An aberrant expression and/or activation of the proto-oncogene c-Src kinase, which is the oldest and most studied member of the family, has long been demonstrated to play a major role in the development, growth, progression and metastasis of numerous human cancers, including colon, breast, gastric, pancreatic, lung and brain carcinomas. For these reasons, the pharmacological inhibition of c-Src activity represents an effective anticancer strategy and a few compounds targeting c-Src, together with other kinases, have been approved as drugs for cancer therapy, while others are currently undergoing preclinical studies. Nevertheless, the development of potent and selective inhibitors of c-Src aimed at properly exploiting this biological target for the treatment of cancer still represents a growing field of study. In this review, the co-crystal structures of c-Src kinase in complex with inhibitors discovered in the past two decades have been described, highlighting the key ligand–protein interactions necessary to obtain high potency and the features to be exploited for addressing selectivity and drug resistance issues, thus providing useful information for the design of new and potent c-Src kinase inhibitors

Thyroid nodules treated with percutaneous radiofrequency thermal ablation: a comparative study

Percutaneous radiofrequency thermal ablation (RTA) was reported as an effective tool for the management of thyroid nodules (TNs). The aim of this study was to investigate the effects of RTA and to establish whether they were treatment-related by comparison with a matched, untreated control group

The Link Between Income, Income Inequality, and Prosocial Behavior Around the World

Abstract. The questions of whether high-income individuals are more prosocial than low-income individuals and whether income inequality moderates this effect have received extensive attention. We shed new light on this topic by analyzing a large-scale dataset with a representative sample of respondents from 133 countries ( N = 948,837). We conduct a multiverse analysis with 30 statistical models: 15 models predicting the likelihood of donating money to charity and 15 models predicting the likelihood of volunteering time to an organization. Across all model specifications, high-income individuals were more likely to donate their money and volunteer their time than low-income individuals. High-income individuals were more likely to engage in prosocial behavior under high (vs. low) income inequality. Avenues for future research and potential mechanisms are discussed. </jats:p

Effectiveness of Lactobacillus-containing vaginal tablets in the treatment of symptomatic bacterial vaginosis

AbstractThe purpose of this study was to determine the effectiveness of Lactobacillus-containing vaginal tablets in the treatment of bacterial vaginosis (BV) and in the restoration of a healthy vaginal flora. Thirty-nine women with BV were enrolled in a double-blind, placebo-controlled clinical trial. Patients received either one Lactobacillus-containing tablet or placebo daily for 7 days. Clinical criteria, vaginal Gram stain scores and symptoms were compared with those at the initial visit and those at completion of therapy and 2 weeks later. After completion of therapy, all of the patients in the Lactobacillus-treated group (n = 18) were free of BV, showing a normal (83%) or intermediate (17%) vaginal flora, as compared with only two patients free of BV with intermediate flora (12%) from among the 16 placebo-treated women (p <0.001). Two weeks after completion of therapy, treatment was successful (score <7) in 61% of Lactobacillus-treated patients as compared with 19% of those in the placebo group (p <0.05). In the treatment group, the total number of symptomatic patients and the intensity of their symptoms, in particular vaginal malodour, were significantly reduced at both follow-up visits. The data indicate that intravaginal administration of exogenous selected strains of lactobacilli can restore a normal vaginal microbiota and be used in treating bacterial vaginosis

Discovery of monoacylglycerol lipase (MAGL) inhibitors based on a pharmacophore-guided virtual screening study

Monoacylglycerol lipase (MAGL) is an important enzyme of the endocannabinoid system that catalyzes the degradation of the major endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL is associated with pathological conditions such as pain, inflammation and neurodegenerative diseases like Parkinson's and Alzheimer's disease. Furthermore, elevated levels of MAGL have been found in aggressive breast, ovarian and melanoma cancer cells. Due to its different potential therapeutic implications, MAGL is considered as a promising target for drug design and the discovery of novel small-molecule MAGL inhibitors is of great interest in the medicinal chemistry field. In this context, we developed a pharmacophore-based virtual screening protocol combined with molecular docking and molecular dynamics simulations, which showed a final hit rate of 50% validating the reliability of the in silico workflow and led to the identification of two promising and structurally different reversible MAGL inhibitors, VS1 and VS2. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent MAGL inhibitors

Preoperative insulin-like growth factor-binding protein-3 (IGFBP-3) blood level predicts gleason sum upgrading

In this study, we evaluated the ability of preoperative IGFBP-2, IGFBP-3, IL-6, and SIL-6R serum levels to predict Gleason score upgrade in 52 PCa patients