An insight about the mechanism of action (MoA) of R-bicalutamide on the androgen receptor homodimer using molecular dynamic.

R-bicalutamide is a first-line therapy used to treat prostate cancer (PCa) inhibiting the androgen receptor (AR) which plays an important role in the development and the progression of PCa. However, after a protracted drug administration, many patients develop a form of androgen insensitivity since R-bicalutamide starts to exhibit some agonistic properties lead by the W741L AR mutation in the ligand-binding pocket even if the mechanism of the antagonist-agonist switch is still not clear. To study the drug-resistant mechanism, we explored the structural effects of the antagonist R-bicalutamide on the homodimer stability considering both the AR wild-type and W741L employing molecular dynamic (MD) simulations. The results obtained indicate that the binding of R-bicalutamide in the two AR monomers induces a great instability in the homodimer, which may determine the monomer's dissociation preventing AR migration into the nucleus and avoiding the transcriptional activity. If the W741L mutation occurs, the homodimer tends to have a behaviour close to the agonistic system where the two monomers are tightly bound, which may explain the effect of the W741L in drug insensitivity from a structural point of view.

The Application of In Silico Methods on Umami Taste Receptor.

The umami taste receptor is a heterodimer composed of two members of the T1R taste receptor family: T1R1 (taste receptor type 1 member 1) and T1R3 (taste receptor type 1 member 3). Taste receptor T1R1-T1R3 can be activated, or modulated, by binding to several natural ligands, such as L-glutamate, inosine-5'-monophosphate (IMP), and guanosine-5'-monophosphate (GMP). Because no structure of the umami taste receptor has been solved until now, in silico techniques, such as homology modelling, molecular docking, and molecular dynamics (MD) simulations, are used to generate a 3D structure model of this receptor and to understand its molecular mechanisms. The purpose of this chapter is to highlight how computational methods can provide a better deciphering of the mechanisms of action of umami ligands in activating the umami taste receptors leading to advancements in the taste research field.

New in Silico Trends in Food Toxicology.

Ever growing numbers of chemicals in food and drinking water make it impossible to address safety by classical approaches in toxicology. In silico chemical methods could be a first-line for hazard characterization, requiring food toxicology to expand the use of approaches currently well applied in medicinal chemistry.

In silico pharmacogenetic approach: The natalizumab case study.

Natalizumab is a humanized monoclonal antibody to α4ß1 integrin and is approved for the treatment of Multiple Sclerosis. In patients there is a great variation in drug response and there is much evidence that genetic contributors play an important role in defining an individual's susceptibility. Natalizumab binds to α4-residues Gln-152, Lys-201, Lys256, and these seem to be essential for its activity. Studies on a range of species in disease model have showed a loss of reactivity when any one of those three residues were different to human. Based on these animal studies, we thought that the single nucleotide polymorphism in the ITGA4 human gene causing a lysine to arginine transversion at amino acid position 256 require further investigations in the context of individual drug susceptibility. So, the aim of our study was to investigate the association between this genetic polymorphism and the resistance to natalizumab. We had applied molecular dynamics simulation to study the possible conformational changes induced by Lys256Arg transversion on the overall structure of integrin and we have analyzed the binding affinities of natalizumab in the non-mutated and mutated structures through HINT score. We found that this SNP does not affect the VLA4-natalizumab interaction. Instead, the binding affinities are slightly higher in the mutated complex than in the wild-type. We reported one of the first work in which MD simulation was applied in the pharmacogenetic context, and this approach is rapid and cost effective, since a population survey is carried out only after the positive prediction of simulation.

Synchronous hepatocellular carcinoma and renal cell carcinoma in young woman with sarcoidosis: A case report.

Hepatocellular carcinoma (HCC) and clear cell renal carcinoma are both frequent cancers, especially in patients with risk factors such as cirrhosis in the first case or genetic mutations such as Li-Fraumeni syndrome in the second case; however, their synchronous appearance is very rare especially in young patients with no apparent predisposing factors. We describe the case of a 33-year-old woman with acute pain onset in right hypochondrium. The ultrasound (US) imaging and the contrast-enhanced computed tomography (CECT) of the abdomen revealed 2 abdominal masses: one in the VI-VII segments of the liver and the other one in the right kidney. The chest CECT study, acquired for staging purpose, detected multiple micronodules with patchy peri-bronchial distribution at both lungs. At the histological examination, the tumor arising from the right kidney was finally diagnosed as clear cell renal carcinoma, whereas the tumor arising from the right lateral hepatic lobe as HCC. The histological examination of lung lesions revealed sarcoidosis granulomas. The patient is still being followed up for the occurrence of lung and lymph node metastases from HCC 14 months later.

Computational methods on food contact chemicals: Big data and in silico screening on nuclear receptors family.

According to Eurostat, the EU production of chemicals hazardous to health reached 211 million tonnes in 2019. Thus, the possibility that some of these chemical compounds interact negatively with the human endocrine system has received, especially in the last decade, considerable attention from the scientific community. It is obvious that given the large number of chemical compounds it is impossible to use in vitro/in vivo tests for identifying all the possible toxic interactions of these chemicals and their metabolites. In addition, the poor availability of highly curated databases from which to retrieve and download the chemical, structure, and regulative information about all food contact chemicals has delayed the application of in silico methods. To overcome these problems, in this study we use robust computational approaches, based on a combination of highly curated databases and molecular docking, in order to screen all food contact chemicals against the nuclear receptor family in a cost and time-effective manner.

Device-Related Complications and Inappropriate Therapies Among Subcutaneous vs. Transvenous Implantable Defibrillator Recipients: Insight Monaldi Rhythm Registry.

Introduction: In the context of randomized clinical trials, subcutaneous implantable cardiac defibrillators (S-ICDs) are non-inferior to transvenous ICDs (T-ICDs) concerning device-related complications or inappropriate shocks in patients with an indication for defibrillator therapy and not in need of pacing. We aimed at describing the clinical features of patients who underwent S-ICD implantation in our clinical practice, as well as the ICD-related complications and the inappropriate therapies among S-ICD vs. T-ICD recipients during a long-term follow-up. Materials and Methods: All patients undergoing ICD, both S-ICD and TV-ICD, at Monaldi Hospital from January 1, 2015 to January 1, 2019 and followed up at our institution were included in the present analysis. The clinical variables associated with S-ICD implantation were evaluated by logistic regression analyses. We collected the ICD inappropriate therapies, ICD-related complications (including both pulse generator and lead-related complications), ICD-related infections, appropriate ICD therapies, and overall mortality. Kaplan-Meier (KM) analyses were performed to assess the risk of clinical outcome events between the two subgroups. A time-dependent Cox regression analysis was performed to adjust the results. Results: Total 607 consecutive patients (mean age 53.8 ± 16.8, male 77.8%) with both TV-ICD (n: 290, 47.8%) and S-ICD (n: 317, 52.2%), implanted and followed at our center for a mean follow-up of 1614 ± 1018 days, were included in the study. At multivariate logistic regression analysis, an independent association between S-ICD implantation and ionic channel disease [OR: 6.01 (2.26-15.87); p < 0.0001] and ischemic cardiomyopathy [OR: 0.20 (0.12-0.35); p < 0.0001] was shown. The KM analysis did not show a significantly different risk of the inappropriate ICD therapies (log rank p = 0.64) between the two subgroups; conversely, a significant increase in the risk of ICD-related complications (log rank p = 0.02) and infections (log rank p = 0.02) in TV-ICD group was shown. The adjusted risk for ICD-related infections [OR: 0.07 (0.009-0.55), p = 0.01] and complications [0.31 (0.12-0.81), p = 0.01] was significantly lower among patients with S-ICD. Conclusions: The choice to implant S-ICD was mainly driven by younger age and the presence of ionic channel disease; conversely ischemic cardiomyopathy reduces the probability to use this technology. No significant differences in inappropriate ICD therapies were shown among S-ICD vs. TV-ICD group; moreover, S-ICD is characterized by a lower rate of infectious and non-infectious complications leading to surgical revision or extraction.

Polymorphism rs7214723 in CAMKK1: a new genetic variant associated with cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of deaths worldwide. CVDs have a complex etiology due to the several factors underlying its development including environment, lifestyle, and genetics. Given the role of calcium signal transduction in several CVDs, we investigated via PCR-restriction fragment length polymorphism (RFLP) the single nucleotide polymorphism (SNP) rs7214723 within the calcium/calmodulin-dependent kinase kinase 1 (CAMKK1) gene coding for the Ca2+/calmodulin-dependent protein kinase kinase I. The variant rs7214723 causes E375G substitution within the kinase domain of CAMKK1. A cross-sectional study was conducted on 300 cardiac patients. RFLP-PCR technique was applied, and statistical analysis was performed to evaluate genotypic and allelic frequencies and to identify an association between SNP and risk of developing specific CVD. Genotype and allele frequencies for rs7214723 were statistically different between cardiopathic and several European reference populations. A logistic regression analysis adjusted for gender, age, diabetes, hypertension, BMI and previous history of malignancy was applied on cardiopathic genotypic data and no association was found between rs7214723 polymorphism and risk of developing specific coronary artery disease (CAD) and aortic stenosis (AS). These results suggest the potential role of rs7214723 in CVD susceptibility as a possible genetic biomarker.

Risk-benefit in food safety and nutrition - Outcome of the 2019 Parma Summer School.

Risk-benefit assessment is the comparison of the risk of a situation to its related benefits, i.e. a comparison of scenarios estimating the overall health impact. The risk-benefit analysis paradigm mirrors the classical risk analysis one: risk-benefit assessment goes hand-in-hand with risk-benefit management and risk-benefit communication. The various health effects associated with food consumption, together with the increasing demand for advice on healthy and safe diets, have led to the development of different research disciplines in food safety and nutrition. In this sense, there is a clear need for a holistic approach, including and comparing all of the relevant health risks and benefits. The risk-benefit assessment of foods is a valuable approach to estimate the overall impact of food on health. It aims to assess together the negative and positive health effects associated with food intake by integrating chemical and microbiological risk assessment with risk and benefit assessment in food safety and nutrition. The 2019 Parma Summer School on risk-benefit in food safety and nutrition had the objective was to provide an opportunity to learn from experts in the field of risk-benefit approach in food safety and nutrition, including theory, case studies, and communication of risk-benefit assessments plus identify challenges for the future. It was evident that whereas tools and approaches have been developed, more and more case studies have been performed which can form an inherent validation of the risk-benefit approach. Executed risk-benefit assessment case studies apply the steps and characteristics developed: a problem formulation (with at least 2 scenarios), a tiered approach until a decision can be made, one common currency to describe both beneficial and adverse effects (DALYs in most instances). It was concluded that risk-benefit assessment in food safety and nutrition is gaining more and more momentum, while also many challenges remain for the future. Risk-benefit is on the verge of really enrolling into the risk assessment and risk analysis paradigm. The interaction between risk-benefit assessors and risk-benefit managers is pivotal in this, as is the interaction with risk-benefit communicators.

Gene polymorphisms in calcium-calmodulin pathway: Focus on cardiovascular disease.

Cardiovascular disease is the leading cause of death in industrialized countries and affects an increasing number of people. Several risk factors play an important role in the etiology of this disease, such as an unhealthy lifestyle. It is increasingly clear that genetic factors influencing the molecular basis of excitation-contraction mechanisms in the heart could contribute to modify the individual's risk. Thanks to the progress that has been made in understanding calcium signaling in the heart, it is assumed that calmodulin can play a crucial role in the excitation-contraction coupling. In fact, calmodulin (CaM) binds calcium and consequently regulates calcium channels. Several works show how some polymorphic variants can be considered predisposing factors to complex pathologies. Therefore, we hypothesize that the identification of polymorphic variants of proteins involved in the CaM pathway could be important for understanding how genetic traits can influence predisposition to myocardial infarction. This review considers each pathway of the three different isoforms of calmodulin (CaM1; CaM2; CaM3) and focuses on some common proteins involved in the three pathways, with the aim of analyzing the polymorphisms studied in the literature and understanding if they are associated with cardiovascular disease.

Molecular modelling methods in food safety: Bisphenols as case study.

Bisphenol A (BPA), a synthetic compound widely used as a building block for polycarbonate plastics, has been declared in the European Union (EU) as a substance of very high concern (SVHC). A series of BPA alternatives and derivatives (bisphenols/BPs) with similar physical-chemical properties have been produced and used by companies for substituting it. To evaluate the estrogenic and androgenic binding activity of 26 BPs, a non-statistical in silico approach has been applied. The results of molecular docking analyses applied on six different nuclear receptors (NRs) have revealed that: i) some BPA metabolites could lower the harmful effects of BPA exposure; ii) BPS is a lower interactor for all NRs, but it does not appear safer at all for androgen receptor (AR), for which its binding activity is found similar to a pharmacological anti-androgen; iii) only a BP has been found as a safer compound for all NRs considered. Moreover, molecular dynamic simulation of three BPs on ERα have revealed that the presence of negative hydrophobic interactions could induce a decrease in receptor activity. Overall, the present results demonstrate that in silico methods could be a valid approach to screen estrogenic and androgenic activity of food contact materials (FCMs).