A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.

A network-based computational and experimental framework for repurposing compounds toward the treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is among the most common liver pathologies, however, none approved condition-specific therapy yet exists. The present study introduces a drug repositioning (DR) approach that combines in vitro steatosis models with a network-based computational platform, constructed upon genomic data from diseased liver biopsies and compound-treated cell lines, to propose effectively repositioned therapeutic compounds. The introduced in silico approach screened 20'000 compounds, while complementary in vitro and proteomic assays were developed to test the efficacy of the 46 in silico predictions. This approach successfully identified six compounds, including the known anti-steatogenic drugs resveratrol and sirolimus. In short, gallamine triethiotide, diflorasone, fenoterol, and pralidoxime ameliorate steatosis similarly to resveratrol/sirolimus. The implementation holds great potential in reducing screening time in the early drug discovery stages and in delivering promising compounds for in vivo testing.

Intravenous lidocaine does not affect the anesthetic depth during rapid sequence induction and intubation as assessed by Bispectral Index monitoring: a randomized double blind study.

INTRODUCTION: We investigated the impact of intravenous lidocaine on anesthetic depth, as assessed by Bispectral Index score (BIS), and hemodynamic responses to rapid sequence induction/intubation. MATERIAL AND METHODS: Eighty-four surgical patients with risk factors for regurgitation/aspiration were randomized to receive either lidocaine 1.5 mg/kg or normal saline in a double-blind fashion. Propofol 2 mg/kg, lidocaine or normal saline, followed by rocuronium 1 mg/kg were administered intravenously and trachea was intubated under cricoid pressure application. The BIS scores were recorded before induction of anesthesia, immediately after, at 30 s and 1 min after rocuronium injection and every 30 s after intubation, for 10 min. Systolic/diastolic blood pressure and heart rate were measured before induction, immediately after and at 1 min following rocuronium administration, and every minute for 10 min after intubation. RESULTS: Data from 78 patients were analyzed. Demograpic characteristics did not differ between the study groups. A total of 24 BIS scores were recorded for each patient. No difference was found in BIS values between lidocaine and control groups at any time point (F = 2.936, p = 0.91). Also no difference was detected in heart rate, systolic and diastolic blood pressure at any time point of the study period between the two groups (F = 0.063, p = 0.80, F = 0.007, p = 0.93, F = 0.435, p = 0.51 respectively). No episodes of significant bradycardia occurred and none of the patients reported awareness/recall of the procedure. CONCLUSIONS: Lidocaine 1.5 mg/kg given intravenously during rapid sequence induction does not affect BIS values, or blunt the hemodymanic response to laryngoscopy and intubation.