A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

Funder: Fundación Científica Asociación Española Contra el Cáncer (ES)Funder: Cancer Focus Northern Ireland and Department for Employment and LearningFunder: Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USAAbstract: Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support. Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases

E-waste valorisation by recovering valuable metals with microorganisms

The effectiveness of bioleaching in copper recovery from printed circuit boards by Acidithiobacillus ferrooxidans has been evaluated under a wide range of conditions demonstrating the suitability of the technology and their limits. The process has been tested using a column reactor simulating conditions found at industrial scale and operating in continuous mode. Moreover, new strategies have been adapted to increase the efficiency of the operation and to reduce the time required for this purpose. Taking into account the complex composition of electronic waste, the limitations of applicability, for instance due to the accumulation of toxic metals in the solution, have been also identified by microrespirometric measurements. Experiments carried out at laboratory scale verifies the proof of concept of the biotechnology for this application, recovering 37% of copper using flasks with a concentration of 7.5 g/L of e-waste in 6 hours. This efficiency was improved in the case of the packed column, where 50% of copper was recovered using the same amount of e-waste at the same period time. New strategy was developed to increase the kinetic of reaction and overcome transport limitations for the leaching solution, achieving copper recoveries up to 80% in the same period than previously reported. Regarding toxicity assays, the methodology used allows to identify that, depending on the concentration and the time exposed, nickel, copper and aluminium affected the microorganisms’ activity, inactivating them. It was concluded that aluminium resulted more toxic than copper, which in turn was more toxic than nickel, at the conditions tested.Peer Reviewe

E-waste valorisation by recovering valuable metals with microorganisms

The effectiveness of bioleaching in copper recovery from printed circuit boards by Acidithiobacillus ferrooxidans has been evaluated under a wide range of conditions demonstrating the suitability of the technology and their limits. The process has been tested using a column reactor simulating conditions found at industrial scale and operating in continuous mode. Moreover, new strategies have been adapted to increase the efficiency of the operation and to reduce the time required for this purpose. Taking into account the complex composition of electronic waste, the limitations of applicability, for instance due to the accumulation of toxic metals in the solution, have been also identified by microrespirometric measurements. Experiments carried out at laboratory scale verifies the proof of concept of the biotechnology for this application, recovering 37% of copper using flasks with a concentration of 7.5 g/L of e-waste in 6 hours. This efficiency was improved in the case of the packed column, where 50% of copper was recovered using the same amount of e-waste at the same period time. New strategy was developed to increase the kinetic of reaction and overcome transport limitations for the leaching solution, achieving copper recoveries up to 80% in the same period than previously reported. Regarding toxicity assays, the methodology used allows to identify that, depending on the concentration and the time exposed, nickel, copper and aluminium affected the microorganisms’ activity, inactivating them. It was concluded that aluminium resulted more toxic than copper, which in turn was more toxic than nickel, at the conditions tested.Peer Reviewe

Endoscopic treatments for Barrett's esophagus: a systematic review of safety and effectiveness compared to esophagectomy

<p>Abstract</p> <p>Background</p> <p>Recently, several new endoscopic treatments have been used to treat patients with Barrett's esophagus with high grade dysplasia. This systematic review aimed to determine the safety and effectiveness of these treatments compared with esophagectomy.</p> <p>Methods</p> <p>A comprehensive literature search was undertaken to identify studies of endoscopic treatments for Barrett's esophagus or early stage esophageal cancer. Information from the selected studies was extracted by two independent reviewers. Study quality was assessed and information was tabulated to identify trends or patterns. Results were pooled across studies for each outcome. Safety (occurrence of adverse events) and effectiveness (complete eradication of dysplasia) were compared across different treatments.</p> <p>Results</p> <p>The 101 studies that met the selection criteria included 8 endoscopic techniques and esophagectomy; only 12 were comparative studies. The quality of evidence was generally low. Methods and outcomes were inconsistently reported. Protocols, outcomes measured, follow-up times and numbers of treatment sessions varied, making it difficult to calculate pooled estimates.</p> <p>The surgical mortality rate was 1.2%, compared to 0.04% in 2831 patients treated endoscopically (1 death). Adverse events were more severe and frequent with esophagectomy, and included anastomotic leaks (9.4%), wound infections (4.1%) and pulmonary complications (4.1%). Four patients (0.1%) treated endoscopically experienced bleeding requiring transfusions. The stricture rate with esophagectomy (5.3%) was lower than with porfimer sodium photodynamic therapy (18.5%), but higher than aminolevulinic acid (ALA) 60 mg/kg PDT (1.4%). Dysphagia and odynophagia varied in frequency across modalities, with the highest rates reported for multipolar electrocoagulation (MPEC). Photosensitivity, an adverse event that occurs only with photodynamic therapy, was experienced by 26.4% of patients who received porfimer sodium.</p> <p>Some radiofrequency ablation (RFA) or argon plasma coagulation (APC) studies (used in multiple sessions) reported rates of almost 100% for complete eradication of dysplasia. But the study methods and findings were not adequately described. The other studies of endoscopic treatments reported similarly high rates of complete eradication.</p> <p>Conclusions</p> <p>Endoscopic treatments offer safe and effective alternatives to esophagectomy for patients with Barrett's esophagus and high grade dysplasia. Unfortunately, shortcomings in the published studies make it impossible to determine the comparative effectiveness of each of the endoscopic treatments.</p