Diet Quality and Upper Gastrointestinal Cancers Risk:A Meta-Analysis and Critical Assessment of Evidence Quality

We aimed to assess the effect of a high-quality diet on the risk of upper gastrointestinal cancer and to evaluate the overall quality of our findings by searching PubMed, EMBASE, Web of Science, Cochrane, and the references of related articles to February 2020. Two reviewers independently retrieved the data and performed the quality assessments. We defined the highest-quality diet as that with the lowest Diet Inflammatory Index category and the highest Mediterranean Diet Score category. Overall odds ratios and 95% confidence intervals were estimated for upper gastrointestinal cancer risk comparing the highest- versus lowest-diet quality. A random-effects meta-analysis was then applied with Review Manager, and the quality of the overall findings was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation approach. The highest-quality diets were significantly associated with reduced risk of upper gastrointestinal cancers, achieving odds ratios of 0.59 (95% confidence interval: 0.48-0.72) for the Diet Inflammatory Index, pooling the findings from nine studies, and 0.72 (95% confidence interval: 0.61-0.88) for the Mediterranean Diet Score, pooling the findings from 11 studies. We observed a minimum of 69% heterogeneity in the pooled results. The pooled results were graded as low quality of evidence. Although it may be possible to offer evidence-based general dietary advice for the prevention of upper gastrointestinal cancers, the evidence is currently of insufficient quality to develop dietary recommendations

RGD-avidin–biotin pretargeting to αvβ3 integrin enhances the proapoptotic activity of TNFα related apoptosis inducing ligand (TRAIL)

Recombinant TNF-related apoptosis-inducing ligand (TRAIL) is considered a powerful and selective inducer of tumor cell death. We hypothesize that TRAIL’s potential as anticancer agent can be enhanced further by promoting its accumulation in tumor tissue. For this purpose, we developed TRAIL complexes that bind to angiogenic endothelial cells. We employed an avidin–biotin pretargeting approach, in which biotinylated TRAIL interacted with RGD-equipped avidin. The assembled complexes killed tumor cells (Jurkat T cells) via apoptosis induction. Furthermore, we demonstrated that the association of the RGD-avidin-TRAIL complex onto endothelial cells enhanced the tumor cell killing activity. Endothelial cells were not killed by TRAIL nor its derived complexes. Our approach can facilitate the enrichment of TRAIL onto angiogenic blood vessels, which may enhance intratumoral accumulation. Furthermore, it offers a versatile technology for the complexation of targeting ligands with therapeutic recombinant proteins and by this a novel way to enhance their specificity and activity

Not interesting enough to be followed by the NSA: An analysis of Dutch privacy attitudes

Open curtains and a careless attitude. The Dutch are described as holding an indifferent stance towards privacy in the aftermath of Snowden’s revelations of far-reaching government surveillance. But are Dutch reactions as aloof as often claimed? This study provides an in-depth overview of privacy attitudes in the Dutch debate about the National Security Agency (NSA) leaks, showing a greater variety of sentiments than anticipated. A qualitative frame analysis and a quantitative descriptive analysis resulted in six frames, which convey distinct privacy attitudes. Online and offline as well as professional and non-journalistic content in the debate displays a different distribution of frames. The frames, ranging from an “End justifies the means” attitude to an anxious fear of an “Orwellian dystopia”, are placed in a larger framework as the research demonstrates the connection to existing theories about privacy and surveillance. Dutch discussions about the NSA revelations often display a trade-off narrative balancing safety against privacy, and include (de)legitimisation strategies. These outcomes are in line with previous studies about mediated surveillance debates, which indicates that privacy attitudes transcend national boundaries. However, the inclusion of user-generated content adds an individual dimension to the existing body of research and reveals a personal perspective on surveillance issues

Cementitious Barriers Partnership FY2013 End-Year Report

In FY2013, the Cementitious Barriers Partnership (CBP) demonstrated continued tangible progress toward fulfilling the objective of developing a set of software tools to improve understanding and prediction of the long‐term structural, hydraulic and chemical performance of cementitious barriers used in nuclear applications. In November 2012, the CBP released “Version 1.0” of the CBP Software Toolbox, a suite of software for simulating reactive transport in cementitious materials and important degradation phenomena. In addition, the CBP completed development of new software for the “Version 2.0” Toolbox to be released in early FY2014 and demonstrated use of the Version 1.0 Toolbox on DOE applications. The current primary software components in both Versions 1.0 and 2.0 are LeachXS/ORCHESTRA, STADIUM, and a GoldSim interface for probabilistic analysis of selected degradation scenarios. The CBP Software Toolbox Version 1.0 supports analysis of external sulfate attack (including damage mechanics), carbonation, and primary constituent leaching. Version 2.0 includes the additional analysis of chloride attack and dual regime flow and contaminant migration in fractured and non‐fractured cementitious material. The LeachXS component embodies an extensive material property measurements database along with chemical speciation and reactive mass transport simulation cases with emphasis on leaching of major, trace and radionuclide constituents from cementitious materials used in DOE facilities, such as Saltstone (Savannah River) and Cast Stone (Hanford), tank closure grouts, and barrier concretes. STADIUM focuses on the physical and structural service life of materials and components based on chemical speciation and reactive mass transport of major cement constituents and aggressive species (e.g., chloride, sulfate, etc.). THAMES is a planned future CBP Toolbox component focused on simulation of the microstructure of cementitious materials and calculation of resultant hydraulic and constituent mass transfer parameters needed in modeling. Two CBP software demonstrations were conducted in FY2013, one to support the Saltstone Disposal Facility (SDF) at SRS and the other on a representative Hanford high‐level waste tank. The CBP Toolbox demonstration on the SDF provided analysis on the most probable degradation mechanisms to the cementitious vault enclosure caused by sulfate and carbonation ingress. This analysis was documented and resulted in the issuance of a SDF Performance Assessment Special Analysis by Liquid Waste Operations this fiscal year. The two new software tools supporting chloride attack and dual‐regime flow will provide additional degradation tools to better evaluate performance of DOE and commercial cementitious barriers. The CBP SRNL experimental program produced two patent applications and field data that will be used in the development and calibration of CBP software tools being developed in FY2014. The CBP software and simulation tools varies from other efforts in that all the tools are based upon specific and relevant experimental research of cementitious materials utilized in DOE applications. The CBP FY2013 program involved continuing research to improve and enhance the simulation tools as well as developing new tools that model other key degradation phenomena not addressed in Version 1.0. Also efforts to continue to verify the various simulation tools through laboratory experiments and analysis of field specimens are ongoing and will continue into FY2014 to quantify and reduce the uncertainty associated with performance assessments. This end‐year report summarizes FY2013 software development efforts and the various experimental programs that are providing data for calibration and validation of the CBP developed software

The distributed ASCI supercomputer project

The Distributed ASCI Supercomputer (DAS) is a homogeneous wide-area distributed system consisting of four cluster computers at different locations. DAS has been used for research on communication software, parallel languages and programming systems, schedulers, parallel applications, and distributed applications. The paper gives a preview of the most interesting research results obtained so far in the DAS project

The 1000IBD project:multi-omics data of 1000 inflammatory bowel disease patients; data release 1

BackgroundInflammatory bowel disease (IBD) is a chronic complex disease of the gastrointestinal tract. Patients with IBD can experience a wide range of symptoms, but the pathophysiological mechanisms that cause these individual differences in clinical presentation remain largely unknown. In consequence, IBD is currently classified into subtypes using clinical characteristics. If we are to develop a more targeted treatment approach, molecular subtypes of IBD need to be discovered that can be used as new drug targets. To achieve this, we need multiple layers of molecular data generated from the same IBD patients.Construction and contentWe initiated the 1000IBD project (https://1000ibd.org) to prospectively follow more than 1000 IBD patients from the Northern provinces of the Netherlands. For these patients, we have collected a uniquely large number of phenotypes and generated multi-omics profiles. To date, 1215 participants have been enrolled in the project and enrolment is on-going. Phenotype data collected for these participants includes information on dietary and environmental factors, drug responses and adverse drug events. Genome information has been generated using genotyping (ImmunoChip, Global Screening Array and HumanExomeChip) and sequencing (whole exome sequencing and targeted resequencing of IBD susceptibility loci), transcriptome information generated using RNA-sequencing of intestinal biopsies and microbiome information generated using both sequencing of the 16S rRNA gene and whole genome shotgun metagenomic sequencing.Utility and discussionAll molecular data generated within the 1000IBD project will be shared on the European Genome-Phenome Archive (https://ega-archive.org, accession no: EGAS00001002702). The first data release, detailed in this announcement and released simultaneously with this publication, will contain basic phenotypes for 1215 participants, genotypes of 314 participants and gut microbiome data from stool samples (315 participants) and biopsies (107 participants) generated by tag sequencing the 16S gene. Future releases will comprise many more additional phenotypes and -omics data layers. 1000IBD data can be used by other researchers as a replication cohort, a dataset to test new software tools, or a dataset for applying new statistical models.ConclusionsWe report on the establishment and future development of the 1000IBD project: the first comprehensive multi-omics dataset aimed at discovering IBD biomarker profiles and treatment targets

Cementitious Barriers Partnership (CBP): Training and Release of CBP Toolbox Software, Version 1.0 -13480

ABSTRACT The Cementitious Barriers Partnership (CBP) Project is a multi-disciplinary, multi-institutional collaboration supported by the Office of Tank Waste Management within the Office of Environmental Management of U.S. Department of Energy (US DOE). The CBP program has developed a set of integrated tools (based on state-of-the-art models and leaching test methods) that improve understanding and predictions of the long-term hydraulic and chemical performance of cementitious barriers used in nuclear applications. Tools selected for and developed under this program are intended to evaluate and predict the behavior of cementitious barriers used in near-surface engineered waste disposal systems for periods of performance up to or longer than 100 years for operating facilities and longer than 1,000 years for waste management purposes. CBP software tools were made available to selected DOE Office of Environmental Management and field site users for training and evaluation based on a set of important degradation scenarios, including sulfate ingress/attack and carbonation of cementitious materials. The tools were presented at two-day training workshops held at U.S. National Institute of Standards and Technology (NIST), Savannah River, and Hanford included LeachXS™/ORCHESTRA, STADIUM®, and a CBP-developed GoldSim Dashboard interface. Collectively, these components form the CBP Software ToolBox. The new U.S. Environmental Protection Agency leaching test methods based on the Leaching Environmental Assessment Framework (LEAF) were also presented. The CBP Dashboard uses a custom Dynamic-link library developed by CBP to couple to the LeachXS™/ORCHESTRA and STADIUM® codes to simulate reactive transport and degradation in cementitious materials for selected performance assessment scenarios. The first day of the workshop introduced participants to the software components via presentation materials, and the second day included hands-on tutorial exercises followed by discussions of enhancements desired by participants. Tools were revised based on feedbac

Targeted delivery of a designed sTRAIL mutant results in superior apoptotic activity towards EGFR-positive tumor cells

Previously, we have shown that epidermal growth factor receptor (EGFR)-selective delivery of soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL), by genetic fusion to antibody fragment scFv425, enhances the tumor-selective pro-apoptotic activity of sTRAIL. Insight into the respective contribution of the agonistic receptors TRAIL-R1 and TRAIL-R2 to TRAIL-induced apoptosis may provide a rational approach to further optimize TRAIL-based therapy. Recently, this issue has been investigated using sTRAIL mutants designed to selectively bind to either receptor. However, the relative contribution of the respective TRAIL receptors, in particular TRAIL-R1, in TRAIL signaling is still unresolved. Here, we fused scFv425 to designed sTRAIL mutant sTRAILmR1–5, reported to selectively activate TRAIL-R1, and investigated the therapeutic apoptotic activity of this novel fusion protein. EGFR-specific binding of scFv425:sTRAILmR1–5 potently induced apoptosis, which was superior to the apoptotic activity of scFv425:sTRAIL-wt and a nontargeted MOCK-scFv:sTRAILmR1–5. During cotreatment with cisplatin or the histone deacetylase inhibitor valproic acid, scFv425:sTRAILmR1–5 retained its superior pro-apoptotic activity compared to scFv425:sTRAIL-wt. However, in catching-type Enzyme-Linked ImmunoSorbent Assays with TRAIL-R1:Fc and TRAIL-R2:Fc, scFv425:sTRAILmR1–5 was found to not only bind to TRAIL-R1 but also to TRAIL-R2. Binding to TRAIL-R2 also had functional consequences because the apoptotic activity of scFv425:sTRAILmR1–5 was strongly inhibited by a TRAIL-R2 blocking monoclonal antibody. Moreover, scFv425:sTRAILmR1–5 retained apoptotic activity upon selective knockdown of TRAIL-R1 using small inhibitory RNA. Collectively, these data indicate that both agonistic TRAIL receptors are functionally involved in TRAIL signaling by scFv425:sTRAILmR1–5 in solid tumor cells. Moreover, the superior target cell-restricted apoptotic activity of scFv425:sTRAILmR1–5 indicates its therapeutic potential for EGFR-positive solid tumors