High Mean Corpuscular Volume Predicts Poor Outcome for Patients With Gastroesophageal Adenocarcinoma.

BACKGROUND: Elevated mean corpuscular volume (MCV) is associated with a diminished prognosis for various tumor entities. This study aimed to evaluate the association between preoperative serum MCV levels and both overall (OS) and disease-free survival (DFS) for patients with resectable adenocarcinomas of the esophagogastric junction (AEG). METHODS: This study included consecutive patients undergoing surgical resection between 1992 and 2016. Measured preoperative MCV levels were stratified into quintiles and correlated with patients' survival and clinicopathologic characteristics. RESULTS: The study analyzed 314 patients with a median OS of 36.8 months and a median DFS of 20.6 months. The multivariate analysis showed that preoperatively elevated MCV is a significant prognostic factor for OS (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.03-1.08; P < 0.001) and DFS (HR, 1.05; 95% CI, 1.03-1.08; P < 0.001). In the subgroup analysis of neoadjuvantly treated and untreated patients, MCV remained an independent prognostic factor for OS (HR, 1.08; 95% CI, 1.04-1.12; P < 0.001) and DFS (HR, 1.07; 95% CI, 1.03-1.12; P < 0.001) in both groups. In the univariate analysis, tumor stage and differentiation, adjuvant chemotherapy, MCV, mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were significantly correlated with diminished OS and DFS. CONCLUSION: Preoperatively elevated MCV is an independent prognostic factor for patients with adenocarcinomas of the esophagus and the gastroesophageal junction.

ReproPhylo: An Environment for Reproducible Phylogenomics.

The reproducibility of experiments is key to the scientific process, and particularly necessary for accurate reporting of analyses in data-rich fields such as phylogenomics. We present ReproPhylo, a phylogenomic analysis environment developed to ensure experimental reproducibility, to facilitate the handling of large-scale data, and to assist methodological experimentation. Reproducibility, and instantaneous repeatability, is built in to the ReproPhylo system and does not require user intervention or configuration because it stores the experimental workflow as a single, serialized Python object containing explicit provenance and environment information. This 'single file' approach ensures the persistence of provenance across iterations of the analysis, with changes automatically managed by the version control program Git. This file, along with a Git repository, are the primary reproducibility outputs of the program. In addition, ReproPhylo produces an extensive human-readable report and generates a comprehensive experimental archive file, both of which are suitable for submission with publications. The system facilitates thorough experimental exploration of both parameters and data. ReproPhylo is a platform independent CC0 Python module and is easily installed as a Docker image or a WinPython self-sufficient package, with a Jupyter Notebook GUI, or as a slimmer version in a Galaxy distribution.

The Use of Non-Variant Sites to Improve the Clinical Assessment of Whole-Genome Sequence Data.

Genetic testing, which is now a routine part of clinical practice and disease management protocols, is often based on the assessment of small panels of variants or genes. On the other hand, continuous improvements in the speed and per-base costs of sequencing have now made whole exome sequencing (WES) and whole genome sequencing (WGS) viable strategies for targeted or complete genetic analysis, respectively. Standard WGS/WES data analytical workflows generally rely on calling of sequence variants respect to the reference genome sequence. However, the reference genome sequence contains a large number of sites represented by rare alleles, by known pathogenic alleles and by alleles strongly associated to disease by GWAS. It's thus critical, for clinical applications of WGS and WES, to interpret whether non-variant sites are homozygous for the reference allele or if the corresponding genotype cannot be reliably called. Here we show that an alternative analytical approach based on the analysis of both variant and non-variant sites from WGS data allows to genotype more than 92% of sites corresponding to known SNPs compared to 6% genotyped by standard variant analysis. These include homozygous reference sites of clinical interest, thus leading to a broad and comprehensive characterization of variation necessary to an accurate evaluation of disease risk. Altogether, our findings indicate that characterization of both variant and non-variant clinically informative sites in the genome is necessary to allow an accurate clinical assessment of a personal genome. Finally, we propose a highly efficient extended VCF (eVCF) file format which allows to store genotype calls for sites of clinical interest while remaining compatible with current variant interpretation software.

Sorbitol-modified hyaluronic acid reduces oxidative stress, apoptosis and mediators of inflammation and catabolism in human osteoarthritic chondrocytes.

OBJECTIVE AND DESIGN: Our study was designed to elucidate the precise molecular mechanisms by which sorbitol-modified hyaluronic acid (HA/sorbitol) exerts beneficial effects in osteoarthritis (OA). METHODS: Human OA chondrocytes were treated with increasing doses of HA/sorbitol ± anti-CD44 antibody or with sorbitol alone and thereafter with or without interleukin-1beta (IL-1ß) or hydrogen peroxide (H2O2). Signal transduction pathways and parameters related to oxidative stress, apoptosis, inflammation, and catabolism were investigated. RESULTS: HA/sorbitol prevented IL-1ß-induced oxidative stress, as measured by reactive oxygen species, p47-NADPH oxidase phosphorylation, 4-hydroxynonenal (HNE) production and HNE-metabolizing glutathione-S-transferase A4-4 expression. Moreover, HA/sorbitol stifled IL-1ß-induced metalloproteinase-13, nitric oxide (NO) and prostaglandin E2 release as well as inducible NO synthase expression. Study of the apoptosis process revealed that this gel significantly attenuated cell death, caspase-3 activation and DNA fragmentation elicited by exposure to a cytotoxic H2O2 dose. Examination of signaling pathway components disclosed that HA/sorbitol prevented IL-1ß-induced p38 mitogen-activated protein kinase and nuclear factor-kappa B activation, but not that of extracellular signal-regulated kinases 1 and 2. Interestingly, the antioxidant as well as the anti-inflammatory and anti-catabolic effects of HA/sorbitol were attributed to sorbitol and HA, respectively. CONCLUSIONS: Altogether, our findings support a beneficial effect of HA/sorbitol in OA through the restoration of redox status and reduction of apoptosis, inflammation and catabolism involved in cartilage damage.

ELISA: a unified, multidimensional view of the protein domain universe.

ELISA (http://romi.bu.edu/elisa/) is a database that was designed for flexibility in defining interesting queries about protein domain evolution. We have defined and included both the inherent characteristics of the domains such as structure and function and comparisons of these characteristics between domains. Thus, the database is useful in defining structural and functional links between related protein domains and by extension sequences that encode them. In this database we introduce and employ a novel method of functional annotation and comparison. For each protein domain we create a probabilistic functional annotation tree using GO. We have designed an algorithm that accurately compares these trees and thus provides a measure of "functional distance" between two protein domains. Along with functional annotation, we have also included structural comparison between protein domains and best sequence comparisons to all known genomes. The latter enables researchers to dynamically do searches for domains sharing similar phylogenetic profiles. This combination of data and tools enables the researcher to design complex queries to carry out research in the areas of protein domain evolution, structure prediction and functional annotation of novel sequences.