The Disease Ontology (DO) database (http://disease-ontology.org) represents a comprehensive knowledge base of 8043 inherited, developmental and acquired human diseases (DO version 3, revision 2510). The DO web browser has been designed for speed, efficiency and robustness through the use of a graph database. Full-text contextual searching functionality using Lucene allows the querying of name, synonym, definition, DOID and cross-reference (xrefs) with complex Boolean search strings. The DO semantically integrates disease and medical vocabularies through extensive cross mapping and integration of MeSH, ICD, NCI's thesaurus, SNOMED CT and OMIM disease-specific terms and identifiers. The DO is utilized for disease annotation by major biomedical databases (e.g. Array Express, NIF, IEDB), as a standard representation of human disease in biomedical ontologies (e.g. IDO, Cell line ontology, NIFSTD ontology, Experimental Factor Ontology, Influenza Ontology), and as an ontological cross mappings resource between DO, MeSH and OMIM (e.g. GeneWiki). The DO project (http://diseaseontology.sf.net) has been incorporated into open source tools (e.g. Gene Answers, FunDO) to connect gene and disease biomedical data through the lens of human disease. The next iteration of the DO web browser will integrate DO's extended relations and logical definition representation along with these biomedical resource cross-mappings.

The factors responsible for maintaining persistent organ fibrosis in systemic sclerosis (SSc) are not known but emerging evidence implicates toll-like receptors (TLRs) in the pathogenesis of SSc. Here we show the expression, mechanism of action and pathogenic role of endogenous TLR activators in skin from patients with SSc, skin fibroblasts, and in mouse models of organ fibrosis. Levels of tenascin-C are elevated in SSc skin biopsy samples, and serum and SSc fibroblasts, and in fibrotic skin tissues from mice. Exogenous tenascin-C stimulates collagen gene expression and myofibroblast transformation via TLR4 signalling. Mice lacking tenascin-C show attenuation of skin and lung fibrosis, and accelerated fibrosis resolution. These results identify tenascin-C as an endogenous danger signal that is upregulated in SSc and drives TLR4-dependent fibroblast activation, and by its persistence impedes fibrosis resolution. Disrupting this fibrosis amplification loop might be a viable strategy for the treatment of SSc.

Background: The human genome has been extensively annotated with Gene Ontology for biological functions, but minimally computationally annotated for diseases.

Purpose: We assessed whether perioperative circulating tumor DNA (ctDNA) could be a biomarker for early detection of molecular residual disease (MRD) and prediction of postoperative relapse in resected non–small cell lung cancer (NSCLC). Experimental Design: Based on our prospective, multicenter cohort on dynamic monitoring of ctDNA in lung cancer surgery patients (LUNGCA), we enrolled 950 plasma samples obtained at three perioperative time points (before surgery, 3 days and 1 month after surgery) of 330 stage I–III NSCLC patients (LUNGCA-1), as a part of the LUNGCA cohort. Using a customized 769-gene panel, somatic mutations in tumor tissues and plasma samples were identified with next-generation sequencing and utilized for ctDNA-based MRD analysis. Results: Preoperative ctDNA positivity was associated with lower recurrence-free survival (RFS; HR = 4.2; P < 0.001). The presence of MRD (ctDNA positivity at postoperative 3 days and/or 1 month) was a strong predictor for disease relapse (HR = 11.1; P < 0.001). ctDNA-based MRD had a higher relative contribution to RFS prediction than all clinicopathologic variables such as the TNM stage. Furthermore, MRD-positive patients who received adjuvant therapies had improved RFS over those not receiving adjuvant therapy (HR = 0.3; P = 0.008), whereas MRD-negative patients receiving adjuvant therapies had lower RFS than their counterparts without adjuvant therapy (HR = 3.1; P < 0.001). After adjusting for clinicopathologic variables, whether receiving adjuvant therapies remained an independent factor for RFS in the MRD-positive population (P = 0.002) but not in the MRD-negative population (P = 0.283). Conclusions: Perioperative ctDNA analysis is effective in early detection of MRD and relapse risk stratification of NSCLC, and hence could benefit NSCLC patient management.

The advent of next-generation sequencing technologies has greatly promoted advances in the study of human diseases at the genomic, transcriptomic, and epigenetic levels. Exome sequencing, where the coding region of the genome is captured and sequenced at a deep level, has proven to be a cost-effective method to detect disease-causing variants and discover gene targets. In this review, we outline the general framework of whole exome sequence data analysis. We focus on established bioinformatics tools and applications that support five analytical steps: raw data quality assessment, pre-processing, alignment, post-processing, and variant analysis (detection, annotation, and prioritization). We evaluate the performance of open-source alignment programs and variant calling tools using simulated and benchmark datasets, and highlight the challenges posed by the lack of concordance among variant detection tools. Based on these results, we recommend adopting multiple tools and resources to reduce false positives and increase the sensitivity of variant calling. In addition, we briefly discuss the current status and solutions for big data management, analysis, and summarization in the field of bioinformatics.