SNOMED CT standard ontology based on the ontology for general medical science

Background: Systematized Nomenclature of Medicine—Clinical Terms (SNOMED CT, hereafter abbreviated SCT) is acomprehensive medical terminology used for standardizing the storage, retrieval, and exchange of electronic healthdata. Some efforts have been made to capture the contents of SCT as Web Ontology Language (OWL), but theseefforts have been hampered by the size and complexity of SCT. Method: Our proposal here is to develop an upper-level ontology and to use it as the basis for defining the termsin SCT in a way that will support quality assurance of SCT, for example, by allowing consistency checks ofdefinitions and the identification and elimination of redundancies in the SCT vocabulary. Our proposed upper-levelSCT ontology (SCTO) is based on the Ontology for General Medical Science (OGMS). Results: The SCTO is implemented in OWL 2, to support automatic inference and consistency checking. Theapproach will allow integration of SCT data with data annotated using Open Biomedical Ontologies (OBO) Foundryontologies, since the use of OGMS will ensure consistency with the Basic Formal Ontology, which is the top-levelontology of the OBO Foundry. Currently, the SCTO contains 304 classes, 28 properties, 2400 axioms, and 1555annotations. It is publicly available through the bioportal athttp://bioportal.bioontology.org/ontologies/SCTO/. Conclusion: The resulting ontology can enhance the semantics of clinical decision support systems and semanticinteroperability among distributed electronic health records. In addition, the populated ontology can be used forthe automation of mobile health applications

New methods for finding disease-susceptibility genes: impact and potential

Improved techniques for defining disease-gene location and evaluating the biological candidacy of regional transcripts will hasten disease-gene discovery

A Path to Implement Precision Child Health Cardiovascular Medicine.

Congenital heart defects (CHDs) affect approximately 1% of live births and are a major source of childhood morbidity and mortality even in countries with advanced healthcare systems. Along with phenotypic heterogeneity, the underlying etiology of CHDs is multifactorial, involving genetic, epigenetic, and/or environmental contributors. Clear dissection of the underlying mechanism is a powerful step to establish individualized therapies. However, the majority of CHDs are yet to be clearly diagnosed for the underlying genetic and environmental factors, and even less with effective therapies. Although the survival rate for CHDs is steadily improving, there is still a significant unmet need for refining diagnostic precision and establishing targeted therapies to optimize life quality and to minimize future complications. In particular, proper identification of disease associated genetic variants in humans has been challenging, and this greatly impedes our ability to delineate gene-environment interactions that contribute to the pathogenesis of CHDs. Implementing a systematic multileveled approach can establish a continuum from phenotypic characterization in the clinic to molecular dissection using combined next-generation sequencing platforms and validation studies in suitable models at the bench. Key elements necessary to advance the field are: first, proper delineation of the phenotypic spectrum of CHDs; second, defining the molecular genotype/phenotype by combining whole-exome sequencing and transcriptome analysis; third, integration of phenotypic, genotypic, and molecular datasets to identify molecular network contributing to CHDs; fourth, generation of relevant disease models and multileveled experimental investigations. In order to achieve all these goals, access to high-quality biological specimens from well-defined patient cohorts is a crucial step. Therefore, establishing a CHD BioCore is an essential infrastructure and a critical step on the path toward precision child health cardiovascular medicine

Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This new prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as a NAFLD-Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de-novo lipogenesis; mitochondrial energy utilization; lipid droplet assembly, lipolytic catabolism and fatty acid compartmentalization; and VLDL assembly and secretion. The NAFLD-Reactome model expands these pathways and allows for hypothesis testing as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and which influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice.Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Valenti, Luca. Università degli Studi di Milano; ItaliaFil: Davidson, Nicholas O.. University of Washington. School of Medicine; Estados Unido

MICRORNA: PROFILING AND FUNCTIONAL IMPLICATIONS IN CANCER AND METABOLISM

MicroRNAs (miRNAs) are a class of ~22 nt short, non-coding RNAs that post-transcriptionally regulate target mRNA expression. To date, ~2,000 mature miRNAs have been identified in humans and they are estimated to regulate about 50% of human genes. miRNAs, due to their ubiquitous target distribution, contribute to diverse processes including cell development, proliferation, differentiation, apoptosis, and metabolism. Dysregulation of miRNA expression has been reported in various cancers and metabolic disorders. miRNA are also implicated in the initiation and progression of those diseases. In my dissertation, I studied the differentially expressed (DE) miRNAs upon prostaglandin E2 (PGE2) stimulation in prostate cancer cells (PC-3). Concurrently I examined mRNA expression profile of the PC-3 system and determined anticorrelated miRNA:mRNA pairs. The DE miRNAs and their putative targets were affected by the induction of PGE2. They were suggested to be involved in PGE2 dysregulated signaling pathways in PC-3 prostate cancer. In the second part of the thesis work, I identified a set of adipose-enriched miRNAs from porcine tissues samples and verified that these miRNAs were conserved in humans. Adipose-enriched miRNAs were reported to be involved in metabolism, inflammation responses, and tumorigenesis. The analysis results of my thesis experiments suggested adipose-enriched miRNAs may have a potential role in connecting obesity, inflammation, and cancer. It is hoped that the understanding of the molecular basis in cancer and metabolic disorders on the miRNA level will provide new diagnostic targets and therapeutic targets for the diseases.Biology and Biochemistry, Department o

MEDIC: a practical disease vocabulary used at the Comparative Toxicogenomics Database

The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the effects of environmental chemicals on human health. CTD biocurators manually curate a triad of chemical–gene, chemical–disease and gene–disease relationships from the scientific literature. The CTD curation paradigm uses controlled vocabularies for chemicals, genes and diseases. To curate disease information, CTD first had to identify a source of controlled terms. Two resources seemed to be good candidates: the Online Mendelian Inheritance in Man (OMIM) and the ‘Diseases’ branch of the National Library of Medicine's Medical Subject Headers (MeSH). To maximize the advantages of both, CTD biocurators undertook a novel initiative to map the flat list of OMIM disease terms into the hierarchical nature of the MeSH vocabulary. The result is CTD’s ‘merged disease vocabulary’ (MEDIC), a unique resource that integrates OMIM terms, synonyms and identifiers with MeSH terms, synonyms, definitions, identifiers and hierarchical relationships. MEDIC is both a deep and broad vocabulary, composed of 9700 unique diseases described by more than 67 000 terms (including synonyms). It is freely available to download in various formats from CTD. While neither a true ontology nor a perfect solution, this vocabulary has nonetheless proved to be extremely successful and practical for our biocurators in generating over 2.5 million disease-associated toxicogenomic relationships in CTD. Other external databases have also begun to adopt MEDIC for their disease vocabulary. Here, we describe the construction, implementation, maintenance and use of MEDIC to raise awareness of this resource and to offer it as a putative scaffold in the formal construction of an official disease ontology

Primrose syndrome: Characterization of the phenotype in 42 patients

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo) submitted versio

Murine cerebral organoids develop network of functional neurons and hippocampal brain region identity

Brain organoids are in vitro three-dimensional (3D) self-organized neural structures, which can enable disease modeling and drug screening. However, their use for standardized large-scale drug screening studies is limited by their high batch-to-batch variability, long differentiation time (10\u201320 weeks), and high production costs. This is particularly relevant when brain organoids are obtained from human induced pluripotent stem cells (iPSCs). Here, we developed, for the first time, a highly standardized, reproducible, and fast (5 weeks) murine brain organoid model starting from embryonic neural stem cells. We obtained brain organoids, which progressively differentiated and self-organized into 3D networks of functional neurons with dorsal forebrain phenotype. Furthermore, by adding the morphogen WNT3a, we generated brain organoids with specific hippocampal region identity. Overall, our results showed the establishment of a fast, robust and reproducible murine 3D in vitro brain model that may represent a useful tool for high-throughput drug screening and disease modeling