Inova Translational Medicine Institute

Falls Church, VA, United States

Inova Translational Medicine Institute

Falls Church, VA, United States
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Vickers A.E.M.,Human Translational Models LLC | Ulyanov A.V.,Inova Translational Medicine Institute | Fisher R.L.,Vitron Inc
International Journal of Molecular Sciences | Year: 2017

Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM), diclofenac (DCF, 1 mM) and etomoxir (ETM, 100 µM). Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 µM) and cyclosporin A (CSA, 10 _M), while GSH was affected more than ATP by methimazole (MMI, 500 _M), terbinafine (TBF, 100 µM), and carbamazepine (CBZ 100 µM). Oxidative stress genes were affected by TBF (18%), CBZ, APAP, and ETM (12%-11%), and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%-6%). Apoptosis genes were affected by DCF (14%), while apoptosis plus necrosis were altered by APAP and ETM (15%). Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%), ETM (66%), DCF, TBF, MMI (61%-60%), APAP, CBZ (57%-56%), and DTL (48%). Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%), CBZ and ETM (44%-43%), APAP and DCF (40%-38%), MMI, TBF and CSA (37%-35%). This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.

Bland K.I.,University of Alabama at Birmingham | Hoyt D.B.,The American College | Hoyt D.B.,University of California at Irvine | Polk Jr. H.C.,University of Louisville | And 2 more authors.
Annals of Surgery | Year: 2011

The surgeon of the future will be required (expected) to engage in leading high performance teams that integrate surgical and nonsurgical skills; he or she will be integral to the evolving systems of health care. Practice will be based on evidence and measured by outcomes that will include some aspect of public reporting. Continuous professional development will be based upon recertification that is founded on practice and objective learning criteria. The processes and goals of CER are of the highest priority and remain in line with the surgeons' practice and professionalism. As we guide the evolution of the health care of the future, our professionalism will be increasingly focused upon accountability. We, as surgeons, must assume this challenge as our legacy, which includes a 100-year history that provides inspiring quality with development of higher standards and improved outcomes for the surgery patient. Copyright © 2011 by Lippincott Williams & Wilkins.

Erikson G.A.,Scripps Research Institute | Bodian D.L.,Inova Translational Medicine Institute | Rueda M.,Scripps Research Institute | Molparia B.,Scripps Research Institute | And 7 more authors.
Cell | Year: 2016

Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype-healthy aging-to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors. Video Abstract: Display Omitted. The genomic characterization of humans that age without developing diseases suggests that healthy aging is a distinct phenotype from exceptional longevity and that it may be enriched with disease-protective genetic factors, such as resistance against cognitive decline. © 2016 Elsevier Inc.

Stittrich A.B.,Institute for Systems Biology | Lehman A.,University of British Columbia | Bodian D.L.,Inova Translational Medicine Institute | Ashworth J.,Institute for Systems Biology | And 15 more authors.
American journal of human genetics | Year: 2014

Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes. Despite the involvement of Notch in many key developmental systems, human mutations in Notch signaling components have mainly been described in disorders with vascular and bone effects. Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects. Using whole-genome sequencing in a cohort of 11 families lacking mutations in the four genes with known roles in AOS pathology (ARHGAP31, RBPJ, DOCK6, and EOGT), we found a heterozygous de novo 85 kb deletion spanning the NOTCH1 5' region and three coding variants (c.1285T>C [p.Cys429Arg], c.4487G>A [p.Cys1496Tyr], and c.5965G>A [p.Asp1989Asn]), two of which are de novo, in four unrelated probands. In a fifth family, we identified a heterozygous canonical splice-site variant (c.743-1 G>T) in an affected father and daughter. These variants were not present in 5,077 in-house control genomes or in public databases. In keeping with the prominent developmental role described for Notch1 in mouse vasculature, we observed cardiac and multiple vascular defects in four of the five families. We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS. Our results suggest that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Hourigan S.K.,Inova Childrens Hospital | Hourigan S.K.,Johns Hopkins University | Hourigan S.K.,Inova Translational Medicine Institute | Sears C.L.,Johns Hopkins University | Oliva-Hemker M.,Johns Hopkins University
Inflammatory Bowel Diseases | Year: 2016

Children with inflammatory bowel disease (IBD) are disproportionately susceptible to Clostridium difficile infection (CDI) and the incidence is increasing. There has also been growing recognition of asymptomatic C. difficile colonization in pediatric IBD, which can sometimes be very difficult to distinguish from symptomatic C. difficile-associated disease in this population. In this study, we discuss the current knowledge of C. difficile infection in children with IBD, reviewing epidemiology, risk factors, and outcomes that often differ from the adult IBD population, and discuss the complexities and dilemmas of diagnosing and treating CDI in pediatric IBD. © 2015 Crohn's & Colitis Foundation of America, Inc.

Hourigan S.K.,Inova Childrens Hospital | Hourigan S.K.,Johns Hopkins University | Hourigan S.K.,Inova Translational Medicine Institute | Oliva-Hemker M.,Johns Hopkins University
Pediatric Research | Year: 2016

There has been a growing interest in fecal microbiota transplantation (FMT) over recent years, in part due to the increasing prevalence of Clostridium difficile infection (CDI) and expanding association of intestinal dysbiosis with a wide range of human diseases. Many adult studies have shown that FMT is an effective treatment for recurrent CDI and may possibly have applications in other illnesses such as inflammatory bowel disease (IBD); however, there is a paucity of data available in children who may differ from adults for many reasons including having a dynamic developing microbiome compared to adults who have a relatively stable microbiome. Here, we review published studies looking at FMT in children, for CDI and IBD, and discuss special considerations needed when conducting FMT in children. © Copyright 2016 International Pediatric Research Foundation, Inc.

Vockley J.G.,Inova Translational Medicine Institute | Vockley J.G.,Virginia Commonwealth University | Niederhuber J.E.,Inova Translational Medicine Institute | Niederhuber J.E.,Johns Hopkins University
BMJ (Online) | Year: 2015

The field of cancer diagnostics is in constant flux as a result of the rapid discovery of new genes associated with cancer, improvements in laboratory techniques for identifying disease causing events, and novel analytic methods that enable the integration of many different types of data. These advances have helped in the identification of novel, informative biomarkers. As more whole genome sequence data are generated and analyzed, emerging information on the baseline variability of the human genome has shown the importance of the ancestral genomic background in patients with a potential disease causing variant. The recent discovery of many novel DNA sequence variants, advances in sequencing and genomic technology, and improved analytic methods enable the impact of germline and somatic genome variation on tumorigenesis and metastasis to be determined. New molecular targets and companion diagnostics are changing the way geneticists and oncologists think about the causes, diagnosis, and treatment of cancer.

Bodian D.L.,Inova Translational Medicine Institute | McCutcheon J.N.,Inova Translational Medicine Institute | McCutcheon J.N.,Life Technologies | Kothiyal P.,Inova Translational Medicine Institute | And 4 more authors.
PLoS ONE | Year: 2014

Technological advances coupled with decreasing costs are bringing whole genome and whole exome sequencing closer to routine clinical use. One of the hurdles to clinical implementation is the high number of variants of unknown significance. For cancer-susceptibility genes, the difficulty in interpreting the clinical relevance of the genomic variants is compounded by the fact that most of what is known about these variants comes from the study of highly selected populations, such as cancer patients or individuals with a family history of cancer. The genetic variation in known cancer-susceptibility genes in the general population has not been well characterized to date. To address this gap, we profiled the nonsynonymous genomic variation in 158 genes causally implicated in carcinogenesis using high-quality whole genome sequences from an ancestrally diverse cohort of 681 healthy individuals. We found that all individuals carry multiple variants that may impact cancer susceptibility, with an average of 68 variants per individual. Of the 2,688 allelic variants identified within the cohort, most are very rare, with 75% found in only 1 or 2 individuals in our population. Allele frequencies vary between ancestral groups, and there are 21 variants for which the minor allele in one population is the major allele in another. Detailed analysis of a selected subset of 5 clinically important cancer genes, BRCA1, BRCA2, KRAS, TP53, and PTEN, highlights differences between germline variants and reported somatic mutations. The dataset can serve a resource of genetic variation in cancersusceptibility genes in 6 ancestry groups, an important foundation for the interpretation of cancer risk from personal genome sequences. © 2014 Bodian et al.

Solomon B.D.,Inova Translational Medicine Institute | Solomon B.D.,Virginia Commonwealth University | Solomon B.D.,National Human Genome Research Institute
Molecular Syndromology | Year: 2015

Evolving sequencing technologies allow more accurate, efficient and affordable genomic analysis. As a result, these technologies are increasingly available, especially to provide molecular diagnoses for patients with suspected genetic disorders. However, there are many challenges to using genomic sequencing to benefit patients, including concerns that there is insufficient evidence that identifying an underlying molecular explanation may positively impact a patient's healthcare. This concern has many repercussions, including funding and/or (in some countries and healthcare systems) insurance reimbursement for genomic sequencing. To investigate this concern, all monogenic disorders were analyzed based on the impact of achieving molecular diagnosis. Of the 2,849 individual genes in which germline mutations cause disorders (not including contiguous gene syndromes or what may be categorized as susceptibility alleles), our analyses showed a specific, available intervention related to at least one affected organ system for 1,419 (49.8%) genes. In 95.6% of these genes, the intervention(s) would be recommended during the pediatric time frame. © 2015 S. Karger AG, Basel.

PubMed | Kaiser Permanente, Maryland Perinatal Associates, Inova Translational Medicine Institute, Mayo Medical School and Childrens National Health System
Type: | Journal: Molecular genetics and metabolism reports | Year: 2016

Trifunctional protein deficiency/Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD/TFP) deficiency is a disorder of fatty acid oxidation and ketogenesis. Severe neonatal lactic acidosis, cardiomyopathy, and hepatic dysfunction are caused by the accumulation of toxic long-chain acylcarnitines. The feasibility of umbilical cord blood use in screening for acylcarnitine analysis and free carnitine has been hypothesized but not reported in LCHAD/TFP neonates. We present a 4week old female who was at risk of inheriting LCHAD/TFP deficiency and was diagnosed at the time of delivery using umbilical cord blood. Umbilical cord blood was collected at delivery and sent for acylcarnitine analysis. Treatment was started immediately. Acylcarnitine analysis demonstrated findings that are consistent with a biochemical diagnosis of LCHAD/TFP deficiency. Patients with LCHAD/TFP deficiency should have treatment initiated as early as possible to avoid acute decompensation and minimize the long-term complications of the disorder including cardiomyopathy. In pregnancies at risk of having a child with LCHAD/TFP deficiency, umbilical cord blood sample is an efficient method to diagnose an inborn error of metabolism such as LCHAD/TFP deficiency.

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