Yetrib Hathout

Children's National Medical Center, Washington, Washington, D.C., United States

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Publications (84)328.92 Total impact

  • Neuromuscular Disorders 10/2015; 25:S314-S315. DOI:10.1016/j.nmd.2015.06.456 · 2.64 Impact Factor
  • R. Heredia · Y. Hathout · S. Moore · M. Katherine · S. Cirak ·

    Neuromuscular Disorders 10/2015; 25:S234. DOI:10.1016/j.nmd.2015.06.180 · 2.64 Impact Factor

  • Neuromuscular Disorders 10/2015; 25:S262-S263. DOI:10.1016/j.nmd.2015.06.279 · 2.64 Impact Factor
  • Yetrib Hathout ·
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    ABSTRACT: Noninvasive molecular biomarkers are becoming attractive tools to monitor disease progression, aid drug development programs and use as surrogate outcome measures in clinical trials. Cutting edge proteomic methods to assay biomarkers in body fluids have been developed in the past few years, but transitioning them to clinical practice has been slow and depends on the qualification of both the method and the biomarker.
    Expert Review of Proteomics 08/2015; 12(4):329-331. DOI:10.1586/14789450.2015.1064771 · 2.90 Impact Factor

  • 07/2015; 2(Suppl 1):A27. DOI:10.1186/2194-7791-2-S1-A27
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    ABSTRACT: Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.
    Proceedings of the National Academy of Sciences 05/2015; 112(23). DOI:10.1073/pnas.1507719112 · 9.67 Impact Factor
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    ABSTRACT: Phosphorodiamidate morpholino oligonucleotides (PMO) are used as a promising exon-skipping gene therapy for Duchenne Muscular Dystrophy (DMD). One potential complication of high dose PMO therapy is its transient accumulation in the kidneys. Therefore new urinary biomarkers are needed to monitor this treatment. Here, we carried out a pilot proteomic profiling study using stable isotope labeling in mammals (SILAM) strategy to identify new biomarkers to monitor the effect of PMO on the kidneys of the dystrophin deficient mouse model for DMD (mdx-23). We first assessed the baseline renal status of the mdx-23 mouse compared to the wild type (C57BL10) mouse, and then followed the renal outcome of mdx-23 mouse treated with a single high dose intravenous PMO injection (800 mg/kg). Surprisingly, untreated mdx-23 mice showed evidence of renal injury at baseline, which was manifested by albuminuria, increased urine output, and changes in established urinary biomarker of acute kidney injury (AKI). The PMO treatment induced further transient renal injury, which peaked at 7 days, and returned to almost the baseline status at 30 days post-treatment. In the kidney, the SILAM approach followed by western blot validation identified changes in Meprin A subunit alpha at day 2, then returned to normal levels at day 7 and 30 after PMO injection. In the urine, SILAM approach identified an increase in Clusterin and γ-glutamyl transpeptidase 1 as potential candidates to monitor the transient renal accumulation of PMO. These results, which were confirmed by Western blots or ELISA, demonstrate the value of the SILAM approach to identify new candidate biomarkers of renal injury in mdx-23 mice treated with high dose PMO.
    Toxicology Reports 05/2015; 9. DOI:10.1016/j.toxrep.2015.05.008
  • J. Staal · L. S. Lau · H. Zhang · Y. Hathout · K. Brown · B. Rood ·

    Neuro-Oncology 04/2015; 17(suppl 3):iii25-iii25. DOI:10.1093/neuonc/nov061.100 · 5.56 Impact Factor
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    ABSTRACT: A significant number of children infected with the HIV-1 virus all over the world are at risk of developing renal diseases that could have a significant impact on their treatment and quality of life. It is necessary to identify children undergoing the early stages of these renal diseases, as well as the potential renal toxicity that could be caused by antiretroviral drugs, in order to prevent the development of cardiovascular complications and chronic renal failure. This article describes the most common renal diseases seen in HIV-infected children, as well as the value and limitations of the clinical markers that are currently being used to monitor their renal function and histological damage in a non-invasive manner. In addition, we discuss the progress made during the last 10 years in the discovery and validation of new renal biomarkers for HIV-infected children and young adults. Although significant progress has been made during the early phases of the biomarkers discovery, more work remains to be done to validate the new biomarkers in a large number of patients. The future looks promising, however, the new knowledge needs to be integrated and validated in the context of the clinical environment where these children are living. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    PROTEOMICS - CLINICAL APPLICATIONS 03/2015; 9(5-6). DOI:10.1002/prca.201400193 · 2.96 Impact Factor
  • Julia Anderson · Haeri Seol · Yetrib Hathout · Christopher Spurney ·

    Journal of the American College of Cardiology 03/2015; 65(10):A997. DOI:10.1016/S0735-1097(15)60997-4 · 16.50 Impact Factor
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    ABSTRACT: MicroRNA 184 (miR-184) is known to play a key role in neurological development and apoptosis and is highly expressed in mouse brain, mouse corneal epithelium, zebrafish lens, and human retinal pigment epithelium (RPE). However, the role of miR-184 in RPE is largely unknown. We investigated the role of miR-184 in RPE and its possible implication in age-related macular degeneration (AMD). Proteomic analysis identified the Ezrin (EZR) gene as a target of miR-184 in human RPE. EZR is a membrane cytoskeleton cross-linker that is also known to bind to Lysosomal-Associated Membrane Protein 1 (LAMP-1) during the formation of phagocytic vacuoles. In ARPE-19 cells, inhibition of miR-184 resulted in up-regulation of EZR mRNA and EZR protein, and induced down-regulation of LAMP-1. The inhibition of miR-184 decreased EZR-bound LAMP-1 protein levels and affected phagocytic activity in ARPE19 cells. In primary culture of human RPE isolated from eyes of AMD donors (AMD RPE), miR-184 was significantly down-regulated compared to control (normal) RPE. Down-regulation of miR-184 was consistent with significantly lower levels of LAMP-1 protein in AMD RPE, and overexpression of MIR-184 in AMD RPE was able to rescue LAMP-1 protein expression to normal levels. All together, these observations suggest a novel role for miR-184 in RPE health and support a model proposing that down-regulation of miR-184 expression during aging may result in dysregulation of RPE function, contributing to retinal degeneration.This article is protected by copyright. All rights reserved.
    FEBS Journal 09/2014; 281(23). DOI:10.1111/febs.13066 · 4.00 Impact Factor
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    ABSTRACT: Epigenomic regulation of the transcriptome by DNA methylation and post-transcriptional gene silencing by miRNAs are potential environmental modulators of skeletal muscle plasticity to chronic exercise in healthy and diseased populations. We utilised transcriptome networks to connect exercise-induced differential methylation and miRNA with functional skeletal muscle plasticity. Biopsies of the Vastus lateralis were collected from middle aged Polynesian men and women with morbid obesity (44 kg/m(2) ± 10) and Type-2 diabetes before and following 16 weeks of resistance (n=9) or endurance training (n=8). Longitudinal transcriptome, methylome, and miRNA responses were obtained via microarray, filtered by novel effect-size based false discovery rate probe selection preceding bioinformatic interrogation. Metabolic and microvascular transcriptome topology dominated the network landscape following endurance exercise. Lipid and glucose metabolism modules were connected to: miR-29a; promoter region hypomethylation of nuclear receptor factor (NRF1) and fatty-acid transporter (SLC27A4), and hypermethylation of fatty acid synthase, and to exon hypomethylation of 6-phosphofructo-2-kinase and Ser/Thr protein kinase. Directional change in the endurance networks was validated by lower intramyocellular lipid, increased capillarity, GLUT4, hexokinase and mitochondrial enzyme activity and proteome. Resistance training also lowered lipid, increased enzyme activity, and caused GLUT4-promoter hypomethylation; however, training was inconsequential to GLUT4, capillarity, and metabolic transcriptome. miR-195 connected to negative regulation of vascular development. To conclude, integrated molecular network modelling revealed differential DNA methylation and miRNA expression changes occur in skeletal muscle in response to chronic exercise training that are most pronounced with endurance training and topographically associated with functional metabolic and microvascular plasticity relevant to diabetes rehabilitation.
    Physiological Genomics 08/2014; 46(20). DOI:10.1152/physiolgenomics.00024.2014 · 2.37 Impact Factor
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    ABSTRACT: It is expected that serum protein biomarkers in DMD will reflect disease pathogenesis, progression and aid future therapy developments. Here, we describe use of quantitative in vivo stable isotope labeling in mammals to accurately compare serum proteomes of wild type and dystrophin-deficient mdx mice. Biomarkers identified in serum from two independent dystrophin deficient mouse models (mdx-Δ52 and mdx-23), were concordant with those identified in sera samples of DMD patients. Of the 355 mouse sera proteins, 23 were significantly elevated and 4 significantly lower in mdx relative to wild type mice (p value<0.001). Elevated proteins were mostly of muscle origin: including myofibrillar proteins (titin, myosin light chain 1/3, myomesin 3, filamin-C), glycolytic enzymes (aldolase, phosphoglycerate mutase 2, beta enolase, and glycogen phosphorylase), transport proteins (fatty acid binding protein, myoglobin and somatic cytochrome-C), and others (creatine kinase M, malate dehydrogenase cytosolic, fibrinogen and parvalbumin). Decreased proteins, mostly of extracellular origin, included adiponectin, lumican, plasminogen and leukemia inhibitory factor receptor. Analysis of sera from 1 week to 7 months old mdx mice revealed age dependent changes in the level of these biomarkers with most biomarkers acutely elevated at 3 weeks of age. Serum analysis of DMD patients, with ages ranging from 4 to 15 years old, confirmed elevation of 20 of the murine biomarkers in DMD, with similar age-related changes. This study provides a panel of biomarkers that reflect muscle-activity and pathogenesis and should prove valuable tool to complement natural history studies and to monitor treatment efficacy in future clinical trials.
    Human Molecular Genetics 07/2014; 23(24). DOI:10.1093/hmg/ddu366 · 6.39 Impact Factor
  • G. Vaidyanathan · S. Gururangan · D. Bigner · M. Zalutsky · M. Morfouace · A. Shelat · J. Megan · B. B. Freeman · S. Robinson · S. Throm · [...] · A. Laureano · W. Brugmann · C. Denman · H. Singh · H. Huls · J. Moyes · D. Sandberg · L. Silla · L. Cooper · D. Lee ·

    Neuro-Oncology 06/2014; 16(suppl 1):i71-i96. DOI:10.1093/neuonc/nou074 · 5.56 Impact Factor
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    ABSTRACT: Objective Myositis is characterized by severe muscle weakness. We and others have previously shown that endoplasmic reticulum (ER) stress plays a role in the pathogenesis of myositis. The present study was undertaken to identify perturbed pathways and assess their contribution to muscle disease in a mouse myositis model. Methods Stable isotope labeling with amino acids in cell culture (SILAC) was used to identify alterations in the skeletal muscle proteome of myositic mice in vivo. Differentially altered protein levels identified in the initial comparisons were validated using a liquid chromatography tandem mass spectrometry spike-in strategy and further confirmed by immunoblotting. In addition, we evaluated the effect of a proteasome inhibitor, bortezomib, on the disease phenotype, using well-standardized functional, histologic, and biochemical assessments. ResultsWith the SILAC technique we identified significant alterations in levels of proteins belonging to the ER stress response, ubiquitin proteasome pathway (UPP), oxidative phosphorylation, glycolysis, cytoskeleton, and muscle contractile apparatus categories. We validated the myositis-related changes in the UPP and demonstrated a significant increase in the ubiquitination of muscle proteins as well as a specific increase in ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL-1) in myositis, but not in muscle affected by other dystrophies or normal muscle. Inhibition of the UPP with bortezomib significantly improved muscle function and also significantly reduced tumor necrosis factor expression in the skeletal muscle of mice with myositis. Conclusion Our findings indicate that ER stress activates downstream UPPs and contributes to muscle degeneration and that UCHL-1 is a potential biomarker for disease progression. UPP inhibition offers a potential therapeutic strategy for myositis.
    Arthritis & Rheumatology 12/2013; 65(12). DOI:10.1002/art.38180 · 7.76 Impact Factor
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    ABSTRACT: The polarity of the conducting airway epithelium is responsible for its directional secretion. This is an essential characteristic of lung integrity and function that dictates interactions between the external environment (apical) and subepithelial structures (basolateral). Defining the directional secretomes in the in vitro human bronchial epithelial (HBE) differentiated model could bring valuable insights into lung biology and pulmonary diseases. Normal primary HBE cells (n=3) were differentiated into respiratory tract epithelium. Apical and basolateral secretions (24h) were processed for proteome profiling and pathway analysis. A total of 243 proteins were identified in secretions from all HBE cultures combined. Of these, 51% were classified as secreted proteins including true secreted proteins (36%) and exosomal proteins (15%). Close examination revealed consistent secretion of 69 apical proteins, 13 basolateral proteins and differential secretion of 25 proteins across all donors. Expression of Annexin A4 in apical secretions and Desmoglein-2 in basolateral secretions was validated using Western blot or ELISA in triplicate independent experiments. To the best of our knowledge, this is the first study defining apical and basolateral secretomes in the in vitro differentitated HBE model. The data demonstrate that epithelial polarity directs protein secretion with different patterns of biological processes to the apical and basolateral surfaces that are consistent with normal bronchial epithelium homeostatic functions. Applying this in vitro directional secretome model to lung diseases may elucidate their molecular pathophysiology and eventually help define potential therapeutic targets.
    American Journal of Respiratory Cell and Molecular Biology 09/2013; 50(2). DOI:10.1165/rcmb.2013-0188OC · 3.99 Impact Factor
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    ABSTRACT: One of the principal goals of glycoprotein research is to correlate glycan structure and function. Such correlation is necessary to understand the mechanisms whereby glycoprotein structure elaborates the functions of myriad proteins. Accurate comparison of glycoforms and quantification of glycosites is an essential step in this direction. Mass spectrometry has emerged as a powerful analytical technique in the field of glycoprotein characterization. Its sensitivity, high dynamic range, and mass accuracy provide both quantitative and sequence/structural information. As part of the 2012 ABRF Glycoprotein Research Group (gPRG) study, we explored the use of mass spectrometry and ancillary methodologies to characterize the glycoforms of two sources of human prostate specific antigen (PSA). PSA is used as a tumor marker for prostate cancer, with increasing blood levels used to distinguish between normal and cancer states. The glycans on PSA are believed to be biantennary N-linked and it has been observed that prostate cancer tissues and cell lines, contain more antennae than the benign form. Thus, the ability to quantify differences in glycosylation associated with cancer has the potential to positively impact use of PSA as a biomarker. We studied standard peptide based proteomics/glycomics methodologies including LC-MS/MS for peptide/glycopeptide sequencing and label-free approaches for differential quantification. We performed an interlaboratory study to determine the ability of different laboratories to correctly characterize the differences in glycoforms between two different sources using mass spectrometry methods. We used clustering analysis and ancillary statistical data treatment on the data sets submitted by participating laboratories to obtain a consensus of the glycoforms and abundances. The results demonstrate the relative strengths and weaknesses of top-down glycoproteomics, bottom-up glycoproteomics, and glycomics methods, respectively.
    Molecular &amp Cellular Proteomics 06/2013; DOI:10.1074/mcp.M113.030643 · 6.56 Impact Factor
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    ABSTRACT: Proteomic analysis of human body fluids is highly challenging, therefore many researchers are redirecting efforts towards secretome profiling. The goal is to define potential biomarkers and therapeutic targets in the secretome that can be traced back in accessible human body fluids. However, currently there is a lack of secretome profiles of normal human primary cells making it difficult to assess the biological meaning of current findings. In this study we sought to establish secretome profiles of human primary cells obtained from healthy donors with the goal of building a human secretome atlas. Such an atlas can be used as a reference for discovery of potential disease associated biomarkers and eventually novel therapeutic targets. As a preliminary study, secretome profiles were established for six different types of human primary cell cultures and checked for overlaps with the three major human body fluids including plasma, cerebrospinal fluid and urine. About 67% of the 1054 identified proteins in the secretome of these primary cells occurred in at least one body fluid. Furthermore, comparison of the secretome profiles of two human glioblastoma cell lines to this new human secretome atlas enabled unambiguous identification of potential brain tumor biomarkers. These biomarkers can be easily monitored in different body fluids using stable isotope labeled standard proteins. The long term goal of this study is to establish a comprehensive online human secretome atlas for future use as a reference for any disease related secretome study.
    Biochimica et Biophysica Acta 04/2013; 1834(11). DOI:10.1016/j.bbapap.2013.04.007 · 4.66 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy results from loss of the protein dystrophin, which links the intracellular cytoskeletal network with the extracellular matrix, but deficiency in this function does not fully explain the onset or progression of the disease. While some intracellular events involved in the degeneration of dystrophin-deficient muscle fibers have been well characterized, changes in their secretory profile are undescribed. To analyze the secretome profile of mdx myotubes independently of myonecrosis, we labeled the proteins of mdx and wild-type myotubes with stable isotope-labeled amino acids (SILAC), finding marked enrichment of vesicular markers in the mdx secretome. These included the lysosomal-associated membrane protein, LAMP1, that co-localized in vesicles with an over-secreted cytoskeletal protein, myosin light chain 1. These LAMP1/MLC1-3-positive vesicles accumulated in the cytosol of mdx myotubes and were secreted into the culture medium in a range of abnormal densities. Restitution of dystrophin expression, by exon skipping, to some 30 % of the control value, partially normalized the secretome profile and the excess LAMP1 accumulation. Together, our results suggest that a lack of dystrophin leads to a general dysregulation of vesicle trafficking. We hypothesize that disturbance of the export of proteins through vesicles occurs before, and then concurrently with, the myonecrotic cascade and contributes chronically to the pathophysiology of DMD, thereby presenting us with a range of new potential therapeutic targets.
    Cellular and Molecular Life Sciences CMLS 01/2013; 70(12). DOI:10.1007/s00018-012-1248-2 · 5.81 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by a mutation in the dystrophin gene. DMD is characterized by progressive weakness of skeletal, cardiac and respiratory muscles. The molecular mechanisms underlying dystrophy-associated muscle weakness and damage are not well understood. Quantitative proteomic techniques would help to identify disease specific pathways. Recent advances in in vivo metabolic labeling of mammals by stable isotope-labeled amino acids [13C6-lysine (SILAC mouse) or 15N (SILAM)] have enabled accurate quantitative analysis of the proteomes of the whole organs and tissues as a function of disease. Here we describe the use of SILAC mouse strategy to define the underlying pathological mechanisms in dystrophin-deficient skeletal muscle. Differential SILAC proteome profiling was performed on the gastrocnemius muscles of 3-week-old (early stage) dystrophin deficient mdx mice versus wild type (normal) mice. Generated data was further confirmed in an independent set of mdx and normal mice using SILAC spike-in strategy. A total of 789 proteins were quantified, of these 73 were found to be significantly altered between mdx and normal mice. Bioinformatics analyses using Ingenuity Pathway software established that the integrin-linked kinase pathway, actin cytoskeleton signaling, mitochondrial energy metabolism, calcium homeostasis are the initial pathways to be affected in dystrophin deficient muscle at early stage of the pathogenesis. Key proteins involved in these pathways were validated by immunoblotting and immunohistochemistry in independent set of mdx mice samples and in human DMD muscle biopsies. The specific involvement of these molecular networks early in dystrophic pathology makes them potential therapeutic targets. In sum, our findings indicate that SILAC mouse strategy has uncovered previously unidentified pathological pathways in mouse models of human skeletal muscle disease.
    Molecular &amp Cellular Proteomics 01/2013; 12(5). DOI:10.1074/mcp.M112.023127 · 6.56 Impact Factor

Publication Stats

2k Citations
328.92 Total Impact Points


  • 2005-2015
    • Children's National Medical Center
      • • Center for Genetic Medicine Research
      • • Children's Research Institute (CRI)
      Washington, Washington, D.C., United States
  • 2014
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 2007-2013
    • George Washington University
      • • Department of Integrative Systems Biology
      • • Department of Pediatrics
      Washington, Washington, D.C., United States
    • Seattle Children’s Research Institute
      Seattle, Washington, United States
  • 1999-2009
    • University of Maryland, College Park
      • Department of Chemistry and Biochemistry
      College Park, MD, United States
  • 1996-1999
    • University of Maryland, Baltimore County
      • Department of Chemistry and Biochemistry
      Baltimore, Maryland, United States