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Mir-155 Expression And Correlation With Clinical Outcome In Pediatric Aml: A Report From Children's Oncology Group., Ranjani Ramamurthy, Maya Hughes, Valerie Morris, Hamid Bolouri, Robert B. Gerbing, Yi-Cheng Wang, Michael R. Loken, Susana C. Raimondi, Betsy A. Hirsch, A S. Gamis, Vivian G. Oehler, Todd A. Alonzo, Soheil Meshinchi

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BACKGROUND: Aberrant expression of microRNA-155 (miR-155) has been implicated in acute myeloid leukemia (AML) and associated with clinical outcome.

PROCEDURE: We evaluated miR-155 expression in 198 children with normal karyotype AML (NK-AML) enrolled in Children's Oncology Group (COG) AML trial AAML0531 and correlated miR-155 expression levels with disease characteristics and clinical outcome. Patients were divided into quartiles (Q1-Q4) based on miR-155 expression level, and disease characteristics were then evaluated and correlated with miR-155 expression.

RESULTS: MiR-155 expression varied over 4-log10-fold range relative to its expression in normal marrow with a median expression level of 0.825 (range 0.043-25.630) for the entire …

Functional Validation Of Novel Compound Heterozygous Variants In B3gat3 Resulting In Severe Osteopenia And Fractures: Expanding The Disease Phenotype., Florian Job, Shuji Mizumoto, Laurie Smith, Natario Couser, Ashley Brazil, Howard Saal, Melanie Patterson, Margaret Gibson, Sarah E. Soden, Neil A. Miller, Isabelle Thiffault, Carol J. Saunders, Shuhei Yamada, Katrin Hoffmann, Kazuyuki Sugahara, Emily G. Farrow

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BACKGROUND: A new disease class of syndromes, described as linkeropathies, which are derived from defects in the glycosaminoglycan-linker region as well as glycosaminoglycan-side chains of proteoglycans is increasingly being recognized as a cause of human disease. Proteoglycans are an essential component of the extracellular matrix. Defects in the enzymatic process of proteoglycan synthesis broadly occur due to the incorrect addition of side chains. Previously, homozygous missense variants within the B3GAT3 gene encoding beta 1,3 glucuronyltransferase 3(GlcAT-I) responsible for the biosynthesis of glycosaminoglycans have been described in 7 individuals.

CASE PRESENTATION: In this study, a 4-year-old patient with a severe phenotype …

The Influence Of Age On The Diagnostic Performance Of White Blood Cell Count And Absolute Neutrophil Count In Suspected Pediatric Appendicitis., Richard G. Bachur, Peter S. Dayan, Nanette C. Dudley, Lalit Bajaj, Michelle D. Stevenson, Charles G. Macias, Manoj K. Mittal, Jonathan Bennett, Kelly A. Sinclair, Michael C. Monuteaux, Anupam B. Kharbanda

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: White blood cell (WBC) count and absolute neutrophil count (ANC) are a standard part of the evaluation of suspected appendicitis. Specific threshold values are utilized in clinical pathways, but the discriminatory value of WBC count and ANC may vary by age. The objective of this study was to investigate whether the diagnostic value of WBC count and ANC varies across age groups and whether diagnostic thresholds should be age-adjusted.

METHODS: This is a multicenter prospective observational study of patients aged 3-18 years who were evaluated for appendicitis. Receiver operator characteristic curves were developed to assess overall discriminative power of …

Toxic Environmental Exposures And Kidney Health In Children., Darcy K. Weidemann, Virginia M. Weaver, Jeffrey J. Fadrowski

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High-level exposures to a number of agents are known to have direct nephrotoxic effects in children. A growing body of literature supports the hypothesis that chronic, relatively low-level exposure to various nephrotoxicants may also increase the risk for chronic kidney disease (CKD) or accelerate its progression. In this review we highlight several environmental nephrotoxicants and their association with CKD in children and adolescents. We also discuss unique epidemiological challenges in the use of kidney biomarkers in environmental nephrotoxicology.

Biallelic Mutations In Tbcd, Encoding The Tubulin Folding Cofactor D, Perturb Microtubule Dynamics And Cause Early-Onset Encephalopathy., Elisabetta Flex, Marcello Niceta, Serena Cecchetti, Isabelle Thiffault, Margaret G. Au, Alessandro Capuano, Emanuela Piermarini, Anna A. Ivanova, Joshua W. Francis, Giovanni Chillemi, Balasubramanian Chandramouli, Giovanna Carpentieri, Charlotte A. Haaxma, Andrea Ciolfi, Simone Pizzi, Ganka V. Douglas, Kara Levine, Antonella Sferra, Maria Lisa Dentici, Rolph R. Pfundt, Jean-Baptist Lepichon, Emily G. Farrow, Frank Baas, Fiorella Piemonte, Bruno Dallapiccola, John M. Graham, Carol J. Saunders, Enrico Bertini, Richard A. Kahn, David A. Koolen, Marco Tartaglia

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Microtubules are dynamic cytoskeletal elements coordinating and supporting a variety of neuronal processes, including cell division, migration, polarity, intracellular trafficking, and signal transduction. Mutations in genes encoding tubulins and microtubule-associated proteins are known to cause neurodevelopmental and neurodegenerative disorders. Growing evidence suggests that altered microtubule dynamics may also underlie or contribute to neurodevelopmental disorders and neurodegeneration. We report that biallelic mutations in TBCD, encoding one of the five co-chaperones required for assembly and disassembly of the αβ-tubulin heterodimer, the structural unit of microtubules, cause a disease with neurodevelopmental and neurodegenerative features characterized by early-onset cortical atrophy, secondary hypomyelination, microcephaly, thin …

Bioactivation Of Trimethoprim To Protein-Reactive Metabolites In Human Liver Microsomes., Jennifer Goldman, Yakov M. Koen, Steven A. Rogers, Kelin Li, J Steven Leeder, Robert P. Hanzlik

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The formation of drug-protein adducts via metabolic activation and covalent binding may stimulate an immune response or may result in direct cell toxicity. Protein covalent binding is a potentially pivotal step in the development of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP)-sulfamethoxazole (SMX) is a combination antibiotic that commonly causes IADRs. Recent data suggest that the contribution of the TMP component of TMP-SMX to IADRs may be underappreciated. We previously demonstrated that TMP is bioactivated to chemically reactive intermediates that can be trapped in vitro by N-acetyl cysteine (NAC), and we have detected TMP-NAC adducts (i.e., mercapturic acids) in the …

Ontogeny Of Hepatic Drug Transporters As Quantified By Lc-Ms/Ms Proteomics., B Prasad, Andrea Gaedigk, M Vrana, R Gaedigk, J Steven Leeder, L Salphati, X Chu, G Xiao, Ceca Hop, R Evers, L Gan, J D Unadkat

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Protein expression of major hepatic uptake and efflux drug transporters in human pediatric (n = 69) and adult (n = 41) livers was quantified by liquid chromatography / tandem mass spectroscopy (LC-MS/MS). Transporter protein expression of OCT1, OATP1B3, P-gp, and MRP3 was age-dependent. Particularly, significant differences were observed in transporter expression (P < 0.05) between the following age groups: neonates vs. adults (OCT1, OATP1B3, P-gp), neonates or infants vs. adolescents and/or adults (OCT1, OATP1B3, and P-gp), infants vs. children (OATP1B3 and P-gp), and adolescents vs. adults (MRP3). OCT1 showed the largest increase, of almost 5-fold, in protein expression with age. Ontogenic expression of OATP1B1 was confounded by genotype and was revealed only in livers harboring SLCO1B1*1A/*1A. In livers >1 year, tissues harboring SLCO1B1*14/*1A showed 2.5-fold higher (P < 0.05) protein expression than SLCO1B1*15/*1A. Integration of these ontogeny data in physiologically based pharmacokinetic (PBPK) models will be a crucial step in predicting hepatic drug disposition in children.

User-Centered Design Of Multi-Gene Sequencing Panel Reports For Clinicians., Elizabeth Cutting, Meghan Banchero, Amber L. Beitelshees, James J. Cimino, Guilherme Del Fiol, Ayse P. Gurses, Mark A. Hoffman, Linda Jo Bone Jeng, Kensaku Kawamoto, Mark Kelemen, Harold Alan Pincus, Alan R. Shuldiner, Marc S. Williams, Toni I. Pollin, Casey Lynnette Overby

Manuscripts, Articles, Book Chapters and Other Papers

The objective of this study was to develop a high-fidelity prototype for delivering multi-gene sequencing panel (GS) reports to clinicians that simulates the user experience of a final application. The delivery and use of GS reports can occur within complex and high-paced healthcare environments. We employ a user-centered software design approach in a focus group setting in order to facilitate gathering rich contextual information from a diverse group of stakeholders potentially impacted by the delivery of GS reports relevant to two precision medicine programs at the University of Maryland Medical Center. Responses from focus group sessions were transcribed, coded and …

Variants In Cxcr4 Associate With Juvenile Idiopathic Arthritis Susceptibility., Terri H. Finkel, Jin Li, Zhi Wei, Wei Wang, Haitao Zhang, Edward M. Behrens, Emma L. Reuschel, Sophie Limou, Carol Wise, Marilynn Punaro, Mara L. Becker, Jane E. Munro, Berit Flatø, Øystein Førre, Susan D. Thompson, Carl D. Langefeld, David N. Glass, Joseph T. Glessner, Cecilia E. Kim, Edward Frackelton, Debra K. Shivers, Kelly A. Thomas, Rosetta M. Chiavacci, Cuiping Hou, Kexiang Xu, James Snyder, Haijun Qiu, Frank Mentch, Kai Wang, Cheryl A. Winkler, Benedicte A. Lie, Justine A. Ellis, Hakon Hakonarson

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA.

METHODS: We performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry. Correlation of SNP genotype and gene expression was investigated. Then we conducted targeted resequencing of a candidate locus, among a subset of 480 cases and 480 controls. SUM test was performed …

Long-Read Single Molecule Real-Time Full Gene Sequencing Of Cytochrome P450-2d6., Wanqiong Qiao, Yao Yang, Robert Sebra, Geetu Mendiratta, Andrea Gaedigk, Robert J. Desnick, Stuart A. Scott

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The cytochrome P450-2D6 (CYP2D6) enzyme metabolizes ∼25% of common medications, yet homologous pseudogenes and copy number variants (CNVs) make interrogating the polymorphic CYP2D6 gene with short-read sequencing challenging. Therefore, we developed a novel long-read, full gene CYP2D6 single molecule real-time (SMRT) sequencing method using the Pacific Biosciences platform. Long-range PCR and CYP2D6 SMRT sequencing of 10 previously genotyped controls identified expected star (*) alleles, but also enabled suballele resolution, diplotype refinement, and discovery of novel alleles. Coupled with an optimized variant-calling pipeline, CYP2D6 SMRT sequencing was highly reproducible as triplicate intra- and inter-run nonreference genotype results were completely concordant. Importantly, …

Cd33 Expression And Its Association With Gemtuzumab Ozogamicin Response: Results From The Randomized Phase Iii Children's Oncology Group Trial Aaml0531., Jessica A. Pollard, Michael Loken, Robert B. Gerbing, Susana C. Raimondi, Betsy A. Hirsch, Richard Aplenc, Irwin D. Bernstein, Alan S. Gamis, Todd A. Alonzo, Soheil Meshinchi

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: CD33 is variably expressed on acute myeloid leukemia (AML) blasts and is targeted by gemtuzumab ozogamicin (GO). GO has shown benefit in both adult and pediatric AML trials, yet limited data exist about whether GO response correlates with CD33 expression level.

PATIENTS AND METHODS: CD33 expression levels were prospectively quantified by multidimensional flow cytometry in 825 patients enrolled in Children's Oncology Group AAML0531 and correlated with response to GO.

RESULTS: Patients with low CD33 expression (lowest quartile of expression [Q1]) had no benefit with the addition of GO to conventional chemotherapy (relapse risk [RR]: GO 36% v No-GO 34%, …

Molecular Evolution And Intraclade Recombination Of Enterovirus D68 During The 2014 Outbreak In The United States., Yi Tan, Ferdaus Hassan, Jennifer E. Schuster, Ari Simenauer, Rangaraj Selvarangan, Rebecca A. Halpin, Xudong Lin, Nadia Fedorova, Timothy B. Stockwell, Tommy Tsan-Yuk Lam, James D. Chappell, Tina V. Hartert, Edward C. Holmes, Suman R. Das

Manuscripts, Articles, Book Chapters and Other Papers

In August 2014, an outbreak of enterovirus D68 (EV-D68) occurred in North America, causing severe respiratory disease in children. Due to a lack of complete genome sequence data, there is only a limited understanding of the molecular evolution and epidemiology of EV-D68 during this outbreak, and it is uncertain whether the differing clinical manifestations of EV-D68 infection are associated with specific viral lineages. We developed a high-throughput complete genome sequencing pipeline for EV-D68 that produced a total of 59 complete genomes from respiratory samples with a 95% success rate, including 57 genomes from Kansas City, MO, collected during the 2014 …

Genetic Loci Associated With Renal Function Measures And Chronic Kidney Disease In Children: The Pediatric Investigation For Genetic Factors Linked With Renal Progression Consortium., Matthias Wuttke, Craig S. Wong, Elke Wühl, Daniel Epting, Li Luo, Anselm Hoppmann, Anke Doyon, Yong Li, Gkdgen Consortium, Betül Sözeri, Daniela Thurn, Martin Helmstädter, Tobias B. Huber, Tom D. Blydt-Hansen, Albrecht Kramer-Zucker, Otto Mehls, Anette Melk, Uwe Querfeld, Susan L. Furth, Bradley A. Warady, Franz Schaefer, Anna Köttgen

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BACKGROUND: Chronic kidney disease (CKD) in children is characterized by rapid progression and a high incidence of end-stage renal disease and therefore constitutes an important health problem. While unbiased genetic screens have identified common risk variants influencing renal function and CKD in adults, the presence and identity of such variants in pediatric CKD are unknown.

METHODS: The international Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) and Cardiovascular …

A Quality Improvement Collaborative To Improve Pediatric Primary Care Genetic Services., Michael L. Rinke, Amy Driscoll, Natalie Mikat-Stevens, Jill Healy, Elizabeth Colantuoni, Abdallah F. Elias, Beth A. Pletcher, Ruth S. Gubernick, Ingrid Larson, Wendy K. Chung, Beth A. Tarini

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: To investigate if a national pediatric primary care quality improvement collaborative (QIC) could improve and sustain adherence with process measures related to diagnosis and management of children with genetic disorders.

METHODS: Thirteen practices in 11 states from the American Academy of Pediatrics' Quality Improvement Innovation Networks participated in a 6-month QIC that included regular educational opportunities, access to genetic professionals, and performance feedback. The QIC identified 11 aims related to improving diagnosis and management of children with genetic disorders. The practices evaluated adherence by reviewing patient records at baseline, monthly for 6 months (active improvement period), and then once …

Safety And Immunogenicity Of Sequential Rotavirus Vaccine Schedules., Romina Libster, Monica Mcneal, Emmanuel B. Walter, Andi L. Shane, Patricia Winokur, Gretchen Cress, Andrea A. Berry, Karen L. Kotloff, Kwabena Sarpong, Christine B. Turley, Christopher J. Harrison, Barbara A. Pahud, Jyothi Marbin, John Dunn, Jill El-Khorazaty, Jill Barrett, Kathryn M. Edwards, Vteu Rotavirus Vaccine Study Work Group

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BACKGROUND AND OBJECTIVES: Although both licensed rotavirus vaccines are safe and effective, it is often not possible to complete the schedule by using the same vaccine formulation. The goal of this study was to investigate the noninferiority of the immune responses to the 2 licensed rotavirus vaccines when administered as a mixed schedule compared with administering a single vaccine formulation alone.

METHODS: Randomized, multicenter, open-label study. Healthy infants (6-14 weeks of age) were randomized to receive rotavirus vaccines in 1 of 5 different schedules (2 using a single vaccine for all doses, and 3 using mixed schedules). The group receiving …

The Challenge Of Analyzing The Results Of Next-Generation Sequencing In Children., Isabelle Thiffault, John Lantos

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In recent years, next-generation sequencing technologies have revolutionized approaches to genetic studies. Whole-exome or whole-genome sequencing allows diagnoses in many patients who have complex phenotypes and unusual clinical presentations. As genomic and exomic testing expands in both the research and clinical settings, pediatricians will need to understand the technology of next-generation sequencing and the complexity of interpreting genomic variants relevant to patient phenotypic features. This article briefly explains the technology by which genomes are sequenced and discusses some of the complexity related to interpreting genomic variants. We conclude with some thoughts on the clinical applications of such testing.

Whole-Genome Sequencing And Disability In The Nicu: Exploring Practical And Ethical Challenges., Michael J. Deem

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Clinical whole-genome sequencing (WGS) promises to deliver faster diagnoses and lead to better management of care in the NICU. However,several disability rights advocates have expressed concern that clinical use of genetic technologies may reinforce and perpetuate stigmatization of and discrimination against disabled persons in medical and social contexts. There is growing need, then, for clinicians and bioethicists to consider how the clinical use of WGS in the newborn period might exacerbate such harms to persons with disabilities. This article explores ways to extend these concerns to clinical WGS in neonatal care. By considering these perspectives during the early phases of …

Introduction To Bioethics Special Supplement V: Ethical Issues In Genomic Testing Of Children., John D. Lantos

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Next-generation genome sequencing of children is one of the most promising and most challenging new technologies in pediatrics. On the one hand, it offers the hope that we will be able to diagnose rare conditions that were previously impossible to diagnose, which, in turn, might lead to new treatments. On the other hand, the technology for sequencing presents daunting problems of interpretation. It is problematic to conduct the research necessary to characterize the pathogenicity of those variants at the same time that we are using them to guide the clinical care of children who have complex medical problems. It is …