Medicine and Health Sciences Commons^™

Regulators Of Oncogenic Mutant Tp53 Gain Of Function., Satomi Yamamoto, Tomoo Iwakuma

Manuscripts, Articles, Book Chapters and Other Papers

The tumor suppressor p53 (TP53) is the most frequently mutated human gene. Mutations in TP53 not only disrupt its tumor suppressor function, but also endow oncogenic gain-of-function (GOF) activities in a manner independent of wild-type TP53 (wtp53). Mutant TP53 (mutp53) GOF is mainly mediated by its binding with other tumor suppressive or oncogenic proteins. Increasing evidence indicates that stabilization of mutp53 is crucial for its GOF activity. However, little is known about factors that alter mutp53 stability and its oncogenic GOF activities. In this review article, we primarily summarize key regulators of mutp53 stability/activities, including genotoxic stress, post-translational modifications, ubiquitin …

Clinical Pharmacology Of Tisagenlecleucel In B-Cell Acute Lymphoblastic Leukemia., Karen Thudium Mueller, Edward Waldron, Stephan A. Grupp, John E. Levine, Theodore W. Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith August, Jason Hamilton, Rakesh Awasthi, Andrew M. Stein, Denise Sickert, Abhijit Chakraborty, Bruce L. Levine, Carl H. June, Lori Tomassian, Sweta S. Shah, Mimi Leung, Tetiana Taran, Patricia A. Wood, Shannon L. Maude

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).

PATIENTS AND METHODS: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN).

RESULTS: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders ( …

Precision Medicine In Pediatric Cancer: Current Applications And Future Prospects., Atif Ahmed, Divya S. Vundamati, Midhat S. Farooqi, Erin M. Guest

Manuscripts, Articles, Book Chapters and Other Papers

Precision oncologic medicine is an emerging approach for cancer treatment that has recently taken giant steps in solid clinical practice. Recent advances in molecular diagnostics that can analyze the individual tumor's variability in genes have provided greater understanding and additional strategies to treat cancers. Although tumors can be tested by several molecular methods, the use of next-generation sequencing (NGS) has greatly facilitated our understanding of pediatric cancer and identified additional therapeutic opportunities. Pediatric tumors have a different genetic make-up, with a fewer number of actionable targets than adult tumors. Nevertheless, precision oncology in the pediatric population has greatly improved the …

Subject Level Clustering Using A Negative Binomial Model For Small Transcriptomic Studies., Qian Li, Janelle R. Noel-Macdonnell, Devin C. Koestler, Ellen L. Goode, Brooke L. Fridley

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BACKGROUND: Unsupervised clustering represents one of the most widely applied methods in analysis of high-throughput 'omics data. A variety of unsupervised model-based or parametric clustering methods and non-parametric clustering methods have been proposed for RNA-seq count data, most of which perform well for large samples, e.g. N ≥ 500. A common issue when analyzing limited samples of RNA-seq count data is that the data follows an over-dispersed distribution, and thus a Negative Binomial likelihood model is often used. Thus, we have developed a Negative Binomial model-based (NBMB) clustering approach for application to RNA-seq studies.

RESULTS: We have developed a Negative …

Autoimmune Hyperphosphatemic Tumoral Calcinosis In A Patient With Fgf23 Autoantibodies., Mary Scott Roberts, Peter D. Burbelo, Daniela Egli-Spichtig, Farzana Perwad, Christopher J. Romero, Shoji Ichikawa, Emily G. Farrow, Michael J. Econs, Lori C. Guthrie, Michael T. Collins, Rachel I. Gafni

Manuscripts, Articles, Book Chapters and Other Papers

Hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive disorder of ectopic calcification due to deficiency of or resistance to intact fibroblast growth factor 23 (iFGF23). Inactivating mutations in FGF23, N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO (KL) have been reported as causing HFTC/HHS. We present what we believe is the first identified case of autoimmune hyperphosphatemic tumoral calcinosis in an 8-year-old boy. In addition to the classical clinical and biochemical features of hyperphosphatemic tumoral calcinosis, the patient exhibited markedly elevated intact and C-terminal FGF23 levels, suggestive of FGF23 resistance. However, no mutations in FGF23, KL, or FGF receptor 1 …

Genetic Predisposition To Necrotizing Enterocolitis In Premature Infants: Current Knowledge, Challenges, And Future Directions., Alain Cuna, Lovya George, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

The role of genetics in the pathogenesis of necrotizing enterocolitis (NEC) was initially informed by epidemiological data indicating differences in prevalence among different ethnic groups as well as concordance in twins. These early observations, together with major advances in genomic research, paved the way for studies that begin to reveal the contribution of genetics to NEC. Using the candidate gene or pathway approach, several potential pathogenic variants for NEC in premature infants have already been identified. More recently, genome-wide association studies and exome-sequencing based studies for NEC have been reported. These advances, however, are tempered by the lack of adequately …

On The Verge Of Diagnosis: Detection, Reporting, And Investigation Of De Novo Variants In Novel Genes Identified By Clinical Sequencing., Isabelle Thiffault, Maxime Cadieux-Dion, Emily G. Farrow, Raymond Caylor, Neil A. Miller, Sarah E. Soden, Carol J. Saunders

Manuscripts, Articles, Book Chapters and Other Papers

The variable evidence supporting gene-disease associations contributes to the difficulty of accurate variant reporting in a clinical setting. An evidence-based scoring system for evaluating the clinical validity of gene-disease associations, proposed by ClinGen, considers experimental as well as genetic evidence. De novo variants are heavily weighted, given the overall rarity in the genome and their contribution to human disease, however they are reported as "genes of unknown significance" in our center when there is insufficient evidence for the gene-disease assertion. We report a collection of 21 de novo variants in genes of unknown clinical significance ascertained via clinical testing, of …

Proteomics Of Human Liver Membrane Transporters: A Focus On Fetuses And Newborn Infants., Bianca D. Van Groen, Evita Van De Steeg, Miriam G. Mooij, Marola M H Van Lipzig, Barbara A E De Koning, Robert M. Verdijk, Heleen M. Wortelboer, R Gaedigk, Chengpeng Bi, J Steven Leeder, Ron H N Van Schaik, Joost Van Rosmalen, Dick Tibboel, Wouter H. Vaes, Saskia N. De Wildt

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study the relation of age with absolute transporter protein expression in a cohort of 62 mainly fetus and newborn samples.

METHODS: Protein expressions of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 and ATP1A1 were quantified with LC-MS/MS in isolated crude membrane fractions of snap-frozen post-mortem fetal and pediatric, and surgical adult liver samples. mRNA expression was quantified using RNA sequencing, and genetic variants with TaqMan assays. We explored relationships between protein expression and age …

A Brief Report Of Immunohistochemical Markers To Identify Aggressive Hepatoblastoma., Vivekanand Singh, Michelle Manalang, Meenal Singh, Udayan Apte

Manuscripts, Articles, Book Chapters and Other Papers

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Although survival of patients has improved significantly over the last 2 decades, a significant number of patients do not respond to standard chemotherapy. We conducted a pilot study to understand if there was immunophenotypic difference between tumors that respond well to chemotherapy versus that do not. We selected 10 cases of HB from children presenting at our hospital. All patients had initial tissue diagnosis, underwent chemotherapy followed by surgical resection. The cases were divided into 2 groups: aggressive group with 5 cases (all of which had a poor response …

Intestinal Carriage Of Third-Generation Cephalosporin-Resistant And Extended-Spectrum Β-Lactamase-Producing Enterobacteriaceae In Healthy Us Children., Shamim Islam, Rangaraj Selvarangan, Neena Kanwar, Rendie Mchenry, James D. Chappell, Natasha Halasa, Mary E. Wikswo, Daniel C. Payne, Parvin H. Azimi, L Clifford Mcdonald, Oscar G. Gomez-Duarte

Manuscripts, Articles, Book Chapters and Other Papers

Background: The epidemiology of antibiotic-resistant Enterobacteriaceae intestinal carriage in healthy US children has not been well characterized.

Methods: Children between 14 days and 14 years of age were enrolled during well-child visits in Oakland, California, Kansas City, Kansas, and Nashville, Tennessee, between December 2013 and March 2015. Data on recent antibiotic use by the child and travel and hospitalization history of all members of each child's household were obtained with a risk-factor survey. Stool specimens collected from the subjects were screened for extended-spectrum β-lactamase-producing (ESBL-P) bacteria using CHROMagar ESBL medium. Putative ESBL-P Escherichia coli and Klebsiella colonies underwent phenotypic confirmation …

An Eqtl Landscape Of Kidney Tissue In Human Nephrotic Syndrome., Christopher E. Gillies, Rosemary Putler, Rajasree Menon, Edgar Otto, Kalyn Yasutake, Viji Nair, Paul Hoover, David Lieb, Shuqiang Li, Sean Eddy, Damian Fermin, Michelle T. Mcnulty, Nephrotic Syndrome Study Network (Neptune), Nir Hacohen, Krzysztof Kiryluk, Matthias Kretzler, Xiaoquan Wen, Matthew G. Sampson, Tarak Srivastava

Manuscripts, Articles, Book Chapters and Other Papers

Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTL studies of human kidney. Here, we used whole-genome sequencing (WGS) and microdissected glomerular (GLOM) and tubulointerstitial (TI) transcriptomes from 187 individuals with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures. Using MatrixEQTL, we performed cis-eQTL analysis on GLOM (n = 136) and TI (n = 166). We used the Bayesian "Deterministic Approximation of Posteriors" (DAP) to fine-map …

Building A Bridge Between Genetics And Outcomes Research: Application In Autism (The Autgo Study)., Zohreh Talebizadeh, Ayten Shah, Pcori Eain-2419 Working Group

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Concerns over the need to improve translational aspects of genetics research studies and engaging community members in the research process have been noted in the literature and raised by patient advocates. In addition to the work done by patient advocacy groups, organizations such as the Patient-Centered Outcomes Research Institute advocate for a change in the culture of research from being researcher-driven to becoming more patient-driven.

OBJECTIVE: Our project, Autism Genetics and Outcomes (AutGO), consists of two phases. The goal for phase I was to initiate a general discussion around the main topic (i.e., linking genetics and outcomes research). We …

Evaluation Of The Illumigene Mycoplasma Direct Dna Amplification Assay, Neena Kanwar, Morgan A. Pence, Donna Mayne, Jeff Michael, Rangaraj Selvarangan

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Copyright © 2018 Kanwar et al. Mycoplasma pneumoniae is a common cause of community-acquired pneumonia. The illumigene Mycoplasma Direct (IMD) DNA amplification assay is a qualitative in vitro test utilizing loop-mediated isothermal amplification (LAMP) technology for the direct detection of M. Pneumoniae DNA in respiratory specimens. The IMD assay does not require the preextraction of nucleic acids from specimens, which is a prerequisite step for the previously approved illumigene Mycoplasma (iM) assay. The aim of this prospective multicenter study was to evaluate the performance characteristics of the newly developed IMD assay, compared with the iM assay. Subjects with symptoms of …

Hla-Dqa1 And Apol1 As Risk Loci For Childhood-Onset Steroid-Sensitive And Steroid-Resistant Nephrotic Syndrome., Adebowale Adeyemo, Christopher Esezobor, Adaobi Solarin, Asiri Abeyagunawardena, Jameela A. Kari, Sherif El Desoky, Larry A. Greenbaum, Margret Kamel, Mahmoud Kallash, Cynthia Silva, Alex Young, Tracey E. Hunley, Nilka De Jesus-Gonzalez, Tarak Srivastava, Rasheed Gbadegesin

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Background: Few data exist for the genetic variants underlying the risk for steroid-sensitive nephrotic syndrome (SSNS) in children. The objectives of this study were to evaluate HLA-DQA1 and APOL1 variants as risk factors for SSNS in African American children and use classic HLA antigen types and amino acid inference to refine the HLA-DQA1 association.

Study design: Case-control study.

Setting & participants: African American children with SSNS or steroid-resistant nephrotic syndrome (SRNS) were enrolled from Duke University and centers participating in the Midwest Pediatric Nephrology Consortium.

Factor: Genetic variants in HLA-DQA1 (C34Y [rs1129740]; F41S [rs1071630]) and APOL1 high-risk alleles.

Outcomes: SSNS …

Mechanotransduction Signaling In Podocytes From Fluid Flow Shear Stress., Tarak Srivastava, Hongying Dai, Daniel P. Heruth, Uri S. Alon, Robert E. Garola, Jianping Zhou, R Scott Duncan, Ashraf El-Meanawy, Ellen T. Mccarthy, Ram Sharma, Mark L. Johnson, Virginia J. Savin, Mukut Sharma

Manuscripts, Articles, Book Chapters and Other Papers

Recently, we and others have found that hyperfiltration-associated increase in biomechanical forces, namely, tensile stress and fluid flow shear stress (FFSS), can directly and distinctly alter podocyte structure and function. The ultrafiltrate flow over the major processes and cell body generates FFSS to podocytes. Our previous work suggests that the cyclooxygenase-2 (COX-2)-PGE2-PGE2 receptor 2 (EP2) axis plays an important role in mechanoperception of FFSS in podocytes. To address mechanotransduction of the perceived stimulus through EP2, cultured podocytes were exposed to FFSS (2 dyn/cm2) for 2 h. Total RNA from cells at the end of FFSS treatment, 2-h post-FFSS, and 24-h …

Effect Of Hemiepiphysiodesis On The Growth Plate: The Histopathological Changes And Mechanism Exploration Of Recurrence In Mini Pig Model., Jing Ding, Jin He, Zhi-Qiang Zhang, Zhen-Kai Wu, Fang-Chun Jin

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Purpose: Hemiepiphysiodesis has been widely used to correct angular deformity of long bone in immature patients. However, there is a limited knowledge about the biomechanical effect of this technique on the histopathological changes of the growth plate and the mechanism of recurrence of malformation after implant removal. We aimed to evaluate the biomechanical effect of hemiepiphysiodesis on the histopathological changes of the growth plate and the mechanism of recurrence of malformation after implant removal in Bama miniature pigs, and to explore the role of asymmetric stress during this procedure.

Methods: Eight 3-month-old male Bama miniature pigs sustained surgeries on the …