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Articles 1 - 30 of 1076

Full-Text Articles in Medical Genetics

Evaluation Of Somatic Mutations In Solid Metastatic Pan-Cancer Patients, Moom Roosan, Isa Mambetsariev, Rebecca Pharaon, Jeremy Fricke, Angel R. Baroz, Joseph Chao, Chen Chen, Mohd W. Nasser, Ramakanth Chirravuri-Venkata, Maneesh Jain, Lynette Smith, Susan E. Yost, Karen L. Reckamp, Raju Pillai, Leonidas Arvanitis, Michelle Afkhami, Edward W. Wang, Vincent Chung, Mihaela Cristea, Marwan Fakih, Marianna Koczywas, Erminia Massarelli, Joanne Mortimer, Yuan Yuan, Surinder K. Batra, Sumanta Pal, Ravi Salgia Jun 2021

Evaluation Of Somatic Mutations In Solid Metastatic Pan-Cancer Patients, Moom Roosan, Isa Mambetsariev, Rebecca Pharaon, Jeremy Fricke, Angel R. Baroz, Joseph Chao, Chen Chen, Mohd W. Nasser, Ramakanth Chirravuri-Venkata, Maneesh Jain, Lynette Smith, Susan E. Yost, Karen L. Reckamp, Raju Pillai, Leonidas Arvanitis, Michelle Afkhami, Edward W. Wang, Vincent Chung, Mihaela Cristea, Marwan Fakih, Marianna Koczywas, Erminia Massarelli, Joanne Mortimer, Yuan Yuan, Surinder K. Batra, Sumanta Pal, Ravi Salgia

Pharmacy Faculty Articles and Research

Metastasis continues to be the primary cause of all cancer-related deaths despite the recent advancements in cancer treatments. To evaluate the role of mutations in overall survival (OS) and treatment outcomes, we analyzed 957 metastatic patients with seven major cancer types who had available molecular testing results with a FoundationOne CDx® panel. The most prevalent genes with somatic mutations were TP53, KRAS, APC, and LRP1B. In this analysis, these genes had mutation frequencies higher than in publicly available datasets. We identified that the somatic mutations were seven mutually exclusive gene pairs and an additional fifty-two co-occurring gene pairs. Mutations in ...


A Screen Of Fda-Approved Drugs Identifies Inhibitors Of Protein Tyrosine Phosphatase 4a3 (Ptp4a3 Or Prl-3), Dylan R. Rivas, Mark Vincent C. Dela Cerna, Caroline N. Smith, Shilpa Sampathi, Blaine G. Patty, Donghan Lee, Jessica S. Blackburn May 2021

A Screen Of Fda-Approved Drugs Identifies Inhibitors Of Protein Tyrosine Phosphatase 4a3 (Ptp4a3 Or Prl-3), Dylan R. Rivas, Mark Vincent C. Dela Cerna, Caroline N. Smith, Shilpa Sampathi, Blaine G. Patty, Donghan Lee, Jessica S. Blackburn

Molecular and Cellular Biochemistry Faculty Publications

Protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity. Two of these broad-spectrum PRL inhibitors, Salirasib and Candesartan, blocked PRL-3-induced migration in human embryonic kidney cells ...


Understanding The Effect Of Adaptive Mutations On The Three-Dimensional Structure Of Rna, Justin Cook May 2021

Understanding The Effect Of Adaptive Mutations On The Three-Dimensional Structure Of Rna, Justin Cook

Undergraduate Research and Scholarship Symposium

Single-nucleotide polymorphisms (SNPs) are variations in the genome where one base pair can differ between individuals.1 SNPs occur throughout the genome and can correlate to a disease-state if they occur in a functional region of DNA.1According to the central dogma of molecular biology, any variation in the DNA sequence will have a direct effect on the RNA sequence and will potentially alter the identity or conformation of a protein product. A single RNA molecule, due to intramolecular base pairing, can acquire a plethora of 3-D conformations that are described by its structural ensemble. One SNP, rs12477830, which ...


Investigation Of Alpl Variant States And Clinical Outcomes: An Analysis Of Adults And Adolescents With Hypophosphatasia Treated With Asfotase Alfa., Priya S. Kishnani, Guillermo Del Angel, Shanggen Zhou, Eric T. Rush May 2021

Investigation Of Alpl Variant States And Clinical Outcomes: An Analysis Of Adults And Adolescents With Hypophosphatasia Treated With Asfotase Alfa., Priya S. Kishnani, Guillermo Del Angel, Shanggen Zhou, Eric T. Rush

Manuscripts, Articles, Book Chapters and Other Papers

Background: Hypophosphatasia (HPP), a rare metabolic disease, can be inherited in an autosomal recessive (biallelic) or an autosomal dominant (monoallelic) manner. Most of the severe, early-onset, frequently lethal HPP in infants is acquired through recessive inheritance; less severe, later-onset, typically nonlethal HPP phenotypes are acquired through either dominant or recessive inheritance. HPP's variable clinical presentation arises from >400 identified ALPL pathogenic variants with likely variable penetrance, especially with autosomal dominant inheritance. This post hoc analysis investigated the relationship between ALPL variant state (biallelic and monoallelic) and clinical outcomes with asfotase alfa in HPP.

Methods: Data were pooled from two ...


Epigenome-Wide Association Study Of Kidney Function Identifies Trans-Ethnic And Ethnic-Specific Loci, Charles E. Breeze, Anna Batorsky, Mi Kyeong Lee, Mindy D. Szeto, Xiaoguang Xu, Daniel L. Mccartney, Rong Jiang, Amit Patki, Holly J. Kramer, James M. Eales, Laura Raffield, Leslie Lange, Ethan Lange, Peter Durda, Yongmei Liu, Russ P. Tracy, David Van Den Berg, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Mesa Multi-Omics Working Group, Kathryn L. Evans, William E. Kraus, Donna K. Arnett Apr 2021

Epigenome-Wide Association Study Of Kidney Function Identifies Trans-Ethnic And Ethnic-Specific Loci, Charles E. Breeze, Anna Batorsky, Mi Kyeong Lee, Mindy D. Szeto, Xiaoguang Xu, Daniel L. Mccartney, Rong Jiang, Amit Patki, Holly J. Kramer, James M. Eales, Laura Raffield, Leslie Lange, Ethan Lange, Peter Durda, Yongmei Liu, Russ P. Tracy, David Van Den Berg, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Mesa Multi-Omics Working Group, Kathryn L. Evans, William E. Kraus, Donna K. Arnett

Epidemiology Faculty Publications

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.

METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear ...


Use Of Antisense Oligonucleotides To Target Notch2 In Mouse Chondrocytes, Gabrielle Viviana Lanza Apr 2021

Use Of Antisense Oligonucleotides To Target Notch2 In Mouse Chondrocytes, Gabrielle Viviana Lanza

Honors Scholar Theses

NOTCH2 is a transmembrane receptor that is part of the Notch receptor family, known for controlling cell differentiation and function. Notch receptors play a crucial role in skeletal development and bone homeostasis. Hajdu Cheney Syndrome (HCS) is a rare monogenic disorder affecting the skeleton caused by a gain-of-function mutation in NOTCH2. Antisense oligonucleotides (ASO) are sequence-specific single-stranded nucleic acids that bind to target mRNA and initiate mRNA degradation. While previous work has explored the role of Notch2 ASOs in osteoblasts and osteoclasts, this paper explores the role of Notch2 and Notch2 ASOs in cells of cartilage tissue. The effect of ...


Ciliary Extracellular Vesicles Are Distinct From The Cytosolic Extracellular Vesicles, Ashraf M. Mohieldin, Rajasekharreddy Pala, Richard Beuttler, James J. Moresco, John R. Yates Iii, Surya M. Nauli Apr 2021

Ciliary Extracellular Vesicles Are Distinct From The Cytosolic Extracellular Vesicles, Ashraf M. Mohieldin, Rajasekharreddy Pala, Richard Beuttler, James J. Moresco, John R. Yates Iii, Surya M. Nauli

Pharmacy Faculty Articles and Research

Extracellular vesicles (EVs) are cell‐derived membrane vesicles that are released into the extracellular space. EVs encapsulate key proteins and mediate intercellular signalling pathways. Recently, primary cilia have been shown to release EVs under fluid‐shear flow, but many proteins encapsulated in these vesicles have never been identified. Primary cilia are ubiquitous mechanosensory organelles that protrude from the apical surface of almost all human cells. Primary cilia also serve as compartments for signalling pathways, and their defects have been associated with a wide range of human genetic diseases called ciliopathies. To better understand the mechanism of ciliopathies, it is imperative ...


Rare Deleterious Mutations Of Hnrnp Genes Result In Shared Neurodevelopmental Disorders., Madelyn A. Gillentine, Tianyun Wang, Kendra Hoekzema, Jill Rosenfeld, Pengfei Liu, Hui Guo, Chang N. Kim, Bert B A De Vries, Lisenka E L M Vissers, Magnus Nordenskjold, Malin Kvarnung, Anna Lindstrand, Ann Nordgren, Jozef Gecz, Maria Iascone, Anna Cereda, Agnese Scatigno, Silvia Maitz, Ginevra Zanni, Enrico Bertini, Christiane Zweier, Sarah Schuhmann, Antje Wiesener, Micah Pepper, Heena Panjwani, Erin Torti, Farida Abid, Irina Anselm, Siddharth Srivastava, Paldeep Atwal, Carlos A. Bacino, Gifty Bhat, Katherine Cobian, Lynne M. Bird, Jennifer Friedman, Meredith S. Wright, Bert Callewaert, Florence Petit, Sophie Mathieu, Alexandra Afenjar, Celenie K. Christensen, Kerry M. White, Orly Elpeleg, Itai Berger, Edward J. Espineli, Christina Fagerberg, Charlotte Brasch-Andersen, Lars Kjærsgaard Hansen, Timothy Feyma, Susan Starling Hughes, Isabelle Thiffault, Bonnie Sullivan, Shuang Yan, Kory Keller, Boris Keren, Cyril Mignot, Frank Kooy, Marije Meuwissen, Alice Basinger, Mary Kukolich, Meredith Philips, Lucia Ortega, Margaret Drummond-Borg, Mathilde Lauridsen, Kristina Sorensen, Anna Lehman, Causes Study, Elena Lopez-Rangel, Paul Levy, Davor Lessel, Timothy Lotze, Suneeta Madan-Khetarpal, Jessica Sebastian, Jodie Vento, Divya Vats, L Manace Benman, Shane Mckee, Ghayda M. Mirzaa, Candace Muss, John Pappas, Hilde Peeters, Corrado Romano, Maurizio Elia, Ornella Galesi, Marleen E H Simon, Koen L I Van Gassen, Kara Simpson, Robert Stratton, Sabeen Syed, Julien Thevenon, Irene Valenzuela Palafoll, Antonio Vitobello, Marie Bournez, Laurence Faivre, Kun Xia, Spark Consortium, Rachel K. Earl, Tomasz Nowakowski, Raphael A. Bernier, Evan E. Eichler Apr 2021

Rare Deleterious Mutations Of Hnrnp Genes Result In Shared Neurodevelopmental Disorders., Madelyn A. Gillentine, Tianyun Wang, Kendra Hoekzema, Jill Rosenfeld, Pengfei Liu, Hui Guo, Chang N. Kim, Bert B A De Vries, Lisenka E L M Vissers, Magnus Nordenskjold, Malin Kvarnung, Anna Lindstrand, Ann Nordgren, Jozef Gecz, Maria Iascone, Anna Cereda, Agnese Scatigno, Silvia Maitz, Ginevra Zanni, Enrico Bertini, Christiane Zweier, Sarah Schuhmann, Antje Wiesener, Micah Pepper, Heena Panjwani, Erin Torti, Farida Abid, Irina Anselm, Siddharth Srivastava, Paldeep Atwal, Carlos A. Bacino, Gifty Bhat, Katherine Cobian, Lynne M. Bird, Jennifer Friedman, Meredith S. Wright, Bert Callewaert, Florence Petit, Sophie Mathieu, Alexandra Afenjar, Celenie K. Christensen, Kerry M. White, Orly Elpeleg, Itai Berger, Edward J. Espineli, Christina Fagerberg, Charlotte Brasch-Andersen, Lars Kjærsgaard Hansen, Timothy Feyma, Susan Starling Hughes, Isabelle Thiffault, Bonnie Sullivan, Shuang Yan, Kory Keller, Boris Keren, Cyril Mignot, Frank Kooy, Marije Meuwissen, Alice Basinger, Mary Kukolich, Meredith Philips, Lucia Ortega, Margaret Drummond-Borg, Mathilde Lauridsen, Kristina Sorensen, Anna Lehman, Causes Study, Elena Lopez-Rangel, Paul Levy, Davor Lessel, Timothy Lotze, Suneeta Madan-Khetarpal, Jessica Sebastian, Jodie Vento, Divya Vats, L Manace Benman, Shane Mckee, Ghayda M. Mirzaa, Candace Muss, John Pappas, Hilde Peeters, Corrado Romano, Maurizio Elia, Ornella Galesi, Marleen E H Simon, Koen L I Van Gassen, Kara Simpson, Robert Stratton, Sabeen Syed, Julien Thevenon, Irene Valenzuela Palafoll, Antonio Vitobello, Marie Bournez, Laurence Faivre, Kun Xia, Spark Consortium, Rachel K. Earl, Tomasz Nowakowski, Raphael A. Bernier, Evan E. Eichler

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which ...


Genetic Perturbation Of Pu.1 Binding And Chromatin Looping At Neutrophil Enhancers Associates With Autoimmune Disease., Stephen Watt, Louella Vasquez, Klaudia Walter, Alice L. Mann, Kousik Kundu, Lu Chen, Ying Sims, Simone Ecker, Frances Burden, Samantha Farrow, Ben Farr, Valentina Iotchkova, Heather Elding, Daniel Mead, Manuel Tardaguila, Hannes Ponstingl, David Richardson, Avik Datta, Paul Flicek, Laura Clarke, Kate Downes, T Pastinen, Peter Fraser, Mattia Frontini, Biola-Maria Javierre, Mikhail Spivakov, Nicole Soranzo Apr 2021

Genetic Perturbation Of Pu.1 Binding And Chromatin Looping At Neutrophil Enhancers Associates With Autoimmune Disease., Stephen Watt, Louella Vasquez, Klaudia Walter, Alice L. Mann, Kousik Kundu, Lu Chen, Ying Sims, Simone Ecker, Frances Burden, Samantha Farrow, Ben Farr, Valentina Iotchkova, Heather Elding, Daniel Mead, Manuel Tardaguila, Hannes Ponstingl, David Richardson, Avik Datta, Paul Flicek, Laura Clarke, Kate Downes, T Pastinen, Peter Fraser, Mattia Frontini, Biola-Maria Javierre, Mikhail Spivakov, Nicole Soranzo

Manuscripts, Articles, Book Chapters and Other Papers

Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a ...


Delta-Like 4 Is Required For Pulmonary Vascular Arborization And Alveolarization In The Developing Lung., Sheng Xia, Heather Menden, Nick Townley, Sherry M. Mabry, Jeffrey J. Johnston, Michael F. Nyp, Daniel P. Heruth, Thomas Korfhagen, Venkatesh Sampath Apr 2021

Delta-Like 4 Is Required For Pulmonary Vascular Arborization And Alveolarization In The Developing Lung., Sheng Xia, Heather Menden, Nick Townley, Sherry M. Mabry, Jeffrey J. Johnston, Michael F. Nyp, Daniel P. Heruth, Thomas Korfhagen, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

The molecular mechanisms by which endothelial cells (ECs) regulate pulmonary vascularization and contribute to alveolar epithelial cell development during lung morphogenesis remain unknown. We tested the hypothesis that delta-like 4 (DLL4), an EC Notch ligand, is critical for alveolarization by combining lung mapping and functional studies in human tissue and DLL4-haploinsufficient mice (Dll4+/lacz). DLL4 expressed in a PECAM-restricted manner in capillaries, arteries, and the alveolar septum from the canalicular to alveolar stage in mice and humans. Dll4 haploinsufficiency resulted in exuberant, nondirectional vascular patterning at E17.5 and P6, followed by smaller capillaries and fewer intermediate blood vessels at ...


Genomic Education – Bench To Bedside: A Novel Approach To Teaching Genetic Diagnosis, J. Keith Williams, Michael M. Segal, Lynn K. Feldman Apr 2021

Genomic Education – Bench To Bedside: A Novel Approach To Teaching Genetic Diagnosis, J. Keith Williams, Michael M. Segal, Lynn K. Feldman

Internet Journal of Allied Health Sciences and Practice

Problem: Teaching genetic diagnosis is required in all medical schools and physician assistant programs. However, with thousands of relevant findings and thousands more rare diseases, lectures and narrative resources are inadequate for the task. Whatever information that is taught is easily forgotten and does not carry over into the clinic. Many rare disease patients suffer through “diagnostic odysseys” (3 to 30 years to correct diagnosis). Approach: We used a commercially available diagnostic decision support system (DDSS) that encompasses all Mendelian disorders with known genes, together with other conditions in their differential diagnosis, and a case-based educational approach to teach diagnostic ...


Hook3 Mutations And Their Contributions To Different Types Of Cancers, Brittny Mikhaiel, Van Vo Ph.D. Apr 2021

Hook3 Mutations And Their Contributions To Different Types Of Cancers, Brittny Mikhaiel, Van Vo Ph.D.

Undergraduate Research Symposium Posters

Hook3 (Hook Microtubule Tethering Protein 3) is a gene that encodes a protein that is localized in the Golgi complex and is linked to cellular trafficking of cargos and the binding of microtubules to organelles. Although there is some literature discussing the known functions of the gene, the phenotypes in mice or humans have not been thoroughly researched and literature on these phenotypes is limited. The literature that is available suggests Hook3 is implicated in diverse phenotypes ranging from bone development to neural development in mice. Since Hook3 is associated with prostate cancer, it is likely that it is involved ...


A Timeline Of Down Syndrome, Christian Guese, Kristina Mcinnes, Kimberly Miranda Apr 2021

A Timeline Of Down Syndrome, Christian Guese, Kristina Mcinnes, Kimberly Miranda

Undergraduate Research Symposium Posters

The purpose of this research timeline is to synthesize the natural history of Down Syndrome (DS) to discover absence of knowledge, discuss the bioethics in prenatal screening and develop a public health message. Our method of research was literature-based. DS is one of the most common aneuploidy disorders in the United States. There are three genetic variations of DS, Trisomy 21, a third copy of chromosome 21, accounts for 95% of cases. DS causes intellectual disability, developmental delays, facial dysmorphia, and low muscle tone. DS also leads to an increased risk for congenital heart defects and Alzheimer’s disease later ...


Discovering Rett Syndrome (Rts) And Understanding Its Enigmatic Development, Fiorella Ramirez-Guasp, Chanel Chan, Sukyeong Kim Apr 2021

Discovering Rett Syndrome (Rts) And Understanding Its Enigmatic Development, Fiorella Ramirez-Guasp, Chanel Chan, Sukyeong Kim

Undergraduate Research Symposium Posters

The purpose of this research project is to compose a comprehensive timeline on the rare disease Rett Syndrome (RTS) in order to better understand its enigmatic development as well as furthering the public’s understanding on this degenerative disease. RTS is a panethnic progressive neurodevelopmental disorder that occurs nearly exclusively in girls. This syndrome is characterized by normal prenatal and neonatal development, followed by an onset of neurological symptoms with a mental stagnation anywhere around 6-18 months of age that involves a rapid loss in speech and acquired motor skills. There is limited knowledge about the molecular cause of Rett ...


The Transcriptional Trajectories Of Pluripotency And Differentiation Comprise Genes With Antithetical Architecture And Repetitive-Element Content., Aristeidis G. Telonis, Isidore Rigoutsos Mar 2021

The Transcriptional Trajectories Of Pluripotency And Differentiation Comprise Genes With Antithetical Architecture And Repetitive-Element Content., Aristeidis G. Telonis, Isidore Rigoutsos

Computational Medicine Center Faculty Papers

BACKGROUND: Extensive molecular differences exist between proliferative and differentiated cells. Here, we conduct a meta-analysis of publicly available transcriptomic datasets from preimplantation and differentiation stages examining the architectural properties and content of genes whose abundance changes significantly across developmental time points.

RESULTS: Analysis of preimplantation embryos from human and mouse showed that short genes whose introns are enriched in Alu (human) and B (mouse) elements, respectively, have higher abundance in the blastocyst compared to the zygote. These highly expressed genes encode ribosomal proteins or metabolic enzymes. On the other hand, long genes whose introns are depleted in repetitive elements have ...


Robust, Flexible, And Scalable Tests For Hardy-Weinberg Equilibrium Across Diverse Ancestries, Alan M. Kwong, Thomas W. Blackwell, Jonathon Lefaive, Mariza De Andrade, John Barnard, Kathleen C. Barnes, John Blangero Mar 2021

Robust, Flexible, And Scalable Tests For Hardy-Weinberg Equilibrium Across Diverse Ancestries, Alan M. Kwong, Thomas W. Blackwell, Jonathon Lefaive, Mariza De Andrade, John Barnard, Kathleen C. Barnes, John Blangero

School of Medicine Publications and Presentations

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in datasets comprised of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and evaluate the impact of population heterogeneity and genotype ...


Genome-Wide Association Meta-Analysis Identifies Pleiotropic Risk Loci For Aerodigestive Squamous Cell Cancers, Corina Lesseur, Aida Ferreiro-Iglesias, James D. Mckay, Yohan Bossé, Mattias Johansson, Valerie Gaborieau, Maria Teresa Landi, David C. Christiani, Neil C. Caporaso, Stig E. Bojesen, Christopher I. Amos, Sanjay Shete, Geoffrey Liu, Gadi Rennert, Demetrius Albanes, Melinda C. Aldrich, Adonina Tardon, Chu Chen, Liloglou Triantafillos, John K. Field, Susanne Arnold Mar 2021

Genome-Wide Association Meta-Analysis Identifies Pleiotropic Risk Loci For Aerodigestive Squamous Cell Cancers, Corina Lesseur, Aida Ferreiro-Iglesias, James D. Mckay, Yohan Bossé, Mattias Johansson, Valerie Gaborieau, Maria Teresa Landi, David C. Christiani, Neil C. Caporaso, Stig E. Bojesen, Christopher I. Amos, Sanjay Shete, Geoffrey Liu, Gadi Rennert, Demetrius Albanes, Melinda C. Aldrich, Adonina Tardon, Chu Chen, Liloglou Triantafillos, John K. Field, Susanne Arnold

Markey Cancer Center Faculty Publications

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta< 5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously ...


Association Of Cardiovascular Health And Epigenetic Age Acceleration, Tess D. Pottinger, Sadiya S. Khan, Yinan Zheng, Wei Zhang, Hilary A. Tindle, Matthew Allison, Gretchen Wells, Aladdin H. Shadyab, Rami Nassir, Lisa Warsinger Martin, Joann E. Manson, Donald M. Lloyd-Jones, Philip Greenland, Andrea A. Baccarelli, Eric A. Whitsel, Lifang Hou Feb 2021

Association Of Cardiovascular Health And Epigenetic Age Acceleration, Tess D. Pottinger, Sadiya S. Khan, Yinan Zheng, Wei Zhang, Hilary A. Tindle, Matthew Allison, Gretchen Wells, Aladdin H. Shadyab, Rami Nassir, Lisa Warsinger Martin, Joann E. Manson, Donald M. Lloyd-Jones, Philip Greenland, Andrea A. Baccarelli, Eric A. Whitsel, Lifang Hou

Nursing Faculty Publications

BACKGROUND: Cardiovascular health (CVH) has been defined by the American Heart Association (AHA) as the presence of the "Life's Simple 7" ideal lifestyle and clinical factors. CVH is known to predict longevity and freedom from cardiovascular disease, the leading cause of death for women in the United States. DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age.

METHODS AND RESULTS: We performed a cross-sectional ...


Racial Disparities In Necrotizing Enterocolitis., Alain Cuna, Venkatesh Sampath, Minesh Khashu Feb 2021

Racial Disparities In Necrotizing Enterocolitis., Alain Cuna, Venkatesh Sampath, Minesh Khashu

Manuscripts, Articles, Book Chapters and Other Papers

Necrotizing enterocolitis (NEC) is a serious disease of the intestinal tract affecting 5-10% of pre-term infants with up to 50% mortality in those that require surgery. There is wide variation in the rates and outcomes of NEC by race and ethnicity, and the reasons for this disparity are poorly understood. In this article, we review the epidemiology and discuss possible explanations for racial and ethnic differences in NEC. Most of the current evidence investigating the role of race in NEC comes from North America and suggests that Hispanic ethnicity and non-Hispanic Black race are associated with higher risk of NEC ...


Sars-Cov-2 Early Infection Signature Identified Potential Key Infection Mechanisms And Drug Targets, Yue Li, Ashley Duche, Michael R. Sayer, Don Roosan, Farid G. Khalafalla, Rennolds S. Ostrom, Jennifer Totonchy, Moom Roosan Feb 2021

Sars-Cov-2 Early Infection Signature Identified Potential Key Infection Mechanisms And Drug Targets, Yue Li, Ashley Duche, Michael R. Sayer, Don Roosan, Farid G. Khalafalla, Rennolds S. Ostrom, Jennifer Totonchy, Moom Roosan

Pharmacy Faculty Articles and Research

Background

The ongoing COVID-19 outbreak has caused devastating mortality and posed a significant threat to public health worldwide. Despite the severity of this illness and 2.3 million worldwide deaths, the disease mechanism is mostly unknown. Previous studies that characterized differential gene expression due to SARS-CoV-2 infection lacked robust validation. Although vaccines are now available, effective treatment options are still out of reach.

Results

To characterize the transcriptional activity of SARS-CoV-2 infection, a gene signature consisting of 25 genes was generated using a publicly available RNA-Sequencing (RNA-Seq) dataset of cultured cells infected with SARS-CoV-2. The signature estimated infection level accurately ...


Long-Term Effects Of Very Low Dose Particle Radiation On Gene Expression In The Heart: Degenerative Disease Risks, Venkata Naga Srikanth Garikipati, Arsen Arakelyan, Eleanor A Blakely, Polly Y Chang, May M Truongcao, Maria Cimini, Vandana Malaredy, Anamika Bajpai, Sankar Addya, Malik Bisserier, Agnieszka Brojakowska, Abrisham Eskandari, Mary K Khlgatian, Lahouaria Hadri, Kenneth M Fish, Raj Kishore, David A Goukassian Feb 2021

Long-Term Effects Of Very Low Dose Particle Radiation On Gene Expression In The Heart: Degenerative Disease Risks, Venkata Naga Srikanth Garikipati, Arsen Arakelyan, Eleanor A Blakely, Polly Y Chang, May M Truongcao, Maria Cimini, Vandana Malaredy, Anamika Bajpai, Sankar Addya, Malik Bisserier, Agnieszka Brojakowska, Abrisham Eskandari, Mary K Khlgatian, Lahouaria Hadri, Kenneth M Fish, Raj Kishore, David A Goukassian

Kimmel Cancer Center Faculty Papers

Compared to low doses of gamma irradiation (γ-IR), high-charge-and-energy (HZE) particle IR may have different biological response thresholds in cardiac tissue at lower doses, and these effects may be IR type and dose dependent. Three- to four-month-old female CB6F1/Hsd mice were exposed once to one of four different doses of the following types of radiation: γ-IR 137Cs (40-160 cGy, 0.662 MeV), 14Si-IR (4-32 cGy, 260 MeV/n), or 22Ti-IR (3-26 cGy, 1 GeV/n). At 16 months post-exposure, animals were sacrificed and hearts were harvested and archived as part of the NASA Space Radiation Tissue Sharing Forum. These ...


Sequencing Of 53,831 Diverse Genomes From The Nhlbi Topmed Program, Daniel Taliun, Daniel N. Harris, Michael D. Kessler, Jedidiah Carlson, John Blangero, Joanne E. Curran, Michael C. Mahaney, Harald H. H. Goring, Ravindranath Duggirala, Juan M. Peralta Feb 2021

Sequencing Of 53,831 Diverse Genomes From The Nhlbi Topmed Program, Daniel Taliun, Daniel N. Harris, Michael D. Kessler, Jedidiah Carlson, John Blangero, Joanne E. Curran, Michael C. Mahaney, Harald H. H. Goring, Ravindranath Duggirala, Juan M. Peralta

School of Medicine Publications and Presentations

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and ...


Impaired Eif5a Function Causes A Mendelian Disorder That Is Partially Rescued In Model Systems By Spermidine., Víctor Faundes, Martin D. Jennings, Siobhan Crilly, Sarah Legraie, Sarah E. Withers, Sara Cuvertino, Sally J. Davies, Andrew G L Douglas, Andrew E. Fry, Victoria Harrison, Jeanne Amiel, Daphné Lehalle, William G. Newman, Patricia Newkirk, Judith Ranells, Miranda Splitt, Laura A. Cross, Carol J. Saunders, Bonnie Sullivan, Jorge L. Granadillo, Christopher T. Gordon, Paul R. Kasher, Graham D. Pavitt, Siddharth Banka Feb 2021

Impaired Eif5a Function Causes A Mendelian Disorder That Is Partially Rescued In Model Systems By Spermidine., Víctor Faundes, Martin D. Jennings, Siobhan Crilly, Sarah Legraie, Sarah E. Withers, Sara Cuvertino, Sally J. Davies, Andrew G L Douglas, Andrew E. Fry, Victoria Harrison, Jeanne Amiel, Daphné Lehalle, William G. Newman, Patricia Newkirk, Judith Ranells, Miranda Splitt, Laura A. Cross, Carol J. Saunders, Bonnie Sullivan, Jorge L. Granadillo, Christopher T. Gordon, Paul R. Kasher, Graham D. Pavitt, Siddharth Banka

Manuscripts, Articles, Book Chapters and Other Papers

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome ...


The Role Of Vascular Endothelial Growth Factor In Leukemia Trafficking, Shaw Powell Jan 2021

The Role Of Vascular Endothelial Growth Factor In Leukemia Trafficking, Shaw Powell

Theses and Dissertations--Medical Sciences

Vascular endothelial growth factor (VEGF) is a signaling protein involved in inducing and regulating endothelial cell proliferation and function (Duffy et al 2000). VEGF is also involved in cancer progression, as it induces vascular permeability and promotes angiogenesis to tumor laden areas, giving cancer cells critical oxygen and nutrients (Hoeppner et al.,2012. Studies indicate VEGF prevents lymphoblast apoptosis, which may contribute to leukemia formation and enable the proliferation of leukemic cells (Duffy et al 2000). Ongoing research seeks to further examine VEGF in leukemia, using a rag2:GFP-Myc expressing transgenic zebrafish as the animal model of T-cell Acute Lymphoblastic ...


Dahili Tıp Bilimleri Tanı Ve Tedavi, Hakan Kaya, Hüseyin Kafadar, Rabia Tutuncu Toker, Ali Topak, Kemal Dinç, Bahar Yılmaz Çankaya, Ferit Durankuş, Fatma Kurt Çolak, Attila Önmez, Mehmet Emin Parlak, Selma Eroğlu, Serçin Taşar Jan 2021

Dahili Tıp Bilimleri Tanı Ve Tedavi, Hakan Kaya, Hüseyin Kafadar, Rabia Tutuncu Toker, Ali Topak, Kemal Dinç, Bahar Yılmaz Çankaya, Ferit Durankuş, Fatma Kurt Çolak, Attila Önmez, Mehmet Emin Parlak, Selma Eroğlu, Serçin Taşar

Health Sciences

Bu kitapta konjenital ayna hareketi bozukluğu, artrografi öncesi intraartiküler enjeksiyonu, otizm spektrum bozuklukları, genetik danışma, hipoglisemi ve diyabetin akut komplikasyonları, çocuklarda akut otitis media, gerçek nörojenik torasik çıkış sendromu, çocukluk çağı tiroid hastalıkları ele alınmıştır.


Epigenetic States Regulate Tumor Aggressiveness And Response To Targeted Therapies In Lung Adenocarcinoma, Fan Chen Jan 2021

Epigenetic States Regulate Tumor Aggressiveness And Response To Targeted Therapies In Lung Adenocarcinoma, Fan Chen

Theses and Dissertations--Toxicology and Cancer Biology

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, 85% of which are lung adenocarcinomas (LUAD). Although molecular studies of NSCLC identified targetable mutations of some oncogenes including BRAF, EGFR and ALK, no targeted therapies exist for most cases. Cancer epigenetics is the study of epigenetic modifications, including histone modifications, that control gene expression in cancer. Recent advances have revealed numerous epigenetic abnormalities in human cancers, and targeting epigenetic regulators could be effective at reversing dysregulated epigenetic programs or driving sensitivity to other targeted therapies.

Inhibitors of the histone methyltransferase EZH2 have recently been approved as ...


Cornelia De Lange Syndrome Research From 1953 To 2020: A Bibliometric Analysis, Dr. Mirza Muhammad Naseer, Dr. Abu Waris Jan 2021

Cornelia De Lange Syndrome Research From 1953 To 2020: A Bibliometric Analysis, Dr. Mirza Muhammad Naseer, Dr. Abu Waris

Library Philosophy and Practice (e-journal)

The present study was conducted to explore various aspects of Cornelia de Lange Syndrome (CdLS) research publications including annual scientific productivity, top contributing authors and their impact, top contributing countries and organizations, most relevant sources of publication, highly cited documents, and most frequently used words. Bibliometric methods were used to investigate these aspects of CdLS research publications. Results of the study disclosed that the annual scientific productivity of CdLS literature is increasing gradually with the passage of time. A. Selicorni contributed the highest number of publications (45) to CdLS literature while I. D. Krantz had the highest impact in the ...


Goblet Cell Carcinoma Of The Appendix: A Case Report On Goblet Cell Carcinoid, Sheliza Kabani, Aubtin Saedi, Austin Lehr, Lina O'Brien Dec 2020

Goblet Cell Carcinoma Of The Appendix: A Case Report On Goblet Cell Carcinoid, Sheliza Kabani, Aubtin Saedi, Austin Lehr, Lina O'Brien

HCA Healthcare Journal of Medicine

Goblet cell carcinoid of the appendix is a rare neoplasm with histological features of both neuroendocrine and adenocarcinomas. The combination of its aggressive behavior, infrequent occurrence, and variable clinical presentation convolutes the management of this tumor. We report the case of a 75-year-old female presenting with acute appendicitis. A laparoscopic appendectomy was performed. The pathology report showed goblet cell carcinoid at the base of the appendix with involvement of the proximal surgical margins. At her postoperative visit, the patient’s pathology report and options for management were reviewed, and the patient agreed to proceed with a right hemicolectomy 8-10 weeks ...


A Case Of Simpson-Golabi-Behmel Syndrome Presenting With Cutaneous Findings, Tessa Mullins, Abigail Russell, Chad Johnston Dec 2020

A Case Of Simpson-Golabi-Behmel Syndrome Presenting With Cutaneous Findings, Tessa Mullins, Abigail Russell, Chad Johnston

HCA Healthcare Journal of Medicine

Simpson-Golabi-Behmel syndrome is a rare, X-linked recessive syndrome associated with mutations in the genes encoding glypican 3 (GPC3). The majority of cases have been described in pediatric males, with those affected showing manifestations of overgrowth, congenital heart defects, and increased incidence of neoplasia. Due to the X-linked nature of this disorder, penetrance is not well understood in female cases. Very few cases of female presentations of Simpson-Golabi-Behmel syndrome have been described, and this case highlights that there may be an association between mutated GPC3 carrier status and other cancers. We present a case of GPC3 gene mutation suggestive of Simpson-Golabi-Behmel ...


Tumor Necrosis Factor Alpha Snp Variant In Promoter Region G308a, Cause Preeclampsia During Pregnancy In Pakistani Women, A Case Control Study, Azizah Ziauddin, Sadia Ahmad, Asad Iqbal, Abdul Majid Khan, Shahid Mahmood Baig Dec 2020

Tumor Necrosis Factor Alpha Snp Variant In Promoter Region G308a, Cause Preeclampsia During Pregnancy In Pakistani Women, A Case Control Study, Azizah Ziauddin, Sadia Ahmad, Asad Iqbal, Abdul Majid Khan, Shahid Mahmood Baig

Journal of Bioresource Management

Preeclampsia (PE) is a very common critical condition during pregnancy. As PE is a high-risk condition during pregnancy, occurring in 25% of all pregnancies, worldwide. In women with PE there is an increase in hypertension and albuminuria. Elevated blood pressure can be life-threatening after 20th week of pregnancy. Single nucleotide variation in gene sequence can be disease causing, among these pathogenic SNPs, a variant in TNF-α, G308A is analyzed in many studies as a causative variant to cause preeclampsia. In this case control study fifty patients and fifty healthy individuals were enrolled for analysis of TNF-α promoter region SNP ...