Dr. Andres Hernandez-Garcia, MD,PhD - BAYLOR COLLEGE OF MEDICINE - SCIENTIST STAFF & LAB. MANAGER & RESEARCH CLINICAL COORDINATOR

Dr. Andres Hernandez-Garcia

MD,PhD

BAYLOR COLLEGE OF MEDICINE

SCIENTIST STAFF & LAB. MANAGER & RESEARCH CLINICAL COORDINATOR

HOUSTON , TEXAS | United States

Main Specialties: Biochemical Genetics, Medical Genetics, Molecular Genetic Pathology

Additional Specialties: MEDICAL GENETICS AND MOLECULAR BIOLOGY

ORCID logohttps://orcid.org/0000-0002-5343-5513


Top Author

Dr. Andres Hernandez-Garcia, MD,PhD - BAYLOR COLLEGE OF MEDICINE - SCIENTIST STAFF & LAB. MANAGER & RESEARCH CLINICAL COORDINATOR

Dr. Andres Hernandez-Garcia

MD,PhD

Introduction

Dr Hernández-García is an exceptionally well qualified geneticist, who received his PhD, from Universidad Autónoma de Nuevo Leon. In 2003, Dr. Hernández-Garcia was the founder of the Biomedical Research Center at Universidad Autónoma de Coahuila, México. Along with his position as a full time Professor Category “C” at Faculty of Medicine, Universidad Autónoma de Coahuila, he became the Dean of the College of Medicine, Biomedical Research Center, General University Hospital and Pediatrics University Hospital of the Universidad Autónoma de Coahuila during the period of March, 1992 to March, 1996. He was also the Founder, Chairman and Consultant of Genetics Department at Faculty of Medicine and University Hospitals of Torreón, Coah. México.
He was a Council Member of the Mexican Association of Faculties and Schools of Medicine and Council Member of the National Certification Program of Faculties and Schools of Medicine of México. Furthermore, he was a contributor in the elaboration of The General Design of Mexican Medical Education Quality Program and active participant in the “Creation of Quality Standards in Mexican Medical Education used in The National Certification System for Mexican Medical Schools”.
With such an extraordinary training and education background Dr. Hernandez- Garcia returned to work in his hometown and former medical school to improve and elevate the standards of medical education and to contribute immensely to medical research of the local community in the city of Torreón, state of Coahuila, Mexico. Some of his recognitions include:
1. - Best Abstract Award at the 4th Annual CVRI Symposium. Baylor College of Medicine Cardiovascular Research Institute. February 4, 2016, 2. - Peer reviewer for Science magazine PLOS ONE (Since 2012), 3. - Molecular Surgeon Young Investigator Award. Michael E. DeBakey Department of Surgery. Baylor College of Medicine. December 19, 2008. Houston, TX. USA. 4. - Award National System for Researchers. Consejo Nacional de Ciencia y Tecnología, México. 2006/2008. 5. - Award in Health Sciences Research UANL-2002. Granted by Universidad Autónoma de Nuevo León. México. September 2003, 6. - Awards in Basic Sciences Research and Clinical Research (1987, 1988.). Universidad Autónoma de Nuevo León México. 7. - Miguel Ramos Arizpe Medal for Academic Worth. Universidad Autónoma de Coahuila. México. 8. - He was once declared Distinguish Citizen by his hometown. (1994).
Dr. Hernández-García earned his medical degree with honors from Universidad Autónoma de Coahuila, México. He served a rotating internship Residency in Biomedical Research at Unidad de Investigación Biomédica IMSS, Centro Médico Nacional. México, D.F. He earned the Specialty in Medical Genetics degree from Instituto Nacional de la Nutrición Salvador Zubirán and Universidad Nacional Autónoma de México. He also spent one year in Master in Education. Universidad Iberoamericana. Campus Laguna, México. Additionally, he earned his Ph.D. in Molecular Biology and Genetic Engineering from the Universidad Autónoma de Nuevo León México. The Promotions Committee recommended award his Ph.D. With the “Magno Cum Lauro” honor.
Dr. Hernandez-Garcia admirable spirit and tenacity to reach excellence is further underscored by the fact that despite his most abundantly clear educational and research accomplishments in Mexico he did not consider his career yet completed. Instead, he came to the United States and further his research by completing an a Postdoctoral Research Fellow in the Department of Pediatric-Hematology/ Oncology, Texas Children’s Hospital in November, 1998, then he continued with his research education further as a Post-doctoral research fellow in the Department of Radiology/Radiation Oncology, Veterans Affairs Medical Center until 31 May, 2001. Lastly, he served for 9 years as a Faculty member at the General Surgery Division of the Michael E. DeBakey Department of Surgery at Baylor College of Medicine (June 01, 2001- May 31, 2009).
During this time he had obtained invaluable experience in the field of gene therapy clinical trials, handling of naive immunodeficient mice, micro surgery, immunohistochemistry/histology, cell culture, animal models, and Molecular Biology Techniques.
Dr. Hernandez-Garcia has been working enthusiastically to delineate the Integration of Cell Signaling Pathways during Liver Regeneration and carcinogenesis. Additionally, his scientific work has made an outstanding contribution in the study of the immunological response against adenoviral vectors, his results in this specific field has been published in a specialized journal with high factor impact in the scientific field (Impact of preimmunization on adenoviral vector expression and toxicity in a subcutaneous mouse cancer model. Molecular Therapy. 2002 Sep; 6 (3): 342-8.)
Dr. Hernandez always had a considerable inclination for biomedical research and teaching and because of this he was always looking for opportunities to gain further knowledge and skills in those areas. His interest in translational research rapidly move up toward the field of suicide gene therapy as a form of drug delivery system that allows for negative selection of malignant cells using a prodrug approach. In this approach malignant cells are transfected with suicide genes, which are genes that mediate the conversion of an inactive drug (“prodrug”) into an agent that is toxic to the cell. The goal will be ensure the presence and expression of suicide genes in as many cancer cells as possible while limiting their presence or expression in normal cells.
After this awesome experience Dr. Hernández-García was able to acquire superior clinical skills and research tools to promptly assume a prominent role in the field of Human genetics.
In keeping with his already ascending career and focused direction to accomplish his professional goals in the medical sciences, Dr. Hernandez has engaged in the pursuit of important basic and translational research within the context of the Molecular and Human Genetics Department at Baylor College of Medicine (since 2009 to date). Currently, he has been actively dedicated to identifying and characterizing genes that cause common, life-threatening birth defects and determining the molecular mechanisms by which they impact human health.
He have been particularly successful in using a combination of cytogenetic data and mouse modeling to understand the molecular and biological pathways involved in the development of congenital diaphragmatic hernia (CDH). Since up to 40% of individuals with CDH also have cardiac defects, many of the genes under his research study—including NR2F2, GATA4, ZFPM2, TBX2 and SOX7—play a critical role in both CDH and cardiovascular development. As a result, his research efforts are becoming increasingly cardiac-focused.
Currently, he is working with Sox7 and Rere conditional knockout mice which will aid us in identifying the molecular mechanisms by which SOX7 and/or RERE deficiency causes abnormalities in embryonic cardiac development and postnatal cardiac function. Recurrent microdeletions of chromosome 8p23.1 that include SOX7 area are associated with a high risk of developing cardiovascular malformations. The results of Dr. Hernandez-Garcia research suggest that deletion of SOX7 may contribute to the development of cardiovascular malformations associated with recurrent 8p23.1 microdeletions.
Most importantly, Dr. Hernandez Garcia has strengthened his research initiative by developing strong collaborative relationships at Baylor College of Medicine and Texas Medical Center with established leaders in the field of Cardiovascular Development, and Human Genetics who have agreed to collaborate with him during the development of his research career development program.
Dr. Hernandez-Garcia has made valuable research contributions in the area of human genetics and gene therapy, he has vast experience in biomedical research and his scientific work has been published in multiple papers, book chapters and abstracts as detailed in his curriculum vitae.
Since his arrival to Baylor College of medicine and the Michael E. DeBakey Veterans Affairs medical Center, Dr. Hernandez has demonstrated that he has an avid interest for translational basic science research. Therefore, The Molecular and Human Genetics Department of Baylor College of Medicine have made a strong commitment to provide Dr. Hernandez with every resource necessary to give him an optimal environment to conduct advanced basic science and translational research taking results from in-vivo animal work to patients at the bedside and confer his research activities a high clinical relevance, since advances in this area of research could potentially have an enormous impact on the health and well-being of human beings as well as on the cost of health care delivery in the United States.

Primary Affiliation: BAYLOR COLLEGE OF MEDICINE - HOUSTON , TEXAS , United States

Specialties:

Additional Specialties:

Research Interests:


View Dr. Andres Hernandez-Garcia’s Resume / CV

Education

Jan 2017
Baylor College of Medicine Department of Molecular and Human Genetics
Scientist, Staff
Department of Molecular and Human Genetics
Jan 2009 - Jan 2016
Baylor College of Medicine Department of Molecular and Human Genetics
Postdoctoral Associate
Department of Molecular and Human Genetics
Jun 2001
Veterans Affairs Medical Center and Baylor College of Medicine. June, 2001 to June, 2009.
Research Instructor
Michael E. DeBakey Department of Surgery
Jan 2000 - Jan 2001
Baylor College of Medicine Michael E DeBakey Department of Surgery
Postdoctoral Research Associate
Department of Radiology/Radiation Oncology,
Jan 1998 - Jan 2001
Universidad Autónoma de Nuevo León Facultad de Medicina
Ph D. in Molecular Biology and Genetic Engineering
Universidad Autónoma de Nuevo León Facultad de Medicina. Monterrey, Nuevo Leon. Mexico.
Jan 1998 - Jan 2000
Texas Children's Hospital/Baylor College of Medicine
Postdoctoral Fellow
Department of Pediatric-Hematology/ Oncology. Texas Children’s Hospital. Houston Tx.
Jan 1978 - Jan 1980
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran
Specialty in Medical Genetics
Universidad Nacional Autonoma de Mexico (UNAM)
Jan 1970 - Jan 1975
Universidad Autónoma de Coahuila Facultad de Medicina Unidad Torreón
Medical Doctor
Universidad Autónoma de Coahuila Facultad de Medicina Unidad Torreón. Saltillo, Coah. Mexico

Experience

Oct 2019
Reviewers' Choice Poster Special Recognition Award. Title: “SOX7 ablation in endocardium results in downregulation of WNT4 and BMP2 and abnormal endocardial cushion development”, abstract scored in the top 10% of posters abstracts. American Society of Human Genetics Conference Committee 2019 at Houston, Texas USA.
Reviewers' Choice Poster Special Recognition Award
American Society of Human Genetics Conference Committee 2019 at Houston, Texas USA.
Oct 2018
Down-regulation of Sox7 impairs epithelial-to-mesenchymal transition and endocardial cushion morphogenesis.
Platform Conference Featured Speaker
PLATFORM (oral) presentation at the 2018 American Society of Human Genetics Annual Meeting in San Diego, California from October 16-20, 2018.
Oct 2016
SOX7 deficiency impairs embryonic vasculogenesis and epithelial-to-mesenchymal transition during atrioventricular endocardial cushion development
ASHG 2016 Annual Conference Poster Special Recognition Award
Reviewers' Choice Abstract, by the American Society of Human Genetics Conference Committee 2016 at Vancouver, Canada..
Feb 2016
Best Abstract Award at the 4th Annual Cardiovascular Research Institute Symposium. Baylor College of Medicine.
Conference Featured Speaker
Best Abstract Award at the 4th Annual Cardiovascular Research Institute Symposium. Baylor College of Medicine. February 4, 2016. Houston, TX. USA.
Jun 2001 - May 2009
Baylor College of Medicine
RESEARCH INSTRUCTOR
SURGERY
Mar 1992 - Mar 1996
Universidad Autonoma de Coahuila - Unidad Torreón
Dean of College of Medicine
DIRECCION GENERAL
Mar 1992 - Mar 1996
Universidad Autónoma de Coahuila Facultad de Medicina Unidad Torreón
Dean of Pediatrics University Hospital
Hospital Infantil Universitario en Torreón

Publications

45Publications

975Reads

55Profile Views

119PubMed Central Citations

Further delineation of the phenotypic spectrum associated with hemizygous loss‐of‐function variants in NONO

American Journal Of MEDICAL gENETICS

Abstract

The non-POU domain containing, octamer-binding gene, NONO, is located on chromosome Xq13.1 and encodes a member of a small family of RNA and DNA binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Hemizygous loss-of-function variants in NONO have been shown to cause mental retardation, X-linked, syndromic 34 in males. Features of this disorder can include a range of neurodevelopmental phenotypes, left ventricular noncompaction (LVNC), congenital heart defects, and CNS anomalies. To date only eight cases have been described in the literature. Here we report two unrelated patients and a miscarried fetus with loss-of-function variants in NONO. Their phenotypes, and a review of previously reported cases, demonstrate that hemizygous loss-of-function variants in NONO cause a recognizable genetic syndrome. The cardinal features of this condition include developmental delay, intellectual disability, hypotonia, macrocephaly, structural abnormalities affecting the corpus callosum and/or cerebellum, LVNC, congenital heart defects, and gastrointestinal/feeding issues. This syndrome also carries an increased risk for strabismus and cryptorchidism and is associated with dysmorphic features that include an elongated face, up/down-slanted palpebral fissures, frontal bossing, and malar hypoplasia.

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December 2019
4 Reads

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Authors:
Benjamin Cogné Sophie Ehresmann Eliane Beauregard-Lacroix Justine Rousseau Thomas Besnard Thomas Garcia Slavé Petrovski Shiri Avni Kirsty McWalter Patrick R Blackburn Stephan J Sanders Kévin Uguen Jacqueline Harris Julie S Cohen Moira Blyth Anna Lehman Jonathan Berg Mindy H Li Usha Kini Shelagh Joss Charlotte von der Lippe Christopher T Gordon Jennifer B Humberson Laurie Robak Daryl A Scott Vernon R Sutton Cara M Skraban Jennifer J Johnston Annapurna Poduri Magnus Nordenskjöld Vandana Shashi Erica H Gerkes Ernie M H F Bongers Christian Gilissen Yuri A Zarate Malin Kvarnung Kevin P Lally Peggy A Kulch Brina Daniels Andres Hernandez-Garcia Nicholas Stong Julie McGaughran Kyle Retterer Kristian Tveten Jennifer Sullivan Madeleine R Geisheker Asbjorg Stray-Pedersen Jennifer M Tarpinian Eric W Klee Julie C Sapp Jacob Zyskind Øystein L Holla Emma Bedoukian Francesca Filippini Anne Guimier Arnaud Picard Øyvind L Busk Jaya Punetha Rolph Pfundt Anna Lindstrand Ann Nordgren Fayth Kalb Megha Desai Ashley Harmon Ebanks Shalini N Jhangiani Tammie Dewan Zeynep H Coban Akdemir Aida Telegrafi Elaine H Zackai Amber Begtrup Xiaofei Song Annick Toutain Ingrid M Wentzensen Sylvie Odent Dominique Bonneau Xénia Latypova Wallid Deb Sylvia Redon Frédéric Bilan Marine Legendre Caitlin Troyer Kerri Whitlock Oana Caluseriu Marine I Murphree Pavel N Pichurin Katherine Agre Ralitza Gavrilova Tuula Rinne Meredith Park Catherine Shain Erin L Heinzen Rui Xiao Jeanne Amiel Stanislas Lyonnet Bertrand Isidor Leslie G Biesecker Dan Lowenstein Jennifer E Posey Anne-Sophie Denommé-Pichon Claude Férec Xiang-Jiao Yang Jill A Rosenfeld Brigitte Gilbert-Dussardier Séverine Audebert-Bellanger Richard Redon Holly A F Stessman Christoffer Nellaker Yaping Yang James R Lupski David B Goldstein Evan E Eichler Francois Bolduc Stéphane Bézieau Sébastien Küry Philippe M Campeau

Am J Hum Genet 2019 03 28;104(3):530-541. Epub 2019 Feb 28.

Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407527PMC
March 2019
36 Reads
10.931 Impact Factor

Prioritization of Candidate Genes for Congenital Diaphragmatic Hernia in a Critical Region on Chromosome 4p16 using a Machine-Learning Algorithm.

J Pediatr Genet 2018 Dec 30;7(4):164-173. Epub 2018 May 30.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.

Wolf-Hirschhorn syndrome (WHS) is caused by partial deletion of the short arm of chromosome 4 and is characterized by dysmorphic facies, congenital heart defects, intellectual/developmental disability, and increased risk for congenital diaphragmatic hernia (CDH). In this report, we describe a stillborn girl with WHS and a large CDH. A literature review revealed 15 cases of WHS with CDH, which overlap a 2.3-Mb CDH critical region. We applied a machine-learning algorithm that integrates large-scale genomic knowledge to genes within the 4p16.3 CDH critical region and identified , , , , , , , and as genes whose haploinsufficiency may contribute to the development of CDH.

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http://dx.doi.org/10.1055/s-0038-1655755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234038PMC
December 2018
123 Reads

RERE deficiency leads to decreased expression of GATA4 and the development of ventricular septal defects.

Disease models & mechanisms

Deletions of chromosome 1p36 are associated with a high incidence of congenital heart defects (CHDs). The arginine-glutamic acid dipeptide repeats gene (RERE) is located in a critical region for CHD on chromosome 1p36 and encodes a cardiac-expressed nuclear receptor co-regulator. Mutations affecting RERE cause atrial and ventricular septal defects (VSDs) in humans, and RERE-deficient mice also develop VSDs. During cardiac development, mesenchymal cells destined to form part of the atrioventricular (AV) septum are generated when endocardial cells in the AV canal undergo epithelial-to-mesenchymal transition (EMT) and migrate into the space between the endocardium and the myocardium. These newly generated mesenchymal cells then proliferate to fill the developing AV endocardial cushions. Here, we demonstrate that RERE-deficient mouse embryos have reduced numbers of mesenchymal cells in their AV endocardial cushions owing to decreased levels of EMT and mesenchymal cell proliferation. In the endocardium, RERE colocalizes with GATA4, a transcription factor required for normal levels of EMT and mesenchymal cell proliferation. Using a combination of in vivo and in vitro studies, we show that Rere and Gata4 interact genetically in the development of CHDs, RERE positively regulates transcription from the Gata4 promoter and GATA4 levels are reduced in the AV canals of RERE-deficient embryos. Tissue-specific ablation of Rere in the endocardium leads to hypocellularity of the AV endocardial cushions, defective EMT and VSDs, but does not result in decreased GATA4 expression. We conclude that RERE functions in the AV canal to positively regulate the expression of GATA4, and that deficiency of RERE leads to the development of VSDs through its effects on EMT and mesenchymal cell proliferation. However, the cell-autonomous role of RERE in promoting EMT in the endocardium must be mediated by its effects on the expression of proteins other than GATA4.This article has an associated First Person interview with the first author of the paper.

http://europepmc.org/articles/PMC6176990

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August 2018
4 Reads

RERE deficiency leads to decreased expression of GATA4 and the development of ventricular septal defects.

Dis Model Mech 2018 08 28;11(9). Epub 2018 Aug 28.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA

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http://dx.doi.org/10.1242/dmm.031534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176990PMC
August 2018
34 Reads
4.973 Impact Factor

The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.

Human molecular genetics

Congenital diaphragmatic hernia (CDH) has been reported twice in individuals with a clinical diagnosis of Fraser syndrome, a genetic disorder that can be caused by recessive mutations affecting FREM2 and FRAS1. In the extracellular matrix, FREM2 and FRAS1 form a self-stabilizing complex with FREM1, a protein whose deficiency causes sac CDH in humans and mice. By sequencing FREM2 and FRAS1 in a CDH cohort, and searching online databases, we identified five individuals who carried recessive or double heterozygous, putatively deleterious variants in these genes which may represent susceptibility alleles. Three of these alleles were significantly enriched in our CDH cohort compared with ethnically matched controls. We subsequently demonstrated that 8% of Frem2ne/ne and 1% of Fras1Q1263*/Q1263* mice develop the same type of anterior sac CDH seen in FREM1-deficient mice. We went on to show that development of sac hernias in FREM1-deficient mice is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. Based on these data, we conclude that deficiency of FREM2, and possibly FRAS1, are associated with an increased risk of developing CDH and that loss of the FREM1/FREM2/FRAS1 complex, or its function, leads to anterior sac CDH development through its effects on mesothelial fold progression.

http://europepmc.org/articles/PMC5985720

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June 2018
6 Reads

Prioritization of Candidate Genes for Congenital Diaphragmatic Hernia in a Critical Region on Chromosome 4p16 using a Machine-Learning Algorithm.

Journal of pediatric genetics

Wolf-Hirschhorn syndrome (WHS) is caused by partial deletion of the short arm of chromosome 4 and is characterized by dysmorphic facies, congenital heart defects, intellectual/developmental disability, and increased risk for congenital diaphragmatic hernia (CDH). In this report, we describe a stillborn girl with WHS and a large CDH. A literature review revealed 15 cases of WHS with CDH, which overlap a 2.3-Mb CDH critical region. We applied a machine-learning algorithm that integrates large-scale genomic knowledge to genes within the 4p16.3 CDH critical region and identified FGFRL1 , CTBP1 , NSD2 , FGFR3 , CPLX1 , MAEA , CTBP1-AS2 , and ZNF141 as genes whose haploinsufficiency may contribute to the development of CDH.

https://doi.org/10.1055/s-0038-1655755

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May 2018
2 Reads

Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO.

Journal of medical genetics

The non-POU domain containing octamer-binding gene (NONO) is located on chromosome Xq13.1 and encodes a member of a small family of RNA-binding and DNA-binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Loss-of-function variants in NONO have been described as a cause of intellectual disability in males but have not been described in association with congenital heart defects or cardiomyopathy. In this article, we seek to further define the phenotypic consequences of NONO depletion in human subjects.We searched a clinical database of over 6000 individuals referred for exome sequencing and over 60 000 individuals referred for CNV analysis.We identified two males with atrial and ventricular septal defects, left ventricular non-compaction (LVNC), developmental delay and intellectual disability, who harboured de novo, loss-of-function variants in NONO. We also identified a male infant with developmental delay, congenital brain anomalies and severe LVNC requiring cardiac transplantation, who inherited a single-gene deletion of NONO from his asymptomatic mother.We conclude that in addition to global developmental delay and intellectual disability, males with loss-of-function variants in NONO may also be predisposed to developing congenital heart defects and LVNC with the penetrance of these cardiac-related problems being influenced by genetic, epigenetic, environmental or stochastic factors. Brain imaging of males with NONO deficiency may reveal structural defects with abnormalities of the corpus callosum being the most common. Although dysmorphic features vary between affected individuals, relative macrocephaly is a common feature.

https://doi.org/10.1136/jmedgenet-2016-104039

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August 2016
7 Reads

De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions

The American Journal of Human Genetics Available online 14 April 2016

The American Journal of Human Genetics

Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are associated with developmental delay, intellectual disability, and defects involving the brain, eye, ear, heart, and kidney. Arginine-glutamic acid dipeptide repeats (RERE) is located in the proximal 1p36 critical region. RERE is a widely-expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects and medical problems seen in individuals with 1p36 deletion syndrome, although human evidence supporting this role has been lacking. In this report, we describe ten individuals with intellectual disability, developmental delay, and/or autism spectrum disorder who carry rare and putatively damaging changes in RERE. In all cases in which both parental DNA samples were available, these changes were found to be de novo. Associated features that were recurrently seen in these individuals included hypotonia, seizures, behavioral problems, structural CNS anomalies, ophthalmologic anomalies, congenital heart defects, and genitourinary abnormalities. The spectrum of defects documented in these individuals is similar to that of a cohort of 31 individuals with isolated 1p36 deletions that include RERE and are recapitulated in RERE-deficient zebrafish and mice. Taken together, our findings suggest that mutations in RERE cause a genetic syndrome and that haploinsufficiency of RERE might be sufficient to cause many of the phenotypes associated with proximal 1p36 deletions.

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April 2016
22 Reads

FBN1 contributing to familial congenital diaphragmatic hernia.

American journal of medical genetics. Part A

Congenital diaphragmatic hernia (CDH) is a relatively common, life--threatening birth defect. We present a family with recurrent CDH--paraesophageal and central--for whom exome sequencing (ES) revealed a frameshift mutation (c.4969_4970insA, p.Ile1657Asnfs*30) in the fibrillin 1 gene (FBN1) that causes Marfan syndrome. A diagnosis of Marfan syndrome had not been considered previously in this family. However, a review of the literature demonstrated that FBN1 mutations have an unusual pattern of CDH in which paraesophageal hernias are particularly common. Subsequent clinical evaluations revealed evidence for ectopia lentis in affected family members supporting a clinical diagnosis of Marfan syndrome. Since only two other cases of familial CDH have been described in association with FBN1 mutations, we investigated an oligogenic hypothesis by examining ES data for deleterious sequence changes in other CDH-related genes. This search revealed putatively deleterious sequence changes in four other genes that have been shown to cause diaphragm defects in humans and/or mice--FREM1, DES, PAX3 and MET. It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. However, their individual contribution is likely to be small compared to that of the frameshift mutation in FBN1. We conclude that ES can be used to identify both major and minor genetic factors that may contribute to CDH. These results also suggest that ES should be considered in the diagnostic evaluation of individuals and families with CDH, particularly when other diagnostic modalities have failed to reveal a molecular etiology.

http://europepmc.org/articles/PMC4522925

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March 2015
5 Reads

Identification of critical regions and candidate genes for cardiovascular malformations and cardiomyopathy associated with deletions of chromosome 1p36.

PLoS One 2014 15;9(1):e85600. Epub 2014 Jan 15.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America ; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085600PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893250PMC
December 2014
52 Reads
9 Citations
3.234 Impact Factor

P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy.

Am J Physiol Gastrointest Liver Physiol 2014 Dec 9;307(11):G1073-87. Epub 2014 Oct 9.

Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Liver Center, Houston, Texas; Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas;

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http://ajpgi.physiology.org/content/ajpgi/307/11/G1073.full.
Web Search
http://ajpgi.physiology.org/content/ajpgi/early/2014/10/06/a
Web Search
http://ajpgi.physiology.org/cgi/doi/10.1152/ajpgi.00092.2014
Publisher Site
http://dx.doi.org/10.1152/ajpgi.00092.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254960PMC
December 2014
77 Reads
7 Citations
3.800 Impact Factor

P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy.

American journal of physiology. Gastrointestinal and liver physiology

Extracellular nucleotides via activation of P2 purinergic receptors influence hepatocyte proliferation and liver regeneration in response to 70% partial hepatectomy (PH). Adult hepatocytes express multiple P2Y (G protein-coupled) and P2X (ligand-gated ion channels) purinergic receptor subtypes. However, the identity of key receptor subtype(s) important for efficient hepatocyte proliferation in regenerating livers remains unknown. To evaluate the impact of P2Y2 purinergic receptor-mediated signaling on hepatocyte proliferation in regenerating livers, wild-type (WT) and P2Y2 purinergic receptor knockout (P2Y2-/-) mice were subjected to 70% PH. Liver tissues were analyzed for activation of early events critical for hepatocyte priming and subsequent cell cycle progression. Our findings suggest that early activation of p42/44 ERK MAPK (5 min), early growth response-1 (Egr-1) and activator protein-1 (AP-1) DNA-binding activity (30 min), and subsequent hepatocyte proliferation (24-72 h) in response to 70% PH were impaired in P2Y2-/- mice. Interestingly, early induction of cytokines (TNF-α, IL-6) and cytokine-mediated signaling (NF-κB, STAT-3) were intact in P2Y2-/- remnant livers, uncovering the importance of cytokine-independent and nucleotide-dependent early priming events critical for subsequent hepatocyte proliferation in regenerating livers. Hepatocytes isolated from the WT and P2Y2-/- mice were treated with ATP or ATPγS for 5-120 min and 12-24 h. Extracellular ATP alone, via activation of P2Y2 purinergic receptors, was sufficient to induce ERK phosphorylation, Egr-1 protein expression, and key cyclins and cell cycle progression of hepatocytes in vitro. Collectively, these findings highlight the functional significance of P2Y2 purinergic receptor activation for efficient hepatocyte priming and proliferation in response to PH.

http://europepmc.org/articles/PMC4254960

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October 2014
22 Reads

Identification of critical regions and candidate genes for cardiovascular malformations and cardiomyopathy associated with deletions of chromosome 1p36.

PloS one

Cardiovascular malformations and cardiomyopathy are among the most common phenotypes caused by deletions of chromosome 1p36 which affect approximately 1 in 5000 newborns. Although these cardiac-related abnormalities are a significant source of morbidity and mortality associated with 1p36 deletions, most of the individual genes that contribute to these conditions have yet to be identified. In this paper, we use a combination of clinical and molecular cytogenetic data to define five critical regions for cardiovascular malformations and two critical regions for cardiomyopathy on chromosome 1p36. Positional candidate genes which may contribute to the development of cardiovascular malformations associated with 1p36 deletions include DVL1, SKI, RERE, PDPN, SPEN, CLCNKA, ECE1, HSPG2, LUZP1, and WASF2. Similarly, haploinsufficiency of PRDM16-a gene which was recently shown to be sufficient to cause the left ventricular noncompaction-SKI, PRKCZ, RERE, UBE4B and MASP2 may contribute to the development of cardiomyopathy. When treating individuals with 1p36 deletions, or providing prognostic information to their families, physicians should take into account that 1p36 deletions which overlie these cardiac critical regions may portend to cardiovascular complications. Since several of these cardiac critical regions contain more than one positional candidate gene-and large terminal and interstitial 1p36 deletions often overlap more than one cardiac critical region-it is likely that haploinsufficiency of two or more genes contributes to the cardiac phenotypes associated with many 1p36 deletions.

http://europepmc.org/articles/PMC3893250

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January 2014
5 Reads

Novel frem1-related mouse phenotypes and evidence of genetic interactions with gata4 and slit3.

PLoS One 2013 11;8(3):e58830. Epub 2013 Mar 11.

Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058830PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594180PMC
December 2013
36 Reads
4 Citations
3.234 Impact Factor

Novel frem1-related mouse phenotypes and evidence of genetic interactions with gata4 and slit3.

PloS one

The FRAS1-related extracellular matrix 1 (FREM1) gene encodes an extracellular matrix protein that plays a critical role in the development of multiple organ systems. In humans, recessive mutations in FREM1 cause eye defects, congenital diaphragmatic hernia, renal anomalies and anorectal malformations including anteriorly placed anus. A similar constellation of findings-microphthalmia, cryptophthalmos, congenital diaphragmatic hernia, renal agenesis and rectal prolapse-have been described in FREM1-deficient mice. In this paper, we identify a homozygous Frem1 missense mutation (c.1687A>T, p.Ile563Phe) in an N-ethyl-N-nitrosourea (ENU)-derived mouse strain, crf11, with microphthalmia, cryptophthalmos, renal agenesis and rectal prolapse. This mutation affects a highly conserved residue in FREM1's third CSPG domain. The p.Ile563Phe change is predicted to be deleterious and to cause decreased FREM1 protein stability. The crf11 allele also fails to complement the previously described eyes2 allele of Frem1 (p.Lys826*) providing further evidence that the crf11 phenotype is due to changes affecting Frem1 function. We then use mice bearing the crf11 and eyes2 alleles to identify lung lobulation defects and decreased anogenital distance in males as novel phenotypes associated with FREM1 deficiency in mice. Due to phenotypic overlaps between FREM1-deficient mice and mice that are deficient for the retinoic acid-responsive transcription factor GATA4 and the extracellular matrix protein SLIT3, we also perform experiments to look for in vivo genetic interactions between the genes that encode these proteins. These experiments reveal that Frem1 interacts genetically with Gata4 in the development of lung lobulation defects and with Slit3 in the development of renal agenesis. These results demonstrate that FREM1-deficient mice faithfully recapitulate many of the phenotypes seen in individuals with FREM1 deficiency and that variations in GATA4 and SLIT3 expression modulate some FREM1-related phenotypes in mice.

http://europepmc.org/articles/PMC3594180

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March 2013
6 Reads

An allelic series of mice reveals a role for RERE in the development of multiple organs affected in chromosome 1p36 deletions.

PloS one

Individuals with terminal and interstitial deletions of chromosome 1p36 have a spectrum of defects that includes eye anomalies, postnatal growth deficiency, structural brain anomalies, seizures, cognitive impairment, delayed motor development, behavior problems, hearing loss, cardiovascular malformations, cardiomyopathy, and renal anomalies. The proximal 1p36 genes that contribute to these defects have not been clearly delineated. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in this region and encodes a nuclear receptor coregulator that plays a critical role in embryonic development as a positive regulator of retinoic acid signaling. Rere-null mice die of cardiac failure between E9.5 and E11.5. This limits their usefulness in studying the role of RERE in the latter stages of development and into adulthood. To overcome this limitation, we created an allelic series of RERE-deficient mice using an Rere-null allele, om, and a novel hypomorphic Rere allele, eyes3 (c.578T>C, p.Val193Ala), which we identified in an N-ethyl-N-nitrosourea (ENU)-based screen for autosomal recessive phenotypes. Analyses of these mice revealed microphthalmia, postnatal growth deficiency, brain hypoplasia, decreased numbers of neuronal nuclear antigen (NeuN)-positive hippocampal neurons, hearing loss, cardiovascular malformations-aortic arch anomalies, double outlet right ventricle, and transposition of the great arteries, and perimembranous ventricular septal defects-spontaneous development of cardiac fibrosis and renal agenesis. These findings suggest that RERE plays a critical role in the development and function of multiple organs including the eye, brain, inner ear, heart and kidney. It follows that haploinsufficiency of RERE may contribute-alone or in conjunction with other genetic, environmental, or stochastic factors-to the development of many of the phenotypes seen in individuals with terminal and interstitial deletions that include the proximal region of chromosome 1p36.

http://europepmc.org/articles/PMC3581587

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February 2013
6 Reads

PIAS1 is a GATA4 SUMO ligase that regulates GATA4-dependent intestinal promoters independent of SUMO ligase activity and GATA4 sumoylation.

PLoS One 2012 23;7(4):e35717. Epub 2012 Apr 23.

Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Michael E DeBakey VA Medical Center, Houston, Texas, United States of America.

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035717PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334497PMC
September 2012
19 Reads
5 Citations
3.234 Impact Factor

Correction: PIAS1 Is a GATA4 SUMO Ligase That Regulates GATA4-Dependent Intestinal Promoters Independent of SUMO Ligase Activity and GATA4 Sumoylation

PLoS One. 2012;7(4):e35717. doi: 10.1371/journal.pone.0035717. Epub 2012 Apr 23.

PLoS ONE DOI: 10.1371/annotation/e56fbda3-1898-4a36-bf93-d33d5a8b2d2e

GATA4 confers cell type-specific gene expression on genes expressed in cardiovascular, gastro-intestinal, endocrine and neuronal tissues by interacting with various ubiquitous and cell-type-restricted transcriptional regulators. By using yeast two-hybrid screening approach, we have identified PIAS1 as an intestine-expressed GATA4 interacting protein. The physical interaction between GATA4 and PIAS1 was confirmed in mammalian cells by coimmunoprecipitation and two-hybrid analysis. The interacting domains were mapped to the second zinc finger and the adjacent C-terminal basic region of GATA4 and the RING finger and the adjoining C-terminal 60 amino acids of PIAS1. PIAS1 and GATA4 synergistically activated IFABP and SI promoters but not LPH promoters suggesting that PIAS1 differentially activates GATA4 targeted promoters. In primary murine enterocytes PIAS1 was recruited to the GATA4-regulated IFABP promoter. PIAS1 promoted SUMO-1 modification of GATA4 on lysine 366. However, sumoylation was not required for the nuclear localization and stability of GATA4. Further, neither GATA4 sumoylation nor the SUMO ligase activity of PIAS1 was required for coactivation of IFABP promoter by GATA4 and PIAS1. Together, our results demonstrate that PIAS1 is a SUMO ligase for GATA4 that differentially regulates GATA4 transcriptional activity independent of SUMO ligase activity and GATA4 sumoylation. DOI: 10.1371/journal.pone.0035717

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September 2012
25 Reads

Contribution of LPP copy number and sequence changes to esophageal atresia, tracheoesophageal fistula, and VACTERL association.

Am J Med Genet A 2012 Jul 25;158A(7):1785-7. Epub 2012 May 25.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

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http://dx.doi.org/10.1002/ajmg.a.35391DOI Listing
July 2012
56 Reads
6 Citations
2.160 Impact Factor

Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1.

Human molecular genetics

Recurrent microdeletions of 8p23.1 that include GATA4 and SOX7 confer a high risk of both congenital diaphragmatic hernia (CDH) and cardiac defects. Although GATA4-deficient mice have both CDH and cardiac defects, no humans with cardiac defects attributed to GATA4 mutations have been reported to have CDH. We were also unable to identify deleterious GATA4 sequence changes in a CDH cohort. This suggested that haploinsufficiency of another 8p23.1 gene may contribute, along with GATA4, to the development of CDH. To determine if haploinsufficiency of SOX7-another transcription factor encoding gene-contributes to the development of CDH, we generated mice with a deletion of the second exon of Sox7. A portion of these Sox7(Δex2/+) mice developed retrosternal diaphragmatic hernias located in the anterior muscular portion of the diaphragm. Anterior CDH is also seen in Gata4(+/-) mice and has been described in association with 8p23.1 deletions in humans. Immunohistochemistry revealed that SOX7 is expressed in the vascular endothelial cells of the developing diaphragm and may be weakly expressed in some diaphragmatic muscle cells. Sox7(Δex2/Δex2) embryos die prior to diaphragm development with dilated pericardial sacs and failure of yolk sac remodeling suggestive of cardiovascular failure. Similar to our experience screening GATA4, no clearly deleterious SOX7 sequence changes were identified in our CDH cohort. We conclude that haploinsufficiency of Sox7 or Gata4 is sufficient to produce anterior CDH in mice and that haploinsufficiency of SOX7 and GATA4 may each contribute to the development of CDH in individuals with 8p23.1 deletions.

http://europepmc.org/articles/PMC3428158

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June 2012
7 Reads

ATP release after partial hepatectomy regulates liver regeneration in the rat.

Journal of hepatology

Paracrine interactions are critical to liver physiology, particularly during regeneration, although physiological involvement of extracellular ATP, a crucial intercellular messenger, remains unclear. The physiological release of ATP into extracellular milieu and its impact on regeneration after partial hepatectomy were investigated in this study.Hepatic ATP release after hepatectomy was examined in the rat and in human living donors for liver transplantation. Quinacrine was used for in vivo staining of ATP-enriched compartments in rat liver sections and isolated hepatocytes. Rats were treated with an antagonist for purinergic receptors (Phosphate-6-azo(benzene-2,4-disulfonic acid), PPADS), and liver regeneration after hepatectomy was analyzed.A robust and transient ATP release due to acute portal hyperpressure was observed immediately after hepatectomy in rats and humans. Clodronate liposomal pre-treatment partly inhibited ATP release in rats. Quinacrine-stained vesicles, co-labeled with a lysosomal marker in liver sections and isolated hepatocytes, were predominantly detected in periportal areas. These vesicles significantly disappeared after hepatectomy, in parallel with a decrease in liver ATP content. PPADS treatment inhibited hepatocyte cell cycle progression after hepatectomy, as revealed by a reduction in bromodeoxyuridine incorporation, phosphorylated histone 3 immunostaining, cyclin D1 and A expression and immediate early gene induction.Extracellular ATP is released immediately after hepatectomy from hepatocytes and Kupffer cells under mechanical stress and promotes liver regeneration in the rat. We suggest that in hepatocytes, ATP is released from a lysosomal compartment. Finally, observations made in living donors suggest that purinergic signalling could be critical for human liver regeneration.

http://europepmc.org/articles/PMC3625734

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October 2009
7 Reads

. Identification of a Novel Epidermal Growth Factor Receptor (EGFR) Binding Activity of Cyclin D1 Promoter During HepG2 Cell Proliferation and in Human Hepatocellular Carcinoma.

JOURNAL OF SURGICAL RESEARCH, Volume 151, Issue 2, February 2009, Pages 188-189. http://dx.doi.org/1

JOURNAL OF SURGICAL RESEARCH,

In hepatocellular carcinoma (HCC), overexpression of cyclin D1 (CD1) leads to unregulated growth. The specific transcription factors that activate the CD1 promoter have not been completely elucidated. Epidermal growth factor receptors (EGFRs) are expressed frequently in HCC and contribute to the aggressive growth of these tumors. Recent reports have shown that EGFRs may translocate to the nucleus and bind to AT-Rich motif sequences (ATRS), but this has not been previously reported in HCC. The purpose of this study was to investigate whether EGFRs translocate to the nucleus and interact with the CD1 promoter. Methods To explore if EGFR nuclear trafficking is regulated by EGF-induced phosphorylation, Western analysis was performed on cell extracts from HepG2, HepG3B, THLE-2 cells and samples obtained from patients with HCC using EGFR and pEGFR (Tyr1173) antibodies. Immunohistochemistry was also used to investigate EGFR nuclear protein expression in the transformed and cancer cell lines. To address the possibility of EGFR as a potential mediator of the observed increase in CD1 expression following EGF stimulation, the regulatory regions of the CD1 promoter were examined and we identified a 40-bp oligonucleotide sequence located at the 5' end of the CD1 promoter Region (CD1PR) encoding two consensus ATRS binding sites flanking an original TATA box-Inr element. To determine the EGFR binding activity of the CD1 promoter, electromobility shift assay (EMSA) was performed by incubating radiolabeled oligonucleotides representing the EGFR element of the CD1 promoter with the nuclear extracts obtained from the HepG2 cells that were grown to 70% confluence and from nuclear extracts obtained from patient HCC samples. The specificity of EGFR binding was confirmed by pre-incubating nuclear extracts with a 100-fold excess of specific (SP) and non-specific (NSP) cold competitors prior to the binding with labeled oligonucleotides. Chromatin immunoprecipitation assay (CHIP) was also performed to confirm binding of EGFR and pol II to the CD1PR in HepG2 cells and patient HCC samples. Results Western blot analysis from HCC specimens demonstrated increased EGFR protein levels in both cytoplasmic and nuclear fractions using wild type EGFR antibody. When pEGFR (Tyr1173) antibody was used, increased EGFR expression was demonstrated only in the nuclear fractions. Additionally, EGFR protein expression was significantly reduced in the cytoplasmic fraction obtained from HepG2 cells following EGF stimulation. Immunohistochemistry using the wild type EGFR antibody performed on THLE-2, Hep-3B and Hep-G2 cells demonstrated high protein expression in the cytoplasm in contrast to high levels in the nucleus when p-EGFR antibody was utilized. In HepG2 cells we demonstrate for the first time EGFR binding activity of the CD1 promoter. Correspondingly, there was increased EGFR binding activity of the CD1 promoter in samples obtained from patients with HCC. CHIP analysis also demonstrated specific DNA binding to the CD1PR for EGFR and pol II in HepG2 cells and HCC samples. Conclusion Our findings for the first time demonstrate that EGFR tyrosine-phosphorylation induces EGFR-nuclear localization and increased EGFR binding to a novel EGFR binding site in the CD1PR in HCC cells lines and HCC samples. Targeting EGFRs through inhibition of tyrosine-phosphorylation, EGFR nuclear trafficking, or its DNA binding activity may have potential therapeutic value in the treatment of HCC.

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February 2009
23 Reads

Extracellular ATP Regulates Liver Regeneration in the Rat.

Extracellular ATP Regulates Liver Regeneration in the Rat. Gonzalez EM, Julien B, Serriere-Lanneau V, Nicou A, Doignon I, Mbiakop M , Hernandez-Garcia A, Awad SS, Thevananther S, Tordimann T. HEPATOLOGY, Volume: 48 Issue:4, 482A-482A. Suppl. OCT. 2008.

Hepatology

https://rdcu.be/bOa5C

http://dx.doi.org/10.1002/hep.22641

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September 2008
7 Reads

Serum lead, cadmium, and zinc levels in newborns with neural tube defects from a polluted zone in Mexico.

Reprod Toxicol 2004 Dec;19(2):149-54

Centro de Investigación Biomédica de la Universidad Autónoma de Coahuila, Biomedical Research Center at the Autonomous University of Coahuila, Mexico.

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http://dx.doi.org/10.1016/j.reprotox.2004.07.003DOI Listing
December 2004
25 Reads
3 Citations
3.230 Impact Factor

Serum lead, cadmium, and zinc levels in newborns with neural tube defects from a polluted zone in Mexico.

Reproductive toxicology (Elmsford, N.Y.)

Serum lead, cadmium and zinc levels from 31 newborns with neural tube defects (NTD), and 54 healthy controls living in a polluted area in Mexico were estimated using atomic absorption spectrophotometry (AAS). NTD family history was found to be of greater importance in the case group (OR 6.95, 95% CI 1.51-36.3, p=0.002). In 25% of the children, serum lead concentrations were above the admissible maximum level (AML) of 10 microg/dL within 24 h of extra-uterine life. Cadmium concentrations were below the AML. Zinc deficiency was found in nine (29%) of the cases and four (9.3%) of the controls (p=0.04). The logistic regression multivariate analysis showed no correlation between NTD and high levels of any of these metals; however, a positive correlation was found to zinc deficiency (OR 5.0, 95% CI 1.07-23.00, p=0.04). These results focus attention to the surrounding nutritional and maternal health factors of major importance in disease etiology.

https://doi.org/10.1016/j.reprotox.2004.07.003

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December 2004
8 Reads

EFECTO DE LA PREINMUNIZACIÓN SOBRE LA EFICACIA TERAPÉUTICA Y TOXICIDAD DE LA TERAPIA GÉNICA ANTITUMORAL

CIENCIA UANL 10/2003; VOL. VI,(No. 4, OCTUBRE-DICIEMBRE 2003):497-507.

CIENCIA UANL

ABSTRACT: Los adenovirus recombinantes de origen humano se utilizan ampliamente en protocolos de terapia génica, tanto en modelos preclínicos como en estudios clínicos en fase I. Su explosiva utilización se debe, en parte, a que los vectores adenovirales de primera generación exhiben una notable y prolongada estabilidad biológica dentro del torrente circulatorio. Esta condición les permite funcionar como excelentes vehículos que transportan genes terapéuticos a varios órganos, diferentes tumores y a diversos tipos de células neoplásicas. A pesar de esta ventaja biológica, existen dos importantes factores que han limitado que se explote el potencial de los vectores adenovirales en protocolos de terapia génica. El primer problema es su carencia de especificidad hacia un solo tipo de células huésped. En efecto, los adenovirus pueden infectar un amplio rango de líneas celulares, lo cual hace difícil restringir el transporte de genes terapéuticos por vía endovenosa hacia un determinado grupo de células o hasta un órgano en particular.1,2 Una segunda desventaja, observada durante el uso de adenovirus en el tratamiento del cáncer, es el desarrollo de una respuesta inmunológica en contra de las partículas virales dentro del paciente.3,4,5 Durante un ciclo inicial de tratamiento, tales vectores pueden infectar un número apropiado de células y producir una alta expresión de la proteína deseada. Pero pronto las respuestas celular y humoral desarrolladas por el paciente interferirán con la expresión del gen terapéutico, y resultarán en la aparición de fenómenos de citotoxicidad.6,7,8,9 Desde otra perspectiva, la presencia de anticuerpos circulantes en contra de adenovirus pudiera ejercer un efecto protector en los tejidos normales y reducir el riesgo de complicaciones, transformándose así en un factor de bioseguridad, ya que permitiría administrar dosis masivas de adenovirus por vía intratumoral, sin la diseminación consecuente del vector, garantizando una elevada expresión y persistencia de los genes terapéuticos. Esta situación se torna especialmente importante después de la muerte de Jesse Gelsinger, afectado por una enfermedad metabólica conocida como deficiencia de Ornitin Transcarbamilasa (OTC). Jesse desarrolló un síndrome de distrés respiratorio del adulto (SDRA) complicado con falla orgánica múlti ple (FOM), mientras participaba en un protocolo de terapia génica diseñado por la Universidad de Pennsylvania. El protocolo fase I en cuestión consistió en inocular una sola dosis (6 X 1011 partículas/Kg) de un adv-vector (H5.001CBhOTC) que expresa el ADNc que codifica para la enzima OTC en la arteria hepática derecha del paciente. Después de este reporte los Institutos Nacionales de Salud (NIH) revisaron los efectos adversos de los adenovirus en macacos, encontrando que todos los simios inoculados con este tipo de vectores desarrollaron fenómenos de hepatotoxicidad y se reportaron severamente enfermos, este hecho, aunado con el conocimiento de que los 18 pacientes pertenecientes al protocolo OTC de la Universidad de Pennsylvania presentaron titulaciones elevadas de anticuerpos neutralizantes en contra del vector H5.001CBhOTC,10 obligó a la Federal Drug Administration de EUA a suspender todos los estudios de terapia génica que se llevaban a cabo en dicha Universidad. El informe final de este organismo destacó que: Jesse Gelsinger sufrió una activación difusa de su sistema inmune tras la inyección del vector, como consecuencia de ello desarrolló los síndromes de SDRA y FOM. En el presente trabajo, utilizamos un modelo murino preinmunizado a través de la inyección intratumoral (IT) de adenovirus, para investigar la posible participación del sistema inmune en la transferencia génica mediada por adv-vectores en el tratamiento de tumores sólidos. La preinmunización provocó un incremento en la titulación de anticuerpos antiadenovirus que ocasionó una disminución en los niveles de transferencia y expresión génica. Los aspectos de toxicidad sistémica fueron determinados por medio de estudios enzimáticos e histológicos. El establecimiento de una respuesta humoral contra adenovirus redujo significativamente la transducción sistémica con el vector. Sin embargo, dicha reducción no se tradujo en un efecto protector en los tejidos normales. Paradójicamente, la respuesta inmune montada en contra del vector resultó en un incremento de los parámetros de toxicidad hepática comparados con los observados en animales controles.

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October 2003
19 Reads

Impact of preimmunization on adenoviral vector expression and toxicity in a subcutaneous mouse cancer model.

Molecular therapy : the journal of the American Society of Gene Therapy

Immune responses against adenoviral vectors may influence the toxicity and therapeutic effectiveness of adenovirus-mediated gene transfer and may be a limiting factor in adenovirus-mediated gene therapy. The purpose of this study was to determine the effects of preimmunization on intratumoral adenoviral transduction and systemic spread. The hypothesis was that increased doses of adenoviral vectors could overcome local neutralization without added systemic toxicity. The level and duration of gene expression were assessed as a function of time and dose after intratumoral delivery of adenoviral vector (AdV) encoding the luciferase reporter gene (AdV-luc) in a subcutaneous mouse mammary tumor model. Preimmunization resulted in significantly decreased gene expression in tumor and normal tissues (P < 0.01). The decrease was significantly greater in liver than in tumor. Increased AdV doses could be used to overcome the intratumoral inhibition without a concomitant increase in liver transduction. However, preimmunized animals showed greater toxicity than nai;ve animals (P < 0.001). The preimmunized group developed histologic evidence of grade 2-3 hepatic toxicity and increases in the average values of hepatic enzymes. In addition, there was a significant increase in mortality (P < 0.01) in the preimmunized group (12 of 20 animals) compared with the naive group (3 of 20 animals). These findings suggest that although preimmunity can inhibit systemic expression from adenoviral vectors, at high vector doses it may potentiate hepatotoxicity.

https://doi.org/10.1006/mthe.2002.0669

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September 2002
6 Reads

[Genetic therapy of cancer].

Rev Invest Clin 2002 Jan-Feb;54(1):57-67

Laboratorio de Genética Molecular, Unidad de Laboratorios de Ingeniería y Expresión Genéticas, Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, N.L., México.

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June 2002
34 Reads

[Advances and perspectives in molecular medicine].

Gac Med Mex 2000 Sep-Oct;136(5):455-75

División de Biología Celular y Molecular, Instituto Mexicano del Seguro Social, México.

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November 2000
7 Reads
0.191 Impact Factor

[The Mexican experience of social service in medicine. Perspectives on an ongoing effort].

Educ Med Salud. 1994 Jul-Sep;28(3):341-54.

Educ Med Salud. 1994 Jul-Sep;28(3):341-54.

ABSTRACT: En México, el servicio social en medicina es una actividad que se lleva a cabo a través de la concertación entre diferentes sectores e instituciones. Consiste fundamentalmente en la atención médica que los egresados de las escuelas y facultades de medicina del país (médicos pasantes) proporcionan. Este servicio se dirige a la población que por sus características geográficas, económicas y sociales presenta limitaciones en cuanto al acceso a los servicios públicos, la educación, la vivienda y la alimentación, entre otros. La conceptualización del servicio social incluye en sí aspectos de tipo social, académico y legal que se realizan de acuerdo con un programa de actividades asistenciales estructurado y dirigido por la Secretaría de Salud, dentro del marco que proporciona el Programa Nacional de Salud. Esta atención se ofrece también en concordancia con un programa académico exprofeso para este fin, responsabilidad legal de las instituciones académicas de procedencia de los médicos pasantes. El aspecto legal del sevicio social lo constituye el requisito que deben cumplir los egresados de la carrera de medicina para obtener su título profesional y, de esa manera, obtener también el registro para su ejercicio ante la Dirección General de Profesiones de la Secretaría de Educación Pública. En México, el servicio social en medicina ha representado históricamente un medio de concertación que, encabezado por el Estado, articula las actividades de los sectores educativo y asistencial, dentro de su propio marco legal. Esta articulación es posible gracias al profundo carácter social de las instituciones educativas y asistenciales. La orientación social proviene de dos fuentes: la filosofía social emanada de la ideología de la Revolución Mexicana y los lineamientos generales del modelo de Estado de Bienestar, Welfare State, configurado en los Estados Unidos de América y proyectado a nivel internacional desde la década de 1930. Dentro de esta filosofía social se anudan los lazos que sostienen el servicio social médico en México.

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July 1994
21 Reads

Induction of sister-chromatid exchanges in Vicia faba by arsenic-contaminated drinking water.

Mutat Res. 1988 Jul;208(3-4):219-24.

Mutation Research

Abstract Arsenic-contaminated drinking water from various towns of Comarca Lagunera, Coahuila, Mexico, was tested for its ability to induce sister-chromatid exchanges (SCE) in Vicia faba. 3-h treatments were applied and the differential staining technique of Tempelaar et al. (1982) was used. Atomic absorption spectrophotometry showed that the arsenic concentration in drinking water was 0.11-0.695 ppm, well over the maximum limit of 0.05 ppm (EPA, 1984). In all cases the SCE frequencies were significantly different from the controls. Some concentrations (0.2, 0.3, 0.5 and 1.0 ppm) of sodium arsenate (V) and potassium arsenite (III) were also applied to Vicia faba and all produced significant SCE frequencies, except 0.2 ppm of sodium arsenate.

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July 1988
22 Reads

Gerodermia osteodysplastica hereditaria: report of three affected brothers and literature review.

Am J Med Genet. 1979;3(4):389-95.

American Journal of Medical Genetics.

Abstract Gerodermia osteodysplastica hereditaria was diagnosed in three Mexican brothers 6, 7, and 8 years old, respectively, who had the distinct facial appearance with sagging cheeks, premature wrinkling of the skin of face, abdomen, and dorsum of hands and feet; malocclusion, span greater than height; hyperextensibility; winging of the scapulae; stooped posture with kyphoscoliosis; protuberant abdomen; and pes planus. Radiologically they had generalized osteoplorosis, platyspondily due to multiple compression fractures, pseudoepiphyses of second metacarpals, and dislocated hips. Three other families with a total of 14 affected individuals have been reported. Inter- and intrafamilial variability can be recognized, particularly regarding the tendency to fractures, upper:lower segment ratio abnormalities, and results of skin biopsies, which have shown fragmentation of the elastic fibers in some cases (including the present family) and not in others. Although inheritance was considered to be X-linked recessive in the first reported family, an analysis of that pedigree together with those of the other reported families, including the present one, suggests that gerodermia osteodrysplastica is inherited in an autosomal recessive manner.

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March 1979
19 Reads

Peroxisomal proliferation induced by treatment with clofibrate in a patient with a peroxisomal disease.

Cell Biochemistry and Biophysics 02/2000; 32 Spring:329-32. DOI:10.1385/CBB:32:1-3:329 ·

Cell Biochemistry and Biophysics

ABSTRACT: The induction of peroxisomal proliferation in liver parenchymal cells of rats fed a diet containing clofibrate, a hypolipidemic drug, is a well-established event. However, the available data on human hepatocytes in vivo and in vitro indicate that agents that induce peroxisomal proliferation in rats and mice have no effect on human liver cells. The authors are reporting the case of a patient with clinical and laboratory diagnosis of X-linked-adrenoleukodystrophy. In an initial liver biopsy, a reduced volume fraction of peroxisomes was found (Vv. = .012) after a morphometric analysis, initiating treatment with clofibrate at a dose of 1.5 g/d. The administration of clofibrate was maintained for 7 yr. Liver biopsies were taken after 2, 4, and 7 yr, to follow the peroxisomal response. Results demonstrated a 500% increase in peroxisomal Vv. (.060) after 2 yr of treatment, compared with the pretreatment Vv. In subsequent biopsies, the peroxisomal Vv. value was maintained at 225 and 183% increases above the pretreatment biopsy (.027 and .022, respectively).

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24 Reads

Top co-authors

Daryl A Scott
Daryl A Scott

Baylor College of Medicine

12
Andrés Hernández-García
Andrés Hernández-García

BAYLOR COLLEGE OF MEDICINE

9
Valerie K Jordan
Valerie K Jordan

Baylor College of Medicine

5
Hitisha P Zaveri
Hitisha P Zaveri

Baylor College of Medicine

5
James R Lupski
James R Lupski

Baylor College of Medicine

5
Tyler F Beck
Tyler F Beck

Baylor College of Medicine

5
Bum Jun Kim
Bum Jun Kim

Kangnam Sacred-Heart Hospital

5
Brendan Lee
Brendan Lee

Baylor College of Medicine

4
Shalini N Jhangiani
Shalini N Jhangiani

Human Genome Sequencing Center

4
Kevin P Lally
Kevin P Lally

Center for Surgical Trials and Evidence-based Practice

4

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