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527P Small molecule adenylosuccinic acid supports muscle metabolism in Adss1 deficient muscle phenotypes

Neuromuscular Disorders 2024年 43卷 104441.703-104441.703页

作者： Rybalka, E. Kourakis, S. Yates, T. Bagaric, R. Qi, B. Ali, B. Khandari, N. Peterson, A. Yan, X. Kuang, J. Nijagal, B. Deveson-Lucas, D. Timpani, C. Victoria University Institute for Health and Sport Melbourne Australia Australian Institute for Musculoskeletal Science Inherited and Acquired Myopathies Program St Albans Australia The University of Melbourne Department of Medicine – Western Health Melbourne Medical School St Albans Australia Monash University Monash Genomics and Bioinformatics Platform Biomedical Discovery Institute Clayton Australia The University of Melbourne Metabolomics Australia Bio21 Institute Parkville Australia

Loss of purine nucleotide cycle function in skeletal muscle due to inherited gene mutation(s) or transcriptional remodelling of adenylosuccinate synthetase isoenzyme 1 (Adds1) expression, is associated with dysfunction, atrophy, and myopathy. This disease mechanism has been implicated in the pathogeneic progression of Duchenne muscular dystrophy, Huntington's disease, amyotrophic lateral sclerosis and the recently classified inborn error of metabolism, ADSS1 deficient myopathy. Using an exercise-exacerbated model of the dystrophin deficient mdx mouse with reduced Adss1 and adenylosuccinate lyase (Adsl) expression secondary to the primary gene defect effecting muscle dystrophin, we tested the hypothesis that treatment with oral small molecule adenylosuccinic acid (ASA), the biosynthetic product of Adss1 and substate of Adsl, could restore purine homeostasis by increasing substrate flux through available enzyme units. Mdx mice were treated with ASA (325mg/kg/day) or vehicle (0.5% methylcellulose) by oral gavage from 3 weeks age and exposed to bi-weekly forced treadmill running for 4 weeks to aggravate metabolic stress. At the experimental endpoint, mice were assessed for neuromuscular function (grip strength, hang time and rotarod). Fast twitch extensor digitorum brevis and slow-twitch soleus muscles were removed and subjected to fatiguing stimuli ex vivo. Immediately snap frozen quadriceps were used to study the impact of purine nucleotide cycle deficiency, and ASA's capacity to correct purine biochemistry, using multi-layered omics. The skeletal muscle metabolome and transcriptome were assessed using LS-HILIC polar metabolomic profiling and bulk RNA sequencing, respectively. In mice, ASA treatment had no effect on steady state functional parameters but improved performance of fast-twitch muscle during ex vivo fatiguing stimulation. Metabolomics revealed that ASA increased muscle bioenergetical charge via purine salvage. ASA treatment normalized upregulated mitochond

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Identification of Genetic Variants and Serum Metabolites Associated with Blood-derived Mitochondrial DNA Copy Number

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Alzheimer's & Dementia 2022年第S6期18卷

作者： Tong Tong John Farrell Congcong Zhu Zainab Khurshid Eden R. Martin William S. Bush Margaret A. Pericak-Vance Li-San Wang Gerard D. Schellenberg Jonathan L. Haines Kathryn L. Lunetta Lindsay A. Farrer Xiaoling Zhang Disease Sequencing Project Boston University School of Medicine Boston MA USA Boston University Bioinformatics Program Boston MA USA John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine Miami FL USA Case Western Reserve University School of Medicine Cleveland OH USA John P. Hussman Institute for Human Genomics Miller School of Medicine University of Miami Miami FL USA University of Pennsylvania Perelman School of Medicine Philadelphia PA USA University of Pennsylvania Perelman School of Medicine Path & Lab Med Stellar Chance Philadelphia PA USA Case Western Reserve University School of Medicine Department of Population & Quantitative Health Sciences Cleveland Institute for Computational Biology Cleveland OH USA Boston University School of Public Health Boston MA USA

Background Mitochondrial DNA Copy Number (mtDNA-CN) can be used to estimate mitochondrial function and it varies across tissues and cell types. Blood-derived mtDNA-CN has been studied in aging-related diseases including Alzheimer’s Disease (AD). However, little is known about the genetic contribution to variation of blood-derived mtDNA-CN and how this variation affects the level of serum metabolites. Method We developed a fast computational pipeline to accurately estimate mtDNA-CN using whole genome sequence data from blood samples from European ancestry (EA, 2,885 AD cases and 2,777 controls), African American (AA, 1,118 AD cases and 1,725 controls), and Caribbean Hispanic (CH, 1,022 AD cases and 1,949 controls) participants of the Alzheimer’s Disease Sequencing Project (ADSP). In the combined sample and within each population group. We tested association of blood-derived mtDNA-CN with 17,569,705 variants (minor allele count≥20) genome-wide using a linear mixed effect model including covariates for age, sex, sequencing center, PCR, AD status, polygenic risk score of blood cell count, and principal components of ancestry. We also tested the associations of mtDNA-CN and levels of 175 serum metabolites in 1,521 subjects from Alzheimer’s Disease Neuroimaging Initiative. Result In the total sample, we identified genome-wide significant (GWS) associations with variants from 24 independent loci. The top-ranked SNP (rs1455130415 in NDUFS8 , (p=3.25x10 -42 ) was also GWS in EAs (p=3.96x10 -28 ) and AAs (p=2.20x10 -27 ). SNP rs997412864 (p=5.13x10 -9 ) in GCAT was found associated with mtDNA-CN in EAs, but not in other groups. Association of SNP rs1237233197 (p=1.40x10 -8 ) in NDUFS7 was specific to AAs. Measurements of two long-chain acylcarnitine, C14:2-OH (p=4.91x10 -7 ) and C18:2 (p=1.81x10 -5 ), were negatively associated with mtDNA-CN after Bonferroni correction (P<2.9x10 -4 ). Ornithine, a non-proteinogenic amino acid, was also negatively associated with mtDNA-CN (p=2

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An automated workflow on data processing (AutoDP) for semiquantitative analysis of urine organic acids with GC-MS to facilitate diagnosis of inborn errors of metabolism

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Clinica chimica acta;international journal of clinical chemistry 2023年 540卷 117230页

作者： San-Yuan Wang Te-I Weng Ju-Yu Chen Ni-Chung Lee Kun-Chen Lee Mei-Ling Lai Yin-Hsiu Chien Wuh-Liang Hwu Guan-Yuan Chen Master Program in Clinical Genomics and Proteomics School of Pharmacy Taipei Medical University Taipei Taiwan. Forensic and Clinical Toxicology Center National Taiwan University Hospital Taipei Taiwan Department and Graduate Institute of Forensic Medicine College of Medicine National Taiwan University Taipei Taiwan Department of Emergency Medicine National Taiwan University Hospital Taipei Taiwan. Department of Pharmacy College of Medicine National Taiwan University Taipei Taiwan. Department of Pediatrics and Medical Genetics National Taiwan University Hospital Taipei Taiwan. Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan. Forensic and Clinical Toxicology Center National Taiwan University Hospital Taipei Taiwan. Department and Graduate Institute of Forensic Medicine College of Medicine National Taiwan University Taipei Taiwan. Electronic address: gychen@ntu.edu.tw.

Determination of urine organic acids (UOAs) is essential to understand the disease progress of inborn errors of metabolism (IEM) and often relies on GC-MS analysis. However, the efficiency of analytical reports is sometimes restricted by data processing due to labor-intensive work if no proper tool is employed. Herein, we present a simple and rapid workflow with an R-based script for automated data processing (AutoDP) of GC-MS raw files to quantitatively analyze essential UOAs. AutoDP features automatic quality checks, compound identification and confirmation with specific fragment ions, retention time correction from analytical batches, and visualization of abnormal UOAs with age-matched references on chromatograms. Compared with manual processing, AutoDP greatly reduces analytical time and increases the number of identifications. Speeding up data processing is expected to shorten the waiting time for clinical diagnosis, which could greatly benefit clinicians and patients with IEM. In addition, with quantitative results obtained from AutoDP, it would be more feasible to perform retrospective analysis of specific UOAs in IEM and could provide new perspectives for studying IEM.

关键词： AutoDP Automation Data processing GC-MS Inborn errors of metabolism

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Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

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Nature genetics 2019年第7期51卷 1192-1193页

作者： Rainer Malik Ganesh Chauhan Matthew Traylor Muralidharan Sargurupremraj Yukinori Okada Aniket Mishra Loes Rutten-Jacobs Anne-Katrin Giese Sander W van der Laan Solveig Gretarsdottir Christopher D Anderson Michael Chong Hieab H H Adams Tetsuro Ago Peter Almgren Philippe Amouyel Hakan Ay Traci M Bartz Oscar R Benavente Steve Bevan Giorgio B Boncoraglio Robert D Brown Adam S Butterworth Caty Carrera Cara L Carty Daniel I Chasman Wei-Min Chen John W Cole Adolfo Correa Ioana Cotlarciuc Carlos Cruchaga John Danesh Paul I W de Bakker Anita L DeStefano Marcel den Hoed Qing Duan Stefan T Engelter Guido J Falcone Rebecca F Gottesman Raji P Grewal Vilmundur Gudnason Stefan Gustafsson Jeffrey Haessler Tamara B Harris Ahamad Hassan Aki S Havulinna Susan R Heckbert Elizabeth G Holliday George Howard Fang-Chi Hsu Hyacinth I Hyacinth M Arfan Ikram Erik Ingelsson Marguerite R Irvin Xueqiu Jian Jordi Jiménez-Conde Julie A Johnson J Wouter Jukema Masahiro Kanai Keith L Keene Brett M Kissela Dawn O Kleindorfer Charles Kooperberg Michiaki Kubo Leslie A Lange Carl D Langefeld Claudia Langenberg Lenore J Launer Jin-Moo Lee Robin Lemmens Didier Leys Cathryn M Lewis Wei-Yu Lin Arne G Lindgren Erik Lorentzen Patrik K Magnusson Jane Maguire Ani Manichaikul Patrick F McArdle James F Meschia Braxton D Mitchell Thomas H Mosley Michael A Nalls Toshiharu Ninomiya Martin J O'Donnell Bruce M Psaty Sara L Pulit Kristiina Rannikmäe Alexander P Reiner Kathryn M Rexrode Kenneth Rice Stephen S Rich Paul M Ridker Natalia S Rost Peter M Rothwell Jerome I Rotter Tatjana Rundek Ralph L Sacco Saori Sakaue Michele M Sale Veikko Salomaa Bishwa R Sapkota Reinhold Schmidt Carsten O Schmidt Ulf Schminke Pankaj Sharma Agnieszka Slowik Cathie L M Sudlow Christian Tanislav Turgut Tatlisumak Kent D Taylor Vincent N S Thijs Gudmar Thorleifsson Unnur Thorsteinsdottir Steffen Tiedt Stella Trompet Christophe Tzourio Cornelia M van Duijn Matthew Walters Nicholas J Wareham Sylvia Wassertheil-Smoller James G Wilson Kerri L Wiggins Qiong Yang Salim Yusuf Joshua C Bis Tomi Institute for Stroke and Dementia Research (ISD) University Hospital LMU Munich Munich Germany. Centre for Brain Research Indian Institute of Science Bangalore India. INSERM U1219 Bordeaux Population Health Research Center University of Bordeaux Bordeaux France. Stroke Research Group Division of Clinical Neurosciences University of Cambridge Cambridge UK. Department of Neurology Institute for Neurodegenerative Disease Bordeaux University Hospital Bordeaux France. Laboratory for Statistical Analysis RIKEN Center for Integrative Medical Sciences Yokohama Japan. Department of Statistical Genetics Osaka University Graduate School of Medicine Osaka Japan. Laboratory of Statistical Immunology Immunology Frontier Research Center (WPI-IFReC) Osaka University Suita Japan. Department of Neurology Massachusetts General Hospital (MGH) Harvard Medical School Boston MA USA. Laboratory of Experimental Cardiology Department of Cardiology Division of Heart and Lungs University Medical Center Utrecht University of Utrecht Utrecht the Netherlands. deCODE genetics/AMGEN Inc. Reykjavik Iceland. Center for Genomic Medicine MGH Boston MA USA. J. Philip Kistler Stroke Research Center Department of Neurology MGH Boston MA USA. Program in Medical and Population Genetics Broad Institute Cambridge MA USA. Population Health Research Institute McMaster University Hamilton Ontario Canada. Department of Epidemiology Erasmus University Medical Center Rotterdam the Netherlands. Department of Radiology and Nuclear Medicine Erasmus University Medical Center Rotterdam the Netherlands. Department of Medicine and Clinical Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan. Department of Clinical Sciences Lund University Malmö Sweden. INSERM Institut Pasteur de Lille LabEx DISTALZ-UMR1167 Risk Factors and Molecular Determinants of Aging-Related Diseases Université Lille Lille France. Centre Hospitalier Université Lille Epidemiology and Public Health D

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Whole-genome sequencing of 1,171 elderly admixed individuals from Brazil (vol 13, 1004, 2022)

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NATURE COMMUNICATIONS 2022年第1期13卷 1-11页

作者： Naslavsky, Michel S. Scliar, Marilia O. Yamamoto, Guilherme L. Wang, Jaqueline Yu Ting Zverinova, Stepanka Karp, Tatiana Nunes, Kelly Ceroni, Jose Ricardo Magliocco de Carvalho, Diego Lima da Silva Simoes, Carlos Eduardo Bozoklian, Daniel Nonaka, Ricardo dos Santos Brito Silva, Nayane da Silva Souza, Andreia de Souza Andrade, Heloisa Passos, Marilia Rodrigues Silva Castro, Camila Ferreira Bannwart Mendes-Junior, Celso T. Mercuri, Rafael L. V. Miller, Thiago L. A. Buzzo, Jose Leonel Rego, Fernanda O. Araujo, Nathalia M. Magalhaes, Wagner C. S. Mingroni-Netto, Regina Celia Borda, Victor Guio, Heinner Rojas, Carlos P. Sanchez, Cesar Caceres, Omar Dean, Michael Barreto, Mauricio L. Lima-Costa, Maria Fernanda Horta, Bernardo L. Tarazona-Santos, Eduardo Meyer, Diogo Galante, Pedro A. F. Guryev, Victor Castelli, Erick C. Duarte, Yeda A. O. Passos-Bueno, Maria Rita Zatz, Mayana Human Genome and Stem Cell Research Center University of São Paulo São Paulo SP Brazil Department of Genetics and Evolutionary Biology Biosciences Institute University of São Paulo São Paulo SP Brazil Hospital Israelita Albert Einstein São Paulo SP Brazil Instituto da Criança Faculdade de Medicina da Universidade de São Paulo São Paulo SP Brazil Orthopedic Research Labs Boston Children’s Hospital and Department of Genetics Harvard Medical School Boston MA USA Laboratório DASA São Paulo Brazil Laboratory of Genome Structure and Ageing European Research Institute for the Biology of Ageing University Medical Center Groningen Groningen Netherlands São Paulo State University (UNESP) Molecular Genetics and Bioinformatics Laboratory School of Medicine Botucatu State of São Paulo Brazil São Paulo State University (UNESP) Department of Pathology School of Medicine Botucatu State of São Paulo Brazil Departamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo Ribeirão Preto São Paulo Brazil Centro de Oncologia Molecular Hospital Sirio-Libanes São Paulo Brazil Department of Biochemistry Institute of Chemistry University of São Paulo São Paulo São Paulo Brazil Bioinformatics Graduate program University of São Paulo São Paulo Brazil Departamento de Genética Ecologia e Evolução Instituto de Ciências Biológicas Universidade Federal de Minas Gerais Belo Horizonte MG Brazil Núcleo de Ensino e Pesquisa Instituto Mário Penna Belo Horizonte MG Brazil Laboratorio de Biotecnologia y Biologia Molecular Instituto Nacional de Salud Lima Peru Universidad de Huánuco Huánuco Peru Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA Instituto de Saúde Coletiva Universidade Federal da Bahia Salvador BA 40110-040 Brazil Center for Data and Knowledge Integration for Health Institute Gonçalo Muniz Fundação Oswaldo Cruz Salvador BA Brazil Instituto de Pesquisas René Rachou Fundação Os

As whole-genome sequencing (WGS) becomes the gold standard tool for studying population genomics and medical applications, data on diverse non-European and admixed individuals are still scarce. Here, we present a high-coverage WGS dataset of 1,171 highly admixed elderly Brazilians from a census-based cohort, providing over 76 million variants, of which ~2 million are absent from large public databases. WGS enables identification of ~2,000 previously undescribed mobile element insertions without previous description, nearly 5 Mb of genomic segments absent from the human genome reference, and over 140 alleles from HLA genes absent from public resources. We reclassify and curate pathogenicity assertions for nearly four hundred variants in genes associated with dominantly-inherited Mendelian disorders and calculate the incidence for selected recessive disorders, demonstrating the clinical usefulness of the present study. Finally, we observe that whole-genome and HLA imputation could be significantly improved compared to available datasets since rare variation represents the largest proportion of input from WGS. These results demonstrate that even smaller sample sizes of underrepresented populations bring relevant data for genomic studies, especially when exploring analyses allowed only by WGS.

关键词： Data publication and archiving Haplotypes Mobile elements Rare variants Structural variation

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Author Correction: Mapping disease regulatory circuits at cell-type resolution from single-cell multiomics data

Nature computational science

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Nature computational science 2023年第9期3卷 805页

作者： Xi Chen Yuan Wang Antonio Cappuccio Wan-Sze Cheng Frederique Ruf Zamojski Venugopalan D Nair Clare M Miller Aliza B Rubenstein German Nudelman Alicja Tadych Chandra L Theesfeld Alexandria Vornholt Mary-Catherine George Felicia Ruffin Michael Dagher Daniel G Chawla Alessandra Soares-Schanoski Rachel R Spurbeck Lishomwa C Ndhlovu Robert Sebra Steven H Kleinstein Andrew G Letizia Irene Ramos Vance G Fowler Christopher W Woods Elena Zaslavsky Olga G Troyanskaya Stuart C Sealfon Center for Computational Biology Flatiron Institute New York NY USA. Lewis-Sigler Institute of Integrative Genomics Princeton University Princeton NJ USA. Department of Computer Science Princeton University Princeton NJ USA. Department of Neurology Icahn School of Medicine at Mount Sinai New York NY USA. Division of Infectious Diseases Department of Medicine Duke University School of Medicine Durham NC USA. Program in Computational Biology and Bioinformatics Yale University New Haven CT USA. Battelle Memorial Institute Columbus OH USA. Division of Infectious Diseases Department of Medicine Weill Cornell Medicine New York NY USA. Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY USA. Department of Pathology and Department of Immunobiology Yale School of Medicine New Haven CT USA. Naval Medical Research Center Silver Spring MD USA. Precision Immunology Institute Icahn School of Medicine at Mount Sinai New York NY USA. Department of Neurology Icahn School of Medicine at Mount Sinai New York NY USA. elena.zaslavsky@mssm.edu. Center for Computational Biology Flatiron Institute New York NY USA. ogt@genomics.princeton.edu. Lewis-Sigler Institute of Integrative Genomics Princeton University Princeton NJ USA. ogt@genomics.princeton.edu. Department of Computer Science Princeton University Princeton NJ USA. ogt@genomics.princeton.edu. Department of Neurology Icahn School of Medicine at Mount Sinai New York NY USA. stuart.sealfon@mssm.edu.

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Correction to: Specific Susceptibility to COVID-19 in Adults with Down Syndrome

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Neuromolecular medicine 2021年第4期23卷 572-573页

作者： Tomer Illouz Arya Biragyn Milana Frenkel-Morgenstern Orly Weissberg Alessandro Gorohovski Eugene Merzon Ilan Green Florencia Iulita Lisi Flores-Aguilar Mara Dierssen Ilario De Toma Hefziba Lifshitz Stylianos E Antonarakis Eugene Yu Yann Herault Marie-Claude Potier Alexandra Botté Randall Roper Benjamin Sredni Ronit Sarid Jacqueline London William Mobley Andre Strydom Eitan Okun The Leslie and Susan Gonda Multidisciplinary Brain Research Center Bar-Ilan University 5290002 Ramat-Gan Israel. The Paul Feder Laboratory On Alzheimer's Disease Research Bar-Ilan University 5290002 Ramat-Gan Israel. Laboratory of Molecular Biology and Immunology NIA Baltimore MD 21224 USA. Cancer Genomics and BioComputing of Complex Diseases Lab Azrieli Faculty of Medicine Bar-Ilan University Safed Israel. Leumit Health Services Department of Family Medicine Sackler School of Medicine Tel Aviv University Tel Aviv-Yafo Israel. Sant Pau Memory Unit Department of Neurology Hospital de La Santa Creu I Sant Pau Barcelona Spain. Biomedical Research Institute Sant Pau Universitat Autònoma de Barcelona Barcelona Spain. Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED) Madrid Spain. Alzheimer-Down Unit Fundación Catalana Síndrome de Down Barcelona Spain. Department of Anatomy and Cell Biology McGill University Montreal Canada. Center for Genomic Regulation The Barcelona Institute for Science and Technology Barcelona Spain. University Pompeu Fabra Barcelona Spain. Biomedical Research Networking Center for Rare Diseases (CIBERER) Barcelona Spain. Cellular & Systems Neurobiology Systems Biology Program The Barcelona Institute of Science and Technology Centre for Genomic Regulation (CRG) Dr. Aiguader 88 08003 Barcelona Spain. Universitat Pompeu Fabra (UPF) Barcelona Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) Madrid Spain. School of Education Bar-Ilan University 5290002 Ramat-Gan Israel. Department of Genetic Medicine and Development University of Geneva 1211 Geneva Switzerland. Medigenome Swiss Institute of Genomic Medicine 1207 Geneva Switzerland. iGE3 Institute of Genetics and Genomics of Geneva 1211 Geneva Switzerland. The Children's Guild Foundation Down Syndrome Research Program Genetics and Genomics Program and Department of Cancer Genetics and Genomics Roswell Park Comprehensi

A correction to this paper has been published: https://***/10.1007/s12017-021-08657-z

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Comparative cellular analysis of motor cortex in human, marmoset and mouse (vol 598, pg 111, 2021)

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NATURE 2022年第7904期604卷 E8-E8页

作者： Bakken, Trygve E. Jorstad, Nikolas L. Hu, Qiwen Lake, Blue B. Tian, Wei Kalmbach, Brian E. Crow, Megan Hodge, Rebecca D. Krienen, Fenna M. Sorensen, Staci A. Eggermont, Jeroen Yao, Zizhen Aevermann, Brian D. Aldridge, Andrew I. Bartlett, Anna Bertagnolli, Darren Casper, Tamara Castanon, Rosa G. Crichton, Kirsten Daigle, Tanya L. Dalley, Rachel Dee, Nick Dembrow, Nikolai Diep, Dinh Ding, Song-Lin Dong, Weixiu Fang, Rongxin Fischer, Stephan Goldman, Melissa Goldy, Jeff Graybuck, Lucas T. Herb, Brian R. Hou, Xiaomeng Kancherla, Jayaram Kroll, Matthew Lathia, Kanan van Lew, Baldur Li, Yang Eric Liu, Christine S. Liu, Hanqing Lucero, Jacinta D. Mahurkar, Anup McMillen, Delissa Miller, Jeremy A. Moussa, Marmar Nery, Joseph R. Nicovich, Philip R. Niu, Sheng-Yong Orvis, Joshua Osteen, Julia K. Owen, Scott Palmer, Carter R. Pham, Thanh Plongthongkum, Nongluk Poirion, Olivier Reed, Nora M. Rimorin, Christine Rivkin, Angeline Romanow, William J. Sedeno-Cortes, Adriana E. Siletti, Kimberly Somasundaram, Saroja Sulc, Josef Tieu, Michael Torkelson, Amy Tung, Herman Wang, Xinxin Xie, Fangming Yanny, Anna Marie Zhang, Renee Ament, Seth A. Behrens, M. Margarita Bravo, Hector Corrada Chun, Jerold Dobin, Alexander Gillis, Jesse Hertzano, Ronna Hof, Patrick R. Hollt, Thomas Horwitz, Gregory D. Keene, C. Dirk Kharchenko, Peter V. Ko, Andrew L. Lelieveldt, Boudewijn P. Luo, Chongyuan Mukamel, Eran A. Pinto-Duarte, Antonio Preiss, Sebastian Regev, Aviv Ren, Bing Scheuermann, Richard H. Smith, Kimberly Spain, William J. White, Owen R. Koch, Christof Hawrylycz, Michael Tasic, Bosiljka Macosko, Evan Z. McCarroll, Steven A. Ting, Jonathan T. Zeng, Hongkui Zhang, Kun Feng, Guoping Ecker, Joseph R. Linnarsson, Sten Lein, Ed S. Allen Institute for Brain Science Seattle WA USA Department of Physiology and Biophysics University of Washington Seattle WA USA Department of Biomedical Informatics Harvard Medical School Boston MA USA Department of Bioengineering University of California San Diego La Jolla CA USA The Salk Institute for Biological Studies La Jolla CA USA Epilepsy Center of Excellence Department of Veterans Affairs Medical Center Seattle WA USA Stanley Institute for Cognitive Genomics Cold Spring Harbor Laboratory Cold Spring Harbor NY USA Department of Genetics Harvard Medical School Boston MA USA Broad Institute of MIT and Harvard Cambridge MA USA LKEB Department of Radiology Leiden University Medical Center Leiden The Netherlands Pattern Recognition and Bioinformatics group Delft University of Technology Delft The Netherlands J. Craig Venter Institute La Jolla CA USA Department of Pathology University of California San Diego CA USA Division of Vaccine Discovery La Jolla Institute for Immunology La Jolla CA USA Genomic Analysis Laboratory The Salk Institute for Biological Studies La Jolla CA USA Computer Science and Engineering Program University of California San Diego La Jolla CA USA Howard Hughes Medical Institute The Salk Institute for Biological Studies La Jolla CA USA Bioinformatics and Systems Biology Graduate Program University of California San Diego La Jolla CA USA Institute for Genomes Sciences University of Maryland School of Medicine Baltimore MD USA Center for Epigenomics Department of Cellular and Molecular Medicine University of California San Diego La Jolla CA USA Ludwig Institute for Cancer Research La Jolla CA USA Department of Computer Science University of Maryland College Park College Park MD USA Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA Biomedical Sciences Program School of Medicine University of California San Diego La Jolla CA USA University of Connecticut Storrs CT USA Department

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Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer

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Nature 2024年第8013期629卷 927-936页

作者： Urszula N Wasko Jingjing Jiang Tanner C Dalton Alvaro Curiel-Garcia A Cole Edwards Yingyun Wang Bianca Lee Margo Orlen Sha Tian Clint A Stalnecker Kristina Drizyte-Miller Marie Menard Julien Dilly Stephen A Sastra Carmine F Palermo Marie C Hasselluhn Amanda R Decker-Farrell Stephanie Chang Lingyan Jiang Xing Wei Yu C Yang Ciara Helland Haley Courtney Yevgeniy Gindin Karl Muonio Ruiping Zhao Samantha B Kemp Cynthia Clendenin Rina Sor William P Vostrejs Priya S Hibshman Amber M Amparo Connor Hennessey Matthew G Rees Melissa M Ronan Jennifer A Roth Jens Brodbeck Lorenzo Tomassoni Basil Bakir Nicholas D Socci Laura E Herring Natalie K Barker Junning Wang James M Cleary Brian M Wolpin John A Chabot Michael D Kluger Gulam A Manji Kenneth Y Tsai Miroslav Sekulic Stephen M Lagana Andrea Califano Elsa Quintana Zhengping Wang Jacqueline A M Smith Matthew Holderfield David Wildes Scott W Lowe Michael A Badgley Andrew J Aguirre Robert H Vonderheide Ben Z Stanger Timour Baslan Channing J Der Mallika Singh Kenneth P Olive Department of Medicine Vagelos College of Physicians and Surgeons Columbia University Irving Medical Center New York NY USA. Herbert Irving Comprehensive Cancer Center Columbia University Irving Medical Center New York NY USA. Revolution Medicines Redwood City CA USA. Department of Cell Biology and Physiology University of North Carolina at Chapel Hill Chapel Hill NC USA. University of Pennsylvania Perelman School of Medicine Department of Medicine Philadelphia PA USA. Cancer Biology and Genetics Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA. Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill NC USA. Department of Pharmacology University of North Carolina at Chapel Hill Chapel Hill NC USA. Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA. Harvard Medical School Boston MA USA. University of Pennsylvania Perelman School of Medicine Abramson Cancer Center Philadelphia PA USA. The Broad Institute of Harvard and MIT Cambridge MA USA. Department of Systems Biology Columbia University Irving Medical Center New York NY USA. Bioinformatics Core Memorial Sloan Kettering Cancer Center New York NY USA. UNC Michael Hooker Proteomics Center University of North Carolina at Chapel Hill Chapel Hill NC USA. Department of Surgery Vagelos College of Physicians and Surgeons Columbia University Irving Medical Center New York NY USA. Department of Pathology H. Lee Moffitt Cancer Center and Research Institute Tampa FL USA. Department of Tumor Microenvironment and Metastasis H. Lee Moffitt Cancer Center and Research Institute Tampa FL USA. Department of Pathology and Cell Biology Columbia University Irving Medical Center New York NY USA. Department of Oncology The Johns Hopkins University School of Medicine Baltimore MD USA. J. P. Sulzberger Columbia Genome Center Columbia University New York NY USA. Department of Biochemistry and Molecular Biop

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

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An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder (vol 6, 22851, 2016)

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SCIENTIFIC REPORTS 2016年第1期6卷 22851-22851页

作者： Lima, Leandro de Araujo Feio-dos-Santos, Ana Cecilia Belangero, Sintia Iole Gadelha, Ary Bressan, Rodrigo Affonseca Salum, Giovanni Abrahao Pan, Pedro Mario Moriyama, Tais Silveira Graeff-Martins, Ana Soledade Tamanaha, Ana Carina Alvarenga, Pedro Krieger, Fernanda Valle Fleitlich-Bilyk, Bacy Jackowski, Andrea Parolin Brietzke, Elisa Sato, Joao Ricardo Polanczyk, Guilherme Vanoni Mari, Jair de Jesus Manfro, Gisele Gus do Rosario, Maria Conceiao Miguel, Euripedes Constantino Puga, Renato David Tahira, Ana Carolina Souza, Viviane Neri Chile, Thais Gouveia, Gisele Rodrigues Simoes, Sergio Nery Chang, Xiao Pellegrino, Renata Tian, Lifeng Glessner, Joseph T. Hashimoto, Ronaldo Fumio Rohde, Luis Augusto Sleiman, Patrick M. A. Hakonarson, Hakon Brentani, Helena Inter-institutional Grad Program on Bioinformatics University of São Paulo São Paulo SP Brazil Center for Applied Genomics The Children’s Hospital of Philadelphia Philadelphia PA USA Department & Institute of Psychiatry University of São Paulo Medical School São Paulo SP Brazil National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq) São Paulo SP Brazil Department of Psychiatry Federal University of São Paulo São Paulo SP Brazil National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq) São Paulo SP Brazil Department of Psychiatry Federal University of São Paulo São Paulo SP Brazil National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq) São Paulo SP Brazil Department of Psychiatry Federal University of São Paulo São Paulo SP Brazil National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq) São Paulo SP Brazil Department of Psychiatry Hospital de Clínicas de Porto Alegre Federal University of Rio Grande do Sul Porto Alegre RS Brazil National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq) São Paulo SP Brazil Department of Psychiatry Federal University of São Paulo São Paulo SP Brazil Department & Institute of Psychiatry University of São Paulo Medical School São Paulo SP Brazil National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq) São Paulo SP Brazil Department of Psychiatry Federal University of São Paulo São Paulo SP Brazil Department & Institute of Psychiatry University of São Paulo Medical School São Paulo SP Brazil National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq) São Paulo SP Brazil National Institute of Developmental Psychiatry for Children and Adolescents (INCT-CNPq) São Paulo SP Brazil Department of Psychiatry Federal University of São Paulo São Paulo SP Brazil Department & Institute of Psychiatry University of S

Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two “in silico” protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

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