Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials.
Identifieur interne : 000118 ( Main/Exploration ); précédent : 000117; suivant : 000119Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials.
Auteurs : Alberto J. Espay [États-Unis] ; Michael A. Schwarzschild [États-Unis] ; Caroline M. Tanner [États-Unis] ; Hubert H. Fernandez [États-Unis] ; David K. Simon [États-Unis] ; James B. Leverenz [États-Unis] ; Aristide Merola [États-Unis] ; Alice Chen-Plotkin [États-Unis] ; Patrik Brundin [États-Unis] ; Marcelo A. Kauffman [Argentine] ; Roberto Erro [Royaume-Uni] ; Karl Kieburtz [États-Unis] ; Daniel Woo [États-Unis] ; Eric A. Macklin [États-Unis] ; David G. Standaert [États-Unis] ; Anthony E. Lang [Canada]Source :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2017.
Abstract
Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: A single-mechanism therapy can affect most of those sharing the classic pathological hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological, and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers), rather than clinical definitions, are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller, but well-defined, subsets of PD amenable to successful neuroprotection. © 2017 International Parkinson and Movement Disorder Society.
DOI: 10.1002/mds.26913
PubMed: 28233927
Affiliations:
- Argentine, Canada, Royaume-Uni, États-Unis
- Alabama, Angleterre, Californie, Grand Londres, Massachusetts, Michigan, Ohio, Ontario, Pennsylvanie, État de New York
- Londres, Toronto
- University College de Londres, Université de Toronto
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Espay</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, UC Gardner Neuroscience Institute, Gardner Center for Parkinson's disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, UC Gardner Neuroscience Institute, Gardner Center for Parkinson's disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Schwarzschild, Michael A" sort="Schwarzschild, Michael A" uniqKey="Schwarzschild M" first="Michael A" last="Schwarzschild">Michael A. 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Tanner</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, University of California-San Francisco and the Parkinson's Disease Research Education and Clinical Center, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, University of California-San Francisco and the Parkinson's Disease Research Education and Clinical Center, San Francisco Veterans Affairs Medical Center, San Francisco, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Fernandez, Hubert H" sort="Fernandez, Hubert H" uniqKey="Fernandez H" first="Hubert H" last="Fernandez">Hubert H. 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Kauffman</name><affiliation wicri:level="1"><nlm:affiliation>Consultorio y Laboratorio de Neurogenética, Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA, and Programa de Medicina de Precision y Genomica Clinica, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral-CONICET, Pilar, Argentina.</nlm:affiliation><country xml:lang="fr">Argentine</country><wicri:regionArea>Consultorio y Laboratorio de Neurogenética, Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA, and Programa de Medicina de Precision y Genomica Clinica, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral-CONICET, Pilar</wicri:regionArea><wicri:noRegion>Pilar</wicri:noRegion></affiliation></author><author><name sortKey="Erro, Roberto" sort="Erro, Roberto" uniqKey="Erro R" first="Roberto" last="Erro">Roberto Erro</name><affiliation wicri:level="4"><nlm:affiliation>Sobell department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Sobell department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region><settlement type="city">Londres</settlement></placeName><orgName type="university">University College de Londres</orgName></affiliation></author><author><name sortKey="Kieburtz, Karl" sort="Kieburtz, Karl" uniqKey="Kieburtz K" first="Karl" last="Kieburtz">Karl Kieburtz</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology and CHET, University of Rochester Medical Center, Rochester, New York, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology and CHET, University of Rochester Medical Center, Rochester, New York</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Woo, Daniel" sort="Woo, Daniel" uniqKey="Woo D" first="Daniel" last="Woo">Daniel Woo</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology and Rehabilitation Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology and Rehabilitation Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Macklin, Eric A" sort="Macklin, Eric A" uniqKey="Macklin E" first="Eric A" last="Macklin">Eric A. Macklin</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Standaert, David G" sort="Standaert, David G" uniqKey="Standaert D" first="David G" last="Standaert">David G. Standaert</name><affiliation wicri:level="2"><nlm:affiliation>Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation></author><author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E" last="Lang">Anthony E. Lang</name><affiliation wicri:level="4"><nlm:affiliation>Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital and The Edmond J. Safra Program in PD, Toronto, Ontario, Canada, University of Toronto, Toronto, Ontario, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital and The Edmond J. Safra Program in PD, Toronto, Ontario, Canada, University of Toronto, Toronto, Ontario</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28233927</idno><idno type="pmid">28233927</idno><idno type="doi">10.1002/mds.26913</idno><idno type="wicri:Area/PubMed/Corpus">000051</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000051</idno><idno type="wicri:Area/PubMed/Curation">000051</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000051</idno><idno type="wicri:Area/PubMed/Checkpoint">000051</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000051</idno><idno type="wicri:Area/Ncbi/Merge">002230</idno><idno type="wicri:Area/Ncbi/Curation">002230</idno><idno type="wicri:Area/Ncbi/Checkpoint">002230</idno><idno type="wicri:Area/Main/Merge">000118</idno><idno type="wicri:Area/Main/Curation">000118</idno><idno type="wicri:Area/Main/Exploration">000118</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials.</title><author><name sortKey="Espay, Alberto J" sort="Espay, Alberto J" uniqKey="Espay A" first="Alberto J" last="Espay">Alberto J. Espay</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, UC Gardner Neuroscience Institute, Gardner Center for Parkinson's disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, UC Gardner Neuroscience Institute, Gardner Center for Parkinson's disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Schwarzschild, Michael A" sort="Schwarzschild, Michael A" uniqKey="Schwarzschild M" first="Michael A" last="Schwarzschild">Michael A. Schwarzschild</name><affiliation wicri:level="2"><nlm:affiliation>MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Tanner, Caroline M" sort="Tanner, Caroline M" uniqKey="Tanner C" first="Caroline M" last="Tanner">Caroline M. Tanner</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, University of California-San Francisco and the Parkinson's Disease Research Education and Clinical Center, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, University of California-San Francisco and the Parkinson's Disease Research Education and Clinical Center, San Francisco Veterans Affairs Medical Center, San Francisco, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Fernandez, Hubert H" sort="Fernandez, Hubert H" uniqKey="Fernandez H" first="Hubert H" last="Fernandez">Hubert H. Fernandez</name><affiliation wicri:level="2"><nlm:affiliation>Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Simon, David K" sort="Simon, David K" uniqKey="Simon D" first="David K" last="Simon">David K. Simon</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Leverenz, James B" sort="Leverenz, James B" uniqKey="Leverenz J" first="James B" last="Leverenz">James B. Leverenz</name><affiliation wicri:level="2"><nlm:affiliation>Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Merola, Aristide" sort="Merola, Aristide" uniqKey="Merola A" first="Aristide" last="Merola">Aristide Merola</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, UC Gardner Neuroscience Institute, Gardner Center for Parkinson's disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, UC Gardner Neuroscience Institute, Gardner Center for Parkinson's disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Chen Plotkin, Alice" sort="Chen Plotkin, Alice" uniqKey="Chen Plotkin A" first="Alice" last="Chen-Plotkin">Alice Chen-Plotkin</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Brundin, Patrik" sort="Brundin, Patrik" uniqKey="Brundin P" first="Patrik" last="Brundin">Patrik Brundin</name><affiliation wicri:level="2"><nlm:affiliation>Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan</wicri:regionArea><placeName><region type="state">Michigan</region></placeName></affiliation></author><author><name sortKey="Kauffman, Marcelo A" sort="Kauffman, Marcelo A" uniqKey="Kauffman M" first="Marcelo A" last="Kauffman">Marcelo A. Kauffman</name><affiliation wicri:level="1"><nlm:affiliation>Consultorio y Laboratorio de Neurogenética, Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA, and Programa de Medicina de Precision y Genomica Clinica, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral-CONICET, Pilar, Argentina.</nlm:affiliation><country xml:lang="fr">Argentine</country><wicri:regionArea>Consultorio y Laboratorio de Neurogenética, Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA, and Programa de Medicina de Precision y Genomica Clinica, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral-CONICET, Pilar</wicri:regionArea><wicri:noRegion>Pilar</wicri:noRegion></affiliation></author><author><name sortKey="Erro, Roberto" sort="Erro, Roberto" uniqKey="Erro R" first="Roberto" last="Erro">Roberto Erro</name><affiliation wicri:level="4"><nlm:affiliation>Sobell department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Sobell department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region><settlement type="city">Londres</settlement></placeName><orgName type="university">University College de Londres</orgName></affiliation></author><author><name sortKey="Kieburtz, Karl" sort="Kieburtz, Karl" uniqKey="Kieburtz K" first="Karl" last="Kieburtz">Karl Kieburtz</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology and CHET, University of Rochester Medical Center, Rochester, New York, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology and CHET, University of Rochester Medical Center, Rochester, New York</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Woo, Daniel" sort="Woo, Daniel" uniqKey="Woo D" first="Daniel" last="Woo">Daniel Woo</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology and Rehabilitation Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology and Rehabilitation Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Macklin, Eric A" sort="Macklin, Eric A" uniqKey="Macklin E" first="Eric A" last="Macklin">Eric A. Macklin</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Standaert, David G" sort="Standaert, David G" uniqKey="Standaert D" first="David G" last="Standaert">David G. Standaert</name><affiliation wicri:level="2"><nlm:affiliation>Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation></author><author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E" last="Lang">Anthony E. Lang</name><affiliation wicri:level="4"><nlm:affiliation>Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital and The Edmond J. Safra Program in PD, Toronto, Ontario, Canada, University of Toronto, Toronto, Ontario, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital and The Edmond J. Safra Program in PD, Toronto, Ontario, Canada, University of Toronto, Toronto, Ontario</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="eISSN">1531-8257</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: A single-mechanism therapy can affect most of those sharing the classic pathological hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological, and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers), rather than clinical definitions, are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller, but well-defined, subsets of PD amenable to successful neuroprotection. © 2017 International Parkinson and Movement Disorder Society.</div></front></TEI><affiliations><list><country><li>Argentine</li><li>Canada</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Alabama</li><li>Angleterre</li><li>Californie</li><li>Grand Londres</li><li>Massachusetts</li><li>Michigan</li><li>Ohio</li><li>Ontario</li><li>Pennsylvanie</li><li>État de New York</li></region><settlement><li>Londres</li><li>Toronto</li></settlement><orgName><li>University College de Londres</li><li>Université de Toronto</li></orgName></list><tree><country name="États-Unis"><region name="Ohio"><name sortKey="Espay, Alberto J" sort="Espay, Alberto J" uniqKey="Espay A" first="Alberto J" last="Espay">Alberto J. Espay</name></region><name sortKey="Brundin, Patrik" sort="Brundin, Patrik" uniqKey="Brundin P" first="Patrik" last="Brundin">Patrik Brundin</name><name sortKey="Chen Plotkin, Alice" sort="Chen Plotkin, Alice" uniqKey="Chen Plotkin A" first="Alice" last="Chen-Plotkin">Alice Chen-Plotkin</name><name sortKey="Fernandez, Hubert H" sort="Fernandez, Hubert H" uniqKey="Fernandez H" first="Hubert H" last="Fernandez">Hubert H. Fernandez</name><name sortKey="Kieburtz, Karl" sort="Kieburtz, Karl" uniqKey="Kieburtz K" first="Karl" last="Kieburtz">Karl Kieburtz</name><name sortKey="Leverenz, James B" sort="Leverenz, James B" uniqKey="Leverenz J" first="James B" last="Leverenz">James B. Leverenz</name><name sortKey="Macklin, Eric A" sort="Macklin, Eric A" uniqKey="Macklin E" first="Eric A" last="Macklin">Eric A. Macklin</name><name sortKey="Merola, Aristide" sort="Merola, Aristide" uniqKey="Merola A" first="Aristide" last="Merola">Aristide Merola</name><name sortKey="Schwarzschild, Michael A" sort="Schwarzschild, Michael A" uniqKey="Schwarzschild M" first="Michael A" last="Schwarzschild">Michael A. Schwarzschild</name><name sortKey="Simon, David K" sort="Simon, David K" uniqKey="Simon D" first="David K" last="Simon">David K. Simon</name><name sortKey="Standaert, David G" sort="Standaert, David G" uniqKey="Standaert D" first="David G" last="Standaert">David G. Standaert</name><name sortKey="Tanner, Caroline M" sort="Tanner, Caroline M" uniqKey="Tanner C" first="Caroline M" last="Tanner">Caroline M. Tanner</name><name sortKey="Woo, Daniel" sort="Woo, Daniel" uniqKey="Woo D" first="Daniel" last="Woo">Daniel Woo</name></country><country name="Argentine"><noRegion><name sortKey="Kauffman, Marcelo A" sort="Kauffman, Marcelo A" uniqKey="Kauffman M" first="Marcelo A" last="Kauffman">Marcelo A. Kauffman</name></noRegion></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Erro, Roberto" sort="Erro, Roberto" uniqKey="Erro R" first="Roberto" last="Erro">Roberto Erro</name></region></country><country name="Canada"><region name="Ontario"><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E" last="Lang">Anthony E. Lang</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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