Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation.
Identifieur interne : 000210 ( Main/Exploration ); précédent : 000209; suivant : 000211Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation.
Auteurs : Khashayar Esfahani [Canada] ; Tho-Alfakar Al-Aubodah [Canada] ; Pamela Thebault [Canada] ; Réjean Lapointe [Canada] ; Marie Hudson [Canada] ; Nathalie A. Johnson [Canada] ; Dana Baran [Canada] ; Najwa Bhulaiga [Canada] ; Tomoko Takano [Canada] ; Jean-François Cailhier [Canada] ; Ciriaco A. Piccirillo [Canada] ; Wilson H. Miller [Canada]Source :
- Nature communications [ 2041-1723 ] ; 2019.
Descripteurs français
- KwdFr :
- Adulte d'âge moyen (MeSH), Défaillance rénale chronique (immunologie), Défaillance rénale chronique (thérapie), Femelle (MeSH), Humains (MeSH), Immunosuppresseurs (usage thérapeutique), Lymphocytes T cytotoxiques (effets des médicaments et des substances chimiques), Lymphocytes T cytotoxiques (immunologie), Lymphocytes T régulateurs (effets des médicaments et des substances chimiques), Lymphocytes T régulateurs (immunologie), Mélanome (immunologie), Mélanome (thérapie), Rejet du greffon (immunologie), Récepteur-1 de mort cellulaire programmée (antagonistes et inhibiteurs), Récepteur-1 de mort cellulaire programmée (métabolisme), Sirolimus (usage thérapeutique), Sérine-thréonine kinases TOR (antagonistes et inhibiteurs), Sérine-thréonine kinases TOR (métabolisme), Tolérance à la transplantation (effets des médicaments et des substances chimiques), Tolérance à la transplantation (immunologie), Transduction du signal (effets des médicaments et des substances chimiques), Transplantation rénale (méthodes).
- MESH :
- antagonistes et inhibiteurs : Récepteur-1 de mort cellulaire programmée, Sérine-thréonine kinases TOR.
- effets des médicaments et des substances chimiques : Lymphocytes T cytotoxiques, Lymphocytes T régulateurs, Tolérance à la transplantation, Transduction du signal.
- immunologie : Défaillance rénale chronique, Lymphocytes T cytotoxiques, Lymphocytes T régulateurs, Mélanome, Rejet du greffon, Tolérance à la transplantation.
- métabolisme : Récepteur-1 de mort cellulaire programmée, Sérine-thréonine kinases TOR.
- méthodes : Transplantation rénale.
- thérapie : Défaillance rénale chronique, Mélanome.
- usage thérapeutique : Immunosuppresseurs, Sirolimus.
- Adulte d'âge moyen, Femelle, Humains.
English descriptors
- KwdEn :
- Female (MeSH), Graft Rejection (immunology), Humans (MeSH), Immunosuppressive Agents (therapeutic use), Kidney Failure, Chronic (immunology), Kidney Failure, Chronic (therapy), Kidney Transplantation (methods), Melanoma (immunology), Melanoma (therapy), Middle Aged (MeSH), Programmed Cell Death 1 Receptor (antagonists & inhibitors), Programmed Cell Death 1 Receptor (metabolism), Signal Transduction (drug effects), Sirolimus (therapeutic use), T-Lymphocytes, Cytotoxic (drug effects), T-Lymphocytes, Cytotoxic (immunology), T-Lymphocytes, Regulatory (drug effects), T-Lymphocytes, Regulatory (immunology), TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (metabolism), Transplantation Tolerance (drug effects), Transplantation Tolerance (immunology).
- MESH :
- chemical , antagonists & inhibitors : Programmed Cell Death 1 Receptor, TOR Serine-Threonine Kinases.
- chemical , metabolism : Programmed Cell Death 1 Receptor, TOR Serine-Threonine Kinases.
- chemical , therapeutic use : Immunosuppressive Agents, Sirolimus.
- drug effects : Signal Transduction, T-Lymphocytes, Cytotoxic, T-Lymphocytes, Regulatory, Transplantation Tolerance.
- immunology : Graft Rejection, Kidney Failure, Chronic, Melanoma, T-Lymphocytes, Cytotoxic, T-Lymphocytes, Regulatory, Transplantation Tolerance.
- methods : Kidney Transplantation.
- therapy : Kidney Failure, Chronic, Melanoma.
- Female, Humans, Middle Aged.
Abstract
Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)-γ+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ+ CD4+ T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.
DOI: 10.1038/s41467-019-12628-1
PubMed: 31624262
PubMed Central: PMC6797722
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
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Piccirillo</name><affiliation wicri:level="1"><nlm:affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada. ciriaco.piccirillo@mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada. ciriaco.piccirillo@mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Microbiology and Immunology, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation><affiliation wicri:level="1"><nlm:affiliation>Program in Infectious Diseases and Immunity in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada. ciriaco.piccirillo@mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Program in Infectious Diseases and Immunity in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation></author><author><name sortKey="Miller, Wilson H" sort="Miller, Wilson H" uniqKey="Miller W" first="Wilson H" last="Miller">Wilson H. Miller</name><affiliation wicri:level="4"><nlm:affiliation>Departments of Medicine and Oncology, Segal Cancer Center, Rossy Cancer Network, McGill University, Montréal, Québec, Canada. wmiller@ldi.jgh.mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Departments of Medicine and Oncology, Segal Cancer Center, Rossy Cancer Network, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation><affiliation wicri:level="1"><nlm:affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada. wmiller@ldi.jgh.mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>McGill Center for Translational Research in Cancer, McGill University, Montréal, Québec, Canada. wmiller@ldi.jgh.mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>McGill Center for Translational Research in Cancer, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:31624262</idno><idno type="pmid">31624262</idno><idno type="doi">10.1038/s41467-019-12628-1</idno><idno type="pmc">PMC6797722</idno><idno type="wicri:Area/Main/Corpus">000175</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000175</idno><idno type="wicri:Area/Main/Curation">000175</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000175</idno><idno type="wicri:Area/Main/Exploration">000175</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation.</title><author><name sortKey="Esfahani, Khashayar" sort="Esfahani, Khashayar" uniqKey="Esfahani K" first="Khashayar" last="Esfahani">Khashayar Esfahani</name><affiliation wicri:level="4"><nlm:affiliation>Departments of Medicine and Oncology, Segal Cancer Center, Rossy Cancer Network, McGill University, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Departments of Medicine and Oncology, Segal Cancer Center, Rossy Cancer Network, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation><affiliation wicri:level="1"><nlm:affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>McGill Center for Translational Research in Cancer, McGill University, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>McGill Center for Translational Research in Cancer, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Al Aubodah, Tho Alfakar" sort="Al Aubodah, Tho Alfakar" uniqKey="Al Aubodah T" first="Tho-Alfakar" last="Al-Aubodah">Tho-Alfakar Al-Aubodah</name><affiliation wicri:level="1"><nlm:affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Microbiology and Immunology, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation><affiliation wicri:level="1"><nlm:affiliation>Program in Infectious Diseases and Immunity in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Program in Infectious Diseases and Immunity in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation></author><author><name sortKey="Thebault, Pamela" sort="Thebault, Pamela" uniqKey="Thebault P" first="Pamela" last="Thebault">Pamela Thebault</name><affiliation wicri:level="1"><nlm:affiliation>University of Montréal Hospital Research Centre, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>University of Montréal Hospital Research Centre, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Institut du cancer de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Institut du cancer de Montréal, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Clinical Immuno-Monitoring Core Facility, CRCHUM, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Clinical Immuno-Monitoring Core Facility, CRCHUM, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, University of Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, University of Montréal, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation></author><author><name sortKey="Lapointe, Rejean" sort="Lapointe, Rejean" uniqKey="Lapointe R" first="Réjean" last="Lapointe">Réjean Lapointe</name><affiliation wicri:level="1"><nlm:affiliation>University of Montréal Hospital Research Centre, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>University of Montréal Hospital Research Centre, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Institut du cancer de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Institut du cancer de Montréal, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Clinical Immuno-Monitoring Core Facility, CRCHUM, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Clinical Immuno-Monitoring Core Facility, CRCHUM, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, University of Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, University of Montréal, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation></author><author><name sortKey="Hudson, Marie" sort="Hudson, Marie" uniqKey="Hudson M" first="Marie" last="Hudson">Marie Hudson</name><affiliation wicri:level="1"><nlm:affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Division of Rheumatology, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, Division of Rheumatology, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Johnson, Nathalie A" sort="Johnson, Nathalie A" uniqKey="Johnson N" first="Nathalie A" last="Johnson">Nathalie A. Johnson</name><affiliation wicri:level="1"><nlm:affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Division of Hematology, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, Division of Hematology, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Baran, Dana" sort="Baran, Dana" uniqKey="Baran D" first="Dana" last="Baran">Dana Baran</name><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Division of Nephrology, Faculty of Medicine, McGill University, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, Division of Nephrology, Faculty of Medicine, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Bhulaiga, Najwa" sort="Bhulaiga, Najwa" uniqKey="Bhulaiga N" first="Najwa" last="Bhulaiga">Najwa Bhulaiga</name><affiliation wicri:level="4"><nlm:affiliation>Departments of Medicine and Oncology, Segal Cancer Center, Rossy Cancer Network, McGill University, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Departments of Medicine and Oncology, Segal Cancer Center, Rossy Cancer Network, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Takano, Tomoko" sort="Takano, Tomoko" uniqKey="Takano T" first="Tomoko" last="Takano">Tomoko Takano</name><affiliation wicri:level="1"><nlm:affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Department of Medicine, Division of Nephrology, Faculty of Medicine, McGill University, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, Division of Nephrology, Faculty of Medicine, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Cailhier, Jean Francois" sort="Cailhier, Jean Francois" uniqKey="Cailhier J" first="Jean-François" last="Cailhier">Jean-François Cailhier</name><affiliation wicri:level="1"><nlm:affiliation>University of Montréal Hospital Research Centre, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>University of Montréal Hospital Research Centre, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Institut du cancer de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Institut du cancer de Montréal, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Clinical Immuno-Monitoring Core Facility, CRCHUM, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Clinical Immuno-Monitoring Core Facility, CRCHUM, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, University of Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, University of Montréal, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation></author><author><name sortKey="Piccirillo, Ciriaco A" sort="Piccirillo, Ciriaco A" uniqKey="Piccirillo C" first="Ciriaco A" last="Piccirillo">Ciriaco A. Piccirillo</name><affiliation wicri:level="1"><nlm:affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada. ciriaco.piccirillo@mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada. ciriaco.piccirillo@mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Microbiology and Immunology, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation><affiliation wicri:level="1"><nlm:affiliation>Program in Infectious Diseases and Immunity in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada. ciriaco.piccirillo@mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Program in Infectious Diseases and Immunity in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation></author><author><name sortKey="Miller, Wilson H" sort="Miller, Wilson H" uniqKey="Miller W" first="Wilson H" last="Miller">Wilson H. Miller</name><affiliation wicri:level="4"><nlm:affiliation>Departments of Medicine and Oncology, Segal Cancer Center, Rossy Cancer Network, McGill University, Montréal, Québec, Canada. wmiller@ldi.jgh.mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Departments of Medicine and Oncology, Segal Cancer Center, Rossy Cancer Network, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation><affiliation wicri:level="1"><nlm:affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada. wmiller@ldi.jgh.mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>McGill Center for Translational Research in Cancer, McGill University, Montréal, Québec, Canada. wmiller@ldi.jgh.mcgill.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>McGill Center for Translational Research in Cancer, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author></analytic><series><title level="j">Nature communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Female (MeSH)</term><term>Graft Rejection (immunology)</term><term>Humans (MeSH)</term><term>Immunosuppressive Agents (therapeutic use)</term><term>Kidney Failure, Chronic (immunology)</term><term>Kidney Failure, Chronic (therapy)</term><term>Kidney Transplantation (methods)</term><term>Melanoma (immunology)</term><term>Melanoma (therapy)</term><term>Middle Aged (MeSH)</term><term>Programmed Cell Death 1 Receptor (antagonists & inhibitors)</term><term>Programmed Cell Death 1 Receptor (metabolism)</term><term>Signal Transduction (drug effects)</term><term>Sirolimus (therapeutic use)</term><term>T-Lymphocytes, Cytotoxic (drug effects)</term><term>T-Lymphocytes, Cytotoxic (immunology)</term><term>T-Lymphocytes, Regulatory (drug effects)</term><term>T-Lymphocytes, Regulatory (immunology)</term><term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term><term>TOR Serine-Threonine Kinases (metabolism)</term><term>Transplantation Tolerance (drug effects)</term><term>Transplantation Tolerance (immunology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte d'âge moyen (MeSH)</term><term>Défaillance rénale chronique (immunologie)</term><term>Défaillance rénale chronique (thérapie)</term><term>Femelle (MeSH)</term><term>Humains (MeSH)</term><term>Immunosuppresseurs (usage thérapeutique)</term><term>Lymphocytes T cytotoxiques (effets des médicaments et des substances chimiques)</term><term>Lymphocytes T cytotoxiques (immunologie)</term><term>Lymphocytes T régulateurs (effets des médicaments et des substances chimiques)</term><term>Lymphocytes T régulateurs (immunologie)</term><term>Mélanome (immunologie)</term><term>Mélanome (thérapie)</term><term>Rejet du greffon (immunologie)</term><term>Récepteur-1 de mort cellulaire programmée (antagonistes et inhibiteurs)</term><term>Récepteur-1 de mort cellulaire programmée (métabolisme)</term><term>Sirolimus (usage thérapeutique)</term><term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term><term>Tolérance à la transplantation (effets des médicaments et des substances chimiques)</term><term>Tolérance à la transplantation (immunologie)</term><term>Transduction du signal (effets des médicaments et des substances chimiques)</term><term>Transplantation rénale (méthodes)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Programmed Cell Death 1 Receptor</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Programmed Cell Death 1 Receptor</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Immunosuppressive Agents</term><term>Sirolimus</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Récepteur-1 de mort cellulaire programmée</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Signal Transduction</term><term>T-Lymphocytes, Cytotoxic</term><term>T-Lymphocytes, Regulatory</term><term>Transplantation Tolerance</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Lymphocytes T cytotoxiques</term><term>Lymphocytes T régulateurs</term><term>Tolérance à la transplantation</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Défaillance rénale chronique</term><term>Lymphocytes T cytotoxiques</term><term>Lymphocytes T régulateurs</term><term>Mélanome</term><term>Rejet du greffon</term><term>Tolérance à la transplantation</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Graft Rejection</term><term>Kidney Failure, Chronic</term><term>Melanoma</term><term>T-Lymphocytes, Cytotoxic</term><term>T-Lymphocytes, Regulatory</term><term>Transplantation Tolerance</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Kidney Transplantation</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Récepteur-1 de mort cellulaire programmée</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="méthodes" xml:lang="fr"><term>Transplantation rénale</term></keywords><keywords scheme="MESH" qualifier="therapy" xml:lang="en"><term>Kidney Failure, Chronic</term><term>Melanoma</term></keywords><keywords scheme="MESH" qualifier="thérapie" xml:lang="fr"><term>Défaillance rénale chronique</term><term>Mélanome</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Immunosuppresseurs</term><term>Sirolimus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Female</term><term>Humans</term><term>Middle Aged</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte d'âge moyen</term><term>Femelle</term><term>Humains</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B<sup>+</sup>, interferon (IFN)-γ<sup>+</sup> CD8<sup>+</sup> cytotoxic T cell and circulating regulatory T (T<sub>reg</sub>) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated T<sub>reg</sub> cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ<sup>+</sup> CD4<sup>+</sup> T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31624262</PMID><DateCompleted><Year>2020</Year><Month>01</Month><Day>24</Day></DateCompleted><DateRevised><Year>2020</Year><Month>10</Month><Day>16</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">2041-1723</ISSN><JournalIssue CitedMedium="Internet"><Volume>10</Volume><Issue>1</Issue><PubDate><Year>2019</Year><Month>10</Month><Day>17</Day></PubDate></JournalIssue><Title>Nature communications</Title><ISOAbbreviation>Nat Commun</ISOAbbreviation></Journal><ArticleTitle>Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation.</ArticleTitle><Pagination><MedlinePgn>4712</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1038/s41467-019-12628-1</ELocationID><Abstract><AbstractText>Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B<sup>+</sup>, interferon (IFN)-γ<sup>+</sup> CD8<sup>+</sup> cytotoxic T cell and circulating regulatory T (T<sub>reg</sub>) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated T<sub>reg</sub> cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ<sup>+</sup> CD4<sup>+</sup> T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Esfahani</LastName><ForeName>Khashayar</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Departments of Medicine and Oncology, Segal Cancer Center, Rossy Cancer Network, McGill University, Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>McGill Center for Translational Research in Cancer, McGill University, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Al-Aubodah</LastName><ForeName>Tho-Alfakar</ForeName><Initials>TA</Initials><AffiliationInfo><Affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Program in Infectious Diseases and Immunity in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Thebault</LastName><ForeName>Pamela</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>University of Montréal Hospital Research Centre, Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institut du cancer de Montréal, Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Clinical Immuno-Monitoring Core Facility, CRCHUM, Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Medicine, University of Montréal, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lapointe</LastName><ForeName>Réjean</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>University of Montréal Hospital Research Centre, Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institut du cancer de Montréal, Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Clinical Immuno-Monitoring Core Facility, CRCHUM, Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Medicine, University of Montréal, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hudson</LastName><ForeName>Marie</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Medicine, Division of Rheumatology, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Johnson</LastName><ForeName>Nathalie A</ForeName><Initials>NA</Initials><AffiliationInfo><Affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Medicine, Division of Hematology, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Baran</LastName><ForeName>Dana</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Medicine, Division of Nephrology, Faculty of Medicine, McGill University, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bhulaiga</LastName><ForeName>Najwa</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Departments of Medicine and Oncology, Segal Cancer Center, Rossy Cancer Network, McGill University, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Takano</LastName><ForeName>Tomoko</ForeName><Initials>T</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-9367-4124</Identifier><AffiliationInfo><Affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Medicine, Division of Nephrology, Faculty of Medicine, McGill University, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cailhier</LastName><ForeName>Jean-François</ForeName><Initials>JF</Initials><AffiliationInfo><Affiliation>University of Montréal Hospital Research Centre, Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institut du cancer de Montréal, Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Clinical Immuno-Monitoring Core Facility, CRCHUM, Montréal, Québec, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Medicine, University of Montréal, Montréal, Québec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Piccirillo</LastName><ForeName>Ciriaco A</ForeName><Initials>CA</Initials><AffiliationInfo><Affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada. ciriaco.piccirillo@mcgill.ca.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada. ciriaco.piccirillo@mcgill.ca.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Program in Infectious Diseases and Immunity in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada. ciriaco.piccirillo@mcgill.ca.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Miller</LastName><ForeName>Wilson H</ForeName><Initials>WH</Initials><AffiliationInfo><Affiliation>Departments of Medicine and Oncology, Segal Cancer Center, Rossy Cancer Network, McGill University, Montréal, Québec, Canada. wmiller@ldi.jgh.mcgill.ca.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada. wmiller@ldi.jgh.mcgill.ca.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>McGill Center for Translational Research in Cancer, McGill University, Montréal, Québec, Canada. wmiller@ldi.jgh.mcgill.ca.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>PJT-148821</GrantID><Agency>CIHR</Agency><Country>Canada</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D002363">Case Reports</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>10</Month><Day>17</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Nat Commun</MedlineTA><NlmUniqueID>101528555</NlmUniqueID><ISSNLinking>2041-1723</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007166">Immunosuppressive Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C105992">PDCD1 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D061026">Programmed Cell Death 1 Receptor</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="C546842">MTOR protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>W36ZG6FT64</RegistryNumber><NameOfSubstance UI="D020123">Sirolimus</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006084" MajorTopicYN="N">Graft Rejection</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007166" MajorTopicYN="N">Immunosuppressive Agents</DescriptorName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007676" MajorTopicYN="N">Kidney Failure, Chronic</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000628" MajorTopicYN="N">therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016030" MajorTopicYN="N">Kidney Transplantation</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008545" MajorTopicYN="N">Melanoma</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000628" MajorTopicYN="N">therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D061026" MajorTopicYN="N">Programmed Cell Death 1 Receptor</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020123" MajorTopicYN="N">Sirolimus</DescriptorName><QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013602" MajorTopicYN="N">T-Lymphocytes, Cytotoxic</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D050378" MajorTopicYN="N">T-Lymphocytes, Regulatory</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D023001" MajorTopicYN="N">Transplantation Tolerance</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year><Month>01</Month><Day>16</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>09</Month><Day>16</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>10</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>10</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>1</Month><Day>25</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">31624262</ArticleId><ArticleId IdType="doi">10.1038/s41467-019-12628-1</ArticleId><ArticleId IdType="pii">10.1038/s41467-019-12628-1</ArticleId><ArticleId IdType="pmc">PMC6797722</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Canada</li></country><region><li>Québec</li></region><settlement><li>Montréal</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Canada"><region name="Québec"><name sortKey="Esfahani, Khashayar" sort="Esfahani, Khashayar" uniqKey="Esfahani K" first="Khashayar" last="Esfahani">Khashayar Esfahani</name></region><name sortKey="Al Aubodah, Tho Alfakar" sort="Al Aubodah, Tho Alfakar" uniqKey="Al Aubodah T" first="Tho-Alfakar" last="Al-Aubodah">Tho-Alfakar Al-Aubodah</name><name sortKey="Al Aubodah, Tho Alfakar" sort="Al Aubodah, Tho Alfakar" uniqKey="Al Aubodah T" first="Tho-Alfakar" last="Al-Aubodah">Tho-Alfakar Al-Aubodah</name><name sortKey="Al Aubodah, Tho Alfakar" sort="Al Aubodah, Tho Alfakar" uniqKey="Al Aubodah T" first="Tho-Alfakar" last="Al-Aubodah">Tho-Alfakar Al-Aubodah</name><name sortKey="Baran, Dana" sort="Baran, Dana" uniqKey="Baran D" first="Dana" last="Baran">Dana Baran</name><name sortKey="Bhulaiga, Najwa" sort="Bhulaiga, Najwa" uniqKey="Bhulaiga N" first="Najwa" last="Bhulaiga">Najwa Bhulaiga</name><name sortKey="Cailhier, Jean Francois" sort="Cailhier, Jean Francois" uniqKey="Cailhier J" first="Jean-François" last="Cailhier">Jean-François Cailhier</name><name sortKey="Cailhier, Jean Francois" sort="Cailhier, Jean Francois" uniqKey="Cailhier J" first="Jean-François" last="Cailhier">Jean-François Cailhier</name><name sortKey="Cailhier, Jean Francois" sort="Cailhier, Jean Francois" uniqKey="Cailhier J" first="Jean-François" last="Cailhier">Jean-François Cailhier</name><name sortKey="Cailhier, Jean Francois" sort="Cailhier, Jean Francois" uniqKey="Cailhier J" first="Jean-François" last="Cailhier">Jean-François Cailhier</name><name sortKey="Esfahani, Khashayar" sort="Esfahani, Khashayar" uniqKey="Esfahani K" first="Khashayar" last="Esfahani">Khashayar Esfahani</name><name sortKey="Esfahani, Khashayar" sort="Esfahani, Khashayar" uniqKey="Esfahani K" first="Khashayar" last="Esfahani">Khashayar Esfahani</name><name sortKey="Hudson, Marie" sort="Hudson, Marie" uniqKey="Hudson M" first="Marie" last="Hudson">Marie Hudson</name><name sortKey="Hudson, Marie" sort="Hudson, Marie" uniqKey="Hudson M" first="Marie" last="Hudson">Marie Hudson</name><name sortKey="Johnson, Nathalie A" sort="Johnson, Nathalie A" uniqKey="Johnson N" first="Nathalie A" last="Johnson">Nathalie A. Johnson</name><name sortKey="Johnson, Nathalie A" sort="Johnson, Nathalie A" uniqKey="Johnson N" first="Nathalie A" last="Johnson">Nathalie A. Johnson</name><name sortKey="Lapointe, Rejean" sort="Lapointe, Rejean" uniqKey="Lapointe R" first="Réjean" last="Lapointe">Réjean Lapointe</name><name sortKey="Lapointe, Rejean" sort="Lapointe, Rejean" uniqKey="Lapointe R" first="Réjean" last="Lapointe">Réjean Lapointe</name><name sortKey="Lapointe, Rejean" sort="Lapointe, Rejean" uniqKey="Lapointe R" first="Réjean" last="Lapointe">Réjean Lapointe</name><name sortKey="Lapointe, Rejean" sort="Lapointe, Rejean" uniqKey="Lapointe R" first="Réjean" last="Lapointe">Réjean Lapointe</name><name sortKey="Miller, Wilson H" sort="Miller, Wilson H" uniqKey="Miller W" first="Wilson H" last="Miller">Wilson H. Miller</name><name sortKey="Miller, Wilson H" sort="Miller, Wilson H" uniqKey="Miller W" first="Wilson H" last="Miller">Wilson H. Miller</name><name sortKey="Miller, Wilson H" sort="Miller, Wilson H" uniqKey="Miller W" first="Wilson H" last="Miller">Wilson H. Miller</name><name sortKey="Piccirillo, Ciriaco A" sort="Piccirillo, Ciriaco A" uniqKey="Piccirillo C" first="Ciriaco A" last="Piccirillo">Ciriaco A. Piccirillo</name><name sortKey="Piccirillo, Ciriaco A" sort="Piccirillo, Ciriaco A" uniqKey="Piccirillo C" first="Ciriaco A" last="Piccirillo">Ciriaco A. Piccirillo</name><name sortKey="Piccirillo, Ciriaco A" sort="Piccirillo, Ciriaco A" uniqKey="Piccirillo C" first="Ciriaco A" last="Piccirillo">Ciriaco A. Piccirillo</name><name sortKey="Takano, Tomoko" sort="Takano, Tomoko" uniqKey="Takano T" first="Tomoko" last="Takano">Tomoko Takano</name><name sortKey="Takano, Tomoko" sort="Takano, Tomoko" uniqKey="Takano T" first="Tomoko" last="Takano">Tomoko Takano</name><name sortKey="Thebault, Pamela" sort="Thebault, Pamela" uniqKey="Thebault P" first="Pamela" last="Thebault">Pamela Thebault</name><name sortKey="Thebault, Pamela" sort="Thebault, Pamela" uniqKey="Thebault P" first="Pamela" last="Thebault">Pamela Thebault</name><name sortKey="Thebault, Pamela" sort="Thebault, Pamela" uniqKey="Thebault P" first="Pamela" last="Thebault">Pamela Thebault</name><name sortKey="Thebault, Pamela" sort="Thebault, Pamela" uniqKey="Thebault P" first="Pamela" last="Thebault">Pamela Thebault</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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