Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease.
Identifieur interne : 000325 ( Main/Exploration ); précédent : 000324; suivant : 000326Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease.
Auteurs : David C. Fajgenbaum ; Ruth-Anne Langan ; Alberto Sada Japp [États-Unis] ; Helen L. Partridge ; Sheila K. Pierson ; Amrit Singh [Canada] ; Daniel J. Arenas ; Jason R. Ruth [États-Unis] ; Christopher S. Nabel [États-Unis] ; Katie Stone [États-Unis] ; Mariko Okumura [États-Unis] ; Anthony Schwarer [Australie] ; Fábio Freire Jose ; Nelson Hamerschlak [Brésil] ; Gerald B. Wertheim [États-Unis] ; Michael B. Jordan [États-Unis] ; Adam D. Cohen [États-Unis] ; Vera Krymskaya ; Arthur Rubenstein ; Michael R. Betts [États-Unis] ; Taku Kambayashi [États-Unis] ; Frits Van Rhee [États-Unis] ; Thomas S. Uldrick [États-Unis]Source :
- The Journal of clinical investigation [ 1558-8238 ] ; 2019.
Descripteurs français
- KwdFr :
- Adolescent (MeSH), Adulte (MeSH), Adulte d'âge moyen (MeSH), Femelle (MeSH), Humains (MeSH), Hyperplasie lymphoïde angiofolliculaire (anatomopathologie), Hyperplasie lymphoïde angiofolliculaire (métabolisme), Hyperplasie lymphoïde angiofolliculaire (traitement médicamenteux), Interleukine-6 (métabolisme), Mâle (MeSH), Phosphatidylinositol 3-kinases (métabolisme), Protéines proto-oncogènes c-akt (métabolisme), Protéomique (MeSH), Sirolimus (pharmacologie), Sérine-thréonine kinases TOR (métabolisme), Transduction du signal (effets des médicaments et des substances chimiques).
- MESH :
- anatomopathologie : Hyperplasie lymphoïde angiofolliculaire.
- effets des médicaments et des substances chimiques : Transduction du signal.
- métabolisme : Hyperplasie lymphoïde angiofolliculaire, Interleukine-6, Phosphatidylinositol 3-kinases, Protéines proto-oncogènes c-akt, Sérine-thréonine kinases TOR.
- pharmacologie : Sirolimus.
- traitement médicamenteux : Hyperplasie lymphoïde angiofolliculaire.
- Adolescent, Adulte, Adulte d'âge moyen, Femelle, Humains, Mâle, Protéomique.
English descriptors
- KwdEn :
- Adolescent (MeSH), Adult (MeSH), Castleman Disease (drug therapy), Castleman Disease (metabolism), Castleman Disease (pathology), Female (MeSH), Humans (MeSH), Interleukin-6 (metabolism), Male (MeSH), Middle Aged (MeSH), Phosphatidylinositol 3-Kinases (metabolism), Proteomics (MeSH), Proto-Oncogene Proteins c-akt (metabolism), Signal Transduction (drug effects), Sirolimus (pharmacology), TOR Serine-Threonine Kinases (metabolism).
- MESH :
- chemical , metabolism : Interleukin-6, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- drug effects : Signal Transduction.
- drug therapy : Castleman Disease.
- metabolism : Castleman Disease, Phosphatidylinositol 3-Kinases.
- pathology : Castleman Disease.
- chemical , pharmacology : Sirolimus.
- Adolescent, Adult, Female, Humans, Male, Middle Aged, Proteomics.
Abstract
BACKGROUND
Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype.
METHODS
We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus.
RESULTS
Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months.
CONCLUSION
This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904).
FUNDING
Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.
DOI: 10.1172/JCI126091
PubMed: 31408438
PubMed Central: PMC6763254
Affiliations:
- Australie, Brésil, Canada, États-Unis
- Arkansas, Massachusetts, Ohio, Pennsylvanie, Washington (État), État de São Paulo
- São Paulo
Links toward previous steps (curation, corpus...)
Le document en format XML
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Wertheim</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Jordan, Michael B" sort="Jordan, Michael B" uniqKey="Jordan M" first="Michael B" last="Jordan">Michael B. Jordan</name><affiliation wicri:level="2"><nlm:affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Cohen, Adam D" sort="Cohen, Adam D" uniqKey="Cohen A" first="Adam D" last="Cohen">Adam D. Cohen</name><affiliation wicri:level="2"><nlm:affiliation>Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Krymskaya, Vera" sort="Krymskaya, Vera" uniqKey="Krymskaya V" first="Vera" last="Krymskaya">Vera Krymskaya</name><affiliation><nlm:affiliation>Department of Medicine and.</nlm:affiliation><wicri:noCountry code="no comma">Department of Medicine and.</wicri:noCountry></affiliation></author><author><name sortKey="Rubenstein, Arthur" sort="Rubenstein, Arthur" uniqKey="Rubenstein A" first="Arthur" last="Rubenstein">Arthur Rubenstein</name><affiliation><nlm:affiliation>Department of Medicine and.</nlm:affiliation><wicri:noCountry code="no comma">Department of Medicine and.</wicri:noCountry></affiliation></author><author><name sortKey="Betts, Michael R" sort="Betts, Michael R" uniqKey="Betts M" first="Michael R" last="Betts">Michael R. Betts</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Kambayashi, Taku" sort="Kambayashi, Taku" uniqKey="Kambayashi T" first="Taku" last="Kambayashi">Taku Kambayashi</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Van Rhee, Frits" sort="Van Rhee, Frits" uniqKey="Van Rhee F" first="Frits" last="Van Rhee">Frits Van Rhee</name><affiliation wicri:level="2"><nlm:affiliation>Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas</wicri:regionArea><placeName><region type="state">Arkansas</region></placeName></affiliation></author><author><name sortKey="Uldrick, Thomas S" sort="Uldrick, Thomas S" uniqKey="Uldrick T" first="Thomas S" last="Uldrick">Thomas S. Uldrick</name><affiliation wicri:level="2"><nlm:affiliation>Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:31408438</idno><idno type="pmid">31408438</idno><idno type="doi">10.1172/JCI126091</idno><idno type="pmc">PMC6763254</idno><idno type="wicri:Area/Main/Corpus">000210</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000210</idno><idno type="wicri:Area/Main/Curation">000210</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000210</idno><idno type="wicri:Area/Main/Exploration">000210</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease.</title><author><name sortKey="Fajgenbaum, David C" sort="Fajgenbaum, David C" uniqKey="Fajgenbaum D" first="David C" last="Fajgenbaum">David C. Fajgenbaum</name><affiliation><nlm:affiliation>Department of Medicine and.</nlm:affiliation><wicri:noCountry code="no comma">Department of Medicine and.</wicri:noCountry></affiliation></author><author><name sortKey="Langan, Ruth Anne" sort="Langan, Ruth Anne" uniqKey="Langan R" first="Ruth-Anne" last="Langan">Ruth-Anne Langan</name><affiliation><nlm:affiliation>Department of Medicine and.</nlm:affiliation><wicri:noCountry code="no comma">Department of Medicine and.</wicri:noCountry></affiliation></author><author><name sortKey="Japp, Alberto Sada" sort="Japp, Alberto Sada" uniqKey="Japp A" first="Alberto Sada" last="Japp">Alberto Sada Japp</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Partridge, Helen L" sort="Partridge, Helen L" uniqKey="Partridge H" first="Helen L" last="Partridge">Helen L. Partridge</name><affiliation><nlm:affiliation>Department of Medicine and.</nlm:affiliation><wicri:noCountry code="no comma">Department of Medicine and.</wicri:noCountry></affiliation></author><author><name sortKey="Pierson, Sheila K" sort="Pierson, Sheila K" uniqKey="Pierson S" first="Sheila K" last="Pierson">Sheila K. Pierson</name><affiliation><nlm:affiliation>Department of Medicine and.</nlm:affiliation><wicri:noCountry code="no comma">Department of Medicine and.</wicri:noCountry></affiliation></author><author><name sortKey="Singh, Amrit" sort="Singh, Amrit" uniqKey="Singh A" first="Amrit" last="Singh">Amrit Singh</name><affiliation wicri:level="1"><nlm:affiliation>Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Arenas, Daniel J" sort="Arenas, Daniel J" uniqKey="Arenas D" first="Daniel J" last="Arenas">Daniel J. Arenas</name><affiliation><nlm:affiliation>Department of Medicine and.</nlm:affiliation><wicri:noCountry code="no comma">Department of Medicine and.</wicri:noCountry></affiliation></author><author><name sortKey="Ruth, Jason R" sort="Ruth, Jason R" uniqKey="Ruth J" first="Jason R" last="Ruth">Jason R. Ruth</name><affiliation wicri:level="2"><nlm:affiliation>Castleman Disease Collaborative Network, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Castleman Disease Collaborative Network, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Nabel, Christopher S" sort="Nabel, Christopher S" uniqKey="Nabel C" first="Christopher S" last="Nabel">Christopher S. Nabel</name><affiliation wicri:level="2"><nlm:affiliation>Dana Farber Cancer Research Institute, Boston, Massachusetts, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dana Farber Cancer Research Institute, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Stone, Katie" sort="Stone, Katie" uniqKey="Stone K" first="Katie" last="Stone">Katie Stone</name><affiliation wicri:level="2"><nlm:affiliation>Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas</wicri:regionArea><placeName><region type="state">Arkansas</region></placeName></affiliation></author><author><name sortKey="Okumura, Mariko" sort="Okumura, Mariko" uniqKey="Okumura M" first="Mariko" last="Okumura">Mariko Okumura</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Schwarer, Anthony" sort="Schwarer, Anthony" uniqKey="Schwarer A" first="Anthony" last="Schwarer">Anthony Schwarer</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology and Oncology, Eastern Health Monash University Clinical School, Melbourne, Victoria, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology and Oncology, Eastern Health Monash University Clinical School, Melbourne, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Jose, Fabio Freire" sort="Jose, Fabio Freire" uniqKey="Jose F" first="Fábio Freire" last="Jose">Fábio Freire Jose</name><affiliation><nlm:affiliation>Department of Rheumatology and.</nlm:affiliation><wicri:noCountry code="no comma">Department of Rheumatology and.</wicri:noCountry></affiliation></author><author><name sortKey="Hamerschlak, Nelson" sort="Hamerschlak, Nelson" uniqKey="Hamerschlak N" first="Nelson" last="Hamerschlak">Nelson Hamerschlak</name><affiliation wicri:level="3"><nlm:affiliation>Department of Hematology, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Department of Hematology, Hospital Israelita Albert Einstein, Sao Paulo</wicri:regionArea><placeName><settlement type="city">São Paulo</settlement><region type="state">État de São Paulo</region></placeName></affiliation></author><author><name sortKey="Wertheim, Gerald B" sort="Wertheim, Gerald B" uniqKey="Wertheim G" first="Gerald B" last="Wertheim">Gerald B. Wertheim</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Jordan, Michael B" sort="Jordan, Michael B" uniqKey="Jordan M" first="Michael B" last="Jordan">Michael B. Jordan</name><affiliation wicri:level="2"><nlm:affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Cohen, Adam D" sort="Cohen, Adam D" uniqKey="Cohen A" first="Adam D" last="Cohen">Adam D. Cohen</name><affiliation wicri:level="2"><nlm:affiliation>Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Krymskaya, Vera" sort="Krymskaya, Vera" uniqKey="Krymskaya V" first="Vera" last="Krymskaya">Vera Krymskaya</name><affiliation><nlm:affiliation>Department of Medicine and.</nlm:affiliation><wicri:noCountry code="no comma">Department of Medicine and.</wicri:noCountry></affiliation></author><author><name sortKey="Rubenstein, Arthur" sort="Rubenstein, Arthur" uniqKey="Rubenstein A" first="Arthur" last="Rubenstein">Arthur Rubenstein</name><affiliation><nlm:affiliation>Department of Medicine and.</nlm:affiliation><wicri:noCountry code="no comma">Department of Medicine and.</wicri:noCountry></affiliation></author><author><name sortKey="Betts, Michael R" sort="Betts, Michael R" uniqKey="Betts M" first="Michael R" last="Betts">Michael R. Betts</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Kambayashi, Taku" sort="Kambayashi, Taku" uniqKey="Kambayashi T" first="Taku" last="Kambayashi">Taku Kambayashi</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Van Rhee, Frits" sort="Van Rhee, Frits" uniqKey="Van Rhee F" first="Frits" last="Van Rhee">Frits Van Rhee</name><affiliation wicri:level="2"><nlm:affiliation>Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas</wicri:regionArea><placeName><region type="state">Arkansas</region></placeName></affiliation></author><author><name sortKey="Uldrick, Thomas S" sort="Uldrick, Thomas S" uniqKey="Uldrick T" first="Thomas S" last="Uldrick">Thomas S. Uldrick</name><affiliation wicri:level="2"><nlm:affiliation>Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of clinical investigation</title><idno type="eISSN">1558-8238</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adolescent (MeSH)</term><term>Adult (MeSH)</term><term>Castleman Disease (drug therapy)</term><term>Castleman Disease (metabolism)</term><term>Castleman Disease (pathology)</term><term>Female (MeSH)</term><term>Humans (MeSH)</term><term>Interleukin-6 (metabolism)</term><term>Male (MeSH)</term><term>Middle Aged (MeSH)</term><term>Phosphatidylinositol 3-Kinases (metabolism)</term><term>Proteomics (MeSH)</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>Signal Transduction (drug effects)</term><term>Sirolimus (pharmacology)</term><term>TOR Serine-Threonine Kinases (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adolescent (MeSH)</term><term>Adulte (MeSH)</term><term>Adulte d'âge moyen (MeSH)</term><term>Femelle (MeSH)</term><term>Humains (MeSH)</term><term>Hyperplasie lymphoïde angiofolliculaire (anatomopathologie)</term><term>Hyperplasie lymphoïde angiofolliculaire (métabolisme)</term><term>Hyperplasie lymphoïde angiofolliculaire (traitement médicamenteux)</term><term>Interleukine-6 (métabolisme)</term><term>Mâle (MeSH)</term><term>Phosphatidylinositol 3-kinases (métabolisme)</term><term>Protéines proto-oncogènes c-akt (métabolisme)</term><term>Protéomique (MeSH)</term><term>Sirolimus (pharmacologie)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term><term>Transduction du signal (effets des médicaments et des substances chimiques)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Interleukin-6</term><term>Proto-Oncogene Proteins c-akt</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Hyperplasie lymphoïde angiofolliculaire</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Castleman Disease</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Castleman Disease</term><term>Phosphatidylinositol 3-Kinases</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Hyperplasie lymphoïde angiofolliculaire</term><term>Interleukine-6</term><term>Phosphatidylinositol 3-kinases</term><term>Protéines proto-oncogènes c-akt</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Castleman Disease</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Sirolimus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Sirolimus</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Hyperplasie lymphoïde angiofolliculaire</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Female</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Proteomics</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adolescent</term><term>Adulte</term><term>Adulte d'âge moyen</term><term>Femelle</term><term>Humains</term><term>Mâle</term><term>Protéomique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND</b></p><p>Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype.</p></div><div type="abstract" xml:lang="en"><p><b>METHODS</b></p><p>We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus.</p></div><div type="abstract" xml:lang="en"><p><b>RESULTS</b></p><p>Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months.</p></div><div type="abstract" xml:lang="en"><p><b>CONCLUSION</b></p><p>This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904).</p></div><div type="abstract" xml:lang="en"><p><b>FUNDING</b></p><p>Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.</p></div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31408438</PMID><DateCompleted><Year>2020</Year><Month>06</Month><Day>15</Day></DateCompleted><DateRevised><Year>2020</Year><Month>06</Month><Day>15</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1558-8238</ISSN><JournalIssue CitedMedium="Internet"><Volume>129</Volume><Issue>10</Issue><PubDate><Year>2019</Year><Month>08</Month><Day>13</Day></PubDate></JournalIssue><Title>The Journal of clinical investigation</Title><ISOAbbreviation>J Clin Invest</ISOAbbreviation></Journal><ArticleTitle>Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease.</ArticleTitle><Pagination><MedlinePgn>4451-4463</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1172/JCI126091</ELocationID><ELocationID EIdType="pii" ValidYN="Y">126091</ELocationID><Abstract><AbstractText Label="BACKGROUND">Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype.</AbstractText><AbstractText Label="METHODS">We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus.</AbstractText><AbstractText Label="RESULTS">Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months.</AbstractText><AbstractText Label="CONCLUSION">This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904).</AbstractText><AbstractText Label="FUNDING">Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Fajgenbaum</LastName><ForeName>David C</ForeName><Initials>DC</Initials><AffiliationInfo><Affiliation>Department of Medicine and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Langan</LastName><ForeName>Ruth-Anne</ForeName><Initials>RA</Initials><AffiliationInfo><Affiliation>Department of Medicine and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Japp</LastName><ForeName>Alberto Sada</ForeName><Initials>AS</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Partridge</LastName><ForeName>Helen L</ForeName><Initials>HL</Initials><AffiliationInfo><Affiliation>Department of Medicine and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pierson</LastName><ForeName>Sheila K</ForeName><Initials>SK</Initials><AffiliationInfo><Affiliation>Department of Medicine and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Singh</LastName><ForeName>Amrit</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Arenas</LastName><ForeName>Daniel J</ForeName><Initials>DJ</Initials><AffiliationInfo><Affiliation>Department of Medicine and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ruth</LastName><ForeName>Jason R</ForeName><Initials>JR</Initials><AffiliationInfo><Affiliation>Castleman Disease Collaborative Network, Philadelphia, Pennsylvania, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nabel</LastName><ForeName>Christopher S</ForeName><Initials>CS</Initials><AffiliationInfo><Affiliation>Dana Farber Cancer Research Institute, Boston, Massachusetts, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stone</LastName><ForeName>Katie</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Okumura</LastName><ForeName>Mariko</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schwarer</LastName><ForeName>Anthony</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Haematology and Oncology, Eastern Health Monash University Clinical School, Melbourne, Victoria, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jose</LastName><ForeName>Fábio Freire</ForeName><Initials>FF</Initials><AffiliationInfo><Affiliation>Department of Rheumatology and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hamerschlak</LastName><ForeName>Nelson</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Hematology, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wertheim</LastName><ForeName>Gerald B</ForeName><Initials>GB</Initials><AffiliationInfo><Affiliation>Department of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jordan</LastName><ForeName>Michael B</ForeName><Initials>MB</Initials><AffiliationInfo><Affiliation>Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cohen</LastName><ForeName>Adam D</ForeName><Initials>AD</Initials><AffiliationInfo><Affiliation>Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Krymskaya</LastName><ForeName>Vera</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Department of Medicine and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rubenstein</LastName><ForeName>Arthur</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Medicine and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Betts</LastName><ForeName>Michael R</ForeName><Initials>MR</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kambayashi</LastName><ForeName>Taku</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Rhee</LastName><ForeName>Frits</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Uldrick</LastName><ForeName>Thomas S</ForeName><Initials>TS</Initials><AffiliationInfo><Affiliation>Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><DataBankList CompleteYN="Y"><DataBank><DataBankName>ClinicalTrials.gov</DataBankName><AccessionNumberList><AccessionNumber>NCT03933904</AccessionNumber></AccessionNumberList></DataBank></DataBankList><GrantList CompleteYN="Y"><Grant><GrantID>R01 HL141408</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</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>08</Month><Day>13</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Clin Invest</MedlineTA><NlmUniqueID>7802877</NlmUniqueID><ISSNLinking>0021-9738</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C508600">IL6 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D015850">Interleukin-6</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>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D051057">Proto-Oncogene Proteins c-akt</NameOfSubstance></Chemical><Chemical><RegistryNumber>W36ZG6FT64</RegistryNumber><NameOfSubstance UI="D020123">Sirolimus</NameOfSubstance></Chemical></ChemicalList><SupplMeshList><SupplMeshName Type="Disease" UI="C537372">Multi-centric Castleman's Disease</SupplMeshName></SupplMeshList><CitationSubset>AIM</CitationSubset><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="CommentIn"><RefSource>J Clin Invest. 2019 Oct 1;129(10):4086-4088</RefSource><PMID Version="1">31524635</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D000293" MajorTopicYN="N">Adolescent</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005871" MajorTopicYN="Y">Castleman Disease</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015850" MajorTopicYN="N">Interleukin-6</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019869" MajorTopicYN="N">Phosphatidylinositol 3-Kinases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D040901" MajorTopicYN="N">Proteomics</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051057" MajorTopicYN="N">Proto-Oncogene Proteins c-akt</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">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="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">Cytokines</Keyword><Keyword MajorTopicYN="Y">Hematology</Keyword><Keyword MajorTopicYN="Y">Immunology</Keyword><Keyword MajorTopicYN="Y">Lymphomas</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>8</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>8</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>6</Month><Day>17</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">31408438</ArticleId><ArticleId IdType="pii">126091</ArticleId><ArticleId IdType="doi">10.1172/JCI126091</ArticleId><ArticleId IdType="pmc">PMC6763254</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Br J Haematol. 2009 Apr;145(1):101-6</Citation><ArticleIdList><ArticleId IdType="pubmed">19208097</ArticleId></ArticleIdList></Reference><Reference><Citation>Clin Cancer Res. 2015 Oct 1;21(19):4294-304</Citation><ArticleIdList><ArticleId IdType="pubmed">26124203</ArticleId></ArticleIdList></Reference><Reference><Citation>Blood. 2002 Jun 15;99(12):4517-24</Citation><ArticleIdList><ArticleId IdType="pubmed">12036883</ArticleId></ArticleIdList></Reference><Reference><Citation>Immunology. 2003 Nov;110(3):304-12</Citation><ArticleIdList><ArticleId IdType="pubmed">14632657</ArticleId></ArticleIdList></Reference><Reference><Citation>N Engl J Med. 1994 Mar 3;330(9):602-5</Citation><ArticleIdList><ArticleId IdType="pubmed">8302342</ArticleId></ArticleIdList></Reference><Reference><Citation>Am J Pathol. 1998 Aug;153(2):587-98</Citation><ArticleIdList><ArticleId IdType="pubmed">9708818</ArticleId></ArticleIdList></Reference><Reference><Citation>J Clin Neurosci. 2014 Dec;21(12):2135-2139</Citation><ArticleIdList><ArticleId IdType="pubmed">25082408</ArticleId></ArticleIdList></Reference><Reference><Citation>JAMA Dermatol. 2013 Feb;149(2):204-8</Citation><ArticleIdList><ArticleId IdType="pubmed">23426475</ArticleId></ArticleIdList></Reference><Reference><Citation>Blood. 1995 Aug 15;86(4):1276-80</Citation><ArticleIdList><ArticleId IdType="pubmed">7632932</ArticleId></ArticleIdList></Reference><Reference><Citation>Blood. 2017 Mar 23;129(12):1646-1657</Citation><ArticleIdList><ArticleId IdType="pubmed">28087540</ArticleId></ArticleIdList></Reference><Reference><Citation>Leuk Lymphoma. 2015 May;56(5):1252-60</Citation><ArticleIdList><ArticleId IdType="pubmed">25120049</ArticleId></ArticleIdList></Reference><Reference><Citation>Transplant Proc. 2016 Jan-Feb;48(1):3-9</Citation><ArticleIdList><ArticleId IdType="pubmed">26915834</ArticleId></ArticleIdList></Reference><Reference><Citation>Front Immunol. 2015 Jan 21;5:674</Citation><ArticleIdList><ArticleId IdType="pubmed">25653650</ArticleId></ArticleIdList></Reference><Reference><Citation>N Engl J Med. 2011 Apr 28;364(17):1595-606</Citation><ArticleIdList><ArticleId IdType="pubmed">21410393</ArticleId></ArticleIdList></Reference><Reference><Citation>Biochem J. 2012 Jan 1;441(1):1-21</Citation><ArticleIdList><ArticleId IdType="pubmed">22168436</ArticleId></ArticleIdList></Reference><Reference><Citation>Lancet. 2018 Mar 24;391(10126):1186-1196</Citation><ArticleIdList><ArticleId IdType="pubmed">29551338</ArticleId></ArticleIdList></Reference><Reference><Citation>Bioinformatics. 2014 Feb 15;30(4):523-30</Citation><ArticleIdList><ArticleId IdType="pubmed">24336805</ArticleId></ArticleIdList></Reference><Reference><Citation>Blood. 1989 Sep;74(4):1360-7</Citation><ArticleIdList><ArticleId IdType="pubmed">2788466</ArticleId></ArticleIdList></Reference><Reference><Citation>Blood. 2005 Oct 15;106(8):2627-32</Citation><ArticleIdList><ArticleId IdType="pubmed">15998837</ArticleId></ArticleIdList></Reference><Reference><Citation>Nat Med. 2002 Feb;8(2):128-35</Citation><ArticleIdList><ArticleId IdType="pubmed">11821896</ArticleId></ArticleIdList></Reference><Reference><Citation>Am J Pathol. 1998 Nov;153(5):1541-50</Citation><ArticleIdList><ArticleId IdType="pubmed">9811346</ArticleId></ArticleIdList></Reference><Reference><Citation>Blood. 2016 Jul 14;128(2):227-38</Citation><ArticleIdList><ArticleId IdType="pubmed">27099149</ArticleId></ArticleIdList></Reference><Reference><Citation>Cell. 2017 Aug 10;170(4):605-635</Citation><ArticleIdList><ArticleId IdType="pubmed">28802037</ArticleId></ArticleIdList></Reference><Reference><Citation>Am J Hematol. 2012 Nov;87(11):997-1002</Citation><ArticleIdList><ArticleId IdType="pubmed">22791417</ArticleId></ArticleIdList></Reference><Reference><Citation>PLoS One. 2010 Dec 07;5(12):e15004</Citation><ArticleIdList><ArticleId IdType="pubmed">21165148</ArticleId></ArticleIdList></Reference><Reference><Citation>Cell. 2017 Mar 9;168(6):960-976</Citation><ArticleIdList><ArticleId IdType="pubmed">28283069</ArticleId></ArticleIdList></Reference><Reference><Citation>PLoS One. 2012;7(8):e42913</Citation><ArticleIdList><ArticleId IdType="pubmed">22900063</ArticleId></ArticleIdList></Reference><Reference><Citation>J Clin Oncol. 2007 Feb 10;25(5):579-86</Citation><ArticleIdList><ArticleId IdType="pubmed">17242396</ArticleId></ArticleIdList></Reference><Reference><Citation>Ann N Y Acad Sci. 2015 Jun;1346(1):33-44</Citation><ArticleIdList><ArticleId IdType="pubmed">25907074</ArticleId></ArticleIdList></Reference><Reference><Citation>J Clin Exp Hematop. 2013;53(1):57-61</Citation><ArticleIdList><ArticleId IdType="pubmed">23801135</ArticleId></ArticleIdList></Reference><Reference><Citation>Acta Virol. 2003;47(2):121-4</Citation><ArticleIdList><ArticleId IdType="pubmed">14524479</ArticleId></ArticleIdList></Reference><Reference><Citation>Microcirculation. 2010 Feb;17(2):128-36</Citation><ArticleIdList><ArticleId IdType="pubmed">20163539</ArticleId></ArticleIdList></Reference><Reference><Citation>Ann N Y Acad Sci. 1993 Jun 23;685:58-67</Citation><ArticleIdList><ArticleId IdType="pubmed">8363266</ArticleId></ArticleIdList></Reference><Reference><Citation>Lancet Haematol. 2016 Apr;3(4):e163-75</Citation><ArticleIdList><ArticleId IdType="pubmed">27063975</ArticleId></ArticleIdList></Reference><Reference><Citation>Am J Hematol. 2018 Jul;93(7):902-912</Citation><ArticleIdList><ArticleId IdType="pubmed">29675946</ArticleId></ArticleIdList></Reference><Reference><Citation>Blood. 2018 Nov 15;132(20):2115-2124</Citation><ArticleIdList><ArticleId IdType="pubmed">30181172</ArticleId></ArticleIdList></Reference><Reference><Citation>J Immunol. 2015 Nov 15;195(10):4615-22</Citation><ArticleIdList><ArticleId IdType="pubmed">26453749</ArticleId></ArticleIdList></Reference><Reference><Citation>Mol Cell Biol. 2002 Oct;22(20):7004-14</Citation><ArticleIdList><ArticleId IdType="pubmed">12242281</ArticleId></ArticleIdList></Reference><Reference><Citation>Cytokine. 2013 May;62(2):232-43</Citation><ArticleIdList><ArticleId IdType="pubmed">23538292</ArticleId></ArticleIdList></Reference><Reference><Citation>Lancet Oncol. 2014 Aug;15(9):966-74</Citation><ArticleIdList><ArticleId IdType="pubmed">25042199</ArticleId></ArticleIdList></Reference><Reference><Citation>J Clin Oncol. 2010 Aug 10;28(23):3701-8</Citation><ArticleIdList><ArticleId IdType="pubmed">20625121</ArticleId></ArticleIdList></Reference><Reference><Citation>PLoS One. 2019 Jun 26;14(6):e0218660</Citation><ArticleIdList><ArticleId IdType="pubmed">31242229</ArticleId></ArticleIdList></Reference><Reference><Citation>Sci Rep. 2017 Feb 13;7:42316</Citation><ArticleIdList><ArticleId IdType="pubmed">28205564</ArticleId></ArticleIdList></Reference><Reference><Citation>Dig Dis Sci. 2009 Oct;54(10):2128-36</Citation><ArticleIdList><ArticleId IdType="pubmed">19052864</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></pubmed><affiliations><list><country><li>Australie</li><li>Brésil</li><li>Canada</li><li>États-Unis</li></country><region><li>Arkansas</li><li>Massachusetts</li><li>Ohio</li><li>Pennsylvanie</li><li>Washington (État)</li><li>État de São Paulo</li></region><settlement><li>São Paulo</li></settlement></list><tree><noCountry><name sortKey="Arenas, Daniel J" sort="Arenas, Daniel J" uniqKey="Arenas D" first="Daniel J" last="Arenas">Daniel J. Arenas</name><name sortKey="Fajgenbaum, David C" sort="Fajgenbaum, David C" uniqKey="Fajgenbaum D" first="David C" last="Fajgenbaum">David C. Fajgenbaum</name><name sortKey="Jose, Fabio Freire" sort="Jose, Fabio Freire" uniqKey="Jose F" first="Fábio Freire" last="Jose">Fábio Freire Jose</name><name sortKey="Krymskaya, Vera" sort="Krymskaya, Vera" uniqKey="Krymskaya V" first="Vera" last="Krymskaya">Vera Krymskaya</name><name sortKey="Langan, Ruth Anne" sort="Langan, Ruth Anne" uniqKey="Langan R" first="Ruth-Anne" last="Langan">Ruth-Anne Langan</name><name sortKey="Partridge, Helen L" sort="Partridge, Helen L" uniqKey="Partridge H" first="Helen L" last="Partridge">Helen L. Partridge</name><name sortKey="Pierson, Sheila K" sort="Pierson, Sheila K" uniqKey="Pierson S" first="Sheila K" last="Pierson">Sheila K. Pierson</name><name sortKey="Rubenstein, Arthur" sort="Rubenstein, Arthur" uniqKey="Rubenstein A" first="Arthur" last="Rubenstein">Arthur Rubenstein</name></noCountry><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Japp, Alberto Sada" sort="Japp, Alberto Sada" uniqKey="Japp A" first="Alberto Sada" last="Japp">Alberto Sada Japp</name></region><name sortKey="Betts, Michael R" sort="Betts, Michael R" uniqKey="Betts M" first="Michael R" last="Betts">Michael R. Betts</name><name sortKey="Cohen, Adam D" sort="Cohen, Adam D" uniqKey="Cohen A" first="Adam D" last="Cohen">Adam D. Cohen</name><name sortKey="Jordan, Michael B" sort="Jordan, Michael B" uniqKey="Jordan M" first="Michael B" last="Jordan">Michael B. Jordan</name><name sortKey="Kambayashi, Taku" sort="Kambayashi, Taku" uniqKey="Kambayashi T" first="Taku" last="Kambayashi">Taku Kambayashi</name><name sortKey="Nabel, Christopher S" sort="Nabel, Christopher S" uniqKey="Nabel C" first="Christopher S" last="Nabel">Christopher S. Nabel</name><name sortKey="Okumura, Mariko" sort="Okumura, Mariko" uniqKey="Okumura M" first="Mariko" last="Okumura">Mariko Okumura</name><name sortKey="Ruth, Jason R" sort="Ruth, Jason R" uniqKey="Ruth J" first="Jason R" last="Ruth">Jason R. Ruth</name><name sortKey="Stone, Katie" sort="Stone, Katie" uniqKey="Stone K" first="Katie" last="Stone">Katie Stone</name><name sortKey="Uldrick, Thomas S" sort="Uldrick, Thomas S" uniqKey="Uldrick T" first="Thomas S" last="Uldrick">Thomas S. Uldrick</name><name sortKey="Van Rhee, Frits" sort="Van Rhee, Frits" uniqKey="Van Rhee F" first="Frits" last="Van Rhee">Frits Van Rhee</name><name sortKey="Wertheim, Gerald B" sort="Wertheim, Gerald B" uniqKey="Wertheim G" first="Gerald B" last="Wertheim">Gerald B. Wertheim</name></country><country name="Canada"><noRegion><name sortKey="Singh, Amrit" sort="Singh, Amrit" uniqKey="Singh A" first="Amrit" last="Singh">Amrit Singh</name></noRegion></country><country name="Australie"><noRegion><name sortKey="Schwarer, Anthony" sort="Schwarer, Anthony" uniqKey="Schwarer A" first="Anthony" last="Schwarer">Anthony Schwarer</name></noRegion></country><country name="Brésil"><region name="État de São Paulo"><name sortKey="Hamerschlak, Nelson" sort="Hamerschlak, Nelson" uniqKey="Hamerschlak N" first="Nelson" last="Hamerschlak">Nelson Hamerschlak</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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