Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K—mTOR pathway in pancreatic adenocarcinoma
Identifieur interne : 000665 ( Istex/Corpus ); précédent : 000664; suivant : 000666Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K—mTOR pathway in pancreatic adenocarcinoma
Auteurs : Olga K. Mirzoeva ; Byron Hann ; Yun K. Hom ; Jayanta Debnath ; Dana Aftab ; Kevan Shokat ; W. Michael KornSource :
- Journal of Molecular Medicine [ 0946-2716 ] ; 2011-09-01.
English descriptors
- KwdEn :
Abstract
Abstract: Targeting of pathways downstream of RAS represents a promising therapeutic strategy for pancreatic cancer, the fourth leading cause of cancer-related death in the USA, since activation of the Raf-MEK-ERK and PI3K-AKT pathways is found frequently in this disease and is associated with poor prognosis. Taking advantage of a panel of human PDAC cell lines and specific inhibitors of PI3K and/or mTOR, we systematically address the question whether dual-targeted inhibition of the PI3K and mTOR pathways offers advantages over single-targeted inhibition of PI3K in PDAC. We observe greater overall susceptibility of cell lines to dual inhibition compared to targeting PI3K alone. However, we find that dual inhibition of PI3K and mTOR induces autophagy to a greater extent than inhibition of each target alone. In agreement with this, we show that combined administration of PI3K/mTOR and autophagy inhibitors results in increased anti-tumor activity in vitro and in vivo in models of pancreatic adenocarcinoma. XL765, a PI3K/mTOR inhibitor used in our in vivo studies, is currently undergoing clinical evaluation in a variety of cancer types, while the autophagy inhibitor chloroquine is a widely used anti-malaria compound. Thus, our studies provide rationale for clinical development of combinations of these compounds for the treatment of pancreatic adenocarcinoma.
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DOI: 10.1007/s00109-011-0774-y
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ISTEX:FFEEE7417834D5D772E6CBCD2EC1C29E357A07EFLe document en format XML
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Taking advantage of a panel of human PDAC cell lines and specific inhibitors of PI3K and/or mTOR, we systematically address the question whether dual-targeted inhibition of the PI3K and mTOR pathways offers advantages over single-targeted inhibition of PI3K in PDAC. We observe greater overall susceptibility of cell lines to dual inhibition compared to targeting PI3K alone. However, we find that dual inhibition of PI3K and mTOR induces autophagy to a greater extent than inhibition of each target alone. In agreement with this, we show that combined administration of PI3K/mTOR and autophagy inhibitors results in increased anti-tumor activity in vitro and in vivo in models of pancreatic adenocarcinoma. XL765, a PI3K/mTOR inhibitor used in our in vivo studies, is currently undergoing clinical evaluation in a variety of cancer types, while the autophagy inhibitor chloroquine is a widely used anti-malaria compound. 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Taking advantage of a panel of human PDAC cell lines and specific inhibitors of PI3K and/or mTOR, we systematically address the question whether dual-targeted inhibition of the PI3K and mTOR pathways offers advantages over single-targeted inhibition of PI3K in PDAC. We observe greater overall susceptibility of cell lines to dual inhibition compared to targeting PI3K alone. However, we find that dual inhibition of PI3K and mTOR induces autophagy to a greater extent than inhibition of each target alone. In agreement with this, we show that combined administration of PI3K/mTOR and autophagy inhibitors results in increased anti-tumor activity in vitro and in vivo in models of pancreatic adenocarcinoma. XL765, a PI3K/mTOR inhibitor used in our in vivo studies, is currently undergoing clinical evaluation in a variety of cancer types, while the autophagy inhibitor chloroquine is a widely used anti-malaria compound. 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type="first">Olga</forename><surname>Mirzoeva</surname></persName><affiliation>Divisions of Gastroenterology and Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Byron</forename><surname>Hann</surname></persName><affiliation>Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Yun</forename><surname>Hom</surname></persName><affiliation>Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Jayanta</forename><surname>Debnath</surname></persName><affiliation>Department of Pathology, University of California San Francisco, San Francisco, CA, USA</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Dana</forename><surname>Aftab</surname></persName><affiliation>Exelixis, Inc, South San Francisco, CA, USA</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Kevan</forename><surname>Shokat</surname></persName><affiliation>Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA</affiliation></author><author xml:id="author-0006" corresp="yes"><persName><forename type="first">W.</forename><surname>Korn</surname></persName><email>Michael.Korn@ucsf.edu</email><affiliation>Divisions of Gastroenterology and Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA</affiliation><affiliation>Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA</affiliation><affiliation>UCSF Divisions of Gastroenterology and 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Taking advantage of a panel of human PDAC cell lines and specific inhibitors of PI3K and/or mTOR, we systematically address the question whether dual-targeted inhibition of the PI3K and mTOR pathways offers advantages over single-targeted inhibition of PI3K in PDAC. We observe greater overall susceptibility of cell lines to dual inhibition compared to targeting PI3K alone. However, we find that dual inhibition of PI3K and mTOR induces autophagy to a greater extent than inhibition of each target alone. In agreement with this, we show that combined administration of PI3K/mTOR and autophagy inhibitors results in increased anti-tumor activity in vitro and in vivo in models of pancreatic adenocarcinoma. XL765, a PI3K/mTOR inhibitor used in our in vivo studies, is currently undergoing clinical evaluation in a variety of cancer types, while the autophagy inhibitor chloroquine is a widely used anti-malaria compound. Thus, our studies provide rationale for clinical development of combinations of these compounds for the treatment of pancreatic adenocarcinoma.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>PI3K</term></item><item><term>mTOR</term></item><item><term>Pancreatic adenocarcinoma</term></item><item><term>EGFR pathway</term></item><item><term>Cancer signal transduction</term></item><item><term>Autophagy</term></item><item><term>Apoptosis</term></item><item><term>Chloroquine</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>Abbreviations</head><item><term>PDAC</term><term>Pancreatic ductal adenocarcinoma</term></item><item><term>PI3K</term><term>Phosphoinositide-3 kinase</term></item><item><term>mTOR</term><term>Mammalian target of rapamycin</term></item><item><term>GI50</term><term>Drug concentration inducing 50% growth inhibition</term></item><item><term>LC50</term><term>Drug concentration inducing 50% lethality</term></item><item><term>AVO</term><term>Acidic vesicular organelles</term></item><item><term>3-MA</term><term>3-Methyladenine</term></item><item><term>CQ</term><term>Chloroquine</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>Biomedicine</head><item><term>Molecular Medicine</term></item><item><term>Human Genetics</term></item><item><term>Internal Medicine</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2011-01-19">Created</change><change when="2011-09-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/VQC-C97Z80MR-P/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus springer-journals not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" 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NumberingStyle="Unnumbered" TocLevels="0"><ArticleID>774</ArticleID><ArticleDOI>10.1007/s00109-011-0774-y</ArticleDOI><ArticleSequenceNumber>6</ArticleSequenceNumber><ArticleTitle Language="En">Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K—mTOR pathway in pancreatic adenocarcinoma</ArticleTitle><ArticleCategory>Original Article</ArticleCategory><ArticleFirstPage>877</ArticleFirstPage><ArticleLastPage>889</ArticleLastPage><ArticleHistory><RegistrationDate><Year>2011</Year><Month>5</Month><Day>24</Day></RegistrationDate><Received><Year>2011</Year><Month>1</Month><Day>19</Day></Received><Revised><Year>2011</Year><Month>4</Month><Day>16</Day></Revised><Accepted><Year>2011</Year><Month>4</Month><Day>20</Day></Accepted><OnlineDate><Year>2011</Year><Month>6</Month><Day>16</Day></OnlineDate></ArticleHistory><ArticleCopyright><CopyrightHolderName>Springer-Verlag</CopyrightHolderName><CopyrightYear>2011</CopyrightYear></ArticleCopyright><ArticleGrants Type="Regular"><MetadataGrant Grant="OpenAccess"></MetadataGrant><AbstractGrant Grant="OpenAccess"></AbstractGrant><BodyPDFGrant Grant="Restricted"></BodyPDFGrant><BodyHTMLGrant Grant="Restricted"></BodyHTMLGrant><BibliographyGrant Grant="Restricted"></BibliographyGrant><ESMGrant Grant="Restricted"></ESMGrant></ArticleGrants></ArticleInfo><ArticleHeader><AuthorGroup><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Olga</GivenName><GivenName>K.</GivenName><FamilyName>Mirzoeva</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff2"><AuthorName DisplayOrder="Western"><GivenName>Byron</GivenName><FamilyName>Hann</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff2"><AuthorName DisplayOrder="Western"><GivenName>Yun</GivenName><GivenName>K.</GivenName><FamilyName>Hom</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff3"><AuthorName DisplayOrder="Western"><GivenName>Jayanta</GivenName><FamilyName>Debnath</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff4"><AuthorName DisplayOrder="Western"><GivenName>Dana</GivenName><FamilyName>Aftab</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff5"><AuthorName DisplayOrder="Western"><GivenName>Kevan</GivenName><FamilyName>Shokat</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1 Aff2 Aff6" CorrespondingAffiliationID="Aff6"><AuthorName DisplayOrder="Western"><GivenName>W.</GivenName><GivenName>Michael</GivenName><FamilyName>Korn</FamilyName></AuthorName><Contact><Phone>+1-415-5022844</Phone><Fax>+1-415-5024787</Fax><Email>Michael.Korn@ucsf.edu</Email></Contact></Author><Affiliation ID="Aff1"><OrgDivision>Divisions of Gastroenterology and Hematology/Oncology, Department of Medicine</OrgDivision><OrgName>University of California San Francisco</OrgName><OrgAddress><City>San Francisco</City><State>CA</State><Country Code="US">USA</Country></OrgAddress></Affiliation><Affiliation ID="Aff2"><OrgDivision>Helen Diller Family Comprehensive Cancer Center</OrgDivision><OrgName>University of California San Francisco</OrgName><OrgAddress><City>San Francisco</City><State>CA</State><Country Code="US">USA</Country></OrgAddress></Affiliation><Affiliation ID="Aff3"><OrgDivision>Department of Pathology</OrgDivision><OrgName>University of California San Francisco</OrgName><OrgAddress><City>San Francisco</City><State>CA</State><Country Code="US">USA</Country></OrgAddress></Affiliation><Affiliation ID="Aff4"><OrgName>Exelixis, Inc</OrgName><OrgAddress><City>South San Francisco</City><State>CA</State><Country Code="US">USA</Country></OrgAddress></Affiliation><Affiliation ID="Aff5"><OrgDivision>Department of Cellular and Molecular Pharmacology</OrgDivision><OrgName>University of California San Francisco</OrgName><OrgAddress><City>San Francisco</City><State>CA</State><Country Code="US">USA</Country></OrgAddress></Affiliation><Affiliation ID="Aff6"><OrgDivision>UCSF Divisions of Gastroenterology and Hematology/Oncology, Department of Medicine</OrgDivision><OrgName>Helen Diller Family Comprehensive Cancer Center</OrgName><OrgAddress><Street>2340 Sutter St., Box 1387</Street><City>San Francisco</City><State>CA</State><Postcode>94115</Postcode><Country Code="US">USA</Country></OrgAddress></Affiliation></AuthorGroup><Abstract ID="Abs1" Language="En" OutputMedium="All"><Heading>Abstract</Heading><Para>Targeting of pathways downstream of RAS represents a promising therapeutic strategy for pancreatic cancer, the fourth leading cause of cancer-related death in the USA, since activation of the Raf-MEK-ERK and PI3K-AKT pathways is found frequently in this disease and is associated with poor prognosis. Taking advantage of a panel of human PDAC cell lines and specific inhibitors of PI3K and/or mTOR, we systematically address the question whether dual-targeted inhibition of the PI3K and mTOR pathways offers advantages over single-targeted inhibition of PI3K in PDAC. We observe greater overall susceptibility of cell lines to dual inhibition compared to targeting PI3K alone. However, we find that dual inhibition of PI3K and mTOR induces autophagy to a greater extent than inhibition of each target alone. In agreement with this, we show that combined administration of PI3K/mTOR and autophagy inhibitors results in increased anti-tumor activity in vitro and in vivo in models of pancreatic adenocarcinoma. XL765, a PI3K/mTOR inhibitor used in our in vivo studies, is currently undergoing clinical evaluation in a variety of cancer types, while the autophagy inhibitor chloroquine is a widely used anti-malaria compound. Thus, our studies provide rationale for clinical development of combinations of these compounds for the treatment of pancreatic adenocarcinoma.</Para></Abstract><KeywordGroup Language="En" OutputMedium="All"><Heading>Keywords</Heading><Keyword>PI3K</Keyword><Keyword>mTOR</Keyword><Keyword>Pancreatic adenocarcinoma</Keyword><Keyword>EGFR pathway</Keyword><Keyword>Cancer signal transduction</Keyword><Keyword>Autophagy</Keyword><Keyword>Apoptosis</Keyword><Keyword>Chloroquine</Keyword></KeywordGroup><AbbreviationGroup><Heading>Abbreviations</Heading><DefinitionList><DefinitionListEntry><Term>PDAC</Term><Description><Para>Pancreatic ductal adenocarcinoma</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>PI3K</Term><Description><Para>Phosphoinositide-3 kinase</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>mTOR</Term><Description><Para>Mammalian target of rapamycin</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>GI50</Term><Description><Para>Drug concentration inducing 50% growth inhibition</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>LC50</Term><Description><Para>Drug concentration inducing 50% lethality</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>AVO</Term><Description><Para>Acidic vesicular organelles</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>3-MA</Term><Description><Para>3-Methyladenine</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>CQ</Term><Description><Para>Chloroquine</Para></Description></DefinitionListEntry></DefinitionList></AbbreviationGroup><ArticleNote Type="ESMHint"><Heading>Electronic supplementary material</Heading><SimplePara>The online version of this article (doi:<ExternalRef><RefSource>10.1007/s00109-011-0774-y</RefSource><RefTarget Address="10.1007/s00109-011-0774-y" TargetType="DOI"></RefTarget></ExternalRef>) contains supplementary material, which is available to authorized users.</SimplePara></ArticleNote></ArticleHeader><NoBody></NoBody></Article></Issue></Volume></Journal></Publisher></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K—mTOR pathway in pancreatic adenocarcinoma</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K—mTOR pathway in pancreatic adenocarcinoma</title></titleInfo><name type="personal"><namePart type="given">Olga</namePart><namePart type="given">K.</namePart><namePart type="family">Mirzoeva</namePart><affiliation>Divisions of Gastroenterology and Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Byron</namePart><namePart type="family">Hann</namePart><affiliation>Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yun</namePart><namePart type="given">K.</namePart><namePart type="family">Hom</namePart><affiliation>Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jayanta</namePart><namePart type="family">Debnath</namePart><affiliation>Department of Pathology, University of California San Francisco, San Francisco, CA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dana</namePart><namePart type="family">Aftab</namePart><affiliation>Exelixis, Inc, South San Francisco, CA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kevan</namePart><namePart type="family">Shokat</namePart><affiliation>Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">W.</namePart><namePart type="given">Michael</namePart><namePart type="family">Korn</namePart><affiliation>Divisions of Gastroenterology and Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA</affiliation><affiliation>Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA</affiliation><affiliation>UCSF Divisions of Gastroenterology and Hematology/Oncology, Department of Medicine, Helen Diller Family Comprehensive Cancer Center, 2340 Sutter St., Box 1387, 94115, San Francisco, CA, USA</affiliation><affiliation>E-mail: Michael.Korn@ucsf.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="OriginalPaper" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>Springer-Verlag</publisher><place><placeTerm type="text">Berlin/Heidelberg</placeTerm></place><dateCreated encoding="w3cdtf">2011-01-19</dateCreated><dateIssued encoding="w3cdtf">2011-09-01</dateIssued><copyrightDate encoding="w3cdtf">2011</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><abstract lang="en">Abstract: Targeting of pathways downstream of RAS represents a promising therapeutic strategy for pancreatic cancer, the fourth leading cause of cancer-related death in the USA, since activation of the Raf-MEK-ERK and PI3K-AKT pathways is found frequently in this disease and is associated with poor prognosis. Taking advantage of a panel of human PDAC cell lines and specific inhibitors of PI3K and/or mTOR, we systematically address the question whether dual-targeted inhibition of the PI3K and mTOR pathways offers advantages over single-targeted inhibition of PI3K in PDAC. We observe greater overall susceptibility of cell lines to dual inhibition compared to targeting PI3K alone. However, we find that dual inhibition of PI3K and mTOR induces autophagy to a greater extent than inhibition of each target alone. In agreement with this, we show that combined administration of PI3K/mTOR and autophagy inhibitors results in increased anti-tumor activity in vitro and in vivo in models of pancreatic adenocarcinoma. XL765, a PI3K/mTOR inhibitor used in our in vivo studies, is currently undergoing clinical evaluation in a variety of cancer types, while the autophagy inhibitor chloroquine is a widely used anti-malaria compound. Thus, our studies provide rationale for clinical development of combinations of these compounds for the treatment of pancreatic adenocarcinoma.</abstract><note>Original Article</note><subject lang="en"><genre>Keywords</genre><topic>PI3K</topic><topic>mTOR</topic><topic>Pancreatic adenocarcinoma</topic><topic>EGFR pathway</topic><topic>Cancer signal transduction</topic><topic>Autophagy</topic><topic>Apoptosis</topic><topic>Chloroquine</topic></subject><subject><genre>Abbreviations</genre><topic>PDAC : Pancreatic ductal adenocarcinoma</topic><topic>PI3K : Phosphoinositide-3 kinase</topic><topic>mTOR : Mammalian target of rapamycin</topic><topic>GI50 : Drug concentration inducing 50% growth inhibition</topic><topic>LC50 : Drug concentration inducing 50% lethality</topic><topic>AVO : Acidic vesicular organelles</topic><topic>3-MA : 3-Methyladenine</topic><topic>CQ : Chloroquine</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Molecular Medicine</title></titleInfo><titleInfo type="abbreviated"><title>J Mol Med</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>Springer</publisher><dateIssued encoding="w3cdtf">2011-08-11</dateIssued><copyrightDate encoding="w3cdtf">2011</copyrightDate></originInfo><subject><genre>Biomedicine</genre><topic>Molecular Medicine</topic><topic>Human Genetics</topic><topic>Internal Medicine</topic></subject><identifier type="ISSN">0946-2716</identifier><identifier type="eISSN">1432-1440</identifier><identifier type="JournalID">109</identifier><identifier type="IssueArticleCount">10</identifier><identifier type="VolumeIssueCount">12</identifier><part><date>2011</date><detail type="volume"><number>89</number><caption>vol.</caption></detail><detail type="issue"><number>9</number><caption>no.</caption></detail><extent unit="pages"><start>877</start><end>889</end></extent></part><recordInfo><recordOrigin>Springer-Verlag, 2011</recordOrigin></recordInfo></relatedItem><identifier type="istex">FFEEE7417834D5D772E6CBCD2EC1C29E357A07EF</identifier><identifier type="ark">ark:/67375/VQC-C97Z80MR-P</identifier><identifier type="DOI">10.1007/s00109-011-0774-y</identifier><identifier type="ArticleID">774</identifier><identifier type="ArticleID">s00109-011-0774-y</identifier><accessCondition type="use and reproduction" contentType="copyright">Springer-Verlag, 2011</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-3XSW68JL-F">springer</recordContentSource><recordOrigin>Springer-Verlag, 2011</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/VQC-C97Z80MR-P/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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