Loading…
Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody
Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and func...
Saved in:
| Published in: | The Journal of experimental medicine 2002-08, Vol.196 (4), p.541-549 |
|---|---|
| Main Authors: | , , , , , , , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c477t-3b2215cee21b861dda8cd636c626eb6caef4b46d55145b87965164c09a073b693 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c477t-3b2215cee21b861dda8cd636c626eb6caef4b46d55145b87965164c09a073b693 |
| container_end_page | 549 |
| container_issue | 4 |
| container_start_page | 541 |
| container_title | The Journal of experimental medicine |
| container_volume | 196 |
| creator | Vicari, Alain P Chiodoni, Claudia Vaure, Céline Aït-Yahia, Smina Dercamp, Christophe Matsos, Fabien Reynard, Olivier Taverne, Catherine Merle, Philippe Colombo, Mario P O'Garra, Anne Trinchieri, Giorgio Caux, Christophe |
| description | Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and function of TIDCs in transplantable and transgenic mouse tumor models. Although TIDCs could encompass various known DC subsets, most had an immature phenotype. We observed that TIDCs were able to present TAA in the context of major histocompatibility complex class I but that they were refractory to stimulation with the combination of lipopolysaccharide, interferon gamma, and anti-CD40 antibody. We could revert TIDC paralysis, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL-10R) antibody. CpG or anti-IL-10R alone were inactive in TIDCs, whereas CpG triggered activation in normal DCs. In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory. |
| doi_str_mv | 10.1084/jem.20020732 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2196048</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>18494775</sourcerecordid><originalsourceid>FETCH-LOGICAL-c477t-3b2215cee21b861dda8cd636c626eb6caef4b46d55145b87965164c09a073b693</originalsourceid><addsrcrecordid>eNqFkU1rFTEUhoMo9ra6cy1ZuXJqkkkyMxtBLtoKBUF0HTLJuTU1k4z5KMwP8H-b2uvXykU4kPOcl_OeF6FnlJxTMvJXN7CcM0IYGXr2AO2o4KSbRD8-RLv2yzpKyHCCTnO-IYRyLuRjdEIZHeXIxQ59_wi3kLL2OB5wqUtMnQu2GrDYQrDJFWewAe_xqpP2W3YZzxverxfYLUsNMRe3VK9LTBuO3l3HUI2HWJwFrINtr7gmWSB5qF9dwJTgBAbWNvGzOUe7PUGPDtpneHqsZ-jzu7ef9pfd1YeL9_s3V53hw1C6fmaMCgPA6DxKaq0ejZW9NJJJmKXRcOAzl1YIysU8DpMUVHJDJt2OM8upP0Ov73XXOi9gDYTSTKk1uUWnTUXt1L-d4L6o63irGJ0k4WMTeHEUSPFbhVzU4vLdeXSAWLMaGKETof1_QTryqXkSDXx5D5oUc05w-L0NJeouYNUCVr8Cbvjzvx38gY-J9j8A4omlaA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>18494775</pqid></control><display><type>article</type><title>Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody</title><source>PubMed Central</source><creator>Vicari, Alain P ; Chiodoni, Claudia ; Vaure, Céline ; Aït-Yahia, Smina ; Dercamp, Christophe ; Matsos, Fabien ; Reynard, Olivier ; Taverne, Catherine ; Merle, Philippe ; Colombo, Mario P ; O'Garra, Anne ; Trinchieri, Giorgio ; Caux, Christophe</creator><creatorcontrib>Vicari, Alain P ; Chiodoni, Claudia ; Vaure, Céline ; Aït-Yahia, Smina ; Dercamp, Christophe ; Matsos, Fabien ; Reynard, Olivier ; Taverne, Catherine ; Merle, Philippe ; Colombo, Mario P ; O'Garra, Anne ; Trinchieri, Giorgio ; Caux, Christophe</creatorcontrib><description>Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and function of TIDCs in transplantable and transgenic mouse tumor models. Although TIDCs could encompass various known DC subsets, most had an immature phenotype. We observed that TIDCs were able to present TAA in the context of major histocompatibility complex class I but that they were refractory to stimulation with the combination of lipopolysaccharide, interferon gamma, and anti-CD40 antibody. We could revert TIDC paralysis, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL-10R) antibody. CpG or anti-IL-10R alone were inactive in TIDCs, whereas CpG triggered activation in normal DCs. In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20020732</identifier><identifier>PMID: 12186845</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Adjuvants, Immunologic ; Animals ; Antibodies, Monoclonal - immunology ; Antigens, Tumor-Associated, Carbohydrate - immunology ; CD40 Antigens - immunology ; CD8-Positive T-Lymphocytes - immunology ; CpG Islands - immunology ; Dendritic Cells - cytology ; Dendritic Cells - immunology ; Female ; Immunity, Active - immunology ; Immunity, Innate - immunology ; Immunologic Memory - immunology ; Interferon-gamma - immunology ; Interferon-gamma - pharmacology ; Killer Cells, Natural - immunology ; Lipopolysaccharides - immunology ; Lipopolysaccharides - pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, SCID ; Oligodeoxyribonucleotides - immunology ; Oligodeoxyribonucleotides - pharmacology ; Receptors, Interleukin - immunology ; Receptors, Interleukin-10 ; Tumor Cells, Cultured</subject><ispartof>The Journal of experimental medicine, 2002-08, Vol.196 (4), p.541-549</ispartof><rights>Copyright © 2002, The Rockefeller University Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-3b2215cee21b861dda8cd636c626eb6caef4b46d55145b87965164c09a073b693</citedby><cites>FETCH-LOGICAL-c477t-3b2215cee21b861dda8cd636c626eb6caef4b46d55145b87965164c09a073b693</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196048/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196048/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12186845$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vicari, Alain P</creatorcontrib><creatorcontrib>Chiodoni, Claudia</creatorcontrib><creatorcontrib>Vaure, Céline</creatorcontrib><creatorcontrib>Aït-Yahia, Smina</creatorcontrib><creatorcontrib>Dercamp, Christophe</creatorcontrib><creatorcontrib>Matsos, Fabien</creatorcontrib><creatorcontrib>Reynard, Olivier</creatorcontrib><creatorcontrib>Taverne, Catherine</creatorcontrib><creatorcontrib>Merle, Philippe</creatorcontrib><creatorcontrib>Colombo, Mario P</creatorcontrib><creatorcontrib>O'Garra, Anne</creatorcontrib><creatorcontrib>Trinchieri, Giorgio</creatorcontrib><creatorcontrib>Caux, Christophe</creatorcontrib><title>Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and function of TIDCs in transplantable and transgenic mouse tumor models. Although TIDCs could encompass various known DC subsets, most had an immature phenotype. We observed that TIDCs were able to present TAA in the context of major histocompatibility complex class I but that they were refractory to stimulation with the combination of lipopolysaccharide, interferon gamma, and anti-CD40 antibody. We could revert TIDC paralysis, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL-10R) antibody. CpG or anti-IL-10R alone were inactive in TIDCs, whereas CpG triggered activation in normal DCs. In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.</description><subject>Adjuvants, Immunologic</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antigens, Tumor-Associated, Carbohydrate - immunology</subject><subject>CD40 Antigens - immunology</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>CpG Islands - immunology</subject><subject>Dendritic Cells - cytology</subject><subject>Dendritic Cells - immunology</subject><subject>Female</subject><subject>Immunity, Active - immunology</subject><subject>Immunity, Innate - immunology</subject><subject>Immunologic Memory - immunology</subject><subject>Interferon-gamma - immunology</subject><subject>Interferon-gamma - pharmacology</subject><subject>Killer Cells, Natural - immunology</subject><subject>Lipopolysaccharides - immunology</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, SCID</subject><subject>Oligodeoxyribonucleotides - immunology</subject><subject>Oligodeoxyribonucleotides - pharmacology</subject><subject>Receptors, Interleukin - immunology</subject><subject>Receptors, Interleukin-10</subject><subject>Tumor Cells, Cultured</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNqFkU1rFTEUhoMo9ra6cy1ZuXJqkkkyMxtBLtoKBUF0HTLJuTU1k4z5KMwP8H-b2uvXykU4kPOcl_OeF6FnlJxTMvJXN7CcM0IYGXr2AO2o4KSbRD8-RLv2yzpKyHCCTnO-IYRyLuRjdEIZHeXIxQ59_wi3kLL2OB5wqUtMnQu2GrDYQrDJFWewAe_xqpP2W3YZzxverxfYLUsNMRe3VK9LTBuO3l3HUI2HWJwFrINtr7gmWSB5qF9dwJTgBAbWNvGzOUe7PUGPDtpneHqsZ-jzu7ef9pfd1YeL9_s3V53hw1C6fmaMCgPA6DxKaq0ejZW9NJJJmKXRcOAzl1YIysU8DpMUVHJDJt2OM8upP0Ov73XXOi9gDYTSTKk1uUWnTUXt1L-d4L6o63irGJ0k4WMTeHEUSPFbhVzU4vLdeXSAWLMaGKETof1_QTryqXkSDXx5D5oUc05w-L0NJeouYNUCVr8Cbvjzvx38gY-J9j8A4omlaA</recordid><startdate>20020819</startdate><enddate>20020819</enddate><creator>Vicari, Alain P</creator><creator>Chiodoni, Claudia</creator><creator>Vaure, Céline</creator><creator>Aït-Yahia, Smina</creator><creator>Dercamp, Christophe</creator><creator>Matsos, Fabien</creator><creator>Reynard, Olivier</creator><creator>Taverne, Catherine</creator><creator>Merle, Philippe</creator><creator>Colombo, Mario P</creator><creator>O'Garra, Anne</creator><creator>Trinchieri, Giorgio</creator><creator>Caux, Christophe</creator><general>The Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20020819</creationdate><title>Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody</title><author>Vicari, Alain P ; Chiodoni, Claudia ; Vaure, Céline ; Aït-Yahia, Smina ; Dercamp, Christophe ; Matsos, Fabien ; Reynard, Olivier ; Taverne, Catherine ; Merle, Philippe ; Colombo, Mario P ; O'Garra, Anne ; Trinchieri, Giorgio ; Caux, Christophe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-3b2215cee21b861dda8cd636c626eb6caef4b46d55145b87965164c09a073b693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Adjuvants, Immunologic</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antigens, Tumor-Associated, Carbohydrate - immunology</topic><topic>CD40 Antigens - immunology</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>CpG Islands - immunology</topic><topic>Dendritic Cells - cytology</topic><topic>Dendritic Cells - immunology</topic><topic>Female</topic><topic>Immunity, Active - immunology</topic><topic>Immunity, Innate - immunology</topic><topic>Immunologic Memory - immunology</topic><topic>Interferon-gamma - immunology</topic><topic>Interferon-gamma - pharmacology</topic><topic>Killer Cells, Natural - immunology</topic><topic>Lipopolysaccharides - immunology</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, SCID</topic><topic>Oligodeoxyribonucleotides - immunology</topic><topic>Oligodeoxyribonucleotides - pharmacology</topic><topic>Receptors, Interleukin - immunology</topic><topic>Receptors, Interleukin-10</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vicari, Alain P</creatorcontrib><creatorcontrib>Chiodoni, Claudia</creatorcontrib><creatorcontrib>Vaure, Céline</creatorcontrib><creatorcontrib>Aït-Yahia, Smina</creatorcontrib><creatorcontrib>Dercamp, Christophe</creatorcontrib><creatorcontrib>Matsos, Fabien</creatorcontrib><creatorcontrib>Reynard, Olivier</creatorcontrib><creatorcontrib>Taverne, Catherine</creatorcontrib><creatorcontrib>Merle, Philippe</creatorcontrib><creatorcontrib>Colombo, Mario P</creatorcontrib><creatorcontrib>O'Garra, Anne</creatorcontrib><creatorcontrib>Trinchieri, Giorgio</creatorcontrib><creatorcontrib>Caux, Christophe</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of experimental medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vicari, Alain P</au><au>Chiodoni, Claudia</au><au>Vaure, Céline</au><au>Aït-Yahia, Smina</au><au>Dercamp, Christophe</au><au>Matsos, Fabien</au><au>Reynard, Olivier</au><au>Taverne, Catherine</au><au>Merle, Philippe</au><au>Colombo, Mario P</au><au>O'Garra, Anne</au><au>Trinchieri, Giorgio</au><au>Caux, Christophe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>2002-08-19</date><risdate>2002</risdate><volume>196</volume><issue>4</issue><spage>541</spage><epage>549</epage><pages>541-549</pages><issn>0022-1007</issn><eissn>1540-9538</eissn><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><notes>ObjectType-Article-1</notes><notes>ObjectType-Feature-2</notes><notes>A. O'Garra's present address is The National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.</notes><notes>Address correspondence to Alain P. Vicari, Schering-Plough Laboratory for Immunological Research, BP11, 27 chemin des Peupliers, 69571 Dardilly, France. Phone: 33-4-72-17-27-00; Fax: 33-4-78-35-47-50; E-mail: alain.vicari@spcorp.com</notes><abstract>Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and function of TIDCs in transplantable and transgenic mouse tumor models. Although TIDCs could encompass various known DC subsets, most had an immature phenotype. We observed that TIDCs were able to present TAA in the context of major histocompatibility complex class I but that they were refractory to stimulation with the combination of lipopolysaccharide, interferon gamma, and anti-CD40 antibody. We could revert TIDC paralysis, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL-10R) antibody. CpG or anti-IL-10R alone were inactive in TIDCs, whereas CpG triggered activation in normal DCs. In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.</abstract><cop>United States</cop><pub>The Rockefeller University Press</pub><pmid>12186845</pmid><doi>10.1084/jem.20020732</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-1007 |
| ispartof | The Journal of experimental medicine, 2002-08, Vol.196 (4), p.541-549 |
| issn | 0022-1007 1540-9538 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2196048 |
| source | PubMed Central |
| subjects | Adjuvants, Immunologic Animals Antibodies, Monoclonal - immunology Antigens, Tumor-Associated, Carbohydrate - immunology CD40 Antigens - immunology CD8-Positive T-Lymphocytes - immunology CpG Islands - immunology Dendritic Cells - cytology Dendritic Cells - immunology Female Immunity, Active - immunology Immunity, Innate - immunology Immunologic Memory - immunology Interferon-gamma - immunology Interferon-gamma - pharmacology Killer Cells, Natural - immunology Lipopolysaccharides - immunology Lipopolysaccharides - pharmacology Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, SCID Oligodeoxyribonucleotides - immunology Oligodeoxyribonucleotides - pharmacology Receptors, Interleukin - immunology Receptors, Interleukin-10 Tumor Cells, Cultured |
| title | Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T17%3A00%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Reversal%20of%20tumor-induced%20dendritic%20cell%20paralysis%20by%20CpG%20immunostimulatory%20oligonucleotide%20and%20anti-interleukin%2010%20receptor%20antibody&rft.jtitle=The%20Journal%20of%20experimental%20medicine&rft.au=Vicari,%20Alain%20P&rft.date=2002-08-19&rft.volume=196&rft.issue=4&rft.spage=541&rft.epage=549&rft.pages=541-549&rft.issn=0022-1007&rft.eissn=1540-9538&rft_id=info:doi/10.1084/jem.20020732&rft_dat=%3Cproquest_pubme%3E18494775%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c477t-3b2215cee21b861dda8cd636c626eb6caef4b46d55145b87965164c09a073b693%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=18494775&rft_id=info:pmid/12186845&rfr_iscdi=true |