Combination electro-gene therapy using herpes virus thymidine kinase and interleukin-12 expression plasmids is highly efficient against murine carcinomas in vivo

We report the use of plasmid DNA-mediated combination gene therapy for tumor-bearing mice using in vivo electroporation, also called electro-gene therapy (EGT), that resulted in uncomplicated and complete cures in more than 90% of the mice. Subcutaneously inoculated CT26 tumors in syngeneic BALB/c m...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Molecular therapy 2004-11, Vol.10 (5), p.929-937
Hauptverfasser: Goto, Tomoaki, Nishi, Toru, Kobayashi, Osamu, Tamura, Takahiko, Dev, Sukhendu B, Takeshima, Hideo, Kochi, Masato, Kuratsu, Jun-ichi, Sakata, Tsuneaki, Ushio, Yukitaka
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 937
container_issue 5
container_start_page 929
container_title Molecular therapy
container_volume 10
creator Goto, Tomoaki
Nishi, Toru
Kobayashi, Osamu
Tamura, Takahiko
Dev, Sukhendu B
Takeshima, Hideo
Kochi, Masato
Kuratsu, Jun-ichi
Sakata, Tsuneaki
Ushio, Yukitaka
description We report the use of plasmid DNA-mediated combination gene therapy for tumor-bearing mice using in vivo electroporation, also called electro-gene therapy (EGT), that resulted in uncomplicated and complete cures in more than 90% of the mice. Subcutaneously inoculated CT26 tumors in syngeneic BALB/c mice were subjected to repeated EGT treatments consisting of intratumoral co-injection of naked plasmids encoding the cytokine interleukin-12 (IL-12) (p35 and p40 subunits) and the suicide gene herpes simplex virus thymidine kinase (HSV-tk), followed by in vivo electroporation. The early anti-tumor effect was always stronger, and the rate of cure, as seen in the long-term follow-up, was always greater in the groups treated with combination EGT than in those treated with IL-12 or HSV-tk EGT alone. Systemic levels of IL-12 and IFN-gamma increased in both combination and IL-12-alone EGT-treated groups. Moreover, combination EGT for established subcutaneous tumors strongly reduced hematogenous lung metastases and increased survival time when live CT26 tumor cells were injected through the tail vein. Limited experiments on C57/B16 mice with murine melanoma also showed very similar trends. These results suggest that this simple and safe method of plasmid-mediated combination EGT may provide a potentially effective gene therapy for cancer.
doi_str_mv 10.1016/j.ymthe.2004.07.028
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_67019176</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>67019176</sourcerecordid><originalsourceid>FETCH-LOGICAL-c374t-3e89b41ac9f1c6c4a268903799f91ec10aa2902229c4d55398061f6c4209b66f3</originalsourceid><addsrcrecordid>eNpdkV2L1DAUhoMo7ucvECQgeNduTtqmzaUMfsGCN-t1yGROZzK2Sc1pl-3P8Z-acQcFr3KSPO-bwMPYGxAlCFB3x3Id5wOWUoi6FG0pZPeCXUIjm0IIWb_8O4O6YFdExzxBo9VrdgFNI3QD4pL92sRx64OdfQwcB3RzisUeA_Jcney08oV82PO8mZD4o08L5at19DufoR85Ssht2HEfZkwDLvmoAMnxaUpIdKqdBkuZJ-6JH_z-MKwc-947j2Hmdm99oJmPSzoVOpucD3G0mQ75ucd4w171diC8Pa_X7Punjw-bL8X9t89fNx_uC1e19VxU2OltDdbpHpxytZWq06Jqte41oANhrdRCSqldvWuaSndCQZ9BKfRWqb66Zu-fe6cUfy5Isxk9ORwGGzAuZFQrQEOrMvjuP_AYlxTy3wy0WnYAVaczVT1TLkWihL2Zkh9tWg0Ic_JnjuaPP3PyZ0Rrsr-cenvuXrYj7v5lzsKq30p1mwk</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1792811389</pqid></control><display><type>article</type><title>Combination electro-gene therapy using herpes virus thymidine kinase and interleukin-12 expression plasmids is highly efficient against murine carcinomas in vivo</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>ProQuest Central UK/Ireland</source><source>Alma/SFX Local Collection</source><creator>Goto, Tomoaki ; Nishi, Toru ; Kobayashi, Osamu ; Tamura, Takahiko ; Dev, Sukhendu B ; Takeshima, Hideo ; Kochi, Masato ; Kuratsu, Jun-ichi ; Sakata, Tsuneaki ; Ushio, Yukitaka</creator><creatorcontrib>Goto, Tomoaki ; Nishi, Toru ; Kobayashi, Osamu ; Tamura, Takahiko ; Dev, Sukhendu B ; Takeshima, Hideo ; Kochi, Masato ; Kuratsu, Jun-ichi ; Sakata, Tsuneaki ; Ushio, Yukitaka</creatorcontrib><description>We report the use of plasmid DNA-mediated combination gene therapy for tumor-bearing mice using in vivo electroporation, also called electro-gene therapy (EGT), that resulted in uncomplicated and complete cures in more than 90% of the mice. Subcutaneously inoculated CT26 tumors in syngeneic BALB/c mice were subjected to repeated EGT treatments consisting of intratumoral co-injection of naked plasmids encoding the cytokine interleukin-12 (IL-12) (p35 and p40 subunits) and the suicide gene herpes simplex virus thymidine kinase (HSV-tk), followed by in vivo electroporation. The early anti-tumor effect was always stronger, and the rate of cure, as seen in the long-term follow-up, was always greater in the groups treated with combination EGT than in those treated with IL-12 or HSV-tk EGT alone. Systemic levels of IL-12 and IFN-gamma increased in both combination and IL-12-alone EGT-treated groups. Moreover, combination EGT for established subcutaneous tumors strongly reduced hematogenous lung metastases and increased survival time when live CT26 tumor cells were injected through the tail vein. Limited experiments on C57/B16 mice with murine melanoma also showed very similar trends. These results suggest that this simple and safe method of plasmid-mediated combination EGT may provide a potentially effective gene therapy for cancer.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1016/j.ymthe.2004.07.028</identifier><identifier>PMID: 15509510</identifier><language>eng</language><publisher>United States: Elsevier Limited</publisher><subject>Animals ; Cancer therapies ; Carcinoma - secondary ; Carcinoma - therapy ; Colorectal cancer ; Cytokines ; Drug Therapy, Combination ; Electroporation ; Experiments ; Gene therapy ; Gene Transfer Techniques ; Genetic Therapy - methods ; Herpes viruses ; Interferon-gamma - analysis ; Interleukin-12 - analysis ; Interleukin-12 - genetics ; Kinases ; Lung Neoplasms - pathology ; Lung Neoplasms - secondary ; Lung Neoplasms - therapy ; Melanoma ; Mice ; Mice, Inbred BALB C ; Neurosurgery ; Plasmids ; Plasmids - genetics ; Simplexvirus - enzymology ; Simplexvirus - genetics ; Thymidine Kinase - genetics ; Tumors</subject><ispartof>Molecular therapy, 2004-11, Vol.10 (5), p.929-937</ispartof><rights>Copyright Nature Publishing Group Nov 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c374t-3e89b41ac9f1c6c4a268903799f91ec10aa2902229c4d55398061f6c4209b66f3</citedby><cites>FETCH-LOGICAL-c374t-3e89b41ac9f1c6c4a268903799f91ec10aa2902229c4d55398061f6c4209b66f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1792811389?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>315,781,785,27926,27927,64387,64389,64391,72471</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15509510$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Goto, Tomoaki</creatorcontrib><creatorcontrib>Nishi, Toru</creatorcontrib><creatorcontrib>Kobayashi, Osamu</creatorcontrib><creatorcontrib>Tamura, Takahiko</creatorcontrib><creatorcontrib>Dev, Sukhendu B</creatorcontrib><creatorcontrib>Takeshima, Hideo</creatorcontrib><creatorcontrib>Kochi, Masato</creatorcontrib><creatorcontrib>Kuratsu, Jun-ichi</creatorcontrib><creatorcontrib>Sakata, Tsuneaki</creatorcontrib><creatorcontrib>Ushio, Yukitaka</creatorcontrib><title>Combination electro-gene therapy using herpes virus thymidine kinase and interleukin-12 expression plasmids is highly efficient against murine carcinomas in vivo</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>We report the use of plasmid DNA-mediated combination gene therapy for tumor-bearing mice using in vivo electroporation, also called electro-gene therapy (EGT), that resulted in uncomplicated and complete cures in more than 90% of the mice. Subcutaneously inoculated CT26 tumors in syngeneic BALB/c mice were subjected to repeated EGT treatments consisting of intratumoral co-injection of naked plasmids encoding the cytokine interleukin-12 (IL-12) (p35 and p40 subunits) and the suicide gene herpes simplex virus thymidine kinase (HSV-tk), followed by in vivo electroporation. The early anti-tumor effect was always stronger, and the rate of cure, as seen in the long-term follow-up, was always greater in the groups treated with combination EGT than in those treated with IL-12 or HSV-tk EGT alone. Systemic levels of IL-12 and IFN-gamma increased in both combination and IL-12-alone EGT-treated groups. Moreover, combination EGT for established subcutaneous tumors strongly reduced hematogenous lung metastases and increased survival time when live CT26 tumor cells were injected through the tail vein. Limited experiments on C57/B16 mice with murine melanoma also showed very similar trends. These results suggest that this simple and safe method of plasmid-mediated combination EGT may provide a potentially effective gene therapy for cancer.</description><subject>Animals</subject><subject>Cancer therapies</subject><subject>Carcinoma - secondary</subject><subject>Carcinoma - therapy</subject><subject>Colorectal cancer</subject><subject>Cytokines</subject><subject>Drug Therapy, Combination</subject><subject>Electroporation</subject><subject>Experiments</subject><subject>Gene therapy</subject><subject>Gene Transfer Techniques</subject><subject>Genetic Therapy - methods</subject><subject>Herpes viruses</subject><subject>Interferon-gamma - analysis</subject><subject>Interleukin-12 - analysis</subject><subject>Interleukin-12 - genetics</subject><subject>Kinases</subject><subject>Lung Neoplasms - pathology</subject><subject>Lung Neoplasms - secondary</subject><subject>Lung Neoplasms - therapy</subject><subject>Melanoma</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Neurosurgery</subject><subject>Plasmids</subject><subject>Plasmids - genetics</subject><subject>Simplexvirus - enzymology</subject><subject>Simplexvirus - genetics</subject><subject>Thymidine Kinase - genetics</subject><subject>Tumors</subject><issn>1525-0016</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpdkV2L1DAUhoMo7ucvECQgeNduTtqmzaUMfsGCN-t1yGROZzK2Sc1pl-3P8Z-acQcFr3KSPO-bwMPYGxAlCFB3x3Id5wOWUoi6FG0pZPeCXUIjm0IIWb_8O4O6YFdExzxBo9VrdgFNI3QD4pL92sRx64OdfQwcB3RzisUeA_Jcney08oV82PO8mZD4o08L5at19DufoR85Ssht2HEfZkwDLvmoAMnxaUpIdKqdBkuZJ-6JH_z-MKwc-947j2Hmdm99oJmPSzoVOpucD3G0mQ75ucd4w171diC8Pa_X7Punjw-bL8X9t89fNx_uC1e19VxU2OltDdbpHpxytZWq06Jqte41oANhrdRCSqldvWuaSndCQZ9BKfRWqb66Zu-fe6cUfy5Isxk9ORwGGzAuZFQrQEOrMvjuP_AYlxTy3wy0WnYAVaczVT1TLkWihL2Zkh9tWg0Ic_JnjuaPP3PyZ0Rrsr-cenvuXrYj7v5lzsKq30p1mwk</recordid><startdate>200411</startdate><enddate>200411</enddate><creator>Goto, Tomoaki</creator><creator>Nishi, Toru</creator><creator>Kobayashi, Osamu</creator><creator>Tamura, Takahiko</creator><creator>Dev, Sukhendu B</creator><creator>Takeshima, Hideo</creator><creator>Kochi, Masato</creator><creator>Kuratsu, Jun-ichi</creator><creator>Sakata, Tsuneaki</creator><creator>Ushio, Yukitaka</creator><general>Elsevier Limited</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>200411</creationdate><title>Combination electro-gene therapy using herpes virus thymidine kinase and interleukin-12 expression plasmids is highly efficient against murine carcinomas in vivo</title><author>Goto, Tomoaki ; Nishi, Toru ; Kobayashi, Osamu ; Tamura, Takahiko ; Dev, Sukhendu B ; Takeshima, Hideo ; Kochi, Masato ; Kuratsu, Jun-ichi ; Sakata, Tsuneaki ; Ushio, Yukitaka</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c374t-3e89b41ac9f1c6c4a268903799f91ec10aa2902229c4d55398061f6c4209b66f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Cancer therapies</topic><topic>Carcinoma - secondary</topic><topic>Carcinoma - therapy</topic><topic>Colorectal cancer</topic><topic>Cytokines</topic><topic>Drug Therapy, Combination</topic><topic>Electroporation</topic><topic>Experiments</topic><topic>Gene therapy</topic><topic>Gene Transfer Techniques</topic><topic>Genetic Therapy - methods</topic><topic>Herpes viruses</topic><topic>Interferon-gamma - analysis</topic><topic>Interleukin-12 - analysis</topic><topic>Interleukin-12 - genetics</topic><topic>Kinases</topic><topic>Lung Neoplasms - pathology</topic><topic>Lung Neoplasms - secondary</topic><topic>Lung Neoplasms - therapy</topic><topic>Melanoma</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Neurosurgery</topic><topic>Plasmids</topic><topic>Plasmids - genetics</topic><topic>Simplexvirus - enzymology</topic><topic>Simplexvirus - genetics</topic><topic>Thymidine Kinase - genetics</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Goto, Tomoaki</creatorcontrib><creatorcontrib>Nishi, Toru</creatorcontrib><creatorcontrib>Kobayashi, Osamu</creatorcontrib><creatorcontrib>Tamura, Takahiko</creatorcontrib><creatorcontrib>Dev, Sukhendu B</creatorcontrib><creatorcontrib>Takeshima, Hideo</creatorcontrib><creatorcontrib>Kochi, Masato</creatorcontrib><creatorcontrib>Kuratsu, Jun-ichi</creatorcontrib><creatorcontrib>Sakata, Tsuneaki</creatorcontrib><creatorcontrib>Ushio, Yukitaka</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Goto, Tomoaki</au><au>Nishi, Toru</au><au>Kobayashi, Osamu</au><au>Tamura, Takahiko</au><au>Dev, Sukhendu B</au><au>Takeshima, Hideo</au><au>Kochi, Masato</au><au>Kuratsu, Jun-ichi</au><au>Sakata, Tsuneaki</au><au>Ushio, Yukitaka</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combination electro-gene therapy using herpes virus thymidine kinase and interleukin-12 expression plasmids is highly efficient against murine carcinomas in vivo</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2004-11</date><risdate>2004</risdate><volume>10</volume><issue>5</issue><spage>929</spage><epage>937</epage><pages>929-937</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>We report the use of plasmid DNA-mediated combination gene therapy for tumor-bearing mice using in vivo electroporation, also called electro-gene therapy (EGT), that resulted in uncomplicated and complete cures in more than 90% of the mice. Subcutaneously inoculated CT26 tumors in syngeneic BALB/c mice were subjected to repeated EGT treatments consisting of intratumoral co-injection of naked plasmids encoding the cytokine interleukin-12 (IL-12) (p35 and p40 subunits) and the suicide gene herpes simplex virus thymidine kinase (HSV-tk), followed by in vivo electroporation. The early anti-tumor effect was always stronger, and the rate of cure, as seen in the long-term follow-up, was always greater in the groups treated with combination EGT than in those treated with IL-12 or HSV-tk EGT alone. Systemic levels of IL-12 and IFN-gamma increased in both combination and IL-12-alone EGT-treated groups. Moreover, combination EGT for established subcutaneous tumors strongly reduced hematogenous lung metastases and increased survival time when live CT26 tumor cells were injected through the tail vein. Limited experiments on C57/B16 mice with murine melanoma also showed very similar trends. These results suggest that this simple and safe method of plasmid-mediated combination EGT may provide a potentially effective gene therapy for cancer.</abstract><cop>United States</cop><pub>Elsevier Limited</pub><pmid>15509510</pmid><doi>10.1016/j.ymthe.2004.07.028</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1525-0016
ispartof Molecular therapy, 2004-11, Vol.10 (5), p.929-937
issn 1525-0016
1525-0024
language eng
recordid cdi_proquest_miscellaneous_67019176
source MEDLINE; EZB-FREE-00999 freely available EZB journals; ProQuest Central UK/Ireland; Alma/SFX Local Collection
subjects Animals
Cancer therapies
Carcinoma - secondary
Carcinoma - therapy
Colorectal cancer
Cytokines
Drug Therapy, Combination
Electroporation
Experiments
Gene therapy
Gene Transfer Techniques
Genetic Therapy - methods
Herpes viruses
Interferon-gamma - analysis
Interleukin-12 - analysis
Interleukin-12 - genetics
Kinases
Lung Neoplasms - pathology
Lung Neoplasms - secondary
Lung Neoplasms - therapy
Melanoma
Mice
Mice, Inbred BALB C
Neurosurgery
Plasmids
Plasmids - genetics
Simplexvirus - enzymology
Simplexvirus - genetics
Thymidine Kinase - genetics
Tumors
title Combination electro-gene therapy using herpes virus thymidine kinase and interleukin-12 expression plasmids is highly efficient against murine carcinomas in vivo
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-18T04%3A47%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Combination%20electro-gene%20therapy%20using%20herpes%20virus%20thymidine%20kinase%20and%20interleukin-12%20expression%20plasmids%20is%20highly%20efficient%20against%20murine%20carcinomas%20in%20vivo&rft.jtitle=Molecular%20therapy&rft.au=Goto,%20Tomoaki&rft.date=2004-11&rft.volume=10&rft.issue=5&rft.spage=929&rft.epage=937&rft.pages=929-937&rft.issn=1525-0016&rft.eissn=1525-0024&rft_id=info:doi/10.1016/j.ymthe.2004.07.028&rft_dat=%3Cproquest_cross%3E67019176%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1792811389&rft_id=info:pmid/15509510&rfr_iscdi=true