IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression
Although temozolomide has shown clinical activity against neuroblastoma, this activity is likely limited by the DNA repair enzyme O 6 -methylguanine DNA methyltransferase (MGMT). We hypothesized that IFN-β could sensitize neuroblastoma cells to the cytotoxic effects of temozolomide through its abili...
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| Veröffentlicht in: | Molecular cancer therapeutics 2008-12, Vol.7 (12), p.3852 |
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| creator | Rosati, Shannon F Williams, Regan F Nunnally, Lindsey C McGee, Mackenzie C Sims, Thomas L Tracey, Lorraine Zhou, Junfang Fan, Meiyun Ng, Catherine Y Nathwani, Amit C Stewart, Clinton F Pfeffer, Lawrence M Davidoff, Andrew M |
| description | Although temozolomide has shown clinical activity against neuroblastoma, this activity is likely limited by the DNA repair
enzyme O 6 -methylguanine DNA methyltransferase (MGMT). We hypothesized that IFN-β could sensitize neuroblastoma cells to the cytotoxic
effects of temozolomide through its ability to down-regulate MGMT expression. In vitro proliferation of three neuroblastoma cell lines treated with IFN-β and temozolomide alone or in combination was examined.
Antitumor activity was assessed in both localized and disseminated neuroblastoma xenografts using single-agent and combination
therapy, with continuous delivery of IFN-β being established by a liver-targeted adeno-associated virus-mediated approach.
Two neuroblastoma cell lines (NB-1691 and SK-N-AS) were found to have high baseline levels of MGMT expression, whereas a third
cell line (CHLA-255) had low levels. Temozolomide had little effect on in vitro proliferation of the neuroblastoma cell lines with high MGMT expression, but pretreatment with IFN-β significantly decreased
MGMT expression and cell counts (NB-1691: 36 ± 3% of control, P = 0.0008; SK-N-AS: 54 ± 7% control, P = 0.003). In vivo , NB-1691 tumors in CB17-SCID mice treated with the combination of IFN-β and temozolomide had lower MGMT expression and a
significantly reduced tumor burden, both localized [percent initial tumor volume: 2,516 ± 680% (control) versus 1,272 ± 330%
(temozolomide), P = 0.01; 1,348 ± 220%, P = 0.03 (IFN-β); 352 ± 110%, P = 0.0001 (combo)] and disseminated [bioluminescent signal: control (1.32e 10 ± 6.5e 9 ) versus IFN-β (2.78e 8 ± 3.09e 8 ), P = 0.025, versus temozolomide (2.06e 9 ± 1.55e 9 ), P = 0.1, versus combination (2.13e 7 ± 7.67e 6 ), P = 0.009]. IFN-β appears to sensitize neuroblastoma cells to the cytotoxic effects of temozolomide through attenuation of
MGMT expression. Thus, IFN-β and temozolomide may be a useful combination for treating children with this difficult disease.
[Mol Cancer Ther 2008;7(12):3852–8] |
| doi_str_mv | 10.1158/1535-7163.MCT-08-0806 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_highw</sourceid><recordid>TN_cdi_pubmed_primary_19056675</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>19056675</sourcerecordid><originalsourceid>FETCH-LOGICAL-h1346-30e5f43835e848da856abeb266baa0df95552c8a78ea3f3db912d4c976d6bd803</originalsourceid><addsrcrecordid>eNo1kNtKxDAQhoMonh9ByaU31aRp0vRS1iN4uNHrMm2m20ibLEmqrm_g6_ggPpOLqzDwDx8fw_ATcsTZKedSn3EpZFZyJU7vZ08Z06thaoPsrrjOtOTF5u--dnbIXowvjHFd5Xyb7PCKSaVKuUs-b68esu8vGtFFm-wHRupwCr4ZICY_Ak2eph4puGTTNPpAoU321aYl9R1NOPoPP_jRGqTNko7eTAMk6-b0UWUjpn45zCdw1iG9eDina5ICuNhhgIgU3xcBY7TeHZCtDoaIh3-5T56vLp9mN9nd4_Xt7Pwu67koVCYYyq4QWkjUhTagpYIGm1ypBoCZrpJS5q2GUiOITpim4rkp2qpURjVGM7FPjtd3F1MzoqkXwY4QlvV_JyvhZC30dt6_2YB1C67FsPoTIbR9XdY8r4WWufgBuBN3kg</addsrcrecordid><sourcetype>Index Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression</title><source>AACR</source><source>MEDLINE</source><source>EZB Electronic Journals Library</source><creator>Rosati, Shannon F ; Williams, Regan F ; Nunnally, Lindsey C ; McGee, Mackenzie C ; Sims, Thomas L ; Tracey, Lorraine ; Zhou, Junfang ; Fan, Meiyun ; Ng, Catherine Y ; Nathwani, Amit C ; Stewart, Clinton F ; Pfeffer, Lawrence M ; Davidoff, Andrew M</creator><creatorcontrib>Rosati, Shannon F ; Williams, Regan F ; Nunnally, Lindsey C ; McGee, Mackenzie C ; Sims, Thomas L ; Tracey, Lorraine ; Zhou, Junfang ; Fan, Meiyun ; Ng, Catherine Y ; Nathwani, Amit C ; Stewart, Clinton F ; Pfeffer, Lawrence M ; Davidoff, Andrew M</creatorcontrib><description>Although temozolomide has shown clinical activity against neuroblastoma, this activity is likely limited by the DNA repair
enzyme O 6 -methylguanine DNA methyltransferase (MGMT). We hypothesized that IFN-β could sensitize neuroblastoma cells to the cytotoxic
effects of temozolomide through its ability to down-regulate MGMT expression. In vitro proliferation of three neuroblastoma cell lines treated with IFN-β and temozolomide alone or in combination was examined.
Antitumor activity was assessed in both localized and disseminated neuroblastoma xenografts using single-agent and combination
therapy, with continuous delivery of IFN-β being established by a liver-targeted adeno-associated virus-mediated approach.
Two neuroblastoma cell lines (NB-1691 and SK-N-AS) were found to have high baseline levels of MGMT expression, whereas a third
cell line (CHLA-255) had low levels. Temozolomide had little effect on in vitro proliferation of the neuroblastoma cell lines with high MGMT expression, but pretreatment with IFN-β significantly decreased
MGMT expression and cell counts (NB-1691: 36 ± 3% of control, P = 0.0008; SK-N-AS: 54 ± 7% control, P = 0.003). In vivo , NB-1691 tumors in CB17-SCID mice treated with the combination of IFN-β and temozolomide had lower MGMT expression and a
significantly reduced tumor burden, both localized [percent initial tumor volume: 2,516 ± 680% (control) versus 1,272 ± 330%
(temozolomide), P = 0.01; 1,348 ± 220%, P = 0.03 (IFN-β); 352 ± 110%, P = 0.0001 (combo)] and disseminated [bioluminescent signal: control (1.32e 10 ± 6.5e 9 ) versus IFN-β (2.78e 8 ± 3.09e 8 ), P = 0.025, versus temozolomide (2.06e 9 ± 1.55e 9 ), P = 0.1, versus combination (2.13e 7 ± 7.67e 6 ), P = 0.009]. IFN-β appears to sensitize neuroblastoma cells to the cytotoxic effects of temozolomide through attenuation of
MGMT expression. Thus, IFN-β and temozolomide may be a useful combination for treating children with this difficult disease.
[Mol Cancer Ther 2008;7(12):3852–8]</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-08-0806</identifier><identifier>PMID: 19056675</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; Dacarbazine - analogs & derivatives ; Dacarbazine - pharmacology ; Drug Resistance, Neoplasm ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Humans ; IFN-β ; Interferon-beta - metabolism ; Interleukins - physiology ; Male ; MGMT ; Mice ; Mice, SCID ; Neoplasm Transplantation ; neuroblastoma ; Neuroblastoma - drug therapy ; Neuroblastoma - metabolism ; O-Methylguanine-DNA Methyltransferase - metabolism ; temozolomide</subject><ispartof>Molecular cancer therapeutics, 2008-12, Vol.7 (12), p.3852</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19056675$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rosati, Shannon F</creatorcontrib><creatorcontrib>Williams, Regan F</creatorcontrib><creatorcontrib>Nunnally, Lindsey C</creatorcontrib><creatorcontrib>McGee, Mackenzie C</creatorcontrib><creatorcontrib>Sims, Thomas L</creatorcontrib><creatorcontrib>Tracey, Lorraine</creatorcontrib><creatorcontrib>Zhou, Junfang</creatorcontrib><creatorcontrib>Fan, Meiyun</creatorcontrib><creatorcontrib>Ng, Catherine Y</creatorcontrib><creatorcontrib>Nathwani, Amit C</creatorcontrib><creatorcontrib>Stewart, Clinton F</creatorcontrib><creatorcontrib>Pfeffer, Lawrence M</creatorcontrib><creatorcontrib>Davidoff, Andrew M</creatorcontrib><title>IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Although temozolomide has shown clinical activity against neuroblastoma, this activity is likely limited by the DNA repair
enzyme O 6 -methylguanine DNA methyltransferase (MGMT). We hypothesized that IFN-β could sensitize neuroblastoma cells to the cytotoxic
effects of temozolomide through its ability to down-regulate MGMT expression. In vitro proliferation of three neuroblastoma cell lines treated with IFN-β and temozolomide alone or in combination was examined.
Antitumor activity was assessed in both localized and disseminated neuroblastoma xenografts using single-agent and combination
therapy, with continuous delivery of IFN-β being established by a liver-targeted adeno-associated virus-mediated approach.
Two neuroblastoma cell lines (NB-1691 and SK-N-AS) were found to have high baseline levels of MGMT expression, whereas a third
cell line (CHLA-255) had low levels. Temozolomide had little effect on in vitro proliferation of the neuroblastoma cell lines with high MGMT expression, but pretreatment with IFN-β significantly decreased
MGMT expression and cell counts (NB-1691: 36 ± 3% of control, P = 0.0008; SK-N-AS: 54 ± 7% control, P = 0.003). In vivo , NB-1691 tumors in CB17-SCID mice treated with the combination of IFN-β and temozolomide had lower MGMT expression and a
significantly reduced tumor burden, both localized [percent initial tumor volume: 2,516 ± 680% (control) versus 1,272 ± 330%
(temozolomide), P = 0.01; 1,348 ± 220%, P = 0.03 (IFN-β); 352 ± 110%, P = 0.0001 (combo)] and disseminated [bioluminescent signal: control (1.32e 10 ± 6.5e 9 ) versus IFN-β (2.78e 8 ± 3.09e 8 ), P = 0.025, versus temozolomide (2.06e 9 ± 1.55e 9 ), P = 0.1, versus combination (2.13e 7 ± 7.67e 6 ), P = 0.009]. IFN-β appears to sensitize neuroblastoma cells to the cytotoxic effects of temozolomide through attenuation of
MGMT expression. Thus, IFN-β and temozolomide may be a useful combination for treating children with this difficult disease.
[Mol Cancer Ther 2008;7(12):3852–8]</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Dacarbazine - analogs & derivatives</subject><subject>Dacarbazine - pharmacology</subject><subject>Drug Resistance, Neoplasm</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>IFN-β</subject><subject>Interferon-beta - metabolism</subject><subject>Interleukins - physiology</subject><subject>Male</subject><subject>MGMT</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Neoplasm Transplantation</subject><subject>neuroblastoma</subject><subject>Neuroblastoma - drug therapy</subject><subject>Neuroblastoma - metabolism</subject><subject>O-Methylguanine-DNA Methyltransferase - metabolism</subject><subject>temozolomide</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kNtKxDAQhoMonh9ByaU31aRp0vRS1iN4uNHrMm2m20ibLEmqrm_g6_ggPpOLqzDwDx8fw_ATcsTZKedSn3EpZFZyJU7vZ08Z06thaoPsrrjOtOTF5u--dnbIXowvjHFd5Xyb7PCKSaVKuUs-b68esu8vGtFFm-wHRupwCr4ZICY_Ak2eph4puGTTNPpAoU321aYl9R1NOPoPP_jRGqTNko7eTAMk6-b0UWUjpn45zCdw1iG9eDina5ICuNhhgIgU3xcBY7TeHZCtDoaIh3-5T56vLp9mN9nd4_Xt7Pwu67koVCYYyq4QWkjUhTagpYIGm1ypBoCZrpJS5q2GUiOITpim4rkp2qpURjVGM7FPjtd3F1MzoqkXwY4QlvV_JyvhZC30dt6_2YB1C67FsPoTIbR9XdY8r4WWufgBuBN3kg</recordid><startdate>20081201</startdate><enddate>20081201</enddate><creator>Rosati, Shannon F</creator><creator>Williams, Regan F</creator><creator>Nunnally, Lindsey C</creator><creator>McGee, Mackenzie C</creator><creator>Sims, Thomas L</creator><creator>Tracey, Lorraine</creator><creator>Zhou, Junfang</creator><creator>Fan, Meiyun</creator><creator>Ng, Catherine Y</creator><creator>Nathwani, Amit C</creator><creator>Stewart, Clinton F</creator><creator>Pfeffer, Lawrence M</creator><creator>Davidoff, Andrew M</creator><general>American Association for Cancer Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20081201</creationdate><title>IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression</title><author>Rosati, Shannon F ; Williams, Regan F ; Nunnally, Lindsey C ; McGee, Mackenzie C ; Sims, Thomas L ; Tracey, Lorraine ; Zhou, Junfang ; Fan, Meiyun ; Ng, Catherine Y ; Nathwani, Amit C ; Stewart, Clinton F ; Pfeffer, Lawrence M ; Davidoff, Andrew M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h1346-30e5f43835e848da856abeb266baa0df95552c8a78ea3f3db912d4c976d6bd803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Dacarbazine - analogs & derivatives</topic><topic>Dacarbazine - pharmacology</topic><topic>Drug Resistance, Neoplasm</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>IFN-β</topic><topic>Interferon-beta - metabolism</topic><topic>Interleukins - physiology</topic><topic>Male</topic><topic>MGMT</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Neoplasm Transplantation</topic><topic>neuroblastoma</topic><topic>Neuroblastoma - drug therapy</topic><topic>Neuroblastoma - metabolism</topic><topic>O-Methylguanine-DNA Methyltransferase - metabolism</topic><topic>temozolomide</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rosati, Shannon F</creatorcontrib><creatorcontrib>Williams, Regan F</creatorcontrib><creatorcontrib>Nunnally, Lindsey C</creatorcontrib><creatorcontrib>McGee, Mackenzie C</creatorcontrib><creatorcontrib>Sims, Thomas L</creatorcontrib><creatorcontrib>Tracey, Lorraine</creatorcontrib><creatorcontrib>Zhou, Junfang</creatorcontrib><creatorcontrib>Fan, Meiyun</creatorcontrib><creatorcontrib>Ng, Catherine Y</creatorcontrib><creatorcontrib>Nathwani, Amit C</creatorcontrib><creatorcontrib>Stewart, Clinton F</creatorcontrib><creatorcontrib>Pfeffer, Lawrence M</creatorcontrib><creatorcontrib>Davidoff, Andrew M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rosati, Shannon F</au><au>Williams, Regan F</au><au>Nunnally, Lindsey C</au><au>McGee, Mackenzie C</au><au>Sims, Thomas L</au><au>Tracey, Lorraine</au><au>Zhou, Junfang</au><au>Fan, Meiyun</au><au>Ng, Catherine Y</au><au>Nathwani, Amit C</au><au>Stewart, Clinton F</au><au>Pfeffer, Lawrence M</au><au>Davidoff, Andrew M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2008-12-01</date><risdate>2008</risdate><volume>7</volume><issue>12</issue><spage>3852</spage><pages>3852-</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Although temozolomide has shown clinical activity against neuroblastoma, this activity is likely limited by the DNA repair
enzyme O 6 -methylguanine DNA methyltransferase (MGMT). We hypothesized that IFN-β could sensitize neuroblastoma cells to the cytotoxic
effects of temozolomide through its ability to down-regulate MGMT expression. In vitro proliferation of three neuroblastoma cell lines treated with IFN-β and temozolomide alone or in combination was examined.
Antitumor activity was assessed in both localized and disseminated neuroblastoma xenografts using single-agent and combination
therapy, with continuous delivery of IFN-β being established by a liver-targeted adeno-associated virus-mediated approach.
Two neuroblastoma cell lines (NB-1691 and SK-N-AS) were found to have high baseline levels of MGMT expression, whereas a third
cell line (CHLA-255) had low levels. Temozolomide had little effect on in vitro proliferation of the neuroblastoma cell lines with high MGMT expression, but pretreatment with IFN-β significantly decreased
MGMT expression and cell counts (NB-1691: 36 ± 3% of control, P = 0.0008; SK-N-AS: 54 ± 7% control, P = 0.003). In vivo , NB-1691 tumors in CB17-SCID mice treated with the combination of IFN-β and temozolomide had lower MGMT expression and a
significantly reduced tumor burden, both localized [percent initial tumor volume: 2,516 ± 680% (control) versus 1,272 ± 330%
(temozolomide), P = 0.01; 1,348 ± 220%, P = 0.03 (IFN-β); 352 ± 110%, P = 0.0001 (combo)] and disseminated [bioluminescent signal: control (1.32e 10 ± 6.5e 9 ) versus IFN-β (2.78e 8 ± 3.09e 8 ), P = 0.025, versus temozolomide (2.06e 9 ± 1.55e 9 ), P = 0.1, versus combination (2.13e 7 ± 7.67e 6 ), P = 0.009]. IFN-β appears to sensitize neuroblastoma cells to the cytotoxic effects of temozolomide through attenuation of
MGMT expression. Thus, IFN-β and temozolomide may be a useful combination for treating children with this difficult disease.
[Mol Cancer Ther 2008;7(12):3852–8]</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>19056675</pmid><doi>10.1158/1535-7163.MCT-08-0806</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular cancer therapeutics, 2008-12, Vol.7 (12), p.3852 |
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| language | eng |
| recordid | cdi_pubmed_primary_19056675 |
| source | AACR; MEDLINE; EZB Electronic Journals Library |
| subjects | Animals Antineoplastic Agents - pharmacology Cell Line, Tumor Dacarbazine - analogs & derivatives Dacarbazine - pharmacology Drug Resistance, Neoplasm Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Humans IFN-β Interferon-beta - metabolism Interleukins - physiology Male MGMT Mice Mice, SCID Neoplasm Transplantation neuroblastoma Neuroblastoma - drug therapy Neuroblastoma - metabolism O-Methylguanine-DNA Methyltransferase - metabolism temozolomide |
| title | IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression |
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