Loading…

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

α-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-08, Vol.106 (33), p.13754-13758
Main Authors: Lladó, Victoria, Terés, Silvia, Higuera, Mónica, Álvarez, Rafael, Noguera-Salva, Maria Antònia, Halver, John E, Escribá, Pablo V, Busquets, Xavier
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-c620t-4982dff02c51dca2ba1eb16e345b7ca2e5a1373ace5d2ff93e84831ae002e9e53
cites cdi_FETCH-LOGICAL-c620t-4982dff02c51dca2ba1eb16e345b7ca2e5a1373ace5d2ff93e84831ae002e9e53
container_end_page 13758
container_issue 33
container_start_page 13754
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 106
creator Lladó, Victoria
Terés, Silvia
Higuera, Mónica
Álvarez, Rafael
Noguera-Salva, Maria Antònia
Halver, John E
Escribá, Pablo V
Busquets, Xavier
description α-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.
doi_str_mv 10.1073/pnas.0907300106
format article
fullrecord <record><control><sourceid>jstor_fao_a</sourceid><recordid>TN_cdi_fao_agris_US201301669083</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><jstor_id>40484313</jstor_id><sourcerecordid>40484313</sourcerecordid><originalsourceid>FETCH-LOGICAL-c620t-4982dff02c51dca2ba1eb16e345b7ca2e5a1373ace5d2ff93e84831ae002e9e53</originalsourceid><addsrcrecordid>eNqFkUtvEzEUhUcIRENhzQqwWCCxmPb6Mc7MBglVvKRKIEHXluO5bpxO7NT2hObf4yFRA2xY2db5zrGPb1U9p3BGYc7PN16nM-jKFoCCfFDNKHS0lqKDh9UMgM3rVjBxUj1JaQUAXdPC4-qEdlLKphWzynxz25D1QGIYkARLerfc9THYMOiMJGI_mqwTkhsfzE0ffnriPMlLJNpnZ7Q3GIk22W1d3k1-Vv_23-1KnjNFcv3T6pHVQ8Jnh_W0uvr44cfF5_ry66cvF-8vayMZ5Fp0LeutBWYa2hvNFprigkrkolnMyxkbTfmca4NNz6ztOLai5VRjqYkdNvy0erfP3YyLNfYGfY56UJvo1jruVNBO_a14t1TXYavYnIGgtAS8OQTEcDtiymrtksFh0B7DmBSDlkIjuwK-_gdchTH6Uq4wtEQxwQp0vodMDClFtPcvoaCm6alpeuo4veJ4-WeBI38YVwHIAZicxzipOFflc5oJefsfRNlxGDLe5cK-2LOrlEO8hwWIchflRX-1160OSl9Hl9TV91KQA5Wyg5bzX6LDw4s</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>201411242</pqid></control><display><type>article</type><title>Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid</title><source>JSTOR Archival Journals and Primary Sources Collection</source><source>PubMed Central (Training)</source><creator>Lladó, Victoria ; Terés, Silvia ; Higuera, Mónica ; Álvarez, Rafael ; Noguera-Salva, Maria Antònia ; Halver, John E ; Escribá, Pablo V ; Busquets, Xavier</creator><creatorcontrib>Lladó, Victoria ; Terés, Silvia ; Higuera, Mónica ; Álvarez, Rafael ; Noguera-Salva, Maria Antònia ; Halver, John E ; Escribá, Pablo V ; Busquets, Xavier</creatorcontrib><description>α-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0907300106</identifier><identifier>PMID: 19666584</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Antineoplastic Agents - pharmacology ; Antineoplastics ; Apoptosis ; Biochemistry ; Biological Sciences ; Cell cycle ; Cell growth ; Cell Line, Tumor ; Cell lines ; Cell Membrane - metabolism ; Cell membranes ; DNA ; Fatty acids ; Fatty Acids - chemistry ; Folic Acid Antagonists - pharmacology ; Humans ; Jurkat Cells ; Leucovorin - chemistry ; Leukemia ; Lipids ; Lipids - chemistry ; Membranes ; Methotrexate - pharmacology ; Neoplasms - drug therapy ; Oleic Acids - chemistry ; Oleic Acids - pharmacology ; Substrate Specificity ; T lymphocytes ; Tetrahydrofolate Dehydrogenase - chemistry ; Tetrahydrofolate Dehydrogenase - physiology</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2009-08, Vol.106 (33), p.13754-13758</ispartof><rights>Copyright National Academy of Sciences Aug 18, 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c620t-4982dff02c51dca2ba1eb16e345b7ca2e5a1373ace5d2ff93e84831ae002e9e53</citedby><cites>FETCH-LOGICAL-c620t-4982dff02c51dca2ba1eb16e345b7ca2e5a1373ace5d2ff93e84831ae002e9e53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/106/33.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/40484313$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/40484313$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793,58238,58471</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19666584$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lladó, Victoria</creatorcontrib><creatorcontrib>Terés, Silvia</creatorcontrib><creatorcontrib>Higuera, Mónica</creatorcontrib><creatorcontrib>Álvarez, Rafael</creatorcontrib><creatorcontrib>Noguera-Salva, Maria Antònia</creatorcontrib><creatorcontrib>Halver, John E</creatorcontrib><creatorcontrib>Escribá, Pablo V</creatorcontrib><creatorcontrib>Busquets, Xavier</creatorcontrib><title>Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>α-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastics</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biological Sciences</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Cell Membrane - metabolism</subject><subject>Cell membranes</subject><subject>DNA</subject><subject>Fatty acids</subject><subject>Fatty Acids - chemistry</subject><subject>Folic Acid Antagonists - pharmacology</subject><subject>Humans</subject><subject>Jurkat Cells</subject><subject>Leucovorin - chemistry</subject><subject>Leukemia</subject><subject>Lipids</subject><subject>Lipids - chemistry</subject><subject>Membranes</subject><subject>Methotrexate - pharmacology</subject><subject>Neoplasms - drug therapy</subject><subject>Oleic Acids - chemistry</subject><subject>Oleic Acids - pharmacology</subject><subject>Substrate Specificity</subject><subject>T lymphocytes</subject><subject>Tetrahydrofolate Dehydrogenase - chemistry</subject><subject>Tetrahydrofolate Dehydrogenase - physiology</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNqFkUtvEzEUhUcIRENhzQqwWCCxmPb6Mc7MBglVvKRKIEHXluO5bpxO7NT2hObf4yFRA2xY2db5zrGPb1U9p3BGYc7PN16nM-jKFoCCfFDNKHS0lqKDh9UMgM3rVjBxUj1JaQUAXdPC4-qEdlLKphWzynxz25D1QGIYkARLerfc9THYMOiMJGI_mqwTkhsfzE0ffnriPMlLJNpnZ7Q3GIk22W1d3k1-Vv_23-1KnjNFcv3T6pHVQ8Jnh_W0uvr44cfF5_ry66cvF-8vayMZ5Fp0LeutBWYa2hvNFprigkrkolnMyxkbTfmca4NNz6ztOLai5VRjqYkdNvy0erfP3YyLNfYGfY56UJvo1jruVNBO_a14t1TXYavYnIGgtAS8OQTEcDtiymrtksFh0B7DmBSDlkIjuwK-_gdchTH6Uq4wtEQxwQp0vodMDClFtPcvoaCm6alpeuo4veJ4-WeBI38YVwHIAZicxzipOFflc5oJefsfRNlxGDLe5cK-2LOrlEO8hwWIchflRX-1160OSl9Hl9TV91KQA5Wyg5bzX6LDw4s</recordid><startdate>20090818</startdate><enddate>20090818</enddate><creator>Lladó, Victoria</creator><creator>Terés, Silvia</creator><creator>Higuera, Mónica</creator><creator>Álvarez, Rafael</creator><creator>Noguera-Salva, Maria Antònia</creator><creator>Halver, John E</creator><creator>Escribá, Pablo V</creator><creator>Busquets, Xavier</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7QO</scope><scope>5PM</scope></search><sort><creationdate>20090818</creationdate><title>Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid</title><author>Lladó, Victoria ; Terés, Silvia ; Higuera, Mónica ; Álvarez, Rafael ; Noguera-Salva, Maria Antònia ; Halver, John E ; Escribá, Pablo V ; Busquets, Xavier</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c620t-4982dff02c51dca2ba1eb16e345b7ca2e5a1373ace5d2ff93e84831ae002e9e53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastics</topic><topic>Apoptosis</topic><topic>Biochemistry</topic><topic>Biological Sciences</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell lines</topic><topic>Cell Membrane - metabolism</topic><topic>Cell membranes</topic><topic>DNA</topic><topic>Fatty acids</topic><topic>Fatty Acids - chemistry</topic><topic>Folic Acid Antagonists - pharmacology</topic><topic>Humans</topic><topic>Jurkat Cells</topic><topic>Leucovorin - chemistry</topic><topic>Leukemia</topic><topic>Lipids</topic><topic>Lipids - chemistry</topic><topic>Membranes</topic><topic>Methotrexate - pharmacology</topic><topic>Neoplasms - drug therapy</topic><topic>Oleic Acids - chemistry</topic><topic>Oleic Acids - pharmacology</topic><topic>Substrate Specificity</topic><topic>T lymphocytes</topic><topic>Tetrahydrofolate Dehydrogenase - chemistry</topic><topic>Tetrahydrofolate Dehydrogenase - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lladó, Victoria</creatorcontrib><creatorcontrib>Terés, Silvia</creatorcontrib><creatorcontrib>Higuera, Mónica</creatorcontrib><creatorcontrib>Álvarez, Rafael</creatorcontrib><creatorcontrib>Noguera-Salva, Maria Antònia</creatorcontrib><creatorcontrib>Halver, John E</creatorcontrib><creatorcontrib>Escribá, Pablo V</creatorcontrib><creatorcontrib>Busquets, Xavier</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Biotechnology Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lladó, Victoria</au><au>Terés, Silvia</au><au>Higuera, Mónica</au><au>Álvarez, Rafael</au><au>Noguera-Salva, Maria Antònia</au><au>Halver, John E</au><au>Escribá, Pablo V</au><au>Busquets, Xavier</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2009-08-18</date><risdate>2009</risdate><volume>106</volume><issue>33</issue><spage>13754</spage><epage>13758</epage><pages>13754-13758</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>α-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>19666584</pmid><doi>10.1073/pnas.0907300106</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0027-8424
ispartof Proceedings of the National Academy of Sciences - PNAS, 2009-08, Vol.106 (33), p.13754-13758
issn 0027-8424
1091-6490
language eng
recordid cdi_fao_agris_US201301669083
source JSTOR Archival Journals and Primary Sources Collection; PubMed Central (Training)
subjects Antineoplastic Agents - pharmacology
Antineoplastics
Apoptosis
Biochemistry
Biological Sciences
Cell cycle
Cell growth
Cell Line, Tumor
Cell lines
Cell Membrane - metabolism
Cell membranes
DNA
Fatty acids
Fatty Acids - chemistry
Folic Acid Antagonists - pharmacology
Humans
Jurkat Cells
Leucovorin - chemistry
Leukemia
Lipids
Lipids - chemistry
Membranes
Methotrexate - pharmacology
Neoplasms - drug therapy
Oleic Acids - chemistry
Oleic Acids - pharmacology
Substrate Specificity
T lymphocytes
Tetrahydrofolate Dehydrogenase - chemistry
Tetrahydrofolate Dehydrogenase - physiology
title Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T21%3A13%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_fao_a&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Pivotal%20role%20of%20dihydrofolate%20reductase%20knockdown%20in%20the%20anticancer%20activity%20of%202-hydroxyoleic%20acid&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Llad%C3%B3,%20Victoria&rft.date=2009-08-18&rft.volume=106&rft.issue=33&rft.spage=13754&rft.epage=13758&rft.pages=13754-13758&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.0907300106&rft_dat=%3Cjstor_fao_a%3E40484313%3C/jstor_fao_a%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c620t-4982dff02c51dca2ba1eb16e345b7ca2e5a1373ace5d2ff93e84831ae002e9e53%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=201411242&rft_id=info:pmid/19666584&rft_jstor_id=40484313&rfr_iscdi=true