A tyrosine kinase inhibitor-induced myocardial degeneration in rats through off-target phosphodiesterase inhibition
ABSTRACT PF‐04254644 is a selective kinase inhibitor of mesenchymal epithelial transition factor/hepatocyte growth factor receptor with known off‐target inhibitory activity against the phosphodiesterase (PDE) family. Rats given repeated oral doses of PF‐04254644 developed a mild to moderate myocardi...
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| Veröffentlicht in: | Journal of applied toxicology 2012-12, Vol.32 (12), p.1008-1020 |
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| creator | Hu, Wenyue Hirakawa, Brad Jessen, Bart Lee, Michelle Aguirre, Shirley |
| description | ABSTRACT
PF‐04254644 is a selective kinase inhibitor of mesenchymal epithelial transition factor/hepatocyte growth factor receptor with known off‐target inhibitory activity against the phosphodiesterase (PDE) family. Rats given repeated oral doses of PF‐04254644 developed a mild to moderate myocardial degeneration accompanied by sustained increase in heart rate and contractility. Investigative studies were conducted to delineate the mechanisms of toxicity. Microarray analysis of Sprague–Dawley rat hearts in a 6 day repeat dose study with PF‐04254644 or milrinone, a selective PDE3 inhibitor, revealed similar perturbation of the cyclic adenosine monophosphate (c‐AMP) pathway. PDE inhibition and activation of c‐AMP were further substantiated using PDE3B immunofluorescence staining and through a c‐AMP response element reporter gene assay. The intracellular calcium and oxidative stress signaling pathways were more perturbed by treatment with PF‐04254644 than milrinone. The rat cardiomyocytes calcium assay found a dose‐dependent increase in intracellular calcium with PF‐04254644 treatment. These data suggest that cardiotoxicity of PF‐04254644 was probably due to activation of c‐AMP signaling, and possibly subsequent disruption of intracellular calcium and oxidative stress signaling pathways. The greater response with PF‐04254644 as compared with milrinone in gene expression and micro‐ and ultrastructural changes is probably due to the broader panel of PDEs inhibition. Copyright © 2012 John Wiley & Sons, Ltd.
PF‐04254644, a HGFR/c‐MET inhibitor with off‐target PDE inhibition, caused cardiomyopathy and sustained increased in heart rate in rats. Investigative studies identified PDEs inhibition, activation of c‐AMP signaling, followed by intracellular calcium and oxidative stress signaling pathways as potential mechanisms of cardiac changes. Our studies substantiate the off‐target mechanisms involved in the toxic effects of PF‐04254644. |
| doi_str_mv | 10.1002/jat.2801 |
| format | Article |
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PF‐04254644 is a selective kinase inhibitor of mesenchymal epithelial transition factor/hepatocyte growth factor receptor with known off‐target inhibitory activity against the phosphodiesterase (PDE) family. Rats given repeated oral doses of PF‐04254644 developed a mild to moderate myocardial degeneration accompanied by sustained increase in heart rate and contractility. Investigative studies were conducted to delineate the mechanisms of toxicity. Microarray analysis of Sprague–Dawley rat hearts in a 6 day repeat dose study with PF‐04254644 or milrinone, a selective PDE3 inhibitor, revealed similar perturbation of the cyclic adenosine monophosphate (c‐AMP) pathway. PDE inhibition and activation of c‐AMP were further substantiated using PDE3B immunofluorescence staining and through a c‐AMP response element reporter gene assay. The intracellular calcium and oxidative stress signaling pathways were more perturbed by treatment with PF‐04254644 than milrinone. The rat cardiomyocytes calcium assay found a dose‐dependent increase in intracellular calcium with PF‐04254644 treatment. These data suggest that cardiotoxicity of PF‐04254644 was probably due to activation of c‐AMP signaling, and possibly subsequent disruption of intracellular calcium and oxidative stress signaling pathways. The greater response with PF‐04254644 as compared with milrinone in gene expression and micro‐ and ultrastructural changes is probably due to the broader panel of PDEs inhibition. Copyright © 2012 John Wiley & Sons, Ltd.
PF‐04254644, a HGFR/c‐MET inhibitor with off‐target PDE inhibition, caused cardiomyopathy and sustained increased in heart rate in rats. Investigative studies identified PDEs inhibition, activation of c‐AMP signaling, followed by intracellular calcium and oxidative stress signaling pathways as potential mechanisms of cardiac changes. Our studies substantiate the off‐target mechanisms involved in the toxic effects of PF‐04254644.</description><identifier>ISSN: 0260-437X</identifier><identifier>EISSN: 1099-1263</identifier><identifier>DOI: 10.1002/jat.2801</identifier><identifier>PMID: 22936366</identifier><identifier>CODEN: JJATDK</identifier><language>eng</language><publisher>Chichester: Blackwell Publishing Ltd</publisher><subject>Activation ; Animals ; Biological and medical sciences ; Calcium ; Calcium - metabolism ; cardiotoxicity ; Cells, Cultured ; Cyclic AMP - metabolism ; Cyclic AMP Response Element-Binding Protein - genetics ; Dose-Response Relationship, Drug ; Gene Expression - drug effects ; Genes, Reporter ; Heart ; Inhibition ; Inhibitors ; Kinases ; Male ; Medical sciences ; Milrinone - pharmacology ; Myocardium - enzymology ; Myocardium - ultrastructure ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - enzymology ; Myocytes, Cardiac - ultrastructure ; Oxidative stress ; Oxidative Stress - drug effects ; Partial differential equations ; Pathways ; PDE inhibition ; Phosphodiesterase Inhibitors - adverse effects ; Protein Kinase Inhibitors - adverse effects ; Quinolines - adverse effects ; Rats ; Rats, Sprague-Dawley ; Toxicology ; tyrosine kinase inhibitor</subject><ispartof>Journal of applied toxicology, 2012-12, Vol.32 (12), p.1008-1020</ispartof><rights>Copyright © 2012 John Wiley & Sons, Ltd.</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4831-2a29d23fe0bfa5808bed4e3742484de14b739eb9a30a80cc4943f860c5d35a603</citedby><cites>FETCH-LOGICAL-c4831-2a29d23fe0bfa5808bed4e3742484de14b739eb9a30a80cc4943f860c5d35a603</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjat.2801$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjat.2801$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26580709$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22936366$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hu, Wenyue</creatorcontrib><creatorcontrib>Hirakawa, Brad</creatorcontrib><creatorcontrib>Jessen, Bart</creatorcontrib><creatorcontrib>Lee, Michelle</creatorcontrib><creatorcontrib>Aguirre, Shirley</creatorcontrib><title>A tyrosine kinase inhibitor-induced myocardial degeneration in rats through off-target phosphodiesterase inhibition</title><title>Journal of applied toxicology</title><addtitle>J. Appl. Toxicol</addtitle><description>ABSTRACT
PF‐04254644 is a selective kinase inhibitor of mesenchymal epithelial transition factor/hepatocyte growth factor receptor with known off‐target inhibitory activity against the phosphodiesterase (PDE) family. Rats given repeated oral doses of PF‐04254644 developed a mild to moderate myocardial degeneration accompanied by sustained increase in heart rate and contractility. Investigative studies were conducted to delineate the mechanisms of toxicity. Microarray analysis of Sprague–Dawley rat hearts in a 6 day repeat dose study with PF‐04254644 or milrinone, a selective PDE3 inhibitor, revealed similar perturbation of the cyclic adenosine monophosphate (c‐AMP) pathway. PDE inhibition and activation of c‐AMP were further substantiated using PDE3B immunofluorescence staining and through a c‐AMP response element reporter gene assay. The intracellular calcium and oxidative stress signaling pathways were more perturbed by treatment with PF‐04254644 than milrinone. The rat cardiomyocytes calcium assay found a dose‐dependent increase in intracellular calcium with PF‐04254644 treatment. These data suggest that cardiotoxicity of PF‐04254644 was probably due to activation of c‐AMP signaling, and possibly subsequent disruption of intracellular calcium and oxidative stress signaling pathways. The greater response with PF‐04254644 as compared with milrinone in gene expression and micro‐ and ultrastructural changes is probably due to the broader panel of PDEs inhibition. Copyright © 2012 John Wiley & Sons, Ltd.
PF‐04254644, a HGFR/c‐MET inhibitor with off‐target PDE inhibition, caused cardiomyopathy and sustained increased in heart rate in rats. Investigative studies identified PDEs inhibition, activation of c‐AMP signaling, followed by intracellular calcium and oxidative stress signaling pathways as potential mechanisms of cardiac changes. Our studies substantiate the off‐target mechanisms involved in the toxic effects of PF‐04254644.</description><subject>Activation</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Calcium</subject><subject>Calcium - metabolism</subject><subject>cardiotoxicity</subject><subject>Cells, Cultured</subject><subject>Cyclic AMP - metabolism</subject><subject>Cyclic AMP Response Element-Binding Protein - genetics</subject><subject>Dose-Response Relationship, Drug</subject><subject>Gene Expression - drug effects</subject><subject>Genes, Reporter</subject><subject>Heart</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Milrinone - pharmacology</subject><subject>Myocardium - enzymology</subject><subject>Myocardium - ultrastructure</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - enzymology</subject><subject>Myocytes, Cardiac - ultrastructure</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Partial differential equations</subject><subject>Pathways</subject><subject>PDE inhibition</subject><subject>Phosphodiesterase Inhibitors - adverse effects</subject><subject>Protein Kinase Inhibitors - adverse effects</subject><subject>Quinolines - adverse effects</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Toxicology</subject><subject>tyrosine kinase inhibitor</subject><issn>0260-437X</issn><issn>1099-1263</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0V1rFDEUBuAgit1WwV8gARG8mZqvSTKXy2KrUhSlonchk5zZzXZ2siYz6P77pnTsgiBehATy5JwkL0IvKDmnhLC3WzueM03oI7SgpGkqyiR_jBaESVIJrn6coNOct4SUPaafohPGGi65lAuUl3g8pJjDAPgmDDYDDsMmtGGMqQqDnxx4vDtEZ5MPtsce1jBAsmOIQ5G4rDIeNylO6w2OXVeNNq1hxPtNzGX4AHks_Fi2nHuGnnS2z_B8ns_Qt4t316v31dXnyw-r5VXlhOa0YpY1nvEOSNvZWhPdghfAlWBCCw9UtIo30DaWE6uJc6IRvNOSuNrz2krCz9Cb-7r7FH9O5SJmF7KDvrcDxCkbqmpec14L9X8qBOeqroUs9NVfdBunNJSHFMWF1lopeizoyufmBJ3Zp7Cz6WAoMXeZmZKZucus0JdzwandgX-Af0Iq4PUMbHa275IdXMhHJ8vnKNIUV927X6GHwz8bmo_L67nx7EPJ6PeDt-nGSFVea75_ujRfpNZsdfHVUH4LFa-8qw</recordid><startdate>201212</startdate><enddate>201212</enddate><creator>Hu, Wenyue</creator><creator>Hirakawa, Brad</creator><creator>Jessen, Bart</creator><creator>Lee, Michelle</creator><creator>Aguirre, Shirley</creator><general>Blackwell Publishing Ltd</general><general>Wiley</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>IQODW</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>7ST</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>K9.</scope><scope>SOI</scope><scope>8FD</scope><scope>FR3</scope><scope>KR7</scope></search><sort><creationdate>201212</creationdate><title>A tyrosine kinase inhibitor-induced myocardial degeneration in rats through off-target phosphodiesterase inhibition</title><author>Hu, Wenyue ; Hirakawa, Brad ; Jessen, Bart ; Lee, Michelle ; Aguirre, Shirley</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4831-2a29d23fe0bfa5808bed4e3742484de14b739eb9a30a80cc4943f860c5d35a603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Activation</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Calcium</topic><topic>Calcium - metabolism</topic><topic>cardiotoxicity</topic><topic>Cells, Cultured</topic><topic>Cyclic AMP - metabolism</topic><topic>Cyclic AMP Response Element-Binding Protein - genetics</topic><topic>Dose-Response Relationship, Drug</topic><topic>Gene Expression - drug effects</topic><topic>Genes, Reporter</topic><topic>Heart</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>Kinases</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Milrinone - pharmacology</topic><topic>Myocardium - enzymology</topic><topic>Myocardium - ultrastructure</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - enzymology</topic><topic>Myocytes, Cardiac - ultrastructure</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>Partial differential equations</topic><topic>Pathways</topic><topic>PDE inhibition</topic><topic>Phosphodiesterase Inhibitors - adverse effects</topic><topic>Protein Kinase Inhibitors - adverse effects</topic><topic>Quinolines - adverse effects</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Toxicology</topic><topic>tyrosine kinase inhibitor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hu, Wenyue</creatorcontrib><creatorcontrib>Hirakawa, Brad</creatorcontrib><creatorcontrib>Jessen, Bart</creatorcontrib><creatorcontrib>Lee, Michelle</creatorcontrib><creatorcontrib>Aguirre, Shirley</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Environment Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Environment Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Civil Engineering Abstracts</collection><jtitle>Journal of applied toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hu, Wenyue</au><au>Hirakawa, Brad</au><au>Jessen, Bart</au><au>Lee, Michelle</au><au>Aguirre, Shirley</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A tyrosine kinase inhibitor-induced myocardial degeneration in rats through off-target phosphodiesterase inhibition</atitle><jtitle>Journal of applied toxicology</jtitle><addtitle>J. Appl. Toxicol</addtitle><date>2012-12</date><risdate>2012</risdate><volume>32</volume><issue>12</issue><spage>1008</spage><epage>1020</epage><pages>1008-1020</pages><issn>0260-437X</issn><eissn>1099-1263</eissn><coden>JJATDK</coden><abstract>ABSTRACT
PF‐04254644 is a selective kinase inhibitor of mesenchymal epithelial transition factor/hepatocyte growth factor receptor with known off‐target inhibitory activity against the phosphodiesterase (PDE) family. Rats given repeated oral doses of PF‐04254644 developed a mild to moderate myocardial degeneration accompanied by sustained increase in heart rate and contractility. Investigative studies were conducted to delineate the mechanisms of toxicity. Microarray analysis of Sprague–Dawley rat hearts in a 6 day repeat dose study with PF‐04254644 or milrinone, a selective PDE3 inhibitor, revealed similar perturbation of the cyclic adenosine monophosphate (c‐AMP) pathway. PDE inhibition and activation of c‐AMP were further substantiated using PDE3B immunofluorescence staining and through a c‐AMP response element reporter gene assay. The intracellular calcium and oxidative stress signaling pathways were more perturbed by treatment with PF‐04254644 than milrinone. The rat cardiomyocytes calcium assay found a dose‐dependent increase in intracellular calcium with PF‐04254644 treatment. These data suggest that cardiotoxicity of PF‐04254644 was probably due to activation of c‐AMP signaling, and possibly subsequent disruption of intracellular calcium and oxidative stress signaling pathways. The greater response with PF‐04254644 as compared with milrinone in gene expression and micro‐ and ultrastructural changes is probably due to the broader panel of PDEs inhibition. Copyright © 2012 John Wiley & Sons, Ltd.
PF‐04254644, a HGFR/c‐MET inhibitor with off‐target PDE inhibition, caused cardiomyopathy and sustained increased in heart rate in rats. Investigative studies identified PDEs inhibition, activation of c‐AMP signaling, followed by intracellular calcium and oxidative stress signaling pathways as potential mechanisms of cardiac changes. Our studies substantiate the off‐target mechanisms involved in the toxic effects of PF‐04254644.</abstract><cop>Chichester</cop><pub>Blackwell Publishing Ltd</pub><pmid>22936366</pmid><doi>10.1002/jat.2801</doi><tpages>13</tpages></addata></record> |
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| subjects | Activation Animals Biological and medical sciences Calcium Calcium - metabolism cardiotoxicity Cells, Cultured Cyclic AMP - metabolism Cyclic AMP Response Element-Binding Protein - genetics Dose-Response Relationship, Drug Gene Expression - drug effects Genes, Reporter Heart Inhibition Inhibitors Kinases Male Medical sciences Milrinone - pharmacology Myocardium - enzymology Myocardium - ultrastructure Myocytes, Cardiac - drug effects Myocytes, Cardiac - enzymology Myocytes, Cardiac - ultrastructure Oxidative stress Oxidative Stress - drug effects Partial differential equations Pathways PDE inhibition Phosphodiesterase Inhibitors - adverse effects Protein Kinase Inhibitors - adverse effects Quinolines - adverse effects Rats Rats, Sprague-Dawley Toxicology tyrosine kinase inhibitor |
| title | A tyrosine kinase inhibitor-induced myocardial degeneration in rats through off-target phosphodiesterase inhibition |
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