Sublethal Doses of an Anti-erbB2 Antibody Leads to Death by Apoptosis in Cardiomyocytes Sensitized by Low Prosenescent Doses of Epirubicin: The Protective Role of Dexrazoxane
The cardiotoxic synergism resulting from the sequential treatment with anthracyclines and trastuzumab has been attributed to the trastuzumab-induced loss of the erbB2-related functions that serve as a salvage pathway against the damaging effects of anthracyclines. Cellular senescence is a novel mech...
Gespeichert in:
| Veröffentlicht in: | The Journal of pharmacology and experimental therapeutics 2010-01, Vol.332 (1), p.87-96 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 96 |
|---|---|
| container_issue | 1 |
| container_start_page | 87 |
| container_title | The Journal of pharmacology and experimental therapeutics |
| container_volume | 332 |
| creator | Spallarossa, Paolo Altieri, Paola Pronzato, Paolo Aloi, Concetta Ghigliotti, Giorgio Barsotti, Antonio Brunelli, Claudio |
| description | The cardiotoxic synergism resulting from the sequential treatment with anthracyclines and trastuzumab has been attributed
to the trastuzumab-induced loss of the erbB2-related functions that serve as a salvage pathway against the damaging effects
of anthracyclines. Cellular senescence is a novel mechanism of cardiotoxicity induced by subapoptotic doses of anthracyclines.
After having identified prosenescent and proapoptotic doses of epirubicin and rat MAb c-erbB2/Her-2/neu Ab-9 clone B10 (B10),
an anti-erbB2 monoclonal antibody, we investigated the effects of the sequential treatment with prosenescent doses of both
drugs on H9c2 cells and neonatal rat cardiomyocytes pretreated with or without the cardioprotective agent dexrazoxane. Cells
were analyzed by senescence-associated β-galactosidase, single-stranded DNA, annexin/propidium double staining, F-actin, and
mitochondrial transmembrane potential. ErbB2 expression levels, AKT activation, and the effects of the inhibition of nicotinamide
adenine dinucleotide phosphate oxidase [NAD(P)H oxidase] and phosphoinositide-3-OH kinase (PI3K) were also assessed. Data
demonstrate that 1) the toxic effects of epirubicin mainly occur through NAD(P)H oxidase activation; 2) the erbB2 overexpression
induced by epirubicin is a redox-sensitive mechanism largely dependent on NAD(P)H oxidase; 3) the loss of erbB2-related functions
caused by B10 determines marginal cellular changes in untreated cells, but causes massive death by apoptosis in cells previously
exposed to a prosenescent dose of epirubicin, 4) dexrazoxane promotes survival pathways, as demonstrated by the activation
of Akt and the PI3K-dependent erbB2 overexpression; and 5) it also prevents epirubicin-induced senescence and renders epirubicin-treated
cells more resistant to treatment with B10. Data underline the importance of NAD(P)H oxidase in epirubicin-induced cardiotoxicity
and shed new light on the protective mechanisms of dexrazoxane. |
| doi_str_mv | 10.1124/jpet.109.159525 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1124_jpet_109_159525</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>19841470</sourcerecordid><originalsourceid>FETCH-LOGICAL-c326t-f9e99a29c46ce2bdc0131bcefc526e36d6705aa7de8b5d89aa16c52d170e186b3</originalsourceid><addsrcrecordid>eNpFkE1v1DAQhi0EokvhzA35wjFbf8RJzG3ZLQVpJRAtZ8sfk8ZVNo5sL236o_iNJN1KPc2M5nnnHb0IfaRkTSkrL-5GyGtK5JoKKZh4hVZUMFoQSvhrtCKEsYKLSpyhdyndEULLsuJv0RmVTUnLmqzQv-uj6SF3use7kCDh0GI94M2QfQHRfGVPrQluwnvQLuEc8A507rCZ8GYMYw7JJ-wHvNXR-XCYgp3yfOcahuSzfwS3kPtwj3_F2WCAZGHIL2aXo49H460fvuCbDhYqg83-L-DfoYcF2cFD1I_hQQ_wHr1pdZ_gw3M9R3--Xd5svxf7n1c_tpt9YTmrctFKkFIzacvKAjPOEsqpsdBawSrglatqIrSuHTRGuEZqTat55WhNgDaV4efo4nTXzk-nCK0aoz_oOClK1JK8WpKfB6lOyc-KTyfFeDQHcC_8c9Qz8PkEdP62u_cR1NjpeNA29OF2UpwzRVVT8_-UOpA9</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Sublethal Doses of an Anti-erbB2 Antibody Leads to Death by Apoptosis in Cardiomyocytes Sensitized by Low Prosenescent Doses of Epirubicin: The Protective Role of Dexrazoxane</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Spallarossa, Paolo ; Altieri, Paola ; Pronzato, Paolo ; Aloi, Concetta ; Ghigliotti, Giorgio ; Barsotti, Antonio ; Brunelli, Claudio</creator><creatorcontrib>Spallarossa, Paolo ; Altieri, Paola ; Pronzato, Paolo ; Aloi, Concetta ; Ghigliotti, Giorgio ; Barsotti, Antonio ; Brunelli, Claudio</creatorcontrib><description>The cardiotoxic synergism resulting from the sequential treatment with anthracyclines and trastuzumab has been attributed
to the trastuzumab-induced loss of the erbB2-related functions that serve as a salvage pathway against the damaging effects
of anthracyclines. Cellular senescence is a novel mechanism of cardiotoxicity induced by subapoptotic doses of anthracyclines.
After having identified prosenescent and proapoptotic doses of epirubicin and rat MAb c-erbB2/Her-2/neu Ab-9 clone B10 (B10),
an anti-erbB2 monoclonal antibody, we investigated the effects of the sequential treatment with prosenescent doses of both
drugs on H9c2 cells and neonatal rat cardiomyocytes pretreated with or without the cardioprotective agent dexrazoxane. Cells
were analyzed by senescence-associated β-galactosidase, single-stranded DNA, annexin/propidium double staining, F-actin, and
mitochondrial transmembrane potential. ErbB2 expression levels, AKT activation, and the effects of the inhibition of nicotinamide
adenine dinucleotide phosphate oxidase [NAD(P)H oxidase] and phosphoinositide-3-OH kinase (PI3K) were also assessed. Data
demonstrate that 1) the toxic effects of epirubicin mainly occur through NAD(P)H oxidase activation; 2) the erbB2 overexpression
induced by epirubicin is a redox-sensitive mechanism largely dependent on NAD(P)H oxidase; 3) the loss of erbB2-related functions
caused by B10 determines marginal cellular changes in untreated cells, but causes massive death by apoptosis in cells previously
exposed to a prosenescent dose of epirubicin, 4) dexrazoxane promotes survival pathways, as demonstrated by the activation
of Akt and the PI3K-dependent erbB2 overexpression; and 5) it also prevents epirubicin-induced senescence and renders epirubicin-treated
cells more resistant to treatment with B10. Data underline the importance of NAD(P)H oxidase in epirubicin-induced cardiotoxicity
and shed new light on the protective mechanisms of dexrazoxane.</description><identifier>ISSN: 0022-3565</identifier><identifier>EISSN: 1521-0103</identifier><identifier>DOI: 10.1124/jpet.109.159525</identifier><identifier>PMID: 19841470</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Actins - metabolism ; Animals ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - adverse effects ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Apoptosis - drug effects ; Cardiotonic Agents - pharmacology ; Cell Culture Techniques ; Cell Death - drug effects ; Cell Line ; Dose-Response Relationship, Drug ; Drug Synergism ; Epirubicin - administration & dosage ; Epirubicin - adverse effects ; Glycoproteins - antagonists & inhibitors ; Immunoblotting ; Membrane Potential, Mitochondrial - drug effects ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - enzymology ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; Rats ; Rats, Sprague-Dawley ; Razoxane - pharmacology ; Receptor, ErbB-2</subject><ispartof>The Journal of pharmacology and experimental therapeutics, 2010-01, Vol.332 (1), p.87-96</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c326t-f9e99a29c46ce2bdc0131bcefc526e36d6705aa7de8b5d89aa16c52d170e186b3</citedby><cites>FETCH-LOGICAL-c326t-f9e99a29c46ce2bdc0131bcefc526e36d6705aa7de8b5d89aa16c52d170e186b3</cites></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/19841470$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Spallarossa, Paolo</creatorcontrib><creatorcontrib>Altieri, Paola</creatorcontrib><creatorcontrib>Pronzato, Paolo</creatorcontrib><creatorcontrib>Aloi, Concetta</creatorcontrib><creatorcontrib>Ghigliotti, Giorgio</creatorcontrib><creatorcontrib>Barsotti, Antonio</creatorcontrib><creatorcontrib>Brunelli, Claudio</creatorcontrib><title>Sublethal Doses of an Anti-erbB2 Antibody Leads to Death by Apoptosis in Cardiomyocytes Sensitized by Low Prosenescent Doses of Epirubicin: The Protective Role of Dexrazoxane</title><title>The Journal of pharmacology and experimental therapeutics</title><addtitle>J Pharmacol Exp Ther</addtitle><description>The cardiotoxic synergism resulting from the sequential treatment with anthracyclines and trastuzumab has been attributed
to the trastuzumab-induced loss of the erbB2-related functions that serve as a salvage pathway against the damaging effects
of anthracyclines. Cellular senescence is a novel mechanism of cardiotoxicity induced by subapoptotic doses of anthracyclines.
After having identified prosenescent and proapoptotic doses of epirubicin and rat MAb c-erbB2/Her-2/neu Ab-9 clone B10 (B10),
an anti-erbB2 monoclonal antibody, we investigated the effects of the sequential treatment with prosenescent doses of both
drugs on H9c2 cells and neonatal rat cardiomyocytes pretreated with or without the cardioprotective agent dexrazoxane. Cells
were analyzed by senescence-associated β-galactosidase, single-stranded DNA, annexin/propidium double staining, F-actin, and
mitochondrial transmembrane potential. ErbB2 expression levels, AKT activation, and the effects of the inhibition of nicotinamide
adenine dinucleotide phosphate oxidase [NAD(P)H oxidase] and phosphoinositide-3-OH kinase (PI3K) were also assessed. Data
demonstrate that 1) the toxic effects of epirubicin mainly occur through NAD(P)H oxidase activation; 2) the erbB2 overexpression
induced by epirubicin is a redox-sensitive mechanism largely dependent on NAD(P)H oxidase; 3) the loss of erbB2-related functions
caused by B10 determines marginal cellular changes in untreated cells, but causes massive death by apoptosis in cells previously
exposed to a prosenescent dose of epirubicin, 4) dexrazoxane promotes survival pathways, as demonstrated by the activation
of Akt and the PI3K-dependent erbB2 overexpression; and 5) it also prevents epirubicin-induced senescence and renders epirubicin-treated
cells more resistant to treatment with B10. Data underline the importance of NAD(P)H oxidase in epirubicin-induced cardiotoxicity
and shed new light on the protective mechanisms of dexrazoxane.</description><subject>Actins - metabolism</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - administration & dosage</subject><subject>Antibodies, Monoclonal - adverse effects</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Apoptosis - drug effects</subject><subject>Cardiotonic Agents - pharmacology</subject><subject>Cell Culture Techniques</subject><subject>Cell Death - drug effects</subject><subject>Cell Line</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Synergism</subject><subject>Epirubicin - administration & dosage</subject><subject>Epirubicin - adverse effects</subject><subject>Glycoproteins - antagonists & inhibitors</subject><subject>Immunoblotting</subject><subject>Membrane Potential, Mitochondrial - drug effects</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - enzymology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Razoxane - pharmacology</subject><subject>Receptor, ErbB-2</subject><issn>0022-3565</issn><issn>1521-0103</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1v1DAQhi0EokvhzA35wjFbf8RJzG3ZLQVpJRAtZ8sfk8ZVNo5sL236o_iNJN1KPc2M5nnnHb0IfaRkTSkrL-5GyGtK5JoKKZh4hVZUMFoQSvhrtCKEsYKLSpyhdyndEULLsuJv0RmVTUnLmqzQv-uj6SF3use7kCDh0GI94M2QfQHRfGVPrQluwnvQLuEc8A507rCZ8GYMYw7JJ-wHvNXR-XCYgp3yfOcahuSzfwS3kPtwj3_F2WCAZGHIL2aXo49H460fvuCbDhYqg83-L-DfoYcF2cFD1I_hQQ_wHr1pdZ_gw3M9R3--Xd5svxf7n1c_tpt9YTmrctFKkFIzacvKAjPOEsqpsdBawSrglatqIrSuHTRGuEZqTat55WhNgDaV4efo4nTXzk-nCK0aoz_oOClK1JK8WpKfB6lOyc-KTyfFeDQHcC_8c9Qz8PkEdP62u_cR1NjpeNA29OF2UpwzRVVT8_-UOpA9</recordid><startdate>20100101</startdate><enddate>20100101</enddate><creator>Spallarossa, Paolo</creator><creator>Altieri, Paola</creator><creator>Pronzato, Paolo</creator><creator>Aloi, Concetta</creator><creator>Ghigliotti, Giorgio</creator><creator>Barsotti, Antonio</creator><creator>Brunelli, Claudio</creator><general>American Society for Pharmacology and Experimental Therapeutics</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></search><sort><creationdate>20100101</creationdate><title>Sublethal Doses of an Anti-erbB2 Antibody Leads to Death by Apoptosis in Cardiomyocytes Sensitized by Low Prosenescent Doses of Epirubicin: The Protective Role of Dexrazoxane</title><author>Spallarossa, Paolo ; Altieri, Paola ; Pronzato, Paolo ; Aloi, Concetta ; Ghigliotti, Giorgio ; Barsotti, Antonio ; Brunelli, Claudio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c326t-f9e99a29c46ce2bdc0131bcefc526e36d6705aa7de8b5d89aa16c52d170e186b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Actins - metabolism</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - administration & dosage</topic><topic>Antibodies, Monoclonal - adverse effects</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Apoptosis - drug effects</topic><topic>Cardiotonic Agents - pharmacology</topic><topic>Cell Culture Techniques</topic><topic>Cell Death - drug effects</topic><topic>Cell Line</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Synergism</topic><topic>Epirubicin - administration & dosage</topic><topic>Epirubicin - adverse effects</topic><topic>Glycoproteins - antagonists & inhibitors</topic><topic>Immunoblotting</topic><topic>Membrane Potential, Mitochondrial - drug effects</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - enzymology</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - pathology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Razoxane - pharmacology</topic><topic>Receptor, ErbB-2</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Spallarossa, Paolo</creatorcontrib><creatorcontrib>Altieri, Paola</creatorcontrib><creatorcontrib>Pronzato, Paolo</creatorcontrib><creatorcontrib>Aloi, Concetta</creatorcontrib><creatorcontrib>Ghigliotti, Giorgio</creatorcontrib><creatorcontrib>Barsotti, Antonio</creatorcontrib><creatorcontrib>Brunelli, Claudio</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Spallarossa, Paolo</au><au>Altieri, Paola</au><au>Pronzato, Paolo</au><au>Aloi, Concetta</au><au>Ghigliotti, Giorgio</au><au>Barsotti, Antonio</au><au>Brunelli, Claudio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sublethal Doses of an Anti-erbB2 Antibody Leads to Death by Apoptosis in Cardiomyocytes Sensitized by Low Prosenescent Doses of Epirubicin: The Protective Role of Dexrazoxane</atitle><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle><addtitle>J Pharmacol Exp Ther</addtitle><date>2010-01-01</date><risdate>2010</risdate><volume>332</volume><issue>1</issue><spage>87</spage><epage>96</epage><pages>87-96</pages><issn>0022-3565</issn><eissn>1521-0103</eissn><abstract>The cardiotoxic synergism resulting from the sequential treatment with anthracyclines and trastuzumab has been attributed
to the trastuzumab-induced loss of the erbB2-related functions that serve as a salvage pathway against the damaging effects
of anthracyclines. Cellular senescence is a novel mechanism of cardiotoxicity induced by subapoptotic doses of anthracyclines.
After having identified prosenescent and proapoptotic doses of epirubicin and rat MAb c-erbB2/Her-2/neu Ab-9 clone B10 (B10),
an anti-erbB2 monoclonal antibody, we investigated the effects of the sequential treatment with prosenescent doses of both
drugs on H9c2 cells and neonatal rat cardiomyocytes pretreated with or without the cardioprotective agent dexrazoxane. Cells
were analyzed by senescence-associated β-galactosidase, single-stranded DNA, annexin/propidium double staining, F-actin, and
mitochondrial transmembrane potential. ErbB2 expression levels, AKT activation, and the effects of the inhibition of nicotinamide
adenine dinucleotide phosphate oxidase [NAD(P)H oxidase] and phosphoinositide-3-OH kinase (PI3K) were also assessed. Data
demonstrate that 1) the toxic effects of epirubicin mainly occur through NAD(P)H oxidase activation; 2) the erbB2 overexpression
induced by epirubicin is a redox-sensitive mechanism largely dependent on NAD(P)H oxidase; 3) the loss of erbB2-related functions
caused by B10 determines marginal cellular changes in untreated cells, but causes massive death by apoptosis in cells previously
exposed to a prosenescent dose of epirubicin, 4) dexrazoxane promotes survival pathways, as demonstrated by the activation
of Akt and the PI3K-dependent erbB2 overexpression; and 5) it also prevents epirubicin-induced senescence and renders epirubicin-treated
cells more resistant to treatment with B10. Data underline the importance of NAD(P)H oxidase in epirubicin-induced cardiotoxicity
and shed new light on the protective mechanisms of dexrazoxane.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>19841470</pmid><doi>10.1124/jpet.109.159525</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-3565 |
| ispartof | The Journal of pharmacology and experimental therapeutics, 2010-01, Vol.332 (1), p.87-96 |
| issn | 0022-3565 1521-0103 |
| language | eng |
| recordid | cdi_crossref_primary_10_1124_jpet_109_159525 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | Actins - metabolism Animals Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - adverse effects Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Apoptosis - drug effects Cardiotonic Agents - pharmacology Cell Culture Techniques Cell Death - drug effects Cell Line Dose-Response Relationship, Drug Drug Synergism Epirubicin - administration & dosage Epirubicin - adverse effects Glycoproteins - antagonists & inhibitors Immunoblotting Membrane Potential, Mitochondrial - drug effects Myocytes, Cardiac - drug effects Myocytes, Cardiac - enzymology Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Rats Rats, Sprague-Dawley Razoxane - pharmacology Receptor, ErbB-2 |
| title | Sublethal Doses of an Anti-erbB2 Antibody Leads to Death by Apoptosis in Cardiomyocytes Sensitized by Low Prosenescent Doses of Epirubicin: The Protective Role of Dexrazoxane |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-22T08%3A31%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Sublethal%20Doses%20of%20an%20Anti-erbB2%20Antibody%20Leads%20to%20Death%20by%20Apoptosis%20in%20Cardiomyocytes%20Sensitized%20by%20Low%20Prosenescent%20Doses%20of%20Epirubicin:%20The%20Protective%20Role%20of%20Dexrazoxane&rft.jtitle=The%20Journal%20of%20pharmacology%20and%20experimental%20therapeutics&rft.au=Spallarossa,%20Paolo&rft.date=2010-01-01&rft.volume=332&rft.issue=1&rft.spage=87&rft.epage=96&rft.pages=87-96&rft.issn=0022-3565&rft.eissn=1521-0103&rft_id=info:doi/10.1124/jpet.109.159525&rft_dat=%3Cpubmed_cross%3E19841470%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/19841470&rfr_iscdi=true |