Prolonged blockade of VEGF receptors does not damage retinal photoreceptors or ganglion cells
It has recently been reported that relatively short‐term inhibition of vascular endothelial growth factor (VEGF) signaling can cause photoreceptor cell death, a potentially clinically important finding since VEGF blockade has become an important modality of treatment of ocular neovascularization and...
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creator | Miki, Akiko Miki, Katsuaki Ueno, Shinji Wersinger, Delphine M. Bonnet Berlinicke, Cynthia Shaw, Gillian C. Usui, Shinichi Wang, Yuxia Zack, Donald J. Campochiaro, Peter A. |
description | It has recently been reported that relatively short‐term inhibition of vascular endothelial growth factor (VEGF) signaling can cause photoreceptor cell death, a potentially clinically important finding since VEGF blockade has become an important modality of treatment of ocular neovascularization and macular edema. However, in a set of studies in which we achieved extended and complete blockage of VEGF‐induced vascular leakage through retinal expression of a VEGF binding protein, we did not observe any toxicity to retinal neurons. To follow‐up on these apparently discrepant findings, we designed a set of experiments with the kinase inhibitor SU4312, which blocks phosphorylation of VEGF receptors, to look directly for evidence of VEGF inhibition‐related retinal toxicity. Using transgenic mice with sustained expression of VEGF in photoreceptors, we determined that periocular injection of 3 µg of SU4312 every 5 days markedly suppressed subretinal neovascularization, indicating effective blockade of VEGF signaling. Wild‐type mice given periocular injections of 5 µg of SU4312 every 5 days for up to 12 weeks showed normal scotopic and photopic electroretinograms (ERGs), no TUNEL stained cells in the retina, and no reduction in outer nuclear layer thickness. Incubation of cultured ganglion cells or retinal cultures containing photoreceptors with high doses of SU4312 did not reduce cell viability. These data suggest that blocking VEGF signaling in the retina for up to 12 weeks does not damage photoreceptors nor alter ERG function and should reassure patients who are receiving frequent injections of VEGF antagonists for choroidal and retinal vascular diseases. J. Cell. Physiol. 224:262–272, 2010 © 2010 Wiley‐Liss, Inc. |
doi_str_mv | 10.1002/jcp.22129 |
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Bonnet ; Berlinicke, Cynthia ; Shaw, Gillian C. ; Usui, Shinichi ; Wang, Yuxia ; Zack, Donald J. ; Campochiaro, Peter A.</creator><creatorcontrib>Miki, Akiko ; Miki, Katsuaki ; Ueno, Shinji ; Wersinger, Delphine M. Bonnet ; Berlinicke, Cynthia ; Shaw, Gillian C. ; Usui, Shinichi ; Wang, Yuxia ; Zack, Donald J. ; Campochiaro, Peter A.</creatorcontrib><description>It has recently been reported that relatively short‐term inhibition of vascular endothelial growth factor (VEGF) signaling can cause photoreceptor cell death, a potentially clinically important finding since VEGF blockade has become an important modality of treatment of ocular neovascularization and macular edema. However, in a set of studies in which we achieved extended and complete blockage of VEGF‐induced vascular leakage through retinal expression of a VEGF binding protein, we did not observe any toxicity to retinal neurons. To follow‐up on these apparently discrepant findings, we designed a set of experiments with the kinase inhibitor SU4312, which blocks phosphorylation of VEGF receptors, to look directly for evidence of VEGF inhibition‐related retinal toxicity. Using transgenic mice with sustained expression of VEGF in photoreceptors, we determined that periocular injection of 3 µg of SU4312 every 5 days markedly suppressed subretinal neovascularization, indicating effective blockade of VEGF signaling. Wild‐type mice given periocular injections of 5 µg of SU4312 every 5 days for up to 12 weeks showed normal scotopic and photopic electroretinograms (ERGs), no TUNEL stained cells in the retina, and no reduction in outer nuclear layer thickness. Incubation of cultured ganglion cells or retinal cultures containing photoreceptors with high doses of SU4312 did not reduce cell viability. These data suggest that blocking VEGF signaling in the retina for up to 12 weeks does not damage photoreceptors nor alter ERG function and should reassure patients who are receiving frequent injections of VEGF antagonists for choroidal and retinal vascular diseases. J. Cell. Physiol. 224:262–272, 2010 © 2010 Wiley‐Liss, Inc.</description><identifier>ISSN: 0021-9541</identifier><identifier>EISSN: 1097-4652</identifier><identifier>DOI: 10.1002/jcp.22129</identifier><identifier>PMID: 20232317</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject><![CDATA[Angiogenesis Inhibitors - administration & dosage ; Angiogenesis Inhibitors - toxicity ; Animals ; Antagonists ; Cell death ; Cell Survival - drug effects ; Cell viability ; Cells, Cultured ; Damage ; Dose-Response Relationship, Drug ; Edema ; Electroretinograms ; Electroretinography ; Growth factors ; Indoles - administration & dosage ; Indoles - toxicity ; Injections ; Kinases ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Phosphorylation ; Photoreception ; Photoreceptor Cells, Vertebrate - drug effects ; Photoreceptor Cells, Vertebrate - metabolism ; Photoreceptor Cells, Vertebrate - pathology ; Photoreceptors ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - toxicity ; Proto-Oncogene Proteins c-akt - metabolism ; Rats ; Receptors ; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors ; Receptors, Vascular Endothelial Growth Factor - genetics ; Receptors, Vascular Endothelial Growth Factor - metabolism ; Retina ; Retinal ganglion cells ; Retinal Ganglion Cells - drug effects ; Retinal Ganglion Cells - metabolism ; Retinal Ganglion Cells - pathology ; Retinal Neovascularization - genetics ; Retinal Neovascularization - metabolism ; Retinal Neovascularization - pathology ; Retinal Neovascularization - prevention & control ; Signal Transduction - drug effects ; Thickness ; Time Factors ; Toxicity ; Transgenic mice ; Vascular diseases ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - antagonists & inhibitors ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism ; Vascularization]]></subject><ispartof>Journal of cellular physiology, 2010-07, Vol.224 (1), p.262-272</ispartof><rights>Copyright © 2010 Wiley‐Liss, Inc.</rights><rights>(c) 2010 Wiley-Liss, Inc.</rights><rights>Copyright Wiley Subscription Services, Inc. Jul 2010</rights><rights>2010 Wiley-Liss, Inc. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4809-e6be0bc38acb6cdfd6f5bf92442069829c6302cf18e6e6904525f901d19013923</citedby><cites>FETCH-LOGICAL-c4809-e6be0bc38acb6cdfd6f5bf92442069829c6302cf18e6e6904525f901d19013923</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%2Fjcp.22129$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcp.22129$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20232317$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miki, Akiko</creatorcontrib><creatorcontrib>Miki, Katsuaki</creatorcontrib><creatorcontrib>Ueno, Shinji</creatorcontrib><creatorcontrib>Wersinger, Delphine M. Bonnet</creatorcontrib><creatorcontrib>Berlinicke, Cynthia</creatorcontrib><creatorcontrib>Shaw, Gillian C.</creatorcontrib><creatorcontrib>Usui, Shinichi</creatorcontrib><creatorcontrib>Wang, Yuxia</creatorcontrib><creatorcontrib>Zack, Donald J.</creatorcontrib><creatorcontrib>Campochiaro, Peter A.</creatorcontrib><title>Prolonged blockade of VEGF receptors does not damage retinal photoreceptors or ganglion cells</title><title>Journal of cellular physiology</title><addtitle>J. Cell. Physiol</addtitle><description>It has recently been reported that relatively short‐term inhibition of vascular endothelial growth factor (VEGF) signaling can cause photoreceptor cell death, a potentially clinically important finding since VEGF blockade has become an important modality of treatment of ocular neovascularization and macular edema. However, in a set of studies in which we achieved extended and complete blockage of VEGF‐induced vascular leakage through retinal expression of a VEGF binding protein, we did not observe any toxicity to retinal neurons. To follow‐up on these apparently discrepant findings, we designed a set of experiments with the kinase inhibitor SU4312, which blocks phosphorylation of VEGF receptors, to look directly for evidence of VEGF inhibition‐related retinal toxicity. Using transgenic mice with sustained expression of VEGF in photoreceptors, we determined that periocular injection of 3 µg of SU4312 every 5 days markedly suppressed subretinal neovascularization, indicating effective blockade of VEGF signaling. Wild‐type mice given periocular injections of 5 µg of SU4312 every 5 days for up to 12 weeks showed normal scotopic and photopic electroretinograms (ERGs), no TUNEL stained cells in the retina, and no reduction in outer nuclear layer thickness. Incubation of cultured ganglion cells or retinal cultures containing photoreceptors with high doses of SU4312 did not reduce cell viability. These data suggest that blocking VEGF signaling in the retina for up to 12 weeks does not damage photoreceptors nor alter ERG function and should reassure patients who are receiving frequent injections of VEGF antagonists for choroidal and retinal vascular diseases. J. Cell. Physiol. 224:262–272, 2010 © 2010 Wiley‐Liss, Inc.</description><subject>Angiogenesis Inhibitors - administration & dosage</subject><subject>Angiogenesis Inhibitors - toxicity</subject><subject>Animals</subject><subject>Antagonists</subject><subject>Cell death</subject><subject>Cell Survival - drug effects</subject><subject>Cell viability</subject><subject>Cells, Cultured</subject><subject>Damage</subject><subject>Dose-Response Relationship, Drug</subject><subject>Edema</subject><subject>Electroretinograms</subject><subject>Electroretinography</subject><subject>Growth factors</subject><subject>Indoles - administration & dosage</subject><subject>Indoles - toxicity</subject><subject>Injections</subject><subject>Kinases</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Phosphorylation</subject><subject>Photoreception</subject><subject>Photoreceptor Cells, Vertebrate - drug effects</subject><subject>Photoreceptor Cells, Vertebrate - metabolism</subject><subject>Photoreceptor Cells, Vertebrate - pathology</subject><subject>Photoreceptors</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Protein Kinase Inhibitors - toxicity</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rats</subject><subject>Receptors</subject><subject>Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors</subject><subject>Receptors, Vascular Endothelial Growth Factor - genetics</subject><subject>Receptors, Vascular Endothelial Growth Factor - metabolism</subject><subject>Retina</subject><subject>Retinal ganglion cells</subject><subject>Retinal Ganglion Cells - drug effects</subject><subject>Retinal Ganglion Cells - metabolism</subject><subject>Retinal Ganglion Cells - pathology</subject><subject>Retinal Neovascularization - genetics</subject><subject>Retinal Neovascularization - metabolism</subject><subject>Retinal Neovascularization - pathology</subject><subject>Retinal Neovascularization - prevention & control</subject><subject>Signal Transduction - drug effects</subject><subject>Thickness</subject><subject>Time Factors</subject><subject>Toxicity</subject><subject>Transgenic mice</subject><subject>Vascular diseases</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor A - genetics</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>Vascularization</subject><issn>0021-9541</issn><issn>1097-4652</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1u1DAUhS0EokNhwQsgS6xYpL22EyfeIKFROy3qn2iBFbIc5ybN1BMHO0Pbt69h2hEs2NiL893PP4eQtwz2GADfX9pxj3PG1TMyY6DKLJcFf05mKWOZKnK2Q17FuAQApYR4SXY4cMEFK2fkx0Xwzg8dNrR23t6YBqlv6beDxSENaHGcfIi08Rjp4CfamJXpMCVTPxhHx2uf8i3mA-3M0LneD9Sic_E1edEaF_HN475Lvh4eXM2PspPzxfH800lm8wpUhrJGqK2ojK2lbdpGtkXdKp7nHKSquLJSALctq1CiVJAXvGgVsIalRSgudsnHjXdc1ytsLA5TME6PoV-ZcK-96fW_ydBf687_0jlAUTKVBO8fBcH_XGOc9NKvQ3pi1AIqUUgQJUvUhw1lg48xYLs9gYH-3YROTeg_TST23d9X2pJPX5-A_Q1w2zu8_79Jf55fPCmzzUQfJ7zbTphwo2UpykJ_P1voL6eLy6vT8lIfiQeyHaKx</recordid><startdate>201007</startdate><enddate>201007</enddate><creator>Miki, Akiko</creator><creator>Miki, Katsuaki</creator><creator>Ueno, Shinji</creator><creator>Wersinger, Delphine M. Bonnet</creator><creator>Berlinicke, Cynthia</creator><creator>Shaw, Gillian C.</creator><creator>Usui, Shinichi</creator><creator>Wang, Yuxia</creator><creator>Zack, Donald J.</creator><creator>Campochiaro, Peter A.</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</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>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>201007</creationdate><title>Prolonged blockade of VEGF receptors does not damage retinal photoreceptors or ganglion cells</title><author>Miki, Akiko ; Miki, Katsuaki ; Ueno, Shinji ; Wersinger, Delphine M. Bonnet ; Berlinicke, Cynthia ; Shaw, Gillian C. ; Usui, Shinichi ; Wang, Yuxia ; Zack, Donald J. ; Campochiaro, Peter A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4809-e6be0bc38acb6cdfd6f5bf92442069829c6302cf18e6e6904525f901d19013923</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Angiogenesis Inhibitors - administration & dosage</topic><topic>Angiogenesis Inhibitors - toxicity</topic><topic>Animals</topic><topic>Antagonists</topic><topic>Cell death</topic><topic>Cell Survival - drug effects</topic><topic>Cell viability</topic><topic>Cells, Cultured</topic><topic>Damage</topic><topic>Dose-Response Relationship, Drug</topic><topic>Edema</topic><topic>Electroretinograms</topic><topic>Electroretinography</topic><topic>Growth factors</topic><topic>Indoles - administration & dosage</topic><topic>Indoles - toxicity</topic><topic>Injections</topic><topic>Kinases</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Phosphorylation</topic><topic>Photoreception</topic><topic>Photoreceptor Cells, Vertebrate - drug effects</topic><topic>Photoreceptor Cells, Vertebrate - metabolism</topic><topic>Photoreceptor Cells, Vertebrate - pathology</topic><topic>Photoreceptors</topic><topic>Protein Kinase Inhibitors - administration & dosage</topic><topic>Protein Kinase Inhibitors - toxicity</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rats</topic><topic>Receptors</topic><topic>Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors</topic><topic>Receptors, Vascular Endothelial Growth Factor - genetics</topic><topic>Receptors, Vascular Endothelial Growth Factor - metabolism</topic><topic>Retina</topic><topic>Retinal ganglion cells</topic><topic>Retinal Ganglion Cells - drug effects</topic><topic>Retinal Ganglion Cells - metabolism</topic><topic>Retinal Ganglion Cells - pathology</topic><topic>Retinal Neovascularization - genetics</topic><topic>Retinal Neovascularization - metabolism</topic><topic>Retinal Neovascularization - pathology</topic><topic>Retinal Neovascularization - prevention & control</topic><topic>Signal Transduction - drug effects</topic><topic>Thickness</topic><topic>Time Factors</topic><topic>Toxicity</topic><topic>Transgenic mice</topic><topic>Vascular diseases</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor A - antagonists & inhibitors</topic><topic>Vascular Endothelial Growth Factor A - genetics</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>Vascularization</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Miki, Akiko</creatorcontrib><creatorcontrib>Miki, Katsuaki</creatorcontrib><creatorcontrib>Ueno, Shinji</creatorcontrib><creatorcontrib>Wersinger, Delphine M. Bonnet</creatorcontrib><creatorcontrib>Berlinicke, Cynthia</creatorcontrib><creatorcontrib>Shaw, Gillian C.</creatorcontrib><creatorcontrib>Usui, Shinichi</creatorcontrib><creatorcontrib>Wang, Yuxia</creatorcontrib><creatorcontrib>Zack, Donald J.</creatorcontrib><creatorcontrib>Campochiaro, Peter A.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cellular physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miki, Akiko</au><au>Miki, Katsuaki</au><au>Ueno, Shinji</au><au>Wersinger, Delphine M. Bonnet</au><au>Berlinicke, Cynthia</au><au>Shaw, Gillian C.</au><au>Usui, Shinichi</au><au>Wang, Yuxia</au><au>Zack, Donald J.</au><au>Campochiaro, Peter A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prolonged blockade of VEGF receptors does not damage retinal photoreceptors or ganglion cells</atitle><jtitle>Journal of cellular physiology</jtitle><addtitle>J. Cell. Physiol</addtitle><date>2010-07</date><risdate>2010</risdate><volume>224</volume><issue>1</issue><spage>262</spage><epage>272</epage><pages>262-272</pages><issn>0021-9541</issn><eissn>1097-4652</eissn><abstract>It has recently been reported that relatively short‐term inhibition of vascular endothelial growth factor (VEGF) signaling can cause photoreceptor cell death, a potentially clinically important finding since VEGF blockade has become an important modality of treatment of ocular neovascularization and macular edema. However, in a set of studies in which we achieved extended and complete blockage of VEGF‐induced vascular leakage through retinal expression of a VEGF binding protein, we did not observe any toxicity to retinal neurons. To follow‐up on these apparently discrepant findings, we designed a set of experiments with the kinase inhibitor SU4312, which blocks phosphorylation of VEGF receptors, to look directly for evidence of VEGF inhibition‐related retinal toxicity. Using transgenic mice with sustained expression of VEGF in photoreceptors, we determined that periocular injection of 3 µg of SU4312 every 5 days markedly suppressed subretinal neovascularization, indicating effective blockade of VEGF signaling. Wild‐type mice given periocular injections of 5 µg of SU4312 every 5 days for up to 12 weeks showed normal scotopic and photopic electroretinograms (ERGs), no TUNEL stained cells in the retina, and no reduction in outer nuclear layer thickness. Incubation of cultured ganglion cells or retinal cultures containing photoreceptors with high doses of SU4312 did not reduce cell viability. These data suggest that blocking VEGF signaling in the retina for up to 12 weeks does not damage photoreceptors nor alter ERG function and should reassure patients who are receiving frequent injections of VEGF antagonists for choroidal and retinal vascular diseases. J. Cell. Physiol. 224:262–272, 2010 © 2010 Wiley‐Liss, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>20232317</pmid><doi>10.1002/jcp.22129</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Angiogenesis Inhibitors - administration & dosage Angiogenesis Inhibitors - toxicity Animals Antagonists Cell death Cell Survival - drug effects Cell viability Cells, Cultured Damage Dose-Response Relationship, Drug Edema Electroretinograms Electroretinography Growth factors Indoles - administration & dosage Indoles - toxicity Injections Kinases Mice Mice, Inbred C57BL Mice, Transgenic Phosphorylation Photoreception Photoreceptor Cells, Vertebrate - drug effects Photoreceptor Cells, Vertebrate - metabolism Photoreceptor Cells, Vertebrate - pathology Photoreceptors Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - toxicity Proto-Oncogene Proteins c-akt - metabolism Rats Receptors Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors Receptors, Vascular Endothelial Growth Factor - genetics Receptors, Vascular Endothelial Growth Factor - metabolism Retina Retinal ganglion cells Retinal Ganglion Cells - drug effects Retinal Ganglion Cells - metabolism Retinal Ganglion Cells - pathology Retinal Neovascularization - genetics Retinal Neovascularization - metabolism Retinal Neovascularization - pathology Retinal Neovascularization - prevention & control Signal Transduction - drug effects Thickness Time Factors Toxicity Transgenic mice Vascular diseases Vascular endothelial growth factor Vascular Endothelial Growth Factor A - antagonists & inhibitors Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism Vascularization |
title | Prolonged blockade of VEGF receptors does not damage retinal photoreceptors or ganglion cells |
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