Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers
•GRHL2 is a master programmer of the epithelial phenotype that sensitized cells to NK killing at the level of NK-target cell synaptogenesis.•Sensitization was mediated by the up-regulation of ICAM-1.•GRHL2-KMT2C/D interactions and p300 inhibition were important for MET, ICAM-1 up-regulation and NK-s...
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| Veröffentlicht in: | Molecular immunology 2019-01, Vol.105, p.137-149 |
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| creator | MacFawn, Ian Wilson, Hannah Selth, Luke A. Leighton, Ian Serebriiskii, Ilya Bleackley, R. Christopher Elzamzamy, Osama Farris, Joshua Pifer, Phillip M. Richer, Jennifer Frisch, Steven M. |
| description | •GRHL2 is a master programmer of the epithelial phenotype that sensitized cells to NK killing at the level of NK-target cell synaptogenesis.•Sensitization was mediated by the up-regulation of ICAM-1.•GRHL2-KMT2C/D interactions and p300 inhibition were important for MET, ICAM-1 up-regulation and NK-sensitization effects.•ICAM-1 expression correlated significantly with GRHL2 expression in lung tumors.
Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing. |
| doi_str_mv | 10.1016/j.molimm.2018.11.006 |
| format | Article |
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Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.</description><identifier>ISSN: 0161-5890</identifier><identifier>EISSN: 1872-9142</identifier><identifier>DOI: 10.1016/j.molimm.2018.11.006</identifier><identifier>PMID: 30508726</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>carcinoma ; Cell Line, Tumor ; DNA-Binding Proteins - immunology ; Epigenesis, Genetic - immunology ; Epigenetic ; epigenetics ; Epithelial-Mesenchymal Transition - immunology ; epithelium ; gene expression regulation ; Grainyhead-like-2 ; histones ; Humans ; hybrids ; ICAM-1 ; Immunity, Cellular ; Immunological Synapses - immunology ; Immunological Synapses - pathology ; intercellular adhesion molecule-1 ; Intercellular Adhesion Molecule-1 - immunology ; Killer Cells, Natural - immunology ; Killer Cells, Natural - pathology ; KMT2C ; KMT2D ; lung neoplasms ; Mesenchymal-to-epithelial transition ; metastasis ; methyltransferases ; natural killer cells ; neoplasm cells ; Neoplasm Proteins - immunology ; Neoplasms - immunology ; Neoplasms - pathology ; NK cells ; p300 ; p300-CBP Transcription Factors - immunology ; phenotype ; synaptogenesis ; Transcription Factors - immunology</subject><ispartof>Molecular immunology, 2019-01, Vol.105, p.137-149</ispartof><rights>2018 Elsevier Ltd</rights><rights>Copyright © 2018 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c496t-5e39ee815ccbf97f68cbc0b173016dd311166d287758ed479c552ccb8571d1dc3</citedby><cites>FETCH-LOGICAL-c496t-5e39ee815ccbf97f68cbc0b173016dd311166d287758ed479c552ccb8571d1dc3</cites><orcidid>0000-0002-2810-2610</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0161589018308022$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30508726$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MacFawn, Ian</creatorcontrib><creatorcontrib>Wilson, Hannah</creatorcontrib><creatorcontrib>Selth, Luke A.</creatorcontrib><creatorcontrib>Leighton, Ian</creatorcontrib><creatorcontrib>Serebriiskii, Ilya</creatorcontrib><creatorcontrib>Bleackley, R. Christopher</creatorcontrib><creatorcontrib>Elzamzamy, Osama</creatorcontrib><creatorcontrib>Farris, Joshua</creatorcontrib><creatorcontrib>Pifer, Phillip M.</creatorcontrib><creatorcontrib>Richer, Jennifer</creatorcontrib><creatorcontrib>Frisch, Steven M.</creatorcontrib><title>Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers</title><title>Molecular immunology</title><addtitle>Mol Immunol</addtitle><description>•GRHL2 is a master programmer of the epithelial phenotype that sensitized cells to NK killing at the level of NK-target cell synaptogenesis.•Sensitization was mediated by the up-regulation of ICAM-1.•GRHL2-KMT2C/D interactions and p300 inhibition were important for MET, ICAM-1 up-regulation and NK-sensitization effects.•ICAM-1 expression correlated significantly with GRHL2 expression in lung tumors.
Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.</description><subject>carcinoma</subject><subject>Cell Line, Tumor</subject><subject>DNA-Binding Proteins - immunology</subject><subject>Epigenesis, Genetic - immunology</subject><subject>Epigenetic</subject><subject>epigenetics</subject><subject>Epithelial-Mesenchymal Transition - immunology</subject><subject>epithelium</subject><subject>gene expression regulation</subject><subject>Grainyhead-like-2</subject><subject>histones</subject><subject>Humans</subject><subject>hybrids</subject><subject>ICAM-1</subject><subject>Immunity, Cellular</subject><subject>Immunological Synapses - immunology</subject><subject>Immunological Synapses - pathology</subject><subject>intercellular adhesion molecule-1</subject><subject>Intercellular Adhesion Molecule-1 - immunology</subject><subject>Killer Cells, Natural - immunology</subject><subject>Killer Cells, Natural - pathology</subject><subject>KMT2C</subject><subject>KMT2D</subject><subject>lung neoplasms</subject><subject>Mesenchymal-to-epithelial transition</subject><subject>metastasis</subject><subject>methyltransferases</subject><subject>natural killer cells</subject><subject>neoplasm cells</subject><subject>Neoplasm Proteins - immunology</subject><subject>Neoplasms - immunology</subject><subject>Neoplasms - pathology</subject><subject>NK cells</subject><subject>p300</subject><subject>p300-CBP Transcription Factors - immunology</subject><subject>phenotype</subject><subject>synaptogenesis</subject><subject>Transcription Factors - immunology</subject><issn>0161-5890</issn><issn>1872-9142</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU9v1DAQxS0EotvCN0AoRy4JniR2nAsSqkqpqOAC4mhl7clmlsRebO-i_fa42lLggjjNYX7vzZ_H2AvgFXCQr7fV4mdalqrmoCqAinP5iK1AdXXZQ1s_ZquMQSlUz8_YeYxbngkuxVN21nDBMydX7Ot1GMgdJxxsOdM3LOvCeDdiiMXHD2VEFynRgdKxSFPw-81UkEsYBpPIu1j8oDQVuKMNOkxkisVbGimrn7En4zBHfH5fL9iXd1efL9-Xt5-uby7f3pam7WUqBTY9ogJhzHrsu1EqszZ8DV2Td7e2AQApba26Tii0bdcbIerMKtGBBWuaC_bm5Lvbrxe0Bl0Kw6x3gZYhHLUfSP_dcTTpjT9oKZRomz4bvLo3CP77HmPSC0WD8zw49Puoa1C9kLyrm_9A214J6DqZ0faEmuBjDDg-bARc38Wnt_oUn76LTwPoHE6WvfzzmgfRr7x-n4v5p4f8aB0NoTNoKaBJ2nr694SfbF-vzA</recordid><startdate>20190101</startdate><enddate>20190101</enddate><creator>MacFawn, Ian</creator><creator>Wilson, Hannah</creator><creator>Selth, Luke A.</creator><creator>Leighton, Ian</creator><creator>Serebriiskii, Ilya</creator><creator>Bleackley, R. Christopher</creator><creator>Elzamzamy, Osama</creator><creator>Farris, Joshua</creator><creator>Pifer, Phillip M.</creator><creator>Richer, Jennifer</creator><creator>Frisch, Steven M.</creator><general>Elsevier Ltd</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><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-2810-2610</orcidid></search><sort><creationdate>20190101</creationdate><title>Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers</title><author>MacFawn, Ian ; Wilson, Hannah ; Selth, Luke A. ; Leighton, Ian ; Serebriiskii, Ilya ; Bleackley, R. Christopher ; Elzamzamy, Osama ; Farris, Joshua ; Pifer, Phillip M. ; Richer, Jennifer ; Frisch, Steven M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c496t-5e39ee815ccbf97f68cbc0b173016dd311166d287758ed479c552ccb8571d1dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>carcinoma</topic><topic>Cell Line, Tumor</topic><topic>DNA-Binding Proteins - immunology</topic><topic>Epigenesis, Genetic - immunology</topic><topic>Epigenetic</topic><topic>epigenetics</topic><topic>Epithelial-Mesenchymal Transition - immunology</topic><topic>epithelium</topic><topic>gene expression regulation</topic><topic>Grainyhead-like-2</topic><topic>histones</topic><topic>Humans</topic><topic>hybrids</topic><topic>ICAM-1</topic><topic>Immunity, Cellular</topic><topic>Immunological Synapses - immunology</topic><topic>Immunological Synapses - pathology</topic><topic>intercellular adhesion molecule-1</topic><topic>Intercellular Adhesion Molecule-1 - immunology</topic><topic>Killer Cells, Natural - immunology</topic><topic>Killer Cells, Natural - pathology</topic><topic>KMT2C</topic><topic>KMT2D</topic><topic>lung neoplasms</topic><topic>Mesenchymal-to-epithelial transition</topic><topic>metastasis</topic><topic>methyltransferases</topic><topic>natural killer cells</topic><topic>neoplasm cells</topic><topic>Neoplasm Proteins - immunology</topic><topic>Neoplasms - immunology</topic><topic>Neoplasms - pathology</topic><topic>NK cells</topic><topic>p300</topic><topic>p300-CBP Transcription Factors - immunology</topic><topic>phenotype</topic><topic>synaptogenesis</topic><topic>Transcription Factors - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MacFawn, Ian</creatorcontrib><creatorcontrib>Wilson, Hannah</creatorcontrib><creatorcontrib>Selth, Luke A.</creatorcontrib><creatorcontrib>Leighton, Ian</creatorcontrib><creatorcontrib>Serebriiskii, Ilya</creatorcontrib><creatorcontrib>Bleackley, R. Christopher</creatorcontrib><creatorcontrib>Elzamzamy, Osama</creatorcontrib><creatorcontrib>Farris, Joshua</creatorcontrib><creatorcontrib>Pifer, Phillip M.</creatorcontrib><creatorcontrib>Richer, Jennifer</creatorcontrib><creatorcontrib>Frisch, Steven M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MacFawn, Ian</au><au>Wilson, Hannah</au><au>Selth, Luke A.</au><au>Leighton, Ian</au><au>Serebriiskii, Ilya</au><au>Bleackley, R. Christopher</au><au>Elzamzamy, Osama</au><au>Farris, Joshua</au><au>Pifer, Phillip M.</au><au>Richer, Jennifer</au><au>Frisch, Steven M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers</atitle><jtitle>Molecular immunology</jtitle><addtitle>Mol Immunol</addtitle><date>2019-01-01</date><risdate>2019</risdate><volume>105</volume><spage>137</spage><epage>149</epage><pages>137-149</pages><issn>0161-5890</issn><eissn>1872-9142</eissn><abstract>•GRHL2 is a master programmer of the epithelial phenotype that sensitized cells to NK killing at the level of NK-target cell synaptogenesis.•Sensitization was mediated by the up-regulation of ICAM-1.•GRHL2-KMT2C/D interactions and p300 inhibition were important for MET, ICAM-1 up-regulation and NK-sensitization effects.•ICAM-1 expression correlated significantly with GRHL2 expression in lung tumors.
Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>30508726</pmid><doi>10.1016/j.molimm.2018.11.006</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-2810-2610</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | carcinoma Cell Line, Tumor DNA-Binding Proteins - immunology Epigenesis, Genetic - immunology Epigenetic epigenetics Epithelial-Mesenchymal Transition - immunology epithelium gene expression regulation Grainyhead-like-2 histones Humans hybrids ICAM-1 Immunity, Cellular Immunological Synapses - immunology Immunological Synapses - pathology intercellular adhesion molecule-1 Intercellular Adhesion Molecule-1 - immunology Killer Cells, Natural - immunology Killer Cells, Natural - pathology KMT2C KMT2D lung neoplasms Mesenchymal-to-epithelial transition metastasis methyltransferases natural killer cells neoplasm cells Neoplasm Proteins - immunology Neoplasms - immunology Neoplasms - pathology NK cells p300 p300-CBP Transcription Factors - immunology phenotype synaptogenesis Transcription Factors - immunology |
| title | Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers |
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