Leveraging immune memory against measles virus as an antitumor strategy in a preclinical model of aggressive squamous cell carcinoma
Viral antigens are among the strongest elicitors of immune responses. A significant proportion of the human population already carries pre-existing immunity against several childhood viruses, which could potentially be leveraged to fight cancer. We sought to provide proof of concept in mouse models...
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| Veröffentlicht in: | Journal for immunotherapy of cancer 2021-10, Vol.9 (10), p.e002170, Article 002170 |
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| creator | Leb-Reichl, Victoria M Kienzl, Melanie Kaufmann, Anna Stoecklinger, Angelika Tockner, Birgit Kitzmueller, Sophie Zaborsky, Nadja Steiner, Markus Brachtl, Gabriele Trattner, Lisa Kreideweiss, Patrick Reinsch, Christian Panzner, Steffen Greil, Richard Strunk, Dirk Bauer, Johann W Gratz, Iris K Guttmann-Gruber, Christina Piñón Hofbauer, Josefina |
| description | Viral antigens are among the strongest elicitors of immune responses. A significant proportion of the human population already carries pre-existing immunity against several childhood viruses, which could potentially be leveraged to fight cancer. We sought to provide proof of concept in mouse models that a pre-existing measles virus (MeV) immunity can be redirected to inhibit tumor growth by directly forcing expression of cognate antigens in the tumor. To this end, we designed DNA vaccines against known MeV cytotoxic and helper T epitopes, and administered these intradermally to mice that were subsequently challenged with syngeneic squamous cancer cells engineered to either express the cognate antigens or not. Alternatively, established wild-type tumors in vaccinated animals were treated intratumorally with in vitro transcribed mRNA encoding the cognate epitopes. Vaccination generated MeV cytotoxic T lymphocyte (CTL) immunity in mice as demonstrated by enhanced interferon gamma production, antigen-specific T cell proliferation, and CTL-mediated specific killing of antigen-pulsed target cells. When challenged with syngeneic tumor cells engineered to express the cognate antigens, 77% of MeV-vaccinated mice rejected the tumor versus 21% in control cohorts. Antitumor responses were largely dependent on the presence of CD8+ cells. Significant protection was observed even when only 25% of the tumor bulk expressed cognate antigens. We therefore tested the strategy therapeutically, allowing tumors to develop in vaccinated mice before intratumoral injection with Viromer nanoparticles complexed with mRNA encoding the cognate antigens. Treatment significantly enhanced overall survival compared with controls, including complete tumor regression in 25% of mice. Our results indicate that redirecting pre-existing viral immunity to fight cancer is a viable alternative that could meaningfully complement current cancer immune therapies such as personalized cancer vaccines and checkpoint inhibitor blockade. |
| doi_str_mv | 10.1136/jitc-2020-002170 |
| format | Article |
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A significant proportion of the human population already carries pre-existing immunity against several childhood viruses, which could potentially be leveraged to fight cancer. We sought to provide proof of concept in mouse models that a pre-existing measles virus (MeV) immunity can be redirected to inhibit tumor growth by directly forcing expression of cognate antigens in the tumor. To this end, we designed DNA vaccines against known MeV cytotoxic and helper T epitopes, and administered these intradermally to mice that were subsequently challenged with syngeneic squamous cancer cells engineered to either express the cognate antigens or not. Alternatively, established wild-type tumors in vaccinated animals were treated intratumorally with in vitro transcribed mRNA encoding the cognate epitopes. Vaccination generated MeV cytotoxic T lymphocyte (CTL) immunity in mice as demonstrated by enhanced interferon gamma production, antigen-specific T cell proliferation, and CTL-mediated specific killing of antigen-pulsed target cells. When challenged with syngeneic tumor cells engineered to express the cognate antigens, 77% of MeV-vaccinated mice rejected the tumor versus 21% in control cohorts. Antitumor responses were largely dependent on the presence of CD8+ cells. Significant protection was observed even when only 25% of the tumor bulk expressed cognate antigens. We therefore tested the strategy therapeutically, allowing tumors to develop in vaccinated mice before intratumoral injection with Viromer nanoparticles complexed with mRNA encoding the cognate antigens. Treatment significantly enhanced overall survival compared with controls, including complete tumor regression in 25% of mice. Our results indicate that redirecting pre-existing viral immunity to fight cancer is a viable alternative that could meaningfully complement current cancer immune therapies such as personalized cancer vaccines and checkpoint inhibitor blockade.</description><identifier>ISSN: 2051-1426</identifier><identifier>EISSN: 2051-1426</identifier><identifier>DOI: 10.1136/jitc-2020-002170</identifier><identifier>PMID: 34675067</identifier><language>eng</language><publisher>LONDON: BMJ Publishing Group Ltd</publisher><subject>Animals ; Antibodies ; Antigens ; Cancer ; Cancer vaccines ; Carcinoma, Squamous Cell - immunology ; CD8-positive T-lymphocytes ; CD8-Positive T-Lymphocytes - immunology ; Cell growth ; cellular ; Cytokines ; Cytotoxicity ; Dendritic cells ; Disease Models, Animal ; Experiments ; Flow cytometry ; Humans ; immunity ; immunogenicity ; Immunologic Memory - immunology ; Immunology ; Immunotherapy ; investigational ; Life Sciences & Biomedicine ; Lymphocytes ; Measles ; Measles virus - immunology ; Mice ; Mutation ; Oncology ; Oncolytic and Local Immunotherapy ; Peptides ; Proteins ; Science & Technology ; Skin cancer ; skin neoplasms ; Squamous cell carcinoma ; therapies ; Tumors ; vaccine ; Vaccines ; Viruses</subject><ispartof>Journal for immunotherapy of cancer, 2021-10, Vol.9 (10), p.e002170, Article 002170</ispartof><rights>Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2021 Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>3</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000711059500001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-b527t-cdfc90154922cdf0a400110fe696f56d076194fe1e57ab4a611e5c38cde94a4f3</citedby><cites>FETCH-LOGICAL-b527t-cdfc90154922cdf0a400110fe696f56d076194fe1e57ab4a611e5c38cde94a4f3</cites><orcidid>0000-0002-8558-9031 ; 0000-0001-8232-5068</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jitc.bmj.com/content/9/10/e002170.full.pdf$$EPDF$$P50$$Gbmj$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://jitc.bmj.com/content/9/10/e002170.full$$EHTML$$P50$$Gbmj$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2118,27933,27934,39267,53800,53802,55359,77670,77696</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34675067$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Leb-Reichl, Victoria M</creatorcontrib><creatorcontrib>Kienzl, Melanie</creatorcontrib><creatorcontrib>Kaufmann, Anna</creatorcontrib><creatorcontrib>Stoecklinger, Angelika</creatorcontrib><creatorcontrib>Tockner, Birgit</creatorcontrib><creatorcontrib>Kitzmueller, Sophie</creatorcontrib><creatorcontrib>Zaborsky, Nadja</creatorcontrib><creatorcontrib>Steiner, Markus</creatorcontrib><creatorcontrib>Brachtl, Gabriele</creatorcontrib><creatorcontrib>Trattner, Lisa</creatorcontrib><creatorcontrib>Kreideweiss, Patrick</creatorcontrib><creatorcontrib>Reinsch, Christian</creatorcontrib><creatorcontrib>Panzner, Steffen</creatorcontrib><creatorcontrib>Greil, Richard</creatorcontrib><creatorcontrib>Strunk, Dirk</creatorcontrib><creatorcontrib>Bauer, Johann W</creatorcontrib><creatorcontrib>Gratz, Iris K</creatorcontrib><creatorcontrib>Guttmann-Gruber, Christina</creatorcontrib><creatorcontrib>Piñón Hofbauer, Josefina</creatorcontrib><title>Leveraging immune memory against measles virus as an antitumor strategy in a preclinical model of aggressive squamous cell carcinoma</title><title>Journal for immunotherapy of cancer</title><addtitle>J Immunother Cancer</addtitle><addtitle>J IMMUNOTHER CANCER</addtitle><addtitle>J Immunother Cancer</addtitle><description>Viral antigens are among the strongest elicitors of immune responses. A significant proportion of the human population already carries pre-existing immunity against several childhood viruses, which could potentially be leveraged to fight cancer. We sought to provide proof of concept in mouse models that a pre-existing measles virus (MeV) immunity can be redirected to inhibit tumor growth by directly forcing expression of cognate antigens in the tumor. To this end, we designed DNA vaccines against known MeV cytotoxic and helper T epitopes, and administered these intradermally to mice that were subsequently challenged with syngeneic squamous cancer cells engineered to either express the cognate antigens or not. Alternatively, established wild-type tumors in vaccinated animals were treated intratumorally with in vitro transcribed mRNA encoding the cognate epitopes. Vaccination generated MeV cytotoxic T lymphocyte (CTL) immunity in mice as demonstrated by enhanced interferon gamma production, antigen-specific T cell proliferation, and CTL-mediated specific killing of antigen-pulsed target cells. When challenged with syngeneic tumor cells engineered to express the cognate antigens, 77% of MeV-vaccinated mice rejected the tumor versus 21% in control cohorts. Antitumor responses were largely dependent on the presence of CD8+ cells. Significant protection was observed even when only 25% of the tumor bulk expressed cognate antigens. We therefore tested the strategy therapeutically, allowing tumors to develop in vaccinated mice before intratumoral injection with Viromer nanoparticles complexed with mRNA encoding the cognate antigens. Treatment significantly enhanced overall survival compared with controls, including complete tumor regression in 25% of mice. Our results indicate that redirecting pre-existing viral immunity to fight cancer is a viable alternative that could meaningfully complement current cancer immune therapies such as personalized cancer vaccines and checkpoint inhibitor blockade.</description><subject>Animals</subject><subject>Antibodies</subject><subject>Antigens</subject><subject>Cancer</subject><subject>Cancer vaccines</subject><subject>Carcinoma, Squamous Cell - immunology</subject><subject>CD8-positive T-lymphocytes</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Cell growth</subject><subject>cellular</subject><subject>Cytokines</subject><subject>Cytotoxicity</subject><subject>Dendritic cells</subject><subject>Disease Models, Animal</subject><subject>Experiments</subject><subject>Flow cytometry</subject><subject>Humans</subject><subject>immunity</subject><subject>immunogenicity</subject><subject>Immunologic Memory - immunology</subject><subject>Immunology</subject><subject>Immunotherapy</subject><subject>investigational</subject><subject>Life Sciences & Biomedicine</subject><subject>Lymphocytes</subject><subject>Measles</subject><subject>Measles virus - immunology</subject><subject>Mice</subject><subject>Mutation</subject><subject>Oncology</subject><subject>Oncolytic and Local Immunotherapy</subject><subject>Peptides</subject><subject>Proteins</subject><subject>Science & Technology</subject><subject>Skin cancer</subject><subject>skin neoplasms</subject><subject>Squamous cell carcinoma</subject><subject>therapies</subject><subject>Tumors</subject><subject>vaccine</subject><subject>Vaccines</subject><subject>Viruses</subject><issn>2051-1426</issn><issn>2051-1426</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>9YT</sourceid><sourceid>ACMMV</sourceid><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNqNks-L1DAUx4so7jLu3ZMEvAhaze-2F0EGfywMeNFzSNPXmqFNZpN0ZO7-4aZ2HXcFQQjkJfm8L--9fIviKcGvCWHyzd4mU1JMcYkxJRV-UFxSLEhJOJUP78QXxVWMe4wxwYzVdf24uGBcVgLL6rL4sYMjBD1YNyA7TbMDNMHkwwnpQVsXUz7qOEJERxvmiHReLq9k05wxFFPQCYYTsvkWHQKY0Tpr9Igm38GIfJ-FhgAx2iOgeDPryWcZA-OIjA7GOj_pJ8WjXo8Rrm73TfH1w_sv20_l7vPH6-27XdkKWqXSdL1pMBG8oTTHWPPcE8E9yEb2Qna4kqThPRAQlW65liRHhtWmg4Zr3rNNcb3qdl7v1SHYSYeT8tqqXxc-DEqHZM0Iqqspo5QRXDUdly3WdddBL2UnoCU9ZVnr7ap1mNsJOgMuT2K8J3r_xdlvavBHVQtGhaizwItbgeBvZohJTTYuc9EO8ogUFTXnrF6q2BTP_0L3fg4ujypTDZMV4azKFF4pE3yMAfpzMQSrxTFqcYxaHKNWx-SUZ3ebOCf89kcGXq7Ad2h9H40FZ-CMZU9V-QNEI_Bir0zX_09vbdLJerf1s0s59dWa2k77P939s_CfSV_trg</recordid><startdate>20211001</startdate><enddate>20211001</enddate><creator>Leb-Reichl, Victoria M</creator><creator>Kienzl, Melanie</creator><creator>Kaufmann, Anna</creator><creator>Stoecklinger, Angelika</creator><creator>Tockner, Birgit</creator><creator>Kitzmueller, Sophie</creator><creator>Zaborsky, Nadja</creator><creator>Steiner, Markus</creator><creator>Brachtl, Gabriele</creator><creator>Trattner, Lisa</creator><creator>Kreideweiss, Patrick</creator><creator>Reinsch, Christian</creator><creator>Panzner, Steffen</creator><creator>Greil, Richard</creator><creator>Strunk, Dirk</creator><creator>Bauer, Johann W</creator><creator>Gratz, Iris K</creator><creator>Guttmann-Gruber, Christina</creator><creator>Piñón Hofbauer, Josefina</creator><general>BMJ Publishing Group Ltd</general><general>Bmj Publishing Group</general><general>BMJ Publishing Group LTD</general><general>BMJ Publishing Group</general><scope>9YT</scope><scope>ACMMV</scope><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-8558-9031</orcidid><orcidid>https://orcid.org/0000-0001-8232-5068</orcidid></search><sort><creationdate>20211001</creationdate><title>Leveraging immune memory against measles virus as an antitumor strategy in a preclinical model of aggressive squamous cell carcinoma</title><author>Leb-Reichl, Victoria M ; Kienzl, Melanie ; Kaufmann, Anna ; Stoecklinger, Angelika ; Tockner, Birgit ; Kitzmueller, Sophie ; Zaborsky, Nadja ; Steiner, Markus ; Brachtl, Gabriele ; Trattner, Lisa ; Kreideweiss, Patrick ; Reinsch, Christian ; Panzner, Steffen ; Greil, Richard ; Strunk, Dirk ; Bauer, Johann W ; Gratz, Iris K ; Guttmann-Gruber, Christina ; Piñón Hofbauer, Josefina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b527t-cdfc90154922cdf0a400110fe696f56d076194fe1e57ab4a611e5c38cde94a4f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Antibodies</topic><topic>Antigens</topic><topic>Cancer</topic><topic>Cancer vaccines</topic><topic>Carcinoma, Squamous Cell - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Journal for immunotherapy of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Leb-Reichl, Victoria M</au><au>Kienzl, Melanie</au><au>Kaufmann, Anna</au><au>Stoecklinger, Angelika</au><au>Tockner, Birgit</au><au>Kitzmueller, Sophie</au><au>Zaborsky, Nadja</au><au>Steiner, Markus</au><au>Brachtl, Gabriele</au><au>Trattner, Lisa</au><au>Kreideweiss, Patrick</au><au>Reinsch, Christian</au><au>Panzner, Steffen</au><au>Greil, Richard</au><au>Strunk, Dirk</au><au>Bauer, Johann W</au><au>Gratz, Iris K</au><au>Guttmann-Gruber, Christina</au><au>Piñón Hofbauer, Josefina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Leveraging immune memory against measles virus as an antitumor strategy in a preclinical model of aggressive squamous cell carcinoma</atitle><jtitle>Journal for immunotherapy of cancer</jtitle><stitle>J Immunother Cancer</stitle><stitle>J IMMUNOTHER CANCER</stitle><addtitle>J Immunother Cancer</addtitle><date>2021-10-01</date><risdate>2021</risdate><volume>9</volume><issue>10</issue><spage>e002170</spage><pages>e002170-</pages><artnum>002170</artnum><issn>2051-1426</issn><eissn>2051-1426</eissn><abstract>Viral antigens are among the strongest elicitors of immune responses. A significant proportion of the human population already carries pre-existing immunity against several childhood viruses, which could potentially be leveraged to fight cancer. We sought to provide proof of concept in mouse models that a pre-existing measles virus (MeV) immunity can be redirected to inhibit tumor growth by directly forcing expression of cognate antigens in the tumor. To this end, we designed DNA vaccines against known MeV cytotoxic and helper T epitopes, and administered these intradermally to mice that were subsequently challenged with syngeneic squamous cancer cells engineered to either express the cognate antigens or not. Alternatively, established wild-type tumors in vaccinated animals were treated intratumorally with in vitro transcribed mRNA encoding the cognate epitopes. Vaccination generated MeV cytotoxic T lymphocyte (CTL) immunity in mice as demonstrated by enhanced interferon gamma production, antigen-specific T cell proliferation, and CTL-mediated specific killing of antigen-pulsed target cells. When challenged with syngeneic tumor cells engineered to express the cognate antigens, 77% of MeV-vaccinated mice rejected the tumor versus 21% in control cohorts. Antitumor responses were largely dependent on the presence of CD8+ cells. Significant protection was observed even when only 25% of the tumor bulk expressed cognate antigens. We therefore tested the strategy therapeutically, allowing tumors to develop in vaccinated mice before intratumoral injection with Viromer nanoparticles complexed with mRNA encoding the cognate antigens. Treatment significantly enhanced overall survival compared with controls, including complete tumor regression in 25% of mice. Our results indicate that redirecting pre-existing viral immunity to fight cancer is a viable alternative that could meaningfully complement current cancer immune therapies such as personalized cancer vaccines and checkpoint inhibitor blockade.</abstract><cop>LONDON</cop><pub>BMJ Publishing Group Ltd</pub><pmid>34675067</pmid><doi>10.1136/jitc-2020-002170</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-8558-9031</orcidid><orcidid>https://orcid.org/0000-0001-8232-5068</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal for immunotherapy of cancer, 2021-10, Vol.9 (10), p.e002170, Article 002170 |
| issn | 2051-1426 2051-1426 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2584438322 |
| source | BMJ Open Access Journals; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; PubMed Central |
| subjects | Animals Antibodies Antigens Cancer Cancer vaccines Carcinoma, Squamous Cell - immunology CD8-positive T-lymphocytes CD8-Positive T-Lymphocytes - immunology Cell growth cellular Cytokines Cytotoxicity Dendritic cells Disease Models, Animal Experiments Flow cytometry Humans immunity immunogenicity Immunologic Memory - immunology Immunology Immunotherapy investigational Life Sciences & Biomedicine Lymphocytes Measles Measles virus - immunology Mice Mutation Oncology Oncolytic and Local Immunotherapy Peptides Proteins Science & Technology Skin cancer skin neoplasms Squamous cell carcinoma therapies Tumors vaccine Vaccines Viruses |
| title | Leveraging immune memory against measles virus as an antitumor strategy in a preclinical model of aggressive squamous cell carcinoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-03T02%3A55%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Leveraging%20immune%20memory%20against%20measles%20virus%20as%20an%20antitumor%20strategy%20in%20a%20preclinical%20model%20of%20aggressive%20squamous%20cell%20carcinoma&rft.jtitle=Journal%20for%20immunotherapy%20of%20cancer&rft.au=Leb-Reichl,%20Victoria%20M&rft.date=2021-10-01&rft.volume=9&rft.issue=10&rft.spage=e002170&rft.pages=e002170-&rft.artnum=002170&rft.issn=2051-1426&rft.eissn=2051-1426&rft_id=info:doi/10.1136/jitc-2020-002170&rft_dat=%3Cproquest_pubme%3E2584438322%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2593671437&rft_id=info:pmid/34675067&rft_doaj_id=oai_doaj_org_article_d8232231079d46b0a8ddef66d5eb1f23&rfr_iscdi=true |