The Antitumor Activity of TCR-Mimic Antibody-Drug Conjugates (TCRm-ADCs) Targeting the Intracellular Wilms Tumor 1 (WT1) Oncoprotein
Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunot...
Gespeichert in:
| Veröffentlicht in: | International journal of molecular sciences 2019-08, Vol.20 (16), p.3912 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | 16 |
| container_start_page | 3912 |
| container_title | International journal of molecular sciences |
| container_volume | 20 |
| creator | Shen, Ying Li, Yi-Ming Zhou, Jing-Jing Zhou, Zhan Xu, Ying-Chun Zhao, Wen-Bin Chen, Shu-Qing |
| description | Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy. |
| doi_str_mv | 10.3390/ijms20163912 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6720711</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2273205166</sourcerecordid><originalsourceid>FETCH-LOGICAL-c412t-c35682aad12cb1f62eef0b76cbe87929b53a8b5582e466d328a02fa06ecbdb5a3</originalsourceid><addsrcrecordid>eNpdkUFr3DAQhUVpaNK0t56LoJcN1Kk0Wsv2pbA4SRtICRSXHIUky44WW9pIcmDv_eH1JmnY5DQD7-PNPB5Cnyg5Zawi3-x6jEAoZxWFN-iILgEyQnjxdm8_RO9jXBMCDPLqHTpkdEnKihVH6G9za_DKJZum0Qe80sne27TFvsNN_Tv7ZUerH3Tl2212FqYe196tp14mE_FiZsZsdVbHE9zI0JtkXY_TbHnpUpDaDMM0yIBv7DBG3DycoHhx09ATfO203wSfjHUf0EEnh2g-Ps1j9OfivKl_ZlfXPy7r1VWmlxRSplnOS5CypaAV7TgY0xFVcK1MWVRQqZzJUuV5CWbJecuglAQ6SbjRqlW5ZMfo-6PvZlKjabXZPTmITbCjDFvhpRUvFWdvRe_vBS-AFJTOBosng-DvJhOTGG3cpZTO-CkKgIIBySnnM_rlFbr2U3BzPAGMMc6LqiQz9fWR0sHHGEz3_AwlYlev2K93xj_vB3iG__fJ_gGTQKEq</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2333667980</pqid></control><display><type>article</type><title>The Antitumor Activity of TCR-Mimic Antibody-Drug Conjugates (TCRm-ADCs) Targeting the Intracellular Wilms Tumor 1 (WT1) Oncoprotein</title><source>MEDLINE</source><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Shen, Ying ; Li, Yi-Ming ; Zhou, Jing-Jing ; Zhou, Zhan ; Xu, Ying-Chun ; Zhao, Wen-Bin ; Chen, Shu-Qing</creator><creatorcontrib>Shen, Ying ; Li, Yi-Ming ; Zhou, Jing-Jing ; Zhou, Zhan ; Xu, Ying-Chun ; Zhao, Wen-Bin ; Chen, Shu-Qing</creatorcontrib><description>Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms20163912</identifier><identifier>PMID: 31408937</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Animals ; Antigens ; Antineoplastic Agents, Immunological - therapeutic use ; Antitumor activity ; Bispecific antibodies ; Cancer ; Cell Line, Tumor ; Chimeric antigen receptors ; Chromatography ; Cytotoxicity ; Epitopes ; Flow cytometry ; Glycosylation ; Histocompatibility antigen HLA ; HLA-A Antigens - immunology ; Humans ; Immunoconjugates - therapeutic use ; Immunoglobulins ; Internalization ; Kidney Neoplasms - drug therapy ; Kidney Neoplasms - immunology ; Leukemia ; Male ; Medical research ; Mice, Inbred BALB C ; Mice, Nude ; Oncoproteins ; Peptides ; Proteins ; Receptors, Antigen, T-Cell - immunology ; T cell receptors ; Tumors ; Wilms Tumor - drug therapy ; Wilms Tumor - immunology ; WT1 protein ; WT1 Proteins - immunology</subject><ispartof>International journal of molecular sciences, 2019-08, Vol.20 (16), p.3912</ispartof><rights>2019. This work is licensed under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 by the authors. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-c35682aad12cb1f62eef0b76cbe87929b53a8b5582e466d328a02fa06ecbdb5a3</citedby><cites>FETCH-LOGICAL-c412t-c35682aad12cb1f62eef0b76cbe87929b53a8b5582e466d328a02fa06ecbdb5a3</cites><orcidid>0000-0002-0792-3735 ; 0000-0002-2730-5483 ; 0000-0003-1380-0237</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720711/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720711/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53770,53772</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31408937$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shen, Ying</creatorcontrib><creatorcontrib>Li, Yi-Ming</creatorcontrib><creatorcontrib>Zhou, Jing-Jing</creatorcontrib><creatorcontrib>Zhou, Zhan</creatorcontrib><creatorcontrib>Xu, Ying-Chun</creatorcontrib><creatorcontrib>Zhao, Wen-Bin</creatorcontrib><creatorcontrib>Chen, Shu-Qing</creatorcontrib><title>The Antitumor Activity of TCR-Mimic Antibody-Drug Conjugates (TCRm-ADCs) Targeting the Intracellular Wilms Tumor 1 (WT1) Oncoprotein</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy.</description><subject>Animals</subject><subject>Antigens</subject><subject>Antineoplastic Agents, Immunological - therapeutic use</subject><subject>Antitumor activity</subject><subject>Bispecific antibodies</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Chimeric antigen receptors</subject><subject>Chromatography</subject><subject>Cytotoxicity</subject><subject>Epitopes</subject><subject>Flow cytometry</subject><subject>Glycosylation</subject><subject>Histocompatibility antigen HLA</subject><subject>HLA-A Antigens - immunology</subject><subject>Humans</subject><subject>Immunoconjugates - therapeutic use</subject><subject>Immunoglobulins</subject><subject>Internalization</subject><subject>Kidney Neoplasms - drug therapy</subject><subject>Kidney Neoplasms - immunology</subject><subject>Leukemia</subject><subject>Male</subject><subject>Medical research</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Oncoproteins</subject><subject>Peptides</subject><subject>Proteins</subject><subject>Receptors, Antigen, T-Cell - immunology</subject><subject>T cell receptors</subject><subject>Tumors</subject><subject>Wilms Tumor - drug therapy</subject><subject>Wilms Tumor - immunology</subject><subject>WT1 protein</subject><subject>WT1 Proteins - immunology</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkUFr3DAQhUVpaNK0t56LoJcN1Kk0Wsv2pbA4SRtICRSXHIUky44WW9pIcmDv_eH1JmnY5DQD7-PNPB5Cnyg5Zawi3-x6jEAoZxWFN-iILgEyQnjxdm8_RO9jXBMCDPLqHTpkdEnKihVH6G9za_DKJZum0Qe80sne27TFvsNN_Tv7ZUerH3Tl2212FqYe196tp14mE_FiZsZsdVbHE9zI0JtkXY_TbHnpUpDaDMM0yIBv7DBG3DycoHhx09ATfO203wSfjHUf0EEnh2g-Ps1j9OfivKl_ZlfXPy7r1VWmlxRSplnOS5CypaAV7TgY0xFVcK1MWVRQqZzJUuV5CWbJecuglAQ6SbjRqlW5ZMfo-6PvZlKjabXZPTmITbCjDFvhpRUvFWdvRe_vBS-AFJTOBosng-DvJhOTGG3cpZTO-CkKgIIBySnnM_rlFbr2U3BzPAGMMc6LqiQz9fWR0sHHGEz3_AwlYlev2K93xj_vB3iG__fJ_gGTQKEq</recordid><startdate>20190812</startdate><enddate>20190812</enddate><creator>Shen, Ying</creator><creator>Li, Yi-Ming</creator><creator>Zhou, Jing-Jing</creator><creator>Zhou, Zhan</creator><creator>Xu, Ying-Chun</creator><creator>Zhao, Wen-Bin</creator><creator>Chen, Shu-Qing</creator><general>MDPI AG</general><general>MDPI</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</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>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0792-3735</orcidid><orcidid>https://orcid.org/0000-0002-2730-5483</orcidid><orcidid>https://orcid.org/0000-0003-1380-0237</orcidid></search><sort><creationdate>20190812</creationdate><title>The Antitumor Activity of TCR-Mimic Antibody-Drug Conjugates (TCRm-ADCs) Targeting the Intracellular Wilms Tumor 1 (WT1) Oncoprotein</title><author>Shen, Ying ; Li, Yi-Ming ; Zhou, Jing-Jing ; Zhou, Zhan ; Xu, Ying-Chun ; Zhao, Wen-Bin ; Chen, Shu-Qing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-c35682aad12cb1f62eef0b76cbe87929b53a8b5582e466d328a02fa06ecbdb5a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Antigens</topic><topic>Antineoplastic Agents, Immunological - therapeutic use</topic><topic>Antitumor activity</topic><topic>Bispecific antibodies</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Chimeric antigen receptors</topic><topic>Chromatography</topic><topic>Cytotoxicity</topic><topic>Epitopes</topic><topic>Flow cytometry</topic><topic>Glycosylation</topic><topic>Histocompatibility antigen HLA</topic><topic>HLA-A Antigens - immunology</topic><topic>Humans</topic><topic>Immunoconjugates - therapeutic use</topic><topic>Immunoglobulins</topic><topic>Internalization</topic><topic>Kidney Neoplasms - drug therapy</topic><topic>Kidney Neoplasms - immunology</topic><topic>Leukemia</topic><topic>Male</topic><topic>Medical research</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Oncoproteins</topic><topic>Peptides</topic><topic>Proteins</topic><topic>Receptors, Antigen, T-Cell - immunology</topic><topic>T cell receptors</topic><topic>Tumors</topic><topic>Wilms Tumor - drug therapy</topic><topic>Wilms Tumor - immunology</topic><topic>WT1 protein</topic><topic>WT1 Proteins - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shen, Ying</creatorcontrib><creatorcontrib>Li, Yi-Ming</creatorcontrib><creatorcontrib>Zhou, Jing-Jing</creatorcontrib><creatorcontrib>Zhou, Zhan</creatorcontrib><creatorcontrib>Xu, Ying-Chun</creatorcontrib><creatorcontrib>Zhao, Wen-Bin</creatorcontrib><creatorcontrib>Chen, Shu-Qing</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shen, Ying</au><au>Li, Yi-Ming</au><au>Zhou, Jing-Jing</au><au>Zhou, Zhan</au><au>Xu, Ying-Chun</au><au>Zhao, Wen-Bin</au><au>Chen, Shu-Qing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Antitumor Activity of TCR-Mimic Antibody-Drug Conjugates (TCRm-ADCs) Targeting the Intracellular Wilms Tumor 1 (WT1) Oncoprotein</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2019-08-12</date><risdate>2019</risdate><volume>20</volume><issue>16</issue><spage>3912</spage><pages>3912-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>31408937</pmid><doi>10.3390/ijms20163912</doi><orcidid>https://orcid.org/0000-0002-0792-3735</orcidid><orcidid>https://orcid.org/0000-0002-2730-5483</orcidid><orcidid>https://orcid.org/0000-0003-1380-0237</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1422-0067 |
| ispartof | International journal of molecular sciences, 2019-08, Vol.20 (16), p.3912 |
| issn | 1422-0067 1661-6596 1422-0067 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6720711 |
| source | MEDLINE; MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Animals Antigens Antineoplastic Agents, Immunological - therapeutic use Antitumor activity Bispecific antibodies Cancer Cell Line, Tumor Chimeric antigen receptors Chromatography Cytotoxicity Epitopes Flow cytometry Glycosylation Histocompatibility antigen HLA HLA-A Antigens - immunology Humans Immunoconjugates - therapeutic use Immunoglobulins Internalization Kidney Neoplasms - drug therapy Kidney Neoplasms - immunology Leukemia Male Medical research Mice, Inbred BALB C Mice, Nude Oncoproteins Peptides Proteins Receptors, Antigen, T-Cell - immunology T cell receptors Tumors Wilms Tumor - drug therapy Wilms Tumor - immunology WT1 protein WT1 Proteins - immunology |
| title | The Antitumor Activity of TCR-Mimic Antibody-Drug Conjugates (TCRm-ADCs) Targeting the Intracellular Wilms Tumor 1 (WT1) Oncoprotein |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T21%3A06%3A48IST&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=The%20Antitumor%20Activity%20of%20TCR-Mimic%20Antibody-Drug%20Conjugates%20(TCRm-ADCs)%20Targeting%20the%20Intracellular%20Wilms%20Tumor%201%20(WT1)%20Oncoprotein&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=Shen,%20Ying&rft.date=2019-08-12&rft.volume=20&rft.issue=16&rft.spage=3912&rft.pages=3912-&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms20163912&rft_dat=%3Cproquest_pubme%3E2273205166%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=2333667980&rft_id=info:pmid/31408937&rfr_iscdi=true |