Inflammatory cytokine-regulated tRNA-derived fragment tRF-21 suppresses pancreatic ductal adenocarcinoma progression
The tumorigenic mechanism for pancreatic ductal adenocarcinoma (PDAC) is not clear, although chronic inflammation is implicated. Here, we identified an inflammatory cytokine-regulated transfer RNA-derived (tRNA-derived) fragment, tRF-21-VBY9PYKHD (tRF-21), as a tumor suppressor in PDAC progression....
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| Veröffentlicht in: | The Journal of clinical investigation 2021-11, Vol.131 (22), p.1-17 |
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| container_title | The Journal of clinical investigation |
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| creator | Pan, Ling Huang, Xudong Liu, Ze-Xian Ye, Ying Li, Rui Zhang, Jialiang Wu, Guandi Bai, Ruihong Zhuang, Lisha Wei, Lusheng Li, Mei Zheng, Yanfen Su, Jiachun Deng, Junge Deng, Shuang Zeng, Lingxing Zhang, Shaoping Wu, Chen Che, Xu Wang, Chengfeng Chen, Rufu Lin, Dongxin Zheng, Jian |
| description | The tumorigenic mechanism for pancreatic ductal adenocarcinoma (PDAC) is not clear, although chronic inflammation is implicated. Here, we identified an inflammatory cytokine-regulated transfer RNA-derived (tRNA-derived) fragment, tRF-21-VBY9PYKHD (tRF-21), as a tumor suppressor in PDAC progression. We found that the biogenesis of tRF-21 could be inhibited by leukemia inhibitory factor and IL-6 via the splicing factor SRSF5. Reduced tRF-21 promoted AKT2/1-mediated heterogeneous nuclear ribonucleoprotein L (hnRNP L) phosphorylation, enhancing hnRNP L to interact with dead-box helicase 17 (DDX17) to form an alternative splicing complex. The provoked hnRNP L-DDX17 activity preferentially spliced Caspase 9 and mH2A1 pre-mRNAs to form Caspase 9b and mH2A1.2, promoting PDAC cell malignant phenotypes. The tRF-21 levels were significantly lower in PDACs than in normal tissues, and patients with low tRF-21 levels had a poor prognosis. Treatment of mouse PDAC xenografts or patient-derived xenografts (PDXs) with tRF-21 mimics repressed tumor growth and metastasis. These results demonstrate that tRF-21 has a tumor-suppressive effect and is a potential therapeutic agent for PDAC. |
| doi_str_mv | 10.1172/JCI148130 |
| format | Article |
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Here, we identified an inflammatory cytokine-regulated transfer RNA-derived (tRNA-derived) fragment, tRF-21-VBY9PYKHD (tRF-21), as a tumor suppressor in PDAC progression. We found that the biogenesis of tRF-21 could be inhibited by leukemia inhibitory factor and IL-6 via the splicing factor SRSF5. Reduced tRF-21 promoted AKT2/1-mediated heterogeneous nuclear ribonucleoprotein L (hnRNP L) phosphorylation, enhancing hnRNP L to interact with dead-box helicase 17 (DDX17) to form an alternative splicing complex. The provoked hnRNP L-DDX17 activity preferentially spliced Caspase 9 and mH2A1 pre-mRNAs to form Caspase 9b and mH2A1.2, promoting PDAC cell malignant phenotypes. The tRF-21 levels were significantly lower in PDACs than in normal tissues, and patients with low tRF-21 levels had a poor prognosis. Treatment of mouse PDAC xenografts or patient-derived xenografts (PDXs) with tRF-21 mimics repressed tumor growth and metastasis. These results demonstrate that tRF-21 has a tumor-suppressive effect and is a potential therapeutic agent for PDAC.</description><identifier>ISSN: 1558-8238</identifier><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI148130</identifier><identifier>PMID: 34779408</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Adenocarcinoma ; AKT2 protein ; Alternative Splicing ; Biomedical research ; Biosynthesis ; Cancer ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - prevention & control ; Care and treatment ; Caspase-9 ; Cell growth ; Cell Line, Tumor ; Cytokines ; Cytokines - physiology ; DEAD-box RNA Helicases - metabolism ; Development and progression ; Disease Progression ; DNA helicase ; Genetic aspects ; Health aspects ; Humans ; Inflammation ; Interleukin 6 ; Leukemia ; Leukemia inhibitory factor ; Medical prognosis ; Metastases ; Metastasis ; Pancreas ; Pancreatic cancer ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - prevention & control ; Pancreatitis ; Patients ; Phenotypes ; Phosphorylation ; Proteins ; Proto-Oncogene Proteins c-akt - physiology ; Ribonucleoproteins - metabolism ; RNA, Transfer - physiology ; Serine-Arginine Splicing Factors - physiology ; Splicing factors ; Transfer RNA ; tRNA ; Tumor suppressor genes ; Tumor Suppressor Proteins ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>The Journal of clinical investigation, 2021-11, Vol.131 (22), p.1-17</ispartof><rights>COPYRIGHT 2021 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Nov 2021</rights><rights>2021 American Society for Clinical Investigation 2021 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c647t-c8bf3741c07f352c12d5521abfed16f799e771f9d0dcd8f27b52e564e1446a93</citedby><cites>FETCH-LOGICAL-c647t-c8bf3741c07f352c12d5521abfed16f799e771f9d0dcd8f27b52e564e1446a93</cites><orcidid>0000-0002-8445-4901 ; 0000-0002-2683-3321 ; 0000-0003-1626-6674</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/PMC8592549/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592549/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34779408$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pan, Ling</creatorcontrib><creatorcontrib>Huang, Xudong</creatorcontrib><creatorcontrib>Liu, Ze-Xian</creatorcontrib><creatorcontrib>Ye, Ying</creatorcontrib><creatorcontrib>Li, Rui</creatorcontrib><creatorcontrib>Zhang, Jialiang</creatorcontrib><creatorcontrib>Wu, Guandi</creatorcontrib><creatorcontrib>Bai, Ruihong</creatorcontrib><creatorcontrib>Zhuang, Lisha</creatorcontrib><creatorcontrib>Wei, Lusheng</creatorcontrib><creatorcontrib>Li, Mei</creatorcontrib><creatorcontrib>Zheng, Yanfen</creatorcontrib><creatorcontrib>Su, Jiachun</creatorcontrib><creatorcontrib>Deng, Junge</creatorcontrib><creatorcontrib>Deng, Shuang</creatorcontrib><creatorcontrib>Zeng, Lingxing</creatorcontrib><creatorcontrib>Zhang, Shaoping</creatorcontrib><creatorcontrib>Wu, Chen</creatorcontrib><creatorcontrib>Che, Xu</creatorcontrib><creatorcontrib>Wang, Chengfeng</creatorcontrib><creatorcontrib>Chen, Rufu</creatorcontrib><creatorcontrib>Lin, Dongxin</creatorcontrib><creatorcontrib>Zheng, Jian</creatorcontrib><title>Inflammatory cytokine-regulated tRNA-derived fragment tRF-21 suppresses pancreatic ductal adenocarcinoma progression</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>The tumorigenic mechanism for pancreatic ductal adenocarcinoma (PDAC) is not clear, although chronic inflammation is implicated. Here, we identified an inflammatory cytokine-regulated transfer RNA-derived (tRNA-derived) fragment, tRF-21-VBY9PYKHD (tRF-21), as a tumor suppressor in PDAC progression. We found that the biogenesis of tRF-21 could be inhibited by leukemia inhibitory factor and IL-6 via the splicing factor SRSF5. Reduced tRF-21 promoted AKT2/1-mediated heterogeneous nuclear ribonucleoprotein L (hnRNP L) phosphorylation, enhancing hnRNP L to interact with dead-box helicase 17 (DDX17) to form an alternative splicing complex. The provoked hnRNP L-DDX17 activity preferentially spliced Caspase 9 and mH2A1 pre-mRNAs to form Caspase 9b and mH2A1.2, promoting PDAC cell malignant phenotypes. The tRF-21 levels were significantly lower in PDACs than in normal tissues, and patients with low tRF-21 levels had a poor prognosis. Treatment of mouse PDAC xenografts or patient-derived xenografts (PDXs) with tRF-21 mimics repressed tumor growth and metastasis. These results demonstrate that tRF-21 has a tumor-suppressive effect and is a potential therapeutic agent for PDAC.</description><subject>Adenocarcinoma</subject><subject>AKT2 protein</subject><subject>Alternative Splicing</subject><subject>Biomedical research</subject><subject>Biosynthesis</subject><subject>Cancer</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - prevention & control</subject><subject>Care and treatment</subject><subject>Caspase-9</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cytokines</subject><subject>Cytokines - physiology</subject><subject>DEAD-box RNA Helicases - metabolism</subject><subject>Development and progression</subject><subject>Disease Progression</subject><subject>DNA helicase</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Interleukin 6</subject><subject>Leukemia</subject><subject>Leukemia inhibitory factor</subject><subject>Medical prognosis</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Pancreas</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - prevention & control</subject><subject>Pancreatitis</subject><subject>Patients</subject><subject>Phenotypes</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - physiology</subject><subject>Ribonucleoproteins - metabolism</subject><subject>RNA, Transfer - physiology</subject><subject>Serine-Arginine Splicing Factors - physiology</subject><subject>Splicing factors</subject><subject>Transfer RNA</subject><subject>tRNA</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Proteins</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>1558-8238</issn><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNklFrFDEQxxdRbK0--AVkQRB82Jpks5vsi3AcVk-KhVp8Dblksk3dTbZJtnjf3hzW8w7uQQLJZPKbfyaZKYrXGJ1jzMiHr8sVphzX6ElxipuGV5zU_OmefVK8iPEOIUxpQ58XJzVlrKOInxZp5cwgx1EmHzal2iT_0zqoAvTzIBPoMl1_W1Qagn3IGxNkP4JL2XtREVzGeZoCxAixnKRTAWSyqtSzSnIopQbnlQzKOj_Kcgq-37LWu5fFMyOHCK8e17Pi5uLTzfJLdXn1ebVcXFaqpSxViq9NzShWiJm6IQoT3TQEy7UBjVvDug4Yw6bTSCvNDWHrhkDTUsjPbGVXnxUf_8hO83oErXLiQQ5iCnaUYSO8tOLwxNlb0fsHwZuONHQr8PZRIPj7GWISd34OLqcsSIs4bhHF6B_VywGEdcZnMTXaqMSi5VknT1ut6gjVg4N8s3dgbHYf8OdH-Dw0jFYdDXh_EJCZBL9SL-cYxer79f-zVz8O2Xd77C3IId1GP8wpFzIeFVXBxxjA7H4aI7HtU7Hr08y-2S_NjvzbmPVvK07heg</recordid><startdate>20211115</startdate><enddate>20211115</enddate><creator>Pan, Ling</creator><creator>Huang, Xudong</creator><creator>Liu, Ze-Xian</creator><creator>Ye, Ying</creator><creator>Li, Rui</creator><creator>Zhang, Jialiang</creator><creator>Wu, Guandi</creator><creator>Bai, Ruihong</creator><creator>Zhuang, Lisha</creator><creator>Wei, Lusheng</creator><creator>Li, Mei</creator><creator>Zheng, Yanfen</creator><creator>Su, Jiachun</creator><creator>Deng, Junge</creator><creator>Deng, Shuang</creator><creator>Zeng, Lingxing</creator><creator>Zhang, Shaoping</creator><creator>Wu, Chen</creator><creator>Che, Xu</creator><creator>Wang, Chengfeng</creator><creator>Chen, Rufu</creator><creator>Lin, Dongxin</creator><creator>Zheng, Jian</creator><general>American Society for Clinical 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cytokine-regulated tRNA-derived fragment tRF-21 suppresses pancreatic ductal adenocarcinoma progression</title><author>Pan, Ling ; Huang, Xudong ; Liu, Ze-Xian ; Ye, Ying ; Li, Rui ; Zhang, Jialiang ; Wu, Guandi ; Bai, Ruihong ; Zhuang, Lisha ; Wei, Lusheng ; Li, Mei ; Zheng, Yanfen ; Su, Jiachun ; Deng, Junge ; Deng, Shuang ; Zeng, Lingxing ; Zhang, Shaoping ; Wu, Chen ; Che, Xu ; Wang, Chengfeng ; Chen, Rufu ; Lin, Dongxin ; Zheng, Jian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c647t-c8bf3741c07f352c12d5521abfed16f799e771f9d0dcd8f27b52e564e1446a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenocarcinoma</topic><topic>AKT2 protein</topic><topic>Alternative Splicing</topic><topic>Biomedical research</topic><topic>Biosynthesis</topic><topic>Cancer</topic><topic>Carcinoma, Pancreatic Ductal - genetics</topic><topic>Carcinoma, Pancreatic Ductal - prevention & control</topic><topic>Care and treatment</topic><topic>Caspase-9</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cytokines</topic><topic>Cytokines - physiology</topic><topic>DEAD-box RNA Helicases - metabolism</topic><topic>Development and progression</topic><topic>Disease Progression</topic><topic>DNA helicase</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Interleukin 6</topic><topic>Leukemia</topic><topic>Leukemia inhibitory factor</topic><topic>Medical prognosis</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Pancreas</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - prevention & control</topic><topic>Pancreatitis</topic><topic>Patients</topic><topic>Phenotypes</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - physiology</topic><topic>Ribonucleoproteins - metabolism</topic><topic>RNA, Transfer - physiology</topic><topic>Serine-Arginine Splicing Factors - physiology</topic><topic>Splicing factors</topic><topic>Transfer RNA</topic><topic>tRNA</topic><topic>Tumor suppressor genes</topic><topic>Tumor Suppressor Proteins</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pan, Ling</creatorcontrib><creatorcontrib>Huang, Xudong</creatorcontrib><creatorcontrib>Liu, Ze-Xian</creatorcontrib><creatorcontrib>Ye, Ying</creatorcontrib><creatorcontrib>Li, Rui</creatorcontrib><creatorcontrib>Zhang, Jialiang</creatorcontrib><creatorcontrib>Wu, Guandi</creatorcontrib><creatorcontrib>Bai, Ruihong</creatorcontrib><creatorcontrib>Zhuang, Lisha</creatorcontrib><creatorcontrib>Wei, Lusheng</creatorcontrib><creatorcontrib>Li, Mei</creatorcontrib><creatorcontrib>Zheng, Yanfen</creatorcontrib><creatorcontrib>Su, 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investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pan, Ling</au><au>Huang, Xudong</au><au>Liu, Ze-Xian</au><au>Ye, Ying</au><au>Li, Rui</au><au>Zhang, Jialiang</au><au>Wu, Guandi</au><au>Bai, Ruihong</au><au>Zhuang, Lisha</au><au>Wei, Lusheng</au><au>Li, Mei</au><au>Zheng, Yanfen</au><au>Su, Jiachun</au><au>Deng, Junge</au><au>Deng, Shuang</au><au>Zeng, Lingxing</au><au>Zhang, Shaoping</au><au>Wu, Chen</au><au>Che, Xu</au><au>Wang, Chengfeng</au><au>Chen, Rufu</au><au>Lin, Dongxin</au><au>Zheng, Jian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inflammatory cytokine-regulated tRNA-derived fragment tRF-21 suppresses pancreatic ductal adenocarcinoma progression</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2021-11-15</date><risdate>2021</risdate><volume>131</volume><issue>22</issue><spage>1</spage><epage>17</epage><pages>1-17</pages><issn>1558-8238</issn><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>The tumorigenic mechanism for pancreatic ductal adenocarcinoma (PDAC) is not clear, although chronic inflammation is implicated. Here, we identified an inflammatory cytokine-regulated transfer RNA-derived (tRNA-derived) fragment, tRF-21-VBY9PYKHD (tRF-21), as a tumor suppressor in PDAC progression. We found that the biogenesis of tRF-21 could be inhibited by leukemia inhibitory factor and IL-6 via the splicing factor SRSF5. Reduced tRF-21 promoted AKT2/1-mediated heterogeneous nuclear ribonucleoprotein L (hnRNP L) phosphorylation, enhancing hnRNP L to interact with dead-box helicase 17 (DDX17) to form an alternative splicing complex. The provoked hnRNP L-DDX17 activity preferentially spliced Caspase 9 and mH2A1 pre-mRNAs to form Caspase 9b and mH2A1.2, promoting PDAC cell malignant phenotypes. The tRF-21 levels were significantly lower in PDACs than in normal tissues, and patients with low tRF-21 levels had a poor prognosis. Treatment of mouse PDAC xenografts or patient-derived xenografts (PDXs) with tRF-21 mimics repressed tumor growth and metastasis. These results demonstrate that tRF-21 has a tumor-suppressive effect and is a potential therapeutic agent for PDAC.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>34779408</pmid><doi>10.1172/JCI148130</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-8445-4901</orcidid><orcidid>https://orcid.org/0000-0002-2683-3321</orcidid><orcidid>https://orcid.org/0000-0003-1626-6674</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of clinical investigation, 2021-11, Vol.131 (22), p.1-17 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8592549 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Adenocarcinoma AKT2 protein Alternative Splicing Biomedical research Biosynthesis Cancer Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - prevention & control Care and treatment Caspase-9 Cell growth Cell Line, Tumor Cytokines Cytokines - physiology DEAD-box RNA Helicases - metabolism Development and progression Disease Progression DNA helicase Genetic aspects Health aspects Humans Inflammation Interleukin 6 Leukemia Leukemia inhibitory factor Medical prognosis Metastases Metastasis Pancreas Pancreatic cancer Pancreatic Neoplasms - genetics Pancreatic Neoplasms - prevention & control Pancreatitis Patients Phenotypes Phosphorylation Proteins Proto-Oncogene Proteins c-akt - physiology Ribonucleoproteins - metabolism RNA, Transfer - physiology Serine-Arginine Splicing Factors - physiology Splicing factors Transfer RNA tRNA Tumor suppressor genes Tumor Suppressor Proteins Tumors Xenograft Model Antitumor Assays Xenografts |
| title | Inflammatory cytokine-regulated tRNA-derived fragment tRF-21 suppresses pancreatic ductal adenocarcinoma progression |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T20%3A37%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Inflammatory%20cytokine-regulated%20tRNA-derived%20fragment%20tRF-21%20suppresses%20pancreatic%20ductal%20adenocarcinoma%20progression&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Pan,%20Ling&rft.date=2021-11-15&rft.volume=131&rft.issue=22&rft.spage=1&rft.epage=17&rft.pages=1-17&rft.issn=1558-8238&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI148130&rft_dat=%3Cgale_pubme%3EA685496859%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2608160410&rft_id=info:pmid/34779408&rft_galeid=A685496859&rfr_iscdi=true |