Transcriptomic Changes Associated with ERBB2 Overexpression in Colorectal Cancer Implicate a Potential Role of the Wnt Signaling Pathway in Tumorigenesis
Colorectal cancer (CRC) remains the third most common cause of cancer mortality worldwide. Precision medicine using OMICs guided by transcriptomic profiling has improved disease diagnosis and prognosis by identifying many CRC targets. One such target that has been actively pursued is an erbb2 recept...
Gespeichert in:
| Veröffentlicht in: | Cancers 2022-12, Vol.15 (1), p.130 |
|---|---|
| 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 | 1 |
| container_start_page | 130 |
| container_title | Cancers |
| container_volume | 15 |
| creator | Abdul Razzaq, Eman A Bajbouj, Khuloud Bouzid, Amal Alkhayyal, Noura Hamoudi, Rifat Bendardaf, Riyad |
| description | Colorectal cancer (CRC) remains the third most common cause of cancer mortality worldwide. Precision medicine using OMICs guided by transcriptomic profiling has improved disease diagnosis and prognosis by identifying many CRC targets. One such target that has been actively pursued is an erbb2 receptor tyrosine kinase 2 (
) (Human Epidermal Growth Factor Receptor 2 (HER2)), which is overexpressed in around 3-5% of patients with CRC worldwide. Despite targeted therapies against HER2 showing significant improvement in disease outcomes in multiple clinical trials, to date, no HER2-based treatment has been clinically approved for CRC. In this study we performed whole transcriptome ribonucleic acid (RNA) sequencing on 11 HER2+ and 3 HER2- CRC patients with advanced stages II, III and IV of the disease. In addition, transcriptomic profiling was carried out on CRC cell lines (HCT116 and HT29) and normal colon cell lines (CCD841 and CCD33), ectopically overexpressing
. Our analysis revealed transcriptomic changes involving many genes in both CRC cell lines overexpressing
and in HER2+ patients, compared to normal colon cell lines and HER2- patients, respectively. Gene Set Enrichment Analysis indicated a role for HER2 in regulating CRC pathogenesis, with Wnt/β-catenin signaling being mediated via a HER2-dependent regulatory pathway impacting expression of the homeobox gene NK2 homeobox 5 (NKX2-5). Results from this study thus identified putative targets that are co-expressed with HER2 in CRC warranting further investigation into their role in CRC pathogenesis. |
| doi_str_mv | 10.3390/cancers15010130 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9817785</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2761977732</sourcerecordid><originalsourceid>FETCH-LOGICAL-c421t-15fb1794012dcebff16bf2a9098d2c83acb4a75f47bf234e4b7e0bf182a8d1413</originalsourceid><addsrcrecordid>eNpdkc1O3DAURq2qVUGUdXeVpW66GfBPJk42lSCiFAkJBIO6tBzPdWKU2KntQHkU3hZPhyKKN7Z8zz269ofQZ0oOOK_JoVZOQ4h0SSihnLxDu4wItijLunj_6ryD9mO8JXlxTkUpPqIdXpaUUVbuosdVUC7qYKfkR6tx0yvXQcRHMXptVYI1vrepxydXx8cMX9xBgD9TgBitd9g63PjBB9BJDbj5Ow4-G6fB6tyJFb70CVyyuXjlB8De4NQD_uUSvradU4N1Hb5Uqb9XDxvZah59sB04iDZ-Qh-MGiLsP-976ObHyar5uTi_OD1rjs4XumA0LejStFTUBaFsraE1hpatYaomdbVmuuJKt4USS1OIfM0LKFoBpDW0Yqpa04LyPfR9653mdoTscCmoQU7Bjio8SK-s_L_ibC87fyfrigpRLbPg27Mg-N8zxCRHGzUMg3Lg5yiZKGkthOAso1_foLd-DvkjthSpa1ZtqMMtpYOPMYB5GYYSuUlevkk-d3x5_YYX_l_O_AmKa64f</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2761099282</pqid></control><display><type>article</type><title>Transcriptomic Changes Associated with ERBB2 Overexpression in Colorectal Cancer Implicate a Potential Role of the Wnt Signaling Pathway in Tumorigenesis</title><source>PubMed Central Open Access</source><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Abdul Razzaq, Eman A ; Bajbouj, Khuloud ; Bouzid, Amal ; Alkhayyal, Noura ; Hamoudi, Rifat ; Bendardaf, Riyad</creator><creatorcontrib>Abdul Razzaq, Eman A ; Bajbouj, Khuloud ; Bouzid, Amal ; Alkhayyal, Noura ; Hamoudi, Rifat ; Bendardaf, Riyad</creatorcontrib><description>Colorectal cancer (CRC) remains the third most common cause of cancer mortality worldwide. Precision medicine using OMICs guided by transcriptomic profiling has improved disease diagnosis and prognosis by identifying many CRC targets. One such target that has been actively pursued is an erbb2 receptor tyrosine kinase 2 (
) (Human Epidermal Growth Factor Receptor 2 (HER2)), which is overexpressed in around 3-5% of patients with CRC worldwide. Despite targeted therapies against HER2 showing significant improvement in disease outcomes in multiple clinical trials, to date, no HER2-based treatment has been clinically approved for CRC. In this study we performed whole transcriptome ribonucleic acid (RNA) sequencing on 11 HER2+ and 3 HER2- CRC patients with advanced stages II, III and IV of the disease. In addition, transcriptomic profiling was carried out on CRC cell lines (HCT116 and HT29) and normal colon cell lines (CCD841 and CCD33), ectopically overexpressing
. Our analysis revealed transcriptomic changes involving many genes in both CRC cell lines overexpressing
and in HER2+ patients, compared to normal colon cell lines and HER2- patients, respectively. Gene Set Enrichment Analysis indicated a role for HER2 in regulating CRC pathogenesis, with Wnt/β-catenin signaling being mediated via a HER2-dependent regulatory pathway impacting expression of the homeobox gene NK2 homeobox 5 (NKX2-5). Results from this study thus identified putative targets that are co-expressed with HER2 in CRC warranting further investigation into their role in CRC pathogenesis.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers15010130</identifier><identifier>PMID: 36612126</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Biopsy ; Breast cancer ; Cancer ; Cancer therapies ; Clinical trials ; Colorectal cancer ; Colorectal carcinoma ; Epidermal growth factor ; ErbB-2 protein ; Gene expression ; Gene set enrichment analysis ; Homeobox ; Medical prognosis ; Metastasis ; Monoclonal antibodies ; Nkx2.5 protein ; Pathogenesis ; Patients ; Precision medicine ; Protein-tyrosine kinase receptors ; Signal transduction ; Transcriptomes ; Transcriptomics ; Tumor cell lines ; Tumorigenesis ; Tumors ; Wnt protein ; β-Catenin</subject><ispartof>Cancers, 2022-12, Vol.15 (1), p.130</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-15fb1794012dcebff16bf2a9098d2c83acb4a75f47bf234e4b7e0bf182a8d1413</citedby><cites>FETCH-LOGICAL-c421t-15fb1794012dcebff16bf2a9098d2c83acb4a75f47bf234e4b7e0bf182a8d1413</cites><orcidid>0000-0001-7344-6095 ; 0000-0002-1402-0868 ; 0000-0003-0130-6004</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/PMC9817785/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9817785/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36612126$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Abdul Razzaq, Eman A</creatorcontrib><creatorcontrib>Bajbouj, Khuloud</creatorcontrib><creatorcontrib>Bouzid, Amal</creatorcontrib><creatorcontrib>Alkhayyal, Noura</creatorcontrib><creatorcontrib>Hamoudi, Rifat</creatorcontrib><creatorcontrib>Bendardaf, Riyad</creatorcontrib><title>Transcriptomic Changes Associated with ERBB2 Overexpression in Colorectal Cancer Implicate a Potential Role of the Wnt Signaling Pathway in Tumorigenesis</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Colorectal cancer (CRC) remains the third most common cause of cancer mortality worldwide. Precision medicine using OMICs guided by transcriptomic profiling has improved disease diagnosis and prognosis by identifying many CRC targets. One such target that has been actively pursued is an erbb2 receptor tyrosine kinase 2 (
) (Human Epidermal Growth Factor Receptor 2 (HER2)), which is overexpressed in around 3-5% of patients with CRC worldwide. Despite targeted therapies against HER2 showing significant improvement in disease outcomes in multiple clinical trials, to date, no HER2-based treatment has been clinically approved for CRC. In this study we performed whole transcriptome ribonucleic acid (RNA) sequencing on 11 HER2+ and 3 HER2- CRC patients with advanced stages II, III and IV of the disease. In addition, transcriptomic profiling was carried out on CRC cell lines (HCT116 and HT29) and normal colon cell lines (CCD841 and CCD33), ectopically overexpressing
. Our analysis revealed transcriptomic changes involving many genes in both CRC cell lines overexpressing
and in HER2+ patients, compared to normal colon cell lines and HER2- patients, respectively. Gene Set Enrichment Analysis indicated a role for HER2 in regulating CRC pathogenesis, with Wnt/β-catenin signaling being mediated via a HER2-dependent regulatory pathway impacting expression of the homeobox gene NK2 homeobox 5 (NKX2-5). Results from this study thus identified putative targets that are co-expressed with HER2 in CRC warranting further investigation into their role in CRC pathogenesis.</description><subject>Biopsy</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Clinical trials</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Epidermal growth factor</subject><subject>ErbB-2 protein</subject><subject>Gene expression</subject><subject>Gene set enrichment analysis</subject><subject>Homeobox</subject><subject>Medical prognosis</subject><subject>Metastasis</subject><subject>Monoclonal antibodies</subject><subject>Nkx2.5 protein</subject><subject>Pathogenesis</subject><subject>Patients</subject><subject>Precision medicine</subject><subject>Protein-tyrosine kinase receptors</subject><subject>Signal transduction</subject><subject>Transcriptomes</subject><subject>Transcriptomics</subject><subject>Tumor cell lines</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Wnt protein</subject><subject>β-Catenin</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><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>eNpdkc1O3DAURq2qVUGUdXeVpW66GfBPJk42lSCiFAkJBIO6tBzPdWKU2KntQHkU3hZPhyKKN7Z8zz269ofQZ0oOOK_JoVZOQ4h0SSihnLxDu4wItijLunj_6ryD9mO8JXlxTkUpPqIdXpaUUVbuosdVUC7qYKfkR6tx0yvXQcRHMXptVYI1vrepxydXx8cMX9xBgD9TgBitd9g63PjBB9BJDbj5Ow4-G6fB6tyJFb70CVyyuXjlB8De4NQD_uUSvradU4N1Hb5Uqb9XDxvZah59sB04iDZ-Qh-MGiLsP-976ObHyar5uTi_OD1rjs4XumA0LejStFTUBaFsraE1hpatYaomdbVmuuJKt4USS1OIfM0LKFoBpDW0Yqpa04LyPfR9653mdoTscCmoQU7Bjio8SK-s_L_ibC87fyfrigpRLbPg27Mg-N8zxCRHGzUMg3Lg5yiZKGkthOAso1_foLd-DvkjthSpa1ZtqMMtpYOPMYB5GYYSuUlevkk-d3x5_YYX_l_O_AmKa64f</recordid><startdate>20221226</startdate><enddate>20221226</enddate><creator>Abdul Razzaq, Eman A</creator><creator>Bajbouj, Khuloud</creator><creator>Bouzid, Amal</creator><creator>Alkhayyal, Noura</creator><creator>Hamoudi, Rifat</creator><creator>Bendardaf, Riyad</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</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/0000-0001-7344-6095</orcidid><orcidid>https://orcid.org/0000-0002-1402-0868</orcidid><orcidid>https://orcid.org/0000-0003-0130-6004</orcidid></search><sort><creationdate>20221226</creationdate><title>Transcriptomic Changes Associated with ERBB2 Overexpression in Colorectal Cancer Implicate a Potential Role of the Wnt Signaling Pathway in Tumorigenesis</title><author>Abdul Razzaq, Eman A ; Bajbouj, Khuloud ; Bouzid, Amal ; Alkhayyal, Noura ; Hamoudi, Rifat ; Bendardaf, Riyad</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c421t-15fb1794012dcebff16bf2a9098d2c83acb4a75f47bf234e4b7e0bf182a8d1413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Biopsy</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Clinical trials</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Epidermal growth factor</topic><topic>ErbB-2 protein</topic><topic>Gene expression</topic><topic>Gene set enrichment analysis</topic><topic>Homeobox</topic><topic>Medical prognosis</topic><topic>Metastasis</topic><topic>Monoclonal antibodies</topic><topic>Nkx2.5 protein</topic><topic>Pathogenesis</topic><topic>Patients</topic><topic>Precision medicine</topic><topic>Protein-tyrosine kinase receptors</topic><topic>Signal transduction</topic><topic>Transcriptomes</topic><topic>Transcriptomics</topic><topic>Tumor cell lines</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><topic>Wnt protein</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Abdul Razzaq, Eman A</creatorcontrib><creatorcontrib>Bajbouj, Khuloud</creatorcontrib><creatorcontrib>Bouzid, Amal</creatorcontrib><creatorcontrib>Alkhayyal, Noura</creatorcontrib><creatorcontrib>Hamoudi, Rifat</creatorcontrib><creatorcontrib>Bendardaf, Riyad</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</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>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Research Library</collection><collection>Biological Science Database</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>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Abdul Razzaq, Eman A</au><au>Bajbouj, Khuloud</au><au>Bouzid, Amal</au><au>Alkhayyal, Noura</au><au>Hamoudi, Rifat</au><au>Bendardaf, Riyad</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transcriptomic Changes Associated with ERBB2 Overexpression in Colorectal Cancer Implicate a Potential Role of the Wnt Signaling Pathway in Tumorigenesis</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2022-12-26</date><risdate>2022</risdate><volume>15</volume><issue>1</issue><spage>130</spage><pages>130-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Colorectal cancer (CRC) remains the third most common cause of cancer mortality worldwide. Precision medicine using OMICs guided by transcriptomic profiling has improved disease diagnosis and prognosis by identifying many CRC targets. One such target that has been actively pursued is an erbb2 receptor tyrosine kinase 2 (
) (Human Epidermal Growth Factor Receptor 2 (HER2)), which is overexpressed in around 3-5% of patients with CRC worldwide. Despite targeted therapies against HER2 showing significant improvement in disease outcomes in multiple clinical trials, to date, no HER2-based treatment has been clinically approved for CRC. In this study we performed whole transcriptome ribonucleic acid (RNA) sequencing on 11 HER2+ and 3 HER2- CRC patients with advanced stages II, III and IV of the disease. In addition, transcriptomic profiling was carried out on CRC cell lines (HCT116 and HT29) and normal colon cell lines (CCD841 and CCD33), ectopically overexpressing
. Our analysis revealed transcriptomic changes involving many genes in both CRC cell lines overexpressing
and in HER2+ patients, compared to normal colon cell lines and HER2- patients, respectively. Gene Set Enrichment Analysis indicated a role for HER2 in regulating CRC pathogenesis, with Wnt/β-catenin signaling being mediated via a HER2-dependent regulatory pathway impacting expression of the homeobox gene NK2 homeobox 5 (NKX2-5). Results from this study thus identified putative targets that are co-expressed with HER2 in CRC warranting further investigation into their role in CRC pathogenesis.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>36612126</pmid><doi>10.3390/cancers15010130</doi><orcidid>https://orcid.org/0000-0001-7344-6095</orcidid><orcidid>https://orcid.org/0000-0002-1402-0868</orcidid><orcidid>https://orcid.org/0000-0003-0130-6004</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2072-6694 |
| ispartof | Cancers, 2022-12, Vol.15 (1), p.130 |
| issn | 2072-6694 2072-6694 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9817785 |
| source | PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Biopsy Breast cancer Cancer Cancer therapies Clinical trials Colorectal cancer Colorectal carcinoma Epidermal growth factor ErbB-2 protein Gene expression Gene set enrichment analysis Homeobox Medical prognosis Metastasis Monoclonal antibodies Nkx2.5 protein Pathogenesis Patients Precision medicine Protein-tyrosine kinase receptors Signal transduction Transcriptomes Transcriptomics Tumor cell lines Tumorigenesis Tumors Wnt protein β-Catenin |
| title | Transcriptomic Changes Associated with ERBB2 Overexpression in Colorectal Cancer Implicate a Potential Role of the Wnt Signaling Pathway in Tumorigenesis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-22T03%3A52%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=Transcriptomic%20Changes%20Associated%20with%20ERBB2%20Overexpression%20in%20Colorectal%20Cancer%20Implicate%20a%20Potential%20Role%20of%20the%20Wnt%20Signaling%20Pathway%20in%20Tumorigenesis&rft.jtitle=Cancers&rft.au=Abdul%20Razzaq,%20Eman%20A&rft.date=2022-12-26&rft.volume=15&rft.issue=1&rft.spage=130&rft.pages=130-&rft.issn=2072-6694&rft.eissn=2072-6694&rft_id=info:doi/10.3390/cancers15010130&rft_dat=%3Cproquest_pubme%3E2761977732%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=2761099282&rft_id=info:pmid/36612126&rfr_iscdi=true |