A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer
Dysregulated Wnt/β-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selectiv...
Gespeichert in:
| Veröffentlicht in: | Science advances 2022-04, Vol.8 (17), p.eabm3108 |
|---|---|
| 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 | 17 |
| container_start_page | eabm3108 |
| container_title | Science advances |
| container_volume | 8 |
| creator | Tanton, Helen Sewastianik, Tomasz Seo, Hyuk-Soo Remillard, David Pierre, Roodolph St Bala, Pratyusha Aitymbayev, Daulet Dennis, Peter Adler, Keith Geffken, Ezekiel Yeoh, Zoe Vangos, Nicholas Garbicz, Filip Scott, David Sethi, Nilay Bradner, James Dhe-Paganon, Sirano Carrasco, Ruben D |
| description | Dysregulated Wnt/β-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between β-catenin and its coactivator BCL9. We identified a compound that consistently bound to β-catenin and specifically inhibited in vivo native β-catenin/BCL9 complex formation in CRC cell lines. This compound inhibited Wnt activity, down-regulated expression of the Wnt/β-catenin signature in gene expression studies, disrupted cholesterol homeostasis, and significantly reduced the proliferation of CRC cell lines and tumor growth in a xenograft mouse model of CRC. This study has therefore identified a specific small-molecule inhibitor of oncogenic Wnt signaling, which may have value as a probe for functional studies and has important implications for the development of novel therapies in patients with CRC. |
| doi_str_mv | 10.1126/sciadv.abm3108 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9054024</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2658233082</sourcerecordid><originalsourceid>FETCH-LOGICAL-c390t-6b24552cb836871a8d11cd8dd218e8e164469501eb4935f7e4e37c3a0a90f13</originalsourceid><addsrcrecordid>eNpVkc9uEzEQxi0EolXolSPysZdN_X-9F6QSlRYpUg8gcbS83kli8Nqp7UTtlUfqg_SZuiihKhePNfPNb2b0IfSRkjmlTF0U5-2wn9t-5JToN-iU8VY2TAr99tX_BJ2V8osQQoVSknbv0Qmf0qpl7Sn6c4lj2kPAT4-NsxWijxdfFssOuzRuA9xjHze-9zVl3IfkfhecokvrSefwz1hx8etog49rbOOAB1_yblsLdpsUoFTIKeBNGiGVaosvE20Ch5TBVRuws9FB_oDerWwocHaMM_T969WPxU2zvL3-trhcNo53pDaqZ0JK5nrNlW6p1QOlbtDDwKgGDVQJoTpJKPSi43LVggDeOm6J7ciK8hn6fKBud_0Ig4NYsw1mm_1o84NJ1pv_K9FvzDrtTUekIExMgPMjIKe73XScGX1xEIKNkHbFMCU145xMzwzND1KXUykZVi9jKDF_nTMH58zRuanh0-vlXuT_fOLPWIyaWw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2658233082</pqid></control><display><type>article</type><title>A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Tanton, Helen ; Sewastianik, Tomasz ; Seo, Hyuk-Soo ; Remillard, David ; Pierre, Roodolph St ; Bala, Pratyusha ; Aitymbayev, Daulet ; Dennis, Peter ; Adler, Keith ; Geffken, Ezekiel ; Yeoh, Zoe ; Vangos, Nicholas ; Garbicz, Filip ; Scott, David ; Sethi, Nilay ; Bradner, James ; Dhe-Paganon, Sirano ; Carrasco, Ruben D</creator><creatorcontrib>Tanton, Helen ; Sewastianik, Tomasz ; Seo, Hyuk-Soo ; Remillard, David ; Pierre, Roodolph St ; Bala, Pratyusha ; Aitymbayev, Daulet ; Dennis, Peter ; Adler, Keith ; Geffken, Ezekiel ; Yeoh, Zoe ; Vangos, Nicholas ; Garbicz, Filip ; Scott, David ; Sethi, Nilay ; Bradner, James ; Dhe-Paganon, Sirano ; Carrasco, Ruben D</creatorcontrib><description>Dysregulated Wnt/β-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between β-catenin and its coactivator BCL9. We identified a compound that consistently bound to β-catenin and specifically inhibited in vivo native β-catenin/BCL9 complex formation in CRC cell lines. This compound inhibited Wnt activity, down-regulated expression of the Wnt/β-catenin signature in gene expression studies, disrupted cholesterol homeostasis, and significantly reduced the proliferation of CRC cell lines and tumor growth in a xenograft mouse model of CRC. This study has therefore identified a specific small-molecule inhibitor of oncogenic Wnt signaling, which may have value as a probe for functional studies and has important implications for the development of novel therapies in patients with CRC.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.abm3108</identifier><identifier>PMID: 35486727</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Animals ; beta Catenin - genetics ; Biochemistry ; Biomedicine and Life Sciences ; Cholesterol ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - metabolism ; Homeostasis ; Humans ; Life Sciences ; Mice ; Neoplasm Proteins - metabolism ; SciAdv r-articles ; Transcription Factors - genetics ; Wnt Signaling Pathway - genetics</subject><ispartof>Science advances, 2022-04, Vol.8 (17), p.eabm3108</ispartof><rights>Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). 2022 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-6b24552cb836871a8d11cd8dd218e8e164469501eb4935f7e4e37c3a0a90f13</citedby><cites>FETCH-LOGICAL-c390t-6b24552cb836871a8d11cd8dd218e8e164469501eb4935f7e4e37c3a0a90f13</cites><orcidid>0000-0002-2694-9068 ; 0000-0002-3861-9242 ; 0000-0002-3748-7559 ; 0000-0001-7686-4700 ; 0000-0003-0824-5929 ; 0000-0002-0129-5870 ; 0000-0002-5548-1564 ; 0000-0001-6849-1852 ; 0000-0001-9638-3533 ; 0000-0003-1422-5318 ; 0000-0003-3243-528X ; 0000-0003-4603-8517 ; 0000-0003-0646-2102 ; 0000-0001-7277-2884</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/PMC9054024/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9054024/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35486727$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tanton, Helen</creatorcontrib><creatorcontrib>Sewastianik, Tomasz</creatorcontrib><creatorcontrib>Seo, Hyuk-Soo</creatorcontrib><creatorcontrib>Remillard, David</creatorcontrib><creatorcontrib>Pierre, Roodolph St</creatorcontrib><creatorcontrib>Bala, Pratyusha</creatorcontrib><creatorcontrib>Aitymbayev, Daulet</creatorcontrib><creatorcontrib>Dennis, Peter</creatorcontrib><creatorcontrib>Adler, Keith</creatorcontrib><creatorcontrib>Geffken, Ezekiel</creatorcontrib><creatorcontrib>Yeoh, Zoe</creatorcontrib><creatorcontrib>Vangos, Nicholas</creatorcontrib><creatorcontrib>Garbicz, Filip</creatorcontrib><creatorcontrib>Scott, David</creatorcontrib><creatorcontrib>Sethi, Nilay</creatorcontrib><creatorcontrib>Bradner, James</creatorcontrib><creatorcontrib>Dhe-Paganon, Sirano</creatorcontrib><creatorcontrib>Carrasco, Ruben D</creatorcontrib><title>A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>Dysregulated Wnt/β-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between β-catenin and its coactivator BCL9. We identified a compound that consistently bound to β-catenin and specifically inhibited in vivo native β-catenin/BCL9 complex formation in CRC cell lines. This compound inhibited Wnt activity, down-regulated expression of the Wnt/β-catenin signature in gene expression studies, disrupted cholesterol homeostasis, and significantly reduced the proliferation of CRC cell lines and tumor growth in a xenograft mouse model of CRC. This study has therefore identified a specific small-molecule inhibitor of oncogenic Wnt signaling, which may have value as a probe for functional studies and has important implications for the development of novel therapies in patients with CRC.</description><subject>Animals</subject><subject>beta Catenin - genetics</subject><subject>Biochemistry</subject><subject>Biomedicine and Life Sciences</subject><subject>Cholesterol</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Mice</subject><subject>Neoplasm Proteins - metabolism</subject><subject>SciAdv r-articles</subject><subject>Transcription Factors - genetics</subject><subject>Wnt Signaling Pathway - genetics</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc9uEzEQxi0EolXolSPysZdN_X-9F6QSlRYpUg8gcbS83kli8Nqp7UTtlUfqg_SZuiihKhePNfPNb2b0IfSRkjmlTF0U5-2wn9t-5JToN-iU8VY2TAr99tX_BJ2V8osQQoVSknbv0Qmf0qpl7Sn6c4lj2kPAT4-NsxWijxdfFssOuzRuA9xjHze-9zVl3IfkfhecokvrSefwz1hx8etog49rbOOAB1_yblsLdpsUoFTIKeBNGiGVaosvE20Ch5TBVRuws9FB_oDerWwocHaMM_T969WPxU2zvL3-trhcNo53pDaqZ0JK5nrNlW6p1QOlbtDDwKgGDVQJoTpJKPSi43LVggDeOm6J7ciK8hn6fKBud_0Ig4NYsw1mm_1o84NJ1pv_K9FvzDrtTUekIExMgPMjIKe73XScGX1xEIKNkHbFMCU145xMzwzND1KXUykZVi9jKDF_nTMH58zRuanh0-vlXuT_fOLPWIyaWw</recordid><startdate>20220429</startdate><enddate>20220429</enddate><creator>Tanton, Helen</creator><creator>Sewastianik, Tomasz</creator><creator>Seo, Hyuk-Soo</creator><creator>Remillard, David</creator><creator>Pierre, Roodolph St</creator><creator>Bala, Pratyusha</creator><creator>Aitymbayev, Daulet</creator><creator>Dennis, Peter</creator><creator>Adler, Keith</creator><creator>Geffken, Ezekiel</creator><creator>Yeoh, Zoe</creator><creator>Vangos, Nicholas</creator><creator>Garbicz, Filip</creator><creator>Scott, David</creator><creator>Sethi, Nilay</creator><creator>Bradner, James</creator><creator>Dhe-Paganon, Sirano</creator><creator>Carrasco, Ruben D</creator><general>American Association for the Advancement of Science</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>5PM</scope><orcidid>https://orcid.org/0000-0002-2694-9068</orcidid><orcidid>https://orcid.org/0000-0002-3861-9242</orcidid><orcidid>https://orcid.org/0000-0002-3748-7559</orcidid><orcidid>https://orcid.org/0000-0001-7686-4700</orcidid><orcidid>https://orcid.org/0000-0003-0824-5929</orcidid><orcidid>https://orcid.org/0000-0002-0129-5870</orcidid><orcidid>https://orcid.org/0000-0002-5548-1564</orcidid><orcidid>https://orcid.org/0000-0001-6849-1852</orcidid><orcidid>https://orcid.org/0000-0001-9638-3533</orcidid><orcidid>https://orcid.org/0000-0003-1422-5318</orcidid><orcidid>https://orcid.org/0000-0003-3243-528X</orcidid><orcidid>https://orcid.org/0000-0003-4603-8517</orcidid><orcidid>https://orcid.org/0000-0003-0646-2102</orcidid><orcidid>https://orcid.org/0000-0001-7277-2884</orcidid></search><sort><creationdate>20220429</creationdate><title>A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer</title><author>Tanton, Helen ; Sewastianik, Tomasz ; Seo, Hyuk-Soo ; Remillard, David ; Pierre, Roodolph St ; Bala, Pratyusha ; Aitymbayev, Daulet ; Dennis, Peter ; Adler, Keith ; Geffken, Ezekiel ; Yeoh, Zoe ; Vangos, Nicholas ; Garbicz, Filip ; Scott, David ; Sethi, Nilay ; Bradner, James ; Dhe-Paganon, Sirano ; Carrasco, Ruben D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-6b24552cb836871a8d11cd8dd218e8e164469501eb4935f7e4e37c3a0a90f13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>beta Catenin - genetics</topic><topic>Biochemistry</topic><topic>Biomedicine and Life Sciences</topic><topic>Cholesterol</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Mice</topic><topic>Neoplasm Proteins - metabolism</topic><topic>SciAdv r-articles</topic><topic>Transcription Factors - genetics</topic><topic>Wnt Signaling Pathway - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tanton, Helen</creatorcontrib><creatorcontrib>Sewastianik, Tomasz</creatorcontrib><creatorcontrib>Seo, Hyuk-Soo</creatorcontrib><creatorcontrib>Remillard, David</creatorcontrib><creatorcontrib>Pierre, Roodolph St</creatorcontrib><creatorcontrib>Bala, Pratyusha</creatorcontrib><creatorcontrib>Aitymbayev, Daulet</creatorcontrib><creatorcontrib>Dennis, Peter</creatorcontrib><creatorcontrib>Adler, Keith</creatorcontrib><creatorcontrib>Geffken, Ezekiel</creatorcontrib><creatorcontrib>Yeoh, Zoe</creatorcontrib><creatorcontrib>Vangos, Nicholas</creatorcontrib><creatorcontrib>Garbicz, Filip</creatorcontrib><creatorcontrib>Scott, David</creatorcontrib><creatorcontrib>Sethi, Nilay</creatorcontrib><creatorcontrib>Bradner, James</creatorcontrib><creatorcontrib>Dhe-Paganon, Sirano</creatorcontrib><creatorcontrib>Carrasco, Ruben D</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>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tanton, Helen</au><au>Sewastianik, Tomasz</au><au>Seo, Hyuk-Soo</au><au>Remillard, David</au><au>Pierre, Roodolph St</au><au>Bala, Pratyusha</au><au>Aitymbayev, Daulet</au><au>Dennis, Peter</au><au>Adler, Keith</au><au>Geffken, Ezekiel</au><au>Yeoh, Zoe</au><au>Vangos, Nicholas</au><au>Garbicz, Filip</au><au>Scott, David</au><au>Sethi, Nilay</au><au>Bradner, James</au><au>Dhe-Paganon, Sirano</au><au>Carrasco, Ruben D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2022-04-29</date><risdate>2022</risdate><volume>8</volume><issue>17</issue><spage>eabm3108</spage><pages>eabm3108-</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>Dysregulated Wnt/β-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between β-catenin and its coactivator BCL9. We identified a compound that consistently bound to β-catenin and specifically inhibited in vivo native β-catenin/BCL9 complex formation in CRC cell lines. This compound inhibited Wnt activity, down-regulated expression of the Wnt/β-catenin signature in gene expression studies, disrupted cholesterol homeostasis, and significantly reduced the proliferation of CRC cell lines and tumor growth in a xenograft mouse model of CRC. This study has therefore identified a specific small-molecule inhibitor of oncogenic Wnt signaling, which may have value as a probe for functional studies and has important implications for the development of novel therapies in patients with CRC.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>35486727</pmid><doi>10.1126/sciadv.abm3108</doi><orcidid>https://orcid.org/0000-0002-2694-9068</orcidid><orcidid>https://orcid.org/0000-0002-3861-9242</orcidid><orcidid>https://orcid.org/0000-0002-3748-7559</orcidid><orcidid>https://orcid.org/0000-0001-7686-4700</orcidid><orcidid>https://orcid.org/0000-0003-0824-5929</orcidid><orcidid>https://orcid.org/0000-0002-0129-5870</orcidid><orcidid>https://orcid.org/0000-0002-5548-1564</orcidid><orcidid>https://orcid.org/0000-0001-6849-1852</orcidid><orcidid>https://orcid.org/0000-0001-9638-3533</orcidid><orcidid>https://orcid.org/0000-0003-1422-5318</orcidid><orcidid>https://orcid.org/0000-0003-3243-528X</orcidid><orcidid>https://orcid.org/0000-0003-4603-8517</orcidid><orcidid>https://orcid.org/0000-0003-0646-2102</orcidid><orcidid>https://orcid.org/0000-0001-7277-2884</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2375-2548 |
| ispartof | Science advances, 2022-04, Vol.8 (17), p.eabm3108 |
| issn | 2375-2548 2375-2548 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9054024 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Animals beta Catenin - genetics Biochemistry Biomedicine and Life Sciences Cholesterol Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Homeostasis Humans Life Sciences Mice Neoplasm Proteins - metabolism SciAdv r-articles Transcription Factors - genetics Wnt Signaling Pathway - genetics |
| title | A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T21%3A04%3A03IST&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=A%20novel%20%CE%B2-catenin/BCL9%20complex%20inhibitor%20blocks%20oncogenic%20Wnt%20signaling%20and%20disrupts%20cholesterol%20homeostasis%20in%20colorectal%20cancer&rft.jtitle=Science%20advances&rft.au=Tanton,%20Helen&rft.date=2022-04-29&rft.volume=8&rft.issue=17&rft.spage=eabm3108&rft.pages=eabm3108-&rft.issn=2375-2548&rft.eissn=2375-2548&rft_id=info:doi/10.1126/sciadv.abm3108&rft_dat=%3Cproquest_pubme%3E2658233082%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=2658233082&rft_id=info:pmid/35486727&rfr_iscdi=true |