Loading…

Thymol has anticancer effects in U-87 human malignant glioblastoma cells

Background Thymol (2-isopropyl-5-methylphenol) is a colorless crystalline derivative of cymene, that possesses pleotropic pharmacological properties, including analgesic, antibacterial, antispasmodic, and anti-inflammatory activities. Thymol has also been recognized for its beneficial effect as an a...

Full description

Saved in:
Bibliographic Details
Published in:Molecular biology reports 2022-10, Vol.49 (10), p.9623-9632
Main Authors: Qoorchi Moheb Seraj, Farid, Heravi-Faz, Niloofar, Soltani, Arash, Ahmadi, Seyed Sajad, shahbeiki, Fatemeh, Talebpour, Amir, Afshari, Amir R., Ferns, Gordon A., Bahrami, Afsane
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c385t-68dfd9af738f3de1107a49b1f0348d22f4571dcebd33fe33aa88d2d8585bce13
cites cdi_FETCH-LOGICAL-c385t-68dfd9af738f3de1107a49b1f0348d22f4571dcebd33fe33aa88d2d8585bce13
container_end_page 9632
container_issue 10
container_start_page 9623
container_title Molecular biology reports
container_volume 49
creator Qoorchi Moheb Seraj, Farid
Heravi-Faz, Niloofar
Soltani, Arash
Ahmadi, Seyed Sajad
shahbeiki, Fatemeh
Talebpour, Amir
Afshari, Amir R.
Ferns, Gordon A.
Bahrami, Afsane
description Background Thymol (2-isopropyl-5-methylphenol) is a colorless crystalline derivative of cymene, that possesses pleotropic pharmacological properties, including analgesic, antibacterial, antispasmodic, and anti-inflammatory activities. Thymol has also been recognized for its beneficial effect as an anti-tumor agent, but the precise mechanism for this has not been fully elucidated. We aimed to identifying whether thymol exerts anti-cancer activity in human U-87 malignant glioblastoma (GB) cells (U-87). Methods and Results Cell viability and apoptosis was evaluated in U-87 cells treated with thymol at different concentrations. Reactive oxygen species (ROS) production, mRNA expressions of apoptosis-related genes and cell cycle characteristics were assessed. The cytotoxic activity of the co-exposure of thymol and temozolomide (TMZ) was also evaluated. The half-maximal inhibitory concentration ( IC50 ) of thymol in the U-87 cells was 230 μM assessed at 24 h after exposure. Thymol did not exhibit any cytotoxic effects on normal L929 cells at this concentration. Thymol treatment increased the expression of Bax and p53, and also increased apoptotic cell death, and excessive generation of ROS. Moreover, the cytotoxic activity of thymol on the U-87 cells may be related to the arrest of the cell cycle at the G0/G1 interface. Combination therapy showed that the cytotoxic effects of thymol synergized with TMZ, and combined treatment had more cytotoxic potential compared to either of the agents alone. Conclusions Our data indicate the potential cytotoxic activities of thymol on U-87 cells. Further studies are required to evaluate the spectrum of the antitumor activity of thymol on GB cells.
doi_str_mv 10.1007/s11033-022-07867-3
format article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2723129343</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2723129343</sourcerecordid><originalsourceid>FETCH-LOGICAL-c385t-68dfd9af738f3de1107a49b1f0348d22f4571dcebd33fe33aa88d2d8585bce13</originalsourceid><addsrcrecordid>eNqNkU1LAzEQhoMoWKt_wFPAi5dokkma7FGKX1DwUs8hm03aLbvZutk99N-buoLgQTwNDM87vMOD0DWjd4xSdZ8YowCEck6o0gtF4ATNmFRARKH0KZpRoIwILdk5ukhpRykVTMkZellvD23X4K1N2MahdjY632MfgndDwnXE70QrvB1bG3Frm3oTM4Y3Td2VjU1D11rsfNOkS3QWbJP81feco_XT43r5QlZvz6_LhxVxoOVAFroKVWGDAh2g8rm2sqIoWaAgdMV5EFKxyvmyAggewFqd15WWWpbOM5ij2-nsvu8-Rp8G09bpWMBG343JcMWB8QIE_AOlUkkmBM_ozS901419zH9kimmhgCqaKT5Rru9S6n0w-75ubX8wjJqjBjNpMFmD-dJgji1gCqUMx43vf07_kfoE7qOJLw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2718473070</pqid></control><display><type>article</type><title>Thymol has anticancer effects in U-87 human malignant glioblastoma cells</title><source>Springer Nature</source><creator>Qoorchi Moheb Seraj, Farid ; Heravi-Faz, Niloofar ; Soltani, Arash ; Ahmadi, Seyed Sajad ; shahbeiki, Fatemeh ; Talebpour, Amir ; Afshari, Amir R. ; Ferns, Gordon A. ; Bahrami, Afsane</creator><creatorcontrib>Qoorchi Moheb Seraj, Farid ; Heravi-Faz, Niloofar ; Soltani, Arash ; Ahmadi, Seyed Sajad ; shahbeiki, Fatemeh ; Talebpour, Amir ; Afshari, Amir R. ; Ferns, Gordon A. ; Bahrami, Afsane</creatorcontrib><description>Background Thymol (2-isopropyl-5-methylphenol) is a colorless crystalline derivative of cymene, that possesses pleotropic pharmacological properties, including analgesic, antibacterial, antispasmodic, and anti-inflammatory activities. Thymol has also been recognized for its beneficial effect as an anti-tumor agent, but the precise mechanism for this has not been fully elucidated. We aimed to identifying whether thymol exerts anti-cancer activity in human U-87 malignant glioblastoma (GB) cells (U-87). Methods and Results Cell viability and apoptosis was evaluated in U-87 cells treated with thymol at different concentrations. Reactive oxygen species (ROS) production, mRNA expressions of apoptosis-related genes and cell cycle characteristics were assessed. The cytotoxic activity of the co-exposure of thymol and temozolomide (TMZ) was also evaluated. The half-maximal inhibitory concentration ( IC50 ) of thymol in the U-87 cells was 230 μM assessed at 24 h after exposure. Thymol did not exhibit any cytotoxic effects on normal L929 cells at this concentration. Thymol treatment increased the expression of Bax and p53, and also increased apoptotic cell death, and excessive generation of ROS. Moreover, the cytotoxic activity of thymol on the U-87 cells may be related to the arrest of the cell cycle at the G0/G1 interface. Combination therapy showed that the cytotoxic effects of thymol synergized with TMZ, and combined treatment had more cytotoxic potential compared to either of the agents alone. Conclusions Our data indicate the potential cytotoxic activities of thymol on U-87 cells. Further studies are required to evaluate the spectrum of the antitumor activity of thymol on GB cells.</description><identifier>ISSN: 0301-4851</identifier><identifier>EISSN: 1573-4978</identifier><identifier>DOI: 10.1007/s11033-022-07867-3</identifier><language>eng</language><publisher>Dordrecht: Springer Netherlands</publisher><subject>Analgesics ; Animal Anatomy ; Animal Biochemistry ; antineoplastic activity ; antineoplastic agents ; Antitumor activity ; Apoptosis ; Biomedical and Life Sciences ; Brain cancer ; Cell cycle ; Cell death ; Cell viability ; Cymene ; Cytotoxicity ; Glioblastoma ; Glioblastoma cells ; Glioma ; Histology ; humans ; Inflammation ; inhibitory concentration 50 ; Life Sciences ; Morphology ; mRNA ; Muscle relaxants ; Original Article ; p53 Protein ; Parasympathetic nervous system ; parasympatholytics ; Reactive oxygen species ; Temozolomide ; therapeutics ; Thymol ; Tumors</subject><ispartof>Molecular biology reports, 2022-10, Vol.49 (10), p.9623-9632</ispartof><rights>The Author(s), under exclusive licence to Springer Nature B.V. 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c385t-68dfd9af738f3de1107a49b1f0348d22f4571dcebd33fe33aa88d2d8585bce13</citedby><cites>FETCH-LOGICAL-c385t-68dfd9af738f3de1107a49b1f0348d22f4571dcebd33fe33aa88d2d8585bce13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Qoorchi Moheb Seraj, Farid</creatorcontrib><creatorcontrib>Heravi-Faz, Niloofar</creatorcontrib><creatorcontrib>Soltani, Arash</creatorcontrib><creatorcontrib>Ahmadi, Seyed Sajad</creatorcontrib><creatorcontrib>shahbeiki, Fatemeh</creatorcontrib><creatorcontrib>Talebpour, Amir</creatorcontrib><creatorcontrib>Afshari, Amir R.</creatorcontrib><creatorcontrib>Ferns, Gordon A.</creatorcontrib><creatorcontrib>Bahrami, Afsane</creatorcontrib><title>Thymol has anticancer effects in U-87 human malignant glioblastoma cells</title><title>Molecular biology reports</title><addtitle>Mol Biol Rep</addtitle><description>Background Thymol (2-isopropyl-5-methylphenol) is a colorless crystalline derivative of cymene, that possesses pleotropic pharmacological properties, including analgesic, antibacterial, antispasmodic, and anti-inflammatory activities. Thymol has also been recognized for its beneficial effect as an anti-tumor agent, but the precise mechanism for this has not been fully elucidated. We aimed to identifying whether thymol exerts anti-cancer activity in human U-87 malignant glioblastoma (GB) cells (U-87). Methods and Results Cell viability and apoptosis was evaluated in U-87 cells treated with thymol at different concentrations. Reactive oxygen species (ROS) production, mRNA expressions of apoptosis-related genes and cell cycle characteristics were assessed. The cytotoxic activity of the co-exposure of thymol and temozolomide (TMZ) was also evaluated. The half-maximal inhibitory concentration ( IC50 ) of thymol in the U-87 cells was 230 μM assessed at 24 h after exposure. Thymol did not exhibit any cytotoxic effects on normal L929 cells at this concentration. Thymol treatment increased the expression of Bax and p53, and also increased apoptotic cell death, and excessive generation of ROS. Moreover, the cytotoxic activity of thymol on the U-87 cells may be related to the arrest of the cell cycle at the G0/G1 interface. Combination therapy showed that the cytotoxic effects of thymol synergized with TMZ, and combined treatment had more cytotoxic potential compared to either of the agents alone. Conclusions Our data indicate the potential cytotoxic activities of thymol on U-87 cells. Further studies are required to evaluate the spectrum of the antitumor activity of thymol on GB cells.</description><subject>Analgesics</subject><subject>Animal Anatomy</subject><subject>Animal Biochemistry</subject><subject>antineoplastic activity</subject><subject>antineoplastic agents</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Biomedical and Life Sciences</subject><subject>Brain cancer</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cell viability</subject><subject>Cymene</subject><subject>Cytotoxicity</subject><subject>Glioblastoma</subject><subject>Glioblastoma cells</subject><subject>Glioma</subject><subject>Histology</subject><subject>humans</subject><subject>Inflammation</subject><subject>inhibitory concentration 50</subject><subject>Life Sciences</subject><subject>Morphology</subject><subject>mRNA</subject><subject>Muscle relaxants</subject><subject>Original Article</subject><subject>p53 Protein</subject><subject>Parasympathetic nervous system</subject><subject>parasympatholytics</subject><subject>Reactive oxygen species</subject><subject>Temozolomide</subject><subject>therapeutics</subject><subject>Thymol</subject><subject>Tumors</subject><issn>0301-4851</issn><issn>1573-4978</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNqNkU1LAzEQhoMoWKt_wFPAi5dokkma7FGKX1DwUs8hm03aLbvZutk99N-buoLgQTwNDM87vMOD0DWjd4xSdZ8YowCEck6o0gtF4ATNmFRARKH0KZpRoIwILdk5ukhpRykVTMkZellvD23X4K1N2MahdjY632MfgndDwnXE70QrvB1bG3Frm3oTM4Y3Td2VjU1D11rsfNOkS3QWbJP81feco_XT43r5QlZvz6_LhxVxoOVAFroKVWGDAh2g8rm2sqIoWaAgdMV5EFKxyvmyAggewFqd15WWWpbOM5ij2-nsvu8-Rp8G09bpWMBG343JcMWB8QIE_AOlUkkmBM_ozS901419zH9kimmhgCqaKT5Rru9S6n0w-75ubX8wjJqjBjNpMFmD-dJgji1gCqUMx43vf07_kfoE7qOJLw</recordid><startdate>20221001</startdate><enddate>20221001</enddate><creator>Qoorchi Moheb Seraj, Farid</creator><creator>Heravi-Faz, Niloofar</creator><creator>Soltani, Arash</creator><creator>Ahmadi, Seyed Sajad</creator><creator>shahbeiki, Fatemeh</creator><creator>Talebpour, Amir</creator><creator>Afshari, Amir R.</creator><creator>Ferns, Gordon A.</creator><creator>Bahrami, Afsane</creator><general>Springer Netherlands</general><general>Springer Nature B.V</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</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>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope></search><sort><creationdate>20221001</creationdate><title>Thymol has anticancer effects in U-87 human malignant glioblastoma cells</title><author>Qoorchi Moheb Seraj, Farid ; Heravi-Faz, Niloofar ; Soltani, Arash ; Ahmadi, Seyed Sajad ; shahbeiki, Fatemeh ; Talebpour, Amir ; Afshari, Amir R. ; Ferns, Gordon A. ; Bahrami, Afsane</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c385t-68dfd9af738f3de1107a49b1f0348d22f4571dcebd33fe33aa88d2d8585bce13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Analgesics</topic><topic>Animal Anatomy</topic><topic>Animal Biochemistry</topic><topic>antineoplastic activity</topic><topic>antineoplastic agents</topic><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>Biomedical and Life Sciences</topic><topic>Brain cancer</topic><topic>Cell cycle</topic><topic>Cell death</topic><topic>Cell viability</topic><topic>Cymene</topic><topic>Cytotoxicity</topic><topic>Glioblastoma</topic><topic>Glioblastoma cells</topic><topic>Glioma</topic><topic>Histology</topic><topic>humans</topic><topic>Inflammation</topic><topic>inhibitory concentration 50</topic><topic>Life Sciences</topic><topic>Morphology</topic><topic>mRNA</topic><topic>Muscle relaxants</topic><topic>Original Article</topic><topic>p53 Protein</topic><topic>Parasympathetic nervous system</topic><topic>parasympatholytics</topic><topic>Reactive oxygen species</topic><topic>Temozolomide</topic><topic>therapeutics</topic><topic>Thymol</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Qoorchi Moheb Seraj, Farid</creatorcontrib><creatorcontrib>Heravi-Faz, Niloofar</creatorcontrib><creatorcontrib>Soltani, Arash</creatorcontrib><creatorcontrib>Ahmadi, Seyed Sajad</creatorcontrib><creatorcontrib>shahbeiki, Fatemeh</creatorcontrib><creatorcontrib>Talebpour, Amir</creatorcontrib><creatorcontrib>Afshari, Amir R.</creatorcontrib><creatorcontrib>Ferns, Gordon A.</creatorcontrib><creatorcontrib>Bahrami, Afsane</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</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</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</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>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><jtitle>Molecular biology reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Qoorchi Moheb Seraj, Farid</au><au>Heravi-Faz, Niloofar</au><au>Soltani, Arash</au><au>Ahmadi, Seyed Sajad</au><au>shahbeiki, Fatemeh</au><au>Talebpour, Amir</au><au>Afshari, Amir R.</au><au>Ferns, Gordon A.</au><au>Bahrami, Afsane</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Thymol has anticancer effects in U-87 human malignant glioblastoma cells</atitle><jtitle>Molecular biology reports</jtitle><stitle>Mol Biol Rep</stitle><date>2022-10-01</date><risdate>2022</risdate><volume>49</volume><issue>10</issue><spage>9623</spage><epage>9632</epage><pages>9623-9632</pages><issn>0301-4851</issn><eissn>1573-4978</eissn><abstract>Background Thymol (2-isopropyl-5-methylphenol) is a colorless crystalline derivative of cymene, that possesses pleotropic pharmacological properties, including analgesic, antibacterial, antispasmodic, and anti-inflammatory activities. Thymol has also been recognized for its beneficial effect as an anti-tumor agent, but the precise mechanism for this has not been fully elucidated. We aimed to identifying whether thymol exerts anti-cancer activity in human U-87 malignant glioblastoma (GB) cells (U-87). Methods and Results Cell viability and apoptosis was evaluated in U-87 cells treated with thymol at different concentrations. Reactive oxygen species (ROS) production, mRNA expressions of apoptosis-related genes and cell cycle characteristics were assessed. The cytotoxic activity of the co-exposure of thymol and temozolomide (TMZ) was also evaluated. The half-maximal inhibitory concentration ( IC50 ) of thymol in the U-87 cells was 230 μM assessed at 24 h after exposure. Thymol did not exhibit any cytotoxic effects on normal L929 cells at this concentration. Thymol treatment increased the expression of Bax and p53, and also increased apoptotic cell death, and excessive generation of ROS. Moreover, the cytotoxic activity of thymol on the U-87 cells may be related to the arrest of the cell cycle at the G0/G1 interface. Combination therapy showed that the cytotoxic effects of thymol synergized with TMZ, and combined treatment had more cytotoxic potential compared to either of the agents alone. Conclusions Our data indicate the potential cytotoxic activities of thymol on U-87 cells. Further studies are required to evaluate the spectrum of the antitumor activity of thymol on GB cells.</abstract><cop>Dordrecht</cop><pub>Springer Netherlands</pub><doi>10.1007/s11033-022-07867-3</doi><tpages>10</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0301-4851
ispartof Molecular biology reports, 2022-10, Vol.49 (10), p.9623-9632
issn 0301-4851
1573-4978
language eng
recordid cdi_proquest_miscellaneous_2723129343
source Springer Nature
subjects Analgesics
Animal Anatomy
Animal Biochemistry
antineoplastic activity
antineoplastic agents
Antitumor activity
Apoptosis
Biomedical and Life Sciences
Brain cancer
Cell cycle
Cell death
Cell viability
Cymene
Cytotoxicity
Glioblastoma
Glioblastoma cells
Glioma
Histology
humans
Inflammation
inhibitory concentration 50
Life Sciences
Morphology
mRNA
Muscle relaxants
Original Article
p53 Protein
Parasympathetic nervous system
parasympatholytics
Reactive oxygen species
Temozolomide
therapeutics
Thymol
Tumors
title Thymol has anticancer effects in U-87 human malignant glioblastoma cells
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T09%3A38%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Thymol%20has%20anticancer%20effects%20in%20U-87%20human%20malignant%20glioblastoma%20cells&rft.jtitle=Molecular%20biology%20reports&rft.au=Qoorchi%20Moheb%20Seraj,%20Farid&rft.date=2022-10-01&rft.volume=49&rft.issue=10&rft.spage=9623&rft.epage=9632&rft.pages=9623-9632&rft.issn=0301-4851&rft.eissn=1573-4978&rft_id=info:doi/10.1007/s11033-022-07867-3&rft_dat=%3Cproquest_cross%3E2723129343%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c385t-68dfd9af738f3de1107a49b1f0348d22f4571dcebd33fe33aa88d2d8585bce13%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2718473070&rft_id=info:pmid/&rfr_iscdi=true