Tumour suppressor gene methylation and cervical cell folate concentration are determinants of high-risk human papillomavirus persistence: a nested case control study
Persistent infection with one or more high-risk human papillomavirus [HR-HPV] types increases the risk of intraepithelial neoplasia and cervical cancer. A nested case-control study was conducted to investigate the importance of cervical cell folate concentration and tumour suppressor gene methylatio...
Gespeichert in:
| Veröffentlicht in: | BMC cancer 2014-11, Vol.14 (1), p.803-803, Article 803 |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 803 |
|---|---|
| container_issue | 1 |
| container_start_page | 803 |
| container_title | BMC cancer |
| container_volume | 14 |
| creator | Flatley, Janet E Sargent, Alexandra Kitchener, Henry C Russell, Jean M Powers, Hilary J |
| description | Persistent infection with one or more high-risk human papillomavirus [HR-HPV] types increases the risk of intraepithelial neoplasia and cervical cancer. A nested case-control study was conducted to investigate the importance of cervical cell folate concentration and tumour suppressor gene methylation as risk factors for HR-HPV persistence.
Cervical cell samples from 955 women with HR-HPV infection and normal, borderline or mild dyskaryosis were retrieved from the archive of a population-based screening trial. Women were classified as cases or controls, reflecting the presence or absence [respectively] of any HR-HPV infection at a follow-up clinic at least 6 months from baseline. Cervical cell folate concentration and promoter methylation of five tumour suppressor genes were measured in independent samples from cases and controls.
A higher cervical cell folate concentration [P = 0.015] was an independent predictor of infection at follow-up, together with infection with HPV-16 or infection with multiple HR-HPV types. Methylation of the tumour suppressor gene DAPK was associated with a 2.64-fold [95% CI, 1.35-5.17] increased likelihood of HPV infection whilst CDH1 methylation was associated with a 0.53-fold [95% CI, 0.331-0.844] likelihood of HR-HPV infection at follow-up. When considering women with normal or abnormal cytology, the predictive effect of higher cervical cell folate was only seen in women with mild cytology [P = 0.021]; similarly the effect of DAPK methylation was seen in women with mild or borderline cytology [P < 0.05].
Higher cervical cell folate concentration and promoter methylation of the tumour suppressor gene, DAPK, in women with cervical cell dyskaryosis, are associated with increased risk of HR-HPV persistence. |
| doi_str_mv | 10.1186/1471-2407-14-803 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4232685</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1635027015</sourcerecordid><originalsourceid>FETCH-LOGICAL-c457t-d413842c0c5da404fd56f118439024578e9f2df4e704083bc7a11784068317873</originalsourceid><addsrcrecordid>eNqNUsuO1DAQjBCIfcCdE7LEhUvAr8QeDkhoBQvSSlyWs-V1OhMviR3seKT5IP6TDjOMFk6cuuSuLrvLVVUvGH3DmG7fMqlYzSVVNZO1puJRdX46evwAn1UXOd9TypSm-ml1xhvRKt7q8-rnbZliSSSXeU6Qc0xkCwHIBMuwH-3iYyA2dMRB2nlnRwTjSPqILSAuBgdhSUdaAtLBAmnywYYlk9iTwW-HOvn8nQxlsoHMdvbjGCe786lkMkPKPi-AMu-IJQEQ4102_9ZeUhxJXkq3f1Y96e2Y4fmxXlbfPn28vfpc33y9_nL14aZ2slFL3UkmtOSOuqazksq-a9oejZJiQzkyNGx63vUSFJVUizunLENLJG21wKrEZfX-oDuXuwm6w3KjmZOfbNqbaL35uxP8YLZxZyQXaGeDAq-PAin-KLiOmXxeLbMBYsmGtaKhXFH2P1T8JdlqRpH66h_qPf5ZQCdWlthseNOuLHpguRRzTtCf3s2oWeNi1jyYNQ-IDMYFR14-3Pc08Ccf4hdFHb4B</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1623992560</pqid></control><display><type>article</type><title>Tumour suppressor gene methylation and cervical cell folate concentration are determinants of high-risk human papillomavirus persistence: a nested case control study</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>PubMed Central Open Access</source><source>Springer Nature OA Free Journals</source><creator>Flatley, Janet E ; Sargent, Alexandra ; Kitchener, Henry C ; Russell, Jean M ; Powers, Hilary J</creator><creatorcontrib>Flatley, Janet E ; Sargent, Alexandra ; Kitchener, Henry C ; Russell, Jean M ; Powers, Hilary J</creatorcontrib><description>Persistent infection with one or more high-risk human papillomavirus [HR-HPV] types increases the risk of intraepithelial neoplasia and cervical cancer. A nested case-control study was conducted to investigate the importance of cervical cell folate concentration and tumour suppressor gene methylation as risk factors for HR-HPV persistence.
Cervical cell samples from 955 women with HR-HPV infection and normal, borderline or mild dyskaryosis were retrieved from the archive of a population-based screening trial. Women were classified as cases or controls, reflecting the presence or absence [respectively] of any HR-HPV infection at a follow-up clinic at least 6 months from baseline. Cervical cell folate concentration and promoter methylation of five tumour suppressor genes were measured in independent samples from cases and controls.
A higher cervical cell folate concentration [P = 0.015] was an independent predictor of infection at follow-up, together with infection with HPV-16 or infection with multiple HR-HPV types. Methylation of the tumour suppressor gene DAPK was associated with a 2.64-fold [95% CI, 1.35-5.17] increased likelihood of HPV infection whilst CDH1 methylation was associated with a 0.53-fold [95% CI, 0.331-0.844] likelihood of HR-HPV infection at follow-up. When considering women with normal or abnormal cytology, the predictive effect of higher cervical cell folate was only seen in women with mild cytology [P = 0.021]; similarly the effect of DAPK methylation was seen in women with mild or borderline cytology [P < 0.05].
Higher cervical cell folate concentration and promoter methylation of the tumour suppressor gene, DAPK, in women with cervical cell dyskaryosis, are associated with increased risk of HR-HPV persistence.</description><identifier>ISSN: 1471-2407</identifier><identifier>EISSN: 1471-2407</identifier><identifier>DOI: 10.1186/1471-2407-14-803</identifier><identifier>PMID: 25367268</identifier><language>eng</language><publisher>England: BioMed Central</publisher><subject>Adult ; Case-Control Studies ; Cervical cancer ; Cervical Intraepithelial Neoplasia - etiology ; Cervix Uteri - metabolism ; Cervix Uteri - pathology ; Cervix Uteri - virology ; DNA Methylation ; Female ; Folic Acid - metabolism ; Genes, Tumor Suppressor ; Human papillomavirus ; Humans ; Kinases ; Medical research ; Papillomaviridae ; Papillomavirus Infections - complications ; Papillomavirus Infections - epidemiology ; Papillomavirus Infections - genetics ; Papillomavirus Infections - metabolism ; Papillomavirus Infections - virology ; Prevalence ; Studies ; Uterine Cervical Neoplasms - etiology ; Womens health ; Young Adult</subject><ispartof>BMC cancer, 2014-11, Vol.14 (1), p.803-803, Article 803</ispartof><rights>2014 Flatley et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.</rights><rights>Flatley et al.; licensee BioMed Central Ltd. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c457t-d413842c0c5da404fd56f118439024578e9f2df4e704083bc7a11784068317873</citedby><cites>FETCH-LOGICAL-c457t-d413842c0c5da404fd56f118439024578e9f2df4e704083bc7a11784068317873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232685/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232685/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25367268$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Flatley, Janet E</creatorcontrib><creatorcontrib>Sargent, Alexandra</creatorcontrib><creatorcontrib>Kitchener, Henry C</creatorcontrib><creatorcontrib>Russell, Jean M</creatorcontrib><creatorcontrib>Powers, Hilary J</creatorcontrib><title>Tumour suppressor gene methylation and cervical cell folate concentration are determinants of high-risk human papillomavirus persistence: a nested case control study</title><title>BMC cancer</title><addtitle>BMC Cancer</addtitle><description>Persistent infection with one or more high-risk human papillomavirus [HR-HPV] types increases the risk of intraepithelial neoplasia and cervical cancer. A nested case-control study was conducted to investigate the importance of cervical cell folate concentration and tumour suppressor gene methylation as risk factors for HR-HPV persistence.
Cervical cell samples from 955 women with HR-HPV infection and normal, borderline or mild dyskaryosis were retrieved from the archive of a population-based screening trial. Women were classified as cases or controls, reflecting the presence or absence [respectively] of any HR-HPV infection at a follow-up clinic at least 6 months from baseline. Cervical cell folate concentration and promoter methylation of five tumour suppressor genes were measured in independent samples from cases and controls.
A higher cervical cell folate concentration [P = 0.015] was an independent predictor of infection at follow-up, together with infection with HPV-16 or infection with multiple HR-HPV types. Methylation of the tumour suppressor gene DAPK was associated with a 2.64-fold [95% CI, 1.35-5.17] increased likelihood of HPV infection whilst CDH1 methylation was associated with a 0.53-fold [95% CI, 0.331-0.844] likelihood of HR-HPV infection at follow-up. When considering women with normal or abnormal cytology, the predictive effect of higher cervical cell folate was only seen in women with mild cytology [P = 0.021]; similarly the effect of DAPK methylation was seen in women with mild or borderline cytology [P < 0.05].
Higher cervical cell folate concentration and promoter methylation of the tumour suppressor gene, DAPK, in women with cervical cell dyskaryosis, are associated with increased risk of HR-HPV persistence.</description><subject>Adult</subject><subject>Case-Control Studies</subject><subject>Cervical cancer</subject><subject>Cervical Intraepithelial Neoplasia - etiology</subject><subject>Cervix Uteri - metabolism</subject><subject>Cervix Uteri - pathology</subject><subject>Cervix Uteri - virology</subject><subject>DNA Methylation</subject><subject>Female</subject><subject>Folic Acid - metabolism</subject><subject>Genes, Tumor Suppressor</subject><subject>Human papillomavirus</subject><subject>Humans</subject><subject>Kinases</subject><subject>Medical research</subject><subject>Papillomaviridae</subject><subject>Papillomavirus Infections - complications</subject><subject>Papillomavirus Infections - epidemiology</subject><subject>Papillomavirus Infections - genetics</subject><subject>Papillomavirus Infections - metabolism</subject><subject>Papillomavirus Infections - virology</subject><subject>Prevalence</subject><subject>Studies</subject><subject>Uterine Cervical Neoplasms - etiology</subject><subject>Womens health</subject><subject>Young Adult</subject><issn>1471-2407</issn><issn>1471-2407</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNUsuO1DAQjBCIfcCdE7LEhUvAr8QeDkhoBQvSSlyWs-V1OhMviR3seKT5IP6TDjOMFk6cuuSuLrvLVVUvGH3DmG7fMqlYzSVVNZO1puJRdX46evwAn1UXOd9TypSm-ml1xhvRKt7q8-rnbZliSSSXeU6Qc0xkCwHIBMuwH-3iYyA2dMRB2nlnRwTjSPqILSAuBgdhSUdaAtLBAmnywYYlk9iTwW-HOvn8nQxlsoHMdvbjGCe786lkMkPKPi-AMu-IJQEQ4102_9ZeUhxJXkq3f1Y96e2Y4fmxXlbfPn28vfpc33y9_nL14aZ2slFL3UkmtOSOuqazksq-a9oejZJiQzkyNGx63vUSFJVUizunLENLJG21wKrEZfX-oDuXuwm6w3KjmZOfbNqbaL35uxP8YLZxZyQXaGeDAq-PAin-KLiOmXxeLbMBYsmGtaKhXFH2P1T8JdlqRpH66h_qPf5ZQCdWlthseNOuLHpguRRzTtCf3s2oWeNi1jyYNQ-IDMYFR14-3Pc08Ccf4hdFHb4B</recordid><startdate>20141103</startdate><enddate>20141103</enddate><creator>Flatley, Janet E</creator><creator>Sargent, Alexandra</creator><creator>Kitchener, Henry C</creator><creator>Russell, Jean M</creator><creator>Powers, Hilary J</creator><general>BioMed Central</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>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</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>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20141103</creationdate><title>Tumour suppressor gene methylation and cervical cell folate concentration are determinants of high-risk human papillomavirus persistence: a nested case control study</title><author>Flatley, Janet E ; Sargent, Alexandra ; Kitchener, Henry C ; Russell, Jean M ; Powers, Hilary J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c457t-d413842c0c5da404fd56f118439024578e9f2df4e704083bc7a11784068317873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Case-Control Studies</topic><topic>Cervical cancer</topic><topic>Cervical Intraepithelial Neoplasia - etiology</topic><topic>Cervix Uteri - metabolism</topic><topic>Cervix Uteri - pathology</topic><topic>Cervix Uteri - virology</topic><topic>DNA Methylation</topic><topic>Female</topic><topic>Folic Acid - metabolism</topic><topic>Genes, Tumor Suppressor</topic><topic>Human papillomavirus</topic><topic>Humans</topic><topic>Kinases</topic><topic>Medical research</topic><topic>Papillomaviridae</topic><topic>Papillomavirus Infections - complications</topic><topic>Papillomavirus Infections - epidemiology</topic><topic>Papillomavirus Infections - genetics</topic><topic>Papillomavirus Infections - metabolism</topic><topic>Papillomavirus Infections - virology</topic><topic>Prevalence</topic><topic>Studies</topic><topic>Uterine Cervical Neoplasms - etiology</topic><topic>Womens health</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Flatley, Janet E</creatorcontrib><creatorcontrib>Sargent, Alexandra</creatorcontrib><creatorcontrib>Kitchener, Henry C</creatorcontrib><creatorcontrib>Russell, Jean M</creatorcontrib><creatorcontrib>Powers, Hilary J</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>Oncogenes and Growth Factors Abstracts</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>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>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</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>MEDLINE - Academic</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>BMC cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Flatley, Janet E</au><au>Sargent, Alexandra</au><au>Kitchener, Henry C</au><au>Russell, Jean M</au><au>Powers, Hilary J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumour suppressor gene methylation and cervical cell folate concentration are determinants of high-risk human papillomavirus persistence: a nested case control study</atitle><jtitle>BMC cancer</jtitle><addtitle>BMC Cancer</addtitle><date>2014-11-03</date><risdate>2014</risdate><volume>14</volume><issue>1</issue><spage>803</spage><epage>803</epage><pages>803-803</pages><artnum>803</artnum><issn>1471-2407</issn><eissn>1471-2407</eissn><abstract>Persistent infection with one or more high-risk human papillomavirus [HR-HPV] types increases the risk of intraepithelial neoplasia and cervical cancer. A nested case-control study was conducted to investigate the importance of cervical cell folate concentration and tumour suppressor gene methylation as risk factors for HR-HPV persistence.
Cervical cell samples from 955 women with HR-HPV infection and normal, borderline or mild dyskaryosis were retrieved from the archive of a population-based screening trial. Women were classified as cases or controls, reflecting the presence or absence [respectively] of any HR-HPV infection at a follow-up clinic at least 6 months from baseline. Cervical cell folate concentration and promoter methylation of five tumour suppressor genes were measured in independent samples from cases and controls.
A higher cervical cell folate concentration [P = 0.015] was an independent predictor of infection at follow-up, together with infection with HPV-16 or infection with multiple HR-HPV types. Methylation of the tumour suppressor gene DAPK was associated with a 2.64-fold [95% CI, 1.35-5.17] increased likelihood of HPV infection whilst CDH1 methylation was associated with a 0.53-fold [95% CI, 0.331-0.844] likelihood of HR-HPV infection at follow-up. When considering women with normal or abnormal cytology, the predictive effect of higher cervical cell folate was only seen in women with mild cytology [P = 0.021]; similarly the effect of DAPK methylation was seen in women with mild or borderline cytology [P < 0.05].
Higher cervical cell folate concentration and promoter methylation of the tumour suppressor gene, DAPK, in women with cervical cell dyskaryosis, are associated with increased risk of HR-HPV persistence.</abstract><cop>England</cop><pub>BioMed Central</pub><pmid>25367268</pmid><doi>10.1186/1471-2407-14-803</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1471-2407 |
| ispartof | BMC cancer, 2014-11, Vol.14 (1), p.803-803, Article 803 |
| issn | 1471-2407 1471-2407 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4232685 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access; Springer Nature OA Free Journals |
| subjects | Adult Case-Control Studies Cervical cancer Cervical Intraepithelial Neoplasia - etiology Cervix Uteri - metabolism Cervix Uteri - pathology Cervix Uteri - virology DNA Methylation Female Folic Acid - metabolism Genes, Tumor Suppressor Human papillomavirus Humans Kinases Medical research Papillomaviridae Papillomavirus Infections - complications Papillomavirus Infections - epidemiology Papillomavirus Infections - genetics Papillomavirus Infections - metabolism Papillomavirus Infections - virology Prevalence Studies Uterine Cervical Neoplasms - etiology Womens health Young Adult |
| title | Tumour suppressor gene methylation and cervical cell folate concentration are determinants of high-risk human papillomavirus persistence: a nested case control study |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T14%3A12%3A06IST&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=Tumour%20suppressor%20gene%20methylation%20and%20cervical%20cell%20folate%20concentration%20are%20determinants%20of%20high-risk%20human%20papillomavirus%20persistence:%20a%20nested%20case%20control%20study&rft.jtitle=BMC%20cancer&rft.au=Flatley,%20Janet%20E&rft.date=2014-11-03&rft.volume=14&rft.issue=1&rft.spage=803&rft.epage=803&rft.pages=803-803&rft.artnum=803&rft.issn=1471-2407&rft.eissn=1471-2407&rft_id=info:doi/10.1186/1471-2407-14-803&rft_dat=%3Cproquest_pubme%3E1635027015%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=1623992560&rft_id=info:pmid/25367268&rfr_iscdi=true |