Ultrasound-guided RNA interference targeting HIF-1 alpha improves the effects of transarterial chemoembolization in rat liver tumors
To investigate whether ultrasound-guided RNA interference (RNAi) targeting hypoxia-inducible factor-1alpha (HIF-1α) can enhance the efficacy of transarterial chemoembolization (TACE) in treating hepatocellular carcinoma. Rats with orthotopic hepatocellular carcinoma were randomized to four groups an...
Gespeichert in:
| Veröffentlicht in: | OncoTargets and therapy 2015-01, Vol.8, p.3539-3548 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3548 |
|---|---|
| container_issue | |
| container_start_page | 3539 |
| container_title | OncoTargets and therapy |
| container_volume | 8 |
| creator | Chen, Cheng-Shi Zhao, Qing Qian, Sheng Li, Hai-Liang Guo, Chen-Yang Zhang, Wei Yan, Zhi-Ping Liu, Rong Wang, Jian-Hua |
| description | To investigate whether ultrasound-guided RNA interference (RNAi) targeting hypoxia-inducible factor-1alpha (HIF-1α) can enhance the efficacy of transarterial chemoembolization (TACE) in treating hepatocellular carcinoma.
Rats with orthotopic hepatocellular carcinoma were randomized to four groups and treated as follows: 1) control; 2) siHIF-1α; 3) TACE; 4) siHIF-1α+TACE. Lentivirus (4×10(8) transfection units) with or without small interfering RNA (siRNA) expression in 0.6 mL transduction reagent was injected into tumors using a standard 1 mL syringe under ultrasonic guidance. In the siHIF-1α+TACE and siHIF-1α groups, rats received siRNA-expressing lentivirus; the rats in the TACE and control groups received lentivirus without siRNA. TACE was performed by placing a microcatheter into the gastroduodenal artery.
The median survival time, body weight, and tumor volume of the siHIF-1α+TACE group were better than those of the TACE, siHIF-1α, and control groups. A comparative analysis of the different treatment groups demonstrated that HIF-1α RNAi could downregulate the levels of HIF-1α and VEGF, inhibit tumor angiogenesis, and lessen metastases; all of these effects were enhanced by TACE.
HIF-1α RNAi, which was administered in vivo in liver tumors under ultrasound guidance, improved the efficacy of TACE in treating hepatocellular carcinoma in an animal model. |
| doi_str_mv | 10.2147/OTT.S94800 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4669929</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A447931325</galeid><sourcerecordid>A447931325</sourcerecordid><originalsourceid>FETCH-LOGICAL-c504t-f7e2c9a3c2b081682a723927ab2db9580ecbe465a4ab0c7ab2fc808589ce09683</originalsourceid><addsrcrecordid>eNptklFrFDEQxxdRbK2--AEkIIgIeybZbHbzUjiKtYViQa_PIZudvU3JJmeSPdBnP7g5rtY7kTwkTH7zn8zkXxSvCV5QwpqPt6vV4ptgLcZPilNCmrbkosJPD84nxYsY7zHmvKXseXFCOeeMVM1p8evOpqCin11frmfTQ4--flki4xKEAQI4DSipsIZk3BpdXV-WBCm7GRUy0yb4LUSURkAwDKBTRH5AWc5FFXK-URbpESYPU-et-amS8S5Lo6ASsmYLAaV58iG-LJ4NykZ49bCfFXeXn1YXV-XN7efri-VNqWvMUjk0QLVQlaYdbkluRTW0ErRRHe07UbcYdAeM14qpDutdeNAtbutWaMCCt9VZcb7X3czdBL0Glx9r5SaYSYUf0isjj2-cGeXabyXjXAgqssD7B4Hgv88Qk5xM1GCtcuDnKEnDBKeYUZbRt_-g934OLrcnKWW0xjVu8F9qrSxI4waf6-qdqFwy1oiKVLTO1OI_VF49TEZ7B4PJ8aOEdwcJIyibxujtvPuAeAx-2IM6-BgDDI_DIFjuzCWzueTeXBl-czi-R_SPm6rfwhLKiw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2242505070</pqid></control><display><type>article</type><title>Ultrasound-guided RNA interference targeting HIF-1 alpha improves the effects of transarterial chemoembolization in rat liver tumors</title><source>Taylor & Francis Open Access</source><source>DOVE Medical Press Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central Open Access</source><source>PubMed Central</source><creator>Chen, Cheng-Shi ; Zhao, Qing ; Qian, Sheng ; Li, Hai-Liang ; Guo, Chen-Yang ; Zhang, Wei ; Yan, Zhi-Ping ; Liu, Rong ; Wang, Jian-Hua</creator><creatorcontrib>Chen, Cheng-Shi ; Zhao, Qing ; Qian, Sheng ; Li, Hai-Liang ; Guo, Chen-Yang ; Zhang, Wei ; Yan, Zhi-Ping ; Liu, Rong ; Wang, Jian-Hua</creatorcontrib><description>To investigate whether ultrasound-guided RNA interference (RNAi) targeting hypoxia-inducible factor-1alpha (HIF-1α) can enhance the efficacy of transarterial chemoembolization (TACE) in treating hepatocellular carcinoma.
Rats with orthotopic hepatocellular carcinoma were randomized to four groups and treated as follows: 1) control; 2) siHIF-1α; 3) TACE; 4) siHIF-1α+TACE. Lentivirus (4×10(8) transfection units) with or without small interfering RNA (siRNA) expression in 0.6 mL transduction reagent was injected into tumors using a standard 1 mL syringe under ultrasonic guidance. In the siHIF-1α+TACE and siHIF-1α groups, rats received siRNA-expressing lentivirus; the rats in the TACE and control groups received lentivirus without siRNA. TACE was performed by placing a microcatheter into the gastroduodenal artery.
The median survival time, body weight, and tumor volume of the siHIF-1α+TACE group were better than those of the TACE, siHIF-1α, and control groups. A comparative analysis of the different treatment groups demonstrated that HIF-1α RNAi could downregulate the levels of HIF-1α and VEGF, inhibit tumor angiogenesis, and lessen metastases; all of these effects were enhanced by TACE.
HIF-1α RNAi, which was administered in vivo in liver tumors under ultrasound guidance, improved the efficacy of TACE in treating hepatocellular carcinoma in an animal model.</description><identifier>ISSN: 1178-6930</identifier><identifier>EISSN: 1178-6930</identifier><identifier>DOI: 10.2147/OTT.S94800</identifier><identifier>PMID: 26664137</identifier><language>eng</language><publisher>New Zealand: Dove Medical Press Limited</publisher><subject>Angiogenesis ; Apoptosis ; Cancer therapies ; Care and treatment ; Experiments ; Gene expression ; Gene therapy ; Genetic aspects ; Hepatoma ; Hypoxia ; Laboratories ; Liver cancer ; Medical prognosis ; Medical research ; Metabolism ; Metastasis ; Methods ; Original Research ; Patient outcomes ; Properties ; Radiation therapy ; Studies ; Therapeutic chemoembolization ; Transcription factors ; Tumors ; Ultrasonic imaging ; Vectors (Biology) ; Veins & arteries</subject><ispartof>OncoTargets and therapy, 2015-01, Vol.8, p.3539-3548</ispartof><rights>COPYRIGHT 2015 Dove Medical Press Limited</rights><rights>2015. This work is licensed under https://creativecommons.org/licenses/by-nc/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Chen et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-f7e2c9a3c2b081682a723927ab2db9580ecbe465a4ab0c7ab2fc808589ce09683</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669929/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669929/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3862,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26664137$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Cheng-Shi</creatorcontrib><creatorcontrib>Zhao, Qing</creatorcontrib><creatorcontrib>Qian, Sheng</creatorcontrib><creatorcontrib>Li, Hai-Liang</creatorcontrib><creatorcontrib>Guo, Chen-Yang</creatorcontrib><creatorcontrib>Zhang, Wei</creatorcontrib><creatorcontrib>Yan, Zhi-Ping</creatorcontrib><creatorcontrib>Liu, Rong</creatorcontrib><creatorcontrib>Wang, Jian-Hua</creatorcontrib><title>Ultrasound-guided RNA interference targeting HIF-1 alpha improves the effects of transarterial chemoembolization in rat liver tumors</title><title>OncoTargets and therapy</title><addtitle>Onco Targets Ther</addtitle><description>To investigate whether ultrasound-guided RNA interference (RNAi) targeting hypoxia-inducible factor-1alpha (HIF-1α) can enhance the efficacy of transarterial chemoembolization (TACE) in treating hepatocellular carcinoma.
Rats with orthotopic hepatocellular carcinoma were randomized to four groups and treated as follows: 1) control; 2) siHIF-1α; 3) TACE; 4) siHIF-1α+TACE. Lentivirus (4×10(8) transfection units) with or without small interfering RNA (siRNA) expression in 0.6 mL transduction reagent was injected into tumors using a standard 1 mL syringe under ultrasonic guidance. In the siHIF-1α+TACE and siHIF-1α groups, rats received siRNA-expressing lentivirus; the rats in the TACE and control groups received lentivirus without siRNA. TACE was performed by placing a microcatheter into the gastroduodenal artery.
The median survival time, body weight, and tumor volume of the siHIF-1α+TACE group were better than those of the TACE, siHIF-1α, and control groups. A comparative analysis of the different treatment groups demonstrated that HIF-1α RNAi could downregulate the levels of HIF-1α and VEGF, inhibit tumor angiogenesis, and lessen metastases; all of these effects were enhanced by TACE.
HIF-1α RNAi, which was administered in vivo in liver tumors under ultrasound guidance, improved the efficacy of TACE in treating hepatocellular carcinoma in an animal model.</description><subject>Angiogenesis</subject><subject>Apoptosis</subject><subject>Cancer therapies</subject><subject>Care and treatment</subject><subject>Experiments</subject><subject>Gene expression</subject><subject>Gene therapy</subject><subject>Genetic aspects</subject><subject>Hepatoma</subject><subject>Hypoxia</subject><subject>Laboratories</subject><subject>Liver cancer</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Metabolism</subject><subject>Metastasis</subject><subject>Methods</subject><subject>Original Research</subject><subject>Patient outcomes</subject><subject>Properties</subject><subject>Radiation therapy</subject><subject>Studies</subject><subject>Therapeutic chemoembolization</subject><subject>Transcription factors</subject><subject>Tumors</subject><subject>Ultrasonic imaging</subject><subject>Vectors (Biology)</subject><subject>Veins & arteries</subject><issn>1178-6930</issn><issn>1178-6930</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</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>eNptklFrFDEQxxdRbK2--AEkIIgIeybZbHbzUjiKtYViQa_PIZudvU3JJmeSPdBnP7g5rtY7kTwkTH7zn8zkXxSvCV5QwpqPt6vV4ptgLcZPilNCmrbkosJPD84nxYsY7zHmvKXseXFCOeeMVM1p8evOpqCin11frmfTQ4--flki4xKEAQI4DSipsIZk3BpdXV-WBCm7GRUy0yb4LUSURkAwDKBTRH5AWc5FFXK-URbpESYPU-et-amS8S5Lo6ASsmYLAaV58iG-LJ4NykZ49bCfFXeXn1YXV-XN7efri-VNqWvMUjk0QLVQlaYdbkluRTW0ErRRHe07UbcYdAeM14qpDutdeNAtbutWaMCCt9VZcb7X3czdBL0Glx9r5SaYSYUf0isjj2-cGeXabyXjXAgqssD7B4Hgv88Qk5xM1GCtcuDnKEnDBKeYUZbRt_-g934OLrcnKWW0xjVu8F9qrSxI4waf6-qdqFwy1oiKVLTO1OI_VF49TEZ7B4PJ8aOEdwcJIyibxujtvPuAeAx-2IM6-BgDDI_DIFjuzCWzueTeXBl-czi-R_SPm6rfwhLKiw</recordid><startdate>20150101</startdate><enddate>20150101</enddate><creator>Chen, Cheng-Shi</creator><creator>Zhao, Qing</creator><creator>Qian, Sheng</creator><creator>Li, Hai-Liang</creator><creator>Guo, Chen-Yang</creator><creator>Zhang, Wei</creator><creator>Yan, Zhi-Ping</creator><creator>Liu, Rong</creator><creator>Wang, Jian-Hua</creator><general>Dove Medical Press Limited</general><general>Taylor & Francis Ltd</general><general>Dove Medical Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</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>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</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></search><sort><creationdate>20150101</creationdate><title>Ultrasound-guided RNA interference targeting HIF-1 alpha improves the effects of transarterial chemoembolization in rat liver tumors</title><author>Chen, Cheng-Shi ; Zhao, Qing ; Qian, Sheng ; Li, Hai-Liang ; Guo, Chen-Yang ; Zhang, Wei ; Yan, Zhi-Ping ; Liu, Rong ; Wang, Jian-Hua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-f7e2c9a3c2b081682a723927ab2db9580ecbe465a4ab0c7ab2fc808589ce09683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Angiogenesis</topic><topic>Apoptosis</topic><topic>Cancer therapies</topic><topic>Care and treatment</topic><topic>Experiments</topic><topic>Gene expression</topic><topic>Gene therapy</topic><topic>Genetic aspects</topic><topic>Hepatoma</topic><topic>Hypoxia</topic><topic>Laboratories</topic><topic>Liver cancer</topic><topic>Medical prognosis</topic><topic>Medical research</topic><topic>Metabolism</topic><topic>Metastasis</topic><topic>Methods</topic><topic>Original Research</topic><topic>Patient outcomes</topic><topic>Properties</topic><topic>Radiation therapy</topic><topic>Studies</topic><topic>Therapeutic chemoembolization</topic><topic>Transcription factors</topic><topic>Tumors</topic><topic>Ultrasonic imaging</topic><topic>Vectors (Biology)</topic><topic>Veins & arteries</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Cheng-Shi</creatorcontrib><creatorcontrib>Zhao, Qing</creatorcontrib><creatorcontrib>Qian, Sheng</creatorcontrib><creatorcontrib>Li, Hai-Liang</creatorcontrib><creatorcontrib>Guo, Chen-Yang</creatorcontrib><creatorcontrib>Zhang, Wei</creatorcontrib><creatorcontrib>Yan, Zhi-Ping</creatorcontrib><creatorcontrib>Liu, Rong</creatorcontrib><creatorcontrib>Wang, Jian-Hua</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</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>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>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</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>OncoTargets and therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Cheng-Shi</au><au>Zhao, Qing</au><au>Qian, Sheng</au><au>Li, Hai-Liang</au><au>Guo, Chen-Yang</au><au>Zhang, Wei</au><au>Yan, Zhi-Ping</au><au>Liu, Rong</au><au>Wang, Jian-Hua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ultrasound-guided RNA interference targeting HIF-1 alpha improves the effects of transarterial chemoembolization in rat liver tumors</atitle><jtitle>OncoTargets and therapy</jtitle><addtitle>Onco Targets Ther</addtitle><date>2015-01-01</date><risdate>2015</risdate><volume>8</volume><spage>3539</spage><epage>3548</epage><pages>3539-3548</pages><issn>1178-6930</issn><eissn>1178-6930</eissn><abstract>To investigate whether ultrasound-guided RNA interference (RNAi) targeting hypoxia-inducible factor-1alpha (HIF-1α) can enhance the efficacy of transarterial chemoembolization (TACE) in treating hepatocellular carcinoma.
Rats with orthotopic hepatocellular carcinoma were randomized to four groups and treated as follows: 1) control; 2) siHIF-1α; 3) TACE; 4) siHIF-1α+TACE. Lentivirus (4×10(8) transfection units) with or without small interfering RNA (siRNA) expression in 0.6 mL transduction reagent was injected into tumors using a standard 1 mL syringe under ultrasonic guidance. In the siHIF-1α+TACE and siHIF-1α groups, rats received siRNA-expressing lentivirus; the rats in the TACE and control groups received lentivirus without siRNA. TACE was performed by placing a microcatheter into the gastroduodenal artery.
The median survival time, body weight, and tumor volume of the siHIF-1α+TACE group were better than those of the TACE, siHIF-1α, and control groups. A comparative analysis of the different treatment groups demonstrated that HIF-1α RNAi could downregulate the levels of HIF-1α and VEGF, inhibit tumor angiogenesis, and lessen metastases; all of these effects were enhanced by TACE.
HIF-1α RNAi, which was administered in vivo in liver tumors under ultrasound guidance, improved the efficacy of TACE in treating hepatocellular carcinoma in an animal model.</abstract><cop>New Zealand</cop><pub>Dove Medical Press Limited</pub><pmid>26664137</pmid><doi>10.2147/OTT.S94800</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1178-6930 |
| ispartof | OncoTargets and therapy, 2015-01, Vol.8, p.3539-3548 |
| issn | 1178-6930 1178-6930 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4669929 |
| source | Taylor & Francis Open Access; DOVE Medical Press Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; PubMed Central |
| subjects | Angiogenesis Apoptosis Cancer therapies Care and treatment Experiments Gene expression Gene therapy Genetic aspects Hepatoma Hypoxia Laboratories Liver cancer Medical prognosis Medical research Metabolism Metastasis Methods Original Research Patient outcomes Properties Radiation therapy Studies Therapeutic chemoembolization Transcription factors Tumors Ultrasonic imaging Vectors (Biology) Veins & arteries |
| title | Ultrasound-guided RNA interference targeting HIF-1 alpha improves the effects of transarterial chemoembolization in rat liver tumors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-06T12%3A29%3A29IST&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=Ultrasound-guided%20RNA%20interference%20targeting%20HIF-1%20alpha%20improves%20the%20effects%20of%20transarterial%20chemoembolization%20in%20rat%20liver%20tumors&rft.jtitle=OncoTargets%20and%20therapy&rft.au=Chen,%20Cheng-Shi&rft.date=2015-01-01&rft.volume=8&rft.spage=3539&rft.epage=3548&rft.pages=3539-3548&rft.issn=1178-6930&rft.eissn=1178-6930&rft_id=info:doi/10.2147/OTT.S94800&rft_dat=%3Cgale_pubme%3EA447931325%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=2242505070&rft_id=info:pmid/26664137&rft_galeid=A447931325&rfr_iscdi=true |