Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation
Up-regulated sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumo...
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| creator | Hirai, Sachiko Endo, Shinji Saito, Rie Hirose, Mitsuaki Ueno, Takunori Suzuki, Hideo Yamato, Kenji Abei, Masato Hyodo, Ichinosuke |
| description | Up-regulated sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53). Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5). In the KatoIII cell line (TP53-null), DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors. |
| doi_str_mv | 10.1371/journal.pone.0102831 |
| format | Article |
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SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53). Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5). In the KatoIII cell line (TP53-null), DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0102831</identifier><identifier>PMID: 25033286</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activating Transcription Factor 6 - metabolism ; Activation ; Anticancer properties ; Antineoplastic Agents - pharmacology ; Antitumor activity ; Apoptosis ; Apoptosis - drug effects ; Benzamides - pharmacology ; Biotechnology ; Camptothecin - analogs & derivatives ; Camptothecin - pharmacology ; Cancer ; Cancer cells ; Cancer therapies ; Cell cycle ; Cell Line ; Cell Line, Tumor ; Cell survival ; Clinical medicine ; Colorectal cancer ; Cytotoxicity ; Death ; Deoxyribonucleic acid ; DNA ; DNA methylation ; Drugs ; eIF-2 Kinase - metabolism ; Endoplasmic reticulum ; Endoplasmic Reticulum Stress - drug effects ; Gastric cancer ; Gastroenterology ; Gene Expression Regulation, Neoplastic - drug effects ; HEK293 Cells ; Histone deacetylase ; Humans ; Immunoglobulins ; Inhibitors ; Investigations ; Kinases ; MCF-7 Cells ; Medical prognosis ; Medicine ; Medicine and Health Sciences ; Mortality ; Mutation ; NAD ; p53 Protein ; Prognosis ; Proteins ; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism ; Senescence ; Signal Transduction - drug effects ; SIRT1 protein ; Sirtuin 1 - antagonists & inhibitors ; Stomach cancer ; Stomach Neoplasms - drug therapy ; Stomach Neoplasms - metabolism ; Survival ; Taxoids - pharmacology ; Toxicity ; Transcription ; Transcription Factor CHOP - metabolism ; Tumor cell lines ; Tumor proteins ; Tumor Suppressor Protein p53 - metabolism ; Up-regulation ; Up-Regulation - drug effects</subject><ispartof>PloS one, 2014-07, Vol.9 (7), p.e102831</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Hirai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Hirai et al 2014 Hirai et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c802t-9f8c58719f7d1ec009b556a2dd1e4a22bb246d52343b9478cdd9fd79cd1152733</citedby><cites>FETCH-LOGICAL-c802t-9f8c58719f7d1ec009b556a2dd1e4a22bb246d52343b9478cdd9fd79cd1152733</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/PMC4102575/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102575/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25033286$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Gartel, Andrei L.</contributor><creatorcontrib>Hirai, Sachiko</creatorcontrib><creatorcontrib>Endo, Shinji</creatorcontrib><creatorcontrib>Saito, Rie</creatorcontrib><creatorcontrib>Hirose, Mitsuaki</creatorcontrib><creatorcontrib>Ueno, Takunori</creatorcontrib><creatorcontrib>Suzuki, Hideo</creatorcontrib><creatorcontrib>Yamato, Kenji</creatorcontrib><creatorcontrib>Abei, Masato</creatorcontrib><creatorcontrib>Hyodo, Ichinosuke</creatorcontrib><title>Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Up-regulated sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53). Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5). In the KatoIII cell line (TP53-null), DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.</description><subject>Activating Transcription Factor 6 - metabolism</subject><subject>Activation</subject><subject>Anticancer properties</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Benzamides - pharmacology</subject><subject>Biotechnology</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Camptothecin - pharmacology</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell survival</subject><subject>Clinical medicine</subject><subject>Colorectal cancer</subject><subject>Cytotoxicity</subject><subject>Death</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>Drugs</subject><subject>eIF-2 Kinase - metabolism</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum Stress - drug effects</subject><subject>Gastric cancer</subject><subject>Gastroenterology</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>HEK293 Cells</subject><subject>Histone deacetylase</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Inhibitors</subject><subject>Investigations</subject><subject>Kinases</subject><subject>MCF-7 Cells</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mortality</subject><subject>Mutation</subject><subject>NAD</subject><subject>p53 Protein</subject><subject>Prognosis</subject><subject>Proteins</subject><subject>Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism</subject><subject>Senescence</subject><subject>Signal Transduction - drug effects</subject><subject>SIRT1 protein</subject><subject>Sirtuin 1 - antagonists & inhibitors</subject><subject>Stomach cancer</subject><subject>Stomach Neoplasms - drug therapy</subject><subject>Stomach Neoplasms - metabolism</subject><subject>Survival</subject><subject>Taxoids - pharmacology</subject><subject>Toxicity</subject><subject>Transcription</subject><subject>Transcription Factor CHOP - metabolism</subject><subject>Tumor cell lines</subject><subject>Tumor proteins</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Up-regulation</subject><subject>Up-Regulation - drug effects</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkluL1DAAhYso7kX_gWhAEITtmGuTvgjD4mVgYcHba0jTtJOhk4xJOui_34zTXaagIHlomnznND05RfECwQUiHL3b-DE4NSx23pkFRBALgh4V56gmuKwwJI9P5mfFRYwbCBkRVfW0OMMMEoJFdV6kpUs2jVsfgOk6o1MEvgMKRBvSaB2wbm0bm3y4Ask4v7eurK6A6pV1MYFexRSsBlo5bQLQZhgi2FsFWqPSGgSjzS5rAQPjrgymHweVrHfPiiedGqJ5Pj0vi-8fP3y7_lze3H5aXS9vSi0gTmXdCc0ER3XHW2Q0hHXDWKVwm9-owrhpMK1ahgklTU250G1bdy2vdYsQw5yQy-LV0Xc3-CinwKJEjDKBMYQ8E6sj0Xq1kbtgtyr8ll5Z-WfBh16qkKwejMzh1RxWiCBRUdyhWpm64lQTLhrBsMpe76evjc3WtNq4FNQwM53vOLuWvd9Lmi-PcZYNXk8Gwf8cTUz_OPJE9SqfyrrOZzO9tVHLJUWCYirE4dcXf6HyaM3W6lyZzub1meDtTJCZZH6lXo0xytXXL__P3v6Ys29O2LVRQ1pHP4yHHsQ5SI-gDj7GYLqH5BCUh8bfpyEPjZdT47Ps5WnqD6L7ipM7DwH6wA</recordid><startdate>20140717</startdate><enddate>20140717</enddate><creator>Hirai, Sachiko</creator><creator>Endo, Shinji</creator><creator>Saito, Rie</creator><creator>Hirose, Mitsuaki</creator><creator>Ueno, Takunori</creator><creator>Suzuki, Hideo</creator><creator>Yamato, Kenji</creator><creator>Abei, Masato</creator><creator>Hyodo, Ichinosuke</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140717</creationdate><title>Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation</title><author>Hirai, Sachiko ; Endo, Shinji ; Saito, Rie ; Hirose, Mitsuaki ; Ueno, Takunori ; Suzuki, Hideo ; Yamato, Kenji ; Abei, Masato ; Hyodo, Ichinosuke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c802t-9f8c58719f7d1ec009b556a2dd1e4a22bb246d52343b9478cdd9fd79cd1152733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Activating Transcription Factor 6 - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</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>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hirai, Sachiko</au><au>Endo, Shinji</au><au>Saito, Rie</au><au>Hirose, Mitsuaki</au><au>Ueno, Takunori</au><au>Suzuki, Hideo</au><au>Yamato, Kenji</au><au>Abei, Masato</au><au>Hyodo, Ichinosuke</au><au>Gartel, Andrei L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-07-17</date><risdate>2014</risdate><volume>9</volume><issue>7</issue><spage>e102831</spage><pages>e102831-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Up-regulated sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53). Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5). In the KatoIII cell line (TP53-null), DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25033286</pmid><doi>10.1371/journal.pone.0102831</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-07, Vol.9 (7), p.e102831 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1545822007 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activating Transcription Factor 6 - metabolism Activation Anticancer properties Antineoplastic Agents - pharmacology Antitumor activity Apoptosis Apoptosis - drug effects Benzamides - pharmacology Biotechnology Camptothecin - analogs & derivatives Camptothecin - pharmacology Cancer Cancer cells Cancer therapies Cell cycle Cell Line Cell Line, Tumor Cell survival Clinical medicine Colorectal cancer Cytotoxicity Death Deoxyribonucleic acid DNA DNA methylation Drugs eIF-2 Kinase - metabolism Endoplasmic reticulum Endoplasmic Reticulum Stress - drug effects Gastric cancer Gastroenterology Gene Expression Regulation, Neoplastic - drug effects HEK293 Cells Histone deacetylase Humans Immunoglobulins Inhibitors Investigations Kinases MCF-7 Cells Medical prognosis Medicine Medicine and Health Sciences Mortality Mutation NAD p53 Protein Prognosis Proteins Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism Senescence Signal Transduction - drug effects SIRT1 protein Sirtuin 1 - antagonists & inhibitors Stomach cancer Stomach Neoplasms - drug therapy Stomach Neoplasms - metabolism Survival Taxoids - pharmacology Toxicity Transcription Transcription Factor CHOP - metabolism Tumor cell lines Tumor proteins Tumor Suppressor Protein p53 - metabolism Up-regulation Up-Regulation - drug effects |
| title | Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-19T16%3A55%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Antitumor%20effects%20of%20a%20sirtuin%20inhibitor,%20tenovin-6,%20against%20gastric%20cancer%20cells%20via%20death%20receptor%205%20up-regulation&rft.jtitle=PloS%20one&rft.au=Hirai,%20Sachiko&rft.date=2014-07-17&rft.volume=9&rft.issue=7&rft.spage=e102831&rft.pages=e102831-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0102831&rft_dat=%3Cgale_plos_%3EA418424883%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1545822007&rft_id=info:pmid/25033286&rft_galeid=A418424883&rft_doaj_id=oai_doaj_org_article_05397061318642f19ae9674c378b852a&rfr_iscdi=true |