Preclinical Evaluation of [18F]THK-5105 Enantiomers: Effects of Chirality on Its Effectiveness as a Tau Imaging Radiotracer
Purpose Noninvasive imaging of tau and amyloid-β pathologies would facilitate diagnosis of Alzheimer’s disease (AD). Recently, we have developed [ 18 F]THK-5105 for selective detection of tau pathology by positron emission tomography (PET). The purpose of this study was to clarify biological propert...
Gespeichert in:
| Veröffentlicht in: | Molecular imaging and biology 2016-04, Vol.18 (2), p.258-266 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 266 |
|---|---|
| container_issue | 2 |
| container_start_page | 258 |
| container_title | Molecular imaging and biology |
| container_volume | 18 |
| creator | Tago, Tetsuro Furumoto, Shozo Okamura, Nobuyuki Harada, Ryuichi Adachi, Hajime Ishikawa, Yoichi Yanai, Kazuhiko Iwata, Ren Kudo, Yukitsuka |
| description | Purpose
Noninvasive imaging of tau and amyloid-β pathologies would facilitate diagnosis of Alzheimer’s disease (AD). Recently, we have developed [
18
F]THK-5105 for selective detection of tau pathology by positron emission tomography (PET). The purpose of this study was to clarify biological properties of optically pure [
18
F]THK-5105 enantiomers.
Procedures
Binding for tau aggregates in AD brain section was evaluated by autoradiography (ARG). In vitro binding assays were performed to evaluate the binding properties of enantiomers for AD brain homogenates. The pharmacokinetics in the normal mouse brains was assessed by ex vivo biodistribution assay
Results
The ARG of enantiomers showed the high accumulation of radioactivity corresponding to the distribution of tau deposits. In vitro binding assays revealed that (
S
)-[
18
F]THK-5105 has slower dissociation from tau than (
R
)-[
18
F]THK-5105. Biodistribution assays indicated that (
S
)-[
18
F]THK-5105 eliminated faster from the mouse brains and blood compared with (
R
)-[
18
F]THK-5105.
Conclusion
(
S
)-[
18
F]THK-5105 could be more suitable than (
R
)-enantiomer for a tau imaging agent. |
| doi_str_mv | 10.1007/s11307-015-0879-8 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1776659937</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3976263381</sourcerecordid><originalsourceid>FETCH-LOGICAL-c541t-d97053268319451fc703b1eaaa7dc9450f789ed338a19f1dbfe1215ba5aeee93</originalsourceid><addsrcrecordid>eNqNkV2L1TAQhoMo7of-AG8k4I031ZmmaRrv5HDWPbigyLkTKXPayTFLP9akXVj886Z0V0QQhEDCvM-8k-QV4gXCGwQwbyOiApMB6gwqY7PqkTjFqoQsB8gfp7NWZYalyk_EWYzXAGgwV0_FSV6iLQDxVPz8HLjp_OAb6uT2lrqZJj8OcnTyK1YX3_aXHzONoOV2oCEpPYf4Tm6d42aKC7X57gN1frqTqWuXaqvmb3ngGCWlJfc0y11PRz8c5Rdq_TgFajg8E08cdZGf3-_nYn-x3W8us6tPH3ab91dZowucstYa0CovK5UurdE1BtQBmYhM26QKOFNZbpWqCK3D9uAYc9QH0sTMVp2L16vtTRh_zBynuvex4a6jgcc51mhMWWprlfkfNMei0AUk9NVf6PU4hyG9Y6HSR1trltm4Uk0YYwzs6pvgewp3NUK9ZFivGdYpw3rJsK5Sz8t75_nQc_u74yG0BOQrEJM0HDn8Mfqfrr8AVqOk1g</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1771719979</pqid></control><display><type>article</type><title>Preclinical Evaluation of [18F]THK-5105 Enantiomers: Effects of Chirality on Its Effectiveness as a Tau Imaging Radiotracer</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><creator>Tago, Tetsuro ; Furumoto, Shozo ; Okamura, Nobuyuki ; Harada, Ryuichi ; Adachi, Hajime ; Ishikawa, Yoichi ; Yanai, Kazuhiko ; Iwata, Ren ; Kudo, Yukitsuka</creator><creatorcontrib>Tago, Tetsuro ; Furumoto, Shozo ; Okamura, Nobuyuki ; Harada, Ryuichi ; Adachi, Hajime ; Ishikawa, Yoichi ; Yanai, Kazuhiko ; Iwata, Ren ; Kudo, Yukitsuka</creatorcontrib><description>Purpose
Noninvasive imaging of tau and amyloid-β pathologies would facilitate diagnosis of Alzheimer’s disease (AD). Recently, we have developed [
18
F]THK-5105 for selective detection of tau pathology by positron emission tomography (PET). The purpose of this study was to clarify biological properties of optically pure [
18
F]THK-5105 enantiomers.
Procedures
Binding for tau aggregates in AD brain section was evaluated by autoradiography (ARG). In vitro binding assays were performed to evaluate the binding properties of enantiomers for AD brain homogenates. The pharmacokinetics in the normal mouse brains was assessed by ex vivo biodistribution assay
Results
The ARG of enantiomers showed the high accumulation of radioactivity corresponding to the distribution of tau deposits. In vitro binding assays revealed that (
S
)-[
18
F]THK-5105 has slower dissociation from tau than (
R
)-[
18
F]THK-5105. Biodistribution assays indicated that (
S
)-[
18
F]THK-5105 eliminated faster from the mouse brains and blood compared with (
R
)-[
18
F]THK-5105.
Conclusion
(
S
)-[
18
F]THK-5105 could be more suitable than (
R
)-enantiomer for a tau imaging agent.</description><identifier>ISSN: 1536-1632</identifier><identifier>EISSN: 1860-2002</identifier><identifier>DOI: 10.1007/s11307-015-0879-8</identifier><identifier>PMID: 26194011</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Alzheimer Disease - blood ; Alzheimer Disease - diagnostic imaging ; Alzheimer Disease - metabolism ; Aniline Compounds - analysis ; Aniline Compounds - chemistry ; Animals ; Autoradiography ; Brain - diagnostic imaging ; Brain - metabolism ; Chromatography, High Pressure Liquid ; Humans ; Imaging ; Male ; Medicine ; Medicine & Public Health ; Metabolome ; Mice ; Positron-Emission Tomography - methods ; Quinolines - analysis ; Quinolines - chemistry ; Radioactive Tracers ; Radioactivity ; Radiology ; Research Article ; Stereoisomerism ; tau Proteins - analysis ; tau Proteins - metabolism</subject><ispartof>Molecular imaging and biology, 2016-04, Vol.18 (2), p.258-266</ispartof><rights>World Molecular Imaging Society 2015</rights><rights>World Molecular Imaging Society 2016</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-d97053268319451fc703b1eaaa7dc9450f789ed338a19f1dbfe1215ba5aeee93</citedby><cites>FETCH-LOGICAL-c541t-d97053268319451fc703b1eaaa7dc9450f789ed338a19f1dbfe1215ba5aeee93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11307-015-0879-8$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11307-015-0879-8$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26194011$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tago, Tetsuro</creatorcontrib><creatorcontrib>Furumoto, Shozo</creatorcontrib><creatorcontrib>Okamura, Nobuyuki</creatorcontrib><creatorcontrib>Harada, Ryuichi</creatorcontrib><creatorcontrib>Adachi, Hajime</creatorcontrib><creatorcontrib>Ishikawa, Yoichi</creatorcontrib><creatorcontrib>Yanai, Kazuhiko</creatorcontrib><creatorcontrib>Iwata, Ren</creatorcontrib><creatorcontrib>Kudo, Yukitsuka</creatorcontrib><title>Preclinical Evaluation of [18F]THK-5105 Enantiomers: Effects of Chirality on Its Effectiveness as a Tau Imaging Radiotracer</title><title>Molecular imaging and biology</title><addtitle>Mol Imaging Biol</addtitle><addtitle>Mol Imaging Biol</addtitle><description>Purpose
Noninvasive imaging of tau and amyloid-β pathologies would facilitate diagnosis of Alzheimer’s disease (AD). Recently, we have developed [
18
F]THK-5105 for selective detection of tau pathology by positron emission tomography (PET). The purpose of this study was to clarify biological properties of optically pure [
18
F]THK-5105 enantiomers.
Procedures
Binding for tau aggregates in AD brain section was evaluated by autoradiography (ARG). In vitro binding assays were performed to evaluate the binding properties of enantiomers for AD brain homogenates. The pharmacokinetics in the normal mouse brains was assessed by ex vivo biodistribution assay
Results
The ARG of enantiomers showed the high accumulation of radioactivity corresponding to the distribution of tau deposits. In vitro binding assays revealed that (
S
)-[
18
F]THK-5105 has slower dissociation from tau than (
R
)-[
18
F]THK-5105. Biodistribution assays indicated that (
S
)-[
18
F]THK-5105 eliminated faster from the mouse brains and blood compared with (
R
)-[
18
F]THK-5105.
Conclusion
(
S
)-[
18
F]THK-5105 could be more suitable than (
R
)-enantiomer for a tau imaging agent.</description><subject>Alzheimer Disease - blood</subject><subject>Alzheimer Disease - diagnostic imaging</subject><subject>Alzheimer Disease - metabolism</subject><subject>Aniline Compounds - analysis</subject><subject>Aniline Compounds - chemistry</subject><subject>Animals</subject><subject>Autoradiography</subject><subject>Brain - diagnostic imaging</subject><subject>Brain - metabolism</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Humans</subject><subject>Imaging</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolome</subject><subject>Mice</subject><subject>Positron-Emission Tomography - methods</subject><subject>Quinolines - analysis</subject><subject>Quinolines - chemistry</subject><subject>Radioactive Tracers</subject><subject>Radioactivity</subject><subject>Radiology</subject><subject>Research Article</subject><subject>Stereoisomerism</subject><subject>tau Proteins - analysis</subject><subject>tau Proteins - metabolism</subject><issn>1536-1632</issn><issn>1860-2002</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</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><recordid>eNqNkV2L1TAQhoMo7of-AG8k4I031ZmmaRrv5HDWPbigyLkTKXPayTFLP9akXVj886Z0V0QQhEDCvM-8k-QV4gXCGwQwbyOiApMB6gwqY7PqkTjFqoQsB8gfp7NWZYalyk_EWYzXAGgwV0_FSV6iLQDxVPz8HLjp_OAb6uT2lrqZJj8OcnTyK1YX3_aXHzONoOV2oCEpPYf4Tm6d42aKC7X57gN1frqTqWuXaqvmb3ngGCWlJfc0y11PRz8c5Rdq_TgFajg8E08cdZGf3-_nYn-x3W8us6tPH3ab91dZowucstYa0CovK5UurdE1BtQBmYhM26QKOFNZbpWqCK3D9uAYc9QH0sTMVp2L16vtTRh_zBynuvex4a6jgcc51mhMWWprlfkfNMei0AUk9NVf6PU4hyG9Y6HSR1trltm4Uk0YYwzs6pvgewp3NUK9ZFivGdYpw3rJsK5Sz8t75_nQc_u74yG0BOQrEJM0HDn8Mfqfrr8AVqOk1g</recordid><startdate>20160401</startdate><enddate>20160401</enddate><creator>Tago, Tetsuro</creator><creator>Furumoto, Shozo</creator><creator>Okamura, Nobuyuki</creator><creator>Harada, Ryuichi</creator><creator>Adachi, Hajime</creator><creator>Ishikawa, Yoichi</creator><creator>Yanai, Kazuhiko</creator><creator>Iwata, Ren</creator><creator>Kudo, Yukitsuka</creator><general>Springer US</general><general>Springer Nature B.V</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>7QO</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</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>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</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>KB0</scope><scope>L6V</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>7X8</scope></search><sort><creationdate>20160401</creationdate><title>Preclinical Evaluation of [18F]THK-5105 Enantiomers: Effects of Chirality on Its Effectiveness as a Tau Imaging Radiotracer</title><author>Tago, Tetsuro ; Furumoto, Shozo ; Okamura, Nobuyuki ; Harada, Ryuichi ; Adachi, Hajime ; Ishikawa, Yoichi ; Yanai, Kazuhiko ; Iwata, Ren ; Kudo, Yukitsuka</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c541t-d97053268319451fc703b1eaaa7dc9450f789ed338a19f1dbfe1215ba5aeee93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Alzheimer Disease - blood</topic><topic>Alzheimer Disease - diagnostic imaging</topic><topic>Alzheimer Disease - metabolism</topic><topic>Aniline Compounds - analysis</topic><topic>Aniline Compounds - chemistry</topic><topic>Animals</topic><topic>Autoradiography</topic><topic>Brain - diagnostic imaging</topic><topic>Brain - metabolism</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Humans</topic><topic>Imaging</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolome</topic><topic>Mice</topic><topic>Positron-Emission Tomography - methods</topic><topic>Quinolines - analysis</topic><topic>Quinolines - chemistry</topic><topic>Radioactive Tracers</topic><topic>Radioactivity</topic><topic>Radiology</topic><topic>Research Article</topic><topic>Stereoisomerism</topic><topic>tau Proteins - analysis</topic><topic>tau Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tago, Tetsuro</creatorcontrib><creatorcontrib>Furumoto, Shozo</creatorcontrib><creatorcontrib>Okamura, Nobuyuki</creatorcontrib><creatorcontrib>Harada, Ryuichi</creatorcontrib><creatorcontrib>Adachi, Hajime</creatorcontrib><creatorcontrib>Ishikawa, Yoichi</creatorcontrib><creatorcontrib>Yanai, Kazuhiko</creatorcontrib><creatorcontrib>Iwata, Ren</creatorcontrib><creatorcontrib>Kudo, Yukitsuka</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>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science & Engineering Collection</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>Technology Collection</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</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 & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</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>Engineering Collection</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular imaging and biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tago, Tetsuro</au><au>Furumoto, Shozo</au><au>Okamura, Nobuyuki</au><au>Harada, Ryuichi</au><au>Adachi, Hajime</au><au>Ishikawa, Yoichi</au><au>Yanai, Kazuhiko</au><au>Iwata, Ren</au><au>Kudo, Yukitsuka</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preclinical Evaluation of [18F]THK-5105 Enantiomers: Effects of Chirality on Its Effectiveness as a Tau Imaging Radiotracer</atitle><jtitle>Molecular imaging and biology</jtitle><stitle>Mol Imaging Biol</stitle><addtitle>Mol Imaging Biol</addtitle><date>2016-04-01</date><risdate>2016</risdate><volume>18</volume><issue>2</issue><spage>258</spage><epage>266</epage><pages>258-266</pages><issn>1536-1632</issn><eissn>1860-2002</eissn><abstract>Purpose
Noninvasive imaging of tau and amyloid-β pathologies would facilitate diagnosis of Alzheimer’s disease (AD). Recently, we have developed [
18
F]THK-5105 for selective detection of tau pathology by positron emission tomography (PET). The purpose of this study was to clarify biological properties of optically pure [
18
F]THK-5105 enantiomers.
Procedures
Binding for tau aggregates in AD brain section was evaluated by autoradiography (ARG). In vitro binding assays were performed to evaluate the binding properties of enantiomers for AD brain homogenates. The pharmacokinetics in the normal mouse brains was assessed by ex vivo biodistribution assay
Results
The ARG of enantiomers showed the high accumulation of radioactivity corresponding to the distribution of tau deposits. In vitro binding assays revealed that (
S
)-[
18
F]THK-5105 has slower dissociation from tau than (
R
)-[
18
F]THK-5105. Biodistribution assays indicated that (
S
)-[
18
F]THK-5105 eliminated faster from the mouse brains and blood compared with (
R
)-[
18
F]THK-5105.
Conclusion
(
S
)-[
18
F]THK-5105 could be more suitable than (
R
)-enantiomer for a tau imaging agent.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>26194011</pmid><doi>10.1007/s11307-015-0879-8</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1536-1632 |
| ispartof | Molecular imaging and biology, 2016-04, Vol.18 (2), p.258-266 |
| issn | 1536-1632 1860-2002 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1776659937 |
| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Alzheimer Disease - blood Alzheimer Disease - diagnostic imaging Alzheimer Disease - metabolism Aniline Compounds - analysis Aniline Compounds - chemistry Animals Autoradiography Brain - diagnostic imaging Brain - metabolism Chromatography, High Pressure Liquid Humans Imaging Male Medicine Medicine & Public Health Metabolome Mice Positron-Emission Tomography - methods Quinolines - analysis Quinolines - chemistry Radioactive Tracers Radioactivity Radiology Research Article Stereoisomerism tau Proteins - analysis tau Proteins - metabolism |
| title | Preclinical Evaluation of [18F]THK-5105 Enantiomers: Effects of Chirality on Its Effectiveness as a Tau Imaging Radiotracer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T15%3A06%3A17IST&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=Preclinical%20Evaluation%20of%20%5B18F%5DTHK-5105%20Enantiomers:%20Effects%20of%20Chirality%20on%20Its%20Effectiveness%20as%20a%20Tau%20Imaging%20Radiotracer&rft.jtitle=Molecular%20imaging%20and%20biology&rft.au=Tago,%20Tetsuro&rft.date=2016-04-01&rft.volume=18&rft.issue=2&rft.spage=258&rft.epage=266&rft.pages=258-266&rft.issn=1536-1632&rft.eissn=1860-2002&rft_id=info:doi/10.1007/s11307-015-0879-8&rft_dat=%3Cproquest_cross%3E3976263381%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1771719979&rft_id=info:pmid/26194011&rfr_iscdi=true |