Loading…

Identification of the bioactive components of Banxia Xiexin Decoction that protect against CPT-11-induced intestinal toxicity via UPLC-based spectrum-effect relationship analyses

Irinotecan (CPT-11) is a valuable chemotherapeutic compound, but its use is associated with severe diarrhea in some patients. The CPT-11 prodrug is converted into the active 7-ethyl-10-hydroxycamptothecin (SN-38) metabolite, which can then be retained for extended periods in the intestine, leading t...

Full description

Saved in:
Bibliographic Details
Published in:Journal of ethnopharmacology 2021-02, Vol.266, p.113421, Article 113421
Main Authors: Shi, Jia-Wen, Li, Zhuang-Zhuang, Wu, Jia-Shuo, Jin, Wei-Yi, Chang, Xiao-Yan, Sun, Hong, Dong, Li, Jiang, Zhi-Ping, Shi, Yue
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-c353t-2abc81174657a8049c026687ec098433cc1d47ac3c233ba2a7a6a331b117a3ff3
cites cdi_FETCH-LOGICAL-c353t-2abc81174657a8049c026687ec098433cc1d47ac3c233ba2a7a6a331b117a3ff3
container_end_page
container_issue
container_start_page 113421
container_title Journal of ethnopharmacology
container_volume 266
creator Shi, Jia-Wen
Li, Zhuang-Zhuang
Wu, Jia-Shuo
Jin, Wei-Yi
Chang, Xiao-Yan
Sun, Hong
Dong, Li
Jiang, Zhi-Ping
Shi, Yue
description Irinotecan (CPT-11) is a valuable chemotherapeutic compound, but its use is associated with severe diarrhea in some patients. The CPT-11 prodrug is converted into the active 7-ethyl-10-hydroxycamptothecin (SN-38) metabolite, which can then be retained for extended periods in the intestine, leading to the onset of diarrhea and related symptoms. Banxia Xiexin Decoction (BXD) is commonly employed for the treatment of gastroenteritis in traditional Chinese medicine (TCM), and in clinical settings, it is used to prevent diarrhea in patients undergoing CPT-11 treatment. To date, however, there have been no studies specifically examining which components of BXD can alleviate the gastrointestinal symptoms associated with CPT-11 administration. This study aimed to identify the main herbal components of BXD associated with protection against CPT-11-induced intestinal toxicity in a murine model system. SN-38 levels were measured by UPLC-ESI-MS/MS in samples collected from mice subjected to CPT-11-induced diarrhea that had been administered BXD or different components thereof. Pearson correlation and Grey relational analyses were then used to explore spectrum-effect relationships between reductions in intestinal SN-38 levels and specific chemical fingerprints in samples from mice administered particular combinations of BXD component herbs. We found that different herbal combinations were associated with significant differences in intestinal SN-38 reductions in treated mice. Our spectrum-effect analysis revealed that BXD components including chrysin 6-C-arabinoside-8-C-glucoside, coptisine, hydroxyl oroxylin A 7-O-glucuronide (hydroxyl wogonoside), baicalin, an isomer of 5,6,7-trihydroxyl-flavanone-7-O-glucuronide, berberine, palmatine, and chrysin-7-O-glucuronide were all directly linked with reductions in intestinal SN-38 levels. We therefore speculate that these compounds are the primary bioactive components of BXD, suggesting that they offer protection against CPT-11-induced diarrhea. By utilizing UPLC to analyze SN-38 levels in mice treated with a variety of herbal combinations, we were able to effectively explore BXD spectrum-effect relationships and to thereby establish the components of this medicinal preparation that were bioactive and capable of preventing CPT-11-induced diarrhea in mice. This and similar spectrum-effect studies represent a robust means of exploring the mechanistic basis for the pharmacological activity of TCM preparations. [Display omitted]
doi_str_mv 10.1016/j.jep.2020.113421
format article
fullrecord <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1016_j_jep_2020_113421</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0378874120333067</els_id><sourcerecordid>33022337</sourcerecordid><originalsourceid>FETCH-LOGICAL-c353t-2abc81174657a8049c026687ec098433cc1d47ac3c233ba2a7a6a331b117a3ff3</originalsourceid><addsrcrecordid>eNp9kMuOEzEQRS0EYsLAB7BB_gEHPzrtHrGCDI-RIjGLGYmdVe2uJhUldst2ouS3-EKcCbBkVbLqnqvyYeytknMlVft-M9_gNNdS17cyjVbP2Ex1Vgu7sOY5m0ljO9HZRl2xVzlvpJRWNfIluzJGam2MnbFfdwOGQiN5KBQDjyMva-Q9RfCFDsh93E0x1Ew-7z5BOBLwH4RHCvwWffRPWFlD4VOKBX3h8BMo5MKX9w9CKUFh2HscOIWCuVCALS_xSJ7KiR9q2eP9ail6yDWSp8qn_U7gOJ6bEm6fzsprmjhU8pQxv2YvRthmfPNnXrPHL58flt_E6vvXu-XHlfBmYYrQ0PtOKdu0CwudbG681G3bWfTypmuM8V4NjQVvfDXRgwYLLRij-sqAGUdzzdSl16eYc8LRTYl2kE5OSXf27zau-ndn_-7ivzLvLsy073c4_CP-Cq-BD5cA1ssPhMllTxiqH0r1x26I9J_63wEcmWI</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Identification of the bioactive components of Banxia Xiexin Decoction that protect against CPT-11-induced intestinal toxicity via UPLC-based spectrum-effect relationship analyses</title><source>ScienceDirect Journals</source><creator>Shi, Jia-Wen ; Li, Zhuang-Zhuang ; Wu, Jia-Shuo ; Jin, Wei-Yi ; Chang, Xiao-Yan ; Sun, Hong ; Dong, Li ; Jiang, Zhi-Ping ; Shi, Yue</creator><creatorcontrib>Shi, Jia-Wen ; Li, Zhuang-Zhuang ; Wu, Jia-Shuo ; Jin, Wei-Yi ; Chang, Xiao-Yan ; Sun, Hong ; Dong, Li ; Jiang, Zhi-Ping ; Shi, Yue</creatorcontrib><description>Irinotecan (CPT-11) is a valuable chemotherapeutic compound, but its use is associated with severe diarrhea in some patients. The CPT-11 prodrug is converted into the active 7-ethyl-10-hydroxycamptothecin (SN-38) metabolite, which can then be retained for extended periods in the intestine, leading to the onset of diarrhea and related symptoms. Banxia Xiexin Decoction (BXD) is commonly employed for the treatment of gastroenteritis in traditional Chinese medicine (TCM), and in clinical settings, it is used to prevent diarrhea in patients undergoing CPT-11 treatment. To date, however, there have been no studies specifically examining which components of BXD can alleviate the gastrointestinal symptoms associated with CPT-11 administration. This study aimed to identify the main herbal components of BXD associated with protection against CPT-11-induced intestinal toxicity in a murine model system. SN-38 levels were measured by UPLC-ESI-MS/MS in samples collected from mice subjected to CPT-11-induced diarrhea that had been administered BXD or different components thereof. Pearson correlation and Grey relational analyses were then used to explore spectrum-effect relationships between reductions in intestinal SN-38 levels and specific chemical fingerprints in samples from mice administered particular combinations of BXD component herbs. We found that different herbal combinations were associated with significant differences in intestinal SN-38 reductions in treated mice. Our spectrum-effect analysis revealed that BXD components including chrysin 6-C-arabinoside-8-C-glucoside, coptisine, hydroxyl oroxylin A 7-O-glucuronide (hydroxyl wogonoside), baicalin, an isomer of 5,6,7-trihydroxyl-flavanone-7-O-glucuronide, berberine, palmatine, and chrysin-7-O-glucuronide were all directly linked with reductions in intestinal SN-38 levels. We therefore speculate that these compounds are the primary bioactive components of BXD, suggesting that they offer protection against CPT-11-induced diarrhea. By utilizing UPLC to analyze SN-38 levels in mice treated with a variety of herbal combinations, we were able to effectively explore BXD spectrum-effect relationships and to thereby establish the components of this medicinal preparation that were bioactive and capable of preventing CPT-11-induced diarrhea in mice. This and similar spectrum-effect studies represent a robust means of exploring the mechanistic basis for the pharmacological activity of TCM preparations. [Display omitted]</description><identifier>ISSN: 0378-8741</identifier><identifier>EISSN: 1872-7573</identifier><identifier>DOI: 10.1016/j.jep.2020.113421</identifier><identifier>PMID: 33022337</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Animals ; Banxia xiexin decoction (BXD) ; Chromatography, High Pressure Liquid ; Diarrhea - chemically induced ; Diarrhea - prevention &amp; control ; Drugs, Chinese Herbal - chemistry ; Drugs, Chinese Herbal - pharmacology ; Female ; Intestinal Diseases - chemically induced ; Intestinal Diseases - prevention &amp; control ; Intestinal toxicity ; Irinotecan (CPT-11) ; Irinotecan - toxicity ; Mice ; Mice, Inbred ICR ; SN-38 ; Spectrum-effect relationship ; Tandem Mass Spectrometry ; Topoisomerase I Inhibitors - toxicity</subject><ispartof>Journal of ethnopharmacology, 2021-02, Vol.266, p.113421, Article 113421</ispartof><rights>2020 Elsevier B.V.</rights><rights>Copyright © 2020 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-2abc81174657a8049c026687ec098433cc1d47ac3c233ba2a7a6a331b117a3ff3</citedby><cites>FETCH-LOGICAL-c353t-2abc81174657a8049c026687ec098433cc1d47ac3c233ba2a7a6a331b117a3ff3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33022337$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shi, Jia-Wen</creatorcontrib><creatorcontrib>Li, Zhuang-Zhuang</creatorcontrib><creatorcontrib>Wu, Jia-Shuo</creatorcontrib><creatorcontrib>Jin, Wei-Yi</creatorcontrib><creatorcontrib>Chang, Xiao-Yan</creatorcontrib><creatorcontrib>Sun, Hong</creatorcontrib><creatorcontrib>Dong, Li</creatorcontrib><creatorcontrib>Jiang, Zhi-Ping</creatorcontrib><creatorcontrib>Shi, Yue</creatorcontrib><title>Identification of the bioactive components of Banxia Xiexin Decoction that protect against CPT-11-induced intestinal toxicity via UPLC-based spectrum-effect relationship analyses</title><title>Journal of ethnopharmacology</title><addtitle>J Ethnopharmacol</addtitle><description>Irinotecan (CPT-11) is a valuable chemotherapeutic compound, but its use is associated with severe diarrhea in some patients. The CPT-11 prodrug is converted into the active 7-ethyl-10-hydroxycamptothecin (SN-38) metabolite, which can then be retained for extended periods in the intestine, leading to the onset of diarrhea and related symptoms. Banxia Xiexin Decoction (BXD) is commonly employed for the treatment of gastroenteritis in traditional Chinese medicine (TCM), and in clinical settings, it is used to prevent diarrhea in patients undergoing CPT-11 treatment. To date, however, there have been no studies specifically examining which components of BXD can alleviate the gastrointestinal symptoms associated with CPT-11 administration. This study aimed to identify the main herbal components of BXD associated with protection against CPT-11-induced intestinal toxicity in a murine model system. SN-38 levels were measured by UPLC-ESI-MS/MS in samples collected from mice subjected to CPT-11-induced diarrhea that had been administered BXD or different components thereof. Pearson correlation and Grey relational analyses were then used to explore spectrum-effect relationships between reductions in intestinal SN-38 levels and specific chemical fingerprints in samples from mice administered particular combinations of BXD component herbs. We found that different herbal combinations were associated with significant differences in intestinal SN-38 reductions in treated mice. Our spectrum-effect analysis revealed that BXD components including chrysin 6-C-arabinoside-8-C-glucoside, coptisine, hydroxyl oroxylin A 7-O-glucuronide (hydroxyl wogonoside), baicalin, an isomer of 5,6,7-trihydroxyl-flavanone-7-O-glucuronide, berberine, palmatine, and chrysin-7-O-glucuronide were all directly linked with reductions in intestinal SN-38 levels. We therefore speculate that these compounds are the primary bioactive components of BXD, suggesting that they offer protection against CPT-11-induced diarrhea. By utilizing UPLC to analyze SN-38 levels in mice treated with a variety of herbal combinations, we were able to effectively explore BXD spectrum-effect relationships and to thereby establish the components of this medicinal preparation that were bioactive and capable of preventing CPT-11-induced diarrhea in mice. This and similar spectrum-effect studies represent a robust means of exploring the mechanistic basis for the pharmacological activity of TCM preparations. [Display omitted]</description><subject>Animals</subject><subject>Banxia xiexin decoction (BXD)</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Diarrhea - chemically induced</subject><subject>Diarrhea - prevention &amp; control</subject><subject>Drugs, Chinese Herbal - chemistry</subject><subject>Drugs, Chinese Herbal - pharmacology</subject><subject>Female</subject><subject>Intestinal Diseases - chemically induced</subject><subject>Intestinal Diseases - prevention &amp; control</subject><subject>Intestinal toxicity</subject><subject>Irinotecan (CPT-11)</subject><subject>Irinotecan - toxicity</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>SN-38</subject><subject>Spectrum-effect relationship</subject><subject>Tandem Mass Spectrometry</subject><subject>Topoisomerase I Inhibitors - toxicity</subject><issn>0378-8741</issn><issn>1872-7573</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kMuOEzEQRS0EYsLAB7BB_gEHPzrtHrGCDI-RIjGLGYmdVe2uJhUldst2ouS3-EKcCbBkVbLqnqvyYeytknMlVft-M9_gNNdS17cyjVbP2Ex1Vgu7sOY5m0ljO9HZRl2xVzlvpJRWNfIluzJGam2MnbFfdwOGQiN5KBQDjyMva-Q9RfCFDsh93E0x1Ew-7z5BOBLwH4RHCvwWffRPWFlD4VOKBX3h8BMo5MKX9w9CKUFh2HscOIWCuVCALS_xSJ7KiR9q2eP9ail6yDWSp8qn_U7gOJ6bEm6fzsprmjhU8pQxv2YvRthmfPNnXrPHL58flt_E6vvXu-XHlfBmYYrQ0PtOKdu0CwudbG681G3bWfTypmuM8V4NjQVvfDXRgwYLLRij-sqAGUdzzdSl16eYc8LRTYl2kE5OSXf27zau-ndn_-7ivzLvLsy073c4_CP-Cq-BD5cA1ssPhMllTxiqH0r1x26I9J_63wEcmWI</recordid><startdate>20210210</startdate><enddate>20210210</enddate><creator>Shi, Jia-Wen</creator><creator>Li, Zhuang-Zhuang</creator><creator>Wu, Jia-Shuo</creator><creator>Jin, Wei-Yi</creator><creator>Chang, Xiao-Yan</creator><creator>Sun, Hong</creator><creator>Dong, Li</creator><creator>Jiang, Zhi-Ping</creator><creator>Shi, Yue</creator><general>Elsevier 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></search><sort><creationdate>20210210</creationdate><title>Identification of the bioactive components of Banxia Xiexin Decoction that protect against CPT-11-induced intestinal toxicity via UPLC-based spectrum-effect relationship analyses</title><author>Shi, Jia-Wen ; Li, Zhuang-Zhuang ; Wu, Jia-Shuo ; Jin, Wei-Yi ; Chang, Xiao-Yan ; Sun, Hong ; Dong, Li ; Jiang, Zhi-Ping ; Shi, Yue</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-2abc81174657a8049c026687ec098433cc1d47ac3c233ba2a7a6a331b117a3ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Banxia xiexin decoction (BXD)</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Diarrhea - chemically induced</topic><topic>Diarrhea - prevention &amp; control</topic><topic>Drugs, Chinese Herbal - chemistry</topic><topic>Drugs, Chinese Herbal - pharmacology</topic><topic>Female</topic><topic>Intestinal Diseases - chemically induced</topic><topic>Intestinal Diseases - prevention &amp; control</topic><topic>Intestinal toxicity</topic><topic>Irinotecan (CPT-11)</topic><topic>Irinotecan - toxicity</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>SN-38</topic><topic>Spectrum-effect relationship</topic><topic>Tandem Mass Spectrometry</topic><topic>Topoisomerase I Inhibitors - toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shi, Jia-Wen</creatorcontrib><creatorcontrib>Li, Zhuang-Zhuang</creatorcontrib><creatorcontrib>Wu, Jia-Shuo</creatorcontrib><creatorcontrib>Jin, Wei-Yi</creatorcontrib><creatorcontrib>Chang, Xiao-Yan</creatorcontrib><creatorcontrib>Sun, Hong</creatorcontrib><creatorcontrib>Dong, Li</creatorcontrib><creatorcontrib>Jiang, Zhi-Ping</creatorcontrib><creatorcontrib>Shi, Yue</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of ethnopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shi, Jia-Wen</au><au>Li, Zhuang-Zhuang</au><au>Wu, Jia-Shuo</au><au>Jin, Wei-Yi</au><au>Chang, Xiao-Yan</au><au>Sun, Hong</au><au>Dong, Li</au><au>Jiang, Zhi-Ping</au><au>Shi, Yue</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of the bioactive components of Banxia Xiexin Decoction that protect against CPT-11-induced intestinal toxicity via UPLC-based spectrum-effect relationship analyses</atitle><jtitle>Journal of ethnopharmacology</jtitle><addtitle>J Ethnopharmacol</addtitle><date>2021-02-10</date><risdate>2021</risdate><volume>266</volume><spage>113421</spage><pages>113421-</pages><artnum>113421</artnum><issn>0378-8741</issn><eissn>1872-7573</eissn><abstract>Irinotecan (CPT-11) is a valuable chemotherapeutic compound, but its use is associated with severe diarrhea in some patients. The CPT-11 prodrug is converted into the active 7-ethyl-10-hydroxycamptothecin (SN-38) metabolite, which can then be retained for extended periods in the intestine, leading to the onset of diarrhea and related symptoms. Banxia Xiexin Decoction (BXD) is commonly employed for the treatment of gastroenteritis in traditional Chinese medicine (TCM), and in clinical settings, it is used to prevent diarrhea in patients undergoing CPT-11 treatment. To date, however, there have been no studies specifically examining which components of BXD can alleviate the gastrointestinal symptoms associated with CPT-11 administration. This study aimed to identify the main herbal components of BXD associated with protection against CPT-11-induced intestinal toxicity in a murine model system. SN-38 levels were measured by UPLC-ESI-MS/MS in samples collected from mice subjected to CPT-11-induced diarrhea that had been administered BXD or different components thereof. Pearson correlation and Grey relational analyses were then used to explore spectrum-effect relationships between reductions in intestinal SN-38 levels and specific chemical fingerprints in samples from mice administered particular combinations of BXD component herbs. We found that different herbal combinations were associated with significant differences in intestinal SN-38 reductions in treated mice. Our spectrum-effect analysis revealed that BXD components including chrysin 6-C-arabinoside-8-C-glucoside, coptisine, hydroxyl oroxylin A 7-O-glucuronide (hydroxyl wogonoside), baicalin, an isomer of 5,6,7-trihydroxyl-flavanone-7-O-glucuronide, berberine, palmatine, and chrysin-7-O-glucuronide were all directly linked with reductions in intestinal SN-38 levels. We therefore speculate that these compounds are the primary bioactive components of BXD, suggesting that they offer protection against CPT-11-induced diarrhea. By utilizing UPLC to analyze SN-38 levels in mice treated with a variety of herbal combinations, we were able to effectively explore BXD spectrum-effect relationships and to thereby establish the components of this medicinal preparation that were bioactive and capable of preventing CPT-11-induced diarrhea in mice. This and similar spectrum-effect studies represent a robust means of exploring the mechanistic basis for the pharmacological activity of TCM preparations. [Display omitted]</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>33022337</pmid><doi>10.1016/j.jep.2020.113421</doi></addata></record>
fulltext fulltext
identifier ISSN: 0378-8741
ispartof Journal of ethnopharmacology, 2021-02, Vol.266, p.113421, Article 113421
issn 0378-8741
1872-7573
language eng
recordid cdi_crossref_primary_10_1016_j_jep_2020_113421
source ScienceDirect Journals
subjects Animals
Banxia xiexin decoction (BXD)
Chromatography, High Pressure Liquid
Diarrhea - chemically induced
Diarrhea - prevention & control
Drugs, Chinese Herbal - chemistry
Drugs, Chinese Herbal - pharmacology
Female
Intestinal Diseases - chemically induced
Intestinal Diseases - prevention & control
Intestinal toxicity
Irinotecan (CPT-11)
Irinotecan - toxicity
Mice
Mice, Inbred ICR
SN-38
Spectrum-effect relationship
Tandem Mass Spectrometry
Topoisomerase I Inhibitors - toxicity
title Identification of the bioactive components of Banxia Xiexin Decoction that protect against CPT-11-induced intestinal toxicity via UPLC-based spectrum-effect relationship analyses
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T08%3A25%3A18IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%20the%20bioactive%20components%20of%20Banxia%20Xiexin%20Decoction%20that%20protect%20against%20CPT-11-induced%20intestinal%20toxicity%20via%20UPLC-based%20spectrum-effect%20relationship%20analyses&rft.jtitle=Journal%20of%20ethnopharmacology&rft.au=Shi,%20Jia-Wen&rft.date=2021-02-10&rft.volume=266&rft.spage=113421&rft.pages=113421-&rft.artnum=113421&rft.issn=0378-8741&rft.eissn=1872-7573&rft_id=info:doi/10.1016/j.jep.2020.113421&rft_dat=%3Cpubmed_cross%3E33022337%3C/pubmed_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c353t-2abc81174657a8049c026687ec098433cc1d47ac3c233ba2a7a6a331b117a3ff3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_id=info:pmid/33022337&rfr_iscdi=true