A chimeric human/dog-DNA vaccine against CSPG4 induces immunity with therapeutic potential in comparative preclinical models of osteosarcoma
The high mortality rate of osteosarcoma (OSA) patients highlights the requirement of alternative strategies. The young age of patients, as well as the rarity and aggressiveness of the disease, limits opportunities for the robust testing of novel therapies, suggesting the need for valuable preclinica...
Gespeichert in:
Veröffentlicht in: | Molecular therapy 2023-08, Vol.31 (8), p.2342-2359 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 2359 |
---|---|
container_issue | 8 |
container_start_page | 2342 |
container_title | Molecular therapy |
container_volume | 31 |
creator | Tarone, Lidia Giacobino, Davide Camerino, Mariateresa Maniscalco, Lorella Iussich, Selina Parisi, Lorenza Giovannini, Giuseppe Dentini, Alfredo Bolli, Elisabetta Quaglino, Elena Merighi, Irene Fiore Morello, Emanuela Buracco, Paolo Riccardo, Federica Cavallo, Federica |
description | The high mortality rate of osteosarcoma (OSA) patients highlights the requirement of alternative strategies. The young age of patients, as well as the rarity and aggressiveness of the disease, limits opportunities for the robust testing of novel therapies, suggesting the need for valuable preclinical systems. Having previously shown the overexpression of the chondroitin sulfate proteoglycan (CSPG)4 in OSA, herein the functional consequences of its downmodulation in human OSA cells were evaluated in vitro, with a significant impairment of cell proliferation, migration, and osteosphere generation. The potential of a chimeric human/dog (HuDo)-CSPG4 DNA vaccine was explored in translational comparative OSA models, including human xenograft mouse models and canine patients affected by spontaneous OSA. The adoptive transfer of HuDo-CSPG4 vaccine-induced CD8+ T cells and sera in immunodeficient human OSA-bearing mice delayed tumor growth and metastasis development. HuDo-CSPG4 vaccination resulted safe and effective in inducing anti-CSPG4 immunity in OSA-affected dogs, which displayed prolonged survival as compared to controls. Finally, HuDo-CSPG4 was also able to induce a cytotoxic response in a human surrogate setting in vitro. On the basis of these results and the high predictive value of spontaneous OSA in dogs, this study paves the way for a possible translation of this approach to humans.
[Display omitted]
Cavallo, Riccardo, et al. exploited human preclinical models and canine patients with spontaneous osteosarcoma to demonstrate that anti-CSPG4 vaccination using a chimeric human/dog plasmid is safe and immunogenic, being able to counteract tumor progression. These results suggest a possible evaluation of this treatment in the human clinical setting. |
doi_str_mv | 10.1016/j.ymthe.2023.06.004 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10421998</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1525001623003155</els_id><sourcerecordid>2825811848</sourcerecordid><originalsourceid>FETCH-LOGICAL-c415t-5362b82bdb6e17e92c4e4a8b53674d4b885352b5c661aeec6689ee7cbd2d7f643</originalsourceid><addsrcrecordid>eNp9kc-O0zAQxiMEYv_AEyAhH7kkazuOkxwQqgq7IK0ACThbjj1tXMV2sJ2ivgMPjUuXCi6cZjTzm29G8xXFC4Irggm_2VUHm0aoKKZ1hXmFMXtUXJKGNiXGlD0-54RfFFcx7nJGmp4_LS7qtiaUNeSy-LlCajQWglFoXKx0N9pvy7cfV2gvlTIOkNxK42JC6y-f7xgyTi8KIjLWLs6kA_ph0ojyGUHOsKSsMvsELhk5ZRYpb2cZZDJ7QHMANRlnVG5Zr2GKyG-Qjwl8lCGT8lnxZCOnCM8f4nXx7fbd1_X78v7T3Yf16r5UjDSpbGpOh44OeuBAWuipYsBkN-R6yzQbuq6pGzo0inMiAXLoeoBWDZrqdsNZfV28OenOy2BBq3xvkJOYg7EyHISXRvzbcWYUW78XBDNK-r7LCq8eFIL_vkBMwpqoYJqkA79EQTvadIR07IjWJ1QFH2OAzXkPweJopNiJ30aKo5ECc5GNzFMv_z7xPPPHuQy8PgH5j7A3EERUBpwCbfKfk9De_HfBL_XUtCY</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2825811848</pqid></control><display><type>article</type><title>A chimeric human/dog-DNA vaccine against CSPG4 induces immunity with therapeutic potential in comparative preclinical models of osteosarcoma</title><source>PubMed Central Free</source><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Tarone, Lidia ; Giacobino, Davide ; Camerino, Mariateresa ; Maniscalco, Lorella ; Iussich, Selina ; Parisi, Lorenza ; Giovannini, Giuseppe ; Dentini, Alfredo ; Bolli, Elisabetta ; Quaglino, Elena ; Merighi, Irene Fiore ; Morello, Emanuela ; Buracco, Paolo ; Riccardo, Federica ; Cavallo, Federica</creator><creatorcontrib>Tarone, Lidia ; Giacobino, Davide ; Camerino, Mariateresa ; Maniscalco, Lorella ; Iussich, Selina ; Parisi, Lorenza ; Giovannini, Giuseppe ; Dentini, Alfredo ; Bolli, Elisabetta ; Quaglino, Elena ; Merighi, Irene Fiore ; Morello, Emanuela ; Buracco, Paolo ; Riccardo, Federica ; Cavallo, Federica</creatorcontrib><description>The high mortality rate of osteosarcoma (OSA) patients highlights the requirement of alternative strategies. The young age of patients, as well as the rarity and aggressiveness of the disease, limits opportunities for the robust testing of novel therapies, suggesting the need for valuable preclinical systems. Having previously shown the overexpression of the chondroitin sulfate proteoglycan (CSPG)4 in OSA, herein the functional consequences of its downmodulation in human OSA cells were evaluated in vitro, with a significant impairment of cell proliferation, migration, and osteosphere generation. The potential of a chimeric human/dog (HuDo)-CSPG4 DNA vaccine was explored in translational comparative OSA models, including human xenograft mouse models and canine patients affected by spontaneous OSA. The adoptive transfer of HuDo-CSPG4 vaccine-induced CD8+ T cells and sera in immunodeficient human OSA-bearing mice delayed tumor growth and metastasis development. HuDo-CSPG4 vaccination resulted safe and effective in inducing anti-CSPG4 immunity in OSA-affected dogs, which displayed prolonged survival as compared to controls. Finally, HuDo-CSPG4 was also able to induce a cytotoxic response in a human surrogate setting in vitro. On the basis of these results and the high predictive value of spontaneous OSA in dogs, this study paves the way for a possible translation of this approach to humans.
[Display omitted]
Cavallo, Riccardo, et al. exploited human preclinical models and canine patients with spontaneous osteosarcoma to demonstrate that anti-CSPG4 vaccination using a chimeric human/dog plasmid is safe and immunogenic, being able to counteract tumor progression. These results suggest a possible evaluation of this treatment in the human clinical setting.</description><identifier>ISSN: 1525-0016</identifier><identifier>ISSN: 1525-0024</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1016/j.ymthe.2023.06.004</identifier><identifier>PMID: 37312451</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Bone Neoplasms - genetics ; Bone Neoplasms - therapy ; CD8-Positive T-Lymphocytes ; Chondroitin Sulfate Proteoglycans ; comparative oncology ; CSPG4 ; DNA vaccination ; Dogs ; Humans ; metastasis ; Mice ; Original ; osteosarcoma ; Osteosarcoma - genetics ; Osteosarcoma - therapy ; Sleep Apnea, Obstructive ; Vaccination ; Vaccines, DNA</subject><ispartof>Molecular therapy, 2023-08, Vol.31 (8), p.2342-2359</ispartof><rights>2023 The American Society of Gene and Cell Therapy</rights><rights>Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.</rights><rights>2023 The American Society of Gene and Cell Therapy. 2023 The American Society of Gene and Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-5362b82bdb6e17e92c4e4a8b53674d4b885352b5c661aeec6689ee7cbd2d7f643</citedby><cites>FETCH-LOGICAL-c415t-5362b82bdb6e17e92c4e4a8b53674d4b885352b5c661aeec6689ee7cbd2d7f643</cites><orcidid>0000-0003-4571-1060</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10421998/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10421998/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37312451$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tarone, Lidia</creatorcontrib><creatorcontrib>Giacobino, Davide</creatorcontrib><creatorcontrib>Camerino, Mariateresa</creatorcontrib><creatorcontrib>Maniscalco, Lorella</creatorcontrib><creatorcontrib>Iussich, Selina</creatorcontrib><creatorcontrib>Parisi, Lorenza</creatorcontrib><creatorcontrib>Giovannini, Giuseppe</creatorcontrib><creatorcontrib>Dentini, Alfredo</creatorcontrib><creatorcontrib>Bolli, Elisabetta</creatorcontrib><creatorcontrib>Quaglino, Elena</creatorcontrib><creatorcontrib>Merighi, Irene Fiore</creatorcontrib><creatorcontrib>Morello, Emanuela</creatorcontrib><creatorcontrib>Buracco, Paolo</creatorcontrib><creatorcontrib>Riccardo, Federica</creatorcontrib><creatorcontrib>Cavallo, Federica</creatorcontrib><title>A chimeric human/dog-DNA vaccine against CSPG4 induces immunity with therapeutic potential in comparative preclinical models of osteosarcoma</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>The high mortality rate of osteosarcoma (OSA) patients highlights the requirement of alternative strategies. The young age of patients, as well as the rarity and aggressiveness of the disease, limits opportunities for the robust testing of novel therapies, suggesting the need for valuable preclinical systems. Having previously shown the overexpression of the chondroitin sulfate proteoglycan (CSPG)4 in OSA, herein the functional consequences of its downmodulation in human OSA cells were evaluated in vitro, with a significant impairment of cell proliferation, migration, and osteosphere generation. The potential of a chimeric human/dog (HuDo)-CSPG4 DNA vaccine was explored in translational comparative OSA models, including human xenograft mouse models and canine patients affected by spontaneous OSA. The adoptive transfer of HuDo-CSPG4 vaccine-induced CD8+ T cells and sera in immunodeficient human OSA-bearing mice delayed tumor growth and metastasis development. HuDo-CSPG4 vaccination resulted safe and effective in inducing anti-CSPG4 immunity in OSA-affected dogs, which displayed prolonged survival as compared to controls. Finally, HuDo-CSPG4 was also able to induce a cytotoxic response in a human surrogate setting in vitro. On the basis of these results and the high predictive value of spontaneous OSA in dogs, this study paves the way for a possible translation of this approach to humans.
[Display omitted]
Cavallo, Riccardo, et al. exploited human preclinical models and canine patients with spontaneous osteosarcoma to demonstrate that anti-CSPG4 vaccination using a chimeric human/dog plasmid is safe and immunogenic, being able to counteract tumor progression. These results suggest a possible evaluation of this treatment in the human clinical setting.</description><subject>Animals</subject><subject>Bone Neoplasms - genetics</subject><subject>Bone Neoplasms - therapy</subject><subject>CD8-Positive T-Lymphocytes</subject><subject>Chondroitin Sulfate Proteoglycans</subject><subject>comparative oncology</subject><subject>CSPG4</subject><subject>DNA vaccination</subject><subject>Dogs</subject><subject>Humans</subject><subject>metastasis</subject><subject>Mice</subject><subject>Original</subject><subject>osteosarcoma</subject><subject>Osteosarcoma - genetics</subject><subject>Osteosarcoma - therapy</subject><subject>Sleep Apnea, Obstructive</subject><subject>Vaccination</subject><subject>Vaccines, DNA</subject><issn>1525-0016</issn><issn>1525-0024</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc-O0zAQxiMEYv_AEyAhH7kkazuOkxwQqgq7IK0ACThbjj1tXMV2sJ2ivgMPjUuXCi6cZjTzm29G8xXFC4Irggm_2VUHm0aoKKZ1hXmFMXtUXJKGNiXGlD0-54RfFFcx7nJGmp4_LS7qtiaUNeSy-LlCajQWglFoXKx0N9pvy7cfV2gvlTIOkNxK42JC6y-f7xgyTi8KIjLWLs6kA_ph0ojyGUHOsKSsMvsELhk5ZRYpb2cZZDJ7QHMANRlnVG5Zr2GKyG-Qjwl8lCGT8lnxZCOnCM8f4nXx7fbd1_X78v7T3Yf16r5UjDSpbGpOh44OeuBAWuipYsBkN-R6yzQbuq6pGzo0inMiAXLoeoBWDZrqdsNZfV28OenOy2BBq3xvkJOYg7EyHISXRvzbcWYUW78XBDNK-r7LCq8eFIL_vkBMwpqoYJqkA79EQTvadIR07IjWJ1QFH2OAzXkPweJopNiJ30aKo5ECc5GNzFMv_z7xPPPHuQy8PgH5j7A3EERUBpwCbfKfk9De_HfBL_XUtCY</recordid><startdate>20230802</startdate><enddate>20230802</enddate><creator>Tarone, Lidia</creator><creator>Giacobino, Davide</creator><creator>Camerino, Mariateresa</creator><creator>Maniscalco, Lorella</creator><creator>Iussich, Selina</creator><creator>Parisi, Lorenza</creator><creator>Giovannini, Giuseppe</creator><creator>Dentini, Alfredo</creator><creator>Bolli, Elisabetta</creator><creator>Quaglino, Elena</creator><creator>Merighi, Irene Fiore</creator><creator>Morello, Emanuela</creator><creator>Buracco, Paolo</creator><creator>Riccardo, Federica</creator><creator>Cavallo, Federica</creator><general>Elsevier Inc</general><general>American Society of Gene & Cell Therapy</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4571-1060</orcidid></search><sort><creationdate>20230802</creationdate><title>A chimeric human/dog-DNA vaccine against CSPG4 induces immunity with therapeutic potential in comparative preclinical models of osteosarcoma</title><author>Tarone, Lidia ; Giacobino, Davide ; Camerino, Mariateresa ; Maniscalco, Lorella ; Iussich, Selina ; Parisi, Lorenza ; Giovannini, Giuseppe ; Dentini, Alfredo ; Bolli, Elisabetta ; Quaglino, Elena ; Merighi, Irene Fiore ; Morello, Emanuela ; Buracco, Paolo ; Riccardo, Federica ; Cavallo, Federica</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-5362b82bdb6e17e92c4e4a8b53674d4b885352b5c661aeec6689ee7cbd2d7f643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Bone Neoplasms - genetics</topic><topic>Bone Neoplasms - therapy</topic><topic>CD8-Positive T-Lymphocytes</topic><topic>Chondroitin Sulfate Proteoglycans</topic><topic>comparative oncology</topic><topic>CSPG4</topic><topic>DNA vaccination</topic><topic>Dogs</topic><topic>Humans</topic><topic>metastasis</topic><topic>Mice</topic><topic>Original</topic><topic>osteosarcoma</topic><topic>Osteosarcoma - genetics</topic><topic>Osteosarcoma - therapy</topic><topic>Sleep Apnea, Obstructive</topic><topic>Vaccination</topic><topic>Vaccines, DNA</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tarone, Lidia</creatorcontrib><creatorcontrib>Giacobino, Davide</creatorcontrib><creatorcontrib>Camerino, Mariateresa</creatorcontrib><creatorcontrib>Maniscalco, Lorella</creatorcontrib><creatorcontrib>Iussich, Selina</creatorcontrib><creatorcontrib>Parisi, Lorenza</creatorcontrib><creatorcontrib>Giovannini, Giuseppe</creatorcontrib><creatorcontrib>Dentini, Alfredo</creatorcontrib><creatorcontrib>Bolli, Elisabetta</creatorcontrib><creatorcontrib>Quaglino, Elena</creatorcontrib><creatorcontrib>Merighi, Irene Fiore</creatorcontrib><creatorcontrib>Morello, Emanuela</creatorcontrib><creatorcontrib>Buracco, Paolo</creatorcontrib><creatorcontrib>Riccardo, Federica</creatorcontrib><creatorcontrib>Cavallo, Federica</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tarone, Lidia</au><au>Giacobino, Davide</au><au>Camerino, Mariateresa</au><au>Maniscalco, Lorella</au><au>Iussich, Selina</au><au>Parisi, Lorenza</au><au>Giovannini, Giuseppe</au><au>Dentini, Alfredo</au><au>Bolli, Elisabetta</au><au>Quaglino, Elena</au><au>Merighi, Irene Fiore</au><au>Morello, Emanuela</au><au>Buracco, Paolo</au><au>Riccardo, Federica</au><au>Cavallo, Federica</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A chimeric human/dog-DNA vaccine against CSPG4 induces immunity with therapeutic potential in comparative preclinical models of osteosarcoma</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2023-08-02</date><risdate>2023</risdate><volume>31</volume><issue>8</issue><spage>2342</spage><epage>2359</epage><pages>2342-2359</pages><issn>1525-0016</issn><issn>1525-0024</issn><eissn>1525-0024</eissn><abstract>The high mortality rate of osteosarcoma (OSA) patients highlights the requirement of alternative strategies. The young age of patients, as well as the rarity and aggressiveness of the disease, limits opportunities for the robust testing of novel therapies, suggesting the need for valuable preclinical systems. Having previously shown the overexpression of the chondroitin sulfate proteoglycan (CSPG)4 in OSA, herein the functional consequences of its downmodulation in human OSA cells were evaluated in vitro, with a significant impairment of cell proliferation, migration, and osteosphere generation. The potential of a chimeric human/dog (HuDo)-CSPG4 DNA vaccine was explored in translational comparative OSA models, including human xenograft mouse models and canine patients affected by spontaneous OSA. The adoptive transfer of HuDo-CSPG4 vaccine-induced CD8+ T cells and sera in immunodeficient human OSA-bearing mice delayed tumor growth and metastasis development. HuDo-CSPG4 vaccination resulted safe and effective in inducing anti-CSPG4 immunity in OSA-affected dogs, which displayed prolonged survival as compared to controls. Finally, HuDo-CSPG4 was also able to induce a cytotoxic response in a human surrogate setting in vitro. On the basis of these results and the high predictive value of spontaneous OSA in dogs, this study paves the way for a possible translation of this approach to humans.
[Display omitted]
Cavallo, Riccardo, et al. exploited human preclinical models and canine patients with spontaneous osteosarcoma to demonstrate that anti-CSPG4 vaccination using a chimeric human/dog plasmid is safe and immunogenic, being able to counteract tumor progression. These results suggest a possible evaluation of this treatment in the human clinical setting.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>37312451</pmid><doi>10.1016/j.ymthe.2023.06.004</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0003-4571-1060</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1525-0016 |
ispartof | Molecular therapy, 2023-08, Vol.31 (8), p.2342-2359 |
issn | 1525-0016 1525-0024 1525-0024 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10421998 |
source | PubMed Central Free; MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
subjects | Animals Bone Neoplasms - genetics Bone Neoplasms - therapy CD8-Positive T-Lymphocytes Chondroitin Sulfate Proteoglycans comparative oncology CSPG4 DNA vaccination Dogs Humans metastasis Mice Original osteosarcoma Osteosarcoma - genetics Osteosarcoma - therapy Sleep Apnea, Obstructive Vaccination Vaccines, DNA |
title | A chimeric human/dog-DNA vaccine against CSPG4 induces immunity with therapeutic potential in comparative preclinical models of osteosarcoma |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T22%3A44%3A23IST&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=A%20chimeric%20human/dog-DNA%20vaccine%20against%20CSPG4%20induces%20immunity%20with%20therapeutic%20potential%20in%20comparative%20preclinical%20models%20of%20osteosarcoma&rft.jtitle=Molecular%20therapy&rft.au=Tarone,%20Lidia&rft.date=2023-08-02&rft.volume=31&rft.issue=8&rft.spage=2342&rft.epage=2359&rft.pages=2342-2359&rft.issn=1525-0016&rft.eissn=1525-0024&rft_id=info:doi/10.1016/j.ymthe.2023.06.004&rft_dat=%3Cproquest_pubme%3E2825811848%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=2825811848&rft_id=info:pmid/37312451&rft_els_id=S1525001623003155&rfr_iscdi=true |