{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T02:33:55Z","timestamp":1787970835287,"version":"build-2784847793"},"reference-count":52,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,2,20]],"date-time":"2022-02-20T00:00:00Z","timestamp":1645315200000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072948"],"award-info":[{"award-number":["82072948"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81772558"],"award-info":[{"award-number":["81772558"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82003169"],"award-info":[{"award-number":["82003169"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82002475"],"award-info":[{"award-number":["82002475"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Anaplastic thyroid carcinoma (ATC) is one of the most aggressive tumours. We previously confirmed that apatinib has potential therapeutic effects on ATC via regulated cell death (RCD). As a newly identified RCD, pyroptosis demonstrates direct antitumour activity different from apoptosis or autophagy. Therefore, the clinical significance, regulatory role and underlying mechanisms of pyroptosis in ATC were focused on in this study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a phase II trial, patients with anaplastic or poorly differentiated thyroid carcinoma received apatinib 500\u00a0mg once daily. Multiple assays were implemented to evaluate the antitumour efficacy of apatinib and\/or melittin in vitro and in vivo. High\u2010throughput sequencing was applied to analyse differential mRNAs expression in ATC cells treated by apatinib with or without melittin. In situ Hoechst 33342\/PI double\u2010staining, LDH release assay and enzyme\u2010linked immunosorbent assay (ELISA) were employed to determine pyroptosis. In mechanism exploration, quantitative RT\u2010PCR, Western blotting and si\u2010RNA knocking down were executed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Seventeen patients were evaluable. Apatinib showed a promising therapeutic effect by a disease control rate (DCR) of 88.2%; however, treatment was terminated in 23.5% of patients due to intolerable toxicity. To reduce adverse events, a pyroptosis\u2010mediated synergistic antitumour effect of apatinib and melittin was identified in treatment of ATC in vitro and in vivo. The caspase\u20101\u2013gasdermin D (GSDMD) axis\u2010mediated pyroptosis was the key to extra antitumour effect of the combination of apatinib and melittin. Moreover, caspase\u20103\u2013gasdermin E (GSDME) pyroptosis pathway also functioned importantly in addition to caspase\u20101\u2013GSDMD pathway. Evidenced by in vitro and in vivo study, a two\u2010way positive feedback interaction was innovatively confirmed between caspase\u20101\u2013GSDMD and caspase\u20103\u2013GSDME axes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Through pyroptosis mediated by caspase\u20101\u2013GSDMD and caspase\u20103\u2013GSDME axes synchronically, low\u2010dosage apatinib and melittin could synergistically achieve a comparable therapeutic potential with reduced AEs. More importantly, a two\u2010way positive feedback interaction is innovatively proposed between these two axes, which provide a new prospect of targeted therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.727","type":"journal-article","created":{"date-parts":[[2022,2,20]],"date-time":"2022-02-20T14:27:30Z","timestamp":1645367250000},"source":"Crossref","is-referenced-by-count":47,"title":["The central role of a two\u2010way positive feedback pathway in molecular targeted therapies\u2010mediated pyroptosis in anaplastic thyroid cancer"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7650-5943","authenticated-orcid":false,"given":"Qiwu","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of General Surgery Ruijin Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 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