{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T15:22:58Z","timestamp":1787844178763,"version":"build-2784847793"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T00:00:00Z","timestamp":1652918400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007321","name":"Finding A Cure for Epilepsy and Seizures","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01AG060882"],"award-info":[{"award-number":["P01AG060882"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004336","name":"Novartis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004336","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Tuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mTOR signaling, resulting in increased cell growth and ribosomal S6 protein phosphorylation (phospho-S6). mTOR inhibitors can reduce TSC tumor growth and seizure frequency, and preclinical FCD studies indicate seizure suppression. This pilot study evaluated safety of mTOR inhibitor everolimus in treatment resistant (failure of &gt;2 anti-seizure medications) TSC and FCD patients undergoing surgical resection and to assess mTOR signaling and molecular pathways.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>We evaluated everolimus in 14 treatment resistant epilepsy patients undergoing surgical resection (4.5 mg\/m<jats:sup>2<\/jats:sup> daily for 7 days; n = 4 Active, mean age 18.3 years, range 4\u201326; n = 10, Control, mean age 13.1, range 3\u201345). Everolimus was well tolerated. Mean plasma everolimus in Active participants were in target range (12.4 ng\/ml). Brain phospho-S6 was similar in Active and Control participants with a lower trend in Active participants, with Ser235\/236 1.19-fold (p = 0.67) and Ser240\/244 1.15-fold lower (p = 0.66). Histologically, Ser235\/236 was 1.56-fold (p = 0.37) and Ser240\/244 was 5.55-fold lower (p = 0.22). Brain proteomics identified 11 proteins at &lt;15% false discovery rate associated with coagulation system (p = 1.45x10<jats:sup>-9<\/jats:sup>) and acute phase response (p = 1.23x10<jats:sup>-6<\/jats:sup>) activation. A weighted gene correlation network analysis (WGCNA) of brain proteomics and phospho-S6 identified 5 significant modules. Higher phospho-S6 correlated negatively with cellular respiration and synaptic transmission and positively with organophosphate metabolic process, nuclear mRNA catabolic process, and neuron ensheathment. Brain metabolomics identified 14 increased features in Active participants, including N-acetylaspartylglutamic acid. Plasma proteomics and cytokine analyses revealed no differences.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Short-term everolimus before epilepsy surgery in TSC and FCD resulted in no adverse events and trending lower mTOR signaling (phospho-S6). Future studies should evaluate implications of our findings, including coagulation system activation and everolimus efficacy in FCD, in larger studies with long-term treatment to better understand molecular and clinical effects.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Clinical trials registration<\/jats:title>\n<jats:p>ClinicalTrials.gov <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02451696\" xlink:type=\"simple\">NCT02451696<\/jats:ext-link>.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0268597","type":"journal-article","created":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T17:49:59Z","timestamp":1652982599000},"page":"e0268597","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":23,"title":["Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and 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