{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:01:09Z","timestamp":1790762469820,"version":"4.1.0"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"19","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2023,10,3]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Anthracycline\u2010induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood\u2010based mRNA expression profiles in anthracycline\u2010exposed childhood cancer survivors with and without cardiomyopathy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              We designed a matched case\u2010control study (Children's Oncology Group\u2010ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline\u2010exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human\u2010induced pluripotent stem cell\u2010derived cardiomyocytes using CRISPR\/Cas9 (clustered regularly interspaced short palindromic repeats\/CRISPR\u2010associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7\u2009years, respectively. Thirty\u2010six differentially expressed genes with fold change \u2265\u00b12 were identified; 35 were upregulated. IPA identified \u201chepatic fibrosis\u201d and \u201ciron homeostasis\u201d pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (\n              <jats:italic>LDHA<\/jats:italic>\n              ) and cluster of differentiation 36 (\n              <jats:italic>CD36<\/jats:italic>\n              ) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (\n              <jats:italic>IL1R1<\/jats:italic>\n              ,\n              <jats:italic>IL1R2<\/jats:italic>\n              ), and matrix metalloproteinase 8, 9 (\n              <jats:italic>MMP8, MMP9<\/jats:italic>\n              ) appeared in multiple canonical pathways.\n              <jats:italic>LDHA<\/jats:italic>\n              \u2010knockout human\u2010induced pluripotent stem cell\u2010derived cardiomyocytes showed increased sensitivity to doxorubicin.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              We identified differential mRNA expression profiles in peripheral blood of anthracycline\u2010exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of\n              <jats:italic>LDHA<\/jats:italic>\n              and\n              <jats:italic>CD36<\/jats:italic>\n              genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors\n              <jats:italic>IL1R1<\/jats:italic>\n              and\n              <jats:italic>IL1R2<\/jats:italic>\n              and matrix metalloproteinases,\n              <jats:italic>MMP8<\/jats:italic>\n              and\n              <jats:italic>MMP9<\/jats:italic>\n              indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.123.029954","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T12:00:46Z","timestamp":1695729646000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline\u2010Induced Cardiomyopathy \u2013 A COG\u2010ALTE03N1 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