{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:38:24Z","timestamp":1791041904036,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministry of Education, Universities and Research","doi-asserted-by":"publisher","award":["D15D18000410001"],"award-info":[{"award-number":["D15D18000410001"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The RAF1:p.Ser257Leu variant is associated with severe Noonan syndrome (NS), progressive hypertrophic cardiomyopathy (HCM), and pulmonary hypertension. Trametinib, a MEK-inhibitor approved for treatment of RAS\/MAPK-mutated cancers, is an emerging treatment option for HCM in NS. We report a patient with NS and HCM, treated with Trametinib and documented by global RNA sequencing before and during treatment to define transcriptional effects of MEK-inhibition. A preterm infant with HCM carrying the RAF1:p.Ser257Leu variant, rapidly developed severe congestive heart failure (CHF) unresponsive to standard treatments. Trametinib was introduced (0.022 mg\/kg\/day) with prompt clinical improvement and subsequent amelioration of HCM at ultrasound. The appearance of pulmonary artery aneurysm and pulmonary hypertension contributed to a rapid worsening after ventriculoperitoneal shunt device placement for posthemorrhagic hydrocephalus: she deceased for untreatable CHF at 3 months of age. Autopsy showed severe obstructive HCM, pulmonary artery dilation, disarrayed pulmonary vascular anatomy consistent with pulmonary capillary hemangiomatosis. Transcriptome across treatment, highlighted robust transcriptional changes induced by MEK-inhibition. Our findings highlight a previously unappreciated connection between pulmonary vascular disease and the severe outcome already reported in patients with RAF1-associated NS. While MEK-inhibition appears a promising therapeutic option for HCM in RASopathies, it appears insufficient to revert pulmonary hypertension.<\/jats:p>","DOI":"10.3390\/genes13010006","type":"journal-article","created":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T01:08:09Z","timestamp":1640135289000},"page":"6","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease"],"prefix":"10.3390","volume":"13","author":[{"given":"Alessandro","family":"Mussa","sequence":"first","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Torino, 10126 Torino, Italy"},{"name":"Clinical Pediatric Genetics Unit, Regina Margherita Children\u2019s Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5690-6504","authenticated-orcid":false,"given":"Diana","family":"Carli","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Torino, 10126 Torino, Italy"},{"name":"Pediatric Onco-Hematology, Stem Cell Transplantation and Cell Therapy Division, Regina Margherita Children\u2019s Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Giorgio","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"},{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Villar","sequence":"additional","affiliation":[{"name":"Pediatric Cardiology Unit, Regina Margherita Children\u2019s Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Cardaropoli","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Carbonara","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Sant\u2019Anna Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Francesca","family":"Campagnoli","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Sant\u2019Anna Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Galletto","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Sant\u2019Anna Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1548-0890","authenticated-orcid":false,"given":"Martina","family":"Palumbo","sequence":"additional","affiliation":[{"name":"Laboratory of Oncogenomics, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6879-5909","authenticated-orcid":false,"given":"Simone","family":"Olivieri","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatric Sciences, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Isella","sequence":"additional","affiliation":[{"name":"Laboratory of Oncogenomics, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"},{"name":"Department of Oncology, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Andelfinger","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics, Department of Pediatrics, CHU Sainte Justine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Botta","sequence":"additional","affiliation":[{"name":"Department of Pathology, Sant\u2019Anna Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8318-7231","authenticated-orcid":false,"given":"Alfredo","family":"Brusco","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Torino, 10126 Torino, Italy"},{"name":"Unit of Medical Genetics, Citt\u00e0 Della Salute e Della Scienza di Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enzo","family":"Medico","sequence":"additional","affiliation":[{"name":"Laboratory of Oncogenomics, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"},{"name":"Department of Oncology, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Battista","family":"Ferrero","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0140-6736(12)61023-X","article-title":"Noonan syndrome","volume":"381","author":"Roberts","year":"2013","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1159\/000276766","article-title":"Noonan syndrome: Clinical aspects and molecular pathogenesis","volume":"1","author":"Tartaglia","year":"2010","journal-title":"Mol. Syndromol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1086\/340847","article-title":"PTPN11 mutations in Noonan syndrome: Molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity","volume":"70","author":"Tartaglia","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1038\/ng2073","article-title":"Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy","volume":"39","author":"Pandit","year":"2007","journal-title":"Nat Genet."},{"key":"ref_5","first-page":"1046","article-title":"Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy","volume":"40","author":"Motta","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ajhg.2013.05.021","article-title":"Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS\/MAPK pathway syndrome","volume":"93","author":"Aoki","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ppedcard.2015.01.002","article-title":"Cardiomyopathies in Noonan syndrome and the other RASopathies","volume":"39","author":"Gelb","year":"2015","journal-title":"Prog. Pediatr. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.hfc.2017.12.005","article-title":"Clinical Presentation and Natural History of Hypertrophic Cardiomyopathy in RASopathies","volume":"14","author":"Calcagni","year":"2018","journal-title":"Heart Fail Clin."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e6","DOI":"10.1017\/S0016672319000041","article-title":"A severe clinical phenotype of Noonan syndrome with neonatal hypertrophic cardiomyopathy in the second case worldwide with RAF1 S259Y neomutation","volume":"101","author":"Jaouadi","year":"2019","journal-title":"Genet. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.ijcard.2017.07.068","article-title":"Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results","volume":"245","author":"Calcagni","year":"2017","journal-title":"Int. J. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1172\/JCI44929","article-title":"MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation","volume":"121","author":"Wu","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.jacc.2019.01.066","article-title":"Hypertrophic Cardiomyopathy in Noonan Syndrome Treated by MEK-Inhibition","volume":"73","author":"Andelfinger","year":"2019","journal-title":"J. Am. Coll Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"EdgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular signatures database (MSigDB) 3.0","volume":"27","author":"Liberzon","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s00412-018-0659-8","article-title":"Ki-67: More than a proliferation marker","volume":"127","author":"Sun","year":"2018","journal-title":"Chromosoma"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1002\/humu.22026","article-title":"Transcriptional hallmarks of noonan syndrome and noonan-like syndrome with loose anagen hair","volume":"33","author":"Ferrero","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/nrg.2016.86","article-title":"Towards precision medicine","volume":"17","author":"Ashley","year":"2016","journal-title":"Nat Rev. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.yjmcc.2011.03.001","article-title":"Cyclosporine attenuates cardiomyocyte hypertrophy induced by RAF1 mutants in Noonan and LEOPARD syndromes","volume":"51","author":"Dhandapany","year":"2011","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Savoia, P., Fava, P., Casoni, F., and Cremona, O. (2019). Targeting the ERK Signaling Pathway in Melanoma. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061483"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1002\/ajmg.a.37024","article-title":"Neonatal pulmonary arterial hypertension and Noonan syndrome: Two fatal cases with a specificRAF1mutation","volume":"167","author":"Hopper","year":"2015","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1097\/MCD.0000000000000194","article-title":"RAF1 variants causing biventricular hypertrophic cardiomyopathy in two preterm infants: Further phenotypic delineation and review of literature","volume":"26","author":"Thompson","year":"2017","journal-title":"Clin. Dysmorphol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/ng2078","article-title":"Germline gain-of-function mutations in RAF1 cause Noonan syndrome","volume":"39","author":"Razzaque","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.recesp.2012.09.017","article-title":"LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated with Hypertrophic Cardiomyopathy","volume":"66","author":"Carcavilla","year":"2013","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"NP13","DOI":"10.1177\/0883073813492384","article-title":"Unique Cerebrovascular Anomalies in Noonan Syndrome With RAF1 Mutation","volume":"29","author":"Zarate","year":"2013","journal-title":"J. Child Neurol."},{"key":"ref_28","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Mirzaa, G.M., and Amemiya, A. (1993\u20132021). Noonan Syndrome with Multiple Lentigines. 30 November 2007 [updated 14 May 2015]. GeneReviews\u00ae [Internet], University of Washington."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1007\/s10038-008-0343-6","article-title":"PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome","volume":"53","author":"Ko","year":"2008","journal-title":"J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.ahj.2012.04.018","article-title":"Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: A study from the Pediatric Cardiomyopathy Registry","volume":"164","author":"Wilkinson","year":"2012","journal-title":"Am. Heart J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/ng.2963","article-title":"RAF1 mutations in childhood-onset dilated cardiomyopathy","volume":"46","author":"Dhandapany","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1159\/000112408","article-title":"Pulmonary Artery Aneurysm as a Cause for Chest Pain in a Patient with Noonan\u2019s Syndrome: A Case Report","volume":"110","author":"Brown","year":"2007","journal-title":"Cardiology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.ejcts.2005.05.004","article-title":"Giant aneurysms of the sinuses of Valsalva and aortic regurgitation in a patient with Noonan\u2019s syndrome","volume":"28","author":"Purnell","year":"2005","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1093\/oxfordjournals.eurheartj.a059462","article-title":"Aneurysms of the sinuses of Valsalva in Noonan\u2032s syndrome","volume":"10","author":"Morgan","year":"1989","journal-title":"Eur. Heart J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/jcu.22962","article-title":"Diagnosis of a giant left atrial appendage aneurysm by contrast-enhanced echocardiography: Case report and literature review","volume":"49","author":"Yanli","year":"2020","journal-title":"J. Clin. Ultrasound"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e009429","DOI":"10.1161\/CIRCIMAGING.119.009429","article-title":"Case of Noonan Syndrome with an Expanding Coronary Arterial Aneurysm","volume":"12","author":"Ogihara","year":"2019","journal-title":"Circ. Cardiovasc. Imaging"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/S0002-8703(05)80035-3","article-title":"Congenital coronary artery anomalies in Noonan\u2019s syndrome","volume":"119","author":"Wong","year":"1990","journal-title":"Am. Heart J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1136\/neurintsurg-2016-012482.rep","article-title":"Republished: Separate origins of the left internal and external carotid arteries from the aortic arch and cervical internal carotid artery aneurysm in a patient with Noonan syndrome","volume":"9","author":"Tahir","year":"2016","journal-title":"J. NeuroInterventional Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"190168","DOI":"10.1183\/16000617.0168-2019","article-title":"Pulmonary capillary haemangiomatosis: A distinct entity?","volume":"29","author":"Weatherald","year":"2020","journal-title":"Eur. Respir. Rev."},{"key":"ref_40","first-page":"877","article-title":"A Case of Congenital Pulmonary Lymphangiectasia in Noonan Syndrome","volume":"40","author":"Lee","year":"1997","journal-title":"J Korean Pediatr. Soc."},{"key":"ref_41","first-page":"6829586","article-title":"Pulmonary Vasculitis and a Horseshoe Kidney in Noonan Syndrome","volume":"2018","author":"Puvabanditsin","year":"2018","journal-title":"Case Rep. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1183\/09059180.00007513","article-title":"Pathogenesis of pulmonary arterial hypertension: Lessons from cancer","volume":"22","author":"Guignabert","year":"2013","journal-title":"Eur. Respir. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"L187","DOI":"10.1152\/ajplung.00303.2015","article-title":"Raf\/ERK drives the proliferative and invasive phenotype of BMPR2-silenced pulmonary artery endothelial cells","volume":"310","author":"Awad","year":"2016","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/ppul.10245","article-title":"Congenital pulmonary capillary hemangiomatosis: Report of two cases and review of the literature","volume":"36","author":"Oviedo","year":"2003","journal-title":"Pediatr. Pulmonol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"389","DOI":"10.3389\/fphys.2020.00389","article-title":"Molecular Mechanism of Hippo-YAP1\/TAZ Pathway in Heart Development, Disease, and Regeneration","volume":"11","author":"Chen","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/j.cellsig.2011.01.006","article-title":"HB-EGF induces cardiomyocyte hypertrophy via an ERK5-MEF2A-COX2 signaling pathway","volume":"23","author":"Lee","year":"2011","journal-title":"Cell. Signal."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/cvr\/cvt100","article-title":"Osteopontin-mediated myocardial fibrosis in heart failure: A role for lysyl oxidase?","volume":"99","author":"Lindner","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e005962","DOI":"10.1161\/CIRCHEARTFAILURE.119.005962","article-title":"Collaborative Regulation of LRG1 by TGF-\u03b21 and PPAR-\u03b2\/\u03b4 Modulates Chronic Pressure Overload-Induced Cardiac Fibrosis","volume":"12","author":"Liu","year":"2019","journal-title":"Circ. Heart Fail."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1309\/AJCP5FP3NAXAXRJE","article-title":"The Transcription Factor LMO2 Is a Robust Marker of Vascular Endothelium and Vascular Neoplasms and Selected Other Entities","volume":"131","author":"Gratzinger","year":"2009","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.vph.2017.10.006","article-title":"Reversal effects of low-dose imatinib compared with sunitinib on monocrotaline-induced pulmonary and right ventricular remodeling in rats","volume":"100","author":"Leong","year":"2018","journal-title":"Vasc. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.trecan.2020.05.009","article-title":"Clinical Development of BRAF plus MEK Inhibitor Combinations","volume":"6","author":"Subbiah","year":"2020","journal-title":"Trends Cancer"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/6\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:50:43Z","timestamp":1760169043000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/1\/6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,21]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["genes13010006"],"URL":"https:\/\/doi.org\/10.3390\/genes13010006","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,21]]}}}