Generation and characterization of three human induced pluripotent stem cell lines (EURACi007-A, EURACi008-A, EURACi009-A) from three different individuals of the same family with arrhythmogenic cardiomyopathy (ACM) carrying the plakophillin2 p.N346Lfs*12 mutation.

Abstract Arrhythmogenic Cardiomyopathy (ACM) is a genetically based cardiomyopathy associated with ventricular arrhythmias and fibro-fatty substitution of cardiac tissue. It is characterized by incomplete penetrance. We generated human iPSCs by episomal reprogramming of blood cells from three members of the same family: the proband, affected by ACM and carrying the heterozygous plakophillin2 p.N346Lfs*12 mutation, one asymptomatic carrier of the same mutation and one apparently healthy control. hiPSCs were characterized according to standard protocols including karyotyping, pluripotency marker expression and differentiation towards the three germ layers. These hiPSC lines can be used to study the mechanisms of ACM incomplete penetrance in vitro

Histone deacetylase adaptation in single ventricle heart disease and a young animal model of right ventricular hypertrophy.

BackgroundHistone deacetylase (HDAC) inhibitors are promising therapeutics for various forms of cardiac diseases. The purpose of this study was to assess cardiac HDAC catalytic activity and expression in children with single ventricle (SV) heart disease of right ventricular morphology, as well as in a rodent model of right ventricular hypertrophy (RVH).MethodsHomogenates of right ventricle (RV) explants from non-failing controls and children born with a SV were assayed for HDAC catalytic activity and HDAC isoform expression. Postnatal 1-day-old rat pups were placed in hypoxic conditions, and echocardiographic analysis, gene expression, HDAC catalytic activity, and isoform expression studies of the RV were performed.ResultsClass I, IIa, and IIb HDAC catalytic activity and protein expression were elevated in the hearts of children born with a SV. Hypoxic neonatal rats demonstrated RVH, abnormal gene expression, elevated class I and class IIb HDAC catalytic activity, and protein expression in the RV compared with those in the control.ConclusionsThese data suggest that myocardial HDAC adaptations occur in the SV heart and could represent a novel therapeutic target. Although further characterization of the hypoxic neonatal rat is needed, this animal model may be suitable for preclinical investigations of pediatric RV disease and could serve as a useful model for future mechanistic studies

Propranolol Treatment of Infantile Hemangiomas: Anticipatory Guidance for Parents and Caretakers

Infantile hemangiomas (IH) are benign tumors of endothelial-like cells. Occurring in 4.5% of children, they are the most common tumor of childhood. The great majority of patients with IH will not need treatment, but 10% require systemic treatment. Many treatments have been described for the treatment of IH, but the Food and Drug Administration has not approved any. Over the last decade, numerous reports of successful treatment of IH with propranolol have been published. Despite its widespread use, little is known regarding the proper dosing, safety monitoring, and during of treatment or long-term outcomes for propranolol treatment of IH. Given its potential side effects, detailed education regarding proper administration of the medication as well as warning signs to watch for is necessary for parents and caretakers. Herein, we provide a parental handout that practitioners can individually tailor for use in their clinics when educating parents and caretakers about the use of propranolol for IH. Updates will also need to be made as more is learned regarding the optimal dosing and safety monitoring when using propranolol for this indication. FORWARD: This article is a little different from the usual Techniques for Tots which have typically focused on examination or surgical techniques. We hope the readers will find it useful as an educational tool for families whose children are receiving propranolol for infantile hemangiomas. Ilona J. Frieden M.D. Lawrence F. Eichenfield M.D. Editors, Pediatric Dermatolog

Propranolol Treatment of Infantile Hemangiomas: Anticipatory Guidance for Parents and Caretakers

Infantile hemangiomas (IH) are benign tumors of endothelial-like cells. Occurring in 4.5% of children, they are the most common tumor of childhood. The great majority of patients with IH will not need treatment, but 10% require systemic treatment. Many treatments have been described for the treatment of IH, but the Food and Drug Administration has not approved any. Over the last decade, numerous reports of successful treatment of IH with propranolol have been published. Despite its widespread use, little is known regarding the proper dosing, safety monitoring, and during of treatment or long-term outcomes for propranolol treatment of IH. Given its potential side effects, detailed education regarding proper administration of the medication as well as warning signs to watch for is necessary for parents and caretakers. Herein, we provide a parental handout that practitioners can individually tailor for use in their clinics when educating parents and caretakers about the use of propranolol for IH. Updates will also need to be made as more is learned regarding the optimal dosing and safety monitoring when using propranolol for this indication

The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability

The chimeric transcription factor TCF3-HLF defines an incurable acute lymphoblastic leukemia subtype. Here we decipher the regulome of endogenous TCF3-HLF and dissect its essential transcriptional components and targets by functional genomics. We demonstrate that TCF3-HLF recruits HLF binding sites at hematopoietic stem cell/myeloid lineage associated (super-) enhancers to drive lineage identity and self-renewal. Among direct targets, hijacking an HLF binding site in a MYC enhancer cluster by TCF3-HLF activates a conserved MYC-driven transformation program crucial for leukemia propagation in vivo. TCF3-HLF pioneers the cooperation with ERG and recruits histone acetyltransferase p300 (EP300), conferring susceptibility to EP300 inhibition. Our study provides a framework for targeting driving transcriptional dependencies in this fatal leukemia

Congenital Cardiac, Aortic Arch, and Vascular Bed Anomalies in PHACE Syndrome (from the International PHACE Syndrome Registry)

PHACE syndrome represents the association of large infantile hemangiomas of the head and neck with brain, cerebrovascular, cardiac, ocular, and ventral or midline defects. Cardiac and cerebrovascular anomalies are the most common extracutaneous features of PHACE, and they also constitute the greatest source of potential morbidity. Congenital heart disease in PHACE is incompletely described, and this study was conducted to better characterize its features. This study of the International PHACE Syndrome Registry represents the largest central review of clinical, radiologic, and histopathologic data for cardiovascular anomalies in patients with PHACE to date. Sixty-two (41%) of 150 subjects had intracardiac, aortic arch, or brachiocephalic vessel anomalies. Aberrant origin of a subclavian artery was the most common cardiovascular anomaly (present in 31 (21%) of 150 subjects). Coarctation was the second most common anomaly, identified in 28 (19%) of 150 subjects, and can be missed clinically in patients with PHACE because of the frequent association of arch obstruction with aberrant subclavian origin. Twenty-three (37%) of 62 subjects with cardiovascular anomalies required procedural intervention. A greater percentage of hemangiomas were located on the left side of the head and neck in patients with coarctation (46% vs 39%); however, hemangioma distribution did not predict the presence of cardiovascular anomalies overall. In conclusion, PHACE is associated with a high risk of congenital heart disease. Cardiac and aortic arch imaging with detailed assessment of arch patency and brachiocephalic origins is essential for any patient suspected of having PHACE. Longitudinal investigation is needed to determine the long-term outcomes of cardiovascular anomalies in PHACE