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PURPOSE OF REVIEW: We aim to improve diagnosis of congenital heart disease (CHD) with cyanosis by physiology for general practitioners to reduce time to appropriate treatment. RECENT FINDINGS: New implementation of the critical congenital heart disease (CCHD) pulse oximetry screen has improved rate of diagnosis of CHD in recent years. However, many infants with cyanotic heart lesions often decompensate before screening in the newborn nursery, or have lesions that are not amenable to pulse oximetry screening and that present later in the emergency room. Recent literature has shown preoperative acidosis because of delayed diagnosis of cyanotic CHD worsens outcomes postoperatively. Wide availability of prostaglandin therapy and catheter procedures help to preoperatively stabilize critical cardiac patients. With a firm grasp of the underlying physiology of neonatal cyanotic CHD, practitioners can appropriately implement these therapies more judiciously. This early recognition will subsequently improve overall outcomes. SUMMARY: Physiologic diagnosis of CHD with cyanosis by general practitioners will allow initiation of appropriate management more quickly and effectively. This may avoid progressive clinical decompensation and acidosis until cardiology consultation and potential intervention are available.
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Cianosis , Cardiopatías Congénitas , Tamizaje Neonatal , Cianosis/complicaciones , Cianosis/etiología , Diagnóstico Tardío , Cardiopatías Congénitas/diagnóstico , Humanos , Lactante , Recién Nacido , OximetríaRESUMEN
BACKGROUND: In 2017, the AHA published revised guidelines for the diagnosis of Kawasaki disease (KD). In the absence of compelling data supporting or refuting the utility of lack of tapering (LT) and perivascular brightness (PB), expert panel consensus removed LT and PB from consideration. We hypothesize that LT and PB are unreliable, subjective findings, non-specific to KD, which can be seen in systemic febrile illnesses without KD and in normal controls. METHODS: We performed a single-center retrospective study from 1/2008 to 12/2016. De-identified coronary artery (CA) echocardiographic clips from patients 0-10 years old were interpreted blindly by six pediatric cardiologists. Subjects were grouped as follows: (1) healthy: afebrile with benign murmur, (2) KD: IVIG treatment, 4-5 clinical criteria at presentation, (3) incomplete KD (iKD): IVIG, 1-3 clinical criteria, (4) Febrile: ≥3 days of fever, no IVIG, KD not suspected. The presence or absence of LT and PB was recorded. Inter-rater and intra-rater reliabilities were analyzed using intra-class correlation coefficient, Fleiss' Kappa and Cohen's Kappa coefficients. RESULTS: We interpreted 117 echocardiograms from healthy (27), KD (30), iKD (32), and febrile (28) subjects. Analysis showed moderate agreement in CA z score measurements. LT and PB were observed by most readers in control groups. LT exhibited fair inter-reader agreement (reliability coefficient 0.36) and PB slight inter-reader agreement (reliability coefficient 0.13). Intra-rater reliability was inconsistent for both parameters. CONCLUSIONS: LT and PB are subjective, poorly reproducible features that can be seen in febrile patients without KD and in healthy children.
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Vasos Coronarios/diagnóstico por imagen , Síndrome Mucocutáneo Linfonodular/diagnóstico por imagen , Estudios de Casos y Controles , Niño , Preescolar , Ecocardiografía , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Síndrome Mucocutáneo Linfonodular/clasificación , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Background: In order to determine whether a method is more successful for treating a grade-II furcation deficiency, this randomized trial will compare demineralized freeze-dried bone allograft (DFDBA) to platelet-rich fibrin with DFDBA. Materials and Methods: Twenty systematically healthy patients between the ages of 30 and 60 with a grade-II furcation were evaluated pre and postoperatively for changes in the modified plaque index, probing depth, relative vertical and horizontal clinical attachment level, gingival marginal level, and radiographic bone defect. Results: The test group significantly outperformed the control group on all clinical and radiological measures. Conclusion: The experimental group improved at both clinical attachment levels and had a higher decrease in probing depth than the control group did.
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Pulmonary hypertension (PH) is a multifactorial, progressive disease with poor outcomes. Group 2 PH is defined by pulmonary vascular disease with elevated pulmonary capillary wedge pressure including both left-sided obstructive lesions and diastolic heart failure (HF). Sildenafil was historically discouraged in this population as pulmonary vasodilation can lead to pulmonary edema. However, evidence suggests that sildenafil can help to treat the precapillary component of PH. This is a single center, retrospective pilot study of pediatric PH patients with left-sided HF who were treated with sildenafil for ≥ 4 weeks. HF patients without mechanical support (HF group) and HF patients with a left ventricular assist device (HF-VAD) were analyzed. The exploratory analysis described the safety and side effects of the drug. Echocardiographic parameters were compared before and after sildenafil treatment in a paired analysis. The changes in medical therapy during treatment, mechanical support, and mortality was reported; 19/22 patients tolerated sildenafil. Pulmonary edema in two patients resolved upon discontinuation of sildenafil. In the HF group, both the right atrial volume and right ventricular diastolic area decreased, and the tricuspid regurgitation (TR) S/D ratio decreased after therapy (p = 0.02). Across both the groups, four patients weaned off milrinone and seven weaned off inhaled nitric oxide. Of the thirteen HF patients, four received a transplant, and all of the nine HF-VAD patients received a transplant. Sildenafil can be safely used in carefully selected patients with HF and mixed pre/postcapillary PH with judicious titration and inpatient surveillance, with patients showing improvements in echocardiographic parameters.
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Cryptococcus gattii is an underrecognized cause of meningitis, especially in nonendemic regions. This report details C gattii disease progression from admission to autopsy in an otherwise healthy 40-year-old male in Texas. It brings awareness to an often unsuspected organism that can cause severe infection requiring early recognition and treatment in immunocompetent individuals.
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Medulloblastoma (MB) is a neoplasm linked to dysregulated cerebellar development. Previously, we demonstrated that the Sonic Hedgehog (SHH) subgroup grows hierarchically, with Sox2+ cells at the apex of tumor progression and relapse. To test whether this mechanism is rooted in a normal developmental process, we studied the role of Sox2 in cerebellar development. We find that the external germinal layer (EGL) is derived from embryonic Sox2+ precursors and that the EGL maintains a rare fraction of Sox2+ cells during the first postnatal week. Through lineage tracing and single-cell analysis, we demonstrate that these Sox2+ cells are within the Atoh1+ lineage, contribute extensively to adult granule neurons, and resemble Sox2+ tumor cells. Critically, constitutive activation of the SHH pathway leads to their aberrant persistence in the EGL and rapid tumor onset. We propose that failure to eliminate this rare but potent developmental population is the tumor initiation mechanism in SHH-subgroup MB.
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Meduloblastoma/etiología , Meduloblastoma/metabolismo , Factores de Transcripción SOXB1/metabolismo , Animales , Linaje de la Célula/genética , Células Cultivadas , Neoplasias Cerebelosas/patología , Cerebelo/embriología , Femenino , Proteínas Hedgehog/metabolismo , Humanos , Masculino , Ratones Noqueados , Ratones Transgénicos , Recurrencia Local de Neoplasia/patología , Células-Madre Neurales/metabolismo , Neurogénesis , Neuronas/metabolismo , Factores de Transcripción SOXB1/fisiología , Transducción de Señal/fisiología , Análisis de la Célula Individual/métodosRESUMEN
BACKGROUND: Our understanding of the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pregnancies and perinatal outcomes is limited. The clinical course of neonates born to women who acquired coronavirus disease 2019 (COVID-19) during their pregnancy has been previously described. However, the course of neonates born with complex congenital malformations during the COVID-19 pandemic is not known. METHODS: We report a case series of seven neonates with congenital heart and lung malformations born to women who tested positive for SARS-CoV-2 during their pregnancy at a single academic medical center in New York City. RESULTS: Six infants had congenital heart disease and one was diagnosed with congenital diaphragmatic hernia. In all seven infants, the clinical course was as expected for the congenital lesion. None of the seven exhibited symptoms generally associated with COVID-19. None of the infants in our case series tested positive by nasopharyngeal test for SARS-CoV-2 at 24 hours of life and at multiple points during their hospital course. CONCLUSIONS: In this case series, maternal infection with SARS-CoV-2 during pregnancy did not result in adverse outcomes in neonates with complex heart or lung malformations. Neither vertical nor horizontal transmission of SARS-CoV-2 was noted.
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COVID-19 , Cardiopatías Congénitas , Hernias Diafragmáticas Congénitas , Complicaciones Infecciosas del Embarazo , SARS-CoV-2/aislamiento & purificación , COVID-19/diagnóstico , COVID-19/transmisión , Femenino , Humanos , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa , Masculino , Pandemias , Embarazo , Complicaciones Infecciosas del Embarazo/diagnóstico , Diagnóstico Prenatal , Síndrome de la Trisomía 13RESUMEN
This corrects the article DOI: 10.1038/ncomms7186.
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This corrects the article DOI: 10.1038/ncomms5999.
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Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1lo GSCs do not. Increasing ASCL1 levels in ASCL1lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Neoplasias Encefálicas/patología , Carcinogénesis/patología , Linaje de la Célula , Cromatina/metabolismo , Glioblastoma/patología , Neuronas/patología , Secuencia de Bases , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Neoplasias Encefálicas/genética , Carcinogénesis/genética , Diferenciación Celular/genética , Progresión de la Enfermedad , Elementos de Facilitación Genéticos/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Humanos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neuronas/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica , Análisis de Secuencia de ARN , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: Agranulocytosis is regarded as a rare side effect of methimazole (MMI) therapy that occurs in a dose dependent manner and that usually develops within the first 3-6 months of treatment. Although delayed development beyond this timeline has been documented in adults, very few children have been reported with this presentation. CASE PRESENTATION: We present a 6-year old patient who developed agranulocytosis 18 months after the start of MMI therapy. CONCLUSIONS: This is an unusual case of a 6-year old patient who developed this serious side effect on stable MMI therapy well beyond the typical timeline. Our review of the literature revealed that there really is inconclusive data on the incidence, time, and dose-dependency of MMI-induced agranulocytosis in the pediatric Graves' disease population.
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Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk-associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.
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Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Mutación , Polimorfismo de Nucleótido Simple , Sistemas CRISPR-Cas , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Secuencias Reguladoras de Ácidos Nucleicos , Factores de Transcripción/metabolismoRESUMEN
Long noncoding RNAs (lncRNAs) represent an attractive class of candidates to mediate cancer risk. Through integrative analysis of the lncRNA transcriptome with genomic data and SNP data from prostate cancer genome-wide association studies (GWAS), we identified 45 candidate lncRNAs associated with risk to prostate cancer. We further evaluated the mechanism underlying the top hit, PCAT1, and found that a risk-associated variant at rs7463708 increases binding of ONECUT2, a novel androgen receptor (AR)-interacting transcription factor, at a distal enhancer that loops to the PCAT1 promoter, resulting in upregulation of PCAT1 upon prolonged androgen treatment. In addition, PCAT1 interacts with AR and LSD1 and is required for their recruitment to the enhancers of GNMT and DHCR24, two androgen late-response genes implicated in prostate cancer development and progression. PCAT1 promotes prostate cancer cell proliferation and tumor growth in vitro and in vivo. These findings suggest that modulating lncRNA expression is an important mechanism for risk-associated SNPs in promoting prostate transformation.
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Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , ARN Largo no Codificante , Animales , Línea Celular Tumoral , Cromatina/metabolismo , Elementos de Facilitación Genéticos , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , ARN Largo no Codificante/genética , Receptores Androgénicos/metabolismo , Factores de Riesgo , Transducción de Señal , Factores de Transcripción/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chromatin interactions connect distal regulatory elements to target gene promoters guiding stimulus- and lineage-specific transcription. Few factors securing chromatin interactions have so far been identified. Here, by integrating chromatin interaction maps with the large collection of transcription factor-binding profiles provided by the ENCODE project, we demonstrate that the zinc-finger protein ZNF143 preferentially occupies anchors of chromatin interactions connecting promoters with distal regulatory elements. It binds directly to promoters and associates with lineage-specific chromatin interactions and gene expression. Silencing ZNF143 or modulating its DNA-binding affinity using single-nucleotide polymorphisms (SNPs) as a surrogate of site-directed mutagenesis reveals the sequence dependency of chromatin interactions at gene promoters. We also find that chromatin interactions alone do not regulate gene expression. Together, our results identify ZNF143 as a novel chromatin-looping factor that contributes to the architectural foundation of the genome by providing sequence specificity at promoters connected with distal regulatory elements.
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Cromatina/metabolismo , Regiones Promotoras Genéticas , Transactivadores/metabolismo , Sitios de Unión , Cromatina/genética , Humanos , Polimorfismo de Nucleótido Simple , Secuencias Reguladoras de Ácidos Nucleicos , Transactivadores/genéticaRESUMEN
Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.
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Neoplasias Encefálicas/metabolismo , Autorrenovación de las Células , Ensamble y Desensamble de Cromatina , Proteínas de Unión al ADN/metabolismo , Glioblastoma/metabolismo , Histonas/metabolismo , Células Madre Neoplásicas/metabolismo , Adolescente , Adulto , Animales , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Diferenciación Celular , Proliferación Celular , Autorrenovación de las Células/efectos de los fármacos , Niño , Preescolar , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Metilación de ADN , Proteínas de Unión al ADN/genética , Diseño de Fármacos , Epigénesis Genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/mortalidad , Glioblastoma/patología , Histonas/genética , Humanos , Estimación de Kaplan-Meier , Ratones Endogámicos NOD , Ratones SCID , Terapia Molecular Dirigida , Mutación , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Pronóstico , Interferencia de ARN , Transducción de Señal , Factores de Tiempo , Transfección , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto JovenRESUMEN
Transcriptional regulatory mechanisms likely contribute to the etiology of inflammatory bowel disease (IBD), as genetic variants associated with the disease are disproportionately found at regulatory elements. However, the transcription factors regulating colonic inflammation are unclear. To identify these transcription factors, we mapped epigenomic changes in the colonic epithelium upon inflammation. Epigenetic marks at transcriptional regulatory elements responded dynamically to inflammation and indicated a shift in epithelial transcriptional factor networks. Active enhancer chromatin structure at regulatory regions bound by the transcription factor hepatocyte nuclear factor 4α (HNF4A) was reduced during colitis. In agreement, upon an inflammatory stimulus, HNF4A was downregulated and showed a reduced ability to bind chromatin. Genetic variants that confer a predisposition to IBD map to HNF4A binding sites in the human colon cell line CaCo2, suggesting impaired HNF4A binding could underlie genetic susceptibility to IBD. Despite reduced HNF4A binding during inflammation, a temporal knockout model revealed HNF4A still actively protects against inflammatory phenotypes and promotes immune regulatory gene expression in the inflamed colonic epithelium. These findings highlight the potential for HNF4A agonists as IBD therapeutics.
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Cromatina/genética , Cromatina/metabolismo , Colitis/genética , Colitis/metabolismo , Redes Reguladoras de Genes , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Animales , Sitios de Unión/genética , Células CACO-2 , Colitis/patología , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Epigénesis Genética , Femenino , Técnicas de Inactivación de Genes , Predisposición Genética a la Enfermedad , Factor Nuclear 4 del Hepatocito/antagonistas & inhibidores , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Elementos Reguladores de la TranscripciónRESUMEN
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.