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Biopsia Guiada por Imagen , Tomografía Computarizada por Rayos X , Humanos , Niño , Biopsia Guiada por Imagen/métodos , Masculino , Femenino , Adolescente , Pulmón/diagnóstico por imagen , Pulmón/patología , Nódulo Pulmonar Solitario/diagnóstico por imagen , Nódulo Pulmonar Solitario/patología , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patologíaRESUMEN
INTRODUCTION: Tracheomalacia (TM) is an important cause of respiratory morbidity. Dynamic flexible bronchoscopy is considered the gold standard for diagnosis. Dynamic airway computed tomography (DACT) is a low radiation, noninvasive diagnostic tool utilizing images obtained continuously over several respiratory cycles. We aimed to assess the accuracy of DACT in TM diagnosis. METHODS: Retrospective analysis of all patients who underwent both DACT and flexible bronchoscopy within 6 months. Airway anterior-posterior (AP) diameter was measured on multiplanar reconstructions CT in both the inspiratory and expiratory phases. Using still images from the bronchoscopy videos, the AP diameter of the trachea was measured at points of maximal and minimal diameter during tidal breathing. Degree of TM on both DACT and flexible bronchoscopy were graded using a scaling system of 50%-74%, 75%-89%, and 90%-100% as described by the European Respiratory Society. RESULTS: Twenty-four patients met inclusion criteria with an average time of 19.5 days between CT and bronchoscopy. The specificity and sensitivity of DACT for the overall diagnosis of TM was 100% and 68%, respectively, with a positive predictive value of 100% and a negative predictive value of 62%. There was a strong positive correlation between DACT and flexible bronchoscopy in the measurement of tracheal AP diameter changes (ρ = 0.773, R2 0.597, p = 0.00001). Mean effective radiation dose for DACT was 0.1 mSv. CONCLUSION: Ultralow dose DACT has excellent specificity and positive predictive value for both detection of TM and categorizing severity of tracheal collapse but is not sufficiently sensitive to rule it out.
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Traqueomalacia , Niño , Humanos , Traqueomalacia/diagnóstico por imagen , Broncoscopía/métodos , Estudios Retrospectivos , Tráquea/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodosRESUMEN
OBJECTIVE: Endobronchial ultrasound-guided transbronchial biopsy and needle aspiration (EBUS-TBB/EBUS-TBNA) are first line investigative modalities for lung and mediastinal pathology in adults. We aimed to characterize and assess the diagnostic yield of EBUS and virtual CT navigation guided biopsies in children. STUDY DESIGN: This single center, retrospective cohort study included patients who underwent radial or linear EBUS procedures (+/- CT navigation) for biopsy of mediastinal lymph nodes, tumors, and pulmonary nodules. Demographic, procedural, and outcome were collected. RESULTS: Sixty procedures were performed in 56 patients aged 2-22 years of age between January 2015 and May 2023. The most common indications for biopsy were pulmonary nodules (45%) and hilar/mediastinal lymphadenopathy (33%). For cases in which a final diagnosis was ascertained by any means, the diagnostic yield for linear EBUS (mediastinal pathology) was 76% and the diagnostic yield from radial EBUS (pulmonary nodules and lung masses) was 85%. The most common diagnoses were infection (45%), malignancy (17%), and sarcoidosis (11%). Among patients in whom infection was the final diagnosis, a total of 31 pathogens were identified. Eighteen were identified on bronchoalveolar lavage and an additional 14 pathogens identified on EBUS-TBB, representing an increase of 77% (p < .005). The sensitivity, specificity, negative and positive predictive values for malignancy detection were 73%, 100%, 94%, and 100%, respectively. CONCLUSION: EBUS-TBB/TBNA is a safe and effective way to diagnose lung and mediastinal pathology in children. Pediatric interventional pulmonology is a growing field offering minimally-invasive diagnostic opportunities for children in whom more invasive procedures were previously the only option.
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Neoplasias Pulmonares , Linfadenopatía , Enfermedades del Mediastino , Neoplasias Torácicas , Adulto , Niño , Humanos , Broncoscopía/métodos , Estudios Retrospectivos , Mediastino/patología , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Enfermedades del Mediastino/diagnóstico , Neoplasias Torácicas/patología , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/métodos , Sensibilidad y Especificidad , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patologíaRESUMEN
RATIONALE: Diagnosing cystic fibrosis (CF) pulmonary exacerbations (PEx) in very young people with CF <3 years (VY-PwCF) is challenging because of the frequency of respiratory viral infections in this age group, and there are limited data on the clinical features associated with the diagnosis of PEx in this age group. The goal of this study was to identify clinical features associated with the diagnosis of PEx in VY-PwCF. METHODS: We reviewed the medical records of VY-PwCF followed at the Children's Hospital of Philadelphia born between 2013 and 2019. We collected data from all encounters with respiratory symptoms. PEx was defined by treatment with oral or intravenous antibiotics. Clinical features of PEx and non-PEx encounters were compared using descriptive statistics, and odds ratios of PEx diagnosis were calculated. RESULTS: A total of 78 patients were included in the analysis. The mean (SD) number of PEx per patient was 6.17 (5.88). The presence of a wet or nighttime cough and symptoms >3 days in duration were significantly associated with PEx diagnosis (p < .001). In contrast, symptoms such as sore throat or rhinorrhea were not associated with a higher likelihood of PEx. CONCLUSIONS: The presence of a wet or night-time cough and longer symptom duration are common features of PEx in VY-PwCF, whereas symptoms suggestive of upper respiratory viral infection are not. Our results will be helpful in counseling families of VY-PwCF in the signs and symptoms of PEx and in planning future research in PEx in this age group.
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Fibrosis Quística , Faringitis , Niño , Lactante , Humanos , Preescolar , Adolescente , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Progresión de la Enfermedad , Pulmón , Tos/tratamiento farmacológico , Faringitis/complicaciones , Faringitis/tratamiento farmacológico , Antibacterianos/uso terapéuticoRESUMEN
STUDY OBJECTIVES: Healthy infants may have a greater apnea hypopnea index (AHI) than older children during the newborn period, but the trajectory of these sleep-related events beyond the first month of life is poorly understood. In this study, we evaluated the longitudinal changes in respiratory indices during sleep in healthy infants during the first six months of life. METHODS: Single-center prospective cohort study. Thirty healthy infants underwent overnight in-lab polysomnography at one and five months of age and findings were compared between assessments. Systematic review of studies evaluating infant polysomnography and meta-analysis was conducted. RESULTS: At one month of age, total AHI, obstructive AHI, and central AHI model-adjusted means (95% confidence interval) were 16.9 events/hour (12.2, 21.5), 10.2 events/hour (7.4, 13.1), and 6.6 events/hour (4.2, 9.0), respectively. 16.8% of events were obstructive apneas and 36.1% central apneas. By five months of age, there were significant reductions in each index to 4.1 events/hour (3.2, 5.0), 1.9 events/hour (1.4, 2.4), and 2.2 events/hour (1.6, 2.9), respectively (p < 0.001 for each), and a lower proportion of events were obstructive apneas (8.6%, p = 0.007) and a greater proportion central apneas (52.3%, p = 0.002). Meta-analysis found high AHI in infants with significant heterogeneity. CONCLUSIONS: Central AHI and obstructive AHI are greater in healthy newborns than older children. There is a significant spontaneous reduction in events and change in type of events in the first six months of life in this low-risk population. These findings may serve as a reference for clinicians evaluating for obstructive sleep apnea in infants.
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Síndromes de la Apnea del Sueño , Apnea Central del Sueño , Apnea Obstructiva del Sueño , Adolescente , Niño , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Estudios Prospectivos , SueñoAsunto(s)
Sarcoma de Células Dendríticas Foliculares , Miastenia Gravis , Síndromes Paraneoplásicos , Pénfigo , Autoanticuerpos , Niño , Sarcoma de Células Dendríticas Foliculares/complicaciones , Humanos , Miastenia Gravis/complicaciones , Síndromes Paraneoplásicos/complicaciones , Pénfigo/complicacionesRESUMEN
AIM: To identify the incidence of Obstetric Cholestasis in a Maternity unit. To compare our investigation, criteria for diagnosis and management plan with National Guidelines. To assess adverse maternal and neonatal outcomes associated with this condition. METHOD: Serum Bile Acid requests are sent to an external laboratory, Biomnis in Dublin, for processing. A log of 2018 requests was obtained from Biochemistry. The pregnant patients with values > 8 mmol/L were selected. A data collection proforma was designed and retrospective chart review performed. RESULTS: Of the 1302 births in SUH in 2018, 42 women met the criteria resulting in a suspected incidence of 3.2% (n = 42). 9.5%(n = 4) of patients had a history of OC in a previous pregnancy. Bile acid values ranged from 8.1 to 124 mmol/L. LFTs were deranged in 81% (n = 34) of patients. Gestation at delivery ranged from 35 weeks to 40 + 9. OC alone was the indication for induction in 57%9n = 24). CS in 43% (n = 20) and Vaginal birth in 57% (n = 25). Neonatal outcome: 7% (n = 3) reduced APGAR, 7% (n = 3) passed meconium, 9% (n = 4) NICU admission, no stillbirths. CONCLUSION: Suspected incidence of 3.2% (n = 42) is significantly higher than the stated 0.7% across multi-ethnic populations. Greater congruence is required on the BA cut off value for diagnosis as there is no specified value in guidelines. While we may be over diagnosing patients based on BA level, we are also undertreating them, with 55% (n = 23) receiving Ursofalc. There was no neonatal mortality.
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Colestasis Intrahepática , Femenino , Humanos , Incidencia , Recién Nacido , Irlanda/epidemiología , Embarazo , Complicaciones del Embarazo , Resultado del Embarazo/epidemiología , Estudios RetrospectivosRESUMEN
As of 18 February 2020, the e-cigarette or vaping product use-associated lung injury (EVALI) epidemic has claimed the lives of 68 patients in the USA with the total number of reported cases standing at 2807 to date. We present the clinical and radiologic findings, course of illness, and treatment of EVALI in seven adolescent patients in Northeast Ohio. Five of our patients required supplemental oxygen with four requiring intensive care unit care for respiratory support during admission. Three patients were treated with systemic steroids while inpatient. Bilateral opacities were seen on radiographic imaging of all seven of our patients. All patients were discharged alive on room air. However, impaired diffusing capacity of the lungs for carbon monoxide (DLCO) with nonobstructive spirometry was seen in patients that were tested postdischarge. This suggests that although recovery from the acute illness process of EVALI is achieved, there may be long-term impact on lung function in these patients. We recommend close follow-up with a pediatric pulmonologist where spirometry and DLCO can be performed.
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Sistemas Electrónicos de Liberación de Nicotina , Lesión Pulmonar/etiología , Vapeo/efectos adversos , Adolescente , Corticoesteroides/uso terapéutico , Cuidados Críticos , Femenino , Hospitalización , Humanos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Lesión Pulmonar/diagnóstico , Lesión Pulmonar/fisiopatología , Lesión Pulmonar/terapia , Masculino , Ohio , Oxígeno/uso terapéutico , EspirometríaRESUMEN
1,25-dihydroxyvitamin D3 (1,25D3) is implicated in many cellular functions, including cell proliferation and differentiation, thus exerting potential antitumor effects. A major limitation for therapeutic use of 1,25D3 are potent calcemic activities. Therefore, synthetic analogs of 1,25D3 for use in anticancer therapy should retain cell differentiating potential, with calcemic activity being reduced. To obtain this goal, the analogs should effectively activate transcription of genes responsible for cell differentiation, leaving the genes responsible for calcium homeostasis less active. In order to better understand this phenomenon, we selected a series of structurally related 19-nor analogs of 1,25D (PRI-5100, PRI-5101, PRI-5105, and PRI-5106) and tested their activities in blood cells and in cells connected to calcium homeostasis. Affinities of analogs to recombinant vitamin D receptor (VDR) protein were not correlated to their pro-differentiating activities. Moreover, the pattern of transcriptional activities of the analogs was different in cell lines originating from various vitamin D-responsive tissues. We thus hypothesized that receptors which participate in transport of the analogs to the cells might contribute to the observed differences. In order to study this hypothesis, we produced renal cells with knock-out of the megalin gene. Our results indicate that megalin has a minor effect on semi-selective activities of vitamin D analogs.
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Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Receptores de Calcitriol/metabolismo , Vitamina D/farmacología , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Concentración 50 Inhibidora , Cinética , Especificidad de Órganos/efectos de los fármacos , Unión Proteica , Receptores de Calcitriol/agonistas , Vitamina D/análogos & derivados , Vitamina D/químicaRESUMEN
BACKGROUND: Mid-adolescence, that twilight era when the human child transitions to adulthood, is an often overlooked developmental age yet harbours a subpopulation of patients with their own myriad of medical problems somewhat unique to their age group. AIMS: Our study is aimed at reviewing the typical presentations to a paediatric emergency department of modern Irish teenagers in mid-adolescence, the profile of which has changed significantly over the past 10 years. METHODS: Hospital electronic databases were used to conduct a retrospective review of the paediatric emergency department presentations of patients aged 14-15 years during the year of 2017. We collated data on the presenting complaint, background history, admission rate and medical specialities involved in each patient's care while in our Emergency Department. RESULTS: A total of 1485 presentations were made, with 1363 being eligible for inclusion in this study. The results highlight the varied and challenging presentations (Table 1) and the high number of specialities required within emergency medicine to care for this unique population (Table 2). CONCLUSION: The results highlight the most common presentations of this subgroup of patients, with trauma, in keeping with recent international data, being the most common presentation. The noted high frequency in the number of mental health/intoxication/self-harm presentations among the Irish teenagers in our region is consistent with trends reported in world literature and serves to emphasise one of the main challenges facing those working in paediatrics in Ireland over the next 10 years.
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Servicio de Urgencia en Hospital/estadística & datos numéricos , Conducta Autodestructiva/epidemiología , Adolescente , Bases de Datos Factuales , Femenino , Humanos , Irlanda , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: Acute myeloid leukemia (AML) cells can be induced to undergo terminal differentiation with subsequent loss of tumorigenicity using 1,25-dihydroxyvitamin D3 (1,25D) alone or in combination with hematopoietic cytokines. KG1 cells are resistant to 1,25D-induced cell differentiation. These cells have the aberrant signal transduction resulting from a constitutively active fusion protein FOP2-FGFR1, a constitutively active STAT1 and a high level of interferon (IFN) stimulated genes (ISGs). METHODS: In this paper we report that in KG1 cells with constitutively activated protein FOP2-FGFR1 delivery of plasmid DNA disrupted FOP2-FGFR1 fusion gene. RESULTS: As a consequence, STAT1 signal transduction pathway became switched off, the expression of vitamin D receptor (VDR) gene was increased and sensitivity to 1,25D-induced differentiation was restored. The activation of ISGs in KG1 cells resulted in resistance to externally added IFNs, and also this effect was reversed in cells with disrupted FOP2-FGFR1 fusion gene. DISCUSSION: In this paper we have documented for the first time a link between constitutively active STAT1 signal transduction pathway, high level of ISGs and low expression of VDR gene. CONCLUSIONS: We show in this paper that delivery of plasmid DNA to the cells may disrupt fusion gene FOP2-FGFR1 which occurs in a disease entity called 8p11 myeloproliferative syndrome. Inhibition of the FOP2-FGFR1 signal transduction pathway restored sensitivity of the cells to 1,25D-induced cell differentiation.
RESUMEN
Structurally similar double-point modified analogues of 1,25-dihydroxyvitamin D2 (1,25D2) were screened in vitro for their pro-differentiating activity against the promyeloid cell line HL60. Their affinities towards human full length vitamin D receptor (VDR) and metabolic stability against human vitamin D 24-hydroxylase (CYP24A1) were also tested. The analogues (PRI-1730, PRI-1731, PRI-1732, PRI-1733 and PRI-1734) contained 5,6-trans modification of the A-ring and of the triene system, additional hydroxyl or unsaturation at C-22 in the side chain and reversed absolute configuration (24-epi) at C-24 of 1,25D2. As presented in this paper, introduction of selected structural modifications simultaneously in two distinct parts of the vitamin D molecule resulted in a divergent group of analogues. Analogues showed lower VDR affinity in comparison to that of the parent hormones, 1,25D2 and 1,25D3, and they caused effective HL60 cell differentiation only at high concentrations of 100 nM and above. Unexpectedly, introducing of a 5,6-trans modification combined with C-22 hydroxyl and 24-epi configuration switched off entirely the cell differentiation activity of the analogue (PRI-1734). However, this analogue remained a moderate substrate for CYP24A1, as it was metabolized at 22%, compared to 35% for 1,25D2. Other analogues from this series were either less (12% for PRI-1731 and PRI-1733) or more (52% for PRI-1732) resistant to the enzymatic deactivation. Although the inactive analogue PRI-1734 failed to show VDR antagonism, when tested in HL60 cells, its structure might be a good starting point for our design of a vitamin D antagonist.
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Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Ergocalciferoles/farmacología , Leucemia/enzimología , Antineoplásicos/química , Diferenciación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ergocalciferoles/química , Células HL-60 , Humanos , Leucemia/tratamiento farmacológico , Leucemia/metabolismo , Estructura Molecular , Receptores de Calcitriol/metabolismo , Relación Estructura-Actividad , Especificidad por Sustrato , Vitamina D3 24-Hidroxilasa/antagonistas & inhibidoresRESUMEN
An improved convergent strategy was developed for the synthesis of the previously obtained side-chain extended and rigidified analogs of 1α,25-dihydroxyvitamin D2, PRI-1906 and PRI-1907. New (24Z) geometric isomers of the analogs, PRI-1916 and PRI-1917, were also obtained and identified. These side-chain isomers were separable by flash chromatography, as C-25 alcohols, from the synthetic precursors of PRI-1906 and PRI-1907, respectively. The structures of new analogs were determined by advanced techniques of 1H and 13C NMR, including COSY, HSQC and HMBC sequences. Binding affinities of the geometric analogs PRI-1906 and PRI-1916 and their respective C-26, C-27 homologs PRI-1907 and PRI-1917 for the full-length human vitamin D receptor were determined by a fluorescence polarization competition assay. The binding affinity of (24Z) methyl analog PRI-1906 was much higher than that of (24E) analog PRI-1906, while the affinity of (24Z) ethyl analog PRI-1917 was lower than that of the respective PRI-1907. Investigation of the metabolism of these compounds by human CYP24A1 revealed they are much more resistant to CYP24A1 than 1α,25-dihydroxyvitamin D2, indicating they could have longer-term biological effects on target tissues.
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Ergocalciferoles/química , Ergocalciferoles/síntesis química , Unión Competitiva , Cromatografía Líquida de Alta Presión , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Escherichia coli/metabolismo , Ésteres/química , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Isoformas de Proteínas , Receptores de Calcitriol/genética , Proteínas Recombinantes/química , Espectrometría de Fluorescencia , Resultado del Tratamiento , Vitamina D3 24-Hidroxilasa/genética , Vitamina D3 24-Hidroxilasa/metabolismoRESUMEN
1,25-dihydroxyvitamin D3 (1,25D), a steroid hormone which regulates calcium/phosphate homeostasis, has a broad spectrum of anti-cancer activities, including differentiation of acute myeloid leukemia (AML) cells. In order to avoid undesirable side effects such as hypercalcemia, low-calcemic analogues should be produced for therapeutic purposes. In this paper, we describe biological activities of double-point modified analogues of vitamin D2 and we compare them to 1,25D and to paricalcitol, the drug used to treat secondary hyperparathyroidism. In vivo, our new analogues have lower calcemic effects, and lower toxicity in comparison to 1,25D. They have enhanced pro-differentiating and transcription-inducing activities in AML cells. Interestingly, differentiation effects do not correlate with the affinities of the analogues to the vitamin D receptor (VDR).
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Ergocalciferoles/química , Ergocalciferoles/síntesis química , Transporte Activo de Núcleo Celular , Animales , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Diferenciación Celular , Evaluación Preclínica de Medicamentos , Ergocalciferoles/genética , Células HL-60 , Homeostasis , Humanos , Hipercalcemia/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Receptores de Lipopolisacáridos/metabolismo , Ratones , Mutación Puntual , Receptores de Calcitriol/metabolismo , Activación Transcripcional/efectos de los fármacos , Regulación hacia Arriba , Vitamina D3 24-Hidroxilasa/metabolismoRESUMEN
Rational design, chemical synthesis, structural analysis, molecular modeling and biological evaluation are reviewed for all the double point modified vitamin D analogs that have been developed as potential therapeutics over the last several years. The idea of double modifications was based on the 3D structure of the ligand binding domain of the model of the vitamin D receptor. It was recently proved that structural modifications in the two remote parts of the vitamin D molecule might have additive biological effects resulting in an increased functional activity and lowered calcemic side effect. Recent in vivo experiments clearly demonstrated the potential use of these analogs in new therapeutic areas such as autoimmune and hyper-proliferative diseases, including cancer and the systemic treatment of psoriasis. Although some of these analogs are already approaching clinical trials, the molecular mechanism of action and their improved efficiency still remain to be fully understood. In this review the key steps of the convergent synthetic strategies that combine the modified A-ring and the CD-ring fragment carrying the altered side-chain are presented. The advantages of using the natural alicyclic and acyclic precursors are demonstrated as well as all the modern synthetic methodologies used for combining structural fragments. The results of molecular mechanics modeling are critically examined as well as the advantages and limitations of the use of the models of vitamin D proteins for the docking experiments and the design of new analogs. The potential use of advanced structural approaches, including high resolution X-ray crystallography, is discussed as to the prospect of providing a better understanding of the observed activity of modified analogs. Biological profiles in vitro and in vivo for groups of analogs are presented in a new tabular form to illustrate structure activity relationships.
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Receptores de Calcitriol/agonistas , Vitamina D/análogos & derivados , Vitamina D/farmacología , Humanos , Estructura Molecular , Receptores de Calcitriol/metabolismo , Vitamina D/síntesis química , Vitamina D/químicaRESUMEN
Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.
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Receptores de Activinas Tipo I/genética , Astrocitoma/genética , Neoplasias Encefálicas/genética , Regulación Neoplásica de la Expresión Génica/genética , Genoma Humano/genética , Mutación/genética , Animales , Secuencia de Bases , Proteínas Morfogenéticas Óseas/metabolismo , Niño , Variaciones en el Número de Copia de ADN/genética , Metilación de ADN/genética , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Proteínas Smad/metabolismoRESUMEN
Reactive oxygen species (ROS) have been long regarded as by-products of a cascade of reactions stemming from cellular oxygen metabolism, which, if they accumulate to toxic levels, can have detrimental effects on cellular biomolecules. However, more recently, the recognition of ROS as mediators of cellular communications has led to their classification as signalling mediators in their own right. The prototypic redox-regulated targets downstream of ROS are the protein tyrosine phosphatases, and the wealth of research that has focused on this area has come to shape our understanding of how redox-signalling contributes to and facilitates protein tyrosine phosphorylation signalling cascades. However, it is becoming increasingly apparent that there is more to this system than simply the negative regulation of protein tyrosine phosphatases. Identification of redox-sensitive kinases such as Src led to the slow emergence of a role for redox regulation of tyrosine kinases. A flow of evidence, which has increased exponentially in recent times as a result of the development of new methods for the detection of oxidative modifications, demonstrates that, by concurrent oxidative activation of tyrosine kinases, ROS fine tune the duration and amplification of the phosphorylation signal. A more thorough understanding of the complex regulatory mechanism of redox-modification will allow targeting of both the production of ROS and their downstream effectors for therapeutic purposes. The present review assesses the most relevant recent literature that demonstrates a role for kinase regulation by oxidation, highlights the most significant findings and proposes future directions for this crucial area of redox biology.