Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application.

Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease. The recent discovery and subsequent development of induced pluripotent stem cell (iPSC) technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases. Utilising iPSCs, researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA. These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research.

Sobrevida de los recién nacidos con cardiopatías congénitas diagnosticadas prenatalmente / Survival of newborns with prenatally diagnosed congenital heart disease

Objetivo: Estimar la sobrevida al año de los recién nacidos con cardiopatías congénitas diagnosticadas prenatalmente y el perfil epidemiológico de sus madres. Método: Cohorte dinámica retrospectiva de 825 pacientes, ingresados entre el 1 de abril de 2003 y el 31 de marzo de 2019, con tiempo de seguimiento de 1 año, que se elaboró utilizando la base de datos del Centro de Referencia Perinatal Oriente (CERPO), Facultad de Medicina, Universidad de Chile. Resultados: Se estimó la función de supervivencia global de la muestra, obteniendo una supervivencia del 70% al año de seguimiento (error estándar (ES): 0,0164; intervalo de confianza del 95% [IC95%]: 0,66-0,73). Los recién nacidos con edad gestacional < 30 semanas tuvieron una menor sobrevida (hazard ratio [HR]: 4,17; IC95%: 1,52-11.44; p < 0,01). Los recién nacidos con un peso < 3000 g tuvieron una menor sobrevida (HR: 1,41; IC95%: 1,09-1,84; p < 0,01). La distribución de las cardiopatías congénitas según la gravedad en esta cohorte fue: riesgo vital 64%, clínicamente relevante 34% y clínicamente no relevante 2%. La menor sobrevida fue para la categoría riesgo vital (HR: 6,005; IC95%: 3,97-9,08; p < 0,01). Conclusiones: La prematuridad, el bajo peso al nacer y la gravedad de la cardiopatía se correlacionaron con una menor sobrevida.

Objective: To estimate the survival at one year of newborns with prenatally diagnosed congenital heart diseases and the epidemiological profile of their mothers. Method: Dynamic retrospective cohort of 825 patients, admitted between April 1, 2003 and March 31, 2019, with a follow-up time of 1 year, which was elaborated using the database of the Centro de Referencia Perinatal Oriente (CERPO), Faculty of Medicine, Universidad de Chile. Results: The overall survival function of the sample was estimated, resulting in a survival of 70% at one year follow-up (standard error (SE): 0.0164; 95% confidence interval [95% CI]: 0.66-0.73). Newborns with gestational age < 30 weeks had a lower survival (hazard ratio [HR]: 4.17; 95% CI: 1.52-11.44; p < 0.01). Newborns with a birth weight < 3000 g had a lower survival (HR: 1.41; 95% CI: 1.09-1.84; p < 0.01). The distribution of congenital heart disease according to severity in this cohort was: life-threatening 64%, clinically relevant 34% and clinically not relevant 2%. With a lower survival for the life-threatening category (HR: 6.005; 95% CI: 3.97-9.08; p < 0.01). Conclusions: Prematurity, low birth weight and severity of congenital heart correlated with a lower survival rate.

Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells.

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN-GAA-Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4-7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

Molecular and Cellular Effects of Hydrogen Peroxide on Human Lung Cancer Cells: Potential Therapeutic Implications.

Lung cancer has a very high mortality-to-incidence ratio, representing one of the main causes of cancer mortality worldwide. Therefore, new treatment strategies are urgently needed. Several diseases including lung cancer have been associated with the action of reactive oxygen species (ROS) from which hydrogen peroxide (H2O2) is one of the most studied. Despite the fact that H2O2 may have opposite effects on cell proliferation depending on the concentration and cell type, it triggers several antiproliferative responses. H2O2 produces both nuclear and mitochondrial DNA lesions, increases the expression of cell adhesion molecules, and increases p53 activity and other transcription factors orchestrating cancer cell death. In addition, H2O2 facilitates the endocytosis of oligonucleotides, affects membrane proteins, induces calcium release, and decreases cancer cell migration and invasion. Furthermore, the MAPK pathway and the expression of genes related to inflammation including interleukins, TNF-α, and NF-κB are also affected by H2O2. Herein, we will summarize the main effects of hydrogen peroxide on human lung cancer leading to suggesting it as a potential therapeutic tool to fight this disease. Because of the multimechanistic nature of this molecule, novel therapeutic approaches for lung cancer based on the use of H2O2 may help to decrease the mortality from this malignancy.

Importancia del manejo del ductus arterioso persistente en la XII Región al implementar el diagnóstico ecográfico y tratamiento quirúrgico a nivel local / Surgical management of persistent ductus arteriosus in the Xllth Region of Chile

Introducción: El Ductus Arterioso Persistente (DAP) representa un problema muy importante en los Recién Nacidos de Pretérmino (RNPT) menores de 1500 g. Diversos adelantos en el Servicio de Pediatría del Hospital Regional de Punta Arenas desde 1997 hicieron posible que iniciáramos la resolución local de ésta patología, tanto en Neonatos como en pacientes Pediátricos. Objetivo: Mostrar la experiencia obtenida después de 9 a±os de iniciado el diagnóstico y cirugía del DAP a nivel regional. Metodología: Evaluación prospectiva-retrospectiva de todos los pacientes operados de DAP desde Septiembre de 1997 hasta Agosto de 2006, recolectando información clínica, técnica quirúrgica y complicaciones, seguimiento y sobrevida. Se separan los pacientes en 2 grupos, los RNPT (Grupo A) y los niños de edad pediátrica (Grupo B). Resultados: Se han intervenido quirúrgicamente 16 pacientes del Grupo A y 10 pacientes del Grupo B. La edad al momento de la operación fluctuó entre 9 días y los 6 años 3 meses. En el grupo A, el peso al momento de la cirugía se encontraba entre 527 g y 2062 g. Para el diagnóstico ecocardiográfico se utilizó desde envío de imágenes por video hasta telemedicina con ecocardiografistas experimentados, hasta lograr la experiencia local. El equipo quirúrgico fue apoyado inicialmente por Cirujano Infantil con experiencia en cirugía Ductal, siendo parte del equipo en el 20 por ciento de las cirugías en el grupo A y en el 60 por ciento del grupo B. Se abordó el tórax por vía transpleural en 4 casos y extrapleural en 22 casos, sin dejar drenajes pleurales. No hubo complicaciones significativas. El tiempo de seguimiento varió entre 2 meses y 9 años, y la sobrevida fue de un 96 por ciento, con 1 paciente fallecido hasta Diciembre 2006. Conclusiones: La resolución quirúrgica de ésta patología es posible en el ámbito local, lo cual tiene gran importancia en los casos en que el traslado sea imposible o riesgoso por las condiciones de los enfermos...

Patent ductus arteriosus (PDA) accounts is a very important problem for extreme premature newborns < 1500 g due to a high associated morbi-mortality in this group of patients. After the arrival of a pediatric cardiac surgeon and training in appropriate echocardiography diagnosis, surgical treatment of this condition began at the Regional Hospital in Punta Arenas, Chile. Aim. to repon local results of PDA surgical treatment in neonates and children during a 9 year period. Method. All patients operated on for closure of PDA from September 1997 to August 2006 were included. A retrospective recollection of data, age weight at time of surgery (preterm neonates), means used to diagnose PDA, co-morbidity, surgical technique, complications and survival, was performed. A separate analysis of preterm neonates (PTN) and pediatric age patients (PA) was carried out. Results. 16 PTN and 10 PA patients were operated on. Overall, age at operation ranged from 9 days to 6 years. Weight of PTN ranged from 572 to 2062 g. Diagnosis was confirmed by echocardiography in all but one patient. Echocardiographic findings were discussed via tele-medicine with experienced specialists in many cases. The local surgical team was supported by an experienced surgeon in 20 percent of PTN and 60 percent of PA patients. A transpleural approach was used in 4 and an extrapleural approach in 22 patients; no pleural drainage was used. There were no significant complications. Only 1 patients has died in follow-up ranging from 2 months to 9 years. Conclusions. Local resolution of PDA in neonates and small children has been made possible in Punta Arenas, avoiding dangerous transfer of these patients. Assistance by trained specialists was essential to accomplish this goal. Use of tele-medicine proved to be an important factor to increase safety in the management of PDA.

Cierre de comunicaciones interauriculares y del foramen oval vía percutánea: sus aspectos ecocardiográficos / Percutaneous closure of atrial septal defects and the patent foramen ovale: echocardiographic aspects

Se presenta el uso de dispositivos para el cierre percutáneo de la comunicación interauricular y el foramen oval persistente, tanto en sus aspectos técnicos como la descripción de ellos. La experiencia del uso en nuestro servicio de Cardioseal y Amplatzer junto a las series significativas en la literatuta se describen. Nuestra conclusión es que si el costo de estos dispositivos disminuyera en nuestro país. la experiencia aumentaría hasta tal punto que la práctica del cierre percutáneo de la comunicación interauricular seía el procedimiento de primera elección, eliminando la necesidad de cirugía de corazón abierto y disminuyendo la estadía hospitalaria y los costos totales