RESUMEN
BACKGROUND: AT/RTs are rare aggressive brain tumours, mainly affecting young children. Most cases present with genetic inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodeling complex. We have performed whole exome- and mRNA-sequencing on an early onset AT/RT case for detection of genetic events potentially contributing to the disease. RESULTS: A de novo germline variant in SMARCB1, c.601C>T p.Arg201∗, in combination with somatic deletion of the healthy allele is likely the major tumour causing event. Only seven somatic small scale mutations were discovered (hitting SEPT03, H2BFM, ZIC4, HIST2H2AB, ZIK1, KRTAP6-3, and IFNA8). All were found with subclonal allele frequencies (range 5.7-17%) and none were expressed. However, besides SMARCB1, candidate genes affected by predicted damaging germline variants that were expressed were detected (KDM5C, NUMA1, and PCM1). Analysis of differently expressed genes revealed many dysregulated pathways in the tumour, such as cell cycle, CXCR4 pathway, GPCR-signalling, and neuronal system. FGFR1, CXCR4, and MDK were upregulated and may represent possible drug targets. CONCLUSION: The loss of SMARCB1 function leads to AT/RT development and deregulated genes and pathways. Additional predisposing events may however contribute. Studies utilizing NGS technologies in larger cohorts will probably identify recurrent genetic and epigenetic alterations and molecular subgroups with implications for clinical practice and development of targeted therapies.
Asunto(s)
Proteínas Cromosómicas no Histona/deficiencia , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Genoma/genética , ARN Mensajero/genética , Tumor Rabdoide/genética , Teratoma/genética , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Lactante , Masculino , Acumulación de Mutaciones , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Proteína SMARCB1 , Análisis de Secuencia de ADN , Transducción de Señal , Factores de Transcripción/metabolismoRESUMEN
Epigenetic alterations and aberrant expression of genes controlling epigenetic mechanisms have been identified in several cancers, including medulloblastoma, the most common brain tumor in children. Here we show that combining drugs that inhibit two of the most important epigenetic factors, gene methylation and post-translational modifications of protein histone-associated DNA, with small molecule inhibitors of receptor tyrosine kinases induces apoptosis. The histone deacetylation inhibitor, 4-phenylbutyrate (4-PB) and the demethylation agent, 5-Aza-2'deoxycytidine (5-Aza-dC) had minor effects on medulloblastoma cell cytotoxity in single agent treatment whereas a significant enhancement in cell cytotoxity was seen when these drugs were combined with Gleevec. Triple treatment of medulloblastoma cells with 4-PB, 5-Aza and Gleevec were associated with reduced DNA methyltransferase activity, reduced global methylation and induction of apoptosis. Taken together these results suggest that a combination of these drugs may be beneficial in the treatment of medulloblastoma.
Asunto(s)
Epigénesis Genética , Meduloblastoma/patología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Línea Celular Tumoral , Metilación de ADN , Humanos , Meduloblastoma/genéticaRESUMEN
Este estudio tuvo como objetivo determinar los niveles de sobrecarga que presenta una muestra de cuidadores de pacientes con demencia tipo Alzheimer. La muestra fue seleccionada por conveniencia, la cual debería tener como labor principal el cuidado y mantenimiento de algún familiar que padezca esta enfermedad. Se evaluaron 52 cuidadores, sin distinción de edad, género, raza o religión. La evaluación de la sobrecarga se hizo a partir de la Escala de Sobrecarga del Cuidador Test de Zarit, la cual busca identificar el nivel de sobrecarga. Simultáneamente se organizaron los datos sociodemográficos y se analizaron a través del programa estadístico SPSS versión 1.9. Los resultados arrojaron que el 65.4% no presenta sobrecarga, el 17.3% presenta sobrecarga leve y el mismo porcentaje presenta sobrecarga intensa. Se determinó que los datos sociodemográficos como el alto nivel de escolaridad, el elevado estrato socioeconómico y el parentesco están relacionados con la no sobrecarga.
This study's objective was to determine the overload levels of caretakers for patients with Alzheimer dementia. The sample was selected by convenience. The main task had to be the care and support of a relative with this disease. 52 caretakers were evaluated, without regard of age, gender, race or religion. The overload evaluation was done using the Overload Scale of Caretaker Zarit Test, which seeks to identify the level of overload. Social demographic data was simultaneously organised and analysed using the SPSS version 1.9 statistics program. Results show that 65.4% did not file overload, 17.3% presents mild overload and the same percentage presents severe overload. It was determined that social demographic data such as highly educated, high socioeconomic status and relationship are related to the overload.
Asunto(s)
Carga de Trabajo , Cuidadores , Enfermedad de Alzheimer , Carga del Cuidador , Pacientes , Clase Social , Enfermedad , Relaciones FamiliaresRESUMEN
We have investigated in vitro effects of anticancer therapy with the histone deacetylase inhibitor (HDACi) 4-phenylbutyrate (4-PB) combined with receptor tyrosine kinase inhibitors (RTKi) gefitinib or vandetanib on the survival of glioblastoma (U343MGa) and medulloblastoma (D324Med) cells. In comparison with individual effects of these drugs, combined treatment with gefitinib/4-PB or vandetanib/4-PB resulted in enhanced cell killing and reduced clonogenic survival in both cell lines. Our results suggest that combined treatment using HDACi and RTKi may beneficially affect the outcome of cancer therapy.