RESUMEN
PURPOSE: Posterior fossa tumour surgery in children entails a high risk for severe speech and language impairments, but few studies have investigated the effect of the tumour on language prior to surgery. The current crosslinguistic study addresses this gap. We investigated the prevalence of preoperative word-finding difficulties, examined associations with medical and demographic characteristics, and analysed lexical errors. METHODS: We included 148 children aged 5-17 years with a posterior fossa tumour. Word-finding ability was assessed by means of a picture-naming test, Wordrace, and difficulties in accuracy and speed were identified by cut-off values. A norm-based subanalysis evaluated performance in a Swedish subsample. We compared the demographic and medical characteristics of children with slow, inaccurate, or combined slow and inaccurate word finding to the characteristics of children without word-finding difficulties and conducted a lexical error analysis. RESULTS: Thirty-seven percent (n = 55) presented with slow word finding, 24% (n = 35) with inaccurate word finding, and 16% (n = 23) with both slow and inaccurate word finding. Children with posterior fossa tumours were twice as slow as children in the norming sample. Right-hemisphere and brainstem location posed a higher risk for preoperative word-finding difficulties, relative to left-hemisphere location, and difficulties were more prevalent in boys than in girls. The most frequent errors were lack of response and semantically related sideordinated words. CONCLUSION: Word-finding difficulties are frequent in children with posterior fossa tumours, especially in boys and in children with right-hemisphere and brainstem tumours. Errors resemble those observed in typical development and children with word-finding difficulties.
Asunto(s)
Neoplasias Encefálicas , Neoplasias Infratentoriales , Niño , Masculino , Femenino , Humanos , Estudios Transversales , Neoplasias Infratentoriales/cirugía , Neoplasias Infratentoriales/complicaciones , Lenguaje , Neoplasias Encefálicas/complicacionesRESUMEN
Our previous data from a human leukemic cell line made resistant to the nucleoside analog (NA) 9-ß-D-arabinofuranosylguanine (AraG) revealed a massive upregulation of fetal hemoglobin (HbF) genes and the ABCB1 gene coding for the multidrug resistance P-glycoprotein (P-gp). The expression of these genes is regulated through the same mechanisms, with activation of the p38-MAPK pathway and inhibition of methylation making transcription factors more accessible to activate these genes. We could show that AraG, as well as other NAs, and P-gp substrates could induce global DNA demethylation and induction of Hbγ and P-gp both at the mRNA and protein expression level. We speculate that the expression of HbF prior to drug exposure or in drug-resistant cell lines is a strategy of the cancer to gain more oxygen, and thereby survival benefits. We also believe that P-gp may be induced in order to excrete Hb degradation products from the cells that would otherwise be toxic. By using Hbγ siRNA and pharmacological inhibitors of HbF production we here present a possible relationship between HbF induction and multi-drug resistance in a human leukemia cell line model.
Asunto(s)
Resistencia a Múltiples Medicamentos/fisiología , Resistencia a Antineoplásicos/fisiología , Hemoglobina Fetal/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Antineoplásicos/farmacología , Arabinonucleósidos/farmacología , Línea Celular Tumoral , Metilación de ADN , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/genética , Hemoglobina Fetal/genética , Expresión Génica/efectos de los fármacos , Humanos , Leucemia/metabolismo , Modelos Biológicos , ARN Interferente Pequeño/genéticaRESUMEN
Activation of nucleoside analogues is dependent on kinases and 5'-nucleotidases and the balance between the activity of these enzymes. The purpose of this study was to analyze deoxycytidine kinase, deoxyguanosine kinase, and 4 different 5'-nucleotidases during cell cycle progression in MOLT-4 cells. The activity of both kinases was cell cycle dependent and increased during proliferation while the activity of cytosolic 5'-nucleotidase I decreased. We could show that the kinase activity was higher than the total nucleotidase activity, which was unchanged or decreased during cell cycle progression. These data may be important in designing modern combination therapy with nucleoside analogues.
Asunto(s)
5'-Nucleotidasa/biosíntesis , Ciclo Celular , Citosol/enzimología , Desoxicitidina Quinasa/biosíntesis , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Fosfotransferasas (Aceptor de Grupo Alcohol)/biosíntesis , Línea Celular Tumoral , Medio de Cultivo Libre de Suero/farmacología , Colorantes Fluorescentes/farmacología , Humanos , Concentración 50 Inhibidora , Nucleósidos/química , Sales de Tetrazolio/farmacología , Tiazoles/farmacología , Factores de TiempoRESUMEN
The SWI/SNF complex is required for the enhancement of transcription by many transcriptional activators in yeast. Genetic and biochemical studies indicate that the complex facilitates activator function by antagonizing chromatin-mediated transcriptional repression. The absence of known DNA-binding motifs in several SWI/SNF subunits and the failure to identify SWI/SNF-dependent DNA-binding activities in crude yeast extracts have led to the belief that the complex does not bind DNA. Here we show that the SWI/SNF complex has a high affinity for DNA and that its DNA-binding properties are similar to those of proteins containing HMG-box domains. The complex interacts with the minor groove of the DNA helix, binds synthetic four-way junction DNA, and introduces positive supercoils into relaxed plasmid DNA. These properties are likely to be important in the remodelling of chromatin structure by the SWI/SNF complex
