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1.
Childs Nerv Syst ; 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591873

RESUMO

PURPOSE: In neurogenesis, ASPM (abnormal spindle-like microcephaly-associated) gene is expressed mainly in the ventricular zone of posterior fossa and is the major determinant in the cerebral cortex. Besides its role in embryonic development, ASPM overexpression promotes tumor growth, including central nervous system (CNS) tumors. This study aims to investigate ASPM expression levels in most frequent posterior fossa brain tumors of childhood and adolescence: medulloblastoma (MB), ependymoma (EPN), and astrocytoma (AS), correlating them with clinicopathological characteristics and tumor solid portion size. METHODS: Quantitative reverse transcription (qRT-PCR) is used to quantify ASPM mRNA levels in 80 pre-treatment tumor samples: 28 MB, 22 EPN, and 30 AS. The tumor solid portion size was determined by IOP-GRAACC Diagnostic Imaging Center. We correlated these findings with clinicopathological characteristics and tumor solid portion size. RESULTS: Our results demonstrated that ASPM gene was overexpressed in MB (p = 0.007) and EPN (p = 0.0260) samples. ASPM high expression was significantly associated to MB samples from patients with worse overall survival (p = 0.0123) and death due to disease progression (p = 0.0039). Interestingly, two patients with AS progressed toward higher grade showed ASPM overexpression (p = 0.0046). No correlation was found between the tumor solid portion size and ASPM expression levels in MB (p = 0.1154 and r = - 0.4825) and EPN (p = 0.1108 and r = - 0.3495) samples. CONCLUSION: Taking in account that ASPM gene has several functions to support cell proliferation, as mitotic defects and premature differentiation, we suggest that its overexpression, presumably, plays a critical role in disease progression of posterior fossa brain tumors of childhood and adolescence.

4.
Childs Nerv Syst ; 34(8): 1497-1509, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29785653

RESUMO

PURPOSE: Histone deacetylate inhibitors (HDACi), as valproic acid (VA), have been reported to enhance efficacy and to prevent drug resistance in some tumors, including medulloblastoma (MB). In the present study, we investigated VA role, combined to cisplatin (CDDP) in cell viability and gene expression of MB cell lines. METHODS: Dose-response curve determined IC50 values for each treatment: (1) VA single, (2) CDDP single, and (3) VA and CDDP combined. Cytotoxicity and flow cytometry evaluated cell viability after exposure to treatments. Quantitative PCR evaluated gene expression levels of AKT, CTNNB1, GLI1, KDM6A, KDM6B, NOTCH2, PTCH1, and TERT, before and after treatment. Besides, we performed next-generation sequencing (NGS) for PTCH1, TERT, and TP53 genes. RESULTS: The most effective treatment to reduce viability was combined for D283MED and ONS-76; and CDDP single for DAOY cells (p < 0.0001). TERT, GLI1, and AKT genes were overexpressed after treatments with VA. D283MED and ONS-76 cells presented variants in TERT and PTCH1, respectively and DAOY cell line presented a TP53 mutation. CONCLUSIONS: MB tumors belonging to SHH molecular subgroup, with TP53MUT, would be the ones that present high risk in relation to VA use during the treatment, while TP53WT MBs can benefit from VA therapy, both SHH and groups 3 and 4. Our study shows a new perspective about VA action in medulloblastoma cells, raising the possibility that VA may act in different patterns. According to the genetic background of MB cell, VA can stimulate cell cycle arrest and apoptosis or induce resistance to treatment via signaling pathways activation.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Neoplasias Cerebelares/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Meduloblastoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ácido Valproico/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/genética , Relação Dose-Resposta a Droga , Variação Genética/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/genética , Proteína Supressora de Tumor p53/genética , Ácido Valproico/farmacologia
6.
Childs Nerv Syst ; 30(7): 1165-72, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24695855

RESUMO

PURPOSE: Infant medulloblastoma (MB) is a malignant neuroepithelial embryonal tumor of the cerebellum, believed to derive from precursor granule cells with stem or progenitor cells appearance, and caused by a change in expression profile of genes related to the development. This work aims to study the expression profile of these genes in MB tumors, correlating with clinicopathological characteristics. METHODS: We quantified, by qPCR in 40 MB tumor samples, the expression of genes in HH (PTCH1, PTCH2, and GLI1), WNT (APC, CTNNB1, WIF1, and DKK2), and NOTCH pathways (NOTCH2 and HES1), which have a crucial role in development, and genes as MYCC, MYCN, and TERT, correlating this findings to patient's clinicopathological characteristics. RESULTS: Considering the universal RNA as our control sample, and considering the median of gene expression in the control samples as our cutoff, we observed that HES1 gene showed decreased expression compared to control (p = 0.0059), but patients with HES1 overexpression were directly related to a shorter survival (p = 0.0165). Individuals with higher GLI1 gene expression had significant shorter survival (p = 0.0469), and high expression was prevalent in patients up to 5 years old (p = 0.0479). Patients showing high PTCH2 expression were related to worse survival (p = 0.0426), and it was correlated with GLI1 high expression (p = 0.0094). We also observed a concomitant overexpression of WIF1 and DKK2 genes in a subgroup of MB samples (n = 11, p = 0.0118). CONCLUSIONS: Our results suggest the presence of activated developmental signaling pathways in MB, which are important for cell proliferation and maintenance, and that may be targeted for novel therapeutic options.


Assuntos
Neoplasias Cerebelares/metabolismo , Proteínas Hedgehog/metabolismo , Meduloblastoma/metabolismo , Células-Tronco Neoplásicas/patologia , Receptores Notch/metabolismo , Proteínas Wnt/metabolismo , Diferenciação Celular , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologia , Transcriptoma
7.
J Neurooncol ; 117(2): 235-42, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24532263

RESUMO

Low-grade astrocytomas comprise about 30 % of the central nervous system tumors in children. Several investigations have searched a correlation between the BRAF gene fusions alterations and mutations at IDH1 and IDH2 genes in low grade pediatric astrocytomas. This study identified the expression of KIAA1549-BRAF fusion gene and BRAF V600E mutation, mutations at exon 4 of the IDH1 and IDH2 genes in samples of pilocytic astrocytomas (PA) and grade-II astrocytomas (A-II) pediatric patients. The correlation between these alterations and the clinical profile of the patients was also evaluated. Eighty-two samples of low-grade astrocytomas (65 PA and 17 A-II) were analyzed by PCR and sequencing for each of the targets identified. We identified the KIAA1549-BRAF fusion transcript in 45 % of the samples. BRAF V600E and BRAFins598T mutations were detected in 7 and 1 % of the samples, respectively. Mutations in the R132/R172 residues of the IDH1/IDH2 genes were detected in only two samples, and the G105G polymorphism (rs11554137:C>T) was identified in ten patients. Additionally, we observed two mutations out of the usual hotspots at IDH1 and IDH2 genes. We observed a smaller frequency of mutations in IDHs genes than previously described, but since the prior studies were composed of adult or mixed (adults and children) samples, we believe that our results represent a relevant contribution to the growing knowledge in low grade childhood astrocytomas.


Assuntos
Astrocitoma/genética , Isocitrato Desidrogenase/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Gradação de Tumores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
8.
Arq Neuropsiquiatr ; 69(1): 9-12, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21359415

RESUMO

Medulloblastoma is the most common malignant tumors of central nervous system in the childhood. The treatment is severe, harmful and, thus, has a dismal prognosis. As PRAME is present in various cancers, including meduloblastoma, and has limited expression in normal tissues, this antigen can be an ideal vaccine target for tumor immunotherapy. In order to find a potential molecular target, we investigated PRAME expression in medulloblastoma fragments and we compare the results with the clinical features of each patient. Analysis of gene expression was performed by real-time quantitative PCR from 37 tumor samples. The Mann-Whitney test was used to analysis the relationship between gene expression and clinical characteristics. Kaplan-Meier curves were used to evaluate survival. PRAME was overexpressed in 84% samples. But no statistical association was found between clinical features and PRAME overexpression. Despite that PRAME gene could be a strong candidate for immunotherapy since it is highly expressed in medulloblastomas.


Assuntos
Antígenos de Neoplasias/genética , Neoplasias Cerebelares/genética , Perfilação da Expressão Gênica/métodos , Meduloblastoma/genética , Proteínas de Neoplasias/genética , Neoplasias Cerebelares/terapia , Criança , Humanos , Imunoterapia , Meduloblastoma/terapia , Reação em Cadeia da Polimerase/métodos , Estatísticas não Paramétricas
9.
Arq. neuropsiquiatr ; 69(1): 9-12, Feb. 2011. graf, tab
Artigo em Inglês | LILACS | ID: lil-598338

RESUMO

Medulloblastoma is the most common malignant tumors of central nervous system in the childhood. The treatment is severe, harmful and, thus, has a dismal prognosis. As PRAME is present in various cancers, including meduloblastoma, and has limited expression in normal tissues, this antigen can be an ideal vaccine target for tumor immunotherapy. In order to find a potential molecular target, we investigated PRAME expression in medulloblastoma fragments and we compare the results with the clinical features of each patient. Analysis of gene expression was performed by real-time quantitative PCR from 37 tumor samples. The Mann-Whitney test was used to analysis the relationship between gene expression and clinical characteristics. Kaplan-Meier curves were used to evaluate survival. PRAME was overexpressed in 84 percent samples. But no statistical association was found between clinical features and PRAME overexpression. Despite that PRAME gene could be a strong candidate for immunotherapy since it is highly expressed in medulloblastomas.


Meduloblastoma é o tumor maligno mais comum em sistema nervoso central na infância. O tratamento é agressivo e o prognóstico é restrito. Como PRAME está presente em vários tumores, incluindo meduloblastoma, e possui baixa expressão em tecidos normais, este antígeno pode ser ideal na imunoterapia. A fim de encontrar um potencial alvo molecular, investigamos a expressão PRAME em fragmentos de meduloblastoma e comparamos os resultados com as características clínicas de cada paciente. Análise da expressão do gene foi realizada por PCR real-time quantitativo em 37 amostras de tumor. O teste de Mann-Whitney foi utilizado para análise da relação entre a expressão do gene e características clínicas e teste de Kaplan-Meier para avaliar a sobrevida. PRAME teve superexpresssão em 84 por cento amostras, mas não houve nenhuma relação estatística entre as características clínicas e superexpressão de PRAME. Apesar disso, o gene PRAME poderia ser um forte candidato para a imunoterapia, pois é altamente expresso em meduloblastomas.


Assuntos
Criança , Humanos , Antígenos de Neoplasias/genética , Neoplasias Cerebelares/genética , Perfilação da Expressão Gênica/métodos , Meduloblastoma/genética , Proteínas de Neoplasias/genética , Neoplasias Cerebelares/terapia , Imunoterapia , Meduloblastoma/terapia , Reação em Cadeia da Polimerase/métodos , Estatísticas não Paramétricas
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