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1.
Oncogene ; 20(55): 8042-4, 2001 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-11753688

RESUMO

The most common malignant germ cell tumor of early childhood is the endodermal sinus tumor (CEST), also known as yolk sac tumor. Previous cytogenetic studies of CEST have demonstrated recurrent deletion of distal regions of chromosomes 1p and 6q. Studies utilizing comparative genomic hybridization have likewise demonstrated loss of distal 6q, however these studies show discrepant data concerning chromosome 1 abnormalities. This study analyses 18 CESTs for loss of heterozygosity (LOH) of distal chromosome 6q utilizing 17 microsatellite markers and 13 tumors were analysed for LOH of distal 1p using two microsatellite markers. LOH of 6q was found in 13/18 tumors (72 %). This data confirms that loss of genetic material on 6q is one of the most common abnormalities in CESTs and narrows the region of loss, enabling candidate tumor suppressor genes to be identified and analysed. In addition, LOH of 1p36 was identified in five of 11 informative tumors, clarifying prior conflicting data and confirming that 1p deletion is a common event in CESTs.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 6/genética , Tumor do Seio Endodérmico/genética , Frequência do Gene/genética , Perda de Heterozigosidade/genética , Repetições de Microssatélites/genética , Pré-Escolar , Humanos , Lactente , Masculino , Neoplasias Testiculares/genética
2.
Cancer Res ; 61(19): 7268-76, 2001 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-11585765

RESUMO

Pediatric germ cell tumors (GCTs) commonly arise at extragonadal sites. It has been proposed that nongonadal GCTs arise from ectopic primordial germ cells that have aberrantly migrated during embryogenesis. During a time between their migration and development to mature gametes, primordial germ cells are characterized by their lack of imprinting, which can be assessed by the evaluation of allelic gene expression and DNA methylation in differentially methylated control regions. To elucidate the cellular origin of nongonadal GCTs, we evaluated the imprinting status of 21 gonadal and 21 nongonadal pediatric GCTs. Allele-specific H19 and IGF-2 expression was assessed with reverse transcription-PCR followed by digestion at polymorphic restriction sites. DNA methylation was evaluated after bisulfite modification, PCR amplification, and restriction digestion at a consistently methylated CpG dinucleotide within the 5' flanking region of the SNRPN gene. These results were compared with genetic gains and losses determined by comparative genomic hybridization. Seven of 15 informative tumors showed biallelic H19 expression, and 8 of 17 informative tumors showed biallelic IGF-2 expression. The frequency of biallelic gene expression was comparable in gonadal and nongonadal GCTs. Sixteen of 19 gonadal GCTs and 17 of 21 nongonadal GCTs showed absence of methylation of SNRPN consistent with loss of imprinting. One testicular GCT and three nongonadal GCTs showed a somatic methylation pattern. Two ovarian teratomas and one mediastinal teratoma showed only methylated SNRPN, consistent with entry into meiosis. Twenty-one of 22 non-GCT control samples showed a somatic methylation pattern. Gonadal and nongonadal germ cell tumors are derived from primordial germ cells that have consistently lost the imprinting of SNRPN and partly lost imprinting of H19 and IGF-2. Because the imprinting pattern of the latter genes differs from that found in testicular GCTs of adult patients, our data suggest that pediatric GCTs arise from a different stage of germ cell development.


Assuntos
Impressão Genômica , Germinoma/genética , Germinoma/patologia , Ribonucleoproteínas Nucleares Pequenas , Adolescente , Adulto , Alelos , Autoantígenos/genética , Criança , Pré-Escolar , Metilação de DNA , Feminino , Expressão Gênica , Humanos , Lactente , Fator de Crescimento Insulin-Like II/genética , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Hibridização de Ácido Nucleico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Longo não Codificante , RNA não Traduzido/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Proteínas Centrais de snRNP
3.
Klin Padiatr ; 213(4): 204-11, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11528555

RESUMO

BACKGROUND: Germ Cell Tumors (GCTs) in children and adolescents constitute a clinically and histologically heterogeneous group of tumors. Compared to GCTs in adults, the numbers of GCTs in children analyzed with cytogenetic and molecular genetic techniques is limited. However, the data available to date reveal a pattern of cytogenetic aberrations different from that in adults. Comparative genomic hybridization (CGH) is a valuable technique for the genetic profiling of tumors that allows screening for chromosomal imbalances consistent with amplification of oncogenes and loss of putative tumor suppressor genes. As CGH does not require tissue culture, it also allows analysing archival tissue samples. PATIENTS: This study focuses exclusively on GCTs in children younger than ten years of age and summarizes the genetic data of 51 tumors. Eighteen teratomas and 33 malignant GCTs were included. Primary sites were the testis (n=10), coccyx (n=13), mediastinum (n=20), ovary (n=5), CNS (n=2), and the face (n=1). METHODS: The experimental procedure includes differential enzymatic fluorescence labeling of tumor and control DNA followed by comparative hybridization to normal male chromosomes, karyotyping and computerized analysis of the fluorescence profiles. RESULTS: With the exception of one testicular and two ovarian tumors, malignant GCTs in children do not show chromosomal gain of 12p, which is characteristic of GCTs in adult patients. Irrespective of the primary site, childhood GCTs show chromosomal imbalances of chromosome 1 (loss of distal 1p, gain of 1q), deletion of 4q and 6q as well as gain of 20q at a high frequency. CONCLUSIONS: These studies will help guiding further investigations elucidating the role of putative tumor suppressor genes at e.g. 1p36 and 6q. In addition, further studies incorporated in prospective therapeutic protocols are necessary to evaluate the prognostic relevance of specific genetic aberrations.


Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos , DNA de Neoplasias/análise , Germinoma/genética , Hibridização de Ácido Nucleico , Adolescente , Adulto , Fatores Etários , Neoplasias do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Análise Citogenética , Tumor do Seio Endodérmico/genética , Neoplasias Faciais/genética , Feminino , Germinoma/classificação , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias do Mediastino/genética , Hibridização de Ácido Nucleico/métodos , Neoplasias Ovarianas/genética , Estudos Retrospectivos , Região Sacrococcígea , Teratoma/genética , Neoplasias Testiculares/genética , Células Tumorais Cultivadas
4.
J Chromatogr B Biomed Appl ; 664(2): 357-63, 1995 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-7780588

RESUMO

This paper describes the determination of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil in urine. The method involves sample clean-up by liquid-liquid extraction with ethyl acetate followed by high-performance liquid chromatographic (HPLC) analysis. The sample preparation may be performed either manually or automatically using a Zymark Py-robotic system. The chloro analog of the parent compound, CV-araU, is used as the internal standard. As low as 0.1 microgram of analyte per ml of urine can be measured. This sensitivity is adequate for pharmacokinetic studies but could be improved quite easily if necessary.


Assuntos
Antivirais/urina , Arabinofuranosiluracila/análogos & derivados , Bromouracila/análogos & derivados , Antivirais/farmacocinética , Arabinofuranosiluracila/farmacocinética , Arabinofuranosiluracila/urina , Autoanálise , Bromouracila/urina , Cromatografia Líquida de Alta Pressão , Humanos , Robótica
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