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1.
Hum Pathol ; 43(10): 1772-6, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22703924

RESUMEN

Peripheral primitive neuroectodermal tumor/Ewing sarcoma and neuroblastoma are distinct malignant tumors belonging to the group of undifferentiated solid pediatric tumors. We report a case of a 14-year-old adolescent girl who presented with a right lower quadrant mass. At surgery, a mobile retroperitoneal mass was entirely removed. Histologic evaluation revealed 2 distinct components; the first, consisting of sheets of undifferentiated cells, was CD99+ and CD56-, whereas the second, consisting of multiple foci of neuropil and maturing neuroblasts, was CD99- and CD56+. Fluorescence in situ hybridization analysis revealed the presence of EWSR1/FLI1 translocation in both histologic distinct components. MYCN (myelocytomatosis viral related oncogene, neuroblastoma derived) was not amplified. The tests for t(11;22) and t(21;22) performed by reverse transcription-polymerase chain reaction were negative. The final diagnosis corresponds to an extraosseous Ewing sarcoma with foci of neuroblastoma-like differentiation. This is the first case, documented by molecular studies, in which neuroblastoma-like differentiation has been noted in primitive neuroectodermal tumor/Ewing sarcoma without prior chemotherapy.


Asunto(s)
Proteínas de Unión a Calmodulina/genética , Proteína Proto-Oncogénica c-fli-1/genética , Proteínas de Unión al ARN/genética , Neoplasias Retroperitoneales/patología , Sarcoma de Ewing/patología , Adolescente , Diferenciación Celular , Femenino , Humanos , Neuroblastoma/patología , Proteína EWS de Unión a ARN , Neoplasias Retroperitoneales/genética , Sarcoma de Ewing/genética , Translocación Genética
2.
Clin Genet ; 81(2): 128-41, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21496010

RESUMEN

Despite a wide range of clinical tools, the etiology of mental retardation and multiple congenital malformations remains unknown for many patients. Array-based comparative genomic hybridization (aCGH) has proven to be a valuable tool in these cases, as its pangenomic coverage allows the identification of chromosomal aberrations that are undetectable by other genetic methods targeting specific genomic regions. Therefore, aCGH is increasingly used in clinical genetics, both in the postnatal and the prenatal settings. While the diagnostic yield in the postnatal population has been established at 10-12%, studies investigating fetuses have reported variable results. We used whole-genome aCGH to investigate fetuses presenting at least one major malformation detected on ultrasound, but for whom standard genetic analyses (including karyotype) failed to provide a diagnosis. We identified a clinically significant chromosomal aberration in 8.2% of tested fetuses (4/49), and a result of unclear clinical significance in 12.2% of tested fetuses (6/49). Our results document the value of whole-genome aCGH as a prenatal diagnostic tool and highlight the interpretation difficulties associated with copy number variations of unclear significance.


Asunto(s)
Anomalías Múltiples/genética , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Cariotipo , Anomalías Múltiples/diagnóstico , Aberraciones Cromosómicas , Feto , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Diagnóstico Prenatal , Reproducibilidad de los Resultados
3.
Cytogenet Genome Res ; 125(3): 176-85, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19738378

RESUMEN

Human telomeres play a major role in stabilizing chromosome ends and preventing fusions. Chromosomes bearing a broken end are rescued by the acquisition of a new telomeric cap without any subtelomeric sequences being present at the breakpoint, a process referred to as chromosome healing. Conversely, a loss of telomeric function or integrity can lead to the presence of interstitial telomeres at the junction site in translocations or ring chromosomes. In order to determine the frequency at which interstitial telomeres or chromosome healing events are observed in target chromosome abnormalities, we conducted a retrospective FISH study using pan-telomeric and chromosome-specific subtelomeric probes on archival material from 40 cases of terminal deletions, translocations or ring chromosomes. Of the 19 terminal deletions investigated, 17 were negative for the subtelomeric probe specific to the deleted arm despite being positive for the pan-telomeric probe. These 17 cases were thus considered as having been rescued through chromosome healing, suggesting that this process is frequent in terminal deletions. In addition, as 2 of these cases were inherited from a parent bearing the same deletion, chromosomes healed by this process are thus stable through mitosis and meiosis. Regarding the 13 cases of translocations and 8 ring chromosomes, 4 and 2 cases respectively demonstrated pan-telomeric sequences at the interstitial junction point. Furthermore, 2 cases of translocations and 1 ring chromosome had both interstitial pan-telomeres and subtelomeres, whereas 2 other cases of ring chromosomes and 1 case of translocation only showed interstitial subtelomeres. Therefore, interstitial (sub)telomeric sequences in translocations and ring chromosomes are more common than previously thought, as we found a frequency of 43% in this study. Moreover, our results illustrate the necessity of performing FISH with both subtelomeric and pan-telomeric probes when investigating these rearrangements, as the breakpoints can be either in the distal part of the pan-telomeres, or in between the 2 types of sequences.


Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos , Telómero , Inestabilidad Cromosómica , Deleción Cromosómica , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Estudios Retrospectivos , Cromosomas en Anillo , Translocación Genética
4.
Cancer Genet Cytogenet ; 125(1): 30-40, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11297765

RESUMEN

Trisomy 8 and monosomy 7 are the two most frequent aneuploidies found in hematological disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, primed in situ labeling (PRINS), fluorescence in situ hybridization (FISH) and conventional cytogenetic approaches were used to investigate 54 cases of hematopoietic disorders. Of these cases, there were 22 cases of trisomy 8, 2 cases of tetrasomy 8, 14 cases of monosomy 7, and 16 cases with two copies of both chromosomes 7 and 8. PRINS was carried out in interphase nuclei of bone marrow samples using primers that can specifically detect alpha-satellite DNA sequences of chromosomes 7 and 8. In parallel, using the alpha-satellite probes for chromosomes 7 and 8, FISH was performed for all the cases. PRINS and FISH techniques showed similar specificity and sensitivity. In comparison to FISH, PRINS is more advantageous since it is a faster, easier, and more cost-effective technique. Additionally, for most of the cases, a higher proportion of aneuploidy was detected in metaphases using conventional cytogenetics, as compared to the one found in interphase nuclei identified with PRINS and FISH techniques. In other words, for these cases, the cells with trisomy 8 or monosomy 7, had a distinct proliferative advantage compared to the disomic cell population. Therefore, to better quantify the proportion of aneuploid cells in bone marrow, we recommend to investigate the frequency of aneuploidy in nuclei using PRINS, rather than studying only the dividing cells as detected by conventional cytogenetic techniques.


Asunto(s)
Médula Ósea/ultraestructura , Cromosomas Humanos Par 7 , Cromosomas Humanos Par 8 , Monosomía , Trisomía , Adulto , Anciano , Secuencia de Bases , Cartilla de ADN , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad
5.
Proc Natl Acad Sci U S A ; 97(18): 10254-9, 2000 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-10944192

RESUMEN

Cyclin-dependent kinases (CDKs) are commonly known to regulate cell proliferation. However, previous reports suggest that in cultured postmitotic neurons, activation of CDKs is a signal for death rather than cell division. We determined whether CDK activation occurs in mature adult neurons during focal stroke in vivo and whether this signal was required for neuronal death after reperfusion injury. Cdk4/cyclin D1 levels and phosphorylation of its substrate retinoblastoma protein (pRb) increase after stroke. Deregulated levels of E2F1, a transcription factor regulated by pRb, are also observed. Administration of a CDK inhibitor blocks pRb phosphorylation and the increase in E2F1 levels and dramatically reduces neuronal death by 80%. These results indicate that CDKs are an important therapeutic target for the treatment of reperfusion injury after ischemia.


Asunto(s)
Proteínas Portadoras , Proteínas de Ciclo Celular , Circulación Cerebrovascular/efectos de los fármacos , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Proteínas de Unión al ADN , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Ataque Isquémico Transitorio/fisiopatología , Piperidinas/farmacología , Proteínas Proto-Oncogénicas , Daño por Reperfusión/prevención & control , Animales , Apoptosis , Encéfalo/irrigación sanguínea , Encéfalo/patología , Encéfalo/fisiopatología , Circulación Cerebrovascular/fisiología , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/metabolismo , Factores de Transcripción E2F , Factor de Transcripción E2F1 , Ataque Isquémico Transitorio/enzimología , Masculino , Neuronas/patología , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Proteína 1 de Unión a Retinoblastoma , Factor de Transcripción DP1 , Factores de Transcripción/metabolismo
6.
Cancer Res ; 57(16): 3390-4, 1997 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-9270002

RESUMEN

Largely on the basis of studies using the potent clastogen ionizing radiation, it has been widely assumed that up-regulation of the cyclin-dependent kinase inhibitor p21(waf1cip1) in cultured cells exposed to DNA-damaging agents is contingent upon the presence of functional p53 tumor suppressor protein. Nevertheless, we demonstrate here that the model mutagen 254-nm UV light induces p21(waf1cip1) protein and concomitant G1 arrest in normal human skin fibroblasts, as well as in p53-deficient fibroblasts derived from cancer-prone Li-Fraumeni syndrome patients. However, as expected, following exposure to ionizing radiation, elevated p21(waf1cip1) protein levels and G1 arrest were observed only in normal fibroblasts. These data provide a prominent and clinically relevant example in which p21(waf1cip1)-mediated growth arrest occurs independently of p53 in human cells treated with a model DNA-damaging agent.


Asunto(s)
Ciclinas/biosíntesis , Proteína p53 Supresora de Tumor/efectos de la radiación , Aneuploidia , Línea Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Daño del ADN , Fibroblastos/metabolismo , Fibroblastos/efectos de la radiación , Fase G1/genética , Fase G1/efectos de la radiación , Humanos , Poliploidía , Fase S/genética , Fase S/efectos de la radiación , Piel/citología , Proteína p53 Supresora de Tumor/metabolismo
7.
Cancer Genet Cytogenet ; 96(1): 17-22, 1997 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-9209464

RESUMEN

The most prominent class of centromeric DNA sequences belongs to the alpha satellite family of tandemly repeated DNA. The human chromosome 7 has been shown to contain two distinct alpha satellite arrays: D7Z1 and D7Z2, separated by 1 Mb. The order of these arrays was analyzed in normal blood cells and in the melanoma cell line IPC182 with two approaches using in situ hybridization: (1) Relative mapping on high-resolution chromosomes in fluorescence and electron microscopy (EM); and (2) simultaneous visualization of the two sequences using fluorochromes of different colors or gold particles of different sizes. The location within the centromeric area of chromosome 7, on the side of the short arm for D7Z2 and near the long arm for D7Z1 is confirmed. In addition, the hybridization signal of D7Z2 is confined to two small areas of the centromeric region in external positions, whereas the D7Z1 signal covers the entire width of the primary constriction. In situ hybridization with D7Z1 and D7Z2, performed on the melanoma cell line IPC 182, allowed characterization of two isochromosomes, i(7)(q10) and idic(7)(q11), as well as the der(7)t(7;12) observed in this cell line. The three-derived chromosomes appeared to result from different breakpoints, but only D7Z1 was conserved in all cases, suggesting the importance of this sequence for the centromeric function.


Asunto(s)
Cromosomas Humanos Par 7/genética , ADN Satélite/genética , Melanoma/genética , Centrómero , Humanos , Hibridación Fluorescente in Situ , Linfocitos , Microscopía Electrónica , Microscopía Fluorescente , Células Tumorales Cultivadas
8.
Chromosoma ; 106(6): 405-11, 1997 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9362549

RESUMEN

Imprinted autosomal loci apparently reside in very large chromosomal domains that exhibit asynchrony in replication of homologous alleles during the DNA synthesis phase. Replication asynchrony can be cytogenetically visualized by a replication-banding discordance between homologous bands of a given pair of chromosomal homologs. The replication time of a chromosomal band at high resolution can be determined by blocking DNA synthesis at the R/G-band transition and using replication banding. The R/G transition reflects the transition from early (R-) to late (G- and C-) band DNA replication. We studied discordance between two groups of homologous chromosomal bands: (a) four bands, 6q26-27, 11p13, 11p15.5 and 15q11.2-12, each containing at least one imprinted gene; and (b) nine bands containing no known imprinted genes. Fifty pairs of chromosomes were analyzed at high resolution after R/G transition blocking and late 5-bromo-2'-deoxyuridine incorporation. The rate of discordance was the same for bands containing imprinted genes and for control bands. Both homologous bands of a pair replicate either before or after the R/G transition and do not straddle the R/G transition. Repression associated with imprinting does not appear to involve late replication at the band level of resolution. Tissue-specific inactivation is associated with DNA methylation and late replication, whereas allele-specific inactivation is associated with DNA methylation but not with delayed or late replication.


Asunto(s)
Bandeo Cromosómico/métodos , Replicación del ADN/genética , Impresión Genómica/genética , Adulto , Alelos , Cromosomas Humanos/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fase S
9.
Hum Genet ; 98(3): 323-7, 1996 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-8707303

RESUMEN

We describe a novel fragile site in a rearranged chromosome, associated with the presence of telomeric repeat sequences at the fusion point of a translocation between chromosomes 13 and Y. The case reported in this study shows a de novo (Y;13) translocation, which appears to represent fusion of an apparently intact chromosome Y with a chromosome 13 that has lost only part of its short arm. Ten percent of the cells show a normal karyotype without the (Y;13) translocation. Molecular cytogenetic studies of the derived Y;13 chromosome revealed three hybridization sites of the telomeric probes-one at each end and one at the breakpoint junction. A fragile site is also observed in the intrachromosomic telomeric region. This coincidence suggests that the telomere repeat sequences (TTAGGG)n, when present at an interstitial chromosomal location, can promote the formation of a novel fragile site.


Asunto(s)
Fragilidad Cromosómica , Cromosomas Humanos Par 13 , Telómero , Translocación Genética , Cromosoma Y , Adolescente , Sitios Frágiles del Cromosoma , Humanos , Hibridación Fluorescente in Situ , Masculino , Secuencias Repetitivas de Ácidos Nucleicos
10.
Am J Med Genet ; 63(3): 454-7, 1996 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-8737651

RESUMEN

A patient with mixed gonadal dysgenesis and Y isochromosomes i(Y) is described. Lymphocyte cultures from peripheral blood contained a high proportion of 45,X cells and several other cell lines with two different marker chromosomes (mars). These markers had either a monocentric (mar1) or a dicentric appearance (mar2). Following high-resolution GTG, RBG, QFQ, and CBG bandings, five cell lines were identified; 45,X/46,X,+mar1/46,X,+mar2/47,X,+mar1x2/47,X,+mar2x 2. The percentages were 66/6/26/1/1%, respectively. Chromosome banding analyses were insufficient for characterization of the markers. In situ hybridization of specific probes for the Y centromere and its short arm showed, both in fluorescence and electron microscopy (EM), two different Y rearrangements. Mar1 is an isochromosome for the short arm i(Yp) and mar2 is a dicentric which was shown by EM to be a double isochromosome Yp, inv dup i(Yp). The breakpoint producing mar1 is within the centromere and the one producing mar2 is within one of the short arms of the Y isochromosome. The findings of different cell populations in peripheral blood lymphocytes indicate the postzygotic instability of this i(Yp).


Asunto(s)
Disgenesia Gonadal 46 XY/genética , Isocromosomas , Cromosoma Y , Adulto , Bandeo Cromosómico , Femenino , Marcadores Genéticos , Humanos , Hibridación Fluorescente in Situ , Microscopía Electrónica
11.
Cytogenet Cell Genet ; 75(2-3): 172-9, 1996.
Artículo en Inglés | MEDLINE | ID: mdl-9040787

RESUMEN

The characteristic band patterns of replication banding (dynamic banding) were analyzed. High-resolution (550-1,250 bands per haploid genome) G- and R-band patterns were obtained after 5-bromo-2'-deoxyuridine (BrdU) incorporation during early or late S phase. Thymidine-BrdU permutation culture methods, which arrest DNA synthesis at the R-band/G-band transition, allow complementary BrdU substitution. The RBI (R bands by BrdU using immunological staining) and GBI (G bands by BrdU using immunological staining) band patterns were complementary for all chromosomes. There was no overlapping, and every part of each chromosome was positively stained by one of the two banding procedures. Comparative analysis of RBG (R bands by BrdU using Giemsa staining) and RBI band patterns, as well as GBG (G bands by BrdU using Giemsa staining) and GBI band patterns, showed good congruency, displaying a very good band-for-band match. The congruency and complementarity found for these band patterns show that high concentrations of both thymidine and BrdU blocked S-phase progression near the R-band to G-band replication transition within the S phase. They also prove that BrdU incorporation is complementary and, therefore, demonstrate the existence of the R/G transition: a possible regulatory checkpoint within the S phase of the cell cycle.


Asunto(s)
Bandeo Cromosómico , Cromosomas Humanos/ultraestructura , Replicación del ADN , Fase S , Adulto , Bromodesoxiuridina/metabolismo , Células Cultivadas , Cromatina/metabolismo , Cromosomas Humanos/metabolismo , Eucromatina , Heterocromatina/metabolismo , Humanos , Persona de Mediana Edad , Timidina/metabolismo
12.
Cytogenet Cell Genet ; 66(2): 107-12, 1994.
Artículo en Inglés | MEDLINE | ID: mdl-8287680

RESUMEN

Analysis of the retinoblastoma locus (RB1) by in situ hybridization at the infragenic level was done using human chromosomes. A high level of resolution was attained with nonisotopic in situ hybridization on banded chromosomes in both fluorescence and electron microscopy. DNA sequences less than 100 kb apart could be positioned on band 13q14 in the order expected from molecular mapping. These observations suggest that the DNA target of hybridized probes on metaphase chromosomes may correspond to nucleoprotein loops giving a resolution comparable to that obtained in interphase nuclei.


Asunto(s)
Genes de Retinoblastoma , Hibridación Fluorescente in Situ , Metafase , Humanos , Microscopía Fluorescente
13.
Prenat Diagn ; 12(11): 909-17, 1992 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-1494544

RESUMEN

A 45,X/46,Xder(Y) mosaicism detected prenatally was shown to have a rare Y inversion-duplication or Y/Y translocation which can only be identified by a combination of high resolution cytogenetics and fluorescence in situ hybridization. The present data indicate the usefulness and importance of chromosome-specific probes in the identification and characterization of chromosome rearrangements.


Asunto(s)
Bandeo Cromosómico , Hibridación Fluorescente in Situ/métodos , Mosaicismo , Aberraciones Cromosómicas Sexuales/diagnóstico , Amniocentesis , Cordocentesis , Sondas de ADN , Femenino , Reordenamiento Génico , Marcadores Genéticos , Humanos , Embarazo , Aberraciones Cromosómicas Sexuales/diagnóstico por imagen , Aberraciones Cromosómicas Sexuales/genética , Ultrasonografía
14.
Cytogenet Cell Genet ; 60(3-4): 187-9, 1992.
Artículo en Inglés | MEDLINE | ID: mdl-1505213

RESUMEN

A method for the detection by electron microscopy of chromosome banding after in situ hybridization of small, nonradioactive DNA sequences is described. Typical high-resolution G-banding is produced by adding 5-bromodeoxyuridine (BrdU) during the last part of the S-phase and by applying a monoclonal antibody against the BrdU-substituted chromosome segments, followed by the addition of protein G, but no further treatment. A protocol for in situ hybridization of small, single-copy biotinylated DNA sequences and their detection by immunogold tagging on banded chromosomes is also described. This combined approach permits high-resolution mapping of small DNA sequences and should be useful in discriminating between neighboring DNA fragments.


Asunto(s)
Bandeo Cromosómico , Mapeo Cromosómico/métodos , Microscopía Inmunoelectrónica , Hibridación de Ácido Nucleico , Anticuerpos Monoclonales , Cromosomas Humanos Par 13 , Sondas de ADN , Genes de Retinoblastoma , Humanos
15.
Proc Natl Acad Sci U S A ; 88(23): 10916-20, 1991 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-1961763

RESUMEN

Electron microscopy (EM) is seldom used with in situ hybridization to localize DNA sequences because banding methods for chromosome identification could not be coupled to EM techniques. We have applied an immunochemical replication-banding method specific for EM to solve this problem. A thymidine synchronization/BrdUrd release protocol allows BrdUrd incorporation only into late replicating bands. A biotinylated DNA probe is hybridized in situ to its complementary sequence. The biotinylated probe and the BrdUrd-substituted DNA are simultaneously localized by different reporter/detection systems using different-sized colloidal gold particles as electron-dense tags. We demonstrate the high precision of this mapping procedure by localizing on long prophase chromosomes (greater than 1000 bands per haploid set) the pXBR-1 sequence to a small subregion of the centromeric subband Xp11.1-Xq11.1. This localization to a part of an individual prophase subband is the most precise localization ever reported on human banded mitotic chromosomes.


Asunto(s)
Bandeo Cromosómico , Oro Coloide , Cromosoma X , Células Cultivadas , Coloides , Sondas de ADN , Oro , Humanos , Linfocitos/citología , Linfocitos/ultraestructura , Microscopía Electrónica/métodos , Mitosis , Hibridación de Ácido Nucleico , Dedos de Zinc/genética
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