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1.
Inorg Chem ; 59(11): 7435-7443, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32428400

RESUMO

A family of neutral bis-cyclometalated Ir(III) complexes based on phenanthridine (phent) derivates as cyclometalating ligands and picolinate as an ancillary ligand are described. The influence of extended conjugation, rigidity, and hydrophobicity as well as the electronic nature of the substituents were investigated in relation to the photoluminescence, PL, and electrochemiluminescence, ECL, properties. A significant increase of ECL in aqueous media is observed upon extension of the aromatic system or by substituting the phenyl with a dibenzofurane moiety, in compounds 2 and 3, respectively. Under real immunoassay conditions, these complexes achieve up to 4-fold higher ECL efficiency than the commercial ruthenium standard. These values, among the highest reported in the literature under these conditions, confirm the potential of iridium complexes as alternative labels in commercial instruments.

2.
Leuk Lymphoma ; 59(10): 2318-2326, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29115891

RESUMO

Small lymphocytic lymphoma (SLL) is considered as the non-leukemic form of presentation of chronic lymphocytic leukemia (CLL). We have compared the features, genomic alterations, and outcome of 890 patients with CLL and SLL. One hundred and thirteen patients presented as SLL and more frequently had unmutated-IGHV, CD38high, ZAP-70high, CD49dhigh, +12, alterations in genes of NOTCH1, cell cycle, RNA metabolism, and NFkB pathways than CLL. During the follow-up, 46% of SLL patients developed CLL. Time to first treatment (TTFT) was shorter in SLL (10-year: 75% vs 62%; p = .006). Binet stage, SLL, and IGHV were independent predictive factors for TTFT. Transformation to diffuse large B-cell lymphoma was higher (10-year: 12% vs 6%; p = .003), and overall survival was shorter in SLL (10-year: 55% vs 66%; p = .004). When A0 CLL patients were excluded, only CD38 and CD49d expression, +12, and 10-year TTFT remained different between the SLL and CLL patients. In summary, SLL showed only minor clinicobiological differences when compared with CLL in similar clinical stages.


Assuntos
Genoma Humano/genética , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Tempo para o Tratamento/estatística & dados numéricos , Adulto Jovem
3.
Anal Chem ; 88(8): 4174-8, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-26978720

RESUMO

A family of neutral bis-cyclometalated iridium complexes [Ir(C^N)2(LX)] has been investigated as ECL labels under immunoassay conditions. Among them, the complex based on phenylphenanthridine (pphent) as the C^N ligand, exhibits outstanding performance and it is a candidate to substitute the commercially available Ru-based label in diagnostics.


Assuntos
Técnicas Eletroquímicas , Irídio/química , Luminescência , Compostos Organometálicos/química , Processos Fotoquímicos , Água/química , Imunoensaio , Soluções
4.
Drug Metab Pers Ther ; 31(1): 25-34, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26863347

RESUMO

Pharmacogenetics and pharmacogenomics (PGx) are rapidly growing fields that aim to elucidate the genetic basis for the interindividual differences in drug response. PGx approaches have been applied to many anticancer drugs in an effort to identify relevant inherited or acquired genetic variations that may predict patient response to chemotherapy and targeted therapies. In this article, we discuss the advances in the field of cancer pharmacogenetics and pharmacogenomics, driven by the recent technological advances and new revolutionary massive sequencing technologies and their application to elucidate the genetic bases for interindividual drug response and the development of biomarkers able to personalize drug treatments. Specifically, we present recent progress in breast cancer molecular classifiers, cell-free circulating DNA as a prognostic and predictive biomarker in cancer, patient-derived tumor xenograft models, chronic lymphocytic leukemia genomic landscape, and current pharmacogenetic advances in colorectal cancer. This review is based on the lectures presented by the speakers of the symposium "Pharmacogenetics and Pharmacogenomics as Tools in Cancer Therapy" from the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF), held in Madrid (Spain) on April 21, 2015.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Farmacogenética/métodos , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Humanos , Terapia de Alvo Molecular , Neoplasias/genética , Medicina de Precisão/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
5.
Mol Carcinog ; 55(5): 705-16, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-25808986

RESUMO

Chromosomal instability resulting in copy number alterations is a hallmark of colorectal cancer (CRC). However, few studies have attempted to characterize the chromosomal changes occurring in early-onset CRC in order to compare them with those taking place within the more extensively studied late-onset CRC subset. Our aim was to characterize the genomic profiles of these two groups of colorectal tumors and to compare them to each other. Array comparative genomic hybridization profiling of 146 colorectal tumors (60 early-onset and 86 late-onset) in combination with an unsupervised analysis was used to define common and specific copy number alterations. We found a number of important differences between the chromosomal instability profiles of each age subset. Thus, losses at 1p36, 1p12, 1q21, 9p13, 14q11, 16p13, and 16p12 were significantly more frequent in younger patients, whereas gains at 7q11 and 7q22 were more frequent in older patients. Moreover, the unsupervised analysis stratified the tumors into two clusters, each one of which was enriched in patients from one of the age subsets. Our findings confirm the existence of substantial differences between the chromosomal instability profiles of the two groups which are more important from a qualitative point of view. Further studies are needed to understand the clinicopathological implications of these dissimilarities.


Assuntos
Instabilidade Cromossômica , Neoplasias Colorretais/genética , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Adulto Jovem
6.
Langmuir ; 30(46): 14021-9, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25347390

RESUMO

Light-emitting electrochemical cells (LECs) showing a white emission have been prepared with Langmuir-Blodgett (LB) films of the metallosurfactant bis[2-(2,4-difluorophenyl)pyridine][2-(1-hexadecyl-1H-1,2,3-triazol-4-yl)pyridine]iridium(III) chloride (1), which work with an air-stable Al electrode. They were prepared by depositing a LB film of 1 on top of a layer of poly(N,N'-diphenyl-N,N'-bis(4-hexylphenyl)-[1,1'-biphenyl]-4,4'-diamine (pTPD) spin-coated on indium tin oxide (ITO). The white color of the electroluminescence of the device contrasts with the blue color of the photoluminescence of 1 in solution and within the LB films. Furthermore, the crystal structure of 1 is reported together with the preparation and characterization of the Langmuir monolayers (π-A compression isotherms and Brewster angle microscopy (BAM)) and LB films of 1 (IR, UV-vis and emission spectroscopy, X-ray photoelectron spectroscopy (XPS), specular X-ray reflectivity (SXR), and atomic force microscopy (AFM)).

7.
Genes Chromosomes Cancer ; 52(8): 753-63, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23686965

RESUMO

The infrequency of translocations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemias (CMML) makes their identification and reporting interesting for the recognition of the recurrent ones and the genes involved in these neoplasias. The aims of this study were to identify new translocations associated with MDS and CMML and to establish their frequency in a cohort of 8,016 patients from the Spanish Group of MDS database. The karyotype was evaluable in 5,654 (70%) patients. Among those, 2,014 (36%) had chromosomal abnormalities, including 213 (10%) translocations identified in 195 patients. The translocations were balanced in 183 (86%) cases and unbalanced in 30 (14%) cases. All chromosomes were found to be involved in translocations, with the single exception of the Y chromosome. The chromosomes most frequently involved were in decreasing frequency: 3, 1, 7, 2, 11, 5, 12, 6, and 17. Translocations were found in karyotypes as the unique chromosomal abnormality (33%), associated with another chromosomal abnormality (11%), as a part of a complex karyotype (17%), and as a part of a monosomal karyotype (38%). There were 155 translocations not previously described in MDS or CMML and nine of them appeared to be recurrent.


Assuntos
Cromossomos Humanos/genética , Leucemia Mielomonocítica Crônica/genética , Síndromes Mielodisplásicas/genética , Translocação Genética/genética , Cromossomos Humanos/classificação , Humanos , Cariótipo , Leucemia Mielomonocítica Crônica/patologia , Síndromes Mielodisplásicas/patologia
8.
Br J Haematol ; 162(1): 74-86, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23614682

RESUMO

Lenalidomide is an effective drug in low-risk myelodysplastic syndromes (MDS) with isolated del(5q), although not all patients respond. Studies have suggested a role for TP53 mutations and karyotype complexity in disease progression and outcome. In order to assess the impact of complex karyotypes on treatment response and disease progression in 52 lenalidomide-treated patients with del(5q) MDS, conventional G-banding cytogenetics (CC), single nucleotide polymorphism array (SNP-A), and genomic sequencing methods were used. SNP-A analysis (with control sample, lymphocytes CD3+, in 30 cases) revealed 5q losses in all cases. Other recurrent abnormalities were infrequent and were not associated with lenalidomide responsiveness. Low karyotype complexity (by CC) and a high baseline platelet count (>280 × 10(9) /l) were associated with the achievement of haematological response (P = 0·020, P = 0·013 respectively). Unmutated TP53 status showed a tendency for haematological response (P = 0·061). Complete cytogenetic response was not observed in any of the mutated TP53 cases. By multivariate analysis, the most important predictor for lenalidomide treatment failure was a platelet count <280 × 10(9) /l (Odds Ratio = 6·17, P = 0·040). This study reveals the importance of a low baseline platelet count, karyotypic complexity and TP53 mutational status for response to lenalidomide treatment. It supports the molecular study of TP53 in MDS patients treated with lenalidomide.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Fatores Imunológicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Talidomida/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Bandeamento Cromossômico , Progressão da Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/mortalidade , Polimorfismo de Nucleotídeo Único , Talidomida/uso terapêutico , Resultado do Tratamento
9.
Inorg Chem ; 52(4): 1812-24, 2013 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-23383706

RESUMO

A series of blue and blue-green emitters based on neutral bis- and tris-cyclometalated Ir(III) complexes with 1-benzyl-4-(2,6-difluorophenyl)-1H-1,2,3-triazole (dfptrBn) as cyclometalating ligand is reported. The bis-cyclometalated complexes of the type [Ir(dfptrBn)(2)(L(^)X)] with different ancillary ligands, L(^)X = picolinate (pic) (2) or 2-(5-(perfluorophenyl)-2H-1,2,4-triazol-3-yl)pyridine (pytrF(5)) (3), are described and their photophysical properties compared with the analogous complexes containing the archetypal 2-(2,4-difluorophenyl)pyridinato (dfppy) as cyclometaled ligand (C(^)N). Complex 2 exhibits a marked solvatochromic behavior, from 475 nm in toluene to 534 nm in formamide, due to the strong MLCT character of its emissive excited state. Complex 3 displays a true-blue emission, narrower in the visible part than FIrpic. In addition, the homoleptic complex [Ir(dfprBn)(3)] (4) and the heteroleptic compounds with mixed arylpyridine/aryltriazole ligands, [Ir(dfptrBn)(2)(C(^)N)] (C(^)N = 2-phenylpyridinato (ppy) (5) or dfppy (6)), have been synthesized and fully characterized. The facial (fac) complex fac-4 is emissive at 77 K showing a deep-blue emission, but it is not luminescent in solution at room temperature similarly to their phenylpyrazole counterparts. However, the fac isomers, fac-5 and fac-6, are highly emissive in solution and thin films, reaching emission quantum yields of 76%, with emission colors in the blue to blue-green region. The photophysical properties for all complexes have been rationalized by means of quantum-chemical calculations. In addition, we constructed electroluminescent devices, organic light-emitting diodes (OLEDs) by sublimation of fac-6, and by solution processed polymer-based devices (PLEDs) using complexes fac-5 or fac-6 as dopants.


Assuntos
Técnicas Eletroquímicas , Irídio/química , Luminescência , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Triazóis/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Teoria Quântica
10.
Methods Mol Biol ; 973: 121-45, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23412787

RESUMO

BAC array-CGH is a powerful method to identify DNA copy number changes (gains, amplifications and deletions) on a genome-wide scale, and to map these changes to genomic sequence. It is based on the analysis of genomic DNA isolated from test and reference cell populations, the differential labelling with fluorescent dyes and the co-hybridization with a genomic array. BAC array-CGH has proven to be a specific, sensitive, and reliable technique, with considerable advantages compared to other methods used for the analysis of DNA copy number changes. The application of genome scanning technologies and the recent advances in bioinformatics tools that enable us to perform a robust and highly sensitive analysis of array-CGH data, useful not only for genome scanning of tumor cells but also in the identification of novel cancer related genes, oncogenes and suppressor genes. Cytogenetic analysis provides essential information for diagnosis and prognosis in patients with hematologic malignancies such as lymphomas. However, the chromosomal interpretation in non-Hodgkin lymphoma (NHL) is sometimes inconclusive. Copy number aberrations identified by BAC array-CGH analyses could be a complementary methodology to chromosomal analysis. In NHL the genomic imbalances might have a prognostic rather than a diagnostic value. In fact, the diagnosis of NHL is based on pathological and molecular cytogenetics data. Furthermore genetic variations and their association with specific types of lymphoma development, and elucidation of the variable genetic pathways leading to lymphoma development, are important directions for future cancer research. Array-CGH, along with FISH and PCR, will be used for routine diagnostic purposes in near future.


Assuntos
Hibridização Genômica Comparativa/métodos , Linfoma Difuso de Grandes Células B/genética , Adulto , Idoso , Aberrações Cromossômicas , Cromossomos Artificiais Bacterianos/genética , DNA/genética , DNA/isolamento & purificação , Feminino , Dosagem de Genes , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto Jovem
11.
Br J Haematol ; 159(3): 311-21, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22958186

RESUMO

Trisomy 8 is the most common chromosomal gain in myelodysplastic syndromes (MDS), however, little is known about the features of MDS with isolated trisomy 8 and the influence of additional cytogenetic aberrations. We determined the characteristics and prognostic factors of 72 patients with trisomy 8 as a single anomaly and analysed also the impact of other aberrations added to trisomy 8 in another 62 patients. According to our study, MDS with isolated trisomy 8 was more frequent in men, with more than one cytopenia in most patients (62%) and having about 4% bone marrow blasts. The multivariate analysis demonstrated that platelet count and percentage bone marrow blasts had the strongest impact on overall survival (OS). The median OS for isolated trisomy 8, trisomy 8 plus one aberration (tr8 + 1), plus two (tr8 + 2) and plus three or more aberrations (tr8 + ≥3) was 34·3, 40, 23·4 and 5·8 months, respectively (P < 0·001). Trisomy 8 confers a poorer prognosis than a normal karyotype in MDS patients with ≥5% bone marrow blasts. This study supports the view that MDS with isolated trisomy 8 should be included in the intermediate cytogenetic risk group.


Assuntos
Aberrações Cromossômicas , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Trissomia , Adulto , Idoso , Cromossomos Humanos Par 8 , Progressão da Doença , Feminino , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Prognóstico , Risco
12.
J Neurooncol ; 110(1): 69-77, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22864683

RESUMO

Even though much progress has been made towards understanding the molecular nature of glioma, the survival rates of patients affected by this tumour have not changed significantly over recent years. Better knowledge of this malignancy is still needed in order to predict its outcome and improve patient treatment. VAV1 is an GDP/GTP exchange factor for Rho/Rac proteins with oncogenic potential that is involved in the regulation of cytoskeletal dynamics and cell migration. Here we report its overexpression in 59 patients diagnosed with high-grade glioma, and the associated upregulation of a number of genes coding for proteins also involved in cell invasion- and migration-related processes. Unexpectedly, immunohistochemical experiments revealed that VAV1 is not expressed in glioma cells. Instead, VAV1 is found in non-tumoural astrocyte-like cells that are located either peritumouraly or perivascularly. We propose that the expression of VAV1 is linked to synergistic signalling cross-talk between cancer and infiltrating cells. Interestingly, we show that the pattern of expression of VAV1 could have a role in the neoplastic process in glioblastoma tumours.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas Proto-Oncogênicas c-vav/biossíntese , Microambiente Tumoral/fisiologia , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Análise por Conglomerados , Hibridização Genômica Comparativa , Intervalo Livre de Doença , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-vav/análise , Receptor Cross-Talk/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
J Integr Bioinform ; 9(3): 206, 2012 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-22829577

RESUMO

Advances in bioinformatics have contributed towards a significant increase in available information. Information analysis requires the use of distributed computing systems to best engage the process of data analysis. This study proposes a multiagent system that incorporates grid technology to facilitate distributed data analysis by dynamically incorporating the roles associated to each specific case study. The system was applied to genetic sequencing data to extract relevant information about insertions, deletions or polymorphisms.


Assuntos
Automação , Biologia Computacional/métodos , Conhecimento , Análise de Sequência/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Interface Usuário-Computador
15.
Ann Surg Oncol ; 19(7): 2367-79, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22395973

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system in adults. Patients with GBM have few treatment options, and their disease is invariably fatal. Molecularly targeted agents offer the potential to improve patient treatment; however, the use of these will require a fuller understanding of the genetic changes in this complex tumor. METHODS: We analyzed a series of 32 patients with GBM with array comparative genomic hybridization in combination with gene expression analysis. We focused on the recurrent breakpoints found by spectral karyotyping (SKY). RESULTS: By SKY we identified 23 recurrent breakpoints of the 202 translocations found in GBM cases. Gains and losses were identified in chromosomal regions close to the breakpoints by array comparative genomic hybridization. We evaluated the genes located in the regions involved in the breakpoints in depth. A list of 406 genes that showed a level of expression significantly different between patients and control subjects was selected to determine their effect on survival. Genes CACNA2D3, PPP2R2B, SIK, MAST3, PROM1, and PPP6C were significantly associated with shorter survival (median 200 days vs. 450 days, P≤0.03). CONCLUSIONS: We present a list of genes located in regions of breakpoints that could be grounds for future studies to determine whether they are crucial in the pathogenesis of this type of tumor, and we provide a list of six genes associated with the clinical outcome of patients with GBM.


Assuntos
Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Perfilação da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Cariotipagem Espectral , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Glioblastoma/mortalidade , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Taxa de Sobrevida
17.
Nat Genet ; 44(1): 47-52, 2011 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-22158541

RESUMO

Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Mutação , Fosfoproteínas/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Sequência de Aminoácidos , Progressão da Doença , Exoma , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Fatores de Processamento de RNA , Alinhamento de Sequência
18.
PLoS One ; 6(9): e24939, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21957467

RESUMO

Splenic marginal zone lymphomas (SMZL) are an uncommon type of B-cell non-Hodgkin's lymphoma (NHL-B) in which no specific chromosomal translocations have been described. In contrast, the most frequent cytogenetic abnormality is the loss of the long arm of chromosome 7 (7q). Previous reports have located this loss in the 7q32 region. In order to better characterize the genomic imbalances in SMZL, molecular studies were carried out in 73 patients with SMZL. To gain insight into the mapping at 7q a tiling array was also used. The results confirmed the loss of 7q as the most frequent change. In addition, several abnormalities, including 4q22.1, 1q21.3-q22, 6q25.3, 20q13.33, 3q28, 2q23.3-q24.1 and 17p13, were also present. A loss of 7q22.1 at 99925039-101348479 bp was observed in half of the cases. The region of 7q22.1 has not previously been characterised in SMZL. Our results confirmed the presence of a new region of loss on chromosome 7 in these NHL.


Assuntos
Cromossomos Humanos Par 7/genética , Linfoma de Zona Marginal Tipo Células B/genética , Neoplasias Esplênicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Deleção Cromossômica , Cromossomos Artificiais Bacterianos/genética , Hibridização Genômica Comparativa , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reprodutibilidade dos Testes
19.
Med. clín (Ed. impr.) ; 137(5): 221-229, sept. 2011.
Artigo em Espanhol | IBECS | ID: ibc-91788

RESUMO

Desde la descripción, en el año 1960, del cromosoma Filadelfia como una alteración asociada con la leucemia mieloide crónica se han descrito una multitud de alteraciones citogenéticas en los enfermos con hemopatías malignas, de manera que, en la actualidad, la realización de estos estudios es imprescindible en estas enfermedades. La presencia de cambios citogenéticos no solo contribuye a un mejor diagnóstico y clasificación de las leucemias y de los linfomas, sino que es un factor pronóstico de primer nivel. Por esto, la clasificación de la Organización Mundial de la Salud las ha incluido como parte fundamental del diagnóstico de las hemopatías malignas. El desarrollo de la hibridación «in situ» fluorescente y, más recientemente, de las micromatrices ha contribuido a un mejor conocimiento de estas enfermedades, por lo que se consideran un complemento de los estudios citogenéticos. Los cambios citogenéticos observados en estos enfermos son, en ocasiones, una pieza clave en el enfoque terapéutico (AU)


In 1960 Ph-chromosome was found associated with the presence of chronic myelogenous leukemia. In these 50 years an increasing number of cytogenetic abnormalities have been found associated with hematological malignancies. The presence of these abnormalities is not only important for the diagnosis of the patient, but it also contributes to the prognosis of patients with leukemia or lymphoma. For this reason the WHO classification of hematological disease has included these studies for the correct characterization of leukemias and lymphomas. In addition, the use of FISH and micromatrix methodologies have refined the genetic lesions present in these malignancies. The cytogenetic changes observed also provide further information in relation to the therapy (AU)


Assuntos
Humanos , Cromossomo Filadélfia , Análise Citogenética/tendências , Análise em Microsséries/tendências , Neoplasias Hematológicas/diagnóstico , Hibridização in Situ Fluorescente/tendências , Leucemia/patologia , Linfoma/patologia
20.
Nature ; 475(7354): 101-5, 2011 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-21642962

RESUMO

Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.


Assuntos
Genoma Humano/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Sequência de Aminoácidos , Animais , Proteínas de Transporte/genética , Análise Mutacional de DNA , Humanos , Carioferinas/genética , Dados de Sequência Molecular , Fator 88 de Diferenciação Mieloide/química , Fator 88 de Diferenciação Mieloide/genética , Receptor Notch1/genética , Receptores Citoplasmáticos e Nucleares/genética , Reprodutibilidade dos Testes
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