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1.
Genes Chromosomes Cancer ; 58(3): 164-174, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30474248

RESUMEN

Although most cutaneous squamous cell carcinomas (cSCCs) develop from actinic keratoses (AKs), the key events in this evolution remain unclear. We have combined the results of different genomic and expression array platforms on matched concomitant samples of sun-exposed skin (SES), AK, and cSCC from 10 immunocompetent patients. Gene expression analysis and copy number alterations were assessed using GeneChip Human Gene 2.0 ST Array (Affymetrix, Santa Clara, CA) and CytoScan HD Cytogenetics Solution (Affymetrix) platforms, respectively. Integration of transcriptome and genome results was evaluated using the DR-Integrator tool. Additional studies (qPCR, immunohistochemistry, and Western blot) were performed for selected genes. FOSL1 and BNC1 encode transcription factors whose expression was increased in cSCC in the expression array and the qPCR. By immunohistochemistry, FOSL1 showed an intense staining at the invasive front of cSCC samples and BNC1 expression varied from a nuclear (SES) to a cytoplasmic location (cSCC). Western blot analyses confirmed the enhancement of FOSL1 and BNC1. In addition, the smallest overlapping regions (SORIs) of genomic imbalance involving at least three of the samples were selected. One of the SORIs was a deletion in the p24.1 band of chromosome 3, shared by seven of the cSCCs. A strong correlation in the integration analysis was found for NEK10, a gene contained in the previously mentioned SORI. Loss of NEK10 expression in cSCC was confirmed by immunohistochemistry and Western blot analyses. In addition, functional studies in NEK10 depleted cells were performed. In conclusion, we identified FOSL1 and BNC1, which could act as tumor drivers, and NEK10, which could function as a tumor suppressor, to be differentially expressed during cSCC development.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Neoplasias Cutáneas/genética , Transcriptoma , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Masculino , Quinasas Relacionadas con NIMA/genética , Quinasas Relacionadas con NIMA/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Neoplasias Cutáneas/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
2.
Hematol Oncol ; 35(4): 778-788, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27140599

RESUMEN

Deoxyribonucleic acid microarrays allow researchers to measure mRNA levels of thousands of genes in a single experiment and could be useful for diagnostic purposes in patients with acute myeloid leukaemia (AML). We assessed the feasibility of the AML profiler (Skyline™ Array) in genetic stratification of patients with de novo AML and compared the results with those obtained using the standard cytogenetic and molecular approach. Diagnostic bone marrow from 31 consecutive de novo AML cases was used to test MLL-PTD, FLT3-ITD and TKD, NPM1 and CEBPAdm mutations. Purified RNA was used to assess RUNX1-RUNX1T1, PML-RARα and CBFß-MYH11 rearrangements. RNA remnants underwent gene expression profiling analysis using the AML profiler, which detects chromosomal aberrations: t(8;21), t(15;17), inv(16), mutations (CEBPAdm, ABD-NPM1) and BAALC and EVI1 expression. Thirty cases were successfully analysed with both methods. Five cases had FLT3-ITD. In one case, a t(8;21) was correctly detected by both methods. Four cases had inv(16); in one, the RNA quality was unsatisfactory and it was not hybridized, and in the other three, the AML profiler detected the genetic lesion - this being a rare type I translocation in one case. Two cases with acute promyelocytic leukaemia were diagnosed by both methods. Results for NPM1 mutations were concordant in all but two cases (2/11, non-ABD mutations). Analysis of costs and turnaround times showed that the AML profiler was no more expensive than the conventional molecular approach. These results suggest that the AML profiler could be useful in multicentre trials to rapidly identify patients with AML with a good prognosis. Copyright © 2016 John Wiley & Sons, Ltd.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Leucemia Mieloide Aguda/genética , Estudios de Factibilidad , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Nucleofosmina , Pronóstico , Riesgo
3.
Am J Pathol ; 181(5): 1585-94, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23083832

RESUMEN

The main challenge for clinical management of prostate cancer is to distinguish tumors that will progress faster and will show a higher tendency to recur from the more indolent ones. We have compared expression profiles of 18 prostate cancer samples (seven with a Gleason score of 6, eight with a Gleason score of 7, and three with a Gleason score of ≥8) and five nonneoplastic prostate samples, using the Affymetrix Human Array GeneChip Exon 1.0 ST. Microarray analysis revealed 99 genes showing statistically significant differences among tumors with Gleason scores of 6, 7, and ≥8. In addition, mRNA expression of 29 selected genes was analyzed by real-time quantitative RT-PCR with microfluidic cards in an extended series of 30 prostate tumors. Of the 29 genes, 18 (62%) were independently confirmed in the extended series by quantitative RT-PCR: 14 were up-regulated and 4 were down-regulated in tumors with a higher Gleason score. Twelve of these genes were differentially expressed in tumors with a Gleason score of 6 to 7 versus ≥8. Finally, IHC validation of the protein levels of two genes from the 12-gene signature (SEC14L1 and TCEB1) showed strong protein expression levels of both genes, which were statistically associated with a high combined Gleason score, advanced stage, and prostate-specific antigen progression. This set of genes may contribute to a better understanding of the molecular basis of prostate cancer. TCEB1 and SELC14L1 are good candidate markers for predicting prognosis and progression of prostate cancer.


Asunto(s)
Biomarcadores de Tumor/genética , Proteínas Portadoras/genética , Progresión de la Enfermedad , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Factores de Transcripción/genética , Transcriptoma , Análisis de Varianza , Biomarcadores de Tumor/metabolismo , Proteínas Portadoras/metabolismo , Supervivencia sin Enfermedad , Elonguina , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias/genética , Humanos , Inmunohistoquímica , Masculino , Invasividad Neoplásica , Antígeno Prostático Específico/genética , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/metabolismo
4.
Ann Hematol ; 90(8): 939-46, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21331593

RESUMEN

This study investigates the differential gene expression profile of JAK2(V617F)-positive myeloproliferative neoplasm (MPN) patients, with and without response to hydroxyurea (HU) treatment. Twenty-one polycythemia vera, 28 essential thrombocythemia, eight secondary erythrocytosis, and 30 controls were studied. Thirty-four genes were overexpressed in patients who did not respond to HU. Of these, some participate in proliferative pathways: MAPK, AKT, Src kinase (SFK), and JAK2 pathway. JAK2 allele burden was similar between groups of responders and nonresponder. A molecular fingerprint distinguishes JAK2(V617F)-positive MPN patients without response to HU treatment, with overexpression of JAK2, MAPK14, PIK3CA, and SFK genes.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hidroxiurea/farmacología , Janus Quinasa 2/genética , Policitemia Vera/tratamiento farmacológico , Trombocitemia Esencial/tratamiento farmacológico , Familia-src Quinasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hidroxiurea/uso terapéutico , Masculino , Persona de Mediana Edad , Policitemia/tratamiento farmacológico , Policitemia/genética , Policitemia Vera/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Trombocitemia Esencial/genética , Factores de Transcripción/efectos de los fármacos , Factores de Transcripción/genética , Adulto Joven
5.
Exp Hematol ; 95: 68-80, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33421548

RESUMEN

Several studies in chronic lymphocytic leukemia (CLL) patients have reported impaired immune cell functions, which contribute to tumor evasion and disease progression. However, studies on CLL-like monoclonal B-cell lymphocytosis (MBL) are scarce. In the study described here, we characterized the immune environment in 62 individuals with clinical MBL, 56 patients with early-stage CLL, and 31 healthy controls. Gene expression arrays and quantitative reverse transcription polymerase chain reaction were performed on RNA from CD4+ peripheral blood cells; serum cytokines were measured with immunoassays; and HLA-DR expression on circulating monocytes, as well as the percentages of Th1, cytotoxic, exhausted, and effector CD4+ T cells, were evaluated by flow cytometry. In addition, cell cultures of clonal B cells and CD14-enriched or -depleted cell fractions were performed. Strikingly, MBL and early-stage CLL differed in pro-inflammatory signatures. An increased inflammatory drive orchestrated mainly by monocytes was identified in MBL, which exhibited enhanced phagocytosis, pattern recognition receptors, interleukin-8 (IL8), HMGB1, and acute response signaling pathways and increased pro-inflammatory cytokines (in particular IL8, interferon γ [IFNγ], and tumor necrosis factor α). This inflammatory signature was diminished in early-stage CLL (reduced IL8 and IFNγ levels, IL8 signaling pathway, and monocytic HLA-DR expression compared with MBL), especially in those patients with mutations in IGHV genes. Additionally, CD4+ T cells of MBL and early-stage CLL exhibited a similar upregulation of Th1 and cytotoxic genes and expanded CXCR3+ and perforin+ CD4+ T cells, as well as PD1+ CD4+ T cells, compared with controls. Cell culture assays disclosed tumor-supporting effects of monocytes similarly observed in MBL and early-stage CLL. These novel findings reveal differences in the inflammatory environment between MBL and CLL, highlighting an active role for antigen stimulation in the very early stages of the disease, potentially related to malignant B-cell transformation.


Asunto(s)
Linfocitos B/patología , Inflamación/patología , Leucemia Linfocítica Crónica de Células B/patología , Paraproteinemias/patología , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/metabolismo , Supervivencia Celular , Células Clonales/metabolismo , Células Clonales/patología , Citocinas/sangre , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Inflamación/sangre , Inflamación/inmunología , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/inmunología , Subgrupos Linfocitarios/inmunología , Masculino , Persona de Mediana Edad , Monocitos/citología , Monocitos/inmunología , Monocitos/metabolismo , Paraproteinemias/sangre , Paraproteinemias/inmunología , ARN Neoplásico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Matrices Tisulares , Escape del Tumor
6.
Int J Lab Hematol ; 43(5): 1032-1040, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33615729

RESUMEN

INTRODUCTION: Dysregulated NK cell-mediated immune responses contribute to tumor evasion in chronic lymphocytic leukemia (CLL), although the NK cell compartment in CLL-like monoclonal B-cell lymphocytosis (MBL) is poorly understood. In healthy individuals, human cytomegalovirus (HCMV) induces the expansion of NK cells expressing high levels of CD94/NKG2C NK cell receptor (NKR) specific for HLA-E. METHODS: We analyzed the expression of NKG2A, NKG2C, ILT2, KIR, CD161, and CD57 in 24 MBL and 37 CLL. NKG2C was genotyped in these patients and in 81 additional MBL/CLL, while NKG2C gene expression was assessed in 26 cases. In 8 CLL patients with increased lymphocytosis (≥20 × 109 /L), tumor HLA-E and HLA-G expression was evaluated. RESULTS: NKR distribution did not significantly differ between MBL and CLL patients, although they exhibited reduced NKG2C+ NK cells compared with a non-CLL group (4.6% vs 12.2%, P = .012). HCMV+ patients showed increased percentages of NKG2C+ NK cells compared with HCMV- (7.3% vs 2.9%, P = .176). Frequencies of NKG2C deletions in MBL/CLL were similar to those of the general population. Low/undetectable NKG2C expression was found among NKG2C+/- (45%) and NKG2C+/+ (12%) patients. CLL cases with increased lymphocytosis displayed especially reduced NKG2C expression (1.8% vs 8.1%, P = .029) and tumor cells with high HLA-E (>98%) and variable HLA-G expression (12.4%, range: 0.5-56.4). CLL patients with low NKG2C expression (<7%) showed shorter time to first treatment (P = .037). CONCLUSION: Reduced percentages of CD94/NKG2C+ NK cells were observed in CLL and MBL patients independently of HCMV serostatus and NKG2C zygosity, particularly in CLL patients with increased lymphocytosis, which could potentially be related to the exposure to tumor cells.


Asunto(s)
Infecciones por Citomegalovirus/complicaciones , Células Asesinas Naturales/patología , Leucemia Linfocítica Crónica de Células B/patología , Linfocitosis/patología , Subfamília C de Receptores Similares a Lectina de Células NK/análisis , Subfamília D de Receptores Similares a Lectina de las Células NK/análisis , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/patología , Estudios de Cohortes , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/patología , Femenino , Eliminación de Gen , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/genética , Linfocitosis/complicaciones , Linfocitosis/genética , Masculino , Persona de Mediana Edad , Subfamília C de Receptores Similares a Lectina de Células NK/genética
7.
J Clin Med ; 9(5)2020 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-32397522

RESUMEN

Risk prediction tools cannot identify most individuals at high coronary artery disease (CAD) risk. Oxidized low-density lipoproteins (oxLDLs) and microRNAs are actively involved in atherosclerosis. Our aim was to examine the association of CAD and oxLDLs-induced microRNAs, and to assess the microRNAs predictive capacity of future CAD events. Human endothelial and vascular smooth muscle cells were treated with oxidized/native low-density lipoproteins, and microRNA expression was analyzed. Differentially expressed and CAD-related miRNAs were examined in serum samples from (1) a case-control study with 476 myocardial infarction (MI) patients and 487 controls, and (2) a case-cohort study with 105 incident CAD cases and 455 randomly-selected cohort participants. MicroRNA expression was analyzed with custom OpenArray plates, log rank tests and Cox regression models. Twenty-one microRNAs, two previously undescribed (hsa-miR-193b-5p and hsa-miR-1229-5p), were up- or down-regulated upon cell treatment with oxLDLs. One of the 21, hsa-miR-122-5p, was also upregulated in MI cases (fold change = 4.85). Of the 28 CAD-related microRNAs tested, 11 were upregulated in MI cases -1 previously undescribed (hsa-miR-16-5p)-, and 1/11 was also associated with CAD incidence (adjusted hazard ratio = 0.55 (0.35-0.88)) and improved CAD risk reclassification, hsa-miR-143-3p. We identified 2 novel microRNAs modulated by oxLDLs in endothelial cells, 1 novel microRNA upregulated in AMI cases compared to controls, and one circulating microRNA that improved CAD risk classification.

8.
Sci Rep ; 7(1): 7725, 2017 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-28798363

RESUMEN

MicroRNAs (miRNAs) have emerged as promising biomarkers of disease. Their potential use in clinical practice requires standardized protocols with very low miRNA concentrations, particularly in plasma samples. Here we tested the most appropriate method for miRNA quantification and validated the performance of a hybridization platform using lower amounts of starting RNA. miRNAs isolated from human plasma and from a reference sample were quantified using four platforms and profiled with hybridization arrays and RNA sequencing (RNA-seq). Our results indicate that the Infinite® 200 PRO Nanoquant and Nanodrop 2000 spectrophotometers magnified the miRNA concentration by detecting contaminants, proteins, and other forms of RNA. The Agilent 2100 Bioanalyzer PicoChip and SmallChip gave valuable information on RNA profile but were not a reliable quantification method for plasma samples. The Qubit® 2.0 Fluorometer provided the most accurate quantification of miRNA content, although RNA-seq confirmed that only ~58% of small RNAs in plasma are true miRNAs. On the other hand, reducing the starting RNA to 70% of the recommended amount for miRNA profiling with arrays yielded results comparable to those obtained with the full amount, whereas a 50% reduction did not. These findings provide important clues for miRNA determination in human plasma samples.


Asunto(s)
MicroARN Circulante , Perfilación de la Expresión Génica , Hibridación de Ácido Nucleico , Biomarcadores , Biología Computacional/métodos , Perfilación de la Expresión Génica/instrumentación , Perfilación de la Expresión Génica/métodos , Humanos , Hibridación de Ácido Nucleico/métodos , Reproducibilidad de los Resultados , Transcriptoma
9.
PLoS One ; 12(4): e0176043, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28441455

RESUMEN

BACKGROUND: Intestinal metaplasia (IM) is a precursor lesion that precedes gastric cancer (GC). There are two IM histological subtypes, complete (CIM) and incomplete (IIM), the latter having higher progression rates to GC. This study was aimed at analysing gene expression and molecular processes involved in the progression from normal mucosa to IM, and also from IM subtypes to GC. METHODOLOGY: We used expression data to compare the transcriptome of healthy gastric mucosa to that of IM not progressing to GC, and the transcriptome of IM subtypes that had progressed to GC to those that did not progress. Some deregulated genes were validated and pathway analyses were performed. RESULTS: Comparison of IM subtypes that had progressed to GC with those that did not progress showed smaller differences in the expression profiles than the comparison of IM that did not progress with healthy mucosa. New transcripts identified in IM not progressing to GC included TRIM, TMEM, homeobox and transporter genes and SNORD116. Comparison to normal mucosa identified non tumoral Warburg effect and melatonin degradation as previously unreported processes involved in IM. Overexpressed antigen processing is common to both IM-subtypes progressing to GC, but IIM showed more over-expressed oncogenic genes and molecular processes than CIM. CONCLUSIONS: There are greater differences in gene expression and molecular processes involved in the progression from normal healthy mucosa to IM than from IM to gastric cancer. While antigen processing is common in both IM-subtypes progressing to GC, more oncogenic processes are observed in the progression of IIM.


Asunto(s)
Mucosa Gástrica/patología , Regulación Neoplásica de la Expresión Génica , Intestinos/patología , Lesiones Precancerosas/genética , Neoplasias Gástricas/genética , Progresión de la Enfermedad , Humanos , Metaplasia/genética , Metaplasia/patología , Lesiones Precancerosas/patología , Neoplasias Gástricas/patología , Transcriptoma
10.
Cancer Genet Cytogenet ; 167(1): 39-42, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16682284

RESUMEN

No specific diagnostic markers have been described in essential thrombocythemia (ET). PRV-1 (polycythemia rubra vera-1), TPO (thrombopoietin), and c-MPL (myeloproliferative leukemia virus oncogene) genes are candidate ET molecular markers because of their implication in the pathogenesis of ET. We have studied the status of PRV-1, TPO, and c-MPL genes in 30 ET patients by a fluorescence in situ hybridization (FISH) technique using three noncommercial, locus-specific probes for PRV-1 (BAC RP11-160A19, located at 19q13.2), TPO (BAC RP11-45NP16, located at 3q27), and c-MPL (BAC RP11-297L5, located at 1p34). FISH study showed no PRV-1, TPO, and c-MPL cytogenetic abnormalities in any of the analyzed cases. Our results suggest a lack of structural and numerical rearrangements (deletions, translocations, or amplifications) of PRV-1, TPO, and c-MPL genes in ET patients.


Asunto(s)
Autoantígenos/genética , Hibridación Fluorescente in Situ , Yoduro Peroxidasa/genética , Proteínas de Unión a Hierro/genética , Isoantígenos/genética , Glicoproteínas de Membrana/genética , Proteínas Proto-Oncogénicas/genética , Receptores de Superficie Celular/genética , Receptores de Citocinas/genética , Trombocitemia Esencial/genética , Estudios de Casos y Controles , Femenino , Proteínas Ligadas a GPI , Humanos , Masculino , Receptores de Trombopoyetina
11.
J Clin Endocrinol Metab ; 100(11): E1467-76, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26252355

RESUMEN

CONTEXT: Molecular mechanisms associated with physiological variations in adipose tissue (AT) are not fully recognized. The most recent reports highlight the critical relevance of microRNAs (miRNAs) found in AT. OBJECTIVE: To identify changes in messenger RNA (mRNA) and miRNA expressions and their interaction in human AT before and after surgery-induced weight loss. Research Design and Setting: Genome-wide mRNA and miRNA expressions were assessed by microarrays in abdominal subcutaneous AT of 16 morbidly obese women before and 2 years after laparoscopic Roux-en-Y gastric bypass. The association of changes in miRNAs with their respective mRNA targets was studied. The results were replicated in publicly available microarray datasets. Validation was made by real-time polymerase chain reaction in additional fat samples from 26 age-matched lean women and in isolated human adipocytes. RESULTS: A total of 5018 different mRNA probe sets and 15 miRNAs were differentially expressed after surgery-induced weight loss. The clustering of similar expression patterns for gene products with related functions revealed molecular footprints that elucidate significant changes in cell cycle, development, lipid metabolism, and the inflammatory response. The participation of inflammation was demonstrated by results assessed in isolated adipocytes. Interestingly, when transcriptomes were analyzed taking into account the presence of miRNA target sites, miRNA target mRNAs were upregulated in obese AT (P value = 2 × 10(-181)) and inflamed adipocytes (P value = 4 × 10(-61)), according to the number of target sites harbored by each transcript. CONCLUSIONS: Current findings suggest impaired miRNA target gene expression in obese AT in close association with inflammation, both improving after weight loss.


Asunto(s)
Regulación hacia Abajo , Derivación Gástrica , MicroARNs/metabolismo , Obesidad Mórbida/cirugía , Grasa Subcutánea Abdominal/metabolismo , Adipocitos Blancos/citología , Adipocitos Blancos/inmunología , Adipocitos Blancos/metabolismo , Adulto , Índice de Masa Corporal , Línea Celular , Células Cultivadas , Estudios de Cohortes , Estudios Transversales , Femenino , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Obesidad Mórbida/genética , Obesidad Mórbida/inmunología , Obesidad Mórbida/metabolismo , ARN Mensajero/metabolismo , Grasa Subcutánea Abdominal/inmunología , Pérdida de Peso
12.
Haematologica ; 88(11): ELT33, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14607769

RESUMEN

We present the study of 16 cases of splenic marginal zone B-cell lymphoma (SMZBL) combining conventional cytogenetics and fluorescence in situ hybridization technique (FISH). We used a locus specific probe (11q22.3) that hybridizes with Ataxia Telangiectasia Mutated gene (ATM) and a centromeric probe of chromosome 11 as a control. Deletions in ATM gene region have been found in B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) and have been considered as an independent prognosis factor in these pathologies. The aim of our study was to determine the ATM status in SMZBL because no specific studies concerning ATM status in SMZBL have been reported and other B-cell malignances have shown ATM deletions. No deletions were detected in any of the 16 cases. ATM deletions could be considered a rare event in SMZBCL.


Asunto(s)
Eliminación de Gen , Genes Supresores de Tumor , Linfoma de Células B/genética , Linfoma no Hodgkin/genética , Proteínas Serina-Treonina Quinasas/genética , Neoplasias del Bazo/genética , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular , Pintura Cromosómica , Cromosomas Humanos Par 11/genética , Proteínas de Unión al ADN , Humanos , Proteínas Supresoras de Tumor
13.
Clin Cancer Res ; 20(4): 1007-19, 2014 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-24352646

RESUMEN

PURPOSE: According to current diagnostic criteria, mantle cell lymphoma (MCL) encompasses the usual, aggressive variants and rare, nonnodal cases with monoclonal asymptomatic lymphocytosis, cyclin D1-positive (MALD1). We aimed to understand the biology behind this clinical heterogeneity and to identify markers for adequate identification of MALD1 cases. EXPERIMENTAL DESIGN: We compared 17 typical MCL cases with a homogeneous group of 13 untreated MALD1 cases (median follow-up, 71 months). We conducted gene expression profiling with functional analysis in five MCL and five MALD1. Results were validated in 12 MCL and 8 MALD1 additional cases by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in 24 MCL and 13 MALD1 cases by flow cytometry. Classification and regression trees strategy was used to generate an algorithm based on CD38 and CD200 expression by flow cytometry. RESULTS: We found 171 differentially expressed genes with enrichment of neoplastic behavior and cell proliferation signatures in MCL. Conversely, MALD1 was enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 were differentially expressed between MCL and MALD1 and confirmed by flow cytometry (median CD38, 89% vs. 14%; median CD200, 0% vs. 24%, respectively). Assessment of both proteins allowed classifying 85% (11 of 13) of MALD1 cases whereas 15% remained unclassified. SOX11 expression by qRT-PCR was significantly different between MCL and MALD1 groups but did not improve the classification. CONCLUSION: We show for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. Assessment of CD38/CD200 by flow cytometry is useful to distinguish most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment.


Asunto(s)
Linfocitos B/fisiología , Ciclina D1/metabolismo , Linfocitosis/diagnóstico , Linfoma de Células del Manto/diagnóstico , Enfermedades Asintomáticas , Estudios de Casos y Controles , Ciclina D1/genética , Diagnóstico Diferencial , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Linfocitosis/metabolismo , Linfoma de Células del Manto/metabolismo , Linfoma de Células del Manto/mortalidad , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Transcriptoma
14.
PLoS One ; 8(1): e54785, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23372767

RESUMEN

Molecular mechanisms associated with pathophysiological changes in ventricular remodelling due to myocardial infarction (MI) remain poorly understood. We analyzed changes in gene expression by microarray technology in porcine myocardial tissue at 1, 4, and 6 weeks post-MI.MI was induced by coronary artery ligation in 9 female pigs (30-40 kg). Animals were randomly sacrificed at 1, 4, or 6 weeks post-MI (n = 3 per group) and 3 healthy animals were also included as control group. Total RNA from myocardial samples was hybridized to GeneChip® Porcine Genome Arrays. Functional analysis was obtained with the Ingenuity Pathway Analysis (IPA) online tool. Validation of microarray data was performed by quantitative real-time PCR (qRT-PCR).More than 8,000 different probe sets showed altered expression in the remodelling myocardium at 1, 4, or 6 weeks post-MI. Ninety-seven percent of altered transcripts were detected in the infarct core and 255 probe sets were differentially expressed in the remote myocardium. Functional analysis revealed 28 genes de-regulated in the remote myocardial region in at least one of the three temporal analyzed stages, including genes associated with heart failure (HF), systemic sclerosis and coronary artery disease. In the infarct core tissue, eight major time-dependent gene expression patterns were recognized among 4,221 probe sets commonly altered over time. Altered gene expression of ACVR2B, BID, BMP2, BMPR1A, LMNA, NFKBIA, SMAD1, TGFB3, TNFRSF1A, and TP53 were further validated.The clustering of similar expression patterns for gene products with related function revealed molecular footprints, some of them described for the first time, which elucidate changes in biological processes at different stages after MI.


Asunto(s)
Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Infarto del Miocardio/genética , Miocardio/metabolismo , Miocardio/patología , Animales , Análisis por Conglomerados , Modelos Animales de Enfermedad , Femenino , Redes Reguladoras de Genes , Reproducibilidad de los Resultados , Transducción de Señal , Porcinos , Factores de Tiempo
15.
Leuk Lymphoma ; 54(5): 986-95, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-22994157

RESUMEN

Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. Del(11q) and del(17p), routinely studied by conventional G-banding cytogenetics (CGC) and fluorescence in situ hybridization (FISH), have been related to progression and shorter overall survival. Recently, array-based karyotyping has gained acceptance as a high-resolution new tool for detecting genomic imbalances. The aim of the present study was to compare genomic arrays with CGC and FISH to ascertain whether the current techniques could be substituted in routine procedures. We analyzed 70 patients with CLL using the Cytogenetics Whole-Genome 2.7M Array and CytoScan HD Array (Affymetrix), CGC and FISH with the classical CLL panel. Whereas 31.4% and 68.6% of patients presented abnormalities when studied by CGC and FISH, respectively, these rates increased when arrays were also analyzed (78.6% and 80%). Although abnormality detection is higher when arrays are applied, one case with del(11q) and three with del(17p) were missed by genomic arrays due to their limited sensitivity. We consider that the complete substitution of CGC and FISH by genomic arrays in routine laboratories could negatively affect the management of some patients harboring 11q or 17p deletions. In conclusion, genomic arrays are valid to detect known and novel genomic imbalances in CLL, but should be maintained as a complementary tool to the current techniques.


Asunto(s)
Hibridación Genómica Comparativa , Genómica , Leucemia Linfocítica Crónica de Células B/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Bandeo Cromosómico , Variaciones en el Número de Copia de ADN , Femenino , Genómica/métodos , Humanos , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/genética , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad
16.
Exp Dermatol ; 14(12): 883-90, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16274455

RESUMEN

The aim of the present study was to identify genetic aberrations in a series of patients with cutaneous large B-cell lymphoma (LBCL) using comparative genomic hybridization (CGH). Eighteen consecutive patients with primary (13 patients) (PCLBCL) and secondary (five patients) (SCLBCL) cutaneous large B-cell lymphoma were included in the study. Nine cases corresponded to PCLBCL leg type and four cases primary cutaneous follicle centre-cell lymphoma (PCFCL). Chromosomal imbalances (CIs) were detected in 14 of 18 samples (77.8%). All of nine cases with PCLBCL leg type and two of four cases with PCFCL showed CIs (100% and 50%, respectively). Regarding SCLBCL, in three of five cases (60%), CIs were detected. The most frequently detected gains involved 2q, 5q, 3 and 7q and amplifications affected 18, 12 and 13. Frequent losses were found in 17p. In PCLBCL leg type, the most frequent gains involved 2q and 7q, amplifications were localized in chromosomes 12, 13 and 18 and losses affected chromosomes 17p and 19. In PCFCL, gains located in 3q, 4 and 7q were found. Our study seems to confirm clear-cut differences between primary cutaneous LBCL and nodal diffuse LBCL, and it suggests the presence of genotypic differences between cases of PCLBCL leg type and cases of PCFCL.


Asunto(s)
Linfoma de Células B/genética , Linfoma de Células B Grandes Difuso/genética , Hibridación de Ácido Nucleico , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Femenino , Amplificación de Genes , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología
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