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Prat-Vidal C.,Heart Health | Galvez-Monton C.,Heart Health | Nonell L.,Institute Hospital Del Mar dInvestigacions Mediques | Puigdecanet E.,Institute Hospital Del Mar dInvestigacions Mediques | And 5 more authors.
PLoS ONE | Year: 2013

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. © 2013 Prat-Vidal et al. Source

Oliveira A.C.,Institute Catala dOncologia | De La Banda E.,Servei dHematologia | Domingo-Domenech E.,Institute Catala dOncologia | Encuentra M.,Institute Catala dOncologia | And 7 more authors.
Leukemia and Lymphoma | Year: 2011

Retrospective series have reported many clinical and biological significant prognostic factors in chronic lymphocytic leukemia (CLL). We describe a prospective cohort of 135 patients with CLL homogeneously studied at diagnosis for prognostic factors. Biological variables analyzed were CD38 and ZAP-70 expression, fluorescence in situ hybridization (FISH) for 13q-, +12, 11q-, and 17p-, and conventional cytogenetics. Univariate and multivariate analysis for progression-free survival (PFS) were performed in patients with early stage (Rai 0-1) CLL. CD38 was positive in 42 (31.6%) patients and ZAP-70 in 47 (35.9%). The most frequent FISH finding was isolated 13q- in 50 (38.5%) patients, and 17p- was found in 11 (8.4%). Among 135 patients, 114 (84.4%) were Rai 0-1 at diagnosis and 39 (28.9%) presented adenopathies. With a median follow-up of 39 months, the presence of lymphadenopathy in patients with Rai 0-1 stage CLL was the only significant variable for predicting PFS in multivariate analysis (odds ratio [OR] 7, 95% confidence interval [CI] 2.2-22, p = 0.001). When only biological factors were analyzed, CD38 expression (OR 3.2, 95% CI 1.1-9.3, p = 0.03) and 17p- (OR 3.5, 95% CI 0.95-13.1, p = 0.05) correlated with worse PFS. A longer follow-up is necessary to analyze the prognostic value of these variables regarding overall survival. © 2011 Informa UK, Ltd. Source

Salgado R.,Laboratori Of Citogenetica Molecular | Salgado R.,Autonomous University of Barcelona | Servitje O.,Hospital Universitari Of Bellvitge Idibell | Gallardo F.,Servei de Dermatologia | And 21 more authors.
Journal of Investigative Dermatology | Year: 2010

Mycosis fungoide (MF) patients who develop tumors or extracutaneous involvement usually have a poor prognosis with no curative therapy available so far. In the present European Organization for Research and Treatment of Cancer (EORTC) multicenter study, the genomic profile of 41 skin biopsies from tumor stage MF (MFt) was analyzed using a high-resolution oligo-array comparative genomic hybridization platform. Seventy-six percent of cases showed genomic aberrations. The most common imbalances were gains of 7q33.3q35 followed by 17q21.1, 8q24.21, 9q34qter, and 10p14 and losses of 9p21.3 followed by 9q31.2, 17p13.1, 13q14.11, 6q21.3, 10p11.22, 16q23.2, and 16q24.3. Three specific chromosomal regions, 9p21.3, 8q24.21, and 10q26qter, were defined as prognostic markers showing a significant correlation with overall survival (OS) (P=0.042, 0.017, and 0.022, respectively). Moreover, we have established two MFt genomic subgroups distinguishing a stable group (>0-5 DNA aberrations) and an unstable group (5 DNA aberrations), showing that the genomic unstable group had a shorter OS (P0.05). We therefore conclude that specific chromosomal abnormalities, such as gains of 8q24.21 (MYC) and losses of 9p21.3 (CDKN2A, CDKN2B, and MTAP) and 10q26qter (MGMT and EBF3) may have an important role in prognosis. In addition, we describe the MFt genomic instability profile, which, to our knowledge, has not been reported earlier. © 2010 The Society for Investigative Dermatology. Source

Casadevall D.,Servei dOncologia Medica | Casadevall D.,Autonomous University of Barcelona | Gimeno J.,Servei de Patologia | Clave S.,Laboratori Of Citogenetica Molecular | And 18 more authors.
Oncotarget | Year: 2015

Objective: We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based patient selection as well as potential surrogate biomarkers of MET activation. Methods: Our study included 120 patients with non-squamous Non-small-cell Lung Cancer (nsNSCLC), of which 47 were incorporated in tissue microarrays (TMA). Four morphologically distinct tumor areas were selected to assess MET heterogeneity. MET positivity by immunohistochemistry (IHC) was defined as an above-median H-score and by +2/+3 staining intensity in >50% of tumor cells (Metmab criteria). MET FISH positivity was defined by MET/CEP7 ratio ≥ 2.0 and/or MET ≥ 5.0. MET staining pattern (cytoplasmic vs. membranous) and mesenchymal markers were investigated as surrogates of MET activation. Results: Median MET H-score was 140 (range 0-400) and 47.8% of patients were MET positive by Metmab criteria. Eight cases (6.8%) were MET FISH positive and showed higher H-scores (p = 0.021). MET positivity by IHC changed in up to 40% of cases among different tumor areas, and MET amplification in 25-50%. Cytoplasmic MET staining and positivity for vimentin predicted poor survival (p = 0.042 and 0.047, respectively). Conclusions: MET status is highly heterogeneous among different nsNSCLC tumor areas, hindering adequate patient selection for MET-targeted therapies. MET cytoplasmic staining and vimentin might represent surrogate markers for MET activation. Source

Jabbour E.,University of Houston | Takahashi K.,University of Houston | Takahashi K.,Kyoto University | Wang X.,University of Houston | And 14 more authors.
American Journal of Hematology | Year: 2013

We hypothesized that the dynamic acquisition of cytogenetic abnormalities (ACA) during the follow up of myelodysplastic syndromes (MDS) could be associated with poor prognosis. We conducted a retrospective analysis of 365 patients with IPSS low or intermediate-1 risk MDS who had at least two consecutive cytogenetic analyses during the follow up. Acquisition of cytogenetic abnormalities was detected in 107 patients (29%). The most frequent alteration involved chromosome 7 in 21% of ACA cases. Median transformation-free and overall survival for patients with and without ACA were 13 vs. 52 months (P=0.01) and 17 vs. 62 months (P=0.01), respectively. By fitting ACA as a time-dependent covariate, multivariate Cox regression analysis showed that patients with ACA had increased risk of transformation (HR=1.40; P=0.03) or death (HR=1.45; P=0.02). Notably, female patients with therapy-related MDS (t-MDS) had an increased risk of developing ACA (OR=5.26; P<0.0001), although subgroup analysis showed that prognostic impact of ACA was not evident in t-MDS. In conclusion, ACA occurs in close to one third of patients with IPSS defined lower risk MDS, more common among patients with t-MDS, but has a significant prognostic impact on de novo MDS. Am. J. Hematol. 88:831-837, 2013. © 2013 Wiley Periodicals, Inc. Source

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