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Search Results: 1 - 10 of 268973 matches for " José Ignacio Martín-Subero "
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Epigenetic Signatures Associated with Different Levels of Differentiation Potential in Human Stem Cells
Pablo Aranda,Xabier Agirre,Esteban Ballestar,Enrique J. Andreu,José Román-Gómez,Inés Prieto,José Ignacio Martín-Subero,Juan Cruz Cigudosa,Reiner Siebert,Manel Esteller,Felipe Prosper
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007809
Abstract: The therapeutic use of multipotent stem cells depends on their differentiation potential, which has been shown to be variable for different populations. These differences are likely to be the result of key changes in their epigenetic profiles.
Frequent and Simultaneous Epigenetic Inactivation of TP53 Pathway Genes in Acute Lymphoblastic Leukemia
Amaia Vilas–Zornoza,Xabier Agirre,Vanesa Martín-Palanco,José Ignacio Martín-Subero,Edurne San José-Eneriz,Leire Garate,Sara álvarez,Estíbaliz Miranda,Paula Rodríguez-Otero,José Rifón,Antonio Torres,María José Calasanz,Juan Cruz Cigudosa,José Román-Gómez,Felipe Prósper
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017012
Abstract: Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n = 48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-2′-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p = 0.001) and mortality (p<0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p = 0.006) and overall survival (OS) (p = 0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL.
TET2 Mutations Are Associated with Specific 5-Methylcytosine and 5-Hydroxymethylcytosine Profiles in Patients with Chronic Myelomonocytic Leukemia
Cristina Pérez, Nicolas Martínez-Calle, José Ignacio Martín-Subero, Victor Segura, Eric Delabesse, Marta Fernandez-Mercado, Leire Garate, Sara Alvarez, José Rifon, Sara Varea, Jacqueline Boultwood, James S. Wainscoat, Juan Cruz Cigudosa, María José Calasanz, Nicholas C. P. Cross, Felipe Prósper, Xabier Agirre
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031605
Abstract: Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes such as TET2 or EZH2 that are implicated in epigenetic mechanisms. We have performed genome-wide DNA methylation arrays and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24 patients with CMML. 249 genes were differentially methylated between CMML patients and controls. Using Ingenuity pathway analysis, we identified enrichment in a gene network centered around PLC, JNK and ERK suggesting that these pathways, whose deregulation has beenrecently described in CMML, are affected by epigenetic mechanisms. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65%), 4 patients (17%) and 1 patient (4%) respectively while no mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients with wild type TET2 clustered separately from patients with TET2 mutations, showed a higher degree of hypermethylation and were associated with higher risk karyotypes. Our results demonstrate the presence of aberrant DNA methylation in CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype with a different epigenetic profile.
DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia
Sara Alvarez,Javier Suela,Ana Valencia,Agustín Fernández,Mark Wunderlich,Xabier Agirre,Felipe Prósper,José Ignacio Martín-Subero,Alba Maiques,Francesco Acquadro,Sandra Rodriguez Perales,María José Calasanz,Jose Roman-Gómez,Reiner Siebert,James C. Mulloy,José Cervera,Miguel Angel Sanz,Manel Esteller,Juan C. Cigudosa
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012197
Abstract: Aberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required.
Array-based DNA methylation profiling of primary lymphomas of the central nervous system
Julia Richter, Ole Ammerpohl, José I Martín-Subero, Manuel Montesinos-Rongen, Marina Bibikova, Eliza Wickham-Garcia, Otmar D Wiestler, Martina Deckert, Reiner Siebert
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-455
Abstract: Using an array-based technology we have assessed the DNA methylation status of 1,505 individual CpG loci in five PCNSL and compared the results to DNA methylation profiles of 49 DLBCL and ten hematopoietic controls.We identified 194 genes differentially methylated between PCNSL and normal controls. Interestingly, Polycomb target genes and genes with promoters showing a high CpG content were significantly enriched in the group of genes hypermethylated in PCNSL. However, PCNSL and systemic DLBCL did not differ in their methylation pattern.Based on the data presented here, PCNSL and DLBCL do not differ in their DNA methylation pattern. Thus, DNA methylation analysis does not support a separation of PCNSL and DLBCL into individual entities. However, PCNSL and DLBCL differ in their DNA methylation pattern from non- malignant controls.Primary lymphomas of the central nervous system (PCNSL) are highly malignant B-cell lymphomas confined to the central nervous system (CNS) with a poor prognosis [1]. They are considered as separate entity within the updated WHO classification [1], although they cannot be distinguished histologically and immunophenotypically from extracerebral diffuse large B-cell lymphoma (DLBCL). However, based on the remarkably worse clinical course and prognosis it is still a matter of debate whether PCNSL differ from systemic DLBCL with respect to their molecular features and pathogenesis. Interphase cytogenetic and molecular genetic studies have shown that PCNSL share a variety of features with systemic DLBCL. These include rearranged immunoglobulin (IG) gene segments with evidence for ongoing somatic hypermutation, aberrant somatic hypermutation of non-IG genes, translocations affecting the IG and BCL6 genes, gains in chromosome band 18q21, and mutations of the PRDM1 gene [2]. With respect to their gene expression profile PCNSL segregate along the spectrum of systemic DLBCL including the ABC- and GCB-types of DLBCL [3,4].Epigenetic silencing of functio
DNA Hypomethylation Affects Cancer-Related Biological Functions and Genes Relevant in Neuroblastoma Pathogenesis
Gemma Mayol,José I. Martín-Subero,José Ríos,Ana Queiros,Marta Kulis,Mariona Su?ol,Manel Esteller,Soledad Gómez,Idoia Garcia,Carmen de Torres,Eva Rodríguez,Patricia Galván,Jaume Mora,Cinzia Lavarino
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048401
Abstract: Neuroblastoma (NB) pathogenesis has been reported to be closely associated with numerous genetic alterations. However, underlying DNA methylation patterns have not been extensively studied in this developmental malignancy. Here, we generated microarray-based DNA methylation profiles of primary neuroblastic tumors. Stringent supervised differential methylation analyses allowed us to identify epigenetic changes characteristic for NB tumors as well as for clinical and biological subtypes of NB. We observed that gene-specific loss of DNA methylation is more prevalent than promoter hypermethylation. Remarkably, such hypomethylation affected cancer-related biological functions and genes relevant to NB pathogenesis such as CCND1, SPRR3, BTC, EGF and FGF6. In particular, differential methylation in CCND1 affected mostly an evolutionary conserved functionally relevant 3′ untranslated region, suggesting that hypomethylation outside promoter regions may play a role in NB pathogenesis. Hypermethylation targeted genes involved in cell development and proliferation such as RASSF1A, POU2F2 or HOXD3, among others. The results derived from this study provide new candidate epigenetic biomarkers associated with NB as well as insights into the molecular pathogenesis of this tumor, which involves a marked gene-specific hypomethylation.
Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications
Maria Carmela Vegliante, Cristina Royo, Jara Palomero, Itziar Salaverria, Balazs Balint, Idoia Martín-Guerrero, Xabier Agirre, Amaia Lujambio, Julia Richter, Silvia Xargay-Torrent, Silvia Bea, Luis Hernandez, Anna Enjuanes, María José Calasanz, Andreas Rosenwald, German Ott, José Roman-Gomez, Felipe Prosper, Manel Esteller, Pedro Jares, Reiner Siebert, Elias Campo, José I. Martín-Subero, Virginia Amador
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021382
Abstract: Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications.
When do the recession cones of a polyhedral complex form a fan?
José Ignacio Burgos Gil,Martín Sombra
Mathematics , 2010,
Abstract: We study the problem of when the collection of the recession cones of a polyhedral complex forms also a complex. We exhibit an example showing that this is no always the case. We also show that if the support of the given polyhedral complex satisfies a Minkowski-Weyl type condition, then the answer is positive. As a consequence, we obtain a classification theorem for proper toric schemes over a discrete valuation ring in terms of complete strongly convex rational polyhedral complexes.
Método de Montessori aplicado à demência: revis?o da literatura
Brand?o, Daniela Filipa Soares;Martín, José Ignacio;
Revista Gaúcha de Enfermagem , 2012, DOI: 10.1590/S1983-14472012000200027
Abstract: the montessori method was initially applied to children, but now it has also been applied to people with dementia. the purpose of this study is to systematically review the research on the effectiveness of this method, using medical literature analysis and retrieval system online (medline) with the keywords dementia and montessori method. we selected 10 studies, in which there were significant improvements in participation and constructive engagement, and reduction of negative affects and passive engagement. nevertheless, systematic reviews about this non-pharmacological intervention in dementia rate this method as weak in terms of effectiveness. this apparent discrepancy can be explained because the montessori method may have, in fact, a small influence on dimensions such as behavioral problems, or because there is no research about this method with high levels of control, such as the presence of several control groups or a double-blind study.
Arithmetic geometry of toric varieties. Metrics, measures and heights
José Ignacio Burgos Gil,Patrice Philippon,Martín Sombra
Mathematics , 2011,
Abstract: We show that the height of a toric variety with respect to a toric metrized line bundle can be expressed as the integral over a polytope of a certain adelic family of concave functions. To state and prove this result, we study the Arakelov geometry of toric varieties. In particular, we consider models over a discrete valuation ring, metrized line bundles, and their associated measures and heights. We show that these notions can be translated in terms of convex analysis, and are closely related to objects like polyhedral complexes, concave functions, real Monge-Amp\`ere measures, and Legendre-Fenchel duality. We also present a closed formula for the integral over a polytope of a function of one variable composed with a linear form. This allows us to compute the height of toric varieties with respect to some interesting metrics arising from polytopes. We also compute the height of toric projective curves with respect to the Fubini-Study metric, and of some toric bundles.
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