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Search Results: 1 - 10 of 22947 matches for " Alberto Fernandez-Gutierrez "
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Olive oil's bitter principle reverses acquired autoresistance to trastuzumab (Herceptin?) in HER2-overexpressing breast cancer cells
Javier A Menendez, Alejandro Vazquez-Martin, Ramon Colomer, Joan Brunet, Alegria Carrasco-Pancorbo, Rocio Garcia-Villalba, Alberto Fernandez-Gutierrez, Antonio Segura-Carretero
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-80
Abstract: Semi-preparative HPLC was used to isolate EVOO polyphenols (i.e., tyrosol, hydroxytyrosol, oleuropein). Both the anti-proliferative and the pro-apoptotic effects of EVOO phenolics were evaluated by using MTT-based quantification of metabolically viable cells and ELISA-based detection of histone-associated DNA fragments, respectively. The nature of the interaction between oleuropein aglycone and the anti-HER2 monoclonal antibody trastuzumab (Herceptin?) was mathematically evaluated by the dose-oriented isobologram technique. HER2-specific ELISAs were employed to quantitatively assess both the basal cleavage of the HER2 extracellular domain (ECD) and the expression level of total HER2. The activation status of HER2 was evaluated by immunoblotting procedures using a monoclonal antibody specifically recognizing the tyrosine phosphorylated (Phosphor-Tyr1248) form of HER2.Among EVOO polyphenols tested, oleuropein aglycone was the most potent EVOO phenolic in decreasing breast cancer cell viability. HER2 gene-amplified SKBR3 cells were ~5-times more sensitive to oleuropein aglycone than HER2-negative MCF-7 cells. Retroviral infection of the HER2 oncogene in MCF-7 cells resulted in a "SKBR3-assimilated" phenotype of hypersensitivity to oleuropein aglycone. An up to 50-fold increase in the efficacy of trastuzumab occurred in the presence of oleuropein aglycone. A preclinical model of acquired autoresistance to trastuzumab (SKBR3/Tzb100 cells) completely recovered trastuzumab sensitivity (> 1,000-fold sensitization) when co-cultured in the presence of oleuropein aglycone. Indeed, the nature of the interaction between oleuropein aglycone and trastuzumab was found to be strongly synergistic in Tzb-resistant SKBR3/Tzb100 cells. Mechanistically, oleuropein aglycone treatment significantly reduced HER2 ECD cleavage and subsequent HER2 auto-phosphorylation, while it dramatically enhanced Tzb-induced down-regulation of HER2 expression.Olive oil's bitter principle (i.e., oleuropein a
tabAnti-HER2 (erbB-2) oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO)
Javier A Menendez, Alejandro Vazquez-Martin, Rocio Garcia-Villalba, Alegria Carrasco-Pancorbo, Cristina Oliveras-Ferraros, Alberto Fernandez-Gutierrez, Antonio Segura-Carretero
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-377
Abstract: Solid phase extraction followed by semi-preparative high-performance liquid chromatography (HPLC) was used to isolate phenolic fractions from commercial EVOO. Analytical capillary electrophoresis coupled to mass spectrometry was performed to check for the composition and to confirm the identity of the isolated fractions. EVOO polyphenolic fractions were tested on their tumoricidal ability against HER2-negative and HER2-positive breast cancer in vitro models using MTT, crystal violet staining, and Cell Death ELISA assays. The effects of EVOO polyphenolic fractions on the expression and activation status of HER2 oncoprotein were evaluated using HER2-specific ELISAs and immunoblotting procedures, respectively.Among the fractions mainly containing the single phenols hydroxytyrosol and tyrosol, the polyphenol acid elenolic acid, the lignans (+)-pinoresinol and 1-(+)-acetoxypinoresinol, and the secoiridoids deacetoxy oleuropein aglycone, ligstroside aglycone, and oleuropein aglycone, all the major EVOO polyphenols (i.e. secoiridoids and lignans) were found to induce strong tumoricidal effects within a micromolar range by selectively triggering high levels of apoptotic cell death in HER2-overexpressors. Small interfering RNA-induced depletion of HER2 protein and lapatinib-induced blockade of HER2 tyrosine kinase activity both significantly prevented EVOO polyphenols-induced cytotoxicity. EVOO polyphenols drastically depleted HER2 protein and reduced HER2 tyrosine autophosphorylation in a dose- and time-dependent manner. EVOO polyphenols-induced HER2 downregulation occurred regardless the molecular mechanism contributing to HER2 overexpression (i.e. naturally by gene amplification and ectopically driven by a viral promoter). Pre-treatment with the proteasome inhibitor MG132 prevented EVOO polyphenols-induced HER2 depletion.The ability of EVOO-derived polyphenols to inhibit HER2 activity by promoting the proteasomal degradation of the HER2 protein itself, together with the f
A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis
Rogelio Palomino-Morales, Carlos Gonzalez-Juanatey, Tomas R Vazquez-Rodriguez, Luis Rodriguez, Jose A Miranda-Filloy, Benjamin Fernandez-Gutierrez, Javier Llorca, Javier Martin, Miguel A Gonzalez-Gay
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar2989
Abstract: Six hundred and twelve patients fulfilling the 1987 American College of Rheumatology classification criteria for RA, seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo and Hospital San Carlos, Madrid, were studied. Patients and controls (n = 865) were genotyped using predesigned TaqMan SNP genotyping assays.No significant differences in allele or genotype frequencies for the MTHFR gene polymorphisms between RA patients and controls were found. Also, no association between the MTHFR 677 C>T polymorphism and CV events or endothelial dysfunction was observed. However, the MTHFR 1298 allele C frequency was increased in patients with CV events after 5 years (38.7% versus 30.3%; odds ratio = 1.45; 95% confidence interval = 1.00 to 2.10; P = 0.04) and 10 years (42.2% versus 31.0%; odds ratio = 1.62; 95% confidence interval = 1.08 to 2.43; P = 0.01) follow up. Moreover, patients carrying the MTHFR 1298 AC and CC genotypes had a significantly decreased flow-mediated endothelium-dependent vasodilatation (4.3 ± 3.9%) compared with those carrying the MTHFR 1298 AA genotype (6.5 ± 4.4%) (P = 0.005).Our results show that the MTHFR 1298 A>C gene polymorphism confers an increased risk for subclinical atherosclerosis and CV events in patients with RA.Patients with rheumatoid arthritis (RA) have increased risk of cardiovascular (CV) disease due to accelerated atherosclerosis [1]. Besides classic CV risk factors, a number of nontraditional CV risk factors have also been implicated in the elevated CV mortality observed in these patients [2].In this regard, chronic inflammation and the genetic background increase the risk of CV events in RA regardless of the presence of traditional CV risk factors [3]. Hyperhomocysteinemia has been found to be an independent nontraditional risk factor for CV disease, including coronary disease, in the general population [4]. Homocysteine is an intermediary amino acid formed during the conversion of methionine to cysteine. High ele
Association between IL-18 gene polymorphisms and biopsy-proven giant cell arteritis
Rogelio J Palomino-Morales, Tomas R Vazquez-Rodriguez, Orlando Torres, Inmaculada C Morado, Santos Casta?eda, Jose A Miranda-Filloy, Jose L Callejas-Rubio, Benjamin Fernandez-Gutierrez, Miguel A Gonzalez-Gay, Javier Martin
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar2962
Abstract: In total, 212 patients diagnosed with biopsy-proven GCA were included in this study. DNA from patients and matched controls was obtained from peripheral blood. Samples were genotyped for the IL18-137 G>C (rs187238), the IL18-607 C>A (rs1946518), and the IL18-1297 T>C (rs360719) gene polymorphisms with polymerase chain reaction, by using a predesigned TaqMan allele discrimination assay.No significant association between the IL18-137 G>C polymorphism and GCA was found. However, the IL18 -607 allele A was significantly increased in GCA patients compared with controls (47.8% versus 40.9% in patients and controls respectively; P = 0.02; OR, 1.32; 95% CI, 1.04 to 1.69). It was due to an increased frequency of homozygosity for the IL18 -607 A/A genotype in patients with GCA (20.4%) compared with controls (13.4%) (IL18 -607 A/A versus IL18 -607 A/C plus IL18 -607 C/C genotypes: P = 0.04; OR, 1.59; 95% CI, 1.02 to 2.46). Also, the IL18-1297 allele C was significantly increased in GCA patients (30.7%) compared with controls (23.0%) (P = 0.003; OR, 1.48; 95% CI, 1.13 to 1.95). In this regard, an increased susceptibility to GCA was observed in individuals carrying the IL18-1297 C/C or the IL18-1297 C/T genotypes compared with those carrying the IL18-1297 T/T genotype (IL18-1297 C/C plus IL18-1297 T/C versus IL18-1297 T/T genotype in GCA patients compared with controls: P = 0.005; OR, 1.61; 95% CI, 1.15 to 2.25). We also found an additive effect of the IL18 -1297 and -607 polymorphisms with TLR4 Asp299Gly polymorphism. The OR for GCA was 1.95 for combinations of genotypes with one or two risk alleles, whereas carriers of three or more risk alleles have an OR of 3.7.Our results show for the first time an implication of IL18 gene-promoter polymorphisms in the susceptibility to biopsy-proven GCA. In addition, an additive effect between the associated IL18 and TLR4 genetic variants was observed.Giant cell, arteritis (GCA) is a large- and medium-sized blood vessel systemic vasculitis
Analysis of TNFAIP3, a feedback inhibitor of nuclear factor-κB and the neighbor intergenic 6q23 region in rheumatoid arthritis susceptibility
Rebeca Dieguez-Gonzalez, Manuel Calaza, Eva Perez-Pampin, Alejandro Balsa, Francisco J Blanco, Juan D Ca?ete, Rafael Caliz, Luis Carre?o, Arturo R de la Serna, Benjamin Fernandez-Gutierrez, Ana Ortiz, Gabriel Herrero-Beaumont, Jose L Pablos, Javier Narvaez, Federico Navarro, Jose L Marenco, Juan J Gomez-Reino, Antonio Gonzalez
Arthritis Research & Therapy , 2009, DOI: 10.1186/ar2650
Abstract: To test this hypothesis, we selected tag-single nucleotide polymorphisms (SNPs) in both loci. They were analyzed in 1,651 patients with RA and 1,619 control individuals of Spanish ancestry.Weak evidence of association was found both in the 6q23 intergenic region and in the TNFAIP3 locus. The rs582757 SNP and a common haplotype in the TNFAIP3 locus exhibited association with RA. In the intergenic region, two SNPs were associated, namely rs609438 and rs13207033. The latter was only associated in patients with anti-citrullinated peptide antibodies. Overall, statistical association was best explained by the interdependent contribution of SNPs from the two loci TNFAIP3 and the 6q23 intergenic region.Our data are consistent with the hypothesis that several RA genetic factors exist in the 6q23 region, including polymorphisms in the TNFAIP3 gene, like that previously described for systemic lupus erythematosus.The etiology of rheumatoid arthritis (RA) includes a genetic component that has become amenable to investigation in recent years. A major development has been the availability of large-scale genome-wide association (GWA) studies. The first GWA studies in RA were readily able to confirm the two clearest RA genetic factors – in the human leukocyte antigen region and in the PTPN22 gene [1-3]. In addition, such studies have found other significant associations. Some of these associations have already been confirmed in additional studies, such as the TRAF1-C5 locus and the intergenic region in the 6q23 chromosome [2-5].Two single nucleotide polymorphisms (SNPs) in 6q23, namely rs6920220 and rs13207033 (or its perfect surrogate rs10499194), have exhibited peak association with RA in an independent manner [2]. This finding has been interpreted as indicating the involvement of multiple genetic variants in RA susceptibility [2]. The associated region does not contain any known protein-coding sequence and lacks any evident functional consequence [2,4], but a strong RA candidate
Proyecciones (Antofagasta) , 2008, DOI: 10.4067/S0716-09172008000100007
Abstract: we first present a solution to a conjecture of (correa, hentzel, labra, 2002) in the positive. we show that if a is a commutative nonassociative algebra over a field of characteristic 6= 2, 3, satisfying the identity x(x(xx)) = 0, then lat1 lat2 · · · lats &8801; 0 if t1 + t2 + · · · + ts 10, where a a.
Proyecciones (Antofagasta) , 2008,
Abstract: We first present a solution to a conjecture of (Correa, Hentzel, Labra, 2002) in the positive. We show that if A is a commutative nonassociative algebra over a field of characteristic 6= 2, 3, satisfying the identity x(x(xx)) = 0, then Lat1 Lat2 · · · Lats &8801; 0 if t1 + t2 + · · · + t s 10, where a A.
El avance de la ciencia biomédica contemporánea
Alberto Gómez Gutierrez
Infectio , 2007,
The Proliferation Index of Specific Bone Marrow Cell Compartments from Myelodysplastic Syndromes Is Associated with the Diagnostic and Patient Outcome
Sergio Matarraz, Cristina Teodosio, Carlos Fernandez, Manuel Albors, María Jara-Acevedo, Antonio López, María Gonzalez-Gonzalez, María Laura Gutierrez, Juan Flores-Montero, Carlos Cerveró, Marlies Pizarro-Perea, María Paz Garrastazul, Gonzalo Caballero, Oliver Gutierrez, Guy Daniel Mendez, Manuel González-Silva, Paula Laranjeira, Alberto Orfao
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044321
Abstract: Myelodysplastic syndromes (MDS) are clonal stem cell disorders which frequently show a hypercellular dysplastic bone marrow (BM) associated with inefficient hematopoiesis and peripheral cytopenias due to increased apoptosis and maturation blockades. Currently, little is known about the role of cell proliferation in compensating for the BM failure syndrome and in determining patient outcome. Here, we analyzed the proliferation index (PI) of different compartments of BM hematopoietic cells in 106 MDS patients compared to both normal/reactive BM (n = 94) and acute myeloid leukemia (AML; n = 30 cases) using multiparameter flow cytometry. Our results show abnormally increased overall BM proliferation profiles in MDS which significantly differ between early/low-risk and advanced/high-risk cases. Early/low-risk patients showed increased proliferation of non-lymphoid CD34+ precursors, maturing neutrophils and nucleated red blood cells (NRBC), while the PI of these compartments of BM precursors progressively fell below normal values towards AML levels in advanced/high-risk MDS. Decreased proliferation of non-lymphoid CD34+ and NRBC precursors was significantly associated with adverse disease features, shorter overall survival (OS) and transformation to AML, both in the whole series and when low- and high-risk MDS patients were separately considered, the PI of NRBC emerging as the most powerful independent predictor for OS and progression to AML. In conclusion, assessment of the PI of NRBC, and potentially also of other compartments of BM precursors (e.g.: myeloid CD34+ HPC), could significantly contribute to a better management of MDS.
Holographic dilatonic model of dark energy
Alberto Rozas-Fernandez
Physics , 2009, DOI: 10.1140/epjc/s10052-010-1536-7
Abstract: We present a dilatonic description of the holographic dark energy by connecting the holographic dark energy density with the dilaton scalar field energy density in a flat Friedmann-Robertson-Walker universe. We show that this model can describe the observed accelerated expansion of our universe with the choice $c\geq1$ and reconstruct the kinetic term as well as the dynamics of the dilaton scalar field.
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