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Search Results: 1 - 10 of 36111 matches for " Alejandro Vazquez-Martin "
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Autophagy Facilitates the Development of Breast Cancer Resistance to the Anti-HER2 Monoclonal Antibody Trastuzumab
Alejandro Vazquez-Martin, Cristina Oliveras-Ferraros, Javier A. Menendez
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006251
Abstract: Autophagy has been emerging as a novel cytoprotective mechanism to increase tumor cell survival under conditions of metabolic stress and hypoxia as well as to escape chemotherapy-induced cell death. To elucidate whether autophagy might also protect cancer cells from the growth inhibitory effects of targeted therapies, we evaluated the autophagic status of preclinical breast cancer models exhibiting auto-acquired resistance to the anti-HER2 monoclonal antibody trastuzumab (Tzb). We first examined the basal autophagic levels in Tzb-naive SKBR3 cells and in two pools of Tzb-conditioned SKBR3 cells (TzbR), which optimally grow in the presence of Tzb doses as high as 200 μg/ml Tzb. Fluorescence microscopic analyses revealed that the number of punctate LC3 structures -a hallmark of autophagy- was drastically higher in Tzb-refractory cells than in Tzb-sensitive SKBR3 parental cells. Immunoblotting analyses confirmed that the lipidation product of the autophagic conversion of LC3 was accumulated to high levels in TzbR cells. High levels of the LC3 lipidated form in Tzb-refractory cells were accompanied by decreased p62/sequestosome-1 protein expression, a phenomenon characterizing the occurrence of increased autophagic flux. Moreover, increased autophagy was actively used to survive Tzb therapy as TzbR pools were exquisitely sensitive to chemical inhibitors of autophagosomal formation/function. Knockdown of LC3 expression via siRNA similarly resulted in reduced TzbR cell proliferation and supra-additively interacted with Tzb to re-sensitize TzbR cells. Sub-groups of Tzb-naive SKBR3 parental cells accumulated LC3 punctate structures and decreased p62 expression after treatment with high-dose Tzb, likely promoting their own resistance. This is the first report showing that HER2-overexpressing breast cancer cells chronically exposed to Tzb exhibit a bona fide up-regulation of the autophagic activity that efficiently works to protect breast cancer cells from the growth-inhibitory effects of Tzb. Therapeutic targeting autophagosome formation/function might represent a novel molecular avenue to reduce the emergence of Tzb resistance in HER2-dependent breast carcinomas.
Circulating fatty acid synthase: an exploratory biomarker to predict efficacy of the dual HER1/HER2 tyrosine kinase inhibitor lapatinib
Cristina Oliveras-Ferraros, Sílvia Cufí, Tamara Sauri-Nadal, Sonia Barco, Bego?a Martin-Castillo, Alejandro Vazquez-Martin, Javier A Menendez
Breast Cancer Research , 2011, DOI: 10.1186/bcr2799
Abstract: AMP-activated protein kinase (AMPK)-activating drugs, by mimicking an elevated AMP/ATP ratio in BC cells, drastically augment the release of extracellular FASN in HER2-positive BC cells [2]. Lapatinib-induced deprivation of tumor cell energy activates AMPK to trigger an entire cascade of metabolic events, including suppression of FASN expression and activity [1,3]. We hypothesized that a differential ability to initiate AMPK-sensed metabolic stress responses may provide information about the efficacy of HER-targeting drugs via changes in the extracellular FASN status. Enzyme-linked immunosorbent assay (ELISA)-based quantitative analyses revealed that lapatinib treatment drastically enhanced extracellular FASN concentration (by at least 8.0-fold) (Figure 1a). Immunoblotting assessment of AMPK phosphorylation at Thr172 confirmed that lapatinib treatment induced a strong activation of AMPK (Figure 1b). A weak but detectable upregulation of PP-AMPKThr172 was observed upon treatment with gefitinib. Trastuzumab, cetuximab, and erlotinib - all of which are unable to promote FASN release - failed to activate AMPK. AMPK knockdown using short interfering RNA (siRNA) transfection [2] fully prevented lapatinib-induced FASN release (Figure 1). Immunoblotting and cell imaging analyses confirmed that FASN was depleted from the cytosol of lapatinib-treated HER2 overexpressors and accumulated in their extracellular milieu (Figure 1).Treatment with lapatinib dramatically increased FASN release (by approximately 17 times) in lapatinib-responsive SKBR3 TzbR cells (Figure 1c), which were selected for long-term outgrowth in trastuzumab-containing culture medium. Extracellular FASN remained unaltered in response to trastuzumab or lapatinib in JIMT-1 BC cells, which exhibit de novo cross-refractoriness to multiple HER1/2-targeted therapies (Figure 1c). Lapatinib treatment significantly activated AMPK and promoted an enormous accumulation of extracellular FASN in lapatinib-hypersensitive MC
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
Mammosphere Formation in Breast Carcinoma Cell Lines Depends upon Expression of E-cadherin
Juan Manuel Iglesias, Izaskun Beloqui, Francisco Garcia-Garcia, Olatz Leis, Alejandro Vazquez-Martin, Arrate Eguiara, Silvia Cufi, Andres Pavon, Javier A. Menendez, Joaquin Dopazo, Angel G. Martin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077281
Abstract: Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.
Ubiquitous Transgenic Overexpression of C-C Chemokine Ligand 2: A Model to Assess the Combined Effect of High Energy Intake and Continuous Low-Grade Inflammation
Esther Rodríguez-Gallego,Marta Riera-Borrull,Anna Hernández-Aguilera,Roger Mariné-Casadó,Anna Rull,Raúl Beltrán-Debón,Fedra Luciano-Mateo,Javier A. Menendez,Alejandro Vazquez-Martin,Juan J. Sirvent,Vicente Martín-Paredero,Angel L. Corbí,Elena Sierra-Filardi,Gerard Aragonès,Anabel García-Heredia,Jordi Camps,Carlos Alonso-Villaverde,Jorge Joven
Mediators of Inflammation , 2013, DOI: 10.1155/2013/953841
Abstract: Excessive energy management leads to low-grade, chronic inflammation, which is a significant factor predicting noncommunicable diseases. In turn, inflammation, oxidation, and metabolism are associated with the course of these diseases; mitochondrial dysfunction seems to be at the crossroads of mutual relationships. The migration of immune cells during inflammation is governed by the interaction between chemokines and chemokine receptors. Chemokines, especially C-C-chemokine ligand 2 (CCL2), have a variety of additional functions that are involved in the maintenance of normal metabolism. It is our hypothesis that a ubiquitous and continuous secretion of CCL2 may represent an animal model of low-grade chronic inflammation that, in the presence of an energy surplus, could help to ascertain the afore-mentioned relationships and/or to search for specific therapeutic approaches. Here, we present preliminary data on a mouse model created by using targeted gene knock-in technology to integrate an additional copy of the CCl2 gene in the Gt(ROSA)26Sor locus of the mouse genome via homologous recombination in embryonic stem cells. Short-term dietary manipulations were assessed and the findings include metabolic disturbances, premature death, and the manipulation of macrophage plasticity and autophagy. These results raise a number of mechanistic questions for future study. 1. Introduction Excessive energy intake is a part of the current human lifestyle that leads to a state of chronic systemic low-grade inflammation, which is thought to play a role in the development of atherosclerosis, cancer, and other noncommunicable diseases. At the same time, it is also plausible that the long-term consequences of prolonged inflammation exacerbate the deleterious effects of continuous nutrient surplus [1–3]. The immune system and metabolism are closely interconnected [4, 5]. During inflammation, the whole body is under metabolic stress, and energy excess management could compromise the relationships among metabolism, oxidation, and inflammation. We reasoned that searching for an adequate animal model [6] might allow us to better understand disease pathogenesis. Chemokines are promising candidates for the design of such a model. Some of the functions of chemokines are associated with the migration of immune cells, and chemokines are important for the correct functioning of metabolism. In humans, C-C chemokine ligand 2 (CCL2; formerly referred as MCP-1 or monocyte chemoattractant protein-1) could be a marker of inflammation; it is overexpressed in noncommunicable diseases and is
The geometry of thermodynamics
Hernando Quevedo,Alejandro Vazquez
Physics , 2007, DOI: 10.1063/1.2902782
Abstract: We present a review of the main aspects of geometrothermodynamics, an approach which allows us to associate a specific Riemannian structure to any classical thermodynamic system. In the space of equilibrium states, we consider a Legendre invariant metric, which is given in terms of the fundamental equation of the corresponding thermodynamic system, and analyze its geometric properties in the case of the van der Waals gas, and black holes. We conclude that the geometry of this particular metric reproduces the thermodynamic behavior of the van der Waals gas, and the Reissner-Nordstr\"om black hole, but it is not adequate for the thermodynamic description of Kerr black holes.
Affine image region detection and description
Ricardo Vazquez Martin
Journal of Physical Agents , 2010,
Abstract: This paper describes a novel approach for affine invariant region detection and description. At the detection stage, a hierarchical clustering mechanism is employed to group image pixels into regions. This process is based on the Bounded Irregular Pyramid (BIP) and takes into account a colour contrast measure, internal region descriptors and attributes of their shared boundaries. High-contrasted regions are selected as salient regions. On the other hand, geometrically and photometrically normalized regions are represented by a kernel-based descriptor. The lenght descriptor is reduced by applying Principal Component Analysis (PCA). The protocol proposed by Mikolajczyk et al. has been conducted to compare the proposed approach with other similar methods. Experimental results prove that the performance of our proposal is high in terms of computational consuming and distinguished region detection and description abilities.
Computational complexity arising from degree correlations in networks
Alexei Vazquez,Martin Weigt
Computer Science , 2002, DOI: 10.1103/PhysRevE.67.027101
Abstract: We apply a Bethe-Peierls approach to statistical-mechanics models defined on random networks of arbitrary degree distribution and arbitrary correlations between the degrees of neighboring vertices. Using the NP-hard optimization problem of finding minimal vertex covers on these graphs, we show that such correlations may lead to a qualitatively different solution structure as compared to uncorrelated networks. This results in a higher complexity of the network in a computational sense: Simple heuristic algorithms fail to find a minimal vertex cover in the highly correlated case, whereas uncorrelated networks seem to be simple from the point of view of combinatorial optimization.
Recovery of Gold and Silver and Removal of Copper, Zinc and Lead Ions in Pregnant and Barren Cyanide Solutions  [PDF]
Gabriela Figueroa, Jesus L. Valenzuela, Jose R. Parga, Victor Vazquez, Alejandro Valenzuela
Materials Sciences and Applications (MSA) , 2015, DOI: 10.4236/msa.2015.62020
Abstract: Over the past decade the concern about toxic metals in freshwater has increased. Environmental laws such as the Clean Water Act have forced industries that produce metal containing wastewater to treat their wastewater prior to discharge. The purpose of this study was to investigate the use of a novel method for the minimization of heavy metals in the wastewater from the mining industry. A very promising electrochemical treatment technique that does not require chemical additions is electrocoagulation (EC) and sulphide precipitation. The present study has been done for the recovery of gold and silver contained in pregnant solution from the cyanidation process using the electrocoagulation technology with iron electrodes; that is a developed alternative technology for the Merril-Crowe process. The average gold and silver content in pregnant solution was 4.27 and 283 ppm respectively and the recoveries were 92% for gold and 95% for silver, with optimum operating parameters of pH 10, residence time of 20 minutes and addition of sodium chloride of 4 gr/L. The results of precipitation process show that the elimination of lead, zinc, cooper and iron ions from the barren solution was successful, with optimum operating parameters of pH 3 and residence time of 15 minutes, and the recoveries were 99% of these ions. Finally the characterization of the solid products of gold and silver formed during the EC process with Scanning Electronic Microscope was performed. Results suggest that magnetite particles and amorphous iron oxyhydroxides (lepidocrocite) were present.
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