| 1. |
- Aguilar, Helena, et al.
(författare)
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VAV3 mediates resistance to breast cancer endocrine therapy
- 2014
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Ingår i: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 16:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process.METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.CONCLUSIONS: This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.
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| 2. |
- Gil, Miguel
(författare)
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La evolución de los sistemas de control administrativos : estudio de caso en un ambiente de incertidumbre
- 2013
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Ingår i: Observatorio de la Economía Latinoamericana. - 1696-8352.
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Tidskriftsartikel (refereegranskat)abstract
- Los Sistemas de Control Administrativos (SCA) son una herramienta muy importante para los gerentes de cualquier empresa, pero cuando la empresa se desarrolla en un ambiente de negocios con gran incertidumbre su aplicación se vuelve bastante compleja. El presente estudio busca encontrar los elementos claves que provocan que los SCA de una empresa con alto nivel de incertidumbre evolucionen. El estudio de caso se enfoca en una pequeña empresa de desarrollo de software que implementa un SCA y que presenta una evolución constante debido al nivel de incertidumbre presente en el ambiente de negocios. El artículo concluye con un análisis crítico sobre lo establecido actualmente en la literatura y los hallazgos empíricos del estudio de caso.
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| 3. |
- Martin-Liberal, J., et al.
(författare)
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Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours
- 2014
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 111:5, s. 858-865
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Tidskriftsartikel (refereegranskat)abstract
- Background: We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine. Methods: Nineteen patients were treated with sirolimus 2 or 5mg daily and gemcitabine 800 or 1000 mg m(-2) on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted. Results: Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment. Conclusions: Recommended dose was sirolimus 5mg per 24 h plus gemcitabine 800 mg m(-2). Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing.
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| 4. |
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| 5. |
- Montalvo, Raúl, et al.
(författare)
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Los determinantes de la confianza del consumidor de vecinos distantes
- 2012
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Ingår i: Optimización-Estocástica-Recursiva-Coherente Sistémica y sus variantes (probabilidad, econometría y estadística aplicada). - : ECORFAN-México. - 9786070059025 ; , s. 359-370
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Bokkapitel (refereegranskat)abstract
- This study tries to find a relationship between consumer sentiment (confidence), inflation levels and the country's economic perception. Given that Consumption is one of the most important elements in the economy of a country, we analyze the cases of Mexico and the United States, in order to verify the results in the two countries and thus to identify the factors determining the consumer confidence in each country. The research proposes long term models, so that the reader can identify the effect of the variables over time.
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| 6. |
- Pérez-Perarnau, Alba, et al.
(författare)
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A trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins
- 2014
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Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 53:38, s. 10150-10154
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Tidskriftsartikel (refereegranskat)abstract
- A new class of small molecules, with an unprecedented trifluorothiazoline scaffold, were synthesized and their pro-apoptotic activity was evaluated. With an EC50 in the low micromolar range, these compounds proved to be potent inducers of apoptosis in a broad spectrum of tumor cell lines, regardless of the functional status of p53. Fast structure-activity relationship studies allowed the preparation of the strongest apoptosis-inducing candidate. Using a high performance affinity purification approach, we identified prohibitins 1 and 2, key proteins involved in the maintenance of cell viability, as the targets for these compounds.
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| 7. |
- Pil, L, et al.
(författare)
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Establishing a method to estimate the cost-effectiveness of a kindergarten-based, family-involved intervention to prevent obesity in early childhood : the ToyBox-study
- 2014
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Ingår i: Obesity Reviews. - : Wiley-Blackwell. - 1467-7881 .- 1467-789X. ; 15:Suppl 3, s. 81-89
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Tidskriftsartikel (refereegranskat)abstract
- Overweight and obesity in children are recognized as a major health problem. The ToyBox-intervention was developed with the aim of preventing obesity in pre-schoolers. Because it is increasingly important to inform policy makers not only on the effects of prevention interventions, but also on their costs and cost-effectiveness, our purpose was to establish a method to estimate the cost-effectiveness of the ToyBox-intervention. In order to estimate the long-term impact of the ToyBox-intervention on health and societal costs, extrapolations of the intervention effect will be conducted to predict children's weight status (based on the body mass index) at adult age. Effects of the adult weight status on the prevalence of obesity-related complications will be modelled through a Markov model, with a total time horizon of 70 years and a cycle length of 1 year. The model will be conducted in six European countries participating in the ToyBox-intervention, based on country-specific economic and epidemiological data. This study describes the methodological rationale and implementation of an analytic model to examine the cost-effectiveness of the ToyBox-intervention for six European countries, in order to inform decision-makers on the value for money of this intervention in the prevention of obesity in pre-schoolers.
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| 8. |
- Viejo, Diego, et al.
(författare)
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Using GNG to improve 3D features extractio - Application to 6DoF Egomotion
- 2012
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Ingår i: Neural Networks. - : Elsevier BV. - 1879-2782 .- 0893-6080. ; 32, s. 138-146
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Tidskriftsartikel (refereegranskat)abstract
- Abstract in UndeterminedSeveral recent works deal with 3D data in mobile robotic problems, e.g. mapping or egomotion. Data comes from any kind of sensor such as stereo vision systems, time of flight cameras or 3D lasers, providing a huge amount of unorganized 3D data. In this paper, we describe an efficient method to build complete 3D models from a Growing Neural Gas (GNG). The GNG is applied to the 3D raw data and it reduces both the subjacent error and the number of points, keeping the topology of the 3D data. The GNG output is then used in a 3D feature extraction method. We have performed a deep study in which we quantitatively show that the use of GNG improves the 3D feature extraction method. We also show that our method can be applied to any kind of 3D data. The 3D features obtained are used as input in an Iterative Closest Point (ICP)-like method to compute the 6DoF movement performed by a mobile robot. A comparison with standard ICP is performed, showing that the use of GNG improves the results. Final results of 3D mapping from the egomotion calculated are also shown. (C) 2012 Elsevier Ltd. All rights reserved.
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