Marketing plan for Datanet Consulting

Treball Final de Grau en Administració d'Empreses. Codi: AE1049. Curs 2017-201

Caracterización de modelos de animales modificados genéticamente para Loxl2 en la fisiología y en la progresión de carcinomas

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 27/06/2014El cáncer es la segunda causa de muerte en el mundo, siendo la metástasis la responsable del 90% de las muertes por esta enfermedad. La metástasis conlleva una serie de etapas que implican invasión, diseminación y colonización de órganos distantes. En el contexto de la progresión de carcinomas, la pérdida del fenotipo epitelial y la adquisición de un fenotipo mesenquimal, un proceso conocido como transición epitelio-mesénquima (TEM), se considera esencial para la invasión y otras etapas de la metástasis. La pérdida de cadherina-E es un evento clave de la TEM, habiéndose descrito numerosos factores de transcripción represores de cadherina-E e inductores de TEM, como Snail1. Trabajos previos de nuestro grupo identificaron a la lisil oxidasa-like 2 (LOXL2) como un regulador positivo de la estabilidad de Snail1 y como inductor de TEM, incluso de manera independiente de Snail1. LOXL2 pertenece a la familia de lisil oxidasas, formada por un conjunto de proteínas cuya función clásica es catalizar el entrecruzamiento de las fibras que componen la matriz extracelular (MEC), participando en procesos fisiológicos y patológicos, como la fibrosis o el cáncer. Sin embargo, en los últimos años, numerosos estudios, incluidos los de nuestro grupo, han demostrado la implicación de LOXL2 en procesos intracelulares, como la transcripción génica. Además, nuestro laboratorio describió la sobreexpresión de LOXL2 intracelular como un nuevo marcador pronóstico de carcinomas escamosos (SCC) de laringe, así como su asociación con la metástasis de carcinomas basales de mama. Con el objetivo de profundizar en las capacidades multifuncionales de LOXL2, en el presente estudio se han generado modelos genéticos de ganancia y pérdida de función de Loxl2 en ratón. Los resultados obtenidos muestran que la deleción constitutiva de Loxl2 provoca letalidad perinatal asociada, en algunos casos, con defectos cardiacos congénitos y/o distensión de los vasos sanguíneos hepáticos. Por otro lado, la sobreexpresión constitutiva de Loxl2 provoca esterilidad en machos debido a disfunciones en el epidídimo y degeneración testicular. La contribución de Loxl2 a la progresión tumoral y la metástasis se ha estudiado en ambos modelos genéticos en dos sistemas experimentales: a) carcinogénesis química de piel inducida por DMBA/TPA, y b) el modelo de cáncer de mama Polyoma Middle T (PyMT). Los resultados obtenidos en la carcinogénesis de piel demuestran la implicación de Loxl2 en la iniciación y progresión maligna actuando como inhibidor de la diferenciación de papilomas a través, al menos en parte, de la regulación negativa de la vía de señalización de Notch. Por otra parte, los estudios en el modelo PyMT demuestran un papel esencial de Loxl2 para la generación de metástasis pulmonares y del nicho pre-metastásico, regulando la movilización de células progenitoras mieloides y la expresión de varias citoquinas, como S100A8/S100A9. Parte de las funciones de Loxl2 durante la metástasis de cáncer de mama se ejercen a través de mecanismos intrínsecos a las células tumorales y de un modo independiente a la remodelación de la matriz extracelular (MEC) que rodea al tumor primario.Cancer is the second cause of death in the world, being metastasis responsible for at least 90% of deaths caused by this disease. The process of metastasis involves different steps including invasion, dissemination, and colonization into distant organs. During carcinoma progression the loss of the epithelial phenotype and the acquisition of a mesenchymal phenotype, a process known as epithelial to mesenchymal transition (EMT), is considered essential for invasion and other metastatic steps. Loss of functional E-cadherin is a key event during EMT. Numerous transcription factors acting as E-cadherin repressors and EMT inducers have been described, including Snail1. Previous data from our group identified lysyl oxisaselike 2 (LOXL2) as a positive regulator of Snail1 stability and EMT inducer, even independently of Snail1. LOXL2 belongs to the lysyl oxidase family, which is composed by several proteins whose classical function is to catalyze extracellular matrix (ECM) fibers crosslinking, participating in physiological and pathologic processes, such as fibrosis and cancer. However, during the last years, studies from our group and others have demonstrated the involvement of LOXL2 in intracellular processes, such as gene transcription. Moreover, our group described increased intracellular LOXL2 expression as a new prognosis marker of larynx squamous cell carcinomas (SCC), as well as its association with basal breast carcinoma metastasis. The aim of the present work was to further investigate the multifunctional LOXL2 abilities by generating genetic mouse models of gain and loss of function for Loxl2. The results obtained show that constitutive deletion of Loxl2 causes perinatal lethality associated, in some cases, with congenital cardiac defects and/or hepatic blood vessels distension. On the other hand, constitutive Loxl2 overexpression provokes male sterility due to epididymal dysfunction and testicular disorganization. The Loxl2 contribution to tumor progression and metastasis has been studied using two different experimental systems: a) DMBA/TPA mouse skin carcinogenesis, and b) Polyoma Middle T (PyMT) breast tumor model. The obtained results demonstrate the involvement of Loxl2 both in initiation and malignant progression of mouse skin carcinogenesis inhibiting papilloma differentiation, at least in part, through the negative regulation of the Notch signaling pathway. On the other hand, the studies performed in the PyMT model demonstrate an essential role for Loxl2 in lung metastasis and pre-metastatic niche formation, through the regulation of myeloid progenitor cells mobilization and the expression of several cytokines, such as S100A8/S100A9. Importantly, during the metastatic process, Loxl2 also acts through tumor cell intrinsic mechanisms and independently of primary tumor ECM remodeling

Urban Water pricing and private interests' lobbying in small rural communities

It is difficult for small municipalities to ensure their urban water cycle complies with the principle of cost recovery established in the European Union (EU) Water Framework Directive. Unlike more populous municipalities, small municipalities face higher average production costs. However, at least in Spain, the price of water is, on average, lower in small municipalities. We question whether the low price of water in rural areas is due, at least in part, to people linked to agriculture, i.e., do farmers constitute a special interest group that hinders increases in the price of water? The main hypothesis was tested with data taken from Torre-Cardela, a municipality in southern Spain with close to 800 inhabitants. In the research, a contingent valuation analysis was carried out to analyze respondents' willingness to pay in the event of a hypothetical increase in the price of water to help cover the service costs. Contrary to expectations, the study yields no evidence that the agricultural population is more resistant to price rises than the rest of the citizens surveyed. In fact, results show that people involved in the agricultural sector would be willing to accept a hypothetical increase in water tariffs in between 15% and 25% over the current tariff, while for the rest of the population this same increase would be lower (in between 9% and 20%)