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2 p., Introduction The BRAFV600E mutation in melanoma is generally associated with activation of the MAPK/ERK signaling pathway, leading to tumor cell proliferation. Targeted therapy with combined BRAFV600E and MEK inhibitors has improved patient survival, but resistance to this treatment is very frequent and represents a serious clinical challenge. Resistance can be intrinsic or can be based on newly-acquired genetic alterations. Moreover, drug tolerant/persister (DTP) clones arising without genetic changes from tumor cells that adapt and survive the initial phases of therapy, can be another source of resistance. The aim of our study is to characterize the mechanisms of resistance to MAPK-targeted therapy in melanoma., Material and Methods We have used the mouse melanoma YUMM cell model to in vitro and in vivo (C57BL/6 mice) generate cells resistant to combined BRAF and MEK inhibitors. Both putative DTP and resistant cell populations have been selected from the in vitro and in vivo platforms, and cell survival and proliferation, and cell signaling and function are being investigated., Results and Discussions DTP and resistant cells display significant changes in growth and in several signaling properties and transition markers, and potential gene differences are currently examined byRNAseq and their functional implications investigated., Conclusion Our in vitro and in vivo models represent useful platforms to mechanistically study drug adaptation and resistance mechanisms in DTP and resistant melanoma cell populations, as well as a system to assess new inhibitors targeting these populations.

Este trabajo tiene como objetivo dise˜nar rutas tur´ısticas que se puedan realizar a pie en la ciudad de Santa Cruz de Tenerife considerando las preferencias generales de los turistas. Para resolver este problema se desarrollan y aplican modelos del tipo Orienteering Problem, en particular formulamos y encontramos soluciones utilizando los modelos Orienteering Problem Time Windows y Team Orienteering Problem Time Windows. La metodolog´ıa utilizada para encontrar las soluciones es una metodolog´ıa aproximada, dado que este problema es complejo para encontrar soluciones a partir de un cierto n´umero de puntos de inter´es. As´ı para la experimentaci´on y obtenci´on de resultados se aplica la metaheur´ıstica de B´usqueda por Entornos Variables Descendente, que es una variante de la B´usqueda por Entornos Variables. Los datos provienen del Observatorio de la Sociedad de Desarrollo del Ayuntamiento de Santa Cruz de Tenerife y del ISTAC. Los resultados ser´an diferentes rutas, con diferentes duraciones, que tendr´an como punto de partida la Plaza Espa˜na, y que maximizar´an las preferencias generales de los turistas. The objetive of this work is to design tourist routes that can be done on foot in the city of Santa Cruz of Tenerife considering the general preferences of tourist. To solve this problem, are developed and applied models of the Orienteering Problem type, in particular we formulate and find solutions using the Orienteering Problem with Time Windows and Team Orienteering Problem with Time Windows models. The methodology used to find the solutions is an approximate methodology, since this problem is complex to find solutions from a certain number of points of interest. Thus, for experimentation and obtaining results, the Variable Neighbourhood Descent metaheuristic is applied, which is a variant of the Variable Neighbourhood Search. The data come from the Observatorio de la Sociedad de Desarrollo del Ayuntamiento de Santa Cruz de Tenerife and the ISTAC. The results will be differents routes with differents durations, which will have as their starting point the Plaza Espa˜na, and which will maximize the generals preferences of tourists. Problemas de Dise˜no de Itineratios Tur´ısticos metaheur´ısticas Problemas de Orientaci´on B´usqueda por entornos variables Trip Tourist Design Problem Metaheuristic Orienteering Problem Variable Neighborhood Search