Estudio del receptor 5HT2A y de la vía Akt/GSK3 como mecanismos moleculares de la psicosis inducida por el consumo crónico de cannabis

La esquizofrenia es una enfermedad mental de carácter crónico que afecta aproximadamente al 1% de la población , principalmente con edades comprendidas entre los 15 y 4 5 años . Se trata de una enfermedad de inicio en la adolescencia o comienzo de la madurez y cuyo potencial discapacitante persiste y se agrava a lo largo de la vida. La etiología de la esquizofrenia es multifactorial con evidencias de factores genéticos y ambientales. El carácter hereditario de la esquizofr e nia se ha estimado en un 73 - 90% y los factores genéticos que predisponen a la enfermedad son múltiples y heterogéneos. Los estudios epidemiológicos parecen sugerir que el mayor riesgo de desarrollar esquizofrenia es prod ucto de interacciones genético/ ambi entales (predisposición genética a agresiones ambientales) y del fenómeno de epistasis (fenotipo dependiente de la interacción entre diversos genes). Las manifestaciones clínicas de la esquizofrenia se dividen en síntomas positivos, síntomas negativos y dé ficits cognitivos. A causa de los déficits asociados y de su carácter crónico, la esquizofrenia se encuentra entre las diez causas principales de discapacidad por enfermedad del mundo y según la World Health Organization (2001), se estima que es la quinta enfermedad más costosa para la s ociedad en términos de atención requ erida y pérdida de productividad, con un coste anual en la Unión Europea que supera los 35 mil millones de €, según Andlin - Sobocki y Rössler (2005) . A nivel nacional, en el año 2009 los an tipsicóticos atípicos más empleados (risperidona y olanzapina) se encontraron entre los 8 primeros fármacos que más gasto generaron, con un coste económico superior a 350 millones de euros (Sistema Nacional de Salud (2010)) . Además, según el estudio de Pal mer et al. (2005), el riesgo de muerte prematura en la población esquizofrénica es aproximadamente dos veces mayor en la población general, siendo el suicidio la principal causa de este exceso de mortalidad, con una prevalencia estimada entre 5 - 10%. En est e sentido, se ha estimado que entre el 25% y 50% de los pacientes con esquizofrenia cometen por lo menos un intento de suicidio en su vida , según el estudio llevado a cabo por Meltzer (2002) . Dada su prevalencia, la tendencia a la cronicidad y el riesgo su icida de pacientes con esquizofrenia así como los elevados costes socio - sanitarios, la investigación de esta enfermedad es un objetivo prioritario de los sistemas de salud mundiales

Angiotensina 1-7-ren eragina giza espermatozoideen mugikortasunean eta Akt-ren fosforilazioan

Ang 1-7-ak duen eragina giza espermatozoideen mugikortasunean aztertu dugu, baita molekula honek Akt-ren fosforilazioan dituen efektuak ere. Bestalde, Mas hartzailearen presentzia espermatozoideetan ikertu dugu.

Novel mechanisms for regulation of cell survival and migration by ceramide 1-phosphate

201 p. : gráf.

Proteómica dirigida en la cirugía del cáncer gástrico

240 p. + anexos

Sphingomyelinase D/Ceramide 1-Phosphate in Cell Survival and Inflammation

Sphingolipids are major constituents of biological membranes of eukaryotic cells. Many studies have shown that sphingomyelin (SM) is a major phospholipid in cell bilayers and is mainly localized to the plasma membrane of cells, where it serves both as a building block for cell architecture and as a precursor of bioactive sphingolipids. In particular, upregulation of (C-type) sphingomyelinases will produce ceramide, which regulates many physiological functions including apoptosis, senescence, or cell differentiation. Interestingly, the venom of some arthropodes including spiders of the genus Loxosceles, or the toxins of some bacteria such as Corynebacterium tuberculosis, or Vibrio damsela possess high levels of D-type sphingomyelinase (SMase D). This enzyme catalyzes the hydrolysis of SM to yield ceramide 1-phosphate (C1P), which promotes cell growth and survival and is a potent pro-inflammatory agent in different cell types. In particular, C1P stimulates cytosolic phospholipase A2 leading to arachidonic acid release and the subsequent formation of eicosanoids, actions that are all associated to the promotion of inflammation. In addition, C1P potently stimulates macrophage migration, which has also been associated to inflammatory responses. Interestingly, this action required the interaction of C1P with a specific plasma membrane receptor, whereas accumulation of intracellular C1P failed to stimulate chemotaxis. The C1P receptor is coupled to Gi proteins and activates of the PI3K/Akt and MEK/ERK1-2 pathways upon ligation with C1P. The proposed review will address novel aspects on the control of inflammatory responses by C1P and will highlight the molecular mechanisms whereby C1P exerts these actions.

Snail heterogeneity in clear cell renal cell carcinoma

Background: Intratumor heterogeneity may be responsible of the unpredictable aggressive clinical behavior that some clear cell renal cell carcinomas display. This clinical uncertainty may be caused by insufficient sampling, leaving out of histological analysis foci of high grade tumor areas. Although molecular approaches are providing important information on renal intratumor heterogeneity, a focus on this topic from the practicing pathologist' perspective is still pending. Methods: Four distant tumor areas of 40 organ-confined clear cell renal cell carcinomas were selected for histopathological and immunohistochemical evaluation. Tumor size, cell type (clear/granular), Fuhrman's grade, Staging, as well as immunostaining with Snail, ZEB1, Twist, Vimentin, E-cadherin, beta-catenin, PTEN, p-Akt, p110 alpha, and SETD2, were analyzed for intratumor heterogeneity using a classification and regression tree algorithm. Results: Cell type and Fuhrman's grade were heterogeneous in 12.5 and 60 % of the tumors, respectively. If cell type was homogeneous (clear cell) then the tumors were low-grade in 88.57 % of cases. Immunostaining heterogeneity was significant in the series and oscillated between 15 % for p110a and 80 % for Snail. When Snail immunostaining was homogeneous the tumor was histologically homogeneous in 100 % of cases. If Snail was heterogeneous, the tumor was heterogeneous in 75 % of the cases. Average tumor diameter was 4.3 cm. Tumors larger than 3.7 cm were heterogeneous for Vimentin immunostaining in 72.5 % of cases. Tumors displaying negative immunostaining for both ZEB1 and Twist were low grade in 100 % of the cases. Conclusions: Intratumor heterogeneity is a common event in clear cell renal cell carcinoma, which can be monitored by immunohistochemistry in routine practice. Snail seems to be particularly useful in the identification of intratumor heterogeneity. The suitability of current sampling protocols in renal cancer is discussed.

Interacción entre quinasas y moléculas apoptóticas en la muerte oligodendroglial excitotóxica

201 p.