A

Abstract:  Glioblastomas (GBs) are the most common primary tumors of the central nervous system. The first-line treatment is surgical resection complemented with chemo and radiotherapy, but due to its late diagnosis and its infiltrative characteristic the survival is low. The chemotherapy used in most GBs is Temozolomide (TMZ). As a second line, other chemotherapeutic agents and oncolytic virotherapy are used. It is known that omega-6 polyunsaturated fatty acids (PUFAs) have a high therapeutic potential in GBs treatment since they exhibit tumoricidal activity without significant side effects. In the present work we study the effects of two omega-6 PUFAs: arachidonic acid (AA, 20:04) and gamma linolenic acid (GLA, 18:03) associated with TMZ on cell viability and proliferation and their relationship with p53 expression in a murine glioblastoma cell line (GL26). The cells were treated with: AA, GLA, TMZ, AA + TMZ or GLA + TMZ [10, 20, 30, 40, 50 and 100 µM] and ethanol (control). We evaluate cell viability by fluorimetry with resazurin; cell proliferation with Ki67 and p53 expression by immunocytochemistry. Lipid cell profile by gas chromatography (GC) and generation of eicosanoids by high pressure liquid chromatography (HPLC). Statistical analysis was performed using the Kruskal Wallis test. Our results show that AA + TMZ and GLA + TMZ significantly reduce the viability compared to TMZ (p <0.05). GLA, TMZ and GLA + TMZ significantly reduce the expression of Ki67 (p <0.01) and increase the expression of p53 (p <0.1) with respect to the control. The percentages of AA and GLA are higher in GL26 cell membranes treated with AA and GLA respectively in relation to cells treated with TMZ. GLA reduce the release of 12-HHT compared to the control. TMZ combined with GLA exerts an antiproliferative effect by decreasing the release of 12-HHT and increasing the expression of p53.Resumen:  Los gliobastomas (GBs) son los tumores primarios más frecuentes del sistema nervioso central. El tratamiento de primera línea es la resección quirúrgica  complementada con quimio y radioterapia pero por su diagnóstico tardío y su poder infiltrativo la supervivencia es baja. El quimioterápico usado en la mayoría de los GBs es la Temozolomida (TMZ). Como segunda línea se emplean otros quimioterapéuticos y viroterapia oncolítica. Se conoce que los ácidos grasos poliinsaturados (AGPs) de la familia omega-6 tienen un alto potencial terapéutico en el tratamiento de GBs ya que exhiben actividad tumoricida sin presentar  efectos secundarios significativos. En el presente trabajo estudiamos los efectos de dos AGPs omega-6: el ácido araquidónico (AA, 20:04) y el ácido gama linolénico (GLA, 18:03) asociados a TMZ sobre la viabilidad y proliferación celular y su relación con la expresión de p53 en una línea celular de glioblastoma murina (GL26). Las células fueron tratadas con: AA, GLA, TMZ, AA+TMZ o GLA+TMZ [10, 20, 30, 40, 50 y 100 µM] y etanol  (control).   Evaluamos viabilidad celular por fluorimetría con resazurina; proliferación celular con Ki67 y expresión de p53 por inmunocitoquímica; perfil celular lipídico por cromatografía de gases (GC) y generación de eicosanoides por cromatografía líquida de alta presión (HPLC). El análisis estadístico se realizó mediante la prueba de Kruskal Wallis. Nuestros resultados mostraron que AA+TMZ y GLA+TMZ redujeron significativamente la viabilidad respecto a TMZ (p<0.05). GLA, TMZ y GLA+TMZ redujeron significativamente la expresión de KI67 (p<0.01) y aumentaron la expresión de p53 (p<0.1) con respecto al control. Los porcentajes de AA y GLA fueron mayores en membranas de células GL26 tratadas con AA y GLA respectivamente en relación a las tratadas con TMZ.  GLA redujo la liberación del eicosanoide 12-HHT respecto al control. La TMZ combinada con GLA ejerce un efecto antiproliferativo disminuyendo la liberación de 12-HHT y aumentando la expresión de p53.

Trace element chemistry and U-Pb dating of zircons from oceanic gabbros and their relationship with whole rock composition (Lanzo, Italian Alps)

The U-Pb ages and the trace element content of zircon U-Pb along with major and trace element whole rock data on gabbroic dikes from the Lanzo lherzolitic massif, N-Italy, have been determined to constrain crustal accretion in ocean-continent transition zones. Three Fe-Ti gabbros were dated from the central and the southern part of the massif providing middle Jurassic ages of 161 +/- 2, 158 +/- 2 and 163 +/- 1 Ma, which argue for magmatic activity over few millions of years. Zircon crystals are characterized by high but variable Th/U ratios, rare earth element patterns enriched in heavy rare earths, pronounced positive Ce and negative Eu-anomalies consistent with crystallization after substantial plagioclase fractionation. The zircon trace element composition coupled with whole rock chemistry was used to reconstruct the crystallization history of the gabbros. A number of gabbros crystallized in situ, and zircon precipitated from trapped, intercumulus liquid, while other gabbros represent residual liquids that were extracted from a cumulus pile and crystallized along syn-magmatic shear zones. We propose a model in which the emplacement mechanism of gabbroic rocks in ocean-continent transition zones evolves from in situ crystallization to stratified crystallization with efficient extraction of residual liquid along syn-magmatic shear zones. Such an evolution of the crystallization history is probably related to the thermal evolution of the underlying mantle lithosphere