Pharmacogenetics of MicroRNAs and MicroRNAs Biogenesis Machinery in Pediatric Acute Lymphoblastic Leukemia

Despite the clinical success of acute lymphoblastic leukemia (ALL) therapy, toxicity is frequent. Therefore, it would be useful to identify predictors of adverse effects. In the last years, several studies have investigated the relationship between genetic variation and treatment-related toxicity. However, most of these studies are focused in coding regions. Nowadays, it is known that regions that do not codify proteins, such as microRNAs (miRNAs), may have an important regulatory function. MiRNAs can regulate the expression of genes affecting drug response. In fact, the expression of some of those miRNAs has been associated with drug response. Genetic variations affecting miRNAs can modify their function, which may lead to drug sensitivity. The aim of this study was to detect new toxicity markers in pediatric B-ALL, studying miRNA-related polymorphisms, which can affect miRNA levels and function. We analyzed 118 SNPs in pre-miRNAs and miRNA processing genes in association with toxicity in 152 pediatric B-ALL patients all treated with the same protocol (LAL/SHOP). Among the results found, we detected for the first time an association between rs639174 in DROSHA and vomits that remained statistically significant after FDR correction. DROSHA had been associated with alterations in miRNAs expression, which could affect genes involved in drug transport. This suggests that miRNA-related SNPs could be a useful tool for toxicity prediction in pediatric B-ALL.

[B_Zalla_Bolunburu] Documentación Geométrica de la Ferrería Bolunburu (Zalla, Bizkaia)

[ES] El conjunto de dos edificios divididos en varias estancias, un canal de captación de aguas y un puente, todo ello arruinado. Los muros aún se mantienen en pie aunque ya no quedan restos de los tejados ni del mobiliario, maquinaria o decoración.

Informe técnico sobre posibles alternativas de valorización energética de residuos forestales

[ES]Mediante este proyecto, se trata de buscar diferentes alternativas de valorización energética de residuos forestales, analizar su proceso y los equipos involucrados, y al final elegir la más adecuada en base a ciertos criterios.

Influencia de la internacionalización en el desempeño social de las empresas

[ES] Recientemente estudios previos han comenzado a plantear la posible relación entre el fenómeno de la internacionalización y responsabilidad social corporativa de las organizaciones. En este trabajo analizamos en qué medida la internacionalización contribuye a una mejora sustancial del desempeño social de las empresas. Usando una muestra de 102 empresas estadounidenses de los sectores químico, energético y de maquinaria industrial, nuestros resultados muestran que no todas las dimensiones de la internacionalización permiten a las empresas adquirir conocimiento valioso que conduzca a una mejora de su desempeño social. Concretamente, comprobamos que, mientras el porcentaje de ventas en mercados extranjeros y la diversificación internacional cultural favorecen la puesta en marcha de prácticas de responsabilidad social corporativa avanzadas que redundan en un mejor desempeño social (cumpliendo con las demandas sociales de los grupos de interés de los distintos mercados donde operan), la diversificación internacional geográfica no tiene efecto directo en el desempeño social de las empresas. Por tanto, no es tan importante el número de mercados donde la empresa actúa, sino el grado de diferenciación cultural existente entre los mismos lo que hace que la propia empresa mejore su desempeño social. El presente trabajo incluye implicaciones relevantes para el mundo académico, directivos y reguladores públicos.

Biomolecule storage on non-modified thermoplastic microfluidic chip by ink-jet printing of ionogels

[EN] This paper reports an innovative technique for reagents storage in microfluidic devices by means of a one-step UV-photoprintable ionogel-based microarray on non-modified polymeric substrates. Although the ionogel and the ink-jet printing technology are well published, this is the first study where both are used for long-term reagent storage in lab-on-a-chip devices. This technology for reagent storage is perfectly compatible with mass production fabrication processes since pre-treatment of the device substrate is not necessary and inkjet printing allows for an efficient reagent deposition process. The functionality of this microarray is demonstrated by testing the release of biotin-647 after being stored for 1 month at room temperature. Analysis of the fluorescence of the ionogel-based microarray that contains biotin-647 demonstrated that 90% of the biotin-647 present was released from the ionogel-based microarray after pumping PBS 0.1% Tween at 37 °C. Moreover, the activity of biotin-647 after being released from the ionogel-based microarray was investigated trough the binding capability of this biotin to a microcontact printed chip surface with avidin. These findings pave the way for a novel, one-step, cheap and mass production on-chip reagents storage method applicable to other reagents such as antibodies and proteins and enzymes.

Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport

Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES). To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs), and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations.