Evidence for classification of c.1852_1853AA > GC in MLH1 as a neutral variant for Lynch syndrome

Background: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS. Methods: The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers. Results: Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients. Conclusions: The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.

Cartas enviadas por Rafael de Arancibia a Justo Garate entre 1941-1978

3 cartas (mecanografiadas) y 1 invitación de boda ; entre 210x274mm y 157x100mm. Ubicación: Caja 1 - Carpeta 38

Carta enviada por Rafael Areitio a Justo Garate en 1992

1 carta (manuscrita) ; 215x156mm. Ubicación: Caja 1 - Carpeta 46

El compromiso como variable mediadora para la predicción de las futuras intenciones de consumo en los servicios. Una aproximación empírica a los consumidores de artes escénicas en España

[ES] El presente trabajo de investigación trata de arrojar luz sobre las relaciones entre las variables Satisfacción, Compromiso, Confianza y Futuras Intenciones de compra. Con este fin, se propone un Modelo de Gestión de las Relaciones con Clientes de Servicios en el que se observa que la variable más importante en la consecución de resultados positivos en lo que respecta a intenciones de asistencia futura de los consumidores es el Compromiso.

Determinantes de la intención del consumidor de ir a un destino turístico. Aplicación al caso de "Mundo Maya-México"

[ES] Cada destino turístico tiene una marca que puede elegir el consumidor a la hora de viajar. Este trabajo examina, a través de un modelo causal que contrastamos empíricamente para el caso de Mundo Maya-México, el papel que desempeña la reputación, las emociones y la confianza en la intención de compra de los consumidores de un destino turístico.

Key business factors for eco-innovation: an overview of recent firm-level empirical studies

[EN] The increasing interest in eco-innovation or environmental innovation as a strategy not only to address the serious global environmental problems but also as a source of competitive advantages for companies and for the emergence of new business areas, leads us to try to identify the different factors that act as determinants of its development and adoption at the micro level.

Las élites vascas en el gobierno de la monarquía borbónica : redes sociales, carreras y hegemonía en el siglo XVIII (1700-1746)

815 p. : il., graf.

¿De qué manera condiciona el Derecho mis derechos?

Duración (en horas): Más de 50 horas. Destinatario: Estudiante y Docente

Nuevas fórmulas publicitarias: los advergames como herramienta de las comunicaciones de marketing

Los advergames son videojuegos orientados a la comunicación publicitaria. Su naturaleza de mensaje híbrido, al combinar contenido publicitario y contenido de entretenimiento, aporta interesantes posibilidades al desarrollo de comunicaciones de marketing en un entorno mediático en el que la publicidad tradicional ha ido perdiendo eficacia. El presente artículo delimita el concepto de advergame, analizando las diferentes tipologías existentes y sus efectos sobre diversos objetivos de marketing y de comunicación. Asimismo, se apuntan algunas recomendaciones a la hora de desarrollar comunicaciones de marketing mediante advergames, así como las cuestiones éticas y morales que deben considerarse

Factores explicativos de la intención de emprender en la mujer. Aspectos diferenciales en la población universitaria según la variable género

El objetivo del presente trabajo de investigación es arrojar luz sobre los factores que explican la menor intencionalidad en la población femenina para involucrarse en procesos de creación de empresas. Para ello, se ha desarrollado un modelo de ecuaciones estructurales que identifica un conjunto de variables que permiten explicar la intención de emprender en la población potencialmente emprendedora. La validación del modelo se ha realizado mediante una encuesta realizada a 1222 estudiantes de 12 titulaciones diferentes de la Universidad de Málaga. La aplicación del modelo a las poblaciones masculina y femenina ha permitido apreciar diferencias significativas en los patrones de comportamiento en función del género, identificando un proceso más complejo y necesitado de apoyo externo en la población femenina con respecto a la masculina.

Fine mapping and functional analysis of the multiple sclerosis risk gene CD6

CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2nd SRCR domain with susceptibility to MS (Pmax(T) permutation=161024). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. – CD4+ naı¨ve cells, P = 0.0001; CD8+ naı¨ve cells, P,0.0001; CD4+ and CD8+ central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4+ and CD8+ T cells.

Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial

Background The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia. Methods A randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety. Results The median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. Conclusions In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation.

Increased opioid dependence in a mouse model of panic disorder

[EN] Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.

A colorectal cancer genome-wide association study in a Spanish cohort identifies two variants associated with colorectal cancer risk at 1p33 and 8p12

Background: Colorectal cancer (CRC) is a disease of complex aetiology, with much of the expected inherited risk being due to several common low risk variants. Genome-Wide Association Studies (GWAS) have identified 20 CRC risk variants. Nevertheless, these have only been able to explain part of the missing heritability. Moreover, these signals have only been inspected in populations of Northern European origin. Results: Thus, we followed the same approach in a Spanish cohort of 881 cases and 667 controls. Sixty-four variants at 24 loci were found to be associated with CRC at p-values <10-5. We therefore evaluated the 24 loci in another Spanish replication cohort (1481 cases and 1850 controls). Two of these SNPs, rs12080929 at 1p33 (P-replication=0.042; P-pooled=5.523x10(-03); OR (CI95%)=0.866(0.782-0.959)) and rs11987193 at 8p12 (P-replication=0.039; P-pooled=6.985x10(-5); OR (CI95%)=0.786(0.705-0.878)) were replicated in the second Phase, although they did not reach genome-wide statistical significance. Conclusions: We have performed the first CRC GWAS in a Southern European population and by these means we were able to identify two new susceptibility variants at 1p33 and 8p12 loci. These two SNPs are located near the SLC5A9 and DUSP4 loci, respectively, which could be good functional candidates for the association signals. We therefore believe that these two markers constitute good candidates for CRC susceptibility loci and should be further evaluated in other larger datasets. Moreover, we highlight that were these two SNPs true susceptibility variants, they would constitute a decrease in the CRC missing heritability fraction.