A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

Fine-mapping identifies multiple prostate cancer risk loci on 5p15 some associating with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.

Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

Risk analysis of prostate cancer in PRACTICAL, a multinational consortium, using 25 known prostate cancer susceptibility loci

Background Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS).We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived agespecific absolute risks of developing prostate cancer by PRS stratum and family history. Results The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact:We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.

Generalizability of established prostate cancer risk variants in men of African ancestry

Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

Evaluación del rendimiento de veinticinco líneas de sorgo (Sorghum bicolor L. Moench) bajo dos niveles de fertilización en el municipio de San Isidro-Matagalpa (2004)

El estudio se realizó en la Finca el Nancite ubicada en la comarca El Bocón del municipio de San Isidro _ Matagalpa, en la época de postrera (agosto _ diciembre) del año 2004. Elobjetivo de esta investigación fue evaluar veinticinco líneas de sorgo (Sorghum bicolor L. Moench), bajo dos niveles de fertilización (37.43 kg N ha-1 y 0 kg N ha-1). Los materiales evaluados son líneas puras y pertenecen al programa ICRISAT/LASIP; ICSVLM, que significa en ingles Sorghum Variety Latín American Program. El diseño que se utilizó para el experimento fue un diseño de bloques completos al azar (BCA). Cada una de las repeticiones estaba constituida por veinticinco parcelas en donde se sembraron las líneas a evaluar. Cada parcela contenía seis surcos de los cuales tres se fertilizaron aplicándosele completo (10-30-10) al momento de la siembra y fertilizante nitrogenado urea al 46% aplicado en forma fraccionada un 50% a los 30 (dds) y el otro 50% a los 45 días después de la siembra (dds), los otros tres surco no recibieron aporte de fertilización química sintética de forma aplicada. Las variables a evaluar en el desarrollo del cultivo fueron: Altura de planta (cm), diámetro del tallo (mm) y número de hojas por planta, estas se evaluaron en tres momentos (45, 60, 75dds). Al momento de la cosecha se evaluaron: Longitud de la panoja (cm.), longitud del raquis (cm), biomasa seca producida (kg ha-1), porcentaje de nitrógeno en la biomasa (%), porcentaje de nitrógeno en el grano (%), rendimiento de grano (kg ha-1), acumulación de nitrógeno en el grano (kg ha-1 ), acumulación de nitrógeno en la biomasa (kg ha-1), eficiencia fisiológica (%), incremento del rendimiento de grano por kg de nitrógeno aplicado (%), eficiencia de uso de nitrógeno por el grano (%). Los resultados obtenidos de las variables evaluadas se procesaron en el paquete estadístico FUALNM (versión 0.5) y separación de medias por Tukey al 95% de confiabilidad (α= 0.05), los resultados obtenidos de acuerdo al análisis, para las variables de desarrollo (altura, numero de hojas y diámetro), para largo de panoja y largo de raquis fueron altamente significativo para ambos factores (A: Líneas, B: Fertilización), en los diferentes momentos evaluados, exceptuando para la variable numero de hojas a los 75 dds para el factor B que fue significativo y para el diámetro del tallo a los 60 dds el factor B que no hubo significancia, todas estas variables mencionadas mostraron diferencias mínimas numéricamente. Para la biomasa seca producida y rendimiento de grano mostraron ser altamente significativo para los dos factoresA y B, obteniendo las líneas ICSVLM-89527, ICSVLM-89551 promedios de 5664 y 4912 kg.ha-1, siendo estos los mayores rendimientos de biomasa de todas las líneas. El rendimiento del grano, los mayores valores lo obtuvieron las líneas ICSVLM-89527 y ICSVLM-89551 con 1526.5 y 1271.8 kg. ha-1. En el incremento de rendimiento por kg. de N aplicado las líneas con mayores resultados fueron la ICSVLM-90538 con 14.7 % y las ICSVLM-93079 con 12.8%. Las líneas que hicieron un mejor uso eficiente de nitrógeno por la biomasa y el grano fueron la JOCORO y el testigo PINOLERO.

La abstracción formal y la validación del razonamiento inductivo

Resumen: Suele admitirse que uno de los problemas pendientes, al menos desde Hume, en la teoría de la ciencia es la justificación crítica de los procesos inductivos, que son los que siguen las ciencias experimentales, como son las ciencias naturales. Frente a las ineficaces explicaciones aportadas por el empirismo o neopositivismo, así como por los racionalismos o idealismos, que son radicalmente incapaces para resolver el problema, nosotros presentamos la respuesta del realismo aristotélico, basada en el correcto concepto de abstracción formal, ignorado o malentendido incluso por muchos aristotélicos tanto antiguos como modernos. La respuesta consiste, en suma, en ver que el término del proceso inductivo, en cuanto llega a conclusiones universales a partir de lo particular, debe estar mediado por un proceso previo de abstracción de la forma, bien entendida, en lo mismo concreto y particular. Ello permite ver que la conclusión universal no desborda las premisas, que es el problema clásico de la epagogé aristotélica.

Normandya Reparaciones SL.Plan de marketing

CASTELLANO: El proyecto realizado es un plan de marketing para la empresa Normandya reparaciones S.L.. El plan de marketing es la herramienta básica de gestión que debe utilizar toda empresa orientada al mercado que quiera ser competitiva. En su puesta en marcha quedarán fijadas las diferentes actuaciones que deben realizarse en el área del marketing, para alcanzar los objetivos establecidos tras haber realizado un análisis previo de la situación en la que se encuentra la empresa.

Análisis de redes de los proyectos de innovación europeos “Leonardo da Vinci”: un ensayo empírico preliminar

[Castellano] En este trabajo se realiza un ensayo empírico preliminar de los proyectos de innovación europeos “Leonardo da Vinci”. La metodología que se utiliza a lo largo del trabajo es el análisis de redes. Se observan grafos e indicadores de redes y se comparan la situación de los agentes que forman las redes. Además no solamente se analiza la situación de los agentes, sino la similitud y causalidad estructural existente entre las redes que conforman dichos proyectos. Este ensayo empírico preliminar da lugar a una futura modelización o a la aplicación de la metodología en otras materias.

A psicologia social e a noção de verdade: do conhecimento do erro à feitura de tramas

Este estudo visa compreender a relação que a psicologia social estabelece com a noção de verdade e de que modo este conceito foi fundamental na aquisição de seu estatuto científico. Tomando como ponto de partida a análise semântica do termo, principalmente a partir do seu paradigma grego (alétheia), a análise teórica se subdivide em três eixos principais. O primeiro deles irá abordar a tensão que se estabelece acerca das exigências do conhecimento entre o movimento sofístico e o modelo platônico. Num segundo momento, serão analisadas as torções promovidas pelas ciências modernas, transformando o método científico e racional num instrumento de classificação de todos os erros. Na parte final, o foco se desloca para as especificidades da psicologia social, buscando apontar um contraste entre as pesquisas de W. Wundt (1832-1920) e sua influência nas experiências clássicas da psicologia experimental e no empirismo radical de W. James (1842-1910). O pensamento de James será analisado dando ênfase à influência indeterminista presente nas suas propostas filosóficas e psicológicas e à análise de uma de suas principais contribuições: a teoria da verdade.

Evolución y transcendencia del sector de las energias renovables en España

Nowadays the energies that still prevail on a global scale as a source of generation of electricity are those that come from fossil resources. Nevertheless, in a few years the future of energy will center on renewable energies. Those countries that are not involved in their development will be at a clear disadvantage at economic level, since the electrical power is the base for the development of human society and the renewable energies are essential for its production. The present work has as a target to show, in a clear and concise form, the current situation of the sector of renewable energies in Spain. In addition, we present in a brief and summarised form, an aspect that has been essential in the development of the renewable energies in Spain is tackled. This is, the legislation on the matter as well as the development plans that Spain has carried out for its promotion. Finally, the study considers the compared situation of the sector of the renewable energies and of the energy sector in general in Spain in the context of the EU. IDIOMA: Ingles

Early Medial Temporal Atrophy Scale (EMTA)

186 p.

O corpo como obra de arte e fundador da experiência estética em MerleauPonty

Este trabalho parte de uma leitura da filosofia de Merleau-Ponty centrada na noção de Corpo como Obra de arte, fundamentando-se no pressuposto de que se trata de um conceito fundamental da fenomenologia contemporânea e da estética. Este trabalho assume a tarefa de mostrar que, Merleau-Ponty discute a questão do corpo como obra de arte não com os pressupostos do intelectualismo, do empirismo, ou antes, da Psicologia Clássica, mas tomando como base o vivido, o corpo como aquele que percebe, que está situado num mundo e que portanto ele tem um corpo que é fundante. É neste sentido que o seu projeto filosófico se fundamenta, em primeiro lugar, na tentativa de estabelecer um retorno ao vivido e a tarefa da compreensão de que a verdadeira filosofia é reaprender a ver o mundo. Por conseguinte, justifica-se uma investigação que irá pensar o corpo como obra de arte e como tal, inacabada e ao mesmo tempo, ele se dá através de seus desdobramentos na medida em que o sentido só é acessível por um contato direto. Do mesmo modo, partindo de uma compreensão merleau-pontiana de corpo como obra de arte, por fim, este trabalho assume também a tarefa de se indagar acerca da repercussão desta mesma afirmação na relação do saber filosófico consigo mesmo, logo, no modo da própria filosofia entender a sua história, estando, pois, a importância desta incursão no ensejo de explicitar o que, para Merleau Ponty, seria um corpo comparado a obra de arte como um nó de significações vivas e não a lei de um certo número de termos co-variantes.