ctDNA analysis reveals different molecular patterns upon disease progression in patients treated with osimertinib

Background: Several clinical trials have demonstrated the efficacy and safety of osimertinib in advanced nonsmall-cell lung cancer (NSCLC). However, there is significant unexplained variability in treatment outcome. Methods: Observational prospective cohort of 22 pre-treated patients with stage IV NSCLC harboring the epidermal growth factor receptor (EGFR) p.T790M resistance mutation and who were treated with osimertinib. Three hundred and twenty-six serial plasma samples were collected and analyzed by digital PCR (dPCR) and next-generation sequencing (NGS). Results: The median progression-free survival (PFS), since the start of osimertinib, was 8.9 [interquartile range (IQR): 4.6–18.0] months. The median treatment durations of sequential gefitinib + osimertinib, afatinib + osimertinib and erlotinib + osimertinib treatments were 30.1, 24.6 and 21.1 months, respectively. The p.T790M mutation was detected in 19 (86%) pre-treatment blood samples. Undetectable levels of the original EGFR-sensitizing mutation after 3 months of treatment were associated with superior PFS (HR: 0.2, 95% CI: 0.05–0.7). Likewise, re-emergence of the original EGFR mutation, alone or together with the p.T790M mutation was significantly associated with shorter PFS (HR: 8.8, 95% CI: 1.1–70.7 and HR: 5.9, 95% CI: 1.2–27.9, respectively). Blood-based monitoring revealed three molecular patterns upon progression to osimertinib: sensitizing+/T790M+/C797S+, sensitizing+/T790M+/C797S–, and sensitizing+/T790M–/ C797S–. Median time to progression in patients showing the triplet pattern (sensitizing+/T790M+/C797S+) was 12.27 months compared with 4.87 months in patients in whom only the original EGFR sensitizing was detected, and 2.17 months in patients showing the duplet pattern (sensitizing+/T790M+). Finally, we found that mutations in exon 545 of the PIK3CA gene were the most frequent alteration detected upon disease progression in patients without acquired EGFR-resistance mutations. Conclusions: Different molecular patterns identified by plasma genotyping may be of prognostic significance, suggesting that the use of liquid biopsy is a valuable approach for tumor monitoring.post-print468 K

Usos del e‐learning en las Universidades Andaluzas: estado de la situación y análisis de buenas prácticas. (Resumen ejecutivo).

Secretaría General de Universidades, Investigación y Tecnología P07-SE-J.0267

Usos del e-learning en las Universidades Andaluzas: Estado de la situación y análisis de buenas prácticas. (Versión completa)

Secretaría General de Universidades, Investigación y Tecnología P07-SE-J.0267

Lack of validation of genetic variants associated with anti-tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis

Introduction: In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations. Methods: The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients. Results: None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis. Conclusion: Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes

Ecos de la academia: Revista de la Facultad de Educación, Ciencia y Tecnología - FECYT Nro 3

Ecos de la academia, Revista de la Facultad de Educación Ciencia y Tecnología es una publicación científica de la Universidad Técnica del Norte, con revisión por pares a doble ciego que publica artículos en idioma español, quichua, portugués e inglés. Se edita con una frecuencia semestral con dos números por año.En ella se divulgan trabajos originales e inéditos generados por los investigadores, docentes y estudiantes de la FECYT, y contribuciones de profesionales de instituciones docentes e investigativas dentro y fuera del país, con calidad, originalidad y relevancia en las áreas de ciencias sociales y tecnología aplicada.Ideología, valores y medios. Un reto de niños, padres y maestros. Características de la violencia intrafamiliar en Imbabura. El mercado del arte contemporáneo: La presencia femenina. Recursos educativos abiertos (REA) con metodología PACIE. Educación y Pedagogía. Diversas aproximaciones. Organizadores gráficos interactivos (OGIS): una alternativa didáctica para el aprendizaje. El pseudoperiodismo de investigación en las cadenas generalistas de televisión en España. Educomunicación y bailoterapia como estrategias para fortalecer la Relación Universidad-Sociedad. Catalanes en Ecuador (siglos XVI-XX). La Arqueología y el Arte: los artistas como arqueólogos. Las nuevas tecnologías: su influencia en la comunicación y en la práctica docente. Validación de un instrumento para evaluar competencias genéricas en la formación del maestro de Educación Infantil Análisis de los factores que motivan a los trabajadores en relación de dependencia de Imbabura. El libro La marca-país en América Latina. Bases teóricas y técnicas para el diseño de la marca-país. El libro Historia del Diseño en América Latina y el Caribe: industrialización y comunicación visual. El diseño de la marca “Editorial UTN”. El cartelismo social y la Ecuador Poster Bienal Aprendiendo Ciencia en el Aula didáctica: retos y potencialidades Normas de presentación de artículos en la revista Ecos de la Academia

Cultura, innovación, internacionalización y vinculación de la Pyme con la Universidad : barómetro económico de la PYME 2011

Este barómetro corresponde al año 2011 y recoge información sobre: •Características generales de la empresa y expectativas. •Grado y capacidad de internacionalización de la empresa. •Relación de la empresa con el medio-ambiente. •Tecnología y grado de innovación de la empresa. •Organización, cultura empresarial y estrategia. •Vinculación de la empresa con la Universidad. •Evolución del rendimiento de la empresa respecto de la competenciaRegión de Murcia, Consejería de Universidades, Empresas e Innovación, INFO (Instituto de Fomento de la Regiñon de Murcia

Rheumatoid arthritis response to treatment across IgG1 allotype - anti-TNF incompatibility: a case-only study.

INTRODUCTION: We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA). METHODS: The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria. RESULTS: An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication. CONCLUSIONS: Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA

Innovación en las enseñanzas universitarias: experiencias presentadas en las III Jornadas de Innovación Educativa de la ULL

En este libro se recoge un conjunto de experiencias de innovación educativa desarrolladas en la ULL en el curso 2011-12. Se abordan distintos ámbitos y ramas del conocimiento, y ocupan temáticas variadas que han sido desarrolladas con rigor, y con un claro potencial para su extrapolación a efectos de la mejora educativa en el ámbito universitario. Esta publicación constituye una primera edición de una serie que irá recogiendo las experiencias de innovación educativa de la ULL. Este es un paso relevante para su impulso en nuestra institución, como lo es el de su vinculación con la investigación educativa, para potenciar su publicación en las revistas científicas en este ámbito cada vez más pujante y relevante para las universidades. Sobre todo representan el deseo y el compromiso del profesorado de la ULL para la mejora del proceso educativo mediante la investigación, la evaluación y la reflexión compartida de nuestras prácticas y planteamientos docentes

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997Ł2010

Abstract Background: Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIVinfected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population. Methods: We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 personyears (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender. Results: Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997. Conclusion: Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection