Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer

KRAS mutations are an established predictor of lack of response to EGFR-targeted therapies in patients with metastatic colorectal cancer (mCRC). However, little is known about the role of the rarer NRAS mutations as a mechanism of primary resistance to the anti-EGFR monoclonal antibody cetuximab in wild-type KRAS mCRC. Using isogenic mCRC cells with a heterozygous knock-in of the NRAS activating mutation Q61K, we aimed to elucidate the mechanism(s) by which mutant NRAS blocks cetuximab from inhibiting mCRC growth. NRASQ61K/+ cells were refractory to cetuximab-induced growth inhibition. Pathway-oriented proteome profiling revealed that cetuximab-unresponsive ERK1/2 phosphorylation was the sole biomarker distinguishing cetuximab-refractory NRASQ61K/+ from cetuximab-sensitive NRAS+/+ cells. We therefore employed four representative MEK1/2 inhibitors (binimetinib, trametinib, selumetinib, and pimasertib) to evaluate the therapeutic value of MEK/ERK signaling in cetuximab-refractory NRAS mutation-induced mCRC. Co-treatment with an ineffective dose of cetuximab augmented, up to more than 1,300-fold, the cytotoxic effects of pimasertib against NRASQ61K/+ cells. Simultaneous combination of MEK1/2 inhibitors with cetuximab resulted in extremely high and dose-dependent synthetic lethal effects, which were executed, at least in part, by exacerbated apoptotic cell death. Dynamic monitoring of real-time cell growth rates confirmed that cetuximab synergistically sensitized NRASQ61K/+ cellsto MEK1/2 inhibition. Our discovery of a synthetic lethal interaction of cetuximab in combination with MEK1/2 inhibition for the NRAS mutant subgroup of mCRC underscores the importance of therapeutic intervention both in the MEK-ERK and EGFR pathways to achieve maximal therapeutic efficacy against NRAS-mutant mCRC tumors

Estudio y planificación de contenidos, materiales y metodologías docentes según el EEES: Itinerario Ocio Digital (Cuarto Curso de Ingeniería Multimedia)

En esta memoria se describe el proyecto realizado para la planificación de contenidos, materiales y metodología docente, y el seguimiento de las asignaturas del itinerario de Creación y Entretenimiento digital del cuarto curso del Grado en Ingeniería Multimedia de la Escuela Politécnica Superior, como continuación del planteamiento realizado en el proyecto de la red de cuarto curso configurada en el año 2012-13 (identificador 2687). En el marco creado por los nuevos estudios dentro del EEES, el proyecto ha tenido como objetivo principal la preparación, coordinación y seguimiento de las asignaturas del citado itinerario, teniendo en cuenta la aplicación de la metodología de Aprendizaje Basado en Proyectos (ABP). A partir de la experiencia adquirida en la planificación de cursos previos, se han elaborado las guías docentes de las asignaturas ajustando las del curso anterior. También se presentan los resultados obtenidos en la primera experiencia llevada a cabo en este curso, expresados en horas de dedicación al proyecto y en grado de satisfacción tanto del alumnado como del profesorado con la metodología ABP. Por último, se ha creado una página web informativa del itinerario explicando todos los aspectos de la metodología, y se han elaborado dos artículos detallando toda la labor realizada

ABPgame+ o cómo hacer del último curso de ingeniería una primera experiencia profesional

Algunos de los aspectos clave en el desarrollo profesional de un ingeniero son su capacidad para trabajar en equipo, para integrar diferentes puntos de vista y para desarrollar grandes proyectos con un alto nivel de incertidumbre. Los planes de estudio de las titulaciones que preparan a estos futuros ingenieros no pueden permanecer ajenos a estas necesidades y deben plantear situaciones lo más cercanas posible a la realidad que se encontrarán nuestros egresados en su vida laboral. Estas razones, nos han llevado a plantear una experiencia innovadora en una titulación de nueva implantación como es el Grado en Ingeniería Multimedia. Hemos elegido, para ello, la metodología del Aprendizaje Basado en Proyectos (ABP), aplicada al itinerario de Creación y Entretenimiento Digital en cuarto curso, donde los estudiantes, agrupados en equipos, desarrollan un único gran proyecto durante el año, que es un videojuego. Queremos destacar dos consecuencias de esta experiencia: primero, el papel fundamental de la asignatura Proyectos Multimedia, sirviendo de apoyo al resto de asignaturas al llevar el peso de la gestión de los equipos y del seguimiento del proyecto. Y después, que los estudiantes pueden obtener un producto terminado al final del curso que les permita inaugurar su portafolio profesional

Coupling a water balance model with forest inventory data to predict drought stress : the role of forest structural changes vs. climate changes

Mechanistic water balance models can be used to predict soil moisture dynamics and drought stress in individual forest stands. Predicting current and future levels of plant drought stress is important not only at the local scale, but also at larger, landscape to regional, scales, because these are the management scales at which adaptation and mitigation strategies are implemented. To obtain reliable predictions of soil moisture and plant drought stress over large extents, water balance models need to be complemented with detailed information about the spatial variation of vegetation and soil attributes. We designed, calibrated and validated a water balance model that produces annual estimates of drought intensity and duration for all plant cohorts in a forest stand. Taking Catalonia (NE Spain) as a case study, we coupled this model with plot records from two Spanish forest inventories in which species identity, diameter and height of plant cohorts were available. Leaf area index of each plant cohort was estimated from basal area using species-specific relationships. Vertical root distribution for each species in each forest plot was estimated by determining the distribution that maximized transpiration in the model, given average climatic conditions, soil attributes and stand density. We determined recent trends (period 1980-2010) in drought stress for the main tree species in Catalonia; where forest growth and densification occurs in many areas as a result of rural abandonment and decrease of forest management. Regional increases in drought stress were detected for most tree species, although we found high variation in stress changes among individual forest plots. Moreover, predicted trends in tree drought stress were mainly due to changes in leaf area occurred between the two forest inventories rather than to climatic trends. We conclude that forest structure needs to be explicitly considered in assessments of plant drought stress patterns and trends over large geographic areas, and that forest inventories are useful sources of data provided that reasonably good estimates of soil attributes and root distribution are available. Our approach coupled with recent improvements in forest survey technologies may allow obtaining spatially continuous and precise assessments of drought stress. Further efforts are needed to calibrate drought-related demographic processes before water balance and drought stress estimates can be fully used for the accurate prediction of drought impacts

Aneurisma de aorta ascendente en pacientes con sustitución valvular aórtica previa

We conclude that an aggressive surgical approach should be adopted in patients with degenerative aortic regurgitation and moderate dilatation of the ascending aorta because of the rapid progression of the aortic disease. We advise complete replacement of the aortic root

Assessment of a Novel Automatic Real-Time PCR Assay on the Cobas 4800 Analyzer as a Screening Platform for Hepatitis C Virus Genotyping in Clinical Practice : Comparison with Massive Sequencing

The unequivocal identification of hepatitis C virus (HCV) subtypes 1a/1b and genotypes 2 to 6 is required for optimizing the effectiveness of interferon-free, direct-acting antiviral therapies. We compared the performance of a new real-time HCV genotyping assay used on the Cobas 4800 system (C4800) with that of high-resolution HCV subtyping (HRCS). In total, 502 samples were used, including 184 samples from chronic HCV patients (from routine laboratory activity during April 2016), 5 stored samples with double HCV genotype infections for testing the limitations of the method, and 313 samples from a screening protocol implemented in our hospital (from May to August 2016) based on the new method to further determine its genotyping accuracy. A total of 282 samples, including 171 from April 2016 (the 13 remaining had too low of a viral load for HRCS), 5 selected with double infections, and 106 from screening, were analyzed by both methods, and 220 were analyzed only by the C4800. The C4800 correctly subtyped 125 of 126 1a/1b samples, and the 1 remaining sample was reported as genotype 1. The C4800 correctly genotyped 38 of 45 non-1a/1b samples (classified by HRCS), and it reported the remaining 7 samples as indeterminate. One hundred two of 106 non-1a/1b genotype samples that were identified using the C4800 for screening were confirmed by HRCS. In the 4 remaining samples, 3 were correctly reported as genotype 1 (without defining the subtype) and 1 was reported as indeterminate. None of the samples were misgenotyped. Four of 7 samples with double HCV infections were correctly genotyped by the C4800. Excluding the 5 selected double-infected samples, the C4800 showed 95.7% concordant results for genotyping HCVs 2 to 6 and 1a/1b subtyping, and 99.2% concordance for subtyping 1a/1b single infections in clinical samples. To improve laboratory workflow, we propose using the C4800 as a first-line test for HCV genotyping and 1a/1b classification, followed by transferring non-1a/1b samples to a center where HRCS is available, if further characterization is needed

Somatostatin subtype-2 receptor-targeted metal-based anticancer complexes

Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl 2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η 6-bip)Os(4-CO 2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η 6-p-cym)RuCl(dap)] + (p-cym = p-cymene) (5), and [(η 6-p-cym)RuCl(imidazole-CO 2H)(PPh 3)] + (6), were synthesized by using a solid-phase approach. Conjugates 3-5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC 50 = 63 ± 2 μ in MCF-7 cells and IC 50 = 26 ± 3 μ in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC 50 = 45 ± 2.6 μ in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically. © 2012 American Chemical Society

Usos y desusos del modelo GPT-3 entre estudiantes de grados de ingeniería

La herramienta ChatGPT, basada en el modelo GPT-3 desarrollado por OpenAI, ya se utiliza por estudiantes de grados de ingeniería como herramienta de apoyo en su proceso de aprendizaje. En este contexto, las implicaciones negativas que presenta el uso de esta herramienta son diversas: dependencia tecnológica, obstaculización del saber y conocer práctico, error en las respuestas, problemas éticos o incluso problemas legales. El uso de esta herramienta sin que los estudiantes hayan recibido formación se considera como problema a investigar. El objetivo es entender en profundidad el contexto tecnológico de la herramienta, cómo se utiliza actualmente entre los estudiantes de ingeniería de un conjunto de universidades privadas y públicas, y su impacto en la educación universitaria. Este artículo es un trabajo en desarrollo donde se presenta el contexto del estudio, la metodología de investigación y unos primeros resultados. Se conduce una encuesta cualitativa-exploratoria con una muestra de más de 360 estudiantes de grados de ingeniería matriculados en diferentes cursos. Se utiliza una estratificación aleatoria para asegurar que la muestra sea representativa de la población. Los resultados sugieren que el modelo GPT-3 puede ser utilizado como una herramienta beneficiosa para los estudiantes de grados de ingeniería.ChatGPT, the tool based on the GPT-3 model developed by OpenAI, is already being used by engineering students for support in their learning process. In this context, the negative implications of using this tool are diverse: technological dependency, hindrance of practical knowledge and understanding, errors in answers, ethical or even legal problems. The use of this tool by students without receiving proper training is considered a problem to be investigated. The goal is to deeply understand the technological context of the tool, how it is currently used among engineering students from a set of private and public universities, and its impact on university education. This paper is a work in progress that presents the context of the study, the research methodology and some preliminary results. A qualitative-exploratory survey is conducted with a sample of more than 360 engineering students enrolled in different courses. Random stratification is used to ensure that the sample is representative of the population. The results suggest that the GPT-3 model can be used as a valuable tool for engineering students

Usos y desusos del modelo GPT-3 entre estudiantes de grados de ingeniería

La herramienta ChatGPT, basada en el modelo GPT-3 desarrollado por OpenAI, ya se utiliza por estudiantes de grados de ingeniería como herramienta de apoyo en su proceso de aprendizaje. En este contexto, las implicaciones negativas que presenta el uso de esta herramienta son diversas: dependencia tecnológica, obstaculización del saber y conocer práctico, error en las respuestas, problemas éticos o incluso problemas legales. El uso de esta herramienta sin que los estudiantes hayan recibido formación se considera como problema a investigar. El objetivo es entender en profundidad el contexto tecnológico de la herramienta, cómo se utiliza actualmente entre los estudiantes de ingeniería de un conjunto de universidades privadas y públicas, y su impacto en la educación universitaria. Este artículo es un trabajo en desarrollo donde se presenta el contexto del estudio, la metodología de investigación y unos primeros resultados. Se conduce una encuesta cualitativa-exploratoria con una muestra de más de 360 estudiantes de grados de ingeniería matriculados en diferentes cursos. Se utiliza una estratificación aleatoria para asegurar que la muestra sea representativa de la población. Los resultados sugieren que el modelo GPT-3 puede ser utilizado como una herramienta beneficiosa para los estudiantes de grados de ingeniería.ChatGPT, the tool based on the GPT-3 model developed by OpenAI, is already being used by engineering students for support in their learning process. In this context, the negative implications of using this tool are diverse: technological dependency, hindrance of practical knowledge and understanding, errors in answers, ethical or even legal problems. The use of this tool by students without receiving proper training is considered a problem to be investigated. The goal is to deeply understand the technological context of the tool, how it is currently used among engineering students from a set of private and public universities, and its impact on university education. This paper is a work in progress that presents the context of the study, the research methodology and some preliminary results. A qualitative-exploratory survey is conducted with a sample of more than 360 engineering students enrolled in different courses. Random stratification is used to ensure that the sample is representative of the population. The results suggest that the GPT-3 model can be used as a valuable tool for engineering students.Peer ReviewedPostprint (published version

Usos y desusos del modelo GPT-3 entre estudiantes de grados de ingeniería

[ES] La herramienta ChatGPT, basada en el modelo GPT-3 desarrollado por OpenAI, ya se utiliza por estudiantes de grados de ingeniería como herramienta de apoyo en su proceso de aprendizaje. En este contexto, las implicaciones negativas que presenta el uso de esta herramienta son diversas: dependencia tecnológica, obstaculización del saber y conocer práctico, error en las respuestas, problemas éticos o incluso problemas legales. El uso de esta herramienta sin que los estudiantes hayan recibido formación se considera como problema a investigar. El objetivo es entender en profundidad el contexto tecnológico de la herramienta, cómo se utiliza actualmente entre los estudiantes de ingeniería de un conjunto de universidades privadas y públicas, y su impacto en la educación universitaria. Este artículo es un trabajo en desarrollo donde se presenta el contexto del estudio, la metodología de investigación y unos primeros resultados. Se conduce una encuesta cualitativa-exploratoria con una muestra de más de 360 estudiantes de grados de ingeniería matriculados en diferentes cursos. Se utiliza una estratificación aleatoria para asegurar que la muestra sea representativa de la población. Los resultados sugieren que el modelo GPT-3 puede ser utilizado como una herramienta beneficiosa para los estudiantes de grados de ingeniería.[EN] ChatGPT, the tool based on the GPT-3 model developed by OpenAI, is already being used by engineering students for support in their learning process. In this context, the negative implications of using this tool are diverse: technological dependency, hindrance of practical knowledge and understanding, errors in answers, ethical or even legal problems. The use of this tool by students without receiving proper training is considered a problem to be investigated. The goal is to deeply understand the technological context of the tool, how it is currently used among engineering students from a set of private and public universities, and its impact on university education. This paper is a work in progress that presents the context of the study, the research methodology and some preliminary results. A qualitative-exploratory survey is conducted with a sample of more than 360 engineering students enrolled in different courses. Random stratification is used to ensure that the sample is representative of the population. The results suggest that the GPT-3 model can be used as a valuable tool for engineering students