Oncogenic context shapes the fitness landscape of tumor suppression

We are grateful to all members of D2G Oncology for expert advice and helpful comments. We thank Explora and The Jackson Laboratory for expert animal care. We would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing (interpretations are the responsibility of the study authors). We thank AstraZeneca, Bristol-Myers Squibb, Revolution Medicines, Merck KGaA, and CureTeq for generously allowing the inclusion of data generated in collaboration with D2G Oncology. L.E.D. is the Burt Gwirtzman Research Scholar in Lung Cancer. D.A.P. and M.M.W. are supported by NIH R01-CA 234349. This work was supported in part by NIH SBIR R44-CA250672.Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged—the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context—and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.American Association for Cancer ResearchACR Project GENIEAstraZenecaBristol-Myers Squibb R01-CA 234349, SBIR R44-CA250672Merck KGa

Asma y proteínas supresoras de la señalización de citocinas (SOCS): evaluación del papel de SOCS3 en la regulación del asma y su aplicación como nueva diana terapéutica para el control del asma

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, Departamento de Bioquímica y Biología Molecular, leída el 17-06-2014Sección Deptal. de Bioquímica y Biología Molecular (Biológicas)Fac. de Ciencias BiológicasTRUEunpu

La paz empieza en casa y continúa en... el IES Aurantia

Mención honorífica de la convocatoria de premios 'Irene: la paz comienza en casa 2009'. Contiene los siguientes anexos: Fotos de la exposición de 'Mujeres e igualdad en la provincia de Almería' prestada por la Diputación de Almería; discurso y fotografías del Sr. Alcalde de Benahadux en la inauguración de la Plaza dedicada a la mujer y la Calle Clara Campoamor; 'El inicio de la lucha por los derechos de la mujer: La Revolución Francesa de 1789'; Coeducar en E. F. 'Eliminando los "estereotipos', Aprendiendo a convivir 'en estéreo'; Tabla de actividades; '¿Estereotipos?' (Resumen del cuestionario); 'La mujer trabajadora'; 'Equiparación de los sexos en EPV'; Memorias del PAM y Espacio de Paz; 'Las mujeres y la salud en el trabajo'; 'Porqué los hombres??' ( Unidad didáctica en Francés); 'El día de la madre' ( Unidad didáctica en Inglés); 'El desarrollo del movimiento feminista: el triunfo del sufragismo 1870-1939'; 'Lectrón' (Un juego educativo). Resumen basado en el de la publicaciónSe plantan estrategias y se analizan multitud de experiencias que han permitido enfoques educativos y métodos de enseñanza orientados al aprendizaje de la convivencia y la participación en una sociedad democrática, con el fin de prevenir actitudes de imposición, violentas, racistas e intolerables y promover el rechazo del pensamiento extremista. Todo ello con la herramienta fundamental de las TIC. Se diseñan y coordinan actuaciones que favorecen, fundamentalmente, el conocimiento de las diferencias entre alumnas y alumnos, entre hombres y mujeres, para establecer las condiciones escolares que permiten establecer relaciones de igualdad, corregir las discriminaciones y estereotipos sexistas y la formación del alumnado en la autonomía personal como base para fomentar el cambio en las relaciones entre sexos.AndalucíaBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 planta; 28014 Madrid; Tel. +34917748000; Fax +34917748026; [email protected]

Treatment efficacy of anti-hypertensive drugs in monotherapy or combination: ATOM systematic review and meta-analysis of randomized clinical trials according to PRISMA statement

The relative efficacy of antihypertensive drugs/combinations is not well known. Identifying the most effective ones and the patients' characteristics associated with best performance of the drugs will improve management of hypertensive patients. Objective: To assess the blood pressure (BP) reduction attributed to antihypertensive drugs and identify characteristics associated with BP decrease. Data sources: MEDLINE, Cochrane Central Register of Controlled Trials from inception through July 2012 and selected papers. Study eligibility criteria: Double-blind, randomized clinical trials whose main result was the reduction in BP by antihypertensive treatment, with study population ≥50 or ≥25 if the study was a crossover, follow-up of at least 8 weeks, and available required data. Study appraisal and synthesis methods: Study data were independently extracted by multiple observers and introduced in an electronic database. Inconsistencies were resolved by discussion and referral back to the original articles. Meta-analysis was performed according to PRISMA statement and using a Bayesian framework. Main Outcome(s) and Measure(s): Mean decrease in systolic (SBP) and diastolic blood pressure (DBP) achieved by each drug or combination. Results: Two hundred eight trials including 94,305 patients were identified. In monotherapy, most drugs achieved 10 to 15 mm Hg SBP and 8 to 10 mm Hg DBP decreases. Olmesartan/amlodipine, olmesartan/hydrochlorothiazide, felodipine/metoprolol, and valsartan/hydrochlorothiazide were the combinations leading to the greatest mean SBP reductions (>20 mm Hg). Female sex and body mass index >25 kg/m 2 were associated with more pronounced SBP and DBP reductions, whereas Afro-American ethnicity was associated with BP reductions smaller than the median. Results were adjusted by study duration, cardiovascular disease, and diabetes mellitus. Still, the estimation was performed using the mean administered doses, which do not exactly match those of the available drug formats. Limitations: Data corresponded to those obtained in each of the included trials; the analysis of the combinations was limited to the most recent ones; estimations were performed using the mean administered doses. Conclusions and implications: Certain drug combinations achieve BP reductions ranging from 20 to 25/10 to 15 mm Hg. Sex, ethnicity, and obesity are associated with antihypertensive response. This information can contribute to better selection of the antihypertensive drug, depending on the magnitude of pretreatment BP elevation. Guidelines should be revise