Generation and characterization of a K-Ras model of Noonan syndrome

Tesis doctoral inédita, leída en Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 02/06/201

EGF Receptor Signaling Is Essential for K-Ras Oncogene-Driven Pancreatic Ductal Adenocarcinoma

SummaryClinical evidence indicates that mutation/activation of EGF receptors (EGFRs) is mutually exclusive with the presence of K-RAS oncogenes in lung and colon tumors. We have validated these observations using genetically engineered mouse models. However, development of pancreatic ductal adenocarcinomas driven by K-Ras oncogenes are totally dependent on EGFR signaling. Similar results were obtained using human pancreatic tumor cell lines. EGFRs were also essential even in the context of pancreatic injury and absence of p16Ink4a/p19Arf. Only loss of p53 made pancreatic tumors independent of EGFR signaling. Additional inhibition of PI3K and STAT3 effectively prevented proliferation of explants derived from these p53-defective pancreatic tumors. These findings may provide the bases for more rational approaches to treat pancreatic tumors in the clinic

Ensino superior e economia solidária para uma abordagem territorial

La crisis evidente en las dimensiones sociales, económicas y ambientales ha convocado a la definición de estrategias desde las universidades, los gobiernos y las organizaciones de la sociedad civil, entre ellas, las de la economía social y solidaria, para crear condiciones que propicien una mejora en la calidad de vida y el desarrollo sostenible. El artículo presenta el avance en el desarrollo de la propuesta de educación en y para la economía solidaria en la Universidad Cooperativa de Colombia, la cual tiene un enfoque por competencias orientado a la activación de ciudadanía, el conocer y hacer visible a la economía solidaria y promover el emprendimiento y la innovación social con impactos en la comunidad interna y externa. El acompañamiento y monitoreo de este proceso, orientado por la metodología de investigación acción revela buenas prácticas, oportunidades de mejoramiento y grandes retos, especialmente en lo que se refiere a los territorios donde la universidad tiene su campo de acción. Seguir avanzando en el fortalecimiento de esta estrategia, cobra especial relevancia por la reciente firma del acuerdo de paz entre la guerrilla de las FARC-EP y el gobierno nacional de Colombia, que invita a un mayor compromiso ciudadano e institucional con la construcción de territorios solidarios para la paz.The evident crisis in the social, economic and environmental dimensions has called for the definition of strategies from universities, governments and civil society organizations, including those of the social and solidarity economy, in order to create conditions conducive to improve the quality of life and sustainable development. This article presents the progress (achieved) in the development of an education proposal in and for solidarity economy in Universidad Cooperativa de Colombia, which has a competency-based approach aimed at activating citizenship, knowing and making visible the solidarity economy, and promoting entrepreneurship and social innovation with impacts on the internal and external community. The accompaniment and monitoring of this process, guided by the action research methodology, reveals good practices, opportunities for improvement and great challenges, especially in regard to the territories where the university has its field of action. Further progress in strengthening this strategy is particularly relevant due to the recent signing of the peace agreement between the FARC-EP guerrilla and the national government of Colombia, which invites greater citizen and institutional commitment to the construction of solidarity territories for peace.A evidente crise nas dimensões social, económica e ambiental tem exigido a definição de estratégias desde as universidades, os governos e as organizações da sociedade civil, inclusive as da economia social e solidaria, para criar condições propícias à melhoria da qualidade de vida e o desenvolvimento sustentável. O artigo apresenta os avanços no desenvolvimento da proposta de educação, em e para a economia solidaria na Universidade Cooperativa da Colômbia, que tem uma abordagem baseada em competências, orientada na ativação da cidadania, o conhecimento, a visibilização da economia solidaria e a promoção do empreendedorismo e a inovação com impactos na comunidade interna e externa. O acompanhamento e monitoramento desse processo, orientado pela metodologia da pesquisa-ação, revela boas práticas, oportunidades de melhoria e grandes desafios, especialmente no que se refere aos territórios onde a universidade tem seu campo de atuação. Avançar no fortalecimento desta estratégia, resulta particularmente importante por causa da recente assinatura do acordo de paz entre a guerrilha das FARC-EP e o governo nacional da Colômbia, que convida a um maior compromisso cidadão e institucional com a construção de territórios solidários para a paz

Molecular alterations in sporadic and sod1-als immortalized lymphocytes: Towards a personalized therapy

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily trans-mitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mito-chondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.This research was funded by Comunidad de Madrid (grant ELA_Madrid B2017/BMD-3813 and S2017/BMD-3688), European Commission MSCA-ITN-ETN (grant DRIVE GA: 765912), ISCiii (CIBERNED CB18/05/000 and CB06/05/0089), Fundela (2019/00325/001) for I.L.-B. and AEI (grant PID2019-105600RB-I00) for, A.M. and I.L.-B

Overview of the History of the Cranial Nerves: From Galen to the 21st Century

Throughout history the description and classification of the cranial nerves has been linked to the development and characteristics of anatomy and the role that it played as a tool in providing rationality to medicine, together with social, cultural, religious, and philosophical factors. Anatomists were interested in the cranial nerves, but they disagreed on their number and their paths. We can divide the history of the cranial nerves into three different periods: the first, early or macroscopic period; the second or microscopic period; and the third period or ontogenesis and genoarchitecture. The main aim of this article is to show how the description and knowledge of the cranial nerves were developed in the course of these three periods, and to highlight the main changes produced and the factors related to these changes. We describe how the first period was mainly focused on establishing the definition, number and paths of the cranial nerves, through contributions ranging from Galen’s studies in the second century to Sömmerring’s Doctoral Dissertation in 1778 that described 12 cranial nerves for the first time. Then, the microscopic period was concentrated on the identification of the real nuclei of origin of the different cranial nerves located in the brain stem. Finally came the third period, or ontogenesis and genoarchitecture of the rhombecephalic and mesencephalic cranial nerve nuclei

Modernización del Sistema Aduanero y su vinculación con la sociedad civil

Informe de investigación--Universidad de Costa Rica, Vicerrectoría de Acción Social, Trabajo Comunal Universitario. 2012. Para mayor información puede escribir a [email protected] documento es una guía a los agroexportadores para que conozcan información general sobre los formularios exigidos en el tema de exportación, tales como modernización del sistema aduanero costarricense, notificaciones previas, el compendio de leyes en materia aduanera, la inscripción como importador, entre otras. La información del presente documento se complementa con las presentaciones adjuntas en este fichero.Universidad de Costa RicaUCR::Vicerrectoría de Acción Social::Trabajo Comunal Universitario (TCU

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio

Labour and social security law in Spain in 2015

El informe ha sido elaborado por la Sección Juvenil de la Asociación Española de Derecho del Trabajo y Seguridad SocialEste Informe deja constancia de los cambios normativos más relevantes y de las tendencias judiciales más paradigmáticas del ordenamiento laboral en 2015. En él se observa el imparable dinamismo del Derecho del Trabajo y de la Seguridad Social en España. El documento, consciente de tal mutabilidad, recoge una minuciosa selección de cuestiones esenciales, a juicio de las personas que abordan cada una de las materias, de las que son especialistas; los autores y las autoras, que forman parte de la Sección Juvenil de la Asociación Española de Derecho del Trabajo y de la Seguridad Social, se adscriben a los grupos temáticos por afinidad con sus principales líneas de investigación y su labor docente universitaria. En síntesis, en el Informe “El Derecho del Trabajo y de la Seguridad Social en España en 2015” se puede encontrar información muy útil para los profesionales del iuslaboralismo en materia de derechos fundamentales inespecíficos, contratación laboral y empleo, vicisitudes del contrato de trabajo, derechos colectivos, igualdad y corresponsabilidad, Seguridad Social o prevención de riesgos laborales.This report has as aim leaving a record of the most relevant normative changes and the most paradigmatic judicial trends in Labour Law in 2015. One can easily observe the unstoppable dynamismof Labour and Social Security Law in Spain. The document, conscious of that mutability, collects a thorough selection of key issues, according to the judgement of the authors, all of them specialists and all of them members of the Young Scholars’ Section of the Spanish Association for Labour and Social Security Law. They are part of thematic groups, linked to their main research lines and their teaching task. Summing up, in this report “Labour and Social Security Law in Spain in 2015”, one can easily find useful information for labour lawyers in subjects such as unspecific fundamental rights, work contracts and employment, issues of the labour relationship, collective rights, equality and co-responsibility, Social Security or occupational risk prevention

El Derecho del Trabajo y de la Seguridad Social en España en 2015. Sección Juvenil de la Asociación Española de Derecho del Trabajo y de la Seguridad Social.

Este Informe deja constancia de los cambios normativos más relevantes y de las tendencias judiciales más paradigmáticas del ordenamiento laboral en 2015. En él se observa el imparable dinamismo del Derecho del Trabajo y de la Seguridad Social en España. El documento, consciente de tal mutabilidad, recoge una minuciosa selección de cuestiones esenciales, a juicio de las personas que abordan cada una de las materias, de las que son especialistas; los autores y las autoras, que forman parte de la Sección Juvenil de la Asociación Española de Derecho del Trabajo y de la Seguridad Social, se adscriben a los grupos temáticos por afinidad con sus principales líneas de investigación y su labor docente universitaria. En síntesis, en el Informe “El Derecho del Trabajo y de la Seguridad Social en España en 2015” se puede encontrar información muy útil para los profesionales del iuslaboralismo en materia de derechos fundamentales inespecíficos, contratación laboral y empleo, vicisitudes del contrato de trabajo, derechos colectivos, igualdad y corresponsabilidad, Seguridad Social o prevención de riesgos laborales. This report has as aim leaving a record of the most relevant normative changes and the most paradigmatic judicial trends in Labour Law in 2015. One can easily observe the unstoppable dynamismof Labour and Social Security Law in Spain. The document, conscious of that mutability, collects a thorough selection of key issues, according to the judgement of the authors, all of them specialists and all of them members of the Young Scholars’ Section of the Spanish Association for Labour and Social Security Law. They are part of thematic groups, linked to their main research lines and their teaching task. Summing up, in this report “Labour and Social Security Law in Spain in 2015”, one can easily find useful information for labour lawyers in subjects such as unspecific fundamental rights, work contracts and employment, issues of the labour relationship, collective rights, equality and co-responsibility, Social Security or occupational risk prevention

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030