Immunotherapies and Future Combination Strategies for Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage and has a dismal prognosis. Nearly 10 years after the approval of cetuximab, anti-PD1/PD-L1 checkpoint inhibitors are the first drugs that have shown any survival benefit for the treatment on platinum-refractory recurrent/metastatic (R/M) HNSCC. Furthermore, checkpoint inhibitors are better tolerated than chemotherapy. The state of the art in the treatment of R/M HNSCC is changing, thanks to improved results for checkpoint inhibitors. Results for these treatments are also awaited in curative settings and for locally advanced HNSCC. Unfortunately, the response rate of immunotherapy is low. Therefore, the identification of predictive biomarkers of response and resistance to anti-PD1/PD-L1 is a key point for better selecting patients that would benefit the most from immunotherapy. Furthermore, the combination of checkpoint inhibitors with various agents is being currently evaluated to improve the response rate, prolong response duration, and even increase the chances for a cure. In this review, we summarize the most important results regarding immune targeting agents for HNSCC, predictive biomarkers for resistance to immune therapies, and future perspectives

¿Asedio a la Justicia Fiscal en Europa? (Reflexiones ante la Jurisprudencia Comunitaria sobre las Cláusulas Antiabuso y la reacción del legislador español)

Tras la sentencia Lankhorst España ha suprimido la subcapitalización y la transparencia fiscal internacional en el ámbito de la Unión Europea. Alemania ha optado por extender la subcapitalización a los préstamos de residentes, pero sometiéndola a tales requisitos que resulta dudosa su eficacia. Si tenemos en cuenta que las libertades comunitarias se proyectan –en parte– sobre los Estados del Espacio Económico Europeo y los Estados Asociados podemos llegar a la conclusión de que la jurisprudencia comunitaria ha puesto sitio a la Justicia fiscal en Europa. El único instrumento que –prácticamente– resta a los Estados miembros es la cláusula general anti-fraude (nuestro antiguo fraude de ley y futuro «conflicto» en la aplicación de las normas), pero tales mecanismos son complejos de aplicar, lo que les resta eficacia si no se completan con cláusulas específicas. Ante esta situación cabría proponer el establecimiento de cláusulas específicas aplicables de modo general a residentes y no residentes basadas en presunciones iuris tantum en el caso de que afecten a no residentes siempre que otra solución resultara impracticable y más perniciosa para las libertades comunitarias. Por otro lado, sería conveniente un giro en la jurisprudencia comunitaria, pues la defensa a ultranza de las libertades comunitarias, al privilegiar a los grandes operadores económicos, está dificultando el pleno ejercicio de dichas libertades por las pequeñas empresas. En este sentido, podría afirmarse que una mínima garantía de la tributación con arreglo a la capacidad económica constituye un presupuesto lógico para un adecuado ejercicio de las libertades comunitarias. También sería preciso reformular el principio de coherencia en la jurisprudencia comunitaria, de modo que se aplique al grupo de sociedades y al conjunto de la situación fiscal teniendo en cuenta también los efectos de los Convenios de Doble Imposición. De este modo el Tribunal se convertiría en un auténtico adalid de las libertades comunitarias sin riesgos de favorecer tan sólo a los grandes grupos económicos

Social participation and quality of health care: the experience of citizens' health representatives in Mexico

OBJETIVO: Analizar la experiencia del aval ciudadano en el sistema de salud mexicano en la mejora de los servicios de salud. METODOS: Estudio de corte cualitativo en ocho estados de México en 2008. Se evaluaron diferentes aspectos del programa nacional para mejorar la calidad de los servicios de salud. Se compara la estrategia de México con otras experiencias en América Latina. RESULTADOS: Se exponen los avances y problemas del funcionamiento del aval ciudadano, figura que promueve la participación social en salud de la población. CONCLUSIONES: El aval ciudadano es una figura con gran potencial para representar a los usuarios en los servicios de salud y transmitir sus demandas de mejora de la calidad de la atención médica.OBJETIVO: Analisar a experiência do aval ciudadano (reforço cidadão) no sistema de saúde mexicano na melhora dos serviços de saúde. MÉTODOS: Estudo de coorte qualitativo em oito estados mexicanos, em 2008. Foram avaliados diferentes aspectos do programa nacional para melhora de qualidade nos serviços de saúde. Compara-se a estratégia no México com outras experiências na América Latina. RESULTADOS: Foram expostos os avanços e problemas de funcionamento do aval ciudadano (reforço cidadão), figura que promove a participação social na saúde da população. CONCLUSÕES: O aval ciudadano (reforço cidadão) é uma figura com grande potencial para representar os usuários dos serviços de saúde e transmitir suas exigências de melhorias na qualidade da atenção médica.OBJECTIVE: This article describes the experience of the aval ciudadano "Citizens' Representative" (CR) in improving the Mexican health care system. METHODS: This is a qualitative study which took place in eight Mexican states in 2008. It evaluates different aspects of a nationwide program to increase the quality of health care services (National Crusade for Quality in Health Services). The Mexican strategy is compared with experiences in other Latin American countries. RESULTS: In this paper, there is the description of achievements and problems encountered by the CR in promoting social participation in the health of the population. CONCLUSIONS: The CR has great influence when representing health service users and passing on their demands for improvements to health care quality

Design and consensus content validity of the questionnaire for b-learning education: A 2-Tuple Fuzzy Linguistic Delphi based Decision Support Tool

This is an open access article under the CC BY-NC-ND licenseEste trabajo presenta un modelo lingüístico de toma de decisión que aporta además una solución software para poder aplicar la validación de constructo mediante juicio de expertos totalmente online y con asistencia al cálculo del consenso y a la toma de decisión en cuanto a los cambios que se debe tomar para mejorar de forma iterativa un instrumento de toma de datos. La idea clave es validar el cuestionario definiendo la validez de cada ítem como un problema de Toma de Decisiones. Tomando la opinión de expertos, medimos el grado de consenso, el grado de consistencia y la puntuación lingüística de cada ítem, con el fin de detectar aquellos ítems que afectan, positiva o negativamente, a la calidad del instrumento. El trabajo aborda un caso real de validación de instrumentos. Para ello se ocupa de la necesidad en contextos educativos de evaluar una experiencia de blended learning con un cuestionario consensuado que abarca dimensiones relativas a Flipped Classroom y Mobile Learning. Además, contribuimos a este problema de consenso desarrollando una herramienta online bajo licencia GPL v3. El software visualiza las valoraciones colectivas para cada iteración y ayuda a determinar qué partes del cuestionario deben modificarse para alcanzar una solución consensuada.This work presents a linguistic decision-making model that also provides a software solution for applying construct validation by means of fully online expert judgment and with assistance in calculating consensus and making decisions regarding the changes to be made to iteratively improve a data collection instrument. The key idea is to validate the questionnaire by defining the validity of each item as a Decision Making problem. Taking expert opinion, we measure the degree of consensus, the degree of consistency and the linguistic score of each item, in order to detect those items that affect, positively or negatively, the quality of the instrument. The model deals with a real case of instrument validation. It deals with the need in educational contexts to evaluate a blended learning experience with a consensual questionnaire that covers dimensions related to Flipped Classroom and Mobile Learning. In addition, we contribute to this consensus problem by developing an online tool under GPL v3 license. The software visualizes the collective ratings for each iteration and helps to determine which parts of the questionnaire should be modified to reach a consensus solution.Instituto Interuniversitario de Investigación en Data Science and Computational Intelligence (DaSCI

Stereoselective Synthesis of Iminosugar 2-Deoxy(thio)glycosides from Bicyclic Iminoglycal Carbamates Promoted by Cerium(IV) Ammonium Nitrate and Cooperative Brønsted Acid-Type Organocatalysis

The first examples of iminosugar-type 2-deoxy(thio)glycoside mimetics are reported. The key step is the activation of a bicyclic iminoglycal carbamate to generate a highly reactive acyliminium cation. Cerium(IV) ammonium nitrate efficiently promoted the formation of 2-deoxy S-glycosides in the presence of thiols, probably by in situ generation of catalytic HNO3, with complete α-stereoselectivity. Cooperative phosphoric acid/Schreiner's thiourea organocatalysis proved better suited for generating 2-deoxy O-glycosides, significantly broadening the scope of the approach.Ministerio de Economía y Competitividad SAF201676083-RMinisterio de Ciencia, Innovación y Universidades RTI2018-097609-B-C21European Cooperation in Science and Technology CA18132Consejo Europeo de Investigación ERC-COG: 64823

SESAR Joint Undertaking report 2010

Abstract Salmonellosis is a gastrointestinal disease caused by non-typhoidal Salmonella serovars such as Salmonella Typhimurium. This pathology is a zoonosis, and food animals with subclinical infection constitute a vast reservoir for disease. After intestinal colonization, Salmonella Typhimurium reaches mesenteric lymph nodes (MLN), where infection is controlled avoiding systemic spread. Although the molecular basis of this infection has been extensively studied, little is known about how microRNA (miRNA) regulate the expression of proteins involved in the Salmonella-host interaction. Using small RNA-seq, we examined expression profiles of MLN 2 days after infection with Salmonella Typhimurium, and we found 110 dysregulated miRNA. Among them, we found upregulated miR-21, miR-155, miR-150, and miR-221, as well as downregulated miR-143 and miR-125, all of them previously linked to other bacterial infections. Integration with proteomic data revealed 30 miRNA potentially regulating the expression of 15 proteins involved in biological functions such as cell death and survival, inflammatory response and antigenic presentation. The inflammatory response was found increased via upregulation of miRNA such as miR-21 and miR-155. Downregulation of miR-125a/b, miR-148 and miR-1 were identified as potential regulators of MHC-class I components PSMB8, HSP90B1 and PDIA3, respectively. Furthermore, we confirmed that miR-125a is a direct target of immunoproteasome component PSMB8. Since we also found miR-130 downregulation, which is associated with upregulation of HSPA8, we suggest induction of both MHC-I and MHC-II antigen presentation pathways. In conclusion, our study identifies miRNA that could regulate critical networks for antigenic presentation, inflammatory response and cytoskeletal rearrangements

Temperature-related excess mortality in German cities at 2 °C and higher degrees of global warming

Background: Investigating future changes in temperature-related mortality as a function of global mean temperature (GMT) rise allows for the evaluation of policy-relevant climate change targets. So far, only few studies have taken this approach, and, in particular, no such assessments exist for Germany, the most populated country of Europe. Methods: We assess temperature-related mortality in 12 major German cities based on daily time-series of all-cause mortality and daily mean temperatures in the period 1993–2015, using distributed-lag non-linear models in a two-stage design. Resulting risk functions are applied to estimate excess mortality in terms of GMT rise relative to pre-industrial levels, assuming no change in demographics or population vulnerability. Results: In the observational period, cold contributes stronger to temperature-related mortality than heat, with overall attributable fractions of 5.49% (95%CI: 3.82–7.19) and 0.81% (95%CI: 0.72–0.89), respectively. Future projections indicate that this pattern could be reversed under progressing global warming, with heat-related mortality starting to exceed cold-related mortality at 3 °C or higher GMT rise. Across cities, projected net increases in total temperature-related mortality were 0.45% (95%CI: −0.02–1.06) at 3 °C, 1.53% (95%CI: 0.96–2.06) at 4 °C, and 2.88% (95%CI: 1.60–4.10) at 5 °C, compared to today's warming level of 1 °C. By contrast, no significant difference was found between projected total temperature-related mortality at 2 °C versus 1 °C of GMT rise. Conclusions: Our results can inform current adaptation policies aimed at buffering the health risks from increased heat exposure under climate change. They also allow for the evaluation of global mitigation efforts in terms of local health benefits in some of Germany's most populated cities. © 2020 The Author