Characterization of tumor reactive CD8 T cells induced by peptide vaccination in melanoma patients

ABSTRACT¦Naturally acquired tumor-specific T-cells can be detected in most advanced cancer patients.¦Yet, they often fail to control or eliminate the disease, in contrast to many virus-specific CD8¦T lymphocytes. Therapeutic vaccines aim at inducing and boosting specific T-cells mediated¦immunity to reduce tumor burden. The properties of CD8 T-cells required for protection from¦infectious disease and cancer are only partially characterized.¦The objectives of this study were to assess effector functions, stage of differentiation and¦clonotype selection of tumor-reactive T lymphocytes following peptide vaccination in¦melanoma patients over time. Results were compared to protective viral-specific T-cell¦responses found in healthy individuals. We also characterized dominant versus low/non¦dominant T-cell clonotypes with the aim to further understand the in vivo function of each set¦of frequency-based specific T-cells.¦Here we developed and applied a novel approach for molecular and functional analysis of¦single T lymphocytes ex vivo. T-cell receptor (TCR) clonotype mapping revealed rapid¦selection and expansion of co-dominant T-cell clonotypes, which made up the majority of the¦highly differentiated "effector" T-cells, but only 25% of the less differentiated "effectormemory"¦cells, mostly composed of non-dominant clonotypes. Moreover, we show that¦advanced effector cell differentiation was indeed clonotype-dependent. Surprisingly, however,¦the acquisition of effector functions (cytokine production, killing) was clonotype-independent.¦Vaccination of melanoma patients with native peptide induced competent effector function in¦both dominant and non-dominant clonotypes, suggesting that most if not all clonotypes¦participating in a T-cell response have the potential to develop equal functional competence.¦In contrast, many T-cells remained poorly functional after vaccination with analog peptide,¦despite similar clonotype-dependent differentiation. Our findings show that the type of¦peptide vaccine has a critical influence on the selection and functional activation of the¦clonotypic T-cell repertoire. They also show that systematic assessment of individual T-cells¦identifies the cellular basis of immune responses, contributing to the rational development of¦vaccines.

Propostes de prevenció de residus en esdeveniments a la ciutat de Sitges

El model actual de consum comporta el malbaratament de recursos, potenciant l’ús desmesurat de materials i productes no reutilitzables, convertint-los en residu. Aquesta generació creixent de residus comporta la necessitat de gestionar-los de manera eficient o impedir generar-los, per minimitzar els impactes ambientals i econòmics. En aquest projecte es pretén actuar en la prevenció de la generació de residus a Sitges, concretament en la promoció d’actuacions de prevenció de residus en esdeveniments. L’estudi analitza la situació actual del municipi en quant a prevenció de residus i, tenint en compte el tipus de residus generats en els esdeveniments, proposa mesures per reduir-los considerant el seu cost econòmic, comptabilitzant les despeses amb i sense l’aplicació de les mesures, i el benefici d’aquestes llarg termini.

THE ROLE OF SPINDLES FOR SLEEP: MANIPULATING OSCILLATORY ACTIVITY IN THE THALAMOCORTICAL NETWORK

Modern urban lifestyle encourages the prolongation of wakefulness, leaving less and less time for sleep. Although the exact functions of sleep remain one of the biggest mysteries in neuroscience, the society is well aware of the negative consequences of sleep loss on human physical and mental health and performance. Enhancing sleep's recuperative functions might allow shortening sleep duration while preserving the beneficial effects of sleep. During sleep, brain activity oscillates across a continuum of frequencies. Individual oscillations have been suggested to underlie distinct functions for sleep and cognition. Gaining control about individual oscillations might allow boosting their specific functions. Sleep spindles are 11 - 15 Hz oscillations characteristic for light non-rapid-eye-movement sleep (NREMS) and have been proposed to play a role in memory consolidation and sleep protection against environmental stimuli. The reticular thalamic nucleus (nRt) has been identified as the major pacemaker of spindles. Intrinsic oscillatory burst discharge in nRt neurons, arising from the interplay of low-threshold (T-type) Ca2+ channels (T channels) and small conductance type 2 (SK2) K+ channels (SK2 channels), underlies this pacemaking function. In the present work we investigated the impact of altered nRt bursting on spindle generation during sleep by studying mutant mice for SK2 channels and for CaV3.3 channels, a subtype of T channels. Using in vitro electrophysiology I showed that nRt bursting was abolished in CaV3.3 knock out (CaV3.3 KO) mice. In contrast, in SK2 channel over-expressing (SK2-OE) nRt cells, intrinsic repetitive bursting was prolonged. Compared to wildtype (WT) littermates, altered nRt burst discharge lead to weakened thalamic network oscillations in vitro in CaV3.3 KO mice, while oscillatory activity was prolonged in SK2-OE mice. Sleep electroencephalographic recordings in CaV3.3 KO and SK2-OE mice revealed that reduced or potentiated nRt bursting respectively weakened or prolonged sleep spindle activity at the NREMS - REMS transition. Furthermore, SK2-OE mice showed more consolidated NREMS and increased arousal thresholds, two correlates of good sleep quality. This thesis work suggests that CaV3.3 and SK2 channels may be targeted in order to modulate sleep spindle activity. Furthermore, it proposes a novel function for spindles in NREMS consolidation. Finally, it provides evidence that sleep quality may be improved by promoting spindle activity, thereby supporting the hypothesis that sleep quality can be enhanced by modulating oscillatory activity in the brain. Le style de vie moderne favorise la prolongation de l'éveil, laissant de moins en moins de temps pour le sommeil. Même si le rôle exact du sommeil reste un des plus grands mystères des neurosciences, la société est bien consciente des conséquences négatives que provoque un manque de sommeil, à la fois sur le plan de la santé physique et mentale ainsi qu'au niveau des performances cognitives. Augmenter les fonctions récupératrices du sommeil pourrait permettre de raccourcir la durée du sommeil tout en en conservant les effets bénéfiques. Durant le sommeil, on observe des oscillations à travers un continuum de fréquences. Il a été proposé que chaque oscillation pourrait être à l'origine de fonctions spécifiques pour le sommeil et la cognition. Pouvoir de contrôler les oscillations individuelles permettrait d'augmenter leurs fonctions respectives. Les fuseaux sont des oscillations de 11 à 15 Hz caractéristiques du sommeil à ondes lentes léger et il a été suggéré qu'elles jouent un rôle majeur pour la consolidation de la mémoire ainsi que dans la protection du sommeil contre les stimuli environnementaux. Le nucleus réticulaire du thalamus (nRt) a été identifié en tant que générateur de rythme des fuseaux. Les bouffées oscillatoires intrinsèques des neurones du nRt, provenant de l'interaction de canaux calciques à bas seuil de type T (canaux T) et de canaux potassiques à faible conductance de type 2 (canaux SK2), sont à l'origine de la fonction de générateur de rythme. Dans ce travail, j'ai étudié l'impact de la modulation de bouffées de nRT sur la génération des fuseaux pendant le sommeil en investiguant des souris génétiquement modifiées pour les canaux SK2 et les canaux CaV3.3, un sous-type de canaux T. En utilisant l'électrophysiologie in vitro j'ai démontré que les bouffées du nRT étaient abolies dans les souris knock-out du type CaV3.3 (CaV3.3 KO). D'autre part, dans les cellules nRT sur-exprimant les canaux SK2 (SK2-OE), les bouffées oscillatoires intrinsèques étaient prolongées. Par rapport aux souris wild type, les souris CaV3.3 KO ont montré un affaiblissement des oscillations thalamiques en réponse à un changement des bouffées de nRT, alors que l'activité oscillatoire était prolongée dans les souris SK2-OE. Des enregistrements EEG du sommeil dans des souris de type CaV3.3 KO et SK2-OE ont révélé qu'une réduction ou augmentation des bouffées nRT ont respectivement affaibli ou prolongé l'activité des fuseaux durant les transitions du sommeil à ondes lentes au sommeil paradoxal. De plus, les souris SK2-OE ont montré des signes de consolidation du sommeil à ondes lentes et un seuil augmenté pour le réveil, deux mesures qui corrèlent avec une bonne qualité du sommeil. Le travail de cette thèse propose que les canaux CaV3.3 et SK2 pourrait être ciblés pour moduler l'activité des fuseaux. De plus, je propose une fonction nouvelle pour les fuseaux dans la consolidation du sommeil à ondes lentes. Finalement je suggère que la qualité du sommeil peut être améliorée en promouvant l'activité des fuseaux, soutenant ainsi l'idée que la qualité du sommeil peut être améliorée en modulant l'activité oscillatoire dans le cerveau.

Institutions, Public Debt and Foreign Finance

We study the role of domestic financial institutions in sustaining capital flows to the private and public sector of a country whose government can default on its debt. As in recent public debt crises, in our model public defaults weaken banks' balance sheets, disrupting domestic financial markets. This effect leads to a novel complementarity between private capital inflows and public borrowing, where the former sustain the latter by boosting the government's cost of default. Our key message is that, by shaping the direction of private capital flows, financial institutions determine whether financial integration improves or reduces government discipline. We explore the implications of this complementarity for financial liberalization and debt-financed bailouts of banks. We present some evidence consistent with complementarity.

Downsizing, Job Insecurity, and Firm Reputation

This paper studies how firms make layoff decisions in the presence of adverse shocks. In this uncertain environment, workers' expectations about their job security affect their on-the-job performance. This productivity effect on job insecurity forces firms to strike a balance between laying off redundant workers and maintaining survivors' commitment when deciding on the amount and timing of downsizing. This framework offers an explanation of conservative employment practices (such as zero or reduced layoffs) based on firms having private information about their future profits. High retention rates and wages can signal that the firm has a bright future, boosting workers' confidence. Moreover, the model provides clear predictions about when waves of downsizing will occur as opposed to one-time massive cuts.

Turismo Cultural e Desenvolvimento Local: um Estudo Sobre o Concelho do Tarrafal, Cabo Verde

Este trabalho tem como o objetivo central analisar o potencial do turismo cultural no Tarrafal e compreender o seu papel na valorização do património e no desenvolvimento local. Procurou-se estudar a perceção dos agentes institucionais, a perceção dos residentes, o perfil dos turistas, a perceção dos alojamentos e dos restaurantes e as suas características. Com a globalização, as diversidades culturais emergem como elementos diferenciadores e dinamizadores do turismo. O turismo cultural tem despertado cada vez mais interesse no palco internacional, revelando-se como um grande veículo estratégico que promove o desenvolvimento local através da valorização do património, mantendo-o conservado, vivo e valorizado. O Concelho do Tarrafal localiza-se na parte norte da ilha de Santiago, a uma distância de 75 quilómetros da cidade da Praia (capital de Cabo Verde). Ocupa uma superfície de 112,4 Km2, representando assim cerca de 11% da área total da ilha de Santiago e 2,8% do território nacional. Possui cerca de 18.565 habitantes, cuja maioria é representada pela população feminina. Este concelho possui um conjunto de recursos culturais de grande interesse turístico que podem contribuir para a diversificação da oferta e transformar o concelho num destino turístico de qualidade, promovendo a melhoria das condições de vida da população como também a sustentabilidade do próprio setor. Este tipo de turismo promove além da apreciação dos objetos, infraestruturas e entre outras formas culturais, a interação entre os turistas e a própria comunidade, entre o setor publico e o privado e entre o turismo e a cultura.

The labor market effects of payroll taxes in a middle-income country: Evidence from Colombia

We use a panel of manufacturing plants from Colombia to analyze how the risein payroll tax rates over the 1980 s and 1990 s affected the labor market.Our estimates indicate that formal wages fall by between 1.4% and 2.3% as aresult of a 10% rise in payroll taxes. This 'less-than-full-shifting' islikely to be the result of weak linkages between benefits and taxes and thepresence of downward wage rigidities induced by a binding minimum wage inColombia. Because the costs of taxation are only partly shifted fromemployers to employees, employment should also fall. Our results indicatethat a 10% increase in payroll taxes lowered formal employment by between4% and 5%. In addition, we find less shifting and larger disemploymenteffects for production than non-production workers. These results suggestthat policies aimed at boosting the relative demand of low-skill workers byreducing social security taxes on those with low earnings may be effectivein a country like Colombia, especially if tax cuts are targeted to indirectbenefits.

Downsizing, job insecurity and firm reputation

This paper studies how firms make layoff decisions in the presence of adverse shocks. In this uncertain environment, workers' expectations about their job security affect their on-the-job performance. This productivity effect on job insecurity forces firms to strike a balance between laying off redundant workers and maintaining survivors' commitment when deciding on the amount and timing of downsizing. This framework offers an explanation of conservative employment practices (such as zero or reduced layoffs) based on firms having private information about their future profits. High retention rates and wages can signal that the firm has a bright future, boosting workers' confidence. Moreover, the model provides clear predictions about when waves of downsizing will occur as opposed to one-time massive cuts.

Service Quality Analysis in the Five Stars Resort Hotels of Cape Verde

The objective of this study was the identification of the attributes and dimensions of service quality affecting the service performance of the five stars resort hotels located in the Cape Verde Islands. The reason boosting the initiative to do this research was the paramount role of the resort hotels in the development of the travel and tourism sector in Cape Verde, and the impact that today this sector has had in the economy of that country. The research opens with a literature review on the service quality theory in the hotel industry, starting from the middle of the 1980s with the classic model of service quality and SERVQUAL instrument to the analysis of recent models of service quality measurement in the hotel industry, as it is an example the scale of items developed in 2003 in the Lodging Quality Index (LQI). Furthermore, the study elaborates an analysis on the importance of the travel and tourism activities in the Cape Verde Islands, and it evidences the enormous importance of those activities in the performance of the Cape Verdean hotel industry. In sequence the study analyzes in details the hotel industry of Cape Verde and it identifies the market size of the five stars resort hotels and their current operators in that market. Moreover, the research develops with an online questionnaire elaborated and sent through the platforms of travel websites and communities to the guests whom have experienced the service of the five stars resort hotels located in the Cape Verde Islands. The scope of the questionnaire was to assess the attributes and dimensions of service quality in the five stars resort hotels of Cape Verde. The results of the questionnaire were in sequence analyzed through descriptive and applied statistics, using Microsoft Excel and the Statistical Package for Social Science (SPSS). Content validity analysis, factor analysis, and reliability analysis of the factors were made to purify an initial scale of 47 items of service quality. An instrument with three dimensions covering twenty four attributes of service quality assessment in the five stars resort hotels of Cape Verde was finally created. The three dimensions found were: staff competence; food and entertainment; and physical facilities. This study on the service in the five stars resort hotels of Cape Verde ends with brief comments on the status of service quality according to the identified dimensions and their attributes. In the conclusion, the study summarizes the whole work and gives some directions for future research.

The Energy metabolism of China and India between 1971-2010: studying the bifurcation

This paper presents a comparison of the changes in the energetic metabolic pattern of China and India, the two most populated countries in the world, with two economies undergoing an important economic transition. The comparison of the changes in the energetic metabolic pattern has the scope to characterize and explain a bifurcation in their evolutionary path in the recent years, using the Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism (MuSIASEM) approach. The analysis shows an impressive transformation of China’s energy metabolism determined by the joining of the WTO in 2001. Since then, China became the largest factory of the world with a generalized capitalization of all sectors ―especially the industrial sector― boosting economic labor productivity as well as total energy consumption. India, on the contrary, lags behind when considering these factors. Looking at changes in the household sector (energy metabolism associated with final consumption) in the case of China, the energetic metabolic rate (EMR) soared in the last decade, also thanks to a reduced growth of population, whereas in India it remained stagnant for the last 40 years. This analysis indicates a big challenge for India for the next decade. In the light of the data analyzed both countries will continue to require strong injections of technical capital requiring a continuous increase in their total energy consumption. When considering the size of these economies it is easy to guess that this may induce a dramatic increase in the price of energy, an event that at the moment will penalize much more the chance of a quick economic development of India.

Imaging of the non-traumatic brachial plexus.

The first line imaging of the non-traumatic brachial plexus is by MRI. Knowledge of the anatomy and commonest variants is essential. Three Tesla imaging offers the possibility of 3D isotropic sequences with excellent spatial and contrast enhancement resolutions, which leads to time saving and quality boosting. The most commonly seen conditions are benign tumor lesions and radiation damage. Gadolinium is required to assess inflammatory or tumour plexopathy. MRI data should be correlated with FDG-PET if tumor recurrence is suspected.

One-sided jet at milliarcsecond scales in LSI+61·303

We present Very Long Baseline Interferometry (VLBI) observations of the high mass X-ray binary LSI+61303, carried out with the European VLBI Network (EVN). Over the 11 hour observing run, performed 10 days after a radio outburst, the radio source showed a constant flux density, which allowed sensitive imaging of the emission distribution. The structure in the map shows a clear extension to the southeast. Comparing our data with previous VLBI observations we interpret the extension as a collimated radio jet as found in several other X-ray binaries. Assuming that the structure is the result of an expansion that started at the onset of the outburst, we derive an apparent expansion velocity of 0.003 c, which, in the context of Doppler boosting, corresponds to an intrinsic velocity of at least 0.4 c for an ejection close to the line of sight. From the apparent velocity in all available epochs we are able to establish variations in the ejection angle which imply a precessing accretion disk. Finally we point out that LSI+61303, like SS433 and Cygnus X-1, shows evidence for an emission region almost orthogonal to the relativistic jet.

Monitoring tumor antigen specific T-cell responses in cancer patients and phase I clinical trials of peptide-based vaccination.

Numerous phase I and II clinical trials testing the safety and immunogenicity of various peptide vaccine formulations based on CTL-defined tumor antigens in cancer patients have been reported during the last 7 years. While specific T-cell responses can be detected in a variable fraction of immunized patients, an even smaller but significant fraction of these patients have objective tumor responses. Efficient therapeutic vaccination should aim at boosting naturally occurring antitumor T- and B-cell responses and at sustaining a large number of tumor antigen specific and fully functional effector T cells at tumor sites. Recent progress in our ability to quantitatively and qualitatively monitor tumor antigen specific CD8 T-cell responses will greatly help in making rapid progress in this field.

Therapeutic cancer vaccines based on molecularly defined human tumor antigens.

The results of numerous phases I and II clinical trials testing the safety and immunogenicity of various cancer vaccine formulations based on cytolytic T lymphocytes (CTLs)-defined tumor antigens have been reported recently. Specific T cell responses can be detected in only a fraction of immunized patients. A smaller but significant fraction of these patients have objective tumor responses. Efficient therapeutic vaccination should aim at boosting naturally occurring anti-tumor responses and at sustaining a large contingent of tumor antigen-specific and fully functional effector T cells at tumor sites.