Estudi d’alteracions genètiques predictores de resposta al tractament amb cetuximab en càncer colorectal

Projecte de recerca elaborat a partir d’una estada al Cancer Center, Massachusetts General Hospital- Harvard School of Medicine, Boston, Estats Units entre gener i juny 2007. El desenvolupament de nous fàrmacs dirigits a dianes moleculars específiques ha suposat un gran avanç en el tractament del càncer. El millor coneixement dels mecanismes que determinen la sensibilitat a aquests tractaments biològics és crucial per poder oferir tractaments selectius, optimitzar l'índex terapèutic i controlar l'elevat cost d'aquests fàrmacs. Tal com ha demostrat el grup liderat pel Dr. Settleman i altres, la sensibilitat del tumor a nous fàrmacs dirigits a diana molecular ve determinada en part per alteracions genètiques de les cèl.lules tumorals. El paradigma és la resposta clínica a fàrmacs inhibidors tirosin-cinasa d’ EGFR dels pacients amb càncer de pulmó amb mutacions d'EGFR. Donada la importància de trobar marcadors predictors de sensibilitat a les noves teràpies biològiques, la detecció a gran escala d' alteraciones genètiques i las seva correlació amb la sensibilitat al tractament amb aquests fàrmacs en models preclínics és un primer pas essencial per a un posterior desenvolupament a nivell clínic. En aquest estudi vam establir una plataforma de cribatge d’alta densitat (high throughput screening) de línies cel.lulars que ens permet detectar alteracions genètiques predictores de resposta a fàrmacs dirigits a diana molecular específica. Presentem el desenvolupament d'aquesta plataforma i el resultat de dues aplicacions específiques(... )

Experimental and computational study on the synthesis and characterization of self-assembling meso/macroporous materials in highly concentrated emulsions

Report for the scientific sojourn carried out at Massachusetts General Hospital Cancer Center-Harvard Medical School, Estats Units, from 2010 to 2011. The project aims to study the aggregation behavior of amphiphilic molecules in the continuous phase of highly concentrated emulsions, which can be used as templates for the synthesis of meso/macroporous materials. At this stage of the project, we have investigated the self-assembly of diblock and triblock surfactants under the effect of a confined geometry being surrounded by the droplets of the dispersed phase. These droplets limit the growth of the aggregates, deeply modify their orientation and hence alter their spatial arrangement as compared to the self-assembly taking place far enough from any boundary surface, that is in the bulk. By performing Monte Carlo simulations, we have showed that the interface between the dispersed and continuous phases as well as its shape has a significant impact on the structural order of the resulting aggregates and hence on the potential applications of highly concentrated emulsions as reaction media, drug delivery systems, or templates for meso/macroporous materials. Due to the combined effect of symmetry breaking and morphological frustration, very intriguing structures, such as square columnar liquid crystals, twisted X-shaped aggregates, and helical phases of cylindrical aggregates, never observed in the bulk for the same model surfactant, have been found. The presence of other more conventional structures, such as micelles and cubic and hexagonal liquid crystals, formed at low and high amphiphilic concentrations, respectively, further enhance the interest on this already rich aggregation behavior.

The histone deactylase SIRT6 is a novel tumor suppressor that regulates cancer metabolism.

Report for the scientific sojourn carried out at the University of Aarhus, Denmark, from 2010 to 2012. Reprogramming of cellular metabolism is a key process during tumorigenesis. This metabolic adaptation is required in order to sustain the energetic and anabolic demands of highly proliferative cancer cells. Despite known for decades (Warburg effect), the precise molecular mechanisms regulating this switch remained unexplored. We have identify SIRT6 as a novel tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of this sirtuin in non-transformed cells leads to tumor formation without activation of known oncogenes, indicating that SIRT6 functions as a first-hit tumor suppressor. Furthermore, transformed SIRT6-deficient cells display increased glycolysis and tumor growth in vivo, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. We provide data demonstrating that the glycolytic switch towards aerobic glycolysis is the main driving force for tumorigenesis in SIRT6-deficient cells, since inhibition of glycolysis in these cells abrogates their tumorigenic potential. By using a conditional SIRT6-targeted allele, we show that deletion of SIRT6 in vivo increases the number, size and aggressiveness of tumors, thereby confirming a role of SIRT6 as a tumor suppressor in vivo. In addition, we describe a new role for SIRT6 as a regulator of ribosome biogenesis by co-repressing MYC transcriptional activity. Therefore, by repressing glycolysis and ribosomal gene expression, SIRT6 inhibits tumor establishment and progression. Further validating these data, SIRT6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict both prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our results provide a potential Achilles’ hill to tackle cancer metabolism.

Inter-American Court, Crimes Against Humanity and Peacebuilding in South America

The present work contains a general overview of the sentences of the Inter-American Court of Human Rights (IACtHR), which have recognised that crimes against humanity are pre-existing in customary law, and do not prescribe, nor can they be subject to amnesty or pardon. Specific attention is paid to the consequent restrictions and opportunities offered by said verdicts to countries such as Argentina, Chile, Uruguay and Peru, which find themselves in postconflict transition processes and where peace has been negotiated with certain groups and state structures that are responsible for carrying out crimes against humanity. In doing so, special attention is paid to the impact of the recognition of the nature of crimes against humanity on the notion of the principle of legality, stricto sensu; on the development and evolution of the doctrine and the practice of international human rights law in the inter-American context; and finally on the aforementioned processes of transitional justice.

The private and fiscal returns to schooling and the effect of public policies on private incentives to invest in education: a general framework and some results for the EU

This paper develops a comprehensive framework for the quantitative analysis of the private and fiscal returns to schooling and of the effect of public policies on private incentives to invest in education. This framework is applied to 14 member states of the European Union. For each of these countries, we construct estimates of the private return to an additional year of schooling for an individual of average attainment, taking into account the effects of education on wages and employment probabilities after allowing for academic failure rates, the direct and opportunity costs of schooling, and the impact of personal taxes, social security contributions and unemployment and pension benefits on net incomes. We also construct a set of effective tax and subsidy rates that measure the effects of different public policies on the private returns to education, and measures of the fiscal returns to schooling that capture the long-term effects of a marginal increase in attainment on public finances under c

General equilibrium with asymmetric information: a dual approach

We study markets where the characteristics or decisions of certain agents are relevant but not known to their trading partners. Assuming exclusive transactions, the environment is described as a continuum economy with indivisible commodities. We characterize incentive efficient allocations as solutions to linear programming problems and appeal to duality theory to demonstrate the generic existence of external effects in these markets. Because under certain conditions such effects may generate non-convexities, randomization emerges as a theoretic possibility. In characterizing market equilibria we show that, consistently with the personalized nature of transactions, prices are generally non-linear in the underlying consumption. On the other hand, external effects may have critical implications for market efficiency. With adverse selection, in fact, cross-subsidization across agents with different private information may be necessary for optimality, and so, the market need not even achieve an incentive efficient allocation. In contrast, for the case of a single commodity, we find that when informational asymmetries arise after the trading period (e.g. moral hazard; ex post hidden types) external effects are fully internalized at a market equilibrium.

Bidding for the surplus: realizing efficient outcomes in general economic environments

In this paper, we consider two classes of economic environments. In the first type, agents are faced with the task of providing local public goods that will benefit some or all of them. In the second type, economic activity takes place via formation of links. Agents need both to both form a network and decide how to share the output generated. For both scenarios, we suggest a bidding mechanism whereby agents bid for the right to decide upon the organization of the economic activity. The subgame perfect equilibria of this game generate efficient outcomes.

A Computable general equilibrium approach to hypothetical extractions and missing links

Identifying key sectors or key locations in an interconnected economy is of paramount importance for improving policy planning and directing economic strategy. Hence the relevance of categorizing them and hence the corresponding need of evaluating their potential synergies in terms of their global economic thrust. We explain in this paper that standard measures based on gross outputs do not and cannot capture the relevant impact due to self- imposed modeling limitations. In fact, common gross output measures will be systematically downward biased. We argue that an economy wide Computable General Equilibrium (CGE) approach provides a modeling platform that overcomes these limitations since it provides (i) a more comprehensive measure of linkages and (ii) an alternate way of accounting for links' relevance that is in consonance with standard macromagnitudes in the National Income and Product Accounts.

Convergence of singular integrals with general measures

We show that L2-bounded singular integrals in metric spaces with respect to general measures and kernels converge weakly. This implies a kind of average convergence almost everywhere. For measures with zero density we prove the almost everywhere existence of principal values.

The Private and fiscal returns to schooling and the effect of public policies on private incentives to invest in education: a general framework and some results for the EU

This paper develops a comprehensive framework for the quantitative analysis of the private and fiscal returns to schooling and of the effect of public policies on private incentives to invest in education. This framework is applied to 14 member states of the European Union. For each of these countries, we construct estimates of the private return to an additional year of schooling for an individual of average attainment, taking into account the effects of education on wages and employment probabilities after allowing for academic failure rates, the direct and opportunity costs of schooling, and the impact of personal taxes, social security contributions and unemployment and pension benefits on net incomes. We also construct a set of effective tax and subsidy rates that measure the effects of different public policies on the private returns to education, and measures of the fiscal returns to schooling that capture the long-term effects of a marginal increase in attainment on public finances under conditions that approximate general equilibrium.

A general construction of internal sheaves in algebraic set theory

We present a solution to the problem of defining a counterpart in Algebraic Set Theory of the construction of internal sheaves in Topos Theory. Our approach is general in that we consider sheaves as determined by Lawvere-Tierney coverages, rather than by Grothen-dieck coverages, and assume only a weakening of the axioms for small maps originally introduced by Joyal and Moerdijk, thus subsuming the existing topos-theoretic results.

A General model of bilateral migration agreements

Unilateral migration policies impose externalities on other countries. In order to try to internalize these externalities, countries sign bilateral migration agreements. One element of these agreements is the emphasis on enforcing migration policies: immigrant-receiving countries agree to allow more immigrants from their emigrant-sending partner if they cooperate in enforcing their migration policy at the border. I present a simple theoretical model that justifies this behavior in a two-country setting with welfare maximizing governments. These governments establish migration quotas that need to be enforced at a cost. I prove that uncoordinated migration policies are inefficient. Both countries can improve welfare by exchanging a more "generous" migration quota for expenditure on enforcement policy. Contrary to what could be expected, this result does not depend on the enforcement technology that both countries employ.