Identification Of Effective New Drugs Combinations Exploiting The Ability Of trabectedin To Modulate Transcription

Ewing’s sarcoma (ES) is the second most common malignant bone tumor of childhood, characterized by the chimeric protein EWS-FLI1 (hallmark of this pathology), that alters the transcription of different genes. The five-year overall survival of patients with localized disease is approximately 70%; unfortunately the majority of patients with a metastatic disease have a poor prognosis with a five-year overall survival around the 30%. Among the recently registered drugs for the therapy of sarcomas, trabectedin could be of potential great interest as it seems very active in some “translocated sarcomas”. Trabectedin exerts its antitumor activity with different mechanisms of action. One of the most important is related to its ability to interfere with DNA repair mechanisms (NER and HR), that cause cell cycle perturbations. Furthermore trabectedin is able to displace the oncogenic EWS-FLI1 chimera from its target promoters, modulating the transcription of these genes, in ES cells. Although trabectedin has shown some activity against ES, the overall clinical results indicated only a marginally activity of trabectedin given as single agent in ES. The thesis is aimed at using the available knowledge on trabectedin mechanism of action to identify some effective combinations. Since trabectedin induces cell cycle perturbations I speculated that its activity could be increased by checkpoint inhibitors. The studies performed on the combination of trabectedin and the WEE1 inhibitor, AZD-1775, have shown that the inhibition of WEE1 enhances the trabectedin activity, thus the combination is synergic. Since trabectedin affects the transcription of several genes, I have developed a new approach based on the use of silencing RNA (siRNA) libraries to identify whether the downregulation of some genes was synthetically lethal when ES cells were pretreated with trabectedin. An important part of the thesis was the development, validation and initial application of this approach

Controlling instabilities along a 3DVar analysis cycle by assimilating in the unstable subspace: a comparison with the EnKF

A hybrid scheme obtained by combining 3DVar with the Assimilation in the Unstable Subspace (3DVar-AUS) is tested in a QG model, under perfect model conditions, with a fixed observational network, with and without observational noise. The AUS scheme, originally formulated to assimilate adaptive observations, is used here to assimilate the fixed observations that are found in the region of local maxima of BDAS vectors (Bred vectors subject to assimilation), while the remaining observations are assimilated by 3DVar. The performance of the hybrid scheme is compared with that of 3DVar and of an EnKF. The improvement gained by 3DVar-AUS and the EnKF with respect to 3DVar alone is similar in the present model and observational configuration, while 3DVar-AUS outperforms the EnKF during the forecast stage. The 3DVar-AUS algorithm is easy to implement and the results obtained in the idealized conditions of this study encourage further investigation toward an implementation in more realistic contexts

The Renewed Lisbon Strategy: the Agenda and the State of Implementation in the Italian Regions

Con questa pubblicazione le Rappresentanze in Italia della Commissione Europea intendono contribuire ad informare l'opinione pubblica sul processo di rilancio della strategia di Lisbona attualmente in atto a livello comunitario per favorire il conseguimento dell¿obiettivo di trasformare entro il 2010 l¿Europa nell'economia basata sulla conoscenza più competitiva e dinamica del mondo. Questa pubblicazione intende in particolare richiamare per brevi punti le tappe principali del rilancio della strategia di Lisbona nell¿Unione Europea iniziata nel 2005 mostrando come per ogni Stato membro, e quindi anche per l¿Italia, il migliore coordinamento tra le azioni e le politiche attuate dalla Commissione Europea e quelle realizzate dal Governo nazionale sia il punto chiave di questo rilancio.JRC.G.9-Econometrics and statistical support to antifrau

Investigating the Efficiency of EU Deposit Guarantee Schemes

This Report considers the various meanings the word "efficiency" can have, the current way Deposit Guarantee Schemes (DGS) operate, and a quantitative analysis investigating the capability of the EU Member States to handle reimbursements or preventive interventions of varying magnitude. Consequently, this Report also describes the various steps of the intervention procedure (both in case of payout and for preventive interventions), the authorities involved and their interaction, and the way DGS manage and invest available funds. Even though it has been difficult to draw general and harmonized conclusions (as each incident was distinctive), some key conclusions can be made.JRC.G.9-Econometrics and statistical support to antifrau

Reference crop evapotranspiration estimate using high-resolution meteorological network's data

Water management authorities need detailed information about each component of the hydrological balance. This document presents a method to estimate the evapotranspiration rate, initialized in order to obtain the reference crop evapotranspiration rate (<i>ET</i><sub>0</sub>). By using an Optimal Interpolation (OI) scheme, the hourly observations of several meteorological variables, measured by a high-resolution local meteorological network, are interpolated over a regular grid. The analysed meteorological fields, containing detailed meteorological information, enter a model for turbulent heat fluxes estimation based on Monin-Obukhov surface layer similarity theory. The obtained <i>ET</i><sub>0</sub> fields are then post-processed and disseminated to the users

The immersive novel

The paper analyzes the emergence of an emotional immersion pattern in the works of authors of the contemporary bestselling such as Nobel prize winner Orhan Pamuk, in particular the novel The Museum of Innocence, the Hunger Games saga by Suzanne Collins and the Carlos Ruiz Zafón’s Tetralogy, El cementerio de los libros olvidados

Suspense is the Key. Narratology, Cognitive Neurosciences and Computer Technology

L'articolo indaga i meccanismi neurocognitivi alla base della suspense sia in ambito letterario che filmico

Selection of Inflatable Bounce Houses Using Data Envelopment Analysis

The decision to purchase one consumer product over another is becoming more challenging as the choices that are made available to consumers have increased. This research studies the decision making process when consumers purchase an inflatable bounce house. In addition to cost, a variety of features such as structure size, weight capacity, weight of product, customer ratings, and the number of customer ratings must be compared. It is difficult to make a direct comparison of each of these individual features through traditional methods. As a result, Data Envelopment Analysis is used to compare the outputs and inputs to determine which inflatable bounce houses are most efficient compared to the others being evaluated. Twelve bounce houses were evaluated through Data Envelopment Analysis and seven were found to be more efficient than other bounce houses that were evaluated. This study also provided some suggestions for the inefficient bounce houses to become efficient

Perché piacciono maghi e vampiri: letteratura, cognitivismo e controfattualità

Recenti test sul potenziale socio-cognitivo e il valore edonico di testi letterari che utilizzano elementi magici rivelano come la controfattualità costituisca una ‘palestra mentale’ per i lettori: essi apprendono a elaborare spiegazioni causali complesse e incrementano i fattori coinvolti nel costituirsi della coesione sociale, sia nel caso di lettori young adult sia nel caso di lettori adulti. Lo psicologo Eugene Subbotsky ha dimostrato che la magia ci rende più sensibili alle operazioni di Teoria della Mente e socialmente empatici, mentre un gruppo di narratologi ha di recente misu- rato i tempi di riassorbimento della dissonanza cognitiva prodotta dall’elemento magico: ciò rie- sce fra l’altro a spiegare il grande successo di Harry Potter e della saga di Twilight.L'articolo indaga i meccanismi contrattuali della letteratura dal punto di vista neurocognitivista

Detecting unstable structures and controlling error growth by assimilation of standard and adaptive observations in a primitive equation ocean model

International audienceOceanic and atmospheric prediction is based on cyclic analysis-forecast systems that assimilate new observations as they become available. In such observationally forced systems, errors amplify depending on their components along the unstable directions; these can be estimated by Breeding on the Data Assimilation System (BDAS). Assimilation in the Unstable Subspace (AUS) uses the available observations to estimate the amplitude of the unstable structures (computed by BDAS), present in the forecast error field, in order to eliminate them and to control the error growth. For this purpose, it is crucial that the observational network can detect the unstable structures that are active in the system. These concepts are demonstrated here by twin experiments with a large state dimension, primitive equation ocean model and an observational network having a fixed and an adaptive component. The latter consists of observations taken each time at different locations, chosen to target the estimated instabilities, whose positions and features depend on the dynamical characteristics of the flow. The adaptive placement and the dynamically consistent assimilation of observations (both relying upon the estimate of the unstable directions of the data-forced system), allow to obtain a remarkable reduction of errors with respect to a non-adaptive setting. The space distribution of the positions chosen for the observations allows to characterize the evolution of instabilities, from deep layers in western boundary current regions, to near-surface layers in the eastward jet area