Increased expression of urokinase-type plasminogen activator mRNA determines adverse prognosis in ErbB2-positive primary breast cancer.

PURPOSE: To evaluate and validate mRNA expression markers capable of identifying patients with ErbB2-positive breast cancer associated with distant metastasis and reduced survival. PATIENTS AND METHODS: Expression of 60 genes involved in breast cancer biology was assessed by quantitative real-time PCR (qrt-PCR) in 317 primary breast cancer patients and correlated with clinical outcome data. Results were validated subsequently using two previously published and publicly available microarray data sets with different patient populations comprising 295 and 286 breast cancer samples, respectively. RESULTS: Of the 60 genes measured by qrt-PCR, urokinase-type plasminogen activator (uPA or PLAU) mRNA expression was the most significant marker associated with distant metastasis-free survival (MFS) by univariate Cox analysis in patients with ErbB2-positive tumors and an independent factor in multivariate analysis. Subsequent validation in two microarray data sets confirmed the prognostic value of uPA in ErbB2-positive tumors by both univariate and multivariate analysis. uPA mRNA expression was not significantly associated with MFS in ErbB2-negative tumors. Kaplan-Meier analysis showed in all three study populations that patients with ErbB2-positive/uPA-positive tumors exhibited significantly reduced MFS (hazard ratios [HR], 4.3; 95% CI, 1.6 to 11.8; HR, 2.7; 95% CI, 1.2 to 6.2; and, HR, 2.8; 95% CI, 1.1 to 7.1; all P < .02) as compared with the group with ErbB2-positive/uPA-negative tumors who exhibited similar outcome to those with ErbB2-negative tumors, irrespective of uPA status. CONCLUSION: After evaluation of 898 breast cancer patients, uPA mRNA expression emerged as a powerful prognostic indicator in ErbB2-positive tumors. These results were consistent among three independent study populations assayed by different techniques, including qrt-PCR and two microarray platforms.

Optimising translational oncology in clinical practice: Strategies to accelerate progress in drug development.

Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer.

Strategies for the successful implementation of viral laboratory automation.

It has been estimated that more than 70% of all medical activity is directly related to information providing analytical data. Substantial technological advances have taken place recently, which have allowed a previously unimagined number of analytical samples to be processed while offering high quality results. Concurrently, yet more new diagnostic determinations have been introduced - all of which has led to a significant increase in the prescription of analytical parameters. This increased workload has placed great pressure on the laboratory with respect to health costs. The present manager of the Clinical Laboratory (CL) has had to examine cost control as well as rationing - meaning that the CL's focus has not been strictly metrological, as if it were purely a system producing results, but instead has had to concentrate on its efficiency and efficacy. By applying re-engineering criteria, an emphasis has had to be placed on improved organisation and operating practice within the CL, focussing on the current criteria of the Integrated Management Areas where the technical and human resources are brought together. This re-engineering has been based on the concepts of consolidating and integrating the analytical platforms, while differentiating the production areas (CORE Laboratory) from the information areas. With these present concepts in mind, automation and virological treatment, along with serology in general, follow the same criteria as the rest of the operating methodology in the Clinical Laboratory.

Análisis de plataformas para la publicación de información geográfica en la nube

Análisis de cinco plataformas, vía navegador, para crear mapas y compartirlos.

Digital beamforming and moving target indication for future spaceborne synthetic aperture radar

During the last decade the interest on space-borne Synthetic Aperture Radars (SAR) for remote sensing applications has grown as testified by the number of recent and forthcoming missions as TerraSAR-X, RADARSAT-2, COSMO-kyMed, TanDEM-X and the Spanish SEOSAR/PAZ. In this sense, this thesis proposes to study and analyze the performance of the state-of-the-Art space-borne SAR systems, with modes able to provide Moving Target Indication capabilities (MTI), i.e. moving object detection and estimation. The research will focus on the MTI processing techniques as well as the architecture and/ or configuration of the SAR instrument, setting the limitations of the current systems with MTI capabilities, and proposing efficient solutions for the future missions. Two European projects, to which the Universitat Politècnica de Catalunya provides support, are an excellent framework for the research activities suggested in this thesis. NEWA project proposes a potential European space-borne radar system with MTI capabilities in order to fulfill the upcoming European security policies. This thesis will critically review the state-of-the-Art MTI processing techniques as well as the readiness and maturity level of the developed capabilities. For each one of the techniques a performance analysis will be carried out based on the available technologies, deriving a roadmap and identifying the different technological gaps. In line with this study a simulator tool will be developed in order to validate and evaluate different MTI techniques in the basis of a flexible space-borne radar configuration. The calibration of a SAR system is mandatory for the accurate formation of the SAR images and turns to be critical in the advanced operation modes as MTI. In this sense, the SEOSAR/PAZ project proposes the study and estimation of the radiometric budget. This thesis will also focus on an exhaustive analysis of the radiometric budget considering the current calibration concepts and their possible limitations. In the framework of this project a key point will be the study of the Dual Receive Antenna (DRA) mode, which provides MTI capabilities to the mission. An additional aspect under study is the applicability of the Digital Beamforming on multichannel and/or multistatic radar platforms, which conform potential solutions for the NEWA project with the aim to fully exploit its capability jointly with MTI techniques.

Identification and characterization of a caspase-2 activating complex

Résumé Les caspases sont des protéases essentielles lors de l'induction de l'apoptose ou pour la maturation de certaines cytokines. Elles peuvent être divisées en deux groupes: les caspases initiatrices, qui sont les premières activées lors d'un signal pro-apoptotique, et les caspases effectrices, qui sont activées par les caspases initiatrices et sont responsables du clivage et de la dégradation des substrats cellulaires. Les caspases initiatrices sont activées dans des complexes de haut poids moléculaire: l'apoptosome pour la caspase-9 et le DISC pour la caspase-8. La caspase-2 est également une caspase initiatrice qui contient un domaine CARD. Cependant son mécanisme d'activation n'est pas encore connu. Lors de cette étude, nous avons découvert et caractérisé le complexe qui permet l'activation de la caspase-2. Ce complexe, appelé le PIDDosome, est composé de PIDD/LRDD, de la protéine adaptatrice RAIDD et de la protéase caspase-2. L'expression forcée de PIDD induit l'activation constitutive de la caspase-2. Cela entraîne la mort ou la sensibilisation à la mort des cellules selon la lignée étudiée. Cet effet est expliqué par une perte du potentiel de membrane de la mitochondrie, certainement dû à un effet direct de la caspase-2. Peu de choses sont connues sur PIDD: c'est une protéine contenant un domaine DD qui peut être induite par p53. Nous avons caractérisé PIDD et montré qu'elle est exprimée de façon ubiquitaire. PIDD est constitutivement auto-clivée environ au milieu de la protéine, ce qui génère deux fragments qui restent liés l'un à l'autre. Le fragment N-terminal a une activité régulatrice et le C-terminal une activité effectrice. De plus, PIDD peut se déplacer entre le cytoplasme et le noyau. Enfin, nous avons découvert que PIDD est également impliquée dans l'induction de NF¬ -κB en réponse à des dommages à l'ADN. PIDD est responsable de la modification par sumo de NEMO, étape nécessaire à l'induction de NF-κB après des dommages à l'ADN. Ainsi PIDD semble être à l'intersection de la décision que prend la cellule entre survivre et réparer les dommages, ou entrer en apoptose. Summary Caspases are a family of proteases that fulfill varied and often critical roles in mammalian apoptosis or proteolytic activation of cytokines. Caspases can be divided into two sub-groups: initiator caspases, which are the first activated after a pro-apoptotic signal, and effector caspases, which are activated by initiator caspases and that are responsible for the cleavage and degradation of cellular components. Initiator caspases are activated in high molecular weight platforms such as the apoptosome for caspase-9 or the DISC for caspase-8. Caspase-2 is a CARD-containing initiator caspase whose mechanism of activation was not yet known. In this study we have identified an activating platform for caspase-2. This high molecular weight complex, called the PIDDosome, is composed of PIDD/LRDD, the adaptor protein RAIDD and caspase-2. Constitutive expression of PIDD led to constitutive activation of caspase-2, which in some cell lines was sufficient to induce cell death while in others it merely sensitizes. Active caspase-2 was found to disturb directly the mitochondria by inducing a partial loss of the transmembrane potential. Very little was known on PIDD. It can be induce by p53 and inhibition of its expression by antisense oligonucleotides diminishes p53-dependent apoptosis. We decided to further characterize PIDD function and expression. PIDD possesses seven LRR, two Zu5 domains and one DD. It is ubiquitously expressed and appears to be constitutively cleaved by auto- processing into two main fragments equal in size. The two fragments remain bound to one another and constitute a regulatory N-terminal fragment and an active C-terminal fragment. In addition, PIDD can shuttle between the cytoplasm and the nucleus. Finally, investigating the possible relevance of new interaction partners, we found that PIDD is implicated in DNA damage-induced NF- κB. PIDD binds to RIP1 and to NEMO. In response to DNA damage, PIDD translocates to the nucleus and mediates sumo- modification of NEMO, a necessary step in DNA damage-induced NF-κB. All together these results raise the possibility that PIDD acts as a molecular switch between proliferation and repair, and apoptosis following DNA damage.

Latest Miocene - Pliocene Larger Foraminifera and depositional environments of the carbonate bank of La Désirade Island, Guadeloupe (French Antilles)

In this paper we present first results of the study of planktonic Foraminifera, large benthic Foraminifera and carbonate facies of La Désirade, aiming at a definition of the age and depositional environments of the Neogene carbonates of this island. The study of planktonic Foraminifera from the Detrital Offshore Limestones (DOL) of the Anciènne Carrière allows to constrain the biochronology of this formation to the lower Zone N19 and indicates a latest Miocene to early Pliocene (5.48 - 4.52 Ma) age. Large benthic Foraminifera were studied both as isolated and often naturally split specimens from the DOL, and in thin sections of limestones from the DOL and the Limestone Table (LT). The assemblages of Foraminifera include Nummulitidae, Amphisteginidae, Asterigerinidae, Peneroplidae, Soritidae, Rotalidae (Globigerinidae: Globigerinoides, Sphaeroidenellopsis, Orbulina) and incrusting Foraminifera (Homotrema and Sporadotrema). The genera Amphistegina, Archaias and Operculina are discussed. Concerning the Nummulitidae we include both "Paraspiroclypeus" chawneri and "Nummulites" cojimarensis, as well as a newly described species, Operculina desiradensis new species, in the genus Operculina, because the differences between these 3 species are rather on the specific than the generic level, while their morphology, studied by SEM, is compatible with the definition of the genus Operculina (D'Orbigny1826, emend. Hottinger 1977). The three species can be easily distinguished on the basis of their differences in spiral growth: while O. desiradensis has an overall logarithmic spiral growth, O. cojimarensis and especially O. chawneri show a tighter and more geometric spiral growth. O. cojimarensis and O. chawneri were originally described from Cuba in outcrops originally dated as Oligocene and later redated as early Pliocene. Therefore, O. chawneri was considered until now as restricted to the early Pliocene. However, in the absence of a detailed morphometric and biostratigraphic study of the Caribbean Neogene nummulitids, it is difficult to evaluate the biochronologic range of these species.The history of the carbonates begins with the initial tectonic uplift and erosion of the Jurassic igneous basement of La Désirade, that must have occurred at latest in late Miocene times, when sea-level oscillated around a long term stable mean. The rhythmic deposition of the Désirade Limestone Table (LT) can be explained by synsedimentary subsidence in a context of rapidly oscillating sea-level due to precession-driven (19-21 kyr) glacio-eustatic sea-level changes during the latest Miocene- Pliocene. Except for a thin reef cap present at the eastern edge of the LT, no other in-place reefal constructions have been observed in the LT. The DOL of western Désirade are interpreted as below wave base gravity deposits that accumulated beneath a steep fore-reef slope. They document the mobilisation of carbonate material (including Larger Foraminifera) from an adjacent carbonate platform by storms and their gravitational emplacement as debris and grain flows. The provenance of both the reefal carbonate debris and the tuffaceous components redeposited in the carbonates of La Désirade must be to the west, i. e. the carbonate platforms of Marie Galante and Grande Terre.

Avaluació de rendiment en plataformes virtualitzades

La motivació d'aquest projecte és establir quina és la diferència en quant a rendiment entre una màquina en format clàssic i una virtual, quan es tracta d'executar aplicacions d'alt rendiment (HPC). A partir de les conclusions extretes, es podrà decidir si és recomanable instal·lar aquest tipus d'aplicacions en servidors virtuals, o per contra, és millor instal·lar-les sobre plataformes clàssiques.

Ultra high throughput sequencing in human DNA variation detection: a comparative study on the NDUFA3-PRPF31 region.

BACKGROUND: Ultra high throughput sequencing (UHTS) technologies find an important application in targeted resequencing of candidate genes or of genomic intervals from genetic association studies. Despite the extraordinary power of these new methods, they are still rarely used in routine analysis of human genomic variants, in part because of the absence of specific standard procedures. The aim of this work is to provide human molecular geneticists with a tool to evaluate the best UHTS methodology for efficiently detecting DNA changes, from common SNPs to rare mutations. METHODOLOGY/PRINCIPAL FINDINGS: We tested the three most widespread UHTS platforms (Roche/454 GS FLX Titanium, Illumina/Solexa Genome Analyzer II and Applied Biosystems/SOLiD System 3) on a well-studied region of the human genome containing many polymorphisms and a very rare heterozygous mutation located within an intronic repetitive DNA element. We identify the qualities and the limitations of each platform and describe some peculiarities of UHTS in resequencing projects. CONCLUSIONS/SIGNIFICANCE: When appropriate filtering and mapping procedures are applied UHTS technology can be safely and efficiently used as a tool for targeted human DNA variations detection. Unless particular and platform-dependent characteristics are needed for specific projects, the most relevant parameter to consider in mainstream human genome resequencing procedures is the cost per sequenced base-pair associated to each machine.

Exploring Cross-layer power management for PGAS applications on the SCC platform

Technological limitations and power constraints are resulting in high-performance parallel computing architectures that are based on large numbers of high-core-count processors. Commercially available processors are now at 8 and 16 cores and experimental platforms, such as the many-core Intel Single-chip Cloud Computer (SCC) platform, provide much higher core counts. These trends are presenting new sets of challenges to HPC applications including programming complexity and the need for extreme energy efficiency.In this work, we first investigate the power behavior of scientific PGAS application kernels on the SCC platform, and explore opportunities and challenges for power management within the PGAS framework. Results obtained via empirical evaluation of Unified Parallel C (UPC) applications on the SCC platform under different constraints, show that, for specific operations, the potential for energy savings in PGAS is large; and power/performance trade-offs can be effectively managed using a cross-layerapproach. We investigate cross-layer power management using PGAS language extensions and runtime mechanisms that manipulate power/performance tradeoffs. Specifically, we present the design, implementation and evaluation of such a middleware for application-aware cross-layer power management of UPC applications on the SCC platform. Finally, based on our observations, we provide a set of recommendations and insights that can be used to support similar power management for PGAS applications on other many-core platforms.

Learning about Distributed Systems

This paper presents the "state of the art" about distributed systems and applications and it's focused on teaching about these systems. It presents different platforms where to run distributed applications and describes some development toolkits whose can be used to develop prototypes, practices and distributed applications. It also presents some existing distributed algorithms useful for class practices, and some tools to help managing distributed environments. Finally, the paper presents some teaching experiences with different approaches on how to teach about distributed systems.

Contribution to Asterisk Open Source Project

With this final master thesis we are going to contribute to the Asterisk open source project. Asterisk is an open source project that started with the main objective of develop an IP telephony platform, completely based on Software (so not hardware dependent) and under an open license like GPL. This project was started on 1999 by the software engineer Mark Spencer at Digium. The main motivation of that open source project was that the telecommunications sector is lack of open solutions, and most of the available solutions are based on proprietary standards, which are close and not compatible between them. Behind the Asterisk project there is a company, Digum, which is the project leading since the project was originated in its laboratories. This company has some of its employees fully dedicated to contribute to the Asterisk project, and also provide the whole infrastructure required by the open source project. But the business of Digium isn't based on licensing of products due to the open source nature of Asterisk, but it's based on offering services around Asteriskand designing and selling some hardware components to be used with Asterisk. The Asterisk project has grown up a lot since its birth, offering in its latest versions advanced functionalities for managing calls and compatibility with some hardware that previously was exclusive of proprietary solutions. Due to that, Asterisk is becoming a serious alternative to all these proprietaries solutions because it has reached a level of maturity that makes it very stable. In addition, as it is open source, it can be fully customized to a givenrequirement, which could be impossible with the proprietaries solutions. Due to the bigness that is reaching the project, every day there are more companies which develop value added software for telephony platforms, that are seriously evaluating the option of make their software fully compatible withAsterisk platforms. All these factors make Asterisk being a consolidated project but in constant evolution, trying to offer all those functionalities offered by proprietaries solutions. This final master thesis will be divided mainly in two blocks totally complementaries. In the first block we will analyze Asterisk as an open source project and Asterisk as a telephony platform (PBX). As a result of this analysis we will generate a document, written in English because it is Asterisk project's official language, which could be used by future contributors as an starting point on joining Asterisk. On the second block we will proceed with a development contribution to the Asterisk project. We will have several options in the form that we do the contribution, such as solving bugs, developing new functionalities or start an Asterisk satellite project. The type of contribution will depend on the needs of the project on that moment.

Where microbiology meets microengineering: design and applications of reporter bacteria.

Bacteria have long been the targets for genetic manipulation, but more recently they have been synthetically designed to carry out specific tasks. Among the simplest of these tasks is chemical compound and toxicity detection coupled to the production of a quantifiable reporter signal. In this Review, we describe the current design of bacterial bioreporters and their use in a range of assays to measure the presence of harmful chemicals in water, air, soil, food or biological specimens. New trends for integrating synthetic biology and microengineering into the design of bacterial bioreporter platforms are also highlighted.

Appropriation of technology in "non-western" societies: an approximation to the case of Bulgaria

The principal focus of the PhD thesis lies in the Social Software area and the appropriation of technology in "non-Western" societies taking the example of Bulgaria. The term "non-Western" is used to explain places considered technologically underdeveloped. The aims have been to capture how Bulgarian users creatively interpret and appropriate Internet identifying the sociocultural, political and subjective conditions in which that appropriation occurs, to identify emerging practices based on the interpretation and use of Internet and the impact they had on society and what conditions could influence the technological interpretation and the meaning these practices had for both users and social configuration of Internet as media in Bulgaria. An ethnographic approach has been used simultaneously in different online and offline contexts. On the one hand, this study is based on exploration of the Bulgarian Internet Space through online participant observation in forums and websites reviews and on the other hand, on semi-structured interviews with different types of users of the virtual platforms found, made both face to face and online and finally online participant observation at the same platforms. It is based on some contributions of the ethnographic work of Christine Hine in virtual environments and the notions of time and space of Barbara Czarniawska contextualized in the modern form of organization that occurs in a network of multiple and fragmented contexts across many movements.

Infectious diseases not immune to genome-wide association.

Two genome-wide association studies for meningococcal disease and tuberculosis identify new loci associated with susceptibility to these infectious diseases. They highlight a role for the acquired and innate immune systems in host control of several human pathogens and demonstrate that denser genotyping platforms and population-specific reference panels are necessary for genetic studies in African populations.