Methods for detection and confirmation of Hematide?/peginesatide in anti-doping samples.

Since the 1990's, cheating athletes have abused substances to increase their oxygen transport capabilities; among these substances, recombinant EPO is the most well known. Currently, other investigational pharmaceutical products are able to produce an effect similar to EPO but without having chemical structures related to EPO; these are the synthetic erythropoiesis stimulating agents (ESAs). Peginesatide (also known as Hematide?) is being developed by Affymax and Takeda and, if approved by regulatory authorities, could soon be released on the international market. To detect potential athletic abuse of this product and deter athletes who consider cheating, we initiated a collaboration to implement a detection test for anti-doping purposes. Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent that is designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. It is undetectable using current anti-doping tests due to its lack of sequence homology to EPO. To detect and deter potential abuse of peginesatide, we initiated an industry/antidoping laboratory collaboration to develop and validate screening and confirmation assays so that they would be available before peginesatide reaches the market. We describe a screening ELISA and a confirmation assay consisting of immune-purification followed by separation with SDS-PAGE and revelation with Western double blotting. Both assays can detect 0.5 ng/mL concentrations of peginesatide in blood samples, enabling detection for several days after administration of a physiologically relevant dose. This initial report describes experimental characterization of these assays, including testing with a blinded set of samples from a clinical study conducted in healthy volunteers.

Alzheimer's Disease Biomarkers, 2009

This report gives a comprehensive and up-to-date review of Alzheimer's disease biomarkers. Recent years have seen significant advances in this field. Whilst considerable effort has focused on A�_ and tau related markers, a substantial number of other molecules have been identified, that may offer new opportunities.This Report : Identifies 60 candidate Alzheimer's (AD) biomarkers and their associated studies. Of these, 49 are single species or single parameters, 7 are combinations or panels and 4 involve the measurement of two species or parameters or their ratios. These include proteins (n=34), genes (n=11), image-based parameters (n=7), small molecules (n=3), proteins + genes (n=2) and others (n=3). Of these, 30 (50%) relate to species identified in CSF and 19 (32%) were found in the blood. These candidate may be classified on the basis of their diagnostic utility, namely those which i) may allow AD to be detected when the disease has developed (48 of 75†= 64%), ii) may allow early detection of AD (18 of 75† = 24%) and iii) may allow AD to be predicted before the disease has begun to develop (9 of 75†= 12%). † Note: Of these, 11 were linked to two or more of these capabilities (e.g. allowed both early-stage detection as well as diagnosis after the disease has developed).Biomarkers: AD biomarkers identified in this report show significant diversity, however of the 60 described, 18 (30%) are associated with amyloid beta (A�_) and 9 (15%) relate to Tau. The remainder of the biomarkers (just over half) fall into a number of different groups. Of these, some are associated with other hypotheses on the pathogenesis of AD however the vast majority are individually unique and not obviously linked with other markers. Analysis and discussion presented in this report includes summaries of the studies and clinical trials that have lead to the identification of these markers. Where it has been calculated, diagnostic sensitivity, specificity and the capacity of these markers to differentiate patients with suspected AD from healthy controls and individuals believed to be suffering from other neurodegenerative conditions, have been indicated. These findings are discussed in relation to existing hypotheses on the pathogenesis of the AD and the current drug development pipeline. Many uncertainties remain in relation to the pathogenesis of AD, in diagnosing and treating the disease and many of the studies carried out to identify disease markers are at an early stage and will require confirmation through larger and longer investigations. Nevertheless, significant advances in the identification of AD biomarkers have now been made. Moreover, whilst much of the research on AD biomarkers has focused on amyloid and tau related species, it is evident that a substantial number of other species may provide important opportunities.Purpose of Report: To provide a comprehensive review of important and recently discovered candidate biomarkers of AD, in particular those with potential to reliably detect the disease or with utility in clinical development, drug repurposing, in studies of the pathogenesis and in monitoring drug response and the course of the disease. Other key goals were to identify markers that support current pipeline developments, indicate new potential drug targets or which advance understanding of the pathogenesis of this disease.Drug Repurposing: Studies of the pathogenesis of AD have identified aberrant changes in a number of other disease areas including inflammation, diabetes, oxidative stress, lipid metabolism and others. These findings have prompted studies to evaluate some existing approved drugs to treat AD. This report identifies studies of 9 established drug classes currently being investigated for potential repurposing.Alzheimer’s Disease: In 2005, the global prevalence of dementia was estimated at 25 million, with more than 4 million new cases occurring each year. It is also calculated that the number of people affected will double every 20 years, to 80 million by 2040, if a cure is not found. More than 50% of dementia cases are due to AD. Today, approximately 5 million individuals in the US suffer from AD, representing one in eight people over the age of 65. Direct and indirect costs of AD and other forms of dementia in the US are around $150 billion annually. Worldwide, costs for dementia care are estimated at $315 billion annually. Despite significant research into this debilitating and ultimately fatal disease, advances in the development of diagnostic tests for AD and moreover, effective treatments, remain elusive.Background: Alzheimer's disease is the most common cause of dementia, yet its clinical diagnosis remains uncertain until an eventual post-mortem histopathology examination is carried out. Currently, therapy for patients with Alzheimer disease only treats the symptoms; however, it is anticipated that new disease-modifying drugs will soon become available. The urgency for new and effective treatments for AD is matched by the need for new tests to detect and diagnose the condition. Uncertainties in the diagnosis of AD mean that the disease is often undiagnosed and under treated. Moreover, it is clear that clinical confirmation of AD, using cognitive tests, can only be made after substantial neuronal cell loss has occurred; a process that may have taken place over many years. Poor response to current therapies may therefore, in part, reflect the fact that such treatments are generally commenced only after neuronal damage has occurred. The absence of tests to detect or diagnose presymptomatic AD also means that there is no standard that can be applied to validate experimental findings (e.g. in drug discovery) without performing lengthy studies, and eventual confirmation by autopsy.These limitations are focusing considerable effort on the identification of biomarkers that advance understanding of the pathogenesis of AD and how the disease can be diagnosed in its early stages and treated. It is hoped that developments in these areas will help physicians to detect AD and guide therapy before the first signs of neuronal damage appears. The last 5-10 years have seen substantial research into the pathogenesis of AD and this has lead to the identification of a substantial number of AD biomarkers, which offer important insights into this disease. This report brings together the latest advances in the identification of AD biomarkers and analyses the opportunities they offer in drug R&D and diagnostics.��

Mechanisms of eosinophil cytokine release

Human eosinophils have been demonstrated to contain a multitude of cytokines and chemokines that exist pre-formed within these cells. This content of pre-formed cytokines, with diverse potential biologic activities, provides eosinophils with capabilities distinct from most other leukocytes. The localization of pre-formed cytokines within eosinophils is both within specific granules and associated with substantial numbers of morphologically distinct cytoplasmic vesicles. Stimulation for release of specific cytokines, such as IL-4, leads to a regulated signal transduction cascade, which is dependent on the formation of leukotriene C4 within eosinophils where it acts as an intracrine mediator. IL-4 release occurs selectively and is by means of vesicular transport. The capabilities of eosinophils not only to rapidly release pre-formed cytokines but also to differentially regulate which cytokines are released endow eosinophils with distinct abilities in innate and acquired immunity.

Health inequalities: third report of session 2008-09, volume I

In the following report, chapter two examines the extent and causes of health inequalities. The causes of inequalities are broad and some of them reach beyond the capabilities and responsibilities of both the Department of Health and the NHS. This report therefore focuses on the effectiveness of the policies of the Department of Health and the NHS.

Gestió de projectes informàtics

Aquesta aplicació es l¿evolució d¿un programa existent, realitzat amb una base de dades d¿escriptori amb capacitats de programació i creació d¿interfícies d¿usuari, que per executar-la cal una llicencia i que ha de funcionar sobre un sistema operatiu privatiu (també amb llicencia). Evoluciona cap a un entorn realitzat sobre programari lliure, que funciona sobre qualsevol sistema operatiu i no es necessari pagar cap llicencia per a fer-lo servir, ni en la part servidora ni en la part client.

BCN­Routing : càlcul web de rutes amb pgRouting, OpenStreetMap i OpenLayers

En aquest projecte s'ha desenvolupat una interfície web per calcular rutes a la ciutat de Barcelona. Les rutes calculades són a peu, entre un punt d'origen qualsevol i un punt d'interès turístic de la ciutat com a destí. Per això s'han extret les dades dels carrers de Barcelona d'OpenStreetMap i s'han insertat a una base de dades postgreSQL/postGIS, juntament amb una capa vectorial de punts d'interès turístic que s'ha creat amb el SIG d'escriptori qGIS. El càlcul de les rutes amb les dades de la base de dades s'ha realitzat amb l'extensió pgRouting, i la interfície web per seleccionar els punts d'origen i destí, mostrar els mapes, i mostrar les rutes resultat, s'ha desenvolupat utilitzant la llibreria OpenLayers.

Elaboració d'un protocol basat en XML per a una xarxa de sensors

La progressiva reducció de dimensió i cost en els dispositius electrònics, la dràstica retallada de consum elèctric i la independència de què això els dota han fet créixer en els últims temps l'interès de les comunitats científiques i tecnològiques per les xarxes sense fils de petits dispositius. Per altra banda, l'XML (eXtensible Markup Language) és un metallenguatge extensible que ha esdevingut un estàndard per a l'intercanvi d'informació estructurada entre diferents plataformes. L'objectiu d'aquest treball és explorar les possibilitats que pot oferir la introducció de l'XML en les xarxes de sensors amb l'elaboració d'un protocol de comunicació basat en aquest llenguatge i demostrar la transparència en el canvi de plataforma. Per fer-ho, es disposa de dos dispositius amb capacitat de comunicació sense fils equipats amb detectors de temperatura, lluminositat, efecte Hall i nivell de càrrega de la bateria. El projecte constarà de dues parts: una, més extensa, dedicada al desenvolupament del programari per a aquests dispositius, encarregat de obtenir les lectures dels diferents sensors i emetre-les per la xarxa utilitzant el llenguatge XML, i una altra, per recollir aquesta informació present a la xarxa, interpretar-la, salvar-la en una base de dades i exposar-la al món en una plana web. El programari dels dispositius sensors s'escriurà en llenguatge nesC dins el sistema tinyOS que és el sistema operatiu que equipen. La part d'explotació de les dades es desenvoluparà sota la plataforma .NET de Microsoft.

Gestió d'amonestacions i sancions a un centre educatiu

L'objectiu d'aquest treball és dissenyar una base de dades que permeti gestionar de formaeficient la disciplina d'un centre educatiu. La base de dades s'ha de poder ampliar a futures funcionalitats, aprofitant tota la informació que tindrà referent a alumnes, cursos, professors i d'altres.

PGPWebmail : cliente de correo web con PGP

Trabajo Final de Carrera en desarrollo .NET: Aplicación web ASP.NET MVC cliente de correo electrónico con cifrado PGP y servicio web WCF que brinda funcionalidades de cifrado PGP.

Construcció d'un HTPC basat en programari lliure

Els avenços tecnològics en els camps de la informàtica i l'entreteniment ha evolucionatmolt ràpidament els darrers anys.Els ordinadors han augmentat la seva potència, han anat adquirint capacitats multimèdia i han arribat al punt de poder reproduir tranquil·lament els nous formats d'alta definició.El televisors i reproductors han passat un procés de sofisticació, el qual els ha dotat de noves característiques, com el teletext, el suport per les funcionalitats de la tdt i capacitat per reproduir formats provinents del àmbit informàtic.Per tant no seria estrany que tots dos mons acabin convergint, de manera que puguemdotar el menjador de casa amb les capacitats que han estat exclusives del món informàtic.Amb el temps han anat apareixent solucions que pretenien cobrir aquestes necessitats,amb més o menys èxit, però amb diversos inconvenients, ja que no deixaven de ser unpedaç sobre un aparell "tradicional".La finalitat d'aquest projecte és la de construir un HTPC (Home Theater PC), és a dir, un equip informàtic dotat de capacitats multimèdia i adequat per manipular des del sofà de casa nostra.Per acomplir aquesta finalitat primer haurem d'adquirir el maquinari. D'entrada el htpc ensí haurà de ser de mides reduïdes i silenciós, haurà de disposar de sortides vga, dvi i hdmi, i a més, ser capaç de reproduir formats d'alta definició sense cap complicació. El control d'aquest s'haurà de realitzar mitjançant algun dispositiu que no requereixi una superfície plana.A continuació caldrà escollir el programari amb el qual anirà equipat, per tant, haurem de triar alguna distribució de GNU/Linux, instal·lar-hi l'entorn d'escriptori KDE4, i la resta de programari específic com el navegador, correu electrònic, reproducció multimèdia, etc.El productes resultant serà un HTPC, que tal com hem dit, el podrem utilitzar des delssofàs de casa nostra de forma còmode i fàcil.

A mi què m'expliques?

Els alumnes i les alumnes de primer cicle d'ESO s'enfronten amb les dificultats de la nova etapa i la necessitat de demostrar les seves competències lingüístiques, quant al redactat i la correcció en l'elaboració de textos diversos. Les noves tecnologies de la informació i la comunicació poden ajudar (i han de propiciar-ho) a desenvolupar aquestes capacitats, i han de ser un element motivador perquè els nois i les noies sentin la necessitat de crear produccions escrites pròpies, adequades lingüísticament, coherents i amb les idees ben organitzades.És necessari, a més, que l'avaluació d'aquestes tasques els serveixi per millorar l'expressió en llengua catalana, gramaticalment i ortogràficament, tot ajudant-los a establir sistemes d'autocorrecció i rectificació d'errors.L'exposició pública (en un mitjà com el d'internet) de les seves obres hauria de reblar l'aspecte de la motivació en la creació d'escrits, de manera que els aporti noves expectatives de comunicació i els animi a participar de l'espai virtual que els ofereix aquesta finestra oberta al món. El meu treball té la intenció de ser un projecte educatiu per aconseguir una millora en l'expressió escrita dels alumnes del primer curs d'ESO amb l'ajuda de les eines de les Tecnologies de la Informació i la Comunicació.

PERSONAL(ONTO) : Personalizing the Learning Process in Virtual Environments by means of Adaptive Formative Itineraries based on Reusable Learning Objects and Ontologies TIN2006-15107-C02

Personalization in e-learning allows the adaptation of contents, learning strategiesand educational resources to the competencies, previous knowledge or preferences of the student. This project takes a multidisciplinary perspective for devising standards-based personalization capabilities into virtual e-learning environments, focusing on the conceptof adaptive learning itinerary, using reusable learning objects as the basis of the system and using ontologies and semantic web technologies.

Clinical pharmacogenomic testing of KRAS, BRAF and EGFR mutations by high resolution melting analysis and ultra-deep pyrosequencing

BACKGROUND: Epidermal growth factor receptor (EGFR) and its downstream factors KRAS and BRAF are mutated in several types of cancer, affecting the clinical response to EGFR inhibitors. Mutations in the EGFR kinase domain predict sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in lung adenocarcinoma, while activating point mutations in KRAS and BRAF confer resistance to the anti-EGFR monoclonal antibody cetuximab in colorectal cancer. The development of new generation methods for systematic mutation screening of these genes will allow more appropriate therapeutic choices. METHODS: We describe a high resolution melting (HRM) assay for mutation detection in EGFR exons 19-21, KRAS codon 12/13 and BRAF V600 using formalin-fixed paraffin-embedded samples. Somatic variation of KRAS exon 2 was also analysed by massively parallel pyrosequencing of amplicons with the GS Junior 454 platform. RESULTS: We tested 120 routine diagnostic specimens from patients with colorectal or lung cancer. Mutations in KRAS, BRAF and EGFR were observed in 41.9%, 13.0% and 11.1% of the overall samples, respectively, being mutually exclusive. For KRAS, six types of substitutions were detected (17 G12D, 9 G13D, 7 G12C, 2 G12A, 2 G12V, 2 G12S), while V600E accounted for all the BRAF activating mutations. Regarding EGFR, two cases showed exon 19 deletions (delE746-A750 and delE746-T751insA) and another two substitutions in exon 21 (one showed L858R with the resistance mutation T590M in exon 20, and the other had P848L mutation). Consistent with earlier reports, our results show that KRAS and BRAF mutation frequencies in colorectal cancer were 44.3% and 13.0%, respectively, while EGFR mutations were detected in 11.1% of the lung cancer specimens. Ultra-deep amplicon pyrosequencing successfully validated the HRM results and allowed detection and quantitation of KRAS somatic mutations. CONCLUSIONS: HRM is a rapid and sensitive method for moderate-throughput cost-effective screening of oncogene mutations in clinical samples. Rather than Sanger sequence validation, next-generation sequencing technology results in more accurate quantitative results in somatic variation and can be achieved at a higher throughput scale.

Innovation strategies in the presence of technology markets: evidence from spanish innovative firms

The development of markets for technology has eased the acquisition of technology and reshaped the innovation strategies of firms that we classify as producers of innovations or as imitators. Innovative activities of firms include research, acquisition of technology and downstream activities. Within an industry, firms producing innovations tend to conduct more research and downstream activities than those imitating innovations. Acquisition of technology is equally important for both. To implement innovation strategies, firms producing innovations require both the capability to scan the external environment for technology and the capability to integrate new technology. Firms producing innovations require both, while firms imitating innovations require scan capabilities only

A compositional data analysis package for R providing multiple approaches

”compositions” is a new R-package for the analysis of compositional and positive data.It contains four classes corresponding to the four different types of compositional andpositive geometry (including the Aitchison geometry). It provides means for computation,plotting and high-level multivariate statistical analysis in all four geometries.These geometries are treated in an fully analogous way, based on the principle of workingin coordinates, and the object-oriented programming paradigm of R. In this way,called functions automatically select the most appropriate type of analysis as a functionof the geometry. The graphical capabilities include ternary diagrams and tetrahedrons,various compositional plots (boxplots, barplots, piecharts) and extensive graphical toolsfor principal components. Afterwards, ortion and proportion lines, straight lines andellipses in all geometries can be added to plots. The package is accompanied by ahands-on-introduction, documentation for every function, demos of the graphical capabilitiesand plenty of usage examples. It allows direct and parallel computation inall four vector spaces and provides the beginner with a copy-and-paste style of dataanalysis, while letting advanced users keep the functionality and customizability theydemand of R, as well as all necessary tools to add own analysis routines. A completeexample is included in the appendix