Development and application of novel analytical methods for molecularly targeted cancer therapeutics

A detailed understanding of correlations of drug levels with drug action is an important aspect of the pre-clinical, clinical development and routine use of anti-cancer drugs. In furtherance of this important aim, the research in this thesis sought to develop and apply novel, highly sensitive, analytical methods to examine and understand correlations of drug levels with drug resistance mechanisms, therapeutic efficacy and side effects. LC-MS/MS is a state of the art analytical technique used to characterise and quantify both bio-molecules and pharmaceutical agents. Based on LC-MS/MS techniques, novel sensitive analytical methods were developed for the quantification of 1) tyrosine kinase inhibitor anti-cancer drugs to examine the interaction of these agents with drug resistance mechanisms, and 2) the multiple myeloma drug thalidomide as a pilot study to identify potential correlations between serum drug levels and toxicity/efficacy. Acquired resistance to chemotherapeutics through the over-expression of ABC transport proteins has presented a significant clinical challenge. The up-regulation of ABC transporters such as P-glycoprotein (P-gp), Breast Cancer Resistant Protein (BCRP) and Multidrug Resistance-associated Protein (MRP-1) is an important cellular mechanism of resistance in vivo and in vitro. Using cell-line models and the developed LC-MS/MS quantification method it was established that dasatinib, an agent used in treatment of chronic myelogenous leukaemia, is a substrate of ABC transporters P-gp and BCRP but not of MRP-1, and that dasatinib does not inhibit these transporters at clinically relevant concentrations. Another Tyrosine Kinase Inhibitor (TKI) being used in breast cancer, Lapatinib, was shown to be an inhibitor of P-gp but not a substrate of this resistance mechanism. Levels of other TKIs were also found to vary in their uptake in primary models of brain cancer. Using LC-MS/MS, the circulating serum levels of thalidomide in multiple myeloma patients were studied. A clear correlation between dosing regime and serum level was seen; however, the research also unearthed evidence of a significant incidence of non-compliance which could have far reaching consequences for patient treatment. Overall, LC-MS/MS methods for the quantification of chemotherapeutic agents in complex biological matrices produced sensitive and accurate data which we successfully exploited to characterise resistance to new drugs and examine correlations between serum levels and treatment variables

Prosociality Inspired by the Charism of the Unity of Chiara Lubich. An Application in the School of Childhood

This article presents two distinct parts. The first tries to answer the questions: How do spiritual or religious intuitions apply in life? Or, better, how do certain evangelical passages come to pass when they pass through a structuring of a system of thought? What application characteristics can a certain charism have when analysed and experimentally applied from a scientific perspective and methodology? In this first part, we present a biographical and professional journey of an academic group that started from a concern and experience of a person, the first author, for about 38 years. This group was trying to develop a theoretical-application model initially originated in the educational field and currently active in various areas of human activity, responding to the spiritual charism of a contemporary woman recognised by an institution as universal by the church. The second part shows one of the last experiences of these applications in the educational field. This experience occurs specifically in the infantile age, which is a crucial stage to mark positive tracks in the development of the personality, as well as positive patterns for the later interpersonal and social relations that employ prosociality and cooperation with a very experimental methodology.Prospołeczność inspirowana charyzmatem jedności Chiary Lubich. Przykład zastosowania w przedszkoluArtykuł składa się z dwóch części. W pierwszej podjęto próbę odpowiedzi na pytania: w jaki sposób duchowe lub religijne intuicje znajdują zastosowanie w życiu? Lub bardziej: co staje się z konkretnymi fragmentami ewangelicznymi, gdy przechodzą przez strukturę systemu myślenia? Jakie charakterystyczne cechy może uzyskać określony charyzmat, gdy analizuje się go i eksperymentalnie wprowadza w życie z naukowej perspektywy i metodologii? W pierwszej części przedstawiamy biograficzną i zawodową podróż grupy akademickiej, która rozpoczęła się od troski i doświadczenia osoby, pierwszego autora, około 38 lat wcześniej. Grupa ta starała się opracować model teoretyczno-aplikacyjny, początkowo osadzony w dziedzinie edukacji, a obecnie wprowadzany w różnych obszarach ludzkiej aktywności, odpowiadając na duchowy charyzmat współczesnej kobiety uznany za uniwersalny przez Kościół. Druga część prezentuje jedno z ostatnich doświadczeń owych aplikacji w dziedzinę edukacji. To doświadczenie odnosi się do wieku niemowlęcego, który jest kluczowym momentem w kształtowaniu pozytywnych rysów w rozwoju osobowości, jak również w budowaniu pozytywnych wzorców dla późniejszych relacji interpersonalnych i społecznych, łącząc prospołeczność i współpracę z bardzo eksperymentalną metodologią

SequencesViewer : comment rendre accessible des motifs séquentiels de gènes trop nombreux ?

National audienceLes techniques d'extraction de connaissances ppliquées aux gros volumes de données, issus de l'analyse de puces ADN, permettent de découvrir des connaissances jusqu'alors inconnues. Or, ces techniques produisent de très nombreux résultats, difficilement exploitables par les experts. Nous proposons un outil dédié à l'accompagnement de ces experts dans l'appropriation et l'exploitation de ces résultats. Cet outil est basé sur trois techniques de visualisation (nuages, systèmes solaire et treemap) qui permettent aux biologistes d'appréhender de grandes quantités de motifs séquentiels (séquences ordonnées de gènes)

Discovering Novelty in Gene Data : From Sequential Patterns to Visualization

International audienceData mining techniques allow users to discover novelty in huge amounts of data. Frequent pattern methods have proved to be efficient, but the extracted patterns are often too numerous and thus difficult to analyse by end-users. In this paper, we focus on sequential pattern mining and propose a new visualization system, which aims at helping end-users to analyse extracted nowledge and to highlight the novelty according to referenced biological document databases. Our system is based on two visualization techniques: Clouds and solar systems. We show that these techniques are very helpful for identifying associations and hierarchical relationships between patterns among related documents. Sequential patterns extracted from gene data using our system were successfully evaluated by two biology laboratories working on Alzheimers disease and cancer

Emotional memory in anxiety: Behavioral and electrophysiological data

Background and Objectives: Recognition memory in anxiety is crucial since association with past experience is particularly important to manage emotional situations. A recognition bias can be the first step in cognitive anxiogenic distortions. The objective of this research was to evaluate the effect of anxiety on recognition memory, including consolidation and retrieval. This is the first study to date to assess recollection and familiarity through an independentremember/know paradigm in anxious participants, both behaviorally and electrophysiologically. Methods: Two groups of 17 participants with low and high anxiety level performed an experimental task of visual recognition memory, using neutral, pleasant and threatening pictures. The experiment was carried out two times, with an interval of 24 hours. The pattern of recognition was analyzed, behaviorally (through an independent Remember/Know paradigm) and with event-related potentials (ERP). Results: Subjects with higher levels of anxiety developed a bias in recognition of arousing stimuli (threatening and pleasant) compared with less anxiety level group. This bias was observed in the subprocess of familiarity and produced a positive modulation of a parietal late positive component (LPC) at approximately 620 milliseconds of latency. This effect was not found 24 hours later. Limitations: A reduced post-study interval limited the experimental effect on consolidation. Anxiety was assessed only dimensionally. Conclusions: The familiarity bias in recognition found in this experiment is a promising way of explaining the memory distortion in anxiety. The way in which an individual recognizes a situation determines their reaction; the recovery of a past experience is essential to manage the present one. According to the familiarity bias, the anxious subject can recognize the arousing stimuli with accuracy but exhibits difficulty in discriminating whether the item is pleasant or potentially dangerous. In addition, anxious individuals cannot recover contextual information that helps them resolve this conflict. In this regard, the process described could be a symptom as well as a factor that perpetuates the anxiety disordersAgencia Nacional de Investigación e Innovació

Analyse de gazouillis en ligne

National audienceLes tweets échangés sur Internet constituent une source d'information importante même si leurs caractéristiques les rendent difficiles à analyser (140 caractères au maximum, notations abrégées, . . .). Dans cet article, nous définissons un modèle d'entrepôt de données permettant de valoriser et d'analyser de gros volumes de tweets en proposant des mesures pertinentes dans un contexte de découverte de connaissances. L'utilisation des entrepôts de données comme outil de stockage et d'analyse de documents textuels n'est pas nouvelle mais les mesures ne sont pas adaptées aux spécificités des données manipulées. Les résultats des expérimentations sur des données réelles soulignent la pertinence de notre proposition. / Exchanged tweets on the Internet are an important information source, even if their characteristics make them difficult to analyze (a maximum of 140 characters, shorthand notations, ...). In this paper, we define a model of data warehouse to develop and analyze large volumes of tweets by proposing relevant measures in a knowledge discovery context. Using data warehouses in order to store and analyze textual documents is not new. Traditionally they adapt classical measures which are not really adapted to the data specificities. Furthermore we propose that, if a hierarchy is available, we can automatically detect the context. Conducted experiments on real data show the relevance of our approach

Towards an On-Line Analysis of Tweets Processing

International audienceTweets exchanged over the Internet represent an important source of information, even if their characteristics make them dicult to analyze (a maximum of 140 characters, etc.). In this paper, we define a data warehouse model to analyze large volumes of tweets by proposing measures relevant in the context of knowledge discovery. The use of data warehouses as a tool for the storage and analysis of textual documents is not new but current measures are not well-suited to the specificities of the manipulated data. We also propose a new way for extracting the context of a concept in a hierarchy. Experiments carried out on real data underline the relevance of our proposal

Programa de prevención de caídas en el hogar dirigido a personas mayores desde terapia ocupacional

Una de cada tres personas mayores de 65 años se cae al menos una vez a lo largo del año, la mayor parte de ellos en el interior del hogar. Desencadena consecuencias como las fracturas, los traumatismos craneoencefálicos o el síndrome post-caídas, suponiendo así una pérdida de autonomía y, por tanto, una disminución de la calidad de vida de la persona.Por lo que con el presente trabajo se ha elaborado un programa a partir del cual se pretende la prevención de este hecho desde el punto de vista de la Terapia Ocupacional en los habitantes de la localidad de Escucha (Teruel).Para ello, se tiene como referencia al marco de trabajo para la práctica de Terapia Ocupacional, Modelo de Ocupación Humana, modelo cognitivo y modelo cinesiológico-biomecánico. Además, se evalúa la situación de los participantes gracias a un cuestionario de elaboración propia y una escala estandarizada conocida como FES-I para poder dar comienzo al programa.Este se realiza a lo largo de un mes, de manera intensiva, donde se abarca las posibles modificaciones en el hogar, actividades de estimulación cognitiva y ejercicio físico y pautas para saber qué hacer cuando la caída ha ocurrido.Al finalizarlo, se obtiene como resultado que solamente una persona se ha caído durante su desarrollo. Por tanto, con el programa se ve el gran interés por los participantes para la prevención de las caídas tanto extrínsecas como intrínsecas al hogar, tomando conciencia de ello.<br /

Prospołeczność inspirowana charyzmatem jedności Chiary Lubich. Przykład wykorzystania w przedszkolu

This article presents two distinct parts. The first tries to answer the questions: How do spiritual or religious intuitions apply in life? Or, better, how do certain evangelical passages come to pass when they pass through a structuring of a system of thought? What application characteristics can a certain charism have when analysed and experimentally applied from a scientific perspective and methodology? In this first part, we present a biographical and professional journey of an academic group that started from a concern and experience of a person, the first author, for about 38 years. This group was trying to develop a theoretical-application model initially originated in the educational field and currently active in various areas of human activity, responding to the spiritual charism of a contemporary woman recognised by an institution as universal by the church. The second part shows one of the last experiences of these applications in the educational field. This experience occurs specifically in the infantile age, which is a crucial stage to mark positive tracks in the development of the personality, as well as positive patterns for the later interpersonal and social relations that employ prosociality and cooperation with a very experimental methodology.Artykuł składa się z dwóch części. W pierwszej podjęto próbę odpowiedzi na pytania: w jaki sposób duchowe lub religijne intuicje znajdują zastosowanie w życiu? Lub bardziej: co staje się z konkretnymi fragmentami ewangelicznymi, gdy przechodzą przez strukturę systemu myślenia? Jakie charakterystyczne cechy może uzyskać określony charyzmat, gdy analizuje się go i eksperymentalnie wprowadza w życie z naukowej perspektywy i metodologii? W pierwszej części przedstawiamy biograficzną i zawodową podróż grupy akademickiej, która rozpoczęła się od troski i doświadczenia osoby, pierwszego autora, około 38 lat wcześniej. Grupa ta starała się opracować model teoretyczno-aplikacyjny, początkowo osadzony w dziedzinie edukacji, a obecnie wprowadzany w różnych obszarach ludzkiej aktywności, odpowiadając na duchowy charyzmat współczesnej kobiety uznany za uniwersalny przez Kościół. Druga część prezentuje jedno z ostatnich doświadczeń owych aplikacji w dziedzinę edukacji. To doświadczenie odnosi się do wieku niemowlęcego, który jest kluczowym momentem w kształtowaniu pozytywnych rysów w rozwoju osobowości, jak również w budowaniu pozytywnych wzorców dla późniejszych relacji interpersonalnych i społecznych, łącząc prospołeczność i współpracę z bardzo eksperymentalną metodologią

The effect of word prediction settings (frequency of use) on text input speed in persons with cervical spinal cord injury: a prospective study

International audiencePurpose: To determine whether activation of the frequency of use and automatic learning parameters ofword prediction software has an impact on text input speed.Methods: Forty-five participants with cervical spinal cord injury between C4 and C8 Asia A or B acceptedto participate to this study. Participants were separated in two groups: a high lesion group for participantswith lesion level is at or above C5 Asia AIS A or B and a low lesion group for participants with lesion isbetween C6 and C8 Asia AIS A or B. A single evaluation session was carried out for each participant. Textinput speed was evaluated during three copying tasks:- without word prediction software (WITHOUT condition)- with automatic learning of words and frequency of use deactivated (NOT_ACTIV condition)- with automatic learning of words and frequency of use activated (ACTIV condition)Results: Text input speed was significantly higher in the WITHOUT than the NOT_ACTIV (p<0.001) orACTIV conditions (p¼0.02) for participants with low lesions. Text input speed was significantly higher inthe ACTIV than in the NOT_ACTIV (p¼0.002) or WITHOUT (p<0.001) conditions for participants with highlesions.Conclusions: Use of word prediction software with the activation of frequency of use and automatic learningincreased text input speed in participants with high-level tetraplegia. For participants with low-leveltetraplegia, the use of word prediction software with frequency of use and automatic learning activatedonly decreased the number of errors