Les syndromes myélodysplasiques (SMD) sont des hémopathies myéloïdes clonales évoluant vers une leucémie aiguë (LA). Les SMD et LA secondaires, survenant après traitement par chimiothérapie et/ou radiothérapie, ont un pronostic très péjoratif. Cependant seule une partie des sujets exposés aux traitements cytotoxiques développent un SMD secondaire, ce qui suggère une composante génétique dans la susceptibilité individuelle au risque de développer un SMD secondaire. Les objectifs de ce travail ont été d’identifier des polymorphismes génétiques de type SNP (Single Nucleotide Polymorphism) significativement associés à des caractères cliniques et biologiques des SMD tel leur caractère secondaire. Une « puce » à façon a sélectionné 384 SNP de fréquence allélique supérieure à 10 % impliqués dans la réparation de l’ADN, le métabolisme, le transport et la détoxication des xénobiotiques. L’ADN constitutionnel de 65 patients atteints de SMD primaire et secondaire a été recueilli et génotypé pour ces 384 SNP. La seule association significative par test exact de Fisher (p = 0,009 après correction de Benjamini-Hochberg) a été observée pour le caractère secondaire des SMD et la présence de l’allèle variant de MGMT (MéthylGuanine MéthylTransférase) sur deux SNP en déséquilibre de liaison, rs2308321 (Ile143Val) et rs2308327 (Lys178Arg). Nous avons recherché le caractère prédictif de la présence de l’allèle variant de MGMT pour le risque de SMD/LA secondaire chez des patientes ayant reçu un traitement cytotoxique pour un cancer du sein, et ayant développé une LA secondaire. Enfin, nous avons construit des lignées cellulaires stables, isogéniques, exprimant soit la forme sauvage soit la forme variante de MGMT. Les études fonctionnelles par tests de cytotoxicité, co-cultures à long terme et étude des demi-vies des protéines, sous traitement alkylant, montrent respectivement des différences de sensibilité, de prolifération ou de dégradation entre les formes variante et sauvage de MGMT. / Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders evolving toward acute myeloid leukaemia (AML). Therapy-related MDS and AML occur after chemo- and/or radiotherapy for previous cancer and have a very poor outcome. However, only a minimal proportion of patients exposed to anticancer drugs develop secondary MDS, suggesting a genetic component in individual susceptibility. The aim of our study was to identify gene polymorphisms significantly associated with MDS in patients. We have selected 384 SNPs (single nucleotide polymorphisms) with allele frequency >10% in genes involved in DNA repair and drug metabolism and transport. DNA extracts were obtained from blood and cheek samples from a population of 65 MDS patients, and the 384 SNPs were genotyped. We analysed the associations existing between each genotype and several pathological features, especially the treatment-related character of MDS. The Fisher exact test with Benjamini-Hochberg correction for multiple testing was applied for statistical analysis. The only significant association (p = 0.009 after correction) was observed for the treatment-related character of MDS and the presence of a variant allele in MGMT (methylguanine methyltransferase, a gene involved in DNA repair), characterised by two SNPs in complete linkage disequilibrium: rs2308321 (Ile143Val) and rs2308327 (Lys178Arg). An epidemiological study was performed to assess the predictive value of the variant allele in MGMT for the development of secondary acute leukaemia among patients treated for breast cancer. We have constructed isogenic stable cell lines expressing either the wild-type or the variant allele of MGMT. Functional studies (analysis of response to alkylating agents, allele quantification of mixed cultures of wild-type and variant cells and half-lives study of the proteins) show differences in sensitivity to DNA-damaging agents, proliferative capacity and MGMT rate of degradation between the wild-type and the variant MGMT.

Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2018-08-29T20:27:02Z No. of bitstreams: 1 2015 - Claudia Cseko Nolasco de Carvalho.pdf: 7996736 bytes, checksum: 4342b7f850b677568441806a801d9047 (MD5) / Made available in DSpace on 2018-08-29T20:27:02Z (GMT). No. of bitstreams: 1 2015 - Claudia Cseko Nolasco de Carvalho.pdf: 7996736 bytes, checksum: 4342b7f850b677568441806a801d9047 (MD5) Previous issue date: 2015-05-27 / Sustainable development requires more detailed soil maps with representative information of local reality, helping to conciliate increasing agriculture production and environmental impacts reduction. It is a hard task to achieve considering the Brazil territorial extension and the absence of governmental programs and resources. The Digital Soil Mapping (DSM), through methodologies implementation, has been consolidated as support technique for conventional mapping. Using DSM techniques, we aimed to evaluate a methodological procedure to generate soil maps with refined scale by fuzzy inference, and to map simpler units, which means more adequate areas for the rural settlement development plans. We carried out the study on an area at the microregion of Mata of Alagoas State and the following attributes were integrated by pedologist knowledge: elevation, slope, curvature and profile, topographic wetness index ? derived from a Digital Elevation Model (built by aerophotogrammetric restitution at scale 1:8 000), and geological data at scale 1:50 000. In a first moment, we integrate the thematic layers of 5m resolution pixel related to the attributes. Possibility maps of predefined classes were generate based on rules established by pedological expertise using fuzzy inference. Then, we integrate the evidence maps of classes by weighted mean inference to produce the soils digital map. The predicted digital soil map was opposed to a map elaborated traditionally, and validated by field observation of transects and pre-existent profiles. The comparison between the digital soil map and the conventional indicated a accuracy of 81.2% between the predicted classes of the digital map and the ones on the conventional map units (described on the legend, however not spatialized). Confronting the predicted classes of the digital soil map and the ones identified on field, the observed accuracy was of 74.65%. The Kappa index found was very good, with 0.696 values for the comparison between the digital map and the conventional map and 0.705 between the digital map and field observations. The results demonstrate that legacy maps data may, through the pedologists knowledge and more detailed attribute data, aggregate information and produce more detailed soil maps. Considering the concepts of minimum mappable area, the definitions of pixel sizes suggested for the digital cartographic scale, and the rules for soil survey, the applied methodology allowed, on the used cartographic base, the amplification of the mapping scale from 1:25 000 to 1:15 000. / O desenvolvimento sustent?vel requer mapas de solo mais detalhados com informa??es representativas da realidade local que permitem conciliar aumento da produ??o agropecu?ria com minimiza??o de impactos ambientais. Essa ? uma tarefa dif?cil considerando a extens?o territorial do Brasil e a falta de programas e recursos governamentais. O Mapeamento Digital de Solos-MDS, atrav?s da implementa??o de metodologias, vem se consolidando como t?cnica de apoio ao mapeamento convencional. Usando t?cnicas de MDS, esse trabalho objetivou avaliar um procedimento metodol?gico para gerar mapa de solos com refinamento de escala usando infer?ncia fuzzy para mapear unidades mais simples, portanto mais adequadas aos planos de desenvolvimento dos assentamentos rurais. A ?rea escolhida para teste est? localizada na microrregi?o da Mata do Estado de Alagoas. Para execu??o do trabalho os atributos do terreno eleva??o, declividade, curvatura em perfil, plano de curvatura e ?ndice de umidade topogr?fica derivados de Modelo Digital de Eleva??o-MDE (gerado por restitui??o aerofotogram?trica na escala 1:8.000) e dados geol?gicos em escala 1:50:000, foram integrados atrav?s do conhecimento de ped?logos. Os planos de informa??es, com pixel de 5 m, a partir de regras estabelecidas pela expertise de ped?logos foram fuzzificados e integrados para gerar os mapas de possibilidades de ocorr?ncia para as classes de solo predefinidas. O mapa digital de solos foi produzido pela integra??o dos mapas de possibilidades das classes por infer?ncia m?dia ponderada. O mapa digital de solos predito foi confrontado com mapa elaborado por m?todo tradicional e validado por observa??es em campo ao longo de transectos e por perfis preexistentes. A an?lise comparativa entre o mapa digital de solos e o convencional obteve acur?cia de 81,2 % entre as classes preditas no mapa digital e as contidas nas unidades do mapa convencional (descritas na legenda, por?m n?o espacializadas). Confrontando as classes preditas no mapa digital e as identificadas no campo a acur?cia encontrada foi de 74,65%. A aferi??o das classes pelo ?ndice de Kappa foi considerada muito boa com valores de 0,696 para a compara??o entre o mapa digital versos mapa convencional e 0,705 entre o mapa digital e as observa??es de campo. A pesquisa mostrou que dados contidos em mapas legados de solo podem atrav?s do conhecimento de ped?logos e de dados detalhados de atributos do terreno agregar informa??es e produzir mapa digital de solo com amplia??o da escala e que neste trabalho ? compat?vel com a de levantamentos detalhados (1:15.000).

Cette étude vise à relier les évaluations physiques et perceptives de différences de restitution du timbre par des enceintes acoustiques. Notre protocole expérimental consiste à enregistrer le champ acoustique rayonné par des enceintes dans une pièce. Ces enregistrements sont soumis à des tests d'écoute au casque, ainsi qu'à des analyses de signal. Les dissemblances objectives et perceptives obtenues sont comparées. La corrélation entre dissemblances est d'abord calculée. Nous abandonnons ensuite le critère de linéarité et prenons en compte le caractère multidimensionnel de notre perception de la reproduction sonore : les deux types de dissemblances sont soumis à une analyse multidimensionnelle, et les espaces obtenus sont comparés visuellement. Nos résultats montrent l'importance d'utiliser des modèles auditifs afin de différencier les signaux d'une manière analogue à celle des auditeurs. Des attributs objectifs décrivant deux des dimensions principales impliquées sont proposés.

<p>Hematopoiesis is the continual process of blood cell generation that primarily occurs in the bone marrow of adult animals. Hematologic neoplasms can also occur in the bone marrow and often result from dysregulation of signal transduction pathways. One example is the activation of the Ras oncogene, which has been linked to a variety of different cancers, including hematologic neoplasms. Ras is located proximal to the cell membrane and can activate many downstream effector pathways, thus it is difficult to determine which downstream pathway is mediating oncogenic Ras function. My thesis work focused on the effect of inappropriate activation of MEK/ERK, a downstream Ras effector pathway, in the hematopoietic system.</p><p>Using a retroviral transduction system, we expressed a constitutively active form of MEK1 in hematopoietic stem cells (HSCs). Mice transplanted with HSCs expressing active MEK developed a lethal myelodysplastic syndrome/myeloproliferative disease (MDS/MPN) characterized by the expansion of granulocytes/macrophages (GM) at the expense of lymphoid cell development. Transplantation of active MEK-induced MDS/MPNs into naïve mice did not result in further disease, suggesting that the MDS/MPN is not a frank leukemia.</p><p>Bcl-2 is an anti-apoptotic molecule that has been shown to play a role in leukemia development and maintenance. Coupling expression of active MEK and Bcl-2 resulted in MDS/MPNs that were phenotypically identical and had very similar disease onset compared to active MEK-induced MDS/MPNs. However, transplantation of Bcl-2/active MEK-induced MDS/MPNs did not result in a myeloid disease; rather, it resulted in the development of T-acute lymphoblastic leukemia (T-ALL) that was marked by activated Notch signaling. </p><p>These results led us to conclude that activation of MEK/ERK was sufficient to cause a pre-leukemic myeloid disease; however, additional oncogenic factors, such as Bcl-2 and Notch, were necessary for frank leukemia development. Moreover, additional oncogenic factors can alter the disease phenotype and disease course. Future analysis of the interplay between oncogenic factors will help shed light on disease development and aid in the development of more effective cancer treatments.</p> / Dissertation

Στόχος της παρούσης διπλωματικής εργασίας είναι η διερεύνηση καταλληλότητας της μεθόδου πολυδιάστατης σταδιακής ανάλυσης για την αξιολόγηση σχεδιασμού ιστοσελίδων. Για την επίτευξη του στόχου, αναπτύχθηκε διαδικτυακή εφαρμογή αξιολόγησης με χρήση μεθόδων πολυδιάστατης σταδιακής ανάλυσης και αξιολογήθηκε τόσο η μέθοδος όσο και η εφαρμογή ως προς την χρησιμότητα της στο πλαίσιο που μας ενδιαφέρει, δηλαδή την αξιολόγηση σχεδιασμού ιστοσελίδων. Η εφαρμογή εκμεταλλεύεται τα πλεονεκτήματα των ιστοσελίδων πλούσιας διαδραστικότητας για την πλήρη υποστήριξη της διαδικασίας αξιολόγησης. / -

Τα μυελοδυσπλαστικά σύνδρομα (ΜΔΣ) χαρακτηρίζονται από μη αποδοτική αιμοποίηση, αναστολή ωρίμανσης των προγονικών κυττάρων του μυελού και αυξημένη ενδομυελική απόπτωση. Η συσχέτιση του ΜΔΣ με την παρουσία αυξημένου οξειδωτικού στρες και οξειδωτικά τροποποιημένων πρωτεϊνών στα προγονικά αιμοποιητικά κύτταρα του μυελού έχει προηγουμένως αναφερθεί. Πρόσφατα βιβλιογραφικά δεδομένα δηλώνουν τη δυνατότητα διάκρισης δύο υποπληθυσμών της μυελικής σειράς βάσει σκεδαστικών χαρακτηριστικών και της έκφρασης του CD45, CD45dim (Neutrophil granulocytic subpopulation-1, NGS1) και CD45high (Neutrophil granulocytic subpopulation-2, NGS2). Ο υποπληθυσμός CD45dim φέρει άωρα κύτταρα, που στην πλειοψηφία τους δεν ωριμάζουν έως τελικού σταδίου[1]. Ο πλήρης χαρακτηρισμός των πληθυσμών αυτών, καθώς επίσης, και η συμμετοχή τους στη μη αποδοτική αιμοποίηση των ΜΔΣ και στην εξέλιξη της νόσου είναι στοιχεία άγνωστα. Σκοπός της παρούσης εργασίας ήταν η διερεύνηση δεικτών απόπτωσης και οξειδωτικού φορτίου (ελεύθερες ρίζες οξυγόνου-ROS) στους υποπληθυσμούς της μυελικής σειράς CD45dim και CD45high. Μελετήθηκαν 17 δείγματα μυελού ασθενών με ΜΔΣ μετά από ανάλυση συνδυασμού 5 χρωμάτων με κυτταρομετρία ροής, για τους δείκτες CD11b/CD16, annexin-V/7-AAD και 2,7-dichlorodihydrofluo-rescein-diacetate(DCF). Η στατιστική ανάλυση των αποτελεσμάτων πραγματοποιήθηκε με τη χρήση του κατάλληλου προγράμματος με μη παραμετρικά κριτήρια (Wilcoxon & Mann-Whitney). Το ποσοστό των αποπτωτικών 7-AAD/annexin-V+ κυττάρων ήταν σημαντικά αυξημένο στα CD45high/ CD11b+/CD16+ της μυελικής σειράς συγκριτικά με τα CD45dim/CD11b+/CD16- κύτταρα. Τα CD45dim και CD45high κύτταρα μυελού με τη χρήση του ειδικού ανιχνευτή των επιπέδων των ελεύθερων ριζών οξυγόνου DCF αναλύθηκαν σε ROSLow και ROSHigh πληθυσμούς. Η ανάλυση με τη χρήση των παραπάνω κριτηρίων έδειξε σημαντική αύξηση του ποσοστού των ROSHigh κυττάρων στα CD45high κύτταρα, συμπεραίνοντας έτσι ότι ο υποπληθυσμός CD45dim έχει χαμηλότερα επίπεδα ενδοκυττάριων ROS εν συγκρίσει με τον CD45high υποπληθυσμό. Ο CD45high υποπληθυσμός της μυελικής σειράς χαρακτηρίζεται από μεγαλύτερα ποσοστά έκφρασης αποπτωτικών δεικτών καθώς επίσης και από τη παρουσία αυξημένου οξειδωτικού φορτίου συγκριτικά με τα CD45dim κύτταρα. Η περεταίρω διερεύνηση του ρόλου των πληθυσμών αυτών στις διαδικασίες ανάπτυξης του ΜΔΣ και στην εξέλιξη της νόσου είναι υπό εξέλιξη. / --

Nowadays people got used to short text answers, likes and shares. Anyone can feel it by entering popular forums or social networks. Modern platforms such as Twitter or Facebook contribute to this situation with their symbols per message limitations. The quality of content produced in such conditions is not high. According to Knight and Burn (2005): “The rapid growth of the Internet and the lack of enforceable standards regarding the information it contains has led to numerous information quality problems.” The possible solution to this problem is called mobile digital storytelling. It replaces traditional communication mechanisms (text, photos) with a digital narrative, thus making a stronger impact on user. Besides, it allows creating interesting content at any location with the help of mobile phone. However, it is hard to make a high quality story from scratch without prior experience. Viewing through previously created high quality content provides such experience. At the same time, reusing this content would allow creating story by combining and rearranging instead of producing from scratch. But state of the art mobile digital storytelling applications don’t provide any possibilities for content reuse. In addition, the influence of content reuse on the story creation process was not studied. Hence, in this work the researcher will explore and try to develop alternative ways to support content reuse in mobile digital storytelling (mDS). For this purpose a mechanism called RecSM (a recommendation system using content from Social Media) is introduced. The main goal of development is to create RecSM for mobile digital storytelling application. The influence of RecSM on mobile content reuse as well as the influence of reuse on storytelling process is the main study goals. The thesis is based on research conducted in Linnaeus University, Sweden. The research is divided into two main parts: gathering requirements for RecSM and the case study. 10 users are involved in both activities. Initial requirements for RecSM are defined after conducting research in the topic but final requirements are determined with the help of users. Based on them the RecSM is developed and added to a mobile digital storytelling application. A case study in Teleborg Castle (Vaxjo, Sweden) follows afterwards. Participants create stories about their castle experience with the help of mDS or mDS-RecSM application. The data for further research is retrieved through field notes, personal interviews and a survey. Then stories and answers of people that used mDS with and without recommender are compared and analyzed. Based on the study outcomes it is concluded that developed RecSM supports content reuse in mobile digital storytelling.

Myelodysplastic Syndrome (MDS) with del(5q) represents a unique WHO entity, which is often treated with lenalidomide according to standard clinical practice. Guidelines concerning treatment duration have thus far not been implemented, but rather comprise an indefinite therapy until loss of response. This review presents three red blood cell (RBC) transfusion-dependent MDS with del(5q) cases, starting with one rare case with an unbalanced translocation t(2;5), involving the breakpoint of del(5q) and loss of the 5q15-5q31 region. To the best of our knowledge, no comparable case has been described before with a response to lenalidomide. Strikingly, treatment-induced and maintained cytogenetic complete remission (cCR) in this patient. Furthermore, we report two cases of classical del(5q), in which lenalidomide was interrupted after a short period of lenalidomide therapy at the time cCR was achieved. Despite drug holiday cCR was maintained for seven and nine years, respectively. Then del(5q) re-emerged in the absence of novel molecular aberrations and re-treatment with lenalidomide could again achieve cCR in both cases. Together, this series presents three cases of personalized therapy of MDS with del(5q)

This research explores how substances of very high concern (SVHC) are tracked today. Tracking the material content of products has grown increasingly important in the last decade. Material tracking is critical for the construction equipment machine builder (OEM) which is used to analyze if materials are clean from the dangerous substance, for example lead. It is important for all businesses to know whether their products are clean. As a result, most factories and businesses require a filter to distinguish between clean and hazardous chemicals. The goal of this research is to design a solution that will track the harmful substance content in products and investigate those that contain SVHC. To accomplish this, there was an evaluation of how the tracking is done today and thereafter the two methods, blockchain and centralized database were compared. A solution based on blockchain technology which will prevent companies from lying about the possession of products that contain SVHC by tracking them was then created based on the results. This thesis conducts qualitative research, which means it was based on qualitative data. The data was gathered using a mix of two types of research methods: semi-structured interviews and theoretical research. Based on the results of the comparison, a blockchain technology solution was devised to facilitate the tracking and to reduce cheating with SVHC. The proposed solution has been implemented in form of a cryptocurrency using the blockchain technology. In conclusion the result of this study was that the problems with the current method were clarified and a blockchain-based solution for tracking SVHC was designed.

Parkinson's disease (PD) is a neurodegenerative disease that affects motor abilities with increasing severity as the disease progresses. Traditional methods for diagnosing PD require specialists scoring qualitative symptoms using the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS-III). Using force-plate data during quiet standing (QS), this study uses machine learning to target the characterization and prediction of PD and UPDRS-III. The purpose of predicting different subscores of the UPDRS-III is to give specialists more tools to help make an informed diagnosis and prognosis. The classification models employed classified PD with a sensitivity of 87.5% and specificity of 83.1%. Stepwise forward regression indicated that features correlated with base of support were most useful in the prediction of head rigidity (r-square = .753). Although there is limited data, this thesis can be used as an exploratory study that evaluates the predictability of UPDRS-III subscores using QS data. Similar prediction models can be implemented to a home setting using low-cost force plates as a novel telemedicine technique to track disease progression.