Despite 35 years of clinical trials, there has been little improvement in one-year survival rates with any chemotherapeutic regimen for the treatment of metastatic melanoma due to resistance to all known agents. Regardless of advances in detection and prevention, diagnosis of metastatic disease remains a death sentence. Resistance mechanisms, including aberrant kinase signaling and drug transport pumps, indicate a need for identification of other therapeutic targets that impinge upon multiple signaling pathways. The Abl family of non-receptor tyrosine kinases (c-Abl, Arg) has been indicted as a causative force in leukemia for more than three decades; however, their role in solid tumors has only recently been described. We first demonstrated that activated Abl family kinases promote breast cancer development and progression, and recently identified them to be novel therapeutic targets in metastatic melanoma cells by demonstrating that they promote proliferation, survival, invasion, and metastasis. We now present evidence that inhibitors of Abl family kinases abrogate resistance to a number of commonly used chemotherapeutics (i.e., 5-fluorouracil, cisplatin, paclitaxel, camptothecin) in a panel of breast cancer cells. We proceed to show that inhibitors of Abl family kinases, likewise, sensitize both breast cancer and melanoma cells to doxorubicin by blocking cell proliferation and dramatically inducing apoptosis. These findings were extended to advanced multi-drug resistant melanoma cells, in which we show for the first time that c- Abl promotes expression of the drug transporter, ABCB1, during acquired resistance, and drugs that inhibit c-Abl/Arg prevent ABCB1 expression and function. Moreover, c-Abl/Arg also promote acquired chemoresistance independent of ABCB1 by modulating multiple survival pathways. We demonstrate that c-Abl/Arg promote chemoresistance by upregulating STAT3, preventing doxorubicin-mediated conversion of NF-κB into a transcriptional repressor, activating an HSP27/p38/Akt survival pathway, and modulating ERK signaling. Therefore, c-Abl/Arg promote chemoresistance in highly resistant melanoma cells by impinging on drug transporter and cell survival pathways. Taken together, these data indicate that c-Abl/Arg inhibitors are likely to reverse acquired resistance in metastatic melanomas harboring activated c-Abl/Arg, and thus, may be effective in a combination regimen.

Thèse diffusée initialement dans le cadre d'un projet pilote des Presses de l'Université de Montréal/Centre d'édition numérique UdeM (1997-2008) avec l'autorisation de l'auteur.

Made available in DSpace on 2016-04-28T19:34:00Z (GMT). No. of bitstreams: 1 Sandra Coimbra da Silva Tavares.pdf: 5264968 bytes, checksum: 763385db1dc379dd6f52a6f5ef94af7b (MD5) Previous issue date: 2015-09-16 / The research is inserted on the text and discourse search field of the oral and written genre. The main objective is to identify the passions of the lecturer (student) uses to compose his opinion article and also identify and examinate how develops the construction the nearly logics arguments during the adolescence period. For this result, has been analyzed school writings (opinion articles) made by nineteen students, among boys and girls, with ages between sixteen and seventeen years old, from the second year of a public state high school, not in downtown area, located in Taboão da Serra SP. The methodology used to develop this research is the rhetorical analysis of eight opinion articles and passion identifying of the current arguments in another eleven of them. The theoretical base for this analysis is focused on Aristóteles studies (2013) about passions and from Perelman & Olbrechts-Tyteca (2014) about arguments. The results acquired by analyzing school writings, appoint the need of a new sight upon to the adjustments made on the text produced by those students, with the purpose of teachers and students notice the argumentative route chosen, and through this way, will have productions better argued over, structured and grounded, essential characteristics to the opinion article within of the referred age and class / Essa pesquisa insere-se na linha de pesquisa Texto e discurso nas modalidades oral e escrita. O objetivo é identificar as paixões que o orador (aluno) movimenta ao redigir seu artigo de opinião e, também, identificar e examinar como desenvolve a construção dos argumentos quase-lógicos na adolescência. Para tal, analisam-se redações (artigos de opinião) elaboradas por dezenove alunos, entre rapazes e moças, com idades que variam entre dezesseis e dezessete anos, do segundo ano do Ensino Médio, de uma escola estadual da periferia da cidade de Taboão da Serra - SP. A metodologia utilizada para desenvolver essa pesquisa é a análise retórica oito artigos de opinião e identificação das paixões e dos argumentos recorrentes em outros onze. A base teórica para a análise centra-se nos estudos de Aristóteles (2013) sobre as paixões e de Perelman & Olbrechts-Tyteca (2014) sobre os argumentos. Os resultados obtidos na análise das redações apontam para a necessidade de um novo olhar para as correções dos textos produzidos pelos alunos, a fim de que alunos e professores observem o percurso argumentativo escolhido e, dessa maneira, garantam uma produção melhor argumentada, estruturada e fundamentada, características fundamentais ao artigo de opinião dentro da referida idade e série

Thèse diffusée initialement dans le cadre d'un projet pilote des Presses de l'Université de Montréal/Centre d'édition numérique UdeM (1997-2008) avec l'autorisation de l'auteur.

Educational simulations can help mitigate the natural gap between traditional education styles and the current professional world. Researchers at BYU have developed an educational simulation solution called Playable Case Studies (PCSs). PCSs are simulations that expose the user to real world scenarios and problems within a pre-built environment. With rising demand and use of these educational simulations, there is a need for easy and inexpensive ways to develop these simulations or Playable Case Studies (PCSs). We propose a content management system (CMS) that is tied to a system that utilizes dynamic modules that make up these simulations. We present a basic design and identify core functionality of the system. We include our results from utilizing this system and what future developments can enable the goal of easy and inexpensive development of PCSs. In this study, we identify the design features needed for an easy to use, efficient content management system for educational playable case studies. We began by identifying both pain points in our old system and the features that would address these issues. We then designed and built a new system that included these features. In the testing of this new system, we primarily looked at the ease of building a new PCS with minimal technical knowledge. Although this project was a success overall, there are still points of failure due to the direct manipulation of JSON by content creators (who were not all developers), among other minor issues that need correcting. Overall, we found that our design was effective in providing an efficient platform for creating and maintaining PCSs.

TINAG, which stands for This is Not a Game, can be defined as "the concept that there are pervasive games, often ARGs, that are designed to immerse players in such a way that they suspend their disbelief in a fictional narrative and act like the world they have entered is real during their play time" (Pohjola 2004). Many designers and educators want to create games that appear real, but they are unsure of how to accomplish this. Increasing TINAG allows designers to create more realistic games while taking advantage of the many benefits that TINAG experiences offer. The purpose of this research was to identify and validate design patterns that enhance TINAG. As part of this research, design patterns to increase TINAG in ARG and PCS games were identified and presented. After defining the design patterns, workshops were completed to validate the design patterns and their usefulness to designers. We were able to verify that both novice and more experienced designers are able to understand the design patterns and apply them, with a few exceptions. We found that the design patterns were helpful tools, especially when used in group settings. All of the design patterns could be used and applied to a PCS and the designers felt like they would be impactful. This suggests that they are applicable to non ARG contexts, even though they were generated primarily from PCSs. Participants were drawn to design patterns that help create more authenticity and give players tools to succeed because they agreed that TINAG can increase transfer of learning into real context (Balzotti & Hansen, 2019). We imagine these design patterns could be used to help designers of ARGs, educational simulations, or escape rooms, or other experienced that have the goal of feeling real or authentic.

Detta arbete har studerat vilka egenskaper i en gångstil som var viktiga för att förmedla ilska. Egenskaperna hög hastighet, framåtlutande överkropp och knutna händer utvärderades för att se hur viktiga de var för känslouttrycket. Resultaten pekade på att hastigheten och händerna inte hade en påtaglig effekt på hur ilskeuttrycket uppfattades. Däremot hade egenskapen framåtlutande överkropp en betydlig skillnad i hur ilska uppfattades i en gångstil. När karaktären hade rak rygg var det betydligt färre deltagare som tyckte att animationen uppfattades som arg. Studien lämnar även utrymme för ytterligare forskning där man exempelvis utvärderar ytterligare ilskeuttryck och effekten av uttrycken i kombination.

Online fandoms are capable of various feats; from influencing the TV shows they watch to funding half-baked convention scams, Tumblr fandoms in particular are infamous across the internet. Their chaotic and intense nature simultaneously leads to intense bouts of creative activity, pumping hundreds of thousands of fan works into the Tumblr ecosystem every year. In November of 2022, the Tumblr community collectively invented a fake Martin Scorsese movie named Goncharov, creating massing amounts of fanart, fanfiction, memes, and posts for a “lost piece of media” that never actually existed. While existing studies have focused on the construction of identity through Tumblr fan communities, or the experiences of LGBTQ social media users on Tumblr, there is little to no research on individual fandom events that affect Tumblr as an entire community. In turn, this study aims to answer the following questions: 1) “How did Goncharov fans collaboratively tell and maintain a cohesive story through the production of transmedia Tumblr posts?” 296 transmedia posts produced by the Goncharov fandom were analyzed by a framework developed around an adapted approach to Critical Discourse Analysis (CDA). Additional theories were incorporated into later analysis, including discussion of transmedial storyworlds, narrative transportation, and collaborative storytelling. The results suggested that the Goncharov fandom was more committed to providing context about its invented nature, rather than committing to a strong sense of immersion. Furthermore, its posts resulted in cases of accidental narrative transportation while simultaneously lacking character and story consistency.

The main drawback of Alternate Reality Gaming, compared to other genres, is that it lacks reusability; typically it cannot be played freely by anyone, anytime, anywhere. However, with the help of modern technology, especially in the mobile devices section, this can be overcome, at least to a certain extent. Therefore, we propose a conceptual framework built upon these challenges raised by other ARGs, a framework meant for game designers and developers that wish to create reusable ARGs, to add reusability to their own ARGs or even turn their digital games into a mixed experience. We designed it by reviewing relevant literature of past ARGs that had a reusable or a digital component, from which we have drawn conclusions and mixed them with our own ideas. Then we tested it iteratively by developing two prototypes and evaluating them through user feedback.

Pour d'évidentes raisons agronomiques et environnementales, être en mesure de concevoir et mettre en place des systèmes de culture dans lesquels les plantes accèdent aux ressources de manière optimale revêt une importance cruciale pour tous les intervenants impliqués dans la production agricole. Les techniques d'intensification telles que la mise en place de cultures d'inter-rang et l'agro-foresterie visent à accroître la productivité globale des terres tout en assurant la durabilité des agro-écosystèmes, via une optimisation de l'utilisation des ressources environnementales (lumière, eau et nutriments) par les plantes et une préservation des cycles géochimiques. En théorie, les moyens d'atteindre ces objectifs sont nombreux mais en pratique, les interactions souterraines sont complexes et difficiles à mesurer, de sorte que les progrès réalisés dans la conception d'agro-écosystèmes améliorés et durables demeurent modestes. Dans ce contexte, l'objectif de ce travail a été d'évaluer, au travers de mesures racinaires detaillées en rhizotron et au champ, les effets des cultures d'inter-rang sur la croissance des jeunes hévéas. La dynamique des interactions souterraines a été étudiée, tant au niveau de la racine individuelle qu'à celui du système racinaire entier, sur la base, notamment, de descriptions numériques détaillées. Une telle approche a permis de proposer, en outre, une voie novatrice pour l'analyse de la dynamique racinaire à l'echelle du systeme racinaire entier, à savoir l'analyse des trajectoires de croissance. Dans le cas de l'association maïs-hévéa, les expérimentations en rhizotron ont permis de mettre en evidence que les interactions souterraines entre ces deux plantes peuvent induire des modifications de la croissance de leurs racines, à la fois à l'échelle de la racine individuelle et à celle du système racinaire entier. Toutefois, une telle coordination des dynamiques racinaires des plantes associées n'a pas pu être confirmée dans le cas des traitements manioc-hévéa et arachide– hévéa. Les expérimentations au terrain ont fourni, de manière assez prévisible, une image complexe des interactions souterraines entre hévéa et cultures d’inter-rang. Toutefois, un premier résultat obtenu par le biais de la mise en place de 'pièges à racines' dans un traitement niébé-hévéa, a été de montrer que ces deux plantes n'avaient pas un comportement compétitif marqué l'une vis-à-vis de l'autre. Il est également apparu que les hévéas paraissent ‘investir’ dans des racines ‘coûteuses’, car de faible longueur spécifique, probablement pour assurer une certaine durabilité de ces organes, tandis que les cultures d’inter-rang favorisent l'allocation des assimilâts vers des racines de longueur spécifique élevée, de construction moins ‘coûteuses’, probablement en réponse a un impératif de croissance plus rapide (suggéré par les taux d’élongation racinaire mesurés au cours des expérimentations en rhizotron). Enfin, excepté le cas du manioc, l’introduction de cultures d’inter-rang telles que le maïs et l'arachide n'a pas eu d'impact significatif sur le développement des jeunes hévéas, comme en attestent l'évolution de leur circonférence, hauteur et développement foliaire. Ce résultat de terrain est compatible avec les résultats des expérimentations en rhizotron qui n'ont démontré aucun effet inhibiteur des cultures d’inter-rang sur le développement de la partie aérienne des hévéas. Bien que les travaux présentés dans ce rapport, ne permettent pas, à eux seuls de conclure de manière définitive sur la façon dont les espèces cultivées en association peuvent se compléter mutuellement sur le plan fonctionnel, ils apportent des éléments de réponse préliminaires à cette question complexe ainsi que des méthodes permettant de les obtenir. Au total, ce travail représente donc une contribution à la conception des agro-écosystèmes durables qui deviennent de plus en plus indispensables dans le contexte d'une demande mondiale croissante en produits alimentaires et matières premières. En outre, certains des résultats obtenus dans le cadre de cette thèse ouvrent des perspectives pour des recherches plus approfondies, avec une finalité agronomique appliquée / For obvious agronomic and environmental reasons, being able to design and implement agro-ecosystems in which crops have optimal access to resources is of pivotal importance to all stakeholders involved in agricultural production. Intensification techniques such as agro-forestry or the introduction of inter-crops aim to increase land productivity while conserving geochemical cycles, to ensure the sustainability of agro-ecosystems through an optimized use of environmental resources (light, water and nutrients). In theory, there are many ways of achieving such a goal, but in practice, below-ground interactions between plants are complex and difficult to measure, so that progress with the development of sustainable agro-ecosystems has been slow and remains modest. In this context, the objective of this work was to assess the effects of inter-crops on the growth of young rubber trees, based on a detailed analysis of below-ground interactions between the associated plants. The dynamics of below-ground interactions has been studied in rhizoboxes, at both the scale of individual roots and that of the whole root system, using detailed numerical descriptions of root architecture. Such an approach resulted in the design of an innovative method for the analysis of the entire root system dynamics, namely, the analysis of growth trajectories. In the case of the maize-rubber tree association, the experiments in rhizoboxes showed that the below-ground interactions between these two plants can induce changes in root growth, at both the individual root and the whole root system levels. However, such a coordination of rooting patterns could not be confirmed in the case of the cassava-rubber tree and groundnut-rubber tree associations. Not unexpectedly, field experiments provided a rather complex picture of the underground interactions between rubber trees and inter-crops. However, initial results obtained using 'root traps' in a cowpea-rubber tree treatment indicated that these two plants were unlikely to have a marked underground competitive behavior relative to each other. Results of field experiments also indicated that, in general, rubber trees seem to 'invest' in 'expensive roots' of low specific root length, presumably to confer some degree of durability to these organs, while inter-crops favoured the allocation of assimilates to 'cheaper' roots, i.e. roots of much higher specific length, probably in response to a 'fast growth imperative' (an hypothesis supported by the root elongation rate values measured during the rhizobox experiments). Finally, to the possible exception of cassava, inter-crops were found to have no significant impact on the development of young rubber trees, as evidenced by measured changes in tree circumference, height and leaf development. This result is consistent with results from the rhizobox experiments which also showed no inhibitory effect of inter-crops on the above-ground development of rubber trees. Although the work presented in this report does not allow, in itself, to conclude firmly on the issue of the functional complementarity between plants grown in association in inter-cropping systems, they provide preliminary answers to this complex issue together with methods to obtain such answers. Overall, this work therefore represents a contribution to the design of sustainable agro-ecosystems which are becoming increasingly needed in the context of a growing global demand for food and raw materials. In addition, some of the results generated by this work open up prospects for future research for the development of sustainable agro-ecosystems