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.

Protein-Arrays sind das Mittel der Wahl, um eine Vielzahl von Proteinen parallel zu untersuchen. Ziele dieser Untersuchungen sind meistens Proteininteraktionsnetzwerke zu entdecken oder besser verstehen zu können. Bisher wurden die benötigten Proteine fast ausschließlich mit biologischen Methoden gewonnen. Diese bieten allerdings keinen generellen Zugang zu posttranslational-modi-fizierten (PTM)-Proteinen. Somit war es bisher nicht möglich den Einfluss von PTMs auf Protein-Protein-Interaktionen (PPIs) im Arrayformat zu untersuchen. Die chemische Synthese kann dagegen Proteine mit ortsspezifischen PTMs liefern. Daher ist es verwunderlich, dass bislang noch keine Berichte über chemisch hergestellte PTM-Protein-Arrays existieren, besonders da PTMs meist entscheidend für proteomische Interaktionsnetzwerke sind. In der vorliegenden Arbeit wird eine Methodik beschrieben, die es ermöglicht PTM-modifizierte Protein-Domänen-Arrays auf der Oberfläche zu synthetisieren und zu analysieren. Mit der Methodik wurden 20 SH3-Domänen synthetisiert und 64 PPIs gemessen. Neben vier Hefe-SH3-Domänen wurden je acht humane (Phospho)SH3-Domänen der Abl- und Arg(Abl2)-Tyrosinkinase synthetisiert und funktionell untersucht. Es wurde gefunden, dass die Ligandenspezifität von Abl-SH3-Domänen durch Phosphorylierung feinreguliert wird. Je nach Phosphorylierungsmustern wurde die Affinität für spezifische Liganden erhöht oder erniedrigt. Der Ursprung dieser Phosphoregulierung wurde für die Abl-SH3-Domäne mit Hilfe der NMR-Spektroskopie und durch Zellexperimente versucht zu entschlüsseln und weiter validiert. / Protein-arrays are the method of choice to investigate a variety of proteins in a parallel fashion. Objectives of these studies are mostly to discover or to investigate protein interaction networks. So far, the necessary proteins were almost exclusively gained by biological methods. Unfortunately, generic access to proteins bearing post-translational modifications (PTM) is not provided by these techniques. Therefore, it was not possible to investigate the impact of PTMs on protein-protein-interactions (PPIs) on arrays so far. Chemical synthesis in contrast offers proteins with site-specific PTM incorporation. In this context, it is surprising, that chemical methods of PTM-protein array synthesis remained virtually unexplored, especially since these modifications are usually crucial for proteomic interaction networks. In this thesis, a methodology is described, that allows to synthesize and functional analyse post-translationally modified protein domain arrays on the surface. By using this methodology, 20 SH3 domains were synthesized and 64 protein-pep-tide interactions were measured. In addition to 4 yeast SH3 domains, 8 human (phospho) SH3 domains of the Abl and Arg(Abl2) tyrosine kinase were synthesized and functionally investigated. The experiments revealed that phosphorylation might serve as a means to fine tune the ligand recognition. Depending on the phosphorylation pattern the affinity to specific interaction partners were enhanced or reduced. The origin of this phosphoregulation was further investigated for the Abl SH3 domain by means of NMR spectroscopy and cellular experiments.