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.

The Covid-19 pandemic heightened attention to airborne microorganisms and their widespread impacts. This dissertation examines two facets about airborne microorganisms: (1) dissemination of antimicrobial resistance in the environment and (2) ionization for disinfection of indoor air. Antimicrobial resistance (AMR) poses a significant threat to public health, exacerbated by the dissemination of antibiotic resistance genes (ARGs) in the atmosphere to an extent that is not yet well understood. Chapters 2 and 3 of this dissertation characterize ARGs in the atmosphere through a literature review and experimental observations at two agricultural sites, respectively. A critical review of 52 studies revealed that ARGs are present in aerosols in urban, rural, hospital, industrial, wastewater treatment plants, composting and landfill sites, and indoor environments. Commonly studied genes include sul1, intI1, beta-lactam ARGs, and tetracycline ARGs, with abundances varying by season and setting. Temporal trends varied based on the type of environment and human activity. Characterization methods included qPCR, ddPCR, and metagenomic analysis; standardized methodologies are needed to unify findings about the dissemination of ARGs in the atmosphere. To address knowledge gaps identified in the literature review, we designed an experimental study at a dairy farm and swine farm, where beta-lactam was the dominant antibiotic used. We quantified ARG concentrations, size distributions, and emission rates in the air and related these to ARGs found in nearby water and soil samples over four seasons. Concentrations of most ARGs were higher during warmer months but varied more by sampling location or exhaust fan usage than time of year. At both farms, blaCTX-M1 concentrations peaked at 104 gene copies per cubic meter (gc m-3), while the exhaust from a building at the swine farm contained genes like intI1, ermF, and qnrA at concentrations up to 105 gc m-3. ARGs were found in aerosol particles of all sizes, and the fraction in coarse particles (>5 m) was enhanced near emission sources. The presence of ARGs in fine (<1 m) and accumulation mode (1-5 m) particles indicates potential for long-range transport. Emission rates reached ~105 gc s-1 for some ARGs, including blaCTX-M1, and 106 gc s-1 for intI1. Inhalation exposure to blaCTX-M1 was comparable to ingestion exposure from soil at the dairy farm. In chapter 4, the effectiveness of an in-duct, bipolar ionization system for reducing airborne pathogens was evaluated in a real-world setting: an in-use lecture hall at a university. There were no significant differences in positive, in-room ion concentrations between periods with the ionizer turned on and turned off; however, negative, in-room ion concentrations were significantly lower when the ionizer was on with constant fan speed. To account for day-to-day variability in total bacteria concentrations, related to occupancy and other factors, we examined the ratio of bacterial colony forming units to 16S rRNA gene copies (CFU gc–1). There were no significant differences in this ratio whether the ionizer was on or off, suggesting limited real-world effectiveness of the treatment technology. Factors such as occupancy and the heating, ventilation, and air conditioning (HVAC) system emerged as the primary drivers of bacterial load in the air. This study highlights the need for further research to validate the potential of ionization to reduce levels of airborne pathogens. / Doctor of Philosophy / The COVID-19 pandemic brought greater awareness of microorganisms in the air and their effects on our health. This dissertation explores two main topics: how antimicrobial resistance spreads in the environment and disinfection of indoor air. Antimicrobial resistance (AMR) is a major public health issue, worsened by the spread of antibiotic resistance genes (ARGs) in the environment. We lack complete understanding of how these genes spread through the air in different places. Chapters 2 and 3 of this dissertation examine ARGs in the air through a literature review and experimental observations at two different farm sites. A review of 52 studies revealed that ARGs are present in the air in urban, rural, hospital, industrial, wastewater treatment plants, composting and landfill sites, and indoor environments. Certain genes were studied more frequently, particularly those associated with antibiotics that have been used for many years, such as penicillin. The concentrations of ARGs in the air varied by season and setting. The genes were detected using three standard biological tests: qPCR, ddPCR, and metagenomic analysis. Standardized methods are needed to gain more information about these genes. To address knowledge gaps identified in the literature review, we designed an experimental study at a dairy farm and swine farm. We measured the levels of ARGs in the air and compared them to those found in nearby water and soil samples over four seasons at each farm. The levels of most ARGs were higher during warmer months. However, their levels were more affected by the sampling location or exhaust fan usage than time of year. At both farms, blaCTX-M1, the ARG associated with the antibiotic used most onsite, was detected at high levels, along with high levels of other genes associated with other types of antibiotics. ARGs were found in particles of all sizes, with larger particles near sources of emissions. Some ARGs could travel long distances in the air. In terms of the amount taken into the body, breathing in blaCTX-M1 at the dairy farm was similar to ingesting it from soil. In chapter 4, we tested an ionization system in a classroom to see if it could reduce airborne pathogens. There were no significant differences in positive ion levels whether the ionizer was on or off, but negative ion levels were lower when the ionizer was on. Normalized bacterial levels did not change significantly, suggesting that the ionizer had limited effectiveness in real-world conditions. Factors like room occupancy and settings of the air handling system had a bigger influence on bacterial levels in the air. More research is needed to confirm the effectiveness of ionization for reducing airborne pathogens in different settings.