As the most frequently diagnosed cancer in North American men, prostate cancer can progress to the androgen independent stage after initial response to androgen ablation therapy. The molecular mechanisms involved in the hormonal progression of prostate cancer are not completely understood. Here, we analyze changes in the transcriptome of prostate cancer cells at different stages of progression to reveal potential mechanisms. Applying Affymetrix GeneChip technology, we identified the transcriptomes in response to stimulation of androgen and PKA pathways in human prostate cancer cells. In addition to PSA, other common target genes were identified. Genes differentially expressed in response to androgen and stimulation of the PKA pathway in vitro were also differentially expressed during hormonal progression in vivo. Upon androgen stimulation, androgen receptor binds to a functional androgen response element within the promoter region of SESN1, a p53 targeted gene, and represses its expression. The expression of SESN1 was induced by castration in LNCaP xenografts, but the expression was eventually suppressed again in the androgen independent stage of prostate cancer. Knockdown of SESN1 promoted the proliferation of prostate cancer cells. Expression patterns of androgen-regulated genes in androgen independent tumours were revealed to be more similar to that from before castration than to the tumors under androgen ablation. The β-catenin, a potent coactivator of the androgen receptor, and Wnt pathway was deregulated in androgen-independent tumours. There was increased nuclear colocalization and interaction of androgen receptor and β-catenin with hormonal progression of prostate cancer. This study provides insight into hormonal effects on prostate cancer and possible pathways involved in the development of androgen independent disease, as well as potential therapeutic targets.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

The limited success of HIV vaccine candidates to date highlights our need to better characterize protective cell-mediated immunity. Understanding correlates CD8+ T cell protection against HIV infection and progressive disease is essential for informing effective vaccine development, design and evaluation. CD8+ T cell responses with a robust polyfunctional and proliferative component are strongly linked to better disease outcomes. However, the specificity of polyfunctional and proliferative CD8+ T cell responses has not been thoroughly investigated. Additionally, the specificity of memory subsets and their connection to polyfunctionality and proliferation responses has not been adequately assessed. We address these gaps in knowledge and provide a better understanding of the fine specificity of HIV-specific CD8+ T cell responses. We hypothesize that the epitopes recognized by central memory (TCM) and effector memory (TEM) CD8+ T cells, defined by functional attributes, differ in chronic HIV-1 infection. Additionally, we hypothesize that polyfunctional and proliferative responses will better correlate with protection in HIV disease progression. The qualities of CD8+ T cell responses were evaluated using polyfunctional flow cytometry measuring both functional and phenotypic attributes of both TEM and TCM subsets in HIV infected individuals. We evaluated the quality and evolution of CD8+ T cell responses in HIV infected individuals shortly after seroconversion through to the chronic phase of infection, finding that early polyfunctional responses may result in better HIV disease outcomes. Additionally, we show that epitope-specificity differs between short-term cytokine/chemokine secretion and long-term proliferative assays. Importantly, we show that, at a cohort level, particular epitopes preferentially elicit specific qualities of CD8+ T cell responses in preference to others. This research improves our understanding of HIV pathogenesis and indicates that we can identify specific epitopes that can elicit protective responses and that early polyfunctional responses may slow HIV disease progression. Understanding the polyfunctional and proliferative capacities of HIV-specific effector and memory cells at various stages of HIV infection is of critical importance to the design of vaccines intended to elicit protective cell-mediated responses.

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[Abstract]: Universities have traditionally focused their efforts on recruiting new students and increasing participation rates. However, higher retention and progression rates of students are likely to have a beneficial effect on the overall performance of universities in terms of their student-based income. The majority of previous studies addressing student retention have largely been focused on younger undergraduate on-campus students therefore this research seeks to investigate the factors which affect the retention and progression of postgraduate business students undertaking their studies by distance education. This study is based on a qualitative exploratory research design comprising twenty semi-structured in-depth interviews conducted with current and former students and university staff members. The key findings of this study indicate that a combination of situational, institutional and dispositional factors impact upon the retention and progression of postgraduate business distance education students. The employment and family commitments of students, whether students believed that their studies would benefit their career goals and the design of the distance education program appear to be the most important factors impacting upon student retention and progression. In contrast to the majority of services marketing literature, it would appear that student satisfaction is not a key factor impacting upon student retention and progression in this context. This research also provides a range of managerial implications and recommendations for postgraduate distance education providers.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (p. 177-191).

Syftet med denna studie är att synliggöra elevers uppfattning av formativ bedömning i matematik. Den riktar sig främst till lärare som önskar förbättra sin undervisning. Huvudresultatet visar på att lärare kan ha en avgörande effekt på elevers lärande med utgångspunkt i om de når eleverna med formativ bedömning eller inte.  Studiens resultat kommer från fyra fokusgruppsintervjuer med totalt 14 tredjeårselever på gymnasiet av heterogen art. Det visas på en risk för eleven att hamna i ett statiskt matematiskt mindset, med låga prestationer, när matematiklärare inte når fram till eleven med formativ bedömning. Om läraren däremot når fram så att eleven ser lärmål, upplever återkoppling och har strategier, så påvisas att chanserna tenderar öka för ett dynamiskt mindset och högre prestationer. Sambandet mellan upplevd formativ bedömning och prestation gör det viktigt hur elever upplever den formativa bedömningen.

Orientador: Maria Inês de Moura Campos Pardini / Banca: Isabel Maria Vicente Guedes Carvalho-Mello / Banca: Domingos Alves Meira / Resumo: O HIV-1 é um retrovirus que possui grande variabilidade genética, principalmente no gene que codifica o envelope viral (env). A diversidade de seqüências encontrada na terceira alça variável (alça V3) da gp120 é relacionada a várias características biológicas virais, tais como: habilidade do vírus a induzir sincício, antigenicidade e tropismo viral. O arco da alça V3 é formado por uma seqüência de aminoácidos relativamente conservada (GPGR) nos vírus do subtipo B. No Brasil, encontramos a variante B’, que possui a seqüência GWGR formando a região do arco e tem sido associada a uma progressão mais lenta da infecção. O fenótipo viral Não Indutor de Sincício (NSI) predomina nas fases assintomáticas, enquanto que o fenótipo Indutor de Sincício (SI) emerge em indivíduos infectados precedendo um declínio acentuado de células T CD4, sendo associado à progressão para aids. A mudança do fenótipo NSI para SI é resultante da substituição de determinados aminoácidos na alça V3. Mutações que alterem a seqüência de aminoácidos da alça V3, incluindo a região do arco podem ser utilizadas como marcadores genéticos para inferir sobre a evolução da infecção. DNA viral foi isolado a partir de leucócitos e utilizado como fonte para amplificação por PCR e seqüenciamento automático da região da alça V3. Um script desenvolvido pelo setor de Bioinformática foi utilizado para identificar os fenótipos SI/NSI e a seqüência de aminoácidos do arco da alça V3 (GPGR/GWGR) em 1279 pacientes estudados no Estado de São Paulo como parte do projeto VGDN. Esse estudo mostrou que 34,8% dos pacientes possuíam os aminoácidos GPGR formando a região do arco enquanto que 22,8% possuíam GWGR. Além disso, análises estatísticas utilizando o Teste de Goodman apontaram uma prevalência significativa de GWGR em pacientes assintomáticos com fenótipo NSI... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Genomic diversity in HIV-1 is a well-characterized feature and although this heterogeneity is distributed throughout the genome, most of the polymorphisms are located in the envelope gene (env). Sequence variability at the env gene third variable region (V3 loop) of HIV-1 is highly correlated with several viral biological features, such as the ability to induce syncytia, antigenicity and viral tropism. The tip of V3 loop consists of a relative conserved amino acid sequence (GPGR) in subtype B and the presence of GWGR motif in this region has been found in Brazilian strains (B' variant). Non-syncytium-inducing (NSI) phenotype variants predominate in the asymptomatic phase and Sincytium-inducing (SI) phenotype variants emerge in infected patients preceding a CD4 cell decline and correlate with progression to clinical manifestations. The switch from an NSI to an SI phenotype was correlated with one or more basic amino acids substitutions in the V3 loop. Genetic mutations modifying the V3 sequence has been associated with alterations in cytopathic abilities and antigenicity. The patterns of the HIV-1 sequences variability can be used as genetic marker to infer about the infection evolution. Viral DNA isolated from leucocytes was used as a source for PCR amplification and automatic sequencing of the V3 loop gene. Home-made PERL scripts were used to identify NSI/SI phenotypes and GPGR/GWGR motif in 1279 patients studied in São Paulo State, Brazil, as part of VGDN Project (www.lemb.icb.usp.br). This study showed that 34.8% of the patients have had GPGR variants and 22.8% GWGR. In addiction, statistical analysis using Goodman's Test showed GWGR prevailed in asymptomatic patients with NSI strains... (Complete abstract click electronic access below) / Mestre

abstract: Cell-cell interactions in a microenvironment under stress conditions play a critical role in pathogenesis and pre-malignant progression. Hypoxia is a central factor in carcinogenesis, which induces selective pressure in this process. Understanding the role of intercellular communications and cellular adaptation to hypoxia can help discover new cancer biosignatures and more effective diagnostic and therapeutic strategies. This dissertation presents a study on transcriptomic and metabolic profiling of pre-malignant progression of Barrett's esophagus. It encompasses two methodology developments and experimental findings of two related studies. To integrate phenotype and genotype measurements, a minimally invasive method was developed for selectively retrieving single adherent cells from cell cultures. Selected single cells can be harvested by a combination of mechanical force and biochemical treatment after phenotype measurements and used for end-point assays. Furthermore, a method was developed for analyzing expression levels of ten genes in individual mammalian cells with high sensitivity and reproducibility without the need of pre-amplifying cDNA. It is inexpensive and compatible with most of commercially available RT-qPCR systems, which warrants a wide applicability of the method to gene expression analysis in single cells. In the first study, the effect of intercellular interactions was investigated between normal esophageal epithelial and dysplastic Barrett's esophagus cells on gene expression levels and cellular functions. As a result, gene expression levels in dysplastic cells were found to be affected to a significantly larger extent than in the normal esophageal epithelial cells. These differentially expressed genes are enriched in cellular movement, TGFβ and EGF signaling networks. Heterotypic interactions between normal and dysplastic cells can change cellular motility and inhibit proliferation in both normal and dysplastic cells. In the second study, alterations in gene transcription levels and metabolic phenotypes between hypoxia-adapted cells and age-matched normoxic controls representing four different stages of pre-malignant progression in Barrett's esophagus were investigated. Through differential gene expression analysis and mitochondrial membrane potential measurements, evidence of clonal evolution induced by hypoxia selection pressure in metaplastic and high-grade dysplastic cells was found. These discoveries on cell-cell interactions and hypoxia adaptations provide a deeper insight into the dynamic evolutionary process in pre-malignant progression of Barrett's esophagus. / Dissertation/Thesis / Ph.D. Biological Design 2014

Denna studie syftar till att genom intervjuer undersöka lärarnas förväntningar på elevernas kunskapsprogression i teknikämnet, utifrån deras tolkningar av det centrala innehållet om egna konstruktioner i kursplanen för teknik och hur denna synliggörs i den beskrivna undervisningen. Undersökningen har genomförts genom kvalitativa intervjuer av verksamma lärare i låg- och mellanstadiet. Intervjusvaren har genomgått en konventionell innehållsanalys utifrån ett läroplansteoretiskt perspektiv. Resultatet visade stor osäkerhet i relation till vilken kunskap som förväntades utvecklas och att progression i undervisning i stort saknades eller var otydlig. Slutsatsen är att det finns svårigheter i att tolka och konkretisera progression i förhållande till det centrala innehållet och att detta grundar sig i flera faktorer. Möjlighet till fördjupad kunskap och undervisning med en tydligare struktur finns dock när lärare får stöd i sin tolkning av kursplanen.