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.

LIV-1, a zinc transporter, is an effector molecule downstream from soluble growth factors. This protein has been shown to promote epithelial-to-mesenchymal transition (EMT) in human pancreatic, breast, and prostate cancer cells. Despite the implication of LIV-1 in cancer growth and metastasis, there has been no study to determine the role of LIV-1 in prostate cancer progression. Moreover, there is no clear delineation of the molecular mechanism underlying LIV-1 function in cancer cells. In this study, we found increased LIV-1 expression in a progresssive manner in benign, PIN, primary and bone metastatic human prostate cancer. We characterized the mechanism by which LIV-1 drives prostate cancer EMT in an androgen-refractory human prostate cancer cell (ARCaP) bone metastasis model. LIV-1, when overexpressed in ARCaPE cells (derivative cells of ARCaP with epithelial phenotype), promoted EMT irreversibly. LIV-1 overexpressed ARCaPE cells had elevated levels of HB-EGF and matrix metalloproteinase (MMP) 2 and MMP 9 proteolytic enzyme activities, without affecting intracellular zinc concentration. The activation of MMPs resulted in the shedding of heparin binding-epidermal growth factor (HB-EGF) from ARCaPE cells, eliciting constitutive epidermal growth factor receptor (EGFR) phosphorylation and its downstream extracellular signal regulated kinase (ERK) signaling. Further investigation of the HB-EGF promoter revealed that both Stat3 and AP-1 controlled HB-EGF promoter activity. Ectopic LIV-1 overexpression induced AP-1 and Stat3 activation. Blockade of both Stat3 and AP-1 by specific inhibitors or dominant negative expression vectors diminished the HB-EGF promoter activity induced by LIV-1 overexpression. These results suggest that LIV-1 is involved in prostate cancer progression as an intracellular target of growth factor receptor signaling which promotes EMT and cancer metastasis. LIV-1 could be an attractive therapeutic target for the eradication of pre-existing human prostate cancer and bone and soft tissue metastases.

Textile composites have a wide variety of applications in the aerospace, sports, automobile, marine and medical industries. Due to the availability of a variety of textile architectures and numerous parameters associated with each, optimal design through extensive experimental testing is not practical. Predictive tools are needed to perform virtual experiments of various options. The focus of this research is to develop a better understanding of linear elastic response, plasticity and material damage induced nonlinear behavior and mechanics of load flow in textile composites. Textile composites exhibit multiple scales of complexity. The various textile behaviors are analyzed using a two-scale finite element modeling. A framework to allow use of a wide variety of damage initiation and growth models is proposed. Plasticity induced non-linear behavior of 2x2 braided composites is investigated using a modeling approach based on Hill’s yield function for orthotropic materials. The mechanics of load flow in textile composites is demonstrated using special non-standard postprocessing techniques that not only highlight the important details, but also transform the extensive amount of output data into comprehensible modes of behavior. The investigations show that the damage models differ from each other in terms of amount of degradation as well as the properties to be degraded under a particular failure mode. When compared with experimental data, predictions of some models match well for glass/epoxy composite whereas other’s match well for carbon/epoxy composites. However, all the models predicted very similar response when damage factors were made similar, which shows that the magnitude of damage factors are very important. Full 3D as well as equivalent tape laminate predictions lie within the range of the experimental data for a wide variety of braided composites with different material systems, which validated the plasticity analysis. Conclusions about the effect of fiber type on the degree of plasticity induced non-linearity in a ±25° braid depend on the measure of non-linearity. Investigations about the mechanics of load flow in textile composites bring new insights about the textile behavior. For example, the reasons for existence of transverse shear stress under uni-axial loading and occurrence of stress concentrations at certain locations were explained.

The multi-speed internal gear hub of a bicycle is a well-closed gear shifting system that works perfectly under any challenging riding environment, and is developed specifically to improve fragile chain-drive derailleur using planetary gear trains. In recent years, bicycle internal hub gears have been developed toward multi-speed transmission, and in the development process of internal gear hubs, the structure of speed changing mechanism has changed from a single planetary gear train to multiple planetary gear trains, and is becoming more complex. The primary purpose of this Study aims to establish a systemized and efficient design process, and develop an effective theory and method for designing multiple-speed internal gear hubs with the design concept and common features of multiple-speed internal gear hub products developed in recent years, to favor the innovation and development of internal gear hubs. First, existing multiple speed internal hub products are analyzed and summarized for their basic features, limitations, and demands as the reference for the design of multiple speed internal gear hubs, and a catalog of usable planetary structures is systematically established with the coupling and connection of basic high and low ratio speed changing modules. Secondly, usable planetary structures that offer best performance of geometric progression speed ratio distribution of gear hub are matched with gear positions, and a table of gear sequence is confirmed; third, based on the maximum external diameter required by design, tooth numbers for every gear in a hub are defined according to the relationship between tooth number and speed ratio, as well as the gear sequences; and finally, the systematic design process above is applied to the development of an easy-to-use computer aided design software with the lowest possible number of variables using Visual Basic 6.0 for designers, in order to favor the innovation and development of internal gear hubs.

<p>Det här arbetets slutgiltiga uppgift har varit att skapa ett första utkast till enövergripande plan för en jämn fördelning av spelmoment för spelet Testament, ett spel som utvecklas för Svenska Kyrkan med syfte att användas inom konfirmandundervisning. Med spelmoment menas exempelvis story, miljö, utrustning och liknande.</p><p>Arbetet ger inledningsvis en kort översikt över hur leveldesignen inom dataspel har utvecklats och går därefter in på det mer specifika området gameplay progression, utvecklat av Mike Lopez, som ger en översyn över vad som krävs för att skapa ett spel med en jämn fördelning av spelmoment.Därefter används denna metod för att analysera det redan befintliga spelet The Legend of Zelda: Twilight Princess, för att testa Lopez metod, innan arbetet med att skapa en egen plan tar vid.</p><p>Resultatet av uppsatsen har nått målet med en övergripande plan för en jämnfördelning av spelmoment för spelet Testament, en plan som dock kommer att behöva ses över och omarbetas under det att utvecklingen av det faktiska spelet tar vid, men som ger en bra överblick över vilka delar som fungerar väl och vilka som kan behöva extra arbete i den stundande utvecklingen.</p>

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 117-143).

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 77-89).

The development of cancer from a population of precancerous cells is a rapid evolutionary process. During progression, cells evolve several new traits for survive and proliferation via a few key `driver' mutations. However, these few driver alterations reside in a cancer genome alongside tens of thousands of additional `passenger' mutations. Passengers are widely believed to have no role in cancer, yet many passengers fall within functional genomic elements that may have potentially deleterious effects on the cancer cells. Here we investigate the potential of moderately deleterious passengers to accumulate and alter neoplastic progression. Evolutionary simulations suggest that moderately-deleterious passengers accumulate during progression and largely evade natural selection. Accumulation is possible because of cancer's unique evolutionary constraints: an initially small population size, an elevated mutation rate, and a need to acquire several driver mutations within a short evolutionary timeframe. Cancer dynamics can be theoretically understood as a tug-of-war between rare, strongly-beneficial drives and frequent mildly-deleterious passengers. In this formalism, passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers collapse. In essence, cancer progression can be subverted by its own unique evolutionary constraints. The collective burden of passengers explain several oncological phenomena that are difficult to explain otherwise. Genomics data confirms that many passengers are likely damaging and have largely evaded negative selection, while age-incidence curves and the distribution of mutation totals suggests that drivers and passengers exhibit competing effects. These data also provide estimates of the strength of drivers and passengers. Finally, we use our model to explore cancer treatments. We identify two broad regimes of adaptive evolutionary dynamics and use these regimes to understand outcomes from various treatment strategies. Our theory explains previously paradoxical treatment outcomes and suggest that passengers could serve as a biomarker of response to mutagenic therapies. Deleterious passengers are targetable by either (i) increasing the mutation rate or (ii) exacerbating their deleterious effects. Our results suggest a unique framework for understanding cancer progression as a balance between driver and passenger mutations.

Understanding chemical reactions is crucial in learning chemistry at all educational levels. Nevertheless, research in science education has revealed that many students struggle to understand chemical processes. Improving teaching and learning about chemical reactions demands that we develop a clearer understanding of student reasoning in this area and of how this reasoning evolves with training in the discipline. Thus, we have carried out a qualitative study using semi-structured interviews as the main data collection tool to explore students reasoning about reaction mechanism and causality. The participants of this study included students at different levels of training in chemistry: general chemistry students (n=22), organic chemistry students (n=16), first year graduate students (n=13) and Ph.D. candidates (n=14). We identified major conceptual modes along critical dimensions of analysis, and illustrated common ways of reasoning using typical cases. Main findings indicate that although significant progress is observed in student reasoning in some areas, major conceptual difficulties seem to persist even at the more advanced educational levels. In addition, our findings suggest that students struggle to integrate important concepts when thinking about mechanism and causality in chemical reactions. The results of our study are relevant to chemistry educators interested in learning progressions, assessment, and conceptual development.

Ο σκοπός της παρούσας έρευνας είναι να εξετάσει, σε μία περίπτωση φοιτητικού πληθυσμού (φοιτητές Τμήματος Γεωλογίας), κατά πόσο οι γνώσεις γύρω από το όριο συνάρτησης και ακολουθίας (ιδιαίτερα και της γεωμετρικής σειράς), τις περισσότερες από τις οποίες έχουν διδαχθεί οι σημερινοί φοιτητές σχολής Θετικών Επιστημών κατά τη διάρκεια της δευτεροβάθμιας εκπαίδευσης είναι γνώσεις οι οποίες έχουν κατανοηθεί σε κάποιο βάθος και αν αυτή η "γνωστική κληρονομιά" μπορεί να αξιοποιηθεί στο χώρο της τριτοβάθμιας εκπαίδευσης. / The purpose of this research is to examine, in one case of student population (Geology students), whether the knowledge about the function limit and the series(specially the geometric series), most of which have been taught to today's "Science's Faculty" students during secondary education, is knowledge which has been understood in sufficient depth and whether this "cognitive legacy" can be used in higher education.