Over-expression of both hepatocyte growth factor (HGF) and its receptor Met frequently occurs in invasive human breast cancer, suggesting that the establishment of an HGF “autocrine loop” may be linked to breast tumour progression. We have recently shown a novel activating function of two signaling molecules, Src tyrosine kinase and the signal transducer and activator of transcription-3 factor (Stat3), on HGF expression in breast epithelial cells. Interestingly, Stat3 is also important in normal breast development,but this function does not require Src. In addition, β1-integrin adhesion occurs minimally in differentiated breast epithelium, but is upregulated during oncogenic progression and is required for transformation by Src. We therefore hypothesize that β1-integrin engagement is necessary for Src/Stat3-dependent activation of HGF transcription and breast tumourigensis. Using specific inhibitors of Src (Dasatinib) and Stat3 (CPA7) we demonstrated that autocrine HGF expression is linked to activation of Src/Stat3 in a malignant breast cell line. Phenotypic reversion (e.g., cell rounding and loss of filopodial extensions) and inhibition of pY705Stat3, HGF and pYMet expression as determined by immunofluorescence was achieved with both inhibitor treatments separately, and a synergistic effect was observed with combined treatment. Furthermore, β-catenin localization was nuclear in malignant cells, but shifted to cortical cytoplasmic following inhibitor treatment, similar to non-malignant mouse breast epithelial cells (EPH4). We are currently extrapolating these findings to a 3D Matrigel culture model in which EPH4 cells form acini-like spheroids with hollow lumen surrounded by a well-polarized outer layer of cells. Under these conditions, Stat3 levels are decreased followed by a reduction in cyclin D1 expression, while Src activation remains at a low baseline level. Interestingly,expression of Stat5, which has a reciprocal relationship with Stat3 in breast development and involution, is increased concomitant with elevated β-casein expression. Moreover, Fibronectin and HGF in combination stimulate tubular outgrowths with lumen filling. These findings suggest that aberrant changes in extracellular matrix milieu may stimulate integrin cross talk resulting in a switch of HGF/Met signaling to a transformation phenotype. Information from this study may lead to novel cancer therapies through targeting the HGF/Met and integrin signaling cascades. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2008-09-19 18:19:22.744

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By extending the diagrams of materials science, the field is broadened in a natural way. For example, binary phase diagrams are like black boxes, used in the design and simulation of microstructures. They explore a balance of two chemical species, but real alloys have several chemical species, and merit a higher dimensional space. The n-dimensional extension is simplified by dividing the problem into discrete and continuous components. / "Discrete" is the identification of behavioural regimes, and their interactions, in a network graph. "Continuous" includes the curvature of boundaries, and the motion through the space. In thermochemical phase spaces, a homogenous alloy is mapped to a particle, whose motion represents the evolution of the alloy. Likewise, non-homogeneous alloys evolve as multidimensional continua. / The classical diagrams may also be hybridized. For example, TTT-curves may be treated as extra dimensions of a thermochemical phase space; the resulting hybrid synthesizes microstructural thermodynamics and kinetics.

The process of fish migration within rivers and streams is important, especially during the spawning season which often coincides with peak spring discharges in Manitoba. Current environmental regulations for fish passage through culverts require that the average velocity be limited to the prolonged swimming speed of the fish species present. In order to examine the validity of this approach, physical model results were used to calibrate and test a commercially available Computational Fluid Dynamics (CFD) model. Detailed analysis showed that CFD models and the empirical equations used were both able to give a better representation of the flow field than the average velocity. However, the empirical equations were able to provide a more accurate velocity distribution within the fully developed region. A relationship was then developed, to estimate the cumulative percent area less than a threshold velocity within CSP culverts, to be used as a guideline during the design phase.

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Der technologische Fortschritt ermöglicht es heute, die moleculare Konfiguration einzelner Zellen oder ganzer Gewebeproben zu untersuchen. Solche in großen Mengen produzierten hochdimensionalen Omics-Daten aus der Molekularbiologie lassen sich zu immer niedrigeren Kosten erzeugen und werden so immer häufiger auch in klinischen Fragestellungen eingesetzt. Personalisierte Diagnose oder auch die Vorhersage eines Behandlungserfolges auf der Basis solcher Hochdurchsatzdaten stellen eine moderne Anwendung von Techniken aus dem maschinellen Lernen dar. In der Praxis werden klinische Parameter, wie etwa der Gesundheitszustand oder die Nebenwirkungen einer Therapie, häufig auf einer ordinalen Skala erhoben (beispielsweise gut, normal, schlecht). Es ist verbreitet, Klassifikationsproblme mit ordinal skaliertem Endpunkt wie generelle Mehrklassenproblme zu behandeln und somit die Information, die in der Ordnung zwischen den Klassen enthalten ist, zu ignorieren. Allerdings kann das Vernachlässigen dieser Information zu einer verminderten Klassifikationsgüte führen oder sogar eine ungünstige ungeordnete Klassifikation erzeugen. Klassische Ansätze, einen ordinal skalierten Endpunkt direkt zu modellieren, wie beispielsweise mit einem kumulativen Linkmodell, lassen sich typischerweise nicht auf hochdimensionale Daten anwenden. Wir präsentieren in dieser Arbeit hierarchical twoing (hi2) als einen Algorithmus für die Klassifikation hochdimensionler Daten in ordinal Skalierte Kategorien. hi2 nutzt die Mächtigkeit der sehr gut verstandenen binären Klassifikation, um auch in ordinale Kategorien zu klassifizieren. Eine Opensource-Implementierung von hi2 ist online verfügbar. In einer Vergleichsstudie zur Klassifikation von echten wie von simulierten Daten mit ordinalem Endpunkt produzieren etablierte Methoden, die speziell für geordnete Kategorien entworfen wurden, nicht generell bessere Ergebnisse als state-of-the-art nicht-ordinale Klassifikatoren. Die Fähigkeit eines Algorithmus, mit hochdimensionalen Daten umzugehen, dominiert die Klassifikationsleisting. Wir zeigen, dass unser Algorithmus hi2 konsistent gute Ergebnisse erzielt und in vielen Fällen besser abschneidet als die anderen Methoden.

Although a large number of works on nanoimprint lithography (NIL) techniques have been reported, the the ability for three-dimensional (3-D) patterning using NIL has not been fully addressed in terms of the mold fabrication and imprint processes. Patterning 3-D and multilevel features are important because they eliminate multiple steps and complex interlevel alignments in the nanofabrication process. The 3-D and multilevel mold design and fabrication, and imprint processes have been studied and investigated in this research work. In the UV-NIL technique, a transparent mold with micro/nanostructure patterns on its surface is allowed to be replicated on UV curable polymer without the need of high applied pressure or temperature. UV-NIL has the potential to fabricate micro/nanostructures with high resolution, high reproducibility, low cost, high throughput and is capable of 3-D patterning. This research focuses on two aspects; the development of mold making and imprint processes. In the process of making a master mold, an EBL technique was employed for writing patterns on e-beam resists. PMMA positive resist was used for 2-D patterning and ma-N2403 negative resist from Microresist Technology was used for 3-D patterning. After being developed, the 3-D mold pattern was transferred onto quartz substrate using a single-step reactive ion etching (RIE) technique. A number of challenging issues such as surface charging, electron scattering and proximity effects surfaced during the EBL pattern writing on insulating and transparent molds. A number of new approaches have been developed for suppressing the charging effects in the 2-D and 3-D patterning. Using thin metallic coating on the quartz substrates or on top of the resist, or conductive polymer coating using PEDOT/PSS on top of the resist has demonstrated excellent results in a 2-D structure with a high aspect-ratio of 1:10 and feature sizes down to 60 nm. In 3-D patterning, two approaches have been followed; the critical energy method and/or a top coating of conductive polymer (PEDOT/PSS) layer. Isolated 3-D structures with feature sizes down to 500 nm were successfully fabricated using the first method while by using the second method, dense 3-D structures patterns with feature sizes down to 300 nm, on 400 nm pitch have been demonstrated. In UV-NIL, the surface roughness Rq(rms) should be less than 5 nm, which is important for replicating optical structures and devices. In this work, the RIE process been optimized to yield 2 nm roughness on a patterned quartz surface. This was achieved by optimizing the RIE process pressure of below 6 mTorr. The other part of this thesis is on replication or imprinting of 2-D and 3-D structures. In the process of replicating the master mold profiles, the imprint processes were carried out using a vacuum operated manual imprint tool which was attached to a Mask Aligner UV illumination system. In 2-D imprinting, resist sticking on the vertical side wall was the main issue, especially on high aspect ratio structures. Meanwhile in 3-D imprinting, the imprint results have shown good reproducibility in up to 15 imprint cycles, where the issue of Ormocomp soft/daughter mold cracking after long UV exposure had limited the repetition of the imprint cycles. In this thesis, the 2-D and 3-D resist patterning on insulating substrates using the EBL technique have been demonstrated with the assistance of a number of developed charge suppression methods. Single-step RIE pattern transfer onto quartz substrates with surface roughness below 5nm has been achieved. Replication of 3-D and multilevel structures reliably make the UV-NIL technique suitable for future applications such as surface texturing, optical devices and many other complex structures including MEMS.