No description available.

Circulating cell adhesion amidst the high shear environment of the vasculature is central to several physiological and pathophysiological processes, including leukocyte recruitment to sites of inflammation, stem cell homing and cancer metastasis. This process is initiated by selectin-mediated adhesion, the molecular “brakes” that slow cells down relative to bulk fluid flow to facilitate cell-cell signaling and eventual firm cell adhesion. Selectin recognition therefore represents a critical step whereby therapeutic interventions aimed towards the interference of cell homing could be targeted. While the force dependency of these high kon and koff rate interactions has been well described, little understanding exists of the long time- and length-scale interactions of different cell subtypes that would best describe the functional capacity of different cell homing via selectins to systemic peripheral tissues. This limits the adequate description of sustained cell adhesion efficiencies in physiological conditions that predicates the effectiveness of cell homing as well as the design effective therapeutic interventions to selectively attenuate metastasis but not normal cell homing using such criteria. To address this issue, we developed a so-called “cell adhesion chromatography” system, a microfluidic-based device designed for use in conjunction with videomicroscopy for the interrogation of the adhesion behavior of cells over long time- and length-scales. In order to achieve uniform contact of a pulse cell suspension input into a selectin-functionalized parallel plate flow chamber, we designed a feature that enables complete cell settling to the chamber bottom based on Stoke’s flow predictions, increasing contact uniformity of the pulse cell input with the substrate upon entry into the main chromatography channel from ~50 to >95%. Using this configuration, residence time distributions for a pulse input of cells perfused at defined shear stresses were generated based on cell elution times from the cell adhesion chromatography system. Selectin-functionalized substrates delayed cell elution times relative to bovine serum albumin coated-substrates by orders of magnitude in a selectin concentration, shear and cation dependent fashion. Preliminary experiments were also performed to begin to define the differences in efficiencies of healthy (human monocyte) versus malignant (human colon carcinoma) cell adhesion to selectins in shear flow. Our results suggest significant differences in the functional capacity of healthy versus malignant cells to sustain adhesion in shear flow and that cell adhesion chromatography is a new tool that provides unique insight into the process of cell adhesion in fluid flow.

Metastasised breast cancer kills. There is no known cure, there are no known preventative measures, there are no drugs available with proven capacity to abate its effects. Early identification and excision of a malignancy prior to metastasis is the only method currently available for reducing the mortality due to breast disease. Automated analysis of mammograms has been proposed as a tool to aid radiologists detect breast disease earlier and with greater efficiency and success. This thesis addresses some of the major difficulties associated with the automated analysis of mammograms, in particular the difficulties caused by the high-frequency, relatively insignificant curvi-linear structures (CLS) comprising the blood vessels, milk-ducts and fibrous tissues. Previous attempts at automation have been overlooked these structures and the resultant complexity of that oversight has been handled inappropriately. We develop a model-based analysis of the CLS features, from the very anatomy of the breast, through mammography and digitisation to the image intensities. The model immediately dictates an algorithm for extracting a high-level feature description of the CLS features. This high-level feature description allows a systematic treatment of these image features prior to searching for instances of breast disease. We demonstrate a procedure for implementing such prior treatment by 'removing' the CLS features from the images. Furthermore, we develop a model of the expected appearance of mammographic densities in the CLS-removed image, which leads directly to an algorithm for their identification. Unfortunately the model also extracts many regions of the image that are not significant mammographic densities, and this therefore requires a subsequent segmentation stage. Unlike previous attempts which apply neural networks to this task, and therefore incorporate inherent insignificance as a consequence of insufficient data availability describing the significant mammographic densities, we illustrate the application of a new statistical method (novelty analysis) for achieving a statistically significant segmentation of the mammographic densities from the plethora of candidates identified at the previous stage. We demonstrate the ability of the CLS feature description to identify instances of radial-scar in mammograms, and note the suitability of the CLS and density descriptions for assessment of bilateral and temporal asymmetry. Some additional potential applications of these feature descriptions in arenas other than mammogram analysis are also noted.

No description available.

No description available.

No description available.

Increased local tumor tissue expression of versican in breast cancer patients is predictive of relapse and has a negative impact on survival rates. It is recognized that bone is a common anatomic site of breast cancer metastasis. The C-terminal G3 domain of versican influences local and systemic tumor invasiveness in pre-clinical murine models. However, the mechanism(s) by which G3 influences breast tumor growth and metastasis is not well characterized. We exogenously expressed a G3 construct in mouse breast cancer cell line 66c14, and found that G3 expression enhanced breast cancer cell proliferation and migration, and spontaneous metastasis to bone in an orthotopic model by upregulating the EGFR-mediated signaling pathway. Possessing anti-apoptotic and drug resistant properties, overexpression of versican was accompanied by selective sensitization to several chemotherapeutic agents. The dual roles of G3 in modulating breast cancer cell resistance to chemotherapeutic agents may, in part, explain breast cancer cell resistance to chemotherapy and EGFR therapy. The apoptotic effects of chemotherapeutics depend upon the activation and balance of down stream signals in the EGFR pathway. New knowledge gained by our experiments includes the understanding that GSK-3β (S9P) appears to function as a key check-point in this balance. In addition, versican G3 enhanced breast cancer cell self-renewal in vitro and in vivo. Versican was expressed at high levels in breast cancer mammosphere cells, which contained a high percentage of SP cells. Reduction of versican’s functionality through anti-versican shRNA or knocking out the EGF-like motifs using G3ΔEGF reduced the effect of versican on enhancing mammosphere and colony formation. Versican promoted breast cancer cell self-renew appears to play a role in enhanced chemotherapeutic drug resistance (including Docetaxel, Doxorubicin, and Epirubicin), which relates partly to its upregulated expression of EGFR signaling. Versican enhances breast cancer bone metastasis not only by enhancing tumor cell mobility, invasion, and survival in bone tissues, but also through mechanisms inhibiting osteoblast cell growth and differentiation, affording favorable microenvironments for tumor metastasis.

Title page, contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / "The present study investigated the expression and function of IGF-1R, CXCR4 and CCR7, in metastatic MDA-MB-231 and non-metastatic MCF-7 cells." / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1295746 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007

Copies of author's previously published articles enclosed. / Bibliography: leaves 217-258. / xxiv, 258 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines recent literature which describes cases of metastatic involvement of laparoscopic port sites, not only in patients with advanced tumors but in patients with early stage carcinoma, and even in patients following laparoscopic procedures during which tumors were not disturbed. This thesis utilises an established small animal model to investigate the aetiology of port site metasrases and the efficacy of preventative strategies in reducing tumor implantation following laparoscopy. / Thesis (Ph.D.)--University of Adelaide, Dept. of Surgery, 2000?

Title page, table of contents and summary only. The complete thesis in print form is available from the University of Adelaide Library. / This thesis describes two studies, one in vitro and one in vivo, which show that Apo2L/TRAIL can prevent breast cancer-induced bone destruction, and highlight the potential of this ligand for the treatment of metastatic breast cancer in bone. They also highlight the complexity of Apo2L/TRAIL signalling, and the need for further studies into this area to fully exploit the potential of Apo2L/TRAIL as an anti-cancer agent for breast and other cancers. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1283688 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2007