Evidence suggests that host immunity has an important bearing on the growth and spread of malignant tumours. Naturally occurring immuno? suppressive substances have been demonstrated in the plasma of cancer patients, but the nature and relevance of such factors to the impaired immunity of cancer patients and to tumour behaviour are poorly understood. Cellular immunity is impaired in malnourished subjects also; although nutritional repletion with fat-free intravenous fluids may improve nutritional and immunological parameters, the immunological consequences of using solutions rich in polyunsaturated fatty acids are largely unknown. The aims of the study were to quantify the lymphocyte suppressive activity of plasma (plasma suppressive activity, PSA) and to identify specific substances associated with suppressive activity in plasma from normal subjects, and patients with benign or malignant diseases and with various degrees of malnutrition. Also, an attempt was made to correlate PSA with tumour behaviour in an animal model, firstly by measuring PSA before, during and after tumour growth, and secondly by observing tumour growth after artificially increasing PSA. In other studies in vitro lymphocyte reactivity was measured firstly after incubation with fat emulsion, and secondly in patients receiving parenteral fat emulsions. The study found that PSA was low in healthy subjects and patients with benign disease, and was associated entirely with the plasma protease inhibitor alpha-2-macroglobulin (A2M). PSA was raised moderately, although significantly, in malnourished patients with benign disease and correlated significantly with the extent of nutritional impairment; PSA was associated mainly with A2M but also with a small molecular weight peptide fraction. Patients with malignant disease had very high PSA which did not correlate with nutritional impairment and which was associated mainly with A2M but also with immune complexes, IgG, Fc fragments and a small molecular weight peptide fraction. Plasma A2M concentrations did not differ significantly between subject groups although the amount of suppressive activity associated with A2M did. PSA increased with tumour growth in the animal model but returned to pre-tumour levels after complete removal of tumours. Tumour growth was increased significantly in animals in which PSA was elevated at the time of tumour transplantation. Intravenous fluids containing fat significantly depressed in vitro lymphocyte reactivity in the laboratory and clinical studies. The study shows that A2M is an important regulator of lymphocyte reactivity in health and in malignant disease, and demonstrates a mechanism of immunological evasion by tumours by way of naturally occurring immunoregulatory plasma factors.

Thesis (Ph.D.)--University of Alberta, 2009. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Food Science and Technology, Department of Agricultural, Food, and Nutritional Science. Title from pdf file main screen (viewed on January 10, 2010). Includes bibliographical references.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Sydney, 2007. / Title from title screen (viewed may 17, 2007). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Biomedical Sciences, Faculty of Health Sciences. Degree awarded 2007; thesis submitted 2006. Includes bibliographical references. Also issued in print.

Small cell lung cancer (SCLC) is a highly aggressive malignancy with extreme mortality and morbidity. Although initially chemo- and radio-sensitive, almost inevitable recurrence and resistance occurs. SCLC patients often present with metastases, making surgery not feasible. Current therapies, rationally designed on underlying pathogenesis, produce in vitro results, however, these have failed to translate into satisfactory clinical outcomes. Recently, research into cancer stem cells (CSCs) has gained momentum and form an attractive target for novel therapies. Based on this concept, CSCs are the cause of neoplastic tissue development that are inherently resistant to chemotherapy, explaining why conventional therapies can shrink the tumour but are unable to eliminate the tumour completely, leading to eventual recurrence. Here I demonstrate that SCLC H345 and H69 cell lines contain a subset of cells expressing CD133, a known CSC marker. CD133+ SCLC sub-population maintained their stem cell-like phenotype over a prolonged period of culture, differentiated in appropriate conditions and expressed the embryonic stem cell marker Oct-4 indicating their stem-like phenotype. Additionally, these cells displayed augmented clonogenic efficacy, were chemoresistant and tumorigenic in vivo, distinct from the CD133- cells. Thus, the SCLC CD133 expressing cells fulfil most criteria of CSClike definition. The molecular mechanisms associated with CD133+ SCLC chemoresistance and growth is unknown. Up-regulated Akt activity, a known promoter of resistance with survival advantage, was observed in CD133+ SCLC cells. Likewise, these cells demonstrated elevated expression of Bcl-2, an anti-apoptotic protein compared to their negative counterpart explaining CD133+ cell chemoresistance phenotype. Additionally, CD133+ cells revealed greater expression of neuropeptide receptors, gastrin releasing peptide (GRP) and V1A receptors compared to the CD133- cells. Addition of exogenous GRP and arginine vasopressin (AVP) to CD133+ SCLC cells promoted their clonogenic growth in semi-solid medium, illustrating for the first time neuropeptide dependent growth of these cells. A novel peptide (peptide-1) was designed based on the known structure of the substance P analogues that have shown benefit in animal models and in early clinical trials. This compound inhibited the growth of SCLC cells in in vitro with improved potency and stability compared to previous analogues and reduced tumorigenicity in vivo. Interestingly, peptide-1 was more effective in CD133+ cells due to increased expression of neuropeptide receptors on these cells. In conclusion, my results show that SCLC cells retain a sub-population of cells that demonstrate CSC-like phenotype. Preferential activation of Akt and Bcl-2 survival pathways and enhanced expression of neuropeptide receptors contribute to CD133+ SCLC chemoresistance and growth. Therefore, it can be proposed that CD133+ cells are the possible cause of SCLC development, treatment resistance and disease recurrence. Despite being chemoresistant, CD133+ cells demonstrated sensitivity to peptide-1. The identification of such new analogue that demonstrates efficacy towards resistant CD133+ SCLC cells is a very exciting step forward in the identification of a potential new therapy for resistant disease.

No description available.

This thesis is the culmination of five years of communication design research (2006 – 2010) on a specific area of healthcare—breast cancer detection and screening. It is a project-­‐based doctoral work, underpinned by a practice-­‐led research journey of a graphic designer. The result is this written thesis with an accompanying set of uniquely designed objects: • a series of posters on breast cancer detection • an educational leaflet and risk assessment form • a series of working website prototypes (see worldwidebreastcancer.com) This thesis offers an in-­‐depth case study that demonstrates and contextualises the need for using communication design in patient engagement and education efforts in order to create a more patient-­‐centred experience in breast cancer detection. The significant contributions of this thesis are: • the development of a human-­‐centred design thinking methodology, known as the ‘USER’ model, which helps a designer develop a product for use within a system in an iterative, intuitive and analytical way. This is the first design thinking model of its kind to embed a framework for analysing objects within a systems framework; • the production and testing of visual metaphor, which was found to improve patient literacy and confidence. The significance of this has been to increase the potential for symptoms to be reported early and decrease mortality rates; • a map illustrating the patient journey of breast cancer screening that illustrates roles, communications and detection activities. This has been developed for general practices and imaging centres in a visually clear and distinct way; • a risk assessment tool that encourages doctors and patients to engage in collaborative decision-­‐making in the planning of breast cancer screening activities. Finally, the work presented here has profound implications for future studies of patient engagement and health literacy in breast cancer detection. The research journey, findings and objects in this thesis may lead to improved patient communication experiences and decreased mortality in breast cancer. This thesis also acts as a model for exploring and developing design solutions for other health causes.

Au cours de la progression des cancers dorigine épithéliale, on observe une disparition des jonctions intercellulaires et une réorganisation de leurs composants. Par ailleurs, cette progression tumorale saccompagne également dune surexpression de certaines chimiokines par les cellules tumorales. Dans ce travail, nous nous sommes attachés à étudier la régulation potentielle de ces chimiokines par certaines molécules dadhérence. Nous avons plus particulièrement examiné linfluence de la caténine beta et de ZO-1 sur lexpression des chimiokines étant donné leur particularité de pouvoir effectuer la navette entre la membrane et le noyau et leur implication dans des voies de signalisation. Dans un premier chapitre de résultats (chapitre III.1.1), nous rapportons notre étude concernant la régulation de MCP-1/CCL2 par la voie de signalisation caténine beta Publication 1 Nos travaux détaillant la régulation de lIL-8/CXCL8 par ZO-1 font lobjet dun second chapitre de résultats (chapitre III.1.2) Publication 2 Parallèlement à notre axe principal de recherche centré sur la régulation de lexpression des chimiokines, nous avons également participé à des travaux montrant linfluence de la voie de signalisation caténine beta sur la régulation de la vimentine lors de la transition épithélio-mésenchymateuse (TEM) associée à la progression tumorale. Un troisième chapitre de résultats est consacré à lexposé de ces travaux (chapitre III.2). Publications 3, 4, 5

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 256-280). Available also in a digital version from Dissertation Abstracts.

Title from title page of PDF (University of Missouri--St. Louis, viewed February 9, 2010). Includes bibliographical reference (p. 165-182).