Ghrelin is a 28 amino acid peptide hormone with a unique octanoic acid modification that has an extensive range of physiological effects, including stimulation of growth hormone (GH) release, appetite regulation, and modulation of reproductive functions. The cognate receptor for ghrelin is the growth hormone secretagogue receptor (GHS-R), a G protein-coupled receptor with two documented isoforms, the functional GHS-R type 1a and the C-terminally truncated GHS-R type 1b. Several ghrelin variants have also been identified in addition to the n-octanoylated form of ghrelin. In our laboratory, we have identified a novel exon 3-deleted preproghrelin variant that retains sequence for the mature ghrelin hormone and also encodes a novel C-terminal peptide (designated as C-terminal 3 peptide). There is emerging evidence to suggest that the ghrelin axis, encompassing ghrelin, several ghrelin variants and both forms of the GHS-R, is implicated in tumour growth. The objective of this project is to investigate the role of the ghrelin axis in hormone-dependent cancer and to further characterise the expression and function of the novel exon 3-deleted preproghrelin isoform. Hormone-dependent cancers, including prostate and breast cancers, are significant causes of morbidity and mortality in the Western world. Improved diagnoses and treatments earlier in the progression of the disease are urgently required to improve patient outcomes. Growth factors play an integral role in prostate and breast cancer, particularly in the emergence of aggressive, hormone-refractory disease that is resistant to standard therapies. We have previously identified ghrelin as being a novel growth factor for prostate cancer cells in vitro and have hypothesised that this may be extended to other hormone-dependent cancer types including breast cancer. In the current study, techniques including real-time quantitative RT-PCR, Western blot analysis and immunohistochemistry have been used to determine and quantitate ghrelin, exon 3-deleted preproghrelin and GHS-R expression in prostate and breast cancer. Ghrelin and exon 3-deleted preproghrelin are highly expressed in prostate cancer tissues compared to expression levels in normal prostate glands. Similarly, breast carcinoma specimens display greater immunoreactivity for ghrelin and exon 3-deleted preproghrelin than normal breast tissues. Expression of the exon 3-deleted preproghrelin mRNA isoform is upregulated in the oestrogen-independent, highly malignant MDA-MB-435 breast cancer cell line compared to the non-tumourigenic MCF-10A breast epithelial cell line, suggesting that augmented transcription of the isoform is associated with an increased malignant potential in breast cancer. The functional GHS-R type 1a is expressed in normal breast tissue and breast cancer specimens and cell lines. In contrast, the truncated GHS-R type 1b isoform is exclusively expressed in breast carcinoma. These data suggest that GHS-R type 1b, ghrelin and exon 3-deleted preproghrelin display potential as novel diagnostic markers for prostate and breast cancer. These studies have been the first to demonstrate that ghrelin may have an important role in cell proliferation in breast and prostate cancer. Functional assays demonstrated that (10nM) ghrelin stimulated proliferation in the LNCaP prostate cancer cell lines (45.0 ± 1.7% above control, P &lt0.01) and rapidly activated the ERK 1/2 mitogen-activated kinase (MAPK) pathway in both PC3 and LNCaP cell lines. It does not, however, protect these cells from chemically-induced apoptosis. The MAPK inhibitors PD98059 and U0126 blocked ghrelin-induced MAPK activation, as well as cell proliferation, in both cell lines. Prostate cancer cells secrete mature ghrelin in vitro, and may therefore stimulate MAPK pathways in an autocrine manner. Ghrelin also appears to act as a growth factor in breast cancer cell proliferation, as the growth of MDA-MB-435 and MDA-MB-231 breast cancer cell lines is significantly increased by ghrelin treatment. Our findings suggest that the ghrelin axis could provide an important new target for adjunctive therapies for both breast and prostate cancer. The C-terminal 3 peptide derived from exon 3-deleted preproghrelin may be an important new component of the ghrelin axis and studies into its function are currently in progress. Although it did not induce MAPK cascades or stimulate proliferation in prostate or breast cancer cell lines, the discovery of a murine counterpart, exon 4-deleted preproghrelin, indicates that it is highly conserved. Exon 4-deleted preproghrelin is expressed in all mouse tissues examined, with stomach being the predominant site of synthesis. Other components of the ghrelin axis were also found to be present in a wide-range of mouse tissues including brain, ovary and prostate. This comprehensive report has paved the way for future work with in vivo mouse models of cancer. This study has provided a substantial basis for the further evaluation of ghrelin, exon 3-deleted preproghrelin and the GHS-R type 1b as novel diagnostic/prognostic markers for prostate and breast cancer and supports the rationale for targeting the ghrelin axis for treatment of these tumours. Keywords: Ghrelin, exon 3-deleted preproghrelin, GHS-R, growth factors, MAPK, ERK 1/2, hormone-dependent cancer, prostate, breast, diagnostic/prognostic marker, therapeutic targets.

Transmissible diseases are re-emerging as a global problem, with Sexually Transmitted Diseases (STDs) becoming endemic. Chlamydia trachomatis is the leading cause of bacterially-acquired STD worldwide, with the Australian cost of infection estimated at $90 - $160 million annually. Studies using animal models of genital tract Chlamydia infection suggested that the hormonal status of the genital tract epithelium at the time of exposure may influence the outcome of infection. Oral contraceptive use also increased the risk of contracting chlamydial infections compared to women not using contraception. Generally it was suggested that the outcome of chlamydial infection is determined in part by the hormonal status of the epithelium at the time of exposure. Using the human endolmetrial cell line ECC-1 this study investigated the effects of C. trachomatis serovar D infection, in conjunction with the female sex hormones, 17β-estradiol and progesterone, on chlamydial gene expression. While previous studies have examined the host response, this is the first study to examine C.trachomatis gene expression under different hormonal conditions. We have highlighted a basic model of C. trachomatis gene regulation in the presence of steroid hormones by identifying 60 genes that were regulated by addition of estradiol and/or progesterone. In addition, the third chapter of this thesis discussed and compared the significance of the current findings in the context of data from other research groups to improve our understanding of the molecular basis of chlamydial persistence under hormonal different conditions. In addition, this study analysed the effects of these female sex hormones and C. trachomatis Serovar D infection, on host susceptibility and bacterial growth. Our results clearly demonstrated that addition of steroid hormones not only had a great impact on the level of infectivity of epithelial cells with C.trachomatis serovar D, but also the morphology of chlamydial inclusions was affected by hormone supplementation.

Includes articles co-authored by the author during the preparation of this thesis. / Includes erratum on back leaf. / Includes bibliographical references (leaves 257-299). / xvii, 300 [27] leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines regional variations in trabecular bone remodelling and bone loss following oophorectomy in the distal femur of the rat. The studies reveal a complex interaction between weight bearing and ovarian hormone deficiency, and show that physiological signals exist which can negate all adverse effects of postmenopausal osteoporosis / Thesis (Ph.D.)--Adelaide University, Dept. of Physiology, 2001

Master of Dental Surgery / It has been considered for the purpose of this review unnecessary to discuss in detail the Morphology of the dental pulp and dentine, as this may be found in any recognised text-book, but to concentrate on the clinical problems involved. The materials discussed are those in current usage for exposed pulp preservation, whilst other materials may be touched upon and it is the endeavour of the author to review as many results as possible in this field and to draw sound conclusion from statements made. The field of corticosteroids in dentistry is comparatively new and here it is the aim to provide a basis from which further research may be undertaken. Thus, this thesis is divided into two distinct sections. The first section dealing with non-corticoid drugs and the second sections dealing with cortico-steriods and their combinations, exclusively, utilising the commercial product Ledermix as their prime example. However, when considering pulp therapy one must delve into the past to understand the thought and effort that has gone into this realm of dentistry and to note the lack of the true scientific attitude by some into this work. This may then allow us to look again at our own statements to note how much controversy there was, and still is concerning a question such as “should an attempt on the pulp once exposed ever be made to maintain its vitality?” It will be shown at a later stage that the pulp has marvellous recuperating powers if treated in a conservative manner, something which was hardly considered even early this century. Castognola, Quigleyand Berman have all reviewed this subject before. However, my aim is to bring together all of their information as a preface to the important work of considering the immediate study being carried out in this field. The first attempted vital capping was carried out by Philip Pfaff in 1756 with a small piece of gold foil adapted to the base of the cavity. Then in 1826 it was reported that Lenoard Koeker cauterized the exposed pulp with a hot iron wire and placed silver or lead caps over the exposures. It then appeared that little further was written concerning pulp capping until the middle of the 19th century when Albrecht (1856) utilised opiates, caustics and eugenol on the exposed pulp. McKown (1859) recommended cotton soaked in creosote and tannic acid, whilst Taft (1859) was in favour of cauterizing recently exposed pulps with nitric acid and placing a filling immediately. These results were purely a subjective evaluation. In fact Mc Kown’s results were produced on one of his own teeth. The history of pulp preservation really begins in the early 1860’s. Allport (1866) and Atkinson (1866-1868) suggested amputation of all projecting cornua of exposed pulps and placement of a temporary filling until it was healthy. Allport used the b lood clot formed during operation as his means of capping. J Foote (1866) also, believed the blood clot to be the best means of covering the pulp. This certainly appeared to be a reasonable assumption, considering medical knowledge of the day.

Thesis (Ph. D.)--Oregon Graduate Center, 1989.

Thesis (M.S.)--University of North Carolina at Greensboro, 2007. / Title from PDF t.p. (viewed Mar. 3, 2008). Directed by Vincent C. Henrich; submitted to the Dept. of Biology. Includes bibliographical references (p. 43-46).

Thesis (Ph. D.)--University of Washington. / Bibliography: l. 72-75.

Thesis (M.S.)--University of Nevada, Reno, 2006. / "August, 2006." Includes bibliographical references (leaves 112-116). Library also has microfilm. Ann Arbor, Mich. : ProQuest Information and Learning Company, [200x]. 1 microfilm reel ; 35 mm. Online version available on the World Wide Web.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Adelaide, Dept. of Animal Science, 1998. / Corrigenda inserted behind title page. Copies of author's previously published articles inserted. Includes bibliographical references (leaves 193-210).