The aim of this study was to investigate COX-2 expression in squamous cell carcinoma of the oesophagus (SCC), and the potential of non-steroidal anti-inflammatory drugs, which inhibit the action of the enzyme, for chemoprevention of this cancer. The epidemiology of SCC and the outcome from surgery for this disease in Hebei Province, China, were reviewed. The rate of postoperative complications and deaths following oesophagectomy fell steadily over the last five decades, but the long-term survival remained disappointing. Improved survival is likely to be dependent on earlier diagnosis and better adjunctive therapies. Tissue was obtained from patients who had an oesophagectomy for SCC over 20 years earlier. The expression of COX-2 was elevated and correlated with TNM stage and lymph node metastases. Survival was longer in those patients whose tumours expressed lower levels of COX-2. The mechanism of action of aspirin, a non-selective COX inhibitor, and NS-398, a selective COX-2 inhibitor, was investigated in vitro. Both drugs inhibited the proliferation of and induced apoptosis in the SCC cell line TE-13. These changes correlated with a reduction in COX-2 mRNA and protein expression, prostaglandin synthesis, inhibition of NF-KappaB nuclear translocation and an increase in cytoplasmic IKappaB. Similar changes were seen in tumour tissue resected from patients given the selective COX-2 inhibitor Mobic daily for 14 days before surgery. These results suggested that aspirin and similar drugs might have value in cancer therapy. A clinical trial was established to determine if treatment with aspirin post-operatively would improve survival of patients who had had an oesophagectomy for SCC. Preliminary results suggested that treatment had no effect on survival in patients operated on for SCC. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1289296 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2007

Cancer is one of the challenges for today's medicine and therefore a great deal of effort is being put into improving known methods of treatment and developing new ones. A new method that has been proposed is magnetic hyperthermia where magnetic nanoparticles linked to the tumor dissipate heat when subjected to an alternating magnetic field and will thus increase the temperature of the tumor. This method makes the tumor more susceptible to radiation therapy and chemotherapy, or can be used to elevate the temperature of the tumor cells to cause cell death. The particles proposed for this are single core and often have a size in the range of 10 nm to 50 nm. To achieve an effective treatment the particles should have a narrow size distribution and the proper size. In this work, a theoretical model for predicting the heating power generated by magnetic nanoparticles was evaluated. The model was compared with experimental results for magnetite particles of size 15 nm to 35 nm dissolved in water. The properties of the particles were characterized, including measurements of the magnetic saturation, the effective anisotropy constant, average size and size distribution. To evaluate the results from the model the AC susceptibility and heating power were experimentally determined. The model is a two-step model. First the out-of-phase component of the AC susceptibility as a function of frequency is calculated. Then this result is used to calculate the heating power. The model gives a correct prediction of the shape of the out-of-phase component of the susceptibility but overestimates its magnitude. Using the experimentally determined out-of-phase component of the susceptibility, the model estimation of the heating power compares quite well with the measured values.

published_or_final_version / Pathology / Master / Master of Philosophy

Background Breast cancer prevalence is increasing in most countries. Not only the threat of death and impact of breast cancer treatment, but also the participation roles during treatment decision making can be substantial, leading to psychological distress and poor quality of life. Previous studies have explored patients’ participation preference, the extent of participation congruence and related factors, revealing that women suffering from breast cancer may benefit from participation in treatment decision making whilst participation incongruity could be potentially detrimental for women with breast cancer. Objectives This study aimed to systematically review the literature and summarize the extent of breast cancer patients’ participation preference, participation congruence, and related factors. Methods Multiple searches for key words were conducted through electronic sources, including PubMed, PsycINFO, and Medline via Ovid databases for all relevant English language literature. Studies were selected basing on specific inclusion/exclusion criteria. The STROBE checklist was applied for reporting quality assessment. Results A total of 778 studies were identified. Twelve eligible studies were included in this review. Twelve factors relating to breast cancer women’s participation congruence in treatment decision making were identified as follows: age, nature of preferred role of treatment decision making, educational level, time related issues, language/ethnicity, marital status, information and recommendations of treatment, offering treatment options, physician characteristics, type of therapy or cancer program, stage of breast cancer, and surgeon volume. Conclusions Three themes (i.e. patient oriented, physician-patient interaction, and medical provision) of intervention points towards patient participation congruence were synthesized and discussed, and they were useful for improving the quality of existing breast cancer treatment decision making by addressing patient’s perceived participation congruence. / published_or_final_version / Public Health / Master / Master of Public Health

Nanoscience and nanotechnology have advanced rapidly in recent years and have made a profound impact in the medical field. Nanoparticles have attracted great attention for their potential as diagnostic and/or therapeutic tools in oncology owing to their unique properties. Theranostics are nanodevices with diagnostic, therapeutic and possibly treatment-monitoring functions for treating cancers. Different noble metal nanoparticles can provide the basic unit for theranostics. Suitably designed and developed noble metal nanoparticle-based theranostics will have multiple functions. In this project, the design, fabrication and performance of novel multifunctional nanodevices for cancer detection and treatment were investigated. The foundation of this project was laid by investigating different types of hybrid nanoparticles for novel theranostics. Different approaches were developed for fabricating core-shell structured hybrid nanoparticles. Highly branched gold and gold-silver bimetallic nanoparticles were firstly made. pH-sensitive folic acid-chitosan (CS-FA) conjugate was then introduced on these nanoparticles to form hybrid nanoparticles with a metal core (Au@CS-FA and Au-Ag@CS-FA). Poly(lactide-co-glycolide) (PLGA) and chitosan (CS) micro- or nanoparticles were also produced to serve as the polymer core for forming hybrid particles with a gold or gold-silver nanoshell (PLGA@Au, CS@Au and PLGA@Ag-Au). Furthermore, Fe3O4@Au nanoparticles having both magnetic and plasmonic properties were investigated. Thermo-sensitive poly(N-isopropylacrylamide) (pNIPAm) polymer or pH-sensitive CS-FA was then coated on Fe3O4@Au nanoparticles, forming new hybrid nanoparticles. The formation mechanisms of nanoparticles and hybrid nanoparticles were studied. Raman reporters (Rhodamine B or 4-mercaptobenzoic acid) and anti-cancer drugs (paclitaxel or 5-fluorouracil) were loaded into the polymer core or shell of hybrid nanoparticles to form multifunctional nanodevices. While the noble metal unit in the nanodevices provided high light-scattering enhancement for achieving photothermal effect, the polymer component encapsulated Raman reporter molecules and put them close to the metal nanoparticles for generating high surface enhanced Raman scattering (SERS) signals. These nanodevices could also serve as excellent drug carriers, and the stimulus-triggered release of incorporated drug was studied. It was shown in this project that the conjugation of targeting ligand (e.g. folic acid) or antibody (e.g. anti-HER2 monoclonal antibody) on hybrid nanoparticles had formed novel theranostics which allowed selective detection, continuous imaging of intracellular behavior and killing of targeted cancer cells. These theranostics could be taken up by specific cancer cells through receptor-mediated endocytosis and internalized into cytoplasma of the cell. These theranostics as stable SERS-active tags and imaging agents for HeLa cells, SK-BR-3 cancer cells or MCF-7 cancer cells were demonstrated. The targeting ability and intracellular uptake of these theranostics were studied. The photothermal effect of the theranostics was investigated using different laser irradiation powers. The anti-cancer treatment could be significantly improved by the synergistic effects of chemo- and photothermal therapy when these theranostics were also tasked as the carrier of anti-cancer drugs. Therefore, combining plasmonic metal nanoparticles with targeting ligand or antibody, magnetic nanoparticles, polymer shell or core, and anti-cancer drug has created advanced theranostics for the early detection and effective treatment of cancers. These novel theranostics have greatly improved capability for cancer detection and can provide multifunctions for cancer cell targeting, sensing/imaging and combined therapy. / published_or_final_version / Mechanical Engineering / Doctoral / Doctor of Philosophy

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related deaths in the world. It is a disease with poor prognosis with unsatisfactory long-term survival of patients, and thus new strategies to control this disease are warranted. T helper (Th) 17 cells and IL-17 have recently been detected with increased frequency in a number of tumors including HCC. Its role in tumor remains controversial but its presence in HCC has been linked to disease progression, possibly involving angiogenesis. Th17 cells could be homed to inflammatory sites such as tumor microenvironment via CCR6/CCL20 axis and expand locally, and studies from other inflammatory diseases such as autoimmune disease has shown that the gut is the potential source of Th17, where its induction is affected by signals from gut microbiota. Yet this link is not yet shown in extra-intestinal tumors. Probiotics are living microorganisms, which when administered in adequate amounts confer a health benefit on the host. They have been reported to relieve chronic inflammatory diseases in animal and in human intervention studies. It is believed that probiotics regulate signals to gut antigen-presenting cells, which act as the pivot in modulating the systemic immune responses and inactivated bacteria also exhibited immunomodulatory effects in this regard. Accordingly, it was hypothesized that oral feeding of probiotics to HCCbearing animals may affect Th17 polarization and distribution and thereby modulate tumor microenvironment, which may have beneficial effect in tumor development, possibly via affecting angiogenesis. To address this hypothesis, wild-type C57BL/6 mice were fed with different heat-inactivated or viable probiotics– Lactobacillus rhamnosus GG (LGG), Escherichia coli Nissle 1917 (EcN), VSL#3 or mixture of probiotics − Prohep (heat-inactivated LGG, heatinactivated VSL#3 and viable EcN) either one week in advance or at the time of subcutaneous tumor inoculation. Probiotic feeding had improved survival in tumor-bearing mice, slowed down tumor growth and reduced tumor burden when monitored for 38 days. Probiotics showed better efficacy when feeding was given in advance. The anti-tumor effect was related to reduced angiogenesis and reduced IL-17 serum and gene expression within tumor. The mechanistic link between IL-17 modulation and tumor development was further studied in animals by IL-17 neutralization. The anti-tumor efficacy of probiotics, in relation to tumor growth and angiogenesis, was lost after IL-17 neutralization, which was linked to recruitment of myeloid suppressor cells. Since cells from both adaptive and innate immune systems could secrete IL-17, the source of IL-17 production was then identified, and found that Th17 was the major IL-17 secretor being modulated by probiotic feeding. Reduced homing of Th17 to tumor via circulation, with a tendency being recruited from gut was observed. Probiotics-mediated Th17 cell modulation in the gut by inducing the skewing of IL-10 secreting type1 regulatory T cells via dendritic cells may link to limited IL-17 mediated angiogenesis in the tumor microenvironment. With better understanding of the immunomodulation properties of probiotics, prophylactic or therapeutic efficacy in management of other inflammation-associated cancer can be availed. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

No description available.

No description available.

The syntheses of 7-N-chloroacetyllavendamycin methyl ester (55), 7-N-butyryllavendamycin methyl ester (56), 7-N-chloroacetyldemethyllavendamycin octyl ester (57), 7-N-butyryldemethyllavendamycin octyl ester (58), 7-N-chloroacetyldemethyllavendamycin isoamyl ester (59), and 7-N-butyryldemethyllavendamycin isoamyl ester (61) are described. Incorporation of the Pictet-Spengler condensation of 7-chloroacetamido-2-formylquinoline-5,8-dione (62) or 7butyramido-2-formylquinoline-5,8-dione (63) with B - methyltryptophan methyl ester (11), L-tryptophan octyl ester (64), or L-tryptophan isoamyl ester (65) in xylene directly afforded six lavendamycin analogs.The aldehydes 62 and 63 were prepared according to the following general procedure. Nitration of 8-hydroxy-2methylquinoline (66) yielded 8-hydroxy-2-methyl-5,772, and 73 are also included. 1H NMR and IR are provided compounds 67, and 71, and 1H NMR is provided for compound dinitroquinoline (67). Compound 67 was then hydrogenated and acylated with chloroacetic anhydride (or butyric anhydride) to yield 5,7-bis(chloroacet4mido)-8-hydroxy-2-methylquinoline (69) (or 5,7-dibutyramido-8-butyroxy-2 methylquinoline (71)).Compound 69 (and 71) was oxidized by potassium dichromate to give the corresponding 5,8-dione 70 (and 72). Treatment of 70 (and 72) with selenium dioxide in refluxing 1,4-dioxane afforded compound 62 (and 63). It was also noted that 71 would hydrolyze to its 8-hydroxy derivative 73 in hot methanol-water.Compound 64 was prepared through the neutralization of Ltryptophan octyl ester hydrochloride with a 14 % ammonium hydroxide solution followed by extraction. Compound 65 was synthesized via a Fischer esterification of L-tryptophan with isoamyl alcohol saturated with hydrogen chloride. The synthesis of H-methyltryptophan (44) was accomplished with the method of Snyder and Matteson.The structures of the novel compounds 55, 56, 57, 58, 59, 60, 62, 63, 69, 70, 72 and 73 were confirmed through 1H NMR, IR, EIMS, and HRMS. Elemental analyses of 62, 63, 69, 70,for 44. / Department of Chemistry

Membrane type I-matrix metalloproteinase (MT1-MMP), a member of the highly active extracellular matrix (ECM)-degrading matrix metalloproteinases (MMPs), is known to be involved in connective tissue remodelling and embryogenesis, as well as tumour invasion and metastasis. Positioned on the leading edge of the invading cell, its proteolytic activity is enhanced by activation of proMMP-2 in a complex with tissue inhibitor of matrix metalloproteinase-2 (TIMP-2). The aim of this study was to attempt to produce highly specific and immunoinhibitory antibodies against human MT1-MMP and to test whether such antibodies are able to stop invasion by blocking MT1-MMP activity. As various MMP domains are highly conserved across species, and within specific MMP groups, and human cancer cells were to be used in invasion assays, sequence alignment of human MT1-MMP domains was used to identify the most variant and, hence, the optimal laboratory species for antibody production, and the chicken was subsequently selected. A hemopexin-like or collagen-binding domain, together with the catalytic domain (PEXcat), the hemopexin-like domain (PEX) and the propeptide and catalytic domain (PROcat) were selected as target domains for antibody production. Escherichia coli or Pichia pastoris expressed PEXcat and PEX domains, respectively, were obtained collaboratively, and an E. coli expression system was used to express the PROcat domain. Urea and β-mercaptoethanol successfully solubilised PROcat inclusion body protein, and Q- and S-Sepharose ion exchange chromatography, removed majority of the E. coli contaminating proteins, yielding >200 mg/litre expressed PROcat protein. Alum adjuvant and unrenatured soluble PEXcat and PEX proteins, or the less soluble, S-Sepharose purified PROcat protein was used for inoculations of chickens. The PROcat antigen, also injected as a homogenised band in acrylamide, proved to be inferior to S-Sepharose-purified PROcat antigen in alum, as it failed to induce an antibody response. The S-Sepharose-purified PROcat antigen, in alum adjuvant, produced the highest overall response, purified anti-PROcat IgY recognising recombinant forms of MT1-MMP (33 kDa and 50 kDa) and a 63 kDa protein in human blood, concluded to be either latent, soluble MT1-MMP or a non-specific protein. These antibodies, however, failed to detect native human and murine MT1-MMP (43 kDa) in cell line homogenates, suggesting that they possibly did not recognise the zinc-binding site of the catalytic domain in the 43 kDa processed MT1-MMP. In contrast to purified IgY, crude anti-PROcat IgY preparations recognised renatured PROcat MT1-MMP (29 kDa), indicating possible binding and removal of anti-human MT1-MMP antibodies during PEG purification. Despite this, the purified IgY resulted in higher immunoinhibition of the renatured PROcat antigen than the crude IgY. Anti-PEXcat antibodies had low titre, recognising native MT1-MMP in human cell (43 kDa) and mouse macrophage homogenates, but did not recognise the original recombinant PEXcat MT1-MMP antigen or PROcat MT1-MMP, possibly due to levels of loaded antigen being too low for detection in the western blots. Although these antibodies also did not seem to recognise the catalytic domain in the western blots, the high immunoinhibitory effect induced by these antibodies suggested otherwise. The PEX antigen induced the weakest antibody response, antibodies detecting only recombinant MT1-MMP (50 kDa). The anti-PROcat IgY, overall, produced denser labelling of the MCF10A and MCF10A-neoT cell lines, than the anti-PEXcat IgY, and these antibodies preferentially recognised the PRO domain of proMT1-MMP, focused in lamellipodia of the MCF10A cell line. Comparisons between the normal and cancer cell line, the anti-PROcat IgY labelled the MCF10A-neoT cells weaker than they labelled the MCF10A cells and the labelling was spread along the plasma membrane and the base of the cell. The anti-PEXcat IgY, in contrast, showed slightly more labelling of MT1-MMP in the MCF10A-neoT cells, compared to the MCF10A cells, which may promote the invasive phenotype of this cell line. In the fixed tissue, anti-PEXcat labelled all forms of MT1-MMP, as expected. Although similar labelling was observed with the anti-PROcat IgY, these antibodies were most likely recognising proMT1-MMP. Renaturation of Q-Sepharose purified PROcat antigen, using 0.5 mM ZnCl 2 gradient dialysis, produced catalytically active, renatured protein for immunoinhibition assays, although the observed higher Km in this study possibly suggested this procedure was not a successful as a one-step dialysis procedure previously reported. Despite this, immunoinhibition assays revealed a 88%, 70% and 34% inhibition of activity by the anti-PEXcat, PROcat and anti-PEX IgY, respectively, suggesting that the anti-PEXcat IgY would be most useful in invasion inhibition studies. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2007.