No description available.

No description available.

The purpose of the present thesis was to better understand the effect of targeting key biological mechanisms in order to improve radiotherapy response. Two important and distinct pathways were targeted using novel agents: (1) the phosphoinoside-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway; (2) the ataxia telangiectasia-mutated-Rad3-related (ATR)/Chkl pathway. The role of the PI3K1mTOR signalling pathway in tumour radiosensitivity and tumour microerivlronment (TME) was examined using three, recently-developed signalling inhibitors obtained from Novartis Pharma: NVP-BEZ235 (dual PI3K1mTOR inhibitor), NVP-BGT226 (dual PI3K1mTOR inhibitor) and NVP-BKM120 (single PI3K inhibitor). The radiosensitising potential of NVP-BEZ235 and NVP-BGT226 was demonstrated in tumour and endothelial cells. Additionally, a thorough research into the effects ofNVP-BKM120 and NVP-BEZ235 on TME showed that oncogenic signalling inhibitors can improve vascular morphology and increase tumour oxygenation and perfusion in tumour xenograft models, resulting in improved radiation response. Furthermore, a highly potent and selective A TR inhibitor, VE-822, that was obtained from Vertex Pharmaceuticals (Europe) Ltd, was tested in pancreatic ductal adenocarcinoma (PDAC) cells and tumour xenograft models. A TR inhibition by VE-822 resulted in sensitisation of tumour cells but not normal cells to radiation and gemcitabine. Similarly, VE-822 strongly enhanced radiation- and chemoradiation-induced tumour growth delay in tumour xenograft models. Importantly, VE-822 did not potentiate radiation-induced gastrointestinal tract epithelial damage. To summarize, the impact of targeting two distinct pathways in combination with radiation and chemoradiation was explored. Inhibition of the PI3K1mTOR and ATRlChkl signalling pathways increases response of tumours to radiotherapy they and might be promising targeting strategies for cancer treatment. Our findings have considerable translational implications and future clinical trials should aim to validate these observations.

University of Macau / Faculty of Health Sciences

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

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.