Pathology - Theses

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    Application of bayesian networks to a longitudinal asthma study
    Walker, Michael Luke ( 2016)
    Asthma is a highly prevalent and often serious condition causing significant illness and sometimes death. It typically consumes between 1-3% of the medical budget in most countries and imposes a disease burden on society comparable to schizophrenia or cirrhosis of the liver. Its causes are as yet unknown but a significant number of risk factors, covering such diverse factors as viral infections during infancy, blood antibody titres, mode of birth and number of siblings have been identified. In recent years there has been increasing recognition of the role played by the microbiome in human health, with a growing understanding that our relationship with the microbes that colonise the different parts of the human body is symbiotic. Disruptions in the microbiome have been implicated in diseases such as obesity, autism and auto-immune diseases, as well as asthma. At the same time there has been an increasing awareness in asthma research that its multi-faceted and multi-factorial nature requires more sophistication than statistical association and regression. In this spirit we employ Bayesian networks, whose properties render them suitable for representing time-direct or even causal relationships, to gain insight into the nature of asthma. We begin with an example of the simplest Bayesian networks, a linear classifier, with which we predict outcomes in the fifth year-of-life according to the statistical distribution of variables from the first two years-of-life. (The qualification linear refers to the neglect of correlation and interaction among the predictive variables.)While classifiers have long been used for prognosis and diagnosis, we use them to identify useful asthma subtypes, called endotypes. Different endotypes often require different treatments and management programs, and driven by different biological factors. These different factors provide different predictors, and a predictor which separates one endotype from the healthy may not do so for a different endotype. We use this to mathematically construct an indicator of when a given predictor is exclusively predictive of a given endotype. Our so-called “exclusivity index” is quantitatively precise, unlike a significance threshold. The Cohort Asthma Study, whose longitudinal data we analyse, includes the relative abundances of genera present in the nasopharyngeal microbiome. In an apparent diversion, we use qq-plots to indicate relationships between the infant microbiome and fifth-year wheeze- and atopy- status. Interestingly, the relative abundance of Streptococcus under certain circumstances was found to be highly predictive of one of the endotypes we identified in the preceding chapter. Finally, we address the problem of mapping out the complicated interactions among multiple variables. Our model is an adaption of a package originally designed for inferring gene-interaction networks, called ARTIVA. This was a non-trivial matter requiring us to augment the discrete data values in order to make them compatible with the underlying mathematics of ARTIVA’s algorithm. With questions from the asthma literature and the posterior probabilities output by ARTIVA, we were guided to networks of the interactions between atopy, wheeze and infection, and could see the difference in the development of immunity-related variables between those who went on to exhibit wheeze in the fifth year-of-life and those who did not. Our model yielded networks indicating that sensitivity to viral infection is an effect and not a cause of atop and wheeze.
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    Investigating the mechanistic link between neuroinflammation and biometal homeostasis in neurodegenerative diseases
    Alukaidey, Lobna ( 2016)
    Neuroinflammation and biometal dyshomeostasis are two pathogenic features underlying a number of neurodegenerative diseases, however the mechanistic link between these two pathways has yet to be delineated. This study examined the hypothesis that impaired biometal homeostasis is associated with neuroinflammatory changes. To test this hypothesis I aimed to investigate the effects of key biometals on inflammatory processes in cultured microglia, and in turn, investigate how inflammatory activation of microglia affects homeostasis of biometals. These relationships were further examined in vivo to determine the effects of the type 1 interferon (IFN) pathway on biometal homeostasis in the CNS. In my in vitro study, primary murine microglial cultures were treated for 24h with maximal sub-toxic doses of biometals, delivered as ferric ammonium chloride (FAC), ZnCl2 and CuCl2 and the biometal chelators, diamsar or N,N,N_,N_-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) with and without concurrent interferon-_ (IFN_) and tumour necrosis factor-_ (TNF_) stimulation. Non-stimulated and IFN_/TNF_ stimulated microglia served as negative and positive controls for inflammatory activated microglia, respectively. I measured the levels of a number of key inflammatory cytokines to assess microglial inflammatory response to biometal and biometal chelator treatments. I found that FAC and CuCl2 treatment, significantly induced Fe and Cu uptake respectively, in both non-stimulated and stimulated microglia and that all biometal treatments, significantly reduced the expression of MCP-1 in stimulated and non-stimulated microglia, indicative of an anti-inflammatory role. In contrast, FAC treatment also induced TNF_ mRNA expression in these cultures, suggesting Fe may play a dual role in neuroinflammation. In addition, to investigate how inflammatory activation of microglia affects biometal homeostasis, the gene expression of the metal-binding protein, metallothionein-1 (MT-1) and the biometal transporter, ZRT/IRT-like transporter protein (Zip7) were also measured. I also found that IFN_/TNF_ stimulation inhibited Fe-induced MT-1 and Zip7 expression in microglia. These findings demonstrate that sub-toxic levels of key biometals have multiple modulatory actions on cultured microglia, with both inhibitory and stimulatory effects on cytokines. These changes may be associated with induction or inhibition of major metal response proteins, such as MT-1 and transporters. To examine the effects of the type 1 IFN pathway on biometal homeostasis in the CNS, I performed a spatio-temporal analysis of Fe, Zn, Cu and Mn levels in the CNS of interferon _ receptor-1 (Ifnar1) knock-out (-/-) mice and wild type (WT) mice at 6 and 10 months of age using ICP-MS analysis. A subset of 6-month-old Ifnar1-/- mice was also stimulated with lipopolysaccharide (LPS) treatment for 6h to determine the effects of Ifnar1-/- on biometals homeostasis under inflammatory conditions. I found reduced Cu and Mn levels in the cerebellum of aged (10-month-old) Ifnar1-/- mice, however, expression of key Cu and Mn transporter and regulatory proteins remained unchanged. I also found no significant alterations to biometals between WT and Ifnar1-/- mice at 6-month of age, however, when mice were challenged with LPS, I found a significant decrease in Fe levels in the cerebellum and cerebrum of WT mice and a significant decrease in Zn levels in the cerebrum of Ifnar1-/- mice compared to naïve mice of their respective genotypes. A significant increase and an upward trend in transferrin receptor1 (TfR1) levels in the cerebrum of LPS-challenged and naïve Ifnar1-/- mice, respectively was also observed. These data demonstrate that the type 1 IFN pathway is involved in the regulation of CNS biometal homoeostasis. The studies provide further evidence to support a major role for biometals in neuroinflammatory pathways, with important implications for neurodegenerative disease in which brain biometal homeostasis is altered.
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    Investigating the predictors of sensitivity to the Chk1 inhibitor PF-00477736 in melanoma
    Wicaksono, Britanto Dani ( 2013)
    Chk1 and Chk2 are two of the most important and highly studied checkpoint kinases that help protect cells from endogenous or exogenous insults which could damage DNA. When activated they arrest cell cycle at specific checkpoints in order for cells to repair damage before resuming the cell cycle and mitosis. Recently, several inhibitors of Checkpoint kinases have been developed which were designed to sensitise TP53 mutant cancers with defective G1 checkpoints to DNA damaging chemotherapy. However, a recent study has demonstrated that TP53 mutation alone does not predict sensitivity to Chk1 inhibitors. Moreover, inhibition of Chk1 by PF-00477736 (PF-736) as a single agent was also recently shown to be effective in mediating p53-dependent apoptosis in lymphoma cells by increasing the level of MYC oncogene-induced DNA damage. Other reports have also shown that mutant BRAF and RAS (NRAS) which are the predominant oncogenes found in melanoma could induce DNA damage in epithelial cells and thyroid cancers, respectively. This led to the hypothesis that melanomas which are predominantly TP53 wild-type and BRAF or NRAS mutant would be responsive to Chk1 inhibitors as single agents. Screening for drug sensitivity across a panel of 30 melanoma cell lines showed a wide range of IC50 values following 3 days treatment with PF-736. BRAF and TP53 mutation status were not found to affect sensitivity to PF-736. Due to unavailability of NRAS mutation data at the time of analysis, it is still unconfirmed whether BRAF and NRAS as the source of oncogene DNA damage in melanoma influence the sensitivity of melanoma to PF-736 treatment. Several cell lines categorised as sensitive was revealed to have high Total Growth Inhibition (TGI) values. This suggests that there may be genetic variations in the cells that have high TGI particularly in cell death activation pathways that affect the sensitivity of these cells to Chk1 inhibition. Previously, it has been reported that up-regulation of p53 negative-regulators such as Mdm4 and Bcl-2 family anti-apoptotic proteins were responsible for the defective p53-mediated apoptosis responses in p53 wild-type melanomas. Overexpression of BCL2 or BCLxl was able to prevent apoptosis in C002-M1, a cell line that underwent apoptosis following PF-736 treatment. However, MCL1 overexpression did not result in similar effect. Assessment of Mdm4 basal protein levels did not reveal any significant correlation with PF-736 IC50. Further assessment utilising MDM4 knockdown by shRNA in the A375 cell line expressing high Mdm4 protein expression did not result in sensitisation to PF-736. These data suggested that the increased levels of Bcl-2 or Bcl-XL proteins were able to decrease the level of apoptosis but did not significantly alter sensitivity to PF-736 in C002-M1 cell line. Additionally knockdown of MDM4 levels did not alter PF-736 IC50 in a cell line with high Mdm4 protein expression. Hence it is possible that other cellular characteristics such as the level of inherent DNA damage recently reported to be important in sensitivity of melanoma to Checkpoint kinase inhibition, could provide more insight in revealing factors that determine the sensitivity of PF-736 in melanoma. γH2AX is a marker of double strand break which can be utilised as a measure of DNA damage. In an attempt to assess γH2AX as a biomarker of sensitivity, the levels of inherent γH2AX and fold change following PF-736 treatment was determined. The result showed that high level of inherent γH2AX showed a significant correlation with low PF-736 IC50, suggesting that high levels of endogenous DNA damage is associated with sensitivity to PF-736. Furthermore, the average fold increase in levels of γH2AX after PF-736 treatment across the entire cell line panel also significantly correlated with PF-736 IC50. Additionally, we discovered that increase in pChk2 T68 levels following PF-736 treatment also correlated with response to PF-736 in the 30 melanoma cell line panel. Increase in pChk1 S345 following Chk1 inhibition, previously reported as a potential pharmacodynamic biomarker of Chk1 inhibition was confirmed across the panel following the same PF-736 treatment demonstrating the biomarkers identified were associated with Chk1 inhibition. A significant component of this project was to identify predictors of sensitivity using a pharmacogenomic whole genome-wide approach and a candidate approach. For the candidate approach, gene expression of selected genes from pathways related to the DNA damage response pathway for the 30 melanoma cell line panel were analysed with IC50 from SRB assay utilising linear regression analysis to search for significant correlation between sensitivity to PF-736 and gene expression. Gene expression of NBN, CHK2, RAD21 and RAD54B, which are components of the DSB repair particularly HR repair, significantly associated with sensitivity to PF-736. An unbiased Pearson correlation analysis between whole-genome gene expression microarray data and IC50 data from SRB assay of the 30 melanoma cell line panel also showed good correlation between DSB repair genes and sensitivity to PF-736. From this analysis, RAD21 and RAD54B were showed to have a good correlation with sensitivity to PF-736. An SVM prediction model built using the gene expression data pre-processed using the Pearson correlation analysis to include only genes that are differentially expressed across the panel and their sensitivity to PF-736 based on IC50, to discover a gene set that can classify melanoma cell lines between sensitive and resistant to PF-736. The result showed that the SVM model was able to predict at 100% accuracy with a cut-off of 2048 nM. Some of the genes included in the gene set for the SVM prediction model were genes that are important for DSB repair particularly HR such as RAD21, RAD54B and NSMCE2 confirming the importance of this specific DNA repair pathway in association with sensitivity to PF-736 particularly in melanoma. In conclusion, this study has revealed the importance of the DSB Response pathway in predicting the sensitivity to the Chk1 specific inhibitor PF-736 in melanoma. As there are also several other cancers which exhibit oncogene-induced DNA damage and aberrant DSB repair pathways, this study may help in predicting the sensitivity of these types of cancers in with single agent Chk1 therapy. Furthermore, this project has verified that melanoma cell lines are sensitive to Chk1 inhibition therapy as a single agent and that the level of inherent DNA damage may provide insight into the sensitivity of melanoma to Chk1 inhibition. Moreover, candidate and genome-wide pharmacogenomic analyses have revealed the importance of DSB repair pathway and Bcl-2 family anti-apoptotic genes in predicting sensitivity to Chk1 inhibition. Although functional study on C002-M1 cell line did not show evidence that the level of Bcl-2 family anti-apoptotic proteins can affect sensitivity, the western blot data, candidate gene and genome wide predictor analysis across the 30 melanoma cell line panel showed that there is a significant correlation between Bcl-2 family anti-apoptotic proteins particularly Bcl-XL to sensitivity to PF-736, which warrants further investigation. As a future direction, the current predictor model will need to be tested with a validation set of samples, to test its robustness in predicting sensitivity to single agent Chk1 inhibition therapy. To progress further the assessment of the usefulness of Chk1 inhibition therapy in melanoma, an investigation on Chk1 inhibition in combination with DNA damaging chemotherapy which was shown to be promising in the preliminary study, will need to be carried out.
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    Some forensic aspects of chemical tests for alcohol
    Bayly, Ronald Cecil ( 1960)
    The problem surrounding the ever-increasing toll of death and injury arising from road accidents is one which is receiving increasing attention as the number of vehicles on the road continues to rise. While it has not been possible to isolate any one factor as the sole or even primary cause of road accidents, several surveys have shown that in many accidents alcohol has been a contributory factor by affecting the faculties of the driver of pedestrian. The thesis then goes on to discuss factors causing individual differences in response to the same blood alcohol concentration and the correlation between impairment of driving and blood alcohol concentration.
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    Functional and molecular changes of mitochondria in human aging: observations in dividing tissues
    Weng, Shan ( 2000)
    Studies in a number of human tissues have revealed that the activities of mitochondrial respiratory chain enzyme complexes decline during the aging process. Other studies have suggested that aging increases the frequency of mitochondrial DNA (mtDNA) mutation and leads to the accumulation of mutant mtDNA species, mainly those with large deletions and point mutations. Although the mitochondrial theory of aging may be more applicable to post mitotic tissues, abnormalities of mtDNA have also been reported in tissues which retain a mitotic capacity. Fresh tissues from elderly patients are difficult to obtain and only a limited number of studies on biochemical examination of respiratory chain enzyme complex activities have been carried out. Prostate tissue is readily available in elderly male subjects because of the high prevalence of benign prostatic hypertrophy in this sub-group of the population, and endoscopic surgery is routinely performed for excision of the diseased prostate. In this study, mitochondrial respiratory function and the mtDNA mutations in prostate tissues of elderly patients (aged from 56 to 92) were studied in 24 subjects. This included the measurement of the activities of the respiratory chain enzyme complexes and screening for mitochondrial point mutations and deletions at sites commonly affected in neurodegenerative diseases. (For complete summary open document)
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    Delineating the tumor suppressive role of Scribble in prostate cancer progression and metastasis
    Borsetti, Yvonne Christine ( 2013)
    Cell and tissue polarity are distinguished by the asymmetrical distribution of cytoplasmic and membrane components that allows the formation of structurally and functionally distinct domains within cells, and the organisation of multilayered tissues. This asymmetry is required for many cellular processes including migration, interaction with the microenvironment, diversification of cell shapes and development. To establish cellular polarity several polarity regulators are required, such as Scribble, whose loss results in deregulated cellular functions. Scribble is localised at the baso-lateral membrane, which is crucial for its normal functionality. Mislocalisation, which appears as diffuse expression within the cytoplasm, also results in disrupted cellular polarity and therefore impacts polarity regulated cellular functions. Scribble is widely accepted as an evolutionarily conserved tumor suppressor that is often deregulated in many human epithelial cancers, and is generally considered to contribute to tumor progression. Loss of cell and tissue polarity is a hallmark of epithelial cancers suggesting a crucial role for polarity regulators in suppressing tumor formation and progression(1). Interestingly, Scribble is also found to be overexpressed in many epithelial cancers, including prostate cancer, while mislocalization in prostate cancer rather than overexpression correlates with poor patient outcome in the clinic. Scribble has been shown to be a weak initiator of prostate neoplasia in mice owing to elevated Ras/MAPK signaling. Furthermore, Scribble depletion and K-Ras-oncogenic activation have been shown to cooperate in vivo, resulting in an increased incidence of invasive prostate carcinoma compared to single mutants, indicating that Scribble loss can contribute to tumor progression in the presence of an additional oncogenic mutation. Nonetheless, the molecular mechanisms underpinning tumour progression in the context of Scribble loss are not well understood. To directly assess the role of Scribble in prostate carcinogensis and metastasis, in vitro functional assessment of PC3 prostate cancer cells expressing constructs to knockdown (shSCRIB7), overexpress (hSCRIB) or mislocalize (SCRIB P305L) Scribble together with in vivo experimental models of metastasis have been performed. This work shows that Scribble is upregulated in PC-3 cells and that Scribble plays a role in coordinating directed cell migration and invasion, but does not mediate PC-3 cell cycle progression or proliferation in vitro. In addition, by employing the well characterized prostate cancer transgenic mouse model (PBCre+;Ptenfl/fl), in combination with Scribble depletion, it appears that loss of Scribble and Pten cooperate to facilitate invasion, associated with a reduction in the cell:cell adhesion molecule E-cadherin. Collectively, these findings establish that Scribble functions to coordinate prostate cancer cell migration and invasion and that deregulation of Scribble (either by over-expression, depletion or mislocalisation) causes aberrant migration and invasion. Further investigations into understanding how Scribble and the polarity network can regulate migration and invasion during prostate cancer on a molecular level may provide valuable insights into the mechanisms behind prostate cancer progression and prove to hold prognostic value in the clinic, as well as identify novel routes of therapeutic intervention.
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    Molecular characterisation of IFN-γ induced Stat1-independent and Erk1/2- and AP-1-dependent signalling pathway and genes that respond to IFN-γ
    Arthur, Helen Anne ( 2013)
    Interferon (IFN)-γ regulates a diverse range of biological activities that includes anti-pathogenic, anti-cancer and immunoregulatory effects. IFN-γ mediates these activities by regulating changes in gene expression via intracellular pathways. Although the canonical IFN-γ-induced Jak/Stat1 signalling pathway is the primary mechanism regulating gene expression, IFN-γ activates multiple intracellular cascades. There is evidence suggesting that Stat1-independent pathways are important for IFN-γ activity since a third of IFN-γ regulated genes (IRGs) were regulated in the absence of Stat1 (Gil, Bohn et al. 2001) and Stat1-/- mice were more resistant to viral challenge than mice deficient in type I and II IFN receptors (Gil, Bohn et al. 2001; Shresta, Sharar et al. 2005). Our laboratory identified the downstream components of a novel Stat1-independent signalling pathway that activated Erk1/2 and AP-1 and regulated transcription of IRGs (Gough, Sabapathy et al. 2007). However, the upstream components of this pathway have not been characterised. Since Stat1 was not required for IFN-γ-induced activation of Erk1/2 and AP-1 I hypothesised that this pathway is entirely independent of canonical IFN-γ Jak/Stat1 signalling. In support of this, studies have shown that IFN-γ-induced engaged multiple membrane-proximal kinases such as the PI-3K/Akt and adapter proteins such as MyD88 independent of Stat1 and/or Jak proteins. Therefore I hypothesised that Jak1 and Jak2 were not required for activation of the IFN-γ induced Stat1-independent Erk1/2 and AP-1 pathway or to regulate transcription of IRGs. Therefore, alternate kinases or membrane associated proteins would be recruited to the IFN-γ receptor (Ifngr) to activate Erk1/2 and AP-1 and regulate gene expression. The most appropriate method to investigate IFN-γ-induced Jak1 and Jak2-independent signalling is the use of a doubly deficient Jak1/Jak2 model. However, since Jak1-deficient and Jak2-deficient mice are not viable, Jak1-/-/Jak2-/- mice are not viable either and there is no published literature on a doubly deficient Jak1/Jak2 model. The studies in this thesis developed and fully characterised the first reported doubly deficient Jak1/Jak2 model. In a novel finding the signalling analyses performed using doubly deficient Jak1/Jak2 cells demonstrated that IFN-γ-induced activation of Erk1/2 and likely AP-1 was independent of Jak1 and Jak2. Therefore building on previous findings by our laboratory the data in this thesis established that IFN-γ-induced a Jak1/Jak2/Stat1-independent and Erk1/2/AP-1-dependent pathway. Since Jak1 and 2 were not involved IFN-γ must engage another mechanism to active downstream Erk1/2. The studies in this thesis excluded a role for c-Src; therefore alternate signalling molecules must be recruited to the Ifngr. Gene expression analyses showed that transcription of the Immediate Early Genes c-Jun and Nfkbia appeared to be independent of Jak2 but not Jak1. Further analyses performed using a larger gene subset of genome wide studies are required to identify a subset of IRGs potentially regulated by Jak1/Jak2/Stat1-independent and Erk1/2/AP-1-dependent pathway. The studies in this thesis suggest that the Erk1/2 and AP-1 pathway may represent a primary yet transient response to IFN-γ that regulates gene expression independent of canonical Jak/Stat1 signal transduction. Determination of the cellular and biological effects regulated by the non-canonical Erk1/2/AP-1 pathway may have important implications for our understanding of the anti-viral, anti-cancer and immunomodulatory effects of IFN-γ.
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    An assay to screen for mutant p53 gain of function using high content imaging
    Brown, Daniel Victor ( 2012)
    The p53 tumour suppressor gene is mutated in approximately half of all human cancers. These mutations not only inactivate the growth inhibitory functions of wild type p53 but certain mutations also confer additional oncogenic properties. These gained functions may contribute to the increased growth rate, resistance to apoptosis, reduced chemosensitivity and increased invasiveness of mutant p53 bearing tumours. For the purposes of discovering novel mediators of mutant p53 gain of function, a multi-parameter assay was developed for future use in a high throughput siRNA screen. Mutant p53 expressing cells were demonstrated to display an increased migratory phenotype in vitro compared to p53 null cells. A wound healing endpoint assay was adapted to a 96 well format using automated liquid handling and image capture. An image analysis algorithm was designed to accurately measure cell migration in a high throughput manner. Performing a low throughput pilot screen of a panel of siRNAs demonstrated that the general migration machinery was necessary for migration. However, knockdown of known components of the mutant p53 pathway failed to provide the robustness necessary for a high throughput screen. p53 protein stability is known to be regulated at multiple levels involving a complex network of feedback loops. Unlike the case with wtp53, the regulation of mutant p53 is only partially understood. A high content assay for mutant p53 stability was developed. The immunofluorescent staining protocol was adapted to a 384 well assay and an algorithm was designed to accurately measure pixel intensity in the nucleus and cytoplasm. A statistically significant and robust downregulation of mutant p53 was measured with siRNA against mutant p53. A pilot screen in endogenous mutant p53 cell lines demonstrated a sufficiently large assay window to identify siRNAs that reduce mutant p53 stability. A genome wide siRNA screen for genes that reduce mutant p53 could uncover novel therapeutic targets, which will enable the design of new molecularly targeted therapeutics. Drugs able to impede the action of mutant p53 will be relevant to a significant proportion of human cancers.
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    The role of involved node radiotherapy (INRT) as a new application of radiotherapy in the management of limited stage lymphomas
    Campbell, Belinda Anne ( 2011)
    Radiotherapy is well recognised as an effective treatment modality for Hodgkin lymphoma (HL), follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), and is routinely incorporated into the treatment strategies for favourable-risk, limited stage disease to optimise local control and thereby improve progression-free survival. However, long-term survivors are at risk of late radiation-induced toxicities, including the risk of second malignancy. The rationale of involved node radiotherapy (INRT) is to reduce the size of the radiotherapy field to cover only the original sites of lymphoma, with the aim of lowering the incidence of radiation-induced toxicities whilst maintaining high rates of local lymphoma control. Reducing the radiotherapy field size lowers the radiation exposure to organs at risk, and this is likely to be associated with a lower incidence of radiation-induced toxicities. However, in practice it is difficult to quantify the risk of late toxicities due to the long latency period and the large numbers of patients required to detect the less common effects. Therefore, reducing the radiation dose parameters of organs at risk is proposed as a surrogate end point for lowered risks of late, radiotherapy-induced toxicities. The aims of this research are to assess the patterns of failure and survival rates of patients treated with INRT for favourable-risk, limited stage lymphoma (HL, FL, DLBCL), compared to patients receiving larger, conventional radiotherapy fields. For each lymphoma group, a population-based, retrospective study is performed to analyse these endpoints. Additionally, a radiotherapy planning study is performed on 10 randomly selected female patients with supra-diaphragmatic HL, to quantify the dosimetric advantages of INRT compared to larger conventional radiotherapy fields, on organs at risk of late toxicities. The results of these studies demonstrate that INRT fields can safely replace larger, conventional radiotherapy fields in patients with limited stage HL, FL and DLBCL, without detrimental effects on prognosis. Furthermore, supra-diaphragmatic INRT fields reduce the radiation exposure to lungs, breasts and thyroid, and may thereby reduce the risk of second malignancy in these organs. In conclusion, replacing conventional radiotherapy fields with smaller INRT fields is likely to improve the therapeutic ratio in long-term survivors of favourable-risk, limited stage HL, FL or DLBCL.
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    PI3K pathway alterations in gastric cancer
    Tran, Thang Nam ( 2011)
    Gastric cancer is a considerable health issue worldwide and remains a major challenge for the oncology community. The phosphatidylinositol-3 kinase (PI3K) signaling pathway is constitutively activated and/or upregulated in various malignancies and activation of this pathway plays a critical role in tumour progression. Alterations of PI3K pathway in gastric cancer and its correlations to clinicopathologic features were investigated followed by exploration of PI3K targeted cancer therapy in vitro. It was shown that PI3K pathway alterations occur frequently in gastric carcinoma. PI3K inhibitor (LY294002) was demonstrated to be sensitive in certain types of gastric cancer cell lines as well as have synergistic effect with conventional cytotoxic agents (5-FU and Oxaliplatin).