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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
281

Young people's experiences of neurofibromatosis type 1

Barke, J. January 2014 (has links)
Neurofibromatosis type 1 (NF1) is a genetic condition which can result in varying degrees of visible difference (disfigurement). There is currently very little research into the psychosocial impact of NF1, particularly during adolescence, a time when health behaviours are consolidated and appearance concerns become more salient. While clinical reviews, research and case studies have suggested that appearance is likely to play an important role in the lives of people with NF1, how young people manage appearance concerns and the possibility of a changing appearance on a day-to-day basis has not specifically been researched. The impact of appearance changes (and potential changes) associated with the condition are therefore an important area to understand further. In order to explore the role of appearance within young people’s experiences of NF1 this thesis takes an exploratory qualitatively driven mixed methods approach. In-depth interviews were carried out with 19 people; nine young people aged 14-24 with a diagnosis of NF1; seven parents of young people with NF1 and three health professionals who work with people with NF1. Interviews were thematically analysed and subsequent themes informed the development of mixed methods surveys of young people with NF1 (n=73), parents (n=55) and health professionals (n=53). Both interview and questionnaire data highlighted the variety in young people’s experiences of NF1. While appearance was important to young people, this was primarily in terms of general appearance evaluations and managing the uncertainty of possible future changes to their appearance rather than how noticeable they felt the condition was. While health professionals agreed with this assessment, an important difference between participant groups was that parents felt that the noticeability of symptoms impacted on their child’s experience. All participant groups underlined the importance of managing social interactions and the reactions of other people. Participants also highlighted a need for greater awareness and understanding of NF1, and access to trustworthy information and advice about their condition. Suggested applications from findings discussed in this thesis include providing young people with age appropriate information regarding their condition, in different formats including access to health professions who are specialists in genetics or NF1. Young people may also benefit from targeted help and support related to social skills, specifically including support in talking about NF1 and answering questions about their condition. It is suggested that future research should explore how young people with NF1 and their parents manage uncertainty and noticeability. This thesis contributes to the literature by providing data from groups who are under researched about an aspect of their experience that has not been explored. By employing a range of methods and including different participant groups an in-depth, detailed understanding of the role that appearance plays within young people’s experiences of NF1 is provided.
282

Patient involvement in multidisciplinary team decision making in head and neck cancer : an ethnographic study

Hamilton, David Winston January 2014 (has links)
Head and neck cancer (HNC) confers a poor prognosis and patients face complex treatment decisions. As with every cancer in the UK, recommendations for treatment are made through a multidisciplinary team (MDT). This thesis critically analyses the working of the MDT: data are presented from an ethnographic study across three head and neck cancer treatment centres. Data collection comprised non-participant observation of 35 MDT meetings and 37 MDT clinic appointments and semi-structured interviews with 19 patients pre- and post-treatment and nine staff members of the MDT. Data generated were analysed using a Constructionist Grounded Theory approach, drawing on symbolic interactionism and dramaturgical analysis. This thesis provides an in depth account of the backstage behaviour of the MDT members. Although an assessment of which treatment is considered ‘best’ drives their discussion, there is often disagreement or uncertainty surrounding this assessment. On delivering the recommendation to the patient, this backstage work often remains hidden, contributing to problems when offering treatment choice. Even when a choice of treatment is acknowledged, the MDT faces barriers in delivering and supporting this in the MDT clinic. For the patient, the majority of the work of decision making takes place away from the MDT clinic, a process which is not always supported by the MDT The difficulties of actively involving patients in the MDT decision process have never been explored, but the complexities of offering treatment choice in the MDT need to be recognised to support patients in this setting. The guiding principles, purpose and limitations of the MDT meeting and the resultant treatment recommendation need to be iii clear. A process of collaborative MDT decision making should allow effective communication of treatment risk and uncertainty, structured elicitation of patient preferences and support for patients to make decisions in line with their preferences and values.
283

Post chemoradiation re-staging of rectal cancer using MRI

Patel, Uday January 2012 (has links)
The role of MRI after preoperative treatment of rectal cancer is unclear. This thesis investigates its diagnostic relevance in patient management. Matching pathology with MR images aimed to characterise post treatment rectal cancer appearances on T2 weighted MRI and verify the proposed MRI tumour regression grading system(mrTRG). Correlation of post-chemoradiation mrTRG, T stage(ymrT), N stage(ymrN) and Circumferential Resection Margin(ymrCRM) with histopathological T stage(ypT), N stage (ypN), and pathological CRM(pCRM) was investigated. These parameters were also compared against survival outcomes. The alternative response assessment methods of tumour volume and length change/RECIST as well as mrTRG and ymrT were evaluated against pathology. The accuracy and reproducibility of MRI parameters in assessing rectal cancer response to neoadjuvant chemotherapy was also investigated. Patients with good response to chemoradiation(assessed by mrTRG) were enrolled into a deferral of surgery trial. Serial MRI-based monitoring enabled evaluation of quantitative imaging methods such as Apparent Diffusion Co-efficient (ADC) measurements in distinguishing tumour vs. complete response. Pathological fibrosis correlated with low signal on MRI, tumour was intermediate signal. mrTRG showed good diagnostic accuracy against ypT&pTRG, ymrT's diagnostic accuracy was fair but improved when grouped into favourable and unfavourable categories. MRI Length&volume assessment were less consistently related. Negative ymrN and potentially clear ymrCRM correlated well with their respective pathological endpoints. Importantly, mrTRG and ymrCRM involvement predicted survival outcomes. mrTRG showed good diagnostic accuracy against pTRG when assessing neoadjuvant chemotherapy response, ymrT correlated less well. Overall mrTRG and ymrT were the most reproducible parameters. ADC values were significantly lower in patients with tumour vs. complete response with ADC measurement of <1.3X10-3/mm2/sec associated with tumour regrowth in 86% of cases. mrTRG and MRI CRM assessment appear the most important post treatment imaging parameters. Grouped ymrT may also be useful. These parameters could be used by the multidisciplinary team to tailor treatment pre-operatively.
284

Study of immunomics and immune regulation in ovarian cancer

Abdul Aziz, Nor Haslinda January 2013 (has links)
Immunological suppression and regulation may be involved in tumour progression in many cancers. An integrated study has been carried out with regard to the protein expression of immune surface markers, soluble cytokines as well as the functional analysis of immune cells and their relationship to ovarian cancer and its prognosis. Peripheral blood, ascites, and tumour tissues were collected from patients with untreated ovarian cancers and benign ovarian tumours. Peripheral Blood Mononuclear Cells (PBMCs) from healthy women were used as a control. The immune cells that had been isolated for phenotypic analysis were analysed for immune surface and activation marker expressions using flow cytometry. Ovarian cancer tissues were used for immunohistochemistry (IHC) and for tissue RNA extraction to screen immune-related genes by quantitative real time PCR (qRT-PCR). Functional and enzymatic assays were performed to further characterise the regulatory and inhibitory molecules in the patients' PBMCs and ascites. It was found that the expression of regulatory T cells and T cell associated programmed death-1 molecule (PD-1) was significantly upregulated in cancer patients on the T cells. The programmed death ligand-1 (PD-L1) expression on monocytes from the patients' PBMCs and ascites was observed to have significantly increased in patients with ovarian cancer compared to women with benign diseases. From the functional results, it was hypothesised that PD-L1 may be involved in T cell dysfunction in ovarian cancer. The PBMCs, ascites, and tissues from ovarian cancer patients were also used to study the expression and potential role of immunomodulatory enzymes such as indoleamine 2,3-dioxygenase (IDO) and arginase in ovarian cancer.
285

Blood DNA methylation biomarkers for breast cancer risk

Brennan, Kevin January 2013 (has links)
Breast cancer is the most common malignancy affecting women worldwide with an average lifetime risk of 12%. Risk is affected by age, family history, genetics, reproductive factors and environmental exposures, however many unknown risk factors may exist. Regular screening, lifestyle advice and preventative therapy may be offered to women at highest risk; however in the absence of high-penetrance mutations, personal breast cancer risk cannot be accurately estimated. Risk biomarkers are therefore required to help improve current risk prediction models. Epigenetic mechanisms control gene expression and genome function, and are influenced by both heritable and environmental factors. DNA methylation, the most widely studied epigenetic mark, is widely deregulated in cancer and cancer precursor lesions; however the contribution to disease risk of DNA methylation variability in normal tissue prior to disease is poorly understood. Several blood DNA methylation markers associated with cancer have been reported, including genome-wide hypomethylation and hypermethylation of the ATM gene associated with breast cancer, however, validation of these associations in samples collected prior to diagnosis (prospectively collected) are required to determine association with breast cancer risk. The aims of this thesis were to 1) validate ATM methylation as a breast cancer risk marker in three nested case-control studies from prospective cohorts; 2) To investigate hypomethylation of LINE1 in the same prospective cohorts and compare this in a metaanalysis with all other published LINE1 data; 3) To investigate potential mechanisms or modifiers of ATM methylation; 4) To perform discovery microarray studies to identify novel DNA methylation markers of breast cancer risk. Herein, we show that ATM hypermethylation showed a 1.9 fold increased risk of breast cancer limited to women in the highest quintile of methylation (OR =1.89 (1.36-2.64), p= 1.64x10-4). There was no evidence of LINE1 methylation associated with cancer risk in the prospective cohort studies. The meta-analysis 3 of LINE1 and other global methylation markers showed little evidence of association with cancer risk for surrogate assays of repetitive elements, but relatively consistent association with cancer risk using HPLC based total methyl-cytosine levels. Investigation of potential modifiers of ATM methylation revealed that methylation was independent of genetic haplotype, but independently associated with age, genotype of the one-carbon metabolism enzyme MTHFR, and serum levels of serum kynurenic acid levels in controls (p=0.02). Surprisingly, ATM methylation was reduced in controls (p= 5.707e-06) and cases (p= 0.008) that had fasted compared to those that had not. The effect of fasting on ATM methylation could be recapitulated by glucose restriction in ex-vivo PBMCs (p=0.046), independent of cell proliferation. Discovery studies to identify novel DNA methylation risk markers were conducted using differential methylation hybridisation and Illumina Infinium HumanMethylayion450 BeadChip microarrays; however, significant associations were not reproducible in validation sample sets. Discussed are prospects and caveats for epigenetics association studies, including the implications of temporal alteration of DNA methylation by environmental exposures, biases associated with genetic influences on DNA methylation, and the potential for investigation of these interactions to better understand the contribution of epigenetics to gene expression and cancer risk.
286

Role of thymidine kinase 1 phosphorylation on 3'-deoxy-3'-[18F]-fluorothymidine uptake by cancer cells : implication for Positron Emission Tomography

Sala, Roberta January 2013 (has links)
Uncontrolled cell proliferation is one of the hallmarks of cancer and its inhibition is desired in cancer therapy. The thymidine analogue 3'-deoxy-3'-[18F]-fluorothymidine ([18F]FLT) is used to image tumour proliferation by positron emission tomography (PET). To be retained in cells, [18F]FLT is phosphorylated by thymidine kinase 1 (TK1), the first enzyme in the salvage pathway for DNA synthesis, and for this reason the cellular incorporation of [18F]FLT is dependent on TK1 activity. Of the mechanisms regulating TK1 activity, TK1 transcription is well recognised while post-translational enzyme modifications are less well understood. TK1 protein phosphorylation was investigated in cancer cells, hypothesising that, throughout the cell cycle, but particularly during G2/M phase, TK1 is subjected to different types of phosphorylation, which are responsible for regulating its activity, and therefore potentially modulating [18F]FLT uptake. An acrylamide phos-tag™ gel method was validated to enable discrimination of phosphorylated TK1. Three different phosphorylated forms of TK1 were detected during progression of cells within the cell cycle, one of which was specifically produced upon G2/M arrest. There were significant changes in [18F]FLT uptake subsequent to cell cycle arrest by biological means and following treatment with anti-cancer drugs and pharmacological modulators. Changes in TK1 enzyme activity were detected as variations in [18F]FLT retention, with significantly reduced uptake upon serum starvation-induced G1 arrest, and marked decreased uptake during S-phase arrest and after nocodazole- or paclitaxel-induced G2/M arrest. Phosphorylation of serine-13 and serine-231 of TK1 were implicated in regulating [18F]FLT uptake. To assess whether or not [18F]FLT-PET highlighted changes in proliferation in vivo, HCT116 tumour-bearing mice were treated with paclitaxel. Although long term treatment resulted in tumour growth delay, in the model and at drug doses and early time points considered for imaging, no significant changes in tumour [18F]FLT retention were observed in treated animals compared to controls. This correlated with similarly unremarkable changes in Ki67 and TK1 expression in excised tumour samples. Investigation of whether or not alternative nucleoside analogue scaffolds were incorporated into the DNA and if they were providing greater sensitivity for detecting cell proliferation, compared to [18F]FLT, was carried out. Two new radiotracers ([18F]FTT and [18F]FOT) were developed and tested for a) phosphorylation by TK1, b) accumulation into cells and c) metabolism and biodistribution. Both radiotracers proved not to be useful, being minimally phosphorylated by TK1 and therefore not retained in cells, and showing catabolism in vivo. Finally, specific mitotic inhibitors were characterised in vitro to determine their effects on TK1 phosphorylation and proteins involved in [18F]FLT uptake, in order to verify if [18F]FLT is a suitable biomarker to highlight mitotic arrest with these modern drugs. The key novel finding to evolve from this thesis is that measurement of tumour proliferation by [18F]FLT-PET is modulated by TK1 phosphorylation. This changes the notion that [18F]FLT uptake simply reflects changes in S-phase arrest/DNA synthesis to one that represents broad sensitivity to proliferation including G2/M arrest. New radiotracers that are specifically incorporated into DNA and whose uptake is TK1-independent could provide additional selectivity for imaging DNA synthesis.
287

Neuropathic pain in leprosy : deep profiling and stratification of patient groups

Haroun, Omer Mohammed Osman Hamid January 2015 (has links)
Leprosy is a chronic granulomatous infectious disease, affecting the skin and nerves. Neuropathic pain (NP), which is defined as pain caused by a lesion or disease of the somatosensory nervous system, is now being recognized as an important complication of leprosy. It occurs in 10-20% of patients as a result of persisting nerve damage. Patient with NP is associated with significant suffering, morbidity and limitation of quality of life. Thus, the accurate identification of NP in patients with pain is required. The clinical aspects of NP in leprosy patients in India were investigated using highly specialised assessment tool; quantitative sensory testing (QST). A case control study was conducted in 90 patients with and without pain. Two validation studies were conducted among healthy volunteers in London (18 participants) and Mumbai (52 participants). Somatosensory profiles were compared in leprosy patients to healthy control subjects. The pattern revealed a novel profile of loss of cool and warm detection thresholds and also mechanical detection but with preservation of vibration detection. This is different to profiles seen in other NP conditions. The QST parameters were effective in detecting neuropathy, but were not able to distinguish between patients with and without NP. Patients with leprosy NP had a high rate of abnormal findings in almost all QST parameters in the maximum pain area over the ulnar nerve. Their sensory profiles were categorised into two subgroups. The majority of patients have spontaneous pain with evidence of sensory loss, but no signs of sensory gain. The second subgroup had profoundly impaired pain and temperature sensation, but light mechanical stimuli often produce pain. Patients with NP had a poor quality of life and psychological well-being compared to pain-free neuropathy.
288

Targeting cancer with reovirus

Comins, Charles J. January 2015 (has links)
There has been increasing interest in oncolytic virotherapy for the treatment of cancer over the past decade. Reovirus is a ubiquitous double-stranded RNA virus that is oncolytic. It has been shown to selectively kill cancer cells in murine, and human models. The mechanism by which reovirus selectively targets and kills cancer cells is slowly being elucidated. Activation of the Ras pathway in transformed cells plays a part in the permissivity of cancer cells to reovirus, in part through the inability of Ras-activated cells to phosphorylate cellular PKR. Our microarray analysis found increased expression of epidermal growth factor receptor (EGFR) in B16 mouse melanoma cells after exposure to reovirus. As EGFR is a component of the Ras pathway, we explored this increased expression and found that in certain cell lines there was an increase in EGFR expression after reovirus exposure both by PCR and western blot analysis. Data is presented looking at the effect of silencing EGFR on cell survival. Early human trials indicate that while reovirus is safe and capable of inducing cancer cell death, single agent activity is likely to be limited. Attention has now focused on combination strategies. We evaluated the combination of reovirus with rapamycin in the B16.F10 murine model of malignant melanoma based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. These include cell cycle arrest, targeting of alternative signalling pathways, and suppression of the antiviral immune response. Rapamycin attenuated viral replication if given prior to or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death. However, we found clear evidence of synergistic antitumour effects of the combination both <i>in vitro</i> and <i>in vivo</i>, which was sequence dependent only in the <i>in vitro</i> setting. Rapamycin showed no systemic immunomodulation and cell cycle effects of reovirus (increased G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. We also conducted a multicentre, phase 1 dose escalation study designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer. Patients received 75mg/m<sup>2</sup> of docetaxel, day 1, and escalating doses of reovirus up to 3 x 10<sup>10</sup> TCID<sub>50</sub>, day 1-5, every 3 weeks. 25 patients were enrolled, with 23 completing at least one cycle and 16 suitable for response assessment. Dose-limiting toxicity of grade 4 neutropaenia was seen in one patient but the maximum tolerated dose was not reached. Antitumour activity was seen with one complete response and 3 partial responses. A disease control rate of 88% was observed. The combination of reovirus and docetaxel was concluded to be safe, with evidence of objective disease responses, and warrants further evaluation in a phase II study at a recommended schedule of 75mg/m<sup>2</sup> of docetaxel, 3 weekly and reovirus 3 x 10<sup>10</sup> TCID<sub>50</sub> day 1-5, every 3 weeks.
289

The role of HOX genes in pancreatic cancer

Gray, Sophie January 2015 (has links)
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of solid cancer with 5-year survival rates approaching a dismal 5%. Novel therapeutic targets need to be identified thus aiding and assisting the design of treatments which will improve survival rates that have not changed in the last 30 years. Of particular interest are homeobox (HOX) genes, a set of 39 evolutionarily conserved transcription factors involved in embryonic antero-posterior patterning. Although expressed in development, HOX genes have been found to be re-expressed and indeed dysregulated in several types of cancer including lung, breast, ovarian and renal neoplasia. Limited research has been undertaken on the dysregulation of HOX genes in PDAC. HOX genes can be antagonised using HXR9, a peptide which competitively inhibits the interaction between HOX genes and their co-factor PBX, subsequently preventing HOX genes to fulfill their role of transcription factors. Cancer-specific tumour-modelling is fundamental to drug testing. There are few animal models that recapitulate the unique tumour architecture and molecular signature of PDAC, particularly the desmoplastic reaction characteristic of this malignancy. The chorioallantoic membrane (CAM) assay, an in ovo model that utilises the immunologically naive properties of the developing chick embryo to grow a solid tumour derived from pancreatic cancer cell lines. The CAM model is not widely used in pancreatic cancer research and more work is needed to evaluate it’s efficacy for tumour remodelling and subsequent drug testing. We have found that the CAM model is suitable for drug testing as it recapitulates the architecture and molecular signature of PDAC. In order to establish the CAM model as appropriate for drug testing in this context, we assessed whether the mitogen-activated protein kinases (MAPK) pathway was conserved, due to the high frequency of mutational activation of the KRAS gene in this cancer. Global gene expression was also carried out to determine genetic changes between cells grown in vitro and cells in a tumour microenvironment in the CAM model. Experimental design We investigated whether there is a signature HOX gene profile unique to this disease. We measured HOX gene expression by RT-PCR in four well-described pancreatic cancer cell lines. HOX gene expression was also measured in commercially obtained RNA and snap-frozen pancreatic cancer tissue from surgical resections. The CAM model was set up by grafting 4 pancreatic cancer cell lines and tumour architecture and molecular signature was evaluated by H&E staining and IHC. Gene expression was assessed by microarray analysis to compare global gene expression in cell-lines and CAM tumours and conservation of mitogen-activated protein kinases (MAPK) pathway was addressed by western blotting. HOX gene expression was measured by RT-PCR in both cell lines and CAM tumours. Finally, the efficacy of HRX9 was measured by generating IC50s using MTS and LDH assays. Levels of apoptosis were measured in vitro using Annexin-V-PE assay and in vivo by cleaved-caspase activation, assessed by IHC. Results: We found that HOX gene expression was elevated in tumour samples compared with normal tissue and in particular a significantly higher expression of HOXA13 in PDAC samples compared with normal pancreas. This was confirmed at the protein level by Immunohistochemistry (IHC). We also showed that the CAM model is suitable for drug testing as it recapitulates the architecture and molecular signature of PDAC. Results showed that MAPK pathway was conserved, due to the high frequency of mutational activation of the KRAS gene in this cancer. Cleaved-caspase activation also supports the hypothesis that tumour cells are driven into apoptosis upon HXR9 treatment. Conclusions HOX gene expression is highly dys-regulated in pancreatic cancer and more work is need to individually evaluate HOX genes on interest highlighted in this study. HOX gene expression can be antagonised by using HXR9. Finally, we have demonstrated the potential for HOX gene targeting as a novel therapy for PDAC.
290

The genetics of oesophageal cancer in South African populations

Bye, Hannah January 2013 (has links)
Oesophageal cancer is a common form of cancer in South Africa. The predominant subtype is oesophageal squamous cell carcinoma (OSCC) and the disease has a very poor prognosis. The aim of this thesis was to investigate the genetics of OSCC in the South African Black and Mixed Ancestry populations. Genetic susceptibility to OSCC was explored initially through case-control association studies of 18 variants with strong evidence of association with the disease in other populations. Most loci did not show association in the South African populations. However, in the Mixed Ancestry population, ALDH2 +82 A>G (rs886205) and RUNX1 rs2014300 were associated with OSCC (odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.55-0.89, P=0.0038; and OR = 1.33, 95% CI = 1.09-1.63, P=0.0055, respectively). Further investigation of PLCE1 in the Black population found Arg548Leu (rs17417407) to be associated with disease (OR = 0.74, 95% CI = 0.60-0.93; P=0.008). These findings suggest that there may be substantial differences in the genetic architecture of OSCC in African populations. Additionally, genetic susceptibility was explored in the Black population using the Immunochip, a genotyping array containing ~200,000 variants. Although no polymorphisms were significantly associated with OSCC, several variants in TGFBR3 showed suggestive evidence of association, which was promising as the TGF-β pathway has been shown to have an important role in the development of the disease. In a pilot study to investigate somatic mutations in OSCC, the whole-exomes of 8 blood-tumour pairs were sequenced, with mutations identified in several tumour suppressor genes, including TP53, KL and APC. Sanger sequencing of two candidate genes, TP53 and PPM1D, in all available samples, showed that 60% of tumours contained TP53 mutations, and that 36% of tumours showed evidence of loss of heterozygosity at the PPM1D locus, suggesting that it may be an important alteration for OSCC development.

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