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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.
41

Biomarker and Therapeutic Studies of Antibodies and Small Molecules that Target EGFR

Mutsaers, Anthony James 17 February 2011 (has links)
The field of targeted cancer therapy has progressed in recent years with the approval of new oncology drugs. Coupled with the benefits that these agents provide, has come an appreciation for challenges that occur when attempting to translate successful experiments from the laboratory into effective clinical trials. One such challenge has been predicting the optimal dose and schedule to take into clinical evaluation, given the possibility that certain targeted therapeutics may exhibit maximal anti-tumour efficacy well below maximum tolerated doses. Recent work with a targeted antibody to the mouse vascular endothelial growth factor receptor-2 demonstrated that detection of increased levels of its endogenous ligand in the plasma, namely VEGF, could address this issue, as maximal increases in VEGF paralleled optimal drug activity. The VEGF result has become recognized as a potential class effect for this family of inhibitors. This thesis summarizes experiments designed to build upon this discovery by investigating whether the utility of ligand measurement might also apply to drugs that inhibit the epidermal growth factor receptor (EGFR), which have also received recent regulatory approval, and inhibit angiogenesis as one of their mechanisms of action. In addition, we investigated the potential application of EGFR inhibitors to influence other markers of tumour angiogenesis, specifically their effects on levels of circulating endothelial progenitor cells (CEPs). Finally, we evaluated combination treatment of EGFR inhibition with anti-angiogenic scheduling of chemotherapy. The EGFR ligand TGF-alpha increased in a dose dependent fashion following treatment with cetuximab, and levels in the circulation paralleled anti-tumour activity. This was a host-dependent effect that was not observed with the lower affinity antibody nimotuzumab. Inhibition of host EGFR also reduced plasma CEPs, but at higher doses these drugs increased off target growth factors VEGF and G-CSF, as well as CEPs. In a model of advanced triple negative breast cancer, the combination of nimotuzumab and metronomic cyclophosphamide was efficacious and well tolerated, leading to a potential new treatment strategy for this aggressive disease. Taken together, these studies identify new and useful applications for EGFR-targeted antibodies, and shed further light on their contributions within the field of tumour angiogenesis and antiangiogenic therapy.
42

Biomarker and Therapeutic Studies of Antibodies and Small Molecules that Target EGFR

Mutsaers, Anthony James 17 February 2011 (has links)
The field of targeted cancer therapy has progressed in recent years with the approval of new oncology drugs. Coupled with the benefits that these agents provide, has come an appreciation for challenges that occur when attempting to translate successful experiments from the laboratory into effective clinical trials. One such challenge has been predicting the optimal dose and schedule to take into clinical evaluation, given the possibility that certain targeted therapeutics may exhibit maximal anti-tumour efficacy well below maximum tolerated doses. Recent work with a targeted antibody to the mouse vascular endothelial growth factor receptor-2 demonstrated that detection of increased levels of its endogenous ligand in the plasma, namely VEGF, could address this issue, as maximal increases in VEGF paralleled optimal drug activity. The VEGF result has become recognized as a potential class effect for this family of inhibitors. This thesis summarizes experiments designed to build upon this discovery by investigating whether the utility of ligand measurement might also apply to drugs that inhibit the epidermal growth factor receptor (EGFR), which have also received recent regulatory approval, and inhibit angiogenesis as one of their mechanisms of action. In addition, we investigated the potential application of EGFR inhibitors to influence other markers of tumour angiogenesis, specifically their effects on levels of circulating endothelial progenitor cells (CEPs). Finally, we evaluated combination treatment of EGFR inhibition with anti-angiogenic scheduling of chemotherapy. The EGFR ligand TGF-alpha increased in a dose dependent fashion following treatment with cetuximab, and levels in the circulation paralleled anti-tumour activity. This was a host-dependent effect that was not observed with the lower affinity antibody nimotuzumab. Inhibition of host EGFR also reduced plasma CEPs, but at higher doses these drugs increased off target growth factors VEGF and G-CSF, as well as CEPs. In a model of advanced triple negative breast cancer, the combination of nimotuzumab and metronomic cyclophosphamide was efficacious and well tolerated, leading to a potential new treatment strategy for this aggressive disease. Taken together, these studies identify new and useful applications for EGFR-targeted antibodies, and shed further light on their contributions within the field of tumour angiogenesis and antiangiogenic therapy.
43

Bioinformatics Approaches to Biomarker and Drug Discovery in Aging and Disease

Fortney, Kristen 11 December 2012 (has links)
Over the past two decades, high-throughput (HTP) technologies such as microarrays and mass spectrometry have fundamentally changed the landscape of aging and disease biology. They have revealed novel molecular markers of aging, disease state, and drug response. Some have been translated into the clinic as tools for early disease diagnosis, prognosis, and individualized treatment and response monitoring. Despite these successes, many challenges remain: HTP platforms are often noisy and suffer from false positives and false negatives; optimal analysis and successful validation require complex workflows; and the underlying biology of aging and disease is heterogeneous and complex. Methods from integrative computational biology can help diminish these challenges by creating new analytical methods and software tools that leverage the large and diverse quantity of publicly available HTP data. In this thesis I report on four projects that develop and apply strategies from integrative computational biology to identify improved biomarkers and therapeutics for aging and disease. In Chapter 2, I proposed a new network analysis method to identify gene expression biomarkers of aging, and applied it to study the pathway-level effects of aging and infer the functions of poorly-characterized longevity genes. In Chapter 4, I adapted gene-level HTP chemogenomic data to study drug response at the systems level; I connected drugs to pathways, phenotypes and networks, and built the NetwoRx web portal to make these data publicly available. And in Chapters 3 and 5, I developed a novel meta-analysis pipeline to identify new drugs that mimic the beneficial gene expression changes seen with calorie restriction (Chapter 3), or that reverse the pathological gene changes associated with lung cancer (Chapter 5). The projects described in this thesis will help provide a systems-level understanding of the causes and consequences of aging and disease, as well as new tools for diagnosis (biomarkers) and treatment (therapeutics).
44

Bioinformatics Approaches to Biomarker and Drug Discovery in Aging and Disease

Fortney, Kristen 11 December 2012 (has links)
Over the past two decades, high-throughput (HTP) technologies such as microarrays and mass spectrometry have fundamentally changed the landscape of aging and disease biology. They have revealed novel molecular markers of aging, disease state, and drug response. Some have been translated into the clinic as tools for early disease diagnosis, prognosis, and individualized treatment and response monitoring. Despite these successes, many challenges remain: HTP platforms are often noisy and suffer from false positives and false negatives; optimal analysis and successful validation require complex workflows; and the underlying biology of aging and disease is heterogeneous and complex. Methods from integrative computational biology can help diminish these challenges by creating new analytical methods and software tools that leverage the large and diverse quantity of publicly available HTP data. In this thesis I report on four projects that develop and apply strategies from integrative computational biology to identify improved biomarkers and therapeutics for aging and disease. In Chapter 2, I proposed a new network analysis method to identify gene expression biomarkers of aging, and applied it to study the pathway-level effects of aging and infer the functions of poorly-characterized longevity genes. In Chapter 4, I adapted gene-level HTP chemogenomic data to study drug response at the systems level; I connected drugs to pathways, phenotypes and networks, and built the NetwoRx web portal to make these data publicly available. And in Chapters 3 and 5, I developed a novel meta-analysis pipeline to identify new drugs that mimic the beneficial gene expression changes seen with calorie restriction (Chapter 3), or that reverse the pathological gene changes associated with lung cancer (Chapter 5). The projects described in this thesis will help provide a systems-level understanding of the causes and consequences of aging and disease, as well as new tools for diagnosis (biomarkers) and treatment (therapeutics).
45

Nutritional and hormonal biomarkers in prostate cancer epidemiology

Price, Alison Jane January 2012 (has links)
Evidence from international comparisons and migrant studies suggest that environmental factors, such as a Western diet, may be important in prostate cancer development, possibly through effects on hormone and growth factor secretion and metabolism. However, despite considerable research, convincing associations between diet and risk for prostate cancer have not been established. Random and systematic measurement error in dietary assessment using traditional survey methods may contribute to inconsistent findings, particularly as they may not capture adequately specific nutritional constituents of the diet that may be associated with risk, such as fatty acids or vitamins. Validated biomarkers of nutritional factors and hormonal activity, as used in this thesis, provide more precise, objective and integrated measures of exposure, with the capacity to clarify potential mechanisms in the causal pathway of prostate cancer development. Nutritional and hormonal biomarkers investigated for their potential role in the development of prostate cancer include: folate and vitamin B<sub>12</sub>, which are essential for DNA methylation, repair and synthesis; phytanic acid, obtained predominantly from ruminant fat intake and associated with an enzyme (α-Methylacyl-Coenzyme A Racemase (AMACR)) that is consistently over-expressed in prostate cancer tissue; and insulin-like growth factor (IGF-I), a growth factor influenced by diet and involved in the regulation of cell proliferation, differentiation, and apoptosis. All work presented in this thesis is from the European Prospective Investigation into Cancer and Nutrition (EPIC) study of 500,000 European men and women, using prospectively collected diet and lifestyle data and biological samples. The large number of prostate cancer cases diagnosed during long-term follow-up of EPIC participants enabled investigation of heterogeneity in risk for prostate cancer by time from recruitment to diagnosis (of particular importance for a disease with a long pre-clinical phase) and cancer characteristics such as disease grade and stage. Plasma phytanic acid concentration was highly correlated with dietary intake of fat from dairy products (r = 0.46) and beef (r = 0.30); capturing differences between countries in consumption of fat from these foods. Although phytanic acid is a useful biomarker of ruminant fat consumption, there was little evidence to support the hypothesis that the association between dairy products and prostate cancer risk (as suggested by previous work in EPIC and other studies) is mediated by phytanic acid (OR for doubling in concentration 1.05; 95%CI 0.91 – 1.21; P <sub>trend</sub> = 0.53). There was strong evidence for an association between higher circulating IGF-I concentration and risk for prostate cancer (OR for highest versus lowest fourth 1.69; 95% CI: 1.35, 2.13; P <sub>trend</sub> = 0.0002). Furthermore, the positive association observed among men diagnosed with advanced stage disease and among men diagnosed more than seven years after blood collection, supports the hypothesis that high IGF-I concentration is associated with clinically significant prostate cancer many years before diagnosis. There was no evidence of an association between prostate cancer risk and dietary folate or vitamin B<sub>12</sub> intake, or between circulating levels of folate (OR for doubling in concentration 1.05; 95%CI 0.95 – 1.15; <en>P <sub>trend</sub> = 0.33) or vitamin B<sub>12</sub> (1.05; 95%CI 0.92 – 1.21; P <sub>trend</sub> = 0.47) and only limited evidence for an increased risk associated with elevated vitamin B<sub>12</sub> in a meta-analysis of six prospective studies, that included the present study. All of these analyses were based on a blood sample taken at one point in time, with the assumption that this reflects the ‘true’ underlying concentration over the long-term. The poor to modest reliability estimates (intra-class correlation coefficients ranging from 0.18 to 0.48) for circulating concentrations of folate, IGF-I, phytanic acid and vitamin B<sub>12</sub> taken in samples approximately six years apart in a sub-sample of participants from EPIC Oxford, show that estimates of usual concentrations based on a single blood measurement weaken the ability to detect associations with disease risk. Where small effect sizes are anticipated, this may bias associations toward the null. In conclusion, there is convincing evidence that IGF-I is an important and potentially modifiable risk factor for prostate cancer many years before diagnosis. However, there is little evidence for an association between biomarkers of folate, vitamin B<sub>12</sub> and phytanic acid concentrations and risk for prostate cancer. Future studies should, where possible, incorporate multiple blood samples taken several years apart to better characterise long term relationships between biomarkers of nutritional and hormonal exposure and disease risk and pool individual participant data from multiple prospective studies to strengthen the power to detect modest associations.
46

Identification of novel miRNAs as diagnostic molecules for detection of breast cancer using in silico approaches

Ferrara, Najua Ali January 2017 (has links)
Magister Scientiae - MSc / Breast cancer (BC) is the most common cancer in women worldwide, and is the second most common cancer in the world, responsible for more than 500 000 deaths annually. Estimates are that 1 in 8 women will develop BC in their lifetime. In South Africa, BC in women affects about 16.6 % of the population and could see a 78 % increase in cases by 2030. The failure of conventional diagnostic tools to detect BC from an early onset has revealed the need for diagnostic tools that would enable early diagnosis of BC. The current diagnostic tools include breast self-examination, mammography magnetic resonance imaging, ultrasonography and serum biomarkers; BRACA1, BRACA2, HER2. These conventional methods lack sensitivity, specificity and positive predictive value, and some of these diagnostic tools may be expensive and quite invasive. Therefore, novel diagnostic tools such as microRNAs which address the short comings of current methods are required for early diagnosis as well as BC management. MicroRNAs are a class of non-coding RNA molecules, which are important in RNA stability and gene expression. Various methodologies have been employed to identify novel microRNAs for diagnostics such as bioinformatics, also referred to as in silico analysis. The aim of this study is to identify novel microRNAs that can potentially detect BC at its earliest stage.
47

The ecotoxicological assessment of complex effluents using invertebrate biomarkers

Astley, Katrina Nicola January 1998 (has links)
A suite of biomarkers was developed using the crab Carcinus maenas and the mussel Mytilus edulis as test organisms. The ability of the biomarkers to differentiate amongst the major toxic components and to indicate the concentration of chemical mixtures was evaluated in the laboratory. Biomarkers were also applied in a field trial and their potential to monitor environmental water quality in a chemically contaminated estuary investigated. The results from the biomarker assays were compared with and validated against two commonly used toxicity tests (Tisbe battagliai LC-50, and Microtox®). Novel methods for recognising patterns of biomarker responses were developed and assessed. The most sensitive and reliable biomarker assays investigated were neutral red retention time in crabs and mussels and heart rate and glutathione-S-transferase activity in crabs. Effects were observed at environmentally realistic concentrations; for example lysosomal enlargement was observed in mussels exposed to a complex mixture containing chemicals at environmental quality standard concentrations. Exposure concentrations required to illicit biomarker responses were similar to toxicity test EC-50 values. The ease of interpretation and clarity of the results was enhanced when data from suites of biomarkers were pooled and analysed using multivariate statistical techniques (multidimensional scaling and cluster analysis). Multivariate analysis differentiated amongst mixtures containing solely organic chemicals, metals and metal and organic chemical mixtures. Exposure response relationships to complex mixtures were established for some of the individual biomarkers tested (crab heart rate and gill metallothionein) and also for suites of biomarkers when multivariate analysis was carried out. In the field biomarkers, in both transplanted and indigenous animals, were able to differentiate between clean and contaminated sites and indicate a pollution gradient along the Tees Estuary. This was not achieved using toxicity tests. The results were displayed clearly using multivariate analysis, enhancing the power of biomarkers as monitoring tools.
48

Semi-quantitative MRI biomarkers of knee osteoarthritis progression in the FNIH biomarkers consortium cohort − Methodologic aspects and definition of change

Roemer, Frank W., Guermazi, Ali, Collins, Jamie E., Losina, Elena, Nevitt, Michael C., Lynch, John A., Katz, Jeffrey N., Kwoh, C. Kent, Kraus, Virginia B., Hunter, David J. 10 November 2016 (has links)
Background: To describe the scoring methodology and MRI assessments used to evaluate the cross-sectional features observed in cases and controls, to define change over time for different MRI features, and to report the extent of changes over a 24-month period in the Foundation for National Institutes of Health Osteoarthritis Biomarkers Consortium study nested within the larger Osteoarthritis Initiative (OAI) Study. Methods: We conducted a nested case-control study. Cases (n = 406) were knees having both radiographic and pain progression. Controls (n = 194) were knee osteoarthritis subjects who did not meet the case definition. Groups were matched for Kellgren-Lawrence grade and body mass index. MRIs were acquired using 3 T MRI systems and assessed using the semi-quantitative MOAKS system. MRIs were read at baseline and 24 months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. We provide the definition and distribution of change in these biomarkers over time. Results: Seventy-three percent of the cases had subregions with BML worsening (vs. 66 % in controls) (p = 0.102). Little change in osteophytes was seen over 24 months. Twenty-eight percent of cases and 10 % of controls had worsening in meniscal scores in at least one subregion (p < 0.001). Seventy-three percent of cases and 53 % of controls had at least one area with worsening in cartilage surface area (p < 0.001). More cases experienced worsening in Hoffa- and effusion synovitis than controls (17 % vs. 6 % (p < 0.001); 41 % vs. 18 % (p < 0.001), respectively). Conclusions: A wide range of MRI-detected structural pathologies was present in the FNIH cohort. More severe changes, especially for BMLs, cartilage and meniscal damage, were detected primarily among the case group suggesting that early changes in multiple structural domains are associated with radiographic worsening and symptomatic progression.
49

Investigation into taxane resistant breast cancer

Kenicer, Juliet Elisabeth Margaret January 2011 (has links)
One group of chemotherapeutics that are used successfully to treat breast cancer, alone or in combination with other agents, are the taxanes; paclitaxel and docetaxel. They act by interfering with the spindle microtubule dynamics of the cell causing cell cycle arrest. However, the complexities underlying the mechanism of action are yet to be fully elucidated. Arguably, one of the most significant problems with taxanes is chemoresistance. Unfortunately, some patients are intrinsically resistant to taxanes and others acquire resistance to taxanes as treatment advances. This problem is exacerbated by a lack of understanding of the mechanisms underlying taxane resistance. Isogenic breast cancer cell lines that were taxane resistant were generated to use as an experimental model. Paclitaxel resistant (PACR) MDA-MB-231, paclitaxel resistant ZR75-1 and docetaxel resistant (DOCR) ZR75-1 cell lines were successfully generated by incrementally increasing taxane dose in respective native cell lines in vitro. An extensive characterisation of each of the resistant cell lines was conducted, focussing primarily on the 25nM resistant cells which were determined to be the most clinically relevant dose of taxane. A suboptimal dose of 5nM, a “superoptimal” dose of 50nM and the native, taxane sensitive cells was included. Dose response cell count experiments were performed that confirmed taxane resistant cells had been generated. It was shown that MDA-MB-231 native cells were more sensitive to paclitaxel than the ZR75-1 native cells, suggesting that ZR75-1 cells may already have low level inherent resistance. The MDA-MB-231 25nM PACR cells were tested to determine whether they retained PACR when maintained in media containing no paclitaxel. MDA-MB-231 25nM PACR cells were maintained in a taxane free environment for six months and then rechallenged with taxane. When rechallenged, the PACR cells previously maintained in the absence of paclitaxel mirrored the pattern of growth of corresponding PACR cells that had been maintained in the presence of paclitaxel. This proved that in the absence of paclitaxel, PACR cells did not revert to parent phenotype. This meant that experiments could be designed to grow cell lines as xenografts in mice, (in the absence of paclitaxel) & bring in vitro experiments into an in vivo setting. Effects of taxane treatment on both native and resistant cells were analysed using flow cytometry. Paclitaxel treatment exerted G2/M block in native MDA-MB-231 cells but when PACR cells were treated with the same dose of paclitaxel no G2/M block was observed, suggesting that PACR cells had developed a mechanism for escaping G2/M block. ZR75-1 native lines were also investigated and we established that treatment with paclitaxel also exerted a G2/M block in these lines. In future studies this process will be repeated to investigate the effect of taxane treatment on the ZR75-1 PACR and DOCR lines. CD 1 nude mice were injected with cells from all five cell lines to grow xenografts, unfortunately MDA-MB-231 PACR cells failed to grow so they could not be used for further xenograft experiments. PACR, DOCR and Native ZR75-1 cells did successfully grow as xenografts in mice and confirmed that all 3 groups showed very similar growth patterns. A cross resistance experiment was conducted and it was determined that the DOCR xenografts maintained a taxane resistant phenotype to docetaxel, and not paclitaxel and the PACR xenografts may be perpetuate the paclitaxel resistant phenotype in xenografts and that there may be cross resistance to docetaxel in the paclitaxel resistant xenografts. This is the first time that taxane resistant cell lines grown in this way have been established as xenografts in mice. These cross resistance experiments represent novel findings and merit further investigation. Extensive genomic and transcriptomic analyses were carried out on the cell lines to help identify potential taxane resistance markers. aCGH experiments were carried out to compliment the illumina experiments. The first set of experiments used DNA from pooled whole female blood as ref sample and DNA from each of the native and taxane resistant cell lines as test samples. The second set of experiments used DNA from native cells as a ref sample and DNA from their respective taxane resistant cells as a test, which allowed areas of loss or gain to be tracked in the genome as resistance increased. In the MDA-MB-231 cell lines the following areas of loss extended with increasing resistance: 1p36.13-q44, 6p25.3-q12, 8p, 10p, 19q, X Chr and the following areas of gain 2p25.3-23.3, 3p24.3-q13.3, 4p16.1-q12, 5q14.3-q31.1, 8q21.13-24.3, 11q15.1-q25, centromeric 12, and centromeric 14. In the ZR75-1 PACR and DOCR cell lines the areas of loss extended with increasing resistance in the following regions: 7q, 12p and 16q. For gene expression analysis RNA was extracted from the MDA-MB-231 cell lines, labelled and hybridised them to illumina human ref 8 vs. 2 chips. Data showed a progressive increase in mRNA dysregulation as paclitaxel resistance increased. Eleven genes were dysregulated across all resistance levels in the PACR MDA-MB-231 cells when compared to the relative cell lines; RGS16, CLDN1, IL7R, P&PP1R14C, COBL, TRPV4, TSPAN8, CD33, NLRP2, P13, and PAGE5. The experiment was repeated using MDA-MB-231 PACR, ZR75-1 PACR and DOCR cells and resulting data was analysed to determine genes commonly dysregulated across resistance levels, between MDA-MB-231 PACR and ZR75-1 PACR and between ZR75-1 PACR and DOCR cell lines. An extensive literature search was conducted and established four genes of interest in the context of our genomic and transcriptomic experiments including AURKA, Mdr-1, Stathmin and YY1. The novel biomarkers identified in the illumina experiments were validated with complimentary qPCR gene expression experiments looking at expression levels of the eleven commonly dysregulated genes identified and a panel of 19 other genes with significantly increased or decreased expression as resistance increased including AURKA, Mdr-1, Stathmin and YY1. Western blots were performed with lysates from the cell lines using a standard panel of predictive breast cancer markers and AURKA, Mdr-1, Stathmin and YY1. Combining the data from the genomic study, the gene expression profile, qPCR and Western blotting it was established that Mdr-1 had increased expression in the taxane resistant ZR75-1 lines and YY1 had increased expression in the MDA-MB-231 PACR line. Material from the LAPATAX trial was used to observe any transcriptomic changes occurring in tumours following treatment with docetaxel and to compare them to changes identified in our in vitro and xenograft models, this allowed the final step to be taken into a translational environment. LAPATAX (EORTC 10054) is a phase I-II study of Lapatanib and Docetaxel as neoadjuvant treatment for HER-2 +ve locally advanced/inflammatory or large operable breast cancer. Tumour material from eighteen core biopsies pre and post treatment was obtained, the mRNA was extracted, labelled and hybridised to the illumina array. This allowed the changes in gene expression pre and post docetaxel treatment to be tracked. The gene expression data from the LAPATAX trial was combined with gene expression data from our cell line panel and identified two novel putative markers of taxane resistance DUSP1 and FOS. Although sample size is small this has provided extremely valuable evidence directly from the clinic. These two novel putative biomarkers are extremely intriguing and certainly merit further investigation, ideally using additional taxane treated breast tumour tissue. Ultimately, an isogenic in vitro model of taxane resistance was developed in two different cell lines and with two different taxanes within one cell line. The cell lines were characterised and the effect of the taxanes on the cell cycle was determined in the native and taxane resistant lines. Selected cell lines were grown as xenografts in mice and performed successful cross resistance studies upon them. A large transcriptomic and genomic analysis was conducted and has identified a panel of potential taxane resistance markers and areas of loss and gain in the genome perpetuated by increasing taxane resistance. This analysis was validated using qPCR and Western blotting. This allowed a panel of novel taxane resistance markers to be identified. In future studies it is hoped that these targets will be knocked down with shRNA to observe if the taxane resistant cell lines revert to the parental phenotype. In vitro studies will be conducted to find agents that may be used to reduce expression of these markers and restore sensitivity to taxanes and consequently restore the efficacy of these drugs in a clinical setting. As far as the author is aware this is the first time that isogenic taxane resistant cell lines have been generated and investigated in this way.
50

Eye as a window to the brain : investigating the clinical utility of retinal imaging derived biomarkers in the phenotyping of neurodegenerative disease

Cameron, James R. January 2018 (has links)
Background: Neurodegenerative diseases, like multiple sclerosis, dementia and motor neurone disease, represent one of the major public health threats of our time. There is a clear persistent need for novel, affordable, and patient-acceptable biomarkers of these diseases, to assist with diagnosis, prognosis and impact of interventions. And these biomarkers need to be sensitive, specific and precise. The retina is an attractive site for exploring this potential, as it is easily accessible to non-invasive imaging. Remarkable technology revolutions in retinal imaging are enabling us to see the retina in microscopic level detail, and measure neuronal and vascular integrity. Aims and objectives: I therefore propose that retinal imaging could provide reliable and accurate markers of these neurological diseases. In this project, I aimed to explore the clinical utility of retinal imaging derived measures of retinal neuronal and vessel size and morphology, and determine their candidacy for being reliable biomarkers in these diseases. I also aimed to detail the methods of retinal imaging acquisition, and processing, and the principles underlying all these stages, in relation to understanding of retinal structure and function. This provides an essential foundation to the application of retinal imaging analysis, highlighting both the strengths and potential weaknesses of retinal biomarkers and how they are interpreted. Methods: After performing detailed systematic reviews and meta-analyses of the existing work on retinal biomarkers of neurodegenerative disease, I carried out a prospective, controlled, cross-sectional study of retinal image analysis, in patients with MS, dementia, and ALS. This involved developing new software for vessel analysis, to add value and maximise the data available from patient imaging episodes. Results: From the systematic reviews, I identified key unanswered questions relating to the detailed analysis and utility of neuroretinal markers, and diseases with no studies yet performed of retinal biomarkers, such as non-AD dementias. I recruited and imaged 961 participants over a two-year period, and found clear patterns of significance in the phenotyping of MS, dementia and ALS. Detailed analysis has provided new insights into how the retina may yield important disease information for the individual patient, and also generate new hypotheses with relation to the disease pathophysiology itself. Conclusions: Overall, the results show that retinal imaging derived biomarkers have an important and specific role in the phenotyping of neurodegenerative diseases, and support the hypothesis that the eye is an important window to neurological brain disease.

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