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1
Orme, Michelle Elaine. "The vascularization of solid tumours : mathematical models of tumour angiogenesis and vascular tumour growth." Thesis, University of Bath, 1996. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362238.
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Kamel, H. M. N. "Ultrastructural aspects of tumours and anti-tumour therapy." Thesis, University of Glasgow, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375440.
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Khan, M. S. "Circulating tumour cells and biomarkers in neuroendocrine tumours." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1380186/.
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Neuroendocrine tumours(NETs) are heterogeneous with respect to biological behavior. Consequently, prognosis is variable and biomarkers predicting survival or tumour progression are required to inform clinical management. The best available biomarker, histological grade, is assigned using Ki-67 or mitotic count. Agreement between these two indices is implied but analysis of 131 pancreatic and 136 midgut NETs suggested discordances of 44% and 38% respectively. Ki-67 was the superior prognostic marker, making the additional value of mitotic count questionable. Detection of Circulating Tumour Cells(CTCs) using the Cellsearch™ platform requires expression of epithelial cell adhesion molecule(EpCAM). I demonstrated EpCAM expression by immunohistochemistry and detected CTCs in patients with metastatic NETs. In 175 patients, ≥1 CTC was detected in 51%(midgut) and 36%(pancreatic). ≥1 CTC was an independent poor prognostic factor, offering better prognostic value than grade or chromogranin A(CgA). Changes in CTCs 3-5 weeks after commencing therapy were predictive of response and survival, suggesting CTCs could provide an early assessment. Using chip-based capillary-electrophoresis, higher concentrations of circulating free DNA(cfDNA) were found in 88 patients with NETs compared to healthy controls with a correlation between cfDNA quantity and CTCs. Since cfDNA was detected in 25% of cases, more sensitive methods of detection are required before studies are conducted to validate cfDNA as a biomarker and to analyse mutations. The hypervascular nature of NETs suggested that circulating endothelial cells(CECs) might be informative. Using immunomagnetic separation and CD105 phenotyping, CECs were demonstrated in 55 patients. Although not significantly elevated, there was a wider range of CECs in NETs compared to controls. Further studies investigating changes with anti-angiogenic therapy could prove valuable. My research suggests circulating biomarkers, specifically CTCs, provide additional and better prognostic information than grade. Furthermore, detection of CTCs and cfDNA in NETs may allow future studies into molecular analysis, which may enhance understanding of NET pathogenesis.
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de, Foy K. "Analysis of candidate tumour suppressor genes in sporadic ovarian tumours." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598448.
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The aim of this thesis was to identify genes which are important in the initiation and/or progression of sporadic ovarian cancer. A series of ovarian teratomas and carcinomas was collected and three candidate tumour suppressor genes were analysed. The c-mos gene is an ovarian teratoma susceptibility gene in mice; its absence causes the growth of these tumours. Twenty human ovarian teratomas were collected and the coding region of the c-mos gene was analysed for somatic and germline mutations. No disease-causing alterations were found. Germline mutations of the BRCA2 gene predispose individuals to breast and ovarian cancer. To determine whether mutations in BRCA2 are important in sporadic ovarian cancer, loss of heterozygosity studies and mutation analysis were carried out on BRCA2 in a series of sporadic epithelial ovarian tumours. Loss of heterozygosity was identified in 46% of tumours. Four truncating mutations were identified in 50 tumours, two of which were germline and two somatic. All four mutations were accompanied by loss of the second allele. These results suggest that BRCA2 behaves as a tumour suppressor gene but that somatic mutations are not a common even in sporadic ovarian cancer. The insulin-like growth factor II receptor gene (IGF2R) on chromosome 6q is in a region which is frequently lost in ovarian tumours. A loss of heterozygosity analysis of the IGF2R locus in 38 informative epithelial ovarian tumours demonstrated 55% with loss of one allele. To perform mutation analysis of IGF2R, the technique of fluorescent chemical cleavage of mismatch was established in the laboratory and used to analyse IGF2R cDNA from 18 tumours. No disease-causing alterations were identified. Antibodies were used to examine the expression of the IGF2R protein through immunohistochemical studies of 53 ovarian tumour tissue sections. Seven tumours were identified in which epithelial tumour cells stained negatively for IGF2R. No correlation could be found between immunohistochemical results and LOH and mutation analysis results, suggesting that IGF2R is probably down-regulated at the level of transcription or translation in those samples which showed negative staining.
5
Chan, Fong Chun. "Clinical Implications of inter-tumour, intra-tumour, and tumour microenvironment heterogeneity in B-cell lymphomas." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61022.
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McDonnell, Alison. "The role of dendritic cells in the cross-presentation of tumour antigens." University of Western Australia. School of Medicine and Pharmacology, 2009. http://theses.library.uwa.edu.au/adt-WU2010.0017.
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[Truncated abstract] A paradox exists in tumour immunology whereby progressive tumour growth exists in parallel with an anti-tumour T cell response. This defective T cell response is thought to result from the induction of T cell tolerance and/or tumour induced immunosuppression, which act to inhibit the activation, differentiation and function of tumour-specific CD8+ T cells. Dendritic cells (DCs) are professional antigen presenting cells (APCs) that are critical to the generation of effective CTL; however their function and phenotype is often defective or altered in tumour-bearing hosts, which may limit their capacity to mount an effective tumour specific T cell response. In this thesis, the role of DCs in the cross-presentation of tumour antigen was assessed in terms of their APC function, migration and location. In doing so the intention was to gain insight into the early processes that potentially contribute to the development of an ineffective anti-tumour immune response. This study examined cross-presentation of the nominal tumour antigen, influenza A hemagglutinin (HA) expressed by the murine malignant mesothelioma cell line, AB1-HA. Cross-presentation was predominantly restricted to the local draining lymph nodes throughout tumour growth and was mediated by CD8a+ and CD8a- DCs. This results in an ineffective CTL response due to the lack of DC activation and the presence of potentially immunosuppressive B7 molecules. However, the capacity of the CD8a- DC subset to cross-present antigen suggested a role for migratory tumour-resident DCs in this process. Analysis of tumour infiltrating DCs showed that they were paralysed in their capacity to cross-present tumour antigen and were immobilised at the tumour site. Conversely, cross-presentation of tumour antigen in the local draining lymph node was dependent on the continuous traffic of antigen from the tumour microenvironment. In this vein, small numbers of metastatic tumour cells were detected in the draining lymph nodes, however their isolation was dependent on the removal of DCs and T cells, suggesting immune control of metastatic spread. Thus, tumour cells may be the source of antigen for cross-presentation by DCs in the tumour draining lymph nodes. .... In conclusion, the results presented in this thesis support a role for DCs in the generation of tumour-specific T cell responses that fail to control tumour growth. In addition the results provide a basis for further investigation into the effects of chemotherapy on the source and form of tumour antigen for cross-presentation by specific DC subsets in the tumour bearing host. These findings may have important implications for the development of future anti-cancer immune therapies targeting DCs.
7
Liu, Lu. "Oncogenes and tumour suppressor genes in human central nervous system tumours /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3532-7/.
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Lord, Stacey Marie. "Anti-tumour compounds." Thesis, University of Leeds, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441232.
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Marr, Robert Anthony. "Tumour gene therapy using adenoviral vectors expressing tumour necrosis factor alpha." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0029/NQ66283.pdf.
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Discenza, Maria Teresa. "Regulation of expression of the Wilms' tumour 1 tumour suppressor gene." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82855.
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Wilms' tumour, a pediatric kidney cancer that affects 1 in 10 000 children, is an excellent paradigm for studying the relationship between cancer and development. The Wilms' tumour suppressor 1 ( WT1) gene was identified through the study of hereditary cases of Wilms' tumour showing cytogenetic deletions at chromosome position 11p13. The WT1 gene encodes a zinc finger transcription factor necessary for the development of the genitourinary system. WT1 functions as an activator or a repressor, interacts with a number of different protein partners and regulates the expression of several genes important for cellular growth and differentiation. WT1 mRNA is present in tissues of mesodermal origin that undergo a mesenchymal to epithelial transition. Expression of WT1 is tightly regulated both temporally and spatially during development of the urogenital system.We have identified a novel trans-acting factor, named complex D, which shows sequence specific binding to the WT1 promoter. By electrophoretic mobility shift assays (EMSA), we demonstrate that the transcription factor Sp1 binds the WT1 promoter at a site overlapping the complex D binding site. Molecular mass determination experiments and in situ UV crosslinking indicate that complex D is approximately 130 kDa and consists of at least two proteins. Transient transfection assays show that the integrity of the complex D binding site is necessary for maximal activation of a reporter gene, suggesting that complex D may function as an activator.
Similar to WT1, the ETS-domain transcription factor Pea3 is expressed in tissues where mesenchymal-epithelial interactions occur and both gene products are implicated in regulating the expression of genes necessary for the epithelialization of common organs. Transient transfection assays using WT1 promoter-reporter gene constructs identified a Pea3 responsive element in the WT1 promoter. Overexpression of Pea3 transactivates the WT1 promoter and the presence of the intact Pea3 responsive element is necessary for the transactivation. We demonstrate, by EMSA, the sequence specific binding of Pea3 to the responsive element.
WT1 and the paired box domain transcription factor Paired box 2 (Pax2) are expressed at the initial stages of metanephric kidney development and are critical for the initiation of nephrogenesis. We generated WT1/Pax2 compound heterozygous mutant mice to provide an in vivo model for studying the interplay between WT1 and Pax2 during nephrogenesis. WT1+/-/Pax2 1Neu/+ kidneys were 50% smaller that wild type kidneys and displayed a more severe underdevelopment of the medulla, renal calyces and renal pelvis compared to Pax21Neu/+ kidneys. We demonstrate that WT1 and Pax2 proteins physically interact in vitro and in vivo. Our data suggest that WT1 is a modifier of the Pax2 mutant phenotype and that both proteins may be implicated in a common pathway in the transcriptional network governing metanephric development.
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Gillmore, Roopinder. "Studies of the Wilms' tumour 1 gene in patients with solid tumours." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432012.
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Byrne, Niall Maurice. "Importance of the tumour microenvironment in the treatment response of prostate tumours." Thesis, Ulster University, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.674729.
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Androgen deprivation therapy (ADT) such as bicalutamide (BCA) has become the mainstay of treatment for locally-advanced prostate cancer (PCa). Despite initial remissions, ADT resistance almost inevitably occurs with progression to metastatic castrate-resistant PCa. Hypoxia is a common hallmark of many solid tumours and is associated with treatment failure and malignant progression; androgen withdrawal has been shown to induce profound hypoxia in androgen-sensitive tissue. This prompted an investigation into the effect of ADT on tumour oxygenation and malignant progression in PCa. Androgen-dependent luciferase-expressing PCa xenografts (LNCaP-luc) were implanted in SCID mice. When tumours reached -150mm3 mice were treated daily with SCA (2 or 6mg/kg). A reduction in tumour oxygen was observed within 24hrs (Oxylite™ oxygenelectrode); this continued to a nadir of 0.1 % oxygen at day 3 or 7 respectively. Tumours remained profoundly hypoxic until day 14-21 when oxygen levels began to rise, concomitant to time-dependent remodelling of the tumour vasculature (dorsal skin fold model). By day 28, BCA-treated xenografts were more malignant and showed greater metastatic spread to the lungs. Gene expression changes during BCA treatment of LNCaP xenografts were investigated using qPCR arrays; significant differences were found in the expression many genes involved in angiogenesis, invasion and metastasis, apoptosis resistance and the PI3K1AktimTOR signalling pathway. Informed treatment regimens combining SCA with a unidirectional hypoxia activated prod rug (AQ4N and its novel analogue OCT1002; 50mg/kg, day 7) or an Akt inhibitor (30mg/kg t.i.w) resulted in a reduction in tumour growth and metastatic spread to the lungs. When the anti-angiogenic VEGF-inhibitor (B20.4.1.1; 5mg/kg, day 14) was combined with bicalutamide, this blocked the revascularisation associated with BCA alone. This study shows that BCA-induced hypoxia induces critical changes in the tumour microenvironment which cause modified gene expression and drives malignant progression. Targeted therapeutic regimens, informed by this knowledge, may improve treatment outcomes of androgen-dependent PCa.
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Bundell, Christine Stephanie. "Immune recognition and editing of tumours expressing multiple antigenic epitopes in two murine models." University of Western Australia. School of Medicine and Pharmacology, 2007. http://theses.library.uwa.edu.au/adt-WU2007.0067.
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[Truncated abstract] The design of effective immunotherapies, using tumour antigens to stimulate a functional effector cytotoxic T cell (CTL) response in a tumour bearing host, requires an understanding of the 'real time' in vivo relationship between the host immune system and antigens expressed by the developing tumour. However, effector function of endogenous anti-tumour CTLs generated during tumour progression has largely been assessed by indirect ex vivo assays and often focused on a single antigen. Therefore, studies in this thesis evaluated the endogenous in vivo CTL response to multiple tumour antigenic epitopes in murine tumour models using Lewis lung carcinoma cells transfected with ovalbumin (an antigen that contains several intra-molecular MHC class I epitopes with a defined hierarchy) or a polyepitope (that contains a string of immunodominant MHC class I epitopes). Potent effector CTLs were generated to multiple dominant tumour antigenic epioptes early in tumour progression. However, in general, these CTL effectors only transiently retarded tumour growth, and at the later time points of tumour growth they were no longer generated in tumour draining lymph nodes. This coincided with diminished tumour antigen presentation in the same nodes which was found to be due to antigen loss. In both models antigen loss was the result of two processes; immuno-editing of the tumour by the host immune response and genetic instability resulting in antigen loss variants that could evade immune surveillance. A third model was generated that maintained low level tumour antigen expression throughout tumour progression. ... The impact of pre-existing endogenous dominant-epitope specific CTLs on tumour expressing the same epitope was also assessed, and resulted in a reduced tumour incidence and a CTL response restricted to a single antigen of the same MHC allele. Finally, the effects of two different immunotherapy regimens were examined. Intratumoural IL-2 treatment enhanced pre-existing CTL responses to the dominant epitopes leading to tumour regression. In addition, use of a multiple peptide vaccination regimen that avoided T cells competing for peptide-MHC complexes on APC was far more likely to be effective than one that did not. These results demonstrate that immunotherapies targeting tumours that express several dominant neo antigenic epitopes can be effective. The caveat for this approach is that it will only be effective in tumours that have generated an endogenous CTL response and must be used before antigen loss variants emerge.
14
Marcar, Lynnette Nongkynrih. "Inhibition of p53 tumour suppressor function by tumour associated MAGE-A proteins." Thesis, University of Dundee, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521696.
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Grundy, Richard Guy. "A molecular genetic analysis of Wilms tumour and Wilms tumour predisposition syndromes." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267737.
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Richards, R. "Understanding the role of the solid tumour microenvironment in brain tumour progression." Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3005579/.
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Glioblastoma (GBM) is the most common malignant brain tumour and has an extremely poor prognosis. The invasion of tumour cells into normal brain tissue makes complete surgical removal impossible; GBM is also resistant to treatment with chemotherapy and radiotherapy. Our aim was to investigate how GBM cell proliferation, survival and invasion is affected by the solid tumour microenvironment. Although GBM is highly vascularised, the abnormal structure and function of tumour blood vessels results in an inadequate supply of oxygen (hypoxia). Hypoxia is known to promote tumour progression; however, the effect of hypoxia on cell proliferation has not been well characterised. We performed a systematic investigation into the effects of different oxygen levels on the cell cycle. In contrast to the prevailing hypothesis, we found that long-term exposure to pathophysiological levels of hypoxia (1–8% O2) does not affect cell proliferation and viability and that even severe hypoxia (0.1% O2) has only minimal effects. We next sought to characterise the effect of hypoxia in multicellular tumour spheroids: 3D cell clusters that replicate important aspects of the tumour microenvironment. We characterised spheroids in terms of proliferation, survival and oxygenation and found that, in this more complex model, hypoxia was associated with reduced proliferation. We then used spheroids to develop a novel method for imaging cellular migration and invasion in 3D using lightsheet fluorescence microscopy (LSFM). We imaged spheroids over 24 h and then quantified the movements of up to 1200 cells per spheroid in terms of speed and straightness of movement. We were able to compare the movement of cells in different regions of spheroids, gaining insight into the behaviour of quiescent cells in the core of large (~500 μm), heterogeneous spheroids that had been exposed to hypoxia. This technique can be used to investigate the effect of the tumour microenvironment on cell motility and to gain insight into the mechanism of drugs that hinder the process of invasion.
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Basingab, Fatemah Salem. "Disabling factors mediating anti-tumour cytotoxic T lymphocyte suppression and tumour progression." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.702223.
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Tumour cells are able to shape their microenvironment (TME) to promote further proliferation as well as promote immune suppression. Understanding the mechanisms of tumour-mediated immune suppression will enable the development of effective immunotherapies to combat cancer. Studies described in this thesis focus on understanding some of the mechanisms of suppressing anti-tumour CTL responses. We utilised BALB/c mouse renal carcinoma cells (Renca) expressing the haemagglutinin (HA) protein from influenza virus A/PR/8/H1N1 (PR8), as a model tumour antigen that can be recognised by KdHA-specific TcR transgenic CL4 CD8+ T cells. Renca-HA cells do not form metastatic tumours in vivo and so priming na'ive CL4 T cells to form CTLs relies upon cross presentation of KdHA epitopes by DCs to naive CL4 T cells within the tumour draining lymph nodes (TDLNs). However following priming, although CL4 CTLs can enter the tumour, they lose their CTL function and fail to control tumour growth. Our studies show that continuous growth of Renca-HA cells in vivo is associated with the presence of increased numbers of CD4+CD25+Foxp3+ and CD8+IFN-y+IL-10+ regulatory tumour-infiltrating T lymphocytes (TILs). The majority of these regulatory TILs also express the ectoenzymes: CD39 and CD73, which facilitate the production of adenosine within the TME. Critically, we show that antagonising adenosine receptors: A1, A2A, A28 and A3 on CL4 T cells protects them from the inhibitory effect of adenosine within the TME, by decreasing expression of immune checkpoint molecules: TIM-3 and TIGIT. In another study we show that when Renca-HA cells were made to overexpress COX-2 (Renca-T3 cells), the resulting overproduction of PGE2 caused them to metastasise to the TDLNs. However, despite this ability to metastasise, rather than enabling Renca-T3 cells to directly activate naive CL4 T cells to become CTLs, the overproduction of PGE2 actually inhibited the direct priming of tumour-specific CL4 CTLs by preventing the IFN-y-dependent up-regulation of ICAM-1, which is vital during the initial priming phase. Significantly, the addition of exogenous IFN-y was shown to act in a positive feedback manner, upregulating ICAM-1 expression by Renca-T3 cells, thus enhancing further IFN-y production, proliferation and CTL effector function amongst PGE2-treated CL4 T cells; which could prevent tumour growth in vivo. We also examined the role of B-cell lymphoma 3-encoded protein (BCL-3) in generating CL4 T cell responses. Data show that although COX-2/PGE2-overexpressing Renca-T3 cells upregulate BCL-3 expression, overexpression of BCL-3 by Renca-HA cells does not increase COX-2/PGE2 expression. However, BCL-3-overexpression does accelerate tumour growth in vivo, and this is associated with an increase in CD8+IFN-y+IL-10+TILs. Taken together these findings advocate that several different mechanisms exist to suppress the efficacy of anti-tumour CTL responses in vivo against metastatic and non-metastatic tumours, and that finding ways to block these pathways either separately or in combination will therefore help to control tumour growth.
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Chambers, George. "A study of the production of the selected cytokines interleukin 1, interleukin 6, and tumour necrosis factor by certain tumours and tumour cell lines." Thesis, University of Glasgow, 1996. http://theses.gla.ac.uk/4041/.
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An investigation was carried out to examine the production of the inflammatory cytokines IL1, IL1, IL6, TNF, and TNF in two tumour cell lines, the MCF-7 breast cell line and the T-24 bladder cell line, and in samples of breast, bladder, lung and ovarian tumours. Two methods were used to investigate cytokine production. These were the polymerase chain reaction method (PCR) to examine cytokine mRNA production and immuno-staining of frozen or paraffin-embedded tissue sections to demonstrate the presence of the cytokine polypeptide directly. In the PCR experiments, the most frequently found cytokine was IL6, followed by IL1. Only a few tumours of any type displayed TNF, and even fewer produced TNF. In the immunostaining experiments performed on frozen sections, IL1 and IL6 proteins were detected in sections of tumours which gave positive results with PCR. Cell phenotyping indicated that the IL1 and IL6 were probably being synthesised by the tumour cells themselves although there was lymphocyte infiltration in every section examined. In the immuno-histology study performed on the paraffin-embedded sections, a new collection of tumours was used. These tumours were not subjected to parallel PCR due to size of tumour samples being too small. The results obtained from these experiments conflicted with the results observed in the PCR study. IL1 was detected in all of the breast tumours used for immuno-histology but in none of the breast tumours in the PCR experiments. While the conflict could not definately be resolved, it was thought that the results of the immuno-histology experiments were more accurate as they detected expression of cytokine protein on a cellular scale. The immuno-histology experiments demonstrated that some tumour cells produced IL1 in breast and bladder carcinomas, and some produced IL6 in breast and lung carcinomas.
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Chan, Hock Yee. "Studies on tumour angiogenesis." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299162.
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Kay, S. "Specificity of tumour rejection." Thesis, University of Nottingham, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376148.
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Ricketts, K. P. M. "Nanoparticles for tumour diagnostics." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1348030/.
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X-ray fluorescence techniques have proven beneficial for identifying and quantifying trace elements in biological tissues. A novel approach has been developed that employs x-ray fluorescence with an aim to locate the presence of nanoparticles, such as gold, which are embedded into tissues. The nanoparticles can be functionalised to act as markers for tumour characteristics to map the disease state, and then imaged to inform cancer therapy regimes. The uptake of nanoparticles by cancer cells could also enable detection of small clusters of infiltrating cancer cells which are currently missed by commonly used imaging modalities. The novel system, consisting of an energy resolving silicon drift detector with high spectral resolution, and a synchrotron source, showed potential in both quantification of and sensitivity to nanoparticle concentrations typically found in tumours. A linear relationship between fluorescence intensity and nanoparticle concentration was found down to 0.001 mgAu/ml, the detection limit of the system. A successful translation using a more clinically available bench-top x-ray tube was demonstrated, and found not to degrade the linearity or detection limit. The achieved system sensitivity suggests clinical usefulness in measuring tumour uptake in vivo. A set of bio-phantoms consisting of collagen type 1 gel, populated with colorectal cancer cells (HT29) and healthy murine fibroblast cells (3T3) that have been incubated with gold nanoparticles (GNPs), were created. The bio-samples were successfully used to (i) demonstrate GNP uptake in cells, and (ii) demonstrate the use of the novel benchtop system in measuring GNP uptake in cells. Translation to a 2D imaging technique was undertaken, using polycapillary optic technology to acquire positional information of gold XRF emissions, and energy resolving single channel and pixellated detectors. The GNP-imaging capabilities of the XRF technique were demonstrated using Perspex phantoms incorporating different GNP concentrations. Details of phantoms with concentrations as low as 0.025 mgAu/ml have been successfully imaged, with potential to image lower concentrations. It can be inferred from feasibility data collected that the x-ray fluorescence technique can be combined with x-ray diffraction methods to form a novel multi-modality system that is sensitive to GNP distribution and can discriminate biological tissue. Future work will develop this combined system to locate tumours and provide information on tumour characteristics.
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Bonda, Ulrich. "The prostatic tumour stroma." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-208301.
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The majority of cancer research projects mainly focus on the epithelial cancer cell, while the role of the tumour stroma has been largely neglected. Conventional 2D techniques, such as well plates and other kinds of tissue culture plastic, and animal models are mainly used to broaden our understanding of how tumours arise, develop, and induce metastasis. However, there is accumulating evidence suggesting a tremendous impact of the non‐cancerous tumour stroma on carcinogenesis, while other publications illustrate the great importance of advanced 3D in vitro models for cancer research.
The overall goal of this work was to investigate how cancer associated fibroblasts (CAFs; the most abundant component in the tumour stroma) and normal prostate fibroblasts (NPFs), isolated from patients diagnosed with aggressive forms of prostate cancer, contribute to angiogenesis, an important hallmark of cancer progression. For this purpose, a 3D in vitro angiogenesis co‐culture model was established. At first, two (semi‐) synthetic hydrogel platforms, gelatine methacrylate (GelMA) and star‐shaped (star)PEG‐heparin hydrogels were characterised and their physicochemical properties were compared with each other. Interestingly, GelMA gels shrank while starPEG‐heparin gels swelled in cell culture medium over the course of 24 hours. The cell concentration, in addition to the stiffness, was critical for the formation of endothelial networks, and the knowledge of swelling behaviour enabled the adjustment of initial cell density to ensure the density between both gel types was comparable. Moreover, preliminary tests with mesenchymal stem cells demonstrated that the hydrogel can be actively remodelled, as evaluated by stiffness parameters at day one and seven of incubation.
Growth factors (GFs) affect cellular fate and behaviour, and storage, presentation and administration of such chemokines can be critical for certain cellular applications. Due to the high anionic charge density of heparin, starPEG‐heparin hydrogels are known to reversibly immobilise several GFs and thereby might mimic the GF reservoir of the extra cellular matrix. Thus, transport processes of GFs with low and high heparin affinity inside these hydrogels were analysed by fluorescence correlation spectroscopy and a bulk diffusion approach. Results indicated that diffusion constants were synergistically decreased with increasing size and heparin affinity of the diffusant.
Next, the capability of endothelial cells (ECs) to self‐assemble and organise into 3D capillary networks was tested in GelMA, starPEG‐heparin and Matrigel hydrogels. Only starPEG‐heparin hydrogels allowed the formation of interconnected capillaries in macroscopic hydrogel samples. However, as it is widely used to test for pro‐ and anti‐angiogenic agents, the 2D Matrigel angiogenesis assay was included for subsequent co‐culture experiments of ECs and fibroblasts in order to investigate how the stromal cells influence the formation of endothelial networks. For a detailed characterisation of 3D structures, a conventionally applied 2D method (Maximum Intensity Projection for 3D reconstructed images, MIP) was compared to an optimised 3D analysing tool. As a result, it was discovered that MIP analysis did not allow for an accurate determination of 3D endothelial network parameters, and can result in misleading interpretations of the data set.
Indirect co‐cultures of hydrogel‐embedded ECs with a 2D layer of fibroblasts showed that fibroblast‐derived soluble factors, including stromal cell‐derived factor 1 and interleukin 8, affected endothelial network properties. However, only co‐encapsulation of ECs and fibroblasts in starPEG‐heparin hydrogel discs revealed remarkable changes in endothelial network parameters between CAF and NPF samples. In detail, the total length and branching of the capillaries was increased. For two donor pairs, the diameter of capillaries was decreased in CAF samples compared to NPF samples, underlining the high physiological relevance of this model. In contrast, significant differences in 2D Matrigel assays were not detected between, CAF, NPF and control (ECs only) samples.
In summary, a 3D angiogenesis co‐culture system was successfully developed and used to characterise stromal‐endothelial interactions in detail. The combination of advanced biomaterials (starPEG‐heparin) and 3D analysing techniques goes beyond conventional 2D in vitro cancer research, and opens new avenues for the development of more complex models to further improve the acquisition of more biologically relevant data.
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Burns, Alice Sin Ying Wai. "The role of the p53 tumour suppressor pathway in central primitive neuroectodermal tumours." Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300357.
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Harwood, Reuben. "The response of tumour-infiltrating myeloid cells to the chemotherapy-treatment of tumours." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/6640/.
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Myeloid cells are a major component of most forms of malignant tumour. The plasticity of such cells means that they can alter their phenotype in response to changes in the tumour microenvironment, including the pronounced ones that take place after chemotherapy. Tumour cell death, as well as the various cytokines and chemokines released by cells in tumours after such treatments, are now known to alter both the recruitment and function of myeloid cells. Recent studies have shown that monocytes recruited into tumours during/following chemotherapy can promote tumour chemoresistance and metastasis. The data presented in this thesis suggest that, following chemotherapy, tumour-associated macrophages (TAMs) may increase their expression of the neutrophil-recruiting chemokines, CXCL1, CXCL2 and CXCL5, and possibly stimulate the intratumoural accumulation of neutrophils. Responding to these CXC chemokines (and possibly other secreted factors in chemotherapy-treated tumours), neutrophils may then upregulate their expression of such inflammatory cytokines as TNFα, CCL2 and CCL3. Furthermore, data from in vitro invasion assays suggest that neutrophil-derived TNFα is capable of inducing tumour cell invasiveness. Notably, the number of tumour-infiltrating neutrophils was significantly increased after chemotherapy in 3 of the 4 mouse tumour models used. Furthermore, in all 4 tumour models there were significantly more TNFα+ neutrophils after chemotherapy compared to control tumours. Combined treatment with chemotherapy and SB 265610, a CXCR2 antagonist that inhibits CXCL1, CXCL2 and CXCL5 signalling, successfully reduced both the number of these tumour-infiltrating, TNFα+ neutrophils, and the overall level of immunodetectable TNFα in tumours after chemotherapy. Although TNFα is known to be capable of supporting tumour growth, angiogenesis and metastasis, it remains to be seen whether such an increase in neutrophil TNFα expression contributes significantly to the post-chemotherapy regrowth of either primary or metastatic tumours. This could be achieved by giving chemotherapy to mice in which TNFα has been selectively knocked out/down in neutrophils. Data presented here suggest that combining chemotherapy with CXCR2 inhibitors like SB 265610 to inhibit the above neutrophil-mediated events could improve patient tumour responsiveness to chemotherapy and reduce tumour relapse.
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Aricò, Arianna. "Interaction between tumour and microenvironment - molecular mechanisms of cell migration in canine tumours." Doctoral thesis, Università degli studi di Padova, 2013. http://hdl.handle.net/11577/3423396.
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Different steps forward have been made in the recent years to identify the molecular determinants in carcinogenesis and the evidence of a multistep process where cancer cells accumulate multiple and consecutive genetic alterations has been formulated. Recently, tumour progression has been recognized as the product of a complex crosstalk between tumour cells and their surrounding and supporting tissue, named tumour stroma.
This stroma is known to influence the growth of cancer and it is composed by several types of cells, including endothelial cells of blood and lymphatic circulation, stromal fibroblasts and a variety of bone marrow-derived cells, such as macrophages, mast cells, neutrophils, lymphocytes and mesenchymal stem cells. The supportive microenvironment is generate and modulated by cancer cells through the production and activation of stroma growth factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta). Concomitant with altered growth-factor expressions, induced by their autocrine and paracrine effect on the tumour and stromal cells, cancer cells are able to produce proteolytic enzymes, such as Matrix metalloproteinases (MMPs), which operate the remodelling of extracellular matrix (ECM) and basement membrane, thus activating cell-surface and ECM-bound growth factors. All these processes are described to contribute to the extensive crosstalk between the microenvironment and the cancer cells.
Therefore, the microenvironment is implicated in the regulation of cell growth, determining angiogenesis, tumour invasion and metastasis, and impacting the outcome. Even if stromal cells are not malignant, their role in supporting cancer growth is vital to the survival of the tumour. For this purpose, cells of microenvironment have become an attractive target for therapeutic agents.
The present project has been divided in different tasks to identify the molecular mechanisms implicated in cell migration, angiogenesis and tumour growth led by stroma cells and their crosstalk with cancer cells in different neoplasia in dog. Canine mammary tumour, cutaneous mast cell tumour, lymphoid leukaemia and lymphoma were selected for the study and gene expression profiling and proteomic analysis of different growth factors (VEGF-TGF-beta-PDGF) and MMPs were analyzed in association with their possible prognostic and predictive role and crosstalk.
Several important results have obtained highlighting the background of the tumour progression and the role of microenvironment in veterinary oncology. Selected results are shown below:
- MMP-2, MT1-MMP, MMP-9 were significantly involved in canine mammary tumour and a significant role of the stromal compartment was described;
- MMP-9 and VEGF-A were associated with the histological tumour grade in cutaneous mast cell tumour;
- MMP-9, MT1-MMP, TIMP-1 and VEGF were correlated in T-cell lymphoma and in dogs with higher stage;
- A potential role of MT1-MMP and TIMP-2 in the pathogenesis of canine acute lymphoblastic leukaemia has been discovered;
- In chronic lymphocytic leukaemia, residual normal leukocytes have shown a significative influence in the expression of MMP-9, MT1-MMP, VEGF and TIMPs;
- Lymphoma and leukaemia in vitro model exhibited a significative discrepancy that enhanced the importance of microenvironment in vivo;
- PDGF-B mRNA expression was identified in canine T-cell lymphoma and cutaneous lymphomas. A functional autocrine and/or paracrine loop of growth stimulation was proposed due to the co-expression of PDGFs and PDGFRs at different time point during disease.
Therefore, the obtained results may significantly improve the understanding of cancerogenesis of the most frequent tumours in dogs. The summarized data here show a primary role for the microenvironment during carcinogenesis. Development of novel cancer therapies that target the process of metastasis formation, tumour growth and differentiation, by interfering with the ability of cancer cells to transmigrate into blood and lymph vessels and to invade the connective tissue, is widely expected in veterinary oncology. Further data are necessary to indicate that the use of chemopreventive agents to control the function and behaviour of cells in the microenvironment might be an important approach to the overall control of cancer.Negli ultimi anni nell’ambito dell’oncologia, diversi studi hanno identificato diverse molecole target implicate nella cancerogenesi e sono stati evidenziati numerosi processi attraverso cui le cellule tumorali sono in grado di accumulare alterazioni genetiche. Recentemente, la progressione del tumore è stata riconosciuta come il prodotto di un complesso crosstalk tra le cellule tumorali e il tessuto circostante, chiamato stroma tumorale. Questo stroma è noto per influenzare la crescita del tumore ed è composto da diverse tipologie cellulari, che comprendono cellule endoteliali della circolazione sanguigna e linfatica, fibroblasti stromali ed una varietà di cellule derivate dal midollo osseo, come macrofagi, mastociti, neutrofili, linfociti e cellule staminali mesenchimali. Ulteriormente, il microambiente di supporto è generato e modulato da cellule tumorali attraverso la produzione e attivazione di fattori di crescita prodotti dallo stroma stesso, come Vascular Endothelial Growth Factor (VEGF), Platelet-Derived Growth Factor (PDGF) e Transforming Growth Factor-beta (TGF). Concomitante all’alterata espressione di questi fattori e per il loro effetto autocrino e paracrino sulle cellule tumorali e su quelle stromali, le cellule neoplastiche iniziano a produrre enzimi proteolitici, come metalloproteasi di matrice (Matrix metalloproteinases - MMPs). Le MMPs operano il rimodellamento della matrice extra cellulare e della membrana basale, attivando così fattori di crescita legati alla superficie cellulare e alla matrice stessa. Tutti questi processi contribuiscono all’esteso crosstalk tra il microambiente e le cellule tumorali. Il microambiente quindi è implicato nella regolazione della crescita cellulare, determinando neoangiogenesi, invasione, metastasi tumorali e influenzando il risultato della terapia. Anche se le cellule stromali non sono considerabili fenotipicamente maligne, il loro ruolo nel sostenere la crescita della neoplasia è essenziale per la sopravvivenza del tumore. Con questo presupposto, le cellule del microambiente sono diventate un bersaglio attrattivo per diversi agenti terapeutici. Il progetto di ricerca è stato suddiviso in diverse fasi per identificare i meccanismi molecolari implicati nella migrazione cellulare, nell'angiogenesi e nella crescita neoplastica, da parte di cellule stromali e dal loro crosstalk con le cellule tumorali, in diverse neoplasie del cane. Per lo studio sono state selezionate le tipologie tumorali più frequenti nel cane: tumore mammario, mastocitoma cutaneo, leucemie linfoidi e linfoma, analizzando i profili di espressione genica e proteica di diversi fattori di crescita (VEGF-TGF-beta-PDGF) e delle MMPs, in associazione al loro crosstalk e ad un loro eventuale ruolo prognostico. Sono stati ottenuti importanti risultati evidenziando lo scenario della progressione tumorale e il ruolo del microambiente in oncologia veterinaria. E’ stato dimostrato che: - MMP-2, MT1-MMP, MMP-9 sono significativamente coinvolte nel tumore mammario ed è stato descritto un loro ruolo rilevante del compartimento stromale; - MMP-9 e VEGF-A sono associati al grado istologico nei mastocitomi cutanei; - MMP-9, MT1-MMP, TIMP-1 e VEGF sono correlate nel linfoma T e nei cani con linfoma con stadio clinico più alto; - MT1-MMP e TIMP-2 hanno un ruolo nella patogenesi nelle leucemie linfoblastiche acute; - Nella leucemia linfocitica cronica, i leucociti residui normali mostrano un'influenza significativa nell'espressione di MMP-9, MT1-MMP, VEGF e dei TIMPs; - Il linfoma e la leucemia nel modello in vitro mostrano una considerevole discrepanza per alcune MMPs e VEGF che avvalora l'importanza del microambiente in vivo; - L’espressione genica del PDGF-B è significativa nei linfomi T e nei linfomi cutanei. E’ stato inoltre proposto un loop funzionale autocrino e/o paracrino di stimolazione della crescita della neoplasia, dovuto alla co-espressione dei PDGFs e dei recettori in diversi tempi durante la malattia. I risultati ottenuti potrebbero migliorare significativamente la comprensione della cancerogenesi nei tumori più frequenti nel cane. I dati qui sintetizzati mostrano un ruolo primario del microambiente durante la carcinogenesi. Lo sviluppo di nuove terapie antitumorali che colpiscano il processo di formazione di metastasi, la crescita e la differenziazione della neoplasia, interferendo con la capacità delle cellule tumorali di trasmigrare nel sangue e nei vasi linfatici e di invadere il tessuto connettivo, sarà ampiamente perseguito in oncologia veterinaria nel futuro prossimo. Sono però necessari ulteriori studi per indicare se l'uso di agenti chemio-preventivi per controllare la funzione ed il comportamento delle cellule nel microambiente possa essere un importante approccio al controllo complessivo del cancro.
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Al-Husari, Maymona. "Mathematical modelling of the tumour microenvironment : the causes and consequences of tumour acidity." Thesis, University of Strathclyde, 2012. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=18965.
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Extracellular acidity and high levels of lactate are commonly observed in solid tumours. Some tumours also exhibit a reversed cellular pH gradient with an intracellular pH that is higher than the extracellular. This has been shown to play a crucial part in not only the invasive and metastatic cascade of tumours, but also on their response to therapies. In this thesis, we present four different mathematical models that examine the possible causes of tumour acidity and its effect on cell metabolism and tumour invasion. In the second chapter, we derive an ordinary differential equation model that explicitly focus on the interplay between H+-ions and lactate. We subject the model to qualitative and quantitative analysis and, in particular, we study the effect in the variations of key parameter estimates on the emergence of a reversed transmembrane pH gradient within the tumour. The model predicts that a re- versed pH gradient is attainable under aerobic conditions when sourc es of H+-ions other than those from glycolysis are decreased and the lactate/H+ cell membrane transporter (MCT) activity is increased - but we find the intra- and extracellular pH values in this case to be too alkaline to be physiological. Under anaerobic conditions, we find that decreasing the sources of H+-ions other than those from glycolysis and also the glycolytic rate gives rise to a reversed cellular pH gradient, but again for intra- and extracellular pH values that are far from realistic biologically. In the third chapter, we present an extension to the first model by including the spatial diffusion of hydrogen ions and lactate. This spatial extension also predicts ii a reversed transmembrane pH gradient but this time for more realistic intra- and extracellular pH values. We find that low levels of blood lactate can give rise to a reversed pH gradient throughout the spatial domain independent of the levels of tissue lactate. Likewise, we have found the existence of a negative pH gradient to be strongly dependent on the combined activity of a lactate/H+ cell membrane transporter and other sources of H+-ion. In the fourth chapter, we study the role of oxygen and pH on early tumour growth using a hybrid cellular automaton model. We examine whether the levels of oxygen, intra- or extracellular pH are the dominating metabolites driving tumour growth and phenotypic transformations. This model predicts that when tumour cells are strongly sensitive to changes in the intracellular pH, a low activity of the Na+/H+ cell membrane transporter (NHE) or a high rate of anaerobic glycolysis can give rise to a "fingering" morphology. Furthermore, we show that as the activity of the MCT transporter increases, all the tumour cells within the spheroid can exhibit a reversed transmembrane pH gradient. In the fifth chapter, we examine the effect of extracellular acidity on tumour invasion focusing, in particular, on cellular adhesion, matrix-degrading enz yme activity and cellular proliferation. Our numerical simulations using a cellular Potts model show that, under acidic extracellular pH, cell-ECM adhesion strength has a comparable effect on tumour invasiveness as the rate at which the ECM is degraded by proteolytic enzymes. We also show that tumour cells cultured under physiological pH tend to be larger and develop a "diffuse" morphology compared to those cultured at acidic pH which display protruding "fingers" at the advancing tumour front.
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Balahmar, Reham Mohammed. "Trophoblast models for tumour studies : understanding the similarities of tumour and trophoblast invasion." Thesis, Nottingham Trent University, 2016. http://irep.ntu.ac.uk/id/eprint/31901/.
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Cell proliferation, migration and invasion are the important features of tumour metastasis. Interestingly, during embryonic development, trophoblast cells show similar attributes like tumour cells to establish foeto-maternal communications and support normal pregnancy. The invasive nature of tumour as well as trophoblast cells (especially during the first trimester) are believed to be enhanced by a collection of "stem-like cells" (SLCs) called "spheroid bodies". This sub-population of SLCs within tumour or trophoblast cells can proliferate to form a heterogeneous cell groups with different functional attributes. However, tumour SLCs proliferate during invasion; while trophoblast cells proliferate and then invade. Although several previous studies have produced SLCs from tumour cell lines in vitro, limited attempts were made to produce SLCs from trophoblast cells. Therefore, this study firstly aimed to produce and characterise SLCs from transformed first trimester trophoblast cell lines (HTR8sv/neo and TEV-1) and choriocarcinoma (trophoblast tumour cell lines JEG-3 and BeWo) in relation to a non-placental tumour cell line MCF-7. Secondly, to date, the factors that are responsible for there uncontrolled versus controlled invasion are not fully understood. On the other hand, it is worth noting that in pre-eclampsia (PE), the invasion of first trimester trophoblast cells is found to be reduced. Therefore, it was hypothesised that it would be possible to identify the important molecules that may be involved in the controlled trophoblast invasion by comparing the status of different factors that are identified with altered expression in tumour cells between (a) normotensive (NT) and PE placentae, and (b) in the SLCs produced in vitro from trophoblast cells. SLCs from transformed trophoblast and choriocarcinoma cells were produced by growing in non-attachable or ultra-low attachment flasks with or without doxorubicin (DOX) to produce DOX-resistant and non-resistant spheroids. The “stemness” feature of these spheroids was characterised by comparing the expressions of stem cell markers. The migration and invasive capacities of DOX-resistant and non-resistant spheroids were compared with their parental cells by wound-healing and 2-D/3-D invasion assays. The status and expression of novel factors that may be involved in cell proliferation and invasion was checked by quantitative real-time PCR and western blotting. Also a comparative proteomic (SWATH-MS) analysis was carried out to identify and compare the global changes of the peptide expression during SLCs transformation. In addition the RNA and protein expression of factors that are involved in trophoblast invasion were compared in 13 NT and 12 PE placentae. Both the transformed trophoblastic cell lines (HTR8/Sv-neo and TEV-1,) and gestational choriocarcinoma cell lines (JEG-3 and BeWo) were able to produce non- spheroidal cells (non-resistant and drug resistant) under 3-D conditions. These spheroids showed increased protein expression of stem cells markers, such as OCT4, SOX2 and NANOG. On the other hand, both trophoblast CDX2 and the cell fate determining transcription factor, NOTCH1, were reduced in spheroidal cells confirming the "stem-like" transformation. Moreover, the 2-D invasion assay showed a statistically significant increase in the invasive potential (number invaded cells) of spheroids. This significance was found to be higher in untreated spheroids from transformed trophoblast cells; P < 0.0005 (for both HTR8svneo and TEV-1) and in one of the choriocarcinoma cells JEG-3; whilst the significance between untreated spheroids of BeWo and their parental cells was slightly less (P < 0.05). The 3-D invasion assays have shown a significant time dependent increase in the invasions of non-resistant spheroidal cells in comparison with DOX-resistant counterpart, especially the non-resistant spheroidal cells produced from HTR8/Svneo (p < 0.0005) at 48 hours. Spheriodal cell invasion of non-resistant TEV-1 and choricarcinoma cells was significantly higher than DOX-resistant cells (p < 0.005). Therefore this study has produced spheroidal cells from (a) transformed first trimester trophoblast (HTR8/Svneo and TEV-1) and (b) choriocarcinoma (JEG-3 and BeWo) cells. Since these cell lines are of trophoblast origin, it is possible to use these spheroids as comparative models to study the effects of chemotherapeutic agents on (a) physiologically rapidly dividing cells (HTR8/Svneo and TEV-1) and (b) tumour models (JEG-3 and BeWo) of similar origins. Comparisons of mRNA and protein expression between NT and PE placentae have shown a statistically significant increase in the expressions of ALDH3A1, AURK-A, PDGFRα, and TWIST1 in PE placentae (p < 0.05); whilst AURK-C and JAG-1 expression was down-regulated. SWATH-MS analysis has also highlighted up-regulation of novel proteins that are associated with proliferation, invasion and cell cycle control in the spheroids produced from these cell lines. These proteins include plasminogen, vitronectin and ALDH1A3. However, the function of most of these factors have not been fully investigated in placenta. In summary the study has generated and characterised "stem-like" spheroids from transformed trophoblast and choriocarcinoma cells. These spheroidal cells may be useful as in vitro toxicological models to study the in vivo cellular effects on rapidly dividing cells.
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Zumel, Marne María Ángela 1984. "Environmental factors and brain tumour risk in young people." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/668182.
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Risk factors and diagnosis in young people have been little explored, despite brain tumours (BT) is one of the most frequent tumour type in children and adolescents. The purpose of this doctoral thesis is to study 1) the clinical characteristics and symptoms of BTs in young people, based on the international MOBI-Kids case-control study; 2) a systematic review (SR) of the literature on risk of BTs in young people in relation to environmental factors; 3) the BT risk in relation to chemicals present in drinking water and to heavy metals.
The analyses of clinical characteristics revealed that the vast majority of tumours were neuroepithelial (mostly gliomas), followed by embryonal tumours and meningiomas. Overall, the most frequent symptoms were headache, followed by focal neurological signs and symptoms, nausea/ vomiting and visual signs and symptoms, being a 4% of the cases asymptomatic. The average time of diagnosis tended to be short (median 1.42 months), though this varied according to tumour type, age and type of symptom.
I found many studies that showed an association between environmental factors (including tobacco smoke, pesticides and diet, among other exposures) and BT risk in the SR. Because of methodological limitations however, the evidence about the role of these factors in the aetiology of this disease is still uncertain.
Our analyses in relation to water chemicals showed ORs below 1 for exposures to THMs, and ORs above 1 for nitrate exposure, for both pre- and postnatal exposure periods, some statistically significant so. Our analyses of heavy metals showed ORs below 1for exposures to chromium. However, literature is scarce about this association.
Overall, this thesis served to fill a gap in knowledge concerning 1) the clinical characteristics of BT in young people, useful to both clinical practice and aetiological research; 2) causes of this disease; 3) the role of heavy metals and ubiquitous chemicals in water. Further research needs on the aetiology and prevention of BTs in young people are provided.Los factores de riesgo y el diagnóstico en los jóvenes han sido poco explorados, a pesar de que los tumores cerebrales (TC) son uno de los tipos de tumores más frecuentes en los niños y jóvenes. El propósito de esta tesis doctoral es el estudio de 1) de las características clínicas y los síntomas de los TC en los jóvenes, basados en el estudio internacional de casos y controles MOBI-Kids; 2) una revisión sistemática de la literatura sobre el riesgo de TC en jóvenes en relación con factores ambientales; 3) el riesgo de TC en relación con los productos químicos presentes en el agua potable y con los metales pesados. Los análisis de las características clínicas revelaron que la gran mayoría de los tumores eran neuroepiteliales (principalmente gliomas), seguidos de tumores embrionarios y meningiomas. En general, los síntomas más frecuentes fueron dolor de cabeza, seguido de signos y síntomas neurológicos focales, náuseas/ vómitos y problemas en la visión, siendo un 4% de los casos asintomáticos. El tiempo promedio de diagnóstico tendió a ser corto (mediana 1,42 meses), aunque esto varió según el tipo de tumor, la edad y el tipo de síntoma. Encontré muchos estudios que encontraron asociación entre los factores ambientales (incluido el humo del tabaco, los pesticidas y la dieta, entre otras exposiciones) y el riesgo de TC en la revisión sistemática. Sin embargo, debido a limitaciones metodológicas, la evidencia sobre el papel de estos factores en la etiología de esta enfermedad aún es incierta. Nuestros análisis en relación con los productos químicos del agua mostraron unos OR por debajo de 1 para exposiciones a THMs, y OR por encima de 1 para exposición a nitrato, tanto en períodos de exposición prenatales como postnatales, algunos estadísticamente significativos. Nuestros análisis de metales pesados mostraron ORs por debajo de 1 para la exposición al cromo. Sin embargo, la literatura es escasa sobre esta asociación. En general, esta tesis sirvió para llenar un vacío en el conocimiento sobre 1) las características clínicas de la TC en los jóvenes, útiles tanto para la práctica clínica como para la investigación etiológica; 2) causas de esta enfermedad; 3) el papel de los metales pesados y los químicos ubicuos en el agua. Se ha identificado la necesidad de realizar más investigaciones sobre la etiología y la prevención de las TC en los jóvenes.
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Higgins, Geoffrey S. "A siRNA screen to identify molecular determinants of tumour radiosensitivity." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:dd1472c2-225c-47df-80a6-67adf2fdaae7.
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The effectiveness of radiotherapy treatment could be significantly improved if tumour cells could be rendered more sensitive to ionising radiation without altering the sensitivity of normal tissues. However, many of the key mechanisms that determine intrinsic tumour radiosensitivity are largely unknown. This thesis is concerned with the identification of novel determinants of tumour radiosensitivity. A siRNA screen of 200 genes involved in DNA damage repair was conducted using γH2AX foci post-irradiation as a marker of cell damage. This screen identified POLQ as a potential tumour-specific contributor to radioresistance. Subsequent investigations demonstrated that POLQ knockdown resulted in radiosensitisation of a panel of tumour cell lines, whilst having little or no effect on normal tissue cell lines. It was subsequently shown that POLQ depletion rendered tumour cells significantly more sensitive to several classes of cytotoxic agents. Following exposure to etoposide, it was found that tumour cells depleted of POLQ had reduced RAD51 foci formation, suggesting that POLQ is involved in homologous recombination. A homologous recombination assay was used to confirm that POLQ depletion does indeed result in reduced homologous recombination efficiency. These findings led to the investigation of the clinical significance of tumour overexpression of POLQ. The clinical outcomes of patients with early breast cancer were correlated with tumour expression levels of POLQ. It was found that POLQ overexpression was correlated with ER negative disease and high tumour grade, both of which are associated with poor clinical outcomes. POLQ overexpression was associated with extremely poor relapse free survival rates, independently of any other clinical or pathological feature. The mechanism that causes this adverse outcome may in part arise from resistance to adjuvant chemotherapy and radiotherapy treatment. These findings, combined with the limited normal tissue expression of POLQ, make it an appealing target for possible clinical exploitation.
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Seng, Tzer Jing. "Identification of candidate tumour suppressor genes on chromosome 22 in central nervous system tumours." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615650.
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King-Underwood, Linda. "The role of the Wilms tumour gene WT1 in leukaemia and familial Wilms tumour." Thesis, Institute of Cancer Research (University Of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286450.
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Higgins, Catherine Ann. "Tumour associated macrophages, tumour infiltrating lymphocytes, apoptotic and mitotic cells in human colorectal cancer." Thesis, University of Ulster, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268556.
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Moro, Monica. "Manipulation of anti-tumour immune response by tumour targeting with soluble immuno-modulatory molecules." Thesis, Open University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323271.
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Jordaan, Carike. "The relationship between tumour characteristics, depressive symptoms, and neuropsychological profiles in brain tumour patients." Thesis, Stellenbosch : Stellenbosch University, 2015. http://hdl.handle.net/10019.1/96700.
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Thesis (MA)--Stellenbosch University, 2015ENGLISH ABSTRACT : Worldwide there are various reports on the prevalence of depression in patients diagnosed with brain tumours. In South Africa, psychological research in relation to psychiatric symptoms among patients with brain tumours is lacking. The aims of this study were to determine the incidence of depression in patients diagnosed with brain tumours and to clarify our understanding of the relationship between depression and tumour localisation, histopathological type of tumour, and participant characteristics. The study sample consisted of 35 patients (11 males and 24 females) aged between 21 and 64 years with a solitary primary brain tumour. The patients were treated at the neurosurgery clinics located at Tygerberg Hospital in the Western Cape and Universitas Hospital in the Free State between mid-2010 and 2013. The major histological subgroup consisted of meningiomas (47%), glioblastomas (22%), astrocytomas (19%), gliomas (9%) and epidiomas (3%). The tumour distribution was as follows: 52% in the left hemisphere, 37% in the right hemisphere, and 11 % in the midline. The psychiatric symptoms of the patients were assessed before treatment by the Beck Depression Inventory and Mini International Neuropsychiatric Interview. In addition, the patients’ neuropsychological functions were evaluated by a short neuropsychological test battery (Mini Mental State Examination, Trail Making Test (Part A), Letter Number Sequencing subtest, Hopkins Verbal Learning Test – Revised, and Brief Visuospatial Memory Test – Revised). Results from the quantitative data, showed the prevalence of mild depression was 26% for men and 43% for women. Overall 37% of the total sample had depressive symptoms. No significant relationship was found between depression and tumour location or between the various neuropsychological characteristics and neurological symptoms and tumour location. The study showed that depression is a common symptom in patients diagnosed with brain tumours and therefore depression symptoms have to be recognised and treated by psycho-educating the patients and their families, pharmacotherapy, or psychotherapy as soon as possible. However, due to the relatively small sample size, the results are of limited generalisability.
AFRIKAANSE OPSOMMING : Wêreldwyd is daar verskeie verslae oor die voorkoms van depressie in pasiënte gediagnoseer met breingewasse. In Suid-Afrika is daar ’n tekort aan sielkundige navorsing met betrekking tot psigiatriese simptome by pasiënte. Die doel van hierdie studie was om die voorkoms van depressie te bepaal in pasiënte gediagnoseer met breingewasse en om duidelikheid te kry oor die verband tussen depressie en die ligging van breingewasse, histopatologiese tipe gewas en karakter eienskappe van die deelnemers. Die steekproef van die studie het bestaan uit 35 pasiënte (11 mans en 24 vroue) tussen die ouderdomme 21 en 64 jaar met ‘n soliede breingewas. Die pasiënte is behandel by die neurochirurgiese klinieke by Tygerberg Hospitaal in die Wes-Kaap en by Universitas Hospitaal in die Vrystaat vanaf middel 2010 tot 2013. Die mees algemene histologiese subgroep het bestaan uit meningiome (47%), glioblastomas (22%), astrocytomas (19%), gliomas (9%) en epidiomas (3%). Die verspreiding van die gewasse was soos volg: 52% in die linkerhemisfeer, 37% in die regterhemisfeer en 11% in die middel. Die psigiatriese simptome van die pasiënte is voor behandeling geëvalueer met behulp van die Beck Depression Inventory en die Mini International Neuropsychiatric Interview. Bykomend is die pasiënte se neurosielkundige funksies geëvalueer met behulp van ‘n neurosielkundige toetsbattery (Mini Mental State Examination, Trail Making Test (Part A), Letter Number Sequencing subtest, Hopkins Verbal Learning Test – Revised en Brief Visuospatial Memory Test – Revised). Die resultate van die kwantitatiewe data het getoon die voorkoms van matige depressie was 26% vir mans en 43% vir vroue. In geheel het 37% van die totale steekproef depressiewe simptome getoon. Daar was geen beduidende verhouding tussen depressie en die ligging van die gewas of tussen die verskeie neurosielkundige eienskappe en die ligging van die gewas nie. Die studie het getoon dat depressie ’n algemene simptoom is in pasiënte gediagnoseer met breingewasse en daarom moet depressiewe simptome herken en so gou as moontlik behandel word deur psigo-opvoeding van die pasiënte en hul familie, farmakoterapie of psigoterapie. As gevolg van die relatiewe klein steekproef grootte het die resultate ’n beperkte veralgemeenbaarheid.
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Salimu, Josephine. "Tumour antigen cross-presentation from irradiated tumour cells and the role of tlr4 polymorphism." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/64217/.
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Immune responses contribute to the success of radiation therapy of solid tumours; however, the mechanism of triggering CD8+ T cell responses is poorly understood. Antigen cross-presentation from tumour cells by dendritic cells (DC) is a likely dominant mechanism to achieve CD8+ T cell stimulation. We established a cross-presentation model in prostate cancer in which DC present a naturally expressed oncofetal tumour antigen (5T4) from irradiated DU145 tumour cells to 5T4-specific T cells. Ionising radiation (12 Gy) caused G2/M cell cycle arrest and cell death, increased cellular 5T4 and high-mobility protein group-B1 (HMGB1) levels and upregulated surface calreticulin and Hsp70 expression in DU145 cells. Co-culture of DC with irradiated tumour cells lead to efficient phagocytosis of tumour cells and upregulation of CD86 and HLA-DR on DC. CD8+ 5T4-specific T cells, stimulated with these DC, proliferated and produced IFNγ. Inhibition of HMGB1 decreased T cell stimulation but not DC activation, while TRIF/MyD88 inhibition only had a marginal effect on T cell stimulation. Unlike previous reports, I found no functional evidence that DC with Asp299Gly toll-like receptor-4 (TLR4) single nucleotide polymorphism had impaired ability to cross-present tumour antigen. However, I observed a highly significant and robust prevention of antigen cross-presentation when tumour cells were pretreated with the novel Hsp70 inhibitor, VER 155008. The inhibitor also prevented CD86 upregulation on DC co-cultured with irradiated tumour cells. Together, the results in this thesis demonstrate that radiation induces immunologically relevant changes in tumour cells, which can trigger CD8+ T cell responses via a predominantly Hsp70-dependent antigen cross-presentation process.
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Newsom-Davis, Thomas Edmund. "Fas Ligand and Tumour Immunology." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486884.
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Fas ligand (FasL) is a transmembrane protein which induces apoptosis in cells expressing its receptor, Fas. The FasL/Fas pathway is one ofthe major mediators of cell death in the immune system but more recently an inflammatory role has been suggested. This thesis investigated the finding that when injected into mice, FasL-expressing (FasL+) tumours recruit a massive polymorphonuclear neutrophil (PMN) infiltration and are then rejected, which is followed by the development of antibody mediated tumour immunity. . In this work, eight IgM and one IgG2a monoclonal antibodies (mAbs) were produced from mice vaccinated with FasL+ murine melanoma. They recognised various syngeneic and allogeneic murine tumours cell lines. One mAb, TMIO, also recognised a range of human tumours cell lines but not untransformed cells. The epitopes of all the mAbs were carbohydrates expressed on proteins and/or lipids. The epitope of TMIO were high-mannose clusters on N-linked glycoproteins whilst another antibody, KM5.2, was recognising the glycolipid GM4. Both are novel tumour antigens. The IgG2a mAb had in vivp anti-tumour activity, protecting mice against the development ofboth cutaneous and metatstatic melanoma through antibody dependent cellular cytotoxicity. T~e mechanism behind the rejection and immunity to FasL+ tumours was studied using human cells. FasL promoted the production of chemokines by PMNs. PMNs, but not FasL, induced maturation of dendritic cells with a corresponding increase in T cell proliferation. FasL inhibited the generation of the THI subset ofCD4+ T cells, whereas PMNs promoted THI polansation and increased 1NFa and IL-22 production. -- , A model is proposed in which PMNs attracted to the tumour site promote rejection of FasL+ tumours by creating an inflammatory environment whilst recruiting and activating effector cells. They then induce antibody-mediated tumour immunity by facilitating the T cell help required. PMNs therefore act as a bridge between the innate and adaptive immune responses.
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Moorehead, Roger A. "Mitochondrial alterations in tumour cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ30106.pdf.
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Dick, Elizabeth Ann. "Magnetic resonance guided tumour ablation." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404556.
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Clark, S. R. "The investigation of tumour metastasis." Thesis, University of Oxford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370241.
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Modlich, Ute. "Approaches to tumour vascular targeting." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393467.
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Chen, Jianmeizi. "Functionalised liposomes for tumour targeting." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505002.
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Morphy, John Richard. "Functionalised macrocycles for tumour targeting." Thesis, Durham University, 1988. http://etheses.dur.ac.uk/6407/.
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Monoclonal antibodies which recognise tumour-associated antigens provide a means of targeting radionuclides selectively to tumour cells. (^99m)Tc and (^64)Cu are potentially useful isotopes for radioimmunoimaging;(^ 90)Y and (^67)Cu may be suitable for radioimmunotherapy. The synthesis of functionalised macrocycles for binding these four radioisotopes to antibodies is described. In each case, a macrocycle has been selected to provide a complex which is kinetically inert, thereby preventing dissociation of the radiolabel in vivo. A novel strategy for conjugating a C-alkylated cyclam derivative (for binding Tc and Cu) to an antibody is described. This method facilitates the selective acylation of an exocyclic primary amino group in the presence of the secondary ring nitrogens. Unfortunately, the labelling of antibody-bound cyclam with (^99m)Tc required conditions (pH 11) which produced extensive binding of the radiolabel to the protein backbone. "Non-specific" (^99m) Tc was subsequently found to dissociate in vivo. Pre-labelling the macrocycle with (^99m)Tc solved the "non-specifics" problem but required a pH which meant that the conjugation step was too slow for sufficient specific activity to be bound. A phenol-pendent derivative of cyclam was found to incorporate (^99m)Tc at a lower pH than cyclam itself. The "non-specific" binding of copper to the protein was minimised using a low pH labelling strategy in conjunction with a chelate wash. Macrocycle antibody conjugates labelled manner provide very promising biodistribution profiles in normal mice. A labelling buffer was selected to enhance the rate of uptake of copper by the macrocycle at low pH. Macrocycle-antibody conjugates containing 13N(_4), which was found to provide faster association kinetics than cyclam, have been prepared and await radiolabelling studies. A derivative of I3N(_4), containing 4 carboxylic acid donor sites, has been functionalised for conjugation to an antibody to act as a (^90)Y binder.
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Johnson, Timothy Scott. "Transglutaminase apoptosis and tumour progression." Thesis, Nottingham Trent University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283035.
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Smith, Fiona Calder. "Tumour targeting with macrocyde conjugates." Thesis, Durham University, 1995. http://etheses.dur.ac.uk/5456/.
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Complexes of the radionuclides (^67)Ga and (^III)In, or of the paramagnetic contrast agent Gd, used in MRI, provide a means of imaging tumours. The stability of the (^71)Ga- NOTA complex was verified by in vivo NMR spectroscopy. The novel phosphinic acid NOTA analogue, bearing an isopropyl substituent on phosphorus was prepared and its lipophilicity and (^III)In biodistribution in mice determined. The crystal structure of the yttrium complex of N,N"-bis(benzylcarbamoylmethyl)diethylenetriamine-N,N',N"-triacetic acid revealed amide carbonyl ligation in a distorted mono-capped square antiprismatic structure, with one metal-bound water. The biodistribution of the analogous Gd complex was examined. A novel series of 9N3 based ligands incorporating three further N donor atoms, carboxymethyl groups and a potentially larger cavity size were synthesised. The analogous series containing phosphinic acid groups and the 12N3 counterparts were also prepared. The former series formed complexes with Gd and the biodistribution in mice was studied. The 12N3 analogues failed to form Gd complexes.2-Nitroimidazoles are known to selectively target hypoxic tumour tissue. Two conjugates of 2-nitroimidazole for tumour imaging were prepared, the Gd complex of a DTPA-bis(2-nitroimidazole) amide and the (^III)In complex of a C-functionalised NOTA- nitroimidazole conjugate. The biodistribution in mice of each was studied and luminescence experiments on the Tb complex of the former revealed one metal bound water molecule. Novel conjugates of the tetrapeptide tuftsin and a complexing agent based on the 12N4 skeleton and an N-linked NOTA derivative were synthesised. Biodistributions of the Gd and In complexes respectively are being carried out. Acridine intercalators reversibly bind DNA, possibly enhancing the effectiveness of tumour targeting conjugates. Novel multifunctionally labelled acridines based on tris(2- aminoethyl) amine were sought. The p-nitrophenolate active ester of 9-acridine carbamoyl-2-(2-aminoethyl)-2-methyl amine was also prepared as a versatile agent for acridine labelling.
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MacManus, Michael Patrick. "Erthropoietin, anaemia and tumour hypoxia." Thesis, Queen's University Belfast, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335941.
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Akbar, Shazia. "Tumour localisation in histopathology images." Thesis, University of Dundee, 2015. https://discovery.dundee.ac.uk/en/studentTheses/c282ab9c-5776-400f-8440-f5ac9cf2f4ba.
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Immunohistochemical (IHC) assessment in cancer research is important for understanding the distribution and localisation of biomarkers at the cellular level. However currently IHC analyses are predominantly performed manually, increasing workloads and introducing inter- and intra-observer variability. Automation shows great potential in clinical research to reduce pathologists' workloads and speed up cancer research in large clinical studies. Whilst recent advancements in digital pathology have enabled IHC measurements to be performed automatically, the acquisition of manual annotations of tumours in scanned digital slides is still a limiting factor. In this thesis, an automated solution to tumour localisation is explored with the aim of replacing manual annotations. As an exemplar, human breast tissue microarrays stained with estrogen receptor are considered. Methods for automated tumour localisation are described with a focus on capturing structural information in tissue by adopting superpixel properties in a rotation invariant manner, suitable for histopathology images. To incorporate essential contextual information, methods which utilise posterior tumour probabilities in an iterative manner are proposed. Results showed pixel-level agreements between automated and manual tumour segmentation masks (κ=0.811) approach inter-rater agreement between expert pathologists (κ=0.908). A large proportion of disagreements between automated and manual segmentations were shown to correlate to minor discrepancies, inconsequential for IHC assessment. IHC scores extracted from automated and manual tumour segmentation masks showed strong agreements (Allred: κˆ=0.911; Quickscore: κˆ=0.922), demonstrating the potential of automation in clinical practice across large clinical trials.
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Chen, Wei. "Modelling of tumour-induced angiogenesis." Thesis, Northumbria University, 2015. http://nrl.northumbria.ac.uk/30235/.
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Controlled by extracellular signals, tumour-induced angiogenesis is a crucial step in the development of tumours. Among the many cell signals already identified, the VEGF and Notch signalling pathways play a critical role in controlling endothelial cells (ECs) during angiogenesis. Although this regulatory mechanism has become a current research focus in biology, its computational modelling is still rare. We focus on developing a computational model to simulate the VEGF and Notch signalling regulatory mechanism to perceive the micro procedure of angiogenesis in silico and fill the gap between biology and computer engineering. We first developed a mathematical model with nonlinear partial differential equations (PDEs) to describe the migration of endothelial tip cells during tumour-induced angiogenesis. The simulation results show that both chemotaxis and haptotaxis have impacts on the migration of ECs in velocity and density, and the impacts depend on the gradient and direction of tumour angiogenenic factor (TAF), and fibronectin, implying a possible malignant mechanism for some subgroups of tumour. We then developed the model further to simulate the regression, recurrence or clearance of tumours due to tumour cytotoxic factors, including the immune system and drugs delivered through the vessels formed during angiogenesis, providing a broader understanding of tumours. Based on the PDE model which provided parameters of continuum mathematical model, we finally developed an enzymatic catalysed regulating model in the form of ordinary differential equations (ODEs) with agent-based modelling (ABM) using Java and MATLAB languages, to visually realise the sprouting regulated by VEGF and Notch signalling during angiogenesis. The simulation describes the process of how an endothelial stalk cell becomes an endothelial tip cell, and sprouts under the influence of VEGF and Notch signalling, revealing the relationship between sprouting and branching. As the simulation results are consistent with reported in vitro and in vivo assays, the study bridges angiogenesis research and computer modelling from the dynamic regulatory mechanism perspective, offering a huge leap over previous studies in computationally simulating tumour-induced angiogenesis. It is hoped that the results will assist researchers in both the experimental and theoretical angiogenesis communities to improve understanding of the complexity and identify the fundamental principles of angiogenesis, whilst also using modelling approaches that will enrich knowledge for computational scientists in this field.
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Kayaga, Justina. "Allogenic tumour vaccines for melanoma." Thesis, St George's, University of London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394404.
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Mulligan, Helen D. "Mechanisms of tumour-induced cachexia." Thesis, Aston University, 1991. http://publications.aston.ac.uk/12595/.
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The effect of cancer cachexia on host metabolism has been studied in mice transplanted with either the MAC 16 adenocarcinoma which induces profound loss of host body weight and depletion of lipid stores or, the MAC13 adenocarcinoma which is of the same histological type, but which grows without an effect on host body weight. Oxidation of D-[U-14C]glucose was elevated in both tumour-bearing states irrespective of cachexia, when compared with non tumour-bearing controls. Both the MAC16 and MAC13 tumours in vivo utilised glucose at the expense of the brain, where its use was partially replaced by 3-hydroxybutyratc, a ketone body. Oxidation of both [U-l4C]palmitic acid and [l-14C]triolein was significantly increased in MAC16 tumour-bearing animals and decreased in MAC 13 tumour-bearing animals when compared with non tumour-bearing controls, suggesting that in cachectic tumour-bearing animals, mobilisation of body lipids is accompanied by an increased utilisation by the host. Weight loss in MAC16 tumour-bearing animals is associated with the production of a lipolytic factor. Injection of this partially purified lipolytic factor induced weight loss in recipient animals which could be maintained over time in tumour-bearing animals. This suggests that the tumour acts as a sink for the free fatty acids liberated as a result of the mobilisatation of adipose stores. Lipids are important as an energy source in cachectic animals because of their high calorific value and because glucose is being diverted away from host tissues to support tumour growth. Their importance is further demonstrated by the evidence of a MAC 16 tumour-associated lipolytic factor. This lipolytic factor is the key to understanding the alterations in host metabolism that occur in tumour-induced cachexia, and may provide future alternatives for the reversal of cachexia and the treatment of cancer itself.
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Chowdhury, S. "Retroviral targeting to tumour antigens." Thesis, University College London (University of London), 2004. http://discovery.ucl.ac.uk/1446889/.
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The development of efficient, cell surface targeted retroviral vectors is critical for successful gene therapy as gene delivery to non-target cells may be harmful and would deplete the pool of viral particles. To date, the only surface-targeting strategies that have allowed efficient infection by retroviral vectors in vivo are those that have limited the tropism of amphotropic murine leukaemia virus (MLV-A), which can infect cells of many mammals, by modification of the envelope glycoprotein. To this end we have explored tumour targeting of vectors based on MLV-A by modification of the retroviral surface protein (SU) backbone of the envelope chimera. The first approach used a receptor co-operation strategy to target human tumour cells by linking single chain antibodies (scFv) recognising tumour antigens (carcinoembryonic antigen (CEA) and high molecular weight melanoma-associated antigen (HMWMAA)) via proline-rich spacers to the amphotropic murine leukaemia virus surface protein. This approach showed selective targeting to both CEA and HMWMAA in vitro. The second approach used a protease targeting strategy to target tumour cells expressing CEA. We fused a single-chain variable fragment (scFv) directed against CEA to the amphotropic murine leukaemia virus envelope. A proline-rich hinge and matrix metalloprotease cleavage site linked the two proteins. Following attachment to CEA, MMP cleavage of the envelope at the cell surface removed the scFv and proline-rich hinge allowing infection. This approach showed selective targeting to carcinoembryonic antigen (CEA) both in vitro and in vivo with up to 10% infection of cells within a CEA-positive tumour xenograft. No infected cells were detected after delivery of targeted vectors to CEA-negative tumour xenografts. Intraperitoneal injection of amphotropic producer cells resulted in transduction in spleen, liver and kidney, which was not detected when targeted producer cells were used. These results demonstrate the feasibility of using targeted retroviral vectors for in vivo gene delivery and highlight the safety benefits of targeted vectors that do not infect other host tissues.