+publisher:"University of Manchester" +contributor:("Williams, Kaye")

University of Manchester

1. Blount, Kathryn. Cancer Systems Biology: Is the devil in the glycolytic detail?.

Degree: 2014, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:222501

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An approach to investigating cancer that has recently seen resurgence of interest is the “Warburg effect”. Otto Warburg originally described the altered metabolism of cancer… (more)

Subjects/Keywords: Glycolysis; Enzyme Kinetics; Metabolomics; Mathematical Modelling; Breast Cancer Cell lines

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APA (6^th Edition):

Blount, K. (2014). Cancer Systems Biology: Is the devil in the glycolytic detail?. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:222501

Chicago Manual of Style (16^th Edition):

Blount, Kathryn. “Cancer Systems Biology: Is the devil in the glycolytic detail?.” 2014. Doctoral Dissertation, University of Manchester. Accessed December 15, 2019. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:222501.

MLA Handbook (7^th Edition):

Blount, Kathryn. “Cancer Systems Biology: Is the devil in the glycolytic detail?.” 2014. Web. 15 Dec 2019.

Vancouver:

Blount K. Cancer Systems Biology: Is the devil in the glycolytic detail?. [Internet] [Doctoral dissertation]. University of Manchester; 2014. [cited 2019 Dec 15]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:222501.

Council of Science Editors:

Blount K. Cancer Systems Biology: Is the devil in the glycolytic detail?. [Doctoral Dissertation]. University of Manchester; 2014. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:222501

University of Manchester

2. Bryant, Jennifer. Neuroendocrine and epithelial markers of small cell lung cancer.

Degree: 2015, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:259793

► Small cell lung cancer (SCLC) is an extremely aggressive disease characterized by early metastasis and acquired resistance to therapy. SCLC is distinguished by its neuroendocrine… (more)

▼ Small cell lung cancer (SCLC) is an extremely aggressive disease characterized by early metastasis and acquired resistance to therapy. SCLC is distinguished by its neuroendocrine (NE) component; the role of which is not fully understood in metastasis and response to therapy. Patients respond exceptionally well to first round chemotherapy; however, relapse with therapy-resistant tumours is virtually inevitable. Hypoxic regions within tumours can contribute towards metastasis and therapy resistance, highlighting hypoxia-targeted therapy as a novel approach for improving treatment for SCLC patients. Tumours are highly phenotypically heterogeneous, raising debate over the roles played by each cell type. Analysis of NE and epithelial markers in SCLC cell lines highlighted this inter-tumour heterogeneity. Further heterogeneity is displayed in SCLC xenograft tumours that show areas of dual epithelial and NE marker expression as well as regions negative for both markers. Irradiating xenograft tumours enhanced heterogeneity of the NE marker, pro-opiomelanocortin (POMC), which is ectopically secreted by a subset of SCLC tumours. Examining changes in marker expression post-therapy could provide vital information regarding transitions that can serve to guide therapy. SCLC is a highly metastatic disease. The role of the NE phenotype in human SCLC is not fully understood, but is considered essential for metastasis in murine models. Sub-cutaneous, intravenous and intra-splenic injection were carried out and resulted in no metastasis, spontaneous tumour generation and peripheral liver tumour growth, respectively. POMC expression was present and extremely heterogeneous within the liver, suggesting that NE properties are maintained in metastases; however, further work is necessary to develop a more consistent metastatic model that can be used to assess responses to therapy in a more clinically relevant setting. SCLC tumours proliferate rapidly and outgrow their nutrient and oxygen supplies, resulting in hypoxic conditions. Here, carbonic anhydrase IX (CA IX) becomes up-regulated in order to maintain pH levels suitable for survival. The specific CA IX inhibitor, S4, induces hypoxia-specific cell death in vitro and impairs tumour growth in vivo. This response is further accentuated by combining S4 with single or repeated cisplatin doses. Combination treatment reduced gene expression of S-phase kinase-associated protein (Skp2), associated with cisplatin resistance. CA IX inhibition combined with cisplatin chemotherapy therefore presents a novel treatment for SCLC tumours that could reduce therapy resistance. In summary, heterogeneity is extremely important when choosing treatment options for SCLC and must be considered when basing treatment on single biopsies. NE and epithelial markers are present within sub-cutaneous and liver tumours; however, a reliable multi-organ metastatic model is necessary to fully appreciate the role of these markers in the spread of SCLC. Hypoxic regions within sub-cutaneous xenograft tumours upregulate CA IX.… Advisors/Committee Members: WILLIAMS, KAYE KJ, White, Anne, Williams, Kaye.

Subjects/Keywords: small cell lung cancer; Neuroendocrine; Heterogeneity; Metastasis; Xenograft; Hypoxia; Carbonic anhydrase IX

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APA (6^th Edition):

Bryant, J. (2015). Neuroendocrine and epithelial markers of small cell lung cancer. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:259793

Chicago Manual of Style (16^th Edition):

Bryant, Jennifer. “Neuroendocrine and epithelial markers of small cell lung cancer.” 2015. Doctoral Dissertation, University of Manchester. Accessed December 15, 2019. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:259793.

MLA Handbook (7^th Edition):

Bryant, Jennifer. “Neuroendocrine and epithelial markers of small cell lung cancer.” 2015. Web. 15 Dec 2019.

Vancouver:

Bryant J. Neuroendocrine and epithelial markers of small cell lung cancer. [Internet] [Doctoral dissertation]. University of Manchester; 2015. [cited 2019 Dec 15]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:259793.

Council of Science Editors:

Bryant J. Neuroendocrine and epithelial markers of small cell lung cancer. [Doctoral Dissertation]. University of Manchester; 2015. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:259793

University of Manchester

3. Morris, Olivia Ann. Development and Application of a Generic Platform for Radiolabelling Affinity Peptides & Proteins with PET Isotopes.

Degree: 2017, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309488

► Positron emission tomography (PET) is a quantitative and non-invasive investigative tool, which permits the identification of pivotal biomarkers and their role in disease onset, transformation… (more)

▼ Positron emission tomography (PET) is a quantitative and non-invasive investigative tool, which permits the identification of pivotal biomarkers and their role in disease onset, transformation and progression. Quantitative detection of these disease biomarkers has qualified PET as a pioneering approach to rapid diagnosis. The tool is a powerful approach to patient diagnosis and investigation of inter- and intra- patient disease heterogeneity thereby supporting patient stratification and forging a truly personalised medicine approach. The sensitivity of PET is complemented by use of highly selective radiopharmaceuticals; this has fuelled the popularity of radiolabelled affinity peptides and proteins (APPs). Inspired by the high selectivity and affinity of biological protein-protein interactions, APP-based radiotracers are an increasingly popular class of radiotracer. Monoclonal antibodies (mAbs) are an important category of APP-based radiotracer; their prevalence in the field is attributed to their high target selectivity and affinity characteristics, which, will likely, uphold their popularity in the field. Yet, advancements in protein engineering has transformed the landscape of APP-based radiotracers, indicated by a preference for small radiolabelled APPs which exhibit rapid pharmacokinetics whilst retaining high target specificity and affinity. Their fast pharmacokinetics is matched by the half-life of 18F which has been defined as an ideal PET radionuclide. 18F APP radiolabelling hasn’t yet met its full potential due to its inherent challenges; many approaches have been adopted, ranging from non-site specific radiolabelling with amine reactive prosthetic groups to site-specific methods including oxime bond formation. The radiochemistry of 18F APP radiolabelling is diverse and evolving; yet ideal goals are apparent including site-specificity, fast reaction kinetics, mild labelling conditions and applicability to automation. Automation is challenging for multi-step 18F APP radiolabelling methods, but is a key developmental step. Automation helps with conformance to good manufacturing practice (GMP) by enhancing process robustness, consistency and reliability. It also permits the radiosynthesis of clinically relevant radiotracer doses. The development of an automated generic platform, or a method that adopts a general approach, for APP radiolabelling with 18F would assist in [18F]APPs meeting their potential in PET and, importantly, aid their translation from bench-to-bedside. Advisors/Committee Members: WILLIAMS, KAYE KJ, Williams, Kaye, Mcmahon, Adam.

Subjects/Keywords: 18F prosthetic group; peptide radiolabelling; PET

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APA (6^th Edition):

Morris, O. A. (2017). Development and Application of a Generic Platform for Radiolabelling Affinity Peptides & Proteins with PET Isotopes. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309488

Chicago Manual of Style (16^th Edition):

Morris, Olivia Ann. “Development and Application of a Generic Platform for Radiolabelling Affinity Peptides & Proteins with PET Isotopes.” 2017. Doctoral Dissertation, University of Manchester. Accessed December 15, 2019. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309488.

MLA Handbook (7^th Edition):

Morris, Olivia Ann. “Development and Application of a Generic Platform for Radiolabelling Affinity Peptides & Proteins with PET Isotopes.” 2017. Web. 15 Dec 2019.

Vancouver:

Morris OA. Development and Application of a Generic Platform for Radiolabelling Affinity Peptides & Proteins with PET Isotopes. [Internet] [Doctoral dissertation]. University of Manchester; 2017. [cited 2019 Dec 15]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309488.

Council of Science Editors:

Morris OA. Development and Application of a Generic Platform for Radiolabelling Affinity Peptides & Proteins with PET Isotopes. [Doctoral Dissertation]. University of Manchester; 2017. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:309488

4. Rowling, Emily. Pre-clinical evaluation of novel anti-metastatic targets.

Degree: 2014, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:240986

► Background: Radiotherapy is used in the treatment of over 50% of cancer patients and bar surgery, is the most effective cancer intervention. However, in the… (more)

▼ Background: Radiotherapy is used in the treatment of over 50% of cancer patients and bar surgery, is the most effective cancer intervention. However, in the clinic secondary malignancies have been observed following radiotherapy and in vitro increased cell migration and invasion have been seen following radiation. The Src/FAK signalling pathway is known to play an important role in the metastatic phenotype through its involvement in cell adhesion, migration and invasion and we have previously demonstrated that radiotherapy can activate this pathway along with the phosphoinositide 3-kinase (PI3K) pathway, also associated with tumour metastases and an aggressive phenotype. Using pharmacological inhibitors, we have investigated combination approaches to evaluate whether Src and PI3K targeting is beneficial in a radiotherapy context, especially focusing on metastatic phenotype. We wished to relate pathway activation to cellular phenotype and increase understanding of the metastatic cascade, the processes involved and the signalling pathways taking the lead.Method: Using thyroid carcinoma cell lines FTC133 and 8505c the effects of Src inhibition using AZD0530, FAK inhibition using FAKi and PI3K inhibition using GDC-0941 were studied. The effects of radiotherapy alone, and in combination with the above inhibitors, were also studied. In vitro MTT, apoptosis and clonogenic assays were used to assess cell proliferation and cell survival and scratch assays, cell adhesion and cell spreading assays were used to assess the effects of the drugs on metastatic characteristics. In vivo tumour growth, survival and ex vivo clonogenics were used to measure the effects of AZD0530 and GDC-0941. Western blotting, immunofluorescence and immunohistochemistry was used to observe the effects on pathway activation and protein localisation.Results: Src and FAK inhibition reduced metastatic characteristics of thyroid carcinoma cell lines in vitro such as cell spreading and migration. FAK inhibition showed a greater effect on cell survival by MTT, clonogenic and apoptosis. In the thyroid carcinoma cell lines radiotherapy enhanced the metastatic phenotype. This was seen by enhanced activation of the Src and PI3K pathways, increased migration and invasion in vitro and enhanced tumour metastasis in vivo. By combining Src inhibition with radiation a reduction in metastatic characteristics was observed and by combining PI3K inhibition with radiotherapy radiosensitivity could be improved. With the triple combination of Src and PI3K inhibition with radiotherapy a significant reduction in cell survival was demonstrated in vitro compared to radiation alone and either inhibitor combined with radiation, with a corresponding significant reduction in tumour growth being observed in vivo. With the combination of Src and PI3K inhibition significant reductions in metastatic characteristics were also observed both in vitro and in vivo seen by a reduction in cell migration and tumour metastasis. Finally combined inhibition of the Src and PI3K pathway reduced the… Advisors/Committee Members: Williams, Kaye.

Subjects/Keywords: Src; metastasis; Radiotherapy; PI3K; Thyroid

…related rights in it (the “Copyright”) and she has given The University of Manchester…

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APA (6^th Edition):

Rowling, E. (2014). Pre-clinical evaluation of novel anti-metastatic targets. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:240986

Chicago Manual of Style (16^th Edition):

Rowling, Emily. “Pre-clinical evaluation of novel anti-metastatic targets.” 2014. Doctoral Dissertation, University of Manchester. Accessed December 15, 2019. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:240986.

MLA Handbook (7^th Edition):

Rowling, Emily. “Pre-clinical evaluation of novel anti-metastatic targets.” 2014. Web. 15 Dec 2019.

Vancouver:

Rowling E. Pre-clinical evaluation of novel anti-metastatic targets. [Internet] [Doctoral dissertation]. University of Manchester; 2014. [cited 2019 Dec 15]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:240986.

Council of Science Editors:

Rowling E. Pre-clinical evaluation of novel anti-metastatic targets. [Doctoral Dissertation]. University of Manchester; 2014. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:240986

5. Kinnersley, Janet. Evaluation of novel anti-metastatic therapy.

Degree: 2011, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:141162

► The occurrence of metastasis from the primary tumour to distant organs is the primary cause of cancer mortality and therefore a highly attractive therapeutic target… (more)

▼ The occurrence of metastasis from the primary tumour to distant organs is the primary cause of cancer mortality and therefore a highly attractive therapeutic target to improve cancer survival rates. Targeted anti-metastatic therapies hold the potential for lower cancer mortality rates, lower rates of reoccurrence and better quality of life for cancer patients. Src is a non receptor tyrosine kinase, and the first recognized oncogene, which is known to play a role in metastasis. Increased activity of SFKs has been found in many human tumours, correlating with invasiveness and poor prognosis, and in experimental tumour cell lines, contributing to enhanced cell migration and invasion, adhesion independent growth, survival and proliferation. Despite a body of evidence in pre-clinical trials demonstrating that inhibition of Src reduces the occurrence of cellular events associated with metastasis in vitro, and reduces tumour metastasis to distant organs in in vivo models, efficacy has not translated to phase II clinical trials. One such recent failure has been a phase II trial with the Src inhibitor AZD0530 in recurrent advanced or metastatic soft tissue sarcoma. Here we investigate the anti-metastatic effects of Src inhibition in the HT1080 fibrosarcoma cell in vitro in order to elucidate further the effects of SFK inhibition in sarcoma cells laying the ground work for future in vivo work investigating potential compensatory mechanism overcoming SFK inhibition in sarcoma cells. We found that SFK inhibition of HT1080 cells with AZD0530 inhibited cell migration and spreading but had no effect on cell polarization. AZD0530 treatment caused active paxillin (Tyr31-p) to relocalize from focal adhesions to the cytoplasm but had no effect on staining of active FAK (Tyr861-p). Paradoxically AZD0530 treatment led to increased phosphorylation of Src at the negative regulatory site Tyr 530. Results seen here provide evidence to warrant further elucidation of the effects of Src inhibition in HT1080 cells in order to elucidate potential combination therapies and biomarkers of tumour sensitivity to Src inhibition. Advisors/Committee Members: Williams, Kaye.

…University of Manchester). 2.3 Treatments The src inhibitor, AZD0530 was supplied by Astra…

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APA (6^th Edition):

Kinnersley, J. (2011). Evaluation of novel anti-metastatic therapy. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:141162

Chicago Manual of Style (16^th Edition):

Kinnersley, Janet. “Evaluation of novel anti-metastatic therapy.” 2011. Doctoral Dissertation, University of Manchester. Accessed December 15, 2019. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:141162.

MLA Handbook (7^th Edition):

Kinnersley, Janet. “Evaluation of novel anti-metastatic therapy.” 2011. Web. 15 Dec 2019.

Vancouver:

Kinnersley J. Evaluation of novel anti-metastatic therapy. [Internet] [Doctoral dissertation]. University of Manchester; 2011. [cited 2019 Dec 15]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:141162.

Council of Science Editors:

Kinnersley J. Evaluation of novel anti-metastatic therapy. [Doctoral Dissertation]. University of Manchester; 2011. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:141162

University of Manchester

6. Henderson, Fiona Rae. Mass Spectrometry Imaging of Lipid Profiles in Disease.

Degree: 2017, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:308361

► It is well established that lipids play an important role in diseases such as non-alcoholic fatty liver disease and cardiovascular diseases. However, in the past… (more)

▼ It is well established that lipids play an important role in diseases such as non-alcoholic fatty liver disease and cardiovascular diseases. However, in the past decade, it has come to light that lipids may be important in other diseases; particularly in cancer and neurological disorders. Here, lipid metabolism has been investigated using pre-clinical cancer models for melanoma, glioma, non-small-cell lung cancer and colorectal cancer. The role of lipids in the recovery post-stroke has also been studied. Mass spectrometry imaging offers an ideal tool to study lipids in tissue ex-vivo. Lipids ionise well in a number of mass spectrometry modalities, and hundreds of lipids can be imaged in one mass spectrometry imaging experiment. Furthermore, mass spectrometry imaging offers excellent spatial resolution. In this work, both MALDI-MS and DESI-MS have been used for mass spectrometry imaging.Tumour lipid heterogeneity has been a particular focus of this this project. Heterogeneity exists within tumours, as well as between tumours in the same patient; and this causes major problems for therapy. Owing to the untargeted nature, and high spatial resolution of mass spectrometry imaging, it is an excellent technique to study lipid heterogeneity. Adjacent sections (or in some cases the same section used for mass spectrometry imaging), were used for immunofluorescence and H&E staining. By comparing mass spectrometry images with staining techniques, biological reasons for lipid heterogeneity can be established. Here, a particular focus has been on hypoxia (low oxygen tensions), which is a key contributor to tumour heterogeneity, and is associated with aggressive cancers. Additionally, hypoxia is a feature of ischaemic stroke, and lipids in ischaemic stroke have also been investigated. PET is a non-invasive imaging technique which is able to image a radiolabelled molecule (tracer) in the body. Here, PET has been used as a complementary in-vivo technique to mass spectrometry imaging. The tracers [11C] acetate and [18F]-FTHA have been used to image fatty acid synthase and fatty acid uptake in tumours; both of which are hypothesised to be key in cancer progression. REIMS is a newly established mass spectrometry technique. It is ideal for analysing lipids in cells, as sample preparation is minimal. Here, approaches for cell pellet analysis have been tested, and used to detect lipids in cancer cell lines. Advisors/Committee Members: MCMAHON, ADAM AW, Williams, Kaye, Mcmahon, Adam.

Subjects/Keywords: Mass spectrometry imaging; Lipids; Cancer

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APA (6^th Edition):

Henderson, F. R. (2017). Mass Spectrometry Imaging of Lipid Profiles in Disease. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:308361

Chicago Manual of Style (16^th Edition):

Henderson, Fiona Rae. “Mass Spectrometry Imaging of Lipid Profiles in Disease.” 2017. Doctoral Dissertation, University of Manchester. Accessed December 15, 2019. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:308361.

MLA Handbook (7^th Edition):

Henderson, Fiona Rae. “Mass Spectrometry Imaging of Lipid Profiles in Disease.” 2017. Web. 15 Dec 2019.

Vancouver:

Henderson FR. Mass Spectrometry Imaging of Lipid Profiles in Disease. [Internet] [Doctoral dissertation]. University of Manchester; 2017. [cited 2019 Dec 15]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:308361.

Council of Science Editors:

Henderson FR. Mass Spectrometry Imaging of Lipid Profiles in Disease. [Doctoral Dissertation]. University of Manchester; 2017. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:308361

7. Leung, Travis. The regulation of CYP2E1 gene expression and its role in breast cancer.

Degree: 2013, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:188013

► Cytochromes(CYP) P450 are class of heme-containing enzymes involved in Phase I metabolism of a large number of xenobiotics. The CYP family member CYP2E1 is involved… (more)

▼ Cytochromes(CYP) P450 are class of heme-containing enzymes involved in Phase I metabolism of a large number of xenobiotics. The CYP family member CYP2E1 is involved in the metabolism of many xenobiotics and procarcinogens including ethanol, acetone, nitrosamine, pyridine, isoniazid and carbon tetrachloride (CCl4), which are also CYP2E1-inducing agents. CYP2E1 comprises approximately 7% of the liver CYP content and it is also expressed in kidney, lung, brain, gastrointestinal tract and breast tissue implying that this enzyme is implicated in other biological processes aside from its role in Phase I metabolism. Several studies converge to the conclusion that CYP2E1 is induced under many pathological conditions including cancer, obesity, and type 2 diabetes. Increased hepatic ketogenesis and insulin resistance are the possible mechanisms mediating CYP2E1 induction in these conditions. Elevated CYP2E1 expression has been reported in the presence of proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). CYP2E1 generates the highest level of reactive oxygen species (ROS) among the CYP450 superfamily and transient overexpression of this CYP family member in COS cells increases the production of mitochondrial ROS, even in the absence of substrate. Oxidative stress induced by CYP2E1 disturbs the folding capacity of the endoplasmic reticulum (ER), with concomitant alterations in the mRNA and protein expression of the ER stress proteins GRP78 and GRP94. Initially the unfolded protein response (UPR) restores ER homeostasis, and cell viability, but at later stages the accumulation of unfolded proteins stimulates pro-apoptotic signals. Cell death induced by ER stress has been reported in several conditions including hypoxia, and diseases such as diabetes and heart disease. To gain better understanding of the factors regulating CYP2E1 gene expression in breast cancer cells we studied CYP2E1 mRNA and protein levels in MCF7 (p53wt) and MDA-MB-231 (p53 mutated) breast cancer cells and identified that CYP2E1 was under p53 and HIF-1α transcriptional control in both of these cell lines treated with etoposide or desferrioxamine respectively. In addition, CYP2E1 was differentially expressed in the low metastatic potential MCF7 cell line compared to highly metastatic MDA-MB-231 cells in accord with clinical studies indicating that CYP2E1 isoenzyme is expressed in lower levels in patients at clinical stages II, III, and IV which exhibit higher metastatic potential than in patients at stage I of breast cancer. To further investigate the functional significance of the difference in CYP2E1 levels the generation of ROS in breast cancer cells ectopically overexpressing CYP2E1 or in cells in which CYP2E1 expression had been silenced was assessed. Our results indicated that CYP2E1 overexpression resulted in higher ROS generation, which coincided with increased autophagy biomarker expression, increased endoplasmic reticulum stress, detected by XBP1 mRNA splicing in fluorescent reporter assays, and inhibition… Advisors/Committee Members: WILLIAMS, KAYE KJ, Williams, Kaye, Demonacos, Constantinos.

…any copyright in it (the “Copyright”) and s/he has given The University of… …Manchester the right to use such Copyright for any administrative, promotional, educational and/or…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Leung, T. (2013). The regulation of CYP2E1 gene expression and its role in breast cancer. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:188013

Chicago Manual of Style (16^th Edition):

Leung, Travis. “The regulation of CYP2E1 gene expression and its role in breast cancer.” 2013. Doctoral Dissertation, University of Manchester. Accessed December 15, 2019. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:188013.

MLA Handbook (7^th Edition):

Leung, Travis. “The regulation of CYP2E1 gene expression and its role in breast cancer.” 2013. Web. 15 Dec 2019.

Vancouver:

Leung T. The regulation of CYP2E1 gene expression and its role in breast cancer. [Internet] [Doctoral dissertation]. University of Manchester; 2013. [cited 2019 Dec 15]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:188013.

Council of Science Editors:

Leung T. The regulation of CYP2E1 gene expression and its role in breast cancer. [Doctoral Dissertation]. University of Manchester; 2013. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:188013

8. Telfer, Brian. Application of the dorsal window chamber to tumour vasculature manipulation studies.

Degree: 2012, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:156044

► Developing and applying pre-clinical tumour models in order to determine the mechanistic action of applied therapies is essential if we aim to improve antitumour strategies… (more)

▼ Developing and applying pre-clinical tumour models in order to determine the mechanistic action of applied therapies is essential if we aim to improve antitumour strategies in the clinical setting. The chaotic nature of tumour vasculature impacts directly on the effectiveness of combined chemo-radiotherapy and antiangiogenic (AA) strategies and as such warrants closer study. This work looked at the effects of novel AAs combined with clinically relevant radiotherapy (RT) using both conventional murine xenograft growth delay studies and real-time imaging. The imaging methodology was the non-invasive Dorsal Window Chamber/Intra Vital Microscopy (DWC/IVM) model which allows the study of real-time vascular responses to these therapies. The DWC/IVM model was applied to determine whether the DNA repair inhibitors Nicotinamide, AG14361 and AGO14699 had additional modes of action which could contribute to tumour radioresistance/radiosensitivity. Using the DWC/IVM model a secondary quantifiable mechanistic function was determined where these drugs also increased tumour vessel permeability. The DWC/IVM model was also used to investigate the effects of AZD2171 and AZD6244 combined with radiotherapy. These agents can inhibit angiogenic signalling pathways and it was demonstrated that both drugs worked by reducing tumour microvascular density when used in combination with radiation. In studies looking at the influence of hypoxia inducible factor-1(HIF-1) on tumour response to radiation the DWC/IVM model provided measurable differences in the microvascular density between HIF-1 deficient and HIF-1 competent tumours. The DWC/IVM model allowed the direct visualisation and quantification of the less well developed vasculature in HIF-1 deficient tumours compared to that found in HIF-1 competent tumours. The results provide a mechanistic basis for understanding the improved response to radiotherapy of HIF-1 deficient tumours.By applying the DWC/IVM model to conventional murine xenograft models the DWC/IVM proved itself as a useful research tool where continuous real-time non-invasive measurements could be made without the need for large numbers of time points or laborious histological analysis. Advisors/Committee Members: WILLIAMS, KAYE KJ, Stratford, Ian, Williams, Kaye.

Subjects/Keywords: Tumour vascular dorsal window radiation model

…rights in it (the ―Copyright‖) and s/he has given The University of Manchester… …his work at the University of Manchester in the Department of Anatomy and trained as a…

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APA (6^th Edition):

Telfer, B. (2012). Application of the dorsal window chamber to tumour vasculature manipulation studies. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:156044

Chicago Manual of Style (16^th Edition):

Telfer, Brian. “Application of the dorsal window chamber to tumour vasculature manipulation studies.” 2012. Doctoral Dissertation, University of Manchester. Accessed December 15, 2019. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:156044.

MLA Handbook (7^th Edition):

Telfer, Brian. “Application of the dorsal window chamber to tumour vasculature manipulation studies.” 2012. Web. 15 Dec 2019.

Vancouver:

Telfer B. Application of the dorsal window chamber to tumour vasculature manipulation studies. [Internet] [Doctoral dissertation]. University of Manchester; 2012. [cited 2019 Dec 15]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:156044.

Council of Science Editors:

Telfer B. Application of the dorsal window chamber to tumour vasculature manipulation studies. [Doctoral Dissertation]. University of Manchester; 2012. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:156044

9. Burke, Daniel. Development of Robust Multimodal Imaging Biomarkers of the Non-viable Tumour Component for Cancer Drug Development.

Degree: 2013, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:204162

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This project was initiated with the objective of obtaining a magnetic resonance imaging (MRI) derived measure of the non-viable cell fraction of a tumour. The… (more)

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This project was initiated with the objective of obtaining a magnetic resonance imaging (MRI) derived measure of the non-viable cell fraction of a tumour. The word “biomarker” pervades much of the quantitative imaging literature. There exist a variety of imaging parameters which purport to convey information about the underlying pathophysiology. These are generically labelled as “biomarkers”, although a review of the literature indicates that there is little, (or often contradictory) evidence to support this assertion. Indeed, the absence of robust validation is in evidence across the broad spectrum of imaging modalities. As the development of novel chemotherapeutic agents progresses from in vitro studies performed in a Petri dish to in vivo animal experiments, treatment efficacy can be gauged by a number of methods, one of which is imaging. Translational imaging offers the opportunity of developing and validating imaging techniques in the preclinical setting, with potential for their adoption into a clinical trial. The Apparent Diffusion Coefficient (ADC) of water proton spins has emerged as a potential “biomarker” of cell death. Two studies were performed to investigate the relationship between ADC and the pathophysiologic changes occurring subsequent to radiotherapy or chemotherapy in preclinical cancer models. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is purported to offer a means of quantifying the non-viable cell fraction through the pharmacokinetic parameter “ve”, the extravascular extracellular space volume per unit volume of tissue. Performing a DCE-MRI experiment requires measurements of T1 before and after the administration of a contrast agent. To this end, methods development undertaken included extensive validation experiments to determine the accuracy and reproducibility of the T1 relaxation time for use in a DCE-MRI study. Validation of ADC measurements was performed through the use of a novel ice water phantom designed for a narrow bore preclinical MRI scanner. A means of determining the quantity of contrast agent within a tumour can be performed through the use of ICP-MS (Inductively Coupled Plasma Mass Spectrometry). A validation experiment was performed through the preparation of a phantom of known quantity of contrast agent and comparison against that returned from ICP-MS analysis. This thesis contends that the development of an MRI derived measure of the non-viable cell fraction does not appear viable within the framework of the present pharmacokinetic models and imaging hardware available. The literature fails to address significant confounds in the scientific method, indeed this is in evidence in the variability of observed imaging parameters.

This project was initiated with the objective of obtaining a magnetic resonance imaging (MRI) derived measure of the non-viable cell fraction of a tumour. The word “biomarker” pervades much of the quantitative imaging literature. There exist a variety of imaging parameters which purport to convey information about the underlying…

Advisors/Committee Members: WILLIAMS, KAYE KJ, O'CONNOR, JAMES JP, Williams, Kaye, O'Connor, James, Waterton, John.

Subjects/Keywords: Magnetic resonance imaging; Apparent diffusion coefficient; Longitudinal relaxation time

…observed imaging parameters. Institution : The University of Manchester Candidate : Daniel Peter… …x28;the “Copyright”) and s/he has given the University of Manchester certain rights to…

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APA (6^th Edition):

Burke, D. (2013). Development of Robust Multimodal Imaging Biomarkers of the Non-viable Tumour Component for Cancer Drug Development. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:204162

Chicago Manual of Style (16^th Edition):

Burke, Daniel. “Development of Robust Multimodal Imaging Biomarkers of the Non-viable Tumour Component for Cancer Drug Development.” 2013. Doctoral Dissertation, University of Manchester. Accessed December 15, 2019. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:204162.

MLA Handbook (7^th Edition):

Burke, Daniel. “Development of Robust Multimodal Imaging Biomarkers of the Non-viable Tumour Component for Cancer Drug Development.” 2013. Web. 15 Dec 2019.

Vancouver:

Burke D. Development of Robust Multimodal Imaging Biomarkers of the Non-viable Tumour Component for Cancer Drug Development. [Internet] [Doctoral dissertation]. University of Manchester; 2013. [cited 2019 Dec 15]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:204162.

Council of Science Editors:

Burke D. Development of Robust Multimodal Imaging Biomarkers of the Non-viable Tumour Component for Cancer Drug Development. [Doctoral Dissertation]. University of Manchester; 2013. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:204162

10. Kotze, Helen. Systems Biology of Chemotherapy in Hypoxia Environments.

Degree: 2012, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:182472

► Introduction: Hypoxia is found in solid cancerous tumours. The presence of hypoxia within tumours inhibits anti-cancer treatment strategies such as chemotherapy from being completely effective… (more)

▼ Introduction: Hypoxia is found in solid cancerous tumours. The presence of hypoxia within tumours inhibits anti-cancer treatment strategies such as chemotherapy from being completely effective and it is suspected that multiple mechanisms contribute to the resistance. Methods: In this project a systems biology approach was applied to determine how the toxicity of doxorubicin is affected by hypoxia at the metabolome level. A multitude of analytical techniques were applied to analyse the intracellular metabolism of a monolayer of cancer cells (MDA-MB-231). Metabolic profiling was used to determine metabolite markers related to hypoxia-induced chemoresistance. For this gas chromatography mass spectrometry (GC-MS) and ultra high performance liquid chromatography mass spectrometry (UHPLC-MS) were used. Furthermore, network-based correlation analysis was developed as a novel tool to bridge the gap between metabolomics dataset and systems biology modelling. This methodology was applied to elucidate novel metabolic pathways as potential therapeutic targets to overcome hypoxia-induced chemoresistance. This algorithm determines significant correlation differences between different physiological states, and through applying graph-theory on large genome scale models; it is possible to construct a metabolic network of the pathways connecting the pair-wise correlation. Finally, imaging mass spectrometry using time-of-flight secondary ion mass spectrometry (ToF-SIMS) was developed as a tool for in situ metabolite analysis to investigate the metabolic response to chemotherapy in multi-tumour spheroids (MTSs). Results: Metabolic fingerprinting analysis characterised a snapshot of cells exposed to various environmental perturbations. Metabolite markers associated with hypoxia-induced chemoresistance were related to metabolic pathways including gluconeogenesis, DNA synthesis and fatty acid synthesis. Furthermore, network-based correlation analysis revealed specific metabolites in the fatty acid synthesis pathways were contributing to drug resistance, which included malonyl-CoA, 3-oxoeicosanoyl-CoA, stearoyl-CoA and octadecanoic acid. To facilitate the detection of metabolites in ToF SIMS datasets, a series of metabolites standard spectra were acquired. Hypoxic metabolite markers detected in ToF-SIMS data of cell lysates included glycine, lactic acid and succinic acid, which were also shown to be metabolite markers in GC-MS metabolic data. Furthermore, MTS sections were imaged using ToF-SIMS to profile the chemical response to chemotherapy treatment within the oxygen gradient. Loadings from image PCA were explored to determine the metabolic response in the highly oxygenated outer region and hypoxic inner region of the MTS. Conclusion: A multitude of analytical techniques were able to contribute to elucidating the metabolic mechanisms associated with hypoxia-induced chemoresistance. Metabolic profiling combined with a systems biology approach was further able to identify potential underlying metabolic regulation of resistance. Finally… Advisors/Committee Members: GOODACRE, ROY R, WILLIAMS, KAYE KJ, MCMAHON, ADAM AW, Lockyer, Nicholas, Goodacre, Roy, Williams, Kaye, Mcmahon, Adam, Westerhoff, Hans.

Subjects/Keywords: Metabolomics; Hypoxia; ToF-SIMS; Chemotherapy; Systems biology

…81 14 The University of Manchester Faculty of Engineering and Physical Sciences ABSTRACT… …x29; and s/he has given The University of Manchester certain rights to use such Copyright…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kotze, H. (2012). Systems Biology of Chemotherapy in Hypoxia Environments. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:182472

Chicago Manual of Style (16^th Edition):

Kotze, Helen. “Systems Biology of Chemotherapy in Hypoxia Environments.” 2012. Doctoral Dissertation, University of Manchester. Accessed December 15, 2019. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:182472.

MLA Handbook (7^th Edition):

Kotze, Helen. “Systems Biology of Chemotherapy in Hypoxia Environments.” 2012. Web. 15 Dec 2019.

Vancouver:

Kotze H. Systems Biology of Chemotherapy in Hypoxia Environments. [Internet] [Doctoral dissertation]. University of Manchester; 2012. [cited 2019 Dec 15]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:182472.

Council of Science Editors:

Kotze H. Systems Biology of Chemotherapy in Hypoxia Environments. [Doctoral Dissertation]. University of Manchester; 2012. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:182472

11. Armitage, Emily Grace. Systems Biology of HIF Metabolism in Cancer.

Degree: 2012, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:177044

► AbstractThe University of ManchesterFaculty of Engineering and Physical SciencesAbstract of thesis entitled ‘Systems Biology of HIF Metabolism in Cancer’Submitted by Emily Grace Armitage for the… (more)

▼ AbstractThe University of ManchesterFaculty of Engineering and Physical SciencesAbstract of thesis entitled ‘Systems Biology of HIF Metabolism in Cancer’Submitted by Emily Grace Armitage for the degree of Doctor of Philosophy, September 2012Cancer is one of the most devastating human diseases that cause a vast number of mortalities worldwide each year. Cancer research is one of the largest fields in the life sciences and despite many astounding breakthroughs and contributions over the past few decades, there is still a considerable amount to unveil on the function of cancer that would improve diagnostics, prognostics and therapy. Since cancer is known to involve a wide range of processes, applying methods to study it from a systems perspective could reveal new properties of cancer. Systems biology is becoming an increasingly popular tool in the life sciences. The approach has been applied to many biological and biomedical analyses drawing upon recent advancements in technology that make high throughput analyses of samples and computational modelling possible. In this thesis, the effect of hypoxia inducible factor-1 (HIF-1) on cancer metabolism, the entity considered most closely related to phenotype has been investigated. This transcription factor is known to regulate a multitude of genes and proteins to promote survival in a low oxygen environment that is prevalent in solid tumours. However its effect on the metabolome is less well characterised. By revealing the effect of HIF-1 on the metabolome as a system it is hoped that phenotypic signatures, key metabolic pathways indicative of cancer function and potential targets for future cancer therapy, can be revealed.The system has been studied using two cell models: mouse hepatocellular carcinoma and human colon carcinoma, whereby metabolism has been profiled using a range of analytical platforms. In each model, wild type cells have been compared to cells deficient in HIF-1 to reveal its effect on cellular metabolism. Gas chromatography mass spectrometry (GC MS) and ultra high performance liquid chromatography - mass spectrometry (UHPLC MS) have been employed for metabolic profiling of cells exposed to a range of oxygen conditions. Additionally, time-of-flight secondary ion mass spectrometry (ToF SIMS) has been employed for imaging mass spectrometric analysis of multicellular tumour spheroids cultured from wild type cells and cells with dysfunctional HIF-1 to represent small initiating tumours. Using these techniques in metabolic profiling it has been possible to reveal metabolites associated with the effect of oxygen and HIF-1 on cancer metabolism along with key pathways and hubs that could be targeted in future therapy. Using imaging mass spectrometry it has been possible to localise metabolites in situ revealing how tumour structure relates to function. Finally, a novel approach to consider how metabolites are correlated with one another in the response to oxygen level or presence or absence of functional HIF-1 has been undertaken to better understand the systems… Advisors/Committee Members: LOCKYER, NICHOLAS NP, GOODACRE, ROY R, MCMAHON, ADAM AW, WESTERHOFF, HANS HV, Lockyer, Nicholas, Goodacre, Roy, Williams, Kaye, Mcmahon, Adam, Westerhoff, Hans.

Subjects/Keywords: Cancer; Systems Biology; Metabolomics; Mass Spectrometry

…130 11 Abstract The University of Manchester Faculty of Engineering and Physical Sciences… …given The University of Manchester certain rights to use such Copyright, including for… …Acknowledgements I would firstly like to thank my supervisors at The University of Manchester. They… …Biology Doctoral Training Centre student here at the University of Manchester. Together Helen… …Doctoral Training Centre for Integrative Systems Biology in The University of Manchester in the…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Armitage, E. G. (2012). Systems Biology of HIF Metabolism in Cancer. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:177044

Chicago Manual of Style (16^th Edition):

Armitage, Emily Grace. “Systems Biology of HIF Metabolism in Cancer.” 2012. Doctoral Dissertation, University of Manchester. Accessed December 15, 2019. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:177044.

MLA Handbook (7^th Edition):

Armitage, Emily Grace. “Systems Biology of HIF Metabolism in Cancer.” 2012. Web. 15 Dec 2019.

Vancouver:

Armitage EG. Systems Biology of HIF Metabolism in Cancer. [Internet] [Doctoral dissertation]. University of Manchester; 2012. [cited 2019 Dec 15]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:177044.

Council of Science Editors:

Armitage EG. Systems Biology of HIF Metabolism in Cancer. [Doctoral Dissertation]. University of Manchester; 2012. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:177044

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