FUNDED PROJECTS CANCER
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Details of Funded Projects The following projects represent the core of the research sponsored by Cancer Research Wales To see further details of those projects click on the title. Immune Responses to SV40 Large T Antigen in Malignant Pleural Mesothelioma Patients Identifying Tumour Antigens on Malignant Pleural Mesothelioma Cells Shielding Design in Radiotherapy using Monte Carlo Techniques Network support for cancer patient management Evidence Based minimum datasets for the pathology of urological cancers Adhesion and signalling of B-cell exosomes CD44 isoforms and their role in prostate cancer Immune Responses to SV40 Large T Antigen in Malignant Pleural Mesothelioma Patients Coleman, S., Churchill, L., Butchart, E., Gibbs, A., Mason, D.M., Jasani, B., Tabi, Z.
Malignant pleural mesothelioma (MPM) is an aggressive tumour, resistant to chemo- and radiotherapy and usually not suitable for surgical resection. There is however evidence of immune responses against MPM, the most encouraging ones were demonstrated in rare cases of spontaneous regression. The antigens on mesothelioma cells which can be the targets of this immune response are not well characterised. The purpose of our study is to determine whether immune responses against a virus (SV40) which is often found in this type of tumour, can be found in MPM patients and can eliminate the tumour cells which carry the virus. So far we received blood and tumour samples from 35 MPM patients undergoing tumour reducing surgery at the Cardiothoracic Surgery Unit at the Heath Hospital. Immune responses specific for SV40 were detected in a higher proportion of MPM patients than in healthy volunteers. We have mapped the exact part of the viral antigen, against which the immune response was directed, in one of the patients. These mapping experiments are crucial for the design of a vaccine against the virus and will be continued next year. Ongoing experiments (Ross, K.) are analysing the presence of viral DNA in the tumour samples and will provide crucial information for drawing conclusions from our data. Monitoring CD8+ T Cell Responses to Recall Antigens in Cancer Patients; A Useful Tool for Determining Immunocompetence Tabi, Z., Coleman, S., Adams, M., Clayton, A., Churchill, L., Jasani, B., Mason, DM. As part of our ongoing investigation of immune responses in MPM patients, there was a need to develop a reliable positive control to be included in the SV40 experiments. We established a method for the detection of general immune responsiveness by using peptide antigens of common viruses most people encountered (flu, cytomegalovirus, Epstein-Barr virus) and thus have immunological memory against these viral antigens (hence: recall responses). The method is specifically designed for clinical settings where some special factors, such as low cell numbers, lack of access to repeated samples and the need to freeze the samples before using them, had to be considered. This new immune-monitoring method proved to be efficient, sensitive and highly reproducible. It is now used as a general positive control in our immunological experiments and can be further developed by using different antigenic peptides, suitable for the detection of tumour-specific immune responses. The clinical relevance of the results has been demonstrated in ovarian cancer patients, attending Velindre Hospital, revealing varying levels of immunocompetence. The immune responsiveness strongly depended on the tumour load: patients with small tumour load (low Ca125 level) had strong recall immune responses, while patients with progressing tumours showed no recall responses. This observation is leading us onto another new project; namely, the study of the immunosuppressive effects of tumour cells. Identifying Tumour Antigens on Malignant Pleural Mesothelioma Cells Navabi, H., Reece, A., Coleman, S., Churchill, L., Jasani, B., Mason, D.M., Tabi Z. A possible strategy to control tumour progression in mesothelioma patients is combining traditional treatments with immunotherapy (see our first abstract). The development of successful immunotherapeutic strategies requires the identification and characterization of immunogenic tumour antigens that will be recognised by the host immune system and lead to tumour rejection. The presence of known tumour associated antigens : Ca125, MUC-1, p53, L-Meso, HER-2 and a viral antigen (SV40 large T antigen) associated with mesothelioma, were tested on established mesothelioma cell lines from 10 MPM patients. 1/10 expressed Ca125 and L-Meso, 5/10 MUC-1, 3/10 HER-2, 7/10 p53 and 4/10 SV40Tag, though the level of expression in the cell lines varied greatly. These investigations are ongoing with a larger cohort of patients and antigens to identify mesothelioma-associated tumour antigens which may be suitable for immunological targeting.
Aberrant Tumour Suppressor Gene Expression and the Genetic Predisposition to Radiation Induced Malignant Disease Dr S M Bowen, Mrs M Savoury School of Applied Sciences, University of Wales Institute, Cardiff. Prof I Bowen School of Medical Biosciences, Cardiff University, Cardiff. Each person has two copies of the Ataxia Telangiectasia gene. When both copies of the gene are altered, the risk of cancer is estimated to be 61-184 times higher than normal. People with one abnormal copy of the gene (carriers) make up 1% of the general population. Their risk of developing cancer of any type is estimated to be 2 - 6 times higher than for non-carriers. Carriers are particularly predisposed to breast cancer, and may account for 9-18% of all breast cancer cases. This study has investigated the feasibility of developing a screening procedure that will identify such carriers. Results show that it is possible to detect a carrier when the alteration results in shortening of the protein. Supervisors: Dr. S.M. Bowen, Prof. I.D. Bowen. PhD. Researcher: Mrs. M. Savoury. Androgen and PPARg Ligand Ciglitizone, Regulates Cell Proliferation, Cyclin D1 Levels and Cyclin Dependent Kinase Inhibitors p27Kip1 and p57Kip2 in Prostate Cancer Cells Dr. Gaynor Davies, Mr Gregory M. Harrison and Dr Wen G. Jiang. Metastasis & Angiogenesis Research Group, University Department of Surgery, University of Wales College of Medicine, Cardiff, UK. Professor Malcolm D. Mason. Department of Medicine, Section of Oncology and Palliative Medicine, Velindre NHS-Trust, Whitchurch, Cardiff, UK. Introduction: Peroxisome proliferator-activated receptor gamma (PPARg) belongs to a nuclear hormone receptor superfamily that includes receptors for vitamin D, retinoic acid, oestrogen and androgen receptors. PPARg functions as a transcription factor after it forms a complex with its co-activators PGC-1 or PGC-2, that in turn regulates gene expression. Ligands for PPARg such as ciglitizone and troglitazone have been shown to inhibit the growth of cancer cells. This study tested the effect of ciglitizone and/or testosterone on cell growth, and cell cycle regulators in prostate cancer cells. Materials and Methods: Invasive prostate cancer cell lines DU-145 and PC-3 were used in this study. RT-PCR and Q-RT-PCR were used to assess the degree of PPARg, PGC-1, AR, cyclin D1, p27Kip1 and p57Kip2 expression at the mRNA level. Cell growth was measured using RibogreenTM Technology. The possible contribution of PPARg to biological effects was evaluated by using PPARg antisense oligo.
Results: Using a cell growth assay, PPARg agonist ciglitizone inhibited the growth of DU-145 cells. A combination of testosterone and ciglitizone significantly (P = 0.003) enhanced the effect of ciglitizone. The action of testosterone and ciglitizone on cell growth was reversed after the expression of PPARg was eliminated by antisense oligo to PPARg. High levels of PPARg and its co-activator receptor PGC-1 were detected in DU-145 cells. DU-145 and PC-3 cells expressed transcripts for the androgen receptor. Cyclin D1 levels were down regulated in DU-145 and PC-3 cells after incubation with ciglitizone (20mM), testosterone (100mM) or a combination of both. Cyclin dependent kinase inhibitors p27Kip1 and p57Kip2 were both up regulated in prostate cancer cells by these compounds. Conclusion: Androgen receptor agonists and PPARg agonists have synergistic effects on the growth of prostate cancer cells. This effect is at least partly mediated via the action of agonists on cell cycle regulators, including cyclin D1, p27Kip1 and P57Kip2. Down-regulation of tumour suppressor KiSS-1, in human prostate cancer cells by hepatocyte growth factor/scatter factor (HGF/SF) Dr. Gaynor Davies, Mr Gregory M. Harrison and Dr Wen G. Jiang. Metastasis & Angiogenesis Research Group, University Department of Surgery, University of Wales College of Medicine, Cardiff, UK. Professor Malcolm D. Mason. Department of Medicine, Section of Oncology and Palliative Medicine, Velindre NHS-Trust, Whitchurch, Cardiff, UK. Introduction: KiSS-1 has been identified as a metastasis suppressor and is reduced in its expression in some forms of metastatic cancers. Hepatocyte growth factor/scatter factor (HGF/SF) is a cytokine known to promote cell motility, invasion and migration in epithelial derived cells through activation of its tyrosine kinase receptor c-Met. This factor has demonstrable effects on the metastatic process of cancer cells. Our study evaluated the possible role of HGF/SF on KiSS-1 expression in prostate cancer cells. Materials and Methods: The effect of rh-HGF/SF (40ng/ml) was assessed in DU-145 and PC-3 cells for up to 24hours and RNA was subsequently extracted. The expression of KiSS-1 was assessed using Q-RT-PCR, and protein assessed using Western blotting. Results: Exposure of prostate cancer cells to HGF/SF significantly reduced the transcript levels of KiSS-1 in DU-145 cells over a 24 hour culture period (0.00061 copies/62ng RNA with HGF, vs. 0.0173 copies without HGF; p<0.01). Similarly, exposure to HGF/SF reduced the level of KiSS-1 in PC-3 cells (0.003 copies with HGF, vs. 0.0898 copies without HGF group). Conclusions: We conclude that expression of the tumour suppressor KiSS-1 can be down-regulated by hepatocyte growth factor in human prostate cancer cells, which may contribute to the growth of prostate cancer cells.
Shielding Design in Radiotherapy using Monte Carlo Techniques
SJS Ryde, AF Woodward, TJ Meacham, SC Evans Department of Medical Physics & Clinical Engineering, Singleton Hospital, Swansea NHS Trust, Sketty Lane, Swansea SA2 8QA. CJ Evans Department of Health Science, University of Wales Swansea, Singleton Park, Swansea SA2 8PP The objective of this project is to utilise mathematical techniques to augment the design of radiotherapy treatment bunkers. Bunkers are used to house high-energy linear accelerators for the delivery of intense radiation beams, used in the treatment of cancer. The design of the bunker is critical to ensure the safe operation of the accelerator for staff and patients alike; the walls must be of sufficient thickness (usually a little over 2m) to attenuate the radiation beam to acceptable and safe levels but not overly thick such that additional constructional costs are incurred or unnecessary floor space is consumed. By using mathematical simulation of radiation transport, together with knowledge from established designs, this project has sought to optimise the design of the bunkers constructed at Singleton Hospital. Network support for cancer patient management Dr. D Morray, Clinical Information Unit, Velindre NHS Trust, Professor W A Gray, Department of Computer Science, Cardiff University Ph D Student Dr. Omnia Allam Overview of the project: The overall aim of this project is to investigate and determine the information needed to link primary care to the existing ISCO information system in order to support cancer care teams whose members have diverse skills and work at different levels in the health care spectrum (primary, secondary and tertiary). Then, the objective is to supply this information in an effective way to team members. Approach to the project The pilot study: A pilot interface was implemented and evaluated. The main aim of this rapid implementation was to assess the feasibility of the project's goal namely that it is possible to provide information across the different levels of the health care spectrum and to ensure that the benefits resulting from this system would outweigh its cost. The outcome of this pilot project demonstrated that there is a broad acceptance of the project aims by care team members at all levels. The current work: The main aim at this point is to determine the information requirements needed to build an appropriate system. This is based on the investigator's wide knowledge of the domain, resulting from her medical background and work as a hospital doctor for several years, together with the knowledge and experience gained from the pilot study and her recent training in IT. Collaboration: Clinical Information Unit, Velindre NHS Trust Professor N.J. Fiddian (Department of Computer Science, Cardiff University)
The Object & Knowledge based Systems research group. Department of Computer Science, Cardiff University Cancer Services Coordinating Group, NHS Wales Ms Branston, Wales Cancer Trials Network Statistics and Data Analysis Jon Court and David Morrey Clinical Information Unit, Velindre NHS Trust Statistical analysis of data is an important part of laboratory and clinical research. Over the past year we have continued to develop analytical methods using the statistical package SPlus, which has a particularly sophisticated suite of routines that can be applied to almost any analytical problem. The SPlus package is funded jointly by Cancer Research Wales and Velindre Cancer Centre and is intended to be a central analysis facility designed to be easily applicable to clinical data generated by the ISCO database. This is especially valuable in cases where data are intended for publication and clinical audit. However, the routines in SPlus do not provide an output that is easily converted into straightforward significances that can be included in a publication. In addition, the graphical output, though of high visual quality, is not always labelled in a satisfactory way. To correct these shortcomings, we are developing an additional library (VLib) that can be incorporated into the main package, and will allow fast modification of the standard visual and numeric output so that manual labelling of graphical images is no longer necessary. Basically, this means that more time can be spent in a consideration of the results and less on their deciphering and formatting. It also means that high quality graphs can be produced at short notice, which is often an important issue in clinical audit. To date, we have concentrated on those routines that are useful in survival analysis, since this is almost invariably central to publications that describe the benefit of anti-cancer therapy. However, we have also applied this analysis in a novel way to data produced by Nuria Marquez Almuina, of Professor Paul Smith's group at the University of Wales College of Medicine. In this study, the fate of cultured cells has been followed using sophisticated optical and computing technology. The endpoint was the time to cell division, death, or the formation of giant cells. Since this endpoint is essentially the same as the time to an event in a treated patient, we were able to apply logrank and Cox methods to determine the significance of the difference between control cells and those treated with the anti-cancer drug cisplatin. This is important because cisplatin, in common with radiotherapy and several other drugs, is known to induce a block in the cell cycle and so reduce the rate of cell division. We are also interested in the problem of deriving summary statistics from publications that provide only a graph of the survival of patients given a particular treatment. This problem commonly arises when data are needed for a meta-analysis, as in the Cochrane Collaboration. In a meta-analysis, the results of several publications are combined to see if there is a significant common trend in the results of a particular treatment, or if the studies disagree concerning the outcome. In order to do this, the summary data must be presented in a common numerical form, and although this is rarely the case, it is common to find a survival curve that shows the difference between two treatments. It is agreed that the best summary statistic from such a graph is the hazard ratio, which is essentially the weighted mean of the ratio of the slopes of the two curves. The higher the hazard ratio, the greater the difference between the two treatments. We are currently assessing the usefulness of a method proposed by Max Parmar and colleagues (Parmar et al., 1998), which splits the curves up into time intervals and calculates a mean hazard ratio. The method is fairly easily to program, and it is also possible to perform Monte Carlo studies, whereby survival curves are generated at random and the Parmar method applied to each one, so that the result can be compared to the parameters used to generate each curve. These simulations so far indicate that it is not straightforward to extract a hazard ratio from any given curve, though on average the Parmar method provides a good estimate. The difficulties are due mainly to the fact that some patients are lost to follow-up, so their outcome is not known. Not all publications give enough information regarding these losses, so that assumptions have to be made which reduce confidence in the final result. An alternative approach is to fit a parametric survival function to the data and to use the fitted curve to derive a hazard ratio, and we propose to follow this approach in the near future. Clinical Trials Unit Report Professor Tim Maughan (Director) Sara Shankland (CTU Manager) Velindre Hospital Clinical Trials Unit Whenever a new treatment is developed it has to be carefully evaluated to ensure that it is safe, that it works and that it is at least as good if not better than current treatments. This is the role of clinical trials in cancer. At Velindre, the Clinical Trials Unit has been running for nearly 10 years and the staff work with the medical staff in explaining to patients about new treatments and offering patients the opportunity to participate in a clinical trial. During 2003 a total of 371 patients volunteered for entry to clinical trials at Velindre. In addition we have calculated that over 800 patients remained on follow up of the 1500 entered since 2002. This area of work is rightly the subject of stringent oversight and regulation. In September 2003, the Velindre CTU became the first unit of its kind in the UK to be the subject of a voluntary inspection by the Medicines and Health products Regulatory Authority (MHRA). The unit was found to be working to very high standards, and this puts us in excellent preparation for the forthcoming EU legislation which is planned to be enshrined in UK law in May 2004. The Wales Cancer Trials Network is the umbrella organisation for all clinical cancer research in Wales. The Velindre CTU plays a key role in this organisation and was therefore intimately involved in the Programme Grant application to the National Assembly of Wales and Cancer Research UK in November 2003. The international review panel graded the work as being at the forefront internationally and will be agreeing funding for the coming 4 years in light of that excellent review. Characterisation of exosomes following cell stress: A simple method for improving their immunological potency
Aled Clayton, Jacquelyn Court, Attila Turkes, Malcolm D Mason, Zsuzsanna Tabi, Section of Clinical Oncology, Department of Medicine, University of Wales College of Medicine, Velindre Hospital, Whitchurch, Cardiff CF14 2TL.
Exosomes are small vesicles that are naturally produced by cells, which may be useful as future cancer vaccines. Among the many molecules associated with exosomes are members of the heat-shock protein (hsp) family. In healthy cells hsp play important roles in protection from environmental stress. The importance of exosome-hsp has not been previously studied. We have shown that exosome alterations occur under conditions of cell stress, becoming enriched in many heat shock proteins. Immunological studies highlighted that exosomes isolated from stressed-cells were more potent than exosomes from healthy non-stressed cells. Our findings demonstrate that exosomal-hsp are functionally important, and that subjecting cells to stress may be a useful method for potentiating future exosome-vaccines.
Evidence Based minimum datasets for the pathology of urological cancers Dr. M. Shelley, Ms. S. Kletzka, Mrs. B. Coles, Dr. P. Harnden, Prof M. Mason, Cochrane Prostatic Diseases and Urological Cancers Unit, Research Department, Velindre NHS Trust Evidence based medicine has become increasingly important in the last few years. It aims to eliminate bias and helps both clinicians and patients in making well-informed decisions based on information from high-quality clinical and scientific research. This project, jointly undertaken by the Cochrane unit at Velindre NHS Trust and the Department of Histopathology, St James's University Hospital, Leeds, aims to use this fact-based approach to develop minimum datasets for the pathology (characteristics of a disease) of cancers of the genitourinary tract, i.e. kidney, bladder, prostate, testis and penis. The initial step of this project was to develop relevant terms that could be used to search a number of scientific and medical electronic databases for clinical studies correlating tumour pathology with patient treatment and prognosis. The next step was to gather relevant articles found from the search and tabulate their information. These tables form the basis of the minimum datasets, which will ensure pathologists report all important features of a cancer, that we have shown, from our evidence search, to affect patient treatment and prognosis. This will enable clinicians to make well-informed decisions on the best treatment available and thereby improve patient outcome and quality of life.
Adhesion and signalling of B-cell exosomes
Aled Clayton, Attila Turkes, Jacquelyn Court, Zsuzsanna Tabi, Malcolm D Mason Section of Clinical Oncology, Department of Medicine, University of Wales College of Medicine, Velindre Hospital, Whitchurch, Cardiff CF14 2TL. Robert Steadman, Sharron Dewitt Institute of Nephrology, Department of Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN Maurice Hallett Neutrophil Signalling Group, Department of Surgery, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN.
Summary. Exosomes are small vesicles, which are released by different cell types, whose role(s) in biology are poorly understood. We and others, and we have investigated the potential for exosomes in controlling immune responses. Exosomes, however, may have other functions that may impact on our ability to manipulate them as cancer vaccines. We have studied molecules on the surface of exosomes, termed integrins, for their ability to act as molecular anchors. We demonstrated the ability of exosomes to bind to a variety of non-cellular materials through their integrins. Exosomes could also bind to cell surfaces, but only under conditions mimicking inflammation. Interestingly, following attachment, the cells became activated, (measured by oscillations in calcium). Exosomes, therefore, are capable of more wide-ranging and complex interactions than was originally thought, and may have important functions in processes such as inflammation.
Monte Carlo Portal Dosimetry
PW Chin and DG Lewis Department of Medical Physics, Velindre Cancer Centre, Cardiff CF14 2TL
There is more to X-rays than mapping inner body structures * they can also be used for treating cancer. Generally the therapy X-rays are of somewhat higher energy than those used for imaging. Since this radiation can affect both cancerous and healthy cells, it is vital to pinpoint the target while sparing the surrounding tissues. To this end, the orientation, intensity and shape of each beam is carefully optimised during planning. When such complex beams are delivered to the patient, it must be verified that the delivery had been faithful to the plan. This challenge is met by capturing an X-ray picture (known as a portal verification image) during treatment using the therapy beam. Our project combines the above plan-and-verify process with computer simulations, involving the so-called Monte Carlo technique. The idea is to calculate the dose by simulating how the therapy X-rays traverse a computer-based model of the patient's anatomy, derived from diagnostic computed tomography (CT) scans. Since the start of the project we have introduced solutions to several limitations due to both the Monte Carlo code and the scanning device, e.g. artefacts from the portal image detector. Preliminary clinical application of this work is under way at Velindre Cancer Centre, involving complex conformal treatments and eventually intensity modulated radiotherapy cases.
CD44 isoforms and their role in prostate cancer.
G. M. Harrison, G. Davies, W. G. Jiang Department of Surgery, University of Wales College of Medicine, Cardiff. UK. M. D. Mason Department of Clinical Oncology, University of Wales College of Medicine,Cardiff. UK.
CD44 is a cell adhesion protein that has been implicated in tumour spread (metastasis) and progression. Investigations funded by Cancer Research Wales (CRW) into the expression of CD44 in prostate tumour cells revealed different CD44 proteins are expressed on tumour cells and the amount of CD44 protein is increased with substances known to enhance tumour metastasis. Furthermore CD44 was observed to cluster with another cell protein, ezrin, and both clustered at the point tumour cells had interacted with blood vessel (endothelial) cells raising the possibility of ezrin involvement in tumour migration. In addition, MMP14, an enzyme that is known to be involved in metastasis appears to be reduced in cells modified to express a particular form of CD44 (CD44v3-v10). In conclusion, certain CD44 proteins when expressed on tumour cells may cause a reduction in metastasis. Publications Publications: Zsuzsanna Tabi Coleman S, Clayton A, Mason DM, Jasani B, Adams M, Tabi Z. (2004). Monitoring CD8+ T cell responses to recall antigens from PBMC of cancer patients. An optimised method using synthetic peptides. Clinical Cancer Research. Moutaftsi, M., Brennan, P., Spector, S. A., and Tabi, Z. (2004). Impaired lymphoid chemokine-mediated migration due to a block on the chemokine receptor switch in human cytomegalovirus-infected dendritic cells. Journal of Virology 78, 3046-3054. http://research.bmn.com/medline/search/record?uid=MDLN.14990723 Moutaftsi, M., Mehl, A. M., Borysiewicz, L. K., and Tabi, Z. (2002). Human cytomegalovirus inhibits maturation and impairs function of monocyte-derived dendritic cells. Blood 99, 2913-2921. http://research.bmn.com/medline/search/record?uid=MDLN.11929782 Tabi, Z., Moutaftsi, M., and Borysiewicz, L. K. (2001). Human cytomegalovirus pp65- and immediate early 1 antigen-specific HLA class I-restricted cytotoxic T cell responses induced by cross-presentation of viral antigens. Journal of Immunology (Baltimore, Md : 1950) 166, 5695-5703. http://research.bmn.com/medline/search/record?uid=MDLN.11313411 Publications: Aled Clayton Clayton, A., Harris, C. L., Court, J., Mason, M. D., and Morgan, B. P. (2003) Antigen presenting cell exosomes are protected from complement mediated lysis by expression of CD55 and CD59. Eur. J. Immunol 33, 552-531 Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=PubMed&list;_uids=12645951&dopt;=Abstract Savage, P., Cowburn, P., Clayton, A., Man, S., Lawson, T., Ogg, G., Lemoine, N., McMichael, A., and Epenetos, A. (2002) Anti-viral cytotoxic T cells inhibit the growth of cancer cells with antibody targeted HLA-Class I/peptide complexes in SCID mice. International Journal of Cancer 98, 561-566 Medline Abstract http://research.bmn.com/medline/jbrowse/record?uid=MDLN.11920616&rendertype;=full Savage, P., Cowburn, P., Clayton, A., Man, S., McMichael, A., Lemoine, N., Epenetos, A., and Ogg, G. (2002) Induction of viral and tumour specific CTL responses using antibody targeted HLA-Class I/peptide complexes. Br J Cancer 86, 1336-1342 Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=PubMed&list;_uids=11953895&dopt;=Abstract Clayton, A., Court, J., Navabi, H., Adams, M., Mason, M. D., Hobot, J. A., Newman, G. R., and Jasani, B. (2001) Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. Journal of Immunological Methods 247, 163-174 Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=PubMed&list;_uids=11150547&dopt;=Abstract Navabi, H., Jasani, B., Adams, M., Evans, A., Crosby, T., Mason, M., and Borysiewicz, L. (1997) Generation of in vitro autologous human cytotoxic T-cell response to E7 and HER-2/neu oncogene products using ex-vivo peptide loaded dendritic cells. Adv. Exp. Med. Biol. 147, 583-589 Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=pubmed&dopt;=Abstract&list;_uids=9286422 Publications: Gaynor Davies Davies G, Jiang WG and Mason MD. E-cadherin and associated molecules in the invasion and progression of prostate cancer. Oncol Rep 5: 1567-1576, 1998. Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=pubmed&dopt;=Abstract&list;_uids=9769407 Davies G, Jiang WG and Mason MD. Cell-cell adhesion molecules and their associated proteins in bladder cancer cells and their role in mitogen induced cell-cell dissociation and invasion. Anticancer Res 19: 547-552, 1999. Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=pubmed&dopt;=Abstract&list;_uids=10226596 Davies G, Jiang WG and Mason MD. Cell-cell adhesion molecules and signalling intermediates and their role in the invasive potential of prostate cancer cells. J Urol 163: 985-992, 2000. Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=pubmed&dopt;=Abstract&list;_uids=10688036 Davies G, Jiang WG, Mason MD. The interaction between beta-catenin, GSK3beta and APC after motogen induced cell-cell dissociation, and their involvement in signal transduction pathways in prostate cancer. Int J Oncol 18: 843-847, 2001. Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=pubmed&dopt;=Abstract&list;_uids=11251183 Davies G, Jiang WG, Mason MD. HGF/SF modifies the interaction between
its receptor c-Met, and the E-cadherin/catenin complex in prostate
cancer cells. Int J Mol Med 7: 385-388, 2001. Pub Med Abstract Parr C, Davies G, Nakamura T, Matsumoto K, Mason MD, Jiang WG. The HGF/SF-induced phosphorylation of paxillin, matrix adhesion, and invasion of prostate cancer cells were suppressed by NK4, an HGF/SF variant. Biochem Biophys Res Commun 285: 1330-1337, 2001. Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=pubmed&dopt;=Abstract&list;_uids=11478803 Davies G, Jiang WG and Mason MD. Matrilysin mediates extracellular cleavage of E-cadherin from prostate cancer cells: a key mechanism in hepatocyte growth factor/scatter factor-induced cell-cell dissociation and in vitro invasion. Clin Cancer Res 7: 3289-3297, 2001. Full article text http://clincancerres.aacrjournals.org/cgi/reprint/7/10/3289 Mason MD, Davies G and Jiang WG: Cell adhesion molecules and adhesion abnormalities in prostate cancer. Crit Rev in Oncol Hematol 41: 11-28, 2002. Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=pubmed&dopt;=Abstract&list;_uids=11796229 Harrison GM, Davies G, Martin TA, Jiang WG and Mason MD. Distribution and expression of CD44 isoforms and Ezrin during prostate cancer-endothelial interaction. Int J Oncol 21: 935-40, 2002. Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=pubmed&dopt;=Abstract&list;_uids=12370738 Harrison GM, Davies G, Martin TA, Jiang WG, and Mason MD. Distribution and expression of CD44 isoforms and ezrin during prostate cancer-endothelium interaction. International Journal of Oncology, 2002, 21, 935-94 Pub Med Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi? Davies G, Mason MD, Martin TA, Parr C, Watkins G, Lane J, Nakamura T, Matsumoto K and Jiang WG. The HGF/SF antagonist NK4, reverses fibroblast- and HGF-induced prostate tumour growth and angiogenesis in vivo. Int J Cancer 106: 348-354, 2003. Pub Med Abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db;=pubmed&dopt;=Abstract&list;_uids=12845672 Jiang WG, Grimshaw D, Martin TA, Davies G, Parr C, Watkins G, Lane J, Abounader R, Laterra J and Mansel RE. Reduction of stromal fibroblast-induced mammary tumour growth, by retroviral ribozyme transgenes to hepatocyte growth factor/scatter factor and its receptor c-Met. Clin Cancer Research 9: 4274-4281, 2003. Full article text http://clincancerres.aacrjournals.org/cgi/reprint/9/11/4274 Martin TA, Parr C, Davies G, Watkins G, Lane J, Matsumoto K, Nakamura T, Mansel RE and Jiang WG. Growth and angiogenesis of human breast cancer in a nude mouse tumour model is reduced by NK4, a HGF/SF antagonist. Carcinogenesis 24: 1317-1323, 2003. Full article text http://carcin.oupjournals.org/cgi/reprint/24/8/1317 Davies G, Cunnick GH, Mansel RE, Mason MD and Jiang WG. Levels
of expression of endothelial markers specific to tumour-associated
endothelial cells and their correlation with prognosis in patients
with breast cancer. Clin Exp Metastasis 21: 31-37, 2004. Pub Med
Abstract Davies G, Watkins G, Mason MD and Jiang WG. Targeting the HGF/SF receptor c-Met using a hammerhead ribozyme transgene reduces in vitro invasion and migration in prostate cancer cells. The Prostate 9999: 1-8, 2004. Zsuzsanna Tabi’s Presentations to Societies Coleman S, Jasani B, Gibbs A, Butchart E, Evans E M-L, Adams M, Mason M, Tabi Z. T cell responsiveness of malignant pleural mesothelioma (MPM) patients and the potential for immunotherapy. 4th World Congress on Vaccines and Immunization. Japan 2004. Navabi H, Reece A, Clayton A, Tabi Z, Mason M, Donninger C, Jasani B, Adams M. Ampligen (poly[I]:poly[C12U]; a GMP-grade agent which is a powerful inducer of dendritic cell maturation. FOCIS, 12th International Immunology Meeting, Montreal. July (2004) Tabi Z, Coleman S, Clayton A, Mason MD, Jasani B and Adams M. Immunocompetence of cancer patients - how can we monitor it? Cancer and the Immune system. I3 IRG meeting, Cardiff, 2004. Coleman S, Clayton A, Mason MD, Jasani B and Tabi Z. Monitoring CD8+ T cell responses to recall antigens from PBMC of cancer patients. An optimised method using synthetic peptides. 3rd International PIVAC Meeting (Progress in vaccination against cancer). Oxford, 2003. Moutaftsi M and Tabi Z. Human cytomegalovirus inhibits dendritic cell migration by interfering with the chemokine receptor-switch. 7th International Symposium on Dendritic cells. Bamberg, Germany. 2002. Tabi Z, Jasani B, Gibbs A, Butchart E, Evans E M-L, Adams M and Mason M. T cell responses to SV40 large T antigen (TAg) in malignant pleural mesothelioma (MPM) patients. 3rd World Congress on Vaccines and Immunization. Opatija, Croatia. 2002. Moutaftsi M, Borysiewicz LK and Tabi Z. Human cytomegalovirus inhibits maturation and impairs function of monocyte derived dendritic cells. 26th International Herpesvirus Workshop, Regensburg, Germany. 2001. Tabi Z, Moutaftsi M and Borysiewicz LK. Uninfected dendritic cells cross-present human cytomegalovirus antigens to CD8+ CTL. Keystone Symposia. Molecular aspects of Viral Immunity. Keystone, Colorado, USA. 2001. (Winner of poster category).
Aled Clayton, Atilla Turkes, Malcolm David Mason, Zsuzsanna Tabi.
“Cellular stress generates heat shock protein enriched exosomes;
implications for immunological control” A. Clayton, Zsuzsanna Tabi, Bharat Jasani, Malcolm Adams, Malcolm D. Mason. “Exosomes released by Epstein Barr Virus-transformed B lymphoblastoid cell lines carry viral antigens and heat shock proteins”. American Association for Cancer Research, Toronto April (2003). A. Clayton, C. Harris, J. Court, MD. Mason, B.P. Morgan. “Antigen Presenting Cell Exosomes express functional CD59 and CD55, which confers protection from complement deposition and lysis”. American Association of Cancer Research, San Francisco April (2002). Aled Clayton, Claire L. Harris, Jacquelyn Court, Malcolm D Mason, B. Paul Morgan. Antigen presenting cell exosomes are protected from complement-mediated lysis by expression of CD55 and CD59. International Immunopharmacology 2:1261(2002) A. Clayton, C. Harris, J. Court, MD. Mason, B.P. Morgan. “CD59
expressed by antigen presenting cell exosomes is functional in protection
from complement lysis”. Keystone Symposium, Taos New Mexico
March (2001). Gaynor Davies’s Presentations to Societies (peer reviewed abstracts) Davies G, Jiang WG and Mason MD. Cell-cell adhesion molecules and their associated proteins in bladder cancer cells and their role in motogen-induced cell-cell dissociation and invasion. Presented to the 5th UK Adhesion Meeting, held at the Glaxo-Wellcome Laboratories in Stevenage, Hertfordshire, December 1997. Davies G, Jiang WG and Mason MD. Expression of cell-cell adhesion molecules and their associated molecules in bladder cancer cells and their role in motogen induced cell-cell dissociation and invasion. Presented to the AACR in New Orleans USA. In: Proceedings of the American Association for Cancer Research 39: 400-401, 1998. Davies G, Jiang WG and Mason MD. Expression of cell adhesion and
tumour suppressor Davies G, Jiang WG and Mason MD. The influence of the tumour suppressor molecule APC and cell-cell adhesion molecules on in vitro prostate cancer invasion. In: Proceedings of the 13th Annual Postgraduate Research Day (ISSN 0967-7496; issue number 6), held at UWCM in Cardiff, October, 1998. Davies G, Hiscox S, Llafaffian I, Jiang WG and Mason MD. The interection of APC, GSK3-ß and ß-catenin on the invasiveness of human prostate cancer cells. Presented to the AACR in Philadelphia USA. In: Proceedings of the American Association for Cancer Research 40: 459, 1999. Davies G, Jiang WG and Mason MD. HGF/SF influences the interaction between beta-catenin, GSK3-beta and APC and its impact on the in vitro invasiveness of prostate cancer. Presented to the British Cancer Conference. In: British Journal of Cancer 80: (suppl 2) 36, 1999. Davies G, Hiscox S, Llafaffian I, Jiang WG and Mason MD. Interactions between APC GSK3-beta and beta-catenin, after mitogen induced cell-cell dissociation and in vitro invasion in prostate cancer. In: Proceedings of the 14th Annual Postgraduate Research Day (ISSN 0967-7496; issue number 7), held at UWCM in Cardiff, October, 1999. Davies G, Hiscox S, Llafaffian I, Jiang WG and Mason MD. Interaction between APC, GSK3-beta and beta-catenin, its impact on cell adhesion and in vitro invasion in prostate cancer. Third World Congress on Urological Research held in Paris, France. In: European Urology 36: (5), 494, 1999. Davies G, Jiang WG and Mason MD. Matrilysin mediates HGF/SF induced E-cadherin shedding in prostate cancer cells. Presented to the Royal Society of Medicine, Oncology Section Meeting, held in London, March 2000 (oral presentation). Parr C, Davies G, Hiscox S, Nakamura T, Matsumoto K, Jiang WG and Mansel RE. The HGF/SF antagonist NK4, suppressed HGF/SF-induced matrix adhesion, invasion and phosphorylation of paxillin in human cancer cell lines. In: Proceedings of the 15th Annual Postgraduate Research Day (ISSN 0967-7496; issue number 8), held at UWCM in Cardiff, December, 2000. Davies G, Jiang WG and Mason MD. HGF/SF modifies the interaction between its receptor c-MET the E-cadherin/ß-catenin complex and molecules involved in signal transduction pathways. Presented to the British Prostate Group Meeting, Manchester, April, 2001. In: Prostate Cancer and Prostatic Diseases 4: 182, 2001. Davies G, Jiang WG and Mason MD. The effects of motogen induced cell-cell dissociationi on the E-caehrin/catenin complex and the association of ß-catenin with molecules involved in signal transduction pathways in prostate cancer cells. Presented to the British Cancer Conference, held in Leeds, July, 2001. In: British Journal of Cancer 85: (Suppl 1) 86, 2001. Harrison GM, Davies G, Martin TA, Jiang WG and Mason MD. Co- localisation of CD44 and ezrin during prostate cancer-endothelial interactions. Presented to the British Prostate Group Meeting, held in London, September, 2001. Davies G, Jiang WG, and Mason MD. Matrilysin mediates HGF/SF-induced E-cadherin cleavage in prostate cancer cells. Presented to the Cell Adhesion in Health and Disease, Amsterdam, October, 2001. Harrison GM, Davies G, Martin TA, Jiang WG and Mason MD. Expression and localisation of CD44 and ezrin during prostate cancer-endothelial interactions. Presented to the Cell Adhesion in Health and Disease, Amsterdam, October, 2001. Harrison GM, Davies G, Martin TA, Jiang WG and Mason MD. Co- localisation of CD44 and ezrin during prostate cancer-endothelial interactions. In: Proceedings of the 16th Annual Postgraduate Research Day (ISSN 0967-7496; issue number 9), held at UWCM in Cardiff, November, 2001. Davies G, Martin TA, Parr C, Mason MD and, Jiang WG. Growth of PC-3 prostatic carcinoma cells in vivo is suppressed by the HGF/SF antagonist NK4. Presented to the AACR in San Francisco USA. In: Proceedings of the American Association for Cancer Research 43: 673, 2002 (awarded scholar in training award). Martin TA, Parr C, Davies G, Mansel RE and Jiang WG. Tumour invasion and growth in breast cancer models is reduced by NK4, the HGF/SF antagonist. Presented to the AACR in San Francisco USA. In: Proceedings of the American Association for Cancer Research 43: 88, 2002. Davies G, Jiang WG and Mason MD. Loss of E-cadherin from prostate cancer cells is mediated by matrilysin, a novel mechanism in HGF/SF-induced cellular scattering. Presented to the Association of Physicians, Cardiff UK, April 18th-19th, 2002. Davies G, Cunnick GH, Mansel RE, Mason MD and Jiang WG. Levels
of tumour endothelial markers and their correlation with prognosis
in patients with cancer. Presented to the 25th Annual San Antonio
Breast Cancer Symposium in Texas USA, December 11th-14th 2002. Davies G, Watkins G, Mason MD and Jiang WG. Androgen receptor agonist and PPAR-gamma agonist on the growth and cell cycle regulators in human prostate cancer. Presented to the 5th World Congress on Urological Research, in London UK September 24-27th 2003. Davies G, Jiang WG and Mason MD. A hammerhead ribozyme transgene
to HGF receptor inhibits the Davies G, Harrison G, Hurle R, Watkins G, Mason MD and Jiang WG. Is psoriasin involved in the migration of motogen-induced prostate cancer cells? Presented to the British Prostate Group, Royal College of Surgeons, in London March 11th 2004. In: Prostate and Prostatic Diseases, (in press) 2004. Davies G, Mason MD, Martin TA. Parr C, Watkins G, Lane J and Jiang
WG. Down regulation of tumour suppressor, KiSS-1, in human prostate
cancer cells and prostate tumours by hepatocyte growth factor/scatter
factor (HGF/SF). Presented to the AACR in Orlando Florida, USA March
27th-31st 2004.
Davies G, Jiang WG and Mason MD. The role of HGF/SF and its receptor c-Met, on prostate cancer metastasis. In: Cancer metastasis: Biology and treatment, (Ablin RJ and Mason MD eds). Kluwer Academic Publishers. Dordrecht, The Netherlands (in press). Davies G, Harrison GM, Jiang WG and Mason MD. ß-catenin, its binding partners and signalling mechanisms: Implications in prostate cancer. In: Cancer metastasis: Biology and treatment, (Ablin RJ and Mason MD eds). Kluwer Academic Publishers. Dordrecht, The Netherlands (in press). |
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