Thesis (doctoral)--Universität Hamburg, 1979.

No description available.

Malignant mesothelioma is an aggressive cancer with increasing incidence worldwide. Exposure to asbestos is believed to be the main mechanistic basis of malignant transformation of mesothelial cells. Despite decades of efforts, treatment options for this malignancy are still limited to traditional surgery and chemotherapy, which do not provide significant survival benefits, highlighting the importance of finding novel therapeutic and preventive approaches to fight mesothelioma. For this reason, we aimed to examine the efficacy of immunotherapy strategy using DNA vaccines targeting tumor-expressing antigens. Immunotherapy targeting tumor associated self-antigen WT1 with conventional and PD1-based DNA vaccines was unable to induce tumor regression or improved survival in a quantitative mouse malignant mesothelioma model due to insufficient levels of antigen-specific immune responses being elicited. While why PD1-based DNA vaccine does not improve self-antigen WT1-specific immune responses remains to be investigated, it becomes important to define the level of vaccine-elicited immune responses for protection. To date, the immune correlates of vaccine-elicited immunity remains poorly understood for the prevention and eradication of malignant mesothelioma. With the development of a malignant mesothelioma mouse model stably expressing HIV-1 GAG model antigen, we utilized the remarkably enhanced antigen-specific T cell responses elicited from our PD1-based HIV-1 GAG p24 vaccine to define antitumor responses. It has been demonstrated in this study that vaccine-elicited host immunity not only achieved complete and long-lasting protection against murine mesothelioma cell challenges but also resulted in therapeutic eradication of pre-existing mesothelioma after four consecutive DNA vaccinations. Vaccine-elicited 〖CD8〗^+ T cells attributed primarily and dose-dependently to the protective efficacy in both preventive and therapeutic settings. Moreover, the consecutive vaccinations activated polyfunctional 〖CD8〗^+ T effector cells via T-bet and Eomes-mediated pathways, leading to the rejection of mesothelioma by releasing inflammatory IFN-γ and TNF-α in the vicinity of target cells and by triggering the TRAIL induced apoptosis. Importantly, the vaccination not only activated 〖CD8〗^+ T cells and maintained their effector function but also overcame immunosuppressive networks by downregulating inhibitory PD1 and Tim-3 molecule expression on 〖CD8〗^+ cells and reducing suppressor cells such as myeloid-derived suppressor cells (MDSCs) and Treg, leading to the shift of tumor immune oediting from progression to elimination. Taken together, the generation of malignant mesothelioma mouse models in our study can enable targeting immunotherapy strategies to be evaluated in a quantitative way. Our data suggested that high frequency of vaccine-elicited 〖CD8〗^+ T cells could prevent and eradicate malignant mesothelioma. The activation of quantitatively and qualitatively enhanced CD8+ T cells caneliminate theimmune suppressive network contributing to the complete tumor rejection. / published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy

Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Aims: The primary aim of this thesis was to explore the role of palliative radiotherapy in the treatment of pain in malignant pleural mesothelioma (MPM). The effect of radiotherapy on other symptoms was also examined. Biomarkers which might predict response to radiotherapy (Quantitative Sensory Testing – QST) were explored and objective evidence of response was sought via interpretation of Computed Tomography (CT) scans. The thesis also examined the role of Positron Emission Tomography (PET)-CT in radiotherapy planning and characterising pain in MPM. Methods: A narrative review of the challenges of pain management in MPM and a systematic review of the evidence supporting the use of palliative radiotherapy for pain control in MPM, were undertaken. In addition, a multi-centre, single arm phase II trial was conducted which examined the role of radiotherapy in pain control in MPM. This trial also assessed the role of PET-CT in radiotherapy planning and allowed for a characterisation of MPM-related pain. These components form the basis of this thesis. Results: Palliative radiotherapy at a dose of 20 Gy in five daily fractions using 6 Megavoltage (MV) photons improves pain in a significant proportion of patients with MPM. It does not have a beneficial effect on other symptoms or on quality of life. QST does not appear to be a useful clinical biomarker indicating likelihood of response to radiotherapy. Objective evidence of response via CT is low. Incorporation of PET-CT in the radiotherapy planning process alters the anatomical location of the target volume in patients with MPM. There is also an association between the Standard Uptake Value (SUV) uptake and pain, with the areas with highest SUV uptake being associated with the areas of pain. PET-CT results in upstaging of a significant proportion of patients. Pain is often severe and debilitating for patients with MPM and it has often a combination of neuropathic and nociceptive mechanisms. The presence of a neuropathic component to the pain is not associated with an increased likelihood of response to radiotherapy. Conclusions: Radiotherapy is effective at relieving pain in a proportion of patients with MPM and should be considered for all patients with MPM-related pain. PET-CT improves multiple parameters in the radiotherapy planning process compared with CT alone. QST parameters have not been shown to predict those patients who are likely to respond to radiotherapy.

No description available.

This thesis reports the results of a prospective multicentred case-control study of mesothelioma carried out in South Africa. The objectives of the study were: 1) to examine asbestos exposure of cases in detail with respect to source, risk occupations, fibre type and duration; 2) to determine relative risks for level (certainty) of exposure (definite, probable, possible, unlikely), for category of exposure (occupational, environmental), and for fibre type and skin colour; 3) to determine whether cases without recall of exposure were exposed to other non-asbestos putative agents; 4) to investigate the possible protective effect of certain dietary components. Previous studies of mesothelioma in South Africa had, with the exception of one incidence study, focused on particular occupational or case material, exposure data had been gathered in a non-systematic way, often indirectly from surrogates, and non-asbestos agents had not been investigated. In this case-control study these issues are all addressed. In addition, special efforts were made to minimise potential sources of bias (e.g. interviewer bias) and so to furnish reliable effect estimates. The study incorporated the following methodological features: 1) a prospective approach to gather exposure and dietary information directly from the cases and controls in life and so avoid the use of surrogates for this information; 2) the study was multicentred with study teams established in six cities, each with a major referral hospital, to maximise nation-wide coverage; 3) information was gathered with interviewers blind (at least at the beginning of the study) to study objectives and case control status at the time of the interview; 4) rigorous pathologic review was used to establish the diagnosis of mesothelioma; 5) two controls were selected for each case, a cancer and a non-cancer patient matched for hospital, sex, age and skin colour; 6) in analysis the case control datasets were treated separately (i.e cases and cancer controls, and cases and non-cancer controls were treated as two separate datasets). One hundred and twenty three cases were accepted into the study. No case was documented with purely chrysotile exposure nor exposure to a putative non-asbestos cause of the tumour without some evidence of asbestos exposure. A minimum of 22 cases (18%) had exclusively environmental exposure, 20 were from the NW Cape (a crocidolite mining region). Fifty eight percent had occupational exposure, three of whom had mined amosite. The relative risks associated environmental exposure in the NW Cape were larger than for environmental exposure in the NE Transvaal: 21.9 versus 7.1 for the cancer control dataset and 50.9 versus 12.0 for the medical control dataset. Increasing consumption of carotene rich fruit was found to be protective for mesothelioma when adjusted for asbestos exposure. The results confirm the high disease burden due to occupational exposure, the importance of environmental exposure in the crocidolite mining area of the NW Cape, the relative paucity of cases linked to amosite, the rarity of chrysotile cases, and are consistent with the view that there is a fibre gradient in mesotheliomagenic potential for South African asbestos with crocidolite > amosite > chrysotile. The evidence for a protective effect of carotene rich fruit is new in the South African context.

Malignant mesothelioma (MM) is an aggressive malignancy that originates from mesothelial cells and is highly resistant to conventional forms of anti-cancer therapy. Defects in apoptotic pathways are believed to play a major role in determining resistance to chemotherapy. The characterization of these pathways in mesothelioma is essential in order to develop more effective therapies. The inhibitor of apoptosis proteins (IAPs) are a family of proteins that regulate apoptosis and have been implicated in the resistance of malignant cells. There is evidence that upregulation of specific IAP molecules can influence tumour progression and response to chemotherapy. In this study we examined the apoptotic signalling in MM cells and the potential role of IAPs in both cell proliferation and chemosensitivity. We examined expression of six IAP genes or isoforms in both malignant and normal mesothelial cells. Results demonstrated that XIAP, IAP-1, IAP-2, survivin and Bruce were expressed in all four MM cell lines and four primary mesothelial cultures. There was no evidence for differential expression of these genes between MM and mesothelial cultures. Livin expression was detected in only one MM cell line. Various aspects of apoptotic signalling pathways in response to the chemotherapeutic drug cisplatin were also analysed including: a) the mitochondrial integrity, b) caspase activation, c) cell viability and d) phosphatidylserine translocation. In order to further characterize the role of IAPs, the transcriptional regulation of these genes in response to cisplatin was investigated using real-time RT-PCR. The results of these experiments indicated that there was no significant regulation of IAPs at the transcriptional level in the cells examined during cisplatin-induced apoptosis. Overall the data was consistent with cisplatin inducing apoptosis in MM cells via intrinsic signalling pathways in a dose dependent manner. Regulation of IAP expression was not seen at the RNA transcription level as has been described in other tumour types but may occur through protein posttranslational events. In order to further investigate IAP function we performed analyses of two IAPs which had previously been proposed as having a role in mesothelioma: XIAP and survivin. Protocols for RNAi knockdown at the protein expression level were established. Although the data indicated significant reduction in protein expression, the effects on cell survival after treatment with cisplatin were moderate. These studies were then extended to other molecules that are known to interact with and modulate the function of IAPs. We characterized the expression of the proteins: XAF1, HTRA2, ARTS in MM cells. RT-PCR data showed that HTRA2 and XAF1 genes were expressed in MM cell lines, however we did not see expression of ARTS. On the basis of recently published data we examined the XAF1 splice variants expressed in MM cell lines by sequence determination and PCR screening.