1. Altogether eleven different antioxidative enzymes were studied in pilocytic astrocytomas.
All AOEs (MnSOD, GLCL-C, GLCL-R, Trx, TrxR, and Prx I-VI) were expressed in pilocytic astrocytomas suggesting that oxidative damage and consequent defence take place during the progression of the tumors. AOEs correlated with degenerative features and angiogenesis, possibly associating with reactive oxygen species derived cellular damage.
Moreover, the expression of the AOEs was associated with each other in terms of concurrent activation of the enzymes. With the exception of manganese superoxide dismutase (MnSOD), a strong expression of AOEs was generally associated with higher cell proliferation. Prx VI seemed to have a positive association with a longer recurrence-free interval.
2. When five AOEs (MnSOD, GLCL-C, GLCL-R, Trx, TrxR) were studied in ependymomas, some AOEs seemed to be associated with tumor grade and location in ependymomas. Lower C and R expression was associated with higher tumor grade. MnSOD, GLCL-C and TrxR expressions were significantly higher in tumors located in the spinal cord compared to those in the brain. Interestingly, decreased expression of Trx predicted worse outcome for the patients. This finding may have clinical relevance when planning the treatment modalities and follow-up for the patients.
3. Carbonic anhydrases II, IX, and XII were widely expressed in medulloblastomas and PNETs. CA XII was associated with young patient age. Interestingly, CA IX was found to be of prognostic importance in medulloblastomas and PNETs. Previous studies have shown that CA IX is an attractive target molecule for anticancer treatment. Additional studies will be needed to analyse whether CA IX could also be used in practice in the case of medulloblastomas and PNETs.
4. Claudins 2, 3, 5, 7, and 10 were widely expressed in ependymomas. CLDN5 tends to be related to more aggressive tumors compared with CLDN2 and 10, which tend to display a better degree of differentiation and a better prognosis. There were also differences associated location of the tumor and between primary and recurrent tumors in the expression of claudins; CLDNs 3 and 5 were more often found in the cerebrum than in other sites and CLDN7 in primary tumors compared with recurrent ones. Evidently claudins influence the growth of and differentiation in ependymomas.
8 ACKNOWLEDGEMENTS
The present study was carried out at the Department of Pathology, University Hospital of Tampere.
My deep gratitude goes to the entire staff working there and the professor of the department, Timo Paavonen, M.D., Ph.D.
I am greatly indebt to my supervisors, Docent Hannu Haapasalo, M.D., Ph.D. for his consistent encouragement in the field of science, and Professor Ylermi Soini, M.D., Ph.D., the most efficient and reliable researcher. They both have introduced me to scientific thinking and working. Many thanks for your support and patience.
I thank Professor Seppo Parkkila, M.D., Ph.D. and Docent Anna-Kaisa Parkkila, M.D., Ph.D. for their work as the members of the supervisory committee and collaborators. They have both given me wise advice and new ideas.
I appreciate the time, constructive criticism and suggestions given by Professor Riitta Herva, M.D., Ph.D, and Docent Olli Lohi, M.D., Ph.D, the official referees of this manuscript.
I wish to thank my collaborators, Professors Hannu Kalimo, M.D., Ph.D, Vuokko Kinnula, M.D., Ph.D, Silvia Pastorekova, M.D., Ph.D, Jaromir Pastorek, M.D., Ph.D, Abdul Waheed, M.D., Ph.D, and William S. Sly, M.D., Ph.D. for their valuable co-work. I sincerely thank Docents Leo Paljärvi, M.D., Ph.D, Pauli Helén, M.D., Ph.D, Jukka Laine, M.D., Ph.D, and Anders Paetau, M.D., Ph.D for their expertise. I would like to thank also Sally Järvelä, M.D., Ph.D, Pauli Sallinen, M.D., Ph.D, Miia Jansson M.D., and Anssi Niemelä, M.D. Especially I acknowledge Miikka Korja, M.D., Ph.D, who has taught me that only the sky is the limit.
Special thanks to Mrs Reija Randen, Mrs Eila Pohjola, Ms Aija Parkkinen, Mrs Aulikki Lehmunen, Mrs Riitta Koivisto, Mr Jorma Lampinen, Mrs Päivi Koukkula and Mr Manu Tuovinen for skillful, technical assistance. I also thank Docent Mikko Arola, M.D., Ph.D., for his expertise on pediatric oncology in the third manuscript. I thank Nick Bolton, Ph.D. for revising the first study.Prakash Oommen, M.D. and Mike Nelson, Ph.D. are acknowledged for their help in revising the language of the second manuscript. The Proofreading247 Team is acknowledged for revising this thesis.
My parents Liisa and Heimo I would like to thank for their love. They have encouraged me to study medicine and kept my feet on the ground when needed. I am grateful to my sisters Hannele and Katri and their families for support, kindness and being interested in my work. I warmly thank all my friends for great moments and relaxing company.
This study was financially supported by the Nona and Kullervo Väre Foundation, the Finnish Medical Society, Competitive Research Funding of the Tampere Medical Research Fund of Tampere University Hospital (Grants 9L067, 9J013 and 9M010), by the Irja Karvonen Cancer Trust, by the Orion-Farmos Research Foundation, the EVO foundation of the Northern Savo
district, the Finnish Cancer Society, the anti-tuberculous association of Finland, EU 6th Framework programme (DeZnIT), and the Kevo funding of Kuopio University Hospital. They are all
acknowledged.
And the last and the dearest thanks go to my husband, Joonas. Never have I met such a person, who is so enthusiastic about research. Joonas has pushed me forward when needed and supported me every step of the way. There are no words to describe the gratitude. Thank you for your patience and love.
Tampere, August 2011
Kristiina Nordfors
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