Free Prostate-specific Antigen Forms and Kallikrein-related Peptidase 2: Tools for Prostate Cancer Diagnostics

Prostate-specific antigen (PSA) is a marker that is commonly used in estimating prostate cancer risk. Prostate cancer is usually a slowly progressing disease, which might not cause any symptoms whatsoever. Nevertheless, some cases of cancer are aggressive and need to be treated before they become life-threatening. However, the blood PSA concentration may rise also in benign prostate diseases and using a single total PSA (tPSA) measurement to guide the decision on further examinations leads to many unnecessary biopsies, over-detection, and overtreatment of indolent cancers which would not require treatment. Therefore, there is a need for markers that would better separate cancer from benign disorders, and would also predict cancer aggressiveness. The aim of this study was to evaluate whether intact and nicked forms of free PSA (fPSA-I and fPSA-N) or human kallikrein-related peptidase 2 (hK2) could serve as new tools in estimating prostate cancer risk. First, the immunoassays for fPSA-I and free and total hK2 were optimized so that they would be less prone to assay interference caused by interfering factors present in some blood samples. The optimized assays were shown to work well and were used to study the marker concentrations in the clinical sample panels. The marker levels were measured from preoperative blood samples of prostate cancer patients scheduled for radical prostatectomy. The association of the markers with the cancer stage and grade was studied. It was found that among all tested markers and their combinations especially the ratio of fPSA-N to tPSA and ratio of free PSA (fPSA) to tPSA were associated with both cancer stage and grade. They might be useful in predicting the cancer aggressiveness, but further follow-up studies are necessary to fully evaluate the significance of the markers in this clinical setting. The markers tPSA, fPSA, fPSA-I and hK2 were combined in a statistical model which was previously shown to be able to reduce unnecessary biopsies when applied to large screening cohorts of men with elevated tPSA. The discriminative accuracy of this model was compared to models based on established clinical predictors in reference to biopsy outcome. The kallikrein model and the calculated fPSA-N concentrations (fPSA minus fPSA-I) correlated with the prostate volume and the model, when compared to the clinical models, predicted prostate cancer in biopsy equally well. Hence, the measurement of kallikreins in a blood sample could be used to replace the volume measurement which is time-consuming, needs instrumentation and skilled personnel and is an uncomfortable procedure. Overall, the model could simplify the estimation of prostate cancer risk. Finally, as the fPSA-N seems to be an interesting new marker, a direct immunoassay for measuring fPSA-N concentrations was developed. The analytical performance was acceptable, but the rather complicated assay protocol needs to be improved until it can be used for measuring large sample panels.

Puun ja turpeen seospolton vaikutus tuhkan hyötykäyttökohteisiin

Työn tavoitteena oli selvittää puun ja turpeen seospolton vaikutukset tuhkien hyötykäyttökohteiden valintaan laitoksella tehtävien koeajojen ja kustannus- sekä SWOT-analyysien avulla. Lisäksi tavoitteena oli selvittää lainsäädännön vaikutukset tuhkien hyötykäyttöön. Kustannusanalyysissä tarkasteltiin tuhkien hyödyntämisen nykytilan lisäksi rakeistuslaitosinvestointia ja selvitettiin eri hyötykäyttövaihtoehtojen etuja ja haittoja. Lainsäädäntö vaikuttaa oleellisesti tuhkien hyötykäyttöön. Hyötykäyttöä säädellään sekä kansallisella että EU-tasolta tulevalla lainsäädännöllä. Ympäristölainsäädännön ja etenkin jätelainsäädännön kokonaisuudistuksen myötä myös hyötykäyttöä koskevat lainsäädäntö uudistui. Energiantuotannon tuhkat tulivat jäteverolain piiriin ja lannoiteasetuksenuudistuksella pyrittiin helpottamaan tuhkien lannoitekäyttöä. Myös jäteluokittelu ja sen päättyminen tuhkien osalta vaikuttaa olennaisesti tuhkien käsittelymenetelmien ja hyödyntämisen kannattavuuteen. Jäteluokituksen päättyminen voi viedä tuhkat kemikaalilainsäädännön piiriin. Kustannus- ja SWOT-analyysissä selvitettiin tuhkien hyödyntämisen kannalta keskeiset kustannustekijät. Rakeistuslaitosinvestoinnissa huomioitiin erilaiset tuhkien käsittelymäärät ja niiden vaikutukset kustannuksiin ja investoinnin kannattavuuteen. SWOT-analyysin avulla selvitettiin hyödyntämisen vahvuudet, heikkoudet, mahdollisuudet ja uhkatekijät. Polttoainesuhteella ei ollut poissulkevaa vaikutusta tuhkien hyötykäyttövalintaan. Lentotuhkat soveltuivat parhaiten lannoitehyötykäyttöön ja pohjatuhkat maarakennushyötykäyttöön. Rakeistuslaitosinvestointi olisi kannattava etenkin suuremmilla tuhkamäärillä.

The Roots of Neurofibromas in Neurofibromatosis 1 — A Question of Multipotency, Differentiation and Hiding

Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome that affects about 1 in 3500 individuals worldwide. NF1 is caused by mutations in the NF1 gene that encodes the tumor suppressor protein neurofibromin, an inactivator of the Ras oncogene. The hallmarks of NF1 include pigmentary lesions of the skin, Lisch nodules of the iris and cutaneous neurofibromas. Cutaneous neurofibromas are benign tumors composed of all the cell types of normal peripheral nerve. The traditional view of neurofibroma development has been that cutaneous neurofibromas arise from the disruption of the small nerve tributaries of the skin and subsequent proliferation of the resident cells. The second hit mutation in the NF1 gene has been considered as a prerequisite for neurofibroma development. The second hit is detectable in a subpopulation of primary Schwann cells cultured from neurofibromas. This thesis challenges the traditional concept of neurofibroma development. The results show that cutaneous neurofibromas are intimately associated with hair follicular structures and contain multipotent precursor cells (NFPs), suggesting that neurofibromas may arise from the multipotent cells which reside in hair follicles. Furthermore, this study presents that neurofibroma-derived Schwann cells that harbor bi-allelic inactivation in the NF1 gene express HLA class II genes and may act as nonprofessional antigen presenting cells. The CD4- and FoxP3-positive cells detected in cutaneous neurofibromas suggest that these cells may represent regulatory T cells (Tregs) which interact with HLA II –positive cells and aid the tumor cells in hiding from the immune system and are thus mediators of immune tolerance. This thesis also investigated neurofibroma development in the oral cavity and the use of different biomarkers to characterize cellular differentiation in neurofibromas. The results revealed that oral neurofibromas are not rare, but they usually appear as solitary lesions contrary to multiple cutaneous neurofibromas and present high heterogeneity within and between tumors. The use of class III beta-tubulin as a marker for neuronal differentiation led to an unexpected finding showing that multiple cell types express class III beta-tubulin during mitosis. The increased understanding of the multipotency of tumor cells, cellular differentiation and ability to hide from immune system will aid in the development of future treatments. Specifically, targeting Tregs in NF1 patients could provide a novel therapeutic approach to interfere with the development of neurofibromas.

Strategic alliances as an international entry strategy: Finnish cleantech SMEs and the Indian market

The demand for environmental technologies, also called cleantech, is growing globally but the need is especially high in emerging markets such as India where the rising economy and rapid industrialisation have led to increasing energy needs and environmental degradation. The market is of great potential also for the Finnish cleantech cluster that represents advanced expertise in several fields of environmental technologies. However, most of the Finnish companies in the field are SMEs that face challenges in their internationalisation due to their limited resources. The objective of this study was to estimate, whether strategic alliances could be an efficient entry strategy for Finnish cleantech SMEs entering the Indian market. This was done by studying what are the key factors influencing the international entry mode decision of Finnish cleantech SMEs, what are the major factors affecting the entry of Finnish cleantech SMEs to the Indian market and how do Finnish cleantech SMEs use strategic alliances in their internationalisation process. The study was realised as a qualitative multi-case study through theme interviews of Finnish cleantech SME representatives. The results indicated that Finnish cleantech SMEs prefer to enter international markets through non-equity and collaborative modes of entry. These entry modes are chosen because of the small size and limited resources of companies, but also because they want to protect their innovative technologies from property rights violations. India is an attracting market for Finnish cleantech SMEs mainly because of its size and growth, but insufficient environmental regulation and high import tariffs have hindered entry to the market. Finnish cleantech SMEs commonly use strategic alliances in their internationalisation process but the use is rather one-sided. Most of the formed strategic alliances are low-commitment, international contractual agreement in sales and distribution. Alliance partner selection receives less attention. In the future, providing Finnish cleantech SMEs with international experience and training could help in diversifying the use of strategic alliances and increase their benefits to SME internationalisation.

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