Novel cancer-related regulatory targets for the signalling sphingolipids sphingosine-1-phosphate and sphingosylphosphorylcholine

The signalling sphingolipid sphingosine-1-phosphate (S1P) is necessary for development of the immune system and vasculature and on a cellular level regulates migration, proliferation and survival. Due to these traits S1P has an important role in cancer biology. It is considered a primarily cancer-promoting factor and the enzyme which produces it, sphingosine kinase (SphK), is often over-expressed in tumours. S1P is naturally present in the blood, lymph, tissue fluids and cell cytoplasm and functions through its cell surface receptors (S1P1-5) and as an intracellular second messenger. Sphingosylphosphorylcholine (SPC) is closely related to S1P and has similar regulatory functions but has not been extensively studied. Both S1P and SPC are able to evoke either stimulatory or inhibitory effects on cancer cells depending on the context. The aim of this thesis work was to study novel regulatory targets of S1P and SPC, which mediate the effects of S1P/SPC signalling on cancer cell behaviour. The investigated targets are the transcription factor hypoxia-inducible factor 1 (HIF-1), the intermediate filament protein vimentin and components of the Hippo signalling pathway. HIF-1 has a central role in cancer biology, as it regulates a multitude of cancer-related genes and is potently activated by intratumoural hypoxia through stabilization of the regulatory subunit HIF-1α. Tumours typically harbour high HIF-1α levels and HIF-1, in turn, facilitates tumour angiogenesis and metastasis and regulates cancer cell metabolism. We found S1P to induce follicular thyroid cancer cell migration in normal oxygen conditions by increasing HIF-1α synthesis and stability and subsequently HIF-1 activity. Vimentin is a central regulator of cell motility and is also commonly over-expressed in cancers. Vimentin filaments form a cytoskeletal network in mesenchymal cells as well as epithelial cancer cells which have gone through epithelial-mesenchymal transition (EMT). Vimentin is heavily involved in cancer cell invasion and gives tumours metastatic potential. We saw both S1P and SPC induce phosphorylation of vimentin monomers and reorganization of the vimentin filament network in breast and anaplastic thyroid cancer cells. We also found vimentin to mediate the anti-migratory effect of S1P/SPC on these cells. The Hippo pathway is a novel signalling cascade which controls cancer-related processes such as cellular proliferation and survival in response to various extracellular signals. The core of the pathway consists of the transcriptional regulators YAP and TAZ, which activate predominantly cancer-promoting genes, and the tumour suppressive kinases Lats1 and Lats2 which inhibit YAP/TAZ. Increased YAP expression and activity has been reported for a wide variety of cancers. We found SPC to regulate Hippo signalling in breast cancer cells in a two-fold manner through effects on phosphorylation status, activity and/or expression of YAP and Lats2. In conclusion, this thesis reveals new details of the signalling function of S1P and SPC and regulation of the central oncogenic factors HIF-1 and vimentin as well as the novel cancer-related pathway Hippo.

Pretraining Convolutional Neural Networks for Visual Recognition

Convolutional Neural Networks (CNN) have become the state-of-the-art methods on many large scale visual recognition tasks. For a lot of practical applications, CNN architectures have a restrictive requirement: A huge amount of labeled data are needed for training. The idea of generative pretraining is to obtain initial weights of the network by training the network in a completely unsupervised way and then fine-tune the weights for the task at hand using supervised learning. In this thesis, a general introduction to Deep Neural Networks and algorithms are given and these methods are applied to classification tasks of handwritten digits and natural images for developing unsupervised feature learning. The goal of this thesis is to find out if the effect of pretraining is damped by recent practical advances in optimization and regularization of CNN. The experimental results show that pretraining is still a substantial regularizer, however, not a necessary step in training Convolutional Neural Networks with rectified activations. On handwritten digits, the proposed pretraining model achieved a classification accuracy comparable to the state-of-the-art methods.

The role of diaspora networks in opportunity exploitation by ethnic entrepreneurs in Finland

The thesis explores the role of diaspora network in opportunity exploitation by ethnic entrepreneurs in Finland. The purpose of this study is to how ethnic entrepreneurs in Finland can exploit diaspora networks and how significant support of these networks in comparison with governmental and other official institutional support. Increased mobility of the global population and number of immigrants all around the world contribute into interest of academics to this topic. At the same time, in comparison with other European countries for Finland this phenomenon is new. However, increasing number of immigrants add to academic interest to this topic. The theoretical background of this thesis consists of the collection of studies done on diaspora networks and ethnic entrepreneurs as internationally as in Finland. The concept of cooperation between diaspora and ethnic entrepreneurs describes how diaspora can support ethnic entrepreneur and emphasize importance of diaspora ties for business. At the end of the theoretical section theoretical a special grid was proposed as summary of the academic literature review. The empirical research for this study is based on the interviews with five ethnic entrepreneurs in Finland. Empirical data was analyzed and compared with the similar studies done internationally. During the interviews analyses were stressed aspects of the significance of governmental and other official institutional support. During the interviews analyses were stressed aspects of the significance of the governmental and other official institutional support. According to the main findings diaspora can play positive and in some cases crucial role in the business of ethnic entrepreneurs in Finland. Moreover, diaspora can be a facilitator of internationalization of ethnic entrepreneurs. At the same time, there are several factors which might increase or decrease role of diaspora. The ways of the utilization of diaspora network were combined in the empirical grid. The study enhance understanding of the challenges of ethnic entrepreneurs and provides certain recommendations for the policy makers, ethnic entrepreneurs and managers of official institutions involved in cooperation with ethnic entrepreneurs

The Role Of Social Networks In New Venture Internationalization: Case Of Russian And Finnish Firms

The purpose of current master thesis research is to investigate the role of social networks in internationalization of Russian and Finnish firms. Literature review of existing empirical researches on the topic is conducted in order to identify the gap, which is fulfilled by empirical research of 4 Russian and 1 Finnish firm that have established international operations no later than 8 years since their foundation. In-depth semi-structured interviews have shown that business network has been an influencing factor in firms’ internationalization and that even if social network is not the driver of internationalization, it becomes important when a company has established international presence and is working on its enlargement. The study has both theoretical and practical contribution by contributing to research of Russian and Finnish firms’ internationalization and by showing examples of successful foreign market entry of companies from different industries. General practical implication of current thesis is that it shows the efficient ways of entrepreneurs’ social network usage in business development in international scope.

Managing Finnish-Russian Business Relationships and Networks During Conflicts

This thesis examines management of business relationships during conflicts. The context of this study is the international political conflict which started in 2013 and is still affecting international trade relations in 2016. More specifically, this study researches the effects of the conflict in Finnish-Russian trade. The research aim is to identify the implications of a political conflict in the Finnish-Russian business relationships and networks. Furthermore, the study will explore how does a company adapt or overcome the challenges and barriers posed by the international business environment. This research combines relevant theories in management of business relationships and networks in order to review the research data through a critical research frame. The theoretical frameworks are different structures of business relationship development processes, various stages of interaction, and characteristics and functions of business relationships. Moreover, this study will examine the effect of interdependency, commitment and trust in trade relations. Also, what are the important exchange processes and how do these processes affect business relationship and overall performance of joint business operations. Qualitative single case study method was used in this research. Case company was a Finnish multinational company. To understand the changes, the data was collected and analysed through process research approach by pattern-matching and drawing temporal bracketing over two different periods of time, first period in years 2011-2013 and second period in years 2014-2016. Empirical data was collected through a semi-structured interview and additional data was collected from internal and external secondary data sources. The findings of the study confirmed the relationship between trade and conflict. However, the effects are not significant for a company in grocery retail industry which has had earlier experience in Russia and has managed its business relationships and operations effectively. Macroeconomic factors affect companies operating in foreign dynamic markets and in order to sustain changes and to adapt, companies should invest in their business relationships. Trust-based relationships and a higher level of commitment allow companies to have more efficient and beneficial outcomes before and during uncertainty. Furthermore, well-maintained and coordinated business relationships provide the ability to adapt and overcome challenges during uncertainty. Such relationships have information, financial and social exchange processes which allow the partnering firms to have successful business relationship management in dynamic market environments.