Genetically Engineered Oncolytic Adenoviruses for the Treatment of Kidney and Breast Cancer

Metastatic kidney and breast cancer are devastating diseases currently lacking efficient treatment options. One promising developmental approach in cancer treatment are oncolytic adenoviruses, which have demonstrated excellent safety in many clinical trials. However, antitumor efficacy needs to be improved in order to make oncolytic viruses a viable treatment alternative. To be able to follow oncolytic virus replication in vivo, we set up a non-invasive imaging system based on coinjection of a replication deficient luciferase expressing virus and a replication competent virus. The system was validated in vitro and in vivo and used in other projects of the thesis. In another study we showed that capsid modifications on adenoviruses result in enhanced gene transfer and increased oncolytic effect on renal cancer cells in vitro. Moreover, capsid modified oncolytic adenoviruses demonstrated significantly improved antitumor efficacy in murine kidney cancer models. To transcriptionally target kidney cancer tissue we evaluated two hypoxia response elements for their usability as tissue specific promoters using a novel dual luciferase imaging system. Based on the results of the promoter evaluation and the studies on capsid modifications, we constructed a transcriptionally and transductionally targeted oncolytic adenovirus armed with an antiangiogenic transgene for enhanced renal cell cancer specificity and improved antitumor efficacy. This virus exhibited kidney cancer specific replication and significantly improved antitumor effect in a murine model of intraperitoneal disseminated renal cell cancer. Cancer stem cells are thought to be resistant to conventional cancer drugs and might play an important role in breast cancer relapse and the formation of metastasis. Therefore, we examined if capsid modified oncolytic adenoviruses are able to kill these cells proposed to be breast cancer initiating. Efficient oncolytic effect and significant antitumor efficacy on tumors established with breast cancer initiating cells was observed, suggesting that oncolytic adenoviruses might be able to prevent breast cancer relapse and could be used in the treatment of metastatic disease. In conclusion, the results presented in this thesis suggest that genetically engineered oncolytic adenoviruses have great potential in the treatment of metastatic kidney and breast cancer.

Role of heat treatment in the processing and quality of oat flakes

This thesis reports on investigations into the influence of heat treatment on the manufacturing of oat flakes. Sources of variation in the oat flake quality are reviewed, including the whole chain from the farm to the consumer. The most important quality parameters of oat flakes are the absence of lipid hydrolysing enzymes, specific weight, thickness, breakage (fines), water absorption. Flavour, colour and pasting properties are also important, but were not included in the experimental part of this study. Of particular interest was the role of heat processing. The first possible heat treatment may occur already during grain drying, which in Finland generally happens at the farm. At the mill, oats are often kilned to stabilise the product by inactivating lipid hydrolysing enzymes. Almost invariably steaming is used during flaking, to soften the groats and reduce flake breakage. This thesis presents the use of a material science approach to investigating a complex system, typical of food processes. A combination of fundamental and empirical rheological measurements was used together with a laboratory scale process to simulate industrial processing. The results were verified by means of industrial trials. Industrially produced flakes at three thickness levels (nominally 0.75, 0.85 and 0.90 mm) were produced from kilned and unkilned oat groats, and the flake strength was measured at different moisture contents. Kilning was not found to significantly affect the force required to puncture a flake with a 2mm cylindrical probe, which was taken as a measure of flake strength. To further investigate how heat processing contributes to flake quality, dynamic mechanical analysis was used to characterise the effect of heat on the mechanical properties of oats. A marked stiffening of the groat, of up to about 50% increase in storage modulus, was observed during first heating at around 36 to 57°C. This was also observed in tablets prepared from ground groats and extracted oat starch. This stiffening was thus attributed to increased adhesion between starch granules. Groats were steamed in a laboratory steamer and were tempered in an oven at 80 110°C for 30 90 min. The maximum force required to compress the steamed groats to 50% strain increased from 50.7 N to 57.5 N as the tempering temperature was increased from 80 to 110°C. Tempering conditions also affected water absorption. A significantly higher moisture content was observed for kilned (18.9%) compared to unkilned (17.1%) groats, but otherwise had no effect on groat height, maximum force or final force after a 5 s relaxation time. Flakes were produced from the tempered groats using a laboratory flaking machine, using a roll gap of 0.4 mm. Apart from specific weight, flake properties were not influenced by kilning. Tempering conditions however had significant effects on the specific weight, thickness and water absorption of the flakes, as well as on the amount of fine material (<2 mm) produced during flaking. Flake strength correlated significantly with groat strength and flake thickness. Trial flaking at a commercial mill confirmed that groat temperature after tempering influenced water absorption. Variation in flake strength was observed , but at the groat temperatures required to inactivate lipase, it was rather small. Cold flaking of groats resulted in soft, floury flakes. The results presented in this thesis suggest that heating increased the adhesion between starch granules. This resulted in an increase in the stiffness and brittleness of the groat. Brittle fracture, rather than plastic flow, during flaking could result in flaws and cracks in the flake. These would be expected to increase water absorption. This was indeed observed as tempering temperature increased. Industrial trials, conducted with different groat temperatures, confirmed the main findings of the laboratory experiments. The approach used in the present study allowed the systematic study of the effect of interacting process parameters on product quality. There have been few scientific studies of oat processing, and these results can be used to understand the complex effects of process variables on flake quality. They also offer an insight into what happens as the oat groat is deformed into a flake.

Beatific Enjoyment in Scholastic Philosophy and Theology: 1240-1335

This dissertation examines the concept of beatific enjoyment (fruitio beatifica) in scholastic theology and philosophy in the thirteenth and early fourteenth century. The aim of the study is to explain what is enjoyment and to show why scholastic thinkers were interested in discussing it. The dissertation consists of five chapters. The first chapter deals with Aurelius Augustine's distinction between enjoyment and use and the place of enjoyment in the framework of Augustine's view of the passions and the human will. The first chapter also focuses upon the importance of Peter Lombard's Sentences for the transmission of Augustine's treatment of enjoyment in scholastic thought as well as upon Lombard's understanding of enjoyment. The second chapter treats thirteenth-century conceptions of the object and psychology of enjoyment. Material for this chapter is provided by the writings - mostly Sentences commentaries - of Alexander of Hales, Albert the Great, Bonaventure, Thomas Aquinas, Peter of Tarentaise, Robert Kilwardby, William de la Mare, Giles of Rome, and Richard of Middleton. The third chapter inspects early fourteenth-century views of the object and psychology of enjoyment. The fourth chapter focuses upon discussions of the enjoyment of the Holy Trinity. The fifth chapter discusses the contingency of beatific enjoyment. The main writers studied in the third, fourth and fifth chapters are John Duns Scotus, Peter Aureoli, Durandus of Saint Pourçain, William of Ockham, Walter Chatton, Robert Holcot, and Adam Wodeham. Historians of medieval intellectual history have emphasized the significance of the concept of beatific enjoyment for understanding the character and aims of scholastic theology and philosophy. The concept of beatific enjoyment was developed by Augustine on the basis of the insight that only God can satisfy our heart's desire. The possibility of satisfying this desire requires a right ordering of the human mind and a detachment of the will from the relative goals of earthly existence. Augustine placed this insight at the very foundation of the notion of Christian learning and education in his treatise On Christian Doctrine. Following Augustine, the twelfth-century scholastic theologian Peter Lombard made the concept of enjoyment the first topic in his plan of systematic theology. The official inclusion of Lombard's Sentences in the curriculum of theological studies in the early universities stimulated vigorous discussions of enjoyment. Enjoyment was understood as a volition and was analyzed in relation to cognition and other psychic features such as rest and pleasure. This study shows that early fourteenth-century authors deepened the analysis of enjoyment by concentrating upon the relationship between enjoyment and mental pleasure, the relationship between cognition and volition, and the relationship between the will and the beatific object (i.e., the Holy Trinity). The study also demonstrates the way in which the idea of enjoyment was affected by changes in the method of theological analysis - the application of Aristotelian logic in a Trinitarian context and the shift from virtue ethics to normative ethics.

Ethics in a Technological World : Framing the Questions and Three Approaches

This study addresses the following question: How to think about ethics in a technological world? The question is treated first thematically by framing central issues in the relationship between ethics and technology. This relationship has three distinct facets: i) technological advance poses new challenges for ethics, ii) traditional ethics may become poorly applicable in a technologically transformed world, and iii) the progress in science and technology has altered the concept of rationality in ways that undermine ethical thinking itself. The thematic treatment is followed by the description and analysis of three approaches to the questions framed. First, Hans Jonas s thinking on the ontology of life and the imperative of responsibility is studied. In Jonas s analysis modern culture is found to be nihilistic because it is unable to understand organic life, to find meaning in reality, and to justify morals. At the root of nihilism Jonas finds dualism, the traditional Western way of seeing consciousness as radically separate from the material world. Jonas attempts to create a metaphysical grounding for an ethic that would take the technologically increased human powers into account and make the responsibility for future generations meaningful and justified. The second approach is Albert Borgmann s philosophy of technology that mainly assesses the ways in which technological development has affected everyday life. Borgmann admits that modern technology has liberated humans from toil, disease, danger, and sickness. Furthermore, liberal democracy, possibilities for self-realization, and many of the freedoms we now enjoy would not be possible on a large scale without technology. Borgmann, however, argues that modern technology in itself does not provide a whole and meaningful life. In fact, technological conditions are often detrimental to the good life. Integrity in life, according to him, is to be sought among things and practices that evade technoscientific objectification and commodification. Larry Hickman s Deweyan philosophy of technology is the third approach under scrutiny. Central in Hickman s thinking is a broad definition of technology that is nearly equal to Deweyan inquiry. Inquiry refers to the reflective and experiential way humans adapt to their environment by modifying their habits and beliefs. In Hickman s work, technology consists of all kinds of activities that through experimentation and/or reflection aim at improving human techniques and habits. Thus, in addition to research and development, many arts and political reforms are technological for Hickman. He argues for recasting such distinctions as fact/value, poiesis/praxis/theoria, and individual/society. Finally, Hickman does not admit a categorical difference between ethics and technology: moral values and norms need to be submitted to experiential inquiry as well as all the other notions. This study mainly argues for an interdisciplinary approach to the ethics of technology. This approach should make use of the potentialities of the research traditions in applied ethics, the philosophy of technology, and the social studies on science and technology and attempt to overcome their limitations. This study also advocates an endorsement of mid-level ethics that concentrate on the practices, institutions, and policies of temporal human life. Mid-level describes the realm between the instantaneous and individualistic micro-level and the universal and global macro level.

Ihanteena vapaaehtoisuus : Diakoniatyö Porvoon hiippakunnan seurakunnissa, erityisesti Iitin ja Tampereen rovastikunnissa vuosina 1897-1923

The Ideal of Volunteerism. An institutional approach to social welfare work in the parishes of the Diocese of Porvoo especially in the deaneries of Iitti and Tampere, Finland, in the years 1897-1923 Social welfare work (also known as diakonia) has achieved a high status in the Evangelical Lutheran Church of Finland. Since 1944, provisions of the Finnish Church Act have obliged each parish to employ at least one deacon or deaconess. This study sets out to examine the background and development of social welfare work in the Evangelical Lutheran Church of Finland from the 1890s to the 1920s, by which time social welfare work had become an established practice in the Church. The study investigates the development of social welfare work on the level of parishes. The main source material was collected from sixteen parishes in the Diocese of Porvoo especially in the deaneries of Iitti and Tampere. In the 1890s, two approaches were used in church social work in Finland. The dioceses of Kuopio, Savonlinna and Turku pursued a congregational approach to social work, while the Diocese of Porvoo employed an institutional approach, mainly because of the influence of Bishop Herman Råbergh. This study charts the formation of church social work in Finnish parishes, which took place during a period of tension between the two approaches. The institutional approach to church social work adopted by the Diocese of Porvoo was based on the German system of Asisters= houses@, in which deaconess institutes sent parish sisters to serve congregations. The parish or, in many cases, a separate association dedicated to church social work paid an annual fee to the deaconess institute, which took care of the parish sisters in old age. In the institutional approach, volunteers were recruited to carry out church social work. It was considered as inappropriate to use tax revenue or other public funding for church social work, which was supposed to be based on Christian love for one=s fellow humans and the needy, and for which only voluntary financial contributions were supposed to be used. In the congregational approach, church social work was directly based on the efforts of the parish. The approach relied on the administrative bodies of parishes and the Church, and tax revenue collected by the parishes, as well as other forms of public funding, could be used to carry out the social welfare work. The parishes employed deacons and deaconesses and paid their salaries. The approaches described above were not pursued in their ideal forms; instead, many variations existed. However, in principle, the social welfare work undertaken by the parishes of the Diocese of Porvoo was based on the institutional approach, while the congregational approach was largely employed elsewhere in Finland. Both of the approaches were viable. Parishes began to employ deacons and deaconesses as of the 1890s. The number of parishes which had hired a deacon or deaconess increased particularly in the 1910s, by which time 60% of parishes had employed one. This level was maintained until 1944 when each parish in the Evangelical Lutheran Church of Finland was obliged to employ a deacon or deaconess. Deaconesses usually worked as travelling nurses. The autonomous status of Finland as part of the Russian Empire did not give Finns the right to develop legislation on social affairs and health care. Consequently, the legislation process did not begin until Finland gained its independence in 1917. The social welfare work carried out by parishes and a number of voluntary organisations satisfied the emerging need for medical treatment in Finnish society. Neither the government nor the municipalities had sufficient resources to provide this treatment. Based on the ideal of volunteerism, the institutional social work practiced in the Diocese of Porvoo ran into serious difficulties at the end of the First World War. Because of severe inflation, prices began to rise as of 1915 and tripled in 1917-1918. During the same period, Finnish society went through a deep crisis which escalated into Civil War in spring 1918. This period of economic and social turmoil marked a turning-point which led to a weakening of the status of institutional social work in parishes. Voluntary efforts were no longer sufficient to maintain the practice. In contrast, congregational social work, which was based on public funding, was able to cope with the changes and survived the crisis. The approach to social work adopted by the Diocese of Porvoo turned out to be no more than a brief detour in the history of social work in the Evangelical Lutheran Church of Finland. At the start of the 1920s, the two approaches were integrated into a common vision for establishing church social work as a statutory practice in parishes.

Towards a Critique of the Concept of the Right to Self-Determination in Africa : A Conceptual Examination and the Cases of Western Sahara, Southern Sudan and Eritrea

This thesis examines the right to self-determination which is a norm used for numerous purposes by multiple actors in the field of international relations, with relatively little clarity or agreement on the actual and potential meaning of the right. In international practice, however, the main focus in applying the right has been in the context of decolonization as set by the United Nations in its early decades. Thus, in Africa the right to self-determination has traditionally implied that the colonial territories, and particularly the populations within these territories, were to constitute the people who were entitled to the right. That is, self-determination by decolonization provided a framework for the construction of independent nation-states in Africa whilst other dimensions of the right remained largely or totally neglected. With the objective of assessing the scope, content, developments and interpretations of the right to self-determination in Africa, particularly with regard to the relevance of the right today, the thesis proceeds on two fundamental hypotheses. The first is that Mervyn Frost s theory of settled norms, among which he lists the right to self-determination, assumes too much. Even if the right to self-determination is a human right belonging to all peoples stipulated, inter alia, in the first Article of the 1966 International Human Rights Covenants, it is a highly politicized and context-bound right instead of being settled and observed in a way that its denial would need special justification. Still, the suggested inconsistency or non-compliance with the norm of self-determination is not intended to prove the uselessness or inappropriateness of the norm, but, on the contrary, to invite and encourage debate on the potential use and coverage of the right to self-determination. The second hypothesis is that within the concept of self-determination there are two normative dimensions. One is to do with the idea and practice of statehood, the nation and collectivity that may decide to conduct itself as an independent state. The other one is to do with self-determination as a human right, as a normative condition, to be enjoyed by people and peoples within states that supersedes state authority. These external and internal dimensions need to be seen as complementary and co-terminous, not as mutually exclusive alternatives. The thesis proceeds on the assumption that the internal dimension of the right, with human rights and democracy at its core, has not been considered as important as the external. In turn, this unbalanced and selective interpretation has managed to put the true normative purpose of the right making the world better and bringing more just polity models into a somewhat peculiar light. The right to self-determination in the African context is assessed through case studies of Western Sahara, Southern Sudan and Eritrea. The study asks what these cases say about the right to self-determination in Africa and what their lessons learnt could contribute to the understanding and relevance of the right in today s Africa. The study demonstrates that even in the context of decolonization, the application of the right to self-determination has been far from the consistent approach supposedly followed by the international community: in many respects similar colonial histories have easily led to rather different destinies. While Eritrea secured internationally recognized right to self-determination in the form of retroactive independence in 1993, international recognition of distinct Western Sahara and Southern Sudan entities is contingent on complex and problematic conditions being satisfied. Overall, it is a considerable challenge for international legality to meet empirical political reality in a meaningful way, so that the universal values attached to the norm of self-determination are not overlooked or compromised but rather reinforced in the process of implementing the right. Consequently, this thesis seeks a more comprehensive understanding of the right to self-determination with particular reference to post-colonial Africa and with an emphasis on the internal, human rights and democracy dimensions of the norm. It is considered that the right to self-determination cannot be perceived only as an inter-state issue as it is also very much an intra-state issue, including the possibility of different sub-state arrangements exercised under the right, for example, in the form of autonomy. At the same time, the option of independent statehood achieved through secession remains a mode of exercising and part of the right to self-determination. But in whatever form or way applied, the right to self-determination, as a normative instrument, should constitute and work as a norm that comprehensively brings more added value in terms of the objectives of human rights and democracy. From a normative perspective, a peoples right should not be allowed to transform and convert itself into a right of states. Finally, in light of the case studies of Western Sahara, Southern Sudan and Eritrea, the thesis suggests that our understanding of the right to self-determination should now reach beyond the post-colonial context in Africa. It appears that both the questions and answers to the most pertinent issues of self-determination in the cases studied must be increasingly sought within the postcolonial African state rather than solely in colonial history. In this vein, the right to self-determination can be seen not only as a tool for creating states but also as a way to transform the state itself from within. Any such genuinely post-colonial approach may imply a judicious reconsideration, adaptation or up-dating of the right and our understanding of it in order to render it meaningful in Africa today.

Essays in Philosophical Moral Psychology

The dissertation consists of four essays and a comprehensive introduction that discusses the topics, methods, and most prominent theories of philosophical moral psychology. I distinguish three main questions: What are the essential features of moral thinking? What are the psychological conditions of moral responsibility? And finally, what are the consequences of empirical facts about human nature to normative ethics? Each of the three last articles focuses on one of these issues. The first essay and part of the introduction are dedicated to methodological questions, in particular the relationship between empirical (social) psychology and philosophy. I reject recent attempts to understand the nature of morality on the basis of empirical research. One characteristic feature of moral thinking is its practical clout: if we regard an action as morally wrong, we either refrain from doing it even against our desires and interests, or else feel shame or guilt. Moral views seem to have a conceptual connection to motivation and emotions – roughly speaking, we can’t conceive of someone genuinely disapproving an action, but nonetheless doing it without any inner motivational conflict or regret. This conceptual thesis in moral psychology is called (judgment) internalism. It implies, among other things, that psychopaths cannot make moral judgments to the extent that they are incapable of corresponding motivation and emotion, even if they might say largely the words we would expect. Is internalism true? Recently, there has been an explosion of interest in so-called experimental philosophy, which is a methodological view according to which claims about conceptual truths that appeal to our intuitions should be tested by way of surveys presented to ordinary language users. One experimental result is that the majority of people are willing to grant that psychopaths make moral judgments, which challenges internalism. In the first article, ‘The Rise and Fall of Experimental Philosophy’, I argue that these results pose no real threat to internalism, since experimental philosophy is based on a too simple conception of the relationship between language use and concepts. Only the reactions of competent users in pragmatically neutral and otherwise conducive circumstances yield evidence about conceptual truths, and such robust intuitions remain inaccessible to surveys for reasons of principle. The epistemology of folk concepts must still be based on Socratic dialogue and critical reflection, whose character and authority I discuss at the end of the paper. The internal connection between moral judgment and motivation led many metaethicists in the past century to believe along Humean lines that judgment itself consists in a pro-attitude rather than a belief. This expressivist view, as it is called these days, has far-reaching consequences in metaethics. In the second essay I argue that perhaps the most sophisticated form of contemporary expressivism, Allan Gibbard’s norm-expressivism, according to which moral judgments are decisions or contingency plans, is implausible from the perspective of the theory of action. In certain circumstances it is possible to think that something is morally required of one without deciding to do so. Morality is not a matter of the will. Instead, I sketch on the basis of Robert Brandom’s inferentialist semantics a weak form of judgment internalism, according to which the content of moral judgment is determined by a commitment to a particular kind of practical reasoning. The last two essays in the dissertation emphasize the role of mutual recognition in the development and maintenance of responsible and autonomous moral agency. I defend a compatibilist view of autonomy, according to which agents who are unable to recognize right and wrong or act accordingly are not responsible for their actions – it is not fair to praise or blame them, since they lacked the relevant capacity to do otherwise. Conversely, autonomy demands an ability to recognize reasons and act on them. But as a long tradition in German moral philosophy whose best-known contemporary representative is Axel Honneth has it, both being aware of reasons and acting on them requires also the right sort of higher-order attitudes toward the self. Without self-respect and self-confidence we remain at the mercy of external pressures, even if we have the necessary normative competence. These attitudes toward the self, in turn, are formed through mutual recognition – we value ourselves when those who we value value us. Thus, standing in the right sort of relations of recognition is indirectly necessary for autonomy and moral responsibility. Recognition and valuing are concretely manifest in actions and institutions, whose practices make possible participation on an equal footing. Seeing this opens the way for a kind of normative social criticism that is grounded in the value of freedom and automomy, but is not limited to defending negative rights. It thus offers a new way to bridge the gap between liberalism and communitarianism.

Ecological impacts of Phlebiopsis gigantea biocontrol treatment against Heterobasidion spp. as revealed by fungal community profiling and population analyses

Wood decay fungi belonging to the species complex Heterobasidion annosum sensu lato are among the most common and economically important species causing root rot and stem decay in conifers of the northern temperate regions. New infections by these pathogens can be suppressed by tree stump treatments using chemical or biological control agents. In Finland, the corticiaceous fungus Phlebiopsis gigantea has been formulated into a commercial biocontrol agent called Rotstop (Verdera Ltd.). This thesis addresses the ecological impacts of Rotstop biocontrol treatment on the mycoflora of conifer stumps. Locally, fungal communities within Rotstop-treated and untreated stumps were analyzed using a novel method based on DGGE profiling of small subunit ribosomal DNA fragments amplified directly from wood samples. Population analyses for P. gigantea and H. annosum s.l. were conducted to evaluate possible risks associated with local and/or global distribution of the Rotstop strain. Based on molecular community profiling by DGGE, we detected a few individual wood-inhabiting fungal species (OTUs) that seemed to have suffered or benefited from the Rotstop biocontrol treatment. The DGGE analyses also revealed fungal diversity not retrieved by cultivation and some fungal sequence types untypical for decomposing conifer wood. However, statistical analysis of DGGE community profiles obtained from Rotstop-treated and untreated conifer stumps revealed that the Rotstop treatment had not caused a statistically significant reduction in the species diversity of wood-inhabiting fungi within our experimental forest plots. Locally, ISSR genotyping of cultured P. gigantea strains showed that the Rotstop biocontrol strain was capable of surviving up to six years within treated Norway spruce stumps, while in Scots pine stumps it was sooner replaced by successor fungal species. In addition, the spread of resident P. gigantea strains into Rotstop-treated forest stands seemed effective in preventing the formation of genetically monomorphic populations in the short run. On a global scale, we detected a considerable level of genetic differentiation between the interfertile European and North American populations of P. gigantea. These results strongly suggest that local biocontrol strains should be used in order to prevent global spread of P. gigantea and hybrid formation between geographically isolated populations. The population analysis for H. annosum s.l. revealed a collection of Chinese fungal strains that showed a high degree of laboratory fertility with three different allopatric H. annosum s.l. taxa. However, based on the molecular markers, the Chinese strains could be clearly affiliated with the H. parviporum taxonomical cluster, which thus appears to have a continuous distribution range from Europe through southern Siberia to northern China. Keywords: Rotstop, wood decay, DGGE, ISSR fingerprinting, ribosomal DNA