Choosing the Arranged One, Arranging the Chosen One – Imagining an Indian Modernity: Reconciling Love, Marriage and Family On and Off the Screen

This is a study on the changing practices of kinship in Northern India. The change in kinship arrangements, and particularly in intermarriage processes, is traced by analysing the reception of Hindi popular cinema. Films and their role and meaning in people´s lives in India was the object of my research. Films also provided me with a methodology for approaching my other subject-matters: family, marriage and love. Through my discussion of cultural change, the persistence of family as a core value and locus of identity, and the movie discourses depicting this dialogue, I have looked for a possibility of compromise and reconciliation in an Indian context. As the primary form of Indian public culture, cinema has the ability to take part in discourses about Indian identity and cultural change, and alleviate the conflicts that emerge within these discourses. Hindi popular films do this, I argue, by incorporating different familiar cultural narratives in a resourceful way, thus creating something new out of the old elements. The final word, however, is the one of the spectator. The “new” must come from within the culture. The Indian modernity must be imaginable and distinctively Indian. The social imagination is not a “Wild West” where new ideas enter the void and start living a life of their own. The way the young women in Dehra Dun interpreted family dramas and romantic movies highlights the importance of family and continuity in kinship arrangements. The institution of arranged marriage has changed its appearance and gained new alternative modes such as love cum arranged marriage. It nevertheless remains arranged by the parents. In my thesis I have offered a social description of a cultural reality in which movies act as a built-in part. Movies do not work as a distinct realm, but instead intertwine with the social realities of people as a part of a continuum. The social imagination is rooted in the everyday realities of people, as are the movies, in an ontological and categorical sense. According to my research, the links between imagination and social life were not so much what Arjun Appadurai would call global and deterritorialised, but instead local and conventional.

Doing marriage and parenthood: The division of household labour across two life course events

The current study is a longitudinal investigation into changes in the division of household labour across transitions to marriage and parenthood in the UK. Previous research has noted a more traditional division of household labour, with women performing the majority of housework, amongst spouses and couples with children. However, the bulk of this work has been cross-sectional in nature. The few longitudinal studies that have been carried out have been rather ambiguous about the effect of marriage and parenthood on the division of housework. Theoretically, this study draws on gender construction theory. The key premise of this theory is that gender is something that is performed and created in interaction, and, as a result, something fluid and flexible rather than fixed and stable. The idea that couples ‘do gender’ through housework has been a major theoretical breakthrough. Gender-neutral explanations of the division of household labour, positing rational acting individuals, have failed to explicate why women continue to perform an unequal share of housework, regardless of socio-economic status. Contrastingly, gender construction theory situates gender as the key process in dividing household labour. By performing and avoiding certain housework chores, couples fulfill social norms of what it means to be a man and a woman although, given the emphasis on human agency in producing and contesting gender, couples are able to negotiate alternative gender roles which, in turn, feed back into the structure of social norms in an ever-changing societal landscape. This study adds extra depth to the doing gender approach by testing whether or not couples negotiate specific conjugal and parent roles in terms of the division of household labour. Both transitions hypothesise a more traditional division of household labour. Data comes from the British Household Panel Survey, a large, nationally representative quantitative survey that has been carried out annually since 1991. Here, data tracks the same 776 couples at two separate time points – 1996 and 2005. OLS regression is used to test whether or not transitions to marriage and parenthood have a significant impact on the division of household labour whilst controlling for host of relevant socio-economic factors. Results indicate that marriage has no significant effect on how couples partition housework. Those couples making the transition from cohabitation to marriage do not show significant changes in housework arrangements from those couples who remain cohabiting in both waves. On the other hand, becoming parents does lead to a more traditional division of household labour whilst controlling for socio-economic factors which accompany the move to parenthood. There is then some evidence that couples use the site of household labour to ‘do parenthood’ and generate identities which both use and inform socially prescribed notions of what it means to be a mother and a father. Support for socio-economic explanations of the division of household labour was mixed although it remains clear that they, alone, cannot explain how households divide housework.

Doing marriage and parenthood: The division of household labour across two life course events

The current study is a longitudinal investigation into changes in the division of household labour across transitions to marriage and parenthood in the UK. Previous research has noted a more traditional division of household labour, with women performing the majority of housework, amongst spouses and couples with children. However, the bulk of this work has been cross-sectional in nature. The few longitudinal studies that have been carried out have been rather ambiguous about the effect of marriage and parenthood on the division of housework. Theoretically, this study draws on gender construction theory. The key premise of this theory is that gender is something that is performed and created in interaction, and, as a result, something fluid and flexible rather than fixed and stable. The idea that couples 'do gender' through housework has been a major theoretical breakthrough. Gender-neutral explanations of the division of household labour, positing rational acting individuals, have failed to explicate why women continue to perform an unequal share of housework, regardless of socioeconomic status. Contrastingly, gender construction theory situates gender as the key process in dividing household labour. By performing and avoiding certain housework chores, couples fulfill social norms of what it means to be a man and a woman although, given the emphasis on human agency in producing and contesting gender, couples are able to negotiate alternative gender roles which, in turn, feed back into the structure of social norms in an ever-changing societal landscape. This study adds extra depth to the doing gender approach by testing whether or not couples negotiate specific conjugal and parent roles in terms of the division of household labour. Both transitions hypothesise a more traditional division of household labour. Data comes from the British Household Panel Survey, a large, nationally representative quantitative survey that has been carried out annually since 1991. Here, data tracks the same 776 couples at two separate time points - 1996 and 2005. OLS regression is used to test whether or not transitions to marriage and parenthood have a significant impact on the division of household labour whilst controlling for host of relevant socio-economic factors. Results indicate that marriage has no significant effect on how couples partition housework. Those couples making the transition from cohabitation to marriage do not show significant changes in housework arrangements from those couples who remain cohabiting in both waves. On the other hand, becoming parents does lead to a more traditional division of household labour whilst controlling for socio-economic factors which accompany the move to parenthood. There is then some evidence that couples use the site of household labour to 'do parenthood' and generate identities which both use and inform socially prescribed notions of what it means to be a mother and a father. Support for socio-economic explanations of the division of household labour was mixed although it remains clear that they, alone, cannot explain how households divide housework.

Managers Talk about Gender: What Managers in Large Transnational Corporations Say about Gender Policies, Structures and Practices

Mainstream research on management generally continues to ignore gender relations. Even so, over recent years there has been a major growth of international research on gender relations in organizations. Yet, most of this has focused on gender relations in lower or middle levels rather than at the apex of the organization. This book draws on research on gender policies, structures and practices of management in large Finnish corporations. It builds on earlier survey work of gender policies in the 100 largest corporations in Finland, to examine, through qualitative interviews, more detailed gendered processes in seven selected corporations. These represent corporations that are ‘relatively active’, ‘moderately active’, and ‘not active’ in relation to gender equality. Key issues include contrasts between formal policies and organizational practices; different corporate contexts and individual managers’ views; definition and scope of gender policy; and the relation of gender policies and diversity policy. This focus on gender policies is understood and located within organizational structures, most obviously gendered corporate hierarchies. Important structures include national context in relation to transnationalization, relations of headquarters and subsidiaries, and interrelations of management, policy development and policy implementation. Gender relations in practice and gender practices are considered in more detail. These women and men managers operate at the intersections of gendered transnational managerial work, careers and family-type relations, including marriage and children, or lack thereof. Women and men managers may be part of the same management levels or management teams, but have totally different family-type situations and gendered experiences. Interconnections of management, domestic life and transnationalizations are intensely gendered matters. The debate on the public/private continues to be important for both gender relations and organizational relations, but complicated through transnationalizations. The modern transnational corporation is considered in terms of gender divisions and gender power, with particular reference to top management. The concluding discussion notes implications for research and policy.

Ballistic Trauma in Finland : An Epidemiologic and Clinical Study of Firearm and Explosion Injuries

The occurrence and nature of civilian firearm- and explosion-injuries in Finland, and the nature of severe gunshot injuries of the extremities were described in seven original articles. The main data sources used were the National Hospital Discharge Register, the Cause-of-Death Register, and the Archive of Death Certificates at Statistics Finland. The present study was population based. Epidemiologic methods were used in six and clinical analyses in five papers. In these clinical studies, every original hospital record and death certificate was critically analyzed. The trend of hospitalized firearm injuries has slightly declined in Finland from the late 1980s to the early 2000s. The occurrence decreased from 5.1 per 100 000 person-years in 1990 to 2.6 in 2003. The decline was found in the unintentional firearm injuries. A high incidence of unintentional injuries by firearms was characteristic of the country, while violence and homicides by firearms represented a minor problem. The incidence of fatal non-suicidal firearm injuries has been stable, 1.8 cases per 100 000 person-years. Suicides using firearms were eight times more common during the period studied. This is contrary to corresponding reports from many other countries. However, the use of alcohol and illegal drugs or substances was detected in as many as one-third of the injuries studied. The median length of hospitalization was three days and it was significantly associated (p<0.001) with the type of injury. The mean length of hospital stay has decreased from the 1980s to the early 2000s. In this study, there was a special interest in gunshot injuries of the extremities. From a clinical point of view, the nature of severe extremital gunshot wounds, as well as the primary operative approach in their management, varied. The patients with severe injuries of this kind were managed at university and central hospital emergency departments, by general surgeons in smaller hospitals and by cardiothoracic or vascular surgeons in larger hospitals. Injuries were rarities and as such challenges for surgeons on call. Some noteworthy aspects of the management were noticed and these should be focused on in the future. On the other hand, the small population density and the relatively large geographic area of Finland do not favor high volume, centralized trauma management systems. However, experimental war surgery has been increasingly taught in the country from the 1990s, and excellent results could be expected during the present decade. Epidemiologically, explosion injuries can be considered a minor problem in Finland at present, but their significance should not be underestimated. Fatal explosion injuries showed up sporadically. An increase occurred from 2002 to 2004 for no obvius reason. However, in view of the historical facts, a possibility for another rare major explosion involving several people might become likely within the next decade. The national control system of firearms is mainly based on the new legislations from 1998 and 2002. However, as shown in this study, there is no reason to assume that the national hospitalization policies, or the political climate, or the legislation might have changed over the study period and influenced the declining development, at least not directly. Indeed, the reason for the decline to appear in the incidence of unintentional injuries only remains unclear. It may derive from many practical steps, e.g. locked firearm cases, or from the stability of the community itself. For effective reduction of firearm-related injuries, preventive measures, such as education and counseling, should be targeted at recreational firearm users. To sum up, this study showed that the often reported increasing trend in firearm as well as explosion-related injuries has not manifested in Finland. Consequently, it can be recognized that, overall, the Finnish legislation together with the various strategies have succeeded in preventing firearm- and explosion-related injuries in the country.

Consumption in Rural Bangladesh : Households, Lifestyles, and Identities

Bangladesh, often better known to the outside world as a country of natural calamities, is one of the most densely populated countries in the world. Despite rapid urbanization, more than 75% of the people still live in rural areas. The density of the rural population is also one of the highest in the world. Being a poor and low-income country, its main challenge is to eradicate poverty through increasing equitable income. Since its independence in 1971, Bangladesh has experienced many ups and downs, but over the past three decades, its gross domestic product (GDP) has grown at an impressive rate. Consequently, the country s economy is developing and the country has outperformed many low-income countries in terms of several social indicators. Bangladesh has achieved the Millennium Development Goal (MDG) of eliminating gender disparity in primary and secondary school enrollment. A sharp decline in child and infant mortality rates, increased per capita income, and improved food security have placed Bangladesh on the track to achieving in the near future the status of a middle-income country. All these developments have influenced the consumption pattern of the country. This study explores the consumption scenario of rural Bangladesh, its changing consumption patterns, the relationship between technology and consumption in rural Bangladesh, cultural consumption in rural Bangladesh, and the myriad reasons why consumers nevertheless feel compelled to consume chemically treated foods. Data were collected in two phases in the summers of 2006 and 2008. In 2006, the empirical data were collected from the following three sources: interviews with consumers, producers/sellers, and doctors and pharmacists; observations of sellers/producers; and reviews of articles published in the national English and Bengali (the national language of Bangladesh) daily newspapers. A total of 110 consumers, 25 sellers/producers, 7 doctors, and 7 pharmacists were interviewed and observed. In 2008, data were collected through semi-structured in-depth qualitative interviews, ethnography, and unstructured conversations substantiated by secondary sources and photographs; the total number of persons interviewed was 22. -- Data were also collected on the consumption of food, clothing, housing, education, medical facilities, marriage and dowry, the division of labor, household decision making, different festivals such as Eid (for Muslims), the Bengali New Year, and Durga puja (for Hindus), and leisure. Qualitative methods were applied to the data analysis and were supported by secondary quantitative data. The findings of this study suggest that the consumption patterns of rural Bangladeshis are changing over time along with economic and social development, and that technology has rendered aspects of daily life more convenient. This study identified the perceptions and experiences of rural people regarding technologies in use and explored how culture is associated with consumption. This study identified the reasons behind the use of hazardous chemicals (e.g. calcium carbide, sodium cyclamate, cyanide and formalin, etc.) in foods as well as the extent to which food producers/sellers used such chemicals. In addition, this study assessed consumer perceptions of and attitudes toward these contaminated food items and explored how adulterated foods and food stuffs affect consumer health. This study also showed that consumers were aware that various foods and food stuffs contained hazardous chemicals, and that these adulterated foods and food stuffs were harmful to their health.

Rauta ja Ristilukki : Vilho Helasen salapoliisiromaanisarja

Vilho Helanen (1899 1952) was a right-wing opinion leader in interwar Finland. But following the Second World War, the political situation in the country changed dramatically, and Helanen lost his job as well as his influential social station. He began to write detective fiction, and between 1946 and 1952 published seven novels (one had already been published in 1941). The novels protagonist is Kaarlo Rauta, a lawyer who acts as a private investigator. This doctoral dissertation analyzes the Rauta series from three different points of view. It investigates the extent to which the author s life and his strong political background appears in the series. The study also situates the series within Finnish society during and after the war. Finally, the study examines the Rauta series in terms of the genre conventions of detective fiction, that is, the study compares the Rauta series with other Finnish crime fiction and international crime fiction written during the 1940s. The Iron and The Cross Spider uses the term citizenship education when analyzing how Helanen implicitly continued his political teaching when writing crime fiction. The series includes a didactic register, which instructs the middle class in appropriate behaviour and manners, and the social roles entailed by gender. A special area of focus in this didacticism are norms of correct masculinity and femininity. The study devotes specific attention to the status of character in the series. The masculine detective and his beautiful wife are prominent, as is the fictive community and the tensions that criss-cross it. After the war, the Rauta series takes on a positive tone. Men can earn their place in society by fighting at the front, and after the war a homosocial bond exists between all the former soldiers. Women are shut out of the war experience. The detective hero has served in the war, but he is physically and psychologically untouched by it. The community is threatened by artists and immoral bohemians, but not the working class. Artists have affairs outside of marriage and abnormal sexual habits. The members of the upper class are also described as immoral in the series. Sadistic sexuality is often characteristic of the criminals, who are mostly femme fatales in the fashion of hard-boiled detective stories and film noir. Also, strong feelings have a negative connotation in the series, and showing them is forbidden behaviour. Men become criminals when they are insufficiently masculine or when they have not carried out their duty by fighting in the war. Helanen portrayed the communists, his political opponents from the 1930s, as criminals in his post-war series, but they were not openly represented as Russians or communists. Instead, Helanen used the cross spider as their symbol, a symbol which the readers of the time would recognize.

Petusta pitsaan : Ruokahuollon järjestelyt kriisiaikojen Suomessa

From bark bread to pizza - Food and exceptional circumstances: reactions of Finnish society to crises of food supply This study on the food supply under exceptional circumstances lies within the nutritional, historical and social sciences. The perspective and questions come under nutrition science, but are part of social decision-making. The study focuses on the first and second world wars as well as on contemporary society at the beginning of the 21st century. The main purpose of this study is to explore how Finnish society has responded to crises and what measures it has taken to sustain institutional food services and the food supply of households. The particular study interests include the school catering and food services in hospitals during the world wars. The situation in households is reflected in the counseling work carried out by state-run or civic organisations. Interest also focuses on the action of the scientific community. The decisions made in Finland are projected onto the solutions developed in some other European countries. The study is based primarily on the archive documents and annual reports prepared by food and health care authorities. Major source materials include scientific and professional publications. The evaluation of the situation in contemporary Finnish society is based on corresponding emergency plans and guidelines. The written material is supplemented by discussions with experts. Food rationing during the WWI and WWII differed in extent, details and unity. The food intake of some population groups was occasionally inadequate both in quantity, quality and safety. The counseling of the public focused on promoting self-sufficiency, improving cooking skills and widening food habits. One of the most vulnerable groups in regard to nutrition was long-term patients in institutions. As for future development, the world wars were never-theless important periods for public food services and counseling practices. WWII was also an important period for product development in the food industry. Significant work on food substitutes was carried out by Professor Carl Tigerstedt during WWI. The research of Professors A. I. Virtanen and Paavo Simola during WWII focused on vitamins. Crises threatening societies now differ from those faced a hundred years ago. Finland is bet-ter prepared, but in many ways more vulnerable to and dependent on other actors. Food rationing is a severe means of handling the scarcity of food, which is why contemporary society relies primarily on preparedness planning. Civic organisations played a key role during the world wars, and establishing an emergency food supply remains on their agenda. Although the objective of protecting the population remains the same for nutrition, food production, and food consumption, threat scenarios and the knowledge and skill levels of citizens are constantly changing. Continuous monitoring and evaluation is therefore needed.

Avioliiton teologia Englannin kirkossa ja Suomen evankelis-luterilaisessa kirkossa vuosina 1963-2006

The theology of marriage in the Church of England(CofE) and in the Evangelical Lutheran Church of Finland(ELCF)1963–2006 The method of the study is a systematic analysis of the sources. In the CofE marriage stems from creation, but it is also sacramental, grounded in the theology of love and redemption. Man and woman have a connection between them that is a mystical union in character because of the one between Christ and the Church; therefore every marriage is sacramental. The purposes of marriage have been expressed in a different order than earlier. A caring relationship and sexuality are set before childbirth as the causes of marriage. The remedial cause of marriage is also moved to the background and it cannot be found in the recent wedding formulas. A personal relationship and marriage as a school of faith and love have a central place in the theology of marriage. The theology of love unites the love of God and marriage. In the CofE the understanding of divorce and co-habiting has changed, too. Co-habiting can now be understood as a stage towards marriage. Divorce has been understood as a phenomenon that must be taken as a fact after an irretrievable breakdown of marriage. Thus the church must concentrate on pastoral care after divorce. Similarly, the ELCF also maintains that the order of creation is the origin of marriage as a lifelong institution. This is also an argument for the solemnization of marriage in the church. Faith and grace are not needed for real marriage because marriage is the culmination of reason and natural law. The society defines marriage and the church gives its blessing to the married couples if so requested. Luther’s view of marriage is different from this because he saw marriage as a school of love and faith, similar to CofE. He saw faith as essential to enable the fullfillment of natural law. Marriage in the ELCF is mostly a matter of natural ethics. An ideal form of life is sought through the Golden Rule. This interpretation of marriage means that it does not presuppose Christian education for children to follow. The doctrine of the two kingdoms is definitely essential as background. It has been impugned by scholars, however, as a permanent foundation of marriage. There is a difference between the marriage formulas and the other sources concerning the purposes of marriage in the ELCF. The formulas do not include sexuality, childbirth or children and their education as purposes of marriage. The formulas include less theological vocabulary than in the CofE. The liturgy indicates the doctrine in CofE. In the Lutheran churches there is not any need to express the doctrine in the wedding formulas. This has resulted in less theology of marriage in the formulas. The theology of Luther is no longer any ruling principle in the theology of marriage. The process of continuing change in society refines the terms for marriage more than the theological arguments do.

Dracocephalum moldavica L. and Melissa officinalis L. : Chemistry and Bioactivities Relevant in Alzheimer’s Disease Therapy

Oksidatiivisen stressin eli liiallisen reaktiivisten happiyhdisteiden määrän soluissa on jo pitkään arveltu olevan tärkeä Alzheimerin taudin kehittymiseen ja etenemiseen vaikuttava tekijä. Tämän vuoksi kiinnostus erilaisten antioksidanttien (yhdisteitä, jotka neutraloivat näitä happiradikaaleja soluissa) mahdollisia terapeuttisia ominaisuuksia Alzheimerin taudin hoidossa on tutkittu laajalti. Tähän mennessä ei kuitenkaan ole vielä onnistuttu löytämään antioksidanttia, joka olisi hyödyksi Alzheimerin taudin hoidossa. Tämän vuoksi on tärkeää pyrkiä löytämään uusia antioksidanttien lähteitä sekä tutkia niistä löytyviä aktiivisia yhdisteitä. Kiinnostus luonnon antioksidantteja kohtaan on kasvanut voimakkaasti viime aikoina. Huomio on kiinnittynyt erityisesti aromaattisista sekä lääkekasveista löytyviin antioksidantteihin. Lamiaceae- perheeseen kuuluvia tuoksuampiaisyrttiä (Dracocephalum moldavica L.) ja sitruunamelissaa (Melissa officinalis L.) on käytetty Iranissa pitkään sekä ruoanlaitossa että lääkinnässä, minkä vuoksi näiden kasvien uutteiden antioksidanttisisältöä päätettiin analysoida käyttäen useaa erilaista in vitro- menetelmää. Näissä kokeissa ilmeni, että uutteilla oli useita antioksidanttisia vaikutuksia. Näistä antioksidanttisista vaikutuksista vastaavia yhdisteitä pyrittiin tunnistamaan käyttäen HPLC-PDA- tekniikkaa, minkä seurauksena niiden havaittiin sisältävän erilaisia polyfenoleita, kuten hydroksyloituneita bentsoeeni- ja cinnamamidihapon johdannaisia sekä flavonoideja. Kummankin kasvin uutteissa runsaimmin esiintynyt yhdiste oli rosmariinihappo. Sitruunamelissaa (M. officinalis) on käytetty antiikin ajoista alkaen kognitiivisten toimintojen häiriöiden hoidossa. Perustuen tietoon kasvin käytöstä perinteisessä lääkinnässä, sen tehoa Alzheimerin taudin hoidossa on tutkittu viime aikoina kliinisin kokein. Sitruunamelissan todettiinkin olevan hyödyksi lievää ja keskivaikeaa Alzheimeimerin tautia sairastavien potilaiden hoidossa. Väitöskirjan osanan olevasta kooste-artikkelista käy ilmi, että tutkimalla lääkekasvien ominaisuuksia voidaan saada arvokkaita suuntaa-antavia vihjeitä Alzheimerin taudin lääkehoidon kehittämiseen. Tämän perusteella päätettiinkin testatata myös sitruunamelissauutteen kykyä estää asetyylikoliiniesteraasin (AChE) toimintaa, koska tämän entsyymin toiminna estämisen tiedetään olevan hyödyksi Alzheimerin taudin hoidossa. Uute kykeni estämään AChE:n toimintaa, minkä vuoksi uutteen sisältämiä komponentteja päätettiin tutkia terkemmin. Uute jaettiin erilaisiin fraktioihin käyttäen HPLC-menetelmää, minkä jälkeen testattiin jokaisen fraktion kykyä inhiboida AchE. Suurin osa fraktioista kykeni inhiboimaan AChE:n toimintaa selkeästi tehokkaammin, kuin raakauute. Kaikista tehokkainta fraktiota analysoitiin tarkemmin sen aktiivisten yhdisteiden tunnistamiseksi, minkä seurauksena sen sisältämät yhdisteet tunnistettiin cis ja trans-rosmariinihapoiksi. Tässä tutkimuksessa tunnistettujen yhdisteiden hyödyllisyyttä Alzheimerin taudin hoidossa tulisi seuraavaksi tutkia erilaisissa in vivo-malleissa. Lisäksi jäljellä olevien fraktioiden kemiallinen koostumus tulisi selvittää sekä antioksidanttiaktiivisuuden ja AChE:n toiminnan inhiboinnin välistä mahdollista yhteyttä tulisi tutkia tarkemmin. Tämä tutkimus osoittaa tuoksuampiasyrtin (D. moldavica) sekä sitruunamelissan (M. officinalis) sisältävän monenlaisia aktiivisia antioksidantteja. Lisäksi sitruunamelissan sisältämät yhdisteet kykenivät estämään asetyylikoliiniesteraasin (AchE) toimintaa. Nämä tulokset tukevat osaltaan väitöskirjan osana olevan kooste-artikkelin johtopäätöksiä, joiden mukaan etnofarmakologinen kasvitutkimus voi osoittautua erittäin hyödylliseksi kehitettäessä uutta lääkehoitoa Alzheimerin tautiin. Lisäksi tässä väitöskirjassa kuvattu tutkimus osoittaakin, että perinteisesti lääkekasvina käytettyä sitruunamelissaa voidaan mahdollisesti hyödyntää uusien Alzheimerin taudin hoitoon käytettävien lääkkeiden kehityksessä.

Microarrays in Molecular Profiling of Ewing Sarcoma Family of Tumors and CDKN2A Aberrations

Background: The Ewing sarcoma family of tumors (ESFT) are rare but highly malignant neoplasms that occur mainly in bone or but also in soft tissue. ESFT affects patients typically in their second decade of life, whereby children and adolescents bear the heaviest incidence burden. Despite recent advances in the clinical management of ESFT patients, their prognosis and survival are still disappointingly poor, especially in cases with metastasis. No targeted therapy for ESFT patients is currently available. Moreover, based merely on current clinical and biological characteristics, accurate classification of ESFT patients often fails at the time of diagnosis. Therefore, there is a constant need for novel molecular biomarkers to be applied in tandem with conventional parameters to further intensify ESFT risk-stratification and treatment selection, and ultimately to develop novel targeted therapies. In this context, a greater understanding of the genetics and immune characteristics of ESFT is needed. Aims: This study sought to open novel insights into gene copy number changes and gene expression in ESFT and, further, to enlighten the role of inflammation in ESFT. For this purpose, microarrays were used to provide gene-level information on a genomewide scale. In addition, this study focused on screening of 9p21.3 deletion sizes and frequencies in ESFT and, in another pediatric cancer, acute lymphocytic leukemia (ALL), in order to define more exact criteria for highrisk patient selection and to provide data for developing a more reliable diagnostic method to detect CDKN2A deletions. Results: In study I, 20 novel ESFT-associated suppressor genes and oncogenes were pinpointed using combined array CGH and expression analysis. In addition, interesting chromosomal rearrangements were identified: (1) Duplication of derivative chromosome der(22)(11;22) was detected in three ESFT patients. This duplication included the EWSR1-FLI1 fusion gene leading to increase in its copy number; (2) Cryptic amplifications on chromosomes 20 and 22 were detected, suggesting a novel translocation between chromosomes 20 and 22, which most probably produces a fusion between EWSR1 and NFATC2. In study II, bioinformatic analysis of ESFT expression profiles showed that inflammatory gene activation is detectable in ESFT patient samples and that the activation is characterized by macrophage gene expression. Most interestingly, ESFT patient samples were shown to express certain inflammatory genes that were prognostically significant. High local expression of C5 and JAK1 at the tumor site was shown to associate with favorable clinical outcome, whereas high local expression of IL8 was shown to be detrimental. Studies III and IV showed that the smallest overlapping region of deletion in 9p21.3 includes CDKN2A in all cases and that the length of this region is 12.2 kb in both Ewing sarcoma and ALL. Furthermore, our results showed that the most widely used commercial CDKN2A FISH probe creates false negative results in the narrowest microdeletion cases (<190 kb). Therefore, more accurate methods should be developed for the detection of deletions in the CDKN2A locus. Conclusions: This study provides novel insights into the genetic changes involved in the biology of ESFT, in the interaction between ESFT cells and immune system, and in the inactivation of CDKN2A. Novel ESFT biomarker genes identified in this study serve as a useful resource for future studies and in developing novel therapeutic strategies to improve the survival of patients with ESFT.

Adenoviral Gene Therapy for Advanced Head and Neck Cancer

Advanced stage head and neck cancers (HNC) with distant metastasis, as well as prostate cancers (PC), are devastating diseases currently lacking efficient treatment options. One promising developmental approach in cancer treatment is the use of oncolytic adenoviruses, especially in combination therapy with conventional cancer therapies. The safety of the approach has been tested in many clinical trials. However, antitumor efficacy needs to be improved in order to establish oncolytic viruses as a viable treatment alternative. To be able to test in vivo the effects on anti-tumor efficiency of a multimodal combination therapy of oncolytic adenoviruses with the standard therapeutic combination of radiotherapy, chemotherapy and Cetuximab monoclonal antibody (mAb), a xenograft HNC tumor model was developed. This model mimics the typical clinical situation as it is initially sensitive to cetuximab, but resistance develops eventually. Surprisingly, but in agreement with recent findings for chemotherapy and radiotherapy, a higher proportion of cells positive for HNC cancer stem cell markers were found in the tumors refractory to cetuximab. In vitro as well as in vivo results found in this study support the multimodal combination therapy of oncolytic adenoviruses with chemotherapy, radiotherapy and monoclonal antibody therapy to achieve increased anti-tumor efficiency and even complete tumor eradication with lower treatment doses required. In this study, it was found that capsid modified oncolytic viruses have increased gene transfer to cancer cells as well as an increased antitumor effect. In order to elucidate the mechanism of how oncolytic viruses promote radiosensitization of tumor cells in vivo, replicative deficient viruses expressing several promising radiosensitizing viral proteins were tested. The results of this study indicated that oncolytic adenoviruses promote radiosensitization by delaying the repair of DNA double strand breaks in tumor cells. Based on the promising data of the first study, two tumor double-targeted oncolytic adenoviruses armed with the fusion suicide gene FCU1 or with a fully human mAb specific for human Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) were produced. FCU1 encodes a bifunctional fusion protein that efficiently catalyzes the direct conversion of 5-FC, a relatively nontoxic antifungal agent, into the toxic metabolites 5-fluorouracil and 5-fluorouridine monophosphate, bypassing the natural resistance of certain human tumor cells to 5-fluorouracil. Anti-CTLA4 mAb promotes direct killing of tumor cells via apoptosis and most importantly immune system activation against the tumors. These armed oncolytic viruses present increased anti-tumor efficacy both in vitro and in vivo. Furthermore, by taking advantage of the unique tumor targeted gene transfer of oncolytic adenoviruses, functional high tumor titers but low systemic concentrations of the armed proteins were generated. In addition, supernatants of tumor cells infected with Ad5/3-24aCTLA4, which contain anti-CTLA4 mAb, were able to effectively immunomodulate peripheral blood mononuclear cells (PBMC) of cancer patients with advanced tumors. -- In conclusion, the results presented in this thesis suggest that genetically engineered oncolytic adenoviruses have great potential in the treatment of advanced and metastatic HNC and PC.