Väitöstiivistelmät

Recent Submissions

  • Kangaskoski, Matti (Unigrafia, 2017)
    This study concentrates on reading digital poetry. Reading entails the act of reading, strategies of analysis, and the means of understanding. Specifically, this study constructs a model of reading and interpreting poetry in digital form by close analysis of three complex case studies. Broadly, this study concerns the aesthetic means and meanings of poetry in the contemporary moment, where new and old media are in visible negotiation with each other. In digital poetry artistic expression, digital media, technology and cultural practices clash and combine to produce new poetic forms. With new forms of poetry come new challenges to reading, analysis, and interpretation. Digital poetry presents new material, literary, technical, and rhetorical strategies and techniques that offer novel possibilities – and restrictions – for reading. Thus, my broad question is: How do we read digital poetry? This broad question is broken down to a subset of research questions. These deal with the material medium, readerly action, and the processes of the poem, which are all to be seen as constituent of its effects and meanings. In answering these questions, I construct a new model for reading digital poetry. The model is distilled from my close readings of the case studies. The readings are literary, cultural, media-historical and media-specific. The background methodology for the investigation comes from the notion of close reading (sensu Culler 2010; Simanowski 2011; Pressman 2014). My reading model consists of three main elements: interface, interaction, and interpretation. I further divide the interface into elements of data (e.g. text, music, images), processes (e.g. temporal control, text generation), and medium (as material and conceptual). Interaction consists of logic, performance, and effect, which designate the mode of engagement with the work, the joint performance of the poem and the reader, and the effects these produce. Interpretation includes the articulation of effects and meanings. Whereas the effects are created in interaction with the work, articulating them is seen as part of interpretation. Interpretation includes the articulation of the meanings and connections the poem invites. In other words, the poem’s interface guides the concrete act of reading, interaction guides the reader’s mode of engagement with the interface, and interpretation guides the means of understanding what is read. The case studies renegotiate the interrelated and overlapping arenas of print and digital poetry, old and new media, and traditional and digital literary criticism. The first includes Cia Rinne’s zaroum (2001), archives zaroum (2008; with Christian Yde Frostholm) and notes for soloists (2009). The second is Young-Hae Chang Heavy Industries’ Dakota (2002). And the third is Stephanie Strickland’s “V-project”, which includes two print books (V:WaveSon.nets /Losing L’Una 2002; V: WaveTercets /Losing L’Una 2014) two web applications (V:Vniverse Shockwave application 2002 with Cynthia Lawson-Jaramillo; Errand Upon Which We Came 2001; with M. D. Coverley), and an iPad application (Vniverse 2014; with Ian Hatcher). The emphasis in the case studies is on examining strategies of reading and interpretation as well as producing new readings and interpretations of the poetry in question. I investigate the interdependence of traditional print-based and emerging digital strategies of reading poetry, and combine print-based scholarly approaches with digital-based scholarship.
  • Immanen, Mikko (Unigrafia, 2017)
    As prominent figures in continental philosophy, both Martin Heidegger and the Frankfurt School critical theorists Theodor W. Adorno, Max Horkheimer, and Herbert Marcuse have all been studied extensively. However, there has been little interest in a comparative approach toward these giants of twentieth-century European thought. This is understandable considering that during their lifetimes the relationship between Heidegger and the neo-Marxist Frankfurt School thinkers was mostly hostile or ignorant. Heidegger never commented on the critical theorists in his published works, and after World War II the German Jewish critical theorists attacked Heidegger’s refusal to apologize for his Nazi politics as symptomatic of the wider German incapacity to come to terms with the past. While this antagonistic image reigns widely today, recent years have seen attempts to disclose unexpected parallels in Heidegger’s and Frankfurt School’s post-war concerns about “oblivion of being” and “dialectic of enlightenment” and in their emphasis on aesthetic experience as an antidote to the one-dimensionality of the modern technological mindset. Although inspired by these philosophical openings, this thesis focuses on the overlooked Weimar period, and, using the methods of intellectual history, shows that during their philosophically formative years in 1927–1933 – also the period between the publication of Heidegger’s magnum opus, "Being and Time," and his Nazi turn – Adorno, Horkheimer, and Marcuse saw Heidegger’s promise of philosophical concreteness as a serious, if flawed, effort to make philosophy relevant to life again. Rather than claiming that Heidegger influenced the critical theorists in a positive way, as Marx and Freud for instance did, the thesis argues that the critical theorists saw Heidegger’s existentialism as the most provocative challenge and competitor to their nascent materialist diagnoses of the discontents and prospects of European modernity. Demonstrating Heidegger’s surprising presence in the works of the twentieth century’s most important leftist social theorists, the thesis not only offers a groundbreaking historical reconstruction of the Frankfurt School’s unacknowledged early confrontation with their later arch-enemy, but also contributes to our understanding of Heidegger’s major impact on twentieth-century philosophy, an impact hitherto reconstructed by studies on his influence on key French, American, and Jewish thinkers.
  • Haikala, Heidi (2017)
    MYC is a transcription factor and a proto-oncogene, which is overexpressed in almost 50% of all breast cancers. Cell cycle promoting oncogenic MYC supports the altered energetic needs of continuously proliferating cancer cells, since there is an immense requirement for nucleic acids, proteins, and lipids to support the cell division. MYC supports the metabolic switch by enhancing the main nutrient (glucose and glutamine) uptake, increasing glycolysis and glutamine utilization, as well as by instructing the normally ATP generating citric acid cycle to serve biosynthetic growth promoting reactions. In this study we found that the metabolic changes induced by MYC lead to decreased production of ATP and the consequent activation of a key cellular energy sensor protein AMP-activated kinase (AMPK). AMPK is a metabolic guardian, which instructs cells to perform catabolic reactions to restore the ATP levels. However, persistent AMPK activity directs MYC-transformed cells towards apoptotic cell death. We found that MYC-activated AMPK phosphorylated the tumor suppressor protein p53, which accumulated on the mitochondrial surface. In the mitochondria, p53 primed the cell death promoting protein BAK for apoptotic cell death induction, thus connecting MYC-driven metabolic transformation to apoptotic sensitivity. In addition, we discovered a novel synthetic lethal and potentially druggable interaction between MYC activation and inhibition of a small GTPase RhoA. We found that RhoA assists MYC to upregulate glutamine metabolism, which highlights the relevance of metabolism as a sweet spot for targeting oncogenic MYC. Furthermore, we found that supraphysiological, highly expressed MYC is globally repressing the transcriptional targets of serum response factor (SRF), a RhoA downstream target, thus exposing new pathways needed for cancer cell survival. In addition, the same study contributed to a finding that supraphysiological MYC represses a set of genes related to luminal identity of breast epithelial cells, which possibly affects the cell differentiation and apoptotic sensitivity in vivo. The described mechanisms suggest a possible answer to the old paradox why cancerous MYC expression levels, but not physiological MYC, sensitize cells to apoptosis. Finally we studied how the altered metabolism-derived sensitivity to apoptosis could be exploited as a potential therapeutic strategy to kill MYC expressing cancer cells. In a rationalized drug combination screen, we found that the pharmacological superactivation of AMPK is able to potentiate the anticancer activity of apoptosis targeting therapies, which usually do not show great efficacy in solid tumors as single agents. The described combination proved substantial efficacy against highly MYC expressing breast cancer models in vitro, in vivo and in ex vivo. Thus, we describe the first pharmacological MYC apoptosis activation strategy that could be easily translated to the benefit of breast cancer patients, and currently clinical trials to test the combination are under consideration. In addition to the described scientific findings, the ex vivo and in vivo preclinical research models of breast cancers developed during this study are likely to serve breast cancer research community by providing more predictive and more translationally relevant platforms for studies of breast cancer biology and drug discovery.
  • Rajavuori, Anna (Työväen historian ja perinteen tutkimuksen seura, 2017)
    The politics of performance. Socialist agitation in the country side of central Finland in 1906–1908 The study examines oral agitation by the Finnish Social Democratic Party in the eastern electoral district of Vaasa before and after the first parliamentary elections. Research on political speeches is rather scarce, partly due to the fact that there are no recordings and only few manuscripts for these have survived. Agitation has usually been examined as a means to spread political viewpoints among the populace, and its success has been determined according to votes cast in elections. In this study agitation and events where this was performed are referenced through a performance theory viewpoint as bodily interaction. The performance is viewed as a lens, through which history, culture, and political and social reality manifests itself. The sources for this study include newspapers, oral history, historical documents and prose. These have been examined in relation to central issues within performance theory, namely identity, social roles and the possibilities of individuals. The study shows that socialist agitation was varied both in form and content. The nature of the performance was dictated by the audience. The performance of agitation borrowed from other types of performance of the era. The agitators made use of Christian rhetoric and their motives drew from the ideals of enlightenment. The central message of agitation, putting into words the class based society and class differences, could be made visible via performance. The agitator attempted to find conflict with the “bourgeoisie”, thus creating a clash between different social classes and a feeling of togetherness within their own. A key objective of agitation was creating a conscious working class identity based on the actions of an inner circle of actors. The study offers new perspectives into political action and the creation of political identity in a rural environment as part of the modernization process. Socialist agitators assisted the people in becoming political actors and strengthened their experience of participation and citizenship. In addition to political and social effects, agitation also had a profound cultural effect, because of the diverse nature of the gatherings, where it was performed. The viewpoint into political performance and the politics of performance offered in this study also presents a point of comparison into modern political culture. Keywords: agitation, agitators, labour movement, the Social Democratic Party of Finland, the 20th century, political performance, socialism, election campaign
  • Maddirala Venkata, Siva Prasada Reddy (2017)
    ABSTRACT Pharmacies are convenient for most people to get to and there is no need for an appointment to see pharmacist which makes them natural first port of call healthcare providers in the society. Worldwide, pharmacists are potentially a vital link in healthcare chain. Since public health services do not cater to all the population, pharmacies and private health providers can play a major role in the healthcare system. This also applies to India with a population of over 1.3 billion. Though there is a large presence, pharmacists both in public as well as in private sector remain largely an untapped resource in India. Aims and objectives The objective of this study was to assess public health and patient care aspects in pharmacy education and the role of pharmacists in national public health programs (NPHPs) in India. The research goal was to find out possibilities and ways of extending pharmacists involvement in national public health programs and how pharmacist education could partly facilitate this shift. The research was divided into four studies which were published as separate original publications. Two of the studies were programmatic studies (I, II) and two cross-sectional surveys (III, IV). The studies I-IV had the following specific objectives: to review pharmacy education system in India from public health and patient care perspective. to compare curriculum of different Indian pharmacy programs (DPharm, BPharm, and PharmD) to see overall differences with a focus on the amount of time devoted for pharmaceutical policies and public health, patient care and pharmacy practice aspects in the programs (I). to compare Indian pharmacy curriculum at all levels with pharmacy curriculum of USA, Finland and Denmark (II). to explore acquaintance of final year pharmacy students with 11 major National Public Health Programs and their attitude on pharmacists involvement in public health and patient care (III). to characterize physician perceptions on the role of pharmacists in public health and patient care (IV). Comparison of curricula (I,II) The programmatic studies (I, II) were conducted between March 2012 and 2014. The curricula collected from the statutory bodies were used for the comparison to see the overall differences with a focus on the amount of time devoted for pharmaceutical policies and public health, patient care and pharmacy practice aspects in the programs. (I) Syllabi of courses leading to 1) registered pharmacist title in India (DPharm, BPharm and PharmD), 2) USA (PharmD, curriculum from University of Florida), 3) Finland (Master of Science in Pharmacy program from University of Helsinki), and 4) Denmark (Master of Science in Pharmacy program from University of Copenhagen) were used for comparison. (II) The results indicate that Indian DPharm and BPharm programs were industry focused, and only PharmD has focus on clinical pharmacy and patient oriented services (I). Indian and US PharmD programs contain most and Indian DPharm and BPharm least public health and patient care aspects (II). DPharm holders are mainstays of pharmacy practice in India but their degree least contains patient care and public health aspects. There is a gap in curriculum, particularly at DPharm level. (I) Pharmacy Students Perceived Knowledge and Attitude on their role in NPHPs (III) This study was conducted as a classroom survey among final year DPharm, BPharm and PharmD students in India to explore acquaintance with 11 major NPHPs and their attitude on pharmacists involvement in public health and patient care (III). A survey instrument was prepared and distributed in a classroom survey to 326 students from 5 randomly selected pharmacy colleges from Southern part of India. (III) Students had positive attitudes on pharmacists involvement in NPHPs, although their attitudes varied in different student groups, PharmD and DPharm students being most positive towards involvement in NPHPs (III). The study also revealed the need for increasing contents supporting NPHPs to all pharmacy programs, particularly to BPharm program. Physician perceptions on the role of pharmacists in NPHPs (IV) A cross-sectional survey was designed to a convenience sample of physicians in Southern part of India. This small-scale pilot study was designed to develop a method for characterizing physicians perceptions on the role of pharmacists in public health and patient care in India. Six volunteers visited 800 physicians in Southern region in India and collected data in 2014. Survey instrument consisted of 28 structured questions based on NPHPs. The data were collated and extracted and descriptive statistical analysis was conducted by SAS (version 9.3). (IV) Among 129 responding physicians, 98% were comfortable with pharmacists roles in general, 96% comfortable to collaborate and 82% regarded pharmacists as part of health care team (IV). Physicians with shorter professional practice experience were more positive on pharmacists involvement in NPHPs than physicians having at least 11 years experience. Overall response of accepting pharmacists role and involvement in NPHPs was positive, Pulse Polio, HIV/AIDS, Tuberculosis and Tobacco control, and Leprosy eradication programs being the top NPHPs where physicians perceived pharmacists had a role to play. Conclusions and recommendations Upcoming PharmD graduates with 6 years education (training initiated in 2008) focused mainly towards clinical and patient care aspects should be able to change collaborative practice models and pharmacists involvement in patient care and NPHPs. It also would be useful to have an alternative curriculum line focusing on patient care and pharmacy practice aspects in Indian DPharm and BPharm programs. Practicing pharmacists would benefit from easily accessible continuing education to cover their knowledge gaps in patient care and enhance their contributions to NPHPs. This study is first of its kind to evaluate pharmacy curriculum contents in India from patient care and public health perspective. It will be helpful to statutory authorities and curriculum reform committees in India and other countries where pharmacists role is continuing to evolve towards inclusion of public health and patient care. Further research with a scope of detailed national level analysis to identity pharmacists potential in NPHPs is needed.
  • Koivusalo, Anna (Helsingin yliopisto, 2017)
    This study examines honor and honorable emotional expressions in the nineteenth-century American South. I argue that honor was a behavior that facilitated emotional expression in three ways: recognizing acceptable emotions; navigating in society by expressing acceptable emotions; and identifying and achieving life goals. This can be seen in the life and political career of James Chesnut, Jr. (1815–1885), a prominent southern statesman. This study also approaches southern society more broadly. First, I suggest that rather than an unequivocal or static code, the prevailing idea of honor was shaped by multiple individual interpretations of honor. Individuals had to constantly recalibrate their notion of honor to coincide with other peoples’ notions of honor. Second, I propose that honor was a tool for identifying and expressing appropriate emotions. I have used James Chesnut as a case study because his life choices and actions can be read as responses to the requirements of southern honor and prevailing emotional guidelines. I use specific examples of the use of honor as a guideline. I discuss how parents inculcated a sense of honor in their sons, inducing young men to develop an understanding of honor and to recognize honorable emotional expression. Later, as adults, men had to acknowledge the requirements of honor in every life choice and action. I propose that honor helped Southerners formulate and express emotions: instead of displaying the raw emotions of the private sphere, one was expected to demonstrate their noble counterparts, the emotions of the public sphere. I also suggest that the unstable nature of honor was most obvious in times of crisis, such as during the Civil War and Reconstruction. Then, the role of honor and the importance of honor-related emotional expression intensified. Because of major changes in society, however, individual goals changed and the necessity to forcefully alter the understanding of honor arose. This work is a conceptual study: it examines the features of honor in a specific context, the nineteenth-century American South. It is, nonetheless, also a study on the history of emotions, exploring southern emotionologies or emotion repertoires. Textual analysis is, therefore, especially important for this study which examines how emotional expression was formulated into words.
  • Marjosola, Heikki (Helsingin yliopisto, 2017)
    This dissertation studies the institutional transformation of the European Union s regulatory framework for financial markets and institutions. The dissertation is based on four articles, which deal with several challenges of the transformation: they analyse the economic rationale behind the institutional reforms; identify possible gaps, missing pieces, and problems that remain; and examine how the Court of Justice of the European Union (CJEU) has handled certain difficult questions about the legality of the new powers and institutional arrangements. The institutional innovations in the EU since the financial crisis have consisted primarily of increasingly hierarchical and supranational means of control, which have been buttressed by a far-reaching maximum harmonisation agenda. The dissertation argues that these choices have not been balanced with due consideration of their costs and trade-offs. Alternative governance strategies, such as the use of general courts as tools of ex post, principles-based enforcement, have been neglected. On the other hand, in certain critical areas of prudential financial regulation, the transfer of competences to the EU level seems incomplete. These arguments will be developed with the help of a novel approach to the study of financial regulation. Drawing on transaction cost economics and contract theory, the approach builds on the notion of law being incomplete and subject to various hazards of opportunism. Two specific governance problems will be examined, each of which can diminish the effectiveness of regulation and threaten the stability of the regulatory contract: (1) the problem of financial innovation, and (2) the problem of regulatory arbitrage and regulatory competition. Especially the latter can also lead to the underproduction of financial stability as a public good. The dissertation also considers the constitutional framework of the institutional transformation. Constitutional rules, whose function is to constrain the use of public power, limit the alternatives of policy-makers and regulators. However, the post-crisis case law of the CJEU, such as the fleshing out by the Court of new intervention powers from a vague Treaty basis, supports the view that the Lisbon Treaty can be seen as a type of highly adjustable relational contract. However, owing to the possibly conflicting relationship between the new financial stability oriented executive powers, and the more complete and directly effective free movement rights, the EU s economic constitution must deal with more fundamental design problems, which might jeopardise its consistency and continuity.
  • Boyd, Sonja (Unigrafia, 2017)
    Primary sclerosing cholangitis (PSC) is particularly common in the Nordic countries. Most (70-80%) PSC patients have concomitant inflammatory bowel disease (IBD). The majority of patients are male. Increased levels of serum cholestasis markers in IBD patients lead to PSC suspicion, and diagnosis is verified with magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiography (ERC). PSC patients usually become symptomatic over time, and PSC may lead to liver fibrosis and finally to cirrhosis. Cholangiocarcinoma (CCA) develops in 7-13% of PSC patients. The prognosis of CCA is poor. Dysplasia of the bile ducts is thought to precede the development of CCA. Liver transplantation (LT) may be performed in end-stage PSC cirrhosis, but premalignant biliary changes may also be a partial indication for LT even if the patient is asymptomatic. At Helsinki University Hospital, PSC patients regularly undergo systematic dysplasia surveillance with ERC and brush cytology (BC) to detect dysplastic changes of the bile ducts and to determine disease progression. ERC changes are graded according to the modified Amsterdam ERC score. If suspicion of dysplasia is repeatedly seen in BC, patients are referred to liver surgeons for consideration of LT. Our aims were to evaluate the relevance of the screening protocol at PSC diagnosis and later during the disease course to identify risk factors for biliary neoplasia, and to evaluate the utility of ERC, BC and ploidy analysis of biliary epithelium in detecting biliary neoplasia. In their first, diagnostic ERC (n=261), 81% of PSC patients were asymptomatic, but 43% already had advanced ERC changes. Seven percent had malignancy or malignancy suspicion in BC. Those who had elevated liver enzymes and advanced ERC changes were most likely diagnosed with biliary neoplasia during follow-up. Female patients had milder ERC changes and a lower cumulative risk of biliary neoplasia. During the follow-up period (median 4.7 years), 2.7% were diagnosed with CCA and 3.1% with biliary dysplasia. Independent risk factors for biliary neoplasia were elevated extrahepatic ERC score, suspicious/malignant BC and elevated serum alanine aminotransferase. During surveillance (median 6 years) with ERC and BC, 3.8% out of 447 PSC patients were diagnosed with CCA, and 5.1% had dysplasia in the explanted liver. ERC score, male gender, elevated liver enzymes, serum tumour markers, suspicious BC and inflammation or aneuploidy in BC were risk factors for CCA. All patients with biliary neoplasia had intra- and extrahepatic ERC changes. 126 PSC patients underwent liver transplantation in Helsinki University Hospital during 1984-2012, and 28% of these LTs were due to neoplasia suspicion for asymptomatic patients. The combined sensitivity of BC and ploidy analysis to detect biliary neoplasia was 68% with 86% specificity. The ten-year survival of asymptomatic patients after LT was 91%. Screening and surveillance of PSC patients with ERC and BC may help find patients that are most prone to develop CCA. Patients with advanced extrahepatic ERC changes and elevated liver enzymes are most likely to be later diagnosed with CCA. On the other hand, patients with intrahepatic ERC changes only have a negligible CCA risk. If BC is repeatedly suspicious, even asymptomatic patients should be referred to evaluation of LT.
  • Koskela, Katja (Juvenes Print, 2017)
    A biological threat is an epidemic or its threat caused by a microbe or biological material of a magnitude that would overwhelm healthcare services due to the contagiousness or wide distribution of infections. A biological threat can be naturally occurring, such as the West African Ebola epidemic of 2014-2016, or the consequence of an intentional release of a microbe or toxin. The aim of this thesis was to develop and use molecular methods in order to reliably and rapidly identify potential biological threat agents. The focus was on the detection and typing of biological threat agents, whether they are naturally occurring or intentionally released. Different molecular methods were used: polymerase chain reaction (PCR) to detect and differentiate pathogenic from non-pathogenic bacterial strains, 16S ribosomal RNA (rRNA) gene sequencing to investigate polymicrobial samples, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) spacer comparison for bacterial strain typing. Cholera, a disease caused by Vibrio cholerae bacterium, is a major public health problem worldwide and a potential bioterrorism agent, according to the Centers for Disease Control and Prevention (CDC). In this thesis, an accurate PCR-based method was developed to detect V. cholerae strains: one assay for pathogenic strains and another for all V. cholerae strains. In addition, three different PCR platforms were compared. The PCR assays proved to be suitable for the reliable identification and differentiation of V. cholerae strains. The PCR platforms gave identical results, which indicate that the assays can be transferred between the platforms while maintaining sufficient sensitivity and specificity. Two 16S rRNA gene-based detection methods, using Sanger sequencing or pyrosequencing, were employed to study the presence of bacterial residues in carotid artery tissue samples and in livers of splenomegalic voles. The objectives were to observe the utility of the two methods and compare their performance. Both methods were found to be convenient approaches to detect and identify bacterial species present in different matrices and thus could be employed when investigating polymicrobial samples. In addition, the two methods gave similar results which emphasises the reliability of the methods and their results. The Yersinia genus includes three human pathogens; Y. pestis, the causal agent of plague and a potential biothreat agent, as well as Y. enterocolitica and Y. pseudotuberculosis, which commonly cause self-limiting enteritis. Due to the high level of DNA similarity between Y. pestis and Y. pseudotuberculosis, typing of Yersinia species and distinguishing them from each other has been challenging. Here, CRISPR spacers were used for typing Yersinia pseudotuberculosis complex strains. This method proved to be a promising tool, although the large diversity of different spacer sequences hindered the clustering of different strains. In addition, CRISPR data of Y. pseudotuberculosis and Y. pestis were compared to examine phylogenetic relationships, but surprising lack of shared spacers limited any further resolution from being made. In this thesis, molecular methods were developed and used to detect, identify, and type potential biological threat agents. PCR assays developed can be transferred to a field-deployable instrument and thus employed close to the patient, for example, during epidemics. PCR results were ready within a few hours, enabling a rapid and appropriate medical response. The 16S rRNA gene-based methods can be utilized in detection of biological agents, which are challenging or laborious to identify using traditional methods. The CRISPR-based sequencing method can be used for typing different strains of Y. pseudotuberculosis, if a comprehensive reference database is made available. DNA sequencing and recently next-generation sequencing have become powerful tools to identify and type biological agents. Sequencing methods can also be utilized in epidemiological investigations and source tracking. Different molecular methods have evolved recently and detection has become fast and more reliable. Rapid detection of microbes enables swift medical countermeasures, and accurate identification and typing methods facilitate the ability to distinguish a natural outbreak from an intentional release.
  • Räsänen, Minna (Helsingin yliopisto, 2017)
    Aims: Rectal cancer, one of the most common cancers worldwide, causes significant mortality. After curative rectal cancer surgery, local recurrences (LR) are detected in 4-10% and distant metastases in 20-31% of the patients. For diagnosing recurrence, the surveillance is recommended, but the optimal frequency, length and methods are not well established. This study analysed the pattern of rectal cancer recurrence, the usefulness of surveillance and the different surveillance instruments available. Nowadays, low colorectal or coloanal anastomosis is performed whenever possible because most patients prefer anus-preserving surgery over a permanent stoma. The covering stoma is used to facilitate anastomosis healing and to protect against fatal complications. In this study, we determined the cumulative risk of and the risk factors for failure of low colorectal or coloanal anastomosis. In locally advanced rectal cancer, when the tumour has invaded the adjacent organs, a multivisceral en bloc -resection is needed. In these resections, morbidity and mortality are higher than in standard resections. An attempt is made to decrease tumour size by neoadjuvant long-course (LC) chemoradiotherapy (CRT); the goal is to achieve clear resection margins. The oncological results of multivisceral resections for rectal cancer were evaluated, as were the risk factors for LR and survival. The response to CRT seen in response magnetic resonance imaging (MRI) and the histopathology report was analysed. In addition, the usefulness of the response seen in MRI and the pathological specimen in predicting curative resection, risk of LR and survival was investigated. Neoadjuvant short-course radiotherapy (SCRT) has been reported to diminish the rate of LR. Anyhow, meticulous total mesorectal excision (TME) surgery has good local control without RT in so-called good T2-T3N0-1 tumours , and the use of SCRT has been questioned in many countries because of side-effects and uncertainty of utility. The aim of this study was to determine, whether SCRT prevents LR in pT3N1-2 patients compared with those operated on without RT. Patients and methods: A total of 952 rectal cancer patients were operated on at Helsinki University Hospital between January 2005 and June 2014. Study I comprised 481 consecutive rectal cancer patients treated with radical intention during 2005-2011. Study II comprised all patients (n= 273) operated on with anterior resection (AR) combined with low colorectal or coloanal anastomosis and covering stoma during 2005-2011. The Study III population consisted of 94 patients, operated on because of locally advanced rectal cancer by multivisceral resection between 2005 and 2013. In Study IV, 151 patients operated on because of pT3N1-2 rectal cancer during January 2005-June 2014 were included. Of these 151 patients, 57 did not have radiotherapy (RT) before the operation and 94 had received short-course RT before surgery. Data were retrospectively collected from patient records. Results: Local recurrence occurred in 8.3% and distant metastases in 23.3% of patients treated with curative intention. The median time to recurrence was 1.3 years after operation, and 75% of recurrences were diagnosed during the first two postoperative years. Recurrences were detected significantly earlier by the follow-up visits than by symptoms. All of the surveillance instruments used, were equally useful for finding recurrences. Curative re-operation was possible in 41.1% of patients with disease recurrence. The colorectal or coloanal anastomosis was switched to a permanent stoma in 23 (8.5%) of 271 patients. Protective stoma was not closed in five patients (1.8%). Total permanent stoma rate was 10.3%. The risk factors for failure of low colorectal or coloanal anastomosis were tumour location under 6 cm from anal verge, coloanal anastomosis, early anastomotic complication, anastomotic fistula, anal incontinence, and LR. After multivisceral resection, LR occurred in 10.6%. The median time for detecting a recurrence was 1.4 years (0.7-5.2). The 5-year overall survival (OS) for the whole population was 51.8% and for curatively treated patients (n=83) 59.2%; the 5-year disease-free survival (DFS) for the latter group was 64.2%. A significant risk factor for LR and survival was R1 resection. Poor or no response in post-treatment MRI predicted LR and also seemed to predict DFS in curatively treated patients. Of patients having pT3N1-2 rectal cancer, LR occurred in altogether 11.3%. The rate of LR in the surgery only group was 14% and in the RT + surgery group 9.6%. Risk factors in univariate analysis for LR were tumour location under 6 cm from anal verge, positive circumferential resection margin (CRM), tumour perforation and mucinous histology. In multivariate analysis, the risk factors were tumour location under 6 cm from anal verge and positive CRM. The short-course RT did not prevent LR. Conclusions: The most intensive follow-up should fall within two to three years for all patients treated with curative intent, and thereafter, only patients with known risk factors for recurrence should be followed. The risk of permanent stoma after low anterior resection in our study population was low, most probably due to routine use of covering stoma. Multivisceral resection is safe and has an over 50% 5-year OS and almost 90% local control. Poor response for CRT in post-treatment MRI predicts LR and seems to be associated with decreased DFS in curatively treated patients. Achievement of R0 multivisceral resection is most important concerning LR and also survival. Short-course radiotherapy did not affect LR risk in pT3N1-2 rectal cancer patients. Larger studies allowing analysis of subgroups with different T3 classes and N1 and N2 groups separately are needed to evaluate the role of short-course neoadjuvant radiotherapy in T3N+ tumours.
  • Hämäläinen, Satu (Helsingin yliopisto, 2017)
    Osteoarthritis (OA) is the most common joint disease and a frequent cause of pain and disability, with the joints of the hand being the most frequently affected site. OA is a complex disorder that results from the interplay of genetic and environmental factors. It becomes more prevalent with age, and after the age of 50 a higher proportion of women are affected than men. We examined some possible genetic risk factors of hand OA with consideration of previously proposed risk mechanisms, namely: loading of cartilage structure, inflammation, and overweight. We also attempted to replicate previously found associations between hand OA and susceptibility genes, and to analyse in our material the findings of earlier publications that reported associations of gene variants with OA in joint sites other than the hand. The participants in this study were 542 dentists and teachers from the Helsinki metropolitan region. The single nucleotide polymorphism (SNP) in the COL2A1 gene, which encodes for the main collagen present in normal cartilage, and was previously associated with generalised OA, was also associated with OA in the hand; among dentists the risk was doubled in carriers of this allele compared with those with the major allele. A history of repetitive hand loading tasks combined with carrying the minor allele further increased the risk. Minor alleles of the pro-inflammatory TNFα SNPs, and their haplotype, were associated with an increased risk of hand OA. Further, interactions between TNFα, IL4R, and IL10 SNPs were found, which suggest that the effect of the TNFα polymorphisms on hand OA was modified by the IL4R and IL10 gene variants. Minor alleles of the adipokine RETN SNPs, and the haplotype containing these minor alleles, decreased the risk of ROA. The association of the haplotype with the decreased risk of hand OA was stronger in overweight women. In contrast, the RARRES2 SNP minor allele and LEPR haplotype increased the risk of hand OA. The LEP haplotype, however, was associated with a lower risk of ROA only among overweight women. These findings suggests that BMI is an effect modifier of these associations. A replication study found that the A2BP1 SNP minor allele decreased the risk of ROA, which confirms the original finding. The minor allele of the spinal OA candidate gene TGFB1 almost doubled the risk of symptomatic DIP OA. Teachers with the minor allele of ESR1 rs9340799 SNP had an almost tripled risk of symptomatic DIP OA. Furthermore, we observed interactions between SNPs and occupation in their relation to hand OA. In conclusion, 43 SNPs from 27 candidate genes were analyzed in this study and SNPs in eight of them (COL2A1, TNFα, LEP, LEPR, RARRES2, RETN, A2BP1, and TGFB1) were found to be associated with susceptibility to hand OA. Interactions between the genotypes, occupational loading and BMI were also observed.
  • Mätlik, Kert (Helsingin Yliopisto, 2017)
    Acute ischemic stroke is among the leading causes of long-term disability in developed countries. Among the contributing factors are our inability to limit brain damage in the acute-phase of stroke and the infrequency of complete spontaneous functional recovery. Effective pharmacological therapies that would protect neurons from ischemia-induced death are not available. Moreover, as of now, there are no proven pharmacological treatments to enhance the limited neurological recovery process in stroke patients. Neurotrophic factors MANF (mesencephalic astrocyte-derived neurotrophic factor) and CDNF (cerebral dopamine neurotrophic factor) are currently among the most promising molecules for the treatment for Parkinson s disease (PD). Namely, both have shown great therapeutic potential in rodent models that mimic the most conspicuous and debilitating symptoms of PD, caused by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). However, in these preclinical studies the fate of CDNF and MANF after their therapeutic intracerebral administration has been poorly characterized. While MANF has been shown to protect cortical neurons from death in a rat model of ischemic brain injury, it is unknown whether CDNF has a similar effect. Moreover, the neurorestorative effects CDNF and MANF have been shown to have in animal models of PD raise the question of whether these factors could act similarly after cerebral ischemic damage and enhance functional recovery. In order to have a better understanding of what happens to recombinant human CDNF (rhCDNF) in brain tissue, we studied its distribution, intracellular localization and clearance after infusion into rat brain. We present the pharmacokinetic properties of striatally infused rhCDNF and describe the main intracellular localization patterns after its neuronal uptake. We also present data that after intrastriatal infusion, the rhCDNF found in the SN is almost exclusively localized to the DA neurons, thus showing that it is retrogradely transported. To shed light on the possible neuroprotective potential of CDNF for ischemic stroke, we studied the effect of CDNF in the rat model of ischemic brain injury achieved by temporary unilateral occlusion of the middle cerebral artery. We show that CDNF is protective against cortical ischemic injury when administered as a recombinant protein, but unlike MANF, not when delivered via a CDNF-expressing adeno-associated virus vector (AAV-CDNF). Our findings thus unmask an important difference in MANF and CDNF s capacity for therapeutic action. Using the same rat model of ischemic stroke, we studied the effect of delayed AAV-MANF administration on post-stroke behavioural recovery, taking advantage of the delivery method we have developed in order to target the expression of AAV vector-delivered genes to the peri-infarct area. We report that AAV-MANF, delivered to the peri-infarct area two days after transient ischemia, accelerates the reversal of ischemia-induced behavioral deficits without affecting lesion size. While histological analyses of brain tissue could not point out which cellular process mediates MANF s effect, an unbiased transcriptomics approach implies modulation of the activity of innate immune cells as a possible mechanism. In summary, MANF should be considered as a possible therapeutic agent or a drug target for promoting functional recovery after stroke. In addition, we show that in cultured peripheral neurons MANF needs to be in the endoplasmic reticulum in order to exert its intracellular survival-promoting activity. We also present data on the importance of two sequence motifs of MANF for its intracellular survival-promoting activity and the neuroprotective efficacy that extracellularly applied recombinant human MANF has in the rat model of cortical ischemic injury. In summary, this work has extended the knowledge on MANF and CDNF s capacity for therapeutic action, and the pharmacokinetic and structural properties important for their therapeutic use in further studies.
  • Ciragan, Annika (2017)
    At the present time resistance to every main class of antibiotic has been observed. Therefore, the continuous development of new-generation antibiotics is crucial to combat the rise of antibiotic resistant strains. Identification of potential antibiotic targets and investigation of their structure and function represent a rational approach to developing a better understanding of the essential processes in which they are involved, and may lead to finding a mechanism to inhibit these processes. The first part of this thesis covers structural characterization and functional studies of the potential antibiotic targets TonB protein and the cell shape determining protein MreC. TonB is needed for TonB-dependent uptake of scarce nutrients, such as iron and vitamin B 12. The cell shape determining protein MreC is involved in cell wall synthesis, which is the target of penicillin and its derivatives. In this study, the three dimensional structures of the C-terminal domain of Helicobacter pylori TonB of different lengths and the C-terminal domain of Bacillus subtilis MreC were determined using nuclear magnetic resonance (NMR) spectroscopy. Additionally, interaction studies of MreC with penicillin-binding proteins were done using NMR spectroscopy and a bacterial two-hybrid system. NMR spectroscopy is a versatile tool to investigate protein structure, dynamics and interactions. One of the advantages of NMR is that proteins can be studied in solution under nearly physiological conditions. However, with increasing molecular size (> 25 – 30 kDa), structural investigation by NMR becomes more complex and often requires specific labelling techniques and alternative methodologies for NMR measurements. Segmental isotopic labelling, where only a part of the protein is stable isotopic labelled, is an attractive method to overcome the challenges of studying large proteins by NMR. Segmental isotopic labelling allows, e.g. investigation of individual protein domains in a full-length context. Furthermore, NMR is a powerful tool to study the integrity of a protein. Certain requirements, however, have to be fulfilled: the protein has to be soluble at high concentrations and stable over the whole measurement time. Therefore it is important to optimize protein production in order to obtain soluble, properly folded proteins at high concentrations. In the second part of this study, TonB has been used as a model protein to show traceless intein-mediated segmental isotopic labelling by salt induced protein trans splicing using a halophilic intein. This approach facilitates structural investigations of TonB by NMR. TonB consists of a well-structured C-terminal domain and a flexible proline-rich region, which would severely interfere with spectral quality in a uniformly labelled sample. Furthermore TonB was used as a model protein to show the benefit in protein expression of using tandem SUMO fusion vectors as tools for the expression of more soluble proteins, which tend to be expressed in an insoluble form. Both of these applications are beneficial for structural investigation of proteins by NMR and can be applied to other proteins.
  • Ahonen, Paavo (Suomen kirkkohistoriallinen seura, 2017)
    This study examines the attitudes toward the Jews among the leaders and the most important clerics of the Evangelical Lutheran Church of Finland. The study focuses especially on anti-Semitic views. The research falls within the scope of general church history, and it is made from the perspective of the history of ideas. Research sources include Evangelical Lutheran newspapers, theological and religious literature and ephemera, church records, as well as bishops' and major religious organizations' archives. The study shows that there were quite sharp anti-Semitic views in the Evangelical Lutheran Church of Finland and that almost all of the key actors of the Church approved the moderate anti-Semitic perceptions of the era according to which the influence of Jews was growing. Until now, anti-Semitism in the Church of Finland has mainly been studied in other fields of historical research, but the ecclesiastical anti-Semitic atmosphere, in the early 1920s in particular, has not been properly analyzed. Anti-Semitism was present in all key benchmark church groups, and five out the six Finnish-speaking bishops, that is Gustaf Johansson, I. O. Colliander, J. R. Koskimies, Erkki Kaila and Lauri Ingman, presented anti-Semitic ideas, but Ingman only before becoming Archbishop. Jaakko Gummerus was an exception, but he did not defend Jews either, when a strong anti-Semitic campaign broke out in his diocese at the turn of the 1930s, but rather referred to it as a side effect of anti-Communist activity. The anti-Semitism in the Finnish Church had a religious background and was justified as a part of the Christian interpretation of history, in which the Jews were subject to the curse. Anti-Semitism was, therefore, a part of an overall vision of the religious interpretation of the world. Only in a few cases the anti-Semitism was purely political or national. The Finnish Church lacked three internationally significant features of the phenomenon. Even though Jews were considered a race, this was not a clear concept. The churchmen did not underline interracial hierarchy, and Jews were never presented as a lower race. Secondly, none of the ecclesiastical key figures planned or encouraged anyone to take anti-Semitic action. The plan of new civil rights for Jews met with calls for limitations during the process, and after the passing of the law some priests considered granting the civil rights to be a mistake. Nevertheless, none of the prominent clerics proposed canceling them or imposing other restrictions on the lives of Finnish Jews. Thirdly, hatred for Jews was not preached in the Church. The anti-Semitism in the church was not an isolated phenomenon separate from ecclesiastical, political and international life. It was always tied to world events, movements of the anti-Semitic ideology, as well as internal discussions and dynamics of the Church. New openings for conversation, of course, occurred, but when examined carefully, none of the anti-Semitic outbursts were separate from the internal discussions of the church or general developments of the phenomenon. None of the leading clerics considered themselves anti-Semites, because anti-Semitism as a concept was understood in a narrow way either as hatred of Jews or as a political movement aimed at limiting their rights. On the other hand, although enmities were clearly dissociated from, none of the central ecclesiastical opinion leaders publicly questioned the prevailing notion of the negativity of Jewish aspects and practice. This study demonstrates, how flexibly, in a suitable atmosphere, the key ideas of modern anti-Semitism were connected to the Christian conception of history and the image of Jews. This study also shows, that anti-Semitism was much more common phenomenon throughout the Evangelical Lutheran Church of Finland and it even extended to the leadership of the Church.
  • Hilander, Taru (Hansaprint, 2017)
    Proteins, consisting of amino acids, work as building blocks in the cells. In addition, they carry out vast amounts of cellular functions. Accurate protein synthesis is thus crucial for the normal function of cells. The first step of protein synthesis is the charging of transfer-RNAs (tRNAs) with their cognate amino acids. Evolutionarily conserved and extremely old proteins, aminoacyl-tRNA synthetases (aaRSs), carry out this step and each amino acid-tRNA pair has its own synthetase for the task. However, in some cases the amino acids are so similar in size and structure that they cannot be separated well enough by the aaRSs. To avoid mischarging and the subsequent protein misfolding, some of the synthetases have an editing domain, which recognizes and hydrolyses incorrect amino acid-tRNA pairs. In addition, cells have other important quality control mechanisms to ensure protein homeostasis, the capacity of cells to maintain internal stability of the proteome. Patient mutations in genes connected to protein synthesis and quality control are found to cause different diseases, the mechanisms of which are not yet, however, well known. Research on these topics is thus important. The aim of this thesis was to study the molecular mechanisms of different tRNA-charging defects and protein quality control mechanisms in both protein-translating compartments of a eukaryotic cell, cytosol and mitochondria. The first part of the thesis describes the molecular mechanism and the clinical phenotype of a special cytosolic tRNA charging defect caused by mutations in SEPSECS gene. The corresponding protein is involved in charging of the 21st amino acid, selenocysteine, to its tRNA. We identified mutations in this gene and showed them to lead to a decreased amount of selenocysteine-containing proteins, selenoproteins, in the brain of a patient with a severe early onset encephalopathy. Our study also indicated increased protein oxidation in the patient brain. This study extends the clinical phenotypes connected to SEPSECS mutations, and indicates that selenoprotein synthesis defect can resemble mitochondrial disease with lactate elevation. In the second part of this thesis, the potential of an amino acid analogue of arginine, canavanine, to induce protein misfolding in mitochondria was studied. The results demonstrated that mitochondrial protein translation machinery does not distinguish canavanine from arginine. The amino acid analog was incorporated into mitochondrially encoded proteins causing protein instability and formation of aberrant polypeptides. Surprisingly, however, canavanine did not induce mitochondrial unfolded protein response (UPRmt), a previously described signalling pathway induced by accumulation of misfolded proteins inside mitochondria. The study showed that none of the protein quality control mechanisms were able to solve protein misfolding caused by canavanine, which led to a severe respiratory chain defect. Canavanine has been used previously in a large number of studies to induce cytosolic protein misfolding, but the impact of canavanine for mitochondrial function has been largely ignored. Canavanine can be used in future as a tool to study further the consequences of protein misfolding in mitochondria, and for studying how mitochondria solve stalled ribosomes, which was also detected to be a consequence of canavanine in our study. The goal of the third part of the thesis was to study UPRmt in an animal model. The purpose was to generate a mouse model that has a mutation in the editing domain of mitochondrial alanyl-tRNA synthetase, leading to amino acid mischarging and formation of unfolded proteins inside mitochondria in vivo. The result of the study indicated for the first time the importance of amino acid editing by a tRNA synthetase as an essential quality control mechanism in mammalian mitochondria. The work presented in this thesis provides new information concerning the mechanisms of different tRNA charging defects and their consequences for the cell and organism. Special emphasis was on mitochondrial function.