Doctoral dissertations

Recent Submissions

  • Fink, Christoph (Helsingin yliopisto, 2021)
    Data from digital media are increasingly used in conservation science. They help researchers and policymakers learn about the beliefs and values of people and their interactions with non-human nature, and observe relevant news and events on a global scale. In the ongoing global biodiversity crisis, this know­ledge becomes crucial. It is predominantly human activities that drive plant and animal species into extinction and destroy sensitive ecosystems (on which our wellbeing and survival depends). Knowing about people’s environmental perceptions is an important stepping stone in promoting a change away from unsustainable habits and a transition to more sustainable lifestyles. In this thesis, I explore, develop, and evaluate novel methods and approaches to unlock the new opportunities digital media offer to conservation science. The five individual publications that form chapters of the thesis build upon each other: first, I present a comprehensive review of relevant data sources and methods. In the second chapter, I discuss the data privacy implications of using digital media data in conservation science research. The third chapter presents a general framework to collect, filter, and identify social media data related to illegal wildlife trade. The fourth and fifth chapters, then, combine the findings of the first three: I demonstrate how to identify conservation-relevant events from the public opinion on social media and in online news, and investigate the online songbird trade in Indonesia, its price structure and the spatial characteristics of its supply chain. The concepts, the methods, and the openly-available tools presented in this thesis can guide conservation scientists and practitioners, as well as researchers in other fields, and inspire them to use digital media data in their own work.
  • Knif, Leena (Helsingin yliopisto, 2021)
    Diverse Visual Arts: engaging spaces, equality acts, artistically known agency. Finnish basic education is based on the principles of equality and parity. However, studies have shown that the acts and practices of education, despite the best intentions, often strengthen inequality. Diversity education has not yet found a functional way of implementation in Finnish basic education or in teacher training. The task of this doctoral thesis is to clarify how diversity can be supported in visual arts education at the primary level of basic education. The task builds on the theories of equality and parity that aim for social justice, acknowledging priorities, building meanings and researching one’s place in a society and are common to both diversity education and visual arts education. The basis of practical visual arts education supporting diversity has been studied and developed through the stages of an empirical case study. The study consists of three qualitative and action-based and art-based case studies connected through the themes of diversity, the visual arts in primary education and the aim of developing education through participatory methodology. The first case focused on cultural codes and images as cultural texts. The data in this case consisted of 5th grade pupils’ (N=57) writings about Finnish national artworks in 2013. The second case was the Myrsky-community art project, held at a primary school in 2013-2014. The data for this case comprised observations of plans, actions and the artistic processes of the project and the knowledge gained during it, through interviews, questionnaires and the work diaries of pupils (N=45). The third case was a visual arts course at the University of Helsinki in class teacher training in 2016, in which students (N=25) planned and executed visual arts workshops for primary schools in the theme “equality and parity”. The data consists of the students’ study diaries. The data were analyzed using the methods of qualitative content analysis. This article-based doctoral thesis consists of four published articles and this compilation part. The study made the paradigm changes visible both in diversity and visual arts edu-cation. It strengthened the notion of the white Finnish norm and showed that its visual orders are strongly present at the primary school pupils´ conceptions of Finnishness. The study emphasized the importance of recognizing the inequalities and the importance of equality as the starting point of all education. The visual arts can be a functional platform for supporting diversity through its own way of knowing and building social engagement, agency and positions. The visual arts can work performatively through active continual processes, when the focus is not on the results but on the social categories, not on the products but on the community, in which meanings, interpretations, identities and cultures build and rebuild in polyphonic dialogue, artistic negotiations. Since social engagement is seen as communal empowerment and competence, it requires the development of critical and aware agency and creativity that can rebuild the culture. In that task, visual arts education as a critical, aware and creative subject, can offer a functional diversity supporting space of learning even in primary education.
  • Štukelj, Jernej (Helsingin yliopisto, 2021)
    The two parameters used to characterize the effect of a drug in the body are potency and selectivity. Despite their importance, the biopharmaceutical classification system (BCS) and the developability classification system (DCS) are constructed based on permeability and solubility. Furthermore, solubility is not only a molecular property as it is highly affected by the solid-state of a compound. Thus, obtaining a complete understanding of the solid-state impact on the solubility of a drug candidate early in the drug development process is crucial for well-informed decision-making. The overall aim of this thesis was to detect, investigate and quantify the impact of different solid-state forms on the solubility of pharmaceutical compounds using the image-based single-particle analysis (SPA) method. First, the apparent solubility of polymorphs in different solvents was measured. It was demonstrated that the solubility ratio between the two polymorphs is determined by the difference in Gibbs free energy between the polymorphs and it is not affected by changes in pH, ionic-strength and surfactant concentration in dissolution media. Next, the amorphous solubility of a particulate quench-cooled amorphous sample was measured directly. The results correlated well with the two orthogonal methods – standardized supersaturation and precipitation method, and theoretical estimation based on thermal analysis. Moreover, the direct approach of measuring amorphous solubility has proven superior when dealing with highly hygroscopic and fast crystallizing samples. Furthermore, the newly established direct approach of measuring amorphous solubility was then, concurrently with X-ray powder diffraction, used to track two amorphous samples stored at different conditions over an extended period of time. Differences in the crystallization process and its impact on solubility were observed. Machine-vision-detected solid-state changes were demonstrated to provide additional information for the interpretation of the measured pH-solubility profiles of pharmaceutical salts. Based on pH-solubility profiles, values such as pKa, pHmax and Ksp were easily obtained. Moreover, the potential effect of the microenvironmental pH shift was evaluated in the context of solubility measurements. Finally, the solubility of extremely poorly soluble drug – itraconazole – and its co-crystals was measured across a wide pH range and also in biorelevant buffers. A considerable improvement in solubility was detected upon co-crystal formation. Moreover, the solubility of itraconazole in biorelevant buffers was in good agreement with the results in literature obtained previously by the conventional shake-flask method. In summary, all of the above was achieved with less than 100 μg of a sample per measurement. Moreover, non-specificity and the demonstrated broad applicability make the SPA method highly suitable for use in the early stages of the drug discovery and development. The possibility of acquiring a broad level of physicochemical characterization using a single analytical method could significantly accelerate and improve data acquisition leading to enhanced understating of solid-state impact on solubility. Furthermore, with the data quality comparable to the current ‘gold standard’ technique the SPA method could thread the path towards more accurate in silico solubility predictions. Thus, eventually leading to more informed decision-making processes and, finally, optimized and more affordable drug products.
  • Karhu, Tuuli (Helsingin yliopisto, 2021)
    Heart failure is a common costly disease that remains one of the leading causes of mortality in the world. Current treatments benefit heart failure patients by relieving the symptoms and improving the quality of life; however, they do not provide a cure for the disease. The adult human heart has a very limited capacity to regenerate cardiomyocytes. Therefore, following cardiac injury, the cell loss results in the formation of a fibrotic scar and consequent remodelling process, which includes thickening and stiffening of the ventricular wall. Eventually, this leads to impaired cardiac function. The fundamental goal of heart failure therapy is to restore the cardiac function and to prevent the pathological remodelling process. The transcription factor GATA4 plays an important role in cell survival, myocardial regeneration, and cardiomyocyte hypertrophy, and is therefore considered as an attractive drug target for cardiac repair. On the other hand, several studies have suggested that protein kinase C (PKC) plays a role in cardiac fibrosis. However, the results are conflicting and the role of PKC specifically in cardiac fibroblasts is unclear. Early drug discovery projects have traditionally used immortalized cell lines and primary cells from experimental animals to assess the effects of novel compounds. The translatability of the results from these models to human, however, is limited. Today, the emergence of the human induced pluripotent stem cell (hiPSC) technology allows for the production of human-based cell models, which more closely resemble the physiological cell types. The aim of this thesis project was to characterise pharmacological and toxicological effects of small molecules targeted to GATA4 or PKC, to compare different cell models in in vitro compound testing, and to establish a chronic cardiotoxicity model using human-based cardiomyocytes. In the study, nine different cell models were utilised, including hiPSCs, cardiomyocytes derived from hiPSCs, cardiomyocytes isolated from neonatal rats, and cardiac fibroblasts isolated from adult mice. The effects of the small molecules on cell viability, proliferation, and morphology were investigated using colorimetric cytotoxicity assays, immunocytochemistry, and high-content analysis (HCA). The effects on gene expression, protein levels, and cellular kinase activity were studied using the quantitative polymerase chain reaction (qPCR), western blotting, and AlphaLISA® technology, respectively. The toxicity screening of GATA4-targeted compounds revealed a characteristic molecular structure that is predominantly responsible for the toxic outcome in hiPSCs, which proved to be the most sensitive screening tool to identify toxicity. The results also demonstrate that long-term low-dose exposure of hiPSC-derived cardiomyocytes can be used as an in vitro model of delayed doxorubicin-induced cardiotoxicity and provide evidence that targeting GATA4 by small molecules may counteract doxorubicin-induced cardiotoxicity. Finally, the results reveal distinct PKC-dependent regulation of cardiac fibroblast transdifferentiation and proliferation and suggest that fibroblast-targeted PKC activation may be a promising strategy to inhibit cardiac fibrosis. Overall, the results highlight the importance of selecting an appropriate cell type and experimental model for compound testing and support further development of both GATA4-targeted compounds and PKC activators.
  • Michallik, Radoslaw Markus (Helsingin yliopisto, 2021)
    The Luumäki gem-beryl bearing pegmatite belongs to the miarolitic pegmatites, a comparatively rare and little studied pegmatite class. However, it is the miarolitic pegmatites that give raise to the scientific hypothesis about the involvement of aqueous fluids during pegmatite formation. The controversy regarding the involvement of a separate aqueous fluid was renewed in view of recent interpretations of giant crystal growth and graphic granite textures, which are both quite unique for pegmatites. And recent understanding favors a model where pegmatites are being formed by rapid cooling and crystallization from a volatile-rich melt, instead of very slow cooling of an undercooled, water-saturated granite melt. Some argue that H2O is essential for reducing the viscosity of granite melts and the element transport to form giant crystals in pegmatites, based on fluid inclusion studies and the water-saturated melt model proposed by Richard Jahns and Wayne Burnham. Recently this model has been redefined by studies on melt and fluid inclusions suggesting a melt-melt immiscibility with subsequent aqueous fluid exsolution, as suggested by Rainer Thomas. Others reason that refining of a melt, similar to the metallurgical process of zone refining, is key for pegmatite consolidation, and a separate H2O phase plays a minor role if any at all. The proposed model is the constitutional zone refining (CZR) by David London. My study supports the view of a separate aqueous phase in the late stage of pegmatite crystallization and demonstrates that in the case of the Luumäki pegmatite, an aqueous phase separated at the onset of pocket formation at about 380 °C and 1.2 kbar. Furthermore, it is shown that a pegmatite melt is very heterogeneous and within the same pegmatite body one miarolitic pocket can clearly show evidence for a hydrothermally dominated system, while another represents a magmatic dominated process of formation without clear evidence of the involvement of an aqueous fluid. Also, pegmatite bodies within the same geological framework can differ in their appearance, showing that within a small area of just a few hundred of meters one pegmatite body can show extensive hydrothermal activity whereas the other lacks any evidence of an aqueous fluid separation. The research of pegmatites and their fluid inclusions is a somewhat complicated endeavor, similar to solving a puzzle, in which most pieces appear very similar to one another, and many more studies need to be conducted to solve such a puzzle. Powerful analytical methods such as in-situ fluid inclusion analysis by means of LA-ICP-MS is a step in the right direction and will hopefully encourage many more to engage in this tedious, yet gratifying search for the bigger picture by looking at the small individual pieces in greater detail as ever before.
  • Niskanen, Lauri A. (Helsingin yliopisto, 2021)
    A Hubbub of Phenomenon: The Finnish and Swedish Polyphonic Translations of James Joyce’s Ulysses explores James Joyce’s Ulysses (1922) and its Finnish and Swedish translations and retranslations as polyphonic intertextual processes. I call this new, experimental view of translation – presenting translation and retranslation as a polyphonic hubbub of voices, a choir of competing and supplementary comments on a source text – the Polyphonic Translation Model (PTM). Every translation is fundamentally polyphonic, as translation can never carry the source text over to a new target audience as such but must always rather represent the original text in its place in the new lingual and cultural context. In A Hubbub of Phenomenon, however, the focus is on translations of explicit cases of literary intertextuality and intermediality. The study construes the process in which translations and retranslations form a polyglot macrotext, in which the source text is commented on, reread, and rewritten. The question is approached through Gérard Genette’s notion of palimpsest: the source text and earlier translations are present “under the surface” of a new translation. The relationships between these texts are studied from the viewpoint of intertextuality. The study focuses on James Joyce’s Ulysses, a source text in which the implicit intertextual nature of all texts is made explicit through intertextual literary techniques such as pastiche, parody, and the musicalization of fiction. In my thesis, I study the way Joyce’s influential novel exists for Finnish and Swedish readers. The material of the study is the Finnish and Swedish translations of the book, which vary widely in their translation project and the horizon of the translators: Thomas Warburton’s Odysseus (1946/1993), Pentti Saarikoski’s Odysseus (1964), Erik Andersson’s Ulysses (2012), and Leevi Lehto’s Ulysses (2012). Comparisons between these translations and retranslations make the problematic of translating intertextual literary structure become clearly visible. Furthermore, much of the cultural and literary value bestowed upon Ulysses was originally “found in translation”, as Stuart Gilbert wrote the first major study of the book on the basis of his conversations with Joyce during the process of the first French translation of the book. In A Hubbub of Phenomenon I study how different translations re-create the intertextual material of Joyce’s Ulysses in a new cultural context. Literary translation is understood as a process, a polyphonic dialogue, in which various texts – the source text, its various translations into different languages, and different translations into a single language – act as agents. The polyphonic model is based on Mikhail Bakhtin’s notion of literary polyphony as well as the productive translation criticism of Antoine Berman. Berman sees first translations and retranslations as a continuous, self-correcting process. In Berman’s method, translations are analysed on the basis of the translating position, the translation project, and the horizon of the translator. Berman calls the norms and expectations that define translation in a certain culture and a certain time, and the translator’s relationship to this discourse, the translating position. The conception of what the first translator or retranslator sets out to achieve, the composite of the translating position and the demands of the task at hand, Berman calls the translation project, an articulated purpose. The translating position and the translation project together are what Berman calls the horizon of the translator, the horizon of understanding in which the translation is received. The study of the translations of Ulysses uncovers explicitly something usually implicit in the processes of translation and retranslation, but conversely the study of these particular translations also uncovers new aspects of Ulysses, and more widely the techniques of intertextuality employed in it: parody, pastiche, and the musicalization of fiction. In light of the focus on intertextual structure in the dissertation, the episodes analysed through close reading are episode 12, ‘Cyclops’ for parody, episode 14 ‘Oxen of the Sun’ for pastiche, and chapter 11, ‘Sirens’ for intermediality, namely the musicalization of fiction. For the analysis of episode 14, ‘Oxen of the Sun’, I have created a digital companion for the study, The Oxen of the Sun hypertext (OSH). This novel and experimental device, employing the methods of the digital humanities, works as a machine-assisted tool for the reader of this dissertation. It allows a more extensive and intensive analysis on how the hypertext of the ‘Oxen of the Sun’ episode refers to its hypotexts from the history of English prose, and how these imitations are conveyed in the four Finnish and Swedish target texts.
  • Lantto, Juulia (Helsingin yliopisto, 2021)
    Changes in oxygenation and placental function affect foetal cardiac function and circulation. Congenital heart defects alter normal circulation of blood flow, which may further alter cardiac development and function. In distress, the foetus can adapt to the situation by altering energy consumption, enhancing cardiac function, and redirecting blood to critically vital organs. The main objective of this thesis was to investigate the responses of foetal cardiovascular function to hypoxaemia and in situations when the normal circulation is altered either by pharmacologically increasing the placental vascular resistance or by mechanically occluding the ventricular outflow tracts. The specific aims were to study the factors affecting the redistribution of blood flow to critical organs, the responses of the ventricles and the role of different foetal shunts during changes in blood flow. Chronically instrumented late gestation foetal sheep were studied. Foetal hypoxaemia was induced by increasing placental vascular resistance with angiotensin II (ATII) infusion (I) or by maternal hypo-oxygenation (IV). In addition, blood circulation was altered by mechanically occluding the foetal ascending aorta (AaO, II) or the main pulmonary artery (PaO, III). In each study, foetal cardiac function and central and peripheral haemodynamics were assessed with spectral and pulsed-wave Doppler ultrasonography concomitantly with invasively monitored foetal blood pressures and arterial blood samples. Additionally, tissue Doppler imaging (TDI) was used in studies I-III to study myocardial systolic and diastolic function. ATII infusion led to foetal hypoxaemia and metabolic acidaemia (I). The earliest signs of cardiac dysfunction were seen on TDI parameters describing diastolic function, and these changes were seen earlier in the left ventricle (LV). AaO led to LV systolic and diastolic dysfunction, while the right ventricle (RV) was able to improve its systolic function; however, RV diastolic dysfunction developed (II). There were signs that the AoI could not provide adequate blood flow to the cerebral circulation (II). During PaO, the FO blood flow slightly increased, but it could not fully compensate for the drop in RV cardiac output and pulmonary return (III). In addition, PaO led to RV systolic and diastolic dysfunction, and LV systolic dysfunction developed, while LV diastolic function was preserved. During foetal hypoxaemia without placental compromise, the peripheral chemoreflex was seen to function even during prolonged hypoxaemia and metabolic acidaemia (IV). AoI was able to increase blood flow towards the brain, however, the perfusion pressure towards the brain decreased. The findings of the current study show that the foetal special circulatory areas, such as FO and AoI, may have limited capacity to support adequate redistribution of highly oxygenated blood towards cerebral circulation in late-term pregnancy. In addition, the cardiac outputs did not increase during hypoxaemia and metabolic acidaemia. This is of great importance as foetuses with congenital heart defects have altered circulation and cardiac function, and foetuses with placental insufficiency have diminished reserves to enhance their oxygenation and cardiac function. These foetuses could be at great risk of foetal compromise in late-term gestation.
  • Awad, Shady (Helsingin yliopisto, 2021)
    Chronic myeloid leukemia (CML) is an adulthood leukemia that accounts for 15% of all leukemia patients. The hallmark of the disease is the BCR-ABL1 fusion gene. The development of Tyrosine kinase inhibitors targeted therapy has led to dramatic improvement in CML management with the life expectancy of CML patients approaching normal rates. Nevertheless, certain challenges in CML management remain unmet. CML progression from the chronic phase (CP) to the blast phase (BP) occurs in 5% of CML patients and is associated with dismal survival. Additionally, a minority of CML patients express p190-BCR-ABL1 isoform, which is associated with inferior treatment responses. Characterization of the mechanisms underlying the pathogenesis of high-risk CML is warranted to enable optimization of the therapeutic approaches for these patients. We aimed to investigate the role of mutations at different phases of CML, and to identify genetic biomarkers that allow better risk assessment and optimization of CML management. Furthermore, we integrated genetic and drug sensitivity profiling to identify effective drugs in a personalized medicine approach. In study I, we applied comprehensive sequencing techniques to a cohort of 59 CML patients, including 19 BP and 40 CP patients. In comparison to CP, BP patients demonstrated higher mutational load and were associated with recurrent mutations involving ABL1, ASXL1, and RUNX1 genes. Fusion genes were also identified as recurrent genetic abnormalities in BP patients. Cancer-associated gene mutations correlated with inferior treatment outcomes in CP patients. Finally, we presented two BP patients who were managed using a personalized approach and achieved good responses, highlighting the potential power of this strategy in BP management. In study II, RUNX1 was selected as an example driver mutation in CML progression. RUNX1 mutations were identified in 35% of patients. We also identified mutagenic AID/RAG axis activity which was specific to RUNX1-mutated patients. RUNX1-mutated BP patients demonstrated the overexpression of lymphoid transcription factors as well as aberrant expression of lymphoid antigens (CD19/CD7). We identified targeted therapies with enhanced sensitivities in RUNX1-mutated blasts. We further used CRISPR/Cas9 gene editing to model RUNX1 mutations in cell lines. Finally, we demonstrated the efficiency of CD19 CAR T-cell immunotherapy in targeting RUNX1-mutated blasts. In study III, we performed genomic and phosphorylation profiling for four p190-CML patients and validated findings in two progenitor cell lines (Ba/f3 and HPC-LSK). We demonstrated novel evidence for the p190-specific activation of IFN/JAK1/STAT1 pathway in CML. Other important signaling pathways included Src and PAK1 signaling. We also identified novel p190-specific drug vulnerabilities. Finally, we validated these findings in a cohort of Ph+ ALL patients. In conclusion, our study provides novel insights into the molecular pathogenesis of high-risk CML patients, including BP-CML and p190-CML patients. We identified potential biomarkers, which can be involved in the risk-assessment of CML. Integration of genetic and drug screening data enabled the identification of promising drug candidates. Taken together, we highlighted the potential value of the personalized medicine approach for optimizing the management of high-risk CML patients.
  • Ala-Houhala, Mari (Helsingin yliopisto, 2021)
    Invasive fungal diseases (IFD) cause significant morbidity and mortality in immunocompromised and critically ill patients. Candida is the most frequent species that causes IFDs. However, other invasive mycoses such as aspergillosis and infections caused by other rarer fungal pathogens, have been reported to emerge. Diagnosis of IFDs is challenging. Culture and histopathology are the foundation of the diagnosis. However, more accurate and rapid diagnostic methods are needed. The purpose of this study was to assess the clinical use of panfungal polymerase chain reaction (PCR) in diagnosing IFD. The study also aimed to provide recent epidemiological data for candidemia in the hospital district of Helsinki and Uusimaa and to analyse the risk factors for 30-day mortality in candidemia. The risk factors for persistent and characteristics of recurrent candidemia were also analysed. Study I was a retrospective cohort study that analysed the clinical use of panfugal PCR to diagnose IFD. We focused on specimens taken from normally sterile tissues and fluids. We compared results of panfungal PCR test to the results of culture and histopathology in 307 specimens. The likelihood of an IFD was evaluated with the criteria of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG). Studies II-IV were retrospective, cohort studies. All patients with candidemia were identified from the microbiological database between 2007 and 2016. Study II included 350 patients with a positive blood culture results for Candida species. The study period was divided into two 5-year periods to analyse the changes in the epidemiology of candidemia. The main outcome mesure was 30-day overall mortality after the diagnosis of candidemia. In study III, we compared the patients with persistent candidemia (PC) with non-persistent cases. PC was defined as an isolation of the same Candida species from blood culture ≥5 days. In study IV, we compared patients with late recurrent (LR) candidemia and patients with a single candidemia episode to analyse the characteristics of LR candidemia. LR candidemia was defined as having at least two episodes of candidemia ≥30 days apart. Panfungal PCR was positive in 48 specimens, and 23 patients of these had a proven or probable IFD. The sensitivity and specificity of panfungal PCR in diagnosing IFD was 61% and 92%, respectively; the negative predictive value and positive predictive value were 93% and 54%, respectively. C. albicans was the leading cause of candidemia and the distribution of Candida species showed no significant change during the study period. The overall 30-day mortality was 31%. McCabe score 3, ICU stay at the onset of candidemia and age >65 years were independent risk factors for 30-day mortality. An association between 30-day mortality and early start of effective antifungal treatment was not observed, although an effective antifungal treatment was a protective factor against mortality. PC was observed in 75 (21%) patients. Metastatic infection foci, presence of central venous catheter (CVC) and ineffective empirical antifungal therapy were independent risk factors for PC. LR candidemia was an uncommon event and diagnosed in 6% of all patients with candidemia. LR candidemia was associated with a history of intravenous drug use (IDU) and underlying gastrointestinal diseases. Diagnosis of IFDs remains challenging. Our results show that panfungal PCR aids in the diagnosis of IFDs; however, panfungal PCR should be combined with other diagnostic methods. A significant shift to non-albicans Candida species causing candidemia was not observed in our hospital district during the study period. An early start of effective antifungal agent was not a protective factor against 30-day mortality. Effective antifungal treatment is beneficial in candidemia, but the early initiation of the medication seems not to be as crucial as it is in bacterial septic shock. Removal of CVC as early as possible, and search and treatment for metastatic infection foci are key elements for preventing PC.
  • Parri, Elina (Helsingin yliopisto, 2021)
    Dysregulated cellular signaling pathways provide cancer cells survival advantage and support their abnormal growth. In large granular lymphocytic leukemia and aggressive NK-cell malignancies, signal transducer and activator of transcription 3 (STAT3) is frequently mutated, resulting in a constitutively active protein, but do not alone explain the development of the disease. In addition, mutations in tumor suppressor p53 (TP53) worsen the prognosis of NK-cell malignancies. In cancers, activation of the STAT3 is associated with enhanced cellular transformation, increased metastasis and drug resistance. Direct therapeutic targeting of STAT3 has proven to be challenging and only a few direct STAT3 inhibitors have entered early phase clinical trials. So far, the most promising inhibitors of JAK/STAT-signaling are Janus-kinase (JAK) inhibitors, of which several are clinically approved. Using RNA-interference and drug screening applications, we identified new approaches for targeting hyperactive STAT3 and identified drug combinations for targeting JAK/STAT dependent malignant NK-cells. Furthermore, we have used biochemical screens for validating novel computationally predicted kinase-compound interactions. In study I, we identified novel kinases (CDC7, CSNK2, DDR2, CDK8, PI4KII, CSK) and a phosphatase (PTPRH) that regulate oncogenic STAT3 activity. By using inhibitors targeting identified kinases, we observed a reduction of STAT3 activity both at the transcriptional and phosphorylation level. In study II, using drug screens and extended drug perturbations, we found that malignant NK-cells did not develop resistance against drug combinations containing a JAK inhibitor ruxolitinib. Our data suggest that tipifarnib-ruxolitinib and idasanutlin-ruxolitinib combinations are effective depending on the STAT3 or TP53 mutational status of the malignant NK-cells. In contrast, dexamethasone-ruxolitinib was effective independently of the mutational status. Among these, the dexamethasone-ruxolitinib combination is under clinical evaluation for other hematological malignancies such as multiple myeloma. In studies III and IV, we validated computationally pre-screened kinase-compound interactions. Using a combined computational-experimental approach, we identified novel off-target effects for vascular endothelial growth factor receptor (VEGFR) inhibitor tivozanib and unveiled new lead-molecules targeting protein kinases. This thesis gives a new understanding on oncogenic STAT3 signaling, provides approaches for indirect STAT3 targeting and, based on in vitro data, suggests novel drug combinations for targeting NK-cell malignancies. The collaboration efforts of combining computational-experimental methods provide a better understanding of compound-kinase interactions and allow cost-effective in silico pre-screening tools for advancing identification of leads and off-target effects of kinase inhibitors.
  • Koev, Evgenii (Eugen) (Helsingin yliopisto, 2021)
    The dissertation consists of an introduction and three esssays. Each essay focuses on certain specific empirical and methodological questions in the field of economics of gender and gender inequality. The first essay investigates the association between feminization and returns of Finnish master's degree-programs. Results from a panel data model show that, for graduates from master's degree programs in Finland, during the period between 1987 and 2017, a systematic positive association existed between the programs' female share changes and the income changes of its graduates. I discuss two mechanisms that could explain the result. On the other hand, repeated cross-section analysis suggests that the return on markedly feminine degree programs has further deteriorated. This finding requires further investigation but is likely to be linked to the role of public sector employment for graduates from these programs, public sector budget constraints, and the public sector's role in determining the supply of university education in Finland. The second essay is a methodological contribution to the so-called Oaxaca-Blinder decomposition, which is at the heart of empirical gender wage gap research. I show that part of the categorical variable's wage-structure difference effect in the detailed Oaxaca-Blinder gender wage gap decomposition is identified without coefficient restrictions or other additional assumptions. The finding means that the wage gap contribution of each categorical variable that affects wages can be evaluated more comprehensively than has been thought up to now. Empirical results showed that in the Finnish private sector, between 28 and 35 per cent of the gender wage gap in 1995 and between 15 and 25 per cent in 2013 is accounted for by wage-structure differences traceable to specific variables. In the third essay, I study the importance of the firm-specific wage components for the gender wage gap in private sector blue-collar occupations in Finland. It turned out that firm-specific wage premiums differ both by gender and by gender dominance of the occupation. Firm-specific factors account for 1/3 of the gender wage gap in female-dominated blue-collar occupations. For male-dominated blue-collar occupations, the results are somewhat inconclusive, but firm factors may be a much less important source of the gender wage gap in this group. I contribute to the method used in this type of study in two ways. Firstly, in the empirical analysis, I use the fact that the gender wage gap effect arising from within-firm differences in male and female wage premiums (the bargaining effect) is partly identified directly from the wage model. Under plausible assumptions, this effect is a lower bound of the full bargaining effect. Secondly, I also quantify the uncertainty associated with identifying the full bargaining effect. This uncertainty is high for male-dominated blue-collar occupations in the data.
  • Hackman, Greetta (Helsingin yliopisto, 2021)
    Prostate cancer is the second most common cancer worldwide and the most common cancer in Finland among men. While the prognosis of low-risk localised prostate cancer is excellent, a substantial proportion of prostate cancer patients experience disease progression after first-line treatment. This doctoral dissertation includes four studies that focused on active treatment options for prostate cancer patients with adverse pathologic features or risk factors associated with increased disease recurrence and/or mortality. Epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in prostate cancer and resistance to radiotherapy in several solid tumours. In the first two non-randomised trials, the objective was to evaluate the safety and efficacy of 250 mg once daily gefitinib, an orally active EGFR inhibitor, in prostate cancer patients. In the first (phase I/II) trial, 42 patients with nonmetastatic prostate cancer received gefitinib in combination with radical radiotherapy as the first-line treatment. In the second (phase II) trial, 30 patients with biochemical recurrence following radical treatment received gefitinib monotherapy. The third study was a retrospective patient series of 46 patients with previously untreated metastatic prostate cancer—a diagnosis that continues to have poor overall survival. This study evaluated the safety and efficacy of multimodal treatment, including androgen deprivation and radical radiotherapy. In addition, the patients received various individually planned treatments. The fourth study was a multicentre trial that randomised 250 radical prostatectomy-treated patients into an adjuvant radiation (126 patients) or observation (124 patients) group. All patients had positive surgical margins or extracapsular extension, both of which have been associated with increased prostate cancer progression; however, it was unclear whether these patients benefit from adjuvant radiation after surgery. While most of the adverse events in the first study were mild to moderate, the toxicity of gefitinib in combination with radiation was unacceptable, considering that most patients had low-risk prostate cancer with a favourable prognosis even without any active treatments. In studies II–IV, the toxicity was acceptable. The efficacy of gefitinib in prostate cancer patients was modest, both in combination with radical radiotherapy and as a monotherapy. The multimodal treatment approach in metastatic prostate cancer was promising but requires further confirmation in randomised trials. Adjuvant radiotherapy following radical prostatectomy resulted in significant improvement in patients’ biochemical recurrence-free survival when compared to surgery alone. However, salvage radiation upon biochemical recurrence following surgery appeared equally effective in terms of overall survival. Prostate cancer patients with adverse pathologic features or risk factors form a heterogeneous group of patients with different prognoses. To balance the subjective experience of treatment toxicity and the treatment’s expected efficacy on survival, the patient must be adequately informed about the toxicity profiles of the treatments available as well as the risk for later disease progression. The aims of future research include more accurate risk-profiling for each prostate cancer patient, a better understanding of individual disease characteristics, and, thus, the identification of optimal treatments.
  • Kaartokallio, Tea (Helsingin yliopisto, 2021)
    Pre-eclampsia is a complex vascular pregnancy disorder characterised by systemic endothelial dysfunction and often impaired placental development. The course of the disease is unpredictable and severe forms of the disease may threaten the lives of both the mother and her child. Indeed, pre-eclampsia is a major cause for maternal and perinatal mortality, especially in countries with limited access to maternal and neonatal health care. The risk of pre-eclampsia involves a genetic component conveyed by both the maternal and fetal genomes. Based on the largest genome-wide association study on maternal pre-eclampsia, the risk of the disease is influenced by many of the genetic loci previously implicated in hypertension. However, the hypertension risk variants do not fully explain the genetic risk of pre-eclampsia and variants involved in other physiological processes, such as placental development, are also likely to play a role. As pre-eclampsia reduces reproductive success, any predisposing large-impact variants are assumed to be pruned out to low population frequencies by negative evolutionary selection. Deleterious low-frequency variation, on the other hand, is enriched in population isolates, where evolutionary selection has not had enough time to effectively prune out the harmful variation. Due to the consequent boost in statistical power to detect genetic associations, studies in population isolates, such as the Finnish population, offer a feasible option for exploring especially low-frequency pathogenic variation. The aim of this thesis was to identify genetic risk factors of pre-eclampsia in the Finnish population isolate. The thesis includes two studies on a protective candidate gene HMOX1 that is crucial for vascular and placental function and has previously been linked to cardiometabolic diseases. In the other two studies, we performed genome- and exome-wide scans in families and sporadic cases of pre-eclampsia, respectively. The main sources for the samples in the thesis were the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) case-control cohort and the pre-eclampsia family cohort predominantly originating from a north-eastern population isolate. Initial findings of the screening studies were also evaluated in samples from two large population-based studies, Sequencing Initiative Suomi (SISu) and FinnGen. In the HMOX1 studies, we found that a functional promoter microsatellite was associated with both maternal and fetal pre-eclampsia. The long maternal repeat was associated with the late-onset, less severe phenotype whereas the fetal association was observed especially for the early-onset and severe forms of the disease. In accordance with these findings, we confirmed the previously reported impact of the microsatellite length on the heme oxygenase 1 (HO-1) protein levels, but here for the first time during pregnancy. The long maternal repeat was associated with reduced gestational serum HO-1 while the long fetal repeat showed an association with decreased HO-1 levels in placenta. These results suggest that HMOX1 is associated with pre-eclampsia through both maternal and fetal genomes, likely acting through separate mechanisms. In the exome-wide screen, we searched for pre-eclampsia-enriched low-frequency variants based on whole-exome sequencing data from a hundred pre-eclamptic women and aimed to validate the identified candidates by testing their association with pre-eclampsia in a larger set of case-control samples (1344 cases and 6817 controls). Four variants were nominally associated with pre-eclampsia, but none of them reached statistical significance after correcting for multiple testing. We conclude that larger sample sizes will likely be needed to reveal large-impact risk variants of sporadic pre-eclampsia, even in a population isolate like Finland. In the family study of pre-eclampsia, we performed linkage analysis in 15 extended families, both for the maternal and fetal phenotypes, using genome-wide imputed SNP markers and parametric linkage analysis. We identified 15 maternal and 27 fetal loci that segregated with the disease. In order to evaluate if there was an overlap between the risk loci in the families and the general population, we tested whether the suggestive case-control association signals from the maternal meta-analysis of ~90 000 samples and fetal analysis of ~1700 samples would be enriched in the linkage regions. Evidence of such enrichment was, however, not observed in our study, implying that the risk loci identified might be largely specific to the families. Finally, we searched for linkage region candidate variants in 21 exome sequenced pre-eclamptic women from 6 families and genotyped the identified variants in the whole family cohort. Four previously unknown or rare missense variants in the linkage region genes COL6A3, DGKB, EEPD1, and PITPNM1 were found to segregate with pre-eclampsia either fully or partially. As each of the candidates was found in only one of the families, additional support from independent genetic or functional studies will be required to establish their connection with pre-eclampsia. In conclusion, the studies of the thesis shed light on genetic susceptibility of pre-eclampsia by identifying novel risk variants and loci for both the maternal and fetal phenotypes. We also demonstrate the benefits of utilising the family and population isolate based designs, especially in the search for rare risk variants of complex reproductive diseases such as pre-eclampsia.
  • Seppälä, Miia (Helsingin yliopisto, 2021)
    Tongue squamous cell carcinoma (TSCC) is one of the most aggressive cancers in the oral cavity or oropharynx. Its 5-year survival rate is approximately 70%. TSCC has a poor prognosis due to early metastasis via lymphatic vessels. This thesis describes the immunoexpression of CIP, IDO, Podoplanin, vWf, and CDH3 in primary tumor, tumor recurrence, and lymph-node metastasis in the mobile tongue and base of TSCC. We also determined the level of mucosal inflammation, lymphatic vessel density, and diameter and their predictive role in TSCC. We characterized the clinical background, operation, follow-up treatment, and outcomes. We performed immunohistochemistry on whole-section slides from primary tumors, recurrent tumors, and lymph nodes. CIP2A was similarly detected in TSCC and tongue hyperplasia, whereas local inflammation was stronger in cancer. CIP2A expression was increased in metastasized cancer compared to non-metastasized cancer. IDO had stronger expression in tongue hyperplasia than in TSCC. However, IDO expression was associated with poor survival in the subgroups with primary tumor stage T2 to T4 and in the sub-group with strong inflammation at the tumor invasive front. Strong CDH3 expression was associated with better disease-specific and overall survival in the group of tumor size T3. In TSCC patients who had recurrence during follow up, strong CDH3 expression in the primary tumor was associated with poor disease-specific and overall survival. CDH3 expression in lymph nodes without metastasis was negative in all cases. Lymph nodes with extranodal extension CDH3 expression in lymph-node metastasis were positive in all cases. CDH3 expression in lymph-node metastasis was not associated with patient disease-specific survival or overall survival. The high relative density of lymphatic vessels (≥ 80 %) was associated with poor prognosis in TSCC. The relative density of lymphatic vessels was associated with poor prognosis in the group of primary tumor size T1 to T2 and in the group of non-metastatic cancer. In conclusion, CIP2A, IDO, and CDH3 do not appear to be specific biomarkers for TSCC. CIP2A may have some use as it was associated with progression of TSCC. IDO may have some use as it was associated with progression of primary tumor stage T2 and T3 in TSCC. CDH3 may have some use as it was associated with patient survival for tumor recurrence in TSCC. The density and diameter of lymphatic vessels were not associated with TSCC survival. On the other hand, high relative density of lymphatic vessels was associated with tumor invasiveness and poor survival. Thus, the relative density of lymphatic vessels could have a role as a prognostic marker.
  • Lindh, Ilona (Helsingin yliopisto, 2021)
    This study focuses on the rhetorical resources and devices characteristic to travel narratives based on subjective experience. The theoretical framework is based on a dialogical view of language use and theory of narrative as rhetorical action. The analysis combines concepts of narratology and life writing studies with the methods of linguistic discourse analysis. The research material of the study consists of four texts by three Finnish authors. A short travel narrative called “Mamma ok” by Antti Tuuri is published in a collection of travel narratives Matkoilla Euroopassa (‘Travels in Europe’, 2011). His Bospor Express (2013) is a book-long literary travel narrative. Vanhan rouvan lokikirja (‘Old lady’s logbook’, 2004) by Kyllikki Villa is a travel journal by form, adapted to a published book. Afrikan poikki (‘Across Africa’, 2009) by Juha Vakkuri combines the telling of personal experiences with informative passages based on literary sources. Through these four texts, we get to see the rhetorical variety and potential of the travel narrative genre. The analyses show, that (i) temporal choices are rhetorically important as they define the position of the reader in relation to the narration. Temporality also affects the “I” of the text so that the protagonist is on the level of the story, while the reporting and evaluating narrator is on the level of discourse. Another central set of rhetorical resources is connected to (ii) intertextuality and contextuality which can be used to emphasize the narrator’s expertise and place the work in its literary tradition. These polyphonic resources may offer conversational positions to the reader. A third set of resources is (iii) the ways of representing spaces and landscapes in order to convey the traveler’s experiences to the reader. Spaces are often seen as surroundings for the traveler’s needs and interests. While spaces are experienced inside, landscapes are observed from the distance. A fourth set of narrative resources is related to (iv) the traveler’s personal encounters during the journey. The representations of the encountered are often based on some kind of categorizing, and the assumption is that the reader recognizes those categories at least partly. Some of the represented people have a more central role in the course of the narrative and they can be regarded as equivalent to characters in fiction, having synthetic, thematic and mimetic functions. The research reveals that travel narratives can activate or acknowledge the reader in various ways. In the context of 21st century travel and media cultures, the primary function of a travel narrative is not to deliver encyclopedic knowledge, but to emphasize the tellability of personal experiences and observations, and their interpretations. The narratives accentuate both particular and typical aspects of the journey. The narrator’s authority is built on the ability to report, evaluate and contextualize. Keywords: non-fiction studies, travel writing studies, life writing studies, Finnish language, Finnish travel writing, narrative theory, narratology, narration, rhetoric, discourse studies, text analysis
  • Turkia, Heidi (Helsingin yliopisto, 2021)
    In this research, I examine the development of cooperation and case management between Kela and Eksote (the South Karelia Social and Health District) in the context of a social work development project from 1 January 2017 to 31 July 2019. The aim of this study was to create new information on issues affecting cooperation and to develop and study what kind of cooperation models can be used to support cooperation and case management between Kela and the municipalities, especially for the most vulnerable customers. A local working group was set up for the project in South Karelia, with a total of 21 employees. Employees were from Kela’s customer services and benefits services, from Eksote’s adult social work and immigration services and an employee from the Centre of Expertise on Social Welfare in SouthEast Finland (Socom). The study material included memos and project documents, questionnaire surveys, a group interview, an individual interview, a final survey conducted for the working group and a research diary. The theoretical framework consisted of professions, multidisciplinary collaboration, case management and social rights. The study explored what kind challenges were involved in cooperation and case management at the beginning of the project. Based on these were developed collaboration and case management models. Good models included getting to know the work of others, information for Kela employees, regular service at another organization’s premises, Kela information for immigrants, and case management service. The development of multidisciplinary cooperation and case management between Kela and the municipalities can increase the knowledge and appreciation of each other’s work. One of the most important goals of the cooperation is to ensure that customers who need social services are identified. For those who need special support, a targeted service can support the holistic perception of the customers’ situation and guide them toward the required services. Keywords: multisectorality, cooperation (general), income support, action research, social work, development projects, customers, direction (instruction and guidance), social rights, social services, professions, hospital districts, municipalities, Social Insurance Institution of Finland
  • Wasonga, Daniel (Helsingin yliopisto, 2021)
    Cassava (Manihot esculenta Crantz) is a staple food for millions of people in the tropics, providing high energy and nutritional value. Problems associated with cassava in the arid tropics are low yield, high cyanide concentration, and low mineral and vitamin A availability in leaves and roots. These factors hinder the utilization of cassava greatly and are highly influenced by the plant water status and potassium (K) availability in the growth environment. The productivity of cassava in such environments could be improved using irrigation strategies not based on full crop water requirements, such as deficit irrigation combined with K nutrition to ensure sustainable quantity and quality production. Additionally, employing systems that can allow non-destructive estimation of plant performance, such as the use of plant imaging techniques, could provide early information on plant performance, which would facilitate phenotyping, as well as assist in the mitigation of abiotic challenges in cassava production. This study investigated how irrigation water, K fertigation and their interactions affect the growth responses of biofortified cassava during the early growth phase. It was also investigated whether K fertigation could improve the nutritional and reduce the anti-nutritional qualities of biofortified cassava growing under typical conditions of water deficit. The ability to use red-green-blue (RGB) and multispectral sensors to detect the effects of water deficit and low K in cassava, and whether the crop quality changes due to low moisture and low K could be observed from the images, were also examined. Pot experiments were conducted at early developmental stages of cassava under controlled greenhouse conditions at the University of Helsinki. Young biofortified cassava plants were established using cuttings. The plants were subjected to three irrigation treatments (30%, 60%, 100% pot capacity) that were split into five K (0.01 mM, 1 mM, 4 mM, 16 mM, 32 mM) application rates beginning 30 days after planting (DAP) and ended at 90 DAP, when plants were harvested. Irrigation treatments and K application rates significantly affected leaf water potential, leaf osmotic potential, net photosynthesis, stomatal conductance, leaf temperature, leaf chlorophyll, water usage, plant leaf area, plant height, tuber number and whole-plant biomass. The interaction was also statistically significant for these properties. Irrigation treatments and K application rates also affected leaf turgor, but the interaction was not statistically significant. Irrigation at 30% together with 16 mM K lowered the leaf water potential by 69%, leaf osmotic potential by 41%, net photosynthesis by 35%, stomatal conductance by 41%, water usage by 50%, leaf area by 17%, and whole-plant dry mass by 41%, compared with fully irrigated plants. Lowering the K application rate below 16 mM reduced the values further. Most importantly, the growth was decreased least when irrigation was decreased to 60% together with 16 mM K, compared with optimal applications. The combined effect of irrigation treatments and K applications was statistically significant for starch, energy, minerals, total carotenoids, and cyanide, but the interaction was not statistically significant for dietary fibre and crude protein in the leaves and roots. In the leaves and roots, water deficit and lower K applications inhibited starch, carotenoids, crude protein, and fibre synthesis. Water deficit interrupted the uptake of minerals by the cassava roots from the soil and ultimately to the leaves. Improved uptake of calcium, phosphorous, magnesium, zinc, iron, sulphur, and chloride to the leaves was recorded with increased K application regardless of water deficit. K application also mitigated the effect of water deficit at 30% irrigation. Crude protein, carotenoids, and minerals were revealed to be more abundant in the leaves than in the roots, while the inverse was the case for starch content and iron. Cyanide was diminished in the leaves and roots of the cassava with increases in both irrigation and K application rates. Full irrigation (100%) with 16 mM K application produced the highest nutritional quality and the least cyanide concentration. Also, 16 mM K significantly improved the nutritional qualities and diminished the cyanide concentration irrespective of the irrigation treatment. High estimation accuracy (R2 = 0.90) for biomass, chlorophyll, and net photosynthesis were recorded. The estimated leaf area associated strongly (R = 0.98) with the measured leaf area. The estimated biomass also associated strongly with the measured biomass. Starch, energy, total carotenoids, and cyanide were estimated reasonably (R2 > 0.80) and showed strong correlations with the most of spectral indices. The estimation accuracy for all mineral elements was low, and weak relationships existed between the mineral elements and the spectral indices. The regression models identified normalized difference vegetation index, green area index, and simple ratio index as the best estimators of growth and key nutritional traits in cassava. Moreover, irrigation at 30% together with 0.01 mM K reduced all the index values but increased crop senescence index. Regardless of water deficit, increasing K application rate to 16 mM resulted in high values for all the spectral indices but low senescence index. In conclusion, adjusting K fertigation rates in combination with deficit irrigation may improve the growth and dietary quality of young cassava, and reduce cyanide concentration. Findings from this work can be utilized as a foundation to develop agronomic management practices involving K application for cassava growing in water-limited environments. The study also shows that RGB and multispectral sensors can be used to provide indirect measurements of growth and key nutritional traits in cassava, thus representing a tool that breeders may use to facilitate evaluation of cultivars, especially in the developing areas. Information from imaging data may also be used to facilitate corrective measures to avert stress, such as the decision to irrigate or apply fertilizers. Nonetheless, laboratory analysis of plant samples should support sensor estimates, especially under field conditions, when all possible factors affecting plant growth are difficult to forecast. Future studies could place emphasis on field conditions with multiple cassava cultivars and employ different imaging techniques.
  • Palojärvi, Ansa (Helsingin yliopisto, 2021)
    Agricultural productivity has improved significantly in recent decades. World food production has more than tripled through intensive crop production. In addition to improved food production and safety, environmental problems have also increased. However, due to global population growth, food production needs to be further intensified. This thesis is related to the sustainable intensification of crop production and the improvement of crop resilience. The study examined the effects of agricultural management practices on soil microbial communities and the ecosystem services they provide. In particular, the possibilities to improve the plant disease suppression of field microbiota and appearance of arbuscular mycorrhizal fungi (AMF) by tillage methods and crop diversity were in focus. In addition, the amount and location of different carbon fractions in the soil profile were investigated. The aim was also to identify useful indicators for beneficial soil microbial activity for soil quality monitoring. The studies utilized the field experiments and a cross-site comparison of several long-term tillage fields. The ability of soil microbiota to suppress fungi (fungistasis) and general disease suppression was often enhanced by the long-term reduced and no-tillage practices, compared with conventional mouldboard ploughing. The result could not be generalized to specific management but could be linked to the higher biomass of soil microbiota and fungi as well as the soil labile carbon content. Based on the results, the strengthening of soil disease suppression was reflected in lower prevalence of the test pathogen (F. culmorum) in the cereals, suggesting an impact on crop production. Reduced tillage was shown to alter the vertical distribution of carbon fractions and accumulate soil organic carbon (SOC), labile carbon, and microbial biomass in the topsoil layer. However, the SOC sequestration in the whole soil profile was not necessarily increased. Mycotrophy of host plants varied considerably between the special plants studied. Mycotrophy of the crop plant had a strong effect on the concentration of AMF in the rhizosphere and bulk soil. Field observations confirmed that the ecosystem services of microbiota could be enhanced by the choice of agricultural management although the effects of a specific management method may not be directly and generally related to the activity. The effects on the fungal community and crop performance should be considered in relation to the crop sequence used. In addition to this, potentially, single management practices have a combined effect on soil health. Soil microbiological ecosystem services need simple indicators to be used in developing and monitoring sustainable agricultural production. The intensity of disease suppression in the soil could be reliably assessed by a simple laboratory test. Soil labile carbon (POM-C, Cmic) is potentially a useful indicator for disease suppression. Cell membrane lipid assays (PLFA, NLFA) proved to be effective indicators for estimating AMF biomass in arable soil. Cultivation measures were shown to have a significant impact on the community structure and function of the field microbiota. In the light of these results, it is absolutely essential to take into account the functionality of the whole soil microbiome in the design of sustainable intensification of agricultural management practices.
  • Karjalainen, Essi (Helsingin yliopisto, 2021)
    Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown aetiology. UC is associated with increased risk of colorectal cancer (CRC). The risk of CRC has declined over recent decades, but the risk is still approximately 2-fold. CRC is one of the indications for surgery, but most UC patients undergo surgery due to medically refractory disease, suggesting that they often use immunomodulative medication and corticosteroids prior to surgery. The most common operation performed is proctocolectomy with ileal pouch-anal anastomosis (PC-IPAA), avoiding a permanent ileostomy. Controversy exists about whether or not a diverting ileostomy should be constructed. The most common long-term complication of PC-IPAA is pouchitis. Episodes of pouchitis are frequently successfully treated with antibiotics. However, a chronic antibiotic-refractory pouchitis can be difficult to manage. Aims: The dissertation comprises four original studies. The aims of these studies were to determine the incidence and prognosis of UC-associated CRC (Study I), to assess the effect of preoperative anti-tumour necrosis factor (TNF) therapy and corticosteroids on postoperative complications and pouch failure (Study II), to determine the effect of covering ileostomy on postoperative morbidity after IPAA (Study III), and to investigate the efficacy and safety of faecal microbiota transplantation (FMT) in the treatment of chronic pouchitis (Study IV). Patients and methods: All studies were carried out at Helsinki University Hospital, Finland. Studies I, II, and III were retrospective. Study I included all 71 patients with UC-associated CRC who were operated on at Helsinki University Hospital between 1991 and 2018. Moreover, 108 patients with dysplasia in the surgical specimen were analysed. Study III included all 510 consecutive patients who underwent PC-IPAA or proctectomy with IPAA between January 2005 and June 2016. A diverting ileostomy was constructed in 119 of these patients. Study II was a subgroup of Study III that excluded patients who underwent proctectomy or were using tacrolimus or vedolizumab prior to surgery. In total, 445 patients were included. Study IV was a randomized, double-blinded, placebo-controlled trial. We randomly allocated 26 patients in a 1:1 ratio to either donor FMT or autologous transplant (placebo). The recruitment was implemented between December 2017 and August 2018. Results: In Study I, CRC was diagnosed preoperatively in 47 patients (66.2%). Altogether 34 patients (47.9%) had synchronous CRC or dysplasia. The incidence of CRC among patients undergoing surgery has not changed during the 28-year study period (P = 0.113). The overall survival was 71.8%, while the 5-year CRC-specific survival was 81.5%. In Study II, anti-TNF therapy was not associated with postoperative complications. Corticosteroids with a dose equivalent to prednisolone 20 mg or more increased the incidence of anastomotic leak (12.6% vs. 2.5%, P = 0.002) and wound dehiscence (4.2% vs. 0%, P = 0.019), but not pouch failure (2.1% vs. 0%, P = 0.141). Patients with a lower dose of corticosteroids had more pouch failures than patients without corticosteroid treatment (4.4% vs. 0%, P = 0.015). In Study III, patients with a diverting ileostomy had more postoperative complications than patients without ileostomy (55.4% vs. 30.2%, P < 0.0001). Although clinical anastomotic leak was more common in patients without an ileostomy (6.6% vs. 1.7%, P = 0.04), the re-laparotomy rate due to an early complication did not differ between the groups (P = 0.58). Re-admission rate was higher among patients with an ileostomy (42.0% vs. 13.0%, P < 0.0001). Of patients, 43.4% had problems with an ileostomy after discharge. There was no difference in pouch failure rate between the groups (1.7% vs. 2.8%, P = 0.74). In Study IV, relapse-free survival was similar between the groups (log rank P = 0.183; HR 1.90, 95% CI 0.73 to 4.98, P = 0.190). Patients reported no major adverse effects. Conclusions: The incidence of UC-associated CRC has remained constant among patients undergoing surgery. The prognosis of patients with UC-associated CRC was no worse than the prognosis of all CRC patients in the Finnish population. The most important finding in Study I was that one-third of the CRCs were not diagnosed until surgery. Moreover, synchronous lesions were common. These findings are alarming and should be considered before the endoscopic management of UC-associated dysplasia. Anti-TNF agents seem to be safe prior to surgery. By contrast, corticosteroids were associated with a higher incidence of anastomotic leak, wound dehishence, and pouch failure. An ileostomy is associated with a considerable number of complications without any reduction in pouch failure rate. Based on our results, a single-stage PC-IPAA is safe in low-risk UC patients. FMT was not effective in the treatment of chronic pouchitis with the FMT treatment protocol used in our trial. The safety profile of FMT was good with no major adverse effects.

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