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Tausta: Pelaamisen suosion kasvaessa ovat tutkijat havainneet patologista negatiivisesti terveyteen vaikuttavaa pelaamista. Tästä ongelmapelaamisen käsitteestä on kehitetty ICD-11 tautiluokitukseen Pelaamisriippuvuus-diagnoosi, jonka kriteereitä ja ominaisuuksia tämä tutkielma käsittelee. Tutkimusmenetelmät: Tutkimusta varten suoritettiin kirjallisuushaku Pubmed tietokannassa. Haku kohdennettiin ICD-11 tautiluokituksen pelaamisriippuvuutta käsitteleviin tutkimuksiin tutkimustavoitteiden mukaisesti. Artikkelihaku tuotti 210 osumaa ja mukaan valikoitui lopulta 32 artikkelia. Tulokset: Pelaamisriippuvuuden kriteerit perustuvat DSM-5 tautiluokituksen nettipelaamisriippuvuuden kriteereihin, joilla taas on taustaa päihderiippuvuuskriteereissä ja internetriippuvuudessa. ICD-11 mukaisella pelaamisriippuvuudella näyttäisi olevan korkeampi diagnostinen kynnys nettipelaamisriippuvuuteen verrattuna, ja pelaajilla patologisempia pelaamistapoja ja vahvempaa oireilua. Tutkimusten vertailua vaikeuttaa kuitenkin epäyhtenäinen ongelmapelaamisen määrittely. Pelaamisriippuvuudessa korostui monenlaista pelaajataustaa sekä riippuvuuteen myötävaikuttavaa ja altistavaa tekijää, jotka vaikuttavat toisiinsa eri tavoin. Pelaaminen selviytymiskeinona ja toimintakyvyn aleneminen osoittautuivat tuloksia tarkasteltaessa keskeisiksi tekijöiksi pelaamisriippuvuuden arvioinnissa. Myös pelaamismotivaatioiden, pelien sekä pelaajan ominaisuuksien yhteensopivuuden on arvioitu saattavan heijastua pelaamisriippuvuuden riskiin. Psyykkisten häiriöiden ja oireiden kausaliteettia pelaamisriippuvuuden syntyyn on tutkimuksissa ollut vaikea arvioida, negatiivisen kehän mahdollisesti syntyessä psyykkisten oireiden ja pelaamisriippuvuuden oireiden limittyessä. Pelaamisriippuvaisilla on kuitenkin vaikuttanut esiintyvän enemmän psyykkistä oireilua. Pohdinta: Pelien ja pelaajien ominaisuuksien vaikutus pelaamisriippuvuuden ilmenemiseen oli monimutkaista ja vaihtelevaa. Oheissairastavuuksien merkitystä pelaamisriippuvuuden ilmenemiseen on vaikea arvioida, vaikka jonkinlainen yhteys näyttäisi olevan. Tutkimuskenttä vaatii yhtenäistä kansainvälistä määritelmää ja mittaria pelaamisriippuvuuden ja siihen liittyvien ominaisuuksien käsitteellistämiseksi.

Recently, several novel post-translational modifications (PTMs) have been identified as important regulators in biology. Succinylation, the reversible addition of a succinyl group from a free succinyl-CoA into a protein lysine, is one such novel PTM. The last decade of research has unveiled succinylation as a powerful regulator of metabolism, prevalent in every organism it has been studied in and with functional effects on target proteins in several key metabolic pathways. A major contribution of this thesis is to catalogue the recent advances in succinylation research into the most comprehensive literary review currently available on succinylation. While the biological role of this PTM is being established, the relevance of succinylation in human disease has remained unclear. Meanwhile, mitochondrial DNA depletion syndrome caused by defective SUCLA2 (SUCLA2 disease) is a progressive hereditary mitochondrial disease with no available treatment. SUCLA2 disease is caused by defective mutations in the ß-subunit SUCLA2 of the TCA cycle enzyme succinyl-CoA synthetase. While the characteristic manifestations, including impairment of respiratory complexes, and the etiological mutations in this disease are well established, the pathogenic model for SUCLA2 disease has remained incomplete. As succinyl-CoA synthetase shares a substrate, succinyl-CoA, with succinylation, this thesis set out to probe SUCLA2 mutants for a potential succinylation phenotype. An extensive hypersuccinylation phenotype was characterized in fibroblasts and tissue samples from SUCLA2 mutant patients by immunochemical methods. The hypersuccinylation target identities in SUCLA2 mutants were revealed with proteomics by mass-spectrometry. Hypersuccinylation in SUCLA2 mutants was shown to be enriched in proteins participating in mitochondrial energy metabolism, including respiratory complex proteins. In addition, several novel metabolic phenotypes were characterized in SUCLA2 mutants with metabolomics by mass-spectrometry, most prominently a significant depletion of aspartate metabolism. While identification of extensive hypersuccinylation in SUCLA2 mutants establishes a novel concept of succinylation relevance in human metabolic disease, the prospect of altered regulation of the respiratory complexes due to hypersuccinylation lays the foundation for a novel pathogenic model for SUCLA2 disease. Meanwhile, the observed novel metabolic phenotypes significantly contribute to the current understanding on SUCLA2 mutant metabolism and inspire a hypothetical model on how the defective succinyl-CoA synthetase could be circumvented in the TCA cycle of SUCLA2 mutants.

Charcot-Marie-Tooth (CMT) neuropathy is one of the most common forms of inherited peripheral neuropathies with the prevalence of one in 2500 individuals. CMT is phenotypically and genetically a very heterogeneous disease. It can be inherited as an autosomal recessive, dominant or X-linked trait. CMT is characterized by distal muscle weakness, atrophy and deformity of the feet as well as clumsiness of gait. The onset of CMT varies and also the symptoms of the disease can vary even among the members of a single family. So far more than 40 genes have been identified for CMT and the list is estimated to grow by 30-50 genes. Whole exome sequencing (WES) is a next generation sequencing technique, which targets the protein coding area of the genome. Through WES analysis it is possible to search for disease causing mutations with all kinds of inheritance patterns. Patients suffering from CMT are good candidates for WES analysis because of the genetic heterogeneity of their disease. WES can be used for diagnosing Mendelian disorders with atypical symptoms as well as diseases, which are difficult to confirm using clinical criteria alone and which require costly evaluation, e.g. CMT. In this master study new disease causing mutations for early-onset neuropathies are identified by whole exome sequencing. The aims of this study include using WES for the molecular diagnosis of four patients suffering from early-onset axonal neuropathies, the functional analysis of possible causative variants and improving and developing the process of analyzing variants from whole exome sequencing data, especially the analyzing steps of insertion and deletion variants. Finding causative variants among the insertion and deletion variants has previously been often left out from the WES analysis because of the lack of systematic analysis technique. As a result of the WES data analysis a new candidate disease gene, tripartite motif containing 2 (TRIM2) was identified. A missense mutation c.761T>A (p.E254V) and a deletion c.1779delA (p.K594Rfs7X) were found in patient 2, who suffers from severe CMT type 2. The carrier frequency was analysed to see whether the variants are present in the general population or not. The functional analysis of TRIM2 was started by preparing constructs carrying the missense mutation and the deletion and by setting up conditions for western blotting.

Ovarian cancer is known as "the silent killer" because it is generally diagnosed at a late stage, and is therefore responsible for more deaths than any other gynecological malignancy. Although the genetic background of high-grade serous carcinoma (HGSC) is highly heterogeneous, almost all HGSCs harbor TP53 mutations, and mutations in BRCA1 and BRCA2 are also frequent. Less is known about the chromosomal rearrangements that function as drivers of HGSC. The aim of this thesis project was to identify and validate novel and recurrent chromosomal rearrangements that may have a functional relevance in the tumorigenesis of high-grade serous carcinoma. We searched for recurrent rearrangements detected by a computational algorithm (BreakDancer) in 44 HGSC whole-genome sequences that were obtained from The Cancer Genome Atlas database. We identified five samples to harbor a novel region that was affected by recurrent deletions of similar size. This region was located upstream of the gene TUBB4A on chromosome 19. We used PCR to screen for rearrangements within this region in 11 Finnish patient tumor tissues. None of these samples displayed rearrangements within this region. Further studies with larger sample sizes are required to validate whether this region indeed is recurrently affected by chromosomal abnormalities. Identifying chromosomal rearrangements of functional relevance will pave the way towards the use of personalized medicine.

STK11/LKB1 is a tumor suppressor gene and mutated in 18% of lung adenocarcinomas. Tumor suppressor liver kinase B1 (LKB1) is known to activate adenosine monophosphate-activated protein kinase (AMPK) and 12 AMPK-related kinases (ARKs) by phosphorylating a conserved threonine residue in their T-loop region. A number of studies focused on investigating the influence of LKB1-AMPK signaling on cancer cell proliferation. However, there is no systematic study for identifying the critical LKB1 kinase substrates in suppressing lung cancer cell growth. In this project, the LKB1-deficient lung adenocarcinoma cell line A549 cells were sequentially overexpressed with constitutively active mutants of AMPKα1, AMPKα2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3. The overexpression status was confirmed at both genetic and protein levels by qPCR and Western blotting, correspondingly. In vitro growth assays demonstrated up to 33% reduced growth rate of A549 cells overexpressing AMPKα1, AMPKα2 and NUAK1. Furthermore, siRNA knockdown of the selected substrates in LKB1-overexpressing A549 cells significantly rescued the cell growth defect. These findings suggest, that AMPKα1, AMPKα2 and NUAK1 kinases are critical for LKB1-mediated cell growth defect in lung adenocarcinoma.

Epithelial tissue is characterized by close cell-cell and cell-extracellular matrix (ECM) contacts as well as by apico-basal polarization. Integrity of these two features is important for functionality of epithelium. Additionally, proteins regulating polarity and cell junctions have been linked to cell cycle and apoptosis control. Consequently, defects in many of the polarity proteins have been linked to oncogenic events and loss of polarity is a hallmark of advanced cancers but whether it is causal to tumorigenesis is yet unknown. However, large body of knowledge on apico-basal polarity regulation and its connection on homeostasis control is derived from studies in Drosophila. This is mainly due to fact that efficient high throughput organotypic three dimensional (3D) culture methods enabling apico-basal polarization have not been available until the last decade. Large screens for epithelial polarity regulators have not been carried out in mammalian cells. Moreover, as cancer is the leading cause of death in developed countries and most of the cancers originate from epithelial tissues, knowledge of polarity regulation can be medically relevant. Oncogene MYC is overexpressed or amplified in variety of human cancers. The tumorigenic function of MYC is mainly due to its ability to drive cell cycle. We have previously shown that intact epithelial architecture is protective from cell cycle deregulating activities of MYC in 3D MCF10A mammary epithelial cell model and in vivo. This resistance can be overcome by inactivating LKB1 which is the human homologue of the polarity protein PAR4 implying a tumour suppressive role for epithelial architecture in mammalian cells. To identify regulators of epithelial architecture in mammalian cells, we have established lentiviral shRNA library (human epithelial architecture library, hEAL) encompassing 219 constructs targeting 77 genes associated with polarity regulation in Drosophila. We have previously screened the shRNA constructs for downregulation and quantified their effects on acinar morphology in the MCF10A 3D model. In this Master's Thesis I have validated the downregulation and phenotypes observed in a subset of the shRNAs during primary screening of the constructs of the library. Additionally, the possible co-operation with downregulation of the polarity regulators and conditional activation of MYC was determined. Most dramatically, downregulation of Wnt pathway gene DVL3 was shown to cause formation of enlarged multiacinar structures, which have increased proliferation. Additionally, downregulation of another Wnt pathway gene, GSK3β, resulted in acini with increased size and filled lumens. Thus these results propose a role for these genes in epithelial architecture regulation and tumour suppression in the used model even though apico-basal polarization of the acini was intact and no synergy with MYC was observed. Interestingly, no role in epithelial architecture regulation for Hippo pathway related genes FAT4 and MOBKL1A was found. Importantly, this study was able to validate primary screen showing relevance of the pipeline. Lastly, the study characterized the synthetic lethality phenotype found in the primary screen caused by downregulation of GTPase RHOA and chronic MYC activation. The shRHOA acini exhibited perturbed α6-integrin localization. When combined with MYC activation, the percentage of apoptotic acini was significantly increased. Importantly, the results suggest the observed synthetic lethality to be specific for the 3D context and to be associated with MEK/ERK and ROCK pathways. Taken together, in this study I have validated the role of novel epithelial architecture regulators and candidate tumour suppressors in MCF10A cells which may have medical relevance by helping to characterize tumorigenic processes. Furthermore, I characterized a novel 3D specific RHOA-MYC synthetic lethal interaction, which may prove to have therapeutic significance in MYC-driven cancers in future.

Objectives: Happiness is considered to be a major life goal. Moreover, experienced happiness has a positive influence on many life domains. Psychological factors, such as personality and identity, seem to be significant components in human well-being and happiness. Identity diffusion has been linked to several adverse phenomena, such as mental disorders. The aim of the current study was to investigate the relationship between identity diffusion and experienced happiness as well as their prevalence at the population level. In addition, this study aimed to examine whether the possible relationship between identity diffusion and experienced happiness persists when the effects of demographic factors and psychiatric disorders are controlled. Methods: The current study utilized a comprehensive English cross-sectional data set. The study sample consisted of 6,058 participants, of which 58 % were women. The relationship between identity diffusion and experienced happiness was examined by using logistic regression analysis. Controlled variables were demographic factors, borderline personality disorder, conduct disorder, and common mental disorders. Results and Conclusions: Greater levels of identity diffusion were associated with lower levels of experienced happiness. Common mental disorders partly explained the association, especially in the presence of severe identity diffusion, also known as identity disturbance. As much as 23 % of the population had experienced symptoms related to identity diffusion, and 2 % of them filled the criteria for identity disturbance. Identity diffusion and related identity disturbance are not only associated with psychiatric symptoms, but they are also associated with lower levels of experienced happiness. Using early interventions and addressing support actions to promote healthy identity development may contribute to individual’s emotional well-being and prevent later psychiatric symptoms.

IgG4-associerad sjukdom är ett relativt nyligen upptäckt fibroinflammatoriskt tillstånd med mycket varierande manifestationer. Den vanligaste manifestationen är autoimmunpankreatit, men även bl.a. IgG4-associerad kolangit, Mikulicz sjukdom, retroperitoneal fibros, Riedels tyreoidit och orbitala manifestationer kan förekomma. Typiskt för IgG4-associerad sjukdom är lymfocytinfiltration med rikligt av IgG4-positiva plasmaceller i vävnaden, fibros och en förhöjd IgG4-koncentration i serum. Målen med studien var att utreda betydelsen av en förhöjd IgG4-koncentration i serum, samt att noggrant beskriva 6 utvalda patientfall. Som material användes IgG4-bestämningar gjorda vid HUSLAB mellan 1 maj 2010 och 1 maj 2011, samt patientjournaler i HUCS databaser. I studien framkom att en förhöjd IgG4-koncentration i serum är ett relativt vanligt fynd bland patienter på sjukhus. Dessutom varierade IgG4-koncentrationen hos patienter som diagnostiserats med IgG4-associerad sjukdom. IgG4-koncentrationen i serum visade sig vara förhöjd i även många andra sjukdomar än IgG4-associerad sjukdom. Bland dessa var skleroserande kolangit och astma, allergi, sinuit eller atopiska utslag de vanligaste. I materialet på 253 patienter framkom 14 patienter med IgG4-associerad sjukdom. Av dessa hade 10 patienter pankreatit, 9 kolangit, 3 Mikulicz sjukdom, 2 lymfadenopati, 2 Riedels tyreoidit, en mediastinal fibros och en retroperitoneal fibros. IgG4-associerad sjukdom är ett tillstånd som omfattar många medicinska specialområden och är viktigt att beakta i differentialdiagnostiken av oklara inflammatoriska och fibrotiska sjukdomar.

Objectives. Even over one third of information security breaches are caused by human actions, which makes knowing the factors behind information security behaviour especially important in today’s world. The objective of this study was to investigate what kind of individual and organisational factors affect the way we act with personal and organisational data. The research model of this study combined the Theory of Reasoned Action (TRA) and personality traits as predictors of information security behaviour. In TRA, the best predictor of an action is the intention to do it, which in turn is affected by the attitude towards the action and subjective norms. Scenario method was used to investigate if TRA predicts actions also in concrete scenarios The included personality theories were Big Five and Dark Triad theories, of which the latter has not yet been studied in information security research. Methods. The data in this study was a sample of the students in the University of Helsinki and the National Defence University (N=408). The participants completed a survey which measured personality traits and the elements of TRA. Personality was assessed with Short Five and Short Dark Triad inventories. In addition, the participants read three scenarios where information security was at risk. After this they rated their probability to act in a similar way (intention) and their evaluation of the presented act (attitude). The scenarios in this study where divided in three groups according to their level of risk and each participant received scenarios only from a same level. The relationship between personality traits and responses in scenario situations was assessed with regression analysis. The measurement model was assessed with path analysis. Results and conclusions. The measurement model fit the data when it was used to predict security attitudes and the harm presented in the scenarios was mild. The TRA structure was therefore found to predict attitudes in concrete situations as well. The relationship between personality traits and scenario responses was different for intentions and attitudes. Higher scores in two Dark Triad traits were linked to higher intentions. Higher extroversion predicted both lower intentions and attitudes. In addition, higher openness was linked to more positive attitudes, and these two connections remained in the measurement model. This study provided more information about the relationship between personality traits and information security behaviour and gave insight on which factors to improve to secure information in organisations.

Ihomelanooman ilmaantuvuus on kasvanut viime vuosikymmeninä merkittävästi, ja varhaisdiagnostiikan mahdollisuuksia melanoomasta aiheutuvan sairastavuuden ja kuolleisuuden alentamiseksi on tutkittu runsaasti. Vantaalla melanooman ja muiden ihosyöpien ilmaantuvuuden kasvuun on reagoitu perustamalla Myyrmäen ja Tikkurilan terveysasemille ihomuutospoliklinikat, joiden tarkoituksena on madaltaa kynnystä hakeutua näyttämään ihomuutoksia lääkärin vastaanotolle ja tehostaa ihosyöpien diagnostiikkaa. Ihomuutospoliklinikoilla työskentelevät lääkärit ovat yleislääkäreitä. Tutkimuksessa selvitetään laajan kirjallisuuskatsauksen kautta, onko ihomuutospoliklinikoiden avulla tutkimuksen valossa mahdollista parantaa melanooman diagnostiikkaa sekä löytää melanoomia varhaisemmassa vaiheessa ja siten vaikuttaa potilaiden ennusteeseen ja sairastavuuteen. Samalla paneudutaan lähemmin melanooman ja dysplastisen luomen diagnostiikkaan, histopatologisiin ennustetekijöihin ja kliiniseen kuvaan. Dysplastisten luomien merkitystä melanooman riskitekijänä ja tämän riskitekijän vaikutusta dysplastisten luomien hoitokäytäntöihin arvioidaan. Tutkimus osoittaa, että melanooman seulonnan tai melanoomaan erikoistuneiden pigmenttileesioklinikoiden vaikutusta melanoomakuolleisuuden alentamiseen ei ole kyetty selkeästi osoittamaan. Hyvänlaatuisten ihomuutoksien vuoksi tehtävien toimenpiteiden määrät ovat lisääntyneet. Ylidiagnostiikka ja elintapojen muutokset ovat merkittäviä melanooman ilmaantuvuuden kasvua selittäviä tekijöitä. Yleislääkärit poistavat enemmän hyvänlaatuisia ihomuutoksia yhden melanooman diagnosoimiseksi verrattuna ihotautilääkäreihin. On todennäköistä, että ihomuutospoliklinikoiden toiminnalla ei ole vaikutusta melanoomasta aiheutuvaan kuolleisuuteen. Osa melanoomista on nopeakasvuisia ja jo lähtökohtaisesti huonompiennusteisia, eikä niitä välttämättä saada ajoissa kiinni ihomuutospoliklinikoilla. Ihomuutospoliklinikoiden avulla ihomuutosten arvioinnin keskittäminen ja sitä kautta ihomuutosten hoitoketjujen tehostuminen ovat mahdollisia seurauksia. Hyvänlaatuisten ihomuutoksien poistamisen tulisi vähentyä, mikäli diagnostiikan spesifisyys paranee. (200 sanaa)