Studies on drug resistance and molecular biomarkers in acute myeloid leukemia

Acute myeloid leukemia (AML) is a clonal disease of immature hematopoietic cells. Treatment of AML patients is based on conventional chemotherapy and stem cell transplantation, but the majority of patients still suffer from relapse and poor overall survival. A growing body of evidence suggests that the BM microenvironment plays an important role in protecting leukemic cells from drug-induced apoptosis, which consequently leads to accumulation of residual leukemic cells and eventual relapse. Although several factors are involved in leukemic cell-BM interactions, the exact mechanisms of these interactions and comprehensive knowledge of their impact on the activity of different drug classes is lacking. Better understanding of the molecular mechanisms of drug resistance could facilitate the development of improved treatment strategies, and means to monitor patients who are at risk for developing drug resistance. Modern technologies, such as RNA sequencing and proteomics, are widening our possibilities to learn more about the molecular basis of AML and to discover predictive biomarkers for therapy resistance. In study I, we evaluated the effect of stromal cell secreted soluble factors on ex vivo drug responses in AML. We comprehensively evaluated how mononuclear cells (MNCs) collected from AML patients respond to 304 different inhibitors in stromal cell-conditioned medium compared to standard cell culture medium. From this study, we discovered that the stroma-derived factors altered response to 12% (36/304) of the drugs. Amongst the drugs, sensitivity to BCL-2 inhibitor venetoclax was significantly reduced by the stromal conditions. In follow-up experiments, we found that this effect could be overcome by inhibition of activated JAK/STAT signaling. In study II, we investigated gene expression profiles that were associated with resistance to BCL-2 inhibitor venetoclax. Ex vivo and in vitro analyses of AML showed that high expression of S100A8 and S100A9 calcium binding family genes correlates positively with venetoclax resistance. In contrast, BET (bromodomain and extraterminal) inhibitor OTX-015 acted synergistically with venetoclax in resistant AML cell lines and patient samples. In study III, our aim was to determine the applicability of proteins in biomarker discovery. We compared marker panels from proteomic and microarray transcriptomic assays using reproducibility optimized test statistic (ROTS) in the context of AML dysregulated processes and networks. The analysis led to discovery of protein markers specific for AML using LC-MS/MS derived data. In summary, this thesis shows that JAK/STAT inhibitors can counteract BM stroma-mediated resistance to the BCL-2 inhibitor venetoclax. Furthermore, we discovered a gene expression profile that correlates with ex vivo venetoclax resistance in AML and provide evidence of AML-related biomarkers from a proteomics dataset.Akuutti myelooinen leukemia (AML) on myeloproliferatiivinen tauti, joka johtuu erilaistumattomien kantasolujen hallitsemattomasta jakautumisesta luuytimessä. AML:n hoito pohjautuu kemoterapiaan ja allogeeniseen kantasolusiirtoon, sekä nykyisin myös tiettyihin molekyylitason muutoksiin kohdistuviin täsmähoitoihin. Lääkehoitojen kehityksestä huolimatta lääkeresistenssi on merkittävä taudin uusiutumiseen ja hoitoon liittyvä ongelma. Luuytimen mikroympäristön tuottamien kasvutekijöiden sekä solujen välisen kontaktin tiedetään vaikuttavan AML-solujen selviytymiseen luuytimessä. Kyseisten vuorovaikutusten myötä leukemiasolut voivat välttyä lääkkeiden indusoimalta apoptoosilta johtaen resistenttien leukemiasolujen kerääntymiseen luuytimeen ja suurentuneeseen taudin uusiutumisriskiin. Näin ollen syvempi ymmärrys lääkeresistenttiin johtavista molekyylimekanismeista ja tieto luuytimen mikroympäristön vaikutuksesta eri lääkeryhmien aktiivisuuteen ovat tärkeitä jäännöstaudin estämisen kannalta. Nykyaikaiset menetelmät, kuten RNA-sekvensointi ja kvantitatiivinen proteomiikka mahdollistavat AML:n molekyylibiologian perusteellisen ymmärtämisen sekä resistenssiä ennustavien biomarkkereiden löytämisen potilaille. Tutkimuksessa I arvioimme stroomasolujen erittämien kasvutekijöiden vaikutusta AML-solujen ex vivo lääkevasteeseen. Tutkimuksen tavoitteena oli määrittää, kuinka ihmisen luuytimen stromaasolulinjasta kerätty kasvatusliuos vaikuttaa AML-potilaiden leukemiasolujen herkkyyteen yli 300:lle lääkkeelle. Tutkimuksen perusteella huomasimme, että strooma-peräiset kasvutekijät muuttivat AML-solujen vastetta 12%:lle (36/304) lääkkeistä. AML-solujen herkkyys BCL-2-estäjä venetoklaksille heikentyi merkittävästi stroomasolujen vaikutuksesta. Jatkokokeissa havaitsimme aktivoidun JAK/STAT-signaloinnin estämisen parantavan BCL-2-estäjien tehoa in vivo hiirimalleissa. Tutkimuksessa II tutkimme venetoklaksin resistenssiä ennustavia tekijöitä AML:ssa. AML-solujen ex vivo ja in vitro geeniekspressio- ja lääkeherkkyystulokset osoittivat kalsiumia sitovien S100A8- ja S100A9-geenien korkean ilmentymän korreloivan venetoklaksi-resistenssin kanssa. Sitä vastoin BET bromodomain proteiinin estäjä OTX-015 indusoi AML-solujen apoptoosia synergistisesti venetoklaksin kanssa AML-solulinjoissa ja potilasnäytteissä. Tutkimuksessa III tavoitteena oli selvittää, kuinka proteiinitason määritykset voivat tuoda lisätietoa AML:n tautibiologiaan verrattuna mRNA-tason määrityksiin. Tutkimus perustui AML potilaiden ja terveiden luovuttajien proteiini- ja mRNA-tason löydösten vertailuun käyttäen ROTS (Reproducibility optimized test statistic) tilastollista menetelmää. Tutkimuksessa löysimme uusia AML-spesifisiä proteiinitason biomarkkereita kvantitatiiviseen proteomiikkaan pohjautuvista tuloksista. Yhteenvetona, tässä väitöskirjassa löysimme, että JAK/STAT-signalointivälityksen estäjät voivat torjua luuytimen mikroympäristön kasvutekijöiden välittämän resistenssin BCL-2-estäjä venetoklaksille. Tämän lisäksi havaitsimme kohonneen S100A8- ja S100A9-geenien ilmentymän ennakoivan AML-soluissa kehittyvää venetoklaksi-resistenssiä ja löysimme AML:aan assosioituvia proteiinitason biomarkkereita

CP-vammaisille lapsille ja nuorille suositellut toimintakyvyn arviointimenetelmät toimintaterapiassa

Toimintaterapiassa keskitytään osallistumisen mahdollistamiseen yksilölle merkityksellisissä toiminnoissa. CP-vammaisille lapsille ja nuorille suositellut arviointimenetelmät ovat tavallisesti painottuneet ICF-luokituksen kehon ja ruumiin toimintoihin. WHO:n toimintakyvyn, toimintarajoitteiden ja terveyden kansainvälisen luokituksen julkaisemisen jälkeen kuntoutuksessa ja tarkemmin toimintakyvyn arvioinnissa ollaan yhä kiinnostuneempia yksilön suorituksista ja osallistumisesta. Toimintaterapiassa on jo pitkään ollut käytännön työn malleja, kuten Inhimillisen toiminnan malli, jossa keskiössä ovat toiminnallinen suoriutuminen sekä osallistuminen. Elämänlaadun käsite ei sisälly ICF-luokitukseen, mutta sen arvioinnin tarve nousee kuntoutusalan asiantuntijoiden suositusten pohjalta. Opinnäytetyömme on osa VATA-hanketta. Yhteistyökumppaninamme toimi oppimis- ja ohjaamiskeskus Valterin Tervaväylän toimipiste Oulussa. Työn tarkoituksena oli integroidun kirjallisuuskatsauksen avulla kerätä tietoa CP-vammaisille lapsille ja nuorille suositeltavista suoritusten, osallistumisen sekä elämänlaadun arviointimenetelmistä. Tutkimusaineisto kerättiin seuraavista tietokannoista: Can Child, BioMedCentral, EBSCO, Elsevier Science Direct, Kuntoutusportti, OTseeker, OTDBASE, PubMed, SAGE Premier ja Google Scholar. Kirjallisuuskatsaukseen valikoitui kansainvälisistä tieteellisistä julkaisuista yhteensä kymmenen tutkimusta, joista neljä oli määrällistä ja kaksi laadullista tutkimusta, kolme systemaattista kirjallisuuskatsausta ja yksi strukturoitu kirjallisuuskatsaus. Kirjallisuuskatsauksen aineistossa suositellaan kolmeatoista arviointimenetelmää CP-vammaisten lasten ja nuorten suoritusten, osallistumisen sekä elämänlaadun arviointiin toimintaterapiassa. Menetelmistä kymmenen arvioi osallistumista ja suorituksia ja kolme elämänlaatua. Jokaisen suositellun menetelmän reliabiliteetti sekä validiteetti oli todettu hyväksi. Toimintaterapeutit voivat hyödyntää kirjallisuuskatsauksessa suositeltuja menetelmiä käytännön työssään CP-vammaisten lasten ja nuorten toimintakyvyn arvioinnissa.Occupational therapy focuses on abling participation in meaningful activities. Instruments recommended earlier to be used when assessing children and adolecents with cerebral palsy have mainly focused on assessing body functioning and structures. After the World Health Organization published the International Classification of Functioning, Disability and Health, there has been growing interest towards assessing an individual’s activity and participation. Although, in occupational therapy there has for a long time been practical models such as the Model of Human Occupation that consentrate on performance and participation. The concept of quality of life is not included in the ICF classification but the need for assessing it rises from recommondations made by rehabilitation experts. Our thesis is a part of the VATA project, which aims to develop evidence based practice in social and health care in Finland. The method of this study was integrated literature review. The data was analyzed by using content analysis method. The purpose of this study was to find recommended assessment tools to be used with children and adolescent with cerebral palsy when assessing their activity, participation and quality of life. Research material for this study was gathered from following databases: CanChild, BioMedCentral, EBSCO, Elsevier Science Direct, Kuntoutusportti, OTseeker, OTDBASE, PubMed, SAGE Premier and Google Scholar. Ten studies were accepted to this literature review from peer-evaluated publishers. Four quantitative and two qualitative studies, one structured review and two systematic reviews were included. According to the results of this study there are currently thirteen assessment tools recommended for children and adolecents with cerebral palsy when measuring their activity, participation and quality of life. Ten of these tools are developed for assessing performance and participation. Three tools are recommended for assessing quality of life. Each tool has good reliability and validity. Occupational therapists can use these tools in practice when evaluating activity, participation and quality of life with children and adolecents with cerebral palsy

Diseases with oral manifestations among adult asthmatics in Finland : a population-based matched cohort study

Objectives Many comorbidities are associated with adult asthma and may exacerbate the asthma burden of disease. This study aims to investigate the risk for major oral diseases or oral-manifesting diseases in asthmatic compared with non-asthmatic adults. Design We conducted a population-based matched cohort study with a 13.8-year follow-up. Setting A baseline questionnaire was completed by participants in 1997 and follow-up data were extracted from the national hospital discharge registry of the National Institute for Health and Welfare in Finland from 1997 to 2014. Participants A total of 1394 adults with asthma were matched with 2398 adults without asthma based on sex, age and area of residence. Asthmatic adults were identified from the Drug Reimbursement Register of the Finnish Social Insurance Institution based on a special drug reimbursement right resulting from asthma. Participants without asthma were identified from the Population Register. Main outcomes and measures Oral health-related primary diagnoses were retrieved using codes from the International Classification of Diseases, 10th edition and divided into groups of diseases. Cox's proportional hazards models stratified by matching unit and models matched and adjusted for pack-years, education level and body mass index (when possible) were used to evaluate the matched and further adjusted HRs for diseases comparing asthmatic and non-asthmatic cohorts. Results Adult asthma was associated with a higher risk for any oral-manifesting disease (adjusted HR 1.41, 95% CI 1.11 to 1.80), herpes zoster (adjusted HR 6.18, 95% CI 1.21 to 31.6), benign tumours of the oral cavity and pharynx (matched HR 1.94, 95% CI 1.05 to 3.56) and dermatological diseases (pemphigus, pemphigoid, dermatitis herpetiformis, psoriasis and lichen planus, HR 1.67, 95% CI 1.01 to 2.78). Conclusions In this study, adult asthmatics experienced a higher risk for a major oral disease or oral-manifesting disease.Peer reviewe

Risk factors for severe adult-onset asthma : a multi-factor approach

Background The aim was to identify risk factors for severe adult-onset asthma. Methods We used data from a population-based sample (Adult Asthma in Finland) of 1350 patients with adult-onset asthma (age range 31-93 years) from Finnish national registers. Severe asthma was defined as self-reported severe asthma and asthma symptoms causing much harm and regular impairment and >= 1 oral corticosteroid course/year or regular oral corticosteroids or waking up in the night due to asthma symptoms/wheezing >= a few times/month. Sixteen covariates covering several domains (personal characteristics, education, lifestyle, early-life factors, asthma characteristics and multiple morbidities) were selected based on the literature and were studied in association with severe asthma using logistic regressions. Results The study population included 100 (7.4%) individuals with severe asthma. In a univariate analysis, severe asthma was associated with male sex, age, a low education level, no professional training, ever smoking, >= 2 siblings, >= 1 chronic comorbidity and non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) (p = 2 siblings (2.51 [1.17-5.41]). There was a dose-response effect of the total sum of these five factors on severe asthma (OR [95% CI] = 2.30 [1.81-2.93] for each one-unit increase in the score). Conclusions Male sex, smoking, NERD, comorbidities, and >= 2 siblings were independent risk factors for self-reported severe asthma. The effects of these factors seem to be cumulative; each additional risk factor gradually increases the risk of severe asthma.Peer reviewe

Kestävä ja terveellinen liikkuminen

Peer reviewe

The Finnish experience to save asthma costs by improving care in 1987-2013

The Finnish National Asthma Program 1994-2004 markedly improved asthma care in the 1990s. We evaluated the changes in costs during 26 years from 1987 to 2013. Direct and indirect costs were calculated by using data from national registries. Costs from both the societal and patient perspectives were included. The costs were based on patients with persistent, physician-diagnosed asthma verified by lung function measurements. We constructed minimum and maximum scenarios to assess the effect of improved asthma care on total costs. The number of patients with persistent asthma in the national drug reimbursement register increased from 83,000 to 247,583. Improved asthma control reduced health care use and disability, resulting in major cost savings. Despite a 3-fold increase in patients, the total costs decreased by 14%, from (SIC)222 million to (SIC)191 million. Costs for medication and primary care visits increased, but overall annual costs per patient decreased by 72%, from (SIC)2656 to (SIC)749. The theoretical total cost savings for 2013, comparing actual with predicted costs, were between (SIC)120 and (SIC)475 million, depending on the scenario used. The Finnish Asthma Program resulted in significant cost savings at both the societal and patient levels during a 26-year period.Peer reviewe

Going carless in different urban fabrics : socio-demographics of household car ownership

Diverse physical features of urban areas alongside socio-demographic characteristics affect car ownership, and hence the daily mobility choices. As a case of sustainable mobility, we explore how various urban environments and socio-demographics associate with the spatial and social distribution of household car ownership and carlessness in the Helsinki Metropolitan Area, Finland. Three urban fabrics characterizing the study area are established based on the transportation mode (walking, public transportation, or automobile) the physical urban environment primarily supports. The national level Monitoring System of Spatial Structure and Urban Form database, and the National Travel Survey (2016) are utilized to further include spatial and socio-demographic variables into our analysis across these fabrics. Our results show that households with and without cars differ in terms of residential distance to the city center, neighborhood density, house type, and socio-demographic profiles. Single pensioners and students are most likely to be carless, whereas families represent the opposite. Within the carless households the differences are also evident between different groups. For the more affluent households residing in dense and well-connected areas, and mostly possessing driver's licenses, carlessness is presumably a choice. Contrarily, many other carless households represent the less affluent often located in the more distant, low-density, and less accessible areas, while also possessing less driver's licenses, making carlessness more of a constraint, as the local urban fabric does not support such lifestyle. Consequently, carless households should be increasingly recognized as a focus group in sustainable urban planning in terms of identifiable best practices and potential vulnerability.Peer reviewe

Season of birth affects the risk of adult-onset asthma in Finland

Non peer reviewe

Machine learning algorithms performed no better than regression models for prognostication in traumatic brain injury

Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury. Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study. Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations. (C) 2020 The Authors. Published by Elsevier Inc.Peer reviewe