157 research outputs found
Analysis of somatic mutations in leukemias
No full textThis thesis describes three studies on the identification and analysis of somatic mutations in three respective types of leukemia: large granular lymphocytic leukemia (LGL leukemia), B-cell precursor acute lymphoblastic leukemia (ALL) with TCF3-PBX1/t(1;19) fusion (TCF3-PBX1 BCP-ALL), and acute myeloid leukemia (AML).
In the first study, we analyzed the somatic mutations in an LGL leukemia index patient and identified a mutation in STAT3. A subsequent cohort analysis found that the STAT3 gene was mutated in 40% of LGL leukemia patients. Functional validation showed that the identified STAT3 mutations are activating oncogenic mutations. Our results indicate that STAT3 mutations can be used as mutational biomarkers in the diagnosis of LGL leukemia.
In the second study, we analyzed the somatic mutations, aberrant gene expression, and drug sensitivities in a relapsed TCF3-PBX1 BCP-ALL patient. We found that the patient’s cells were exceptionally sensitive to the phosphoinositide 3-kinase inhibitor idelalisib. Idelalisib has been previously approved for the treatment of chronic lymphocytic leukemia. The patient’s leukemia was highly sensitive to Idelalisib despite harboring loss-of-function mutations in TP53, which are associated with poor prognosis in ALL. Idelalisib sensitivity was confirmed in TCF3-PBX1 BCP-ALL cell lines. Our results indicate that idelalisib is a promising drug for the treatment of relapsed TCF3-PBX1 BCP-ALL.
In the third study, we analyzed somatic mutations, copy number, and cytogenetic aberrations in newly diagnosed and relapsed AML patients. By comparing mutations frequencies in these two conditions, we found that mutations in CBL, PTPN11, NF1, and KRAS are both enriched and selected for in relapsed AML patients. Mutations in these genes have been shown to induce cytokine hypersensitivity which may confer cytokine protection and increased survival of leukemic cells during therapy. Our results show that mutations in these genes are common in relapsed AML patients and are under positive selection. We also found that mutations in TP53, WT1, PHF6 as well as trisomy 8 and monosomy 7/del(7q) are enriched and selected for in relapsed AML patients.Leukemiat ovat valkosolujen esi-asteiden syöpiä, jotka aiheutuvat soluihin muodostuvista mutaatioista. Somaattiset mutaatiot ovat hankinnaisia DNA:n muutoksia, joita syntyy soluihin ikääntymisen aikana. Somaattiset mutaatiot muuttavat solujen DNA:ta ja voivat johtaa solujen muuntautumiseen syöpäsoluksi niiden kohdistuessa syövän kehittymiseen vaikuttaviin geeneihin. Syöpää aiheuttavien geenien mutaatiot voidaan tunnistaa DNA:n sekvensointimenetelmillä. Tunnistettuja syöpämutaatioita voidaan käyttää leukemioiden diagnosoinnissa ja hoidon valinnassa.
Tutkimuksen tavoitteena on tunnistaa leukemiaa aiheuttavia mutaatioita kolmessa leukemia tyypissä. Tutkimuksessa käytettiin uuden sukupolven DNA sekvensointia sekä laskennallisia menetelmiä mutaatioiden tunnistamiseen ja analysointiin.
Väitöskirjan ensimmäisessä osa-julkaisussa todettiin aiemmin tuntematon STAT3-geenin mutaatio 40 %:lla suurten granulaaristen lymfosyyttien leukemiaa (LGL leukemia) sairastavista potilaista. Tunnistetut STAT3-geenin mutaatiot johtavat yliaktiivisen, mutatoituneen Stat3 proteiinin ilmentymiseen ja geenisäätelyn häiriintymiseen tavalla, joka edesauttaa LGL leukemian kehittymistä. Tutkimustulosten pohjalta STAT3 geenin mutaatioita voidaan hyödyntää LGL leukemian diagnosoinnissa.
Toisessa osa-julkaisussa tutkimme somaattisia mutaatioita, poikkeavaa geeniekspressiota ja lääkeaineherkkyyksiä relapsoituneessa TCF3-PBX1 fuusiogeeni mutaation aiheuttamassa akuutissa lymfaattisessa leukemiassa (ALL). Relapsoituneen indeksi potilaan leukemiasolut olivat poikkeuksellisen herkkiä fosfoinositidi-3-kinaasi-delta-estäjä idelalisibille. Idelalisib on käytössä kroonisen lymfosyyttisen leukemian hoidossa. Idelalisib-herkkyys voitiin todeta myös TCF3-PBX1 positiivisissa leukemia solulinjoissa. Tuloksemme osoittavat idelalisibin olevan lupaava lääke relapsoituneen TCF3-PBX1 positiivisen ALL:n hoitoon.
Kolmannessa osa-julkaisussa tutkimme mutaatioita, jotka liittyvät hoitoresistenssin kehittymiseen akuutissa myelooisessa leukemiassa (AML). AML:ää hoidetaan monisolunsalpaajahoidolla, joka on useimpien potilaiden kohdalla tehokas taudin alkuvaiheessa. AML kuitenkin kehittyy usein hoidon aikana resistentiksi. Tutkimuksessa tunnistimme mutaatiot eksomisekvensoinnilla 124:n AML-potilaan leukemianäytteistä. Tutkimuksen tulokset osoittavat, että mutaatiot geeneissä, jotka lisäävät leukemiasolujen herkkyyttä sytokiinistimulaatiolle, valikoituvat hoidon vaikutuksesta. Resistenssiin vaikuttavien mutaatioiden tunnistaminen edesauttaa ymmärtämään mekanismeja, jotka johtavat resistenssin kehittymiseenei saavutettav
Abstract 424: Landscape of somatic mutations in drug-resistant acute myeloid leukemia
No full textAbstract
Introduction: Most patients with acute myeloid leukemia (AML) initially respond to cytarabine-anthracycline induction chemotherapy. However, in many patients, the disease recurs in a lethal drug-resistant form. Somatic mutations underlying the pathogenesis of AML have been extensively characterized by sequencing of newly diagnosed AMLs. However, the mutations driving therapy resistance and disease progression at relapse have not been well characterized. In this study, we have exome sequenced a cohort of relapsed and refractory AMLs and compared the landscape of somatic mutations at relapse to diagnosis phase AMLs to identify mutations that contribute to therapy resistance and disease progression.
Materials and Methods: We performed exome sequencing of diagnosis phase AMLs (n=70) and relapsed or primary refractory AMLs (n=54). Patients with AML M3 subtype were excluded from the study. Paired diagnosis and relapse samples were available from 27 patients. A skin biopsy was used as the germline control. Nine patients had received an allogeneic hematopoietic stem cell transplant before relapse. Somatic mutations were called using varscan2 and copy number aberrations using copyCat. Since the identification of large insertions from next-generation sequencing data remains challenging using existing algorithms, FLT3 internal tandem duplications (FLT3-ITDs) were identified using a novel custom algorithm optimized for FLT3-ITD detection. Population variants were filtered out to remove donor-derived germline variants in chimeric post-transplant relapse samples.
Results: Comparison of somatic mutation frequencies in diagnosis and relapse and refractory samples showed that on average relapsed tumors have a higher number of driver mutations than tumors at diagnosis. WT1, TP53, CBL, IDH1 and PTPN11 were mutated at a higher frequency in relapsed samples than at diagnosis, with 13 %, 11 %, 11 %, 9 % and 9 % of relapsed or refractory samples and 4 %, 6 %, 3 %, 4 % and 7 % of diagnosis mutated respectively. Analysis of paired diagnosis-relapse samples showed that in patients with WT1, CBL or PTPN11 mutation at diagnosis the second allele is frequently mutated or lost due to uniparental disomy occurring at relapse.
Conclusions: On average relapsed AMLs have a higher number of driver mutations than diagnosis phase AMLs indicating that acquisition of additional driver mutations contributes to relapse. AMLs frequently acquire additional mutations in the same genes and pathways that already harbored mutations at diagnosis.
Citation Format: Samuli Eldfors, Mika Kontro, Yevhen Akimov, Olli Kallioniemi, Kimmo Porkka, Caroline Heckman. Landscape of somatic mutations in drug-resistant acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 424. doi:10.1158/1538-7445.AM2017-424</jats:p
KRIITTISTEN LAITTEIDEN ENNAKKOHUOLTO
No full textTIIVISTELMÄ
Oulun ammattikorkeakoulu
Kone ja tuotantotekniikan tutkinto-ohjelma
Tekijä: Samuli Pietarila
Opinnäytetyön nimi: Kriittisten laitteiden ennakkohuolto
Työn ohjaajat: Kari Penson ja Kai Jokinen
Työn valmistumislukukausi ja -vuosi: Syksy 2016 Sivumäärä: 45 + 5 liitettä
Opinnäytetyö on tehty Paroc Oy Ab Oulun kivivillatehtaalle. Työn tavoitteena oli löytää prosessilinjan alkupään osalta kriittisimmät laitteet sekä kehittää näiden laitteiden toimintavarmuutta ennakoivalla kunnossapidolla. Toimintavarmuutta kehitettiin selvittämällä kriittisten laitteiden varaosasaatavuudet, huollettavuudet sekä mahdolliset korvaavat laitemuutokset.
Huoltokohteet kartoitettiin kriittisyysanalyysin, tehtaan historiadokumenttien sekä laitevalmistajan toimittamien laitedokumenttien pohjalta. Tarkasteltavana alueena oli prosessilinjan alkupää, joka käsittää prosessin laitteistosta vanhinta laitekantaa. Kriittisille laitteille luotiin ennakoivat kunnonvalvonta- ja huolto-ohjelmat.
Työn tuloksena selvisi prosessin alkupään vikaherkimmät laitteet. Kriittisille laitteille kehitettiin ennakkohuolto-ohjelma, selvitettiin varaosien saatavuus sekä löydettiin korvaavat uudenaikaiset laitteet. Suurimmat haasteet tulivat tehtaan laitehistorian dokumentoinnin vajavaisuudesta, jolloin laitteiden vikahistoria on haastavaa selvittää jälkeenpäin.ABSTRACT
Oulu University of Applied Sciences
Mechanical and production engineering
Author: Samuli Pietarila
Title of thesis: Preventive Maintenance of Critical Equipment
Supervisors: Kari Penson and Kai Jokinen
Term and year when the thesis was submitted: Autumn 2016 Pages: 45 + 5 appendices
This thesis was made for Paroc Oy Ab Oulu stone wool factory. The objective was to identify the critical equipment at the beginning of the process line and to improve the reliability of such equipment with preventive maintenance. Reliability was developed by studying the availability of the spare parts of critical equipment as well as the serviceability, and potential compensatory devices of critical equipment.
Service points were mapped by using criticality analysis, on the basis of the documents provided by the machine history and the documents provided by the manufacturer. The focus of the examination was on the beginning of the process line where the machinery is oldest. Predictive condition monitoring and maintenance programs were created for the critical equipment.
The results showed the most fault-sensitive devices at the beginning of the process. A preventive maintenance program was developed for the critical equipment, the availability of spare parts was examined and modern replacement devices were found. The biggest challenges came from the incomplete documentation of the history of the devices. When the documentation is incomplete the fault history of the equipment is difficult to find out afterwards
Bilder i bruk Samuli Paulaharjus fotografier i dokumentasjonens og illustrasjonens tjeneste
No full textSince the late 1970s, Norwegian historians have debated the standing of photographs in historical research. Efforts have been made to establish photographs as sources, not merely illustrations in historical narratives. The present article discusses the use of photographs taken in Northern Norway in the 1920s and 1930s by the Finnish author Samuli Paulaharju, best known for his research on Finnish folk culture. Paulaharju’s photographs have been, and still are, used to tell many different stories. While Paulaharju himself used these photographs in his books to illustrate Finnish culture and history as it manifested itself among the Finnish-speaking minority on the shores of Arctic Ocean, in Norway his photographs have been used to illustrate and partly also document Northern Norwegian cultural and social history and Kven history. The analysis also shows that the photographs are widely used in a positivistic manner: they are seen as representing historical reality, whereas in practice the meaning ascribed to the photographs is contingent on the context of
their deployment. In a consequence, we argue that the position of photographs as a source must be reinforced, and that the usual rules of source criticism must also be applied to photographs
Abstract 410: Identifying ovarian cancer specific targeted drugs using high-throughput drug sensitivity profiles of primary cancer cells
No full textAbstract
Ovarian cancer (OvCa) is the sixth most common cancer in women and leading cause of death from gynecologic diseases. Poor prognosis in OvCa is due to late diagnosis and acquired resistance to the commonly used platinum-based regimens. A significant setback for OvCa treatment is the lack of reliable biomarkers and effective targeted therapies. In order to discover novel therapeutic opportunities with approved and emerging drugs for OvCa, we have established primary cultures using ascites or tumor tissue samples from chemo-refractory ovarian cancer patients for ex vivo Drug Sensitivity and Resistance Testing (DSRT) and genomic profiling. In addition, we have performed DSRT with 31 established OvCa cell lines. Comparison of the drug sensitivity profiles of ten primary cancer cell cultures and 31 OvCa cell lines revealed previously unanticipated cancer selective drug vulnerabilities. Several drug groups were identified suggesting that the sensitive samples were addicted to the corresponding signaling networks. For example, in a 53-year old chemorefractory low grade serous OvCa patient, genomic and transcriptomic analyses revealed a fusion gene of NRG-1, a target that was recently reported to involve the NRG1/ERBB3 activation loop in OvCa. We found high expression of ERBB2 and ERBB3 by RNA-seq as well as high levels of phospho-ERBB3, phospho-ERBB2 and phospho-EGFR by immunohistochemistry. In agreement with the molecular mechanism, DSRT analysis identified significant sensitivity of primary cancer cells to EGFR inhibitors, such as erlotinib and to dual EGFR and Her2 inhibitor afatinib. The patient has received combination therapy of gemcitabine and erlotinib during nine months, followed by afatinib monotheraphy that has lead to complete remission after six months treatment. We have detected activated NRG1/ERBB3 activation loop also in several additional ovarian cancer patient cases, highlighting the importance of this signaling pathway in ovarian cancer pathogenesis. Our study reveals that a subset of serous ovarian cancer patients with activating NRG1/ERBB3 signaling loop have clinical benefits from repurposing dual EGFR/Her2 inhibitor afatinib, providing a basis for the clinical use of EGFR and dual EGFR/Her2 tyrosine kinase inhibitors in clinical treatment. In conclusion, DSRT technology together with molecular profiling provides a powerful strategy to identify tumor driver signals and select clinically actionable inhibitors. Hence, this type of systems medicine approach can significantly improve the power of mainly genomics-oriented personalized medicine approaches.
Citation Format: Astrid Murumägi, Akira Hirasawa, Suleiman Khan, Daniela Ungureanu, Mariliina Arjama, Teijo Pellinen, Samuli Eldfors, Riitta Koivisto-Korander, Arto Leminen, Ralf Bützow, Tero Aittokallio, Olli Kallioniemi. Identifying ovarian cancer specific targeted drugs using high-throughput drug sensitivity profiles of primary cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 410. doi:10.1158/1538-7445.AM2017-410</jats:p
Rethinking 'Jacobs Spillovers,' or how diverse cities actually make individuals more creative and economically successful
No full text
The effects of applying IFRS for SMEs for preparers and users of financial statements in Europe
No full textPk-yritykset ovat nousseet merkittäväksi puheenaiheeksi viime vuosina niiden työllistävän vaikutuksen vuoksi. Iso osa uusista työpaikoista on syntynyt pk-yrityksiin eikä suuriin yrityksiin. Samalla kansainvälistymiskehitys on ollut aikamme suurimpia muutosvoimia, jotka vaikuttavat talouselämään. Kansainvälistymällä yritykset ovat saaneet uusia väyliä hankkia rahoitusta, laajentaneet ja monipuolistaneet asiakaskuntaansa ja hankkineet skaalaetuja.
Kansainvälisyys aiheuttaa haasteita yritysten taloudelliselle raportoinnille, joten pk-yrityksille luotiin pk-IFRS –standardisto. Sen tarkoituksena on parantaa vertailukelpoisuutta eri maista tulevien yritysten välillä ja keventää raportoinnin raskautta. Tässä tutkielmassa selvitettiin, miten pk-IFRS:n soveltaminen vaikuttaa tilinpäätösten tekijöihin ja käyttäjiin. Tutkielma alkaa teoria-osuudesta, jossa käytiin läpi tuoreita tutkimuksia, minkä pohjalta esiin nousseita kysymyksiä käyttäen tehtiin empiria-osuudessa analysoitava haastattelu.
Tutkimuksessa saatiin selville, että tutkijoiden ja haastateltavan näkemykset pk-IFRS:tä ovat pääosin samanlaiset. Pk-IFRS:n ongelmia on sen lyhyys, mikä aiheuttaa tulkintaongelmia ja monimutkaisuus, joka kuormittaa raportoijan resursseja. Pk-yritykset toimivat useimmin vain kotimaassa, jolloin hyödyt jäävät rajallisiksi. Pienemmissä pk-yrityksissä tilinpäätöksiä käyttäviä sidosryhmiä on vähän, jolloin käyttäjien saamat hyödyt ovat pienet. Kuitenkin käypään arvoon arvostus ja tiedon annon vaatimukset voivat helpottaa rahoituksen saantia joillekin yrityksille, jos pk-IFRS:ää aletaan soveltaa samalla tavalla joka maassa ja yrityksessä.Abstract.
Author: Samuli Seppälä
Title: The effects of applying IFRS for SMEs for preparers and users of financial statements in Europe
Faculty: LUT School of Business and Management
Degree Program: Financial Management
Instructor: Helena Sjögren
Small and medium sized enterprises (SMEs) have become a major topic in recent years due to their effect on employment. A considerable number of jobs are created in SMEs instead of big companies. At the same time globalization has been one of the biggest forces of change in the economy. The discussion on globalization has mainly focused on large and international corporations. Thanks to globalization, companies have found new channels to find financing, expand and diversify their clientele and benefit from economies of scale. SMEs, having a significant position in the economy, should also have ways to benefit from these trends.
IFRS for SMEs was created because globalization created challenges to financial reporting. It aims to enhance comparability between companies from different countries and to reduce the workload of financial reporting. The goal of this thesis was to find out how IFRS for SMEs affects the preparers and the users of financial statements. This thesis consist of a theoretical part and a research part, where answers to a questionnaire are analyzed.
This research highlights the fact that the opinions in the corporate world and in the science community are similar. The biggest problems with IFRS for SMEs are its lack of proper guidance and complexity which takes resources. SMEs usually do business mainly in their home country and especially smaller SMEs have a small number of stakeholders which limits the benefits of IFRS for SMEs. On the other hand the valuation in fair value and the disclosures might help SMEs to find financing
Random tree besov priors – towards fractal imaging
No full textWe propose alternatives to Bayesian prior distributions that are frequently used in the study of inverse problems. Our aim is to construct priors that have similar good edge-preserving properties as total variation or Mumford-Shah priors but correspond to well-defined infinite-dimensional random variables, and can be approximated by finite-dimensional random vari-ables. We introduce a new wavelet-based model, where the non-zero coefficients are chosen in a systematic way so that prior draws have certain fractal behaviour. We show that realisations of this new prior take values in Besov spaces and have singularities only on a small set τ with a certain Hausdorff dimension. We also introduce an efficient algorithm for calculating the MAP estimator, arising from the the new prior, in the denoising problem.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Statistic
Schielke Samuli, Migrant Dreams. Egyptian Workers in the Gulf States
No full textMigrant Dreams (2020) results from subsequent investigations on Egyptian male workers’ migrating to Qatar, by the very innovative angle of dreams and hope. Very short, the book is approximately 110 pages, divided into 15 chapters of not more than 10 pages each. This concise format is explained by the fact that it is the resumption of a previous book – hata yantahi al-nafṭ (“Until the End of Oil”) published in 2017, in which the author examines the political and economic dynamics of Egyptian ..
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