Novel insights into genetic predisposition to myeloid malignancies

Familial clustering in hematological malignancies is well known. Although many factors have been identified as predisposing to acute myeloid leukemia (AML) and other myeloid disorders, there are still clinical challenges in the recognition. Identification of inherited mutations is important for the screening of family members and other individuals at higher risk of developing a myeloid malignancy. The aim of this thesis was to study germline alterations in myeloid disorders. The first aim was to discover the germline mutations in genes associated with AML pathogenesis and DNA repair in an unselected series of adult AML patients. We identified 34 variants of uncertain significance (VUS) or mutations in 42/68 (62%) patients with exomes available. Most of the identified gene alterations were found in DNA repair genes. The fraction of potentially pathogenic mutations was 9%. This study implicates that germline defects possibly associated with AML can also be identified in older cases without a known family history of cancer. The second aim of this study was to identify novel candidate predisposition genes to a myeloproliferative neoplasm named polycythemia vera (PV) by conducting an exome sequencing analysis in a family with four PV patients. Three variants shared by all the patients were identified in the genes ZXDC, ATN1, and LRRC3. The variants were screened in six other families with PV clustering, but those patients did not carry the variants. However, exome sequencing is very feasible in identifying new candidate variants. The third aim of this study was to investigate an X-chromosome-linked telomere biology disorder in three female siblings with a heterozygous germline DKC1 mutation. Two brothers in the family were diagnosed with dyskeratosis congenita (DC), which predisposes to e.g. AML. All three female mutation carriers showed DC-like manifestations; usually, X-chromosome inactivation (XCI) silences the defective X-chromosome in females, protecting them from symptoms. We examined the XCI status and mutant allele expression in different tissue samples. The results showed expression of both alleles in e.g. blood in two out of three females. Further, two of the females showed shortened telomere length. Recognition and follow-up of the females carrying mutations is important.Hematologisten sairauksien suvuttaista esiintymistä havaitaan säännöllisesti. Perinnöllisen syöpäalttiuden tunnistaa usein siitä, että syöpään sairastutaan jo nuorena tai että lähisuvussa on useampi sairastunut. Vain osa sairastumisriskiä nostavista geenivirheistä tunnetaan, mutta kehittyneillä sekvensointimenetelmillä voidaan löytää ennestään tuntemattomia mutaatioita. Akuutti myelooinen leukemia (AML) on verisyöpä, jota hoidetaan mm. kantasolusiirrolla. Perinnöllisyysselvittely mahdollistaa kantasoluluovuttajaseulonnat, jotta sama mutaatio ei siirry lähisukulaiselta potilaalle. Tässä väitöskirjassa tutkittiin perinnöllisten muutosten roolia hematologisten myelooisten (luuydinperäisten) tautien kehittymisessä. Osatyössä 1 tutkimme AML:lle mahdollisesti altistavia ituratavariantteja geeneissä, jotka liittyvät leukemian patogeneesiin tai DNA-korjausmekanismeihin. Identifioimme 34 pahanlaatuista tai merkitykseltään epävarmaa varianttia 62%:lla valikoimattomista potilaista, joista eksomidata oli saatavilla. Suurin osa varianteista havaittiin DNA-korjausgeeneissä, ja kaikkiaan potentiaalisesti patogeenisten mutaatioiden osuus oli 9%. Tutkimus osoitti, että mahdollisesti AML:lle altistavia ituratavariantteja voidaan diagnosoida myös vanhemmilla potilailla, joilla ei tiettävästi ole sairautta suvussa Osatyössä 2 tutkimme myeloproliferatiivisiin tauteihin kuuluvan polysytemia veran mahdollisia altistusvariantteja perheessä, jossa on diagnosoitu neljä PV-tapausta. Havaitsimme potilaille yhteiset ja ennusteeltaan pahanlaatuiset variantit geeneissä ZXDC, ATN1 ja LRRC3. Vaikka muiden perheiden PV-potilaat eivät kantaneet kyseisiä variantteja, on eksomisekvensointi soveltuva menetelmä tämän tyyppiseen tutkimukseen. Osatyössä 3 tutkimme perhettä, jossa nuorilla veljeksillä diagnosoitiin X-kromosomaalisesti periytyvä dyskeratoosi, joka aiheuttaa mm. luuytimen vajaatoimintaa. Mutaatio identifioitiin telomeraasikompleksin osaa koodittavassa DKC1-geenissä, mikä johtaa solujen telomeerien nopeaan lyhenemiseen. Perheen kolmella vanhemmalla mutaatiokantajanaisella havaittiin dyskeratoosiin liittyviä oireita. Tutkimme ilmiötä perehtyen esimerkiksi X-inaktivaatioon ja geenin kahden alleelin ilmentymiseen naisten kudoksissa. Kumpaakin alleelia ilmennettiin esim. veressä kahdella kolmesta naisesta. Lisäksi kahdella naisista havaittiin lyhentyneet telomeerit, mikä viittaa telomeeribiologian häiriöön ja vaatii seurantaa

Vieraalle kielelle käännetyt lehdistötiedotteet yrityksen viestinnässä

Press releases are one means that enterprises use in order to increase customers’ and other inter-est groups’ knowledge of their business operations and products. This article describes briefly how press releases were written, translated, revised and accepted in one international company in Finland. The aim of the actual study is firstly to investigate if the native revisors of the press releases translated into the foreign language tried to decrease the conventionality of the translated texts caused by the translation process itself or translation into the foreign language. In this study, conventionality means that translated texts contain more conventional lexis and grammar than similar texts originally produced in a given language. Secondly, the study investigates if the native revisors tried to make the translated texts fit the conventions of special-field press releases better. The preliminary results seem to confirm both hypotheses

New biocide active substances:needs and challenges in the EU as viewed by industry

Emerging regulatory initiatives in the EU are driving towards more environmentally safe chemicals, used as such or in a wide range of products and applications. The aim of the regulations is also to foster and support the emergence of new or safer alternatives and to drive innovations thereof. Biocides are chemicals, which are used in a vast and steadily growing number of applications in order to preserve product safety and quality, however, the number of the Active Substances (AS) used in biocides is decreasing in the EU concurrent with the implementation of the Biocidal Product Directive (BPD). Accordingly, the present study attempts to elucidate views of representatives of the biocide industry in order to identify some of the present drivers and challenges of new AS development in the different biocide application areas, with emphasis on the economic feasibility of safer biocide development in the future. Notably, the costs of vertebrate testing are a major factor in development of new AS. Therefore, an evaluation of the costs of such tests and their total proportion of total AS development costs is also discussed. Industry expectations for the implementation of the BPD and impacts thereof are presented.<br

Whole-exome sequencing identifies novel candidate predisposition genes for familial polycythemia vera

Background: Polycythemia vera (PV), characterized by massive production of erythrocytes, is one of the myeloproliferative neoplasms. Most patients carry a somatic gain-of-function mutation in JAK2, c.1849G > T (p.Val617Phe), leading to constitutive activation of JAK-STAT signaling pathway. Familial clustering is also observed occasionally, but high-penetrance predisposition genes to PV have remained unidentified. Results: We studied the predisposition to PV by exome sequencing (three cases) in a Finnish PV family with four patients. The 12 shared variants (maximum allowed minor allele frequency G (p.Phe418Leu) in ZXDC, c.1931C > G (p.Pro644Arg) in ATN1, and c.701G > A (p.Arg234Gln) in LRRC3. We also observed a rare, predicted benign germline variant c.2912C > G (p.Ala971Gly) in BCORL1 in all four patients. Somatic mutations in BCORL1 have been reported in myeloid malignancies. We further screened the variants in eight PV patients in six other Finnish families, but no other carriers were found. Conclusions: Exome sequencing provides a powerful tool for the identification of novel variants, and understanding the familial predisposition of diseases. This is the first report on Finnish familial PV cases, and we identified three novel candidate variants that may predispose to the disease.Peer reviewe

Nanosuspensions of a poorly soluble investigational molecule ODM-106 : Impact of milling bead diameter and stabilizer concentration

Aqueous solubility of a drug substance is an important attribute affecting oral bioavailability. Nanonization, particle size reduction to submicron level, is an elegant approach to improve drug solubility and dissolution by increasing the surface energy, which in turn necessitates the use of stabilizers. The purpose of this study was to develop a nanosuspension of a practically water-insoluble investigational molecule by nanomilling approach using wet media milling. A variety of polymeric and surface active excipients were tested for their wettability. A combination of hydroxypropyl methylcellulose and sodium lauryl sulfate (SLS) were selected as stabilizers on the bases of compatibility studies and efficient wettability behaviour in contact angle measurements (≈80˚). A factorial design set-up was used to study the effect of milling bead diameter and stabilizer concentration on the efficiency of particle size reduction. Nanonization outcome was different when milling beads of 0.5 mm and 1 mm diameter were used at different concentrations of the stabilizers, which demonstrated the complex nature of the whole system. Storage of the nanosuspensions under different temperature conditions resulted only in minor changes of the particle size fractions.Peer reviewe

Practical aspects of sentinel node biopsy in oral cavity cancer: all nodes that emit a signal are important

Background and objectivesSentinel node biopsy (SNB) is a safe and effective way to examine an N0 neck in early-stage oral cavity cancer (OCC). In this study, we evaluated the variables of SNB detection, surgery, and outcome.Material and methods Ninety-two patients with N0 OCC examined with SNB were included. Number and brightness of nodes detected on preoperative imaging and during surgery were analyzed and compared with histological findings. Patients with recurrent disease were evaluated separately and the effect of smoking and alcohol consumption was analyzed.ResultsEighteen patients had at least malignant cells in the sentinel lymph node (SLN); 18 patients had recurrent disease and nine patients died from the cancer. The negative predictive value of SNB was 95%. Six patients did not have metastases in the node with the strongest signal, but metastases were found in an SLN with a weaker signal. Smoking and alcohol consumption did not affect disease-specific or overall survival.Conclusion and significanceSNB has been confirmed to be safe and effective in early stage N0 OCC. However, it is important to carefully harvest up to four hottest SLNs that emit a signal. Treatment of patients with only isolated tumor cells (ITC) in the SLN appears to be necessary.</p

Use of health services one year before primary colorectal cancer

BACKGROUND: Colorectal cancer (CRC) patient pathways focus typically on periods after confirmed diagnosis and only limited data are available on pathways prior to cancer diagnosis. The aim of the study was to describe the use of health services (HS) one year before diagnosis among CRC patients in Finland. We also studied the role of sex, age, stage, and university hospital district in relation to the use of HS during the pre-diagnostic phase. This information is expected to bring light on the question why CRC is often not found in its early stages. METHODS: Incident CRC cases (N = 3115) concerning year 2015 were retrieved from the Finnish Cancer Registry and linked with data from the Finnish Institute for Health and Welfare on primary or specialised care outpatient visits or inpatient episodes over one year prior to CRC diagnosis. We modelled the average number of HS events per patient using Poisson regression model with log-link. Change points for monthly HS event rates and 95% CIs one year before diagnosis were evaluated using Poisson broken line regression models. RESULTS: Around 10% of patients diagnosed in 2015 had no events prior to cancer leaving 2816 CRCs in the study. Of all pre-diagnostic events (N = 23268), 86% were outpatient events and 14% inpatient episodes. More than half of the inpatient episodes (65%) started as urgent admissions. The use of HS started to increase 3-4 months before diagnosis. The average number of pre-diagnostic HS events per patient varied by sex, age, stage and university hospital district. Overall, men had more events per patient than women and older patients had more events than younger patients. CONCLUSIONS: The amount of inpatient episodes starting as urgent admissions indicate potential bottlenecks in the access to health services. An increase in service use only 3-4 months prior to diagnosis reflects a need for advice both for health care professionals and the general population in recognising symptoms of CRC.publishedVersionPeer reviewe

Iloa vanhemmuuteen : vanhemmuutta tukeva teematapahtuma

Kehittämistyömme tarkoituksena oli suunnitella ja toteuttaa lapsiperheille suunnattu, vanhemmuutta vahvistava teematapahtuma kolmessa Helsinkiläisessä neuvolassa. Tavoitteena oli tuottaa kuusi neuvolaympäristöön soveltuvaa tieto- ja toimintapakettia sekä niihin liittyvä materiaali sekä järjestää vanhemmille iloinen, ideoita antava ja voimauttava hetki arjen keskelle ja arkea tukemaan. Pyrimme tuottamaan sisällöllisesti innostavan ja voimauttavan kokonaisuuden, joka olisi vanhempia osallistava. Kokeilimme teematapahtumaa terveyden edistämisen työmenetelmänä vastaamaan neuvolatyön haasteisiin vanhemmuuden tukemisen alueella. Lähtökohtana tälle kehittämistyölle oli sekä käytännön neuvolatyöstä että tutkimuksista esiin noussut tarve tukea perheitä entistä enemmän vanhemmuuteen, kasvatustyöhön, voimavaroihin ja arjessa selviytymiseen liittyen. Kehittämistyömme tuotoksena oli kolme vanhemmuutta vahvistavaa teematapahtumaa sekä tapahtuman toteutukseen tarvittava materiaali. Teematapahtumat koostuivat seuraavista osa-alueista: Vauvan kehollisuus- vauvahieronta ja vauvatus, Liikkeelle vauvan kanssa, Vauvavuoden kulku, Kontakti lapseen - sadutus ja lapsihieronta, Mitä tehdä lapsen kanssa kotona ja kodin ulkopuolella sekä Tahtoikäisen kanssa selviytyminen. Teematapahtuman nimeksi muotoutui Iloa vanhemmuteen. Iloa vanhemmuuteen -tapahtumissa oli yhteensä 78 osallistujaa ja palaute oli positiivista. Osallistujat olivat pääosin vauvojen ja varhaisleikki-ikäisten lasten äitejä, mutta paikalla oli myös joitakin isiä ja terveysaseman henkilökuntaa. Osallistujat kiersivät, keskustelivat ja keräsivät tietoa tarjolla olleista aiheista. Terveydenhoitajaopiskelijoiden ja osallistujien välinen keskustelu oli rakentavaa ja tietoa välittävää, vaikkakin keskustelu jäi enimmäkseen pinnalliseksi, mahdollisesti tapahtuman messumaisen luonteen vuoksi. Tällaisen projektiluonteisen kehittämistyön tekeminen oli mielenkiintoinen, kehittävä ja opettava kokemus. Tapahtuman toteuttaminen kolmessa eri toimipisteessä mahdollisti kolmen varsin erilaisen kokemuksen saannin. Jatkoa ajatelleen olisi tärkeää löytää motivoituneet yhteistyöneuvolat sekä sopiva paikka tapahtuman järjestämiselle, jotta se tavoittaisi mahdollisimman suuren osan kohderyhmästään eli neuvolan asiakkaista.The purpose of this final project was to plan and organise an event that was directed at families with children under school age and conducted in three maternity and child health centres in Helsinki. The aim of this project was to produce informative material that can be used when holding similar events in the future, and to arrange an event with a focus on strengthening parenthood and parental resources. Our aim was also to get into interaction with the maternity and child health centres and their customers. The starting point for this project was that both practice and research show that parents of today need even more support than before regarding parenthood, parenting, parental resources, and everyday life with small children. As an output, we organized three events with a turnout of seventy-eight parents most of which were mothers of small babies. The material consisted of topics concerning parenthood and parenting. The parents gathered up information by talking with the students and by collecting the provided material. Organizing an event such as this one was an interesting and informative experience. Because the event was organized three times in three different locations we were left with three diverse learning experiences that can be of use for future reference. When planning an event similar to this one attention should be paid to finding motivated maternity and child health centres for partners in co-operation and a more suitable location for the event to reach as many parents as possible

Vastasyntyneiden hätätilanteiden koulutusohjelma suomalaisiin synnytyssairaaloihin

Hätätilanteisiin varautuminen on keskeinen potilasturvallisuuden elementti. Suomen Perinatologisen Seuran neonatologijaos laati vastasyntyneiden hätätilanteiden koulutusohjelman parantamaan syntymän turvallisuutta