Presence of Stromal Cells Enhances Epithelial-to-Mesenchymal Transition (EMT) Induction in Lung Bronchial Epithelium after Protracted Exposure to Oxidative Stress of Gamma Radiation

The aim of the study was to investigate the role of a microenvironment in the induction of epithelial-to-mesenchymal transition (EMT) as a sign of early stages of carcinogenesis in human lung epithelial cell lines after protracted low-dose rate gamma-radiation exposures. BEAS-2B and HBEC-3KT lung cell lines were irradiated with low-dose rate gamma-rays (Cs-137, 1.4 or 14 mGy/h) to 0.1 or 1 Gy with or without adding TGF-beta. TGF-beta-treated samples were applied as positive EMT controls and tested in parallel to find out if the radiation has a potentiating effect on the EMT induction. To evaluate the effect of the stromal component, the epithelial cells were irradiated in cocultures with stromal MRC-9 lung fibroblasts. On day 3 post treatment, the EMT markers: alpha-SMA, vimentin, fibronectin, and E-cadherin, were analyzed. The oxidative stress levels were evaluated by 8-oxo-dG analysis in both epithelial and fibroblast cells. The protracted exposure to low Linear Energy Transfer (LET) radiation at the total absorbed dose of 1 Gy was able to induce changes suggestive of EMT. The results show that the presence of the stromal component and its signaling (TGF-beta) in the cocultures enhances the EMT. Radiation had a minor cumulative effect on the TGF-beta-induced EMT with both doses. The oxidative stress levels were higher than the background in both epithelial and stromal cells post chronic irradiation (0.1 and 1 Gy); as for the BEAS-2B cell line, the increase was statistically significant. We suggest that the induction of EMT in bronchial epithelial cells by radiation requires more than single acute exposure and the presence of stromal component might enhance the effect through free radical production and accumulation.Peer reviewe

The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency

<p>Abstract</p> <p>Background</p> <p>Fumarate hydratase (HGNC approved gene symbol – <it>FH</it>), also known as fumarase, is an enzyme of the tricarboxylic acid (TCA) cycle, involved in fundamental cellular energy production. First described by Zinn <it>et al </it>in 1986, deficiency of FH results in early onset, severe encephalopathy. In 2002, the Multiple Leiomyoma Consortium identified heterozygous germline mutations of <it>FH </it>in patients with multiple cutaneous and uterine leiomyomas, (MCUL: OMIM 150800). In some families renal cell cancer also forms a component of the complex and as such has been described as hereditary leiomyomatosis and renal cell cancer (HLRCC: OMIM 605839). The identification of FH as a tumor suppressor was an unexpected finding and following the identification of subunits of succinate dehydrogenase in 2000 and 2001, was only the second description of the involvement of an enzyme of intermediary metabolism in tumorigenesis.</p> <p>Description</p> <p>The <it>FH </it>mutation database is a part of the TCA cycle gene mutation database (formerly the succinate dehydrogenase gene mutation database) and is based on the Leiden Open (source) Variation Database (LOVD) system. The variants included in the database were derived from the published literature and annotated to conform to current mutation nomenclature. The <it>FH </it>database applies HGVS nomenclature guidelines, and will assist researchers in applying these guidelines when directly submitting new sequence variants online. Since the first molecular characterization of an <it>FH </it>mutation by Bourgeron <it>et al </it>in 1994, a series of reports of both FH deficiency patients and patients with MCUL/HLRRC have described 107 variants, of which 93 are thought to be pathogenic. The most common type of mutation is missense (57%), followed by frameshifts & nonsense (27%), and diverse deletions, insertions and duplications. Here we introduce an online database detailing all reported <it>FH </it>sequence variants.</p> <p>Conclusion</p> <p>The <it>FH </it>mutation database strives to systematically unify all current genetic knowledge of <it>FH </it>variants. We believe that this knowledge will assist clinical geneticists and treating physicians when advising patients and their families, will provide a rapid and convenient resource for research scientists, and may eventually assist in gaining novel insights into FH and its related clinical syndromes.</p

Valtionavustuslain muutosten vaikutukset avustusprosessiin: case aluehallintovirastojen kirjasto-, liikunta- ja nuorisotoimet

Tämän opinnäytetyön tavoitteena on selvittää, millaisia vaikutuksia vuoden 2023 alussa voimaan tulleilla valtionavustuslain muutoksilla on aluehallintovirastojen kirjasto-, liikunta- ja nuorisotoimien valtionavustusprosessiin ja millaisia toimenpiteitä aluehallintovirastoilta edellytetään lakimuutosten vuoksi. Lainsäädännön näkökulmasta muutokset keskittyvät valtionavustustoiminnan tietovarannon käyttöönottoon, mihin kytkeytyy kysymyksiä tietosuojasta, rekisteröidyn oikeuksien toteutumisesta sekä hyvästä hallinnosta. Toimeksiantajana opinnäytetyössä on Itä-Suomen aluehallintovirasto. Opinnäytetyössä pyritään tekemään näkyväksi aluehallintovirastojen kirjasto-, liikunta- ja nuorisotoimien nykyiset valtionavustusprosessit ja kiinnittämään huomiota prosessinvaiheisiin, joita tulee muuttaa lainsäädännön uudistumisen myötä sekä niihin vaiheisiin, joissa käytäntö on ristiriitainen suhteessa lainsäädäntöön. Opinnäytetyön teoreettinen viitekehys rakentuu valtionavustuslain, siihen liittyvien asetusten ja substanssilakien sekä hallintolain ympärille. Lisäksi keskeistä on tietosuojaan liittyvä sääntely. Työ rakentuu aluehallintovirastoja ohjaavien lakien tulkinnan kautta valtionavustustoimintaa säätelevän lainsäädännön tulkitsemiseen. Erityistä huomiota kiinnitetään tietosuojan ja hyvän hallinnon periaatteiden kytkemiseen valtionapuviranomaisen toimintaan. Tutkimusmenetelmänä tässä opinnäytetyössä käytetään lainoppia eli oikeusdogmatiikkaa, jolla pyritään selvittämään, mikä on voimassa olevan oikeuden sisältö käsiteltävässä oikeusongelmassa tulkitsemisen kautta. Lisäksi opinnäytetyössä selvitettiin teemahaastatteluja hyödyntämällä valtionavustusprosessien nykytilaa. Lainsäädännöllisesti uudistuksessa keskeistä on valtionavustustietovarannon käyttöönottaminen, johon kytkeytyy kysymyksiä tietosuojasta ja yhteisrekisterinpitäjän tehtävistä suhteessa asiakkaisiin. Opinnäytetyössä annetaan kehittämis- ja toimenpide-ehdotuksia aluehallintovirastoille valtionavustusprosessin kehittämiseen. Tällaisia ovat esimerkki ehdotukset asiakkaille suunnatun viestinnän kehittämiseen sekä sisäisen yhteistyön kehittämiseen

Genetic aberrations and their clinical significance in breast and ovarian cancer

Abstract In tumourigenesis, genetic alterations accumulate in the genes responsible for cell growth, proliferation and DNA repair: proto-oncogenes, tumour suppressor and DNA repair genes. Inactivation of tumour suppressor gene function is commonly recognised as a deletion of one of the two alleles; LOH, loss of heterozygosity. In the present study, LOH of several chromosomal regions was studied in both breast and ovarian cancer. LOH for chromosome region 11q was examined in a large breast cancer consortium cohort (N = 988) and in a Finnish ovarian cancer cohort (N = 78), and the clinical significance of these alterations was evaluated. In breast cancer, LOH of the studied markers at 11q23.1, harbouring approximately 2 Mb of DNA, was seen to be associated with shortened cancer-specific survival. Two candidate genes, ATM (the ataxia telangiectasia disorder gene) and DDX10 (a putative RNA helicase gene) map to this chromosomal region. In ovarian cancer, LOH at 11q23.1–q24 was assigned mainly to two chromosomal regions, A and B, which are proximal and distal to 11q23.2–q23.3, respectively. Only the distal B region was seen to be associated with an aggressive disease course. Therefore, it appears that inactivation of the ATM or DDX10 genes is not crucial for determining the outcome of ovarian cancer. The CHK1 gene at 11q24, encoding a protein kinase required for DNA damage checkpoint function, is a putative target gene at the B region. On the basis of the present results, the main TSG in the studied region involved in the progression of breast cancer maps to 11q23.1 and the corresponding gene for ovarian cancer more distally to 11q23.3-q24. In addition, LOH at 3p, 6q, 8p, 11p, 16q and 17p was examined and their role in the genetic evolution of ovarian cancer was evaluated. Of the studied chromosomal regions, LOH at 17p appeared to be an early event and LOH at 16q24.3, 11q23.3/q24 and 11p appear to occur later in the progression of ovarian cancer