Pirfenidone decreases mesothelioma cell proliferation and migration via inhibition of ERK and AKT and regulates mesothelioma tumor microenvironment in vivo

Malignant mesothelioma is an aggressive cancer with poor prognosis. It is characterized by prominent extracellular matrix, mesenchymal tumor cell phenotypes and chemoresistance. In this study, the ability of pirfenidone to alter mesothelioma cell proliferation and migration as well as mesothelioma tumor microenvironment was evaluated. Pirfenidone is an anti-fibrotic drug used in the treatment of idiopathic pulmonary fibrosis and has also anti-proliferative activities. Mesothelioma cell proliferation was decreased by pirfenidone alone or in combination with cisplatin. Pirfenidone also decreased significantly Transwell migration/ invasion and 3D collagen invasion. This was associated with increased BMP pathway activity, decreased GREM1 expression and downregulation of MAPK/ERK and AKT/mTOR signaling. The canonical Smad-mediated TGF-beta signaling was not affected by pirfenidone. However, pirfenidone blocked TGF-beta induced upregulation of ERK and AKT pathways. Treatment of mice harboring mesothelioma xenografts with pirfenidone alone did not reduce tumor proliferation in vivo. However, pirfenidone modified the tumor microenvironment by reducing the expression of extracellular matrix associated genes. In addition, GREM1 expression was downregulated by pirfenidone in vivo. By reducing two major upregulated pathways in mesothelioma and by targeting tumor cells and the microenvironment pirfenidone may present a novel anti-fibrotic and anti-cancer adjuvant therapy for mesothelioma.Peer reviewe

Low vs. high radioiodine activity to ablate the thyroid after thyroidectomy for cancer : a randomized study

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Vesienhoidon vuorovaikutteinen ja kokonaisvaltainen suunnittelu. Yhteenveto Karvianjoen tulevaisuustarkastelut -hankkeen tuloksista

Tässä julkaisussa esitetään vuosina 2008–2012 toteutetun Karvianjoen tulevaisuustarkastelut (KarTuTa) -hankkeen tärkeimmät tulokset ja johtopäätökset. Hankkeen keskeisenä tavoitteena on ollut laajentaa, syventää ja tarkentaa. Karvianjoen vesistöalueelle laaditun vesiensuojelun toimenpideohjelman tarkasteluja. Hankkeessa on esitelty ja kehitetty menetelmiä vesienhoidon suunnitteluun ja sovellettu niitä Karvianjoen vesistössä. Tarkoituksena on ollut tuottaa sellaista tietoa vesienhoitoa varten, joka auttaa määrittämään uskottavia tavoitteita ja toimenpiteitä. Työssä on poikkeuksellisen monipuolisesti ja kattavasti arvioitu vesistön tilaa, siihen vaikuttavia tekijöitä sekä toimenpiteiden kustannuksia ja hyötyjä. Hankkeessa sovellettiin liki kahtakymmentä erilaista menetelmää tai vuorovaikutteiseen suunnittelun tukena käytettävää tekniikkaa. Hankkeen tarkastelut painottuivat Karvianjärvelle, Karhijärvelle ja Isojärvelle. Järvikohtaisesti on arvioitu ulkoisen ja sisäisen fosforikuormituksen alentamistarvetta, tunnistettu kustannustehokkaimpia vesiensuojelu-toimenpiteitä sekä esitetty toimenpidesuosituksia hyvän ekologisen tilan saavuttamiseksi. Lisäksi on arvioitu vedenlaadun paranemisesta virkistyskäytölle syntyviä hyötyjä sekä vertailtu toimenpiteiden kustannuksia ja hyötyjä. Vesistöalueelle laadittujen tulevaisuuskuvien avulla on selvitetty, kuinka maankäytön ja ihmistoiminnan muutokset vaikuttavat vesien tilalle asetettujen tavoitteiden saavuttamiseen. Lisäksi on mallinnettu ilmastonmuutoksen vaikutusta fosforikuormitukseen ja järvien veden fosforipitoisuuksiin. Julkaisu jakaantuu neljään osaan. Osassa I kuvataan hanke ja sen toteutus, osassa II hankkeessa sovelletut menetelmät,osassa III tarkastelujen tulokset ja järvikohtaiset toimenpidesuositukset sekä osassa IV johtopäätökset menetelmien soveltuvuudesta vesienhoitoon

Concordance and discordance in how patients and therapists experience the psychotherapy process in the treatment of depression

Despite the extensive literature on the outcome and process of psychotherapy in the treatment of depression, little is known about how the underlying factors of depression and the therapy process are experienced by the patients and therapists. In particular, the recognition of themes that are discordantly experienced by patients and therapists may have practical significance for how the therapy process should be conducted. We have previously developed a process description questionnaire to explore the views of patients with major depression and their therapists during the psychodynamic therapy process. In this study, we used factor analysis on the data collected with the process description questionnaire to explore the perceptions of the patients and therapists at different stages of the therapy process. We derived 15 clusters of variables from the questionnaire, on which we conducted primary and secondary factor analysis. The formation of the factors was found to be largely consistent between the patients and therapists regarding the alliance and affectively neutral aspects of the treatment process, whereas the variables of the patients vs. therapists concerning symptoms of depression and their underlying factors dispersed to a greater extent into separate factors. Dispersion was found especially in the experience of processing affectively laden themes and the developmental background factors underlying depression. Our findings refer to a defective insight of the patients into the developmental, interactional and affective factors underlying their symptoms. These factors should be especially targeted in psychotherapy of depression

A distinctive DNA methylation pattern in insufficient sleep

Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia. We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 +/- 7.3), and in relation to shift work disorder in an occupational cohort (26 men, aged 44.9 +/- 9.0). The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: "Nervous System Development" (FDR P value <0.05). We found that 78% of the DMPs were hypomethylated in cases in both cohorts, suggesting that insufficient sleep may be associated with loss of DNA methylation. A karyoplot revealed clusters of DMPs at various chromosomal regions, including 12 DMPs on chromosome 17, previously associated with Smith-Magenis syndrome, a rare condition comprising disturbed sleep and inverse circadian rhythm. Our findings give novel insights into the DNA methylation patterns associated with sleep loss, possibly modifying processes related to neuroplasticity and neurodegeneration. Future prospective studies are needed to confirm the observed associations.Peer reviewe

Estimation of the Timber Quality of Scots Pine with Terrestrial Laser Scanning

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Biomassa-atlas. Biomassojen kestävän käytön työväline. Esiselvityksen loppuraportti.

Esiselvityshankkeen tavoitteena oli selvittää tarve ja sisällöt valtakunnalliselle paikkatietokannalle, joka kokoaisi yhteen keskeiset biomassatietovarannot. Jo lähtöajatuksena oli, että tietokantoihin tulisi päästä käsiksi kartta- ja selainpohjaisen käyttöliittymän kautta. Tavoiteltu työkalu nimettiin Biomassa-atlakseksi. Tämän raportin päätulos on suunnitelma siitä, millaisena ja miten biomassatiedot kokoava karttakäyttöliittymä eli Biomassa-atlas tulisi toteuttaa. Hankkeen aikana toteutettiin internetissä laaja käyttäjäkysely ja lisäksi haastateltiin biomassatiedon käyttäjiä hallinnosta toiminnan tasolle. Biomassatiedolle on selvä tarve, sillä kaikille biomassatiedoille olisi hyödyntäjiä, ja tiedonhankinta koetaan nykyisin vaativaksi. Kaksi kolmannesta vastaajista piti Biomassaatlaksen kaltaista sovellusta tärkeänä ja lähes kaikki vähintäänkin hyödyllisenä. Tärkeimpiä tiedolle esitettyjä vaatimuksia ovat tiedon ajantasaisuus ja luotettavuus. Maatalouden, metsätalouden ja vesistöjen biomassoja sekä turvetta koskevat merkittävimmät tietokannat ja tietoja keräävät sekä paikkatiedon jakelua kehittävät hankkeet kartoitettiin. Valtakunnallisia biomassatietokantoja on valmiina metsäbiomassoista, jätteistä ja lannasta. Soiden turvevarantoja on kartoitettu laajasti Etelä-Suomessa. Pellot ja viljelykasvit rekisteröidään vuosittain, ja niistä on mahdollista laskea vuosittaiset biomassatiedot. Vesistöbiomassoja kuten järviruokoa ja kaloja koskeva tiedonkeruu on kehittymässä ja niitä koskevia biomassapaikkatietoja voidaan odottaa saatavaksi lähivuosina. Useimmat tiedot biomassoista on mahdollista esittää avoimesti. Tarkkojen sijaintitietojen avoimuutta rajoittaa lähinnä henkilötietolaki. Biomassa-aineistojen lisäksi hankkeessa kartoitettiin aineistoja ja työkaluja, jotka auttavat arvioimaan biomassojen korjuun ja käytön vaikutuksia. Hankkeessa tehtiin suunnitelma tietokannan ja käyttöliittymän toteuttamiseksi. Suunnitelma sisältää tekniset määrittelyt ja ehdotuksia yhteistyömallista, jonka puitteissa järjestelmää voidaan kehittää. Järjestelmä on mahdollista toteuttaa avoimella tai kaupallisella lähdekoodilla. Tekniikan valintaa voidaan tarkentaa hankintaneuvotteluissa ohjelmistotoimittajien kanssa. Biomassa-atlas-tietojärjestelmän ylläpito edellyttää aineistojen säännöllistä päivittämistä ja järjestelmän versiopäivityksistä ja tietoturvasta huolehtimista. Ylläpitoon tulee varata jatkuva ulkopuolinen rahoitus ja riittävä osaaminen. Biomassa-atlaksesta on mahdollista tulla biotalousstrategian toteuttamisen merkittävin yksittäinen työkalu. Jotta strategiaa voitaisiin edistää parhaalla mahdollisella tavalla, tulisi Biomassa-atlaksen huomioida myös eri biomassojen hyödyntämisen vaikutukset ympäristöön, talouteen ja sosiaaliseen kestävyyteen.The main objective of the project was to study the need and content for a GIS-database and application which would assemble essential national databases of biomass. From the very beginning, it was recognized that databases should be accessible via the Internet and by map-based user interface. The tool was named Biomass Atlas. The main result of this report is the plan to realize Biomass Atlas: how the web-based user interface utilizing refined biomass data should be put into practice. Users of biomass data were interviewed in personal meetings as well as via an Internet survey during the project. Users were recognized widely from the administrative to the operational level. There is an explicit need for biomass data of every biomass type. The acquisition of data is considered to be demanding. Two-thirds of respondents viewed the Biomass Atlas-like application as important, and almost all viewed it as at least useful. The most important demands for the data were reliability and up-to-date status. The most important biomass databases or methods to develop them with regard to biomass from agriculture, forestry and watersheds as well as peat were examined, as well as other related projects enhancing GIS data distribution. There are nationwide databases ready for forest biomass, waste and manure. Peat from wetlands is mapped widely in Southern Finland. Fields and crops are registered annually, which makes it possible to count the yearly biomass data. Data acquisition of biomass from watersheds such as common reed and fish is going to proceed in the years to come, and we can therefore expect to obtain GIS data from them. It is possible to open most of the biomass data covered in this study. Pointing out precise location information in high resolution is restricted by the Finnish personal data act. In addition to biomass data, data and tools helping to evaluate impacts of biomass harvest and use were mapped within the project. The plan was made to develop the database and user interface. The plan consists of technical definitions and suggestions towards a cooperative model which can be used for system development. The system is possible to implement in either an open or closed manner, i.e. using a commercial source code. The choice of technology can be defined during the procurement-based negotiations with software companies. Maintenance of the Biomass Atlas system requires regular updates of the data and system versions and ensuring information security. Continuous external funding and sufficient know-how are needed to secure these requirements. It is possible that Biomass Atlas shall become the most significant single tool for implementing the Finnish bioeconomy strategy. In order to enhance the strategy in the best possible way, Biomass Atlas should also take into account impacts to the environment, economy and social sustainability caused by the utilization of various biomass type

Progressive Myoclonus Epilepsy Caused by a Homozygous Splicing Variant of SLC7A6OS

Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected individuals from both families shared a rare, homozygous c.191A > G variant affecting a splice site in SLC7A6OS. Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a similar to 0.85cM shared genomic region on chromosome 16q encompassing the c.191A > G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss-of-function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2020Peer reviewe

Compressive stress-mediated p38 activation required for ER alpha plus phenotype in breast cancer

Breast cancer is now globally the most frequent cancer and leading cause of women's death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ER alpha + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ER alpha-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ER alpha + breast cancer models. The ER alpha + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ER alpha is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ER alpha signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ER alpha phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK. Reliable luminal estrogen receptor (ER alpha+) breast cancer models are limited. Here, the authors use patient derived breast epithelial and breast cancer explant cultures grown in several extracellular matrix scaffolds and show that ER alpha expression is regulated by matrix stiffness via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation.Peer reviewe

Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes

Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.Peer reviewe