FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis

Cancer cells balance with the equilibrium of cell death and growth to expand and metastasize. The activity of mammalian sterile20-like kinases (MST1/2) has been linked to apoptosis and tumor suppression via YAP/Hippo pathway-independent and -dependent mechanisms. Using a kinase substrate screen, we identified here MST1 and MST2 among the top substrates for fibroblast growth factor receptor 4 (FGFR4). In COS-1 cells, MST1 was phosphorylated at Y433 residue in an FGFR4 kinase activity-dependent manner, as assessed by mass spectrometry. Blockade of this phosphorylation by Y433F mutation induced MST1 activation, as indicated by increased threonine phosphorylation of MST1/2, and the downstream substrate MOB1, in FGFR4-overexpressing T47D and MDA-MB-231 breast cancer cells. Importantly, the specific knockdown or short-term inhibition of FGFR4 in endogenous models of human HER2(+) breast cancer cells likewise led to increased MST1/2 activation, in conjunction with enhanced MST1 nuclear localization and generation of N-terminal cleaved and autophosphorylated MST1. Unexpectedly, MST2 was also essential for this MST1/N activation and coincident apoptosis induction, although these two kinases, as well as YAP, were differentially regulated in the breast cancer models analyzed. Moreover, pharmacological FGFR4 inhibition specifically sensitized the HER2(+) MDA-MB-453 breast cancer cells, not only to HER2/EGFR and AKT/mTOR inhibitors, but also to clinically relevant apoptosis modulators. In TCGA cohort, FGFR4 overexpression correlated with abysmal HER2(+) breast carcinoma patient outcome. Therefore, our results uncover a clinically relevant, targetable mechanism of FGFR4 oncogenic activity via suppression of the stress-associated MST1/2-induced apoptosis machinery in tumor cells with prominent HER/ERBB and FGFR4 signaling-driven proliferation.Peer reviewe

Joint effects of alcohol use, smoking and body mass index as an explanation for the alcohol harm paradox : causal mediation analysis of eight cohort studies

Background and aims Lower socio-economic status (SES) is associated with higher alcohol-related harm despite lower levels of alcohol use. Differential vulnerability due to joint effects of behavioural risk factors is one potential explanation for this 'alcohol harm paradox'. We analysed to what extent socio-economic inequalities in alcohol-mortality are mediated by alcohol, smoking and body mass index (BMI), and their joint effects with each other and with SES. DesignCohort study of eight health examination surveys (1978-2007) linked to mortality data. Setting Finland.ParticipantsA total of 53 632 Finnish residents aged 25+ years.MeasurementsThe primary outcome was alcohol-attributable mortality. We used income as an indicator of SES. We assessed the joint effects between income and mediators (alcohol use, smoking and BMI) and between the mediators, adjusting for socio-demographic indicators. We used causal mediation analysis to calculate the total, direct, indirect and mediated interactive effects using Aalen's additive hazards models. Findings During 1 085 839 person-years of follow-up, we identified 865 alcohol-attributable deaths. We found joint effects for income and alcohol use and income and smoking, resulting in 46.8 and 11.4 extra deaths due to the interaction per 10 000 person-years. No interactions were observed for income and BMI or between alcohol and other mediators. The lowest compared with the highest income quintile was associated with 5.5 additional alcohol deaths per 10 000 person-years (95% confidence interval = 3.7, 7.3) after adjusting for confounders. The proportion mediated by alcohol use was negative (-69.3%), consistent with the alcohol harm paradox. The proportion mediated by smoking and BMI and their additive interactions with income explained 18.1% of the total effect of income on alcohol-attributable mortality. Conclusions People of lower socio-economic status appear to be more vulnerable to the effects of alcohol use and smoking on alcohol-attributable mortality. Behavioural risk factors and their joint effects with income may explain part of the alcohol harm paradox.Peer reviewe

Nuoret seksuaalirikoksen kokijana : Alle 20-vuotiaiden seksuaaliväkivaltaa kokeneiden nuorten psykososiaalinen tuki ja sen kehittäminen

Nuoren riski altistua seksuaaliväkivallalle on muita ikäkausia suurempi, sillä suurin osa lapsiin kohdistuvasta seksuaaliväkivallasta kohdistuu yli 13-vuotiaisiin. Nuoruusikäisten huomioiminen seksuaalirikoksen uhreille tarkoitetuissa palveluissa on tähän saakka ollut pirstaleista ja puutteellista. Nuorisosensitiivistä työtä on kehitetty Barnahus-hankkeessa vuodesta 2019 lähtien yhteistyössä yliopistosairaaloiden ja pääasiassa Seri-tukikeskusten kanssa. Nuorisosensitiiviset työntekijät, psykososiaalisen tuen koordinaattorit, ovat antaneet nuorille akuuttitukea seksuaaliväkivallan aiheuttamasta traumaattisesta kriisistä toipumiseen ja pyrkineet varmistamaan tarpeiden mukaiselle palvelupolulle. Kehittämistyön aikana on parannettu myös nuorten seksuaaliväkivallan uhrien hoidon saatavuutta ja hoitopolkuja sekä palveluita. Lisäksi on koulutettu nuorten kanssa työskenteleviä ammattilaisia. Työmuoto on osoittautunut tarpeelliseksi. Sitä ei kuitenkaan voida jättää pelkästään hanketyön varaan. Työn juurruttamista ja kansallista yhtenäisyyttä tulee vahvistaa. Barnahus-hankkeen osalta työn tukeminen jatkuu osin vuoteen 2025 saakka

First Search for Exclusive Diphoton Production at High Mass with Tagged Protons in Proton-Proton Collisions at root s=13 TeV

A search for exclusive two-photon production via photon exchange in proton-proton collisions, pp -> p gamma gamma p with intact protons, is presented. The data correspond to an integrated luminosity of 9.4 fb(-1) collected in 2016 using the CMS and TOTEM detectors at a center-of-mass energy of 13 TeVat the LHC. Events are selected with a diphoton invariant mass above 350 GeVand with both protons intact in the final state, to reduce backgrounds from strong interactions. The events of interest are those where the invariant mass and rapidity calculated from the momentum losses of the forward-moving protons match the mass and rapidity of the central, two-photon system. No events are found that satisfy this condition. Interpreting this result in an effective dimension-8 extension of the standard model, the first limits are set on the two anomalous four-photon coupling parameters. If the other parameter is constrained to its standard model value, the limits at 95% confidence level are vertical bar zeta(1)vertical bar < 2.9 x 10(-1)3 GeV-4 and vertical bar zeta(2)vertical bar < 6.0 x 10(-13) GeV-4.Peer reviewe

Vastuujaon hajauttaminen HR-prosesseissa linjajohtajien ja HR-osaston välillä

Tämä tutkielma on tutkimusmatka erittäin mielenkiintoisella alalla toimivan yrityksen hr-prosessien kehittämiseksi. Tutkimusongelmana on selvittää, miten henkilöstöosasto eli HR-osasto (Human Resource) sekä linjajohtajat käsittävät oman vastuunsa rekrytointi-, perehdyttämis-, palkka-, ja kehityskeskusteluprosessien eri vaiheissa. Tutkimustuloksissa käsitellään monipuolisesti erilaisia linjajohtajien ja henkilöstöammattilaisten näkökulmia, jotka ovat sekä yhteneviä että myös osittain eriäviä suhteessa aiempaan tutkimustietoon. Tutkimus koettiin toimeksiantoyrityksessä erittäin hyödylliseksi ja kattavaksi kartoitukseksi yrityksen nykytilanteesta. Tutkielman teoreettisena viitekehyksenä toimivat useiden eri tutkijoiden määritelmät tutkittavien prosessien vaiheista sekä erittäin paljon viime aikoina tutkittu vastuun hajauttaminen. Empiriaosuus toteutettiin teemahaastatteluna, koska tällä tavoin saatiin kerättyä laajasti tietoa siitä, miten haastateltavat kokivat vastuujaon olevan. Haastateltavia on yhteensä 14, joista kymmenen ovat linjajohtajia ja neljä henkilöstöammattilaisia. Tutkielman tärkeimpiä keskeisiä käsitteitä ovat HR-prosessit, hajauttaminen, keskittäminen, linjajohtaja sekä HR-osasto. Tutkimustulokset on salattu.fi=Opinnäytetyö kokotekstinä PDF-muodossa.|en=Thesis fulltext in PDF format.|sv=Lärdomsprov tillgängligt som fulltext i PDF-format

Hyvinvointi o sellast normaalii elämist : miten lastensuojelulaitoksessa asuvat nuoret kokevat oman hyvinvointinsa

Opinnäytetyöni aiheena on lastensuojelulaitoksessa asuvien nuoren hyvinvointi heidän itsensä kokemana, sekä se miten aikuiset voivat heidän hyvinvointiaan enemmän tukea. Tutkimukseni pohjana olen käyttänyt tietoa nuorten hyvinvoinnista, lastensuojelulaista sekä lastensuojelulaitoksesta asuinpaikkana. Myös syyt jotka johtavat lapsen sijoitukseen kodin ulkopuolelle ovat tutkimuksen perustana. Opinnäytetyöni on laadullinen tutkimus. Aineiston tutkimukseeni sain haastattelemalla neljää lastensuojelulaitoksessa asuvaa nuorta. Haastattelut toteutin teemahaastatteluina. Analyysimenetelmänä työssäni käytin teemoittelua. Tutkimuksen tuloksista voi todeta, että lastensuojelun piirissä olevat nuoret kokevat tärkeäksi tulla kuulluksi ja nähdyksi itsenään, yksilöinä. Nuoret haluavat myös mahdollisuuden vaikuttaa omiin asioihinsa. Lisäksi he pitivät tärkeänä aikuisten kunnioittavaa ja luottamuksellista suhtautumista heihin. Myös rajojen tuoman turvallisuuden merkitys korostuu tutkimuksessa. Lastenkodissa asuvan nuoren hyvinvointiin vaikuttavat monet asiat, muun muassa heidän rikkonainen lapsuutensa. Kehittämisajatuksia nousi esiin motivointiin ja yhteisöllisyyteen liittyvissä asioissa.The grounds for my thesis are the welfare of young people living at the children´s home experienced by themselves and how the adults could more be able to support their welfare. I have based my thesis on the information about the welfare of young people, law of childcare and children´s home as a place of residence, but also on the reasons bringing about the placement of a child outside of the home. The thesis of my studies is a qualitative one. The substance of the thesis I received by interviewing four young people living at the children´s home. The interviews were carried out by thematic method. For the analysis thematic method was as well exploited. About the results of the thesis I may summarize that young people living at the childrens home feel crucial to be heard and seen as individuals. The young people also want a possibility to contribute to the concerns of their own. Additionally they consider important the respectful and confidential attitude of the adults towards them. Also the safety created by limitations is emphasized in the study. The welfare of young people living at the children´s home is influenced by many matters among them their chattered childhood. Ideas of improvement woke up concerning matters related to motivation and individuality

PTPRA Phosphatase Regulates GDNF-Dependent RET Signaling and Inhibits the RET Mutant MEN2A Oncogenic Potential

The RET proto-oncogene encodes receptor tyrosine kinase, expressed primarily in tissues of neural crest origin. De-regulation of RET signaling is implicated in several human cancers. Recent phosphatome interactome analysis identified PTPRA interacting with the neurotrophic factor (GDNF)-dependent RET-Ras-MAPK signaling-axis. Here, by identifying comprehensive interactomes of PTPRA and RET, we reveal their close physical and functional association. The PTPRA directly interacts with RET, and using the phosphoproteomic approach, we identify RET as a direct dephosphorylation substrate of PTPRA both in vivo and in vitro. The protein phosphatase domain-1 is indispensable for the PTPRA inhibitory role on RET activity and downstream Ras-MAPK signaling, whereas domain-2 has only minor effect. Furthermore, PTPRA also regulates the RET oncogenic mutant variant MEN2A activity and invasion capacity, whereas the MEN2B is insensitive to PTPRA. In sum, we discern PTPRA as a novel regulator of RET signaling in both health and cancer.Peer reviewe

Adipocytes as a Link Between Gut Microbiota-Derived Flagellin and Hepatocyte Fat Accumulation

While the role of both elevated levels of circulating bacterial cell wall components and adipose tissue in hepatic fat accumulation has been recognized, it has not been considered that the bacterial components-recognizing adipose tissue receptors contribute to the hepatic fat content. In this study we found that the expression of adipose tissue bacterial flagellin (FLG)-recognizing Toll-like receptor (TLR) 5 associated with liver fat content (r = 0.699, p = 0.003) and insulin sensitivity (r = -0.529, p = 0.016) in humans (n = 23). No such associations were found for lipopolysaccharides (LPS)-recognizing TLR4. To study the underlying molecular mechanisms of these associations, human HepG2 hepatoma cells were exposed in vitro to the conditioned culture media derived from FLG or LPS-challenged human adipocytes. The adipocyte-mediated effects were also compared to the effects of direct HepG2 exposure to FLG and LPS. We found that the media derived from FLG-treated adipocytes stimulated fat accumulation in HepG2 cells, whereas either media derived from LPS-treated adipocytes or direct FLG or LPS exposure did not. This is likely due to that FLG-treatment of adipocytes increased lipolysis and secretion of glycerol, which is known to serve a substrate for triglyceride synthesis in hepatocytes. Similarly, only FLG-media significantly decreased insulin signaling-related Akt phosphorylation, IRS1 expression and mitochondrial respiratory chain ATP5A. In conclusion, our results suggest that the FLG-induced TLR5 activation in adipocytes increases glycerol secretion from adipocytes and decreases insulin signaling and mitochondrial functions, and increases fat accumulation in hepatocytes. These mechanisms could, at least partly, explain the adipose tissue TLR5 expression associated with liver fat content in humans.peerReviewe