Spekulatiivinen fiktio nyrjäyttää ihmiskeskeisen ajattelun rutiinit

Non peer reviewe

Cytosolic SH3-interactions of ADAM12-disintegrin-metalloprotease

Background: ADAM proteins (a disintegrin and metalloprotease) are membrane proteins that consist of several functional domains. ADAM proteins are able to mediate cell adhesion through their disintegrin domain and selective protein cleavage (e.g. ectodomain shedding) carried out by the metalloprotease domain. ADAM12 is an important sheddase, expressed widely in different tissues. ADAM12 has been associated with e.g. regulation of muscle and adipose tissue differentiation, cell fusion, cell adhesion, and EGFR-ligand activation. ADAM12 cytosolic tail contains several recognition motifs for adaptor and signaling proteins and interactions with such proteins are thought to regulate the function of ADAM12. In this study the focus was on ADAM12-SH3 interactions and the main objective was to identify the SH3 proteins that bind to human ADAM12 cytosolic tails and to further characterize these binding interactions. Methods: Human ADAM12 cytosolic tail was expressed as recombinant GST-fusion protein. The SH3 domains that can bind to ADAM12 cytosolic tail were identified using phage display method and selected individual ADAM12-SH3 interactions as well as the SH3-binding motifs of the ADAM12 cytosolic tail were further characterized in peptide array. Results: The screening of SH3-phage display library revealed altogether 50 SH3 proteins that bound to human ADAM12 cytosolic tail. The phage display and peptide array screens showed that ADAM12 cytosolic tail motifs differed in their SH3-binding specificity. The peptide screen results indicate that the proline cluster P3 mediated more SH3-interactions than other proline clusters in the ADAM12 cytosolic tail. Conclusions: The proline-rich regions of ADAM12 cytosolic tail clearly mediate SH3-interactions. The large number of identified interacting SH3 proteins can be seen as an indicator of potential importance of ADAM12 in different physiological processes such as signaling pathways as an active mediator or in a more structural role. Altogether, identification of candidate regulatory interactions provides important clues for future studies addressing the functional regulation of ADAM12. Asiasanat: ADAM12-disintegrin-metalloprotease, SH3 domain interaction, phage display, peptide arra

Cytosolic SH3-interactions of ADAM12-disintegrin-metalloprotease

Background: ADAM proteins (a disintegrin and metalloprotease) are membrane proteins that consist of several functional domains. ADAM proteins are able to mediate cell adhesion through their disintegrin domain and selective protein cleavage (e.g. ectodomain shedding) carried out by the metalloprotease domain. ADAM12 is an important sheddase, expressed widely in different tissues. ADAM12 has been associated with e.g. regulation of muscle and adipose tissue differentiation, cell fusion, cell adhesion, and EGFR-ligand activation. ADAM12 cytosolic tail contains several recognition motifs for adaptor and signaling proteins and interactions with such proteins are thought to regulate the function of ADAM12. In this study the focus was on ADAM12-SH3 interactions and the main objective was to identify the SH3 proteins that bind to human ADAM12 cytosolic tails and to further characterize these binding interactions. Methods: Human ADAM12 cytosolic tail was expressed as recombinant GST-fusion protein. The SH3 domains that can bind to ADAM12 cytosolic tail were identified using phage display method and selected individual ADAM12-SH3 interactions as well as the SH3-binding motifs of the ADAM12 cytosolic tail were further characterized in peptide array. Results: The screening of SH3-phage display library revealed altogether 50 SH3 proteins that bound to human ADAM12 cytosolic tail. The phage display and peptide array screens showed that ADAM12 cytosolic tail motifs differed in their SH3-binding specificity. The peptide screen results indicate that the proline cluster P3 mediated more SH3-interactions than other proline clusters in the ADAM12 cytosolic tail. Conclusions: The proline-rich regions of ADAM12 cytosolic tail clearly mediate SH3-interactions. The large number of identified interacting SH3 proteins can be seen as an indicator of potential importance of ADAM12 in different physiological processes such as signaling pathways as an active mediator or in a more structural role. Altogether, identification of candidate regulatory interactions provides important clues for future studies addressing the functional regulation of ADAM12. Asiasanat: ADAM12-disintegrin-metalloprotease, SH3 domain interaction, phage display, peptide arra

Mielenterveyskuntoutujan ohjaus opas: Myllypuron tukiasunnoille

TIIVISTELMÄ Kaisa Keinänen & Katja Teittinen Asumisen ohjauspaketti-Myllypuron tukiasunnoille 24 sivua ja 1 liite. Kevät 2022 Diakonia-ammattikorkeakoulu Hoitotyönkoulutusohjelma Sairaanhoitaja (AMK) Opinnäytetyö on kehittämispainotteinen ja tuloksena syntyi Jst-Solumin mielenterveyskuntoutujille asumisen opas. Oppaan tarkoituksena on tukea mielenterveyskuntoutujan itseohjautuvuutta asumisessa ja toimia työntekijöille ohjauksen tukivälineenä. Opinnäytetyössä on avattu mielenterveyskuntoutuksen keskeisiä käsitteitä. Käsitteet tuovat esille mielenterveyskuntoutujan toiminnanohjauksen- ja kognitiivistentaitojen haasteita. Jst-Solumin esimiehen ja vastuuohjaajan kanssa neuvoteltiin sisällöstä. Mielenterveyskuntoutujat ovat mielipiteensä antaneet oppaan sisältöön, jotta oppaan sisältö kohdistuu tarpeeseen. Oppaan wc:n siivousohjetta on testattu käytännössä mielenterveyskuntoutujalla. Asumisen oppaassa on selkeä kirjoitusasu, visuaaliset kuvat. Opas on tarkoituksella pidetty lyhyenä, käyttäjäkuntaa huomioiden. Asiasanat: asumisen taidot, kognitiiviset taidot, mielenterveyskuntoutuja, ohjaus, tehostettu tukiasuminen, toiminnanohjaus, toimintakyky

Observational study on the evolution of systemic treatments for advanced renal cell carcinoma in Southwest Finland between 2010 and 2021

Background: Novel receptor tyrosine kinase inhibitors and immune checkpoint inhibitors have been introduced to the treatment of advanced renal cell carcinoma (aRCC) during the past decade. However, the adoption of novel treatments into clinical practice has been unknown in Finland. Objectives: Our aim was to evaluate the use of systemic treatments and treatment outcomes of aRCC patients in Southwest Finland during 2010–2021. Design and Methods: Clinical characteristics, treatments for aRCC, healthcare resource utilization, and overall survival (OS) were retrospectively obtained from electronic medical records. Patients were stratified using the International Metastatic RCC Database Consortium (IMDC) risk classification. Results: In total, 1112 RCC patients were identified, 336 (30%) patients presented with aRCC, and 57% of them ( n  = 191) had received systemic treatment. Pre-2018, sunitinib (79%) was the most common first-line treatment, and pazopanib (17%), axitinib (17%), and cabozantinib (5%) were frequently used in the second-line. Post-2018, sunitinib (52%), cabozantinib (31%), and the combination of ipilimumab and nivolumab (10%) were most commonly used in the first-line, and cabozantinib (23%) in the second-line. Median OS for patients with favorable, intermediate, and poor risk were 61.9, 28.6, and 8.1 months, respectively. A total of 73%, 74%, and 35% of the patients with favorable, intermediate, and poor risk had received second-line systemic treatment. In poor-risk patients, the number of hospital inpatient days was twofold higher compared to intermediate and fourfold higher compared to favorable-risk patients. Conclusion: New treatment options were readily adopted into routine clinical practice after becoming reimbursed in Finland. OS and the need for hospitalization depended significantly on the IMDC risk category. Upfront combination treatments are warranted for poor-risk patients as the proportion of patients receiving second-line treatment is low. Registration: Clinical trial identifier: ClinicalTrials.gov NCT05363072

Virtsarakkosyövän avohoito lisääntyi ja kustannusten kasvu tasoittui

Lähtökohdat :Tarkastelemme virtsarakkosyövän vuosittaisia diagnoosi- ja toimenpidemääriä sekä levinnyttä tautia sairastavien elossaoloa. Selvitämme myös potilaiden palvelunkäytön kustannuksia ja Kelan maksamia korvauksia. Menetelmät : Tämä retrospektiivinen tutkimus pohjautuu kansallisiin rekistereihin. Aineisto koostuu suomalaisista virtsarakkosyöpäpotilaista vuosilta 2011–2019. Heidät luokiteltiin kolmeen ryhmään: pinnallinen, paikallisesti edennyt ja levinnyt tauti. Tulokset : Avohoitokäyntien määrä erikoissairaanhoidossa lisääntyi. Palvelujen käytön kokonaiskustannukset vuonna 2019 olivat 17 % suuremmat kuin vuonna 2011. Hoidon kustannukset kasvoivat vuosina 2015–2018 vain 2 %, vaikka hoidossa olevien määrä kasvoi samaan aikaan noin 10 %. Keskimääräinen kustannus potilasta kohden pieneni pinnallista ja paikallisesti edennyttä syöpää sairastavilla potilailla, mutta kasvoi levinnyttä syöpää sairastavilla. Päätelmät : Rakkosyöpäpotilaiden hoito noudattaa yleistä suuntausta, eli avohoito on lisääntynyt merkittävästi. Resurssien käyttöä, kustannuksia ja hoidon vaikutuksia tulee seurata, jotta voidaan valita vaikuttava hoito.Peer reviewe

Transcription-coupled genetic instability marks acute lymphoblastic leukemia structural variation hotspots

Progression of malignancy to overt disease requires multiple genetic hits. Activation-induced deaminase (AID) can drive lymphomagenesis by generating off-target DNA breaks at loci that harbor highly active enhancers and display convergent transcription. The first active transcriptional profiles from acute lymphoblastic leukemia (ALL) patients acquired here reveal striking similarity at structural variation (SV) sites. Specific transcriptional features, namely convergent transcription and Pol2 stalling, were detected at breakpoints. The overlap was most prominent at SV with recognition motifs for the recombination activating genes (RAG). We present signal feature analysis to detect vulnerable regions and quantified from human cells how convergent transcription contributes to R-loop generation and RNA polymerase stalling. Wide stalling regions were characterized by high DNAse hypersensitivity and unusually broad H3K4me3 signal. Based on 1382 pre-B-ALL patients, the ETV6-RUNX1 fusion positive patients had over ten-fold elevation in RAG1 while high expression of AID marked pre-B-ALL lacking common cytogenetic changes

Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia

Approximately 20%-25% of childhood acute lymphoblastic leukemias carry the ETV6-RUNX1 (E/R) fusion gene, a fusion of two central hematopoietic transcription factors, ETV6 (TEL) and RUNX1 (AML1). Despite its prevalence, the exact genomic targets of E/R have remained elusive. We evaluated gene loci and enhancers targeted by E/R genome-wide in precursor B acute leukemia cells using global run-on sequencing (GRO-seq). We show that expression of the E/R fusion leads to widespread repression of RUNX1 motif-containing enhancers at its target gene loci. Moreover, multiple super-enhancers from the CD19(+)/CD20(+)-lineage were repressed, implicating a role in impediment of lineage commitment. In effect, the expression of several genes involved in B cell signaling and adhesion was down-regulated, and the repression depended on the wild-type DNA-binding Runt domain of RUNX1. We also identified a number of E/R-regulated annotated and de novo noncoding genes. The results provide a comprehensive genome-wide mapping between E/R-regulated key regulatory elements and genes in precursor B cell leukemia that disrupt normal B lymphopoiesis.De två sista författarna delar sistaförfattarskapet.</p