Extended Working Life Policies

Finland’s population is ageing due to declining fertility and increasing life expectancy rates. This creates pressure to maintain high employment rates. Lately, Finland has focused on extending working careers by raising statutory pension age and facilitating part-time employment for pensioners. Finland faces high unemployment rates, low re-employment among over 55-year olds and high gender inequality in pension levels. Gender and educational inequality in pensions reflect the employment gaps and sectoral segregation that have accumulated along lifecourses. Finland aims to extend working life by promoting wellbeing at work, increasing labour market flexibility and supporting workers’ competitiveness through various strategies. The latest reforms on unemployment activation and possible future reforms on the regional government, health and social services and basic income will likely affect pension intentions. To ensure equal levels of pensions, future reforms should focus on whole lifecourses and account for breaks in working life, such as parental leave and unemployment periods. </p

Transforming Growth Factor-β Induces Collagenase-3 Expression by Human Gingival Fibroblasts via p38 Mitogen-activated Protein Kinase

Human collagenase-3 (matrix metalloproteinase 13 (MMP-13)) is characterized by exceptionally wide substrate specificity and restricted tissue specific expression. Human skin fibroblasts in culture express MMP-13 only when they are in three-dimensional collagen (Ravanti, L., Heino, J., Lopez-Otin, C., and Kahari. V.-M. (1999) J. Biol. Chem. 274, 2446-2455). Here we show that MMP-13 is expressed by fibroblasts during normal human gingival wound repair. Expression of MMP-13 by human gingival fibroblasts cultured in monolayer or in collagen gel was induced by transforming growth factor-beta1 (TGF-beta1). Treatment of gingival fibroblasts with TGF-beta1 activated two distinct mitogen-activated protein kinases (MAPKs): extracellular signal-regulated kinase 1/2 (ERK1/2) in 15 min and p38 MAPK in 1 and 2 h. Induction of MMP-13 expression by TGF-beta1 was blocked by SB203580, a specific inhibitor of p38 MAPK, but not by PD98059, a selective inhibitor of ERK1/2 activation. Adenovirus-mediated expression of dominant negative p38alpha and c-Jun potently inhibited induction of MMP-13 expression in gingival fibroblasts by TGF-beta1. Infection of gingival fibroblasts with adenovirus for constitutively active MEK1 resulted in activation of ERK1/2 and JNK1 and up-regulation of collagenase-1 (MMP-1) and stromelysin-1 (MMP-3) production but did not induce MMP-13 expression. In addition, activation of p38 MAPK by constitutively active MKK6b or MKK3b was not sufficient to induce MMP-13 expression. These results show that TGF-beta-elicited induction of MMP-13 expression by gingival fibroblasts is dependent on the activity of p38 MAPK and the presence of functional AP-1 dimers. These observations demonstrate a fundamental difference in the regulation of collagenolytic capacity between gingival and dermal fibroblasts and suggest a role for MMP-13 in rapid turnover of collagenous matrix during repair of gingival wounds, which heal with minimal scarring

Robo4 contributes to the turnover of Peyer’s patch B cells

All leukocytes can get entrance into the draining lymph nodes via the afferent lymphatics but only lymphoid cells can leave the nodes. The molecular mechanisms behind this phenomenon have remained unknown. We employed genome wide microarray analyses of the subcapsular sinus and lymphatic sinus (LS) endothelial cells and found Robo4 to be selectively expressed on LS lymphatics. Further analyses showed high Robo4 expression in lymphatic vessels of Peyer’s patches, which only have efferent lymphatic vessels. In functional assays, Robo4-deficient animals showed accumulation of naïve  B cells (CD19+/CD62Lhi/CD44lo) in Peyer’s patches, whereas no difference was seen within other lymphocyte subtypes. Short-term lymphocyte homing via high endothelial venules to peripheral and mesenteric lymph nodes and Peyer’s patches was also slightly impaired in Robo4 knockout animals. These results show for the first time, selective expression of Robo4 in the efferent arm of the lymphatics and its role in controlling the turnover of a subset of B lymphocytes from Peyer’s patches.</p

Kapillaarivirtausmenetelmän optimointi hiiren endoteelisoluilla

Tämän opinnäytetyön tavoitteena oli tutkia leukosyyttien tarttumista hiiren endoteelisoluihin. Tarkoituksena oli löytää olosuhteet, joissa leukosyyttejä tarttuisi, pyörisi ja transmigroituisi endoteeliin in vitro –olosuhteissa. Opinnäytetyön toimeksiantajana oli leukosyyttien liikennettä tutkiva tutkimusryhmä Turun Yliopiston lääketieteellisessä tiedekunnassa. Menetelmää tullaan hyödyntämään myöhemmin käyttämällä poistogeenisiä hiirikantoja ja tutkimalla niistä eristettyjen endoteelisolujen kykyä sitoa valkosoluja. Työssä hyödynnettiin tutkimuslaboratorion henkilökunnan asiantuntemusta. Puolet opinnäytetyöstä koostui verisuonten endoteelisolujen eristyskeinon löytämisestä ja optimoinnista. Hiiren kudoksista eristettäviin soluihin käytettiin kahta magnetismia hyödyntävää eristysmenetelmää. Toinen puoli työstä oli löytää olosuhteet leukosyyttien tarttumiselle kapillaarivirtausmenetelmällä. Kapillaarivirtausmenetelmässä virtauskammioon istutettiin endoteelisoluja, joille aiheutettiin tulehdusreaktio stimuloimalla soluja kasvainkuoliotekijä-:lla. Kammion läpi laitettiin virtaamaan leukosyyttejä, joiden tarttumista endoteelinpintaan virtausolosuhteissa tutkittiin mikroskoopin avulla. Kokeissa käytettiin kahta kaupallista solulinjaa ja eristettyjä primaarisoluja. Opinnäytetyössä saatiin optimoitua olosuhteet, joilla endoteelisoluja onnistuttiin eristämään kapillaarivirtausmenetelmän tarkoituksiin. Solumäärät olivat kohtuullisen vähäiset, joten menetelmä ei ole vielä riittävän tehokas. Kapillaarivirtausmenetelmä saatiin kuitenkin toimimaan hiiren endoteelisoluilla ja leukosyyttejä saatiin tarttumaan endoteeliin. Tarttuneiden solujen määrä kasvoi kokeen alussa lisäämällä leukosyyttien määrää. Kasvainkuoliotekijä-:n stimulaatioajan kasvattaminen vaikutti tarttuneiden solujen määrään lisääntymiseen. Kapillaarivirtausmenetelmä saatiin pystytettyä hiiren endoteelisoluille käytettäväksi ja primaarisia endoteelisoluja saatiin eristettyä kapillaarivirtausmenetelmän kokeisiin.The objective of this Bachelor’s Thesis was to investigate leukocyte adhesion to mouse endothelial cells. The aim was to find conditions where leukocytes would adhere, roll and transmigrate onto, along and through the endothelium in in vitro conditions. The study was commissioned by a research group studying leukocyte trafficking at Turku University Faculty of Medicine. This protocol will later be utilized on specific knockout mice population endothelial cells to investigate their ability to adhere leukocytes. The expertise of the laboratory personnel was utilized during this Bachelor’s Thesis project. The first half of this project consisted of finding and optimizing an isolation method for vascular endothelial cells. Two magnetic isolation methods were used to isolate the cells from mouse tissue. The second half of this thesis was to find conditions where leukocytes would adhere using a flow assay research method. Endothelial cells were seeded into a flow chamber and induced with an inflammation-causing stimulant in the flow assay method. A cytokine, mouse tumor necrosis factor- was used as a stimulant. Leukocytes were subjected to flow through the chamber and their adhesion to the endothelium was observed with a microscope. Two commercial cell lines and isolated primary cells were used in these experiments. The conditions where endothelial cells were successfully isolated for the flow assay purpose were optimized in this project. However, the number of cells was relatively low, and thus, the protocol is not as efficient as it could be. A flow assay was successfully established for mouse endothelial cells and leukocyte adhesion to the endothelium was achieved. The number of adhered cells increased as the amount of leukocytes was increased in the flow chamber experiments. Also the stimulation time applied to the endothelium had a positive impact on the number of adhering cells

Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias

From Crossref journal articles via Jisc Publications RouterHistory: epub 2021-03-05, issued 2021-03-05, ppub 2021-05-15Publication status: PublishedFunder: Sigrid Juselius FoundationFunder: Turku Doctoral Program of Molecular MedicineFunder: Turku University Hospital ERVA; Grant(s): 13283, 13336Funder: Päivikki and Sakari Sohlbergin Foundation; FundRef: 10.13039/501100004212Funder: Cancer Foundation Väre; FundRef: 10.13039/100010128Funder: Finnish Cultural Foundation; FundRef: 10.13039/501100003125Abstract Purpose: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56α. However, CIP2A mRNA variants remain uncharacterized. Here, we report the discovery of a CIP2A splicing variant, novel CIP2A variant (NOCIVA). Experimental Design: Characterization of CIP2A variants was performed by both 3′ and 5′ rapid amplification of cDNA ends from cancer cells. The function of NOCIVA was assessed by structural and molecular biology approaches. Its clinical relevance was studied in an acute myeloid leukemia (AML) patient cohort and two independent chronic myeloid leukemia (CML) cohorts. Results: NOCIVA contains CIP2A exons 1 to 13 fused to 349 nucleotides from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA-specific sequence are in the coding frame with exon 13 of CIP2A and code for a 13-amino acid peptide tail nonhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56α, but, whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to the nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, AML and CML patient samples overexpress NOCIVA, but not CIP2A mRNA. In AML, a high NOCIVA/CIP2A mRNA expression ratio is a marker for adverse overall survival. In CML, high NOCIVA expression is associated with inferior event-free survival among imatinib-treated patients, but not among patients treated with dasatinib or nilotinib. Conclusions: We discovered a novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias