Institute of Basic Medical science

Oslo, Norway

Institute of Basic Medical science

Oslo, Norway
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Szodoray P.,University of Oslo | Papp G.,Medical and Health Science Center | Nakken B.,Institute of Basic Medical science | Harangi M.,Debrecen University | Zeher M.,Medical and Health Science Center
Autoimmunity Reviews | Year: 2010

Extracorporeal photochemotherapy, or photopheresis is a low-risk therapeutical intervention, which has been introduced in a variety of hematological malignancies, autoimmune conditions and transplantation. The mode of action of photopheresis encompasses apoptosis-induction and modifications of immunoregulatory processes, leading to the elimination of malignant cells, as well as the down-modulation of harmful immune responses. Although the beneficial effects of the therapy have been depicted in numerous studies, little is known about the exact benefits and the molecular mechanisms behind. The aim of the present review was to portray some aspects of the molecular and clinical rationale of extracorporeal photochemotherapy in autoimmune diseases, malignancies and transplantation, and to provide an overview of the treatment in the modern clinical management of these diseases. © 2009 Elsevier B.V. All rights reserved.


Tollefsen I.M.,University of Oslo | Tollefsen I.M.,Institute of Basic Medical science | Hem E.,Institute of Basic Medical science | Ekeberg O.,University of Oslo | Ekeberg O.,Institute of Basic Medical science
BMC Psychiatry | Year: 2012

Background: Reliable suicide statistics are a prerequisite for suicide monitoring and prevention. The aim of this study was to assess the reliability of suicide statistics through a systematic review of the international literature. Methods: We searched for relevant publications in EMBASE, Ovid Medline, PubMed, PsycINFO and the Cochrane Library up to October 2010. In addition, we screened related studies and reference lists of identified studies. We included studies published in English, German, French, Spanish, Norwegian, Swedish and Danish that assessed the reliability of suicide statistics. We excluded case reports, editorials, letters, comments, abstracts and statistical analyses. All three authors independently screened the abstracts, and then the relevant full-text articles. Disagreements were resolved through consensus. Results: The primary search yielded 127 potential studies, of which 31 studies met the inclusion criteria and were included in the final review. The included studies were published between 1963 and 2009. Twenty were from Europe, seven from North America, two from Asia and two from Oceania. The manner of death had been reevaluated in 23 studies (40-3,993 cases), and there were six registry studies (195-17,412 cases) and two combined registry and re-evaluation studies. The study conclusions varied, from findings of fairly reliable to poor suicide statistics. Thirteen studies reported fairly reliable suicide statistics or under-reporting of 0-10%. Of the 31 studies during the 46-year period, 52% found more than 10% under-reporting, and 39% found more than 30% underreporting or poor suicide statistics. Eleven studies reassessed a nationwide representative sample, although these samples were limited to suicide within subgroups. Only two studies compared data from two countries. Conclusions: The main finding was that there is a lack of systematic assessment of the reliability of suicide statistics. Few studies have been done, and few countries have been covered. The findings support the general under-reporting of suicide. In particular, nationwide studies and comparisons between countries are lacking. © 2012 Tøllefsen et al.


Dammen T.,Institute of Basic Medical science | Papageorgiou C.,Priory Hospital Altrincham | Wells A.,Royal Infirmary
Nordic Journal of Psychiatry | Year: 2015

Background: Preliminary data support the implementation of individual metacognitive therapy (MCT) for depression. Given the focus of MCT on transpersonal processes, we hypothesized that this treatment should translate well to a group format. In this study, the effects and feasibility associated with group MCT for depression are reported. Methods: Eleven patients who were consecutively referred by general practitioners to a specialist psychiatric practice in Norway participated in an open trial of the effects and feasibility associated with group MCT for depression. All of the patients met the DSM-IV criteria for major depressive disorder (MDD) and were monitored in a baseline period before attending 90-min weekly treatment sessions of group MCT for 10 weeks. The primary symptom outcome measure was severity of depression whilst secondary outcome measures included levels of anxiety, rumination and metacognitive beliefs. We also assessed recovery rates and changes in comorbid Axis I and Axis II diagnoses. Results: Large clinically significant improvements across all measures were detected at post-treatment and these were maintained at follow-up. Based on objectively defined recovery criteria, all patients were classified as recovered at post-treatment and 91% at 6 months follow-up. The intervention was also associated with significant reductions in comorbid diagnoses. Conclusions: These preliminary data indicate that group MCT in the treatment of depression is effective, well accepted and it extends clinical application of MCT for depression to group formats as a potential cost-effective intervention. © 2014 Informa Healthcare.


Pajuelo D.,University of Valencia | Lee C.-T.,Institute of Basic Medical science | Roig F.J.,University of Valencia | Hor L.-I.,Institute of Basic Medical science | And 2 more authors.
Environmental Microbiology | Year: 2015

Vibrio vulnificus is a marine bacterium associated with human and fish (mainly farmed eels) diseases globally known as vibriosis. The ability to infect and overcome eel innate immunity relies on a virulence plasmid (pVvbt2) specific for biotype 2 (Bt2) strains. In the present study, we demonstrated that pVvbt2 encodes a host-specific iron acquisition system that depends on an outer membrane receptor for eel transferrin called Vep20. The inactivation of vep20 did not affect either bacterial growth in human plasma or virulence for mice, while bacterial growth in eel blood/plasma was abolished and virulence for eels was significantly impaired. Furthermore, vep20 is an iron-regulated gene overexpressed in eel blood during artificially induced vibriosis both in vitro and in vivo. Interestingly, homologues to vep20 were identified in the transferable plasmids of two fish pathogen species of broad-host range, Vibrio harveyi (pVh1) and Photobacterium damselae subsp. damselae (pPHDD1). These data suggest that Vep20 belongs to a new family of plasmid-encoded fish-specific transferrin receptors, and the acquisition of these plasmids through horizontal gene transfer is likely positively selected in the fish-farming environment. Moreover, we propose Ftbp (fish transferrin binding proteins) as a formal name for this family of proteins. © 2015 Society for Applied Microbiology and John Wiley & Sons Ltd.


Chen H.-M.,Institute of Basic Medical science | Lin Y.-H.,Institute of Basic Medical science | Lin Y.-H.,National Cheng Kung University | Cheng Y.-M.,National Cheng Kung University | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Uterine leiomyoma, the most common tumors found in the women of the reproductive age, may cause abnormal uterine bleeding and be life threatening. Compared with myometrium, leiomyoma contains excessive extracellular matrix (ECM). However, the pathological roles of ECM in the development of leiomyoma remain largely unknown. Integrins are the major adhesion molecules on cell surface to interact with ECM. The interactions of ECM with integrins regulate cell adhesion and initiate signals for cell growth, differentiation, and migration. Objective: The aim of this study was to investigate the expression and functional role of integrin-β1 in leiomyoma pathogenesis. Design: Levels of integrin-β1 protein were determined by Western blotting in paired normal and leiomyomal tissues (n = 15). Knockdown of integrin-β1 and inhibition of ECM-integrin interaction by disintegrin were used to evaluate the impact of integrin-β1 in cell adhesion, spreading, and proliferation. Results: Levels of integrin-β1 were significantly up-regulated in leiomyomal cells compared with their normal counterparts. Knockdown of integrin-β1 did not affect cell adhesion on fibronectin or laminin matrix but significantly inhibits cell spreading ability. Consistent with this notion, the phosphorylation of focal adhesion kinase and the recruitment of paxillin to the focal contact were decreased in integrin-β1 knockdown cells, which attenuates contraction force. The inability of cell spreading leads to inhibition of cyclin D1 expression and impedes cell cycle progression. More importantly, disruption of ECM-integrin interaction by the small protein, disintegrin inhibited cyclin D1 expression and cell proliferation. Conclusion: These data demonstrate that integrin-β1 is a critical ligand to enhance cell-ECM contact force and thus promotes cell proliferation. Disruption of ECM-integrin-β1 signaling may serve as an option to inhibit the progression of leiomyoma. Copyright © 2013 by The Endocrine Society.


Hsieh K.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Lee Y.K.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Londos C.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Raaka B.M.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | And 3 more authors.
Journal of Cell Science | Year: 2012

Perilipin family proteins (Plins) coat the surface of intracellular neutral lipid storage droplets in various cell types. Studies across diverse species demonstrate that Plins regulate lipid storage metabolism through recruitment of lipases and other regulatory proteins to lipid droplet surfaces. Mammalian genomes have distinct Plin gene members and additional protein forms derived from specific mRNA splice variants. However, it is not known if the different Plins have distinct functional properties. Using biochemical, cellular imaging and flow cytometric analyses, we now show that within individual cells of various types, the different Plin proteins preferentially sequester to separate pools of lipid storage droplets. By examining ectopically expressed GFP fusions and all endogenous Plin protein forms, we demonstrate that different Plins sequester to different types of lipid droplets that are composed of either triacylcerides or cholesterol esters. Furthermore, Plins with strong association preferences to triacylceride (or cholesterol ester) droplets can re-direct the relative intracellular triacylceride-cholesterol ester balance toward the targeted lipid. Our data suggest diversity of Plin function, alter previous assumptions about shared collective actions of the Plins, and indicate that each Plin can have separate and unique functions. © 2012.


The role of autophagy during leukemia treatment is unclear. On the one hand, autophagy might be induced as a prosurvival response to therapy, thereby reducing treatment efficiency. On the other hand, autophagy may contribute to degradation of fusion oncoproteins, as recently demonstrated for promyelocytic leukemia-retinoic acid receptor α and breakpoint cluster region-abelson, thereby facilitating leukemia treatment. Here, we investigated these opposing roles of autophagy in t(8;21) acute myeloid leukemia (AML) cells, which express the most frequently occurring AML fusion oncoprotein, AML1-eight-twenty-one (ETO). We demonstrate that autophagy is induced by AML1-ETO-targeting drugs, such as the histone deacetylase inhibitors (HDACis) valproic acid (VPA) and vorinostat. Furthermore, we show that autophagy does not mediate degradation of AML1-ETO but rather has a prosurvival role in AML cells, as inhibition of autophagy significantly reduced the viability and colony-forming ability of HDACi-treated AML cells. Combined treatment with HDACis and autophagy inhibitors such as chloroquine (CQ) led to a massive accumulation of ubiquitinated proteins that correlated with increased cell death. Finally, we show that VPA induced autophagy in t(8;21) AML patient cells, and combined treatment with CQ enhanced cell death. Because VPA and CQ are well-tolerated drugs, combinatorial therapy with VPA and CQ could represent an attractive treatment option for AML1-ETO-positive leukemia.


Maghazachi A.A.,Institute of Basic Medical science
Current Topics in Microbiology and Immunology | Year: 2010

Natural killer (NK) cells represent a major subpopulation of lymphocytes. These cells have effector functions as they recognize and kill transformed cells as well as microbially infected cells. In addition, alloreactive NK cells have been successfully used to treat patients with acute myeloid leukemia and other hematological malignancies. NK cells are also endowed with immunoregulatory functions since they secrete cytokines such as IFN-γ, which favor the development of T helper 1 (Th1) cells, and chemokines such as CCL3/MIP-1α and CCL4/MIP- 1β, which recruit various inflammatory cells into sites of inflammation. In human blood, NK cells are divided into CD56 bright CD16 dim and CD56 dim CD16 bright subsets. These subsets have different phenotypic expression and may have different functions; the former subset is more immunoregulatory and the latter is more cytolytic. The CD5 6brightCD16 dim NK cells home into tissues such as the peripheral lymph nodes (LNs) under physiological conditions because they express the LN homing receptor CCR7 and they respond to CCL19/MIP-3β and CCL21/SLC chemokines. They also distribute into adenoid tissues or decidual uterus following the CXCR3/CXCL10 or CXCR4/CXCL12 axis. On the other hand, both NK cell subsets migrate into inflammatory sites, with more CD5 6dimCD16 bright NK cells distributing into inflamed liver and lungs. CCR5/CCL5 axis plays an important role in the accumulation of NK cells in virally infected sites as well as during parasitic infections. CD56 brightCD16 dim cells also migrate into autoimmune sites such as inflamed synovial fluids in patients having rheumatoid arthritis facilitated by the CCR5/CCL3/CCL4/CCL5 axis, whereas they distribute into inflamed brains aided by the CX3CR1/CX 3CL1 axis. On the other hand, CD56 dimCD16 bright NK cells accumulate in the liver of patients with primary biliary disease aided by the CXCR1/CXCL8 axis. However, the types of chemokines that contribute to their accumulation in target organs during graft vs. host (GvH) disease are not known. Further, chemokines activate NK cells to become highly cytolytic cells known as CC chemokine-activated killer (CHAK) cells that kill tumor cells. In summary, chemokines whether secreted in an autocrine or paracrine fashion regulate various biological functions of NK cells. Depending on the tissue and the chemokine secreted, NK cells may ameliorate the disease such as their roles in combating tumors or virally infected cells, and their therapeutic potentials in treating leukemias and other hematological malignancies, as well as reducing the incidence of GvH disease. In contrast, they may exacerbate the disease by damaging the affected tissues through direct cytotoxicity or by the release of multiple inflammatory cytokines and chemokines. Examples are their deleterious roles in autoimmune diseases such as rheumatoid arthritis and primary biliary cirrhosis. © Springer-Verlag Berlin Heidelberg 2010.


Peripheral norepinephrine release is facilitated by presynaptic β-adrenoceptors, believed to involve the β2-subtype exclusively. However, β1-selective blockers are the most commonly used β-blockers in hypertension. Here the author tested the hypothesis that β1AR may function as presynaptic, release-facilitating auto-receptors. Since β1AR-blockers are injected during myocardial infarction, their influence on the cardiovascular response to acute norepinephrine release was also studied. By a newly established method, using tyramine-stimulated release through the norepinephrine transporter (NET), presynaptic control of catecholamine release was studied in normotensive and spontaneously hypertensive rats. β1AR-selective antagonists (CGP20712A, atenolol, metoprolol) reduced norepinephrine overflow to plasma equally efficient as β2AR-selective (ICI-118551) and β1+2AR (nadolol) antagonists in both strains. Neither antagonist lowered epinephrine secretion. Atenolol, which does not cross the blood-brain barrier, reduced norepinephrine overflow after adrenalectomy (AdrX), AdrX + ganglion blockade, losartan, or nephrectomy. Atenolol and metoprolol reduced resting cardiac work load. During tyramine-stimulated norepinephrine release, they had little effect on work load, and increased the transient rise in total peripheral vascular resistance, particularly atenolol when combined with losartan. In conclusion, β1AR, like β2AR, stimulated norepinephrine but not epinephrine release, independent of adrenal catecholamines, ganglion transmission, or renal renin release/angiotensin AT1 receptor activation. β1AR therefore functioned as a peripheral, presynaptic, facilitating auto-receptor. Like tyramine, hypoxia may induce NET-mediated release. Augmented tyramine-induced vasoconstriction, as observed after injection of β1AR-blocker, particularly atenolol combined with losartan, may hamper organ perfusion, and may have clinical relevance in hypoxic conditions such as myocardial infarction. © 2014 Berg.


Sexton J.,Institute of Basic Medical science | Laake P.,Institute of Basic Medical science
Statistics and Computing | Year: 2012

Regression methods typically construct a mapping from the covariates into the real numbers. Here, however, we consider regression problems where the task is to form a mapping from the covariates into a set of (univariate) real-valued functions. Examples are given by conditional density estimation, hazard regression and regression with a functional response. Our approach starts by modeling the function of interest using a sum of B-spline basis functions. To model dependence on the covariates, the coefficients of this expansion are each modeled as functions of the covariates. We propose to estimate these coefficient functions using boosted tree models. Algorithms are provided for the above three situations, and real data sets are used to investigate their performance. The results indicate that the proposed methodology performs well. In addition, it is both straightforward, and capable of handling a large number of covariates. © 2011 The Author(s).

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