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Sökning: WFRF:(Fredlund Erik)

  • Resultat 1-10 av 54
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  • Cepeda, Diana, et al. (författare)
  • CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
  • 2013
  • Ingår i: EMBO Molecular Medicine. - : Federation of European Neuroscience Societies and Blackwell Publishing Ltd. - 1757-4676 .- 1757-4684. ; 5:7, s. 1067-1086
  • Tidskriftsartikel (refereegranskat)abstract
    • SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer.
  • Cirenajwis, Helena, et al. (författare)
  • Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy.
  • 2015
  • Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12297-12309
  • Tidskriftsartikel (refereegranskat)abstract
    • Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.
  • Johansson, Henrik J., et al. (författare)
  • Breast cancer quantitative proteome and proteogenomic landscape
  • 2019
  • Ingår i: ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.
  • Kucharzewska, Paulina, et al. (författare)
  • Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development.
  • 2013
  • Ingår i: Proceedings of the National Academy of Sciences. - : National Acad Sciences. - 1091-6490. ; 110:18, s. 7312-7317
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypoxia, or low oxygen tension, is a major regulator of tumor development and aggressiveness. However, how cancer cells adapt to hypoxia and communicate with their surrounding microenvironment during tumor development remain important questions. Here, we show that secreted vesicles with exosome characteristics mediate hypoxia-dependent intercellular signaling of the highly malignant brain tumor glioblastoma multiforme (GBM). In vitro hypoxia experiments with glioma cells and studies with patient materials reveal the enrichment in exosomes of hypoxia-regulated mRNAs and proteins (e.g., matrix metalloproteinases, IL-8, PDGFs, caveolin 1, and lysyl oxidase), several of which were associated with poor glioma patient prognosis. We show that exosomes derived from GBM cells grown at hypoxic compared with normoxic conditions are potent inducers of angiogenesis ex vivo and in vitro through phenotypic modulation of endothelial cells. Interestingly, endothelial cells were programmed by GBM cell-derived hypoxic exosomes to secrete several potent growth factors and cytokines and to stimulate pericyte PI3K/AKT signaling activation and migration. Moreover, exosomes derived from hypoxic compared with normoxic conditions showed increased autocrine, promigratory activation of GBM cells. These findings were correlated with significantly enhanced induction by hypoxic compared with normoxic exosomes of tumor vascularization, pericyte vessel coverage, GBM cell proliferation, as well as decreased tumor hypoxia in a mouse xenograft model. We conclude that the proteome and mRNA profiles of exosome vesicles closely reflect the oxygenation status of donor glioma cells and patient tumors, and that the exosomal pathway constitutes a potentially targetable driver of hypoxia-dependent intercellular signaling during tumor development.
  • Lovén, Jakob, et al. (författare)
  • MYCN-regulated microRNAs repress estrogen receptor-{alpha} (ESR1) expression and neuronal differentiation in human neuroblastoma.
  • 2010
  • Ingår i: Proceedings of the National Academy of Sciences. - : National Acad Sciences. - 1091-6490. ; 107:4, s. 1553-1558
  • Tidskriftsartikel (refereegranskat)abstract
    • MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17 approximately 92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-alpha (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.
  • Mark, Andreas, 1980, et al. (författare)
  • Microstructure Simulation of Early Paper Forming Using Immersed Boundary Methods
  • 2011
  • Ingår i: Paper360. - 1933-3684. ; 10:11, s. 23-30
  • Tidskriftsartikel (refereegranskat)abstract
    • Paper forming is the first step in the paper machine where a fibersuspension leaves the headbox and flows through a forming fabric.Complex physical phenomena occur during paper forming due to theinteraction between fibers, fillers and fines as well as chemicalsadded to the suspension. Understanding this process is important forthe development of improved paper products because the configurationof the fibers during this step has a large influence on the finalpaper quality. Since the effective paper properties depend on themicro-structure of the fiber web, a continuum model is inadequate andthe properties of each fiber need to be accounted for in thesimulations.In the present work, a framework for microstructure simulation ofearly paper forming has been developed. The simulation frameworkincludes a Navier-Stokes solver and immersed boundary methods are usedto resolve the flow around the fibers. The fibers are modeled with afinite element discretization of the Euler-Bernoulli beam equation ina co-rotational formulation. The contact model is based on a penaltymethod and includes friction as well as elastic and inelasticcollisions.The fiber model and the contact model are validated against demandingtest cases from the literature with excellent results. Thefluid-structure interaction in the model is examined by simulating anelastic beam oscillating in a cross flow. Finally, a simulation ofearly paper forming is performed to demonstrate the potential of theproposed framework. The unique modeling approach can be used toincrease the fundamental understanding of paper forming and supportprocess optimization.
  • Mark, Andreas, 1980, et al. (författare)
  • Microstructure Simulation of Early Paper Forming Using Immersed Boundary Methods
  • 2011
  • Ingår i: Progress in Paper Physics Seminar. ; , s. 283-290
  • Konferensbidrag (refereegranskat)abstract
    • Paper forming is the first step in the paper machinewhere a fiber suspension leaves the headbox and flowsthrough a forming fabric. Understanding this processis important for the development of improved paperproducts because the configuration of the fibers duringthis step has a large influence on the final paperquality.The simulation framework includes IBOFlow, a stateof-the-art Navier-Stokes solver, and PaperGeo, the virtualpaper structure generator in GeoDict. ImmersedBoundary Methods are used to resolve the flow aroundthe fibers. The fibers are modeled with a finite elementdiscretization of the Euler-Bernoulli beam equationin a co-rotational formulation. The contact modelis based on a penalty method and includes friction aswell as elastic and inelastic collisions.The fiber model and the contact model are validatedagainst demanding test problems from the literaturewith excellent result. The fluid-structure interaction inthe model is examined by simulating an elastic beamoscillating in a cross flow. Finally, a simulation of initialpaper forming is performed, which demonstratesthe capabilities of the simulation framework.
  • Svenning, Erik, 1986, et al. (författare)
  • Multiphase Simulation of Fiber Suspension Flows Using Immersed Boundary Methods
  • 2012
  • Ingår i: Nordic Pulp and Paper Research Journal. - 0283-2631. ; 27:2, s. 184-191
  • Tidskriftsartikel (refereegranskat)abstract
    • Fiber suspension simulations are challenging since they involve transient fluid flow with immersed solid objects subject to large displacements and rotations. In the present work, a beam model in co-rotational formulation is coupled with a fluid solver using immersed boundary methods. The model is used to simulate a fiber in a shear flow and excellent agreement is found with Jeffery's equations. The shapes of fibers deforming in a shear flow are found to be in qualitative agreement with shapes observed in experiments.The flow of a fiber suspension is studied by simulating early paper forming with one-way and semi-two-way coupling. It is found that the flow through the fiber web needs to be resolved in order to predict the retention of fibers in the fiber web.
  • Andrä, Heiko, et al. (författare)
  • Micromechanical network model for the evaluation of quality controls of paper
  • 2011
  • Ingår i: Progress in Paper Physics Seminar. ; , s. 49-55
  • Konferensbidrag (refereegranskat)abstract
    • In this paper, we discuss the challenges in modelling and simulating infinitesimal and large deformations of cellulose fiber networks, mainly in the context of the prediction of quality controls for paper.Understanding the influence and sensitivity of macroscopic production parameters like grammage and thickness of paperboard and understanding the influence of the fiber suspension on the quality of paper is important for the development of better papers and for preserving raw materials and energy.The new simulation framework consists of the virtual stochastic paper structure generator PaperGeo, that was integrated in the GeoDict 1 software suite, and the finite element solver FeelMath (Finite Elements for Elastic Materials and Homogenization) for solving the equations of elasticity. The fibers and the contacts are modelled by using geometrically exact beams of Simo-type [1].The microstructural model and the fiber network model are validated against standard measurements of existing papers in the following way: At first we perform tensile and bending tests to measure the macroscopic stress-strain relations. In the next step we apply a representative macroscopic stress or strain onto the boundaries of realizations of the stochastic fiber network model and compute by homogenization the effective (stiffness) coefficients. Finally we compare the numerical results with the measurements.This procedure can also be used for an identification of elastic parameters on the microscale and to study the sensitivity of the effective (macroscopic) stiffness with regard to the parameters of the microstructure
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