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  • 1.
    Chand, Damini
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Yamazaki, Yasuo
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Ruuth, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Schönherr, Christina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Martinsson, Tommy
    Gothenburg, Sweden.
    Kogner, Per
    Stockholm, Sweden.
    Attiyeh, Edward F
    Philadelphia, PA 19104, USA .
    Maris, John
    Philadelphia, PA 19104, USA .
    Morozova, Olena
    Vancouver, British Columbia V5Z 4S6, Canada .
    Marra, Marco A
    Vancouver, British Columbia V5Z 4S6, Canada .
    Ohira, Miki
    Chiba 260-8717, Japan.
    Nakagawara, Akira
    Chiba 260-8717, Japan.
    Sandström, Per-Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Palmer, Ruth H
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma2013In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 6, no 2, p. 373-382Article in journal (Refereed)
    Abstract [en]

    Neuroblastoma is a childhood extracranial solid tumor which is associated with a number of genetic changes. Included in these genetic alterations are mutations in the kinase domain of the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK), which have been found in both somatic and familial neuroblastoma. In order to treat patients accordingly required characterisation of these mutations in terms of their response to ALK tyrosine kinase inhibitors (TKIs). Here, we report the identification and characterisation of two novel neuroblastoma ALK mutations (A1099T and 1464STOP) which we have investigated together with several previously reported but uncharacterised ALK mutations (T1087I, D1091N, T1151M, M1166R, F1174I and A1234T). In order to understand the potential role of these ALK mutations in neuroblastoma progression we have employed cell culture based systems together with the model organism Drosophila as a readout for ligand-independent activity. Mutation of ALK at position F1174I generates a gain-of-function receptor capable of activating intracellular targets, such as ERK (extracellular signal regulated kinase) and STAT3 (signal transducer and activator of transcription 3) in a ligand independent manner. Analysis of these previously uncharacterised ALK mutants and comparison with ALK(F1174) mutants suggests that ALK mutations observed in neuroblastoma fall into three classes. These are: (i) gain-of-function ligand independent mutations such as ALK(F1174), (ii) kinase-dead ALK mutants, e.g. ALK(I1250T)(Schonherr et al 2011a) or (iii) ALK mutations which are ligand-dependent in nature. Irrespective of the nature of the observed ALK mutants, in every case the activity of the mutant ALK receptors could be abrogated by the ALK inhibitor crizotinib (PF-02341066, Xalkori), albeit with differing levels of sensitivity.

  • 2. Guan, J.
    et al.
    Tucker, E. R.
    Wan, H.
    Chand, D.
    Danielson, L. S.
    Ruuth, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    El Wakil, A.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Witek, B.
    Jamin, Y.
    Umapathy, G.
    Robinson, S. P.
    Johnson, T. W.
    Smeal, T.
    Martinsson, T.
    Chesler, L.
    Palmer, R. H.
    Hallberg, B.
    The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN2016In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 9, no 9, p. 941-952Article in journal (Refereed)
    Abstract [en]

    The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo. In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN. Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.

  • 3.
    Hagglund, Anna-Carin
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Jones, Iwan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of Tsc1 disrupts ciliary body and iris development2017In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 10, no 3, p. 245-257Article in journal (Refereed)
    Abstract [en]

    Development of the cornea, lens, ciliary body and iris within the anterior segment of the eye involves coordinated interaction between cells originating from the ciliary margin of the optic cup, the overlying periocular mesenchyme and the lens epithelium. Anterior segment dysgenesis (ASD) encompasses a spectrum of developmental syndromes that affect these anterior segment tissues. ASD conditions arise as a result of dominantly inherited genetic mutations and result in both ocular-specific and systemic forms of dysgenesis that are best exemplified by aniridia and Axenfeld-Rieger syndrome, respectively. Extensive clinical overlap in disease presentation amongst ASD syndromes creates challenges for correct diagnosis and classification. The use of animal models has therefore proved to be a robust approach for unravelling this complex genotypic and phenotypic heterogeneity. However, despite these successes, it is clear that additional genes that underlie several ASD syndromes remain unidentified. Here, we report the characterisation of a novel mouse model of ASD. Conditional deletion of Tsc1 during eye development leads to a premature upregulation of mTORC1 activity within the ciliary margin, periocular mesenchyme and lens epithelium. This aberrant mTORC1 signalling within the ciliary margin in particular leads to a reduction in the number of cells that express Pax6, Bmp4 and Msx1. Sustained mTORC1 signalling also induces a decrease in ciliary margin progenitor cell proliferation and a consequent failure of ciliary body and iris development in postnatal animals. Our study therefore identifies Tsc1 as a novel candidate ASD gene. Furthermore, the Tsc1-ablated mouse model also provides a valuable resource for future studies concerning the molecular mechanisms underlying ASD and acts as a platform for evaluating therapeutic approaches for the treatment of visual disorders.

  • 4.
    Jones, Iwan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hägglund, Anna-Carin
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Törnqvist, Gunilla
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development2015In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 8, no 12, p. 1517-1529Article in journal (Refereed)
    Abstract [en]

    Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that is best characterised by neurodevelopmental deficits and the presence of benign tumours (called hamartomas) in affected organs. This multi-organ disorder results from inactivating point mutations in either the TSC1 or the TSC2 genes and consequent activation of the canonical mammalian target of rapamycin complex 1 signalling (mTORC1) pathway. Because lesions to the eye are central to TSC diagnosis, we report here the generation and characterisation of the first eye-specific TSC mouse model. We demonstrate that conditional ablation of Tsc1 in eye-committed progenitor cells leads to the accelerated differentiation and subsequent ectopic radial migration of retinal ganglion cells. This results in an increase in retinal ganglion cell apoptosis and consequent regionalised axonal loss within the optic nerve and topographical changes to the contra- and ipsilateral input within the dorsal lateral geniculate nucleus. Eyes from adult mice exhibit aberrant retinal architecture and display all the classic neuropathological hallmarks of TSC, including an increase in organ and cell size, ring heterotopias, hamartomas with retinal detachment, and lamination defects. Our results provide the first major insight into the molecular etiology of TSC within the developing eye and demonstrate a pivotal role for Tsc1 in regulating various aspects of visual-pathway development. Our novel mouse model therefore provides a valuable resource for future studies concerning the molecular mechanisms underlying TSC and also as a platform to evaluate new therapeutic approaches for the treatment of this multi-organ disorder.

  • 5.
    Olsson, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Honkala, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Karhunen, Pekka J.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kok, Eloise H.
    HSV presence in brains of individuals without dementia: the TASTY brain series2016In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 9, no 11, p. 1349-1355Article in journal (Refereed)
    Abstract [en]

    Herpes simplex virus (HSV) type 1 affects a majority of the population and recent evidence suggests involvement in Alzheimer's disease aetiology. We investigated the prevalence of HSV type 1 and 2 in the Tampere Autopsy Study (TASTY) brain samples using PCR and sero-positivity in plasma, and associations with Alzheimer's disease neuropathology. HSV was shown to be present in human brain tissue in 11/584 (1.9%) of samples in the TASTY cohort, of which six had Alzheimer's disease neuropathological amyloid beta (A beta) aggregations. Additionally, serological data revealed 86% of serum samples tested were IgG-positive for HSV. In conclusion, we report epidemiological evidence of the presence of HSV in brain tissue free from encephalitis symptoms in a cohort most closely representing the general population (a minimum prevalence of 1.9%). Whereas 6/11 samples with HSV DNA in the brain tissue had A beta aggregations, most of those with A beta aggregations did not have HSV present in the brain tissue.

1 - 5 of 5
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  • nn-NO
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