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Berlin Brandenburg

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  • 1
    Language: English
    In: PLoS ONE, 2011, Vol.6(3), p.e17126
    Description: An obstacle to early stem cell transplantation into the acutely injured spinal cord is poor survival of transplanted cells. Transplantation of embryonic stem cells as substrate adherent embryonic stem cell-derived neural aggregates (SENAs) consisting mainly of neurons and radial glial cells has been shown to enhance survival of grafted cells in the injured mouse brain. In the attempt to promote the beneficial function of these SENAs, murine embryonic stem cells constitutively overexpressing the neural cell adhesion molecule L1 which favors axonal growth and survival of grafted and imperiled cells in the inhibitory environment of the adult mammalian central nervous system were differentiated into SENAs and transplanted into the spinal cord three days after compression lesion. Mice transplanted with L1 overexpressing SENAs showed improved locomotor function when compared to mice injected with wild-type SENAs. L1 overexpressing SENAs showed an increased number of surviving cells, enhanced neuronal differentiation and reduced glial differentiation after transplantation when compared to SENAs not engineered to overexpress L1. Furthermore, L1 overexpressing SENAs rescued imperiled host motoneurons and parvalbumin-positive interneurons and increased numbers of catecholaminergic nerve fibers distal to the lesion. In addition to encouraging the use of embryonic stem cells for early therapy after spinal cord injury L1 overexpression in the microenvironment of the lesioned spinal cord is a novel finding in its functions that would make it more attractive for pre-clinical studies in spinal cord regeneration and most likely other diseases of the nervous system.
    Keywords: Research Article ; Biology ; Medicine ; Neuroscience ; Neurological Disorders
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: PLoS ONE, 2011, Vol.6(5), p.e19121
    Description: Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB) prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods. ; The particles were prepared by a high-pressure solvent evaporation technique using 1% polyvinylalcohol (PLGA/PVA) or human serum albumin (PLGA/HSA) as stabilizers. Additionally, lecithin-containing PLGA/HSA particles (Dox-Lecithin-PLGA/HSA) were prepared. For evaluation of the antitumour efficacy the glioblastoma-bearing rats were treated intravenously with the doxorubicin-loaded nanoparticles coated with poloxamer 188 using the following treatment regimen: 3×2.5 mg/kg on day 2, 5 and 8 after tumour implantation; doxorubicin and poloxamer 188 solutions were used as controls. On day 18, the rats were sacrificed and the antitumour effect was determined by measurement of tumour size, necrotic areas, proliferation index, and expression of GFAP and VEGF as well as Isolectin B4, a marker for the vessel density. ; The results reveal a considerable anti-tumour effect of the doxorubicin-loaded nanoparticles. The overall best results were observed for Dox-Lecithin-PLGA/HSA. These data demonstrate that the poloxamer 188-coated PLGA nanoparticles enable delivery of doxorubicin across the blood-brain barrier in the therapeutically effective concentrations.
    Keywords: Research Article ; Biology ; Medicine ; Immunology ; Oncology
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(5), p.e63118
    Description: The only approved pharmacological treatment for ischemic stroke is intravenous administration of plasminogen activator (tPA) to re-canalize the occluded cerebral vessel. Not only reperfusion but also tPA itself can induce an inflammatory response. Microglia are the innate immune cells of the central nervous system and the first immune cells to become activated in stroke. Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia. To examine neuroserpin-dependent mechanisms of neuroprotection in stroke, we studied neuroserpin deficient (Ns(-/-))mice in an animal model of temporal focal ischemic stroke. Infarct size and neurological outcome were worse in neuroserpin deficient mice even though the fibrinolytic activity in the ischemic brain was increased. The increased infarct size was paralleled by a selective increase in proinflammatory microglia activation in Ns(-/-) mice. Our results show excessive microglial activation in Ns(-/-) mice mediated by an increased activity of tPA. This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    In: Nature, 2013, Vol.495(7442), p.474
    Description: CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clp1 (Clp1K/K) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues Clp1K/K mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53. [PUBLICATION ]
    Keywords: Amyotrophic Lateral Sclerosis–Metabolism ; Animals–Pathology ; Animals, Newborn–Innervation ; Axons–Metabolism ; Axons–Pathology ; Cell Death–Genetics ; Diaphragm–Metabolism ; Embryo Loss–Pathology ; Embryo, Mammalian–Metabolism ; Embryo, Mammalian–Pathology ; Exons–Genetics ; Female–Metabolism ; Fibroblasts–Cytology ; Male–Deficiency ; Mice–Metabolism ; Mice, Inbred C57bl–Metabolism ; Mice, Knockout–Genetics ; Mice, Transgenic–Metabolism ; Motor Neurons–Metabolism ; Motor Neurons–Metabolism ; Muscular Atrophy, Spinal–Metabolism ; Neuromuscular Diseases–Metabolism ; Neuromuscular Diseases–Metabolism ; Oxidative Stress–Metabolism ; RNA Processing, Post-Transcriptional–Metabolism ; RNA, Transfer, Tyr–Metabolism ; RNA, Transfer, Tyr–Metabolism ; Respiration–Metabolism ; Spinal Nerves–Metabolism ; Transcription Factors–Metabolism ; Transcription Factors–Metabolism ; Tumor Suppressor Protein P53–Metabolism ; Tyrosine–Metabolism ; Tyrosine–Metabolism ; Neurons ; Proteins ; Mutation ; Rodents ; Kinases ; Hexim1 Protein, Mouse ; RNA, Transfer, Tyr ; Transcription Factors ; Tumor Suppressor Protein P53 ; Tyrosine;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 5
    Language: English
    In: International Journal of Pharmaceutics, 2011, Vol.415(1), pp.244-251
    Description: Glioblastomas belong to the most devastating cancer diseases. For this reason, polysorbate 80 (Tween 80 )-coated poly(isohexyl cyanoacrylate) (PIHCA) (Monorex ) nanoparticles loaded with doxorubicin were developed and tested for their use for the treatment of glioblastomas. The preparation of the nanoparticles resulted in spherical particles with high doxorubicin loading. The physico-chemical properties and the release of doxorubicin from the PIHCA-nanoparticles were analysed, and the influence on cell viability of the rat glioblastoma 101/8-cell line was investigated. In vitro, the empty nanoparticles did not show any toxicity, and the anti-cancer effects of the drug-loaded nanoparticles were increased in comparison to doxorubicin solution, represented by IC values. The in vivo efficacy was then tested in intracranially glioblastoma 101/8-bearing rats. Rats were treated with 3 × 1.5 mg/kg doxorubicin and were sacrificed 18 days after tumour transplantation. Histological and immunohistochemical analyses were carried out to assess the efficacy of the nanoparticles. Tumour size, proliferation activity, vessel density, necrotic areas, and expression of glial fibrillary acidic protein demonstrated that doxorubicin-loaded PIHCA-nanoparticles were much more efficient than the free drug. The results suggest that poly(isohexyl cyanoacrylate) nanoparticles hold great promise for the non-invasive therapy of human glioblastomas.
    Keywords: Doxorubicin ; Nanoparticles ; Poly(Isohexyl Cyanoacrylate) ; Glioblastoma ; Histology ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0378-5173
    E-ISSN: 1873-3476
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  • 6
    In: Brain Pathology, November 2017, Vol.27(6), pp.839-845
    Description: IgG4‐related disease is an immune‐mediated disease with manifestations in most organ systems among them the pituitary gland. To date, few cases of histologically confirmed cases of IgG‐related hypophysitis have been reported. The aim of this study was to retrospectively determine the prevalence of IgG4‐related hypophysitis among cases previously diagnosed as primary hypophysitis (lymphocytic hypophysitis, granulomatous hypophysitis and hypophysitis not otherwise specified). Histological and immunohistochemical analysis revealed that 12 of 29 cases (41.4%) previously diagnosed as primary hypophysitis fulfilled the criteria for IgG4‐related disease and, thus, IgG4‐related hypophysitis should always be considered in the differential diagnosis of primary hypophysitis. All cases of IgG4‐related hypophysitis showed a dense lymphoplasmacytic infiltrate with more than 10 IgG4‐positive cells per high power field and a ratio of IgG4/IgG‐positive cells of more than 40%, whereas storiform fibrosis was an inconsistent histological feature and was also seen in few cases of non‐IgG‐related hypophysitis, thus lacking sensitivity and specificity. Obliterative phlebitis was not seen in any case. Thus, histological criteria defined for IgG4‐related disease in other organs should be modified for IgG4‐related hypophysitis, accordingly.
    Keywords: Igg4 ; Histological Criteria ; Hypophysitis ; Prevalence
    ISSN: 1015-6305
    E-ISSN: 1750-3639
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  • 7
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 01 December 2010, Vol.16(23), pp.5781-95
    Description: Glioblastomas are the most common and most deadly primary brain tumors. Here, we evaluated the chemotherapeutic effect of the natural polyphenol curcumin on glioma cells in vitro and in vivo using an immunocompetent orthotopic mouse model. Curcumin's effects on proliferation, cell cycle, migration, invasion, JAK/STAT3 signaling, STAT3 target gene expression, and STAT3C rescue experiments were determined in murine glioma cell lines in vitro. Therapeutic effects of curcumin in vivo were evaluated in tumor-bearing mice fed a Western-type diet fortified with curcumin (0.05%, w/w) and in control animals. Tumor growth patterns and survival were evaluated by immunohistochemistry, morphometric analyses, and Kaplan-Meier plots. In vitro, curcumin inhibited JAK1,2/STAT3 tyrosine-phosphorylation in a dose-dependent fashion in murine glioma cell lines. Real-time RT-PCR revealed that curcumin downregulated transcription of the STAT3 target genes c-Myc, MMP-9, Snail, and Twist, and of the proliferation marker Ki67. Curcumin dose-dependently suppressed cell proliferation by inducing a G2/M phase arrest. In wound healing and Matrigel invasion assays, curcumin treatment resulted in a dose-dependent attenuation of the glioma cells' migratory and invasive behavior, which could be rescued by constitutively active STAT3C. In vivo, curcumin intake reduced the growth and midline crossing of intracranially implanted tumors and proliferation of tumor cells ensuing in significant long-term survival compared with control diet. This preclinical study shows that curcumin is capable of suppressing malignant glioma growth in vitro and in vivo. Our data suggest that the pharmacologically safe agent curcumin holds promise for clinical application in glioma therapy.
    Keywords: Brain Neoplasms -- Pathology ; Cell Growth Processes -- Drug Effects ; Curcumin -- Pharmacology ; Glioma -- Pathology ; Janus Kinase 1 -- Antagonists & Inhibitors ; Janus Kinase 2 -- Antagonists & Inhibitors ; Stat3 Transcription Factor -- Antagonists & Inhibitors
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 8
    In: Stroke, 2014, Vol.45(11), pp.3395-3402
    Description: BACKGROUND AND PURPOSE—: Brain injury during stroke results in oxidative stress and the release of factors that include extracellular Ca, hydrogen peroxide, adenosine diphosphate ribose, and nicotinic acid adenine dinucleotide phosphate. These alterations of the extracellular milieu change the activity of transient receptor potential melastatin subfamily member 2 (TRPM2), a nonselective cation channel expressed in the central nervous system and the immune system. Our goal was to evaluate the contribution of TRPM2 to the tissue damage after stroke. METHODS—: In accordance with current quality guidelines, we independently characterized Trpm2 in a murine ischemic stroke model in 2 different laboratories. RESULTS—: Gene deficiency of Trpm2 resulted in significantly improved neurological outcome and decreased infarct size. Besides an already known moderate neuroprotective effect of Trpm2 deficiency in vitro, ischemic brain invasion by neutrophils and macrophages was particularly reduced in Trpm2-deficient mice. Bone marrow chimeric mice revealed that Trpm2 deficiency in the peripheral immune system is responsible for the protective phenotype. Furthermore, experiments with mixed bone marrow chimeras demonstrated that Trpm2 is essential for the migration of neutrophils and, to a lesser extent, also of macrophages into ischemic hemispheres. Notably, the pharmacological TRPM2 inhibitor, N-(p-amylcinnamoyl)anthranilic acid, was equally protective in the stroke model. CONCLUSIONS—: Although a neuroprotective effect of TRPM2 in vitro is well known, we can show for the first time that the detrimental role of TRPM2 in stroke primarily depends on its role in activating peripheral immune cells. Targeting TRPM2 systemically represents a promising therapeutic approach for ischemic stroke.
    Keywords: Medicine;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 9
    In: Stroke, 2017
    Description: BACKGROUND AND PURPOSE—: Inflammatory mechanisms can exacerbate ischemic tissue damage and worsen clinical outcome in patients with stroke. Both αβ and γδ T cells are established mediators of tissue damage in stroke, and the role of dendritic cells (DCs) in inducing the early events of T cell activation and differentiation in stroke is not well understood. METHODS—: In a murine model of experimental stroke, we defined the immune phenotype of infiltrating DC subsets based on flow cytometry of surface markers, the expression of ontogenetic markers, and cytokine levels. We used conditional DC depletion, bone marrow chimeric mice, and IL-23 (interleukin-23) receptor-deficient mice to further explore the functional role of DCs. RESULTS—: We show that the ischemic brain was rapidly infiltrated by IRF4/CD172a conventional type 2 DCs and that conventional type 2 DCs were the most abundant subset in comparison with all other DC subsets. Twenty-four hours after ischemia onset, conventional type 2 DCs became the major source of IL-23, promoting neutrophil infiltration by induction of IL-17 (interleukin-17) in γδ T cells. Functionally, the depletion of CD11c cells or the genetic disruption of the IL-23 signaling abrogated both IL-17 production in γδ T cells and neutrophil infiltration. Interruption of the IL-23/IL-17 cascade decreased infarct size and improved neurological outcome after stroke. CONCLUSIONS—: Our results suggest a central role for interferon regulatory factor 4-positive IL-23–producing conventional DCs in the IL-17–dependent secondary tissue damage in stroke.
    Keywords: Animals–Genetics ; Brain Ischemia–Immunology ; Dendritic Cells–Pathology ; Disease Models, Animal–Immunology ; Interferon Regulatory Factors–Pathology ; Interleukin-17–Genetics ; Interleukin-23–Immunology ; Mice–Genetics ; Mice, Knockout–Immunology ; Neutrophil Infiltration–Genetics ; Neutrophils–Immunology ; Receptors, Antigen, T-Cell, Gamma-Delta–Genetics ; Stroke–Immunology ; T-Lymphocytes–Immunology ; T-Lymphocytes–Pathology ; T-Lymphocytes–Genetics ; T-Lymphocytes–Immunology ; T-Lymphocytes–Genetics ; T-Lymphocytes–Immunology ; T-Lymphocytes–Pathology ; T-Lymphocytes–Immunology ; T-Lymphocytes–Pathology ; Interferon Regulatory Factors ; Interleukin-17 ; Interleukin-23 ; Receptors, Antigen, T-Cell, Gamma-Delta ; Interferon Regulatory Factor-4 ; Dendritic Cells ; Inflammation ; Interleukin-17 ; Interleukin-23 ; Stroke;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 10
    Language: English
    In: Anticancer research, February 2011, Vol.31(2), pp.591-6
    Description: Hyperostosis is the most common skull change associated with meningioma. Five hyperostosis cases of meningioma en plaque infiltrating the skull processed without previous decalcification of the bone tissue were investigated histologically and immunohistochemically with antibodies against somatostatin receptor 2A (SSR2A). Undecalcified bone biopsies embedded in methylmethacrylate and paraffin-embedded extraosseous tumor tissues were analyzed. All five cases were well-differentiated meningotheliomatous meningiomas en plaque according to the WHO classification of tumors and revealed areas of hyperosteoidosis. Furthermore, all five meningiomas en plaque presented strong positive reactions to antibodies against SSR2A in both the intraosseous and extraosseous tumor proliferates. In summary, similar morphological changes characterized by hyperosteoidosis were observed in a small cohort of meningioma en plaque associated with expression of SSR2A and reports in the literature of the histogenesis of hyperostosis in meningioma en plaque are discussed.
    Keywords: Bone and Bones -- Pathology ; Meningeal Neoplasms -- Pathology ; Meningioma -- Pathology ; Skull Neoplasms -- Secondary
    ISSN: 02507005
    E-ISSN: 1791-7530
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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