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        Preclinical Assessment of the Anticancer Drug Response of Plexiform Neurofbroma Tissue Using Primary Cultures

        Wei Jiang,Victor-F. Mautner,Reinhard E. Friedrich,Lan Kluwe 대한신경과학회 2015 Journal of Clinical Neurology Vol.11 No.2

        Background and Purpose Individualized drug testing for tumors using a strategy analogous to antibiotic tests for infectious diseases would be highly desirable for personalized andindividualized cancer care. Methods Primary cultures containing tumor and nontumor stromal cells were utilized in anovel strategy to test drug responses with respect to both efcacy and specifcity. Te strategytested in this pilot study was implemented using four primary cultures derived from plexiformneurofbromas. Responses to two cytotoxic drugs (nilotinib and imatinib) were measured byfollowing dose-dependent changes in the proportions of tumor and nontumor cells, determined by staining them with cell-type-specifc antibodies. Te viability of the cultured cellsand the cytotoxic efect of the drugs were also measured using proliferation and cytotoxicityassays. Results Te total number of cells decreased afer the drug treatment, in accordance with theobserved reduction in proliferation and increased cytotoxic efect upon incubation with thetwo anticancer drugs. Te proportions of Schwann cells and fbroblasts changed dose-dependently, although the patterns of change varied between the tumor samples (from diferent sources) and between the two drugs. Te highly variable in vitro drug responses probably refect thelarge variations in the responses of tumors to therapies between individual patients in vivo. Conclusions Tese preliminary results suggest that the concept of assessing in vitro drug responses using primary cultures is feasible, but demands the extensive further development ofan application for preclinical drug selection and drug discovery.

      • Treatment of orthotopic malignant peripheral nerve sheath tumors with oncolytic herpes simplex virus

        Antoszczyk, Slawomir,Spyra, Melanie,Mautner, Victor Felix,Kurtz, Andreas,Stemmer-Rachamimov, Anat O.,Martuza, Robert L.,Rabkin, Samuel D. Oxford University Press 2014 Neuro-oncology Vol.16 No.8

        <P><B>Backgrounds</B></P><P>Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive and often lethal sarcoma that frequently develops in patients with neurofibromatosis type 1 (NF1). We developed new preclinical MPNST models and tested the efficacy of oncolytic herpes simplex viruses (oHSVs), a promising cancer therapeutic that selectively replicates in and kills cancer cells.</P><P><B>Methods</B></P><P>Mouse NF1<SUP>−</SUP> MPNST cell lines and human NF1<SUP>−</SUP> MPNST stemlike cells (MSLCs) were implanted into the sciatic nerves of immunocompetent and athymic mice, respectively. Tumor growth was followed by external measurement and sciatic nerve deficit using a hind-limb scoring system. Oncolytic HSV G47Δ as well as “armed” G47Δ expressing platelet factor 4 (PF4) or interleukin (IL)-12 were injected intratumorally into established sciatic nerve tumors.</P><P><B>Results</B></P><P>Mouse MPNST cell lines formed tumors with varying growth kinetics. A single intratumoral injection of G47Δ in sciatic nerve tumors derived from human S462 MSLCs in athymic mice or mouse M2 (37-3-18-4) cells in immunocompetent mice significantly inhibited tumor growth and prolonged survival. Local IL-12 expression significantly improved the efficacy of G47Δ in syngeneic mice, while PF4 expression prolonged survival. Injection of G47Δ directly into the sciatic nerve of athymic mice resulted in only mild symptoms that did not differ from phosphate buffered saline control.</P><P><B>Conclusions</B></P><P>Two new orthotopic MPNST models are described, including in syngeneic mice, expanding the options for preclinical testing. Oncolytic HSV G47Δ exhibited robust efficacy in both immunodeficient and immunocompetent MPNST models while maintaining safety. Interleukin-12 expression improved efficacy. These studies support the clinical translation of G47Δ for patients with MPNST.</P>

      • Effector T cell subclasses associate with tumor burden in neurofibromatosis type 1 patients

        Farschtschi, Said,Park, Su-Jin,Sawitzki, Birgit,Oh, Su-Jun,Kluwe, Lan,Mautner, Victor F.,Kurtz, Andreas Springer Berlin Heidelberg 2016 Cancer immunology, immunotherapy Vol.65 No.9

        <P>Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome caused by mutations of the <I>NF1</I> gene and resulting dysregulation of the Ras-pathway. In addition to peripheral nerve tumors, affected tissues include the musculoskeletal and cardiovascular system. The immune system has recently been suggested as a possible modulator NF1-related phenotypes. Therefore, we determined the immune phenotype in NF1 patients and investigated its relationship with the phenotypic severity of NF1-related tumor manifestations. We quantified global leukocytes and lymphocyte subpopulations of peripheral blood from 37 NF1 patients and 21 healthy controls by flow cytometry. To associate immune phenotype with tumor phenotype, all NF1 patients underwent whole-body magnetic resonance imaging and total internal tumor volume was calculated. The immunophenotypes were compared among four NF1 groups with different total internal tumor burdens and between NF1 patients and non-NF1 subjects. We found that NF1 patients show a generalized lymphopenia. Closer analysis revealed that the CD8<SUP>+</SUP>/CD27<SUP>−</SUP> and CD8<SUP>+</SUP>/CD57<SUP>+</SUP> effector T cell fractions strongly increase in NF1 patients with low tumor load and decrease to levels below control in patients with high tumor load. Moreover, increased production of IL2, IFN-γ and TNF-α was found in T cells of NF1 patients upon phorbol-12-myristate acetate (PMA) stimulation compared to healthy controls. The data indicate that decreasing CD8<SUP>+</SUP>/CD57<SUP>+</SUP> and CD27<SUP>−</SUP> T cell fractions correspond to increasing tumor load in NF1 patients, potentially making these populations useful marker for internal tumor burden.</P>

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