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  • 1
    In: Neuro-Oncology, 2015, Vol. 17(suppl5), pp.v57-v57
    Description: Malignant gliomas, the largest group of primary intracerebrial tumors, are one of the most-difficult-to-cure cancers. The outcome has not significantly improved in recent years, despite considerable advances in our understanding of the molecular pathogenesis and improvement of surgical techniques, radio- and chemo-therapy. For glioblastoma multiforme (GBM), the most malignant form of glioma, the median survival time is approximately 15 months after diagnosis. Although complete remission of experimental GBM on MRI has been reported by using a lentiviral vector based suicide gene therapy approach1, recurrence of tumors at distant sites is common which is mainly caused by invasive glioma cells that escape treatment. Thus, a better distribution of the suicide gene is needed in order to target and efficiently kill the infiltrative glioma cells to prolong recurrence-free time span and improve the therapeutic effect. By introducing EGFR, a gene that has been reported to promote invasion of glioma cells2 into our LCMV-pseudotyped lentiviral vector system, we want to enhance the distribution of the suicide gene HSV-TK. This might lead to a more efficient killing of glioma cells in both tumor core and invasive areas.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    In: Circulation, 2018, Vol.138(Suppl_1 Suppl 1), pp.A13408-A13408
    Description: Introduction: We have previously shown that engineered heart tissue (EHT) from neonatal rat heart cells responds to sustained mechanical or pharmacological stress stimuli similarly as hearts in vivo. Inter alia, EHTs showed a decline in contractile force, prolongation of relaxation, cardiomyocyte hypertrophy, reactivation of fetal genes (e.g. natriuretic peptides) and fibrotic changes. However, human EHTs containing cardiomyocytes obtained by differentiating human induced pluripotent stem cells (hiPSCs) did not respond to stress stimuli. We hypothesized that non-cardiomyocytes might account for this difference and sought a method to produce human EHTs containing all major cardiac cell types.Methods and Results: HiPSCs produced from fibroblasts of a healthy donor were expanded and split into 4 groups. Each group was transduced with lentiviruses encoding different fluorescent proteins. Mesodermal induction was initiated for all groups, but then blue (BFP) cells were differentiated to cardiomyocytes via inhibition of Wnt-signaling, green (Venus) cells were differentiated via VEGF to endothelial cells, orange (mOrange2) cells via TGFβ, bFGF and additional activation of Wnt-signaling to smooth muscle cells, and red (Katushka2) cells via bFGF and additional activation of Wnt-signaling to fibroblasts. All 4 differentiated cell types showed bright fluorescence and were clearly discernible by mRNA-markers and functional or histological parameters: cardiomyocytes (alpha actinin, spontaneous beating), endothelial cells (CD31, tube formation), smooth muscle cells (alpha smooth muscle actin, stress fibers), fibroblasts (periostin, collagen-production). Beating multicellular human EHTs could be successfully produced and the survival of all cell types for several weeks was verified, quantified and visualized by flow cytometry and confocal microscopy. The first multicellular EHTs produced did not develop higher contractile forces than unicellular EHTs (containing only cardiomyocytes). Whether multicellular human EHTs respond differently to stress stimuli than unicellular EHTs, is still to be investigated.Conclusion: Multicellular human EHTs can be produced from color-coded hiPSCs and will enable the investigation of different cell compositions on contractility under basal and stressed conditions. Cell-type specific analyses will be possible following simple FACS-separation by color.
    ISSN: 0009-7322
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  • 3
    Language: English
    In: Blood, 12 April 2018, Vol.131(15), pp.1755-1758
    Keywords: Clonal Anergy ; Leukemia, Lymphocytic, Chronic, B-Cell -- Immunology ; Neoplasm Proteins -- Immunology ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 -- Immunology
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 4
    In: Brain, 2014, Vol. 137(8), pp.2312-2328
    Description: Increased neurogenesis has been reported in neurodegenerative disease, but its significance is unclear. In a mouse model of prion disease, Gomez-Nicola et al. detect increased neurogenesis in the dentate gyrus that partially counteracts neuronal loss. Targeting neurogenesis may have therapeutic potential. The study of neurogenesis during chronic neurodegeneration is crucial in order to understand the intrinsic repair mechanisms of the brain, and key to designing therapeutic strategies. In this study, using an experimental model of progressive chronic neurodegeneration, murine prion disease, we define the temporal dynamics of the generation, maturation and integration of new neurons in the hippocampal dentate gyrus, using dual pulse-chase, multicolour γ-retroviral tracing, transmission electron microscopy and patch-clamp. We found increased neurogenesis during the progression of prion disease, which partially counteracts the effects of chronic neurodegeneration, as evidenced by blocking neurogenesis with cytosine arabinoside, and helps to preserve the hippocampal function. Evidence obtained from human post-mortem samples, of both variant Creutzfeldt-Jakob disease and Alzheimer’s disease patients, also suggests increased neurogenic activity. These results open a new avenue into the exploration of the effects and regulation of neurogenesis during chronic neurodegeneration, and offer a new model to reproduce the changes observed in human neurodegenerative diseases.
    Keywords: Neural Stem Cells ; Adult Neurogenesis ; Alzheimer’s Disease ; Variant Cjd
    ISSN: 0006-8950
    E-ISSN: 1460-2156
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  • 5
    Language: English
    In: International Journal of Radiation Oncology, Biology, Physics, 15 March 2018, Vol.100(4), pp.1044-1056
    Description: To investigated the influence of radiation therapy (RT), surgery (OP), radio-chemotherapy (RChT), or chemotherapy (ChT) on small cell lung cancer metastases in 2 xenograft models. A total of 1 × 10 human small cell lung cancer cells (OH1, H69) were subcutaneously injected into severe combined immunodeficiency mice to form a local primary tumor node at the lower trunk. Radiation therapy, OP, RChT, or ChT were started after development of palpable tumors. Chemotherapy was given as a single intraperitoneal injection of cisplatin. Radiation therapy was 5 × 10 Gy on the local tumor node. Two additional groups were implemented to assess primary tumors and distant metastases in untreated mice at the beginning (control group A) and at the end of the experiment (control group B). Proapoptotic, antiproliferative, antiangiogenic, and hypoxic effects were assessed by Feulgen, Ki67, S1P1 receptor, and hypoxia-inducible factor 1α staining, respectively. Quantitative –polymerase chain reaction was used to determine circulating tumor cells in the blood, and disseminated tumor cells in the lungs, bone marrow, liver, and brain. In both xenograft models, RT and RChT abrogated local tumor growth, indicated by increased apoptosis, decreased cell proliferation, and reduced microvessel density (equally affecting vessels of all diameters). Regarding metastases, RT and RChT not only counteracted the time-dependent increase of dissemination but also decreased the metastatic load pre-existing at therapy induction in the blood, lungs, and liver. Only in the case of relapse-free surgery could similar effects be achieved by OP. Our models provide evidence that RT and RChT ablate the primary tumor and inhibit metastasis development over time. Upon local recurrence, RT showed beneficial effects compared with OP with regard to suppression of circulating tumor cells and disseminated tumor cells.
    Keywords: Medicine
    ISSN: 0360-3016
    E-ISSN: 1879-355X
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  • 6
    In: PLoS ONE, 2018, Vol.13(2)
    Description: Finding additional functional targets for combination therapy could improve the outcome for melanoma patients. In a spontaneous metastasis xenograft model of human melanoma a shRNA mediated knockdown of L1CAM more than sevenfold reduced the number of lung metastases after the induction of subcutaneous tumors for two human melanoma cell lines (MeWo, MV3). Whole genome expression arrays of the initially L1CAM high MeWo subcutaneous tumors revealed unchanged or downregulated genes involved in epithelial to mesenchymal transition (EMT) except an upregulation of Jagged 1, indicating a compensatory change in Notch signaling especially as Jagged 1 expression showed an increase in MeWo L1CAM metastases and Jagged 1 was expressed in metastases of the initially L1CAM low MV3 cells as well. Expression of 17 genes showed concordant regulation for L1CAM knockdown tumors of both cell lines. The changes in gene expression indicated changes in the EMT network of the melanoma cells and an increase in p53/p21 and p38 activity contributing to the reduced metastatic potential of the L1CAM knockdowns. Taken together, these data make L1CAM a highly interesting therapeutic target to prevent further metastatic spread in melanoma patients.
    Keywords: Research Article ; Research And Analysis Methods ; Medicine And Health Sciences ; Medicine And Health Sciences ; Medicine And Health Sciences ; Medicine And Health Sciences ; Biology And Life Sciences ; Medicine And Health Sciences ; Biology And Life Sciences ; Research And Analysis Methods
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: Molecular Therapy, May 2015, Vol.23, pp.S256-S256
    Keywords: Medicine ; Biology
    ISSN: 1525-0016
    E-ISSN: 1525-0024
    Source: ScienceDirect Journals (Elsevier)
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  • 8
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(4), p.e92327
    Description: Metastasis formation is the major reason for the extremely poor prognosis in small cell lung cancer (SCLC) patients. The molecular interaction partners regulating metastasis formation in SCLC are largely unidentified, however, from other tumor entities it is known that tumor cells use the adhesion molecules of the leukocyte adhesion cascade to attach to the endothelium at the site of the future metastasis. Using the human OH-1 SCLC line as a model, we found that these cells expressed E- and P-selectin binding sites, which could be in part attributed to the selectin binding carbohydrate motif sialyl Lewis A. In addition, protein backbones known to carry these glycotopes in other cell lines including PSGL-1, CD44 and CEA could be detected in in vitro and in vivo grown OH1 SCLC cells. By intravital microscopy of murine mesenterial vasculature we could capture SCLC cells while rolling along vessel walls demonstrating that SCLC cells mimic leukocyte rolling behavior in terms of selectin and selectin ligand interaction in vivo indicating that this mechanism might indeed be important for SCLC cells to seed distant metastases. Accordingly, formation of spontaneous distant metastases was reduced by 50% when OH-1 cells were xenografted into E-/P-selectin-deficient mice compared with wild type mice (p = 0.0181). However, as metastasis formation was not completely abrogated in selectin deficient mice, we concluded that this adhesion cascade is redundant and that other molecules of this cascade mediate metastasis formation as well. Using several of these adhesion molecules as interaction partners presumably make SCLC cells so highly metastatic.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 9
    In: Scientific Reports, 2014, Vol.4
    Description: In neuroscience it is a technical challenge to identify and follow the temporal and spatial distribution of cells as they differentiate. We hypothesised that RGB marking, the tagging of individual cells with unique hues resulting from simultaneous expression of the three basic colours red, green and blue, provides a convenient toolbox for the study of the CNS anatomy at the single-cell level. Using γ-retroviral and lentiviral vector sets we describe for the first time the in-vivo multicolour RGB marking of neurons in the adult brain. RGB marking also enabled us to track the spatial and temporal fate of neural stem cells in the adult brain. The application of different viral envelopes and promoters provided a useful approach to track the generation of neurons vs. glial cells at the neurogenic niche, allowing the identification of the prominent generation of new astrocytes to the striatum. Multicolour RGB marking could serve as a universal and reproducible method to study and manipulate the CNS at the single-cell level, in both health and disease.
    Keywords: Biology;
    ISSN: 20452322
    E-ISSN: 20452322
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  • 10
    In: Scientific Reports, 2014, Vol.4
    Description: TAL-effector nucleases (TALENs) are attractive tools for sequence-specific genome modifications, but their delivery still remains problematic. It is well known that the presence of multiple sequence repeats in TALEN genes hampers the use of lentiviral vectors. We report that lentiviral vectors readily package full-length vector mRNAs encoding TALENs, but recombination during reverse transcription prevents successful delivery. We reasoned that preventing reverse transcription of lentiviral-vector RNA would allow transfer of TALENs as mRNA. We demonstrate that lentiviral particles containing genetically inactivated reverse transcriptase (RT) mediated efficient transduction of cultured cells and supported transient transgene expression. For proof-of-principle, we transferred CCR5- and TCR-specific TALEN pairs for efficient targeted genome editing and abrogated expression for each of the receptor proteins in different cell lines. Combining the high specificity of TALENs with efficient lentiviral gene delivery should advance genome editing in vitro and potentially in vivo, and RT-deficient lentiviral vectors may be useful for transient expression of various other genes-of-interest.
    Keywords: Genomes ; RNA-Directed DNA Polymerase ; Ccr5 Protein ; Nucleotide Sequence ; T-Cell Receptor ; Genomes ; Expression Vectors ; Reverse Transcription ; Recombination ; Cell Lines ; Gene Transfer;
    ISSN: 20452322
    E-ISSN: 20452322
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