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      A Human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine

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          Abstract

          A high throughput histology (microTMA) platform was applied for testing drugs against tumors in a novel 3D heterotypic glioblastoma brain sphere (gBS) model consisting of glioblastoma tumor cells, iPSC-derived neurons, glial cells and astrocytes grown in a spheroid. The differential responses of gBS tumors and normal neuronal cells to sustained treatments with anti-cancer drugs temozolomide (TMZ) and doxorubicin (DOX) were investigated. gBS were exposed to TMZ or DOX over a 7-day period. Untreated gBS tumors increased in size over a 4-week culture period, however, there was no increase in the number of normal neuronal cells. TMZ (100 uM) and DOX (0.3 uM) treatments caused ~30% (P~0.07) and ~80% (P < 0.001) decreases in the size of the tumors, respectively. Neither treatment altered the number of normal neuronal cells in the model. The anti-tumor effects of TMZ and DOX were mediated in part by selective induction of apoptosis. This platform provides a novel approach for screening new anti-glioblastoma agents and evaluating different treatment options for a given patient.

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          Glioblastoma Model Using Human Cerebral Organoids

          SUMMARY We have developed a cancer model of gliomas in human cerebral organoids that allows direct observation of tumor initiation as well as continuous microscopic observations. We used CRISPR/Cas9 technology to target an HRasG12V-IRES-tdTomato construct by homologous recombination into the TP53 locus. Results show that transformed cells rapidly become invasive and destroy surrounding organoid structures, overwhelming the entire organoid. Tumor cells in the organoids can be orthotopically xenografted into immunodeficient NOD/SCID IL2RG−/− animals, exhibiting an invasive phenotype. Organoid-generated putative tumor cells show gene expression profiles consistent with mesenchymal subtype human glioblastoma. We further demonstrate that human-organoid-derived tumor cell lines or primary human-patient-derived glioblastoma cell lines can be transplanted into human cerebral organoids to establish invasive tumor-like structures. Our results show potential for the use of organoids as a platform to test human cancer phenotypes that recapitulate key aspects of malignancy.
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            Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials

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              A Human Brain Microphysiological System Derived from Induced Pluripotent Stem Cells to Study Neurological Diseases and Toxicity

              Summary Human in vitro models of brain neurophysiology are needed to investigate molecular and cellular mechanisms associated with neurological disorders and neurotoxicity. We have developed a reproducible iPSC-derived human 3D brain microphysiological system (BMPS), comprised of differentiated mature neurons and glial cells (astrocytes and oligodendrocytes) that reproduce neuronal-glial interactions and connectivity. BMPS mature over eight weeks and show the critical elements of neuronal function: synaptogenesis and neuron-to-neuron (e.g., spontaneous electric field potentials) and neuronal-glial interactions (e.g., myelination), which mimic the microenvironment of the central nervous system, rarely seen in vitro before. The BMPS shows 40% overall myelination after 8 weeks of differentiation. Myelin was observed by immunohistochemistry and confirmed by confocal microscopy 3D reconstruction and electron microscopy. These findings are of particular relevance since myelin is crucial for proper neuronal function and development. The ability to assess oligodendroglial function and mechanisms associated with myelination in this BMPS model provide an excellent tool for future studies of neurological disorders such as multiple sclerosis and other demyelinating diseases. The BMPS provides a suitable and reliable model to investigate neuron-neuroglia function as well as pathogenic mechanisms in neurotoxicology.
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                Author and article information

                Contributors
                simonplummer@micromatrices.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                5 February 2019
                5 February 2019
                2019
                : 9
                : 1407
                Affiliations
                [1 ]MicroMatrices Associates Ltd, Dundee, DD15JJ Scotland
                [2 ]ISNI 0000 0004 0397 2876, GRID grid.8241.f, Dundee University Imaging Facility, School of Life Sciences, University of Dundee, ; Dundee, DD1 5EH Scotland
                [3 ]ISNI 0000 0001 2176 1341, GRID grid.419236.b, PerkinElmer, ; 68 Elm Street, Hopkinton, Massachusetts 01748 USA
                [4 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Department of Neurosurgery, , Mayo Clinic College of Medicine, ; Jacksonville, FL USA
                [5 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Center for Alternatives to Animal Testing (CAAT), , Johns Hopkins University, ; 615 North Wolfe Street, Baltimore, MD 21205 USA
                [6 ]ISNI 0000 0001 0658 7699, GRID grid.9811.1, CAAT-Europe, University of Konstanz, ; Konstanz, Germany
                [7 ]ISNI 0000 0001 2165 4204, GRID grid.9851.5, Department of Physiology, , University of Lausanne, ; Lausanne, Switzerland
                Author information
                http://orcid.org/0000-0002-6526-2306
                http://orcid.org/0000-0003-1359-7689
                http://orcid.org/0000-0002-1224-573X
                Article
                38130
                10.1038/s41598-018-38130-0
                6363784
                30723234
                611a20cc-c15a-4920-be3a-93648b516685
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 22 August 2018
                : 19 December 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH);
                Award ID: CA183827
                Award ID: CA195503
                Award Recipient :
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