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1
Rutka, James T., Masaji Murakami, Peter B. Dirks, Sherri Lynn Hubbard, Laurence E. Becker, Kozo Fukuyama, Shin Jung, and Kazuhito Matsuzawa. "Role of glial filaments in cells and tumors of glial origin: a review." Neurosurgical Focus 3, no. 1 (July 1997): E2. http://dx.doi.org/10.3171/foc.1997.3.1.2.
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In the adult human brain, normal astrocytes constitute nearly 40% of the total central nervous system (CNS) cell population and may assume a star-shaped configuration resembling epithelial cells insofar as the astrocytes remain intimately associated, through their cytoplasmic extensions, with the basement membrane of the capillary endothelial cells and the basal lamina of the glial limitans externa. Although their exact function remains unknown, in the past, astrocytes were thought to subserve an important supportive role for neurons, providing a favorable ionic environment, modulating extracellular levels of neurotransmitters, and serving as spacers that organize neurons. In immunohistochemical preparations, normal, reactive, and neoplastic astrocytes may be positively identified and distinguished from other CNS cell types by the expression of the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). This GFAP is a 50-kD intracytoplasmic filamentous protein that constitutes a portion of, and is specific for, the cytoskeleton of the astrocyte. This protein has proved to be the most specific marker for cells of astrocytic origin under normal and pathological conditions. Interestingly, with increasing astrocytic malignancy, there is progressive loss of GFAP production. As the human gene for GFAP has now been cloned and sequenced, this review begins with a summary of the molecular biology of GFAP including the proven utility of the GFAP promoter in targeting genes of interest to the CNS in transgenic animals. Based on the data provided the authors argue cogently for an expanded role of GFAP in complex cellular events such as cytoskeletal reorganization, maintenance of myelination, cell adhesion, and signaling pathways. As such, GFAP may not represent a mere mechanical integrator of cellular space, as has been previously thought. Rather, GFAP may provide docking sites for important kinases that recognize key cellular substrates that enable GFAP to form a dynamic continuum with microfilaments, integrin receptors, and the extracellular matrix.
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Rutka, James T., Masaji Murakami, Peter B. Dirks, Sherri Lynn Hubbard, Laurence E. Becker, Kozo Fukuyama, Shin Jung, Atsushi Tsugu, and Kazuhito Matsuzawa. "Role of glial filaments in cells and tumors of glial origin: a review." Journal of Neurosurgery 87, no. 3 (September 1997): 420–30. http://dx.doi.org/10.3171/jns.1997.87.3.0420.
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✓ In the adult human brain, normal astrocytes constitute nearly 40% of the total central nervous system (CNS) cell population and may assume a star-shaped configuration resembling epithelial cells insofar as the astrocytes remain intimately associated, through their cytoplasmic extensions, with the basement membrane of the capillary endothelial cells and the basal lamina of the glial limitans externa. Although their exact function remains unknown, in the past, astrocytes were thought to subserve an important supportive role for neurons, providing a favorable ionic environment, modulating extracellular levels of neurotransmitters, and serving as spacers that organize neurons. In immunohistochemical preparations, normal, reactive, and neoplastic astrocytes may be positively identified and distinguished from other CNS cell types by the expression of the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). Glial fibrillary acidic protein is a 50-kD intracytoplasmic filamentous protein that constitutes a portion of, and is specific for, the cytoskeleton of the astrocyte. This protein has proved to be the most specific marker for cells of astrocytic origin under normal and pathological conditions. Interestingly, with increasing astrocytic malignancy, there is progressive loss of GFAP production. As the human gene for GFAP has now been cloned and sequenced, this review begins with a summary of the molecular biology of GFAP including the proven utility of the GFAP promoter in targeting genes of interest to the CNS in transgenic animals. Based on the data provided the authors argue cogently for an expanded role of GFAP in complex cellular events such as cytoskeletal reorganization, maintenance of myelination, cell adhesion, and signaling pathways. As such, GFAP may not represent a mere mechanical integrator of cellular space, as has been previously thought. Rather, GFAP may provide docking sites for important kinases that recognize key cellular substrates that enable GFAP to form a dynamic continuum with microfilaments, integrin receptors, and the extracellular matrix.
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Gasque, Philippe, Jane Jones, Sim K. Singhrao, and B. Morgan. "Identification of an Astrocyte Cell Population from Human Brain that Expresses Perforin, a Cytotoxic Protein Implicated in Immune Defense." Journal of Experimental Medicine 187, no. 4 (February 16, 1998): 451–60. http://dx.doi.org/10.1084/jem.187.4.451.
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The brain is an immunoprivileged organ isolated from the peripheral immune system. However, it has been shown that resident cells, notably astrocytes and microglia, can express numerous innate immune molecules, providing the capacity to generate a local antipathogen system. Perforin is a cytolytic protein present in the granules of cytotoxic T lymphocytes and natural killer cells. Expression in cells other than those of the hemopoetic lineage has not been described. We report here that fetal astrocytes in culture (passages 2 to 15), astrocytoma, and adult astrocytes expressed perforin. Reverse transcriptase polymerase chain reaction followed by Southern blot was carried out using multiple specific primers and all cDNAs were cloned and sequenced. Human fetal astrocyte perforin cDNA sequence was ∼100% identical to the reported perforin cDNA cloned from T cells. Western blot analysis using monoclonal and polyclonal antiperforin peptide antibodies revealed a protein of 65 kD in both human fetal astrocyte and rat natural killer cell lysates (n = 4). Immunostaining followed by FACS® and confocal and electron microscopy analysis revealed that perforin was expressed by 40–50% of glial fibrillary acidic protein positive cells present in the fetal brain culture (n = 11). Perforin was not localized to granules in astrocytes but was present throughout the cytoplasm, probably in association with the endoplasmic reticulum. Perforin was not detected in normal adult brain tissue but was present in and around areas of inflammation (white and grey matter) in multiple sclerosis and neurodegenerative brains. Perforin-positive cells were identified as reactive astrocytes. These findings demonstrate that perforin expression is not unique to lymphoid cells and suggest that perforin produced by a subpopulation of astrocytes plays a role in inflammation in the brain.
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Gasque, Philippe, Sim K. Singhrao, Jim W. Neal, Piao Wang, Sakina Sayah, Marc Fontaine, and B. Paul Morgan. "The Receptor for Complement Anaphylatoxin C3a Is Expressed by Myeloid Cells and Nonmyeloid Cells in Inflamed Human Central Nervous System: Analysis in Multiple Sclerosis and Bacterial Meningitis." Journal of Immunology 160, no. 7 (April 1, 1998): 3543–54. http://dx.doi.org/10.4049/jimmunol.160.7.3543.
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Abstract The complement anaphylatoxins C5a and C3a are released at the inflammatory site, where they contribute to the recruitment and activation of leukocytes and the activation of resident cells. The distribution of the receptor for C5a (C5aR) has been well studied; however, the receptor for C3a (C3aR) has only recently been cloned, and its distribution is uncharacterized. Using a specific affinity-purified anti-C3aR peptide Ab and oligonucleotides for reverse transcriptase-PCR analysis, C3aR expression was characterized in vitro on myeloid and nonmyeloid cells and in vivo in the brain. C3aR was expressed by adult astrocytes, astrocyte cell lines, monocyte lines THP1 and U937, neutrophils, and monocytes, but not by K562 or Ramos. C3aR staining was confirmed by flow cytometry, confocal imaging, and electron microscopy analysis. A 65-kDa protein was immunoprecipitated by the anti-C3aR from astrocyte and monocyte cell lysates. Our results at the protein level were confirmed at the mRNA level. Using reverse transcriptase-PCR, Southern blot, and sequencing we found that C3aR mRNA was expressed by fetal astrocytes, astrocyte cell lines, and THP1, but not by K562 or Ramos. The astrocyte C3aR cDNA was identical with the reported C3aR cDNA. C3aR expression was not detected in normal brain sections. However, a strong C3aR staining was evident in areas of inflammation in multiple sclerosis and bacterial meningitis. In meningitis, C3aR was abundantly expressed by reactive astrocytes, microglia, and infiltrating cells (macrophages and neutrophils). In multiple sclerosis, infiltrating lymphocytes did not express C3aR, but a strong staining was detected on smooth muscle cells (pericytes) surrounding blood vessels.
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Kurihara, Toshihide, Peter D. Westenskow, Tim U. Krohne, Edith Aguilar, Randall S. Johnson, and Martin Friedlander. "Astrocyte pVHL and HIF-α isoforms are required for embryonic-to-adult vascular transition in the eye." Journal of Cell Biology 195, no. 4 (November 14, 2011): 689–701. http://dx.doi.org/10.1083/jcb.201107029.
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Successful transition from embryonic to adult circulation is critical for survival of mammalian organisms. This shift occurs in the central cardiovascular circulation and in the eye as oxygen tension increases. However, its regulation is not well understood. We have used combinatorial gene deletion and overexpression assays to assess the effect of astrocyte-targeted deletion of von Hippel–Lindau tumor suppressor (Vhl), hypoxia-inducible factor-αs (Hif-αs), and Vegf on the normal regression of the hyaloidal vessels, the fetal ocular circulation system. Astrocytic Vhl deletion induced accelerated hyaloidal regression and subsequent massive secondary outgrowth. Combinatorial gene deletion involving Vhl, Hif-αs, and Vegf genes revealed that HIF-2α/vascular endothelial growth factor signaling induces secondary outgrowth in Vhl mutants. Conversely, HIF-1α regulated macrophage migration inhibitory factor and promoted macrophage infiltration that accelerates hyaloidal vessel regression. The phenotype observed in Vhl mutants strongly resembles human persistent hyperplastic primary vitreous cases and may provide insights into vascular remodeling mechanisms in other systems.
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Juul, Sandra E., Anthony T. Yachnis, Amyn M. Rojiani, and Robert D. Christensen. "Immunohistochemical Localization of Erythropoietin and Its Receptor in the Developing Human Brain." Pediatric and Developmental Pathology 2, no. 2 (March 1999): 148–58. http://dx.doi.org/10.1007/s100249900103.
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We have previously shown erythropoietin (Epo) and its receptor (Epo-R) to be present in the fetal human central nervous system (CNS), and Epo to be present in the spinal fluid of normal preterm and term infants. To investigate the cellular specificities and developmental patterns of expression of these polypeptides in the human brain—areas that have not been well researched—we designed the following study. Human brains ranging in maturity from 5 weeks post-conception to adult were preserved at the time of elective abortion, surgical removal (tubal pregnancy, or removal for temporal lobe epilepsy), or autopsy. Immunohistochemistry was used to localize Epo and Epo-R reactivity in brains of different stages of development. Astrocytes, neurons, and microglia were identified in sequential tissue sections by specific antibodies. At 5 to 6 weeks post-conception, both Epo and Epo-R localized to cells in the periventricular germinal zone. At 10 weeks post-conception, Epo immunoreactivity was present throughout the cortical wall, with the most intense immunoreactivity present in the ventricular and subventricular zones. Epo-R, in contrast, was localized primarily to the subventricular zone, with little staining evident in the ventricular zone. In late fetal brains, Epo-R reactivity was most prominent in astrocytic cells, although modest reactivity was observed in certain neuron populations. In contrast, Epo staining localized primarily to neurons in fetal brains, although a subpopulation of astrocytes was also immunoreactive. In postnatal brains, both astrocyte and neuron populations were immunoreactive with antibodies to Epo-R and Epo. From these results it is clear that Epo and its receptor are present in the developing human brain as early as 5 weeks post-conception, and each protein shows a specific distribution that changes with development. We speculate that Epo is important in neurodevelopment, and that it also plays a role in brain homeostasis later in life, functioning in an autocrine or paracrine manner.
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Nagai, Shoichi, Kazuo Washiyama, Masanori Kurimoto, Akira Takaku, Shunro Endo, and Toshiro Kumanishi. "Aberrant nuclear factor-κB activity and its participation in the growth of human malignant astrocytoma." Journal of Neurosurgery 96, no. 5 (May 2002): 909–17. http://dx.doi.org/10.3171/jns.2002.96.5.0909.
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Object. It has been suggested that nuclear factor (NF)-κB, a pleiotropic transcription factor, controls cell proliferation. The authors examined NF-κB activity and its participation in the growth of human malignant astrocytoma. Methods. The authors examined NF-κB activity in human malignant astrocytoma cell lines and high-grade astrocytoma tissues by using electrophoretic mobility shift assays and immunohistochemical studies, respectively. In addition, messenger (m)RNA expression of p50 and RelA, which are representative subunits of NF-κB, and IκBα, which is a representative inhibitory protein of NF-κB, were analyzed using Northern blot hybridization in the astrocytoma cell lines. Furthermore, alterations in DNA synthesis and cell growth in the astrocytoma cell lines were examined after inhibition of NF-κB activity by RelA antisense oligodeoxynucleotide. The authors found NF-κB activity in all astrocytoma cell lines and high-grade astrocytoma tissues that were examined, but not in the fetal astrocyte strain or in normal cerebral tissue. Expression of p50, RelA, and IκBα mRNA was found in the fetal astrocyte strain and normal adult brain tissue, in addition to the astrocytoma cell lines. The relative levels of expression of these mRNAs were similar among these cell lines, the cell strain, and normal tissue. The RelA antisense oligodeoxynucleotide specifically reduced the levels of RelA mRNA expression and NF-κB activity in the astrocytoma cell lines, thus significantly inhibiting their DNA synthesis and cell growth. Conclusions. Human malignant astrocytoma cells have aberrant NF-κB activity, which promotes their growth. This activity is not associated with aberrant expression of p50 and RelA.
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Couldwell, William T., Garnet Fraser, Genvieve De Vellis, Jack P. Antel, Jean-Guy Villemure, and Voon Wee Yong. "Malignant Glioma-Derived Soluble Factors Regulate Proliferation of Normal Adult Human Astrocytes." Journal of Neuropathology and Experimental Neurology 51, no. 5 (September 1992): 506–13. http://dx.doi.org/10.1097/00005072-199209000-00005.
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Tada, Mitsuhiro, Annie-Claire Diserens, Isabelle Desbaillets, and Nicolas de Tribolet. "Analysis of cytokine receptor messenger RNA expression in human glioblastoma cells and normal astrocytes by reverse-transcription polymerase chain reaction." Journal of Neurosurgery 80, no. 6 (June 1994): 1063–73. http://dx.doi.org/10.3171/jns.1994.80.6.1063.
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✓ To elucidate which cytokine receptors may be expressed by human glioblastoma and normal astrocytic cells, the presence of messenger ribonucleic acid (RNA) for a number of cytokine receptors was examined in 16 glioblastoma cell lines and adult and fetal astrocytes. A complementary deoxyribonucleic acid copy of total RNA was synthesized and amplified with specific primers using the polymerase chain reaction method. The receptors studied were interleukin (IL)-1 receptor type I (IL-1RI) and type II (IL-1RII), p75 and p55 tumor necrosis factor (TNF) receptors (p75TNFR and p55TNFR), interferon (IFN)-α/β and -γ receptors (IFN-α/βR and IFN-γR), granulocyte-macrophage (GM) colony-stimulating factors receptor α subunit (GM-CSFR), G-CSF receptor (G-CSFR), M-CSF receptor (c-fms, M-CSFR), stem cell factor receptor (c-kit, SCFR), IL-6 receptor (IL-6R), and IL-8 receptor (IL-8R). Transcripts for IL-1RI, p55TNFR, IFN-α/βR, and IFN-γR were present in all cell lines. The presence of IL-1RII, p75TNFR, GM-CSFR, M-CSFR, SCFR, IL-6R, and IL-8R was identified in 13, eight, seven, eight, 14, three, and one cell lines, respectively. Normal astrocytes were positive for IL-1RI, p75TNFR, p55TNFR, IFN-α/βR, IFN-γR, M-CSFR, and SCFR, showing a similarity to glioblastoma cells. Expression of IL-1RII was observed in adult astrocytes but not in fetal astrocytes. Furthermore, gene expression was assessed in normal brain tissue and 11 glioblastoma tissue specimens. The normal brain tissue expressed IL-lRI, IL-1RII, IFN-α/βR, M-CSFR, and SCFR. Of the 11 glioblastoma tissue specimens, IL-1RI was positive in 11, IL-1RII in 10, p75TNFR in nine, p55TNFR in nine, IFN-α/βR in 10, IFN-γR in 10, GM-CSFR in two, G-CSFR in three, IL-8R in eight, and M-CSFR and SCFR in 11. These expressions were consistent with those in the cell lines, except for IL-8R. It is concluded that glioblastoma cells and normal astrocytes express a similar set of cytokine receptor genes in vitro and in vivo. Possible autocrine loops are suggested for IL-1α/IL-1RI, TNF-α/p55TNFR, IFN-β/IFN-α/βR, M-CSF/M-CSFR, and SCF/SCFR in glioblastomas.
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González-Martínez, Jorge A., William E. Bingaman, Steven A. Toms, and Imad M. Najm. "Neurogenesis in the postnatal human epileptic brain." Journal of Neurosurgery 107, no. 3 (September 2007): 628–35. http://dx.doi.org/10.3171/jns-07/09/0628.
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Object The normal adult human telencephalon does not reveal evidence of spontaneous neuronal migration and differentiation despite the robust germinal capacity of the subventricular zone (SVZ) astrocyte ribbon that contains neural stem cells. This might be because it is averse to accepting new neurons into an established neuronal network, probably representing an evolutionary acquisition to prevent the formation of anomalous neuronal circuits. Some forms of epilepsy, such as malformations of cortical development, are thought to be due to abnormal corticogenesis during the embryonic and early postnatal periods. The role of postnatal architectural reorganization and possibly postnatal neurogenesis in some forms of epilepsy in humans remains unknown. In this study the authors used resected specimens of epileptic brain to determine whether neurogenesis could occur in the diseased tissue. Methods The authors studied freshly resected brain tissue obtained in 47 patients who underwent neurosurgical procedures and four autopsies. Forty-four samples were harvested in patients who underwent resection for the treatment of pharmacoresistant epilepsy. Results Using organotypic brain slice preparations cultured with 5-bromodeoxyuridine (a marker for cell proliferation), immunohistochemistry, and cell trackers, the authors demonstrate the presence of spontaneous cell proliferation, migration, and neuronal differentiation in the adult human telencephalon that starts in the SVZ and progresses to the adjacent white matter and neocortex in human neocortical pathological structures associated with epilepsy. No cell migration or neuronal differentiation was found in the control group. Conclusions The presence of spontaneous neurogenesis associated with some forms of human neocortical epilepsy may represent an erroneous and maladaptive mechanism for neuronal circuitry repair, or it may be an intrinsic part of the pathogenic process.
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Suresh, Rahul, Sophie Fiola, Jamie Beaulieu, and Roberto Diaz. "PATH-14. ALPHA CARDIAC ACTIN EXPRESSION IS OBSERVED IN AGGRESSIVE GLIOMA SUBTYPES AND GLIOBLASTOMA STEM CELLS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi117. http://dx.doi.org/10.1093/neuonc/noab196.466.
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Abstract BACKGROUND Alterations in actin subunit expression have previously been observed in multiple cancers. In glioblastoma (GBM), the expression of ACTC1 has been associated with a more invasive phenotype and with shorter survival. We sought to explore the diversity of actin subunit expression across glioma subtypes and patient derived glioblastoma stem cells (GSCs). METHODS Bioinformatic analysis of multiple glioma databases was performed to profile actin subunit (ACTA1, ACTA2, ACTC1, ACTG1, ACTG2, and ACTB) mRNA levels. Expression levels were also evaluated in normal brain in comparison to liver and heart tissue. Western blot was used to analyze protein expression in GSCs, surgical tissue and human fetal astrocytes. RESULTS The primary actin subunits expressed in normal brain are beta actin (ACTB) and gamma actin (ACTG1). RNA sequencing of tissue from multiple glioma subtypes or different brain regions reveals a global increase in ACTG1 and ACTB abundance in gliomas compared to normal brain. LGG-GCIMP high and LGG-co-deleted glioma subtypes have the lowest ACTC1 expression. LGG-GCIMP low (HR 9.75, P< 0.001), LGG-mesenchymal-like (HR11.1, P< 0.001), LGG-classic-like (HR10.96, P< 0.001) subtypes are associated with ACTC1 expression. ACTC1, ACTCB, and ACTG protein expression was observed in GSCs, freshly resected GBM tissue, and human fetal astrocytes. CONCLUSIONS Gliomas have a specific pattern of actin subunit expression that differs in actin subunit type and abundance when compared to normal adult brain. Expression of ACTC1 is found in aggressive glioma subtypes and is shared by GSCs and human fetal astrocytes. Investigation into the neurodevelopmental role of ACTC1 and its contribution to oncogenic transformation in GBM is warranted.
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Brodkey, Jason A., Eric D. Laywell, Thomas F. O'Brien, Andreas Faissner, Kari Stefansson, H. Ulrich Dörries, Melitta Schachner, and Dennis A. Steindler. "Focal brain injury and upregulation of a developmentally regulated extracellular matrix protein." Journal of Neurosurgery 82, no. 1 (January 1995): 106–12. http://dx.doi.org/10.3171/jns.1995.82.1.0106.
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✓ Tenascin is an extracellular matrix glycoprotein expressed during both normal development and neoplastic growth in both neural and nonneural tissues. During development of the central nervous system (CNS), tenascin is synthesized by glial cells, in particular by immature astrocytes, and is concentrated in transient boundaries around emerging groups of functionally distinct neurons. In the mature CNS, only low levels of the glycoprotein can be detected. The present study demonstrates that following trauma to the adult human cerebral cortex, discrete populations of reactive astrocytes upregulate their expression of tenascin and dramatically increase their transcription of the tenascin gene. The enhanced expression of tenascin may be involved in CNS wound healing, and may also affect neurite growth within and around a brain lesion.
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Khosla, Kanika, Christian C. Naus, and Wun Chey Sin. "Cx43 in Neural Progenitors Promotes Glioma Invasion in a 3D Culture System." International Journal of Molecular Sciences 21, no. 15 (July 23, 2020): 5216. http://dx.doi.org/10.3390/ijms21155216.
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The environment that envelops the cancer cells intimately affects the malignancy of human cancers. In the case of glioma, an aggressive adult brain cancer, its high rate of recurrence after total resection is responsible for a poor prognosis. Connexin43 (Cx43) is a gap junction protein with a prominent presence in glioma-associated normal brain cells, specifically in the reactive astrocytes. We previously demonstrated that elimination of Cx43 in these astrocytes reduces glioma invasion in a syngeneic mouse model. To further our investigation in human glioma cells, we developed a scaffold-free 3D platform that takes into account both the tumor and its interaction with the surrounding tissue. Using cell-tracking dyes and 3D laser scanning confocal microscopy, we now report that the elimination of Cx43 protein in neural progenitor spheroids reduced the invasiveness of human brain tumor-initiating cells, confirming our earlier observation in an intact mouse brain. By investigating the glioma invasion in a defined multicellular system with a tumor boundary that mimics the intact brain environment, our findings strengthen Cx43 as a candidate target for glioma control.
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Chiarini, Anna, Ubaldo Armato, Raffaella Pacchiana, and Ilaria Dal Pra. "Proteomic analysis of GTP cyclohydrolase 1 multiprotein complexes in cultured normal adult human astrocytes under both basal and cytokine-activated conditions." PROTEOMICS 9, no. 7 (April 2009): 1850–60. http://dx.doi.org/10.1002/pmic.200800561.
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Gladson, C. L., J. N. Wilcox, L. Sanders, G. Y. Gillespie, and D. A. Cheresh. "Cerebral microenvironment influences expression of the vitronectin gene in astrocytic tumors." Journal of Cell Science 108, no. 3 (March 1, 1995): 947–56. http://dx.doi.org/10.1242/jcs.108.3.947.
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Expression of the vitronectin gene was detected in advanced human astrocytoma by in situ hybridization, whereas vitronectin mRNA was undetectable in low grade tumors or in normal adult brain, indicating that vitronectin is a marker of malignant astrocytoma. We established a model of human astrocytoma by transplanting U-251MG human astrocytoma cells intracerebrally into acid mice (C.B.17 severe combined immunodeficient mice). In this model, tumors progressed rapidly and vitronectin mRNA was preferentially detected at the invading tumor margins, i.e. where tumor cells were adjacent to the normal brain tissue. Surprisingly, when U-251MG cells were injected subcutaneously into scid mice, vitronectin mRNA was undetectable throughout the tumor. Moreover, vitronectin mRNA or protein could not be detected among these cells in culture under a wide variety of growth conditions. These findings demonstrate that the cerebral microenvironment influences the expression of the vitronectin gene in malignant astrocytoma. Importantly, the vitronectin binding integrins alpha v beta 3 and alpha v beta 5 localized to distinct sites within these tumors, with beta 3 mRNA synthesized among invading cells, and alpha v and beta 5 mRNAs detected throughout the tumor. In vitro, both of these receptors were capable of promoting adhesion and invasion of astrocytoma cells on a vitronectin substratum. These findings implicate the expression of the vitronectin gene as a contributing factor to the biological behavior of astrocytomas within the cerebral microenvironment.
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Guo, Tangjun, Aijun Bao, Yandong Xie, Jianting Qiu, and Haozhe Piao. "Single-Cell Sequencing Analysis Identified ASTN2 as a Migration Biomarker in Adult Glioblastoma." Brain Sciences 12, no. 11 (October 30, 2022): 1472. http://dx.doi.org/10.3390/brainsci12111472.
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Glioblastoma is the most common and aggressive primary central nervous system malignant tumors. With the development of targeted sequencing and proteomic profiling technology, some new tumor types have been established and a series of novel molecular markers have also been identified. The 2021 updated World Health Organization classification of central nervous system tumors first mentioned the classification of adult glioma and pediatric glioma based on the molecular diagnosis. Thus, we used single-cell RNA sequencing analysis to explore the diversity and similarities in the occurrence and development of adult and pediatric types. ASTN2, which primarily encodes astrotactin, has been reported to be dysregulated in various neurodevelopmental disorders. Although some studies have demonstrated that ASTN2 plays an important role in glial-guided neuronal migration, there are no studies about its impact on glioblastoma cell migration. Subsequent single-cell RNA sequencing revealed ASTN2 to be a hub gene of a cell cluster which had a poor effect on clinical prognosis. Eventually, a western blot assay and a wound-healing assay first confirmed that ASTN2 expression in glioblastoma cell lines is higher than that in normal human astrocytes and affects the migration ability of glioblastoma cells, making it a potential therapeutic target.
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Yao, Li, Kimmy Tran, and Diana Nguyen. "Collagen Matrices Mediate Glioma Cell Migration Induced by an Electrical Signal." Gels 8, no. 9 (August 29, 2022): 545. http://dx.doi.org/10.3390/gels8090545.
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Glioma cells produce an increased amount of collagen compared with normal astrocytes. The increasing amount of collagen in the extracellular matrix (ECM) modulates the matrix structure and the mechanical properties of the microenvironment, thereby regulating tumor cell invasion. Although the regulation of tumor cell invasion mainly relies on cell–ECM interaction, the electrotaxis of tumor cells has attracted great research interest. The growth of glioma cells in a three-dimensional (3D) collagen hydrogel creates a relevant tumor physiological condition for the study of tumor cell invasion. In this study, we tested the migration of human glioma cells, fetal astrocytes, and adult astrocytes in a 3D collagen matrix with different collagen concentrations. We report that all three types of cells demonstrated higher motility in a low concentration of collagen hydrogel (3 mg/mL and 5 mg/mL) than in a high concentration of collagen hydrogel (10 mg/mL). We further show that human glioma cells grown in collagen hydrogels responded to direct current electric field (dcEF) stimulation and migrated to the anodal pole. The tumor cells altered their morphology in the gels to adapt to the anodal migration. The directedness of anodal migration shows a field strength-dependent response. EF stimulation increased the migration speed of tumor cells. This study implicates the potential role of an dcEF in glioma invasion and as a target of treatment.
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Shah, Farah, and Zhi Sheng. "Using PIK3CB and connexin-43 inhibition to sensitize pediatric glioblastoma cells to temozolomide." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e13572-e13572. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e13572.
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e13572 Background: Glioblastoma (GBM) is one of the most common high grade gliomas in pediatric patients, accounting for 2.8% of central nervous system tumors. Standard of care for glioblastoma includes surgical resection, radiation, and temozolomide chemotherapy. However, many pediatric patients are not suitable candidates for surgery, and their tumors inevitably develop temozolomide resistance. Despite aggressive treatment, temozolomide (TMZ) resistance leads to tumor recurrence in 90% of patients. Thus, outcome for children with pediatric GBM remains poor with a 2-year survival rate ranging from 10-30%, highlighting the need for new therapeutic approaches. Connexin-43 (Cx43) and PIK3CB are proteins involved in conferring temozolomide resistance in glioblastoma. Combined inhibition of these proteins could improve temozolomide sensitivity and help develop a selective therapy that significantly improves quality of life and prognosis in pediatric glioblastoma patients. Methods: Primary GBM cells were plated in a 96-well plate and treated with vehicle (DMSO), TMZ (50 μmol/L), TGX-221 (20 μmol/L), αCT1 (30 μmol/L), or a combination of the latter three drugs. Cell viability was measured using the MTS assay. Primary pediatric GBM cell lines SJ-GBM2 and CHLA-200 were tested. These drug combinations were also tested in normal human astrocytes to make sure there were no off-target effects. Results: We found that targeting PIK3CB and Cx43 in primary pediatric GBM increases their sensitivity to TMZ. The triple combination of TMZ, TGX-221, and αCT1 significantly decreased cell viability than each drug alone while sparing normal human astrocytes. Conclusions: Our findings suggest that inhibiting PIK3CB and Cx43 enhances therapeutic response to TMZ and limits off-target effects in pediatric GBM. These findings closely mirror our results using the triple combination in adult glioblastoma as well, thus laying the groundwork for a novel combination therapeutic that can be used across age groups.
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Kanemura, Yonehiro, Hayato Fukusumi, Yukako Handa, and Tomoko Shofuda. "DDIS-30. EVALUATION OF THE SUSCEPTIBILITY OF NEURONS DERIVED FROM HUMAN INDUCED PLURIPOTENT STEM CELLS TO ANTICANCER DRUGS FOR CNS TUMORS." Neuro-Oncology 21, Supplement_6 (November 2019): vi69—vi70. http://dx.doi.org/10.1093/neuonc/noz175.281.
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Abstract Various chemical substances, including pharmaceuticals, pose potential risks of inducing acute or delayed neurotoxicity in adults and causing developmental neurotoxicity in fetuses or children. To ensure the safety of chemical substances and drugs, neurotoxicity risk assessment is critical, and an appropriate evaluation platform for neurotoxicity is desired. At present, several anticancer reagents, including temozolomide, cisplatin, and etoposide, are used for treatment of high-grade astrocytic tumors or medulloblastomas. In comparison to lots of information about anti-tumor cells effects of these reagents, their neurotoxicity to normal neurons, especially human derived cells, have been poorly investigated because of the low accessibility of human central nervous system (CNS) tissues, the technical difficulties related to neuron isolation from adult human CNS tissues, and the higher ethical controversy surrounding the use of human CNS tissues and/or fetal cells compared to animal tissues or cells. In this study, to overcome these issues, we made human induced pluripotent stem cells derived neurons (hiPSC-neurons) for preparing alternative assay for in vitro test using primary human neuronal cells, and evaluated their susceptibility to six commonly used anticancer drugs (temozolomide, nimustine, cisplatin, etoposide, mercaptopurine, and methotrexate). Human iPSC-neurons were differentiated using 5-week monolayer culture from hiPSC-derived neural stem/progenitor cells (hiPSC-NSPCs) established by combination the dual SMAD inhibition method with neurosphere culture. In vitro cytotoxic effects of six drugs on hiPSC-neurons and their parental hiPSC-NSPCs were evaluated by ATP assay and immunocytostaining. The hiPSC-neurons were generally more resistant to the anticancer drugs than hiPSC-NSPCs, although a high dose of cisplatin decreased the levels of the neuronal marker protein ELAVL3/4 in the hiPSC-neurons after a 48-h drug treatment. These results suggest that our methodology is potentially applicable for efficient determination of the toxicity of any drug to hiPSC-neurons.
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Chiarini, Anna, Ubaldo Armato, Peng Hu, and Ilaria Dal Prà. "CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical Astrocytes." Cells 9, no. 6 (June 2, 2020): 1386. http://dx.doi.org/10.3390/cells9061386.
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Available evidence shows that human cortical neurons’ and astrocytes’ calcium-sensing receptors (CaSRs) bind Amyloid-beta (Aβ) oligomers triggering the overproduction/oversecretion of several Alzheimer’s disease (AD) neurotoxins—effects calcilytics suppress. We asked whether Aβ•CaSR signaling might also play a direct pro-neuroinflammatory role in AD. Cortical nontumorigenic adult human astrocytes (NAHAs) in vitro were untreated (controls) or treated with Aβ25–35 ± NPS 2143 (a calcilytic) and any proinflammatory agent in their protein lysates and growth media assayed via antibody arrays, enzyme-linked immunosorbent assays (ELISAs), and immunoblots. Results show Aβ•CaSR signaling upregulated the synthesis and release/shedding of proinflammatory interleukin (IL)-6, intercellular adhesion molecule-1 (ICAM-1) (holoprotein and soluble [s] fragment), Regulated upon Activation, normal T cell Expressed and presumably Secreted (RANTES), and monocyte chemotactic protein (MCP)-2. Adding NPS 2143 (i) totally suppressed IL-6′s oversecretion while remarkably reducing the other agents’ over-release; and (ii) more effectively than Aβ alone increased over controls the four agents’ distinctive intracellular accumulation. Conversely, NPS 2143 did not alter Aβ-induced surges in IL-1β, IL-3, IL-8, and IL-16 secretion, consequently revealing their Aβ•CaSR signaling-independence. Finally, Aβ25–35 ± NPS 2143 treatments left unchanged MCP-1′s and TIMP-2′s basal expression. Thus, NAHAs Aβ•CaSR signaling drove four proinflammatory agents’ over-release that NPS 2143 curtailed. Therefore, calcilytics would also abate NAHAs’ Aβ•CaSR signaling direct impact on AD’s neuroinflammation.
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Husemann, Jens, and Samuel C. Silverstein. "Expression of Scavenger Receptor Class B, Type I, by Astrocytes and Vascular Smooth Muscle Cells in Normal Adult Mouse and Human Brain and in Alzheimer’s Disease Brain." American Journal of Pathology 158, no. 3 (March 2001): 825–32. http://dx.doi.org/10.1016/s0002-9440(10)64030-8.
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Öz, Gülin, Elizabeth R. Seaquist, Anjali Kumar, Amy B. Criego, Luke E. Benedict, Jyothi P. Rao, Pierre-Gilles Henry, Pierre-Francois Van De Moortele, and Rolf Gruetter. "Human brain glycogen content and metabolism: implications on its role in brain energy metabolism." American Journal of Physiology-Endocrinology and Metabolism 292, no. 3 (March 2007): E946—E951. http://dx.doi.org/10.1152/ajpendo.00424.2006.
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The adult brain relies on glucose for its energy needs and stores it in the form of glycogen, primarily in astrocytes. Animal and culture studies indicate that brain glycogen may support neuronal function when the glucose supply from the blood is inadequate and/or during neuronal activation. However, the concentration of glycogen and rates of its metabolism in the human brain are unknown. We used in vivo localized 13C-NMR spectroscopy to measure glycogen content and turnover in the human brain. Nine healthy volunteers received intravenous infusions of [1-13C]glucose for durations ranging from 6 to 50 h, and brain glycogen labeling and washout were measured in the occipital lobe for up to 84 h. The labeling kinetics suggest that turnover is the main mechanism of label incorporation into brain glycogen. Upon fitting a model of glycogen metabolism to the time courses of newly synthesized glycogen, human brain glycogen content was estimated at ∼3.5 μmol/g, i.e., three- to fourfold higher than free glucose at euglycemia. Turnover of bulk brain glycogen occurred at a rate of 0.16 μmol·g−1·h−1, implying that complete turnover requires 3–5 days. Twenty minutes of visual stimulation ( n = 5) did not result in detectable glycogen utilization in the visual cortex, as judged from similar [13C]glycogen levels before and after stimulation. We conclude that the brain stores a substantial amount of glycogen relative to free glucose and metabolizes this store very slowly under normal physiology.
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Gangadharan, Achintyan, Yusha Sun, Cavan Bailey, Trever Carter, Alexsandra Espejo, Christopher Whitehead, Judith Leopold, and Joya Chandra. "DDRE-31. EVALUATION OF HIGHLY POTENT AND SELECTIVE SINGLE-MOLECULE DUAL EGFR/PI3K INHIBITORS IN ADULT AND PEDIATRIC HIGH-GRADE GLIOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii68. http://dx.doi.org/10.1093/neuonc/noaa215.276.
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Abstract High grade gliomas (HGG) carry poor prognosis with median survival rates under 15 months post diagnosis. Due to dysregulation of kinase signaling pathways within these tumors, targeted kinase inhibition has been considered as a promising clinical strategy. However in HGG, many single-agent inhibitors of EGFR or PI3K have shown limited response due to activation of compensatory signaling. Single-molecule multikinase inhibitors may decrease resistance, present a single pharmacokinetic dosage profile, and reduce risks of multi-agent toxicities, supporting this strategy over dual drug combination approaches. To test this concept, a panel of inhibitors exploiting known binding modes of structurally-related ATP binding site inhibitors of EGFR/PI3K were synthesized and characterized. Of these, MTX-241 was least likely to act as a substrate for drug efflux proteins such as P-glycoprotein. Treatment of MTX-241 in a panel of eight human adult and pediatric HGG lines showed strong cytotoxic potency measured by growth inhibitory activity, with IC50s in the < 10 µM range. Tumor selectivity of MTX-241 was observed, with normal human astrocytes (NHA) nearly insensitive to MTX-241 even at >100 µM. MTX-241 was significantly more potent than clinically relevant inhibitors targeting EGFR/RTKs (gefitinib, lapatinib, dasatinib, imatinib) or PI3K (alpelisib, idelalisib). Synthesis and evaluation of a new series of compounds based on MTX-241 structure, but optimized for improved stability is ongoing. Our data suggests that a dual inhibitor of EGFR and PI3K, represents a viable therapeutic strategy in adult and pediatric HGG. Future studies will focus on evaluation of in vivo efficacy in tumor bearing mouse models.
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Harris, Micah, Vivekanand Yadav, Stefanie Stallard, Rinette Woo, Robert Siddaway, Tingting Qin, Brendan Mullan, et al. "EXTH-47. THERAPEUTIC REVERSAL OF PRENATAL PONTINE ID1 SIGNALING IN DIPG." Neuro-Oncology 21, Supplement_6 (November 2019): vi92. http://dx.doi.org/10.1093/neuonc/noz175.379.
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Abstract Diffuse intrinsic pontine gliomas (DIPGs) are lethal brain tumors with no effective therapies other than radiation. Inhibitor of DNA binding (ID) proteins are key regulators of tissue and lineage-specific gene differentiation during embryogenesis. Previous work has shown that H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes, but this has not been validated in human DIPG, nor has the regulation and targetability of ID1 been explored in DIPG. Analysis of multi-focal post-mortem tumor and normal brain tissue (n=52) as well as multiple human datasets revealed ID1 to be elevated in DIPG. Elevated ID1 was found to correlate with reduced survival in DIPG. In a multi-focal autopsy DIPG case, we found ID1 expression to be heterogeneous and to correlate with tumor invasion. Chromatin immunoprecipitation-qPCR (ChIP-qPCR) was used to quantify H3K27ac and H3K27me3 at ID1 gene regulatory regions (promoters/enhancers) in multi-focal post-mortem tissue. The ID1 loci was found to be epigenetically poised for up-regulation (elevated H3K27ac and low H3K27me3) in DIPG tissue, regardless of H3 or ACVR1 mutation status, compared to normal brain. Analysis of publically-available ISH and ChIP-sequencing data revealed elevated ID1 expression and ID1-enhancer H3K27ac in prenatal mouse hindbrain compared to prenatal forebrain, prenatal midbrain, and all postnatal brain regions. ID1 shRNA-mediated knockdown of primary human H3K27M DIPG cells (DIPG007) resulted in significantly reduced invasion and migration. As cannabidiol (CBD) has successfully been used to therapeutically target ID1 in pre-clinical models of adult human cancers, we treated DIPG007 cells with CBD and found reduced viability at clinically relevant dosing (IC50=2.4 uM) with dose-dependent reduction in ID1 protein. ID1 knockdown and CBD treatment studies in murine models of DIPG are ongoing. These findings indicate that a multifactorial (genetic and regionally-based) epigenetic upregulation of ID1 drives DIPG invasiveness and is targetable with CBD.
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Schupp, Patrick, and Michael Oldham. "TAMI-22. VARIATION AMONG INTACT TISSUE SAMPLES REVEALS THE CORE TRANSCRIPTIONAL IDENTITIES OF CELL TYPES IN THE GLIOMA MICROENVIRONMENT." Neuro-Oncology 22, Supplement_2 (November 2020): ii218. http://dx.doi.org/10.1093/neuonc/noaa215.911.
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Abstract Adult low-grade gliomas generally progress to glioblastoma, a more aggressive CNS tumor with an extremely poor prognosis. Despite intensive efforts, numerous promising glioma therapies have failed to provide survival benefits. These failures reflect many factors, including intertumoral heterogeneity and immunosuppression by the tumor microenvironment (TME). We propose a novel approach to addresses these challenges through integrative deconvolution of bulk gene expression data generated from more than 5000 human gliomas and 7000 normal human brain samples. Inherent variation in the cellular composition and cellular activities of these samples allowed us to identify highly correlated modules of genes that represent specific cell types and cell states. By comparing gene coexpression modules in glioma vs. normal human brain, we have identified cell type-specific gene expression changes in the glioma TME that are highly reproducible. In contrast to single-cell methods, which sample only a fraction of the tumor tissue and fail to capture major nonmalignant cell-types, our results derive from billions of cells and thousands of individuals and are therefore highly robust. We find that a number of genes encoding cell-surface proteins are specifically up-regulated in immune and vascular cells of the glioma TME. Surprisingly, among those genes up-regulated in glioma vasculature are multiple members of the angiotensin pathway, suggesting non-canonical roles for these proteins in the glioma setting. We propose that these proteins may form a specific ‘zip code’ for glioma within the brain’s vasculature that can be targeted directly or by conjugation with existing drugs. More generally, our analytical approach has revealed reproducible gene expression changes in specific cell types of the glioma TME that provide more stable therapeutic targets than those that are expressed by genetically mutable malignant cells. We have also discovered novel, aberrantly coexpressed genes in microglia, oligodendrocytes, and astrocytes which we are testing in state-of-the-art human brain assembloid systems.
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Vannucci, Susan J., and Ian A. Simpson. "Developmental switch in brain nutrient transporter expression in the rat." American Journal of Physiology-Endocrinology and Metabolism 285, no. 5 (November 2003): E1127—E1134. http://dx.doi.org/10.1152/ajpendo.00187.2003.
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Normal development of both human and rat brain is associated with a switch in metabolic fuel from a combination of glucose and ketone bodies in the immature brain to a nearly total reliance on glucose in the adult. The delivery of glucose, lactate, and ketone bodies from the blood to the brain requires specific transporter proteins, glucose and monocarboxylic acid transporter proteins (GLUTs and MCTs), respectively. Developmental expression of the GLUTs in rat brain, i.e., 55-kDa GLUT1 in the blood-brain barrier (BBB), 45-kDa GLUT1 and GLUT3 in vascular-free brain, corresponds to maturational increases in cerebral glucose uptake and utilization. It has been suggested that MCT expression peaks during suckling and sharply declines thereafter, although a comparable detailed study has not been done. This study investigated the temporal and regional expression of MCT1 and MCT2 mRNA and protein in the BBB and the nonvascular brain during postnatal development in the rat. The results confirmed maximal MCT1 mRNA and protein expression in the BBB during suckling and a decline with maturation, coincident with the switch to glucose as the predominant cerebral fuel. However, nonvascular MCT1 and MCT2 levels do not reflect changes in cerebral energy metabolism, suggesting a more complex regulation. Although MCT1 assumes a predominantly glial expression in postweanling brain, the concentration remains fairly constant, as does that of MCT2 in neurons. The maintenance of nonvascular MCT levels in the adult brain implies a major role for these proteins, in concert with the GLUTs in both neurons and astrocytes, to transfer glycolytic intermediates during cerebral energy metabolism.
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Spatz, Jordan Matthew, Ming Ru Wu, Karen Weisinger, Tim Lu, and Manish Aghi. "3352 Surgical Adjuvant of Immunomodulatory Gene Circuits for Treatment of Glioblastoma." Journal of Clinical and Translational Science 3, s1 (March 2019): 155. http://dx.doi.org/10.1017/cts.2019.355.
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OBJECTIVES/SPECIFIC AIMS: Glioblastoma (GBM) is a brain cancer with a devastatingly short overall survival of under two years. The poor prognosis of GBM is largely due to cell invasion and maintenance of cancer initiating cells that evade the brain’s innate and adaptive immune responses which enables escape from surgical resection and drives inevitable recurrence. While targeting the brain’s immune microenvironment has long been proposed as a strategy for treating GBM, translational progress has been slow, underscoring the need to investigate the brain’s immune microenvironment for therapeutic avenues. METHODS/STUDY POPULATION: Recent advancements in tunable synthetic immunomodulatory gene circuits targeting metastatic cancers has demonstrated the novel ability to use engineering principles to induce infiltrative cancer cells to express combinatorial immunomodulatory outputs that enable T-cell killing4. Our central hypothesis is: we will be able to significantly improve survival with a lasting immune-mediated control of GBM by using synthetic immunomodulatory gene circuits driving GBM cells to express a local combination of immunomodulatory proteins: human IL15, a surface T-cell engager, PD-L1-CD3 bispecific antibody, and the protein, LIGHT (TNFRSF14). Importantly, the co-expression of LIGHT and anti-PD-L1 therapies was recently shown to rescue PD-L1 checkpoint blockage in the preclinical models of brain tumors and significant enhance survival outcomes highlighting the benefits of novel combinations of immunomodulatory proteins for treatment of GBM. To identify genes whose expression is dramatically upregulated in GBM compared to normal human brain cells, a pooled of six thousand lentiviral oncogene promoters that drive expression of a red-fluorescent protein has been infected into three human GBM cell lines. RESULTS/ANTICIPATED RESULTS: We have successfully infected our GBM cells and are preparing samples for next generation DNA sequencing to determine highly active promoters in GBM that are not expressed in multiple normal brain cells types, astrocytes and neurons. These chosen promoters will then be used to drive an AND gate logic gene circuit immunotherapy outputs which is currently under development for both in-vitro and in-vivo experiments. DISCUSSION/SIGNIFICANCE OF IMPACT: We anticipate that local expression of multiple immune effectors proteins will significantly enhance tumor control and survival in both synergistic murine and human-murine xenograft pre-clinical models of GBM. Ultimately, our goal is to rapidly translate this technology advance into the clinical trial for adult GBM patients.
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Bouvier, Corinne, Catherine Bartoli, Lucinda Aguirre-Cruz, Isabelle Virard, Carole Colin, Carla Fernandez, Joany Gouvernet, and Dominique Figarella-Branger. "Shared oligodendrocyte lineage gene expression in gliomas and oligodendrocyte progenitor cells." Journal of Neurosurgery 99, no. 2 (August 2003): 344–50. http://dx.doi.org/10.3171/jns.2003.99.2.0344.
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Object. Gliomas (astrocytic and oligodendroglial) are the most frequently occurring primary neoplasms in the central nervous system (CNS). Histological classification, which can be performed to distinguish astrocytomas from oligodendrogliomas, is essentially based on pathological features and has great prognostic and therapeutic value but lacks reproducibility. Specific markers of cell lineage, especially those for oligodendrogliomas, are still lacking. The oligodendrocyte lineage (OLIG) genes, transcriptional factors of the basic helix-loop-helix family, have been recently identified in oligodendrocyte progenitor cells (OPCs) in the CNS of developing and adult rodents. Data from a few studies have shown in a small series of brain tumors that OLIG genes characterize oligodendrogliomas. To search for a differential expression of the OLIG genes in subgroups of brain tumors, the authors investigated OLIG1 and OLIG2 gene expression. Methods. Using semiquantitative reverse transcription—polymerase chain reaction (RT-PCR), the authors analyzed a series of 89 tumors (71 astrocytic and oligodendroglial tumors, eight ependymomas, three medulloblastomas, four meningiomas, and three schwannomas) and normal human brain tissue samples. It was demonstrated that OLIG gene expression was largely limited to glial tumors, that is, astrocytomas and oligodendrogliomas. A very low level was detected in ependymomas, whereas other tumors lacked OLIG gene expression altogether. Surprisingly, OLIG1 and OLIG2 expression was not limited to oligodendroglial tumors, but was observed in astrocytic lesions as well, independent of tumor grade. Interestingly, these genes were expressed at the highest level in pilocytic astrocytomas according to semiquantitative RT-PCR results, which were confirmed on dot blot analysis. In situ hybridization showed that the OLIG2 gene was expressed by tumor cells in pilocytic astrocytomas as well as those in oligodendrogliomas. Conclusions. The OLIG genes are additional markers shared by all gliomas and OPCs. These markers may help to classify gliomas, to improve understanding of their histogenesis, and to identify new therapeutic targets.
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Mersich, Ian, and Biplab Dasgupta. "EXTH-40. THERAPEUTICALLY TARGETING DE NOVO PURINE BIOSYNTHESIS IN DIFFUSE INTRINSIC PONTINE GLIOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii95—ii96. http://dx.doi.org/10.1093/neuonc/noaa215.394.
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Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem malignancy in children with median survival less than 1 year and 5-year overall survival only 2 percent. Little progress has been made in treating this deadly disease due to its inoperable location and treatments aimed at targets defined in adult gliomas. Despite recent advances in genetic characterization of DIPGs there are still no targeted therapies that significantly improve overall survival. We recently generated a metabolic profile for DIPG elucidating an upregulation in purine metabolism, specifically in de novo purine biosynthesis (DNPB). Normally nucleotide salvage maintains cellular purine levels by recycling degraded bases, however DNPB is needed when purine levels are depleted. Purine metabolism provides the basic components of nucleotides needed for tumor proliferation and thus considered a high-priority target in cancer treatment. DNPB is a sequential ten step enzymatic process resulting in the production of inosine monophosphate. The last step in DNPB is carried out by the bifunctional enzyme ATIC which is upregulated in DIPG cell lines, and in patient tumors. Our preliminary data demonstrates DIPG cell lines are sensitive to pharmacological inhibition and genetic ablation of multiple enzymes in the DNPB pathway. Strikingly, cell viability could be rescued by purine supplementation when inhibiting this pathway except when ATIC is inhibited indicating the mechanism of cell death for ATIC inhibition is independent of purine nucleotide levels. Furthermore, there is a therapeutic window for targeting ATIC in DIPG cell lines relative to normal neural stem cells and normal human astrocytes. Metabolic flux experiments have demonstrated DNPB is upregulated in DIPG cell lines and the reason these cells are more sensitive to ATIC inhibition is likely related to the rapid accumulation of a cytotoxic metabolite upstream of ATIC. In vivo studies are currently underway in pre-clinical mouse models for DIPG.
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de Trizio, Ignazio, Mariella Errede, Antonio d'Amati, Francesco Girolamo, and Daniela Virgintino. "Expression of P-gp in Glioblastoma: What we can Learn from Brain Development." Current Pharmaceutical Design 26, no. 13 (May 6, 2020): 1428–37. http://dx.doi.org/10.2174/1381612826666200318130625.
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P-Glycoprotein (P-gp) is a 170-kDa transmembrane glycoprotein that works as an efflux pump and confers multidrug resistance (MDR) in normal tissues and tumors, including nervous tissues and brain tumors. In the developing telencephalon, the endothelial expression of P-gp, and the subcellular localization of the transporter at the luminal endothelial cell (EC) plasma membrane are early hallmarks of blood-brain barrier (BBB) differentiation and suggest a functional BBB activity that may complement the placental barrier function and the expression of P-gp at the blood-placental interface. In early fetal ages, P-gp has also been immunolocalized on radial glia cells (RGCs), located in the proliferative ventricular zone (VZ) of the dorsal telencephalon and now considered to be neural progenitor cells (NPCs). RG-like NPCs have been found in many regions of the developing brain and have been suggested to give rise to neural stem cells (NSCs) of adult subventricular (SVZ) neurogenic niches. The P-gp immunosignal, associated with RG-like NPCs during cortical histogenesis, progressively decreases in parallel with the last waves of neuroblast migrations, while ‘outer’ RGCs and the deriving astrocytes do not stain for the efflux transporter. These data suggest that in human glioblastoma (GBM), P-gp expressed by ECs may be a negligible component of tumor MDR. Instead, tumor perivascular astrocytes may dedifferentiate and resume a progenitor-like P-gp activity, becoming MDR cells and contribute, together with perivascular P-gpexpressing glioma stem-like cells (GSCs), to the MDR profile of GBM vessels. In conclusion, the analysis of Pgp immunolocalization during brain development may contribute to identify the multiple cellular sources in the GBM vessels that may be involved in P-gp-mediated chemoresistance and can be responsible for GBM therapy failure and tumor recurrence.
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Pollack, Ian F., Margaret S. Randall, Matthew P. Kristofik, Robert H. Kelly, Robert G. Selker, and Frank T. Vertosick. "Response of malignant glioma cell lines to activation and inhibition of protein kinase C-mediated pathways." Journal of Neurosurgery 73, no. 1 (July 1990): 98–105. http://dx.doi.org/10.3171/jns.1990.73.1.0098.
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✓ To evaluate the role of protein kinase C-mediated pathways in the proliferation of malignant gliomas, this study examined the effect of a protein kinase C (PKC)-activating phorbol ester (12-O-tetradecanoyl-13-phorbol acetate or TPA) and a protein kinase C inhibitor (polymyxin B) on deoxyribonucleic acid (DNA) synthesis of malignant glioma cells in vitro. A serum-free chemically defined medium, MCDB 105, was employed for all studies. Two established human malignant glioma cell lines (T98G and U138), two rat glioma lines (9L and C6), and two low-passage human glioma lines (obtained from surgical specimens) were studied. With the exception of the C6 line, all tumors responded in a dose-dependent fashion to nanomolar concentrations of TPA with a median effective dose that varied from 0.5 ng/ml for the U138 glioma to 1 ng/ml for the T98G glioma. At optimal concentrations (5 to 10 ng/ml), TPA produced a two- to five-fold increase in the rate of DNA synthesis (p < 0.05) as assessed by incorporation of 3H-thymidine. However, TPA had no additive effect on the mitogenic response produced by epidermal growth factor (EGF) or platelet-derived growth factor (PDGF). Inhibition of PKC using the antibiotic polymyxin B (20 µg/ml) abolished the TPA-induced mitogenic response in the five responsive lines tested. In two tumors (U138 and 9L), polymyxin B also eliminated EGF-, PDGF-, and serum-induced DNA synthesis as well as abolishing baseline DNA synthesis. These cells remained viable, however, as assessed by trypan blue exclusion; after removal of polymyxin B from the medium, they were able to resume DNA synthesis in response to TPA and serum. In the three other tumors (T98G and the two low-passage human glioma lines), growth factor-induced and serum-induced DNA synthesis were inhibited by approximately 25% to 85%. It is concluded that PKC-mediated pathways affect DNA synthesis in the human malignant glial tumors studied. The response of the glioma cells to TPA is similar to the responses seen in fetal astrocytes, but differs significantly from those reported for normal adult glial cultures. Because the response of the 9L glioma to TPA is similar to the responses seen in the human tumors, the 9L rat glioma model may prove useful for examining the role of PKC-mediated pathways in controlling glioma growth in vivo.
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Nieto-Sampedro, Manuel. "Astrocyte mitogenic activity in aged normal and Alzheimer's human brain." Neurobiology of Aging 8, no. 3 (May 1987): 249–52. http://dx.doi.org/10.1016/0197-4580(87)90009-1.
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Will, John, Emily Thompson, Megan Harrigan, James Smyth, Zhi Sheng, Robert Gourdie, Harry Sontheimer, Johan Foster, and Samy Lamouille. "STEM-28. NANOPARTICLES ENCAPSULATING A CONNEXIN43 MIMETIC PEPTIDE LIMIT GLIOMA STEM CELL SURVIVAL AND GLIOBLASTOMA PROGRESSION." Neuro-Oncology 22, Supplement_2 (November 2020): ii202. http://dx.doi.org/10.1093/neuonc/noaa215.845.
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Abstract Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor in the US. The current treatment regimen for GBM still retains an alarmingly poor prognosis, with median survival of only 14.6 months. Failure to generate more effective treatment strategies is due to the infiltrative nature of GBM tumor cells, which hinders complete surgical resection, and cellular heterogeneity within GBM tumors, with a sub-population of glioma stem cells (GSCs) resistant to irradiation treatment and chemotherapeutic agents including temozolomide. As a result, all treated GBM patients will experience tumor recurrence, highlighting the need for novel approaches in targeting such refractory tumor cell populations to successfully treat GBM tumors and prevent recurrence. Using super resolution localization microscopy, we have identified that increased interaction of connexin43 (Cx43) with microtubules in GSCs confers tumorigenic behavior to these cells. We employed a Cx43 mimetic peptide named JM2 (juxtamembrane 2) that encompasses the microtubule binding sequence of the Cx43 carboxy-terminus. This peptide drug efficiently and specifically disrupts the interaction of Cx43 with microtubules and limits GSC survival, proliferation, and migration, without affecting normal human astrocytes. Next, we implemented the therapeutic strategy of JM2 encapsulation within biodegradable polymeric nanoparticles (NPs) to reduce administration frequency and patient discomfort, and increase peptide stability and activity. We confirmed sustained release of JM2 from these poly(lactic-co-glycolic) acid biodegradable NPs, and JM2 bioactivity through disruption of Cx43 interaction with microtubules. Administration of JM2-NPs inhibits GSC-derived neurosphere formation in vitro and patient GBM-derived organoid growth ex vivo. Finally, using an orthotopic xenograft brain tumor mouse model, we demonstrate in vivo that JM2-NPs significantly decrease the number of GSCs within brain tumors, and inhibit the formation of highly invasive GBM tumors. Our findings on generation of JM2-NPs to target GSC survival lays the foundation for future clinical trials in newly diagnosed GBM patients.
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Rzepka, Zuzanna, Jakub Rok, Michalina Respondek, Justyna Pawlik, Artur Beberok, Dorota Gryko, and Dorota Wrześniok. "Cobalamin Deficiency: Effect on Homeostasis of Cultured Human Astrocytes." Cells 8, no. 12 (November 24, 2019): 1505. http://dx.doi.org/10.3390/cells8121505.
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Cobalamin deficiency is an important health problem. The major non-hematological symptoms of hypocobalaminemia are nervous system disorders, but the molecular and cellular mechanisms underlying this phenomenon have not yet been fully explained. Increasing scientific evidence is stressing the pivotal role of astrocyte dysfunction in the pathogenesis of a wide range of neurological disorders. In light of the above, the aim of this study was to develop an in vitro model of cobalamin deficiency by optimizing the conditions of astrocyte culture in the presence of vitamin B12 antagonist, and then the model was used for multidirectional analysis of astrocyte homeostasis using image cytometry, immunoenzymatic and colorimetric assays, and fluorescence spectroscopy. Our results indicated that long-term incubation of normal human astrocytes with hydroxycobalamin(c-lactam) causes an increase of extracellular homocysteine level, a reduction of cell proliferation, and an accumulation of cells in the G2/M cell cycle phase. Moreover, we observed dramatic activation of caspases and an increase of catalase activity. Interestingly, we excluded extensive apoptosis and oxidative stress. The study provided significant evidence for astrocyte homeostasis disturbance under hypocobalaminemia, thus indicating an important element of the molecular mechanism of nervous system diseases related to vitamin B12 deficiency.
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NIELSEN, H. I., and P. DON. "Culture of normal adult human melanocytes*." British Journal of Dermatology 110, no. 5 (July 29, 2006): 569–80. http://dx.doi.org/10.1111/j.1365-2133.1984.tb04680.x.
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Goddard, Diane R., Rowena A. D. Bunning, and M. Nicola Woodroofe. "Astrocyte and endothelial cell expression of ADAM 17 (TACE) in adult human CNS." Glia 34, no. 4 (2001): 267–71. http://dx.doi.org/10.1002/glia.1060.
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Scolding, Neil. "Glial Precursor Cells in the Adult Human Brain." Neuroscientist 4, no. 4 (July 1998): 264–72. http://dx.doi.org/10.1177/107385849800400415.
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Oligodendrocytes, the glial cells responsible for laying down and maintaining myelin sheaths in the central nervous system, were first described only 75 years ago. The lineage of these cells, and its relationship with that of the second type of macroglia, the astrocyte, was much studied in vivo and in situ in the rodent over the next 60 years. In the early 1980s, progress in oligodendrocyte biology was markedly amplified by the application of tissue culture techniques–-not without some element of controversy, although this is now largely resolved. Oligodendrocytes have always been given more attention than many other cells as a consequence of their role as a key target in human demyelinating diseases; in fact, few studies of rodent oligodendrocytes fail to draw conclusions regarding multiple sclerosis. Now, however, techniques for studying human glia and their lineage more directly have emerged, and differences in rodent and human oligodendrocyte biology are becoming apparent. It is increasingly clear that some caution must accompany the uncritical extrapolation of rodent experimental data to human oligodendrocyte biology and, indeed, to human disease.
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Dobri, Ana-Maria, Elena Codrici, Ionela-Daniela Popescu, Lucian Albulescu, Emanuel Tudor Fertig, Ana-Maria Enciu, Cristiana Tanase, and Mihail E. Hinescu. "Low-Concentrations of Fatty Acids Induce an Early Increase in IL-8 Levels in Normal Human Astrocytes." Metabolites 12, no. 4 (April 6, 2022): 329. http://dx.doi.org/10.3390/metabo12040329.
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Fatty acids (FAs) have been shown to exhibit a pro-inflammatory response in various cell types, but astrocytes have been mostly overlooked. FAs, both saturated and unsaturated, have previously been shown to induce pro-inflammatory responses in astrocytes at high concentrations of hundreds of µg/mL. SSO (Sulfo-N-succinimidyl Oleate sodium), an inhibitor of FA translocase CD36, has been shown to prevent inflammation in the mouse brain by acting on local microglia and infiltrating monocytes. Our hypothesis was that SSO treatment would also impact astrocyte pro-inflammatory response to FA. In order to verify our assumption, we evaluated the expression of pro- and anti-inflammatory cytokines in normal human astrocyte cell culture pre-treated (or not) with SSO, and then exposed to low concentrations of both saturated (palmitic acid) and unsaturated (oleic acid) FAs. As a positive control for astrocyte inflammation, we used fibrillary amyloid. Neither Aβ 1–42 nor FAs induced CD36 protein expression in human astrocytes in cell culture At low concentrations, both types of FAs induced IL-8 protein secretion, and this effect was specifically inhibited by SSO pre-treatment. In conclusion, low concentrations of oleic acid are able to induce an early increase in IL-8 expression in normal human astrocytes, which is specifically downregulated by SSO.
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Tran, Meryssa, Georgios Batsios, Céline Taglang, Anne Marie Gillespie, Javad Nazarian, Sabine Mueller, and Pavithra Viswanath. "TAMI-40. PEDIATRIC H3K27M MUTANT GLIOMAS UNDERGO METABOLIC REPROGRAMMING THAT CAN BE LEVERAGED FOR NON-INVASIVE METABOLIC IMAGING." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi206—vi207. http://dx.doi.org/10.1093/neuonc/noab196.824.
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Abstract Diffuse midline gliomas (DMGs) are a universally lethal form of childhood cancer. The infiltrative nature of DMGs makes them difficult to visualize by conventional magnetic resonance imaging. Genomics studies indicate that DMGs are driven by unique histone H3K27M mutations that result in broad epigenetic dysregulation. Many of the resulting changes in gene expression have the potential to induce metabolic reprogramming, which has been identified as a hallmark of cancer. The goal of this study was to dissect metabolic reprogramming in preclinical DMG models in order to identify novel magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers that can be exploited for non-invasive imaging. First, we used 1H-MRS, which reports on steady-state metabolism, to examine H3K27M mutant SF7761 cells and H3 wild-type normal human astrocytes (NHA). Lactate, glutathione and phosphocholine, which are involved in glycolysis, redox and phospholipid metabolism respectively, were elevated in SF7761 cells relative to NHAs. Mechanistically, these metabolic alterations were associated with upregulation of key enzymes including hexokinase 2, glutamate cysteine ligase and choline kinase a. Importantly, in vivo 1H-MRS showed elevated lactate, glutathione and total choline (combined signal from choline, phosphocholine and glycerophosphocholine) in mice bearing orthotopic SF7761 tumors relative to tumor-free controls. We then examined alterations in dynamic metabolic pathways in our models. Using thermally-polarized 13C-MRS, we identified elevated production of [2-13C]-lactate from [2-13C]-glucose in SF7761 cells relative to NHAs. Hyperpolarized 13C-MRS is a method of enhancing the 13C-MR signal such that metabolic fluxes can be interrogated with high sensitivity. Hyperpolarized [1-13C]-pyruvate flux to [1-13C]-lactate non-invasively monitors glycolysis and is in clinical trials in adult glioma patients. Importantly, hyperpolarized [1-13C]-pyruvate metabolism to lactate was elevated in SF7761 cells relative to NHAs. Collectively, our studies suggest that H3K27M mutant DMGs undergo reprogramming of glucose, redox and phospholipid metabolism that can be leveraged for non-invasive 1H- and hyperpolarized 13C-MRS-based imaging.
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Allahyari, R. Vivian, Nicolette M. Heinsinger, Daniel Hwang, David A. Jaffe, Javad Rasouli, Stephanie Shiers, Samantha J. Thomas, Theodore J. Price, Abdolmohamad Rostami, and Angelo C. Lepore. "Response of Astrocyte Subpopulations Following Spinal Cord Injury." Cells 11, no. 4 (February 18, 2022): 721. http://dx.doi.org/10.3390/cells11040721.
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There is growing appreciation for astrocyte heterogeneity both across and within central nervous system (CNS) regions, as well as between intact and diseased states. Recent work identified multiple astrocyte subpopulations in mature brain. Interestingly, one subpopulation (Population C) was shown to possess significantly enhanced synaptogenic properties in vitro, as compared with other astrocyte subpopulations of adult cortex and spinal cord. Following spinal cord injury (SCI), damaged neurons lose synaptic connections with neuronal partners, resulting in persistent functional loss. We determined whether SCI induces an enhanced synaptomodulatory astrocyte phenotype by shifting toward a greater proportion of Population C cells and/or increasing expression of relevant synapse formation-associated genes within one or more astrocyte subpopulations. Using flow cytometry and RNAscope in situ hybridization, we found that astrocyte subpopulation distribution in the spinal cord did not change to a selectively synaptogenic phenotype following mouse cervical hemisection-type SCI. We also found that spinal cord astrocytes expressed synapse formation-associated genes to a similar degree across subpopulations, as well as in an unchanged manner between uninjured and SCI conditions. Finally, we confirmed these astrocyte subpopulations are also present in the human spinal cord in a similar distribution as mouse, suggesting possible conservation of spinal cord astrocyte heterogeneity across species.
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Essbaiheen, Fahad, Tarek Hegazi, and Lorne Rosenbloom. "The Normal Adult Human Internal Auditory Canal." Otology & Neurotology 38, no. 6 (July 2017): 904–6. http://dx.doi.org/10.1097/mao.0000000000001388.
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Gatzonis, S. "Dimensionality estimation of adult normal human EEG." Electroencephalography and Clinical Neurophysiology 103, no. 1 (July 1997): 158. http://dx.doi.org/10.1016/s0013-4694(97)88733-4.
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Innes, Jeffrey T., and Larry C. Carey. "Normal pancreatic dimensions in the adult human." American Journal of Surgery 167, no. 2 (February 1994): 261–63. http://dx.doi.org/10.1016/0002-9610(94)90088-4.
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Mohn, Tal C., and Andrew O. Koob. "Adult Astrogenesis and the Etiology of Cortical Neurodegeneration." Journal of Experimental Neuroscience 9s2 (January 2015): JEN.S25520. http://dx.doi.org/10.4137/jen.s25520.
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As more evidence points to a clear role for astrocytes in synaptic processing, synaptogenesis and cognition, continuing research on astrocytic function could lead to strategies for neurodegenerative disease prevention. Reactive astrogliosis results in astrocyte proliferation early in injury and disease states and is considered neuroprotective, indicating a role for astrocytes in disease etiology. This review describes the different types of human cortical astrocytes and the current evidence regarding adult cortical astrogenesis in injury and degenerative disease. A role for disrupted astrogenesis as a cause of cortical degeneration, with a focus on the tauopathies and synucleinopathies, will also be considered.
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Karpuk, Nikolay, Maria Burkovetskaya, and Tammy Kielian. "Neuroinflammation alters voltage-dependent conductance in striatal astrocytes." Journal of Neurophysiology 108, no. 1 (July 1, 2012): 112–23. http://dx.doi.org/10.1152/jn.01182.2011.
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Neuroinflammation has the capacity to alter normal central nervous system (CNS) homeostasis and function. The objective of the present study was to examine the effects of an inflammatory milieu on the electrophysiological properties of striatal astrocyte subpopulations with a mouse bacterial brain abscess model. Whole cell patch-clamp recordings were performed in striatal glial fibrillary acidic protein (GFAP)-green fluorescent protein (GFP)+ astrocytes neighboring abscesses at postinfection days 3 or 7 in adult mice. Cell input conductance ( Gi) measurements spanning a membrane potential ( Vm) surrounding resting membrane potential (RMP) revealed two prevalent astrocyte subsets. A1 and A2 astrocytes were identified by negative and positive Gi increments vs. Vm, respectively. A1 and A2 astrocytes displayed significantly different RMP, Gi, and cell membrane capacitance that were influenced by both time after bacterial exposure and astrocyte proximity to the inflammatory site. Specifically, the percentage of A1 astrocytes was decreased immediately surrounding the inflammatory lesion, whereas A2 cells were increased. These changes were particularly evident at postinfection day 7, revealing increased cell numbers with an outward current component. Furthermore, RMP was inversely modified in A1 and A2 astrocytes during neuroinflammation, and resting Gi was increased from 21 to 30 nS in the latter. In contrast, gap junction communication was significantly decreased in all astrocyte populations associated with inflamed tissues. Collectively, these findings demonstrate the heterogeneity of striatal astrocyte populations, which experience distinct electrophysiological modifications in response to CNS inflammation.
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Taniura, Seijiro, Hideki Kamitani, Takashi Watanabe, and Thomas E. Eling. "Transcriptional Regulation of Cyclooxygenase-1 by Histone Deacetylase Inhibitors in Normal Human Astrocyte Cells." Journal of Biological Chemistry 277, no. 19 (May 2002): 16823–30. http://dx.doi.org/10.1074/jbc.m200527200.
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MCKHANN, GUY. "Unique Astrocyte Ribbon in Adult Human Brain Contains Neural Stem Cells But Lacks Chain Migration." Neurosurgery 54, no. 5 (May 2004): N9. http://dx.doi.org/10.1227/01.neu.0000309634.00854.33.
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Sanai, Nader, Anthony D. Tramontin, Alfredo Quiñones-Hinojosa, Nicholas M. Barbaro, Nalin Gupta, Sandeep Kunwar, Michael T. Lawton, et al. "Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration." Nature 427, no. 6976 (February 2004): 740–44. http://dx.doi.org/10.1038/nature02301.
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Whittemore, Scott R., Joseph T. Neary, Naomi Kleitman, Henry R. Sanon, Adelaida Benigno, Roger P. Donahue, and Michael D. Norenberg. "Isolation and characterization of conditionally immortalized astrocyte cell lines derived from adult human spinal cord." Glia 10, no. 3 (March 1994): 211–26. http://dx.doi.org/10.1002/glia.440100308.
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Wang, Jing, Jia Li, Liping Chen, Zhenyu Fan, and Jilin Cheng. "MicroRNA-499 Suppresses the Growth of Hepatocellular Carcinoma by Downregulating Astrocyte Elevated Gene-1." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382092025. http://dx.doi.org/10.1177/1533033820920253.
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The aim of this study is to investigate the role of microRNA-499 (miR-499) in hepatocellular carcinoma tumor growth and the underlying molecular mechanisms. The expression of miR-499 was significantly decreased in hepatocellular carcinoma tissues compared with that in adjacent normal tissues. Furthermore, miR-499 overexpression in HEPG2 cell was related to the tumor growth in nude mice xenograft models. Likewise, miR-499 mimic or inhibitor decreased or accelerated cell proliferation, respectively. Mechanistically, miR-499 directly targeted the 3′- untranslated region of astrocyte elevated gene-1 and downregulate astrocyte elevated gene-1 expression. Restoration of astrocyte elevated gene-1 expression in hepatocellular carcinoma cells reversed the inhibitory effect of miR-499 on cell growth. In addition, astrocyte elevated gene-1 and miR-499 expression were inversely correlated in human and mice hepatocellular carcinoma tissues. Our study identified miR-499 as a tumor-suppressive miR in hepatocellular carcinoma, thus providing a candidate therapeutic target for the future diagnosis or treatment of hepatocellular carcinoma.