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Article ; Online: Comparative Transcriptomic Analysis of Cerebellar Astrocytes across Developmental Stages and Brain Regions.

Kwon, Wookbong / Choi, Dong-Joo / Yu, Kwanha / Williamson, Michael R / Murali, Sanjana / Ko, Yeunjung / Woo, Junsung / Deneen, Benjamin

International journal of molecular sciences

2024 Volume 25, Issue 2

Abstract: Astrocytes are the most abundant glial cell type in the central nervous system, and they play a crucial role in normal brain function. While gliogenesis and glial differentiation occur during perinatal cerebellar development, the processes that occur ... ...

Abstract	Astrocytes are the most abundant glial cell type in the central nervous system, and they play a crucial role in normal brain function. While gliogenesis and glial differentiation occur during perinatal cerebellar development, the processes that occur during early postnatal development remain obscure. In this study, we conducted transcriptomic profiling of postnatal cerebellar astrocytes at postnatal days 1, 7, 14, and 28 (P1, P7, P14, and P28), identifying temporal-specific gene signatures at each specific time point. Comparing these profiles with region-specific astrocyte differentially expressed genes (DEGs) published for the cortex, hippocampus, and olfactory bulb revealed cerebellar-specific gene signature across these developmental timepoints. Moreover, we conducted a comparative analysis of cerebellar astrocyte gene signatures with gene lists from pediatric brain tumors of cerebellar origin, including ependymoma and medulloblastoma. Notably, genes downregulated at P14, such as Kif11 and HMGB2, exhibited significant enrichment across all pediatric brain tumor groups, suggesting the importance of astrocytic gene repression during cerebellar development to these tumor subtypes. Collectively, our studies describe gene expression patterns during cerebellar astrocyte development, with potential implications for pediatric tumors originating in the cerebellum.
MeSH term(s)	Child ; Female ; Pregnancy ; Humans ; Astrocytes ; Gene Expression Profiling ; Brain ; Transcriptome ; Cerebellum ; Brain Neoplasms ; Cerebellar Neoplasms
Language	English
Publishing date	2024-01-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25021021
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Article ; Online: Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model.

Hatcher, Asante / Yu, Kwanha / Meyer, Jochen / Aiba, Isamu / Deneen, Benjamin / Noebels, Jeffrey L

The Journal of clinical investigation

2020 Volume 130, Issue 5, Page(s) 2286–2300

Abstract: Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmaco-resistant ... ...

Abstract	Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmaco-resistant epilepsies. Studies in immunodeficient xenograft models have identified local interneuron loss and excess glial glutamate release as chief contributors to network disinhibition, but how hyperexcitability in the peritumoral microenvironment evolves in an immunocompetent brain is unclear. We generated gliomas in WT mice via in utero deletion of key tumor suppressor genes and serially monitored cortical epileptogenesis during tumor infiltration with in vivo electrophysiology and GCAMP7 calcium imaging, revealing a reproducible progression from hyperexcitability to convulsive seizures. Long before seizures, coincident with loss of inhibitory cells and their protective scaffolding, gain of glial glutamate antiporter xCT expression, and reactive astrocytosis, we detected local Iba1+ microglial inflammation that intensified and later extended far beyond tumor boundaries. Hitherto unrecognized episodes of cortical spreading depolarization that arose frequently from the peritumoral region may provide a mechanism for transient neurological deficits. Early blockade of glial xCT activity inhibited later seizures, and genomic reduction of host brain excitability by deleting MapT suppressed molecular markers of epileptogenesis and seizures. Our studies confirmed xenograft tumor-driven pathobiology and revealed early and late components of tumor-related epileptogenesis in a genetically tractable, immunocompetent mouse model of glioma, allowing the complex dissection of tumor versus host pathogenic seizure mechanisms.
MeSH term(s)	Animals ; Brain/metabolism ; Brain/pathology ; Brain/physiopathology ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Brain Neoplasms/physiopathology ; CRISPR-Cas Systems ; Gene Deletion ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Glioblastoma/physiopathology ; Mice ; Mice, Knockout ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/pathology ; Neoplasms, Experimental/physiopathology ; Seizures/genetics ; Seizures/metabolism ; Seizures/pathology ; Seizures/physiopathology ; Synaptic Transmission
Language	English
Publishing date	2020-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI133316
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Article: 5-aminolevulinic acid, fluorescein sodium, and indocyanine green for glioma margin detection: analysis of operating wide-field and confocal microscopy in glioma models of various grades.

Belykh, Evgenii / Bardonova, Liudmila / Abramov, Irakliy / Byvaltsev, Vadim A / Kerymbayev, Talgat / Yu, Kwanha / Healey, Debbie R / Luna-Melendez, Ernesto / Deneen, Benjamin / Mehta, Shwetal / Liu, James K / Preul, Mark C

Frontiers in oncology

2023 Volume 13, Page(s) 1156812

Abstract: Introduction: Surgical resection remains the first-line treatment for gliomas. Several fluorescent dyes are currently in use to augment intraoperative tumor visualization, but information on their comparative effectiveness is lacking. We performed ... ...

Abstract	Introduction: Surgical resection remains the first-line treatment for gliomas. Several fluorescent dyes are currently in use to augment intraoperative tumor visualization, but information on their comparative effectiveness is lacking. We performed systematic assessment of fluorescein sodium (FNa), 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX), and indocyanine green (ICG) fluorescence in various glioma models using advanced fluorescence imaging techniques. Methods: Four glioma models were used: GL261 (high-grade model), GB3 (low-grade model), and an Results: Our systematic analysis showed that wide-field imaging of highly malignant gliomas is equally efficient with 5-ALA, FNa, and ICG, although FNa is associated with more false-positive staining of the normal brain. In low-grade gliomas, wide-field imaging cannot detect ICG staining, can detect FNa in only 50% of specimens, and is not sensitive enough for PpIX detection. With confocal imaging of low-intermediate grade glioma models, PpIX outperformed FNa. Discussion: Overall, compared to wide-field imaging, confocal microscopy significantly improved diagnostic accuracy and was better at detecting low concentrations of PpIX and FNa, resulting in improved tumor delineation. Neither PpIX, FNa, nor ICG delineated all tumor boundaries in studied tumor models, which emphasizes the need for novel visualization technologies and molecular probes to guide glioma resection. Simultaneous administration of 5-ALA and FNa with use of cellular-resolution imaging modalities may provide additional information for margin detection and may facilitate maximal glioma resection.
Language	English
Publishing date	2023-05-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1156812
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Article ; Online: Sox9 directs divergent epigenomic states in brain tumor subtypes.

Sardar, Debosmita / Chen, Hsiao-Chi / Reyes, Amanda / Varadharajan, Srinidhi / Jain, Antrix / Mohila, Carrie / Curry, Rachel / Lozzi, Brittney / Rajendran, Kavitha / Cervantes, Alexis / Yu, Kwanha / Jalali, Ali / Rao, Ganesh / Mack, Stephen C / Deneen, Benjamin

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 29, Page(s) e2202015119

Abstract: Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations; however, the molecular mechanisms responsible for these ... ...

Abstract	Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations; however, the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here, we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). Using our autochthonous mouse models, we found that Sox9 suppresses HGG growth and expands associated H3K27ac states, while promoting ZFTA-RELA (ZR
MeSH term(s)	Animals ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Carcinogenesis/genetics ; Ependymoma/genetics ; Ependymoma/pathology ; Epigenesis, Genetic ; Mice ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/pathology ; SOX9 Transcription Factor/genetics ; SOX9 Transcription Factor/physiology
Chemical Substances	SOX9 Transcription Factor ; Sox9 protein, mouse
Language	English
Publishing date	2022-07-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2202015119
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Article ; Online: In vivo functional characterization of EGFR variants identifies novel drivers of glioblastoma.

Yu, Kwanha / Kong, Kathleen / Lozzi, Brittney / Luna-Figueroa, Estefania / Cervantes, Alexis / Curry, Rachel / Mohila, Carrie A / Rao, Ganesh / Jalali, Ali / Mills, Gordon B / Scott, Kenneth L / Deneen, Benjamin

Neuro-oncology

2022 Volume 25, Issue 3, Page(s) 471–481

Abstract: Background: Glioblastoma is the most common and aggressive primary brain tumor. Large-scale sequencing initiatives have cataloged its mutational landscape in hopes of elucidating mechanisms driving this deadly disease. However, a major bottleneck in ... ...

Abstract	Background: Glioblastoma is the most common and aggressive primary brain tumor. Large-scale sequencing initiatives have cataloged its mutational landscape in hopes of elucidating mechanisms driving this deadly disease. However, a major bottleneck in harnessing this data for new therapies is deciphering "driver" and "passenger" events amongst the vast volume of information. Methods: We utilized an autochthonous, in vivo screening approach to identify driver, EGFR variants. RNA-Seq identified unique molecular signatures of mouse gliomas across these variants, which only differ by a single amino acid change. In particular, we identified alterations to lipid metabolism, which we further validated through an unbiased lipidomics screen. Results: Our screen identified A289I as the most potent EGFR variant, which has previously not been characterized. One of the mechanisms through which A289I promotes gliomagenesis is to alter cellular triacylglycerides through MTTP. Knockout of Mttp in mouse gliomas, reduces gliomagenesis in multiple models. Conclusions: EGFR variants that differ by a single amino acid residue differentially promote gliomagenesis. Among the identified mechanism that drives glioma growth include lipid metabolism through MTTP. Understanding triacylglyceride accumulation may present a prospective therapeutic pathway for this deadly disease.
MeSH term(s)	Mice ; Animals ; Glioblastoma/pathology ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Mice, Knockout ; Glioma/drug therapy ; Mutation ; Brain Neoplasms/drug therapy
Chemical Substances	ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2022-08-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1093/neuonc/noac215
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Zs.A 5307: Show issues

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Article ; Online: POT1 Regulates Proliferation and Confers Sexual Dimorphism in Glioma.

Jalali, Ali / Yu, Kwanha / Beechar, Vivek / Bosquez Huerta, Navish A / Grichuk, Anthony / Mehra, Deepika / Lozzi, Brittney / Kong, Kathleen / Scott, Kenneth L / Rao, Ganesh / Bainbridge, Matthew N / Bondy, Melissa L / Deneen, Benjamin

Cancer research

2021 Volume 81, Issue 10, Page(s) 2703–2713

Abstract: Germline POT1 mutations are found in a spectrum of cancers and confer increased risk. Recently, we identified a series of novel germline POT1 mutations that predispose carrier families to the development of glioma. Despite these strong associations, how ... ...

Abstract	Germline POT1 mutations are found in a spectrum of cancers and confer increased risk. Recently, we identified a series of novel germline POT1 mutations that predispose carrier families to the development of glioma. Despite these strong associations, how these glioma-associated POT1 mutations contribute to glioma tumorigenesis remains undefined. Here we show that POT1-G95C increases proliferation in glioma-initiating cells
MeSH term(s)	Animals ; Carcinogenesis/genetics ; Carcinogenesis/metabolism ; Carcinogenesis/pathology ; Cell Cycle ; Cell Proliferation ; Female ; Glioma/genetics ; Glioma/immunology ; Glioma/metabolism ; Glioma/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation ; Sex Characteristics ; Shelterin Complex ; Telomere-Binding Proteins/genetics ; Telomere-Binding Proteins/metabolism ; Transcriptome
Chemical Substances	POT1 protein, human ; Shelterin Complex ; Telomere-Binding Proteins
Language	English
Publishing date	2021-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-20-3755
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Article ; Online: Floor plate-derived sonic hedgehog regulates glial and ependymal cell fates in the developing spinal cord.

Yu, Kwanha / McGlynn, Sean / Matise, Michael P

Development (Cambridge, England)

2013 Volume 140, Issue 7, Page(s) 1594–1604

Abstract: Cell fate specification in the CNS is controlled by the secreted morphogen sonic hedgehog (Shh). At spinal cord levels, Shh produced by both the notochord and floor plate (FP) diffuses dorsally to organize patterned gene expression in dividing neural and ...

Abstract	Cell fate specification in the CNS is controlled by the secreted morphogen sonic hedgehog (Shh). At spinal cord levels, Shh produced by both the notochord and floor plate (FP) diffuses dorsally to organize patterned gene expression in dividing neural and glial progenitors. Despite the fact that two discrete sources of Shh are involved in this process, the individual contribution of the FP, the only intrinsic source of Shh throughout both neurogenesis and gliogenesis, has not been clearly defined. Here, we have used conditional mutagenesis approaches in mice to selectively inactivate Shh in the FP (Shh(FP)) while allowing expression to persist in the notochord, which underlies the neural tube during neurogenesis but not gliogenesis. We also inactivated Smo, the common Hh receptor, in neural tube progenitors. Our findings confirm and extend prior studies suggesting an important requirement for Shh(FP) in specifying oligodendrocyte cell fates via repression of Gli3 in progenitors. Our studies also uncover a connection between embryonic Shh signaling and astrocyte-mediated reactive gliosis in adults, raising the possibility that this pathway is involved in the development of the most common cell type in the CNS. Finally, we find that intrinsic spinal cord Shh signaling is required for the proper formation of the ependymal zone, the epithelial cell lining of the central canal that is also an adult stem cell niche. Together, our studies identify a crucial late embryonic role for Shh(FP) in regulating the specification and differentiation of glial and epithelial cells in the mouse spinal cord.
MeSH term(s)	Animals ; Body Patterning/genetics ; Cell Differentiation/genetics ; Embryo, Mammalian ; Ependyma/cytology ; Ependyma/embryology ; Ependyma/metabolism ; Gene Expression Regulation, Developmental ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism ; Hedgehog Proteins/physiology ; Mice ; Mice, Transgenic ; Neural Plate/embryology ; Neural Plate/metabolism ; Neurogenesis/genetics ; Neurogenesis/physiology ; Neuroglia/metabolism ; Neuroglia/physiology ; Notochord/embryology ; Notochord/metabolism ; Spinal Cord/embryology ; Spinal Cord/metabolism
Chemical Substances	Hedgehog Proteins ; Shh protein, mouse
Language	English
Publishing date	2013-04-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.090845
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Zs.MG 91: Show issues

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Article ; Online: PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis.

Yu, Kwanha / Lin, Chia-Ching John / Hatcher, Asante / Lozzi, Brittney / Kong, Kathleen / Huang-Hobbs, Emmet / Cheng, Yi-Ting / Beechar, Vivek B / Zhu, Wenyi / Zhang, Yiqun / Chen, Fengju / Mills, Gordon B / Mohila, Carrie A / Creighton, Chad J / Noebels, Jeffrey L / Scott, Kenneth L / Deneen, Benjamin

Nature

2020 Volume 578, Issue 7793, Page(s) 166–171

Abstract: Glioblastoma is a universally lethal form of brain cancer that exhibits an array of pathophysiological phenotypes, many of which are mediated by interactions with the neuronal ... ...

Abstract	Glioblastoma is a universally lethal form of brain cancer that exhibits an array of pathophysiological phenotypes, many of which are mediated by interactions with the neuronal microenvironment
MeSH term(s)	Animals ; Brain Neoplasms/enzymology ; Brain Neoplasms/pathology ; Carcinogenesis/genetics ; Carcinogenesis/metabolism ; Class I Phosphatidylinositol 3-Kinases/chemistry ; Class I Phosphatidylinositol 3-Kinases/genetics ; Class I Phosphatidylinositol 3-Kinases/metabolism ; Disease Models, Animal ; Glioblastoma/enzymology ; Glioblastoma/pathology ; Glypicans/metabolism ; Mice
Chemical Substances	GPC3 protein, mouse ; Glypicans ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137)
Language	English
Publishing date	2020-01-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-020-1952-2
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Article ; Online: Cooperative p16 and p21 action protects female astrocytes from transformation.

Kfoury, Najla / Sun, Tao / Yu, Kwanha / Rockwell, Nathan / Tinkum, Kelsey L / Qi, Zongtai / Warrington, Nicole M / McDonald, Peter / Roy, Anuradha / Weir, Scott J / Mohila, Carrie A / Deneen, Benjamin / Rubin, Joshua B

Acta neuropathologica communications

2018 Volume 6, Issue 1, Page(s) 12

Abstract: Mechanisms underlying sex differences in cancer incidence are not defined but likely involve dimorphism (s) in tumor suppressor function at the cellular and organismal levels. As an example, sexual dimorphism in retinoblastoma protein (Rb) activity was ... ...

Abstract	Mechanisms underlying sex differences in cancer incidence are not defined but likely involve dimorphism (s) in tumor suppressor function at the cellular and organismal levels. As an example, sexual dimorphism in retinoblastoma protein (Rb) activity was shown to block transformation of female, but not male, murine astrocytes in which neurofibromin and p53 function was abrogated (GBM astrocytes). Correlated sex differences in gene expression in the murine GBM astrocytes were found to be highly concordant with sex differences in gene expression in male and female GBM patients, including in the expression of components of the Rb and p53 pathways. To define the basis of this phenomenon, we examined the functions of the cyclin dependent kinase (CDK) inhibitors, p16, p21 and p27 in murine GBM astrocytes under conditions that promote Rb-dependent growth arrest. We found that upon serum deprivation or etoposide-induced DNA damage, female, but not male GBM astrocytes, respond with increased p16 and p21 activity, and cell cycle arrest. In contrast, male GBM astrocytes continue to proliferate, accumulate chromosomal aberrations, exhibit enhanced clonogenic cell activity and in vivo tumorigenesis; all manifestations of broad sex differences in cell cycle regulation and DNA repair. Differences in tumorigenesis disappeared when female GBM astrocytes are also rendered null for p16 and p21. These data elucidate mechanisms underlying sex differences in cancer incidence and demonstrate sex-specific effects of cytotoxic and targeted therapeutics. This has critical implications for lab and clinical research.
MeSH term(s)	Animals ; Astrocytes/drug effects ; Astrocytes/metabolism ; Cell Cycle/drug effects ; Cell Cycle/genetics ; Cell Survival/drug effects ; Cell Survival/genetics ; Cell Transformation, Neoplastic/drug effects ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Culture Media, Serum-Free/pharmacology ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/genetics ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Dose-Response Relationship, Drug ; Embryo, Mammalian ; Etoposide/pharmacology ; Female ; Flow Cytometry ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Expression Regulation, Neoplastic/genetics ; Glial Fibrillary Acidic Protein/metabolism ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Glioblastoma/physiopathology ; Karyotyping ; Male ; Mice ; Neurofibromin 1/deficiency ; Neurofibromin 1/genetics ; Phosphorylation ; Piperazines/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Pyridines/pharmacology ; RNA, Messenger/metabolism ; Retinoblastoma Protein/metabolism ; Serum/metabolism ; Sex Characteristics ; Transfection ; Tumor Cells, Cultured
Chemical Substances	Culture Media, Serum-Free ; Cyclin-Dependent Kinase Inhibitor p16 ; Cyclin-Dependent Kinase Inhibitor p21 ; Glial Fibrillary Acidic Protein ; Neurofibromin 1 ; Piperazines ; Protein Kinase Inhibitors ; Pyridines ; RNA, Messenger ; Retinoblastoma Protein ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; Etoposide (6PLQ3CP4P3) ; palbociclib (G9ZF61LE7G)
Language	English
Publishing date	2018-02-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-018-0513-5
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Article ; Online: Identification of diverse astrocyte populations and their malignant analogs.

John Lin, Chia-Ching / Yu, Kwanha / Hatcher, Asante / Huang, Teng-Wei / Lee, Hyun Kyoung / Carlson, Jeffrey / Weston, Matthew C / Chen, Fengju / Zhang, Yiqun / Zhu, Wenyi / Mohila, Carrie A / Ahmed, Nabil / Patel, Akash J / Arenkiel, Benjamin R / Noebels, Jeffrey L / Creighton, Chad J / Deneen, Benjamin

Nature neuroscience

2017 Volume 20, Issue 3, Page(s) 396–405

Abstract: Astrocytes are the most abundant cell type in the brain, where they perform a wide array of functions, yet the nature of their cellular heterogeneity and how it oversees these diverse roles remains shrouded in mystery. Using an intersectional ... ...

Abstract	Astrocytes are the most abundant cell type in the brain, where they perform a wide array of functions, yet the nature of their cellular heterogeneity and how it oversees these diverse roles remains shrouded in mystery. Using an intersectional fluorescence-activated cell sorting-based strategy, we identified five distinct astrocyte subpopulations present across three brain regions that show extensive molecular diversity. Application of this molecular insight toward function revealed that these populations differentially support synaptogenesis between neurons. We identified correlative populations in mouse and human glioma and found that the emergence of specific subpopulations during tumor progression corresponded with the onset of seizures and tumor invasion. In sum, we have identified subpopulations of astrocytes in the adult brain and their correlates in glioma that are endowed with diverse cellular, molecular and functional properties. These populations selectively contribute to synaptogenesis and tumor pathophysiology, providing a blueprint for understanding diverse astrocyte contributions to neurological disease.
MeSH term(s)	Aldehyde Dehydrogenase/metabolism ; Animals ; Astrocytes/metabolism ; Astrocytes/physiology ; Brain/metabolism ; Coculture Techniques ; Female ; Flow Cytometry ; Glioma/metabolism ; Glioma/physiopathology ; Humans ; Male ; Mice ; Mice, Transgenic ; Neurons/physiology ; Oxidoreductases Acting on CH-NH Group Donors ; Seizures/physiopathology ; Synapses/physiology ; Transcriptome
Chemical Substances	Aldehyde Dehydrogenase (EC 1.2.1.3) ; Oxidoreductases Acting on CH-NH Group Donors (EC 1.5.-) ; formyltetrahydrofolate dehydrogenase (EC 1.5.1.6)
Language	English
Publishing date	2017-02-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/nn.4493
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