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  • Immunohistochemistry
  • Nature Publishing Group (NPG)  (3)
  • American Chemical Society
  • Essen : Verl. Glückauf
  • 2015-2019
  • 2005-2009  (3)
  • 1985-1989
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  • 1
    Publikationsdatum: 2008-10-25
    Beschreibung: Glioblastoma (GBM) is a highly lethal brain tumour presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as a high-grade disease that typically harbours mutations in EGFR, PTEN and INK4A/ARF (also known as CDKN2A), and the secondary GBM subtype evolves from the slow progression of a low-grade disease that classically possesses PDGF and TP53 events. Here we show that concomitant central nervous system (CNS)-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with notable clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted TP53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as the expected PTEN mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives increased Myc protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of NSCs doubly null for p53 and Pten (p53(-/-) Pten(-/-)) as well as tumour neurospheres (TNSs) derived from this model. Myc also serves to maintain robust tumorigenic potential of p53(-/-) Pten(-/-) TNSs. These murine modelling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumour suppressor mutation profile in human primary GBM and establish Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051433/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051433/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Hongwu -- Ying, Haoqiang -- Yan, Haiyan -- Kimmelman, Alec C -- Hiller, David J -- Chen, An-Jou -- Perry, Samuel R -- Tonon, Giovanni -- Chu, Gerald C -- Ding, Zhihu -- Stommel, Jayne M -- Dunn, Katherine L -- Wiedemeyer, Ruprecht -- You, Mingjian J -- Brennan, Cameron -- Wang, Y Alan -- Ligon, Keith L -- Wong, Wing H -- Chin, Lynda -- DePinho, Ronald A -- 5P01CA95616/CA/NCI NIH HHS/ -- P01 CA095616/CA/NCI NIH HHS/ -- P01 CA095616-01A19003/CA/NCI NIH HHS/ -- R01 CA099041/CA/NCI NIH HHS/ -- R01 CA099041-05/CA/NCI NIH HHS/ -- R01CA99041/CA/NCI NIH HHS/ -- U01 CA84313/CA/NCI NIH HHS/ -- England -- Nature. 2008 Oct 23;455(7216):1129-33. doi: 10.1038/nature07443.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18948956" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Brain Neoplasms/genetics/*pathology ; *Cell Differentiation ; Cell Proliferation ; Gene Expression Regulation ; Glioblastoma/genetics/pathology ; Glioma/genetics/*pathology ; Humans ; Immunohistochemistry ; Mice ; Neoplastic Stem Cells/metabolism/*pathology ; Neurons/metabolism/*pathology ; PTEN Phosphohydrolase/genetics/*metabolism ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
    Publikationsdatum: 2008-10-14
    Beschreibung: Although the cochlea is an amplifier and a remarkably sensitive and finely tuned detector of sounds, it also produces conspicuous mechanical and electrical waveform distortions. These distortions reflect nonlinear mechanical interactions within the cochlea. By allowing one tone to suppress another (masking effect), they contribute to speech intelligibility. Tones can also combine to produce sounds with frequencies not present in the acoustic stimulus. These sounds compose the otoacoustic emissions that are extensively used to screen hearing in newborns. Because both cochlear amplification and distortion originate from the outer hair cells-one of the two types of sensory receptor cells-it has been speculated that they stem from a common mechanism. Here we show that the nonlinearity underlying cochlear waveform distortions relies on the presence of stereocilin, a protein defective in a recessive form of human deafness. Stereocilin was detected in association with horizontal top connectors, lateral links that join adjacent stereocilia within the outer hair cell's hair bundle. These links were absent in stereocilin-null mutant mice, which became progressively deaf. At the onset of hearing, however, their cochlear sensitivity and frequency tuning were almost normal, although masking was much reduced and both acoustic and electrical waveform distortions were completely lacking. From this unique functional situation, we conclude that the main source of cochlear waveform distortions is a deflection-dependent hair bundle stiffness resulting from constraints imposed by the horizontal top connectors, and not from the intrinsic nonlinear behaviour of the mechanoelectrical transducer channel.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338146/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338146/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Verpy, Elisabeth -- Weil, Dominique -- Leibovici, Michel -- Goodyear, Richard J -- Hamard, Ghislaine -- Houdon, Carine -- Lefevre, Gaelle M -- Hardelin, Jean-Pierre -- Richardson, Guy P -- Avan, Paul -- Petit, Christine -- 071394/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2008 Nov 13;456(7219):255-8. doi: 10.1038/nature07380. Epub 2008 Oct 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Pasteur, Unite de Genetique et Physiologie de l'Audition, F75015 Paris, France. everpy@pasteur.fr〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18849963" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Acoustic Stimulation ; Animals ; Cochlea/*physiology ; Female ; Gene Expression Regulation ; Hair Cells, Auditory/cytology/*metabolism/ultrastructure ; Immunohistochemistry ; Male ; Mice ; Mice, Knockout ; Proteins/*genetics/*metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 3
    Publikationsdatum: 2008-12-05
    Beschreibung: Haematopoietic stem cell (HSC) niches, although proposed decades ago, have only recently been identified as separate osteoblastic and vascular microenvironments. Their interrelationships and interactions with HSCs in vivo remain largely unknown. Here we report the use of a newly developed ex vivo real-time imaging technology and immunoassaying to trace the homing of purified green-fluorescent-protein-expressing (GFP(+)) HSCs. We found that transplanted HSCs tended to home to the endosteum (an inner bone surface) in irradiated mice, but were randomly distributed and unstable in non-irradiated mice. Moreover, GFP(+) HSCs were more frequently detected in the trabecular bone area compared with compact bone area, and this was validated by live imaging bioluminescence driven by the stem-cell-leukaemia (Scl) promoter-enhancer. HSCs home to bone marrow through the vascular system. We found that the endosteum is well vascularized and that vasculature is frequently localized near N-cadherin(+) pre-osteoblastic cells, a known niche component. By monitoring individual HSC behaviour using real-time imaging, we found that a portion of the homed HSCs underwent active division in the irradiated mice, coinciding with their expansion as measured by flow assay. Thus, in contrast to central marrow, the endosteum formed a special zone, which normally maintains HSCs but promotes their expansion in response to bone marrow damage.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xie, Yucai -- Yin, Tong -- Wiegraebe, Winfried -- He, Xi C -- Miller, Diana -- Stark, Danny -- Perko, Katherine -- Alexander, Richard -- Schwartz, Joel -- Grindley, Justin C -- Park, Jungeun -- Haug, Jeff S -- Wunderlich, Joshua P -- Li, Hua -- Zhang, Simon -- Johnson, Teri -- Feldman, Ricardo A -- Li, Linheng -- England -- Nature. 2009 Jan 1;457(7225):97-101. doi: 10.1038/nature07639. Epub 2008 Dec 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, Missouri 64110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052548" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Antigens, CD31/analysis ; Blood Vessels/cytology ; Bone Marrow/pathology ; Cadherins/analysis ; Cell Division ; *Cell Movement ; Cell Separation ; Femur/cytology ; Hematopoietic Stem Cells/*cytology ; Immunoassay/*methods ; Immunohistochemistry ; Mice ; Models, Animal ; Osteoblasts/cytology ; Stem Cell Niche/*cytology ; Tibia/cytology
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Erwartet Verfügbarkeit
    BibTip Andere fanden auch interessant ...
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