Papers by Timothy Van Meter
International Review of Psychiatry, Sep 24, 2019
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Abstract The pathological protein posttranslational modification (PTM) known as citrullination ha... more Abstract The pathological protein posttranslational modification (PTM) known as citrullination has been associated with a range of neurodegenerative disorders including multiple sclerosis, Alzheimer’s disease, and prion disease. This PTM is the irreversible conversion of the amino acid arginine to citrulline, due to the deimination of the side chain. Despite substantial evidence of aberrations in calcium signaling following traumatic brain injury (TBI), there is little understanding of how TBI alters protein citrullination in the brain. It is known that citrullination can result in the formation of antigenic epitopes and the production of autoantibodies in other disease, therefore it may play a role in a similar manner in TBI and contribute to some of the chronic dysfunction following TBI. If so, citrullinated proteins or antigenic epitopes could be used as predictive biomarkers for disease progression and secondary effects of injury. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein enriched in activated astrocytes and provides an example of a highly brain-enriched protein that has been shown to be citrullinated in brain diseases. Today, studies suggest that detection of GFAP in the blood can be used as an indication of TBI. However, it is an extensively modified protein as there are several single-nucleotide polymorphisms, transcriptional variants (isoforms), and numerous different PTMs, suggesting that GFAP is under considerable biological regulation. The present chapter addresses some of the knowledge gap by focusing primarily on studies that show the association of protein citrullination in TBI and citrullination-linked alterations in GFAP, that could further explain the long-term effects of TBI.
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Sleep, Jul 24, 2018
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Brain Injury, Feb 5, 2023
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International Journal of Oncology, Dec 1, 1998
Matrix metalloproteinases (MMPs) are a growing family of zinc-dependent endopeptidases which are ... more Matrix metalloproteinases (MMPs) are a growing family of zinc-dependent endopeptidases which are characterised by their ability to degrade various extracellular matrix (ECM) components. The family includes collagenases, gelatinases, stromelysins, metalloelastase and membrane type metalloproteinases. Consistent with their proteolytic activities, MMPs have been implicated in a variety of physiological and pathological conditions, such as normal embryogenesis, tissue morphogenesis and are thought to play a role in facilitating tumour cell invasion of the normal brain. In this comparative study, we have used zymography, immunohistochemical and immunocytochemical techniques to demonstrate the expression of gelatinase-A and B (MMP-2 and 9, respectively) and membrane type metalloproteinase (MMP-14) in 8 intrinsic human primary brain tumours of various histological type and grade. Zymography results showed that MMP-2 was the most prominent proteolytic enzyme in all the cell lines studied (with one exception), while MMP-9 was only faintly expressed. However, the corresponding paraffin sections showed no expression of either MMP-2, 9 or 14 within the tumour cells, positivity being confined to haematogenous cells and the vascular endothelium. Fluorescence immunocytochemical studies, using monoclonal antibodies to MMP-2, 9 and 14, showed granular cytoplasmic reactivity in vitro. In addition, there was strong focal positivity at the cell membrane with MMP-14 in some high grade tumours suggesting that MMPs are produced at the leading edge of the cell by individual subpopulations of invading glia, in small quantities and on demand in vivo. It can be concluded that local microenvironmental conditions in vitro appear to stimulate such MMP activity.
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Journal of Neuro-oncology, Feb 27, 2011
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Springer eBooks, 2018
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Supplementary Data from Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, comp... more Supplementary Data from Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion
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Nature, Nov 29, 2022
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Nature
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Journal of Neurotrauma, 2021
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Background ETMRs are a newly recognized rare paediatric brain tumor with alterations of the C19MC... more Background ETMRs are a newly recognized rare paediatric brain tumor with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and limited clinical data, disease features and determinants of outcome are poorly defined. We performed an integrated clinico-pathologic and molecular analyses of 159 primary ETMRs to define clinical phenotypes, identify predictors of survival and critical treatment modalities for this orphan disease. Methods Primary ETMR patients were identified from the Rare Brain Tumor Consortium (rarebraintumorconsortium.ca) global registry using histopathologic and molecular assays. Event-Free (EFS) and Overall Survival (OS) for 108 patients treated with curative multi-modal regimens were determined using Cox proportional hazard and log rank analyses. Findings ETMRs were predominantly non-metastatic (73%) tumors arising from multiple sites; 55% were cerebral tumors, 45% arose at sites characteristic of other brain tumors. Hallmark C19MC alteration...
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Cancer Cell, 2019
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Brain Injury, 2019
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Frontiers in Neurology, 2017
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Annals of Emergency Medicine, 2017
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Annals of Emergency Medicine, 2017
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Neuro-Oncology, 2012
ABSTRACT Ependymomas represent the third most common paediatric brain tumour, yet effective chemo... more ABSTRACT Ependymomas represent the third most common paediatric brain tumour, yet effective chemotherapeutics are lacking and 5-year survival rates remain poor at approximately 50%. Previous studies have shown that the majority of ependymomas possess telomerase, an enzyme that maintains telomere length and permits limitless growth potential. The objective of this study was to elucidate whether telomerase is an effective therapeutic target in ependymoma using the telomerase inhibitors MST-312 and Imetelstat. Paediatric ependymoma cell lines R254 and BXD-1425EPN were treated for 72 hours with MST-312 in parallel with telomerase-negative control cells. R254 ependymoma cells were also treated with Imetelstat for 17 weeks in parallel with mismatch control and untreated cells. Cell number, apoptosis (TUNEL), senescence (beta-galactosidase), telomerase activity (telomere repeat amplification protocol), cell cycle arrest (flow cytometry) and DNA damage (immunofluorescence (gammaH2AX)) was assessed following telomerase inhibition by either compound. MST-312 telomerase inhibition reduced proliferation by 50%, increased γH2AX associated DNA damage 2.2-fold and induced a marked increase in G2 cell populations in both R254 and BXD-1425EPN ependymoma cells but not in telomerase-deficient control cells. Imetelstat treatment of R254 ependymoma cells decreased proliferation after 6 weeks and induced growth arrest following 15 weeks of treatment while no effect was observed in mismatch control or untreated cells. The observed growth arrest was associated with an 80% increase in senescence and 20% decrease in viability. These findings suggest that telomerase inhibition may represent a potential therapeutic strategy for paediatric ependymoma.
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Molecular Cancer Research, 2010
Medulloblastomas are the most frequent malignant brain tumors in children. Sunitinib is an oral m... more Medulloblastomas are the most frequent malignant brain tumors in children. Sunitinib is an oral multitargeted tyrosine kinase inhibitor used in clinical trials as an antiangiogenic agent for cancer therapy. In this report, we show that sunitinib induced apoptosis and inhibited cell proliferation of both a short-term primary culture (VC312) and an established cell line (Daoy) of human medulloblastomas. Sunitinib treatment resulted in the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase and upregulation of proapoptotic genes, Bak and Bim, and inhibited the expression of survivin, an antiapoptotic protein. Sunitinib treatment also downregulated cyclin E, cyclin D2, and cyclin D3 and upregulated p21Cip1, all of which are involved in regulating cell cycle. In addition, it inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) and AKT (protein kinase B) in the tumor cells. Dephosphorylation of STAT3 (Tyr705) induced by sunitinib was help...
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Papers by Timothy Van Meter