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Search Results: 1 - 10 of 199084 matches for " Charles G. Eberhart "
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Decreased 5-Hydroxymethylcytosine Is Associated with Neural Progenitor Phenotype in Normal Brain and Shorter Survival in Malignant Glioma
Brent A. Orr, Michael C. Haffner, William G. Nelson, Srinivasan Yegnasubramanian, Charles G. Eberhart
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041036
Abstract: Epigenetic modification of DNA by cytosine methylation to produce 5-methylcytosine (5mC) has become well-recognized as an important epigenetic process in human health and disease. Recently, further modification of 5mC by the ten eleven translocated (TET) family of enzymes to produce 5-hydroxymethylcytosine (5hmC) has been described. In the present study, we used immunohistochemistry to evaluate the distribution of 5hmC in human brain during different periods of development and in a large series of gliomas (n = 225). We found that during development, 5hmC levels are high in more differentiated compartments like the fetal cortex, but low in the periventricular progenitor cell regions. In adults, we found 5hmC levels to be highest in the cortex, but present in all intrinsic cell types in the brain including stromal elements. In brain tumors, 5hmC levels were high in low grade tumors and reduced in malignant glioma, but did not exhibit any correlation with IDH1 mutation status. Additionally, we identified a significant relationship between low levels of 5hmC and reduced survival in malignant glioma. This observation was further supported by in silico analysis showing differential expression of genes involved in 5hmC homeostasis in aggressive subsets of glioblastoma. Finally, we show that several genes involved in regulating the levels of 5hmC are also prognostic in malignant glioma. These findings suggest that 5hmC regulation in malignant glioma may represent an important determinant of tumor differentiation and aggressive behavior, as well as a potential therapeutic target.
Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus
Charles G Eberhart, Aneeka Chaudhry, Richard W Daniel, Leila Khaki, Keerti V Shah, Patti E Gravitt
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-19
Abstract: p53 protein levels were evaluated semi-quantitatively in 64 medulloblastomas, 3 atypical teratoid rhabdoid tumors (ATRT), and 8 supratentorial primitive neuroectodermal tumors (sPNET) using immunohistochemistry. JC viral sequences were analyzed in DNA extracted from 33 frozen medulloblastoma and PNET samples using quantitative polymerase chain reaction.p53 expression was detected in 18% of non-anaplastic medulloblastomas, 45% of anaplastic medulloblastomas, 67% of ATRT, and 88% of sPNET. The increased p53 immunoreactivity in anaplastic medulloblastoma, ATRT, and sPNET was statistically significant. Log rank analysis of clinical outcome revealed significantly shorter survival in patients with p53 immunopositive embryonal tumors. No JC virus was identified in the embryonal brain tumor samples, while an endogenous human retrovirus (ERV-3) was readily detected.Immunoreactivity for p53 protein is more common in anaplastic medulloblastomas, ATRT and sPNET than in non-anaplastic tumors, and is associated with worse clinical outcomes. However, JC virus infection is not responsible for increased levels of p53 protein.The current World Health Organization classification for tumors of the nervous system includes medulloblastoma, medulloepithelioma, ependymoblastoma, supratentorial primitive neuroectodermal tumor (sPNET) and atypical teratoid/rhabdoid tumor (ATRT) in the category of embryonal brain neoplasms [1]. These tumors are united by their primitive cytological appearance and the ability to differentiate into multiple cell types. However, recent studies indicate that these lesions are genetically, and to some extent clinically, separable. ATRT are defined by the presence of rhabdoid cells, contain INI1 mutations, and cause particularly grim clinical outcomes [2]. Medulloblastomas commonly contain isochromosome 17q, but this chromosomal alteration is rarely detected in sPNET or ATRT [3]. Global gene expression profiles also suggest that medulloblastoma, sPNET and ATRT are
Identification of astrocytoma associated genes including cell surface markers
Kathy Boon, Jennifer B Edwards, Charles G Eberhart, Gregory J Riggins
BMC Cancer , 2004, DOI: 10.1186/1471-2407-4-39
Abstract: We generated and analyzed the SAGE transcription profiles of 25 primary grade II, III and IV astrocytomas [1]. These profiles were produced as part of the Cancer Genome Anatomy Project's SAGE Genie [2], and were used in an in silico search for candidate therapeutic targets by comparing astrocytoma to normal brain transcription. Real-time PCR and immunohistochemistry were used for the validation of selected candidate target genes in 2 independent sets of primary tumors.A restricted set of tumor-associated genes was identified for each grade that included genes not previously associated with astrocytomas (e.g. VCAM1, SMOC1, and thymidylate synthetase), with a high percentage of cell surface genes. Two genes with available antibodies, Aquaporin 1 and Topoisomerase 2A, showed protein expression consistent with transcript level predictions.This survey of transcription in malignant and normal brain tissues reveals a small subset of human genes that are activated in malignant astrocytomas. In addition to providing insights into pathway biology, we have revealed and quantified expression for a significant portion of cell surface and extra-cellular astrocytoma genes.Astrocytomas are the most frequent malignant primary brain tumors in adults. Clinically, this group of tumors can be divided into four World Health Organization (WHO) grades. Pilocytic astrocytomas (WHO grade I) are generally slow growing and non-infiltrative pediatric tumors, which are rarely fatal. For the infiltrating astrocytomas, survival decreases with increasing grade. Grade II astrocytomas patients survive an average of over 5 years, but survival drops to 3 years for anaplastic astrocytomas (grade III). Grade IV astrocytomas (glioblastoma multiforme or GBM) account for about half of all astrocytic tumors, with a median survival of less than a year. Effective treatment options for the invasive grade II to IV tumors are still limited to surgery and radiation therapy, with most chemotherapy regimens showing
Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma
Mehdi H Shahi, Mohammad Afzal, Subrata Sinha, Charles G Eberhart, Juan A Rey, Xing Fan, Javier S Castresana
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-614
Abstract: We silenced GLI1 expression in medulloblastoma and astrocytic cell lines by transfection of siRNA against GLI1. Subsequently, we performed RT-PCR and quantitative real time RT-PCR (qRT-PCR) to assay the expression of downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6. We also attempted to correlate the pattern of expression of GLI1 and its regulated genes in 14 cell lines and 41 primary medulloblastoma and astrocytoma tumor samples. We also assessed the methylation status of the Cyclin D2 and PTCH1 promoters in these 14 cell lines and 58 primary tumor samples.Silencing expression of GLI1 resulted up-regulation of all target genes in the medulloblastoma cell line, while only PTCH1 was up-regulated in astrocytoma. We also observed methylation of the cyclin D2 promoter in a significant number of astrocytoma cell lines (63%) and primary astrocytoma tumor samples (32%), but not at all in any medulloblastoma samples. PTCH1 promoter methylation was less frequently observed than Cyclin D2 promoter methylation in astrocytomas, and not at all in medulloblastomas.Our results demonstrate different regulatory mechanisms of Shh-GLI1 signaling. These differences vary according to the downstream target gene affected, the origin of the tissue, as well as epigenetic regulation of some of these genes.The Sonic hedgehog (Shh) signaling pathway is crucial for embryonic development and is involved in the fate of many tissues during organogenesis, including the central nervous system [1-4]. Additionally, the Shh signaling pathway has been implicated in stem cell renewal [5] as well as in the development of tumors such as medulloblastoma [1,6], prostate cancer [2,7,8] colorectal carcinoma [9], and glioma [10].This pathway is initiated by ligation of the Shh protein with its receptor PTCH1 on a target cell. Its binding relieves the inhibition of Smoothened (SMO) by PTCH1. The active SMO enters the cytoplasm and activates GLI1. GLI1 is then phosphorylated by the fused ser
Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells
André O von Bueren, Tarek Shalaby, Julia Rajtarova, Duncan Stearns, Charles G Eberhart, Lawrence Helson, Alexandre Arcaro, Michael A Grotzer
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-19
Abstract: To study MB cell responses to NBT-272 and their dependence on the level of c-MYC expression, DAOY (wild-type, empty vector transfected or c-MYC transfected), D341 (c-MYC amplification) and D425 (c-MYC amplification) human MB cells were used. The cells were treated with different concentrations of NBT-272 and the impact on cell proliferation, apoptosis and c-MYC expression was analyzed.NBT-272 treatment resulted in a dose-dependent inhibition of cellular proliferation (IC50 in the range of 1.7 – 9.6 ng/ml) and in a dose-dependent increase in apoptotic cell death in all human MB cell lines tested. Treatment with NBT-272 resulted in up to 90% down-regulation of c-MYC protein, as demonstrated by Western blot analysis, and in a significant inhibition of c-MYC binding activity. Anti-proliferative effects were slightly more prominent in D341 and D425 human MB cells with c-MYC amplification and slightly more pronounced in c-MYC over-expressing DAOY cells compared to DAOY wild-type cells. Moreover, treatment of synchronized cells by NBT-272 induced a marked cell arrest at the G1/S boundary.In human MB cells, NBT-272 treatment inhibits cellular proliferation at nanomolar concentrations, blocks cell cycle progression, induces apoptosis, and down-regulates the expression of the oncogene c-MYC. Thus, NBT-272 may represent a novel drug candidate to inhibit proliferation of human MB cells in vivo.Medulloblastomas (MB) are the most common malignant brain tumors in children and constitute 20% of all pediatric brain tumors [1]. With current treatment strategies, nearly half of all patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal.The c-MYC oncoprotein plays a pivotal role as a regulator of tumorigenesis in numerous human cancers of diverse origin [2-5]. In childhood MB, c-MYC gene amplification has been demonstrated in ~8% of primary tumors [6-11]. Disparity between c-MYC gene copy number and c-MYC mRNA expressi
Expression of stabilized β-catenin in differentiated neurons of transgenic mice does not result in tumor formation
John E Kratz, Duncan Stearns, David L Huso, Hilda H Slunt, Donald L Price, David R Borchelt, Charles G Eberhart
BMC Cancer , 2002, DOI: 10.1186/1471-2407-2-33
Abstract: Wild-type and mutant human β-catenin transgenes were expressed under the control of a murine PrP promoter fragment that drives high level postnatal expression in the CNS. Mutant β-catenin was stabilized by a serine to phenylalanine alteration in codon 37.Expression of the mutant transgene resulted in an approximately two-fold increase in β-catenin protein levels in the cortex and cerebellum of adult animals. Immunohistochemical analysis revealed nuclear β-catenin in hippocampal, cortical and cerebellar neurons of transgenic animals but not in non-transgenic controls. Tail kinking was observed in some transgenic animals, but no CNS malformations or tumors were detected.No tumors or morphologic alterations were detected in the brains of transgenic mice expressing stabilized β-catenin, suggesting that postnatal Wnt signaling in differentiated neurons may not be sufficient to induce CNS tumorigenesis.Medulloblastomas, embryonal neoplasms arising in the cerebellum, are the most common malignant pediatric brain tumor. In man, three inherited syndromes associated with medulloblastomas have been described: Turcot's, Gorlin's and Li Fraumeni (reviewed in [1]). Li Fraumeni syndrome is caused by inherited mutations in the p53 tumor suppressor gene. Affected individuals develop a large spectrum of CNS and extra-CNS neoplasms, including medulloblastomas [2]. Interestingly, alterations in p53 are relatively rare in sporadic medulloblastomas, with mutations detected in 5% or less of cases [3,4].The genes most commonly altered in medulloblastoma are members of developmental signaling pathways. Gorlin's syndrome results from inherited mutations in the Hedgehog receptor PTCH that constitutively activate the pathway. Mutations in the Hedgehog pathway members PTCH, PTCH 2, SUFU and Smo, have all been identified in sporadic medulloblastomas as well, with approximately 25% of cases containing mutations affecting these genes [5-9]. A murine medulloblastoma model was recently developed by
RNA interference-mediated c-MYC inhibition prevents cell growth and decreases sensitivity to radio- and chemotherapy in childhood medulloblastoma cells
André O von Bueren, Tarek Shalaby, Christoph Oehler-J?nne, Lucia Arnold, Duncan Stearns, Charles G Eberhart, Alexandre Arcaro, Martin Pruschy, Michael A Grotzer
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-10
Abstract: To study the role of c-MYC in MB biology, we down-regulated c-MYC expression by using small interfering RNA (siRNA) and investigated changes in cellular proliferation, cell cycle analysis, apoptosis, telomere maintenance, and response to ionizing radiation (IR) and chemotherapeutics in a representative panel of human MB cell lines expressing different levels of c-MYC (DAOY wild-type, DAOY transfected with the empty vector, DAOY transfected with c-MYC, D341, and D425).siRNA-mediated c-MYC down-regulation resulted in an inhibition of cellular proliferation and clonogenic growth, inhibition of G1-S phase cell cycle progression, and a decrease in human telomerase reverse transcriptase (hTERT) expression and telomerase activity. On the other hand, down-regulation of c-MYC reduced apoptosis and decreased the sensitivity of human MB cells to IR, cisplatin, and etoposide. This effect was more pronounced in DAOY cells expressing high levels of c-MYC when compared with DAOY wild-type or DAOY cells transfected with the empty vector.In human MB cells, in addition to its roles in growth and proliferation, c-MYC is also a potent inducer of apoptosis. Therefore, targeting c-MYC might be of therapeutic benefit when used sequentially with chemo- and radiotherapy rather than concomitantly.Medulloblastomas (MB) are the most common malignant pediatric neoplasms of the central nervous system. MB constitute 20% of all pediatric brain tumors [1] and are characterized by their aggressive clinical behavior and a high risk of leptomeningeal dissemination. With current treatment strategies, nearly half of all patients eventually die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal.The c-MYC proto-oncogene encodes a nuclear phosphoprotein involved in the transcription of genes central to regulating the cell cycle [2-4], proliferation [5,6], apoptosis [7-9], telomere maintenance [10,11], angiogenesis [12], and differentiation [13]. Th
c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients
André O von Bueren, Christoph Oehler, Tarek Shalaby, Katja von Hoff, Martin Pruschy, Burkhardt Seifert, Nicolas U Gerber, Monika Warmuth-Metz, Duncan Stearns, Charles G Eberhart, Rolf D Kortmann, Stefan Rutkowski, Michael A Grotzer
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-74
Abstract: We used DAOY and UW228 human MB cells engineered to stably express different levels of c-MYC, and tested whether c-MYC expression has an effect on radio- and chemosensitivity using the colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay, clonogenic survival, apoptosis assays, cell cycle analysis, and western blot assessment. In an effort to validate our results, we analyzed c-MYC mRNA expression in formalin-fixed paraffin-embedded tumor samples from well-documented patients with postoperative residual tumor and compared c-MYC mRNA expression with response to radio- and chemotherapy as examined by neuroradiological imaging.In DAOY - and to a lesser extent in UW228 - cells expressing high levels of c-MYC, the cytotoxicity of cisplatin, and etoposide was significantly higher when compared with DAOY/UW228 cells expressing low levels of c-MYC. Irradiation- and chemotherapy-induced apoptotic cell death was enhanced in DAOY cells expressing high levels of c-MYC. The response of 62 of 66 residual tumors was evaluable and response to postoperative radio- (14 responders (CR, PR) vs. 5 non-responders (SD, PD)) or chemotherapy (23 CR/PR vs. 20 SD/PD) was assessed. c-MYC mRNA expression was similar in primary MB samples of responders and non-responders (Mann-Whitney U test, p = 0.50, ratio 0.49, 95% CI 0.008-30.0 and p = 0.67, ratio 1.8, 95% CI 0.14-23.5, respectively).c-MYC sensitizes MB cells to some anti-cancer treatments in vitro. As we failed to show evidence for such an effect on postoperative residual tumors when analyzed by imaging, additional investigations in xenografts and larger MB cohorts may help to define the exact function of c-MYC in modulating response to treatment.Medulloblastomas (MB) are the most common malignant brain tumors of childhood and constitute 20% of all pediatric brain tumors [1]. Progress in the treatment of MB has been achieved in multiple areas including neurosurgical tech
Interleukin-17 Retinotoxicity Is Prevented by Gene Transfer of a Soluble Interleukin-17 Receptor Acting as a Cytokine Blocker: Implications for Age-Related Macular Degeneration
Daniel Ardeljan, Yujuan Wang, Stanley Park, Defen Shen, Xi Kathy Chu, Cheng-Rong Yu, Mones Abu-Asab, Jingsheng Tuo, Charles G. Eberhart, Timothy W. Olsen, Robert F. Mullins, Gary White, Sam Wadsworth, Abraham Scaria, Chi-Chao Chan
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095900
Abstract: Age-related macular degeneration (AMD) is a common yet complex retinal degeneration that causes irreversible central blindness in the elderly. Pathology is widely believed to follow loss of retinal pigment epithelium (RPE) and photoreceptor degeneration. Here we report aberrant expression of interleukin-17A (IL17A) and the receptor IL17RC in the macula of AMD patients. In vitro, IL17A induces RPE cell death characterized by the accumulation of cytoplasmic lipids and autophagosomes with subsequent activation of pro-apoptotic Caspase-3 and Caspase-9. This pathology is reduced by siRNA knockdown of IL17RC. IL17-dependent retinal degeneration in a mouse model of focal retinal degeneration can be prevented by gene therapy with adeno-associated virus vector encoding soluble IL17 receptor. This intervention rescues RPE and photoreceptors in a MAPK-dependent process. The IL17 pathway plays a key role in RPE and photoreceptor degeneration and could hold therapeutic potential in AMD.
Ferromagnetic Dissection in a Rat Glioma Model  [PDF]
Sina Tok, Marian C. Neidert, Momen Sharab, I-Mei Siu, Jeanine P. Reyes, Vanessa Charubhumi, Robert T. Wicks, Charles Eberhart, George I. Jallo, Betty M. Tyler
Journal of Cancer Therapy (JCT) , 2015, DOI: 10.4236/jct.2015.67067
Abstract: Background: We compared cutting and coagulation of a novel ferromagnetic tool (FMwand) with modalities currently used in the clinical setting. Methods: 24 F344 rats with 9L gliosarcoma flank tumours were randomized into 2 groups (n = 12): 1) Five parallel incisions were made into the tumor of each rat using monopolar electrosurgery (MES) cut mode, MES coagulation (coag) mode, FMwand, carbon dioxide (CO2) laser and cold scalpel. 2) Two parallel incisions were made comparing the MES and the FMwand, both with resecting loop tips. The study was then repeated by a second surgeon. The surgeons applied a grading scale (1 = worst, 5 = best) based on their observations. Results: Average scores for FMwand were superior in ease of tissue dissection (3.58), distortion upon tissues (3.67), and smoke production (2.87). CO2 laser led in effectiveness of hemostasis (4.32). MES cut mode had the highest scores for ease of cleaning of tip (3.17) and speed of dissection (3.92). The FMwand loop device led in all attributes except for ease of cleaning. Conclusions: The FMwand outperformed CO2 laser significantly in ease and speed. It was superior compared to MES cut mode for hemostasis and superior compared to coag mode in ease and speed, distortion upon tissues and smoke production. The FMwand loop was significantly better compared to MES loop for hemostasis, distortion, ease and speed. The FMwand was shown to be safe and effective for hemostatic soft tissue cutting and coagulation.
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