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  • 1
    Language: English
    In: Journal of Neuroscience Methods, 30 April 2012, Vol.206(1), pp.15-22
    Description: ► We described the multichannel preamplifier for neuronal recordings in small animals. ► The device may be used in any kinds of tasks including swimming in Morris water maze. ► Reusable headstage can adopt both chronically implanted and movable wire electrodes. ► For the first time multichannel recordings of neuronal activity were made in swimming mice. The design of a miniature multichannel preamplifier for extracellular recordings of single unit activity in freely moving and swimming small animals is presented. The advantages of this design include perfect protection of the critical components and electric contacts from water. Thus, neuronal activity and EEG may be recorded differentially in any kinds of behavioral tasks including swimming in Morris water maze. Recordings are stable even if an animal is diving and swimming under the water surface. The reusable dismountable base can adopt different types of chronically implanted fine wire electrodes and movable arrays. Electrodes may be implanted to any desired depth. The assembly weight is less than 240 mg. Thus, the construction is light enough even for mice. This work is the first successful attempt for multichannel recording of neuronal activity in mice performing spatial task in Morris water maze.
    Keywords: Multichannel Preamplifier ; Reusable Base ; Microdrive ; Fine Wire Electrodes ; Single Unit Activity ; Freely Moving Animals ; Swimming Mice and Rats ; Water Maze ; Medicine ; Anatomy & Physiology
    ISSN: 0165-0270
    E-ISSN: 1872-678X
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  • 2
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 01 June 2011, Vol.17(11), pp.3631-7
    Description: Ependymomas are glial tumors of presumably radial glial origin that share morphologic similarities with ependymal cells. The molecular genetics of ependymomas of supratentorial, infratentorial, and spinal location is heterogeneous. We aimed at identifying pathways operative in the development of infratentorial ependymomas. To do so, gene expression profiles of tumor cells laser microdissected from infratentorial ependymomas (n = 15) were compared with that of nonneoplastic ependymal cells laser microdissected from autopsy tissue (n = 7). Among 31 genes significantly overexpressed (〉5-fold) in ependymomas, transcription factor EVI1 (ecotropic viral integration site 1) showed the highest overexpression (35-fold). Evi-1 protein expression could be confirmed in formalin-fixed, paraffin-embedded samples of 26 of 28 infratentorial ependymomas but only in 7 of 47 nonependymal glial tumors (P 〈 0.001). Furthermore, MDS1/EVI1 fusion transcripts were detectable in 17 of 28 infratentorial ependymomas and significantly correlated with MGMT (O6-methylguanine-DNA-methyltransferase) promoter hypermethylation (P 〈 0.05). In primary infratentorial ependymoma cells, transfection with EVI1-specific siRNAs resulted in significant growth inhibition [48 hours: 87% ± 2% and 74% ± 10% as compared with control (mean ± SD; P 〈 0.001)]. The prognostic role of EVI1 could further be validated in an independent cohort of 39 infratentorial and 26 supratentorial ependymomas on the basis of mRNA expression profiling. Although in supratentorial ependymomas EVI1 expression status had no prognostic impact, in infratentorial ependymomas, high EVI1 expression was associated with shorter overall survival and progression-free survival. To conclude, the transcription factor Evi-1 is overexpressed in infratentorial ependymomas, promotes proliferation of ependymal tumor cells, and is prognostically unfavorable.
    Keywords: Cell Proliferation ; DNA-Binding Proteins -- Biosynthesis ; Ependymoma -- Metabolism ; Infratentorial Neoplasms -- Metabolism ; Transcription Factors -- Biosynthesis
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 3
    Language: English
    In: Cancer, 15 August 2005, Vol.104(4), pp.825-32
    Description: In patients with glioblastoma, age 〈 50 years was identified as a consistent prognostic variable. In addition, the prognosis for these patients may be determined by a complex interaction between age and genetic alterations. The objective of the current study was the molecular analysis of glioblastomas from adult patients age 〈 50 years ("young adults"). The authors analyzed a set of 189 glioblastoma specimens. Fluorescence in situ hybridization was performed with a set of 10 chromosome probes (1p36, 1q25, centomere probe 7 [CEP7], 7p12/epidermal growth factor receptor gene (EGFR), CEP9, 9p21/p16, CEP10, 10q23/phosphatase and tesnin homolog gene (PTEN), 19p13, and 19q13). Patient age or = 40 years frequently showed EGFR amplification, loss of 9p, loss of 10q, and gain of chromosome 19. The patients with - 19q were age 40 years were examined separately. Consequently, EGFR amplification, - 9p, and + 9 were significant for both age groups, whereas gain of chromosome 7 and loss of 10q showed clinical importance only among patients age 〉 40 years. Adult patients age 〈 50 years with glioblastoma had molecularly distinct disease, and the age-dependent heterogeneity seen on the chromosomal level also applied at the clinical level.
    Keywords: Brain Neoplasms -- Genetics ; Glioblastoma -- Genetics
    ISSN: 0008-543X
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  • 4
    Language: English
    In: World Neurosurgery, 2010, Vol.74(4), pp.532-537
    Description: A less favorable outcome is usually claimed for ETV in formerly shunted patients, and continuous bias exists on using endoscopy in cases with malfunctioning CSF shunts. A cohort of 60 patients with obstructive triventricular hydrocephalus (mean age 22 years, range 1–68) underwent an ETV instead of shunt revision. Fourteen patients had a history of multiple shunt-related surgeries (more than three times). Median follow-up lasted 2 years (range 1 month–8 years). Data on patients' preoperative condition and their history, including particularities of the surgery, were studied to define the impact of any given variable on the outcome. The Mann-Whitney test was used to assess differences among groups. Sixteen patients did not improve and needed permanent shunts anyway. The remaining 44 patients improved and became free of shunt (72%). No reliable correlation has been found regarding final outcome and data, characterizing patients' profile, for example, etiology of hydrocephalus, the history of intraventricular bleeding and/or CNS infection, age at onset and age at the first shunting, number of shunt surgeries, the origin of shunt malfunction, and complicated ventricular anatomy. There were no deaths, and overall cases with morbidity comprised 20% (12 cases); among them, serious complications with neurologic deficit were noted in three (5%) patients. Patients with obstructive hydrocephalus could benefit from ETV in case of their shunt malfunction and if carefully selected have about 70% probability to become shunt free. In formerly shunted patients, endoscopy has somewhat greater risk of serious complications; thus a wider experience is essential when offering them an ETV.
    Keywords: Cerebrospinal Fluid Shunts ; Endoscopic Third Ventriculostomy ; Obstructive Hydrocephalus ; Outcome
    ISSN: 1878-8750
    E-ISSN: 1878-8769
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  • 5
    Language: English
    In: Acta Neuropathologica, 2011, Vol.121(2), pp.283-285
    Description: Byline: Marco Gessi (1), Stefan Pfister (2,3), Volkmar H. Hans (4), Andrey Korshunov (5,6), Torsten Pietsch (1) Author Affiliation: (1) Institute of Neuropathology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53127, Bonn, Germany (2) Department of Pediatric Haematology and Oncology, University of Heidelberg, Heidelberg, Germany (3) Molecular Genetics of Pediatric Brain Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany (4) Institute of Neuropathology, Evangelisches Krankenhaus Bielefeld, Bielefeld, Germany (5) Institute of Neuropathology, University of Heidelberg, Heidelberg, Germany (6) Clinical Cooperation Unit German Cancer Research Center (DKFZ), Heidelberg, Germany Article History: Registration Date: 06/11/2010 Received Date: 12/10/2010 Accepted Date: 06/11/2010 Online Date: 18/11/2010
    Keywords: Cancer Research ; Genetic Research ; Molecular Genetics ; Brain Tumors ; Universities And Colleges;
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 6
    In: Nature, 2016
    Description: Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.
    Keywords: Medulloblastoma -- Genetic Aspects ; Cancer Genetics -- Research ; Cancer Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 7
    In: Nature, 2014, Vol.510(7506), p.537
    Description: Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.
    Keywords: Gene Expression Regulation, Neoplastic ; Gene Silencing ; DNA Methylation -- Genetics ; Medulloblastoma -- Genetics ; Sequence Analysis, DNA -- Methods;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 8
    Language: English
    In: Cancer, 15 March 2004, Vol.100(6), pp.1230-1237
    Description: BACKGROUND: Ependymomas account for 3-5% of all intracranial malignancies and occur most often in children and young adults. These neoplasms continue to generate considerable controversy with regard to their rational clinical management. It has been shown that the histologic classification of ependymoma is a significant predictor of clinical outcome in patients with ependymoma.METHODS: Ependymomas from 258 patients who underwent microsurgery at a single institution were evaluated histologically to elucidate the prognostic utility of a recently proposed grading scheme. Pathologic and clinical data then were compared using univariate and multivariate analyses.RESULTS: Increasing grade of ependymoma malignancy was found to be associated strongly and independently with worse clinical outcomes in terms of both event-free survival and overall survival. The effect of radiotherapy also was found to be related to histologic grade and was more beneficial for patients who had anaplastic ependymomas and had undergone complete tumor removal.CONCLUSIONS: The application of a uniform diagnostic criteria for grading ependymomas highlighted the key role of tumor histology in clinical outcome in a cohort of patients who were treated in the microsurgical era. The recently proposed grading scheme is likely to be practically useful, reproducible, and clinically applicable.
    Keywords: Ependymoma ; Histology ; Malignancy Grade ; Prognosis ; Radiotherapy
    ISSN: 0008-543X
    E-ISSN: 1097-0142
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  • 9
    Language: English
    In: International Journal of Cancer, 01 November 2011, Vol.129(9), pp.2297-2303
    Description: Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated Ras/Raf/MEK/ERK signaling. Common genetic lesions observed in PA, which are linked to aberrant ERK pathway activity, include either inactivation, or gain‐of‐function mutations. To investigate the mutation spectrum within the proto‐oncogene encoding the Ser/Thr‐kinase B‐Raf in more detail, we analyzed 64 primary tumor samples from children with PA including two patients with neurofibromatosis type 1 (NF1). The well‐known mutation was found in 6/64 (9.38%) of our samples. For the first time, we report concomitant presence of a somatic mutation in an NF1 patient indicating that more than one Ras/ERK pathway component can be affected in PA. Furthermore, 2/64 (3.13%) of our samples carried a 3‐bp insertion in resulting in the duplication of threonine 599. This conserved residue is located within the activation segment and, if phosphorylated in a Ras‐dependent manner, plays a key role in Raf activation. Here, we demonstrate that this mutant (B‐Raf) and another B‐Raf mutant, which carries two additional threonine residues at this position, display an kinase activity and cellular MEK/ERK activation potential comparable to those of B‐Raf. Notably, replacement of threonines by valine residues had similar effects on B‐Raf activity, suggesting that the distortion of the peptide backbone by additional amino acids rather than the insertion of additional, potential phosphorylation sites destabilizes the inactive conformation of the kinase domain. We also demonstrate that B‐Raf and B‐Raf, but not B‐Raf, provoke drastic morphological alterations in human astrocytes.
    Keywords: Pilocytic Astrocytoma ; Neurofibromatosis Type 1 ; B‐Raf ; Insertion Mutagenesis ; Mapk Pathway
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 10
    Language: English
    In: Zhurnal voprosy neirokhirurgii imeni N. N. Burdenko, 2016, Vol.80(4), pp.13-20
    Description: The study objective was to develop a rational approach for defining the extent of posterior decompression in children with Chiari 1 malformation. Posterior decompression was performed in 76 children with Chiari 1 malformation, under 18 years of age, in the period between 2001 and 2015. Fifty two (68%) children had syringomyelia. Extradural decompression (EDD) was performed in 14 (18%) cases, extra-arachnoid duraplasty (EAD) in 21 (28%) cases, intra-arachnoid dissection and duraplasty in 21 (28%) cases, and foramen of Magendie stenting and duraplasty in 20 (26%) cases. Complications occurred in 15 (20%) patients, with one of them being fatal (case fatality rate, 1.3%). The complication rate was higher after (1) intra-arachnoid dissection (p=0.0009) and stenting (p=0.02). Re-operation was required in 8 (11%) patients. The overall rate of complications and re-operations was lowest after EAD (10%). EAD is the method of choice for Chiari 1 malformation in children. EDD can be adopted as a primary option, but it requires selection of relevant patients. Intra-arachnoid dissection, with/without stenting, is not advisable as a primary intervention, but may be inevitable in the re-operation case.
    Keywords: Arnold-Chiari Malformation -- Surgery ; Decompression, Surgical -- Methods ; Syringomyelia -- Surgery
    ISSN: 0042-8817
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