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Work 1-4 of 4

Sorted by relevance

Article

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

by Marc Remke; Vijay Ramaswamy; John Peacock; David J. H. Shih; Christian Koelsche; Paul A. Northcott; Nadia Hill; Florence M. G. Cavalli; Marcel Kool; Xin Wang; Stephen C. Mack; Mark Barszczyk; A. Sorana Morrissy; Xiaochong Wu; Sameer Agnihotri; Betty Luu ; David T.W. Jones; Livia Garzia; Adrian M. Dubuc; Nataliya Zhukova; Robert Vanner; Johan M. Kros; Pim J. French; Erwin Van Meir; Rajeev Vibhakar; Karel Zitterbart; Jennifer A. Chan; Laszlo Bognar; Almos Klekner; Boleslaw Lach ; Shin Jung; Ali G. Saad; Linda M. Liau; Steffen Albrecht; Massimo Zollo; Michael Cooper; Reid C. Thompson; Oliver O. Delattre; Franck Bourdeaut; Francois F. Doz; Miklos Garami; Peter Hauser; Carlos G. Carlotti; Timothy E. Van Meter; Luca Massimi; Daniel Fults; Scott L. Pomeroy; Toshiro Kumabe ; Young Shin Ra; Jeffrey R. Leonard; Samer K. Elbabaa; Jaume Mora; Joshua B. Rubin; Yoon-Jae Cho; Roger E. McLendon; Darrell D. Bigner; Charles G. Eberhart; Maryam Fouladi; Robert J. Wechsler-Reya; Claudia C. Faria; Sidney E. Croul; Annie Huang ; Eric Bouffet; Cynthia E. Hawkins ; Peter B. Dirks; William A. Weiss ; Ulrich Schuller; Ian F. Pollack; Stefan Rutkowski; David Meyronet; Anne Jouvet; Michelle Fevre-Montange; Nada Jabado; Marta Perek-Polnik; Wieslawa A. Grajkowska; Seung-Ki Kim; James T. Rutka ; David Malkin; Uri Tabori; Stefan M. Pfister; Andrey Korshunov; Andreas von Deimling

2013

Subjects
  • Biology, Neuroscience
  • Health Sciences, Pathology
  • File Download
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Abstract:Close

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in < 5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.

Article

Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer's Disease Dementia in Individuals With Mild Cognitive Impairment

by Yong Shen; Haibo Wang; Qiying Sun; Hailan Yao; Andrew P Keegan; Mike Mullan; Jeffrey Wilson; Simone Lista; Thomas Leyhe; Christoph Laske; Dan Rujescu; Allan Levey; Anders Wallin; Kaj Blennow; Rena Li; Harald Hampel

2018

Subjects
  • Biology, Neuroscience
  • Biology, Physiology
  • Psychology, Cognitive
  • File Download
  • View Abstract

Abstract:Close

Background: Increased beta-secretase 1 (BACE1) activity has consistently been detected in brain tissue and cerebrospinal fluid of subjects with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD) compared with control subjects. The collection of cerebrospinal fluid by lumbar puncture is invasive. We sought to identify the presence of plasma BACE1 activity and determine potential alterations in subjects with MCI with clinical follow-up examinations for 3 years using patients with diagnosed probable AD dementia compared with healthy control subjects. Methods: Seventy-five patients with probable AD, 96 individuals with MCI, and 53 age-matched and sex-matched healthy control subjects were recruited from three independent international academic memory clinics and AD research expert centers. Plasma BACE1 activity was measured by a synthetic fluorescence substrate enzyme-linked immunosorbent assay. BACE1 protein expression was assessed by Western blotting using three different antibodies that recognize the epitopes of the N-terminus, C-terminus, and full-length BACE1. Results: Compared with healthy control subjects, plasma BACE1 activity (V max ) significantly increased by 53.2% in subjects with MCI and by 68.9% in patients with probable AD. Subjects with MCI who converted to probable AD dementia at follow-up examinations exhibited significantly higher BACE1 activity compared with cognitively stable MCI nonconverters and showed higher levels of BACE1 activity than patients with AD. Conclusions: Plasma BACE1 activity is significantly increased in MCI converters and patients with probable AD. The sensitivities and specificities of BACE1 activity for the patients were 84% and 88%, respectively. Our results indicate that plasma BACE1 activity may be a biomarker for AD risk and could predict progression from prodromal to probable AD dementia.

Article

Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot-Marie-Tooth Type 2d

by Emily L. Spaulding; James N. Sleigh; Kathryn H. Morelli; Martin Pinter; Robert W. Burgess; Kevin L. Seburn

2016

Subjects
  • Biology, Neuroscience
  • Health Sciences, General
  • File Download
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Abstract:Close

Patients with Charcot–Marie–Tooth Type 2D (CMT2D), caused by dominant mutations in Glycl tRNA synthetase (GARS), present with progressive weakness, consistently in the hands, but often in the feet also. Electromyography shows denervation, and patients often report that early symptoms include cramps brought on by cold or exertion. Based on reported clinical observations, and studies of mouse models of CMT2D, we sought to determine whether weakened synaptic transmission at the neuromuscular junction (NMJ) is an aspect of CMT2D. Quantal analysis of NMJs in two different mouse models of CMT2D (GarsP278KY, GarsC201R), found synaptic deficits that correlated with disease severity and progressed with age. Results of voltage-clamp studies revealed presynaptic defects characterized by: (1) decreased frequency of spontaneous release without any change in quantal amplitude (miniature endplate current), (2) reduced amplitude of evoked release (endplate current) and quantal content, (3) age-dependent changes in the extent of depression in response to repetitive stimulation, and (4) release failures at some NMJs with high-frequency, long-duration stimulation. Drugs that modify synaptic efficacy were tested to see whether neuromuscular performance improved. The presynaptic action of 3,4 diaminopyridine was not beneficial, whereas postsynaptic-acting physostigmine did improve performance. Smaller mutant NMJs with correspondingly fewer vesicles and partial denervation that eliminates some release sites also contribute to the reduction of release at a proportion of mutant NMJs. Together, these voltage-clamp data suggest that a number of release processes, while essentially intact, likely operate suboptimally at most NMJs of CMT2D mice.

Article

Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes

by Amanda M. Saratsis; Madhuri Kambhampati; Kendall Snyder; Sridevi Yadavilli; Joe Devaney; Brennan Harmon; Jordan Hall; Eric H. Raabe; Ping An; Melanie Weingart; Brian R. Rood; Suresh Magge; Tobey MacDonald; Roger J. Packer; Javad Nazarian

2014

Subjects
  • Biology, Neuroscience
  • Health Sciences, Oncology
  • Health Sciences, Medicine and Surgery
  • File Download
  • View Abstract

Abstract:Close

Diffuse intrinsic pontine glioma (DIPG) is a highly morbid form of pediatric brainstem glioma. Here, we present the first comprehensive protein, mRNA, and methylation profiles of fresh-frozen DIPG specimens (n = 14), normal brain tissue (n = 10), and other pediatric brain tumors (n = 17). Protein profiling identified 2,305 unique proteins indicating distinct DIPG protein expression patterns compared to other pediatric brain tumors. Western blot and immunohistochemistry validated upregulation of Clusterin (CLU), Elongation Factor 2 (EF2), and Talin-1 (TLN1) in DIPGs studied. Comparisons to mRNA expression profiles generated from tumor and adjacent normal brain tissue indicated two DIPG subgroups, characterized by upregulation of Myc (N-Myc) or Hedgehog (Hh) signaling. We validated upregulation of PTCH, a membrane receptor in the Hh signaling pathway, in a subgroup of DIPG specimens. DNA methylation analysis indicated global hypomethylation of DIPG compared to adjacent normal tissue specimens, with differential methylation of 24 genes involved in Hh and Myc pathways, correlating with protein and mRNA expression patterns. Sequencing analysis showed c.83A>T mutations in the H3F3A or HIST1H3B gene in 77 % of our DIPG cohort. Supervised analysis revealed a unique methylation pattern in mutated specimens compared to the wild-type DIPG samples. This study presents the first comprehensive multidimensional protein, mRNA, and methylation profiling of pediatric brain tumor specimens, detecting the presence of two subgroups within our DIPG cohort. This multidimensional analysis of DIPG provides increased analytical power to more fully explore molecular signatures of DIPGs, with implications for evaluating potential molecular subtypes and biomarker discovery for assessing response to therapy.
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