Abstract:
:Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.
journal_name
Acta Neuropatholjournal_title
Acta neuropathologicaauthors
Barszczyk M,Buczkowicz P,Castelo-Branco P,Mack SC,Ramaswamy V,Mangerel J,Agnihotri S,Remke M,Golbourn B,Pajovic S,Elizabeth C,Yu M,Luu B,Morrison A,Adamski J,Nethery-Brokx K,Li XN,Van Meter T,Dirks PB,Rutka JT,Taydoi
10.1007/s00401-014-1327-6subject
Has Abstractpub_date
2014-12-01 00:00:00pages
863-77issue
6eissn
0001-6322issn
1432-0533journal_volume
128pub_type
杂志文章abstract::Psammoma bodies at the perivascular area in five cases of meningioma were examined with the electron microscope. In general, meningocytic cells invest the outer aspect of blood vessels, which are constituted by multilayered basal laminae, collagen fibers, microfibrils, and pericytes. Remnants of degenerated cells are ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00688693
更新日期:1985-01-01 00:00:00
abstract::Rat sciatic nerve was assayed for total collagen and total protein both immediately post-mortem and at weekly intervals after death. No significant difference was found in collagen and protein content between corresponding nerve segments assayed fresh and up to 4 weeks post mortem. However, variation was found in peri...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00692870
更新日期:1980-01-01 00:00:00
abstract::The microtubule-associated protein tau accumulates as cytoplasmic inclusions in Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We investigated the immunoreactivity of tau-positive structures using a panel of antibodies to epitopes spanning the ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-003-0671-8
更新日期:2003-05-01 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutati...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-012-1043-z
更新日期:2013-02-01 00:00:00
abstract::An experiment was designed to examine the course of degeneration, phagocytosis, and regeneration in the central nervous system following surgical deafferentation. The anterior cerebellar vermis was ablated in young male rats. The animals were sacrificed by perfusion at postoperative times ranging from 24 hrs to 6 mont...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00688396
更新日期:1975-12-19 00:00:00
abstract::Motor dysfunction is frequently noted in human immunodeficiency virus type 1 (HIV-1)-infected patients. Until recently, neuropathological changes found in the basal ganglia were advanced as pathogenetic mechanisms. In the present study, further brain structures involved in motor control were analyzed morphometrically....
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050502
更新日期:1996-08-01 00:00:00
abstract::A desmoplastic primary cerebral neuroblastoma originating in the frontal lobe of a boy who died at the age of 6 years contained dense core vesicles within the cytoplasm of neoplastic cells as evidence of neuronal differentiation. Sarcomatous transformation had occurred at the time of recurrence. At autopsy, he also ha...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00688540
更新日期:1980-01-01 00:00:00
abstract::Clinical and morphological findings in an 8-year-old Jewish girl with spongy leukodystrophy are presented. Ultrastructural changes indicated that this may be a form of Canavan's disease with some atypical features. Biochemical measurements indicated that synaptosomal membranes prepared from the striatum but not from t...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00691321
更新日期:1981-01-01 00:00:00
abstract::Using a fluorescent antibody technique, sections of the brains of patients with senile dementia or Alzheimer's disease containing senile plaques were treated with rabbit antihuman immunoglobulins labelled with FITC (fluorescein isothiocyanate, BBL). The senile plaques and the cerebral amyloid angiopathy (drusige Entar...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00689569
更新日期:1975-08-11 00:00:00
abstract::Adult white rats were injected daily for 1 month with aluminum chloride and killed. Aluminum was identified, quantitated, and localized in the brains of these rats. The only detectable anomalies were crystals of aluminum and phosphorus in lysosomes and lipofuscin granules in the cytoplasm of neurons. ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00707114
更新日期:1980-01-01 00:00:00
abstract::Human immune deficiency virus (HIV) disease may be associated, neuropathologically, with significant neuronal loss and clinically with a severe dementia. However, the significance of neuronal loss in the development of dementia has not been established. In this study we have undertaken a stereological determination of...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00296490
更新日期:1994-01-01 00:00:00
abstract::Dysferlin is a newly identified sarcolemmal protein related to Miyoshi myopathy and limb-girdle muscular dystrophy. Although its function is still unknown, it is inferred from the presence of C2 domains and a transmembrane domain in its sequence that dysferlin may be expressed or located not only at the sarcolemma but...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-003-0686-1
更新日期:2003-06-01 00:00:00
abstract::A mixed lymphoblastic T cell lymphoma and gonadotroph cell pituitary adenoma occurred 25 years after first resection of the adenoma. Within 1 year the lymphoma overgrew the adenoma, but was still restricted to the sellar region. Histologically, lymphoma and adenoma components were tightly admixed. Possible pathogeneti...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050990
更新日期:1999-03-01 00:00:00
abstract::The identification of the alpha-synuclein gene on chromosome 4q as a locus for familial Lewy-body parkinsonism and of alpha-synuclein as a component of Lewy bodies has heralded a new era in the study of Parkinson's disease. We have identified a large family with Lewy body parkinsonism linked to a novel locus on chromo...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010051177
更新日期:2000-06-01 00:00:00
abstract::Rats were given daily injections of 0.2 or 0.5 g/kg chlorophenoxyisobutyrate (clofibrate) for 9 to 46 days. Lower leg muscles were studied with light and electron microscopy. Daily treatment with 0.5 g/kg of the drug for 26--46 days caused myopathic changes. ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00703319
更新日期:1977-08-16 00:00:00
abstract::Endoneurial cell response and type of nerve fibre damage were studied after perineural injections of 7% phenol-aqua and pure glycerol. Our previous studies have shown that phenol and glycerol induce different types of nerve fibre degeneration after intraneural injections: phenol dissolves axons and Schwann cells insid...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-004-0896-1
更新日期:2004-10-01 00:00:00
abstract::Progressive myopathy developed in two women who consumed ipecac syrup containing emetine hydrochloride to induce vomiting as part of their anorexia nervosa. Muscle biopsy specimens were characterized by severe disruption of the sarcomeres. The ultrastructural spectrum extended from "Z-band streaming" to the formation ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00686202
更新日期:1988-01-01 00:00:00
abstract::The kidney of a 7-month-old male Cairn terrier with globoid cell leukodystrophy (GLD) was investigated with light and electron microscopes. A few tubular epithelial cells in the inner medulla as well as some exfoliated cells in the lumina revealed PAS-positive cytoplasm in which needle-like structures were to be seen ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00687036
更新日期:1986-01-01 00:00:00
abstract::CD44 antigen (CD44), the principle cell surface receptor for hyaluronate, is up-regulated in the human demyelinating disease multiple sclerosis on fibrous astrocytes. As astrocytes are the main target cell of canine distemper virus (CDV), the consequences of a CDV infection on the CD44 expression and distribution in b...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/pl00007417
更新日期:2000-02-01 00:00:00
abstract::The pathological changes in the nucleus basalis of Meynert (nbM) in 10 autopsied cases with Pick's disease were studied in comparison with 15 age-matched controls. Both the number and density of nerve cells and the degree of fibrillary gliosis were examined at the anterior, intermediate, and posterior divisions of the...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00687402
更新日期:1989-01-01 00:00:00
abstract::Histomorphological and histochemical variability was studied in muscle specimens from 30 patients with congenital muscular dystrophy (CMD). We found involvement of the central nervous system in 8 patients (Fukuyama CMD, F-CMD), involvement of the brain and the eyes in 5 patients (muscle, eye and brain disease, MEB-D) ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00369452
更新日期:1993-01-01 00:00:00
abstract::Neurotrophins regulate the proliferation and differentiation of neurons in the central nervous system via a family of specialized receptors, including TrkA, TrkB, and TrkC. As little is known about their expression or potential role in human glial tissues and glial tumors, we undertook an immunohistochemical analysis ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050906
更新日期:1998-10-01 00:00:00
abstract::Acetylcholinesterase and butyrylcholinesterase have been associated with structures undergoing neurofibrillary degeneration, as well as with all types of senile plaques, in non-demented aged and Alzheimer's brains. At the electron microscope level, the reaction product of both enzymes, appeared to decorate paired heli...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00296744
更新日期:1994-01-01 00:00:00
abstract::Research efforts during the last decade have deciphered the basic molecular mechanisms governing mitochondrial fusion and fission. We now know that in mammalian cells mitochondrial fission is mediated by the large GTPase dynamin-related protein 1 (Drp1) acting in concert with outer mitochondrial membrane (OMM) protein...
journal_title:Acta neuropathologica
pub_type: 杂志文章,评审
doi:10.1007/s00401-011-0930-z
更新日期:2012-02-01 00:00:00
abstract::Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet the mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress-ac...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-001-0481-9
更新日期:2002-04-01 00:00:00
abstract::The choroid plexus is an epithelial-endothelial vascular convolute within the ventricular system of the vertebrate brain. It consists of epithelial cells, fenestrated blood vessels, and the stroma, dependent on various physiological or pathological conditions, which may contain fibroblasts, mast cells, macrophages, gr...
journal_title:Acta neuropathologica
pub_type: 杂志文章,评审
doi:10.1007/s00401-009-0627-8
更新日期:2010-01-01 00:00:00
abstract::Considering the possibility of a paracellular pathway for edema resolution, we studied the intracerebral movement of proteins and ionic lanthanum in rats with experimental hydrocephalus. Hydrocephalus was induced by injection of kaolin suspension into the cisterna magna. After induction of hydrocephalus, horseradish p...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00687004
更新日期:1985-01-01 00:00:00
abstract::Numerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a la...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-013-1078-9
更新日期:2013-04-01 00:00:00
abstract::We investigated whether the brainstem is affected by the pathologic process of sporadic Creutzfeldt-Jakob disease (sCJD), with particular attention to brainstem atrophy, neuronal loss, pyramidal tract degeneration, and prion protein (PrP) deposition, in 33 patients with sCJD. Brainstem atrophy, particularly in the pon...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-005-0981-0
更新日期:2005-06-01 00:00:00
abstract::Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-015-1406-3
更新日期:2015-05-01 00:00:00