12 results on '"Hawkins, Cynthia"'
Search Results
2. cIMPACT‐NOW: a practical summary of diagnostic points from Round 1 updates.
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Louis, David N., Ellison, David W., Brat, Daniel J., Aldape, Kenneth, Capper, David, Hawkins, Cynthia, Paulus, Werner, Perry, Arie, Reifenberger, Guido, Figarella‐Branger, Dominique, Deimling, Andreas, and Wesseling, Pieter
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TUMOR classification ,ASTROCYTOMAS ,ADULT-child relationships ,GLIOMAS - Abstract
cIMPACT‐NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications. From 2016 to 2019 (Round 1), cIMPACT published four updates. Update 1 clarified the use of the term NOS (Not Otherwise Specified) and proposed use of the additional term NEC (Not Elsewhere Classified). Update 2 issued clarifications regarding two diagnoses: Diffuse Midline Glioma, H3 K27M‐mutant and Diffuse Astrocytoma/Anaplastic Astrocytoma, IDH‐mutant. Update 3 proposed molecular criteria that could be used in the setting of an IDH‐wildtype diffuse or anaplastic astrocytic glioma without histological features of glioblastoma to infer that the tumor would behave similarly to a grade IV glioblastoma. Update 4 suggested that, in children and young adults, subtypes of IDH‐wildtype/H3‐wildtype diffuse gliomas may have distinct clinical features in the setting of a BRAFV600E mutation, FGFR1 alteration, other MAPK pathway alteration, or a MYB or MYBL1 rearrangement. The practical diagnostic relevance of these cIMPACT proposals is highlighted in this summary. [ABSTRACT FROM AUTHOR]
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- 2019
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3. Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study.
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Krishnatry, Rahul, Zhukova, Nataliya, Guerreiro Stucklin, Ana S., Pole, Jason D., Mistry, Matthew, Fried, Iris, Ramaswamy, Vijay, Bartels, Ute, Huang, Annie, Laperriere, Normand, Dirks, Peter, Nathan, Paul C., Greenberg, Mark, Malkin, David, Hawkins, Cynthia, Bandopadhayay, Pratiti, Kieran, Mark W., Manley, Peter E., Bouffet, Eric, and Tabori, Uri
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GLIOMAS ,NERVOUS system tumors ,ASTROCYTOMAS ,GLIOBLASTOMA multiforme ,MEDULLOBLASTOMA ,BRAIN tumor treatment ,GLIOMA treatment ,AGE distribution ,BRAIN tumors ,CANCER relapse ,CANCER invasiveness ,CONFIDENCE intervals ,DATABASES ,LONGITUDINAL method ,MULTIVARIATE analysis ,PROGNOSIS ,REGRESSION analysis ,SEX distribution ,SURVIVAL analysis (Biometry) ,TIME ,TUMOR classification ,ACQUISITION of data ,PROPORTIONAL hazards models ,RETROSPECTIVE studies ,KAPLAN-Meier estimator - Abstract
Background: The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown.Methods: This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database.Results: At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes.Conclusions: The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients. [ABSTRACT FROM AUTHOR]- Published
- 2016
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4. Pediatric thalamic tumors in the MRI era: a Canadian perspective.
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Steinbok, Paul, Gopalakrishnan, Chittur, Hengel, Alexander, Vitali, Aleksander, Poskitt, Ken, Hawkins, Cynthia, Drake, James, Lamberti-Pasculli, Maria, Ajani, Olufemi, Hader, Walter, Mehta, Vivek, McNeely, P., McDonald, Patrick, Ranger, Adrianna, Vassilyadi, Michael, Atkinson, Jeff, Ryall, Scott, Eisenstat, David, and Hukin, Juliette
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THALAMUS ,MAGNETIC resonance imaging ,HEALTH outcome assessment ,TUMOR treatment ,TUMORS in children ,ASTROCYTOMAS ,TUMORS - Abstract
Background: Thalamic gliomas are rare. The natural history is unpredictable, and the optimal management of these tumors in children is poorly defined. The aim was to identify outcomes, prognostic factors, and response to various modalities of treatment in a relatively large population of pediatric thalamic tumors from many centers within a fairly homogeneous health care system. Methods: We performed a Canadian multicenter retrospective review of pediatric thalamic tumors presenting during the MRI era (1989-2012). Radiology and pathology were reviewed by central independent reviewers. Paraffin shavings for RNA extraction were taken and tested for fusion events involving KIAA1549:BRAF. Tumors were classified as unilateral or bithalamic based on their origin on imaging. Univariate and multivariate analyses on factors influencing survival were performed. Results: Seventy-two thalamic tumors were identified from 11 institutions. Females represented 53 % of the study population, and the mean age at presentation was 8.9 years. Sixty-two tumors were unilateral and 10 bithalamic. Unilateral tumors had a greater propensity to grow inferiorly towards the brainstem. These tumors were predominantly low grade in comparison to bithalamic tumors which were high-grade astrocytomas. The 5-year overall survival was 61 ± 13 % for unithalamic tumors compared to 37 ± 32 % for bithalamic tumors ( p = 0.097). Multivariate analysis indicated tumor grade as the only significant prognostic factor for unithalamic tumors. Six unilateral tumors, all low grade, were BRAF fusion positive. Conclusion: Unilateral and bilateral thalamic tumors behave differently. Surgical resection is an appropriate treatment option in unilateral tumors, most of which are low grade, but outcome is not related to extent of resection (EOR). Bilateral thalamic tumors have a poorer prognosis, but the occasional patient does remarkably well. The efficacy of chemotherapy and radiotherapy has not been clearly demonstrated. Novel therapeutic approaches are required to improve the prognosis for malignant unilateral thalamic tumors and bilateral thalamic tumors. [ABSTRACT FROM AUTHOR]
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- 2016
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5. Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers.
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Ichimura, Koichi, Narita, Yoshitaka, and Hawkins, Cynthia
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ASTROCYTOMAS ,PATHOLOGY ,TUMORS ,MOLECULAR pathology ,ISOCITRATE dehydrogenase ,GLIOBLASTOMA multiforme - Abstract
Diffusely infiltrating astrocytomas include diffuse astrocytomas WHO grade II and anaplastic astrocytomas WHO grade III and are classified under astrocytic tumours according to the current WHO Classification. Although the patients generally have longer survival as compared to those with glioblastoma, the timing of inevitable malignant progression ultimately determines the prognosis. Recent advances in molecular genetics have uncovered that histopathologically diagnosed astrocytomas may consist of two genetically different groups of tumours. The majority of diffusely infiltrating astrocytomas regardless of WHO grade have concurrent mutations of IDH1 or IDH2, TP53 and ATRX. Among these astrocytomas, no other genetic markers that may distinguish grade II and grade III tumours have been identified. Those astrocytomas without IDH mutation tend to have a distinct genotype and a poor prognosis comparable to that of glioblastomas. On the other hand, diffuse astrocytomas that arise in children do not harbour IDH/ TP53 mutations, but instead display mutations of BRAF or structural alterations involving MYB/ MYBL1 or FGFR1. A molecular classification may thus help delineate diffusely infiltrating astrocytomas into distinct pathogenic and prognostic groups, which could aid in determining individualised therapeutic strategies. [ABSTRACT FROM AUTHOR]
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- 2015
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6. Pathology, molecular genetics, and epigenetics of diffuse intrinsic pontine glioma.
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Buczkowicz, Pawel, Hawkins, Cynthia, Giles, Keith, Puliyappadamba, Vinesh, and Dunham, Chris
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MOLECULAR genetics ,EPIGENETICS ,GLIOMAS ,CHILDHOOD cancer ,ASTROCYTOMAS ,HISTONES - Abstract
Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with no effective therapy. Histological similarity of DIPG to supratentorial high-grade astrocytomas of adults has led to assumptions that these entities possess similar underlying molecular properties and therefore similar therapeutic responses to standard therapies. The failure of all clinical trials in the last 30years to improve DIPG patient outcome has suggested otherwise. Recent studies employing next-generation sequencing and microarray technologies have provided a breadth of evidence highlighting the unique molecular genetics and epigenetics of this cancer, distinguishing it from both adult and pediatric cerebral high-grade astrocytomas. This review describes the most common molecular genetic and epigenetic signatures of DIPG in the context of molecular subgroups and histopathological diagnosis, including this tumor entity's unique mutational landscape, copy number alterations, and structural variants, as well as epigenetic changes on the global DNA and histone levels. The increased knowledge of DIPG biology and histopathology has opened doors to new diagnostic and therapeutic avenues. [ABSTRACT FROM AUTHOR]
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- 2015
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7. Clinical, EEG, MRI, MEG, and surgical outcomes of pediatric epilepsy with astrocytic inclusions versus focal cortical dysplasia.
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Alshafai, Laila, Ochi, Ayako, Go, Cristina, McCoy, Blathnaid, Hawkins, Cynthia, Otsubo, Hiroshi, Snead, Orlando C., Rutka, James, and Widjaja, Elysa
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DYSPLASIA ,ASTROCYTOMAS ,CHILDHOOD epilepsy ,ELECTROENCEPHALOGRAPHY ,MAGNETOENCEPHALOGRAPHY ,MAGNETIC resonance imaging ,SPASMS - Abstract
Objective Astrocytic inclusions ( AIs) have been identified on histologic specimens of patients with early onset seizures, and the proteomic contents have been described. The aim of this study was to compare the clinical, electroencephalography ( EEG), magnetoencephalography ( MEG), magnetic resonance imaging ( MRI), and surgical outcomes of AIs relative to focal cortical dysplasia ( FCD). Methods We assessed the clinical manifestations, semiology, ictal and interictal features on video- EEG, MEG, MRI features, and surgical outcomes of children with histologically proven AIs compared to FCD. Results Six children had AIs and 27 had FCD. Children with AIs had an earlier age at seizure onset, periodic spasms (all children), and interictal epileptiform discharges consisting of a mixture of generalized or diffuse hemispheric slow waves, sharp waves, spikes and polyspikes. Children with FCD were less likely to have spasms (4/27 [15%]), and the morphology of the diffuse hemispheric or generalized discharges were different from those of AI, consisting of spike-and-waves, polyspike-and-waves, sharp-and-slow waves, and paroxysmal fast activity. Patients with AIs were less likely to have tightly clustered MEG spike sources (3/6 [50%] vs. 23/27 [85%]), and more likely to demonstrate abnormal sulcation and gyration pattern (4/6 [67%] vs. 2/27 [7%]) and gray matter heterotopia (2/6 [33%] vs. 0/27 [0%]) than patients with FCD. Four children with AIs had resection and two had biopsy but did not undergo resection. Children with AIs had lower rates of seizure freedom after surgery compared to FCD (1/4 [25%] vs. 15/27 [56%], respectively). Significance Although there were some similarities between AIs and FCD, patients with AIs were more likely to present with early onset periodic spasms, have unusual interictal epileptiform discharges, abnormal sulcation, gyration pattern, and gray matter heterotopia, and were less likely to be seizure free following surgical resection relative to FCD. Further study with a larger sample size is needed to validate our findings. [ABSTRACT FROM AUTHOR]
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- 2014
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8. Aurora Kinase B Is a Potential Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma.
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Buczkowicz, Pawel, Zarghooni, Maryam, Bartels, Ute, Morrison, Andrew, Misuraca, Katherine L., Chan, Tiffany, Bouffet, Eric, Huang, Annie, Becher, Oren, and Hawkins, Cynthia
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AURORA kinases ,ASTROCYTOMAS ,GENE expression ,CELL lines ,CELL cycle ,POLYMERASE chain reaction - Abstract
Pediatric high-grade astrocytomas ( HGAs) account for 15-20% of all pediatric central nervous system tumors. These neoplasms predominantly involve the supratentorial hemispheres or the pons-diffuse intrinsic pontine gliomas ( DIPG). Assumptions that pediatric HGAs are biologically similar to adult HGAs have recently been challenged, and the development of effective therapeutic modalities for DIPG and supratentorial HGA hinges on a better understanding of their biological properties. Here, 20 pediatric HGAs (9 DIPGs and 11 supratentorial HGAs) were subject to gene expression profiling following approval by the research ethics board at our institution. Many of these tumors showed expression signatures composed of genes that promote G1/S and G2/M cell cycle progression. In particular, Aurora kinase B ( AURKB) was consistently and highly overexpressed in 6/9 DIPGs and 8/11 HGAs. Array data were validated using quantitative real-time PCR and immunohistochemistry, as well as cross-validation of our data set with previously published series. Inhibition of Aurora B activity in DIPG and in pediatric HGA cell lines resulted in growth arrest accompanied by morphological changes, cell cycle aberrations, nuclear fractionation and polyploidy as well as a reduction in colony formation. Our data highlight Aurora B as a potential therapeutic target in DIPG. [ABSTRACT FROM AUTHOR]
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- 2013
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9. A proteomic analysis of pediatric seizure cases associated with astrocytic inclusions.
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Visanji, Naomi P., Wong, Janice C., Wang, Simon X., Cappel, Blair, Kleinschmidt-DeMasters, Bette K., Handler, Michael H., Ochi, Ayako, Otsubo, Hiroshi, Rutka, James T., Go, Cristina, Weiss, Shelly, Vinters, Harry V., Hawkins, Cynthia E., DeSouza, Leroi V., Siu, K.W. Michael, and Hazrati, Lili-Naz
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INFANTILE spasms ,ASTROCYTOMAS ,PROTEOMICS ,PROTEINS ,CATALASE ,CARBONIC anhydrase ,ASTROCYTES - Abstract
Summary Cerebral hyaline astrocytic inclusions have been observed in a subset of patients with early onset epilepsy, brain structural anomalies, and developmental delay, which indicates that it may represent a unique clinicopathologic entity. To further characterize this condition we use proteomics to investigate differentially expressed proteins in epileptic brain tissue from three pediatric epileptic patients with cerebral hyaline astrocytic inclusions, ranging in age from 5-13 years, and compare to brain tissue from two normal controls. Catalase and carbonic anhydrase I both exhibited increased expression in epileptic brain tissue compared to controls. These findings were confirmed by Western blot analysis. Furthermore, both proteins were localized to astrocytes and in epileptic brain were located within the cerebral hyaline astrocytic inclusions, suggesting a potential role in the generation of this pathologic feature of early onset epilepsy with cerebral hyaline astrocytic inclusions. [ABSTRACT FROM AUTHOR]
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- 2012
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10. GATA6 is an astrocytoma tumor suppressor gene identified by gene trapping of mouse glioma model.
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Kamnasaran, Deepak, Baoping Qian, Hawkins, Cynthia, Stanford, William L., and Guha, Abhijit
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TUMOR suppressor genes ,ASTROCYTOMAS ,BRAIN tumors ,TRANSCRIPTION factors ,ASTROCYTES ,CELL proliferation ,CELL lines ,MUTAGENESIS - Abstract
Malignant astrocytomas are the most common and lethal adult primary brain tumor. Retroviral gene trapping of nontransformed neonatal astrocytes from a glial fibrillary acidic protein (GFAP):
V12 Ha-Ras murine astrocytoma model led to isolation of the transcription factor Gata6. Loss of Gata6 resulted in enhanced proliferation and transformation of astrocytes. Human malignant astrocytoma cell lines, explant xenografts, and operative specimens demonstrated loss of GATA6 expression. Loss-of-function GATA6 mutations with loss of heterozygosity of the GATA6 locus were found in human malignant astrocytoma specimens but not in lower-grade astrocytomas or normal adult astrocytes. Knockdown of Gata6 expression inV12 Ha-Ras or p53-/- astrocytes, but not in parental murine or human astrocytes, led to acceleration of tumorgenesis. Knockin GATA6 expression in human malignant astrocytoma cells reduced their tumorgenic growth with decreased VEGF expression. Collectively, these data demonstrate that GATA6, isolated from a murine astrocytoma model, is a novel tumor suppressor gene that is a direct target of mutations during malignant progression of murine and human astrocytomas. This work also demonstrates the utility of random mutagenesis strategies, such as gene trapping, on murine cancer models toward discovery of novel genetic alterations in corresponding human cancers. [ABSTRACT FROM AUTHOR]- Published
- 2007
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11. Pathological Findings of a Subependymal Giant Cell Astrocytoma Following Treatment With Rapamycin.
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Cheng, Sylvia, Hawkins, Cynthia, Taylor, Michael D., and Bartels, Ute
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ASTROCYTOMAS , *HYDROCEPHALUS , *RAPAMYCIN , *HERITABILITY , *MTOR protein , *CLINICAL trials , *THERAPEUTICS - Abstract
Background Tuberous sclerosis complex is a heritable multisystem disorder associated with genes involved in the formation of a tumor-suppressor complex acting through the Ras homologue enriched in brain protein to limit activation of the mammalian target of rapamycin complex I. Mutations in these genes result in enhanced mammalian target of rapamycin signaling and may cause neurological manifestations including brain tubers, subependymal nodules, and subependymal giant cell astrocytomas. These astrocytomas are tumors that arise near the foramen of Monro and may lead to obstructive hydrocephalus. Standard therapy has been surgical resection. More recently, mammalian target of rapamycin inhibitor, everolimus, has been approved for treatment after demonstration of efficacy in prospective clinical trials. Methods We report a 15 year-old girl with tuberous sclerosis complex who proceeded to surgical resection of her subependymal giant cell astrocytoma after 3 months of treatment with mammalian target of rapamycin inhibition. We compared her subependymal giant cell astrocytoma tissue specimen with 12 untreated subependymal giant cell astrocytomas accessed from The Hospital for Sick Children in Toronto, Canada. Results This girl's histopathological findings were consistent with subependymal giant cell astrocytomas with no exposure to mammalian target of rapamycin inhibitors. There were no major differences identified on immunohistochemistry at targets downstream of mammalian target of rapamycin complex 1 or in neighboring signaling pathways. The majority of cells were reactive to glial fibrillary acidic protein, mitogen-activated protein kinase, phospho-S6, caspase 3 (95% positivity), and NP-1. Conclusion In this one individual, rapamycin therapy did not change the histopathological characteristics of subependymal giant cell astrocytoma. Mammalian target of rapamycin inhibition involves complex signaling pathways inducing subependymal giant cell astrocytoma shrinkage. However, its effect is not easily characterized within tumor tissue. [ABSTRACT FROM AUTHOR]
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- 2015
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12. Telomerase inhibition induces acute ATM-dependent growth arrest in human astrocytomas
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Wong, Vincent C.H., Ma, Jing, and Hawkins, Cynthia E.
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ASTROCYTOMAS , *TELOMERASE , *CHILDHOOD cancer , *DNA damage , *CELLULAR signal transduction , *TUMOR growth - Abstract
Abstract: The purpose of the study was to examine the degree of hTERT, the catalytic subunit of telomerase, expression in paediatric high-grade astrocytoma and to explore the potential of telomerase inhibition as a therapy for these tumours. hTERT was expressed at high levels in 36 of 44 paediatric astrocytomas. Telomerase inhibition induced acute DNA damage and ATM-pathway-dependent G2/M cell cycle arrest in astrocytomas in vitro, both occurring prior to telomere shortening itself. Our data suggest that telomerase inhibition could be a useful adjuvant therapy for high-grade astrocytomas, potentially inducing tumour growth arrest following short-term treatment. [Copyright &y& Elsevier]
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- 2009
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