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Berlin Brandenburg

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  • 1
    Language: English
    In: Oncotarget, 26 July 2016, Vol.7(30), pp.47918-47926
    Description: Pilocytic astrocytoma and ganglioglioma may occur in inaccessible or surgically difficult areas. In case of incomplete resection, the availability of biological predictors of tumour progression could be particularly important. To this end, an analysis of p53 codon 72 polymorphism and assessment of its role as prognostic marker were performed.The status of the p53 Arg72Pro polymorphism was evaluated by pyrosequencing method in a multicenter cohort of 170 paediatric patients. Genotype/phenotype associations were investigated either by means of bivariate or multivariate analyses.In the partially resected pilocytic astrocytomas, the Arg/Arg variant predicts early tumour progression (median survival time: 23.1 months) and is associated with poor event-free survival (p value = 0.0009). This finding remains true also in case of adjuvant therapies, with a 5-year event-free survival of 30.6% for cases with Arg/Arg variant vs. 78.7% for those with other genotypes. There is no association between ganglioglioma and the polymorphism.The assessment of Arg/Arg variant could improve the management of pilocytic astrocytoma. TP53 codon 72 analysis could distinguish low-risk cases, in which surgery could be conservative, from high-risk cases needing an aggressive surgery plan.
    Keywords: Tp53 ; Low-Grade Gliomas ; Paediatric ; Pilocytic Astrocytoma ; Polymorphism ; Astrocytoma -- Genetics ; Brain Neoplasms -- Genetics ; Tumor Suppressor Protein P53 -- Genetics
    E-ISSN: 1949-2553
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  • 2
    Language: English
    In: Oncotarget, 20 September 2016, Vol.7(38), pp.61860-61873
    Description: Ependymomas in children can arise throughout all compartments of the central nervous system (CNS). Highly malignant paediatric ependymoma subtypes are Group A tumours of the posterior fossa (PF-EPN-A) and RELA-fusion positive (ST-EPN-RELA) tumours in the supratentorial compartment. It was repeatedly reported in smaller series that accumulation of p53 is frequently observed in ependymomas and that immunohistochemical staining correlates with poor clinical outcome, while TP53 mutations are rare. Our TP53 mutation analysis of 130 primary ependymomas identified a mutation rate of only 3%. Immunohistochemical analysis of 398 ependymomas confirmed previous results correlating the accumulation of p53 with inferior outcome. Among the p53-positive ependymomas, the vast majority exhibited a RELA fusion leading to the hypothesis that p53 inactivation might be linked to RELA positivity.In order to assess the potential of p53 reactivation through MDM2 inhibition in ependymoma, we evaluated the effects of Actinomycin-D and Nutlin-3 treatment in two preclinical ependymoma models representing the high-risk subtypes PF-EPN-A and ST-EPN-RELA. The IC-50 of the agent as determined by metabolic activity assays was in the lower nano-molar range (0.2-0.7 nM). Transcriptome analyses of high-dose (100 nM), low-dose (5 nM) and non-treated cells revealed re-expression of p53 dependent genes including p53 upregulated modulator of apoptosis (PUMA) after low-dose treatment. At the protein level, we validated the Actinomycin-D induced upregulation of PUMA, and of p53 interaction partners MDM2 and p21. Proapoptotic effects of low-dose application of the agent were confirmed by flow cytometry. Thus, Actinomycin-D could constitute a promising therapeutic option for ST-EPN-RELA ependymoma patients, whose tumours frequently exhibit p53 inactivation.
    Keywords: Actinomycin-D ; Rela ; Ependymoma ; P53 ; Dactinomycin -- Therapeutic Use ; Ependymoma -- Drug Therapy ; Transcription Factor Rela -- Genetics ; Tumor Suppressor Protein P53 -- Genetics
    E-ISSN: 1949-2553
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  • 3
    Language: English
    In: Oncotarget, 17 April 2018, Vol.9(29), pp.20747-20760
    Description: Survival rates of pediatric sarcoma patients stagnated during the last two decades, especially in adolescents and young adults (AYAs). Targeted therapies offer new options in refractory cases. Gene expression profiling provides a robust method to characterize the transcriptome of each patient's tumor and guide the choice of therapy. Twenty patients with refractory pediatric sarcomas (age 8-35 years) were assessed with array profiling: ten had Ewing sarcoma, five osteosarcoma, and five soft tissue sarcoma. Overexpressed genes and deregulated pathways were identified as actionable targets and an individualized combination of targeted therapies was recommended. Disease status, survival, adverse events (AEs), and quality of life (QOL) were assessed in patients receiving targeted therapy (TT) and compared to patients without targeted therapy (non TT). Actionable targets were identified in all analyzed biopsies. Targeted therapy was administered in nine patients, while eleven received no targeted therapy. No significant difference in risk factors between these two groups was detected. Overall survival (OS) and progression free survival (PFS) were significantly higher in the TT group (OS: P=0.0014, PFS: P=0.0011). Median OS was 8.83 versus 4.93 months and median PFS was 6.17 versus 1.6 months in TT versus non TT group, respectively. QOL did not differ at baseline as well as at four week intervals between the two groups. TT patients had less grade 1 AEs (P=0.009). The frequency of grade 2-4 AEs did not differ. Overall, expression based targeted therapy is a feasible and likely beneficial approach in patients with refractory pediatric sarcomas that warrants further study.
    Keywords: Adolescents and Young Adults ; Expression Profiling ; Pediatric Cancer ; Sarcoma ; Targeted Therapy
    E-ISSN: 1949-2553
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  • 4
    Language: English
    In: Oncotarget, 14 February 2017, Vol.8(7), pp.11460-11479
    Description: Pilocytic astrocytoma (PA) is the most frequent pediatric brain tumor. Activation of the MAPK pathway is well established as the oncogenic driver of the disease. It is most frequently caused by KIAA1549:BRAF fusions, and leads to oncogene induced senescence (OIS). OIS is thought to be a major reason for growth arrest of PA cells in vitro and in vivo, preventing establishment of PA cultures. Hence, valid preclinical models are currently very limited, but preclinical testing of new compounds is urgently needed. We transduced the PA short-term culture DKFZ-BT66 derived from the PA of a 2-year old patient with a doxycycline-inducible system coding for Simian Vacuolating Virus 40 Large T Antigen (SV40-TAg). SV40-TAg inhibits TP53/CDKN1A and CDKN2A/RB1, two pathways critical for OIS induction and maintenance. DNA methylation array and KIAA1549:BRAF fusion analysis confirmed pilocytic astrocytoma identity of DKFZ-BT66 cells after establishment. Readouts were analyzed in proliferating as well as senescent states, including cell counts, viability, cell cycle analysis, expression of SV40-Tag, CDKN2A (p16), CDKN1A (p21), and TP53 (p53) protein, and gene-expression profiling. Selected MAPK inhibitors (MAPKi) including clinically available MEK inhibitors (MEKi) were tested in vitro. Expression of SV40-TAg enabled the cells to bypass OIS and to resume proliferation with a mean doubling time of 45h allowing for propagation and long-term culture. Withdrawal of doxycycline led to an immediate decrease of SV40-TAg expression, appearance of senescent morphology, upregulation of CDKI proteins and a subsequent G1 growth arrest in line with the re-induction of senescence. DKFZ-BT66 cells still underwent replicative senescence that was overcome by TERT expression. Testing of a set of MAPKi revealed differential responses in DKFZ-BT66. MEKi efficiently inhibited MAPK signaling at clinically achievable concentrations, while BRAF V600E- and RAF Type II inhibitors showed paradoxical activation. Taken together, we have established the first patient-derived long term expandable PA cell line expressing the KIAA1549:BRAF-fusion suitable for preclinical drug testing.
    Keywords: Kiaa1549:Braf-Fusion ; Mapk-Inhibitors ; Oncogene-Induced Senescence (Ois) ; Pediatric Low Grade Glioma ; Pilocytic Astrocytoma ; Astrocytoma ; Brain Neoplasms ; Cell Culture Techniques ; Cell Line, Tumor ; Cellular Senescence -- Physiology
    E-ISSN: 1949-2553
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  • 5
    Language: English
    In: ONCOTARGET, 2016
    Description: The systemic and resistant nature of metastatic neuroblastoma renders it largely incurable with current multimodal treatment. Clinical progression stems mainly from the increasing burden of metastatic colonization. Therapeutically inhibiting the migration-invasion-metastasis cascade would be of great benefit, but the mechanisms driving this cycle are as yet poorly understood. In-depth transcriptome analyses and ChIP-qPCR identified the cell surface glycoprotein, CD9, as a major downstream player and direct target of the recently described GRHL1 tumor suppressor. CD9 is known to block or facilitate cancer cell motility and metastasis dependent upon entity. High-level CD9 expression in primary neuroblastomas correlated with patient survival and established markers for favorable disease. Low-level CD9 expression was an independent risk factor for adverse outcome. MYCN and HDAC5 colocalized to the CD9 promoter and repressed transcription. CD9 expression diminished with progressive tumor development in the TH-MYCN transgenic mouse model for neuroblastoma, and CD9 expression in neuroblastic tumors was far below that in ganglia from wildtype mice. Primary neuroblastomas lacking MYCN amplifications displayed differential CD9 promoter methylation in methyl-CpG-binding domain sequencing analyses, and high-level methylation was associated with advanced stage disease, supporting epigenetic regulation. Inducing CD9 expression in a SH-EP cell model inhibited migration and invasion in Boyden chamber assays. Enforced CD9 expression in neuroblastoma cells transplanted onto chicken chorioallantoic membranes strongly reduced metastasis to embryonic bone marrow. Combined treatment of neuroblastoma cells with HDAC/DNA methyltransferase inhibitors synergistically induced CD9 expression despite hypoxic, metabolic or cytotoxic stress. Our results show CD9 is a critical and indirectly druggable suppressor of the invasion-metastasis cycle in neuroblastoma.
    Keywords: Medicine And Health Sciences ; Antimetastatic Therapy ; Chromatin Modulation ; Histone Deacetylases ; Grainyhead-Like Transcription Factor Family ; Tetraspanin Family ; High-Risk Neuroblastoma ; Activating Mutations ; Alk Kinase ; N-Myc ; Expression ; Gene ; Differentiation ; Classification ; Rearrangements ; Association
    ISSN: 1949-2553
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