Hewer Ekkehard, Beck Jürgen, Vassella Erik, Vajtai Istvan (2014), Anaplastic oligodendroglioma arising from the brain stem and featuring 1p/19q co-deletion., in Neuropathology : official journal of the Japanese Society of Neuropathology
, 34(1), 32-8.
Haemmig S, Baumgartner U, Glück A, Zbinden S, Tschan M P, Kappeler A, Mariani L, Vajtai I, Vassella E (2014), miR-125b controls apoptosis and temozolomide resistance by targeting TNFAIP3 and NKIRAS2 in glioblastomas., in Cell death & disease
, 5, 1279-1279.
Hewer Ekkehard, Beck Jürgen, Murek Michael, Kappeler Andreas, Vassella Erik, Vajtai Istvan (2014), Polymorphous oligodendroglioma of Zülch revisited: a genetically heterogeneous group of anaplastic gliomas including tumors of bona fide oligodendroglial differentiation., in Neuropathology : official journal of the Japanese Society of Neuropathology
, 34(4), 323-32.
Leu Severina, von Felten Stefanie, Frank Stephan, Vassella Erik, Vajtai Istvan, Taylor Elisabeth, Schulz Marianne, Hutter Gregor, Hench Jürgen, Schucht Philippe, Boulay Jean-Louis, Mariani Luigi (2013), IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival., in Neuro-oncology
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Thommen François, Hewer Ekkehard, Schäfer Stephan C, Vassella Erik, Kappeler Andreas, Vajtai Istvan (2013), Rosette-forming glioneuronal tumor of the cerebellum in statu nascendi: an incidentally detected diminutive example indicates derivation from the internal granule cell layer., in Clinical neuropathology
, 32(5), 370-6.
Galli Serena, Kappeler Andreas, Vassella Erik, Sahli Rahel, Vajtai Istvan (2012), Incongruous differential immunoexpression of the MGMT protein in a double adenoma of the pituitary with homogeneous nonmethylated MGMT promoter genotype., in Clinical neuropathology
, 31(2), 99-103.
Vajtai Istvan, Vassella Erik, Hewer Ekkehard, Kappeler Andreas, Reinert Michael M (2012), Sarcomatous evolution of oligodendroglioma ("oligosarcoma"): confirmatory report of an uncommon pattern of malignant progression in oligodendroglial tumors., in Pathology, research and practice
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Background: microRNAs (miRNAs) are short regulatory sequences that constitute a new layer of gene expression at the post-transcriptional level. They play key roles in cell fate specification, proliferation and cell death and function as tumour suppressors or oncogenes. We plan to investigate, if some of these miRNAs confer chemoresistance of gliomas. These brain tumours are among the most prognostically discouraging neoplasia in human and there is basically no curative option for glioma patients.Working hypothesis: miRNAs are implicated in conferring resistance to chemotherapy in gliomas. Specific aims: O6-methylguanine-DNA-methyltransferase (MGMT) and nuclear factor ?B (NF-?B) are two key effectors associated with the development of resistance to alkylating agent-based chemotherapy in glioma tumours. It was shown previously that NF-?B plays an important role in MGMT regulation, indicating that these two pathways are linked, but the underlying molecular mechanisms, leading to dysregulation of these pathways in gliomas, are poorly understood. The aim of this work is to investigate microRNAs that interfere with these pathways for their role in conferring chemoresistance, apoptosis and proliferation of glioma tumours.Experimental design: The project is divided into two parts. In a first part, we aim to identify microRNAs that affect the expression of components of the NF-?B pathway and MGMT, and will investigate these miRNAs for their role in proliferation, apoptosis and chemoresistance of glioma cell lines. We were able to show that the intracellular NF-?B activity is significantly increased upon transfection of glioma cells with miR-125a precursor. This can be, in part, explained by our finding that TNFAIP3, a negative regulator of this pathway, is directly targeted by miR-125a. However, the expression of other negative regulatory components of the NF-?B pathway may also be affected by miR-125a, which will be further analysed. In addition, we plan to investigate if there is a link between the activity of NF-?B and the expression of MGMT and if the latter gene is also regulated by microRNAs. Interesting miRNA candidates will be analysed for their expression in tissues of low grade gliomas from the archive of the institute of pathology of Bern and the institute of pathology of Basel. The results of this analysis will be correlated with target gene expression, the glioma patients’ overall survival, tumour progression and response to chemotherapy. In a second part of this project, we will perform a functional screening of glioma cells transduced with a lentiviral miRNA library for miRNAs conferring temozolomide resistance. In parallel, microRNAs that are differentially regulated between chemosensitive and chemoresistant low grade gliomas will be identified by expression profiling (supported by the Bernese Cancer league). Those microRNAs identified by the functional screening that are differentially regulated between chemosensitive and chemoresistant tumours are most promising candidates for conferring chemoresistance in glioma tumours. Experiments are planed similar to those described for miR-125a, to further characterize these miRNAs.Expected value of the proposed project: The experiments described in the research proposal may provide important information about the role of miRNAs in conferring proliferation, apoptosis and chemoresistance of gliomas. In future, some of these miRNAs might be used as predictive markers for chemotherapy or prognostic markers for survival. In addition, overexpressing some of these miRNAs or antisense miRNAs might potentially be used in adjuvant therapy for the treatment of glioma patients.