Genetic-epigenetic interactions in neuroblastoma

The solid childhood cancer neuroblastoma arises from cells of the sympathetic nervous system. Neuroblastoma is the most common childhood cancer in children younger than one year old worldwide and accounts for 28% of all cancers diagnosed in Europe and the U.S. in infants. 25% of neuroblastomas bear an amplification of the proto-oncogene MYCN; in addition to this genetic alteration, epigenetic modifications such as transcriptional silencing of tumour suppressor genes by promoter DNA hypermethylation and histone modifications can occur. Previous studies have shown an interaction between MYC and DNA hypermethylation, through recruitment of de novo DNA methyltransferases to the promoter of MYC target genes, in order to repress their transcription. We hypothesised that MYCN might be similarly capable of repressing its target genes. Our results revealed that MYCN interacts with the maintenance and de novo methyltransferase DNMT1 and DNMT3A, respectively in MYCN amplified neuroblastoma cell lines and all three bind the promoter region of the hypermethylated gene RASSF1A. However, only minor changes in DNA methylation of RASSF1A were shown by pyrosequencing analysis upon MYCN knock-down. This probably indicates only a small involvement of MYCN in epigenetically-induced gene silencing by DNA hypermethylation. The important role of MYCN in gene activation was highlighted from DNA methylation microarray studies on neuroblastoma cell lines compared to human neural crest cells. 73% of all hit genes showed hypomethylation, which led to the conclusion that a more open chromatin configuration and thus increased gene expression is favoured in high stage neuroblastoma cell lines, where MYCN and MYC compensate each others protein levels. The same study also led to the discovery of a novel methylated gene MEGF10 in neuroblastoma. The importance of epigenetic silencing in neuroblastoma was also highlighted by the ability of DNA demethylating agent 5-Aza-2'-deoxycytidine to re-sensitise chemotherapeutic resistant neuroblastoma cells to commonly used cytotoxic drugs.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Pulse design trade-offs for spectrum-efficient PDM-WDM coherent optical transmission systems

We study the joint effect of pulse spectral rolloff and impulse-response truncation length on the performance of densely packed root-raised-cosine pulse-shaped 32.5 GBaud PDMQPSK and 16QAM, through extensive bit-error-rate and spectrum measurements. © OSA 2014.SCOPUS: cp.pinfo:eu-repo/semantics/publishe

Decision-feedback equalization of bandwidth-constrained N-WDM coherent optical communication systems

Nyquist Wavelength division multiplexing (N-WDM), is a promising scheme in order to enhance the spectral efficiency of future coherent optical communication systems. In N-WDM systems, the channel bandwidth and spacing are selected to maximize the spectral efficiency while maintaining acceptable levels of inter-carrier and inter symbol interference. To further increase the spectral efficiency, bandwidth constrained N-WDM, where baudrate is higher than channel bandwidth can be considered. We propose to combine the bandwidth-constrained N-WDM scheme with a decision feedback equalizer (DFE) designed according to the minimum mean square error (MMSE) criterion. We show that the enhanced resilience to the inter symbol interference offered by DFE provides an effective gain on spectral efficiency. We compare system benefits of DFE and maximum a posteriori sequence detection (MAP) for coherent optical receivers, and show that DFE is as efficient as MAP in mitigating inter symbol interference at a considerably lower complexity.info:eu-repo/semantics/publishe

Multicarrier offset-QAM for long-haul coherent optical communications

The availability of high-speed digital-to-Analog converters for coherent optical communication systems makes it possible to digitally divide the available electrical bandwidth into subchannels on each optical carrier which enables a parallel implementation of the digital signal processing. In this paper, we use electrical multicarrier offset-QAM modulations to achieve crosstalk-free modulation for subcarriers spaced at the symbol rate. We show that in coherent optical communication systems, several impairments are bound to break the subcarrier orthogonality and cause failures of payload symbol recovering. We propose a dedicated digital signal processing architecture which implements channel estimation and a new algorithm to track the phase in multicarrier offset-QAM modulation. We experimentally compare the latter with conventional multicarrier and single carrier QAM modulation so as to assess the benefits of crosstalk mitigation via offset-QAM modulation. We carry out experiments to test the transmission performance of multicarrier offset-QAM modulation in a dispersion-unmanaged long-haul transmission link.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Multicarrier offset-QAM modulations for coherent optical communication systems

We study the performance of multicarrier offset modulation and root-raised-cosine shaped multicarrier modulation with aggregate 32.5 GBd symbol rate and show that offset modulation is preferable for non-zero rolloff factors.info:eu-repo/semantics/publishe

Decision feedback equalization for bandwidth-constrained 28Gbaud nyquist-WDM PDM-8QAM over 37.5 GHz grid

info:eu-repo/semantics/publishe

Design rules for pulse shaping in PDM-QPSK and PDM- 16QAM nyquist-WDM coherent optical transmission systems

info:eu-repo/semantics/publishe

Epigenetic deregulation of GATA3 in neuroblastoma is associated with increased GATA3 protein expression and with poor outcomes

International audienceTo discover epigenetic changes that may underly neuroblastoma pathogenesis, we identified differentially methylated genes in neuroblastoma cells compared to neural crest cells, the presumptive precursors cells for neuroblastoma, by using genome-wide DNA methylation analysis. We previously described genes that were hypermethylated in neuroblastoma; in this paper we report on 67 hypomethylated genes, which were filtered to select genes that showed transcriptional over-expression and an association with poor prognosis in neuroblastoma, highlighting GATA3 for detailed studies. Specific methylation assays confirmed the hypomethylation of GATA3 in neuroblastoma, which correlated with high expression at both the RNA and protein level. Demethylation with azacytidine in cultured sympathetic ganglia cells led to increased GATA3 expression, suggesting a mechanistic link between GATA3 expression and DNA methylation. Neuroblastomas that had completely absent GATA3 methylation and/or very high levels of protein expression, were associated with poor prognosis. Knock-down of GATA3 in neuroblastoma cells lines inhibited cell proliferation and increased apoptosis but had no effect on cellular differentiation. These results identify GATA3 as an epigenetically regulated component of the neuroblastoma transcriptional control network, that is essential for neuroblastoma proliferation. This suggests that the GATA3 transcriptional network is a promising target for novel neuroblastoma therapies. Neuroblastoma (NB) is one of the commonest extra-cranial solid malignancies of childhood, which arises as a result of disordered development of the sympathetic nervous system from neural crest cells 1,2. Neuroblastoma is clinically heterogeneous, with younger patients (18months) mostly have disseminated tumours at diagnosis and poor outcomes 3. The clinical heterogeneity of neuroblastoma is reflected in its molecular pathogenesis, where no single pathway has been identified as being critical for tumour development. Oncogene activations were the first genetic alterations identified in neuroblastoma; initially MYCN amplification was identified in high-risk tumours 4 and later ALK mutations were discovered in inherited neuroblastoma and some sporadic high-risk tumours 5,6. Mutations in tumour suppressor genes such as PHOX2B 7 and NF1 8 have also been reported. Recent genome-wide analyses have identified genomic mutations and other alterations in chromatin remodelling genes such as ATRX, ARID1A and ARID1B, in components of the RAC-RHO pathway 9-11 and in TERT 12,13 , with relapsed tumours demonstrating an increased mutation rate 14,15. Like most childhood cancers, neuroblastomas contain fewer mutations than adult cancers 16,17 , with some tumours apparently containing no detectable driver mutations 9-11. In low-risk neuroblastomas, copy-number changes may drive tumorigenesis 18 , but the lack of driver mutations in many cases, emphasises the need to consider other mechanisms of pathogenesis, such as epigenetic alterations 19