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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 20 November 2012, Vol.109(47), pp.19190-5
    Description: Neuroblastoma is a pediatric tumor of the sympathetic nervous system. MYCN (V-myc myelocytomatosis viral-related oncogene, neuroblastoma derived [avian]) is amplified in 20% of neuroblastomas, and these tumors carry a poor prognosis. However, tumors without MYCN amplification also may have a poor outcome. Here, we identified downstream targets of MYCN by shRNA-mediated silencing MYCN in neuroblastoma cells. From these targets, 157 genes showed an expression profile correlating with MYCN mRNA levels in NB88, a series of 88 neuroblastoma tumors, and therefore represent in vivo relevant MYCN pathway genes. This 157-gene signature identified very poor prognosis tumors in NB88 and independent neuroblastoma cohorts and was more powerful than MYCN amplification or MYCN expression alone. Remarkably, this signature also identified poor outcome of a group of tumors without MYCN amplification. Most of these tumors have low MYCN mRNA levels but high nuclear MYCN protein levels, suggesting stabilization of MYCN at the protein level. One tumor has an MYC amplification and high MYC expression. Chip-on-chip analyses showed that most genes in this signature are directly regulated by MYCN. MYCN induces genes functioning in cell cycle and DNA repair while repressing neuronal differentiation genes. The functional MYCN-157 signature recognizes classical neuroblastoma with MYCN amplification, as well as a newly identified group marked by MYCN protein stabilization.
    Keywords: Gene Expression Profiling ; Gene Amplification -- Genetics ; Neuroblastoma -- Genetics ; Nuclear Proteins -- Genetics ; Oncogene Proteins -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Atmospheric Environment, 2014, Vol.84, p.35(4)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.atmosenv.2013.11.037 Byline: Jan Reent Koster, Klaus Dittert, Karl-Hermann Muhling, Henning Kage, Andreas Pacholski Abstract: Anaerobic digestates (AD) from biogas production are applied to agricultural land as organic fertilizers, but pose an ammonia (NH.sub.3) emission source. However, data about NH.sub.3 emissions of cold season AD land spreading is still lacking. Therefore, in the present study NH.sub.3 emissions of AD application under winter conditions were determined. AD was applied via trail hoses to a field plot of 27 ha in Northern Germany during the winter with temperatures around the freezing point and partly frozen soil. NH.sub.4.sup.+ N application rate was, including a preceding urea application, 123 kg NH.sub.4.sup.+ and urea N ha.sup.-1. The NH.sub.3 volatilization was monitored using Open Path Fourier Transform Infrared spectroscopy in combination with a micrometeorological transport model. Cumulative NH.sub.3 volatilization during the six day measurements was 17.5 kg NH.sub.3 N ha.sup.-1 which corresponds to 33.1% of the NH.sub.4.sup.+ N in applied AD. This NH.sub.3 loss is relatively high for low temperature conditions and was most likely caused by the frozen soil restricting AD infiltration. Author Affiliation: (a) Institute of Plant Nutrition and Soil Science, Kiel University, Hermann-Rodewald-Str. 2, 24118 Kiel, Germany (b) Department of Crop Science, Section of Plant Nutrition and Crop Physiology, University of Goettingen, Carl-Sprengel-Weg 1, 37075 Goettingen, Germany (c) Agronomy and Crop Science, Institute of Crop Science and Plant Breeding, Kiel University, Hermann-Rodewald-Stra[sz]e 9, 24118 Kiel, Germany (d) Graduate School/Inkubator, Leuphana University Luneburg, Scharnhorststr. 1, 21335 Luneburg, Germany Article History: Received 1 August 2013; Revised 11 November 2013; Accepted 14 November 2013
    Keywords: Biogas – Analysis ; Biogas – Environmental Aspects ; Biomass Energy – Analysis ; Biomass Energy – Environmental Aspects ; Ammonia – Analysis ; Ammonia – Environmental Aspects ; Urea – Analysis ; Urea – Environmental Aspects ; Organic Fertilizers – Analysis ; Organic Fertilizers – Environmental Aspects
    ISSN: 1352-2310
    Source: Cengage Learning, Inc.
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  • 3
    Language: English
    In: Cancer Research, 11/15/2015, Vol.75(22 Supplement 2), pp.B1-05-B1-05
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 4
    Language: English
    In: Journal of Molecular Biology, 2014, Vol.426(2), pp.332-346
    Description: textabstractOrnithine decarboxylase (ODC) is the sentinel enzyme in polyamine biosynthesis. Both ODC and polyamines regulate cell division, proliferation, and apoptosis. Sepiapterin reductase (SPR) catalyzes the last step in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase, and has been implicated in neurological diseases but not yet in cancer. In this study, we present compelling evidence that native ODC and SPR physically interact, and we defined the individual amino acid residues involved in both enzymes using in silico protein-protein docking simulations. The resulting heterocomplex is a surprisingly compact structure, featuring two energetically and structurally equivalent binding modes both in monomer and in dimer conformations. The novel interaction between ODC and SPR proteins was confirmed under physiological conditions by co-immunoprecipitation and co-localization in neuroblastoma (NB) cells. Importantly, we showed that siRNA (small interfering RNA)-mediated knockdown of SPR expression significantly reduced endogenous ODC enzyme activity in NB cells, thus demonstrating the biological relevance of the ODC-SPR interaction. Finally, in a cohort of 88 human NB tumors, we found that high SPR mRNA expression correlated significantly with poor survival prognosis using a Kaplan-Meier analysis (log-rank test, P = 5 × 10- 4), suggesting an oncogenic role for SPR in NB tumorigenesis. In conclusion, we showed that ODC binds SPR and thus propose a new concept in which two well-characterized biochemical pathways converge via the interaction of two enzymes. We identified SPR as a novel regulator of ODC enzyme activity and, based on clinical evidence, present a model in which SPR drives ODC-mediated malignant progression in NB.
    Keywords: Docking Simulation ; Ornithine Decarboxylase ; Pediatric Neuroblastoma ; Protein-Protein Interaction ; Sepiapterin Reductase
    ISSN: 00222836
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  • 5
    Language: English
    In: European Journal of Cancer, March 2012, Vol.48(5), pp.763-771
    Description: The BIRC5 (Survivin) gene is located at chromosome 17q in the region that is frequently gained in high risk neuroblastoma. BIRC5 is strongly over expressed in neuroblastoma tumour samples, which correlates to a poor prognosis. We recently validated BIRC5 as a potential therapeutic target by showing that targeted knock down with shRNA’s triggers an apoptotic response through mitotic catastrophe. We now tested YM155, a novel small molecule selective BIRC5 suppressant that is currently in phase I/II clinical trials. Drug response curves showed IC50 values in the low nM range (median: 35 nM, range: 0.5–〉10,000 nM) in a panel of 23 neuroblastoma cell lines and four TIC-lines, which resulted from an apoptotic response. Nine out of 23 cell lines were relatively resistant to YM155 with IC50 values 〉200 nM, although in the same cells shRNA mediated knock down of BIRC5 caused massive apoptosis. Analysis of differentially expressed genes between five most sensitive and five most resistant cell lines using Affymetrix mRNA expression data revealed ABCB1 (MDR1) as the most predictive gene for resistance to YM155. Inhibition of the multi-drug resistance pump ABCB1 with cyclosporine or knockdown with shRNA prior to treatment with YM155 demonstrated that cell lines with ABCB1 expression became 27–695 times more sensitive to YM155 treatment. We conclude that most neuroblastoma cell lines are sensitive to YM155 in the low nM range and that resistant cells can be sensitised by ABCB1 inhibitors. Therefore YM155 is a promising novel compound for treatment of neuroblastoma with low ABCB1 expression.
    Keywords: Neuroblastoma ; Birc5 ; Apoptosis ; Ym155 ; Abcb1 ; Cancer ; Medicine
    ISSN: 0959-8049
    E-ISSN: 1879-0852
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  • 6
    Language: English
    In: Geochimica et Cosmochimica Acta, June 1, 2014, Vol.134, p.55(19)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.gca.2014.03.010 Byline: Dominika Lewicka-Szczebak, Reinhard Well, Jan Reent Koster, Roland Fu[sz], Mehmet Senbayram, Klaus Dittert, Heiner Flessa Abstract: Quantifying denitrification in arable soils is crucial in predicting nitrogen fertiliser losses and N.sub.2O emissions. Stable isotopologue analyses of emitted N.sub.2O ([delta].sup.15N, [delta].sup.18O and SP=.sup.15N site preference within the linear N.sub.2O molecule) may help to distinguish production pathways and to quantify N.sub.2O reduction to N.sub.2. However, such interpretations are often ambiguous due to insufficient knowledge on isotopic fractionation mechanisms. Here we present a complex experimental approach to determine the net fractionation factors (I*) associated with denitrification. This determination is based on three laboratory experiments differing in their experimental set-up and soil properties. Static and dynamic incubation techniques were compared. All available methods for independent determination of N.sub.2O reduction contribution were used, namely, N.sub.2-free atmosphere incubation, acetylene inhibition technique and.sup.15N gas-flux method. For N.sub.2O production: (i) the determined difference in [delta].sup.18O between soil water and produced N.sub.2O vary from +18a[degrees] to +42a[degrees] and show very strict negative correlation with soil water saturation; (ii) the determined I*.sup.15N of N.sub.2O production vary from -55a[degrees] to -38a[degrees] and the fractionation decreases with decreasing substrate availability; (iii) the determined SP of produced N.sub.2O vary from -3a[degrees] to +9a[degrees]. For N.sub.2O reduction: (i) the determined I*.sup.18O and I*.sup.15N of N.sub.2O reduction vary in very wide ranges from -18a[degrees] to +4a[degrees] and from -11a[degrees] to +12a[degrees], respectively, and depend largely on the differences in experimental setups; whereas (ii) the determined I*SP of N.sub.2O reduction shows a very consistent value with all previous studies and varies in a rather narrow range from -2a[degrees] to -8a[degrees]. It can be concluded that I* values of N.sub.2O production determined during laboratory incubations yield only roughly estimates for respective values expectable under field study conditions. I*.sup.18O and I*.sup.15N associated with N.sub.2O reduction may vary largely, probably depending on spatial and temporal coincidence of N.sub.2O production and reduction, and are hence not yet predictable for natural conditions. However, the I*SP of N.sub.2O reduction appeared to be relatively robust and a most probable value of about -5a[degrees] can be used to constrain N.sub.2O reduction based on SP of soil emitted N.sub.2O. Article History: Received 26 December 2013; Accepted 7 March 2014 Article Note: (miscellaneous) Associate editor: Jack J. Middelburg
    Keywords: Soils -- Analysis ; Acetylene -- Analysis ; Soil Moisture -- Analysis ; Denitrification -- Analysis
    ISSN: 0016-7037
    Source: Cengage Learning, Inc.
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  • 7
    In: International Journal of Cancer, 15 August 2015, Vol.137(4), pp.868-877
    Description: Several gene expression‐based prognostic signatures have been described in neuroblastoma, but none have successfully been applied in the clinic. Here we have developed a clinically applicable prognostic gene signature, both with regards to number of genes and analysis platform. Importantly, it does not require comparison between patients and is applicable amongst high‐risk patients. The signature is based on a two‐gene score (R‐score) with prognostic power in high‐stage tumours (stage 4 and/or amplified diagnosed after 18 months of age). QPCR‐based and array‐based analyses of matched cDNAs confirmed cross platform (array‐qPCR) transferability. We also defined a fixed cut‐off value identifying prognostically differing subsets of high‐risk patients on an individual patient basis. This gene expression signature independently contributes to the current neuroblastoma classification system, and if prospectively validated could provide further stratification of high‐risk patients, and potential upfront identification of a group of patients that are in need of new/additional treatment regimens. What's new? Children with highly aggressive neuroblastoma respond in different ways to intense, high‐risk treatments. For those children whose tumors show little or no response, such treatments can be particularly harmful. With prognostic gene‐expression signatures, however, it may be possible to tailor therapeutic strategies to individual patients. The present study describes a gene‐expression signature based on two genes, and , which are associated with poor prognosis and good prognosis, respectively. The two‐gene analysis was performed across qPCR and array platforms and was applicable to high‐risk patients, potentially enabling early identification of patients who require changes in treatment regimens.
    Keywords: Neuroblastoma ; Prognosis ; High‐Risk ; R‐Score
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 8
    Language: English
    In: PLoS ONE, 2011, Vol.6(10), p.e26058
    Description: Both OTX2 and MYC are important oncogenes in medulloblastoma, the most common malignant brain tumor in childhood. Much is known about MYC binding to promoter regions, but OTX2 binding is hardly investigated. We used ChIP-on-chip data to analyze the binding patterns of both transcription factors in D425 medulloblastoma cells. When combining the data for all promoter regions in the genome, OTX2 binding showed a remarkable bi-modal distribution pattern with peaks around −250 bp upstream and +650 bp downstream of the transcription start sites (TSSs). Indeed, 40.2% of all OTX2-bound TSSs had more than one significant OTX2-binding peak. This OTX2-binding pattern was very different from the TSS-centered single peak binding pattern observed for MYC and other known transcription factors. However, in individual promoter regions, OTX2 and MYC have a strong tendency to bind in proximity of each other. OTX2-binding sequences are depleted near TSSs in the genome, providing an explanation for the observed bi-modal distribution of OTX2 binding. This contrasts to the enrichment of E-box sequences at TSSs. Both OTX2 and MYC binding independently correlated with higher gene expression. Interestingly, genes of promoter regions with multiple OTX2 binding as well as MYC binding showed the highest expression levels in D425 cells and in primary medulloblastomas. Genes within this class of promoter regions were enriched for medulloblastoma and stem cell specific genes. Our data suggest an important functional interaction between OTX2 and MYC in regulating gene expression in medulloblastoma.
    Keywords: Research Article ; Biology ; Medicine ; Genetics And Genomics ; Oncology ; Pediatrics And Child Health ; Biochemistry
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: PLoS ONE, 2013, Vol.8(8), pp.urn:issn:1932-6203
    Description: CD44 marks stem cell-like cells in a number of tumour types, including colorectal cancer (CRC), while aberrant CD44 expression conveys increased tumourigenic, invasive, and metastatic potential. Previous data indicate that CD44 is a direct target of p53-mediated transcriptional repression in breast cancer. Since inactivating p53 mutations are frequent genetic events in CRC these could unleash expression of CD44. In the present study, we therefore explored the relation between p53 mutational status and CD44 expression in a cohort of 90 localized primary CRCs and studied the effect of radiation-induced p53 activation on CD44 expression. Interestingly, we observed that, in contrast to breast cancer, loss of function p53 mutations were not associated with elevated CD44 expression in colon cancer. Moreover, DNA-damage induced p53 activation did not result in repression of CD44 expression, neither in colon cancer cells nor in normal intestinal epithelial cells. Our data demonstrate that CD44 expression in normal and malignant intestinal epithelial cells is not regulated by p53, implying that regulation of this potentially important therapeutic target is tissue and cancer-type specific
    Keywords: Research Article ; Biology ; Medicine;
    ISSN: 1932-6203
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  • 10
    Language: English
    In: Cancer Research, 10/01/2018, Vol.78(19 Supplement), pp.IA10-IA10
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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