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  • 1
    Language: English
    In: Redox Biology, January 2019, Vol.20, pp.60-67
    Description: Enzymes from the histone deacetylase (HDAC) family are highly regulated by different mechanisms. However, only very limited knowledge exists about the regulation of HDAC8, an established target in multiple types of cancer. A previous dedicated study of HDAC class I enzymes identified no redox-sensitive cysteinyl thiol in HDAC8. This is in contrast to the observation that HDAC8 preparations show different enzyme activities depending on the addition of reducing agents. In the light of the importance of HDAC8 in tumorigenesis a possible regulation by redox signaling was investigated using biochemical and biophysical methods combined with site directed mutagenesis. The occurrence of a characteristic disulfide bond under oxidizing conditions is associated with a complete but reversible loss of enzyme activity. Cysteines 102 and 153 are the integral components of the redox-switch. A possible regulation of HDAC8 by redox signal transduction is suggested by the observed relationship between inhibition of reactive oxygen species generating NOX and concomitant increased HDAC8 activity in neuroblastoma tumor cells. The slow kinetics for direct oxidation of HDAC8 by hydrogen peroxide suggests that transmitters of oxidative equivalents are required to transfer the H O signal to HDAC8.
    Keywords: Hdac8 Stability ; Redox Kinetics ; Redox Signaling ; Nox ; Disulfide Bond ; Ros ; Hydrogen Peroxide ; Biology
    ISSN: 2213-2317
    E-ISSN: 2213-2317
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  • 2
    Language: English
    In: Cellular and Molecular Life Sciences, 2012, Vol.69(11), pp.1799-1811
    Description: Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in PA, mostly in a mutually exclusive manner, with constitutive BRAF kinase activation subsequent to gene fusion being the most frequent. The high specificity of this fusion to PA when compared with other CNS tumors has diagnostic utility. In addition, the frequency of alteration of this key pathway provides an opportunity for molecularly targeted therapy in this tumor. Here, we review the current knowledge on mechanisms of MAPK activation in PA and some of the downstream consequences of this activation, which are now starting to be elucidated both in vitro and in vivo, as well as clinical considerations and possible future directions.
    Keywords: Pilocytic ; Astrocytoma ; Low grade glioma ; LGG ; BRAF ; Fusion ; MAPK ; Senescence
    ISSN: 1420-682X
    E-ISSN: 1420-9071
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  • 3
    In: Biometrical Journal, January 2014, Vol.56(1), pp.86-106
    Description: Adaptive designs were originally developed for independent and uniformly distributed ‐values. There are trial settings where independence is not satisfied or where it may not be possible to check whether it is satisfied. In these cases, the test statistics and ‐values of each stage may be dependent. Since the probability of a type I error for a fixed adaptive design depends on the true dependence structure between the ‐values of the stages, control of the type I error rate might be endangered if the dependence structure is not taken into account adequately. In this paper, we address the problem of controlling the type I error rate in two‐stage adaptive designs if any dependence structure between the test statistics of the stages is admitted (worst case scenario). For this purpose, we pursue a copula approach to adaptive designs. For two‐stage adaptive designs without futility stop, we derive the probability of a type I error in the worst case, that is for the most adverse dependence structure between the ‐values of the stages. Explicit analytical considerations are performed for the class of inverse normal designs. A comparison with the significance level for independent and uniformly distributed ‐values is performed. For inverse normal designs without futility stop and equally weighted stages, it turns out that correcting for the worst case is too conservative as compared to a simple Bonferroni design.
    Keywords: Adaptive Designs ; Copulas ; Dependent Test Statistics ; Inflation Of Type I Error Rate ; Inverse Normal Method
    ISSN: 0323-3847
    E-ISSN: 1521-4036
    Source: John Wiley & Sons, Inc.
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  • 4
    Language: English
    In: Cells, 01 April 2015, Vol.4(2), pp.135-168
    Description: The exploitation of autophagy by some cancer entities to support survival and dodge death has been well-described. Though its role as a constitutive process is important in normal, healthy cells, in the milieu of malignantly transformed and highly proliferative cells, autophagy is critical for escaping metabolic and genetic stressors. In recent years, the importance of histone deacetylases (HDACs) in cancer biology has been heavily investigated, and the enzyme family has been shown to play a role in autophagy, too. HDAC inhibitors (HDACi) are being integrated into cancer therapy and clinical trials are ongoing. The effect of HDACi on autophagy and, conversely, the effect of autophagy on HDACi efficacy are currently under investigation. With the development of HDACi that are able to selectively target individual HDAC isozymes, there is great potential for specific therapy that has more well-defined effects on cancer biology and also minimizes toxicity. Here, the role of autophagy in the context of cancer and the interplay of this process with HDACs will be summarized. Identification of key HDAC isozymes involved in autophagy and the ability to target specific isozymes yields the potential to cripple and ultimately eliminate malignant cells depending on autophagy as a survival mechanism.
    Keywords: Histone Deacetylase Inhibitor ; Cancer ; Hdac6 ; Hdac10 ; Autophagic Flux ; Targeted Therapy ; Biology
    E-ISSN: 2073-4409
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  • 5
    Language: English
    In: Autophagy, 05 December 2013, Vol.9(12), pp.2163-2165
    Description: Neuroblastoma is the most common extracranial solid tumor in childhood. Despite intense multimodal therapy and many improvements through basic scientific and clinical research, the successful response of advanced-stage patients to chemotherapy remains poor. Autophagy is a cytoprotective mechanism...
    Keywords: Hdac10 ; Neuroblastoma ; Drug Resistance ; Hdac-Inhibitor ; Lysosome ; Macroautophagy ; Biology
    ISSN: 1554-8627
    E-ISSN: 1554-8635
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  • 6
    Language: English
    In: FEBS Letters, 1997, Vol.408(3), pp.255-260
    Description: In contrast to the cell-cycle-dependent histone genes, replacement histone genes are transcribed independently of DNA replication and their expression is upregulated during differentiation. We have investigated the transcriptional regulation of the recently characterized human replacement histone gene H3.3B. Using reporter gene assays of promoter-luciferase gene-constructs, we show that promoter activity largely depends on an intact Oct and CRE/TRE element within the proximal 145 bp of the promoter. DNase I footprinting revealed binding of proteins to a 40-bp region covering these two elements. Band shift experiments identified binding proteins as Oct-1 and factors of the CREB/ATF and AP-1 family, respectively. The unexpected transcriptional regulation of this replacement histone gene is discussed.
    Keywords: Histone Gene Regulation ; Replacement Histone Gene ; Histone H3.3b ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0014-5793
    E-ISSN: 1873-3468
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  • 7
    In: Nature Genetics, 2017
    Description: Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.
    Keywords: Gene Expression -- Research ; Enzyme Inhibitors -- Testing ; Retrotransposons -- Properties ; Genetic Research;
    ISSN: 1061-4036
    E-ISSN: 1546-1718
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  • 8
    Language: English
    In: Human Genetics, 2016, Vol.135(5), pp.469-475
    Description: Neurofibromatosis type 1 (NF1) is a common monogenic disorder whereby affected individuals are predisposed to developing CNS tumors, including optic pathway gliomas (OPGs, occurring in ~15 to 20 % of cases). So far, no definite genotype–phenotype correlation determining NF1 patients at risk for tumor formation has been described, although enrichment for mutations in the 5′ region of the NF1 gene in OPG patients has been suggested. We used whole exome sequencing, targeted sequencing, and copy number analysis to screen 77 unrelated NF1 patients with ( n  = 41) or without ( n  = 36; age ≥10 years) optic pathway glioma for germline NF1 alterations. We identified germline NF1 mutations in 69 of 77 patients (90 %), but no genotype–phenotype correlation was observed. Our data using a larger patient cohort did not confirm the previously reported clustering of mutations in the 5′ region of the NF1 gene in patients with OPG. Thus, NF1 mutation location should not currently be used as a clinical criterion to assess the risk of developing OPGs.
    Keywords: Phenotype Correlation ; Exome Sequencing ; Optic Pathway Glioma ; Exome Enrichment ; Somatic Copy Number Alteration
    ISSN: 0340-6717
    E-ISSN: 1432-1203
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  • 9
    Language: English
    In: Cell, 20 January 2012, Vol.148(1-2), pp.59-71
    Description: Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer. ► Complex chromosomal alterations (chromothripsis) observed in medulloblastomas ► Cancers with such alterations harbor TP53 mutations ► Context-specific link between the status of p53 and likelihood of chromothripsis ► p53 status and chromothripsis also correlate with aggressive acute myeloid leukemia Connecting p53 status and chromothripsis in specific types of cancer provides a genetic basis for the more aggressive forms of medulloblastoma and leukemia.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 10
    Language: English
    In: Nature medicine, 2016, Vol.22(11), pp.1314-1320
    Description: Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in similar to 10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response
    Keywords: Medicine ; Biology;
    ISSN: 1078-8956
    ISSN: 1546-170x
    E-ISSN: 1546170X
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