216 research outputs found
Orofacial pain in older people with dementia
Lobbezoo, F. [Promotor]Hertogh, C.M.P.M. [Promotor]Scherder, E.J.A. [Copromotor]Perez, R.S.G.M. [Copromotor
Oral health and orofacial pain in older people with dementia:a systematic review with focus on dental hard tissues
Orofacial pain and its potential oral causes in older people with mild cognitive impairment or dementia
Pain Assessment in Impaired Cognition (PAIC):Content validity of the Dutch version of a new and universal tool to measure pain in dementia
Prognostically useful gene-expression profiles in acute myeloid leukemia
BACKGROUND: In patients with acute myeloid leukemia (AML) a combination of
methods must be used to classify the disease, make therapeutic decisions,
and determine the prognosis. However, this combined approach provides
correct therapeutic and prognostic information in only 50 percent of
cases. METHODS: We determined the gene-expression profiles in samples of
peripheral blood or bone marrow from 285 patients with AML using
Affymetrix U133A GeneChips containing approximately 13,000 unique genes or
expression-signature tags. Data analyses were carried out with Omniviz,
significance analysis of microarrays, and prediction analysis of
microarrays software. Statistical analyses were performed to determine the
prognostic significance of cases of AML with specific molecular
signatures. RESULTS: Unsupervised cluster analyses identified 16 groups of
patients with AML on the basis of molecular signatures. We identified the
genes that defined these clusters and determined the minimal numbers of
genes needed to identify prognostically important clusters with a high
degree of accuracy. The clustering was driven by the presence of
chromosomal lesions (e.g., t(8;21), t(15;17), and inv(16)), particular
genetic mutations (CEBPA), and abnormal oncogene expression (EVI1). We
identified several novel clusters, some consisting of specimens with
normal karyotypes. A unique cluster with a distinctive gene-expression
signature included cases of AML with a poor treatment outcome.
CONCLUSIONS: Gene-expression profiling allows a comprehensive
classification of AML that includes previously identified genetically
defined subgroups and a novel cluster with an adverse prognosis
Lethal neonatal bone marrow failure syndrome with multiple congenital abnormalities, including limb defects, due to a constitutional deletion of 3’ MECOM
Phosphorylation of the Leukemic Oncoprotein EVI1 on Serine 196 Modulates DNA Binding, Transcriptional Repression and Transforming Ability
The EVI1 (ecotropic viral integration site 1) gene at 3q26 codes for a transcriptional regulator with an essential role in haematopoiesis. Overexpression of EVI1 in acute myeloid leukaemia (AML) is frequently associated with 3q26 rearrangements and confers extremely poor prognosis. EVI1 mediates transcriptional regulation, signalling, and epigenetic modifications by interacting with DNA, proteins and protein complexes. To explore to what extent protein phosphorylation impacts on EVI1 functions, we analysed endogenous EVI1 protein from a high EVI1 expressing Fanconi anaemia (FA) derived AML cell line. Mass spectrometric analysis of immunoprecipitated EVI1 revealed phosphorylation at serine 196 (S196) in the sixth zinc finger of the N-terminal zinc finger domain. Mutated EVI1 with an aspartate substitution at serine 196 (S196D), which mimics serine phosphorylation of this site, exhibited reduced DNA-binding and transcriptional repression from a gene promotor selectively targeted by the N-terminal zinc finger domain. Forced expression of the S196D mutant significantly reduced EVI1 mediated transformation of Rat1 fibroblasts. While EVI1-mediated serial replating of murine haematopoietic progenitors was maintained by EVI1-S196D, this was associated with significantly higher Evi1-trancript levels compared with WT-EVI1 or EVI1-S196A, mimicking S196 non-phosphorylated EVI1. These data suggest that EVI1 function is modulated by phosphorylation of the first zinc finger domain
HeatMapper: powerful combined visualization of gene expression profile correlations, genotypes, phenotypes and sample characteristics
BACKGROUND: Accurate interpretation of data obtained by unsupervised analysis of large scale expression profiling studies is currently frequently performed by visually combining sample-gene heatmaps and sample characteristics. This method is not optimal for comparing individual samples or groups of samples. Here, we describe an approach to visually integrate the results of unsupervised and supervised cluster analysis using a correlation plot and additional sample metadata. RESULTS: We have developed a tool called the HeatMapper that provides such visualizations in a dynamic and flexible manner and is available from . CONCLUSION: The HeatMapper allows an accessible and comprehensive visualization of the results of gene expression profiling and cluster analysis
RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBP alpha- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction
Acute myeloid leukemia (AML) is associated with mutations in transcriptional and epigenetic regulator
genes impairing myeloid differentiation. The t(8;21)
(q22;q22) translocation generates the RUNX1-ETO
fusion protein, which interferes with the hematopoietic master regulator RUNX1. We previously showed
that the maintenance of t(8;21) AML is dependent on
RUNX1-ETO expression. Its depletion causes extensive changes in transcription factor binding, as well
as gene expression, and initiates myeloid differentiation. However, how these processes are connected
within a gene regulatory network is unclear. To
address this question, we performed Promoter-Capture Hi-C assays, with or without RUNX1-ETO depletion and assigned interacting cis-regulatory elements
to their respective genes. To construct a RUNX1-
ETO-dependent gene regulatory network maintaining
AML, we integrated cis-regulatory element interactions with gene expression and transcription factor
binding data. This analysis shows that RUNX1-ETO
participates in cis-regulatory element interactions.
However, differential interactions following RUNX1-
ETO depletion are driven by alterations in the binding
of RUNX1-ETO-regulated transcription factors
The Oncoprotein EVI1 and the DNA Methyltransferase Dnmt3 Co-Operate in Binding and De Novo Methylation of Target DNA
EVI1 has pleiotropic functions during murine embryogenesis and its targeted disruption leads to prenatal death by severely affecting the development of virtually all embryonic organs. However, its functions in adult tissues are still unclear. When inappropriately expressed, EVI1 becomes one of the most aggressive oncogenes associated with human hematopoietic and solid cancers. The mechanisms by which EVI1 transforms normal cells are unknown, but we showed recently that EVI1 indirectly upregulates self-renewal and cell-cycling genes by inappropriate methylation of CpG dinucleotides in the regulatory regions of microRNA-124-3 (miR-124-3), leading to the repression of this small gene that controls normal differentiation and cell cycling of somatic cells. We used the regulatory regions of miR-124-3 as a read-out system to investigate how EVI1 induces de novo methylation of DNA. Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro. This protein complex targets and binds to a precise region of miR-124-3 that is necessary for repression of a reporter gene by EVI1. Based on our findings, we propose that in cooperation with Dnmt3a/b EVI1 regulates the methylation of DNA as a sequence-specific mediator of de novo DNA methylation and that inappropriate EVI1 expression contributes to carcinogenesis through improper DNA methylation
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