A5005937429- Neuroblastoma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- FOXO transcription factor regulation
- HIV Research and Treatment
- RNA Interference and Gene Delivery
- Cancer therapeutics and mechanisms
- Ubiquitin and proteasome pathways
- Microtubule and mitosis dynamics
- Immune Cell Function and Interaction
- Virus-based gene therapy research
- Cell death mechanisms and regulation
- Lung Cancer Research Studies
- Glioma Diagnosis and Treatment
- T-cell and B-cell Immunology
- Protein Degradation and Inhibitors
- Genetics, Aging, and Longevity in Model Organisms
- Education and Teacher Training
- Advanced biosensing and bioanalysis techniques
- Neuroendocrine Tumor Research Advances
- Adipose Tissue and Metabolism
- Dietary Effects on Health
- Herpesvirus Infections and Treatments
- Hippo pathway signaling and YAP/TAZ
- Biochemical and Molecular Research
- Lung Cancer Treatments and Mutations
Amsterdam University Medical Centers
2019-2023
University of Amsterdam
2011-2023
Amsterdam UMC Location University of Amsterdam
2010-2023
Cancer Center Amsterdam
2021-2023
Cancer Genomics Centre
2023
Center for Human Genetics
2012
KU Leuven
2010
Ghent University Hospital
2010
Emma Kinderziekenhuis
2010
Inserm
2010
Whole-genome sequencing of neuroblastoma, a childhood tumour the nervous system, shows that chromothripsis (a local shredding chromosomes) and mutations in genes regulating neurite growth are associated with most aggressive tumours. is used here to identify genetic defects 87 people peripheral sympathetic system. Analyses revealed few recurrent amino-acid-changing mutations, but series functioning neuritogenesis extension neuronal cones were deleted high-stage Chromothripsis, localized...
Short-term assays have suggested that RNA interference (RNAi) may be a powerful new method for intracellular immunization against human immunodeficiency virus type 1 (HIV-1) infection. However, RNAi has not yet been shown to protect cells HIV-1 in long-term replication assays. We stably introduced vectors expressing small interfering RNAs (siRNAs) directed the genome into T by retroviral transduction. report here an siRNA viral Nef gene (siRNA-Nef) confers resistance replication. This block...
HIV-1 replication can be efficiently inhibited by intracellular expression of an siRNA targeting the viral RNA. However, escape variants emerged after prolonged culturing. These RNAi-resistant viruses contain nucleotide substitutions or deletions in near targeted sequence. We observed inverse correlation between level resistance and stability siRNA/target-RNA duplex. two showed a higher than expected based on duplex stability. demonstrate that these mutations induce alternative folding RNA...
Abstract Transition between differentiation states in development occurs swift but the mechanisms leading to epigenetic and transcriptional reprogramming are poorly understood. The pediatric cancer neuroblastoma includes adrenergic (ADRN) mesenchymal (MES) tumor cell types, which differ phenotype, super-enhancers (SEs) core regulatory circuitries. These types can spontaneously interconvert, mechanism remains largely unknown. Here, we unravel how a NOTCH3 intracellular domain reprogrammed...
Two genes have a synthetically lethal relationship when the silencing or inhibiting of 1 gene is only in context mutation activation second gene. This situation offers an attractive therapeutic strategy, as inhibition such will trigger cell death tumor cells with activated oncogene but spare normal without oncogene. Here we present evidence that CDK2 to neuroblastoma MYCN amplification and over-expression. Neuroblastomas are childhood tumors often outcome. Twenty percent amplification, these...
Abstract Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with highly variable prognosis. Activation phosphoinositide 3-kinase (PI3K)/AKT pathway in neuroblastoma correlated poor patient prognosis, but precise downstream effectors mediating this effect have not been determined. Here we identify forkhead transcription factor FOXO3a as key target PI3K/AKT neuroblastoma. expression was elevated low-stage tumors and normal embryonal neuroblasts, reduced late-stage...
RNAi efficiency is influenced by local RNA structure of the target sequence. We studied this structure-based resistance in detail targeting a perfect hairpin and subsequently destabilized its tight mutation, thereby gradually exposing Although tightest hairpins were completely resistant to RNAi, we observed an inverse correlation between overall stability within specific thermodynamic (ΔG) range. Increased was shown be caused improved binding siRNA hairpins. The mutational effects vary for...
The tightly controlled network of cell cycle genes consists a core cyclin dependent kinases (CDKs) that are activated by periodically expressed cyclins. activity the cyclin-CDK complexes is regulated kinase inhibitors (CDKIs) and multiple signal transduction routes converge on cycle. Neuroblastoma pediatric tumors belong to group small round blue tumors, characterized fast proliferation. Here, we present high throughput analyses regulating in neuroblastoma. We analyzed series 82...
// Laurel T. Bate-Eya 1 , Ilona J.M. den Hartog Ida van der Ploeg Linda Schild Jan Koster Evan E. Santo Ellen M. Westerhout Rogier Versteeg Huib N. Caron 2 J. Molenaar Emmy Dolman Department of Oncogenomics, University Amsterdam, The Netherlands Pediatric Oncology, Emma Kinderziekenhuis, Academic Medical Center, Correspondence to: Dolman, e-mail: memdolman@gmail.com Keywords: neuroblastoma, ABT199, BCL-2, MCL-1, resistance Received: November 26, 2015 Accepted: March 18, 2016 Published: April...
Abstract Cancer therapy frequently fails due to the emergence of resistance. Many tumors include phenotypically immature tumor cells, which have been implicated in Neuroblastoma cells can adopt a lineage-committed adrenergic (ADRN) or an mesenchymal (MES) state. They differ epigenetic landscape and transcription factors, MES are more resistant chemotherapy. Here we analyzed response targeted drugs. Activating anaplastic lymphoma kinase (ALK) mutations found neuroblastoma ALK inhibitors...
Despite intensive therapy, children with high-risk neuroblastoma are at risk of treatment failure. We applied a multiomic system approach to evaluate metabolic vulnerabilities in human neuroblastoma. combined metabolomics, CRISPR screening, and transcriptomic data across more than 700 solid tumor cell lines identified dihydroorotate dehydrogenase (DHODH), critical enzyme pyrimidine synthesis, as potential target. Of note, DHODH inhibition is currently under clinical investigation patients...
RNA interference (RNAi) has proven to be a powerful tool suppress gene expression and can used as therapeutic strategy against human pathogenic viruses such immunodeficiency virus type 1 (HIV-1). Theoretically, RNAi-mediated inhibition occur at two points in the replication cycle, upon viral entry before reverse transcription of genome, on newly transcribed transcripts. There have been conflicting results whether RNAi target genome infecting HIV-1 particles. We addressed this issue with...
Eradication of HIV-1 from an infected individual cannot be achieved by current drug regimens. Viral reservoirs established early during the infection remain unaffected anti-retroviral therapy and are able to replenish systemic upon interruption treatment. Therapeutic targeting viral latency will require a better understanding basic mechanisms underlying establishment long-term maintenance in resting memory CD4 T cells, most prominent reservoir transcriptional silent provirus. However,...
Intronic single-nucleotide polymorphisms (SNPs) in FOXO3A are associated with human longevity. Currently, it is unclear how these SNPs alter functionality and physiology, thereby influencing lifespan. Here, we identify a primate-specific transcriptional isoform, FOXO3A-Short (FOXO3A-S), encoding major longevity-associated SNP, rs9400239 (C or T), within its 5' untranslated region. The FOXO3A-S mRNA highly expressed the skeletal muscle has very limited expression other tissues. We find that...
Abstract Background Neuroblastoma are pediatric tumors of the sympathetic nervous system with a poor prognosis. Apoptosis is often deregulated in cancer cells, but only few defects apoptotic routes have been identified neuroblastoma. Methods Here we investigated genomic aberrations affecting genes intrinsic pathway We analyzed DNA profiling data (CGH and SNP arrays) mRNA expression 31 dataset 88 neuroblastoma using R2 bioinformatic platform ( http://r2.amc.nl ). BIRC6 was selected for...
The latent HIV-1 reservoir in treated patients primarily consists of resting memory CD4+ T cells. Stimulating the T-cell receptor (TCR), which facilitates transition into effector cells, is most effective strategy to purge these latently infected Here we supply evidence that TCR-stimulated cells still frequently harbor HIV-1.Primary were used a latency assay with or without dendritic (DCs) and reversion was determined, presence absence specific pathway inhibitors.Renewed TCR-stimulation...
Human pathogenic viruses can be targeted by therapeutic strategies based on RNA interference. Whereas the administration of synthetic short interfering RNAs (siRNAs) may transiently inhibit viral replication, long-term inhibition achieved through stable intracellular expression siRNAs or hairpin (shRNAs). Both approaches face serious problems with delivery to right cells in an infected individual. We explored potential a replicating HIV-based vector deliver antiviral shRNA cassette into...
Abstract Neuroblastoma is a pediatric tumor of the adrenergic sympathetic lineage. Most high risk neuroblastoma go in complete clinical remission by chemotherapy, which subsequently complemented retinoic acid (RA) maintenance therapy. However, unresolved mechanisms most tumors ultimately relapse as therapy-resistant disease. cell lines were recently found to include, besides lineage committed (ADRN) cells, also immature mesenchymal (MES) cells. Here, we report that MES-type cells synthesize...