A5014165324- DNA Repair Mechanisms
- Advanced Fluorescence Microscopy Techniques
- Pancreatic and Hepatic Oncology Research
- Cell Image Analysis Techniques
- DNA and Nucleic Acid Chemistry
- PARP inhibition in cancer therapy
- CRISPR and Genetic Engineering
- Cellular transport and secretion
- Genomics and Chromatin Dynamics
- Bacteriophages and microbial interactions
- Gallbladder and Bile Duct Disorders
- Diffusion and Search Dynamics
- Retinal Development and Disorders
- RNA and protein synthesis mechanisms
- Microtubule and mitosis dynamics
- Advanced Electron Microscopy Techniques and Applications
- Protease and Inhibitor Mechanisms
- Advanced biosensing and bioanalysis techniques
- Ubiquitin and proteasome pathways
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Receptor Mechanisms and Signaling
- Phosphodiesterase function and regulation
- Bacterial Genetics and Biotechnology
- Peptidase Inhibition and Analysis
- Analytical Chemistry and Sensors
The Netherlands Cancer Institute
2015-2024
Oncode Institute
2018-2024
Erasmus MC Cancer Institute
2023-2024
Erasmus MC
2022-2023
Erasmus University Rotterdam
2022-2023
Cancer Genomics Centre
2016-2018
Hospital Universitario de Gran Canaria Doctor Negrín
2018
Institute of Cell Biology
2014
Leiden University
2009-2013
Vrije Universiteit Amsterdam
2005-2010
We investigated genome folding across the eukaryotic tree of life. find two types three-dimensional (3D) architectures at chromosome scale. Each type appears and disappears repeatedly during evolution. The architecture that an organism exhibits correlates with absence condensin II subunits. Moreover, depletion converts human to a state resembling seen in organisms such as fungi or mosquitoes. In this state, centromeres cluster together nucleoli, heterochromatin domains merge. propose...
Single Molecule Localization super-resolution Microscopy (SMLM) has become a powerful tool to study cellular architecture at the nanometer scale. In SMLM, single fluorophore labels are made repeatedly switch on and off ("blink"), their exact locations determined by mathematically finding centers of individual blinks. The image quality obtainable SMLM critically depends efficacy blinking (brightness, fraction molecules in on-state) preparation longevity labeling density. Recent work...
When DNA-binding proteins search for their specific binding site on a DNA molecule they alternate between linear 1-dimensional diffusion along the molecule, mediated by nonspecific binding, and 3-dimensional volume excursion events successive dissociation from rebinding to DNA. If is kept in straight configuration, instance, optical tweezers, these excursions may be divided into long short hops These correspond immediate rebindings after such that event occurs at close of preceding...
Many genetic processes depend on proteins interacting with specific sequences DNA. Despite the large excess of nonspecific DNA in cell, can locate their targets rapidly. After initial binding, they are believed to find target site by 1D diffusion (“sliding”) interspersed 3D dissociation/reassociation, a process usually referred as facilitated diffusion. The events combine short intrasegmental “hops” along contour, intersegmental “jumps” between nearby segments, and longer volume...
Abstract Clathrin lattices at the plasma membrane coat both invaginated and flat regions forming clathrin-coated pits clathrin plaques, respectively. The function regulation of in endocytosis are well understood but plaques remain enigmatic nanodomains. Here we use super-resolution microscopy, molecular genetics cell biology to show that contain machinery for clathrin-mediated adhesion, associate with filamentous actin. We also find actin polymerization promoted by N-WASP through Arp2/3...
BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, relevance the clinic remains elusive. To investigate which BRCA1/2-independent drive spontaneous vivo, we combine molecular profiling with...
A photodegradable, covalently crosslinked hydrogel system has been constructed from the biocompatible polymers dextran and poly(ethylene glycol) using acrylate–thiol Michael addition as crosslinking method. Light sensitivity of was introduced by placing a non-toxic photolabile o-nitrobenzyl moiety in between backbone acrylate group. Hydrogels were prepared under physiological conditions without need any additional reagents mixing solutions functionalized with acrylate-modified moieties...
The faithful repair of DNA double-strand breaks (DSBs) is essential to safeguard genome stability. DSBs elicit a signaling cascade involving the E3 ubiquitin ligases RNF8/RNF168 and ubiquitin-dependent assembly BRCA1-Abraxas-RAP80-MERIT40 complex. association BRCA1 with conjugates through RAP80 known be inhibitory DSB by homologous recombination (HR). However, precise regulation this mechanism remains poorly understood. Through genetic screens we identified USP26 USP37 as key...
Abstract The glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation frequently used to alleviate therapy-related side-effects. While prior studies have shown might anti-proliferative action on tumours, the underpinnings and its direct effectors non-lymphoid solid cancers remain elusive. Here, we study mechanisms response, focusing lung We show that induces reversible cancer cell dormancy...
The endosomal system constitutes a highly dynamic vesicle network used to relay materials and signals between the cell its environment.1 Once internalized, endosomes gradually mature into late acidic compartments acquire multivesicular body (MVB) organization through invagination of limiting membrane (LM) form intraluminal vesicles (ILVs).2 Cargoes sequestered ILVs can either be delivered lysosomes for degradation or secreted following fusion MVB with plasma membrane.3 It has been speculated...
To assess the feasibility, proficiency, and mastery learning curves for robotic pancreatoduodenectomy (RPD) in "second-generation" RPD centers following a multicenter training program adhering to IDEAL framework.The long reported from "pioneering" expert may discourage interested starting an program. However, be shorter that participated dedicated programs, although data are lacking. We report on trained nationwide program.Post hoc analysis of all consecutive patients undergoing 7 LAELAPS-3...
Abstract Background Although robotic pancreatoduodenectomy has shown promising outcomes in experienced high-volume centres, it is unclear whether implementation on a nationwide scale safe and beneficial. The aim of this study was to compare the early experience with versus open Netherlands. Methods This retrospective cohort all consecutive patients who underwent or were registered mandatory Dutch Pancreatic Cancer Audit (18 2014–2021), starting from first procedure per centre. main endpoints...
Cellular senescence is a largely irreversible form of cell cycle arrest triggered by various types damage and stress, including oncogene expression (termed oncogene-induced or OIS). We others have previously demonstrated that OIS occurs in human benign lesions, acting as potent tumor suppressor mechanism. Numerous phenotypic changes occur during OIS, both the cytoplasm nucleus. These include activation autophagy, catabolic process operating downregulation lamin B1, component nuclear lamina....
We report a novel technique for long-term parallel three dimensional (3D)-tracking of gold nanorods in live cells with nanometer resolution. Gold feature strong plasmon-enhanced two-photon luminescence, can be easily functionalized, and have been shown to nontoxic. These properties make very suitable vivo luminescence microscopy. By rapid multifocal scanning, we combine the advantages 3D molecular tracking methods using wide-field imaging Isolated localized resolution 4 nm xy-plane 8...
The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment enhances signaling vitronectin binding interactions with integrins. Full-length released from surface, but mechanism significance shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as GPI-specific phospholipase C...
ABSTRACT Super-resolution microscopy (SRM) allows precise localization of proteins in cellular organelles and structures, including the actin cytoskeleton. Yet sample preparation protocols for SRM are rather anecdotal still being optimized. Thus, SRM-based imaging cytoskeleton associated often remains challenging poorly reproducible. Here, we show that proper paraformaldehyde (PFA)-based preserves architecture almost as faithfully gold-standard glutaraldehyde fixation. We this fixation is...
Double strand breaks (DSBs) are highly toxic to a cell, property that is exploited in radiation therapy. A critical component for the damage induction cellular oxygen, making hypoxic tumor areas refractory efficacy of treatment. During fractionated regimen, these can be re-oxygenated. Nonetheless, hypoxia still constitutes negative prognostic factor patient’s outcome. We hypothesized this might attributed specific hypoxia-induced traits maintained upon reoxygenation. Here, we show...
Type II restriction endonucleases protect bacteria against phage infections by cleaving recognition sites on foreign double-stranded DNA (dsDNA) with extraordinary specificity. This capability arises primarily from large conformational changes in enzyme and/or upon target sequence recognition. In order to elucidate the connection between mechanics and chemistry of cleavage, we used a single-molecule approach measure rate reaction pathway EcoRV BamHI as function tension. We show that...