A5012879897- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- PARP inhibition in cancer therapy
- Carcinogens and Genotoxicity Assessment
- Pesticide and Herbicide Environmental Studies
- Genetics, Bioinformatics, and Biomedical Research
- Genetically Modified Organisms Research
- Cancer-related Molecular Pathways
- BRCA gene mutations in cancer
- Weed Control and Herbicide Applications
- Genetics, Aging, and Longevity in Model Organisms
- Genomics, phytochemicals, and oxidative stress
- Advanced Chemical Sensor Technologies
- Chemical Reactions and Isotopes
- bioluminescence and chemiluminescence research
- Pluripotent Stem Cells Research
- Computational Drug Discovery Methods
- Effects and risks of endocrine disrupting chemicals
- Integrated Circuits and Semiconductor Failure Analysis
- Mitochondrial Function and Pathology
- Microtubule and mitosis dynamics
- Venous Thromboembolism Diagnosis and Management
- Endoplasmic Reticulum Stress and Disease
- Advanced Breast Cancer Therapies
- Science, Research, and Medicine
AcXys Technologies (France)
2021-2025
Erasmus MC
2015-2020
Oncode Institute
2018-2019
Erasmus University Rotterdam
2012-2019
Breast Cancer Now
2017-2018
Institute of Cancer Research
2017-2018
Cell and Gene Therapy Catapult
2017
Although PARP inhibitors (PARPi) target homologous recombination defective tumours, drug resistance frequently emerges, often via poorly understood mechanisms. Here, using genome-wide and high-density CRISPR-Cas9 "tag-mutate-enrich" mutagenesis screens, we identify close to full-length mutant forms of PARP1 that cause in vitro vivo PARPi resistance. Mutations both within outside the DNA-binding zinc-finger domains alter trapping, as does a mutation found clinical case This reinforces...
Proper repair of DNA double strand breaks (DSBs) is vital for the preservation genomic integrity. There are two main pathways that DSBs, Homologous recombination (HR) and Non-homologous end-joining (NHEJ). HR restricted to S G2 phases cell cycle due requirement sister chromatid as a template, while NHEJ active throughout does not rely on template. The balance between both essential genome stability numerous assays have been developed measure efficiency pathways. Several proteins known affect...
Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to cancer. BRCA1 plays an important role DNA double-strand break (DSB) repair via homologous recombination (HR), which is for tumor suppression. Although BRCA1-deficient cells are highly sensitive treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors clinical trials. It...
Elevated APOBEC3B expression in tumours correlates with a kataegic pattern of localised hypermutation. We assessed the cellular phenotypes associated high-level and influence p53 status on these using an isogenic system. used RNA interference cells inducible DNA damage response (DDR) biomarkers. The mutational effects were whole-genome sequencing. In vitro small-molecule inhibitor sensitivity profiling was to identify candidate therapeutic vulnerabilities. Although increased incorporation...
Whether glyphosate-based herbicides (GBHs) are more potent than glyphosate alone at activating cellular mechanisms, which drive carcinogenesis remain controversial. As GBHs cytotoxic glyphosate, we reasoned they may also be capable of carcinogenic pathways. We tested this hypothesis by comparing the effects with Roundup both in vitro and vivo. First, was compared representative GBHs, namely MON 52276 (European Union), 76473 (United Kingdom), 76207 States) using mammalian stem cell-based...
Abstract Although PARP inhibitors target BRCA1- or BRCA2-mutant tumor cells, drug resistance is a problem. inhibitor sometimes associated with the presence of secondary “revertant” mutations in BRCA1 BRCA2. Whether mutant cells are selected for Darwinian fashion by treatment unclear. Furthermore, how might be therapeutically targeted also poorly understood. Using CRISPR mutagenesis, we generated isogenic cell models BRCA2 mutations. these heterogeneous vitro culture vivo xenograft...
The toxicity of co-formulants present in glyphosate-based herbicides (GBHs) has been widely discussed leading to the European Union banning polyoxyethylene tallow amine (POEA). We identified most commonly used POEA, known as POE-15 (POE-15), US GBH RangerPro. Cytotoxicity assays using human intestinal epithelial Caco-2 and hepatocyte HepG2 cell lines showed that RangerPro are far more cytotoxic than glyphosate alone. but not caused necrosis both lines, oxidative stress cells. further tested...
The current generation of carcinogenicity tests is often insufficient to predict cancer outcomes from pesticide exposures. In order facilitate health risk assessment, International Agency for Research on Cancer identified 10 key characteristics which are commonly exhibited by human carcinogens. ToxTracker panel six validated GFP-based mouse embryonic stem reporter cell lines designed measure a number these carcinogenic properties namely DNA damage, oxidative stress and the unfolded protein...
ABSTRACT N‐Nitrosamines (NAs) are probable human carcinogens and were detected as impurities in pharmaceuticals, which led to a concern for health. NAs require metabolic activation before they become mutagenic, not all mutagenic since their reactivity is related structure. While some potent mutagens vivo, vitro metabolization with exogenous S9 liver extract generally less efficient. an enhanced bacterial mutagenicity protocol was recently developed, uses increased concentrations of extracts,...
Abstract Background Testing for developmental toxicity according to the current regulatory guidelines requires large numbers of animals, making these tests very resource intensive, time‐consuming, and ethically debatable. Over past decades, several alternative in vitro assays have been developed, but often suffered from low predictability inability provide a mechanistic understanding toxicity. Methods To identify embryotoxic compounds, we developed human induced pluripotent stem cells...
The tumor suppressor BRCA2 is essential for homologous recombination (HR), replication fork stability and DNA interstrand crosslink (ICL) repair in vertebrates. We show that ectopic production of HSF2BP, a BRCA2-interacting protein required meiotic HR during mouse spermatogenesis, non-germline human cells acutely sensitize them to ICL-inducing agents (mitomycin C cisplatin) PARP inhibitors, resulting phenotype characteristic from Fanconi anemia (FA) patients. biochemically recapitulate the...
Abstract Understanding the mode-of-action (MOA) of genotoxic compounds and differentiating between direct DNA interaction indirect genotoxicity is crucial for their reliable safety assessment. ToxTracker a stem cell-based reporter assay that detects activation various cellular responses are associated with cancer. consists 6 different GFP cell lines can detect induction damage, oxidative stress, protein damage in single test. The thereby provide insight into MOA compounds. Genotoxicity...
The DNA damage response (DDR) is a designation for number of pathways that protects our from various damaging agents. In normal cells, the DDR extremely important maintaining genome integrity, but in cancer cells these mechanisms counteract therapy-induced damage. Inhibition could therefore be used to increase efficacy anti-cancer treatments. Hyperthermia an example such treatment-it inhibits sub-pathway DDR, called homologous recombination (HR). It does so by inducing proteasomal...
ToxTracker is an in vitro mammalian stem cell-based reporter assay that detects activation of specific cellular signaling pathways (DNA damage, oxidative stress, and/or protein damage) upon chemical exposure using flow cytometry. Here we used quantitative methods to empirically analyze historical control data, and dose-response data across a wide range reference chemicals. First, analyzed define fold-change threshold for identification significant positive response. Next, the benchmark dose...
In vitro (geno)toxicity assessment of electronic vapour products (EVPs), relative to conventional cigarette, currently uses assays, including the micronucleus and Ames tests. Whilst informative on induction a finite endpoint risk posed by test articles, such assays could benefit from mechanistic supplementation. The ToxTracker Aneugen Clastogen Evaluation analysis can indicate activation reporters associated with (geno)toxicity, DNA damage, oxidative stress, p53-related stress response...
Bladder cancer has a high incidence with significant morbidity and mortality. Attenuated expression of the DNA damage response protein Xeroderma Pigmentosum complementation group C (XPC) been described in bladder cancer. XPC plays an essential role as main initiator damage-detector global genome nucleotide excision repair (NER) UV-induced lesions, bulky adducts intrastrand crosslinks, such those made by chemotherapeutic agent Cisplatin. Hence, might be informative biomarker to guide...
Extrachromosomal DNA can integrate into the genome with no sequence specificity producing an insertional mutation. This process, which is referred to as random integration (RI), requires a double stranded break (DSB) in genome. Inducing DSBs by various means, including ionizing radiation, increases frequency of integration. Here we report that non-lethal physiologically relevant doses radiation (10-100 mGy), within range produced medical imaging equipment, stimulate RI transfected and viral...
Cobalt metal and cobalt sulfate are carcinogenic in rodents following inhalation exposure. The pre-carcinogenic effects associated with exposure to these substances include oxidative stress genotoxicity. Some, but not all, induce vitro clastogenicity or an increase micronuclei. As a result, classified genotoxic carcinogens, having major impacts on their risk assessment, e.g. assumption of non-thresholded dose response. Here, we investigated the potential nine cause genotoxicity using...
Abstract Whether glyphosate-based herbicides (GBHs) are more potent than glyphosate alone at activating cellular mechanisms, which drive carcinogenesis remains controversial. As GBHs cytotoxic that glyphosate, we reasoned they may also be capable of carcinogenic pathways. We tested this hypothesis by comparing the effects with Roundup both in vitro and vivo . First, was compared representative namely MON 52276 (EU), 76473 (UK) 76207 (USA) using mammalian stem cell-based ToxTracker system....
To determine the utility of ToxTracker assay in animal alternative testing strategies, genotoxic potential four fragrance materials (2-octen-4-one, lauric aldehyde, veratraldehyde, and p-methoxy cinnamaldehyde) were tested assay. These have been previously evaluated an vitro as well vivo micronucleus assay, conducted per OECD guidelines. In addition to these studies, reconstructed human skin studies on all materials. All positive but negative both 3D assays. The combination with silico...