A5044639892- Markov Chains and Monte Carlo Methods
- Advanced Breast Cancer Therapies
- Stochastic processes and statistical mechanics
- CRISPR and Genetic Engineering
- Cryptographic Implementations and Security
- DNA Repair Mechanisms
- Chaos-based Image/Signal Encryption
- Immunotherapy and Immune Responses
- Algorithms and Data Compression
- Coding theory and cryptography
- Cancer Treatment and Pharmacology
- Protein Degradation and Inhibitors
- Point processes and geometric inequalities
- Cancer, Hypoxia, and Metabolism
- Cell Image Analysis Techniques
- CAR-T cell therapy research
- Mathematical Dynamics and Fractals
- Cancer Immunotherapy and Biomarkers
- Advanced Combinatorial Mathematics
- Computational Drug Discovery Methods
- Advanced Graph Theory Research
- Cryptography and Data Security
- bioluminescence and chemiluminescence research
- Histone Deacetylase Inhibitors Research
- Cancer Research and Treatments
The Netherlands Cancer Institute
2017-2025
Oncode Institute
2019-2024
University of California, Davis
2006-2023
The University of Texas MD Anderson Cancer Center
2022
Dutch Cancer Society
2022
Rockefeller University
2018
Cancer Genomics Centre
2017
Elizabeth City State University
2016
University of California System
2003-2014
Indiana University Bloomington
2005
Senescence is a proliferation arrest that can result from variety of stresses. Cancer cells also undergo senescence, but the stresses provoke cancer to senescence are unclear. Here, we use both functional genetic and compound screens in harboring reporter activated during find targets induce senescence. We show suppression SWI/SNF component SMARCB1 induces melanoma through strong activation MAP kinase pathway. From screen, identified multiple aurora inhibitors as potent inducers RAS mutant...
DNA double-strand break (DSB) repair is mediated by multiple pathways. It thought that the local chromatin context affects pathway choice, but underlying principles are poorly understood. Using a multiplexed reporter assay in combination with Cas9 cutting, we systematically measure relative activities of three DSB pathways as function >1,000 genomic locations. This reveals non-homologous end-joining (NHEJ) broadly biased toward euchromatin, while contribution microhomology-mediated (MMEJ)...
Abstract Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity such aberrant signaling. Although inhibition signaling has been explored extensively, there is increasing evidence overactivation same can also disrupt cancer cause lethality. We show here protein phosphatase 2A (PP2A) hyperactivates multiple engages responses in colon cells. Genetic compound screens...
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...
Drug-tolerant persisters (DTPs) are a rare subpopulation of cells within tumor that can survive therapy through nongenetic adaptive mechanisms to develop relapse and repopulate the following drug withdrawal. Using cancer cell line with an engineered suicide switch kill proliferating cells, we perform both genetic screens compound identify inhibition bromodomain extraterminal domain (BET) proteins as selective vulnerability DTPs. BET inhibitors especially detrimental DTPs have reentered cycle...
β-catenin is a transcriptional cofactor crucial in forming biomolecular condensates that drive WNT target gene transcription. Its pathological accumulation the nucleus critical step WNT-driven cancers, such as colorectal cancer. Disrupting promising cancer treatment strategy, but no clinical applications currently exist. In this study, we developed Nanobody Enabled Condensate Observation (NECO) screening platform to identify small molecules modulate condensates. The revealed compounds either...
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...
DNA double-strand breaks are repaired by multiple pathways, including non-homologous end-joining (NHEJ) and microhomology-mediated (MMEJ). The balance of these pathways is dependent on the local chromatin context, but underlying mechanisms poorly understood. By combining knockout screening with a dual MMEJ:NHEJ reporter inserted in 19 different environments, we identified dozens repair proteins that modulate pathway state. Proteins favor NHEJ mostly synergize euchromatin, while MMEJ...
Kras-driven non–small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels Ezh2, the enzymatic subunit polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice orthotopic NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes...
We solve an open problem concerning the mixing time of symmetric random walk on n-dimensional cube truncated by a hyperplane, showing that it is polynomial in n. As consequence, we obtain fully randomized approximation scheme for counting feasible solutions 0-1 knapsack problem. The results extend to case any fixed number hyperplanes. key ingredient our analysis combinatorial construction call "balanced almost uniform permutation," which independent interest.
Abstract The efficiency and outcome of CRISPR/Cas9 editing depends on the chromatin state at cut site. It has been shown that changing can influence both repair outcome, epigenetic drugs have used to improve Cas9 editing. However, because target proteins these are not homogeneously distributed across genome, efficacy may be expected vary from locus locus. Here, we systematically analyzed this context-dependency for 160 drugs. We a human cell line with 19 stably integrated reporters induce...
// Amy J.C. Dohmen 1 , Xiaohang Qiao 2 Anja Duursma Ruud H. Wijdeven Cor Lieftink 3 Floor Hageman 4 Ben Morris Pasi Halonen Conchita Vens Michiel W.M. van den Brekel 1, 5 Huib Ovaa 6, 7 Jacques Neefjes and Charlotte L. Zuur Department of Head Neck Oncology Surgery, Antoni Leeuwenhoek Hospital, Amsterdam, The Netherlands Division Cell Biology, Cancer Institute, NKI Robotics Screening Center, Biological Stress Response, Oral Maxillofacial Academic Medical University 6 Chemical Immunology,...
Abstract Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion is regulated via ubiquitination of PCNA, independently polymerase REV1. The division labor between PCNA-ubiquitination REV1 in interstrand crosslink unclear. Inhibition either these pathways has been proposed as a strategy to increase cytotoxicity platinating agents cancer treatment. Here, we defined importance for DNA mammalian ICL...
Abstract Cross-presentation of tumor antigens by dendritic cells (DC) is crucial to prime, stimulate and restimulate CD8+ T cells. This process important in initiating maintaining an antitumor response. Here, we show that the presence conventional type 1 DCs (cDC1), a DC subtype excels cross-presentation, correlated with response neoadjuvant immune checkpoint blockade (ICB) melanoma. led us hypothesize patients failing respond ICB could benefit from enhanced cross-presentation antigens. We...
We obtain a tight bound of O(L2logk) for the mixing time exclusion process in Zd/LZd with k≤½Ld particles. Previously best bound, based on log Sobolev constant determined by Yau, was not small k. When dependence dimension d is considered, our bounds are an improvement all also get relaxation that lower order than previous estimates: O(L2logd) improves earlier O(L2d) obtained Quastel. Our proof auxiliary Markov chain we call chameleon process, which may be independent interest.
We solve an open problem concerning the relaxation time (inverse spectral gap) of zero range process in Zd/LZd with constant rate, proving a tight upper bound O((ρ+1)2L2), where ρ is density particles.
Abstract Antibody production by the B cell compartment is a crucial part of adaptive immune response. Dysregulated antibody in form autoantibodies can cause autoimmune disease. To date, B‐cell depletion with anti‐CD20 antibodies commonly applied autoimmunity, but pre‐existing plasma cells are not eliminated this way. Alternative ways more selective inhibition would add to treatment these diseases. explore novel therapeutic targets signaling pathways essential for plasmablast formation and/or...