A5003472571- Biomedical Ethics and Regulation
- Cancer Genomics and Diagnostics
- Neuroblastoma Research and Treatments
- PARP inhibition in cancer therapy
- Single-cell and spatial transcriptomics
- DNA Repair Mechanisms
- CAR-T cell therapy research
- Sarcoma Diagnosis and Treatment
- Cell Image Analysis Techniques
- Cancer Research and Treatments
- Cancer therapeutics and mechanisms
- RNA modifications and cancer
- Computational Drug Discovery Methods
- Acute Myeloid Leukemia Research
- Science, Research, and Medicine
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Pesticide Exposure and Toxicity
- Folate and B Vitamins Research
- Immune cells in cancer
- Retinal Development and Disorders
- Tumors and Oncological Cases
- Cancer Cells and Metastasis
- Cell death mechanisms and regulation
St. Jude Children's Research Hospital
2019-2024
University of Tennessee Health Science Center
2021
Children's Research Hospital
2019
Mayo Clinic
2010-2016
WinnMed
2010-2016
University Medical Center
2012
University Hospital and Clinics
2012
Université Laval
2012
Mayo Clinic in Arizona
2011
Johannes Gutenberg University Mainz
2007
Abstract Single-cell genomics is essential to chart tumor ecosystems. Although single-cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated fresh tumors, single-nucleus (snRNA-Seq) needed profile frozen or hard-to-dissociate tumors. Each requires customization different tissue and types, posing a barrier adoption. Here, we have developed systematic toolbox for profiling clinical samples using scRNA-Seq snRNA-Seq, respectively. We analyzed 216,490 nuclei 40 across 23 specimens spanning...
Poly(ADP-ribose) polymerase (PARP) inhibitors are strikingly toxic to cells with defects in homologous recombination (HR). The mechanistic basis for these findings is incompletely understood. Here, we show that PARP inhibitor treatment induces phosphorylation of DNA-dependent protein kinase substrates and stimulates error-prone nonhomologous end joining (NHEJ) selectively HR-deficient cells. Notably, inhibiting activity reverses the genomic instability previously reported after inhibition....
We report herein thermally responsive elastin-like polypeptides (ELPs) in a linear AB diblock architecture with an N-terminal peptide ligand that self-assemble into spherical micelles when heated slightly above body temperature. A series of 10 ELP block copolymers (ELP(BC)'s ) different molecular weights and hydrophilic-to-hydrophobic ratios were genetically synthesized by recursive directional ligation. The self-assembly these polymers from unimers was investigated light scattering,...
Abstract Gene expression is regulated by promoters and enhancers marked histone H3 lysine 27 acetylation (H3K27ac), which established the paralogous acetyltransferases (HAT) EP300 CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized cancer cells. We demonstrate that majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. controls enhancer interacting with TFAP2β, transcription factor member...
Abstract Purpose: Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination (HR)-deficient tumors and ability to enhance the action of certain DNA-damaging agents. Compared with other PARP development, iniparib (4-iodo-3-nitrobenzamide) is notable its simple structure reported intracellular metabolite 4-iodo-3-nitrosobenzamide covalently inhibit PARP1 under cell-free conditions. The present preclinical...
SUMMARY Neuroblastoma is a pediatric cancer arising from the developing sympathoadrenal lineage with complex inter- and intra-tumoral heterogeneity. To chart this complexity, we generated comprehensive cell atlas of 55 neuroblastoma patient tumors, collected two institutions, spanning range clinical, genetic, histologic features. Our combines single-cell/nucleus RNA-seq (sc/scRNA-seq), bulk RNA-seq, whole exome sequencing, DNA methylation profiling, spatial transcriptomics, proteomic...
Abstract Background Neuroblastoma is a common pediatric cancer, where preclinical studies suggest that mesenchymal-like gene expression program contributes to chemotherapy resistance. However, clinical outcomes remain poor, implying we need better understanding of the relationship between patient tumor heterogeneity and models. Results Here, generate single-cell RNA-seq maps neuroblastoma cell lines, patient-derived xenograft models (PDX), genetically engineered mouse model (GEMM). We...
Abstract Rhabdomyosarcoma (RMS) is a pediatric tumor that resembles undifferentiated muscle cells; yet the extent to which cell state heterogeneity shared with human development has not been described. Using single-cell/nucleus RNA sequencing from patient tumors, patient-derived xenografts, primary in vitro cultures, and lines, we identify four dominant muscle-lineage states: progenitor, proliferative, differentiated, ground cells. We stratify these RMS cells/nuclei along continuum of show...
A number of established and investigational anticancer drugs slow the religation step DNA topoisomerase I (topo I). These agents induce cytotoxicity by stabilizing topo I-DNA covalent complexes, which in turn interact with advancing replication forks or transcription complexes to generate lethal lesions. Despite importance it has been difficult detect these lesions within intact cells tumors. Here, we report development a monoclonal antibody that specifically recognizes but not free DNA,...
Single-cell RNA sequencing (scRNA-seq) greatly advanced the understanding of intratumoral heterogeneity by identifying distinct cancer cell subpopulations. However, translating biological differences into treatment strategies is challenging due to a lack tools facilitate efficient drug discovery that tackles heterogeneous tumors. Developing such approaches requires accurate prediction response at single-cell level offer therapeutic options specific Here, we developed transparent...
Abstract Super-enhancers are expansive regions of genomic DNA comprised multiple putative enhancers that contribute to the dynamic gene expression patterns during development. This is particularly important in neurogenesis because many essential transcription factors have complex developmental stage– and cell–type specific across central nervous system. In developing retina, Vsx2 expressed retinal progenitor cells maintained differentiated bipolar neurons Müller glia. A single super-enhancer...
Abstract 5-Fluorouracil (5-FU) and 5-fluorodeoxyuridine (FdUrd, floxuridine) have activity in multiple tumors, both agents undergo intracellular processing to active metabolites that disrupt RNA DNA metabolism. These cause imbalances deoxynucleotide triphosphate levels the accumulation of uracil 5-FU genome, events activate ATR- ATM-dependent checkpoint signaling pathways base excision repair (BER) pathway. Here, we assessed which damage response processes influence FdUrd toxicity ovarian...
DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP shown activity solid tumors with homologous recombination (HR). This study was performed to assess MPN sensitivity inhibitors ex vivoHR pathway integrity circulating myeloid cells evaluated by assessing the formation RAD51 foci after treatment ionizing radiation or inhibitors. Sensitivity erythroid and progenitors using colony assays.Six 14 primary samples had reduced exposure...