A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 (EWS-FLI1), created from a chromosomal translocation, is implicated in driving the majority of Ewing sarcomas (ES) by modulation of transcription and alternative splicing. The small molecule YK-4-279 inhibits EWS-FLI1 function and induces apoptosis. We tested 69 anti-cancer drugs in combination with YK-4-279 and found that vinca alkaloids exhibited synergy with YK-4-279 in five ES cell lines. The combination of YK-4-279 and vincristine reduced tumor burden and increased survival in mice bearing ES xenografts. We determined that independent drug-induced events converged to cause this synergistic therapeutic effect. YK-4-279 rapidly induced G2/M arrest, increased the abundance of cyclin B1, and decreased EWS-FLI1–mediated expression of microtubule-associated proteins, which rendered cells more susceptible to microtubule depolymerization by vincristine. YK-4-279 reduced the expression of the EWS-FLI1 target gene encoding ubiquitin ligase UBE2C, and this in part contributed to the increase in cyclin B1. Biochemical assays revealed that YK-4-279 also increased the abundance of proapoptotic isoforms of MCL1 and BCL2, presumably through inhibition of alternative splicing by EWS-FLI1, thus promoting cell death in response to vincristine. Thus a combination of vincristine and YK-4-279 might be therapeutically effective in ES patients. Overall design: Examination of mRNA profiles of TC32 on knockdown of EWS-FLI1 or treatment with YK-4-279: 3 samples Total: 1 TC32 WT Control, 1 TC32 shEF, 1 TC32 YK
Inhibition of the oncogenic fusion protein EWS-FLI1 causes G<sub>2</sub>-M cell cycle arrest and enhanced vincristine sensitivity in Ewing's sarcoma.
Cell line, Subject
View SamplesZika virus (ZIKV) is responsible for a major current outbreak in the Americas and has been causally associated with fetal microcephaly as well as Guillain-Barre syndrome in adults. However, the immune responses associated with controlling ZIKV replication remain poorly characterized. Here we report a detailed analysis of innate and adaptive immune responses following ZIKV infection in 16 rhesus monkeys. A robust proinflammatory innate immune response was observed within the first few days of infection, including upregulation of type 1 interferon, which correlated directly with viral loads. Immunomodulatory pathways, including IL-10 and TGF-, were also upregulated. ZIKV-specific neutralizing antibodies emerged rapidly by day 7 and correlated inversely with viral loads, which were undetectable in peripheral blood by day 6-10. In contrast, virus replication persisted in cerebrospinal fluid (CSF) for at least 21-42 days in 75% (3 of 4) of the monkeys that received the lowest dose of ZIKV tested, and ZIKV-specific antibodies were essentially undetectable in CSF. These data suggest that antibodies play a critical role in the rapid control of acute viremia in the periphery but were largely excluded from the central nervous system, allowing viral persistence at this immuonoprivileged site.
Zika Virus Persistence in the Central Nervous System and Lymph Nodes of Rhesus Monkeys.
Time
View SamplesTo compare up-regulation of genes following CpG activation, we performed microarray analysis of activated macrophages from B6 and F1(B6xMOLF) mouse strains. Cells were activated for 0, 2 and 4 hrs with 200nM of type B CpG. Levels of mRNA for many genes differened dramatically between the strains
Mannose receptor 1 mediates cellular uptake and endosomal delivery of CpG-motif containing oligodeoxynucleotides.
Specimen part, Treatment
View SamplesIn this study, we report the performance of one such technique denoted as sparse full length sequencing (SFL), a ribosomal RNA depletion-based RNA sequencing approach that allows for the simultaneous sequencing of 96 samples and higher. We offer comparisons to well established single-sample techniques, including: full coverage Poly-A capture RNA-seq and microarray, as well as another low-cost highly multiplexed technique known as 3' digital gene expression (3' DGE). Data was generated for a set of exposure experiments on immortalized human lung epithelial (AALE) cells in a two-by-two study design, in which samples received both genetic and chemical perturbations of known oncogenes/tumor suppressors and lung carcinogens. SFL demonstrated improved performance over 3' DGE in terms of coverage, power to detect differential gene expression, and biological recapitulation of patterns of differential gene expression from in vivo lung cancer mutation signatures. Overall design: 3' Digital Gene Expression (3'DGE) for immortalized human bronchial epithelial cells (AALE) exposed to chemical and genotypic perturbations
Assessment of a Highly Multiplexed RNA Sequencing Platform and Comparison to Existing High-Throughput Gene Expression Profiling Techniques.
Specimen part, Cell line, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
PCB congener specific oxidative stress response by microarray analysis using human liver cell line.
Age
View SamplesExposure to Polychlorobiphenyls (PCBs) is known to cause serious health effects in human but the gene expression profiles leading to development of differnet diseases is not fully understood. The knowledge of global gene expression will help us to devlop early diagnostic biomarkers for PCB induced health effects.
PCB congener specific oxidative stress response by microarray analysis using human liver cell line.
Age
View SamplesExposure to Polychlorobiphenyls (PCBs) is known to cause serious health effects in human but the gene expression profiles leading to development of different diseases is not fully understood. The knowledge of global gene expression will help us to develop early diagnostic biomarkers for PCB induced health effects.
PCB congener specific oxidative stress response by microarray analysis using human liver cell line.
Age
View SamplesSRC-1 affects the expression of complex I of the mitochondrial electron transport chain, a set of enzymes responsible for the conversion of NADH to NAD(+). NAD(+) and NADH were subsequently identified as metabolites that underlie SRC-1's response to glucose deprivation. Knockdown of SRC-1 in glycolytic cancer cells abrogated their ability to grow in the absence of glucose consistent with SRC-1's role in promoting cellular adaptation to reduced glucose availability
Steroid receptor coactivator 1 is an integrator of glucose and NAD+/NADH homeostasis.
Cell line, Treatment
View SamplesGenome-wide analysis of decidual transcriptome in pre-eclampsia compared with normotensive controls to find differentially expressed genes/pathways.
Genome-wide transcriptome directed pathway analysis of maternal pre-eclampsia susceptibility genes.
Specimen part, Disease stage
View SamplesLCM was perfomed on adjacent tumor and stromal cells to identify differentially expressed genes in triple negative breast cancer.
Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection.
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