A5033838605- Sarcoma Diagnosis and Treatment
- RNA modifications and cancer
- Neurofibromatosis and Schwannoma Cases
- Chromatin Remodeling and Cancer
- Virus-based gene therapy research
- Protein Degradation and Inhibitors
- RNA Research and Splicing
- Vascular Tumors and Angiosarcomas
- Neuroblastoma Research and Treatments
- Cancer Research and Treatments
- Ubiquitin and proteasome pathways
- Melanoma and MAPK Pathways
- Kruppel-like factors research
- Bone Tumor Diagnosis and Treatments
- Angiogenesis and VEGF in Cancer
- RNA Interference and Gene Delivery
- interferon and immune responses
- Cancer Genomics and Diagnostics
- Cancer, Hypoxia, and Metabolism
- Cancer-related gene regulation
- Retinal Diseases and Treatments
- Nuclear Structure and Function
- Musculoskeletal synovial abnormalities and treatments
- Soft tissue tumors and treatment
- Cancer Mechanisms and Therapy
Children's Hospital of Philadelphia
2022-2024
Van Andel Institute
2012-2024
Michigan State University
2013
University of Michigan
2013
Colorado State University
2013
Grand Rapids Community College
2013
Growth factors, such as insulin, can induce both acute and long-term glucose uptake into cells. Apart from the rapid, insulin-induced fusion of transporter (GLUT)4 storage vesicles with cell surface that occurs in muscle adipose tissues, mechanism behind induction has been unclear other systems. Thioredoxin interacting protein (TXNIP) shown to be a negative regulator cellular uptake. TXNIP is transcriptionally induced by reduces influx promoting GLUT1 endocytosis. Here, we report direct...
There is a great need to develop novel approaches target oncogenic transcription factors with small molecules. Ewing sarcoma emblematic of this need, as it depends on the continued activity EWS-FLI1 factor maintain malignant phenotype. We have previously shown that molecule trabectedin interferes EWS-FLI1. Here, we report important mechanistic advances and second-generation inhibitor provide insight into therapeutic targeting discovered functionally inactivated by redistributing protein...
Purpose.: To identify inflammatory cytokines significantly elevated and independent of VEGF levels in the vitreous proliferative diabetic retinopathy (PDR) patients that may serve as novel diagnostic factors or therapeutic targets. Methods.: Thirty-nine chemokines were measured from 72 undergoing vitrectomy (29 controls 43 PDR) via a magnetic bead-based immunoassay. Patient information, including sex, age, history smoking, cancer diagnosis treatment, presence diabetes hypertension also...
Abstract Purpose: The successful clinical translation of compounds that target specific oncogenic transcription factors will require an understanding the mechanism suppression to optimize dose and schedule administration. We have previously shown trabectedin reverses gene signature EWS-FLI1 factor. In this report, we establish use it justify reevaluation drug in clinic patients with Ewing sarcoma. Experimental Design: demonstrate a novel epigenetic using biochemical fractionation chromatin...
The importance of cellular context to the synergy DNA damage response (DDR)-targeted agents is important for tumors with mutations in DDR pathways, but less well-established driven by oncogenic transcription factors. In this study, we exploit widespread transcriptional dysregulation EWS-FLI1 factor identify an effective DDR-targeted combination therapy Ewing sarcoma.
Malignant peripheral nerve sheath tumors (MPNST) are highly resistant sarcomas that occur in up to 13% of individuals with neurofibromatosis type I (NF1). Genomic analysis longitudinally collected tumor samples a case MPNST disease progression revealed early hemizygous microdeletions NF1 and TP53, progressive amplifications MET, HGF, EGFR To examine the role MET progression, we developed mice enhanced expression Nf1 ablation (Nf1fl/ko;lox-stop-loxMETtg/+;Plp-creERTtg/+ ; referred as...
There is a need to develop novel approaches improve the balance between efficacy and toxicity for transcription factor-targeted therapies. In this study, we exploit context-dependent differences in RNA polymerase II processivity as an approach activity limit of EWS-FLI1-targeted small molecule, mithramycin, Ewing sarcoma. The clinical mithramycin sarcoma limited by off-target liver that restricts serum concentration levels insufficient inhibit EWS-FLI1. perform siRNA screen druggable genome...
Anthrax toxin (AnTx) plays a key role in the pathogenesis of anthrax. AnTx is composed three proteins: protective antigen (PA), edema factor, and lethal factor (LF). PA not toxic but serves to bind cells translocate or LF moieties cytosol. Recently, low-density lipoprotein receptor-related protein LRP6 has been reported mediate internalization lethality AnTx. Based on its similarity LRP6, we hypothesized that LRP5 may also play cellular uptake We assayed PA-dependent anthrax cytotoxic fusion...
Abstract We hypothesized that signaling through multiple mitogen-activated protein kinase (MAPK) (MKK) pathways is essential for the growth and vascularization of soft-tissue sarcomas, which are malignant tumors derived from mesenchymal tissues. tested this using HT-1080, NCI, Shac fibrosarcoma-derived cell lines anthrax lethal toxin (LeTx), a bacterial inactivates MKKs. Western blots confirmed LeTx treatment reduced levels phosphorylated extracellular signal-regulated p38 MAPK in vitro....
Angiosarcoma is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As model for human angiosarcoma, we studied primary cells tumorgrafts derived from canine hemangiosarcoma (HSA), which also an malignancy with similar presentation histology. Primary isolated HSA showed constitutive extracellular signal-regulated kinase (ERK) activation. The mitogen-activated protein/extracellular (MEK) inhibitor CI-1040 reduced ERK activation the viability...
Abstract Desmoplastic small round cell tumor (DSRCT) is a rare pediatric sarcoma with poor overall survival. This absolutely dependent on the continued expression and activity of its defining molecular lesion, EWS–WT1 transcription factor. Unfortunately, therapeutic targeting factors challenging, there critical need to identify compounds that inhibit EWS–WT1. Here we show compound lurbinectedin inhibits by redistributing protein within nucleus nucleolus. nucleolar redistribution interferes...
A crippling dwarfism was first described in the Miniature Poodle Great Britain 1956. Here, we resolve genetic basis of this recessively inherited disorder. case-control analysis (8∶8) genotype data from 173 k SNPs revealed a single associated locus on CFA14 (Praw <10–8). All affected dogs were homozygous for an ancestral haplotype consistent with founder effect and identical-by-descent mutation. Systematic failure nine, nearly contiguous SNPs, observed solely dogs, suggesting deletion causal...
Abstract Purpose: In this study, we tested the hypothesis that inhibition of mitogen-activated protein kinase kinases (MKK) inhibits tumor growth by acting on angiogenic signaling and extension may form basis an effective strategy for treatment Kaposi's sarcoma. Experimental Design: Murine endothelial cells expressing human herpes virus 8 G protein–coupled receptor (vGPCR-SVEC) were treated with anthrax lethal toxin (LeTx). LeTx is a binary ordinarily secreted Bacillus anthracis composed two...
Ewing sarcoma is a bone and soft-tissue tumor that depends on the activity of EWS-FLI1 transcription factor for cell survival. Although number compounds have been shown to inhibit in vitro, clinical EWS-FLI1-directed therapy has not achieved. One problem plaguing drug development efforts lack suitable, non-invasive, pharmacodynamic marker activity. Here we show 18F-FLT PET (18F- 3'-deoxy-3'-fluorothymidine positron emission tomography) reflects cells both vitro vivo. transported into by ENT1...
Lethal factor, the enzymatic moiety of anthrax lethal toxin (LeTx) is a protease that inactivates mitogen activated protein kinase kinases (MEK or MKK). In vitro and in vivo studies demonstrate LeTx targets endothelial cells. However, effects on cells are incompletely characterized. To gain insight into this process we used developmental model vascularization murine retina. We hypothesized application would disrupt normal retinal vascularization, specifically during angiogenic phase vascular...
Anthrax toxin receptor 1/tumor endothelial marker 8 (Antxr1 or TEM8) is up-regulated in tumor vasculature and serves as a for anthrax toxin, but its physiologic function unclear. The objective of this study was to evaluate the role Antxr1 arteriogenesis. arteriogenesis tested by measuring gene expression immunohistochemistry mouse model hindlimb ischemia using wild-type ANTXR1-/- mice. Additional tests were performed vitro models fluid shear stress hypoxia, well human muscle tissues obtained...
To evaluate the role of mitogen-activated protein kinase (MKK) signaling in a mouse model oxygen-induced retinopathy (OIR) that mimics prematurity (ROP).Postnatal day 7 mice were exposed to elevated oxygen for 5 days induce retinopathy. Anthrax lethal toxin (LeTx), an MKK inhibitor, was injected into vitreous after restoration normoxia, and its effects on vascular growth analyzed by whole mount immunofluorescence confocal microscopy. Pericyte coverage determined PDGFR-β α-SMA staining....
Abstract Background: Ewing sarcoma (ES) is a malignant bone tumor characterized by the oncogenic fusion protein EWS-FLI1. EWS-FLI1 acts as an aberrant transcription factor, inducing and silencing genes involved with increasing cell proliferation survival. We have previously shown that lurbinectedin, trabectedin analog, effectively inactivates transcriptional activity of redistributing it within nucleus to nucleolus. Interestingly, this process activates gene signature like DNA damage...
Abstract Background: Tumor necrosis factor receptor superfamily member 10b (TNFRSF10b, also known as DR5) agonists are attractive targeted agents for cancer cells because these activate cellular apoptosis. Ewing sarcoma (ES) is a bone and soft-tissue occurring in adolescence defined by t(11;22)(q24;q12) balanced chromosomal translocation that results chimeric transcription oncogenic driver protein, EWS-FLI1. Independent studies unbiased cell line screens have reported ES to be sensitive DR5...
<div>AbstractPurpose:<p>The importance of cellular context to the synergy DNA damage response (DDR)-targeted agents is important for tumors with mutations in DDR pathways, but less well-established driven by oncogenic transcription factors. In this study, we exploit widespread transcriptional dysregulation EWS-FLI1 factor identify an effective DDR-targeted combination therapy Ewing sarcoma.</p>Experimental Design:<p>We used matrix drug screening evaluate between a...