A5047543960- Advanced Breast Cancer Therapies
- Pancreatic and Hepatic Oncology Research
- HER2/EGFR in Cancer Research
- PI3K/AKT/mTOR signaling in cancer
- Asthma and respiratory diseases
- Cancer Mechanisms and Therapy
- Sphingolipid Metabolism and Signaling
- Animal Virus Infections Studies
- Colorectal Cancer Treatments and Studies
- Cancer Treatment and Pharmacology
- Cytokine Signaling Pathways and Interactions
- Cellular transport and secretion
- Herpesvirus Infections and Treatments
- Long-Term Effects of COVID-19
- Lipid Membrane Structure and Behavior
- CRISPR and Genetic Engineering
- Infectious Encephalopathies and Encephalitis
- Virus-based gene therapy research
- Viral Infections and Immunology Research
- Nitric Oxide and Endothelin Effects
- Osteoarthritis Treatment and Mechanisms
- Pediatric health and respiratory diseases
- Chronic Lymphocytic Leukemia Research
- Multiple Myeloma Research and Treatments
- Viral gastroenteritis research and epidemiology
Washington University in St. Louis
2015-2024
Saint Louis University
2022
Pfizer (United States)
2006-2013
Monsanto (United States)
1988-2000
University of Pennsylvania
1985-1988
The Wistar Institute
1985
Multiple Sclerosis Research Institute
1984
SphK (sphingosine kinase) is the major source of bioactive lipid and GPCR (G-protein-coupled receptor) agonist S1P 1-phosphate). promotes cell growth, survival migration, a key regulator lymphocyte trafficking. Inhibition signalling has been proposed as strategy for treatment inflammatory diseases cancer. In present paper we describe discovery characterization PF-543, novel cell-permeant inhibitor SphK1. PF-543 inhibits SphK1 with K(i) 3.6 nM, sphingosine-competitive more than 100-fold...
The formation of the powerful oxidant peroxynitrite (PN) from reaction superoxide anion with nitric oxide has been shown to be a kinetically favored contributing cellular injury and death at sites tissue inflammation. PN molecule is highly reactive causing lipid peroxidation as well nitration both free protein-bound tyrosine. We present evidence for pharmacological manipulation decomposition catalysts capable converting it nitrate. In target cells challenged exogenously added synthetic PN,...
Abstract Colorectal cancer (CRC) is the most common gastrointestinal malignancy in U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding long non-coding RNAs (lncRNAs) primary colon cancer, their role mCRC treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing normal, primary, distant tissues we find 148 differentially expressed Associated with Metastasis ( RAMS ). We prioritize RAMS11 due to its...
Mouse hepatitis virus strain A59 produces chronic central nervous system demyelination in rodents. As late as 6 months after intracerebral inoculation of mice 4 to weeks old, when infectious cannot be recovered and viral antigens detected the systems livers these animals, primary is still evident. Using cloned virus-specific DNAs highly sensitive specific technique situ hybridization, we have low levels mouse RNA 10 inoculation. We suggest that persistence may play a role A59-induced demyelination.
Abstract In metastatic breast cancer, HER2-activating mutations frequently co-occur with in PIK3CA, TP53, or CDH1. Of these co-occurring mutations, HER2 and PIK3CA are the most commonly comutated gene pair, approximately 40% of HER2-mutated cancers also having activating PIK3CA. To study effects we generated genetically engineered mice HER2V777L; PIK3CAH1047R transgenes (HP mice) studied resulting both vivo as well ex using cancer organoids. HP showed accelerated tumor formation increased...
The coronavirus, mouse hepatitis virus strain A59 (MHV-A59), causes mild encephalitis and chronic demyelination. Immunohistochemical techniques showed that MHV-A59-infected C57BL/6 mice contained dense deposits of viral antigen in the subthalamic nucleus substantia nigra, with fewer signs infection other regions brain. animals extra- intracellular vacuolation, neuronal loss, gliosis subthalamic-nigral region. Such localization is unprecedented among known encephalitides humans species. This...
Sphingosine kinase (SphK) is the major source of lipid mediator and G protein-coupled receptor agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival, migration a key regulator lymphocyte trafficking. Inhibition signaling has been proposed as strategy for treatment inflammatory diseases cancer. Two different formats an enzyme-based high-throughput screen yielded two attractive chemotypes capable inhibiting formation in cells. The molecular combination these screening hits...
Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need. Targeting KRAS, the oncogene that present in >95% of PDAC, a heavily pursued strategy, but remains unsuccessful clinic. Therefore, targeting key effector cascades KRAS oncoprotein, particularly mitogenic RAF-MEK-ERK pathway, represents next best strategy. However, RAF or MEK inhibitors have failed to show clinical efficacy PDAC. Several studies shown cancer cells treated with adopt multiple...
Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of number diseases including inflammatory bowel disease (IBD) and psoriasis. Since action LTA(4) hydrolase rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target suppression production. From in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as potent inhibitor hydrolase. Structure-activity...
To facilitate discovery of compounds modulating sphingosine-1-phosphate (S1P) signaling, the authors used high-throughput mass spectrometry technology to measure S1P formation in human whole blood. Since blood contains endogenous sphingosine (SPH) and S1P, was chosen detect conversion an exogenously added 17-carbon-long variant sphingosine, C17SPH, into C17S1P. The developed procedures achieve homogeneous mixing 384-well plates for a method requiring minimal manipulations extract from 96-...
Leukotriene B(4) (LTB(4)) is a potent, proinflammatory mediator involved in the pathogenesis of number diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, and asthma. The enzyme LTA(4) hydrolase represents an attractive target for pharmacological intervention these disease states, since action this rate-limiting step production LTB(4). Our previous efforts focused on exploration series analogues related to screening hit SC-22716 (1,...
In an effort to introduce foreign genes into chickens, the bacterial neomycin phosphotransferase (NPT-II) gene was cloned infectious avian retroviral vector derived from Schmidt-Ruppin A strain of RSV. The NPT-II stable in during passage vitro and infected cells were resistant G418. Fertilized chicken embryos inoculated with recombinant virus on day 0 screened 20 for blood cell DNA. Approximately 12% positive gene. Screening DNA brain, muscle, liver foot indicated that copy number could vary...
Coronaviruses produce both acute and chronic diseases in various animal species. A recent review summarizes the biology pathogenesis of coronaviruses.1 Of special interest is demyelinating disease produced by mouse hepatitis virus (MHV) rodents. This model has been used to study mechanisms virus-induced demyelination. Information acquired from such an experimental system may shed light on human disease.
Despite the clinical success of vascular endothelial growth factor (VEGF) blockade in metastatic colorectal cancers (mCRC), resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated development therapy. Levocetirizine is a second generation H1 antihistamine with anti-inflammatory suppression properties. We conducted phase II trial combining levocetirizine capecitabine bevacizumab potentially overcome therapy patients refractory mCRC.This was...
Several approaches were taken to identify improved helper cell lines for the production of replication-defective avian retroviral vectors transformation. Both QT6 and D17 cells engineered become reticuloendotheliosis virus vectors. The results showed that majority from D17, QT6, D17C3 produced titers in 102 103 cfu/mL range, with one line producing 105 cfu/mL. This high producer was relatively free when restricted low passage. An amphotropic murine a 6- 10-fold higher amount had comparable...
Abstract Background: HER2 activating mutations occur in 2-5% of metastatic breast cancer (MBC) patients, and three phase II or basket clinical trials have shown that the irreversible pan-HER tyrosine kinase inhibitor, neratinib, has good single agent efficacy for mutated MBC patients. Current are combining neratinib with other targeted therapies to increase response rate progression free survival these Methods: We established patient derived xenografts (PDX) organoids from two patients...
Abstract In metastatic breast cancer, HER2 activating mutations frequently co-occur with in the TP53 gene and patients these two co-occuring have a lower response rate to neratinib. order address this clinical problem, we bred mutant transgenic mice different alleles of TP53. We used R172H mutation, which is murine homolog human hotspot R175H TP53flox/flox allele, mimics truncating seen cancers. All three H53 genotypes (H53null, H53172/WT, H53172/null) developed cancers faster than H mice,...
<div>Abstract<p>In metastatic breast cancer, HER2 activating mutations frequently co-occur with in the PIK3CA, TP53, or E-cadherin genes. Of these co-occurring mutations, and PIK3CA are most prevalent gene pair, approximately 40% of mutated cancers also having PIK3CA. To study effects we bred genetically engineered mice HER2V777L; PIK3CAH1047R transgenes (HP mice) studied resulting both vivo as well ex using cancer organoids. HP show accelerated tumor formation increased invasion...