22 results on '"Stephanie T. Murphy"'
Search Results
2. Data from Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer
- Author
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Charles S. Craik, Henry F. VanBrocklin, Joe W. Gray, Byron Hann, Francois Pepin, Stephanie T. Murphy, Sai Duriseti, and Aaron M. LeBeau
- Abstract
Components of the plasminogen activation system, which are overexpressed in aggressive breast cancer subtypes, offer appealing targets for development of new diagnostics and therapeutics. By comparing gene expression data in patient populations and cultured cell lines, we identified elevated levels of the urokinase plasminogen activation receptor (uPAR, PLAUR) in highly aggressive breast cancer subtypes and cell lines. Recombinant human anti-uPAR antagonistic antibodies exhibited potent binding in vitro to the surface of cancer cells expressing uPAR. In vivo these antibodies detected uPAR expression in triple negative breast cancer (TNBC) tumor xenografts using near infrared imaging and 111In single-photon emission computed tomography. Antibody-based uPAR imaging probes accurately detected small disseminated lesions in a tumor metastasis model, complementing the current clinical imaging standard 18F-fluorodeoxyglucose at detecting non-glucose-avid metastatic lesions. A monotherapy study using the antagonistic antibodies resulted in a significant decrease in tumor growth in a TNBC xenograft model. In addition, a radioimmunotherapy study, using the anti-uPAR antibodies conjugated to the therapeutic radioisotope 177Lu, found that they were effective at reducing tumor burden in vivo. Taken together, our results offer a preclinical proof of concept for uPAR targeting as a strategy for breast cancer diagnosis and therapy using this novel human antibody technology. Cancer Res; 73(7); 2070–81. ©2013 AACR.
- Published
- 2023
3. Supplementary Figure 4 from Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer
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Charles S. Craik, Henry F. VanBrocklin, Joe W. Gray, Byron Hann, Francois Pepin, Stephanie T. Murphy, Sai Duriseti, and Aaron M. LeBeau
- Abstract
PDF file - 38K, Determining the half-life of the 111In-labeled antibodies in vivo (n = 3 mice / antibody)
- Published
- 2023
4. Supplementary Figure 8 from Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer
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Charles S. Craik, Henry F. VanBrocklin, Joe W. Gray, Byron Hann, Francois Pepin, Stephanie T. Murphy, Sai Duriseti, and Aaron M. LeBeau
- Abstract
PDF file - 62K, FDG avid lesion not detected by 111In-2G10
- Published
- 2023
5. Supplementary Figure Legend from Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer
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Charles S. Craik, Henry F. VanBrocklin, Joe W. Gray, Byron Hann, Francois Pepin, Stephanie T. Murphy, Sai Duriseti, and Aaron M. LeBeau
- Abstract
PDF file - 62K
- Published
- 2023
6. Supplemental Figures S1-S6 from Imaging Active Urokinase Plasminogen Activator in Prostate Cancer
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Henry F. VanBrocklin, Charles S. Craik, Henry Lowman, James West, Daniel R. Hostetter, Stephanie T. Murphy, Michael B. Winter, Kate Markham, Natalia Sevillano, and Aaron M. LeBeau
- Abstract
Supplemental Figures S1-S6. U33 Fab Sequence (S1); Inhibition constant calculation of U33 Fab (S2); U33 does not bind to the uPA-PAI1 complex (S3); Selectivity of U33 IgG for active uPA versus inactive uPA (S4); Dependence of U33 IgG binding on an accessible uPA active site (S5); Selectivity of U33 IgG for human uPA compared to highly related serine proteases (S6).
- Published
- 2023
7. Supplementary Figure 1 from Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer
- Author
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Charles S. Craik, Henry F. VanBrocklin, Joe W. Gray, Byron Hann, Francois Pepin, Stephanie T. Murphy, Sai Duriseti, and Aaron M. LeBeau
- Abstract
PDF file - 41K, The affinity of 2G10 and 3C6 Fabs and IgGs for MDA-MB-231 cells was determined by equilibrium binding flow cytometry. Isotherms were fit using non-linear regression methods to calculate KDs
- Published
- 2023
8. Supplementary Figure 7 from Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer
- Author
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Charles S. Craik, Henry F. VanBrocklin, Joe W. Gray, Byron Hann, Francois Pepin, Stephanie T. Murphy, Sai Duriseti, and Aaron M. LeBeau
- Abstract
PDF file - 101K, Mouse model recreating the inflammation observed in Figure 4C. A nude mouse was injected subcutaneously with 100�l of turpentine oil. After 72hrs, the animal was injected with 258°Ci of FDG and imaged 60 minutes later. Probe uptake by the inflammatory cells is only observed with FDG and not with the uPAR probe
- Published
- 2023
9. Supplementary Figure 2 from Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer
- Author
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Charles S. Craik, Henry F. VanBrocklin, Joe W. Gray, Byron Hann, Francois Pepin, Stephanie T. Murphy, Sai Duriseti, and Aaron M. LeBeau
- Abstract
PDF file - 71K, Scrambled matched isotype control IgGs labeld with AlexaFlupr 680 at 72hrs in MDA-MB-231 xenografts imaged in the Cy 5.5 channel at 72hr
- Published
- 2023
10. Supplementary Figure 3 from Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer
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Charles S. Craik, Henry F. VanBrocklin, Joe W. Gray, Byron Hann, Francois Pepin, Stephanie T. Murphy, Sai Duriseti, and Aaron M. LeBeau
- Abstract
PDF file - 40K, Time activity curves for 111In-labeled 2G10 and 3C6 in MDA-MB-231 orthotopic xenograft tumor-bearing mice
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- 2023
11. Supplementary Figure 6 from Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer
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Charles S. Craik, Henry F. VanBrocklin, Joe W. Gray, Byron Hann, Francois Pepin, Stephanie T. Murphy, Sai Duriseti, and Aaron M. LeBeau
- Abstract
PDF file - 58K, 177Lu-2G10 SPECT/CT imaging of a mouse enrolled in the RIT study. The mouse was injected with 2.5�g of 2G10 labeled with 75°Ci of 177Lu. The image shown is a coronal view acquitted at 24hrs post-injection. The represented data was processed using AMIDE software
- Published
- 2023
12. A high-affinity [ 18 F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer
- Author
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Clifford E. Berkman, Hendry Cahaya, Stephanie T. Murphy, Joseph E. Blecha, Shorouk Dannoon, Tanushree Ganguly, Salma Jivan, Ella F. Jones, Cyril Barinka, Christopher R. Drake, Henry F. VanBrocklin, and Mark R. Hopkins
- Subjects
Models, Molecular ,Glutamate Carboxypeptidase II ,Male ,Pathology ,Fluorine Radioisotopes ,Aging ,Cancer Research ,Peptidomimetic ,Protein Conformation ,Phosphoramidate ,urologic and male genital diseases ,Mice ,Drug Stability ,Models ,Glutamate carboxypeptidase II ,Tissue Distribution ,Cancer ,Tumor ,Prostate Cancer ,Imaging agent ,3. Good health ,Surface ,Flourine-18 ,Nuclear Medicine & Medical Imaging ,Radiology Nuclear Medicine and imaging ,Isotope Labeling ,Antigens, Surface ,Biomedical Imaging ,Molecular Medicine ,Urologic Diseases ,medicine.medical_specialty ,Biodistribution ,Clinical Sciences ,Article ,Cell Line ,Inhibitory Concentration 50 ,In vivo ,Cell Line, Tumor ,LNCaP ,medicine ,PSMA ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Phosphoric Acids ,Protease Inhibitors ,Antigens ,business.industry ,Prostatic Neoplasms ,Molecular ,Biological Transport ,Amides ,In vitro ,PET ,Positron-Emission Tomography ,Cancer research ,Peptidomimetics ,business - Abstract
Introduction In this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated. Methods p-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [ 18 F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(−) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4h post injection in mice bearing CWR22Rv1 tumor, with or without blocking agent. Results The crystallographic data showed interaction of the p -fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [ 18 F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(−) cells (0.08%) at 4h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4h. Conclusions We have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [ 18 F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa. Advances in Knowledge The only FDA-approved imaging agent for PCa, Prostascint®, targets PSMA but suffers from inherent shortcomings. The data acquired in this manuscript confirmed that our new generation of [ 18 F]-labeled PSMA inhibitor exhibited promising in vivo performance as a PET imaging agent for PCa and is well-positioned for subsequent clinical trials. Implications for Patient Care Our preliminary data demonstrate that this tracer possesses the required imaging characteristics to be sensitive and specific for PCa imaging in patients at all stages of the disease.
- Published
- 2015
- Full Text
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13. Imaging the Urokinase Plasminongen Activator Receptor in Preclinical Breast Cancer Models of Acquired Drug Resistance
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Stephanie T. Murphy, Natalia Sevillano, Aaron M. LeBeau, Henry F. VanBrocklin, Laura L. Murphy, Mandy L. King, Charles S. Craik, and Sai Duriseti
- Subjects
Pathology ,Medicine (miscellaneous) ,urokinase plasminogen activator receptor ,Multimodal Imaging ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,skin and connective tissue diseases ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,0303 health sciences ,biology ,single-photon emission computed tomography ,Indium Radioisotopes ,Optical Imaging ,3. Good health ,Paclitaxel ,030220 oncology & carcinogenesis ,MCF-7 Cells ,drug-resistant breast cancer ,Female ,Antibody ,human antibody ,Research Paper ,medicine.drug ,phage display ,medicine.medical_specialty ,tamoxifen resistance ,Antineoplastic Agents ,Breast Neoplasms ,Antibodies ,Receptors, Urokinase Plasminogen Activator ,03 medical and health sciences ,Breast cancer ,In vivo ,medicine ,Animals ,Humans ,Doxorubicin ,030304 developmental biology ,Tomography, Emission-Computed, Single-Photon ,Urokinase ,business.industry ,medicine.disease ,Urokinase receptor ,Tamoxifen ,chemistry ,Drug Resistance, Neoplasm ,Immunoglobulin G ,biology.protein ,Cancer research ,Tomography, X-Ray Computed ,business - Abstract
Subtype-targeted therapies can have a dramatic impact on improving the quality and quantity of life for women suffering from breast cancer. Despite an initial therapeutic response, cancer recurrence and acquired drug-resistance are commonplace. Non-invasive imaging probes that identify drug-resistant lesions are urgently needed to aid in the development of novel drugs and the effective utilization of established therapies for breast cancer. The protease receptor urokinase plasminogen activator receptor (uPAR) is a target that can be exploited for non-invasive imaging. The expression of uPAR has been associated with phenotypically aggressive breast cancer and acquired drug-resistance. Acquired drug-resistance was modeled in cell lines from two different breast cancer subtypes, the uPAR negative luminal A subtype and the uPAR positive triple negative subtype cell line MDA-MB-231. MCF-7 cells, cultured to be resistant to tamoxifen (MCF-7 TamR), were found to significantly over-express uPAR compared to the parental cell line. uPAR expression was maintained when resistance was modeled in triple-negative breast cancer by generating doxorubicin and paclitaxel resistant MDA-MB-231 cells (MDA-MB-231 DoxR and MDA-MB-231 TaxR). Using the antagonistic uPAR antibody 2G10, uPAR was imaged in vivo by near-infrared (NIR) optical imaging and (111)In-single photon emission computed tomography (SPECT). Tumor uptake of the (111)In-SPECT probe was high in the three drug-resistant xenografts (46 %ID/g) and minimal in uPAR negative xenografts at 72 hours post-injection. This preclinical study demonstrates that uPAR can be targeted for imaging breast cancer models of acquired resistance leading to potential clinical applications.
- Published
- 2014
14. Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer
- Author
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Henry F. VanBrocklin, Joe W. Gray, Byron Hann, Sai Duriseti, Aaron M. LeBeau, Charles S. Craik, Francois Pepin, and Stephanie T. Murphy
- Subjects
Cancer Research ,Receptor, ErbB-2 ,Image Processing ,medicine.medical_treatment ,Nude ,Messenger ,Immunoenzyme Techniques ,Mice ,Computer-Assisted ,ErbB-2 ,Receptors ,Monoclonal ,Image Processing, Computer-Assisted ,Tumor Cells, Cultured ,Longitudinal Studies ,skin and connective tissue diseases ,Progesterone ,Triple-negative breast cancer ,Cancer ,Cultured ,Reverse Transcriptase Polymerase Chain Reaction ,Indium Radioisotopes ,Antibodies, Monoclonal ,Recombinant Proteins ,Tumor Cells ,Gene Expression Regulation, Neoplastic ,Receptors, Estrogen ,Oncology ,5.1 Pharmaceuticals ,Urokinase Plasminogen Activator ,Radioimmunotherapy ,Biomedical Imaging ,Female ,Development of treatments and therapeutic interventions ,Antibody ,Receptors, Progesterone ,Receptor ,Biotechnology ,medicine.drug ,Oncology and Carcinogenesis ,Mice, Nude ,Breast Neoplasms ,Biology ,Real-Time Polymerase Chain Reaction ,Article ,Antibodies ,Receptors, Urokinase Plasminogen Activator ,Breast cancer ,In vivo ,Breast Cancer ,medicine ,Animals ,Humans ,RNA, Messenger ,Oncology & Carcinogenesis ,Urokinase ,Neoplastic ,5.2 Cellular and gene therapies ,Surface Plasmon Resonance ,medicine.disease ,Estrogen ,Xenograft Model Antitumor Assays ,Urokinase-Type Plasminogen Activator ,Molecular biology ,Urokinase receptor ,Gene Expression Regulation ,Cancer cell ,biology.protein ,Cancer research ,RNA - Abstract
Components of the plasminogen activation system, which are overexpressed in aggressive breast cancer subtypes, offer appealing targets for development of new diagnostics and therapeutics. By comparing gene expression data in patient populations and cultured cell lines, we identified elevated levels of the urokinase plasminogen activation receptor (uPAR, PLAUR) in highly aggressive breast cancer subtypes and cell lines. Recombinant human anti-uPAR antagonistic antibodies exhibited potent binding in vitro to the surface of cancer cells expressing uPAR. In vivo these antibodies detected uPAR expression in triple negative breast cancer (TNBC) tumor xenografts using near infrared imaging and 111In single-photon emission computed tomography. Antibody-based uPAR imaging probes accurately detected small disseminated lesions in a tumor metastasis model, complementing the current clinical imaging standard 18F-fluorodeoxyglucose at detecting non-glucose-avid metastatic lesions. A monotherapy study using the antagonistic antibodies resulted in a significant decrease in tumor growth in a TNBC xenograft model. In addition, a radioimmunotherapy study, using the anti-uPAR antibodies conjugated to the therapeutic radioisotope 177Lu, found that they were effective at reducing tumor burden in vivo. Taken together, our results offer a preclinical proof of concept for uPAR targeting as a strategy for breast cancer diagnosis and therapy using this novel human antibody technology. Cancer Res; 73(7); 2070–81. ©2013 AACR.
- Published
- 2013
15. PET Imaging and Biodistribution of Chemically Modified Bacteriophage MS2
- Author
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Gary J. Tong, Stephanie T. Murphy, Christopher R. Behrens, Matthew B. Francis, James P. O'Neil, Ioana L. Aanei, and Michelle E. Farkas
- Subjects
Biodistribution ,Mice, Nude ,Pharmaceutical Science ,Nanotechnology ,Polyethylene Glycols ,Mice ,chemistry.chemical_compound ,Capsid ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Bacteriophage MS2 ,PEG ratio ,Animals ,DOTA ,Tissue Distribution ,Levivirus ,biology ,Chemistry ,biology.organism_classification ,Copper Radioisotopes ,Positron-Emission Tomography ,Drug delivery ,MCF-7 Cells ,PEGylation ,Biophysics ,Molecular Medicine ,Female ,Ex vivo - Abstract
The fields of nanotechnology and medicine have merged in the development of new imaging and drug delivery agents based on nanoparticle platforms. As one example, a mutant of bacteriophage MS2 can be differentially modified on the exterior and interior surfaces for the concurrent display of targeting functionalities and payloads, respectively. In order to realize their potential for use in in vivo applications, the biodistribution and circulation properties of this class of agents must first be investigated. A means of modulating and potentially improving the characteristics of nanoparticle agents is the appendage of PEG chains. Both MS2 and MS2-PEG capsids possessing interior DOTA chelators were labeled with (64)Cu and injected intravenously into mice possessing tumor xenografts. Dynamic imaging of the agents was performed using PET-CT on a single animal per sample, and the biodistribution at the terminal time point (24 h) was assessed by gamma counting of the organs ex vivo for 3 animals per agent. Compared to other viral capsids of similar size, the MS2 agents showed longer circulation times. Both MS2 and MS2-PEG bacteriophage behaved similarly, although the latter agent showed significantly less uptake in the spleen. This effect may be attributed to the ability of the PEG chains to mask the capsid charge. Although the tumor uptake of the agents may result from the enhanced permeation and retention (EPR) effect, selective tumor imaging may be achieved in the future by using exterior targeting groups.
- Published
- 2012
16. Biodistribution of Antibody-MS2 Viral Capsid Conjugates in Breast Cancer Models
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Michelle E. Farkas, Adel M. ElSohly, Matthew B. Francis, Chawita Netirojjanakul, James P. O'Neil, Ioana L. Aanei, Youngho Seo, Stephanie T. Murphy, and Melanie Regan
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Biodistribution ,viruses ,Pharmaceutical Science ,Mice, Nude ,Breast Neoplasms ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Antibodies ,Mice ,Breast cancer ,Capsid ,In vivo ,Positron Emission Tomography Computed Tomography ,Drug Discovery ,Bacteriophage MS2 ,medicine ,Animals ,Humans ,Receptor ,Levivirus ,Mice, Inbred BALB C ,Bioconjugation ,Microscopy, Confocal ,biology ,Chemistry ,021001 nanoscience & nanotechnology ,medicine.disease ,biology.organism_classification ,Flow Cytometry ,Virology ,0104 chemical sciences ,biology.protein ,Cancer research ,MCF-7 Cells ,Molecular Medicine ,Nanoparticles ,Capsid Proteins ,Female ,Antibody ,0210 nano-technology - Abstract
A variety of nanoscale scaffolds, including virus-like particles (VLPs), are being developed for biomedical applications; however, little information is available about their in vivo behavior. Targeted nanoparticles are particularly valuable as diagnostic and therapeutic carriers because they can increase the signal-to-background ratio of imaging agents, improve the efficacy of drugs, and reduce adverse effects by concentrating the therapeutic molecule in the region of interest. The genome-free capsid of bacteriophage MS2 has several features that make it well-suited for use in delivery applications, such as facile production and modification, the ability to display multiple copies of targeting ligands, and the capacity to deliver large payloads. Anti-EGFR antibodies were conjugated to MS2 capsids to construct nanoparticles targeted toward receptors overexpressed on breast cancer cells. The MS2 agents showed good stability in physiological conditions up to 2 days and specific binding to the targeted receptors in in vitro experiments. Capsids radiolabeled with
- Published
- 2016
17. The WD40 and FYVE domain containing protein 2 defines a class of early endosomes necessary for endocytosis
- Author
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Silvia Corvera, Akira Hayakawa, Stephanie T. Murphy, Karl D. Bellve, Martha C. Soto, Clive Standley, Kevin E. Fogarty, Deborah M. Leonard, Susan J. Hayes, Craig C. Mello, and David G. Lambright
- Subjects
Protein family ,Endosome ,Green Fluorescent Proteins ,Molecular Sequence Data ,Endocytic cycle ,Endosomes ,Biology ,Endocytosis ,EEA1 ,Phosphatidylinositol Phosphates ,Chlorocebus aethiops ,Animals ,Humans ,Amino Acid Sequence ,Caenorhabditis elegans ,Multidisciplinary ,Cell Membrane ,Intracellular Signaling Peptides and Proteins ,Receptor-mediated endocytosis ,Biological Sciences ,biology.organism_classification ,Protein Structure, Tertiary ,Cell biology ,Biochemistry ,COS Cells ,FYVE domain ,HeLa Cells - Abstract
The FYVE domain binds with high specificity and avidity to phosphatidylinositol 3-phosphate. It is present in ≈30 proteins in humans, some of which have been implicated in functions ranging from early endosome fusion to signal transduction through the TGF-β receptor. To develop a further understanding of the biological roles of this protein family, we turned to the nematode Caenorhabditis elegans , which contains only 12 genes predicted to encode for phosphatidylinositol 3-phosphate binding, FYVE domain-containing proteins, all of which have homologs in the human genome. Each of these proteins was targeted individually by RNA interference. One protein, WDFY2, produced a strong inhibition of endocytosis when silenced. WDFY2 contains WD40 motifs and a FYVE domain, is highly conserved between species, and localizes to a set of small endosomes that reside within 100 nm from the plasma membrane. These endosomes are involved in transferrin uptake but lack the classical endosomal markers Rab5 and EEA1. Silencing of WDFY2 by siRNA in mammalian cells impaired transferrin endocytosis. These studies reveal the important, conserved role of WDFY2 in endocytosis, and the existence of a subset of early endosomes, closely associated with the plasma membrane, that may constitute the first stage of endocytic processing of internalized cargo.
- Published
- 2006
18. Longitudinal Evaluation of Myocardial Fatty Acid and Glucose Metabolism in Fasted and Nonfasted Spontaneously Hypertensive Rats Using MicroPET/CT
- Author
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James P. O'Neil, Mustafa Janabi, Grant T. Gullberg, Andrew M. Hernandez, Stephanie T. Murphy, Youngho Seo, Kathleen M. Brennan, and J.S. Huber
- Subjects
Male ,Pathology ,030204 cardiovascular system & hematology ,Left ventricular hypertrophy ,quantitation in molecular imaging ,030218 nuclear medicine & medical imaging ,chemistry.chemical_compound ,0302 clinical medicine ,Rats, Inbred SHR ,Positron Emission Tomography Computed Tomography ,lcsh:QH301-705.5 ,chemistry.chemical_classification ,cardiovascular ,Fatty Acids ,animal models of disease ,Glucose analog ,Condensed Matter Physics ,Nuclear Medicine & Medical Imaging ,lcsh:R855-855.5 ,Fatty acid analog ,Hypertension ,Biomedical Imaging ,Molecular Medicine ,Heptadecanoic acid ,Perfusion ,Research Article ,Biotechnology ,medicine.medical_specialty ,Inbred SHR ,lcsh:Medical technology ,Biomedical Engineering ,Carbohydrate metabolism ,cardiac imaging ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Nutrition ,Fatty acid metabolism ,Animal ,molecular modeling ,business.industry ,Myocardium ,Prevention ,animal pet ,Fatty acid ,medicine.disease ,Rats ,Disease Models, Animal ,Glucose ,Endocrinology ,lcsh:Biology (General) ,chemistry ,Disease Models ,business - Abstract
Using longitudinal micro positron emission tomography (microPET)/computed tomography (CT) studies, we quantified changes in myocardial metabolism and perfusion in spontaneously hypertensive rats (SHRs), a model of left ventricular hypertrophy (LVH). Fatty acid and glucose metabolism were quantified in the hearts of SHRs and Wistar-Kyoto (WKY) normotensive rats using long-chain fatty acid analog 18 F-fluoro-6-thia heptadecanoic acid ( 18 F-FTHA) and glucose analog 18 F-fluorodeoxyglucose ( 18 F-FDG) under normal or fasting conditions. We also used 18 F-fluorodihydrorotenol ( 18 F-FDHROL) to investigate perfusion in their hearts without fasting. Rats were imaged at 4 or 5 times over their life cycle. Compartment modeling was used to estimate the rate constants for the radiotracers. Blood samples were obtained and analyzed for glucose and free fatty acid concentrations. SHRs demonstrated no significant difference in 18 F-FDHROL wash-in rate constant ( P = .1) and distribution volume ( P = .1), significantly higher 18 F-FDG myocardial influx rate constant ( P = 4×10 −8 ), and significantly lower 18 F-FTHA myocardial influx rate constant ( P = .007) than WKYs during the 2009-2010 study without fasting. SHRs demonstrated a significantly higher 18 F-FDHROL wash-in rate constant ( P = 5×10 −6 ) and distribution volume ( P = 3×10 −8 ), significantly higher 18 F-FDG myocardial influx rate constant ( P = 3×10 −8 ), and a higher trend of 18 F-FTHA myocardial influx rate constant (not significant, P = .1) than WKYs during the 2011–2012 study with fasting. Changes in glucose plasma concentrations were generally negatively correlated with corresponding radiotracer influx rate constant changes. The study indicates a switch from preferred fatty acid metabolism to increased glucose metabolism with hypertrophy. Increased perfusion during the 2011-2012 study may be indicative of increased aerobic metabolism in the SHR model of LVH.
- Published
- 2017
19. EHMTI-0125. Studying the permeability of the blood-brain barrier during migraine attacks using [11C]-dihydroergotamine
- Author
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Till Sprenger, Christoph J. Schankin, Michael A. Eller, Peter J. Goadsby, Joseph E. Blecha, Farooq H. Maniyar, Youngho Seo, Stephanie T. Murphy, Shashidar Kori, and Henry F. VanBrocklin
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business.industry ,Clinical Neurology ,General Medicine ,Pharmacology ,medicine.disease ,Blood–brain barrier ,Dihydroergotamine ,3. Good health ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Migraine ,Molecular size ,Permeability (electromagnetism) ,Meeting Abstract ,cardiovascular system ,medicine ,Neurology (clinical) ,business ,Neuroscience ,medicine.drug - Abstract
Due to unfavorable molecular size and lipophilicity, migraine-specific medications such as dihydroergotamine (DHE) are not expected to penetrate the blood-brain barrier (BBB). A breakdown of the BBB during migraine attacks has been postulated as the mechanism in which DHE accesses postulated central sites of action.
- Published
- 2014
20. A novel fluorine-18 β-fluoroethoxy organophosphate positron emission tomography imaging tracer targeted to central nervous system acetylcholinesterase
- Author
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S. Kaleem Ahmed, Henry F. VanBrocklin, Stephanie T. Murphy, Charles M. Thompson, Shelly L. James, Michael Braden, Yamina Belabassi, and John M. Gerdes
- Subjects
Male ,Fluorine Radioisotopes ,Physiology ,Cognitive Neuroscience ,organophosphate ,brain ,Central nervous system ,PET imaging ,Biochemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Medicinal and Biomolecular Chemistry ,In vivo ,TRACER ,medicine ,Animals ,Radionuclide Imaging ,Tomography ,Nerve agent ,medicine.diagnostic_test ,Radiosynthesis ,Organophosphate ,Skull ,Neurosciences ,Brain ,Cell Biology ,General Medicine ,Acetylcholinesterase ,radiotracer ,Spine ,Organophosphates ,Rats ,X-Ray Computed ,medicine.anatomical_structure ,chemistry ,Spinal Cord ,Positron emission tomography ,Biophysics ,fluorine-18 ,Biomedical Imaging ,Sprague-Dawley ,Radiopharmaceuticals ,Tomography, X-Ray Computed ,medicine.drug - Abstract
Radiosynthesis of a fluorine-18 labeled organophosphate (OP) inhibitor of acetylcholinesterase (AChE) and subsequent positron emission tomography (PET) imaging using the tracer in the rat central nervous system are reported. The tracer structure, which contains a novel β-fluoroethoxy phosphoester moiety, was designed as an insecticide-chemical nerve agent hybrid to optimize handling and the desired target reactivity. Radiosynthesis of the β-fluoroethoxy tracer is described that utilizes a [(18)F]prosthetic group coupling approach. The imaging utility of the [(18)F]tracer is demonstrated in vivo within rats by the evaluation of its brain penetration and cerebral distribution qualities in the absence and presence of a challenge agent. The tracer effectively penetrates brain and localizes to cerebral regions known to correlate with the expression of the AChE target. Brain pharmacokinetic properties of the tracer are consistent with the formation of an OP-adducted acetylcholinesterase containing the fluoroethoxy tracer group. Based on the initial favorable in vivo qualities found in rat, additional [(18)F]tracer studies are ongoing to exploit the technology to dynamically probe organophosphate mechanisms of action in mammalian live tissues.
- Published
- 2014
21. Longitudinal evaluation of left ventricular substrate metabolism, perfusion, and dysfunction in the spontaneously hypertensive rat model of hypertrophy using small-animal PET/CT imaging
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Andrew M. Hernandez, Stephanie T. Murphy, Mustafa Janabi, Grant T. Gullberg, James P. O'Neil, Kathleen M. Brennan, Youngho Seo, Gengsheng L. Zeng, and J.S. Huber
- Subjects
Male ,Aging ,medicine.medical_treatment ,Perfusion scanning ,Fatty Acids, Nonesterified ,Left ventricular hypertrophy ,Cardiovascular ,Multimodal Imaging ,Muscle hypertrophy ,Rats, Inbred SHR ,Medicine ,Insulin ,Longitudinal Studies ,Tomography ,F-18-fluorodihydrorotenol ,Ejection fraction ,Fatty Acids ,Myocardial Perfusion Imaging ,Left Ventricular ,X-Ray Computed ,Nuclear Medicine & Medical Imaging ,Phenotype ,Heart Disease ,Hypertension ,Cardiology ,Biomedical Imaging ,Hypertrophy, Left Ventricular ,Perfusion ,myocardial perfusion ,medicine.medical_specialty ,spontaneously hypertensive rat ,Inbred SHR ,Heart Ventricles ,Clinical Sciences ,F-18-fluoro-6-thia-heptadecanoic acid ,Article ,Spontaneously hypertensive rat ,Fluorodeoxyglucose F18 ,Internal medicine ,Animals ,18F-fluoro-6-thia-heptadecanoic acid ,Radiology, Nuclear Medicine and imaging ,cardiovascular diseases ,business.industry ,Animal ,Hypertrophy ,medicine.disease ,Rats ,Disease Models, Animal ,Endocrinology ,Heart failure ,Positron-Emission Tomography ,Disease Models ,Nonesterified ,myocardial substrate metabolism ,myocardial substrate ,Tomography, X-Ray Computed ,business ,metabolism ,18F-fluorodihydrorotenol - Abstract
UnlabelledMyocardial metabolic and perfusion imaging is a vital tool for understanding the physiologic consequences of heart failure. We used PET imaging to examine the longitudinal kinetics of (18)F-FDG and 14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid ((18)F-FTHA) as analogs of glucose and fatty acid (FA) to quantify metabolic substrate shifts with the spontaneously hypertensive rat (SHR) as a model of left ventricular hypertrophy (LVH) and failure. Myocardial perfusion and left ventricular function were also investigated using a newly developed radiotracer (18)F-fluorodihydrorotenol ((18)F-FDHROL).MethodsLongitudinal dynamic electrocardiogram-gated small-animal PET/CT studies were performed with 8 SHR and 8 normotensive Wistar-Kyoto (WKY) rats over their life cycle. We determined the myocardial influx rate constant for (18)F-FDG and (18)F-FTHA (Ki(FDG) and Ki(FTHA), respectively) and the wash-in rate constant for (18)F-FDHROL (K1(FDHROL)). (18)F-FDHROL data were also used to quantify left ventricular ejection fraction (LVEF) and end-diastolic volume (EDV). Blood samples were drawn to independently measure plasma concentrations of glucose, insulin, and free fatty acids (FFAs).ResultsKi(FDG) and Ki(FTHA) were higher in SHRs than WKY rats (P < 3 × 10(-8) and 0.005, respectively) independent of age. A decrease in Ki(FDG) with age was evident when models were combined (P = 0.034). The SHR exhibited higher K1(FDHROL) (P < 5 × 10(-6)) than the control, with no age-dependent trends in either model (P = 0.058). Glucose plasma concentrations were lower in SHRs than controls (P < 6 × 10(-12)), with an age-dependent rise for WKY rats (P < 2 × 10(-5)). Insulin plasma concentrations were higher in SHRs than controls (P < 3 × 10(-3)), with an age-dependent decrease when models were combined (P = 0.046). FFA levels were similar between models (P = 0.374), but an increase with age was evident only in SHR (P < 7 × 10(-6)).ConclusionThe SHR exhibited alterations in myocardial substrate use at 8 mo characterized by increased glucose and FA utilizations. At 20 mo, the SHR had LVH characterized by decreased LVEF and increased EDV, while simultaneously sustaining higher glucose and similar FA utilizations (compared with WKY rats), which indicates maladaptation of energy substrates in the failing heart. Elevated K1(FDHROL) in the SHR may reflect elevated oxygen consumption and decreased capillary density in the hypertrophied heart. From our findings, metabolic changes appear to precede mechanical changes of LVH progression in the SHR model.
- Published
- 2013
22. Tumor dosimetry using [124I]m-iodobenzylguanidine microPET/CT for [131I]m-iodobenzylguanidine treatment of neuroblastoma in a murine xenograft model
- Author
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Chang-Lae Lee, W. Clay Gustafson, William A. Weiss, Stephanie T. Murphy, Daphne A. Haas-Kogan, Shorouk Dannoon, Erin A. Nekritz, Youngho Seo, Henry F. VanBrocklin, Miguel Hernandez-Pampaloni, and Katherine K. Matthay
- Subjects
Cancer Research ,X-ray microtomography ,Mice, Nude ,3-Iodobenzylguanidine ,Radiation Dosage ,Article ,Iodine Radioisotopes ,Mice ,Neuroblastoma ,Imaging, Three-Dimensional ,medicine ,Dosimetry ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,PET-CT ,Norepinephrine Plasma Membrane Transport Proteins ,medicine.diagnostic_test ,biology ,business.industry ,X-Ray Microtomography ,M-Iodobenzylguanidine ,medicine.disease ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,Oncology ,Norepinephrine transporter ,Positron emission tomography ,Organ Specificity ,Positron-Emission Tomography ,biology.protein ,Nuclear medicine ,business - Abstract
[(124)I]m-iodobenzylguanidine ((124)I-mIBG) provides a quantitative tool for pretherapy tumor imaging and dosimetry when performed before [(131)I]m-iodobenzylguanidine ((131)I-mIBG) targeted radionuclide therapy of neuroblastoma. (124)I (T (1/2) = 4.2 days) has a comparable half-life to that of (131)I (T (1/2) = 8.02 days) and can be imaged by positron emission tomography (PET) for accurate quantification of the radiotracer distribution. We estimated expected radiation dose in tumors from (131)I-mIBG therapy using (124)I-mIBG microPET/CT imaging data in a murine xenograft model of neuroblastoma transduced to express high levels of the human norepinephrine transporter (hNET).In order to enhance mIBG uptake for in vivo imaging and therapy, NB 1691-luciferase (NB1691) human neuroblastoma cells were engineered to express high levels of hNET protein by lentiviral transduction (NB1691-hNET). Both NB1691 and NB1691-hNET cells were implanted subcutaneously and into renal capsules in athymic mice. (124)I-mIBG (4.2-6.5 MBq) was administered intravenously for microPET/CT imaging at 5 time points over 95 h (0.5, 3-5, 24, 48, and 93-95 h median time points). In vivo biodistribution data in normal organs, tumors, and whole-body were collected from reconstructed PET images corrected for photon attenuation using the CT-based attenuation map. Organ and tumor dosimetry were determined for (124)I-mIBG. Dose estimates for (131)I-mIBG were made, assuming the same in vivo biodistribution as (124)I-mIBG.All NB1691-hNET tumors had significant uptake and retention of (124)I-mIBG, whereas unmodified NB1691 tumors did not demonstrate quantifiable mIBG uptake in vivo, despite in vitro uptake. (124)I-mIBG with microPET/CT provided an accurate three-dimensional tool for estimating the radiation dose that would be delivered with (131)I-mIBG therapy. For example, in our model system, we estimated that the administration of (131)I-mIBG in the range of 52.8-206 MBq would deliver 20 Gy to tumors.The overexpression of hNET was found to be critical for (124)I-mIBG uptake and retention in vivo. The quantitative (124)I-mIBG PET/CT is a promising new tool to predict tumor radiation doses with (131)I-mIBG therapy of neuroblastoma. This methodology may be applied to tumor dosimetry of (131)I-mIBG therapy in human subjects using (124)I-mIBG pretherapy PET/CT data.
- Published
- 2012
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