The Experts below are selected from a list of 20094 Experts worldwide ranked by ideXlab platform
Leslie A Khawli - One of the best experts on this subject based on the ideXlab platform.
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effects of anti vegf on predicted antibody biodistribution roles of vascular volume interstitial volume and blood flow
PLOS ONE, 2011Co-Authors: Andrew C Boswell, Eduardo E Mundo, Daniela Bumbaca, Michelle G Schweiger, Paul J Fielder, Gregory Z Ferl, Frankpeter Theil, Leslie A KhawliAbstract:Background The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences. Methodology/Principal Findings Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naive or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and Rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naive versus anti-VEGF-administered mice. Conclusions/Significance These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF.
Nicholas A. Delamere - One of the best experts on this subject based on the ideXlab platform.
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Na,K-ATPase Polypeptide Upregulation Responses in Lens Epithelium
2013Co-Authors: Nicholas A. Delamere, William L Dean, Robert E. Manning, Lixia Liu, Amy E. MoseleyAbstract:PURPOSE. In a previous study, an increase in Na,K-ATPase a2 expression was detected in the epithelium of porcine lenses exposed to amphotericin B, an ionophore that also increases lens sodium and stimulates active sodium transport. The purpose of the present study was to determine whether an increase of Na,K-ATPase a2 synthesis is a response to an episode of rapid Na-K transport or whether the increase in lens sodium alone can initiate the response. METHODS. Western blot analyses were conducted to probe for Na,K-ATPase a polypeptides in membrane material isolated from porcine lens epithelium. Ouabain-sensitive adenosine triphosphate hydrolysis was used as an index of Na,K-ATPase activity, and lens ion content was determined by atomic absorption spectrophotometry. 86-Rubidium ( 86 Rb) uptake was measured as an indicator for active potassium transport. RESULTS. 86 Rb uptake was markedly diminished in lenses exposed to dihydro-ouabain (DHO), signifying inhibition of active sodium-potassium transport. Consistent with this, the sodium content of DHO-treated lenses increased. By western blot analysis, a marked increase of Na,K-ATPase a2 polypeptide could be detected in the epithelium of DHO-treated lenses. To rule out the possibility that apparent stimulation of Na,K-ATPase a2 synthesis stemmed from binding of DHO t
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Vacuolar ATPase driven potassium transport in highly metastatic breast cancer cells
Biochimica et biophysica acta, 2013Co-Authors: Sarah A. Salyer, Jordan R. Olberding, Anthony A. Distler, Eleanor D. Lederer, Barbara J. Clark, Nicholas A. Delamere, Syed J. KhundmiriAbstract:Abstract Breast cancer is the second leading cause of death in women and thus has received a great deal of attention by researchers. Recent studies suggested decreased occurrence of cancer in patients treated with cardiac glycosides (CGs) for heart conditions. Because CGs induce their cellular effects via the Na + , K + ATPase (Na–K), we treated four breast cancer cell lines (MCF-7, T47D, MDA-MB453, and MDA-MB231) and a non-cancerous breast ductal epithelial cell line (MCF-10A) with ouabain, a well-characterized CG, and measured cell proliferation by measuring bromodeoxyuridine incorporation. Ouabain (1 μM) decreased cell proliferation in all cell lines studied except MDA-MB453 cells. Western blot of Na–K α and β subunits showed α1, α3, and β1 expression in all cell lines except MDA-MB453 cells where Na–K protein and mRNA were absent. Potassium uptake, measured as Rubidium ( 86 Rb) flux, and intracellular potassium were both significantly higher in MDA-MB453 cells compared to MCF-10A cells. RT-qPCR suggested a 7 fold increase in voltage-gated potassium channel (KCNQ2) expression in MDA-MB453 cells compared to MCF-10A cells. Inhibition of KCNQ2 prevented cell growth and 86 Rb uptake in MDA-MB453 cells but not in MCF-10A cells. All cancer cells had significantly higher vacuolar H-ATPase (V-ATPase) activity than MCF-10A cells. Inhibition of V-ATPase decreased 86 Rb uptake and intracellular potassium in MDA-MB453 cells but not in MCF-10A cells. The findings point to the absence of Na–K, high hERG and KCNQ2 expression, elevated V-ATPase activity and sensitivity to V-ATPase inhibitors in MDA-MB453. We conclude that cancer cells exhibit fundamentally different metabolic pathways for maintenance of intracellular ion homeostasis.
Andrew C Boswell - One of the best experts on this subject based on the ideXlab platform.
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effects of anti vegf on predicted antibody biodistribution roles of vascular volume interstitial volume and blood flow
PLOS ONE, 2011Co-Authors: Andrew C Boswell, Eduardo E Mundo, Daniela Bumbaca, Michelle G Schweiger, Paul J Fielder, Gregory Z Ferl, Frankpeter Theil, Leslie A KhawliAbstract:Background The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences. Methodology/Principal Findings Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naive or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and Rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naive versus anti-VEGF-administered mice. Conclusions/Significance These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF.
Gregory Z Ferl - One of the best experts on this subject based on the ideXlab platform.
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effects of anti vegf on predicted antibody biodistribution roles of vascular volume interstitial volume and blood flow
PLOS ONE, 2011Co-Authors: Andrew C Boswell, Eduardo E Mundo, Daniela Bumbaca, Michelle G Schweiger, Paul J Fielder, Gregory Z Ferl, Frankpeter Theil, Leslie A KhawliAbstract:Background The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences. Methodology/Principal Findings Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naive or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and Rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naive versus anti-VEGF-administered mice. Conclusions/Significance These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF.
Paul J Fielder - One of the best experts on this subject based on the ideXlab platform.
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effects of anti vegf on predicted antibody biodistribution roles of vascular volume interstitial volume and blood flow
PLOS ONE, 2011Co-Authors: Andrew C Boswell, Eduardo E Mundo, Daniela Bumbaca, Michelle G Schweiger, Paul J Fielder, Gregory Z Ferl, Frankpeter Theil, Leslie A KhawliAbstract:Background The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences. Methodology/Principal Findings Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naive or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and Rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naive versus anti-VEGF-administered mice. Conclusions/Significance These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF.
