40 results on '"Bready J"'
Search Results
2. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels
- Author
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Falcón, B L, Hashizume, H, Koumoutsakos, P, Chou, J, Bready, J V, Coxon, A, Oliner, J D, McDonald, D M, and University of Zurich
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2734 Pathology and Forensic Medicine ,SX00 SystemsX.ch ,SX15 WingX ,570 Life sciences ,biology - Published
- 2009
3. The effects of keratinocyte growth factor in preclinical models of mucositis
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Farrell, C. L., Rex, K. L., Chen, J. N., Bready, J. V., DiPalma, C. R., Kaufman, S. A., Rattan, A., Scully, S., and Lacey, D. L.
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Fibroblast Growth Factors ,Disease Models, Animal ,Radiation Injuries, Experimental ,Stomatitis ,Fibroblast Growth Factor 7 ,Mouth Mucosa ,Animals ,Original Articles - Abstract
The epithelium of the oral cavity and small intestine of the gastrointestinal tract have a high rate of cell renewal and as such, are sensitive to cytotoxic therapies that kill rapidly dividing cells. Mucositis is a complication of cancer therapy where impairment of the regenerative capacity of the epithelium leads to atrophy, ulceration and a loss of barrier function. Keratinocyte growth factor (KGF) is an epithelial cell‐specific growth and differentiation factor that is trophic for the mucosal epithelium of the gastrointestinal tract. In this study, KGF in normal animals caused epithelial thickening in the squamous epithelium of the oral cavity and increased crypt depth and villus height of the small intestine. It also appeared to regulate gene expression in these tissues including that of some antioxidant enzymes and intestinal trefoil protein. KGF has been shown to be efficacious in several preclinical models of mucositis where KGF pretreatment reduced weight loss typically seen during and after the course of therapy and significantly improved survival. At a tissue level KGF reduced atrophy, accelerated regrowth, and decreased ulcer formation of the oral epithelium after irradiation, and improved crypt survival and prevented villus atrophy in the small intestine of irradiated or chemotherapy‐treated mice. Preliminary studies suggest that its efficacy may be partly a consequence of the growth and differentiation effect, and also partly due to regulation of the expression of genes that play a role in mucosal protection. These data suggest that KGF may be useful for the prevention or treatment of mucositis in patients treated with regimens of cancer therapy that have gastrointestinal toxicity.
- Published
- 2002
4. 174 EFFECTS OF LEAD ON CULTURED CEREBRAL MICROVESSEL ENDOTHELIUM
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Maxwell, K., Vinters, H. V., Berliner, J. A., Bready, J. V., and Cancilla, P. A.
- Published
- 1984
5. 173 INSULIN STIMULATES DNA SYNTHESIS IN CEREBRAL MICROVESSEL ENDOTHELIUH AND SMOOTH MUSCLE
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Vinters, H. V., Berliner, J. A., Maxwell, K., Bready, J. V., and Cancilla, P. A.
- Published
- 1984
6. Crystal Structure of human JNK3 complexed with N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)naphthalen-1-yl)-1H-benzo[d]imidazol-2-amine
- Author
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Cee, V.J., primary, Cheng, A.C., additional, Romero, K., additional, Bellon, S., additional, Mohr, C., additional, Whittington, D.A., additional, Bready, J., additional, Caenepeel, S., additional, Coxon, A., additional, Deak, H.L., additional, Hodous, B.L., additional, Kim, J.L., additional, Lin, J., additional, Nguyen, H., additional, Olivieri, P.R., additional, Patel, V.F., additional, Wang, L., additional, Hughes, P., additional, and Geuns-Meyer, S., additional
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- 2009
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7. Glass Debris in Rollover Accidents
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Perl, T. R., primary, Bready, J. E., additional, Nordhagen, R. P., additional, and Warner, M. H., additional
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- 2008
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8. The effects of keratinocyte growth factor in preclinical models of mucositis
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Farrell, C. L., primary, Rex, K. L., additional, Chen, J. N., additional, Bready, J. V., additional, DiPalma, C. R., additional, Kaufman, S. A., additional, Rattan, A., additional, Scully, S., additional, and Lacey, D. L., additional
- Published
- 2002
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9. Detection of platelet-derived growth factor (PDGF)-AA in actively healing human wounds treated with recombinant PDGF-BB and absence of PDGF in chronic nonhealing wounds.
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Pierce, G F, primary, Tarpley, J E, additional, Tseng, J, additional, Bready, J, additional, Chang, D, additional, Kenney, W C, additional, Rudolph, R, additional, Robson, M C, additional, Vande Berg, J, additional, and Reid, P, additional
- Published
- 1995
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10. The antiproliferative activity of c-myb and c-myc antisense oligonucleotides in smooth muscle cells is caused by a nonantisense mechanism.
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Burgess, T L, primary, Fisher, E F, additional, Ross, S L, additional, Bready, J V, additional, Qian, Y X, additional, Bayewitch, L A, additional, Cohen, A M, additional, Herrera, C J, additional, Hu, S S, additional, and Kramer, T B, additional
- Published
- 1995
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11. F29. Shear stress induced endothelial cell and platelet activation in a damaged endothelial monolayer model
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DEBELAK, J, primary, BREADY, J, additional, FEIGEN, L, additional, and GIORGIO, T, additional
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- 1995
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12. Regulation of brain capillary endothelial thrombomodulin mRNA expression.
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Tran, N D, Wong, V L, Schreiber, S S, Bready, J V, and Fisher, M
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- 1996
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13. Insulin stimulates DNA synthesis in cerebral microvessel endothelium and smooth muscle.
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Vinters, Harry V., Berliner, Judith A., Beck, David W., Maxwell, Karen, Bready, James V., Cancilia, Pasquale A., Vinters, H V, Berliner, J A, Beck, D W, Maxwell, K, Bready, J V, and Cancilla, P A
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- 1985
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14. 103 UPTAKE OF GLUCOSE ANALOGUES INTO CULTURED CEREBRAL MICROVESSEL ENDOTHELIUM
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Vinters, H. V., primary, Cancilia, P. A., additional, Bready, J., additional, Beck, D. w., additional, Hart, M. N., additional, and Tomiyasu, U., additional
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- 1983
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15. FLUORESCENCE-ACTIVATED SORTING OF RETINAL VASCULAR ENDOTHELIUM
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Fratkin, J. D., primary, Cancilla, P. A., additional, and Bready, J. V., additional
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- 1982
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16. The Nutritional Requirements of Termites in Axenic Cultures. 2. Studies on the Effectiveness of Antibiotics in the Sterilization of Workers of Reliculitermes flavipes12
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Bready, J. K., primary and Friedman, S., additional
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- 1963
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17. The Quantitative Determination of Gallium in Micro Samples by the Graphite Spark
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Murt, E. M., primary and Bready, J. C., additional
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- 1961
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18. The Nutritional Requirements of Termites in Axenic Cultures. 1. Sterilization of Eggs of Reticulitermes flavipes and the Requirements of First-Instar Nymphs12
- Author
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Bready, J. K., primary and Friedman, S., additional
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- 1963
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19. A Positive Side of Deployment: Vicarious Posttraumatic Growth in U.S. Military Nurses Who Served in the Iraq and Afghanistan Wars.
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Doherty ME, Scannell-Desch E, and Bready J
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- Adult, Afghan Campaign 2001-, Aged, Cross-Sectional Studies, Female, Humans, Iraq War, 2003-2011, Male, Middle Aged, Military Personnel statistics & numerical data, Surveys and Questionnaires, United States, Military Deployment psychology, Military Nursing, Military Personnel psychology, Posttraumatic Growth, Psychological
- Abstract
Purpose: To describe vicarious posttraumatic growth in U.S. military nurses who served in the Iraq and Afghanistan wars., Design: A cross-sectional descriptive design was used., Methods: Respondents were asked to complete the Posttraumatic Growth Inventory (PTGI), Core Beliefs Inventory (CBI), and six open-ended write-in questions as an electronic survey., Findings: Appreciation of life and Personal strength were the strongest dimensions on the PTGI. This was also evident in participant responses to the open-ended questions. The five dimensions of the PTGI were significantly correlated, indicating as growth increased in one dimension, growth increased in all dimensions. The CBI showed moderate to strong positive correlations with all items. Thus, the relationship between the total PTGI scores and the total CBI scores showed a strong, positive correlation, which indicated higher overall core belief scores associated with more growth in total PTGI scores., Conclusions: This study provided initial evidence that some nurses who served in the Iraq and Afghanistan wars experienced posttraumatic growth. While healthcare providers need to be educated about their vulnerability when exposed to trauma, they also need to be aware of potential growth when caring for casualties., Clinical Relevance: Nurses preparing to serve in war, as well as those returning, need to pay attention to their physical, psychological, emotional, and spiritual health. Following return from war deployment, the military services need to take deliberate and careful measures to ensure that no returning personnel "fall through the cracks" in getting the help they need., (© 2020 Sigma Theta Tau International.)
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- 2020
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20. AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, inhibits angiogenesis in models of ocular neovascular diseases.
- Author
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Oliner JD, Bready J, Nguyen L, Estrada J, Hurh E, Ma H, Pretorius J, Fanslow W, Nork TM, Leedle RA, Kaufman S, and Coxon A
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- Angiogenesis Inhibitors pharmacokinetics, Angiopoietin-1 antagonists & inhibitors, Angiopoietin-2 antagonists & inhibitors, Animals, Animals, Newborn, Autoradiography, Capillary Permeability drug effects, Choroidal Neovascularization metabolism, Choroidal Neovascularization pathology, Eye metabolism, Female, Fluorescein Angiography, Humans, In Situ Hybridization, Infant, Newborn, Macaca fascicularis, Male, Mice, Mice, Inbred C57BL, Recombinant Fusion Proteins pharmacokinetics, Retinal Neovascularization metabolism, Retinal Neovascularization pathology, Retinal Vessels drug effects, Retinopathy of Prematurity metabolism, Retinopathy of Prematurity pathology, Tissue Distribution, Angiogenesis Inhibitors pharmacology, Choroidal Neovascularization prevention & control, Disease Models, Animal, Recombinant Fusion Proteins pharmacology, Retinal Neovascularization prevention & control, Retinopathy of Prematurity prevention & control
- Abstract
Purpose: To determine whether systemic treatment with AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, inhibits neovascular processes in animal models of ocular disease., Methods: AMG 386 was tested in a laser-induced choroidal neovascularization (CNV) model in monkeys using fluorescein angiography. The biodistribution of (125)I-AMG 386 was determined in cynomolgus monkeys by whole-body autoradiography and radioanalysis of ocular tissues. A murine retinopathy of prematurity (ROP) model was used to examine the effect of AMG 386 on established and newly formed retinal vessels, either as a single agent or when combined with VEGF inhibition.AMG 386 pharmacokinetics were evaluated in each model., Results: In the CNV model, AMG 386 significantly decreased fluorescent angiographic leakage and reduced fibroplasia, indicating an impaired healing response consistent with angiogenesis blockade. Radiolabeled AMG 386 was widely distributed across ocular tissues, with highest concentrations in the choroid, cornea, retinal pigmented epithelium, iris/ciliary body, and sclera. In the ROP model, AMG 386 prevented pathologic retinal angiogenesis when administered from P8 to P16 but transiently impeded regression of these abnormal vessels when administered from P17 to P23. Combining AMG 386 with VEGF inhibition led to cooperative prevention of retinal angiogenesis in this model. No AMG 386-related ocular toxicities occurred, and no treatment-related clinical observations were made in any of the studies., Conclusions: In this study, AMG 386 inhibited angiogenesis in animal models of CNV and ROP, supporting investigation of AMG 386 for the treatment of ocular neovascular diseases in the clinical setting.
- Published
- 2012
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21. Context-dependent role of angiopoietin-1 inhibition in the suppression of angiogenesis and tumor growth: implications for AMG 386, an angiopoietin-1/2-neutralizing peptibody.
- Author
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Coxon A, Bready J, Min H, Kaufman S, Leal J, Yu D, Lee TA, Sun JR, Estrada J, Bolon B, McCabe J, Wang L, Rex K, Caenepeel S, Hughes P, Cordover D, Kim H, Han SJ, Michaels ML, Hsu E, Shimamoto G, Cattley R, Hurh E, Nguyen L, Wang SX, Ndifor A, Hayward IJ, Falcón BL, McDonald DM, Li L, Boone T, Kendall R, Radinsky R, and Oliner JD
- Subjects
- Amino Acid Sequence, Animals, Cornea blood supply, Enzyme-Linked Immunosorbent Assay, Female, Mice, Mice, Nude, Molecular Sequence Data, Neoplasms, Experimental blood supply, Ovarian Follicle blood supply, Rats, Rats, Sprague-Dawley, Angiopoietin-1 antagonists & inhibitors, Cell Division drug effects, Neoplasms, Experimental pathology, Neovascularization, Pathologic prevention & control, Recombinant Fusion Proteins pharmacology
- Abstract
AMG 386 is an investigational first-in-class peptide-Fc fusion protein (peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 (Ang1) and Ang2 with their receptor, Tie2. Although the therapeutic value of blocking Ang2 has been shown in several models of tumorigenesis and angiogenesis, the potential benefit of Ang1 antagonism is less clear. To investigate the consequences of Ang1 neutralization, we have developed potent and selective peptibodies that inhibit the interaction between Ang1 and its receptor, Tie2. Although selective Ang1 antagonism has no independent effect in models of angiogenesis-associated diseases (cancer and diabetic retinopathy), it induces ovarian atrophy in normal juvenile rats and inhibits ovarian follicular angiogenesis in a hormone-induced ovulation model. Surprisingly, the activity of Ang1 inhibitors seems to be unmasked in some disease models when combined with Ang2 inhibitors, even in the context of concurrent vascular endothelial growth factor inhibition. Dual inhibition of Ang1 and Ang2 using AMG 386 or a combination of Ang1- and Ang2-selective peptibodies cooperatively suppresses tumor xenograft growth and ovarian follicular angiogenesis; however, Ang1 inhibition fails to augment the suppressive effect of Ang2 inhibition on tumor endothelial cell proliferation, corneal angiogenesis, and oxygen-induced retinal angiogenesis. In no case was Ang1 inhibition shown to (a) confer superior activity to Ang2 inhibition or dual Ang1/2 inhibition or (b) antagonize the efficacy of Ang2 inhibition. These results imply that Ang1 plays a context-dependent role in promoting postnatal angiogenesis and that dual Ang1/2 inhibition is superior to selective Ang2 inhibition for suppression of angiogenesis in some postnatal settings.
- Published
- 2010
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22. Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase.
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Cee VJ, Cheng AC, Romero K, Bellon S, Mohr C, Whittington DA, Bak A, Bready J, Caenepeel S, Coxon A, Deak HL, Fretland J, Gu Y, Hodous BL, Huang X, Kim JL, Lin J, Long AM, Nguyen H, Olivieri PR, Patel VF, Wang L, Zhou Y, Hughes P, and Geuns-Meyer S
- Subjects
- Administration, Oral, Benzimidazoles administration & dosage, Benzimidazoles chemistry, Biological Availability, Crystallography, X-Ray, HeLa Cells, Humans, Models, Molecular, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemistry, Benzimidazoles pharmacology, Protein Kinase Inhibitors pharmacology, Receptor, TIE-2 antagonists & inhibitors
- Abstract
Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis. Reported herein is the optimization of a nonselective scaffold into a potent and highly selective inhibitor of Tie-2 kinase.
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- 2009
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23. Evaluation of indazole-based compounds as a new class of potent KDR/VEGFR-2 inhibitors.
- Author
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Bauer D, Whittington DA, Coxon A, Bready J, Harriman SP, Patel VF, Polverino A, and Harmange JC
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- Animals, Capillary Permeability drug effects, Cells, Cultured, Crystallography, X-Ray, Drug Evaluation, Preclinical, Humans, Indazoles chemical synthesis, Indazoles chemistry, Indazoles metabolism, Male, Mice, Mice, Nude, Protein Binding physiology, Protein Kinase Inhibitors classification, Rats, Rats, Sprague-Dawley, Vascular Endothelial Growth Factor Receptor-2 metabolism, Indazoles pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
A novel class of potent and selective inhibitors of KDR incorporating an indazole moiety 1 is reported. The discovery, synthesis, and structure-activity relationships of this series of inhibitors have been investigated. The most promising compounds were also profiled to determine their pharmacokinetic properties and evaluated in a VEGF-induced vascular permeability assay.
- Published
- 2008
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24. Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.
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Weiss MM, Harmange JC, Polverino AJ, Bauer D, Berry L, Berry V, Borg G, Bready J, Chen D, Choquette D, Coxon A, DeMelfi T, Doerr N, Estrada J, Flynn J, Graceffa RF, Harriman SP, Kaufman S, La DS, Long A, Neervannan S, Patel VF, Potashman M, Regal K, Roveto PM, Schrag ML, Starnes C, Tasker A, Teffera Y, Whittington DA, and Zanon R
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- Administration, Oral, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Corneal Neovascularization blood, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Design, Drug Evaluation, Preclinical, Female, Humans, Inhibitory Concentration 50, Injections, Intravenous, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Microsomes, Liver drug effects, Models, Molecular, Molecular Structure, Naphthalenes chemical synthesis, Naphthalenes chemistry, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Rats, Rats, Sprague-Dawley, Reproducibility of Results, Stereoisomerism, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Endothelial Cells drug effects, Naphthalenes pharmacology, Protein Kinase Inhibitors pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.
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- 2008
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25. Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation.
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Harmange JC, Weiss MM, Germain J, Polverino AJ, Borg G, Bready J, Chen D, Choquette D, Coxon A, DeMelfi T, DiPietro L, Doerr N, Estrada J, Flynn J, Graceffa RF, Harriman SP, Kaufman S, La DS, Long A, Martin MW, Neervannan S, Patel VF, Potashman M, Regal K, Roveto PM, Schrag ML, Starnes C, Tasker A, Teffera Y, Wang L, White RD, Whittington DA, and Zanon R
- Subjects
- Administration, Oral, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Corneal Neovascularization blood, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Design, Drug Evaluation, Preclinical, Female, Humans, Inhibitory Concentration 50, Injections, Intravenous, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Microsomes, Liver drug effects, Models, Molecular, Molecular Structure, Naphthalenes chemical synthesis, Naphthalenes chemistry, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Rats, Rats, Sprague-Dawley, Reproducibility of Results, Stereoisomerism, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Endothelial Cells drug effects, Naphthalenes pharmacology, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors
- Abstract
A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.
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- 2008
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26. Discovery of N-phenyl nicotinamides as potent inhibitors of Kdr.
- Author
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Dominguez C, Smith L, Huang Q, Yuan C, Ouyang X, Cai L, Chen P, Kim J, Harvey T, Syed R, Kim TS, Tasker A, Wang L, Zhang M, Coxon A, Bready J, Starnes C, Chen D, Gan Y, Neervannan S, Kumar G, Polverino A, and Kendall R
- Subjects
- Cell Line, Tumor, Humans, Niacinamide pharmacology, Protein Kinase Inhibitors pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
Inhibition of tumor-induced angiogenesis is a promising strategy in anticancer research. Neovascularization is a process required for both tumor growth and metastasis. Enhanced understanding of the underlying molecular mechanisms has led to the discovery of a variety of pharmaceutically attractive targets. Decades of investigation suggest that vascular endothelial growth factor (VEGF) and its receptors, in particular VEGFR2 or kinase insert-domain-containing receptor (Kdr), play a critical role in the growth and survival of endothelial cells in newly forming vasculature. The clinical utility of inhibitors of this receptor tyrosine kinase is currently under intense investigation. Herein we report our efforts in this arena.
- Published
- 2007
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27. Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors.
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Potashman MH, Bready J, Coxon A, DeMelfi TM Jr, DiPietro L, Doerr N, Elbaum D, Estrada J, Gallant P, Germain J, Gu Y, Harmange JC, Kaufman SA, Kendall R, Kim JL, Kumar GN, Long AM, Neervannan S, Patel VF, Polverino A, Rose P, Plas Sv, Whittington D, Zanon R, and Zhao H
- Subjects
- Administration, Oral, Angiogenesis Inhibitors pharmacokinetics, Angiogenesis Inhibitors pharmacology, Animals, Benzimidazoles pharmacokinetics, Benzimidazoles pharmacology, Benzoxazoles pharmacokinetics, Benzoxazoles pharmacology, Biological Availability, Capillary Permeability drug effects, Cell Proliferation drug effects, Cells, Cultured, Cornea blood supply, Cornea drug effects, Crystallography, X-Ray, Drug Design, Endothelial Cells cytology, Endothelial Cells drug effects, Female, Humans, Male, Mice, Mice, Nude, Models, Molecular, Molecular Structure, Pyridines pharmacokinetics, Pyridines pharmacology, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Umbilical Veins cytology, Vascular Endothelial Growth Factor Receptor-2 chemistry, Angiogenesis Inhibitors chemical synthesis, Benzimidazoles chemical synthesis, Benzoxazoles chemical synthesis, Pyridines chemical synthesis, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).
- Published
- 2007
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28. Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.
- Author
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Hodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Bready J, Caenepeel S, Cee VJ, Chaffee SC, Coxon A, Emery M, Fretland J, Gallant P, Gu Y, Hoffman D, Johnson RE, Kendall R, Kim JL, Long AM, Morrison M, Olivieri PR, Patel VF, Polverino A, Rose P, Tempest P, Wang L, Whittington DA, and Zhao H
- Subjects
- Administration, Oral, Angiogenesis Inhibitors pharmacokinetics, Angiogenesis Inhibitors pharmacology, Animals, Benzamides pharmacokinetics, Benzamides pharmacology, Binding Sites, Blood Proteins metabolism, Crystallography, X-Ray, Female, Humans, Injections, Intraperitoneal, Injections, Intravenous, Male, Mice, Models, Molecular, Molecular Structure, Phosphorylation, Protein Binding, Pyridines pharmacokinetics, Pyridines pharmacology, Rats, Rats, Sprague-Dawley, Receptor, TIE-2 chemistry, Receptor, TIE-2 metabolism, Structure-Activity Relationship, Triazines pharmacokinetics, Triazines pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors, Angiogenesis Inhibitors chemical synthesis, Benzamides chemical synthesis, Pyridines chemical synthesis, Receptor, TIE-2 antagonists & inhibitors, Triazines chemical synthesis
- Abstract
Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.
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- 2007
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29. Alkynylpyrimidine amide derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase.
- Author
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Cee VJ, Albrecht BK, Geuns-Meyer S, Hughes P, Bellon S, Bready J, Caenepeel S, Chaffee SC, Coxon A, Emery M, Fretland J, Gallant P, Gu Y, Hodous BL, Hoffman D, Johnson RE, Kendall R, Kim JL, Long AM, McGowan D, Morrison M, Olivieri PR, Patel VF, Polverino A, Powers D, Rose P, Wang L, and Zhao H
- Subjects
- Adenosine Triphosphate metabolism, Alkynes pharmacokinetics, Alkynes pharmacology, Amides pharmacokinetics, Amides pharmacology, Angiogenesis Inhibitors pharmacokinetics, Angiogenesis Inhibitors pharmacology, Animals, Binding Sites, Blood Proteins metabolism, Cell Line, Female, Humans, In Vitro Techniques, Lung drug effects, Lung enzymology, Male, Mice, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Phosphorylation, Protein Binding, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Rats, Rats, Sprague-Dawley, Receptor, TIE-2 metabolism, Stereoisomerism, Structure-Activity Relationship, Alkynes chemical synthesis, Amides chemical synthesis, Angiogenesis Inhibitors chemical synthesis, Pyrimidines chemical synthesis, Receptor, TIE-2 antagonists & inhibitors
- Abstract
The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.
- Published
- 2007
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30. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts.
- Author
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Polverino A, Coxon A, Starnes C, Diaz Z, DeMelfi T, Wang L, Bready J, Estrada J, Cattley R, Kaufman S, Chen D, Gan Y, Kumar G, Meyer J, Neervannan S, Alva G, Talvenheimo J, Montestruque S, Tasker A, Patel V, Radinsky R, and Kendall R
- Subjects
- Animals, Carcinoma, Squamous Cell drug therapy, Cell Line, Cell Line, Tumor, Endothelium, Vascular drug effects, Endothelium, Vascular physiology, Female, Fibroblasts drug effects, Humans, Indoles chemical synthesis, Leukemia, Megakaryoblastic, Acute drug therapy, Mice, Mice, Nude, Niacinamide chemical synthesis, Niacinamide therapeutic use, Oligonucleotides, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Rats, Rats, Sprague-Dawley, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors, Skin drug effects, Transplantation, Heterologous, Umbilical Veins physiology, Angiogenesis Inhibitors pharmacology, Indoles therapeutic use, Niacinamide analogs & derivatives, Proto-Oncogene Proteins c-kit drug effects
- Abstract
The growth of solid tumors is dependent on the continued stimulation of endothelial cell proliferation and migration resulting in angiogenesis. The angiogenic process is controlled by a variety of factors of which the vascular endothelial growth factor (VEGF) pathway and its receptors play a pivotal role. Small-molecule inhibitors of VEGF receptors (VEGFR) have been shown to inhibit angiogenesis and tumor growth in preclinical models and in clinical trials. A novel nicotinamide, AMG 706, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4, platelet-derived growth factor receptor, and Kit receptors in preclinical models. AMG 706 inhibited human endothelial cell proliferation induced by VEGF, but not by basic fibroblast growth factor in vitro, as well as vascular permeability induced by VEGF in mice. Oral administration of AMG 706 potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts. AMG 706 was well tolerated and had no significant effects on body weight or on the general health of the animals. Histologic analysis of tumor xenografts from AMG 706-treated animals revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. In summary, AMG 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies.
- Published
- 2006
- Full Text
- View/download PDF
31. Stimulatory effects of B7-related protein-1 on cellular and humoral immune responses in mice.
- Author
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Guo J, Stolina M, Bready JV, Yin S, Horan T, Yoshinaga SK, and Senaldi G
- Subjects
- Abatacept, Administration, Cutaneous, Animals, Antigens, CD administration & dosage, Antigens, Differentiation administration & dosage, Asthma immunology, B7-1 Antigen administration & dosage, B7-2 Antigen, Bronchoalveolar Lavage Fluid cytology, Bronchoalveolar Lavage Fluid immunology, CTLA-4 Antigen, Dermatitis, Contact immunology, Dermatitis, Contact pathology, Drug Administration Schedule, Drug Combinations, Female, Hemocyanins administration & dosage, Hemocyanins immunology, Humans, Immunoglobulin Fc Fragments administration & dosage, Inducible T-Cell Co-Stimulator Ligand, Injections, Intraperitoneal, Lymph Nodes immunology, Lymph Nodes pathology, Lymphocyte Count, Membrane Glycoproteins administration & dosage, Mice, Mice, Inbred BALB C, Oxazolone administration & dosage, Oxazolone immunology, Recombinant Fusion Proteins administration & dosage, Recombinant Fusion Proteins immunology, Skin immunology, Skin pathology, Spleen cytology, Spleen immunology, Adjuvants, Immunologic administration & dosage, B-Lymphocytes immunology, B7-1 Antigen immunology, Immunoconjugates, Immunoglobulin G biosynthesis, T-Lymphocytes immunology
- Abstract
Inducible costimulator (ICOS) and B7-related protein-1 (B7RP-1) constitute a receptor-ligand pair involved in T cell costimulation. In this study, the stimulatory effects of B7RP-1 on cellular and humoral immune responses were investigated giving mice a construct with the extracellular domain of murine B7RP-1 fused with human IgG1 Fc (B7RP-1-Fc). B7RP-1-Fc stimulated contact hypersensitivity (CH) given near either the time of sensitization or challenge with oxazolone. When given near challenge time, B7RP-1-Fc stimulated CH more than a construct containing the extracellular domain of murine B7.2 and Fc (B7.2-Fc). B7RP-1-Fc increased the number of cells in lymph nodes draining the skin sensitized with oxazolone, especially activated T cells. B7RP-1-Fc also increased the ability of the cells in these lymph nodes to induce CH when transfused into naive mice. B7RP-1-Fc stimulated the production of anti-keyhole limpet hemocyanin (KLH) Ab, increasing anti-KLH IgG, IgG2a, and IgE, whereas B7.2-Fc did not affect this production. B7RP-1-Fc also increased the number of cells in lymph nodes draining the skin immunized with KLH and their production of IFN-gamma, IL-4, and IL-10 in response to KLH. Finally, B7RP-1-Fc increased the presence of eosinophils in the bronchoalveolar lavage and lungs of mice sensitized and challenged with OVA so to mount an asthmatic reaction. B7RP-1-Fc stimulates both cellular and humoral immune responses in vivo by increasing number and function of T and B cells reacting to Ag exposure.
- Published
- 2001
- Full Text
- View/download PDF
32. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality.
- Author
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Farrell CL, Bready JV, Rex KL, Chen JN, DiPalma CR, Whitcomb KL, Yin S, Hill DC, Wiemann B, Starnes CO, Havill AM, Lu ZN, Aukerman SL, Pierce GF, Thomason A, Potten CS, Ulich TR, and Lacey DL
- Subjects
- Animals, Female, Fibroblast Growth Factor 10, Fibroblast Growth Factor 7, Growth Substances administration & dosage, Humans, Intestinal Diseases prevention & control, Intestinal Mucosa drug effects, Mice, Mice, Nude, Neoplasms, Experimental mortality, Recombinant Proteins pharmacology, Recombinant Proteins therapeutic use, Survival Analysis, Antineoplastic Agents adverse effects, Fibroblast Growth Factors, Growth Substances therapeutic use, Intestinal Mucosa injuries, Neoplasms, Experimental drug therapy, Neoplasms, Experimental radiotherapy, Radiation Injuries, Experimental prevention & control
- Abstract
Keratinocyte growth factor (KGF) stimulates the proliferation and differentiation of epithelial cells including those of the gastrointestinal tract. Although chemotherapeutics and radiation exposure kill rapidly proliferating tumor cells, rapidly dividing normal cells of the host's gastrointestinal tract are also frequently damaged, leading to the clinical condition broadly termed "mucositis." In this report, recombinant human KGF used as a pretreatment in several mouse models of chemotherapy and/or radiation-induced gastrointestinal injury significantly improved mouse survival. Using multiple-dose 5-fluorouracil, methotrexate, and radiation in combination and total body radiation alone models, KGF increased survival by 55% or greater. In the models that used chemotherapy with or without radiation, KGF significantly ameliorated weight loss after injury and accelerated weight gain during recovery. The basis of these systemic benefits appears to be due in part to the trophic effects of the growth factor on the intestinal epithelium because KGF pretreatment caused an increase in measures of mucosal thickness (villus height and crypt depth) that persisted during the course of 5-fluorouracil chemotherapy. Treatment with KGF also afforded a 3.5-fold improvement in crypt survival in the small intestine, suggesting that KGF also has a direct effect on the crypt stem cells. These data indicate that KGF may be therapeutically useful to lessen the intestinal side effects of current cancer therapy regimens.
- Published
- 1998
33. The uptake and distribution of phosphorothioate oligonucleotides into vascular smooth muscle cells in vitro and in rabbit arteries.
- Author
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Farrell CL, Bready JV, Kaufman SA, Qian YX, and Burgess TL
- Subjects
- Animals, Base Sequence, Biological Transport, Catheterization adverse effects, Cells, Cultured, Dextrans, Female, Femoral Artery metabolism, Femoral Artery pathology, Fluorescein-5-isothiocyanate analogs & derivatives, Fluorescent Dyes, Molecular Sequence Data, Muscle, Smooth, Vascular pathology, Oligonucleotides, Antisense chemical synthesis, Oligonucleotides, Antisense pharmacokinetics, Rabbits, Aorta metabolism, Muscle, Smooth, Vascular metabolism, Oligonucleotides, Antisense metabolism, Thionucleotides
- Abstract
Oligonucleotides are a class of compounds with potential as therapeutics for a variety of clinical applications. Local delivery of oligonucleotides to the arterial wall is a challenging aspect of the development of these therapeutics for restenosis, and herein we report experiments characterizing the uptake and distribution of phosphorothiate oligonucleotides into vascular smooth muscle cells in primary cultures and in rabbit arteries. Primary cultures of smooth muscle cells incubated with rhodamine-oligonucleotides showed uptake only into cytoplasmic vesicles. No nuclear or cytosolic localization was detected. In normal arteries there was no visible tissue or cellular uptake of oligonucleotides after intralumenal administration. However, in balloon-injured arteries there was significant oligonucleotide uptake into the tissue with apparent cytoplasmic delivery to the medial smooth muscle cells, as evinced by intense staining of their nuclei with labeled oligonucleotides. Measurement of FITC-oligonucleotide in artery extracts showed significantly greater uptake in injured, compared with normal arteries. Light and electron microscopic studies demonstrated a correlation between the degree of damage and the amount of uptake. These results demonstrate that oligonucleotides penetrate easily into the arterial wall of balloon-injured arteries and accumulate in the medial smooth muscle cells-the target cells for antirestenosis therapeutics following balloon angioplasty.
- Published
- 1995
- Full Text
- View/download PDF
34. Expression of mRNA for glial fibrillary acidic protein after experimental cerebral injury.
- Author
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Cancilla PA, Bready J, Berliner J, Sharifi-Nia H, Toga AW, Santori EM, Scully S, and deVellis J
- Subjects
- Animals, Autoradiography, Blood-Brain Barrier, Brain Injuries pathology, Epitopes, Female, Freezing, Glial Fibrillary Acidic Protein immunology, Horseradish Peroxidase, Immunohistochemistry, Mice, Mice, Inbred Strains, Tissue Distribution, Brain Injuries metabolism, Glial Fibrillary Acidic Protein genetics, RNA, Messenger metabolism
- Abstract
This study was undertaken to determine whether a mRNA for glial fibrillary acidic protein (GFAP) was present in increased amounts as a response to injury and, if so, how was its temporal expression related to the demonstration of GFAP by immunocytochemical techniques. A cerebral freeze-injury was produced in mice and at intervals thereafter the animals were anesthetized, perfused with formalin and histological sections of the brain through the injured area were prepared. A riboprobe for GFAP mRNA labeled with S35 and an immunocytochemical probe for GFAP were utilized to localize mRNA and GFAP immunoreactivity, respectively. For mRNA studies, the histological slide exposed to either sense or antisense probe was overlaid with x-ray film or dipped in photographic emulsion. The developed film was quantitated by digital image analysis. Emulsions were examined by dark-field microscopy. The results indicate that mRNA for GFAP is increased in the cortex in the environs of the injury by 6 hours, becomes maximal at 4-5 days, and is present in increased amounts up to 14 days. The message is enhanced in the adjacent cortex, the subpial region, the adjacent corpus callosum and in the ipsilateral and contralateral callosal radiations. This pattern of enhancement follows the distribution of post-injury edema. Glial fibrillary acidic protein is demonstrable at 24-48 hours after injury. Thus, there is a rapid response of the astrocyte to injury with increased mRNA expression that is followed by expression of GFAP immunoreactivity.
- Published
- 1992
- Full Text
- View/download PDF
35. In vitro interaction of astrocytes and pericytes with capillary-like structures of brain microvessel endothelium.
- Author
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Minakawa T, Bready J, Berliner J, Fisher M, and Cancilla PA
- Subjects
- Animals, Cattle, Cells, Cultured, Chemotaxis, Extracellular Matrix, In Vitro Techniques, Intercellular Junctions ultrastructure, Microscopy, Electron, Astrocytes cytology, Brain blood supply, Capillaries cytology, Endothelium, Vascular cytology, Microcirculation cytology
- Abstract
A new method to study the interaction of astrocytes and pericytes with cerebral capillary endothelial cells in vitro is described. Endothelial cells derived from bovine brain were cultured on gelatin coated slides and covered with type 1 collagen. Endothelial cells aggregated and formed capillary-like structures (CS) within 3 days. The lining cells of the CS stained immunohistochemically for factor VIII-related antigen. Astrocytes isolated from neonatal mice or pericytes from bovine brain were added to the preparations after the formation of CS. After various periods of co-culture, the slides were fixed with methanol and examined with the immunohistochemical stain for glial fibrillary acidic protein or smooth muscle actin to demonstrate astrocytes or pericytes respectively. Five hours after addition, only 10% of astrocytes were associated with CS. However, by 24 hours, 70% of the astrocytes had assumed a position adjacent to the CS. The astrocytes then developed processes which were intimately apposed to the CS by 3 days, at which time they resembled the in vivo structural relationship between astrocytes and microvessels that occur in areas of central nervous system injury. Progressive elongation of the astrocytes or their processes at the CS was evident at 6 and 9 days of co-culture. The cross-section of CS co-cultured with astrocytes showed continuous cells surrounding a lumen, and the endothelial cells appeared to be connected by tight junctions. When pericytes were added to CS cultures they also preferentially associated with CS, but the contact occurred more rapidly than with astrocytes, 50% being associated with CS by 5 hours. The CS were almost completely covered with elongated pericytes by 24 hours. A chemotactic assay was developed that showed that there was a chemotactic attraction of pericytes to the CS. Thus an in vitro system is now available to study the interrelationships of these cell types and their interaction in development, regeneration and differentiation of the blood-brain barrier.
- Published
- 1991
36. Astrocyte growth stimulation by a soluble factor produced by cerebral endothelial cells in vitro.
- Author
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Estrada C, Bready JV, Berliner JA, Pardridge WM, and Cancilla PA
- Subjects
- Animals, Astrocytes drug effects, Capillaries cytology, Capillaries metabolism, Capillaries physiology, Cattle, Cell Division drug effects, Cells, Cultured, Culture Media analysis, Culture Media pharmacology, DNA biosynthesis, Endothelium, Vascular metabolism, Endothelium, Vascular physiology, Growth Substances analysis, Growth Substances metabolism, Interleukin-1 pharmacology, Mice, Thymidine metabolism, Tritium metabolism, Astrocytes cytology, Brain blood supply, Endothelium, Vascular cytology, Growth Substances physiology
- Abstract
Conditioned medium from isolated cerebral capillary endothelial cells (ECCM) was found to promote DNA synthesis in astrocytes and pericytes, but not in oligodendrocytes or endothelial cells (EC) in vitro. The astrocyte was the cell of primary interest and the cell tested in the following experiments. The effect of ECCM on astrocytes was concentration and time dependent. The growth factor was released by EC into the medium in a cumulative manner for up to 72 hours. This release was not the result of a nonspecific leakage of an internal store, since the DNA synthetic activity of cell lysates was negligible. The growth factor secretion per cell was higher in sparse than in confluent EC cultures and was partially inhibited by preincubation of EC with interleukin-1. The DNA synthetic activity was due to a peptide, different from basic fibroblast growth factor, transferrin, bovine fibronectin and platelet derived growth factor, with a molecular weight greater than 50,000. The peptide derived from the cerebral capillary EC could be involved in the local signaling between cell types that control new vessel formation in development, in regeneration after brain tissue injury, or in tumor formation.
- Published
- 1990
- Full Text
- View/download PDF
37. Choline uptake by cerebral capillary endothelial cells in culture.
- Author
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Estrada C, Bready J, Berliner J, and Cancilla PA
- Subjects
- Animals, Biological Transport, Capillaries, Cells, Cultured, Endothelium, Vascular cytology, Osmolar Concentration, Regression Analysis, Cerebrovascular Circulation, Choline metabolism, Endothelium, Vascular metabolism
- Abstract
A passage of choline from blood to brain and vice versa has been demonstrated in vivo. Because of the presence of the blood-brain barrier, such passage takes place necessarily through endothelial cells. To get a better understanding of this phenomenon, the choline transport properties of cerebral capillary endothelial cells have been studied in vitro. Bovine endothelial cells in culture were able to incorporate [3H]choline by a carrier-mediated mechanism. Nonlinear regression analysis of the uptake curves suggested the presence of two transport components in cells preincubated in the absence of choline. One component showed a Km of 7.59 +/- 0.8 microM and a maximum capacity of 142.7 +/- 9.4 pmol/2 min/mg of protein, and the other one was not saturable within the concentration range used (1-100 microM). When cells were preincubated in the presence of choline, a single saturable component was observed with a Km of 18.5 +/- 0.6 microM and a maximum capacity of 452.4 +/- 42 pmol/2 min/mg of protein. [3H]Choline uptake by endothelial cells was temperature dependent and was inhibited by the choline analogs hemicholinium-3, deanol, and AF64A. The presence of ouabain or 2,4-dinitrophenol did not affect the [3H]choline transport capacity of endothelial cells. Replacement of sodium by lithium and cell depolarization by potassium partially inhibited choline uptake. When cells had been preincubated without choline, recently transported [3H]choline was readily phosphorylated and incorporated into cytidine-5'-diphosphocholine and phospholipids; however, under steady-state conditions most (63%) accumulated [3H]choline was not metabolized within 1 h.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1990
- Full Text
- View/download PDF
38. Effect of inorganic lead on some functions of the cerebral microvessel endothelium.
- Author
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Maxwell K, Vinters HV, Berliner JA, Bready JV, and Cancilla PA
- Subjects
- 3-O-Methylglucose, Analysis of Variance, Animals, Brain metabolism, Carbon Radioisotopes, Cell Division drug effects, Endothelium drug effects, Endothelium metabolism, Glucose metabolism, In Vitro Techniques, Methylglucosides metabolism, Mice, Thymidine metabolism, Tritium, Brain drug effects, Lead pharmacology, Organometallic Compounds
- Abstract
The effect of inorganic lead on two functions of cerebral microvessel endothelium, cell division and glucose analog uptake, was investigated. Lead concentrations considered to be toxic in humans inhibited both functions in cultured endothelial cells. Both effects were dependent on the length of lead exposure and dose over the range of 10(-4) to 10(-6) M lead acetate. After 4 days of exposure there were 76% fewer cells in 10(-4) M lead-exposed cultures relative to control cultures. After 4 days of exposure to 10(-5) M lead there were 55% fewer cells, and after 10(-6) M lead exposure there were 15% fewer cells. Two days after 10(-4) M lead exposure [methyl-3H]thymidine incorporation into endothelial cells was inhibited by 71%. Incorporation was inhibited 47% by 10(-5) M lead but 10(-6) M lead did not inhibit incorporation after 2 days of exposure. Glucose analog uptake was inhibited in both contact-inhibited and log-phase cells; however, the latter were more sensitive to lead and this increased sensitivity correlated with a higher lead content in this cell population. Both the specific carrier-mediated and the nonspecific components of glucose analog uptake were inhibited by exposure of the endothelial cells to lead. A lead exposure of 40 min produced a significant effect on the uptake mechanism. In order to manifest its effects the lead had to be present in serum-containing medium, suggesting that some serum component was necessary to present the lead to the endothelial cells. These findings imply that the initial target of inorganic lead in the CNS may be the plasma membrane of the capillary endothelial cells, and that lead may act by altering the physiological function of these membranes.
- Published
- 1986
- Full Text
- View/download PDF
39. Spontaneous spongy degeneration of the mouse brain.
- Author
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Azzam NA, Bready JV, Vinters HV, and Cancilla PA
- Subjects
- Animals, Astrocytes ultrastructure, Brain ultrastructure, Brain Diseases genetics, Brain Diseases pathology, Cerebral Cortex ultrastructure, Female, Male, Pedigree, Rodent Diseases genetics, Brain Diseases veterinary, Mice, Rodent Diseases pathology
- Abstract
A spontaneously-occurring spongy disorder of the white matter of the central nervous system was discovered in the Charles River strain of Swiss-Webster mice and is described in this report. The disorder was transmitted with an autosomal recessive pattern of inheritance. Clinical characteristics of the affected animals included enlargement of the cranium, failure to thrive and tremor of the hind limbs when held by the tail in a suspended position. Maintenance of the colony with propagation of the disease was achieved by selective in-breeding of litter mates. Light microscopic examination of the central nervous system revealed a spongy degeneration of the white matter of the entire neuraxis. Ultrastructural studies localized the abnormality to the cell body and processes of the astrocyte which appeared distended and enlarged with dispersion of cytoplasmic organelles. Hemidesmosomes were prominent in the foot processes of astrocytes. This animal model bears a similar morphology and pattern of inheritance to Canavan's spongy degeneration of the white matter in humans and should provide a base for future investigations aimed at gaining insight into the pathogenesis of the human and this animal neurological disorder.
- Published
- 1984
- Full Text
- View/download PDF
40. Uptake of glucose analogues into cultured cerebral microvessel endothelium.
- Author
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Vinters HV, Beck DW, Bready JV, Maxwell K, Berliner JA, Hart MN, and Cancilla PA
- Subjects
- 3-O-Methylglucose, Animals, Antimetabolites pharmacology, Biological Transport drug effects, Cell Line, Endothelium metabolism, Hexoses pharmacology, Insulin pharmacology, Mice, Microcirculation metabolism, Phosphorylation, Brain blood supply, Deoxy Sugars metabolism, Deoxyglucose metabolism, Glucose metabolism, Methylglucosides metabolism, Methylglycosides metabolism
- Abstract
Tritiated glucose analogues 3-O-methylglucose (3-OMG) and 2-deoxyglucose (2-DG) were used to study glucose uptake properties in established lines of cultured mouse cerebral microvessel endothelium. Uptake of both analogues was similar in terms of rate and absolute amount for the first two minutes. Thereafter, intracellular accumulation of 2-DG continued at a more rapid rate because of intracellular phosphorylation of this substrate. The uptake of 3-OMG uptake was temperature-dependent, independent of Na+, and not inhibited by ouabain or 2,4-dinitrophenol. Phloretin and cytochalasin B both significantly inhibited 3-OMG uptake. Other hexoses in high concentration acted as competitive inhibitors at the endothelial cell membrane. Pre-incubation of cells with 50 mM D-glucose resulted in higher levels of 3-OMG accumulation than in control cells (counter-transport phenomenon). In contrast to findings at the blood-brain barrier in vivo, insulin was found to stimulate 3-OMG uptake. Maximal stimulation of approximately 3-fold was found at ambient insulin concentrations of 1,000 ng/ml or higher. The findings provide support at the cellular level for some components of the model of carrier-mediated glucose transport across the blood-brain barrier which has been postulated to exist in vivo. The effect of insulin is discussed in the light of new data that show stimulation of glucose analogue transport into isolated cerebral capillaries.
- Published
- 1985
- Full Text
- View/download PDF
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