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4. The Quest for a New Local Government Model in South Africa A Visionary Perspective.

Author

Breed, J., Jones, C., Pillay, P., and Zondi, S.

Subjects
BUSINESS models, LOCAL government, ORGANIZATIONAL performance, COMMUNITY development
Abstract

Enormous efforts, capital and energy are spent in local institutionalism in South Africa to impact social change, socio-economic growth, and community development towards a better life for citizens. The expected rate of return on these endless attempts does not produce the desired outcomes for the development of the country. Local government produces too little, at too high a price. This institutional mechanism's unlocked potential is capable of a game-changing impact. However, in many communities, local government does not realise the expressions of frustration that have been escalating over years, with enormous negative consequences and damage. Drastic trajectory changes have become evident. For local governments, the potential to be found in the immense vaults of human capital to create and invent opportunities, should be unlocked. The model's framework that is envisioned in this article should mediate and discuss a completely new hybrid business model for the development of exceptional technocratic and institutional behaviour, thought and performance modification. Unfortunately, local government's credo to create, produce, innovate, and fulfil opportunities is often strangled by obsoleteness, narrow mindedness, and traditional conventionalism. A new model should not focus on repair - it should rather envision and trace a completely new strategic and transformative local governmental model aimed at unlocking all possible assets available to and latent in local societal silos. Although local institutionalism's nemesis is generally regarded as service delivery, local government should be much more than this pursuit. It also needs to act as a co-creator of wealth. All these objectives, among others, should be characteristics of a new envisioned local government model. [ABSTRACT FROM AUTHOR]

Published
2023

6. KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe

Author

Bery, N, Legg, S, Debreczeni, J, Breed, J, Embrey, K, Stubbs, C, Kolasinska-Zwierz, P, Barrett, N, Marwood, R, Watson, J, Tart, J, Overman, R, Miller, A, Phillips, C, Minter, R, and Rabbitts, T

Subjects
endocrine system diseases, Molecular biology, Science, Antineoplastic Agents, Article, Proto-Oncogene Proteins p21(ras), Peptide Library, Cell Line, Tumor, Neoplasms, Humans, Histidine, lcsh:Science, neoplasms, X-ray crystallography, Cancer, Drug discovery, Cell Membrane, digestive system diseases, respiratory tract diseases, Ankyrin Repeat, Isoenzymes, HEK293 Cells, Drug Design, lcsh:Q, Drug Screening Assays, Antitumor, Protein Multimerization, Allosteric Site, Protein Binding, Signal Transduction
Abstract

Inhibiting the RAS oncogenic protein has largely been through targeting the switch regions that interact with signalling effector proteins. Here, we report designed ankyrin repeat proteins (DARPins) macromolecules that specifically inhibit the KRAS isoform by binding to an allosteric site encompassing the region around KRAS-specific residue histidine 95 at the helix α3/loop 7/helix α4 interface. We show that these DARPins specifically inhibit KRAS/effector interactions and the dependent downstream signalling pathways in cancer cells. Binding by the DARPins at that region influences KRAS/effector interactions in different ways, including KRAS nucleotide exchange and inhibiting KRAS dimerization at the plasma membrane. These results highlight the importance of targeting the α3/loop 7/α4 interface, a previously untargeted site in RAS, for specifically inhibiting KRAS function., Mutant RAS family members occur in a wide range of tumour types, and there is a great interest in identifying isoform-specific inhibitors. Here, the authors characterise two designed ankyrin repeat proteins (DARPins) that specifically inhibit the KRAS isoform by binding to the region around the KRAS-specific residue histidine 95 and show that they affect KRAS/effector interactions in different ways.

Published
2019

10. Abstracts of papers clinical pharmacological meeting

Author

van der Klauw, M. M., Stricker, B. H. Ch., Ottervanger, J. P., van der Meché, F. G. A., van Griensven, J. M. T., Lemkes, H. H. P. J., Kroon, J. M., Schoemaker, H. C., Cohen, A. F., Schellens, J. H. M., Loos, W., van Acker, B., de Boer-Dennert, M., Planting, A. S. T., van der Burg, M. E. L., Stoter, G., Krediet, R., Verweij, J., Blaak, E. E., van Baak, M. A., Kemerink, G. J., Pakbiers, M. T. W., Heidendal, G. A. K., Saris, W. H. M., Bouckaert, S., Vakaet, L., Dhont, M., Remon, J. P., van den Broek, S. A. J., de Graeff, P. A., van Gilst, W. H., van Veldhuisen, D. J., Hillige, H. L., Wesseling, H., Lie, K. I., Gaillard, C. A., van Es, P. N., de Leeuw, P. W., Van Bortel, L. M. A. B., Kool, M. J. F., Lustermans, F. A. T., Breed, J. G. S., Hoeks, A. P. G., Boudier, H. A. J. Struijker, Pickkers, R. P., Smits, P., Baadenhuysen, H., van 't Laar, A., Thien, Th., Elseviers, M. M., De Broe, M. E., van der Ven, A. J. A. M., Koopmans, P. P., Peters, W. H. M., Vree, T. B., van der Meer, J. W. M., Snoeck, E., Van Peer, A., Sack, M., Horton, M., Mannens, G., Woestenborghs, R., Heykants, J., Meibach, R., van Witsen, T. B., Valkenburg, H. A., Vander Stichele, R. H., De Potter, B., Vyncke, P., Bogaert, M. G., Burggraaf, J., Wollersheim, H., van Aalen, J., Schoemaker, R. G., Du, X. Y., Bax, W. A., Bos, E., Saxena, P. R., Rongen, G. A., van Heiningen, P. N. M., Schwietert, H. R., Kortboyer, J. M., Sollie, F. A. E., Piraube, C., Desché, P., Jonkman, J. H. G., Blok, W. L., Gyssens, I. C., Hekster, Y. A., Koopmans, P. P., van der Meer, J. W. M., Jansen P. A. F., Sival R. C., van Nieuwkerk J. F., Klaverwiiden B., de Bruijn, E. A., and Driessen, O.

Published
1993
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14. Human KRAS in complex with darpin K19

Author

Debreczeni, J.E., primary, Bery, N., additional, Legg, S., additional, Breed, J., additional, Embrey, K., additional, Stubbs, C., additional, Kolasinska-Zwierz, P., additional, Barrett, N., additional, Marwood, R., additional, Watson, J., additional, Tart, J., additional, Overman, R., additional, Miller, A., additional, Phillips, C., additional, Minter, R., additional, and Rabbitts, T.H., additional

Published
2019
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17. Putting patients at the center of kidney care transitions: PREPARE NOW, a cluster randomized controlled trial

Author

Green, J.A., primary, Ephraim, P.L., additional, Hill-Briggs, F.F., additional, Browne, T., additional, Strigo, T.S., additional, Hauer, C.L., additional, Stametz, R.A., additional, Darer, J.D., additional, Patel, U.D., additional, Lang-Lindsey, K., additional, Bankes, B.L., additional, Bolden, S.A., additional, Danielson, P., additional, Ruff, S., additional, Schmidt, L., additional, Swoboda, A., additional, Woods, P., additional, Vinson, B., additional, Littlewood, D., additional, Jackson, G., additional, Pendergast, J.F., additional, St. Clair Russell, J., additional, Collins, K., additional, Norfolk, E., additional, Bucaloiu, I.D., additional, Kethireddy, S., additional, Collins, C., additional, Davis, D., additional, dePrisco, J., additional, Malloy, D., additional, Diamantidis, C.J., additional, Fulmer, S., additional, Martin, J., additional, Schatell, D., additional, Tangri, N., additional, Sees, A., additional, Siegrist, C., additional, Breed, J., additional, Medley, A., additional, Graboski, E., additional, Billet, J., additional, Hackenberg, M., additional, Singer, D., additional, Stewart, S., additional, Alkon, A., additional, Bhavsar, N.A., additional, Lewis-Boyer, L., additional, Martz, C., additional, Yule, C., additional, Greer, R.C., additional, Saunders, M., additional, Cameron, B., additional, and Boulware, L.E., additional

Published
2018
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21. Crystal structure of human RAS in complex with darpin K27

Author

Debreczeni, J.E., primary, Guillard, S., additional, Kolasinska-Zwierz, P., additional, Breed, J., additional, Zhang, J., additional, Bery, N., additional, Marwood, R., additional, Tart, J., additional, Overman, R., additional, Stocki, P., additional, Mistry, B., additional, Phillips, C., additional, Rabbitts, T., additional, Jackson, R., additional, and Minter, R., additional

Published
2017
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23. Human KRAS in complex with darpin K27

Author

Debreczeni, J.E., primary, Guillard, S., additional, Kolasinska-Zwierz, P., additional, Breed, J., additional, Zhang, J., additional, Bery, N., additional, Marwood, R., additional, Tart, J., additional, Stocki, P., additional, Mistry, B., additional, Phillips, C., additional, Rabbitts, T., additional, Jackson, R., additional, and Minter, R., additional

Published
2017
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26. Structural Characterisation Reveals Mechanism of IL-13-Neutralising Monoclonal Antibody Tralokinumab as Inhibition of Binding to IL-13Rα1 and IL-13Rα2

Author

Popovic, B., primary, Breed, J., additional, Rees, D.G., additional, Gardener, M.J., additional, Vinall, L.M.K., additional, Kemp, B., additional, Spooner, J., additional, Keen, J., additional, Minter, R., additional, Uddin, F., additional, Colice, G., additional, Wilkinson, T., additional, Vaughan, T., additional, and May, R.D., additional

Published
2017
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30. Successful percutaneous management of symptomatic central posterior epidural Baastrup cyst: a potential surgical sparing option?.

Author

Breed J., Goldschlager T., Chandra R.V., Breed J., Goldschlager T., and Chandra R.V.

Abstract

Background Context Neurogenic claudication from posterior epidural extension of a Baastrup interspinous bursal cyst is rare. Surgical decompression is the gold standard of treatment. This case report describes successful percutaneous treatment with good early clinicoradiological outcome. Purpose This study aimed to describe the successful percutaneous treatment of a central posterior epidural Baastrup cyst causing neurogenic claudication. Study Design This is a case report study. Methods A 62-year-old man presented with neurogenic claudication on a background of previous lymphoma treated with chemotherapy, chronic obstructive pulmonary disease, chronic venous insufficiency, and obesity. Conservative therapy with narcotic analgesia had failed, with new requirement of a walking aid and marked reduction in walking distance. Magnetic resonance imaging confirmed severe L3-L4 canal stenosis from central posterior epidural extension of a Baastrup interspinous bursal cyst. Under conscious sedation, initial percutaneous computed tomography (CT)-guided interspinous bursography indirectly opacified the cyst and facilitated trans-laminar direct needle access to the epidural cyst. Aspiration was performed before needle fenestration and epidural steroid injection. Results Six-week review revealed significant improvement in pain and mobility, with no analgesic or walking aid requirement, and restoration of the patient's baseline walking distance. At 3 months, repeat magnetic resonance imaging (MRI) confirmed significant reduction in cyst size as the mediator of the treatment effect. Improvement in back and leg symptoms was durable at 24-month follow-up. Conclusions In selected cases, percutaneous treatment of symptomatic central posterior epidural cysts as part of Baastrup phenomena may be feasible. This treatment approach avoided general anesthesia, avoided the procedural risks of surgical decompression, and was performed in the outpatient setting, with good early clinicoradiolog

Published
2016

37. Potent and selective inhibitors of MTH1 probe its role in cancer cell survival

Author

Kettle, J.G., primary, Alwan, H., additional, Bista, M., additional, Breed, J., additional, Kack, H., additional, Eckersley, K., additional, Foote, K.M., additional, Fillery, S., additional, Goodwin, L., additional, Jones, D., additional, Lau, A., additional, Nissink, J.W.M., additional, Read, J., additional, Scott, J., additional, Taylor, B., additional, Walker, G., additional, and Wissler, L., additional

Published
2016
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41. FGFR1 in complex with AZD4547.

Author

Tucker, J., primary, Klein, T., additional, Breed, J., additional, Breeze, A., additional, Overman, R., additional, Phillips, C., additional, and Norman, R.A., additional

Published
2014
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43. FGFR1 in complex with ponatinib.

Author

Tucker, J., primary, Klein, T., additional, Breed, J., additional, Breeze, A., additional, Overman, R., additional, Phillips, C., additional, and Norman, R.A., additional

Published
2014
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44. Human DPP1 in complex with (2S)-N-((1S)-1-cyano-2-(4-(4-cyanophenyl) phenyl)ethyl)piperidine-2-carboxamide

Author

Debreczeni, J., primary, Edman, K., additional, Furber, M., additional, Tiden, A., additional, Gardiner, P., additional, Mete, T., additional, Ford, R., additional, Millichip, I., additional, Stein, L., additional, Mather, A., additional, Kinchin, E., additional, Luckhurst, C., additional, Cage, P., additional, Sanghanee, H., additional, Breed, J., additional, and Wissler, L., additional

Published
2014
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45. Human DPP1 in complex with (2S)-2-amino-N-((1S)-1-cyano-2-(4- phenylphenyl)ethyl)butanamide

Author

Debreczeni, J., primary, Edman, K., additional, Furber, M., additional, Tiden, A., additional, Gardiner, P., additional, Mete, T., additional, Ford, R., additional, Millichip, I., additional, Stein, L., additional, Mather, A., additional, Kinchin, E., additional, Luckhurst, C., additional, Cage, P., additional, Sanghanee, H., additional, Breed, J., additional, and Wissler, L., additional

Published
2014
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46. Human DPP1 in complex with 4-amino-N-((1S)-1-cyano-2-(4-(4- cyanophenyl)phenyl)ethyl)tetrahydropyran-4-carboxamide

Author

Debreczeni, J., primary, Edman, K., additional, Furber, M., additional, Tiden, A., additional, Gardiner, P., additional, Mete, T., additional, Ford, R., additional, Millichip, I., additional, Stein, L., additional, Mather, A., additional, Kinchin, E., additional, Luckhurst, C., additional, Cage, P., additional, Sanghanee, H., additional, Breed, J., additional, and Wissler, L., additional

Published
2014
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47. Human DPP1 in complex with (2S,4S)-N-((1S)-1-cyano-2-(4-(4- cyanophenyl)phenyl)ethyl)-4-hydroxy-piperidine-2-carboxamide

Author

Debreczeni, J., primary, Edman, K., additional, Furber, M., additional, Tiden, A., additional, Gardiner, P., additional, Mete, T., additional, Ford, R., additional, Millichip, I., additional, Stein, L., additional, Mather, A., additional, Kinchin, E., additional, Luckhurst, C., additional, Cage, P., additional, Sanghanee, H., additional, Breed, J., additional, and Wissler, L., additional

Published
2014
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48. Alamethicin channels in a membrane: molecular dynamics simulations: molecular dynamics simulations

Author

Tieleman, D.P, Breed, J., Berendsen, H.J.C., Sansom, M.S.P., Moleculaire Dynamica, Faculty of Science and Engineering, and Groningen Biomolecular Sciences and Biotechnology

Subjects
HYDROGEN-BOND STABILITIES, ESCHERICHIA-COLI, EXCHANGE MEASUREMENTS, GRAMICIDIN CHANNEL, LIPID BILAYERS, POTASSIUM CHANNEL, NICOTINIC ACETYLCHOLINE-RECEPTOR, GATED ION-CHANNEL, ALPHA-HELICES, INFLUENZA-A VIRUS
Published
1998

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