Hypertension and renal toxicity during angiogenesis inhibition

Abstract Angiogenesis inhibition, by targeting VEGF or its receptors, has become an established treatment for various tumor types but is associated with adverse effects including hypertension, proteinuria and renal injury with activation of the endothelin-1 system. Sunitinib is an orally active angiogenesis inhibitor that blocks VEGF receptors -1, -2 and -3 and other tyrosine kinase receptors, including platelet derived growth factor (PDGF) and c-Kit receptors. VEGFR-1 and VEGFR-2 are predominantly expressed on vascular endothelial cells and peritubular capillary endothelial cells, whereas VEGFR-3, stimulated by VEGF-C, is restricted to lymphatic endothelial cells. Since the occurrence of side effects can be a reason to lower the sunitinib dose or even to discontinue anticancer therapy, thereby compromising its potential efficacy, exploring therapeutic approaches to counteract these side effects is important, not only from an academic point of view, but also from a clinical point of view. To determine the most optimal way to prevent the sunitinib-induced adverse effects and to explore their interdependency, we investigate in Chapter 4 the therapeutic potential of the dual endothelin receptor antagonist macitentan, the calcium channel blocker amlodipine, the angiotensin-converting enzyme inhibitor captopril and the phosphodiesterase type 5 inhibitor sildenafil. In Chapter 5 we test the dose-dependency of these side effects, using a low, intermediate and high dose of sunitinib, aiming to find a dose that, with regard to hemodynamic and renal side effects, is comparable to the dose applied in patients. With this approach, we also want to explore whether the proteinuria observed during antiangiogenic treatment occurs irrespective of the presence of glomerular histological changes. In Chapter 6 we aimed to explore the salt dependency of angiogenesis inhibition-induced hypertension by exposing animals to a low and high salt diet in combination with sunitinib, using a dose of sunitinib that does not impair renal function as based on the findings obtained in chapter 5. As a second aim, we explore whether sunitinib administration impairs the formation of lymph vessels within the skin, leading to skin sodium accumulation and salt-sensitivity of blood pressure. In Chapter 7, we investigate the consequences of a high salt diet in combination with sunitinib administration on renal histopathology. Especially, we want to explore whether in addition to glomerular lesions, the combination of a high salt diet and sunitinib is accompanied by tubulointerstitial injury and/or peritubular rarefaction. The renal injury during angiogene

Architecture Analysis

This chapter also explains what the added value of enterprise architecture analysis techniques is in addition to existing, more detailed, and domain-specific ones for business processes or software, for example. Analogous to the idea of using the ArchiMate enterprise modelling language to integrate detailed design models, the chapter demonstrates that analysis, when considered at a global architectural level, can play a role in the integration of existing detailed techniques or of their results

Achtergronddocument Midterm meting Monitor Effectindicatoren Agenda Vitaal Platteland

De Monitor AVP is een systeem waarin eenduidige gegevens worden opgenomen voor monitoring van effecten, resultaten en prestaties van de beleidsdoelstellingen opgenomen in de Agenda Vitaal Platteland (AVP) van het ministerie van Economische Zaken, Landbouw & Innovatie (EL&I). Dit document geeft de resultaten en achtergrondinformatie van de midterm meting en de methoden van de metingen van de afzonderlijke effectindicatoren van de Monitor AVP. De effectindicatoren zijn bedoeld om de maatschappelijke effecten van de Agenda Vitaal Platteland inzichtelijk te maken. Dit achtergronddocument is opgesteld om de continuïteit voor toekomstige herhalingsmetingen te waarborgen

Therapeutic efficacy of microtube-embedded chondroitinase ABC in a canine clinical model of spinal cord injury

Many hundreds of thousands of people around the world are living with the long-term consequences of spinal cord injury and they need effective new therapies. Laboratory research in experimental animals has identified a large number of potentially translatable interventions but transition to the clinic is not straightforward. Further evidence of efficacy in more clinically-relevant lesions is required to gain sufficient confidence to commence human clinical trials. Of the many therapeutic candidates currently available, intraspinally applied chondroitinase ABC has particularly well documented efficacy in experimental animals. In this study we measured the effects of this intervention in a double-blinded randomized controlled trial in a cohort of dogs with naturally-occurring severe chronic spinal cord injuries that model the condition in humans. First, we collected baseline data on a series of outcomes: forelimb-hindlimb coordination (the prespecified primary outcome measure), skin sensitivity along the back, somatosensory evoked and transcranial magnetic motor evoked potentials and cystometry in 60 dogs with thoracolumbar lesions. Dogs were then randomized 1:1 to receive intraspinal injections of heat-stabilized, lipid microtube-embedded chondroitinase ABC or sham injections consisting of needle puncture of the skin. Outcome data were measured at 1, 3 and 6 months after intervention; skin sensitivity was also measured 24 h after injection (or sham). Forelimb-hindlimb coordination was affected by neither time nor chondroitinase treatment alone but there was a significant interaction between these variables such that coordination between forelimb and hindlimb stepping improved during the 6-month follow-up period in the chondroitinase-treated animals by a mean of 23%, but did not change in controls. Three dogs (10%) in the chondroitinase group also recovered the ability to ambulate without assistance. Sensitivity of the dorsal skin increased at 24 h after intervention in both groups but subsequently decreased to normal levels. Cystometry identified a non-significant improvement of bladder compliance at 1 month in the chondroitinase-injected dogs but this did not persist. There were no overall differences between groups in detection of sensory evoked potentials. Our results strongly support a beneficial effect of intraspinal injection of chondroitinase ABC on spinal cord function in this highly clinically-relevant model of chronic severe spinal cord injury. There was no evidence of long-term adverse effects associated with this intervention. We therefore conclude that this study provides strong evidence in support of initiation of clinical trials of chondroitinase ABC in humans with chronic spinal cord injury

Lagrangian Views of the Pathways of the Atlantic Meridional Overturning Circulation

The Lagrangian method-where current location and intensity are determined by tracking the movement of flow along its path-is the oldest technique for measuring the ocean circulation. For centuries, mariners used compilations of ship drift data to map out the location and intensity of surface currents along major shipping routes of the global ocean. In the mid-20th century, technological advances in electronic navigation allowed oceanographers to continuously track freely drifting surface buoys throughout the ice-free oceans and begin to construct basin-scale, and eventually global-scale, maps of the surface circulation. At about the same time, development of acoustic methods to track neutrally buoyant floats below the surface led to important new discoveries regarding the deep circulation. Since then, Lagrangian observing and modeling techniques have been used to explore the structure of the general circulation and its variability throughout the global ocean, but especially in the Atlantic Ocean. In this review, Lagrangian studies that focus on pathways of the upper and lower limbs of the Atlantic Meridional Overturning Circulation (AMOC), both observational and numerical, have been gathered together to illustrate aspects of the AMOC that are uniquely captured by this technique. These include the importance of horizontal recirculation gyres and interior (as opposed to boundary) pathways, the connectivity (or lack thereof) of the AMOC across latitudes, and the role of mesoscale eddies in some regions as the primary AMOC transport mechanism. There remain vast areas of the deep ocean where there are no direct observations of the pathways of the AMOC

Beheers- en ontwikkelingsplan 2004 MNP-modellen: kennismodel effecten landschap kwaliteit monitoring schaal belevingsGIS

Dit plan ontwikkeld door het Natuurplanbureau, geeft een visie op drie modellen voor de graadmeters landschap, beleving en recreatie. Het gaat om: KELK (kennismodel effecten landschapkwaliteit); monitoringsysteem schaalkenmerken; belevingsGIS. Met het huidige systeem kunnen de gevolgen van veranderingen in grondgebruik aangegeven worden voor: herkenbaarheid van de ontstaansgeschiedenis, de belevingswaarde en de (recreatieve) gebruikswaard

Towards interoperability through inter-enterprise collaboration architectures

Most enterprise architectures published so far are capable of generating reasonably good descriptive models for individual enterprises to enable integration, organization and synchronization of enterprise elements: organizational structure, business processes, information systems and technology infrastructure, among others. However, research in this field applied to the extended enterprise or inter-enterprise architectures that takes into account the growing trend towards complex collaborative environments is very scarce. In this sense, this article seeks to analyze, link and synthesize the researches that has addressed the disciplines of enterprise architecture and business collaboration, in order to identify possible future research needs from the conceptualization made.Vargas, A.; Boza Garcia, A.; Cuenca, L. (2011). Towards interoperability through inter-enterprise collaboration architectures. En On the Move to Meaningful Internet Systems: OTM 2011 Workshops. Springer Verlag (Germany). 7046:102-111. doi:10.1007/978-3-642-25126-9_18S1021117046Adam, O., Hofer, A., Zang, S., Hammer, C., Jerrentrup, M., Leinenbach, S.: A Collaboration Framework for Cross-enterprise Business Process Management. In: First International Conference on Interoperability of Enterprise Software and Application, Geneva (2005)Chalmeta, R., Grangel, R.: ARDIN extension for virtual enterprise integration. The Journal of Systems and Software 67, 141–152 (2003)Choi, Y., Kang, D., Chae, H., Kim, K.: An enterprise architecture framework for collaboration of virtual enterprise chains. The International Journal of Advanced Manufacturing Technology 35, 1065–1078 (2008)Schekkerman, J.: Extended Enterprise Architecture Framework Essentials Guide. Institute For Enterprise Architecture Developments, IFEAD (2006), http://www.enterprise-architecture.info/index.htmISO 15704. Industrial automation systems - Requirements for enterprise-reference architectures and methodologies.: International Organization for Standardization (2000)Kosanke, K., Vernadat, F., Zelm, M.: CIMOSA: Enterprise engineering and integration. Computers in Industry 40, 83–97 (1999)Cuenca, L.: Marco arquitectónico para la propuesta IE-GIP. Extensión de la arquitectura CIMOSA. Aplicación a una empresa del sector cerámico. PhD thesis. Universidad Politécnica de ValenciaMolina, A., Panetto, H., Chen, D., Whitman, L.: Enterprise Integration and Networking: challenges and trends. Studies in Informatics and Control 16(4), 353–368 (2007)Ortiz, A., Lario, F., Ros, L.: Enterprise Integration—Business Processes Integrated Management: a proposal for a methodology to develop Enterprise Integration Programs. Computers in Industry 40, 155–171 (1999)Chalmeta, R., Campos, C., Grangel, R.: References architectures for enterprise integration. The Journal of Systems and Software 57, 175–191 (2001)Vernadat, F.: Enterprise modeling and integration (EMI): Current status and research perspectives. Annual Reviews in Control 26, 15–25 (2002)Williams, T., Li, H.: PERA and GERAM enterprise reference architectures in enterprise integration. Information Infrastructure Systems for Manufacturing, 1–27 (1998)Lankhorst, M.: Enterprise Architecture at Work: Modelling, Communication and Analysis. Springer, Heidelberg (2009)Arango, M., Londoño, J., Zapata, J.: Arquitectura empresarial- Una visión general. Revista Ingenierías Universidad de Medellín 9(16), 101–111 (2010)Bernard, S.: An introduction to enterprise architecture. AuthorHouse, Bloomington (2005)Cuenca, L., Ortiz, A., Boza, A.: Arquitectura de Empresa. Visión General. In: IX Congreso de Ingeniería de Organización, Gijón (2005)Maya, E.: Arquitectura empresarial: un nuevo reto para las empresas de hoy. Centro de Investigación de las Telecomunicaciones. INTERACTIC: Interacción con la información (2010), http://www.interactic.org.co/THE OPEN GROUP.: ARCHIMATE, The Power of Enterprise Architecture (2009), http://www.archimate.org/en/home/Stelzer, D.: Enterprise Architecture Principles: Literature Review and Research Directions. In: Dan, A., Gittler, F., Toumani, F. (eds.) ICSOC/ServiceWave 2009. LNCS, vol. 6275, pp. 12–21. Springer, Heidelberg (2010)Schekkerman, J.: Enterprise architecture validation. Achieving business-aligned and validated enterprise architectures. Institute For Enterprise Architecture Developments, IFEAD (2004), http://www.enterprise-architecture.info/index.htmKosanke, K.: CIMOSA Primer on key concepts, purpose and business value (1996), http://cimosa.cnt.pl/Chen, D., Vallespir, B., Doumeingts, G.: GRAI integrated methodology and its mapping onto generic enterprise reference architecture and methodology. Computers in Industry 33, 387–394 (1997)Rathwell, G.: PERA Enterprise Integration Web Site (2005), http://www.pera.net/Williams, T., Rathwell, G., Li, H.: A handbook on master planning and implementation for enterprise integration programs. PERA Enterprise Integration Web Site (2001), http://www.pera.net/IFIP.: GERAM: Generalised Enterprise Reference Architecture and Methodology. International Federation for Information Processing (1999), http://dl.ifip.org/index.php/index/indexOrtiz, A.: Propuesta para el Desarrollo de Programas de Integración Empresarial en Empresas Industriales. Aplicación a una Empresa del Sector Cerámico. Universidad Politécnica de Valencia (1998)Cuenca, L., Boza, A., Ortiz, A.: Architecting business and IS/IT strategic alignment for extend enterprises. Studies in Informatics and Control 20(1), 7–18 (2011)The Open Group (2011), https://www.opengroup.org/index.htmGrangel, R.: Propuesta para el Modelado del Conocimiento Empresarial. PhD thesis Universidad Jaume I de Castello (2007)Scheer, A., Schneider, K.: ARIS – Architecture of Integrated Information. Handbook on Architectures of Information Systems. International Handbooks on Information Systems 3, 605–623 (2006)ISO/CEN 19439. Enterprise integration - Framework for enterprise modelling.: International Organization for Standardization (2006)Stadtler, H., Kilger, C.: Supply Chain Management and advance planning. Concepts, Models, Sofware and Cases Studies. Springer, Heidelberg (2002)Alarcón, F., Ortiz, A., Alemany, M., Lario, F.: Planificación Colaborativa en un contexto de varias Cadenas de Suministro: ventajas y desventajas. In: VIII Congreso de Ingeniería de Organización, Leganés, pp. 857–866 (2004)Alarcón, F.: Desarrollo de una Arquitectura para la definición del proceso de Comprometer Pedidos en contextos de Redes de Suministro Colaborativas. Aplicación a una Red compuesta por Cadenas de Suministro en los Sectores Cerámico y del Mueble. PhD thesis Universidad Politécnica de Valencia (2005)Petersen, K., Ragatz, G., Monczka, R.: An Examination of Collaborative Planning Effectiveness and Supply Chain Performance. The Journal of Supply Chain Management 41(2), 14–25 (2005)Ribas, I., Companys, R.: Estado del arte de la planificación colaborativa en la cadena de suministro: Contexto determinista e incierto. Intangible Capital, 91–121 (2007)Ribas, I., Lario, F., Companys, R.: Modelos para la planificación colaborativa en la cadena de suministro: contexto determinista e incierto. In: Congreso de ingeniería de organización, Valencia, pp. 1–10 (2006)Dudek, G.: Collaborative Planning in Supply Chains. Supply Chain Management and Collaborative Planning. Springer, Heidelberg (2009)Stadtler, H.: A framework for collaborative planning and state-of-the-art. OR Spectrum 31, 5–30 (2009)Kilger, C., Reuter, B., Stadtler, H.: Collaborative Planning. In: Stadtler, H., Kilger, C. (eds.) Supply Chain Management and Advanced Planning-—Concepts, Models Software and Case Studies, pp. 263–284. Springer, Heidelberg (2008)Audy, J., Lehoux, N., D’Amours, S.: A framework for an efficient implementation of logistics collaborations. International Transactions in Operational Research, 1–25 (2010)Zachman, J.: A Framework for Information Systems Architecture. IBM Systems Journal 26(3), 454–470 (1987