Augmenting the Protein C Pathway with Endothelial Targeted Biotherapeutics: Strategies to Promote Partnering of TM and EPCR

The design of targeted recombinant biotherapeutics is a rapidly growing area of translational biomedical research, with particular relevance to acute and life-threatening conditions, in which the available treatment options have narrow therapeutic indices. Although vascular immunotargeting typically has been thought of as a strategy for controlling and altering pharmacokinetics, in the context of biotherapeutic delivery, precise localization may be the primary goal, allowing optimal interaction of drug with endogenous partners. The protein C pathway has important protective roles in a variety of human illnesses, including sepsis and acute lung injury. We recently reported a strategy for augmenting this pathway by anchoring thrombomodulin (TM, CD141) to the endothelium via an affinity ligand to platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31). Endothelial PECAM-1, however, is believed to localize to a different portion of the cell membrane than the majority of endogenous TM and its key co-factor, the endothelial protein C receptor (EPCR, CD201). The current document includes new data indicating that recombinant TM anchored to endothelial PECAM-1 does not partner effectively with EPCR and describes the design, implementation, and validation of two strategies for more effectively replicating the enzymatic partnering of these two molecules. In both cases, proximity of these co-factors on the surface of the endothelial membrane appears to be the key variable and has significant implications, affecting not only functional activity in vitro but therapeutic efficacy in vivo. These findings underscore the complexity of targeting biotherapeutics to the plasmalemma, and suggest that precision on a nanometer scale is necessary for optimal biotherapeutic effect

Agile Leadership - A Comparison of Agile Leadership Styles

Leadership has been the focus of research in the social sciences since the early 1930s. However, no generally valid theory exists to date. In recent years, theories relating to agile leadership have also increasingly emerged. The aim of this paper is to give an overview of the current state of research on agile leadership. For this purpose, a systematic literature analysis is conducted. The different terms used in the context of agile leadership are restricted by means of selection criteria. Furthermore, characteristics of agile leadership will be analyzed and consolidated. This results in a catalogue of criteria with which the selected leadership styles. The evaluation shows that there are overlaps in the styles, which also can be identified in the research

DESIGN AND EVALUATING A TOOL FOR CONTINUOUSLY ASSESSING AND IMPROVING AGILE PRACTICES FOR INCREASED ORGANIZATIONAL AGILITY

Many organizations struggle to measure, control, and manage agility in a manner of continuous improvement. Therefore, we draw on Design Science Research to develop and test a tool for Continuously Assessing and Improving Agile Practices (CAIAP). CAIAP helps agile practitioners to monitor the alignment of “as is” agile practices on individual, team levels with the overall agile strategy of the organization. To develop CAIAP, we first empirically gather requirements, draw on the ICAP framework to base the tool development on a solid conceptual and theoretical basis. CAIAP helps agile practitioners to constantly monitor their agile practices on individual and team levels and to identify areas for improvement to gain greater organizational agility. To researchers, CAIAP helps to make the unit of analysis of agile work explainable, predictable and helps researchers to guide their own empirical research as well as serve as a basis for designing further tool support

Conceptualizing the Agile Work Organization: A systematic literature review, framework and research agenda

The ongoing discussion of the Agile Work Organization (AO) in research and practice permeates a multitude of research areas. However, no clear conceptualization of the AO has been provided. In this paper, we conduct a Systematic Literature Review to investigate what constitutes and defines the AO. The SLR reveals three dimensions in the research field of the AO: Strategic, Functional and Operative Agility. These dimensions define the AO through different unique capabilities by influencing and enhancing the overall goal of the AO in adaptation and flexibility. Building up on the insights from the review, we develop proposition which describe the interrelationship between the dimensions and towards the AO. Furthermore, implications for academia and practice as well as a research agenda are provided in order to trigger and guide further discussions and research surrounding the AO

Novice Secondary Teachers’ Perceived Efficacy and Projected Responses to Bullying Behaviors

This study was a quantitative exploration of the relationship between novice secondary teachers’ perceived levels of self-efficacy and their projected responses to specific bullying behaviors. The theoretical foundation was Bandura’s self-efficacy theory. The relationship between novice teachers’ perceived levels of self-efficacy, their reported ability to recognize different types of bullying behaviors, their responses to these bullying behaviors, and importance of a mentoring program were explored in this quantitative study. The sample was a convenience sample consisting of 159 teachers in different school settings in Pennsylvania. Vignettes about different types of bullying behaviors were presented to the participants. Likert scale questions followed each vignette to ascertain perceived level of confidence in dealing with the identified bullying behavior and the participant’s projected likelihood of intervening in the identified situation. Comparisons were made between perceived level of efficacy and importance of formal mentoring. Correlations were found between novice secondary teachers’ levels of self-efficacy and the impact of formal mentoring on novice teachers’ attitudes and actions towards different types of bullying behaviors. Implications for positive social change support increased education for novice teachers related to cyberbullying, modifications to teacher training program curriculums, and implementation of formal mentoring programs

Complement Activation in Emergency Department Patients With Severe Sepsis

This study assessed the extent and mechanism of complement activation in community-acquired sepsis at presentation to the emergency department (ED) and following 24 hours of quantitative resuscitation.A prospective pilot study of patients with severe sepsis and healthy controls was conducted among individuals presenting to a tertiary care ED. Resuscitation, including antibiotics and therapies to normalize central venous and mean arterial pressure (MAP) and central venous oxygenation, was performed on all patients. Serum levels of Factor Bb (alternative pathway), C4d (classical and mannose-binding lectin [MBL] pathway), C3, C3a, and C5a were determined at presentation and 24 hours later among patients.Twenty patients and 10 healthy volunteer controls were enrolled. Compared to volunteers, all proteins measured were abnormally higher among septic patients (C4d 3.5-fold; Factor Bb 6.1-fold; C3 0.8-fold; C3a 11.6-fold; C5a 1.8-fold). Elevations in C5a were most strongly correlated with alternative pathway activation. Surprisingly, a slight but significant inverse relationship between illness severity (by sequential organ failure assessment [SOFA] score) and C5a levels at presentation was noted. Twenty-four hours of structured resuscitation did not, on average, affect any of the mediators studied.Patients with community-acquired sepsis have extensive complement activation, particularly of the alternative pathway, at the time of presentation that was not significantly reversed by 24 hours of aggressive resuscitation.ACADEMIC EMERGENCY MEDICINE 2010; 17:353–359 © 2010 by the Society for Academic Emergency MedicinePeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79343/1/j.1553-2712.2010.00713.x.pd

Bivalent engagement of endothelial surface antigens is critical to prolonged surface targeting and protein delivery in vivo

Targeted drug delivery to the endothelium has the potential to generate localized therapeutic effects at the blood- tissue interface. For some therapeutic cargoes, it is essential to maintain contact with the bloodstream to exert protective effects. The pharmacokinetics (PK) of endothelial surface- targeted affinity ligands and biotherapeutic cargo remain a largely unexplored area, despite obvious translational implications for this strategy. To bridge this gap, we site- specifically radiolabeled mono- (scFv) and bivalent (mAb) affinity ligands specific for the endothelial cell adhesion molecules, PECAM- 1 (CD31) and ICAM- 1 (CD54). Radiotracing revealed similar lung biodistribution at 30 minutes post- injection (79.3% ± 4.2% vs 80.4% ± 10.6% ID/g for αICAM and 58.9% ± 3.6% ID/g vs. 47.7% ± 5.8% ID/g for αPECAM mAb vs. scFv), but marked differences in organ residence time, with antibodies demonstrating an order of magnitude greater area under the lung concentration vs. time curve (AUCinf 1698 ± 352 vs. 53.3 ± 7.9 ID/g*hrs for αICAM and 1023 ± 507 vs. 114 ± 37 ID/g*hrs for αPECAM mAb vs scFv). A physiologically based pharmacokinetic model, fit to and validated using these data, indicated contributions from both superior binding characteristics and prolonged circulation time supporting multiple binding- detachment cycles. We tested the ability of each affinity ligand to deliver a prototypical surface cargo, thrombomodulin (TM), using one- to- one protein conjugates. Bivalent mAb- TM was superior to monovalent scFv- TM in both pulmonary targeting and lung residence time (AUCinf 141 ± 3.2 vs 12.4 ± 4.2 ID/g*hrs for ICAM and 188 ± 90 vs 34.7 ± 19.9 ID/g*hrs for PECAM), despite having similar blood PK, indicating that binding strength is more important parameter than the kinetics of binding. To maximize bivalent target engagement, we synthesized an oriented, end- to- end anti- ICAM mAb- TM conjugate and found that this therapeutic had the best lung residence time (AUCinf 253 ± 18 ID/g*hrs) of all TM modalities. These observations have implications not only for the delivery of TM, but also potentially all therapeutics targeted to the endothelial surface.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156501/3/fsb220760_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156501/2/fsb220760-sup-0001-Supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156501/1/fsb220760.pd

Collaborative Enhancement of Antibody Binding to Distinct PECAM-1 Epitopes Modulates Endothelial Targeting

Antibodies to platelet endothelial cell adhesion molecule-1 (PECAM-1) facilitate targeted drug delivery to endothelial cells by “vascular immunotargeting.” To define the targeting quantitatively, we investigated the endothelial binding of monoclonal antibodies (mAbs) to extracellular epitopes of PECAM-1. Surprisingly, we have found in human and mouse cell culture models that the endothelial binding of PECAM-directed mAbs and scFv therapeutic fusion protein is increased by co-administration of a paired mAb directed to an adjacent, yet distinct PECAM-1 epitope. This results in significant enhancement of functional activity of a PECAM-1-targeted scFv-thrombomodulin fusion protein generating therapeutic activated Protein C. The “collaborative enhancement” of mAb binding is affirmed in vivo, as manifested by enhanced pulmonary accumulation of intravenously administered radiolabeled PECAM-1 mAb when co-injected with an unlabeled paired mAb in mice. This is the first demonstration of a positive modulatory effect of endothelial binding and vascular immunotargeting provided by the simultaneous binding a paired mAb to adjacent distinct epitopes. The “collaborative enhancement” phenomenon provides a novel paradigm for optimizing the endothelial-targeted delivery of therapeutic agents

Partner randomized controlled trial: study protocol and coaching intervention

<p>Abstract</p> <p>Background</p> <p>Many children with asthma live with frequent symptoms and activity limitations, and visits for urgent care are common. Many pediatricians do not regularly meet with families to monitor asthma control, identify concerns or problems with management, or provide self-management education. Effective interventions to improve asthma care such as small group training and care redesign have been difficult to disseminate into office practice.</p> <p>Methods and design</p> <p>This paper describes the protocol for a randomized controlled trial (RCT) to evaluate a 12-month telephone-coaching program designed to support primary care management of children with persistent asthma and subsequently to improve asthma control and disease-related quality of life and reduce urgent care events for asthma care. Randomization occurred at the practice level with eligible families within a practice having access to the coaching program or to usual care. The coaching intervention was based on the transtheoretical model of behavior change. Targeted behaviors included 1) effective use of controller medications, 2) effective use of rescue medications and 3) monitoring to ensure optimal control. Trained lay coaches provided parents with education and support for asthma care, tailoring the information provided and frequency of contact to the parent's readiness to change their child's day-to-day asthma management. Coaching calls varied in frequency from weekly to monthly. For each participating family, follow-up measurements were obtained at 12- and 24-months after enrollment in the study during a telephone interview.</p> <p>The primary outcomes were the mean change in 1) the child's asthma control score, 2) the parent's quality of life score, and 3) the number of urgent care events assessed at 12 and 24 months. Secondary outcomes reflected adherence to guideline recommendations by the primary care pediatricians and included the proportion of children prescribed controller medications, having maintenance care visits at least twice a year, and an asthma action plan. Cost-effectiveness of the intervention was also measured.</p> <p>Discussion</p> <p>Twenty-two practices (66 physicians) were randomized (11 per treatment group), and 950 families with a child 3-12 years old with persistent asthma were enrolled. A description of the coaching intervention is presented.</p> <p>Trial registration</p> <p>ClinicalTrials.gov identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT00860834">NCT00860834</a>.</p