Defibrotide modulates pulmonary endothelial cell activation and protects against lung inflammation in pre-clinical models of LPS-induced lung injury and idiopathic pneumonia syndrome

IntroductionA multiple organ dysfunction syndrome (MODS) workshop convened by the National Institute of Child Health and Human Development in 2015 identified acute respiratory distress syndrome (ARDS) and complications of allogeneic blood and marrow transplantation (allo-BMT) as contributors to MODS in pediatric patients. Pulmonary dysfunction also remains a significant complication of allo-BMT. Idiopathic pneumonia syndrome (IPS) defines non-infectious, acute, lung injury that occurs post-transplant. Injury and activation to endothelial cells (ECs) contribute to each form of lung inflammation.MethodsTwo murine models were employed. In an ARDS model, naïve B6 mice receive an intravenous (i.v.) injection of lipopolysaccharide (LPS). In the established model of IPS, naïve B6D2F1 mice receive lethal total body irradiation followed by BMT from either allogeneic (B6) or syngeneic (B6D2F1) donors. Lung inflammation was subsequently assessed in each scenario.ResultsIntravenous injection of LPS to B6 mice resulted in enhanced mRNA expression of TNFα, IL-6, Ang-2, E-, and P-selectin in whole lung homogenates. The expression of Ang-2 in this context is regulated in part by TNFα. Additionally, EC activation was associated with increased total protein and cellularity in broncho-alveolar lavage fluid (BALF). Similar findings were noted during the development of experimental IPS. We hypothesized that interventions maintaining EC integrity would reduce the severity of ARDS and IPS. Defibrotide (DF) is FDA approved for the treatment of BMT patients with sinusoidal obstruction syndrome and renal or pulmonary dysfunction. DF stabilizes activated ECs and protect them from further injury. Intravenous administration of DF before and after LPS injection significantly reduced mRNA expression of TNFα, IL6, Ang-2, E-, and P-selectin compared to controls. BALF showed decreased cellularity, reflecting less EC damage and leak. Allogeneic BMT mice were treated from day -1 through day 14 with DF intraperitoneally, and lungs were harvested at 3 weeks. Compared to controls, DF treatment reduced mRNA expression of TNFα, IL6, Ang-2, E-, and P- selectin, BALF cellularity, and lung histopathology.ConclusionThe administration of DF modulates EC injury in models of ARDS and IPS. Cytokine inhibition in combination with agents that stabilize EC integrity may be an attractive strategy for patients in each setting

What we talk about when we talk about "global mindset": managerial cognition in multinational corporations

Recent developments in the global economy and in multinational corporations have placed significant emphasis on the cognitive orientations of managers, giving rise to a number of concepts such as “global mindset” that are presumed to be associated with the effective management of multinational corporations (MNCs). This paper reviews the literature on global mindset and clarifies some of the conceptual confusion surrounding the construct. We identify common themes across writers, suggesting that the majority of studies fall into one of three research perspectives: cultural, strategic, and multidimensional. We also identify two constructs from the social sciences that underlie the perspectives found in the literature: cosmopolitanism and cognitive complexity and use these two constructs to develop an integrative theoretical framework of global mindset. We then provide a critical assessment of the field of global mindset and suggest directions for future theoretical and empirical research

Transplant for non-malignant disorders: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee report on the role of alternative donors, stem cell sources and graft engineering

: Hematopoietic stem cell transplantation (HSCT) is curative for many non-malignant disorders. As HSCT and supportive care technologies improve, this life-saving treatment may be offered to more and more patients. With the development of new preparative regimens, expanded alternative donor availability, and graft manipulation techniques, there are many options when choosing the best regimen for patients. Herein the authors review transplant considerations, transplant goals, conditioning regimens, donor choice, and graft manipulation strategies for patients with non-malignant disorders undergoing HSCT