Phage-Derived Fully Human Monoclonal Antibody Fragments to Human Vascular Endothelial Growth Factor-C Block Its Interaction with VEGF Receptor-2 and 3

Vascular endothelial growth factor C (VEGF-C) is a key mediator of lymphangiogenesis, acting via its receptors VEGF-R2 and VEGF-R3. High expression of VEGF-C in tumors correlates with increased lymphatic vessel density, lymphatic vessel invasion, sentinel lymph node metastasis and poor prognosis. Recently, we found that in a chemically induced skin carcinoma model, increased VEGF-C drainage from the tumor enhanced lymphangiogenesis in the sentinel lymph node and facilitated metastatic spread of cancer cells via the lymphatics. Hence, interference with the VEGF-C/VEGF-R3 axis holds promise to block metastatic spread, as recently shown by use of a neutralizing anti-VEGF-R3 antibody and a soluble VEGF-R3 (VEGF-C/D trap). By antibody phage-display, we have developed a human monoclonal antibody fragment (single-chain Fragment variable, scFv) that binds with high specificity and affinity to the fully processed mature form of human VEGF-C. The scFv binds to an epitope on VEGF-C that is important for receptor binding, since binding of the scFv to VEGF-C dose-dependently inhibits the binding of VEGF-C to VEGF-R2 and VEGF-R3 as shown by BIAcore and ELISA analyses. Interestingly, the variable heavy domain (VH) of the anti-VEGF-C scFv, which contains a mutation typical for camelid heavy chain-only antibodies, is sufficient for binding VEGF-C. This reduced the size of the potentially VEGF-C-blocking antibody fragment to only 14.6 kDa. Anti-VEGF-C VH-based immunoproteins hold promise to block the lymphangiogenic activity of VEGF-C, which would present a significant advance in inhibiting lymphatic-based metastatic spread of certain cancer types

IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality

Acute lung injury (ALI) is an inflammatory disease with a high mortality rate. Although typically seen in individuals with sepsis, ALI is also a major complication in severe acute pancreatitis (SAP). The pathophysiology of SAP-associated ALI is poorly understood, but elevated serum levels of IL-6 is a reliable marker for disease severity. Here, we used a mouse model of acute pancreatitis–associated (AP-associated) ALI to determine the role of IL-6 in ALI lethality. Il6-deficient mice had a lower death rate compared with wild-type mice with AP, while mice injected with IL-6 were more likely to develop lethal ALI. We found that inflammation-associated NF-κB induced myeloid cell secretion of IL-6, and the effects of secreted IL-6 were mediated by complexation with soluble IL-6 receptor, a process known as trans-signaling. IL-6 trans-signaling stimulated phosphorylation of STAT3 and production of the neutrophil attractant CXCL1 in pancreatic acinar cells. Examination of human samples revealed expression of IL-6 in combination with soluble IL-6 receptor was a reliable predictor of ALI in SAP. These results demonstrate that IL-6 trans-signaling is an essential mediator of ALI in SAP across species and suggest that therapeutic inhibition of IL-6 may prevent SAP-associated ALI

Thermoelektrische Generatoren (TEG) zur Effizienzsteigerung von modernen Nutzfahrzeugen

Fuel consumption and emissions from commercial vehicles account for a large proportion of road transport emissions and without further technical innovation, significant reductions are unlikely. Part of this problem is that about 2/3 of the chemical energy in the fuel of current diesel vehicles is lost in the form of waste heat via the engine coolant and exhaust system. Thermoelectric generators offer a solution with low complexity and a competitive cost-benefit ratio compared to other efficiency technologies. In this research study, a holistic modelling approach that includes all vehicle interactions is used. The objectives of the study are conventional heavy-duty diesel vehicles and natural gas vehicles. In the context of the transformation of the transport sector, the potentials for future powertrains, such as hydrogen combustion engines and fuel cells, are also presented. The holistic approach enables the evaluation of the technology based on fuel and emission reduction as well as payback time for current and future commercial vehicles. The use of a thermoelectric generator appears to be techno-economically advantageous for current and future powertrains. The results are highly dependent on the load point and the application profile of the vehicles. For example, the fuel savings for a current diesel vehicle are in the range of 0.5-1.5% and the payback period is between 1.4 and over 10 years. For current natural gas vehicles, it is 1.8-2.6% and 0.7-2.5 years. The holistic research approach and highly integrated design of the system have enabled power densities of up to 250 W/dm3 for diesel vehicles and up to 570 W/dm3 for natural gas vehicles. These values represent significant increases in the state of the art. The thermoelectric waste heat recovery technology is of interest for vehicle applications with gasoline, diesel, natural gas, hydrogen combustion engines and fuel cells