Antiangiogenic Activity of 2-Deoxy-D-Glucose

During tumor angiogenesis, endothelial cells (ECs) are engaged in a number of energy consuming biological processes, such as proliferation, migration, and capillary formation. Since glucose uptake and metabolism are increased to meet this energy need, the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) on in vitro and in vivo angiogenesis were investigated.In cell culture, 2-DG inhibited EC growth, induced cytotoxicity, blocked migration, and inhibited actively forming but not established endothelial capillaries. Surprisingly, 2-DG was a better inhibitor of these EC properties than two more efficacious glycolytic inhibitors, 2-fluorodeoxy-D-glucose and oxamate. As an alternative to a glycolytic inhibitory mechanism, we considered 2-DG's ability to interfere with endothelial N-linked glycosylation. 2-DG's effects were reversed by mannose, an N-linked glycosylation precursor, and at relevant concentrations 2-DG also inhibited synthesis of the lipid linked oligosaccharide (LLO) N-glycosylation donor in a mannose-reversible manner. Inhibition of LLO synthesis activated the unfolded protein response (UPR), which resulted in induction of GADD153/CHOP and EC apoptosis (TUNEL assay). Thus, 2-DG's effects on ECs appeared primarily due to inhibition of LLOs synthesis, not glycolysis. 2-DG was then evaluated in two mouse models, inhibiting angiogenesis in both the matrigel plug assay and the LH(BETA)T(AG) transgenic retinoblastoma model.In conclusion, 2-DG inhibits endothelial cell angiogenesis in vitro and in vivo, at concentrations below those affecting tumor cells directly, most likely by interfering with N-linked glycosylation rather than glycolysis. Our data underscore the importance of glucose metabolism on neovascularization, and demonstrate a novel approach for anti-angiogenic strategies

Quasi-analytical kinetic model for natural rubber and polybutadiene rubber blends

A very simple kinetic model for natural rubber (NR) and polybutadiene (PB) blends is presented. The model is characterized by a completely uncoupled curing between NR and PB, NR being modeled with a primary vulcanization and a subsequent de-vulcanization and PB only by a simple first order model of vulcanization. The assumptions made are roughly in agreement with the actual experimental behavior of the constituent materials in a rheometer chamber, where PB exhibits a quite stable behavior even at high curing temperatures and long vulcanization times. As a result of the simplifications assumed into the curing model adopted, the numerical approach uses only on three kinetic constants, two for NR and one for PB. Such assumptions allow for a quite straightforward determination of the kinetic constants by means of a simple semi-analytical approach. The reliability of the procedure proposed is benchmarked on some 70% NR- 30% PB blends with two different accelerants (N-terbutyl, 2-benzothiazylsulfenamide TBBS and N,N-diphenylguanidine DPG) in different concentrations tested experimentally on a standard rheometer chamber at 170 and 180 °C. Quite good match is found between numerical predictions and normalized rheometer curves, with a clear practical impact into the Finite Element FE modelling of vulcanization of real items

Tectonic forcings of Maastrichtian ocean-climate evolution

A global compilation of deep-sea isotopic records suggests that Maastrichtian ocean-climate evolution tvas tectonically driven. During the early Maastrichtian the Atlantic intermediate-deep ocean was isolated from the Pacific, Indian, and Southern Oceans; deep water formed in the high-latitude North Atlantic and North Pacific. At the early/late Maastrichtian boundary a major reorganization of oceanic circulation patterns occurred, resulting in the development of a thermohaline circulation system similar to that of the modem oceans. A combination of isotopic and plate kinematic data suggests that this event was triggered by the final breaching of tectonic sills in the South Atlantic and the initiation of north-south flow of intermediate and deep water in the Atlantic. The onset of Laramide tectonism during the mid Maastrichtian led to the concurrent draining of major epicontinental seaways. Together, these events caused cooling, increased latitudinal temperature gradients, increased ventilation of the deep ocean, and affected a range of marine biota