Amplification of the Angiogenic Signal through the Activation of the TSC/mTOR/HIF Axis by the KSHV vGPCR in Kaposi's Sarcoma

Background: Kaposi’s sarcoma (KS) is a vascular neoplasm characterized by the dysregulated expression of angiogenic and inflammatory cytokines. The driving force of the KS lesion, the KSHV-infected spindle cell, secretes elevated levels of vascular endothelial growth factor (VEGF), essential for KS development. However, the origin of VEGF in this tumor remains unclear. Methodology/Principal Findings: Here we report that the KSHV G protein-coupled receptor (vGPCR) upregulates VEGF in KS through an intricate paracrine mechanism. The cytokines secreted by the few vGPCR-expressing tumor cells activate in neighboring cells multiple pathways (including AKT, ERK, p38 and IKK$\beta$) that, in turn, converge on TSC1/2, promoting mTOR activation, HIF upregulation, and VEGF secretion. Conditioned media from vGPCR-expressing cells lead to an mTORdependent increase in HIF-1$\alpha$ and HIF-2$\alpha$ protein levels and VEGF upregulation. In a mouse allograft model for KS, specific inhibition of the paracrine activation of mTOR in non-vGPCR-expressing cells was sufficient to inhibit HIF upregulation in these cells, and abolished the ability of the vGPCR-expressing cells to promote tumor formation $in$ $vivo$. Similarly, pharmacologic inhibition of HIF in this model blocked VEGF secretion and also lead to tumor regression. Conclusions/Significance: Our findings provide a compelling explanation for how the few tumor cells expressing vGPCR can contribute to the dramatic amplification of VEGF secretion in KS, and further provide a molecular mechanism for how cytokine dysregulation in KS fuels angiogenesis and tumor development. These data further suggest that activation of HIF by vGPCR may be a vulnerable target for the treatment of patients with KS

Stability analysis and simulation based on an improved Aw-Rascle model

In this paper, the improved Aw-Rascle model with viscosity term is developed to a new nonlinear dynamical system composed of ordinary differential equations, by using traveling wave substitution and a kind of variable substitution. The stability of the system is discussed by the method of phase plane analysis after getting the travelling-wave solutions, then the final data is simulated by Matlab to verify the analysis conclusion

Out-of-Plane Bending and Shear Behaviors of Steel Plate-Concrete Walls for Nuclear Power Plants

The steel plate-concrete structure, with its advantages of modular construction, good seismic capacity, and strong impact resistance, has been gradually replacing the reinforced concrete structure in the containment vessel and internal workshop structure of nuclear power plants in recent years. In this study, the out-of-plane single-point loading test and parametric finite element simulation analysis were conducted on five steel plate-concrete wall slab specimens with different stud spacings, shear span ratios, and steel contents. Results showed that the steel plate-concrete wall slab under the out-of-plane load had the same failure mode as that of an ordinary reinforced concrete wall. The out-of-plane shear capacity of the steel plate-concrete wall slab increased significantly in the case of numerous studs. With the increase in shear span ratio, steel plate-concrete members suffered a bending failure. When the steel content was low, they had diagonal tension failure, such as a rare-reinforced concrete wall. The out-of-plane bending and shear mechanism of the steel plate-concrete shear wall was studied theoretically, and the calculation formulas of the bending and shearing capacities were derived

Flavonoids as Vasorelaxant Agents: Synthesis, Biological Evaluation and Quantitative Structure Activities Relationship (QSAR) Studies

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The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor

SummaryThe Kaposi's sarcoma-associated herpesvirus (KSHV), the infectious causative agent of Kaposi's sarcoma (KS), encodes a G protein-coupled receptor (vGPCR) implicated in the initiation of KS. Here we demonstrate that Kaposi's sarcomagenesis involves stimulation of tuberin (TSC2) phosphorylation by vGPCR, promoting the activation of mTOR through both direct and paracrine mechanisms. Pharmacologic inhibition of mTOR with rapamycin prevented vGPCR sarcomagenesis, while overactivation of this pathway was sufficient to render endothelial cells oncogenic. Moreover, mice haploinsufficient for TSC2 are predisposed to vascular sarcomas remarkably similar to KS. Collectively, these results implicate mTOR in KS initiation and suggest that the sarcomagenic potential of KSHV may be a direct consequence of the profound sensitivity of endothelial cells to vGPCR dysregulation of the TSC2/mTOR pathway