Two vascular growth factor families, VEGF and the angiopoietins, play critical and coordinate roles in tumor progression and metastasis. A single inhibitor targeting both VEGF and angiopoietins is not available. Here, we developed a chimeric decoy receptor, namely double anti-angiogenic protein (DAAP), which can simultaneously bind VEGF-A and angiopoietins, blocking their actions. Compared to VEGF-Trap or Tie2-Fc, which block either VEGF-A or angiopoietins alone, we believe DAAP is a highly effective molecule for regressing tumor angiogenesis and metastasis in implanted and spontaneous solid tumors; it can also effectively reduce ascites formation and vascular leakage in an ovarian carcinoma model. Thus, simultaneous blockade of VEGF-A and angiopoietins with DAAP is an effective therapeutic strategy for blocking tumor angiogenesis, metastasis, and vascular leakage.

The mandibular canal divides into the mental and incisive canals at the premolar region, forms the anterior loop which crosses anterior to the mental foramen, and turns back to reach the mental foramen. The aim of this study was to elucidate the general anatomical structure of the anterior loop of the mandibular canal using morphometry. Twenty-six hemimandibles from 19 cadavers (16 males, 3 females; mean age at death, 54.4 years) were studied by meticulous dissection with the aid of a surgical microscope. The location of the anterior loop, the diameters of the mandibular, mental, and incisive canals, and their distances from bony landmarks were measured using digital calipers. The anterior loop of the mandibular canal was located 3.05±1.15 mm (mean±SD) anterior to the anterior margin of the mental foramen and 2.72±1.41 mm inferior to the superior margin of the mental foramen, and was 4.34±1.46 mm long. The diameters of the mandibular, mental, and incisive canals were 2.8±0.49, 2.63±0.64, and 2.22±0.59 mm, respectively. The distances between the inferior border of the mandible and each of these canals were 7.82±1.52, 10.11±1.27, and 9.08±1.66 mm, respectively. The anterior loop of the mandibular canal was located a mean of 3.1 mm anterior and 2.7 mm inferior to the mental foramen, and continued upward and backward into the mental canal, and forward into the incisive canal. These detailed morphological features of the anterior loop of the mandibular canal represent useful practical anatomical knowledge regarding the interforaminal region.

Lipopolysaccharide (LPS), the Gram-negative bacterial outer membrane glycolipid, induces sepsis through its interaction with myeloid differentiation protein-2 (MD-2) and Toll-like receptor 4 (TLR4). To block interaction between LPS/MD-2 complex and TLR4, we designed and generated soluble fusion proteins capable of binding MD-2, dubbed TLR4 decoy receptor (TOY) using ‘the Hybrid leucine-rich repeats (LRR) technique’. TOY contains the MD-2 binding ectodomain of TLR4, the LRR motif of hagfish variable lymphocyte receptor (VLR), and the Fc domain of IgG1 to make it soluble, productive, and functional. TOY exhibited strong binding to MD-2, but not to the extracellular matrix (ECM), resulting in a favorable pharmacokinetic profile in vivo. TOY significantly extended the lifespan, when administered in either preventive or therapeutic manners, in both the LPS- and cecal ligation/puncture-induced sepsis models in mice. TOY markedly attenuated LPS-triggered NF-κB activation, secretion of proinflammatory cytokines, and thrombus formation in multiple organs. Taken together, the targeting strategy for sequestration of LPS/MD-2 complex using the decoy receptor TOY is effective in treating LPS- and bacteria-induced sepsis; furthermore, the strategy used in TOY development can be applied to the generation of other novel decoy receptor proteins.

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