IntroductionSeptic shock syndrome resulting from excessive host immune responses induced by infectious organisms is a leading cause of death in hospitalized patients. [1][2][3] Pathophysiologic changes in sepsis involve the pathogen-induced uncontrolled release from immune cells, particularly monocytes and macrophages, of proinflammatory mediators. 4 Gram-negative bacterial infection is one of the major causes of systemic bacterial sepsis. 5 Lipopolysaccharide (LPS), a constituent of the Gram-negative outer membrane, is the leading cause of sepsis. LPS induces a rapid increase of proinflammatory mediators, leading to lethal systemic tissue damage and multiple organ failure, which mimics the inflammatory responses of septic syndrome. 6 In mammals, membrane-bound CD14 and toll-like receptor 4 (TLR4)-MD-2 participate in cellular recognition of LPS. 7 Binding of LPS to TLR4 triggers the activation of members of the mitogen-activated protein kinase (MAPK) pathway including p38, p42/p44 extracellular signal-regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK). 8 In resting unstimulated cells, nuclear factor-B (NF-B), a heterodimeric complex composed of 50-and 65-kDa (p50/p65) protein subunits, 9 retains as an inactive complex bound to inhibitory B␣ (IB␣) in the cytoplasm. While the cells are under proinflammatory stimulation by LPS, phosphorylation and degradation of IB␣ permit NF-B nuclear translocation and promote the expression of inflammatory genes including inducible nitric oxide synthase (iNOS), tumor necrosis factor-␣ (TNF-␣), and others. 9Thrombomodulin (TM) is a 557 amino acid type I glycosylated transmembrane protein 10 with an NH 2 -terminal lectinlike region (domain 1; D1) followed by 6 epidermal growth factor (EGF)-like structures (domain 2; D2), an O-glycosylation site-rich domain (domain 3; D3), a transmembrane domain (domain 4; D4), and a cytoplasmic tail domain (domain 5; D5). TM domain 2 (TMD2) EGF-like structures are responsible for the anticoagulant activity of TM via the alteration of thrombin substrate specificity. TMD2-thrombin complex sequentially activates anticoagulant protein C inactivating procoagulant cofactors Va and VIIIa. 11 TM expression also occurs in keratinocytes, 12 polymorphonuclear neutrophils (PMNs), 13 monocytes, 14 and endothelial cells, 15 indicating additional functions of TM besides anticoagulation. 16 Indeed TM domains function as an adhesion molecule, 17 an angiogenic factor, 18 and an anti-inflammatory agent through protein C-dependent and -independent mechanisms. 16,19 Recently, anti-inflammatory activity of TM domain 1 (TMD1) was implied by observing that mice with a deleted TM lectinlike domain (TM LeD/LeD ) become more sensitive to LPS challenge through the suppressed expression of adhesion molecules via NFB and MAPK signaling pathways. 20 Moreover, mice with a mutation in the TM gene (TM pro/pro ) strongly reduce the capacity to generate activated protein C, an anti-inflammatory agent in treatment of sepsis. 21 Mice harboring the latter mutation display an u...

Background:Accumulating data shows that exon 19 deletions and L858R, both activating epidermal growth factor receptor mutations in non-small-cell lung cancers (NSCLCs), are just two different entities in terms of prognosis and treatment response to tyrosine kinase inhibitors (TKIs).Methods:A systematic review and meta-analysis of randomized controlled trials comparing TKIs with conventional chemotherapy was performed. Eight trials of 1498 patients and five trials of 1279 patients with either exon 19 deletions or L858R were included in the meta-analysis.Results:TKI treatment demonstrated progression-free survival benefit in patients with exon 19 deletions (hazard ratio (HR): 0.27, 95% confidence interval (CI): 0.21–0.35) and L858R (HR: 0.45, 95% CI: 0.35–0.58). Patients with exon 19 deletions had significant overall survival (OS) benefit under TKI treatment (HR: 0.72, 95% CI: 0.60–0.88). Subgroup analyses showed that irreversible TKIs, but not reversible TKIs, had statistically significant OS benefit in these patients (irreversible TKIs, HR: 0.59, 95% CI: 0.47–0.73; reversible TKIs, HR: 0.84, 95% CI: 0.69–1.02). Patients with L858R demonstrated no OS benefit under first-line TKI use (HR: 1.15, 95% CI: 0.95–1.39).Conclusions:In patients with advanced NSCLC harbouring exon 19 deletions, TKIs are associated with better OS compared with conventional chemotherapy. Future clinical trials should take exon 19 deletions and L858R as distinct disease entities and evaluate the treatment efficacy separately.

Background-Thrombomodulin is an anticoagulant, endothelial-cell-membrane glycoprotein. A recombinant thrombomodulin domain containing 6 epidermal growth factor-like structures exhibits mitogenic activity. This study explored the novel angiogenic effects of the recombinant domain using in vitro and in vivo models. Methods and Results-Human recombinant thrombomodulin containing 6 epidermal growth factor-like structures (TMD2) and TMD2 plus a serine and threonine-rich domain (TMD23) were prepared using the Pichia pastoris expression system. Combined with purified TMD2 or TMD23, thrombin effectively activated protein C. TMD23 had higher activity than TMD2 in stimulating DNA synthesis in cultured human umbilical vein endothelial cells. Additionally, TMD23 stimulated chemotactic motility and capillarylike tube formation in human umbilical vein endothelial cells, an effect mediated through phosphorylation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase and the phosphatidylinositol-3 kinase/Akt/endothelial nitric oxide synthase pathway. TMD23 also stimulated endothelial cell expression of matrix metalloproteinases and plasminogen activators, which mediated extracellular proteolysis, leading to endothelial cell invasion and migration during angiogenesis. Furthermore, TMD23-containing implants in rat cornea induced ingrowth of new blood vessels from the limbus. With the murine angiogenesis assay, TMD23 not only induced neovascularization coinjected with Matrigel and heparin but also enhanced angiogenesis in Matrigel containing melanoma A2058 cells in nude mice. Conclusions-The

No abstract

No abstract