Objective-Endothelial progenitor cells (EPCs) play an important role in the self-healing of a vascular injury by participating in the reendothelialization that limits vascular remodeling. We evaluated whether prostaglandin I 2 plays a role in the regulation of the function of EPCs to limit vascular remodeling. Ϫ cKit ϩ Flk-1 ϩ cells) were isolated from the bone marrow (BM) of wild-type (WT) mice or mice lacking the prostaglandin I 2 receptor IP (IP Ϫ/Ϫ mice). Reverse transcription-polymerase chain reaction analysis showed that EPCs among BM cells specifically express IP. The cellular properties of EPCs, adhesion, migration, and proliferation on fibronectin were significantly attenuated in IP-deficient EPCs compared with WT EPCs. In contrast, IP agonists facilitated these functions in WT EPCs, but not in IP-deficient EPCs. The specific deletion of IP in BM cells, which was performed by transplanting BM cells of IP Ϫ/Ϫ mice to WT mice, accelerated wire injury-mediated neointimal hyperplasia in the femoral artery. Notably, transfused WT EPCs, but not IP-deficient EPCs, were recruited to the injured vessels, participated in reendothelialization, and efficiently rescued the accelerated vascular remodeling. Key Words: vascular remodeling Ⅲ prostaglandin I 2 Ⅲ endothelial progenitor cells Ⅲ fibronectin Ⅲ adhesion V ascular remodeling characterized by neointimal hyperplasia frequently accompanies angioplasty and atherosclerosis. 1 The development of vascular remodeling is limited by a process of reendothelialization, 2 which is accomplished by covering the neointimal surface with a functional endothelial monolayer. Recently, endothelial progenitor cells (EPCs) have been established as the cells participating in reendothelialization. 3,4 EPCs, which originate in bone marrow (BM), are mobilized into peripheral circulation in response to vascular injury. 5,6 After mobilization, they are recruited to the injured vessels, differentiate into mature endothelial cells, and contribute to reendothelialization to a variable extent depending on the nature of the vascular injury. 7-9 Accordingly, the infusion of exogenous EPCs 8,9 or EPC-mobilizing factors, 7,10 which increases circulatory EPCs, facilitated reendothelialization of the injured vessels and thereby suppressed neointimal formation. Methods and Results-EPCs (Lin Conclusion-These See accompanying article on page 457Prostaglandin (PG) I 2 (prostacyclin), a potent antiatherogenic lipid mediator, is the major prostanoid in the cardiovascular system and is produced mainly by vascular endothelial cells. PGI 2 exerts a variety of actions via binding to the specific receptor IP and, thus, induces vascular relaxation, inhibits proliferation of vascular smooth muscle cells, and potently inhibits platelet activation. 11 Accordingly, mice lacking the IP (IP Ϫ/Ϫ mice) have shown the phenotypes characterized by enhanced vascular remodeling with augmented neointimal hyperplasia after a vascular injury 12 and by facilitated atherosclerosis when having a concomitant loss of apoprote...

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These findings indicate that NAMPT is a potent therapeutic target in the treatment of EGFR-gene-mutated NSCLC.

Abstract. The efficacy of adjuvant chemotherapy with S-1 in patients with completely resected non-small cell lung cancer (NSCLC) has yet to be clarified, and the appropriate schedule for the adjuvant chemotherapy with S-1 remains unknown. A phase II study was conducted to evaluate the feasibility and efficacy of adjuvant chemotherapy with S-1. Patients enrolled in this study were 20-75 years old, had pathological stage IB-IIIA NSCLC, and had received complete resection of NSCLC. S-1 (80 mg/m 2 ) was administered orally to the patients for four weeks followed by a two-week rest period (conventional schedule), for a maximum of eight cycles. The primary endpoint was relative dose intensity (RDI), while the secondary endpoints were safety and 1 year of disease-free survival (1y-DFS). Between

Mutations in RAS oncogenes are frequently observed in human cancers, and the mutations result in activation of the RAS-RAF-MEK-ERK pathway, leading to cell proliferation and survival. The pathway is, therefore, a potent therapeutic target in the RAS-mutant cancers. MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the RAS-mutant cancers. As RAS proteins activate other downstream signaling proteins in addition to the RAS-RAF-MEK-ERK pathway, combination therapeutic approaches with MEK inhibitors are also being evaluated. Moreover, MEK inhibitors can arrest cancer cells in G 1 phase and repress prosurvival Bcl2 family proteins such as MCL1 and BCL2/BCLXL, and increase expression of Bim, a proapoptotic BH3-only family protein. This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors. A better understanding of the pathway will help us with development of rational combinations for the treatment of the RAS-mutant cancers.