Objective-We examined the effects of FKHRL1 (forkhead transcription factor in rhabdomyosarcoma like-1) overexpression on vascular smooth muscle cell (VSMC) proliferation, apoptosis, and cell cycle, in vitro, and the role of FKHRL1 and p27 in the pathophysiology of neointimal growth after balloon angioplasty, in vivo. Furthermore, we tested whether FKHRL1 overexpression can inhibit neointimal hyperplasia in a rat carotid artery model. Methods and Results-Adenovirus expressing the constitutively active FKHRL1 (FKHRL1-TM; triple mutant) with 3 Akt phosphorylation sites mutated was transfected to subconfluent VSMCs. FKHRL1 overexpression in cultured VSMCs increased p27 expression, leading to G1 phase cell-cycle arrest and increased apoptosis. In vivo, the phosphorylation of FKHRL1 increased significantly 3 hours after balloon injury and decreased thereafter, with the subsequent downregulation of p27. Although the phosphorylation of FKHRL1 was greatest at 3 hours, the downregulation of p27 showed a temporal delay, only slightly starting to decrease after 3 hours and reaching a nadir at 72 hours after balloon injury. Gene transfer of FKHRL1-TM increased p27, decreased proliferation, and increased apoptosis of VSMCs, which resulted in a marked reduction in neointima formation (intima-to-media ratio: 0.31Ϯ0.13 versus 1.17Ϯ0.28, for FKHRL1-TM versus Adv-GFP; PϽ0.001). D espite the recent advances in strategies to prevent neointimal growth after angioplasty, it still remains the major limitation of percutaneous coronary interventions. 1 Although the pathogenic mechanism of restenosis is complex, the proliferation and migration of vascular smooth muscle cells (VSMCs) after balloon injury seems to be a major factor in this process. 2-4 Therefore, we along with many investigators have targeted VSMC proliferation and migration as a means to counter restenosis. 5,6 FKHRL1 (forkhead transcription factor in rhabdomyosarcoma-like 1, FOXO3a) is a member of the forkhead transcription factor family, which is emerging as a key factor in pathways that regulate differentiation, metabolism, proliferation, and survival of cells. 7 FKHRL1 is negatively regulated by the PI3K/Akt pathway. 8 -10 Phosphorylation of FKHRL1 by Akt leads to cytoplasmic retention and impairment of its nuclear transcriptional activity. Past studies have shown that the key actions of forkhead family transcription factors are cell-cycle arrest 11-14 and apoptosis. 9 Taken together, FHKRL1 may affect the cell cycle and apoptosis of VSMCs, and may serve as a therapeutic target to inhibit neointimal growth after angioplasty. In the present study, we examined the effects of FKHRL1 on VSMC survival and proliferation in vitro. We also investigated whether FKHRL1 plays a role in neointima formation after balloon injury, and we tested whether the cytotoxic and cytostatic properties FKHRL1 can reduce neointimal hyperplasia after balloon injury in a rat carotid injury model. Conclusion-Balloon

Background-The forkhead factor, FOXO3a, is known to induce apoptosis in endothelial cells (ECs). However, its effects on extracellular matrices (ECM), which are important in EC survival, remained unknown. Here, we evaluated the role of FOXO3a on EC-ECM interaction. Methods and Results-Constitutively active FOXO3a was transduced to human umbilical vein endothelial cells by adenoviral vector (Ad-TM-FOXO3a). Ad-TM-FOXO3a transfection led to dehiscence of ECs from fibronectin-coated plates, resulting in anoikis, which was significantly reversed by matrix metalloproteinase (MMP) inhibitor, GM6001. FOXO3a increased the expression of MMP-3 (stromelysin-1) but decreased the expression of tissue inhibitors of metalloproteinases-1 (TIMP-1), which was associated with increased MMP enzymatic activity in zymography. Pathophysiologic conditions such as serum starvation or heat shock also induced activation of endogenous FOXO3a, leading to activation of MMP-3 and apoptosis, which was reversed by GM6001. Delivery of Ad-TM-FOXO3a to the intraluminal surface in vivo led to EC denudation, disrupted vascular integrity, and impaired endothelium-dependent vasorelaxation. Conclusion-Activation

BackgroundIt is important to know and decide when to end regimen for the quality of life of the patients. However, there is currently no clear agreement on when to terminate palliative chemotherapy. We investigated the duration between the last chemotherapy and death, and associated factors affecting patients receiving palliative care after the last chemotherapy.MethodsWe studied 242 patients who were put into palliative care ward after receiving chemotherapy and died during hospitalization from 2008 to 2009. Electronic medical records were used to gather information on demographic characteristics, types of primary cancer, and palliative chemotherapy. Then we analyzed the relationship between the clinical characteristics of patients and interval between last chemotherapy and death.ResultsThe average survival time of patients after referral to palliative care was 17.5 days; survival time after discontinuation of chemotherapy was 103 days. Also, 104 (43.0%) patients died within 3 months and 14 (5.8%) patients died within 1 month of persistent palliative chemotherapy. Chemotherapy on patients within 3 months from their death was not associated with the social characteristics of the population.ConclusionThe patients who were referred to palliative care were found to have continued to receive chemotherapy within 3 months before death. However, only a small number of patients received chemotherapy within 1 month before death, which confirms that futile chemotherapy that extends to the end of life was less frequent. Doctors should be able to recognize the implications of excessive and aggressive use of chemotherapy and should actively communicate with patients about therapeutic choices.