Prevalence of airflow limitation in Japan is higher than previously reported, suggesting a high degree of under-recognition of COPD. The high prevalence of smoking coupled with an aging population threatens to further increase the burden of COPD, highlighting the need for enhanced screening efforts and interventions of prevention and treatment.

Approximately 17% of the human genome is comprised of long interspersed nuclear element 1 (LINE-1, L1) non-LTR retrotransposons. L1 retrotransposition is known to be the cause of several genetic diseases, such as hemophilia A, Duchene muscular dystrophy, and so on. The L1 retroelements are also able to cause colon cancer, suggesting that L1 transposition could occur not only in germ cells, but also in somatic cells if innate immunity would not function appropriately. The mechanisms of L1 transposition restriction in the normal cells, however, are not fully defined. We here show that antiretroviral innate proteins, human APOBEC3 (hA3) family members, from hA3A to hA3H, differentially reduce the level of L1 retrotransposition that does not correlate either with antiviral activity against Vif-deficient HIV-1 and murine leukemia virus, or with patterns of subcellular localization. Importantly, hA3G protein inhibits L1 retrotransposition, in striking contrast to the recent reports. Inhibitory effect of hA3 family members on L1 transposition might not be due to deaminase activity, but due to novel mechanism(s). Thus, we conclude that all hA3 proteins act to differentially suppress uncontrolled transposition of L1 elements.

Abstract-Hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of vascular endothelial growth factor (VEGF) and other hypoxia-responsive genes. Transgenic expression of a constitutively stable HIF-1␣ mutant increases the number of vascular vessels without vascular leakage, tissue edema, or inflammation. This study aimed to investigate the molecular basis by which HIF-1 mediates the angiogenic response to hypoxia. In primary human endothelial cells, hypoxia, desferrioxamine, or infection with Ad2/HIF-1␣/VP16, an adenoviral vector encoding a constitutively stable hybrid form of HIF-1␣, increased the mRNA and protein levels of VEGF, angiopoietin-2 (Ang-2), and angiopoietin-4 (Ang-4). Infection with Ad2/CMVEV (a control vector expressing no transgene) had no effect. Angiopoietin-1 (Ang-1) expression was not detected in human endothelial cells. Ang-4 was also induced by hypoxia or Ad2/HIF-1␣/VP16 in human cardiac cells, whereas Ang-1 expression remained unchanged. Recombinant Ang-4 protein protected endothelial cells against serum starvation-induced apoptosis and increased cultured endothelial cell migration and tube formation. Ad2/HIF-1␣/VP16 stimulated endothelial cell proliferation and tube formation. Hypoxia-or Ad2/HIF-1␣/VP16-induced tube formation was significantly reduced by a Tie-2 inhibitor. These results suggest that HIF-1 mediates the angiogenic response to hypoxia by upregulating the expression of multiple angiogenic factors. Ang-4 can function similarly as Ang-1 and substitute for Ang-1 to participate in hypoxia-induced angiogenesis. Activation of the angiopoietin/Tie-2 system may play a role in the ability of HIF-1 to induce hypervascularity without excessive permeability. (Circ Res. 2003;93:664-673.)Key Words: hypoxia-inducible factor-1 Ⅲ hypoxia Ⅲ angiogenesis Ⅲ angiopoietins Ⅲ vascular endothelial growth factor A dministration of a single growth factor in the form of protein or gene has been shown to promote tissue neovascularization in animal models and patients. 1,2 However, transgenic overexpression of vascular endothelial growth factor (VEGF) alone in mice results in increased numbers of primarily leaky vascular vessels with tissue edema and inflammation, 3,4 suggesting that VEGF needs to work in conjunction with other angiogenic factors to produce a healthy vasculature. 5,6 In a variety of conditions, such as malignant tumors, wound healing, and myocardial ischemia, hypoxia is a fundamental stimulus for angiogenesis. 7,8 Activation of hypoxia-responsive genes including VEGF is mediated by hypoxia-inducible factor-1 (HIF-1), a heterodimeric basic helix-loop-helix-PAS domain transcription factor. 9,10 HIF-1 is composed of two subunits, HIF-1␣ and HIF-1␤ (aryl hydrocarbon nuclear translocator). Whereas the ␤-subunit protein is constitutively present, the stability of the ␣-subunit and its transcriptional activity are precisely controlled by the intracellular oxygen concentration. [11][12][13][14][15] Knocking-out the HIF-1␣ alleles in mice results in embryonic lethality with vascul...

Amrubicin exhibits significant activity against SCLC, with predictable and manageable toxicities; this agent deserves to be studied more extensively in additional trials.