1H-NMR investigation of the interaction between RNase T1 and a novel substrate analog, 2′-deoxy-2′-fluoroguanylyl-(3′–5′)uridine

AbstractThe interaction between RNase T1 and a non-hydrolysable substrate analog, 2′-deoxy-2′-fluoroguanylyl-(3′–5′)uridine (GfpU), was investigated using 1H-NMR spectroscopy. In the complex, the Gfp portion takes the syn form around the glycosidic bond and the 3′-endo form for the ribose moiety, similar to those found in 3′-GMP and 2′-deoxy-2′-fluoroguanosine 3′-monophosphate (Gfp). However, in contrast to the cases of these two inhibitors, the complex formation with GfpU at pH 6.0 was found to shift the His-40 C2 proton resonance of RNase T1 to high field as much as 1 ppm. At pH 6.0, this histidine residue appears to be unprotonated in the complex, but is protonated in the free enzyme (pKa of His-40 being 7.9). His-40, rather than Glu-58, is probably involved in the catalytic mechanism as a Lewis base, supporting the recent results from site-directed mutagenesis

Pathological Vascular Invasion and Tumor Differentiation Predict Cancer Recurrence in Stage ia Non–Small-Cell Lung Cancer After Complete Surgical Resection

Introduction:The appropriate therapeutic strategy and postoperative management for patients with stage IA non–small-cell lung cancer (NSCLC) still remain a matter of debate because of the prognostic heterogeneity of this population, including the risk of cancer recurrence. The objective of the current study was to identify the clinicopathological factors that affect overall prognosis and cancer recurrence of stage IA NSCLC.Methods:We reviewed the data of 532 patients in whom complete resection of stage IA NSCLC had been performed. Overall survival and recurrence-free proportion (RFP) were estimated using the Kaplan–Meier method. RFP was estimated from the date of the primary tumor resection to the date of the first recurrence or last follow-up. We performed univariate and multivariate analyses to determine the independent prognostic factors.Results:On multivariate analyses, three variables were shown to be independently significant recurrence risk factors: histological differentiation (hazard ratio [HR] = 1.925), blood-vessel invasion (HR = 1.712), and lymph-vessel invasion (HR = 1.751). On subgroup analyses combining these risk factors, the 5-year RFP was 91.3% for patients with no risk factors, 79.5% for those with either poorly differentiated carcinoma or vascular invasion, (p < 0.001 for both), and 62.9% for those with both poorly differentiated carcinoma and vascular invasion (p = 0.068).Conclusion:These results indicated that vascular invasion and tumor differentiation have a significant impact on the prediction of cancer recurrence in patients with stage IA NSCLC. Patients with these predictive factors of recurrence may be good candidates for adjuvant chemotherapy

On the shape of a D-brane bound state and its topology change

As is well known, coordinates of D-branes are described by NxN matrices. From generic non-commuting matrices, it is difficult to extract physics, for example, the shape of the distribution of positions of D-branes. To overcome this problem, we generalize and elaborate on a simple prescription, first introduced by Hotta, Nishimura and Tsuchiya, which determines the most appropriate gauge to make the separation between diagonal components (D-brane positions) and off-diagonal components. This prescription makes it possible to extract the distribution of D-branes directly from matrices. We verify the power of it by applying it to Monte-Carlo simulations for various lower dimensional Yang-Mills matrix models. In particular, we detect the topology change of the D-brane bound state for a phase transition of a matrix model; the existence of this phase transition is expected from the gauge/gravity duality, and the pattern of the topology change is strikingly similar to the counterpart in the gravity side, the black hole/black string transition. We also propose a criterion, based on the behavior of the off-diagonal components, which determines when our prescription gives a sensible definition of D-brane positions. We provide numerical evidence that our criterion is satisfied for the typical distance between D-branes. For a supersymmetric model, positions of D-branes can be defined even at a shorter distance scale. The behavior of off-diagonal elements found in this analysis gives some support for previous studies of D-brane bound states.Comment: 29 pages, 16 figure

ZD1839 (Gefitinib, 'Iressa'), an epidermal growth factor receptor-tyrosine kinase inhibitor, enhances the anti-cancer effects of TRAIL in human esophageal squamous cell carcinoma

The EGF (epidermal growth factor) receptor-tyrosine kinase inhibitor ZD1839 (Gefitinib, 'Iressa') blocks the cell signaling pathways involved in cell proliferation, survival, and angiogenesis in various cancer cells. TNF-related death apoptosis inducing ligand (TRAIL) acts as an anticancer agent. We investigated the antitumor effects of ZD1839 alone or in combination with TRAIL against human esophageal squamous cell cancer (ESCC) lines. Although all ESCC cells expressed EGF receptor at a protein level, the effect of ZD1839 on cell growth did not correlate with the level of EGFR expression and phosphorylation of EGF receptor protein in ESCC lines. ZD1839 caused a dose-dependent growth arrest at G0–G1 phase associated with increased p27 expression. As TE8 cells are resistant to TRAIL, we tested whether ZD1839 combined with TRAIL induced apoptosis of TE8 cells via the inhibition of EGF receptor signaling by ZD1839. ZD1839 inhibited the phosphorylation of Akt, and enhanced TRAIL-induced apoptosis via activation of caspase-3 and caspase-9, and inactivation of Bcl-xL. Our results indicated that ZD1839 has anti-cancer properties against human esophageal cancer cells. ZD1839 also augmented the anti-cancer activity of TRAIL, even in TRAIL-resistant tumors. These results suggest that treatment with ZD1839 and TRAIL may have potential in the treatment of ESCC patients

Arctic weather in 2012 summer and influences on Arctic Environment

第3回極域科学シンポジウム/特別セッション「これからの北極研究」11月28日（水） 国立極地研究所 2階大会議