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Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a recently identified oncogene localized at 1q21, a frequently amplified region in hepatocellular carcinoma (HCC). To explore its oncogenic mechanisms, we set out to identify CHD1L-regulated genes using a chromatin immunoprecipitation-based (ChIP-based) cloning strategy in a human HCC cell line. We then further characterized 1 identified gene, ARHGEF9, which encodes a specific guanine nucleotide exchange factor (GEF) for the Rho small GTPase Cdc42. Overexpression of ARHGEF9 was detected in approximately half the human HCC samples analyzed and positively correlated with CHD1L overexpression. In vitro and in vivo functional studies in mice showed that CHD1L contributed to tumor cell migration, invasion, and metastasis by increasing cell motility and inducing filopodia formation and epithelial-mesenchymal transition (EMT) via ARHGEF9-mediated Cdc42 activation. Silencing ARHGEF9 expression by RNAi effectively abolished the invasive and metastatic abilities of CHD1L in mice. Furthermore, investigation of clinical HCC specimens showed that CHD1L and ARHGEF9 were markedly overexpressed in metastatic HCC tissue compared with healthy tissue. Increased expression of CHD1L was often observed at the invasive front of HCC tumors and correlated with venous infiltration, microsatellite tumor nodule formation, and poor disease-free survival. These findings suggest that CHD1L-ARHGEF9-Cdc42-EMT might be a novel pathway involved in HCC progression and metastasis.

BackgroundThere is strong evidence of FFR-guided treatment in multi-vessel disease. The presence of a concomitant CTO may influence the FFR measurement in donor vessel. We sought to investigate the influence of collateral regression after successful CTO recanalisation on donor vessel pressure-derived indices.Methods28 out of 34 consecutive patients underwent successful PCI to RCA CTOs and completed the follow up study (at 3 months post CTO-PCI). Resting Pd/Pa,iFR and FFR were measured pre and post successful CTO PCI and at follow-up in donor vessels.ResultsThe mean resting Pd/Pa, iFR and FFR pre and post-RCA CTO PCI and at follow-up procedures in major donor vessel were (0.893, 0.862, 0.764), (0.907, 0.886, 0.753) and (0.918, 0.901, 0.787) respectively. The mean resting Pd/Pa, iFR and FFR pre and post-RCA CTO PCI and at follow-up procedures in minor donor vessel were (0.979, 0.966, 0.890), (0.983, 0.979, 0.880) and (0.981, 0.974, 0.898) respectively. Changes in pressure-derived indices are summarised in table 1.Abstract 8 Table 1Changes in coronary pressure-derived measurements in donor vessel pre and post RCA CTO PCI and at fellow-up (FU: follow-up; PdPa: resting Pd/Pa; PCI: percutaneous coronary intervention; IFR: instantaneous wave-free ratio; FFR: fractional flow reserve; CTO: chronic total occlusion)ConclusionSuccessful recanalisation of a RCA CTO results in a significant increase in coronary pressure-derived indices of the major donor vessel at follow-up associated with a regression of collateral function. The expected change and the optimal timing to perform PCI in donor vessel should be considered when planning multi-vessel revascularisation in this setting.

BackgroundThe presence of a concomitant CTO may influence the FFR measurement in donor vessel. We sought to investigate the immediate physiological impact of CTO recanalisation on donor vessel pressure-derived indices.Methods34 out of 40 consecutive patients underwent successful PCI to RCA CTOs. Resting Pd/Pa,iFR and FFR were measured pre and post-successful CTO PCI in donor vessels and collateral FFR in the CTO vessel.ResultsThe angiographic details are as outlined in table 1. The mean resting Pd/Pa, iFR and FFR pre and post CTO PCI in major donor vessel were (0.891,0.858, 0.759) and (0.903, 0.882, 0.746) (p=0.109, p=0.012, p=0.388) respectively. iFR in the major donor vessel increased from 0.858 to 0.882 (difference, 0.02412; p=0.012). The mean resting Pd/Pa, iFR and FFR pre and post CTO PCI in minor donor vessel were (0.982, 0.969, 0.894) and (0.985, 0.979, 0.885), (p=0.534, p=0.152, p=0.183) respectively. The mean collateral FFR was 0.310. The mean total ischaemic burden on baseline cardiac MRI in RCA territory was 12.6%.ConclusionSuccessful recanalisation of a RCA CTO results in a significant increase in the iFR of the major donor vessel but no significant difference was seen in resting Pd/Pa and FFR. Complete collateral regression was not observed in all patients immediately post RCA CTO PCI and this may account for the non-significant change in FFR values.Abstract 20 Table 1Angiographic characteristics (CTO: chronic total occlusion; RCA: right coronary artery; LAD: left anterior descending artery; LCX: left circumflex artery; PCI: percutaneous coronary intervention)

Fractional flow reserve (FFR) uses pressure-based measurements to assess the severity of a coronary stenosis. Distal pressure (Pd) is often at a different vertical height to that of the proximal aortic pressure (Pa). The difference in pressure between Pd and Pa due to hydrostatic pressure, may impact FFR calculation. One hundred computed tomography coronary angiographies were used to measure height differences between the coronary ostia and points in the coronary tree. Mean heights were used to calculate the hydrostatic pressure effect in each artery, using a correction factor of 0.8 mmHg/cm. This was tested in a simulation of intermediate coronary stenosis to give the \"corrected FFR\" (cFFR) and percentage of values, which crossed a threshold of 0.8. The mean height from coronary ostium to distal left anterior descending (LAD) was +5.26 cm, distal circumflex (Cx) -3.35 cm, distal right coronary artery-posterior left ventricular artery (RCA-PLV) -5.74 cm and distal RCA-posterior descending artery (PDA) +1.83 cm. For LAD, correction resulted in a mean change in FFR of +0.042, -0.027 in the Cx, -0.046 in the PLV and +0.015 in the PDA. Using 200 random FFR values between 0.75 and 0.85, the resulting cFFR crossed the clinical treatment threshold of 0.8 in 43% of LAD, 27% of Cx, 47% of PLV and 15% of PDA cases. There are significant vertical height differences between the distal artery (Pd) and its point of normalization (Pa). This is likely to have a modest effect on FFR, and correcting for this results in a proportion of values crossing treatment thresholds. Operators should be mindful of this phenomenon when interpreting FFR values.

Lysine 5,6-aminomutase is an adenosylcobalamin and pyridoxal-5′-phosphate-dependent enzyme that catalyzes a 1,2 rearrangement of the terminal amino group of DL-lysine and of L-β-lysine. We have solved the x-ray structure of a substrate-free form of lysine-5,6-aminomutase from Clostridium sticklandii. In this structure, a Rossmann domain covalently binds pyridoxal-5′-phosphate by means of lysine 144 and positions it into the putative active site of a neighboring triosephosphate isomerase barrel domain, while simultaneously positioning the other cofactor, adenosylcobalamin, ≈25 Å from the active site. In this mode of pyridoxal-5′-phosphate binding, the cofactor acts as an anchor, tethering the separate polypeptide chain of the Rossmann domain to the triosephosphate isomerase barrel domain. Upon substrate binding and transaldimination of the lysine-144 linkage, the Rossmann domain would be free to rotate and bring adenosylcobalamin, pyridoxal-5′-phosphate, and substrate into proximity. Thus, the structure embodies a locking mechanism to keep the adenosylcobalamin out of the active site and prevent radical generation in the absence of substrate.

BACKGROUND. Hepatitis C virus (HCV) genotype 1 is the most prevalent genotype in Western countries, and treatment with pegylated interferon (pegIFN) plus ribavirin fails in 50%-60% of patients. Genetic variability within the NS5A dsRNA-dependent protein kinase binding domain (PKRbd) of HCV-1b has been associated with responsiveness to IFN- alpha . Little is known about NS5A sequences of HCV-1a. We investigated whether genetic variability of HCV-1a NS5A correlates with the early HCV kinetics during treatment. Twenty-four treatment-naive, HCV-1a-infected patients were treated with standard doses of pegIFN- alpha 2a plus ribavirin. HCV viremia was quantitated at days 0, 1, 2, and 3 and weeks 1, 2, 4, 8, and 12 of treatment. According to HCV kinetics, patients were classified as early rapid responders, early moderate responders, or early slow responders. The full-length HCV NS5A was sequenced at baseline and at week 1. At baseline, variability of the NS5A C terminus (concentrated in the PKRbd) is associated with interferon efficacy but not with the second phase of the early viral decline that has been associated with a sustained virologic response. Comparisons between baseline and week-1 full-length sequences did not show significant increases in mutations. Genetic variability of HCV-1a NS5A does not predict responsiveness to IFN- alpha . Differences in early kinetics during combination therapy are not due to selection of IFN-resistant HCV strains.

According to the now classical basal ganglia-thalamocortical circuitry model, the chorea of Huntington's disease (HD) and the hypokinesia in Parkinson's disease (PD) are explained by a decrease in the inhibitory output (reduced firing rates) from the globus pallidus internus (GPi) in HD and increased output in PD. Differences between firing patterns might also be a factor contributing to the different symptoms, however. To test the predictions of the model we examined neuronal firing rates and patterns in two HD patients and 14 PD patients. Single-cell, microelectrode recordings were obtained from awake patients undergoing stereotactic surgery for implantation of deep brain stimulating (DBS) electrodes in the GPi. The mean neuronal firing rate in the GPi of HD patients was 81.8+/-4.3 Hz (mean+/-SEM), which was not significantly different from that in PD patients (89.9+/-3.0 Hz). Firing pattern analyses using measurements of burst index, coefficient of variation, and percentage participation of spikes in bursts revealed, however, that GPi neurons in HD patients fired in a more regular pattern (fewer \"bursts\") than in PD patients. These results suggest that the rate-based model does not adequately explain the motor abnormalities present in the two HD patients studied. Furthermore, the findings did reveal a difference between firing patterns in the HD and PD groups, thereby supporting the role of altered firing patterns in the pathophysiology of these diseases.

Users of compact smart products with small screens often have trouble learning the menu structure. If they cannot master the menu structure, users are not able to fully utilize the products. It is argued in this paper that using visual momentum in menu representation design helps users develop effective mental maps of menu structures and promotes learning of the user interface. To assess the effect of visual momentum in this study, four types of menu representations were developed. Additionally, two menu hierarchies, two types of function key layout, and two types of function key labeling were assessed to examine the effects of menu dimension and compatibility. Experimental results indicated that participants using a partial menu map with visual momentum design performed the best, and participants using a partial menu map without visual momentum performed the poorest, even worse than those-using command-only representation. The results also showed that the menu navigation problem appeared to be particularly significant with a deep menu hierarchy. Actual or potential applications of this research include menu representation design for compact smart products.

This is the second paper of a three-part series which discusses total quality management (TQM) implementation in a service context. While Part I covers the implementation of TQM in financial services by analysing three case studies, Part II covers three case studies in higher education. Commonly reported benefits from the three cases have been pulled out.