Clinical significance of serum vascular cell adhesion molecule-1 levels in patients with hepatocellular carcinoma

Aim: To evaluate the correlation between serum vascular cellular adhesion molecule-1 (VCAM-1) levels and clinicopathological features in patients with hepatocellular carcinoma (HCC). Methods: Ninety-six patients who underwent HCC resection were recruited in the study. Preoperative serum levels of soluble VCAM-1 were measured by enzyme-linked immunosorbent assay. Results: Serum VCAM-1 level in HCC patients was inversely correlated with platelet count (r=-0.431, P<0.001) and serum albumin level (r=-0.279, P<0.001), and positively correlated with serum bilirubin level (r=-0.379, P<0.001). Serum VCAM-1 level was not associated with tumor characteristics such as tumor size, venous invasion, presence of microsatellite nodules, tumor grade and tumor stage. Serum VCAM-1 level was significantly higher in HCC patients with cirrhosis compared with those without cirrhosis (median 704 vs 546 ng/mL, P<0.001). Furthermore, a significantly better disease-free survival was observed in HCC patients with low VCAM-1 level (P=0.019). Conclusion: Serum VCAM-1 level appears to reflect the severity of underlying chronic liver disease rather than the tumor status in HCC patients, and low preoperative serum VCAM-1 level is predictive of better disease-free survival after surgery. Copyright © 2004 by The WJG Press.published_or_final_versio

Clinicopathological and prognostic implications of endoglin (CD105) expression in hepatocellular carcinoma and its adjacent non-tumorous liver

Aim: The expression pattern of endoglin (CD105) in hepatocellular carcinoma (HCC) has not been reported so far. We hypothesized that CD105 could differentially highlight a subset of microvessels in HCC, and intratumoral microvessel density (IMVD) by CD105 immunostaining (IMVD-CD105) could provide better prognostic information than IMVD by CD34 immunostaining (IMVD-CD34). Methods: Paraffin blocks of tumor and adjacent non-tumorous liver tissues from 86 patients who underwent curative resection of HCC were used for this study. Serial sections were stained for CD105 and CD34, respectively, to highlight the microvessels. IMVD was counted according to a standard protocol. Results: In the HCC tissues, CD105 was either negatively or positively stained only in a subset of microvessels. In contrast, CD34 showed positive and more extensive microvessel staining in all cases examined. However, in the adjacent non-tumorous liver sections, CD105 showed a diffuse pattern of microvessel staining in 20 of 86 cases, while CD34 showed negative or only focal staining of the sinusoids around portal area. Correlation with clinicopathological data demonstrated that lower scores of IMVD-CD105 were found in larger sized tumors [mean 41.4/0.74 mm 2 (>5 cm tumor) vs 65.9/0.74 mm 2 (≤5 cm tumor), P = 0.043] and more aggressive tumors, as indicated by venous infiltration [36.8/0.74 mm 2 (present) vs 64.2/0.74 mm 2 (absent), P = 0.020], microsatellite nodules [35.1/0.74 mm 2 (present) vs 65.9/0.74 mm 2 (absent), P = 0.012], and advanced TNM tumor stage [38.8/0.74 mm 2 (stage 3 or 4) vs 68.3/0.74 mm 2 (stage 1 or 2), P = 0.014]. No prognostic significance was observed when median values were used as cut-off points using either IMVD-CD105 or IMVD-CD34. However, the presence of the diffuse pattern of CD105 expression in the adjacent non-tumorous liver tissues predicted a poorer disease-free survival (median 8.6 vs 21.5 mo, P = 0.026). Conclusion: Our data demonstrate that a lower IMVD-CD105 is associated with larger and more aggressive tumors. In this study, IMVD-CD105 did not provide significant prognostic information. However, active angiogenesis as highlighted by diffuse CD105 staining of the microvessels in the adjacent non-tumorous liver tissues is predictive of early recurrence. © 2005 The WJG Press and Elsevier Inc. All rights reserved.published_or_final_versio

SUMO chain formation is required for response to replication arrest in S. pombe

SUMO is a ubiquitin-like protein that is post-translationally attached to one or more lysine residues on target proteins. Despite having only 18% sequence identity with ubiquitin, SUMO contains the conserved betabetaalphabetabetaalphabeta fold present in ubiquitin. However, SUMO differs from ubiquitin in having an extended N-terminus. In S. pombe the N-terminus of SUMO/Pmt3 is significantly longer than those of SUMO in S. cerevisiae, human and Drosophila. Here we investigate the role of this N-terminal region. We have used two dimensional gel electrophoresis to demonstrate that S. pombe SUMO/Pmt3 is phosphorylated, and that this occurs on serine residues at the extreme N-terminus of the protein. Mutation of these residues (in pmt3-1) results in a dramatic reduction in both the levels of high Mr SUMO-containing species and of total SUMO/Pmt3, indicating that phosphorylation of SUMO/Pmt3 is required for its stability. Despite the significant reduction in high Mr SUMO-containing species, pmt3-1 cells do not display an aberrant cell morphology or sensitivity to genotoxins or stress. Additionally, we demonstrate that two lysine residues in the N-terminus of S. pombe SUMO/Pmt3 (K14 and K30) can act as acceptor sites for SUMO chain formation in vitro. Inability to form SUMO chains results in aberrant cell and nuclear morphologies, including stretched and fragmented chromatin. SUMO chain mutants are sensitive to the DNA synthesis inhibitor, hydroxyurea (HU), but not to other genotoxins, such as UV, MMS or CPT. This implies a role for SUMO chains in the response to replication arrest in S. pomb

Treatment of rising damp in historical buildings: wall base ventilation

Intervention in older buildings increasingly requires extensive and objective knowledge of what one will be working with. The multifaceted aspect of work carried out on buildings tends to encompass a growing number of specialities, with marked emphasis on learning the causes of many of the problems that affect these buildings and the possible treatments that can solve them. Moisture transfer in walls of old buildings, which are in direct contact with the ground, leads to a migration of soluble salts responsible for many building pathologies.http://www.sciencedirect.com/science/article/B6V23-4H7T0H7-1/1/f5e8a4ec173c5dadf120770678facf4

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Decadal prediction of the North Atlantic subpolar gyre in the HiGEM high-resolution climate model

This paper presents an analysis of initialised decadal hindcasts of the North Atlantic subpolar gyre (SPG) using the HiGEM model, which has a nominal grid-spacing of 90 km in the atmosphere, and 1/3 ∘∘ in the ocean. HiGEM decadal predictions (HiGEM-DP) exhibit significant skill at capturing 0–500 m ocean heat content in the SPG, and outperform historically forced transient integrations and persistence for up to a decade ahead. An analysis of case-studies of North Atlantic decadal change, including the 1960s cooling, the mid-1990s warming, and the post-2005 cooling, show that changes in ocean circulation and heat transport dominate the predictions of the SPG. However, different processes are found to dominate heat content changes in different regions of the SPG. Specifically, ocean advection dominates in the east, but surface fluxes dominate in the west. Furthermore, compared to previous studies, we find a smaller role for ocean heat transport changes due to ocean circulation anomalies at the latitudes of the SPG, and, for the 1960s cooling, a greater role for surface fluxes. Finally, HiGEM-DP predicts the observed positive state of the North Atlantic Oscillation in the early 1990s. These results support an important role for the ocean in driving past changes in the North Atlantic region, and suggest that these changes were predictable

The effect of acute vs chronic magnesium supplementation on exercise and recovery on resistance exercise, blood pressure and total peripheral resistance on normotensive adults

© 2015 Kass and Poeira; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Magnesium supplementation has previously shown reductions in blood pressure of up to 12 mmHg. A positive relationship between magnesium supplementation and performance gains in resistance exercise has also been seen. However, no previous studies have investigated loading strategies to optimise response. The aim of this study was to assess the effect of oral magnesium supplementation on resistance exercise and vascular response after intense exercise for an acute and chronic loading strategy on a 2-day repeat protocol. Methods: The study was a randomised, double-blind, cross-over design, placebo controlled 2 day repeat measure protocol (n = 13). Intense exercise (40 km time trial) was followed by bench press at 80% 1RM to exhaustion, with blood pressure and total peripheral resistance (TPR) recorded. 300 mg/d elemental magnesium was supplemented for either a 1 (A) or 4 (Chr) week loading strategy. Food diaries were recorded. Results: Dietary magnesium intake was above the Reference Nutrient Intake (RNI) for all groups. Bench press showed a significant increase of 17.7% (p = 0.031) for A on day 1. On day 2 A showed no decrease in performance whilst Chr showed a 32.1% decrease. On day 2 post-exercise systolic blood pressure (SBP) was significantly lower in both A (p = 0.0.47) and Chr (p = 0.016) groups. Diastolic blood pressure (DBP) showed significant decreases on day 2 solely for A (p = 0.047) with no changes in the Chr. TPR reduced for A on days 1 and 2 (p = 0.031) with Chr showing an increase on day 1 (p = 0.008) and no change on day 2. Conclusion: There was no cumulative effect of Chr supplementation compared to A. A group showed improvement for bench press concurring with previous research which was not seen in Chr. On day 2 A showed a small non-significant increase but not a decrement as expected with Chr showing a decrease. DBP showed reductions in both Chr and A loading, agreeing with previous literature. This is suggestive of a different mechanism for BP reduction than for muscular strength. TPR showed greater reductions with A than Chr, which would not be expected as both interventions had reductions in BP, which is associated with TPR.Peer reviewedFinal Published versio

TonEBP/NFAT5 promotes obesity and insulin resistance by epigenetic suppression of white adipose tissue beiging

Tonicity-responsive enhancer binding protein (TonEBP or NFAT5) is a regulator of cellular adaptation to hypertonicity, macrophage activation and T-cell development. Here we report that TonEBP is an epigenetic regulator of thermogenesis and obesity. In mouse subcutaneous adipocytes, TonEBP expression increases &gt; 50-fold in response to high-fat diet (HFD) feeding. Mice with TonEBP haplo-deficiency or adipocyte-specific TonEBP deficiency are resistant to HFD-induced obesity and metabolic defects (hyperglycemia, hyperlipidemia, and hyperinsulinemia). They also display increased oxygen consumption, resistance to hypothermia, and beiging of subcutaneous fat tissues. TonEBP suppresses the promoter of beta 3-adrenoreceptor gene, a critical regulator of lipolysis and thermogenesis, in ex vivo and cultured adipocytes. This involves recruitment of DNMT1 DNA methylase and methylation of the promoter. In human subcutaneous adipocytes TonEBP expression displays a correlation with body mass index but an inverse correlation with beta 3-adrenoreceptor expression. Thus, TonEBP is an attractive therapeutic target for obesity, insulin resistance, and hyperlipidemia

Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability

Long-term, high frequency in situ measurements of intertidal mussel bed temperatures using biomimetic sensors

At a proximal level, the physiological impacts of global climate change on ectothermic organisms are manifest as changes in body temperatures. Especially for plants and animals exposed to direct solar radiation, body temperatures can be substantially different from air temperatures. We deployed biomimetic sensors that approximate the thermal characteristics of intertidal mussels at 71 sites worldwide, from 1998-present. Loggers recorded temperatures at 10-30 min intervals nearly continuously at multiple intertidal elevations. Comparisons against direct measurements of mussel tissue temperature indicated errors of similar to 2.0-2.5 degrees C, during daily fluctuations that often exceeded 15 degrees-20 degrees C. Geographic patterns in thermal stress based on biomimetic logger measurements were generally far more complex than anticipated based only on 'habitat-level' measurements of air or sea surface temperature. This unique data set provides an opportunity to link physiological measurements with spatially-and temporally-explicit field observations of body temperature