Alpha-1-acid glycoprotein as potential biomarker for alpha-fetoprotein-low hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of late diagnosis. We determined the performances of α -1-acid glycoprotein (AAG) and des-γ-carboxy prothrombin (DCP) for the diagnosis of HCC, especially for α-fetoprotein (AFP)-low HCC.</p> <p>Methods</p> <p>Of the 220 patients included in this retrospective study, 124 had HCC, and 61 (49%) of these were AFP-low HCC (AFP ≤ 20 ng/mL). The remaining 96 patients, including 49 with chronic hepatitis B or C and 47 with cirrhosis, were considered as control. Plasma AAG was analyzed using high performance liquid chromatography (HPLC) and confirmed using Western blot technique.</p> <p>Results</p> <p>When all patients with HCC were evaluated, the area under receiver operating characteristic (ROC) curves for AAG (0.94, 95% CI: 0.91-0.97) and DCP (0.92, 95% CI: 0.88-0.95) were similar (<it>P </it>= 0.40). AAG had better area under ROC curve (0.96, 95% CI: 0.94-0.99) than DCP (0.87, 95% CI: 0.81-0.93) for AFP-low HCC (<it>P </it>< 0.05). At the specificity 95%, the sensitivity of AAG was higher in AFP-low HCC than in AFP-high HCC (82% and 62%, respectively). In contrast, higher sensitivity was obtained from DCP in discriminating HCC patients with low AFP than that in high AFP (57% and 90%, respectively).</p> <p>Conclusion</p> <p>Our cross-sectional study showed that AAG was better performance in diagnosing HCC patients with low AFP, while DCP did better in those with high AFP.</p

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Agreement between pedometer and accelerometer in measuring physical activity in overweight and obese pregnant women

<p>Abstract</p> <p>Background</p> <p>Inexpensive, reliable objective methods are needed to measure physical activity (PA) in large scale trials. This study compared the number of pedometer step counts with accelerometer data in pregnant women in free-living conditions to assess agreement between these measures.</p> <p>Methods</p> <p>Pregnant women (n = 58) with body mass index ≥25 kg/m²at median 13 weeks' gestation wore a GT1M Actigraph accelerometer and a Yamax Digi-Walker CW-701 pedometer for four consecutive days. The Spearman rank correlation coefficients were determined between pedometer step counts and various accelerometer measures of PA. Total agreement between accelerometer and pedometer step counts was evaluated by determining the 95% limits of agreement estimated using a regression-based method. Agreement between the monitors in categorising participants as active or inactive was assessed by determining Kappa.</p> <p>Results</p> <p>Pedometer step counts correlated moderately (r = 0.36 to 0.54) with most accelerometer measures of PA. Overall step counts recorded by the pedometer and the accelerometer were not significantly different (medians 5961 vs. 5687 steps/day, p = 0.37). However, the 95% limits of agreement ranged from -2690 to 2656 steps/day for the mean step count value (6026 steps/day) and changed substantially over the range of values. Agreement between the monitors in categorising participants to active and inactive varied from moderate to good depending on the criteria adopted.</p> <p>Conclusions</p> <p>Despite statistically significant correlations and similar median step counts, the overall agreement between pedometer and accelerometer step counts was poor and varied with activity level. Pedometer and accelerometer steps cannot be used interchangeably in overweight and obese pregnant women.</p

Population analysis of vitamin D receptor polymorphisms and the role of genetic ancestry in an admixed population

The vitamin D receptor (VDR) is an essential protein related to bone metabolism. Some VDR alleles are differentially distributed among ethnic populations and display variable patterns of linkage disequilibrium (LD). In this study, 200 unrelated Brazilians were genotyped using 21 VDR single nucleotide polymorphisms (SNPs) and 28 ancestry informative markers. The patterns of LD and haplotype distribution were compared among Brazilian and the HapMap populations of African (YRI), European (CEU) and Asian (JPT+CHB) origins. Conditional regression and haplotype-specific analysis were performed using estimates of individual genetic ancestry in Brazilians as a quantitative trait. Similar patterns of LD were observed in the 5′ and 3′ gene regions. However, the frequency distribution of haplotype blocks varied among populations. Conditional regression analysis identified haplotypes associated with European and Amerindian ancestry, but not with the proportion of African ancestry. Individual ancestry estimates were associated with VDR haplotypes. These findings reinforce the need to correct for population stratification when performing genetic association studies in admixed populations

GOLPH2 protein expression as a novel tissue biomarker for prostate cancer: implications for tissue-based diagnostics

GOLPH2 is coding the 73-kDa type II Golgi membrane antigen GOLPH2/GP73. Upregulation of GOLPH2 mRNA has been recently reported in expression array analyses of prostate cancer. As GOLPH2 protein expression in prostate tissues is currently unknown, this study aimed at a comprehensive analysis of GOLPH2 protein in benign and malignant prostate lesions. Immunohistochemically detected GOLPH2 protein expression was compared with the basal cell marker p63 and the prostate cancer marker α-methylacyl-CoA racemase (AMACR) in 614 radical prostatectomy specimens. GOLPH2 exhibited a perinuclear Golgi-type staining pattern and was preferentially seen in prostatic gland epithelia. Using a semiquantitative staining intensity score, GOLPH2 expression was significantly higher in prostate cancer glands compared with normal glands (P<0.001). GOLPH2 protein was upregulated in 567 of 614 tumours (92.3%) and AMACR in 583 of 614 tumours (95%) (correlation coefficient 0.113, P=0.005). Importantly, GOLPH2 immunohistochemistry exhibited a lower level of intratumoral heterogeneity (25 vs 45%). Further, GOLPH2 upregulation was detected in 26 of 31 (84%) AMACR-negative prostate cancer cases. These data clearly suggest GOLPH2 as an additional ancillary positive marker for tissue-based diagnosis of prostate cancer

Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis

The consequences of delaying insulin initiation in UK type 2 diabetes patients failing oral hyperglycaemic agents: a modelling study

<p>Abstract</p> <p>Background</p> <p>Recent data have shown that type 2 diabetes patients in the UK delay initiating insulin on average for over 11 years after first being prescribed an oral medication. Using a published computer simulation model of diabetes we used UK-specific data to estimate the clinical consequences of immediately initiating insulin versus delaying initiation for periods in line with published estimates.</p> <p>Methods</p> <p>In the base case scenario simulated patients, with characteristics based on published UK data, were modelled as either initiating insulin immediately or delaying for 8 years. Clinical outcomes in terms of both life expectancy and quality-adjusted life expectancy and also diabetes-related complications (cumulative incidence and time to onset) were projected over a 35 year time horizon. Treatment effects associated with insulin use were taken from published studies and sensitivity analyses were performed around time to initiation of insulin, insulin efficacies and hypoglycaemia utilities.</p> <p>Results</p> <p>For patients immediately initiating insulin there were increases in (undiscounted) life expectancy of 0.61 years and quality-adjusted life expectancy of 0.34 quality-adjusted life years versus delaying initiation for 8 years. There were also substantial reductions in cumulative incidence and time to onset of all diabetes-related complications with immediate versus delayed insulin initiation. Sensitivity analyses showed that a reduced delay in insulin initiation or change in insulin efficacy still demonstrated clinical benefits for immediate versus delayed initiation.</p> <p>Conclusion</p> <p>UK type 2 diabetes patients are at increased risk of a large number of diabetes-related complications due to an unnecessary delay in insulin initiation. Despite clear guidelines recommending tight glycaemic control this failure to begin insulin therapy promptly is likely to result in needlessly reduced life expectancy and compromised quality of life.</p