Citations

Hyperphosphorylation and aggregation of tau are observed in multiple neurodegenerative diseases termed tauopathies. Tau has also been implicated in the pathogenesis of Parkinson's disease (PD) and parkinsonisms. Some PD patients with mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene exhibit tau pathology. Mutations in LRRK2 are a major risk factor for PD, but LRRK2 protein function remains unclear. The most common mutation, G2019S, is located in the kinase domain of LRRK2 and enhances kinase activity in vitro. This suggests that the kinase activity of LRRK2 may underlie its cellular toxicity. Recently, in vitro studies have suggested a direct interaction between tubulin‐bound tau and LRRK2 that results in tau phosphorylation at one identified site. Here we present data suggesting that microtubules (MTs) enhance LRRK2‐mediated tau phosphorylation at three different epitopes. We also explore the effect of divalent cations as catalytic cofactors for G2019S LRRK2‐mediated tau phosphorylation and show that manganese does not support kinase activity but inhibits the efficient ability of magnesium to catalyze LRRK2‐mediated phosphorylation of tau. These results suggest that cofactors such as MTs and cations in the cellular milieu have an important impact on LRRK2‐tau interactions and resultant tau phosphorylation. © 2015 Wiley Periodicals, Inc.

Circulating tumor cells (CTCs) in blood are associated with poor survival of patients with breast, prostate, or colon cancer. We hypothesized that CTCs are associated with poor survival of patients with cholangiocarcinoma (CCA). Eighty‐eight patients with CCA were prospectively enrolled at Mayo Clinic Rochester between June 2010 and September 2014. The CellSearch system by Veridex was used for detection of CTCs in peripheral blood. Associations between CTC, patient and tumor characteristics, and survival were examined using the Cox's proportional hazards model. Fifteen patients (17%) were positive for CTC ≥2 and 8 patients (9%) for CTC ≥5. CTCs were associated with tumor extent. CTC ≥2 (hazard ratio [HR]: 2.5; 95% confidence interval [CI]: 1.1‐5.4; P = 0.02) and CTC ≥5 (HR, 4.1; 95% CI: 1.4‐10.8; P = 0.01) were both independent predictors of survival. In subgroup analyses, CTC ≥2 (HR, 8.2; 95% CI: 1.8‐57.5; P < 0.01) and CTC ≥5 (HR, 7.7; 95% CI: 1.4‐42.9; P = 0.02) were both associated with shorter survival among patients with metastasis. There was a trend toward association of CTC ≥5 with shorter survival in patients with nonmetastatic CCA (HR, 4.3; 95% CI: 1.0‐13.8; P = 0.06). CTC ≥2 (HR, 10.5; 95% CI: 2.2‐40.1; P < 0.01) and CTC ≥5 (HR, 10.2; 95% CI: 1.5‐42.3; P = 0.02) were both associated with shorter survival among patients with perihilar/distal CCA. CTC ≥5 was associated with shorter survival of patients with intrahepatic CCA (HR, 4.2; 95% CI: 1.1‐14.1; P = 0.04). Conclusion: CTCs were associated with more‐aggressive tumor characteristics and independently associated with survival in patients with CCA. Assessment of CTCs may be useful for identifying CCA patients at risk of early mortality. (Hepatology 2016;63:148–158)

Abstract BACKGROUND Initial reports suggest that concentrations of high-sensitivity cardiac troponin T (hs-cTnT) (Roche Diagnostics Elecsys®) below the limit of blank (LoB) (3 ng/L) or limit of detection (LoD) (5 ng/L) of the assay have almost 100% negative predictive value (NPV) for acute myocardial infarction (AMI), particularly among patients without electrocardiograph (ECG) evidence of ischemia. We aimed to prospectively validate those findings. METHODS We included adults presenting to the emergency department with suspected cardiac chest pain. Standard troponin T (cTnT) and hs-cTnT (both Roche Elecsys) were tested in samples drawn on arrival. The primary outcome was AMI, adjudicated by 2 investigators on the basis of clinical data and ≥12-h cTnT testing. We also evaluated diagnostic performance when AMI was readjudicated on the basis of hs-cTnT (≥12-h) concentrations. RESULTS Of 463 patients included, 79 (17.1%) had AMI. Twenty-four patients (5.2%) had hs-cTnT concentrations below the LoB, although none had AMI. Ninety-six patients (20.7%) had hs-cTnT concentrations below the LoD, 1 of whom had AMI. Thus, diagnostic sensitivity was 98.7% (95% CI 87.5%–98.6%) and NPV was 99.0% (95% CI 94.3%–100.0%). Of the 17.3% (n = 80) patients with hs-cTnT below the LoD and no ECG ischemia, none had AMI. Thus, diagnostic sensitivity was 100.0% (95% CI 95.4%–100.0%) and NPV was 100.0% (95% CI 95.5%–100.0%). Sensitivity and NPV were maintained when AMI was readjudicated on the basis of hs-cTnT. CONCLUSIONS Our findings confirm that patients with nonischemic ECG and undetectable hs-cTnT at presentation have a very low probability of AMI, although the proportion of patients affected was smaller than in previous research.

Background— Early studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction. Methods and Results— A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (−0.29±0.28 mm Hg/mL versus +0.02±0.29, P =0.008) and tended to improve reactive hyperemia index (+0.30±0.45 versus −0.17±0.30, P =0.054). In contrast, left ventricular contractility was reduced by 11% to 16% with sildenafil compared with placebo (ΔPWR/EDV −52±70 versus +0±40 mm Hg/s, P =0.006; ΔSW/EDV +0.3±5.8 versus −6.0±5.1 mm Hg, P =0.04). Sildenafil had no effect on pulmonary artery systolic pressure. Conclusions— In subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00094302.

Growing evidence suggests that pretransplant alpha‐fetoprotein (AFP) predicts outcomes of hepatocellular carcinoma (HCC) patients treated with liver transplantation. We aimed to determine whether pretransplant AFP, Lens culinaris agglutinin‐reactive alpha‐fetoprotein (AFP‐L3), and des‐gamma‐carboxyprothrombin (DCP) predicted HCC recurrence after transplantation. A retrospective cohort study of 313 HCC patients undergoing transplantation between 2000 and 2008 was conducted, and 48 (15.3%) developed recurrence during a median follow‐up of 90.8 months. The 127 patients with available serum drawn before transplantation were included; they included 86 without recurrence and 41 with recurrence. Serum was tested for AFP, AFP‐L3%, and DCP in a blinded fashion with the μTASWako i30 immunoanalyzer. All biomarkers were significantly associated with HCC recurrence. The hazard ratios (HRs) were 3.5 [95% confidence interval (CI), 1.9‐6.7; P < 0.0001] for DCP ≥ 7.5 ng/mL and 2.8 (95% CI, 1.4‐5.4; P = 0.002) for AFP ≥ 250 ng/mL. The HR increased to 5.2 (95% CI, 2.3‐12.0; P < 0.0001) when AFP ≥ 250 ng/mL and DCP ≥7.5 ng/mL were considered together. When they were combined with the Milan criteria, the HR increased from 2.6 (95% CI, 1.4‐4.7; P = 0.003) for outside the Milan criteria to 8.6 (95% CI, 3.0‐24.6; P < 0.0001) for outside the Milan criteria and AFP ≥ 250 ng/mL and to 7.2 (95% CI, 2.8‐18.1; P < 0.0001) for outside the Milan criteria and DCP ≥7.5 ng/mL. Our findings suggest that biomarkers are useful for predicting the risk of HCC recurrence after transplantation. Using both biomarkers and the Milan criteria may be better than using the Milan criteria alone in optimizing the decision of liver transplantation eligibility. Liver Transpl 21:599–606, 2015. © 2015 AASLD.

Abstract Background & Aims Hepatocellular carcinoma ( HCC ) is the second most common cause of cancer deaths worldwide. The global HCC BRIDGE study was a multiregional, large‐scale, longitudinal cohort study undertaken to improve understanding of real‐life management of patients with HCC , from diagnosis to death. Methods Data were collected retrospectively from January 2005 to September 2012 by chart reviews of eligible patients newly diagnosed with HCC at participating institutions. Results Forty‐two sites in 14 countries contributed final data for 18 031 patients. Asia accounted for 67% of patients, Europe for 20% and North America for 13%. As expected, the most common risk factor was hepatitis C virus in North America, Europe and Japan, and hepatitis B virus in China, South Korea and Taiwan. The most common Barcelona Clinic Liver Cancer stage at diagnosis was C in North America, Europe, China and South Korea, and A in Taiwan and Japan. Across all stages, first HCC treatment was most frequently transarterial chemoembolization in North America, Europe, China and South Korea, percutaneous ethanol injection or radiofrequency ablation in Japan and resection in Taiwan. Survival from first HCC treatment varied significantly by region, with median overall survival not reached for Taiwan and 60, 33, 31, 24 and 23 months for Japan, North America, South Korea, Europe and China respectively ( P < 0.0001). Conclusions Initial results from the BRIDGE study confirm previously reported regional trends in patient demographic characteristics and HCC risk factors, document the heterogeneity of treatment approaches across regions/countries and underscore the need for earlier HCC diagnosis worldwide.

Current guidelines recommend surgical resection as the primary treatment for a single hepatocellular cancer (HCC) with Child's A cirrhosis, normal serum bilirubin, and no clinically significant portal hypertension. We determined how frequently guidelines were followed and whether straying from them impacted survival. BRIDGE is a multiregional cohort study including HCC patients diagnosed between January 1, 2005 and June 30, 2011. A total of 8,656 patients from 20 sites were classified into four groups: (A) 718 ideal resection candidates who were resected; (B) 144 ideal resection candidates who were not resected; (C) 1,624 nonideal resection candidates who were resected; and (D) 6,170 nonideal resection candidates who were not resected. Median follow‐up was 27 months. Log‐rank and Cox's regression analyses were conducted to determine differences between groups and variables associated with survival. Multivariate analysis of all ideal candidates for resection (A+B) revealed a higher risk of mortality with treatments other than resection. For all resected patients (A+C), portal hypertension and bilirubin >1 mg/dL were not associated with mortality. For all patients who were not ideal candidates for resection (C+D), resection was associated with better survival, compared to embolization and “other” treatments, but was inferior to ablation and transplantation. Conclusions : The majority of patients undergoing resection would not be considered ideal candidates based on current guidelines. Not resecting ideal candidates was associated with higher mortality. The study suggests that selection criteria for resection may be modestly expanded without compromising outcomes, and that some nonideal candidates may still potentially benefit from resection over other treatment modalities. (H epatology 2015;62:440–451