Retrospective studies have shown that two-dimensional magnetic resonance elastography (2D-MRE), a novel MR method for assessment of liver stiffness, correlates with advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Prospective data on diagnostic accuracy of 2D-MRE in the detection of advanced fibrosis in NAFLD are needed. The aim of this study is to prospectively assess the diagnostic accuracy of 2D-MRE, a noninvasive imaging biomarker, in predicting advanced fibrosis (stage 3 or 4) in well-characterized patients with biopsy-proven NAFLD. This is a cross-sectional analysis of a prospective study including 117 consecutive patients (56% women) with biopsy-proven NAFLD who underwent a standardized research visit: history, exam, liver biopsy assessment (using the nonalcoholic steatohepatitis Clinical Research Network histological scoring system), and 2D-MRE from 2011 to 2013. The radiologist and pathologist were blinded to clinical and pathology/imaging data, respectively. Receiver operating characteristics (ROCs) were examined to assess the diagnostic test performance of 2D-MRE in predicting advanced fibrosis. The mean (± standard deviation) of age and body mass index was 50.1 (± 13.4) years and 32.4 (± 5.0) kg/m2, respectively. The median time interval between biopsy and 2D-MRE was 45 days (interquartile range: 50 days). The number of patients with fibrosis stages 0, 1, 2, 3, and 4 was 43, 39, 13, 12, and 10, respectively. The area under the ROC curve for 2D-MRE discriminating advanced fibrosis (stage 3-4) from stage 0-2 fibrosis was 0.924 (P < 0.0001). A threshold of >3.63 kPa had a sensitivity of 0.86 (95% confidence interval [CI]: 0.65-0.97), specificity of 0.91 (95% CI: 0.83-0.96), positive predictive value of 0.68 (95% CI: 0.48-0.84), and negative predictive value of 0.97 (95% CI: 0.91-0.99). Conclusions: MRE is accurate in predicting advanced fibrosis and may be utilized for noninvasive diagnosis of advanced fibrosis in patients with NAFLD. (Hepatology 2014;60:1920–1928)

Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging-derived proton density-fat fraction (MRI-PDFF) and liver histology in patients with biopsy-proven NASH. In this randomized, double-blind, placebo-controlled trial, 50 patients with biopsy-proven NASH were randomized to either ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two-dimensional and three-dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI-PDFF (mean difference between the ezetimibe and placebo arms -1.3%, P = 0.4). Compared to baseline, however, end-of-treatment MRI-PDFF was significantly lower in the ezetimibe arm (15%-11.6%, P < 0.016) but not in the placebo arm (18.5%-16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two-dimensional and three-dimensional magnetic resonance elastography-derived liver stiffness between the ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI-PDFF (-4.35 ± 4.9% versus -0.30 ± 4.1%, P < 0.019). Conclusions: Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI-PDFF-derived fat maps and magnetic resonance elastography-derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH. (Hepatology 2015;61:1239–1250)

ATP-dependent chromatin remodeling by the CHD family of proteins plays an important role in the regulation of gene transcription. Here we report that full-length CHD8 interacts directly with ␤-catenin and that CHD8 is also recruited specifically to the promoter regions of several ␤-catenin-responsive genes. Our results indicate that CHD8 negatively regulates ␤-catenin-targeted gene expression, since short hairpin RNA against CHD8 results in the activation of several ␤-catenin target genes. This regulation is also conserved through evolution; RNA interference against kismet, the apparent Drosophila ortholog of CHD8, results in a similar activation of ␤-catenin target genes. We also report the first demonstration of chromatin remodeling activity for a member of the CHD6-9 family of proteins, suggesting that CHD8 functions in transcription through the ATP-dependent modulation of chromatin structure.The alteration of chromatin structure provides a key regulatory step for all processes that act upon DNA (41). The factors that regulate this structure, commonly referred to as chromatin remodeling enzymes, can be grouped into two broad categories: complexes that alter chromatin structure via the covalent modification of histones (25,42,83) and complexes that use the energy of ATP hydrolysis to alter the structure or position of the nucleosome (6,47,57,67).ATP-dependent chromatin remodeling enzymes modulate the contacts between histones and DNA. In vitro, these enzymes catalyze structural changes that allow factors to access nucleosomal DNA, reposition nucleosomes on a template, transfer histone octamers to donor DNA, and replace histones with histone variants (27,43,80). In vivo, these activities are crucial for transcription, replication, repair, and recombination of the eukaryotic genome (2,21,59,65). These remodeling enzymes can be divided into numerous families based on domain architecture. One such family is the CHD (chromodomain, helicase, DNA binding) group of proteins, which are critical regulators of chromatin structure (23,26,29,49). These enzymes are characterized by tandem chromodomains N-terminal to their catalytic Snf2 helicase domain.The CHD family can be further subdivided into three subfamilies: CHD1-2, CHD3-5, and CHD6-9. While the first two subfamilies have been extensively studied, very little is known about the CHD6-9 family (29, 49). Previous studies have indicated that CHD8 may regulate the Wnt signaling pathway, since an N-terminal fragment of CHD8 was previously identified as a protein in Rattus norvegicus that binds ␤-catenin both in vivo and in vitro (61). This N-terminal fragment, termed Duplin, contains only the chromodomains and lacks the Snf2 helicase domain and C-terminal sequences. Overexpression of this N-terminal fragment results in inhibition of Tcf4-dependent transcription, and studies of Xenopus embryos demonstrated that this fragment inhibited axis formation and ␤-catenin-mediated axis duplication (61).The "canonical" Wnt signaling pathway functions by controlling the soluble pool ...

Objective Recent studies show two-dimensional (2D)-MRE is accurate in diagnosing advanced fibrosis (stages 3 and 4) in nonalcoholic fatty liver disease (NAFLD) patients. 3D-MRE is a more advanced version of the technology that can image shear-wave fields in 3D of the entire liver. The aim of this study was to prospectively compare the diagnostic accuracy of 3D-MRE and 2D-MRE for diagnosing advanced fibrosis in patients with biopsy-proven NAFLD. Design This cross-sectional analysis of a prospective study included 100 consecutive patients (56% women) with biopsy-proven NAFLD who also underwent MRE. Area under the receiver operating characteristic (AUROC) ana3lysis was performed to assess the accuracy of 2D and 3D-MRE in diagnosing advanced fibrosis. Results The mean (±sd) of age and BMI was 50.2 (±13.6) yrs and 32.1 (±5.0) kg/m2, respectively. The AUROC for diagnosing advanced fibrosis was 0.981 for 3D-MRE at 40 Hz, 0.927 for 3D-MRE at 60 Hz (standard shear-wave frequency), and 0.921 for 2D-MRE at 60 Hz (standard shear-wave frequency). At a threshold of 2.43 kPa, 3D-MRE at 40 Hz had sensitivity 1.0, specificity 0.94, positive predictive value 0.72, and negative predictive value 1.0 for diagnosing advanced fibrosis. 3D-MRE at 40 Hz had significantly higher AUROC (p<0.05) than 2D-MRE at 60 Hz for diagnosing advanced fibrosis. Conclusion Utilizing a prospective study design, we demonstrate that 3D MRE at 40 Hz has the highest diagnostic accuracy in diagnosing NAFLD advanced fibrosis. Both 2D and 3D-MRE at 60 Hz, the standard shear-wave frequency, are also highly accurate in diagnosing NAFLD advanced fibrosis.

BACKGROUND:The distinction of benign from malignant mesothelial proliferations in cytologic specimens can be problematic. In this study, the authors investigated the utility of immunohistochemical (IHC) markers in making this distinction. METHODS: Archival paraffin-embedded cell blocks of pleural and peritoneal fluids from 52 patients with malignant meothelioma (MM) and 64 patients with reactive mesothelial hyperplasia (MH) were retrieved. IHC stains included desmin, epithelial membrane antigen (EMA), glucose-transport protein 1 (GLUT-1), Ki67, and p53. RESULTS: Desmin was positive in 84% (54 of 64) cases of reactive MH and in 6% (3 of 52) of MM cases (P < .001). EMA was positive in 9% (6 of 64) of benign and 100% (52 of 52) of malignant cases (P < .001). GLUT-1 was positive in 12% (5 of 43) of benign and 47% (7 of 15) of malignant cases. Ki67 showed strong nuclear positivity in >40% of mesothelial cells in 9% (6 of 64) of benign and 16% (8 of 49) of malignant cases (P ¼ .38). p53 showed strong nuclear positivity in 2% (1 of 46) of benign and 47% (7 of 15) of malignant cases (P < .001). EMA positivity and desmin negativity were found in 2% (1 of 64) of reactive MH cases and 98% (49 of 52) of MM cases (P < .001). EMA negativity and desmin positivity were found in 86% (55 of 64) of reactive MH cases and 0% of MM cases. CONCLUSIONS: The combination of positive EMA and negative desmin strongly favors MM; conversely, a combination of negative EMA and positive desmin favors a reactive process. Likewise, strong membranous positivity for GLUT-1 and/or strong nuclear staining for p53 favors a mesothelioma. Ki67 proliferative index showed no significant difference between reactive MH and MM cases. Cancer (Cancer Cytopathol) 2010;118:90-6.