Differential Methylation Patterns in Lean and Obese Non-Alcoholic Steatohepatitis-Associated Hepatocellular Carcinoma

BACKGROUND: Nonalcoholic fatty liver disease affects about 24% of the world\u27s population and may progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). While more common in those that are obese, NASH-HCC can develop in lean individuals. The mechanisms by which HCC develops and the role of epigenetic changes in the context of obesity and normal weight are not well understood. METHODS: In this study, we used previously generated mouse models of lean and obese HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to evaluate methylation differences in HCC progression in lean versus obese mice. Differentially methylated regions were determined using reduced representation bisulfite sequencing. RESULTS: A larger number of differentially methylated regions (DMRs) were seen in NASH-HCC progression in the obese mice compared to the non-obese mice. No overlap existed in the DMRs with the largest methylation differences between the two models. In lean NASH-HCC, methylation differences were seen in genes involved with cancer progression and prognosis (including HCC), such as CHCHD2, FSCN1, and ZDHHC12, and lipid metabolism, including PNPLA6 and LDLRAP1. In obese NASH- HCC, methylation differences were seen in genes known to be associated with HCC, including RNF217, GJA8, PTPRE, PSAPL1, and LRRC8D. Genes involved in Wnt-signaling pathways were enriched in hypomethylated DMRs in the obese NASH-HCC. CONCLUSIONS: These data suggest that differential methylation may play a role in hepatocarcinogenesis in lean versus obese NASH. Hypomethylation of Wnt signaling pathway-related genes in obese mice may drive progression of HCC, while progression of HCC in lean mice may be driven through other signaling pathways, including lipid metabolism

Differential progression of unhealthy dietinduced hepatocellular carcinoma in obese and non-obese mice

Background Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25–30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood. Methods In this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/ fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice. Results Obese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice. Conclusions Unhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis

Differential Progression of Unhealthy Diet-Induced Hepatocellular Carcinoma in Obese and Non-Obese Mice

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25-30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood. METHODS: In this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice. RESULTS: Obese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice. CONCLUSIONS: Unhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis

Differential progression of unhealthy dietinduced hepatocellular carcinoma in obese and non-obese mice

Background Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25–30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood. Methods In this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/ fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice. Results Obese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice. Conclusions Unhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis

Medium-range interactions and crossover to classical critical behavior

We study the crossover from Ising-like to classical critical behavior as a function of the range R of interactions. The power-law dependence on R of several critical amplitudes is calculated from renormalization theory. The results confirm the predictions of Mon and Binder, which were obtained from phenomenological scaling arguments. In addition, we calculate the range dependence of several corrections to scaling. We have tested the results in Monte Carlo simulations of two-dimensional systems with an extended range of interaction. An efficient Monte Carlo algorithm enabled us to carry out simulations for sufficiently large values of R, so that the theoretical predictions could actually be observed.Comment: 16 pages RevTeX, 8 PostScript figures. Uses epsf.sty. Also available as PostScript and PDF file at http://www.tn.tudelft.nl/tn/erikpubs.htm

Prognostic value of programmed death ligand 1, p53, and Ki-67 in patients with advanced stage colorectal cancer

Current prognostic indicators are ineffective for identifying advanced stage colorectal cancer (CRC) patients with high risk of recurrence after surgical resection. We investigated the prognostic value of p53, Ki-67, and programmed death ligand 1 (PD-L1) in 254 patients with stage II and III CRC. The expression of p53 was positive in 63% of cases. Up-regulation of p53 was associated with smaller tumor size (P = .001) and higher Ki-67 labeling index (LI) (P = .031). The tumor Ki-67 LI was high (≥ 20%) in 197 (78%) of the patients. High Ki-67 LI was associated with higher TNM stage (P = .031), positive p53 expression (P = .031), and negative PD-L1 expression (P = .003). The five-year relapse-free survivals (RFS) were 53% and 89%, respectively, for the p53-positive and Ki-67 LI-high patients and the p53-negative and Ki-67 LI-low patients (P < .001). In univariate analysis, negative p53 (P = .001), low Ki-67 LI (P = .006), low PD-L1 expression (P = .044), low TNM stage (P < .001), recto-sigmoid location (P = .026), and small size (P = .013) were significantly related to RFS. In multivariate Cox regression analysis, positive p53 expression (hazard ratio [HR]: 2.48; 95% confidence interval: 1.34–4.59, P = .004), high Ki-67 LI (HR: 2.62; 95% CI: 1.12–6.14, P = .027) and high TNM stage (HR: 2.598, 95% CI: 1.55–4.37, P < .001,) were independent predictors of unfavorable prognosis. In summary, PD-L1, Ki-67, and p53 staining individually had significant prognostic value for patients with stage II and III CRC. Moreover, combining p53 H-score ≥ 35 and Ki-67 LI ≥ 20% identifies patients with poor clinical outcome

Nonmonotonical crossover of the effective susceptibility exponent

We have numerically determined the behavior of the magnetic susceptibility upon approach of the critical point in two-dimensional spin systems with an interaction range that was varied over nearly two orders of magnitude. The full crossover from classical to Ising-like critical behavior, spanning several decades in the reduced temperature, could be observed. Our results convincingly show that the effective susceptibility exponent gamma_eff changes nonmonotonically from its classical to its Ising value when approaching the critical point in the ordered phase. In the disordered phase the behavior is monotonic. Furthermore the hypothesis that the crossover function is universal is supported.Comment: 4 pages RevTeX 3.0/3.1, 5 Encapsulated PostScript figures. Uses epsf.sty. Accepted for publication in Physical Review Letters. Also available as PostScript and PDF file at http://www.tn.tudelft.nl/tn/erikpubs.htm

TMPRSS2â ERG gene fusion is rare compared to PTEN deletions in stage T1a prostate cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136332/1/mc22535.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136332/2/mc22535_am.pd

From Capillary Condensation to Interface Localization Transitions in Colloid Polymer Mixtures Confined in Thin Film Geometry

Monte Carlo simulations of the Asakura-Oosawa (AO) model for colloid-polymer mixtures confined between two parallel repulsive structureless walls are presented and analyzed in the light of current theories on capillary condensation and interface localization transitions. Choosing a polymer to colloid size ratio of q=0.8 and studying ultrathin films in the range of D=3 to D=10 colloid diameters thickness, grand canonical Monte Carlo methods are used; phase transitions are analyzed via finite size scaling, as in previous work on bulk systems and under confinement between identical types of walls. Unlike the latter work, inequivalent walls are used here: while the left wall has a hard-core repulsion for both polymers and colloids, at the right wall an additional square-well repulsion of variable strength acting only on the colloids is present. We study how the phase separation into colloid-rich and colloid-poor phases occurring already in the bulk is modified by such a confinement. When the asymmetry of the wall-colloid interaction increases, the character of the transition smoothly changes from capillary condensation-type to interface localization-type. The critical behavior of these transitions is discussed, as well as the colloid and polymer density profiles across the film in the various phases, and the correlation of interfacial fluctuations in the direction parallel to the confining walls. The experimental observability of these phenomena also is briefly discussed.Comment: 36 pages, 15 figure

A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells

AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing α and regulatory β and γ subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPKα1 expression is relatively consistent across colon cancer cell lines, AMPKα1 depletion does not induce cell death. Conversely, AMPKα2 is expressed at variable levels in colon cancer cells. In high expressing SW480 and moderate expressing HCT116 colon cancer cells, siRNA-mediated depletion induces cell death. These data suggest that AMPK kinase inhibition may be a useful component of future therapeutic strategies. We used Functional Signature Ontology (FUSION) to screen a natural product library to identify compounds that were inhibitors of AMPK to test its potential for detecting small molecules with preferential toxicity toward human colon tumor cells. FUSION identified 5′-hydroxy-staurosporine, which competitively inhibits AMPK. Human colon cancer cell lines are notably more sensitive to 5′-hydroxy-staurosporine than are non-transformed human colon epithelial cells. This study serves as proof-of-concept for unbiased FUSION-based detection of small molecule inhibitors of therapeutic targets and highlights its potential to identify novel compounds for cancer therapy development