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Moylan, Cynthia Ann

Overview:

My research interests focus on the study of chronic liver disease and primary liver cancer, particularly from nonalcoholic fatty liver disease (NAFLD).  As part of the NAFLD Research Team at Duke, I am investigating the role of epigenetics and genetics on the development of advanced fibrosis from NAFLD.  The long term goal of our research is to develop non-invasive biomarkers to identify those patients at increased risk for cirrhosis and end stage liver disease in order to risk stratify patients as well as to develop better preventative and therapeutic strategies.  

Positions:

Assistant Professor of Medicine

Medicine, Gastroenterology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2002

M.D. — University of Miami

Resident, Medicine

Duke University

Fellow In Gastroenterology, Medicine

Duke University

Grants:

Duke Training Grant in Digestive Diseases and Nutrition

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1988
End Date
June 30, 2021

Epigenetics and the Development of Nonalcoholic Fatty Liver Disease

Administered By
Medicine, Gastroenterology
AwardedBy
American College of Gastroenterology
Role
Principal Investigator
Start Date
July 01, 2015
End Date
June 30, 2018

Role of the Stroma in Fibrolamellar Hepatocellular Carcinoma

Administered By
Medicine, Gastroenterology
AwardedBy
Fibrolamellar Cancer Foundation
Role
Investigator
Start Date
December 08, 2016
End Date
December 07, 2017

Lumena PSC

Administered By
Medicine, Gastroenterology
AwardedBy
Lumena Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
August 01, 2014
End Date
May 02, 2017

Characterizing Alcohol's Effects on Repair of Liver Injury

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 2009
End Date
August 31, 2012
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Awards:

Tyor Award. Division of Gastroenterology.

Type
Department
Awarded By
Division of Gastroenterology
Date
January 01, 2017

Publications:

Reply to Kim et al.

Authors
Patel, YA; Henao, R; Moylan, CA; Guy, CD; Piercy, DL; Diehl, AM; Abdelmalek, MF
MLA Citation
Patel, YA, Henao, R, Moylan, CA, Guy, CD, Piercy, DL, Diehl, AM, and Abdelmalek, MF. "Reply to Kim et al." The American journal of gastroenterology 112.5 (May 2017): 807-808.
PMID
28469220
Source
epmc
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
112
Issue
5
Publish Date
2017
Start Page
807
End Page
808
DOI
10.1038/ajg.2017.45

DIFFERENTIAL DNA METHYLATION IN WHOLE BLOOD REFLECTS THAT IN LIVER AND DISTINGUISHES PATIENTS WITH ADVANCED NAFLD FIBROSIS FROM THOSE WITH NORMAL HISTOLOGY: A POTENTIAL NON-INVASIVE TOOL

Authors
Moylan, CA; Giraldo, RH; Murphy, SK; Diehl, AM; Abdelmalek, MF
MLA Citation
Moylan, CA, Giraldo, RH, Murphy, SK, Diehl, AM, and Abdelmalek, MF. "DIFFERENTIAL DNA METHYLATION IN WHOLE BLOOD REFLECTS THAT IN LIVER AND DISTINGUISHES PATIENTS WITH ADVANCED NAFLD FIBROSIS FROM THOSE WITH NORMAL HISTOLOGY: A POTENTIAL NON-INVASIVE TOOL." April 2017.
Source
wos-lite
Published In
Gastroenterology
Volume
152
Issue
5
Publish Date
2017
Start Page
S1069
End Page
S1070

NAFLD is associated with methylation shifts with relevance for the expression of genes involved in lipoprotein particle composition.

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides, cholesterol and toxic free fatty acids and is related to low vitamin D levels. In an analysis of specific gene sets we elucidate to what extent NAFLD associates to epigenetic and related transcriptional changes in gene networks regulating lipid, energy and vitamin D balance. Two gene clusters responsible for lipid homeostasis (74 genes) and vitamin D and energy balance (31 genes) were investigated with regard to average epigenetic shifts within the first 1500bp next to the transcriptional start site. Three cohorts from two published genome wide driven studies that used a microarray approach were investigated including altogether 103 NAFLD and 75 liver healthy subjects. In the first two steps associations between NAFLD abundance, strength of fibrosis and methylation were investigated in two cohorts by multiple linear regression analyses, correcting for important clinical and demographic parameters. Methylation associated strength of transcription in genes showing significant NAFLD related methylation changes were studied in a third step using a third cohort and applying Pearson's correlation and robust linear regression analyses. 41 genes in gene cluster 1 and 14 genes in cluster 2 were significantly differentially methylated in dependency of NAFLD and hepatic fibrosis. We detect new genes significantly changed in methylation, including APO family members (lipid transport), NPC1L1, STARD (cholesterol transport) and GRHL (energy homeostasis). Our results allow novel insights into the hepatic epigenetic regulation of genes important for lipid and vitamin D balance in NAFLD.

Authors
Mwinyi, J; Boström, AE; Pisanu, C; Murphy, SK; Erhart, W; Schafmayer, C; Hampe, J; Moylan, C; Schiöth, HB
MLA Citation
Mwinyi, J, Boström, AE, Pisanu, C, Murphy, SK, Erhart, W, Schafmayer, C, Hampe, J, Moylan, C, and Schiöth, HB. "NAFLD is associated with methylation shifts with relevance for the expression of genes involved in lipoprotein particle composition." Biochimica et biophysica acta 1862.3 (March 2017): 314-323.
PMID
27993651
Source
epmc
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
1862
Issue
3
Publish Date
2017
Start Page
314
End Page
323
DOI
10.1016/j.bbalip.2016.12.005

Vitamin D is Not Associated With Severity in NAFLD: Results of a Paired Clinical and Gene Expression Profile Analysis.

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is complex. Vitamin D (VitD) has been implicated in NAFLD pathogenesis because it has roles in immune modulation, cell differentiation and proliferation, and regulation of inflammation. We evaluated the association of VitD levels, hepatic gene expression for VitD metabolizing genes, and NAFLD histological severity.Two adult cohorts, controls (n=39) and NAFLD (n=244), who underwent liver biopsy were compared. Two-sided t-tests or Wilcoxon's rank-sum tests for continuous predictors and chi-squared tests or Fisher's exact tests for categorical variables were used to analyze the association of VitD and NAFLD. Generalized linear models were used to analyze the association of VitD levels and VitD metabolizing genes with histological severity of NAFLD while adjusting for potential confounders and correcting for multiple comparisons.NAFLD patients were more likely than controls to have higher HbA1c (6.5±1.2 vs 5.9±1.0; P=0.009), a risk factor for VitD deficiency. However, no difference in VitD levels was observed between groups. VitD levels did not correlate with the severity of hepatic steatosis, lobular or portal inflammation, or ballooned hepatocytes after adjusting for confounding factors. Furthermore, no association was noted between VitD deficiency or differential expression of genes involved in VitD metabolism and severity of hepatic fibrosis or any other histologic feature of NAFLD.Neither VitD deficiency, nor hepatic expression of VitD-related genes, associate with the presence or histologic severity of NAFLD in patients. Hence, despite preclinical evidence implicating VitD in NAFLD pathogenesis, VitD deficiency does not appear to be associated with NAFLD severity in humans.

Authors
Patel, YA; Henao, R; Moylan, CA; Guy, CD; Piercy, DL; Diehl, AM; Abdelmalek, MF
MLA Citation
Patel, YA, Henao, R, Moylan, CA, Guy, CD, Piercy, DL, Diehl, AM, and Abdelmalek, MF. "Vitamin D is Not Associated With Severity in NAFLD: Results of a Paired Clinical and Gene Expression Profile Analysis." The American journal of gastroenterology 111.11 (November 2016): 1591-1598.
PMID
27644736
Source
epmc
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
111
Issue
11
Publish Date
2016
Start Page
1591
End Page
1598
DOI
10.1038/ajg.2016.406

Hepatic estrogen transcriptional activity and estrogen receptor a gene expression are negatively correlated with fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD)

Authors
Suzuki, A; Spencer, HJ; Moylan, CA; Dranoff, JA; Abdelmalek, MF; Guy, CD; Diehl, AM
MLA Citation
Suzuki, A, Spencer, HJ, Moylan, CA, Dranoff, JA, Abdelmalek, MF, Guy, CD, and Diehl, AM. "Hepatic estrogen transcriptional activity and estrogen receptor a gene expression are negatively correlated with fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD)." October 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Publish Date
2016
Start Page
105A
End Page
105A

BCAT1 is Associated with Clinical Decompensation in NAFLD: A Pilot Study

Authors
Wegermann, K; Henao, R; Pan, Y; Diehl, AM; Abdelmalek, MF; Moylan, CA
MLA Citation
Wegermann, K, Henao, R, Pan, Y, Diehl, AM, Abdelmalek, MF, and Moylan, CA. "BCAT1 is Associated with Clinical Decompensation in NAFLD: A Pilot Study." October 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Publish Date
2016
Start Page
577A
End Page
577A

Vitamin D is Not Associated with Histologic Severity in NAFLD: Results of a Paired Clinical and Hepatic Gene Expression Profile Analysis

Authors
Patel, YA; Henao, R; Moylan, CA; Guy, CD; Piercy, DL; Diehl, AM; Abdelmalek, MF
MLA Citation
Patel, YA, Henao, R, Moylan, CA, Guy, CD, Piercy, DL, Diehl, AM, and Abdelmalek, MF. "Vitamin D is Not Associated with Histologic Severity in NAFLD: Results of a Paired Clinical and Hepatic Gene Expression Profile Analysis." October 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Publish Date
2016
Start Page
577A
End Page
577A

DNA Methylation: Basic Principles

© 2016 Elsevier Inc. All rights reserved. DNA methylation is a stable yet reversible epigenetic modification that regulates gene expression. New technologies have provided deep insights into the distribution and function of DNA methylation in humans, including the Human Roadmap Epigenome Project that defined genomewide methylation profiles across tissues and developmental stages, with the data available to anyone with Internet access. Exciting recent discoveries have revealed that 5-methylcytosine can be modified by ten-eleven translocase dioxygenases (TET1, 2, and 3) to form 5-hydroxymethylcytosine (5hmC). 5hmC is enriched in brain tissues and in embryonic stem cells and appears to have a regulatory role distinct from that of 5-methylcytosine (5mC). 5hmC also acts as a substrate for further modifications by the TET enzymes (5-formylcytosine and 5-carboxylcytosine) which undergo base excision repair by thymine DNA glycosylase (TDG) with replacement by unmethylated cytosine. These revelations present new challenges, including the need for technologies to quantify these modifications, determine their role in pathologies, and ways to target these modified bases and involved pathways to improve patient outcomes. Strategies to reverse abnormal hypermethylation of 5mC at specific loci are being developed and will eventually improve on the generalized toxicity associated with current DNA methyltransferase inhibitor therapies. Finally, exposures to endogenous and exogenous agents can lead to changes in methylation levels that increase disease risk. The sum combinatorial changes comprise what we refer to as each individual's unique "epigenoprint" that may be useful for determining risk of disease, best strategies for prevention and individualized interventions, likelihood of positive therapeutic response, and lead to improved prognoses.

Authors
Moylan, CA; Murphy, SK
MLA Citation
Moylan, CA, and Murphy, SK. "DNA Methylation: Basic Principles." Medical Epigenetics. July 1, 2016. 11-31.
Source
scopus
Publish Date
2016
Start Page
11
End Page
31
DOI
10.1016/B978-0-12-803239-8.00002-8

Role of patient factors, preferences, and distrust in health care and access to liver transplantation and organ donation.

Despite major improvements in access to liver transplantation (LT), disparities remain. Little is known about how distrust in medical care, patient preferences, and the origins shaping those preferences contribute to differences surrounding access. We performed a single-center, cross-sectional survey of adults with end-stage liver disease and compared responses between LT listed and nonlisted patients as well as by race. Questionnaires were administered to 109 patients (72 nonlisted; 37 listed) to assess demographics, health care system distrust (HCSD), religiosity, and factors influencing LT and organ donation (OD). We found that neither HCSD nor religiosity explained differences in access to LT in our population. Listed patients attained higher education levels and were more likely to be insured privately. This was also the case for white versus black patients. All patients reported wanting LT if recommended. However, nonlisted patients were significantly less likely to have discussed LT with their physician or to be referred to a transplant center. They were also much less likely to understand the process of LT. Fewer blacks were referred (44.4% versus 69.7%; P = 0.03) or went to the transplant center if referred (44.4% versus 71.1%; P = 0.02). Fewer black patients felt that minorities had as equal access to LT as whites (29.6% versus 57.3%; P < 0.001). For OD, there were more significant differences in preferences by race than listing status. More whites indicated OD status on their driver's license, and more blacks were likely to become an organ donor if approached by someone of the same cultural or ethnic background (P < 0.01). In conclusion, our analysis demonstrates persistent barriers to LT and OD. With improved patient and provider education and communication, many of these disparities could be successfully overcome. Liver Transplantation 22 895-905 2016 AASLD.

Authors
Wilder, JM; Oloruntoba, OO; Muir, AJ; Moylan, CA
MLA Citation
Wilder, JM, Oloruntoba, OO, Muir, AJ, and Moylan, CA. "Role of patient factors, preferences, and distrust in health care and access to liver transplantation and organ donation." Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 22.7 (July 2016): 895-905.
Website
http://hdl.handle.net/10161/12749
PMID
27027394
Source
epmc
Published In
Liver Transplantation
Volume
22
Issue
7
Publish Date
2016
Start Page
895
End Page
905
DOI
10.1002/lt.24452

Liver Transplantation for Nonalcoholic Fatty Liver Disease: Role of Bariatric Surgery for Comorbid Obesity

MLA Citation
"Liver Transplantation for Nonalcoholic Fatty Liver Disease: Role of Bariatric Surgery for Comorbid Obesity." Journal of Advanced Nutrition and Human Metabolism (June 23, 2016).
Source
crossref
Published In
Journal of Advanced Nutrition and Human Metabolism
Publish Date
2016
DOI
10.14800/janhm.1327

A targeted analysis reveals relevant shifts in the methylation and transcription of genes responsible for bile acid homeostasis and drug metabolism in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk for liver cirrhosis and cancer. Recent studies demonstrate that NAFLD significantly impacts on the genome wide methylation and expression reporting top hit genes to be associated with e.g. diabetes mellitus. In a targeted analysis we specifically investigate to what extent NAFLD is associated with methylation and transcriptional changes in gene networks responsible for drug metabolism (DM) and bile acid (BA) homeostasis, which may trigger liver and system toxic events.We performed a systematic analysis of 73 genes responsible for BA homeostasis and DM based on liver derived methylation and expression data from three cohort studies including 103 NAFLD and 75 non-NAFLD patients. Using multiple linear regression models, we detected methylation differences in proximity to the transcriptional start site of these genes in two NAFLD cohorts and correlated the methylation of significantly changed CpG sites to transcriptional expression in a third cohort using robust multiple linear regression approaches.We detected 64 genes involved in BA homeostasis and DM to be significantly differentially methylated. In 26 of these genes, methylation significantly correlated with RNA expression, detecting i.e. genes such as CYP27A1, OSTɑ, and SLC27A5 (BA homeostasis), and SLCO2B1, SLC47A1, and several UGT and CYP genes (DM) to be NAFLD dependently modulated.NAFLD is associated with significant shifts in the methylation of key genes responsible for BA and DM that are associated with transcriptional modulations. These findings have implications for BA composition, BA regulated metabolic pathways and for drug safety and efficacy.

Authors
Schiöth, HB; Boström, A; Murphy, SK; Erhart, W; Hampe, J; Moylan, C; Mwinyi, J
MLA Citation
Schiöth, HB, Boström, A, Murphy, SK, Erhart, W, Hampe, J, Moylan, C, and Mwinyi, J. "A targeted analysis reveals relevant shifts in the methylation and transcription of genes responsible for bile acid homeostasis and drug metabolism in non-alcoholic fatty liver disease." BMC genomics 17 (June 14, 2016): 462-.
PMID
27301979
Source
epmc
Published In
BMC Genomics
Volume
17
Publish Date
2016
Start Page
462
DOI
10.1186/s12864-016-2814-z

Nonalcoholic Fatty Liver Disease: Key Considerations Before and After Liver Transplantation.

Nonalcoholic fatty liver disease (NAFLD) is the most common etiology of chronic liver disease in developed countries and is on trajectory to become the leading indication for liver transplantation in the USA and much of the world. Patients with NAFLD cirrhosis awaiting liver transplant face unique challenges and increased risk for waiting list stagnation and dropout due to burdensome comorbidities including obesity, diabetes, cardiovascular disease, and kidney disease. Thus far, patients transplanted for NAFLD cirrhosis have excellent mid- and long-term patient and graft survival, but concerns regarding short-term morbidity and mortality continue to exist. Post-liver transplantation, NAFLD occurs as both a recurrent and de novo manifestation, each with unique outcomes. NAFLD in the donor population is of concern given the growing demand for liver transplantation and mounting pressure to expand the donor pool. This review addresses key issues surrounding NAFLD as an indication for transplantation, including its increasing prevalence, unique patient demographics, outcomes related to liver transplantation, development of post-liver transplantation NAFLD, and NAFLD in the liver donor population. It also highlights exciting areas where further research is needed, such as the role of bariatric surgery and preconditioning of marginal donor grafts.

Authors
Patel, YA; Berg, CL; Moylan, CA
MLA Citation
Patel, YA, Berg, CL, and Moylan, CA. "Nonalcoholic Fatty Liver Disease: Key Considerations Before and After Liver Transplantation." Digestive diseases and sciences 61.5 (May 2016): 1406-1416. (Review)
PMID
26815171
Source
epmc
Published In
Digestive Diseases and Sciences
Volume
61
Issue
5
Publish Date
2016
Start Page
1406
End Page
1416
DOI
10.1007/s10620-016-4035-3

Veterans health administration hepatitis B testing and treatment with anti-CD20 antibody administration.

To evaluate pretreatment hepatitis B virus (HBV) testing, vaccination, and antiviral treatment rates in Veterans Affairs patients receiving anti-CD20 Ab for quality improvement.We performed a retrospective cohort study using a national repository of Veterans Health Administration (VHA) electronic health record data. We identified all patients receiving anti-CD20 Ab treatment (2002-2014). We ascertained patient demographics, laboratory results, HBV vaccination status (from vaccination records), pharmacy data, and vital status. The high risk period for HBV reactivation is during anti-CD20 Ab treatment and 12 mo follow up. Therefore, we analyzed those who were followed to death or for at least 12 mo after completing anti-CD20 Ab. Pretreatment serologic tests were used to categorize chronic HBV (hepatitis B surface antigen positive or HBsAg+), past HBV (HBsAg-, hepatitis B core antibody positive or HBcAb+), resolved HBV (HBsAg-, HBcAb+, hepatitis B surface antibody positive or HBsAb+), likely prior vaccination (isolated HBsAb+), HBV negative (HBsAg-, HBcAb-), or unknown. Acute hepatitis B was defined by the appearance of HBsAg+ in the high risk period in patients who were pretreatment HBV negative. We assessed HBV antiviral treatment and the incidence of hepatitis, liver failure, and death during the high risk period. Cumulative hepatitis, liver failure, and death after anti-CD20 Ab initiation were compared by HBV disease categories and differences compared using the χ(2) test. Mean time to hepatitis peak alanine aminotransferase, liver failure, and death relative to anti-CD20 Ab administration and follow-up were also compared by HBV disease group.Among 19304 VHA patients who received anti-CD20 Ab, 10224 (53%) had pretreatment HBsAg testing during the study period, with 49% and 43% tested for HBsAg and HBcAb, respectively within 6 mo pretreatment in 2014. Of those tested, 2% (167/10224) had chronic HBV, 4% (326/7903) past HBV, 5% (427/8110) resolved HBV, 8% (628/8110) likely prior HBV vaccination, and 76% (6022/7903) were HBV negative. In those with chronic HBV infection, ≤ 37% received HBV antiviral treatment during the high risk period while 21% to 23% of those with past or resolved HBV, respectively, received HBV antiviral treatment. During and 12 mo after anti-CD20 Ab, the rate of hepatitis was significantly greater in those HBV positive vs negative (P = 0.001). The mortality rate was 35%-40% in chronic or past hepatitis B and 26%-31% in hepatitis B negative. In those pretreatment HBV negative, 16 (0.3%) developed acute hepatitis B of 4947 tested during anti-CD20Ab treatment and follow-up.While HBV testing of Veterans has increased prior to anti-CD20 Ab, few HBV+ patients received HBV antivirals, suggesting electronic health record algorithms may enhance health outcomes.

Authors
Hunt, CM; Beste, LA; Lowy, E; Suzuki, A; Moylan, CA; Tillmann, HL; Ioannou, GN; Lim, JK; Kelley, MJ; Provenzale, D
MLA Citation
Hunt, CM, Beste, LA, Lowy, E, Suzuki, A, Moylan, CA, Tillmann, HL, Ioannou, GN, Lim, JK, Kelley, MJ, and Provenzale, D. "Veterans health administration hepatitis B testing and treatment with anti-CD20 antibody administration." World journal of gastroenterology 22.19 (May 2016): 4732-4740.
Website
http://hdl.handle.net/10161/11950
PMID
27217704
Source
epmc
Published In
World journal of gastroenterology : WJG
Volume
22
Issue
19
Publish Date
2016
Start Page
4732
End Page
4740
DOI
10.3748/wjg.v22.i19.4732

Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches.

The ductular reaction (DR) involves mobilisation of reactive-appearing duct-like cells (RDC) along canals of Hering, and myofibroblastic (MF) differentiation of hepatic stellate cells (HSC) in the space of Disse. Perivascular cells in stem cell niches produce pleiotrophin (PTN) to inactivate the PTN receptor, protein tyrosine phosphatase receptor zeta-1 (PTPRZ1), thereby augmenting phosphoprotein-dependent signalling. We hypothesised that the DR is regulated by PTN/PTPRZ1 signalling.PTN-GFP, PTN-knockout (KO), PTPRZ1-KO, and wild type (WT) mice were examined before and after bile duct ligation (BDL) for PTN, PTPRZ1 and the DR. RDC and HSC from WT, PTN-KO, and PTPRZ1-KO mice were also treated with PTN to determine effects on downstream signaling phosphoproteins, gene expression, growth, and migration. Liver biopsies from patients with DRs were also interrogated.Although quiescent HSC and RDC lines expressed PTN and PTPRZ1 mRNAs, neither PTN nor PTPRZ1 protein was demonstrated in healthy liver. BDL induced PTN in MF-HSC and increased PTPRZ1 in MF-HSC and RDC. In WT mice, BDL triggered a DR characterised by periportal accumulation of collagen, RDC and MF-HSC. All aspects of this DR were increased in PTN-KO mice and suppressed in PTPRZ1-KO mice. In vitro studies revealed PTN-dependent accumulation of phosphoproteins that control cell-cell adhesion and migration, with resultant inhibition of cell migration. PTPRZ1-positive cells were prominent in the DRs of patients with ductal plate defects and adult cholestatic diseases.PTN, and its receptor, PTPRZ1, regulate the DR to liver injury by controlling the migration of resident cells in adult liver progenitor niches.

Authors
Michelotti, GA; Tucker, A; Swiderska-Syn, M; Machado, MV; Choi, SS; Kruger, L; Soderblom, E; Thompson, JW; Mayer-Salman, M; Himburg, HA; Moylan, CA; Guy, CD; Garman, KS; Premont, RT; Chute, JP; Diehl, AM
MLA Citation
Michelotti, GA, Tucker, A, Swiderska-Syn, M, Machado, MV, Choi, SS, Kruger, L, Soderblom, E, Thompson, JW, Mayer-Salman, M, Himburg, HA, Moylan, CA, Guy, CD, Garman, KS, Premont, RT, Chute, JP, and Diehl, AM. "Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches." Gut 65.4 (April 2016): 683-692.
Website
http://hdl.handle.net/10161/13095
PMID
25596181
Source
epmc
Published In
Gut
Volume
65
Issue
4
Publish Date
2016
Start Page
683
End Page
692
DOI
10.1136/gutjnl-2014-308176

Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches

Authors
Michelotti, GA; Tucker, A; Swiderska-Syn, M; Machado, MV; Choi, SS; Kruger, L; Soderblom, E; Thompson, JW; Mayer-Salman, M; Himburg, HA; Moylan, CA; Guy, CD; Garman, KS; Premont, RT; Chute, JP; Diehl, AM
MLA Citation
Michelotti, GA, Tucker, A, Swiderska-Syn, M, Machado, MV, Choi, SS, Kruger, L, Soderblom, E, Thompson, JW, Mayer-Salman, M, Himburg, HA, Moylan, CA, Guy, CD, Garman, KS, Premont, RT, Chute, JP, and Diehl, AM. "Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches." GUT 65.4 (April 2016): 683-692.
Source
wos-lite
Published In
Gut
Volume
65
Issue
4
Publish Date
2016
Start Page
683
End Page
692
DOI
10.1136/gutjnl-2014-308176

Systematic transcriptome analysis reveals elevated expression of alcohol-metabolizing genes in NAFLD livers.

Obese animals and non-alcoholic fatty liver disease (NAFLD) patients exhibit elevated blood alcohol, suggesting potential contributions of alcohol metabolism to the development of NAFLD. Liver gene expression in patients with biopsy-proven mild (N = 40) and severe (N = 32) NAFLD were compared to that in healthy liver donors (N = 7) and alcoholic hepatitis (AH; N = 15) using microarrays. Principal components analyses (PCA) revealed similar gene expression patterns between mild and severe NAFLD which clustered with those of AH but were distinct from those of healthy livers. Differential gene expression between NAFLD and healthy livers was consistent with established NAFLD-associated genes and NAFLD pathophysiology. Alcohol-metabolizing enzymes including ADH, ALDH, CYP2E1, and CAT were up-regulated in NAFLD livers. The expression level of alcohol-metabolizing genes in severe NAFLD was similar to that in AH. The NAFLD gene expression profiles provide new directions for future investigations to identify disease markers and targets for prevention and treatment, as well as to foster our understanding of NAFLD pathogenesis and pathophysiology. Particularly, increased expression of alcohol-metabolizing genes in NAFLD livers supports a role for endogenous alcohol metabolism in NAFLD pathology and provides further support for gut microbiome therapy in NAFLD management. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley © Sons, Ltd.

Authors
Zhu, R; Baker, SS; Moylan, CA; Abdelmalek, MF; Guy, CD; Zamboni, F; Wu, D; Lin, W; Liu, W; Baker, RD; Govindarajan, S; Cao, Z; Farci, P; Diehl, AM; Zhu, L
MLA Citation
Zhu, R, Baker, SS, Moylan, CA, Abdelmalek, MF, Guy, CD, Zamboni, F, Wu, D, Lin, W, Liu, W, Baker, RD, Govindarajan, S, Cao, Z, Farci, P, Diehl, AM, and Zhu, L. "Systematic transcriptome analysis reveals elevated expression of alcohol-metabolizing genes in NAFLD livers." The Journal of pathology 238.4 (March 2016): 531-542.
PMID
26415102
Source
epmc
Published In
The Journal of Pathology
Volume
238
Issue
4
Publish Date
2016
Start Page
531
End Page
542
DOI
10.1002/path.4650

Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model.

Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation.We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH.CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD diet-fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH.Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were increased in mice with NASH. Decreased hepatic free CoA content was associated with increased caspase-2 activity and correlated with worse liver cell apoptosis, inflammation, and fibrosis. Treatment with pantothenate and N-acetylcysteine did not inhibit caspase-2 activation, improve NASH, normalize PANK expression, or restore free CoA levels in MCD diet-fed mice.In mice with NASH, hepatic CoA metabolism is impaired, leading to decreased free CoA content, activation of caspase-2, and increased liver cell apoptosis. Dietary supplementation with CoA precursors did not restore CoA levels or improve NASH, suggesting that alternative approaches are necessary to normalize free CoA during NASH.

Authors
Machado, MV; Kruger, L; Jewell, ML; Michelotti, GA; Pereira, TDA; Xie, G; Moylan, CA; Diehl, AM
MLA Citation
Machado, MV, Kruger, L, Jewell, ML, Michelotti, GA, Pereira, TDA, Xie, G, Moylan, CA, and Diehl, AM. "Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model." Digestive diseases and sciences 61.1 (January 2016): 137-148.
PMID
26403427
Source
epmc
Published In
Digestive Diseases and Sciences
Volume
61
Issue
1
Publish Date
2016
Start Page
137
End Page
148
DOI
10.1007/s10620-015-3871-x

Treatment Outcomes of Veterans with Decompensated Cirrhosis Receiving All Oral Direct Acting Antiviral Hepatitis C Therapy

Authors
Rabatin, A; Hashem, M; Townsend, ML; Bryan, WE; Moylan, CA; Choi, SS; Naggie, S
MLA Citation
Rabatin, A, Hashem, M, Townsend, ML, Bryan, WE, Moylan, CA, Choi, SS, and Naggie, S. "Treatment Outcomes of Veterans with Decompensated Cirrhosis Receiving All Oral Direct Acting Antiviral Hepatitis C Therapy." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
773A
End Page
773A

Plasma Metabolomic Profiles Predict Advanced Hepatic Fibrosis in Patients with Nonalcoholic Fatty Liver Disease

Authors
Henao, R; Hasanaliyeva, N; Bell, LN; Wulff, J; Perichon, R; Moylan, CA; Lu, JT; Guy, CD; Diehl, AM; Abdelmalek, MF
MLA Citation
Henao, R, Hasanaliyeva, N, Bell, LN, Wulff, J, Perichon, R, Moylan, CA, Lu, JT, Guy, CD, Diehl, AM, and Abdelmalek, MF. "Plasma Metabolomic Profiles Predict Advanced Hepatic Fibrosis in Patients with Nonalcoholic Fatty Liver Disease." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
290A
End Page
291A

DNA Methylation Profiles of Fibrosis-Associated Gene in Blood Reflects Liver Fibrosis Severity in Human Nonalcoholic Fatty Liver Disease

Authors
Moylan, CA; Murphy, SK; Grenier, C; Abdelmalek, MF; Diehl, AM
MLA Citation
Moylan, CA, Murphy, SK, Grenier, C, Abdelmalek, MF, and Diehl, AM. "DNA Methylation Profiles of Fibrosis-Associated Gene in Blood Reflects Liver Fibrosis Severity in Human Nonalcoholic Fatty Liver Disease." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
648A
End Page
649A

Hepatitis B Testing Prior to Administration of Rituximab, Ofatumumab and Obinutuzumab in the National Veterans Affairs Health Healthcare System, 2002-2014

Authors
Hunt, CM; Beste, LA; Ioannou, GN; Lowy, E; Provenzale, DT; Kelley, MJ; Suzuki, A; Moylan, CA; Oloruntoba, OO; Tillmann, HL; Lim, JK; Ross, D
MLA Citation
Hunt, CM, Beste, LA, Ioannou, GN, Lowy, E, Provenzale, DT, Kelley, MJ, Suzuki, A, Moylan, CA, Oloruntoba, OO, Tillmann, HL, Lim, JK, and Ross, D. "Hepatitis B Testing Prior to Administration of Rituximab, Ofatumumab and Obinutuzumab in the National Veterans Affairs Health Healthcare System, 2002-2014." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
478A
End Page
479A

Systematic Analysis of NAFLD Transcriptome Revealed Elevated Expression of Alcohol Metabolizing Genes in Mild and Severe NAFLD Livers

Authors
Zhu, R; Baker, SS; Moylan, CA; Abdelmalek, MF; Guy, CD; Zamboni, F; Wu, D; Lin, W; Liu, W; Baker, RD; Govindarajan, S; Cao, Z; Farci, P; Diehl, AM; Zhu, L
MLA Citation
Zhu, R, Baker, SS, Moylan, CA, Abdelmalek, MF, Guy, CD, Zamboni, F, Wu, D, Lin, W, Liu, W, Baker, RD, Govindarajan, S, Cao, Z, Farci, P, Diehl, AM, and Zhu, L. "Systematic Analysis of NAFLD Transcriptome Revealed Elevated Expression of Alcohol Metabolizing Genes in Mild and Severe NAFLD Livers." April 2015.
Source
wos-lite
Published In
Gastroenterology
Volume
148
Issue
4
Publish Date
2015
Start Page
S1054
End Page
S1054

Gender-based disparities in access to and outcomes of liver transplantation.

Despite comprising 35% of transplants, the number of female transplant recipients has continued to decline. Accordingly, there is a growing attention to the issue of access to and outcomes of liver transplantation in women. The purpose of this review is to critically evaluate the published literature on etiologies contributing to gender-based disparities in liver transplantation focusing on the steps from chronic liver disease through transplantation including disparities in liver disease prevalence, access to liver transplant centers and transplant waiting list, receipt of liver transplantation once listed and disparities in post-liver transplantation outcomes. Our review finds factors contributing to this disparity may include gender differences in the etiology of underlying liver disease and patient and physician referral patterns, lifestyle and health care, but also utilization of an imperfect organ allocation system based on the model for end stage liver disease score and donor-recipient liver size matching. The review also highlights the need for further research in the area of gender disparity in order to develop appropriate approaches to address it and to improve allocation of this precious resource in the future.

Authors
Oloruntoba, OO; Moylan, CA
MLA Citation
Oloruntoba, OO, and Moylan, CA. "Gender-based disparities in access to and outcomes of liver transplantation." World journal of hepatology 7.3 (March 2015): 460-467. (Review)
PMID
25848470
Source
epmc
Published In
World Journal of Hepatology
Volume
7
Issue
3
Publish Date
2015
Start Page
460
End Page
467
DOI
10.4254/wjh.v7.i3.460

Role of Fn14 in acute alcoholic steatohepatitis in mice.

TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14(+) progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-α increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high-fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl₄ for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl₄ treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline content, and quantitative immunohistochemistry. During liver injury, Fn14 expression, apoptosis, inflammation, hepatocyte replication, progenitor and myofibroblast accumulation, and fibrosis increased in WT mice fed either diet. Mice fed either diet expressed similar TWEAK/Fn14 levels, but ETOH-fed mice had higher TNF-α expression. The ETOH-fed group developed more apoptosis, inflammation, fibrosis, and regenerative responses. Fn14 deletion did not reduce hepatic TNF-α expression but improved all injury parameters in mice fed the control diet. In ETOH-fed mice, Fn14 deletion inhibited TNF-α induction and increased acute mortality, despite improvement in liver injury. Fn14 mediates wound-healing responses that are necessary to survive acute liver injury during alcohol exposure.

Authors
Karaca, G; Xie, G; Moylan, C; Swiderska-Syn, M; Guy, CD; Krüger, L; Machado, MV; Choi, SS; Michelotti, GA; Burkly, LC; Diehl, AM
MLA Citation
Karaca, G, Xie, G, Moylan, C, Swiderska-Syn, M, Guy, CD, Krüger, L, Machado, MV, Choi, SS, Michelotti, GA, Burkly, LC, and Diehl, AM. "Role of Fn14 in acute alcoholic steatohepatitis in mice." American journal of physiology. Gastrointestinal and liver physiology 308.4 (February 2015): G325-G334.
PMID
25524063
Source
epmc
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
308
Issue
4
Publish Date
2015
Start Page
G325
End Page
G334
DOI
10.1152/ajpgi.00429.2013

Abstract 4117: Utilizing RNA aptamers for biomarker discovery in a novel cell culture system for hepatocellular carcinoma

Authors
Naqvi, IA; White, RR; Moylan, CA; Diehl, AM; Choi, SS
MLA Citation
Naqvi, IA, White, RR, Moylan, CA, Diehl, AM, and Choi, SS. "Abstract 4117: Utilizing RNA aptamers for biomarker discovery in a novel cell culture system for hepatocellular carcinoma." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
4117
End Page
4117
DOI
10.1158/1538-7445.AM2014-4117

Reply

Authors
Moylan, CA; Pang, H; Michelotti, G; Diehl, AM
MLA Citation
Moylan, CA, Pang, H, Michelotti, G, and Diehl, AM. "Reply." Hepatology 60.4 (October 2014): 1445-1446.
Source
crossref
Published In
Hepatology
Volume
60
Issue
4
Publish Date
2014
Start Page
1445
End Page
1446
DOI
10.1002/hep.27038

Reply: To PMID 23913408.

Authors
Moylan, CA; Pang, H; Michelotti, G; Diehl, AM
MLA Citation
Moylan, CA, Pang, H, Michelotti, G, and Diehl, AM. "Reply: To PMID 23913408." Hepatology (Baltimore, Md.) 60.4 (October 2014): 1445-1446. (Letter)
PMID
24493022
Source
epmc
Published In
Hepatology
Volume
60
Issue
4
Publish Date
2014
Start Page
1445
End Page
1446
DOI
10.1002/hep.27038

Gene Expression and Pathway Analyses Reveal Distinctions Between Hepatocellular Carcinoma Arising in Fibrotic and Non-Fibrotic Nonalcoholic Fatty Liver Disease

Authors
Moylan, CA; Owzar, K; Muir, AJ; Cauchy, F; Belghiti, J; Diehl, AM; Paradis, V
MLA Citation
Moylan, CA, Owzar, K, Muir, AJ, Cauchy, F, Belghiti, J, Diehl, AM, and Paradis, V. "Gene Expression and Pathway Analyses Reveal Distinctions Between Hepatocellular Carcinoma Arising in Fibrotic and Non-Fibrotic Nonalcoholic Fatty Liver Disease." May 2014.
Source
wos-lite
Published In
Gastroenterology
Volume
146
Issue
5
Publish Date
2014
Start Page
S998
End Page
S999

Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease.

UNLABELLED: Clinicians rely upon the severity of liver fibrosis to segregate patients with well-compensated nonalcoholic fatty liver disease (NAFLD) into subpopulations at high- versus low-risk for eventual liver-related morbidity and mortality. We compared hepatic gene expression profiles in high- and low-risk NAFLD patients to identify processes that distinguish the two groups and hence might be novel biomarkers or treatment targets. Microarray analysis was used to characterize gene expression in percutaneous liver biopsies from low-risk, "mild" NAFLD patients (fibrosis stage 0-1; n = 40) and high-risk, "severe" NAFLD patients (fibrosis stage 3-4; n = 32). Findings were validated in a second, independent cohort and confirmed by real-time polymerase chain reaction and immunohistochemistry (IHC). As a group, patients at risk for bad NAFLD outcomes had significantly worse liver injury and more advanced fibrosis (severe NAFLD) than clinically indistinguishable NAFLD patients with a good prognosis (mild NAFLD). A 64-gene profile reproducibly differentiated severe NAFLD from mild NAFLD, and a 20-gene subset within this profile correlated with NAFLD severity, independent of other factors known to influence NAFLD progression. Multiple genes involved with tissue repair/regeneration and certain metabolism-related genes were induced in severe NAFLD. Ingenuity Pathway Analysis and IHC confirmed deregulation of metabolic and regenerative pathways in severe NAFLD and revealed overlap among the gene expression patterns of severe NAFLD, cardiovascular disease, and cancer. CONCLUSION: By demonstrating specific metabolic and repair pathways that are differentially activated in livers with severe NAFLD, gene profiling identified novel targets that can be exploited to improve diagnosis and treatment of patients who are at greatest risk for NAFLD-related morbidity and mortality.

Authors
Moylan, CA; Pang, H; Dellinger, A; Suzuki, A; Garrett, ME; Guy, CD; Murphy, SK; Ashley-Koch, AE; Choi, SS; Michelotti, GA; Hampton, DD; Chen, Y; Tillmann, HL; Hauser, MA; Abdelmalek, MF; Diehl, AM
MLA Citation
Moylan, CA, Pang, H, Dellinger, A, Suzuki, A, Garrett, ME, Guy, CD, Murphy, SK, Ashley-Koch, AE, Choi, SS, Michelotti, GA, Hampton, DD, Chen, Y, Tillmann, HL, Hauser, MA, Abdelmalek, MF, and Diehl, AM. "Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease." Hepatology 59.2 (February 2014): 471-482.
PMID
23913408
Source
pubmed
Published In
Hepatology
Volume
59
Issue
2
Publish Date
2014
Start Page
471
End Page
482
DOI
10.1002/hep.26661

Whole Exome Sequencing of Extreme Phenotypes of NAFLD Identifies Potential Genetic Risk Factors for Advanced Hepatic Fibrosis

Authors
Urban, TJ; Moylan, CA; Rein, M; Abdelmalek, MF; Goldstein, DB; Diehl, AM
MLA Citation
Urban, TJ, Moylan, CA, Rein, M, Abdelmalek, MF, Goldstein, DB, and Diehl, AM. "Whole Exome Sequencing of Extreme Phenotypes of NAFLD Identifies Potential Genetic Risk Factors for Advanced Hepatic Fibrosis." 2014.
Source
wos-lite
Published In
Hepatology
Volume
60
Publish Date
2014
Start Page
744A
End Page
744A

The Influence of Race on Patient Preferences and Access to Orthotopic Liver Transplantation and Organ Donation

Authors
Oloruntoba, OO; Wilder, JM; Smith, AD; Muir, AJ; Moylan, CA
MLA Citation
Oloruntoba, OO, Wilder, JM, Smith, AD, Muir, AJ, and Moylan, CA. "The Influence of Race on Patient Preferences and Access to Orthotopic Liver Transplantation and Organ Donation." 2014.
Source
wos-lite
Published In
Hepatology
Volume
60
Publish Date
2014
Start Page
963A
End Page
963A

Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting noninvasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression. METHODS: We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0-1 (mild) and F3-4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome. RESULTS: Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P < .05). Methylation at fibroblast growth factor receptor 2, methionine adenosyl methyltransferase 1A, and caspase 1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, and genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and underexpressed. CONCLUSIONS: Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD.

Authors
Murphy, SK; Yang, H; Moylan, CA; Pang, H; Dellinger, A; Abdelmalek, MF; Garrett, ME; Ashley-Koch, A; Suzuki, A; Tillmann, HL; Hauser, MA; Diehl, AM
MLA Citation
Murphy, SK, Yang, H, Moylan, CA, Pang, H, Dellinger, A, Abdelmalek, MF, Garrett, ME, Ashley-Koch, A, Suzuki, A, Tillmann, HL, Hauser, MA, and Diehl, AM. "Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease." Gastroenterology 145.5 (November 2013): 1076-1087.
PMID
23916847
Source
pubmed
Published In
Gastroenterology
Volume
145
Issue
5
Publish Date
2013
Start Page
1076
End Page
1087
DOI
10.1053/j.gastro.2013.07.047

Hedgehog-Induced Serine Biogenesis is Required for Activation of Hepatic Stellate Cells

Authors
Chen, Y; Michelotti, GA; Xie, G; Moylan, CA; Diehl, AM
MLA Citation
Chen, Y, Michelotti, GA, Xie, G, Moylan, CA, and Diehl, AM. "Hedgehog-Induced Serine Biogenesis is Required for Activation of Hepatic Stellate Cells." October 2013.
Source
wos-lite
Published In
Hepatology
Volume
58
Publish Date
2013
Start Page
572A
End Page
572A

IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients.

Authors
Garrett, ME; Abdelmalek, MF; Ashley-Koch, A; Hauser, MA; Moylan, CA; Pang, H; Diehl, AM; Tillmann, HL
MLA Citation
Garrett, ME, Abdelmalek, MF, Ashley-Koch, A, Hauser, MA, Moylan, CA, Pang, H, Diehl, AM, and Tillmann, HL. "IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients." J Hepatol 58.2 (February 2013): 402-403. (Letter)
PMID
23063570
Source
pubmed
Published In
Journal of Hepatology
Volume
58
Issue
2
Publish Date
2013
Start Page
402
End Page
403
DOI
10.1016/j.jhep.2012.09.035

IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients

Authors
Garrett, ME; Abdelmalek, MF; Ashley-Koch, A; Hauser, MA; Moylan, CA; Pang, H; Diehl, AM; Tillmann, HL
MLA Citation
Garrett, ME, Abdelmalek, MF, Ashley-Koch, A, Hauser, MA, Moylan, CA, Pang, H, Diehl, AM, and Tillmann, HL. "IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients." Journal of Hepatology 58.2 (2013): 402-403.
Source
scival
Published In
Journal of Hepatology
Volume
58
Issue
2
Publish Date
2013
Start Page
402
End Page
403
DOI
10.1016/j.jhep.2012.09.035

Hedgehog controls hepatic stellate cell fate by regulating metabolism.

BACKGROUND & AIMS: The pathogenesis of cirrhosis, a disabling outcome of defective liver repair, involves deregulated accumulation of myofibroblasts derived from quiescent hepatic stellate cells (HSCs), but the mechanisms that control transdifferentiation of HSCs are poorly understood. We investigated whether the Hedgehog (Hh) pathway controls the fate of HSCs by regulating metabolism. METHODS: Microarray, quantitative polymerase chain reaction, and immunoblot analyses were used to identify metabolic genes that were differentially expressed in quiescent vs myofibroblast HSCs. Glycolysis and lactate production were disrupted in HSCs to determine if metabolism influenced transdifferentiation. Hh signaling and hypoxia-inducible factor 1α (HIF1α) activity were altered to identify factors that alter glycolytic activity. Changes in expression of genes that regulate glycolysis were quantified and localized in biopsy samples from patients with cirrhosis and liver samples from mice following administration of CCl(4) or bile duct ligation. Mice were given systemic inhibitors of Hh to determine if they affect glycolytic activity of the hepatic stroma; Hh signaling was also conditionally disrupted in myofibroblasts to determine the effects of glycolytic activity. RESULTS: Transdifferentiation of cultured, quiescent HSCs into myofibroblasts induced glycolysis and caused lactate accumulation. Increased expression of genes that regulate glycolysis required Hh signaling and involved induction of HIF1α. Inhibitors of Hh signaling, HIF1α, glycolysis, or lactate accumulation converted myofibroblasts to quiescent HSCs. In diseased livers of animals and patients, numbers of glycolytic stromal cells were associated with the severity of fibrosis. Conditional disruption of Hh signaling in myofibroblasts reduced numbers of glycolytic myofibroblasts and liver fibrosis in mice; similar effects were observed following administration of pharmacologic inhibitors of Hh. CONCLUSIONS: Hedgehog signaling controls the fate of HSCs by regulating metabolism. These findings might be applied to diagnosis and treatment of patients with cirrhosis.

Authors
Chen, Y; Choi, SS; Michelotti, GA; Chan, IS; Swiderska-Syn, M; Karaca, GF; Xie, G; Moylan, CA; Garibaldi, F; Premont, R; Suliman, HB; Piantadosi, CA; Diehl, AM
MLA Citation
Chen, Y, Choi, SS, Michelotti, GA, Chan, IS, Swiderska-Syn, M, Karaca, GF, Xie, G, Moylan, CA, Garibaldi, F, Premont, R, Suliman, HB, Piantadosi, CA, and Diehl, AM. "Hedgehog controls hepatic stellate cell fate by regulating metabolism." Gastroenterology 143.5 (November 2012): 1319-29.e1-11-.
PMID
22885334
Source
pubmed
Published In
Gastroenterology
Volume
143
Issue
5
Publish Date
2012
Start Page
1319-29.e1-11
DOI
10.1053/j.gastro.2012.07.115

Expression QTL analysis of a gene expression signature which predicts advanced non-alcoholic fatty liver disease

Authors
Garrett, ME; Moylan, CA; Gibson, J; Yang, H; Pang, H; Dellinger, A; Suzuki, A; Tillmann, HL; Guy, CD; Abdelmalek, MF; Murphy, SK; Diehl, AM; Hauser, M; Ashley-Koch, AE
MLA Citation
Garrett, ME, Moylan, CA, Gibson, J, Yang, H, Pang, H, Dellinger, A, Suzuki, A, Tillmann, HL, Guy, CD, Abdelmalek, MF, Murphy, SK, Diehl, AM, Hauser, M, and Ashley-Koch, AE. "Expression QTL analysis of a gene expression signature which predicts advanced non-alcoholic fatty liver disease." October 2012.
Source
wos-lite
Published In
Hepatology
Volume
56
Publish Date
2012
Start Page
267A
End Page
268A

CASE 6--2012: suspected amiodarone hepatotoxicity after cardiac surgery.

Authors
Thiele, RH; Williams, J; Moylan, CA; Rao, SV; Bennett-Guerrero, E
MLA Citation
Thiele, RH, Williams, J, Moylan, CA, Rao, SV, and Bennett-Guerrero, E. "CASE 6--2012: suspected amiodarone hepatotoxicity after cardiac surgery." Journal of cardiothoracic and vascular anesthesia 26.4 (August 2012): 729-732.
PMID
22516469
Source
epmc
Published In
Journal of Cardiothoracic and Vascular Anesthesia
Volume
26
Issue
4
Publish Date
2012
Start Page
729
End Page
732
DOI
10.1053/j.jvca.2012.02.002

A pre-marketing ALT signal predicts post-marketing liver safety.

Drug induced liver injury during drug development is evidenced by a higher incidence of serum alanine aminotransferase (ALT) elevations in treated versus placebo populations and termed an "ALT signal". We sought to quantify whether an ALT signal in pre-marketing clinical trials predicted post-marketing hepatotoxicity. Incidence of ALT elevations (ALT ≥ 3 times upper limits normal [× ULN]) for drug and placebo of new chemical entities and approved drugs associated with hepatotoxicity was calculated using the Food and Drug Administration (FDA) website. Post-marketing liver safety events were identified using the FDA Adverse Event Reporting System (AERS). The association of FDA AERS signal score (EB05 ≥ 2) and excess risk of pre-marketing ALT elevation (difference in incidence of ALT ≥ 3× ULN in treated versus placebo) was examined. An ALT signal of ≥ 1.2% was significantly associated with a post-marketing liver safety signal (p ≤ 0.013) and a 71.4% positive predictive value. An absent ALT signal was associated with a high likelihood of post-marketing liver safety; negative predictive value of 89.7%. Daily drug dose information improved the prediction of post-marketing liver safety. A cut-off of 1.2% increase in ALT ≥ 3× ULN in treated versus placebo groups provides an easily calculated method for predicting post-marketing liver safety.

Authors
Moylan, CA; Suzuki, A; Papay, JI; Yuen, NA; Ames, M; Hunt, CM
MLA Citation
Moylan, CA, Suzuki, A, Papay, JI, Yuen, NA, Ames, M, and Hunt, CM. "A pre-marketing ALT signal predicts post-marketing liver safety." Regul Toxicol Pharmacol 63.3 (August 2012): 433-439.
PMID
22668747
Source
pubmed
Published In
Regulatory Toxicology and Pharmacology
Volume
63
Issue
3
Publish Date
2012
Start Page
433
End Page
439
DOI
10.1016/j.yrtph.2012.05.016

Epigenetic Regulation of Gene Expression in NAFLD

Authors
Moylan, CA; Yang, H; Pang, H; Dellinger, A; Suzuki, A; Tillmann, HL; Guy, CD; Ashley-Koch, AE; Garrett, ME; Abdelmalek, MF; Hauser, MA; Murphy, SK; Diehl, AM
MLA Citation
Moylan, CA, Yang, H, Pang, H, Dellinger, A, Suzuki, A, Tillmann, HL, Guy, CD, Ashley-Koch, AE, Garrett, ME, Abdelmalek, MF, Hauser, MA, Murphy, SK, and Diehl, AM. "Epigenetic Regulation of Gene Expression in NAFLD." May 2012.
Source
wos-lite
Published In
Gastroenterology
Volume
142
Issue
5
Publish Date
2012
Start Page
S929
End Page
S929

Retraction: Acharya CR, et al. Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer. JAMA. 2008;299(13):1574-1587.

Authors
Acharya, CR; Hsu, DS; Anders, CK; Anguiano, A; Salter, KH; Walters, KS; Redman, RC; Tuchman, SA; Moylan, CA; Mukherjee, S; Barry, WT; Dressman, HK; Ginsburg, GS; Marcom, KP; Garman, KS; Lyman, GH; Nevins, JR; Potti, A
MLA Citation
Acharya, CR, Hsu, DS, Anders, CK, Anguiano, A, Salter, KH, Walters, KS, Redman, RC, Tuchman, SA, Moylan, CA, Mukherjee, S, Barry, WT, Dressman, HK, Ginsburg, GS, Marcom, KP, Garman, KS, Lyman, GH, Nevins, JR, and Potti, A. "Retraction: Acharya CR, et al. Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer. JAMA. 2008;299(13):1574-1587." JAMA 307.5 (February 1, 2012): 453-.
PMID
22228686
Source
pubmed
Published In
JAMA : the journal of the American Medical Association
Volume
307
Issue
5
Publish Date
2012
Start Page
453
DOI
10.1001/jama.2012.2

HEDGEHOG PATHWAY INHIBITION BY GDC-0449 CAUSES REGRESSION OF HEPATOCELLULAR CARCINOMAS AND IMPROVES LIVER FIBROSIS IN MDR2-DEFICIENT MICE

Authors
Chan, IS; Philips, GM; Zdanowicz, M; Teaberry, V; Karaca, G; Rangwala, F; Guy, CD; Moylan, CA; Venkatraman, T; Feuerlein, S; Syn, W-K; Jung, Y; Witek, RP; Michelotti, GA; Choi, SS; Merkle, EM; Lascola, C; Diehl, AM
MLA Citation
Chan, IS, Philips, GM, Zdanowicz, M, Teaberry, V, Karaca, G, Rangwala, F, Guy, CD, Moylan, CA, Venkatraman, T, Feuerlein, S, Syn, W-K, Jung, Y, Witek, RP, Michelotti, GA, Choi, SS, Merkle, EM, Lascola, C, and Diehl, AM. "HEDGEHOG PATHWAY INHIBITION BY GDC-0449 CAUSES REGRESSION OF HEPATOCELLULAR CARCINOMAS AND IMPROVES LIVER FIBROSIS IN MDR2-DEFICIENT MICE." October 2011.
Source
wos-lite
Published In
Hepatology
Volume
54
Publish Date
2011
Start Page
1278A
End Page
1278A

TRANSITION OF QUIESCENT STELLATE CELLS INTO MYOFIBROBLASTS REQUIRES HEDGEHOG-MEDIATED INDUCTION OF GLYCOLYSIS

Authors
Chen, Y; Choi, SS; Michelotti, GA; Moylan, CA; Karaca, G; Zdanowicz, M; Xie, G; Kruger, L; Diehl, AM
MLA Citation
Chen, Y, Choi, SS, Michelotti, GA, Moylan, CA, Karaca, G, Zdanowicz, M, Xie, G, Kruger, L, and Diehl, AM. "TRANSITION OF QUIESCENT STELLATE CELLS INTO MYOFIBROBLASTS REQUIRES HEDGEHOG-MEDIATED INDUCTION OF GLYCOLYSIS." October 2011.
Source
wos-lite
Published In
Hepatology
Volume
54
Publish Date
2011
Start Page
422A
End Page
422A

HEDGEHOG PATHWAY INHIBITION INDUCES HCC TUMOR NECROSIS BY REPRESSING EXPRESSION OF ANGIOPOIETIN-2 AND ITS COGNATE RECEPTOR, TIE-2

Authors
Philips, GM; Chan, IS; Choi, SS; Xie, G; Michelotti, GA; Zdanowicz, M; Teaberry, V; Rangwala, F; Guy, CD; Karaca, G; Venkatraman, T; Feuerlein, S; Moylan, CA; Syn, W-K; Jung, Y; Witek, RP; Merkle, EM; Lascola, C; Diehl, AM
MLA Citation
Philips, GM, Chan, IS, Choi, SS, Xie, G, Michelotti, GA, Zdanowicz, M, Teaberry, V, Rangwala, F, Guy, CD, Karaca, G, Venkatraman, T, Feuerlein, S, Moylan, CA, Syn, W-K, Jung, Y, Witek, RP, Merkle, EM, Lascola, C, and Diehl, AM. "HEDGEHOG PATHWAY INHIBITION INDUCES HCC TUMOR NECROSIS BY REPRESSING EXPRESSION OF ANGIOPOIETIN-2 AND ITS COGNATE RECEPTOR, TIE-2." October 2011.
Source
wos-lite
Published In
Hepatology
Volume
54
Publish Date
2011
Start Page
1280A
End Page
1280A

Coffee's Beneficial Effect on Liver Disease Confirmed in NASH Cohort, but Only Partially Confirmation of In Vitro Pre-Described Differentially Expressed Genes in This Patient Cohort

Authors
Tillmann, HL; Pang, H; Dellinger, A; Suzuki, A; Guy, CD; Moylan, CA; Piercy, D; Smith, M; Hauser, MA; Diehl, AM; Abdelmalek, ME
MLA Citation
Tillmann, HL, Pang, H, Dellinger, A, Suzuki, A, Guy, CD, Moylan, CA, Piercy, D, Smith, M, Hauser, MA, Diehl, AM, and Abdelmalek, ME. "Coffee's Beneficial Effect on Liver Disease Confirmed in NASH Cohort, but Only Partially Confirmation of In Vitro Pre-Described Differentially Expressed Genes in This Patient Cohort." May 2011.
Source
wos-lite
Published In
Gastroenterology
Volume
140
Issue
5
Publish Date
2011
Start Page
S987
End Page
S987

COFFEE CONSUMPTION INCREASES HEPATIC EXPRESSION OF CYTOCHROME P450S AND SIGNIFICANTLY REDUCES LIVER FIBROSIS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Authors
Tillmann, H; Suzuki, A; Pang, H; Dellinger, A; Guy, CD; Moylan, CA; Piercy, D; Smith, M; Hauser, MA; Diehl, AME; Abdelmalek, MF
MLA Citation
Tillmann, H, Suzuki, A, Pang, H, Dellinger, A, Guy, CD, Moylan, CA, Piercy, D, Smith, M, Hauser, MA, Diehl, AME, and Abdelmalek, MF. "COFFEE CONSUMPTION INCREASES HEPATIC EXPRESSION OF CYTOCHROME P450S AND SIGNIFICANTLY REDUCES LIVER FIBROSIS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)." March 2011.
Source
wos-lite
Published In
Journal of Hepatology
Volume
54
Publish Date
2011
Start Page
S346
End Page
S347

Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. Recently, we showed that NASH-related cirrhosis is associated with Hedgehog (Hh) pathway activation. The gene encoding osteopontin (OPN), a profibrogenic extracellular matrix protein and cytokine, is a direct transcriptional target of the Hh pathway. Thus, we hypothesize that Hh signaling induces OPN to promote liver fibrosis in NASH. Hepatic OPN expression and liver fibrosis were analyzed in wild-type (WT) mice, Patched-deficient (Ptc(+/-) ) (overly active Hh signaling) mice, and OPN-deficient mice before and after feeding methionine and choline-deficient (MCD) diets to induce NASH-related fibrosis. Hepatic OPN was also quantified in human NASH and nondiseased livers. Hh signaling was manipulated in cultured liver cells to assess direct effects on OPN expression, and hepatic stellate cells (HSCs) were cultured in medium with different OPN activities to determine effects on HSC phenotype. When fed MCD diets, Ptc(+/-) mice expressed more OPN and developed worse liver fibrosis (P < 0.05) than WT mice, whereas OPN-deficient mice exhibited reduced fibrosis (P < 0.05). In NASH patients, OPN was significantly up-regulated and correlated with Hh pathway activity and fibrosis stage. During NASH, ductular cells strongly expressed OPN. In cultured HSCs, SAG (an Hh agonist) up-regulated, whereas cyclopamine (an Hh antagonist) repressed OPN expression (P < 0.005). Cholangiocyte-derived OPN and recombinant OPN promoted fibrogenic responses in HSCs (P < 0.05); neutralizing OPN with RNA aptamers attenuated this (P < 0.05).OPN is Hh-regulated and directly promotes profibrogenic responses. OPN induction correlates with Hh pathway activity and fibrosis stage. Therefore, OPN inhibition may be beneficial in NASH.

Authors
Syn, W-K; Choi, SS; Liaskou, E; Karaca, GF; Agboola, KM; Oo, YH; Mi, Z; Pereira, TA; Zdanowicz, M; Malladi, P; Chen, Y; Moylan, C; Jung, Y; Bhattacharya, SD; Teaberry, V; Omenetti, A; Abdelmalek, MF; Guy, CD; Adams, DH; Kuo, PC; Michelotti, GA; Whitington, PF; Diehl, AM
MLA Citation
Syn, W-K, Choi, SS, Liaskou, E, Karaca, GF, Agboola, KM, Oo, YH, Mi, Z, Pereira, TA, Zdanowicz, M, Malladi, P, Chen, Y, Moylan, C, Jung, Y, Bhattacharya, SD, Teaberry, V, Omenetti, A, Abdelmalek, MF, Guy, CD, Adams, DH, Kuo, PC, Michelotti, GA, Whitington, PF, and Diehl, AM. "Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis." Hepatology (Baltimore, Md.) 53.1 (January 2011): 106-115.
PMID
20967826
Source
epmc
Published In
Hepatology
Volume
53
Issue
1
Publish Date
2011
Start Page
106
End Page
115
DOI
10.1002/hep.23998

Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.

OBJECTIVE: Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/-) mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC. METHODS: Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/-) mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. RESULTS: Unlike controls, Mdr2(-/-) mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. CONCLUSIONS: Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.

Authors
Philips, GM; Chan, IS; Swiderska, M; Schroder, VT; Guy, C; Karaca, GF; Moylan, C; Venkatraman, T; Feuerlein, S; Syn, W-K; Jung, Y; Witek, RP; Choi, S; Michelotti, GA; Rangwala, F; Merkle, E; Lascola, C; Diehl, AM
MLA Citation
Philips, GM, Chan, IS, Swiderska, M, Schroder, VT, Guy, C, Karaca, GF, Moylan, C, Venkatraman, T, Feuerlein, S, Syn, W-K, Jung, Y, Witek, RP, Choi, S, Michelotti, GA, Rangwala, F, Merkle, E, Lascola, C, and Diehl, AM. "Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer." PLoS One 6.9 (2011): e23943-.
Website
http://hdl.handle.net/10161/11084
PMID
21912653
Source
pubmed
Published In
PloS one
Volume
6
Issue
9
Publish Date
2011
Start Page
e23943
DOI
10.1371/journal.pone.0023943

Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma.

Hedgehog (Hh) pathway activation promotes many processes that occur during fibrogenic liver repair. Whether the Hh pathway modulates the outcomes of virally mediated liver injury has never been examined. Gene-profiling studies of human hepatocellular carcinomas (HCCs) demonstrate Hh pathway activation in HCCs related to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Because most HCCs develop in cirrhotic livers, we hypothesized that Hh pathway activation occurs during fibrogenic repair of liver damage due to chronic viral hepatitis, and that Hh-responsive cells mediate disease progression and hepatocarciongenesis in chronic viral hepatitis. Immunohistochemistry and qRT-PCR analysis were used to analyze Hh pathway activation and identify Hh-responsive cell types in liver biopsies from 45 patients with chronic HBV or HCV. Hh signaling was then manipulated in cultured liver cells to directly assess the impact of Hh activity in relevant cell types. We found increased hepatic expression of Hh ligands in all patients with chronic viral hepatitis, and demonstrated that infection with HCV stimulated cultured hepatocytes to produce Hh ligands. The major cell populations that expanded during cirrhosis and HCC (ie, liver myofibroblasts, activated endothelial cells, and progenitors expressing markers of tumor stem/initiating cells) were Hh responsive, and higher levels of Hh pathway activity associated with cirrhosis and HCC. Inhibiting pathway activity in Hh-responsive target cells reduced fibrogenesis, angiogenesis, and growth. In conclusion, HBV/HCV infection increases hepatocyte production of Hh ligands and expands the types of Hh-responsive cells that promote liver fibrosis and cancer.

Authors
Pereira, TDA; Witek, RP; Syn, W-K; Choi, SS; Bradrick, S; Karaca, GF; Agboola, KM; Jung, Y; Omenetti, A; Moylan, CA; Yang, L; Fernandez-Zapico, ME; Jhaveri, R; Shah, VH; Pereira, FE; Diehl, AM
MLA Citation
Pereira, TDA, Witek, RP, Syn, W-K, Choi, SS, Bradrick, S, Karaca, GF, Agboola, KM, Jung, Y, Omenetti, A, Moylan, CA, Yang, L, Fernandez-Zapico, ME, Jhaveri, R, Shah, VH, Pereira, FE, and Diehl, AM. "Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma." Lab Invest 90.12 (December 2010): 1690-1703.
Website
http://hdl.handle.net/10161/11085
PMID
20697376
Source
pubmed
Published In
Laboratory Investigation
Volume
90
Issue
12
Publish Date
2010
Start Page
1690
End Page
1703
DOI
10.1038/labinvest.2010.147

Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the hedgehog pathway.

Trans-differentiation of quiescent hepatic stellate cells (Q-HSCs), which exhibit epithelial and adipocytic features, into myofibroblastic-HSC (MF-HSCs) is a key event in liver fibrosis. Culture models demonstrated that Hedgehog (Hh) pathway activation is required for transition of epithelioid/adipocytic Q-HSCs into MF-HSCs. Hh signaling inhibits adiposity and promotes epithelial-to-mesenchymal transitions (EMTs). Leptin (anti-adipogenic, pro-EMT factor) promotes HSC trans-differentiation and liver fibrosis, suggesting that the pathways may interact to modulate cell fate. This study aimed to determine whether leptin activates Hh signaling and whether this is required for the fibrogenic effects of leptin. Cultures of primary HSCs from lean and fa/fa rats with an inherited ObRb defect were examined. Inhibitors of PI3K/Akt, JAK/STAT, and Hh signaling were used to delineate how ObRb activation influenced Hh signaling and HSC trans-differentiation. Fibrogenesis was compared in wild type and db/db mice (impaired ObRb function) to assess the profibrotic role of leptin. The results demonstrate that leptin-ObR interactions activate Hh signaling with the latter necessary to promote trans-differentiation. Leptin-related increases in Hh signaling required ObR induction of PI3K/Akt, which was sufficient for leptin to repress the epithelioid/adipocytic program. Leptin-mediated induction of JAK/STAT was required for mesenchymal gene expression. Leptin-ObRb interactions were not necessary for HSC trans-differentiation to occur in vitro or in vivo but are important because liver fibrogenesis was attenuated in db/db mice. These findings reveal that leptin activates Hh signaling to alter gene expression programs that control cell fate and have important implications for liver fibrosis and other leptin-regulated processes involving EMTs, including development, obesity, and cancer metastasis.

Authors
Choi, SS; Syn, W-K; Karaca, GF; Omenetti, A; Moylan, CA; Witek, RP; Agboola, KM; Jung, Y; Michelotti, GA; Diehl, AM
MLA Citation
Choi, SS, Syn, W-K, Karaca, GF, Omenetti, A, Moylan, CA, Witek, RP, Agboola, KM, Jung, Y, Michelotti, GA, and Diehl, AM. "Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the hedgehog pathway." J Biol Chem 285.47 (November 19, 2010): 36551-36560.
PMID
20843817
Source
pubmed
Published In
The Journal of biological chemistry
Volume
285
Issue
47
Publish Date
2010
Start Page
36551
End Page
36560
DOI
10.1074/jbc.M110.168542

CO-CULTURE OF LIVER EPITHELIAL CELLS STABLY TRANSFECTED WITH HEPATITIS B VIRUS X PROTEIN PROMOTES MYOFIBROBLASTIC ACTIVATION AND ACCUMULATION VIA A HEDGEHOG-MEDIATED PROCESS IN RAT HEPATIC STELLATE CELLS

Authors
Choi, SS; Pereira, TA; Syn, W-K; Agboola, KM; Moylan, CA; Omenetti, A; Karaca, GF; Rangwala, F; Jhaveri, R; Diehl, AM
MLA Citation
Choi, SS, Pereira, TA, Syn, W-K, Agboola, KM, Moylan, CA, Omenetti, A, Karaca, GF, Rangwala, F, Jhaveri, R, and Diehl, AM. "CO-CULTURE OF LIVER EPITHELIAL CELLS STABLY TRANSFECTED WITH HEPATITIS B VIRUS X PROTEIN PROMOTES MYOFIBROBLASTIC ACTIVATION AND ACCUMULATION VIA A HEDGEHOG-MEDIATED PROCESS IN RAT HEPATIC STELLATE CELLS." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
977A
End Page
978A

NASH INCREASES THE RISK OF PORTAL VEIN THROMBOSIS IN PATIENTS ON THE LIVER TRANSPLANT WAITING LIST

Authors
Forssen, U; Kobayashi, M; Moylan, CA; Ludema, CM; Theodore, D
MLA Citation
Forssen, U, Kobayashi, M, Moylan, CA, Ludema, CM, and Theodore, D. "NASH INCREASES THE RISK OF PORTAL VEIN THROMBOSIS IN PATIENTS ON THE LIVER TRANSPLANT WAITING LIST." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
911A
End Page
911A

OSTEOPONTIN PROMOTES NONALCOHOLIC FATTY LIVER DISEASE PROGRESSION

Authors
Syn, W-K; Choi, SS; Liaskou, E; Karaca, GF; Oo, YH; Pereira, TA; Bhattacharya, SD; Moylan, CA; Agboola, KM; Omenetti, A; Schroder, VT; Mi, Z; Guy, CD; Abdelmalek, MF; Potti, A; Kuo, PC; Michelotti, GA; Adams, DH; Diehl, AM
MLA Citation
Syn, W-K, Choi, SS, Liaskou, E, Karaca, GF, Oo, YH, Pereira, TA, Bhattacharya, SD, Moylan, CA, Agboola, KM, Omenetti, A, Schroder, VT, Mi, Z, Guy, CD, Abdelmalek, MF, Potti, A, Kuo, PC, Michelotti, GA, Adams, DH, and Diehl, AM. "OSTEOPONTIN PROMOTES NONALCOHOLIC FATTY LIVER DISEASE PROGRESSION." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
350A
End Page
351A

CONSERVED GENE EXPRESSION PATTERNS IN MYOFIBROBLASTIC MURINE AND HUMAN HEPATIC STELLATE CELLS AND NAFLD PATIENTS WITH LIVER FIBROSIS COMPATIBLE WITH EPITHELIAL-TO-MESENCHYMAL LIKE TRANSITION

Authors
Moylan, CA; Choi, SS; Dellinger, A; Pang, H; Abdelmalek, MF; Hampton, D; Chen, Y; Omenetti, A; Suzuki, A; Tillmann, HL; Acharya, CR; Potti, A; Hauser, MA; Diehl, AM
MLA Citation
Moylan, CA, Choi, SS, Dellinger, A, Pang, H, Abdelmalek, MF, Hampton, D, Chen, Y, Omenetti, A, Suzuki, A, Tillmann, HL, Acharya, CR, Potti, A, Hauser, MA, and Diehl, AM. "CONSERVED GENE EXPRESSION PATTERNS IN MYOFIBROBLASTIC MURINE AND HUMAN HEPATIC STELLATE CELLS AND NAFLD PATIENTS WITH LIVER FIBROSIS COMPATIBLE WITH EPITHELIAL-TO-MESENCHYMAL LIKE TRANSITION." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
1286A
End Page
1287A

SIGNALS FROM THE FIBROTIC LIVER IN PATIENTS WITH NAFLD MAY PROMOTE DIABETES AND OBESITY

Authors
Moylan, CA; Abdelmalek, MF; Pang, H; Dellinger, A; Choi, SS; Omenetti, A; Chen, Y; Hampton, D; Syn, W-K; Suzuki, A; Tillmann, HL; Acharya, CR; Potti, A; Hauser, MA; Diehl, AM
MLA Citation
Moylan, CA, Abdelmalek, MF, Pang, H, Dellinger, A, Choi, SS, Omenetti, A, Chen, Y, Hampton, D, Syn, W-K, Suzuki, A, Tillmann, HL, Acharya, CR, Potti, A, Hauser, MA, and Diehl, AM. "SIGNALS FROM THE FIBROTIC LIVER IN PATIENTS WITH NAFLD MAY PROMOTE DIABETES AND OBESITY." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
1049A
End Page
1050A

Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells.

Hepatic accumulation of myofibroblastic hepatic stellate cells (MF-HSCs) is pivotal in the pathogenesis of cirrhosis. Two events are necessary for MF-HSCs to accumulate in damaged livers: transition of resident, quiescent hepatic stellate cells (Q-HSCs) to MF-HSCs and expansion of MF-HSC numbers through increased proliferation and/or reduced apoptosis. In this study, we identified two novel mediators of MF-HSC accumulation: Ras-related C3 botulinum toxin substrate 1 (Rac1) and Hedgehog (Hh). It is unclear whether Rac1 and Hh interact to regulate the accumulation of MF-HSCs. We evaluated the hypothesis that Rac1 promotes activation of the Hh pathway, thereby stimulating signals that promote transition of Q-HSCs into MF-HSCs and enhance the viability of MF-HSCs. Using both in vitro and in vivo model systems, Rac1 activity was manipulated through adenoviral vector-mediated delivery of constitutively active or dominant-negative rac1. Rac1-transgenic mice with targeted myofibroblast expression of a mutated human rac1 transgene that produces constitutively active Rac1 were also examined. Results in all models demonstrated that activating Rac1 in HSC enhanced Hh signaling, promoted acquisition/maintenance of the MF-HSC phenotype, increased MF-HSC viability, and exacerbated fibrogenesis. Conversely, inhibiting Rac1 with dominant-negative rac1 reversed these effects in all systems examined. Pharmacologic manipulation of Hh signaling demonstrated that profibrogenic actions of Rac1 were mediated by its ability to activate Hh pathway-dependent mechanisms that stimulated myofibroblastic transition of HSCs and enhanced MF-HSC viability.These findings demonstrate that interactions between Rac1 and the Hh pathway control the size of MF-HSC populations and have important implications for the pathogenesis of cirrhosis.

Authors
Choi, SS; Witek, RP; Yang, L; Omenetti, A; Syn, W-K; Moylan, CA; Jung, Y; Karaca, GF; Teaberry, VS; Pereira, TA; Wang, J; Ren, X-R; Diehl, AM
MLA Citation
Choi, SS, Witek, RP, Yang, L, Omenetti, A, Syn, W-K, Moylan, CA, Jung, Y, Karaca, GF, Teaberry, VS, Pereira, TA, Wang, J, Ren, X-R, and Diehl, AM. "Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells." Hepatology (Baltimore, Md.) 52.1 (July 2010): 278-290.
PMID
20578145
Source
epmc
Published In
Hepatology
Volume
52
Issue
1
Publish Date
2010
Start Page
278
End Page
290
DOI
10.1002/hep.23649

Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis.

Myofibroblastic hepatic stellate cells (MF-HSC) are derived from quiescent hepatic stellate cells (Q-HSC). Q-HSC express certain epithelial cell markers and have been reported to form junctional complexes similar to epithelial cells. We have shown that Hedgehog (Hh) signaling plays a key role in HSC growth. Because Hh ligands regulate epithelial-to-mesenchymal transition (EMT), we determined whether Q-HSC express EMT markers and then assessed whether these markers change as Q-HSC transition into MF-HSC and whether the process is modulated by Hh signaling. Q-HSC were isolated from healthy livers and cultured to promote myofibroblastic transition. Changes in mRNA and protein expression of epithelial and mesenchymal markers, Hh ligands, and target genes were monitored in HSC treated with and without cyclopamine (an Hh inhibitor). Studies were repeated in primary human HSC and clonally derived HSC from a cirrhotic rat. Q-HSC activation in vitro (culture) and in vivo (CCl(4)-induced cirrhosis) resulted in decreased expression of Hh-interacting protein (Hhip, an Hh antagonist), the EMT inhibitors bone morphogenic protein (BMP-7) and inhibitor of differentiation (Id2), the adherens junction component E-cadherin, and epithelial keratins 7 and 19 and increased expression of Gli2 (an Hh target gene) and mesenchymal markers, including the mesenchyme-associated transcription factors Lhx2 and Msx2, the myofibroblast marker alpha-smooth muscle actin, and matrix molecules such as collagen. Cyclopamine reverted myofibroblastic transition, reducing mesenchymal gene expression while increasing epithelial markers in rodent and human HSC. We conclude that Hh signaling plays a key role in transition of Q-HSC into MF-HSC. Our findings suggest that Q-HSC are capable of transitioning between epithelial and mesenchymal fates.

Authors
Choi, SS; Omenetti, A; Witek, RP; Moylan, CA; Syn, W-K; Jung, Y; Yang, L; Sudan, DL; Sicklick, JK; Michelotti, GA; Rojkind, M; Diehl, AM
MLA Citation
Choi, SS, Omenetti, A, Witek, RP, Moylan, CA, Syn, W-K, Jung, Y, Yang, L, Sudan, DL, Sicklick, JK, Michelotti, GA, Rojkind, M, and Diehl, AM. "Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis." Am J Physiol Gastrointest Liver Physiol 297.6 (December 2009): G1093-G1106.
PMID
19815628
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
297
Issue
6
Publish Date
2009
Start Page
G1093
End Page
G1106
DOI
10.1152/ajpgi.00292.2009

Disparities in liver transplantation before and after introduction of the MELD score.

CONTEXT: In February 2002, the allocation system for liver transplantation became based on the Model for End-Stage Liver Disease (MELD) score. Before MELD, black patients were more likely to die or become too sick to undergo liver transplantation compared with white patients. Little information exists regarding sex and access to liver transplantation. OBJECTIVE: To determine the association between race, sex, and liver transplantation following introduction of the MELD system. DESIGN, SETTING, AND PATIENTS: A retrospective cohort of black and white patients (> or = 18 years) registered on the United Network for Organ Sharing liver transplantation waiting list between January 1, 1996, and December 31, 2000 (pre-MELD cohort, n = 21 895) and between February 28, 2002, and March 31, 2006 (post-MELD cohort, n = 23 793). MAIN OUTCOME MEASURES: Association between race, sex, and receipt of a liver transplant. Separate multivariable analyses evaluated cohorts within each period to identify predictors of time to death and the odds of dying or receiving liver transplantation within 3 years of listing. Patients with hepatocellular carcinoma were analyzed separately. RESULTS: Black patients were younger (mean [SD], 49.2 [10.7] vs 52.4 [9.2] years; P < .001) and sicker (MELD score at listing: median [interquartile range], 16 [12-22] vs 14 [11-19]; P < .001) than white patients on the waiting list for both periods. In the pre-MELD cohort, black patients were more likely to die or become too sick for liver transplantation than white patients (27.0% vs 21.7%) within 3 years of registering on the waiting list (odds ratio [OR], 1.51; 95% confidence interval (CI), 1.15-1.98; P = .003). In the post-MELD cohort, black race was no longer associated with increased likelihood of death or becoming too sick for liver transplantation (26.5% vs 22.0%, respectively; OR, 0.96; 95% CI, 0.74-1.26; P = .76). Black patients were also less likely to receive a liver transplant than white patients within 3 years of registering on the waiting list pre-MELD (61.6% vs 66.9%; OR, 0.75; 95% CI, 0.59-0.97; P = .03), whereas post-MELD, race was no longer significantly associated with receipt of a liver transplant (47.5% vs 45.5%, respectively; OR, 1.04; 95% CI, 0.84-1.28; P = .75). Women were more likely than men to die or become too sick for liver transplantation post-MELD (23.7% vs 21.4%; OR, 1.30; 95% CI, 1.08-1.47; P = .003) vs pre-MELD (22.4% vs 21.9%; OR, 1.08; 95% CI, 0.91-1.26; P = .37). Similarly, women were less likely than men to receive a liver transplant within 3 years both pre-MELD (64.8% vs 67.6%; OR, 0.80; 95% CI, 0.70-0.92; P = .002) and post-MELD (39.9% vs 48.7%; OR, 0.70; 95% CI, 0.62-0.79; P < .001). CONCLUSION: Following introduction of the MELD score to the liver transplantation allocation system, race was no longer associated with receipt of a liver transplant or death on the waiting list, but disparities based on sex remain.

Authors
Moylan, CA; Brady, CW; Johnson, JL; Smith, AD; Tuttle-Newhall, JE; Muir, AJ
MLA Citation
Moylan, CA, Brady, CW, Johnson, JL, Smith, AD, Tuttle-Newhall, JE, and Muir, AJ. "Disparities in liver transplantation before and after introduction of the MELD score." JAMA 300.20 (November 26, 2008): 2371-2378.
PMID
19033587
Source
pubmed
Published In
JAMA : the journal of the American Medical Association
Volume
300
Issue
20
Publish Date
2008
Start Page
2371
End Page
2378
DOI
10.1001/jama.2008.720

GENE EXPRESSION PROFILES COUPLED WITH SIGNATURES OF ONCOGENIC PATHWAY DYSREGULATION PROVIDE A RATIONAL APPROACH TO DISSECTING THE MOLECULAR HETEROGENEITY OF HEPATOCELLULAR CARCINOMA

Authors
Moylan, CA; Choi, SS; Acharya, CR; Salter, K; Muir, AJ; Potti, A; Diehl, AM
MLA Citation
Moylan, CA, Choi, SS, Acharya, CR, Salter, K, Muir, AJ, Potti, A, and Diehl, AM. "GENE EXPRESSION PROFILES COUPLED WITH SIGNATURES OF ONCOGENIC PATHWAY DYSREGULATION PROVIDE A RATIONAL APPROACH TO DISSECTING THE MOLECULAR HETEROGENEITY OF HEPATOCELLULAR CARCINOMA." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
1120A
End Page
1120A

Intersection of child abuse and children's exposure to domestic violence.

This review addresses research on the overlap in physical child abuse and domestic violence, the prediction of child outcomes, and resilience in children exposed to family violence. The authors explore current findings on the intersection of physical child abuse and domestic violence within the context of other risk factors, including community violence and related family and environmental stressors. Evidence from the studies reviewed suggests considerable overlap, compounding effects, and possible gender differences in outcomes of violence exposure. The data indicate a need to apply a broad conceptualization of risk to the study of family violence and its effects on children. Further testing of competing theoretical models will advance understanding of the pathways through which exposure leads to later problems in youth, as well as protective factors and processes through which resilience unfolds.

Authors
Herrenkohl, TI; Sousa, C; Tajima, EA; Herrenkohl, RC; Moylan, CA
MLA Citation
Herrenkohl, TI, Sousa, C, Tajima, EA, Herrenkohl, RC, and Moylan, CA. "Intersection of child abuse and children's exposure to domestic violence." Trauma Violence Abuse 9.2 (April 2008): 84-99. (Review)
PMID
18296571
Source
pubmed
Published In
Trauma, Violence, & Abuse
Volume
9
Issue
2
Publish Date
2008
Start Page
84
End Page
99
DOI
10.1177/1524838008314797

Predicting CD4 lymphocyte count

Clinical criteria are recommended to select HIV-infected patients for initiation of antiretroviral therapy when CD4 lymphocyte testing is unavailable. We evaluated the performance characteristics of WHO staging criteria, anthropometrics, and simple laboratory measurements for predicting CD4 lymphocyte count (CD4 count) or=120 mm/h, or the presence of mucocutaneous manifestations yielded a sensitivity of 0.85 and specificity of 0.63 for predicting CD4 count or=120 mm/h was a strong predictor of CD4 count

Authors
Morpeth, SC; Crump, JA; Shao, HJ; Ramadhani, HO; Kisenge, PR; Moylan, CA; Naggie, S; Caram, LB; Landman, KZ; Sam, NE; Itemba, DK; Shao, JF; Bartlett, JA; Thielman, NM
MLA Citation
Morpeth, SC, Crump, JA, Shao, HJ, Ramadhani, HO, Kisenge, PR, Moylan, CA, Naggie, S, Caram, LB, Landman, KZ, Sam, NE, Itemba, DK, Shao, JF, Bartlett, JA, and Thielman, NM. "Predicting CD4 lymphocyte count." AIDS research and human retroviruses 23.10 (October 2007): 1230-1236. (Academic Article)
Source
manual
Published In
AIDS Research and Human Retroviruses
Volume
23
Issue
10
Publish Date
2007
Start Page
1230
End Page
1236

Predicting CD4 lymphocyte count <200 cells/mm(3) in an HIV type 1-infected African population.

Clinical criteria are recommended to select HIV-infected patients for initiation of antiretroviral therapy when CD4 lymphocyte testing is unavailable. We evaluated the performance characteristics of WHO staging criteria, anthropometrics, and simple laboratory measurements for predicting CD4 lymphocyte count (CD4 count) <200 cells/mm(3) among HIV-infected patients in Tanzania. A total of 202 adults, diagnosed with HIV infection through community-based testing, underwent a detailed evaluation including staging history and examination, anthropometry, complete blood count, erythrocyte sedimentation rate (ESR), and CD4 count. Univariable analysis and recursive partitioning were used to identify characteristics associated with CD4 count 200 cells/mm(3). Of 202 participants 109 (54%) had a CD4 count <200 cells/mm(3). Characteristics most strongly associated with CD4 count <200 cells/mm(3) (p-value <0.0001) were the presence of mucocutaneous manifestations (72% vs. 28%), lower total lymphocyte count (TLC) (median 1,450 vs. 2,200 cells/mm(3)), lower total white blood cell count (median 4,200 vs. 5,500 cells/mm(3)), and higher ESR (median 95 vs. 53 mm/h). In a partition tree model, TLC <1,200 cells/mm(3), ESR >or=120 mm/h, or the presence of mucocutaneous manifestations yielded a sensitivity of 0.85 and specificity of 0.63 for predicting CD4 count <200 cells/mm(3). The sensitivity of the 2006 WHO Staging system improved from 0.75 to 0.93 with inclusion of these parameters, at the expense of specificity (0.36 to 0.26). The presence of mucocutaneous manifestations, TLC <1,200 cells/mm(3), or ESR >or=120 mm/h was a strong predictor of CD4 count <200 cells/mm(3) and enhanced the sensitivity of the 2006 WHO staging criteria for identifying patients likely to benefit from antiretrovirals.

Authors
Morpeth, SC; Crump, JA; Shao, HJ; Ramadhani, HO; Kisenge, PR; Moylan, CA; Naggie, S; Caram, LB; Landman, KZ; Sam, NE; Itemba, DK; Shao, JF; Bartlett, JA; Thielman, NM
MLA Citation
Morpeth, SC, Crump, JA, Shao, HJ, Ramadhani, HO, Kisenge, PR, Moylan, CA, Naggie, S, Caram, LB, Landman, KZ, Sam, NE, Itemba, DK, Shao, JF, Bartlett, JA, and Thielman, NM. "Predicting CD4 lymphocyte count <200 cells/mm(3) in an HIV type 1-infected African population." AIDS Res Hum Retroviruses 23.10 (October 2007): 1230-1236.
PMID
17961109
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
23
Issue
10
Publish Date
2007
Start Page
1230
End Page
1236
DOI
10.1089/aid.2007.0053

Factors influencing participation in hepatitis C research trials

Authors
Robertson, KD; Moylan, CA; Brady, CW; Muir, AJ
MLA Citation
Robertson, KD, Moylan, CA, Brady, CW, and Muir, AJ. "Factors influencing participation in hepatitis C research trials." September 2007.
Source
wos-lite
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
102
Publish Date
2007
Start Page
S224
End Page
S224

Treatment of hepatitis C in special populations.

Treatment options for hepatitis C virus (HCV) infection have improved significantly in recent years, however, treatment recommendations came from large clinical trials of highly selected patient populations. HCV infection has increased prevalence in African Americans and also in patients who have HIV infection, end-stage renal disease, and hemophilia. This article reviews recent findings from research in these patient groups and examines future directions and treatment trials.

Authors
Moylan, CA; Muir, AJ
MLA Citation
Moylan, CA, and Muir, AJ. "Treatment of hepatitis C in special populations." Clin Liver Dis 9.4 (November 2005): 567-v. (Review)
PMID
16207564
Source
pubmed
Published In
Clinics in Liver Disease
Volume
9
Issue
4
Publish Date
2005
Start Page
567
End Page
v
DOI
10.1016/j.cld.2005.07.005
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