Publications by authors named "Michael Charlton"

203 Publications

Risk of Hepatocellular Carcinoma in Patients With Nonalcoholic Steatohepatitis.

Authors:
Michael Charlton

Gastroenterol Hepatol (N Y) 2018 Apr;14(4):247-249

Professor of Medicine Director, Center for Liver Diseases The University of Chicago Medicine Chicago, Illinois.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009190PMC
April 2018

Class III obesity is a risk factor for the development of acute-on-chronic liver failure in patients with decompensated cirrhosis.

J Hepatol 2018 09 28;69(3):617-625. Epub 2018 Apr 28.

Division of Gastroenterology and Hepatology, Alameda Health System, Highland Hospital, Oakland, CA, United States.

Background & Aims: Acute-on-chronic liver failure (ACLF) is a syndrome of systemic inflammation and organ failures. Obesity, also characterized by chronic inflammation, is a risk factor among patients with cirrhosis for decompensation, infection, and mortality. Our aim was to test the hypothesis that obesity predisposes patients with decompensated cirrhosis to the development of ACLF.

Methods: We examined the United Network for Organ Sharing (UNOS) database, from 2005-2016, characterizing patients at wait-listing as non-obese (body mass index [BMI] <30), obese class I-II (BMI 30-39.9) and obese class III (BMI ≥40). ACLF was determined based on the CANONIC study definition. We used Cox proportional hazards regression to assess the association between obesity and ACLF development at liver transplantation (LT). We confirmed our findings using the Nationwide Inpatient Sample (NIS), years 2009-2013, using validated diagnostic coding algorithms to identify obesity, hepatic decompensation and ACLF. Logistic regression evaluated the association between obesity and ACLF occurrence.

Results: Among 387,884 patient records of decompensated cirrhosis, 116,704 (30.1%) were identified as having ACLF in both databases. Multivariable modeling from the UNOS database revealed class III obesity to be an independent risk factor for ACLF at LT (hazard ratio 1.24; 95% CI 1.09-1.41; p <0.001). This finding was confirmed using the NIS (odds ratio 1.30; 95% CI 1.25-1.35; p <0.001). Regarding specific organ failures, analysis of both registries demonstrated patients with class I-II and class III obesity had a greater prevalence of renal failure.

Conclusion: Class III obesity is a newly identified risk factor for ACLF development in patients with decompensated cirrhosis. Obese patients have a particularly high prevalence of renal failure as a component of ACLF. These findings have important implications regarding stratifying risk and preventing the occurrence of ACLF.

Lay Summary: In this study, we identify that among patients with decompensated cirrhosis, class III obesity (severe/morbid obesity) is a modifiable risk factor for the development of acute-on-chronic liver failure (ACLF). We further demonstrate that regarding the specific organ failures associated with ACLF, renal failure is significantly more prevalent in obese patients, particularly those with class III obesity. These findings underscore the importance of weight management in cirrhosis, to reduce the risk of ACLF. Patients with class III obesity should be monitored closely for the development of renal failure.
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http://dx.doi.org/10.1016/j.jhep.2018.04.016DOI Listing
September 2018

Model combining pre-transplant tumor biomarkers and tumor size shows more utility in predicting hepatocellular carcinoma recurrence and survival than the BALAD models.

World J Gastroenterol 2018 Mar;24(12):1321-1331

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States.

Aim: To assess the performance of BALAD, BALAD-2 and their component biomarkers in predicting outcome of hepatocellular carcinoma (HCC) patients after liver transplant.

Methods: BALAD score and BALAD-2 class are derived from bilirubin, albumin, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP). Pre-transplant AFP, AFP-L3 and DCP were measured in 113 patients transplanted for HCC from 2000 to 2008. Hazard ratios (HR) for recurrence and death were calculated. Univariate and multivariate regression analyses were conducted. C-statistics were used to compare biomarker-based to predictive models.

Results: During a median follow-up of 12.2 years, 38 patients recurred and 87 died. The HRs for recurrence in patients with elevated AFP, AFP-L3, and DCP defined by BALAD cut-off values were 2.42 (1.18-5.00), 1.86 (0.98-3.52), and 2.83 (1.42-5.61), respectively. For BALAD, the HRs for recurrence and death per unit increased score were 1.48 (1.15-1.91) and 1.59 (1.28-1.97). For BALAD-2, the HRs for recurrence and death per unit increased class were 1.45 (1.06-1.98) and 1.38 (1.09-1.76). For recurrence prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs. 0.64, 0.61, 0.53, and 0.53 for BALAD, BALAD-2, Milan, and UCSF, respectively. Similarly, for death prediction, the combination of three biomarkers had the highest c-statistic of 0.66 0.65, 0.61, 0.52, and 0.50 for BALAD, BALAD-2, Milan, and UCSF. A new model combining biomarkers with tumor size at the time of transplant (S-LAD) demonstrated the highest predictive capability with c-statistics of 0.71 and 0.69 for recurrence and death.

Conclusion: BALAD and BALAD-2 are valid in transplant HCC patients, but less predictive than the three biomarkers in combination or the three biomarkers in combination with maximal tumor diameter (S-LAD).
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http://dx.doi.org/10.3748/wjg.v24.i12.1321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871827PMC
March 2018

Baseline Factors Associated With Improvements in Decompensated Cirrhosis After Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection.

Gastroenterology 2018 06 11;154(8):2111-2121.e8. Epub 2018 Mar 11.

Beth Israel Deaconess Medical Center, Boston, Massachusetts. Electronic address:

Background & Aims: Treatment with direct-acting antiviral (DAA) agents can reduce Model for End-Stage Liver Disease and Child-Pugh-Turcotte (CPT) scores in patients with decompensated cirrhosis caused by hepatitis C virus. However, many of these patients still die or require liver transplantation. We collected data on baseline features of patients and aimed to develop a scoring system to predict response to DAA therapy.

Methods: We performed a retrospective analysis of data from 4 trials on the effects of sofosbuvir-based therapy in patients with hepatitis C virus-associated decompensated cirrhosis (502 of CPT class B and 120 of CPT class C). In these trials, patients were given 12 or 24 weeks of treatment with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin. We collected demographic, clinical, treatment response, and laboratory data from patients and tested their associations with patient outcomes at 36 weeks. The primary outcome was factors associated with reduction of CPT score to class A.

Results: The presence of ascites or encephalopathy, serum level of albumin <3.5 g/dL or alanine aminotransferase <60 U/L, and body mass index >25 kg/m were associated with an increased risk of not achieving a reduction in CPT to class A, independent of sustained viral response to therapy. Serum level of albumin <2.8 g/dL and abnormal level of bilirubin were associated with an increased risk of liver transplantation or death. We developed a scoring system based on 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated significantly with patient outcomes, which we called the "BE3A score." For patients with scores of 4-5, the hazard ratio for reduction of CPT score to class A was 52.3 (95% confidence interval, 15.2-179.7).

Conclusions: We identified 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated with a reduction of CPT score to class A in patients with hepatitis C virus-associated decompensated cirrhosis receiving DAA therapy. We developed a predictive score using these factors, called the BE3A score, which can be used as a shared decision-making tool, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis.
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http://dx.doi.org/10.1053/j.gastro.2018.03.022DOI Listing
June 2018

FGF-19 agonism for NASH: a short study of a long disease.

Authors:
Michael Charlton

Lancet 2018 03 5;391(10126):1124-1126. Epub 2018 Mar 5.

Center for Liver Diseases, University of Chicago, Chicago, IL 60637, USA. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(18)30425-2DOI Listing
March 2018

International Liver Transplantation Society Consensus Statement on Immunosuppression in Liver Transplant Recipients.

Transplantation 2018 05;102(5):727-743

Center Hépato-Biliaire, Hospital Paul-Brousse, Paris, France.

Effective immunosupression management is central to achieving optimal outcomes in liver transplant recipients. Current immunosuppression regimens and agents are highly effective in minimizing graft loss due to acute and chronic rejection but can also produce a substantial array of toxicities. The utilization of immunosuppression varies widely, contributing to the wide disparities in posttransplant outcomes reported between transplant centers. The International Liver Transplantation Society (ILTS) convened a consensus conference, comprised of a global panel of expert hepatologists, transplant surgeons, nephrologists, and pharmacologists to review the literature and experience pertaining to immunosuppression management to develop guidelines on key aspects of immunosuppression. The consensus findings and recommendations of the ILTS Consensus guidelines on immunosuppression in liver transplant recipients are presented in this article.
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http://dx.doi.org/10.1097/TP.0000000000002147DOI Listing
May 2018

-Leucinyl Benzenesulfonamides as Structurally Simplified Leucyl-tRNA Synthetase Inhibitors.

ACS Med Chem Lett 2018 Feb 18;9(2):84-88. Epub 2018 Jan 18.

Oxford Drug Design Ltd., Oxford Centre for Innovation, New Road, Oxford, OX1 1BY. U.K.

-Leucinyl benzenesulfonamides have been discovered as a novel class of potent inhibitors of leucyl-tRNA synthetase. The binding of inhibitors to the enzyme was measured by using isothermal titration calorimetry. This provided information on enthalpy and entropy contributions to binding, which, together with docking studies, were used for structure-activity relationship analysis. Enzymatic assays revealed that -leucinyl benzenesulfonamides display remarkable selectivity for leucyl-tRNA synthetase compared to and human orthologues. The simplest analogue of the series, -leucinyl benzenesulfonamide (R = H), showed the highest affinity against leucyl-tRNA synthetase and also exhibited antibacterial activity against Gram-negative pathogens (the best MIC = 8 μg/mL, ATCC 25922), which renders it as a promising template for antibacterial drug discovery.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807874PMC
February 2018

Improvement of hepatic fibrosis and patient-reported outcomes in non-alcoholic steatohepatitis treated with selonsertib.

Liver Int 2018 10 22;38(10):1849-1859. Epub 2018 Feb 22.

Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA.

Background: Patient-reported outcomes (PROs) represent patients' perspective about their well-being.

Aim: To assess PRO changes in patients with non-alcoholic steatohepatitis (NASH) after treatment with selonsertib (SEL) and to associate them with different biomarkers.

Methods: Patients with NASH and stage 2-3 fibrosis received SEL 6 mg or 18 mg orally QD alone or in combination with simtuzumab (SIM, 125 mg SC weekly) or SIM alone for 24 weeks. Biopsies were obtained at baseline and at treatment week 24. PROs were assessed using SF-36, CLDQ and WPAI:SHP.

Results: Seventy-two patients with NASH were included (54 ± 10 years, 31% male, 65% stage 3, 71% diabetes). Baseline physical health-related PRO scores were significantly lower than population norms (P < .05). During treatment, there were no consistent differences in treatment-emergent PRO changes between different regimens (P > .05). However, NASH subjects who experienced ≥2 decrease in NAFLD Activity Score or ≥1-stage reduction in fibrosis showed significant improvements in their PROs (up to +15.5% of a PRO range size, P < .05). Additionally, improvements in PROs (up to +21.5%, P < .05) were noted in patients with at least 50% relative reduction in collagen, while NASH subjects with >17% increase in their collagen experienced PRO worsening (up to -13.9%, P < .05). Baseline serum CK-18, IL-6 and CRP significantly correlated with PROs (rho from -0.24 to -0.38, P < .05).

Conclusions: A decrease in hepatic collagen is the most prominently associated with improvement of PROs in NASH patients with F2-F3 treated with SEL. Furthermore, serum cytokines are associated with baseline PROs and with treatment-emergent changes in PROs in patients with NASH.
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http://dx.doi.org/10.1111/liv.13706DOI Listing
October 2018

DNA methylation signatures reflect aging in patients with nonalcoholic steatohepatitis.

JCI Insight 2018 01 25;3(2). Epub 2018 Jan 25.

Duke Clinical Research Institute, Durham, North Carolina, USA.

A DNA methylation (DNAm) signature (the "Horvath clock") has been proposed as a measure of human chronological and biological age. We determined peripheral blood DNAm in patients with nonalcoholic steatohepatitis (NASH) and assessed whether accelerated aging occurs in these patients. DNAm signatures were obtained in patients with biopsy-proven NASH and stage 2-3 fibrosis. The DNAm profile from one test and two validation cohorts served as controls. Age acceleration was calculated as the difference between DNAm age and the predicted age based on the linear model derived from controls. Hepatic collagen content was assessed by quantitative morphometry. The Horvath clock accurately predicts the chronological age of the entire cohort. Age acceleration was observed among NASH subjects compared with control data sets and our test controls. Age acceleration in NASH subjects did not differ by fibrosis stage but correlated with hepatic collagen content. A set of 152 differentially methylated CpG islands between NASH subjects and controls identified gene set enrichment for transcription factors and developmental pathways. Patients with NASH exhibit epigenetic age acceleration that correlates with hepatic collagen content.
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http://dx.doi.org/10.1172/jci.insight.96685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821203PMC
January 2018

Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis.

Hepatology 2018 07;68(1):349-360

Arizona State University.

Nonalcoholic fatty liver disease (NAFLD) is a spectrum comprised of isolated steatosis, nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. The majority of NAFLD subjects do not have NASH and do not carry a significant risk for liver-related adverse outcomes (cirrhosis and mortality). Globally, the prevalence of NAFLD is approximately 25%. In Asia, a gradient of high to low prevalence rates is noted from urban to rural areas. Given the prevalence of NAFLD, the clinical and economic burden of NAFLD and NASH can be substantial. With increasing recognition of NASH as an important liver disease, the diagnosis of NASH still requires a liver biopsy that is suboptimal. Although liver biopsy is the most accurate modality to diagnose and stage the severity of NASH, this method suffers from being invasive, costly, associated with potential complications, and plagued with interobserver variability of individual pathological features. A number of noninvasive modalities to diagnose NASH and stage liver fibrosis are being developed. These modalities include predictive models (NAFLD fibrosis score) and serum biomarkers such as enhanced liver fibrosis (ELF). Other tests are based on radiological techniques, such as transient elastography (TE) or magnetic resonance elastography (MRE), which are used to estimate liver stiffness as a potential surrogate of hepatic fibrosis. Although a dynamic field of research, most of these diagnostic modalities have area under the curve ranging between 0.76 and 0.90%, with MRE having the best predictive performance. In summary, developing safe and easily accessible noninvasive modalities to accurately diagnose and monitor NASH and associated fibrosis is of utmost importance in clinical practice and clinical research. These tests are not only important to risk stratify subjects at the greatest risk for progressive liver disease, but also to serve as appropriate surrogate endpoints for therapeutic clinical trials of NASH. (Hepatology 2018;68:349-360).
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http://dx.doi.org/10.1002/hep.29721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511364PMC
July 2018

Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Hepatology 2018 07;68(1):361-371

College of Health Solutions, Arizona State University, Phoenix, AZ.

Nonalcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH), are rapidly becoming among the top causes of cirrhosis, hepatocellular carcinoma, and indications for liver transplantation. Other than lifestyle modification through diet and exercise, there are currently no other approved treatments for NASH/NAFLD. Although weight loss can be effective, it is difficult to achieve and sustain. In contrast, bariatric surgery can improve metabolic conditions associated with NAFLD, and has been shown to improve liver histology. To have approved regimens for the treatment of NASH/NAFLD, several issues must be addressed. First, all stakeholders must agree on the most appropriate clinical trial endpoints for NASH. Currently, resolution of NASH (without worsening fibrosis) or reduction of fibrosis stage (without worsening NASH) are the accepted endpoints by the regulatory authorities. It is important to recognize the prognostic implication of histologic features of NASH. In this context, although histologic NASH has been associated with advanced fibrosis, it is not an independent predictor of long-term mortality. In contrast, there are significant data to suggest that fibrosis stage is the only robust and independent predictor of liver-related mortality. In addition to the primary endpoints, several important secondary endpoints, including noninvasive biomarkers, long-term outcomes, and patient-reported outcomes must be considered. In 2018, a few phase 3 clinical trials for the treatment of NASH have been initiated. Additionally, a number of phase 2a and 2b clinical trials targeting different pathogenic pathways in NASH are in the pipeline of emerging therapies.

Conclusion: Over the next 5 years, some of these regimens are expected to provide potential new treatment options for patients with NASH/NAFLD. (Hepatology 2018;68:361-371).
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http://dx.doi.org/10.1002/hep.29724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508084PMC
July 2018

Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma.

Clin Liver Dis 2018 02;22(1):201-211

Division of Gastroenterology and Hepatology, University of Chicago, Center for Liver Diseases, The University of Chicago Biological Sciences, 5841 South Maryland Avenue, Room M-454, Chicago, IL 60637, USA. Electronic address:

Although hepatocellular carcinoma (HCC) is more common in the setting of cirrhosis, there is increasing evidence that it can develop in the setting of noncirrhotic nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and that steatosis alone can promote carcinogenesis. In addition, obesity, diabetes, and metabolic syndrome are recognized risks for the development of HCC. A better understanding of the mechanisms involved in the development of NAFLD/NASH-related HCC will allow the discovery of new targets for therapeutic and preventive intervention. The surveillance for HCC in the setting of noncirrhotic NAFLD/NASH, obesity, diabetes, and metabolic syndrome remains an area of uncertainty.
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http://dx.doi.org/10.1016/j.cld.2017.08.014DOI Listing
February 2018

The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial.

Hepatology 2018 02 26;67(2):549-559. Epub 2017 Dec 26.

Intermountain Medical Center, Salt Lake City, UT.

Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatology 2018;67:549-559).
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http://dx.doi.org/10.1002/hep.29514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814892PMC
February 2018

Everolimus Is Associated With Less Weight Gain Than Tacrolimus 2 Years After Liver Transplantation: Results of a Randomized Multicenter Study.

Transplantation 2017 12;101(12):2873-2882

Mayo Clinic, Rochester, MN.

Background: Weight gain early after transplant is a risk factor for posttransplant metabolic syndrome (PTMS), cardiovascular events, and renal insufficiency. The impact of mammalian target of rapamycin inhibition on posttransplant weight gain and the development of PTMS components postliver transplantation were examined in a randomized, controlled study.

Methods: After a run-in period, patients (N = 719) were randomized at 30 ± 5 days posttransplant in a 1:1:1 ratio to 3 treatment groups: (i) everolimus (EVR) + reduced tacrolimus (TAC) (n = 245); (ii) TAC control (n = 243) or (iii) TAC elimination (n = 231). In this post hoc analysis, weight change at 12 and 24 months was compared between groups. Vital signs, lipids, and laboratory parameters at 12 and 24 months and rates of PTMS were assessed.

Results: Mean increase in weight from baseline was higher at month 12 in the TAC control arm (8.15 ± 9.27 kg) than in the EVR + reduced TAC (5.88 ± 12.60 kg, P = 0.056) and the TAC elimination arms (4.76 ± 9.94 kg, P = 0.007). At month 24, the TAC control arm displayed a significantly greater weight increase (9.54 ± 10.21 kg) than either the EVR + reduced TAC (6.69 ± 8.37 kg, P = 0.011) or the TAC elimination groups (6.01 ± 9.98 kg, P = 0.024). Rates of PTMS were similar for the EVR + reduced TAC (71.8%), TAC elimination (70.3%) and TAC control (67.4%) arms (P = NS).

Conclusions: EVR with reduced-exposure TAC attenuated weight gain at 1 and 2 years posttransplant compared with a standard TAC immunosuppression regimen. Rates of PTMS were comparable between EVR-containing and TAC control regimens.
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http://dx.doi.org/10.1097/TP.0000000000001913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704647PMC
December 2017

International Liver Transplantation Society Consensus Statement on Hepatitis C Management in Liver Transplant Recipients.

Transplantation 2017 05;101(5):956-967

1 Hepatology and Transplant Surgery, University of California San Francisco, San Francisco, CA. 2 Liver Unit, Hospital Universitario y Politécnico La Fe, Universidad Valencia and CIBEREHD, Valencia, Spain. 3 Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia. 4 Liver Unit, Hospital Italiano, Buenos Aires, Argentina. 5 Multiorgan Transplant, University Health Network/Toronto General Hospital, Toronto Hospital, Toronto, Ontario, Canada. 6 Hepatology, AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Univ Paris-Sud, Université Paris-Saclay, Villejuif, France. 7 Department of Medicine, Stanford University, Palo Alto, CA. 8 Institute of Liver Studies, Kings College Hospital, London, United Kingdom. 9 Liver Center, Beth Israel Deaconess Medical Center, Boston, MA. 10 Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Begamo, Italy. 11 The Liver Transplant Center, Queen Mary Hospital, Hong Kong. 12 New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand. 13 Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MI. 14 Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy. 15 Utah Intermountain Transplant and Regenerative Medicine Center, Salt Lake City, UT. 16 Division of Gastroenterology and Hepatology, University of São Paulo School of Medicine, São Paulo, Brazil. 17 Australian National Liver Transplant Unit, Centenary Research Institute, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.

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http://dx.doi.org/10.1097/TP.0000000000001704DOI Listing
May 2017

International Liver Transplantation Society Consensus Statement on Hepatitis C Management in Liver Transplant Candidates.

Transplantation 2017 05;101(5):945-955

1 Hepatology and Transplant Surgery, University of California San Francisco, San Francisco, CA. 2 Australian National Liver Transplant Unit, Centenary Research Institute, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia. 3 Liver Center, Beth Israel Deaconess Medical Center, Boston, MA. 4 New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand. 5 Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Begamo, Italy. 6 The Liver Transplant Center, Queen Mary Hospital, High West, Hong Kong. 7 Institute of Liver Studies, Kings College Hospital, London, United Kingdom. 8 Multiorgan Transplant, University Health Network/Toronto General Hospital, Toronto, Ontario, Canada. 9 Australian National Liver Transplant Unit, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia. 10 Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MI. 11 Liver Unit, Hospital Italiano, Buenos Aires, Argentina. 12 Department of Medicine, Stanford University, Palo Alto, CA. 13 Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy. 14 Hepatology, AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Univ Paris-Sud, Université Paris-Saclay, Villejuif, France. 15 Utah Intermountain Transplant and Regenerative Medicine Center, Salt Lake City, UT. 16 Division of Gastroenterology and Hepatology, University of São Paulo School of Medicine, São Paulo, Brazil. 17 Liver Unit, Hospital Universitario y Politécnico La Fe, Universidad Valencia and CIBEREHD, Valencia, Spain.

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http://dx.doi.org/10.1097/TP.0000000000001708DOI Listing
May 2017

Patient-reported outcomes with sofosbuvir and velpatasvir with or without ribavirin for hepatitis C virus-related decompensated cirrhosis: an exploratory analysis from the randomised, open-label ASTRAL-4 phase 3 trial.

Lancet Gastroenterol Hepatol 2016 10 3;1(2):122-132. Epub 2016 Aug 3.

Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA.

Background: Hepatitis C virus (HCV) treatment regimens with direct-acting antivirals have not been extensively studied in patients with decompensated cirrhosis. We assessed patient-reported outcomes (PROs) in patients with decompensated cirrhosis given a fixed-dose combination of sofosbuvir and velpatasvir with and without ribavirin.

Methods: This study was an exploratory analysis of data collected in a randomised, open-label phase 3 trial (ASTRAL-4) in which patients with HCV-related decompensated cirrhosis were randomly assigned to an all-oral fixed-dose combination of sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks, sofosbuvir and velpatasvir plus oral ribavirin (weight-based 1000 mg or 1200 mg) for 12 weeks, or sofosbuvir and velpatasvir for 24 weeks. Eligible patients were aged 18 years or older with any HCV genotype and decompensated cirrhosis at screening. PROs were collected for the intention-to-treat population using four questionnaires, Short Form (36) Health Survey version 2 (SF-36v2), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), the Chronic Liver Disease Questionnaire-HCV Version (CLDQ-HCV), and the Work Productivity Activity Index:HCV (WPAI), which were given prospectively to patients before, during, and after treatment. The ASTRAL-4 study is registered with ClinicalTrials.gov, number NCT02201901.

Findings: Patients were enrolled at 47 hepatology outpatient practices in the USA from Aug 19, 2014, to Dec 19, 2014. 267 patients with HCV-related decompensated cirrhosis were included. In patients given sofosbuvir and velpatasvir for 12 weeks (n=90), clinically significant improvements in PROs started 4 weeks after treatment initiation (+4·4 to +7·5 points on a 0-100 scale at treatment week 4). By the end of treatment, mean improvements in PROs of +5·3 to +16·0 points were noted in all PROs except for role emotional, mental component summary, and social wellbeing scores and work productivity metrics by WPAI:HCV. Similar end-of-treatment improvements (+3·8 to +17·0 points) were observed in patients given sofosbuvir and velpatasvir for 24 weeks (n=90). In patients given sofosbuvir and velpatasvir plus ribavirin (n=87), PRO scores decreased within 4 weeks of treatment (-3·6 to -6·9 points), although scores returned to the baseline levels by the end of treatment. After treatment cessation, significant improvements in all PROs were similar between the treatment groups (all p>0·01) and, by post-treatment week 24, improvements were between +4·9 and +21·2 points. In multivariate analysis, predictors of PRO impairment were treatment naivety, anxiety, use of anxiolytics, use of antidepressants, use of opioids, ribavirin use, the presence of ascites, encephalopathy, insomnia, and depression.

Interpretation: A clinically significant early (within 4 weeks) and sustained improvement in PROs was observed in patients with HCV-related decompensated cirrhosis who were given sofosbuvir and velpatasvir without ribavirin. A similar regimen with ribavirin resulted in a temporary decrease in PROs, which completely resolved after 8 weeks of treatment. Accompanied by high efficacy, the favourable effect of treatment on PROs improves patients' experience in this difficult-to-treat population with HCV.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2468-1253(16)30009-7DOI Listing
October 2016

Predictors of Cardiovascular Events After Liver Transplantation.

Clin Liver Dis 2017 05 20;21(2):367-379. Epub 2017 Feb 20.

Intermountain Transplant Center, Intermountain Medical Center, 5169 South Cottonwood Street, Suite 320, Murray, UT 84107, USA. Electronic address:

Indications for liver transplant have been extended, and older and sicker patients are undergoing transplantation. Infectious, malignant, and cardiovascular diseases account for the most posttransplant deaths. Cirrhotic patients can develop heart disease through systemic diseases affecting the heart and the liver, cirrhosis-specific heart disease, or common cardiovascular. No single factor can predict posttransplant cardiovascular complications. Patients with history of cardiovascular disease, and specific abnormalities on echocardiography, electrocardiography, or serum markers of heart disease seem to be at increased risk of complications. Pretransplant cardiovascular evaluation is essential to detecting these risk factors so their effects can be mitigated through appropriate intervention.
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http://dx.doi.org/10.1016/j.cld.2016.12.009DOI Listing
May 2017

A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition.

Am J Physiol Gastrointest Liver Physiol 2017 Jun 23;312(6):G666-G680. Epub 2017 Feb 23.

Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota;

The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) is incompletely understood. Hence, we investigated the chronology of whole body, tissue, and cellular events that occur during the evolution of diet-induced NASH. Male C57Bl/6 mice were assigned to a fast-food (FF; high calorie, high cholesterol, high fructose) or standard-chow (SC) diet over a period of 36 wk. Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression, and hepatic lipid content were analyzed. Insulin resistance [homeostasis model assessment-insulin resistance (HOMA-IR)] increased 10-fold after 4 wk. Fibrosing NASH was fully established by 16 wk. Total hepatic lipids increased by 4 wk and remained two- to threefold increased throughout. Hepatic triglycerides declined from sixfold increase at 8 wk to threefold increase by 36 wk. In contrast, hepatic cholesterol levels steadily increased from baseline at 8 wk to twofold by 36 wk. The hepatic immune cell population altered over time with macrophages persisting beyond 16 wk. Mitochondrial oxygen flux rates of FF mice diet were uniformly lower with all the tested substrates (13-276 pmol·s·ml per unit citrate synthase) than SC mice (17-394 pmol·s·ml per unit citrate synthase) and was accompanied by decreased mitochondrial:nuclear gene copy number ratios after 4 wk. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased at 24 wk in FF mice. Expression of dismutases and catalase was also decreased in FF mice. The evolution of NASH in the FF diet-induced model is multiphasic, particularly in terms of hepatic lipid composition. Insulin resistance precedes hepatic inflammation and fibrosis. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively, these observations provide a unique overview of the sequence of changes that coevolve with the histological evolution of NASH. This study demonstrates in a first of kind longitudinal analysis, the evolution of nonalcoholic steatohepatitis (NASH) on a fast-food diet-induced model. Key findings include ) hepatic lipid composition changes in a multiphasic fashion as NASH evolves; ) insulin resistance precedes hepatic inflammation and fibrosis, answering a longstanding chicken-and-egg question regarding the relationship of insulin resistance to liver histology in NASH; and ) mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent.
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http://dx.doi.org/10.1152/ajpgi.00213.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146305PMC
June 2017

Changes in the Prevalence of Hepatitis C Virus Infection, Nonalcoholic Steatohepatitis, and Alcoholic Liver Disease Among Patients With Cirrhosis or Liver Failure on the Waitlist for Liver Transplantation.

Gastroenterology 2017 04 11;152(5):1090-1099.e1. Epub 2017 Jan 11.

Intermountain Medical Center, Murray, Utah.

Background & Aims: Concurrent to development of more effective drugs for treatment of hepatitis C virus (HCV) infection, there has been an increase in the incidence of nonalcoholic fatty liver disease. Data indicate that liver transplantation prolongs survival times of patient with acute hepatitis associated with alcoholic liver disease (ALD). We compared data on disease prevalence in the population with data from liver transplantation waitlists to evaluate changes in the burden of liver disease in the United States.

Methods: We collected data on the prevalence of HCV from the 2010 and 2013-2014 cycles of the National Health and Nutrition Examination Survey. We also collected data from the HealthCore Integrated Research Database on patients with cirrhosis and chronic liver failure (CLF) from 2006 through 2014, and data on patients who received transplants from the United Network for Organ Sharing from 2003 through 2015. We determined percentages of new waitlist members and transplant recipients with HCV infection, stratified by indication for transplantation, modeling each calendar year as a continuous variable using the Spearman rank correlation, nonparametric test of trends, and linear regression models.

Results: In an analysis of data from the National Health and Nutrition Examination Survey (2013-2014), we found that the proportion of patients with a positive HCV antibody who had a positive HCV RNA was 0.5 (95% confidence interval, 0.42-0.55); this value was significantly lower than in 2010 (0.64; 95% confidence interval, 0.59-0.73) (P = .03). Data from the HealthCore database revealed significant changes (P < .05 for all) over time in percentages of patients with compensated cirrhosis (decreases in percentages of patients with cirrhosis from HCV or ALD, but increase in percentages of patients with cirrhosis from nonalcoholic steatohepatitis [NASH]), CLF (decreases in percentages of patients with CLF from HCV or ALD, with an almost 3-fold increase in percentage of patients with CLF from NASH), and hepatocellular carcinoma (HCC) (decreases in percentages of patients with HCC from HCV or ALD and a small increase in HCC among persons with NASH). Data from the United Network for Organ Sharing revealed that among patients new to the liver transplant waitlist, or undergoing liver transplantation, for CLF, there was a significant decrease in the percentage with HCV infection and increases in percentages of patients with nonalcoholic fatty liver disease or ALD. Among patients new to the liver transplant waitlist or undergoing liver transplantation for HCC, proportions of those with HCV infection, nonalcoholic fatty liver disease, or ALD did not change between 2003 and 2015.

Conclusions: In an analysis of 3 different databases (National Health and Nutrition Examination Survey, HealthCore, and United Network for Organ Sharing), we found the proportion of patients on the liver transplant waitlist or undergoing liver transplantation for chronic HCV infection to be decreasing and fewer patients to have cirrhosis or CLF. However, the percentages of patients on the waitlist or receiving liver transplants for NASH or ALD are increasing, despite different relative burdens of disease among the entire population of patients with cirrhosis.
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http://dx.doi.org/10.1053/j.gastro.2017.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367965PMC
April 2017

Sofosbuvir and Velpatasvir Combination Improves Patient-reported Outcomes for Patients With HCV Infection, Without or With Compensated or Decompensated Cirrhosis.

Clin Gastroenterol Hepatol 2017 03 12;15(3):421-430.e6. Epub 2016 Nov 12.

Center for Outcomes Research, Washington, District of Columbia.

Background & Aims: The combination of sofosbuvir and velpatasvir is used to treat patients with hepatitis C virus (HCV) infection of different genotypes. We compared the effects of this treatment regimen, with and without ribavirin, on outcomes reported by patients (patient-reported outcomes [PROs]) with HCV infection, with or without cirrhosis.

Methods: We performed a post hoc analysis of data collected from phase 3 clinical trials (ASTRAL-1, -2, -3, and -4) of 1701 patients infected with HCV of different genotypes treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks (n = 87), sofosbuvir with ribavirin for 12 or 24 weeks (n = 401), and ribavirin-free sofosbuvir and velpatasvir for 12 or 24 weeks (n = 1213). In all trials, participants completed 4 PRO questionnaires (while blinded to their HCV RNA levels): the Short Form-36, the Functional Assessment of Chronic Illness Therapy-Fatigue, the Chronic Liver Disease Questionnaire-HCV Version, and the Work Productivity and Activity Impairment: Specific Health Problem, at multiple time points. We compared baseline PROs and changes in PROs following treatment in patients without cirrhosis (n = 1112), with compensated cirrhosis (n = 338), and with decompensated cirrhosis (n = 251).

Results: Baseline PRO scores were as much as 33.5% lower in patients with decompensated cirrhosis than in patients without cirrhosis (P < .05). Following treatment with ribavirin-containing regimens, changes in PRO scores were similar among patients with compensated and decompensated cirrhosis (all P > .01). Treatment with these regimens increased some PRO scores by as much as 11.8% from baseline (P < .05) and reduced others, by as much as 7.1% (P < .05). Despite this, by 12 weeks after cessation of treatment with ribavirin-containing regimens, all PRO decrements resolved; PRO scores increased by as much as 14.2%, and as much as 17.1% at 24 weeks after treatment, regardless of cirrhosis status (all P > .01 between cirrhosis groups). In contrast, treatment with ribavirin-free sofosbuvir and velpatasvir increased PRO scores for patients with compensated cirrhosis, and even more so in patients with decompensated cirrhosis starting at treatment Week 4; no statistically significant decrement was observed at any time point (all 1-sided P values > .05). In multivariate analysis, compensated cirrhosis was associated with a 2.3% to 5.0% greater increase in PRO scores following treatment with sofosbuvir and velpatasvir (P < .05); decompensated cirrhosis was associated with a 5.5%-9.1% greater increase (P < .002). Clinicaltrials.gov number, NCT02201940, NCT02220998, NCT02201953, NCT02201901.

Conclusions: In an analysis of data from 4 phase 3 clinical trials, we found that patients with HCV infection (especially those with decompensated cirrhosis) have significant increases in their PRO scores during treatment with sofosbuvir and velpatasvir and after achieving a sustained virologic response.
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http://dx.doi.org/10.1016/j.cgh.2016.10.037DOI Listing
March 2017

Roadmap for improving patient and graft survival in the next 10 years.

Liver Transpl 2016 11;22(S1):71-78

Liver Transplantation Program, Department of Hepatology, Intermountain Medical Center, Murray, UT.

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http://dx.doi.org/10.1002/lt.24602DOI Listing
November 2016

New organ allocation policy in liver transplantation in the United States.

Clin Liver Dis (Hoboken) 2016 Oct 27;8(4):108-112. Epub 2016 Oct 27.

Intermountain Transplant and Regenerative Medicine Institute Intermountain Medical Center Murray UT.

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http://dx.doi.org/10.1002/cld.580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490206PMC
October 2016

Familial Risk of Biliary Tract Cancers: A Population-Based Study in Utah.

Dig Dis Sci 2016 12 21;61(12):3627-3632. Epub 2016 Sep 21.

Cancer Control and Population Sciences, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.

Background And Objectives: Biliary tract cancers (BTC) including, cholangiocarcinoma (CC) and gallbladder cancer (GBC), are rare and highly fatal malignancies. The etiology and inherited susceptibility of both malignancies are poorly understood. We quantified the risk of BTC in first-degree (FDR), second-degree (SDR), and first cousin (FC) relatives of individuals with BTC, stratified by tumor subsite.

Methods: BTC diagnosed between 1980 and 2011 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and gender-matched BTC-free controls were selected to form the comparison group for determining BTC risk in relatives using Cox regression analysis.

Results: Of the 1302 index patients diagnosed with BTC, 550 (42.2 %) were located in the gallbladder and 752 (57.8 %) were cholangiocarcinomas. There was no elevated risk of BTC (all subsites combined) in FDRs (HR 0.94, 95 % CI 0.29-3.0), SDRs (HR 0.25, 95 % CI 0.06-1.03), and FCs (HR 0.96, 95 % CI 0.61-1.51) of BTC cases compared to cancer-free controls. Similarly, no increased familial risk of GBC or CC was found in relatives of BTC patients stratified by tumor subsite compared to relatives of controls.

Conclusions: Relatives of BTC patients are not at an increased risk of GBC or CC in a statewide population. This suggests that biliary tract cancer risk is not associated with a familial predisposition and may be mitigated more strongly by environmental modifiers.
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http://dx.doi.org/10.1007/s10620-016-4310-3DOI Listing
December 2016

Alcoholic Liver Disease and Liver Transplantation.

Clin Liver Dis 2016 08;20(3):521-34

Intermountain Transplant Center, Intermountain Medical Center, 5169 South Cottonwood Street, Suite 320, Murray, UT 84107, USA. Electronic address:

Excessive alcohol use is a common health care problem worldwide and is associated with significant morbidity and mortality. Alcoholic liver disease represents the second most frequent indication for liver transplantation in North America and Europe. The pretransplant evaluation of patients with alcoholic liver disease should aim at identifying those at high risk for posttransplant relapse of alcohol use disorder, as return to excessive drinking can be deleterious to graft and patient survival. Carefully selected patients with alcoholic liver disease, including those with severe alcoholic hepatitis, will have similar short-term and long-term outcomes when compared with other indications for liver transplantation.
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http://dx.doi.org/10.1016/j.cld.2016.02.009DOI Listing
August 2016

Hepatitis C Virus RNA Persists in Liver Explants of Most Patients Awaiting Liver Transplantation Treated With an Interferon-Free Regimen.

Gastroenterology 2016 10 1;151(4):633-636.e3. Epub 2016 Jul 1.

Liver Unit, Hospital Clinic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain. Electronic address:

We assessed the presence of hepatitis C virus (HCV) RNA in liver explants from 39 patients awaiting liver transplantation who were treated with an interferon-free regimen and had undetectable serum HCV RNA at the time of liver transplantation. Interestingly, HCV RNA was detected in most liver explants (67%). Patients with HCV RNA-positive explants had received shorter courses of treatment, and HCV RNA was undetectable in serum for shorter periods before transplantation compared to patients with HCV RNA-negative explants (P = .014 and P = .013, respectively). Levels of HCV RNA in explants were significantly higher in patients with a relapse of HCV infection than patients who responded to treatment (P = .016), but most patients (85%) with residual HCV-RNA in the explant achieved a sustained virologic response after receiving their liver transplant.
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http://dx.doi.org/10.1053/j.gastro.2016.06.025DOI Listing
October 2016

Are the physicochemical properties of antibacterial compounds really different from other drugs?

J Cheminform 2016 3;8:30. Epub 2016 Jun 3.

InhibOx Limited, Oxford Centre for Innovation, New Road, Oxford, OX1 1BY UK ; University of Buckingham, Hunter Street, Buckingham, MK18 1EG UK.

Background: It is now widely recognized that there is an urgent need for new antibacterial drugs, with novel mechanisms of action, to combat the rise of multi-drug resistant bacteria. However, few new compounds are reaching the market. Antibacterial drug discovery projects often succeed in identifying potent molecules in biochemical assays but have been beset by difficulties in obtaining antibacterial activity. A commonly held view, based on analysis of marketed antibacterial compounds, is that antibacterial drugs possess very different physicochemical properties to other drugs, and that this profile is required for antibacterial activity.

Results: We have re-examined this issue by performing a cheminformatics analysis of the literature data available in the ChEMBL database. The physicochemical properties of compounds with a recorded activity in an antibacterial assay were calculated and compared to two other datasets extracted from ChEMBL, marketed antibacterials and drugs marketed for other therapeutic indications. The chemical class of the compounds and Gram-negative/Gram-positive profile were also investigated. This analysis shows that compounds with antibacterial activity have physicochemical property profiles very similar to other drug classes.

Conclusions: The observation that many current antibacterial drugs lie in regions of physicochemical property space far from conventional small molecule therapeutics is correct. However, the inference that a compound must lie in one of these "outlier" regions in order to possess antibacterial activity is not supported by our analysis. Graphical abstract.
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http://dx.doi.org/10.1186/s13321-016-0143-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891840PMC
June 2016

Humanized mice efficiently engrafted with fetal hepatoblasts and syngeneic immune cells develop human monocytes and NK cells.

J Hepatol 2016 08 2;65(2):334-43. Epub 2016 May 2.

Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA; Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA. Electronic address:

Background & Aims: Human liver chimeric mice are useful models of human hepatitis virus infection, including hepatitis B and C virus infections. Independently, immunodeficient mice reconstituted with CD34(+) hematopoietic stem cells (HSC) derived from fetal liver reliably develop human T and B lymphocytes. Combining these systems has long been hampered by inefficient liver reconstitution of human fetal hepatoblasts. Our study aimed to enhance hepatoblast engraftment in order to create a mouse model with syngeneic human liver and immune cells.

Methods: The effects of human oncostatin-M administration on fetal hepatoblast engraftment into immunodeficient fah(-/-) mice was tested. Mice were then transplanted with syngeneic human hepatoblasts and HSC after which human leukocyte chimerism and functionality were analyzed by flow cytometry, and mice were challenged with HBV.

Results: Addition of human oncostatin-M enhanced human hepatoblast engraftment in immunodeficient fah(-/-) mice by 5-100 fold. In contrast to mice singly engrafted with HSC, which predominantly developed human T and B lymphocytes, mice co-transplanted with syngeneic hepatoblasts also contained physiological levels of human monocytes and natural killer cells. Upon infection with HBV, these mice displayed rapid and sustained viremia.

Conclusions: Our study provides a new mouse model with improved human fetal hepatoblast engraftment and an expanded human immune cell repertoire. With further improvements, this model may become useful for studying human immunity against viral hepatitis.

Lay Summary: Important human pathogens such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus only infect human cells which complicates the development of mouse models for the study of these pathogens. One way to make mice permissive for human pathogens is the transplantation of human cells into immune-compromised mice. For instance, the transplantation of human liver cells will allow the infection of these so-called "liver chimeric mice" with hepatitis B virus and hepatitis C virus. The co-transplantation of human immune cells into liver chimeric mice will further allow the study of human immune responses to hepatitis B virus or hepatitis C virus. However, for immunological studies it will be crucial that the transplanted human liver and immune cells are derived from the same human donor. In our study we describe the efficient engraftment of human fetal liver cells and immune cells derived from the same donor into mice. We show that liver co-engraftment resulted in an expanded human immune cell repertoire, including monocytes and natural killer cells in the liver. We further demonstrate that these mice could be infected with hepatitis B virus, which lead to an expansion of natural killer cells. In conclusion we have developed a new mouse model that could be useful to study human immune responses to human liver pathogens.
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http://dx.doi.org/10.1016/j.jhep.2016.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955758PMC
August 2016
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