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Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency.

Wed, 08/09/2017 - 12:45

Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency.

Lancet Gastroenterol Hepatol. 2017 Sep;2(9):670-679

Authors: Pericleous M, Kelly C, Wang T, Livingstone C, Ala A

Abstract
Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme. The severity of the resulting disease depends on the nature of the underlying mutation and magnitude of its effect on enzymatic function. Wolman's disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months. Cholesteryl ester storage disorder arises later in life and is less severe, although the two diseases share many common features, including dyslipidaemia and transaminitis. The prevalence of these diseases has been estimated at one in 40 000 to 300 000, but many cases are undiagnosed and unreported, and awareness among clinicians is low. Lysosomal acid lipase deficiency-which can be diagnosed using dry blood spot testing-is often misdiagnosed as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hereditary dyslipidaemia, or cryptogenic cirrhosis. There are no formal guidelines for treatment of these patients, and treatment options are limited. In this Review we appraise the existing literature on Wolman's disease and cholesteryl ester storage disease, and discuss available treatments, including enzyme replacement therapy, oral lipid-lowering therapy, stem-cell transplantation, and liver transplantation.

PMID: 28786388 [PubMed - in process]

Should all dialysis patients with hepatitis C be treated? If so, before or after kidney transplantation?

Wed, 08/09/2017 - 12:45
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Should all dialysis patients with hepatitis C be treated? If so, before or after kidney transplantation?

Semin Dial. 2017 Aug 07;:

Authors: Jadoul M, Martin P

Abstract
HCV infection by genotype 1 and 4 can now be cured in close to 100% of patients with stage 4 or 5 CKD, including dialysis patients. Several regimens are available, all interferon-free and given for only 12 weeks. Thus unless life expectancy is short, HCV infection should be treated. The optimal timing of antiviral treatment will be dependent on several parameters: the possibility of being transplanted rapidly (either with a HCV+ graft or from a living donor) calls for treatment after transplantation. On the contrary, severe liver fibrosis, especially with portal hypertension calls for immediate treatment of HCV. Finally specific HCV genotype also impacts the treatment decision as genotypes 2,3,5 and 6 currently can be treated more easily after restoration of kidney function rather than in the presence of severe CKD, although this is anticipated to change soon once newer pangenotypic regimens are licensed.

PMID: 28786139 [PubMed - as supplied by publisher]

Tobacco Use is a Modifiable Risk Factor for Post-Transplant Biliary Complications.

Wed, 08/09/2017 - 12:45
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Tobacco Use is a Modifiable Risk Factor for Post-Transplant Biliary Complications.

J Gastrointest Surg. 2017 Aug 07;:

Authors: Dulaney DT, Dokus KM, McIntosh S, Al-Judaibi B, Ramaraju GA, Tomiyama K, Levstik M, Hernandez-Alejandro R, Orloff MS, Kashyap R

Abstract
PURPOSE: Biliary complications following liver transplantation are a significant source of morbidity, potentially leading to graft failure necessitating retransplantation. We sought to evaluate smoking as an independent risk factor for post-transplant biliary complications.
METHODS: The clinical course of all adult primary deceased donor liver transplants at our center from 1992 to 2012 was reviewed. Eligible patients were assigned to cohorts based on their lifetime tobacco exposure: never smokers indicating 0 pack-year exposure and all others were ever smokers. Biliary complications were defined as strictures, leaks, or bilomas requiring intervention. Complication rates were analyzed using univariate regression models correlated with donor and recipient characteristics. Associations found during univariate analysis were included in the final multivariate Cox model.
RESULTS: Eight hundred sixty-five subjects were followed for a median of 65 months; 482 (55.7%) of patients had a positive smoking history at the time of transplant. In univariate analysis, positive tobacco smoking history (HR = 1.36; p = 0.037) and increased time from quit date to transplantation (HR = 0.998; p = 0.011) were positive and negative predictors of biliary complication, respectively. Lifetime tobacco exposure remained a significant predictor of biliary complication on multivariate analysis (HR = 1.408; p = 0.023).
CONCLUSIONS: Smoking status is an independent predictor of post-transplant biliary complications, and the data presented reinforces the importance of early smoking cessation in the pre-transplantation period.

PMID: 28785937 [PubMed - as supplied by publisher]

Extended Liver Venous Deprivation Leads to a Higher Increase in Liver Function that ALPPS in Early Assessment : A comment to "Sparrelid, E. et al. Dynamic Evaluation of Liver Volume and Function in Associating Liver Partition and Portal Vein Ligation...

Wed, 08/09/2017 - 12:45
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Extended Liver Venous Deprivation Leads to a Higher Increase in Liver Function that ALPPS in Early Assessment : A comment to "Sparrelid, E. et al. Dynamic Evaluation of Liver Volume and Function in Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy. Journal of Gastrointestinal Surgery (2017)".

J Gastrointest Surg. 2017 Aug 07;:

Authors: Deshayes E, Schadde E, Piron L, Quenet F, Guiu B

PMID: 28785933 [PubMed - as supplied by publisher]

Common Variable Immunodeficiency and Liver Involvement.

Wed, 08/09/2017 - 12:45
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Common Variable Immunodeficiency and Liver Involvement.

Clin Rev Allergy Immunol. 2017 Aug 07;:

Authors: Song J, Lleo A, Yang GX, Zhang W, Bowlus CL, Eric Gershwin M, Leung PSC

Abstract
Common variable immunodeficiency (CVID) is a primary B-cell immunodeficiency disorder, characterized by remarkable hypogammaglobulinemia. The disease can develop at any age without gender predominance. The prevalence of CVID varies widely worldwide. The underlying causes of CVID remain largely unknown; primary B-cell dysfunctions, defects in T cells and antigen-presenting cells are involved. Although some monogenetic defects have been identified in some CVID patients, it is likely that CVID is polygenic. Patients with CVID develop recurrent and chronic infections (e.g., bacterial infections of the respiratory or gastrointestinal tract), autoimmune diseases, lymphoproliferation, malignancies, and granulomatous lesions. Interestingly, autoimmunity can be the only clinical manifestation of CVID at the time of diagnosis and may even develop prior to hypogammaglobulinemia. The diagnosis of CVID is largely based on the criteria established by European Society for Immunodeficiencies and Pan-American Group for Immunodeficiency (ESID/PAGID) and with some recent modifications. The disease can affect multiple organs, including the liver. Clinical features of CVID patients with liver involvement include abnormal liver biochemistries, primarily elevation of alkaline phosphatase (ALP), nodular regenerative hyperplasia (NRH), or liver cirrhosis and its complications. Replacement therapy with immunoglobulin (Ig) and anti-infection therapy are the primary treatment regimen for CVID patients. No specific therapy for liver involvement of CVID is currently available, and liver transplantation is an option only in select cases. The prognosis of CVID varies widely. Further understanding in the etiology and pathophysiology will facilitate early diagnosis and treatments to improve prognosis.

PMID: 28785926 [PubMed - as supplied by publisher]

Corrigendum to "Assessment of School Readiness in Chronic Cholestatic Liver Disease: A Pilot Study Examining Children with and without Liver Transplantation".

Wed, 08/09/2017 - 12:45
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Corrigendum to "Assessment of School Readiness in Chronic Cholestatic Liver Disease: A Pilot Study Examining Children with and without Liver Transplantation".

Can J Gastroenterol Hepatol. 2017;2017:3125082

Authors: Gold A, Rogers A, Cruchley E, Rankin S, Parmar A, Kamath BM, Avitzur Y, Ng VL

Abstract
[This corrects the article DOI: 10.1155/2017/9873945.].

PMID: 28785552 [PubMed - in process]

Down-regulation of metabolic proteins in hepatocellular carcinoma with portal vein thrombosis.

Wed, 08/09/2017 - 12:45
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Down-regulation of metabolic proteins in hepatocellular carcinoma with portal vein thrombosis.

Clin Proteomics. 2017;14:29

Authors: Lee WC, Chou HS, Wu TJ, Lee CF, Hsu PY, Hsu HY, Wu TH, Chan KM

Abstract
BACKGROUND: Hepatocellular carcinoma is an aggressive malignancy with poor prognosis and easy to recur even the tumor is totally removed by surgery. Portal vascular invasion is one of the major factors contributing to tumor recurrence and poor prognosis. However, why hepatocellular carcinoma is easy to grow into vessels is unclear.
METHODS: Surgical specimens from seven hepatocellular carcinoma patients with portal vein thrombosis and seven patients without vascular invasion were utilized to analyze protein expression by proteomic technique. The proteins in the tumors were separated by 2-dimensional electrophoresis. Protein patterns in the gels were recorded as digitalized images. The differences of expression in hepatocellular carcinoma with or without portal vein thrombosis were identified by mass spectrometry.
RESULTS: Clinically, the tumors with portal vein thrombosis were larger than those without portal vein thrombosis. The median survival time for the patients with portal vein thrombosis was much shorter [4 (ranged 2.5-47) vs. 53 (ranged 33-85) months, p = 0.002]. By analyzing the protein expression in cancer tissues with or without portal vein thrombosis, the differences of protein expression were mainly metabolic enzymes. Carbonic anhydrase I, betaine-homocysteine S-methyltransferase 1, fumarate hydratase, isovaleryl-CoA dehydrogenase, short-chain specific acyl-CoA dehydrogenase and arginase-1 were all down-regulated in the tumors with portal vein thrombosis.
CONCLUSION: Metabolic enzymes and cytosol carbonic anhydrases were downregulated in hepatocellular carcinoma with portal vein thrombus. The deficiency of metabolic enzymes and cytosol carbonic anhydrases may alter cellular metabolisms and acid-base balance in hepatocellular carcinoma, which may facilitate to invade portal vein.

PMID: 28785178 [PubMed]

Human liver chimeric mouse model based on diphtheria toxin-induced liver injury.

Wed, 08/09/2017 - 12:45
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Human liver chimeric mouse model based on diphtheria toxin-induced liver injury.

World J Gastroenterol. 2017 Jul 21;23(27):4935-4941

Authors: Ren XN, Ren RR, Yang H, Qin BY, Peng XH, Chen LX, Li S, Yuan MJ, Wang C, Zhou XH

Abstract
AIM: To establish an inducible liver injury mouse model and transplant human hepatocytes to obtain liver-humanized mice.
METHODS: We crossed three mouse strains, including albumin (Alb)-cre transgenic mice, inducible diphtheria toxin receptor (DTR) transgenic mice and severe combined immune deficient (SCID)-beige mice, to create Alb-cre/DTR/SCID-beige (ADSB) mice, which coincidentally harbor Alb-cre and DTR transgenes and are immunodeficient. As the Cre expression is driven by the liver-specific promoter Alb (encoding ALB), the DTR stop signal flanked by two loxP sites can be deleted in the ADSB mice, resulting in DTR expression in the liver. ADSB mice aged 8-10 wk were injected intraperitoneally (i.p.) with diphtheria toxin (DT) and liver damage was assessed by serum alanine aminotransferase (ALT) level. Two days later, mouse livers were sampled for histological analysis, and human hepatocytes were transplanted into the livers on the same day. A human ALB enzyme-linked immunosorbent assay was performed 7, 14, 21 and 28 d after transplantation. Human CD68 immunohistochemistry was performed 30 and 90 d after transplantation.
RESULTS: We crossed Alb-cre with DTR and SCID-beige mice to obtain ADSB mice. These mice were found to have liver damage 4 d after i.p. injection of 2.5 ng/g bodyweight DT. Bodyweight began to decrease on day 2, increased on day 7, and was lowest on day 4 (range, 10.5%-13.4%). Serum ALT activity began to increase on day 2 and reached a peak value of 289.7 ± 16.2 IU/mL on day 4, then returned to background values on day 7. After transplantation of human liver cells, peripheral blood human ALB level was 1580 ± 454.8 ng/mL (range, 750.2-3064.9 ng/mL) after 28 d and Kupffer cells were present in the liver at 30 d in ADSB mice.
CONCLUSION: Human hepatocytes were successfully repopulated in the livers of ADSB mice. The inducible mouse model of humanized liver in ADSB mice may have functional applications, such as hepatocyte transplantation, hepatic regeneration and drug metabolism.

PMID: 28785147 [PubMed - in process]

Comparative Peripheral Blood T Cells Analysis Between Adult Deceased Donor Liver Transplantation (DDLT) and Living Donor Liver Transplantation (LDLT).

Wed, 08/09/2017 - 12:45
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Comparative Peripheral Blood T Cells Analysis Between Adult Deceased Donor Liver Transplantation (DDLT) and Living Donor Liver Transplantation (LDLT).

Ann Transplant. 2017 Aug 08;22:475-483

Authors: Kim JM, Kwon CHD, Joh JW, Choi GS, Kang ES, Lee SK

Abstract
BACKGROUND T lymphocytes are an essential component of allograft rejection and tolerance. The aim of the present study was to analyze and compare the characteristics of T cell subsets in patients who underwent deceased donor liver transplantation (DDLT) versus living donor liver transplantation (LDLT). MATERIAL AND METHODS Between April 2013 and June 2014, 64 patients underwent adult liver transplantation. The distribution of peripheral blood T lymphocyte subsets before transplantation and at 4, 8, 12, and 24 weeks post-transplantation were monitored serially. RESULTS In the serial peripheral blood samples, the absolute CD3+ T cell counts in the LDLT group were higher than those in the DDLT group (p=0.037). The CD4+, CD8+, CD4/CD8, Vδ1, Vδ2, and γδ T cell counts did not change significantly over time in either group. The Vδ1/Vδ2 ratio was higher in patients with cytomegalovirus (CMV) infection than in patients without CMV infection (0.12 versus 0.26; p=0.033). The median absolute CD3+ and CD8+ T cell counts in patients with biopsy-proven acute rejection (BPAR) were 884 (range, 305-1,320) and 316 (range, 271-1,077), respectively, whereas they were 320 (range, 8-1,167) and 257 (range, 58-1,472) in patients without BPAR. The absolute CD3+ and CD8 T cell counts were higher in patients with BPAR than in patients without BPAR (p=0.007 and p=0.039, respectively). CONCLUSIONS With the exception of CD3+ T cells, T cell populations did not differ significantly between patients who received DDLT versus LDLT. In liver transplantation patients, CMV infection and BPAR were closely associated with T cell population changes.

PMID: 28784939 [PubMed - in process]

Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice.

Wed, 08/09/2017 - 12:45
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Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice.

Biochem Biophys Res Commun. 2017 Aug 04;:

Authors: Chen Z, Ding T, Ma CG

Abstract
Hepatic ischemia/reperfusion (I/R) injury could arise as a complication of liver surgery and transplantation. No specific therapeutic strategies are available to attenuate I/R injury. NOD-, LRR-and CARD-containing 5 (NLRC5), a member of the NOD-like protein family, has been suggested to negatively regulate nuclear factor kappa B (NF-κB) through interacting with IKKα and blocking their phosphorylation. Dexmedetomidine (DEX) has been shown to attenuate liver injury. In the current study, we investigated the pre-treatment of DEX on hepatic I/R injury in wild type (WT) and NLRC5 knockout (NLRC5(-/-)) mice. Our results indicated that NLRC5(-/-) showed significantly stronger histologic damage, inflammatory response, oxidative stress and apoptosis after I/R compared to the WT group of mice, indicating the protective role of NLRC5 against liver I/R injury. Importantly, I/R-induced increase of NLRC5 was reduced by DEX pre-treatment. After hepatic I/R injury, WT and NLRC5(-/-) mice pre-treated with DEX exhibited attenuated histological disruption, and reduced pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β and inducible nitric oxide synthase (iNOS), which was associated with the inactivated NF-κB pathway. Moreover, suppression of oxidative stress and apoptosis was observed in DEX-treated mice with I/R injury, probably through enhancing nuclear factor erythroid 2-related factor 2 (Nrf2), reducing mitogen-activated protein kinases (MAPKs) and Caspase-3/poly (ADP-ribose) polymerase (PARP) pathways. In vitro, the results were further confirmed in WT and NLRC5(-/-) hepatocytes pre-treated with or without DEX. Together, the findings illustrated that lack of NLRC5 resulted in severer liver I/R injury, which could be alleviated by DEX pre-treatment.

PMID: 28784305 [PubMed - as supplied by publisher]

Anesthesia for Intestinal Transplantation.

Wed, 08/09/2017 - 12:45
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Anesthesia for Intestinal Transplantation.

Anesthesiol Clin. 2017 Sep;35(3):509-521

Authors: Nguyen-Buckley C, Wong M

Abstract
The diagnosis of irreversible intestinal failure confers significant morbidity, mortality, and decreased quality of life. Patients with irreversible intestinal failure may be treated with intestinal transplantation. Intestinal transplantation may include intestine only, liver-intestine, or other visceral elements. Intestinal transplantation candidates present with systemic manifestations of intestinal failure requiring multidisciplinary evaluation at an intestinal transplantation center. Central access may be difficult in intestinal transplantation candidates. Intestinal transplantation is a complex operation with potential for hemodynamic and metabolic instability. Patient and graft survival are improving, but graft failure remains the most common postoperative complication.

PMID: 28784223 [PubMed - in process]

Anesthesia for Liver Transplantation.

Wed, 08/09/2017 - 12:45
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Anesthesia for Liver Transplantation.

Anesthesiol Clin. 2017 Sep;35(3):491-508

Authors: Adelmann D, Kronish K, Ramsay MA

Abstract
The provision of anesthesia for a liver transplant program requires a dedicated team of anesthesiologists. Liver transplant anesthesiologists must have an understanding of liver physiology and anatomy; the spectrum of clinical disease associated with liver dysfunction; the impact of warm and cold ischemia times, surgical techniques in liver transplantation, and the impact of ischemia-reperfusion syndrome; and optimal practices to protect the liver. The team must provide a 24-hour service, be actively involved in the selection committee process, and stay current with advances in the subspecialty.

PMID: 28784222 [PubMed - in process]

Anesthetic Management of Pediatric Liver and Kidney Transplantation.

Wed, 08/09/2017 - 12:45
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Anesthetic Management of Pediatric Liver and Kidney Transplantation.

Anesthesiol Clin. 2017 Sep;35(3):421-438

Authors: Wasson NR, Deer JD, Suresh S

Abstract
Pediatric patients with liver dysfunction and renal failure may exhibit many comorbidities. There are often associated congenital syndromes to be taken into account. Liver and renal transplantation offer a solution and substantial improvement in quality of life. Anesthetic management of pediatric liver and renal transplantation has not been well described. There are key differences between adults and children undergoing these procedures, and acknowledgment of some key principles provide a solid foundation to optimize perioperative outcomes. This article provides an overview of the perioperative management and considerations in pediatric patients undergoing liver and renal transplantation.

PMID: 28784218 [PubMed - in process]

Infectious Complications and Malignancies Arising After Liver Transplantation.

Wed, 08/09/2017 - 12:45
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Infectious Complications and Malignancies Arising After Liver Transplantation.

Anesthesiol Clin. 2017 Sep;35(3):381-393

Authors: Idossa DW, Simonetto DA

Abstract
Since the first liver transplant was performed in 1963, great advancements have been made in hepatic transplantation. Surgical techniques have been revised and improved, diagnostic methods for identifying and preventing infections have been developed, and a more conservative use of immunosuppressive agents has resulted in better long-term posttransplant outcomes. A total of 7841 liver transplantations were performed in the United States in 2016, resulting in greater than 85% survival at 1 year posttransplant. However, technical surgical complications, infections, rejections, and chronic medical conditions persist. This article discusses the infectious complications and malignancies that may arise after liver transplantation.

PMID: 28784215 [PubMed - in process]

Secreted phosphoprotein 24kD (Spp24) inhibits growth of hepatocellular carcinoma in vivo.

Wed, 08/09/2017 - 12:45
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Secreted phosphoprotein 24kD (Spp24) inhibits growth of hepatocellular carcinoma in vivo.

Environ Toxicol Pharmacol. 2017 Apr;51:51-55

Authors: Lao L, Shen J, Tian H, Zhong G, Murray SS, Wang JC

Abstract
Several studies have shown that secreted phosphoprotein 24kD (Spp24) inhibits tumor growth. However, the effects of spp24 on hepatocellular carcinoma are not quite clear. In this study, we observed the inhibitory effect of spp24 on hepatocellular carcinoma in vivo. A subcutaneous hepatocellular carcinoma mice model was established by using Hep G2 cells. After sacrifice at day 40, tumor growth was assessed and tumor cell apoptosis and tumor cells proliferation were assessed by TUNEL assay and immunochemical analysis, respectively. BMP2 slightly stimulated the subcutaneous tumor growth compared with the control. Spp24 significantly inhibited the tumor growth and also abolished the BMP2-induced tumor growth (p<0.05). TUNEL assay and immunochemical analysis further showed that spp24 could enhance tumor cell apoptosis and inhibit cell proliferation (p<0.01). Our data show that spp24 can inhibit the growth of hepatocellular carcinoma. Spp24 may have great potential for cancer treatment.

PMID: 28286322 [PubMed - indexed for MEDLINE]

Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6.

Wed, 08/09/2017 - 12:45
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Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6.

Gastroenterology. 2017 May;152(6):1477-1491

Authors: Lai KKY, Kweon SM, Chi F, Hwang E, Kabe Y, Higashiyama R, Qin L, Yan R, Wu RP, Lai K, Fujii N, French S, Xu J, Wang JY, Murali R, Mishra L, Lee JS, Ntambi JM, Tsukamoto H

Abstract
BACKGROUND & AIMS: Stearoyl-CoA desaturase (SCD) synthesizes monounsaturated fatty acids (MUFAs) and has been associated with the development of metabolic syndrome, tumorigenesis, and stem cell characteristics. We investigated whether and how SCD promotes liver fibrosis and tumor development in mice.
METHODS: Rodent primary hepatic stellate cells (HSCs), mouse liver tumor-initiating stem cell-like cells (TICs), and human hepatocellular carcinoma (HCC) cell lines were exposed to Wnt signaling inhibitors and changes in gene expression patterns were analyzed. We assessed the functions of SCD by pharmacologic and conditional genetic manipulation in mice with hepatotoxic or cholestatic induction of liver fibrosis, orthotopic transplants of TICs, or liver tumors induced by administration of diethyl nitrosamine. We performed bioinformatic analyses of SCD expression in HCC vs nontumor liver samples collected from patients, and correlated levels with HCC stage and patient mortality. We performed nano-bead pull-down assays, liquid chromatography-mass spectrometry, computational modeling, and ribonucleoprotein immunoprecipitation analyses to identify MUFA-interacting proteins. We examined the effects of SCD inhibition on Wnt signaling, including the expression and stability of low-density lipoprotein-receptor-related proteins 5 and 6 (LRP5 and LRP6), by immunoblot and quantitative polymerase chain reaction analyses.
RESULTS: SCD was overexpressed in activated HSC and HCC cells from patients; levels of SCD messenger RNA (mRNA) correlated with HCC stage and patient survival time. In rodent HSCs and TICs, the Wnt effector β-catenin increased sterol regulatory element binding protein 1-dependent transcription of Scd, and β-catenin in return was stabilized by MUFAs generated by SCD. This loop required MUFA inhibition of binding of Ras-related nuclear protein 1 (Ran1) to transportin 1 and reduced nuclear import of elav-like protein 1 (HuR), increasing cytosolic levels of HuR and HuR-mediated stabilization of mRNAs encoding LRP5 and LRP6. Genetic disruption of Scd and pharmacologic inhibitors of SCD reduced HSC activation and TIC self-renewal and attenuated liver fibrosis and tumorigenesis in mice. Conditional disruption of Scd2 in activated HSCs prevented growth of tumors from TICs and reduced the formation of diethyl nitrosamine-induced liver tumors in mice.
CONCLUSIONS: In rodent HSCs and TICs, we found SCD expression to be regulated by Wnt-β-catenin signaling, and MUFAs produced by SCD provided a forward loop to amplify Wnt signaling via stabilization of Lrp5 and Lrp6 mRNAs, contributing to liver fibrosis and tumor growth. SCD expressed by HSCs promoted liver tumor development in mice. Components of the identified loop linking HSCs and TICs might be therapeutic targets for liver fibrosis and tumors.

PMID: 28143772 [PubMed - indexed for MEDLINE]

Efficacy of Ledipasvir Plus Sofosbuvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2 Infection.

Wed, 08/09/2017 - 12:45
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Efficacy of Ledipasvir Plus Sofosbuvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2 Infection.

Gastroenterology. 2017 May;152(6):1366-1371

Authors: Gane EJ, Hyland RH, Yang Y, Svarovskaia E, Stamm LM, Brainard DM, McHutchison JG, Stedman CAM

Abstract
BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) genotype 2 have high rates of response to treatment with sofosbuvir and ribavirin. However, ribavirin is associated with hemolytic events and is poorly tolerated by some patients. We evaluated the effectiveness of sofosbuvir and ledipasvir in treatment-naïve and treatment-experienced patients with HCV genotype 2, comparing 12 versus 8 weeks of treatment.
METHODS: This Phase 2, open-label study included 2 cohorts in New Zealand. The first received a fixed-dose combination tablet of ledipasvir-sofosbuvir (90/400 mg) once daily for 12 weeks. If this cohort had a 90% rate of sustained virologic response (SVR) 4 weeks after treatment, a second cohort receiving 8 weeks of ledipasvir-sofosbuvir was to be enrolled. The primary endpoint in both cohorts was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after therapy (SVR12).
RESULTS: SVR12 rates were 96% (25/26; 95% CI, 80%-100%) for 12 weeks and 74% (20/27; 95% CI, 54%-89%) for 8 weeks of ledipasvir-sofosbuvir. The single patient receiving 12 weeks of ledipasvir-sofosbuvir who did not reach SVR12 did not complete treatment because of withdrawing consent after receiving 1 dose of study drug. Six of the 7 patients who did not reach SVR12 after 8 weeks of treatment experienced virologic relapse after stopping therapy. The most common adverse events were headache (26% of patients), fatigue (21%), and nausea (17%). No patients discontinued treatment because of an adverse event.
CONCLUSIONS: For treatment-naïve and -experienced patients, ledipasvir-sofosbuvir for 12 weeks is highly effective for the treatment of HCV genotype 2 (ClinicalTrials.gov: NCT02202980).

PMID: 28137593 [PubMed - indexed for MEDLINE]

Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice.

Wed, 08/09/2017 - 12:45
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Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice.

Gastroenterology. 2017 May;152(6):1492-1506.e24

Authors: Endo S, Nakata K, Ohuchida K, Takesue S, Nakayama H, Abe T, Koikawa K, Okumura T, Sada M, Horioka K, Zheng B, Mizuuchi Y, Iwamoto C, Murata M, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M

Abstract
BACKGROUND & AIMS: Pancreatic stellate cells (PSCs) change from a quiescent to activated state in the tumor environment and secrete extracellular matrix (ECM) molecules and cytokines to increase the aggressiveness of tumors. However, it is not clear how PSCs are activated to produce these factors, or whether this process can be inhibited. PSCs have morphologic and functional similarities to hepatic stellate cells, which undergo autophagy to promote fibrosis and tumor growth. We investigated whether autophagy activates PSCs, which promotes development of the tumor stroma and growth of pancreatic tumors in mice.
METHODS: We used immunofluorescence microscopy and immunohistochemistry to analyze pancreatic tumor specimens from 133 patients who underwent pancreatectomy in Japan from 2000 to 2009. PSCs were cultured from pancreatic tumor tissues or tissues of patients with chronic pancreatitis; these were analyzed by immunofluorescence microscopy, immunoblots, quantitative reverse transcription polymerase chain reaction, and in assays for invasiveness, proliferation, and lipid droplets. Autophagy was inhibited in PSCs by administration of chloroquine or transfection with small interfering RNAs. Proteins were knocked down in immortalized PSCs by expression of small hairpin RNAs. Cells were transplanted into pancreatic tails of nude mice, and tumor growth and metastasis were quantified.
RESULTS: Based on immunohistochemical analyses, autophagy was significantly associated with tumor T category (P = .018), histologic grade (P = .001), lymph node metastases (P < .001), stage (P = .009), perilymphatic invasion (P = .001), and perivascular invasion (P = .003). Autophagy of PSCs was associated with shorter survival times of patients with pancreatic cancer. PSC expression of microtubule-associated protein 1 light chain 3, a marker of autophagosomes, was associated with poor outcomes (shorter survival time, disease recurrence) for patients with pancreatic cancer (relative risk of shorter survival time, 1.56). Immunoblots showed that PSCs from pancreatic tumor samples expressed higher levels of markers of autophagy than PSCs from chronic pancreatitis samples. Inhibitors of autophagy increased the number of lipid droplets of PSCs, indicating a quiescent state of PSCs, and reduced their production of ECM molecules and interleukin 6, as well as their proliferation and invasiveness in culture. PSCs exposed to autophagy inhibitors formed smaller tumors in nude mice (P = .001) and fewer liver metastases (P = .018) with less peritoneal dissemination (P = .018) compared to PSCs not exposed to autophagy inhibitors.
CONCLUSIONS: Autophagic PSCs produce ECM molecules and interleukin 6 and are associated with shorter survival times and disease recurrence in patients with pancreatic cancer. Inhibitors of PSC autophagy might reduce pancreatic tumor invasiveness by altering the tumor stroma.

PMID: 28126348 [PubMed - indexed for MEDLINE]

Role of High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Men With Previously Treated Germ Cell Tumors.

Wed, 08/09/2017 - 12:45
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Role of High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Men With Previously Treated Germ Cell Tumors.

J Clin Oncol. 2017 Apr 01;35(10):1036-1040

Authors: Pagliaro LC

Abstract
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 39-year-old, previously healthy man presented with a left testicular mass, confirmed on ultrasound. He underwent left inguinal orchiectomy, which disclosed testicular carcinoma composed of 90% choriocarcinoma, 9% seminoma, and 1% teratoma. Imaging revealed numerous metastases in the lungs, liver, and brain. Prechemotherapy levels of serum tumor markers were alpha-fetoprotein (AFP) 2.0 ng/mL, human chorionic gonadotropin (hCG) 151,111 IU/L, and lactate dehydrogenase 588 U/L. He received four courses of etoposide, ifosfamide, and cisplatin chemotherapy, given without bleomycin because of the anticipated need for postchemotherapy thoracic surgery. He had an incomplete response to induction chemotherapy. The serum hCG level was 8.1 IU/L, and there were residual lesions in the liver and lungs whereas the brain metastases had nearly resolved. His Eastern Cooperative Oncology Group performance status was zero. He had no symptoms of ototoxicity or peripheral neurotoxicity. Repeat serum hCG levels after chemotherapy were 12.3 IU/L at 2 weeks and 325 IU/L at 4 weeks. He was referred to discuss optimal ongoing treatment.

PMID: 27992270 [PubMed - indexed for MEDLINE]

Lipopolysaccharide promotes tumorigenicity of hepatic progenitor cells by promoting proliferation and blocking normal differentiation.

Wed, 08/09/2017 - 12:45
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Lipopolysaccharide promotes tumorigenicity of hepatic progenitor cells by promoting proliferation and blocking normal differentiation.

Cancer Lett. 2017 Feb 01;386:35-46

Authors: Li XY, Yang X, Zhao QD, Han ZP, Liang L, Pan XR, Zhu JN, Li R, Wu MC, Wei LX

Abstract
Hepatic progenitor cells (HPCs) are bipotential stem cells that can differentiate into mature hepatocytes or biliary epithelial cells (BECs). They are thought to be involved in repair of liver injury and the incidence of hepatic carcinoma. Their physiology is closely associated with the microenvironment where they reside. Lipopolysaccharide (LPS), an important component of the hepatic pathological microenvironment, is stored in the liver and affects many types of cells in various hepatosis. HPCs may also be influenced by LPS. In this paper, mouse ED13.5 E-cadherin(+) foetal liver cells were isolated as mouse hepatic progenitor cells (mHPCs). Proliferation of mHPCs was promoted under LPS conditions both in vivo and in vitro. Moreover, LPS enhanced colony formation ability of mHPCs, and blocked them differentiation into mature hepatocytes and formation of a bile duct-liked structure. More importantly, long-term treatment with LPS promoted tumorigenesis of mHPCs in nude mice. Thus, we conclude that LPS may promote aberrant proliferation of mHPCs and restrict their normal differentiation. Long-term exposure of mHPCs to LPS increased the risk of tumour formation. These data provide insight into the links between LPS, HPCs fate, and tumorigenesis, and present novel insight into the relationship between HPCs and their microenvironment.

PMID: 27864114 [PubMed - indexed for MEDLINE]

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