Abstract:
BACKGROUND & AIMS:Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. We evaluated the therapeutic potential of MLN0128 vs. gemcitabine/oxaliplatin in a novel ICC mouse model. METHODS:We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis. Gemcitabine/oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor-bearing mice to study their anti-tumor efficacy in vivo. Multiple human ICC cell lines were used for in vitro experiments. Hematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied for the characterization and mechanistic study. RESULTS:Co-expression of myr-AKT and YapS127A promoted ICC development in mice. Both mTORC1 and mTORC2 complexes were required for AKT/YapS127A ICC development. Gemcitabine/oxaliplatin had limited efficacy in treating late stage AKT/YapS127A ICC. In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A cholangiocarcinogenesis. Furthermore, when MLN0128 was administered in the early stage of AKT/YapS127A carcinogenesis, it led to disease stabilization. Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling both in vivo and in vitro, inducing strong ICC cell apoptosis and only marginally affecting proliferation. CONCLUSIONS:This study suggests that mTOR kinase inhibitors may be beneficial for the treatment of ICC, even in tumors that are resistant to standard of care chemotherapeutics, such as gemcitabine/oxaliplatin-based regimens, especially in the subset of tumors exhibiting activated AKT/mTOR cascade. Lay summary: We established a novel mouse model of intrahepatic cholangiocarcinoma (ICC). Using this new preclinical model, we evaluated the therapeutic potential of mTOR inhibitor MLN0128 vs. gemcitabine/oxaliplatin (the standard chemotherapy for ICC treatment). Our study shows the anti-neoplastic potential of MLN0128, suggesting that it may be superior to gemcitabine/oxaliplatin-based chemotherapy for the treatment of ICC, especially in the tumors exhibiting activated AKT/mTOR cascade.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Zhang S,Song X,Cao D,Xu Z,Fan B,Che L,Hu J,Chen B,Dong M,Pilo MG,Cigliano A,Evert K,Ribback S,Dombrowski F,Pascale RM,Cossu A,Vidili G,Porcu A,Simile MM,Pes GM,Giannelli G,Gordan J,Wei L,Evert M,Cong W,Cdoi
10.1016/j.jhep.2017.07.006subject
Has Abstractpub_date
2017-12-01 00:00:00pages
1194-1203issue
6eissn
0168-8278issn
1600-0641pii
S0168-8278(17)32149-9journal_volume
67pub_type
杂志文章abstract:BACKGROUND & AIMS:This study aimed to identify preoperative magnetic resonance (MR) imaging biomarkers for predicting microvascular invasion (MVI), to determine their diagnostic performance and to evaluate whether they are associated with early recurrence after surgery for single hepatocellular carcinoma (HCC). METHOD...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2017.04.024
更新日期:2017-09-01 00:00:00
abstract::The etiologic agent responsible for epidemics of enterically-transmitted non-A, non-B hepatitis has been molecularly characterized as the hepatitis E virus (HEV). The cloning of a portion of the Burma strain of HEV (HEV(B); 'Old World' strain) has been described together with the isolation of a contiguous overlapping ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(91)90050-l
更新日期:1991-01-01 00:00:00
abstract:BACKGROUND & AIMS:SIRT1 is a class III histone deacetylase that plays diverse roles in various cancers. However, the clinical significance of SIRT1 in hepatocellular carcinoma (HCC) remains unknown. METHODS:We analysed p53 mutations and the activation of SIRT1 in 252 hepatitis B virus-positive HCC cases. None of the p...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2014.08.007
更新日期:2015-01-01 00:00:00
abstract:BACKGROUND/AIMS:Norfloxacin is useful to prevent infections in hospitalized cirrhotic patients with low ascitic fluid protein concentrations. It is also effective in preventing the recurrence of spontaneous bacterial peritonitis. The aim of our study was to determine the efficacy of norfloxacin in the primary prophylax...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1016/s0168-8278(98)80061-5
更新日期:1998-09-01 00:00:00
abstract:BACKGROUND/AIM:Liver cirrhosis is accompanied by a fall in whole-body protein turnover and alterations of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. However, the influence of liver cirrhosis on the GH/IGF-1 axis in the perioperative period, and the contribution of the GH/IGF-1 axis alteration in...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(99)80224-4
更新日期:1999-08-01 00:00:00
abstract:BACKGROUND/AIM:Steatosis is commonly present in chronic hepatitis C. Our aim was to evaluate host- and disease-specific factors associated with its occurrence. METHODS:Histologic findings in 60 patients were correlated with body mass index, human leukocyte antigens, and other conventional parameters. Comparisons were ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(98)80004-4
更新日期:1998-08-01 00:00:00
abstract::Experimental autoimmune hepatitis was induced in C57BL/6 mice by immunization with syngeneic liver protein and adjuvant. Hepatitis was characterized by marked cellular infiltrates, but hepatic necrosis was mild to moderate. A small dose of endotoxin (25 micrograms/mouse) produced lethal hepatitis with elevation of ser...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(05)80548-3
更新日期:1993-11-01 00:00:00
abstract:BACKGROUND/AIMS:Angiogenesis plays a key role in development of portal hypertension (PHT) and represents a potential therapeutic target. We aimed to evaluate the molecular effects of sorafenib, a multiple tyrosine kinase inhibitor, on splanchnic hemodynamics in rats with partial portal vein ligation (PPVL). METHODS:Th...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2009.06.024
更新日期:2009-11-01 00:00:00
abstract:BACKGROUND/AIMS:The relationship between HCV RNA levels and the severity of HCV-related liver disease has been addressed in a few studies, which has led to conflicting results. To clarify this point, we studied serum HCV RNA levels in patients with HCV liver disease at various stages, using a second-generation branched...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(99)80336-5
更新日期:1999-10-01 00:00:00
abstract:BACKGROUND/AIMS:The Peroxisome Proliferator-Activated Receptor (PPAR) alpha belongs to the superfamily of Nuclear Receptors and plays an important role in numerous cellular processes, including lipid metabolism. It is known that PPARalpha also has an anti-inflammatory effect, which is mainly achieved by down-regulating...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2006.11.019
更新日期:2007-05-01 00:00:00
abstract:BACKGROUND & AIMS:Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease in Western countries. It is unclear how infiltrating leukocytes affect NASH-development. Our study aims to investigate the role of the homing/receptor, pair mucosal addressin cell adhesion molecule-1 (MAdCAM-1)/β7-Integri...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2017.02.001
更新日期:2017-06-01 00:00:00
abstract:BACKGROUND & AIMS:Chronic hepatitis C virus (HCV)-infected patients with cirrhosis are a high-priority population for treatment. To help inform the benefit-risk profile of the all-oral direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir (OBV/PTV/r±DSV)...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2017.06.011
更新日期:2017-10-01 00:00:00
abstract:BACKGROUND/AIMS:The glycosphingolipid alpha-galactosylceramide has been shown to activate invariant natural killer T cells when presented in the context of CD1d and induces powerful antiviral immune responses via the production of inflammatory cytokines. The aim of this study was to investigate the safety and the antiv...
journal_title:Journal of hepatology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1016/j.jhep.2007.04.018
更新日期:2007-09-01 00:00:00
abstract::Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2020.08.009
更新日期:2021-01-01 00:00:00
abstract:BACKGROUND & AIMS:The pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD) is still incompletely understood. Several nuclear receptors play a role in liver lipid metabolism and can promote hepatosteatosis, but the possible role of vitamin D receptor (VDR) in NAFLD has not been investigated. METHOD...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2016.05.031
更新日期:2016-10-01 00:00:00
abstract:BACKGROUND/AIMS:Despite anti-HBs immunoglobulin therapy, hepatitis B virus (HBV) infection recurs in a high proportion of patients transplanted for HBsAg positive and serum HBV DNA negative chronic liver disease. The contribution of HBV genetic variability to disease recurrence has not been yet thoroughly addressed. We...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(97)80035-9
更新日期:1997-02-01 00:00:00
abstract::Linoleic and alpha-linolenic acids are the fatty acids designated as "essential" since they are not synthesized by mammalian cells and must be provided in the diet. The recent dietary shift towards the consumption of n-6 (omega-6) at the expense of n-3 (omega-3) polyunsaturated fatty acids (PUFAs) is thought to be a p...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2007.08.005
更新日期:2007-11-01 00:00:00
abstract:BACKGROUND/AIMS:The efficacy and safety of rifaximin in comparison with lactitol in the treatment of acute hepatic encephalopathy was assessed in a prospective randomized, double-blind, double-dummy, controlled trial. METHODS:A total of 103 patients with grade I-III acute hepatic encephalopathy were randomized to rece...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/s0168-8278(02)00350-1
更新日期:2003-01-01 00:00:00
abstract:BACKGROUND/AIMS:A distinct subgroup of angiotensin II type 1 receptor (AT1R) blockers (ARBs) have been reported to suppress the development of hepatic steatosis. These effects were generally explained by selective peroxisome proliferator-activated receptor (PPAR) gamma modulating properties of ARBs, independent of thei...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2009.01.018
更新日期:2009-06-01 00:00:00
abstract::To summarize, nowadays it seems clear that in patients with cirrhosis: (a) the pulmonary circulation is usually markedly dilated. (b) This vasodilation is due to a loss of vascular tone and it is characterized by a poor (or even absent) vascular reactivity in front of the hypoxic stimulus. (c) This abnormal behaviour ...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/0168-8278(90)90061-u
更新日期:1990-03-01 00:00:00
abstract:BACKGROUND & AIMS:Biliary atresia represents obstructive cholangiopathy in infants progressing rapidly to cirrhosis and end-stage liver disease. Activated NK cells expressing Nkg2d have been linked to bile duct injury and obstruction by establishing contact with cholangiocytes. To define the mechanisms used by cytotoxi...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2013.09.021
更新日期:2014-02-01 00:00:00
abstract:BACKGROUND/AIMS:We have previously shown that an abnormality in cardiac autonomic reflexes (AN) is an independent predictor of mortality in patients with chronic liver disease. Aim of this study was to determine whether there was an association between prolonged QTc interval and cardiac AN. METHODS:Cardiac AN and QTc ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(01)00217-3
更新日期:2001-12-01 00:00:00
abstract:BACKGROUND & AIMS:Most cholesterol gallstones have a core consisting of inorganic and/or organic calcium salts, although the mechanisms of core formation are poorly understood. We examined whether the paracellular permeability of ions at hepatic tight junctions is involved in the core formation of cholesterol gallstone...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2018.08.025
更新日期:2018-12-01 00:00:00
abstract:BACKGROUND/AIMS:Failure to induce apoptosis triggered by members of the death receptor family has been described in hepatocellular carcinoma (HCC) and sensitization of malignant cells to pro-apoptotic molecules such as TRAIL has been proposed as an alternative cancer therapy. Limiting to this approach are the resistanc...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2006.10.010
更新日期:2007-04-01 00:00:00
abstract::All routinely available assays to detect hepatitis C virus (HCV) infection are based on the specific reaction of serum antibodies to corresponding viral antigens. The only method to detect viral nucleic acids in serum or liver is the enzymatic amplification of reversely transcribed HCV-RNA by polymerase chain reaction...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(92)90074-y
更新日期:1992-07-01 00:00:00
abstract:BACKGROUND/AIMS:The impact of heterozygous HFE mutations on the course of chronic hepatitis C and iron indices was studied. METHODS:Ferritin, transferrin saturation (TS), serum iron, C282Y and H63D mutations were determined in 401 patients with chronic hepatitis C virus (HCV) infection and 295 healthy controls. Liver ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(02)00415-4
更新日期:2003-03-01 00:00:00
abstract:BACKGROUND & AIMS:Hepatitis B virus (HBV) has developed strategies to evade immune responses. However, the mechanisms involved remain unclear. The NLRP3 inflammasome plays crucial roles in antiviral host defense and its downstream factor IL-1β has been shown to inhibit HBV infection in vivo. This study aims to assess w...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2016.12.018
更新日期:2017-04-01 00:00:00
abstract:BACKGROUND & AIMS:Myeloproliferative neoplasms (MPNs) are the most frequent cause of non-tumoural non-cirrhotic splanchnic vein thrombosis (NC-SVT). Diagnosis of MPN is based on blood cell count alterations, bone marrow histology, and detection of specific gene mutations. Next-generation sequencing (NGS) allows the sim...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2020.06.045
更新日期:2021-01-01 00:00:00
abstract:BACKGROUND & AIMS:IL28B polymorphisms, jaundice, decline in HCV-RNA, IP-10, and gender have been proposed to be indicative of spontaneous clearance of acute hepatitis C virus infection. The aim of this study was to define a score enabling the discrimination of patients with spontaneous clearance of HCV from those with ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2013.06.028
更新日期:2013-11-01 00:00:00
abstract:BACKGROUND & AIMS:Antibiotic resistance has been increasingly reported in patients with decompensated cirrhosis in single-center studies. Prospective investigations reporting broad epidemiological data are scarce. We aimed to analyze epidemiological changes in bacterial infections in patients with decompensated cirrhos...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2018.10.027
更新日期:2019-03-01 00:00:00