IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction

Approximately 3% of the world population is chronically infected with the hepatitis C virus (HCV), with potential development of cirrhosis and hepatocellular carcinoma. Despite the availability of new antiviral agents, treatment remains suboptimal. Genome-wide association studies (GWAS) identified rs12979860, a polymorphism nearby IL28B, as an important predictor of HCV clearance. We report the identification of a novel TT/-G polymorphism in the CpG region upstream of IL28B, which is a better predictor of HCV clearance than rs12979860. By using peripheral blood mononuclear cells (PBMCs) from individuals carrying different allelic combinations of the TT/-G and rs12979860 polymorphisms, we show that induction of IL28B and IFN-γ–inducible protein 10 (IP-10) mRNA relies on TT/-G, but not rs12979860, making TT/-G the only functional variant identified so far. This novel step in understanding the genetic regulation of IL28B may have important implications for clinical practice, as the use of TT/G genotyping instead of rs12979860 would improve patient management.

Intermediate hepatocellular carcinoma: current treatments and future perspectives

Current guidelines recommend transarterial chemoembolization (TACE) as the standard treatment of Barcelona-Clinic Liver Cancer (BCLC)-B patients. However, the long-term survival outcomes of patients managed with this technique do not appear fully satisfactory; in addition, intermediate-stage hepatocellular carcinoma (HCC) includes a heterogeneous population of patients with varying tumour burdens, liver function and disease aetiology. Therefore, not all patients with intermediate-stage HCC may derive similar benefit from TACE, and some patients may benefit from other treatment options, which are currently approved or being explored. These include different TACE modalities, such as selective TACE or drug-eluting beads TACE and radioembolization. The introduction of sorafenib in the therapeutic armamentarium for HCC has provided a new therapeutic option for the treatment of BCLC-B patients who are unsuitable to TACE or in whom TACE resulted in unacceptable toxicity. In addition, clinical trials aimed at investigating the potential role of this molecule in the treatment of patients with intermediate-stage HCC within combination therapeutic regimens are ongoing. This narrative review will present and discuss the most recent evidence on the locoregional or medical treatment with sorafenib in patients with intermediate-stage HCC.

Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma

BACKGROUND & AIMS: Recently, genetic variations in MICA (lead single nucleotide polymorphism [SNP] rs2596542) were identified by a genome-wide association study (GWAS) to be associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) in Japanese patients. In the present study, we sought to determine whether this SNP is predictive of HCC development in the Caucasian population as well. METHODS: An extended region around rs2596542 was genotyped in 1924 HCV-infected patients from the Swiss Hepatitis C Cohort Study (SCCS). Pair-wise correlation between key SNPs was calculated both in the Japanese and European populations (HapMap3: CEU and JPT). RESULTS: To our surprise, the minor allele A of rs2596542 in proximity of MICA appeared to have a protective impact on HCC development in Caucasians, which represents an inverse association as compared to the one observed in the Japanese population. Detailed fine-mapping analyses revealed a new SNP in HCP5 (rs2244546) upstream of MICA as strong predictor of HCV-related HCC in the SCCS (univariable p=0.027; multivariable p=0.0002, odds ratio=3.96, 95% confidence interval=1.90-8.27). This newly identified SNP had a similarly directed effect on HCC in both Caucasian and Japanese populations, suggesting that rs2244546 may better tag a putative true variant than the originally identified SNPs. CONCLUSIONS: Our data confirms the MICA/HCP5 region as susceptibility locus for HCV-related HCC and identifies rs2244546 in HCP5 as a novel tagging SNP. In addition, our data exemplify the need for conducting meta-analyses of cohorts of different ethnicities in order to fine map GWAS signals.

Hepatocellular carcinoma in a non-cirrhotic patient with Wilson's disease

We report the exceptional case of hepatocellular carcinoma in a non-cirrhotic patient, whose Wilson's disease was diagnosed at the unusual age of 58 years. The liver histology revealed macrovesicular steatosis with fibrosis, but no cirrhosis. The disease was treated with D-penicillamine for 3 years until acute discomfort in the right upper quadrant led to detection of multifocal hepatocellular carcinoma, which was successfully resected. The histological examination confirmed the malignant nature of the 4 lesions, which were classified according to Edmondson and Steiner as poorly differentiated hepatocellular carcinoma grade 3. The non-tumoral parenchyma showed 80% steatosis with ballooned cells, lobular inflammation, septal fibrosis but no cirrhosis. Hepatocellular carcinoma is rare in Wilson's disease, especially in the absence of cirrhosis. The literature's 28 published cases are reviewed and the contributory role of copper in the hepatocarcinogenic process is discussed.

Tissue metabolomics of hepatocellular carcinoma: Tumor energy metabolism and the role of transcriptomic classification

Hepatocellular carcinoma (HCC) is one of the commonest causes of death from cancer. A plethora of metabolomic investigations of HCC have yielded molecules in biofluids that are both up- and down-regulated but no real consensus has emerged regarding exploitable biomarkers for early detection of HCC. We report here a different approach, a combined transcriptomics and metabolomics study of energy metabolism in HCC. A panel of 31 pairs of HCC tumors and corresponding nontumor liver tissues from the same patients was investigated by gas chromatography-mass spectrometry (GCMS)-based metabolomics. HCC was characterized by ∼2-fold depletion of glucose, glycerol 3- and 2-phosphate, malate, alanine, myo-inositol, and linoleic acid. Data are consistent with a metabolic remodeling involving a 4-fold increase in glycolysis over mitochondrial oxidative phosphorylation. A second panel of 59 HCC that had been typed by transcriptomics and classified in G1 to G6 subgroups was also subjected to GCMS tissue metabolomics. No differences in glucose, lactate, alanine, glycerol 3-phosphate, malate, myo-inositol, or stearic acid tissue concentrations were found, suggesting that the Wnt/β-catenin pathway activated by CTNNB1 mutation in subgroups G5 and G6 did not exhibit specific metabolic remodeling. However, subgroup G1 had markedly reduced tissue concentrations of 1-stearoylglycerol, 1-palmitoylglycerol, and palmitic acid, suggesting that the high serum α-fetoprotein phenotype of G1, associated with the known overexpression of lipid catabolic enzymes, could be detected through metabolomics as increased lipid catabolism. Conclusion: Tissue metabolomics yielded precise biochemical information regarding HCC tumor metabolic remodeling from mitochondrial oxidation to aerobic glycolysis and the impact of molecular subtypes on this process.

Study of the cellular mechanism of Sunitinib mediated inactivation of activated hepatic stellate cells and its implications in angiogenesis

The development of hepatocellular carcinomas from malignant hepatocytes is frequently associated with intra- and peritumoral accumulation of connective tissue arising from activated hepatic stellate cells (HSC). Inhibition of receptor tyrosine kinase (RTK) signaling showed promise in the treatment of hepatocellular carcinoma. However, there is a lack of knowledge about the effects of RTK inhibitors on the tumor supportive cells. We performed in vitro experiments to study whether Sunitinib, a platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) RTKs' inhibitor, could block both activated HSC functions and angiogenesis and thus prevent the progression of cirrhotic liver to hepatocellular carcinoma. In immortalized human activated HSC LX-2, treatment with Sunitinib 100 nM blocked collagen synthesis by 47%, as assessed by Sirius Red staining, attenuated HSC contraction by 65%, and reduced cell migration by 28% as evaluated using a Boyden's chamber, without affecting cell viability, measured by Trypan blue staining, and apoptosis, measured by propidium iodide (PI) incorporation assay. Our data revealed that Sunitinib treatment blocked the transdifferentiation of primary human HSC (hHSC) to activated myofibroblast-like cells by 65% without affecting hHSC apoptosis and migration. In in vitro angiogenic assays, Sunitinib 100 nM reduced endothelial cells (EC) ring formation by 46% and tube formation by 68%, and decreased vascular sprouting in aorta ring assay and angiogenesis in vascular bed of chick embryo. In conclusion, the present study demonstrates that the RTK inhibitor Sunitinib blocks the activation of HSC and angiogenesis suggesting its potential as a drug candidate in pathological conditions like liver fibrosis and hepatocellular carcinoma.

Thinking Time : a multidisiplinary perspective on time

"Time" has been much less widely studied in psychology and related disciplines than has "space". This book offers theoretical and empirical insights into the study of time-related perception, memory, identity, learning, and reasoning. With carefully selected chapters by a truly international and interdisciplinary team of authors, this book provides an unterstanding of time and mind that goes beyond psychophysiology and experimental psychology to encompass wider phenomena, both social and eduational. By providing a philosophical basis for understanding how the mind "graps" the concept of time and the timing of behavior in a cultural context, this unique book should help promote a cross-fertilization of research on this important dimension, which ist so often neglected in cognitive and sociocultural research.

Spring temperature variability and eutrophication history inferred from sedimentary pigments in the varved sediments of Lake Żabińskie, north-eastern Poland, AD 1907–2008

Varved lake sediments are excellent natural archives providing quantitative insights into climatic and environmental changes at very high resolution and chronological accuracy. However, due to the multitude of responses within lake ecosystems it is often difficult to understand how climate variability interacts with other environmental pressures such as eutrophication, and to attribute observed changes to specific causes. This is particularly challenging during the past 100 years when multiple strong trends are superposed. Here we present a high-resolution multi-proxy record of sedimentary pigments and other biogeochemical data from the varved sediments of Lake Żabińskie (Masurian Lake District, north-eastern Poland, 54°N–22°E, 120 m a.s.l.) spanning AD 1907 to 2008. Lake Żabińskie exhibits biogeochemical varves with highly organic late summer and winter layers separated by white layers of endogenous calcite precipitated in early summer. The aim of our study is to investigate whether climate-driven changes and anthropogenic changes can be separated in a multi-proxy sediment data set, and to explore which sediment proxies are potentially suitable for long quantitative climate reconstructions. We also test if convoluted analytical techniques (e.g. HPLC) can be substituted by rapid scanning techniques (visible reflectance spectroscopy VIS-RS; 380–730 nm). We used principal component analysis and cluster analysis to show that the recent eutrophication of Lake Żabińskie can be discriminated from climate-driven changes for the period AD 1907–2008. The eutrophication signal (PC1 = 46.4%; TOC, TN, TS, Phe-b, high TC/CD ratios total carotenoids/chlorophyll-a derivatives) is mainly expressed as increasing aquatic primary production, increasing hypolimnetic anoxia and a change in the algal community from green algae to blue-green algae. The proxies diagnostic for eutrophication show a smooth positive trend between 1907 and ca 1980 followed by a very rapid increase from ca. 1980 ± 2 onwards. We demonstrate that PC2 (24.4%, Chl-a-related pigments) is not affected by the eutrophication signal, but instead is sensitive to spring (MAM) temperature (r = 0.63, pcorr < 0.05, RMSEP = 0.56 °C; 5-yr filtered). Limnological monitoring data (2011–2013) support this finding. We also demonstrate that scanning visible reflectance spectroscopy (VIS-RS) data can be calibrated to HPLC-measured chloropigment data and be used to infer concentrations of sedimentary Chl-a derivatives {pheophytin a + pyropheophytin a}. This offers the possibility for very high-resolution (multi)millennial-long paleoenvironmental reconstructions.

Hepatitis C: a changing epidemic.

Approximately 3% of the world population is estimated to have a chronic hepatitis C virus (HCV) infection and 500,000 individuals die from its consequences yearly. Persons who inject drugs (PWID) bear the majority of the disease burden in high-income countries. Drug substitution programmes have helped reduce HCV transmissions among PWID. However, recent epidemics of sexually transmitted HCV infections in HIV-infected men who have sex with men demonstrated the changing nature of the HCV epidemic. HCV therapy is undergoing a revolution, as new interferon-free, oral treatments eradicate HCV infections in almost all treated patients. As a consequence, the eradication of HCV has become a matter of debate and is becoming an important future public health target. However, for this to be achieved, many challenges need to be addressed, including the poor uptake of HCV testing, the high cost of the new antiviral combinations and the high frequency of re-infections after treatment in some populations.

Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment-induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFNλ4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNλ4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFNλ4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNλ4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.