Epigenetic aspects of genotoxic and non-genotoxic hepatocarcinogenesis: Studies in rodents

Hepatocellular carcinoma, which is one of the most prevalent life-threatening human cancers, is showing an increased incidence worldwide. Recent evidence indicates that the development of hepatocellular carcinoma is associated with not only genetic alterations, but also with profound epigenetic changes. This review summarizes the current knowledge about epigenetic alterations during rodent hepatocarcinogenesis, considers the similarities and differences in epigenetic effects of genotoxic and non-genotoxic rodent liver carcinogens, and discusses the possible role of these effects in the causality of liver tumor development

Tyrosine kinase Inhibitors in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma is the third leading cause of cancer-related mortality in the world. Locoregional therapy is used for early stage hepatocellular carcinoma. Tyrosine kinase inhibitors have been the mainstay of treatment for advanced hepatocellular carcinoma. Sorafenib was the first drug approved based on data from two pivotal phase III trials. Although sorafenib provided a survival benefit, development of adverse events limits its use in some patients. These adverse events, such as hand–foot syndrome and diarrhea, have a significant impact on the quality of life and, in some circumstances, are severe enough to prompt cessation of the drug. In recent times, a range of new therapeutic options have come on the scene including lenvatinib, regorafenib, and cabozantinib. Lenvatinibis now approved as an alternative first-line agent for hepatocellular carcinoma. Regorafenib and cabozantinib are both second-line agents. These medications provide a promising range of treatment options for patients who progress on sorafenib or are intolerant to it. This chapter provides an insight into the range of tyrosine kinase inhibitors available for the treatment of hepatocellular carcinoma

Mouse models of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents a major and steadily increasing global health challenge as the most common primary liver malignancy and leading cause of death in cirrhotic patients. The only hope for curative treatment or significant increase in life expectancy is early detection. Once patients have progressed towards end-stage HCC, effective treatment options are extremely limited on the background of a very high degree of heterogeneity in clinical presentation and outcome. Experimental chronic liver injury and cancer have been used extensively to mimic the human disease. In particular, mouse studies have advanced the field due to the ability to easily manipulate the mouse genome and transcriptome for mechanistic evaluations. In addition, they offer the opportunity to screen new therapeutic strategies cost effectively and in quick high-throughput, large-scale formats. The most commonly used mouse models in HCC research can be categorized as chemotoxic, diet-induced, and genetically engineered models. It is important to note that no particular model mimics all features of a given HCC etiology or histological subtype, and each model poses advantages and disadvantages that need to be carefully considered

Mouse Models of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) represents a major and steadily increasing global health challenge as the most common primary liver malignancy and leading cause of death in cirrhotic patients. The only hope for curative treatment or significant increase in life expectancy is early detection. Once patients have progressed towards end-stage HCC, effective treatment options are extremely limited on the background of a very high degree of heterogeneity in clinical presentation and outcome. Experimental chronic liver injury and cancer have been used extensively to mimic the human disease. In particular, mouse studies have advanced the field due to the ability to easily manipulate the mouse genome and transcriptome for mechanistic evaluations. In addition, they offer the opportunity to screen new therapeutic strategies cost-effectively and in quick high-throughput, large-scale formats. The most commonly used mouse models in HCC research can be categorized as chemotoxic, diet-induced, and genetically engineered models. It is important to note that no particular model mimics all features of a given HCC etiology or histological subtype, and each model poses advantages and disadvantages that need to be carefully considered

Re-evaluation of l(+)-tartaric acid (E 334), sodium tartrates (E 335), potassium tartrates (E 336), potassium sodium tartrate (E 337) and calcium tartrate (E 354) as food additives

Acknowledgements: The FAF Panel wishes to thank Claude Lambre and Lieve Herman for the support provided to this scientific output. The FAF Panel wishes to acknowledge all European competent institutions, Member State bodies and other organisations that provided data for this scientific output.Publisher PD

Expression profiling of the spermidine synthase3 (SPDS3) and spermine synthase ( SPMS) genes during the life of Arabidopsis

Polyamines are low molecular weight nitrogenous compounds found in all living organisms. These omnipresent molecules have been extensively studied in plant systems and have been implicated in a number of physiological responses including growth, development, and stress response. The proposed role of polyamines in vital processes such as cell division and differentiation has sparked enthusiasm in further investigation of this relatively small biosynthetic pathway. Very little is known about the regulation of polyamine biosynthetic genes, an aspect that can elucidate further functions of these ubiquitous compounds. In the following study, the expression profiles of two of these genes, spermidine synthase3 (SPDS3) and spermine synthase (SPMS), were analyzed in the model plant, Arabidopsis thaliana. The promoter::GUS fusion technique was used to provide a detailed expression profile of both genes during the entire life cycle of A. thaliana. Three constructs were designed for each gene containing different segments of the putative promoter region, the entire 5\u27UTR, and in some cases, a portion of the open reading frame. Each construct was individually transformed into A. thaliana and transformed plants were assayed for GUS activity in every organ, during various time points of development. Overall, the expression of SPDS3 was found to be high in young developing tissues with continued, but weaker, expression in the vascular tissue of mature plants. A similar expression profile was observed for SPMS, however, expression was observed in meristematic and elongating regions of tissue. In addition to the developmental profile, the changes in expression were observed during various abiotic stress conditions. Overall, both SPDS3 and SPMS appear to be induced in response to drought and 100 mM salt stress. There appears to be a slight increase in expression during chilling stress, but expression soon decreased over a 24 h period. SPDS3 was also induced during wounding

Dietary iron overload. the generation of reactive oxygen species and hepatocarcinogenesis in experimental rats (Part 1)

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand In fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, 2003Dietary iron (Fe) overload, originally referred to as Bantu Visceral Siderosis, is an Reloading condition that is still prevalent in rural populations of sub-Saharan Africa. The better known Fe loading disease, hereditary haemochromatosis (HFI) is frequently complicated by hepatocellular carcinoma (HCC) and, in rare instances this occurs in the absence of cirrhosis. The latter, together with recent evidence that dietary Fe overload in the Black African carries an increased risk for HCC, suggests that excessive hepatic iron may itself be carcinogenic. The aim of the study was to determine if Fe alone could induce HCC in experimental rat models and, if so, to investigate possible mechanisms of hepatocarcinogenesis. 360 Wistar albino rats (Rattus norvegicus) were divided into 6 groups. The first group, the control animals, was designated C group. Groups 2-6 were Fe-fed alone or in combination with other chemicals: group 2 Fe alone (Fe group), group 3 (Fe + V) vitamins A & E supplementation [50 mg all trans-retinol (vitamin A) and 500 mg a-tocopherol (vitamin E) per kg diet], group 4 (Fe - V) received a diet totally devoid of vitamins A & E, group 5 (Fe + ASA) received 20 mg aspirin (ASA) per day, group 6 (Fe + Cu) received 300 mg/kg diet of copper sulphate (CuS04) supplementation for 12 months followed by 3% copper hydroxide carbonate [CuC03»Cu(0H)2]IT201