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The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation.
Sartorius, K, An, P, Winkler, C, Chuturgoon, A, Li, X, Makarova, J, Kramvis, A
Frontiers in immunology. 2021;:661204
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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Epidemiology of Liver Cancer in Africa: Current and Future Trends.
Okeke, E, Davwar, PM, Roberts, L, Sartorius, K, Spearman, W, Malu, A, Duguru, M
Seminars in liver disease. 2020;(2):111-123
Abstract
Hepatocellular carcinoma (HCC) is a disease of global public health significance with mortality on the rise, despite the preventable nature of its risk factors especially in Africa. It is now the sixth most common cancer worldwide, fifth in males, and ninth in females. HCC incidence and mortality are predicted to increase in African countries constrained by limited resources to combat endemic levels of viral infection and synergistic environmental risk factors. The changing nature of HCC etiology is particularly illustrated here with the traditional risk factors like viral hepatitis coexisting alongside high human immunodeficiency virus (HIV) prevalence and rapidly increasing urbanization that have promoted a sharp increase in additional risk factors like coinfection, type 2 diabetes mellitus, and obesity. Although there are some differences in etiology between North Africa and sub-Saharan Africa, risk factors like chronic viral hepatitis B and C, aflatoxin exposure, and iron overload predominate. Aggressive hepatitis B genotypes, combined with hepatitis B virus/hepatitis C virus/HIV coinfections and aflatoxin exposure, promote a more aggressive molecular phenotype. In parallel to a better understanding of the molecular etiology of HCC, policy and planning initiatives to address the burden of HCC must be anchored within the reality of the limited resources available. Establishment and coordination of cancer registries across Africa is needed to improve the quality of data necessary to galvanize action. Preventive measures including hepatitis B vaccination programs, measures to prevent maternal-to-child and child-to-child transmission, delivery of universally accessible antiretroviral and antiviral treatments, and reduction of dietary aflatoxin exposure can contribute markedly to reduce HCC incidence. Finally, the development of biomarkers and new therapeutic interventions will need a better understanding of the unique genetic and epigenetic characteristics of HCC on the continent. We present a narrative review of HCC in Africa, discussing present and future trends.
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Does high-carbohydrate intake lead to increased risk of obesity? A systematic review and meta-analysis.
Sartorius, K, Sartorius, B, Madiba, TE, Stefan, C
BMJ open. 2018;8(2):e018449
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As overweight and obesity is rising globally, better understanding its cause is important to help with prevention and management of disease. The objective of this meta-analysis is to investigate the relationship between carbohydrate intake and obesity, particularly at the differences between low and high carbohydrate diets. Based on 22 articles that met the inclusion criteria, a high-carbohydrate diet, or increased proportion of energy intake in the form of carbohydrates, does not increase the risk of being obese. Based on these results, the authors iterate further studies are required to better understand obesity risk with regards different carbohydrate groups including refined versus unrefined carbohydrates.
Abstract
OBJECTIVES The present study aimed to test the association between high and low carbohydrate diets and obesity, and second, to test the link between total carbohydrate intake (as a percentage of total energy intake) and obesity. SETTING, PARTICIPANTS AND OUTCOME MEASURES We sought MEDLINE, PubMed and Google Scholar for observation studies published between January 1990 and December 2016 assessing an association between obesity and high-carbohydrate intake. Two independent reviewers selected candidate studies, extracted data and assessed study quality. RESULTS The study identified 22 articles that fulfilled the inclusion and exclusion criteria and quantified an association between carbohydrate intake and obesity. The first pooled strata (high-carbohydrate versus low-carbohydrate intake) suggested a weak increased risk of obesity. The second pooled strata (increasing percentage of total carbohydrate intake in daily diet) showed a weak decreased risk of obesity. Both these pooled strata estimates were, however, not statistically significant. CONCLUSIONS On the basis of the current study, it cannot be concluded that a high-carbohydrate diet or increased percentage of total energy intake in the form of carbohydrates increases the odds of obesity. A central limitation of the study was the non-standard classification of dietary intake across the studies, as well as confounders like total energy intake, activity levels, age and gender. Further studies are needed that specifically classify refined versus unrefined carbohydrate intake, as well as studies that investigate the relationship between high fat, high unrefined carbohydrate-sugar diets. PROSPERO REGISTRATION NUMBER CRD42015023257.
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Carbohydrate intake, obesity, metabolic syndrome and cancer risk? A two-part systematic review and meta-analysis protocol to estimate attributability.
Sartorius, B, Sartorius, K, Aldous, C, Madiba, TE, Stefan, C, Noakes, T
BMJ open. 2016;(1):e009301
Abstract
INTRODUCTION Linkages between carbohydrates, obesity and cancer continue to demonstrate conflicting results. Evidence suggests inconclusive direct linkages between carbohydrates and specific cancers. Conversely, obesity has been strongly linked to a wide range of cancers. The purpose of the study is to explore linkages between carbohydrate intake and cancer types using a two-step approach. First the study will evaluate the linkages between carbohydrate intake and obesity, potentially stratified by metabolic syndrome status. Second, the estimated attributable fraction of obesity ascribed to carbohydrate intake will be multiplied against obesity attributable fractions for cancer types to give estimated overall attributable fraction for carbohydrate versus cancer type. METHODS AND ANALYSIS We will perform a comprehensive search to identify all possible published and unpublished studies that have assessed risk factors for obesity including dietary carbohydrate intake. Scientific databases, namely PubMed MEDLINE, EMBASE, EBSCOhost and ISI Web of Science will be searched. Following study selection, paper/data acquisition, and data extraction and synthesis, we will appraise the quality of studies and risk of bias, as well as assess heterogeneity. Meta-weighted attributable fractions of obesity due to carbohydrate intake will be estimated after adjusting for other potential confounding factors (eg, physical inactivity, other dietary intake). Furthermore, previously published systematic reviews assessing the cancer-specific risk associated with obesity will also be drawn. These estimates will be linked with the attributability of carbohydrate intake in part 1 to estimate the cancer-specific burden that can be attributed to dietary carbohydrates. This systematic review protocol has been developed according to the 'Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) 2015'. ETHICS AND DISSEMINATION The current study will be based on published literature and data, and, as such, ethics approval is not required. The final results of this two part systematic review (plus multiplicative calculations) will be published in a relevant international peer-reviewed journal. TRIAL REGISTRATION NUMBER PROSPERO CRD42015023257.