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Journal of Articles in Support of the Null Hypothesis
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In conclusion, epigenetic changes, including DNA breakage, checkpoint failure, aberrant DNA methylation and histone modifications, which increase the frequency of permanent genetic mutation will, indeed, lead to the development of cancer.
Co-infection with HBV, HCV and HIV
The prevalence of cases of histologically-proven cirrhosis among patients with chronic HBV/HCV concurrent infection is higher than those with HCV infection alone (). Due to severe clinical presentations observed during this concurrent infection and HBV superinfection in HCV chronic carriers, there is a need for HBV vaccination in all HBsAg-negative chronic hepatitis patients (). In addition, a large number of cases of patients infected with HBV and/or HCV who are co-infected with HIV have been reported (,). Due to the high prevalence of multiple viral hepatitis infections (HBV/HCV, HBV/hepatitis D virus [HDV], HBV/HCV/HDV) in HIV-positive patients, management of these patients should take into account the mechanism of action of each drug. Liver enzymes should be monitored during antiretroviral treatment.
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Damage to DNA, Proteins, Lipids and Other Macromolecules
DNA damage has been associated with oxidative stress, induced by some chemicals acting through free radicals after being metabolically activated. During chronic inflammatory hepatic disease or infection, activated macrophages and leucocytes release ROS/RNS, which damage DNA (), despite a complex mechanism of histone modifications that have evolved to protect DNA from spontaneous breakages (,). It has been demonstrated that HCV expression, replication and infection can induce oxidative stress in vitro and also in vivo (,,). The viral infection seems to be particularly associated with double-stranded DNA (dsDNA) damage pathways because of its core E1 and NS proteins that are reported to be potent inducers of ROS/RNS (,). Oxidized proteins and genotoxic products generated by lipid peroxidation of polyunsaturated fatty acids within cell membranes, as a result of free radical attack, may also be important mediators of DNA damage that contribute significantly to the induction of cancer (,).
Telomeres, Cell Cycle Arrest and Apoptosis
Telomeres are stretches of DNA at the ends of chromosomes, and are part of highly specialized nucleoprotein structures that maintain genomic stability by stabilizing and protecting the ends of linear chromosomes. However, due to the limitation of the replication system in synthesizing new DNA to the very end of linear chromosomes, replication results in progressive erosion of telomeric DNA (,). Under oxidative stress, their length may be shortened further, thus signalling more rapidly for cell death and/or cancer by activating telomerase, which prevents the shortening of telomeres. Telomeres bind to telomeric-repeat binding factor (TRF), and their stability is maintained by telomerase, which protects telomeres from the loss of sequences during DNA replication (). Inhibition of these factors by oxidative stress leads to the activation of ATM kinase and may induce cell cycle arrest and apoptosis because they will be considered broken DNA ends under these circumstances. Various DNA damage responses, including histone H2AX and ChK2 phosphorylation, p53 accumulation and apoptosis, can occur (,). In particular, apoptosis will occur as a result of inhibition of telomeric-repeat binding factor 2 (TRF2). In some cells, shortening of telomeres, occurring at each cell division, is associated with cancer and may trigger cell death (). One can then imagine that the increased rate of DNA unwinding consecutive to DNA assault by ROS/RNS may accelerate the shortening of telomeres during replication by telomerase activation. In addition, telomere attrition and hypoxia contribute to checkpoint activation and genomic instability ().
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Hepatitis C Virus
About 130-170 million people worldwide are infected with HCV, mostly in Central America, Africa and Asia. Like HBV, HCV is transmitted by transfusion and intravenous drug use. Patients infected with HCV can develop cirrhosis and HCC after many years ().
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A member of the Hepacivirus genus in the Flaviviridae family, HCV is a single-stranded, positive-sense RNA virus with seven genotypes. Unlike HBV, there is currently no vaccine against HCV. Vertical transmission during pregnancy and at delivery from an infected mother to child can also occur (). Thus, screening blood products before transfusion or organ transplantation can significantly reduce the risk of infection.
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Figure 1 | Sequence of events implicating oxidative stress in the mechanisms of HCC development: induction of oxidative stress by viral infection, stimulation of DNA unwinding, intercalation of aflatoxin into DNA strands with its concomitant epoxide metabolites, inactivation/mutation of the p53 gene and progression of HCC.
Gul M, Goktas S. OA Medical Hypothesis 2014 Aug 18;2(2):15.
Mycotoxins are secondary metabolites generated by microfungi, which can be used as antibiotics or growth promoters, but, unfortunately, they can also cause toxicity and disease in humans and animals. The extent of mycotoxin production depends on certain conditions that favour mould growth such as drought stress, storage in relative humidity and temperature of surroundings (,). The optimum temperature for the biosynthesis of most mycotoxins is within a more mesophilic range (20 to 30ºC).
Yokoya M. OA Medical Hypothesis 2014 Jun 16;2(2):12.
Viral particles composed of lipid and protein form the surface of the virion and are referred to as “hepatitis B surface antigen” (HBsAg). Soon after infection, viral DNA is found in the nucleus. Four known genes are encoded by the genome, called C, P, S and X. While the function of genes C (HBcAg), P (HBpAg) and S (HBsAg) are well known, that of gene X (HBxAg) is not fully understood (). Hepatitis B virus gene X is believed to stimulate genes involved in cell growth and inactivation of growth-regulating molecules (). It has been reported that HBV gene X promotes more hepatic tumors in aflatoxin B1 (AFB1)-treated mice than in wild-type mice (). In areas of high aflatoxin exposure, 50% of HCC cases have been reported to bear a specific AGG to AGT point mutation in codon 249 of the p53 tumor suppressor gene (codon 249ser mutation)3. More research is needed to clarify the sensitisation of hepatocytes by viral infection to the carcinogenic effects of AFB1. This sensitisation is considered one of the mechanisms underlying the association of HCC with HBV/hepatitis C virus (HCV) infection and the consumption of AFB1-contaminated food.
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