Genetic variations in DNA-repair genes (XRCC1, 3, and 7) and the susceptibility to hepatocellular carcinoma in a cohort of Egyptians.

Chronic hepatitis C (CHC) is a worldwide etiology of chronic hepatic insult particularly in Egypt. DNA-repair systems are responsible for maintaining genomic integrity by countering threats posed by DNA lesions. Deficiency in the repair capacity due to genetic alterations in DNA-repair genes can lead to genomic instability and increased risk of cancer development. The present work aimed at studying the possible association between XRCC1-G28152A (rs25487), XRCC3-C18067T (rs861539), and XRCC7-G6721T (rs7003908) single nucleotide polymorphisms (SNPs) and the susceptibility to hepatocellular carcinoma (HCC) in Egyptian population. The study was conducted on 100 newly diagnosed HCC patients and 100 age- and sex-matched healthy controls. Laboratory workup revealed that all HCC patients have chronic hepatitis C viral infection. Genotyping of the studied SNPs was performed by real-time PCR. The heteromutant genotype of XRCC1 (GA) conferred an almost two-fold increased risk of HCC (OR , 2.35; 95% CI, 1.33-4.04). Regarding XRCC7, the heteromutant (TG) genotype conferred a two-fold increased risk of HCC (OR , 2.17; 95% CI, 1.23-3.82). Coinheritance of the polymorphic genotypes of XRCC1 and 7 was significantly higher in HCC cases than controls and was associated with an 11-fold increased risk of HCC (OR , 11.66; 95% CI, 2.77-49.13). The frequency of XRCC3 polymorphic genotypes in HCC patients was close to that of the controls.

Genetic variations in death receptor domain 4 gene and the susceptibility to hepatitis C related hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, particularly in Egypt. The role of apoptosis in tumorigenesis has been well-documented and resistance to apoptosis is a hallmark of cancer. Several studies discussed the association between death receptor 4 (DR4) genetic variants and HCC risk. AIM: To study the possible link between DR4 gene polymorphisms and the susceptibility to HCC. METHODS: Genotyping of DR4-C626G, -A683C, and DR4-A1322G single nucleotide polymorphisms (SNP) was determined by polymerase chain reaction assay for 100 de novo HCV-related HCC patients, 100 chronic hepatitis C-related liver cirrhosis patients, and 150 healthy controls. RESULTS: DR4-A1322G polymorphic genotypes (AG and GG) were significantly higher in HCC and cirrhotic patients than controls. The AG genotype conferred two-fold increased risk of HCC (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.56-3.51) and the risk increased to three-fold for the GG genotype (OR, 3.51; 95%CI, 2.33-5.28). The frequency of DR4-C626G and -A683C SNPs in HCC and cirrhotic patients were not significantly different from the controls. Combined genotype analysis showed that coinheritance of the polymorphic genotypes of DR4-C626G and -A1322G conferred nine-fold increased risk of HCC (OR, 9.34; 95%CI, 3.76-23.12). The risk increased to be 12-fold when DR4-A683C and -A1322G variants were coinherited (OR, 11.9; 95%CI, 4.82-29.39). Coexistence of the variant genotypes of the three SNPs conferred almost 10-fold increased risk of HCC (OR, 9.75; 95%CI, 1.86-51.19). CONCLUSIONS: The G allele of DR4 -A1322G could be considered as a novel independent molecular predictor for HCV-related HCC in the Egyptian population.

Neutrophil apoptosis: impact of granulocyte macrophage colony stimulating factor on cell survival and viability in chronic kidney disease and hemodialysis patients.

INTRODUCTION: Altered neutrophil apoptosis might be responsible for recurrent bacterial infections encountered in hemodialysis (HD) and chronic kidney disease (CKD) patients. This work was designed to assess the neutrophil apoptotic activity and the impact of implementation of granulocyte macrophage colony stimulating factor (GM-CSF), as a survival factor, on neutrophil apoptosis among these patients. MATERIAL AND METHODS: Twenty-five patients on regular HD along with 34 CKD patients on conservative treatment, as well as 15 healthy controls, were investigated for apoptotic rate via assessment of neutrophil expression of Annexin-V by flow cytometry, before and after 20 h culture in absence and presence of GM-CSF. Neutrophil viability was determined using light microscopy. The preservation of neutrophil activation in these patients was analyzed by flow cytometric CD18 neutrophil expression. Chronic inflammatory state was evaluated by estimating C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1). Obtained data were statistically analyzed. RESULTS: Compared to controls, both HD and CKD groups had a significant increase of Annexin-V and CD18 expression and significant decrease in neutrophil viability. Culture of their neutrophils with GM-CSF showed significant decrease of apoptosis accompanied by improvement of neutrophil viability compared to their cultured cells without GM-CSF. These patients also showed significant elevation of CRP and sICAM-1. CONCLUSIONS: Granulocyte macrophage colony stimulating factor demonstrated an evident impact on improving in vitro neutrophil survival and viability in HD and CKD patients. Therefore, this may represent promising preventive and/or therapeutic strategies against infection frequently observed in these patients and causing morbidity and mortality.

The use of whey protein concentrate in management of chronic hepatitis C virus - a pilot study.

INTRODUCTION: Whey protein contains biologically active ingredients that can prevent and attenuate disease besides being nutritive. The aim of the study was to clarify the effects of oral administration of whey protein on viral load and host defence mechanisms, in particular, phagocytic function of neutrophils, selected immunomodulatory cytokines and serum inflammatory markers, in compensated chronic hepatitis C virus (HCV) patients. MATERIAL AND METHODS: Twenty-seven HCV patients (20 males and 7 females) recruited from the hepatology clinic of the Theodor Bilharz Research Institute (TBRI) were given whey protein concentrate (WPC) twice daily for two months. In addition, 15 age and sex matched healthy participants were included in the study, as a control group. Neutrophil phagocytic activity, serum intercellular adhesion molecule (sICAM), interleukin-2 (IL-2), nitric oxide (NO), as well as HCV-RNA levels and routine investigations were determined for patients, before and after WPC supplementation and once for the control group. RESULTS: There was a significant decrease in viral load and markers of active inflammation, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), while serum albumin, total leucocyte counts and absolute neutrophil counts showed significant elevation accompanied by improvement of neutrophil phagocytic activity after WPC supplementation compared to pre-treated levels. The oral WPC supplementation was well tolerated without any serious adverse events. CONCLUSIONS: Oral supplementation of WPC has promising results as a new therapeutic strategy against HCV and its sequelae by decreasing the viral load and active inflammation as well as improving the synthetic capacity of the liver and the phagocytic function of neutrophils, in these patients.

Assessment of platelet activation in coupled schistosomiasis and viral hepatitis infection: contribution to complexity of course and development of complications.

This study assessed platelet activation and its possible contribution to the pathogenesis of liver cirrhosis (LC), hepatocellular carcinoma (HCC) and portal vein thrombosis (PVT). Forty-five patients with LC caused by dual schistosomiasis and viral hepatitis infections were enrolled in the study, 15 had LC only, 15 were complicated with HCC, and 15 were complicated with PVT, in addition to 15 healthy controls. Platelet morphological parameters including platelet count, platelet crit, mean platelet volume (MPV) and platelet distribution width (PDW), as well as platelet activation as evidenced by measuring soluble platelet selectin (sP-selectin) level and the release of beta-thromboglobulin (beta-TG), transforming growth factor beta-1 (TGF-beta1) and platelet derived growth factor-AA (PDGF-AA) were evaluated. The results obtained revealed significant reduction in platelet count, platelet crit and MPV while PDW was significantly increased in all LC patients in comparison to controls. sP-selectin, beta-TG, TGF-beta1 & PDGF-AA revealed significant increase in all diseased groups when compared to control group. Patients complicated with HCC or PVT demonstrated significant increase in the aforementioned parameters in comparison to patients with LC only. Patients with PVT showed significant increase versus HCC patients. These findings indicate that platelet activation is a prominent feature in LC and its serious complications HCC & PVT. This activation can play an important role in the pathogenesis of LC, HCC & PVT in patients with mixed schistosomiasis and viral hepatitis infections. Such patients need careful medical attention and effective treatment. Stabilization of the activated platelets and the dual suppression of PDGF & TGF-beta1 could be new therapeutic strategies against LC and its sequels.