The Molecular Background Associated with the Progression of Hepatitis C to Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a major health problem worldwide. The DNA PM of cancer-related genes plays an important role in the development and progression of HCC. The data reported in our studies provide evidence that PM of p73, p14, and O6-MGMT is associated with HCC, whereas PM of the APC gene is more common in chronic hepatitis (CH) cases. Thus, it could be used as a maker for early detection of HCV-induced chronic active hepatitis. A panel of four genes APC, p73, p14, and O6-MGMT independently affected the classification of cases into HCC and CH with accuracy (89.9%), sensitivity (83.9%), and specificity (94.7%). Also, the detection of PM of APC, FHIT, p15, p16, and E-cadherin in peripheral blood of HCV-infected patients is a highly sensitive and specific. Therefore, blood could be used as efficiently as tissue biopsies to assess PM of different genes. This could help in the follow-up of CH patients and early detection of HCC. We did not observe a significant difference in the methylation status according to the virus type HBV versus HCV. So, plasma DNA is a reliable resource for methylation studies in the future, irrespective of the type of hepatitis infection

Repressed induction of interferon-related microRNAs miR-146a and miR-155 in peripheral blood mononuclear cells infected with HCV genotype 4

AbstractMicroRNAs regulate the expression of many genes and subsequently control various cellular processes, such as the immune response to viral infections mediated by type I interferon (IFN). In this study, the expression pattern of two interferon-related microRNAs, miR-146a and miR-155, was examined in healthy and HCV-genotype-4-infected peripheral blood mononuclear cells (PBMCs) using qRT-PCR. In contrast to other viral infections, the expression pattern was similar in both healthy and infected PBMCs. This could be attributed to attenuation of IFN pathway by HCV, which was assessed by investigating the expression of MxA, an interferon-stimulated gene, that showed lower expression in HCV-infected PBMCs. To determine the site of interference of HCV in the IFN pathway, expression of both microRNAs was examined following stimulation of PBMCs with IFN-α2a, an activator of the JAK/STAT pathway as well as with imiquimod, a toll-like receptor-7 (TLR-7) agonist that promotes interferon release. IFN stimulation induced the expression of miR-146a and miR-155 in HCV-infected and healthy PBMCs. Stimulation with imiquimod led to a down-regulation of both microRNAs in infected PBMCs, while it increased their expression in healthy PBMCs, indicating that HCV might interfere with miR-146a and miR-155 expression at sites upstream of interferon release, specifically in the TLR-7 pathway. The pattern of expression of both miR-146a and miR-155 was very similar with a strong positive correlation, but showed no correlation to the patients’ clinical or histopathological parameters or response to treatment. In conclusion, HCV infection might repress the induction of miR-146a and miR-155 by interfering with TLR-7 signaling

Did salvage ICE chemotherapy improve the outcome in primary resistant/relapsing stage III/IV neuroblastoma?

AbstractBackground and purposeNeuroblastoma is the most common extracranial and deadly solid tumor in children. It accounts for 15% of the deaths from cancer in the pediatric age group. Approximately half of the newly diagnosed children are at “high risk” of treatment failure.The aim of this study is to evaluate the response rate of salvage chemotherapy by the ICE (Ifosfamide, Carboplatin, and Etoposide) regimen when administered to previously treated primary refractory or progressive high risk neuroblastoma patients.Patients and methodsSixty-six patients from the National Cancer Institute (NCI), Cairo University and the Children Cancer Hospital Egypt (CCHE) received salvage chemotherapy (ICE) either due to primary resistance in 51/66 (77.2%) or due to disease progression on primary chemotherapy in 15/66 (22.8%).ResultsThey were 40 males (60.6%) and 26 females (39.4%). Patients’ age ranged between 3months and 12.5years. The most common tumor site was suprarenal, followed by retroperitoneal mass. Two patients (3%) died from chemotherapy toxicity during ICE administration. Evaluation of tumor response in the remaining 64 patients showed the following: CR/PR in 24 patients (36.5%), SD in 11 patients (16.6%), and PD in 29 patients (43.9%).Fourteen patients (21.2%) were considered eligible for auto BMT, while 50/64 patients (78.8%) failed this second line (salvage) chemotherapy and had palliative lines of therapy.By the end of the study (May 2010), 47/66 (71.2%) of the patients were still alive, while 19/66 (28.8%) were dead. Two out of 14 patients (14.2%) who underwent HSCT died from post transplantation disease progression, while 12/14 (85.8%) were in CCR.ConclusionChemotherapy by ICE for primary resistant or progressive stage III/IV NB seems well tolerated. With a 36.6% response rate, 18% CCR, and 3% treatment mortality rate, it could be considered a good salvage therapy in the category of patients who are condemned for palliation

Hepatitis B virus (HBV) genotypes in Egyptian pediatric cancer patients with acute and chronic active HBV infection

<p>Abstract</p> <p>Background</p> <p>There are eight genotypes of hepatitis B virus (A-H) and subgenotypes are recognized. Genotyping can be accomplished based on a partial sequence of HBV genome such as the pre-S or S gene. Several methods have been developed and used for HBV genotyping. This study was undertaken to determine the HBV genotypes in Egyptian pediatric cancer patients with acute and chronic liver disease.</p> <p>Methods</p> <p>HBV genotypes were determined in 22 patients who had acute forms of liver disease (AH) and in 48 patients with chronic active hepatitis (CAH). A type-specific primer based the nested-PCR method was employed in the HBV genotyping.</p> <p>Results</p> <p>This study showed that HBV infections in pediatric cancer patients are attributed predominantly to viral genotypes D and B that constituted 37.1% and 25.7%, respectively of the total infections. In addition, there was a relatively high prevalence of mixed infections of 15.7% among the studied group especially mixed A/D genotype infections. Genotype D was found significantly more often in patients with CAH than in patients with AH [23/48(47.9%) <it>v </it>3/22 (13.6%)].</p> <p>Conclusion</p> <p>These findings show the distribution of HBV A-D genotypes in pediatric cancer Egyptian patients. Furthermore, our results indicate a markedly high prevalence of mixed A/D genotype infections in subjects with CAH and a possible association of mixed infections with the severity of liver diseases.</p

Genetic profile of Egyptian hepatocellular-carcinoma associated with hepatitis C virus Genotype 4 by 15 K cDNA microarray: Preliminary study

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Genetic distance and heterogenecity between quasispecies is a critical predictor to IFN response in Egyptian patients with HCV genotype-4

BACKGROUND: HCV is one of the major health problems in Egypt, where it is highly prevalent. Genotype 4 is the most common genotype of HCV and its response to treatment is still a controversy. METHODS: HCV genotype 4 quasispecies diversity within the 5' untranslated region (5'UTR) was studied in a series of 22 native Egyptian patients with chronic hepatitis C virus with no previous treatment who satisfied all NIH criteria for combined treatment of pegylated IFN and ribavirine and was correlated with the outcome of treatment. The study also included 7 control patients with no antiviral treatment. HCV sequencing was done using the TRUGENE HCV 5-NC genotyping kit. RESULTS: At the 48(th )week of treatment, 15 patients (68%) showed virological response. Whereas HCV-RNA was still detected in 7 patients (32%) in this period; of those, 6 experienced a partial virological response followed by viral breakthrough during treatment. Only one patient did not show any virological or chemical response. The four females included in this study were all responders. There was a significant correlation between the response rate and lower fibrosis (p = 0.026) as well as the total number of mutation spots (including all the insertions, deletions, transitions and transversions) (p = 0.007, p = 0.035). CONCLUSION: Patients who responded to interferon treatment had statistically significant less number in both transitions (p = 0.007) and the genetic distances between the quasispecies (p = 0.035). So, viral genetic complexity and variability may play a role in the response to IFN treatment. The consensus alignment of all three groups revealed no characteristic pattern among the three groups. However, the G to A transitions at 160 was observed among non responders who need further study to confirm this observation