How did hepatitis B virus effect the host genome in the last decade?

The principal reason of chronic liver disease, cirrhosis and hepatocellular carcinoma is chronic viral hepatitis all over the world. Hepatitis B virus (HBV) has some mutagenic effects on the host genome. HBV may be exhibiting these mutagenic effects through integrating into the host genome, through its viral proteins or through some epigenetic mechanisms related with HBV proteins. This review aims to summarize the molecular mechanisms used by HBV for effecting host genome determined in the last decade. The focus will be on the effects of integration, HBV proteins, especially HBV X protein and epigenetic mechanisms on the host genome. These interactions between HBV and the host genome also forms the underlying mechanisms of the evolution of hepatocellular carcinoma.

Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression.

The immunosuppressive tumor microenvironment represents a major hurdle to cancer therapy. We developed a gene transfer strategy into hematopoietic stem cells (HSCs) to target transgene expression to tumor-infiltrating monocytes/macrophages. Using a combination of transcriptional and microRNA-mediated control, we achieved selective expression of an interferon-α (IFN-α) transgene in differentiated monocytes of human hematochimeric mice. We show that IFN-α transgene expression does not impair engraftment and long-term multilineage repopulation of NSG (NOD/LtSz-scidIL2Rγ(null)) mice by transplanted human HSCs. By providing a source of human cytokines in the mice, we improved the functional reconstitution of human myeloid, natural killer, and T cell lineages, and achieved enhanced immune-mediated clearance of transplanted human breast tumors when hematopoiesis was engineered for tumor-targeted IFN-α expression. By applying our strategy to mouse breast cancer models, we achieved inhibition of tumor progression and experimental metastases in an autologous setting, likely through enhanced generation of effector T cells and their recruitment to the neoplastic tissues. By forcing IFN-α expression in tumor-infiltrating macrophages, we blunted their innate protumoral activity and reprogrammed the tumor microenvironment toward more effective dendritic cell activation and immune effector cell cytotoxicity. Overall, our studies validate the feasibility, safety, and therapeutic potential of a new cancer gene therapy strategy, and open the way to test this approach as adjuvant therapy in advanced breast cancer patients.

Potential genotoxic effect of 186Re-HEDP on human lymphocyte cells: in-vitro evaluation with micronucleus-FISH analysis.

AIM: Systemic and local therapies can be used to treat painful bone metastases. It has been shown that certain pharmaceuticals such as 186Re (rhenium-186) are effective in the treatment of pains caused by bone metastasis and a correlation between bone metastases and T cells has also been shown. The aim of this study was to investigate the genotoxic effect of 186Re-1,1-hydroxyethylidenediphosphonate (186Re-HEDP) on the cultured peripheral blood lymphocytes using an micronucleus (MN)-fluorescence in-situ hybridization assay. METHODS: Two lymphocyte cultures, with and without 186Re-HEDP, were set up from 20 healthy individuals. MN frequencies were determined by a classical cytokinesis-blocked micronucleus assay and samples with the highest MN frequencies were used for fluorescent in-situ hybridization analyses with the 'all human centromeres' probe. RESULTS: Our results show a significant increase in the MN frequency in 186Re-treated lymphocytes compared with the untreated group (P<0.001). The frequencies of centromere-positive [CEN(+)] and centromere-negative [CEN(-)] MN in the 186Re-treated and untreated groups were found to be similar; however, the ratio of CEN(-)/CEN(+) MN frequency was lower in 186Re-treated samples. CONCLUSION: These preliminary results support the idea that 186Re-HEDP is a highly genotoxic radiopharmaceutical and shows a proaneugenic effect. Causing genotoxicity in lymphocytes, especially in T cells, that regulate bone metastases and tumor growth in bone, might be a mechanism of this pharmaceutical to reduce the pain of patients.