IL17A gene polymorphisms: relationship to predisposition for chronic viral hepatitis and progression to liver cirrhosis in kazakh population.

Introduction: This work is the first genetic association study of a potential relationship of single nucleotide polymorphisms rs8193036 and rs2275913 located in the IL17A promoter on chromosome 6p12 to chronic viral hepatitis and its progression in Kazakh population. Purpose: Evaluation of the effect of IL17A polymorphism on predisposition for chronic hepatitis B and C and its progression to liver cirrhosis. Materials and Methods: A total of 862 individuals were enrolled in the retrospective case-control association study. Among the participants, 100 patients had chronic hepatitis B and/or C and liver cirrhosis, and 341 patients had chronic viral hepatitis only. Four hundred twenty-one (421) healthy HBV- and HCV-negative donors without liver diseases were recruited as population control. single nucleotide polymorphisms rs8193036[T/C] and rs2275913[G/A] were genotyped by TaqMan assays using genomic DNA extracted from peripheral blood cells. Results. Minor allele frequencies of rs8193036[C] and rs2275913[A] in the groups of patients were very similar to those observed in the control population, 0.4 and 0.3, respectively. Multivariate logistic regression analysis revealed odds ratios close to 1.0 and confidence intervals overlapping with the value of 1.0 and statistical significance p > 0.4 for any groups under comparison in the multiplicative model of inheritance. conclusion: No significant association between two single nucleotide polymorphisms, rs8193036 and rs2275913 in the IL17A promoter, and susceptibility to chronic viral hepatitis C and/or B and disease progression to liver cirrhosis in Kazakh population were found.

Inhibition of ABL tyrosine kinase potentiates radiation-induced terminal growth arrest in anaplastic thyroid cancer cells.

Gleevec, a selective tyrosine kinase inhibitor, retarded the growth of anaplastic thyroid cancer cell lines in vitro and in vivo through selective inhibition of ABL tyrosine kinase activity. In the present study, we investigated the ability of Gleevec to modulate the in vitro and in vivo radiation response of anaplastic thyroid cancer cells. Cell growth assays, colony formation assays and xenograft models were used to quantify the radiosensitizing effect of Gleevec in cells of the anaplastic thyroid cancer cell lines ARO and FRO. FACS, Western blotting and histochemical techniques were employed to study the mechanisms of radiation response after exposure to Gleevec. Gleevec (7.0 microM) increased the anti-proliferative effect of radiation on the growth ARO and FRO cells in vitro. Clonogenic analysis demonstrated that Gleevec reduced cell survival after irradiation. Gleevec combined with radiation produced an increase in tumor growth inhibition compared to treatment with either modality alone in mice bearing anaplastic thyroid cancer xenografts. The drug suppressed radiation-induced ABL activation and promoted CDKN1A (p21(cip1)) accumulation in irradiated anaplastic thyroid cancer cells. Gleevec had an additional effect on radiation-induced apoptosis in cells of both cell lines and potentiated the induction of terminal growth arrest accompanied by the expression of senescence-associated beta-galactosidase. The antitumor effect of Gleevec is potentiated in adjunctive therapy with radiation not only due to inhibition of proliferative cell growth with transient cell cycle arrest and apoptosis, but also due to the terminal growth arrest associated with senescence, suggesting that tumor cell senescence is a mechanism for tumor targeting therapy in combination with ionizing radiation.

Radiation-inducible hSNK gene is transcriptionally regulated by p53 binding homology element in human thyroid cells.

We identified a species relevant to polo-like kinase family, a human homologue of mouse serum-inducible kinase, hSNK gene, whose mRNA expression was rapidly increased in cultured human thyroid cells after X-ray irradiation. The cDNA cloning and genomic analysis of the hSNK gene showed the presence of 14 exons spanning over 6 kb of genomic DNA that encodes a 2.9-kb mRNA product. Promoter analysis demonstrated possible existence of a radiation-responsive element in the p53 binding homology element (p53RE) localized to near upstream of basal promoter of the hSNK gene. Nuclear protein extracts from HeLa and various human thyroid carcinoma cell lines bound selectively to p53RE. Anti-p53 or anti-p73 antibodies, however, failed to recognize the p53RE-protein complex formed in the presence of such nuclear extracts. These results suggest that radiation-responsive transcription factor(s) directly participates in the regulation of hSNK gene expression via the binding to p53RE in promoter region.