Stochastic epigenetic mutations as possible explanation for phenotypical discordance among twins with congenital hypothyroidism.

PURPOSE: The elevated frequency of discordance for congenital hypothyroidism (CH) phenotype between monozygotic twins suggests the involvement of non-mendelian mechanisms. The aim of the study was to investigate the role of epigenetics in CH pathogenesis. METHODS: A genome-wide DNA methylation analysis was performed on the peripheral blood of 23 twin pairs (10 monozygotic and 13 dizygotic), 4 concordant and 19 discordant pairs for CH at birth. RESULTS: Differential methylation analysis did not show significant differences in methylation levels between CH cases and controls, but a different methylation status of several genes may explain the CH discordance of a monozygotic twin couple carrying a monoallelic nonsense mutation of DUOX2. In addition, the median number of hypo-methylated Stochastic Epigenetic Mutations (SEMs) resulted significantly increased in cases compared to controls. The prioritization analysis for CH performed on the genes epimutated exclusively in the cases identified SLC26A4, FOXI1, NKX2-5 and TSHB as the genes with the highest score. The analysis of significantly SEMs-enriched regions led to the identification of two genes (FAM50B and MEG8) that resulted epigenetically dysregulated in cases. CONCLUSION: Epigenetic modifications may potentially account for CH pathogenesis and explain discordance among monozygotic twins.

Antitumor activity of interferon-ß1a in hormone refractory prostate cancer with neuroendocrine differentiation.

PURPOSE: Type I interferons (IFN-α and IFN-ß) are a class of cytokines that exert several biological activities, such as modulation of cell proliferation and differentiation and of the immune system. Although these cytokines interact with a common receptor complex, IFN-ß showed a more potent antitumor activity than IFN-α in several tumor models. New recombinant human IFN-ß products, such as IFN-ß1a and IFN-ß1b, have been produced in order to improve the stability and bioavailability of natural IFN-ß. In this report, we analyzed the effects of recombinant IFN-ß1a on the cell proliferation of two human androgen-resistant prostate cancer cell lines with neuroendocrine differentiation (DU-145, PC-3) and related mechanisms of action. METHODS: The effects of IFN-ß1a on the cell growth proliferation, cell cycle, and apoptosis have been evaluated in DU-145 and PC-3 cells through MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, respectively. Moreover, the expression of neuron-specific enolase (NSE), cleaved caspase-3, caspase-8, and PARP was evaluated through Western blotting. RESULTS: IFN-ß1a showed a significant anti-proliferative activity in both androgen-resistant cell lines. This effect was related to cell cycle perturbation and induction in apoptosis, as shown by flow cytometric analysis, the activation of caspase-3 and caspase-8 and PARP cleavage during incubation with IFN-ß1a. Moreover, this cytokine reduced the expression of NSE in both cell lines. CONCLUSIONS: Recombinant IFN-ß1a (Rebif) showed a potent in vitro anti-proliferative activity in androgen-resistant prostate cancer cells, and it could represent a promising tool for the treatment of this tumor.