Identification of new drugs is strongly needed for sarcomas.

The role of inherited and somatic mutations of mitochondrial DNA (mtDNA) in aging and longevity is complex and highly controversial, owing to its peculiar genetics, including the phenomenon of heteroplasmy. Most of the data on mtDNA and longevity have been obtained on humans and particularly on centenarians, i. e., people who escaped or delayed the major age-related pathologies and reached the extreme limit of human lifespan. In this review we summarize the most recent advances in this field that suggest a consistent role in human longevity of both germ-line inherited and somatically acquired mutations. The particular case of the association with longevity of the somatic C150T mutation is extensively discussed, challenging the tenet that mtDNA mutations are basically detrimental. We also stress several limitations of our present knowledge, regarding the difficulty in extrapolating to humans the results obtained in animal models, owing to a variety of biological differences, including the very limited genetic variability of mtDNA in the strains used in laboratory experiments. The use of high-throughput technologies and the extensive analysis, possibly at the single cell level, of different tissues and cell types derived from the same individual will help in disentangling the complexity of mtDNA in aging and longevity.

The aim of the present study was to assess whether exposure to a sinusoidal extremely low frequency magnetic field (ELF-MF; 50 Hz, 1 mT) can affect proliferation and differentiation in the human neuroblastoma cell line BE(2)C, which is representative of high risk neuroblastomas. Cells were subjected to ELF-MF exposure in the presence or absence of a neuronal differentiating agent (all-trans-retinoic acid, ATRA) for 24-72 h. In each experiment, ELF-MF-exposed samples were compared to sham-exposed samples. Cells exposed to ELF-MF combined with retinoic treatment showed a decreased cellular proliferation and an increased proportion of G(0)/G(1) phase cells compared to cells exposed to either treatment alone. Moreover, ELF-MF- and ATRA-treated cells showed more differentiated morphological traits (a higher neurite number/cell, an increased neurite length), together with a significant increase of mRNA levels of p21(WAF1/CIP1) and cdk5 genes, both involved in neuronal differentiation. In addition, the expression of cyp19 gene, which is involved both in neuronal differentiation and stress response, was evaluated; cyp19 gene expression was enhanced by ATRA treatment and significantly enhanced further by ELF-MF exposure combined with ATRA. In conclusion, our data suggest that ELF-MF exposure can strengthen ATRA effects on neuroblastoma cells.

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BackgroundMembers of the Ikaros family of transcription factors have been implicated in controlling the characteristic phenotype of regulatory T cells (Tregs). Ikaros family zinc finger 4 (IKZF4, Eos) mediates Foxp3-dependent gene silencing and is required to maintain the phenotype of Foxp3-positive Tregs, whereas IKFZ2 (Helios) is involved in the suppression of IL2 gene transcription and upregulation of Foxp3. An important regulation level of tissue-specific gene-expression is DNA methylation. In particular, Treg-specific gene expression is controlled by DNA methylation within characteristic clusters, Treg-specific demethylation regions.ObjectivesTo analyze the DNA methylation status of Treg-specific demethylated regions of Helios and Eos in T cells from patients with rheumatoid arthritis (RA) and to compare the level of methylation to that in T cells from healthy controls.MethodsIn both genes, DNA methylation was assessed by bisulfite sequencing in a CpG island located in an intragenic conserved non-coding sequence (CNS). In addition, a CpG-rich region in exon 6 of the Helios gene was also analyzed.ResultsAll analyzed regions were completely methylated in effector T cells from RA patients and controls. In contrast, considerable degrees of demethylation were detected in the regions of interest in CD25+CD127- T cells, in line with the hypothesis of an important regulatory mechanism facilitating Treg-specific gene expression. Importantly, the methylation rate of the CNS CpG island in the Helios gene was significantly higher in Tregs from RA patients than in those from controls (55% vs. 40%, p<0.05). Similarly, the CpGs within exon 6 of the Helios gene were demethylated to a significantly different level between RA patients and controls (50% vs. 40% methylation, respectively; p<0.05). Finally, in the CNS CpG island of the Eos gene, the methylation level in Tregs from RA patients was also significantly higher as compared to healthy control Tregs (68% vs. 53%, p<0.01).ConclusionsThe data are consistent with the hypothesis of Treg specific expression of Helios and Eos regulated by DNA methylation within Treg-specific demethylation regions. Furthermore, the data suggest that impaired function Tregs in RA might be related to an altered expression of Helios and Eos as a consequence of increased DNA methylation. This mechanism might provide a molecular epigenetic insight into the pathogenesis of autoimmune diseases.Disclosure of InterestNone declared