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Brigati C.,Tumor Genetics and Epigenetics | Banelli B.,Tumor Genetics and Epigenetics | Casciano I.,Tumor Genetics and Epigenetics | Di Vinci A.,Tumor Genetics and Epigenetics | And 5 more authors.
Molecular Immunology

ΔNp73 is an anti-apoptotic product of the TP73 gene whose function in the immune system has not been extensively studied. We analyzed human tonsil B cell subpopulations physically subdivided into resting or activated fractions and found ΔNp73 gene expression essentially in cells bearing features of activation. Moreover, and accordingly, both these fractions proved to be sensitive to treatment in culture with the polyclonal activator TPA that caused substantial increase in ΔNp73 mRNA and protein expression. We also analyzed the TP73 oncogenic-relevant internal promoter 2 (P2) and identified epigenetics as its major regulatory factor since active DNA and histone configurations strictly correlated with ΔNp73 expression upon activation by agents capable of loosening chromatin compaction. Finally, in line with the known TPA pathway, we found that nuclear proteins could bind a sequence corresponding to a unique AP1 site on promoter 2 selectively in the activated cell fraction. Our results suggest a ΔNp73 function in B cell immunity, indicate epigenetics as master TP73 P2 regulator, and point to AP1 site occupancy as playing an putative mechanistic role in this process. © 2010 Elsevier Ltd. Source

Santonocito M.,University of Catania | Guglielmino M.R.,University of Catania | Vento M.,Servizio di PMA Azienda Ospedaliera Cannizzaro | Ragusa M.,University of Catania | And 8 more authors.

Fully competent oocytes represent the final outcome of a highly selective process. The decline of oocyte competence with ageing, coupled to quantitative decrease of ovarian follicles has been well established; on the contrary, its molecular bases are still poorly understood. Through quantitative high throughput PCR, we investigated the role of apoptotic machinery (AM) in this process. To this aim, we determined AM transcriptome in mature MII oocyte pools from women aged more than 38 years (cohort A), and compared to women aged up to 35 years (cohort B). Subsequently, 10 representative AM genes were selected and analyzed in 33 single oocytes (15 from cohort A and 18 from cohort B). These investigations led us to identify: (1) the significant upregulation of proapoptotic genes such us CD40, TNFRSF10A, TNFRSF21 and the downregulation of antiapoptotic genes such as BCL2 and CFLAR in cohort A respect to cohort B; (2) AM transcripts that have not previously been reported in human oocytes (BAG3, CD40, CFLAR, TNFRSF21, TRAF2, TRAF3). Our results demonstrated that during maturation the oocytes from older women selectively accumulate mRNAs that are able to trigger the extrinsic apoptotic pathway. These data contribute to clarify the molecular mechanisms of AM involvement in the natural selection strategy of removing low quality oocytes and preventing unfit or poorly fit embryos. © 2012 Springer Science+Business Media New York. Source

Banelli B.,Tumor Genetics and Epigenetics | Merlo D.F.,Epidemiology | Allemanni G.,Tumor Genetics and Epigenetics | Forlani A.,Tumor Genetics and Epigenetics | Romani M.,Tumor Genetics and Epigenetics

Approximately 20% of stage 4 high-risk neuroblastoma patients are alive and disease-free 5 years after disease onset while the remaining experience rapid and fatal progression. Numerous findings underline the prognostic role of methylation of defined target genes in neuroblastoma without taking into account the clinical and biological heterogeneity of this disease. In this report we have investigated the methylation of the PCDHB cluster, the most informative member of the "Methylator Phenotype" in neuroblastoma, hypothesizing that if this epigenetic mark can predict overall and progression free survival in high-risk stage 4 neuroblastoma, it could be utilized to improve the risk stratification of the patients, alone or in conjunction with the previously identified methylation of the SFN gene (14.3.3sigma) that can accurately predict outcome in these patients. We have utilized univariate and multivariate models to compare the prognostic power of PCDHB methylation in terms of overall and progression free survival, quantitatively determined by pyrosequencing, with that of other markers utilized for the patients' stratification utilizing methylation thresholds calculated on neuroblastoma at stage 1-4 and only on stage 4, high-risk patients. Our results indicate that PCDHB accurately distinguishes between high- and intermediate/low risk stage 4 neuroblastoma in agreement with the established risk stratification criteria. However PCDHB cannot predict outcome in the subgroup of stage 4 patients at high-risk whereas methylation levels of SFN are suggestive of a "methylation gradient" associated with tumor aggressiveness as suggested by the finding of a higher threshold that defines a subset of patients with an extremely severe disease (OS <24 months). Because of the heterogeneity of neuroblastoma we believe that clinically relevant methylation markers should be selected and tested on homogeneous groups of patients rather than on patients at all stages. © 2013 Banelli et al. Source

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