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F Basolo, R Giannini, P Faviana, G Fontanini, A Patricelli Malizia, C Ugolini, R Elisei, P Miccoli, and A Toniolo

The expression of Fas in thyroid tumours and Graves' disease was analysed by mRNA transcript expression. As compared with unaffected thyroid tissue, Fas expression was enhanced in Graves' disease, adenomas, and papillary and follicular carcinomas. This pattern was also reflected in immunohistochemical studies. The PCR single-strand conformational polymorphism (SSCP) method and DNA sequencing were used to analyse Fas exons 1-9. The study was carried out on five different histotypes of thyroid tumours (n=93) and tissue from Graves' disease patients. As compared with a group of healthy blood donors (n=64), a significant association (P=0.006) emerged between papillary thyroid carcinoma and a silent single nucleotide polymorphism (SNP, 988C-->T) in exon 7 of the Fas gene. Other forms of thyroid pathology were not associated with the above polymorphism. Patients with neoplasia showed the same SNP in tumour tissue, in the unaffected contralateral thyroid lobe, and in peripheral blood cells. Thus, the 988C-->T polymorphism appeared to be of germ-line origin.

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S Giannini, B Cresci, L Pala, A Ciucci, A Franchini, C Manuelli, Y Fujita-Yamaguchi, P Cappugi, R Zonefrati, and CM Rotella

Insulin-like growth factor binding proteins (IGFBPs) are important local factors in the development of proliferative diabetic retinopathy. We investigated the effects of IGF-I and increased glucose concentrations on the release of IGFBPs and the growth of human retinal endothelial cells (HRECs). HRECs secrete IGFBPs-2 to -5. IGF-I stimulated thymidine incorporation and modified the pattern of IGFBPs, decreasing the inhibitory IGFBP-4 through down-regulation of its mRNA, and increasing IGFBP-5 which, per se, was able to modulate HREC growth, exerting post-transcriptional control. Studies using an antibody (alpha IR3) against the IGF-I receptor, and compounds with low affinity for IGFBPs, such as insulin and des(1-3)IGF-I, showed that an interaction between IGF-I and IGFBP-5 was necessary to detach this IGFBP from its binding sites. The dose of IGF-I that significantly decreased the IGFBP-4/IGFBP-5 ratio was the same that stimulated HREC growth. Chronic exposure to high concentrations of glucose was able to reduce HREC mitogenesis, interacting with the IGF system through a decrease in the stimulatory IGFBPs-2, -3 and -5, leaving the concentration of the inhibitory IGFBP-4 constant. These results extend our previous observations in endothelial cells and suggest that the IGFBP-4/IGFBP-5 ratio regulates IGF-I-induced growth of HRECs, whereas a general decrease in IGFBPs (except for IGFBP-4) was the anti-proliferative effect of chronic exposure to high glucose concentrations.