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Several experimental and clinical studies have shown that oxidized low-density lipoprotein and oxidation-sensitive mechanisms are central in the pathogenesis of vascular dysfunction and atherogenesis. Here, we have used p66 Shc؊/؊ and WT mice to investigate the effects of high-fat diet on both systemic and tissue oxidative stress and the development of early vascular lesions. To date, the p66 Shc؊/؊ mouse is the unique genetic model of increased resistance to oxidative stress and prolonged life span in mammals. Computer-assisted image analysis revealed that chronic 21% highfat treatment increased the aortic cumulative early lesion area by Ϸ21% in WT mice and only by 3% in p66 Shc؊/؊ mice. Early lesions from p66 Shc؊/؊ mice had less content of macrophage-derived foam cells and apoptotic vascular cells, in comparison to the WT. Furthermore, in p66 Shc؊/؊ mice, but not WT mice, we found a significant reduction of systemic and tissue oxidative stress (assessed by isoprostanes, plasma low-density lipoprotein oxidizability, and the formation of arterial oxidation-specific epitopes). These results support the concept that p66 Shc؊/؊ may play a pivotal role in controlling systemic oxidative stress and vascular diseases. Therefore, p66 Shc might represent a molecular target for therapies against vascular diseases.atherosclerosis ͉ oxygen radicals ͉ transgenic mouse T he p66Shc protein is one of the three isoforms encoded by the mammalian Shc locus. The Shc overlapping proteins (p66 Shc , p52 Shc , and p46 Shc ) share a C-terminal Src homology 2 (SH2) domain, a central collagen-homologous (CH) region, and an N-terminal phosphotyrosine binding domain and differ for N termini of different lengths. P66 Shc , in particular, is characterized by an additional CH region at the N terminus. Shc proteins are cytoplasmic substrates of activated tyrosine kinases and have been implicated in the transmission of activation signals from tyrosine kinases to Ras proteins (1-3). In 1999, it became clear that Shc proteins might serve broad cellular functions. Homozygous mutation of p66Shc in mice was shown to induce increased resistance to oxidative stress and lifespan extension (4). Recently, it has been demonstrated that the p66 Shc longevity gene increases intracellular reactive oxygen species (ROS), thereby affecting the rate of oxidative damage to nucleic acids; in advance p66 Shc function on ROS, metabolism is necessary for appropriate p53-dependent apoptosis (5).Cells within the arterial wall produce several species of free radicals, and, as is well known, an important functional index of healthy status is represented by vascular function (reviewed in refs. 6 and 7). A multitude of clinical studies and reports with experimental animal models have shown that oxidized lowdensity lipoprotein (oxLDL) and redox-sensitive pathways are key modulators of vascular dysfunction and atherogenesis (reviewed in refs. 8-10). Interestingly, oxLDL and its byproducts may induce early proatherogenic events not only in adults but also in arteries of the ...

Typing somatostatin receptor expression in neuroendocrine tumors is of relevance to target somatostatin analogue-based diagnostic approach and treatment. The expanding use of immunohistochemistry to detect somatostatin receptors is to date not paralleled by an accurate methodological setting and standardized interpretation of the results. A multicentric study was designed to compare somatostatin receptor immunohistochemical expression with in vivo scintigraphic data and verify its usefulness in the clinical management of neuroendocrine tumors. After methodological setting by testing different somatostatin receptor antibodies, 107 cases of neuroendocrine tumors with available somatostatin receptor scintigraphy data and pathological material were retrospectively analyzed for somatostatin receptor types 2A, 3 and 5 immunohistochemical expression, and compared with scintigraphic images and, whenever available, with the clinical response to somatostatin analogue treatment. Restricting 'positive cases' to the presence of a membrane pattern of staining, an overall somatostatin receptor type 2A immunohistochemistry/somatostatin receptor scintigraphy agreement of 77% (v 2 test Po0.0001) was reached. Lower concordance ratios were detected in preoperative and metastatic tumor samples, possibly as a consequence of somatostatin receptor expression heterogeneity. Pure somatostatin receptor type 2A cytoplasmic staining showed poor correlation with somatostatin receptor scintigraphy (54% concordance rate). The immunohistochemical detection of somatostatin receptor types 3 and 5, which showed almost exclusively a cytoplasmic pattern, did not improve the concordance with scintigraphic data. In a pilot series, somatostatin receptor type 2A immunohistochemistry correlated with clinical response in 75% of cases. In conclusion, we propose a scoring system for somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors correlated with in vivo data, based on the evidence that only membrane (rather that cytoplasmic) staining should be considered for a reliable, standardized and clinically relevant report.

Squamous cell carcinoma of the oral region (OSCC) is one of the most common and highly aggressive malignancies worldwide, despite the fact that significant results have been achieved during the last decades in its detection, prevention and treatment. Although many efforts have been made to define the molecular signatures that identify the clinical outcome of oral cancers, OSCC still lacks reliable prognostic molecular markers. Scientific evidence indicates that transition from normal epithelium to pre-malignancy, and finally to oral carcinoma, depends on the accumulation of genetic and epigenetic alterations in a multistep process. Unlike genetic alterations, epigenetic changes are heritable and potentially reversible. The most common examples of such changes are DNA methylation, histone modification, and small non-coding RNAs. Although several epigenetic changes have been currently linked to OSCC initiation and progression, they have been only partially characterized. Over the last decade, it has been demonstrated that especially aberrant DNA methylation plays a critical role in oral cancer. The major goal of the present paper is to review the recent literature about the epigenetic modifications contribution in early and later phases of OSCC malignant transformation; in particular we point out the current evidence of epigenetic marks as novel markers for early diagnosis and prognosis as well as potential therapeutic targets in oral cancer.