Deregulated sphingolipid metabolism and membrane organization in neurodegenerative disorders.

Sphingolipids are polar membrane lipids present as minor components in eukaryotic cell membranes. Sphingolipids are highly enriched in nervous cells, where they exert important biological functions. They deeply affect the structural and geometrical properties and the lateral order of cellular membranes, modulate the function of several membrane-associated proteins, and give rise to important intra- and extracellular lipid mediators. Sphingolipid metabolism is regulated along the differentiation and development of the nervous system, and the expression of a peculiar spatially and temporarily regulated sphingolipid pattern is essential for the maintenance of the functional integrity of the nervous system: sphingolipids in the nervous system participate to several signaling pathways controlling neuronal survival, migration, and differentiation, responsiveness to trophic factors, synaptic stability and synaptic transmission, and neuron-glia interactions, including the formation and stability of central and peripheral myelin. In several neurodegenerative diseases, sphingolipid metabolism is deeply deregulated, leading to the expression of abnormal sphingolipid patterns and altered membrane organization that participate to several events related to the pathogenesis of these diseases. The most impressive consequence of this deregulation is represented by anomalous sphingolipid-protein interactions that are at least, in part, responsible for the misfolding events that cause the fibrillogenic and amyloidogenic processing of disease-specific protein isoforms, such as amyloid beta peptide in Alzheimer's disease, huntingtin in Huntington's disease, alpha-synuclein in Parkinson's disease, and prions in transmissible encephalopathies. Targeting sphingolipid metabolism represents today an underexploited but realistic opportunity to design novel therapeutic strategies for the intervention in these diseases.

Proton magnetic resonance spectroscopy predicts proliferative activity in diffuse low-grade gliomas.

The aim of the study was to investigate the ability of (1)HMRS to reflect proliferative activity of diffuse low-grade gliomas (WHO grade II). Between November 2002 and March 2007, a prospective study was performed on consecutive patients with suspected supratentorial hemispheric diffuse low-grade tumors. All the patients underwent MR examination using uniform procedures, and then surgical resection or biopsy within 2 weeks of the MR examination. Proliferative activity of the tumors was assessed by Ki-67 immunochemistry (Mb-1) on paraffin embedded tumor sections. Spectroscopic data was compared with Ki-67 labeling index and other histologic data such as histological subtype, cellular atypia, cellular density using univariate and multivariate analysis. 82 of 97 consecutive patients had histologically confirmed WHO grade 2 gliomas. Ki-67 proliferation index (PI) was correlated with specific spectral patterns: (1) low PI (<4%) was associated with increased Cho/Cr and absence of both free lipids or lactates; (2) intermediate PI (4-8%) was associated with resonance of lactates; and (3) high PI (>8%) was characterized by a resonance of free lipids. On multivariate analysis, resonance of lactates and resonance of free lipids appeared as independent predictors of intermediate PI (P < 0.001) and high PI (P < 0.001), respectively; moreover, free lipids resonance was correlated with cellular atypia (P < 0.05). This study suggests that (1)HMRS is a reliable tool to evaluate the proliferation activity of WHO grade 2 glioma and to identify potentially more aggressive clinical behavior.

Bcl-2 expression correlates with lymphovascular invasion and long-term prognosis in breast cancer.

Alterations in the mechanisms of apoptosis are responsible not only for the progression of breast cancer, but for different responses to treatment as well. Among the genes regulators of apoptosis, the tumor suppressor gene p53 and the bcl-2 gene have raised interest for their possible role as predictors of response to therapy and markers of prognosis. The purpose of our study was to prospectively analyze the prognostic value of the expression of p53 and bcl-2 genes in a series of 235 consecutive patients operated on for breast cancer at the Department of General Surgery and Surgical Oncology of the University of Siena, Italy.p53 and bcl-2 expression were evaluated by immunohistochemistry, their association with conventional clinicopathological factors was analyzed by univariate analysis and their prognostic impact was evaluated by multivariate analysis.p53 and bcl-2 were detected respectively in 15.7 and 75.7% of cases, and resulted significantly related to presence of estrogen receptors for p53 over-expression and presence of peritumor lymphovascular invasion (LVI) for bcl-2 expression. With a median follow-up of 79 months, an independent negative prognostic impact on disease free and overall survival was observed for presence of LVI, absence of bcl-2 expression and number of involved axillary lymphnodes. The expression of bcl-2 improved the prognosis of LVI positive tumors up to values similar to LVI negative cases, while its absence associated to presence of LVI resulted in a poor outcome with only 28% of patients alive at 8 years. These data may indicate that expression of bcl-2 is a marker of breast cancers with reduced capability of distant colonization, even in presence of LVI, and may be particularly useful in the clinical setting, allowing to identify a subset of patients with an high risk of relapse.