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San Raffaele Cimena, Italy

Moretti S.,French National Center for Scientific Research | Moretti S.,University of Paris Dauphine | Fragnelli V.,University of Piemonte Orientale | Patrone F.,University of Genoa | Bonassi S.,Unit of Clinical and Molecular Epidemiology
Bioinformatics | Year: 2010

Motivation: The interpretation of gene interaction in biological networks generates the need for a meaningful ranking of network elements. Classical centrality analysis ranks network elements according to their importance but may fail to reflect the power of each gene in interaction with the others. Results: We introduce a new approach using coalitional games to evaluate the centrality of genes in networks keeping into account genes' interactions. The Shapley value for coalitional games is used to express the power of each gene in interaction with the others and to stress the centrality of certain hub genes in the regulation of biological pathways of interest. The main improvement of this contribution, with respect to previous applications of game theory to gene expression analysis, consists in a finer resolution of the gene interaction investigated in the model, which is based on pairwise relationships of genes in the network. In addition, the new approach allows for the integration of a priori knowledge about genes playing a key function on a certain biological process. An approximation method for practical computation on large biological networks, together with a comparison with other centrality measures, is also presented. © The Author 2010. Published by Oxford University Press. All rights reserved. Source

Russo P.,I-Systems | Frustaci A.,Unit of Clinical and Molecular Epidemiology | Bufalo A.D.,I-Systems | Fini M.,Scientific Direction | And 2 more authors.
Current Medicinal Chemistry | Year: 2013

The etiopathology of Alzheimer's disease (AD) is extremely complex and heterogeneous, often associated with comorbidities. As a result it may be unlikely that AD may be mitigated by drug acting on a single specific target. The current tendency in drug design and discovery in AD is the rational design or 'serendipitous' discovery of new drug entities challenging multiple targets. Since two of the presently approved drugs for AD are based on natural products (galantamine and the physostigmine-derivative rivastigmine), many plants are now under investigation as a potential source of new drugs. Multifunctional drugs often have their origin in natural sources. This review is limited to plant chemicals having different targets with actual (galantamine) or promising (drugs from Crocus sativus, Ginkgo biloba, Salvia species, and Huperzia serrata) clinical evidence in people with dementia or AD. © 2013 Bentham Science Publishers. Source

Peters S.,University Utrecht | Portengen L.,University Utrecht | Bonassi S.,Unit of Clinical and Molecular Epidemiology | Sram R.,Academy of Sciences of the Czech Republic | Vermeulen R.,University Utrecht
American Journal of Epidemiology | Year: 2011

Chromosomal aberration frequency in peripheral lymphocytes of healthy individuals has been found to be predictive of future cancer risk. The variability of chromosomal aberrations over time, which is largely unknown, should be clarified to interpret the strength of this association and to determine its use in cancer prediction. Intra-and interindividual variability in chromosomal aberration frequency was therefore determined. From a pooled database comprising 11 national cohorts (1965-2002), the authors included 9,433 blood samples from 3,550 subjects with at least one repeated chromosomal aberration measurement. The generalized concordance correlation coefficient of 0.19 was low, indicating high intraindividual variability compared with interindividual variability, resulting in a high likelihood of misclassification. The relation between chromosomal aberration frequency and future cancer risk has probably been underestimated in previous studies. A single chromosomal aberration measurement seems not to be representative of the whole lifespan level of chromosome instability and greatly limits the use of chromosomal aberration frequency-as measured with Giemsa staining-for individual risk assessment. © 2011 The Author. Source

Giannetta E.,University of Rome La Sapienza | Feola T.,University of Rome La Sapienza | Gianfrilli D.,University of Rome La Sapienza | Pofi R.,University of Rome La Sapienza | And 5 more authors.
BMC Medicine | Year: 2014

Background: The myocardial effects of phosphodiesterase type 5 inhibitors (PDE5i) have recently received consideration in several preclinical studies. The risk/benefit ratio in humans remains unclear. Methods: We performed a meta-analysis of randomized, placebo-controlled trials (RCTs) to evaluate the efficacy and safety of PDE5i on cardiac morphology and function. From March 2012 to December 2013 (update: May 2014), we searched English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and SCOPUS-selecting RCTs of continuous PDE5i administration that reported cardiovascular outcomes: cardiac geometry and performance, afterload, endothelial function and safety. The pooled estimate of a weighted mean difference between treatment and placebo was obtained for all outcomes using a random effects model. A test for heterogeneity was performed and the I2 statistic calculated. Results: Overall, 1,622 subjects were treated, with 954 randomized to PDE5i and 772 to placebo in 24 RCTs. According to our analysis, sustained PDE5 inhibition produced: (1) an anti-remodeling effect by reducing cardiac mass (-12.21 g/m2, 95% confidence interval (CI): -18.85; -5.57) in subjects with left ventricular hypertrophy (LVH) and by increasing end-diastolic volume (5.00 mL/m2; 95% CI: 3.29; 6.71) in non-LVH patients; (2) an improvement in cardiac performance by increasing cardiac index (0.30 L/min/m2, 95% CI: 0.202; 0.406) and ejection fraction (3.56%, 95% CI: 1.79; 5.33). These effects are parallel to a decline of N-terminal-pro brain natriuretic peptide (NT-proBNP) in subjects with severe LVH (-486.7 pg/ml, 95% CI: -712; -261). PDE5i administration also produced: (3) no changes in afterload parameters and (4) an improvement in flow-mediated vasodilation (3.31%, 95% CI: 0.53; 6.08). Flushing, headache, epistaxis and gastric symptoms were the commonest side effects. Conclusions: This meta-analysis suggests for the first time that PDE5i have anti-remodeling properties and improve cardiac inotropism, independently of afterload changes, with a good safety profile. Given the reproducibility of the findings and tolerability across different populations, PDE5i could be reasonably offered to men with cardiac hypertrophy and early stage heart failure. Given the limited gender data, a larger trial on the sex-specific response to long-term PDE5i treatment is required. © 2014 Giannetta et al.; licensee BioMed Central Ltd. Source

Sanchez-Flores M.,University of La Coruna | Pasaro E.,University of La Coruna | Bonassi S.,Unit of Clinical and Molecular Epidemiology | Laffon B.,University of La Coruna | Valdiglesias V.,University of La Coruna
Toxicological Sciences | Year: 2015

H2AX histone phosphorylation represents an early event in the cellular response against DNA double-strand breaks (DSBs), and plays a central role in sensing and repairing DNA damage. Therefore, the analysis of H2AX phosphorylated (cH2AX) may be possibly used as biomarker of genotoxicity and genomic instability with a number of applications in human epidemiology. However, the lack of an experimental standard leads to a wide heterogeneity in the results obtained and their interpretation, affecting the reliability of the assay. To address the most critical issues limiting the use of the cH2AX assay in human population studies, a flow cytometry analysis was performed to establish differences in cH2AX levels between fresh or cryopreserved peripheral blood lymphocytes, and to assess the influence of phytohemagglutinin (PHA) stimulation. To this purpose, cells were treated with 4 known genotoxic chemicals with different mechanisms of DSB induction, ie, bleomycin, methyl methanesulfonate, camptothecin, and actinomycin. According to our results, both unstimulated and stimulated fresh lymphocytes can be efficiently employed to evaluate cH2AX levels, but the sensitivity of the assay is depending upon the kind of damage observed. On the other hand, cryopreserved lymphocytes require PHA stimulation since unstimulated cells showed too high basal damage. Consequently, the protocol conditions will depend on the expected mechanism of production of DSB and the characteristics of the study design (sample collection and storage conditions, type of epidemiological study). Further studies are required to standardize the protocol of cH2AX assay to be employed as biomarker of genotoxicity or genomic instability in human population studies. © VC The Author 2015. Source

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