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Milano, Italy

Balistreri C.R.,University of Palermo | Caruso C.,University of Palermo | Carruba G.,University of Palermo | Miceli V.,University of Palermo | And 5 more authors.
Current Pharmaceutical Design | Year: 2010

Host genetic factors are crucial risk determinants for many human cancers. In this framework, an interesting model is represented by prostate cancer (PC), which is featured by a complex pathophysiology with a strong genetic component. Multiple genes seem to influence PC risk and several single nucleotide polymorphisms (SNPs) of candidate genes modifying PC susceptibility have been identified. It is noteworthy the potential association of common SNPs in pro-inflammatory genes with PC risk, since chronic inflammation is assumed to play a key role in prostate carcinogenesis. With the aim to identify candidate genes as an experimental basis to develop new strategies for both prevention and treatment of PC, we have investigated the potential role of common SNPs of a gene cluster (TLR4, TLR2, PTGS2 and 5-Lo), involved in innate and inflammatory response, in PC cases, age-matched controls and centenarians from Sicily. Six SNPs were genotyped and their association with PC risk determined. Statistical analysis evidenced a significant association of some pro-inflammatory gene SNPs with an increased risk of PC. Furthermore, significant differences were observed comparing the three groups in the combined presence of a "high responder" pro-inflammatory profile. Overall, the present results suggest the likely association of these SNPs and PC risk, clearly motivating the need of larger studies to confirm the role of these genes in PC development and/or progression. © 2010 Bentham Science Publishers Ltd. Source

Ghosh S.,Experimental Oncology | McLaughlin J.R.,Population Studies and Surveillance | McLaughlin J.R.,University of Toronto | McLaughlin J.R.,Samuel Lunenfeld Research Institute | And 5 more authors.
Journal of Occupational and Environmental Medicine | Year: 2011

OBJECTIVE: The present study aims to identify occupational exposures associated with incidence of multiple myeloma (MM). METHODS: A population-based case-control study of MM (ICD-9 203) was conducted among Canadian males, with a total of 342 cases and 1506 controls contributing to the final analyses. Conditional logistic regression was used to estimate odds ratios (OR) and confidence intervals (CI), stratifying by age groups and province of residence. RESULTS: Based on the most parsimonious multivariable model, the following variables were significantly associated with an increased incidence of MM: exposure to coal dust (OR 1.7, 95% CI 1.2-2.4), long-held occupations as a carpenter (OR 3.2, 95% CI 1.4-7.1) or a machinist (OR 2.4, 95% CI 1.0-5.8); and immediate family member having been previously diagnosed with certain cancers (OR 1.4, 95% CI 1.1-1.8). CONCLUSION: In this study of Canadian men, a higher risk of MM may be associated with exposure to coal dust, long-held occupations as a carpenter or machinist, and a positive family history of cancer. ©2011The American College of Occupational and Environmental Medicine. Source

Balistreri C.R.,University of Palermo | Candore G.,University of Palermo | Lio D.,University of Palermo | Carruba G.,Experimental Oncology
Cancer Gene Therapy | Year: 2014

Several pathologies affect human prostate, such as prostate cancer (PC), which is the most common non-skin malignant cancer in Western male populations. A complex interaction between genetic and environmental factors (i.e. infectious agents, dietary carcinogens) and hormonal imbalances has been reported to have a fundamental role in PC pathophysiology by evoking chronic inflammation. Thus, chronic inflammation drives prostate carcinogenesis and neoplastic progression. No adequate biomarkers exist until now to guide PC prognosis and treatment. Accordingly, the research has particularly focused its attention on genetic variants in genes, codifying molecules of signaling innate immune/inflammatory and steroid metabolism pathways, which are able to modify the PC genetic susceptibility and clinical disease outcome. Single-nucleotide polymorphisms (SNPs) may operate in combination to create a 'risk profile'. Combinations of several inflammatory and sex steroid hormone pathway SNPs are found in PC patients. Thus, their combinations might be used as promising biomarkers in a pre-and post-treatment clinical PC setting. Indeed, their identification may hold promise for the realization of a personalized PC medicine. Many of these aspects are summarized in this report through the elucidation of literature data and the results of our studies. © 2014 Nature America, Inc. Source

Righi M.,National Research Council Italy | Righi M.,University of Milan | Giacomini A.,Humanitas Clinical and Research Center | Cleris L.,Experimental Oncology | And 2 more authors.
PLoS ONE | Year: 2013

Quantitative characterization of the in vivo effects of vascular-targeted therapies on tumor vessels is hampered by the absence of useful 3D vascular network descriptors aside from microvessel density. In this study, we extended the quantification of planar vessel distribution to the analysis of vascular volumes by studying the effects of antiangiogenic (sorafenib and sunitinib) or antivascular (combretastatin A4 phosphate) treatments on the quantity and spatial distributions of thin microvessels. These observations were restricted to perinecrotic areas of treated human multiple myeloma tumors xenografted in immunodeficient mice and to microvessels with an approximate cross-sectional area lower than 75 μm2. Finally, vessel skeletonization minimized artifacts due to possible differential wall staining and allowed a comparison of the various treatment effects. Antiangiogenic drug treatment reduced the number of vessels of every caliber (at least 2-fold fewer vessels vs. controls; p<0.001, n = 8) and caused a heterogeneous distribution of the remaining vessels. In contrast, the effects of combretastatin A4 phosphate mainly appeared to be restricted to a homogeneous reduction in the number of thin microvessels (not more than 2-fold less vs. controls; p<0.001, n = 8) with marginal effects on spatial distribution. Unexpectedly, these results also highlighted a strict relationship between microvessel quantity, distribution and cross-sectional area. Treatment-specific changes in the curves describing this relationship were consistent with the effects ascribed to the different drugs. This finding suggests that our results can highlight differences among vascular-targeted therapies, providing hints on the processes underlying sample vascularization together with the detailed characterization of a pathological vascular tree. © 2013 Righi et al. Source

Servida F.,University of Milan | Lecis D.,Experimental Oncology | Scavullo C.,University of Milan | Drago C.,Centro Interdisciplinare Of Studi Biomolecolari E Applicazioni Industriali Cisi | And 9 more authors.
Investigational New Drugs | Year: 2011

The Inhibitor of Apoptosis Proteins (IAPs) are important regulators of programmed cell death. XIAP is the most potent among them and is over-expressed in several hematological malignancies. Its activity is endogenously antagonized by SMAC/DIABLO, and also by small molecules mimicking Smac that can induce apoptosis in tumor cells. Here we describe the activity of 56 newly synthesized Smac-mimetics in human leukemic cell lines and normal CD34 + progenitor cells. Our compounds bind to XIAP with high affinity, reduce the levels of cIAP1 and are cytotoxic at nanomolar or low micromolar concentrations. Furthermore, the Smac-mimetics synergize with Cytarabine, Etoposide and especially with TRAIL in combination treatments. Apoptosis activation was clearly detectable by the occurrence of sub G1 apoptotic peak and the accumulation of cleaved PARP, caspase 8 and caspase 3. Interestingly, the down-regulation of XIAP sensitized Jurkat cells to drugs too, confirming the role of this protein in drug-resistance. In conclusion, while being very active in leukemic cells, our Smac-mimetics have modest effects on normal hematopoietic progenitors, suggesting their promising therapeutic potential as a new class of anticancer drugs in onco-hematology, particularly when combined with TRAIL, to overcome the resistance of cancer cells. © Springer Science+Business Media, LLC 2010. Source

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