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de Bonis P.,Unita di Genetica Medica | Laborante A.,Unita di Oculistica | Pizzicoli C.,University of Foggia | Stallone R.,Unita di Genetica Medica | And 5 more authors.
Molecular Vision | Year: 2011

Purpose: To evaluate the involvement of Visual System Homeobox 1 (VSX1), Secreted Protein Acidic and Rich in Cysteine (SPARC), Superoxide Dismutase 1 (SOD1), Lysyl Oxidase (LOX), and Tissue Inhibitor of Metalloproteinase 3 (TIMP3) in sporadic and familial keratoconus. Methods: Mutational analysis of the five genes was performed by sequencing and fragment analysis in a large cohort of 302 Italian patients, with a diagnosis of keratoconus based on clinical examination and corneal topography. The variants identified in VSX1 and SPARC were also assessed in the available relatives of the probands. Results: A novel mutation p.G239R and previously reported mutations were found in VSX1. Novel and already reported variants were identified in SPARC and SOD1, whose pathogenic significance has not been established. No pathogenic variants have been identified in LOX and TIMP3. Conclusions: Molecular analysis of the five genes in a cohort of 225 sporadic and 77 familial keratoconus cases confirms the possible pathogenic role of VSX1 though in a small number of patients; a possible involvement of LOX and TIMP3 could be excluded; and the role played by SOD1 and SPARC in determining the disease as not been definitively clarified. Further studies are required to identify other important genetic factors involved in the pathogenesis and progression of the disease that in the authors' opinion, and according with several authors, should be considered as a complex disease. © 2011 Molecular Vision.


Parrella P.,Laboratorio Of Oncologia | Parrella P.,Oncology Laboratory
Breast Care | Year: 2010

There is now a compelling body of evidences sustaining the importance of epigenetic mechanisms in the development and progression of cancer. DNA methylation, post-translational histone and other protein modifications, microRNA expression, and nucleosome positioning, all act together to exert their cellular effects. The epigenome is responsible for controlling gene expression thus defining cell differentiation and tissue specificity. This review will focus on DNA methylation and histone modification because these epigenetic events are widely implicated in cancer development and progression. We will in particular address the translational aspects of breast cancer epigenomics including the development of biomarkers and the prospects for epigenetic based pharmacologic treatments. The analysis of DNA methylation has the advantage over other molecular methods (e.g. single gene mutation, microsatellite analysis) that it can be detected with a very high degree of specificity even in the presence of excess unmethylated DNA. Furthermore, the presence of specific CpG methylation signatures makes methylation-based markers attractive diagnostic, prognostic, and predictive tools for better management of breast cancer patients. Copyright © 2010 S. Karger AG, Basel.


Pistoia V.,Laboratorio Of Oncologia | Pezzolo A.,Laboratorio Of Oncologia
Journal of Immunology Research | Year: 2016

High mobility group box 1 (HMGB1) is a member of the "danger associated molecular patterns" (DAMPs) than can localize in various compartments of the cell (from the nucleus to the cell surface) and subserve different functions accordingly. HMGB1 is implicated in maintenance of genomic stability, autophagy, immune regulation, and tumor growth. HMGB1-induced autophagy promotes tumor resistance to chemotherapy, as shown in different models of malignancy, for example, osteosarcoma, leukemia, and gastric cancer. To the best of our knowledge, there is virtually no information on the relationships between HMGB1 and resistance to immunotherapy. A recent study from our group has shed new light on this latter issue. We have demonstrated that targeting of tumor-derived endothelial cells with an anti-human CD31 monoclonal antibody in a human neuroblastoma model was unsuccessful due to a complex chain of events involving the participation of HMGB1. These results are discussed in detail since they provide the first evidence for a role of HMGB1 in resistance of tumor cells to monoclonal antibody-based immunotherapy. © 2016 Vito Pistoia and Annalisa Pezzolo.


Morandi F.,Laboratorio Of Oncologia | Horenstein A.L.,University of Turin | Chillemi A.,University of Turin | Quarona V.,University of Turin | And 7 more authors.
Journal of Immunology | Year: 2015

Recent studies suggested that human CD56brightCD16- NK cells may play a role in the regulation of the immune response. Since the mechanism(s) involved have not yet been elucidated, in the present study we have investigated the role of nucleotidemetabolizing enzymes that regulate the extracellular balance of nucleotides/nucleosides and produce the immunosuppressive molecule adenosine (ADO). Peripheral blood CD56dimCD16+ and CD56brightCD16- NK cells expressed similar levels of CD38. CD39, CD73, and CD157 expression was higher in CD56brightCD16- than in CD56dimCD16+ NK cells. CD57 was mostly expressed by CD56dimCD16+ NK cells. CD203a/PC-1 expression was restricted to CD56brightCD16- NK cells. CD56brightCD16- NK cells produce ADO and inhibit autologous CD4+ T cell proliferation. Such inhibition was 1) reverted pretreating CD56brightCD16- NK cells with a CD38 inhibitor and 2) increased pretreating CD56brightCD16- NK cells with a nucleoside transporter inhibitor, which increase extracellular ADO concentration. CD56brightCD16- NK cells isolated from the synovial fluid of juvenile idiopathic arthritis patients failed to inhibit autologous CD4+ T cell proliferation. Such functional impairment could be related to 1) the observed reduced CD38/CD73 expression, 2) a peculiar ADO production kinetics, and 3) a different expression of ADO receptors. In contrast, CD56brightCD16- NK cells isolated from inflammatory pleural effusions display a potent regulatory activity. In conclusion, CD56brightCD16- NK cells act as "regulatory cells" through ADO produced by an ectoenzymes network, with a pivotal role of CD38. This function may be relevant for the modulation of the immune response in physiological and pathological conditions, and it could be impaired during autoimmune/inflammatory diseases. Copyright © 2015 by The American Association of Immunologists, Inc.


Pezzolo A.,Laboratorio Of Oncologia | Pistorio A.,Epidemiologia e Biostatistica | Gambini C.,Laboratorio Of Anatomia Patologica | Haupt R.,Epidemiologia e Biostatistica | And 3 more authors.
Oncotarget | Year: 2015

The purpose of the work was to investigate telomere length (TL) and mechanisms involved in TL maintenance in individual neuroblastoma (NB) tumors. Primary NB tumors from 102 patients, ninety Italian and twelve Spanish, diagnosed from 2000 to 2008 were studied. TL was investigated by quantitative fluorescence in situ hybridization (IQ-FISH) that allows to analyze individual cells in paraffin-embedded tissues. Fluorescence intensity of chromosome 2 centromere was used as internal control to normalize TL values to ploidy. Human telomerase reverse transcriptase (hTERT) expression was detected by immunofluorescence in 99/102 NB specimens. The main findings are the following: 1) two intratumoral subpopulations of cancer cells displaying telomeres of different length were identified in 32/102 tumors belonging to all stages. 2) hTERT expression was detected in 99/102 tumors, of which 31 displayed high expression and 68 low expression. Alternative lengthening of telomeres (ALT)-mechanism was present in 60/102 tumors, 20 of which showed high hTERT expression. Neither ALT-mechanism nor hTERT expression correlated with heterogeneous TL. 3) High hTERT expression and ALT positivity were associated with significantly reduced Overall Survival. 4) High hTERT expression predicted relapse irrespective of patient age. Intratumoral diversity in TL represents a novel feature in NB. In conclusion, diversity of TL in individual NB tumors was strongly associated with disease progression and death, suggesting that these findings are of translational relevance. The combination of high hTERT expression and ALT positivity may represent a novel biomarker of poor prognosis that deserves further investigation.

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