Glioblastoma (GBM) is the most common and aggressive tumor of the Central Nervous System (CNS). Unfortunately, patients afflicted with this disease have a very poor prognosis, due to high level of invasiveness and resistance to standard therapies (1). Although the molecular profile of GBM has been extensively investigated, the events responsible for its pathogenesis and progression remain largely unknown. Reports have indicated that HDAC (Histone deacetylases) dependent epigenetic modifications (2) and the Tgfβ/Smad pathway (3) play roles in GBM tumorigenesis. The aim of this study was to evaluate the involvement and the possible interaction between these two molecular cascades in the pathogenesis, therapeutic responsiveness and prognosis of GBM. Immunohistochemestry (IHC) was performed on microdissected GBM samples, collected from 14 patients (n.8 men and n.6 women) ranging in age from 43 to 74 years. The patients were previously divided, on the basis of their overall survival (OS), into three groups: low, intermediate and high OS. Patients with poor prognosis showed hyperexpression of HDAC4 and HDAC6, an activation of the Tgfβ/Smad pathway, with high levels of IL-13, Smad2, PDGF and MMP3 expression, compared to the intermediate and high OS groups, whereas the expression of Smad7 was reduced. The high OS group also exhibits an increase in p21 immunostaining, which represents a common target of the two cascades. The IHC data was confirmed by Immunoblotting. Our results suggest that both HDAC4 and HDAC6 together with the Tgfβ/Smad pathway are involved in progression of GBM and could be a useful prognostic markers and may predict responsive to therapy.

Glioblastoma (GBM) is the most common and aggressive tumor of the central nervous system. Unfortunately, patients affected by this disease have a very poor prognosis, due to high level of invasiveness and resistance to standard therapies. Although the molecular profile of GBM has been extensively investigated, the events responsible for its pathogenesis and progression remain largely unknown. Histone Deacetylases (HDAC) dependent epigenetic modifications and transforming growth factor (TGF)-β/Smad pathway seem to play an important role in GBM tumorigenesis, resistance to common therapies and poor clinical outcome. The aim of this study was to evaluate the involvement and the possible interaction between these two molecular cascades in the pathogenesis and prognosis of GBM. Immunohistochemistry (IHC) was performed on microdissected GBM samples, collected from 14 patients (6 men and 8 women) ranging in age from 43 to 74 years. The patients were previously divided, on the basis of their overall survival (OS), into two groups: short and long OS. Patients with poor prognosis showed hyperexpression of HDAC4 and HDAC6, an activation of the TGF-β/Smad pathway, with high levels of IL-13, SMAD2, PDGF and MMP3 expression, compared to the long survivors. The short OS group exhibits a decrease in SMAD7 expression and also low levels of p21 immunostaining, which represents a common target of the two pathways. The IHC data was confirmed by quantitative analysis and Immunoblotting. Our preliminary results suggest that both HDAC4 and HDAC6 together with the TGF-β/Smad pathway may be involved in progression of GBM and this cross talking could be a useful prognostic marker in this deadly disease.

Glioblastoma is the most common and lethal primary malignant brain tumor. Although standard treatments have been improving, the clinical outcome remains unacceptably poor. Several genetic alterations are supposed to be involved in the eti- ology of different grades of astrocytoma, including epimutations. Histone deacety - lases (HDACs) are involved in the post-translational modification on the lysines of histone tails. For this reason HDACs are recognized as promising targets for cancer treatment (1). In the past several years, HDAC inhibitors (HDACis) have been used as radiosensitizers in glioblastoma treatment. However, no study has demonstrated the status of global HDAC expression in gliomas and its possible correlation to the use of HDACis (2). Aim of our study was to evaluate with an immunohistochemi - cal and immunoblotting analyses the expression of different classes of HDACs (Class I: HDAC 1-2-3-8; class II: HDAC 4-6) in microdissected glioblastoma. Tumor sam - ples were taken from 14 patients (n.8 men and n.6 women) ranging in age from 43 to 74 years. HDAC1 and HDAC3 expression was not significantly different between the two proteins and was predominantely located at cytoplasmic level of cancer cells with different intensity of immureaction from mild to moderate whereas HDAC2 staining was localized to the nucleous of neoplastic cells. The pattern of HDAC4 immureactivity was always cytoplasmatic and showed a marked and diffuse increase of immunostaining in neoplastic areas. HDAC8 was always absent in cancer cells and the only positivity was located in the endothelial cells of the vessels. HDAC6 was often absent and, if present, showed a very low cytoplasmic immunopositivity in cancer cells. HDAC1, HDAC2 and HDAC3 levels were not significantly different in immunoblotting results; HDAC4 showed a marked increase while HDAC6 and HDAC8 expression was poor, confirming the IHC data. These previous results dem - onstrate a different pattern of HDAC expression and could suggest a more addressed therapeutical use of HDACis in glioblastoma.

Intestinal fibrosis is a progressive process characterized by de novo synthesis and uncontrolled deposition of extracellular matrix components (ECM) following a tissue chronic inflammation mainly regulated by Transforming Growth Factor (TGF)β/ Smads pathway. Frequently associated to Inflammatory Bowel Disease (IBD), intestinal fibrosis may lead to stenosis and obstructions that require surgery up to 75% of patients as drugs currently used in IBD are unable to improve fibrostenosis lesions (1). Peroxisome proliferator-activated receptor (PPAR)-γ is able to antagonize (TGF) β/Smads and could be an crucial target to develop novel antifibrotic therapeutic strategies (2). Aim of this study is to evaluate the antifibrotic action of a novel PPARγ agonist, GED 0507-34 levo, in colonic fibrosis in mice. Immunohistochemistry and immunoblotting evaluations, TGFβ1, CTGF, Collagen types I-III, Smad3, α-SMA, were performed in in three groups of C57BL/6 mice: Dextran Sulphate Sodium (DSS) colitis group, DSS+GED group and controls. Evident macroscopic and microscopic lesions in the most of colons of DSS treated mice were observed compared to DSS+GED mice and controls. The tissue levels of the main markers of fibrosis resulted significantly increased in DSS mice and restored by administration of GED. GED seems to prevents ECM colonic deposition and to improve the intestinal fibrotic lesions by its ability in controlling TGFβ/Smads pathway signalling activation.