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Search Results: 1 - 10 of 5100 matches for " Giuseppe Ragona "
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Sensitivity to cisplatin in primary cell lines derived from human glioma correlates with levels of EGR-1 expression
Antonella Calogero, Antonio Porcellini, Vincenza Lombari, Cinzia Fabbiano, Antonietta Arcella, Massimo Miscusi, Donatella Ponti, Giuseppe Ragona
Cancer Cell International , 2011, DOI: 10.1186/1475-2867-11-5
Abstract: Cytotoxicity assays were performed on cells derived from fresh tumor explants of 18 human cases of malignant glioma. In addition to EGR-1, tumor cultures were investigated for genetic alterations and the expression of cancer regulating factors, related to the p53 pathway.We found that sensitivity to cisplatin correlates significantly with levels of EGR-1 expression in tumors with wild-type p53/INK4a/p16 status.Increased knowledge of the mechanisms regulating EGR-1 expression in wild-type p53/INK4a/p16 cases of glioma may help in the design of new chemotherapeutic strategies for these tumors.Malignant brain tumors of glial origin are highly invasive and poorly sensitive to anti-proliferative drugs, with only 20-30% of patients responding to chemotherapy. The biological basis of drug resistance in these tumors is complex, being dependent to some extent on the genetic make-up of the tumor. The prognostic value of molecular markers has been investigated either retrospectively, in patients treated with standard therapy, or in tumor cells cultured in vitro and exposed to different chemotherapics, but no clear results have emerged [1]. The role of p53 gene status [2], the presence of deletions in the INK4a/INK4b locus coding for the tumor suppressors and cell cycle regulators p16, p15 and p14ARF [3], the MGMT (O6-methylguanine DNA methyltransferase) levels [4] and the levels of expression for several players and regulators of apoptosis [5] were all studied to predict the response of the tumor to specific drugs. The rationale of these studies was that tumor cells react to the genotoxic insult by p53-dependent cell cycle arrest, or by undergoing apoptosis [6]. However, from these studies none of these factors, except MGMT, emerged as a major determinant of chemoresistance [7].Many genes are found to be defective and others are deregulated in gliomas [8]. We have recently found that EGR-1 expression is downregulated in malignant gliomas [9]. EGR-1 encodes a nuclear transcript
DNA instability in replicating Huntington's disease lymphoblasts
Milena Cannella, Vittorio Maglione, Tiziana Martino, Giuseppe Ragona, Luigi Frati, Guo-Min Li, Ferdinando Squitieri
BMC Medical Genetics , 2009, DOI: 10.1186/1471-2350-10-11
Abstract: Although most lymphoblastoid cell lines (88%) showed little or no repeat instability even after six or more months culture, in lymphoblasts with large expansion repeats beyond 60 CAG repeats the mutation size and triplet mosaicism always increased during replication, implying that the repeat mutability for highly expanded mutations may quantitatively depend on the triplet expansion size. None of the investigated genetic factors, potentially acting in cis to the mutation, significantly influence the repeat changes. Finally, in our experiments certain drugs controlled triplet expansion in two prone-to-expand HD cell lines carrying large CAG mutations.Our data support quantitative evidence that the inherited CAG length of expanded alleles has a major influence on somatic repeat variation. The longest triplet expansions show wide somatic variations and may offer a mechanistic model to study triplet drug-controlled instability and genetic factors influencing it.The Huntington's disease (HD) mutation influences age at onset through its CAG repeat length, a genetic feature that is unstable during intergenerational parent-child transmission [1]. Transmitting males generally cause the highest expansions in successive generations. Expansion size progressively increases through a so-called multi-step mechanism [2,3], thus providing the molecular explanation for onset anticipation. Large CAG expansions above 60 repeats cause a severe phenotype leading to juvenile HD (JHD) [4]. The higher the expanded repeat length, the more instable is the triplet stretch in somatic and germline tissues [5-10]. In the brain of patients with another CAG expansion mutation disease, dentato-rubral pallido-luysian atrophy (DRPLA), dividing glial cells carry the largest CAG mutations [11,12], whereas, in HD, differentiating nonreplicating neurons carry the largest expansion mutations [13,14]. In other non-CAG triplet diseases with an excess of repeat expansions involving thousands of trinucleotides,
The Inhibition of KCa3.1 Channels Activity Reduces Cell Motility in Glioblastoma Derived Cancer Stem Cells
Paola Ruggieri, Giorgio Mangino, Bernard Fioretti, Luigi Catacuzzeno, Rosa Puca, Donatella Ponti, Massimo Miscusi, Fabio Franciolini, Giuseppe Ragona, Antonella Calogero
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047825
Abstract: In the present study we evaluated the expression of the intermediate conductance calcium-activated potassium (KCa3.1) channel in human glioblastoma stem-like cells (CSCs) and investigated its role in cell motility. While the KCa3.1 channel is not expressed in neuronal- and glial-derived tissues of healthy individuals, both the KCa3.1 mRNA and protein are present in the glioblastoma tumor population, and are significantly enhanced in CSCs derived from both established cell line U87MG and a primary cell line, FCN9. Consistent with these data, voltage-independent and TRAM-34 sensitive potassium currents imputable to the KCa3.1 channel were recorded in the murine GL261 cell line and several primary human glioblastoma cells lines. Moreover, a significantly higher KCa3.1 current was recorded in U87MG-CD133 positive cells as compared to the U87MG-CD133 negative subpopulation. Further, we found that the tumor cell motility is strongly associated with KCa3.1 channel expression. Blockade of the KCa3.1 channel with the specific inhibitor TRAM-34 has in fact a greater impact on the motility of CSCs (reduction of 75%), which express a high level of KCa3.1 channel, than on the FCN9 parental population (reduction of 32%), where the KCa3.1 channel is expressed at lower level. Similar results were also observed with the CSCs derived from U87MG. Because invasion of surrounding tissues is one of the main causes of treatment failure in glioblastoma, these findings can be relevant for future development of novel cancer therapeutic drugs.
Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma
Antonella Calogero, Vincenza Lombari, Giorgia De Gregorio, Antonio Porcellini, Severine Ucci, Antonietta Arcella, Riccardo Caruso, Franco Gagliardi, Alberto Gulino, Gaetano Lanzetta, Luigi Frati, Dan Mercola, Giuseppe Ragona
Cancer Cell International , 2004, DOI: 10.1186/1475-2867-4-1
Abstract: Low levels of EGR-1 protein were found in all primary cultures examined, with lower values present in grade IV tumors and in cultures carrying wild-type copies of p53 gene. The levels of EGR-1 protein were significantly correlated to the amount of intracellular fibronectin, but only in tumors carrying wild-type copies of the p53 gene (R = 0,78, p = 0.0082). Duplication time, plating efficiency, colony formation in agarose, and contact inhibition were also altered in the p53 mutated tumor cultures compared to those carrying wild-type p53. Growth arrest was achieved in both types of tumor within 1–2 weeks following infection with a recombinant adenovirus overexpressing EGR-1 but not with the control adenovirus.Suppression of EGR-1 is a common event in gliomas and in most cases this is achieved through down-regulation of gene expression. Expression of EGR-1 by recombinant adenovirus infection almost completely abolishes the growth of tumor cells in vitro, regardless of the mutational status of the p53 gene.EGR-1 encodes a nuclear phosphoprotein that binds to DNA and regulates transcription through a GC-rich consensus sequence [1-4]. EGR-1 is involved in the regulation of cell responses to a wide array of stimuli such as mitogens, growth factors and stress stimuli [5-7]. Recent studies have shown that EGR-1 expression is altered in several types of neoplasia, compared to normal tissue [1,8,9]. Gene deletion or EGR-1 mutations have been reported in sporadic hematological malignancies [10]. EGR-1 expression has been found to be either decreased or undetectable in human breast cancer tissue and small cell lung carcinoma [11,12]. EGR-1 is altered in a different manner in prostate cancer, where higher levels of EGR-1 expression are found correlated to more advanced stages of malignancy [13]. Later studies confirmed in two independent mouse models that EGR-1 up-regulates tumor progression [14,15]. From these various studies it is clear that EGR-1 is involved in regulation of
The Transcription Factor EGR1 Localizes to the Nucleolus and Is Linked to Suppression of Ribosomal Precursor Synthesis
Donatella Ponti, Gian Carlo Bellenchi, Rosa Puca, Daniela Bastianelli, Marella Maroder, Giuseppe Ragona, Pascal Roussel, Marc Thiry, Dan Mercola, Antonella Calogero
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096037
Abstract: EGR1 is an immediate early gene with a wide range of activities as transcription factor, spanning from regulation of cell growth to differentiation. Numerous studies show that EGR1 either promotes the proliferation of stimulated cells or suppresses the tumorigenic growth of transformed cells. Upon interaction with ARF, EGR1 is sumoylated and acquires the ability to bind to specific targets such as PTEN and in turn to regulate cell growth. ARF is mainly localized to the periphery of nucleolus where is able to negatively regulate ribosome biogenesis. Since EGR1 colocalizes with ARF under IGF-1 stimulation we asked the question of whether EGR1 also relocate to the nucleolus to interact with ARF. Here we show that EGR1 colocalizes with nucleolar markers such as fibrillarin and B23 in the presence of ARF. Western analysis of nucleolar extracts from HeLa cells was used to confirm the presence of EGR1 in the nucleolus mainly as the 100 kDa sumoylated form. We also show that the level of the ribosomal RNA precursor 47S is inversely correlated to the level of EGR1 transcripts. The EGR1 iseffective to regulate the synthesis of the 47S rRNA precursor. Then we demonstrated that EGR1 binds to the Upstream Binding Factor (UBF) leading us to hypothesize that the regulating activity of EGR1 is mediated by its interaction within the transcriptional complex of RNA polymerase I. These results confirm the presence of EGR1 in the nucleolus and point to a role for EGR1 in the control of nucleolar metabolism.
Automated Heuristic Optimization of Prostate VMAT Treatment Planning  [PDF]
Christian Fiandra, Alessandro Alparone, Elena Gallio, Claudio Vecchi, Gabriella Balestra, Sara Bartoncini, Samanta Rosati, Riccardo Ragona, Umberto Ricardi
International Journal of Medical Physics,Clinical Engineering and Radiation Oncology (IJMPCERO) , 2018, DOI: 10.4236/ijmpcero.2018.73034
Abstract: Purpose: To investigate a genetic algorithm approach to automatic treatment planning. Methods: A Python script based on genetic algorithm (GA) was implemented for VMAT treatment planning of prostate tumor. The script was implemented in RayStation treatment planning system using Python code. Two different clinical prescriptions were considered: 78 Gy prescribed to planning target volume in 39 fractions (GROUP 1) and simultaneous integrated boost (70.2 Gy to prostate bed and 61.1 Gy to seminal vesicles) in 26 fractions (GROUP 2). The script automatically optimizes doses to PTV and OARs according to GA. A comparison with corresponding plans created with Monaco TPS (M) and Auto-Planning module of Pinnacle3 (AP) was carried out. The plans were evaluated with a total score (TS) of PlanIQ software in terms of target coverage and sparing of OARs as well as clinical score (CS) performed by a Radiation Oncologist. Results: In GROUP 1, mean value of TS were 150.6 ± 30.7, 146.3 ± 36.1 and 137.4 ± 35.7 for AP, GA and M respectively. For GROUP 2, mean value for TS were 163.5 ± 16.8, 163.4 ± 24.7 and 162.9 ± 16.6 for AP, GA and M respectively with no significance differences. In terms of CS, the highest value has been attributed to GA in four patients out of five for both GROUP 1 and 2. Conclusions: Genetic approach is practicable for prostate VMAT plan generation and studies are underway in other anatomical sites such as Head and Neck and Rectum.
Investigating the Dynamic Aspects of Drug-Protein Recognition through a Combination of MD and NMR Analyses: Implications for the Development of Protein-Protein Interaction Inhibitors
Massimiliano Meli, Katiuscia Pagano, Laura Ragona, Giorgio Colombo
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097153
Abstract: In this paper, we investigate the dynamic aspects of the molecular recognition between a small molecule ligand and a flat, exposed protein surface, representing a typical target in the development of protein-protein interaction inhibitors. Specifically, we analyze the complex between the protein Fibroblast Growth Factor 2 (FGF2) and a recently discovered small molecule inhibitor, labeled sm27 for which the binding site and the residues mainly involved in small molecule recognition have been previously characterized. We have approached this problem using microsecond MD simulations and NMR-based characterizations of the dynamics of the apo and holo states of the system. Using direct combination and cross-validation of the results of the two techniques, we select the set of conformational states that best recapitulate the principal dynamic and structural properties of the complex. We then use this information to generate a multi-structure representation of the sm27-FGF2 interaction. We propose this kind of representation and approach as a useful tool in particular for the characterization of systems where the mutual dynamic influence between the interacting partners is expected to play an important role. The results presented can also be used to generate new rules for the rational expansion of the chemical diversity space of FGF2 inhibitors.
Supercritical Fluid Adsorption of Domperidone on Silica Aerogel  [PDF]
Giuseppe Caputo
Advances in Chemical Engineering and Science (ACES) , 2013, DOI: 10.4236/aces.2013.33024

Silica aerogel (SA) was loaded with domperidone to demonstrate the potentiality of adsorption processes based on the usage of supercritical carbon dioxide to treat poorly water-soluble drugs, forming new kinds of drug delivery systems. The effects of pressure, temperature and solution concentration on loaded SA were studied. Adsorption isotherms were measured at 35and 45 and fitted with Langmuir model. Release kinetics of the adsorbed drug were also evaluated by in vitro dissolution tests. Results showed that domperidone can be uniformly dispersed into the aerogel and that the release rate of domperidone from the composite, constituted by drug and silica aerogel, is much faster than that of the crystalline drug. The proposed adsorption method is suitable for the production of domperidone fast release tablets.

Modeling and simulation in tissue biomechanics: Modern tools to face an ancient challenge  [PDF]
Giuseppe Vairo
Journal of Biomedical Science and Engineering (JBiSE) , 2013, DOI: 10.4236/jbise.2013.612A001

This is the editorial for the specail issue on Modeling and Simulation in Tissue Biomechanics published in Journal of Biomedical Science and Engineering

Archimedes’ Psammites and the Tradition of Italic Thought of Science  [PDF]
Giuseppe Boscarino
Advances in Historical Studies (AHS) , 2015, DOI: 10.4236/ahs.2015.41002
Abstract: It is intended to confute the opinion of a Platonic Archimedes, through the study of the fundamental theses of his Sandreckoner (Psammites) and of its particular logical-linguistic aspects, but especially of an Aristotelic Archimedes, as Delsedine (1970) maintains in his article “L’infini numérique dans l’Arénaire d’Archimède”. He writes: The Sandreckonerrépond à la nécessitè d’adapter la notation numérique à l’idée de l’infinité potentielle de l’ensamble des nombres naturales”1. First, it is focused on the general aspects of the work, which highlight its Enlightenment and Py-thagorean—Democritean character, then it is passed to the analysis of its particular linguistic and logical aspects and of its fundamental theses, translated into symbolic form, in which it is still giving prominence to its Pythagorean-Democritean or Italic character (Boscarino, 1999, 2010, 2011, 2012).
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