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Pozzilli, Italy

Capalbo C.,University of Rome La Sapienza | Marchetti P.,Medical Oncology | Marchetti P.,University of Rome La Sapienza | Coppa A.,University of Rome La Sapienza | And 12 more authors.
Cancer Biology and Therapy | Year: 2014

As the knowledge on cancer genetic alterations progresses, it fosters the need for more personalized therapeutic intervention in modern cancer management. Recently, mutations in KRAS, BRAF, and PIK3CA genes have emerged as important mechanisms of resistance to EGFR-targeted therapy in metastatic colorectal cancer (mCRC). Here we report the first case of a mCRC patient whose disease had progressed on standard lines of treatment and for which we devised a personalized therapeutic approach consisting of vemurafenib (ZelborafTM) and panitumumab (VectibixTM), based on the following molecular profile: BRAFV600E-mutant, amplified EGFR (double positive) and WT KRAS, WT PIK3CA, not-amplified HER2 (triple negative). This new combination therapy was well tolerated and resulted in a strong control of the disease. In particular, the vemurafenib-panitumumab combination appears to limit the typical toxicity of single agents, since no cutaneous toxic effects typically associated with vemurafenib were observed. Here we report the first clinical evidence that the combination of an anti-EGFR (panitumumab) and an inhibitor of BRAFV600E (vemurafenib) is well tolerated and results in a strong disease control in an extensively pretreated mCRC patient. © 2014 Landes Bioscience.

Cascella R.,University of Rome Tor Vergata | Cascella R.,Emotest Laboratory | Strafella C.,University of Rome Tor Vergata | Gambardella S.,Neuromed IRCCS | And 6 more authors.
Electrophoresis | Year: 2016

The hypoacusia can be classified in two clinical forms: Syndromic (SHL) and Nonsyndromic (NSHL). In particular, the NSHL describes the 70-80% of hypoacusia cases and it is mainly due to genetic factors, which are causative of the deafness at the birth. The genetic hypoacusia presents different inheritance patterns: autosomal dominant (20%), autosomal recessive (80%), X-linked (1%), and mitochondrial (1%), respectively. To date, about 35 deafness-causative genes have been identified and most of them codify for connexin transmembrane proteins. Approximately 1:2500 children with NSHL carries mutations in the GJB2 and GJB6 (13q12) genes, which code for connexin 26 (Cx26) and connexin 30 (Cx30), respectively. In the Caucasian population, the most common mutations are 35delG, M34T and 167delT, and D13S1830. Given the frequency distribution of the four mutations in the Caucasian population and the pathogenic connection with NSHL, the development of accurate, rapid, and "low-cost" molecular assays should be strongly encouraged. To this purpose, we set up two different molecular assays (namely the Cx26 and Cx26-30 molecular assays) for the fast and inexpensive detection of 35delG, M34T, 167delT, and D13S1830 mutations. Both the molecular approaches showed to be accurate, sensitive, reproducible, and "low-cost" alternatives for the proper evaluation of the GJB2 and GJB6 genes, which are causative of NSHL. In conclusion, the Cx26 and Cx26-30 molecular assays can be applied to individual, preconception, prenatal, or postnatal screening for the causative-mutations of NSHL. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cascella R.,University of Rome Tor Vergata | Strafella C.,University of Rome Tor Vergata | Ragazzo M.,University of Rome Tor Vergata | Zampatti S.,University of Rome Tor Vergata | And 6 more authors.
Pharmacogenomics Journal | Year: 2015

One of the most successful applications of pharmacogenetics research is the genetic screening for HLA-B∗57:01, strongly associated with an increased risk to develop hypersensitivity reaction in HIV-positive patients following abacavir administration. Taking into consideration the limits of current genotyping methodologies, we have developed and validated (150 buccal swabs) an inexpensive pharmacogenetic approach for HLA-B∗57:01 typing. In our assay DNA extraction and amplification are combined in one single step (direct PCR protocol), which is performed directly on the biological sample without the need of extraction and sequencing passages. The amplicons obtained by direct PCR can be easily separated on the agarose gel under ultraviolet. As per our results, the direct PCR represents a good alternative to the traditional methods of HLA-B∗57:01 pharmacogenetic test, especially for those laboratories or countries where currently available approaches are often not available or not affordable. Furthermore it is an innovative approach, promoting a personalized, safer and cost-effective therapy. © 2015 Macmillan Publishers Limited All rights reserved.

Sciaccaluga M.,University of Rome La Sapienza | Fioretti B.,University of Perugia | Catacuzzeno L.,University of Perugia | Pagani F.,University of Rome La Sapienza | And 10 more authors.
American Journal of Physiology - Cell Physiology | Year: 2010

The activation of ion channels is crucial during cell movement, including glioblastoma cell invasion in the brain parenchyma. In this context, we describe for the first time the contribution of intermediate conductance Ca 2+-activated K (IKCa) channel activity in the chemotactic response of human glioblastoma cell lines, primary cultures, and freshly dissociated tissues to CXC chemokine ligand 12 (CXCL12), a chemokine whose expression in glioblastoma has been correlated with its invasive capacity. We show that blockade of the IKCa channel with its specific inhibitor 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) or IKCa channel silencing by short hairpin RNA (shRNA) completely abolished CXCL12-induced cell migration. We further demonstrate that this is not a general mechanism in glioblastoma cell migration since epidermal growth factor (EGF), which also activates IKCa channels in the glioblastoma-derived cell line GL15, stimulate cell chemotaxis even if the IKCa channels have been blocked or silenced. Furthermore, we demonstrate that both CXCL12 and EGF induce Ca2+ mobilization and IKCa channel activation but only CXCL12 induces a long-term upregulation of the IKCa channel activity. Furthermore, the Ca2+-chelating agent BAPTA-AM abolished the CXCL12-induced, but not the EGF-induced, glioblastoma cell chemotaxis. In addition, we demonstrate that the extracellular signal-regulated kinase (ERK)1/2 pathway is only partially implicated in the modulation of CXCL12-induced glioblastoma cell movement, whereas the phosphoinositol-3 kinase (PI3K) pathway is not involved. In contrast, EGF-induced glioblastoma migration requires both ERK1/2 and PI3K activity. All together these findings suggest that the efficacy of glioblastoma invasiveness might be related to an array of nonoverlapping mechanisms activated by different chemotactic agents. Copyright © 2010 the American Physiological Society.

Catalano M.,University of Rome La Sapienza | D'Alessandro G.,University of Rome La Sapienza | Lepore F.,University of Rome Tor Vergata | Corazzari M.,University of Rome Tor Vergata | And 8 more authors.
Molecular Oncology | Year: 2015

Cell migration and invasion are highly regulated processes involved in both physiological and pathological conditions. Here we show that autophagy modulation regulates the migration and invasion capabilities of glioblastoma (GBM) cells. We observed that during autophagy occurrence, obtained by nutrient deprivation or by pharmacological inhibition of the mTOR complexes, GBM migration and chemokine-mediated invasion were both impaired. We also observed that SNAIL and SLUG, two master regulators of the epithelial-mesenchymal transition (EMT process), were down-regulated upon autophagy stimulation and, as a consequence, we found a transcriptional and translational up-regulation of N- and R-cadherins. Conversely, in BECLIN 1-silenced GBM cells, an increased migration capability and an up-regulation of SNAIL and SLUG was observed, with a resulting decrease in N- and R-cadherin mRNAs. ATG5 and ATG7 down-regulation also resulted in an increased migration and invasion of GBM cells combined to an up-regulation of the two EMT regulators. Finally, experiments performed in primary GBM cells from patients largely confirmed the results obtained in established cell cultures.Overall, our results indicate that autophagy modulation triggers a molecular switch from a mesenchymal phenotype to an epithelial-like one in GBM cellular models. Since the aggressiveness and lethality of GBM is defined by local invasion and resistance to chemotherapy, we believe that our evidence provides a further rationale for including autophagy/mTOR-based targets in the current therapeutical regimen of GBM patients. © 2015 Federation of European Biochemical Societies.

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