Neuromed IRCCS

Pozzilli, Italy

Neuromed IRCCS

Pozzilli, Italy

Time filter

Source Type

Roseti C.,Instituto Fisiologia Umana | Fucile S.,University of Rome La Sapienza | Lauro C.,University of Rome La Sapienza | Martinello K.,Neuromed IRCCS | And 10 more authors.
Epilepsia | Year: 2013

Summary Purpose The chemokine fractalkine/CX3CL1 and its receptor CX3CR1 are widely expressed in the central nervous system (CNS). Recent evidence showed that CX3CL1 participates in inflammatory responses that are common features of CNS disorders, such as epilepsy. Mesial temporal lobe epilepsy (MTLE) is the prevalent form of focal epilepsy in adults, and hippocampal sclerosis (HS) represents the most common underlying pathologic abnormality, as demonstrated at autopsy and postresection studies. Relevant features of MTLE are a characteristic pattern of neuronal loss, as are astrogliosis and microglia activation. Several factors affect epileptogenesis in patients with MTLE, including a lack of γ-aminobutyric acid (GABA)ergic inhibitory efficacy. Therefore, experiments were designed to investigate whether, in MTLE brain tissues, CX3CL1 may influence GABAA receptor (GABAAR) mediatedtransmission, with a particular focus on the action of CX3CL1 on the use-dependent decrease (rundown) of the GABA-evoked currents (IGABA), a feature underlying the reduction of GABAergic function in epileptic tissue. Methods Patch-clamp recordings were obtained from cortical pyramidal neurons in slices from six MTLE patients after surgery. Alternatively, the cell membranes from epileptic brain tissues of 17 MTLE patients or from surgical samples and autopsies of nonepileptic patients were microtransplanted into Xenopus oocytes, and IGABA were recorded using the standard two-microelectrode voltage-clamp technique. Immunohistochemical staining and double-labeling studies were carried out on the same brain tissues to analyze CX3CR1 expression. Key Findings In native pyramidal neurons from cortical slices of patients with MTLE, CX3CL1 reduced IGABA rundown and affected the recovery of IGABA amplitude from rundown. These same effects were confirmed in oocytes injected with cortical and hippocampal MTLE membranes, whereas CX3CL1 did not influence IGABA in oocytes injected with nonepileptic tissues. Consistent with a specific effect of CX3CL1 on tissues from patients with MTLE, CX3CR1 immunoreactivity was higher in MTLE sclerotic hippocampi than in control tissues, with a prominent expression in activated microglial cells. Significance These findings indicate a role for CX3CL1 in MTLE, supporting recent evidence on the relevance of brain inflammation in human epilepsies. Our data demonstrate that in MTLE tissues the reduced GABAergic function can be modulated by CX3CL1. The increased CX3CR1 expression in microglia and the modulation by CX3CL1 of GABAergic currents in human epileptic brain suggests new therapeutic approaches for drug-resistant epilepsies based on the evidence that the propagation of seizures can be influenced by inflammatory processes. © Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.


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 10 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.


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.


PubMed | University of Rome La Sapienza, University of Rome Tor Vergata, IRCCS Santa Lucia Foundation, Danish Cancer Society and Neuromed IRCCS
Type: Journal Article | Journal: 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.


Monacelli G.,Neuromed IRCCS | Ceci F.,Paride Stefanini Umberto i Policlinic | Prezzemoli G.,University of Rome La Sapienza | Spagnoli A.,University of Rome La Sapienza | And 2 more authors.
Journal of Neurosurgical Sciences | Year: 2011

Aim. The posterior interosseous nerve palsy is a neuropathy of radial nerve interesting its deep motor branch. The neuropathy can appear with a hollow in the proximal half of the forearm without significant swelling, a complete loss of extension of the fingers with radial deviation of the wrist during extension. In some cases, PIN compression may simulate tendon rupture in rheumatologic diseases, because the pain and the paralysis occur suddenly, so often can be difficult to make a diagnosis. The palsy is caused by compression of the posterior interosseous nerve from soft tissue tumours or tumour-like masses: ganglions, lipomas, rheumatoid synovitis, synovial chondromatosis, fibromas, neurofibromas, bursitis, synovial cysts of the elbow and radioulnar proximal joints. The aim of our research was to individuate the better treatment for the posterior interosseous nerve palsy. Methods. From 2002 to 2007 we examined 8 patients: 2 female and 6 male. Median age was 43 years. The diagnosis was made by clinical examination, ultrasound, nerve conduction studies and magnetic resonance imaging (MRI). Patients underwent to decompressing posterior interosseous nerve surgery. Results. After the surgical exploration in 8 cases a globular mass of around 2.5 cm to 4.5 cm diameter was discovered. At the histological examination, a synovial cyst of the elbow joint was found in 7 out of 8 patients and an hemangioma tumor in the one remaining patient. 12 months was the median time for a complete recovery after the operation, confirmed by EMG. Conclusion. The surgical treatment offers a complete resolution in all cases.


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.


Bolchi C.,University of Milan | Gotti C.,CNR Institute of Neuroscience | Binda M.,University of Milan | Fumagalli L.,University of Milan | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2011

A series of unichiral 7-substituted 2-(1′-methyl-2′- pyrrolidinyl)-1,4-benzodioxanes were synthesized and tested for the affinity for the α4β2 and α7 central nicotinic receptors; the 2R,2′S diastereomer of the 7-OH analogue [(R,S)-7], unique in the series, has a high α4β2 affinity (12nM K i). N-Demethylation and configuration inversion of the stereocenters greatly weaken its α4β2 affinity, confirming that such a rigid molecule can be considered a new template for α4β2 ligands. Docking analysis showed how (R,S)-7 is capable of strongly and specifically interacting with the amino acidic counterpart of the α4β2 receptor binding site. Further pharmacological characterization demonstrated that (R,S)-7 also has a high affinity for the α6β2 receptor, and in vitro functional tests indicated that it is a potent α4β2 and α6β2 partial agonist, with modest affinity and potency for the α3β4 receptor. Comparison with varenicline, a well-known nicotinic partial agonist used as a smoking cessation aid, interestingly reveals similar nicotinoid profiles. © 2011 American Chemical Society.


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.


Berardelli A.,University of Rome La Sapienza | Conte A.,University of Rome La Sapienza | Fabbrini G.,University of Rome La Sapienza | Bologna M.,Neuromed I.R.C.C.S | And 3 more authors.
Parkinsonism and Related Disorders | Year: 2012

In Parkinson's disease (PD), nigral degeneration determines an altered neuronal ouput from the subthalamic nucleus and globus pallidus, and as a consequence functional changes in the motor circuits linking basal ganglia to the motor cortical areas. Movement slowness, rigidity and tremor are among the principal motor symptoms of PD. Studies of movement execution have shown that PD patients have difficulty in performing simultaneous and sequential movements. In executing sequential movements the abnormalities of PD patients worsen as the sequence progresses. This phenomenon, called sequential effect, may be one of the mechanisms underlying the fatigue of PD patients. Cortical deafferentation is thought to be responsible for the motor disturbances of PD and studies using transcranial magnetic stimulation showed that in PD patients there are abnormalities in cortical plasticity and in cortical connectivity. Sensorimotor integration refers to the processes that link sensory input to motor output to produce appropriate voluntary movements. Sensory information is important for motor preparation and execution in parkinsonian patients, and PD patients have greater difficulty in performing movements when no external cues are provided. Investigating the role of sensory information, several studies provided evidence that PD patients have numerous somatosensory deficits, including tactile temporal discrimination threshold. Neurophysiological testing in PD has also found altered central somatosensory processing. Finally PD patients may experience painful sensations after the onset of the disease and various evidence suggests an abnormal nociceptive input processing in the central nervous system that might predispose PD patients to developing pain. © 2011 Elsevier Ltd.


PubMed | Neuromed IRCCS
Type: Journal Article | Journal: Journal of neurosurgical sciences | Year: 2011

The posterior interosseous nerve palsy is a neuropathy of radial nerve interesting its deep motor branch. The neuropathy can appear with a hollow in the proximal half of the forearm without significant swelling, a complete loss of extension of the fingers with radial deviation of the wrist during extension. In some cases, PIN compression may simulate tendon rupture in rheumatologic diseases, because the pain and the paralysis occur suddenly, so often can be difficult to make a diagnosis. The palsy is caused by compression of the posterior interosseous nerve from soft tissue tumours or tumour-like masses: ganglions, lipomas, rheumatoid synovitis, synovial chondromatosis, fibromas, neurofibromas, bursitis, synovial cysts of the elbow and radioulnar proximal joints. The aim of our research was to individuate the better treatment for the posterior interosseous nerve palsy.From 2002 to 2007 we examined 8 patients: 2 female and 6 male. Median age was 43 years. The diagnosis was made by clinical examination, ultrasound, nerve conduction studies and magnetic resonance imaging (MRI). Patients underwent to decompressing posterior interosseous nerve surgery.After the surgical exploration in 8 cases a globular mass of around 2.5 cm to 4.5 cm diameter was discovered. At the histological examination, a synovial cyst of the elbow joint was found in 7 out of 8 patients and an hemangioma tumor in the one remaining patient. 12 months was the median time for a complete recovery after the operation, confirmed by EMG.The surgical treatment offers a complete resolution in all cases.

Loading Neuromed IRCCS collaborators
Loading Neuromed IRCCS collaborators