Publications by authors named "Eleonora Vannini"

21 Publications

  • Page 1 of 1

Old Stars and New Players in the Brain Tumor Microenvironment.

Front Cell Neurosci 2021 6;15:709917. Epub 2021 Oct 6.

Neuroscience Institute, Consiglio Nazionale delle Ricerche (CNR), Pisa, Italy.

In recent years, the direct interaction between cancer cells and tumor microenvironment (TME) has emerged as a crucial regulator of tumor growth and a promising therapeutic target. The TME, including the surrounding peritumoral regions, is dynamically modified during tumor progression and in response to therapies. However, the mechanisms regulating the crosstalk between malignant and non-malignant cells are still poorly understood, especially in the case of glioma, an aggressive form of brain tumor. The presence of unique brain-resident cell types, namely neurons and glial cells, and an exceptionally immunosuppressive microenvironment pose additional important challenges to the development of effective treatments targeting the TME. In this review, we provide an overview on the direct and indirect interplay between glioma and neuronal and glial cells, introducing new players and mechanisms that still deserve further investigation. We will focus on the effects of neural activity and glial response in controlling glioma cell behavior and discuss the potential of exploiting these cellular interactions to develop new therapeutic approaches with the aim to preserve proper brain functionality.
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http://dx.doi.org/10.3389/fncel.2021.709917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527006PMC
October 2021

Narrow and Broad γ Bands Process Complementary Visual Information in Mouse Primary Visual Cortex.

eNeuro 2021 Nov-Dec;8(6). Epub 2021 Nov 4.

The Biorobotics Institute, Scuola Superiore Sant'Anna, Pisa 56025, Italy

γ Band plays a key role in the encoding of visual features in the primary visual cortex (V1). In rodents V1 two ranges within the γ band are sensitive to contrast: a broad γ band (BB) increasing with contrast, and a narrow γ band (NB), peaking at ∼60 Hz, decreasing with contrast. The functional roles of the two bands and the neural circuits originating them are not completely clear yet. Here, we show, combining experimental and simulated data, that in mice V1 (1) BB carries information about high contrast and NB about low contrast; (2) BB modulation depends on excitatory-inhibitory interplay in the cortex, while NB modulation is because of entrainment to the thalamic drive. In awake mice presented with alternating gratings, NB power progressively decreased from low to intermediate levels of contrast where it reached a plateau. Conversely, BB power was constant across low levels of contrast, but it progressively increased from intermediate to high levels of contrast. Furthermore, BB response was stronger immediately after contrast reversal, while the opposite held for NB. These complementary modulations were reproduced by a recurrent excitatory-inhibitory leaky integrate-and-fire network provided that the thalamic inputs were composed of a sustained and a periodic component having complementary sensitivity ranges. These results show that in rodents the thalamic-driven NB plays a specific key role in encoding visual contrast. Moreover, we propose a simple and effective network model of response to visual stimuli in rodents that might help in investigating network dysfunctions of pathologic visual information processing.
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http://dx.doi.org/10.1523/ENEURO.0106-21.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570688PMC
November 2021

Longitudinal Bottom-Up Proteomics of Serum, Serum Extracellular Vesicles, and Cerebrospinal Fluid Reveals Candidate Biomarkers for Early Detection of Glioblastoma in a Murine Model.

Molecules 2021 Oct 2;26(19). Epub 2021 Oct 2.

Fondazione Pisana per la Scienza ONLUS, 56017 San Giuliano Terme, Italy.

Glioblastoma Multiforme (GBM) is a brain tumor with a poor prognosis and low survival rates. GBM is diagnosed at an advanced stage, so little information is available on the early stage of the disease and few improvements have been made for earlier diagnosis. Longitudinal murine models are a promising platform for biomarker discovery as they allow access to the early stages of the disease. Nevertheless, their use in proteomics has been limited owing to the low sample amount that can be collected at each longitudinal time point. Here we used optimized microproteomics workflows to investigate longitudinal changes in the protein profile of serum, serum small extracellular vesicles (sEVs), and cerebrospinal fluid (CSF) in a GBM murine model. Baseline, pre-symptomatic, and symptomatic tumor stages were determined using non-invasive motor tests. Forty-four proteins displayed significant differences in signal intensities during GBM progression. Dysregulated proteins are involved in cell motility, cell growth, and angiogenesis. Most of the dysregulated proteins already exhibited a difference from baseline at the pre-symptomatic stage of the disease, suggesting that early effects of GBM might be detectable before symptom onset.
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http://dx.doi.org/10.3390/molecules26195992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8512455PMC
October 2021

CTX-CNF1 Recombinant Protein Selectively Targets Glioma Cells In Vivo.

Toxins (Basel) 2021 03 8;13(3). Epub 2021 Mar 8.

Neuroscience Institute, National Research Council (CNR), via G. Moruzzi 1, 56124 Pisa, Italy.

Current strategies for glioma treatment are only partly effective because of the poor selectivity for tumoral cells. Hence, the necessity to identify novel approaches is urgent. Recent studies highlighted the effectiveness of the bacterial protein cytotoxic necrotizing factor 1 (CNF1) in reducing tumoral mass, increasing survival of glioma-bearing mice and protecting peritumoral neural tissue from dysfunction. However, native CNF1 needs to be delivered into the brain, because of its incapacity to cross the blood-brain barrier (BBB) per se, thus hampering its clinical translation. To allow a non-invasive administration of CNF1, we here developed a chimeric protein (CTX-CNF1) conjugating CNF1 with chlorotoxin (CTX), a peptide already employed in clinics due to its ability of passing the BBB and selectively binding glioma cells. After systemic administration, we found that CTX-CNF1 is able to target glioma cells and significantly prolong survival of glioma-bearing mice. Our data point out the potentiality of CTX-CNF1 as a novel effective tool to treat gliomas.
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http://dx.doi.org/10.3390/toxins13030194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998600PMC
March 2021

Synaptic Vesicles Dynamics in Neocortical Epilepsy.

Front Cell Neurosci 2020 10;14:606142. Epub 2020 Dec 10.

Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom.

Neuronal hyperexcitability often results from an unbalance between excitatory and inhibitory neurotransmission, but the synaptic alterations leading to enhanced seizure propensity are only partly understood. Taking advantage of a mouse model of neocortical epilepsy, we used a combination of photoconversion and electron microscopy to assess changes in synaptic vesicles pools . Our analyses reveal that epileptic networks show an early onset lengthening of active zones at inhibitory synapses, together with a delayed spatial reorganization of recycled vesicles at excitatory synapses. Proteomics of synaptic content indicate that specific proteins were increased in epileptic mice. Altogether, our data reveal a complex landscape of nanoscale changes affecting the epileptic synaptic release machinery. In particular, our findings show that an altered positioning of release-competent vesicles represent a novel signature of epileptic networks.
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http://dx.doi.org/10.3389/fncel.2020.606142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758433PMC
December 2020

Proteomics analysis of serum small extracellular vesicles for the longitudinal study of a glioblastoma multiforme mouse model.

Sci Rep 2020 11 24;10(1):20498. Epub 2020 Nov 24.

Fondazione Pisana per la Scienza ONLUS, 56107, San Giuliano Terme, PI, Italy.

Longitudinal analysis of disease models enables the molecular changes due to disease progression or therapeutic intervention to be better resolved. Approximately 75 µl of serum can be drawn from a mouse every 14 days. To date no methods have been reported that are able to analyze the proteome of small extracellular vesicles (sEV's) from such low serum volumes. Here we report a method for the proteomics analysis of sEV's from 50 µl of serum. Two sEV isolation procedures were first compared; precipitation based purification (PPT) and size exclusion chromatography (SEC). The methodological comparison confirmed that SEC led to purer sEV's both in terms of size and identified proteins. The procedure was then scaled down and the proteolytic digestion further optimized. The method was then applied to a longitudinal study of serum-sEV proteome changes in a glioblastoma multiforme (GBM) mouse model. Serum was collected at multiple time points, sEV's isolated and their proteins analyzed. The protocol enabled 274 protein groups to be identified and quantified. The longitudinal analysis revealed 25 deregulated proteins in GBM serum sEV's including proteins previously shown to be associated with GBM progression and metastasis (Myh9, Tln-1, Angpt1, Thbs1).
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http://dx.doi.org/10.1038/s41598-020-77535-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686310PMC
November 2020

Voluntary Physical Exercise Reduces Motor Dysfunction and Hampers Tumor Cell Proliferation in a Mouse Model of Glioma.

Int J Environ Res Public Health 2020 08 5;17(16). Epub 2020 Aug 5.

Neuroscience Institute, National Research Council (CNR), 56124 Pisa, Italy.

Currently, high-grade gliomas are the most difficult brain cancers to treat and all the approved experimental treatments do not offer long-term benefits regarding symptom improvement. Epidemiological studies indicate that exercise decreases the risk of brain cancer mortality, but a direct relationship between physical exercise and glioma progression has not been established so far. Here, we exploited a mouse model of high-grade glioma to directly test the impact of voluntary physical exercise on the tumor proliferation and motor capabilities of affected animals. We report that exposing symptomatic, glioma-bearing mice to running wheels (i) reduced the proliferation rate of tumors implanted in the motor cortex and (ii) delayed glioma-induced motor dysfunction. Thus, voluntary physical exercise might represent a supportive intervention that complements existing neuro-oncologic therapies, contributing to the preservation of functional motor ability and counteracting the detrimental effects of glioma on behavioral output.
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http://dx.doi.org/10.3390/ijerph17165667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460183PMC
August 2020

Differential roles of pyramidal and fast-spiking, GABAergic neurons in the control of glioma cell proliferation.

Neurobiol Dis 2020 07 11;141:104942. Epub 2020 May 11.

Neuroscience Institute, National Research Council (CNR), via G. Moruzzi 1, 56124 Pisa, Italy; Department of Biomedical Sciences, University of Padua, via G. Colombo 3, 35121 Padua, Italy. Electronic address:

Recent studies have demonstrated an active role for neurons in glioma progression. Specifically, peritumoral neurons establish functional excitatory synapses with glioma cells, and optogenetic stimulation of cortical pyramidal neurons drives tumor progression. However, the specific role of different subsets of cortical neurons, such as GABAergic interneurons, remains unexplored. Here, we directly compared the effects of optogenetic stimulation of pyramidal cells vs. fast-spiking, GABAergic neurons. In mice inoculated with GL261 cells into the motor cortex, we show that optogenetic stimulation of pyramidal neurons enhances glioma cell proliferation. In contrast, optogenetic stimulation of fast-spiking, parvalbumin-positive interneurons reduces proliferation as measured by BrdU incorporation and Ki67 immunolabelling. Since both principal cells and fast-spiking interneurons are directly activated by sensory afferent input, we next placed tumors in the occipital cortex to test the impact of visual stimulation/deprivation. We report that total lack of visual input via dark rearing enhances the density of proliferating glioma cells, while daily visual stimulation by gratings of different spatial frequencies and contrast reduces tumor growth. The effects of sensory input are region-specific, as visual deprivation has no significant effect on tumor proliferation in mice with gliomas in the motor cortex. We also report that sensory stimulation combined with temozolomide administration delays the loss of visual responses in peritumoral neurons. Altogether, these data demonstrate complex effects of different neuronal subtypes in the control of glioma proliferation.
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http://dx.doi.org/10.1016/j.nbd.2020.104942DOI Listing
July 2020

Bacterial Toxins and Targeted Brain Therapy: New Insights from Cytotoxic Necrotizing Factor 1 (CNF1).

Int J Mol Sci 2018 May 31;19(6). Epub 2018 May 31.

CNR Neuroscience Institute, via G. Moruzzi 1, 56124 Pisa, Italy.

Pathogenic bacteria produce toxins to promote host invasion and, therefore, their survival. The extreme potency and specificity of these toxins confer to this category of proteins an exceptionally strong potential for therapeutic exploitation. In this review, we deal with cytotoxic necrotizing factor (CNF1), a cytotoxin produced by affecting fundamental cellular processes, including cytoskeletal dynamics, cell cycle progression, transcriptional regulation, cell survival and migration. First, we provide an overview of the mechanisms of action of CNF1 in target cells. Next, we focus on the potential use of CNF1 as a pharmacological treatment in central nervous system's diseases. CNF1 appears to impact neuronal morphology, physiology, and plasticity and displays an antineoplastic activity on brain tumors. The ability to preserve neural functionality and, at the same time, to trigger senescence and death of proliferating glioma cells, makes CNF1 an encouraging new strategy for the treatment of brain tumors.
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http://dx.doi.org/10.3390/ijms19061632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032336PMC
May 2018

Dynamical properties of LFPs from mice with unilateral injection of TeNT.

Biosystems 2017 Nov 14;161:57-66. Epub 2017 Sep 14.

Institute of Biophysics, CNR-National Research Council, 56124 Pisa, Italy. Electronic address:

Local field potential (LFP) recordings were performed from the visual cortex (V1) of a focal epilepsy mouse model. Epilepsy was induced by a unilateral injection of the synaptic blocker tetanus neurotoxin (TeNT). LFP signals were simultaneously recorded from V1 of both hemispheres of each animal under acute and chronic conditions (i.e. during and after the period of TeNT action). All data were analysed by using nonlinear time series methods. Suitable values of the lag time and embedding dimension for phase space reconstruction were estimated by employing well-known methods. The results showed that lag times are sensitive to the presence of TeNT. Interestingly, TeNT promoted an increase in the level of linear and nonlinear correlation of LFP signals. The values of the embedding dimension failed to show any dependence on the presence of the neurotoxin. However, a local nonlinear prediction method showed that the presence of TeNT increases the predictability, quantified by the normalized prediction error, of the neural recordings. From a neurophysiological point of view, the above results suggest that TeNT injected in one hemisphere strongly impacts the local electrical activity of the neural populations in the opposite hemisphere. We hypothesize that this could arise from a qualitative and quantitative alteration of the transmission properties of the callosal fibers.
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http://dx.doi.org/10.1016/j.biosystems.2017.09.009DOI Listing
November 2017

Progression of motor deficits in glioma-bearing mice: impact of CNF1 therapy at symptomatic stages.

Oncotarget 2017 Apr;8(14):23539-23550

Institute of Neuroscience, National Research Council (CNR), Pisa, Italy.

Glioblastoma (GBM) is the most aggressive type of brain tumor. In this context, animal models represent excellent tools for the early detection and longitudinal mapping of neuronal dysfunction, that are critical in the preclinical validation of new therapeutic strategies. In a mouse glioma model, we developed sensitive behavioral readouts that allow early recognizing and following neurological symptoms. We injected GL261 cells into the primary motor cortex of syngenic mice and we used a battery of behavioral tests to longitudinally monitor the dysfunction induced by tumor growth. Grip strength test revealed an early onset of functional deficit associated to the glioma growth, with a significant forelimb weakness appearing 9 days after tumor inoculation. A later deficit was observed in the rotarod and in the grid walk tasks. Using this model, we found reduced tumor growth and maintenance of behavioral functions following treatment with Cytotoxic Necrotizing Factor 1 (CNF1) at a symptomatic stage. Our data provide a detailed and precise examination of how tumor growth reverberates on the behavioral functions of glioma-bearing mice, providing normative data for the study of therapeutic strategies for glioma treatment. The reduced tumor volume and robust functional sparing observed in CNF1-treated, glioma-bearing mice strengthen the notion that CNF1 delivery is a promising strategy for glioma therapy.
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http://dx.doi.org/10.18632/oncotarget.15328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410325PMC
April 2017

Vitamin D protects against Aβ peptide cytotoxicity in differentiated human neuroblastoma SH- SY5Y cells: A role for S1P1/p38MAPK/ATF4 axis.

Neuropharmacology 2017 04 7;116:328-342. Epub 2017 Jan 7.

Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Molecular and Applied Biology Research Unit, University of Florence, Viale GB Morgagni 50, 5134 Firenze, Italy; Interuniversitary Miology Institutes, Italy. Electronic address:

Besides its classical function of bone metabolism regulation, 1alpha, 25-dihydroxyvitamin D3 (1,25(OH)D), acts on a variety of tissues including the nervous system, where the hormone plays an important role as neuroprotective, antiproliferating and differentiating agent. Sphingolipids are bioactive lipids that play critical and complex roles in regulating cell fate. In the present paper we have investigated whether sphingolipids are involved in the protective action of 1,25(OH)D We have found that 1,25(OH)D prevents amyloid-β peptide (Aβ(1-42)) cytotoxicity both in differentiated SH-SY5Y human neuroblastoma cells and in vivo. In differentiated SH-SY5Y cells, Aβ(1-42) strongly reduces the sphingosine-1-phosphate (S1P)/ceramide (Cer) ratio while 1,25(OH)D partially reverts this effect. 1,25(OH)D reverts also the Aβ(1-42)-induced reduction of sphingosine kinase activity. We have also studied the crosstalk between 1,25(OH)D and S1P signaling pathways downstream to the activation of S1P receptor subtype S1P1. Notably, we found that 1,25(OH)D prevents the reduction of S1P1 expression promoted by Aβ(1-42) and thereby it modulates the downstream signaling leading to ER stress damage (p38MAPK/ATF4). Similar effects were observed by using ZK191784. In addition, chronic treatment with 1,25(OH)D protects from aggregated Aβ(1-42)-induced damage in the CA1 region of the rat hippocampus and promotes cell proliferation in the hippocampal dentate gyrus of adult mice. In conclusion, these results represent the first evidence of the role of 1,25(OH)D and its structural analogue ZK191784 in counteracting the Aβ(1-42) peptide-induced toxicity through the modulation of S1P/S1P1/p38MAPK/ATF4 pathway in differentiated SH-SY5Y cells.
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http://dx.doi.org/10.1016/j.neuropharm.2017.01.003DOI Listing
April 2017

Electrophysiology of glioma: a Rho GTPase-activating protein reduces tumor growth and spares neuron structure and function.

Neuro Oncol 2016 12 13;18(12):1634-1643. Epub 2016 Jun 13.

CNR Neuroscience Institute, Pisa, Italy (E.V., F.O., L.B., M.C., Mat.C.); CNR Cellular Biology and Neurobiology Institute, Rome, Italy (S.M., M.A.-T.); Fondazione Pisana per la Scienza, Mass Spectrometry and Proteomics, Pisa, Italy (E.L.d.G., L.M.); Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Freiburg, Germany (G.S.); Istituto Superiore di Sanità, Rome, Italy (A.F., C.F.); Scuola Normale Superiore, Pisa, Italy (M.C., Mat.C.).

Background: Glioblastomas are the most aggressive type of brain tumor. A successful treatment should aim at halting tumor growth and protecting neuronal cells to prevent functional deficits and cognitive deterioration. Here, we exploited a Rho GTPase-activating bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1), to interfere with glioma cell growth in vitro and vivo. We also investigated whether this toxin spares neuron structure and function in peritumoral areas.

Methods: We performed a microarray transcriptomic and in-depth proteomic analysis to characterize the molecular changes triggered by CNF1 in glioma cells. We also examined tumor cell senescence and growth in vehicle- and CNF1-treated glioma-bearing mice. Electrophysiological and morphological techniques were used to investigate neuronal alterations in peritumoral cortical areas.

Results: Administration of CNF1 triggered molecular and morphological hallmarks of senescence in mouse and human glioma cells in vitro. CNF1 treatment in vivo induced glioma cell senescence and potently reduced tumor volumes. In peritumoral areas of glioma-bearing mice, neurons showed a shrunken dendritic arbor and severe functional alterations such as increased spontaneous activity and reduced visual responsiveness. CNF1 treatment enhanced dendritic length and improved several physiological properties of pyramidal neurons, demonstrating functional preservation of the cortical network.

Conclusions: Our findings demonstrate that CNF1 reduces glioma volume while at the same time maintaining the physiological and structural properties of peritumoral neurons. These data indicate a promising strategy for the development of more effective antiglioma therapies.
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http://dx.doi.org/10.1093/neuonc/now114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791516PMC
December 2016

Altered sensory processing and dendritic remodeling in hyperexcitable visual cortical networks.

Brain Struct Funct 2016 07 12;221(6):2919-36. Epub 2015 Jul 12.

CNR Neuroscience Institute, via G. Moruzzi 1, 56124, Pisa, Italy.

Epilepsy is characterized by impaired circuit function and a propensity for spontaneous seizures, but how plastic rearrangements within the epileptic focus trigger cortical dysfunction and hyperexcitability is only partly understood. Here we have examined alterations in sensory processing and the underlying biochemical and neuroanatomical changes in tetanus neurotoxin (TeNT)-induced focal epilepsy in mouse visual cortex. We documented persistent epileptiform electrographic discharges and upregulation of GABAergic markers at the completion of TeNT effects. We also found a significant remodeling of the dendritic arbors of pyramidal neurons, with increased dendritic length and branching, and overall reduction in spine density but significant preservation of mushroom, mature spines. Functionally, spontaneous neuronal discharge was increased, visual responses were less reliable, and electrophysiological and behavioural visual acuity was consistently impaired in TeNT-injected mice. These data demonstrate robust, long-term remodeling of both inhibitory and excitatory circuitry associated with specific disturbances of network function in neocortical epilepsy.
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http://dx.doi.org/10.1007/s00429-015-1080-1DOI Listing
July 2016

The bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1) provides long-term survival in a murine glioma model.

BMC Cancer 2014 Jun 18;14:449. Epub 2014 Jun 18.

CNR Neuroscience Institute, Via Moruzzi 1, 56124 Pisa, Italy.

Background: Glioblastomas are largely unresponsive to all available treatments and there is therefore an urgent need for novel therapeutics. Here we have probed the antineoplastic effects of a bacterial protein toxin, the cytotoxic necrotizing factor 1 (CNF1), in the syngenic GL261 glioma cell model. CNF1 produces a long-lasting activation of Rho GTPases, with consequent blockade of cytodieresis in proliferating cells and promotion of neuron health and plasticity.

Methods: We have tested the antiproliferative effects of CNF1 on GL261 cells and human glioma cells obtained from surgical specimens. For the in vivo experiments, we injected GL261 cells into the adult mouse visual cortex, and five days later we administered either a single intracerebral dose of CNF1 or vehicle. To compare CNF1 with a canonical antitumoral drug, we infused temozolomide (TMZ) via minipumps for 1 week in an additional animal group.

Results: In culture, CNF1 was very effective in blocking proliferation of GL261 cells, leading them to multinucleation, senescence and death within 15 days. CNF1 had a similar cytotoxic effect in primary human glioma cells. CNF1 also inhibited motility of GL261 cells in a scratch-wound migration assay. Low dose (2 nM) CNF1 and continuous TMZ infusion significantly prolonged animal survival (median survival 35 days vs. 28 days in vehicle controls). Remarkably, increasing CNF1 concentration to 80 nM resulted in a dramatic enhancement of survival with no obvious toxicity. Indeed, 57% of the CNF1-treated animals survived up to 60 days following GL261 glioma cell transplant.

Conclusions: The activation of Rho GTPases by CNF1 represents a novel potential therapeutic strategy for the treatment of central nervous system tumors.
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http://dx.doi.org/10.1186/1471-2407-14-449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075618PMC
June 2014

[Small renal oncocytoma (≤ 4 cm): enhancement patterns on triphasic spiral computed tomography].

Recenti Prog Med 2012 Nov;103(11):477-82

Universita di Perugia.

In 18 patients with 19 RO, 9 hypervascularity and hypovascularity was identified in 9 and 10 RO, respectively, in the cortico-medullary phase (CMP). Hypervascular RO showed increased density in the CMP (151.4±38.5 HU) and a gradual wash-out in the nephrographic phase (133.8±34.6 HU) and excretory phase (79±23 HU). Hypovascular RO showed increased density in the CMP (87.8±20.1 UH) and a gradual wash-out in the nephrographic phase (100.3±33 UH) and excretory phase (20.9±86.9 UH).
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http://dx.doi.org/10.1701/1166.12892DOI Listing
November 2012

The role of activity in synaptic degeneration in a protein misfolding disease, prion disease.

PLoS One 2012 16;7(7):e41182. Epub 2012 Jul 16.

National Research Council Neuroscience Institute, Pisa, Italy.

In chronic neurodegenerative diseases associated with aggregates of misfolded proteins (such as Alzheimer's, Parkinson's and prion disease), there is an early degeneration of presynaptic terminals prior to the loss of the neuronal somata. Identifying the mechanisms that govern synapse degeneration is of paramount importance, as cognitive decline is strongly correlated with loss of presynaptic terminals in these disorders. However, very little is known about the processes that link the presence of a misfolded protein to the degeneration of synapses. It has been suggested that the process follows a simple linear sequence in which terminals that become dysfunctional are targeted for death, but there is also evidence that high levels of activity can speed up degeneration. To dissect the role of activity in synapse degeneration, we infused the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of mice with prion disease and assessed synapse loss at the electron microscopy level. We found that injection of BoNT/A in naïve mice caused a significant enlargement of excitatory presynaptic terminals in the hippocampus, indicating transmission impairment. Long-lasting blockade of activity by BoNT/A caused only minimal synaptic pathology and no significant activation of microglia. In mice with prion disease infused with BoNT/A, rates of synaptic degeneration were indistinguishable from those observed in control diseased mice. We conclude that silencing synaptic activity neither prevents nor enhances the degree of synapse degeneration in prion disease. These results challenge the idea that dysfunction of synaptic terminals dictates their elimination during prion-induced neurodegeneration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041182PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397974PMC
January 2013

New signalling pathway involved in the anti-proliferative action of vitamin D₃ and its analogues in human neuroblastoma cells. A role for ceramide kinase.

Neuropharmacology 2012 Sep 8;63(4):524-37. Epub 2012 May 8.

Department of Biochemical Sciences, University of Florence, Viale GB Morgagni 50, 50134 Firenze, Italy.

1α,25-Dihydroxyvitamin D3 (1,25(OH)₂D₃), a crucial regulator of calcium/phosphorus homeostasis, has important physiological effects on growth and differentiation in a variety of malignant and non-malignant cells. Synthetic structural hormone analogues, with lower hypercalcemic side effects, are currently under clinical investigation. Sphingolipids appear to be crucial bioactive factors in the control of the cell fate: the phosphorylated forms, sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), are mitogenic factors, whereas sphingosine and ceramide (Cer) usually act as pro-apoptotic agents. Although many studies correlate S1P function to impaired cell growth, the relevance of C1P/Cer system and its involvement in neuroblastoma cells remain to be clarified. Here, we demonstrated the anti-proliferative effect of 1,25(OH)₂D₃ as well as of its structural analogues, ZK156979 and ZK191784, in human SH-SY5Y cells, as judged by [³H]thymidine incorporation, cell growth and evaluation of active ERK1/2 levels. The inhibition of ceramide kinase (CerK), the enzyme responsible for C1P synthesis, by specific gene silencing or pharmacological inhibition, drastically reduced cell proliferation. 1,25(OH)₂D₃ and ZK191784 treatment induced a significant decrease in CerK expression and C1P content, and an increase of Cer. Notably, the treatment of SH-SY5Y cells with ZK159222, antagonist of 1,25(OH)₂D₃ receptor, trichostatin A, inhibitor of histone deacetylases, and COUP-TFI-siRNA prevented the decrease of CerK expression elicited by 1,25(OH)₂D₃ supporting the involvement of VDR/COUP-TFI/histone deacetylase complex in CerK regulation. Altogether, these findings provide the first evidence that CerK/C1P axis acts as molecular effector of the anti-proliferative action of 1,25(OH)₂D₃ and its analogues, thereby representing a new possible target for anti-cancer therapy of human neuroblastoma.
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http://dx.doi.org/10.1016/j.neuropharm.2012.04.026DOI Listing
September 2012

Tetanus neurotoxin-induced epilepsy in mouse visual cortex.

Epilepsia 2012 Jul 11;53(7):e132-6. Epub 2012 May 11.

CNR Neuroscience Institute, Pisa, Italy.

Tetanus neurotoxin (TeNT) is a metalloprotease that cleaves the synaptic protein VAMP/synaptobrevin, leading to focal epilepsy. Although this model is widely used in rats, the time course and spatial specificity of TeNT proteolytic action have not been precisely defined. Here we have studied the biochemical, electrographic, and anatomic characteristics of TeNT-induced epilepsy in mouse visual cortex (V1). We found that VAMP cleavage peaked at 10 days, was reduced at 21 days, and completely extinguished 45 days following TeNT delivery. VAMP proteolysis was restricted to the injected V1 and ipsilateral thalamus, whereas it was undetectable in other cortical areas. Electrographic epileptiform activity was evident both during and after the time window of TeNT effects, indicating development of chronic epilepsy. Anatomic analyses found no evidence for long-term tissue damage, such as neuronal loss or microglia activation. These data show that TeNT reliably induces nonlesional epilepsy in mouse cortex. Due to the excellent physiologic knowledge of the visual cortex and the availability of mouse transgenic strains, this model will be useful for examining the network and cellular alterations underlying hyperexcitability within an epileptic focus.
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http://dx.doi.org/10.1111/j.1528-1167.2012.03510.xDOI Listing
July 2012

Non-orthopaedic causes of shoulder pain: what the shoulder expert must remember.

Musculoskelet Surg 2012 May 18;96 Suppl 1:S63-8. Epub 2012 Apr 18.

E Agnelli Hospital, Via Brigata Cagliari 39, 10064 Pinerolo, Turin, Italy.

Aim of this review is to underline some specific patterns of shoulder pain that are not related to musculoskeletal diseases but are manifestations of gastrointestinal, neurological, cardiological or rheumatological diseases. The most important pathologies (like gallstones, myocardial ischaemia and Parsonage-Turner syndrome...) that can manifest with shoulder pain will be presented by specialty doctors and elements for differential diagnosis will be discussed. Orthopaedic shoulder surgeons should always suspect other causes of pain, different from those related to bone, tendons and joint. If there is something unfair, patients should be referred to family doctor for further investigations in order to exclude major systemic diseases.
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http://dx.doi.org/10.1007/s12306-012-0192-5DOI Listing
May 2012

Activation of Rho GTPases triggers structural remodeling and functional plasticity in the adult rat visual cortex.

J Neurosci 2011 Oct;31(42):15163-72

CNR Neuroscience Institute, 56124 Pisa, Italy.

A classical example of age-dependent plasticity is ocular dominance (OD) plasticity, triggered by monocular deprivation (MD). Sensitivity of cortical circuits to a brief period of MD is maximal in juvenile animals and downregulated in adult age. It remains unclear whether a reduced potential for morphological remodeling underlies this downregulation of physiological plasticity in adulthood. Here we have tested whether stimulation of structural rearrangements is effective in promoting experience-dependent plasticity in adult age. We have exploited a bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1), that regulates actin dynamics and structure of neuronal processes via a persistent activation of Rho GTPases. Injection of CNF1 into the adult rat visual cortex triggered a long-lasting activation of the Rho GTPase Rac1, with a consequent increase in spine density and length in pyramidal neurons. Adult rats treated with CNF1, but not controls, showed an OD shift toward the open eye after MD. CNF1-mediated OD plasticity was selectively attributable to the enhancement of open-eye responses, whereas closed-eye inputs were unaffected. This effect correlated with an increased density of geniculocortical terminals in layer IV of monocularly deprived, CNF1-treated rats. Thus, Rho GTPase activation reinstates OD plasticity in the adult cortex via the potentiation of more active inputs from the open eye. These data establish a direct link between structural remodeling and functional plasticity and demonstrate a role for Rho GTPases in brain plasticity in vivo. The plasticizing effects of Rho GTPase activation may be exploited to promote brain repair.
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http://dx.doi.org/10.1523/JNEUROSCI.2617-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6623549PMC
October 2011
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