Ioris R.M.,University of GenevaGeneva |
Galie M.,University of GenevaGeneva |
Galie M.,University of VeronaVerona |
Ramadori G.,University of GenevaGeneva |
And 13 more authors.
Cell Reports | Year: 2017
Cancer stem cells (CSCs) have high tumorigenic capacity. Here, we show that stem-like traits of specific human cancer cells are reduced by overexpression of the histone deacetylase sirtuin 6 (SIRT6). SIRT6-sensitive cancer cells bear mutations that activate phosphatidylinositol-3-kinase (PI3K) signaling, and overexpression of SIRT6 reduces growth, progression, and grade of breast cancer in a mouse model with PI3K activation. Tumor metabolomic and transcriptomic analyses reveal that SIRT6 overexpression dampens PI3K signaling and stem-like characteristics and causes metabolic rearrangements in this cancer model. Ablation of a PI3K activating mutation in otherwise isogenic cancer cells is sufficient to convert SIRT6-sensitive into SIRT6-insensitive cells. SIRT6 overexpression suppresses PI3K signaling at the transcriptional level and antagonizes tumor sphere formation independent of its histone deacetylase activity. Our data identify SIRT6 as a putative molecular target that hinders stemness of tumors with PI3K activation. © 2017 The Author(s)
PubMed | University of Trento, University of VeronaVerona, Idealab, S.C.A. Associates Rome and 2 more.
Type: | Journal: Frontiers in behavioral neuroscience | Year: 2016
Aphasia therapy focusing on abstract properties of language promotes both item-specific effects and generalization to untreated materials. Neuromodulation with transcranial Direct Current Stimulation (tDCS) has been shown to enhance item-specific improvement, but its potential to enhance generalization has not been systematically investigated. Here, we test the efficacy of ACTION (a linguistically motivated protocol) and tDCS in producing item-specific and generalized improvement in aphasia.Nine individuals with post-stroke aphasia participated in this study. Participants were pre-tested with a diagnostic language battery and a cognitive screening. Experimental tasks were administered over multiple baselines. Production of infinitives, of finite verbs and of full sentences were assessed before and after each treatment phase. Nonword repetition was used as a control measure. Each subject was treated in two phases. Ten daily 1-h treatment sessions were provided per phase, in a double-blind, cross-over design. Linguistically-motivated language therapy focusing on verb inflection and sentence construction was provided in both phases. Each session began with 20 min of real or sham tDCS. Stimulation site was determined individually, based on MRI scans.Group data showed improved production of treated and untreated verbs, attesting the efficacy of behavioral treatment, and its potential to yield generalization. Each individual showed significant item-specific improvement. Generalization occurred in the first phase of treatment for all subjects, and in the second phase for two subjects. Stimulation effects at the group level were significant for treated and untreated verbs altogether, but a ceiling effect for Sham cannot be excluded, as scores between real tDCS and Sham differed only before treatment.Our data demonstrate the efficacy of ACTION and suggest that tDCS may enhance both item-specific effects and generalization.
PubMed | Martini ZiekenhuisGroningen, Dana-Farber Cancer Institute, Wren LaboratoriesBranford, IEO European Institute of Oncology Milan and 21 more.
Type: Journal Article | Journal: Endocrine connections | Year: 2016
The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n=33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.
Montioli R.,University of VeronaVerona |
Oppici E.,University of VeronaVerona |
Dindo M.,University of VeronaVerona |
Roncador A.,University of VeronaVerona |
And 4 more authors.
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2015
Abstract Liver peroxisomal alanine:glyoxylate aminotransferase (AGT), a pyridoxal 5′-phosphate (PLP) enzyme, exists as two polymorphic forms, the major (AGT-Ma) and the minor (AGT-Mi) haplotype. Deficit of AGT causes Primary Hyperoxaluria Type 1 (PH1), an autosomal recessive rare disease. Although ∼ one-third of the 79 disease-causing missense mutations segregates on AGT-Mi, only few of them are well characterized. Here for the first time the molecular and cellular defects of G47R-Mi are reported. When expressed in Escherichia coli, the recombinant purified G47R-Mi variant exhibits only a 2.5-fold reduction of its kcat, and its apo form displays a remarkably decreased PLP binding affinity, increased dimer-monomer equilibrium dissociation constant value, susceptibility to thermal denaturation and to N-terminal region proteolytic cleavage, and aggregation propensity. When stably expressed in a mammalian cell line, we found ∼ 95% of the intact form of the variant in the insoluble fraction, and proteolyzed (within the N-terminal region) and aggregated forms both in the soluble and insoluble fractions. Moreover, the intact and nicked forms have a peroxisomal and a mitochondrial localization, respectively. Unlike what already seen for G41R-Mi, exposure of G47R-Mi expressing cells to pyridoxine (PN) remarkably increases the expression level and the specific activity in a dose-dependent manner, reroutes all the protein to peroxisomes, and rescues its functionality. Although the mechanism of the different effect of PN on the variants G47R-Mi and G41R-Mi remains elusive, the chaperoning activity of PN may be of value in the therapy of patients bearing the G47R mutation. © 2015 The Authors.
Burti L.,University of VeronaVerona
International Journal of Mental Health | Year: 2016
Abstract: There is no mental health without respect for the dignity of mental patients on an equal basis with all other citizens. Rehabilitation is no exception, and deinstitutionalization is its necessary prerequisite. Italy has embraced these principles its 1978 mental health reform, which did away with the mental hospital. After thirty-plus years of community psychiatry, the nation has now the opportunity of exploring further enlightening developments of rehabilitation in the never-ending process of promoting the role of mental patients in society at large. © 2016, Copyright © Taylor & Francis Group, LLC.
PubMed | University of California at San Diego and University of VeronaVerona
Type: | Journal: Frontiers in human neuroscience | Year: 2016
The visual system leverages organizational regularities of perceptual elements to create meaningful representations of the world. One clear example of such function, which has been formalized in the Gestalt psychology principles, is the perceptual grouping of simple visual elements (e.g., lines and arcs) into unitary objects (e.g., forms and shapes). The present study sought to characterize automatic attentional capture and related cognitive processing of Gestalt-like visual stimuli at the psychophysiological level by using event-related potentials (ERPs). We measured ERPs during a simple visual reaction time task with bilateral presentations of physically matched elements with or without a Gestalt organization. Results showed that Gestalt (vs. non-Gestalt) stimuli are characterized by a larger N2pc together with enhanced ERP amplitudes of non-lateralized components (N1, N2, P3) starting around 150 ms post-stimulus onset. Thus, we conclude that Gestalt stimuli capture attention automatically and entail characteristic psychophysiological signatures at both early and late processing stages. Highlights We studied the neural signatures of the automatic processes of visual attention elicited by Gestalt stimuli. We found that a reliable early correlate of attentional capture turned out to be the N2pc component. Perceptual and cognitive processing of Gestalt stimuli is associated with larger N1, N2, and P3.