78 results on '"Mellone, M"'
Search Results
2. Mathematical Thinking Classroom: un nuovo modo di portare i problemi in classe
- Author
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Mellone M., Pacelli T., Mellone, M., and Pacelli, T.
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problem solving ,task matematici, trasposizione culturale - Abstract
La capacità di affrontare e risolvere problemi è ampiamente riconosciuta, sia in contesto internazionale (NCTM, 2020) che nazionale (MIUR, 2012), come una delle competenze matematiche più importanti da sviluppare negli studenti duran- te il loro percorso scolastico in matematica—non solo, naturalmente—e da por- tarsi come bagaglio per la vita. Nonostante i traguardi per competenze delle In- dicazioni Ministeriali per il primo e secondo ciclo facciano esplicitamente riferi- mento alla competenza di problem-solving, l’impressione è che la risoluzione di problemi sia ancora la cenerentola dell’attività matematica a tutti i livelli scolari: sembrano prevalere, talvolta in modo quasi esclusivo, le attività che richiedono un approccio riproduttivo, piuttosto che quelle che mettono in gioco il pensiero produttivo. In questo articolo parleremo di una metodologia di lavoro con il problem-solving matematico, sviluppata da Peter Liljedahl (Simon Fraser University, Vancouver, Canada): la Mathematical Thinking Classroom, metodologia che ha sperimentato per anni e descritto in un libro (Liljedahl, 2020). Durante un recente periodo di visiting del professore canadese presso il nostro Dipartimento di Matematica e Applicazioni «R. Caccioppoli» dell’Università degli studi di Napoli Federico II, abbiamo avuto l’opportunità di osservarlo condurre attività coerenti con l’approccio della Thinking Classroom con studenti dell’indi- rizzo didattico. In questo articolo, dopo una breve descrizione di tale approccio, lo esemplificheremo a partire dall’esperienza di due studenti.
- Published
- 2021
3. PTU-143 Authentication and characterisation of a new oesophageal adenocarcinoma cell line: mfd-1
- Author
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Garcia, E, Hayden, A, Cowie, A, Mellone, M, Derouet, M, Duriez, P, Noble, F, White, MJ, Primrose, J, Thomas, G, Fitzgerald, R, and Underwood, TJ
- Published
- 2015
- Full Text
- View/download PDF
4. Un progetto di educazione matematica informale per prevenire la dispersione scolastica
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Carotenuto, G., Mellone, M., Sabena, C., and Lattaro, P.
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atteggiamento verso la matematica ,didattica inclusiva ,dispersione scolastica ,educazione matematica informale ,educazione matematica informale, dispersione scolastica, atteggiamento verso la matematica, didattica inclusiva - Published
- 2020
5. NMDA receptor GluN2D subunit participates to levodopa-induced dyskinesia pathophysiology
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Mellone, M., Zianni, E., Stanic, J., Campanelli, Federica, Marino, G., Ghiglieri, V., Longhi, A., Thiolat, M. -L., Li, Q., Calabresi, Paolo, Bezard, E., Picconi, B., Di Luca, M., Gardoni, F., Calabresi P. (ORCID:0000-0003-0326-5509), Mellone, M., Zianni, E., Stanic, J., Campanelli, Federica, Marino, G., Ghiglieri, V., Longhi, A., Thiolat, M. -L., Li, Q., Calabresi, Paolo, Bezard, E., Picconi, B., Di Luca, M., Gardoni, F., and Calabresi P. (ORCID:0000-0003-0326-5509)
- Abstract
In the striatum, specific N-methyl-D-aspartate receptor (NMDAR) subtypes are found in different neuronal cells. Spiny projection neurons (SPNs) are characterized by NMDARs expressing GluN2A and GluN2B subunits, while GluN2D is exclusively detected in striatal cholinergic interneurons (ChIs). In Parkinson's disease (PD), dopamine depletion and prolonged treatment with levodopa (L-DOPA) trigger adaptive changes in the glutamatergic transmission from the cortex to the striatum, also resulting in the aberrant function of striatal NMDARs. While modifications of GluN2A- and GluN2B-NMDARs in SPNs have been extensively documented, only few studies report GluN2D dysfunction in PD and no data are available in L-DOPA-induced dyskinesia (LID). Here we investigate the contribution of a specific NMDAR subtype (GluN2D-NMDAR) to PD and LID, and whether this receptor could represent a candidate for future pharmacological interventions. Our results show that GluN2D synaptic abundance is selectively augmented in the striatum of L-DOPA-treated male parkinsonian rats displaying a dyskinetic phenotype. This event is associated to a dramatic increase in GluN2D binding to the postsynaptic protein scaffold PSD-95. Moreover, immunohistochemistry and electrophysiology experiments reveal that GluN2D-NMDARs are expressed not only by striatal ChIs but also by SPNs in dyskinetic rats. Notably, in vivo treatment with a well-characterized GluN2D antagonist ameliorates the severity of established dyskinesia in L-DOPA-treated animals. Our findings support a role for GluN2D-NMDARs in LID, and they confirm that cell-type and subunit specific modifications of NMDARs underlie the pathophysiology of LID.
- Published
- 2019
6. A miRNA-145/TGF-β1 Negative Feedback Loop Regulates the Cancer-Associated Fibroblast Phenotype
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Melling, G.E., Flannery, S.E., Abidin, S.A., Clemmens, H., Prajapati, P., Hinsley, E.E., Hunt, S., Catto, J.W.F., Coletta, R.D., Mellone, M., Thomas, G.J., Parkinson, E.K., Prime, S.S., Paterson, I.C., Buttle, D.J., and Lambert, D.W.
- Abstract
The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-β1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblast, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF.Here we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-β1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-β signaling pathway. miR-145 was also over-expressed in CAF derived from oral cancers. Over-expression of miR-145 blocked TGF-β1-induced myofibroblastic differentiation and revert CAF towards a normal fibroblast phenotype.We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.
- Published
- 2018
7. Prospective teachers' interpretative knowledge: giving sense to subtraction algorithms
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DI MARTINO, Pietro, Mellone, M., Minichini, C., and Ribeiro, M.
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Prospective teachers’ interpretative knowledge ,prospective teachers’ beliefs ,subtraction algorithms - Published
- 2017
8. Cultural Transposition as a theoretical framework to foster teaching innovation
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Mellone, M., Ramploud, A., Di Paola, B., and Martignone, F.
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Cultural transposition - Published
- 2017
9. Un’esperienza educativa di trasposizione culturale nella scuola primaria
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Mellone, M, Martignone, F., Di Paola, B., Ramploud, A., Di Paola, B., Mellone, M., Martignone, F., Ramploud, A., Mellone, Maria, Alessandro, Ramploud, Francesca, Martignone, and Benedetto di, Paola
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didattica della matematica in diverse culture ,Trasposizione Culturale, didattica della matematica in diverse culture ,Settore MAT/04 - Matematiche Complementari ,Didactic, Chinese, cognitive process, comparative studies ,Trasposizione Culturale - Abstract
La nostra ricerca vuole mostrare come lo studio di approcci sviluppati in diversi contesti culturali può essere importante per riflettere sulle nostre pratiche didattiche e per progettare nuove sperimentazioni nelle classi. In particolare abbiamo studiato le rappresentazioni grafiche usate per descrivere e risolvere problemi additivi nella scuola primaria in Russia e Cina. In questo articolo introdurremo l’idea di trasposizione culturale che sarà anche esemplificata attraverso la descrizione e analisi di due percorsi didattici realizzati in una II e in una V primaria italiane.
- Published
- 2015
10. Safinamide Modulates Striatal Glutamatergic Signaling in a Rat Model of Levodopa-Induced Dyskinesia
- Author
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Gardoni, F., primary, Morari, M., additional, Kulisevsky, J., additional, Brugnoli, A., additional, Novello, S., additional, Pisanò, C. A., additional, Caccia, C., additional, Mellone, M., additional, Melloni, E., additional, Padoani, G., additional, Sosti, V., additional, Vailati, S., additional, and Keywood, C., additional
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- 2018
- Full Text
- View/download PDF
11. Publisher Correction: Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target
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Borroni, B., primary, Stanic, J., additional, Verpelli, C., additional, Mellone, M., additional, Bonomi, E., additional, Alberici, A., additional, Bernasconi, P., additional, Culotta, L., additional, Zianni, E., additional, Archetti, S., additional, Manes, M., additional, Gazzina, S., additional, Ghidoni, R., additional, Benussi, L., additional, Stuani, C., additional, Di Luca, M., additional, Sala, C., additional, Buratti, E., additional, Padovani, A., additional, and Gardoni, F., additional
- Published
- 2018
- Full Text
- View/download PDF
12. Fibroblast activation and senescence in oral cancer
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Prime, SS, Cirillo, N, Hassona, Y, Lambert, DW, Paterson, IC, Mellone, M, Thomas, GJ, James, ENL, Parkinson, EK, Prime, SS, Cirillo, N, Hassona, Y, Lambert, DW, Paterson, IC, Mellone, M, Thomas, GJ, James, ENL, and Parkinson, EK
- Abstract
There is now compelling evidence that the tumour stroma plays an important role in the pathogenesis of cancers of epithelial origin. The pre-eminent cell type of the stroma is carcinoma-associated fibroblasts. These cells demonstrate remarkable heterogeneity with activation and senescence being common stress responses. In this review, we summarise the part that these cells play in cancer, particularly oral cancer, and present evidence to show that activation and senescence reflect a unified programme of fibroblast differentiation. We report advances concerning the senescent fibroblast metabolome, mechanisms of gene regulation in these cells and ways in which epithelial cell adhesion is dysregulated by the fibroblast secretome. We suggest that the identification of fibroblast stress responses may be a valuable diagnostic tool in the determination of tumour behaviour and patient outcome. Further, the fact that stromal fibroblasts are a genetically stable diploid cell population suggests that they may be ideal therapeutic targets and early work in this context is encouraging.
- Published
- 2017
13. Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesias
- Author
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Stanic, J., Mellone, M., Napolitano, F., Racca, C., Zianni, E., Minocci, D., Ghiglieri, V., Thiolat, M. -L., Li, Q., Longhi, A., De Rosa, A., Picconi, B., Bezard, E., Calabresi, Paolo, Di Luca, M., Usiello, A., Gardoni, F., Calabresi P. (ORCID:0000-0003-0326-5509), Stanic, J., Mellone, M., Napolitano, F., Racca, C., Zianni, E., Minocci, D., Ghiglieri, V., Thiolat, M. -L., Li, Q., Longhi, A., De Rosa, A., Picconi, B., Bezard, E., Calabresi, Paolo, Di Luca, M., Usiello, A., Gardoni, F., and Calabresi P. (ORCID:0000-0003-0326-5509)
- Abstract
N-methyl-D-aspartate receptor (NMDAR) subunit composition strictly commands receptor function and pharmacological responses. Changes in NMDAR subunit composition have been documented in brain disorders such as Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesias (LIDs), where an increase of NMDAR GluN2A/GluN2B subunit ratio at striatal synapses has been observed. A therapeutic approach aimed at rebalancing NMDAR synaptic composition represents a valuable strategy for PD and LIDs. To this, the comprehension of the molecular mechanisms regulating the synaptic localization of different NMDAR subtypes is required. We have recently demonstrated that Rabphilin 3A (Rph3A) is a new binding partner of NMDARs containing the GluN2A subunit and that it plays a crucial function in the synaptic stabilization of these receptors. Considering that protein-protein interactions govern the synaptic retention of NMDARs, the purpose of this work was to analyse the role of Rph3A and Rph3A/NMDAR complex in PD and LIDs, and to modulate Rph3A/GluN2A interaction to counteract the aberrant motor behaviour associated to chronic L-DOPA administration. Thus, an array of biochemical, immunohistochemical and pharmacological tools together with electron microscopy were applied in this study. Here we found that Rph3A is localized at the striatal postsynaptic density where it interacts with GluN2A. Notably, Rph3A expression at the synapse and its interaction with GluN2A-containing NMDARs were increased in parkinsonian rats displaying a dyskinetic profile. Acute treatment of dyskinetic animals with a cell-permeable peptide able to interfere with Rph3A/GluN2A binding significantly reduced their abnormal motor behaviour. Altogether, our findings indicate that Rph3A activity is linked to the aberrant synaptic localization of GluN2A-expressing NMDARs characterizing LIDs. Thus, we suggest that Rph3A/GluN2A complex could represent an innovative therapeutic target for those pathological conditio
- Published
- 2017
14. Authentication and characterisation of a new oesophageal adenocarcinoma cell line: MFD-1
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Garcia, E, Hayden, A, Birts, C, Britton, E, Cowie, A, Pickard, K, Mellone, M, Choh, C, Derouet, M, Duriez, P, Noble, F, White, MJ, Primrose, JN, Strefford, JC, Rose-Zerilli, M, Thomas, GJ, Ang, Y, Sharrocks, AD, Fitzgerald, RC, Underwood, TJ, MacRae, S, Grehan, N, Abdullahi, Z, De la Rue, R, Noorani, A, Elliott, RF, De Silva, N, Bornschein, J, O’Donovan, M, Contino, G, Yang, T-P, Chettouh, H, Crawte, J, Nutzinger, B, Edwards, PAW, Smith, L, Miremadi, A, Malhotra, S, Cluroe, A, Hardwick, R, Davies, J, Ford, H, Gilligan, D, Safranek, P, Hindmarsh, A, Sujendran, V, Carroll, N, Turkington, R, Hayes, SJ, Preston, SR, Oakes, S, Bagwan, I, Save, V, Skipworth, RJE, Hupp, TR, O’Neill, JR, Tucker, O, Taniere, P, Owsley, J, Crichton, C, Schusterreiter, C, Barr, H, Shepherd, N, Old, O, Lagergren, J, Gossage, J, Davies, A, Chang, F, Zylstra, J, Sanders, G, Berrisford, R, Harden, C, Bunting, D, Lewis, M, Cheong, E, Kumar, B, Parsons, SL, Soomro, I, Kaye, P, Saunders, J, Lovat, L, Haidry, R, Eneh, V, Igali, L, Welch, I, Scott, M, Sothi, S, Suortamo, S, Lishman, S, Beardsmore, D, Anderson, C, Smith, ML, Secrier, M, Eldridge, MD, Bower, L, Achilleos, A, Lynch, AG, and Tavare, S
- Abstract
New biological tools are required to understand the functional significance of genetic events revealed by whole genome sequencing (WGS) studies in oesophageal adenocarcinoma (OAC). The MFD-1 cell line was isolated from a 55-year-old male with OAC without recombinant-DNA transformation. Somatic genetic variations from MFD-1, tumour, normal oesophagus, and leucocytes were analysed with SNP6. WGS was performed in tumour and leucocytes. RNAseq was performed in MFD-1, and two classic OAC cell lines FLO1 and OE33. Transposase-accessible chromatin sequencing (ATAC-seq) was performed in MFD-1, OE33, and non-neoplastic HET1A cells. Functional studies were performed. MFD-1 had a high SNP genotype concordance with matched germline/tumour. Parental tumour and MFD-1 carried four somatically acquired mutations in three recurrent mutated genes in OAC: TP53, ABCB1 and SEMA5A, not present in FLO-1 or OE33. MFD-1 displayed high expression of epithelial and glandular markers and a unique fingerprint of open chromatin. MFD-1 was tumorigenic in SCID mouse and proliferative and invasive in 3D cultures. The clinical utility of whole genome sequencing projects will be delivered using accurate model systems to develop molecular-phenotype therapeutics. We have described the first such system to arise from the oesophageal International Cancer Genome Consortium project.
- Published
- 2016
15. AN EDUCATIONAL EXPERIENCE OF CULTURAL TRANSPOSITION IN PRIMARY SCHOOL: PROBLEMS WITH VARIATION
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Bartolini Bussi Maria Giuseppina, Di Paola Benedetto, Martignone, F., Mellone, M., Ramploud, A., Csaba Csíkos, C, Rausch,A, Szitányi, J, Bartolini Bussi Maria Giuseppina, Di Paola Benedetto, Martignone Francesca, Mellone Maria, and Ramploud Alessandro
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Settore MAT/04 - Matematiche Complementari ,Math Education, Chinese, Problems with variation - Abstract
Since several years, politicians, researchers and educators from different countries are debating on possible reasons for the success of Confucian area students in interactional assessment projects (such as PISA). Starting from the study of teaching practices developed in this East area, in Italy we developed an educational research based on the process of cultural transposition (Mellone & Ramploud, 2015). With this term we mean the process of change that develops considering two or more cultural-educational backgrounds with the aim to maintain their differences without “translating” them from one culture to another, but rather highlighting these in order to review their meaning processes and daily use in classrooms. In this article we present two educational experiences developed in a second and fifth grades Italian classroom on the cultural transposition of the pictorial equations approach of the Chinese curriculum inserted in the typical structure of Chinese word problems, called problems with variation (Bartolini Bussi et al., 2013). According to Cai and Knuth (2011) in China this symbolic representation is used since the early school years as a possible support for “constructing” a bridge to the “informal algebra”. In the Russian curriculum it is possible to find an analogous approach called intermediate strategies of graphic representation (Davydov, 1982) referred to similar pictorial equations. Our experience of cultural transposition in the Italian context have shown the potentialities of the use of problems with variation as well as the crucial role of the figural equation.
- Published
- 2016
16. The role of osteopontin isoforms in cholangiocarcinoma
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Briones, MA, Coombes, JD, Mellone, M, Rispoli, R, Tolosa, E, Manka, PP, Kitamura, N, Quaglia, A, Canbay, A, Alpini, G, Glaser, SS, Williams, R, Papa, S, Fernandez-Zapico, ME, Syn, W-K, and Foundation for Liver Research
- Subjects
Science & Technology ,Gastroenterology & Hepatology ,1101 Medical Biochemistry And Metabolomics ,Medizin ,1103 Clinical Sciences ,ComputingMethodologies_GENERAL ,Life Sciences & Biomedicine - Abstract
Poster Abstract
- Published
- 2016
17. Safinamide modulates levodopa induced striatal glutamatergic overactivity in a rat model of Parkinson's disease
- Author
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Gardoni, F., primary, Morari, M., additional, Kulisevsky, J., additional, Brugnoli, A., additional, Caccia, C., additional, Mellone, M., additional, Melloni, E., additional, Padoani, G., additional, Sosti, M.V., additional, Vailati, S., additional, and Keywood, C.G.A., additional
- Published
- 2017
- Full Text
- View/download PDF
18. Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target
- Author
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Borroni, B., primary, Stanic, J., additional, Verpelli, C., additional, Mellone, M., additional, Bonomi, E., additional, Alberici, A., additional, Bernasconi, P., additional, Culotta, L., additional, Zianni, E., additional, Archetti, S., additional, Manes, M., additional, Gazzina, S., additional, Ghidoni, R., additional, Benussi, L., additional, Stuani, C., additional, Di Luca, M., additional, Sala, C., additional, Buratti, E., additional, Padovani, A., additional, and Gardoni, F., additional
- Published
- 2017
- Full Text
- View/download PDF
19. Additive structure: an educational experience of cultural transposition
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Mellone, M. and Ramploud, A.
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educational cultural transposition ,pictorial equation ,educational cultural transposition, pictorial equation - Published
- 2015
20. Osteopontin-c isoform promotes a mesenchymal phenotype in human cholangiocarcinoma cells
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Briones-Orta, M. A., Coombes, J. D., Mellone, M., Rispoli, R., Manka, P. P., Younis, R., Kitamura, N., Glaser, S. S., Alpini, G., Quaglia, A., Williams, R., Papa, S., Canbay, Aliekber, and Syn, W. K.
- Subjects
Medizin - Published
- 2015
21. Modulation of serotonergic transmission by eltoprazine in L-DOPA-induced dyskinesia: Behavioral, molecular, and synaptic mechanisms
- Author
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Ghiglieri, V., Mineo, D., Vannelli, A., Cacace, F., Mancini, M., Pendolino, V., Napolitano, F., di Maio, A., Mellone, M., Stanic, J., Tronci, E., Fidalgo, C., Stancampiano, R., Carta, M., Calabresi, Paolo, Gardoni, F., Usiello, A., Picconi, B., Calabresi P. (ORCID:0000-0003-0326-5509), Ghiglieri, V., Mineo, D., Vannelli, A., Cacace, F., Mancini, M., Pendolino, V., Napolitano, F., di Maio, A., Mellone, M., Stanic, J., Tronci, E., Fidalgo, C., Stancampiano, R., Carta, M., Calabresi, Paolo, Gardoni, F., Usiello, A., Picconi, B., and Calabresi P. (ORCID:0000-0003-0326-5509)
- Abstract
L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs) represent the main side effect of Parkinson's Disease (PD) therapy. Among the various pharmacological targets for novel therapeutic approaches, the serotonergic system represents a promising one. In experimental models of PD and in PD patients the development of abnormal involuntarymovements (AIMs) and LIDs, respectively, is accompanied by the impairment of bidirectional synaptic plasticity in key structures such as striatum. Recently, it has been shown that the 5-HT1A/1B receptor agonist, eltoprazine, significantly decreased LIDs in experimental PD and human patients. Despite the fact that several papers have tested this and other serotonergic drugs, nothing is known about the electrophysiological consequences on this combined serotonin receptors modulation at striatal neurons. The present study demonstrates that activation of 5-HT1A/1B receptors reduces AIMs via the restoration of Long-Term Potentiation (LTP) and synaptic depotentiation in a sub-set of striatal spiny projection neurons (SPNs). This recovery is associated with the normalization of D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, and the recovery of NMDA receptor subunits balance, indicating these events as key elements in AIMs induction. Moreover, we analyzed whether the manipulation of the serotonergic system might affect motor behavior and cognitive performances. We found that a defect in locomotor activity in parkinsonian and L-DOPA-treated rats was reversed by eltoprazine treatment. Conversely, the impairment in the striataldependent learning was found exacerbated in L-DOPA-treated rats and eltoprazine failed to recover it.
- Published
- 2016
22. Fibroblast activation and senescence in oral cancer
- Author
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Prime, S. S., primary, Cirillo, N., additional, Hassona, Y., additional, Lambert, D. W., additional, Paterson, I. C., additional, Mellone, M., additional, Thomas, G. J., additional, James, E. N. L., additional, and Parkinson, E. K., additional
- Published
- 2016
- Full Text
- View/download PDF
23. NMDA receptor gluN2A/gluN2B subunit ratio as synaptic trait of levodopa-induced dyskinesias: From experimental models to patients
- Author
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Mellone, M., Stanic, J., Hernandez, L. F., Iglesias, E., Zianni, E., Longhi, A., Prigent, A., Picconi, B., Calabresi, P., Hirsch, E. C., Obeso, J. A., Luca, M. D., Gardoni, F., Calabresi P. (ORCID:0000-0003-0326-5509), Mellone, M., Stanic, J., Hernandez, L. F., Iglesias, E., Zianni, E., Longhi, A., Prigent, A., Picconi, B., Calabresi, P., Hirsch, E. C., Obeso, J. A., Luca, M. D., Gardoni, F., and Calabresi P. (ORCID:0000-0003-0326-5509)
- Abstract
Levodopa-induced dyskinesias (LIDs) are major complications in the pharmacological management of Parkinson's disease (PD). Abnormal glutamatergic transmission in the striatum is considered a key factor in the development of LIDs. This work aims at: (i) characterizing N-methyl-D-aspartate (NMDA) receptor GluN2A/GluN2B subunit ratio as a common synaptic trait in rat and primate models of LIDs as well as in dyskinetic PD patients; and (ii) validating the potential therapeutic effect of a cell- permeable peptide (CPP) interfering with GluN2A synaptic localization on the dyskinetic behavior of these experimental models of LIDs. Here we demonstrate an altered ratio of synaptic GluN2A/GluN2B-containing NMDA receptors in the striatum of levodopa- treated dyskinetic rats and monkeys as well as in post-mortem tissue from dyskinetic PD patients. The modulation of synaptic NMDA receptor composition by a cell- permeable peptide interfering with GluN2A subunit interaction with the scaffolding protein postsynaptic density protein 95 (PSD-95) leads to a reduction in the dyskinetic motor behavior in the two animal models of LIDs. Our results indicate that targeting synaptic NMDA receptor subunit composition may represent an intriguing therapeutic approach aimed at ameliorating levodopa motor side effects.
- Published
- 2015
24. The time is out of joint. Teacher subjectivity during COVID-19
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Silvia Funghi, Alessandro Ramploud, Maria Mellone, Ramploud, A., Funghi, S., and Mellone, M.
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Subjectivity ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Teacher education ,Teacher’s subjectivity · Crisis · Teacher education · Lacan ,General Mathematics ,Field (Bourdieu) ,05 social sciences ,Distance education ,050301 education ,Article ,Education ,Crisis ,Teacher’s subjectivity ,Mathematics education ,Lacan ,0501 psychology and cognitive sciences ,Joint (building) ,Philosophy of education ,0503 education ,050104 developmental & child psychology - Abstract
In this study, we address the issue of mathematics teachers' personal and professional responsiveness to changing circumstances, such as the shift in external demands made on teacher practice due to the COVID-19 pandemic. For investigating a such delicate issue, we take a theoretical approach, which is quite novel in the field of mathematics education: Lacan's psychoanalytical lens. Specifically, we will use this psychoanalytical lens to analyze a case study focusing on a primary school teacher during the first lockdown in Italy, during which school was organized exclusively in the form of distance education. The analysis of the teacher’s crisis and the strategies she adopted to overcome this crisis give some suggestions about possible directions and issues to consider for future mathematics teacher training proposals.
- Published
- 2021
25. An introduction to multiple perspectives on Davydov’s approach in the XXI century
- Author
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Maria Mellone, Luis Radford, Elena Polotskaia, Linda Venenciano, Venenciano, L., Polotskaia, E., Mellone, M., and Radford, L.
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Davydov, algebra, mathematics education ,General Mathematics ,Sociology ,Education ,Epistemology - Abstract
In many countries, the twentieth century philosophy and social sciences were marked by a dialectical materialist understanding of humans and the world. This understanding revolves around the idea that human collective activity and material and ideational culture (e.g., symbols, language) play a central role in learning and development. In socialist Russia, dialectical materialist was the main philosophy that shaped research in psychology and education.
- Published
- 2021
26. An experience of cultural transposition of the El’konin-Davydov curriculum
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Maria Mellone, Alessandro Ramploud, Gemma Carotenuto, Mellone, M., Ramploud, A., and Carotenuto, G.
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Underpinning ,Process (engineering) ,General Mathematics ,Cultural transposition ,05 social sciences ,Perspective (graphical) ,Professional development ,Davydov’s curriculum ,Algebraic thinking ,050301 education ,Educational awarene ,Education ,Cultural transposition . Davydov’s curriculum . Unthought . Algebraic thinking . Educational awareness ,Pedagogy ,0501 psychology and cognitive sciences ,Transposition (logic) ,Sociology ,Deconstruction ,Unthought ,0503 education ,Curriculum ,Implementation ,050104 developmental & child psychology - Abstract
We will present cultural transposition as a particular perspective to frame the use of foreign mathematics education practices as an opportunity for questioning the didactic practices of one’s own cultural context. This requires a process activated by researchers, who deconstruct the cultural layers underpinning the foreign education practice before proposing it to teachers. We discuss the theoretical premises of this approach and, in accordance with them, we propose a transposition process of the El’konin-Davydov curriculum. In particular, we will show how our deconstruction process has affected the design and implementations of particular Professional Development courses (PDs) in Italy. Finally, we will present a case study of a teacher involved in one of these PDs to observe her new educational awareness.
- Published
- 2020
27. Mathematics teachers’ interpretative knowledge of students’ errors and non-standard reasoning
- Author
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Tiziana Pacelli, Piera Romano, Arne Jakobsen, Gemma Carotenuto, Miguel Ribeiro, Maria Mellone, Mellone, M., Ribeiro, M., Jakobsen, A., Carotenuto, G., Romano, P., and Pacelli, T.
- Subjects
General Mathematics ,Teaching method ,Knowledge level ,05 social sciences ,050301 education ,Thinking skills ,Teacher education ,Education ,Interpretative knowledge, teacher education, prospective teachers ,Work (electrical) ,Graduate students ,0502 economics and business ,Mathematics education ,Mathematics instruction ,0503 education ,050203 business & management - Abstract
In this work, we examined mathematical knowledge mobilised by mathematics teachers while interpreting students’ answers, which we denote as Interpretative Knowledge (IK). In particular, we analysed the IK of prospective mathematics teachers (PTs), who were students of a Mathematics Education course for the Master’s Degree in Mathematics. In order to study the possible development of the IK of these students, we explored their interpretations of secondary students’ productions and compared those given before, during, and after a collective discussion about these productions. Our findings reveal considerable differences in PTs’ knowledge and interpretations provided during the three activities, confirming that these and similar activities can be useful in training mathematics teachers in order to develop their IK.
- Published
- 2020
28. Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesias
- Author
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Paolo Calabresi, Jennifer Stanic, Claudia Racca, Alessandro Usiello, Fabrizio Gardoni, Marie Laure Thiolat, Arianna De Rosa, Veronica Ghiglieri, Francesco Napolitano, Manuela Mellone, Monica Di Luca, Elisa Zianni, Barbara Picconi, Qin Li, Daiana Minocci, Annalisa Longhi, Erwan Bezard, Stanic, J, Mellone, M, Napolitano, F, Racca, C, Zianni, E, Minocci, D, Ghiglieri, V, Thiolat, Ml, Li, Q, Longhi, A, De Rosa, A, Picconi, B, Bezard, E, Calabresi, P, Di Luca, M, Usiello, A, Gardoni, F., and Napolitano, Francesco
- Subjects
Male ,0301 basic medicine ,Dyskinesia, Drug-Induced ,Vesicular Transport Proteins ,Plasma protein binding ,Antiparkinson Agents ,Levodopa ,Rats, Sprague-Dawley ,Tissue Culture Techniques ,Levodopa-induced dyskinesias ,Synapse ,chemistry.chemical_compound ,0302 clinical medicine ,Receptors ,80 and over ,Receptor ,Aged, 80 and over ,Chemistry ,Cell-permeable peptides ,N-methyl-D-aspartate receptor ,Pharmacological target ,Neurology ,Adaptor Proteins ,Settore MED/26 - NEUROLOGIA ,NMDA receptor ,Female ,Oxidopamine ,Protein Binding ,N-Methyl-D-Aspartate ,medicine.drug ,Protein subunit ,Nerve Tissue Proteins ,Receptors, N-Methyl-D-Aspartate ,lcsh:RC321-571 ,03 medical and health sciences ,Parkinsonian Disorders ,medicine ,Animals ,Humans ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Adaptor Proteins, Signal Transducing ,Aged ,Cell-permeable peptide ,Dyskinesia ,Signal Transducing ,Post-Synaptic Density ,Levodopa-induced dyskinesia ,Macaca mulatta ,Corpus Striatum ,Rats ,030104 developmental biology ,nervous system ,Drug-Induced ,Synapses ,Sprague-Dawley ,Postsynaptic density ,Neuroscience ,030217 neurology & neurosurgery - Abstract
N-methyl-d-aspartate receptor (NMDAR) subunit composition strictly commands receptor function and pharmacological responses. Changes in NMDAR subunit composition have been documented in brain disorders such as Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesias (LIDs), where an increase of NMDAR GluN2A/GluN2B subunit ratio at striatal synapses has been observed. A therapeutic approach aimed at rebalancing NMDAR synaptic composition represents a valuable strategy for PD and LIDs. To this, the comprehension of the molecular mechanisms regulating the synaptic localization of different NMDAR subtypes is required. We have recently demonstrated that Rabphilin 3A (Rph3A) is a new binding partner of NMDARs containing the GluN2A subunit and that it plays a crucial function in the synaptic stabilization of these receptors. Considering that protein-protein interactions govern the synaptic retention of NMDARs, the purpose of this work was to analyse the role of Rph3A and Rph3A/NMDAR complex in PD and LIDs, and to modulate Rph3A/GluN2A interaction to counteract the aberrant motor behaviour associated to chronic L-DOPA administration. Thus, an array of biochemical, immunohistochemical and pharmacological tools together with electron microscopy were applied in this study. Here we found that Rph3A is localized at the striatal postsynaptic density where it interacts with GluN2A. Notably, Rph3A expression at the synapse and its interaction with GluN2A-containing NMDARs were increased in parkinsonian rats displaying a dyskinetic profile. Acute treatment of dyskinetic animals with a cell-permeable peptide able to interfere with Rph3A/GluN2A binding significantly reduced their abnormal motor behaviour. Altogether, our findings indicate that Rph3A activity is linked to the aberrant synaptic localization of GluN2A-expressing NMDARs characterizing LIDs. Thus, we suggest that Rph3A/GluN2A complex could represent an innovative therapeutic target for those pathological conditions where NMDAR composition is significantly altered. N-methyl-(D)-aspartate receptor (NMDAR) subunit composition strictly commands receptor function and pharmacological responses. Changes in NMDAR subunit composition have been documented in brain disorders such as Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesias (LIDs), where an increase of NMDAR GluN2A/G1uN2B subunit ratio at striatal synapses has been observed. A therapeutic approach aimed at rebalancing NMDAR synaptic composition represents a valuable strategy for PD and LIDs. To this, the comprehension of the molecular mechanisms regulating the synaptic localization of different NMDAR subtypes is required.We have recently demonstrated that Rabphilin 3A (Rph3A) is a new binding partner of NMDARs containing the GIuN2A subunit and that it plays a crucial function in the synaptic stabilization of these receptors. Considering that protein-protein interactions govern the synaptic retention of NMDARs, the purpose of this work was to analyse the role of Rph3A and Rph3A/NMDAR complex in PD and LIDs, and to modulate Rph3A/GIuN2A interaction to counteract the aberrant motor behaviour associated to chronic L-DOPA administration. Thus, an array of biochemical, immunohistochemical and pharmacological tools together with electron microscopy were applied in this study. Here we found that Rph3A is localized at the striatal postsynaptic density where it interacts with G1uN2A. Notably, Rph3A expression at the synapse and its interaction with GIuN2A-containing NMDARs were increased in parkinsonian rats displaying a dyskinetic profile. Acute treatment of dyskinetic animals with a cell-permeable peptide able to interfere with Rph3A/GIuN2A binding significantly reduced their abnormal motor behaviour.Altogether, our findings indicate that Rph3A activity is linked to the aberrant synaptic localization of GIuN2Aexpressing NMDARs characterizing LIDs. Thus, we suggest that Rph3A/GIuN2A complex could represent an innovative therapeutic target for those pathological conditions where NMDAR composition is significantly altered. (C) 2017 The Authors. Published by Elsevier Inc.
- Published
- 2017
29. Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure
- Author
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Fabrizio Gardoni, Alberto Benussi, Manuela Mellone, Diego Scheggia, Alessandro Padovani, Francesca Palese, Elena Marcello, Monica Di Luca, Anna Pittaluga, Alessia Casamassa, Francesca Cisani, Barbara Borroni, Tommaso Nuzzo, Elisa Zianni, Antonella Alberici, Elisa Bonomi, Alessandro Usiello, Palese, F, Bonomi, E, Nuzzo, T, Benussi, A, Mellone, M, Zianni, E, Cisani, F, Casamassa, A, Alberici, A, Scheggia, D, Padovani, A, Marcello, E, Di Luca, M, Pittaluga, A, Usiello, A, Borroni, B, and Gardoni, F
- Subjects
0301 basic medicine ,AMPA receptors ,Autoimmunity ,Cerebrospinal fluid ,Dementia ,Glutamate ,Synapses ,Adult ,Male ,Aging ,Female ,Frontotemporal Dementia ,Glutamates ,Humans ,Middle Aged ,Receptors, AMPA ,Autoantibodies ,Synaptic Transmission ,AMPA receptor ,Neuropathology ,Neurotransmission ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Neurochemical ,Receptors ,AMPA ,mental disorders ,medicine ,business.industry ,General Neuroscience ,Glutamate receptor ,medicine.disease ,Synapse ,030104 developmental biology ,Neurology (clinical) ,Geriatrics and Gerontology ,business ,Neuroscience ,030217 neurology & neurosurgery ,Developmental Biology ,Frontotemporal dementia - Abstract
Despite the great effort of the scientific community in the field, the pathogenesis of frontotemporal dementia (FTD) remains elusive. Recently, a role for autoimmunity and altered glutamatergic neurotransmission in triggering disease onset has been put forward. We reported the presence of autoantibodies recognizing the GluA3 subunit of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in about 25% of FTD cases. In this study, we evaluated the mechanisms involved in anti-GluA3 autoimmunity, through molecular/neurochemical analyses conducted on patients' brain specimens with frontotemporal lobar degeneration–tau neuropathology. We then corroborated these results in vivo in FTD patients with transcranial magnetic stimulation and glutamate, D-serine, and L-serine dosages in the cerebrospinal fluid and serum. We observed that GluA3 autoantibodies affect glutamatergic neurotransmission, decreasing glutamate release and altering GluA3-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor levels. These alterations were accompanied by changes of scaffolding proteins involved in receptor synaptic retention/internalization. The above results were confirmed by transcranial magnetic stimulation, suggesting a significant impairment of indirect measures of glutamatergic neurotransmission in FTD patients compared with controls, with further add-on harmful effect in those FTD patients with anti-GluA3 antibodies. Finally, FTD patients showed a significant increase of glutamate, D-serine, and L-serine levels in the cerebrospinal fluid.
- Published
- 2019
30. Modulation of serotonergic transmission by eltoprazine in L-DOPA-induced dyskinesia: Behavioral, molecular, and synaptic mechanisms
- Author
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Camino Fidalgo, Fabrizio Cacace, Valentina Pendolino, Alessandro Usiello, Maria Luisa Mancini, Paolo Calabresi, Veronica Ghiglieri, Fabrizio Gardoni, Francesco Napolitano, Elisabetta Tronci, Manuela Mellone, Anna Di Maio, Manolo Carta, Barbara Picconi, Desiree Mineo, Roberto Stancampiano, Jennifer Stanic, Anna Vannelli, Ghiglieri, Veronica, Mineo, Desiree, Vannelli, Anna, Cacace, Fabrizio, Mancini, Maria, Pendolino, Valentina, Napolitano, Francesco, di Maio, Anna, Mellone, Manuela, Stanic, Jennifer, Tronci, Elisabetta, Fidalgo, Camino, Stancampiano, Roberto, Carta, Manolo, Calabresi, Paolo, Gardoni, Fabrizio, Usiello, Alessandro, Picconi, Barbara, Ghiglieri, V, Mineo, D, Vannelli, A, Cacace, F, Mancini, M, Pendolino, V, Napolitano, F, di Maio, A, Mellone, M, Stanic, J, Tronci, E, Fidalgo, C, Stancampiano, R, Carta, M, Calabresi, P, Gardoni, F, and Picconi, B.
- Subjects
0301 basic medicine ,Male ,Dyskinesia, Drug-Induced ,Wistar ,Levodopa treatment ,Pharmacology ,Synaptic Transmission ,Piperazines ,Levodopa ,0302 clinical medicine ,Parkinson's disease animal model ,Neurons ,Neuronal Plasticity ,Behavior, Animal ,TOR Serine-Threonine Kinases ,Eltoprazine ,Long-term potentiation ,Bidirectional synaptic plasticity ,Serotonin Receptor Agonists ,Parkinson's disease animal models ,Settore MED/26 - NEUROLOGIA ,Neurology ,NMDA receptor ,MAP Kinase Signaling System ,Biology ,Neurotransmission ,Motor Activity ,Medium spiny neuron ,Serotonergic ,lcsh:RC321-571 ,03 medical and health sciences ,Parkinsonian Disorders ,Animals ,Rats, Wistar ,Oxidopamine ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Serotonergic transmission ,Behavior ,Dyskinesia ,Animal ,Abnormal involuntary movement ,Corpus Striatum ,Rats ,030104 developmental biology ,nervous system ,Drug-Induced ,Synaptic plasticity ,Synapses ,Neuroscience ,030217 neurology & neurosurgery - Abstract
L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs) represent the main side effect of Parkinson's Disease (PD) therapy. Among the various pharmacological targets for novel therapeutic approaches, the serotonergic system represents a promising one. In experimental models of PD and in PD patients the development of abnormal involuntary movements (AIMs) and LIDs, respectively, is accompanied by the impairment of bidirectional synaptic plasticity in key structures such as striatum. Recently, it has been shown that the 5-HT1A/1B receptor agonist, eltoprazine, significantly decreased LIDs in experimental PD and human patients. Despite the fact that several papers have tested this and other serotonergic drugs, nothing is known about the electrophysiological consequences on this combined serotonin receptors modulation at striatal neurons.The present study demonstrates that activation of 5-HT1A/1B receptors reduces AIMs via the restoration of Long-Term Potentiation (LTP) and synaptic depotentiation in a sub-set of striatal spiny projection neurons (SPNs). This recovery is associated with the normalization of D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, and the recovery of NMDA receptor subunits balance, indicating these events as key elements in AIMs induction. Moreover, we analyzed whether the manipulation of the serotonergic system might affect motor behavior and cognitive performances. We found that a defect in locomotor activity in parkinsonian and L-DOPA-treated rats was reversed by eltoprazine treatment. Conversely, the impairment in the striatal-dependent learning was found exacerbated in L-DOPA-treated rats and eltoprazine failed to recover it.
- Published
- 2016
31. Early Algebra: Pensiero Algebrico come competenza verticale
- Author
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M. , Mellone, Giacardi L., Mosca M., Sabena C., and Mellone, M.
- Abstract
Partendo da alcune evidenze che mostrano la presenza di competenze algebriche in bambini molto piccoli, si presentano due episodi avvenuti durante dei percorsi sperimentali sviluppati in una seconda e una quinta elementare. In queste classi erano stati proposti dei particolari problemi allo scopo di far emergere forme di pensiero algebrico nei bambini. Si presentano inoltre alcuni esempi di manipolazioni di superfici di rettangoli nella soluzione di problemi secondo grado del periodo Babilonese, per poi passare a discutere un loro possibile utilizzo nella presentazioni della risoluzione di equazioni di secondo grado nella scuola superiore.
- Published
- 2017
32. Author Correction: mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.
- Author
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Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, Raguz S, Acosta JC, Innes AJ, Banito A, Georgilis A, Montoya A, Wolter K, Dharmalingam G, Faull P, Carroll T, Martínez-Barbera JP, Cutillas P, Reisinger F, Heikenwalder M, Miller RA, Withers D, Zender L, Thomas GJ, and Gil J
- Published
- 2024
- Full Text
- View/download PDF
33. COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells.
- Author
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McHugh D, Sun B, Gutierrez-Muñoz C, Hernández-González F, Mellone M, Guiho R, Duran I, Pombo J, Pietrocola F, Birch J, Kallemeijn WW, Khadayate S, Dharmalingam G, Vernia S, Tate EW, Martínez-Barbera JP, Withers DJ, Thomas GJ, Serrano M, and Gil J
- Subjects
- Mice, Animals, Golgi Apparatus metabolism, Cellular Senescence, Fibrosis, Senotherapeutics, Neoplasms metabolism
- Abstract
Drugs that selectively kill senescent cells (senolytics) improve the outcomes of cancer, fibrosis and age-related diseases. Despite their potential, our knowledge of the molecular pathways that affect the survival of senescent cells is limited. To discover senolytic targets, we performed RNAi screens and identified coatomer complex I (COPI) vesicle formation as a liability of senescent cells. Genetic or pharmacological inhibition of COPI results in Golgi dispersal, dysfunctional autophagy, and unfolded protein response-dependent apoptosis of senescent cells, and knockdown of COPI subunits improves the outcomes of cancer and fibrosis in mouse models. Drugs targeting COPI have poor pharmacological properties, but we find that N-myristoyltransferase inhibitors (NMTi) phenocopy COPI inhibition and are potent senolytics. NMTi selectively eliminated senescent cells and improved outcomes in models of cancer and non-alcoholic steatohepatitis. Our results suggest that senescent cells rely on a hyperactive secretory apparatus and that inhibiting trafficking kills senescent cells with the potential to treat various senescence-associated diseases., (© 2023. The Author(s).)
- Published
- 2023
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34. Study of Alerting, Orienting, and Executive Control Attentional Networks in Bilingual and Monolingual Primary School Children: The Role of Socioeconomic Status.
- Author
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Federico F, Mellone M, Volpi F, and Orsolini M
- Abstract
For decades, researchers have suggested the existence of a bilingual cognitive advantage, especially in tasks involving executive functions such as inhibition, shifting, and updating. Recently, an increasing number of studies have questioned whether bilingualism results in a change in executive functions, highlighting conflicting data published in the literature. The present study compared the performance of third-, fourth-, and fifth-grade bilingual and monolingual children on attentional and cognitive tasks. The participants were 61 monolingual and 74 bilingual children ( M = 114.6 months; SD = 8.48 months) who were tested on two versions of the attention network task (ANT), with and without social stimuli, as well as tests investigating working memory, short-term memory, narrative memory, and receptive vocabulary. Data on families' socioeconomic status and children's reasoning abilities were also collected. The results showed that bilingualism and socioeconomic status affected attentional networks in tasks involving social stimuli. In tasks involving non-social stimuli, socioeconomic status only affected the alerting and executive conflict networks. Consistent with the literature, a positive relationship emerged between socioeconomic status and executive control in the context of social stimuli, and a negative relationship emerged between socioeconomic status and the alerting network in the context of non-social stimuli. Interestingly, neither socioeconomic status nor social attentional networks correlated with working memory. Therefore, although more investigations are required, the results suggest that differences in social contexts mainly affect attentional functions.
- Published
- 2023
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- View/download PDF
35. The Effects of Social Processing and Role Type on Attention Networks: Insights from Team Ball Athletes.
- Author
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Passarello N, Mellone M, Sorrentino P, Chirico A, Lucidi F, Mandolesi L, and Federico F
- Abstract
(1) Background: Several findings have shown how social stimuli can influence attentional processes. Social attention is crucial in team ball sports, in which players have to react to dynamically changing, unpredictable, and externally paced environments. Our study aimed at demonstrating the influence of social processing on team ball sports athletes' attentional abilities. (2) Methods: A total of 103 male players divided by sport (soccer, handball, and basketball) and by role (striker, midfielder, or defender) were tested through a modified version of the Attention Network Test (ANT) in which they were exposed to both social and non-social stimuli. (3) Results: Social stimuli positively impacted the athletes' abilities to focus on target stimuli and ignore conflicting environmental requests (t = -2.600, p = 0.011 *). We also found that the athletes' roles impacted their performance accuracy. Specifically, differences were found in the ability to maintain a general state of reactivity between athletes (strikers vs. midfielders: t = 3.303, p = 0.004 **; striker vs. defenders: t = -2.820, p = 0.017 *; midfielders vs. defenders: t = -5.876, p < 001 ***). (4) Conclusion: These findings revealed that social stimuli are crucial for performance enhancement in team ball sports athletes. Further, we suggest that it is possible to draw specific attentional profiles for athletes in different roles.
- Published
- 2023
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- View/download PDF
36. ATM Regulates Differentiation of Myofibroblastic Cancer-Associated Fibroblasts and Can Be Targeted to Overcome Immunotherapy Resistance.
- Author
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Mellone M, Piotrowska K, Venturi G, James L, Bzura A, Lopez MA, James S, Wang C, Ellis MJ, Hanley CJ, Buckingham JF, Cox KL, Hughes G, Valge-Archer V, King EV, Beers SA, Jaquet V, Jones GDD, Savelyeva N, Sayan E, Parsons JL, Durant S, and Thomas GJ
- Subjects
- Humans, Cell Differentiation, Myofibroblasts metabolism, Drug Resistance, Neoplasm, Ataxia Telangiectasia Mutated Proteins metabolism, Cancer-Associated Fibroblasts metabolism, Immunotherapy, Neoplasms
- Abstract
Myofibroblastic cancer-associated fibroblast (myoCAF)-rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting the potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of the myoCAF phenotype. Differentiating myofibroblasts in vitro and myoCAFs cultured ex vivo display activated ATM signaling, and targeting ATM genetically or pharmacologically could suppress and reverse differentiation. ATM activation was regulated by the reactive oxygen species-producing enzyme NOX4, both through DNA damage and increased oxidative stress. Targeting fibroblast ATM in vivo suppressed myoCAF-rich tumor growth, promoted intratumoral CD8 T-cell infiltration, and potentiated the response to anti-PD-1 blockade and antitumor vaccination. This work identifies a novel pathway regulating myoCAF differentiation and provides a rationale for using ATM inhibitors to overcome CAF-mediated immunotherapy resistance., Significance: ATM signaling supports the differentiation of myoCAFs to suppress T-cell infiltration and antitumor immunity, supporting the potential clinical use of ATM inhibitors in combination with checkpoint inhibition in myoCAF-rich, immune-cold tumors., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
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- View/download PDF
37. Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR-200 levels in extracellular vesicles.
- Author
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Bhome R, Emaduddin M, James V, House LM, Thirdborough SM, Mellone M, Tulkens J, Primrose JN, Thomas GJ, De Wever O, Mirnezami AH, and Sayan AE
- Subjects
- Animals, Fibroblasts metabolism, Humans, Mice, Phenotype, Colorectal Neoplasms genetics, Epithelial-Mesenchymal Transition genetics, Extracellular Vesicles genetics, Extracellular Vesicles metabolism, MicroRNAs genetics, MicroRNAs metabolism
- Abstract
Colorectal cancer (CRC) with a mesenchymal gene expression signature has the greatest propensity for distant metastasis and is characterised by the accumulation of cancer-associated fibroblasts in the stroma. We investigated whether the epithelial to mesenchymal transition status of CRC cells influences fibroblast phenotype, with a focus on the transfer of extracellular vesicles (EVs), as a controlled means of cell-cell communication. Epithelial CRC EVs suppressed TGF-β-driven myofibroblast differentiation, whereas mesenchymal CRC EVs did not. This was driven by miR-200 (miR-200a/b/c, -141), which was enriched in epithelial CRC EVs and transferred to recipient fibroblasts. Ectopic miR-200 expression or ZEB1 knockdown, in fibroblasts, similarly suppressed myofibroblast differentiation. Supporting these findings, there was a strong negative correlation between miR-200 and myofibroblastic markers in a cohort of CRC patients in the TCGA dataset. This was replicated in mice, by co-injecting epithelial or mesenchymal CRC cells with fibroblasts and analysing stromal markers of myofibroblastic phenotype. Fibroblasts from epithelial tumours contained more miR-200 and expressed less ACTA2 and FN1 than those from mesenchymal tumours. As such, these data provide a new mechanism for the development of fibroblast heterogeneity in CRC, through EV-mediated transfer of miRNAs, and provide an explanation as to why CRC tumours with greater metastatic potential are CAF rich., (© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)
- Published
- 2022
- Full Text
- View/download PDF
38. The ZEB2-dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer.
- Author
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Sreekumar R, Al-Saihati H, Emaduddin M, Moutasim K, Mellone M, Patel A, Kilic S, Cetin M, Erdemir S, Navio MS, Lopez MA, Curtis N, Yagci T, Primrose JN, Price BD, Berx G, Thomas GJ, Tulchinsky E, Mirnezami A, and Sayan AE
- Subjects
- Animals, Cell Line, Tumor, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Drug Resistance, Neoplasm, Fluorouracil therapeutic use, Humans, Leucovorin therapeutic use, Liver Neoplasms secondary, Mice, Organoplatinum Compounds therapeutic use, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colorectal Neoplasms genetics, DNA Repair genetics, DNA-Binding Proteins genetics, Endonucleases genetics, Epithelial-Mesenchymal Transition genetics, Transcription, Genetic, Zinc Finger E-box Binding Homeobox 2 physiology
- Abstract
Resistance to adjuvant chemotherapy is a major clinical problem in the treatment of colorectal cancer (CRC). The aim of this study was to elucidate the role of an epithelial to mesenchymal transition (EMT)-inducing protein, ZEB2, in chemoresistance of CRC, and to uncover the underlying mechanism. We performed IHC for ZEB2 and association analyses with clinical outcomes on primary CRC and matched CRC liver metastases in compliance with observational biomarker study guidelines. ZEB2 expression in primary tumours was an independent prognostic marker of reduced overall survival and disease-free survival in patients who received adjuvant FOLFOX chemotherapy. ZEB2 expression was retained in 96% of liver metastases. The ZEB2-dependent EMT transcriptional programme activated nucleotide excision repair (NER) pathway largely via upregulation of the ERCC1 gene and other components in NER pathway, leading to enhanced viability of CRC cells upon oxaliplatin treatment. ERCC1-overexpressing CRC cells did not respond to oxaliplatin in vivo, as assessed using a murine orthotopic model in a randomised and blinded preclinical study. Our findings show that ZEB2 is a biomarker of tumour response to chemotherapy and risk of recurrence in CRC patients. We propose that the ZEB2-ERCC1 axis is a key determinant of chemoresistance in CRC., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Published
- 2021
- Full Text
- View/download PDF
39. NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors.
- Author
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Ford K, Hanley CJ, Mellone M, Szyndralewiez C, Heitz F, Wiesel P, Wood O, Machado M, Lopez MA, Ganesan AP, Wang C, Chakravarthy A, Fenton TR, King EV, Vijayanand P, Ottensmeier CH, Al-Shamkhani A, Savelyeva N, and Thomas GJ
- Subjects
- Animals, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Humans, Immunotherapy, Mice, NADPH Oxidase 4, Reactive Oxygen Species, Cancer-Associated Fibroblasts, Neoplasms
- Abstract
Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8
+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 "normalized" CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/9/1846/F1.large.jpg. See related commentary by Hayward, p. 1799 ., (©2020 American Association for Cancer Research.)- Published
- 2020
- Full Text
- View/download PDF
40. Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure.
- Author
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Palese F, Bonomi E, Nuzzo T, Benussi A, Mellone M, Zianni E, Cisani F, Casamassa A, Alberici A, Scheggia D, Padovani A, Marcello E, Di Luca M, Pittaluga A, Usiello A, Borroni B, and Gardoni F
- Subjects
- Adult, Autoimmunity, Female, Humans, Male, Middle Aged, Autoantibodies, Frontotemporal Dementia etiology, Frontotemporal Dementia immunology, Frontotemporal Dementia physiopathology, Glutamates cerebrospinal fluid, Receptors, AMPA immunology, Synapses physiology, Synaptic Transmission
- Abstract
Despite the great effort of the scientific community in the field, the pathogenesis of frontotemporal dementia (FTD) remains elusive. Recently, a role for autoimmunity and altered glutamatergic neurotransmission in triggering disease onset has been put forward. We reported the presence of autoantibodies recognizing the GluA3 subunit of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in about 25% of FTD cases. In this study, we evaluated the mechanisms involved in anti-GluA3 autoimmunity, through molecular/neurochemical analyses conducted on patients' brain specimens with frontotemporal lobar degeneration-tau neuropathology. We then corroborated these results in vivo in FTD patients with transcranial magnetic stimulation and glutamate, D-serine, and L-serine dosages in the cerebrospinal fluid and serum. We observed that GluA3 autoantibodies affect glutamatergic neurotransmission, decreasing glutamate release and altering GluA3-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor levels. These alterations were accompanied by changes of scaffolding proteins involved in receptor synaptic retention/internalization. The above results were confirmed by transcranial magnetic stimulation, suggesting a significant impairment of indirect measures of glutamatergic neurotransmission in FTD patients compared with controls, with further add-on harmful effect in those FTD patients with anti-GluA3 antibodies. Finally, FTD patients showed a significant increase of glutamate, D-serine, and L-serine levels in the cerebrospinal fluid., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2020
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41. Linking NMDA Receptor Synaptic Retention to Synaptic Plasticity and Cognition.
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Franchini L, Stanic J, Ponzoni L, Mellone M, Carrano N, Musardo S, Zianni E, Olivero G, Marcello E, Pittaluga A, Sala M, Bellone C, Racca C, Di Luca M, and Gardoni F
- Abstract
NMDA receptor (NMDAR) subunit composition plays a pivotal role in synaptic plasticity at excitatory synapses. Still, the mechanisms responsible for the synaptic retention of NMDARs following induction of plasticity need to be fully elucidated. Rabphilin3A (Rph3A) is involved in the stabilization of NMDARs at synapses through the formation of a complex with GluN2A and PSD-95. Here we used different protocols to induce synaptic plasticity in the presence or absence of agents modulating Rph3A function. The use of Forskolin/Rolipram/Picrotoxin cocktail to induce chemical LTP led to synaptic accumulation of Rph3A and formation of synaptic GluN2A/Rph3A complex. Notably, Rph3A silencing or use of peptides interfering with the GluN2A/Rph3A complex blocked LTP induction. Moreover, in vivo disruption of GluN2A/Rph3A complex led to a profound alteration of spatial memory. Overall, our results demonstrate a molecular mechanism needed for NMDAR stabilization at synapses after plasticity induction and to trigger downstream signaling events necessary for cognitive behavior., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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42. Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration.
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Durante V, de Iure A, Loffredo V, Vaikath N, De Risi M, Paciotti S, Quiroga-Varela A, Chiasserini D, Mellone M, Mazzocchetti P, Calabrese V, Campanelli F, Mechelli A, Di Filippo M, Ghiglieri V, Picconi B, El-Agnaf OM, De Leonibus E, Gardoni F, Tozzi A, and Calabresi P
- Subjects
- Animals, Corpus Striatum drug effects, Corpus Striatum pathology, Humans, Long-Term Potentiation drug effects, Long-Term Potentiation physiology, Male, Mice, Mice, Transgenic, Organ Culture Techniques, Protein Subunits antagonists & inhibitors, Protein Subunits metabolism, Rats, Rats, Wistar, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Spatial Memory drug effects, Synapses drug effects, Visual Perception drug effects, alpha-Synuclein administration & dosage, Corpus Striatum metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Spatial Memory physiology, Synapses physiology, Visual Perception physiology, alpha-Synuclein toxicity
- Abstract
Parkinson's disease is a progressive neurodegenerative disorder characterized by altered striatal dopaminergic signalling that leads to motor and cognitive deficits. Parkinson's disease is also characterized by abnormal presence of soluble toxic forms of α-synuclein that, when clustered into Lewy bodies, represents one of the pathological hallmarks of the disease. However, α-synuclein oligomers might also directly affect synaptic transmission and plasticity in Parkinson's disease models. Accordingly, by combining electrophysiological, optogenetic, immunofluorescence, molecular and behavioural analyses, here we report that α-synuclein reduces N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents and impairs corticostriatal long-term potentiation of striatal spiny projection neurons, of both direct (D1-positive) and indirect (putative D2-positive) pathways. Intrastriatal injections of α-synuclein produce deficits in visuospatial learning associated with reduced function of GluN2A NMDA receptor subunit indicating that this protein selectively targets this subunit both in vitro and ex vivo. Interestingly, this effect is observed in spiny projection neurons activated by optical stimulation of either cortical or thalamic glutamatergic afferents. We also found that treatment of striatal slices with antibodies targeting α-synuclein prevents the α-synuclein-induced loss of long-term potentiation and the reduced synaptic localization of GluN2A NMDA receptor subunit suggesting that this strategy might counteract synaptic dysfunction occurring in Parkinson's disease., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
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- 2019
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43. HPV, tumour metabolism and novel target identification in head and neck squamous cell carcinoma.
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Fleming JC, Woo J, Moutasim K, Mellone M, Frampton SJ, Mead A, Ahmed W, Wood O, Robinson H, Ward M, Woelk CH, Ottensmeier CH, King E, Kim D, Blaydes JP, and Thomas GJ
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- Cell Line, Tumor, Gene Expression Regulation, Neoplastic genetics, Glycolysis genetics, Humans, Monocarboxylic Acid Transporters isolation & purification, Monocarboxylic Acid Transporters metabolism, Neoplasm Invasiveness genetics, Neoplasm Invasiveness pathology, Oxidative Phosphorylation, Papillomaviridae genetics, Papillomaviridae metabolism, Papillomavirus Infections diagnostic imaging, Papillomavirus Infections pathology, Papillomavirus Infections virology, Positron-Emission Tomography, Radiation Tolerance, Sequence Analysis, RNA, Squamous Cell Carcinoma of Head and Neck diagnostic imaging, Squamous Cell Carcinoma of Head and Neck pathology, Squamous Cell Carcinoma of Head and Neck virology, Symporters isolation & purification, Symporters metabolism, Monocarboxylic Acid Transporters genetics, Papillomaviridae pathogenicity, Papillomavirus Infections genetics, Squamous Cell Carcinoma of Head and Neck genetics, Symporters genetics
- Abstract
Background: Metabolic changes in tumour cells are used in clinical imaging and may provide potential therapeutic targets. Human papillomavirus (HPV) status is important in classifying head and neck cancers (HNSCC), identifying a distinct clinical phenotype; metabolic differences between these HNSCC subtypes remain poorly understood., Methods: We used RNA sequencing to classify the metabolic expression profiles of HPV
+ve and HPV-ve HNSCC, performed a meta-analysis on FDG-PET imaging characteristics and correlated results with in vitro extracellular flux analysis of HPV-ve and HPV+ve HNSCC cell lines. The monocarboxylic acid transporter-1 (MCT1) was identified as a potential metabolic target and tested in functional assays., Results: Specific metabolic profiles were associated with HPV status, not limited to carbohydrate metabolism. There was dominance of all energy pathways in HPV-negative disease, with elevated expression of genes associated with glycolysis and oxidative phosphorylation. In vitro analysis confirmed comparative increased rates of oxidative phosphorylation and glycolysis in HPV-negative cell lines. PET SUV(max) scores however were unable to reliably differentiate between HPV-positive and HPV-negative tumours. MCT1 expression was significantly increased in HPV-negative tumours, and inhibition suppressed tumour cell invasion, colony formation and promoted radiosensitivity., Conclusion: HPV-positive and negative HNSCC have different metabolic profiles which may have potential therapeutic applications.- Published
- 2019
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44. Author Correction: Authentication and characterisation of a new oesophageal adenocarcinoma cell line: MFD-1.
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Garcia E, Hayden A, Birts C, Britton E, Rogerson C, Bleaney CW, Cowie A, Pickard K, Mellone M, Choh C, Derouet M, Duriez P, Noble F, White MJ, Primrose JN, Strefford JC, Rose-Zerilli M, Thomas GJ, Ang Y, Sharrocks AD, Fitzgerald RC, and Underwood TJ
- Abstract
A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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- 2019
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45. NMDA receptor GluN2D subunit participates to levodopa-induced dyskinesia pathophysiology.
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Mellone M, Zianni E, Stanic J, Campanelli F, Marino G, Ghiglieri V, Longhi A, Thiolat ML, Li Q, Calabresi P, Bezard E, Picconi B, Di Luca M, and Gardoni F
- Subjects
- Animals, Cholinergic Neurons metabolism, Disease Models, Animal, Disks Large Homolog 4 Protein metabolism, Interneurons metabolism, Levodopa administration & dosage, Macaca mulatta, Male, Rats, Sprague-Dawley, Synapses metabolism, Corpus Striatum metabolism, Dyskinesia, Drug-Induced metabolism, Neurons metabolism, Parkinson Disease metabolism, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
In the striatum, specific N-methyl-d-aspartate receptor (NMDAR) subtypes are found in different neuronal cells. Spiny projection neurons (SPNs) are characterized by NMDARs expressing GluN2A and GluN2B subunits, while GluN2D is exclusively detected in striatal cholinergic interneurons (ChIs). In Parkinson's disease (PD), dopamine depletion and prolonged treatment with levodopa (L-DOPA) trigger adaptive changes in the glutamatergic transmission from the cortex to the striatum, also resulting in the aberrant function of striatal NMDARs. While modifications of GluN2A- and GluN2B-NMDARs in SPNs have been extensively documented, only few studies report GluN2D dysfunction in PD and no data are available in L-DOPA-induced dyskinesia (LID). Here we investigate the contribution of a specific NMDAR subtype (GluN2D-NMDAR) to PD and LID, and whether this receptor could represent a candidate for future pharmacological interventions. Our results show that GluN2D synaptic abundance is selectively augmented in the striatum of L-DOPA-treated male parkinsonian rats displaying a dyskinetic phenotype. This event is associated to a dramatic increase in GluN2D binding to the postsynaptic protein scaffold PSD-95. Moreover, immunohistochemistry and electrophysiology experiments reveal that GluN2D-NMDARs are expressed not only by striatal ChIs but also by SPNs in dyskinetic rats. Notably, in vivo treatment with a well-characterized GluN2D antagonist ameliorates the severity of established dyskinesia in L-DOPA-treated animals. Our findings support a role for GluN2D-NMDARs in LID, and they confirm that cell-type and subunit specific modifications of NMDARs underlie the pathophysiology of LID., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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46. Fibrinogen does not relate to cardiovascular or muscle manifestations in COPD: cross-sectional data from the ERICA study.
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Mohan D, Forman JR, Allinder M, McEniery CM, Bolton CE, Cockcroft JR, MacNee W, Fuld J, Marchong M, Gale NS, Fisk M, Nagarajan S, Cheriyan J, Lomas DA, Calverley PMA, Miller BE, Tal-Singer R, Wilkinson IB, and Polkey MI
- Subjects
- Aged, Aorta, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Muscle Contraction, Muscle Weakness blood, Muscle Weakness complications, Prospective Studies, Pulmonary Disease, Chronic Obstructive blood, Pulmonary Disease, Chronic Obstructive complications, Pulse Wave Analysis, Quadriceps Muscle physiopathology, Fibrinogen metabolism, Muscle Weakness physiopathology, Pulmonary Disease, Chronic Obstructive physiopathology, Vascular Stiffness
- Abstract
Cardiovascular and skeletal muscle manifestations constitute important comorbidities in COPD, with systemic inflammation proposed as a common mechanistic link. Fibrinogen has prognostic role in COPD. We aimed to determine whether aortic stiffness and quadriceps weakness are linked in COPD, and whether they are associated with the systemic inflammatory mediator-fibrinogen. Aortic pulse wave velocity (aPWV), quadriceps maximal volitional contraction (QMVC) force and fibrinogen were measured in 729 patients with stable, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II-IV COPD. The cardiovascular and muscular manifestations exist independently (P=0.22, χ
2 ). Fibrinogen was not associated with aPWV or QMVC (P=0.628 and P=0.621, respectively), making inflammation, as measured by plasma fibrinogen, an unlikely common aetiological factor., Competing Interests: Competing interests: MIP has received payment to his institution or himself for advice on skeletal muscle weakness in COPD from GSK, Novartis, AZ, Pfizer, Lilly and Astellas. DM is an employee and shareholder of GSK. JRF, CMM, MM, SN and NSG have no conflict of interest to report. CEB reports grants from Innovate UK (formerly Technology Strategy Board (TSB) UK) during the conduct of the study; advisory board fees from GSK paid to their institution, grants from GSK and grants from MRC/ABPI outside the submitted work. JRC reports grants from TSB/MRC, during the conduct of the study; personal fees from GSK, outside the submitted work. WM received research support from GlaxoSmithKline and Pfizer, and was on advisory committees of Almirall, GlaxoSmithKline, Novartis and Pfizer; he was a speaker for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen and Novartis. JF received speaker fees from GSK. MF acknowledges receipt of an imaging fellowship award from GSK. JRC is employed full-time by Cambridge University Hospitals National Health Service Foundation Trust and is obligated to spend 50% of his time on GSK clinical trial research, representing a significant relationship; however, he receives no other benefits or compensations from GSK. DAL reports grants and personal fees from GSK, and personal fees from Grifols, outside the submitted work. PMAC has advised Boehringer Ingelheim, GSK, AstraZeneca and Takeda on the design and conduct of clinical trials, and has spoken at meetings sponsored by these companies and by Novartis; he has no stock holdings in any pharmaceutical company or connection with the tobacco industry. BEM and RT-S are shareholders and employees of GSK. IBW reports grants from TSB and GSK during the conduct of the study, and grants from GSK outside the submitted work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)- Published
- 2018
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47. Glutamatergic mechanisms in L-DOPA-induced dyskinesia and therapeutic implications.
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Mellone M and Gardoni F
- Subjects
- Animals, Antiparkinson Agents adverse effects, Dyskinesia, Drug-Induced physiopathology, Excitatory Amino Acid Antagonists pharmacology, Humans, Levodopa adverse effects, Neurons drug effects, Neurons metabolism, Receptors, Glutamate drug effects, Dyskinesia, Drug-Induced metabolism, Glutamic Acid metabolism, Receptors, Glutamate metabolism
- Abstract
Overactivation of the glutamatergic synapse leading to maladaptive synaptic plasticity in the basal ganglia is a well-demonstrated process involved in the onset of L-DOPA-induced dyskinesia (LID). Changes in glutamate release are paralleled by compensatory modifications of the expression and/or synaptic localization of both ionotropic and metabotropic glutamate receptors (mGluRs). Accordingly, compounds targeting N-methyl-D-aspartate glutamate receptors (NMDARs) and specific subtypes of metabotropic glutamate receptors (mGluR4 and mGluR5) have been tested both in preclinical and clinical studies. At present, amantadine, a low-affinity non-competitive NMDAR antagonist, represents the only recommended add-on agent with a moderate anti-dyskinetic activity. The present review describes recent advances in basic research, preclinical and early clinical studies in the attempt of identifying innovative strategies for an accurate modulation of both pre- and postsynaptic glutamate receptors to reduce the severity of LID. Even if a complete understanding of LID molecular bases is still lacking, several compounds demonstrated an anti-dyskinetic activity in preclinical and early clinical studies. These results indicate that modulation of the glutamatergic system remains one of the most promising pharmacological strategies in the field.
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- 2018
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48. Corrigendum: A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype.
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Melling GE, Flannery SE, Abidin SA, Clemmens H, Prajapati P, Hinsley EE, Hunt S, Catto JWF, Coletta RD, Mellone M, Thomas GJ, Parkinson EK, Prime SS, Paterson IC, Buttle DJ, and Lambert DW
- Published
- 2018
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49. PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells.
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Georgilis A, Klotz S, Hanley CJ, Herranz N, Weirich B, Morancho B, Leote AC, D'Artista L, Gallage S, Seehawer M, Carroll T, Dharmalingam G, Wee KB, Mellone M, Pombo J, Heide D, Guccione E, Arribas J, Barbosa-Morais NL, Heikenwalder M, Thomas GJ, Zender L, and Gil J
- Subjects
- Alternative Splicing, Animals, Cell Proliferation, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Female, Gene Expression Regulation, Neoplastic, Heterogeneous-Nuclear Ribonucleoproteins genetics, Humans, Inflammation genetics, Inflammation pathology, Inflammation therapy, MCF-7 Cells, Mice, Inbred C57BL, Mice, Transgenic, Neoplasms genetics, Neoplasms pathology, Neoplasms prevention & control, Paracrine Communication, Phenotype, Polypyrimidine Tract-Binding Protein genetics, RNA Interference, Signal Transduction, Tumor Burden, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism, Cell Transformation, Neoplastic metabolism, Cellular Senescence, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Inflammation metabolism, Neoplasms metabolism, Polypyrimidine Tract-Binding Protein metabolism
- Abstract
Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2018
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50. A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype.
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Melling GE, Flannery SE, Abidin SA, Clemmens H, Prajapati P, Hinsley EE, Hunt S, Catto JWF, Coletta RD, Mellone M, Thomas GJ, Parkinson EK, Prime SS, Paterson IC, Buttle DJ, and Lambert DW
- Subjects
- Cell Differentiation physiology, Cell Line, Tumor, Humans, Myofibroblasts metabolism, Phenotype, Signal Transduction physiology, Tumor Microenvironment physiology, Cancer-Associated Fibroblasts metabolism, MicroRNAs metabolism, Mouth Neoplasms metabolism, Transforming Growth Factor beta1 metabolism
- Abstract
The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-β1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-β1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-β signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-β1-induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.
- Published
- 2018
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