44 results on '"Cutillo, L."'
Search Results
2. ADHD Dimension, Childhood trauma and Perceived Stress: an observational study on peripartum women affected by mood and anxiety disorders
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Bilotta, I., primary, Anibaldi, G., additional, Stampatore, L., additional, Concolato, C., additional, Medugno, M., additional, Fattorini, A., additional, Cutillo, L., additional, Bernardi, S., additional, Culicchia, G., additional, Bassi de Toni, A., additional, Del Casale, A., additional, Pompili, M., additional, and Angeletti, G., additional
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- 2023
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3. Network Clustering by Embedding of Attribute-augmented Graphs
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D'Ambra P, De Santis C, Vassilevski P, and Cutillo L
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graph embedding ,spectral clustering ,algebraically smooth vectors ,AMG ,attributed networks ,MathematicsofComputing_DISCRETEMATHEMATICS - Abstract
In this paper we propose a new approach to detect clusters in undirected graphs with attributed vertices. The aim is to group vertices which are similar not only in terms of structural connectivity but also in terms of attribute values. We incorporate structural and attribute similarities between the vertices in an augmented graph by creating additional vertices and edges as proposed in [Cheng et al. 2011; Zhou et al. 2009]. The augmented graph is then embedded in a Euclidean space associated to its Laplacian where a modified K-means algorithm is applied to identify clusters. The modified K-means relies on a vector distance measure where to each original vertex we assign a suitable vector-valued set of coordinates depending on both structural connectivity and attribute similarities, so that each original graph node is thought as representative ofm + 1 nodes of the augmented graph, ifm is the number of vertex attributes. To define the coordinate vectors we employ our recently proposed algorithm based on an adaptive AMG (Algebraic MultiGrid) method, which identifies the coordinate directions in the embedding Euclidean space in terms of algebraically smooth vectors with respect to the augmented graph Laplacian, and thus extending our previous result for graphs without attributes.We demonstrate the effectiveness of our proposed clustering method on a large set of synthetic graphs, where our method identifies dense and very homogeneous clusters also when modular structure is weak and attribute values are perturbed. Results on some real-world attributed graphs confirm the validity of our approach.
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- 2021
4. Localized empirical discriminant analysis
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Cutillo, L. and Amato, U.
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- 2008
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5. Advanced TTT composite materials for aeronautical purposes: Compression after impact (CAI) behaviour
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Scarponi, C., Perillo, A.M., Cutillo, L., and Foglio, C.
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- 2007
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6. Impact of mother's childhood trauma on development of psychopathological dimensions in patients with peripartum mental disorders.
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Bassi de Toni, A., Culicchia, G., Del Casale, A., Tinè, M., Vallerga, A. V., Cutillo, L., Bernardi, S., Bilotta, I., Fattorini, A., D'Alessio, R., De Felici, D., Pompili, M., and Angeletti, G.
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ADVERSE childhood experiences ,CHILD development ,MINNESOTA Multiphasic Personality Inventory ,PERSONALITY ,MENTAL illness ,HYPOMANIA - Abstract
Introduction: Peripartum mental disorders (PPMD) are characterized by heterogeneous psychopathological symptoms related to specific personality traits, which are only taken into account by a few preventive and therapeutic strategies. Traumatic experiences during childhood could predispose to develop those disorders during adulthood, especially in more stressful conditions, such as pregnancy and postpartum. Objectives: Our study aims to evaluate the correlation between mother's childhood trauma and the development of certain psychopathological dimensions during peripartum and which of these dimensions could be indicative of mother's childhood trauma. Methods: The sample included 74 women, recruited from Sant'Andrea Hospital in Rome between 2011 and 2022, diagnosed with a psychiatric disorder during peripartum, according to criteria of DSM-5. All recruited women were administered the Childhood Trauma Questionnaire – Short Form (CTQ-SF) and the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). We performed a linear regression using the total CTQ score as a dependent variable and the MMPI-2 scale's scores as independent variables. Results: The linear regression used showed two significant models, of which the most inclusive explained 60% of the variance (R2 = 0.597), resulting significant (F = 31.141; p < 0.001). This model showed that a greater expression of childhood traumatic aspects was associated with greater expression of Pa (paranoia) (t = 4.04; p < 0.001) and Ma (hypomania) (t = 3.873; p < 0.001) in the clinical scales of the MMPI-2, which were indicative of childhood trauma. Conclusions: Our study shows that paranoiac and hypomanic symptoms in PPMD, assumed by the MMPI-2 scale, are indicative of previous traumatic dimension. Thus, in the presence of a positive history of trauma, clinicians should pay attention especially to these aspects, in order to optimally set both pharmacological and psychotherapeutic treatment. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]
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- 2024
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7. Wavelet density estimation for weighted data
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Cutillo, L., De Feis, I., Nikolaidou, C., Sapatinas, Theofanis, and Sapatinas, Theofanis [0000-0002-6126-4654]
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Statistics and Probability ,Applied Mathematics ,Kernel density estimation ,Weighted distributions ,Estimator ,Density estimation ,Wavelets ,Fourier series ,Multivariate kernel density estimation ,Wavelet ,Variable kernel density estimation ,Mean integrated squared error ,Kernel (statistics) ,Statistics ,Kernel smoother ,Kernel smoothing ,Applied mathematics ,Statistics, Probability and Uncertainty ,Mathematics - Abstract
We consider the estimation of a density function on the basis of a random sample from a weighted distribution. We propose linear and nonlinear wavelet density estimators, and provide their asymptotic formulae for mean integrated squared error. In particular, we derive an analogue of the asymptotic formula of the mean integrated square error in the context of kernel density estimators for weighted data, admitting an expansion with distinct squared bias and variance components. For nonlinear wavelet density estimators, unlike the analogous situation for kernel or linear wavelet density estimators, this asymptotic formula of the mean integrated square error is relatively unaffected by assumptions of continuity, and it is available for densities which are smooth only in a piecewise sense. We illustrate the behavior of the proposed linear and nonlinear wavelet density estimators in finite sample situations both in simulations and on a real-life dataset. Comparisons with a kernel density estimator are also given. © 2013 Elsevier B.V. 146 1 19 Cited By :2
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- 2014
8. Modelling the European Central Bank official rate: a stochastic approach
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Carfora M.F., Cutillo L., and Orlando A.
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- 2011
9. Identify regulatory sites using neighbourhood species
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Angelini C., Cutillo L., De Feis I., Lio' P., and van der Wath R.
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transcription Factors ,variable selection - Abstract
The annotation of transcription binding sites in new sequenced genomes is an important and challenging problem. We have previously shown how a regression model that linearly relates gene expression levels to the matching scores of nucleotide patterns allows us to identify DNA-binding sites from a collection of co-regulated genes and their nearby non-coding DNA sequences. Our methodology uses Bayesian models and stochastic search techniques to select transcription factor binding site candidates. Here we show that this methodology allows us to identify binding sites in nearby species. We present examples of annotation crossing from Schizosaccharomyces pombe to Schizosaccharomyces japonicus. We found that the eng1 motif is also regulating a set of 9 genes in S. japonicus. Our framework may have an effective interest in conveying information in the annotation process of a new species. Finally we discuss a number of statistical and biological issues related to the identification of binding sites through covariates of genes expression and sequences.
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- 2007
10. Materiali Compositi Stitched Avanzati per Impiego Aeronautico: Comportamento a Test di Tipo CAI (Compression After Impact)
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Scarponi, Claudio, Barboni, Renato, Caneva, Claudio, Cutillo, L., and Perillo, A. M.
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Compositi ,Stitched ,CAI-TEST - Published
- 2003
11. Analysis of Privacy in Online Social Networks from the Graph Theory Perspective
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Cutillo, L. A., primary, Molva, R., additional, and Onen, M., additional
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- 2011
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12. Statistical cloud detection from SEVIRI multispectral images
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Amato, U., primary, Antoniadis, A., additional, Cuomo, V., additional, Cutillo, L., additional, Franzese, M., additional, Murino, L., additional, and Serio, C., additional
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- 2008
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13. P0193 SAFETY OF INTRAFAMILIAL LIVING-RELATED LIVER TRANSPLANTATION FOR PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS
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Cutillo, L., primary, Wanty, C., additional, Janssens, M., additional, Reding, R., additional, De Ville de Goyet, J., additional, Otte, J. B., additional, and Sokal, E. M., additional
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- 2004
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14. Epidemiological study on comorbidity of mental disorders and substance-related disorders in Italian Mental Health Care Trusts: Preliminary results | Studio epidemiologico sulla comorbidità tra disturbi mentali e disturbi correlati all'uso di sostanze nei Dipartimenti di Salute Mentale italiani: Risultati preliminari
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Clerici, M., Carrà, G., Segagni Lusignani, G., Sciarini, P., Borrelli, P., Popa, I., Di Giannantonio, M., Montomoli, C., Favaretto, G., Morandin, I., Vincenzo De Leo, Corrivetti, G., Mellado, C., Gesuele, F., Marco, F., Gabrielli, D., Vanetti, M., Marasco, M., Lo Magro, M., Vinci, F., Carbonaro, C., Scicolone, I., Comis, B., Argentino, P., Bazzano, L., Filippone, L., Angelino, J., Guerrieri, R., Sgarlata, G., Mastroianni, L., Bianchin, G., Citron, A., Alacqua, M., Galvano, O., Iannone, V., Pertile, I., Rocco, P., Sabbadin, E., Salce, G., Sanzovo, S., Sartoretto, M., Novello, M., Bearzi, C., Luciano, L., Russo, M. C., Capocasale, F., Panella, D., Piombo, L., Cicco, G., Fasulo, E., Leonetti, G., Chianura, P., Maffei, V., Lonigro, L., Orsi, D., Cramarossa, F., Valente, R., Desiderato, E., Lanave, L., Panaro, V., Carofiglio, A., Scorpiniti, F., Scarone, F., D Urso, N., Tagliavini, G., Sferrazza, M. G., Rizzo, M., Pismataro, P., Pellizer, M., Panetta, B., Mormandi, G., Mori, P., Mari, L., Giroletti, A., Girardi, T., Ferri, S., Dragoni, C., Cittone, L., Cauli, G., Bianchi, I., Alietti, M., Paudice, C., Ariano, M., Buongiglio, G., Coppola, C., Ianuale, N., Mocerino, F., Rivellini, M., Romano, D., Uliveto, A., Ciriello, R., Giamundo, G., Francese, B., Gatti, E., Fagioli, L., Ragazzini, S., Belletti, S., Marni, A., Magnani, G., Sommi, M., Fietta, P., Soavi, G., Nuzzi, A., Tresca, E., Celani, T., Ortano, G., Nugnes, E., Cappellari, L., Zara, M., Bonifaci, G., Carraro, C., Compagno, S., Loschi, S., Meneghetti, L., Riolo, R., Rossi, E., Turella, E., Bontempelli, S., Gatto, A., Padoani, W., Pauro, P., Santucci, M. G., Scalabrin, M., Tosin, C., Pinciara, B., Somenzini, G., Allevi, L., Brambilla, S., Caparrelli, S., Gadaldi, R., Giunta, G., Lanfranconi, M., Orlando, G., Tommesani, P., Zecca, G., Nano, D., Pollastro, F., Feri, C., Moretti, R., Arslanian, A., Valsesia, R., Viglino, R., Campus, M., Maffi, M. M., Giacobone, C., Nicali, E., Risso, F., Marchiaro, L., Costanzo, F., Madaro, A., Ciotta, V., Cinapro, M., Belvisi, G., Rosso, V., Pacilli, A. M., Arduini, L., Palomba, U., Saragò, R., Rabboni, M., Pellegris, M., Pinto, M., Daniele, M. T., Arpea, M. P., Trasatti, G., Caroppo, E., Condemi, G. M., Gori, P., Cutillo, L., D Auria, A., Ferri, E., Fiore, V., Lanza, F., Manna, V., Secchiaroli, L., Tallarida, R., Tombolini, L., Bellini, M., Candotti, S., Di Fiorino, M., Miniati, M., Bani, A., Martinucci, M., Paoli, G., Lorusso, P., Negri, C., Casazza, M., Lizzos, F., Sforzini, A., Bertolotti, L., Papale, L., Aroasio, P. L., Buscaglia, V., Caronna, P., Weiss, G., Marino, R., Simonetti, N., Fenoglio, L., Salvaneschi, A., Taddia, G., Bertuzzi, M., Perazzi, M., Nannini, M., Vaschetto, P., Acerra, A., Ruggiero, F. S., Pirolo, D., Torti, C., Garbini, M., Barontini, S., Pupeschi, L., Meschi, M., Garofalo, A., Paoli, R., Galli, L., Frare, F., Pirfo, E., and Barile, C.
15. Epidemiological study on comorbidity of mental disorders and substance-related disorders in Italian Mental Health Care Trusts: Preliminary results,Studio epidemiologico sulla comorbidità tra disturbi mentali e disturbi correlati all'uso di sostanze nei Dipartimenti di Salute Mentale italiani: Risultati preliminari
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Clerici, M., Carrà, G., Segagni Lusignani, G., Sciarini, P., Borrelli, P., Popa, I., Di Giannantonio, M., Cristina Montomoli, Favaretto, G., Morandin, I., Leo, V., Corrivetti, G., Mellado, C., Gesuele, F., Marco, F., Gabrielli, D., Vanetti, M., Marasco, M., Lo Magro, M., Vinci, F., Carbonaro, C., Scicolone, I., Comis, B., Argentino, P., Bazzano, L., Filippone, L., Angelino, J., Guerrieri, R., Sgarlata, G., Mastroianni, L., Bianchin, G., Citron, A., Alacqua, M., Galvano, O., Iannone, V., Pertile, I., Rocco, P., Sabbadin, E., Salce, G., Sanzovo, S., Sartoretto, M., Novello, M., Bearzi, C., Luciano, L., Russo, M. C., Capocasale, F., Panella, D., Piombo, L., Cicco, G., Fasulo, E., Leonetti, G., Chianura, P., Maffei, V., Lonigro, L., Orsi, D., Cramarossa, F., Valente, R., Desiderato, E., Lanave, L., Panaro, V., Carofiglio, A., Scorpiniti, F., Scarone, F., D Urso, N., Tagliavini, G., Sferrazza, M. G., Rizzo, M., Pismataro, P., Pellizer, M., Panetta, B., Mormandi, G., Mori, P., Mari, L., Giroletti, A., Girardi, T., Ferri, S., Dragoni, C., Cittone, L., Cauli, G., Bianchi, I., Alietti, M., Paudice, C., Ariano, M., Buongiglio, G., Coppola, C., Ianuale, N., Mocerino, F., Rivellini, M., Romano, D., Uliveto, A., Ciriello, R., Giamundo, G., Francese, B., Gatti, E., Fagioli, L., Ragazzini, S., Belletti, S., Marni, A., Magnani, G., Sommi, M., Fietta, P., Soavi, G., Nuzzi, A., Tresca, E., Celani, T., Ortano, G., Nugnes, E., Cappellari, L., Zara, M., Bonifaci, G., Carraro, C., Compagno, S., Loschi, S., Meneghetti, L., Riolo, R., Rossi, E., Turella, E., Bontempelli, S., Gatto, A., Padoani, W., Pauro, P., Santucci, M. G., Scalabrin, M., Tosin, C., Pinciara, B., Somenzini, G., Allevi, L., Brambilla, S., Caparrelli, S., Gadaldi, R., Giunta, G., Lanfranconi, M., Orlando, G., Tommesani, P., Zecca, G., Nano, D., Pollastro, F., Feri, C., Moretti, R., Arslanian, A., Valsesia, R., Viglino, R., Campus, M., Maffi, M. M., Giacobone, C., Nicali, E., Risso, F., Marchiaro, L., Costanzo, F., Madaro, A., Ciotta, V., Cinapro, M., Belvisi, G., Rosso, V., Pacilli, A. M., Arduini, L., Palomba, U., Saragò, R., Rabboni, M., Pellegris, M., Pinto, M., Daniele, M. T., Arpea, M. P., Trasatti, G., Caroppo, E., Condemi, G. M., Gori, P., Cutillo, L., D Auria, A., Ferri, E., Fiore, V., Lanza, F., Manna, V., Secchiaroli, L., Tallarida, R., Tombolini, L., Bellini, M., Candotti, S., Di Fiorino, M., Miniati, M., Bani, A., Martinucci, M., Paoli, G., Lorusso, P., Negri, C., Casazza, M., Lizzos, F., Sforzini, A., Bertolotti, L., Papale, L., Aroasio, P. L., Buscaglia, V., Caronna, P., Weiss, G., Marino, R., Simonetti, N., Fenoglio, L., Salvaneschi, A., Taddia, G., Bertuzzi, M., Perazzi, M., Nannini, M., Vaschetto, P., Acerra, A., Ruggiero, F. S., Pirolo, D., Torti, C., Garbini, M., Barontini, S., Pupeschi, L., Meschi, M., Garofalo, A., Paoli, R., Galli, L., Frare, F., Pirfo, E., and Barile, C.
16. Hypofractionated breast cancer radiotherapy. Helical tomotherapy in supine position or classic 3DConformal radiotherapy in prone position: Which is better?
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Cammarota, F., Giugliano, F. M., Iadanza, L., Cutillo, L., Muto, M., Toledo, D., Vincenzo Ravo, Falivene, S., and Muto, P.
17. Reverse engineering a mouse embryonic stem cell-specific transcriptional network reveals a new modulator of neuronal differentiation
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Simona Iacobacci, gemma flore, Joachim Klose, Elizabeth Illingworth, Luisa Cutillo, Gennaro Gambardella, Mario Lauria, Rossella De Cegli, Lei Mao, Diego di Bernardo, Sandro Banfi, De Cegli, R., Iacobacci, S., Flore, G., Gambardella, G., Mao, L., Cutillo, L., Lauria, M., Klose, J., Illingworth, E., Banfi, S., DI BERNARDO, Diego, De Cegli, R, Iacobacci, S, Flore, G, Gambardella, G, Mao, L, Cutillo, L, Lauria, M, Klose, J, Illingworth, E, Banfi, Sandro, and di Bernardo, D.
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Chromosomal Proteins, Non-Histone ,Cellular differentiation ,Neurogenesis ,Nerve Tissue Proteins ,Biology ,Cell Line ,Mice ,Gene expression ,Protein Interaction Mapping ,Genetics ,Transcriptional regulation ,medicine ,Animals ,Gene Regulatory Networks ,Transgenes ,Embryonic Stem Cells ,Gene Expression Profiling ,Systems Biology ,Brain ,Computational Biology ,Embryonic stem cell ,Cell biology ,Gene expression profiling ,medicine.anatomical_structure ,nervous system ,Neuron differentiation ,Neuroglia ,Transcriptome - Abstract
Gene expression profiles can be used to infer previously unknown transcriptional regulatory interaction among thousands of genes, via systems biology 'reverse engineering' approaches. We 'reverse engineered' an embryonic stem (ES)-specific transcriptional network from 171 gene expression profiles, measured in ES cells, to identify master regulators of gene expression ('hubs'). We discovered that E130012A19Rik (E13), highly expressed in mouse ES cells as compared with differentiated cells, was a central 'hub' of the network. We demonstrated that E13 is a protein-coding gene implicated in regulating the commitment towards the different neuronal subtypes and glia cells. The overexpression and knock-down of E13 in ES cell lines, undergoing differentiation into neurons and glia cells, caused a strong up-regulation of the glutamatergic neurons marker Vglut2 and a strong down-regulation of the GABAergic neurons marker GAD65 and of the radial glia marker Blbp. We confirmed E13 expression in the cerebral cortex of adult mice and during development. By immuno-based affinity purification, we characterized protein partners of E13, involved in the Polycomb complex. Our results suggest a role of E13 in regulating the division between glutamatergic projection neurons and GABAergic interneurons and glia cells possibly by epigenetic-mediated transcriptional regulation.
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- 2013
18. MicroRNA target prediction by expression analysis of host genes
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Marco Sardiello, Santosh Anand, Vincenza Maselli, Sandro Banfi, Raffaella Avellino, Andrea Ballabio, Nicola Meola, Luisa Cutillo, Vincenzo A. Gennarino, Gennarino, Va, Sardiello, M, Avellino, R, Meola, N, Maselli, V, Anand, S, Cutillo, L, Ballabio, A, Banfi, Sandro, Ballabio, Andrea, and Banfi, S.
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Resource ,Microarray ,Sequence analysis ,Biology ,Expression Analysis ,Mirna ,microRNA ,Gene expression ,Genetics ,Humans ,Gene silencing ,Gene ,Genetics (clinical) ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Sequence Analysis, RNA ,Gene Expression Profiling ,Gene expression profiling ,MicroRNAs ,Gene Expression Regulation ,Genes ,Algorithms ,Forecasting ,HeLa Cells - Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that control gene expression by inducing RNA cleavage or translational inhibition. Most human miRNAs are intragenic and are transcribed as part of their hosting transcription units. We hypothesized that the expression profiles of miRNA host genes and of their targets are inversely correlated and devised a novel procedure, HOCTAR (host gene oppositely correlated targets), which ranks predicted miRNA target genes based on their anti-correlated expression behavior relative to their respective miRNA host genes. HOCTAR is the first tool for systematic miRNA target prediction that utilizes the same set of microarray experiments to monitor the expression of both miRNAs (through their host genes) and candidate targets. We applied the procedure to 178 human intragenic miRNAs and found that it performs better than currently available prediction softwares in pinpointing previously validated miRNA targets. The high-scoring HOCTAR predicted targets were enriched in Gene Ontology categories, which were consistent with previously published data, as in the case of miR-106b and miR-93. By means of overexpression and loss-of-function assays, we also demonstrated that HOCTAR is efficient in predicting novel miRNA targets and we identified, by microarray and qRT-PCR procedures, 34 and 28 novel targets for miR-26b and miR-98, respectively. Overall, we believe that the use of HOCTAR significantly reduces the number of candidate miRNA targets to be tested compared to the procedures based solely on target sequence recognition. Finally, our data further confirm that miRNAs have a significant impact on the mRNA levels of most of their targets.
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- 2008
19. Mantra 2.0: An online collaborative resource for drug mode of action and repurposing by network analysis
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Diego Carrella, Francesco Napolitano, Luisa Cutillo, Diego di Bernardo, Rossella Rispoli, Mario Miglietta, Annamaria Carissimo, Francesco Gregoretti, Francesco Sirci, Carrella, D, Napolitano, F, Rispoli, R, Miglietta, M, Carissimo, A, Cutillo, L, Sirci, F, Gregoretti, F, and DI BERNARDO, Diego
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Statistics and Probability ,Drug ,Computer science ,media_common.quotation_subject ,Netwok ,Biochemistry ,mode of action ,World Wide Web ,Mantra ,Transcriptome ,Drug treatment ,Drug Discovery ,Cooperative Behavior ,Drug Repositioning ,Gene Expression Profiling ,Internet ,Software ,Mode of action ,Molecular Biology ,Repurposing ,media_common ,Drug discovery ,Pipeline (software) ,Computer Science Applications ,Computational Mathematics ,Drug repositioning ,ComputingMethodologies_PATTERNRECOGNITION ,Computational Theory and Mathematics ,Drug development ,Molecular targets - Abstract
Summary: Elucidation of molecular targets of a compound [mode of action (MoA)] and its off-targets is a crucial step in drug development. We developed an online collaborative resource (MANTRA 2.0) that supports this process by exploiting similarities between drug-induced transcriptional profiles. Drugs are organized in a network of nodes (drugs) and edges (similarities) highlighting ‘communities’ of drugs sharing a similar MoA. A user can upload gene expression profiles before and after drug treatment in one or multiple cell types. An automated processing pipeline transforms the gene expression profiles into a unique drug ‘node’ embedded in the drug-network. Visual inspection of the neighbouring drugs and communities helps in revealing its MoA and to suggest new applications of known drugs (drug repurposing). MANTRA 2.0 allows storing and sharing user-generated network nodes, thus making MANTRA 2.0 a collaborative ever-growing resource. Availability and implementation: The web tool is freely available for academic use at http://mantra.tigem.it. Contact: dibernardo@tigem.it
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- 2014
20. Evidence of key role of Cdk2 overexpression in pemphigus vulgaris
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Amelia Casamassimi, Raffaele Rossiello, Fernando Gombos, Fiolomena de Nigris, Concetta Schiano, Monica Rienzo, Claudio Napoli, Alessandro Lanza, Felice Femiano, Nicola Cirillo, Luigi Rossiello, Luisa Cutillo, Lanza, Alessandro, Cirillo, N, Rossiello, Raffaele, Rienzo, M, Cutillo, L, Casamassimi, Amelia, de NIGRIS, Filomena, Schiano, C, Rossiello, L, Femiano, Felice, Gombos, F, and Napoli, Claudio
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Keratinocytes ,Small interfering RNA ,acantholysi ,Biology ,Biochemistry ,Adherens junction ,Mice ,Gene expression ,medicine ,Animals ,Humans ,pemphigus vulgari ,RNA, Small Interfering ,Molecular Biology ,roscovitine ,Cells, Cultured ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Mice, Inbred BALB C ,Cdk2-dependent ,Microarray analysis techniques ,Acantholysis ,Pemphigus vulgaris ,Cell Cycle ,Cyclin-Dependent Kinase 2 ,Cell Biology ,Cell cycle ,medicine.disease ,Molecular biology ,Cell biology ,Enzyme Activation ,Disease Models, Animal ,Animals, Newborn ,Gene Expression Regulation ,Pemphigus - Abstract
The pathogenesis of pemphigus vulgaris (PV) is still poorly understood. Autoantibodies present in PV patients can promote detrimental effects by triggering altered transduction of signals, which results in a final acantholysis. To investigate mechanisms involved in PV, cultured keratinocytes were treated with PV serum. PV sera were able to promote the cell cycle progression, inducing the accumulation of cyclin-dependent kinase 2 (Cdk2). Microarray analysis on keratinocytes detected that PV serum induced important changes in genes coding for one and the same proteins with known biological functions involved in PV disease (560 differentially expressed genes were identified). Then, we used two different approaches to investigate the role of Cdk2. First, small interfering RNA depletion of Cdk2 prevented cell-cell detachment induced by PV sera. Second, pharmacological inhibition of Cdk2 activity through roscovitine prevented blister formation and acantholysis in the mouse model of the disease. In vivo PV serum was found to alter multiple different pathways by microarray analysis (1463 differentially expressed genes were identified). Major changes in gene expression induced by roscovitine were studied through comparison of effects of PV serum alone and in association with roscovitine. The most significantly enriched pathways were cell communication, gap junction, focal adhesion, adherens junction, and tight junction. Our data indicate that major Cdk2-dependent multiple gene regulatory events are present in PV. This alteration may influence the evolution of PV and its therapy. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.
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- 2008
21. Coexistence of hereditary spherocytosis (HS) due to band 3 deficiency and beta-thalassaemia trait: partial correction of HS phenotype
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Silverio Perrotta, L Cutillo, Achille Iolascon, L. Pinto, E. Miraglia del Giudice, Bruno Nobili, MIRAGLIA DEL GIUDICE, Emanuele, Perrotta, Silverio, Nobili, Bruno, Pinto, L, Cutillo, L, and Iolascon, A.
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Hemolytic anemia ,Adult ,Male ,medicine.medical_specialty ,Reticulocytosis ,Spherocytosis ,Spherocytosis, Hereditary ,Hereditary spherocytosis ,hemic and lymphatic diseases ,Internal medicine ,Anion Exchange Protein 1, Erythrocyte ,medicine ,Humans ,Spectrin ,Band 3 ,biology ,beta-Thalassemia ,Infant ,Hematology ,Middle Aged ,medicine.disease ,Haemolysis ,Pedigree ,Endocrinology ,Hemoglobinopathy ,Phenotype ,biology.protein ,Female ,medicine.symptom - Abstract
A kindred with hereditary spherocytosis and beta-thalassaemia trait was identified. Detailed studies of the red cell membrane proteins on polyacrylamide gels with sodium dodecyl sulphate (SDS-PAGE) demonstrated the presence of band 3 (anion transporter) deficiency in all HS subjects (20-25% reduction) whereas spectrin content was in the normal range. The molecular defect of beta thalassaemia in this kindred was due to a beta(0) codon 39 (C-T) mutation, as assessed by beta globin gene amplification and ASO-probe hybridization. Seven subjects of this family were studied: two were normal, two had HS alone, two co-inherited HS and beta-thalassaemia trait, and one had beta-thalassaemia trait only. The two subjects with HS alone had a typical clinical form of spherocytosis with anaemia, reticulocytosis and increased red cell osmotic fragility. The two with both HS and beta-thalassaemia trait were not anaemic and showed a small, well-compensated haemolysis. Hence the finding of red cells with abnormalities of both HS and beta-thalassaemia indicates that beta-thalassaemic trait 'silences' HS caused by band 3 deficiency.
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- 1993
22. Disease Rescue and Increased Lifespan in a Model of Cardiomyopathy and Muscular Dystrophy by Combined AAV Treatments
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Alberto Auricchio, Giovanni Di Salvo, Stefania Faraso, Carmen Vitiello, Gerardo Nigro, Raffaele Calabrò, Vincenzo Nigro, Luisa Cutillo, Edoardo Nusco, Nicolina Cristina Sorrentino, Vitiello, C, Faraso, S, Sorrentino, Nc, DI SALVO, Giovanni, Nusco, E, Nigro, Gerardo, Cutillo, L, Calabro', Raffaele, Auricchio, A, and Nigro, Vincenzo
- Subjects
Pathology ,Animals ,Cardiomyopathies ,Cricetinae ,DNA, Complementary ,Dependovirus ,Genetic Therapy ,Genetic Vectors ,Humans ,Muscle, Skeletal ,Muscular Dystrophies ,Myocardium ,Sarcoglycans ,Survival Rate ,Transduction, Genetic ,Cardiomyopathy ,lcsh:Medicine ,Complementary ,Muscular dystrophy ,lcsh:Science ,Neurological Disorders/Movement Disorders ,Multidisciplinary ,Ejection fraction ,Skeletal ,Sarcoglycan ,medicine.anatomical_structure ,muscle disease ,Systemic administration ,Muscle ,Cardiovascular Disorders/Myopathies ,Research Article ,medicine.medical_specialty ,BIO14.6 hamster ,Muscle disorder ,adeno-associated viral (AAV) vectors to transduce heart togethe ,Transduction ,Genetic ,Internal medicine ,medicine ,business.industry ,Genetics and Genomics/Gene Therapy ,lcsh:R ,Skeletal muscle ,DNA ,medicine.disease ,Endocrinology ,Heart failure ,lcsh:Q ,business ,cardiomyopathy - Abstract
Background The BIO14.6 hamster is an excellent animal model for inherited cardiomyopathy, because of its lethal and well-documented course, due to a spontaneous deletion of delta-sarcoglycan gene promoter and first exon. The muscle disease is progressive and average lifespan is 11 months, because heart slowly dilates towards heart failure. Methodology/Principal Findings Based on the ability of adeno-associated viral (AAV) vectors to transduce heart together with skeletal muscle following systemic administration, we delivered human delta-sarcoglycan cDNA into male BIO14.6 hamsters by testing different ages of injection, routes of administration and AAV serotypes. Body-wide restoration of delta-SG expression was associated with functional reconstitution of the sarcoglycan complex and with significant lowering of centralized nuclei and fibrosis in skeletal muscle. Motor ability and cardiac functions were completely rescued. However, BIO14.6 hamsters having less than 70% of fibers recovering sarcoglycan developed cardiomyopathy, even if the total rescued protein was normal. When we used serotype 2/8 in combination with serotype 2/1, lifespan was extended up to 22 months with sustained heart function improvement. Conclusions/Significance Our data support multiple systemic administrations of AAV as a general therapeutic strategy for clinical trials in cardiomyopathies and muscle disorders.
- Published
- 2009
23. IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy.
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Tanner G, Barrow R, Ajaib S, Al-Jabri M, Ahmed N, Pollock S, Finetti M, Rippaus N, Bruns AF, Syed K, Poulter JA, Matthews L, Hughes T, Wilson E, Johnson C, Varn FS, Brüning-Richardson A, Hogg C, Droop A, Gusnanto A, Care MA, Cutillo L, Westhead DR, Short SC, Jenkinson MD, Brodbelt A, Chakrabarty A, Ismail A, Verhaak RGW, and Stead LF
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- Humans, Neoplasm Recurrence, Local genetics, Brain pathology, DNA Methylation, Gene Expression Regulation, Neoplastic, Tumor Microenvironment, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma pathology, Brain Neoplasms genetics, Brain Neoplasms pathology
- Abstract
Background: Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur., Results: Using RNA sequencing data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumors, we identify two responder subtypes based on longitudinal changes in gene expression. In two thirds of patients, a specific subset of genes is upregulated from primary to recurrence (Up responders), and in one third, the same genes are downregulated (Down responders), specifically in neoplastic cells. Characterization of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms that are associated with distinct changes in the tumor microenvironment. In Up responders, recurrent tumors are enriched in quiescent proneural GBM stem cells and differentiated neoplastic cells, with increased interaction with the surrounding normal brain and neurotransmitter signaling, whereas Down responders commonly undergo mesenchymal transition. ChIP-sequencing data from longitudinal GBM tumors suggests that the observed transcriptional reprogramming could be driven by Polycomb-based chromatin remodeling rather than DNA methylation., Conclusions: We show that the responder subtype is cancer-cell intrinsic, recapitulated in in vitro GBM cell models, and influenced by the presence of the tumor microenvironment. Stratifying GBM tumors by responder subtype may lead to more effective treatment., (© 2024. The Author(s).)
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- 2024
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24. Identification of genes with oscillatory expression in glioblastoma: the paradigm of SOX2.
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Fu RZ, Cottrell O, Cutillo L, Rowntree A, Zador Z, Wurdak H, Papalopulu N, and Marinopoulou E
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- Humans, Cell Division, Computational Biology, Gene Expression, SOXB1 Transcription Factors genetics, Glioblastoma genetics, Neural Stem Cells
- Abstract
Quiescence, a reversible state of cell-cycle arrest, is an important state during both normal development and cancer progression. For example, in glioblastoma (GBM) quiescent glioblastoma stem cells (GSCs) play an important role in re-establishing the tumour, leading to relapse. While most studies have focused on identifying differentially expressed genes between proliferative and quiescent cells as potential drivers of this transition, recent studies have shown the importance of protein oscillations in controlling the exit from quiescence of neural stem cells. Here, we have undertaken a genome-wide bioinformatic inference approach to identify genes whose expression oscillates and which may be good candidates for controlling the transition to and from the quiescent cell state in GBM. Our analysis identified, among others, a list of important transcription regulators as potential oscillators, including the stemness gene SOX2, which we verified to oscillate in quiescent GSCs. These findings expand on the way we think about gene regulation and introduce new candidate genes as key regulators of quiescence., (© 2024. The Author(s).)
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- 2024
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25. DRD2, DRD3, and HTR2A Single-Nucleotide Polymorphisms Involvement in High Treatment Resistance to Atypical Antipsychotic Drugs.
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Del Casale A, Simmaco M, Modesti MN, Zocchi C, Arena JF, Bilotta I, Alcibiade A, Sarli G, Cutillo L, Antonelli G, La Spina E, De Luca O, Preissner R, Borro M, Gentile G, Girardi P, and Pompili M
- Abstract
Background: The objective of this study was to investigate the DRD2 rs1800497, rs1799732, rs1801028, DRD3 rs6280, and HTR2A rs6314, rs7997012, and rs6311 single-nucleotide polymorphism (SNP) correlations with resistance to second-generation antipsychotics (SGAs) in a real-world sample of patients with treatment-resistant mental disorders., Methods: We divided 129 participants into a high treatment resistance (HTR) group (current treatment with two SGAs, or clozapine, or classic neuroleptics for a failure of previous SGAs trials) and a low treatment resistance (LTR) group (current treatment with one atypical antipsychotic). We used Next-Generation Sequencing on DNA isolated from peripheral blood samples to analyze the polymorphisms. We performed logistic regression to search for predictors of HTR membership., Results: A diagnosis of schizophrenia significantly predicted the HTR membership compared to other diagnoses. Other predictors were the DRD3 rs6280 C|T (OR = 22.195) and T|T (OR = 18.47) vs. C|C, HTR2A rs7997012 A|G vs. A|A (OR = 6.859) and vs. G|G (OR = 2.879), and DRD2 rs1799732 I|I vs. D|I (OR = 12.079) genotypes., Conclusions: A diagnosis of schizophrenia and the DRD2 rs1799732, DRD3 rs6280, and HTR2A rs7997012 genotypes can predict high treatment resistance to SGAs.
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- 2023
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26. SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis.
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Castelli LM, Cutillo L, Souza CDS, Sanchez-Martinez A, Granata I, Lin YH, Myszczynska MA, Heath PR, Livesey MR, Ning K, Azzouz M, Shaw PJ, Guarracino MR, Whitworth AJ, Ferraiuolo L, Milo M, and Hautbergue GM
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- Amyotrophic Lateral Sclerosis pathology, Animals, Drosophila, Humans, Neurons pathology, Neuroprotection physiology, Active Transport, Cell Nucleus physiology, Amyotrophic Lateral Sclerosis metabolism, C9orf72 Protein metabolism, Neurons metabolism, RNA metabolism, Serine-Arginine Splicing Factors metabolism
- Abstract
Background: Loss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to progressive paralysis and death. Dysregulation of thousands of RNA molecules with roles in multiple cellular pathways hinders the identification of ALS-causing alterations over downstream changes secondary to the neurodegenerative process. How many and which of these pathological gene expression changes require therapeutic normalisation remains a fundamental question., Methods: Here, we investigated genome-wide RNA changes in C9ORF72-ALS patient-derived neurons and Drosophila, as well as upon neuroprotection taking advantage of our gene therapy approach which specifically inhibits the SRSF1-dependent nuclear export of pathological C9ORF72-repeat transcripts. This is a critical study to evaluate (i) the overall safety and efficacy of the partial depletion of SRSF1, a member of a protein family involved itself in gene expression, and (ii) a unique opportunity to identify neuroprotective RNA changes., Results: Our study shows that manipulation of 362 transcripts out of 2257 pathological changes, in addition to inhibiting the nuclear export of repeat transcripts, is sufficient to confer neuroprotection in C9ORF72-ALS patient-derived neurons. In particular, expression of 90 disease-altered transcripts is fully reverted upon neuroprotection leading to the characterisation of a human C9ORF72-ALS disease-modifying gene expression signature. These findings were further investigated in vivo in diseased and neuroprotected Drosophila transcriptomes, highlighting a list of 21 neuroprotective changes conserved with 16 human orthologues in patient-derived neurons. We also functionally validated the high neuroprotective potential of one of these disease-modifying transcripts, demonstrating that inhibition of ALS-upregulated human KCNN1-3 (Drosophila SK) voltage-gated potassium channel orthologs mitigates degeneration of human motor neurons and Drosophila motor deficits., Conclusions: Strikingly, the partial depletion of SRSF1 leads to expression changes in only a small proportion of disease-altered transcripts, indicating that not all RNA alterations need normalization and that the gene therapeutic approach is safe in the above preclinical models as it does not disrupt globally gene expression. The efficacy of this intervention is also validated at genome-wide level with transcripts modulated in the vast majority of biological processes affected in C9ORF72-ALS. Finally, the identification of a characteristic signature with key RNA changes modified in both the disease state and upon neuroprotection also provides potential new therapeutic targets and biomarkers., (© 2021. The Author(s).)
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- 2021
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27. OscoNet: inferring oscillatory gene networks.
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Cutillo L, Boukouvalas A, Marinopoulou E, Papalopulu N, and Rattray M
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- Cell Cycle, Circadian Clocks genetics, Gene Expression Regulation, Human Embryonic Stem Cells metabolism, Humans, Oligonucleotide Array Sequence Analysis, RNA, Messenger genetics, RNA, Messenger metabolism, Statistics, Nonparametric, Time Factors, Gene Regulatory Networks, Software
- Abstract
Background: Oscillatory genes, with periodic expression at the mRNA and/or protein level, have been shown to play a pivotal role in many biological contexts. However, with the exception of the circadian clock and cell cycle, only a few such genes are known. Detecting oscillatory genes from snapshot single-cell experiments is a challenging task due to the lack of time information. Oscope is a recently proposed method to identify co-oscillatory gene pairs using single-cell RNA-seq data. Although promising, the current implementation of Oscope does not provide a principled statistical criterion for selecting oscillatory genes., Results: We improve the optimisation scheme underlying Oscope and provide a well-calibrated non-parametric hypothesis test to select oscillatory genes at a given FDR threshold. We evaluate performance on synthetic data and three real datasets and show that our approach is more sensitive than the original Oscope formulation, discovering larger sets of known oscillators while avoiding the need for less interpretable thresholds. We also describe how our proposed pseudo-time estimation method is more accurate in recovering the true cell order for each gene cluster while requiring substantially less computation time than the extended nearest insertion approach., Conclusions: OscoNet is a robust and versatile approach to detect oscillatory gene networks from snapshot single-cell data addressing many of the limitations of the original Oscope method.
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- 2020
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28. Benchmark and Parameter Sensitivity Analysis of Single-Cell RNA Sequencing Clustering Methods.
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Krzak M, Raykov Y, Boukouvalas A, Cutillo L, and Angelini C
- Abstract
Single-cell RNA-seq (scRNAseq) is a powerful tool to study heterogeneity of cells. Recently, several clustering based methods have been proposed to identify distinct cell populations. These methods are based on different statistical models and usually require to perform several additional steps, such as preprocessing or dimension reduction, before applying the clustering algorithm. Individual steps are often controlled by method-specific parameters, permitting the method to be used in different modes on the same datasets, depending on the user choices. The large number of possibilities that these methods provide can intimidate non-expert users, since the available choices are not always clearly documented. In addition, to date, no large studies have invistigated the role and the impact that these choices can have in different experimental contexts. This work aims to provide new insights into the advantages and drawbacks of scRNAseq clustering methods and describe the ranges of possibilities that are offered to users. In particular, we provide an extensive evaluation of several methods with respect to different modes of usage and parameter settings by applying them to real and simulated datasets that vary in terms of dimensionality, number of cell populations or levels of noise. Remarkably, the results presented here show that great variability in the performance of the models is strongly attributed to the choice of the user-specific parameter settings. We describe several tendencies in the performance attributed to their modes of usage and different types of datasets, and identify which methods are strongly affected by data dimensionality in terms of computational time. Finally, we highlight some open challenges in scRNAseq data clustering, such as those related to the identification of the number of clusters., (Copyright © 2019 Krzak, Raykov, Boukouvalas, Cutillo and Angelini.)
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- 2019
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29. Inclusion of oligonucleotide antimicrobials in biocompatible cationic liposomes: A structural study.
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Mamusa M, Barbero F, Montis C, Cutillo L, Gonzalez-Paredes A, and Berti D
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- Anti-Infective Agents chemistry, Cations chemistry, Oligonucleotides chemistry, Anti-Infective Agents administration & dosage, Liposomes chemistry, Oligonucleotides administration & dosage, Phosphatidylcholines chemistry, Phosphatidylethanolamines chemistry, Tacrine analogs & derivatives
- Abstract
Hypothesis: Transcription factor decoys (TFD) are short oligonucleotides designed to block essential genetic pathways in bacteria and defeat resistant infections. TFD protection in biological fluids and their delivery to the site of infection require formulation in appropriate delivery systems. In this work, we build on a classical phosphatidylcholine/phosphatidylethanolamine (POPC/DOPE) scaffold to design TFD-loaded cationic liposomes by combining the DNA-complexing abilities of a bolaamphiphile, (1,1'-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride (12-bis-THA), with the biocompatible cationic lipid ethyl-phosphatidylcholine (DPePC). The goal is to perform a structural study to determine the impact of the bolaamphiphile and TFD incorporation on the liposome structure, the capacity for TFD encapsulation, and the colloidal stability in saline media and cell culture environments., Experiments: The systems are characterized by means of dynamic light scattering, small-angle X-ray scattering, and ζ-potential measurements, to provide a clear picture of the liposome structure. Circular dichroism (CD) spectroscopy is used to assess the compaction of the oligonucleotide in a psi form, while steady-state fluorescence and fluorescence correlation spectroscopies give insight into the entrapment rate and distribution of the TFD in the liposomes., Findings: We found that the combination of the two cationic species, 12-bis-THA and DPePC, allows encapsulation of 90% of the TFD. Results of CD experiments revealed that the TFD is condensed, therefore likely protected from the lytic action of serum nucleases. Finally, the systems showed colloidal stability in aqueous dispersion with ionic strength comparable to biologically relevant media., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2017
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30. The impact of microRNAs on transcriptional heterogeneity and gene co-expression across single embryonic stem cells.
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Gambardella G, Carissimo A, Chen A, Cutillo L, Nowakowski TJ, di Bernardo D, and Blelloch R
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- Animals, Cell Cycle, Cell Size, Gene Expression Regulation physiology, Mice, Mice, Knockout, MicroRNAs genetics, Principal Component Analysis, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Single-Cell Analysis, Transcription, Genetic, Embryonic Stem Cells metabolism, MicroRNAs metabolism
- Abstract
MicroRNAs act posttranscriptionally to suppress multiple target genes within a cell population. To what extent this multi-target suppression occurs in individual cells and how it impacts transcriptional heterogeneity and gene co-expression remains unknown. Here we used single-cell sequencing combined with introduction of individual microRNAs. miR-294 and let-7c were introduced into otherwise microRNA-deficient Dgcr8 knockout mouse embryonic stem cells. Both microRNAs induce suppression and correlated expression of their respective gene targets. The two microRNAs had opposing effects on transcriptional heterogeneity within the cell population, with let-7c increasing and miR-294 decreasing the heterogeneity between cells. Furthermore, let-7c promotes, whereas miR-294 suppresses, the phasing of cell cycle genes. These results show at the individual cell level how a microRNA simultaneously has impacts on its many targets and how that in turn can influence a population of cells. The findings have important implications in the understanding of how microRNAs influence the co-expression of genes and pathways, and thus ultimately cell fate.
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- 2017
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31. An atlas of gene expression and gene co-regulation in the human retina.
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Pinelli M, Carissimo A, Cutillo L, Lai CH, Mutarelli M, Moretti MN, Singh MV, Karali M, Carrella D, Pizzo M, Russo F, Ferrari S, Ponzin D, Angelini C, Banfi S, and di Bernardo D
- Subjects
- Adult, Aged, Alternative Splicing, Atlases as Topic, Chromosome Mapping, Exons, Eye Proteins metabolism, Female, Gene Expression Profiling, Gene Ontology, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mitochondrial Proteins metabolism, Molecular Sequence Annotation, Protein Isoforms genetics, Protein Isoforms metabolism, Retina cytology, Eye Proteins genetics, Gene Regulatory Networks, Genome, Human, Mitochondrial Proteins genetics, Retina metabolism, Transcriptome
- Abstract
The human retina is a specialized tissue involved in light stimulus transduction. Despite its unique biology, an accurate reference transcriptome is still missing. Here, we performed gene expression analysis (RNA-seq) of 50 retinal samples from non-visually impaired post-mortem donors. We identified novel transcripts with high confidence (Observed Transcriptome (ObsT)) and quantified the expression level of known transcripts (Reference Transcriptome (RefT)). The ObsT included 77 623 transcripts (23 960 genes) covering 137 Mb (35 Mb new transcribed genome). Most of the transcripts (92%) were multi-exonic: 81% with known isoforms, 16% with new isoforms and 3% belonging to new genes. The RefT included 13 792 genes across 94 521 known transcripts. Mitochondrial genes were among the most highly expressed, accounting for about 10% of the reads. Of all the protein-coding genes in Gencode, 65% are expressed in the retina. We exploited inter-individual variability in gene expression to infer a gene co-expression network and to identify genes specifically expressed in photoreceptor cells. We experimentally validated the photoreceptors localization of three genes in human retina that had not been previously reported. RNA-seq data and the gene co-expression network are available online (http://retina.tigem.it)., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2016
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32. Mantra 2.0: an online collaborative resource for drug mode of action and repurposing by network analysis.
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Carrella D, Napolitano F, Rispoli R, Miglietta M, Carissimo A, Cutillo L, Sirci F, Gregoretti F, and Di Bernardo D
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- Cooperative Behavior, Internet, Transcriptome drug effects, Drug Discovery methods, Drug Repositioning methods, Gene Expression Profiling, Software
- Abstract
Summary: Elucidation of molecular targets of a compound [mode of action (MoA)] and its off-targets is a crucial step in drug development. We developed an online collaborative resource (MANTRA 2.0) that supports this process by exploiting similarities between drug-induced transcriptional profiles. Drugs are organized in a network of nodes (drugs) and edges (similarities) highlighting 'communities' of drugs sharing a similar MoA. A user can upload gene expression profiles before and after drug treatment in one or multiple cell types. An automated processing pipeline transforms the gene expression profiles into a unique drug 'node' embedded in the drug-network. Visual inspection of the neighbouring drugs and communities helps in revealing its MoA and to suggest new applications of known drugs (drug repurposing). MANTRA 2.0 allows storing and sharing user-generated network nodes, thus making MANTRA 2.0 a collaborative ever-growing resource., Availability and Implementation: The web tool is freely available for academic use at http://mantra.tigem.it., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2014
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33. Predicted and measured resting energy expenditure in children with spinal muscular atrophy 2.
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Cutillo L, Pizziconi C, Tozzi AE, Verrillo E, Testa MB, and Cutrera R
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- Adolescent, Calorimetry, Indirect methods, Case-Control Studies, Child, Child, Preschool, Female, Humans, Infant, Male, Basal Metabolism, Spinal Muscular Atrophies of Childhood metabolism
- Abstract
We investigated in children with spinal muscular atrophy type 2 the consistency of 4 different equations for predicting resting energy expenditure (REE) compared with measured REE by using indirect calorimetry. In patients with spinal muscular atrophy type 2, measured REE was lower than predicted. We also found a correlation between energy consumption and motor skills., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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34. Hypofractionated breast cancer radiotherapy. Helical tomotherapy in supine position or classic 3D-conformal radiotherapy in prone position: which is better?
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Cammarota F, Giugliano FM, Iadanza L, Cutillo L, Muto M, Toledo D, Ravo V, Falivene S, and Muto P
- Subjects
- Adult, Female, Follow-Up Studies, Humans, Middle Aged, Organs at Risk, Prognosis, Prone Position, Radiometry, Radiotherapy Planning, Computer-Assisted, Retrospective Studies, Supine Position, Breast Neoplasms radiotherapy, Dose Fractionation, Radiation, Imaging, Three-Dimensional, Radiotherapy, Conformal, Radiotherapy, Intensity-Modulated
- Abstract
We propose a comparative dosimetric study of whole-breast hypofractionated radiation therapy using helical tomotherapy (HT) in supine position and 3-D conformal radiotherapy (3D-CRT) in prone position. Twelve patients undergoing breast-conserving therapy were retrospectively selected from October to December 2012. Specific dose-volume parameters were selected for the study. The target coverage was adequate in all patients for both techniques. Significant differences in lung dose distribution were observed: maximum dose (mean value over the 12 plans) was 23.41 Gy in HT plans and 6.65 Gy in 3D-CRT; V20 (i.e. the lung volume receiving 20 Gy) was 0.31% in HT plans and 0.0% in 3D-CRT plans. The mean dose to the heart was 5.57 Gy and 0.93 Gy, respectively. The differences between the two techniques were significant (p<0.05) only for some parameters. We noted better results in the prone position, but with HT, dose constraints were mentioned for the whole set of considered organs.
- Published
- 2014
35. Reverse engineering a mouse embryonic stem cell-specific transcriptional network reveals a new modulator of neuronal differentiation.
- Author
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De Cegli R, Iacobacci S, Flore G, Gambardella G, Mao L, Cutillo L, Lauria M, Klose J, Illingworth E, Banfi S, and di Bernardo D
- Subjects
- Animals, Brain embryology, Brain metabolism, Cell Line, Chromosomal Proteins, Non-Histone, Gene Expression Profiling, Mice, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Protein Interaction Mapping, Systems Biology methods, Transcriptome, Transgenes, Embryonic Stem Cells metabolism, Gene Regulatory Networks, Nerve Tissue Proteins physiology, Neurogenesis genetics
- Abstract
Gene expression profiles can be used to infer previously unknown transcriptional regulatory interaction among thousands of genes, via systems biology 'reverse engineering' approaches. We 'reverse engineered' an embryonic stem (ES)-specific transcriptional network from 171 gene expression profiles, measured in ES cells, to identify master regulators of gene expression ('hubs'). We discovered that E130012A19Rik (E13), highly expressed in mouse ES cells as compared with differentiated cells, was a central 'hub' of the network. We demonstrated that E13 is a protein-coding gene implicated in regulating the commitment towards the different neuronal subtypes and glia cells. The overexpression and knock-down of E13 in ES cell lines, undergoing differentiation into neurons and glia cells, caused a strong up-regulation of the glutamatergic neurons marker Vglut2 and a strong down-regulation of the GABAergic neurons marker GAD65 and of the radial glia marker Blbp. We confirmed E13 expression in the cerebral cortex of adult mice and during development. By immuno-based affinity purification, we characterized protein partners of E13, involved in the Polycomb complex. Our results suggest a role of E13 in regulating the division between glutamatergic projection neurons and GABAergic interneurons and glia cells possibly by epigenetic-mediated transcriptional regulation.
- Published
- 2013
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36. Tbx1 is a negative modulator of Mef2c.
- Author
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Pane LS, Zhang Z, Ferrentino R, Huynh T, Cutillo L, and Baldini A
- Subjects
- Alleles, Animals, Cell Differentiation, Genotype, MEF2 Transcription Factors, Mice, Mice, Transgenic, Myogenic Regulatory Factors metabolism, Phenotype, T-Box Domain Proteins metabolism, Transcriptome, Transfection, Up-Regulation, Myogenic Regulatory Factors genetics, T-Box Domain Proteins genetics
- Abstract
The developmental role of the T-box transcription factor Tbx1 is exquisitely dosage-sensitive. In this study, we performed a microarray-based transcriptome analysis of E9.5 embryo tissues across a previously generated Tbx1 mouse allelic series. This analysis identified several genes whose expression was affected by Tbx1 dosage. Interestingly, we found that the expression of the gene encoding the cardiogenic transcription factor Mef2c was negatively correlated to Tbx1 dosage. In vivo data revealed Mef2c up-regulation in the second heart field (SHF) of Tbx1 null mutant embryos compared with wild-type littermates at E9.5. Conversely, Mef2c expression was decreased in the SHF and in somites of Tbx1 gain-of-function mutants. These results are consistent with the described role of Tbx1 in suppressing cardiac progenitor cell differentiation and indicate also a negative effect of Tbx1 on Mef2c during skeletal muscle differentiation. We show that Tbx1 occupies conserved regulatory regions of the Mef2c locus, suggesting a direct effect on Mef2c transcription. However, we also show that Tbx1 interferes with the Gata4→ Mef2c regulatory pathway. Overall, our study uncovered a target of Tbx1 with critical developmental roles, so highlighting the power of the dosage gradient approach that we used.
- Published
- 2012
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37. Network selection: a method for ranked lists selection.
- Author
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Cutillo L, Carissimo A, and Figini S
- Subjects
- Algorithms, Computational Biology, Data Mining, Models, Statistical
- Abstract
We consider the problem of finding the set of rankings that best represents a given group of orderings on the same collection of elements (preference lists). This problem arises from social choice and voting theory, in which each voter gives a preference on a set of alternatives, and a system outputs a single preference order based on the observed voters' preferences. In this paper, we observe that, if the given set of preference lists is not homogeneous, a unique true underling ranking might not exist. Moreover only the lists that share the highest amount of information should be aggregated, and thus multiple rankings might provide a more feasible solution to the problem. In this light, we propose Network Selection, an algorithm that, given a heterogeneous group of rankings, first discovers the different communities of homogeneous rankings and then combines only the rank orderings belonging to the same community into a single final ordering. Our novel approach is inspired by graph theory; indeed our set of lists can be loosely read as the nodes of a network. As a consequence, only the lists populating the same community in the network would then be aggregated. In order to highlight the strength of our proposal, we show an application both on simulated and on two real datasets, namely a financial and a biological dataset. Experimental results on simulated data show that Network Selection can significantly outperform existing related methods. The other way around, the empirical evidence achieved on real financial data reveals that Network Selection is also able to select the most relevant variables in data mining predictive models, providing a clear superiority in terms of predictive power of the models built. Furthermore, we show the potentiality of our proposal in the bioinformatics field, providing an application to a biological microarray dataset.
- Published
- 2012
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38. MicroRNA target prediction by expression analysis of host genes.
- Author
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Gennarino VA, Sardiello M, Avellino R, Meola N, Maselli V, Anand S, Cutillo L, Ballabio A, and Banfi S
- Subjects
- Algorithms, Forecasting methods, Genes, HeLa Cells, Humans, Sequence Analysis, RNA methods, Gene Expression Profiling methods, Gene Expression Regulation physiology, MicroRNAs genetics, MicroRNAs physiology, Oligonucleotide Array Sequence Analysis methods
- Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that control gene expression by inducing RNA cleavage or translational inhibition. Most human miRNAs are intragenic and are transcribed as part of their hosting transcription units. We hypothesized that the expression profiles of miRNA host genes and of their targets are inversely correlated and devised a novel procedure, HOCTAR (host gene oppositely correlated targets), which ranks predicted miRNA target genes based on their anti-correlated expression behavior relative to their respective miRNA host genes. HOCTAR is the first tool for systematic miRNA target prediction that utilizes the same set of microarray experiments to monitor the expression of both miRNAs (through their host genes) and candidate targets. We applied the procedure to 178 human intragenic miRNAs and found that it performs better than currently available prediction softwares in pinpointing previously validated miRNA targets. The high-scoring HOCTAR predicted targets were enriched in Gene Ontology categories, which were consistent with previously published data, as in the case of miR-106b and miR-93. By means of overexpression and loss-of-function assays, we also demonstrated that HOCTAR is efficient in predicting novel miRNA targets and we identified, by microarray and qRT-PCR procedures, 34 and 28 novel targets for miR-26b and miR-98, respectively. Overall, we believe that the use of HOCTAR significantly reduces the number of candidate miRNA targets to be tested compared to the procedures based solely on target sequence recognition. Finally, our data further confirm that miRNAs have a significant impact on the mRNA levels of most of their targets.
- Published
- 2009
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39. Disease rescue and increased lifespan in a model of cardiomyopathy and muscular dystrophy by combined AAV treatments.
- Author
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Vitiello C, Faraso S, Sorrentino NC, Di Salvo G, Nusco E, Nigro G, Cutillo L, Calabrò R, Auricchio A, and Nigro V
- Subjects
- Animals, Cricetinae, DNA, Complementary administration & dosage, Genetic Vectors, Humans, Muscle, Skeletal metabolism, Myocardium metabolism, Sarcoglycans genetics, Survival Rate, Transduction, Genetic, Cardiomyopathies therapy, Dependovirus genetics, Genetic Therapy methods, Muscular Dystrophies therapy, Sarcoglycans administration & dosage
- Abstract
Background: The BIO14.6 hamster is an excellent animal model for inherited cardiomyopathy, because of its lethal and well-documented course, due to a spontaneous deletion of delta-sarcoglycan gene promoter and first exon. The muscle disease is progressive and average lifespan is 11 months, because heart slowly dilates towards heart failure., Methodology/principal Findings: Based on the ability of adeno-associated viral (AAV) vectors to transduce heart together with skeletal muscle following systemic administration, we delivered human delta-sarcoglycan cDNA into male BIO14.6 hamsters by testing different ages of injection, routes of administration and AAV serotypes. Body-wide restoration of delta-SG expression was associated with functional reconstitution of the sarcoglycan complex and with significant lowering of centralized nuclei and fibrosis in skeletal muscle. Motor ability and cardiac functions were completely rescued. However, BIO14.6 hamsters having less than 70% of fibers recovering sarcoglycan developed cardiomyopathy, even if the total rescued protein was normal. When we used serotype 2/8 in combination with serotype 2/1, lifespan was extended up to 22 months with sustained heart function improvement., Conclusions/significance: Our data support multiple systemic administrations of AAV as a general therapeutic strategy for clinical trials in cardiomyopathies and muscle disorders.
- Published
- 2009
- Full Text
- View/download PDF
40. BATS: a Bayesian user-friendly software for analyzing time series microarray experiments.
- Author
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Angelini C, Cutillo L, De Canditiis D, Mutarelli M, and Pensky M
- Subjects
- Algorithms, Gene Expression, Gene Expression Profiling methods, Humans, Research Design, Sample Size, Time Factors, Bayes Theorem, Oligonucleotide Array Sequence Analysis methods, User-Computer Interface
- Abstract
Background: Gene expression levels in a given cell can be influenced by different factors, namely pharmacological or medical treatments. The response to a given stimulus is usually different for different genes and may depend on time. One of the goals of modern molecular biology is the high-throughput identification of genes associated with a particular treatment or a biological process of interest. From methodological and computational point of view, analyzing high-dimensional time course microarray data requires very specific set of tools which are usually not included in standard software packages. Recently, the authors of this paper developed a fully Bayesian approach which allows one to identify differentially expressed genes in a 'one-sample' time-course microarray experiment, to rank them and to estimate their expression profiles. The method is based on explicit expressions for calculations and, hence, very computationally efficient., Results: The software package BATS (Bayesian Analysis of Time Series) presented here implements the methodology described above. It allows an user to automatically identify and rank differentially expressed genes and to estimate their expression profiles when at least 5-6 time points are available. The package has a user-friendly interface. BATS successfully manages various technical difficulties which arise in time-course microarray experiments, such as a small number of observations, non-uniform sampling intervals and replicated or missing data., Conclusion: BATS is a free user-friendly software for the analysis of both simulated and real microarray time course experiments. The software, the user manual and a brief illustrative example are freely available online at the BATS website: http://www.na.iac.cnr.it/bats.
- Published
- 2008
- Full Text
- View/download PDF
41. Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice.
- Author
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Allocca M, Doria M, Petrillo M, Colella P, Garcia-Hoyos M, Gibbs D, Kim SR, Maguire A, Rex TS, Di Vicino U, Cutillo L, Sparrow JR, Williams DS, Bennett J, and Auricchio A
- Subjects
- ATP-Binding Cassette Transporters genetics, ATP-Binding Cassette Transporters metabolism, Animals, Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Cell Cycle Proteins, Cytoskeletal Proteins, Dyneins genetics, Dyneins metabolism, Electroretinography, Genetic Therapy, Humans, Mice, Mice, Inbred BALB C, Mice, Knockout, Molecular Sequence Data, Myosin VIIa, Myosins genetics, Myosins metabolism, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Dependovirus genetics, Dependovirus metabolism, Gene Transfer Techniques, Genetic Vectors genetics, Genetic Vectors metabolism, Retina cytology, Retina metabolism, Serotyping
- Abstract
Vectors derived from adeno-associated virus (AAV) are promising for human gene therapy, including treatment for retinal blindness. One major limitation of AAVs as vectors is that AAV cargo capacity has been considered to be restricted to 4.7 kb. Here we demonstrate that vectors with an AAV5 capsid (i.e., rAAV2/5) incorporated up to 8.9 kb of genome more efficiently than 6 other serotypes tested, independent of the efficiency of the rAAV2/5 production process. Efficient packaging of the large murine Abca4 and human MYO7A and CEP290 genes, which are mutated in common blinding diseases, was obtained, suggesting that this packaging efficiency is independent of the specific sequence packaged. Expression of proteins of the appropriate size and function was observed following transduction with rAAV2/5 carrying large genes. Intraocular administration of rAAV2/5 encoding ABCA4 resulted in protein localization to rod outer segments and significant and stable morphological and functional improvement of the retina in Abca4(-/-) mice. This use of rAAV2/5 may be a promising therapeutic strategy for recessive Stargardt disease, the most common form of inherited macular degeneration. The possibility of packaging large genes in AAV greatly expands the therapeutic potential of this vector system.
- Published
- 2008
- Full Text
- View/download PDF
42. Evidence of key role of Cdk2 overexpression in pemphigus vulgaris.
- Author
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Lanza A, Cirillo N, Rossiello R, Rienzo M, Cutillo L, Casamassimi A, de Nigris F, Schiano C, Rossiello L, Femiano F, Gombos F, and Napoli C
- Subjects
- Animals, Animals, Newborn, Cell Cycle, Cells, Cultured, Cyclin-Dependent Kinase 2 genetics, Disease Models, Animal, Enzyme Activation, Humans, Keratinocytes enzymology, Mice, Mice, Inbred BALB C, Oligonucleotide Array Sequence Analysis, Pemphigus genetics, Pemphigus pathology, RNA, Small Interfering genetics, Cyclin-Dependent Kinase 2 metabolism, Gene Expression Regulation, Pemphigus enzymology
- Abstract
The pathogenesis of pemphigus vulgaris (PV) is still poorly understood. Autoantibodies present in PV patients can promote detrimental effects by triggering altered transduction of signals, which results in a final acantholysis. To investigate mechanisms involved in PV, cultured keratinocytes were treated with PV serum. PV sera were able to promote the cell cycle progression, inducing the accumulation of cyclin-dependent kinase 2 (Cdk2). Microarray analysis on keratinocytes detected that PV serum induced important changes in genes coding for one and the same proteins with known biological functions involved in PV disease (560 differentially expressed genes were identified). Then, we used two different approaches to investigate the role of Cdk2. First, small interfering RNA depletion of Cdk2 prevented cell-cell detachment induced by PV sera. Second, pharmacological inhibition of Cdk2 activity through roscovitine prevented blister formation and acantholysis in the mouse model of the disease. In vivo PV serum was found to alter multiple different pathways by microarray analysis (1463 differentially expressed genes were identified). Major changes in gene expression induced by roscovitine were studied through comparison of effects of PV serum alone and in association with roscovitine. The most significantly enriched pathways were cell communication, gap junction, focal adhesion, adherens junction, and tight junction. Our data indicate that major Cdk2-dependent multiple gene regulatory events are present in PV. This alteration may influence the evolution of PV and its therapy.
- Published
- 2008
- Full Text
- View/download PDF
43. Safety of living-related liver transplantation for progressive familial intrahepatic cholestasis.
- Author
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Cutillo L, Najimi M, Smets F, Janssen M, Reding R, de Ville de Goyet J, and Sokal EM
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Cholestasis, Intrahepatic genetics, Female, Humans, Liver Function Tests, Living Donors, Male, Middle Aged, Treatment Outcome, Cholestasis, Intrahepatic surgery, Liver Transplantation
- Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a severe cholestatic liver disease of early life often requiring liver transplantation. Organ shortage leads to consider living-related liver transplantation. Because of possible partial metabolic defect in heterozygotes, the use of familial donors might be questionable. We therefore evaluated the safety of this procedure, for both donors and recipients. We compared a series of seven parental-children pairs, having participated in the living related liver transplant program for PFIC between 1994 and 2001, with that of a series of seven parental-children pairs, performed for biliary atresia (BA) during the same period. No primary graft dysfunction was observed. There was no difference in the course of transaminases, gamma-glutamyl transpeptidase and bilirubin levels after transplantation in both donor and recipient series. Thirteen recipients and 14 donors are alive and well 3-10 yr post-surgery. One PFIC recipient died nine months post-orthotopic liver transplantation from sepsis. We conclude that PFIC heterozygote status of the donor does not increase the risk of liver dysfunction in either recipients or donors, with a similar course compared with BA recipients and donors.
- Published
- 2006
- Full Text
- View/download PDF
44. Coexistence of hereditary spherocytosis (HS) due to band 3 deficiency and beta-thalassaemia trait: partial correction of HS phenotype.
- Author
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Miraglia del Giudice E, Perrotta S, Nobili B, Pinto L, Cutillo L, and Iolascon A
- Subjects
- Adult, Female, Humans, Infant, Male, Middle Aged, Pedigree, Phenotype, Spherocytosis, Hereditary blood, Spherocytosis, Hereditary genetics, beta-Thalassemia blood, beta-Thalassemia genetics, Anion Exchange Protein 1, Erythrocyte deficiency, Spherocytosis, Hereditary complications, beta-Thalassemia complications
- Abstract
A kindred with hereditary spherocytosis and beta-thalassaemia trait was identified. Detailed studies of the red cell membrane proteins on polyacrylamide gels with sodium dodecyl sulphate (SDS-PAGE) demonstrated the presence of band 3 (anion transporter) deficiency in all HS subjects (20-25% reduction) whereas spectrin content was in the normal range. The molecular defect of beta thalassaemia in this kindred was due to a beta(0) codon 39 (C-T) mutation, as assessed by beta globin gene amplification and ASO-probe hybridization. Seven subjects of this family were studied: two were normal, two had HS alone, two co-inherited HS and beta-thalassaemia trait, and one had beta-thalassaemia trait only. The two subjects with HS alone had a typical clinical form of spherocytosis with anaemia, reticulocytosis and increased red cell osmotic fragility. The two with both HS and beta-thalassaemia trait were not anaemic and showed a small, well-compensated haemolysis. Hence the finding of red cells with abnormalities of both HS and beta-thalassaemia indicates that beta-thalassaemic trait 'silences' HS caused by band 3 deficiency.
- Published
- 1993
- Full Text
- View/download PDF
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