Author: "Mario Capasso" / Topic: humans - Searchworks@Jio Institute Digital Library Search Results

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91 results on '"Mario Capasso"'

1. Somatic Mutations Enriched in Cis-Regulatory Elements Affect Genes Involved in Embryonic Development and Immune System Response in Neuroblastoma

Author: Vito Alessandro Lasorsa, Annalaura Montella, Sueva Cantalupo, Matilde Tirelli, Carmen de Torres, Sanja Aveic, Gian Paolo Tonini, Achille Iolascon, Mario Capasso, Lasorsa, Vito Alessandro, Montella, Annalaura, Cantalupo, Sueva, Tirelli, Matilde, de Torres, Carmen, Aveic, Sanja, Tonini, Gian Paolo, Iolascon, Achille, and Capasso, Mario
Subjects: DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Neuroblastoma, Cancer Research, Oncology, Immune System, Mutation, Embryonic Development, Humans, Transcription Factors
Abstract: Noncoding cis-regulatory variants have gained interest as cancer drivers, yet progress in understanding their significance is hindered by the numerous challenges and limitations of variant prioritization. To overcome these limitations, we focused on active cis-regulatory elements (aCRE) to design a customized panel for the deep sequencing of 56 neuroblastoma tumor and normal DNA sample pairs. To search for driver mutations, aCREs were defined by reanalysis of H3K27ac chromatin immunoprecipitation sequencing peaks in 25 neuroblastoma cell lines. These regulatory genomic regions were tested for an excess of somatic mutations and assessed for statistical significance using a global approach that accounted for chromatin accessibility and replication timing. Additional validation was provided by whole genome sequence analysis of 151 neuroblastomas. Analysis of HiC data determined the presence of candidate target genes interacting with mutated regions. An excess of somatic mutations in aCREs of diverse genes were identified, including IPO7, HAND2, and ARID3A. CRISPR-Cas9 editing was utilized to assess the functional consequences of mutations in the IPO7-aCRE. Patients with noncoding mutations in aCREs showed inferior overall and event-free survival independent of age at diagnosis, stage, risk stratification, and MYCN status. Expression of aCRE-interacting genes correlated strongly with negative prognostic markers and low survival rates. Moreover, a convergence between the biological functions of aCRE target genes and transcription factors with mutated binding motifs was associated with embryonic development and immune system response. Overall, this strategy enabled the identification of somatic mutations in regulatory elements that collectively promote neuroblastoma tumorigenesis. Significance: Assessment of noncoding cis-regulatory variants and long-range interaction data highlight the combined effect of somatic mutations in regulatory elements in driving neuroblastoma.
Published: 2022
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2. Restoration of the molecular clock is tumor suppressive in neuroblastoma

Author: Nagireddy Putluri, Eveline Barbieri, John Hicks, Karthik reddy kami reddy, Pavel Sumazin, Thomas P. Burris, Simone Di Giacomo, Baharan Fekry, Ling Tao, Bokai Zhu, Mario Capasso, Giorgio Milazzo, Giovanni Perini, Sanjeev A. Vasudevan, Myrthala Moreno-Smith, Kristin Eckel-Mahan, Mahmoud A. Mohammad, Roshan Borkar, Moreno-Smith M., Milazzo G., Tao L., Fekry B., Zhu B., Mohammad M.A., Di Giacomo S., Borkar R., Reddy K.R.K., Capasso M., Vasudevan S.A., Sumazin P., Hicks J., Putluri N., Perini G., Eckel-Mahan K., Burris T.P., Barbieri E., Moreno-Smith, M., Milazzo, G., Tao, L., Fekry, B., Zhu, B., Mohammad, M. A., Di Giacomo, S., Borkar, R., Reddy, K. R. K., Capasso, M., Vasudevan, S. A., Sumazin, P., Hicks, J., Putluri, N., Perini, G., Eckel-Mahan, K., Burris, T. P., and Barbieri, E.
Subjects: 0301 basic medicine, General Physics and Astronomy, Stimulation, Antineoplastic Agent, Mice, Neuroblastoma, 0302 clinical medicine, MYCN, Promoter Regions, Genetic, Cancer, N-Myc Proto-Oncogene Protein, Multidisciplinary, Chemistry, ARNTL Transcription Factors, Nuclear Receptor Subfamily 1, Group F, Member 1, ARNTL Transcription Factor, 030220 oncology & carcinogenesis, Benzamides, Lipogenesis, Human, Agonist, Cell biology, tumor, medicine.drug_class, Cell Survival, Science, Repressor, Antineoplastic Agents, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Benzamide, Cell Line, Tumor, medicine, Oscillation (cell signaling), Animals, Humans, neoplasms, Activator (genetics), Animal, Lipogenesi, Promoter, General Chemistry, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Cancer research, RNA-seq
Abstract: MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORα could serve as a therapeutic strategy for MYCN-amplified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN., MYCN is frequently amplified in neuroblastomas. Here, the authors show that MYCN disrupts the molecular clock by downregulating clock activator RORα and that the reactivation of RORα restores BMAL1 activity, and inhibits lipid metabolism and neuroblastoma growth
Published: 2021

3. Kinome multigenic panel identified novel druggable EPHB4‐V871I somatic variant in high‐risk neuroblastoma

Author: Vito Alessandro Lasorsa, Barbara Eleni Rosato, Francesco Manna, Daniela Formicola, Mario Capasso, Immacolata Andolfo, Achille Iolascon, Andolfo, Immacolata, Lasorsa, Vito A, Manna, Francesco, Rosato, Barbara E, Formicola, Daniela, Iolascon, Achille, and Capasso, Mario
Subjects: 0301 basic medicine, Somatic cell, kinase, Receptor, EphB4, high‐risk neuroblastoma, Biology, 03 medical and health sciences, Neuroblastoma, 0302 clinical medicine, Germline mutation, Aurora kinase, Cell Movement, Cell Line, Tumor, EPHB6, medicine, Anaplastic lymphoma kinase, Humans, Kinome, EPHB4, somatic mutation, Neoplasm Metastasis, high-risk neuroblastoma, Cell Proliferation, Neovascularization, Pathologic, Kinase, drug, Cell Biology, Original Articles, personalized medicine, medicine.disease, 030104 developmental biology, kinases, 030220 oncology & carcinogenesis, Mutation, Cancer research, Molecular Medicine, Original Article, Protein Kinases, Signal Transduction
Abstract: Neuroblastoma (NB) is the most common extracranial neoplasm in children. The overall outcome for high‐risk NB patients is still unacceptable, therefore, it is critical to deeply understand molecular mechanisms associated with NB, which in turn can be utilized for developing drugs towards the treatment of NB. Protein kinases (TKs) play an essential role in the regulation of cell survival and proliferation. Different kinases, such as anaplastic lymphoma kinase (ALK), Aurora kinase, RET receptor tyrosine kinase, are potential therapeutic targets in various cancers, including NB. We analysed a cohort of 45 high‐risk NB patients and 9 NB cell lines by a targeted—(t)NGS custom gene panel (genes codifying for the kinase domains of 90 TKs). We identified somatic variants in four TK genes (ALK, EPHB4, LMTK3 and EPHB6) in NB patients and we functionally characterized an interesting somatic variant, V871I, in EPHB4 gene. EPHB4 plays a crucial role in cardiovascular development and regulates vascularization in cancer‐promoting angiogenesis, tumour growth and metastasis. Several EPHB4 mutations have previously been identified in solid and haematological tumour specimens but EPHB4 mutations were not described until now in NB. Interestingly, a re‐analysis of public CGH‐array showed that the EPHB4 gain is associated with advanced diseases in NB. We further demonstrated that higher EPHB4 expression is correlated to stage 4 of NB and with poor overall survival. Additionally, we also revealed that the EPHB4‐V871I accounts for increased proliferation, migration and invasion properties in two NB cell lines by acting on VEGF, c‐RAF and CDK4 target genes and by increasing the phosphorylation of ERK1‐2 pathway. The use of two EPHB4 inhibitors, JI‐101 and NVP‐BHG712, was able to rescue the phenotype driven by the variant. Our study suggested that EPHB4 is a promising therapeutic target in high‐risk NB.
Published: 2020

4. Methylome Analysis in Nonfunctioning and GH-Secreting Pituitary Adenomas

Author: Giuseppe Giuffrida, Valeria D’Argenio, Francesco Ferraù, Vito Alessandro Lasorsa, Francesca Polito, Federica Aliquò, Marta Ragonese, Oana Ruxandra Cotta, Ylenia Alessi, Rosaria Oteri, Federica Di Maggio, Alessio Asmundo, Petronilla Daniela Romeo, Federica Spagnolo, Lucio Pastore, Filippo Flavio Angileri, Mario Capasso, Salvatore Cannavò, M’Hammed Aguennouz, Giuffrida, G., D'Argenio, V., Ferrau, F., Lasorsa, V. A., Polito, F., Aliquo, F., Ragonese, M., Cotta, O. R., Alessi, Y., Oteri, R., Di Maggio, F., Asmundo, A., Romeo, P. D., Spagnolo, F., Pastore, L., Angileri, F. F., Capasso, M., Cannavo, S., and Aguennouz, M.
Subjects: Adenoma, Epigenome, NFPA, pituitary tumors, Pituitary Gland, Endocrinology, Diabetes and Metabolism, Humans, pituitary adenoma, Pituitary Neoplasms, methylation, GH-OMA, Growth Hormone-Secreting Pituitary Adenoma
Abstract: Pituitary adenomas (PAs), usually benign lesions, can sometimes present with “aggressive” features (rapid growth, local invasiveness, scarce response to conventional treatments). Despite the fact that a few genetic alterations have been associated to this clinical behavior, the role of epigenetic modifications, mainly methylation and miRNAs activity, is now opening new frontiers in this field. We evaluated the methylation profile of 21 PA (11 GH-omas, 10 nonfunctioning tumors—NFPAs) samples from TNS surgery and 5 normal pituitaries, collected at our neurosurgery between 2015 and 2017. DNA was extracted and sequenced, selecting 184,841 target regions. Moreover, methylation profiles were correlated with demographic, radiological, and clinicopathological features. NFPAs showed higher methylation levels vs. GH-omas, with 178 differentially methylated regions (DMRs) mainly consisting of noncoding and intronic sequences, and mostly localized in the open sea regions. We also found three hypermethylated genes (C7orf50, GNG7, and BAHCC1) involved in tumorigenesis processes and potentially influencing pituitary tumor pathophysiology. Among the clinicopathological features, only the maximum diameter resulted significantly higher in NFPAs. Our data provide further evidence of the complex epigenetic background of pituitary tumors. In line with the current literature, we confirmed a significant prevalence of hypermethylation in NFPAs vs. GH-omas, whose pathophysiological consequence is yet to be defined.
Published: 2022
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5. An explainable model of host genetic interactions linked to COVID-19 severity

Author: Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi, Francesco GEN-COVID Multicenter Study: Francesca Mari, Sergio, Daga, Elisa, Benetti, Mirella, Bruttini, Maria, Palmieri, Susanna, Croci, Sara, Amitrano, Ilaria, Meloni, Elisa, Frullanti, Gabriella, Doddato, Mirjam, Lista, Giada, Beligni, Floriana, Valentino, Kristina, Zguro, Rossella, Tita, Annarita, Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca, Ariani, Laura Di Sarno, Francesca, Montagnani, Mario, Tumbarello, Ilaria, Rancan, Massimiliano, Fabbiani, Barbara, Rossetti, Laura, Bergantini, Miriana, D'Alessandro, Paolo, Cameli, David, Bennett, Federico, Anedda, Simona, Marcantonio, Sabino, Scolletta, Federico, Franchi, Maria Antonietta Mazzei, Susanna, Guerrini, Edoardo, Conticini, Luca, Cantarini, Bruno, Frediani, Danilo, Tacconi, Chiara Spertilli Raffaelli, Marco, Feri, Alice, Donati, Raffaele, Scala, Luca, Guidelli, Genni, Spargi, Marta, Corridi, Cesira, Nencioni, Leonardo, Croci, Gian Piero Caldarelli, Davide, Romani, Paolo, Piacentini, Maria, Bandini, Elena, Desanctis, Silvia, Cappelli, Anna, Canaccini, Agnese, Verzuri, Valentina, Anemoli, Manola, Pisani, Agostino, Ognibene, Alessandro, Pancrazzi, Maria, Lorubbio, Massimo, Vaghi, Antonella D'Arminio Monforte, Federica Gaia Miraglia, Raffaele, Bruno, Marco, Vecchia, Massimo, Girardis, Sophie, Venturelli, Stefano, Busani, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Arianna, Emiliozzi, Stefano, Rusconi, Matteo, Siano, Arianna, Gabrieli, Agostino, Riva, Daniela, Francisci, Elisabetta, Schiaroli, Francesco, Paciosi, Andrea, Tommasi, Umberto, Zuccon, Lucia, Vietri, Pier Giorgio Scotton, Francesca, Andretta, Sandro, Panese, Stefano, Baratti, Renzo, Scaggiante, Francesca, Gatti, Saverio Giuseppe Parisi, Francesco, Castelli, Eugenia, Quiros-Roldan, Melania Degli Antoni, Isabella, Zanella, Matteo Della Monica, Carmelo, Piscopo, Mario, Capasso, Roberta, Russo, Immacolata, Andolfo, Achille, Iolascon, Giuseppe, Fiorentino, Massimo, Carella, Marco, Castori, Filippo, Aucella, Pamela, Raggi, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Alessandra, Guarnaccia, Serafina, Valente, Oreste De Vivo, Elena, Bargagli, Marco, Mandalà, Alessia, Giorli, Lorenzo, Salerni, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Gianluca, Lacerenza, Domenico, A Coviello, Cristina, Mussini, Enrico, Martinelli, Luisa, Tavecchia, Mary Ann Belli, Lia, Crotti, Gianfranco, Parati, Maurizio, Sanarico, Filippo, Biscarini, Alessandra, Stella, Marco, Rizzi, Franco, Maggiolo, Diego, Ripamonti, Claudia, Suardi, Tiziana, Bachetti, Maria Teresa La Rovere, Simona, Sarzi-Braga, Maurizio, Bussotti, Katia, Capitani, Simona, Dei, Sabrina, Ravaglia, Rosangela, Artuso, Elena, Andreucci, Giulia, Gori, Angelica, Pagliazzi, Erika, Fiorentini, Antonio, Perrella, Francesco, Bianchi, Paola, Bergomi, Emanuele, Catena, Riccardo, Colombo, Sauro, Luchi, Giovanna, Morelli, Paola, Petrocelli, Sarah, Iacopini, Sara, Modica, Silvia, Baroni, Francesco Vladimiro Segala, Francesco, Menichetti, Marco, Falcone, Giusy, Tiseo, Chiara, Barbieri, Tommaso, Matucci, Grassi, Davide, Ferri, Claudio, Marinangeli, Franco, Brancati, Francesco, Antonella, Vincenti, Valentina, Borgo, Lombardi, Stefania, Mirco, Lenzi, Massimo Antonio Di Pietro, Francesca, Vichi, Benedetta, Romanin, Letizia, Attala, Cecilia, Costa, Andrea, Gabbuti, Roberto, Menè, Marta, Colaneri, Patrizia, Casprini, Giuseppe, Merla, Gabriella Maria Squeo, Marcello, Maffezzoni, Stefania, Mantovani, Mario, U Mondelli, Serena, Ludovisi, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, nbsp, Multicenter Study, GEN-COVID, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi, Francesco, Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, and Ludovisi, S
Subjects: Genetics, Coronavirus disease 2019 (COVID-19), Host (biology), COVID-19, Medicine (miscellaneous), Settore BIO/11 - Biologia Molecolare, Biology, Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA, Whole Exome Sequencing, General Biochemistry, Genetics and Molecular Biology, machine learning, Phenotype, Exome Sequencing, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, General Agricultural and Biological Sciences, COVID, Human
Abstract: We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with training of multiple supervised classifiers, to predict severity on the basis of screened features. Feature importance analysis from tree-based models allowed to identify a handful of 16 variants with highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with good accuracy (ACC=81.88%; ROC_AUC=96%; MCC=61.55%). Principal Component Analysis (PCA) and clustering of patients on important variants orthogonally identified two groups of individuals with a higher fraction of severe cases. Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response, such as JAK-STAT, Cytokine, Interleukin, and C-type lectin receptor signaling. It also identified additional processes cross-talking with immune pathways, such as GPCR signalling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, confirming their link with COVID-19 severity outcome. Taken together, our analysis suggests that curated genetic information can be effectively integrated along with other patient clinical covariates to forecast COVID-19 disease severity and dissect the underlying host genetic mechanisms for personalized medicine treatments.
Published: 2022
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6. Characteristics and survival of patients with primary biliary cholangitis and hepatocellular carcinoma

Author: Edoardo G. Giannini, Giulia Pieri, Sara Labanca, Maria Corina Plaz Torres, Antonio Gasbarrini, Elisabetta Biasini, Claudia Campani, Nora Cazzagon, Francesco Giuseppe Foschi, Andrea Mega, Alberto Masotto, Giovanni Raimondo, Gian Ludovico Rapaccini, Rodolfo Sacco, Eugenio Caturelli, Maria Guarino, Francesco Tovoli, Gianpaolo Vidili, Maurizia Rossana Brunetto, Gerardo Nardone, Gianluca Svegliati-Baroni, Donatella Magalotti, Francesco Azzaroli, Giuseppe Cabibbo, Maria Di Marco, Angelo Sangiovanni, Franco Trevisani, Maurizio Biselli, Paolo Caraceni, Annagiulia Gramenzi, Francesca Benevento, Alessandro Granito, Luca Muratori, Fabio Piscaglia, Federica Bertellini, Fabio Farinati, Giorgio Palano, Filippo Pelizzaro, Barbara Penzo, Elisa Pinto, Gloria Allegrini, Calogero Cammà, Ciro Celsa, Paolo Giuffrida, Caterina Stornello, Mauro Grova, Carmelo Marco Giacchetto, Gabriele Rancatore, Maria Vittoria Grassini, Valentina Adotti, Stefano Gitto, Fabio Marra, Martina Rosi, Vittoria Bevilacqua, Alberto Borghi, Andrea Casadei Gardini, Fabio Conti, Lucia Napoli, Marco Domenicali, Maria Teresa Migliano, Nicoletta de Matthaeis, Francesca Romana Ponziani, Andrea Olivani, Gabriele Missale, Valentina Cossiga, Mario Capasso, Filomena Morisco, Ester Marina Cela, Antonio Facciorusso, Valentina Lauria, Giorgia Ghittoni, Giorgio Pelecca, Fabrizio Chegai, Fabio Coratella, Mariano Ortenzi, Serena Dell'Isola, Maria Stella Franzè, Carlo Saitta, Assunta Sauchella, Elton Dajti, Federico Ravaioli, Filippo Oliveri, Gabriele Ricco, Veronica Romagnoli, Alessandro Inno, Fabiana Marchetti, Pietro Coccoli, Antonio Malerba, Alberta Cappelli, Rita Golfieri, Cristina Mosconi, Matteo Renzulli, Giannini, Edoardo G, Pieri, Giulia, Labanca, Sara, Plaz Torres, Maria Corina, Gasbarrini, Antonio, Biasini, Elisabetta, Campani, Claudia, Cazzagon, Nora, Foschi, Francesco Giuseppe, Mega, Andrea, Masotto, Alberto, Raimondo, Giovanni, Rapaccini, Gian Ludovico, Sacco, Rodolfo, Caturelli, Eugenio, Guarino, Maria, Tovoli, Francesco, Vidili, Gianpaolo, Brunetto, Maurizia Rossana, Nardone, Gerardo, Svegliati-Baroni, Gianluca, Magalotti, Donatella, Azzaroli, Francesco, Cabibbo, Giuseppe, Di Marco, Maria, Sangiovanni, Angelo, Trevisani, Franco, Giannini, E. G., Pieri, G., Labanca, S., Plaz Torres, M. C., Gasbarrini, A., Biasini, E., Campani, C., Cazzagon, N., Foschi, F. G., Mega, A., Masotto, A., Raimondo, G., Rapaccini, G. L., Sacco, R., Caturelli, E., Guarino, M., Tovoli, F., Vidili, G., Brunetto, M. R., Nardone, G., Svegliati-Baroni, G., Magalotti, D., Azzaroli, F., Cabibbo, G., Di Marco, M., Sangiovanni, A., Trevisani, F., Biselli, M., Caraceni, P., Gramenzi, A., Benevento, F., Granito, A., Muratori, L., Piscaglia, F., Bertellini, F., Farinati, F., Palano, G., Pelizzaro, F., Penzo, B., Pinto, E., Allegrini, G., Camma, C., Celsa, C., Giuffrida, P., Stornello, C., Grova, M., Giacchetto, C. M., Rancatore, G., Grassini, M. V., Adotti, V., Gitto, S., Marra, F., Rosi, M., Bevilacqua, V., Borghi, A., Gardini, A. C., Conti, F., Napoli, L., Domenicali, M., Migliano, M. T., de Matthaeis, N., Ponziani, F. R., Olivani, A., Missale, G., Cossiga, V., Capasso, M., Morisco, F., Cela, E. M., Facciorusso, A., Lauria, V., Ghittoni, G., Pelecca, G., Chegai, F., Coratella, F., Ortenzi, M., Dell'Isola, S., Franze, M. S., Saitta, C., Sauchella, A., Dajti, E., Ravaioli, F., Oliveri, F., Ricco, G., Romagnoli, V., Inno, A., Marchetti, F., Coccoli, P., Malerba, A., Cappelli, A., Golfieri, R., Mosconi, C., and Renzulli, M.
Subjects: Male, Carcinoma, Hepatocellular, Cholestatic liver disease, Outcome, Surveillance, Survival, Treatment, Hepatology, Prognosi, Liver Cirrhosis, Biliary, Risk Factor, Settore MED/12 - GASTROENTEROLOGIA, Liver Neoplasms, Gastroenterology, Prognosis, Risk Factors, Humans, Female, Human, Aged
Abstract: Background: Comprehensive and contemporary data pertaining large populations of patients with Primary Biliary Cholangitis (PBC) and hepatocellular carcinoma (HCC) are missing. Aim: To describe main characteristics and outcome of PBC patients with HCC diagnosed in the new millennium. Methods: Analysing the Italian Liver Cancer registry we identified 80 PBC patients with HCC diagnosed after the year 2000, and described their clinical characteristics, access to treatment and survival. Results: Median age of patients was 71 years and 50.0% were males. Cirrhosis was present in 86.3% of patients, being well-compensated in 58.0%. Median HCC diameter was smaller in patients under surveillance (2.6vs 4.0cm, P=0.007). Curative treatment, feasible in 50.0% of patients, was associated with improved survival compared to palliative and supportive care (42vs 33vs 6 months, P
Published: 2022

7. Genetic Analysis in African American Children Supports Ancestry-Specific Neuroblastoma Susceptibility

Author: Alessandro Testori, Zalman Vaksman, Sharon J. Diskin, Hakon Hakonarson, Mario Capasso, Achille Iolascon, John M. Maris, Marcella Devoto, Testori, A., Vaksman, Z., Diskin, S. J., Hakonarson, H., Capasso, M., Iolascon, A., Maris, J. M., and Devoto, M.
Subjects: Genotype, Epidemiology, genetic risk, Polymorphism, Single Nucleotide, Article, Black or African American, neuroblastoma, Oncology, Humans, Genetic Predisposition to Disease, neuroblastoma, African American, genetic risk, Child, African American, Human, Genome-Wide Association Study
Abstract: Background: Neuroblastoma is rarer in African American (AA) children compared with American children of European descent. AA children affected with neuroblastoma, however, more frequently develop the high-risk form of the disease. Methods: We have genotyped an AA cohort of 629 neuroblastoma cases (254 high-risk) and 2,990 controls to investigate genetic susceptibility to neuroblastoma in AAs. Results: We confirmed the known neuroblastoma susceptibility gene BARD1 at genome-wide significance in the subset of high-risk cases. We also estimated local admixture across the autosomal genome in the AA cases and controls and detected a signal at 4q31.22 where cases show an increase in European ancestry. A region at 17p13.1 showed increased African ancestry in the subgroup of high-risk cases with respect to intermediate- and low-risk cases. Using results from our published European American (EA) genome-wide association study (GWAS), we found that a polygenic score that included all independent SNPs showed a highly significant association (P value = 1.8 × 10−73) and explained 19% of disease risk variance in an independent EA cohort. In contrast, the best fit polygenic score (P value = 3.2 × 10−11) in AAs included only 22 independent SNPs with association P value < 2.75 × 10−6 in the EA GWAS, and explained 2% of neuroblastoma risk variance. The significance of the polygenic score dropped rapidly with inclusion of additional SNPs. Conclusions: These findings suggest that several common variants contribute to risk of neuroblastoma in an ancestry-specific fashion. Impact: This work supports the need for GWAS to be performed in populations of all races and ethnicities.
Published: 2022

8. Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation of OBFC1

Author: Massimiliano Scalvenzi, Alessandro Testori, Michiel Vermeulen, Annalaura Montella, Nicola Zambrano, Marijke P. Baltissen, Vito Alessandro Lasorsa, Marianna Avitabile, Kevin M. Brown, Sueva Cantalupo, Flora Cimmino, Antonella Cardinale, Mai Xu, Mark M. Iles, Achille Iolascon, Paola Ghiorzo, Fabrizio Ayala, Ferdinando Bonfiglio, Mariangela Succoio, Matthew Law, Daniela Formicola, Matteo Esposito, Mario Capasso, Cardinale, Antonella, Cantalupo, Sueva, Lasorsa, Vito Alessandro, Montella, Annalaura, Cimmino, Flora, Succoio, Mariangela, Vermeulen, Michiel, Baltissen, Marijke P, Esposito, Matteo, Avitabile, Marianna, Formicola, Daniela, Testori, Alessandro, Bonfiglio, Ferdinando, Ghiorzo, Paola, Scalvenzi, Massimiliano, Ayla, Fabrizio, Zambrano, Nicola, Iles, Mark M, Xu, Mai, Law, Matthew H, Brown, Kevin M, Iolascon, Achille, and Capasso, Mario
Subjects: Genetics, Skin Neoplasms, Single-nucleotide polymorphism, Locus (genetics), General Medicine, Biology, Polymorphism, Single Nucleotide, Minor allele frequency, Humans, Genetic Predisposition to Disease, General Article, Allele, Enhancer, Gene, Transcription factor, Molecular Biology, Melanoma, Genetics (clinical), Epigenomics
Abstract: The 10q24.33 locus is known to be associated with susceptibility to cutaneous malignant melanoma (CMM), but the mechanisms underlying this association have been not extensively investigated. We carried out an integrative genomic analysis of 10q24.33 using epigenomic annotations and in vitro reporter gene assays to identify regulatory variants. We found two putative functional single nucleotide polymorphisms (SNPs) in an enhancer and in the promoter of OBFC1, respectively, in neural crest and CMM cells, one, rs2995264, altering enhancer activity. The minor allele G of rs2995264 correlated with lower OBFC1 expression in 470 CMM tumors and was confirmed to increase the CMM risk in a cohort of 484 CMM cases and 1801 controls of Italian origin. Hi-C and chromosome conformation capture (3C) experiments showed the interaction between the enhancer-SNP region and the promoter of OBFC1 and an isogenic model characterized by CRISPR-Cas9 deletion of the enhancer-SNP region confirmed the potential regulatory effect of rs2995264 on OBFC1 transcription. Moreover, the presence of G-rs2995264 risk allele reduced the binding affinity of the transcription factor MEOX2. Biologic investigations showed significant cell viability upon depletion of OBFC1, specifically in CMM cells that were homozygous for the protective allele. Clinically, high levels of OBFC1 expression associated with histologically favorable CMM tumors. Finally, preliminary results suggested the potential effect of decreased OBFC1 expression on telomerase activity in tumorigenic conditions. Our results support the hypothesis that reduced expression of OBFC1 gene through functional heritable DNA variation can contribute to malignant transformation of normal melanocytes.
Published: 2022

9. A New Butyrate Releaser Exerts a Protective Action against SARS-CoV-2 Infection in Human Intestine

Author: Lorella Paparo, Maria Antonia Maglio, Maddalena Cortese, Cristina Bruno, Mario Capasso, Erika Punzo, Veronica Ferrucci, Vito Alessandro Lasorsa, Maurizio Viscardi, Giovanna Fusco, Pellegrino Cerino, Alessia Romano, Riccardo Troncone, Massimo Zollo, Paparo, L., Maglio, M. A., Cortese, M., Bruno, C., Capasso, M., Punzo, E., Ferrucci, V., Lasorsa, V. A., Viscardi, M., Fusco, G., Cerino, P., Romano, A., Troncone, R., and Zollo, M.
Subjects: Male, Pharmaceutical Science, Organic chemistry, Gene Expression, Antiviral Agents, COVID-19, viral infection, transmembrane protease serine 2, angiotensin-converting enzyme-2, intestinal models, Analytical Chemistry, QD241-441, Drug Discovery, Humans, Physical and Theoretical Chemistry, SARS-CoV-2, Intestinal model, Transmembrane protease serine 2, COVID-19 Drug Treatment, Intestines, Butyrates, Enterocytes, Gene Expression Regulation, Chemistry (miscellaneous), Viral infection, Molecular Medicine, Angiotensin-converting enzyme-2, Caco-2 Cells
Abstract: Butyrate is a major gut microbiome metabolite that regulates several defense mechanisms against infectious diseases. Alterations in the gut microbiome, leading to reduced butyrate production, have been reported in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A new butyrate releaser, useful for all the known applications of butyrate, presenting physiochemical characteristics suitable for easy oral administration, (N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), has been recently developed. We investigated the protective action of FBA against SARS-CoV-2 infection in the human small intestine and enterocytes. Relevant aspects of SARS-CoV-2 infection were assessed: infectivity, host functional receptor angiotensin-converting enzyme-2 (ACE2), transmembrane protease serine 2 (TMPRSS2), neuropilin-1 (NRP1), pro-inflammatory cytokines expression, genes involved in the antiviral response and the activation of Nf-kB nuclear factor (erythroid-derived 2-like) 2 (Nfr2) pathways. We found that FBA positively modulates the crucial aspects of the infection in small intestinal biopsies and human enterocytes, reducing the expression of ACE2, TMPRSS2 and NRP1, pro-inflammatory cytokines interleukin (IL)-15, monocyte chemoattractant protein-1 (MCP-1) and TNF-α, and regulating several genes involved in antiviral pathways. FBA was also able to reduce the number of SARS-CoV-2-infected cells, and ACE2, TMPRSS2 and NRP1 expression. Lastly, through the inhibition of Nf-kB and the up-regulation of Nfr2, it was also able to reduce the expression of pro-inflammatory cytokines IL-15, MCP-1 and TNF-α in human enterocytes. The new butyrate releaser, FBA, exerts a preventive action against SARS-CoV-2 infection. It could be considered as an innovative strategy to limit COVID-19.
Published: 2022

10. Osteogenesis Imperfecta/Ehlers–Danlos Overlap Syndrome and Neuroblastoma—Case Report and Review of Literature

Author: Letteria Anna Morabito, Anna Elsa Maria Allegri, Anna Paola Capra, Mario Capasso, Valeria Capra, Alberto Garaventa, Mohamad Maghnie, Silvana Briuglia, and Malgorzata Gabriela Wasniewska
Subjects: Heterozygote, genotype/phenotype correlation, Ehlers–Danlos syndrome, osteogenesis imperfecta, osteogenesis imperfecta/Ehlers–Danlos overlap syndrome, Collagen Type I, short stature, Neuroblastoma, Genetics, neuroblastoma, Collagen Type I, alpha 1 Chain, Female, Humans, Ehlers-Danlos Syndrome, Osteogenesis Imperfecta, alpha 1 Chain, Genetics (clinical)
Abstract: Osteogenesis imperfecta/Ehlers–Danlos (OI/EDS) overlap syndrome is a recently described disorder of connective tissue, characterized by mutation of COL1A1 (17q21.33) or COL1A2 (7q21.3) genes, that are involved in α-1 and α-2 chains of type 1 collagen synthesis. The clinical spectrum of this new clinical entity is broad: patients could present a mixed phenotype that includes features of both osteogenesis imperfecta (bone fragility, long bone fractures, blue sclerae, short stature) and Ehlers–Danlos syndrome (joint hyperextensibility, soft and hyperextensible skin, abnormal wound healing, easy bruising, vascular fragility). We reported the case of a young Caucasian girl with severe short stature and a previous history of neuroblastoma, who displayed the compound phenotype of OI/EDS. Next generation sequencing was applied to the proband and her parent genome. Our patient presented a de novo heterozygous COL1A1 variant (c.3235G>A, p.Gly1079Ser), whose presence might be indicative of diagnosis of OI/EDS overlap syndrome. We also hypothesize that the association with the previous history of neuroblastoma could be influenced by the presence of COL1A1 mutation, whose role has been already described in the behavior and progression of some cancers.
Published: 2022

11. Durability of Humoral Immune Responses to SARS-CoV-2 in Citizens of Ariano Irpino (Campania, Italy): A Longitudinal Observational Study With an 11.5-Month Follow-Up

Author: Annachiara Coppola, Carlo Buonerba, Davide Cardinale, Gabriella Lo Conte, Donato Sansone, Giuseppe Rofrano, Sabato De Vita, Maria Morgante, Maria Triassi, Luigi Atripaldi, Gianfranco Brambilla, Rocco Sabatino, Andrea Pierri, Daniela Pacella, Antonio Pizzolante, Biancamaria Pierri, Veronica Ferrucci, Massimo Zollo, Mario Capasso, Silvia Stringhini, Paolo Antonio Ascierto, Sante Roperto, Pellegrino Cerino, Coppola, A., Buonerba, C., Cardinale, D., Lo Conte, G., Sansone, D., Rofrano, G., De Vita, S., Morgante, M., Triassi, M., Atripaldi, L., Brambilla, G., Sabatino, R., Pierri, A., Pacella, D., Pizzolante, A., Pierri, B., Ferrucci, V., Zollo, M., Capasso, M., Stringhini, S., Ascierto, P. A., Roperto, S., and Cerino, P.
Subjects: Adult, seroprevalence, SARS-CoV-2, screening, Seroepidemiologic Studie, Public Health, Environmental and Occupational Health, COVID-19, antibody response, Middle Aged, Follow-Up Studie, Immunity, Humoral, Seroepidemiologic Studies, Humans, Female, Public Health, immunoassay, Public aspects of medicine, RA1-1270, Human, Follow-Up Studies, Original Research
Abstract: As of November 17, 2021, SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2), the causative agent of COVID-19 (COronaVIrus Disease 19), has infected ~250 million people worldwide, causing around five million deaths. Titers of anti-SARS-CoV-2 neutralizing antibodies were relatively stable for at least 9 months in a population-based study conducted in Wuhan, China, both in symptomatic and in asymptomatic individuals. In the mass screening campaign conducted in the town of Ariano Irpino (Avellino, Italy) in May, 2020, 5.7% (95% CI: 5.3-6-1) of the 13,444 asymptomatic citizens screened were positive for anti-nucleocapsid antibodies against SARS-CoV-2. Among these, 422 citizens were re-tested for anti SARS-CoV-2 antibodies in January, 2021 and/or in April, 2021 and enrolled in this longitudinal observational study. Median (interquartile range) age of the study cohort was 46 years (29–59), with 47 (11.1%) participants of minor age, while 217 (51.4%) participants were females. There was no evidence of re-infection in any of the subjects included. Presence of anti-nuclear antibodies antibodies (Elecysis, Roche) was reported in 95.7 and 93.7% of evaluable participants in January and April, 2021. Multiple logistic regression analysis used to explore associations between age, sex and seroprevalence showed that adults vs. minors had significantly lower odds of having anti-S1 antibodies (Biorad) both in January, 2021 and in April, 2021. Our findings showed that antibodies remained detectable at least 11.5 months after infection in >90% of never symptomatic cases. Further investigation is required to establish duration of immunity against SARS-CoV-2.
Published: 2021
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12. Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

Author: Fallerini, Chiara, Picchiotti, Nicola, Baldassarri, Margherita, Zguro, Kristina, Daga, Sergio, Fava, Francesca, Benetti, Elisa, Amitrano, Sara, Bruttini, Mirella, Palmieri, Maria, Croci, Susanna, Lista, Mirjam, Beligni, Giada, Valentino, Floriana, Meloni, Ilaria, Tanfoni, Marco, Minnai, Francesca, Colombo, Francesca, Cabri, Enrico, Fratelli, Maddalena, Gabbi, Chiara, Mantovani, Stefania, Frullanti, Elisa, Gori, Marco, Crawley, Francis P, Butler-Laporte, Guillaume, Richards, Brent, Zeberg, Hugo, Lipcsey, Miklos, Hultström, Michael, Ludwig, Kerstin U, Schulte, Eva C, Pairo-Castineira, Erola, Baillie, John Kenneth, Schmidt, Axel, Frithiof, Robert, Mari, Francesca, Renieri, Alessandra, Furini, Simone Simone Furini, Francesca, Montagnani, Mario, Tumbarello, Ilaria, Rancan, Massimiliano, Fabbiani, Barbara, Rossetti, Laura, Bergantini, Miriana, D'Alessandro, Paolo, Cameli, David, Bennett, Federico, Anedda, Simona, Marcantonio, Sabino, Scolletta, Federico, Franchi, Maria Antonietta Mazzei, Susanna, Guerrini, Edoardo, Conticini, Luca, Cantarini, Bruno, Frediani, Danilo, Tacconi, Chiara Spertilli Raffaelli, Marco, Feri, Alice, Donati, Raffaele, Scala, Luca, Guidelli, Genni, Spargi, Marta, Corridi, Cesira, Nencioni, Leonardo, Croci, Gian Piero Caldarelli, Maurizio, Spagnesi, Davide, Romani, Paolo, Piacentini, Maria, Bandini, Elena, Desanctis, Silvia, Cappelli, Anna, Canaccini, Agnese, Verzuri, Valentina, Anemoli, Manola, Pisani, Agostino, Ognibene, Alessandro, Pancrazzi, Maria, Lorubbio, Massimo, Vaghi, Antonella, D 'Arminio Monforte, Federica Gaia Miraglia, Mario, U Mondelli, Massimo, Girardis, Sophie, Venturelli, Stefano, Busani, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Arianna, Emiliozzi, Stefano, Rusconi, Matteo, Siano, Arianna, Gabrieli, Agostino, Riva, Daniela, Francisci, Elisabetta, Schiaroli, Francesco, Paciosi, Andrea, Tommasi, Pier Giorgio Scotton, Francesca, Andretta, Sandro, Panese, Stefano, Baratti, Renzo, Scaggiante, Francesca, Gatti, Saverio Giuseppe Parisi, Francesco, Castelli, Eugenia, Quiros-Roldan, Melania Degli Antoni, Isabella, Zanella, Matteo Della Monica, Carmelo, Piscopo, Mario, Capasso, Roberta, Russo, Immacolata, Andolfo, Achille, Iolascon, Giuseppe, Fiorentino, Massimo, Carella, Marco, Castori, Filippo, Aucella, Pamela, Raggi, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Alessandra, Guarnaccia, Serafina, Valente, Oreste De Vivo, Gabriella, Doddato, Rossella, Tita, Annarita, Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Valentina, Perticaroli, Francesca, Ariani, Miriam Lucia Carriero, Laura Di Sarno, Diana, Alaverdian, Elena, Bargagli, Marco, Mandalà, Alessia, Giorli, Lorenzo, Salerni, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Leonardo Gianluca Lacerenza, Domenico, A Coviello, Cristina, Mussini, Enrico, Martinelli, Sandro, Mancarella, Luisa, Tavecchia, Mary Ann Belli, Lia, Crotti, Gianfranco, Parati, Maurizio, Sanarico, Francesco, Raimondi, Filippo, Biscarini, Alessandra, Stella, Marco, Rizzi, Franco, Maggiolo, Diego, Ripamonti, Claudia, Suardi, Tiziana, Bachetti, Maria Teresa La Rovere, Simona, Sarzi-Braga, Maurizio, Bussotti, Katia, Capitani, Simona, Dei, Sabrina, Ravaglia, Rosangela, Artuso, Elena, Andreucci, Giulia, Gori, Angelica, Pagliazzi, Erika, Fiorentini, Antonio, Perrella, Francesco, Bianchi, Paola, Bergomi, Emanuele, Catena, Riccardo, Colombo, Sauro, Luchi, Giovanna, Morelli, Paola, Petrocelli, Sarah, Iacopini, Sara, Modica, Silvia, Baroni, Francesco Vladimiro Segala, Francesco, Menichetti, Marco, Falcone, Giusy, Tiseo, Chiara, Barbieri, Tommaso, Matucci, Grassi, Davide, Ferri, Claudio, Marinangeli, Franco, Brancati, Francesco, Antonella, Vincenti, Valentina, Borgo, Lombardi, Stefania, Mirco, Lenzi, Massimo Antonio Di Pietro, Francesca, Vichi, Benedetta, Romanin, Letizia, Attala, Cecilia, Costa, Andrea, Gabbuti, Menè, Roberto, Umberto, Zuccon, Lucia, Vietri, Stefano, Ceri, Pietro, Pinoli, Patrizia, Casprini, Giuseppe, Merla, Gabriella Maria Squeo, Marcello, Maffezzoni, Raffaele, Bruno, Marco, Vecchia, Marta, Colaneri, Serena, Ludovisi, Yanara, Marincevic-Zuniga, Jessica, Nordlund, Tomas, Luther, Anders, Larsson, Katja Hanslin Anna Gradin, Sarah, Galien, Sara Bulow Anderberg, Jacob, Rosén, Sten, Rubertsson, Hugo, Zeberg, Robert, Frithiof, Miklós, Lipcsey, Michael, Hultström, Sara Clohisey Peter Horby, Johnny, Millar, Julian, Knight, Hugh, Montgomery, David, Maslove, Lowell, Ling, Alistair, Nichol, Charlotte, Summers, Tim, Walsh, Charles, Hinds, Malcolm, G Semple, Peter J, M Openshaw, Manu, Shankar-Hari, Antonia, Ho, Danny, Mcauley, Chris, Ponting, Kathy, Rowan, J Kenneth Baillie, Fiona, Griffiths, Wilna, Oosthuyzen, Jen, Meikle, Paul, Finernan, James, Furniss, Ellie, Mcmaster, Andy, Law, Sara, Clohisey, Trevor, Paterson, Tony, Wackett, Ruth, Armstrong, Lee, Murphy, Angie, Fawkes, Richard, Clark, Audrey, Coutts, Lorna, Donnelly, Tammy, Gilchrist, Katarzyna, Hafezi, Louise, Macgillivray, Alan, Maclean, Sarah, Mccafferty, Kirstie, Morrice, Jane, Weaver, Ceilia, Boz, Ailsa, Golightly, Mari, Ward, Hanning, Mal, Helen, Szoor-McElhinney, Adam, Brown, Ross, Hendry, Andrew, Stenhouse, Louise, Cullum, Dawn, Law, Sarah, Law, Rachel, Law, Max Head Fourman, Maaike, Swets, Nicky, Day, Filip, Taneski, Esther, Duncan, Marie, Zechner, Nicholas, Parkinson, Erola, Pairo-Castineira, Lucija, Klaric, Andrew, D Bretherick, Konrad, Rawlik, Dorota, Pasko, Susan, Walker, Nick, Parkinson, Clark, D Russell, Anne, Richmond, Elvina, Gountouna, David, Harrison, Wang, Bo, Yang, Wu, Alison, Meynert, Athanasios, Kousathanas, Loukas, Moutsianas, Zhijian, Yang, Ranran, Zhai, Chenqing, Zheng, Graeme, Grimes, Jonathan, Millar, Barbara, Shih, Jian, Yang, Xia, Shen, Chris, P Ponting, Albert, Tenesa, Andrew, Law, Veronique, Vitart, James, F Wilson, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthorpe, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Shankar-Hari, M, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, O Jones, T, Whitton, C, Marotti, M, Arbane, G, Bonner, S, Hugill, K, Reid, J, Welters, I, Waugh, V, Williams, K, Shaw, D, J Fernandez Roman, M Lopez Martinez, Johnson, E, Waite, A, Johnson, B, Hamilton, O, Mulla, S, Mcphail, M, Smith, J, K Baillie, J, Barclay, L, Hope, D, Mcculloch, C, Mcquillan, L, Clark, S, Singleton, J, Priestley, K, Rea, N, Callaghan, M, Campbell, R, Andrew, G, Marshall, L, Mckechnie, S, Hutton, P, Bashyal, A, Davidson, N, Summers, C, Polgarova, P, Stroud, K, Pathan, N, Elston, K, Agrawal, S, Battle, C, Newey, L, Rees, T, Harford, R, Brinkworth, E, Williams, M, Murphy, C, White, I, Croft, M, Bandla, N, Gellamucho, M, Tomlinson, J, Turner, H, Davies, M, Quinn, A, Hussain, I, Thompson, C, Parker, H, Bradley, R, Griffiths, R, Scriven, J, Gill, J, Puxty, A, Cathcart, S, Salutous, D, Turner, L, Duffy, K, Puxty, K, Joseph, A, Herdman-Grant, R, Simms, R, Swain, A, Naranjo, A, Crowe, R, Sollesta, K, Loveridge, A, Baptista, D, Morino, E, Davey, M, Golden, D, Jones, J, J Moreno Cuesta, Haldeos, A, Bakthavatsalam, D, Vincent, R, Elhassan, M, Xavier, K, Ganesan, A, Purohit, D, Abdelrazik, M, Morgan, J, Akeroyd, L, Bano, S, Warren, D, Bromley, M, Sellick, K, Gurr, L, Wilkinson, B, Nagarajan, V, Szedlak, P, Cupitt, J, Stoddard, E, Benham, L, Preston, S, Slawson, N, Bradshaw, Z, Brown, J, Caswell, M, Smelling, Bamford, P, Faulkner, M, Cawley, K, Jeffrey, H, London, E, Sainsbury, H, Nagra, I, Nasir, F, Dunmore, Ce, Jones, R, Abraheem, A, Al-Moasseb, M, Girach, R, Brantwood, C, Alexander, P, Bradley-Potts, J, Allen, S, Felton, T, Manna, S, Farnell-Ward, S, Leaver, S, Queiroz, J, Maccacari, E, Dawson, D, C Castro Delgado, R Pepermans Saluzzio, Ezeobu, O, Ding, L, Sicat, C, Kanu, R, Durrant, G, Texeira, J, Harrison, A, Samakomva, T, Willis, H, Hopkins, B, Thrasyvoulou, L, Jackson, M, Zaki, A, Tibke, C, Bennett, S, Woodyatt, W, Kent, A, Goodwin, E, Brandwood, C, Clark, R, Smith, L, Rooney, K, Thomson, N, Rodden, N, Hughes, E, Mcglynn, D, Clark, C, Clark, P, Abel, L, Sundaram, R, Gemmell, L, Brett, M, Hornsby, J, Macgoey, P, Price, R, Digby, B, O'Neil, P, Mcconnell, P, Henderson, P, Henderson, S, Sim, M, Kennedy-Hay, S, Mcparland, C, Rooney, L, Baxter, N, Pogson, D, Rose, S, Daly, Z, Brimfield, L, K Phull, M, Hussain, M, Pogreban, T, Rosaroso, L, E Salciute, L Grauslyte, Brealey, D, Wraith, E, Maccallum, N, Bercades, G, Hass, I, Smyth, D, Reyes, A, Martir, G, D Clement, I, Webster, K, Hays, C, Gulati, A, Hodgson, L, Margarson, M, Gomez, R, Baird, Y, Thirlwall, Y, Folkes, L, Butler, A, Meadows, E, Moore, S, Raynard, D, Fox, H, Riddles, L, King, K, Kimber, S, Hobden, G, Mccarthy, A, Cannons, V, Balagosa, I, Chadbourn, I, Gardner, A, Horner, D, Mclaughlanv, D, Charles, B, Proudfoot, N, Marsden, T, L Mc Morrow, Blackledge, B, Pendlebury, J, Harvey, A, Apetri, E, Basikolo, C, Catlow, L, Doonan, R, Knowles, K, Lee, S, Lomas, D, Lyons, C, Perez, J, Poulaka, M, Slaughter, M, Slevin, K, Thomas, V, Walker, D, Harris, J, Drummond, A, Tully, R, Dearden, J, Philbin, J, Munt, S, Rishton, C, O'Connor, G, Mulcahy, M, Dobson, E, Cuttler, J, Edward, M, Rose, A, Sloan, B, Buckley, S, Brooke, H, Smithson, E, Charlesworth, R, Sandu, R, Thirumaran, M, Wagstaff, V, J Cebrian Suarez, Kaliappan, A, Vertue, M, Nicholson, A, Riches, J, Solesbury, A, Kittridge, L, Forsey, M, Maloney, G, Cole, J, Davies, R, Hill, H, Thomas, E, Williams, A, Duffin, D, Player, B, Radhakrishnan, J, Gibson, S, Lyle, A, Mcneela, F, Patel, B, Gummadi, M, Sloane, G, Dormand, N, Salmi, S, Farzad, Z, Cristiano, D, Liyanage, K, Thwaites, V, Varghese, M, Meredith, M, Mills, G, Willson, J, Harrington, K, Lenagh, B, Cawthron, K, Masuko, S, Raithatha, A, Bauchmuller, K, Ahmad, N, Barker, J, Jackson, Y, Kibutu, F, Bird, S, Watson, G, Martin, J, Bevan, E, C Wrey Brown, Trodd, D, English, K, Bell, G, Wilcox, L, Katary, A, Gopal, S, Lake, V, Harris, N, Metherell, S, Radford, E, Moore, F, Bancroft, H, Daglish, J, Sangombe, M, Carmody, M, Rhodes, J, Bellamy, M, Garg, A, Kuravi, A, Virgilio, E, Ranga, P, Butler, J, Botfield, L, Dexter, C, Fletcher, J, Shanmugasundaram, P, Hambrook, G, Burn, I, Manso, K, Thornton, D, Tebbutt, J, Penn, R, Hulme, J, Hussain, S, Maqsood, Z, Joseph, S, Colley, J, Hayes, A, Ahmed, C, Haque, R, Clamp, S, Kumar, R, Purewal, M, Baines, B, Frise, M, Jacques, N, Coles, H, Caterson, J, S Gurung Rai, Brunton, M, Tilney, E, Keating, L, Walden, A, Antcliffe, D, Gordon, A, Templeton, M, Rojo, R, Banach, D, S Sousa Arias, Fernandez, Z, Coghlan, P, Williams, D, Jardine, C, Bewley, J, Sweet, K, Grimmer, L, Johnson, R, Garland, Z, Gumbrill, B, Phillips, C, L Ortiz-Ruiz de Gordoa, Peasgood, E, Tridente, A, K Shuker, S Greer, Lynch, C, Pothecary, C, Roche, L, Deacon, B, Turner, K, Singh, J, G Sera Howe, Paul, P, Gill, M, Wynter, I, Ratnam, V, Shelton, S, Naisbitt, J, Melville, J, Baruah, R, Morrison, S, Mcgregor, A, Parris, V, Mpelembue, M, Srikaran, S, Dennis, C, Sukha, A, Verlande, M, Holding, K, Riches, K, Downes, C, Swan, C, Rostron, A, Roy, A, Woods, L, Cornell, S, Wakinshaw, F, Creagh-Brown, B, Blackman, H, Salberg, A, Smith, E, Donlon, S, Mtuwa, S, Michalak-Glinska, N, Stone, S, Beazley, C, Pristopan, V, Nikitas, N, Lankester, L, Wells, C, S Raj, A, Fletcher, K, Khade, R, Tsinaslanidis, G, Mcmahon, M, Fowler, S, Coventry, T, Stewart, R, Wren, L, Mwaura, E, Mew, L, Scaletta, D, Williams, F, Inweregbu, K, Lancaster, N, Cunningham, M, Daniels, A, Harrison, L, Hope, S, Jones, S, Crew, A, Wray, G, Matthews, J, Crawley, R, Carter, J, Birkinshaw, I, Ingham, J, Scott, Z, Howard, K, Joy, R, Roche, S, Clark, M, Purvis, S, Morrison, A, Strachan, D, Clements, S, Black, K, Parmar, C, Altabaibeh, A, Simpson, K, Mostoles, L, Gilbert, K, L, Ma, Alvaro, A, Thomas, M, Faulkner, B, Worner, R, Hayes, K, Gendall, E, Blakemore, H, Borislavova, B, Goff, E, Vuylsteke, A, Mwaura, L, Zamikula, J, Garner, L, Mitchell, A, Mepham, S, Cagova, L, Fofano, A, Holcombe, H, Praman, K, Szakmany, T, E Heron, A, Cherian, S, Cutler, S, Roynon-Reed, A, Randell, G, Convery, K, K Stammers, D Fottrell-Gould, Hudig, L, Keshet-Price, J, Peters, M, O'Neill, L, Ray, S, Belfield, H, Mchugh, T, Jones, G, Akinkugbe, O, Tomas, A, Abaleke, E, Beech, E, Meghari, H, Yussuf, S, Bamford, A, Hairsine, B, Dooks, E, Farquhar, F, Packham, S, Bates, H, Armstrong, L, Kaye, C, Allan, A, Medhora, J, Liew, J, Botello, A, Anderson, F, Cusack, R, Golding, H, Prager, K, Williams, T, Leggett, S, Golder, K, Male, M, Jones, O, Criste, K, Marani, M, Anumakonda, V, Amin, V, Karthik, K, Kausar, R, Anastasescu, E, Reid, K, Jacqui, M, Hormis, A, Walker, R, Duncan, T, Uriel, A, Ustianowski, A, T-Michael, H, Bruce, M, Connolly, K, Smith, K, Partridge, R, Griffin, D, Mcdonald, M, Muchenje, N, Martin, D, Filipe, H, Eastgate, C, Jackson, C, Gratrix, A, Foster, L, Martinson, V, Stones, E, Caroline, Abernathy, Parkinson, P, Reed, A, Prendergast, C, Rogers, P, Woodruff, M, Shokkar, R, Kaul, S, Barron, A, Collins, C, Beavis, S, Whileman, A, Dale, K, Hawes, J, Pritchard, K, Gascoyne, R, Stevenson, L, Jha, R, Lim, L, Krishnamurthy, V, Parker, R, Turner-Bone, I, Wilding, L, Reddy, A, Whiteley, S, Wilby, E, Howcroft, C, Aspinwall, A, Charlton, S, Ogg, B, Menzies, D, Pugh, R, Allan, E, Lean, R, Davies, F, Easton, J, Qiu, X, Kumar, S, Darlington, K, Houston, G, O'Brien, P, Geary, T, Allan, J, Meikle, A, Hughes, G, Balasubramaniam, M, Latham, S, Mckenna, E, Flanagan, R, Sathe, S, Davies, E, Chablani, M, Kirkby, A, Netherton, K, Archer, S, Yates, B, Ashbrook-Raby, C, Cole, S, Casey, M, Cabrelli, L, Chapman, S, Austin, P, Hutcheon, A, Whyte, C, Almaden-Boyle, C, Pattison, N, Cruz, C, Vochin, A, Kent, H, Thomas, A, Murdoch, S, David, B, Penacerrada, M, Lubimbi, G, Bastion, V, Wulandari, R, Valentine, J, Clarke, D, Serrano-Ruiz, A, Hierons, S, Ramos, L, Demetriou, C, Mitchard, S, White, K, White, N, Pitts, S, Branney, D, Frankham, J, Watters, M, Langton, H, Prout, R, Page, V, Varghes, T, Cowton, A, Kay, A, Potts, K, Birt, M, Kent, M, Wilkinson, A, Jude, E, Turner, V, Savill, H, Mccormick, J, Coulding, M, Siddiqui, S, Mercer, O, Rehman, H, Potla, D, Capps, N, Donaldson, D, Button, H, Martin, T, Hard, K, Agasou, A, Tonks, L, Arden, T, Boyle, P, Carnahan, M, Strickley, J, Adams, C, Childs, D, Rikunenko, R, Leigh, M, Breekes, M, Wilcox, R, Bowes, A, Tiveran, H, Hurford, F, Summers, J, Carter, A, Hussain, Y, Ting, L, Javaid, A, Motherwell, N, Moore, H, Millward, H, Jose, S, Schunki, N, Noakes, A, Clulow, C, Sadera, G, Jacob, R, Jones, C, Blunt, M, Coton, Z, Curgenven, H, S Mohamed Ally, Beaumont, K, Elsaadany, M, Fernandes, K, I Ali Mohamed Ali, Rangarajan, H, Sarathy, V, Selvanayagam, S, Vedage, D, White, M, Smith, M, Truman, N, Chukkambotla, S, Keith, S, Cockerill-Taylor, J, Ryan-Smith, J, Bolton, R, Springle, P, Dykes, J, Thomas, J, Khan, M, T Hijazi, M, Massey, E, Croston, G, Reschreiter, H, Camsooksai, J, Patch, S, Jenkins, S, Humphrey, C, Wadams, B, Bhatia, N, Msiska, M, Adanini, O, Attwood, B, Parsons, P, Tatham, K, Jhanji, S, Black, E, A Dela Rosa, Howle, R, Thomas, B, Bemand, T, Raobaikady, R, Saha, R, Staines, N, Daniel, A, Finn, J, Hutter, J, Doble, P, Shovelton, C, Pawley, C, Kannan, T, Hill, M, Combes, E, Monnery, S, Joefield, T, Popescu, M, Thankachen, M, Oblak, M, Little, J, Mcivor, S, Brady, A, Whittle, H, Prady, H, Chan, R, Ahmed, A, Morris, A, Gibson, C, Gordon, E, Keenan, S, Quinn, H, Benyon, S, Marriott, S, Zitter, L, Park, L, Baines, K, Lyons, M, Holland, M, Keenan, N, Young, M, Garrioch, S, Dawson, J, Tolson, M, Scholefield, B, R, Bi, Richardson, N, Schumacher, N, Cosier, T, Millen, G, Higham, A, Turki, S, Allen, L, Crisp, N, Hazleton, T, Knight, A, Deery, J, Price, C, Turney, S, Tilbey, S, Beranova, E, Wright, D, Georg, L, Twiss, S, Wadd, S, Postlethwaite, K, Gondo, P, Masunda, B, Kayani, A, Hadebe, B, Whiteside, J, Clarke, N, Donnison, P, Trim, F, Leadbitter, I, Butcher, D, O'Sullivan, S, Purewal, B, Bell, S, Rivers', V, O'Leary, R, Birch, J, Collins, E, Anderson, S, Hammerton, K, Andrews, E, Burns, K, Edmond, I, Todd, A, Donnachie, J, Turner, P, Prentice, L, Symon, L, Runciman, N, Auld, F, Halkes, M, Mercer, P, Thornton, L, Debreceni, G, Wilkins, J, Brown, A, Crickmore, V, Subramanian, G, Marshall, R, Jennings, C, Latif, M, Bunni, L, Spivey, M, Bean, S, Burt, K, Linnett, V, Ritzema, J, Sanderson, A, Mccormick, W, Bokhari, M, Kapoor, R, Loader, D, Ayers, A, Harrison, W, North, J, Belagodu, Z, Parasomthy, R, Olufuwa, O, Gherman, A, Fuller, B, Stuart, C, Kelsall, O, Davis, C, Wild, L, Wood, H, Thrush, J, Durie, A, Austin', K, Archer, K, Anderson, P, Vigurs, C, Thorpe, C, Knights, E, Boyle, N, Price, A, Kubisz-Pudelko, A, Wood, D, Lewis, A, Board, S, Pippard, L, Perry, J, Beesley, K, Rattray, A, Lee, E, Lennon, L, Douglas, K, Bell, D, Boyle, R, Glass, L, M Nauman Akhtar, Dent, K, Potoczna, D, Pearson, S, Horsley, E, Spencer, S, Mullan, D, Skinner, D, Gaylard, J, Ortiz-Ruizdegordoa, L, Barber, R, Hewitt, C, Hilldrith, A, Shepardson, S, Wills, M, Jackson-Lawrence, K, Gupta, A, Easthope, A, Timlick, E, Gorman, C, Otaha, I, Gales, A, Coetzee, S, Raj, M, Peiu, M, Quaid, S, Watson, E, Elliott, K, Mallinson, J, Chandler, B, Turnbull, A, Finch, C, Holl, C, Cooper, J, Evans, A, Khaliq, W, Collins, A, E Treus Gude, Love, N, L van Koutrik, Hunt, J, Kaye, D, Fisher, E, Brayne, A, Tuckey, V, Jackson, P, Parkin, J, Raith, E, Tariq, A, Houlden, H, Tucci, A, Hardy, J, Moncur, E, Highgate, J, Cowley, A, Mitra, A, Stead, R, Behan, T, Burnett, C, Newton, M, Heeney, E, Pollard, R, Hatton, J, Patel, A, Kasipandian, V, Allibone, S, M Genetu, R, Otahal, I, O'Brien, L, Omar, Z, Perkins, E, Davies, K, Tetla, D, Shelley, B, Irvine, V, Williams, S, Williams, P, Goodsell, J, Tutton, R, Bough, L, Winter-Goodwin, B, Kitson, R, Pinnell, J, Wilson, A, Nortcliffe, T, Wood, T, Home, M, Holdroyd, K, Robinson, M, Shaw, R, Greig, J, Brady, M, Haigh, A, Matupe, L, Usher, M, Mellor, S, Dale, S, Gledhill, L, Shaw, L, Turner, G, Kelly, D, Anwar, B, Riley, H, Sturgeon, H, Ali, A, Thomis, L, Melia, D, Dance, A, Hanson, K, Humphreys, S, Frost, I, Gopal, V, Godden, J, Holden, A, Swann, S, Smith, T, Clapham, M, Poultney, U, Harper, R, Rice, P, Reece-Anthony, R, Gurung, B, Moultrie, S, Odam, M, Mayer, A, Bellini, A, Pickard, A, Bryant, J, Roe, N, Sowter, J, Lang, K, Taylor, J, Barry, P, Hobrok, M, Tench, H, Wolf-Roberts, R, Mcguinness, H, Loosley, R, Hawcutt, D, Rad, L, O'Malley, L, Saunderson, P, Seddon, G, Anderson, T, Rogers, N, Ruddy, J, Harkins, M, Beith, C, Mcalpine, A, Ferguson, L, Grant, P, Macfadyen, S, Mclaughlin, M, Baird, T, Rundell, S, Welsh, B, Hamill, R, Fisher, F, Gregory, J, Axel, Schmidt, Kerstin, U Ludwig, Selina, Rolker, Markus, M Nöthen, Julia, Fazaal, Verena, Keitel, Björn, Jensen, Torsten, Feldt, Lisa, Knopp, Julia, Schröder, Carlo, Maj, Fabian, Brand, Marc, M Berger, Thorsten, Brenner, Anke, Hinney, Oliver, Witzke, Robert, Bals, Christian, Herr, Nicole, Ludwig, Jörn, Walter, Jochen, Schneider, Johanna, Erber, Christoph, D Spinner, Clemens, M Wendtner, Christof, Winter, Ulrike, Protzer, Nicolas, Casadei, Stephan, Ossowski, Olaf, H Riess, Eva, C Schulte, J Brent Richards, Guillaume, Butler-Laporte, Mirosław, Kwasniewski, Urszula, Korotko, Karolina, Chwialkowska, Magdalena, Niemira, Jerzy, Jaroszewicz, Barbara, Sobala-Szczygiel, Beata, Puzanowska, Anna, Parfieniuk-Kowerda, Diana, Martonik, Anna, Moniuszko-Malinowska, Sławomir, Pancewicz, Dorota, Zarębska-Michaluk, Krzysztof, Simon, Monika, Pazgan-Simon, Iwona, Mozer-Lisewska, Maciej, Bura, Agnieszka, Adamek, Krzysztof Tomasiewicz Małgorzata Pawłowska, Anna, Piekarska, Aleksandra, Berkan-Kawinska, Andrzej, Horban, Justyna, Kowalska, Regina, Podlasin, Piotr, Wasilewski, Arsalin, Azzadin, Miroslaw, Czuczwar, Slawomir, Czaban, Paweł, Olszewski, Jacek, Bogocz, Magdalena, Ochab, Anna, Kruk, Sandra, Uszok, Agnieszka, Bielska, Anna, Szałkowska, Justyna, Raczkowska, Gabriela, Sokołowska, Joanna, Chorostowska-Wynimko, Aleksandra, Jezela-Stanek, Adriana, Roży, Urszula, Lechowicz, Urszula, Polowianiuk, Kamil, Grubczak, Aleksandra, Starosz, Andrzej, Eljaszewicz, Wiktoria, Izdebska, Adam, Krętowski, Robert, Flisiak, Marcin Moniuszko Malak Abedalthagafi Manal Alaamery, Salam, Massadeh, Mohamed, Fawzy, Hadeel, Albardis, Nora, Aljawini, Moneera, Alsuwailm, Faisal, Almalki, Serghei, Mangul, Junghyun, Jung, Hamdi, Mbarek, Chadi, Saad, Yaser, Al-Sarraj, Wadha, Al-Muftah, Radja, Badji, Asma Al Thani, Said, I Ismail, HGI, WES/WGS Working Group Within the, Consortium, GenOMICC, Study, GEN-COVID Multicenter, Renieri, Alessandra [0000-0002-0846-9220], Apollo - University of Cambridge Repository, NIHR, Fallerini, C, Picchiotti, N, Baldassarri, M, Zguro, K, Daga, S, Fava, F, Benetti, E, Amitrano, S, Bruttini, M, Palmieri, M, Croci, S, Lista, M, Beligni, G, Valentino, F, Meloni, I, Tanfoni, M, Minnai, F, Colombo, F, Cabri, E, Fratelli, M, Gabbi, C, Mantovani, S, Frullanti, E, Gori, M, Crawley, F, Butler-Laporte, G, Richards, B, Zeberg, H, Lipcsey, M, Hultström, M, Ludwig, K, Schulte, E, Pairo-Castineira, E, Baillie, J, Schmidt, A, Frithiof, R, Mari, F, Renieri, A, Furini, S, and Crotti, L
Subjects: Male, Medicin och hälsovetenskap, Linkage disequilibrium, Medizin, severity, Genome-wide association study, Disease, WES/WGS Working Group Within the HGI, Logistic regression, Severity of Illness Index, Medical and Health Sciences, Whole Exome Sequencing, Cohort Studies, 0302 clinical medicine, Lasso (statistics), GEN-COVID Multicenter Study, Germany, 80 and over, Genetics (clinical), Exome sequencing, Original Investigation, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Adult, Aged, COVID-19, Female, Humans, Italy, Middle Aged, Polymorphism, Single Nucleotide, Quebec, SARS-CoV-2, Sweden, United Kingdom, Genetic Predisposition to Disease, Phenotype, Single Nucleotide, covid-19, 1104 Complementary and Alternative Medicine, GenOMICC Consortium, Human, coding variants, Computational biology, Biology, 03 medical and health sciences, Exome Sequencing, Genetics, Polymorphism, Gene, 030304 developmental biology, 0604 Genetics, 1114 Paediatrics and Reproductive Medicine, Cohort Studie, 030217 neurology & neurosurgery, Coding (social sciences)
Abstract: The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. Supplementary Information The online version contains supplementary material available at 10.1007/s00439-021-02397-7.
Published: 2021
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13. Improving the culture of safety among healthcare workers: Integration of different instruments to gain major insights and drive effective changes

Author: Stefano Tardivo, Donatella Visentin, Mario Capasso, Livio Dalla Barba, Ilaria Tocco Tussardi, Valentina Niero, and Francesca Moretti
Subjects: Safety Management, Attitude of Health Personnel, media_common.quotation_subject, Health Personnel, Manchester patient safety framework, Stress recognition, Safety climate, healthcare quality, safety climate, Patient safety, Nursing, Safety Attitude Questionnaire, patient safety culture, subcultures, Perception, Surveys and Questionnaires, Health care, Humans, Safety culture, media_common, Response rate (survey), business.industry, Health Policy, Organizational Culture, Small hospital, Patient Safety, business, Psychology
Abstract: The Safety Attitude Questionnaire (SAQ) and Manchester Patient Safety Framework (MaPSaF) are known as effective tools to assess patient safety culture and climate and develop targeted strategies. However, they are seldom applied in an integrated way. The aim of this study was to conduct an implementation project through a novel use of both instruments to gain unique insights. The Italian version of MaPSaF and SAQ were administered to 1,759 healthcare workers from three Italian hospitals (response rate: MaPSaF 70.5%, SAQ 61.6%). MaPSaF evaluation proved an overall bureaucratic level of patient safety culture. SAQ scores showed a predominance of neutral scores (75.99%). The dimension perception of management gained the lowest mean score (53.32), while Stress recognition obtained the highest (75.17). Safety climate perception differed significantly among groups: working in a small hospital, in a medical department, and being a physician were associated with the most positive results. The majority (67.1%) of responders to both MaPSaF and SAQ considered the two instruments as providing with different and complementary information. Overall, results showed that an integrated approach in the evaluation of an organisation's safety culture may result useful for an in-depth analysis of the criticalities and the adoption of appropriate improvement strategies.
Published: 2021

14. The Serum Metabolome of Moderate and Severe COVID-19 Patients Reflects Possible Liver Alterations Involving Carbon and Nitrogen Metabolism

Author: Anna Annunziata, Francesco Maria Fusco, Alessandro Di Minno, Margherita Ruoppolo, Giuseppe Castaldo, Chiara Dell’Isola, Roberta Russo, Armando Cevenini, Immacolata Andolfo, Mario Capasso, Giuseppe Fiorentino, Roberta Fedele, Gabriella Fabbrocini, Cecilia Calabrese, Marianna Caterino, Michele Costanzo, Ivan Gentile, Monica Gelzo, Roberto Parrella, Maurizio D’Abbraccio, Caterino, Marianna, Costanzo, Michele, Fedele, Roberta, Cevenini, Armando, Gelzo, Monica, DI MINNO, Alessandro, Andolfo, Immacolata, Capasso, Mario, Russo, Roberta, Annunziata, Anna, Calabrese, Cecilia, Fiorentino, Giuseppe, D’Abbraccio, Maurizio, Dell’Isola, Chiara, Maria Fusco, Francesco, Parrella, Roberto, Fabbrocini, Gabriella, Gentile, Ivan, Castaldo, Giuseppe, Ruoppolo, Margherita, Caterino, M., Costanzo, M., Fedele, R., Cevenini, A., Gelzo, M., Di Minno, A., Andolfo, I., Capasso, M., Russo, R., Annunziata, A., Calabrese, C., Fiorentino, G., D'Abbraccio, M., Dell'Isola, C., Fusco, F. M., Parrella, R., Fabbrocini, G., Gentile, I., Castaldo, G., and Ruoppolo, M.
Subjects: coronavirus, Physiology, Disease, medicine.disease_cause, Severity of Illness Index, Medicine, Biology (General), Amino Acids, Spectroscopy, Coronavirus, mass spectrometry, Discriminant Analysis, General Medicine, metabolomics, Pathophysiology, Computer Science Applications, Amino Acid, Chemistry, Liver, Metabolome, Cytokines, Discriminant Analysi, Metabolic Networks and Pathways, Human, QH301-705.5, Nitrogen, Coronaviru, Context (language use), Metabolomic, serum cytokines, Catalysis, Article, Inorganic Chemistry, Metabolomics, Severity of illness, Humans, Physical and Theoretical Chemistry, Least-Squares Analysis, Serum cy-tokine, Cytokine, Molecular Biology, QD1-999, Least-Squares Analysi, business.industry, SARS-CoV-2, Organic Chemistry, lactic acid, Metabolic Networks and Pathway, COVID-19, Biomarker, Metabolism, Carbon, business, Biomarkers
Abstract: COVID-19 is a global threat that has spread since the end of 2019, causing severe clinical sequelae and deaths, in the context of a world pandemic. The infection of the highly pathogenetic and infectious SARS-CoV-2 coronavirus has been proven to exert systemic effects impacting the metabolism. Yet, the metabolic pathways involved in the pathophysiology and progression of COVID-19 are still unclear. Here, we present the results of a mass spectrometry-based targeted metabolomic analysis on a cohort of 52 hospitalized COVID-19 patients, classified according to disease severity as mild, moderate, and severe. Our analysis defines a clear signature of COVID-19 that includes increased serum levels of lactic acid in all the forms of the disease. Pathway analysis revealed dysregulation of energy production and amino acid metabolism. Globally, the variations found in the serum metabolome of COVID-19 patients may reflect a more complex systemic perturbation induced by SARS-CoV-2, possibly affecting carbon and nitrogen liver metabolism.
Published: 2021

15. Germline mutations and new copy number variants among 40 pediatric cancer patients suspected for genetic predisposition

Author: Sabrina Giglio, Gianluca De Rosa, Valentina Contestabile, Antonella Gambale, Lucia De Martino, Barbara Pasini, Lucia Quaglietta, Roberta Russo, Rita Genesio, Immacolata Andolfo, Piero Pignataro, Achille Iolascon, Mario Capasso, Rosanna Parasole, Gambale, A., Russo, Roberta, Andolfo, I., Quaglietta, L., De Rosa, G., Contestabile, Valentina, De Martino, L., Genesio, R., Pignataro, P., Giglio, S., Capasso, M., Parasole, R., Pasini, B., and Iolascon, A.
Subjects: cancer predisposition syndrome, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, genotype-phenotype relationship, 030105 genetics & heredity, Germline, genetic testing, 03 medical and health sciences, Germline mutation, Neoplasms, Internal medicine, cancer predisposition syndromes, Gene duplication, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Copy-number variation, Child, Alleles, Genetic Association Studies, Germ-Line Mutation, Genetics (clinical), Genetic testing, medicine.diagnostic_test, business.industry, Age Factors, Infant, Astrocytoma, Genomics, medicine.disease, Pediatric cancer, 030104 developmental biology, Child, Preschool, Female, business
Abstract: Cancer predisposition syndromes (CPS) result from germline pathogenic variants, and they are increasingly recognized in the etiology of many pediatric cancers. Herein, we report the genetic/genomic analysis of 40 pediatric patients enrolled from 2016 to 2018. Our diagnostic workflow was successful in 50% of screened cases. Overall, the proportion of CPS in our case series is 10.9% (20/184) of enrolled patients. Interestingly, 12.5% of patients achieved a conclusive diagnosis through the analysis of chromosomal imbalance. Indeed, we observed germline microdeletions/duplications of regions encompassing cancer-related genes in 50% of patients undergoing array-CGH: EIF3H duplication in a patient with infantile desmoplastic astrocytoma and low-grade Glioma; SLFN11 deletion, SOX4 duplication, and PARK2 partial deletion in three neuroblastoma patients; a PTPRD partial deletion in a child diagnosed with glioblastoma multiforme. Finally, we identified two cases due to DICER1 germline mutations.
Published: 2019
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16. Humoral Response to 2-dose BNT162b2 mRNA COVID-19 Vaccination in Liver Transplant Recipients

Author: Maria Guarino, Ilaria Esposito, Giuseppe Portella, Valentina Cossiga, Ilaria Loperto, Raffaella Tortora, Michele Cennamo, Mario Capasso, Daniela Terracciano, Alfonso Galeota Lanza, Sarah Di Somma, Francesco Paolo Picciotto, Filomena Morisco, Giuseppina Pontillo, Luca Pignata, Maria Rosaria Attanasio, Raffaele Lieto, Francesco Cutolo, and Marianna Cuomo
Subjects: Adult, Male, OR, Odds Ratio, COVID-19 Vaccines, Antimetabolites, BMI, body mass index, Antibodies, Viral, NAFLD, Non-Alcoholic fatty liver disease, Article, Humans, RNA, Messenger, BNT162 Vaccine, Vaccines, Synthetic, immunosuppression, liver transplantation, Hepatology, SARS-CoV-2, Vaccination, Gastroenterology, COVID-19, Middle Aged, Sars-CoV-2 vaccination, Transplant Recipients, 95%CI, 95% confidence intervals, Immunoglobulin G, COVID-19, SARS-CoV-2 infection, ALD, Alcoholic liver disease, Female, mRNA Vaccines, HCC, hepatocellular carcinoma, LT, liver transplant
Abstract: In the context of the Italian severe acute respiratory syndrome coronavirus 2 vaccination program, liver transplant (LT) recipients were prioritized for vaccine administration, although the lower response to vaccines is a well-known problem in this population. We aimed to evaluate immunogenicity of BNT162b2 mRNA vaccine in LT recipients and healthy controls and to identify factors associated with negative response to vaccine.In a cohort of adult patients with LT, we prospectively evaluated the humoral response (with anti-Spike protein IgG-LIAISON SARS-CoV-2 S1/S2-IgG chemiluminescent assay) at 1 and 3 months after 2-dose vaccination. A group of 307 vaccinated health care workers, matched by age and sex, served as controls.Overall, 492 LT patients were enrolled (75.41% male; median age, 64.85 years). Detectable antibodies were observed in the 75% of patients, with a median value of 73.9 AU/mL after 3 months from 2-dose vaccination. At multivariable analysis, older age (40 years; P = .016), shorter time from liver transplantation (5 years; P = .004), and immunosuppression with antimetabolites (P = .029) were significantly associated with non-response to vaccination. Moreover, the LT recipients showed antibody titers statistically lower than the control group (103 vs 261 AU/mL; P.0001). Finally, in both controls and LT patients, we found a trend of inverse correlation between age and antibody titers (correlation coefficients: -0.2023 and -0.2345, respectively).Three months after vaccination, LT recipients showed humoral response in 75% of cases. Older age, shorter time from transplantation, and use of antimetabolites were factors associated with non-response to vaccination, and LT recipients at risk of non-response to vaccination needed to be kept under close monitoring.
Published: 2022
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17. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author: Matteo D’Antonio, Jennifer P. Nguyen, Timothy D. Arthur, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Kelly A. Frazer, Benjamin M. Neale, Mark Daly, Andrea Ganna, Christine Stevens, Gita A. Pathak, Shea J. Andrews, Masahiro Kanai, Mattia Cordioli, Juha Karjalainen, Renato Polimanti, Matti Pirinen, Nadia Harerimana, Kumar Veerapen, Brooke Wolford, Huy Nguyen, Matthew Solomonson, Rachel G. Liao, Karolina Chwialkowska, Amy Trankiem, Mary K. Balaconis, Caroline Hayward, Anne Richmond, Archie Campbell, Marcela Morris, Chloe Fawns-Ritchie, Joseph T. Glessner, Douglas M. Shaw, Xiao Chang, Hannah Polikowski, Petty E. Lauren, Hung-Hsin Chen, Zhu Wanying, Hakon Hakonarson, David J. Porteous, Jennifer Below, Kari North, Joseph B. McCormick, Paul R.H.J. Timmers, James F. Wilson, Albert Tenesa, Kenton D’Mellow, Shona M. Kerr, Mari E.K. Niemi, Lindokuhle Nkambul, Kathrin Aprile von Hohenstaufen, Ali Sobh, Madonna M. Eltoukhy, Amr M. Yassen, Mohamed A.F. Hegazy, Kamal Okasha, Mohammed A. Eid, Hanteera S. Moahmed, Doaa Shahin, Yasser M. El-Sherbiny, Tamer A. Elhadidy, Mohamed S. Abd Elghafar, Jehan J. El-Jawhari, Attia A.S. Mohamed, Marwa H. Elnagdy, Amr Samir, Mahmoud Abdel-Aziz, Walid T. Khafaga, Walaa M. El-Lawaty, Mohamed S. Torky, Mohamed R. El-shanshory, Chiara Batini, Paul H. Lee, Nick Shrine, Alexander T. Williams, Martin D. Tobin, Anna L. Guyatt, Catherine John, Richard J. Packer, Altaf Ali, Robert C. Free, Xueyang Wang, Louise V. Wain, Edward J. Hollox, Laura D. Venn, Catherine E. Bee, Emma L. Adams, Ahmadreza Niavarani, Bahareh Sharififard, Rasoul Aliannejad, Ali Amirsavadkouhi, Zeinab Naderpour, Hengameh Ansari Tadi, Afshar Etemadi Aleagha, Saeideh Ahmadi, Seyed Behrooz Mohseni Moghaddam, Alireza Adamsara, Morteza Saeedi, Hamed Abdollahi, Abdolmajid Hosseini, Pajaree Chariyavilaskul, Monpat Chamnanphon, Thitima B. Suttichet, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Watsamon Jantarabenjakul, Opass Putchareon, Pattama Torvorapanit, Thanyawee Puthanakit, Pintip Suchartlikitwong, Nattiya Hirankarn, Voraphoj Nilaratanakul, Pimpayao Sodsai, Ben M. Brumpton, Kristian Hveem, Cristen Willer, Wei Zhou, Tormod Rogne, Erik Solligard, Bjørn Olav Åsvold, Malak Abedalthagafi, Manal Alaamery, Saleh Alqahtani, Dona Baraka, Fawz Al Harthi, Ebtehal Alsolm, Leen Abu Safieh, Albandary M. Alowayn, Fatimah Alqubaishi, Amal Al Mutairi, Serghei Mangul, Abdulraheem Alshareef, Mona Sawaji, Mansour Almutairi, Nora Aljawini, Nour Albesher, Yaseen M. Arabi, Ebrahim S. Mahmoud, Amin K. Khattab, Roaa T. Halawani, Ziab Z. Alahmadey, Jehad K. Albakri, Walaa A. Felemban, Bandar A. Suliman, Rana Hasanato, Laila Al-Awdah, Jahad Alghamdi, Deema AlZahrani, Sameera AlJohani, Hani Al-Afghani, May Alrashed, Nouf AlDhawi, Hadeel AlBardis, Sarah Alkwai, Moneera Alswailm, Faisal Almalki, Maha Albeladi, Iman Almohammed, Eman Barhoush, Anoud Albader, Salam Massadeh, Abdulaziz AlMalik, Sara Alotaibi, Bader Alghamdi, Junghyun Jung, Mohammad S. Fawzy, Yunsung Lee, Per Magnus, Lill-Iren S. Trogstad, Øyvind Helgeland, Jennifer R. Harris, Massimo Mangino, Tim D. Spector, Duncan Emma, Sandra P. Smieszek, Bartlomiej P. Przychodzen, Christos Polymeropoulos, Vasilios Polymeropoulos, Mihael H. Polymeropoulos, Israel Fernandez-Cadenas, Jordi Perez-Tur, Laia Llucià-Carol, Natalia Cullell, Elena Muiño, Jara Cárcel-Márquez, Marta L. DeDiego, Lara Lloret Iglesias, Anna M. Planas, Alex Soriano, Veronica Rico, Daiana Agüero, Josep L. Bedini, Francisco Lozano, Carlos Domingo, Veronica Robles, Francisca Ruiz-Jaén, Leonardo Márquez, Juan Gomez, Eliecer Coto, Guillermo M. Albaiceta, Marta García-Clemente, David Dalmau, Maria J. Arranz, Beatriz Dietl, Alex Serra-Llovich, Pere Soler, Roger Colobrán, Andrea Martín-Nalda, Alba Parra Martínez, David Bernardo, Silvia Rojo, Aida Fiz-López, Elisa Arribas, Paloma de la Cal-Sabater, Tomás Segura, Esther González-Villa, Gemma Serrano-Heras, Joan Martí-Fàbregas, Elena Jiménez-Xarrié, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastian García-Madrona, Anna Domínguez-Mayoral, Joan Montaner Villalonga, Paloma Menéndez-Valladares, Daniel I. Chasman, Julie E. Buring, Paul M. Ridker, Giulianini Franco, Howard D. Sesso, JoAnn E. Manson, Joseph R. Glessner, Carolina Medina-Gomez, Andre G. Uitterlinden, M. Arfan Ikram, Kati Kristiansson, Sami Koskelainen, Markus Perola, Kati Donner, Katja Kivinen, Aarno Palotie, Samuli Ripatti, Sanni Ruotsalainen, Mari Kaunisto, null FinnGen, Tomoko Nakanishi, Guillaume Butler-Laporte, Vincenzo Forgetta, David R. Morrison, Biswarup Ghosh, Laetitia Laurent, Alexandre Belisle, Danielle Henry, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk Branka Vulesevic, Meriem Bouab, Charlotte Guzman, Louis Petitjean, Chris Tselios, Xiaoqing Xue, Erwin Schurr, Jonathan Afilalo, Marc Afilalo, Maureen Oliveira, Bluma Brenner, Pierre Lepage, Jiannis Ragoussis, Daniel Auld, Nathalie Brassard, Madeleine Durand, Michaël Chassé, Daniel E. Kaufmann, G. Mark Lathrop, Vincent Mooser, J. Brent Richards, Rui Li, Darin Adra, Souad Rahmouni, Michel Georges, Michel Moutschen, Benoit Misset, Gilles Darcis, Julien Guiot, Julien Guntz, Samira Azarzar, Stéphanie Gofflot, Yves Beguin, Sabine Claassen, Olivier Malaise, Pascale Huynen, Christelle Meuris, Marie Thys, Jessica Jacques, Philippe Léonard, Frederic Frippiat, Jean-Baptiste Giot, Anne-Sophie Sauvage, Christian Von Frenckell, Yasmine Belhaj, Bernard Lambermont, Sara Pigazzini, Lindokuhle Nkambule, Michelle Daya, Jonathan Shortt, Nicholas Rafaels, Stephen J. Wicks, Kristy Crooks, Kathleen C. Barnes, Christopher R. Gignoux, Sameer Chavan, Triin Laisk, Kristi Läll, Maarja Lepamets, Reedik Mägi, Tõnu Esko, Ene Reimann, Lili Milani, Helene Alavere, Kristjan Metsalu, Mairo Puusepp, Andres Metspalu, Paul Naaber, Edward Laane, Jaana Pesukova, Pärt Peterson, Kai Kisand, Jekaterina Tabri, Raili Allos, Kati Hensen, Joel Starkopf, Inge Ringmets, Anu Tamm, Anne Kallaste, Pierre-Yves Bochud, Carlo Rivolta, Stéphanie Bibert, Mathieu Quinodoz, Dhryata Kamdar, Noémie Boillat, Semira Gonseth Nussle, Werner Albrich, Noémie Suh, Dionysios Neofytos, Véronique Erard, Cathy Voide, null FHoGID, null RegCOVID, null P-PredictUs, null SeroCOVID, null CRiPSI, Rafael de Cid, Iván Galván-Femenía, Natalia Blay, Anna Carreras, Beatriz Cortés, Xavier Farré, Lauro Sumoy, Victor Moreno, Josep Maria Mercader, Marta Guindo-Martinez, David Torrents, Manolis Kogevinas, Judith Garcia-Aymerich, Gemma Castaño-Vinyals, Carlota Dobaño, Alessandra Renieri, Francesca Mari, Chiara Fallerini, Sergio Daga, Elisa Benetti, Margherita Baldassarri, Francesca Fava, Elisa Frullanti, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Giada Beligni, Andrea Tommasi, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Stefano Busani, Raffaele Bruno, Marco Vecchia, Mary Ann Belli, Nicola Picchiotti, Maurizio Sanarico, Marco Gori, Simone Furini, Stefania Mantovani, Serena Ludovisi, Mario Umberto Mondelli, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Massimo Vaghi, Stefano Rusconi, Matteo Siano, Francesca Montagnani, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Elena Bargagli, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Maria Bandini, Gian Piero Caldarelli, Paolo Piacentini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Massimo Girardis, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Stefano Baratti, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Chiara Gabbi, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Biscarini, Alessandra Stella, Kristina Zguro, Katia Capitani, Claudia Suardi, Simona Dei, Gianfranco Parati, Sabrina Ravaglia, Rosangela Artuso, Giordano Bottà, Paolo Di Domenico, Ilaria Rancan, Antonio Perrella Francesco Bianchi, Davide Romani, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Marco Tanfoni, Antonella Vincenti, Claudio Ferri, Davide Grassi, Gloria Pessina, Mario Tumbarello, Massimo Di Pietro, Ravaglia Sabrina, Sauro Luchi, Chiara Barbieri, Donatella Acquilini, Elena Andreucci, Francesco Vladimiro Segala, Giusy Tiseo, Marco Falcone, Mirjam Lista, Monica Poscente, Oreste De Vivo, Paola Petrocelli, Alessandra Guarnaccia, Silvia Baroni, Albert V. Smith, Andrew P. Boughton, Kevin W. Li, Jonathon LeFaive, Aubrey Annis, Anne E. Justice, Tooraj Mirshahi, Geetha Chittoor, Navya Shilpa Josyula, Jack A. Kosmicki, Manuel A.R. Ferreira, Joseph B. Leader, Dave J. Carey, Matthew C. Gass, Julie E. Horowitz, Michael N. Cantor, Ashish Yadav, Aris Baras, Goncalo R. Abecasis, David A. van Heel, Karen A. Hunt, Dan Mason, Qin Qin Huang, Sarah Finer, null Genes & Health Research Team, Bhavi Trivedi, Christopher J. Griffiths, Hilary C. Martin, John Wright, Richard C. Trembath, Nicole Soranzo, Jing Hua Zhao, Adam S. Butterworth, John Danesh, Emanuele Di Angelantonio, Lude Franke Marike Boezen, Patrick Deelen, Annique Claringbould, Esteban Lopera, Robert Warmerdam, Judith.M. Vonk, Irene van Blokland, Pauline Lanting, Anil P.S. Ori, Brooke Wolford Sebastian Zöllner, Jiongming Wang, Andrew Beck, Gina Peloso, Yuk-Lam Ho, Yan V. Sun, Jennifer E. Huffman, Christopher J. O’Donnell, Kelly Cho, Phil Tsao, J. Michael Gaziano, Michel (M.G.) Nivard, Eco (E.J.C.) de geus, Meike Bartels, Jouke Jan Hottenga, Scott T. Weiss, Elizabeth W. Karlson, Jordan W. Smoller, Robert C. Green, Yen-Chen Anne Feng, Josep Mercader, Shawn N. Murphy, James B. Meigs, Ann E. Woolley, Emma F. Perez, Daniel Rader, Anurag Verma, Marylyn D. Ritchie, Binglan Li, Shefali S. Verma, Anastasia Lucas, Yuki Bradford, Hugo Zeberg, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Lindo Nkambul, Nicolas Tardif, Olav Rooyackers, Jonathan Grip, Tomislav Maricic, Konrad J. Karczewski, Elizabeth G. Atkinson, Kristin Tsuo, Nikolas Baya, Patrick Turley, Rahul Gupta, Shawneequa Callier, Raymond K. Walters, Duncan S. Palmer, Gopal Sarma, Nathan Cheng, Wenhan Lu, Sam Bryant, Claire Churchhouse, Caroline Cusick, Jacqueline I. Goldstein, Daniel King, Cotton Seed, Hilary Finucane, Alicia R. Martin, F. Kyle Satterstrom, Daniel J. Wilson, Jacob Armstrong, Justine K. Rudkin, Gavin Band, Sarah G. Earle, Shang-Kuan Lin, Nicolas Arning, Derrick W. Crook, David H. Wyllie, Anne Marie O’Connell, Chris C.A. Spencer, Nils Koelling, Mark J. Caulfield, Richard H. Scott, Tom Fowler, Loukas Moutsianas, Athanasios Kousathanas, Dorota Pasko, Susan Walker, Augusto Rendon, Alex Stuckey, Christopher A. Odhams, Daniel Rhodes, Georgia Chan, Prabhu Arumugam, Catherine A. Ball, Eurie L. Hong, Kristin Rand, Ahna Girshick, Harendra Guturu, Asher Haug Baltzell, Genevieve Roberts, Danny Park, Marie Coignet, Shannon McCurdy, Spencer Knight, Raghavendran Partha, Brooke Rhead, Miao Zhang, Nathan Berkowitz, Michael Gaddis, Keith Noto, Luong Ruiz, Milos Pavlovic, Laura G. Sloofman, Alexander W. Charney, Noam D. Beckmann, Eric E. Schadt, Daniel M. Jordan, Ryan C. Thompson, Kyle Gettler, Noura S. Abul-Husn, Steven Ascolillo, Joseph D. Buxbaum, Kumardeep Chaudhary, Judy H. Cho, Yuval Itan, Eimear E. Kenny, Gillian M. Belbin, Stuart C. Sealfon, Robert P. Sebra, Irene Salib, Brett L. Collins, Tess Levy, Bari Britvan, Katherine Keller, Lara Tang, Michael Peruggia, Liam L. Hiester, Kristi Niblo, Alexandra Aksentijevich, Alexander Labkowsky, Avromie Karp, Menachem Zlatopolsky, Michael Preuss, Ruth J.F. Loos, Girish N. Nadkarni, Ron Do, Clive Hoggart, Sam Choi, Slayton J. Underwood, Paul O’Reilly, Laura M. Huckins, Marissa Zyndorf, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology
Subjects: Medical Physiology, Gene Expression, Genome-wide association study, Genome, Severity of Illness Index, colocalization, Gene expression, Databases, Genetic, Ethnicity, 2.1 Biological and endogenous factors, GWAS, Aetiology, Biology (General), Lung, Genetics, Chromosome Mapping, Single Nucleotide, Organ Specificity, Biotechnology, Cell type, QH301-705.5, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, eQTL, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Databases, Genetic, SNP, Humans, Genetic Predisposition to Disease, COVID-19 Host Genetics Initiative, Polymorphism, Gene, COVID-19, SARS-CoV-2, Gene Expression Profiling, Prevention, Human Genome, Computational Biology, Genetic Variation, Good Health and Well Being, Expression quantitative trait loci, Biochemistry and Cell Biology, Transcriptome, Genome-Wide Association Study
Abstract: Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.
Published: 2022
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18. Regulatory noncoding and predicted pathogenic coding variants of ccr5 predispose to severe covid-19

Author: Vito Alessandro Lasorsa, Biancamaria Pierri, Barbara Eleni Rosato, Giulia Frisso, Giuseppe Russo, Matteo Della Monica, Roberta Russo, Pellegrino Cerino, Giuseppe Servillo, Giuseppe D'Alterio, Sueva Cantalupo, Gian Marco Cassese, Mario Capasso, Massimo Zollo, Pasquale Abete, Carlo Buonerba, Ivan Gentile, Immacolata Andolfo, Carmelo Piscopo, Giuseppe Fiorentino, Achille Iolascon, Cantalupo, S., Lasorsa, V. A., Russo, R., Andolfo, I., D'Alterio, G., Rosato, B. E., Frisso, G., Abete, P., Cassese, G. M., Servillo, G., Gentile, I., Piscopo, C., Monica, M. D., Fiorentino, G., Russo, G., Cerino, P., Buonerba, C., Pierri, B., Zollo, M., Iolascon, A., and Capasso, M.
Subjects: Genotype, Receptors, CCR5, QH301-705.5, SNP, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Bronchi, Biology, Polymorphism, Single Nucleotide, Catalysis, Article, Inorganic Chemistry, Cohort Studies, CCR5, Exome Sequencing, Databases, Genetic, Humans, GWAS, Chromosomes, Human, Genetic Predisposition to Disease, Physical and Theoretical Chemistry, Allele, Biology (General), Molecular Biology, Gene, QD1-999, Lung, Spectroscopy, Exome sequencing, Alleles, Genetic association, Genetics, SARS-CoV-2, Organic Chemistry, Whole exome sequencing, COVID-19, Computational Biology, General Medicine, Computer Science Applications, Chemistry, Cohort Studie, Genome-Wide Association Study, Human
Abstract: Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10−5) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of CCR5 in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of CCR5.
Published: 2021

19. The tnfrsf13c h159y variant is associated with severe covid-19: A retrospective study of 500 patients from southern italy

Author: Gian Marco Cassese, Mario Capasso, Giuseppe Fiorentino, Achille Iolascon, Immacolata Andolfo, Gabriella Esposito, Giuseppe Servillo, Biancamaria Pierri, Vito Alessandro Lasorsa, Pellegrino Cerino, Matteo Della Monica, Massimo Zollo, Pasquale Abete, Roberta Marra, Carmelo Piscopo, Ivan Gentile, Carlo Buonerba, Roberta Russo, Giulia Frisso, Sueva Cantalupo, Giuseppe Russo, Russo, R., Andolfo, I., Lasorsa, V. A., Cantalupo, S., Marra, R., Frisso, G., Abete, P., Cassese, G. M., Servillo, G., Esposito, G., Gentile, I., Piscopo, C., Della Monica, M., Fiorentino, G., Russo, G., Cerino, P., Buonerba, C., Pierri, B., Zollo, M., Iolascon, A., and Capasso, M.
Subjects: 0301 basic medicine, Male, macromolecular substances, QH426-470, Asymptomatic, Polymorphism, Single Nucleotide, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Severity of illness, Genetics, TNFRSF13C, Medicine, Humans, Gene, Allele frequency, Genetics (clinical), Exome sequencing, Retrospective Studies, business.industry, SARS-CoV-2, Communication, Point mutation, CVID, COVID-19, Retrospective cohort study, Middle Aged, Minor allele frequency, 030104 developmental biology, Italy, 030220 oncology & carcinogenesis, Whole-exome sequencing, Immunology, Female, medicine.symptom, SNP genotyping, business, B-Cell Activation Factor Receptor
Abstract: To identify host genetic determinants involved in humoral immunity and associated with the risk of developing severe COVID-19, we analyzed 500 SARS-CoV-2 positive subjects from Southern Italy. We examined the coding sequences of 10 common variable immunodeficiency-associated genes obtained by the whole-exome sequencing of 121 hospitalized patients. These 10 genes showed significant enrichment in predicted pathogenic point mutations in severe patients compared with the non-severe ones. Moreover, in the TNFRSF13C gene, the minor allele of the p.His159Tyr variant, which is known to increase NF-kB activation and B-cell production, was significantly more frequent in the 38 severe cases compared to both the 83 non-severe patients and the 375 asymptomatic subjects further genotyped. This finding identified a potential genetic risk factor of severe COVID-19 that not only may serve to unravel the mechanisms underlying the disease severity but, also, may contribute to build the rationale for individualized management based on B-cell therapy.
Published: 2021

20. Genetic mechanisms of critical illness in COVID-19

Author: Pairo-Castineira, Erola, Clohisey, Sara, Klaric, Lucija, Bretherick, Andrew D, Rawlik, Konrad, Pasko, Dorota, Walker, Susan, Parkinson, Nick, Fourman, Max Head, Russell, Clark D, Furniss, James, Richmond, Anne, Gountouna, Elvina, Wrobel, Nicola, Harrison, David, Wang, Bo, Yang, Wu, Meynert, Alison, Griffiths, Fiona, Oosthuyzen, Wilna, Kousathanas, Athanasios, Moutsianas, Loukas, Yang, Zhijian, Zhai, Ranran, Zheng, Chenqing, Grimes, Graeme, Beale, Rupert, Millar, Jonathan, Shih, Barbara, Keating, Sean, Zechner, Marie, Haley, Chris, Porteous, David J, Hayward, Caroline, Yang, Jian, Knight, Julian, Summers, Charlotte, Shankar-Hari, Manu, Klenerman, Paul, Turtle, Lance, Antonia, Ho, Moore, Shona C, Hinds, Charles, Horby, Peter, Nichol, Alistair, Maslove, David, Ling, Lowell, Mcauley, Danny, Montgomery, Hugh, Walsh, Timothy, Pereira, Alexandre C, Renieri, Johnny, Millar, Alistair, Nichol, Tim, Walsh, Manu, Shankar-Hari, Chris, Ponting, Jen, Meikle, Paul, Finernan, Ellie, Mcmaster, Andy, Law, J Kenneth Baillie, Trevor, Paterson, Tony, Wackett, Ruth, Armstrong, Richard, Clark, Audrey, Coutts, Lorna, Donnelly, Tammy, Gilchrist, Katarzyna, Hafezi, Louise, Macgillivray, Alan, Maclean, Sarah, Mccafferty, Kirstie, Morrice, Jane, Weaver, Ceilia, Boz, Ailsa, Golightly, Mari, Ward, Hanning, Mal, Helen, Szoor-McElhinney, Adam, Brown, Ross, Hendry, Andrew, Stenhouse, Louise, Cullum, Dawn, Law, Sarah, Law, Rachel, Law, Maaike, Swets, Nicky, Day, Filip, Taneski, Esther, Duncan, Nicholas, Parkinson, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthope, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Shankar-Hari, M, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, O Jones, T, Whitton, C, Marotti, M, Arbane, G, Bonner, S, Hugill, K, Reid, J, Welters, I, Waugh, V, Williams, K, Shaw, D, J Fernandez Roman, M Lopez Martinez, Johnson, E, Waite, A, Johnston, B, Hamilton, D, Mulla, S, Mcphail, M, Smith, J, K Baillie, J, Barclay, L, Hope, D, Mcculloch, C, Mcquillan, L, Clark, S, Singleton, J, Priestley, K, Rea, N, Callaghan, M, Campbell, R, Andrew, G, Marshall, L, Mckechnie, S, Hutton, P, Bashyal, A, Davidson, N, Summers, C, Polgarova, P, Stroud, K, Pathan, N, Elston, K, Agrawal, S, Battle, C, Newey, L, Rees, T, Harford, R, Brinkworth, E, Williams, M, Murphy, C, White, I, Croft, M, Bandla, N, Gellamucho, M, Tomlinson, J, Turner, H, Davies, M, Quinn, A, Hussain, I, Thompson, C, Parker, H, Bradley, R, Griffiths, R, Scriven, J, Nilsson, A, Bates, M, Dasgin, J, Gill, J, Puxty, A, Cathcart, S, Salutous, D, Turner, L, Duffy, K, Puxty, K, Joseph, A, Herdman-Grant, R, Simms, R, Swain, A, Naranjo, A, Crowe, R, Sollesta, K, Loveridge, A, Baptista, D, Morino, E, Davey, M, Golden, D, Jones, J, J Moreno Cuesta, Haldeos, A, Bakthavatsalam, D, Vincent, R, Elhassan, M, Xavier, K, Ganesan, A, Purohit, D, Abdelrazik, M, Morgan, J, Akeroyd, L, Bano, S, Lawton, T, Warren, D, Bromley, M, Sellick, K, Gurr, L, Wilkinson, B, Nagarajan, V, Szedlak, P, Cupitt, J, Stoddard, E, Benham, L, Preston, S, Laha, S, Slawson, N, Bradshaw, Z, Brown, J, Caswell, M, Melling, S, Bamford, P, Faulkner, M, Cawley, K, Jeffrey, H, London, E, Sainsbury, H, Nagra, I, Nasir, F, Dunmore, C, Jones, R, Abraheem, A, Al-Moasseb, M, Girach, R, Padden, G, Egan, J, Brantwood, C, Alexander, P, Bradley-Potts, J, Allen, S, Felton, T, Manna, S, Farnell-Ward, S, Leaver, S, Queiroz, J, Maccacari, E, Dawson, D, C Castro Delgado, R Pepermans Saluzzio, Ezeobu, O, Ding, L, Sicat, C, Kanu, R, Durrant, G, Texeira, J, Harrison, A, Samakomva, T, Willis, H, Hopkins, B, Thrasyvoulou, L, Jackson, M, Zaki, A, Tibke, C, Bennett, S, Woodyatt, W, Kent, A, Goodwin, E, Brandwood, C, Clark, R, Smith, L, Rooney, K, Thomson, N, Rodden, N, Hughes, E, Mcglynn, D, Clark, C, Clark, P, Abel, L, Sundaram, R, Gemmell, L, Brett, M, Hornsby, J, Macgoey, P, Price, R, Digby, B, O'Neil, P, Mcconnell, P, Henderson, P, Henderson, S, Sim, M, Kennedy-Hay, S, Mcparland, C, Rooney, L, Baxter, N, Pogson, D, Rose, S, Daly, Z, Brimfield, L, K Phull, M, Hussain, M, Pogreban, T, Rosaroso, L, Salciute, E, Grauslyte, L, Brealey, D, Raith, E, Maccallum, N, Bercades, G, Hass, I, Smyth, D, Reyes, A, Martir, G, D Clement, I, Webster, K, Hays, C, Gulati, A, Hodgson, L, Margarson, M, Gomez, R, Baird, Y, Thirlwall, Y, Folkes, L, Butler, A, Meadows, E, Moore, S, Raynard, D, Fox, H, Riddles, L, King, K, Kimber, S, Hobden, G, Mccarthy, A, Cannons, V, Balagosa, I, Chadbourn, I, Gardner, A, Horner, D, Mclaughlanv, D, Charles, B, Proudfoot, N, Marsden, T, Mcmorrow, L, Blackledge, B, Pendlebury, J, Harvey, A, Apetri, E, Basikolo, C, Catlow, L, Doonan, R, Knowles, K, Lee, S, Lomas, D, Lyons, C, Perez, J, Poulaka, M, Slaughter, M, Slevin, K, Thomas, V, Walker, D, Harris, J, Drummond, A, Tully, R, Dearden, J, Philbin, J, Munt, S, Rishton, C, O'Connor, G, Mulcahy, M, Dobson, E, Cuttler, J, Edward, M, Norris, J, Hanson, K, Poole, A, Rose, A, Sloan, B, Buckley, S, Brooke, H, Smithson, E, Charlesworth, R, Sandhu, R, Thirumaran, M, Wagstaff, V, J Cebrian Suarez, Kaliappan, A, Vertue, M, Nicholson, A, Riches, J, Solesbury, A, Kittridge, L, Forsey, M, Maloney, G, Cole, J, Davies, R, Hill, H, Thomas, E, Williams, A, Duffin, D, Player, B, Radhakrishnan, J, Gibson, S, Lyle, A, Mcneela, F, Patel, B, Gummadi, M, Sloane, G, Dormand, N, Salmi, S, Farzad, Z, Cristiano, D, Liyanage, K, Thwaites, V, Varghese, M, Meredith, M, Mills, G, Willson, J, Harrington, K, Lenagh, B, Cawthron, K, Masuko, S, Raithatha, A, Bauchmuller, K, Wiles, M, Ahmad, N, Barker, J, Jackson, Y, Kibutu, F, Bird, S, Watson, G, Martin, J, Bevan, E, C Wrey Brown, Trodd, D, English, K, Bell, G, Wilcox, L, Katary, A, Gopal, S, Lake, V, Harris, N, Metherell, S, Radford, E, Moore, F, Bancroft, H, Daglish, J, Sangombe, M, Carmody, M, Rhodes, J, Bellamy, M, Garg, A, Kuravi, A, Virgilio, E, Ranga, P, Butler, J, Botfield, L, Dexter, C, Fletcher, J, Shanmugasundaram, P, Hambrook, G, Burn, I, Manso, K, Thornton, D, Tebbutt, J, Penn, R, Hulme, J, Hussain, S, Maqsood, Z, Joseph, S, Colley, J, Hayes, A, Ahmed, C, Haq, R, Clamp, S, Kumar, R, Purewal, M, Baines, B, Frise, M, Jacques, N, Coles, H, Caterson, J, S Gurung Rai, Brunton, M, Tilney, E, Keating, L, Walden, A, Antcliffe, D, Brett, S, Gordon, A, Templeton, M, Rojo, R, Banach, D, S Sousa Arias, Fernandez, Z, Coghlan, P, Williams, D, Jardine, C, Bewley, J, Sweet, K, Grimmer, L, Johnson, R, Garland, Z, Gumbrill, B, Phillips, C, L Ortiz-Ruiz de Gordoa, Peasgood, E, Tridente, A, Shuker, K, Greer, S, Lynch, C, Pothecary, C, Roche, L, Deacon, B, Turner, K, Singh, J, G Sera Howe, Paul, P, Gill, M, Wynter, I, Ratnam, V, Shelton, S, Naisbitt, J, Melville, J, Baruah, R, Morrison, S, Mcgregor, A, Parris, V, Mpelembue, M, Srikaran, S, Dennis, C, Sukha, A, Verlander, M, Holding, K, Riches, K, Downes, C, Swan, C, Rostron, A, Roy, A, Woods, L, Cornell, S, Wakinshaw, F, Creagh-Brown, B, Blackman, H, Salberg, A, Smith, E, Donlon, S, Mtuwa, S, Michalak-Glinska, N, Stone, S, Beazley, C, Pristopan, V, Nikitas, N, Lankester, L, Wells, C, S Raj, A, Fletcher, K, Khade, R, Tsinaslanidis, G, Macmahon, M, Fowler, S, Coventry, T, Stewart, R, Wren, L, Mwaura, E, Mew, L, Scaletta, D, Williams, F, Inweregbu, K, Lancaster, N, Cunningham, M, Daniels, A, Harrison, L, Hope, S, Jones, S, Crew, A, Wray, G, Matthews, J, Crawley, R, Carter, J, Birkinshaw, I, Ingham, J, Scott, Z, Pearson, H, Howard, K, Joy, R, Roche, S, Clark, M, Purvis, S, Morrison, A, Strachan, D, Clements, S, Black, K, Parmar, C, Altabaibeh, A, Simpson, K, Mostoles, L, Gilbert, K, L, Ma, Alvaro, A, Thomas, M, Faulkner, B, Worner, R, Hayes, K, Gendall, E, Blakemore, H, Borislavova, B, Goff, E, Vuylsteke, A, Mwaura, L, Zamikula, J, Garner, L, Mitchell, A, Mepham, S, Cagova, L, Fofano, A, Holcombe, H, Praman, K, Szakmany, T, E Heron, A, Cherian, S, Cutler, S, Roynon-Reed, A, Randell, G, Convery, K, Stammers, K, Fottrell-Gould, D, Hudig, L, Keshet-Price, J, Peters, M, O'Neill, L, Ray, S, Belfield, H, Mchugh, T, Jones, G, Akinkugbe, O, Tomas, A, Abaleke, E, Beech, E, Meghari, H, Yussuf, S, Bamford, A, Hairsine, B, Dooks, E, Farquhar, F, Packham, S, Bates, H, Armstrong, L, Kaye, C, Allan, A, Medhora, J, Liew, J, Botello, A, Anderson, F, Cusack, R, Golding, H, Prager, K, Williams, T, Leggett, S, Golder, K, Male, M, Jones, O, Criste, K, Marani, M, Anumakonda, V, Amin, V, Karthik, K, Kausar, R, Anastasescu, E, Reid, K, Smith, M, Hormis, A, Walker, R, Duncan, T, Uriel, A, Ustianowski, A, T-Michael, H, Bruce, M, Connolly, K, Smith, K, Partridge, R, Griffin, D, Mupudzi, M, Muchenje, N, Martin, D, Filipe, H, Eastgate, C, Jackson, C, Gratrix, A, Foster, L, Martinson, V, Stones, E, Caroline, Abernathy, Parkinson, P, Reed, A, Prendergast, C, Rogers, P, Woodruff, M, Shokkar, R, Kaul, S, Barron, A, Collins, C, Beavis, S, Whileman, A, Dale, K, Hawes, J, Pritchard, K, Gascoyne, R, Stevenson, L, Jha, R, Lim, L, Krishnamurthy, V, Parker, R, Turner-Bone, I, Wilding, L, Reddy, A, Whiteley, S, Wilby, E, Howcroft, C, Aspinwall, A, Charlton, S, Ogg, B, Menzies, D, Pugh, R, Allan, E, Lean, R, Davies, F, Easton, J, Qiu, X, Kumar, S, Darlington, K, Houston, G, O'Brien, P, Geary, T, Allan, J, Meikle, A, Hughes, G, Balasubramaniam, M, Latham, S, Mckenna, E, Flanagan, R, Sathe, S, Davies, E, Chablani, M, Kirkby, A, Netherton, K, Archer, S, Yates, B, Ashbrook-Raby, C, Cole, S, Casey, M, Cabrelli, L, Chapman, S, Hutcheon, A, Whyte, C, Almaden-Boyle, C, Pattison, N, Cruz, C, Vochin, A, Kent, H, Thomas, A, Murdoch, S, David, B, Penacerrada, M, Lubimbi, G, Bastion, V, Wulandari, R, Lorusso, R, Valentine, J, Clarke, D, Serrano-Ruiz, A, Hierons, S, Eckbad, C, Ramos, L, Demetriou, C, Mitchard, S, White, K, White, N, Pitts, S, Branney, D, Frankham, J, Watters, M, Langton, H, Prout, R, Page, V, Varghes, T, Cowton, A, Kay, A, Potts, K, Birt, M, Kent, M, Wilkinson, A, B Jude, E, Turner, V, Savill, H, Mccormick, J, Coulding, M, Siddiqui, S, Mercer, O, Rehman, H, Potla, D, Capps, N, Donaldson, D, Button, H, Martin, T, Hard, K, Agasou, A, Tonks, L, Arden, T, Boyle, P, Carnahan, M, Strickley, J, Adams, C, Childs, D, Rikunenko, R, Leigh, M, Breekes, M, Wilcox, R, Bowes, A, Tiveran, H, Hurford, F, Summers, J, Carter, A, Hussain, Y, Ting, L, Javaid, A, Motherwell, N, Moore, H, Millward, H, Jose, S, Schunki, N, Noakes, A, Clulow, C, Sadera, G, Jacob, R, Jones, C, Blunt, M, Coton, Z, Curgenven, H, S Mohamed Ally, Beaumont, K, Elsaadany, M, Fernandes, K, I Ali Mohamed Ali, Rangarajan, H, Sarathy, V, Selvanayagam, S, Vedage, D, White, M, Truman, N, Chukkambotla, S, Keith, S, Cockerill-Taylor, J, Ryan-Smith, J, Bolton, R, Springle, P, Dykes, J, Thomas, J, Khan, M, T Hijazi, M, Massey, E, Croston, G, Reschreiter, H, Camsooksai, J, Patch, S, Jenkins, S, Humphrey, C, Wadams, B, Msiska, M, Adanini, O, Attwood, B, Parsons, P, Tatham, K, Jhanji, S, Black, E, A Dela Rosa, Howle, R, Thomas, B, Bemand, T, Raobaikady, R, Saha, R, Staines, N, Daniel, A, Finn, J, Hutter, J, Doble, P, Shovelton, C, Pawley, C, Kannan, T, Hill, M, Combes, E, Monnery, S, Joefield, T, Popescu, M, Thankachen, M, Oblak, M, Little, J, Mcivor, S, Brady, A, Whittle, H, Prady, H, Chan, R, Ahmed, A, Morris, A, Gibson, C, Gordon, E, Keenan, S, Quinn, H, Benyon, S, Marriott, S, Zitter, L, Park, L, Baines, K, Lyons, M, Holland, M, Keenan, N, Young, M, Garrioch, S, Dawson, J, Tolson, M, Scholefield, B, R, Bi, Richardson, N, Schumacher, N, Cosier, T, Millen, G, Higham, A, Turki, S, Allen, L, Crisp, N, Hazleton, T, Knight, A, Deery, J, Price, C, Turney, S, Tilbey, S, Beranova, E, Wright, D, George, L, Twiss, S, Wadd, S, Postlethwaite, K, Gondo, P, Masunda, B, Kayani, A, Hadebe, B, Whiteside, J, Clarke, N, Donnison, P, Trim, F, Leadbitter, I, Butcher, D, O'Sullivan, S, Purewal, B, Bell, S, Rivers, V, O'Leary, R, Birch, J, Collins, E, Anderson, S, Hammerton, K, Andrews, E, Burns, K, Edmond, I, Todd, A, Donnachie, J, Turner, P, Prentice, L, Symon, L, Runciman, N, Auld, F, Halkes, M, Mercer, P, Thornton, L, Debreceni, G, Wilkins, J, Brown, A, Crickmore, V, Subramanian, G, Marshall, R, Jennings, C, Latif, M, Bunni, L, Spivey, M, Bean, S, Burt, K, Linnett, V, Ritzema, J, Sanderson, A, Mccormick, W, Bokhari, M, Kapoor, R, Loader, D, Ayers, A, Harrison, W, North, J, Belagodu, Z, Paramsothy, R, Olufuwa, O, Gherman, A, Fuller, B, Stuart, C, Kelsall, O, Davis, C, Wild, L, Wood, H, Thrush, J, Durie, A, Austin, K, Archer, K, Anderson, P, Vigurs, C, Thorpe, C, Knights, E, Boyle, N, Price, A, Kubisz-Pudelko, A, Wood, D, Lewis, A, Board, S, Pippard, L, Perry, J, Beesley, K, Rattray, A, Lee, E, Lennon, L, Douglas, K, Bell, D, Boyle, R, Glass, L, M Nauman Akhtar, Dent, K, Potoczna, D, Pearson, S, Horsley, E, Spencer, S, Mullan, D, Skinner, D, Gaylard, J, Barber, R, Hewitt, C, Hilldrith, A, Shepardson, S, Wills, M, Jackson-Lawrence, K, Gupta, A, Timlick, E, Gorman, C, Otahal, I, Gales, A, Coetzee, S, Sell, C, Raj, M, Peiu, M, Quaid, S, Watson, E, Elliott, K, Mallinson, J, Chandler, B, Turnbull, A, Finch, C, Holl, C, Cooper, J, Evans, A, Khaliq, W, Collins, A, E Treus Gude, Love, N, L van Koutrik, Hunt, J, Kaye, D, Fisher, E, Brayne, A, Tuckey, V, Jackson, P, Parkin, J, Tariq, A, Houlden, H, Tucci, A, Hardy, J, Moncur, E, Highgate, J, Cowley, A, Mitra, A, Stead, R, Behan, T, Burnett, C, Newton, M, Heeney, E, Pollard, R, Hatton, J, Patel, A, Kasipandian, V, Allibone, S, M Genetu, R, O'Brien, L, Omar, Z, Perkins, E, Davies, K, Tetla, D, Shelley, B, Irvine, V, Williams, S, Williams, P, Goodsell, J, Tutton, R, Bough, L, Winter-Goodwin, B, Kitson, R, Pinnell, J, Wilson, A, Nortcliffe, T, Wood, T, Home, M, Holdroyd, K, Robinson, M, Shaw, R, Greig, J, Brady, M, Haigh, A, Matupe, L, Usher, M, Mellor, S, Dale, S, Gledhill, L, Shaw, L, Turner, G, Kelly, D, Anwar, B, Riley, H, Sturgeon, H, Ali, A, Thomis, L, Melia, D, Dance, A, Humphreys, S, Frost, I, Gopal, V, Godden, J, Holden, A, Swann, S, Smith, T, Clapham, M, Poultney, U, Harper, R, Rice, P, Reece-Anthony, R, Gurung, B, Moultrie, S, Odam, M, Mayer, A, Bellini, A, Pickard, A, Bryant, J, Roe, N, Sowter, J, Lang, K, Taylor, J, Barry, P, Hobrok, M, Tench, H, Wolf-Roberts, R, Mcguinness, H, Loosley, R, Hawcutt, D, Rad, L, O'Malley, L, Saunderson, P, Seddon, G, Anderson, T, Rogers, N, Ruddy, J, Harkins, M, Beith, C, Mcalpine, A, Ferguson, L, Grant, P, Macfadyen, S, Mclaughlin, M, Baird, T, Rundell, S, Welsh, B, Hamill, R, Fisher, F, Gregory, J, Campbell, A, Smuts, S, Gail, Carson, Beatrice, Alex, Benjamin, Bach, Wendy, S Barclay, Debby, Bogaert, Meera, Chand, Graham, S Cooke, Annemarie, B Docherty, Jake, Dunning, Ana da Silva Filipe, Tom, Fletcher, Christoper, A Green, Ewen, M Harrison, Julian, A Hiscox, Antonia Ying Wai Ho, Peter, W Horby, Samreen, Ijaz, Saye, Khoo, Paul, Klenerman, Wei Shen Lim, Alexander, J Mentzer, Laura, Merson, Alison, M Meynert, Mahdad, Noursadeghi, Shona, C Moore, Massimo, Palmarini, William, A Paxton, Georgios, Pollakis, Nicholas, Price, Andrew, Rambaut, David, L Robertson, Vanessa, Sancho-Shimizu, Janet, T Scott, Thushan de Silva, Louise, Sigfrid, Tom, Solomon, Shiranee, Sriskandan, David, Stuart, Richard, S Tedder, Emma, C Thomson, A Roger Thompson, A, Ryan, S Thwaites, Lance C, W Turtle, Maria, Zambon, Hayley, Hardwick, Chloe, Donohue, Ruth, Lyons, Lisa, Norman, Riinu, Pius, Thomas, M Drake, Cameron, J Fairfield, Stephen, R Knight, Kenneth, A Mclean, Derek, Murphy, Catherine, A Shaw, Dalton, Jo, Michelle, Girvan, Egle, Saviciute, Stephanie, Roberts, Janet, Harrison, Laura, Marsh, Marie, Connor, Sophie, Halpin, Clare, Jackson, Carrol, Gamble, Gary, Leeming, Murray, Wham, William, Greenhalf, Victoria, Shaw, Sara, Mcdonald, Seán, Keating, Andrea, Ganna, Patrick, Sulem, David, A van Heel, Mattia, Cordioli, Gardar, Sveinbjornsson, Mari E, K Niemi, Janie, F Shelton, Anjali, J Shastri, Chelsea, Ye, Catherine, H Weldon, Teresa, Filshtein-Sonmez, Daniella, Coker, Antony, Symons, Jorge, Esparza-Gordillo, Stella, Aslibekyan, Adam, Auton, Jose, E Krieger, Emmanuelle, Marques, Cinthia, E Jannes, Mari, Francesca, Daga, Sergio, Baldassarri, Margherita, Benetti, Elisa, Simone, Furini, Fallerini, Chiara, Fava, Francesca, Floriana, Valentino, Gabriella, Doddato, Annarita, Giliberti, Tita, Rossella, Amitrano, Sara, Bruttini, Mirella, Croci, Susanna, Meloni, Ilaria, Pinto, ANNA MARIA, Frullanti, Elisa, Mencarelli, MARIA ANTONIETTA, LO RIZZO, Caterina, Montagnani, Francesca, DI SARNO, Laura, Tommasi, Andrea, Palmieri, Maria, Emiliozzi, Arianna, Fabbiani, Massimiliano, Rossetti, Barbara, Zanelli, Giacomo, Bargagli, Elena, Bergantini, Laura, D'Alessandro, Miriana, Cameli, Paolo, David, Bennet, Anedda, Federico, Marcantonio, Simona, Scolletta, Sabino, Franchi, Federico, Mazzei, MARIA ANTONIETTA, Guerrini, Susanna, Conticini, Edoardo, Cantarini, Luca, Frediani, Bruno, Danilo, Tacconi, SPERTILLI RAFFAELLI, Chiara, Marco, Feri, Alice, Donati, Scala, Raffaele, Luca, Guidelli, Genni, Spargi, Marta, Corridi, Cesira, Nencioni, Croci, Leonardo, Gian Piero Caldarelli, Maurizio, Spagnesi, Paolo, Piacentini, Maria, Bandini, Elena, Desanctis, Cappelli, Silvia, Anna, Canaccini, Verzuri, Agnese, Valentina, Anemoli, Agostino, Ognibene, Massimo, Vaghi, Antonella D'Arminio Monforte, Esther, Merlini, Mario, U Mondelli, Stefania, Mantovani, Serena, Ludovisi, Massimo, Girardis, Sophie, Venturelli, Marco, Sita, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Stefano, Rusconi, Matteo, Siano, Arianna, Gabrieli, Agostino, Riva, Daniela, Francisci, Elisabetta, Schiaroli, Pier Giorgio Scotton, Francesca, Andretta, Sandro, Panese, Renzo, Scaggiante, Francesca, Gatti, Saverio Giuseppe Parisi, Francesco, Castelli, Maria Eugenia Quiros-Roldan, Paola, Magro, Isabella, Zanella, Matteo Della Monica, Carmelo, Piscopo, Mario, Capasso, Roberta, Russo, Immacolata, Andolfo, Achille, Iolascon, Giuseppe, Fiorentino, Massimo, Carella, Marco, Castori, Giuseppe, Merla, Filippo, Aucella, Pamela, Raggi, Carmen, Marciano, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Valente, Serafina, Marco, Mandalà, Giorli, Alessia, Salerni, Lorenzo, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Stefano, Baratti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Domenico, A Coviello, Cristina, Mussini, Giancarlo, Bosio, Enrico, Martinelli, Sandro, Mancarella, Luisa, Tavecchia, Lia, Crotti, Nicola, Picchiotti, Marco, Gori, Chiara, Gabbi, Maurizio, Sanarico, Stefano, Ceri, Pietro, Pinoli, Francesco, Raimondi, Filippo, Biscarini, Alessandra, Stella, Alessandra, Shen, Xia, Ponting, Chris P, Fawkes, Angie, Tenesa, Albert, Caulfield, Mark, Scott, Richard, Rowan, Kathy, Murphy, Lee, Openshaw, Peter J M, Semple, Malcolm G, Law, Andrew, Vitart, Veronique, Wilson, James F, Baillie, J Kenneth, Pairo-Castineira, E, Clohisey, S, Klaric, L, Bretherick, A, Rawlik, K, Pasko, D, Walker, S, Parkinson, N, Fourman, M, Russell, C, Furniss, J, Richmond, A, Gountouna, E, Wrobel, N, Harrison, D, Wang, B, Wu, Y, Meynert, A, Griffiths, F, Oosthuyzen, W, Kousathanas, A, Moutsianas, L, Yang, Z, Zhai, R, Zheng, C, Grimes, G, Beale, R, Millar, J, Shih, B, Keating, S, Zechner, M, Haley, C, Porteous, D, Hayward, C, Yang, J, Knight, J, Summers, C, Shankar-Hari, M, Klenerman, P, Turtle, L, Ho, A, Moore, S, Hinds, C, Horby, P, Nichol, A, Maslove, D, Ling, L, Mcauley, D, Montgomery, H, Walsh, T, Pereira, A, Renieri, A, Ponting, C, Meikle, J, Finernan, P, Mcmaster, E, Law, A, Baillie, J, Paterson, T, Wackett, T, Armstrong, R, Clark, R, Coutts, A, Donnelly, L, Gilchrist, T, Hafezi, K, Macgillivray, L, Maclean, A, Mccafferty, S, Morrice, K, Weaver, J, Boz, C, Golightly, A, Ward, M, Mal, H, Szoor-McElhinney, H, Brown, A, Hendry, R, Stenhouse, A, Cullum, L, Law, D, Law, S, Law, R, Swets, M, Day, N, Taneski, F, Duncan, E, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthope, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, Jones, T, Whitton, C, Marotti, M, Arbane, G, Bonner, S, Hugill, K, Reid, J, Welters, I, Waugh, V, Williams, K, Shaw, D, Roman, J, Martinez, M, Johnson, E, Waite, A, Johnston, B, Hamilton, D, Mulla, S, Mcphail, M, Smith, J, Barclay, L, Hope, D, Mcculloch, C, Mcquillan, L, Clark, S, Singleton, J, Priestley, K, Rea, N, Callaghan, M, Campbell, R, Andrew, G, Marshall, L, Mckechnie, S, Hutton, P, Bashyal, A, Davidson, N, Polgarova, P, Stroud, K, Pathan, N, Elston, K, Agrawal, S, Battle, C, Newey, L, Rees, T, Harford, R, Brinkworth, E, Williams, M, Murphy, C, White, I, Croft, M, Bandla, N, Gellamucho, M, Tomlinson, J, Turner, H, Davies, M, Quinn, A, Hussain, I, Thompson, C, Parker, H, Bradley, R, Griffiths, R, Scriven, J, Nilsson, A, Bates, M, Dasgin, J, Gill, J, Puxty, A, Cathcart, S, Salutous, D, Turner, L, Duffy, K, Puxty, K, Joseph, A, Herdman-Grant, R, Simms, R, Swain, A, Naranjo, A, Crowe, R, Sollesta, K, Loveridge, A, Baptista, D, Morino, E, Davey, M, Golden, D, Jones, J, Moreno Cuesta, J, Haldeos, A, Bakthavatsalam, D, Vincent, R, Elhassan, M, Xavier, K, Ganesan, A, Purohit, D, Abdelrazik, M, Morgan, J, Akeroyd, L, Bano, S, Lawton, T, Warren, D, Bromley, M, Sellick, K, Gurr, L, Wilkinson, B, Nagarajan, V, Szedlak, P, Cupitt, J, Stoddard, E, Benham, L, Preston, S, Laha, S, Slawson, N, Bradshaw, Z, Brown, J, Caswell, M, Melling, S, Bamford, P, Faulkner, M, Cawley, K, Jeffrey, H, London, E, Sainsbury, H, Nagra, I, Nasir, F, Dunmore, C, Jones, R, Abraheem, A, Al-Moasseb, M, Girach, R, Padden, G, Egan, J, Brantwood, C, Alexander, P, Bradley-Potts, J, Allen, S, Felton, T, Manna, S, Farnell-Ward, S, Leaver, S, Queiroz, J, Maccacari, E, Dawson, D, Delgado, C, Saluzzio, R, Ezeobu, O, Ding, L, Sicat, C, Kanu, R, Durrant, G, Texeira, J, Harrison, A, Samakomva, T, Willis, H, Hopkins, B, Thrasyvoulou, L, Jackson, M, Zaki, A, Tibke, C, Bennett, S, Woodyatt, W, Kent, A, Goodwin, E, Brandwood, C, Smith, L, Rooney, K, Thomson, N, Rodden, N, Hughes, E, Mcglynn, D, Clark, C, Clark, P, Abel, L, Sundaram, R, Gemmell, L, Brett, M, Hornsby, J, Macgoey, P, Price, R, Digby, B, O'Neil, P, Mcconnell, P, Henderson, P, Henderson, S, Sim, M, Kennedy-Hay, S, Mcparland, C, Rooney, L, Baxter, N, Pogson, D, Rose, S, Daly, Z, Brimfield, L, Phull, M, Hussain, M, Pogreban, T, Rosaroso, L, Salciute, E, Grauslyte, L, Brealey, D, Raith, E, Maccallum, N, Bercades, G, Hass, I, Smyth, D, Reyes, A, Martir, G, Clement, I, Webster, K, Hays, C, Gulati, A, Hodgson, L, Margarson, M, Gomez, R, Baird, Y, Thirlwall, Y, Folkes, L, Butler, A, Meadows, E, Raynard, D, Fox, H, Riddles, L, King, K, Kimber, S, Hobden, G, Mccarthy, A, Cannons, V, Balagosa, I, Chadbourn, I, Gardner, A, Horner, D, Mclaughlanv, D, Charles, B, Proudfoot, N, Marsden, T, Mcmorrow, L, Blackledge, B, Pendlebury, J, Harvey, A, Apetri, E, Basikolo, C, Catlow, L, Doonan, R, Knowles, K, Lee, S, Lomas, D, Lyons, C, Perez, J, Poulaka, M, Slaughter, M, Slevin, K, Thomas, V, Walker, D, Harris, J, Drummond, A, Tully, R, Dearden, J, Philbin, J, Munt, S, Rishton, C, O'Connor, G, Mulcahy, M, Dobson, E, Cuttler, J, Edward, M, Norris, J, Hanson, K, Poole, A, Rose, A, Sloan, B, Buckley, S, Brooke, H, Smithson, E, Charlesworth, R, Sandhu, R, Thirumaran, M, Wagstaff, V, Suarez, J, Kaliappan, A, Vertue, M, Nicholson, A, Riches, J, Solesbury, A, Kittridge, L, Forsey, M, Maloney, G, Cole, J, Davies, R, Hill, H, Thomas, E, Williams, A, Duffin, D, Player, B, Radhakrishnan, J, Gibson, S, Lyle, A, Mcneela, F, Patel, B, Gummadi, M, Sloane, G, Dormand, N, Salmi, S, Farzad, Z, Cristiano, D, Liyanage, K, Thwaites, V, Varghese, M, Meredith, M, Mills, G, Willson, J, Harrington, K, Lenagh, B, Cawthron, K, Masuko, S, Raithatha, A, Bauchmuller, K, Wiles, M, Ahmad, N, Barker, J, Jackson, Y, Kibutu, F, Bird, S, Watson, G, Martin, J, Bevan, E, Brown, C, Trodd, D, English, K, Bell, G, Wilcox, L, Katary, A, Gopal, S, Lake, V, Harris, N, Metherell, S, Radford, E, Moore, F, Bancroft, H, Daglish, J, Sangombe, M, Carmody, M, Rhodes, J, Bellamy, M, Garg, A, Kuravi, A, Virgilio, E, Ranga, P, Butler, J, Botfield, L, Dexter, C, Fletcher, J, Shanmugasundaram, P, Hambrook, G, Burn, I, Manso, K, Thornton, D, Tebbutt, J, Penn, R, Hulme, J, Hussain, S, Maqsood, Z, Joseph, S, Colley, J, Hayes, A, Ahmed, C, Haq, R, Clamp, S, Kumar, R, Purewal, M, Baines, B, Frise, M, Jacques, N, Coles, H, Caterson, J, Rai, S, Brunton, M, Tilney, E, Keating, L, Walden, A, Antcliffe, D, Brett, S, Gordon, A, Templeton, M, Rojo, R, Banach, D, Arias, S, Fernandez, Z, Coghlan, P, Williams, D, Jardine, C, Bewley, J, Sweet, K, Grimmer, L, Johnson, R, Garland, Z, Gumbrill, B, Phillips, C, Ortiz-Ruiz de Gordoa, L, Peasgood, E, Tridente, A, Shuker, K, Greer, S, Lynch, C, Pothecary, C, Roche, L, Deacon, B, Turner, K, Singh, J, Howe, G, Paul, P, Gill, M, Wynter, I, Ratnam, V, Shelton, S, Naisbitt, J, Melville, J, Baruah, R, Morrison, S, Mcgregor, A, Parris, V, Mpelembue, M, Srikaran, S, Dennis, C, Sukha, A, Verlander, M, Holding, K, Riches, K, Downes, C, Swan, C, Rostron, A, Roy, A, Woods, L, Cornell, S, Wakinshaw, F, Creagh-Brown, B, Blackman, H, Salberg, A, Smith, E, Donlon, S, Mtuwa, S, Michalak-Glinska, N, Stone, S, Beazley, C, Pristopan, V, Nikitas, N, Lankester, L, Wells, C, Raj, A, Fletcher, K, Khade, R, Tsinaslanidis, G, Macmahon, M, Fowler, S, Coventry, T, Stewart, R, Wren, L, Mwaura, E, Mew, L, Scaletta, D, Williams, F, Inweregbu, K, Lancaster, N, Cunningham, M, Daniels, A, Harrison, L, Hope, S, Jones, S, Crew, A, Wray, G, Matthews, J, Crawley, R, Carter, J, Birkinshaw, I, Ingham, J, Scott, Z, Pearson, H, Howard, K, Joy, R, Roche, S, Clark, M, Purvis, S, Morrison, A, Strachan, D, Clements, S, Black, K, Parmar, C, Altabaibeh, A, Simpson, K, Mostoles, L, Gilbert, K, Ma, L, Alvaro, A, Thomas, M, Faulkner, B, Worner, R, Hayes, K, Gendall, E, Blakemore, H, Borislavova, B, Goff, E, Vuylsteke, A, Mwaura, L, Zamikula, J, Garner, L, Mitchell, A, Mepham, S, Cagova, L, Fofano, A, Holcombe, H, Praman, K, Szakmany, T, Heron, A, Cherian, S, Cutler, S, Roynon-Reed, A, Randell, G, Convery, K, Stammers, K, Fottrell-Gould, D, Hudig, L, Keshet-Price, J, Peters, M, O'Neill, L, Ray, S, Belfield, H, Mchugh, T, Jones, G, Akinkugbe, O, Tomas, A, Abaleke, E, Beech, E, Meghari, H, Yussuf, S, Bamford, A, Hairsine, B, Dooks, E, Farquhar, F, Packham, S, Bates, H, Armstrong, L, Kaye, C, Allan, A, Medhora, J, Liew, J, Botello, A, Anderson, F, Cusack, R, Golding, H, Prager, K, Williams, T, Leggett, S, Golder, K, Male, M, Jones, O, Criste, K, Marani, M, Anumakonda, V, Amin, V, Karthik, K, Kausar, R, Anastasescu, E, Reid, K, Smith, M, Hormis, A, Walker, R, Duncan, T, Uriel, A, Ustianowski, A, T-Michael, H, Bruce, M, Connolly, K, Smith, K, Partridge, R, Griffin, D, Mupudzi, M, Muchenje, N, Martin, D, Filipe, H, Eastgate, C, Jackson, C, Gratrix, A, Foster, L, Martinson, V, Stones, E, Abernathy, C, Parkinson, P, Reed, A, Prendergast, C, Rogers, P, Woodruff, M, Shokkar, R, Kaul, S, Barron, A, Collins, C, Beavis, S, Whileman, A, Dale, K, Hawes, J, Pritchard, K, Gascoyne, R, Stevenson, L, Jha, R, Lim, L, Krishnamurthy, V, Parker, R, Turner-Bone, I, Wilding, L, Reddy, A, Whiteley, S, Wilby, E, Howcroft, C, Aspinwall, A, Charlton, S, Ogg, B, Menzies, D, Pugh, R, Allan, E, Lean, R, Davies, F, Easton, J, Qiu, X, Kumar, S, Darlington, K, Houston, G, O'Brien, P, Geary, T, Allan, J, Meikle, A, Hughes, G, Balasubramaniam, M, Latham, S, Mckenna, E, Flanagan, R, Sathe, S, Davies, E, Chablani, M, Kirkby, A, Netherton, K, Archer, S, Yates, B, Ashbrook-Raby, C, Cole, S, Casey, M, Cabrelli, L, Chapman, S, Hutcheon, A, Whyte, C, Almaden-Boyle, C, Pattison, N, Cruz, C, Vochin, A, Kent, H, Thomas, A, Murdoch, S, David, B, Penacerrada, M, Lubimbi, G, Bastion, V, Wulandari, R, Lorusso, R, Valentine, J, Clarke, D, Serrano-Ruiz, A, Hierons, S, Eckbad, C, Ramos, L, Demetriou, C, Mitchard, S, White, K, White, N, Pitts, S, Branney, D, Frankham, J, Watters, M, Langton, H, Prout, R, Page, V, Varghes, T, Cowton, A, Kay, A, Potts, K, Birt, M, Kent, M, Wilkinson, A, Jude, E, Turner, V, Savill, H, Mccormick, J, Coulding, M, Siddiqui, S, Mercer, O, Rehman, H, Potla, D, Capps, N, Donaldson, D, Button, H, Martin, T, Hard, K, Agasou, A, Tonks, L, Arden, T, Boyle, P, Carnahan, M, Strickley, J, Adams, C, Childs, D, Rikunenko, R, Leigh, M, Breekes, M, Wilcox, R, Bowes, A, Tiveran, H, Hurford, F, Summers, J, Carter, A, Hussain, Y, Ting, L, Javaid, A, Motherwell, N, Moore, H, Millward, H, Jose, S, Schunki, N, Noakes, A, Clulow, C, Sadera, G, Jacob, R, Jones, C, Blunt, M, Coton, Z, Curgenven, H, Ally, S, Beaumont, K, Elsaadany, M, Fernandes, K, Ali Mohamed Ali, I, Rangarajan, H, Sarathy, V, Selvanayagam, S, Vedage, D, White, M, Truman, N, Chukkambotla, S, Keith, S, Cockerill-Taylor, J, Ryan-Smith, J, Bolton, R, Springle, P, Dykes, J, Thomas, J, Khan, M, Hijazi, M, Massey, E, Croston, G, Reschreiter, H, Camsooksai, J, Patch, S, Jenkins, S, Humphrey, C, Wadams, B, Msiska, M, Adanini, O, Attwood, B, Parsons, P, Tatham, K, Jhanji, S, Black, E, Dela Rosa, A, Howle, R, Thomas, B, Bemand, T, Raobaikady, R, Saha, R, Staines, N, Daniel, A, Finn, J, Hutter, J, Doble, P, Shovelton, C, Pawley, C, Kannan, T, Hill, M, Combes, E, Monnery, S, Joefield, T, Popescu, M, Thankachen, M, Oblak, M, Little, J, Mcivor, S, Brady, A, Whittle, H, Prady, H, Chan, R, Ahmed, A, Morris, A, Gibson, C, Gordon, E, Keenan, S, Quinn, H, Benyon, S, Marriott, S, Zitter, L, Park, L, Baines, K, Lyons, M, Holland, M, Keenan, N, Young, M, Garrioch, S, Dawson, J, Tolson, M, Scholefield, B, Bi, R, Richardson, N, Schumacher, N, Cosier, T, Millen, G, Higham, A, Turki, S, Allen, L, Crisp, N, Hazleton, T, Knight, A, Deery, J, Price, C, Turney, S, Tilbey, S, Beranova, E, Wright, D, George, L, Twiss, S, Wadd, S, Postlethwaite, K, Gondo, P, Masunda, B, Kayani, A, Hadebe, B, Whiteside, J, Clarke, N, Donnison, P, Trim, F, Leadbitter, I, Butcher, D, O'Sullivan, S, Purewal, B, Bell, S, Rivers, V, O'Leary, R, Birch, J, Collins, E, Anderson, S, Hammerton, K, Andrews, E, Burns, K, Edmond, I, Todd, A, Donnachie, J, Turner, P, Prentice, L, Symon, L, Runciman, N, Auld, F, Halkes, M, Mercer, P, Thornton, L, Debreceni, G, Wilkins, J, Crickmore, V, Subramanian, G, Marshall, R, Jennings, C, Latif, M, Bunni, L, Spivey, M, Bean, S, Burt, K, Linnett, V, Ritzema, J, Sanderson, A, Mccormick, W, Bokhari, M, Kapoor, R, Loader, D, Ayers, A, Harrison, W, North, J, Belagodu, Z, Paramsothy, R, Olufuwa, O, Gherman, A, Fuller, B, Stuart, C, Kelsall, O, Davis, C, Wild, L, Wood, H, Thrush, J, Durie, A, Austin, K, Archer, K, Anderson, P, Vigurs, C, Thorpe, C, Knights, E, Boyle, N, Price, A, Kubisz-Pudelko, A, Wood, D, Lewis, A, Board, S, Pippard, L, Perry, J, Beesley, K, Rattray, A, Lee, E, Lennon, L, Douglas, K, Bell, D, Boyle, R, Glass, L, Nauman Akhtar, M, Dent, K, Potoczna, D, Pearson, S, Horsley, E, Spencer, S, Mullan, D, Skinner, D, Gaylard, J, Barber, R, Hewitt, C, Hilldrith, A, Shepardson, S, Wills, M, Jackson-Lawrence, K, Gupta, A, Timlick, E, Gorman, C, Otahal, I, Gales, A, Coetzee, S, Sell, C, Raj, M, Peiu, M, Quaid, S, Watson, E, Elliott, K, Mallinson, J, Chandler, B, Turnbull, A, Finch, C, Holl, C, Cooper, J, Evans, A, Khaliq, W, Collins, A, Gude, E, Love, N, van Koutrik, L, Hunt, J, Kaye, D, Fisher, E, Brayne, A, Tuckey, V, Jackson, P, Parkin, J, Tariq, A, Houlden, H, Tucci, A, Hardy, J, Moncur, E, Highgate, J, Cowley, A, Mitra, A, Stead, R, Behan, T, Burnett, C, Newton, M, Heeney, E, Pollard, R, Hatton, J, Patel, A, Kasipandian, V, Allibone, S, Genetu, R, O'Brien, L, Omar, Z, Perkins, E, Davies, K, Tetla, D, Shelley, B, Irvine, V, Williams, S, Williams, P, Goodsell, J, Tutton, R, Bough, L, Winter-Goodwin, B, Kitson, R, Pinnell, J, Wilson, A, Nortcliffe, T, Wood, T, Home, M, Holdroyd, K, Robinson, M, Shaw, R, Greig, J, Brady, M, Haigh, A, Matupe, L, Usher, M, Mellor, S, Dale, S, Gledhill, L, Shaw, L, Turner, G, Kelly, D, Anwar, B, Riley, H, Sturgeon, H, Ali, A, Thomis, L, Melia, D, Dance, A, Humphreys, S, Frost, I, Gopal, V, Godden, J, Holden, A, Swann, S, Smith, T, Clapham, M, Poultney, U, Harper, R, Rice, P, Reece-Anthony, R, Gurung, B, Moultrie, S, Odam, M, Mayer, A, Bellini, A, Pickard, A, Bryant, J, Roe, N, Sowter, J, Lang, K, Taylor, J, Barry, P, Hobrok, M, Tench, H, Wolf-Roberts, R, Mcguinness, H, Loosley, R, Hawcutt, D, Rad, L, O'Malley, L, Saunderson, P, Seddon, G, Anderson, T, Rogers, N, Ruddy, J, Harkins, M, Beith, C, Mcalpine, A, Ferguson, L, Grant, P, Macfadyen, S, Mclaughlin, M, Baird, T, Rundell, S, Welsh, B, Hamill, R, Fisher, F, Gregory, J, Campbell, A, Smuts, S, Kenneth Baillie, J, Carson, G, Alex, B, Bach, B, Barclay, W, Bogaert, D, Chand, M, Cooke, G, Docherty, A, Dunning, J, da Silva Filipe, A, Fletcher, T, Green, C, Harrison, E, Hiscox, J, Ijaz, S, Khoo, S, Lim, W, Mentzer, A, Merson, L, Noursadeghi, M, Palmarini, M, Paxton, W, Pollakis, G, Price, N, Rambaut, A, Robertson, D, Sancho-Shimizu, V, Scott, J, de Silva, T, Sigfrid, L, Solomon, T, Sriskandan, S, Stuart, D, Tedder, R, Thomson, E, Thompson, A, Thwaites, R, Zambon, M, Hardwick, H, Donohue, C, Lyons, R, Norman, L, Pius, R, Drake, T, Fairfield, C, Knight, S, Mclean, K, Murphy, D, Shaw, C, Dalton, J, Girvan, M, Saviciute, E, Roberts, S, Harrison, J, Marsh, L, Connor, M, Halpin, S, Gamble, C, Leeming, G, Wham, M, Greenhalf, W, Shaw, V, Mcdonald, S, Ganna, A, Sulem, P, van Heel, D, Cordioli, M, Sveinbjornsson, G, Niemi, M, Shelton, J, Shastri, A, Ye, C, Weldon, C, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, Auton, A, Krieger, J, Marques, E, Jannes, C, Mari, F, Daga, S, Baldassarri, M, Benetti, E, Furini, S, Fallerini, C, Fava, F, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Pinto, A, Frullanti, E, Mencarelli, M, Rizzo, C, Montagnani, F, Di Sarno, L, Tommasi, A, Palmieri, M, Emiliozzi, A, Fabbiani, M, Rossetti, B, Zanelli, G, Bargagli, E, Bergantini, L, D'Alessandro, M, Cameli, P, Bennet, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, G, Spagnesi, M, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Vaghi, M, D'Arminio Monforte, A, Merlini, E, Mondelli, M, Mantovani, S, Ludovisi, S, Girardis, M, Venturelli, S, Sita, M, Cossarizza, A, Antinori, A, Vergori, A, Rusconi, S, Siano, M, 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Konrad [0000-0002-0010-370X], Walker, Susan [0000-0002-5016-6426], Fourman, Max Head [0000-0001-7381-2278], Russell, Clark D [0000-0002-9873-8243], Gountouna, Elvina [0000-0001-7870-2780], Wang, Bo [0000-0002-1580-797X], Wu, Yang [0000-0002-0128-7280], Kousathanas, Athanasios [0000-0001-6265-6521], Moutsianas, Loukas [0000-0001-5453-345X], Zhai, Ranran [0000-0002-5834-9120], Beale, Rupert [0000-0002-6705-8560], Keating, Sean [0000-0001-8552-5604], Haley, Chris [0000-0002-9811-0210], Porteous, David J [0000-0003-1249-6106], Hayward, Caroline [0000-0002-9405-9550], Yang, Jian [0000-0003-2001-2474], Knight, Julian [0000-0002-0377-5536], Summers, Charlotte [0000-0002-7269-2873], Shankar-Hari, Manu [0000-0002-5338-2538], Turtle, Lance [0000-0002-0778-1693], Moore, Shona C [0000-0001-8610-2806], Hinds, Charles [0000-0001-5094-8324], McAuley, Danny [0000-0002-3283-1947], Montgomery, Hugh [0000-0001-8797-5019], Renieri, Alessandra [0000-0002-0846-9220], Shen, Xia [0000-0003-4390-1979], Ponting, Chris P [0000-0003-0202-7816], Tenesa, Albert [0000-0003-4884-4475], Caulfield, Mark [0000-0001-9295-3594], Rowan, Kathy [0000-0001-8217-5602], Murphy, Lee [0000-0001-6467-7449], Openshaw, Peter JM [0000-0002-7220-2555], Semple, Malcolm G [0000-0001-9700-0418], Law, Andrew [0000-0003-1868-2364], Vitart, Veronique [0000-0002-4991-3797], Wilson, James F [0000-0001-5751-9178], Baillie, J Kenneth [0000-0001-5258-793X], Apollo - University of Cambridge Repository, Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A. 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O., Whitton, C., Marotti, M., Arbane, G., Bonner, S., Hugill, K., Reid, J., Welters, I., Waugh, V., Williams, K., Shaw, D., Roman, J. F., Martinez, M. 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T., Massey, E., Croston, G., Reschreiter, H., Camsooksai, J., Patch, S., Jenkins, S., Humphrey, C., Wadams, B., Msiska, M., Adanini, O., Attwood, B., Parsons, P., Tatham, K., Jhanji, S., Black, E., Dela Rosa, A., Howle, R., Thomas, B., Bemand, T., Raobaikady, R., Saha, R., Staines, N., Daniel, A., Finn, J., Hutter, J., Doble, P., Shovelton, C., Pawley, C., Kannan, T., Hill, M., Combes, E., Monnery, S., Joefield, T., Popescu, M., Thankachen, M., Oblak, M., Little, J., Mcivor, S., Brady, A., Whittle, H., Prady, H., Chan, R., Ahmed, A., Morris, A., Gibson, C., Gordon, E., Keenan, S., Quinn, H., Benyon, S., Marriott, S., Zitter, L., Park, L., Baines, K., Lyons, M., Holland, M., Keenan, N., Young, M., Garrioch, S., Dawson, J., Tolson, M., Scholefield, B., Bi, R., Richardson, N., Schumacher, N., Cosier, T., Millen, G., Higham, A., Turki, S., Allen, L., Crisp, N., Hazleton, T., Knight, A., Deery, J., Price, C., Turney, S., Tilbey, S., Beranova, E., Wright, D., George, L., Twiss, S., Wadd, S., Postlethwaite, K., Gondo, P., Masunda, B., Kayani, A., Hadebe, B., Whiteside, J., Clarke, N., Donnison, P., Trim, F., Leadbitter, I., Butcher, D., O'Sullivan, S., Purewal, B., Bell, S., Rivers, V., O'Leary, R., Birch, J., Collins, E., Anderson, S., Hammerton, K., Andrews, E., Burns, K., Edmond, I., Todd, A., Donnachie, J., Turner, P., Prentice, L., Symon, L., Runciman, N., Auld, F., Halkes, M., Mercer, P., Thornton, L., Debreceni, G., Wilkins, J., Crickmore, V., Subramanian, G., Marshall, R., Jennings, C., Latif, M., Bunni, L., Spivey, M., Bean, S., Burt, K., Linnett, V., Ritzema, J., Sanderson, A., Mccormick, W., Bokhari, M., Kapoor, R., Loader, D., Ayers, A., Harrison, W., North, J., Belagodu, Z., Paramsothy, R., Olufuwa, O., Gherman, A., Fuller, B., Stuart, C., Kelsall, O., Davis, C., Wild, L., Wood, H., Thrush, J., Durie, A., Austin, K., Archer, K., Anderson, P., Vigurs, C., Thorpe, C., Knights, E., Boyle, N., Price, A., Kubisz-Pudelko, A., Wood, D., Lewis, A., Board, S., Pippard, L., Perry, J., Beesley, K., Rattray, A., Lee, E., Lennon, L., Douglas, K., Bell, D., Boyle, R., Glass, L., Nauman Akhtar, M., Dent, K., Potoczna, D., Pearson, S., Horsley, E., Spencer, S., Mullan, D., Skinner, D., Gaylard, J., Barber, R., Hewitt, C., Hilldrith, A., Shepardson, S., Wills, M., Jackson-Lawrence, K., Gupta, A., Timlick, E., Gorman, C., Otahal, I., Gales, A., Coetzee, S., Sell, C., Raj, M., Peiu, M., Quaid, S., Watson, E., Elliott, K., Mallinson, J., Chandler, B., Turnbull, A., Finch, C., Holl, C., Cooper, J., Evans, A., Khaliq, W., Collins, A., Gude, E. T., Love, N., van Koutrik, L., Hunt, J., Kaye, D., Fisher, E., Brayne, A., Tuckey, V., Jackson, P., Parkin, J., Tariq, A., Houlden, H., Tucci, A., Hardy, J., Moncur, E., Highgate, J., Cowley, A., Mitra, A., Stead, R., Behan, T., Burnett, C., Newton, M., Heeney, E., Pollard, R., Hatton, J., Patel, A., Kasipandian, V., Allibone, S., Genetu, R. M., O'Brien, L., Omar, Z., Perkins, E., Davies, K., Tetla, D., Shelley, B., Irvine, V., Williams, S., Williams, P., Goodsell, J., Tutton, R., Bough, L., Winter-Goodwin, B., Kitson, R., Pinnell, J., Wilson, A., Nortcliffe, T., Wood, T., Home, M., Holdroyd, K., Robinson, M., Shaw, R., Greig, J., Brady, M., Haigh, A., Matupe, L., Usher, M., Mellor, S., Dale, S., Gledhill, L., Shaw, L., Turner, G., Kelly, D., Anwar, B., Riley, H., Sturgeon, H., Ali, A., Thomis, L., Melia, D., Dance, A., Humphreys, S., Frost, I., Gopal, V., Godden, J., Holden, A., Swann, S., Smith, T., Clapham, M., Poultney, U., Harper, R., Rice, P., Reece-Anthony, R., Gurung, B., Moultrie, S., Odam, M., Mayer, A., Bellini, A., Pickard, A., Bryant, J., Roe, N., Sowter, J., Lang, K., Taylor, J., Barry, P., Hobrok, M., Tench, H., Wolf-Roberts, R., Mcguinness, H., Loosley, R., Hawcutt, D., Rad, L., O'Malley, L., Saunderson, P., Seddon, G., Anderson, T., Rogers, N., Ruddy, J., Harkins, M., Beith, C., Mcalpine, A., Ferguson, L., Grant, P., Macfadyen, S., Mclaughlin, M., Baird, T., Rundell, S., Welsh, B., Hamill, R., Fisher, F., Gregory, J., Campbell, A., Smuts, S., Kenneth Baillie, J., Carson, G., Alex, B., Bach, B., Barclay, W. S., Bogaert, D., Chand, M., Cooke, G. S., Docherty, A. B., Dunning, J., da Silva Filipe, A., Fletcher, T., Green, C. A., Harrison, E. M., Hiscox, J. A., Ho, A. Y. W., Horby, P. W., Ijaz, S., Khoo, S., Lim, W. S., Mentzer, A. J., Merson, L., Meynert, A. M., Noursadeghi, M., Palmarini, M., Paxton, W. A., Pollakis, G., Price, N., Rambaut, A., Robertson, D. L., Sancho-Shimizu, V., Scott, J. T., de Silva, T., Sigfrid, L., Solomon, T., Sriskandan, S., Stuart, D., Tedder, R. S., Thomson, E. C., Thompson, A. A. R., Thwaites, R. S., Turtle, L. C. W., Zambon, M., Hardwick, H., Donohue, C., Lyons, R., Norman, L., Pius, R., Drake, T. M., Fairfield, C. J., Knight, S. R., Mclean, K. A., Murphy, D., Shaw, C. A., Dalton, J., Girvan, M., Saviciute, E., Roberts, S., Harrison, J., Marsh, L., Connor, M., Halpin, S., Gamble, C., Leeming, G., Wham, M., Greenhalf, W., Shaw, V., Mcdonald, S., Ganna, A., Sulem, P., van Heel, D. A., Cordioli, M., Sveinbjornsson, G., Niemi, M. E. K., Shelton, J. F., Shastri, A. J., Ye, C., Weldon, C. H., Filshtein-Sonmez, T., Coker, D., Symons, A., Esparza-Gordillo, J., Aslibekyan, S., Auton, A., Krieger, J. E., Marques, E., Jannes, C. E., Mari, F., Daga, S., Baldassarri, M., Benetti, E., Furini, S., Fallerini, C., Fava, F., Valentino, F., Doddato, G., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Pinto, A. M., Frullanti, E., Mencarelli, M. A., Rizzo, C. L., Montagnani, F., Di Sarno, L., Tommasi, A., Palmieri, M., Emiliozzi, A., Fabbiani, M., Rossetti, B., Zanelli, G., Bargagli, E., Bergantini, L., D'Alessandro, M., Cameli, P., Bennet, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Spertilli, C., Feri, M., Donati, A., Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Spagnesi, M., Piacentini, P., Bandini, M., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Ognibene, A., Vaghi, M., D'Arminio Monforte, A., Merlini, E., Mondelli, M. U., Mantovani, S., Ludovisi, S., Girardis, M., Venturelli, S., Sita, M., Cossarizza, A., Antinori, A., Vergori, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Gatti, F., Parisi, S. G., Castelli, F., Quiros-Roldan, M. E., Magro, P., Zanella, I., Della Monica, M., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Merla, G., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, M., Masucci, L., Valente, S., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Baratti, S., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Bosio, G., Martinelli, E., Mancarella, S., Tavecchia, L., Crotti, L., Picchiotti, N., Gori, M., Gabbi, C., Sanarico, M., Ceri, S., Pinoli, P., Raimondi, F., Biscarini, F., Stella, A., Shen, X., Ponting, C. P., Fawkes, A., Tenesa, A., Caulfield, M., Scott, R., Rowan, K., Murphy, L., Openshaw, P. J. M., Semple, M. G., Vitart, V., and Wilson, J. F.
Subjects: 0301 basic medicine, Male, CCR2, Chromosomes, Human, Pair 21, Genome-wide association study, Receptor, Interferon alpha-beta, Disease, Bioinformatics, Genome-wide association studies, 23andMe Investigators, Interferon alpha-beta, 0302 clinical medicine, Receptors, 2',5'-Oligoadenylate Synthetase, Pair 12, genetics, Lung, BRACOVID Investigators, Multidisciplinary, GenOMICC Investigators, Tyrosine kinase 2, 030220 oncology & carcinogenesis, Multigene Family, Medical genetics, Female, Dipeptidyl-Peptidases and Tripeptidyl-Peptidase, 5'-Oligoadenylate Synthetase, Human, Receptor, medicine.medical_specialty, Critical Care, Receptors, CCR2, General Science & Technology, Critical Illness, Chromosomes, 03 medical and health sciences, Intensive care, Mendelian randomization, Immunogenetics, medicine, Humans, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Gen-COVID Investigators, Inflammation, TYK2 Kinase, Chromosomes, Human, Pair 12, Pair 19, SARS-CoV-2, business.industry, Drug Repositioning, COVID-19, United Kingdom, COVID-19 Human Genetics Initiative, 030104 developmental biology, Viral infection, Chromosomes, Human, Pair 19, Genome-Wide Association Study, Pharmacogenomics, ISARICC Investigators, Pair 21, 2', business
Abstract: Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079,P=1.65×10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1,OAS2andOAS3); on chromosome 19p13.2 (rs74956615,P=2.3×10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069,P=3.98× 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757,P=4.99×10−8) in the interferon receptor geneIFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression ofIFNAR2, or high expression ofTYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptorCCR2is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.
Published: 2020
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21. Dysregulation of lipid metabolism and pathological inflammation in patients with COVID-19

Author: Gabriella Fabbrocini, Caterina Missero, Roberta Russo, Monica Gelzo, Aurora Daniele, Maurizio D’Abbraccio, Immacolata Andolfo, Giuseppe Castaldo, Marianna Caterino, Roberto Parrella, Mario Capasso, Chiara Dell’Isola, Stefano Sol, Giuseppe Fiorentino, Anna Annunziata, Ivan Gentile, Emanuela Marchese, Margherita Ruoppolo, Rita Polito, Cecilia Calabrese, Francesco Maria Fusco, Roberta Fedele, Michele Costanzo, Caterino, M., Gelzo, M., Sol, S., Fedele, R., Annunziata, A., Calabrese, C., Fiorentino, G., D'Abbraccio, M., Dell'Isola, C., Fusco, F. M., Parrella, R., Fabbrocini, G., Gentile, I., Andolfo, I., Capasso, M., Costanzo, M., Daniele, A., Marchese, E., Polito, R., Russo, R., Missero, C., Ruoppolo, M., Castaldo, G., Caterino, M, Gelzo, M, Sol, S, Fedele, R, Annunziata, A, Calabrese, C, Fiorentino, G, D'Abbraccio, M, Dell'Isola, C, Fusco, Fm, Parrella, R, Fabbrocini, G, Gentile, I, Andolfo, I, Capasso, M, Costanzo, M, Daniele, A, Marchese, E, Polito, R, Russo, R, Missero, C, and Ruoppolo, M
Subjects: Male, Science, medicine.medical_treatment, Diseases, Disease, medicine.disease_cause, Severity of Illness Index, Biochemistry, Virus, Article, Proinflammatory cytokine, Pathogenesis, Intensive care, medicine, Alarmins, Humans, Least-Squares Analysis, Cytokine, Coronavirus, Least-Squares Analysi, Multidisciplinary, Molecular medicine, business.industry, SARS-CoV-2, COVID-19, Discriminant Analysis, Lipid metabolism, Lipid, Middle Aged, Lipid Metabolism, Lipids, Alarmin, Immunology, Medicine, Cytokines, Female, Discriminant Analysi, business, Human, Biotechnology
Abstract: In recent months, Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread throughout the world. COVID-19 patients show mild, moderate or severe symptoms with the latter ones requiring access to specialized intensive care. SARS-CoV-2 infections, pathogenesis and progression have not been clearly elucidated yet, thus forcing the development of many complementary approaches to identify candidate cellular pathways involved in disease progression. Host lipids play a critical role in the virus life, being the double-membrane vesicles a key factor in coronavirus replication. Moreover, lipid biogenesis pathways affect receptor-mediated virus entry at the endosomal cell surface and modulate virus propagation. In this study, targeted lipidomic analysis coupled with proinflammatory cytokines and alarmins measurement were carried out in serum of COVID-19 patients characterized by different severity degree. Serum IL-26, a cytokine involved in IL-17 pathway, TSLP and adiponectin were measured and correlated to lipid COVID-19 patient profiles. These results could be important for the classification of the COVID-19 disease and the identification of therapeutic targets.
Published: 2020

22. The Pro12Ala polymorphism of PPARγ2 modulates beta cell function and failure to oral glucose-lowering drugs in patients with type 2 diabetes

Author: Angela A. Rivellese, Maria Masulli, Amalia Gastaldelli, Marco Russo, Mario Capasso, Olga Vaccaro, Gabriele Riccardi, S. Cocozza, Pasquale Dolce, Giuseppe Della Pepa, Piero Pignataro, Marilena Vitale, Masulli, M., Della Pepa, G., Cocozza, S., Capasso, M., Pignataro, P., Vitale, M., Gastaldelli, A., Russo, M., Dolce, P., Riccardi, G., Rivellese, A. A., and Vaccaro, O.
Subjects: medicine.medical_specialty, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Administration, Oral, 030209 endocrinology & metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, beta cell function, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Diabetes mellitus, Insulin-Secreting Cells, Internal Medicine, medicine, insulin sensitivity, pioglitazone, Humans, Hypoglycemic Agents, Cumulative incidence, Treatment Failure, Polymorphism, Genetic, business.industry, Hazard ratio, medicine.disease, Sulfonylurea, Metformin, PPAR gamma, Diabetes Mellitus, Type 2, PPARγ2, type 2 diabetes, business, Pioglitazone, Body mass index, medicine.drug
Abstract: Background: We evaluate whether the Pro12Ala polymorphism of peroxisome proliferator-activated receptor γ2 (PPARγ2) has a role in the progression of diabetes by modulating the occurrence of treatment failure to glucose-lowering drugs. Methods: We studied 215 patients with type 2 diabetes participating in the Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents Intervention Trial study. All participants were insufficiently controlled (glycated haemoglobin [HbA1c] 7.0%-9.0%) with metformin 2 g/day and were randomly allocated to add-on pioglitazone or a sulfonylurea. Treatment failure was defined as HbA1c ≥8% on two consecutive visits, 3 months apart. Results: Carriers or non-carriers of the polymorphism had similar age, body mass index, and diabetes duration. Ala carriers had lower fasting plasma insulin, better insulin sensitivity (Homeostasis Model Assessment [HOMA]2-%S), and worse beta cell secretion (HOMA2-%B) than non-carriers. During 24 months of follow-up, 32.5% among the Ala carriers and 8.6% among non-carriers (P < 0.001) developed treatment failure with a cumulative incidence of 18.6 vs 4.6/100 person-years. Those patients who developed treatment failure were older, had a younger age at diabetes diagnosis (48 ± 10 vs 52 ± 7 years; P = 0.032), higher HbA1c (8.1 ± 0.5 vs 7.7 ± 0.5%; P < 0.001), and lower HOMA2-%B (30 ± 12 vs 46 ± 29; P = 0.015) at study entry, as compared to those who did not develop treatment failure. At multivariate analysis, the Pro12Ala polymorphism was significantly associated with treatment failure (hazard ratio [HR] 4.45; 95% confidence interval [CI] 1.79-11.1; P < 0.001); HbA1c at study entry was the other independent predictor of failure in this study population. Conclusion: The Pro12Ala polymorphism is associated with a greater insulin sensitivity, reduced beta cell function and a substantially increased risk of treatment failure.
Published: 2020

23. BAP1 induces cell death via interaction with 14-3-3 in neuroblastoma

Author: Ramin Massoumi, Yasmin Abassi, Sven Kjellström, Julie Bonne Køhler, Mario Capasso, Qiankun Niu, Katarzyna Chmierlarska Masoumi, Reihaneh Zarrizi, Vito Alessandro Lasorsa, Haian Fu, and Wondossen Sime
Subjects: 0301 basic medicine, Cancer Research, Programmed cell death, DNA damage, Cellular differentiation, Immunology, Mice, Nude, Apoptosis, Article, Mice, Neuroblastoma, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cell Line, Tumor, medicine, Animals, Humans, lcsh:QH573-671, bcl-2-Associated X Protein, BAP1, Chemistry, lcsh:Cytology, Tumor Suppressor Proteins, Cell Cycle, Intrinsic apoptosis, Cell Biology, Cell cycle, medicine.disease, Cell biology, Gene Expression Regulation, Neoplastic, 030104 developmental biology, 14-3-3 Proteins, Proto-Oncogene Proteins c-bcl-2, Female, Ubiquitin Thiolesterase
Abstract: BRCA1-associated protein 1 (BAP1) is a nuclear deubiquitinating enzyme that is associated with multiprotein complexes that regulate key cellular pathways, including cell cycle, cellular differentiation, cell death, and the DNA damage response. In this study, we found that the reduced expression of BAP1 pro6motes the survival of neuroblastoma cells, and restoring the levels of BAP1 in these cells facilitated a delay in S and G2/M phase of the cell cycle, as well as cell apoptosis. The mechanism that BAP1 induces cell death is mediated via an interaction with 14-3-3 protein. The association between BAP1 and 14-3-3 protein releases the apoptotic inducer protein Bax from 14-3-3 and promotes cell death through the intrinsic apoptosis pathway. Xenograft studies confirmed that the expression of BAP1 reduces tumor growth and progression in vivo by lowering the levels of pro-survival factors such as Bcl-2, which in turn diminish the survival potential of the tumor cells. Patient data analyses confirmed the finding that the high-BAP1 mRNA expression correlates with a better clinical outcome. In summary, our study uncovers a new mechanism for BAP1 in the regulation of cell apoptosis in neuroblastoma cells.
Published: 2018
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24. A non-invasive method for the diagnosis of upper GI diseases

Author: Alberto, Barchi, Chiara, Miraglia, Alessandra, Violi, Ginevra, Cambiè, Antonio, Nouvenne, Mario, Capasso, Gioacchino, Leandro, Tiziana, Meschi, Gian, Luigi de’ Angelis, and Francesco, Di Mario
Subjects: Helicobacter pylori, Pepsinogens, diagnosis, Gastrin-17, gastritis, Stomach Diseases, Review, GERD, Esophageal Diseases, Antibodies, Bacterial, digestive system diseases, Endoscopy, Gastrointestinal, Helicobacter Infections, Diagnostic Techniques, Digestive System, Gastrins, Humans, Dyspepsia, stomach, Biomarkers
Abstract: Upper-GI diseases are one of the most relevant issue in primary care. Nowadays they are still responsible for about 100 million ambulatory care visits only in the US. The diagnosis of almost every upper-GI condition is still deputed to invasive tests such as upper gastrointestinal endoscopy, gastroesophageal manometry or radiography. The possibility of analysing serum markers like Pepsinogens I and II, produced by gastric mucosa, in order to assess the functional characteristics of the upper GI tract has spread itself since the 80’s especially in the diagnosis of peptic ulcer. The discovery of Helicobacter pylori by Marshall and Warren in 1983 and the scientific consecration of its role in the pathogenesis of gastric cancer and peptic ulcer (crystallized in Peleo Correa’s Cascade, 1992), led to an increase importance of non-invasive tests, raising the attention towards the assessment of both immunoglobulins anti-H.p. and Gastrin hormone produced by antral G cells, as an implementation of the panel of gastric markers. This narrative review aims to analyze the huge landscape of non-invasive tests for diagnosis of GI diseases, studying the literature of the recent years. (www.actabiomedica.it)
Published: 2018

25. Development and usefulness of the new endoscopic classification: DICA

Author: Ginevra, Cambiè, Alessandra, Violi, Chiara, Miraglia, Alberto, Barchi, Antonio, Nouvenne, Mario, Capasso, Gioacchino, Leandro, Tiziana, Meschi, Gian, Luigi de’ Angelis, and Francesco, Di Mario
Subjects: diverticulitis, diverticular disease, Diverticulosis, Colonic, Humans, colonic diverticulosis, Review, Colonoscopy, Constriction, Pathologic, endoscopy, Symptom Assessment, DICA classification, Gastrointestinal Hemorrhage, Severity of Illness Index
Abstract: Colonic Diverticulosis is one of the most common anatomical findings during colonoscopy. This condition has 60% incidence in the population over 60 years old. About 20% of patients will develop Diverticular Disease, and 5% of them will evolve into Diverticulitis. Until the last years there weren’t any approaches for the endoscopic classification of this pathology. In 2013, in Florence, the first endoscopic classification was developed: DICA (Diverticular Inflammation and Complication Assessment). The aim of this article is to focus on the process of the development and the validation of the classification by the pool of gastroenterology experts, and, as well, its usefulness during the clinical practice. (www.actabiomedica.it)
Published: 2018

26. The role of TMPRSS6 and HFE variants in iron deficiency anemia in celiac disease

Author: Achille Iolascon, Antonio Rispo, Mariasole Bruno, Luigia De Falco, Annalisa Castagna, Nicola Imperatore, Mario Capasso, Domenico Girelli, Raffaella Tortora, Nicola Caporaso, De Falco, Luigia, Tortora, Raffaella, Imperatore, Nicola, Bruno, Mariasole, Capasso, Mario, Girelli, Domenico, Castagna, Annalisa, Caporaso, Nicola, Iolascon, Achille, and Rispo, Antonio
Subjects: Erythrocyte Indices, Male, 0301 basic medicine, Disease, Gastroenterology, Pathogenesis, Hemoglobins, 0302 clinical medicine, Gene Frequency, hemic and lymphatic diseases, Genotype, Medicine, Prospective Studies, iron deficiency anemia (IDA), Anemia, Iron-Deficiency, biology, medicine.diagnostic_test, Serine Endopeptidases, Hematology, Treatment Outcome, TMPRSS6, iron deficiency anemia (IDA), celiac disease (CD), Serum iron, Female, 030211 gastroenterology & hepatology, Iron, Dietary, Adult, medicine.medical_specialty, TMPRSS6, Iron, Mutation, Missense, Diet, Gluten-Free, Young Adult, 03 medical and health sciences, Hepcidins, Hepcidin, Internal medicine, Humans, Hemochromatosis Protein, Allele frequency, Alleles, Autoantibodies, celiac disease (CD), business.industry, Membrane Proteins, nutritional and metabolic diseases, medicine.disease, Celiac Disease, 030104 developmental biology, Intestinal Absorption, Iron-deficiency anemia, Ferritins, biology.protein, business
Abstract: We investigated the role of HFE C282Y, H63D, and TMPRSS6 A736V variants in the pathogenesis of iron deficiency anemia (IDA) in celiac disease (CD) patients, at diagnosis and after 1 year of gluten-free diet (GFD). Demographic and clinical features were prospectively recorded for all CD patients between 2013 and 2017. C282Y, H63D, and A736V variants were evaluated for CD patients and controls. Finally, 505 consecutive CD patients and 539 age-matched control subjects were enrolled. At diagnosis, 229 CD subjects had IDA (45.3%), with a subgroup of anemic patients (45.4%) presented persistent IDA at follow-up. C282Y allele frequency was significantly increased in CD compared with controls (1.1% vs 0.2%, P = .001), whereas H63D and A736V allele frequencies were similar among patients and controls (P = .92 and .84, respectively). At diagnosis, C282Y variant in anemic CD patients was significantly increased compared to nonanemic group (2% and 0.5%, P = .04). At follow-up, A736V was significantly increased in IDA persistent than in IDA not persistent (57.7% vs 35.2%, P
Published: 2017
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27. The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

Author: Mike R. Russell, Flora Cimmino, Sharon J. Diskin, Lee D. McDaniel, Mario Capasso, Kristina A. Cole, Pichai Raman, Daniela Formicola, Andrea Cirino, Capasso, Mario, Mcdaniel, Lee D, Cimmino, Flora, Cirino, Andrea, Formicola, Daniela, Russell, Mike R, Raman, Pichai, Cole, Kristina A, and Diskin, Sharon J.
Subjects: Risk, 0301 basic medicine, genetic association, SNP, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Neuroblastoma, 03 medical and health sciences, Gene Frequency, Cell Line, Tumor, Genotype, medicine, Humans, GWAS, Genetic Predisposition to Disease, Allele, Promoter Regions, Genetic, Alleles, Genetic association, Genetics, Brain Neoplasms, Original Articles, Cell Biology, medicine.disease, Gene Expression Regulation, Neoplastic, HEK293 Cells, 030104 developmental biology, CDKN1B, Case-Control Studies, Cancer research, Molecular Medicine, Original Article, rs34330, Cyclin-Dependent Kinase Inhibitor p27, Genome-Wide Association Study, Plasmids
Abstract: The genetic aetiology of sporadic neuroblastoma is still largely unknown. We have identified diverse neuroblastoma susceptibility loci by genomewide association studies (GWASs); however, additional SNPs that likely contribute to neuroblastoma susceptibility prompted this investigation for identification of additional variants that are likely hidden among signals discarded by the multiple testing corrections used in the analysis of genomewide data. There is evidence suggesting the CDKN1B, coding for the cycle inhibitor p27Kip1, is involved in neuroblastoma. We thus assess whether genetic variants of CDKN1B are associated with neuroblastoma. We imputed all possible genotypes across CDKN1B locus on a discovery case series of 2101 neuroblastoma patients and 4202 genetically matched controls of European ancestry. The most significantly associated rs34330 was analysed in an independent Italian cohort of 311 cases and 709 controls. In vitro functional analysis was carried out in HEK293T and in neuroblastoma cell line SHEP‐2, both transfected with pGL3‐CDKN1B‐CC or pGL3‐CDKN1B‐TT constructs. We identified an association of the rs34330 T allele (‐79C/T) with the neuroblastoma risk (Pcombined = 0.002; OR = 1.17). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27Kip1 promoter (P < 0.05). Three independent sets of neuroblastoma tumours carrying ‐79TT genotype showed a tendency towards lower CDKN1B mRNA levels. Our study shows that a functional variant, associated with a reduced CDKN1B gene transcription, influences neuroblastoma susceptibility.
Published: 2017
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28. miR-622 is a novel potential biomarker of breast carcinoma and impairs motility of breast cancer cells through targeting NUAK1 kinase

Author: Mario Capasso, Raffaela Mariarosaria Mariniello, Anna Elisa De Stefano, Paola Lucia Chiara Iervolino, Francesca Maria Orlandella, Mariarosaria Incoronato, Rosa Giannatiempo, Francesco Messina, Peppino Mirabelli, Vito Alessandro Lasorsa, Giuliana Salvatore, Andrea Soricelli, Maria Rongo, Marco Salvatore, Orlandella, F. M., Mariniello, R. M., Mirabelli, P., De Stefano, A. E., Iervolino, P. L. C., Lasorsa, V. A., Capasso, M., Giannatiempo, R., Rongo, M., Incoronato, M., Messina, F., Salvatore, M., Soricelli, A., and Salvatore, G.
Subjects: Cancer Research, Prognosi, 3' Untranslated Region, Protein Kinase, NUAK1, Motility, Down-Regulation, Context (language use), Breast Neoplasms, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, MCF-7 Cell, Downregulation and upregulation, Cell Movement, Cell Line, Tumor, microRNA, Biomarkers, Tumor, Medicine, Humans, skin and connective tissue diseases, 3' Untranslated Regions, 030304 developmental biology, Cancer, 0303 health sciences, Kinase, business.industry, MicroRNA, Repressor Protein, medicine.disease, Prognosis, Repressor Proteins, Gene Expression Regulation, Neoplastic, MicroRNAs, Oncology, 030220 oncology & carcinogenesis, Cancer research, MCF-7 Cells, Female, Breast carcinoma, business, Protein Kinases, Breast Neoplasm, Human
Abstract: Background Aberrant expression of microRNAs (miR) has been proposed as non-invasive biomarkers for breast cancers. The aim of this study was to analyse the miR-622 level in the plasma and in tissues of breast cancer patients and to explore the role of miR-622 and its target, the NUAK1 kinase, in this context. Methods miR-622 expression was analysed in plasma and in tissues samples of breast cancer patients by q-RT-PCR. Bioinformatics programs, luciferase assay, public dataset analysis and functional experiments were used to uncover the role of miR-622 and its target in breast cancer cells. Results miR-622 is downregulated in plasma and in tissues of breast cancer patients respect to healthy controls and its downregulation is significantly associated with advanced grade and high Ki67 level. Modulation of miR-622 affects the motility phenotype of breast cancer cells. NUAK1 kinase is a functional target of miR-622, it is associated with poor clinical outcomes of breast cancer patients and is inversely correlated with miR-622 level. Conclusions miR-622/NUAK1 axis is deregulated in breast cancer patients and affects the motility phenotype of breast cancer cells. Importantly, miR-622 and NUAK1 hold promises as biomarkers and as targets for breast cancers.
Published: 2020

29. Neural crest-derived tumor neuroblastoma and melanoma share 1p13.2 as susceptibility locus that shows a long-range interaction with the SLC16A1 gene

Author: Mark M. Iles, Massimiliano Scalvenzi, Annalaura Montella, Zalman Vaksman, Mario Capasso, Daniela Formicola, Stefania Staibano, Alessandro Testori, Vito Alessandro Lasorsa, Hakon Hakonarson, Matteo Esposito, Sueva Cantalupo, Jan Koster, Paola Ghiorzo, Fabrizio Ayala, Sharon J. Diskin, Marcella Devoto, Antonella Cardinale, Marianna Avitabile, Flora Cimmino, Maria Fiammetta Romano, Maria Valeria Corrias, Mariangela Succoio, Nicola Zambrano, Virginia Andreotti, Matthew Law, Kevin M. Brown, Achille Iolascon, Avitabile, Marianna, Succoio, Mariangela, Testori, Alessandro, Cardinale, Antonella, Vaksman, Zalman, Lasorsa, Vito Alessandro, Cantalupo, Sueva, Esposito, Matteo, Cimmino, Flora, Montella, Annalaura, Formicola, Daniela, Koster, Jan, Andreotti, Virginia, Ghiorzo, Paola, Romano, Maria Fiammetta, Staibano, Stefania, Scalvenzi, Massimiliano, Ayala, Fabrizio, Hakonarson, Hakon, Corrias, Maria Valeria, Devoto, Marcella, Law, Matthew H, Iles, Mark M, Brown, Kevin, Diskin, Sharon, Zambrano, Nicola, Iolascon, Achille, Capasso, Mario, Oncogenomics, and CCA - Cancer biology and immunology
Subjects: 0301 basic medicine, Male, Monocarboxylic Acid Transporters, Cancer Research, Neuroblastoma, malignant cutaneous melanoma, neural crest cells, GWAS, Skin Neoplasms, Adrenal Gland Neoplasms, Genome-wide association study, Locus (genetics), Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, medicine, Humans, Genetic Predisposition to Disease, Allele, Melanoma, Cancer Biomarkers and Molecular Epidemiology, Symporters, Neural crest, Cell Differentiation, General Medicine, Cell cycle, medicine.disease, 030104 developmental biology, Chromosomes, Human, Pair 1, Neural Crest, 030220 oncology & carcinogenesis, Cancer research, Female, Carcinogenesis, Genome-Wide Association Study
Abstract: Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10−8). We also detected a suggestive (P < 10−7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10−4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1.
Published: 2020

30. Transcription factors involved in tumorigenesis are over-represented in mutated active DNA-binding sites in neuroblastoma A C

Author: Carmen de Torres, Aurora Castellano, Mario Capasso, Martina Morini, Vito Alessandro Lasorsa, Annalaura Montella, Biagio De Angelis, Flora Cimmino, Sueva Cantalupo, Franco Locatelli, Achille Iolascon, Marianna Avitabile, Capasso, M., Lasorsa, V. A., Cimmino, F., Avitabile, M., Cantalupo, S., Montella, A., De Angelis, B., Morini, M., De Torres, C., Castellano, A., Locatelli, F., and Iolascon, A.
Subjects: 0301 basic medicine, Cancer Research, neuroblastoma, RNA, coding mutations, Carcinogenesis, Biology, Regulatory Sequences, Nucleic Acid, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, medicine, Biomarkers, Tumor, Humans, Transcription factor, Gene, Regulation of gene expression, Genetics, Mutation, Binding Sites, Whole Genome Sequencing, DNA, Neoplasm, Noncoding DNA, DNA binding site, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, 030220 oncology & carcinogenesis, NEUROBLASTOMA, Protein Binding, Transcription Factors
Abstract: The contribution of coding mutations to oncogenesis has been largely clarified, whereas little is known about somatic mutations in noncoding DNA and their role in driving tumors remains controversial. Here, we used an alternative approach to interpret the functional significance of noncoding somatic mutations in promoting tumorigenesis. Noncoding somatic mutations of 151 neuroblastomas were integrated with ENCODE data to locate somatic mutations in regulatory elements specifically active in neuroblastoma cells, nonspecifically active in neuroblastoma cells, and nonactive. Within these types of elements, transcription factors (TF) were identified whose binding sites were enriched or depleted in mutations. For these TFs, a gene expression signature was built to assess their implication in neuroblastoma. DNA- and RNA-sequencing data were integrated to assess the effects of those mutations on mRNA levels. The pathogenicity of mutations was significantly higher in transcription factor binding site (TFBS) of regulatory elements specifically active in neuroblastoma cells, as compared with the others. Within these elements, there were 18 over-represented TFs involved mainly in cell-cycle phase transitions and 15 under-represented TFs primarily regulating cell differentiation. A gene expression signature based on over-represented TFs correlated with poor survival and unfavorable prognostic markers. Moreover, recurrent mutations in TFBS of over-represented TFs such as EZH2 affected MCF2L and ADP-ribosylhydrolase like 1 expression, among the others. We propose a novel approach to study the involvement of regulatory variants in neuroblastoma that could be extended to other cancers and provide further evidence that alterations of gene expression may have relevant effects in neuroblastoma development. Significance: These findings propose a novel approach to study regulatory variants in neuroblastoma and suggest that noncoding somatic mutations have relevant implications in neuroblastoma development.
Published: 2020

31. Co-administration of fendiline hydrochloride enhances chemotherapeutic efficacy of cisplatin in neuroblastoma treatment

Author: Mario Capasso, Antonella Brizzolara, Luca Longo, Serena Vella, Raffaella Barbieri, Patrizia Garbati, Tullio Florio, Alessandro Quattrone, Aldo Pagano, Matilde Calderoni, Gian Paolo Tonini, Brizzolara, A., Garbati, P., Vella, S., Calderoni, M., Quattrone, A., Tonini, G. P., Capasso, M., Longo, L., Barbieri, R., Florio, T., and Pagano, A.
Subjects: RNA, Untranslated, Cellular differentiation, Cell, Pharmaceutical Science, Apoptosis, Mice, SCID, Analytical Chemistry, Antineoplastic Agent, Neuroblastoma, Mice, 0302 clinical medicine, Mice, Inbred NOD, Antineoplastic Combined Chemotherapy Protocols, Drug Discovery, 0303 health sciences, Fendiline, Brain Neoplasms, Chemistry, Drug Synergism, NDM29, Gene Expression Regulation, Neoplastic, GD2, fendiline hydrochloride, neuroblastoma, non-coding RNA, medicine.anatomical_structure, Chemistry (miscellaneous), 030220 oncology & carcinogenesis, Molecular Medicine, medicine.drug, Human, Cell Survival, Antineoplastic Agents, Article, lcsh:QD241-441, Brain Neoplasm, 03 medical and health sciences, lcsh:Organic chemistry, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Physical and Theoretical Chemistry, Non-coding RNA, neoplasms, 030304 developmental biology, Cell Proliferation, Cisplatin, Antineoplastic Combined Chemotherapy Protocol, Cell growth, Animal, Organic Chemistry, Apoptosi, medicine.disease, Fendiline hydrochloride, Cancer research, Neoplasm Transplantation
Abstract: Despite significant improvement of neuroblastoma (NB) patients&rsquo, survival due to recent treatment advancements in recent years, NB is still associated with high mortality rate. In search of novel strategies to increase NB&rsquo, s susceptibility to pharmacological treatments, we investigated the in vitro and in vivo effects of fendiline hydrochloride as an enhancer of cisplatin antitumor activity. To assess the modulation of fendiline treatment on cisplatin responses, we used in vitro (evaluating NB cell proliferation by XCELLigence technology and colony formation, and gene expression by RT-PCR) and in vivo (NB cell grafts in NOD-SCID mice) models of NB. NB cell treatment with fendiline induced the expression of the ncRNA NDM29, leading to cell differentiation and to the reduction of the expression of MDRs/ABC transporters linked to multidrug resistance. These events were correlated to higher NB cell susceptibility to cisplatin and, consequently, increased its cytotoxic potency. In vivo, this drug interaction causes an enhanced ability of cisplatin to induce apoptosis in NB masses, resulting in tumor growth reduction and prolonged animal survival rate. Thus, the administration of fendiline might be a possible novel therapeutic approach to increase cisplatin efficacy in aggressive and poorly responsive NB cases.
Published: 2020

32. Association of PARP1 polymorphisms with response to chemotherapy in patients with high-risk neuroblastoma

Author: Annalaura Montella, Vito Alessandro Lasorsa, Mario Capasso, Maria Valeria Corrias, Alberto Garaventa, Flora Cimmino, Loredana Amoroso, Alessandro Quattrone, Achille Iolascon, Riccardo Haupt, Dalila Capasso, Antonella Cardinale, Sueva Cantalupo, Marianna Avitabile, Avitabile, M., Lasorsa, V. A., Cantalupo, S., Cardinale, A., Cimmino, F., Montella, A., Capasso, D., Haupt, R., Amoroso, L., Garaventa, A., Quattrone, A., Corrias, M. V., Iolascon, A., and Capasso, M.
Subjects: 0301 basic medicine, Male, pharmacogenomic, DNA Repair, Genotype, DNA repair, Poly (ADP-Ribose) Polymerase-1, SNP, Single-nucleotide polymorphism, chemotherapy, Polymorphism, Single Nucleotide, PARP1, 03 medical and health sciences, neuroblastoma, 0302 clinical medicine, Neuroblastoma, Medicine, Humans, RNA, Messenger, Allele, Alleles, Genetic Association Studies, pharmacogenomics, business.industry, Cytotoxins, Cancer, Infant, Promoter, Cell Biology, Original Articles, medicine.disease, Prognosis, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Real-time polymerase chain reaction, Pharmacogenetics, 030220 oncology & carcinogenesis, Child, Preschool, oncology, Cancer research, Molecular Medicine, DNA mismatch repair, Female, Original Article, business, DNA Damage
Abstract: The genetic aetiology and the molecular mechanisms that characterize high‐risk neuroblastoma are still little understood. The majority of high‐risk neuroblastoma patients do not take advantage of current induction therapy. So far, one of the main reasons liable for cancer therapeutic failure is the acquisition of resistance to cytotoxic anticancer drugs, because of the DNA repair system of tumour cells. PARP1 is one of the main DNA damage sensors involved in the DNA repair system and genomic stability. We observed that high PARP1 mRNA level is associated with unfavourable prognosis in 3 public gene expression NB patients’ datasets and in 20 neuroblastomas analysed by qRT‐PCR. Among 4983 SNPs in PARP1, we selected two potential functional SNPs. We investigated the association of rs907187, in PARP1 promoter, and rs2048426 in non‐coding region with response chemotherapy in 121 Italian patients with high‐risk NB. Results showed that minor G allele of rs907187 associated with induction response of patients (P = .02) and with decrease PARP1 mRNA levels in NB cell line (P = .003). Furthermore, rs907187 was predicted to alter the binding site of E2F1 transcription factor. Specifically, allele G had low binding affinity with E2F1 whose expression positively correlates with PARP1 expression and associated with poor prognosis of patients with NB. By contrast, we did not find genetic association for the SNP rs2048426. These data reveal rs907187 as a novel potential risk variant associated with the failure of induction therapy for high‐risk NB.
Published: 2019

33. Exploring Shared Susceptibility between Two Neural Crest Cells Originating Conditions: Neuroblastoma and Congenital Heart Disease

Author: Maria Giovanna Russo, Bernard Keavney, Alessandro Testori, Achille Iolascon, Marianna Avitabile, Giuseppe Limongelli, Heather J. Cordell, Mario Capasso, Vito Alessandro Lasorsa, Antonella Cardinale, John M. Maris, Flora Cimmino, Sharon J. Diskin, Sueva Cantalupo, Marcella Devoto, Testori, A., Lasorsa, V. A., Cimmino, F., Cantalupo, S., Cardinale, A., Avitabile, M., Limongelli, G., Russo, M. G., Diskin, S., Maris, J., Devoto, M., Keavney, B., Cordell, H. J., Iolascon, A., Capasso, M., Russo, MARIA GRAZIA, and DEL VOLGO-GORI, MARIE JOSE
Subjects: 0301 basic medicine, Heart Defects, Congenital, lcsh:QH426-470, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Genome wide association studie, Article, Linkage Disequilibrium, 03 medical and health sciences, Neuroblastoma, 0302 clinical medicine, Genetics, Genetic predisposition, neuroblastoma, congenital heart disease, genome wide association studies, SNP, Humans, Genetic Predisposition to Disease, Epigenetics, Gene, Genetics (clinical), Neural crest, Genetic architecture, lcsh:Genetics, 030104 developmental biology, Neural Crest, 030220 oncology & carcinogenesis, Human
Abstract: In the past years, genome wide association studies (GWAS) have provided evidence that inter-individual susceptibility to diverse pathological conditions can reveal a common genetic architecture. Through the analysis of congenital heart disease (CHD) and neuroblastoma (NB) GWAS data, we aimed to dissect the genetic susceptibility shared between these conditions, which are known to arise from neural crest cell (NCC) migration or development abnormalities, via identification and functional characterization of common regions of association. Two loci (2q35 and 3q25.32) harbor single nucleotide polymorphisms (SNPs) that are associated at a p-value &lt, 10&minus, 3 with conotruncal malformations and ventricular septal defect respectively, as well as with NB. In addition, the lead SNP in 4p16.2 for atrial septal defect and the lead SNP in 3q25.32 for tetralogy of Fallot are less than 250 Kb distant from the lead SNPs for NB at the same genomic regions. Some of these shared susceptibility loci regulate the expression of relevant genes involved in NCC formation and developmental processes (such as BARD1, MSX1, and SHOX2) and are enriched in several epigenetic markers from NB and fetal heart cell lines. Although the clinical correlation between NB and CHD is unclear, our exploration of a possible common genetic basis between NB and a subset of cardiac malformations can help shed light on their shared embryological origin and pathogenetic mechanisms.
Published: 2019
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34. Genomic coamplification of CDK4/MDM2/FRS2 is associated with very poor prognosis and atypical clinical features in neuroblastoma patients

Author: Annalisa Tondo, Aurora Castellano, Martina Morini, Alberto Garaventa, Mario Capasso, Vito Alessandro Lasorsa, Annalisa Pezzolo, Andrea Di Cataldo, Massimo Conte, Marzia Ognibene, Paolo D'Angelo, Marina Podestà, Loredana Amoroso, Amoroso, L., Ognibene, M., Morini, M., Conte, M., Di Cataldo, A., Tondo, A., D'Angelo, P., Castellano, A., Garaventa, A., Lasorsa, V. A., Podesta, M., Capasso, M., and Pezzolo, A.
Subjects: Cancer Research, Genome, 12q genomic amplification, atypical clinical features, 03 medical and health sciences, Neuroblastoma, 0302 clinical medicine, FRS2 gene, Gene duplication, Exome Sequencing, Genetics, medicine, atypical clinical feature, Biomarkers, Tumor, Humans, Child, neoplasms, Survival rate, Gene, Adaptor Proteins, Signal Transducing, Retrospective Studies, Comparative Genomic Hybridization, Chromosomes, Human, Pair 12, biology, neuroblastoma, Gene Amplification, Cyclin-Dependent Kinase 4, Membrane Proteins, Proto-Oncogene Proteins c-mdm2, medicine.disease, Prognosis, GREB1, Survival Rate, 030220 oncology & carcinogenesis, Genomic Profile, biology.protein, Cancer research, Mdm2
Abstract: Neuroblastoma (NB) is the most common extracranial malignant tumor of childhood and is characterized by a broad heterogeneity in clinical presentation and evolution. Recent advances in pangenomic analysis of NB have revealed different recurrent chromosomal aberrations. Indeed, it is now well established that the overall genomic profile is important for treatment stratification. In previous studies, 11 genes were shown to be recurrently amplified (ODC1, ALK, GREB1, NTSR2, LIN28B, MDM2, CDK4, MYEOV, CCND1, TERT, and MYC) besides MYCN, with poor survival of NB patients harboring these amplifications being suggested. Genomic profiles of 628 NB samples analyzed by array-comparative genome hybridization (a-CGH) were re-examined to identify gene amplifications other them MYCN amplification. Clinical data were retrospectively collected. We additionally evaluated the association of FRS2 gene expression with NB patient outcome using the public R2 Platform. We found eight NB samples with high grade amplification of one or two loci on chromosome arm 12q. The regional amplifications were located on bands 12q13.3-q14.1 and 12q15-q21.1 involving the genes CDK4, MDM2, and the potential oncogenic gene FRS2. The CDK4, MDM2, and FRS2 loci were coamplified in 8/8 samples. The 12q amplifications were associated with very poor prognosis and atypical clinical features of NB patients. Further functional and clinical investigations are needed to confirm or refute these associations.
Published: 2019

35. Preliminary data of VEGF-A and VEGFR-2 polymorphisms as predictive factors of radiological response and clinical outcome in iodine-refractory differentiated thyroid cancer treated with sorafenib

Author: Gerardo Botti, Concetta Sciammarella, Annamaria Colao, Claudia Pivonello, Alessandro Testori, Antongiulio Faggiano, Maria Grazia Chiofalo, Mario Capasso, Vincenzo Marotta, Luciano Pezzullo, Rosario Pivonello, Marotta, Vincenzo, Sciammarella, Concetta, Capasso, Mario, Testori, Alessandro, Pivonello, Claudia, Chiofalo, Maria Grazia, Pivonello, Rosario, Pezzullo, Luciano, Botti, Gerardo, Colao, Annamaria, and Faggiano, Antongiulio
Subjects: Male, Vascular Endothelial Growth Factor A, Oncology, Sorafenib, medicine.medical_specialty, iodine-refractory, Endocrinology, Diabetes and Metabolism, VEGF receptors, differentiated thyroid cancer, chemistry.chemical_element, 030209 endocrinology & metabolism, Iodine, Iodine Radioisotopes, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, VEGF pathway, Refractory, Predictive Value of Tests, Diabetes mellitus, Internal medicine, Tyrosine-kinase inhibitors, Humans, Medicine, Thyroid Neoplasms, Thyroid cancer, Polymorphism, Genetic, biology, business.industry, Middle Aged, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, Treatment Outcome, chemistry, 030220 oncology & carcinogenesis, Radiological weapon, biology.protein, Female, business, medicine.drug
Published: 2016
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36. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

Author: Carmen Torres, Achille Iolascon, Francesco Maria Calabrese, Vito Alessandro Lasorsa, Piero Pignataro, Jaume Mora, Michael D. Hogarty, Flora Cimmino, Maria Rosaria Esposito, Marilena De Mariano, Luca Longo, Marcella Pantile, Mario Capasso, Daniela Formicola, Carlo Zanon, Gian Paolo Tonini, Lasorsa, Vito Alessandro, Formicola, Daniela, Pignataro, Piero, Cimmino, Flora, Calabrese, Francesco Maria, Mora, Jaume, Esposito, Maria Rosaria, Pantile, Marcella, Zanon, Carlo, De Mariano, Marilena, Longo, Luca, Hogarty, Michael D, de Torres, Carmen, Tonini, Gian Paolo, Iolascon, Achille, and Capasso, Mario
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Adolescent, high risk, Bioinformatics, neuroblastoma, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Neuroblastoma, Internal medicine, Humans, Medicine, Exome, somatic mutation, Child, cancer driver genes, CHEK2, Exome sequencing, ATRX, business.industry, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Infant, Cancer, medicine.disease, Actin cytoskeleton, Survival Analysis, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Child, Preschool, NGS, 030220 oncology & carcinogenesis, Mutation, Disease Progression, cancer driver gene, business, Signal Transduction, Research Paper
Abstract: // Vito Alessandro Lasorsa 1,2 , Daniela Formicola 1,2 , Piero Pignataro 1,2 , Flora Cimmino 1,2 , Francesco Maria Calabrese 3 , Jaume Mora 4 , Maria Rosaria Esposito 5 , Marcella Pantile 5 , Carlo Zanon 5 , Marilena De Mariano 6 , Luca Longo 6 , Michael D. Hogarty 7 , Carmen de Torres 4 , Gian Paolo Tonini 5 , Achille Iolascon 1,2 and Mario Capasso 1,2,8 1 University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy 2 CEINGE Biotecnolgie Avanzate, Naples, Italy 3 University of Bari, Department of Biology, Bari, Italy 4 Hospital Sant Joan de Deu, Developmental Tumor Biology Laboratory and Department of Oncology, Esplugues de Llobregat, Barcelona, Spain 5 Pediatric Research Institute (IRP), Fondazione Citta della Speranza, Neuroblastoma Laboratory, Padua, Italy 6 U.O.C. Bioterapie, IRCCS AOU San Martino-IST, National Cancer Research Institute, Genoa, Italy 7 Children’s Hospital of Philadelphia, Division of Oncology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America 8 IRCCS SDN, Istituto di Ricerca Diagnostica e Nucleare, Naples, Italy Correspondence: Mario Capasso, email: // Flora Cimmino, email: // Keywords : NGS, neuroblastoma, high risk, somatic mutation, cancer driver genes Received : December 22, 2015 Accepted : February 09, 2016 Published : March 18, 2016 Abstract The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma. Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines. We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9 , a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK . Other genes ( PTK2 , NAV3 , NAV1 , FZD1 and ATRX ), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%. Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression. Notably BARD1 , CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants. In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression.
Published: 2016
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37. HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia

Author: Marianna Avitabile, Lucia Pezone, Flora Cimmino, Sueva Cantalupo, Vito Alessandro Lasorsa, Achille Iolascon, Feliciano Visconte, Annalaura Montella, Maria Valeria Corrias, Mario Capasso, Cimmino, Flora, Avitabile, Marianna, Lasorsa, Vito Alessandro, Montella, Annalaura, Pezone, Lucia, Cantalupo, Sueva, Visconte, Feliciano, Corrias, Maria Valeria, Iolascon, Achille, and Capasso, Mario
Subjects: 0301 basic medicine, lcsh:Internal medicine, lcsh:QH426-470, Cellular differentiation, Hypoxia inducible factor HIF1A, 030105 genetics & heredity, Biology, Epigenesis, Genetic, 03 medical and health sciences, Neuroblastoma, Genetic, Transcription (biology), Cell Line, Tumor, Genetics, medicine, Gene silencing, Humans, Gene Regulatory Networks, Epigenetics, Gene Silencing, lcsh:RC31-1245, Transcription factor, Genetics (clinical), Neurons, DNA methylation, Sequence Analysis, RNA, Gene Expression Profiling, Cell Differentiation, RNA sequencing, Hypoxia (medical), Hypoxia-Inducible Factor 1, alpha Subunit, Prognosis, Cell Hypoxia, lcsh:Genetics, 030104 developmental biology, HIF1A, Cancer research, CpG Islands, medicine.symptom, Research Article
Abstract: Background HIF1A (Hypoxia-Inducible-Factor 1A) expression in solid tumors is relevant to establish resistance to therapeutic approaches. The use of compounds direct against hypoxia signaling and HIF1A does not show clinical efficiency because of changeable oxygen concentrations in solid tumor areas. The identification of HIF1A targets expressed in both normoxia and hypoxia and of HIF1A/hypoxia signatures might meliorate the prognostic stratification and therapeutic successes in patients with high-risk solid tumors. Methods In this study, we conducted a combined analysis of RNA expression and DNA methylation of neuroblastoma cells silenced or unsilenced for HIF1A expression, grown in normoxia and hypoxia conditions. Results The analysis of pathways highlights HIF-1 (heterodimeric transcription factor 1) activity in normoxia in metabolic process and HIF-1 activity in hypoxia in neuronal differentiation process. HIF1A driven transcriptional response in hypoxia depends on epigenetic control at DNA methylation status of gene regulatory regions. Furthermore, low oxygen levels generate HIF1A-dependent or HIF1A-independent signatures, able to stratify patients according to risk categories. Conclusions These findings may help to understand the molecular mechanisms by which low oxygen levels reshape gene signatures and provide new direction for hypoxia targeting in solid tumor. Electronic supplementary material The online version of this article (10.1186/s12881-019-0767-1) contains supplementary material, which is available to authorized users.
Published: 2019

38. Epidemiology and risk factors for diverticular disease

Author: Alessandra, Violi, Ginevra, Cambiè, Chiara, Miraglia, Alberto, Barchi, Antonio, Nouvenne, Mario, Capasso, Gioacchino, Leandro, Tiziana, Meschi, Gian Luigi, De' Angelis, and Francesco, Di Mario
Subjects: Diverticular Diseases, Adult, Male, Serotonin, Developed Countries, Incidence, diverticular disease, diverticulosis, Comorbidity, Review, Middle Aged, Global Health, Diet, Gastrointestinal Microbiome, Age Distribution, Risk Factors, Prevalence, Humans, Female, epidemiology, Obesity, Gastrointestinal Motility, Developing Countries, Life Style, Aged
Abstract: Diverticulosis of the colon is the most frequent anatomical alteration diagnosed at colonoscopy. The prevalence of the disease is higher in elderly patients over 65 years old, recent studies show an increment also in youngers over 40 years old. Even its large prevalence in the population, its pathophysiology still remain poorly understood. It’s widely accepted that diverticula are likely to be the result of complex interactions among genetic factors, alteration of colonic motility, lifestyle conditions such as smoking, obesity, alcohol consumption, fiber and meat intake with diet. Recently many authors considered also alterations in colonic microbiota composition, co-morbidity with diabetes and hypertension and the chronic assumption of certain medications like PPI, ARB and aspirin, as important risk factors for the development of diverticulosis. The aim of this narrative review is to summarise current knowledges on this topic. (www.actabiomedica.it)
Published: 2018

39. Somatic mutations in specific and connected sub-pathways are associated to short neuroblastoma patients' survival and indicate proteins targetable at onset of disease

Author: Marcella Pantile, Roberto Luksch, Maria Rosaria Esposito, Mario Capasso, Andrea Binatti, Vito Alessandro Lasorsa, Luca Longo, Gian Paolo Tonini, Stefania Bortoluzzi, Alessandro Coppe, Katia Mazzocco, Esposito, M. R., Binatti, A., Pantile, M., Coppe, A., Mazzocco, K., Longo, L., Capasso, M., Lasorsa, V. A., Luksch, R., Bortoluzzi, Sara, and Tonini, G. P.
Subjects: Male, 0301 basic medicine, Whole Exome Sequencing, gene networks, neuroblastoma, pathways, somatic mutations, target protein, Cancer Research, Adolescent, MAP Kinase Signaling System, Somatic cell, Biology, medicine.disease_cause, Neoplasm Protein, Cohort Studies, Pathogenesis, 03 medical and health sciences, Neuroblastoma, medicine, Humans, somatic mutation, Gene Regulatory Networks, whole-exome sequencing, Child, Gene, Exome sequencing, Mutation, Gene Regulatory Network, pathway, Infant, medicine.disease, Neoplasm Proteins, Survival Rate, 030104 developmental biology, Oncology, Child, Preschool, gene network, SMARCA4, Cancer research, MMP14, Female, Cohort Studie, Human
Abstract: Neuroblastoma (NB) is an embryonic malignancy of the sympathetic nervous system with heterogeneous biological, morphological, genetic and clinical characteristics. Although genomic studies revealed the specific biological features of NB pathogenesis useful for new therapeutic approaches, the improvement of high-risk (HR)-NB patients overall survival remains unsatisfactory. To further clarify the biological basis of disease aggressiveness, we used whole-exome sequencing to examine the genomic landscape of HR-NB patients at stage M with short survival (SS) and long survival (LS). Only a few genes, including SMARCA4, SMO, ZNF44 and CHD2, were recurrently and specifically mutated in the SS group, confirming the low recurrence of common mutations in this tumor. A systems biology approach revealed that in the two patient groups, mutations occurred in different pathways. Mutated genes (ARHGEF11, CACNA1G, FGF4, PTPRA, PTK2, ANK3, SMO, NTNG2, VCL and NID2) regulate the MAPK pathway associated with the organization of the extracellular matrix, cell motility through PTK2 signaling and matrix metalloproteinase activity. Moreover, we detected mutations in LAMA2, PTK2, LAMA4, and MMP14 genes, impairing MET signaling, in SFI1 and CHD2 involved in centrosome maturation and chromosome remodeling, in AK7 and SPTLC2, which regulate the metabolism of nucleotides and lipoproteins, and in NALCN, SLC12A1, SLC9A9, which are involved in the transport of small molecules. Notably, connected networks of somatically mutated genes specific for SS patients were identified. The detection of mutated genes present at the onset of disease may help to address an early treatment of HR-NB patients using FDA-approved compounds targeting the deregulated pathways.
Published: 2018

40. A High-Content Screening of Anticancer Compounds Suggests the Multiple Tyrosine Kinase Inhibitor Ponatinib for Repurposing in Neuroblastoma Therapy

Author: Mario Capasso, Alessandro Quattrone, Laura Emionite, Viktoryia Sidarovich, Silvano Ferrini, Pamela Gatto, Luca Longo, Valentina Adami, Marianna Avitabile, Gian Paolo Tonini, Michele Cilli, Silvia Pizzini, Luigi Pasini, Michela Croce, Aldo Pagano, Michael Pancher, Federica Parodi, Marilena De Mariano, Flora Cimmino, Sanja Aveic, Sidarovich, V., De Mariano, M., Aveic, S., Pancher, M., Adami, Riccardo, Gatto, P., Pizzini, Barbara, Pasini, L., Croce, M., Parodi, F., Cimmino, F., Avitabile, M., Emionite, L., Cilli, M., Ferrini, S., Pagano, A., Capasso, M., Quattrone, Cristina, Tonini, G. P., and Longo, L.
Subjects: 0301 basic medicine, Cancer Research, Gene Expression, Apoptosis, Tyrosine-kinase inhibitor, Antineoplastic Agent, chemistry.chemical_compound, Mice, Neuroblastoma, 0302 clinical medicine, Genes, Reporter, Ponatinib, Cell Cycle, Imidazoles, Axitinib, Pyridazines, Drug repositioning, Oncology, 030220 oncology & carcinogenesis, Pyridazine, Tyrosine kinase, medicine.drug, Human, Xenograft Model Antitumor Assay, medicine.drug_class, Cell Survival, Protein Kinase Inhibitor, Reproducibility of Result, Antineoplastic Agents, 03 medical and health sciences, Therapeutic index, Cell Line, Tumor, medicine, Animals, Humans, Viability assay, Imidazole, Protein Kinase Inhibitors, Cell Proliferation, Animal, Drug Repositioning, Apoptosi, Reproducibility of Results, medicine.disease, Xenograft Model Antitumor Assays, High-Throughput Screening Assays, Disease Models, Animal, 030104 developmental biology, chemistry, Cancer research, Drug Screening Assays, Antitumor
Abstract: Novel druggable targets have been discovered in neuroblastoma (NB), paving the way for more effective treatments. However, children with high-risk NB still show high mortality rates prompting for a search of novel therapeutic options. Here, we aimed at repurposing FDA-approved drugs for NB treatment by performing a high-content screening of a 349 anticancer compounds library. In the primary screening, we employed three NB cell lines, grown as three-dimensional (3D) multicellular spheroids, which were treated with 10 μmol/L of the library compounds for 72 hours. The viability of 3D spheroids was evaluated using a high-content imaging approach, resulting in a primary hit list of 193 compounds. We selected 60 FDA-approved molecules and prioritized drugs with multi-target activity, discarding those already in use for NB treatment or enrolled in NB clinical trials. Hence, 20 drugs were further tested for their efficacy in inhibiting NB cell viability, both in two-dimensional and 3D models. Dose-response curves were then supplemented with the data on side effects, therapeutic index, and molecular targets, suggesting two multiple tyrosine kinase inhibitors, ponatinib and axitinib, as promising candidates for repositioning in NB. Indeed, both drugs showed induction of cell-cycle block and apoptosis, as well as inhibition of colony formation. However, only ponatinib consistently affected migration and inhibited invasion of NB cells. Finally, ponatinib also proved effective inhibition of tumor growth in orthotopic NB mice, providing the rationale for its repurposing in NB therapy. Mol Cancer Ther; 17(7); 1405–15. ©2018 AACR.
Published: 2017

41. Association Study Between Coronary Artery Disease and rs1333049 Polymorphism at 9p21.3 Locus in Italian Population

Author: Piero Pignataro, Lucia Pezone, Giuseppe Di Gioia, Danilo Franco, Guido Iaccarino, Achille Iolascon, Michele Ciccarelli, Mario Capasso, Pignataro, Piero, Pezone, Lucia, Di Gioia, Giuseppe, Franco, Danilo, Iaccarino, Guido, Iolascon, Achille, Ciccarelli, Michele, and Capasso, Mario
Subjects: 0301 basic medicine, Male, SNP, Pharmaceutical Science, Coronary Artery Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Risk Factors, Genetics, Odds Ratio, GWAS, Cyclin-Dependent Kinase Inhibitor p18, Humans, Genetic Predisposition to Disease, Genetics (clinical), Cyclin-Dependent Kinase Inhibitor p16, Genetic Association Studies, Cyclin-Dependent Kinase Inhibitor p15, Middle Aged, Protective Factors, 030104 developmental biology, Phenotype, Italy, Case-Control Studies, Molecular Medicine, 9p21.3, Coronary artery disease, Risk factors, 3003, Cardiology and Cardiovascular Medicine, Female, Risk factor, Chromosomes, Human, Pair 9
Abstract: In this study, we verify the association between the rs1333049 single nucleotide polymorphism (9p21.3) within CDKN2A-CDKN2B and coronary artery disease (CAD) in an Italian population. We replicated rs1333049_G allele association with a significantly reduced risk of CAD (OR = 0.816; 95% confidence interval [0.705-0.945]; p = 0.0065) in 711 CAD patients and 755 normal healthy individuals. This effect is maintained even stratifying patients by gender and by risk factors. A significant association was found with age of CAD onset. Interestingly, we found a protective trend of association between the rs1333049_G allele and peripheral artery disease, a progressive atherosclerotic condition in which plaque builds up in the arteries that carry blood to the head, organs, and limbs (OR = 0.724; 95% CI [0.520-1.007]; p = 0.054). No genotype-phenotype association was found with more severe CAD clinical parameters. If certain genetic factors predispose individuals to adverse outcomes, the knowledge of a patient's genotype may influence clinical management.
Published: 2017

42. Induction of natural killer antibody-dependent cell cytotoxicity and of clinical activity of cetuximab plus avelumab in non-small cell lung cancer

Author: Maria Lucia Iacovino, Alessandro Morabito, Mario Capasso, Vincenzo Sforza, Vincenzo Famiglietti, Evaristo Maiello, Flora Cimmino, Giuseppe Viscardi, Morena Fasano, Achille Iolascon, Carminia Maria Della Corte, Giusi Barra, Francesca Sparano, Raimondo Di Liello, Vincenza Ciaramella, Fernando Paragliola, Fortunato Ciardiello, Floriana Morgillo, Fasano, M., Della Corte, C. M., Di Liello, R., Barra, G., Sparano, F., Viscardi, G., Iacovino, M. L., Paragliola, F., Famiglietti, V., Ciaramella, V., Cimmino, F., Capasso, M., Iolascon, A., Sforza, V., Morabito, A., Maiello, E., Ciardiello, F., and Morgillo, F.
Subjects: Cancer Research, Lung Neoplasms, NK cells, Antibodies, Monoclonal, Humanized, NSCLC, lcsh:RC254-282, Avelumab, chemistry.chemical_compound, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Lactate dehydrogenase, cetuximab, Humans, Medicine, NK cell, Progression-free survival, Cytotoxicity, Lung cancer, neoplasms, Original Research, Antibody-dependent cell-mediated cytotoxicity, Cetuximab, business.industry, Antibody-Dependent Cell Cytotoxicity, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Killer Cells, Natural, Oncology, chemistry, Immunoglobulin G, Cancer research, avelumab, ADCC, business, Ex vivo, medicine.drug
Abstract: Background Antibody-dependent cell-mediated cytotoxicity (ADCC) may mediate antitumour activity of IgG1-isotype monoclonal antibody (mAb), suggesting as potential treatment combination of IgG1-mAbs, anti-epidermal growth factor receptor cetuximab and anti-programmed death-ligand-1 avelumab. Methods We evaluated ADCC induction in lung cancer cells by lactate dehydrogenase (LDH) release assay. Antitumour activity and safety of cetuximab plus avelumab were explored in a single-arm proof-of-concept study in pre-treated non-small cell lung cancer (NSCLC) patients (pt) (Cetuximab-AVElumab-lung, CAVE-Lung). Search for predictive biomarkers of response was done. Results Avelumab plus cetuximab induced ADCC in NSCLC cells in vitro in presence of natural killers (NK) from healthy donors (HD) or NSCLC pt, as effectors. Sixteen relapsed NSCLC pt were treated with avelumab plus cetuximab. Antitumour activity was observed in 6/16 pt, defined by progression free survival (PFS) ≥8 months, with 4 of them still on treatment at data lock time (range, 14–19 months). Of note, 3/6 responders had received as previous line anti-programmed death-1 therapy. In responders, clinical benefit was accompanied by significant increase in LDH release over baseline at the first radiological evaluation (8 weeks) (p=0.01) and by early skin toxicity; while in the 10 non-responders, that had PFS ≤5 months, LDH release tends to reduce. Baseline circulating DNA levels were higher in non-responders compared with responders and HD (p=0.026) and decrease in responders during therapy. Mutations in DNA damage responsive family genes were found in responders. Conclusion Cetuximab and avelumab activates NSCLC pt NK cells. Ex vivo evaluation of ADCC, circulating DNA levels and early skin toxicity may predict response to cetuximab plus avelumab in NSCLC. EUDRACT 2017-004195-58
Published: 2020
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43. Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma

Author: Derek A. Oldridge, Achille Iolascon, Lee D. McDaniel, Sharon J. Diskin, Nazneen Rahman, Karina L. Conkrite, Millicent Horn, Anna Zachariou, Mario Capasso, Hakon Hakonarson, Maura Diamond, Marcella Devoto, Xiao Chang, Zalman Vaksman, Cuiping Hou, Mcdaniel, Lee D, Conkrite, Karina L, Chang, Xiao, Capasso, Mario, Vaksman, Zalman, Oldridge, Derek A, Zachariou, Anna, Horn, Millicent, Diamond, Maura, Hou, Cuiping, Iolascon, Achille, Hakonarson, Hakon, Rahman, Nazneen, Devoto, Marcella, and Diskin, Sharon J.
Subjects: 0301 basic medicine, Male, Cancer Research, Heredity, Genome-wide association study, Cell Cycle Proteins, Carboxypeptidases, Carboxypeptidase, medicine.disease_cause, Neuroblastoma, Cell Signaling, Medicine and Health Sciences, Blastomas, Ethnicities, Case-Control Studies, Cell Line, Tumor, Cell Proliferation, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 4, Female, Gene Silencing, Homozygote, Humans, Nuclear Proteins, Proteins, Polymorphism, Single Nucleotide, Ecology, Evolution, Behavior and Systematics, Molecular Biology, Genetics, Genetics (clinical), Nuclear Protein, Cultured Tumor Cells, African Americans, Tumor, Ecology, Chemical Reactions, Genomics, Single Nucleotide, Population groupings, 3. Good health, DNA-Binding Proteins, Chemistry, Genetic Mapping, Oncology, Pair 4, Pair 3, Physical Sciences, Biological Cultures, Case-Control Studie, Genomic Signal Processing, Research Article, Signal Transduction, Human, lcsh:QH426-470, Evolution, Single-nucleotide polymorphism, Variant Genotypes, Biology, Carboxypeptidase Z, Research and Analysis Methods, Methylation, Chromosomes, Cell Line, 03 medical and health sciences, Behavior and Systematics, medicine, Genome-Wide Association Studies, Allele, Polymorphism, Protein, Biology and Life Sciences, Computational Biology, Cancers and Neoplasms, Human Genetics, Odds ratio, Cell Biology, Cell Cultures, medicine.disease, Genome Analysis, lcsh:Genetics, 030104 developmental biology, Genetic Loci, Cancer research, Neuroblastoma Cells, People and places, Carcinogenesis, Myeloid leukemia factor 1
Abstract: Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly presents in young children and accounts for approximately 12% of pediatric oncology deaths. Here, we report on a genome-wide association study (GWAS) in a discovery cohort or 2,101 cases and 4,202 controls of European ancestry. We identify two new association signals at 3q25 and 4p16 that replicated robustly in multiple independent cohorts comprising 1,163 cases and 4,396 controls (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16–1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21–1.40). The 4p16 signal maps within the carboxypeptidase Z (CPZ) gene. The 3q25 signal resides within the arginine/serine-rich coiled-coil 1 (RSRC1) gene and upstream of the myeloid leukemia factor 1 (MLF1) gene. Increased expression of MLF1 was observed in neuroblastoma cells homozygous for the rs6441201 risk allele (P = 0.02), and significant growth inhibition was observed upon depletion of MLF1 (P < 0.0001) in neuroblastoma cells. Taken together, we show that common DNA variants within CPZ at 4p16 and upstream of MLF1 at 3q25 influence neuroblastoma susceptibility and MLF1 likely plays an important role in neuroblastoma tumorigenesis., Author summary Neuroblastoma is an embryonal tumor of the developing sympathetic nervous system that accounts for 12% of childhood cancer deaths. Approximately 1–2% of cases are inherited in an autosomal dominant fashion. These familial cases often harbor germline mutations in ALK or PHOX2B. However, the vast majority of neuroblastomas appear to arise sporadically. We are studying sporadic neuroblastoma through an ongoing genome-wide association study (GWAS). To date, this effort has identified single nucleotide polymorphisms (SNPs) within or upstream of CASC15 and CASC14, BARD1, LMO1, DUSP12, HSD17B12, DDX4/IL31RA, HACE1, LIN28B, and TP53, along with a common copy number variation (CNV) within NBPF23 at chromosome 1q21.1, each being highly associated with neuroblastoma. Here, we report on genome-wide association study (GWAS) comprising 3,264 neuroblastoma patients and 8,598 control subjects. We identify two new association signals at 3q25 and 4p16 (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16–1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21–1.40). The 3q25 signal resides upstream of the MLF1 gene and the 4p16 signal maps to the CPZ gene. We further demonstrate that neuroblastoma cells homozygous for the risk allele at 3q25 express higher levels of MLF1 and that silencing of MLF1 in neuroblastoma cells results in significant growth inhibition.
Published: 2017

44. FKBP51s signature in peripheral blood mononuclear cells of melanoma patients as a possible predictive factor for immunotherapy

Author: Maria Romano, Vito Alessandro Lasorsa, Anna D'Angelillo, Simona Romano, Michele Russo, Nicola Zambrano, Mario Capasso, Paolo A. Ascierto, Ester Simeone, Paolo D'Arrigo, Romano, Simona, Simeone, Ester, D'Angelillo, Anna, D'Arrigo, Paolo, Russo, Michele, Capasso, Mario, Lasorsa, Vito Alessandro, Zambrano, Nicola, Ascierto, Paolo A, and Romano, MARIA FIAMMETTA
Subjects: 0301 basic medicine, Male, Cancer Research, medicine.medical_treatment, Immunology, Ipilimumab, Tregs, Peripheral blood mononuclear cell, Immunophenotyping, Tacrolimus Binding Proteins, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, Humans, Melanoma, Aged, business.industry, Immunotherapy, medicine.disease, Immune checkpoint, 030104 developmental biology, FKBP5, Oncology, 030220 oncology & carcinogenesis, Leukocytes, Mononuclear, Female, business, Immunophenotype, medicine.drug
Abstract: The inhibitory immune checkpoint PD-L1/PD1 promotes the alternative splicing of the FKBP5 gene, resulting in increased expression of its variant 4 in the peripheral blood mononuclear cells of melanoma patients. The variant 4 transcript is translated into the truncated FKBP51s protein. Given the importance of co-inhibitory signalling in tumour immune escape, here we tested the potential for using FKBP51s expression to predict immunotherapy outcomes. To do this, we immunophenotyped PBMCs from 118 melanoma patients and 77 age- and sex-matched healthy controls. Blood samples were collected before patients underwent ipilimumab treatment. In 64 of the 118 patients, FKBP51s expression was also assessed in regulatory T cells (Tregs). We found that each PBMC subset analysed contained an FKBP51s(pos) fraction, and that this fraction was greater in the melanoma patients than healthy controls. In CD4 T lymphocytes, the FKBP51s(neg) fraction was significantly impaired. Tregs count was increased in melanoma patients, which is in line with previous studies. Also, by analyses of FKBP51s in Tregs, we identified a subgroup of ipilimumab nonresponder patients (p = 0.002). In conclusion, FKBP51s-based immunophenotyping of melanoma patients revealed several profiles related to a negative immune regulatory control and identified an unknown Treg subset. These findings are likely to be useful in the selection of the patients that are candidate for immunotherapy.
Published: 2017

45. LSD1 mediates MYCN control of epithelial-mesenchymal transition through silencing of metastatic suppressor NDRG1 gene

Author: Susanna Ambrosio, Stefano Amente, Barbara Majello, Raffaele A. Calogero, Mario Capasso, Luigi Lania, Carmen D. Saccà, Ambrosio, Susanna, Amente, Stefano, Saccà, Carmen D, Capasso, Mario, Calogero, Raffaele A, Lania, Luigi, and Majello, Barbara
Subjects: 0301 basic medicine, animal structures, Epithelial-Mesenchymal Transition, LSD1, Cell Cycle Proteins, Biology, Metastasis, Epigenesis, Genetic, 03 medical and health sciences, Gene Knockout Techniques, Neuroblastoma, 0302 clinical medicine, Cell Movement, Cell Line, Tumor, MYCN, Transcriptional regulation, medicine, Gene silencing, Humans, Metastasis suppressor, Epithelial–mesenchymal transition, Promoter Regions, Genetic, neoplasms, Genetics, Histone Demethylases, N-Myc Proto-Oncogene Protein, EMT, NDRG1, Oncology, Intracellular Signaling Peptides and Proteins, medicine.disease, Molecular medicine, Survival Analysis, Gene Expression Regulation, Neoplastic, 030104 developmental biology, HEK293 Cells, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Research Paper
Abstract: // Susanna Ambrosio 1 , Stefano Amente 2 , Carmen D. Sacca 1 , Mario Capasso 2,3 , Raffaele A. Calogero 4 , Luigi Lania 2 and Barbara Majello 1 1 Department of Biology, University of Naples ‘Federico II’, Naples, Italy 2 Department of Molecular Medicine and Medical Biotechnologies, University of Naples, ‘Federico II’, Naples, Italy 3 CEINGE Biotecnologie Avanzate, Napoli, Italy 4 Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy Correspondence to: Barbara Majello, email: // Keywords : MYCN; LSD1; NDRG1; EMT; neuroblastoma Received : July 20, 2016 Accepted : October 14, 2016 Published : November 22, 2016 Abstract Neuroblastoma (NB) with MYCN amplification is a highly aggressive and metastatic tumor in children. The high recurrence rate and resistance of NB cells to drugs urgently demands a better therapy for this disease. We have recently found that MYCN interacts with the lysine-specific demethylase 1 (LSD1), a histone modifier that participates in key aspects of gene transcription. In cancer cells, LSD1 contributes to the genetic reprogramming that underlies to Epithelial-Mesenchymal Transition (EMT) and tumor metastasis. Here, we show that LSD1 affects motility and invasiveness of NB cells by modulating the transcription of the metastasis suppressor NDRG1 (N-Myc Downstream-Regulated Gene 1). At mechanistic level, we found that LSD1 co-localizes with MYCN at the promoter region of the NDRG1 gene and inhibits its expression. Pharmacological inhibition of LSD1 relieves repression of NDRG1 by MYCN and affects motility and invasiveness of NB cells. These effects were reversed by overexpressing NDRG1. In NB tissues, high levels of LSD1 correlate with low levels of NDRG1 and reduced patients survival. Collectively, our findings elucidate a mechanism of how MYCN/LSD1 control motility and invasiveness of NB cells through transcription regulation of NDRG1 expression and suggest that pharmacological targeting of LSD1 represents a valuable approach for NB therapy.
Published: 2017

46. Kinome expression profiling of human neuroblastoma tumors identifies potential drug targets for ultra highrisk patients

Author: Maddalena Raia, Giampietro Viola, Lucia Pezone, Marianna Avitabile, Matthias Fischer, Fiorina Casale, Flora Cimmino, Roberta Russo, Jan Koster, Concetta Langella, Mario Capasso, Achille Iolascon, Francesco Manna, CCA - Cancer biology and immunology, Oncogenomics, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Russo, Roberta, Cimmino, Flora, Pezone, Lucia, Manna, Francesco, Avitabile, Marianna, Langella, Concetta, Koster, Jan, Casale, Fiorina, Raia, Maddalena, Viola, Giampietro, Fischer, Matthia, Iolascon, Achille, and Capasso, Mario
Subjects: 0301 basic medicine, Oncology, Enzymologic, Cancer Research, Antineoplastic Agents, Cell Cycle, Cell Line, Tumor, Cell Survival, Enzyme Inhibitors, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HSP90 Heat-Shock Proteins, Histone Deacetylase Inhibitors, Humans, Macrolides, Molecular Targeted Therapy, Neuroblastoma, Phosphotransferases, Bioinformatics, Antineoplastic Agent, chemistry.chemical_compound, 0302 clinical medicine, Histone Deacetylase Inhibitor, Enzyme Inhibitor, Medicine, Kinome, Tumor, Standard treatment, Phosphotransferase, General Medicine, Cell cycle, Radicicol, 030220 oncology & carcinogenesis, Macrolide, Human, medicine.medical_specialty, Cell Line, 03 medical and health sciences, Internal medicine, Survival rate, Neoplastic, business.industry, Gene signature, medicine.disease, Gene expression profiling, HSP90 Heat-Shock Protein, 030104 developmental biology, chemistry, Gene Expression Regulation, business
Abstract: Neuroblastoma (NBL) accounts for >7% of malignancies in patients younger than 15 years. Low- and intermediate-risk patients exhibit excellent or good prognosis after treatment, whereas for high-risk (HR) patients, the estimated 5-year survival rates is still
Published: 2017

47. Exercise intensity and technical demands of small-sided soccer games for under-12 and under-14 players: effect of area per player

Author: Moreno Giacobbe, Annamaria Mancini, Adriano Capobianco, Domenico Martone, Esther Imperlini, Pasqualina Buono, Mario Capasso, Stefania Orrù, Martone, Domenico, Giacobbe, Moreno, Capobianco, Adriano, Imperlini, Esther, Mancini, Annamaria, Capasso, Mario, Buono, Pasqualina, and Orrù, Stefania
Subjects: Male, medicine.medical_specialty, Adolescent, Physical conditioning, business.industry, Physical Therapy, Sports Therapy and Rehabilitation, 030229 sport sciences, General Medicine, Athletic Performance, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Heart Rate, Soccer, Heart rate, medicine, Exercise intensity, Technical training, Humans, Orthopedics and Sports Medicine, Child, business, 030217 neurology & neurosurgery, Physical Conditioning, Human
Abstract: The aim of this study was to evaluate the effects of 6 different areas per player (AP) on exercise intensity (EI) measured during small-sided games (SSGs) and expressed as percentage of maximal heart rate (%MHR) and technical actions (TAs) involvement with the ball, crosses, headers, tackles, shots on goal, dribbling, passing, and target passing-in U-12 and U-14 soccer players during SSGs. Seventeen male U-12 soccer players (age 10.0 ± 0.5 years, body mass 39.3 ± 5.3 kg, and height 143.8 ± 4.6 cm) and 16 male U-14 soccer players (age 13.2 ± 0.3 years, body mass 46.6 ± 11.9 kg, and height 154.8 ± 8.5 cm) performed SSGs with different AP: 40, 50, 66.7, 90, 112.5, and 150 m. Our results indicate that at larger AP, the U-12 group's mean EI values were significantly higher than those at smaller AP (p ≤ 0.05); in addition, intergroup comparison showed that EI was higher in U-12 than that in U-14 players when AP of 112.5 and 150 m were considered (p ≤ 0.05). Technical action analysis evidenced that moving from smaller to larger AP, U-14 players adapted better to AP changes. In conclusion, these results suggest that AP influences differently EI and TAs in U-12 and U-14 players. Our results could be taken into account by conditioning coaches to better tailor the physiological and technical training in young players through the modulation of AP.
Published: 2017

48. Germline polymorphisms of the VEGF-pathway predict recurrence in non-advanced differentiated thyroid cancer

Author: Vincenzo Marotta, Antongiulio Faggiano, Antonio Antonino, Gerardo Botti, Alessandro Testori, Annamaria Colao, Rosario Pivonello, Luigi Santini, Paolo Emidio Macchia, Claudio Gambardella, Annamaria Annunziata, Claudia Pivonello, Simona Losito, Marica Grasso, Maria Grazia Chiofalo, Luciano Pezzullo, Concetta Sciammarella, Mario Capasso, Marotta, Vincenzo, Sciammarella, Concetta, Capasso, Mario, Testori, Alessandro, Pivonello, Claudia, Chiofalo, Maria Grazia, Gambardella, Claudio, Grasso, Marica, Antonino, Antonio, Annunziata, Annamaria, Macchia, PAOLO EMIDIO, Pivonello, Rosario, Santini, Luigi, Botti, Gerardo, Losito, Simona, Pezzullo, Luciano, Colao, Annamaria, and Faggiano, Antongiulio
Subjects: Male, Vascular Endothelial Growth Factor A, 0301 basic medicine, Oncology, Pathology, Angiogenesis, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, CD34, Biochemistry, Germline, angiogenesis, 0302 clinical medicine, Endocrinology, Genotype, thyroid cancer, Thyroid cancer, vegf, Neovascularization, Pathologic, Middle Aged, SNP genotyping, 030220 oncology & carcinogenesis, Female, VEGF Pathway, gremlin polymorphisms, Nonadvanced Differentiated Thyroid Cancer, Adult, medicine.medical_specialty, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Disease-Free Survival, Young Adult, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, TaqMan, Humans, Thyroid Neoplasms, Aged, Neoplasm Staging, Retrospective Studies, Biochemistry (medical), medicine.disease, Vascular Endothelial Growth Factor Receptor-2, 030104 developmental biology, Microvessels, prognosis, Neoplasm Recurrence, Local, polymorphisms, Follow-Up Studies
Abstract: Context: Tumor angiogenesis is determined by host genetic background rather than environment. Germline single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) pathway have demonstrated prognostic value in different tumors. Objectives: Our main objective was to test the prognostic value of germline SNPs of the VEGF pathway in nonadvanced differentiated thyroid cancer (DTC). Secondarily, we sought to correlate analyzed SNPs with microvessel density (MVD). Design: Multicenter, retrospective, observational study. Setting: Four referral centers. Patients: Blood samples were obtained from consecutive DTC patients. Genotyping was performed according to the TaqMan protocol, including 4 VEGF-A (-2578C>A, -460T>C, +405G>C, and +936C>T) and 2 VEGFR-2 (+1192 C>T and +1719 T>A) SNPs. MVD was estimated by means of CD34 staining. Outcome measures: Rate of recurrent structural disease/disease-free survival (DFS). Difference in MVD between tumors from patients with different genotype. Results: Two hundred four patients with stage I-II DTC (mean follow-up, 73 ± 64 months) and 240 patients with low- to intermediate-risk DTC (mean follow-up, 70 ± 60 months) were enrolled. Two "risk" genotypes were identified by combining VEGF-A SNPs -2578 C>A, -460 T>C, and +405 G>C. The ACG homozygous genotype was protective in both stage I-II (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.01 to 1.43; P = 0.018) and low- to intermediate-risk (OR, 0.14; 95% CI, 0.01 to 1.13; P = 0.035) patients. The CTG homozygous genotype was significantly associated with recurrence in stage I-II (OR, 5.47; 95% CI, 1.15 to 26.04; P = 0.018) and was slightly deleterious in low- to intermediate-risk (OR, 3.39; 95% CI, 0.8 to 14.33; P = 0.079) patients. MVD of primary tumors from patients harboring a protective genotype was significantly lower (median MVD, 76.5 ± 12.7 and 86.7 ± 27.9, respectively; P = 0.024). Conclusions: Analysis of germline VEGF-A SNPs could empower a prognostic approach to DTC.
Published: 2017

49. A comprehensive characterization of rare mitochondrial DNA variants in neuroblastoma

Author: Gian Paolo Tonini, Francesco Maria Calabrese, Giuseppe Gasparre, Achille Iolascon, Vito Alessandro Lasorsa, Michael D. Hogarty, Mario Capasso, Piero Pignataro, Massimo Conte, Rosanna Clima, Aurora Castellano, Calabrese, Francesco Maria, Clima, Rosanna, Pignataro, Piero, Lasorsa, Vito Alessandro, Hogarty, Michael D, Castellano, Aurora, Conte, Massimo, Tonini, Gian Paolo, Iolascon, Achille, Gasparre, Giuseppe, Capasso, Mario, and Hogarty, Michael D.
Subjects: 0301 basic medicine, medicine.medical_specialty, Mitochondrial DNA, DNA Mutational Analysis, DNA, Mitochondrial, Germline, 03 medical and health sciences, neuroblastoma, Germline mutation, Neuroblastoma, medicine, Humans, Exome, Child, Exome sequencing, Alleles, mitochondrial DNA mutations, Genetics, business.industry, Brain Neoplasms, Infant, Newborn, Computational Biology, Genetic Variation, Infant, medicine.disease, Heteroplasmy, 030104 developmental biology, Phenotype, germline mutation, mitochondrial DNA mutation, Oncology, Italy, Child, Preschool, Mutation, Medical genetics, WES, somatic mutations, germline mutations, business, Neuroblastoma, mitochondrial DNA mutations, Research Paper
Abstract: // Francesco Maria Calabrese 1, * , Rosanna Clima 2, * , Piero Pignataro 3, 4 , Vito Alessandro Lasorsa 3, 4 , Michael D. Hogarty 5 , Aurora Castellano 6 , Massimo Conte 7 , Gian Paolo Tonini 8 , Achille Iolascon 3, 4 , Giuseppe Gasparre 2, # , Mario Capasso 3, 4, 9, # 1 Department of Biology, University of Bari “Aldo Moro”, Bari, Italy 2 Department of Medical and Surgical Sciences-DIMEC, Medical Genetics Unit, University of Bologna, Bologna, Italy 3 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy 4 CEINGE Biotecnologie Avanzate, Napoli, Italy 5 Department of Pediatrics, Division of Oncology, Children’s Hospital of Philadelphia, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, USA 6 Paediatric Haematology/Oncology Department, IRCCS, Ospedale Pediatrico Bambino Gesu, Rome, Italy 7 Oncology Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy 8 Pediatric Research Institute (IRP) – Fondazione Citta della Speranza, Neuroblastoma Laboratory, Padua, Italy 9 IRCCS SDN, Istituto di Ricerca Diagnostica e Nucleare, Naples, Italy * These authors contributed equally to this work # Co-last authors Correspondence to: Mario Capasso, email: mario.capasso@unina.it Keywords: neuroblastoma, mitochondrial DNA mutations, WES, somatic mutations, germline mutations Received: April 21, 2016 Accepted: June 09, 2016 Published: June 24, 2016 ABSTRACT Background: Neuroblastoma, a tumor of the developing sympathetic nervous system, is a common childhood neoplasm that is often lethal. Mitochondrial DNA (mtDNA) mutations have been found in most tumors including neuroblastoma. We extracted mtDNA data from a cohort of neuroblastoma samples that had undergone Whole Exome Sequencing (WES) and also used snap-frozen samples in which mtDNA was entirely sequenced by Sanger technology. We next undertook the challenge of determining those mutations that are relevant to, or arisen during tumor development. The bioinformatics pipeline used to extract mitochondrial variants from matched tumor/blood samples was enriched by a set of filters inclusive of heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity. Results: Our in silico multistep workflow applied both on WES and Sanger-sequenced neuroblastoma samples, allowed us to identify a limited burden of somatic and germline mitochondrial mutations with a potential pathogenic impact. Conclusions: The few singleton germline and somatic mitochondrial mutations emerged, according to our in silico analysis, do not appear to impact on the development of neuroblastoma. Our findings are consistent with the hypothesis that most mitochondrial somatic mutations can be considered as ‘passengers’ and consequently have no discernible effect in this type of cancer.
Published: 2016

50. Decreased concentration of adiponectin together with a selective reduction of its high molecular weight oligomers is involved in metabolic complications of myotonic dystrophy type 1

Author: Carola Porcile, Maria Ludovica Monaco, Mariorosario Masullo, Giovannangelo Oriani, Gioacchino Tedeschi, Mario de Cristofaro, Aurora Daniele, Mario Capasso, Alfonso Di Costanzo, Anna De Rosa, Daniele, Aurora, De Rosa, A, De Cristofaro, M, Monaco, Ml, Masullo, M, Porcile, C, Capasso, M, Tedeschi, Gioacchino, Oriani, G, Di Costanzo, A., Daniele, A1, Capasso, Mario, and Tedeschi, G
Subjects: Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Type 2 diabetes, Biology, Myotonic dystrophy, Young Adult, Endocrinology, Insulin resistance, Internal medicine, medicine, Humans, Myotonic Dystrophy, Adiponectin, Insulin, Quantitative insulin sensitivity check index, General Medicine, Middle Aged, medicine.disease, Female, Insulin Resistance, Protein Multimerization, Biomarkers, Homeostasis, Hormone
Abstract: ObjectiveThe hormone adiponectin exerts beneficial pleiotropic effects on biological and metabolic processes. Although a well-recognized insulin sensitizer, its characteristic has yet to be clearly defined. Myotonic dystrophy type 1 (DM1) is a rare genetic disorder that features muscle wasting and metabolic comorbidity, and patients have an increased risk of developing type 2 diabetes. We analyzed circulating levels of adiponectin and its oligomers to determine whether their expression correlates with metabolic alterations in DM1 patients.Design and methodsWe measured the anthropometric and biochemical features and three insulin resistance (IR) indices (homeostasis model assessment, quantitative insulin sensitivity check index, and McAuley) of 21 DM1 patients and of 82 age-, sex-, and weight-matched controls. In the blood samples of patients and controls, adiponectin levels were measured by ELISA, and its oligomers were characterized by using western blotting and gel filtration. The adiponectin gene was molecularly analyzed in patients.ResultsDM1 patients had significantly higher body mass index, waist circumference, triglycerides (TGs), glucose, tumor necrosis factor α, and IR; conversely, they had significantly lower concentrations of total serum adiponectin with a selective, pronounced decrease of its high molecular weight (HMW) oligomers. There was a strong negative correlation between adiponectin and TGs in DM1 patients.ConclusionsOur results endorse the hypothesis that decreased expression of adiponectin together with a selective reduction of its HMW oligomers contributes to the worsening of IR and its metabolic complications in DM1 patients. These findings suggest that adiponectin and HMW oligomers may serve as biomarkers and are promising therapeutic agents for IR and its consequences in DM1.
Published: 2011
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