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6. Terricolous lichen communities in Thero-Airion dry grasslands of the Po Plain (Northern Italy): syntaxonomy, ecology and conservation value

Author

Gheza, G, Barcella, M, Assini, S, Gheza, G, Barcella, M, and Assini, S

Subjects
Cladonia, Cladonietum foliaceae, Pycnothelio-Cladonietum cervicornis, Cladonion rei, lichen vegetation
Abstract

Terricolous lichen vegetation has been partially studied in Italy so far, particularly in the Po Plain. Here, pioneer acidic Thero-Airion dry grasslands host rich terricolous lichen communities which often include lichen species of conservation concern. Overall, 288 phytosociological releves were carried out with the Braun-Blanquet method using standard plots of 30 cm x 30 cm in lichen-rich stands within Thero-Airion dry grasslands located in 16 localities of the western Po Plain, an area with continental climate. Releves were manually sorted and species composition was analyzed through Principal Component Analysis (PCA) and non-parametric MANOVA. Biological, ecological, chorological and rarity spectra were computed and analyzed with Kruskal-Wallis tests to assess differences among the communities. Nine lichen communities were recognized. One community dominated by Cladonia pulvinata referred to the Pycnothelio-Cladonietum cervicornis. Three communities referred to the Cladonietum foliaceae are dominated respectively by C. foliacea, C. furcata and C. rangiformis. Three communities referred to the Cladonietum rei are dominated respectively by C. rei, C. polycarpoides and C. coccifera. Two communities dominated respectively by C. peziziformis and C. cariosa are referred to an undescribed association, temporarily attributed to the Cladonion rei. All communities significantly differ in the mean ecological indicator values - soil pH, light, aridity, eutrophication, poleotolerance. The communities Pycnothelio-Cladonietum cervicornis, Cladonietum foliaceae (C. foliacea facies) and the C. peziziformis-C. cariosa community are pioneer communities. The Cladonietum rei (C. rei facies) and the Cladonietum foliaceae (C. rangiformis facies) are the more mature communities, respectively in disturbed and undisturbed sites. This study shows that terricolous lichen communities represent an important component of biodiversity in Thero-Airion dry grasslands, due to their diversification in different syntaxa and, in some cases, to their role as microhabitats for lichen species of conservation concern. Thus, our study contributes to the knowledge on Thero-Airion dry grasslands, which is a key component in the choice of management and conservation strategies.

Published
2019

10. An overview of the Italian forest biodiversity and its conservation level, based on the first outcomes of the 4th Habitat Report ex-Art. 17

Author

Gigante, D., Selvaggi, A., Acosta Alicia, T., Adorni, M., Allegrezza, M., Angiolini, C., Armiraglio, S., Assini, S., Attorre, F., Bagella, S., Barcella, M., Giuseppe Bazan, Bertacchi, A., Bolpagni, R., Bonari, G., Buffa, G., Caccianiga Marco Stefano, Cacciatori, C., Carmela, C., Casavecchia, S., Casella, L., Cerabolini Bruno, E., Ciaschetti, G., Ciccarelli, D., Cogoni, A., Cutini, M., De Sanctis Michele, De Simone Walter, Del Vecchio Silvia, Di Cecco Valter, Di Martino Luciano, Di Musciano Michele, Fantinato, E., Filesi, L., Foggi, B., Forte, L., Frattaroli Anna Rita, Galdenzi, D., Gangale, C., lorenzo gianguzzi, Giusso Del Galdo Gianpietro, Grignetti, A., Riccardo Guarino, Lasen, C., Maneli, F., Marcenò, C., Mariotti Mauro Giorgio, Oriolo, G., Paura, B., Perrino, E., Pesaresi, S., Pezzi, G., Pisanu, S., Poponessi, S., Prisco, I., Puglisi, M., Rivieccio, G., Sciandrello, S., Spampinato, G., Stinca, A., Strumia, S., Taffetani, F., Tesei, G., Tomaselli, V., Venanzoni, R., Viciani, D., Villani, M., Wagensommer Robert Philipp, Zanatta, K., Angelini, P., Società Botanica Italiana, Gigante, Daniela, Selvaggi, Alberto, Acosta Alicia, T. R., Adorni, Michele, Allegrezza, Marina, Angiolini, Claudia, Armiraglio, Stefano, Assini, Silvia, Attorre, Fabio, Bagella, Simonetta, Barcella, Matteo, Bazan, Giuseppe, Bertacchi, Andrea, Bolpagni, Rossano, Bonari, Gianmaria, Buffa, Gabriella, Caccianiga Marco, Stefano, Cacciatori, Cecilia, Caria Maria, Carmela, Casavecchia, Simona, Casella, Laura, Cerabolini Bruno, E. L., Ciaschetti, Giampiero, Ciccarelli, Daniela, Cogoni, Annalena, Cutini, Maurizio, De Sanctis, Michele, De Simone, Walter, Del Vecchio, Silvia, Di Cecco, Valter, Di Martino, Luciano, Di Musciano, Michele, Fantinato, Edy, Filesi, Leonardo, Foggi, Bruno, Forte, Luigi, Frattaroli Anna, Rita, Galdenzi, Diana, Gangale, Carmen, Gianguzzi, Lorenzo, Giusso Del Galdo, Gianpietro, Grignetti, Alessandra, Guarino, Riccardo, Lasen, Cesare, Maneli, Fabio, Marcenò, Corrado, Mariotti Mauro, Giorgio, Oriolo, Giuseppe, Paura, Bruno, Perrino, Enrico, Pesaresi, Simone, Pezzi, Giovanna, Pisanu, Stefania, Poponessi, Silvia, Prisco, Irene, Puglisi, Marta, Rivieccio, Giovanni, Sciandrello, Saverio, Spampinato, Giovanni, Stinca, Adriano, Strumia, Sandro, Taffetani, Fabio, Tesei, Giulio, Tomaselli, Valeria, Venanzoni, Roberto, Viciani, Daniele, Villani, Mariacristina, Wagensommer Robert, Philipp, Zanatta, Katia, Angelini, Paola, and Gigante Daniela, Selvaggi Alberto, Acosta Alicia T.R., Adorni Michele, Allegrezza Marina, Angiolini Claudia, Armiraglio Stefano, Assini Silvia, Attorre Fabio, Bagella Simonetta, Barcella Matteo, Bazan Giuseppe, Bertacchi Andrea, Bolpagni Rossano, Bonari Gianmaria, Buffa Gabriella, Caccianiga Marco Stefano, Cacciatori Cecilia, Caria Maria.Carmela, Casavecchia Simona, Casella Laura, Cerabolini Bruno E.L., Ciaschetti Giampiero, Ciccarelli Daniela, Cogoni Annalena, Cutini Maurizio, De Sanctis Michele, De Simone Walter, Del Vecchio Silvia, Di Cecco Valter, Di Martino Luciano, Di Musciano Michele, Fantinato Edy, Filesi Leonardo, Foggi Bruno, Forte Luigi, Frattaroli Anna Rita, Galdenzi Diana, Gangale Carmen, Gianguzzi Lorenzo, Giusso Del Galdo Gianpietro, Grignetti Alessandra, Guarino Riccardo, Lasen Cesare, Maneli Fabio, Marcenò Corrado, Mariotti Mauro Giorgio, Oriolo Giuseppe, Paura Bruno, Perrino Enrico, Pesaresi Simone, Pezzi Giovanna, Pisanu Stefania, Poponessi Silvia, Prisco Irene, Puglisi Marta, Rivieccio Giovanni, Sciandrello Saverio, Spampinato Giovanni, Stinca Adriano, Strumia Sandro, Taffetani Fabio, Tesei Giulio, Tomaselli Valeria, Venanzoni Roberto, Viciani Daniele, Villani Mariacristina, Wagensommer Robert Philipp, Zanatta Katia, Angelini Paola

Subjects
Habitat, Habitat, Italian forests, Vegetation Science, Natura 2000, Biodiversity conservation, Italian forests
Abstract

In 2019 the 4th Report ex-Art. 17 on the conservation status (CS) of Annex I Habitats of the 92/43/EEC Directive was expected by every EU/28 country, with reference to the period 2013-18. In Italy, the process was in charge to the Italian Institute for Environmental Protection and Research (ISPRA), on behalf of the Ministry for Environment, Land and Sea Protection (MATTM), with the scientific support of the Italian Botanical Society (SBI). A large group of thematic and territorial experts elaborated the available data concerning the 124 types of terrestrial and inland water Habitats present in Italy, 39 of which are represented by Forest Habitats (Group 9),. The main aim of the work was the evaluation of the overall CS of each Habitat by Biogeographic Region (Mediterranean, Continental and Alpine), for a total amount of 294 assessments. A high proportion of these (92, corresponding to 31% of the total) referred to Forest Habitats, including 20 marginal types for which the CS was not requested. The analysis was carried out at different scales: a) administrative territory, through the data contained in the ISPRA database, whose compilation was in charge to the Regions and Autonomous Provinces; b) Natura 2000 site, with the latest updates available (Standard Data Forms updated to 2018); c) national scale, implementing the distribution maps for each Habitat based on the European grid ETRS89-LAEA5210 (10x10 km2 mesh); d) Biogeographic Region, scale of the final assessment. Cartographic outcomes, associated databases and additional data used for the assessments will be available online on the ISPRA Portal as soon as the validation process by the European Commission will be completed. A dedicated archive named "HAB_IT" has been created in the national database "VegItaly" (1), managed by the Italian Society of Vegetation Science, where the phytosociological relevés representative of the various Annex I Habitats in Italy will be archived and freely accessible. An overview of the results regarding the Forest habitats is here provided, including a comparison with the outcomes of the former reporting cycle, the 3rd Report ex-Art. 17 (2). In several cases (e.g. 9120, 91L0), the distribution maps have been remarkably improved due to better knowledge and more fitful interpretation. The conservation status resulted as Favourable (FV) for 6,7%, Inadequate (U1) for 58,7% and Bad (U1) for 32,0% of the 72 assessed forest Habitat types. In no case there was an improvement of the conservation status, while in 6 cases a worsening of the conditions resulted from the data analysis, pointing out the Habitats types with a higher need of action. Similarly to other projects carried out as a team by the network of Annex I Habitat experts of the Italian Botanical Society and the Italian Society for Vegetation Science (e.g. 3, 4), this is another step in the direction of supporting the implementation of the 92/43/EEC "Habitat" Directive in Italy and Europe. On this ground, the high biodiversity of the Italian forest Habitats could be emphasized, however results pointed out that some rare or endemic types (e.g. Alnus cordata or Betula aetnensis-dominated forests) are still scarcely acknowledged by the most prominent EU conservation tools such as the Annex I to the "Habitat" Directive. 1) F. Landucci et al. (2012) Plant Biosyst., 146(4), 756-763 2) P. Genovesi et al. (2014) ISPRA, Serie Rapporti, 194/2014 3) E. Biondi et al. (2009) Società Botanica Italiana, MATTM, D.P.N., http://vnr.unipg.it/habitat/ 4) D. Gigante et al. (2016) Plant Sociology, 53(2), 77-87

Published
2019

11. Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

Nolte, IM, Munoz, ML, Tragante, V, Amare, AT, Jansen, R, Vaez, A, Von Der Heyde, B, Avery, CL, Bis, JC, Dierckx, B, Van Dongen, J, Gogarten, SM, Goyette, P, Hernesniemi, J, Huikari, V, Hwang, SJ, Jaju, D, Kerr, KF, Kluttig, A, Krijthe, BP, Kumar, J, Van Der Laan, SW, Lyytikäinen, LP, Maihofer, AX, Minassian, A, Van Der Most, PJ, Müller-Nurasyid, M, Nivard, M, Salvi, E, Stewart, JD, Thayer, JF, Verweij, N, Wong, A, Zabaneh, D, Zafarmand, MH, Abdellaoui, A, Albarwani, S, Albert, C, Alonso, A, Ashar, F, Auvinen, J, Axelsson, T, Baker, DG, De Bakker, PIW, Barcella, M, Bayoumi, R, Bieringa, RJ, Boomsma, D, Boucher, G, Britton, AR, Christophersen, IE, Dietrich, A, Ehret, GB, Ellinor, PT, Eskola, M, Felix, JF, Floras, JS, Franco, OH, Friberg, P, Gademan, MGJ, Geyer, MA, Giedraitis, V, Hartman, CA, Hemerich, D, Hofman, A, Hottenga, JJ, Huikuri, H, Hutri-Kähönen, N, and Jouven, X

Abstract

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74

Published
2017
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12. LEUKEMIA RELAPSE AFTER ALLOGENENIC HSCT DISPLAYS A DISTINCTIVE IMMUNE-RELATED SIGNATURE, WITH FUNCTIONALLY RELEVANT ALTERATIONS IN HLA CLASS II ANTIGEN PRESENTATION AND T CELL COSTIMULATION

Author

Toffalori C, Riba M, Zito L, Oliveira G, Bucci G, Barcella M, Spinelli O, Crucitti L, Cieri N, Cittaro D, Lazarevic D, Peccatori J, Bernardi M, Bonini C, Rambaldi A, Barlassina C, Stupka E, Bianchi M, Ciceri F, Fleischhauer K, Vago L, Toffalori, C, Riba, M, Zito, L, Oliveira, G, Bucci, G, Barcella, M, Spinelli, O, Crucitti, L, Cieri, N, Cittaro, D, Lazarevic, D, Peccatori, J, Bernardi, M, Bonini, C, Rambaldi, A, Barlassina, C, Stupka, E, Bianchi, M, Ciceri, F, Fleischhauer, K, and Vago, L

Published
2015

13. LEUKEMIA RELAPSES AFTER ALLOGENENIC HSCT DISPLAY A DISTINCTIVE IMMUNE-RELATED SIGNATURE, WITH FUNCTIONALLY RELEVANT ALTERATIONS IN HLA CLASS II ANTIGEN PRESENTATION AND T CELL COSTIMULATION

Author

Toffalori, C., Riba, M., Zito, L., Oliveira, G., Bucci, G., Barcella, M., Spinelli, O., Crucitti, L., Cieri, N., Cittaro, D., Lazarevic, D., Peccatori, J., Bernardi, M., Bonini, C., Rambaldi, A., Barlassina, C., Stupka, E., Bianchi, M., Ciceri, F., Fleischhauer, Katharina, Vago, L., Toffalori, C, Riba, M, Zito, L, Oliveira, G, Bucci, G, Barcella, M, Spinelli, O, Crucitti, L, Cieri, N, Cittaro, D, Lazarevic, D, Peccatori, J, Bernardi, M, Bonini, C, Rambaldi, A, Barlassina, C, Stupka, E, Bianchi, M, Ciceri, F, Fleischhauer, K, and Vago, L

Subjects
Medizin
Published
2015

14. Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index

Author

Hoggart, C, Venturini, G, Mangino, M, Gomez, F, Ascari, G, Zhao, J, Teumer, A, Winkler, T, Tšernikova, N, Luan, J, Mihailov, E, Ehret, G, Zhang, W, Lamparter, D, Esko, T, Macé, A, Rüeger, S, Bochud, P, Barcella, M, Dauvilliers, Y, Benyamin, B, Evans, D, Hayward, C, Lopez, M, Franke, L, Russo, A, Heid, I, Salvi, E, Vendantam, S, Arking, D, Boerwinkle, E, Chambers, J, Fiorito, G, Grallert, H, Guarrera, S, Homuth, G, Huffman, J, Porteous, D, Berg, J, Blackwood, D, Campbell, H, Cavanagh, J, Connell, J, Connor, M, Cunningham Burley, S, Deary, I, Dominiczak, A, Ellis, P, Fitzpatrick, B, Ford, I, Gertz, R, Grau, A, Haddow, G, Jackson, C, Kerr, S, Lindsay, R, Mcgilchrist, M, Mcintyre, D, Morris, A, Morton, R, Muir, W, Murray, G, Palmer, C, Pell, J, Philp, A, Porteous, M, Procter, R, Ralston, S, Reid, D, Sinnott, R, Smith, B, St Clair, D, Sullivan, F, Sweetland, M, Ure, J, Watt, G, Wolf, R, Wright, A, de Bakker, P, Bültmann, U, Geleijnse, M, Harst, P, Koppelman, G, Rosmalen, J, van Rossum, L, Smidt, H, Swertz, M, Stolk, R, Alizadeh, B, de Boer, R, Boezen, H, Bruinenberg, M, van der Harst, P, Hillege, H, van der Klauw, M, Navis, G, Ormel, J, Postma, D, Slaets, J, Snieder, H, Wolffenbuttel, B, Wijmenga, C, Berndt, S, Gustafsson, S, Mägi, R, Ganna, A, Wheeler, E, Feitosa, M, Justice, A, Monda, K, Croteau Chonka, D, Day, F, Fall, T, Ferreira, T, Gentilini, D, Jackson, A, Randall, J, Vedantam, S, Willer, C, Wood, A, Workalemahu, T, Hu, Y, Lee, S, Liang, L, Lin, D, Min, J, Neale, B, Thorleifsson, G, Yang, J, Albrecht, E, Amin, N, Bragg Gresham, J, Cadby, G, den Heijer, M, Eklund, N, Fischer, K, Goel, A, Hottenga, J, Jarick, I, Johansson, A, Johnson, T, Kanoni, S, Kleber, M, König, I, Kristiansson, K, Kutalik, Z, Lamina, C, Lecoeur, C, Li, G, Mcardle, W, Medina Gomez, C, Müller Nurasyid, M, Ngwa, J, Nolte, I, Paternoster, L, Pechlivanis, S, Perola, M, Peters, M, Preuss, M, Rose, L, Shi, J, Shungin, D, Smith, A, Strawbridge, R, Surakka, I, Trip, M, Tyrer, J, Van Vliet Ostaptchouk, J, Vandenput, L, Waite, L, Absher, D, Asselbergs, F, Atalay, M, Attwood, A, Balmforth, A, Basart, H, Beilby, J, Bonnycastle, L, BRAMBILLA, PAOLO, Chasman, D, Chines, P, Collins, F, Cookson, W, de Faire, U, de Vegt, F, Dei, M, Dimitriou, M, Edkins, S, Estrada, K, Farrall, M, Ferrario, M, Ferrières, J, Frau, F, Gejman, P, Grönberg, H, Gudnason, V, Hall, A, Hall, P, Hartikainen, A, Heard Costa, N, Heath, A, Hebebrand, J, Hu, F, Hunt, S, Hyppönen, E, Iribarren, C, Jacobs, K, Jansson, J, Jula, A, Kähönen, M, Kathiresan, S, Kee, F, Khaw, K, Kivimaki, M, Koenig, W, Kraja, A, Kumari, M, Karikuulasmaa, N, Kuusisto, J, Laitinen, J, Lakka, T, Langenberg, C, Launer, L, Lind, L, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Lorentzon, M, Madden, P, Magnusson, P, Manunta, P, Marek, D, März, W, Leach, I, Mcknight, B, Medland, S, Milani, L, Montgomery, G, Mooser, V, Mühleisen, T, Munroe, P, Musk, A, Narisu, N, Nicholson, G, Nohr, E, Ong, K, Oostra, B, Palotie, A, Peden, J, Pedersen, N, Peters, A, Polasek, O, Pouta, A, Pramstaller, P, Prokopenko, I, Pütter, C, Radhakrishnan, A, Raitakari, O, Rendon, A, Rivadeneira, F, Rudan, I, Saaristo, T, Sambrook, J, Sanders, A, Sanna, S, Saramies, J, Schipf, S, Schreiber, S, Schunkert, H, Shin, S, Signorini, S, Sinisalo, J, Skrobek, B, Soranzo, N, Stancakova, A, Stark, K, Stephens, J, Stirrups, K, Stumvoll, M, Swift, A, Theodoraki, E, Thorand, B, Tregouet, D, Tremoli, E, Van der Klauw, M, van Meurs, J, Vermeulen, S, Viikari, J, Virtamo, J, Vitart, V, Waeber, G, Wang, Z, Widen, E, Wild, S, Willemsen, G, Winkelmann, B, Witteman, J, Wong, A, Zillikens, M, Amouyel, P, Boehm, B, Boomsma, D, Caulfield, M, Chanock, S, Cupples, L, Cusi, D, Dedoussis, G, Erdmann, J, Eriksson, J, Franks, P, Froguel, P, Gieger, C, Gyllensten, U, Hamsten, A, Harris, T, Hengstenberg, C, Hicks, A, Hingorani, A, Hinney, A, Hofman, A, Hovingh, K, Hveem, K, Illig, T, Jarvelin, M, Jöckel, K, Keinanen Kiukaanniemi, S, Kiemeney, L, Kuh, D, Laakso, M, Lehtimäki, T, Levinson, D, Martin, N, Metspalu, A, Nieminen, M, Njølstad, I, Ohlsson, C, Oldehinkel, A, Ouwehand, W, Palmer, L, Penninx, B, Power, C, Province, M, Psaty, B, Qi, L, Rauramaa, R, Ridker, P, Ripatti, S, Salomaa, V, Samani, N, Sørensen, T, Spector, T, Stefansson, K, Tönjes, A, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, Vollenweider, P, Wallaschofski, H, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Abecasis, G, Assimes, T, Barroso, I, Boehnke, M, Borecki, I, Deloukas, P, Fox, C, Frayling, T, Groop, L, Haritunian, T, Hunter, D, Kaplan, R, Karpe, F, Miriammoffatt, N, Mohlke, K, O'Connell, J, Pawitan, Y, Schadt, E, Schlessinger, D, Steinthorsdottir, V, Strachan, D, Thorsteinsdottir, U, van Duijn, C, Visscher, P, Di Blasio, A, Hirschhorn, J, Lindgren, C, Meyre, D, Scherag, A, Mccarthy, M, Speliotes, E, North, K, Loos, R, Ingelsson, E, Moradpour, D, Iranzo, A, Kemp, J, Lammers, G, Aubert, V, Heim, M, Peraita Adrados, R, Santamaria, J, Negro, F, Schmidt, C, Scott, R, Strauch, K, Völzke, H, Yuan, W, Bell, J, Chakravarti, A, Kooner, J, Matullo, G, Whitfield, J, Paccaud, F, Bergmann, S, Beckmann, J, Tafti, M, Hastie, N, Bochud, M, Da Smith, G, Rousson, V, Rivolta, C, Kutalik, Z., Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Hoggart, Clive J, Venturini, Giulia, Mangino, Massimo, Gomez, Felicia, Benyamin, Beben, Kutalik, Zoltan, Generation Scotland Consortium, GIANT Consortium, LifeLines Cohort study, Cardiology, Vascular Medicine, Plastic, Reconstructive and Hand Surgery, Amsterdam Cardiovascular Sciences, Medical Research Council (MRC), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Haartman Institute (-2014), Transplantation Laboratory, Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Hoggart, Cj, Venturini, G, Mangino, M, Gomez, F, Ascari, G, Zhao, Jh, Teumer, A, Winkler, Tw, Tšernikova, N, Luan, J, Mihailov, E, Ehret, Gb, Zhang, W, Lamparter, D, Esko, T, Macé, A, Rüeger, S, Bochud, Py, Barcella, M, Dauvilliers, Y, Benyamin, B, Evans, Dm, Hayward, C, Lopez, Mf, Franke, L, Russo, A, Heid, Im, Salvi, E, Vendantam, S, Arking, De, Boerwinkle, E, Chambers, Jc, Fiorito, G, Grallert, H, Guarrera, S, Homuth, G, Huffman, Je, Porteous, D, GENERATION SCOTLAND, Consortium, LIFELINES COHORT, Study, Giant, Consortium, Manunta, Paolo, Moradpour, D, Iranzo, A, Hebebrand, J, Kemp, Jp, Lammers, Gj, Aubert, V, Heim, Mh, Martin, Ng, Montgomery, Gw, PERAITA ADRADOS, R, Santamaria, J, Negro, F, Schmidt, Co, Scott, Ra, Spector, Td, Strauch, K, Völzke, H, Wareham, Nj, Yuan, W, Bell, Jt, Chakravarti, A, Kooner, J, Peters, A, Matullo, G, Wallaschofski, H, Whitfield, Jb, Paccaud, F, Vollenweider, P, Bergmann, S, Beckmann, J, Tafti, M, Hastie, Nd, Cusi, D, Bochud, M, Frayling, Tm, Metspalu, A, Jarvelin, Mr, Scherag, A, Smith, Gd, Borecki, Ib, Rousson, V, Hirschhorn, Jn, Rivolta, C, Loos, Rj, Kutalik, Z., Hoggart, C, Zhao, J, Winkler, T, Ehret, G, Bochud, P, Evans, D, Lopez, M, Heid, I, Arking, D, Chambers, J, Huffman, J, Berg, J, Blackwood, D, Campbell, H, Cavanagh, J, Connell, J, Connor, M, Cunningham Burley, S, Deary, I, Dominiczak, A, Ellis, P, Fitzpatrick, B, Ford, I, Gertz, R, Grau, A, Haddow, G, Jackson, C, Kerr, S, Lindsay, R, Mcgilchrist, M, Mcintyre, D, Morris, A, Morton, R, Muir, W, Murray, G, Palmer, C, Pell, J, Philp, A, Porteous, M, Procter, R, Ralston, S, Reid, D, Sinnott, R, Smith, B, St Clair, D, Sullivan, F, Sweetland, M, Ure, J, Watt, G, Wolf, R, Wright, A, de Bakker, P, Bültmann, U, Geleijnse, M, Harst, P, Koppelman, G, Rosmalen, J, van Rossum, L, Smidt, H, Swertz, M, Stolk, R, Alizadeh, B, de Boer, R, Boezen, H, Bruinenberg, M, van der Harst, P, Hillege, H, van der Klauw, M, Navis, G, Ormel, J, Postma, D, Slaets, J, Snieder, H, Wolffenbuttel, B, Wijmenga, C, Berndt, S, Gustafsson, S, Mägi, R, Ganna, A, Wheeler, E, Feitosa, M, Justice, A, Monda, K, Croteau Chonka, D, Day, F, Fall, T, Ferreira, T, Gentilini, D, Jackson, A, Randall, J, Vedantam, S, Willer, C, Wood, A, Workalemahu, T, Hu, Y, Lee, S, Liang, L, Lin, D, Min, J, Neale, B, Thorleifsson, G, Yang, J, Albrecht, E, Amin, N, Bragg Gresham, J, Cadby, G, den Heijer, M, Eklund, N, Fischer, K, Goel, A, Hottenga, J, Jarick, I, Johansson, A, Johnson, T, Kanoni, S, Kleber, M, König, I, Kristiansson, K, Kutalik, Z, Lamina, C, Lecoeur, C, Li, G, Mcardle, W, Medina Gomez, C, Müller Nurasyid, M, Ngwa, J, Nolte, I, Paternoster, L, Pechlivanis, S, Perola, M, Peters, M, Preuss, M, Rose, L, Shi, J, Shungin, D, Smith, A, Strawbridge, R, Surakka, I, Trip, M, Tyrer, J, Van Vliet Ostaptchouk, J, Vandenput, L, Waite, L, Absher, D, Asselbergs, F, Atalay, M, Attwood, A, Balmforth, A, Basart, H, Beilby, J, Bonnycastle, L, Brambilla, P, Chasman, D, Chines, P, Collins, F, Cookson, W, de Faire, U, de Vegt, F, Dei, M, Dimitriou, M, Edkins, S, Estrada, K, Farrall, M, Ferrario, M, Ferrières, J, Frau, F, Gejman, P, Grönberg, H, Gudnason, V, Hall, A, Hall, P, Hartikainen, A, Heard Costa, N, Heath, A, Hu, F, Hunt, S, Hyppönen, E, Iribarren, C, Jacobs, K, Jansson, J, Jula, A, Kähönen, M, Kathiresan, S, Kee, F, Khaw, K, Kivimaki, M, Koenig, W, Kraja, A, Kumari, M, Karikuulasmaa, N, Kuusisto, J, Laitinen, J, Lakka, T, Langenberg, C, Launer, L, Lind, L, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Lorentzon, M, Madden, P, Magnusson, P, Manunta, P, Marek, D, März, W, Leach, I, Mcknight, B, Medland, S, Milani, L, Montgomery, G, Mooser, V, Mühleisen, T, Munroe, P, Musk, A, Narisu, N, Nicholson, G, Nohr, E, Ong, K, Oostra, B, Palotie, A, Peden, J, Pedersen, N, Polasek, O, Pouta, A, Pramstaller, P, Prokopenko, I, Pütter, C, Radhakrishnan, A, Raitakari, O, Rendon, A, Rivadeneira, F, Rudan, I, Saaristo, T, Sambrook, J, Sanders, A, Sanna, S, Saramies, J, Schipf, S, Schreiber, S, Schunkert, H, Shin, S, Signorini, S, Sinisalo, J, Skrobek, B, Soranzo, N, Stancakova, A, Stark, K, Stephens, J, Stirrups, K, Stumvoll, M, Swift, A, Theodoraki, E, Thorand, B, Tregouet, D, Tremoli, E, Van der Klauw, M, van Meurs, J, Vermeulen, S, Viikari, J, Virtamo, J, Vitart, V, Waeber, G, Wang, Z, Widen, E, Wild, S, Willemsen, G, Winkelmann, B, Witteman, J, Wong, A, Zillikens, M, Amouyel, P, Boehm, B, Boomsma, D, Caulfield, M, Chanock, S, Cupples, L, Dedoussis, G, Erdmann, J, Eriksson, J, Franks, P, Froguel, P, Gieger, C, Gyllensten, U, Hamsten, A, Harris, T, Hengstenberg, C, Hicks, A, Hingorani, A, Hinney, A, Hofman, A, Hovingh, K, Hveem, K, Illig, T, Jarvelin, M, Jöckel, K, Keinanen Kiukaanniemi, S, Kiemeney, L, Kuh, D, Laakso, M, Lehtimäki, T, Levinson, D, Martin, N, Nieminen, M, Njølstad, I, Ohlsson, C, Oldehinkel, A, Ouwehand, W, Palmer, L, Penninx, B, Power, C, Province, M, Psaty, B, Qi, L, Rauramaa, R, Ridker, P, Ripatti, S, Salomaa, V, Samani, N, Sørensen, T, Spector, T, Stefansson, K, Tönjes, A, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Abecasis, G, Assimes, T, Barroso, I, Boehnke, M, Borecki, I, Deloukas, P, Fox, C, Frayling, T, Groop, L, Haritunian, T, Hunter, D, Kaplan, R, Karpe, F, Miriammoffatt, N, Mohlke, K, O'Connell, J, Pawitan, Y, Schadt, E, Schlessinger, D, Steinthorsdottir, V, Strachan, D, Thorsteinsdottir, U, van Duijn, C, Visscher, P, Di Blasio, A, Hirschhorn, J, Lindgren, C, Meyre, D, Mccarthy, M, Speliotes, E, North, K, Loos, R, Ingelsson, E, Kemp, J, Lammers, G, Heim, M, Peraita Adrados, R, Schmidt, C, Scott, R, Bell, J, Whitfield, J, Hastie, N, and Da Smith, G

Subjects
Epigenomics, Male, Netherlands Twin Register (NTR), body mass index, gene, SNP, Cancer Research, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Potassium Channels, Glucose Transport Proteins, Facilitative, Medizin, Genome-wide association study, CHILDREN, ddc:616.07, FAMILIES, Body Mass Index, 0302 clinical medicine, Polymorphism (computer science), Genotype, LifeLines Cohort study, GENETICS & HEREDITY, Tandem Pore Domain, Genetics (clinical), ASSOCIATIONS, ddc:616, Genetics, 0303 health sciences, QUANTITATIVE TRAIT LOCI, Ecology, Genomics, Single Nucleotide, Generation Scotland Consortium, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], OBESITY, Physical Sciences, KCNK9 protein, Epigenetics, Female, ALCOHOLISM, Glucose Transport Proteins, Life Sciences & Biomedicine, Statistics (Mathematics), Human, Research Article, VARIANCES, Adult, PENETRANCE, GENES, lcsh:QH426-470, Evolution, European Continental Ancestry Group, Single-nucleotide polymorphism, Biostatistics, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Genomic Imprinting, Potassium Channels, Tandem Pore Domain, Genetic, Behavior and Systematics, SDG 3 - Good Health and Well-being, Genetic linkage, GIANT Consortium, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Statistical Methods, Allele, Polymorphism, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Gene Expression Regulation, Genome-Wide Association Study, Obesity, 030304 developmental biology, 0604 Genetics, Science & Technology, LINKAGE ANALYSIS, SLC2A10 protein, Biology and Life Sciences, Computational Biology, Facilitative, Genome Analysis, Ecology, Evolution, Behavior and Systematic, lcsh:Genetics, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], 3111 Biomedicine, Genomic imprinting, Mathematics, 030217 neurology & neurosurgery, Developmental Biology
Abstract

The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P, Author Summary Large genetic association studies have revealed many genetic factors influencing common traits, such as body mass index (BMI). These studies assume that the effect of genetic variants is the same regardless of whether they are inherited from the mother or the father. In our study, we have developed a new approach that allows us to investigate variants whose impact depends on their parental origin (parent-of-origin effects), in unrelated samples when the parental origin cannot be inferred. This is feasible because at genetic markers at which such effects occur there is increased variability of the trait among individuals who inherited different genetic codes from their mother and their father compared to individuals who inherited the same genetic code from both parents. We applied this methodology to discover genetic markers with parent-of-origin effects (POEs) on BMI. This resulted in six candidate markers showing strong POE association. We then attempted to replicate the POE effects of these markers in family studies (where one can infer the parental origin of the inherited variants). Two of our candidates showed significant association in the family studies, the paternal and maternal effects of these markers were in the opposite direction.

Published
2014
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15. CIITA-DEPENDENT TRANSCRIPTIONAL DOWNREGULATION OF HLA CLASS II RESULTS IN LEUKEMIA IMMUNE ESCAPE AND RELAPSE AFTER ALLOGENEIC HSCT

Author

Toffalori, C., Riba, M., Zito, L., Barcella, M., Spinelli, O., Crucitti, L., Peccatori, J., Bernardi, M., Bonini, C., Cittaro, D., Lazarevic, D., Rambaldi, A., Barlassina, C., Stupka, E., Ciceri, F., Fleischhauer, Katharina, Vago, L., Toffalori, C, Riba, M, Zito, L, Barcella, M, Spinelli, O, Crucitti, L, Peccatori, J, Bernardi, M, Bonini, C, Cittaro, D, Lazarevic, D, Rambaldi, A, Barlassina, C, Stupka, E, Ciceri, F, Fleischhauer, K, and Vago, L

Subjects
Medizin, ComputingMethodologies_GENERAL
Abstract

Poster Abstract

Published
2014

17. Towards an integrative model of the PI3K/Akt metabolic effects

Author

Mosca E.(1), Barcella M.(1), Alfieri R.(1), Bevilacqua A.(2, and Milanesi L.(1)

Abstract

Cancer cells differ from their normal counterparts more in terms of regulatory networks than of specific molecules. A recently recognized hallmark of cancer is the increased uptake of nutrients, particularly glucose, associated with a higher lactate pro- duction. A common step of tumorigenesis, which influences these metabolic alterations, is the constitutive activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Fol- lowing an integrative systems biology approach, we propose a model for the in silico investigation of the PI3K/Akt pathway effects on the central metabolism. This model represents a useful tool for the computational analysis of the metabolic differences be- tween normal and pathological conditions.

Published
2011

23. A phytosociological survey of the Corynephorus canescens (L.) Beauv. communities of Italy.

Author

Assini, S., Mondino, G.P., Varese, P., Barcella, M., and Bracco, F.

Subjects
PLANT communities, CORYNEPHORUS, GRASSLANDS
Abstract

In Italy, Corynephorus communities are distributed along the medium course of the Ticino river and Sesia river and the internal sand dunes of Lomellina (through the Vercelli, Novara and Pavia provinces); these stations represent the southern limit of European distribution of this habitat. A phytosociological study was carried out to gain better knowledge of their composition; of their affinity or diversity against the central European communities; of their distribution and of the main threats to their conservation. Original and literature relevés (114) were elaborated producing a cluster analysis; correspondence analysis (CA), principal component analysis and Kruskal–Wallis test were carried on to characterize the clusters of relevés taking into consideration biological forms, chorological groups, Ellenberg indicator values and floristic groups. Italian Corynephorus communities can be attributed to the following syntaxa: Spergulo vernalis-Corynephoretum canescentis, Spergulo vernalis-Corynephoretum canescentis cladonietosum, Spergulo vernalis-Corynephoretum canescentis silenetosum nutantis and Spergulo vernalis-Corynephoretum canescentis artemisietosum campestris. Italian Corynephorus communities are included in the Habitat 2330 of the EU Habitat Directive. They are threatened by different factors (such as restricted areas of occurrence, alien plant invasion and natural dynamics) and they need to be managed if we want to conserve them. [ABSTRACT FROM AUTHOR]

Published
2013
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24. Early Intervention Programme for Young Adults in Northern Italy: A 10‐Year Analysis of Socio‐Demographic and Clinical Characteristics.

Author

Pellegrino, R., Bonetto, C., Isaia, P., and Barcella, M.

Subjects
*MENTAL health services, *PSYCHOTHERAPY, *YOUNG adults, *PSYCHIATRIC treatment, *ANXIETY disorders
Abstract

ABSTRACT Introduction Methods Results Conclusions Early intervention represents an opportunity to contain psychological distress and intervene promptly on conditions that, otherwise, could assume a chronic course. Based on these observations, an early intervention programme for people 18–25 years old, the ‘Progetto Giovani’ (Youth Project), was implemented in two adult mental health services (AMHSs) in the northwest of Italy.This study aims to describe the socio‐demographic and clinical characteristics of the patients included in the Youth Project from 1 January 2013 to 31 December 2022. A retrospective observational design was used.In 10 years, 323 patients were taken into care. More than half (56.3%) were females; the mean age was 20.7 years (SD 2.3). The most frequent diagnosis was anxiety disorder (38%). Seventy per cent of subjects benefitted from psychological treatment, and 60.8% had a pharmacological prescription. In 87.8% of cases, the care pathway was ≤ 24 months, and more than two‐thirds of the subjects did not go to another AMHS after discharge. More than 90% of subjects did not require hospitalisation in the psychiatric diagnostic and treatment service.These findings suggest that early intervention programmes may be a valuable tool for AMHSs to improve patient outcomes and reduce the burden on the healthcare system. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Shedding light on typical species: Implications for habitat monitoring

Author

Gianmaria Bonari, Edy Fantinato, Lorenzo Lazzaro, Marta Gaia Sperandii, Alicia Teresa Rosario Acosta, Marina Allegrezza, Silvia Assini, Marco Caccianiga, Valter Di Cecco, Annarita Frattaroli, Daniela Gigante, Giovanni Rivieccio, Giulio Tesei, Barbara Valle, Daniele Viciani, Giulia Albani Rocchetti, Claudia Angiolini, Emilio Badalamenti, Davide Barberis, Matteo Barcella, Giuseppe Bazan, Andrea Bertacchi, Rossano Bolpagni, Federica Bonini, Alessandro Bricca, Gabriella Buffa, Mariasole Calbi, Silvia Cannucci, Luigi Cao Pinna, Maria Carmela Caria, Emanuela Carli, Silvia Cascone, Mauro Casti, Bruno Enrico Leone Cerabolini, Riccardo Copiz, Maurizio Cutini, Leopoldo De Simone, Andrea De Toma, Michele Dalle Fratte, Luciano Di Martino, Romeo Di Pietro, Leonardo Filesi, Bruno Foggi, Paola Fortini, Roberto Gennaio, Gabriele Gheza, Michele Lonati, Andrea Mainetti, Marco Malavasi, Corrado Marcenò, Carla Micheli, Chiara Minuzzo, Michele Mugnai, Carmelo Maria Musarella, Francesca Napoleone, Ginevra Nota, Giovanna Piga, Marco Pittarello, Ilaria Pozzi, Safiya Praleskouskaya, Francesco Rota, Giacomo Santini, Simona Sarmati, Alberto Selvaggi, Giovanni Spampinato, Adriano Stinca, Francesco Pio Tozzi, Roberto Venanzoni, Mariacristina Villani, Katia Zanatta, Magda Zanzottera, Simonetta Bagella, Bonari G., Fantinato E., Lazzaro L., Sperandii M.G., Acosta A.T.R., Allegrezza M., Assini S., Caccianiga M., Di Cecco V., Frattaroli A., Gigante D., Rivieccio G., Tesei G., Valle B., Viciani D., Rocchetti G.A., Angiolini C., Badalamenti E., Barberis D., Barcella M., Bazan G., Bertacchi A., Bolpagni R., Bonini F., Bricca A., Buffa G., Calbi M., Cannucci S., Pinna L.C., Caria M.C., Carli E., Cascone S., Casti M., Cerabolini B.E.L., Copiz R., Cutini M., de Simone L., de Toma A., Fratte M.D., Di Martino L., Di Pietro R., Filesi L., Foggi B., Fortini P., Gennaio R., Gheza G., Lonati M., Mainetti A., Malavasi M., Marceno C., Micheli C., Minuzzo C., Mugnai M., Musarella C.M., Napoleone F., Nota G., Piga G., Pittarello M., Pozzi I., Praleskouskaya S., Rota F., Santini G., Sarmati S., Selvaggi A., Spampinato G., Stinca A., Tozzi F.P., Venanzoni R., Villani M., Zanatta K., Zanzottera M., Bagella S., Bonari, G., Fantinato, E., Lazzaro, L., Sperandii, M. G., Acosta, A. T. R., Allegrezza, M., Assini, S., Caccianiga, M., Di Cecco, V., Frattaroli, A., Gigante, D., Rivieccio, G., Tesei, G., Valle, B., Viciani, D., Rocchetti, G. A., Angiolini, C., Badalamenti, E., Barberis, D., Barcella, M., Bazan, G., Bertacchi, A., Bolpagni, R., Bonini, F., Bricca, A., Buffa, G., Calbi, M., Cannucci, S., Pinna, L. C., Caria, M. C., Carli, E., Cascone, S., Casti, M., Cerabolini, B. E. L., Copiz, R., Cutini, M., de Simone, L., de Toma, A., Fratte, M. D., Di Martino, L., Di Pietro, R., Filesi, L., Foggi, B., Fortini, P., Gennaio, R., Gheza, G., Lonati, M., Mainetti, A., Malavasi, M., Marceno, C., Micheli, C., Minuzzo, C., Mugnai, M., Musarella, C. M., Napoleone, F., Nota, G., Piga, G., Pittarello, M., Pozzi, I., Praleskouskaya, S., Rota, F., Santini, G., Sarmati, S., Selvaggi, A., Spampinato, G., Stinca, A., Tozzi, F. P., Venanzoni, R., Villani, M., Zanatta, K., Zanzottera, M., and Bagella, S.

Subjects
Structure and function, diagnostic and characteristic species, habitat monitoring, keystone species, Natura 2000, plant community, structure and functions, typical species, 92/43/EEC Directive, Keystone specie, Settore BIO/02 - Botanica Sistematica, Typical species, Plant culture, Diagnostic and characteristic species, Plant community, SB1-1110, Diagnostic and characteristic specie, 92/43/EEC Directive, Habitat monitoring, Keystone species, Natura 2000, Structure and functions, QK900-989, Plant ecology, Settore BIO/03 - Botanica Ambientale e Applicata
Abstract

Habitat monitoring in Europe is regulated by Article 17 of the Habitats Directive, which suggests the use of typical species to assess habitat conservation status. Yet, the Directive uses the term “typical” species but does not provide a definition, either for its use in reporting or for its use in impact assessments. To address the issue , a n online workshop was organized by the Italian Society for Vegetation Science (SISV) to shed light on the diversity of perspectives regarding the different concepts of typical species, and to discuss the possible implications for habitat monitoring. To this aim, we inquired 73 people with a very different degree of expertise in the field of vegetation science by means of a tailored survey composed of six questions. We analysed the data using Pearson's Chi-squared test to verify that the answers diverged from a random distribution and checked the effect of the degree of experience of the surveyees on the results. We found that most of the surveyees agreed on the use of the phytosociological method for habitat monitoring and of the diagnostic and characteristic species to evaluate the structural and functional conservation status of habitats. With this contribution, we shed light on the meaning of “typical” species in the context of habitat monitoring.

Published
2021

28. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation

Author

Leo Luznik, Luca Vago, Dietrich W. Beelen, Elisa Montaldo, Matteo Barcella, Robert Zeiser, Bernhard Gentner, Gabriele Bucci, Raynier Devillier, Renato Ostuni, Matteo Carrabba, Masahiro Onozawa, Valentina Gambacorta, Orietta Spinelli, Miguel Waterhouse, Katharina Fleischhauer, Elia Stupka, Ivana Gojo, Chiara Bonini, Cristina Toffalori, Lara Crucitti, Laura Zito, Raffaella Greco, Michela Riba, Matteo Maria Naldini, Dejan Lazarevic, Massimo Bernardi, Maddalena Noviello, Davide Cittaro, Takanori Teshima, Didier Blaise, Jacopo Peccatori, Cristina Barlassina, Francesco Manfredi, Giovanni Tonon, Giacomo Oliveira, Alessandro Rambaldi, Constantijn J.M. Halkes, Marieke Griffioen, Maher Hanoun, Nicoletta Cieri, Fabio Ciceri, Jürgen Finke, Toffalori, C., Zito, L., Gambacorta, V., Riba, M., Oliveira, G., Bucci, G., Barcella, M., Spinelli, O., Greco, R., Crucitti, L., Cieri, N., Noviello, M., Manfredi, F., Montaldo, E., Ostuni, R., Naldini, M. M., Gentner, B., Waterhouse, M., Zeiser, R., Finke, J., Hanoun, M., Beelen, D. W., Gojo, I., Luznik, L., Onozawa, M., Teshima, T., Devillier, R., Blaise, D., Halkes, C. J. M., Griffioen, M., Carrabba, M. G., Bernardi, M., Peccatori, J., Barlassina, C., Stupka, E., Lazarevic, D., Tonon, G., Rambaldi, A., Cittaro, D., Bonini, C., Fleischhauer, K., Ciceri, F., Vago, L., Toffalori, C, Zito, L, Gambacorta, V, Riba, M, Oliveira, G, Bucci, G, Barcella, M, Spinelli, O, Greco, R, Crucitti, L, Cieri, N, Noviello, M, Manfredi, F, Montaldo, E, Ostuni, R, Naldini, M, Gentner, B, Waterhouse, M, Zeiser, R, Finke, J, Hanoun, M, Beelen, D, Gojo, I, Luznik, L, Onozawa, M, Teshima, T, Devillier, R, Blaise, D, Halkes, C, Griffioen, M, Carrabba, M, Bernardi, M, Peccatori, J, Barlassina, C, Stupka, E, Lazarevic, D, Tonon, G, Rambaldi, A, Cittaro, D, Bonini, C, Fleischhauer, K, Ciceri, F, and Vago, L

Subjects
0301 basic medicine, Myeloid, medicine.medical_treatment, Antigen presentation, Medizin, Reproducibility of Result, Hematopoietic stem cell transplantation, Lymphocyte Activation, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Recurrence, hemic and lymphatic diseases, medicine, Humans, Transplantation, Homologous, RNA, Messenger, Transplantation, Homologou, business.industry, Gene Expression Regulation, Leukemic, Gene Expression Profiling, Histocompatibility Antigens Class II, Hematopoietic Stem Cell Transplantation, Reproducibility of Results, Myeloid leukemia, General Medicine, medicine.disease, Transplantation, Haematopoiesis, Leukemia, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, business, CD80, Human
Abstract

Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-gamma or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.

Published
2019

29. Occurrence of L1M Elements in Chromosomal Rearrangements Associated to Chronic Myeloid Leukemia (CML): Insights from Patient-Specific Breakpoints Characterization

Author

Alberto L’Abbate, Vittoria Moretti, Ester Pungolino, Giovanni Micheloni, Roberto Valli, Annalisa Frattini, Matteo Barcella, Francesco Acquati, Rolland A Reinbold, Lucy Costantino, Fulvio Ferrara, Alessandra Trojani, Mario Ventura, Giovanni Porta, Roberto Cairoli, L’Abbate, A, Moretti, V, Pungolino, E, Micheloni, G, Valli, R, Frattini, A, Barcella, M, Acquati, F, A Reinbold, R, Costantino, L, Ferrara, F, Trojani, A, Ventura, M, Porta, G, and Cairoli, R

Subjects
chronic myeloid leukemia, rearrangement, LINE, L1M, BCR-ABL1
Abstract

Chronic myeloid leukemia (CML) is a rare myeloproliferative disorder caused by the reciprocal translocation t(9;22)(q34;q11) in hematopoietic stem cells (HSCs). This chromosomal translocation results in the formation of an extra-short chromosome 22, called a Philadelphia chromosome (Ph), containing the BCR-ABL1 fusion gene responsible for the expression of a constitutively active tyrosine kinase that causes uncontrolled growth and replication of leukemic cells. Mechanisms behind the formation of this chromosomal rearrangement are not well known, even if, as observed in tumors, repetitive DNA may be involved as core elements in chromosomal rearrangements. We have participated in the explorative investigations of the PhilosoPhi34 study to evaluate residual Ph+ cells in patients with negative FISH analysis on CD34+/lin- cells with gDNA qPCR. Using targeted next-generation deep sequencing strategies, we analyzed the genomic region around the t(9;22) translocations of 82 CML patients and one CML cell line and assessed the relevance of interspersed repeat elements at breakpoints (BP). We found a statistically higher presence of LINE elements, in particular belonging to the subfamily L1M, in BP cluster regions of both chromosome 22 and 9 compared to the whole human genome. These data suggest that L1M elements could be potential drivers of t(9;22) translocation leading to the generation of the BCR-ABL1 chimeric gene and the expression of the active BCR-ABL1-controlled tyrosine kinase chimeric protein responsible for CML.

Published
2023

30. Morphological and Chemical Traits of Cladonia Respond to Multiple Environmental Factors in Acidic Dry Grasslands

Author

Silvia Paola Assini, Chiara Vallese, Paolo Giordani, Matteo Barcella, Luca Di Nuzzo, Renato Benesperi, Juri Nascimbene, Gabriele Gheza, Gheza G., Di Nuzzo L., Vallese C., Barcella M., Benesperi R., Giordani P., Nascimbene J., and Assini S.

Subjects
0106 biological sciences, Microbiology (medical), Open dry habitat, Climate change, Lichen, 010603 evolutionary biology, 01 natural sciences, Microbiology, Article, Secondary metabolite, species traits, Virology, Colonization, lichens, Lichens, Open dry habitats, Reproduction strategy, Secondary metabolites, Species traits, Thallus growth forms, Vegetation dynamics, lcsh:QH301-705.5, Thallus growth form, reproduction strategy, Cladonia, biology, Ecology, secondary metabolites, vegetation dynamics, biology.organism_classification, Substrate (marine biology), Thallus, lcsh:Biology (General), Habitat, Disturbance (ecology), thallus growth forms, open dry habitats, Species trait, 010606 plant biology & botany
Abstract

Terricolous lichen communities in lowlands occur especially in open dry habitats. Such communities are often dominated by species of the genus Cladonia, which are very variable in morphology, reproduction strategies, and secondary metabolites. In this work, we investigated traits-environment relationships considering vegetation dynamics, substrate pH, disturbance, and climate. A total of 122 plots were surveyed in 41 acidic dry grasslands in the western Po Plain (Northern Italy). Relationships between Cladonia traits and environmental variables were investigated by means of a model-based Fourth Corner Analysis. Thallus morphology and metabolites responded to vegetation dynamics, substrate pH, disturbance, and climate, whereas reproduction strategies responded only to vegetation dynamics. Traits’ correlations with vegetation dynamics elucidate their colonization patterns in open dry habitats or suggest biotic interactions with bryophytes and vascular plants. In addition, correlations between metabolites and environmental factors support interpretations of their ecological roles. Our results also stress the importance of studying traits’ relationships with climatic factors as an alert towards lichen reactions to climate change.

Published
2021

31. Notulae to the Italian flora of algae, bryophytes, fungi and lichens: 12

Author

Pier Luigi Nimis, Giovanni Maiorca, Matteo Barcella, Marta Puglisi, Michele Puntillo, Silvia Paola Assini, Romina Ciotti, Gabriele Gheza, Silvia Poponessi, Antonio De Agostini, Silvia Ongaro, Francesco Dovana, Giulio Pandeli, Davide Dagnino, Filippo Prosser, Antonio B. De Giuseppe, Chiara Vallese, Nicodemo G. Passalacqua, Gabriele Berta, Domenico Puntillo, Alfredo Vizzini, Giovanni Sicoli, Marco Clericuzio, Mauro Mariotti, Ilaria Bonini, Giovanna Pezzi, Deborah Isocrono, Fabrizio Boccardo, Annalena Cogoni, Sonia Ravera, Juri Nascimbene, Francesca Bottegoni, Claudia Turcato, Ravera, Sonia, Puglisi, Marta, Vizzini, Alfredo, Assini, Silvia, Barcella, Matteo, Berta, Gabriele, Boccardo, Fabrizio, Bonini, Ilaria, Bottegoni, Francesca, Ciotti, Romina, Clericuzio, Marco, Cogoni, Annalena, Dagnino, Davide, De Agostini, Antonio, De Giuseppe, Antonio B., Dovana, Francesco, Gheza, Gabriele, Isocrono, Deborah, Maiorca, Giovanni, Mariotti, Mauro, Nascimbene, Juri, Nimis, Pier Luigi, Ongaro, Silvia, Pandeli, Giulio, Passalacqua, Nicodemo G., Pezzi, Giovanna, Poponessi, Silvia, Prosser, Filippo, Puntillo, Domenico, Puntillo, Michele, Sicoli, Giovanni, Turcato, Claudia, Vallese, Chiara, Ravera S., Puglisi M., Vizzini A., Assini S., Barcella M., Berta G., Boccardo F., Bonini I., Bottegoni F., Ciotti R., Clericuzio M., Cogoni A., Dagnino D., de Agostini A., de Giuseppe A.B., Dovana F., Gheza G., Isocrono D., Maiorca G., Mariotti M., Nascimbene J., Nimis P.L., Ongaro S., Pandeli G., Passalacqua N.G., Pezzi G., Poponessi S., Prosser F., Puntillo D., Puntillo M., Sicoli G., Turcato C., and Vallese C.

Subjects
Flora, Ascomycota, biology, Basidiomycota, Biodiversity, Botany, Plant Science, biology.organism_classification, lichen, lichen, biodiversity, Bryidae, Geography, Algae, QK1-989, Ascomycota, Basidiomycota, Bryidae, Lichen, Ecology, Evolution, Behavior and Systematics, biodiversity
Abstract

In this contribution, new data concerning bryophytes, fungi and lichens of the Italian flora are presented. It includes new records, confirmations or exclusions for the bryophyte genera Acaulon, Campylopus, Entosthodon, Homomallium, Pseudohygrohypnum, and Thuidium, the fungal genera Entoloma, Cortinarius, Mycenella, Oxyporus, and Psathyrella and the lichen genera Anaptychia, Athallia, Baeomyces, Bagliettoa, Calicium, Nephroma, Pectenia, Phaeophyscia, Polyblastia, Protoparmeliopsis, Pyrenula, Ramalina, and Sanguineodiscus.

Published
2021

32. gDNA qPCR is statistically more reliable than mRNA analysis in detecting leukemic cells to monitor CML

Author

Andrea Conti, Anna Michelato, Cristina Barlassina, Giovanni Micheloni, Alessia Rainero, Giorgia Millefanti, Matteo Barcella, Francesca D'Avila, Eleonora Piscitelli, Ksenija Buklijas, Silvia M. Sirchia, Cristina Pirrone, Orietta Spinelli, Emanuela Maserati, Fabrizio Angaroni, R. Casalone, Giovanni Porta, Lucia Tararà, Massimo Caccia, Roberto Valli, Rainero, A, Angaroni, F, Conti, A, Pirrone, C, Micheloni, G, Tarara, L, Millefanti, G, Maserati, E, Valli, R, Spinelli, O, Buklijas, K, Michelato, A, Casalone, R, Barlassina, C, Barcella, M, Sirchia, S, Piscitelli, E, Caccia, M, and Porta, G

Subjects
Male, 0301 basic medicine, Cancer Research, Immunology, Fusion Proteins, bcr-abl, Leukemia, Myelogenous, Chronic,Treatment Outcome, Real-Time Polymerase Chain Reaction, Article, Follow-Up Studie, Fusion gene, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Cancer stem cell, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, hemic and lymphatic diseases, Humans, Medicine, RNA, Messenger, lcsh:QH573-671, Protein Kinase Inhibitors, Aged, Cell Biology, Reverse Transcriptase Polymerase Chain Reaction, business.industry, lcsh:Cytology, Reproducibility of Results, Myeloid leukemia, DNA, Middle Aged, Protein-Tyrosine Kinases, medicine.disease, genomic DNA, Leukemia, Haematopoiesis, Treatment Outcome, 030104 developmental biology, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Imatinib Mesylate, Neoplastic Stem Cells, Cancer research, Female, Stem cell, business, Follow-Up Studies
Abstract

Chronic Myeloid Leukemia (CML) is a stem cell cancer that arises when t(9;22) translocation occurs in a hematopoietic stem cells. This event results in the expression of the BCR-ABL1 fusion gene, which codes for a constitutively active tyrosine kinase that is responsible for the transformation of a HSC into a CML stem cell, which then gives rise to a clonal myeloproliferative disease. The introduction of Tyrosine Kinase Inhibitors (TKIs) has revolutionized the management of the disease. However, these drugs do not seem to be able to eradicate the malignancy. Indeed, discontinuation trials (STIM; TWISER; DADI) for those patients who achieved a profound molecular response showed 50% relapsing within 12 months. We performed a comparative analysis on 15 CML patients and one B-ALL patient, between the standard quantitative reverse-transcriptase PCR (qRT–PCR) and our genomic DNA patient-specific quantitative PCR assay (gDNA qPCR). Here we demonstrate that gDNA qPCR is better than standard qRT–PCR in disease monitoring after an average follow-up period of 200 days. Specifically, we statistically demonstrated that DNA negativity is more reliable than RNA negativity in indicating when TKIs therapy can be safely stopped.

Published
2018
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33. Aeolian inputs as parent materials for Podzols and terra-rossa soils in a dolomitic landscape in the Italian Alps (Salmezza, BG, Italy)

Author

Michele D'Amico, Franco Previtali, Marco Barcella, Enrico Casati, D'Amico, EM, Casati, E, Barcella, M, Previtali, F, and D'Amico, E

Subjects
Dolostone, Podzols, Terra rossa, Karst, Terra rossa, Soil water, GEO/04 - GEOGRAFIA FISICA E GEOMORFOLOGIA, Geochemistry, Aeolian processes, Geology, Podzol
Abstract

On an unglaciated karst landscape in the Lombard Pre-Alps (Salmezza, Bergamo, Italy), an extremely high pedodiversity occurs across a few hectares on Norian dolostone. The rock is locally enriched in well crystallized sand-grained quartz. The climate of the area is suboceanic, with >1500 mm of annual rainfall, and an average temperature around 6-8°C. Rendzic Leptosols and Phaeozems are developed on the steepest slopes, Podzols, Cambisols and Luvisols on flatter areas, while Rhodic Luvisols/Alisols (Terra-Rossa soils) are found in doline cracks and crevices. The sand-grained quartz content of the parent rock seems to be the main soil differentiating factor: where it is abundant (ca. 10-20% in volume), it is responsible for the genesis of Podzols.We sampled and analyzed 9 soil profiles from the Salmezza area, thus characterizing all pedogenic processes active in the area. In particular, we analyzed standard soil chemical properties (pH, organic carbon, base status and Cation Exchange Capacity, dithionite and oxalate-extractable Fe and Al); we performed a total elemental analysis on most samples and on substrate samples, in order to calculate mass balance and element loss and enrichment; we observed thin sections and performed XRD analysis in powder samples and on the clay fraction of most pedogenic horizons as well.The parent material is a rather pure dolostone, composed of dolomite, locally enriched in quartz. No other minerals have been observed. Very little amounts of Fe, Al and other elements are thus included in the parent rock (almost completely composed of Ca, Mg and Si), often very close to the analytical detection limit. Ca and Mg were almost completely lost during most soil forming processes in this temperate humid climate, while the enrichment in Si, Fe, Al varies broadly amidst the different soils, thanks to different pedogenic processes. Fe and Al, in particular, were up to 120 times more concentrated in Bt and Bhs horizons than in the parent rock. The ratios between stable elements in rocks and soils verifies important inputs of aeolian materials. The values are, however, different also amidst different soils, so an univocal origin of aeolian materials cannot be hypothesized. The mineralogy of the clay fraction is also strongly modified by pedogenesis, so that each soil type is characterized by a different mineralogical assemblage, making it difficult to detect signatures of specific aeolian origins as well.

Published
2020

34. 53° Congresso della Società Italiana di scienza della vegetazione. Gestione sostenibile degli habitat: plant traits, biodiversità e servizi ecosistemici. Abstract book

Author

D. Gigante, A. Selvaggi, A. T. R. Acosta, M. Adorni, M. Allegrezza, C. Angiolini, S. Armiraglio, S. Assini, F. Attorre, S. Bagella, M. Barcella, G. Bazan, A. Bertacchi, R. Bolpagni, G. Bonari, G. Buffa, M. Caccianiga, C. Cacciatori, M. C. Caria, S. Casavecchia, L. Casella, B. E. L. Cerabolini, G. Ciaschetti, D. Ciccarelli, A. Cogoni, M. Cutini, M. De Sanctis, W. De Simone, S. Del Vecchio, V. Di Cecco, L. Di Martino, M. Di Musciano, E. Fantinato, L. Filesi, B. Foggi, L. Forte, A. R. Frattaroli, D. Galdenzi, C. Gangale, L. Gianguzzi, G. Giusso Del Galdo, A. Grignetti, R. Guarino, C. Lasen, F. Maneli, C. Marcenò, M. G. Mariotti, G. Oriolo, B. Paura, E. Perrino, S. Pesaresi, G. Pezzi, S. Pisanu, S. Poponessi, I. Prisco, M. Puglisi, G. Rivieccio, S. Sciandrello, G. Spampinato, A. Stinca, S. Strumia, F. Taffetani, G. Tesei, V. Tomaselli, R. Venanzoni, D. Viciani, M. Villani, R. Wagensommer, K. Zanatta, P. Angelini, Società Italiana di Scienza della Vegetazione, Gigante, D., Selvaggi, A., Acosta, A. T. R., Adorni, M., Allegrezza, M., Angiolini, C., Armiraglio, S., Assini, S., Attorre, F., Bagella, S., Barcella, M., Bazan, G., Bertacchi, A., Bolpagni, R., Bonari, G., Buffa, G., Caccianiga, M., Cacciatori, C., Caria, M. C., Casavecchia, S., Casella, L., Cerabolini, B. E. L., Ciaschetti, G., Ciccarelli, D., Cogoni, A., Cutini, M., De Sanctis, M., De Simone, W., Del Vecchio, S., Di Cecco, V., Di Martino, L., Di Musciano, M., Fantinato, E., Filesi, L., Foggi, B., Forte, L., Frattaroli, A. R., Galdenzi, D., Gangale, C., Gianguzzi, L., Giusso Del Galdo, G., Grignetti, A., Guarino, R., Lasen, C., Maneli, F., Marcenò, C., Mariotti, M. G., Oriolo, G., Paura, B., Perrino, E., Pesaresi, S., Pezzi, G., Pisanu, S., Poponessi, S., Prisco, I., Puglisi, M., Rivieccio, G., Sciandrello, S., Spampinato, G., Stinca, A., Strumia, S., Taffetani, F., Tesei, G., Tomaselli, V., Venanzoni, R., Viciani, D., Villani, M., Wagensommer, R., Zanatta, K., and Angelini, P.

Published
2019

35. Target Sequencing, Cell Experiments, and a Population Study Establish Endothelial Nitric Oxide Synthase (eNOS) Gene as Hypertension Susceptibility Gene

Author

Salvi, Erika, Kuznetsova, Tatiana, Thijs, Lutgarde, Lupoli, Sara, Stolarz-Skrzypek, Katarzyna, D'Avila, Francesca, Tikhonoff, Valerie, De Astis, Silvia, Barcella, Matteo, Seidlerova, Jitka, Benaglio, Paola, Malyutina, Sofia, Frau, Francesca, Velayutham, Dinesh, Benfante, Roberta, Zagato, Laura, Title, Alexandra, Braga, Daniele, Marek, Diana, Kawecka-Jaszcz, Kalina, Casiglia, Edoardo, Filipovsky, Jan, Nikitin, Yuri, Rivolta, Carlo, Manunta, Paolo, Beckmann, Jacques S., Barlassina, Cristina, Cusi, Daniele, Staessen, Jan A., Czarnecka, Danuta, Gąsowski, Jerzy, Grodzicki, Tomasz, Kloch-Badełek, Małgorzata, Olszanecka, Agnieszka, Wizner, Barbara, Epidemiologie, RS: CARIM School for Cardiovascular Diseases, Salvi, E, Kuznetsova, T, Thijs, L, Lupoli, S, STOLARZ SKRZYPEK, K, D'Avila, F, Tikhonoff, V, DE ASTIS, S, Barcella, M, Seidlerová, J, Benaglio, P, Malyutina, S, Frau, F, Velayutham, D, Benfante, R, Zagato, L, Title, A, Braga, D, Marek, D, KAWECKA JASZCZ, K, Casiglia, E, Filipovsky, J, Nikitin, Y, Rivolta, C, Manunta, Paolo, Beckmann, J, Barlassina, C, Cusi, D, and Staessen, J. A.

Subjects
Adult, Male, medicine.medical_specialty, hypertension, Genotype, Nitric Oxide Synthase Type III, Endothelium, Population, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, target sequencing, population science, Enos, Internal medicine, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, endothelial nitric oxide synthase gene, Allele, Promoter Regions, Genetic, education, Alleles, 030304 developmental biology, 0303 health sciences, education.field_of_study, blood pressure, Promoter, Middle Aged, biology.organism_classification, Molecular biology, Endocrinology, medicine.anatomical_structure, Blood pressure, transfection, Case-Control Studies, Population study, Female, Endothelium, Vascular
Abstract

A case–control study revealed association between hypertension and rs3918226 in the endothelial nitric oxide synthase ( eNOS ) gene promoter (minor/major allele, T/C allele). We aimed at substantiating these preliminary findings by target sequencing, cell experiments, and a population study. We sequenced the 140-kb genomic area encompassing the eNOS gene. In HeLa and HEK293T cells transfected with the eNOS promoter carrying either the T or the C allele, we quantified transcription by luciferase assay. In 2722 randomly recruited Europeans (53.0% women; mean age 40.1 years), we studied blood pressure change and incidence of hypertension in relation to rs3918226, using multivariable-adjusted models. Sequencing confirmed rs3918226, a binding site of E-twenty six transcription factors, as the single nucleotide polymorphism most closely associated with hypertension. In T compared with C transfected cells, eNOS promoter activity was from 20% to 40% ( P TT homozygotes and by 3.8/1.9 mm Hg in 2694 C allele carriers ( P ≤0.0004). The blood pressure rise was 5.9 mm Hg systolic (confidence interval [CI], 0.6–11.1; P =0.028) and 4.8 mm Hg diastolic (CI, 1.5–8.2; P =0.0046) greater in TT homozygotes, with no differences between the CT and CC genotypes ( P ≥0.90). Among 2013 participants normotensive at baseline, 692 (34.4%) developed hypertension. The hazard ratio and attributable risk associated with TT homozygosity were 2.04 (CI, 1.24–3.37; P =0.0054) and 51.0%, respectively. In conclusion, rs3918226 in the eNOS promoter tags a hypertension susceptibility locus, TT homozygosity being associated with lesser transcription and higher risk of hypertension.

Published
2013

36. Network analysis of phenological units to detect important species in plant-pollinator assemblages: Can it inform conservation strategies?

Author

Silvia Paola Assini, Jeff Ollerton, Matteo Barcella, Paolo Biella, Biella, P, Ollerton, J, Barcella, M, and Assini, S

Subjects
0106 biological sciences, Biodiversity, Endangered species, Hub, Modularity, Biology, 010603 evolutionary biology, 01 natural sciences, Connectance, Ecosystem, Pollination, Ecology, Evolution, Behavior and Systematics, QK914, Habitat management, Modularity (networks), Ecology, business.industry, 010604 marine biology & hydrobiology, Environmental resource management, Nestedne, Grassland, Ecological network, Phenology, Animal ecology, Community analysi, Nestedness, QK926, business, Network analysis
Abstract

Conservation of species is often focused either only on those that are endangered, or on maximising the number recorded on species lists. However, species share space and time with others, thus interacting and building frameworks of relationships that can be unravelled by community-level network analysis. It is these relationships that ultimately drive ecosystem function via the transfer of energy and nutrients. However interactions are rarely considered in conservation planning. Network analysis can be used to detect key species ("hubs") that play an important role\ud in cohesiveness of networks. We applied this approach to plant-pollinator communities on two montane Northern Apennine grasslands, paying special attention to the modules and the identity of hubs. We performed season-wide sampling and then focused the network analyses on time units consistent with plant phenology. After testing for significance of modules, only some modules were found to be significantly segregated from others. Thus, networks were organized around a structured core of modules with a set of companion species that were not organized into compartments. Using a network approach we obtained a list of important plant and pollinator species, including three Network Hubs of utmost importance, and other hubs of particular biogeographical interest. By having a lot of links and high partner diversity, hubs should convey stability to networks. Due to their role in the networks, taking into account such key species when considering the management of sites could help to preserve the greatest number of interactions and thus support many other species.

Published
2017

37. Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population

Author

Lotte Jacobs, Xabier L. Aranguren, Paolo Manunta, Giulia Coppiello, Zhenyu Zhang, Nicholas Cauwenberghs, Lutgarde Thijs, Daniele Cusi, Aernout Luttun, Cristina Barlassina, Matteo Barcella, Fang Fei Wei, Jan A. Staessen, Peter Verhamme, Wen-Yi Yang, Erika Salvi, Thibault Petit, Tatiana Kuznetsova, Judita Knez, Simona Delli Carpini, Lorena Citterio, Yu Mei Gu, Azusa Hara, Epidemiologie, RS: CARIM - R3 - Vascular biology, Yang, Wy, Petit, T, Thijs, L, Zhang, Zy, Jacobs, L, Hara, A, Wei, Ff, Salvi, E, Citterio, L, DELLI CARPINII, S, Gu, Ym, Knez, J, Cauwenberghs, N, Barcella, M, Barlassina, C, Manunta, Paolo, Coppiello, G, Aranguren, Xl, Kuznetsova, T, Cusi, D, Verhamme, P, Luttun, A, and Staessen, Ja

Subjects
Adult, Male, Genotype, Population, Single-nucleotide polymorphism, Comorbidity, Coronary Artery Disease, Biology, Polymorphism, Single Nucleotide, Coronary artery disease, Young Adult, Belgium, Genetics, medicine, Basic Helix-Loop-Helix Transcription Factors, Ethnicity, Humans, Genetics(clinical), Myocardial infarction, Clinical genetics, education, Genetics (clinical), TCF15, Homeodomain Proteins, education.field_of_study, MEOX2, Incidence (epidemiology), Incidence, Hazard ratio, Haplotype, Genetic Variation, Translational research, Middle Aged, medicine.disease, Confidence interval, 3. Good health, Coronary heart disease, Haplotypes, Population science, Female, Research Article
Abstract

Background In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD). Results In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25–2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16–3.31), 1.87 (1.20–2.91) and 3.16 (1.41–7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %). Conclusions Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms. Electronic supplementary material The online version of this article (doi:10.1186/s12863-015-0272-2) contains supplementary material, which is available to authorized users.

Published
2015

38. Acute Myeloid Leukemia Relapses after Allogenenic HSCT Display a Distinctive Immune-Related Signature, with Frequent and Functionally Relevant Alterations in HLA Class II Antigen Presentation and T Cell Costimulation

Author

Elia Stupka, Katharina Fleischhauer, Nicoletta Cieri, Chiara Bonini, Cristina Toffalori, Lara Crucitti, Laura Zito, Davide Cittaro, Luca Vago, Matteo Barcella, Dejan Lazarevic, Michela Riba, Cristina Barlassina, Alessandro Rambaldi, Massimo Bernardi, Fabio Ciceri, Jacopo Peccatori, Orietta Spinelli, Toffalori, C, Riba, M, Zito, L, Barcella, M, Spinelli, O, Crucitti, L, Cieri, N, Peccatori, J, Bernardi, M, Bonini, C, Cittaro, D, Lazarevic, D, Rambaldi, A, Barlassina, C, Stupka, E, Ciceri, F, Fleischhauer, K, and Vago, L

Subjects
medicine.medical_treatment, T cell, Immunology, Antigen presentation, Medizin, Myeloid leukemia, Cell Biology, Hematology, Human leukocyte antigen, Hematopoietic stem cell transplantation, Biology, medicine.disease, Biochemistry, Histocompatibility, Leukemia, medicine.anatomical_structure, hemic and lymphatic diseases, Lymphocyte costimulation, medicine
Abstract

INTRODUCTION: Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) represents an effective form of adoptive immunotherapy for Acute Myeloid Leukemia (AML), thanks to the antitumor effect mediated by donor immune cells infused as part of the graft. Unfortunately, post-transplantation relapses remain a frequent observation, warranting further investigation on AML immunobiology. Our group demonstrated that relapses after partially HLA-incompatible HSCT are frequently due to the outgrowth of immune-resistant mutant AML clones characterized by genomic loss the mismatched histocompatibility determinants targeted by alloreactive donor T cells, and have thus gained a selective advantage upon pressure from the transplanted immune system, in a process called “leukemia immunoediting” (Vago et al., N Engl J Med, 2009). In the present study, we took advantage of high-throughput technologies to profile post-transplantation AML relapses with no genomic loss of HLA, to identify novel targets of the leukemia immunoediting process. METHODS: Serial AML samples were collected and FACS-purified from 9 patients at diagnosis, relapse after sole chemotherapy and relapse after allo-HSCT, and employed for whole transcriptome profiling using Illumina HumanHT12 microarrays. Deregulated genes were identified by pair-wise LIMMA analysis, and unsupervised enrichment analysis was performed interrogating the Gene Ontology database. High-throughput results were confirmed in a validation cohort of 12 patients by ad hoc designed qPCR assays, immunophenotypic analyses and functional experiments. In particular, co-cultures were performed using as responders peripheral blood lymphocytes harvested from patients after allo-HSCT, and as stimulators and targets their respective AML blasts collected at diagnosis or at relapse: read-outs included antigen-specific T cell activation, cytotoxicity, and cytokine release. RESULTS: Amongst all the genes expressed by purified AML blasts, a 110-gene signature (p CONCLUSIONS: Our results demonstrate that the deregulation of immune-related processes, and in particular of molecules and pathways involved in T cell-mediated allo-recognition, are pervasive and distinctive features of AML relapses after allo-HSCT. Identification of patient-specific mechanisms of immune evasion might be translated into personalized therapeutic approaches, tailored to restore or circumvent inefficient antigen presentation and T cell costimulation. Disclosures Bonini: MolMed S.p.A.: Consultancy.

Published
2014

40. A p38 MAPK-ROS axis fuels proliferation stress and DNA damage during CRISPR-Cas9 gene editing in hematopoietic stem and progenitor cells.

Author

Della Volpe L, Midena F, Vacca R, Tavella T, Alessandrini L, Farina G, Brandas C, Lo Furno E, Giannetti K, Carsana E, Naldini MM, Barcella M, Ferrari S, Beretta S, Santoro A, Porcellini S, Varesi A, Gilioli D, Conti A, Merelli I, Gentner B, Villa A, Naldini L, and Di Micco R

Subjects
Animals, Mice, Humans, Mice, Inbred C57BL, Cell Differentiation genetics, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Hematopoietic Stem Cells metabolism, CRISPR-Cas Systems genetics, p38 Mitogen-Activated Protein Kinases metabolism, p38 Mitogen-Activated Protein Kinases genetics, Gene Editing methods, DNA Damage genetics, Cell Proliferation genetics, Reactive Oxygen Species metabolism
Abstract

Ex vivo activation is a prerequisite to reaching adequate levels of gene editing by homology-directed repair (HDR) for hematopoietic stem and progenitor cell (HSPC)-based clinical applications. Here, we show that shortening culture time mitigates the p53-mediated DNA damage response to CRISPR-Cas9-induced DNA double-strand breaks, enhancing the reconstitution capacity of edited HSPCs. However, this results in lower HDR efficiency, rendering ex vivo culture necessary yet detrimental. Mechanistically, ex vivo activation triggers a multi-step process initiated by p38 mitogen-activated protein kinase (MAPK) phosphorylation, which generates mitogenic reactive oxygen species (ROS), promoting fast cell-cycle progression and subsequent proliferation-induced DNA damage. Thus, p38 inhibition before gene editing delays G1/S transition and expands transcriptionally defined HSCs, ultimately endowing edited cells with superior multi-lineage differentiation, persistence throughout serial transplantation, enhanced polyclonal repertoire, and better-preserved genome integrity. Our data identify proliferative stress as a driver of HSPC dysfunction with fundamental implications for designing more effective and safer gene correction strategies for clinical applications., Competing Interests: Declaration of interests R.D.M., L.d.V., F.M., A.C., L.N., and S.F. are inventors of patents on applications of gene editing in HSPCs owned and managed by the San Raffaele Scientific Institute and the Telethon Foundation. L.N. is a founder and quota holder of GeneSpire., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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41. Functioning Management and Recovery, a psychoeducational intervention for psychiatric residential facilities: a multicenter follow-up study.

Author

Veltro F, Latte G, Pontarelli C, Barcella M, Silveri L, Cardone G, Nicchiniello I, Pontarelli I, Zappone L, Luso S, and Leggero P

Subjects
Humans, Male, Female, Follow-Up Studies, Adult, Italy, Middle Aged, Residential Facilities, Patient Education as Topic methods, Schizophrenia therapy, Treatment Outcome, Psychotic Disorders therapy, Psychotic Disorders psychology
Abstract

Aim: Functional Management and Recovery is a standardized Psychoeducational Intervention, derived from "Integro", an effective salutogenic-psychoeducational intervention for people in recovery journey, designed to improve recovery and functioning of individuals with psychotic disorders in Psychiatric Residential Facilities (PRFs). The aim of this study is to evaluate the primary and secondary outcomes of this intervention elaborated specifically for PRFs where evidence based structured interventions seem rare and desirable., Methods: 66 individuals with psychotic disorders were recruited in 9 PRFs dislocated in the North, Center and South Italy and 63 underwent a multicenter follow-up study with a two time-point evaluation (t0, pre-treatment and t1, 6 months; ). At each time point, social functioning was assessed as primary outcome by the Personal and Social Performance scale (PSP); furthermore, psychopathological status was assessed by Brief Psychiatric Rating Scale (BPRS), Recovery by Recovery Assessment Scale (RAS), Cognitive Functioning by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Stress management by Stress-Scale, Cognitive Flexibility by Modified Five-Point Test (M-FPT), Emotional Intelligence by Emotional Intelligence Index (EI-I), the PRF Atmosphere and the Opinion of users about the PFR by an ad hoc questionnaire. The Abilities Knowledge, the Utility and Pleasantness of sessions were measured by an ad hoc list of items., Results: 63 individuals out of 66, 52 (82,5%) affected by schizophrenia and 11 (17,5%) by bipolar I disorder with psychotic symptoms according to DSM-5-TR completed the study. At the end of the study, 43 (68,3%) were male, 57 (90.5%) were single, 5 (7.9%) engaged, 1 (1.6%) married; 45 (71.4%) unemployed. The total scores of PSP, RAS, BPRS, BANS, Stress management, Abilities Knowledge, Utility and Pleasantness of sessions showed a statistically significant improvement at t1 vs. t0. Two sub-scales out of 5 of M-FPT showed a statistically significant improvement. The Emotional Intelligence, the Unit Atmosphere and the Opinion of Users about PFR improved without statistical significance. Six months after the end of the follow-up study 22 individuals of the sample were dismissed with a very high turnover., Conclusions: After a six-month follow-up (a short period of time), these results showed improvement in functioning, the primary outcome, as well as in the following secondary outcome variables: RAS, BPRS, BANS, Stress management, Abilities Knowledge, two sub-scales out of 5 of M-FPT, Utility and Pleasantness of sessions. Overall, a remarkable impact of psychoeducational structured intervention on the key Recovery variables is observed. Further studies are needed to address extent and duration of these improvements., (© 2024. The Author(s).)

Published
2024
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42. Genotoxic effects of base and prime editing in human hematopoietic stem cells.

Author

Fiumara M, Ferrari S, Omer-Javed A, Beretta S, Albano L, Canarutto D, Varesi A, Gaddoni C, Brombin C, Cugnata F, Zonari E, Naldini MM, Barcella M, Gentner B, Merelli I, and Naldini L

Subjects
Humans, CRISPR-Cas Systems genetics, DNA Breaks, Double-Stranded, Animals, Mice, DNA Repair genetics, DNA Damage, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells drug effects, Gene Editing methods
Abstract

Base and prime editors (BEs and PEs) may provide more precise genetic engineering than nuclease-based approaches because they bypass the dependence on DNA double-strand breaks. However, little is known about their cellular responses and genotoxicity. Here, we compared state-of-the-art BEs and PEs and Cas9 in human hematopoietic stem and progenitor cells with respect to editing efficiency, cytotoxicity, transcriptomic changes and on-target and genome-wide genotoxicity. BEs and PEs induced detrimental transcriptional responses that reduced editing efficiency and hematopoietic repopulation in xenotransplants and also generated DNA double-strand breaks and genotoxic byproducts, including deletions and translocations, at a lower frequency than Cas9. These effects were strongest for cytidine BEs due to suboptimal inhibition of base excision repair and were mitigated by tailoring delivery timing and editor expression through optimized mRNA design. However, BEs altered the mutational landscape of hematopoietic stem and progenitor cells across the genome by increasing the load and relative proportions of nucleotide variants. These findings raise concerns about the genotoxicity of BEs and PEs and warrant further investigation in view of their clinical application., (© 2023. The Author(s).)

Published
2024
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44. Circulating hematopoietic stem/progenitor cell subsets contribute to human hematopoietic homeostasis.

Author

Quaranta P, Basso-Ricci L, Jofra Hernandez R, Pacini G, Naldini MM, Barcella M, Seffin L, Pais G, Spinozzi G, Benedicenti F, Pietrasanta C, Cheong JG, Ronchi A, Pugni L, Dionisio F, Monti I, Giannelli S, Darin S, Fraschetta F, Barera G, Ferrua F, Calbi V, Ometti M, Di Micco R, Mosca F, Josefowicz SZ, Montini E, Calabria A, Bernardo ME, Cicalese MP, Gentner B, Merelli I, Aiuti A, and Scala S

Subjects
Animals, Humans, Mice, Single-Cell Analysis, Hematopoiesis, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Homeostasis
Abstract

Abstract: In physiological conditions, few circulating hematopoietic stem/progenitor cells (cHSPCs) are present in the peripheral blood, but their contribution to human hematopoiesis remain unsolved. By integrating advanced immunophenotyping, single-cell transcriptional and functional profiling, and integration site (IS) clonal tracking, we unveiled the biological properties and the transcriptional features of human cHSPC subpopulations in relationship to their bone marrow (BM) counterpart. We found that cHSPCs reduced in cell count over aging and are enriched for primitive, lymphoid, and erythroid subpopulations, showing preactivated transcriptional and functional state. Moreover, cHSPCs have low expression of multiple BM-retention molecules but maintain their homing potential after xenotransplantation. By generating a comprehensive human organ-resident HSPC data set based on single-cell RNA sequencing data, we detected organ-specific seeding properties of the distinct trafficking HSPC subpopulations. Notably, circulating multi-lymphoid progenitors are primed for seeding the thymus and actively contribute to T-cell production. Human clonal tracking data from patients receiving gene therapy (GT) also showed that cHSPCs connect distant BM niches and participate in steady-state hematopoietic production, with primitive cHSPCs having the highest recirculation capability to travel in and out of the BM. Finally, in case of hematopoietic impairment, cHSPCs composition reflects the BM-HSPC content and might represent a biomarker of the BM state for clinical and research purposes. Overall, our comprehensive work unveiled fundamental insights into the in vivo dynamics of human HSPC trafficking and its role in sustaining hematopoietic homeostasis. GT patients' clinical trials were registered at ClinicalTrials.gov (NCT01515462 and NCT03837483) and EudraCT (2009-017346-32 and 2018-003842-18)., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Published
2024
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45. A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID.

Author

Cesana D, Cicalese MP, Calabria A, Merli P, Caruso R, Volpin M, Rudilosso L, Migliavacca M, Barzaghi F, Fossati C, Gazzo F, Pizzi S, Ciolfi A, Bruselles A, Tucci F, Spinozzi G, Pais G, Benedicenti F, Barcella M, Merelli I, Gallina P, Giannelli S, Dionisio F, Scala S, Casiraghi M, Strocchio L, Vinti L, Pacillo L, Draghi E, Cesana M, Riccardo S, Colantuono C, Six E, Cavazzana M, Carlucci F, Schmidt M, Cancrini C, Ciceri F, Vago L, Cacchiarelli D, Gentner B, Naldini L, Tartaglia M, Montini E, Locatelli F, and Aiuti A

Subjects
Humans, Male, Retroviridae genetics, Adenosine Deaminase deficiency, Adenosine Deaminase genetics, Genetic Therapy methods, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogene Mas, Severe Combined Immunodeficiency therapy, Severe Combined Immunodeficiency genetics, Genetic Vectors genetics, Hematopoietic Stem Cell Transplantation, Agammaglobulinemia therapy, Agammaglobulinemia genetics
Abstract

Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient's specific factors., (© 2024. The Author(s).)

Published
2024
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46. Exonic knockout and knockin gene editing in hematopoietic stem and progenitor cells rescues RAG1 immunodeficiency.

Author

Castiello MC, Brandas C, Ferrari S, Porcellini S, Sacchetti N, Canarutto D, Draghici E, Merelli I, Barcella M, Pelosi G, Vavassori V, Varesi A, Jacob A, Scala S, Basso Ricci L, Paulis M, Strina D, Di Verniere M, Sergi Sergi L, Serafini M, Holland SM, Bergerson JRE, De Ravin SS, Malech HL, Pala F, Bosticardo M, Brombin C, Cugnata F, Calzoni E, Crooks GM, Notarangelo LD, Genovese P, Naldini L, and Villa A

Subjects
Animals, Humans, Mice, Exons, Hematopoietic Stem Cells metabolism, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Gene Editing methods, Hematopoietic Stem Cell Transplantation
Abstract

Recombination activating genes ( RAGs ) are tightly regulated during lymphoid differentiation, and their mutations cause a spectrum of severe immunological disorders. Hematopoietic stem and progenitor cell (HSPC) transplantation is the treatment of choice but is limited by donor availability and toxicity. To overcome these issues, we developed gene editing strategies targeting a corrective sequence into the human RAG1 gene by homology-directed repair (HDR) and validated them by tailored two-dimensional, three-dimensional, and in vivo xenotransplant platforms to assess rescue of expression and function. Whereas integration into intron 1 of RAG1 achieved suboptimal correction, in-frame insertion into exon 2 drove physiologic human RAG1 expression and activity, allowing disruption of the dominant-negative effects of unrepaired hypomorphic alleles. Enhanced HDR-mediated gene editing enabled the correction of human RAG1 in HSPCs from patients with hypomorphic RAG1 mutations to overcome T and B cell differentiation blocks. Gene correction efficiency exceeded the minimal proportion of functional HSPCs required to rescue immunodeficiency in Rag1 -/- mice, supporting the clinical translation of HSPC gene editing for the treatment of RAG1 deficiency.

Published
2024
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47. miR-126 identifies a quiescent and chemo-resistant human B-ALL cell subset that correlates with minimal residual disease.

Author

Caserta C, Nucera S, Barcella M, Fazio G, Naldini MM, Pagani R, Pavesi F, Desantis G, Zonari E, D'Angiò M, Capasso P, Lombardo A, Merelli I, Spinelli O, Rambaldi A, Ciceri F, Silvestri D, Valsecchi MG, Biondi A, Cazzaniga G, and Gentner B

Subjects
Adult, Humans, Child, Neoplasm, Residual genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Burkitt Lymphoma, MicroRNAs genetics, MicroRNAs metabolism
Abstract

Complete elimination of B-cell acute lymphoblastic leukemia (B-ALL) by a risk-adapted primary treatment approach remains a clinical key objective, which fails in up to a third of patients. Recent evidence has implicated subpopulations of B-ALL cells with stem-like features in disease persistence. We hypothesized that microRNA-126, a core regulator of hematopoietic and leukemic stem cells, may resolve intratumor heterogeneity in B-ALL and uncover therapy-resistant subpopulations. We exploited patient-derived xenograft (PDX) models with B-ALL cells transduced with a miR-126 reporter allowing the prospective isolation of miR-126(high) cells for their functional and transcriptional characterization. Discrete miR-126(high) populations, often characterized by MIR126 locus demethylation, were identified in 8/9 PDX models and showed increased repopulation potential, in vivo chemotherapy resistance and hallmarks of quiescence, inflammation and stress-response pathway activation. Cells with a miR-126(high) transcriptional profile were identified as distinct disease subpopulations by single-cell RNA sequencing in diagnosis samples from adult and pediatric B-ALL. Expression of miR-126 and locus methylation were tested in several pediatric and adult B-ALL cohorts, which received standardized treatment. High microRNA-126 levels and locus demethylation at diagnosis associate with suboptimal response to induction chemotherapy (MRD > 0.05% at day +33 or MRD+ at day +78)., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2023
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48. Occurrence of L1M Elements in Chromosomal Rearrangements Associated to Chronic Myeloid Leukemia (CML): Insights from Patient-Specific Breakpoints Characterization.

Author

L'Abbate A, Moretti V, Pungolino E, Micheloni G, Valli R, Frattini A, Barcella M, Acquati F, Reinbold RA, Costantino L, Ferrara F, Trojani A, Ventura M, Porta G, and Cairoli R

Subjects
Humans, Philadelphia Chromosome, Translocation, Genetic, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Myeloproliferative Disorders genetics
Abstract

Chronic myeloid leukemia (CML) is a rare myeloproliferative disorder caused by the reciprocal translocation t(9;22)(q34;q11) in hematopoietic stem cells (HSCs). This chromosomal translocation results in the formation of an extra-short chromosome 22, called a Philadelphia chromosome (Ph), containing the BCR-ABL1 fusion gene responsible for the expression of a constitutively active tyrosine kinase that causes uncontrolled growth and replication of leukemic cells. Mechanisms behind the formation of this chromosomal rearrangement are not well known, even if, as observed in tumors, repetitive DNA may be involved as core elements in chromosomal rearrangements. We have participated in the explorative investigations of the PhilosoPhi34 study to evaluate residual Ph+ cells in patients with negative FISH analysis on CD34+/lin- cells with gDNA qPCR. Using targeted next-generation deep sequencing strategies, we analyzed the genomic region around the t(9;22) translocations of 82 CML patients and one CML cell line and assessed the relevance of interspersed repeat elements at breakpoints (BP). We found a statistically higher presence of LINE elements, in particular belonging to the subfamily L1M, in BP cluster regions of both chromosome 22 and 9 compared to the whole human genome. These data suggest that L1M elements could be potential drivers of t(9;22) translocation leading to the generation of the BCR-ABL1 chimeric gene and the expression of the active BCR-ABL1 -controlled tyrosine kinase chimeric protein responsible for CML.

Published
2023
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49. Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia.

Author

Naldini MM, Casirati G, Barcella M, Rancoita PMV, Cosentino A, Caserta C, Pavesi F, Zonari E, Desantis G, Gilioli D, Carrabba MG, Vago L, Bernardi M, Di Micco R, Di Serio C, Merelli I, Volpin M, Montini E, Ciceri F, and Gentner B

Subjects
Humans, Neoplastic Stem Cells metabolism, Recurrence, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, MicroRNAs metabolism
Abstract

Acute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 (NPM1) mutation calling or chromosomal monosomy detection in single-cell transcriptomes, we discriminate LSCs from regenerating hematopoiesis, and assess their longitudinal response to chemotherapy. Chemotherapy induced a generalized inflammatory and senescence-associated response. Moreover, we observe heterogeneity within progenitor AML cells, some of which proliferate and differentiate with expression of oxidative-phosphorylation (OxPhos) signatures, while others are OxPhos (low) miR-126 (high) and display enforced stemness and quiescence features. miR-126 (high) LSCs are enriched at diagnosis in chemotherapy-refractory AML and at relapse, and their transcriptional signature robustly stratifies patients for survival in large AML cohorts., (© 2023. The Author(s).)

Published
2023
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50. Case Report: Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency.

Author

Barzaghi F, Cicalese MP, Zoccolillo M, Brigida I, Barcella M, Merelli I, Sartirana C, Zanussi M, Calbi V, Bernardo ME, Tucci F, Migliavacca M, Giglio F, Doglio M, Canarutto D, Ferrua F, Consiglieri G, Prunotto G, Saettini F, Bonanomi S, Rovere-Querini P, Di Colo G, Jofra T, Fousteri G, Penco F, Gattorno M, Hershfield MS, Bongiovanni L, Ponzoni M, Marktel S, Milani R, Peccatori J, Ciceri F, Mortellaro A, and Aiuti A

Subjects
Adenosine Deaminase genetics, Granulocyte Colony-Stimulating Factor, Humans, Intercellular Signaling Peptides and Proteins, Severe Combined Immunodeficiency, Tumor Necrosis Factor Inhibitors, Twins, Monozygotic genetics, Agammaglobulinemia diagnosis, Agammaglobulinemia genetics, Neutropenia, Polyarteritis Nodosa
Abstract

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including vasculitis, immunodeficiency, and hematologic manifestations, potentially progressing over time. The present study describes the long-term evolution of the immuno-hematological features and therapeutic challenge of two identical adult twin sisters affected by DADA2. The absence of plasmatic adenosine deaminase 2 (ADA2) activity in both twins suggested the diagnosis of DADA2, then confirmed by genetic analysis. Exon sequencing revealed a missense (p.Leu188Pro) mutation on the paternal ADA2 allele. While, whole genome sequencing identified an unreported deletion (IVS6_IVS7del*) on the maternal allele predicted to produce a transcript missing exon 7. The patients experienced the disease onset during childhood with early strokes (Patient 1 at two years, Patient 2 at eight years of age), subsequently followed by other shared DADA2-associated features, including neutropenia, hypogammaglobulinemia, reduced switched memory B cells, inverted CD4:CD8 ratio, increased naïve T cells, reduced follicular regulatory T cells, the almost complete absence of NK cells, T-large granular cell leukemia, and osteoporosis. Disease evolution differed: clinical manifestations presented several years earlier and were more pronounced in Patient 1 than in Patient 2. Due to G-CSF refractory life-threatening neutropenia, Patient 1 successfully underwent an urgent hematopoietic stem cell transplantation (HSCT) from a 9/10 matched unrelated donor. Patient 2 experienced a similar, although delayed, disease evolution and is currently on anti-TNF therapy and anti-infectious prophylaxis. The unique cases confirmed that heterozygous patients with null ADA2 activity deserve deep investigation for possible structural variants on a single allele. Moreover, this report emphasizes the importance of timely recognizing DADA2 at the onset to allow adequate follow-up and detection of disease progression. Finally, the therapeutic management in these identical twins raises significant concerns as they share a similar phenotype, with a delayed but almost predictable disease evolution in one of them, who could benefit from a prompt definitive treatment like elective allogeneic HSCT. Additional data are required to assess whether the absence of enzymatic activity at diagnosis is associated with hematological involvement and is also predictive of bone marrow dysfunction, encouraging early HSCT to improve functional outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barzaghi, Cicalese, Zoccolillo, Brigida, Barcella, Merelli, Sartirana, Zanussi, Calbi, Bernardo, Tucci, Migliavacca, Giglio, Doglio, Canarutto, Ferrua, Consiglieri, Prunotto, Saettini, Bonanomi, Rovere-Querini, Di Colo, Jofra, Fousteri, Penco, Gattorno, Hershfield, Bongiovanni, Ponzoni, Marktel, Milani, Peccatori, Ciceri, Mortellaro and Aiuti.)

Published
2022
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