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2. Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML

Author

Marchesini, M, Gherli, A, Simoncini, E, Tor, L, Montanaro, A, Thongon, N, Vento, F, Liverani, C, Cerretani, E, D'Antuono, A, Pagliaro, L, Zamponi, R, Spadazzi, C, Follini, E, Cambò, B, Giaimo, M, Falco, A, Sammarelli, G, Todaro, G, Bonomini, S, Adami, V, Piazza, S, Corbo, C, Lorusso, B, Mezzasoma, F, Lagrasta, C, Martelli, M, La Starza, R, Cuneo, A, Aversa, F, Mecucci, C, Quaini, F, Colla, S, Roti, G, Marchesini, Matteo, Gherli, Andrea, Simoncini, Elisa, Tor, Lucas Moron Dalla, Montanaro, Anna, Thongon, Natthakan, Vento, Federica, Liverani, Chiara, Cerretani, Elisa, D'Antuono, Anna, Pagliaro, Luca, Zamponi, Raffaella, Spadazzi, Chiara, Follini, Elena, Cambò, Benedetta, Giaimo, Mariateresa, Falco, Angela, Sammarelli, Gabriella, Todaro, Giannalisa, Bonomini, Sabrina, Adami, Valentina, Piazza, Silvano, Corbo, Claudia, Lorusso, Bruno, Mezzasoma, Federica, Lagrasta, Costanza Anna Maria, Martelli, Maria Paola, La Starza, Roberta, Cuneo, Antonio, Aversa, Franco, Mecucci, Cristina, Quaini, Federico, Colla, Simona, Roti, Giovanni, Marchesini, M, Gherli, A, Simoncini, E, Tor, L, Montanaro, A, Thongon, N, Vento, F, Liverani, C, Cerretani, E, D'Antuono, A, Pagliaro, L, Zamponi, R, Spadazzi, C, Follini, E, Cambò, B, Giaimo, M, Falco, A, Sammarelli, G, Todaro, G, Bonomini, S, Adami, V, Piazza, S, Corbo, C, Lorusso, B, Mezzasoma, F, Lagrasta, C, Martelli, M, La Starza, R, Cuneo, A, Aversa, F, Mecucci, C, Quaini, F, Colla, S, Roti, G, Marchesini, Matteo, Gherli, Andrea, Simoncini, Elisa, Tor, Lucas Moron Dalla, Montanaro, Anna, Thongon, Natthakan, Vento, Federica, Liverani, Chiara, Cerretani, Elisa, D'Antuono, Anna, Pagliaro, Luca, Zamponi, Raffaella, Spadazzi, Chiara, Follini, Elena, Cambò, Benedetta, Giaimo, Mariateresa, Falco, Angela, Sammarelli, Gabriella, Todaro, Giannalisa, Bonomini, Sabrina, Adami, Valentina, Piazza, Silvano, Corbo, Claudia, Lorusso, Bruno, Mezzasoma, Federica, Lagrasta, Costanza Anna Maria, Martelli, Maria Paola, La Starza, Roberta, Cuneo, Antonio, Aversa, Franco, Mecucci, Cristina, Quaini, Federico, Colla, Simona, and Roti, Giovanni

Abstract

The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogates EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACis-based combination therapies in patients with 3q26 AML.

Published
2024

3. Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies

Author

Leonetti, A., primary, Verzè, M., additional, Minari, R., additional, Perrone, F., additional, Gnetti, L., additional, Bordi, P., additional, Pluchino, M., additional, Nizzoli, R., additional, Azzoni, C., additional, Bottarelli, L., additional, Lagrasta, C. A. M., additional, Mazzaschi, G., additional, Buti, S., additional, Gasparro, D., additional, Cosenza, A., additional, Ferri, L., additional, Majori, M., additional, De Filippo, M., additional, Ampollini, L., additional, La Monica, S., additional, Alfieri, R., additional, Silini, E. M., additional, and Tiseo, M., additional

Published
2023
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4. GCN5 contributes to intracellular lipid accumulation in human primary cardiac stromal cells from patients affected by Arrhythmogenic cardiomyopathy

Author

Volani, C, Pagliaro, A, Rainer, J, Paglia, G, Porro, B, Stadiotti, I, Foco, L, Cogliati, E, Paolin, A, Lagrasta, C, Frati, C, Corradini, E, Falco, A, Matzinger, T, Picard, A, Ermon, B, Piazza, S, De Bortoli, M, Tondo, C, Philippe, R, Medici, A, Lavdas, A, Blumer, M, Pompilio, G, Sommariva, E, Pramstaller, P, Troppmair, J, Meraviglia, V, Rossini, A, Volani C., Pagliaro A., Rainer J., Paglia G., Porro B., Stadiotti I., Foco L., Cogliati E., Paolin A., Lagrasta C., Frati C., Corradini E., Falco A., Matzinger T., Picard A., Ermon B., Piazza S., De Bortoli M., Tondo C., Philippe R., Medici A., Lavdas A. A., Blumer M. J. F., Pompilio G., Sommariva E., Pramstaller P. P., Troppmair J., Meraviglia V., Rossini A., Volani, C, Pagliaro, A, Rainer, J, Paglia, G, Porro, B, Stadiotti, I, Foco, L, Cogliati, E, Paolin, A, Lagrasta, C, Frati, C, Corradini, E, Falco, A, Matzinger, T, Picard, A, Ermon, B, Piazza, S, De Bortoli, M, Tondo, C, Philippe, R, Medici, A, Lavdas, A, Blumer, M, Pompilio, G, Sommariva, E, Pramstaller, P, Troppmair, J, Meraviglia, V, Rossini, A, Volani C., Pagliaro A., Rainer J., Paglia G., Porro B., Stadiotti I., Foco L., Cogliati E., Paolin A., Lagrasta C., Frati C., Corradini E., Falco A., Matzinger T., Picard A., Ermon B., Piazza S., De Bortoli M., Tondo C., Philippe R., Medici A., Lavdas A. A., Blumer M. J. F., Pompilio G., Sommariva E., Pramstaller P. P., Troppmair J., Meraviglia V., and Rossini A.

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a genetic disease associated with sudden cardiac death and cardiac fibro-fatty replacement. Over the last years, several works have demonstrated that different epigenetic enzymes can affect not only gene expression changes in cardiac diseases but also cellular metabolism. Specifically, the histone acetyltransferase GCN5 is known to facilitate adipogenesis and modulate cardiac metabolism in heart failure. Our group previously demonstrated that human primary cardiac stromal cells (CStCs) contribute to adipogenesis in the ACM pathology. Thus, this study aims to evaluate the role of GCN5 in ACM intracellular lipid accumulation. To do so, CStCs were obtained from right ventricle biopsies of ACM patients and from samples of healthy cadaveric donors (CTR). GCN5 expression was increased both in ex vivo and in vitro ACM samples compared to CTR. When GCN5 expression was silenced or pharmacologically inhibited by the administration of MB-3, we observed a reduction in lipid accumulation and a mitigation of reactive oxygen species (ROS) production in ACM CStCs. In agreement, transcriptome analysis revealed that the presence of MB-3 modified the expression of pathways related to cellular redox balance. Altogether, our findings suggest that GCN5 inhibition reduces fat accumulation in ACM CStCs, partially by modulating intracellular redox balance pathways.

Published
2022

9. Cancer Treatment-Induced Cardiotoxicity: a Cardiac Stem Cell Disease?

Author

Prezioso, L., Tanzi, S., Galaverna, F., Frati, C., Testa, B., Savi, M., Graiani, G., Lagrasta, C., Cavalli, S., Galati, S., Madeddu, D., Rizzini, E. Lodi, Ferraro, F., Musso, E., Stilli, D., Urbanek, K., Piegari, E., De Angelis, A., Maseri, A., Rossi, F., Quaini, E., and Quaini, F.

Published
2010

11. Abstract

Author

Andries, L. J., Sys, S. U., Meulemans, A. L., Schuurkes, J. A. J., Vanheel, B., Van de Voorde, J., De Smet, P., Li, J., Van Driessche, W., Flamion, B., Foulon, S., Abramow, M., Calders, P., Eechaute, W., Lacroix, E., Weyne, I., Hoeben, D., Burvenich, C., Fransen, P., Andries, L. J., Van Bedaf, D., Demolder, M., Sys, S. U., Ouedraogo, R., Lebrun, P., Herchuelz, A., Antoine, M. -H., Vandenput, S., Votion, D., Anciaux, N., Duvivier, D. H., Art, T., Lekeux, P., Votion, D., Ghafir, Y., Vandenput, S., Art, T., Lekeux, P., Geurts, M., Hermans, E., Maloteaux, J. -M., Perrad, B., Noel, B., Lagache, F., Bister, J. L., Paquay, R., Bister, J. L., Derycke, G., Vandermeir, M. A., Paquay, R., de Brouwer, S., Porret, C. -A., Stergiopulos, N., Meister, J. -J., Verbeke, M., Van de Voorde, J., Lameire, N., De Clerck, N. M., De Schuytter, J., Tytgato, J., Buyse, G., Eggermont, J., Droogmans, G., Nilius, B., Daenens, P., Salomone, S., Feron, O., Dessy, C., Morel, N., Godfraind, T., Aloisi, A. M., Sacerdote, P., Lodi, L., Carli, G., Carobi, C., Garinei, G., Miniaci, U. C., Scotto, P., Sabatino, M., Sardo, P., Iurato, L., La Grutta, V., Bagni, M. A., Cecchi, G., Cecchini, E., Colomo, F., Garzella, P., Bottinelli, R., Harridge, S. D. H., Canepari, M., Reggiani, C., Reggiani, Saltin, Bambagioni, D., Fanò, G., Menchetti, G,, Danieli-Betto, P., Esposito, A., Betto, R., Megighian, A., Midrio, M., Betto, D. Danieli, Esposito, A., Megighian, A., Midrio, M., Orizio, C., Liberati, D., Locatelli, C., De Grandis, D., Veicsteinas, A., Angoli, D., Delia, D., Wanke, E., Bramucci, M., Miano, A., Quassinti, L., Maccari, E., Murri, O., Amici, D., Cibelli, G., Jüngling, S., Schoch, S., Gerdest, H. H., Thiel, G., Demori, I., Bottazzi, C., Voci, A., Fugassa, E., Barreca, A., Minuto, F., Gallo, G., Fulle, S., Belia, S., Menchetti, G., Cacchio, M., Fanò, G., Gastaldi, G., Laforenza, U., Ferrari, G., Rindi, G., Doni, M. G., Padoin, E., Residori, O., Cesaro, M., Toma, L., Rubini, A., Mutinelli, F, Paulesu, L., Romagnolie, R., Cintorino, M., Pippia, P., Meloni, M. A., Sciola, L., Spano, A., Cogoli-Greuter, M., Cogoli, A., Sardini, A., Mintenig, G. M., Valverde, M. A., Sepùlveda, F. V., Gill, D. R., Hyde, S. C., Higgins, C. F., McNaughton, P. A., Spena, A., Arcuri, M. T., Bonofiglio, S., Chimenti, R., Covello, C., De Cicco, T., Mazzulla, S., Martino, G., Tottene, A., Moretti, A., Pietrobon, D., Baccari, M. C., Calamai, F., Staderini, G., Cova, E., Marelli, R., Sommi, P., Ventura, U., Lombardi, A. M., Fabris, R., Pagano, C., Federspil, G., Vettor, R., Mancinelli, R., Tonali, P., Servidei, S., Romani, R., Tringali, A., Azzena, G. B., Mulè, F., Serio, R., Postorino, A., Pagano, C., Rizzato, M., Granzotto, M., Lombardi, A. M., Fabris, R., Vettor, R., Federspil, G., Sommi, P., Ricci, V., Romano, M., Ivey, K. J., Ventura, U., Vacca, G., Papillo, B., Mary, D. A. S. G., Battaglia, A., Grossini, E., Vacca, G., Papillo, B., Battaglia, A., Grossini, E., Accili, E. A., Redaelli, G., DiFrancesco, D., Antoniotti, S., Distasi, C., Lovisolo, D., Munaron, L., Bertaso, F., Assandri, R., Mazzanti, M., Bianchi, L., Arcangeli, A., Faravelli, L., Becchetti, A., Coronello, M., Mini, E., Francini, F., Olivotto, M., Wanke, E., Bigiani, A., Kim, D. -J., Roper, S. D., Carabelli, V., Lovallo, M., Magnelli, V., Zucker, H., Carbone, E., D’Angelo, E., Rossi, P., De Filippi, G., Taglietti, V., Faravelli, L., Bianchi, L., Arcangeli, A., Francini, F., Olivotto, M., Wanke, E., Francini, F., Bencini, C., Squecco, R., Guatteo, E., Bacci, A., Franceschetti, S., Avanzini, G., Wanke, E., Magnelli, V., Carbone, E., Mazzanti, M., Assandri, R., Ferroni, A., DiFrancesco, D., Navangione, A., Vellani, V., Rispoli, G., Peres, A., Centinaio, E., Giovannardi, S., Russo, G., Marcotti, W., Prigioni, I., Trequattrini, C., Harper, A. A., Petris, A., Franciolini, F., Zaza, A., Micheletti, M., Brioschi, A., Antonutto, G., Capelli, C., Girardis, M., Zamparo, P., di Prampero, P. E., Antonutto, G., Girardis, M., Tuniz, D., di Prampero, P. E., Filippi, G. M., Troiani, D., Grassi, B., Poole, D. C., Richardson, R. S., Knight, D. R., Erickson, B. K., Wagner, P. D., Aimi, B., Stilli, D., Gallo, P., Sgoifo, A., Lagrasta, C., Olivetti, G., Reali, N., Casti, A., Musso, E., Alloatti, G., Penna, C., Gallo, M. P., Levi, R. C., Fenoglio, I., Appendino, G., Gallo, P., Sgoifo, A., Medici, D., Aimi, B., Manghi, M., Stilli, D., Musso, E., Sgoifo, A., Pasini, E., Gallo, P., Aimi, B., Stilli, D., Ceconi, C., Musso, E., Baldissera, F., Cavallari, P., Locatelli, M., Bartesaghi, R., Gessi, T., Benfenati, F., Valtorta, F., Onofri, F., Poo, M., Greengard, P., Biagini, G., Sala, D., Viani§, P., Kozlov, A. V., Zini, I., Bravin, M., Tempia, F., Strata, P., Brescia, G., Di Benedetto, C., Corsi, P., Cangiano, G., Buttiglione, M., Ambrosini, M., Gennarini, G., Casadio, A., Levi, R. C., Montarolo, P. G., Cesare, P., Stoughton, R., McNaughton, P. A., D’Arcangelo, G., Dodt, H. U., Brancati, A., Zieglgänsberger, W., Errico, P., Ferraresi, A., Barmack, N. H., Pettorossi, V. E., Gasparini, S., D’Ambrosio, R., Janigro, D., DiFrancesco, D., Gritti, I., Marintti, M., Calcaterra, R., Freddi, R., Mancia, M., Imeri, I., Bianchi, S., Mancia, M., Lui, F., Gregory, K. M., Blanks, R. H. I., Giolli, R. A., Benassi, C., Corazza, R., Magherini, P. C., Bardoni, R., Belluzzi, O., Mancinelli, R., Manni, E., Azzena, G. B., Tringali, A., Romani, R., Diana, M., Fratta, W., Manzoni, D., Andre, P., Pompeiano, O., Mazzocchio, R., Rossi, A., Melis, F., Kitura, A., Caria, M. A., Asanuma, H., Melone, M, De Biasi, S, Minelli, A, Conti, F, Minelli, A, Karschin, C, DeBiasi, S, Brecha, N C, Conti, F, Monda, M., Amaro, S., Sullo, A., De Luca, B., Monda, M., Amaro, S., Sullo, A., De Luca, B., Pantò, M. R., Cicirata, F., Parenti, R., Serapide, M. F., Parenti, R., Wassef, M., Cicirata, F., Podda, M. V., Solinas, A., Chessa, G., Deriu, F., Mameli, O., Tolu, E., Pompeiano, O., Andre, P., Manzoni, D., Porro, C. A., Francescato, M. P., Cettolo, V., Diamond, M. E., Baraldi, P., Bazzocchi, M., Rivosecchi, R., Konnerth, A., Rossi, M. L., Martini, M., Pelucchi, B., Fesce, R., Santarelli, L., Schacher, S., Montarolo, P. G., Santarelli, R., Grassi, C., Valente, A., Nisticò, S., Bagetta, G., Azzena, G. B., Scuri, Rossana, Garcia-Gil, Mercedes, Mozzachiodi, Riccardo, Brunelli, Marcello, Stefani, G., Onofri, F., Vaccaro, P., Nielander, H. B., Benfenati, F., Tancredi, V., D’Antuono, M., Siniscalchi, A., Brancati, A., Avoli, M., Vellani, V., Navangione, A., Rispoli, G., Verzè, L., Buffo, A., Rossi, F., Oestreicher, A. B., Gispen, W. H., Strata, P., Zamboni, G., Amici, R., Jones, C. A., Perez, E., Domeniconi, R., Parmeggiani, P. L., Zoli, Michele, Le Novàre, Nicolas, Changeux, Jean -Pierre, Lafortuna, C. L., Reinach, E., Saibene, F., Scotto, P., Zocchi, L., Agostoni, E., and Cremaschi, D.

Published
1996
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15. Differentially regulated high-throughput CT imaging features correlate to distinct tumor immune contextures portraying a radiomic signature with prognostic impact on surgically resected NSCLC

Author

Mazzaschi, G., primary, Quaini, F., additional, Milanese, G., additional, Madeddu, D., additional, Bocchialini, G., additional, Ampollini, L., additional, Gnetti, L., additional, Lagrasta, C., additional, Silva, M., additional, Roti, G., additional, Sverzellati, N., additional, and Tiseo, M., additional

Published
2019
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16. BLOOD AND LYMPHATIC VESSELS CONSTITUTE AN ESSENTIAL COMPONENT OF THE IMMUNE MICROENVIRONMENT AND ITS IMPACT ON NON SMALL CELL LUNG CANCER (NSCLC) CLINICAL OUTCOME

Author

QUAINI, Federico, Armani, G., MADEDDU, Denise, MAZZASCHI, GIULIA, BOCCHIALINI, GIOVANNI, SOGNI, FRANCESCO, FRATI, Caterina, URBANEK, KONRAD ARKADIUSZ, LORUSSO, BRUNO, FALCO, Angela, Lagrasta, C. A., Quaini, E., Carbognani, P., AMPOLLINI, Luca, Quaini, Federico, Armani, G., Madeddu, Denise, Mazzaschi, Giulia, Bocchialini, Giovanni, Sogni, Francesco, Frati, Caterina, Urbanek, KONRAD ARKADIUSZ, Lorusso, Bruno, Falco, Angela, Lagrasta, C. A., Quaini, E., Carbognani, P., and Ampollini, Luca

Published
2017

17. Advanced CT imaging features reflect distinct tissue immune profiles and exhibit high prognostic impact on NSCLC

Author

Mazzaschi, G., primary, Pagano, P., additional, Milanese, G., additional, Madeddu, D., additional, Falco, A., additional, Armani, G., additional, Bocchialini, G., additional, Marturano, D., additional, Ampollini, L., additional, Lorusso, B., additional, Lagrasta, C., additional, Sverzellati, N., additional, Silva, M., additional, Tiseo, M., additional, Quaini, F., additional, and Roti, G., additional

Published
2018
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19. Notch Activation Modulates Bevacizumab Activity by CD44 Positive Cancer Stem Cells in Advanced Colon Cancer

Author

Giuseppe Pedrazzi, Cinzia Azzoni, Lorena Bottarelli, Rosa Porzio, Francesca Negri, Andrea Gervasi, I. Tamagnini, Cecilia Bozzetti, L. Gnetti, Stefano Cascinu, Pellegrino Crafa, Francesco Leonardi, Lagrasta C, Anna Squadrilli, A. Ardizzoni, Angela Falco, F. Quaini, Gianluca Tomasello, Roberto Sala, A. Bisagni, Denise Madeddu, and Ragazzi M

Subjects
CD31, biology, Bevacizumab, Colorectal cancer, Angiogenesis, business.industry, CD44, Notch signaling pathway, medicine.disease, Cancer stem cell, medicine, biology.protein, Cancer research, Stem cell, business, medicine.drug
Abstract

Background: Notch pathway is involved in regulating colon cancer stem cells (CSCs), which play an important role in angiogenesis and resistance to conventional therapies. CD44 and CD133 are transmembrane glycoproteins reported as putative markers for isolating CSCs. High expression of Notch Intracellular Cleaved Domain (NICD) has been associated with resistance to anti-vascular endothelial growth factor therapy. Based on these reports, we evaluated NICD, CD44 and CD133 expression in a series of consecutive metastatic colon cancer patients treated with bevacizumab-based chemotherapy within first-line clinical trials. Methods: Histological samples obtained from 45 primary adenocarcinomas were tested by immunohistochemistry for NICD, CD44 and CD133. A scoring system based on staining intensity and percentage of stained cells was used. Vessels density was measured in hot-spot areas by CD31 antibody. Results: CD44 levels were higher in high NICD cases than in low NICD cases (63% vs. 16%, respectively, p=0.014). High NICD and CD44 levels predicted shorter progression-free (p

Published
2017
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20. Divergent PD-1 expression in tissue and circulating CD8 lymphocytes defines an immune profile predictive of the response to nivolumab in advanced NSCLC

Author

Mazzaschi, G., primary, Madeddu, D., additional, Veneziani, M., additional, Sogni, F., additional, Armani, G., additional, Frati, C., additional, Lagrasta, C., additional, Falco, A., additional, Lorusso, B., additional, Vilella, R., additional, Mangiaracina, C., additional, Bocchialini, G., additional, Silini, E.M., additional, Facchinetti, F., additional, Ardizzoni, A., additional, Missale, G., additional, Tiseo, M., additional, and Quaini, F., additional

Published
2017
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21. F-066BLOOD AND LYMPHATIC VESSELS CONSTITUTE AN ESSENTIAL COMPONENT OF THE IMMUNE MICROENVIRONMENT AND ITS IMPACT ON NON-SMALL CELL LUNG CANCER CLINICAL OUTCOME

Author

Quaini, Federico, primary, Armani, G, additional, Madeddu, D, additional, Mazzaschi, G, additional, Bocchialini, G, additional, Sogni, F, additional, Frati, C, additional, Urbanek, K, additional, Lorusso, B, additional, Falco, A, additional, Lagrasta, C A, additional, Quaini, E, additional, Carbognani, P, additional, and Ampollini, L, additional

Published
2017
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28. In vitro biological and functional properties of human endothelial cells from different sources exposed to different beta-blockers

Author

Lorusso, B., primary, Madeddu, D., additional, Falco, A., additional, Gervasi, A., additional, Frati, C., additional, Manni, S., additional, Rinaldi, L., additional, Nannetti, A., additional, Spigoni, V., additional, Pilato, F.P., additional, Gnetti, L., additional, Lagrasta, C., additional, Frusca, T., additional, Cerasoli, G., additional, and Quaini, F., additional

Published
2015
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35. Involvement of HER-2/neu and metastasis-related proteins in the development of ileal neuroendocrine tumors

Author

Azzoni, C, Bottarelli, L, Cecchini, S, Lagrasta, C, Pizzi, S, D'Adda, T, Tamburini, E, Rindi, Guido, Bordi, C., Rindi, Guido (ORCID:0000-0003-2996-4404), Azzoni, C, Bottarelli, L, Cecchini, S, Lagrasta, C, Pizzi, S, D'Adda, T, Tamburini, E, Rindi, Guido, Bordi, C., and Rindi, Guido (ORCID:0000-0003-2996-4404)

Abstract

HER-2/neu overexpression and/or gene amplification occurs in several human malignancies, frequently correlates with tumor aggressiveness, and provides the basis for treatment with trastuzumab. Among neuroendocrine neoplasms (NEN) of the gastroenteropancreatic (GEP) tract, ileal neuroendocrine tumors show peculiar features of malignancy with frequent metastases at the diagnosis. We investigated the overexpression and/or amplification of HER-2/neu and the involvement of the metastasis-related proteins c-Met, MTA-1, and VEGF in 24 primary ileal NEN by immunohistochemistry and fluorescence in situ hybridization (FISH). Data were compared with those of 43 GEP endocrine tumors of other sites. All primary ileal NEN showed an intense membranous and cytoplasmic immunostaining for HER-2/neu. According to the breast cancer scoring system, 17% of ileal carcinoids showed a score of 3+ and 71% with a score of 2+ with a significant difference respect the non-ileal GEP endocrine tumors (p < 0.0000). FISH analysis revealed chromosome 17 polysomy in 33% of 2+/3+ ileal tumors but not HER-2/neu gene amplification. The c-Met and MTA-1 but not VEGF were overexpressed in almost all ileal NEN, whereas VEGF presented more frequently a normal staining. The comparisons with the other GEP NEN demonstrated significant differences for all the three proteins (p < 0.0000, p < 0.0002, and p < 0.001, respectively). These findings suggest that in ileal NEN, HER-2/neu overexpression plays a role in the carcinogenetic process and by triggering the altered expression of c-Met and MTA-1, may activate the molecular pathway(s) promoting tumor progression and metastasis development. Ileal HER-2/neu overexpressing neuroendrocrine tumors may constitute potential candidates for target therapy with specific humanized monoclonal antibodies.

Published
2011

41. Myocyte cellular hypertrophy and hyperplasia contribute to ventricular wall remodeling in anemia-induced cardiac hypertrophy in rats

Author

Olivetti, G., Quaini, F., Lagrasta, C., Ricci, R., Tiberti, G., Capasso, J. M., and Anversa, P.

Subjects
Male, Hyperplasia, Myocardium, Hemodynamics, Anemia, Blood Pressure, Cardiomegaly, Cell Count, Rats, Inbred Strains, Hypertrophy, Organ Size, Rats, Microscopy, Electron, Animals, Research Article
Abstract

To determine the effects of chronic anemia on the functional and structural characteristics of the heart, 1-month-old male rats were fed a diet deficient in iron and copper, which led to a hemoglobin concentration of 4.63 g/dl, for 8 weeks. At sacrifice, under fentanyl citrate and droperidol anesthesia, systolic, diastolic, and mean arterial blood pressures were decreased, whereas differential pressure was increased. Left ventricular systolic pressure and the ventricular rate of pressure rise (mmHg/s) were reduced by 9% and 14%, respectively. Moreover, developed peak systolic ventricular pressure and maximal dP/dt diminished 14% and 12%. After perfusion fixation of the coronary vasculature and the myocardium, at a left ventricular intracavitary pressure equal to the in vivo measured end diastolic pressure, a 10% thickening of the left ventricular wall was measured in association with a 13% increase in the equatorial cavitary diameter and a 44% augmentation in ventricular mass. The 52% hypertrophy of the right ventricle was characterized by an 11% thicker wall and a 37% larger ventricular area. The 33% expansion in the aggregate myocyte volume of the left ventricle was found to be due to a 14% myocyte cellular hypertrophy and a 17% myocyte cellular hyperplasia. These cellular parameters were calculated from the estimation of the number of myocyte nuclei per unit volume of myocardium in situ and the evaluation of the distribution of nuclei per cell in enzymatically dissociated myocytes. Myocyte cellular hyperplasia provoked a 9% increase in the absolute number of cells across the left ventricular wall. In contrast, myocyte cellular hypertrophy (42%) was responsible for the increase in myocyte volume of the right ventricle. The proliferative response of left ventricular myocytes was not capable of restoring diastolic cell stress, which was enhanced by the changes in ventricular anatomy with anemia. In conclusion, chronic anemia induced an unbalanced load on the left ventricle, which evoked a hyperplastic reaction of preexisting myocytes, in an attempt to normalize diastolic wall and myocyte stress.

Published
1992

43. Enalapril prevents cardiac fibrosis and arrhythmias in hypertensive rats

Author

Pahor, M, Bernabei, Roberto, Gambassi, Giovanni, Sgadari, Antonio, Lo Giudice, P, Pacifici, L, Ramacci, Mt, Lagrasta, C, Olivetti, G, Carbonin, Pierugo, Bernabei, Roberto (ORCID:0000-0002-9197-004X), Gambassi, Giovanni (ORCID:0000-0002-7030-9359), Sgadari, Antonio (ORCID:0000-0002-8296-043X), Pahor, M, Bernabei, Roberto, Gambassi, Giovanni, Sgadari, Antonio, Lo Giudice, P, Pacifici, L, Ramacci, Mt, Lagrasta, C, Olivetti, G, Carbonin, Pierugo, Bernabei, Roberto (ORCID:0000-0002-9197-004X), Gambassi, Giovanni (ORCID:0000-0002-7030-9359), and Sgadari, Antonio (ORCID:0000-0002-8296-043X)

Abstract

To evaluate the effects of hypertension on cardiac hypertrophy, on myocardial structure, and on ventricular arrhythmias, 27 3-month-old spontaneously hypertensive rats were treated with enalapril (10 mg/kg) daily for 11 months and compared with 26 untreated control rats. Systolic arterial pressure was significantly decreased in treated rats, and at the end of the experiment, it was 199 +/- 3 mm Hg (treated) versus 237 +/- 3 mm Hg (controls) (p less than 0.001). At this time, spontaneous arrhythmias and induced arrhythmias either by programmed electrical stimulation (train of stimuli +1 or 2 extrastimuli) or by trains of eight stimuli at decreasing coupling intervals were observed in isolated heart preparations. Comparing enalapril-treated and control rats, spontaneous arrhythmias (9 of 27 versus 20 of 26, respectively; p less than 0.01), programmed stimulation-induced arrhythmias (3 of 26 versus 12 of 23, respectively; p less than 0.01), and trains of stimuli-induced arrhythmias (4 of 26 versus 14 of 19, respectively, p less than 0.001) were less frequent in the enalapril group. Left ventricular weight was decreased in treated rats by 18% (p less than 0.001). Enalapril administration diminished the fraction of myocardium occupied by foci of replacement fibrosis normally occurring in control rats by 59% (p less than 0.001). Finally, a significant correlation was found between left ventricular weight, the extent of myocardial fibrosis, and the occurrence of ventricular fibrillation. It was concluded that chronic treatment with enalapril, which resulted in attenuation of systemic arterial pressure by limiting cardiac hypertrophy and myocardial fibrosis, decreases the propensity of the heart of hypertensive rats to arrhythmogenesis.

Published
1991

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