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1. BRAFV600E mutation impinges on gut microbial markers defining novel biomarkers for serrated colorectal cancer effective therapies

Author

Trivieri, N, Pracella, R, Cariglia, M, Panebianco, C, Parrella, P, Visioli, A, Giani, F, Soriano, A, Barile, C, Canistro, G, Latiano, T, Dimitri, L, Bazzocchi, F, Cassano, D, Vescovi, A, Pazienza, V, Binda, E, Trivieri N., Pracella R., Cariglia M. G., Panebianco C., Parrella P., Visioli A., Giani F., Soriano A. A., Barile C., Canistro G., Latiano T. P., Dimitri L., Bazzocchi F., Cassano D., Vescovi A. L., Pazienza V., Binda E., Trivieri, N, Pracella, R, Cariglia, M, Panebianco, C, Parrella, P, Visioli, A, Giani, F, Soriano, A, Barile, C, Canistro, G, Latiano, T, Dimitri, L, Bazzocchi, F, Cassano, D, Vescovi, A, Pazienza, V, Binda, E, Trivieri N., Pracella R., Cariglia M. G., Panebianco C., Parrella P., Visioli A., Giani F., Soriano A. A., Barile C., Canistro G., Latiano T. P., Dimitri L., Bazzocchi F., Cassano D., Vescovi A. L., Pazienza V., and Binda E.

Abstract

Background: Colorectal cancer (CRC) harboring BRAFV600E mutation exhibits low response to conventional therapy and poorest prognosis. Due to the emerging correlation between gut microbiota and CRC carcinogenesis, we investigated in serrated BRAFV600E cases the existence of a peculiar fecal microbial fingerprint and specific bacterial markers, which might represent a tool for the development of more effective clinical strategies. Methods: By injecting human CRC stem-like cells isolated from BRAFV600E patients in immunocompromised mice, we described a new xenogeneic model of this subtype of CRC. By performing bacterial 16S rRNA sequencing, the fecal microbiota profile was then investigated either in CRC-carrying mice or in a cohort of human CRC subjects. The microbial communities’ functional profile was also predicted. Data were compared with Mann-Whitney U, Welch’s t-test for unequal variances and Kruskal-Wallis test with Benjamini–Hochberg false discovery rate (FDR) correction, extracted as potential BRAF class biomarkers and selected as model features. The obtained mean test prediction scores were subjected to Receiver Operating characteristic (ROC) analysis. To discriminate the BRAF status, a Random Forest classifier (RF) was employed. Results: A specific microbial signature distinctive for BRAF status emerged, being the BRAF-mutated cases closer to healthy controls than BRAF wild-type counterpart. In agreement, a considerable score of correlation was also pointed out between bacteria abundance from BRAF-mutated cases and the level of markers distinctive of BRAFV600E pathway, including those involved in inflammation, innate immune response and epithelial-mesenchymal transition. We provide evidence that two candidate bacterial markers, Prevotella enoeca and Ruthenibacterium lactatiformans, more abundant in BRAFV600E and BRAF wild-type subjects respectively, emerged as single factors with the best performance in distinguishing BRAF status (AUROC = 0.72 and 0.74, res

Published
2020

2. Assessment of neurological manifestations in hospitalized patients with COVID-19

Author

Luigetti, Marco, Iorio, Raffaele, Bentivoglio, Anna Rita, Tricoli, Luca, Riso, Vittorio, Marotta, Jessica, Piano, Carla, Primiano, Guido Alessandro, Zileri Del Verme, L., Lo Monaco, Maria Rita, Calabresi, Paolo, Abbate, V., Acampora, N., Addolorato, G., Agostini, F., Ainora, M. E., Akacha, K., Amato, E., Andreani, F., Andriollo, G., Annetta, Maria Giuseppina, Annicchiarico, B. E., Antonelli, Massimo, Antonucci, G., Anzellotti, G. M., Armuzzi, A., Baldi, F., Barattucci, I., Barillaro, C., Barone, F., Bellantone, R. D. A., Bellieni, A., Bello, G., Benicchi, A., Benvenuto, F., Berardini, L., Berloco, F., Bernabei, R., Bianchi, A., Biasucci, D. G., Biasucci, L. M., Bibbo, S., Bini, A., Bisanti, A., Biscetti, F., Bocci, M. G., Bonadia, N., Bongiovanni, F., Borghetti, A., Bosco, G., Bosello, Silvia Laura, Bove, V., Bramato, G., Brandi, V., Bruni, T., Bruno, C., Bruno, D., Bungaro, M. C., Buonomo, A., Burzo, L., Calabrese, A., Calvello, M. R., Cambieri, A., Cambise, C., Camma, G., Candelli, M., Canistro, G., Cantanale, A., Capalbo, G., Capaldi, L., Capone, E., Capristo, E., Carbone, L., Cardone, S., Carelli, S., Carfi, A., Carnicelli, A., Caruso, C., Casciaro, F. A., Catalano, L., Cauda, R., Cecchini, A. L., Cerrito, L., Cesarano, M., Chiarito, A., Cianci, Rossella, Cicchinelli, S., Ciccullo, A., Cicetti, M., Ciciarello, F., Cingolani, A., Cipriani, M. C., Consalvo, M. L., Coppola, G., Corbo, G. M., Corsello, A., Costante, F., Costanzi, M., Covino, M., Crupi, D., Cutuli, S. L., D'Addio, S., D'Alessandro, A., D'Alfonso, M. E., D'Angelo, E., D'Aversa, F., Damiano, F., De Berardinis, G. M., De Cunzo, T., De Gaetano, D. K., De Luca, G., De Matteis, G., De Pascale, G., De Santis, P., De Siena, M., De Vito, F., Del Gatto, V., Del Giacomo, P., Del Zompo, F., Dell'Anna, A. M., Della, P. D., Di Gialleonardo, L., Di Giambenedetto, S., Di Luca, R., Di Maurizio, L., Di Muro, M., Dusina, A., Eleuteri, D., Esperide, A., Fachechi, D., Faliero, D., Falsiroli, C., Fantoni, M., Fedele, A., Feliciani, D., Ferrante, C., Ferrone, G., Festa, R., Fiore, M. C., Flex, A., Forte, E., Franceschi, Francesco, Francesconi, A., Franza, L., Funaro, B., Fuorlo, M., Fusco, D., Gabrielli, M., Gaetani, E., Galletta, C., Gallo, A., Gambassi, G., Garcovich, M., Gasbarrini, A., Gasparrini, I., Gelli, S., Giampietro, A., Gigante, L., Giuliano, G., Giupponi, B., Gremese, E., Grieco, Domenico Luca, Guerrera, M., Guglielmi, V., Guidone, C., Gulli, A., Iaconelli, A., Iafrati, A., Ianiro, Gianluca, Iaquinta, A., Impagnatiello, M., Inchingolo, R., Intini, E., Iorio, R., Izzi, I. M., Jovanovic, T., Kadhim, C., La Macchia, R., La Milia, D. I., Landi, F., Landi, G., Landi, R., Landolfi, R., Leo, M., Leone, P. M., Levantesi, L., Liguori, A., Liperoti, R., Lizzio, M. M., Lo Monaco Maria, R., Locantore, P., Lombardi, F., Lombardi, G., Lopetuso, L., Loria, V., Losito, A. R., Lucia, M. B. P., Macagno, F., Macerola, N., Maggi, G., Maiuro, G., Mancarella, F., Mangiola, F., Manno, A., Marchesini, D., Maresca, G. M., Marrone, G., Martis, I., Martone, A. M., Marzetti, Emanuele, Mattana, C., Matteo, M. V., Maviglia, R., Mazzarella, A., Memoli, C., Miele, Luca, Migneco, A., Mignini, I., Milani, A., Milardi, D., Montalto, M., Montemurro, G., Monti, F., Montini, Luca, Morena, T. C., Morra, V., Morretta, C., Moschese, D., Murace, C. A., Murdolo, M., Murri, Rita, Napoli, M., Nardella, E., Natalello, G., Natalini, D., Navarra, S. M., Nesci, A., Nicoletti, A., Nicoletti, R., Nicoletti, T. F., Nicolo, R., Nicolotti, N., Nista, E. C., Nuzzo, E., Oggiano, M., Ojetti, V., Pagano, F. C., Paiano, G., Pais, C., Pallavicini, F., Palombo, A., Paolillo, F., Papa, Alfredo, Papanice, D., Papparella, L. G., Paratore, M., Parrinello, G., Pasciuto, G., Pasculli, P., Pecorini, G., Perniola, S., Pero, E., Petricca, L., Petrucci, M., Picarelli, C., Piccioni, A., Piccolo, A., Piervincenzi, E., Pignataro, G., Pignataro, R., Pintaudi, G., Pisapia, L., Pizzoferrato, M., Pizzolante, F., Pola, R., Policola, C., Pompili, M., Pontecorvi, F., Pontecorvi, V., Ponziani, F., Popolla, V., Porceddu, E., Porfidia, A., Porro, L. M., Potenza, A., Pozzana, F., Privitera, G., Pugliese, D., Pulcini, G., Racco, S., Raffaelli, F., Ramunno, V., Rapaccini, G. L., Richeldi, Luca, Rinninella, Emanuele, Rocchi, S., Romano, B., Romano, S., Rosa, F., Rossi, L., Rossi, R., Rossini, E., Rota, E., Rovedi, F., Rubino, C., Rumi, G., Russo, A., Sabia, L., Salerno, A., Salini, S., Salvatore, L., Samori, D., Sandroni, Claudio, Sanguinetti, M., Santarelli, L., Santini, P., Santolamazza, D., Santoliquido, A., Santopaolo, F., Santoro, M. C., Sardeo, F., Sarnari, C., Saviano, A., Saviano, L., Scaldaferri, Franco, Scarascia, R., Schepis, T., Schiavello, F., Scoppettuolo, G., Sedda, D., Sessa, F., Sestito, L., Settanni, C., Siciliano, M., Siciliano, V., Sicuranza, R., Simeoni, B., Simonetti, J., Smargiassi, A., Soave, P. M., Sonnino, C., Staiti, D., Stella, C., Stella, L., Stival, E., Taddei, E., Talerico, R., Tamburello, E., Tamburrini, E., Tanzarella, E. S., Tarascio, E., Tarli, C., Tersali, A., Tilli, P., Timpano, J., Torelli, E., Torrini, F., Tosato, M., Tosoni, A., Tricoli, L., Tritto, M., Tumbarello, M., Tummolo, A. M., Vallecoccia, M. S., Valletta, F., Varone, F., Vassalli, F., Ventura, G., Verardi, L., Vetrone, L., Vetrugno, G., Visconti, E., Visconti, F., Viviani, A., Zaccaria, R., Zaccone, C., Zelano, L., Zileri Dal Verme, L., Zuccala, G., Luigetti M. (ORCID:0000-0001-7539-505X), Iorio R. (ORCID:0000-0002-6270-0956), Bentivoglio A. R. (ORCID:0000-0002-9663-095X), Tricoli L., Riso V., Marotta J., Piano C., Primiano G., Lo Monaco M. R. (ORCID:0000-0002-1457-7981), Calabresi P. (ORCID:0000-0003-0326-5509), Annetta M. G. (ORCID:0000-0001-7574-1311), Antonelli M. (ORCID:0000-0003-3007-1670), Bosello S. (ORCID:0000-0002-4837-447X), Cianci R. (ORCID:0000-0001-5378-8442), Franceschi F. (ORCID:0000-0001-6266-445X), Grieco D. L. (ORCID:0000-0002-4557-6308), Ianiro G. (ORCID:0000-0002-8318-0515), Marzetti E. (ORCID:0000-0001-9567-6983), Miele L. (ORCID:0000-0003-3464-0068), Montini L. (ORCID:0000-0003-4602-5134), Murri R. (ORCID:0000-0003-4263-7854), Papa A. (ORCID:0000-0002-4186-7298), Richeldi L. (ORCID:0000-0001-8594-1448), Rinninella E. (ORCID:0000-0002-9165-2367), Sandroni C. (ORCID:0000-0002-8878-2611), Scaldaferri F. (ORCID:0000-0001-8334-7541), Luigetti, Marco, Iorio, Raffaele, Bentivoglio, Anna Rita, Tricoli, Luca, Riso, Vittorio, Marotta, Jessica, Piano, Carla, Primiano, Guido Alessandro, Zileri Del Verme, L., Lo Monaco, Maria Rita, Calabresi, Paolo, Abbate, V., Acampora, N., Addolorato, G., Agostini, F., Ainora, M. E., Akacha, K., Amato, E., Andreani, F., Andriollo, G., Annetta, Maria Giuseppina, Annicchiarico, B. E., Antonelli, Massimo, Antonucci, G., Anzellotti, G. M., Armuzzi, A., Baldi, F., Barattucci, I., Barillaro, C., Barone, F., Bellantone, R. D. A., Bellieni, A., Bello, G., Benicchi, A., Benvenuto, F., Berardini, L., Berloco, F., Bernabei, R., Bianchi, A., Biasucci, D. G., Biasucci, L. M., Bibbo, S., Bini, A., Bisanti, A., Biscetti, F., Bocci, M. G., Bonadia, N., Bongiovanni, F., Borghetti, A., Bosco, G., Bosello, Silvia Laura, Bove, V., Bramato, G., Brandi, V., Bruni, T., Bruno, C., Bruno, D., Bungaro, M. C., Buonomo, A., Burzo, L., Calabrese, A., Calvello, M. R., Cambieri, A., Cambise, C., Camma, G., Candelli, M., Canistro, G., Cantanale, A., Capalbo, G., Capaldi, L., Capone, E., Capristo, E., Carbone, L., Cardone, S., Carelli, S., Carfi, A., Carnicelli, A., Caruso, C., Casciaro, F. A., Catalano, L., Cauda, R., Cecchini, A. L., Cerrito, L., Cesarano, M., Chiarito, A., Cianci, Rossella, Cicchinelli, S., Ciccullo, A., Cicetti, M., Ciciarello, F., Cingolani, A., Cipriani, M. C., Consalvo, M. L., Coppola, G., Corbo, G. M., Corsello, A., Costante, F., Costanzi, M., Covino, M., Crupi, D., Cutuli, S. L., D'Addio, S., D'Alessandro, A., D'Alfonso, M. E., D'Angelo, E., D'Aversa, F., Damiano, F., De Berardinis, G. M., De Cunzo, T., De Gaetano, D. K., De Luca, G., De Matteis, G., De Pascale, G., De Santis, P., De Siena, M., De Vito, F., Del Gatto, V., Del Giacomo, P., Del Zompo, F., Dell'Anna, A. M., Della, P. D., Di Gialleonardo, L., Di Giambenedetto, S., Di Luca, R., Di Maurizio, L., Di Muro, M., Dusina, A., Eleuteri, D., Esperide, A., Fachechi, D., Faliero, D., Falsiroli, C., Fantoni, M., Fedele, A., Feliciani, D., Ferrante, C., Ferrone, G., Festa, R., Fiore, M. C., Flex, A., Forte, E., Franceschi, Francesco, Francesconi, A., Franza, L., Funaro, B., Fuorlo, M., Fusco, D., Gabrielli, M., Gaetani, E., Galletta, C., Gallo, A., Gambassi, G., Garcovich, M., Gasbarrini, A., Gasparrini, I., Gelli, S., Giampietro, A., Gigante, L., Giuliano, G., Giupponi, B., Gremese, E., Grieco, Domenico Luca, Guerrera, M., Guglielmi, V., Guidone, C., Gulli, A., Iaconelli, A., Iafrati, A., Ianiro, Gianluca, Iaquinta, A., Impagnatiello, M., Inchingolo, R., Intini, E., Iorio, R., Izzi, I. M., Jovanovic, T., Kadhim, C., La Macchia, R., La Milia, D. I., Landi, F., Landi, G., Landi, R., Landolfi, R., Leo, M., Leone, P. M., Levantesi, L., Liguori, A., Liperoti, R., Lizzio, M. M., Lo Monaco Maria, R., Locantore, P., Lombardi, F., Lombardi, G., Lopetuso, L., Loria, V., Losito, A. R., Lucia, M. B. P., Macagno, F., Macerola, N., Maggi, G., Maiuro, G., Mancarella, F., Mangiola, F., Manno, A., Marchesini, D., Maresca, G. M., Marrone, G., Martis, I., Martone, A. M., Marzetti, Emanuele, Mattana, C., Matteo, M. V., Maviglia, R., Mazzarella, A., Memoli, C., Miele, Luca, Migneco, A., Mignini, I., Milani, A., Milardi, D., Montalto, M., Montemurro, G., Monti, F., Montini, Luca, Morena, T. C., Morra, V., Morretta, C., Moschese, D., Murace, C. A., Murdolo, M., Murri, Rita, Napoli, M., Nardella, E., Natalello, G., Natalini, D., Navarra, S. M., Nesci, A., Nicoletti, A., Nicoletti, R., Nicoletti, T. F., Nicolo, R., Nicolotti, N., Nista, E. C., Nuzzo, E., Oggiano, M., Ojetti, V., Pagano, F. C., Paiano, G., Pais, C., Pallavicini, F., Palombo, A., Paolillo, F., Papa, Alfredo, Papanice, D., Papparella, L. G., Paratore, M., Parrinello, G., Pasciuto, G., Pasculli, P., Pecorini, G., Perniola, S., Pero, E., Petricca, L., Petrucci, M., Picarelli, C., Piccioni, A., Piccolo, A., Piervincenzi, E., Pignataro, G., Pignataro, R., Pintaudi, G., Pisapia, L., Pizzoferrato, M., Pizzolante, F., Pola, R., Policola, C., Pompili, M., Pontecorvi, F., Pontecorvi, V., Ponziani, F., Popolla, V., Porceddu, E., Porfidia, A., Porro, L. M., Potenza, A., Pozzana, F., Privitera, G., Pugliese, D., Pulcini, G., Racco, S., Raffaelli, F., Ramunno, V., Rapaccini, G. L., Richeldi, Luca, Rinninella, Emanuele, Rocchi, S., Romano, B., Romano, S., Rosa, F., Rossi, L., Rossi, R., Rossini, E., Rota, E., Rovedi, F., Rubino, C., Rumi, G., Russo, A., Sabia, L., Salerno, A., Salini, S., Salvatore, L., Samori, D., Sandroni, Claudio, Sanguinetti, M., Santarelli, L., Santini, P., Santolamazza, D., Santoliquido, A., Santopaolo, F., Santoro, M. C., Sardeo, F., Sarnari, C., Saviano, A., Saviano, L., Scaldaferri, Franco, Scarascia, R., Schepis, T., Schiavello, F., Scoppettuolo, G., Sedda, D., Sessa, F., Sestito, L., Settanni, C., Siciliano, M., Siciliano, V., Sicuranza, R., Simeoni, B., Simonetti, J., Smargiassi, A., Soave, P. M., Sonnino, C., Staiti, D., Stella, C., Stella, L., Stival, E., Taddei, E., Talerico, R., Tamburello, E., Tamburrini, E., Tanzarella, E. S., Tarascio, E., Tarli, C., Tersali, A., Tilli, P., Timpano, J., Torelli, E., Torrini, F., Tosato, M., Tosoni, A., Tricoli, L., Tritto, M., Tumbarello, M., Tummolo, A. M., Vallecoccia, M. S., Valletta, F., Varone, F., Vassalli, F., Ventura, G., Verardi, L., Vetrone, L., Vetrugno, G., Visconti, E., Visconti, F., Viviani, A., Zaccaria, R., Zaccone, C., Zelano, L., Zileri Dal Verme, L., Zuccala, G., Luigetti M. (ORCID:0000-0001-7539-505X), Iorio R. (ORCID:0000-0002-6270-0956), Bentivoglio A. R. (ORCID:0000-0002-9663-095X), Tricoli L., Riso V., Marotta J., Piano C., Primiano G., Lo Monaco M. R. (ORCID:0000-0002-1457-7981), Calabresi P. (ORCID:0000-0003-0326-5509), Annetta M. G. (ORCID:0000-0001-7574-1311), Antonelli M. (ORCID:0000-0003-3007-1670), Bosello S. (ORCID:0000-0002-4837-447X), Cianci R. (ORCID:0000-0001-5378-8442), Franceschi F. (ORCID:0000-0001-6266-445X), Grieco D. L. (ORCID:0000-0002-4557-6308), Ianiro G. (ORCID:0000-0002-8318-0515), Marzetti E. (ORCID:0000-0001-9567-6983), Miele L. (ORCID:0000-0003-3464-0068), Montini L. (ORCID:0000-0003-4602-5134), Murri R. (ORCID:0000-0003-4263-7854), Papa A. (ORCID:0000-0002-4186-7298), Richeldi L. (ORCID:0000-0001-8594-1448), Rinninella E. (ORCID:0000-0002-9165-2367), Sandroni C. (ORCID:0000-0002-8878-2611), and Scaldaferri F. (ORCID:0000-0001-8334-7541)

Abstract

Background and purpose: The objective of this study was to assess the neurological manifestations in a series of consecutive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients, comparing their frequency with a population hospitalized in the same period for flu/respiratory symptoms, finally not related to SARS-CoV-2. Methods: Patients with flu/respiratory symptoms admitted to Fondazione Policlinico Gemelli hospital from 14 March 2020 to 20 April 2020 were retrospectively enrolled. The frequency of neurological manifestations of patients with SARS-CoV-2 infection was compared with a control group. Results: In all, 213 patients were found to be positive for SARS-CoV-2, after reverse transcriptase polymerase chain reaction on nasal or throat swabs, whilst 218 patients were found to be negative and were used as a control group. Regarding central nervous system manifestations, in SARS-CoV-2-positive patients a higher frequency of headache, hyposmia and encephalopathy always related to systemic conditions (fever or hypoxia) was observed. Furthermore, muscular involvement was more frequent in SARS-CoV-2 infection. Conclusions: Patients with COVID-19 commonly have neurological manifestations but only hyposmia and muscle involvement seem more frequent compared with other flu diseases.

Published
2020

4. BRAFV600E mutation impinges on gut microbial markers defining novel biomarkers for serrated colorectal cancer effective therapies

Author

Valerio Pazienza, Francesca Bazzocchi, Tiziana Latiano, Angelo L. Vescovi, Concetta Panebianco, Giuseppe Canistro, Dario P. Cassano, Riccardo Pracella, Elena Binda, Alberto Visioli, Maria Grazia Cariglia, Chiara Barile, Fabrizio Giani, Nadia Trivieri, Amata Amy Soriano, Paola Parrella, Lucia Dimitri, Trivieri, N, Pracella, R, Cariglia, M, Panebianco, C, Parrella, P, Visioli, A, Giani, F, Soriano, A, Barile, C, Canistro, G, Latiano, T, Dimitri, L, Bazzocchi, F, Cassano, D, Vescovi, A, Pazienza, V, and Binda, E

Subjects
0301 basic medicine, Oncology, False discovery rate, Cancer Research, medicine.medical_specialty, CRC patient-tailored strategie, endocrine system diseases, Colorectal cancer, CRC biology and biomarkers, CRC non-invasive diagnosi, Gut microbiota, Gut flora, medicine.disease_cause, BRAF V600E CRC non-invasive diagnosis, lcsh:RC254-282, BRAF, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Anti-BRAF, neoplasms, Serrated human BRAF, Serrated human BRAF V600E colorectal carcinoma (CRC), biology, Transition (genetics), Receiver operating characteristic, CRC biology and biomarker, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, biology.organism_classification, medicine.disease, digestive system diseases, 030104 developmental biology, colorectal carcinoma (CRC), Anti-BRAF V600E CRC patient-tailored strategies, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Carcinogenesis, V600E
Abstract

Background Colorectal cancer (CRC) harboring BRAFV600E mutation exhibits low response to conventional therapy and poorest prognosis. Due to the emerging correlation between gut microbiota and CRC carcinogenesis, we investigated in serrated BRAFV600E cases the existence of a peculiar fecal microbial fingerprint and specific bacterial markers, which might represent a tool for the development of more effective clinical strategies. Methods By injecting human CRC stem-like cells isolated from BRAFV600E patients in immunocompromised mice, we described a new xenogeneic model of this subtype of CRC. By performing bacterial 16S rRNA sequencing, the fecal microbiota profile was then investigated either in CRC-carrying mice or in a cohort of human CRC subjects. The microbial communities’ functional profile was also predicted. Data were compared with Mann-Whitney U, Welch’s t-test for unequal variances and Kruskal-Wallis test with Benjamini–Hochberg false discovery rate (FDR) correction, extracted as potential BRAF class biomarkers and selected as model features. The obtained mean test prediction scores were subjected to Receiver Operating characteristic (ROC) analysis. To discriminate the BRAF status, a Random Forest classifier (RF) was employed. Results A specific microbial signature distinctive for BRAF status emerged, being the BRAF-mutated cases closer to healthy controls than BRAF wild-type counterpart. In agreement, a considerable score of correlation was also pointed out between bacteria abundance from BRAF-mutated cases and the level of markers distinctive of BRAFV600E pathway, including those involved in inflammation, innate immune response and epithelial-mesenchymal transition. We provide evidence that two candidate bacterial markers, Prevotella enoeca and Ruthenibacterium lactatiformans, more abundant in BRAFV600E and BRAF wild-type subjects respectively, emerged as single factors with the best performance in distinguishing BRAF status (AUROC = 0.72 and 0.74, respectively, 95% confidence interval). Furthermore, the combination of the 10 differentially represented microorganisms between the two groups improved performance in discriminating serrated CRC driven by BRAF mutation from BRAF wild-type CRC cases (AUROC = 0.85, 95% confidence interval, 0.69–1.01). Conclusion Overall, our results suggest that BRAFV600E mutation itself drives a distinctive gut microbiota signature and provide predictive CRC-associated bacterial biomarkers able to discriminate BRAF status in CRC patients and, thus, useful to devise non-invasive patient-selective diagnostic strategies and patient-tailored optimized therapies.

Published
2020

5. Hydroxyl radical generation, levels of tumor necrosis factor-alpha, and progression to heart failure after acute myocardial infarction

Author

M. Valgimigli, E. Merli, P. Malagutti, O. Soukhomovskaia, G. Cicchitelli, G. Francolini, G. Macr, 305, `, F. Mastrorilli, R. Ferrari, ANTELLI, ALESSANDRA, CANISTRO, DONATELLA, PAOLINI, MORENO, M. Valgimigli, E. Merli, P. Malagutti, O. Soukhomovskaia, G. Cicchitelli, A. Antelli, D. Canistro, G. Francolini, G. Macr&#305, and `, F. Mastrorilli, M. Paolini, R. Ferrari

Subjects
Male, HF, Heart disease, medicine.medical_treatment, dihydroxybenzoic acid, heart failure, medicine.disease_cause, Gastroenterology, Receptors, Tumor Necrosis Factor, Etanercept, Coronary artery disease, LV, ·, OH, acetylsalicylic acid, ASA, DHBA, hydroxyl radical, IL, interleukin, left ventricular, MI, myocardial infarction, OSS, oxidative stress status, reactive oxygen species, ROS, SA, salicylic acid, sTNFR, Prospective Studies, Myocardial infarction, Disease Progression, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Sialoglycoproteins, acute miocardial infarction, radical generation, human, Internal medicine, medicine, Humans, Aged, Interleukin-6, Tumor Necrosis Factor-alpha, business.industry, Vitamin E, Case-control study, medicine.disease, Interleukin 1 Receptor Antagonist Protein, Endocrinology, Case-Control Studies, Immunoglobulin G, Heart failure, Myocardial infarction complications, business, Oxidative stress
Abstract

Objectives We used acetylsalicylic acid (ASA) as a probing agent to quantify hydroxyl radical (·OH) in Controls and patients with coronary artery disease and to prospectively investigate ·OH production in patients with myocardial infarction (MI) complicated by heart failure (HF). Background Oxidative stress status (OSS) is a mechanism for transition to HF in experimental heart injury models, but evidence for its causal role in humans is still limited. Methods Thirty healthy subjects (Controls), 12 patients with stable angina (Group 1), and 74 patients with ST-segment elevation MI (Group 2) were enrolled. A dose of 250 mg Flectadol was given intravenously before each blood collection to determine the 2,3-dihydroxybenzoic acid/salicylic acid (DHBA/SA) ratio. We also quantified vitamin E and coenzyme Q10to monitor antioxidant reserve, as well as tumor necrosis factor (TNF)-alpha, TNF-soluble receptors, interleukin (IL)-6, and IL-1ra to assess inflammatory status. All measurements were repeated at month 6 in Group 2. Results There were no differences between Controls and Group 1. Group 2 showed increased ·OH production, peaking at 24 h, whereas vitamin E and coenzyme Q10progressively declined. Group 2 patients developing HF during hospitalization (Group 2Bi) presented with an increase of both ·OH production at discharge and inflammatory status, as compared with patients without HF (Group 2Ai), persisting at month 6 in post-MI patients with HF (Group 2Bii). Conclusions We found a distinct pattern of ·OH generation in post-MI patients who show progression to HF. The interplay between OSS and inflammatory status should be targeted as a possible mechanism of progression to post-MI left ventricular dysfunction.

Published
2004

7. A powerful machine learning approach to identify interactions of differentially abundant gut microbial subsets in patients with metastatic and non-metastatic pancreatic cancer.

Author

Villani A, Fontana A, Panebianco C, Ferro C, Copetti M, Pavlovic R, Drago D, Fiorentini C, Terracciano F, Bazzocchi F, Canistro G, Pisati F, Maiello E, Latiano TP, Perri F, and Pazienza V

Subjects
Humans, Male, Female, RNA, Ribosomal, 16S genetics, Middle Aged, Feces microbiology, Aged, Metagenomics, Pancreatic Neoplasms microbiology, Pancreatic Neoplasms pathology, Gastrointestinal Microbiome, Machine Learning, Bacteria classification, Bacteria genetics, Bacteria isolation & purification, Neoplasm Metastasis
Abstract

Pancreatic cancer has a dismal prognosis, as it is often diagnosed at stage IV of the disease and is characterized by metastatic spread. Gut microbiota and its metabolites have been suggested to influence the metastatic spread by modulating the host immune system or by promoting angiogenesis. To date, the gut microbial profiles of metastatic and non-metastatic patients need to be explored. Taking advantage of the 16S metagenomic sequencing and the PEnalized LOgistic Regression Analysis (PELORA) we identified clusters of bacteria with differential abundances between metastatic and non-metastatic patients. An overall increase in Gram-negative bacteria in metastatic patients compared to non-metastatic ones was identified using this method. Furthermore, to gain more insight into how gut microbes can predict metastases, a machine learning approach (iterative Random Forest) was performed. Iterative Random Forest analysis revealed which microorganisms were characterized by a different level of relative abundance between metastatic and non-metastatic patients and established a functional relationship between the relative abundance and the probability of having metastases. At the species level, the following bacteria were found to have the highest discriminatory power: Anaerostipes hadrus , Coprobacter secundus , Clostridium sp. 619, Roseburia inulinivorans , Porphyromonas and Odoribacter at the genus level, and Rhodospirillaceae , Clostridiaceae and Peptococcaceae at the family level. Finally, these data were intertwined with those from a metabolomics analysis on fecal samples of patients with or without metastasis to better understand the role of gut microbiota in the metastatic process. Artificial intelligence has been applied in different areas of the medical field. Translating its application in the field of gut microbiota analysis may help fully exploit the potential information contained in such a large amount of data aiming to open up new supportive areas of intervention in the management of cancer.

Published
2024
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8. BRAF V600E mutation impinges on gut microbial markers defining novel biomarkers for serrated colorectal cancer effective therapies.

Author

Trivieri N, Pracella R, Cariglia MG, Panebianco C, Parrella P, Visioli A, Giani F, Soriano AA, Barile C, Canistro G, Latiano TP, Dimitri L, Bazzocchi F, Cassano D, Vescovi AL, Pazienza V, and Binda E

Subjects
Aged, Aged, 80 and over, Animals, Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms microbiology, Female, Humans, Male, Mice, Mice, SCID, Middle Aged, Prognosis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor metabolism, Colorectal Neoplasms pathology, Feces microbiology, Gastrointestinal Microbiome, Mutation, Proto-Oncogene Proteins B-raf genetics
Abstract

Background: Colorectal cancer (CRC) harboring BRAF V600E mutation exhibits low response to conventional therapy and poorest prognosis. Due to the emerging correlation between gut microbiota and CRC carcinogenesis, we investigated in serrated BRAF V600E cases the existence of a peculiar fecal microbial fingerprint and specific bacterial markers, which might represent a tool for the development of more effective clinical strategies., Methods: By injecting human CRC stem-like cells isolated from BRAF V600E patients in immunocompromised mice, we described a new xenogeneic model of this subtype of CRC. By performing bacterial 16S rRNA sequencing, the fecal microbiota profile was then investigated either in CRC-carrying mice or in a cohort of human CRC subjects. The microbial communities' functional profile was also predicted. Data were compared with Mann-Whitney U, Welch's t-test for unequal variances and Kruskal-Wallis test with Benjamini-Hochberg false discovery rate (FDR) correction, extracted as potential BRAF class biomarkers and selected as model features. The obtained mean test prediction scores were subjected to Receiver Operating characteristic (ROC) analysis. To discriminate the BRAF status, a Random Forest classifier (RF) was employed., Results: A specific microbial signature distinctive for BRAF status emerged, being the BRAF-mutated cases closer to healthy controls than BRAF wild-type counterpart. In agreement, a considerable score of correlation was also pointed out between bacteria abundance from BRAF-mutated cases and the level of markers distinctive of BRAF V600E pathway, including those involved in inflammation, innate immune response and epithelial-mesenchymal transition. We provide evidence that two candidate bacterial markers, Prevotella enoeca and Ruthenibacterium lactatiformans, more abundant in BRAF V600E and BRAF wild-type subjects respectively, emerged as single factors with the best performance in distinguishing BRAF status (AUROC = 0.72 and 0.74, respectively, 95% confidence interval). Furthermore, the combination of the 10 differentially represented microorganisms between the two groups improved performance in discriminating serrated CRC driven by BRAF mutation from BRAF wild-type CRC cases (AUROC = 0.85, 95% confidence interval, 0.69-1.01)., Conclusion: Overall, our results suggest that BRAF V600E mutation itself drives a distinctive gut microbiota signature and provide predictive CRC-associated bacterial biomarkers able to discriminate BRAF status in CRC patients and, thus, useful to devise non-invasive patient-selective diagnostic strategies and patient-tailored optimized therapies.

Published
2020
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9. Effect of different doses of remifentanil on stress response during laparoscopic cholecystectomy.

Author

Sessa F, Levantesi L, Congedo E, Di Nardo F, Oggiano M, Canistro G, Sicuranza R, Nicosia L, and De Cosmo G

Subjects
Dose-Response Relationship, Drug, Hormones blood, Humans, Prospective Studies, Analgesics, Opioid therapeutic use, Cholecystectomy, Laparoscopic adverse effects, Remifentanil therapeutic use, Stress, Physiological drug effects
Abstract

Objectives: An adequate perioperative analgesia reduces neuroendocrine stress response and postoperative complica-tions. Opioids are the most effective parenteral drugs to control pain and stress response., Design: This is a prospective randomized double-blinded controlled study., Setting: Institutional tertiary level., Patients, Participants: Fifty patients underwent general anesthesia with desflurane for laparoscopic cholecystectomy., Main Outcome Measures: To compare two different doses of remifentanil (0.15 mcg/kg/min or 0.3 mcg/kg/min) in reducing markers of stress. Perioperative stress was assessed through the dosage of adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH), and prolactin (PRL). Three venous blood samples were collected from patients: before transferring the patient to the operating room (Time 0), at the trocar insertion (Time 1), and 1 hour after the end of the surgery (Time 2)., Results: Hemodynamic parameters showed no differences between the two groups. The authors observed an increase of GH and PRL in both groups at trocar insertion (Time 1) ( p = 0.473 and 0.754, respectively). ACTH and cortisol showed a decrease at Time 1 and an increase after surgery (p = 0.586). The modification of stress parameters levels showed no significant differences between the two groups., Conclusions: The results of our study showed that a lower dose of remifentanil is equally effective in controlling stress hormones during laparoscopic cholecystectomy.

Published
2019
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