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1. Genetic Variability in Patients with HCV-Related Hepatocellular Carcinoma

Author

Pisaturo M, Di Fraia A, Occhiello L, Minichini C, Starace M, Iodice V, Farella N, Stanzione M, and Coppola N

Subjects
hepatocellular carcinoma, hcv, viral variability, chronic hepatitis c, chronic infection c, core region, ns5a region, ns3 region, aa substitutions, phylogenesis, Infectious and parasitic diseases, RC109-216
Abstract

Mariantonietta Pisaturo,1 Alessandra Di Fraia,1 Laura Occhiello,1 Carmine Minichini,1 Mario Starace,1 Valentina Iodice,2 Nunzia Farella,2 Maria Stanzione,1 Nicola Coppola1 1Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania “L. Vanvitelli”, Naples, Italy; 2IX Infectious Disease Unit, AORN dei Colli, Naples, ItalyCorrespondence: Nicola CoppolaDepartment of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Via L. Armanni 5, Naples, 80131, ItalyTel +39 081 5666223Fax +39 081 5666013Email nicola.coppola@unicampania.itBackground: The present paper evaluates the genetic variability of HCV in patients with hepatocellular carcinoma (HCC).Methods: Amino acid substitutions (aas) in NS3, NS5A and core regions were analyzed in 17 patients with HCC (Cases) and 13 without HCC (Controls), all naïve to DAAs. For the Cases, a sample of neoplastic liver tissue, non-neoplastic liver tissue and a serum sample were collected; for the Controls, a sample of liver tissue was collected. Sanger sequencing of three regions was performed using homemade protocols.Results: Phylogenetic trees showed that there was no difference in the virus populations in the three compartments analyzed for the three HCV regions in patients with HCC. Low variability and no difference between the Cases and Controls were observed in the core and NS5A regions; however, in the NS3 region, a higher variability was observed in the Cases. No difference was observed in the core region between Cases and Controls. In NS3, aa substitutions at positions 103 and 122 were more frequently found in Cases than Controls (in both cases 50% vs 9.1%, p< 0.05); moreover, aas in positions 32, 44 (p=0.035 for both), 79 (p=0.008) and 121 (p=0.018) were observed in the Cases and absent in the Controls. Finally, considering the NS5A region, aa substitutions at positions 37 and 54 were more frequently identified in the Cases than the Controls, but without statistical significance.Conclusion: These data may suggest a higher aa variability in patients with HCC than in those without, especially in the NS3 region.Keywords: hepatocellular carcinoma, HCV, viral variability, chronic hepatitis C, chronic infection C, core region, NS5A region, NS3 region, aa substitutions, phylogenesis

Published
2021

3. A holistic evaluation of patients with chronic Hepatitis D virus (HDV) infection enrolled in the Italian PITER-B and delta cohort

Author

Kondili, L, Brancaccio, G, Tosti, M, Coco, B, Quaranta, M, Messina, V, Ciancio, A, Morisco, F, Cossiga, V, Claar, E, Rosato, V, Ciarallo, M, Cacciola, I, Ponziani, F, Cerrito, L, Coppola, R, Longobardi, F, Biliotti, E, Rianda, A, Barbaro, F, Coppola, N, Stanzione, M, Barchiesi, F, Fagiuoli, S, Vigano, M, Massari, M, Russo, F, Ferrarese, A, Laccabue, D, Di Marco, V, Blanc, P, Marrone, A, Morsica, G, Federico, A, Ieluzzi, D, Rocco, A, Foschi, F, Soria, A, Maida, I, Chessa, L, Milella, M, Rosselli Del Turco, E, Madonia, S, Chemello, L, Gentile, I, Toniutto, P, Bassetti, M, Surace, L, Baiocchi, L, Pellicelli, A, De Santis, A, Puoti, M, Degasperi, E, Niro, G, Zignego, A, Craxi, A, Raimondo, G, Santantonio, T, Brunetto, M, Gaeta, G, Aghemo, A, Baiguera, C, Battezzati, P, Battistella, S, Bavetta, M, Bertoni, C, Boni, C, Brambilla, P, Bray, A, Briano, F, Carmenini, E, Castelli, F, Cavalletto, L, Cerini, F, Chidichimo, L, Colella, E, Cologni, G, Como, S, Corsini, R, Costa, C, Cotugno, R, Cretella, S, De Angelis, F, De Leo, P, Perri, G, Falbo, E, Ferrigno, L, Fornasiere, E, Francisci, D, Gatti, P, Lampertico, P, Lenci, I, Licata, A, Marzano, A, Mastroianni, A, Mazzaro, C, Monti, M, Nardone, G, Nicolini, L, Passigato, N, Pasticci, M, Pierotti, P, Pinchera, B, Pollicino, T, Porcu, C, Quartini, G, Rancatore, G, Romeo, M, Rumi, M, Saracino, A, Schioppa, O, Serio, I, Soffredini, R, Tata, X, Tizzani, M, Tonnini, M, Torti, C, Valenti, D, Zaltron, S, Zoncada, A, Kondili L. A., Brancaccio G., Tosti M. E., Coco B., Quaranta M. G., Messina V., Ciancio A., Morisco F., Cossiga V., Claar E., Rosato V., Ciarallo M., Cacciola I., Ponziani F. R., Cerrito L., Coppola R., Longobardi F., Biliotti E., Rianda A., Barbaro F., Coppola N., Stanzione M., Barchiesi F., Fagiuoli S., Vigano M., Massari M., Russo F. P., Ferrarese A., Laccabue D., Di Marco V., Blanc P., Marrone A., Morsica G., Federico A., Ieluzzi D., Rocco A., Foschi F. G., Soria A., Maida I., Chessa L., Milella M., Rosselli Del Turco E., Madonia S., Chemello L., Gentile I., Toniutto P., Bassetti M., Surace L., Baiocchi L., Pellicelli A., De Santis A., Puoti M., Degasperi E., Niro G. A., Zignego A. L., Craxi A., Raimondo G., Santantonio T. A., Brunetto M. R., Gaeta G. B., Aghemo A., Baiguera C., Battezzati P. M., Battistella S., Bavetta M. G., Bertoni C., Boni C., Brambilla P., Bray A., Briano F., Carmenini E., Castelli F., Cavalletto L., Cerini F., Chidichimo L., Colella E., Cologni G., Como S., Corsini R., Costa C., Cotugno R., Cretella S., De Angelis F., De Leo P., Perri G. D., Falbo E., Ferrigno L., Fornasiere E., Francisci D., Gatti P., Lampertico P., Lenci I., Licata A., Marzano A., Mastroianni A., Mazzaro C., Monti M., Nardone G., Nicolini L. A., Passigato N., Pasticci M. B., Pierotti P., Pinchera B., Pollicino T., Porcu C., Quartini G., Rancatore G., Romeo M., Rumi M. G., Saracino A., Schioppa O., Serio I., Soffredini R., Tata X., Tizzani M., Tonnini M., Torti C., Valenti D., Zaltron S., Zoncada A., Kondili, L, Brancaccio, G, Tosti, M, Coco, B, Quaranta, M, Messina, V, Ciancio, A, Morisco, F, Cossiga, V, Claar, E, Rosato, V, Ciarallo, M, Cacciola, I, Ponziani, F, Cerrito, L, Coppola, R, Longobardi, F, Biliotti, E, Rianda, A, Barbaro, F, Coppola, N, Stanzione, M, Barchiesi, F, Fagiuoli, S, Vigano, M, Massari, M, Russo, F, Ferrarese, A, Laccabue, D, Di Marco, V, Blanc, P, Marrone, A, Morsica, G, Federico, A, Ieluzzi, D, Rocco, A, Foschi, F, Soria, A, Maida, I, Chessa, L, Milella, M, Rosselli Del Turco, E, Madonia, S, Chemello, L, Gentile, I, Toniutto, P, Bassetti, M, Surace, L, Baiocchi, L, Pellicelli, A, De Santis, A, Puoti, M, Degasperi, E, Niro, G, Zignego, A, Craxi, A, Raimondo, G, Santantonio, T, Brunetto, M, Gaeta, G, Aghemo, A, Baiguera, C, Battezzati, P, Battistella, S, Bavetta, M, Bertoni, C, Boni, C, Brambilla, P, Bray, A, Briano, F, Carmenini, E, Castelli, F, Cavalletto, L, Cerini, F, Chidichimo, L, Colella, E, Cologni, G, Como, S, Corsini, R, Costa, C, Cotugno, R, Cretella, S, De Angelis, F, De Leo, P, Perri, G, Falbo, E, Ferrigno, L, Fornasiere, E, Francisci, D, Gatti, P, Lampertico, P, Lenci, I, Licata, A, Marzano, A, Mastroianni, A, Mazzaro, C, Monti, M, Nardone, G, Nicolini, L, Passigato, N, Pasticci, M, Pierotti, P, Pinchera, B, Pollicino, T, Porcu, C, Quartini, G, Rancatore, G, Romeo, M, Rumi, M, Saracino, A, Schioppa, O, Serio, I, Soffredini, R, Tata, X, Tizzani, M, Tonnini, M, Torti, C, Valenti, D, Zaltron, S, Zoncada, A, Kondili L. A., Brancaccio G., Tosti M. E., Coco B., Quaranta M. G., Messina V., Ciancio A., Morisco F., Cossiga V., Claar E., Rosato V., Ciarallo M., Cacciola I., Ponziani F. R., Cerrito L., Coppola R., Longobardi F., Biliotti E., Rianda A., Barbaro F., Coppola N., Stanzione M., Barchiesi F., Fagiuoli S., Vigano M., Massari M., Russo F. P., Ferrarese A., Laccabue D., Di Marco V., Blanc P., Marrone A., Morsica G., Federico A., Ieluzzi D., Rocco A., Foschi F. G., Soria A., Maida I., Chessa L., Milella M., Rosselli Del Turco E., Madonia S., Chemello L., Gentile I., Toniutto P., Bassetti M., Surace L., Baiocchi L., Pellicelli A., De Santis A., Puoti M., Degasperi E., Niro G. A., Zignego A. L., Craxi A., Raimondo G., Santantonio T. A., Brunetto M. R., Gaeta G. B., Aghemo A., Baiguera C., Battezzati P. M., Battistella S., Bavetta M. G., Bertoni C., Boni C., Brambilla P., Bray A., Briano F., Carmenini E., Castelli F., Cavalletto L., Cerini F., Chidichimo L., Colella E., Cologni G., Como S., Corsini R., Costa C., Cotugno R., Cretella S., De Angelis F., De Leo P., Perri G. D., Falbo E., Ferrigno L., Fornasiere E., Francisci D., Gatti P., Lampertico P., Lenci I., Licata A., Marzano A., Mastroianni A., Mazzaro C., Monti M., Nardone G., Nicolini L. A., Passigato N., Pasticci M. B., Pierotti P., Pinchera B., Pollicino T., Porcu C., Quartini G., Rancatore G., Romeo M., Rumi M. G., Saracino A., Schioppa O., Serio I., Soffredini R., Tata X., Tizzani M., Tonnini M., Torti C., Valenti D., Zaltron S., and Zoncada A.

Abstract

Background and Aims: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility. Methods: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model. Results: Of 5492 HBsAg-positive enrolled patients, 4152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age ≤ 40 years vs. 2.1%; P < 0.001), more often females (males 43.0% vs. 68.6%; P < 0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care. Conclusions: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN.

Published
2024

6. Characterization of a cohort of liver transplant patients for HBV and/or HBV/HDV related complications: results of a Campania multicenter study.

Author

Stornaiuolo, G., Salmoni, L., Russo, A., Angrisani, D., Santonicola, A., Valente, G., Longobardi, F., Morisco, F., Persico, M., Stanzione, M., Sagnelli, C., Pisaturo, M., and Coppola, N.

Abstract

Liver transplantation is a life-saving treatment option for patients with complications related to HBV and/or HBV/HDV-related liver disease. A multicenter retrospective study was conducted including 5 infectious disease or hepatology units in Campania. Patients receiving liver transplants for HBV and/or HBV/HDV-related complications were enrolled in post-transplant follow-up from 1 to a maximum of 20 years. The characteristics of patients with monoinfection were compared with those of HBV/HDV coinfected patients. We enrolled 233 patients, 109 of whom had confirmed HVB/HDV coinfection. Patients were predominantly male (76.4%), with a median age of 56 years, of whom 9.6% were HCVAb positive and 0.7% HIVAb positive; the median years of liver transplantation was 8 years. 64.5% of patients had a diagnosis of HCC at the time of transplantation. The comparison between the subjects transplanted for HBV and HBV/HDV did not show statistically significant epidemiological and demographic differences (table 1). During follow-up, 31.6% of patients had a clinical event: 6.4% liver-related and 27.8% not liver-related. Renal failure (20.9%) and cancer (12.85%) were the most frequent new-onset clinical events, with similar incidence between HBV patients and those with HBV/HDV coinfection (table 2). Patients in whom an adverse clinical event occurred were mostly men (79.7%, n.s.) (table 3). Only 4.2% of patients died during follow-up and of these only one death was related to a hepatic event (table 2). Comparing the characteristics (Table 4): they were all men (100% vs 75.3%; p = 0.122), they had been transplanted for longer (16 years vs 8; p = 0.059), 50% had been transplanted before 2010 and 50% of them were HDV coinfected (50%vs62.7%;p=0.674). our study highlights a good outcome during follow-up and does not show different clinical evolution between liver transplant patients for HBV monoinfection and HBV/HDV coinfection. [ABSTRACT FROM AUTHOR]

Published
2025
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9. Development of a risk score to predict portal vein tumor thrombosis in patients with hepatocellular carcinoma

Author

Tortora R., Farella N., Morisco F., Coppola C., Izzo F., Salomone Megna A., Federico A., Messina V., Nardone G., Piai G., Ragone E., Adinolfi L. E., D'Adamo G., Stanzione M., Francica G., Torre P., De Girolamo V., Coppola N., Guarino M., Dallio M., Rocco L., Di Costanzo G. G., Tortora, R., Farella, N., Morisco, F., Coppola, C., Izzo, F., Salomone Megna, A., Federico, A., Messina, V., Nardone, G., Piai, G., Ragone, E., Adinolfi, L. E., D'Adamo, G., Stanzione, M., Francica, G., Torre, P., De Girolamo, V., Coppola, N., Guarino, M., Dallio, M., Rocco, L., and Di Costanzo, G. G.

Subjects
portal vein tumor thrombosi, hepatocellular carcinoma, risk score, survival
Abstract

Background Portal vein tumor thrombosis (PVTT) is a common complication of hepatocellular carcinoma and is one of the most negative prognostic factors. The management of patients with PVTT is challenging. The aim of the study was to develop a score predictive of tumor thrombosis. Methods Data from a large cohort of 2243 hepatocellular carcinoma patients (all stages) recorded in the Progetto Epatocarcinoma Campania (January 2013-April 2021) database were analyzed. To construct the score, univariate generalized estimated equation models, the bootstrap approach for internal validation, and a regression coefficient-based scoring system were used. Results PVTT (any location) was found in 14.4% of cases and was related to shorter survival. Males, younger patients, and symptomatic cases were more prevalent among the PVTT group. At multivariate analysis, size ≥5 cm, massive or infiltrative hepatocellular carcinoma growth, and alpha-fetoprotein ≥400 ng/mL were significantly associated with PVTT. A risk prediction score of PVTT based on eight variables was developed. Using a continuous score, the risk was associated with an odds ratio (OR) of 1.30 (1.27-1.34; P 8 versus a score ≤8 the OR for PVTT was 11.33 (8.55-15.00; P

Published
2023

11. Cardiovascular System in COVID-19: Simply a Viewer or a Leading Actor?

Author

Mottola F. F., Verde N., Ricciolino R., Di Mauro M., Migliaccio M. G., Carfora V., Spiniello G., Coppola N., Macera M., Calo F., Sagnelli C., Monari C., Martini S., Stornaiuolo G., Stanzione M., De Pascalis S., Cascone A., Bianco A., Gentile V., Camaioni C., De Angelis G., Marino G., Astorri R., Starace M., Minichini C., Di Fraia A., De Sio I., Niosi M., Borrelli S., Celia B., Ceparano M., Cirillo S., De Luca M., Mazzeo G., Paoli G., Russo M. G., Russo A., Mottola, F. F., Verde, N., Ricciolino, R., Di Mauro, M., Migliaccio, M. G., Carfora, V., Spiniello, G., Coppola, N., Macera, M., Calo, F., Sagnelli, C., Monari, C., Martini, S., Stornaiuolo, G., Stanzione, M., De Pascalis, S., Cascone, A., Bianco, A., Gentile, V., Camaioni, C., De Angelis, G., Marino, G., Astorri, R., Starace, M., Minichini, C., Di Fraia, A., De Sio, I., Niosi, M., Borrelli, S., Celia, B., Ceparano, M., Cirillo, S., De Luca, M., Mazzeo, G., Paoli, G., Russo, M. G., and Russo, A.

Subjects
medicine.medical_specialty, Myocarditis, heart failure, Review, Disease, 030204 cardiovascular system & hematology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Pericarditis, 0302 clinical medicine, Diabetes mellitus, Pandemic, medicine, myocardial injury, 030212 general & internal medicine, lcsh:Science, Intensive care medicine, Ecology, Evolution, Behavior and Systematics, business.industry, Mechanism (biology), SARS-CoV-2 infection, Paleontology, Cancer, medicine.disease, Space and Planetary Science, Heart failure, cardiovascular system, lcsh:Q, business
Abstract

As of January 2020, a new pandemic has spread from Wuhan and caused thousands of deaths worldwide. Several studies have observed a relationship between coronavirus disease (COVID-19) infection and the cardiovascular system with the appearance of myocardial damage, myocarditis, pericarditis, heart failure and various arrhythmic manifestations, as well as an increase in thromboembolic risk. Cardiovascular manifestations have been highlighted especially in older and more fragile patients and in those with multiple cardiovascular risk factors such as cancer, diabetes, obesity and hypertension. In this review, we will examine the cardiac involvement associated with SARS-CoV-2 infection, focusing on the pathophysiological mechanism underlying manifestations and their clinical implication, taking into account the main scientific papers published to date.

Published
2020
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12. Effect of hepatitis B virus on steatosis in hepatitis C virus co-infected subjects: A multi-centre study and systematic review

Author

Goossens N, de Vito C, Mangia A, Clément S, Cenderello G, Barrera F, D'Ambrosio R, Coppola N, Zampino R, Stanzione M, Adinolfi LE, Wedemeyer H, Semmo N, Müllhaupt B, Semela D, Malinverni R, Moradpour D, Heim M, Trincucci G, Rubbia-Brandt L, Negro F, Piazzolla V, Santoro Rita, Dufour JF, Brunner B, Weber A, Herranz M, Mathieu A, Clerc O, Elisabetta D, Floriana F, Macera M, Pisaturo M, Stornaiuolo G, Rinaldi L, George JMix C, Cornberg M, Goossens, N, de Vito, C, Mangia, A, Clément, S, Cenderello, G, Barrera, F, D'Ambrosio, R, Coppola, N, Zampino, R, Stanzione, M, Adinolfi, Le, Wedemeyer, H, Semmo, N, Müllhaupt, B, Semela, D, Malinverni, R, Moradpour, D, Heim, M, Trincucci, G, Rubbia-Brandt, L, Negro, F, Piazzolla, V, Santoro, Rita, Dufour, Jf, Brunner, B, Weber, A, Herranz, M, Mathieu, A, Clerc, O, DE FELICE, Elisabetta, Floriana, F, Macera, M, Pisaturo, M, Stornaiuolo, G, Rinaldi, L, George JMix, C, and Cornberg, M

Published
2018

13. VIROLOGICAL PATTERNS OF HCV PATIENTS WITH FAILURE TO INTERFERON-FREE REGIMENS

Author

Starace M, Minichini C, De Pascalis S, Macera M, Occhiello L, Messina V, Sangiovanni V, Adinolfi LE, Claar E, Precone D, Stornaiuolo G, Stanzione M, Ascione T, Caroprese M, Zampino R, Parrilli G, Gentile I, Brancaccio G, Iovinella V, Martini S, Masarone M, Fontanella L, Masiello A, Sagnelli E, Punzi R, Salomone Megna A, Santoro R, Gaeta GB, Coppola N., Zampino R. Parrilli G, Masarone M., Starace, Mario, Minichini, Carmine, De Pascalis, Stefania, Macera, Margherita, Occhiello, Laura, Messina, Vincenzo, Sangiovanni, Vincenzo, Adinolfi, Luigi E, Claar, Ernesto, Precone, Davide, Stornaiuolo, Gianfranca, Stanzione, Maria, Ascione, Tiziana, Caroprese, Mara, Zampino, Rosa, Parrilli, Gianpaolo, Gentile, Ivan, Brancaccio, Giuseppina, Iovinella, Vincenzo, Martini, Salvatore, Masarone, Mario, Fontanella, Luca, Masiello, Addolorata, Sagnelli, Evangelista, Punzi, Rodolfo, Salomone Megna, Angelo, Santoro, Renato, Gaeta, Giovanni B, Coppola, Nicola, Starace, M, Minichini, C, De Pascalis, S, Macera, M, Occhiello, L, Messina, V, Sangiovanni, V, Adinolfi, Le, Claar, E, Precone, D, Stornaiuolo, G, Stanzione, M, Ascione, T, Caroprese, M, Zampino, R, Parrilli, G, Gentile, I, Brancaccio, G, Iovinella, V, Martini, S, Masarone, M, Fontanella, L, Masiello, A, Sagnelli, E, Punzi, R, Salomone Megna, A, Santoro, R, Gaeta, Gb, Coppola, N., Zampino R., Parrilli G, and Masarone, M.

Subjects
0301 basic medicine, Simeprevir, Male, Hepacivirus, Viral Nonstructural Proteins, Hospitals, University, 0302 clinical medicine, Genotype, antiviral therapy, Prevalence, Treatment Failure, Sanger sequencing, Aged, 80 and over, education.field_of_study, virus diseases, Middle Aged, chronic HCV hepatitis, Infectious Diseases, Italy, symbols, DAA failure, 030211 gastroenterology & hepatology, Female, Adult, RASs, medicine.medical_specialty, Population, Mutation, Missense, Antiviral Agents, 03 medical and health sciences, symbols.namesake, Virology, Internal medicine, Drug Resistance, Viral, medicine, Humans, In patient, NS5A, education, DAAs, DAA, Aged, business.industry, Interferon free, Genetic Variation, Sequence Analysis, DNA, Hepatitis C, Chronic, digestive system diseases, Regimen, 030104 developmental biology, Amino Acid Substitution, business, RAS
Abstract

The study characterized the virological patterns and the resistance-associated substitutions (RASs) in patients with failure to IFN-free regimens enrolled in the real-life setting. All 87 consecutive HCV patients with failed IFN-free regimens, observed at the laboratory of the University of Campania, were enrolled. All patients had been treated with DAA regimens according to the HCV genotype, international guidelines, and local availability. Sanger sequencing of NS3, NS5A, and NS5B regions was performed at failure by home-made protocols. Of the 87 patients enrolled, 13 (14.9%) showed a misclassified HCV genotype, probably causing DAA failure, 16 had been treated with a sub-optimal DAA regimen, 19 with a simeprevir-based regimen and 39 with an optimal DAA regimen. A major RAS was identified more frequently in the simeprevir regimen group (68.4%) and in the optimal regimen group (74.4%) than in the sub-optimal regimen group (56.3%). The prevalence of RASs in NS3 was similar in the three groups (30.8-57.9%), that in NS5A higher in the optimal regimen group (71.8%) than in the sub-optimal regimen group (12.5%, P < 0.0001) and in the simeprevir regimen group (31.6%, P < 0.0005), and that in NS5B low in all groups (0-25%). RASs in two or more HCV regions were more frequently identified in the optimal regimen group (46.6%) than in the simeprevir-based regimen group (31.6%) and sub-optimal regimen group (18.7%). In our real-life population the prevalence of RASs was high, especially in NS3 and NS5A and in those treated with suitable DAA regimens. © 2018 Wiley Periodicals, Inc.

Published
2018

15. Influence of ITPase activity on decreases of hemoglobin during treatment with Interferon-free DAA-based and ribavirin in HCV-related cirrhosis

Author

Coppola, N, De Pascalis, S, Messina, V, Di Caprio, G, Martini, S, de Stefano, G, Starace, M, Stornaiuolo, G, Sangiovanni, V, Stanzione, M, Zampino, R, Calo, F, Rinaldi, L, Persico, M, Federico, A, Gaeta, Gb, Filippini, P, BUONOMO, ANTONIO RICCARDO, BORGIA, GUGLIELMO, GENTILE, Ivan, Coppola, N, De Pascalis, S, Messina, V, Di Caprio, G, Martini, S, de Stefano, G, Starace, M, Stornaiuolo, G, Sangiovanni, V, Stanzione, M, Zampino, R, Calo, F, Rinaldi, L, Persico, M, Federico, A, Buonomo, ANTONIO RICCARDO, Borgia, Guglielmo, Gaeta, Gb, Filippini, P, and Gentile, Ivan

Published
2017

16. Interferon-Free Regimens in HBsAg/anti-HCV Patients: The Need to Control HBV Replication to Avoid HBV Reactivation

Author

Macera, M, Stanzione, M, Messina, V, D'Adamo, G, Sangiovanni, V, Mioglioresi, L, Fontanella, L, De Pascalis, S, Stornaiuolo, G, Lanza, Ag, Ascione, T, Gentile, I, Piai, G, GAETA, Giovanni Battista, SAGNELLI, Evangelista, COPPOLA, Nicola, Macera, M, Stanzione, M, Messina, V, D'Adamo, G, Sangiovanni, V, Mioglioresi, L, Fontanella, L, De Pascalis, S, Stornaiuolo, G, Lanza, Ag, Ascione, T, Gaeta, Giovanni Battista, Gentile, I, Piai, G, Sagnelli, Evangelista, and Coppola, Nicola

Published
2017

17. Interferon-Free Regimens in Hepatitis B Surface Antigen/Anti-Hepatitis C Virus Positive Patients: The Need to Control Hepatitis B Virus Replication to Avoid Hepatitis B Virus Reactivation

Author

Macera M, Stanzione M, Messina V, D'Adamo G, Sangiovanni V, Mioglioresi L, Fontanella L, De Pascalis S, Stornaiuolo G, Galeota Lanza A, Ascione T, Sagnelli E, Gentile I, Piai G, Gaeta GB, Coppola N., Macera, M, Stanzione, M, Messina, V, D'Adamo, G, Sangiovanni, V, Mioglioresi, L, Fontanella, L, De Pascalis, S, Stornaiuolo, G, Galeota Lanza, A, Ascione, T, Sagnelli, E, Gentile, I, Piai, G, Gaeta, Gb, and Coppola, N.

Published
2017

19. DEVELOPMENT OF CUTIN-BASED ANTIOXIDANT FILMS.

Author

STANZIONE, M., GALZERANO, B., LAVORGNA, M., ALOUI, H., KHWALDIA, K., and BUONOCORE, G. G.

Subjects
*ACTIVE food packaging, *PACKAGING film, *CAROTENOIDS, *LOW density polyethylene, *POLYMER blends, *MANUFACTURING processes, *POLYVINYL alcohol, *PHARMACEUTICAL industry
Abstract

Polyphenolic-rich and/or carotenoid-rich extracts from tomato possess potential biological properties, such as antioxidant activity, extremely valuable for the food, cosmetic and pharmaceutical industries. Cutin, a component of cuticle of tomato peels, was blended with thermoplastic polymers such as low-density polyethylene and amorphous vinyl alcohol with low environmental impact to produce active flexible food packaging films by using conventional manufacturing processes. The polymer formulations containing the polyphenolic-rich and/or carotenoid-rich extracts were characterized to study the physicochemical, structural properties and the additive induced effects on the functional properties of the obtained active films. [ABSTRACT FROM AUTHOR]

Published
2019

20. NEW ANTIOXIDANT LDPE FILMS CONTAINING APPLE AND GINGER EXTRACT.

Author

GALZERANO, B., STANZIONE, M., LAVORGNA, M., SILVA, A. SANCHES, ANDRADE, M. A., VILARINHO, F., RAMOS, F., and BUONOCORE, G. G.

Subjects
*APPLE varieties, *FOOD additives, *CARROTS, *FOOD packaging, *GINGER, *PACKAGING materials, *APPLES
Abstract

In recent years, a new type of packaging that merges usual food packaging materials with antioxidant substances to extend shelf-life is gaining interest in the packaging industry. Various natural antioxidant compounds can be combined with different types of packaging materials to replace the chemical additives in food industries. In this work, the most suitable fruit extract between apple/ginger and apple/ginger/carrot/beet in term of antioxidant activity has been determined. LDPE-based films have been loaded with apple/ginger (50/50) extract by a melt mixing and compression process. Structural and functional properties of the obtained active films have been investigated together with their antioxidant activity. [ABSTRACT FROM AUTHOR]

Published
2019

21. Cryogel-Supported Stem Cell Factory for Customized Sustained Release of Bispecific Antibodies for Cancer Immunotherapy

Author

Aliperta, R., Welzel, P. B., (0000-0002-8733-4286) Bergmann, R., Freudenberg, R., (0000-0001-6921-0848) Berndt, N., (0000-0001-5099-2448) Feldmann, A., (0000-0002-1285-5052) Arndt, C., Koristka, S., Stanzione, M., Cartellieri, M., Ehninger, A., Ehninger, G., Werner, C., (0000-0002-1610-1493) Pietzsch, J., Steinbach, J., Bornhäuser, M., (0000-0002-8029-5755) Bachmann, M., Aliperta, R., Welzel, P. B., (0000-0002-8733-4286) Bergmann, R., Freudenberg, R., (0000-0001-6921-0848) Berndt, N., (0000-0001-5099-2448) Feldmann, A., (0000-0002-1285-5052) Arndt, C., Koristka, S., Stanzione, M., Cartellieri, M., Ehninger, A., Ehninger, G., Werner, C., (0000-0002-1610-1493) Pietzsch, J., Steinbach, J., Bornhäuser, M., and (0000-0002-8029-5755) Bachmann, M.

Abstract

Combining stem cells with biomaterial scaffolds provides a promising strategy for the development of drug delivery systems. Here we propose an innovative immunotherapeutic organoid by housing human mesenchymal stromal cells (MSCs), gene-modified for the secretion of an anti-CD33-anti-CD3 bispecific antibody (bsAb), in a small biocompatible star-shaped poly(ethylene glycol)-heparin cryogel scaffold as a transplantable and low invasive therapeutic machinery for the treatment of acute myeloid leukemia (AML). The macroporous biohybrid cryogel platform displays effectiveness in supporting proliferation and survival of bsAb-releasing-MSCs overtime in vitro and in vivo, avoiding cell loss and ensuring a constant release of sustained and detectable levels of bsAb capable of triggering T-cell-mediated anti-tumor responses and a rapid regression of CD33+ AML blasts. This therapeutic device results as a promising and safe alternative to the continuous administration of short-lived immunoagents and paves the way for effective bsAb-based therapeutic strategies for future tumor treatments.

Published
2017

23. An elevated degree of genetic variability characterizes Hepatitis Delta Antigen (HDAg) and correlates with high levels of serum HDV-RNA: Implication for disease progression and design of new pharmacological targets

Author

Colagrossi, L., primary, Salpini, R., additional, Scutari, R., additional, Battisti, A., additional, Piermatteo, L., additional, Bertoli, A., additional, Minichini, C., additional, Trimoulet, P., additional, Fleury, H., additional, Nebuloso, E., additional, De Cristofaro, M., additional, Cappiello, G., additional, Spanò, A., additional, Malagnino, V., additional, Mari, T., additional, Barlattani, A., additional, Iapadre, N., additional, Lichtner, M., additional, Mastroianni, C.M., additional, Lenci, I., additional, Pasquazzi, C., additional, De Sanctis, G.M., additional, Galeota Lanza, A., additional, Stanzione, M., additional, Stornaiuolo, G., additional, Marignani, M., additional, Sarmati, L., additional, Andreoni, M., additional, Angelico, M., additional, Perno, C.F., additional, Coppola, N., additional, and Svicher, V., additional

Published
2017
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25. Hepatitis Delta Antigen (HDAg) is characterized by an extensive degree of genetic variability that correlates with elevated levels of serum HDV-RNA

Author

Colagrossi, L., primary, Salpini, R., additional, Scutari, R., additional, Battisti, A., additional, Piermatteo, L., additional, Bertoli, A., additional, Menichini, C., additional, Trimoulet, P., additional, Fleury, H., additional, Nebuloso, E., additional, De Cristofaro, M., additional, Cappiello, G., additional, Spanò, A., additional, Malagnino, V., additional, Mari, T., additional, Barlattani, A., additional, Iapadre, N., additional, Lichtner, M., additional, Mastroianni, C.M., additional, Lenci, I., additional, Pasquazzi, C., additional, De Sanctis, G.M., additional, Lanza, A.G., additional, Stanzione, M., additional, Stornaiuolo, G., additional, Marignani, M., additional, Sarmati, L., additional, Andreoni, M., additional, Angelico, M., additional, Perno, C.F., additional, Coppola, N., additional, and Svicher, V., additional

Published
2017
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26. Effect of hepatitis B virus on steatosis in hepatitis C virus co‐infected subjects: A multi‐centre study and systematic review.

Author

Goossens, N., de Vito, C., Mangia, A., Clément, S., Cenderello, G., Barrera, F., D'Ambrosio, R., Coppola, N., Zampino, R., Stanzione, M., Adinolfi, L. E., Wedemeyer, H., Semmo, N., Müllhaupt, B., Semela, D., Malinverni, R., Moradpour, D., Heim, M., Trincucci, G., and Rubbia‐Brandt, L.

Subjects
HEPATITIS B virus, HEPATITIS C virus, DISEASE prevalence, META-analysis, CLINICAL trials
Abstract

Summary: It remains unclear whether hepatitis B virus (HBV) infection may modify the severity of viral steatosis in patients coinfected with chronic hepatitis C virus (HCV). We examined the influence of coinfection with HBV on prevalence of steatosis in chronic hepatitis C in a multi‐centre cohort of HBV‐HCV subjects, and by performing a systematic review and meta‐analysis of the literature. We centrally and blindly assessed steatosis prevalence and severity in a cohort of HBV‐HCV coinfected subjects compared to HCV and HBV monoinfected controls and we performed a systematic review of studies addressing the prevalence of steatosis in HBV‐HCV subjects compared to HCV controls. In the clinical cohort, we included 85 HBV‐HCV, 69 HBV and 112 HCV subjects from 16 international centres. There was no significant difference in steatosis prevalence between the HBV‐HCV and the HCV groups (33% vs 45%, P = .11). In subgroup analysis, lean HBV‐HCV subjects with detectable HBV DNA had less steatosis than lean HCV subjects matched for HCV viremia (15% vs 45%, P = .02). Our literature search identified 5 additional studies included in a systematic review. Overall, prevalence of steatosis > 5% was similar in HBV‐HCV infection compared to HCV (pooled odds ratio [OR] 0.91, 95% CI 0.53‐1.6) although there was significant heterogeneity (I2 69%, P = .007). In conclusion, although the prevalence of steatosis is similar in HBV‐HCV compared to HCV subjects, our analysis suggests that there may be an inhibitory effect of HCV‐induced steatogenesis by HBV in certain subgroups of patients. [ABSTRACT FROM AUTHOR]

Published
2018
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27. HBV-HDV co-infection constrains HBV genetic evolution in HBsAg

Author

Colagrossi, L., primary, Scutari, R., additional, Salpini, R., additional, Battisti, A., additional, Pollicita, M., additional, Bertoli, A., additional, Minichini, C., additional, Trimoulet, P., additional, Fleury, H., additional, Nebuloso, E., additional, De Cristofaro, M., additional, Cappiello, G., additional, Spanò, A., additional, Malagnino, V., additional, Sarmati, L., additional, Mari, T., additional, Barlattani, A., additional, Iapadre, N., additional, Lichtner, M., additional, Mastroianni, C., additional, Lenci, I., additional, Baiocchi, L., additional, Pasquazzi, C., additional, Sanctis, G. Maria De, additional, Lanza, A.G., additional, Stanzione, M., additional, Stornaiuolo, G., additional, Marignani, M., additional, Andreoni, M., additional, Angelico, M., additional, Perno, C.F., additional, Coppola, N., additional, and Svicher, V., additional

Published
2016
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29. The impact of the CB2-63 polymorphism on the histological presentation of chronic hepatitis B

Author

Coppola, N., primary, Zampino, R., additional, Bellini, G., additional, Stanzione, M., additional, Capoluongo, N., additional, Marrone, A., additional, Macera, M., additional, Pasquale, G., additional, Boemio, A., additional, Maione, S., additional, Adinolfi, L.E., additional, Del Giudice, E. Miraglia, additional, Sagnelli, E., additional, and Rossi, F., additional

Published
2015
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32. THU-142 - Hepatitis Delta Antigen (HDAg) is characterized by an extensive degree of genetic variability that correlates with elevated levels of serum HDV-RNA

Author

Colagrossi, L., Salpini, R., Scutari, R., Battisti, A., Piermatteo, L., Bertoli, A., Menichini, C., Trimoulet, P., Fleury, H., Nebuloso, E., De Cristofaro, M., Cappiello, G., Spanò, A., Malagnino, V., Mari, T., Barlattani, A., Iapadre, N., Lichtner, M., Mastroianni, C.M., Lenci, I., Pasquazzi, C., De Sanctis, G.M., Lanza, A.G., Stanzione, M., Stornaiuolo, G., Marignani, M., Sarmati, L., Andreoni, M., Angelico, M., Perno, C.F., Coppola, N., and Svicher, V.

Published
2017
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33. THU-106 - HBV-HDV Co-Infection Constrains HBV Genetic Evolution in HBsAg

Author

Colagrossi, L., Scutari, R., Battisti, A., Salpini, R., Pollicita, M., Bertoli, A., Minichini, C., Trimoulet, P., Fleury, H., Nebuloso, E., Longo, R., Cappiello, G., Spanó, A., Malagnino, V., Sarmati, L., Mari, T., Barlattani, A., Iapadre, N., Lichtner, M., Mastroianni, C., Lenci, I., Baiocchi, L., Pasquazzi, C., De Sanctis, G.M., Lanza, A.G., Stanzione, M., Stornaiuolo, G., Marignani, M., Andreoni, M., Angelico, M., Perno, C.-F., Coppola, N., and Svicher, V.

Published
2016
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35. Genetic Variability in Patients with HCV-Related Hepatocellular Carcinoma

Author

Mariantonietta Pisaturo, Alessandra Di Fraia, Laura Occhiello, Carmine Minichini, Mario Starace, Valentina Iodice, Nunzia Farella, Maria Stanzione, Nicola Coppola, Pisaturo, M., Di Fraia, A., Occhiello, L., Minichini, C., Starace, M., Iodice, V., Farella, N., Stanzione, M., and Coppola, N.

Subjects
Pharmacology, NS5A region, aa substitutions, viral variability, phylogenesis, Infectious and parasitic diseases, RC109-216, hepatocellular carcinoma, chronic infection C, digestive system diseases, Infectious Diseases, Phylogenesi, core region, Infection and Drug Resistance, HCV, chronic hepatitis C, NS3 region, Pharmacology (medical), Aa substitution, Original Research
Abstract

Mariantonietta Pisaturo,1 Alessandra Di Fraia,1 Laura Occhiello,1 Carmine Minichini,1 Mario Starace,1 Valentina Iodice,2 Nunzia Farella,2 Maria Stanzione,1 Nicola Coppola1 1Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania “L. Vanvitelli”, Naples, Italy; 2IX Infectious Disease Unit, AORN dei Colli, Naples, ItalyCorrespondence: Nicola CoppolaDepartment of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Via L. Armanni 5, Naples, 80131, ItalyTel +39 081 5666223Fax +39 081 5666013Email nicola.coppola@unicampania.itBackground: The present paper evaluates the genetic variability of HCV in patients with hepatocellular carcinoma (HCC).Methods: Amino acid substitutions (aas) in NS3, NS5A and core regions were analyzed in 17 patients with HCC (Cases) and 13 without HCC (Controls), all naïve to DAAs. For the Cases, a sample of neoplastic liver tissue, non-neoplastic liver tissue and a serum sample were collected; for the Controls, a sample of liver tissue was collected. Sanger sequencing of three regions was performed using homemade protocols.Results: Phylogenetic trees showed that there was no difference in the virus populations in the three compartments analyzed for the three HCV regions in patients with HCC. Low variability and no difference between the Cases and Controls were observed in the core and NS5A regions; however, in the NS3 region, a higher variability was observed in the Cases. No difference was observed in the core region between Cases and Controls. In NS3, aa substitutions at positions 103 and 122 were more frequently found in Cases than Controls (in both cases 50% vs 9.1%, p< 0.05); moreover, aas in positions 32, 44 (p=0.035 for both), 79 (p=0.008) and 121 (p=0.018) were observed in the Cases and absent in the Controls. Finally, considering the NS5A region, aa substitutions at positions 37 and 54 were more frequently identified in the Cases than the Controls, but without statistical significance.Conclusion: These data may suggest a higher aa variability in patients with HCC than in those without, especially in the NS3 region.Keywords: hepatocellular carcinoma, HCV, viral variability, chronic hepatitis C, chronic infection C, core region, NS5A region, NS3 region, aa substitutions, phylogenesis

Published
2021

36. How Immunotherapy Has Changed the Continuum of Care in Hepatocellular Carcinoma

Author

Stefania Napolitano, Francesco Selvaggi, Maria Stanzione, Fortunato Ciardiello, Fabrizio Urraro, Erika Martinelli, Alessandro Federico, Giulia Martini, Carminia Maria Della Corte, Valeria Nacca, M. Niosi, Davide Ciardiello, Walter Santaniello, Fernando Paragliola, Marcello Dallio, Martini, G., Ciardiello, D., Paragliola, F., Nacca, V., Santaniello, W., Urraro, F., Stanzione, M., Niosi, M., Dallio, M., Federico, A., Selvaggi, F., Corte, C. M. D., Napolitano, S., Ciardiello, F., and Martinelli, E.

Subjects
Sorafenib, Oncology, Cancer Research, medicine.medical_specialty, AFP, multimodal treatment, Ipilimumab, Immune checkpoint inhibitor, Pembrolizumab, Review, Ramucirumab, immune checkpoint inhibitors, chemistry.chemical_compound, Atezolizumab, Internal medicine, Medicine, HCC, RC254-282, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, biomarkers, Biomarker, digestive system diseases, chemistry, Liver function, Nivolumab, business, Lenvatinib, medicine.drug
Abstract

Simple Summary HCC is a very aggressive disease and patients diagnosed in an advanced/metastatic setting obtain poor survival outcomes with standard treatments. In recent years, the introduction of immunotherapy strategies, such as immune checkpoint inhibitors as single agents and in combination with already approved local and systemic treatments, has strongly changed the therapeutic landscape of HCC. Soon, the discovery of novel potential immune targets, together with the understanding of potential biomarkers of resistance, will help to better define novel treatment opportunities for patients with HCC. Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment of patients with metastatic disease was limited to the use of the multikinase inhibitor (MKI) sorafenib with a marginal effect on survival outcome. New target approaches, such as the oral MKI lenvatinib in first-line treatment and regorafenib, ramucirumab, and cabozantinib in later lines of therapy, have demonstrated efficacy in patients with preserved liver function (Child–Pugh class A) and good performance status. On the other hand, the implementation of immune checkpoint inhibitors directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab), and anti-CTLA4 (ipilimumab) in the management of advanced HCC has strongly changed the continuum of care of HCC. Future research should include the evaluation of molecular biomarkers that can help patient selection and provide new insight on potential combined approaches. In this review, we provide an overview of the clinical evidence of the use of immune checkpoint inhibitors in HCC, and discuss how immunotherapy has been implemented into the continuum of HCC care.

Published
2021

37. Changing epidemiology of patients treated with direct acting antivirals for HCV and persistently high SVR12 in an endemic area for HCV infection in Italy: real-life ‘LIver Network Activity’ (LINA) cohort update results

Author

Salvatore Martini, Simona Mercinelli, Nicola Coppola, Biagio Pinchera, Vincenzo Messina, Carmine Coppola, G. Stornaiuolo, Maria Stanzione, Mariagiovanna Nerilli, Riccardo Scotto, Antonio Riccardo Buonomo, Ivan Gentile, Laura Staiano, Stefania De Pascalis, Letizia Cattaneo, Scotto, R., Buonomo, A. R., De Pascalis, S., Nerilli, M., Pinchera, B., Staiano, L., Mercinelli, S., Cattaneo, L., Stanzione, M., Stornaiuolo, G., Martini, S., Messina, V., Coppola, C., Coppola, N., Gentile, I., Scotto, Riccardo, Buonomo, Antonio Riccardo, De Pascalis, Stefania, Nerilli, Mariagiovanna, Pinchera, Biagio, Staiano, Laura, Mercinelli, Simona, Cattaneo, Letizia, Stanzione, Maria, Stornaiuolo, Gianfranca, Martini, Salvatore, Messina, Vincenzo, Coppola, Carmine, Coppola, Nicola, and Gentile, Ivan

Subjects
Research design, Cyclopropanes, Liver Cirrhosis, Male, Cirrhosis, Aminoisobutyric Acids, Pyrrolidines, Sustained Virologic Response, Hepacivirus, DIRECT ACTING ANTIVIRALS, Liver disease, 0302 clinical medicine, Epidemiology, Prospective Studies, Prospective cohort study, Sulfonamides, Gastroenterology, Imidazoles, Endemic area, Middle Aged, Italy, 030220 oncology & carcinogenesis, Cohort, HCV, 030211 gastroenterology & hepatology, Female, epidemiology, Adult, medicine.medical_specialty, Genotype, Proline, Lactams, Macrocyclic, Antiviral Agents, Heterocyclic Compounds, 4 or More Rings, 03 medical and health sciences, Age Distribution, Leucine, Internal medicine, Quinoxalines, medicine, Humans, real-life, Aged, Benzofurans, Retrospective Studies, DAA, Hepatology, business.industry, Hepatitis C, Chronic, medicine.disease, Amides, SVR12, Benzimidazoles, Carbamates, business
Abstract

Background: Second generation direct acting antivirals (DAAs) drastically changed the landscape of chronic HCV (CHCV). Aim of this paper was to assess the effectiveness of DAAs, also looking at the demographic characteristics of subjects enrolled. Research design and methods: Ambispective multi-center real-life study conducted among patients with CHCV treated with DAAs in Campania Region (Southern Italy). Patient were enrolled in two cohorts according to time of enrolment. Results: 1,479 patients were enrolled. Patients aged ≥60 years were 74.7% in the historic cohort (953 patients) and 70.2% in the prospective cohort (526 patients. Patients aged ≥ 60 years showed a higher prevalence of genotype 1b (p

Published
2021

38. Anticoagulant treatment in COVID-19: a narrative review

Author

Carfora, Vincenzo, Spiniello, Giorgio, Ricciolino, Riccardo, Di Mauro, Marco, Migliaccio, Marco Giuseppe, Mottola, Filiberto Fausto, Verde, Nicoletta, Coppola, Nicola, Sagnelli, Caterina, De Pascalis, Stefania, Stanzione, Maria, Stornaiuolo, Gianfranca, Cascone, Angela, Martini, Salvatore, Macera, Margherita, Monari, Caterina, Calò, Federica, Bianco, Andrea, Russo, Antonio, Gentile, Valeria, Camaioni, Clarissa, De Angelis, Giulia, Marino, Giulia, Astorri, Roberta, De Sio, Ilario, Niosi, Marco, Borrelli, Serena, Celia, Benito, Ceparano, Maria, Cirillo, Salvatore, De Luca, Maria, Mazzeo, Grazia, Paoli, Giorgio, Russo, Maria Giovanna, Carfora, V., Spiniello, G., Ricciolino, R., Di Mauro, M., Migliaccio, M. G., Mottola, F. F., Verde, N., Coppola, N., Sagnelli, C., De Pascalis, S., Stanzione, M., Stornaiuolo, G., Cascone, A., Martini, S., Macera, M., Monari, C., Calo, F., Bianco, A., Gentile, V., Camaioni, C., De Angelis, G., Marino, G., Astorri, R., De Sio, I., Niosi, M., Borrelli, S., Celia, B., Ceparano, M., Cirillo, S., De Luca, M., Mazzeo, G., Paoli, G., Russo, M. G., and Russo, A.

Subjects
medicine.medical_specialty, Disease, 030204 cardiovascular system & hematology, medicine.disease_cause, Article, Pathogenesis, 03 medical and health sciences, Anticoagulation, 0302 clinical medicine, Internal medicine, Pandemic, medicine, Humans, Thrombophilia, Endothelial dysfunction, Intensive care medicine, 030304 developmental biology, Coronavirus, 0303 health sciences, Hematology, business.industry, SARS-CoV-2, Anticoagulants, COVID-19, Thrombosis, medicine.disease, COVID-19 Drug Treatment, Host-Pathogen Interactions, business, Cytokine storm, Cardiology and Cardiovascular Medicine, Algorithms
Abstract

The actual Coronavirus Disease (COVID 19) pandemic is due to Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the coronavirus family. Besides the respiratory involvement, COVID 19 patients frequently develop a pro-coagulative state caused by virus-induced endothelial dysfunction, cytokine storm and complement cascade hyperactivation. It is common to observe diffuse microvascular thrombi in multiple organs, mostly in pulmonary microvessels. Thrombotic risk seems to be directly related to disease severity and worsens patients’ prognosis. Therefore, the correct understanding of the mechanisms underlying COVID-19 induced prothrombotic state can lead to a thorough assessment of the possible management strategies. Hence, we review the pathogenesis and therapy of COVID 19-related thrombosis disease, focusing on the available evidence on the possible treatment strategies and proposing an algorithm for the anticoagulation strategy based on disease severity.

Published
2020
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39. CB2-63 polymorphism and immune-mediated diseases associated with HCV chronic infection

Author

Emanuele Miraglia del Giudice, Margherita Macera, Giulia Bellini, Evangelista Sagnelli, Nicola Coppola, Rosa Zampino, Aldo Marrone, Ivan Gentile, Luigi Elio Adinolfi, Maria Stanzione, Nicolina Capoluongo, Francesca Rossi, Coppola, Nicola, Zampino, Rosa, Bellini, Giulia, Stanzione, Maria, Capoluongo, Nicolina, Marrone, Aldo, Macera, Margherita, Adinolfi, Luigi Elio, Giudice, Emanuele Miraglia Del, Gentile, Ivan, Sagnelli, Evangelista, Rossi, Francesca, Stanzione, M, Capoluongo, N, Macera, M, Giudice, Em, and Gentile, I

Subjects
Adult, Male, medicine.medical_specialty, CB2 polymorphism, Single-nucleotide polymorphism, Hepacivirus, Polymorphism, Single Nucleotide, Gastroenterology, Serology, Receptor, Cannabinoid, CB2, Autoimmune thyroiditis, 03 medical and health sciences, 0302 clinical medicine, Psoriasis, Internal medicine, Epidemiology, medicine, Humans, Autoimmune thyroiditi, Aged, Autoantibodies, Hepatology, business.industry, Medicine (all), Thyroiditis, Autoimmune, Hepatitis C, Chronic, Middle Aged, Non-organ-specific autoantibodie, medicine.disease, Cryoglobulinemia, HCV infection, Lymphoma, Logistic Models, Italy, 030220 oncology & carcinogenesis, Multivariate Analysis, Immunology, Female, 030211 gastroenterology & hepatology, Autoimmune hemolytic anemia, business
Abstract

Aims To evaluate whether CB2 variants are associated with the presence of immune-mediated disorders (IMDs) in patients with chronic HCV infection. Methods One hundred and sixty-eight anti-HCV/HCV-RNA-positive patients were enrolled, 81 with signs of IMDs and 87 without. In the IMDs group, 22 (27.2%) showed ANA positivity (titers ≥1:160), 3 (3.7%) SMA positivity (titers ≥1:160), 24 (29.6%) had cryoglobulinemia, 25 (30.9%) autoimmune thyroiditis, 4 (4.9%) psoriasis, 2 (2.5%) B-cell non-Hodgkin lymphoma and 1 (1.2%) autoimmune hemolytic anemia. All patients were screened for the CNR2 rs35761398 single nucleotide polymorphism using a TaqMan Assay. Results Compared with the 87 patients without IMDs, the 81 with IMDs were more frequently females (65% vs. 45%, p = 0.01), but no significant difference was found in the initial demographic, epidemiological, serological, biochemical or virological data. Instead, the prevalence of patients with the CB2-63 RR variant was significantly higher in the IMD than in the non-IMD group (49.4% vs. 24.1%, p = 0.001). A logistic regression analysis including the CB2-63 receptor (RR vs. QR or QQ), age and sex identified the CB2-63 RR as the only independent predictor of IMDs (p = 0.005). Conclusions The data suggest a significant, previously unknown, independent association between the CB2-63 RR variant and IMDs in anti-HCV-positive patients. The study was approved by the Ethics Committee of the Azienda Ospedaliera Universitaria of the Second University of Naples (n° 214/2012).

Published
2016
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40. Patologie virali tropicali (Flavivirus, Filovirus, Arenavirus, Bunyavirus, Togavirus: Chikungunya

Author

G. Borgia, G. B. Gaeta, I. gentile, N. Coppola, L. Alessio, G. Angarano, S. Babudieri, A. Bartoloni, F. Borgia, F. Borrelli, G. Brancaccio, A. R. Buonomo, B. S. Cacopardo, A. Cascio, C. Contini, S. Esposito, M. Fasano, M. Foggia, M. Gatti, V. Gentile, M. Macera, A. E. Maraolo, A. Marino, C. M. Mastroianni, C. Mussini, G. Nunnari, L. Onorato, M. Pacenti, G. F. Pellicanò, B. Pinchera, G. Pipitone, M. A. Pisaturo, C. Sagnelli, T. A. Santantonio, A. Santoro, A. Saracino, M. Spaziante, M. Spinicci, M. Stanzione, G. Stornaiuolo, G. Taliani, G. Tosone, C. Torti, P. Viale, L. Zammarchi, E. Zappulo, G. Borgia, G.B. Gaeta, I. Gentile, N. Coppola, Borgia, G., Gaeta, G. B., Gentile, I., Coppola, N., Alessio, L., Angarano, G., Babudieri, S., Bartoloni, A., Borgia, F., Borrelli, F., Brancaccio, G., Buonomo, A. R., Cacopardo, B. S., Cascio, A., Contini, C., Esposito, S., Fasano, M., Foggia, M., Gatti, M., Gentile, V., Macera, M., Maraolo, A. E., Marino, A., Mastroianni, C. M., Mussini, C., Nunnari, G., Onorato, L., Pacenti, M., Pellicanò, G. F., Pinchera, B., Pipitone, G., Pisaturo, M. A., Sagnelli, C., Santantonio, T. A., Santoro, A., Saracino, A., Spaziante, M., Spinicci, M., Stanzione, M., Stornaiuolo, G., Taliani, G., Tosone, G., Torti, C., Viale, P., Zammarchi, L., and Zappulo, E.

Published
2019

41. Effect of hepatitis B virus on steatosis in hepatitis C virus co-infected subjects : A multi-centre study and systematic review

Author

Rosa Zampino, David Semela, Laura Rubbia-Brandt, Le Adinolfi, Nicola Coppola, Darius Moradpour, Beat Müllhaupt, Sophie Clément, Giovanni Cenderello, Francesco Negro, Heiner Wedemeyer, Nasser Semmo, Nicolas Goossens, Raffaele Malinverni, Markus H. Heim, Maria Stanzione, Gaia Trincucci, C. De Vito, Roberta D'Ambrosio, Alessandra Mangia, Francisco Barrera, University of Zurich, Goossens, N, de Vito, C, Mangia, A, Clément, S, Cenderello, G, Barrera, F, D'Ambrosio, R, Coppola, Nicola, Zampino, R, Stanzione, M, Adinolfi, Le, Wedemeyer, H, Semmo, N, Müllhaupt, B, Semela, D, Malinverni, R, Moradpour, D, Heim, M, Trincucci, G, Rubbia-Brandt, L, and Negro, F.

Subjects
Adult, Male, medicine.medical_specialty, Hepatitis C virus, Medizin, 610 Medicine & health, ddc:616.07, medicine.disease_cause, Gastroenterology, 03 medical and health sciences, Hepatitis B, Chronic, 0302 clinical medicine, Virology, Internal medicine, Prevalence, medicine, Humans, Retrospective Studies, Hepatitis B virus, ddc:616, Hepatology, Coinfection, business.industry, virus diseases, Retrospective cohort study, 2725 Infectious Diseases, Hepatitis C, Hepatitis C, Chronic, Middle Aged, Hepatitis B, medicine.disease, digestive system diseases, 3. Good health, Fatty Liver, 10219 Clinic for Gastroenterology and Hepatology, Infectious Diseases, 030220 oncology & carcinogenesis, Cohort, 2406 Virology, 2721 Hepatology, Female, 030211 gastroenterology & hepatology, Steatosis, business
Abstract

It remains unclear whether hepatitis B virus (HBV) infection may modify the severity of viral steatosis in patients coinfected with chronic hepatitis C virus (HCV). We examined the influence of coinfection with HBV on prevalence of steatosis in chronic hepatitis C in a multi-centre cohort of HBV-HCV subjects, and by performing a systematic review and meta-analysis of the literature. We centrally and blindly assessed steatosis prevalence and severity in a cohort of HBV-HCV coinfected subjects compared to HCV and HBV monoinfected controls and we performed a systematic review of studies addressing the prevalence of steatosis in HBV-HCV subjects compared to HCV controls. In the clinical cohort, we included 85 HBV-HCV, 69 HBV and 112 HCV subjects from 16 international centres. There was no significant difference in steatosis prevalence between the HBV-HCV and the HCV groups (33% vs 45%, P = .11). In subgroup analysis, lean HBV-HCV subjects with detectable HBV DNA had less steatosis than lean HCV subjects matched for HCV viremia (15% vs 45%, P = .02). Our literature search identified 5 additional studies included in a systematic review. Overall, prevalence of steatosis > 5% was similar in HBV-HCV infection compared to HCV (pooled odds ratio [OR] 0.91, 95% CI 0.53-1.6) although there was significant heterogeneity (I2 69%, P = .007). In conclusion, although the prevalence of steatosis is similar in HBV-HCV compared to HCV subjects, our analysis suggests that there may be an inhibitory effect of HCV-induced steatogenesis by HBV in certain subgroups of patients.

Published
2018

42. ITPase activity modulates the severity of anaemia in HCV-related cirrhosis treated with ribavirin-containing interferon-free regimens

Author

Maria Stanzione, Federica Calò, Carmine Minichini, Rosa Zampino, Mario Starace, Luca Rinaldi, Nicola Coppola, Salvatore Martini, Pietro Filippini, Stefania De Pascalis, Giovanni Battista Gaeta, Antonio Riccardo Buonomo, Ivan Gentile, Giorgio de Stefano, Alessandro Federico, Marcello Persico, Giovanni Di Caprio, Vincenzo Messina, G. Stornaiuolo, Guglielmo Borgia, Tiziana Ascione, Vincenzo Sangiovanni, Coppola, Nicola, De Pascalis, S, Messina, V, Di Caprio, G, Martini, Saturnino, de Stefano, G, Starace, M, Stornaiuolo, G, Stanzione, M, Ascione, T, Minichini, C, Sangiovanni, V, Zampino, Rosa, Calã², F, Rinaldi, L, Persico, M, Federico, Alessandro, Buonomo, Ar, Borgia, G, Gaeta, Giovanni Battista, Filippini, Pietro, Gentile, I., De Pascalis, Stefania, Messina, Vincenzo, Di Caprio, Giovanni, Martini, Salvatore, de Stefano, Giorgio, Starace, Mario, Stornaiuolo, Gianfranca, Stanzione, Maria, Ascione, Tiziana, Minichini, Carmine, Sangiovanni, Vincenzo, Calò, Federica, Rinaldi, Luca, Persico, Marcello, Buonomo, ANTONIO RICCARDO, Borgia, Guglielmo, and Gentile, Ivan

Subjects
Liver Cirrhosis, Male, Cirrhosis, 01 natural sciences, Gastroenterology, Severity of Illness Index, ITPase activity, chemistry.chemical_compound, 0302 clinical medicine, Gene Frequency, Risk Factors, Odds Ratio, Pharmacology (medical), Chronic, Pyrophosphatases, Anemia, Single Nucleotide, Middle Aged, Hepatitis C, Infectious Diseases, Combination, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Female, Disease Susceptibility, INOSINE TRIPHOSPHATASE, medicine.medical_specialty, Aged, Alleles, Antiviral Agents, Enzyme Activation, Genotype, Hepatitis C, Chronic, Humans, Polymorphism, Single Nucleotide, Ribavirin, 010402 general chemistry, 03 medical and health sciences, Drug Therapy, Internal medicine, medicine, Polymorphism, Pharmacology, business.industry, Interferon free, medicine.disease, 0104 chemical sciences, chemistry, business
Abstract

Background To investigate the association between inosine triphosphatase (ITPase) activity and the degree of anaemia occurring during direct-acting antiviral (DAA)/ribavirin (RBV)-based therapy in patients with cirrhosis. Methods In a multicentre, prospective study 227 patients with HCV-related cirrhosis treated with DAA and RBV were enrolled. All patients were screened for the rs1127354 and rs7270101 ITPA single nucleotide polymorphisms using direct sequencing. Results 150 (66.1%) patients had normal (100%) ITPase activity, 48 (21.1%) had moderate (60%) activity and 29 (12.8%) minimal (≤30%) activity. The ITPase activity significantly influenced the haemoglobin concentration: at day 15 it was -1.248 (sd ±0.978) in the 150 patients with an ITPase activity of 100% and -0.616 (±0.862) in the 77 patients with an ITPase activity less than 100% ( P Conclusions This study suggests that the polymorphisms in the ITPA gene influence the severity of anaemia during the first month of a DAA/RBV-based treatment in HCV-related cirrhosis.

Published
2017

43. A holistic evaluation of patients with chronic Hepatitis D virus (HDV) infection enrolled in the Italian PITER-B and delta cohort.

Author

Kondili LA, Brancaccio G, Tosti ME, Coco B, Quaranta MG, Messina V, Ciancio A, Morisco F, Cossiga V, Claar E, Rosato V, Ciarallo M, Cacciola I, Ponziani FR, Cerrito L, Coppola R, Longobardi F, Biliotti E, Rianda A, Barbaro F, Coppola N, Stanzione M, Barchiesi F, Fagiuoli S, Viganò M, Massari M, Russo FP, Ferrarese A, Laccabue D, Di Marco V, Blanc P, Marrone A, Morsica G, Federico A, Ieluzzi D, Rocco A, Foschi FG, Soria A, Maida I, Chessa L, Milella M, Rosselli Del Turco E, Madonia S, Chemello L, Gentile I, Toniutto P, Bassetti M, Surace L, Baiocchi L, Pellicelli A, De Santis A, Puoti M, Degasperi E, Niro GA, Zignego AL, Craxi A, Raimondo G, Santantonio TA, Brunetto MR, and Gaeta GB

Subjects
Humans, Female, Male, Italy epidemiology, Adult, Middle Aged, Cross-Sectional Studies, Cohort Studies, Liver Cirrhosis epidemiology, Liver Cirrhosis virology, Carcinoma, Hepatocellular epidemiology, Carcinoma, Hepatocellular virology, Comorbidity, Aged, Hepatitis B Surface Antigens blood, Liver Neoplasms epidemiology, Liver Neoplasms virology, Interferons therapeutic use, Antiviral Agents therapeutic use, Hepatitis D, Chronic epidemiology, Hepatitis Delta Virus immunology, Hepatitis Delta Virus genetics
Abstract

Background and Aims: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility., Methods: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model., Results: Of 5492 HBsAg-positive enrolled patients, 4152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age ≤ 40 years vs. 2.1%; P < 0.001), more often females (males 43.0% vs. 68.6%; P < 0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care., Conclusions: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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44. Effectiveness of test-and-treat model with direct-acting antiviral for hepatitis C virus infection in migrants: a prospective interventional study in Italy.

Author

Coppola N, Alessio L, De Pascalis S, Macera M, Di Caprio G, Messina V, Onorato L, Minichini C, Stanzione M, Stornaiuolo G, Starace M, Monari C, Calò F, Sagnelli C, and Pisaturo M

Subjects
Humans, Italy epidemiology, Prospective Studies, Male, Female, Adult, Middle Aged, Hepacivirus drug effects, Hepacivirus genetics, Sofosbuvir therapeutic use, Young Adult, Mass Screening, Refugees, Poverty, Antiviral Agents therapeutic use, Hepatitis C drug therapy, Hepatitis C epidemiology, Hepatitis C virology, Transients and Migrants statistics & numerical data
Abstract

Background: Migrants, mainly undocumented and low-income refugees, are at high risk of hepatitis C virus (HCV) infection, but are a difficult-to-reach and to-treat population. The aim of the study was to evaluate the effectiveness of a test and treat model with direct-acting antiviral for HCV infection in these migrants coming from low-income and living in southern Italy., Methods: A prospective, multicenter, collaborative study based on a four-phase-program (educational counseling, screening, linkage-to-care and treatment) was designed in southern Italy; the study started in June 2018, was stopped in February 2020 because of the outbreak of SARS-CoV2 infection in Italy and was resumed in February 2021 until November 2021. After educational counseling on infectious diseases that are transmitted through blood or sexually pseudonymized HCV screening was offered to all undocumented migrants and low-income refugees observed at one of the 1st level clinical centers. The HCV-RNA-positive subjects were referred to one of the 3rd level units of Infectious Diseases (ID) and treated with a 12-week course of sofosbuvir-velpatasvir and observed for 12 weeks after the end of direct antiviral agents (DAA) treatment., Statistical Analysis: For the descriptive analysis, the categorical variables were reported as absolute numbers and relative frequencies. Continuous variables were summarized as mean and standard deviation (SD) if normally distributed, or as a median and interquartile range (IQR) if not normally distributed. We used Pearson chi-square or Fisher's exact test for categorical variables and Student's t test or Mann-Whitney test for continuous variables. A P value < 0.05 was considered to be statistically significant. Analyses were performed with SPSS 21.0., Results: Of the 3501migrants observed in the study period, 3417 (97.6%) agreed to be screened; 185 (4.7%) were anti-HCV-positive and, of these, 53 (28.6%) were HCV-RNA-positive. Of these 53 subjects, 48 (90.5%) were referred to an ID unit and started DAA treatment. The HCV-RNA-positive-subjects were older [median 36 years (IQR: 32-21) vs 27.19 (IQR: 30.5-19.25); P = 0.001], and less frequently males [35 (66.03 %) vs 119 (90.1%), P < 0 .0001] than seronegative participants. They more frequently came from Eastern Europe (70.8%) stayed longer in Italy [months of stay in Italy, mean ± SD: 51.02 ± 52.84 vs 25.7 ± 42.65, P = 0.001], and had more years of schooling [years of schooling, mean ± SD: 9.61±2.81 vs 7.10 ± 4, P = 0.0001]. HCV-RNA-positive-subjects less frequently reported piercing, tattoos and tribal scars as risk factors (23.6%). Of these 48 HCV RNA positive subjects who started DAA, 47 (97.9%) showed a sustained virological response and one dropped-out in follow-up after DAA treatment. No subject had any adverse event., Conclusions: This model of HCV screening and linkage to care seems effective to eliminate HCV infectionin a difficult-to-reach and to-treat population, such as undocumented migrants and low-income refugees. The participation of cultural mediators in the study made possible a better interaction between migrants and physicians, as is evident from the large number of subjects enrolled. Eliminating HCV among migrants will have a long-term positive impact from a public health and healthcare perspective by reducing the number of individuals who potentially develop HCV-related complications such as liver cirrhosis and hepatocellular carcinoma and reducing the circulation of HCV in the regions that host them which often, as in the case of Italy, are low endemic for HCV infection., (© 2024. The Author(s).)

Published
2024
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45. Lead compound profiling for small molecule inhibitors of the REV1-CT/RIR Translesion synthesis Protein-Protein interaction.

Author

Zaino AM, Dash RC, James SJ, MacGilvary N, Crompton A, McPherson KS, Stanzione M, Korzhnev DM, Dyson NJ, Chatterjee N, Cantor SB, and Hadden MK

Subjects
Humans, Animals, Structure-Activity Relationship, Protein Binding, Molecular Structure, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Dose-Response Relationship, Drug, DNA-Directed DNA Polymerase metabolism, Mice, Translesion DNA Synthesis, Nucleotidyltransferases antagonists & inhibitors, Nucleotidyltransferases metabolism, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Small Molecule Libraries chemical synthesis
Abstract

Translesion synthesis (TLS) is a cellular mechanism through which actively replicating cells recruit specialized, low-fidelity DNA polymerases to damaged DNA to allow for replication past these lesions. REV1 is one of these TLS DNA polymerases that functions primarily as a scaffolding protein to organize the TLS heteroprotein complex and ensure replication occurs in the presence of DNA lesions. The C-Terminal domain of REV1 (REV1-CT) forms many protein-protein interactions (PPIs) with other TLS polymerases, making it essential for TLS function and a promising drug target for anti-cancer drug development. We utilized several lead identification strategies to identify various small molecules capable of disrupting the PPI between REV1-CT and the REV1 Interacting Regions (RIR) present in several other TLS polymerases. These lead compounds were profiled in several in vitro potency and PK assays to identify two scaffolds (1 and 6) as the most promising for further development. Both 1 and 6 synergized with cisplatin in a REV1-dependent fashion and demonstrated promising in vivo PK and toxicity profiles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Published
2024
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46. Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs.

Author

Pal Choudhuri S, Girard L, Lim JYS, Wise JF, Freitas B, Yang D, Wong E, Hamilton S, Chien VD, Kim YJ, Gilbreath C, Zhong J, Phat S, Myers DT, Christensen CL, Mazloom-Farsibaf H, Stanzione M, Wong KK, Hung YP, Farago AF, Meador CB, Dyson NJ, Lawrence MS, Wu S, and Drapkin BJ

Subjects
Humans, Mice, Animals, Proto-Oncogene Proteins c-myc genetics, Xenograft Model Antitumor Assays, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma drug therapy, Small Cell Lung Carcinoma pathology, Lung Neoplasms genetics, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Drug Resistance, Neoplasm genetics, Gene Amplification
Abstract

Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a preclinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC., Significance: SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC. This article is featured in Selected Articles from This Issue, p. 695., (©2024 The Authors; Published by the American Association for Cancer Research.)

Published
2024
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47. Seeding the meiotic DNA break machinery and initiating recombination on chromosome axes.

Author

Dereli I, Telychko V, Papanikos F, Raveendran K, Xu J, Boekhout M, Stanzione M, Neuditschko B, Imjeti NS, Selezneva E, Tuncay H, Demir S, Giannattasio T, Gentzel M, Bondarieva A, Stevense M, Barchi M, Schnittger A, Weir JR, Herzog F, Keeney S, and Tóth A

Subjects
Mice, Animals, DNA, Meiosis genetics, Synaptonemal Complex metabolism, Recombination, Genetic, Homologous Recombination, Cell Cycle Proteins metabolism, DNA Breaks, Double-Stranded
Abstract

Programmed DNA double-strand break (DSB) formation is a crucial feature of meiosis in most organisms. DSBs initiate recombination-mediated linking of homologous chromosomes, which enables correct chromosome segregation in meiosis. DSBs are generated on chromosome axes by heterooligomeric focal clusters of DSB-factors. Whereas DNA-driven protein condensation is thought to assemble the DSB-machinery, its targeting to chromosome axes is poorly understood. We uncover in mice that efficient biogenesis of DSB-machinery clusters requires seeding by axial IHO1 platforms. Both IHO1 phosphorylation and formation of axial IHO1 platforms are diminished by chemical inhibition of DBF4-dependent kinase (DDK), suggesting that DDK contributes to the control of the axial DSB-machinery. Furthermore, we show that axial IHO1 platforms are based on an interaction between IHO1 and the chromosomal axis component HORMAD1. IHO1-HORMAD1-mediated seeding of the DSB-machinery on axes ensures sufficiency of DSBs for efficient pairing of homologous chromosomes. Without IHO1-HORMAD1 interaction, residual DSBs depend on ANKRD31, which enhances both the seeding and the growth of DSB-machinery clusters. Thus, recombination initiation is ensured by complementary pathways that differentially support seeding and growth of DSB-machinery clusters, thereby synergistically enabling DSB-machinery condensation on chromosomal axes., (© 2024. The Author(s).)

Published
2024
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48. Zein-Based Nanoparticles as Active Platforms for Sustainable Applications: Recent Advances and Perspectives.

Author

Oleandro E, Stanzione M, Buonocore GG, and Lavorgna M

Abstract

Nanomaterials, due to their unique structural and functional features, are widely investigated for potential applications in a wide range of industrial sectors. In this context, protein-based nanoparticles, given proteins' abundance, non-toxicity, and stability, offer a promising and sustainable methodology for encapsulation and protection, and can be used in engineered nanocarriers that are capable of releasing active compounds on demand. Zein is a plant-based protein extracted from corn, and it is biocompatible, biodegradable, and amphiphilic. Several approaches and technologies are currently involved in zein-based nanoparticle preparation, such as antisolvent precipitation, spray drying, supercritical processes, coacervation, and emulsion procedures. Thanks to their peculiar characteristics, zein-based nanoparticles are widely used as nanocarriers of active compounds in targeted application fields such as drug delivery, bioimaging, or soft tissue engineering, as reported by others. The main goal of this review is to investigate the use of zein-based nanocarriers for different advanced applications including food/food packaging, cosmetics, and agriculture, which are attracting researchers' efforts, and to exploit the future potential development of zein NPs in the field of cultural heritage, which is still relatively unexplored. Moreover, the presented overview focuses on several preparation methods (i.e., antisolvent processes, spry drying), correlating the different analyzed methodologies to NPs' structural and functional properties and their capability to act as carriers of bioactive compounds, both to preserve their activity and to tune their release in specific working conditions.

Published
2024
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49. Seeding the meiotic DNA break machinery and initiating recombination on chromosome axes.

Author

Dereli I, Telychko V, Papanikos F, Raveendran K, Xu J, Boekhout M, Stanzione M, Neuditschko B, Imjeti NS, Selezneva E, Erbasi HT, Demir S, Giannattasio T, Gentzel M, Bondarieva A, Stevense M, Barchi M, Schnittger A, Weir JR, Herzog F, Keeney S, and Tóth A

Abstract

Programmed DNA double-strand break (DSB) formation is a unique meiotic feature that initiates recombination-mediated linking of homologous chromosomes, thereby enabling chromosome number halving in meiosis. DSBs are generated on chromosome axes by heterooligomeric focal clusters of DSB-factors. Whereas DNA-driven protein condensation is thought to assemble the DSB-machinery, its targeting to chromosome axes is poorly understood. We discovered in mice that efficient biogenesis of DSB-machinery clusters requires seeding by axial IHO1 platforms, which are based on a DBF4-dependent kinase (DDK)-modulated interaction between IHO1 and the chromosomal axis component HORMAD1. IHO1-HORMAD1-mediated seeding of the DSB-machinery on axes ensures sufficiency of DSBs for efficient pairing of homologous chromosomes. Without IHO1-HORMAD1 interaction, residual DSBs depend on ANKRD31, which enhances both the seeding and the growth of DSB-machinery clusters. Thus, recombination initiation is ensured by complementary pathways that differentially support seeding and growth of DSB-machinery clusters, thereby synergistically enabling DSB-machinery condensation on chromosomal axes.

Published
2023
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50. Therapy-induced APOBEC3A drives evolution of persistent cancer cells.

Author

Isozaki H, Sakhtemani R, Abbasi A, Nikpour N, Stanzione M, Oh S, Langenbucher A, Monroe S, Su W, Cabanos HF, Siddiqui FM, Phan N, Jalili P, Timonina D, Bilton S, Gomez-Caraballo M, Archibald HL, Nangia V, Dionne K, Riley A, Lawlor M, Banwait MK, Cobb RG, Zou L, Dyson NJ, Ott CJ, Benes C, Getz G, Chan CS, Shaw AT, Gainor JF, Lin JJ, Sequist LV, Piotrowska Z, Yeap BY, Engelman JA, Lee JJ, Maruvka YE, Buisson R, Lawrence MS, and Hata AN

Subjects
Humans, DNA Breaks, Double-Stranded, Genomic Instability, Molecular Targeted Therapy, Mutation, Drug Resistance, Neoplasm, Cytidine Deaminase deficiency, Cytidine Deaminase drug effects, Cytidine Deaminase genetics, Cytidine Deaminase metabolism, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lung Neoplasms pathology
Abstract

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified 1-4 , the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2023
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