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1,295 results on '"Strazzabosco, M."'

2. Adherence to Tumor Board Recommendations in the Treatment of Patients with Hepatocellular Carcinoma

Author

Cao Y, Mezzacappa C, Jaffe A, Strazzabosco M, and Taddei TH

Subjects
compliance, multidisciplinary liver tumor board, hcc, treatment guidelines, Medicine (General), R5-920
Abstract

Yueming Cao,1 Catherine Mezzacappa,1,2 Ariel Jaffe,1,2 Mario Strazzabosco,1,2 Tamar H Taddei1,2 1Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; 2Department of Internal Medicine Digestive Disease Section, Yale School of Medicine, New Haven, CT, USACorrespondence: Tamar H Taddei, Department of Internal Medicine, Yale School of Medicine, PO Box 208019, New Haven, CT, 06520-8019, USA, Tel +1 203-785-7312, Fax +1 203-785-7273, Email tamar.taddei@yale.eduBackground: Hepatocellular carcinoma (HCC) is a heterogeneous disease that typically arises in the setting of chronic liver disease, making treatment selection complex. Multidisciplinary liver tumor boards (MDLTB) have been shown to improve outcomes in patients with HCC. However, in many cases, patients evaluated by MDLTBs ultimately do not receive the board’s recommended treatment.Purpose: This study aims to assess adherence to MDLTB recommendations for the treatment of HCC, the reasons for non-adherence, and the survival of Barcelona Clinic Liver Cancer (BCLC) Stage A patients treated with curative treatment compared to palliative locoregional therapy.Patients and Methods: A single-site, retrospective cohort study was conducted of all patients with treatment-naïve HCC who were evaluated by an MDLTB at a tertiary care center in Connecticut between 2013 and 2016, of which 225 patients met inclusion criteria. Investigators conducted a chart review and recorded adherence to the MDLTB’s recommendations, and in cases of discordance, evaluated and recorded the underlying cause; investigators assessed MDLTB recommendations’ compliance with BCLC guidelines. Survival data was accrued through February 1st of 2022 and analyzed via Kaplan–Meier analysis and multivariate Cox regression.Results: Treatment adherent to MDLTB recommendations occurred in 85.3% of patients (n=192). The majority of non-adherence occurred in the management of BCLC Stage A disease. In cases where adherence was possible but the recommendation was not followed, most discrepancies were whether to treat with curative or palliative intent (20/24), with almost all discrepancies occurring in patients (19/20) with BCLC Stage A disease. For patients with Stage A unifocal HCC, those who received curative therapy lived significantly longer than patients who received palliative locoregional therapy (5.55 years vs 4.26 years, p=0.037).Conclusion: Most forms of non-adherence to MDLTB recommendations were unavoidable; however, treatment discordance in the management of patients with BCLC Stage A unifocal disease may present an opportunity for clinically significant quality improvement.Keywords: compliance, multidisciplinary liver tumor board, HCC, treatment guidelines

Published
2023

3. European Society for Organ Transplantation (ESOT) Consensus Statement on Outcome Measures in Liver Transplantation According to Value-Based Health Care

Author

Carbone, M, Neuberger, J, Rowe, I, Polak, W, Forsberg, A, Fondevila, C, Mantovani, L, Nardi, A, Colli, A, Rockell, K, Schick, L, Cristoferi, L, Oniscu, G, Strazzabosco, M, Cillo, U, Carbone M., Neuberger J., Rowe I., Polak W. G., Forsberg A., Fondevila C., Mantovani L., Nardi A., Colli A., Rockell K., Schick L., Cristoferi L., Oniscu G. C., Strazzabosco M., Cillo U., Carbone, M, Neuberger, J, Rowe, I, Polak, W, Forsberg, A, Fondevila, C, Mantovani, L, Nardi, A, Colli, A, Rockell, K, Schick, L, Cristoferi, L, Oniscu, G, Strazzabosco, M, Cillo, U, Carbone M., Neuberger J., Rowe I., Polak W. G., Forsberg A., Fondevila C., Mantovani L., Nardi A., Colli A., Rockell K., Schick L., Cristoferi L., Oniscu G. C., Strazzabosco M., and Cillo U.

Abstract

Liver transplantation is a highly complex, life-saving, treatment for many patients with advanced liver disease. Liver transplantation requires multidisciplinary teams, system-wide adaptations and significant investment, as well as being an expensive treatment. Several metrics have been proposed to monitor processes and outcomes, however these lack patient focus and do not capture all aspects of the process. Most of the reported outcomes do not capture those outcomes that matter to the patients. Adopting the principles of Value-Based Health Care (VBHC), may provide an opportunity to develop those metrics that matter to patients. In this article, we present a Consensus Statement on Outcome Measures in Liver Transplantation following the principles of VBHC, developed by a dedicated panel of experts under the auspices of the European Society of Organ Transplantation (ESOT) Guidelines’ Taskforce. The overarching goal is to provide a framework to facilitate the development of outcome measures as an initial step to apply the VMC paradigm to liver transplantation.

Published
2024

5. Inflammatory pathways and cholangiocarcinoma risk mechanisms and prevention

Author

Cadamuro, M, Strazzabosco, M, Cadamuro M., Strazzabosco M., Cadamuro, M, Strazzabosco, M, Cadamuro M., and Strazzabosco M.

Abstract

Cholangiocarcinoma (CCA), a neoplasm burdened by a poor prognosis and currently lacking adequate therapeutic treatments, can originate at different levels of the biliary tree, in the intrahepatic, hilar, or extrahepatic area. The main risk factors for the development of CCA are the presence of chronic cholangiopathies of various etiology. To date, the most studied prodromal diseases of CCA are primary sclerosing cholangitis, Caroli's disease and fluke infestations, but other conditions, such as metabolic syndrome, nonalcoholic fatty liver disease and obesity, are emerging as associated with an increased risk of CCA development. In this review, we focused on the analysis of the pro-inflammatory mechanisms that induce the development of CCA and on the role of cells of the immune response in cholangiocarcinogenesis. In very recent times, these cellular mechanisms have been the subject of emerging studies aimed at verifying how the modulation of the inflammatory and immunological responses can have a therapeutic significance and how these can be used as therapeutic targets.

Published
2022

6. The Neglected Role of Bile Duct Epithelial Cells in NASH

Author

Cadamuro, M, Lasagni, A, Sarcognato, S, Guido, M, Fabris, R, Strazzabosco, M, Strain, A, Simioni, P, Villa, E, Fabris, L, Cadamuro M., Lasagni A., Sarcognato S., Guido M., Fabris R., Strazzabosco M., Strain A. J., Simioni P., Villa E., Fabris L., Cadamuro, M, Lasagni, A, Sarcognato, S, Guido, M, Fabris, R, Strazzabosco, M, Strain, A, Simioni, P, Villa, E, Fabris, L, Cadamuro M., Lasagni A., Sarcognato S., Guido M., Fabris R., Strazzabosco M., Strain A. J., Simioni P., Villa E., and Fabris L.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and affects 25% of the population in Western countries. NAFLD is the hepatic manifestation of the metabolic syndrome, linked to insulin resistance, which is the common pathogenetic mechanism. In approximately 40% of NAFLD patients, steatosis is associated with necro-inflammation and fibrosis, resulting in nonalcoholic steatohepatitis (NASH), a severe condition that may progress to cirrhosis and liver cancer. Although the hepatocyte represents the main target of the disease, involvement of the bile ducts occurs in a subset of patients with NASH, and is characterized by ductular reaction and activation of the progenitor cell compartment, which incites portal fibrosis and disease progression. We aim to dissect the multiple biological effects that adipokines and metabolic alterations exert on cholangiocytes to derive novel information on the mechanisms driven by insulin resistance, which promote fibro-inflammation and carcinogenesis in NASH.

Published
2022

7. Tumor microenvironment and immunology of cholangiocarcinoma

Author

Cadamuro, M, Fabris, L, Zhang, X, Strazzabosco, M, Cadamuro M., Fabris L., Zhang X., Strazzabosco M., Cadamuro, M, Fabris, L, Zhang, X, Strazzabosco, M, Cadamuro M., Fabris L., Zhang X., and Strazzabosco M.

Abstract

Cholangiocarcinoma (CCA), an aggressive tumor originating from both intra-and extra-hepatic biliary cells, represents an unmet need in liver oncology, as treatment remains largely unsatisfactory. A typical feature of CCA is the presence of a complex tumor microenvironment (TME) composed of neoplastic cells, a rich inflammatory infiltrate, and cancer-associated fibroblasts and desmoplastic matrix that makes it extremely chemoresistant to traditional chemotherapeutic drugs. In this review, we describe the cell populations within the TME, in particular those involved in the innate and adaptive immune response and how they interact with tumor cells and with matrix proteins. The TME is crucial for CCA to mount an immune escape response and is the battlefield where molecularly targeted therapies and immune therapy, particularly in combination, may actually prove their therapeutic value.

Published
2022

8. Translational Value of Tumor-Associated Lymphangiogenesis in Cholangiocarcinoma

Author

Cadamuro, M, Romanzi, A, Guido, M, Sarcognato, S, Cillo, U, Gringeri, E, Zanus, G, Strazzabosco, M, Simioni, P, Villa, E, Fabris, L, Cadamuro M., Romanzi A., Guido M., Sarcognato S., Cillo U., Gringeri E., Zanus G., Strazzabosco M., Simioni P., Villa E., Fabris L., Cadamuro, M, Romanzi, A, Guido, M, Sarcognato, S, Cillo, U, Gringeri, E, Zanus, G, Strazzabosco, M, Simioni, P, Villa, E, Fabris, L, Cadamuro M., Romanzi A., Guido M., Sarcognato S., Cillo U., Gringeri E., Zanus G., Strazzabosco M., Simioni P., Villa E., and Fabris L.

Abstract

The prognosis of cholangiocarcinoma remains poor in spite of the advances in immunotherapy and molecular profiling, which has led to the identification of several targetable genetic alterations. Surgical procedures, including both liver resection and liver transplantation, still represent the treatment with the best curative potential, though the outcomes are significantly compromised by the early development of lymph node metastases. Progression of lymphatic metastasis from the primary tumor to tumor-draining lymph nodes is mediated by tumor-associated lymphangiogenesis, a topic largely overlooked until recently. Recent findings highlight tumor-associated lymphangiogenesis as paradigmatic of the role played by the tumor microenvironment in sustaining cholangiocarcinoma invasiveness and progression. This study reviews the current knowledge about the intercellular signaling and molecular mechanism of tumor-associated lymphangiogenesis in cholangiocarcinoma in the hope of identifying novel therapeutic targets to halt a process that often limits the success of the few available treatments.

Published
2022

9. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581] (Journal of Hepatology (2021) 75(3) (572–581), (S0168827821003342), (10.1016/j.jhep.2021.04.055))

Author

Cordell H. J., Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byun, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Tarocchi, M, Cordell H. J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byun J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., Mells G. F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P. L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P. M., Benedetti A., Bragazzi M. C., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L. S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G. A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L. A., Overton J. D., Reid J. G., Shuldiner A., Beechert C., Forsythe C., Fuller E. D., Gu Z., Lattari M., Lopez A., Schleicher T. D., Padilla M. S., Toledo K., Widom L., Wolf S. E., Pradhan M., Manoochehri K., Ulloa R. H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E. K., Salerno W., Staples J. C., Jones M. B., Mitnaul L. J., Sturgess R., Healey C., Yeoman A., Gunasekera A. V. J., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J. A., Gorard D. A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M. R., Collins C. E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M. J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I. R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H. M., Ridpath J., Ngatchu T., Bob Grover V. P., Shidrawi R. G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M. A., Curtis H., Matthews H. C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M. I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N. N., Gupta P., Shah A., Evans C. D. J., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S. T., McDonald N., Bathgate A. J., Palmer K., Dillon J. F., Rushbrook S. M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T. J. W., Ryder S., Collier J., Klass H., Cramp M. E., Sharer N., Aspinall R., Ghosh D., Douds A. C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C. L., Rahman M., Whatley G. C. A., Wesley E., Mandal A., Jain S., Pereira S. P., Wright M., Trivedi P., Gordon F. H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A. D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S. J., Bell A., Wong V. S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Tarocchi M., Cordell H. J., Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byun, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Tarocchi, M, Cordell H. J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byun J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., Mells G. F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P. L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P. M., Benedetti A., Bragazzi M. C., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L. S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G. A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L. A., Overton J. D., Reid J. G., Shuldiner A., Beechert C., Forsythe C., Fuller E. D., Gu Z., Lattari M., Lopez A., Schleicher T. D., Padilla M. S., Toledo K., Widom L., Wolf S. E., Pradhan M., Manoochehri K., Ulloa R. H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E. K., Salerno W., Staples J. C., Jones M. B., Mitnaul L. J., Sturgess R., Healey C., Yeoman A., Gunasekera A. V. J., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J. A., Gorard D. A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M. R., Collins C. E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M. J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I. R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H. M., Ridpath J., Ngatchu T., Bob Grover V. P., Shidrawi R. G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M. A., Curtis H., Matthews H. C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M. I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N. N., Gupta P., Shah A., Evans C. D. J., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S. T., McDonald N., Bathgate A. J., Palmer K., Dillon J. F., Rushbrook S. M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T. J. W., Ryder S., Collier J., Klass H., Cramp M. E., Sharer N., Aspinall R., Ghosh D., Douds A. C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C. L., Rahman M., Whatley G. C. A., Wesley E., Mandal A., Jain S., Pereira S. P., Wright M., Trivedi P., Gordon F. H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A. D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S. J., Bell A., Wong V. S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., and Tarocchi M.

Abstract

It has come to our attention that the name of one of the authors in our manuscript was incorrectly spelled ‘Jinyoung Byan’; the correct spelling is ‘Jinyoung Byun’ as in the author list above. In addition, the excel files of the supplementary tables were not included during the online publication of our article. These have now been made available online. We apologize for any inconvenience caused.

Published
2022

11. Intrahepatic cholangiocarcinoma developing in patients with metabolic syndrome is characterized by Osteopontin overexpression in the tumor stroma

Author

Cadamuro, M, Sarcognato, S, Camerotto, R, Girardi, N, Lasagni, A, Zanus, G, Cillo, U, Gringeri, E, Morana, G, Strazzabosco, M, Campello, E, Simioni, P, Guido, M, Fabris, L, Cadamuro, M, Sarcognato, S, Camerotto, R, Girardi, N, Lasagni, A, Zanus, G, Cillo, U, Gringeri, E, Morana, G, Strazzabosco, M, Campello, E, Simioni, P, Guido, M, and Fabris, L

Published
2023

14. Short-term effectiveness of dapagliflozin versus DPP-4 inhibitors in elderly patients with type 2 diabetes: a multicentre retrospective study

Author

Morieri, M. L., Raz, I., Consoli, A., Rigato, M., Lapolla, A., Broglio, F., Bonora, E., Avogaro, A., Fadini, G. P., Ginestra, F., Formoso, G., Andreozzi, F., Sesti, G., Turco, S., Lucibelli, L., Gatti, A., Aldigeri, R., Dei Cas, A., Felace, G., Li Volsi, P., Sorice, G. P., Giaccari, A., Mignogna, C., Buzzetti, R., Filardi, T., Morano, S., Barchetta, I., Gisella Cavallo, M., Malandrucco, I., Frontoni, S., Carletti, S., D'Angelo, P., Leto, G., Leonetti, F., Silvia Morpurgo, P., Fiorina, P., Palmieri, E., Orsi, E., Mantovani, E., Franzetti, I., Querci, F., Bossi, A., Turchi, F., Manfrini, S., Guida, D., Placentino, G., Beccuti, G., Cavalot, F., Nuzzo, A., Aimaretti, G., Lamacchia, O., Cignarelli, A., Laviola, L., Giorgino, F., Devangelio, E., Cazzetta, G., Chianetta, R., Citarrella, R., Tumminia, A., Frittitta, L., Anzaldi, M., Buscema, M., Piro, S., Di Pino, A., Purrello, F., Di Benedetto, A., Russo, G., Anichini, R., Solini, A., Garofolo, M., Del Prato, S., Fattor, B., Paolo Fadini, G., Sartore, G., D'Ambrosio, M., Da Tos, V., Frison, V., Simioni, N., Cigolini, M., Brun, E., Strazzabosco, M., Poli, M., Paccagnella, A., and Vinci, C.

Subjects
Aging, Cardiovascular, Heart failure, Kidney disease, Observational
Published
2023

16. A Bayesian methodology to improve prediction of early graft loss after liver transplantation derived from the Liver Match study

Author

Angelico, M., Cillo, U., Fagiuoli, S., Strazzabosco, M., Caraceni, P., Toniutto, P.L., Nanni Costa, A., Salizzoni, Torino M., Romagnoli, R., Bertolotti, G., Patrono, D., De Carlis, L., Slim, A., Mangoni, J.M.E., Rossi, G., Caccamo, L., Antonelli, B., Mazzaferro, V., Regalia, E., Sposito, C., Colledan, M., Corno, V., Tagliabue, F., Marin, S., Vitale, A., Gringeri, E., Donataccio, M., Donataccio, D., Baccarani, U., Lorenzin, D., Bitetto, D., Valente, U., Gelli, M., Cupo, P., Gerunda, G.E., Rompianesi, G., Pinna, A.D., Grazi, G.L., Cucchetti, A., Zanfi, C., Risaliti, A., Faraci, M.G., Tisone, G., Anselmo, A., Lenci, I., Sforza, D., Agnes, S., Di Mugno, M., Avolio, A.W., Ettorre, G.M., Miglioresi, L., Vennarecci, G., Berloco, P., Rossi, M., Ginanni Corradini, S., Molinaro, A., Calise, F., Scuderi, V., Cuomo, O., Migliaccio, C., Lupo, L., Notarnicola, G., Gridelli, B., Volpes, R., Li Petri, S., Zamboni, F., Carbotta, G., Dedola, S., Nardi, A., Marianelli, T., Gavrila, C., Ricci, A., Vespasiano, F., Angelico, Mario, Nardi, Alessandra, Romagnoli, Renato, Marianelli, Tania, Corradini, Stefano Ginanni, Tandoi, Francesco, Gavrila, Caius, Salizzoni, Mauro, Pinna, Antonio D., Cillo, Umberto, Gridelli, Bruno, De Carlis, Luciano G., Colledan, Michele, Gerunda, Giorgio E., Costa, Alessandro Nanni, and Strazzabosco, Mario

Published
2014
Full Text
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19. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581] (Journal of Hepatology (2021) 75(3) (572–581), (S0168827821003342), (10.1016/j.jhep.2021.04.055))

Author

Cordell, H. J., Fryett, J. J., Ueno, K., Darlay, R., Aiba, Y., Hitomi, Y., Kawashima, M., Nishida, N., Khor, S. -S., Gervais, O., Kawai, Y., Nagasaki, M., Tokunaga, K., Tang, R., Shi, Y., Li, Z., Juran, B. D., Atkinson, E. J., Gerussi, A., Carbone, M., Asselta, R., Cheung, A., de Andrade, M., Baras, A., Horowitz, J., Ferreira, M. A. R., Sun, D., Jones, D. E., Flack, S., Spicer, A., Mulcahy, V. L., Byun, J., Han, Y., Sandford, R. N., Lazaridis, K. N., Amos, C. I., Hirschfield, G. M., Seldin, M. F., Invernizzi, P., Siminovitch, K. A., Ma, X., Nakamura, M., Mells, G. F., Mason, A., Vincent, C., Xie, G., Zhang, J., Affronti, A., Almasio, P. L., Alvaro, D., Andreone, P., Andriulli, A., Azzaroli, F., Battezzati, P. M., Benedetti, A., Bragazzi, M., Brunetto, M., Bruno, S., Calvaruso, V., Cardinale, V., Casella, G., Cazzagon, N., Ciaccio, A., Coco, B., Colli, A., Colloredo, G., Colombo, M., Colombo, S., Cristoferi, L., Cursaro, C., Croce, L. S., Crosignani, A., D'Amato, D., Donato, F., Elia, G., Fabris, L., Fagiuoli, S., Ferrari, C., Floreani, A., Galli, A., Giannini, E., Grattagliano, I., Lampertico, P., Lleo, A., Malinverno, F., Mancuso, C., Marra, F., Marzioni, M., Massironi, S., Mattalia, A., Miele, L., Milani, C., Morini, L., Morisco, F., Muratori, L., Muratori, P., Niro, G. A., O'Donnell, S., Picciotto, A., Portincasa, P., Rigamonti, C., Ronca, V., Rosina, F., Spinzi, G., Strazzabosco, M., Tarocchi, M., Tiribelli, C., Toniutto, P., Valenti, L., Vinci, M., Zuin, M., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Migita, K., Ohira, H., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Tanaka, A., Takikawa, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Kawata, K., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., H, E., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Chalasani, N., Luketic, V., Odin, J., Chopra, K., Abecasis, G., Cantor, M., Coppola, G., Economides, A., Lotta, L. A., Overton, J. D., Reid, J. G., Shuldiner, A., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A., Eom, G., Habegger, L., Hawes, A., Khalid, S., Maxwell, E. K., Salerno, W., Staples, J. C., Jones, M. B., Mitnaul, L. J., Sturgess, R., Healey, C., Yeoman, A., Gunasekera, A. V., Kooner, P., Kapur, K., Sathyanarayana, V., Kallis, Y., Subhani, J., Harvey, R., Mccorry, R., Rooney, P., Ramanaden, D., Evans, R., Mathialahan, T., Gasem, J., Shorrock, C., Bhalme, M., Southern, P., Tibble, J. A., Gorard, D. A., Jones, S., Mells, G., Mulcahy, V., Srivastava, B., Foxton, M. R., Collins, C. E., Elphick, D., Karmo, M., Porras-Perez, F., Mendall, M., Yapp, T., Patel, M., Ede, R., Sayer, J., Jupp, J., Fisher, N., Carter, M. J., Koss, K., Shah, J., Piotrowicz, A., Scott, G., Grimley, C., Gooding, I. R., Williams, S., Tidbury, J., Lim, G., Cheent, K., Levi, S., Mansour, D., Beckley, M., Hollywood, C., Wong, T., Marley, R., Ramage, J., Gordon, H. M., Ridpath, J., Ngatchu, T., Bob Grover, V. P., Shidrawi, R. G., Abouda, G., Corless, L., Narain, M., Rees, I., Brown, A., Taylor-Robinson, S., Wilkins, J., Grellier, L., Banim, P., Das, D., Heneghan, M. A., Curtis, H., Matthews, H. C., Mohammed, F., Aldersley, M., Srirajaskanthan, R., Walker, G., Mcnair, A., Sharif, A., Sen, S., Bird, G., Prince, M. I., Prasad, G., Kitchen, P., Barnardo, A., Oza, C., Sivaramakrishnan, N. N., Gupta, P., Shah, A., Evans, C. D., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Barclay, S. T., Mcdonald, N., Bathgate, A. J., Palmer, K., Dillon, J. F., Rushbrook, S. M., Przemioslo, R., Mcdonald, C., Millar, A., Tai, C., Mitchell, S., Metcalf, J., Shaukat, S., Ninkovic, M., Shmueli, U., Davis, A., Naqvi, A., Lee, T. J., Ryder, S., Collier, J., Klass, H., Cramp, M. E., Sharer, N., Aspinall, R., Ghosh, D., Douds, A. C., Booth, J., Williams, E., Hussaini, H., Christie, J., Mann, S., Thorburn, D., Marshall, A., Patanwala, I., Ala, A., Maltby, J., Matthew, R., Corbett, C., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Mitchison, H., Panter, S., Shearman, J., Bray, G., Roberts, M., Butcher, G., Forton, D., Mahmood, Z., Cowan, M., Ch'Ng, C. L., Rahman, M., Whatley, G. C. A., Wesley, E., Mandal, A., Jain, S., Pereira, S. P., Wright, M., Trivedi, P., Gordon, F. H., Unitt, E., Palejwala, A., Austin, A., Vemala, V., Grant, A., Higham, A. D., Brind, A., Mathew, R., Cox, M., Ramakrishnan, S., King, A., Whalley, S., Fraser, J., Thomson, S. J., Bell, A., Wong, V. S., Kia, R., Gee, I., Keld, R., Ransford, R., Gotto, J., Millson, C., Cordell H.J., Fryett J.J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S.-S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B.D., Atkinson E.J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M.A.R., Sun D., Jones D.E., Flack S., Spicer A., Mulcahy V.L., Byun J., Han Y., Sandford R.N., Lazaridis K.N., Amos C.I., Hirschfield G.M., Seldin M.F., Invernizzi P., Siminovitch K.A., Ma X., Nakamura M., Mells G.F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P.L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P.M., Benedetti A., Bragazzi M.C., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L.S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G.A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L.A., Overton J.D., Reid J.G., Shuldiner A., Beechert C., Forsythe C., Fuller E.D., Gu Z., Lattari M., Lopez A., Schleicher T.D., Padilla M.S., Toledo K., Widom L., Wolf S.E., Pradhan M., Manoochehri K., Ulloa R.H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E.K., Salerno W., Staples J.C., Jones M.B., Mitnaul L.J., Sturgess R., Healey C., Yeoman A., Gunasekera A.V.J., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J.A., Gorard D.A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M.R., Collins C.E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M.J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I.R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H.M., Ridpath J., Ngatchu T., Bob Grover V.P., Shidrawi R.G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M.A., Curtis H., Matthews H.C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M.I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N.N., Gupta P., Shah A., Evans C.D.J., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S.T., McDonald N., Bathgate A.J., Palmer K., Dillon J.F., Rushbrook S.M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T.J.W., Ryder S., Collier J., Klass H., Cramp M.E., Sharer N., Aspinall R., Ghosh D., Douds A.C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C.L., Rahman M., Whatley G.C.A., Wesley E., Mandal A., Jain S., Pereira S.P., Wright M., Trivedi P., Gordon F.H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A.D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S.J., Bell A., Wong V.S., Kia R., Gee I., Keld R., Ransford R., Gotto J., and Millson C.

Subjects
PBC
Abstract

It has come to our attention that the name of one of the authors in our manuscript was incorrectly spelled ‘Jinyoung Byan’; the correct spelling is ‘Jinyoung Byun’ as in the author list above. In addition, the excel files of the supplementary tables were not included during the online publication of our article. These have now been made available online. We apologize for any inconvenience caused.

Published
2022

20. Congenital cystic lesions of the biliary tree

Author

Floreani, A, Lasagni, A, Morana, G, Strazzabosco, M, Fabris, L, Cadamuro, M, Lasagni A., Morana G., Strazzabosco M., Fabris L., Cadamuro M., Floreani, A, Lasagni, A, Morana, G, Strazzabosco, M, Fabris, L, Cadamuro, M, Lasagni A., Morana G., Strazzabosco M., Fabris L., and Cadamuro M.

Abstract

Fibropolycystic liver diseases (FPLDs) encompass a heterogeneous group of rare, congenital disorders of the biliary tree deriving from an abnormal embryogenesis of the primordial ductal plate caused by a genetically determined dysfunction of morphogenetic proteins expressed in the primary cilia of cholangiocytes ("ciliopathies"). Among this group, it is important to notice three different clusters of disease: polycystic liver diseases (PLDs), fibrocystic liver diseases (FLDs), and choledochal cysts (CCs). PLDs are characterized by the development of multiple (>20) fluid-filled biliary cysts widespread throughout liver parenchyma and disconnected from biliary tree. The natural history of PLDs is characterized by growth of cyst during adult age, leading to debilitating hepatomegaly. The ductal dysgenesis may affect, in FLDs, the biliary system at multiple levels, from the small intrahepatic bile ducts (congenital hepatic fibrosis) to the larger intrahepatic bile ducts (Caroli's disease or Caroli's syndrome, when Caroli's disease coexists with congenital hepatic fibrosis), leading to biliary microhamartomas and segmental bile duct dilations, accompanied by progressive fibrogenesis. These fundamental lesions are the hallmark of FLDs and are responsible for the major complications, such as portal hypertension, cholestasis, recurrent cholangitis, sepsis, and cholangiocarcinoma. CCs are congenital alterations resulting from ductal plate malformation, involving the largest intra or extrahepatic bile ducts that mainly affect a paediatric population. Early surgical intervention is pivotal to avoid complications related to obstructive frame, ab extrinseco compression, rupture or malignant evolution. FPLDs often associate with a spectrum of disorders affecting many organs, primarily the kidney, and thus they are collectively termed hepatorenal fibrocystic disease (HRFCD). Among them, the autosomal-dominant and recessive polycystic kidney disease (ARPKD) is the most frequentl

Published
2021

21. Cholangiocarcinoma

Author

Floreani, A, Lasagni, A, Strazzabosco, M, Guido, M, Fabris, L, Cadamuro, M, Lasagni A., Strazzabosco M., Guido M., Fabris L., Cadamuro M., Floreani, A, Lasagni, A, Strazzabosco, M, Guido, M, Fabris, L, Cadamuro, M, Lasagni A., Strazzabosco M., Guido M., Fabris L., and Cadamuro M.

Abstract

Cholangiocarcinoma (CCA) includes a group of different epithelial cancers with features of biliary tract differentiation arising from any tract of the biliary tree. Histologically, they usually are adenocarcinomas. It is a rare cancer accounting about 3% of all gastrointestinal malignancies. Based on its anatomical location, CCA is classified as intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA). Currently, the three types of CCA are considered as distinct cancers since different pathogenic and management features. Cholangiocarcinomas are aggressive tumours, often diagnosed at advanced stages. Most cases are sporadic but conditions leading to chronic inflammation and cholestasis have been recognized as risk factors. Diagnosis needs a multimodal approach, mixing imaging, endoscopy, laboratory tests, including onco-biomarkers, and pathology. Surgical resection with histologically negative margins is the only curative treatment, although it is possible only for few patients; unfortunately, recurrence is frequent. Likewise, liver transplantation is an option for a small subset of selected patients suffering from pCCA. Generally, prognosis is poor for most patients. Desmoplastic nature, highly variable genetics, interaction with a rich tumour microenvironment, all contribute to the resistance of therapy. Advances in targeted-, radio- and immunotherapy will lead to improvement in survival.

Published
2021

22. Fibrocystic liver disease: Novel concepts and translational perspectives

Author

Lasagni, A, Cadamuro, M, Morana, G, Fabris, L, Strazzabosco, M, Lasagni A., Cadamuro M., Morana G., Fabris L., Strazzabosco M., Lasagni, A, Cadamuro, M, Morana, G, Fabris, L, Strazzabosco, M, Lasagni A., Cadamuro M., Morana G., Fabris L., and Strazzabosco M.

Abstract

Fibrocystic liver diseases (FLDs) comprise a heterogeneous group of rare diseases of the biliary tree, having in common an abnormal development of the embryonic ductal plate caused by geneticallydetermined dysfunctions of proteins expressed in the primary cilia of cholangiocytes (and therefore grouped among the "ciliopathies"). The ductal dysgenesis may affect the biliary system at multiple levels, from the small intrahepatic bile ducts [congenital hepatic fibrosis (CHF)], to the larger intrahepatic bile ducts [Caroli disease (CD), or Caroli syndrome (CS), when CD coexists with CHF], leading to biliary microhamartomas and segmental bile duct dilations. Biliary changes are accompanied by progressive deposition of abundant peribiliary fibrosis. Peribiliary fibrosis and biliary cysts are the fundamental lesions of FLDs and are responsible for the main clinical manifestations, such as portal hypertension, recurrent cholangitis, cholestasis, sepsis and eventually cholangiocarcinoma. Furthermore, FLDs often associate with a spectrum of disorders affecting primarily the kidney. Among them, the autosomal recessive polycystic kidney disease (ARPKD) is the most frequent, and the renal function impairment is central in disease progression. CHF, CD/CS, and ARPKD are caused by a number of mutations in polycystic kidney hepatic disease 1 (PKHD1), a gene that encodes for fibrocystin/polyductin, a protein of unclear function, but supposedly involved in planar cell polarity and other fundamental cell functions. Targeted medical therapy is not available yet and thus the current treatment aims at controlling the complications. Interventional radiology or surgical treatments, including liver transplantation, are used in selected cases.

Published
2021

23. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Author

Asselta, R, Paraboschi, E, Gerussi, A, Cordell, H, Mells, G, Sandford, R, Jones, D, Nakamura, M, Ueno, K, Hitomi, Y, Kawashima, M, Nishida, N, Tokunaga, K, Nagasaki, M, Tanaka, A, Tang, R, Li, Z, Shi, Y, Liu, X, Xiong, M, Hirschfield, G, Siminovitch, K, Walker, E, Xie, G, Mason, A, Myers, R, Peltekian, K, Ghent, C, Atkinson, E, Juran, B, Lazaridis, K, Lu, Y, Gu, X, Jing, K, Amos, C, Affronti, A, Brunetto, M, Coco, B, Spinzi, G, Elia, G, Ferrari, C, Lleo, A, Muratori, L, Muratori, P, Portincasa, P, Colli, A, Bruno, S, Colloredo, G, Azzaroli, F, Andreone, P, Bragazzi, M, Alvaro, D, Cardinale, V, Cazzagon, N, Rigamonti, C, Floreani, A, Rosina, F, Ciaccio, A, Cristoferi, L, D'Amato, D, Malinverno, F, Mancuso, C, Massironi, S, Milani, C, O'Donnell, S, Ronca, V, Barisani, D, Lampertico, P, Donato, F, Fagiuoli, S, Almasio, P, Giannini, E, Cursaro, C, Colombo, M, Valenti, L, Miele, L, Andriulli, A, Niro, G, Grattagliano, I, Morini, L, Casella, G, Vinci, M, Battezzati, P, Crosignani, A, Zuin, M, Mattalia, A, Calvaruso, V, Colombo, S, Benedetti, A, Marzioni, M, Galli, A, Marra, F, Tarocchi, M, Picciotto, A, Morisco, F, Fabris, L, Croce, L, Tiribelli, C, Toniutto, P, Strazzabosco, M, Ch'Ng, C, Rahman, M, Yapp, T, Sturgess, R, Healey, C, Czajkowski, M, Gunasekera, A, Gyawali, P, Premchand, P, Kapur, K, Marley, R, Foster, G, Watson, A, Dias, A, Subhani, J, Harvey, R, Mccorry, R, Ramanaden, D, Gasem, J, Evans, R, Mathialahan, T, Shorrock, C, Lipscomb, G, Southern, P, Tibble, J, Gorard, D, Palegwala, A, Jones, S, Dawwas, M, Alexander, G, Dolwani, S, Prince, M, Foxton, M, Elphick, D, Mitchison, H, Gooding, I, Karmo, M, Saksena, S, Mendall, M, Patel, M, Ede, R, Austin, A, Sayer, J, Hankey, L, Hovell, C, Fisher, N, Carter, M, Koss, K, Piotrowicz, A, Grimley, C, Neal, D, Lim, G, Levi, S, Ala, A, Broad, A, Saeed, A, Wood, G, Brown, J, Wilkinson, M, Gordon, H, Ramage, J, Ridpath, J, Ngatchu, T, Grover, B, Shaukat, S, Shidrawi, R, Abouda, G, Ali, F, Rees, I, Salam, I, Narain, M, Brown, A, Taylor-Robinson, S, Williams, S, Grellier, L, Banim, P, Das, D, Chilton, A, Heneghan, M, Curtis, H, Gess, M, Drake, I, Aldersley, M, Davies, M, Jones, R, Mcnair, A, Srirajaskanthan, R, Pitcher, M, Sen, S, Bird, G, Barnardo, A, Kitchen, P, Yoong, K, Chirag, O, Sivaramakrishnan, N, Macfaul, G, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Fraser, A, Mills, P, Shallcross, C, Campbell, S, Bathgate, A, Shepherd, A, Dillon, J, Rushbrook, S, Przemioslo, R, Macdonald, C, Metcalf, J, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Ninkovic, M, Cramp, M, Sharer, N, Aspinall, R, Goggin, P, Ghosh, D, Douds, A, Hoeroldt, B, Booth, J, Williams, E, Hussaini, H, Stableforth, W, Ayres, R, Thorburn, D, Marshall, E, Burroughs, A, Mann, S, Lombard, M, Richardson, P, Patanwala, I, Maltby, J, Brookes, M, Mathew, R, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Panter, S, Shearman, J, Bray, G, Butcher, G, Forton, D, Mclindon, J, Cowan, M, Whatley, G, Mandal, A, Gupta, H, Sanghi, P, Jain, S, Pereira, S, Prasad, G, Watts, G, Wright, M, Neuberger, J, Gordon, F, Unitt, E, Grant, A, Delahooke, T, Higham, A, Brind, A, Cox, M, Ramakrishnan, S, King, A, Collins, C, Whalley, S, Li, A, Fraser, J, Bell, A, Wong, V, Singhal, A, Gee, I, Ang, Y, Ransford, R, Gotto, J, Millson, C, Bowles, J, Thomas, C, Harrison, M, Galaska, R, Kendall, J, Whiteman, J, Lawlor, C, Gray, C, Elliott, K, Mulvaney-Jones, C, Hobson, L, Van Duyvenvoorde, G, Loftus, A, Seward, K, Penn, R, Maiden, J, Damant, R, Hails, J, Cloudsdale, R, Silvestre, V, Glenn, S, Dungca, E, Wheatley, N, Doyle, H, Kent, M, Hamilton, C, Braim, D, Wooldridge, H, Abrahams, R, Paton, A, Lancaster, N, Gibbins, A, Hogben, K, Desousa, P, Muscariu, F, Musselwhite, J, Mckay, A, Tan, L, Foale, C, Brighton, J, Flahive, K, Nambela, E, Townshend, P, Ford, C, Holder, S, Palmer, C, Featherstone, J, Nasseri, M, Sadeghian, J, Williams, B, Rolls, S, Hynes, A, Duggan, C, Crossey, M, Stansfield, G, Macnicol, C, Wilkins, J, Wilhelmsen, E, Raymode, P, Lee, H, Durant, E, Bishop, R, Ncube, N, Tripoli, S, Casey, R, Cowley, C, Miller, R, Houghton, K, Ducker, S, Wright, F, Bird, B, Baxter, G, Keggans, J, Hughes, M, Grieve, E, Young, K, Williams, D, Ocker, K, Hines, F, Martin, K, Innes, C, Valliani, T, Fairlamb, H, Thornthwaite, S, Eastick, A, Tanqueray, E, Morrison, J, Holbrook, B, Browning, J, Walker, K, Congreave, S, Verheyden, J, Slininger, S, Stafford, L, O'Donnell, D, Ainsworth, M, Lord, S, Kent, L, March, L, Dickson, C, Simpson, D, Longhurst, B, Hayes, M, Shpuza, E, White, N, Besley, S, Pearson, S, Wright, A, Jones, L, Gunter, E, Dewhurst, H, Fouracres, A, Farrington, L, Graves, L, Marriott, S, Leoni, M, Tyrer, D, Dali-kemmery, L, Lambourne, V, Green, M, Sirdefield, D, Amor, K, Colley, J, Shinder, B, Jones, J, Mills, M, Carnahan, M, Taylor, N, Boulton, K, Tregonning, J, Brown, C, Clifford, G, Archer, E, Hamilton, M, Curtis, J, Shewan, T, Walsh, S, Warner, K, Netherton, K, Mupudzi, M, Gunson, B, Gitahi, J, Gocher, D, Batham, S, Pateman, H, Desmennu, S, Conder, J, Clement, D, Gallagher, S, Orpe, J, Chan, P, Currie, L, O'Donohoe, L, Oblak, M, Morgan, L, Quinn, M, Amey, I, Baird, Y, Cotterill, D, Cumlat, L, Winter, L, Greer, S, Spurdle, K, Allison, J, Dyer, S, Sweeting, H, Kordula, J, Aiba, Y, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Kawai, Y, Kohn, S, Gervais, O, Migita, K, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Higuchi, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Takikawa, H, Ohira, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Carbone, M, Cardamone, G, Duga, S, Gershwin, M, Seldin, M, Invernizzi, P, Asselta R., Paraboschi E. M., Gerussi A., Cordell H. J., Mells G. F., Sandford R. N., Jones D. E., Nakamura M., Ueno K., Hitomi Y., Kawashima M., Nishida N., Tokunaga K., Nagasaki M., Tanaka A., Tang R., Li Z., Shi Y., Liu X., Xiong M., Hirschfield G., Siminovitch K. A., Walker E., Xie G., Mason A., Myers R., Peltekian K., Ghent C., Atkinson E., Juran B., Lazaridis K., Lu Y., Gu X., Jing K., Amos C., Affronti A., Brunetto M., Coco B., Spinzi G., Elia G., Ferrari C., Lleo A., Muratori L., Muratori P., Portincasa P., Colli A., Bruno S., Colloredo G., Azzaroli F., Andreone P., Bragazzi M., Alvaro D., Cardinale V., Cazzagon N., Rigamonti C., Floreani A., Rosina F., Ciaccio A., Cristoferi L., D'Amato D., Malinverno F., Mancuso C., Massironi S., Milani C., O'Donnell S. E., Ronca V., Barisani D., Lampertico P., Donato F., Fagiuoli S., Almasio P. L., Giannini E., Cursaro C., Colombo M., Valenti L., Miele L., Andriulli A., Niro G. A., Grattagliano I., Morini L., Casella G., Vinci M., Battezzati P. M., Crosignani A., Zuin M., Mattalia A., Calvaruso V., Colombo S., Benedetti A., Marzioni M., Galli A., Marra F., Tarocchi M., Picciotto A., Morisco F., Fabris L., Croce L. S., Tiribelli C., Toniutto P., Strazzabosco M., Ch'ng C. L., Rahman M., Yapp T., Sturgess R., Healey C., Czajkowski M., Gunasekera A., Gyawali P., Premchand P., Kapur K., Marley R., Foster G., Watson A., Dias A., Subhani J., Harvey R., McCorry R., Ramanaden D., Gasem J., Evans R., Mathialahan T., Shorrock C., Lipscomb G., Southern P., Tibble J., Gorard D., Palegwala A., Jones S., Dawwas M., Alexander G., Dolwani S., Prince M., Foxton M., Elphick D., Mitchison H., Gooding I., Karmo M., Saksena S., Mendall M., Patel M., Ede R., Austin A., Sayer J., Hankey L., Hovell C., Fisher N., Carter M., Koss K., Piotrowicz A., Grimley C., Neal D., Lim G., Levi S., Ala A., Broad A., Saeed A., Wood G., Brown J., Wilkinson M., Gordon H., Ramage J., Ridpath J., Ngatchu T., Grover B., Shaukat S., Shidrawi R., Abouda G., Ali F., Rees I., Salam I., Narain M., Brown A., Taylor-Robinson S., Williams S., Grellier L., Banim P., Das D., Chilton A., Heneghan M., Curtis H., Gess M., Drake I., Aldersley M., Davies M., Jones R., McNair A., Srirajaskanthan R., Pitcher M., Sen S., Bird G., Barnardo A., Kitchen P., Yoong K., Chirag O., Sivaramakrishnan N., MacFaul G., Jones D., Shah A., Evans C., Saha S., Pollock K., Bramley P., Mukhopadhya A., Fraser A., Mills P., Shallcross C., Campbell S., Bathgate A., Shepherd A., Dillon J., Rushbrook S., Przemioslo R., Macdonald C., Metcalf J., Shmueli U., Davis A., Naqvi A., Lee T., Ryder S. D., Collier J., Klass H., Ninkovic M., Cramp M., Sharer N., Aspinall R., Goggin P., Ghosh D., Douds A., Hoeroldt B., Booth J., Williams E., Hussaini H., Stableforth W., Ayres R., Thorburn D., Marshall E., Burroughs A., Mann S., Lombard M., Richardson P., Patanwala I., Maltby J., Brookes M., Mathew R., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Panter S., Shearman J., Bray G., Butcher G., Forton D., Mclindon J., Cowan M., Whatley G., Mandal A., Gupta H., Sanghi P., Jain S., Pereira S., Prasad G., Watts G., Wright M., Neuberger J., Gordon F., Unitt E., Grant A., Delahooke T., Higham A., Brind A., Cox M., Ramakrishnan S., King A., Collins C., Whalley S., Li A., Fraser J., Bell A., Wong V. S., Singhal A., Gee I., Ang Y., Ransford R., Gotto J., Millson C., Bowles J., Thomas C., Harrison M., Galaska R., Kendall J., Whiteman J., Lawlor C., Gray C., Elliott K., Mulvaney-Jones C., Hobson L., Van Duyvenvoorde G., Loftus A., Seward K., Penn R., Maiden J., Damant R., Hails J., Cloudsdale R., Silvestre V., Glenn S., Dungca E., Wheatley N., Doyle H., Kent M., Hamilton C., Braim D., Wooldridge H., Abrahams R., Paton A., Lancaster N., Gibbins A., Hogben K., Desousa P., Muscariu F., Musselwhite J., McKay A., Tan L., Foale C., Brighton J., Flahive K., Nambela E., Townshend P., Ford C., Holder S., Palmer C., Featherstone J., Nasseri M., Sadeghian J., Williams B., Rolls S. -A., Hynes A., Duggan C., Crossey M., Stansfield G., MacNicol C., Wilkins J., Wilhelmsen E., Raymode P., Lee H. -J., Durant E., Bishop R., Ncube N., Tripoli S., Casey R., Cowley C., Miller R., Houghton K., Ducker S., Wright F., Bird B., Baxter G., Keggans J., Hughes M., Grieve E., Young K., Williams D., Ocker K., Hines F., Martin K., Innes C., Valliani T., Fairlamb H., Thornthwaite S., Eastick A., Tanqueray E., Morrison J., Holbrook B., Browning J., Walker K., Congreave S., Verheyden J., Slininger S., Stafford L., O'Donnell D., Ainsworth M., Lord S., Kent L., March L., Dickson C., Simpson D., Longhurst B., Hayes M., Shpuza E., White N., Besley S., Pearson S., Wright A., Jones L., Gunter E., Dewhurst H., Fouracres A., Farrington L., Graves L., Marriott S., Leoni M., Tyrer D., Dali-kemmery L., Lambourne V., Green M., Sirdefield D., Amor K., Colley J., Shinder B., Jones J., Mills M., Carnahan M., Taylor N., Boulton K., Tregonning J., Brown C., Clifford G., Archer E., Hamilton M., Curtis J., Shewan T., Walsh S., Warner K., Netherton K., Mupudzi M., Gunson B., Gitahi J., Gocher D., Batham S., Pateman H., Desmennu S., Conder J., Clement D., Gallagher S., Orpe J., Chan P., Currie L., O'Donohoe L., Oblak M., Morgan L., Quinn M., Amey I., Baird Y., Cotterill D., Cumlat L., Winter L., Greer S., Spurdle K., Allison J., Dyer S., Sweeting H., Kordula J., Aiba Y., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Kawai Y., Kohn S. -S., Gervais O., Migita K., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Higuchi N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Takikawa H., Ohira H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Carbone M., Cardamone G., Duga S., Gershwin M. 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F., Invernizzi P., Asselta, R, Paraboschi, E, Gerussi, A, Cordell, H, Mells, G, Sandford, R, Jones, D, Nakamura, M, Ueno, K, Hitomi, Y, Kawashima, M, Nishida, N, Tokunaga, K, Nagasaki, M, Tanaka, A, Tang, R, Li, Z, Shi, Y, Liu, X, Xiong, M, Hirschfield, G, Siminovitch, K, Walker, E, Xie, G, Mason, A, Myers, R, Peltekian, K, Ghent, C, Atkinson, E, Juran, B, Lazaridis, K, Lu, Y, Gu, X, Jing, K, Amos, C, Affronti, A, Brunetto, M, Coco, B, Spinzi, G, Elia, G, Ferrari, C, Lleo, A, Muratori, L, Muratori, P, Portincasa, P, Colli, A, Bruno, S, Colloredo, G, Azzaroli, F, Andreone, P, Bragazzi, M, Alvaro, D, Cardinale, V, Cazzagon, N, Rigamonti, C, Floreani, A, Rosina, F, Ciaccio, A, Cristoferi, L, D'Amato, D, Malinverno, F, Mancuso, C, Massironi, S, Milani, C, O'Donnell, S, Ronca, V, Barisani, D, Lampertico, P, Donato, F, Fagiuoli, S, Almasio, P, Giannini, E, Cursaro, C, Colombo, M, Valenti, L, Miele, L, Andriulli, A, Niro, G, Grattagliano, I, Morini, L, Casella, G, Vinci, M, Battezzati, P, Crosignani, A, Zuin, M, Mattalia, A, Calvaruso, V, Colombo, S, Benedetti, A, Marzioni, M, Galli, A, Marra, F, Tarocchi, M, Picciotto, A, Morisco, F, Fabris, L, Croce, L, Tiribelli, C, Toniutto, P, Strazzabosco, M, Ch'Ng, C, Rahman, M, Yapp, T, Sturgess, R, Healey, C, Czajkowski, M, Gunasekera, A, Gyawali, P, Premchand, P, Kapur, K, Marley, R, Foster, G, Watson, A, Dias, A, Subhani, J, Harvey, R, Mccorry, R, Ramanaden, D, Gasem, J, Evans, R, Mathialahan, T, Shorrock, C, Lipscomb, G, Southern, P, Tibble, J, Gorard, D, Palegwala, A, Jones, S, Dawwas, M, Alexander, G, Dolwani, S, Prince, M, Foxton, M, Elphick, D, Mitchison, H, Gooding, I, Karmo, M, Saksena, S, Mendall, M, Patel, M, Ede, R, Austin, A, Sayer, J, Hankey, L, Hovell, C, Fisher, N, Carter, M, Koss, K, Piotrowicz, A, Grimley, C, Neal, D, Lim, G, Levi, S, Ala, A, Broad, A, Saeed, A, Wood, G, Brown, J, Wilkinson, M, Gordon, H, Ramage, J, Ridpath, J, Ngatchu, T, Grover, B, Shaukat, S, Shidrawi, R, Abouda, G, Ali, F, Rees, I, Salam, 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G, Butcher, G, Forton, D, Mclindon, J, Cowan, M, Whatley, G, Mandal, A, Gupta, H, Sanghi, P, Jain, S, Pereira, S, Prasad, G, Watts, G, Wright, M, Neuberger, J, Gordon, F, Unitt, E, Grant, A, Delahooke, T, Higham, A, Brind, A, Cox, M, Ramakrishnan, S, King, A, Collins, C, Whalley, S, Li, A, Fraser, J, Bell, A, Wong, V, Singhal, A, Gee, I, Ang, Y, Ransford, R, Gotto, J, Millson, C, Bowles, J, Thomas, C, Harrison, M, Galaska, R, Kendall, J, Whiteman, J, Lawlor, C, Gray, C, Elliott, K, Mulvaney-Jones, C, Hobson, L, Van Duyvenvoorde, G, Loftus, A, Seward, K, Penn, R, Maiden, J, Damant, R, Hails, J, Cloudsdale, R, Silvestre, V, Glenn, S, Dungca, E, Wheatley, N, Doyle, H, Kent, M, Hamilton, C, Braim, D, Wooldridge, H, Abrahams, R, Paton, A, Lancaster, N, Gibbins, A, Hogben, K, Desousa, P, Muscariu, F, Musselwhite, J, Mckay, A, Tan, L, Foale, C, Brighton, J, Flahive, K, Nambela, E, Townshend, P, Ford, C, Holder, S, Palmer, C, Featherstone, J, Nasseri, M, Sadeghian, J, Williams, B, Rolls, S, Hynes, A, Duggan, C, Crossey, M, Stansfield, G, Macnicol, C, Wilkins, J, Wilhelmsen, E, Raymode, P, Lee, H, Durant, E, Bishop, R, Ncube, N, Tripoli, S, Casey, R, Cowley, C, Miller, R, Houghton, K, Ducker, S, Wright, F, Bird, B, Baxter, G, Keggans, J, Hughes, M, Grieve, E, Young, K, Williams, D, Ocker, K, Hines, F, Martin, K, Innes, C, Valliani, T, Fairlamb, H, Thornthwaite, S, Eastick, A, Tanqueray, E, Morrison, J, Holbrook, B, Browning, J, Walker, K, Congreave, S, Verheyden, J, Slininger, S, Stafford, L, O'Donnell, D, Ainsworth, M, Lord, S, Kent, L, March, L, Dickson, C, Simpson, D, Longhurst, B, Hayes, M, Shpuza, E, White, N, Besley, S, Pearson, S, Wright, A, Jones, L, Gunter, E, Dewhurst, H, Fouracres, A, Farrington, L, Graves, L, Marriott, S, Leoni, M, Tyrer, D, Dali-kemmery, L, Lambourne, V, Green, M, Sirdefield, D, Amor, K, Colley, J, Shinder, B, Jones, J, Mills, M, Carnahan, M, Taylor, N, Boulton, K, Tregonning, J, Brown, C, Clifford, G, Archer, E, Hamilton, M, Curtis, J, Shewan, T, Walsh, S, Warner, K, Netherton, K, Mupudzi, M, Gunson, B, Gitahi, J, Gocher, D, Batham, S, Pateman, H, Desmennu, S, Conder, J, Clement, D, Gallagher, S, Orpe, J, Chan, P, Currie, L, O'Donohoe, L, Oblak, M, Morgan, L, Quinn, M, Amey, I, Baird, Y, Cotterill, D, Cumlat, L, Winter, L, Greer, S, Spurdle, K, Allison, J, Dyer, S, Sweeting, H, Kordula, J, Aiba, Y, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Kawai, Y, Kohn, S, Gervais, O, Migita, K, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Higuchi, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Takikawa, H, Ohira, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Carbone, M, Cardamone, G, Duga, S, Gershwin, M, Seldin, M, Invernizzi, P, Asselta R., Paraboschi E. M., Gerussi A., Cordell H. J., Mells G. F., Sandford R. N., Jones D. E., Nakamura M., Ueno K., Hitomi Y., Kawashima M., Nishida N., Tokunaga K., Nagasaki M., Tanaka A., Tang R., Li Z., Shi Y., Liu X., Xiong M., Hirschfield G., Siminovitch K. A., Walker E., Xie G., Mason A., Myers R., Peltekian K., Ghent C., Atkinson E., Juran B., Lazaridis K., Lu Y., Gu X., Jing K., Amos C., Affronti A., Brunetto M., Coco B., Spinzi G., Elia G., Ferrari C., Lleo A., Muratori L., Muratori P., Portincasa P., Colli A., Bruno S., Colloredo G., Azzaroli F., Andreone P., Bragazzi M., Alvaro D., Cardinale V., Cazzagon N., Rigamonti C., Floreani A., Rosina F., Ciaccio A., Cristoferi L., D'Amato D., Malinverno F., Mancuso C., Massironi S., Milani C., O'Donnell S. E., Ronca V., Barisani D., Lampertico P., Donato F., Fagiuoli S., Almasio P. L., Giannini E., Cursaro C., Colombo M., Valenti L., Miele L., Andriulli A., Niro G. A., Grattagliano I., Morini L., Casella G., Vinci M., Battezzati P. M., Crosignani A., Zuin M., Mattalia A., Calvaruso V., Colombo S., Benedetti A., Marzioni M., Galli A., Marra F., Tarocchi M., Picciotto A., Morisco F., Fabris L., Croce L. S., Tiribelli C., Toniutto P., Strazzabosco M., Ch'ng C. L., Rahman M., Yapp T., Sturgess R., Healey C., Czajkowski M., Gunasekera A., Gyawali P., Premchand P., Kapur K., Marley R., Foster G., Watson A., Dias A., Subhani J., Harvey R., McCorry R., Ramanaden D., Gasem J., Evans R., Mathialahan T., Shorrock C., Lipscomb G., Southern P., Tibble J., Gorard D., Palegwala A., Jones S., Dawwas M., Alexander G., Dolwani S., Prince M., Foxton M., Elphick D., Mitchison H., Gooding I., Karmo M., Saksena S., Mendall M., Patel M., Ede R., Austin A., Sayer J., Hankey L., Hovell C., Fisher N., Carter M., Koss K., Piotrowicz A., Grimley C., Neal D., Lim G., Levi S., Ala A., Broad A., Saeed A., Wood G., Brown J., Wilkinson M., Gordon H., Ramage J., Ridpath J., Ngatchu T., Grover B., Shaukat S., Shidrawi R., Abouda G., Ali F., Rees I., Salam I., Narain M., Brown A., Taylor-Robinson S., Williams S., Grellier L., Banim P., Das D., Chilton A., Heneghan M., Curtis H., Gess M., Drake I., Aldersley M., Davies M., Jones R., McNair A., Srirajaskanthan R., Pitcher M., Sen S., Bird G., Barnardo A., Kitchen P., Yoong K., Chirag O., Sivaramakrishnan N., MacFaul G., Jones D., Shah A., Evans C., Saha S., Pollock K., Bramley P., Mukhopadhya A., Fraser A., Mills P., Shallcross C., Campbell S., Bathgate A., Shepherd A., Dillon J., Rushbrook S., Przemioslo R., Macdonald C., Metcalf J., Shmueli U., Davis A., Naqvi A., Lee T., Ryder S. D., Collier J., Klass H., Ninkovic M., Cramp M., Sharer N., Aspinall R., Goggin P., Ghosh D., Douds A., Hoeroldt B., Booth J., Williams E., Hussaini H., Stableforth W., Ayres R., Thorburn D., Marshall E., Burroughs A., Mann S., Lombard M., Richardson P., Patanwala I., Maltby J., Brookes M., Mathew R., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Panter S., Shearman J., Bray G., Butcher G., Forton D., Mclindon J., Cowan M., Whatley G., Mandal A., Gupta H., Sanghi P., Jain S., Pereira S., Prasad G., Watts G., Wright M., Neuberger J., Gordon F., Unitt E., Grant A., Delahooke T., Higham A., Brind A., Cox M., Ramakrishnan S., King A., Collins C., Whalley S., Li A., Fraser J., Bell A., Wong V. S., Singhal A., Gee I., Ang Y., Ransford R., Gotto J., Millson C., Bowles J., Thomas C., Harrison M., Galaska R., Kendall J., Whiteman J., Lawlor C., Gray C., Elliott K., Mulvaney-Jones C., Hobson L., Van Duyvenvoorde G., Loftus A., Seward K., Penn R., Maiden J., Damant R., Hails J., Cloudsdale R., Silvestre V., Glenn S., Dungca E., Wheatley N., Doyle H., Kent M., Hamilton C., Braim D., Wooldridge H., Abrahams R., Paton A., Lancaster N., Gibbins A., Hogben K., Desousa P., Muscariu F., Musselwhite J., McKay A., Tan L., Foale C., Brighton J., Flahive K., Nambela E., Townshend P., Ford C., Holder S., Palmer C., Featherstone J., Nasseri M., Sadeghian J., Williams B., Rolls S. -A., Hynes A., Duggan C., Crossey M., Stansfield G., MacNicol C., Wilkins J., Wilhelmsen E., Raymode P., Lee H. -J., Durant E., Bishop R., Ncube N., Tripoli S., Casey R., Cowley C., Miller R., Houghton K., Ducker S., Wright F., Bird B., Baxter G., Keggans J., Hughes M., Grieve E., Young K., Williams D., Ocker K., Hines F., Martin K., Innes C., Valliani T., Fairlamb H., Thornthwaite S., Eastick A., Tanqueray E., Morrison J., Holbrook B., Browning J., Walker K., Congreave S., Verheyden J., Slininger S., Stafford L., O'Donnell D., Ainsworth M., Lord S., Kent L., March L., Dickson C., Simpson D., Longhurst B., Hayes M., Shpuza E., White N., Besley S., Pearson S., Wright A., Jones L., Gunter E., Dewhurst H., Fouracres A., Farrington L., Graves L., Marriott S., Leoni M., Tyrer D., Dali-kemmery L., Lambourne V., Green M., Sirdefield D., Amor K., Colley J., Shinder B., Jones J., Mills M., Carnahan M., Taylor N., Boulton K., Tregonning J., Brown C., Clifford G., Archer E., Hamilton M., Curtis J., Shewan T., Walsh S., Warner K., Netherton K., Mupudzi M., Gunson B., Gitahi J., Gocher D., Batham S., Pateman H., Desmennu S., Conder J., Clement D., Gallagher S., Orpe J., Chan P., Currie L., O'Donohoe L., Oblak M., Morgan L., Quinn M., Amey I., Baird Y., Cotterill D., Cumlat L., Winter L., Greer S., Spurdle K., Allison J., Dyer S., Sweeting H., Kordula J., Aiba Y., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Kawai Y., Kohn S. -S., Gervais O., Migita K., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Higuchi N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Takikawa H., Ohira H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Carbone M., Cardamone G., Duga S., Gershwin M. E., Seldin M. F., and Invernizzi P.

Abstract

Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Published
2021

24. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author

Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tarocchi, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Cordell H. J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byan J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., Mells G. F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P. L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P. M., Benedetti A., Bragazzi M., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L. S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G. A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L. A., Overton J. D., Reid J. G., Shuldiner A., Beechert C., Forsythe C., Fuller E. D., Gu Z., Lattari M., Lopez A., Schleicher T. D., Padilla M. S., Toledo K., Widom L., Wolf S. E., Pradhan M., Manoochehri K., Ulloa R. H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E. K., Salerno W., Staples J. C., Jones M. B., Mitnaul L. J., Sturgess R., Healey C., Yeoman A., Gunasekera A. V., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J. A., Gorard D. A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M. R., Collins C. E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M. J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I. R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H. M., Ridpath J., Ngatchu T., Bob Grover V. P., Shidrawi R. G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M. A., Curtis H., Matthews H. C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M. I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N. N., Gupta P., Shah A., Evans C. D., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S. T., McDonald N., Bathgate A. J., Palmer K., Dillon J. F., Rushbrook S. M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T. J., Ryder S., Collier J., Klass H., Cramp M. E., Sharer N., Aspinall R., Ghosh D., Douds A. C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C. L., Rahman M., Whatley G. C. A., Wesley E., Mandal A., Jain S., Pereira S. P., Wright M., Trivedi P., Gordon F. H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A. D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S. J., Bell A., Wong V. S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tarocchi, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Cordell H. J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byan J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., Mells G. F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P. L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P. M., Benedetti A., Bragazzi M., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L. S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G. A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L. A., Overton J. D., Reid J. G., Shuldiner A., Beechert C., Forsythe C., Fuller E. D., Gu Z., Lattari M., Lopez A., Schleicher T. D., Padilla M. S., Toledo K., Widom L., Wolf S. E., Pradhan M., Manoochehri K., Ulloa R. H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E. K., Salerno W., Staples J. C., Jones M. B., Mitnaul L. J., Sturgess R., Healey C., Yeoman A., Gunasekera A. V., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J. A., Gorard D. A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M. R., Collins C. E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M. J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I. R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H. M., Ridpath J., Ngatchu T., Bob Grover V. P., Shidrawi R. G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M. A., Curtis H., Matthews H. C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M. I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N. N., Gupta P., Shah A., Evans C. D., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S. T., McDonald N., Bathgate A. J., Palmer K., Dillon J. F., Rushbrook S. M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T. J., Ryder S., Collier J., Klass H., Cramp M. E., Sharer N., Aspinall R., Ghosh D., Douds A. C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C. L., Rahman M., Whatley G. C. A., Wesley E., Mandal A., Jain S., Pereira S. P., Wright M., Trivedi P., Gordon F. H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A. D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S. J., Bell A., Wong V. S., Kia R., Gee I., Keld R., Ransford R., Gotto J., and Millson C.

Abstract

Backgrounds & Aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. Conclusions: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Lay summary: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China

Published
2021

25. Pathological characteristics of liver sinusoidal thrombosis in COVID-19 patients: A series of 43 cases

Author

Kondo, R, Kawaguchi, N, Mcconnell, M, Sonzogni, A, Licini, L, Valle, C, Bonaffini, P, Sironi, S, Alessio, M, Previtali, G, Seghezzi, M, Zhang, X, Sun, Z, Utsumi, T, Strazzabosco, M, Iwakiri, Y, Kondo R., Kawaguchi N., McConnell M. J., Sonzogni A., Licini L., Valle C., Bonaffini P. A., Sironi S., Alessio M. G., Previtali G., Seghezzi M., Zhang X., Sun Z., Utsumi T., Strazzabosco M., Iwakiri Y., Kondo, R, Kawaguchi, N, Mcconnell, M, Sonzogni, A, Licini, L, Valle, C, Bonaffini, P, Sironi, S, Alessio, M, Previtali, G, Seghezzi, M, Zhang, X, Sun, Z, Utsumi, T, Strazzabosco, M, Iwakiri, Y, Kondo R., Kawaguchi N., McConnell M. J., Sonzogni A., Licini L., Valle C., Bonaffini P. A., Sironi S., Alessio M. G., Previtali G., Seghezzi M., Zhang X., Sun Z., Utsumi T., Strazzabosco M., and Iwakiri Y.

Abstract

Aim: Coronavirus disease (COVID-19) is characterized by pneumonia with secondary damage to multiple organs including the liver. Liver injury (elevated alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) often correlates with disease severity in COVID-19 patients. The aim of this study is to identify pathological microthrombi in COVID-19 patient livers by correlating their morphology with liver injury, and examine hyperfibrinogenemia and von Willebrand factor (vWF) as mechanisms of their formation. Methods: Forty-three post-mortem liver biopsy samples from COVID-19 patients were obtained from Papa Giovanni XXIII Hospital in Bergamo, Italy. Three morphological features of microthrombosis (sinusoidal erythrocyte aggregation [SEA], platelet microthrombi [PMT], and fibrous thrombi) were evaluated. Results: We found liver sinusoidal microthrombosis in 23 COVID-19 patients (53%) was associated with a higher serum ALT and AST level compared to those without (ALT: 10-fold, p = 0.04; AST: 11-fold, p = 0.08). Of 43 livers, PMT and SEA were observed in 14 (33%) and 19 (44%) cases, respectively. Fibrous thrombi were not observed. Platelet microthrombi were associated with increased ALT (p < 0.01), whereas SEA was not (p = 0.73). In COVID-19 livers, strong vWF staining in liver sinusoidal endothelial cells was associated with significantly increased platelet adhesion (1.7-fold, p = 0.0016), compared to those with weak sinusoidal vWF (2-fold, p < 0.0001). Sinusoidal erythrocyte aggregation in 19 (83%) liver samples was mainly seen in zone 2. Livers with SEA had significantly higher fibrinogen (1.6-fold, p = 0.031) compared to those without SEA in COVID-19 patients. Conclusions: Liver PMT is a pathologically important thrombosis associated with liver injury in COVID-19, while SEA is a unique morphological feature of COVID-19 patient livers. Sinusoidal vWF and hyperfibrinogenemia could contr

Published
2021

26. Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy

Author

Mcconnell, M, Kawaguchi, N, Kondo, R, Sonzogni, A, Licini, L, Valle, C, Bonaffini, P, Sironi, S, Alessio, M, Previtali, G, Seghezzi, M, Zhang, X, Lee, A, Pine, A, Chun, H, Fernandez-Hernando, C, Qing, H, Wang, A, Price, C, Sun, Z, Utsumi, T, Hwa, J, Strazzabosco, M, Iwakiri, Y, McConnell M. J., Kawaguchi N., Kondo R., Sonzogni A., Licini L., Valle C., Bonaffini P. A., Sironi S., Alessio M. G., Previtali G., Seghezzi M., Zhang X., Lee A. I., Pine A. B., Chun H. J., Fernandez-Hernando C., Qing H., Wang A., Price C., Sun Z., Utsumi T., Hwa J., Strazzabosco M., Iwakiri Y., Mcconnell, M, Kawaguchi, N, Kondo, R, Sonzogni, A, Licini, L, Valle, C, Bonaffini, P, Sironi, S, Alessio, M, Previtali, G, Seghezzi, M, Zhang, X, Lee, A, Pine, A, Chun, H, Fernandez-Hernando, C, Qing, H, Wang, A, Price, C, Sun, Z, Utsumi, T, Hwa, J, Strazzabosco, M, Iwakiri, Y, McConnell M. J., Kawaguchi N., Kondo R., Sonzogni A., Licini L., Valle C., Bonaffini P. A., Sironi S., Alessio M. G., Previtali G., Seghezzi M., Zhang X., Lee A. I., Pine A. B., Chun H. J., Fernandez-Hernando C., Qing H., Wang A., Price C., Sun Z., Utsumi T., Hwa J., Strazzabosco M., and Iwakiri Y.

Abstract

Background and Aims: COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. Methods: Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. Results: Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling. Conclusion: IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism beh

Published
2021

27. Clinical outcome indicators in chronic hepatitis B and C: A primer for value-based medicine in hepatology

Author

Strazzabosco, M, Cortesi, P, Conti, S, Okolicsanyi, S, Rota, M, Ciaccio, A, Cozzolino, P, Fornari, C, Gemma, M, Scalone, L, Cesana, G, Fabris, L, Colledan, M, Fagiuoli, S, Ideo, G, Zavaglia, C, Perricone, G, Munari, L, Mantovani, L, Belli, L, Strazzabosco M., Cortesi P. A., Conti S., Okolicsanyi S., Rota M., Ciaccio A., Cozzolino P., Fornari C., Gemma M., Scalone L., Cesana G., Fabris L., Colledan M., Fagiuoli S., Ideo G., Zavaglia C., Perricone G., Munari L. M., Mantovani L. G., Belli L. S., Strazzabosco, M, Cortesi, P, Conti, S, Okolicsanyi, S, Rota, M, Ciaccio, A, Cozzolino, P, Fornari, C, Gemma, M, Scalone, L, Cesana, G, Fabris, L, Colledan, M, Fagiuoli, S, Ideo, G, Zavaglia, C, Perricone, G, Munari, L, Mantovani, L, Belli, L, Strazzabosco M., Cortesi P. A., Conti S., Okolicsanyi S., Rota M., Ciaccio A., Cozzolino P., Fornari C., Gemma M., Scalone L., Cesana G., Fabris L., Colledan M., Fagiuoli S., Ideo G., Zavaglia C., Perricone G., Munari L. M., Mantovani L. G., and Belli L. S.

Abstract

Background & Aims: Chronic liver diseases (CLDs) are major health problems that require complex and costly treatments. Liver-specific clinical outcome indicators (COIs) able to assist both clinicians and administrators in improving the value of care are presently lacking. The Value-Based Medicine in Hepatology (VBMH) study aims to fill this gap, devising and testing a set of COIs for CLD, that could be easily collected during clinical practice. Here we report the COIs generated and recorded for patients with HBV or HCV infection at different stages of the disease. Methods/Results: In the first phase of VBMH study, COIs were identified, based on current international guidelines and literature, using a modified Delphi method and a RAND 9-point appropriateness scale. In the second phase, COIs were tested in an observational, longitudinal, prospective, multicentre study based in Lombardy, Italy. Eighteen COIs were identified for HBV and HCV patients. Patients with CLD secondary to HBV (547) or HCV (1391) were enrolled over an 18-month period and followed for a median of 4 years. The estimation of the proposed COIs was feasible in the real-word clinical practice and COI values compared well with literature data. Further, the COIs were able to capture the impact of new effective treatments like direct-acting antivirals (DAAs) in the clinical practice. Conclusions: The COIs efficiently measured clinical outcomes at different stages of CLDs. While specific clinical practice settings and related healthcare systems may modify their implementation, these indicators will represent an important component of the tools for a value-based approach in hepatology and will positively affect care delivery.

Published
2020

28. Cholangiocyte biology and pathobiology

Author

Arias, IM, Alter, HJ, Boyer, JL, Cohen, DE, Shafritz, DA, Thorgeirsson, SS, Wolkoff, AW, Cadamuro, M, Fioretto, R, Strazzabosco, M, Cadamuro M., Fioretto R., Strazzabosco M., Arias, IM, Alter, HJ, Boyer, JL, Cohen, DE, Shafritz, DA, Thorgeirsson, SS, Wolkoff, AW, Cadamuro, M, Fioretto, R, Strazzabosco, M, Cadamuro M., Fioretto R., and Strazzabosco M.

Abstract

Cholangiocytes are the epithelial cells that line the intrahepatic and extrahepatic biliary tree. The biliary system is a complex network of tubules coated by epithelial cells, or cholangiocytes, which starts from the canals of Hering in the liver lobules, continues outside the liver, and terminates into the ampulla of Vater. The extra- and intrahepatic branches of the biliary tree originate from different embryological areas, explaining their morphological and biological properties. A fundamental function of epithelial cells, including cholangiocytes, is to selectively control the diffusion of ions and molecules through the epithelial barrier. Biliary epithelial cells are usually quiescent, following a liver insult, cholangiocytes activate and/or proliferate as a part of the so-called "hepatic reparative complex". Proliferation of cholangiocytes is fundamental for the maintenance of the normal homeostasis of the biliary tree, and in response to liver damage. A major role in epithelial innate immunity in cholangiocytes is played by toll-like receptors, and by nuclear receptors.

Published
2020

29. Liver Matrix in Benign and Malignant Biliary Tract Disease

Author

Fabris, L, Cadamuro, M, Cagnin, S, Strazzabosco, M, Gores, G, Fabris L., Cadamuro M., Cagnin S., Strazzabosco M., Gores G. J., Fabris, L, Cadamuro, M, Cagnin, S, Strazzabosco, M, Gores, G, Fabris L., Cadamuro M., Cagnin S., Strazzabosco M., and Gores G. J.

Abstract

The extracellular matrix is a highly reactive scaffold formed by a wide array of multifunctional molecules, encompassing collagens and noncollagenous glycoproteins, proteoglycans, glycosaminoglycans, and polysaccharides. Besides outlining the tissue borders, the extracellular matrix profoundly regulates the behavior of resident cells by transducing mechanical signals, and by integrating multiple cues derived from the microenvironment. Evidence is mounting that changes in the biostructure of the extracellular matrix are instrumental for biliary repair. Following biliary damage and eventually, malignant transformation, the extracellular matrix undergoes several quantitative and qualitative modifications, which direct interactions among hepatic progenitor cells, reactive ductular cells, activated myofibroblasts and macrophages, to generate the ductular reaction. Herein, we will give an overview of the main molecular factors contributing to extracellular matrix remodeling in cholangiopathies. Then, we will discuss the structural alterations in terms of biochemical composition and physical stiffness featuring the desmoplastic matrix of cholangiocarcinoma along with their pro-oncogenic effects.

Published
2020

30. The Emerging Role of Macrophages in Chronic Cholangiopathies Featuring Biliary Fibrosis: An Attractive Therapeutic Target for Orphan Diseases

Author

Cadamuro, M, Girardi, N, Gores, G, Strazzabosco, M, Fabris, L, Cadamuro M., Girardi N., Gores G. J., Strazzabosco M., Fabris L., Cadamuro, M, Girardi, N, Gores, G, Strazzabosco, M, Fabris, L, Cadamuro M., Girardi N., Gores G. J., Strazzabosco M., and Fabris L.

Abstract

Cholangiopathies are a heterogeneous group of chronic liver diseases caused by different types of injury targeting the biliary epithelium, such as genetic defects and immune-mediated attacks. Notably, most cholangiopathies are orphan, thereby representing one of the major gaps in knowledge of the modern hepatology. A typical hallmark of disease progression in cholangiopathies is portal scarring, and thus development of effective therapeutic approaches would aim to hinder cellular and molecular mechanisms underpinning biliary fibrogenesis. Recent lines of evidence indicate that macrophages, rather than more conventional cell effectors of liver fibrosis such as hepatic stellate cells and portal fibroblasts, are actively involved in the earliest stages of biliary fibrogenesis by exchanging a multitude of cues with cholangiocytes, which promote their recruitment from the circulating compartment owing to a senescent or an immature epithelial phenotype. Two cholangiopathies, namely primary sclerosing cholangitis and congenital hepatic fibrosis, are paradigmatic of this mechanism. This review summarizes current understandings of the cytokine and extracellular vesicles-mediated communications between cholangiocytes and macrophages typically occurring in the two cholangiopathies to unveil potential novel targets for the treatment of biliary fibrosis.

Published
2020

31. Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Author

Banales, J, Marin, J, Lamarca, A, Rodrigues, P, Khan, S, Roberts, L, Cardinale, V, Carpino, G, Andersen, J, Braconi, C, Calvisi, D, Perugorria, M, Fabris, L, Boulter, L, Macias, R, Gaudio, E, Alvaro, D, Gradilone, S, Strazzabosco, M, Marzioni, M, Coulouarn, C, Fouassier, L, Raggi, C, Invernizzi, P, Mertens, J, Moncsek, A, Rizvi, S, Heimbach, J, Koerkamp, B, Bruix, J, Forner, A, Bridgewater, J, Valle, J, Gores, G, Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C, Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR, Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens JC, Moncsek A, Rizvi S, Heimbach J, Koerkamp BG, Bruix J, Forner A, Bridgewater J, Valle JW, Gores GJ, Banales, J, Marin, J, Lamarca, A, Rodrigues, P, Khan, S, Roberts, L, Cardinale, V, Carpino, G, Andersen, J, Braconi, C, Calvisi, D, Perugorria, M, Fabris, L, Boulter, L, Macias, R, Gaudio, E, Alvaro, D, Gradilone, S, Strazzabosco, M, Marzioni, M, Coulouarn, C, Fouassier, L, Raggi, C, Invernizzi, P, Mertens, J, Moncsek, A, Rizvi, S, Heimbach, J, Koerkamp, B, Bruix, J, Forner, A, Bridgewater, J, Valle, J, Gores, G, Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C, Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR, Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens JC, Moncsek A, Rizvi S, Heimbach J, Koerkamp BG, Bruix J, Forner A, Bridgewater J, Valle JW, and Gores GJ

Abstract

Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.

Published
2020

32. Introduction to the Physiology, Immunology and Pathology of the Liver and Biliary Tree

Author

Neuberger, J, Hirschfield, GM, Carbone, M, Strazzabosco, M, Carbone M., Strazzabosco M., Neuberger, J, Hirschfield, GM, Carbone, M, Strazzabosco, M, Carbone M., and Strazzabosco M.

Abstract

The liver has many functions including metabolic homeostasis, disposal of endotoxins and xenotoxins, metabolism of bilirubin and urea, and bile formation and secretion. The process of bile formation depends on the liver synthesis and the canalicular secretion of bile acids. Besides their roles in dietary lipid absorption and cholesterol homeostasis, bile acids also play a key role as signaling molecules in the regulation of hepatic metabolism and energy homeostasis. The regenerative ability of the liver lies in the multiple niches of biliary tree stem cells.

Published
2020

34. Pathophysiology of Cystic Fibrosis Liver Disease: A Channelopathy Leading to Alterations in Innate Immunity and in Microbiota

Author

Fiorotto, R, Strazzabosco, M, Fiorotto R., Strazzabosco M., Fiorotto, R, Strazzabosco, M, Fiorotto R., and Strazzabosco M.

Abstract

Cystic fibrosis (CF) is a monogenic disease caused by mutation of Cftr. CF-associated liver disease (CFLD) is a common nonpulmonary cause of mortality in CF and accounts for approximately 2.5%–5% of overall CF mortality. The peak of the disease is in the pediatric population, but a second wave of liver disease in CF adults has been reported in the past decade in association with an increase in the life expectancy of these patients. New drugs are available to correct the basic defect in CF but their efficacy in CFLD is not known. The cystic fibrosis transmembrane conductance regulator, expressed in the apical membrane of cholangiocytes, is a major determinant for bile secretion and CFLD classically has been considered a channelopathy. However, the recent findings of the cystic fibrosis transmembrane conductance regulator as a regulator of epithelial innate immunity and the possible influence of the intestinal disease with an altered microbiota on the liver complication have opened new mechanistic insights on the pathogenesis of CFLD. This review provides an overview of the current understanding of the pathophysiology of the disease and discusses a potential target for intervention.

Published
2019

35. Animal models of cholestasis: An update on inflammatory cholangiopathies

Author

Mariotti, V, Cadamuro, M, Spirli, C, Fiorotto, R, Strazzabosco, M, Fabris, L, Mariotti V., Cadamuro M., Spirli C., Fiorotto R., Strazzabosco M., Fabris L., Mariotti, V, Cadamuro, M, Spirli, C, Fiorotto, R, Strazzabosco, M, Fabris, L, Mariotti V., Cadamuro M., Spirli C., Fiorotto R., Strazzabosco M., and Fabris L.

Abstract

Cholestasis is a frequent clinical condition initiating or complicating chronic liver diseases, particularly cholangiopathies, where the biliary epithelium is the primary target of the pathogenetic sequence. Until a few decades ago, understanding of cholestasis relied mostly on the experimental model of bile duct ligation in rodents. However, a simple model of biliary obstruction cannot reproduce the complex mechanisms and networks leading to cholestasis in cholangiopathies. These networks are underpinned by an intricate dysregulation of pro-inflammatory and pro-fibrotic signals involving besides cholangiocytes, multiple cell elements of both innate and adaptive immunity. Therefore, in the last years, a wide range of animal models of biliary injury have been developed, mostly in mice, following three main approaches, chemical induction, immunization and genetic manipulation. In this review, we will give an update of the animal models of the two main cholangiopathies, primary sclerosing cholangitis and primary biliary cholangitis, which have provided us with the most relevant insights into the pathogenesis of these still controversial diseases.

Published
2019

36. The challenges of primary biliary cholangitis: What is new and what needs to be done

Author

Terziroli Beretta-Piccoli, B, Mieli-Vergani, G, Vergani, D, Vierling, J, Adams, D, Alpini, G, Banales, J, Beuers, U, Bjornsson, E, Bowlus, C, Carbone, M, Chazouilleres, O, Dalekos, G, De Gottardi, A, Harada, K, Hirschfield, G, Invernizzi, P, Jones, D, Krawitt, E, Lanzavecchia, A, Lian, Z, Ma, X, Manns, M, Mavilio, D, Quigley, E, Sallusto, F, Shimoda, S, Strazzabosco, M, Swain, M, Tanaka, A, Trauner, M, Tsuneyama, K, Zigmond, E, Gershwin, M, Terziroli Beretta-Piccoli B., Mieli-Vergani G., Vergani D., Vierling J. M., Adams D., Alpini G., Banales J. M., Beuers U., Bjornsson E., Bowlus C., Carbone M., Chazouilleres O., Dalekos G., De Gottardi A., Harada K., Hirschfield G., Invernizzi P., Jones D., Krawitt E., Lanzavecchia A., Lian Z. -X., Ma X., Manns M., Mavilio D., Quigley E. M., Sallusto F., Shimoda S., Strazzabosco M., Swain M., Tanaka A., Trauner M., Tsuneyama K., Zigmond E., Gershwin M. E., Terziroli Beretta-Piccoli, B, Mieli-Vergani, G, Vergani, D, Vierling, J, Adams, D, Alpini, G, Banales, J, Beuers, U, Bjornsson, E, Bowlus, C, Carbone, M, Chazouilleres, O, Dalekos, G, De Gottardi, A, Harada, K, Hirschfield, G, Invernizzi, P, Jones, D, Krawitt, E, Lanzavecchia, A, Lian, Z, Ma, X, Manns, M, Mavilio, D, Quigley, E, Sallusto, F, Shimoda, S, Strazzabosco, M, Swain, M, Tanaka, A, Trauner, M, Tsuneyama, K, Zigmond, E, Gershwin, M, Terziroli Beretta-Piccoli B., Mieli-Vergani G., Vergani D., Vierling J. M., Adams D., Alpini G., Banales J. M., Beuers U., Bjornsson E., Bowlus C., Carbone M., Chazouilleres O., Dalekos G., De Gottardi A., Harada K., Hirschfield G., Invernizzi P., Jones D., Krawitt E., Lanzavecchia A., Lian Z. -X., Ma X., Manns M., Mavilio D., Quigley E. M., Sallusto F., Shimoda S., Strazzabosco M., Swain M., Tanaka A., Trauner M., Tsuneyama K., Zigmond E., and Gershwin M. E.

Abstract

Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid

Published
2019

37. Fibrocystic liver disease

Author

Cristoferi, L, Morana, G, Strazzabosco, M, Fabris, L, Cristoferi L., Morana G., Strazzabosco M., Fabris L., Cristoferi, L, Morana, G, Strazzabosco, M, Fabris, L, Cristoferi L., Morana G., Strazzabosco M., and Fabris L.

Published
2019

38. Economic Consequences of Investing in Anti-HCV Antiviral Treatment from the Italian NHS Perspective: A Real-World-Based Analysis of PITER Data

Author

Marcellusi, A, Viti, R, Kondili, L, Rosato, S, Vella, S, Mennini, F, Quaranta, M, Tosti, M, Weimer, L, Ferrigno, L, D'Angelo, F, Falzano, L, Benedetti, A, Schiada, L, Cucco, M, Giacometti, A, Brescini, L, Castelletti, S, Drenaggi, D, Mazzaro, C, Angarano, G, Milella, M, Dileo, A, Rendina, M, Contaldo, A, Iannone, A, La Fortezza, F, Rizzi, M, Cologni, G, Bolondi, L, Benevento, F, Serio, I, Andreone, P, Caraceni, P, Guarneri, V, Margotti, M, Simonetti, G, Mazzella, G, Verucchi, G, Donati, V, Mian, P, Rimenti, G, Rossini, A, Contessi, G, Castelli, F, Zaltron, S, Spinetti, A, Odolini, S, Leandro, G, Cozzolongo, R, Zappimbulso, M, Russello, M, Benigno, R, Coco, C, Torti, C, Costa, C, Greco, G, Mazzitelli, M, Pisani, V, Cosco, L, Quintieri, F, Desiena, M, Giancotti, F, Vecchiet, J, Falasca, K, Mastroianni, A, Apuzzo, G, Chidichimo, L, Foschi, F, Dall'Aglio, A, Libanore, M, Segala, D, Sighinolfi, L, Bartolozzi, D, Salomoni, E, Blanc, P, Baragli, F, Delpin, B, Mariabelli, E, Mazzotta, F, Poggi, A, Zignego, A, Monti, M, Madia, F, Xheka, A, Cela, E, Santantonio, T, Bruno, S, Viscoli, C, Alessandrini, A, Curti, C, Dibiagio, A, Nicolini, L, Balletto, E, Mastroianni, C, Blerta, K, Prati, D, Raffaele, L, Andreoletti, M, Perboni, G, Costa, P, Manzini, L, Raimondo, G, Filomia, R, Lazzarin, A, Morsica, G, Salpietro, S, Puoti, M, Baiguera, C, Vassalli, S, Rumi, M, Labanca, S, Zuin, M, Giorgini, A, Orellana, D, D'Arminiomonforte, A, Debona, A, Solaro, S, Fargion, S, Valenti, L, Periti, G, Pelusi, S, Galli, M, Calvi, E, Milazzo, L, Peri, A, Lampertico, P, Borghi, M, D'Ambrosio, R, Degasperi, E, Vinci, M, Villa, E, Bernabucci, V, Bristot, L, Pereira, F, Chessa, L, Pasetto, M, Loi, M, Gori, A, Beretta, I, Pastore, V, Soria, A, Strazzabosco, M, Ciaccio, A, Gemma, M, Borgia, G, Foggia, A, Zappulo, E, Gentile, I, Buonomo, A, Abrescia, N, Maddaloni, A, Caporaso, N, Morisco, F, Camera, S, Donnarumma, L, Coppola, C, Amoruso, D, Staiano, L, Saturnino, M, Coppola, N, Martini, S, Monari, C, Federico, A, Dallio, M, Loguercio, C, Gaeta, G, Brancaccio, G, Nardone, G, Sgamato, C, D'Adamo, G, Alberti, A, Gonzo, M, Piovesan, S, Chemello, L, Buggio, A, Cavalletto, L, Barbaro, F, Castelli, E, Floreani, A, Cazzagon, N, Franceschet, I, Russo, F, Zanetto, A, Franceschet, E, Madonia, S, Cannizzaro, M, Montalto, G, Licata, A, Capitano, A, Craxi, A, Petta, S, Calvaruso, V, Rini, F, Ferrari, C, Negri, E, Orlandini, A, Pesci, M, Bruno, R, Lombardi, A, Zuccaro, V, Gulminetti, R, Asti, A, Villaraggia, M, Mondelli, M, Ludovisi, S, Baldelli, F, Di Candilo, F, Parruti, G, Di Stefano, P, Sozio, F, Gizzi, M, Brunetto, M, Colombatto, P, Coco, B, Surace, L, Foti, G, Pellicano, S, Fornaciari, G, Schianchi, S, Vignoli, P, Massari, M, Corsini, R, Garlassi, E, Ballardini, G, Andreoni, M, Cerva, C, Angelico, M, Gasbarrini, A, Siciliano, M, De Siena, M, Nosotti, L, Taliani, G, Biliotti, E, Santori, M, Spaziante, M, Tamburini, F, Vullo, V, D'Ettorre, G, Cavallari, E, Gebremeskel, T, Pavone, P, Cauda, R, Cingolani, A, Lamonica, S, D'Offizi, G, Lionetti, R, Visco Comandini, U, Grieco, A, D'Aversa, F, Picardi, A, De Vincentis, A, Galati, G, Gallo, P, Dell'Unto, C, Aghemo, A, Gatti Comini, A, Persico, M, Masarone, M, Anselmo, M, De Leo, P, Marturano, M, Brunelli, E, Ridolfi, F, Schimizzi, A, Ayoubi Khajekini, M, Framarin, L, Di Perri, G, Cariti, G, Boglione, L, Cardellino, C, Marinaro, L, Saracco, G, Ciancio, A, Toniutto, P, Alterini, G, Capra, F, Ieluzzi, D, Marcellusi A., Viti R., Kondili L. A., Rosato S., Vella S., Mennini F. S., Quaranta M. G., Tosti M. E., Weimer L. E., Ferrigno L., D'Angelo F., Falzano L., Benedetti A., Schiada L., Cucco M., Giacometti A., Brescini L., Castelletti S., Drenaggi D., Mazzaro C., Angarano G., Milella M., DiLeo A., Rendina M., Contaldo A., Iannone A., La Fortezza F., Rizzi M., Cologni G., Bolondi L., Benevento F., Serio I., Andreone P., Caraceni P., Guarneri V., Margotti M., Simonetti G., Mazzella G., Verucchi G., Donati V., Mian P., Rimenti G., Rossini A., Contessi G. B., Castelli F., Zaltron S., Spinetti A., Odolini S., Leandro G., Cozzolongo R., Zappimbulso M., Russello M., Benigno R., Coco C., Torti C., Costa C., Greco G., Mazzitelli M., Pisani V., Cosco L., Quintieri F., DeSiena M., Giancotti F., Vecchiet J., Falasca K., Mastroianni A., Apuzzo G., Chidichimo L., Foschi F. G., Dall'Aglio A. C., Libanore M., Segala D., Sighinolfi L., Bartolozzi D., Salomoni E., Blanc P., Baragli F., DelPin B., Mariabelli E., Mazzotta F., Poggi A., Zignego A. L., Monti M., Madia F., Xheka A., Cela E. M., Santantonio T. A., Bruno S. R., Viscoli C., Alessandrini A. I., Curti C., DiBiagio A., Nicolini L. A., Balletto E., Mastroianni C., Blerta K., Prati D., Raffaele L., Andreoletti M., Perboni G., Costa P., Manzini L., Raimondo G., Filomia R., Lazzarin A., Morsica G., Salpietro S., Puoti M., Baiguera C., Vassalli S., Rumi M. G., Labanca S., Zuin M., Giorgini A., Orellana D., D'ArminioMonforte A., Debona A., Solaro S., Fargion S., Valenti L., Periti G., Pelusi S., Galli M., Calvi E., Milazzo L., Peri A., Lampertico P., Borghi M., D'Ambrosio R., Degasperi E., Vinci M., Villa E., Bernabucci V., Bristot L., Pereira F., Chessa L., Pasetto M. C., Loi M., Gori A., Beretta I., Pastore V., Soria A., Strazzabosco M., Ciaccio A., Gemma M., Borgia G., Foggia A., Zappulo E., Gentile I., Buonomo A. R., Abrescia N., Maddaloni A., Caporaso N., Morisco F., Camera S., Donnarumma L., Coppola C., Amoruso D. C., Staiano L., Saturnino M. R., Coppola N., Martini S., Monari C., Federico A., Dallio M., Loguercio C., Gaeta G. B., Brancaccio G., Nardone G., Sgamato C., D'Adamo G., Alberti A., Gonzo M., Piovesan S., Chemello L., Buggio A., Cavalletto L., Barbaro F., Castelli E., Floreani A., Cazzagon N., Franceschet I., Russo F. P., Zanetto A., Franceschet E., Madonia S., Cannizzaro M., Montalto G., Licata A., Capitano A. R., Craxi A., Petta S., Calvaruso V., Rini F., Ferrari C., Negri E., Orlandini A., Pesci M., Bruno R., Lombardi A., Zuccaro V., Gulminetti R., Asti A., Villaraggia M., Mondelli M., Ludovisi S., Baldelli F., Di Candilo F., Parruti G., Di Stefano P., Sozio F., Gizzi M. C., Brunetto M. R., Colombatto P., Coco B., Surace L., Foti G., Pellicano S., Fornaciari G., Schianchi S., Vignoli P., Massari M., Corsini R., Garlassi E., Ballardini G., Andreoni M., Cerva C., Angelico M., Gasbarrini A., Siciliano M., De Siena M., Nosotti L., Taliani G., Biliotti E., Santori M., Spaziante M., Tamburini F., Vullo V., D'Ettorre G., Cavallari E. N., Gebremeskel T. S., Pavone P., Cauda R., Cingolani A., Lamonica S., D'Offizi G., Lionetti R., Visco Comandini U., Grieco A., D'Aversa F., Picardi A., De Vincentis A., Galati G., Gallo P., Dell'Unto C., Aghemo A., Gatti Comini A., Persico M., Masarone M., Anselmo M., De Leo P., Marturano M., Brunelli E., Ridolfi F., Schimizzi A. M., Ayoubi Khajekini M., Framarin L., Di Perri G., Cariti G., Boglione L., Cardellino C., Marinaro L., Saracco G. M., Ciancio A., Toniutto P., Alterini G., Capra F., Ieluzzi D., Marcellusi, A, Viti, R, Kondili, L, Rosato, S, Vella, S, Mennini, F, Quaranta, M, Tosti, M, Weimer, L, Ferrigno, L, D'Angelo, F, Falzano, L, Benedetti, A, Schiada, L, Cucco, M, Giacometti, A, Brescini, L, Castelletti, S, Drenaggi, D, Mazzaro, C, Angarano, G, Milella, M, Dileo, A, Rendina, M, Contaldo, A, Iannone, A, La Fortezza, F, Rizzi, M, Cologni, G, Bolondi, L, Benevento, F, Serio, I, Andreone, P, Caraceni, P, Guarneri, V, Margotti, M, Simonetti, G, Mazzella, G, Verucchi, G, Donati, V, Mian, P, Rimenti, G, Rossini, A, Contessi, G, Castelli, F, Zaltron, S, Spinetti, A, Odolini, S, Leandro, G, Cozzolongo, R, Zappimbulso, M, Russello, M, Benigno, R, Coco, C, Torti, C, Costa, C, Greco, G, Mazzitelli, M, Pisani, V, Cosco, L, Quintieri, F, Desiena, M, Giancotti, F, Vecchiet, J, Falasca, K, Mastroianni, A, Apuzzo, G, Chidichimo, L, Foschi, F, Dall'Aglio, A, Libanore, M, Segala, D, Sighinolfi, L, Bartolozzi, D, Salomoni, E, Blanc, P, Baragli, F, Delpin, B, Mariabelli, E, Mazzotta, F, Poggi, A, Zignego, A, Monti, M, Madia, F, Xheka, A, Cela, E, Santantonio, T, Bruno, S, Viscoli, C, Alessandrini, A, Curti, C, Dibiagio, A, Nicolini, L, Balletto, E, Mastroianni, C, Blerta, K, Prati, D, Raffaele, L, Andreoletti, M, Perboni, G, Costa, P, Manzini, L, Raimondo, G, Filomia, R, Lazzarin, A, Morsica, G, Salpietro, S, Puoti, M, Baiguera, C, Vassalli, S, Rumi, M, Labanca, S, Zuin, M, Giorgini, A, Orellana, D, D'Arminiomonforte, A, Debona, A, Solaro, S, Fargion, S, Valenti, L, Periti, G, Pelusi, S, Galli, M, Calvi, E, Milazzo, L, Peri, A, Lampertico, P, Borghi, M, D'Ambrosio, R, Degasperi, E, Vinci, M, Villa, E, Bernabucci, V, Bristot, L, Pereira, F, Chessa, L, Pasetto, M, Loi, M, Gori, A, Beretta, I, Pastore, V, Soria, A, Strazzabosco, M, Ciaccio, A, Gemma, M, Borgia, G, Foggia, A, Zappulo, E, Gentile, I, Buonomo, A, Abrescia, N, Maddaloni, A, Caporaso, N, Morisco, F, Camera, S, Donnarumma, L, Coppola, C, Amoruso, D, Staiano, L, Saturnino, M, Coppola, N, Martini, S, Monari, C, Federico, A, Dallio, M, Loguercio, C, Gaeta, G, Brancaccio, G, Nardone, G, Sgamato, C, D'Adamo, G, Alberti, A, Gonzo, M, Piovesan, S, Chemello, L, Buggio, A, Cavalletto, L, Barbaro, F, Castelli, E, Floreani, A, Cazzagon, N, Franceschet, I, Russo, F, Zanetto, A, Franceschet, E, Madonia, S, Cannizzaro, M, Montalto, G, Licata, A, Capitano, A, Craxi, A, Petta, S, Calvaruso, V, Rini, F, Ferrari, C, Negri, E, Orlandini, A, Pesci, M, Bruno, R, Lombardi, A, Zuccaro, V, Gulminetti, R, Asti, A, Villaraggia, M, Mondelli, M, Ludovisi, S, Baldelli, F, Di Candilo, F, Parruti, G, Di Stefano, P, Sozio, F, Gizzi, M, Brunetto, M, Colombatto, P, Coco, B, Surace, L, Foti, G, Pellicano, S, Fornaciari, G, Schianchi, S, Vignoli, P, Massari, M, Corsini, R, Garlassi, E, Ballardini, G, Andreoni, M, Cerva, C, Angelico, M, Gasbarrini, A, Siciliano, M, De Siena, M, Nosotti, L, Taliani, G, Biliotti, E, Santori, M, Spaziante, M, Tamburini, F, Vullo, V, D'Ettorre, G, Cavallari, E, Gebremeskel, T, Pavone, P, Cauda, R, Cingolani, A, Lamonica, S, D'Offizi, G, Lionetti, R, Visco Comandini, U, Grieco, A, D'Aversa, F, Picardi, A, De Vincentis, A, Galati, G, Gallo, P, Dell'Unto, C, Aghemo, A, Gatti Comini, A, Persico, M, Masarone, M, Anselmo, M, De Leo, P, Marturano, M, Brunelli, E, Ridolfi, F, Schimizzi, A, Ayoubi Khajekini, M, Framarin, L, Di Perri, G, Cariti, G, Boglione, L, Cardellino, C, Marinaro, L, Saracco, G, Ciancio, A, Toniutto, P, Alterini, G, Capra, F, Ieluzzi, D, Marcellusi A., Viti R., Kondili L. A., Rosato S., Vella S., Mennini F. S., Quaranta M. G., Tosti M. E., Weimer L. E., Ferrigno L., D'Angelo F., Falzano L., Benedetti A., Schiada L., Cucco M., Giacometti A., Brescini L., Castelletti S., Drenaggi D., Mazzaro C., Angarano G., Milella M., DiLeo A., Rendina M., Contaldo A., Iannone A., La Fortezza F., Rizzi M., Cologni G., Bolondi L., Benevento F., Serio I., Andreone P., Caraceni P., Guarneri V., Margotti M., Simonetti G., Mazzella G., Verucchi G., Donati V., Mian P., Rimenti G., Rossini A., Contessi G. B., Castelli F., Zaltron S., Spinetti A., Odolini S., Leandro G., Cozzolongo R., Zappimbulso M., Russello M., Benigno R., Coco C., Torti C., Costa C., Greco G., Mazzitelli M., Pisani V., Cosco L., Quintieri F., DeSiena M., Giancotti F., Vecchiet J., Falasca K., Mastroianni A., Apuzzo G., Chidichimo L., Foschi F. G., Dall'Aglio A. C., Libanore M., Segala D., Sighinolfi L., Bartolozzi D., Salomoni E., Blanc P., Baragli F., DelPin B., Mariabelli E., Mazzotta F., Poggi A., Zignego A. L., Monti M., Madia F., Xheka A., Cela E. M., Santantonio T. A., Bruno S. R., Viscoli C., Alessandrini A. I., Curti C., DiBiagio A., Nicolini L. A., Balletto E., Mastroianni C., Blerta K., Prati D., Raffaele L., Andreoletti M., Perboni G., Costa P., Manzini L., Raimondo G., Filomia R., Lazzarin A., Morsica G., Salpietro S., Puoti M., Baiguera C., Vassalli S., Rumi M. G., Labanca S., Zuin M., Giorgini A., Orellana D., D'ArminioMonforte A., Debona A., Solaro S., Fargion S., Valenti L., Periti G., Pelusi S., Galli M., Calvi E., Milazzo L., Peri A., Lampertico P., Borghi M., D'Ambrosio R., Degasperi E., Vinci M., Villa E., Bernabucci V., Bristot L., Pereira F., Chessa L., Pasetto M. C., Loi M., Gori A., Beretta I., Pastore V., Soria A., Strazzabosco M., Ciaccio A., Gemma M., Borgia G., Foggia A., Zappulo E., Gentile I., Buonomo A. R., Abrescia N., Maddaloni A., Caporaso N., Morisco F., Camera S., Donnarumma L., Coppola C., Amoruso D. C., Staiano L., Saturnino M. R., Coppola N., Martini S., Monari C., Federico A., Dallio M., Loguercio C., Gaeta G. B., Brancaccio G., Nardone G., Sgamato C., D'Adamo G., Alberti A., Gonzo M., Piovesan S., Chemello L., Buggio A., Cavalletto L., Barbaro F., Castelli E., Floreani A., Cazzagon N., Franceschet I., Russo F. P., Zanetto A., Franceschet E., Madonia S., Cannizzaro M., Montalto G., Licata A., Capitano A. R., Craxi A., Petta S., Calvaruso V., Rini F., Ferrari C., Negri E., Orlandini A., Pesci M., Bruno R., Lombardi A., Zuccaro V., Gulminetti R., Asti A., Villaraggia M., Mondelli M., Ludovisi S., Baldelli F., Di Candilo F., Parruti G., Di Stefano P., Sozio F., Gizzi M. C., Brunetto M. R., Colombatto P., Coco B., Surace L., Foti G., Pellicano S., Fornaciari G., Schianchi S., Vignoli P., Massari M., Corsini R., Garlassi E., Ballardini G., Andreoni M., Cerva C., Angelico M., Gasbarrini A., Siciliano M., De Siena M., Nosotti L., Taliani G., Biliotti E., Santori M., Spaziante M., Tamburini F., Vullo V., D'Ettorre G., Cavallari E. N., Gebremeskel T. S., Pavone P., Cauda R., Cingolani A., Lamonica S., D'Offizi G., Lionetti R., Visco Comandini U., Grieco A., D'Aversa F., Picardi A., De Vincentis A., Galati G., Gallo P., Dell'Unto C., Aghemo A., Gatti Comini A., Persico M., Masarone M., Anselmo M., De Leo P., Marturano M., Brunelli E., Ridolfi F., Schimizzi A. M., Ayoubi Khajekini M., Framarin L., Di Perri G., Cariti G., Boglione L., Cardellino C., Marinaro L., Saracco G. M., Ciancio A., Toniutto P., Alterini G., Capra F., and Ieluzzi D.

Abstract

Objective: We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy. Methods: A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered. Results: The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively. Conclusions: This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV.

Published
2019

39. Liver diseases in the dish: iPSC and organoids as a new approach to modeling liver diseases

Author

Fiorotto, R, Amenduni, M, Mariotti, V, Fabris, L, Spirli, C, Strazzabosco, M, Fiorotto R., Amenduni M., Mariotti V., Fabris L., Spirli C., Strazzabosco M., Fiorotto, R, Amenduni, M, Mariotti, V, Fabris, L, Spirli, C, Strazzabosco, M, Fiorotto R., Amenduni M., Mariotti V., Fabris L., Spirli C., and Strazzabosco M.

Abstract

Liver diseases negatively impact the quality of life and survival of patients, and often require liver transplantation in cases that progress to organ failure. Understanding the cellular and molecular mechanisms of liver development and pathogenesis has been a challenging task, in part for the lack of adequate cellular models directly relevant to the human diseases. Recent technological advances in the stem cell field have shown the potentiality of induced pluripotent stem cells (iPSC) and liver organoids as the next generation tool to model in vitro liver diseases. Hepatocyte-like cells and cholangiocyte are currently being generated from skin fibroblasts and mononuclear blood cells reprogrammed into iPSC and have been successfully used for disease modeling, drug testing and gene editing, with the hope to be able to find application also in regenerative medicine. Protocols to generate other liver cell types are still under development, but the field is advancing rapidly. On the other end, liver cells can now be isolated from liver specimens (liver explants or liver biopsies) and cultured in specific conditions to form polarized 3D organoids. The purpose of this review is to summarize all these recent technological advances and their potential applications but also to analyze the current issues to be addressed before the technology can reach its full potential.

Published
2019

40. Cholangiocyte pathobiology

Author

Banales, J, Huebert, R, Karlsen, T, Strazzabosco, M, Larusso, N, Gores, G, Banales J. M., Huebert R. C., Karlsen T., Strazzabosco M., LaRusso N. F., Gores G. J., Banales, J, Huebert, R, Karlsen, T, Strazzabosco, M, Larusso, N, Gores, G, Banales J. M., Huebert R. C., Karlsen T., Strazzabosco M., LaRusso N. F., and Gores G. J.

Abstract

Cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, are highly specialized cells residing in a complex anatomic niche where they participate in bile production and homeostasis. Cholangiocytes are damaged in a variety of human diseases termed cholangiopathies, often causing advanced liver failure. The regulation of cholangiocyte transport properties is increasingly understood, as is their anatomical and functional heterogeneity along the biliary tract. Furthermore, cholangiocytes are pivotal in liver regeneration, especially when hepatocyte regeneration is compromised. The role of cholangiocytes in innate and adaptive immune responses, a critical subject relevant to immune-mediated cholangiopathies, is also emerging. Finally, reactive ductular cells are present in many cholestatic and other liver diseases. In chronic disease states, this repair response contributes to liver inflammation, fibrosis and carcinogenesis and is a subject of intense investigation. This Review highlights advances in cholangiocyte research, especially their role in development and liver regeneration, their functional and biochemical heterogeneity, their activation and involvement in inflammation and fibrosis and their engagement with the immune system. We aim to focus further attention on cholangiocyte pathobiology and the search for new disease-modifying therapies targeting the cholangiopathies.

Published
2019

41. Modeling of implementation of the new Organ Procurement and Transplantation Network/United Network for Organ Sharing policy for patients with hepatocellular carcinoma

Author

Kokabi, N, Nezami, N, Xing, M, Ludwig, J, Strazzabosco, M, Kim, H, Kokabi N., Nezami N., Xing M., Ludwig J. M., Strazzabosco M., Kim H. S., Kokabi, N, Nezami, N, Xing, M, Ludwig, J, Strazzabosco, M, Kim, H, Kokabi N., Nezami N., Xing M., Ludwig J. M., Strazzabosco M., and Kim H. S.

Abstract

Aim: To simulate effects of the new Organ Procurement and Transplantation Network/United Network for Organ Sharing policy on the patients' characteristics and post orthotopic liver transplantation (OLT) outcome. Materials & methods: The United Network for Organ Sharing database was used to identify patients with hepatocellular carcinoma who were listed for OLT 2002-2014. All patients (actual group) versus simulated group with new 6-month delay in assigning Model for End-Stage Liver Disease score exception and Model for End-Stage Liver Disease exception cap of 34 were compared. Results & conclusion: With the new policy, 7,745 (30.4%) of the transplanted patients would have received a delayed transplantation or not be transplanted. The simulated group also showed significantly higher mean overall survival after OLT (p < 0.002) and received more locoreginal treatments (p < 0.001).

Published
2019

42. The tumour microenvironment and immune milieu of cholangiocarcinoma

Author

Fabris, L, Perugorria, M, Mertens, J, Bjorkstrom, N, Cramer, T, Lleo, A, Solinas, A, Sanger, H, Lukacs-Kornek, V, Moncsek, A, Siebenhuner, A, Strazzabosco, M, Fabris L., Perugorria M. J., Mertens J., Bjorkstrom N. K., Cramer T., Lleo A., Solinas A., Sanger H., Lukacs-Kornek V., Moncsek A., Siebenhuner A., Strazzabosco M., Fabris, L, Perugorria, M, Mertens, J, Bjorkstrom, N, Cramer, T, Lleo, A, Solinas, A, Sanger, H, Lukacs-Kornek, V, Moncsek, A, Siebenhuner, A, Strazzabosco, M, Fabris L., Perugorria M. J., Mertens J., Bjorkstrom N. K., Cramer T., Lleo A., Solinas A., Sanger H., Lukacs-Kornek V., Moncsek A., Siebenhuner A., and Strazzabosco M.

Abstract

Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer-associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour-promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.

Published
2019

43. Economic Consequences of Investing in Anti-HCV Antiviral Treatment from the Italian NHS Perspective: A Real-World-Based Analysis of PITER Data

Author

Marcellusi, Andrea, Viti, Raffaella, Kondili, Loreta A., Rosato, Stefano, Vella, Stefano, Mennini, Francesco Saverio, Kondili, L. A., Vella, S., Quaranta, M. G., Rosato, S., Tosti, M. E., Weimer, L. E., Ferrigno, L., D’Angelo, F., Falzano, L., Benedetti, A., Schiadà, L., Cucco, M., Giacometti, A., Brescini, L., Castelletti, S., Drenaggi, D., Mazzaro, C., Angarano, G., Milella, M., Di Leo, A., Rendina, M., Contaldo, A., Iannone, A., La Fortezza, F., Rizzi, M., Cologni, G., Bolondi, L., Benevento, F., Serio, I., Andreone, P., Caraceni, P., Guarneri, V., Margotti, M., Simonetti, G., Mazzella, G., Verucchi, G., Donati, V., Mian, Peter, Rimenti, G., Rossini, A., Contessi, G. B., Castelli, Fulvio, Zaltron, S., Spinetti, A., Odolini, S., Leandro, G., Cozzolongo, R., Zappimbulso, M., Russello, M., Benigno, R., Coco, C., Torti, C., Costa, C., Greco, G., Mazzitelli, M., Pisani, V., Cosco, Lucia, Quintieri, F., De Siena, Martina, Giancotti, F., Vecchiet, J., Falasca, K., Mastroianni, A., Apuzzo, G., Chidichimo, L., Foschi, F. G., Dall’Aglio, A. C., Libanore, M., Segala, D., Sighinolfi, L., Bartolozzi, D., Salomoni, E., Blanc, P., Baragli, F., DelundefinedPin, B., Mariabelli, E., Mazzotta, F., Poggi, A., Zignego, A. L., Monti, M., Madia, Francesca, Xheka, A., Cela, E. M., Santantonio, T. A., Bruno, S. R., Viscoli, C., Alessandrini, A. I., Curti, C., DiundefinedBiagio, A., Nicolini, L. A., Balletto, E., Mastroianni, Chiara, Blerta, K., Prati, D., Raffaele, L., Andreoletti, M., Perboni, G., Costa, P., Manzini, L., Raimondo, G., Filomia, R., Lazzarin, A., Morsica, G., Salpietro, S., Puoti, M., Baiguera, C., Vassalli, S., Rumi, M. G., Labanca, S., Zuin, M., Giorgini, A., Orellana, D., D’ArminioundefinedMonforte, A., Debona, A., Solaro, S., Fargion, S., Valenti, L., Periti, G., Pelusi, S., Galli, M., Calvi, E., Milazzo, L., Peri, A., Lampertico, P., Borghi, Margherita, D’Ambrosio, R., Degasperi, E., Vinci, Maria Rosaria, Villa, E., Bernabucci, V., Bristot, Luca, Pereira, F., Chessa, L., Pasetto, M. C., Loi, M., Gori, A., Beretta, I., Pastore, V., Soria, A., Strazzabosco, M., Ciaccio, A., Gemma, M., Borgia, G., Foggia, A., Zappulo, E., Gentile, I., Buonomo, A. R., Abrescia, N., Maddaloni, A., Caporaso, N., Morisco, F., Camera, S., Donnarumma, L., Coppola, C., Amoruso, D. C., Staiano, L., Saturnino, M. R., Coppola, N., Martini, S., Monari, C., Federico, Alex, Dallio, M., Loguercio, C., Gaeta, G. B., Brancaccio, G., Nardone, G., Sgamato, C., D’Adamo, G., Alberti, A., Gonzo, M., Piovesan, S., Chemello, L., Buggio, A., Cavalletto, L., Barbaro, F., Castelli, Enrico, Floreani, A., Cazzagon, N., Franceschet, I., Russo, F. P., Zanetto, A., Franceschet, E., Madonia, S., Cannizzaro, Maria Chiara, Montalto, G., Licata, A., Capitano, A. R., Craxì, A., Petta, S., Calvaruso, V., Rini, F., Ferrari, C., Negri, E., Orlandini, A., Pesci, M., Bruno, R., Lombardi, A., Zuccaro, V., Gulminetti, R., Asti, A., Villaraggia, M., Mondelli, M., Ludovisi, S., Baldelli, F., Di Candilo, F., Parruti, G., Di Stefano, Paolo, Sozio, F., Gizzi, M. C., Brunetto, M. R., Colombatto, P., Coco, B., Surace, L., Foti, G., Pellicano, S., Fornaciari, G., Schianchi, S., Vignoli, P., Massari, M., Corsini, R., Garlassi, E., Ballardini, G., Andreoni, M., Cerva, C., Angelico, M., Gasbarrini, Antonio, Siciliano, M., Nosotti, L., Taliani, G., Biliotti, E., Santori, M., Spaziante, M., Tamburini, F., Vullo, V., D’Ettorre, G., Cavallari, E. N., Gebremeskel, T. S., Pavone, P., Cauda, Roberto, Cingolani, Antonella, Lamonica, S., D’Offizi, G., Lionetti, R., Visco Comandini, U., Grieco, Antonio, D’Aversa, F., Picardi, A., De Vincentis, A., Galati, G., Gallo, Patrizia, Dell’Unto, C., Aghemo, A., Gatti Comini, A., Persico, M., Masarone, M., Anselmo, M., De Leo, P., Marturano, Monia, Brunelli, E., Ridolfi, F., Schimizzi, A. M., Ayoubi Khajekini, M., Framarin, L., Di Perri, G., Cariti, G., Boglione, L., Cardellino, C., Marinaro, L., Saracco, G. M., Ciancio, A., Toniutto, P., Alterini, G., Capra, F., Ieluzzi, D., Marcellusi, A, Viti, R, Kondili, L, Rosato, S, Vella, S, Mennini, F, Quaranta, M, Tosti, M, Weimer, L, Ferrigno, L, D'Angelo, F, Falzano, L, Benedetti, A, Schiada, L, Cucco, M, Giacometti, A, Brescini, L, Castelletti, S, Drenaggi, D, Mazzaro, C, Angarano, G, Milella, M, Dileo, A, Rendina, M, Contaldo, A, Iannone, A, La Fortezza, F, Rizzi, M, Cologni, G, Bolondi, L, Benevento, F, Serio, I, Andreone, P, Caraceni, P, Guarneri, V, Margotti, M, Simonetti, G, Mazzella, G, Verucchi, G, Donati, V, Mian, P, Rimenti, G, Rossini, A, Contessi, G, Castelli, F, Zaltron, S, Spinetti, A, Odolini, S, Leandro, G, Cozzolongo, R, Zappimbulso, M, Russello, M, Benigno, R, Coco, C, Torti, C, Costa, C, Greco, G, Mazzitelli, M, Pisani, V, Cosco, L, Quintieri, F, Desiena, M, Giancotti, F, Vecchiet, J, Falasca, K, Mastroianni, A, Apuzzo, G, Chidichimo, L, Foschi, F, Dall'Aglio, A, Libanore, M, Segala, D, Sighinolfi, L, Bartolozzi, D, Salomoni, E, Blanc, P, Baragli, F, Delpin, B, Mariabelli, E, Mazzotta, F, Poggi, A, Zignego, A, Monti, M, Madia, F, Xheka, A, Cela, E, Santantonio, T, Bruno, S, Viscoli, C, Alessandrini, A, Curti, C, Dibiagio, A, Nicolini, L, Balletto, E, Mastroianni, C, Blerta, K, Prati, D, Raffaele, L, Andreoletti, M, Perboni, G, Costa, P, Manzini, L, Raimondo, G, Filomia, R, Lazzarin, A, Morsica, G, Salpietro, S, Puoti, M, Baiguera, C, Vassalli, S, Rumi, M, Labanca, S, Zuin, M, Giorgini, A, Orellana, D, D'Arminiomonforte, A, Debona, A, Solaro, S, Fargion, S, Valenti, L, Periti, G, Pelusi, S, Galli, M, Calvi, E, Milazzo, L, Peri, A, Lampertico, P, Borghi, M, D'Ambrosio, R, Degasperi, E, Vinci, M, Villa, E, Bernabucci, V, Bristot, L, Pereira, F, Chessa, L, Pasetto, M, Loi, M, Gori, A, Beretta, I, Pastore, V, Soria, A, Strazzabosco, M, Ciaccio, A, Gemma, M, Borgia, G, Foggia, A, Zappulo, E, Gentile, I, Buonomo, A, Abrescia, N, Maddaloni, A, Caporaso, N, Morisco, F, Camera, S, Donnarumma, L, Coppola, C, Amoruso, D, Staiano, L, Saturnino, M, Coppola, N, Martini, S, Monari, C, Federico, A, Dallio, M, Loguercio, C, Gaeta, G, Brancaccio, G, Nardone, G, Sgamato, C, D'Adamo, G, Alberti, A, Gonzo, M, Piovesan, S, Chemello, L, Buggio, A, Cavalletto, L, Barbaro, F, Castelli, E, Floreani, A, Cazzagon, N, Franceschet, I, Russo, F, Zanetto, A, Franceschet, E, Madonia, S, Cannizzaro, M, Montalto, G, Licata, A, Capitano, A, Craxi, A, Petta, S, Calvaruso, V, Rini, F, Ferrari, C, Negri, E, Orlandini, A, Pesci, M, Bruno, R, Lombardi, A, Zuccaro, V, Gulminetti, R, Asti, A, Villaraggia, M, Mondelli, M, Ludovisi, S, Baldelli, F, Di Candilo, F, Parruti, G, Di Stefano, P, Sozio, F, Gizzi, M, Brunetto, M, Colombatto, P, Coco, B, Surace, L, Foti, G, Pellicano, S, Fornaciari, G, Schianchi, S, Vignoli, P, Massari, M, Corsini, R, Garlassi, E, Ballardini, G, Andreoni, M, Cerva, C, Angelico, M, Gasbarrini, A, Siciliano, M, De Siena, M, Nosotti, L, Taliani, G, Biliotti, E, Santori, M, Spaziante, M, Tamburini, F, Vullo, V, D'Ettorre, G, Cavallari, E, Gebremeskel, T, Pavone, P, Cauda, R, Cingolani, A, Lamonica, S, D'Offizi, G, Lionetti, R, Visco Comandini, U, Grieco, A, D'Aversa, F, Picardi, A, De Vincentis, A, Galati, G, Gallo, P, Dell'Unto, C, Aghemo, A, Gatti Comini, A, Persico, M, Masarone, M, Anselmo, M, De Leo, P, Marturano, M, Brunelli, E, Ridolfi, F, Schimizzi, A, Ayoubi Khajekini, M, Framarin, L, Di Perri, G, Cariti, G, Boglione, L, Cardellino, C, Marinaro, L, Saracco, G, Ciancio, A, Toniutto, P, Alterini, G, Capra, F, Ieluzzi, D, Kondili LA, Vella S, Quaranta MG, Rosato S, Tosti ME, Weimer LE, Ferrigno L, D'Angelo F, Falzano L, Benedetti A, Schiadà L, Cucco M, Giacometti A, Brescini L, Castelletti S, Drenaggi D, Mazzaro C, Angarano G, Milella M, Di Leo A, Rendina M, Contaldo A, Iannone A, La Fortezza F, Rizzi M, Cologni G, Bolondi L, Benevento F, Serio I, Andreone P, Caraceni P, Guarneri V, Margotti M, Simonetti G, Mazzella G, Verucchi G, Donati V, Mian P, Rimenti G, Rossini A, Contessi GB, Castelli F, Zaltron S, Spinetti A, Odolini S, Leandro G, Cozzolongo R, Zappimbulso M, Russello M, Benigno R, Coco C, Torti C, Costa C, Greco G, Mazzitelli M, Pisani V, Cosco L, Quintieri F, De Siena M, Giancotti F, Vecchiet J, Falasca K, Mastroianni A, Apuzzo G, Chidichimo L, Foschi FG, Dall'Aglio AC, Libanore M, Segala D, Sighinolfi L, Bartolozzi D, Salomoni E, Blanc P, Baragli F, Del Pin B, Mariabelli E, Mazzotta F, Poggi A, Zignego AL, Monti M, Madia F, Xheka A, Cela EM, Santantonio TA, Bruno SR, Viscoli C, Alessandrini AI, Curti C, Di Biagio A, Nicolini LA, Balletto E, Mastroianni C, Blerta K, Prati D, Raffaele L, Andreoletti M, Perboni G, Costa P, Manzini L, Raimondo G, Filomia R, Lazzarin A, Morsica G, Salpietro S, Puoti M, Baiguera C, Vassalli S, Rumi MG, Labanca S, Zuin M, Giorgini A, Orellana D, D'Arminio Monforte A, Debona A, Solaro S, Fargion S, Valenti L, Periti G, Pelusi S, Galli M, Calvi E, Milazzo L, Peri A, Lampertico P, Borghi M, D'Ambrosio R, Degasperi E, Vinci M, Villa E, Bernabucci V, Bristot L, Pereira F, Chessa L, Pasetto MC, Loi M, Gori A, Beretta I, Pastore V, Soria A, Strazzabosco M, Ciaccio A, Gemma M, Borgia G, Foggia A, Zappulo E, Gentile I, Buonomo AR, Abrescia N, Maddaloni A, Caporaso N, Morisco F, Camera S, Donnarumma L, Coppola C, Amoruso DC, Staiano L, Saturnino MR, Coppola N, Martini S, Monari C, Federico A, Dallio M, Loguercio C, Gaeta GB, Brancaccio G, Nardone G, Sgamato C, D'Adamo G, Alberti A, Gonzo M, Piovesan S, Chemello L, Buggio A, Cavalletto L, Barbaro F, Castelli E, Floreani A, Cazzagon N, Franceschet I, Russo FP, Zanetto A, Franceschet E, Madonia S, Cannizzaro M, Montalto G, Licata A, Capitano AR, Craxì A, Petta S, Calvaruso V, Rini F, Ferrari C, Negri E, Orlandini A, Pesci M, Bruno R, Lombardi A, Zuccaro V, Gulminetti R, Asti A, Villaraggia M, Mondelli M, Ludovisi S, Baldelli F, Di Candilo F, Parruti G, Di Stefano P, Sozio F, Gizzi MC, Brunetto MR, Colombatto P, Coco B, Surace L, Foti G, Pellicano S, Fornaciari G, Schianchi S, Vignoli P, Massari M, Corsini R, Garlassi E, Ballardini G, Andreoni M, Cerva C, Angelico M, Gasbarrini A, Siciliano M, De Siena M, Nosotti L, Taliani G, Biliotti E, Santori M, Spaziante M, Tamburini F, Vullo V, D'Ettorre G, Cavallari EN, Gebremeskel TS, Pavone P, Cauda R, Cingolani A, Lamonica S, D'Offizi G, Lionetti R, Visco Comandini U, Grieco A, D'Aversa F, Picardi A, De Vincentis A, Galati G, Gallo P, Dell'Unto C, Aghemo A, Gatti Comini A, Persico M, Masarone M, Anselmo M, De Leo P, Marturano M, Brunelli E, Ridolfi F, Schimizzi AM, Ayoubi Khajekini M, Framarin L, Di Perri G, Cariti G, Boglione L, Cardellino C, Marinaro L, Saracco GM, Ciancio A, Toniutto P, Alterini G, Capra F, Ieluzzi D., Marcellusi, A., Viti, R., Kondili, L. A., Rosato, S., Vella, S., Mennini, F. S., Quaranta, M. G., Tosti, M. E., Weimer, L. E., Ferrigno, L., D'Angelo, F., Falzano, L., Benedetti, A., Schiada, L., Cucco, M., Giacometti, A., Brescini, L., Castelletti, S., Drenaggi, D., Mazzaro, C., Angarano, G., Milella, M., Dileo, A., Rendina, M., Contaldo, A., Iannone, A., La Fortezza, F., Rizzi, M., Cologni, G., Bolondi, L., Benevento, F., Serio, I., Andreone, P., Caraceni, P., Guarneri, V., Margotti, M., Simonetti, G., Mazzella, G., Verucchi, G., Donati, V., Mian, P., Rimenti, G., Rossini, A., Contessi, G. B., Castelli, F., Zaltron, S., Spinetti, A., Odolini, S., Leandro, G., Cozzolongo, R., Zappimbulso, M., Russello, M., Benigno, R., Coco, C., Torti, C., Costa, C., Greco, G., Mazzitelli, M., Pisani, V., Cosco, L., Quintieri, F., Desiena, M., Giancotti, F., Vecchiet, J., Falasca, K., Mastroianni, A., Apuzzo, G., Chidichimo, L., Foschi, F. G., Dall'Aglio, A. C., Libanore, M., Segala, D., Sighinolfi, L., Bartolozzi, D., Salomoni, E., Blanc, P., Baragli, F., Delpin, B., Mariabelli, E., Mazzotta, F., Poggi, A., Zignego, A. L., Monti, M., Madia, F., Xheka, A., Cela, E. M., Santantonio, T. A., Bruno, S. R., Viscoli, C., Alessandrini, A. I., Curti, C., Dibiagio, A., Nicolini, L. A., Balletto, E., Mastroianni, C., Blerta, K., Prati, D., Raffaele, L., Andreoletti, M., Perboni, G., Costa, P., Manzini, L., Raimondo, G., Filomia, R., Lazzarin, A., Morsica, G., Salpietro, S., Puoti, M., Baiguera, C., Vassalli, S., Rumi, M. G., Labanca, S., Zuin, M., Giorgini, A., Orellana, D., D'Arminiomonforte, A., Debona, A., Solaro, S., Fargion, S., Valenti, L., Periti, G., Pelusi, S., Galli, M., Calvi, E., Milazzo, L., Peri, A., Lampertico, P., Borghi, M., D'Ambrosio, R., Degasperi, E., Vinci, M., Villa, E., Bernabucci, V., Bristot, L., Pereira, F., Chessa, L., Pasetto, M. C., Loi, M., Gori, A., Beretta, I., Pastore, V., Soria, A., Strazzabosco, M., Ciaccio, A., Gemma, M., Borgia, G., Foggia, A., Zappulo, E., Gentile, I., Buonomo, A. R., Abrescia, N., Maddaloni, A., Caporaso, N., Morisco, F., Camera, S., Donnarumma, L., Coppola, C., Amoruso, D. C., Staiano, L., Saturnino, M. R., Coppola, N., Martini, S., Monari, C., Federico, A., Dallio, M., Loguercio, C., Gaeta, G. B., Brancaccio, G., Nardone, G., Sgamato, C., D'Adamo, G., Alberti, A., Gonzo, M., Piovesan, S., Chemello, L., Buggio, A., Cavalletto, L., Barbaro, F., Castelli, E., Floreani, A., Cazzagon, N., Franceschet, I., Russo, F. P., Zanetto, A., Franceschet, E., Madonia, S., Cannizzaro, M., Montalto, G., Licata, A., Capitano, A. R., Craxi, A., Petta, S., Calvaruso, V., Rini, F., Ferrari, C., Negri, E., Orlandini, A., Pesci, M., Bruno, R., Lombardi, A., Zuccaro, V., Gulminetti, R., Asti, A., Villaraggia, M., Mondelli, M., Ludovisi, S., Baldelli, F., Di Candilo, F., Parruti, G., Di Stefano, P., Sozio, F., Gizzi, M. C., Brunetto, M. R., Colombatto, P., Coco, B., Surace, L., Foti, G., Pellicano, S., Fornaciari, G., Schianchi, S., Vignoli, P., Massari, M., Corsini, R., Garlassi, E., Ballardini, G., Andreoni, M., Cerva, C., Angelico, M., Gasbarrini, A., Siciliano, M., De Siena, M., Nosotti, L., Taliani, G., Biliotti, E., Santori, M., Spaziante, M., Tamburini, F., Vullo, V., D'Ettorre, G., Cavallari, E. N., Gebremeskel, T. S., Pavone, P., Cauda, R., Cingolani, A., Lamonica, S., D'Offizi, G., Lionetti, R., Visco Comandini, U., Grieco, A., D'Aversa, F., Picardi, A., De Vincentis, A., Galati, G., Gallo, P., Dell'Unto, C., Aghemo, A., Gatti Comini, A., Persico, M., Masarone, M., Anselmo, M., De Leo, P., Marturano, M., Brunelli, E., Ridolfi, F., Schimizzi, A. M., Ayoubi Khajekini, M., Framarin, L., Di Perri, G., Cariti, G., Boglione, L., Cardellino, C., Marinaro, L., Saracco, G. M., Ciancio, A., Toniutto, P., Alterini, G., Capra, F., Ieluzzi, D., Marcellusi, Andrea, Viti, Raffaella, Kondili, Loreta A., Rosato, Stefano, Vella, Stefano, Mennini, Francesco Saverio, Kondili, L.A., Quaranta, M.G., Tosti, M.E., Weimer, L.E., D’Angelo, F., Schiadà, L., Di&nbsp, Leo, A., Contessi, G.B., De&nbsp, Siena, M., Foschi, F.G., Dall’Aglio, A.C., Del&nbsp, Pin, B., Zignego, A.L., Cela, E.M., Santantonio, T.A., Bruno, S.R., Alessandrini, A.I., Biagio, A., Nicolini, L.A., Rumi, M.G., D’Arminio&nbsp, Monforte, A., D’Ambrosio, R., Pasetto, M.C., Buonomo, A.R., Amoruso, D.C., Saturnino, M.R., Gaeta, G.B., D’Adamo, G., Russo, F.P., Capitano, A.R., Craxì, A., Gizzi, M.C., Brunetto, M.R., D’Ettorre, G., Cavallari, E.N., Gebremeskel, T.S., D’Offizi, G., D’Aversa, F., Dell’Unto, C., Schimizzi, A.M., Saracco, G.M., Cosco, Alfredo, Dall’Aglio, A. C., Salomoni, Valentina, Nicolini, Elvira, Calvi, Marta, Soria, Giovanni, D'Adamo, Danilo, ALONSO ALBERTI, MARIA PALOMA CARMEN, Orlandini, Giovanni, DE ASTIS, Fabio, Sozio, Concetta, Terzini, Angelico, DE SIENA, ANDREA URIEL, Taliani, Sabrina, Spaziante, Agata, Lamonica, Emilia, and Capra, Carlo

Subjects
Liver Cirrhosis, Pediatrics, Time Factors, Settore MED/09 - Medicina Interna, National Health Programs, ERADICATION, OUTBREAK, antiviral treatment, anti HCV, economic consequences, Hepacivirus, LIVER FIBROSIS, Severity of Illness Index, Health Services Accessibility, COST-EFFECTIVENESS, Indirect costs, 0302 clinical medicine, Epidemiology, virus infection, 030212 general & internal medicine, health care economics and organizations, cost effectiveness, 030503 health policy & services, Health Policy, Health services research, health, Hepatitis C, Markov Chains, chronic hepatitis C, virus infection, fibrosis progression, cost effectiveness, liver fibrosis, Italy, Pharmacology, Public Health, Environmental and Occupational Health, Cohort, Settore SECS-P/03 - Scienza delle Finanze, Disease Progression, Public Health, 0305 other medical science, Viral hepatitis, Anti-HCV antiviral treatment, CHRONIC HEPATITIS-C, medicine.medical_specialty, Genotype, Settore MED/12 - GASTROENTEROLOGIA, VIRUS-INFECTION, Antiviral Agents, NO, 03 medical and health sciences, Cost Savings, Humans, medicine, MANAGEMENT, chronic hepatitis C, INDUCED DISEASES, METAANALYSIS, Health economics, business.industry, Public health, Environmental and Occupational Health, medicine.disease, FIBROSIS PROGRESSION, business
Abstract

OBJECTIVE:\ud We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy.\ud \ud METHODS:\ud A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered.\ud \ud RESULTS:\ud The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively.\ud \ud CONCLUSIONS:\ud This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV.

Published
2019

45. Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic

Author

Cadamuro, M, Lasagni, A, Lamarca, A, Fouassier, L, Guido, M, Sarcognato, S, Gringeri, E, Cillo, U, Strazzabosco, M, Marin, J, Banales, J, Fabris, L, Marin, JJG, Banales, JM, Cadamuro, M, Lasagni, A, Lamarca, A, Fouassier, L, Guido, M, Sarcognato, S, Gringeri, E, Cillo, U, Strazzabosco, M, Marin, J, Banales, J, Fabris, L, Marin, JJG, and Banales, JM

Abstract

Introduction: Until recently, cholangiocarcinoma (CCA) was a largely overlooked disease, and among CCAs, extrahepatic CCA (eCCA) was even more neglected. Despite the growing impact of molecularly targeted therapies and immunotherapy, prognosis of eCCA is dismal. Therefore, unraveling the complex molecular landscape of eCCA has become an urgent need. Deep phenotyping studies have revealed that eCCA is a heterogeneous tumor, harboring specific alterations categorizable into four classes, ‘Mesenchymal’, ‘Proliferation’, ‘Immune’, ‘Metabolic’. Molecular alterations convey the activation of several pro-oncogenic pathways, where either actionable drivers or outcome predictors can be identified. Areas covered: We offer insights on perturbed pathways, molecular profiling, and actionable targets in eCCA and present a perspective on the potential stepping-stones to future progress. A systematic literature search in PubMed/ClinicalTrials.gov websites was performed by authors from different disciplines according to their specific topic knowledge to identify the newest and most relevant advances in precision medicine of eCCA. Expert opinion: eCCA is a distinct entity with unique features in terms of molecular classes, oncogenic drivers, and tumor microenvironment. Since more prevalent mutations are currently undruggable, and immunotherapy can be offered only to a minority of patients, international collaborations are instrumental to improve the understanding of the molecular underpins of this disease.

Published
2021

46. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Author

Asselta, R., Paraboschi, E. M., Gerussi, A., Cordell, H. J., Mells, G. F., Sandford, R. N., Jones, D. E., Nakamura, M., Ueno, K., Hitomi, Y., Kawashima, M., Nishida, N., Tokunaga, K., Nagasaki, M., Tanaka, A., Tang, R., Li, Z., Shi, Y., Liu, X., Xiong, M., Hirschfield, G., Siminovitch, K. A., Walker, E., Xie, G., Mason, A., Myers, R., Peltekian, K., Ghent, C., Atkinson, E., Juran, B., Lazaridis, K., Lu, Y., Gu, X., Jing, K., Amos, C., Affronti, A., Brunetto, M., Coco, B., Spinzi, G., Elia, G., Ferrari, C., Lleo, A., Muratori, L., Muratori, P., Portincasa, P., Colli, A., Bruno, S., Colloredo, G., Azzaroli, F., Andreone, P., Bragazzi, M., Alvaro, D., Cardinale, V., Cazzagon, N., Rigamonti, C., Floreani, A., Rosina, F., Ciaccio, A., Cristoferi, L., D'Amato, D., Malinverno, F., Mancuso, C., Massironi, S., Milani, C., O'Donnell, S. E., Ronca, V., Barisani, D., Lampertico, P., Donato, Federica, Fagiuoli, Stefano, Almasio, P. L., Giannini, E., Cursaro, C., Colombo, M., Valenti, L., Miele, Luca, Andriulli, A., Niro, G. A., Grattagliano, I., Morini, L., Casella, G., Vinci, Maria Rosaria, Battezzati, P. M., Crosignani, A., Zuin, M., Mattalia, A., Calvaruso, V., Colombo, S., Benedetti, A., Marzioni, M., Galli, A., Marra, F., Tarocchi, M., Picciotto, A., Morisco, F., Fabris, L., Croce, L. S., Tiribelli, C., Toniutto, P., Strazzabosco, M., Ch'Ng, C. L., Rahman, M., Yapp, T., Sturgess, R., Healey, C., Czajkowski, M., Gunasekera, A., Gyawali, P., Premchand, P., Kapur, K., Marley, R., Foster, G., Watson, A., Dias, A., Subhani, J., Harvey, R., Mccorry, R., Ramanaden, D., Gasem, J., Evans, R., Mathialahan, T., Shorrock, C., Lipscomb, G., Southern, P., Tibble, J., Gorard, D., Palegwala, A., Jones, S., Dawwas, M., Alexander, G., Dolwani, S., Prince, M., Foxton, M., Elphick, D., Mitchison, H., Gooding, I., Karmo, M., Saksena, S., Mendall, M., Patel, M., Ede, R., Austin, A., Sayer, J., Hankey, L., Hovell, C., Fisher, N., Carter, M., Koss, K., Piotrowicz, A., Grimley, C., Neal, D., Lim, G., Levi, S., Ala, A., Broad, A., Saeed, A., Wood, G., Brown, J., Wilkinson, M., Gordon, H., Ramage, J., Ridpath, J., Ngatchu, T., Grover, B., Shaukat, S., Shidrawi, R., Abouda, G., Ali, F., Rees, I., Salam, I., Narain, M., Brown, A., Taylor-Robinson, S., Williams, S., Grellier, L., Banim, P., Das, D., Chilton, A., Heneghan, M., Curtis, H., Gess, M., Drake, I., Aldersley, M., Davies, M., Jones, R., Mcnair, A., Srirajaskanthan, R., Pitcher, M., Sen, S., Bird, G., Barnardo, A., Kitchen, P., Yoong, K., Chirag, O., Sivaramakrishnan, N., Macfaul, G., Jones, D., Shah, A., Evans, C., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Fraser, A., Mills, P., Shallcross, C., Campbell, S., Bathgate, A., Shepherd, A., Dillon, J., Rushbrook, S., Przemioslo, R., Macdonald, C., Metcalf, J., Shmueli, U., Davis, A., Naqvi, A., Lee, T., Ryder, S. D., Collier, J., Klass, H., Ninkovic, M., Cramp, M., Sharer, N., Aspinall, R., Goggin, P., Ghosh, D., Douds, A., Hoeroldt, B., Booth, J., Williams, E., Hussaini, H., Stableforth, W., Ayres, R., Thorburn, D., Marshall, E., Burroughs, A., Mann, S., Lombard, M., Richardson, P., Patanwala, I., Maltby, J., Brookes, M., Mathew, R., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Panter, S., Shearman, J., Bray, G., Butcher, G., Forton, D., Mclindon, J., Cowan, M., Whatley, G., Mandal, A., Gupta, H., Sanghi, P., Jain, S., Pereira, S., Prasad, G., Watts, G., Wright, M., Neuberger, J., Gordon, F., Unitt, E., Grant, A., Delahooke, T., Higham, A., Brind, A., Cox, M., Ramakrishnan, S., King, A., Collins, C., Whalley, S., Li, A., Fraser, J., Bell, A., Wong, V. S., Singhal, A., Gee, I., Ang, Y., Ransford, R., Gotto, J., Millson, C., Bowles, J., Thomas, C., Harrison, M., Galaska, R., Kendall, J., Whiteman, J., Lawlor, C., Gray, C., Elliott, K., Mulvaney-Jones, C., Hobson, L., Van Duyvenvoorde, G., Loftus, A., Seward, K., Penn, R., Maiden, J., Damant, R., Hails, J., Cloudsdale, R., Silvestre, V., Glenn, S., Dungca, E., Wheatley, N., Doyle, H., Kent, M., Hamilton, C., Braim, D., Wooldridge, H., Abrahams, R., Paton, A., Lancaster, N., Gibbins, A., Hogben, K., Desousa, P., Muscariu, F., Musselwhite, J., Mckay, A., Tan, L., Foale, C., Brighton, J., Flahive, K., Nambela, E., Townshend, P., Ford, C., Holder, S., Palmer, C., Featherstone, J., Nasseri, M., Sadeghian, J., Williams, B., Rolls, S. -A., Hynes, A., Duggan, C., Crossey, M., Stansfield, G., Macnicol, C., Wilkins, J., Wilhelmsen, E., Raymode, P., Lee, H. -J., Durant, E., Bishop, R., Ncube, N., Tripoli, S., Casey, R., Cowley, C., Miller, R., Houghton, K., Ducker, S., Wright, F., Bird, B., Baxter, G., Keggans, J., Hughes, M., Grieve, E., Young, K., Williams, D., Ocker, K., Hines, F., Martin, K., Innes, C., Valliani, T., Fairlamb, H., Thornthwaite, S., Eastick, A., Tanqueray, E., Morrison, J., Holbrook, B., Browning, J., Walker, K., Congreave, S., Verheyden, J., Slininger, S., Stafford, L., O'Donnell, D., Ainsworth, M., Lord, S., Kent, L., March, L., Dickson, C., Simpson, D., Longhurst, B., Hayes, M., Shpuza, E., White, N., Besley, S., Pearson, S., Wright, A., Jones, L., Gunter, E., Dewhurst, H., Fouracres, A., Farrington, L., Graves, L., Marriott, S., Leoni, M., Tyrer, D., Dali-kemmery, L., Lambourne, V., Green, M., Sirdefield, D., Amor, K., Colley, J., Shinder, B., Jones, J., Mills, M., Carnahan, M., Taylor, N., Boulton, K., Tregonning, J., Brown, C., Clifford, G., Archer, E., Hamilton, M., Curtis, J., Shewan, T., Walsh, S., Warner, K., Netherton, K., Mupudzi, M., Gunson, B., Gitahi, J., Gocher, D., Batham, S., Pateman, H., Desmennu, S., Conder, J., Clement, D., Gallagher, S., Orpe, J., Chan, P., Currie, L., O'Donohoe, L., Oblak, M., Morgan, L., Quinn, M., Amey, I., Baird, Y., Cotterill, D., Cumlat, L., Winter, L., Greer, S., Spurdle, K., Allison, J., Dyer, S., Sweeting, H., Kordula, J., Aiba, Y., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Kawai, Y., Kohn, S. -S., Gervais, O., Migita, K., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Higuchi, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Takikawa, H., Ohira, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Carbone, M., Cardamone, G., Duga, S., Gershwin, M. E., Seldin, M. F., Invernizzi, P., Donato F., Fagiuoli S., Miele L. (ORCID:0000-0003-3464-0068), Vinci M., Asselta, R., Paraboschi, E. M., Gerussi, A., Cordell, H. J., Mells, G. F., Sandford, R. N., Jones, D. E., Nakamura, M., Ueno, K., Hitomi, Y., Kawashima, M., Nishida, N., Tokunaga, K., Nagasaki, M., Tanaka, A., Tang, R., Li, Z., Shi, Y., Liu, X., Xiong, M., Hirschfield, G., Siminovitch, K. A., Walker, E., Xie, G., Mason, A., Myers, R., Peltekian, K., Ghent, C., Atkinson, E., Juran, B., Lazaridis, K., Lu, Y., Gu, X., Jing, K., Amos, C., Affronti, A., Brunetto, M., Coco, B., Spinzi, G., Elia, G., Ferrari, C., Lleo, A., Muratori, L., Muratori, P., Portincasa, P., Colli, A., Bruno, S., Colloredo, G., Azzaroli, F., Andreone, P., Bragazzi, M., Alvaro, D., Cardinale, V., Cazzagon, N., Rigamonti, C., Floreani, A., Rosina, F., Ciaccio, A., Cristoferi, L., D'Amato, D., Malinverno, F., Mancuso, C., Massironi, S., Milani, C., O'Donnell, S. E., Ronca, V., Barisani, D., Lampertico, P., Donato, Federica, Fagiuoli, Stefano, Almasio, P. L., Giannini, E., Cursaro, C., Colombo, M., Valenti, L., Miele, Luca, Andriulli, A., Niro, G. A., Grattagliano, I., Morini, L., Casella, G., Vinci, Maria Rosaria, Battezzati, P. M., Crosignani, A., Zuin, M., Mattalia, A., Calvaruso, V., Colombo, S., Benedetti, A., Marzioni, M., Galli, A., Marra, F., Tarocchi, M., Picciotto, A., Morisco, F., Fabris, L., Croce, L. S., Tiribelli, C., Toniutto, P., Strazzabosco, M., Ch'Ng, C. L., Rahman, M., Yapp, T., Sturgess, R., Healey, C., Czajkowski, M., Gunasekera, A., Gyawali, P., Premchand, P., Kapur, K., Marley, R., Foster, G., Watson, A., Dias, A., Subhani, J., Harvey, R., Mccorry, R., Ramanaden, D., Gasem, J., Evans, R., Mathialahan, T., Shorrock, C., Lipscomb, G., Southern, P., Tibble, J., Gorard, D., Palegwala, A., Jones, S., Dawwas, M., Alexander, G., Dolwani, S., Prince, M., Foxton, M., Elphick, D., Mitchison, H., Gooding, I., Karmo, M., Saksena, S., Mendall, M., Patel, M., Ede, R., Austin, A., Sayer, J., Hankey, L., Hovell, C., Fisher, N., Carter, M., Koss, K., Piotrowicz, A., Grimley, C., Neal, D., Lim, G., Levi, S., Ala, A., Broad, A., Saeed, A., Wood, G., Brown, J., Wilkinson, M., Gordon, H., Ramage, J., Ridpath, J., Ngatchu, T., Grover, B., Shaukat, S., Shidrawi, R., Abouda, G., Ali, F., Rees, I., Salam, I., Narain, M., Brown, A., Taylor-Robinson, S., Williams, S., Grellier, L., Banim, P., Das, D., Chilton, A., Heneghan, M., Curtis, H., Gess, M., Drake, I., Aldersley, M., Davies, M., Jones, R., Mcnair, A., Srirajaskanthan, R., Pitcher, M., Sen, S., Bird, G., Barnardo, A., Kitchen, P., Yoong, K., Chirag, O., Sivaramakrishnan, N., Macfaul, G., Jones, D., Shah, A., Evans, C., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Fraser, A., Mills, P., Shallcross, C., Campbell, S., Bathgate, A., Shepherd, A., Dillon, J., Rushbrook, S., Przemioslo, R., Macdonald, C., Metcalf, J., Shmueli, U., Davis, A., Naqvi, A., Lee, T., Ryder, S. D., Collier, J., Klass, H., Ninkovic, M., Cramp, M., Sharer, N., Aspinall, R., Goggin, P., Ghosh, D., Douds, A., Hoeroldt, B., Booth, J., Williams, E., Hussaini, H., Stableforth, W., Ayres, R., Thorburn, D., Marshall, E., Burroughs, A., Mann, S., Lombard, M., Richardson, P., Patanwala, I., Maltby, J., Brookes, M., Mathew, R., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Panter, S., Shearman, J., Bray, G., Butcher, G., Forton, D., Mclindon, J., Cowan, M., Whatley, G., Mandal, A., Gupta, H., Sanghi, P., Jain, S., Pereira, S., Prasad, G., Watts, G., Wright, M., Neuberger, J., Gordon, F., Unitt, E., Grant, A., Delahooke, T., Higham, A., Brind, A., Cox, M., Ramakrishnan, S., King, A., Collins, C., Whalley, S., Li, A., Fraser, J., Bell, A., Wong, V. S., Singhal, A., Gee, I., Ang, Y., Ransford, R., Gotto, J., Millson, C., Bowles, J., Thomas, C., Harrison, M., Galaska, R., Kendall, J., Whiteman, J., Lawlor, C., Gray, C., Elliott, K., Mulvaney-Jones, C., Hobson, L., Van Duyvenvoorde, G., Loftus, A., Seward, K., Penn, R., Maiden, J., Damant, R., Hails, J., Cloudsdale, R., Silvestre, V., Glenn, S., Dungca, E., Wheatley, N., Doyle, H., Kent, M., Hamilton, C., Braim, D., Wooldridge, H., Abrahams, R., Paton, A., Lancaster, N., Gibbins, A., Hogben, K., Desousa, P., Muscariu, F., Musselwhite, J., Mckay, A., Tan, L., Foale, C., Brighton, J., Flahive, K., Nambela, E., Townshend, P., Ford, C., Holder, S., Palmer, C., Featherstone, J., Nasseri, M., Sadeghian, J., Williams, B., Rolls, S. -A., Hynes, A., Duggan, C., Crossey, M., Stansfield, G., Macnicol, C., Wilkins, J., Wilhelmsen, E., Raymode, P., Lee, H. -J., Durant, E., Bishop, R., Ncube, N., Tripoli, S., Casey, R., Cowley, C., Miller, R., Houghton, K., Ducker, S., Wright, F., Bird, B., Baxter, G., Keggans, J., Hughes, M., Grieve, E., Young, K., Williams, D., Ocker, K., Hines, F., Martin, K., Innes, C., Valliani, T., Fairlamb, H., Thornthwaite, S., Eastick, A., Tanqueray, E., Morrison, J., Holbrook, B., Browning, J., Walker, K., Congreave, S., Verheyden, J., Slininger, S., Stafford, L., O'Donnell, D., Ainsworth, M., Lord, S., Kent, L., March, L., Dickson, C., Simpson, D., Longhurst, B., Hayes, M., Shpuza, E., White, N., Besley, S., Pearson, S., Wright, A., Jones, L., Gunter, E., Dewhurst, H., Fouracres, A., Farrington, L., Graves, L., Marriott, S., Leoni, M., Tyrer, D., Dali-kemmery, L., Lambourne, V., Green, M., Sirdefield, D., Amor, K., Colley, J., Shinder, B., Jones, J., Mills, M., Carnahan, M., Taylor, N., Boulton, K., Tregonning, J., Brown, C., Clifford, G., Archer, E., Hamilton, M., Curtis, J., Shewan, T., Walsh, S., Warner, K., Netherton, K., Mupudzi, M., Gunson, B., Gitahi, J., Gocher, D., Batham, S., Pateman, H., Desmennu, S., Conder, J., Clement, D., Gallagher, S., Orpe, J., Chan, P., Currie, L., O'Donohoe, L., Oblak, M., Morgan, L., Quinn, M., Amey, I., Baird, Y., Cotterill, D., Cumlat, L., Winter, L., Greer, S., Spurdle, K., Allison, J., Dyer, S., Sweeting, H., Kordula, J., Aiba, Y., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Kawai, Y., Kohn, S. -S., Gervais, O., Migita, K., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Higuchi, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Takikawa, H., Ohira, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Carbone, M., Cardamone, G., Duga, S., Gershwin, M. E., Seldin, M. F., Invernizzi, P., Donato F., Fagiuoli S., Miele L. (ORCID:0000-0003-3464-0068), and Vinci M.

Abstract

Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Published
2021

47. Forecasting Hepatitis C liver disease burden on real-life data. Does the hidden iceberg matter to reach the elimination goals?

Author

Kondili, La, Robbins, S, Blach, S, Gamkrelidze, I, Zignego, Al, Brunetto, Mr, Raimondo, G, Taliani, G, Iannone, A, Russo, Fp, Santantonio, Ta, Zuin, M, Chessa, L, Blanc, P, Puoti, M, Vinci, M, Erne, Em, Strazzabosco, M, Massari, M, Lampertico, P, Rumi, Mg, Federico, A, Orlandini, A, Ciancio, A, Borgia, G, Andreone, P, Caporaso, N, Persico, M, Ieluzzi, D, Madonia, S, Gori, A, Gasbarrini, A, Coppola, C, Brancaccio, G, Andriulli, A, Quaranta, Mg, Montilla, S, Razavi, H, Melazzini, M, Vella, S, Craxì, A, PITER Collaborating, Group., Kondili LA, Robbins S, Blach S, Gamkrelidze I, Zignego AL, Brunetto MR, Raimondo G, Taliani G, Iannone A, Russo FP, Santantonio TA, Zuin M, Chessa L, Blanc P, Puoti M, Vinci M, Erne EM, Strazzabosco M, Massari M, Lampertico P, Rumi MG, Federico A, Orlandini A, Ciancio A, Borgia G, Andreone P, Caporaso N, Persico M, Ieluzzi D, Madonia S, Gori A, Gasbarrini A, Coppola C, Brancaccio G, Andriulli A, Quaranta MG, Montilla S, Razavi H, Melazzini M, Vella S, Craxì Antonio, Kondili, Loreta A., Robbins, Sarah, Blach, Sarah, Gamkrelidze, Ivane, Zignego, Anna L., Brunetto, Maurizia R., Raimondo, Giovanni, Taliani, Gloria, Iannone, Andrea, Russo, Francesco P., Santantonio, Teresa A., Zuin, Massimo, Chessa, Luchino, Blanc, Pierluigi, Puoti, Massimo, Vinci, Maria, Erne, Elke M., Strazzabosco, Mario, Massari, Marco, Lampertico, Pietro, Rumi, Maria G., Federico, Alessandro, Orlandini, Alessandra, Ciancio, Alessia, Borgia, Guglielmo, Andreone, Pietro, Caporaso, Nicola, Persico, Marcello, Ieluzzi, Donatella, Madonia, Salvatore, Gori, Andrea, Gasbarrini, Antonio, Coppola, Carmine, Brancaccio, Giuseppina, Andriulli, Angelo, Quaranta, Maria G., Montilla, Simona, Razavi, Homie, Melazzini, Mario, Vella, Stefano, Craxì, Antonio, Kondili, L. A., Robbins, S., Blach, S., Gamkrelidze, I., Zignego, A. L., Brunetto, M. R., Raimondo, G., Taliani, G., Iannone, A., Russo, F. P., Santantonio, T. A., Zuin, M., Chessa, L., Blanc, P., Puoti, M., Vinci, M., Erne, E. M., Strazzabosco, M., Massari, M., Lampertico, P., Rumi, M. G., Federico, A., Orlandini, A., Ciancio, A., Borgia, G., Andreone, P., Caporaso, N., Persico, M., Ieluzzi, D., Madonia, S., Gori, A., Gasbarrini, A., Coppola, C., Brancaccio, G., Andriulli, A., Quaranta, M. G., Montilla, S., Razavi, H., Melazzini, M., Vella, S., Craxi, A., Kondili, L, Robbins, S, Blach, S, Gamkrelidze, I, Zignego, A, Brunetto, M, Raimondo, G, Taliani, G, Iannone, A, Russo, F, Santantonio, T, Zuin, M, Chessa, L, Blanc, P, Puoti, M, Vinci, M, Erne, E, Strazzabosco, M, Massari, M, Lampertico, P, Rumi, M, Federico, A, Orlandini, A, Ciancio, A, Borgia, G, Andreone, P, Caporaso, N, Persico, M, Ieluzzi, D, Madonia, S, Gori, A, Gasbarrini, A, Coppola, C, Brancaccio, G, Andriulli, A, Quaranta, M, Montilla, S, Razavi, H, Melazzini, M, Vella, S, and Craxi, A

Subjects
HCV, WHO, chronic infection, linkage to care, Liver Cirrhosis, medicine.medical_specialty, Carcinoma, Hepatocellular, Sustained Virologic Response, Viral Hepatitis, Settore MED/12 - GASTROENTEROLOGIA, World Health Organization, Antiviral Agents, NO, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Pharmacotherapy, Cost of Illness, Cause of Death, Health care, medicine, Humans, 030212 general & internal medicine, Viremia, chronic infection, HCV, linkage to care, WHO, Disease Eradication, Mortality, Intensive care medicine, Cause of death, Hepatology, business.industry, Public health, Carcinoma, Liver Neoplasms, Hepatocellular, Hepatitis C, medicine.disease, Markov Chains, Italy, 030211 gastroenterology & hepatology, business, Viral hepatitis
Abstract

Background & Aims Advances in direct‐acting antiviral treatment of HCV have reinvigorated public health initiatives aimed at identifying affected individuals. We evaluated the possible impact of only diagnosed and linked‐to‐care individuals on overall HCV burden estimates and identified a possible strategy to achieve the WHO targets by 2030. Methods Using a modelling approach grounded in Italian real‐life data of diagnosed and treated patients, different linkage‐to‐care scenarios were built to evaluate potential strategies in achieving the HCV elimination goals. Results Under the 40% linked‐to‐care scenario, viraemic burden would decline (60%); however, eligible patients to treat will be depleted by 2025. Increased case finding through a targeted screening strategy in 1948‐1978 birth cohorts could supplement the pool of diagnosed patients by finding 75% of F0‐F3 cases. Under the 60% linked‐to‐care scenario, viraemic infections would decline by 70% by 2030 but the patients eligible for treatment will run out by 2028. If treatment is to be maintained, a screening strategy focusing on 1958‐1978 birth cohorts could capture 55% of F0‐F3 individuals. Under the 80% linked‐to‐care scenario, screening limited in 1968‐1978 birth cohorts could sustain treatment at levels required to achieve the HCV elimination goals. Conclusion In Italy, which is an HCV endemic country, the eligible pool of patients to treat will run out between 2025 and 2028. To maintain the treatment rate and achieve the HCV elimination goals, increased case finding in targeted, high prevalence groups is required.

Published
2018

48. Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes 11 Medical and Health Sciences 1103 Clinical Sciences

Author

Mirijello, A, Viazzi, F, Fioretto, P, Giorda, C, Ceriello, A, Russo, G, Guida, P, Pontremoli, R, De Cosmo, S, Cimino, A, Fava, D, Meloncelli, I, Nicolucci, A, Pellegrini, F, Rossi, M, Turco, S, Vespasiani, G, Graziano, G, Lucisano, G, Memmo, R, Pellicciotta, E, Paciotti, V, Pupillo, M, Armentano, G, Giovannini, C, Armentano, V, Laudato, M, Acquati, S, Ciardullo, A, Laffi, G, Felace, G, Taboga, C, Tortul, C, Santantonio, G, Suraci, C, Ghisoni, G, Raffa, M, Genovese, S, Lovagnini-Scher, C, Rampini, P, Rocca, A, Ruggeri, P, Tortato, E, Cotti, L, Cristofaro, M, Tagliaferri, M, Comoglio, M, Fornengo, R, Gentile, F, Gigante, A, Mastinu, F, Di Benedetto, A, Pata, P, Arcangeli, A, Orsini, P, Acler, P, De Blasi, G, Cicioni, G, Pocciati, S, Marangoni, A, Nogara, A, Lanero, M, Bertero, M, Damassino, R, Bergonzini, C, Schumtz, L, Seksich, L, Pipitone, A, Boaretto, M, Manfroi, I, Parmesan, L, Conte, B, Soccol, F, Pagano, A, Papini, E, Rinaldi, R, Petrucci, L, Graziano, F, Chianelli, M, Silvagni, S, 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A., De Berardinis S., Guarnieri I., Pace S., Splendiani M., Di Giuseppe R., Brunato B., Assaloni R., Muraro R., Loro R., Bucciol S., Lavacca C., Rossi M., Sabbatini G., Quadri F., Sambuco L., Santacroce C., Paola Caretta D., Marino C., Micheletti A., Petrelli A., Corda A., Pisano L., Guaita G., Deias C., Trevisan G., Coletti I., Iannarelli R., De Luca A., Minnucci A., Antenucci D., Di Florio C., Angelicola G., Bosco A., Fresco R., Di Marco G., Ugolotti D., Cadossi T., Di Caro P., Mazzocchetti M., Buzzetti R., Leto G., Gnessi C., Cipolloni L., Foffi C., Moretti C., Venditti C., Meniconi R., Bertoli S., Cosimi S., Di Cianni G., Turco A., Richini A., Marconi S., Sannino C., Lemmi P., Giuntoli S., Manfre N., Giannini F., Di Carlo A., Casadidio I., Melandri P., Maolo G., Polenta B., Piccinini N., Vincenti C., Pastore N., Mega P., Magurano E., Cananiello A., Francescutto C. A., Brussa Toi E., Gaspardo G., Angeli L., Ronchese L., Sciangula L., Ciucci A., Contartese A., Banfi E., Castelli E., Tatti P., Bloise D., Di Mauro P., Masselli L., Lo Presti A., Scarpitta A. M., Gambina F., Venezia A., Morea R., Lagonigro G., Copeta G., Iannucci V., Milano V., Trupo M., Lochmann A., Marchetto P. E., Incelli G., De Paola G., Steiger M. M., Gamper M. A., Breitenberger S., Holzner M., Frischmann J., Lambiase C., Di Vece T., D'Aniello M., Fezza M., Giordano C., Leo F., Saitta G., Cucinotta D., Di Vieste G., Pintaudi B., Mancuso T., Musacchio N., Giancaterini A., Pessina L., Salis G., Schivalocchi F., Testori G., Cerutti N., Morpugo P. S., Cavaletto M. L., Bonino G., Morreale F., Mariani G., Ragonesi P. D., Bollati P., Colapinto P., Falqui L., Bortolato L., Cosma A., Pistolato P., Centenaro B., Ceccato A., Campobasso G., Zaurino F., Mazzotta G., Manti R., Da Ros R., Carlucci S., Narduzzi L., Bortolotto D., D'Acunto L., Stanic L., Volpi A., Cospite A. M., Manicardi V., Michelini M., Finardi L., Borghi F., Manicardi E., Lombardi S., Tommasi C., Iaccarino M., Cozza S., Binotto M., Marini F., Mecenero I., Massignani S., Stecco P., Urbani E., Massariol W., Parolin R., Gatti A., Bonavita M., Creso E., Giannettino R., Gobbo M., Iovine C., Riccardi G., Iazzetta N., Giannattasio C., Egione O., Galdieri S., Velotti A., Azzolina A., Annicelli G., Sorrentino T., Gaeta I., Zenari L., Bertolini L., Sorgato C., Grippaldi F., Stroppiana M., Popolizio R., Carbone N., Grasso S., Abate S., Gaggero G. C., Strazzabosco M., Brun E., Carlesi G. P., Garrone S., Cicalo A. M., Clausi C., Cau R., Manconi A., Carboni A., Angius M. F., Pinna A. A., Caria S., Filigheddu G. D., Tonolo G., Carta I., Calebich S., Burlotti C., Saglietti G., Schellino A., Madau G., Cossu M., Mulas F., Zoccheddu S., Balsanelli M., Fetonti M., Rotolo A., Sambo P., Secchi E., Angotzi M. A., Loddoni S., Brundu I., Careddu F., Becciu A., Gabriella Piras G., Novara F., Cipro F., Torchio G., Palumbo P., Bianchi A., Colucci G., La Motta G., Tiengo A., Avogaro A., Bruttomesso D., Crepaldi C., Fadini G., Guarnieri G., Lavagnini M. T., Maran A., Vedovato M., De Kreutzenberg V., Fedele D., Lapolla A., Sartore G., Bax G., Cardone C., Dalfra M. G., Masin M., Toniato R., Piarulli F., Mattina G., Fulantelli M. A., Gioia D., Conti M., Ridola G., D'Agati F., Grossi G., Zavaroni I., Dei Cas A., Franzini L., Usberti E., Antonimi M., Anelli N., Poli R., Ridolfi V., Michela M., Haddoub S., Prampolini G., Muoio A., Filippi D., Bucci F., Tardio S. M., Calderini M. C., Magotti M. G., Quarantelli C., Vernazza M. A., Carolfi A., Saracca R., Picchio E., Del Sindaco P., Spalluto A., Maggiulli L., Torreggiani V., Rastelletti S., Ugolini C., Pucci N., Magi S., Muratori S., La Penna G., Consoli A., Galeone F., Magiar A. V., Gherardini V., Moretti L., Bientinesi M., Landi L., Bernardi A., Del Prato S., Miccoli R., Bianchi C., Penno G., Venditti F., Anichini R., De Bellis A., Bruschi T., Butelli L., Gioffredi M., Gori R., Picciafuochi R., Malagoli R., Bernini A., Gelisio R., Zanon M., Del Bianco A., Bamiston A., Signorato M., Citro G., Calabrese M., Ianni L., Lorenzetti M., Marsocci A., Guizzotti S., Memoli G., Cabasino F., Farci F., Atzori A., Sanna A., Ghiani M., Siotto I., Sedda M., Manis A., Loddo C., Loddo I., Seguro P., Cuomo A., Orlando L., Olanda G. B., Pucci A., Massenzo M., Sardu C., Perrone G., Corazziere F., La Puzza I., Tripodi P. F., Riggio S., Giampaolo A., Mannino D., Aleandri A. R., Guidi M. V., Battisti B., Faraglia M. R., Lilli V., Leotta S., Visalli N., Gagliardi A., Fontana L., Altomare M., Carletti S., Abbruzzese S., Chiaramonte F., Giordano R., Rossini M., Migneco G., Cappelloni D., Urbani A., Piergiovanni F., Simonetta A., Massimiani F., Bulzomi R., Giuliano M., Pennafina M. G., Di Perna P., D'Accinni M. P., Paolucci D., D'Ubaldi A., D'Angelo M. T., Masaro G., Pietrantoni M., Fratini M., La Rosa R., Poggi M., Piccirilli F., Pisano R., Saponara C., Conforti I., Penza A., Scalpone R., Lo Pinto S., Iacovella L., Caccamo C., Sposito S., Teodonio C., Restuccia M. G., Mirto G., Girardello R., Gennaro R., De Moliner L., Bettini E., Mattuzzi A., Speese K., Frisinghelli F., Locatelli F., Nicoletti M., Trojan N., Centis R., L Volsi P., Levis E., Zanette G., Comba G., Ballatore L., Cattaneo A., Aglialoro A., Guido R., Patrone M., Zecchini M., Clementi L., Galetta M., Marconi V., Bordin P., Perale L., Vinci C., Sira Zanon M., Geretto L., Toffolo C., Furlan M. G., Mazzanti G., Vinci M., Sica V., Armeni M., Derai R., Ennas O., Mamusa S., Pisano M. A., Carreras L., Rauseo A., Cervone S., Leggieri A., Pontonio M., Sturaro R., Quattrocchi F., Molinaro M., Trasatti M., Ferretti B., Labarile G., Baule G. M., Gentilini A., Spanu M. A., Fancellu A., Bianco P., Lione L., Massazza G., Bocchio G., Bosco E., Monachesi M., Carta G., Boschetti M., Ceresola E., Venier E., Calcaterra F., Cataldi F., Miola M., Manfrini S., Lai A., Locci B., Putzu D., Tanganelli I., Leonini M., Egger K., Marchiotto W., Vincis L., Orlandini V., Pilloni C., Farci R., Pelligra I., Renier G., Mameli M., Pala A., Devigus E., Fumagalli I., Lalli C., Leandri M., Agliani M., De Pascalis L., Malci F., De Ciocchis A., Diodati M. B., Macerola B., Davi S., Caccavale A., Brocato L., Pognant Gros M., Borla S., Lattanzi E., Piersanti C., Piersanti A., Spinelli I., Tuzzoli L., Tulini V., Quaranta G., Iorio V., Tirabovi M., De Terlizi C., Massarelli M. G., Venturi S., Travaglini A., Draghi P., Pomante P., Richiardi L., Clerico A., Bruno A., Cavallo Perin P., Ghigo E., Porta M., Scuntero P., Arcari R., Bertaina S., Bo S., Broglio F., Bruno G., Degiovanni M., Fornengo P., Grassi G., Inglese V., Maccario M., Maghenzani G., Marena S., Martina V., Passera P., Ruiu G., Tagliabue M., Zanone M., Monge M., Boffano G. M., Macri K., Maio P., Ozzello A., Pergolizzi E., Gaia D., Gennari P., Micali G., Rossetto E., Dalmazzo C., Oreglia M., Stefani T., Dossena C., Paglia P., Bosoni S., Romanelli T., Inchiostro S., Dauriz M., Bossi C. A., Meregalli G., Balini A., Berzi D., Filippini B., Crotto G., Paccagnella A., Orrasch M., Sambataro M., Citro T., Kiwanuka E., Bagolin E., Almoto B., Macchia A., Branca M. T., Filesi M., Candido R., Caroli E., Manca E., Petrucco A., Tommasi E., Jagodnik G., Baskar B., Daris N., Dal Col P., Pellegrini M. A., Tonutti L., Venturini G., Andreani M., Turchi F., Fedrighelli F., Martinelli G., Rongioletti R., Candidi M., Pais M., Moro E., Cervellino F., Sinisi R., Zampino A., Mingardi R., Lora L., Reitano R., Stocchiero C., Simoncini M., Mesturino C. A., Zen F., Di Pietro S., Scoponi C., Tilaro L., Pelliccioni S., Slongo R., Vita E., Garofalo A., Vitale F., Campanella B., Mastrilli V., Borrelli T., D'Avino A., Perbellini A., Mirijello, A, Viazzi, F, Fioretto, P, Giorda, C, Ceriello, A, Russo, G, Guida, P, Pontremoli, R, De Cosmo, S, Cimino, A, Fava, D, Meloncelli, I, Nicolucci, A, Pellegrini, F, Rossi, M, Turco, S, Vespasiani, G, Graziano, G, Lucisano, G, Memmo, R, Pellicciotta, E, Paciotti, V, Pupillo, M, Armentano, G, Giovannini, C, Armentano, V, Laudato, M, Acquati, S, Ciardullo, A, Laffi, G, Felace, G, Taboga, C, Tortul, C, Santantonio, G, Suraci, C, Ghisoni, G, Raffa, M, Genovese, S, Lovagnini-Scher, C, Rampini, P, Rocca, A, Ruggeri, P, Tortato, E, Cotti, L, Cristofaro, M, Tagliaferri, M, Comoglio, M, Fornengo, R, Gentile, F, Gigante, A, Mastinu, F, Di Benedetto, A, Pata, P, Arcangeli, A, Orsini, P, Acler, P, De Blasi, G, Cicioni, G, Pocciati, S, Marangoni, A, Nogara, A, Lanero, M, Bertero, M, Damassino, R, Bergonzini, C, 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Abstract

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage ≥3 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage ≥3 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage ≥3 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 ± 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage ≥3 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage ≥3 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening.

Published
2018

49. Forecasting Hepatitis C liver disease burden on real-life data. Does the hidden iceberg matter to reach the elimination goals?

Author

Kondili, L, Robbins, S, Blach, S, Gamkrelidze, I, Zignego, A, Brunetto, M, Raimondo, G, Taliani, G, Iannone, A, Russo, F, Santantonio, T, Zuin, M, Chessa, L, Blanc, P, Puoti, M, Vinci, M, Erne, E, Strazzabosco, M, Massari, M, Lampertico, P, Rumi, M, Federico, A, Orlandini, A, Ciancio, A, Borgia, G, Andreone, P, Caporaso, N, Persico, M, Ieluzzi, D, Madonia, S, Gori, A, Gasbarrini, A, Coppola, C, Brancaccio, G, Andriulli, A, Quaranta, M, Montilla, S, Razavi, H, Melazzini, M, Vella, S, Craxi, A, Kondili L. A., Robbins S., Blach S., Gamkrelidze I., Zignego A. L., Brunetto M. R., Raimondo G., Taliani G., Iannone A., Russo F. P., Santantonio T. A., Zuin M., Chessa L., Blanc P., Puoti M., Vinci M., Erne E. M., Strazzabosco M., Massari M., Lampertico P., Rumi M. G., Federico A., Orlandini A., Ciancio A., Borgia G., Andreone P., Caporaso N., Persico M., Ieluzzi D., Madonia S., Gori A., Gasbarrini A., Coppola C., Brancaccio G., Andriulli A., Quaranta M. G., Montilla S., Razavi H., Melazzini M., Vella S., Craxi A., Kondili, L, Robbins, S, Blach, S, Gamkrelidze, I, Zignego, A, Brunetto, M, Raimondo, G, Taliani, G, Iannone, A, Russo, F, Santantonio, T, Zuin, M, Chessa, L, Blanc, P, Puoti, M, Vinci, M, Erne, E, Strazzabosco, M, Massari, M, Lampertico, P, Rumi, M, Federico, A, Orlandini, A, Ciancio, A, Borgia, G, Andreone, P, Caporaso, N, Persico, M, Ieluzzi, D, Madonia, S, Gori, A, Gasbarrini, A, Coppola, C, Brancaccio, G, Andriulli, A, Quaranta, M, Montilla, S, Razavi, H, Melazzini, M, Vella, S, Craxi, A, Kondili L. A., Robbins S., Blach S., Gamkrelidze I., Zignego A. L., Brunetto M. R., Raimondo G., Taliani G., Iannone A., Russo F. P., Santantonio T. A., Zuin M., Chessa L., Blanc P., Puoti M., Vinci M., Erne E. M., Strazzabosco M., Massari M., Lampertico P., Rumi M. G., Federico A., Orlandini A., Ciancio A., Borgia G., Andreone P., Caporaso N., Persico M., Ieluzzi D., Madonia S., Gori A., Gasbarrini A., Coppola C., Brancaccio G., Andriulli A., Quaranta M. G., Montilla S., Razavi H., Melazzini M., Vella S., and Craxi A.

Abstract

Background & Aims: Advances in direct-acting antiviral treatment of HCV have reinvigorated public health initiatives aimed at identifying affected individuals. We evaluated the possible impact of only diagnosed and linked-to-care individuals on overall HCV burden estimates and identified a possible strategy to achieve the WHO targets by 2030. Methods: Using a modelling approach grounded in Italian real-life data of diagnosed and treated patients, different linkage-to-care scenarios were built to evaluate potential strategies in achieving the HCV elimination goals. Results: Under the 40% linked-to-care scenario, viraemic burden would decline (60%); however, eligible patients to treat will be depleted by 2025. Increased case finding through a targeted screening strategy in 1948-1978 birth cohorts could supplement the pool of diagnosed patients by finding 75% of F0-F3 cases. Under the 60% linked-to-care scenario, viraemic infections would decline by 70% by 2030 but the patients eligible for treatment will run out by 2028. If treatment is to be maintained, a screening strategy focusing on 1958-1978 birth cohorts could capture 55% of F0-F3 individuals. Under the 80% linked-to-care scenario, screening limited in 1968-1978 birth cohorts could sustain treatment at levels required to achieve the HCV elimination goals. Conclusion: In Italy, which is an HCV endemic country, the eligible pool of patients to treat will run out between 2025 and 2028. To maintain the treatment rate and achieve the HCV elimination goals, increased case finding in targeted, high prevalence groups is required.

Published
2018

50. Animal models of cholangiocarcinoma: What they teach us about the human disease

Author

Cadamuro, M, Brivio, S, Stecca, T, Kaffe, E, Mariotti, V, Milani, C, Fiorotto, R, Spirli, C, Strazzabosco, M, Fabris, L, Cadamuro M., Brivio S., Stecca T., Kaffe E., Mariotti V., Milani C., Fiorotto R., Spirli C., Strazzabosco M., Fabris L., Cadamuro, M, Brivio, S, Stecca, T, Kaffe, E, Mariotti, V, Milani, C, Fiorotto, R, Spirli, C, Strazzabosco, M, Fabris, L, Cadamuro M., Brivio S., Stecca T., Kaffe E., Mariotti V., Milani C., Fiorotto R., Spirli C., Strazzabosco M., and Fabris L.

Abstract

Despite recent advances, pathogenesis of cholangiocarcinoma, a highly lethal cancer, remains enigmatic. Furthermore, treatment options are still limited and often disappointing. For this reason, in the last few years there has been a mounting interest towards the generation of experimental models able to reproduce the main features associated with this aggressive behavior. Toxic and infestation-induced, genetically engineered and cell implantation rodent models have been generated, contributing to a deeper understanding of the complex cell biology of the tumor, sustained by multiple cell interactions and driven by a huge variety of molecular perturbations. Herein, we will overview the most relevant animal models of biliary carcinogenesis, highlighting the methodological strategy, the molecular, histological and clinical phenotypes consistent with the human condition, their particular strengths and weaknesses and the novel therapeutic approaches that have been developed.

Published
2018

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