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1. Hepatic encephalopathy increases the risk for mortality and hospital readmission in decompensated cirrhotic patients: a prospective multicenter study

Author

Oliviero Riggio, Ciro Celsa, Vincenza Calvaruso, Manuela Merli, Paolo Caraceni, Sara Montagnese, Vincenzina Mora, Martina Milana, Giorgio Maria Saracco, Giovanni Raimondo, Antonio Benedetti, Patrizia Burra, Rodolfo Sacco, Marcello Persico, Filippo Schepis, Erica Villa, Antonio Colecchia, Stefano Fagiuoli, Mario Pirisi, Michele Barone, Francesco Azzaroli, Giorgio Soardo, Maurizio Russello, Filomena Morisco, Sara Labanca, Anna Ludovica Fracanzani, Antonello Pietrangelo, Gabriele Di Maria, Silvia Nardelli, Lorenzo Ridola, Antonio Gasbarrini, and Calogero Cammà

Subjects
hepatic encephalopathy, decompensated cirrhosis, orthotopic liver transplant, hospital readmission, mortality, Medicine (General), R5-920
Abstract

IntroductionHepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE.MethodsWe prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT).ResultsDuring follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01–1.06), HE (HR 1.67, 95% CI 1.08–2.56), ascites (HR 2.56, 95% CI 1.55–4.23), and sodium levels (HR 0.94, 95% CI 0.90–0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39–18.49) and BMI (HR 0.86, 95% CI 0.75–0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission.ConclusionIn patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT.

Published
2023
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2. Black Esophagus and Recurrence of Duodenal Ulcers: Two Signs of the Same Pathogenic Pathway? A Case Report

Author

Daniele Balducci, Claudia Quatraccioni, Luigi Maria Daretti, Michele Montori, Emanuele Bendia, Luca Maroni, and Antonio Benedetti

Subjects
black esophagus, circumferential esophageal necrosis, duodenal ulcer, upper gastrointestinal bleeding, coffee ground emesis, case report, Medicine (General), R5-920, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Black esophagus or acute esophageal necrosis is characterized by circumferential black discoloration of the distal esophageal mucosa. It is a rare condition with a multifactorial pathogenesis, and its most common clinical presentation is acute upper gastrointestinal bleeding. It usually affects elderly patients with multiple comorbidities and is associated with a high mortality rate. This is a case report of a 90-year-old man with multiple comorbidities, including diabetes mellitus, atrial fibrillation with complete atrioventricular block, and a history of ischemic stroke, who presented to the emergency department for a syncopal episode followed by coffee ground emesis. Thoraco-abdominal computer tomography showed thickening of the distal esophagus and ruled out major complications such as perforation. The following esophagogastroduodenoscopy showed black circumferential necrosis of the mid and distal esophagus. Multiple irregular ulcers with black necrotic areas were also present in the bulb and second duodenal portion. During the hospitalization, the patient was treated with PPI, NPO nutrition, and broad-spectrum antibiotics with benefits. Two months later, the patient returned to the emergency department due to a new episode of hematemesis with endoscopic evidence of esophageal stricture without necrosis and recurrence of duodenal ulcers. After a few days, the patient died due to worsening of the underlying comorbidities. A black esophagus is associated with duodenal ulcers, which may recur and are possibly due to a common ischemic origin. In this case report, we explore the potential link between black esophagus and duodenal ulcers, discussing the underlying mechanisms and relevant literature supporting this association.

Published
2023
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3. Gastrointestinal Complications after Allogeneic Hematopoietic Stem Cell Transplant: A Multidisciplinary Approach with Early Endoscopic Evaluation

Author

Giuseppe Tarantino, Francesco Saraceni, Giorgia Mancini, Monica Poiani, Luca Maroni, Gaia Goteri, Ilaria Scortechini, Alessandro Fiorentini, Maria Vittoria Dubbini, Francesco Marini, Luigi Daretti, Marco Marzioni, Emanuele Bendia, Antonio Benedetti, and Attilio Olivieri

Subjects
Gastro-intestinal complications (GICs) in allogeneic hematopoietic stem cell transplant (allo-HSCT), graft-versus-host-disease (GVHD), mucositis, endoscopy, intestinal histology, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Gastrointestinal complications (GICs) represent the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Differential diagnosis of GICs is of paramount importance since early and reliable identification of graft-versus-host disease (GVHD) is essential for a correct management of the patients. The aim of the present retrospective study was to evaluate the occurrence of GICs after allo-HSCT and to assess the diagnostic performance of a quick endoscopic and histological assessment in the differential diagnosis between GVHD and other GI conditions. Between January 2015 and August 2019, 122 consecutive patients receiving an allo-HSCT were managed by an interdisciplinary team, supported by a dedicated endoscopic service. Clinical, therapeutic, endoscopic and histological data were analyzed for each patient. Collectively, 94 of the patients developed GICs (77%). A moderate–severe mucositis was the most frequent complication, occurring in 79 patients (84%). Acute GI-GVHD was diagnosed in 35 patients (37% of whom with GICs) and 19 of them with a moderate–severe grade. Infective acute colitis developed in eight patients, mainly due to Clostridium difficile (CD) and Cytomegalovirus infections (8.5%). Rectal biopsy showed the highest sensitivity and specificity (80% and 100%, respectively). However, when biopsy procedures were guided by symptoms and performed on apparently intact mucosa, upper histology also provided a high negative predictive value (80%). Our multidisciplinary approach with a quick endoscopic/histologic investigation in the patients receiving an allo-HSCT and who suffered GICs could improve diagnostic and therapeutic management in this challenging setting.

Published
2021
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4. Gastrointestinal disorders as immune-related adverse events

Author

Daniele Balducci, Claudia Quatraccioni, Antonio Benedetti, Marco Marzioni, and Luca Maroni

Subjects
cytotoxic t-lymphocyte antigen 4, programmed cell death 1, programmed cell death-ligand 1, immune checkpoint, gastrointestinal toxicity, Internal medicine, RC31-1245
Abstract

Immune checkpoint inhibitors, such as cytotoxic T-lymphocyte antigen 4 inhibitors, programmed cell death 1 inhibitors and programmed cell death-ligand 1 inhibitors, have recently emerged as novel drugs in the anti-cancer therapy. Their use in different types of advanced cancer has shown good results and an increase in survival rates. However, immune-related adverse events (irAEs) are frequent and often require special care. IrAEs may affect all the organs, but they are most commonly seen in skin, lungs, endocrine glands and in the gastrointestinal tract where small bowel, colon, the liver and/or the pancreas can be involved. Despite being usually mild and self-resolving, irAEs may present in severe and life-threatening forms, causing the withdrawal of anti-cancer therapy. IrAEs, therefore, represent a challenging condition to manage that often requires the cooperation between the oncologists and the gastroenterologists in order to identify and treat them adequately.

Published
2021
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5. Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases

Author

Claudio Pinto, Elisabetta Ninfole, Antonio Benedetti, Marco Marzioni, and Luca Maroni

Subjects
autophagy, ageing, cholestasis, FXR, Rubicon, cholangiopathies, Cytology, QH573-671
Abstract

Autophagy is a “housekeeping” lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.

Published
2021
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6. Aging-Related Molecular Pathways in Chronic Cholestatic Conditions

Author

Claudio Pinto, Elisabetta Ninfole, Antonio Benedetti, Luca Maroni, and Marco Marzioni

Subjects
aging, PSC, PBC, senescence, therapeutics, inflammation, Medicine (General), R5-920
Abstract

Aging is commonly defined as the time-dependent functional decline of organs and tissues. Average life expectancy has increased considerably over the past century and is estimated to increase even further, consequently also the interest in understanding the aging processes. Although aging is not a disease, it is the major risk factor for the development of many chronic diseases. Pathologies, such as Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC) are cholestatic liver diseases characterized by chronic inflammation, biliary damage and ultimately liver fibrosis, targeting specifically cholangiocytes. To date, the influence of aging in these biliary diseases is not fully understood. Currently, liver transplantation is the only solution because of lacking in efficiently therapies. Although liver cells have a high regenerative capacity, they undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, the cells initially activate protective compensatory processes that, if hyperstimulated, can lead to the decline of regenerative ability and the development of pathologies. Recent studies have introduced novel therapeutic tools for cholangiopathies that have showed to have promising potential as novel therapies for PSC and PBC and for the development of new drugs. The recent advancements in understanding of molecular aging have undoubtedly the potential to unveil new pathways for selective drug treatments, but further studies are needed to deepen their knowledge.

Published
2020
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7. Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

Author

Luca Maroni, Elisabetta Ninfole, Claudio Pinto, Antonio Benedetti, and Marco Marzioni

Subjects
inflammasome, nlrp3, cholangiocyte, gut–liver axis, Cytology, QH573-671
Abstract

The Nlrp3 inflammasome is a multiprotein complex activated by a number of bacterial products or danger signals and is involved in the regulation of inflammatory processes through caspase-1 activation. The Nlrp3 is expressed in immune cells but also in hepatocytes and cholangiocytes, where it appears to be involved in regulation of biliary damage, epithelial barrier integrity and development of fibrosis. Activation of the pathways of innate immunity is crucial in the pathophysiology of hepatobiliary diseases, given the strong link between the gut and the liver. The liver secretes bile acids, which influence the bacterial composition of the gut microbiota and, in turn, are heavily modified by microbial metabolism. Alterations of this balance, as for the development of dysbiosis, may deeply influence the composition of the bacterial products that reach the liver and are able to activate a number of intracellular pathways. This alteration may be particularly important in the pathogenesis of cholangiopathies and, in particular, of primary sclerosing cholangitis, given its strong association with inflammatory bowel disease. In the present review, we summarize current knowledge on the gut−liver axis in cholangiopathies and discuss the role of Nlrp3 inflammasome activation in cholestatic conditions.

Published
2020
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8. HCC development is associated to peripheral insulin resistance in a mouse model of NASH.

Author

Samuele De Minicis, Laura Agostinelli, Chiara Rychlicki, Gian Pio Sorice, Stefania Saccomanno, Cinzia Candelaresi, Andrea Giaccari, Luciano Trozzi, Irene Pierantonelli, Eleonora Mingarelli, Marco Marzioni, Giovanna Muscogiuri, Melania Gaggini, Antonio Benedetti, Amalia Gastaldelli, Maria Guido, and Gianluca Svegliati-Baroni

Subjects
Medicine, Science
Abstract

NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance.we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC.mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA) or its control (CSAA diet) and subjected to a low-dose i.p. injection of CCl4 or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis.CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1-3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl4 groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl4 treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2) and Osteopontin (SPP-1) were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors.the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD.

Published
2014
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10. Management of Helicobacter pylori infection: Guidelines of the Italian Society of Gastroenterology (SIGE) and the Italian Society of Digestive Endoscopy (SIED)

Author

Marco Romano, Antonietta Gerarda Gravina, Leonardo Henry Eusebi, Raffaele Pellegrino, Giovanna Palladino, Leonardo Frazzoni, Elton Dajti, Antonio Gasbarrini, Francesco Di Mario, Rocco Maurizio Zagari, Antonio Benedetti, Bruno Annibale, Patrizia Burra, Marcello Fabio Maida, Francesco Luzza, Luigi Ricciardiello, Maurizio Vecchi, Luca Frulloni, Alessandro Repici, Edoardo Vincenzo Savarino, Luigi Pasquale, Antonio Pisani, Antonietta Lamazza, Gianpaolo Cengia, Enrico Ciliberto, Rita Luisa Conigliaro, Paola Da Massa Carrara, and Bastianello Germanà

Subjects
Adult, Gastrointestinal, Peptic Ulcer, Helicobacter pylori, Hepatology, Settore MED/12 - GASTROENTEROLOGIA, guidelines, H. pylori, Gastroenterology, Endoscopy, Guidelines, Endoscopy, Gastrointestinal, Humans, Helicobacter Infections
Published
2022
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11. Supplementary Figure 4 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Author

Sharon DeMorrow, Antonio Benedetti, Marco Marzioni, Sum P. Lee, Domenico Alvaro, Gabriel Frampton, Monique Coufal, Antonio Franchitto, Paolo Onori, Francesca Bernuzzi, Shelley Kopriva, Julie Venter, Eugenio Gaudio, Pietro Invernizzi, and Gianfranco Alpini

Abstract

Supplementary Figure 4 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Published
2023
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12. Supplementary Table 1 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Author

Sharon DeMorrow, Antonio Benedetti, Marco Marzioni, Sum P. Lee, Domenico Alvaro, Gabriel Frampton, Monique Coufal, Antonio Franchitto, Paolo Onori, Francesca Bernuzzi, Shelley Kopriva, Julie Venter, Eugenio Gaudio, Pietro Invernizzi, and Gianfranco Alpini

Abstract

Supplementary Table 1 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Published
2023
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13. Supplementary Figure 5 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Author

Sharon DeMorrow, Antonio Benedetti, Marco Marzioni, Sum P. Lee, Domenico Alvaro, Gabriel Frampton, Monique Coufal, Antonio Franchitto, Paolo Onori, Francesca Bernuzzi, Shelley Kopriva, Julie Venter, Eugenio Gaudio, Pietro Invernizzi, and Gianfranco Alpini

Abstract

Supplementary Figure 5 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Published
2023
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14. Supplementary Figure 1 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Author

Sharon DeMorrow, Antonio Benedetti, Marco Marzioni, Sum P. Lee, Domenico Alvaro, Gabriel Frampton, Monique Coufal, Antonio Franchitto, Paolo Onori, Francesca Bernuzzi, Shelley Kopriva, Julie Venter, Eugenio Gaudio, Pietro Invernizzi, and Gianfranco Alpini

Abstract

Supplementary Figure 1 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Published
2023
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15. Supplementary Figure 2 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Author

Sharon DeMorrow, Antonio Benedetti, Marco Marzioni, Sum P. Lee, Domenico Alvaro, Gabriel Frampton, Monique Coufal, Antonio Franchitto, Paolo Onori, Francesca Bernuzzi, Shelley Kopriva, Julie Venter, Eugenio Gaudio, Pietro Invernizzi, and Gianfranco Alpini

Abstract

Supplementary Figure 2 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Published
2023
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16. Supplementary Figure Legends 1-5 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Author

Sharon DeMorrow, Antonio Benedetti, Marco Marzioni, Sum P. Lee, Domenico Alvaro, Gabriel Frampton, Monique Coufal, Antonio Franchitto, Paolo Onori, Francesca Bernuzzi, Shelley Kopriva, Julie Venter, Eugenio Gaudio, Pietro Invernizzi, and Gianfranco Alpini

Abstract

Supplementary Figure Legends 1-5 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Published
2023
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17. Supplementary Figure 3 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Author

Sharon DeMorrow, Antonio Benedetti, Marco Marzioni, Sum P. Lee, Domenico Alvaro, Gabriel Frampton, Monique Coufal, Antonio Franchitto, Paolo Onori, Francesca Bernuzzi, Shelley Kopriva, Julie Venter, Eugenio Gaudio, Pietro Invernizzi, and Gianfranco Alpini

Abstract

Supplementary Figure 3 from Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Published
2023
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18. Impact of Surgical Margins on Overall Survival after Gastrectomy for Gastric Cancer: A Validation of Japanese Gastric Cancer Association Guidelines on a Western Series

Author

Marianna Maspero, Carlo Sposito, Antonio Benedetti, Matteo Virdis, Maria Di Bartolomeo, Massimo Milione, and Vincenzo Mazzaferro

Subjects
Japan, Oncology, Gastrectomy, Stomach Neoplasms, Humans, Margins of Excision, Surgery, Neoplasm Staging, Retrospective Studies
Abstract

Purpose No consensus exists on the resection extent needed to ensure oncological safety in gastrectomy for gastric adenocarcinoma (GAC). This study aims to assess the impact of margin adequacy according to Japanese Gastric Cancer Association (JGCA) guidelines on overall survival (OS). Patients and Methods Patients who underwent surgery for stage I–III GAC at our institution between 2010 and 2017 were included. Margin adequacy according to JGCA, National Comprehensive Cancer Network (NCCN), and European Society for Medical Oncology (ESMO) guidelines was assessed, and their predictive value on OS was evaluated with Harrell’s C-index. Patients were analyzed according to their margins’ adherence to JGCA guidelines, and a propensity score matching (PSM) was run. Indication to either total gastrectomy (TG) or distal gastrectomy (DG) according to each guideline was also assessed. Results A total of 279 patients were included, of whom 220 (79%) underwent DG. Adequate margins according to JGCA were obtained in 209 patients (75%). On multivariate analysis, JGCA margin adequacy was independently associated with OS, together with American Society of Anesthesiologist class, neoadjuvant chemotherapy, lymphadenectomy extent, R0 resection, and postoperative N stage. After PSM, patients with JGCA adequate margins showed better OS, recurrence-free survival (RFS), and local RFS than patients with JGCA inadequate margins. For 220 DG, JGCA guidelines would have recommended TG in 25 patients (11%), NCCN in 30 (14%), and ESMO in 90 (41%) (p < 0.001). Conclusion Adequacy of surgical resection margins to JGCA guidelines leads to improved survival outcomes and allows for a more organ-preserving approach than Western guidelines.

Published
2022
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19. Role of autophagy in cholangiocarcinoma: Pathophysiology and implications for therapy

Author

Luca Maroni, Antonio Benedetti, C. Pinto, Marco Marzioni, and Elisabetta Ninfole

Subjects
Cisplatin, Cholangiocytes, Mechanism (biology), business.industry, Autophagolysosome, Autophagy, Cellular homeostasis, Cancer, Minireviews, Apoptosis, General Medicine, medicine.disease, Cholangiocarcinoma, Cancer cell, medicine, Cancer research, Neoplastic transformation, business, Chemoresistance, medicine.drug
Abstract

Cholangiocarcinoma (CCA) is a malignant tumour of the biliary system that originates from the neoplastic transformation of cholangiocytes. CCA is characterized by late diagnosis and poor outcome, with surgery considered as the last option for management. Autophagy is a physiological lysosomal degradation process, essential for cellular homeostasis and ubiquitous in all eukaryotic cells. Several studies have reported a potential involvement of autophagy in cancer, but it remains unclear whether activation of this process represents a survival mechanism of cancer cells. In the present review, we examine the autophagic process and summarize the current knowledge about the involvement of autophagy in the progression of cancer. The link between autophagy and chemoresistance and the use of autophagic markers in diagnosis are also considered in detail. Preliminary evidence shows that the combination of autophagy modulators (activators or inhibitors) with conventional chemotherapeutic agents offers a possible treatment option against signalling pathways that are hyperactivated or altered in CCA. In vitro evidence suggests that combination of chemotherapy agents, such as cisplatin, under activation or inhibition of autophagic processes, in two different CCA cell lines, may improve chemosensitivity and reduce cell survival, respectively. A deeper understanding of these pathways, in both cancer and non-cancer cells, could unveil possible therapeutic targets to treat CCA patients.

Published
2021
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20. Biliary granulomatous peritoneal reaction as consequence of cholecystectomy: a case report and a revision of the literature

Author

Giuseppe Tarantino, Denise Menghini, Maria Eva Argenziano, Miriam Palmieri, Alessandra Mandolesi, Enrico Dalla Bona, Antonio Benedetti, Mario Guerrieri, and Maria Giovanna Danieli

Abstract

Introduction: Bile or gallstone spillage during laparoscopic cholecystectomy occurs in 13 to 40% of cases of surgical dissection and extraction of very inflamed gallbladder with friable or gangrenous walls. Case presentation: We present a case of a patient who developed this rare complication after a difficult cholecystectomy for acute-on-chronic cholecystitis. Our patient, after about 2 years from the surgery, in the follow-up imaging studies, showed multiple nodules disseminated in the peritoneal cavity suggestive for malignancy both on abdomen computer tomography scan and on positron emission tomography. Thus, laparoscopic nodulectomy, lastly allowed histologic diagnosis of biliary peritoneal granulomatous reaction. Even if benign assessment of nodules’ nature, these lesions showed a progressive trend in increasing over the time in number and dimensions. We performed PubMed research of all cases reported in literature, to examine the cases features and to compare our findings with other clinical experiences reported by eleven international canters. Many patients were completely asymptomatic; as an occasional finding mimicking peritoneal seeding, further assessment to define the benign nature of these nodules were performed, so they underwent surgical treatment.In conclusion, development of multiple abdominal nodules resulting from a foreign-body granulomatous reaction to bile/gallstones is a quite rare event after laparoscopic cholecystectomy, but we believe it should be seriously considered in patients undergone complicated surgical procedures on biliary tracts.

Published
2022
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21. Therapeutic effects of dexamethasone-loaded hyaluronan nanogels in the experimental cholestasis

Author

Sabina Di Matteo, Chiara Di Meo, Guido Carpino, Nicole Zoratto, Vincenzo Cardinale, Lorenzo Nevi, Diletta Overi, Daniele Costantini, Claudio Pinto, Elita Montanari, Marco Marzioni, Luca Maroni, Antonio Benedetti, Marco Viola, Tommasina Coviello, Pietro Matricardi, Eugenio Gaudio, and Domenico Alvaro

Subjects
Bicarbonates, Mice, Cholestasis, primary biliary cholangitis, cholestasis, dexamethasone, hyaluronic acid, nanogels, Pharmaceutical Science, Animals, Nanogels, Hyaluronic Acid, Budesonide, Dexamethasone, Rats
Abstract

A major function of the intrahepatic biliary epithelium is bicarbonate excretion in bile. Recent reports indicate that budesonide, a corticosteroid with high receptor affinity and hepatic first pass clearance, increases the efficacy of ursodeoxycholic acid, a choleretic agent, in primary biliary cholangitis patients. We have previously reported that bile ducts isolated from rats treated with dexamethasone or budesonide showed an enhanced activity of the Na+/H+ exchanger isoform 1 (NHE1) and Cl−/HCO3− exchanger protein 2 (AE2) . Increasing the delivery of steroids to the liver may result in three beneficial effects: increase in the choleresis, treatment of the autoimmune or inflammatory liver injury and reduction of steroids’ systemic harmful effects. In this study, the steroid dexamethasone was loaded into nanohydrogels (or nanogels, NHs), in order to investigate corticosteroid-induced increased activities of transport processes driving bicarbonate excretion in the biliary epithelium (NHE-1 isoform) and to evaluate the effects of dexamethasone-loaded NHs (NHs/dex) on liver injury induced by experimental cholestatis. Our results showed that NHs and NHs/dex do not reduce cell viability in vitro in human cholangiocyte cell lines. Primary and immortalized human cholangiocytes treated with NHs/dex show an increase in the functional marker expression of NHE1 cholangiocytes compared to control groups. A mouse model of cholangiopathy treated with NHs/dex shows a reduction in markers of hepatocellular injury compared to control groups (NHs, dex, or sham group). In conclusion, we believe that the NHs/dex formulation is a suitable candidate to be investigated in preclinical models of cholangiopathies. Graphical abstract

Published
2022

22. A prospective study of direct-acting antiviral effectiveness and relapse risk in HCV cryoglobulinemic vasculitis by the Italian PITER cohort

Author

Loreta A. Kondili, Monica Monti, Maria Giovanna Quaranta, Laura Gragnani, Valentina Panetta, Giuseppina Brancaccio, Cesare Mazzaro, Marcello Persico, Mario Masarone, Ivan Gentile, Pietro Andreone, Salvatore Madonia, Elisa Biliotti, Roberto Filomia, Massimo Puoti, Anna Ludovica Fracanzani, Diletta Laccabue, Donatella Ieluzzi, Carmine Coppola, Maria Grazia Rumi, Antonio Benedetti, Gabriella Verucchi, Barbara Coco, Liliana Chemello, Andrea Iannone, Alessia Ciancio, Francesco Paolo Russo, Francesco Barbaro, Filomena Morisco, Luchino Chessa, Marco Massari, Pierluigi Blanc, Anna Linda Zignego, Kondili, L, Monti, M, Quaranta, M, Gragnani, L, Panetta, V, Brancaccio, G, Mazzaro, C, Persico, M, Masarone, M, Gentile, I, Andreone, P, Madonia, S, Biliotti, E, Filomia, R, Puoti, M, Fracanzani, A, Laccabue, D, Ieluzzi, D, Coppola, C, Rumi, M, Benedetti, A, Verucchi, G, Coco, B, Chemello, L, Iannone, A, Ciancio, A, Russo, F, Barbaro, F, Morisco, F, Chessa, L, Massari, M, Blanc, P, Zignego, A, Kondili L.A., Monti M., Quaranta M.G., Gragnani L., Panetta V., Brancaccio G., Mazzaro C., Persico M., Masarone M., Gentile I., Andreone P., Madonia S., Biliotti E., Filomia R., Puoti M., Fracanzani A.L., Laccabue D., Ieluzzi D., Coppola C., Rumi M.G., Benedetti A., Verucchi G., Coco B., Chemello L., Iannone A., Ciancio A., Russo F.P., Barbaro F., Morisco F., Chessa L., Massari M., Blanc P., and Zignego A.L.

Subjects
Vasculitis, mixed cryoglobulinemia, Hepatology, Sustained Virologic Response, Clinical Deterioration, Hepatitis C virus, Clinical Response, Cryoglobulinemic Vasculitis, Direct Acting Antivirals, HCV-chronic infection, Mixed Cryoglobulinemia, Hepacivirus, direct acting antivirals, Hepatitis C, Chronic, Antiviral Agents, Hepatitis C, HCV, Mixed cryoglobulinemia, HCV extraepatic manifestation, vasculitis, viral hepatitis, Cryoglobulinemia, Humans, Prospective Studies, Recurrence, HCV Cryoglobulinemia, Chronic
Abstract

Background and Aims: Mixed cryoglobulinemia is the most common HCV extrahepatic manifestation. We aimed to prospectively evaluate the cryoglobulinemic vasculitis (CV) clinical profile after a sustained virologic response (SVR) over a medium-term to long-term period. Approach and Results: Direct-acting antiviral–treated cryoglobulinemic patients, consecutively enrolled in the multicentric Italian Platform for the Study of Viral Hepatitis Therapy cohort, were prospectively evaluated. Cumulative incidence Kaplan-Meier curves were reported for response, clinical deterioration, relapse and relapse-free survival rates. Cox regression analysis evaluated factors associated with different outcomes. A clinical response was reported in at least one follow-up point for 373 of 423 (88%) patients with CV who achieved SVR. Clinical response increased over time with a 76% improvement rate at month 12 after the end of treatment. A full complete response (FCR) was reached by 164 (38.8%) patients in at least one follow-up point. CV clinical response fluctuated, with some deterioration of the initial response in 49.6% of patients (median time of deterioration, 19months). In patients who achieved FCR and had an available follow-up (137 patients) a relapse was observed in 13% and it was transient in 66.7% of patients. The rate of patients without any deterioration was 58% and 41% at 12 and 24months, respectively. After achieving SVR, a clinical nonresponse was associated with older age and renal involvement; a clinical deterioration/relapse was associated with high pretreatment rheumatoid factor values, and FCR was inversely associated with age, neuropathy, and high cryocrit levels. Conclusion: In patients with CV, HCV eradication may not correspond to a persistent clinical improvement, and clinical response may fluctuate. This implies an attentive approach to post-SVR evaluation through prognostic factors and tailored treatment.

Published
2022

23. The role of tumor microenvironment in cholangiocarcinoma

Author

Maria Eva Argenziano, Michele Montori, Chiara Scorzoni, Antonio Benedetti, Marco Marzioni, and Luca Maroni

Subjects
Oncology, Hepatology
Abstract

Cholangiocarcinoma (CCA) is an extremely aggressive neoplasia, mostly because of diagnostic delay and lack of effective therapies. CCA is typically surrounded by a peculiar microenvironment that includes abundant desmoplastic stroma and various cell types, which support and enhance CCA development. Among the tumor microenvironment (TME) cells, there are tumor infiltrating lymphocytes (TILs), such as CD8+ and CD4+ cells, Tregs, natural killers (NKs) and B lymphocytes. TILs contribute to an immunosuppressive microenvironment that leads to tumor immune escape. Dendritic cells (DCs) may lead to immunotolerance by maturation or antigen-presentation deficiency. Hepatic stellate cells (HSCs) are one of the major precursors of cancer-associated fibroblast (CAFs), which are distinguished in various subpopulations, each with different functions and interactions with other TME cells. CAFs can promote lymphangiogenesis, early lymph-node metastasis and proinflammatory environment, but they can also provide a physical and chemical barrier to protect CCA. Tumor-associated macrophages (TAMs) could be differentiated between two phenotypes, pro- and anti-inflammatory, and they may sustain invasiveness and immunosuppression. Myeloid-derived suppressor cells (MDSCs) impair cytotoxic T lymphocytes (CTLs) function, stimulating tumor proliferation and angiogenesis. Tumor-associated neutrophils (TANs) function is influenced by the TME, leading to tumor-suppressing or tumor-promoting functions. This paper aims to provide an overview of the CCA microenvironment cells, their role in tumor progression and possible correlated diagnostic, therapeutic and prognostic implications.

Published
2023
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24. 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]

Author

Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byun, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, Maria Consiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton V.J. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris D.J. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom J.W. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch'ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, and Charles Millson

Subjects
Science & Technology, Hepatology, Gastroenterology & Hepatology, Italian PBC Study Group, Japan-PBC-GWAS Consortium, UK-PBC Consortium, Chinese PBC Consortium, 1103 Clinical Sciences, US PBC Consortium, Canadian PBC Consortium, Life Sciences & Biomedicine, PBC Consortia, 1117 Public Health and Health Services
Published
2021

25. Cancer-Associated Fibroblasts in Cholangiocarcinoma: Current Knowledge and Possible Implications for Therapy

Author

Michele Montori, Chiara Scorzoni, Maria Eva Argenziano, Daniele Balducci, Federico De Blasio, Francesco Martini, Tiziana Buono, Antonio Benedetti, Marco Marzioni, and Luca Maroni

Subjects
General Medicine
Abstract

Cholangiocarcinoma (CCA) is an aggressive neoplasia with an increasing incidence and mortality. It is characterized by a strong desmoplastic stroma surrounding cancer cells. Cancer-associated fibroblasts (CAFs) are the main cell type of CCA stroma and they have an important role in modulating cancer microenvironments. CAFs originate from multiple lines of cells and mainly consist of fibroblasts and alpha-smooth muscle actin (α-SMA) positive myofibroblast-like cells. The continuous cross-talking between CCA cells and desmoplastic stroma is permitted by CAF biochemical signals, which modulate a number of pathways. Stromal cell-derived factor-1 expression increases CAF recruitment to the tumor reactive stroma and influences apoptotic pathways. The Bcl-2 family protein enhances susceptibility to CAF apoptosis and PDGFRβ induces fibroblast migration and stimulates tumor lymphangiogenesis. Many factors related to CAFs may influence CCA prognosis. For instance, a better prognosis is associated with IL-33 expression and low stromal IL-6 (whose secretion is stimulated by microRNA). In contrast, a worst prognosis is given by the expression of PDGF-D, podoplanin, SDF-1, α-SMA high expression, and periostin. The maturity phenotype has a prognostic relevance too. New therapeutic strategies involving CAFs are currently under study. Promising results are obtained with anti-PlGF therapy, nintedanib (BIBF1120), navitoclax, IPI-926, resveratrol, and controlled hyperthermia.

Published
2022
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27. Anticoagulation and Vessel Recanalization in Cirrhotic Patients with Splanchnic Vein Thrombosis: A Multidisciplinary 'Real Life' Experience

Author

Serena Rupoli, Alessandro Fiorentini, Erika Morsia, Gianluca Svegliati-Baroni, Giorgia Micucci, Luca Maroni, Kimberly Blaine Garvey, Alessandra Riva, Lidia Da Lio, Antonio Benedetti, Massimo Offidani, Attilio Olivieri, and Tarantino Giuseppe

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Multivariate analysis, Cirrhosis, Endocrinology, Diabetes and Metabolism, Hemorrhage, Esophageal and Gastric Varices, Cohort Studies, splanchnic vein thrombosis, Internal medicine, medicine, Humans, Pharmacology (medical), Endoscopy, Digestive System, Prospective Studies, Splanchnic Circulation, Aged, Original Research, Aged, 80 and over, Venous Thrombosis, anticoagulant therapy, business.industry, Incidence (epidemiology), cirrhosis, Public Health, Environmental and Occupational Health, Anticoagulants, Hematology, General Medicine, Middle Aged, medicine.disease, Thrombosis, Vascular Health and Risk Management, Splanchnic vein thrombosis, Cardiology, multidisciplinary approach, Female, vessel recanalization, Liver function, Cardiology and Cardiovascular Medicine, business, Complication, Cohort study
Abstract

Serena Rupoli,1 Alessandro Fiorentini,1 Erika Morsia,1 Gianluca Svegliati-Baroni,2 Giorgia Micucci,1 Luca Maroni,2 Kimberly Blaine Garvey,1 Alessandro Fiorentini Snr,3 Alessandra Riva Snr,4 Lidia Da Lio,5 Antonio Benedetti,2 Massimo Offidani,1 Attilio Olivieri,1 Tarantino Giuseppe2 1Clinica Ematologica, Dipartimento di Medicina Interna, Ancona, Italy; 2SOD Clinica di Gastroenterologia, Epatologia ed Endoscopia Digestiva d’Urgenza, Ancona, Italy; 3SOD Malattie Infettive emergenti e degli immunodepressi, Ospedali Riuniti Ancona, Ancona, Italy; 4SOD Clinica Malattie Infettive tropicali, parassitologia, epatiti croniche, Ancona, Italy; 5SOD Medicina di Laboratorio, Ospedali Riuniti Ancona, Ancona, ItalyCorrespondence: Erika MorsiaClinica Ematologica, Ospedali Riuniti Ancona, via Conca 71, 60126, ItalyEmail erika.morsia@ospedaliriuniti.marche.itBackground and Aim: Splanchnic vein thrombosis (SVT) is a potentially life-threatening complication of liver cirrhosis. This study aimed to evaluate the impact of a multi-disciplinary approach and early anticoagulation therapy (AT) on bleeding/thrombotic events, recanalization rates and outcome of cirrhotic patients with SVT.Methods: This is a single-center, registry-based cohort study. Over 17 years, 149 SVT patients were enrolled and prospectively evaluated. Regarding cirrhotic-SVT, a pre-specified algorithm, guiding initial posology of AT and follow-up visits schedule, was performed. Major bleeding (MB), thrombotic events, functional liver scores and all cause-mortality were investigated. Efficacy of AT was evaluated by radiological imaging.Results: In cirrhotic-SVT, the incidence rate of MB was 8.4 per 100 patient-year (95% CI, 3.83– 15.97), while the incidence rate of thrombosis was 5.6 per 100 patient-year (95% CI, 2.05– 12.2). In incidental SVT treated with AT, MB incidence was 6.5 per 100 patient-year (95% CI: 2.8– 12.82), while in symptomatic SVT was 2.2 per 100 patient-year (95% CI: 0.25– 8.02). All thrombotic recurrences occurred in incidental SVT (7.7 per 100 patient-years; 95% CI, 3.71– 14.26). Overall survival was significantly higher in patients who had at least a partial recanalization (p < 0.01) and partial/total recanalization was independently associated with improved MELD score at multivariate analysis (HR 2.62, 95% CI 1.1– 6.47, p = 0.03).Conclusion: In cirrhotic SVT patients, partial or total resolution of thrombosis ameliorates liver function and is associated with higher overall survival. A multidisciplinary approach together with radiological follow-up at pre-fixed time improves patient selection and monitoring.Keywords: splanchnic vein thrombosis, cirrhosis, anticoagulant therapy, vessel recanalization, multidisciplinary approach

Published
2021

28. Changes in digestive cancer diagnosis during the SARS-CoV-2 pandemic in Italy: A nationwide survey

Author

Gian Luigi de’Angelis, Francesco Buttitta, Elisa Stasi, Socrate Pallio, Maria Antonia Bianco, S. Bargiggia, Costanza Alvisi, Monica Sbrancia, Giancarla Fiori, Maria Carla Di Paolo, Carmelo Luigiano, Carlo Manfrini, Guido Missale, Stefano Rodinò, Bastianello Germanà, Davide Checchin, L.M. Montalbano, Monica Cesarini, Michela Cameletti, Antonietta D'Errico, Franco Bazzoli, Eìlisabetta Buscarini, Adriano Lauri, Vincenzo Giorgio Mirante, Luigi Ricciardiello, Raffaele Manta, Sara Massironi, Cecilia Binda, Matteo Brunacci, Vincenzo Occhipinti, Simona Attardo, Salvatore Russo, Paolo Usai-Satta, Maurizio Giovannone, Giuseppe De Caro, Antonio Benedetti, Marco Di Marco, Giovanni Serio, Francesco Broglia, Clarissa Ferrari, Luca Ferraris, Marco Dal-Fante, Thomas Togliani, Maria Cristina Conti-Bellocchi, Osvaldo Burattini, Orazio La Bianca, Alessandro Mussetto, Luigi Pasquale, Fabio Monica, Andrea Anderloni, Domenica Alvaro, Manuele Dinca, Debora Berretti, Rosamaria Bozzi, Enrico Piras, Bruno Nipote, Buscarini E., Benedetti A., Monica F., Pasquale L., Buttitta F., Cameletti M., Ferrari C., Ricciardiello L., Massironi S., Bianco M.A., Germana B., Rodino S., Anderloni A., Mussetto A., Nipote B., Russo S., Manta R., Lauri A., Occhipinti V., Marco M.D., Giovannone M., Binda C., Sbrancia M., Paolo M.C.D., de'-Angelis G.L., Fiori G., Dal-Fante M., Caro G.D., Usai-Satta P., Cesarini M., Piras E., Stasi E., Serio G., Montalbano L.M., Mirante V.G., Burattini O., Attardo S., Bargiggia S., Dinca M., Missale G., Alvisi C., Broglia F., Ferraris L., Conti-Bellocchi M.C., Luigiano C., Pallio S., Brunacci M., Manfrini C., Bozzi R., Checchin D., Togliani T., D'errico A., Bazzoli F., La Bianca O., Berretti D., and Alvaro D.

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Colorectal cancer, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, Gastric cancer, Pancreatic cancer, SARS-CoV-2, Digestive System Neoplasms, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Surveys and Questionnaires, Pandemic, medicine, Diagnostic Techniques, Digestive System, Gastroenterology, Humans, Infection Control, Italy, Organizational Innovation, Delivery of Health Care, Early Detection of Cancer, Stomach cancer, Hepatology, business.industry, Stomach, Cancer, medicine.disease, Diagnostic Techniques, medicine.anatomical_structure, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, business, Settore SECS-S/01 - Statistica, Digestive System
Abstract

Background The SARS-CoV-2 pandemic has had a huge impact on healthcare systems, resulting in many routine diagnostic procedures either being halted or postponed. Aims To evaluate whether the diagnoses of colorectal, gastric and pancreatic cancers have been impacted by the SARS-CoV-2 pandemic in Italy. Methods A survey designed to collect the number of histologically-proven diagnoses of the three cancers in gastroenterology services across Italy from January 1 to October 31 in 2017–2020. Non-parametric ANOVA for repeated measurements was applied to compare distributions by years and macro-areas. Results Compared to 2019, in 2020 gastric cancer diagnoses decreased by 15.9%, CRC by 11.9% and pancreatic by 9.9%. CRC distributions showed significant differences between all years, stomach cancer between 2018 and 2020 and 2019–2020, and pancreatic cancer only between 2017 and 2019. The 2019–2020 comparison showed fewer CRC diagnoses in the North (-13.7%), Center (-16.5%) and South (-4.1%), fewer stomach cancers in the North (-19.0%) and South (-9.4%), and fewer pancreatic cancers in the North (-14.1%) and Center (-4.7%), with an increase in the South (+12.3%). Distributions of CRC and gastric cancer were significantly different between all years in the North. Conclusions This survey highlights the concerning effects of the COVID-19 pandemic on the diagnostic yield of gastroenterology services for stomach, colorectal and pancreatic cancers in Italy.

Published
2021

29. Gut epithelial impairment, microbial translocation and immune system activation in inflammatory bowel disease-Associated spondyloarthritis

Author

Andrea Costantini, Devis Benfaremo, Chiara Avellini, Armando Gabrielli, Antonio Benedetti, Piergiorgio Mosca, Aroldo Rizzo, Francesco Ciccia, Michele Maria Luchetti, Silvia Svegliati, Tatiana Spadoni, Monica Mattioli Belmonte Cima, Monia Ciferri, Nadia Viola, Alfredo Santinelli, Antonella Berretta, Daniela Marzioni, Luchetti, M. M., Ciccia, F., Avellini, C., Benfaremo, D., Rizzo, A., Spadoni, T., Svegliati, S., Marzioni, D., Santinelli, A., Costantini, A., Viola, N., Berretta, A., Ciferri, M., Mattioli Belmonte Cima, M., Mosca, P., Benedetti, A., and Gabrielli, A.

Subjects
0301 basic medicine, Lipopolysaccharides, T cell, Lipopolysaccharide Receptors, Inflammation, Gut flora, Systemic inflammation, Fatty Acid-Binding Proteins, digestive system, Monocytes, Pathogenesis, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Immune system, Rheumatology, soluble biomarker, Ileum, inflammatory bowel disease, Spondylarthritis, medicine, Humans, Pharmacology (medical), Intestinal Mucosa, Adaptor Proteins, Signal Transducing, 030203 arthritis & rheumatology, Osteoblasts, biology, business.industry, dysbiosi, spondyloarthritis, biology.organism_classification, medicine.disease, Inflammatory Bowel Diseases, epithelial intestinal impairment, Gut Epithelium, 030104 developmental biology, medicine.anatomical_structure, Bacterial Translocation, Case-Control Studies, Immunology, medicine.symptom, business, Dysbiosis, Biomarkers
Abstract

Objectives Gut microbiota has been widely reported to be involved in systemic inflammation through microbial translocation and T cell activation in several diseases. In this work we aimed to investigate bacterial infiltration and epithelial impairment in the gut of patients with IBD-associated SpA (SpA-IBD), as well as the relationship of microbial translocation with immune system activation and their putative role in the pathogenesis of joint inflammation in IBD patients. Methods Tight-junction proteins (TJPs) occludin and claudin-1/-4 and bacteria were assessed by real-time PCR analysis and immunohistochemical staining of the ileum. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharides (LPS), soluble CD14 (sCD14), sclerostin and anti-sclerostin antibodies (anti-sclerostin-IgG) were assayed with ELISAs and peripheral mononuclear blood cells with flow cytometry. LPS and sCD14 were used in vitro to stimulate a human osteoblast cell line. Results Compared with IBD, ileal samples from SpA-IBD patients showed bacterial infiltration, epithelial damage and downregulation of TJPs. In sera, they showed higher serum levels of I-FABP, LPS, sCD14 (the latter correlating with sclerostin and anti-sclerostin-IgG) and higher CD80+/CD163+ and lower CD14+ mononuclear cells. In vitro experiments demonstrated that only the LPS and sCD14 synergic action downregulates sclerostin expression in osteoblast cells. Conclusion SpA-IBD patients are characterized by gut epithelium impairment with consequent translocation of microbial products into the bloodstream, immune system activation and an increase of specific soluble biomarkers. These findings suggest that gut dysbiosis could be involved in the pathogenesis of SpA-IBD and it could hopefully prompt the use of these biomarkers in the follow-up and management of IBD patients.

Published
2021

30. Clinical features and comorbidity pattern of HCV infected migrants compared to native patients in care in Italy: A real-life evaluation of the PITER cohort

Author

Maria Giovanna Quaranta, Luigina Ferrigno, Xhimi Tata, Franca D'Angelo, Marco Massari, Carmine Coppola, Elisa Biliotti, Alessia Giorgini, Diletta Laccabue, Alessia Ciancio, Pier Luigi Blanc, Marzia Margotti, Donatella Ieluzzi, Maurizia Rossana Brunetto, Francesco Barbaro, Francesco Paolo Russo, Ilaria Beretta, Giulia Morsica, Gabriella Verucchi, Annalisa Saracino, Massimo Galli, Loeta A. Kondili, Cesare Mazzaro, Manuela Bertola, Ornella Schioppa, Antonio Benedetti, Laura Schiadà, Monica Cucco, Andrea Giacometti, Laura Brescini, Sefora Castelletti, Alessandro Fiorentini, Gioacchino Angarano, Michele Milella, Alfredo Di Leo, Maria Rendina, Fulvio Salvatore D'abramo, Chiara Lillo, Andrea Iannone, Mariano Piazzolla, Lorenzo Badia, Fabio Piscaglia, Francesca Benevento, Ilaria Serio, Francesco Castelli, Serena Zaltron, Angiola Spinetti, Silvia Odolini, Raffaele Bruno, Mario Mondelli, Luchino Chessa, Martina Loi, Carlo Torti, Chiara Costa, Maria Mazzitelli, Vincenzo Pisani, Vincenzo Scaglione, Enrico Maria Trecarichi, Anna Linda Zignego, Monica Monti, Francesco Madia, Letizia Attala, Piera Pierotti, Elena Salomoni, Elisa Mariabelli, Teresa Antonia Santantonio, Serena Rita Bruno, Ester Marina Cela, Matteo Bassetti, Giovanni Mazzarello, Anna Ida Alessandrini, Antonio Di Biagio, Laura Ambra Nicolini, Giovanni Raimondo, Roberto Filomia, Alessio Aghemo, Rossella Meli, Adriano Lazzarin, Stefania Salpietro, Anna Ludovica Fracanzani, Erika Fatta, Rosa Lombardi, Pietro Lampertico, Marta Borghi, Roberta D'ambrosio, Elisabetta Degasperi, Massimo Puoti, Chiara Baiguera, Federico D'amico, Maria Vinci, Maria Grazia Rumi, Massimo Zuin, Paola Zermiani, Pietro Andreone, Paolo Caraceni, Valeria Guarneri, Erica Villa, Veronica Bernabucci, Laura Bristot, Maria Luisa Paradiso, Guglielmo Migliorino, Alessandra Gambaro, Giuseppe Lapadula, Anna Spolti, Alessandro Soria, Pietro Invernizzi, Antonio Ciaccio, Martina LucÀ, Federica Malinverno, Laura Ratti, Daniela Caterina Amoruso, Federica Pisano, Ferdinando Scarano, Laura Staiano, Filomena Morisco, Valentina Cossiga, Ivan Gentile, Antonio Riccardo Buonomo, Maria Foggia, Emanuela Zappulo, Alessandro Federico, Marcello Dallio, Nicola Coppola, Caterina Sagnelli, Salvatore Martini, Caterina Monari, Gerardo Nardone, Costantino Sgamato, Liliana Chemello, Luisa Cavalletto, Daniela Sterrantino, Alberto Zanetto, Paola Zanaga, Giuseppina Brancaccio, Antonio Craxì, Salvatore Petta, Vincenza Calvaruso, Luciano Crapanzano, Salvatore Madonia, Marco Cannizzaro, Erica Maria Bruno, Anna Licata, Simona Amodeo, Adele Rosaria Capitano, Carlo Ferrari, Elisa Negri, Alessandra Orlandini, Marco Pesci, Roberto Gulminetti, Layla Pagnucco, Giustino Parruti, Paola Di Stefano, Barbara Coco, Romina Corsini, Elisa Garlassi, Massimo Andreoni, Elisabetta Teti, Carlotta Cerva, Lorenzo Baiocchi, Giuseppe Grassi, Antonio Gasbarrini, Maurizio Pompili, Martina De Siena, Gloria Taliani, Martina Spaziante, Marcello Persico, Mario Masarone, Andrea Aglitti, Gemma Calvanese, Marco Anselmo, Pasqualina De Leo, Monica Marturano, Giorgio Maria Saracco, Quaranta M.G., Ferrigno L., Tata X., D'Angelo F., Massari M., Coppola C., Biliotti E., Giorgini A., Laccabue D., Ciancio A., Blanc P.L., Margotti M., Ieluzzi D., Brunetto M.R., Barbaro F., Russo F.P., Beretta I., Morsica G., Verucchi G., Saracino A., Galli M., Kondili L.A., Mazzaro C., Bertola M., Benedetti A., Schiada L., Cucco M., Giacometti A., Brescini L., Castelletti S., Fiorentini A., Angarano G., Milella M., Leo A.D., Rendina M., Salvatore D'ABRAMO F., Lillo C., Iannone A., Piazzolla M., Badia L., Piscaglia F., Benevento F., Serio I., Castelli F., Zaltron S., Spinetti A., Odolini S., Bruno R., Mondelli M., Chessa L., Loi M., Torti C., Costa C., Mazzitelli M., Pisani V., Scaglione V., Trecarichi E.M., Zignego A.L., Monti M., Madia F., Attala L., Pierotti P., Salomoni E., Mariabelli E., Santantonio T.A., Bruno S.R., Cela E.M., Bassetti M., Mazzarello G., Alessandrini A.I., Biagio A.D., Nicolini L.A., Raimondo G., Filomia R., Aghemo A., Meli R., Lazzarin A., Salpietro S., Fracanzani A.L., Fatta E., Lombardi R., Lampertico P., Borghi M., D'ambrosio R., Degasperi E., Puoti M., Baiguera C., D'AMICO F., Vinci M., Rumi M.G., Zuin M., Zermiani P., Andreone P., Caraceni P., Guarneri V., Villa E., Bernabucci V., Bristot L., Paradiso M.L., Migliorino G., Gambaro A., Lapadula G., Spolti A., Soria A., Invernizzi P., Ciaccio A., LucA M., Malinverno F., Ratti L., Amoruso D.C., Pisano F., Scarano F., Staiano L., Morisco F., Cossiga V., Gentile I., Buonomo A.R., Foggia M., Zappulo E., Federico A., Dallio M., Coppola N., Sagnelli C., Martini S., Monari C., Nardone G., Sgamato C., Chemello L., Cavalletto L., Sterrantino D., Zanetto A., Zanaga P., Brancaccio G., Craxi A., Petta S., Calvaruso V., Crapanzano L., Madonia S., Cannizzaro M., Bruno E.M., Licata A., Amodeo S., Capitano A.R., Ferrari C., Negri E., Orlandini A., Pesci M., Gulminetti R., Pagnucco L., Parruti G., Stefano P.D., Coco B., Corsini R., Garlassi E., Andreoni M., Teti E., Cerva C., Baiocchi L., Grassi G., Gasbarrini A., Pompili M., Siena M.D., Taliani G., Spaziante M., Persico M., Masarone M., Aglitti A., Calvanese G., Anselmo M., Leo P.D., Marturano M., Saracco G.M., Quaranta, M, Ferrigno, L, Tata, X, D'Angelo, F, Massari, M, Coppola, C, Biliotti, E, Giorgini, A, Laccabue, D, Ciancio, A, Blanc, P, Margotti, M, Ieluzzi, D, Brunetto, M, Barbaro, F, Russo, F, Beretta, I, Morsica, G, Verucchi, G, Saracino, A, Galli, M, Kondili, L, Mazzaro, C, Bertola, M, Benedetti, A, Schiada, L, Cucco, M, Giacometti, A, Brescini, L, Castelletti, S, Fiorentini, A, Angarano, G, Milella, M, Leo, A, Rendina, M, Salvatore D'ABRAMO, F, Lillo, C, Iannone, A, Piazzolla, M, Badia, L, Piscaglia, F, Benevento, F, Serio, I, Castelli, F, Zaltron, S, Spinetti, A, Odolini, S, Bruno, R, Mondelli, M, Chessa, L, Loi, M, Torti, C, Costa, C, Mazzitelli, M, Pisani, V, Scaglione, V, Trecarichi, E, Zignego, A, Monti, M, Madia, F, Attala, L, Pierotti, P, Salomoni, E, Mariabelli, E, Santantonio, T, Bruno, S, Cela, E, Bassetti, M, Mazzarello, G, Alessandrini, A, Biagio, A, Nicolini, L, Raimondo, G, Filomia, R, Aghemo, A, Meli, R, Lazzarin, A, Salpietro, S, Fracanzani, A, Fatta, E, Lombardi, R, Lampertico, P, Borghi, M, D'Ambrosio, R, Degasperi, E, Puoti, M, Baiguera, C, D'Amico, F, Vinci, M, Rumi, M, Zuin, M, Zermiani, P, Andreone, P, Caraceni, P, Guarneri, V, Villa, E, Bernabucci, V, Bristot, L, Paradiso, M, Migliorino, G, Gambaro, A, Lapadula, G, Spolti, A, Soria, A, Invernizzi, P, Ciaccio, A, Luca, M, Malinverno, F, Ratti, L, Amoruso, D, Pisano, F, Scarano, F, Staiano, L, Morisco, F, Cossiga, V, Gentile, I, Buonomo, A, Foggia, M, Zappulo, E, Federico, A, Dallio, M, Coppola, N, Sagnelli, C, Martini, S, Monari, C, Nardone, G, Sgamato, C, Chemello, L, Cavalletto, L, Sterrantino, D, Zanetto, A, Zanaga, P, Brancaccio, G, Craxi, A, Petta, S, Calvaruso, V, Crapanzano, L, Madonia, S, Cannizzaro, M, Bruno, E, Licata, A, Amodeo, S, Capitano, A, Ferrari, C, Negri, E, Orlandini, A, Pesci, M, Gulminetti, R, Pagnucco, L, Parruti, G, Stefano, P, Coco, B, Corsini, R, Garlassi, E, Andreoni, M, Teti, E, Cerva, C, Baiocchi, L, Grassi, G, Gasbarrini, A, Pompili, M, Siena, M, Taliani, G, Spaziante, M, Persico, M, Masarone, M, Aglitti, A, Calvanese, G, Anselmo, M, Leo, P, Marturano, M, Saracco, G, Quaranta, M. G., Ferrigno, L., Tata, X., D'Angelo, F., Massari, M., Coppola, C., Biliotti, E., Giorgini, A., Laccabue, D., Ciancio, A., Blanc, P. L., Margotti, M., Ieluzzi, D., Brunetto, M. R., Barbaro, F., Russo, F. P., Beretta, I., Morsica, G., Verucchi, G., Saracino, A., Galli, M., Kondili, L. A., Mazzaro, C., Bertola, M., Benedetti, A., Schiada, L., Cucco, M., Giacometti, A., Brescini, L., Castelletti, S., Fiorentini, A., Angarano, G., Milella, M., Leo, A. D., Rendina, M., Salvatore D'ABRAMO, F., Lillo, C., Iannone, A., Piazzolla, M., Badia, L., Piscaglia, F., Benevento, F., Serio, I., Castelli, F., Zaltron, S., Spinetti, A., Odolini, S., Bruno, R., Mondelli, M., Chessa, L., Loi, M., Torti, C., Costa, C., Mazzitelli, M., Pisani, V., Scaglione, V., Trecarichi, E. M., Zignego, A. L., Monti, M., Madia, F., Attala, L., Pierotti, P., Salomoni, E., Mariabelli, E., Santantonio, T. A., Bruno, S. R., Cela, E. M., Bassetti, M., Mazzarello, G., Alessandrini, A. I., Biagio, A. D., Nicolini, L. A., Raimondo, G., Filomia, R., Aghemo, A., Meli, R., Lazzarin, A., Salpietro, S., Fracanzani, A. L., Fatta, E., Lombardi, R., Lampertico, P., Borghi, M., D'Ambrosio, R., Degasperi, E., Puoti, M., Baiguera, C., D'Amico, F., Vinci, M., Rumi, M. G., Zuin, M., Zermiani, P., Andreone, P., Caraceni, P., Guarneri, V., Villa, E., Bernabucci, V., Bristot, L., Paradiso, M. L., Migliorino, G., Gambaro, A., Lapadula, G., Spolti, A., Soria, A., Invernizzi, P., Ciaccio, A., Luca, M., Malinverno, F., Ratti, L., Amoruso, D. C., Pisano, F., Scarano, F., Staiano, L., Morisco, F., Cossiga, V., Gentile, I., Buonomo, A. R., Foggia, M., Zappulo, E., Federico, A., Dallio, M., Coppola, N., Sagnelli, C., Martini, S., Monari, C., Nardone, G., Sgamato, C., Chemello, L., Cavalletto, L., Sterrantino, D., Zanetto, A., Zanaga, P., Brancaccio, G., Craxi, A., Petta, S., Calvaruso, V., Crapanzano, L., Madonia, S., Cannizzaro, M., Bruno, E. M., Licata, A., Amodeo, S., Capitano, A. R., Ferrari, C., Negri, E., Orlandini, A., Pesci, M., Gulminetti, R., Pagnucco, L., Parruti, G., Stefano, P. D., Coco, B., Corsini, R., Garlassi, E., Andreoni, M., Teti, E., Cerva, C., Baiocchi, L., Grassi, G., Gasbarrini, A., Pompili, M., Siena, M. D., Taliani, G., Spaziante, M., Persico, M., Masarone, M., Aglitti, A., Calvanese, G., Anselmo, M., Leo, P. D., Marturano, M., and Saracco, G. M.

Subjects
Male, HCV genotypes, Ethnic group, Linked-to-care patient, Comorbidity, Hepacivirus, Logistic regression, medicine.disease_cause, Comorbidities, Direct acting antivirals, HCV Cohort, Linked-to-care patients, Aged, Antiviral Agents, Coinfection, Female, Hepatitis C, Chronic, Humans, Italy, Middle Aged, Transients and Migrants, 0302 clinical medicine, Medicine, Chronic, Gastroenterology, virus diseases, Hepatitis C, Life evaluation, 030220 oncology & carcinogenesis, Cohort, 030211 gastroenterology & hepatology, Comorbiditie, Human, Hepatitis C virus, Settore MED/12 - GASTROENTEROLOGIA, 03 medical and health sciences, Disease severity, Antiviral Agent, Hepaciviru, Hepatology, business.industry, Settore MED/09 - MEDICINA INTERNA, medicine.disease, digestive system diseases, Direct acting antiviral, business, Demography
Abstract

Background: Direct-acting antivirals are highly effective for the treatment of hepatitis C virus (HCV) infection, regardless race/ethnicity. We aimed to evaluate demographic, virological and clinical data of HCV-infected migrants vs. natives consecutively enrolled in the PITER cohort. Methods: Migrants were defined by country of birth and nationality that was different from Italy. Mann-Whitney U test, Chi-squared test and multiple logistic regression were used. Results: Of 10,669 enrolled patients, 301 (2.8%) were migrants: median age 47 vs. 62 years, (p < 0.001), females 56.5% vs. 45.3%, (p < 0.001), HBsAg positivity 3.8% vs. 1.4%, (p < 0.05). Genotype 1b was prevalent in both groups, whereas genotype 4 was more prevalent in migrants (p < 0.05). Liver disease severity and sustained virologic response (SVR) were similar. A higher prevalence of comorbidities was reported for natives compared to migrants (p < 0.05). Liver disease progression cofactors (HBsAg, HIV coinfection, alcohol abuse, potential metabolic syndrome) were present in 39.1% and 47.1% (p > 0.05) of migrants and natives who eradicated HCV, respectively. Conclusion: Compared to natives, HCV-infected migrants in care have different demographics, HCV genotypes, viral coinfections and comorbidities and similar disease severity, SVR and cofactors for disease progression after HCV eradication. A periodic clinical assessment after HCV eradication in Italians and migrants with cofactors for disease progression is warranted.

Published
2021

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

Author

S. Abiru, John F. Dillon, Yasuhiro Miyake, Piero Portincasa, Giancarlo Spinzi, R. Harvey, T. Ngatchu, Agostino Colli, M. Taniai, K. Flahive, Masanori Abe, B. Hoeroldt, S. Holder, Howard Curtis, María Isabel Colombo, C. MacNicol, Gang Xie, Andrew Chilton, H. Hussaini, Cristina Rigamonti, M. Kato, Shintaro Yagi, G. Abouda, D. Tyrer, Chris D. Evans, Christopher I. Amos, K. Koss, Kazuaki Chayama, P. Premchand, K. Migita, Simon Panter, Marco Marzioni, Silvia Colombo, Konstantinos N. Lazaridis, M. Yagura, Ashley Brown, D. Gocher, Domenico Alvaro, K. Murata, Mark Wright, Piero Luigi Almasio, C. Healey, A. Ciaccio, N. Wheatley, Vincenzo Cardinale, T. Delahooke, Chiara Milani, T. Shewan, W. Stableforth, S. Levi, Mark L. Green, James V. Jones, Y. Baird, Aftab Ala, Burroughs Ak, D. Williams, K. Ario, P. Sanghi, Hemant Gupta, P. Southern, L. Farrington, M. Hamilton, Andrew D. Higham, I. Yabuuchi, H. Yatsuhashi, Lorenzo Morini, T. Yamamoto, Douglas Thorburn, M. Carnahan, N. Nishida, Susan Slininger, M. Koga, K. Honda, Annarosa Floreani, Andrew Douglass, K. Netherton, M. Yasunami, Hirohito Tsubouchi, F. Donato, K. Walker, U. Shmueli, Paolo Muratori, Ray Mathew, J. Maiden, E. Dungca, Subramaniam Ramakrishnan, S. Vyas, Helen Sweeting, Subrata Saha, T. Komeda, T. Komatsu, H. J. Lee, Maria Consiglia Bragazzi, T. Komura, C. Thomas, C. Shallcross, C. Duggan, J. Kordula, F. Muscariu, Lourdes Cumlat, Imran Patanwala, Giulia Cardamone, L. Morgan, J. Brighton, Masao Honda, H. Nakamura, David Jones, Raj Srirajaskanthan, M. E. Gershwin, T. Muro, L. Stafford, N. Fukushima, Graham P. Butcher, Andrea Crosignani, George Lipscomb, K. Hirata, Y. Nagaoki, S. Mann, Paul G. Richardson, David A Elphick, M. Mupudzi, Y. Ohara, E. Grieve, Gayle Clifford, Claudio Tiribelli, M. Quinn, G. Van Duyvenvoorde, E. Archer, Tatsuki Ichikawa, J. Maltby, T. Arinaga-Hino, Simon Williams, A. King, Yasuni Nakanuma, H. Doyle, A. Brind, Nora Cazzagon, H. Ota, Daphne D’Amato, K. Hogben, H. 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Hobson, L. Currie, J. Allison, J. Hails, Noriyo Yamashiki, Massimo Zuin, C. Grimley, Alessio Gerussi, S. Besley, Stefano Duga, A. Piotrowicz, H. Kouno, L. Dali-kemmery, H. Sakai, M. Mizokami, Stefano Fagiuoli, Amy Davis, Pier Maria Battezzati, Masao Nagasaki, Luigi Muratori, A. Mori, S. Desmennu, S. Jones, R. Abrahams, Keith George, F. Makita, J. Brown, D. Gorard, Satoru Joshita, M. Mills, Pierluigi Toniutto, S. Campbell, J. Butterworth, S. Dyer, Filomena Morisco, Norihiro Kokudo, T. Yapp, C. Shorrock, Floriano Rosina, E. Walker, Shinji Uemoto, H. Takahashi, Simon M. Rushbrook, K. Amor, E. Marshall, J. Browning, S. Batham, Luca Fabris, Paul R. Banim, Meenakshi Narain, M. Harada, Dermot Gleeson, N. Hirashima, M. Kikuchi, T. Nikami, Gideon M. Hirschfield, Carlo Ferrari, G. Prasad, O. Chirag, Katsushi Tokunaga, M. Nasseri, Rosanna Asselta, Y. Lu, Ken Shirabe, D. Sirdefield, George F. Mells, K. Sugi, R. Ayres, G. Whatley, A. Singhal, M. Leoni, N. Sivaramakrishnan, T. 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Aldersley, Elizabeth J. Atkinson, Pietro Invernizzi, Heather J. Cordell, 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. 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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., 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 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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., 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 EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, 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 KA, Canadian-US PBC Consortium, Italian PBC Genetics Study Group, UK-PBC Consortium, Japan PBC-GWAS Consortium, Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P, and LiveR North

Subjects
Canadian-US PBC Consortium, 0301 basic medicine, Male, Linkage disequilibrium, Genome-wide association study, Disease, PBC, Settore MED/03 - GENETICA MEDICA, Linkage Disequilibrium, 0302 clinical medicine, UK-PBC Consortium, Genotype, Mitochondrial Precursor Protein Import Complex Proteins, Italian PBC Genetics Study Group, Odds Ratio, X-Wide Association Study, Japan PBC-GWAS Consortium, X chromosome, Genetics, Liver Cirrhosis, Biliary, Gastroenterology, Forkhead Transcription Factors, DNA-Binding Proteins, Shal Potassium Channels, 030211 gastroenterology & hepatology, Female, Adult, Monosaccharide Transport Proteins, Superenhancer, Locus (genetics), Single-nucleotide polymorphism, Biology, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Asian People, Proto-Oncogene Proteins, Endopeptidases, Humans, Cell Lineage, Genetic Predisposition to Disease, Meta-analysi, Genetic association, Chromosomes, Human, X, Gastroenterology & Hepatology, Hepatology, 1103 Clinical Sciences, Meta-analysis, 030104 developmental biology, Genetic Loci, 1114 Paediatrics and Reproductive Medicine, 1109 Neurosciences, Carrier Proteins, Genome-Wide Association Study
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

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

Author

Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, MariaConsiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton VJ. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris DJ. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom JW. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch’ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, Charles Millson, 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.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 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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., Medical Research Council (MRC), LiveR North, 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 HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byan J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF, PBC Consortia, Canadian PBC Consortium, Chinese PBC Consortium, Italian PBC Study Group, Japan-PBC-GWAS Consortium, US PBC Consortium, UK-PBC Consortium, and Calvaruso V. .

Subjects
Liver Cirrhosis, ALSPAC, ERN RARE-LIVER, Genomic co-localization, Network-based in silico drug efficacy screening, UK-PBC, 0301 basic medicine, Candidate gene, Genome-Wide Association Study, Humans, Liver Cirrhosis, Biliary, Italian PBC Study Group, LD SCORE REGRESSION, Japan-PBC-GWAS Consortium, Genome-wide association study, Locus (genetics), Disease, SUSCEPTIBILITY, PBC, Chronic liver disease, Bioinformatics, GENETIC ASSOCIATION, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, UK-PBC Consortium, Genotype, Medicine, Genetic association, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, Biliary, Chinese PBC Consortium, 1103 Clinical Sciences, medicine.disease, PBC Consortia, 030104 developmental biology, Meta-analysis, ERN RARE LIVER, 030211 gastroenterology & hepatology, US PBC Consortium, Canadian PBC Consortium, business, Life Sciences & Biomedicine, Human
Abstract

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic 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 five European and two 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, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some 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, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

Published
2021

33. Endoscopy Units and the Coronavirus Disease 2019 Outbreak: A Multicenter Experience From Italy

Author

Clementina Signorelli, Cesare Hassan, Paolo Beretta, Sergio Segato, Gianpaolo Cengia, F. Lella, Benedetto Mangiavillano, Paolo Cantù, Massimiliano Mutignani, Omero Triossi, Prateek Sharma, Pier Alberto Testoni, Armando Gabbrielli, Georgios Amvrosiadis, Giovanni Aragona, Nicola Gaffuri, Luca De Luca, Thomas Rösch, Marco Dinelli, Carlo Fabbri, Roberto Mingotto, Andrea Anderloni, Giulio Antonelli, Piera Leoni, Luca Ferraris, Fabio Pace, Guido Missale, Piera Alessia Galtieri, Silvia Carrara, Gaia Pellegatta, S. Greco, Alessandro Repici, Cristiano Spada, Luca Maroni, Mauro Giovanardi, R. Salerno, Vincenzo Cennamo, Antonella Scarcelli, Gianpiero Manes, Alessandro Fugazza, Pietro Occhipinti, S. Bargiggia, Federico De Grazia, Costanza Alvisi, Giuseppe De Roberto, Franco Radaelli, Roberto Gabbiadini, Pavlos Lagoussis, Fabrizio Cereatti, Antonio Benedetti, Elisabetta Buscarini, Roberta Maselli, Marco Spadaccini, and Matteo Colombo

Subjects
2019-20 coronavirus outbreak, Infectious Disease Transmission, Patient-to-Professional, Coronavirus disease 2019 (COVID-19), Professional-to-Patient, Gastrointestinal Diseases, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Infectious Disease Transmission, Pneumonia, Viral, medicine.disease_cause, Infectious Disease Transmission, Professional-to-Patient, Patient-to-Professional, Betacoronavirus, Pandemic, medicine, Humans, Endoscopy, Digestive System, Viral, Coronavirus, COVID-19, Endoscopy, Survery, Coronavirus Infections, Critical Pathways, Infection Control, Italy, Pandemics, Personal Protective Equipment, Hepatology, SARS-CoV-2, business.industry, Gastroenterology, Outbreak, Pneumonia, Virology, business, Digestive System
Published
2020
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34. mTOR and STAT3 Pathway Hyper-Activation is Associated with evated Interleukin-6 Levels in Patients with Shwachman-Diamond Syndrome: Further Evidence of Lymphoid Lineage Impairment

Author

Elena Marinelli Busilacchi, Claudio Sorio, Alice Giacomazzi, Tiziana Cestari, Valentino Bezzerri, Monica Borgatti, Seth J. Corey, Marco Cipolli, Giovanna D'Amico, Vincenzo Bronte, Antonella Poloni, Antonio Vella, Elisabetta D'Aversa, Marisole Allegri, Martina Api, Benedetta Fabrizzi, Giulia Breveglieri, Antonio Benedetti, Chiara Bovo, and Gloria Bedini

Subjects
0301 basic medicine, lymphocytes, Cancer Research, Myeloid, Bone Marrow Failure Syndromes, Lymphocytes, MTOR, STAT3, lcsh:RC254-282, Article, stat3, bone marrow failure syndromes, NO, 03 medical and health sciences, 0302 clinical medicine, mtor, medicine, Interleukin 6, mTOR, PI3K/AKT/mTOR pathway, Shwachman–Diamond syndrome, biology, business.industry, Lymphoblast, Mesenchymal stem cell, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, n/a, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Bone marrow, business, human activities
Abstract

Keywords: STAT3, mTOR, Bone Marrow Failure Syndromes, lymphocytes

Published
2020

35. Impact of the COVID-19 pandemic on Gastroenterology Divisions in Italy: A national survey

Author

Lorenzo Fuccio, Edoardo Savarino, Luigi Ricciardiello, Bruno Annibale, Gianluca Ianiro, Patrizia Burra, Antonio Benedetti, Filomena Morisco, Alessandro Vitello, Manuele Furnari, Marcello Maida, Santino Marchi, Domenico Alvaro, Alessandro Repici, Sandro Sferrazza, Gaetano Cristian Morreale, Maida M., Sferrazza S., Savarino E., Ricciardiello L., Repici A., Morisco F., Furnari M., Fuccio L., Morreale G.C., Vitello A., Burra P., Marchi S., Annibale B., Benedetti A., Alvaro D., Ianiro G., Maida, M., Sferrazza, S., Savarino, E., Ricciardiello, L., Repici, A., Morisco, F., Furnari, M., Fuccio, L., Morreale, G. C., Vitello, A., Burra, P., Marchi, S., Annibale, B., Benedetti, A., Alvaro, D., and Ianiro, G.

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Health Personnel, Pneumonia, Viral, Gastroenterology, Article, Covid 19, pandemic, gastrenterology, Tertiary Care Centers, Betacoronavirus, Hospital, ULTRASOUND PROCEDURES, Country level, Internal medicine, Surveys and Questionnaires, Pandemic, Health care, medicine, Humans, Viral, Survey, Pandemics, Personal protective equipment, Personal Protective Equipment, Infection Control, Hepatology, Betacoronaviru, business.industry, SARS-CoV-2, Coronavirus Infection, COVID-19, Impact, Coronavirus Infections, Hospitals, Italy, Outbreak, Endoscopy, Pneumonia, Intensive Care Units, Emergency Service, Hospital, business, Healthcare system, Human
Abstract

Background In Italy, the spread of the COVID-19 pandemic has stressed the entire healthcare system and required a huge re-organization of many Divisions, including those of Gastroenterology. Aims to assess the impact of COVID-19 pandemic on Gastroenterology Divisions across Italy. Methods All members of the Italian Society of Gastroenterology (SIGE) were invited to answer a web-based survey. Results Data of 121 hospitals from all 20 Italian regions were analyzed. Overall, 10.7% Gastroenterology Divisions have been converted to Covid Units. Outpatients consultations, endoscopic and ultrasound procedures were limited to urgencies and oncology indications in 85.1%, 96.2% and 72.2% of Units, respectively, and 46.7% of them suspended the screening for colorectal cancer. Moreover, 72.2% of the staff received a training for use of personal protective equipment, although 45.5% did not have sufficient devices for adequate replacement. Overall, 132 healthcare workers in 41 Gastroenterology Divisions were found to be infected. Conclusion This is the first study to evaluate, at a country level, the impact of COVID-19 outbreak on Gastroenterology Divisions. Substantial changes of practice and reduction of procedures have been recorded in the entire country. The long-term impact of such modifications is difficult to estimate but potentially very risky for many digestive diseases.

Published
2020

36. Corrigendum to: Gut epithelial impairment, microbial translocation and immune system activation in inflammatory bowel disease–associated spondyloarthritis

Author

Michele Maria Luchetti, Francesco Ciccia, Chiara Avellini, Devis Benfaremo, Aroldo Rizzo, Tatiana Spadoni, Silvia Svegliati, Daniela Marzioni, Alfredo Santinelli, Andrea Costantini, Nadia Viola, Antonella Berretta, Monia Ciferri, Monica Mattioli Belmonte Cima, Piergiorgio Mosca, Antonio Benedetti, and Armando Gabrielli

Subjects
Rheumatology, Pharmacology (medical)
Published
2020
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37. Su1536 DUODENOSCOPE-RELATED INFECTIONS: AN ITALIAN PICK IN 2019

Author

Carmelo LuigianoS, Matteo Badalamenti, Armando Gabbrielli, Federico De Grazia, Renzo Gllotta, Nicola Mantovani, Alberto Mariani, Alessandro Fugazza, Andrea Anderloni, Arianna Dal Buono, Franco Radaelli, Pietro Occhipinti, Paolo Beretta, Paolo Cantù, Alessandro Repici, Roberto Gabbiadini, Guido Manfredi, Marco Dinelli, L. Cugia, Gianpiero Manes, Alberto Tringali, Adriano Lauri, Fabrizio Cereatti, D. Paduano, Massimiliano Mutignani, Giuseppe Feliciangeli, Pietro Gambitta, Edoardo Vespa, Roberta Maselli, Giovanni Aragona, Guido Missale, Matteo Colombo, Silvia Carrara, Carlo Fabbri, Piera Leoni, Antonio Capogreco, Alessandro Mussetto, Claudio De Angelis, G. Diamantis, R. Salerno, Marco Paganelli, Mauro Manno, Laura Lamonaca, Mario De Bellis, Cambareri Antonio, Calcedonio Calcara, Giovanna Del Vecchio Blanco, Antonio Benedetti, Mario Traina, Giampiero Macarri, Maria Caterina Parodi, Piegiorgio Mosca, Marco Spadaccini, Lorenzo Camellini, Giovanna Venezia, Mohammad Ayoubi, Nicola Pugliese, Vincenzo Craviotto, Marcella Berni Canani, Marco Bassi, Maria Laura Canfora, Emilio Di Giulio, Gianpaolo Cengia, Costanza Alvisi, Guido Costamagna, and Enzo Masci

Subjects
medicine.medical_specialty, business.industry, General surgery, Gastroenterology, medicine, Radiology, Nuclear Medicine and imaging, business
Published
2020
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38. Ageing-related expression of Twinfilin-1 regulates cholangiocyte biological response to injury

Author

Ibone Labiano, Jesus M. Banales, Stefania Saccomanno, Luciano Trozzi, Malgorzata Milkiewicz, Espen Melum, Debora Maria Giordano, Chiara Rychlicki, Maria Cristina Albertini, Marina Scarpelli, Luca Maroni, Gianluca Svegliati Baroni, Piotr Milkiewicz, Antonio Benedetti, Marco Marzioni, Mauro Provinciali, Daniele Spallacci, Fiorenza Orlando, and C. Pinto

Subjects
0301 basic medicine, Senescence, Aging, Cholangitis, Sclerosing, Biology, Sensitivity and Specificity, Cholangiocyte, 03 medical and health sciences, Mice, Random Allocation, 0302 clinical medicine, Fibrosis, In vivo, microRNA, medicine, Animals, Humans, Biliary Tract, Cells, Cultured, Cellular Senescence, Cell Proliferation, Hepatology, Cell growth, Microfilament Proteins, medicine.disease, Phenotype, Disease Models, Animal, MicroRNAs, 030104 developmental biology, Cancer research, 030211 gastroenterology & hepatology, Intracellular
Abstract

Disorders of the biliary tree develop and progress differently according to patient age. It is currently not known whether the aging process affects the response to injury of cholangiocytes. The aim of this study was to identify molecular pathways associated with cholangiocyte aging and to determine their effects in the biological response to injury of biliary cells. A panel of microRNAs (miRs) involved in aging processes was evaluated in cholangiocytes of young and old mice (2 months and 22 months of age, respectively) and subjected to a model of sclerosing cholangitis. Intracellular pathways that are common to elevated miRs were identified by in silico analysis. Cell proliferation and senescence were evaluated in Twinfilin-1 (Twf1) knocked-down cells. In vivo, senescence-accelerated prone mice (Samp8, a model for accelerated aging), Twf1-/- , or their respective controls were subjected to DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine). Cholangiocytes from DDC-treated mice showed up-regulation of a panel of aging-related miRs. Twf1 was identified by in silico analysis as a common target of the up-regulated miRs. Twf1 expression was increased both in aged and diseased cholangiocytes, and in human cholangiopathies. Knock-down of Twf1 in cholangiocytes reduced cell proliferation. Senescence and senescence-associated secretory phenotype marker expression increased in Twf1 knocked-down cholangiocytes following pro-proliferative and pro-senescent (10-day lipopolysaccharide) stimulation. In vivo, Samp8 mice showed increased biliary proliferation, fibrosis, and Twf1 protein expression level, whereas Twf1-/- had a tendency toward lower biliary proliferation and fibrosis following DDC administration compared with control animals. Conclusion: We identified Twf1 as an important mediator of both cholangiocyte adaptation to aging processes and response to injury. Our data suggest that disease and aging might share common intracellular pathways.

Published
2019

39. Inflammation and the Gut-Liver Axis in the Pathophysiology of Cholangiopathies

Author

Antonio Benedetti, C. Pinto, Luca Maroni, Debora Maria Giordano, and Marco Marzioni

Subjects
0301 basic medicine, cholangiocytes adaptive and immune response, Inflammation, Bile Duct Diseases, Review, Gut flora, digestive system, Catalysis, Proinflammatory cytokine, Primary sclerosing cholangitis, leaky-gut hypothesis, Inorganic Chemistry, lcsh:Chemistry, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Animals, Humans, Physical and Theoretical Chemistry, Molecular Biology, lcsh:QH301-705.5, Spectroscopy, Innate immune system, biology, Liver cell, Organic Chemistry, cholangiopathies, General Medicine, medicine.disease, biology.organism_classification, Immunity, Innate, Gastrointestinal Microbiome, Computer Science Applications, Gastrointestinal Tract, PSC and PBC-microbiota signature, 030104 developmental biology, Liver, lcsh:Biology (General), lcsh:QD1-999, Immunology, 030211 gastroenterology & hepatology, medicine.symptom, Dysbiosis
Abstract

Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous or endogenous stimuli, cholangiocytes undergo extensive modifications of their phenotype. Reactive cholangiocytes actively proliferate and release a set of proinflammatory molecules, which act in autocrine/paracrine manner mediating the cross-talk with other liver cell types and innate and adaptive immune cells. Cholangiocytes themselves activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Gut microbiota has been implicated in the development and progression of the two most common cholangiopathies, i.e., primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), which have distinctive microbiota composition compared to healthy individuals. The impairment of intestinal barrier functions or gut dysbiosis expose cholangiocytes to an increasing amount of microorganisms and may exacerbate inflammatory responses thus leading to fibrotic remodeling of the organ. The present review focuses on the complex interactions between the activation of innate immune responses in reactive cholangiocytes, dysbiosis, and gut permeability to bacterial products in the pathogenesis of PSC and PBC.

Published
2018

40. Safety and efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in patients over 65 years with HCV genotype 1 cirrhosis

Author

Giada Carolo, Veronica Bernabucci, Luchino Chessa, Maria Luisa Russo, Giorgio Maria Saracco, Marzia Montalbano, Barbara Menzaghi, Giovanni Di Perri, Adriano Lazzarin, Silvia La Monica, Raffaele Bruno, Gian Ludovico Rapaccini, Mario U. Mondelli, Anna Maria Schimizzi, Caterina Pasquazzi, Maurizia Rossana Brunetto, Antonio Craxì, Filomena Morisco, Carmela Lo Guercio, Vania Giacomet, Alessia Giorgini, Mario Masarone, Francesca Paolo Russo, T. Zolfino, Vincenzo Sangiovanni, Alessia Ciancio, Antonella d'Arminio Monforte, Savino Bruno, E.M. Erne, Antonio Gasbarrini, Francesco Castelli, Sergio Novara, G. Nardone, Andrea De Luca, Claudio Maria Mastroianni, Gioacchino Angarano, Chiara Dentone, Renato Maserati, Anna Maria Piscaglia, Tiziana Quirino, Giuseppe Tarantino, M. Lichtner, Antonio Chirianni, Giuseppina Brancaccio, S. Paganin, Alfredo Alberti, Silvia Corradori, Edoardo G. Giannini, Carlo Torti, Chiara Boarini, Raffaele Cozzolongo, Marco Di Stefano, Alessandro Soria, Paolo Tundi, Giovanni Cassola, Debora Angrisani, Antonio Grieco, Cecilia Pravadelli, Giuliano Rizzardini, Roberto Gulminetti, Vincenzo Messina, Maria Rendina, Massimo Pirisi, Irene Cacciola, Roberto Ganga, Raffaella Lionetti, Paolo Calabrese, Laura Ponti, Filomena Simeone, Maurizio Russello, Monica Monti, Nicola Boffa, Pierluigi Tarquini, Franco Capra, Ivo Avancini, Domenico Sansonno, Stefano Fagiuoli, Michele Barone, Giacomo Vecchiet, Salvatore Rizzo, Carlo Federico Perno, Teresa Santantonio, Pierluigi Toniutto, Massimo Zuin, Nicola Caporaso, Alessandra Orlandini, Grazielle Marie Pigozzi, Martina Felder, Antonio Cristaudo, Roberto Cecere, Massimo Marignani, Vincenza Calvaruso, G. Abbati, Domenico Potenza, Maria Chiara Piras, Mario Rizzetto, Serena Cima, Marco delle Monache, Alessio Aghemo, D. Ieluzzi, Guglielmo Borgia, Giampaolo Corti, Paolo Poggio, Manuela Merli, Elena Danieli, Andrea Giacometti, Massimo Andreoni, Antonino Picciotto, Mario Angelico, Benedetta Canovari, Sara Piovesan, Anna Linda Zignego, Antonio Benedetti, Emanuele Durante, Erica Villa, Marcello Persico, Antonio Patrizio Termite, Barbara Coco, Maria Vinci, Lucio Boglione, Cristina Rossi, Paolo Angeli, Massimo Memoli, Maria Teresa Giordani, Massimo De Luca, Luisa Pasulo, Vincenzo Vullo, Mario Melazzini, Attilio Solinas, Pietro Gatti, Michele Guerra, Silvia Martini, Antonio Ascione, Massimo Puoti, Roberto Cauda, Giovanna Onnelli, Silvia Magnani, Salvatore Madonna, Giovanni Raimondo, Marco Tabone, Gloria Taliani, Dante Romagnoli, Aldo Marrone, Umberto Vespasiani Gentilucci, Luca Miele, Marcello Tavio, Andrea Antinori, Giampiero D'Offizi, Mirella Onofrio, Valentina Iodice, Lucio Cosco, Guido Piai, Luca Pani, Francesca Ceccherini Silberstein, Simona Montilla, Marco Lenzi, Luca Fontanella, Alessandro Federico, Carlo Ferrari, Giustino Parruti, Antonio Di Biagio, Gabriella Verucchi, Fabio Marsetti, Michele Milella, Maria Grazia Rumi, Antonio Izzi, Marco Marzioni, Francesca Donato, Vanni Borghi, Mariano Quartini, Massimo Colombo, Michele Imparato, Giovanni Battista Gaeta, P.L. Blanc, Alfredo Di Leo, Nicola Coppola, Alessandro Chiodera, Ivana Maida, Davide Campagnolo, Cinzia Antonini, Antonietta Romano, A. Gianstefani, Katia Falasca, Massimo Levrero, Gaetano Serviddio, Maria Paola Trotta, Olivia Morelli, Salvatore Petta, Elisabetta Teti, Maria Rita Parisi, Pietro Andreone, Ascione, Antonio, De Luca, Massimo, Melazzini, Mario, Montilla, Simona, Trotta, Maria Paola, Petta, Salvatore, Puoti, Massimo, Sangiovanni, Vincenzo, Messina, Vincenzo, Bruno, Savino, Izzi, Antonio, Villa, Erica, Aghemo, Alessio, Zignego, Anna Linda, Orlandini, Alessandra, Fontanella, Luca, Gasbarrini, Antonio, Marzioni, Marco, Giannini, Edoardo G., Craxì, Antonio, Abbati, Giuseppe, Alberti, Alfredo, Andreone, Pietro, Andreoni, Massimo, Angeli, Paolo, Angelico, Mario, Angarano, Gioacchino, Angrisani, Debora, Antinori, Andrea, Antonini, Cinzia, Avancini, Ivo, Barone, Michele, Bruno, Raffaele, Benedetti, Antonio, Bernabucci, Veronica, Blanc, Pier, Boarini, Chiara, Boffa, Nicola, Boglione, Lucio, Borghi, Vanni, Borgia, Guglielmo, Brancaccio, Giuseppina, Brunetto, Maurizia, Cacciola, Irene, Calabrese, Paolo, Calvaruso, Vincenza, Campagnolo, Davide, Canovari, Benedetta, Caporaso, Nicola, Capra, Franco, Carolo, Giada, Cassola, Giovanni, Castelli, Francesco, Cauda, Roberto, Silberstein, Francesca Ceccherini, Cecere, Roberto, Chessa, Luchino, Chiodera, Alessandro, Chirianni, Antonio, Ciancio, Alessia, Cima, Serena, Coco, Barbara, Colombo, Massimo, Coppola, Nicola, Corti, Giampaolo, Cosco, Lucio, Corradori, Silvia, Cozzolongo, Raffaele, Cristaudo, Antonio, Danieli, Elena, Monforte, Antonella D’Arminio, Monache, Marco delle, Del Poggio, Paolo, de Luca, Andrea, Dentone, Chiara, Di Biagio, Antonio, Di Leo, Alfredo, Di Perri, Giovanni, Di Stefano, Marco, D’Offizi, Giampiero, Donato, Francesca, Durante, Emanuele, Erne, Elke, Fagiuoli, Stefano, Falasca, Katia, Federico, Alessandro, Felder, Martina, Ferrari, Carlo, Gaeta, Giovanni Battista, Ganga, Roberto, Gatti, Pietro, Giacomet, Vania, Giacometti, Andrea, Gianstefani, Alice, Giordani, Maria, Giorgini, Alessia, Grieco, Antonio, Guerra, Michele, Gulminetti, Roberto, Ieluzzi, Donatella, Imparato, Michele, Iodice, Valentina, La Monica, Silvia, Lazzarin, Adriano, Lenzi, Marco, Levrero, Massimo, Lichtner, Myriam, Lionetti, Raffaella, Guercio, Carmela Lo, Madonna, Salvatore, Magnani, Silvia, Maida, Ivana, Marignani, Massimo, Marrone, Aldo, Marsetti, Fabio, Martini, Silvia, Masarone, Mario, Maserati, Renato, Mastroianni, Claudio Maria, Memoli, Massimo, Menzaghi, Barbara, Merli, Manuela, Miele, Luca, Milella, Michele, Mondelli, Mario, Montalbano, Marzia, Monti, Monica, Morelli, Olivia, Morisco, Filomena, Nardone, Gaetano, Novara, Sergio, Onnelli, Giovanna, Onofrio, Mirella, Paganin, Simona, Pani, Luca, Parisi, Maria Rita, Parruti, Giustino, Pasquazzi, Caterina, Pasulo, Luisa, Perno, Carlo Federico, Persico, Marcello, Piai, Guido, Picciotto, Antonino, Pigozzi, Grazielle Marie, Piovesan, Sara, Piras, Maria Chiara, Pirisi, Massimo, Piscaglia, Anna Maria, Ponti, Laura, Potenza, Domenico, Pravadelli, Cecilia, Quartini, Mariano, Quirino, Tiziana, Raimondo, Giovanni, Rapaccini, Gian Ludovico, Rendina, Maria, Rizzardini, Giuliano, Rizzetto, Mario, Rizzo, Salvatore, Romagnoli, Dante, Romano, Antonietta, Rossi, Cristina, Rumi, Maria Grazia, Russello, Maurizio, Russo, Francesca Paolo, Russo, Maria Luisa, Sansonno, Domenico Ettore, Santantonio, Teresa Antonia, Saracco, Giorgio, Schimizzi, Anna Maria, Serviddio, Gaetano, Simeone, Filomena, Solinas, Attilio, Soria, Alessandro, Tabone, Marco, Taliani, Gloria, Tarantino, Giuseppe, Tarquini, Pierluigi, Tavio, Marcello, Termite, Antonio, Teti, Elisabetta, Toniutto, Pierluigi, Torti, Carlo, Tundi, Paolo, Vecchiet, Giacomo, Verucchi, Gabriella, Gentilucci, Umberto Vespasiani, Vinci, Maria, Vullo, Vincenzo, Zolfino, Teresa, Zuin, Massimo, Ascione, A, De Luca, M, Melazzini, M, Montilla, S, Trotta, M, Petta, S, Puoti, M, Sangiovanni, V, Messina, V, Bruno, S, Izzi, A, Villa, E, Aghemo, A, Zignego, A, Orlandini, A, Fontanella, L, Gasbarrini, A, Marzioni, M, Giannini, E, Craxi, A, Abbati, G, Alberti, A, Andreone, P, Andreoni, M, Angeli, P, Angelico, M, Angarano, G, Angrisani, D, Antinori, A, Antonini, C, Avancini, I, Barone, M, Bruno, R, Benedetti, A, Bernabucci, V, Blanc, P, Boarini, C, Boffa, N, Boglione, L, Borghi, V, Borgia, G, Brancaccio, G, Brunetto, M, Cacciola, I, Calabrese, P, Calvaruso, V, Campagnolo, D, Canovari, B, Caporaso, N, Capra, F, Carolo, G, Cassola, G, Castelli, F, Cauda, R, Silberstein, F, Cecere, R, Chessa, L, Chiodera, A, Chirianni, A, Ciancio, A, Cima, S, Coco, B, Colombo, M, Coppola, N, Corti, G, Cosco, L, Corradori, S, Cozzolongo, R, Cristaudo, A, Danieli, E, Monforte, A, Monache, M, Del Poggio, P, de Luca, A, Dentone, C, Di Biagio, A, Di Leo, A, Di Perri, G, Di Stefano, M, D'Offizi, G, Donato, F, Durante, E, Erne, E, Fagiuoli, S, Falasca, K, Federico, A, Felder, M, Ferrari, C, Gaeta, G, Ganga, R, Gatti, P, Giacomet, V, Giacometti, A, Gianstefani, A, Giordani, M, Giorgini, A, Grieco, A, Guerra, M, Gulminetti, R, Ieluzzi, D, Imparato, M, Iodice, V, La Monica, S, Lazzarin, A, Lenzi, M, Levrero, M, Lichtner, M, Lionetti, R, Guercio, C, Madonna, S, Magnani, S, Maida, I, Marignani, M, Marrone, A, Marsetti, F, Martini, S, Masarone, M, Maserati, R, Mastroianni, C, Memoli, M, Menzaghi, B, Merli, M, Miele, L, Milella, M, Mondelli, M, Montalbano, M, Monti, M, Morelli, O, Morisco, F, Nardone, G, Novara, S, Onnelli, G, Onofrio, M, Paganin, S, Pani, L, Parisi, M, Parruti, G, Pasquazzi, C, Pasulo, L, Perno, C, Persico, M, Piai, G, Picciotto, A, Pigozzi, G, Piovesan, S, Piras, M, Pirisi, M, Piscaglia, A, Ponti, L, Potenza, D, Pravadelli, C, Quartini, M, Quirino, T, Raimondo, G, Rapaccini, G, Rendina, M, Rizzardini, G, Rizzetto, M, Rizzo, S, Romagnoli, D, Romano, A, Rossi, C, Rumi, M, Russello, M, Russo, F, Russo, M, Sansonno, D, Santantonio, T, Saracco, G, Schimizzi, A, Serviddio, G, Simeone, F, Solinas, A, Soria, A, Tabone, M, Taliani, G, Tarantino, G, Tarquini, P, Tavio, M, Termite, A, Teti, E, Toniutto, P, Torti, C, Tundi, P, Vecchiet, G, Verucchi, G, Gentilucci, U, Vinci, M, Vullo, V, Zolfino, T, and Zuin, M

Subjects
Cyclopropanes, Liver Cirrhosis, Male, Cirrhosis, Dasabuvir, Elderly, Ombitasvir, Paritaprevir, Aged, 80 and over, Anilides, Antiviral Agents, Biomarkers, Carbamates, Female, Hepacivirus, Hepatitis C, Chronic, Humans, Macrocyclic Compounds, Ribavirin, Ritonavir, Sulfonamides, Treatment Outcome, Uracil, Drug Therapy, Combination, Genotype, Cirrhosis, Dasabuvir, Elderly, Ombitasvir, Paritaprevir, Microbiology (medical), Infectious Diseases, Aged, 80 and over, Hepatitis C, Chronic, Drug Therapy, Combination, Microbiology (medical), Infectious Diseases, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, 2-Naphthylamine, Medicine, 030212 general & internal medicine, Valine, General Medicine, 030211 gastroenterology & hepatology, Macrocyclic Compound, medicine.drug, Human, medicine.medical_specialty, Proline, Lactams, Macrocyclic, Settore MED/12 - GASTROENTEROLOGIA, Liver Cirrhosi, Sulfonamide, 03 medical and health sciences, Internal medicine, Decompensation, Hepatitis, Antiviral Agent, Cirrhosi, Hepaciviru, business.industry, Settore MED/09 - MEDICINA INTERNA, Anilide, Biomarker, medicine.disease, chemistry, Carbamate, business
Abstract

Purpose: To analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65years. Methods: We collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100mg) and twice-daily dasabuvir (250mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12weeks after the end of treatment (SVR12). Results: Patients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5g/dL (OR 2.04: 95% CI 1.0–4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3–9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2mg/dL (OR 4.9: 95% CI 1.17–20.71, p = 0.029) as the only variable independently associated with SVR12. Conclusion: Our findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65.

Published
2018

41. Activation of the developmental pathway neurogenin-3/microRNA-7a regulates cholangiocyte proliferation in response to injury

Author

Laura Agostinelli, Chiara Rychlicki, Antonio Benedetti, Jesus M. Banales, Stefania Saccomanno, Luciano Trozzi, Samuele De Minicis, Luca Maroni, E. Mingarelli, Cinzia Candelaresi, Gianluca Svegliati Baroni, and Marco Marzioni

Subjects
medicine.medical_specialty, Small interfering RNA, Gene knockdown, Hepatology, biology, Cell growth, Cell, Cholangiocyte proliferation, biology.organism_classification, Neogenesis, Cell biology, Endocrinology, medicine.anatomical_structure, Internal medicine, microRNA, medicine, Signal transduction
Abstract

The activation of the biliary stem-cell signaling pathway hairy and enhancer of split 1/pancreatic duodenal homeobox-1 (Hes-1/PDX-1) in mature cholangiocytes determines cell proliferation. Neurogenin-3 (Ngn-3) is required for pancreas development and ductal cell neogenesis. PDX-1-dependent activation of Ngn-3 initiates the differentiation program by inducing microRNA (miR)−7 expression. Here we investigated the role Ngn-3 on cholangiocyte proliferation. Expression levels of Ngn-3 and miR-7 isoforms were tested in cholangiocytes from normal and cholestatic human livers. Ngn-3 was knocked-down in vitro in normal rat cholangiocytes by short interfering RNA (siRNA). In vivo, wild-type and Ngn-3-heterozygous (+/−) mice were subjected to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding (a model of sclerosing cholangitis) or bile duct ligation (BDL). In the liver, Ngn-3 is expressed specifically in cholangiocytes of primary sclerosing cholangitis (PSC) patients and in mice subjected to DDC or BDL, but not in normal human and mouse livers. Expression of miR-7a-1 and miR-7a-2 isoforms, but not miR-7b, was increased in DDC cholangiocytes compared to normal ones. In normal rat cholangiocytes, siRNA against Ngn-3 blocked the proliferation stimulated by exendin-4. In addition, Ngn-3 knockdown neutralized the overexpression of insulin growth factor-1 (IGF1; promitotic effector) observed after exposure to exendin-4, but not that of PDX-1 or VEGF-A/C. Oligonucleotides anti-miR-7 inhibited the exendin-4-induced proliferation in normal rat cholangiocytes, but did not affect Ngn-3 synthesis. Biliary hyperplasia and collagen deposition induced by DDC or BDL were significantly reduced in Ngn-3+/− mice compared to wild-type. Conclusion: Ngn-3-dependent activation of miR-7a is a determinant of cholangiocyte proliferation. These findings indicate that the reacquisition of a molecular profile typical of organ development is essential for the biological response to injury by mature cholangiocytes. (Hepatology 2014;60:1324–1335)

Published
2014
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42. White Paper of Italian Gastroenterology: Delivery of services for digestive diseases in Italy: Weaknesses and strengths

Author

Giovanni Ferrini, Antonietta Bianco, Paolo Ravelli, Michele Cicala, Aurora Bortoli, Renato Cannizzaro, Piero Leo, Emanuele Meroni, Paolo Spolaore, Gianni Gatto, Manola Lisiero, Filippo Antonini, Angelo Zullo, Antonio Balzano, Sabrina Bianchi, Emanuele Scafato, Giancarlo Spinzi, Lucio Amitrano, Luca Frulloni, Renzo Gullotta, Eugenio Brunelli, O. Triossi, Italo Sorrentini, Mario Marini, Diego Fregonese, Paolo Borro, Danilo Badiali, Giovanni Sansoè, R. Cuppone, Enrico Corazziari, Luciana Framarin, L.M. Montalbano, P. Brosolo, T. Federici, Gianni Testino, Alessandro Sumberaz, Attilio Solinas, A. Salmi, Renato Marin, L. Buri, Ivo Boskovski, Italo Stroppa, Ivano Lorenzini, Giovanni Di Matteo, Salvatore Cucchiara, Ilaria Tarantino, Cesare Hassan, Nicola Muscatiello, Giovanni M. Claar, Stefano Bellentani, Luca Barresi, Francesco Guardascione, Mario Del Piano, Mario Angelico, Luigi Vilardo, Paolo Usai-Satta, Luigi Pasquale, G. Scarpulla, Santino Marchi, Roberto Penagini, Vincenzo Gallo, Luigi Familiari, Francesco Cupella, Livio Cipolletta, Egiziano Peruzzi, Gianfranco Delle Fave, Salvatore Adamo, Luca Elli, S. Crotta, Maurizio Zilli, Antonio Cilona, Bastianello Germanà, Francesco Pallone, Leonardo Tammaro, P. Fracasso, Fabio Pace, Giovanni de Pretis, Alfredo Di Leo, Pietro Familiari, Giorgio Frosini, Giuseppe Milazzo, Maria Teresa Bardella, Michele Di Cillo, Fausto Chilovi, Enrico Ciliberto, Floriano Rosina, Alessandro Zambelli, Franco Bazzoli, Maria Rendina, Francesco Ridolfi, Franco Radaelli, Massimo Conio, Massimiliano Biagini, Massimo Bellini, Claudio De Angelis, Maria Caterina Parodi, Guido Costamagna, Pietro Fusaroli, Gioacchino Leandro, Pier Alberto Testoni, Piero Loriga, Ornella Ancarani, Giacomo Germani, Fabio Farinati, Giancarlo Caletti, Sergio Morini, Carlo Gemme, Antonio Benedetti, Adriano Lauri, Gianmarco Fava, Mauro Borzio, Mario Traina, Marcello Ingrosso, Amuso M, Giampiero Macarri, Rosa Filiberti, A. Marino, Cinzia Quondamcarlo, Francesco Bortoluzzi, L. Piazzi, Raffaele Manta, Salvatore De Stefano, Rita Conigliaro, Michele De Boni, Andrea Ederle, Clara Virgilio, Marco Soncini, Mario Cottone, G.C. Sturniolo, Anna Kohn, Maurizia Rossana Brunetto, Matteo Neri, Elisabetta Buscarini, Nicola D'Imperio, Gennaro D'Amico, Patrizia Burra, Antonio Craxì, S. Peralta, Alessandro Natali, Giuseppe Del Favero, Giovanni Actis, Andrea Nucci, Dario Conte, Stefano Fagiuoli, Santo Monastra, Fabrizio Magnolfi, Buscarini, E, Conte, D, Cannizzaro, R, Bazzoli, F, De Boni, M, Delle Fave, G, Farinati, F, Ravelli, P, Testoni, P, Lisiero, M, Spolaore, P, Fagiuoli, S, Testoni, PIER ALBERTO, Italian Association of Hospital, Gastroenterologist, Endoscopists, Italian Society of, Endoscopy, Italian Society of, Gastroenterology, Buscarini E, Conte D, Cannizzaro R, Bazzoli F, De Boni M, Fave GD, Farinati F, Ravelli P, Testoni PA, Lisiero M, Spolaore P, Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO), Italian Society of Endoscopy (SIED), Italian Society of Gastroenterology (SIGE): [.., Pietro Fusaroli, and ]

Subjects
Male, Gastrointestinal Diseases, Treatment outcome, Diseases, Medical care, Gastroenterology, Cancer, Digestive diseases, Emergency, Gastrointestinal bleeding, Hospital discharge record, Hospital stay, Mortality, Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Emergencies, Female, Gastrointestinal Hemorrhage, Health Planning, Health Services, Health Services Needs and Demand, Hospital Mortality, Hospital Units, Humans, Incidence, Infant, Infant, Newborn, Italy, Length of Stay, Middle Aged, Prevalence, Societies, Medical, Treatment Outcome, Young Adult, Health services, White paper, Digestive disease, italy, 80 and over, Medicine, Hepatology, Settore MED/12 - Gastroenterologia, Incidence (epidemiology), Digestive diseases Emergency Gastroenterology Gastrointestinal bleeding Hospital discharge record Hospital stay Mortality, Christian ministry, gastroenterology, medicine.medical_specialty, Case mix index, Medical, Internal medicine, Cancer, Digestive diseases, Emergency, Gastroenterology, Gastrointestinal bleeding, Hospital discharge record, Hospital stay, Mortality, Preschool, business.industry, Newborn, Societies, business
Abstract

In 2011 the three major Italian gastroenterological scientific societies (AIGO, the Italian Society of Hospital Gastroenterologists and Endoscopists; SIED, the Italian Society of Endoscopy; SIGE, the Italian Society of Gastroenterology) prepared their official document aimed at analysing medical care for digestive diseases in Italy, on the basis of national and regional data (Health Ministry and Lombardia, Veneto, Emilia-Romagna databases) and to make proposals for planning of care. Digestive diseases were the first or second cause of hospitalizations in Italy in 1999–2009, with more than 1,500,000 admissions/year; however only 5–9% of these admissions was in specialized Gastroenterology units. Reported data show a better outcome in Gastroenterology Units than in non-specialized units: shorter average length of stay, in particular for admissions with ICD-9-CM codes proxying for emergency conditions (6.7 days versus 8.4 days); better case mix (higher average diagnosis-related groups weight in Gastroenterology Units: 1 vs 0.97 in Internal Medicine units and 0.76 in Surgery units); lower inappropriateness of admissions (16–25% versus 29–87%); lower in-hospital mortality in urgent admissions (2.2% versus 5.1%); for patients with urgent admissions due to gastrointestinnal haemorrhage, in-hospital mortality was 2.3% in Gastroenterology units versus 4.0% in others. The present document summarizes the scientific societies’ official report, which constitutes the “White paper of Italian Gastroenterology”

Published
2014
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43. Semaphorin 7A Contributes to TGF-β–Mediated Liver Fibrogenesis

Author

David A. Brenner, Federico Mocchegiani, Laura Agostinelli, Luciano Trozzi, Marco Marzioni, Samuele De Minicis, Cinzia Candelaresi, Chiara Rychlicki, Stefania Saccomanno, Cristina Millán, Marco Vivarelli, Gianluca Svegliati-Baroni, Antonio Benedetti, and Ramon Bataller

Subjects
Liver Cirrhosis, Male, Pathology, medicine.medical_specialty, Apoptosis, Smad Proteins, Inflammation, Semaphorins, Biology, GPI-Linked Proteins, Article, Pathology and Forensic Medicine, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigens, CD, Transforming Growth Factor beta, Fibrosis, Pulmonary fibrosis, Hepatic Stellate Cells, medicine, Animals, Humans, Extracellular Signal-Regulated MAP Kinases, Receptor, Cell Proliferation, 030304 developmental biology, Liver injury, 0303 health sciences, medicine.disease, 3. Good health, Mice, Inbred C57BL, Liver, Hepatic stellate cell, Cancer research, 030211 gastroenterology & hepatology, medicine.symptom, Hepatic fibrosis, Proto-Oncogene Proteins c-akt, Biomarkers, Signal Transduction, Transforming growth factor
Abstract

Semaphorin7A (SEMA7A) is a membrane-anchored protein involved in immune and inflammatory responses, exerting an effect on pulmonary fibrosis. Thus, we aimed to investigate the role of SEMA7A in hepatic fibrosis. Liver injury was induced in vivo by carbon tetrachloride i.p. injection or bile duct ligation in wild-type and SEMA7A knockout (KO) mice. Human and mouse liver samples and primary mouse hepatic cell populations were used for Western blot analysis, quantitative real-time RT-PCR, and immunohistochemistry. SEMA7A is highly expressed in hepatic stellate cells (HSCs). The expression of SEMA7A and its receptor β1-integrin subunit increase during liver injury and in activated HSCs. Transforming growth factor β–stimulated HSCs showed increased expression of SEMA7A in a SMAD2/3-independent manner, leading to increased expression of fibrogenic and inflammation markers. This pattern was significantly blunted in SEMA7A KO HSCs. Overexpression of SEMA7A in HSCs showed increased fibrogenic and inflammation markers expression. In vivo , SEMA7A KO mice treated with carbon tetrachloride and bile duct ligation developed reduced fibrosis versus wild-type mice. Moreover, SEMA7A expression increased in liver samples of patients with fibrosis versus healthy controls. SEMA7A was expressed in the liver and was increased in the course of liver fibrosis, both in mice and in humans. SEMA7A was mainly expressed in HSCs with respect to other cell types in the liver and plays a critical role in regulating fibrosis.

Published
2013
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44. Reviewer Acknowledgement

Author

Vered Abitbol, Laurent Abramowitz, Douglas G Adler, Timon Adolph, Alessio Aghemo, Carlo Agostoni, Jawad Ahmad, Guru Aithal, Raied Al Hameedi, Mohammad Al-Haddad, Emanuele Albano, Anna Alisi, Cristina Almansa, Piero Almasio, Marina Aloi, Gianfranco Alpini, Waddah A Alrefai, Domenico Alvaro, Paolo Angeli, Francesco Angelico, Mario Angelico, Vito Annese, Bruno Annibale, Filippo Antonini, Thomas Aparicio, Arcidiacono P.G., Sandro Ardizzone, Alberto Arezzo, Alessandro Armuzzi, Antonio Ascione, Harry Aslanian, Adolfo Francesco Attili, Luis Filipe Azevedo, Jean-Baptiste Bachet, Haibo Bai, John Baillie, Leonardo Baiocchi, Maria Elisabetta Baldassarre, Clara Balsano, Yajnavalka Banerjee, Giovanni Barbara, Maria Teresa Bardella, Edouard Bardou-Jacquet, Nicola Barnich, Todd H Baron, Maximilien Barret, Stefania Basili, Gabrio Bassotti, Giorgio Battaglia, Jacques Belghiti, Stefano Bellentani, Luca Saverio Belli, Massimo Bellini, Shomron Ben-Horin, Robert Benamouzig, Antonio Benedetti, Carsten Bergmann, Helga Bertani, Manuel Berzosa Corella, Federico Biagi, Antonietta Bianco, Anna Monica Bianco, Livia Biancone, Erwin Biecker, Jessica Rose Biesiekierski, Jean-Frédéric Blanc, Olivier Boillot, Emmanuel Boleslawski, Davide Bona, Margherita Bonamico, Jaume Bosch, Gilles Boschetti, Ivo Boskoski, Simona Bota, Guillaume Bouguen, Mathieu Boulin, Jérôme Boursier, Christian Boustière, Anne-Marie Bouvier, Giuseppina Brancaccio, Jean-Pierre Bronowicki, David Bruining, Maurizia Rossana Brunetto, Raffaele Bruno, Savino Bruno, Eugenia Bruzzese, Vered, Abitbol, Laurent, Abramowitz, Douglas, G Adler, Timon, Adolph, Alessio, Aghemo, Carlo, Agostoni, Jawad, Ahmad, Guru, Aithal, Raied Al, Hameedi, Mohammad, Al-Haddad, Emanuele, Albano, Anna, Alisi, Cristina, Almansa, Piero, Almasio, Marina, Aloi, Gianfranco, Alpini, Waddah, A Alrefai, Domenico, Alvaro, Paolo, Angeli, Francesco, Angelico, Mario, Angelico, Vito, Annese, Bruno, Annibale, Filippo, Antonini, Thomas, Aparicio, Arcidiacono, P. G., Sandro, Ardizzone, Alberto, Arezzo, Alessandro, Armuzzi, Antonio, Ascione, Harry, Aslanian, Adolfo Francesco, Attili, Luis Filipe, Azevedo, Jean-Baptiste, Bachet, Haibo, Bai, John, Baillie, Leonardo, Baiocchi, Maria Elisabetta, Baldassarre, Clara, Balsano, Yajnavalka, Banerjee, Giovanni, Barbara, Maria Teresa, Bardella, Edouard, Bardou-Jacquet, Nicola, Barnich, Todd, H Baron, Maximilien, Barret, Stefania, Basili, Gabrio, Bassotti, Giorgio, Battaglia, Jacques, Belghiti, Stefano, Bellentani, Luca Saverio, Belli, Massimo, Bellini, Shomron, Ben-Horin, Robert, Benamouzig, Antonio, Benedetti, Carsten, Bergmann, Helga, Bertani, Manuel Berzosa, Corella, Federico, Biagi, Antonietta, Bianco, Anna Monica, Bianco, Livia, Biancone, Erwin, Biecker, Jessica Rose, Biesiekierski, Jean-Frédéric, Blanc, Olivier, Boillot, Emmanuel, Boleslawski, Davide, Bona, Margherita, Bonamico, Jaume, Bosch, Gilles, Boschetti, Ivo, Boskoski, Simona, Bota, Guillaume, Bouguen, Mathieu, Boulin, Jérôme, Boursier, Christian, Boustière, Anne-Marie, Bouvier, Giuseppina, Brancaccio, Jean-Pierre, Bronowicki, David, Bruining, Maurizia Rossana, Brunetto, Raffaele, Bruno, Savino, Bruno, and Eugenia, Bruzzese

Published
2015

45. Nlrp3 Activation Induces Il-18 Synthesis and Affects the Epithelial Barrier Function in Reactive Cholangiocytes

Author

Samuele De Minicis, Debora Maria Giordano, Luciano Trozzi, C. Pinto, Chiara Rychlicki, Marco Marzioni, Antonio Benedetti, Tom H. Karlsen, Laura Agostinelli, Luca Maroni, Jesus M. Banales, Stefania Saccomanno, Gianluca Svegliati Baroni, and Espen Melum

Subjects
0301 basic medicine, medicine.medical_specialty, Inflammasomes, Cholangitis, Sclerosing, Immunoblotting, Cholangiocyte proliferation, Nod, Biology, Real-Time Polymerase Chain Reaction, Cholangiocyte, Pathology and Forensic Medicine, Proinflammatory cytokine, 03 medical and health sciences, Mice, Internal medicine, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, Humans, Receptor, Mice, Knockout, Gene knockdown, integumentary system, Interleukin-18, Inflammasome, Cell biology, 030104 developmental biology, Endocrinology, Interleukin 18, medicine.drug
Abstract

Microbial products are thought to influence the progression of cholangiopathies, in particular primary sclerosing cholangitis (PSC). Inflammasomes are molecular platforms that respond to microbial products through the synthesis of proinflammatory cytokines. We investigated the role of inflammasome activation in cholangiocyte response to injury. Nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing protein 3 (Nlrp3) expression was tested in cholangiocytes of normal and cholestatic livers. Effects of Nlrp3 activation induced by incubation with lipopolysaccharide and ATP was studied in vitro in normal and siRNA-Nlrp3 knocked-down cholangiocytes. Wild-type and Nlrp3 knockout ( Nlrp3 −/− ) mice were fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; a model of sclerosing cholangitis) for 4 weeks. Nlrp3 and its components were overexpressed in cholangiocytes of mice subjected to DDC and in patients affected by PSC. In vitro , Nlrp3 activation stimulated expression of Il-18 but not of Il-1β and Il-6. Nlrp3 activation had no effect on cholangiocyte proliferation but significantly decreased the expression of Zonulin-1 and E-cadherin, whereas Nlrp3 knockdown increased the permeability of cholangiocyte monolayers. In vivo , the DDC-stimulated number of cytokeratin-19–positive cells in the liver of wild-type animals was slightly reduced in Nlrp3 −/− mice, and expression of E-cadherin was reestablished. In conclusion, Nlrp3 is expressed in reactive cholangiocytes, in both murine models and patients with PSC. Activation of Nlrp3 leads to synthesis of proinflammatory cytokines and influences epithelial integrity of cholangiocytes.

Published
2016

46. Role and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in hepatic fibrosis

Author

David A. Brenner, Christoph H. Österreicher, Samuele De Minicis, Antonio Benedetti, Robert F. Schwabe, Katsumi Miyai, Yuzo Kodama, Ekihiro Seki, Yong Han Paik, Luciano Torozzi, and Johannes Kluwe

Subjects
Liver Cirrhosis, Male, Kupffer Cells, Liver cytology, Biology, Article, Mice, chemistry.chemical_compound, Methionine, Fibrosis, Hepatic Stellate Cells, medicine, Animals, Ligation, Bone Marrow Transplantation, Mice, Knockout, Transplantation Chimera, Hepatology, Nicotinamide, Carbon Tetrachloride Poisoning, NADPH Oxidases, medicine.disease, Molecular biology, Choline Deficiency, Mice, Inbred C57BL, Transplantation, B vitamins, Liver, chemistry, Biochemistry, Hepatic stellate cell, Bile Ducts, Lipid Peroxidation, Reactive Oxygen Species, Hepatic fibrosis, Nicotinamide adenine dinucleotide phosphate
Abstract

Reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate oxidase (NOX) is required for liver fibrosis. This study investigates the role of NOX in ROS production and the differential contribution of NOX from bone marrow (BM)-derived and non-BM-derived liver cells. Hepatic fibrosis was induced by bile duct ligation (BDL) for 21 days or by methionine-choline-deficient (MCD) diet for 10 weeks in wild-type (WT) mice and mice deficient in p47phox (p47phox knockout [KO]), a component of NOX. The p47phox KO chimeric mice were generated by the combination of liposomal clodronate injection, irradiation, and BM transplantation of p47phox KO BM into WT recipients and vice versa. Upon BDL, chimeric mice with p47phox KO BM-derived cells, including Kupffer cells, and WT endogenous liver cells showed a ∼25% reduction of fibrosis, whereas chimeric mice with WT BM-derived cells and p47phox KO endogenous liver cells, including hepatic stellate cells, showed a ∼60% reduction of fibrosis. In addition, p47phox KO compared to WT mice treated with an MCD diet showed no significant changes in steatosis and hepatocellular injury, but a ∼50% reduction in fibrosis. Cultured WT and p47phox KO hepatocytes treated with free fatty acids had a similar increase in lipid accumulation. Free fatty acids promoted a 1.5-fold increase in ROS production both in p47phox KO and in WT hepatocytes.NOX in both BM-derived and non-BM-derived cells contributes to liver fibrosis. NOX does not play a role in experimental steatosis and the generation of ROS in hepatocytes, but exerts a key role in fibrosis.

Published
2010
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47. Ethyl caffeate from Verdicchio wine: Chromatographic purification and in vivo evaluation of its antifibrotic activity

Author

Emanuele Bendia, Antonio Benedetti, Natale G. Frega, Emanuele Boselli, and Giuseppe Di Lecce

Subjects
Liver injury, Chromatography, Formic acid, Ethyl acetate, Filtration and Separation, Ethyl caffeate, Reversed-phase chromatography, medicine.disease, High-performance liquid chromatography, Analytical Chemistry, chemistry.chemical_compound, chemistry, N-Nitrosodimethylamine, medicine, Caffeic acid
Abstract

Ethyl caffeate (CfE, caffeic acid ethyl ester) was extracted from dealcoholized Verdicchio, a white wine from Marche (Italy) with ethyl acetate and then purified with semipreparative reversed-phase high-performance liquid chromatography (RP-HPLC) using an ODS2 column (25 cm x 20 mm id) at an isocratic flow of 5 mL/min (the mobile phase A was formic acid 4.5% in water and the mobile phase B was acetonitrile). The CfE extract administered intraperitoneally at 1 mumol/L in rats previously treated with 10 mg/kg dimethylnitrosamine was able to prevent the dimethylnitrosamine-induced loss in body and liver weight, as well as to reduce the degree of liver injury, as determined by alanine aminotransferase values and necroinflammatory score, after a 1-week treatment. This was associated with a reduced hepatic stellate cells activation (from 16.8 to 8.3% of smooth muscle actin positive parenchyma) and proliferation (from 11.3 to 5.5 cells/mm(2)). The collagen synthesis was also reduced: the percentage of Sirius Red positive parenchyma decreased from 21.7 to 7.2%. The CfE levels of Verdicchio wine determined with RP-HPLC-DAD were about 14 times the active levels tested in the in vivo test. CfE can be considered as a promising natural compound for future application in chronic liver disease.

Published
2009
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48. Serotonin Metabolism Is Dysregulated in Cholangiocarcinoma, which Has Implications for Tumor Growth

Author

Gianfranco Alpini, Gabriel Frampton, Marco Marzioni, Domenico Alvaro, Eugenio Gaudio, Sharon DeMorrow, Antonio Franchitto, Monique Coufal, Shelleyko Kopriva, Antonio Benedetti, Sum P. Lee, Paolo Onori, Francesca Bernuzzi, Pietro Invernizzi, Julie Venter, Alpini, G, Invernizzi, P, Gaudio, E, Venter, J, Kopriva, S, Bernuzzi, F, Onori, P, Franchitto, A, Coufal, M, Frampton, G, Alvaro, D, Lee, S, Marzioni, M, Benedetti, A, and Demorrow, S

Subjects
Male, Serotonin, Cancer Research, medicine.medical_specialty, Monoamine oxidase, Bile Duct Neoplasm, Biology, digestive system, Article, Cholangiocarcinoma, Mice, Chemicals And Cas Registry Numbers, Cell Line, Tumor, Internal medicine, Fenclonine, medicine, Animals, Humans, Monoamine Oxidase, neoplasms, Mice, Inbred BALB C, Animal, Cell growth, Bile duct, Cancer, medicine.disease, digestive system diseases, Bile Ducts, Intrahepatic, medicine.anatomical_structure, Endocrinology, Bile Duct Neoplasms, Oncology, biology.protein, Cancer research, Chromogranin A, Monoamine oxidase A, Human, medicine.drug
Abstract

Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. Symptoms are usually evident after blockage of the bile duct by the tumor, and at this late stage, they are relatively resistant to chemotherapy and radiation therapy. Therefore, it is imperative that alternative treatment options are explored. We present novel data indicating that the metabolism of serotonin is dysregulated in cholangiocarcinoma cell lines, compared with normal cholangiocytes, and tissue and bile from cholangiocarcinoma patients. Specifically, there was an increased expression of tryptophan hydroxylase 1 and a suppression of monoamine oxidase A expression (enzymes responsible for the synthesis and degradation of serotonin, respectively) in cholangiocarcinoma. This resulted in an increased secretion of serotonin from cholangiocarcinoma and increased serotonin in the bile from cholangiocarcinoma patients. Increased local serotonin release may have implications on cholangiocarcinoma cell growth. Serotonin administration increased cholangiocarcinoma cell growth in vitro, whereas inhibition of serotonin synthesis decreases tumor cell growth both in vitro and in vivo. The data presented here represent the first evidence that serotonin metabolism is dysregulated in cholangiocarcinoma and that modulation of serotonin synthesis may represent an alternative target for the development of therapeutic strategies. © 2008 American Association for Cancer Research., link_to_subscribed_fulltext

Published
2008
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49. VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: the ALICE-1 study

Author

Mario Scartozzi, Luca Faloppi, Gianluca Svegliati Baroni, Cristian Loretelli, Massimo Iavarone, Pierluigi Toniutto, Giammarco Fava, Samuele De Minicis, Alessandra Mandolesi, Maristella Bianconi, Riccardo Giampieri, Floriana Facchetti, Davide Bitetto, Sara Vavassori, Stefano Gemini, Massimo Colombo, Italo Bearzi, Antonio Benedetti, Stefano Cascinu, PISCAGLIA, FABIO, GRANITO, ALESSANDRO, MARINELLI, SARA, VENERANDI, LAURA, D'ERRICO, ANTONIETTA, BOLONDI, LUIGI, Scartozzi, Mario, Faloppi, Luca, Svegliati Baroni, Gianluca, Loretelli, Cristian, Piscaglia, Fabio, Iavarone, Massimo, Toniutto, Pierluigi, Fava, Giammarco, De Minicis, Samuele, Mandolesi, Alessandra, Bianconi, Maristella, Giampieri, Riccardo, Granito, Alessandro, Facchetti, Floriana, Bitetto, Davide, Marinelli, Sara, Venerandi, Laura, Vavassori, Sara, Gemini, Stefano, D'Errico, Antonietta, Colombo, Massimo, Bolondi, Luigi, Bearzi, Italo, Benedetti, Antonio, Cascinu, Stefano, Mario Scartozzi, Luca Faloppi, Gianluca Svegliati Baroni, Cristian Loretelli, Fabio Piscaglia, Massimo Iavarone, Pierluigi Toniutto, Giammarco Fava, Samuele De Minici, Alessandra Mandolesi, Maristella Bianconi, Riccardo Giampieri, Alessandro Granito, Floriana Facchetti, Davide Bitetto, Sara Marinelli, Laura Venerandi, Sara Vavassori, Stefano Gemini, Antonietta D'Errico, Massimo Colombo, Luigi Bolondi, Italo Bearzi, Antonio Benedetti, and Stefano Cascinu

Subjects
Male, Vascular Endothelial Growth Factor A, VEGF, angiogenesis, hepatocellular carcinoma, rs2010963, rs4604006, single nucleotide polymorphisms, sorafenib, Adult, Aged, Antineoplastic Agents, Carcinoma, Hepatocellular, Cell Proliferation, Disease-Free Survival, Drug Resistance, Neoplasm, Female, Genotype, Humans, Liver Neoplasms, Lymphangiogenesis, Middle Aged, Neovascularization, Pathologic, Niacinamide, Phenylurea Compounds, Polymorphism, Single Nucleotide, Protein Kinase Inhibitors, Retrospective Studies, Treatment Outcome, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor Receptor-3, Antineoplastic Agent, single nucleotide polymorphism, Retrospective Studie, Neovascularization, Pathologic, Lymphangiogenesi, VEGF, angiogenesis, hepatocellular carcinoma, rs2010963, rs4604006, single nucleotide polymorphisms, sorafenib, Liver Neoplasm, Human, Phenylurea Compound, Carcinoma, Hepatocellular, Protein Kinase Inhibitor, Polymorphism, Single Nucleotide, neoplasms, angiogenesi, Drug Resistance, Neoplasm
Abstract

Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients' progression-free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF-A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF-C alleles T of rs4604006, G of rs664393, VEGFR-2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways.

Published
2014

50. Randomised controlled trial of mesalazine in IBS

Author

Luigi Benini, Bastianello Germanà, Cesare Cremon, Maurizio Vecchi, Matteo Neri, Giovanni Barbara, Michele Cicala, Rosario Cuomo, Vincenzo Stanghellini, Maria Lia Scribano, Franco Bazzoli, Antonio Benedetti, Paola Buldrini, Vito Annese, Giorgio Zoli, Marcello Rodi, Roberto Corinaldesi, Guido Basilisco, Paola Molteni, Massimo Bellini, A. Saggioro, Fabrizio Bossa, Barbara, Giovanni, Cremon, Cesare, Annese, Vito, Basilisco, Guido, Bazzoli, Franco, Bellini, Massimo, Benedetti, Antonio, Benini, Luigi, Bossa, Fabrizio, Buldrini, Paola, Cicala, Michele, Cuomo, Rosario, Germanà, Bastianello, Molteni, Paola, Neri, Matteo, Rodi, Marcello, Saggioro, Alfredo, Scribano, Maria Lia, Vecchi, Maurizio, Zoli, Giorgio, Corinaldesi, Roberto, and Stanghellini, Vincenzo

Subjects
Male, Abdominal pain, Intention to Treat Analysi, Anti-Inflammatory Agents, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Clinical endpoint, Medicine, Mesalamine, Irritable bowel syndrome, INFLAMMATORY CELLS, Anti-Inflammatory Agents, Non-Steroidal, Gastroenterology, Middle Aged, Intention to Treat Analysis, Treatment Outcome, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, medicine.symptom, Non-Steroidal, CLINICAL TRIALS, Human, Adult, medicine.medical_specialty, IRRITABLE BOWEL SYNDROME, Placebo, Drug Administration Schedule, NO, Follow-Up Studie, Neurogastroenterology, 03 medical and health sciences, Mesalazine, Double-Blind Method, Internal medicine, GUT INFLAMMATION, Humans, ABDOMINAL PAIN, Aged, Intention-to-treat analysis, business.industry, medicine.disease, Follow-Up Studies, Irritable Bowel Syndrome, Surgery, Clinical trial, chemistry, business
Abstract

Objective: Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS. Design: We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 weeks, and were followed for additional 12 weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time. Results: A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI -12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI -2.7% to 26.0%) and 5.9% (p=0.404; 95% CI -7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule. Conclusions: Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy. Trial registration number: ClincialTrials.gov number, NCT00626288.

Published
2016

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