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2. Influence of hydrology, hydraulics and temperature on Atlantic salmon habitat : modelling-based approaches for sustainable river management

Author

Fabris, Luca, Soulsby, Chris, Malcolm, Ian, and Tetzlaff, Doerthe

Subjects
550, Atlantic salmon, Hydrology, Stream measurements
Abstract

In this thesis, we improved our understanding of the effects of hydrology, stream hydraulics, and temperature on juvenile Atlantic salmon (Salmo salar L.) habitat. We demonstrated the key role played by stream morphology and flow regime on in-channel hydraulics and consequently on salmonid habitat. Additionally, we showed how riparian afforestation has potential to moderate climate change effects on stream temperature preserving freshwater ecosystems. The Girnock Burn is an upland Scottish river that has been intensively studied to investigate flow generation processes and stream temperature, and has served as a long-term monitoring site for Atlantic salmon population dynamics since 1966. The general approach applied consisted of combining different types of models including: hydraulic, fish habitat, hydrological and heat transfer models with long-term hydrological and climatic data sets, and digital terrain models (DTMs) at different spatio-temporal scales. Our results showed that the extensive presence of roughness elements (e.g. boulders and cobbles) is capable to provide some refuge areas for juvenile salmon fry for a wide range of flows. However, under extreme flow conditions, in-channel hydraulics might represent a limiting factor. Significant inter-site differences occurred and were consistent throughout the years. Evidence of long-term trend in fry habitat quality could be identified only in summer. Since more extreme flow regimes are expected in the future as a result of climate change, we also proposed a novel analytical approach that allowed us to assess the effects of hydroclimatic variation on fish populations outside the range of observations. Finally, we showed the potential of afforestation to reduce daily stream temperature range, moderating both low and high peaks of more than 2 ○C. This makes riparian shading a valuable mitigation strategy to contrast global warming effects on stream temperatures that should be considered for a sustainable catchment management.

Published
2018

3. Sex and Gender in Ageing and Longevity: Highlights from an International Course

Author

Candore, Giuseppina, primary, Accardi, Giulia, additional, Aiello, Anna, additional, Baggio, Giovannella, additional, Bellini, Tiziana, additional, Calabrese, Vittorio, additional, Carreca, Anna Paola, additional, Carreca, Ignazio, additional, Masucci, Anna, additional, Cattaneo, Monica, additional, Dato, Serena, additional, Bona, Danilo Di, additional, Fabris, Luca, additional, Gambino, Caterina, additional, Lorenzo, Gabriele Di, additional, Franceschi, Claudio, additional, Ligotti, Mattia Emanuela, additional, Manfrinato, Maria Cristina, additional, Puca, Annibale Alessandro, additional, Tamburello, Martina, additional, Vassallo, Roberta, additional, and Caruso, Calogero, additional

Published
2024
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5. Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

Author

Weismüller, Tobias J, Trivedi, Palak J, Bergquist, Annika, Imam, Mohamad, Lenzen, Henrike, Ponsioen, Cyriel Y, Holm, Kristian, Gotthardt, Daniel, Färkkilä, Martti A, Marschall, Hanns-Ulrich, Thorburn, Douglas, Weersma, Rinse K, Fevery, Johan, Mueller, Tobias, Chazouillères, Olivier, Schulze, Kornelius, Lazaridis, Konstantinos N, Almer, Sven, Pereira, Stephen P, Levy, Cynthia, Mason, Andrew, Naess, Sigrid, Bowlus, Christopher L, Floreani, Annarosa, Halilbasic, Emina, Yimam, Kidist K, Milkiewicz, Piotr, Beuers, Ulrich, Huynh, Dep K, Pares, Albert, Manser, Christine N, Dalekos, George N, Eksteen, Bertus, Invernizzi, Pietro, Berg, Christoph P, Kirchner, Gabi I, Sarrazin, Christoph, Zimmer, Vincent, Fabris, Luca, Braun, Felix, Marzioni, Marco, Juran, Brian D, Said, Karouk, Rupp, Christian, Jokelainen, Kalle, de Valle, Maria Benito, Saffioti, Francesca, Cheung, Angela, Trauner, Michael, Schramm, Christoph, Chapman, Roger W, Karlsen, Tom H, Schrumpf, Erik, Strassburg, Christian P, Manns, Michael P, Lindor, Keith D, Hirschfield, Gideon M, Hansen, Bettina E, Boberg, Kirsten M, and Group, International PSC Study

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Autoimmune Disease, Clinical Research, Liver Disease, Digestive Diseases - (Gallbladder), Inflammatory Bowel Disease, Digestive Diseases, Rare Diseases, Crohn's Disease, Oral and gastrointestinal, Adult, Age Distribution, Australia, Chi-Square Distribution, Cholangitis, Sclerosing, Colitis, Ulcerative, Crohn Disease, Disease Progression, Europe, Female, Humans, Incidence, Kaplan-Meier Estimate, Liver Transplantation, Male, Middle Aged, Multivariate Analysis, North America, Phenotype, Prognosis, Proportional Hazards Models, Retrospective Studies, Risk Assessment, Risk Factors, Sex Distribution, Time Factors, Young Adult, Risk Stratification, Immune-Mediated Liver Disease, Autoimmune Liver Disease, Cholestasis, International PSC Study Group, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsPrimary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC.MethodsWe performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates.ResultsOf the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002).ConclusionsIn an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.

Published
2017

6. Pinealectomy or light exposure exacerbates biliary damage and liver fibrosis in cholestatic rats through decreased melatonin synthesis

Author

Chen, Lixian, Zhou, Tianhao, Wu, Nan, O'Brien, April, Venter, Julie, Ceci, Ludovica, Kyritsi, Konstantina, Onori, Paolo, Gaudio, Eugenio, Sybenga, Amelia, Xie, Linglin, Wu, Chaodong, Fabris, Luca, Invernizzi, Pietro, Zawieja, David, Liangpunsakul, Suthat, Meng, Fanyin, Francis, Heather, Alpini, Gianfranco, Huang, Qiaobing, and Glaser, Shannon

Published
2019
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11. Angiopoietin-2 and the Vascular Endothelial Growth Factor Promote Migration and Invasion in Hepatocellular Carcinoma- and Intrahepatic Cholangiocarcinoma-Derived Spheroids.

Author

Romanzi, Adriana, Milosa, Fabiola, Marcelli, Gemma, Critelli, Rosina Maria, Lasagni, Simone, Gigante, Isabella, Dituri, Francesco, Schepis, Filippo, Cadamuro, Massimiliano, Giannelli, Gianluigi, Fabris, Luca, and Villa, Erica

Subjects
VASCULAR endothelial growth factors, ANGIOPOIETIN-2, EPITHELIAL-mesenchymal transition
Abstract

Aggressive hepatocellular carcinoma (HCC) overexpressing Angiopoietin-2 (ANG-2) (a protein linked with angiogenesis, proliferation, and epithelial–mesenchymal transition (EMT)), shares 95% of up-regulated genes and a similar poor prognosis with the proliferative subgroup of intrahepatic cholangiocarcinoma (iCCA). We analyzed the pro-invasive effect of ANG-2 and its regulator vascular endothelial growth factor (VEGF) on HCC and CCA spheroids to uncover posUsible common ways of response. Four cell lines were used: Hep3B and HepG2 (HCC), HuCC-T1 (iCCA), and EGI-1 (extrahepatic CCA). We treated the spheroids with recombinant human (rh) ANG-2 and/or VEGF and then observed the changes at the baseline, after 24 h, and again after 48 h. Proangiogenic stimuli increased migration and invasion capability in HCC- and iCCA-derived spheroids and were associated with a modification in EMT phenotypic markers (a decrease in E-cadherin and an increase in N-cadherin and Vimentin), especially at the migration front. Inhibitors targeting ANG-2 (Trebananib) and the VEGF (Bevacizumab) effectively blocked the migration ability of spheroids that had been stimulated with rh-ANG-2 and rh-VEGF. Overall, our findings highlight the critical role played by ANG-2 and the VEGF in enhancing the ability of HCC- and iCCA-derived spheroids to migrate and invade, which are key processes in cancer progression. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Intrahepatic Cholangiocarcinoma Developing in Patients with Metabolic Syndrome Is Characterized by Osteopontin Overexpression in the Tumor Stroma

Author

Cadamuro, Massimiliano, primary, Sarcognato, Samantha, additional, Camerotto, Riccardo, additional, Girardi, Noemi, additional, Lasagni, Alberto, additional, Zanus, Giacomo, additional, Cillo, Umberto, additional, Gringeri, Enrico, additional, Morana, Giovanni, additional, Strazzabosco, Mario, additional, Campello, Elena, additional, Simioni, Paolo, additional, Guido, Maria, additional, and Fabris, Luca, additional

Published
2023
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14. How 15-min City, Tactical Urbanism, and Superblock Concepts Are Affecting Major Cities in the Post-Covid-19 Era?

Author

Fabris, Luca Maria Francesco and Fabris, Luca Maria Francesco

Abstract

Producción Científica, This chapter analyses three strategies proposed to redefine current urban policies to deal with issues inherited from the contemporary city evolution. The case study analysis focuses on applying the concepts of 15-min City, Tactical Urbanism, and Superblock in global cities such as Barcelona, Shanghai, and Milan. Have these cities changed the urban environment and mobility patterns dealing with health, social, and economic inequities? Which have been the impacts of urban regeneration, governance, and inclusion towards achieving the Sustainable Development Goal 11, emphasizing the need for inclusivity and equitability in urban areas? These questions find the answer in three main aspects. First, the regeneration of the existing built environment; second, short-, medium-, and long-term governance issues; third, the concerns about the possible risk of gentrification. An introductive part explains the adopted methodology, follows an analysis of the three case studies, and, eventually, remarks on what we learned. Two are the primary outcomes: a comparison between different global cities and diverse ways to deal with the impacts of people-centered solutions for urban environments and an evaluation of 15-min City, Tactical Urbanism, and Superblocks feasible solutions for sustainable urban transition.

Published
2023

15. Intrahepatic Cholangiocarcinoma Developing in Patients with Metabolic Syndrome Is Characterized by Osteopontin Overexpression in the Tumor Stroma

Author

Cadamuro, M, Sarcognato, S, Camerotto, R, Girardi, N, Lasagni, A, Zanus, G, Cillo, U, Gringeri, E, Morana, G, Strazzabosco, M, Campello, E, Simioni, P, Guido, M, Fabris, L, Cadamuro, Massimiliano, Sarcognato, Samantha, Camerotto, Riccardo, Girardi, Noemi, Lasagni, Alberto, Zanus, Giacomo, Cillo, Umberto, Gringeri, Enrico, Morana, Giovanni, Strazzabosco, Mario, Campello, Elena, Simioni, Paolo, Guido, Maria, Fabris, Luca, Cadamuro, M, Sarcognato, S, Camerotto, R, Girardi, N, Lasagni, A, Zanus, G, Cillo, U, Gringeri, E, Morana, G, Strazzabosco, M, Campello, E, Simioni, P, Guido, M, Fabris, L, Cadamuro, Massimiliano, Sarcognato, Samantha, Camerotto, Riccardo, Girardi, Noemi, Lasagni, Alberto, Zanus, Giacomo, Cillo, Umberto, Gringeri, Enrico, Morana, Giovanni, Strazzabosco, Mario, Campello, Elena, Simioni, Paolo, Guido, Maria, and Fabris, Luca

Abstract

Metabolic syndrome (MetS) is a common condition closely associated with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). Recent meta-analyses show that MetS can be prodromal to intrahepatic cholangiocarcinoma (iCCA) development, a liver tumor with features of biliary differentiation characterized by dense extracellular matrix (ECM) deposition. Since ECM remodeling is a key event in the vascular complications of MetS, we aimed at evaluating whether MetS patients with iCCA present qualitative and quantitative changes in the ECM able to incite biliary tumorigenesis. In 22 iCCAs with MetS undergoing surgical resection, we found a significantly increased deposition of osteopontin (OPN), tenascin C (TnC), and periostin (POSTN) compared to the matched peritumoral areas. Moreover, OPN deposition in MetS iCCAs was also significantly increased when compared to iCCA samples without MetS (non-MetS iCCAs, n = 44). OPN, TnC, and POSTN significantly stimulated cell motility and the cancer-stem-cell-like phenotype in HuCCT-1 (human iCCA cell line). In MetS iCCAs, fibrosis distribution and components differed quantitatively and qualitatively from non-MetS iCCAs. We therefore propose overexpression of OPN as a distinctive trait of MetS iCCA. Since OPN stimulates malignant properties of iCCA cells, it may provide an interesting predictive biomarker and a putative therapeutic target in MetS patients with iCCA.

Published
2023

16. Ecosystem service value evaluation method for local-oriented rural water ecological governance : A case study on Shuiku Village in Shanghai

Author

Dong, Nannan, Fabris, Luca Maria Francesco, Wang, Yongnan, Chen, Xinyue, Dong, Nannan, Fabris, Luca Maria Francesco, Wang, Yongnan, and Chen, Xinyue

Abstract

Ecosystem service assessments play a crucial role in highlighting the importance of ecosystems in human life and guiding regional planning processes. This study examines the significance of rural ecosystems and their diverse ecological services, ranging from agricultural productivity to water purification and esthetic value. At present, the ecological restoration of rural riparian zones in China mainly relies on engineering standards as reference guidelines, lacking responses to surrounding land use patterns (including diverse ecological functional requirements) at the planning and design level. This paper proposes 17 assessment indicators for ecosystem services based on a case analysis of Shuiku Village in Shanghai. Through the evaluation of the supply-demand relationship of ecosystem services in the water network rural riparian zone, the paper suggests feasible restoration approaches based on a comprehensive evaluation of the ecological status to address the diverse needs of rural water ecosystems. The result indicated that using an ecosystem services evaluation framework can provide more precise analysis at a small scale.

Published
2023

17. Criteria for preclinical models of cholangiocarcinoma:scientific and medical relevance

Author

Calvisi, Diego F., Boulter, Luke, Vaquero, Javier, Saborowski, Anna, Fabris, Luca, Rodrigues, Pedro M., Coulouarn, Cédric, Castro, Rui E., Segatto, Oreste, Raggi, Chiara, van der Laan, Luc J.W., Carpino, Guido, Goeppert, Benjamin, Roessler, Stephanie, Kendall, Timothy J., Evert, Matthias, Gonzalez-Sanchez, Ester, Valle, Juan W., Vogel, Arndt, Bridgewater, John, Borad, Mitesh J., Gores, Gregory J., Roberts, Lewis, Marin, Jose J.G., Andersen, Jesper B., Alvaro, Domenico, Forner, Alejandro, Banales, Jesus M., Cardinale, Vincenzo, Macias, Rocio I.R., Vicent, Silve, Chen, Xin, Braconi, Chiara, Verstegen, Monique M.A., Fouassier, Laura, Scheiter, Alexander, Selaru, Florin M., Evert, Katja, Utpatel, Kirsten, Broutier, Laura, Cadamuro, Massimiliano, Huch, Meritxell, Goldin, Robert, Gradilone, Sergio A., Saito, Yoshimasa, Calvisi, Diego F., Boulter, Luke, Vaquero, Javier, Saborowski, Anna, Fabris, Luca, Rodrigues, Pedro M., Coulouarn, Cédric, Castro, Rui E., Segatto, Oreste, Raggi, Chiara, van der Laan, Luc J.W., Carpino, Guido, Goeppert, Benjamin, Roessler, Stephanie, Kendall, Timothy J., Evert, Matthias, Gonzalez-Sanchez, Ester, Valle, Juan W., Vogel, Arndt, Bridgewater, John, Borad, Mitesh J., Gores, Gregory J., Roberts, Lewis, Marin, Jose J.G., Andersen, Jesper B., Alvaro, Domenico, Forner, Alejandro, Banales, Jesus M., Cardinale, Vincenzo, Macias, Rocio I.R., Vicent, Silve, Chen, Xin, Braconi, Chiara, Verstegen, Monique M.A., Fouassier, Laura, Scheiter, Alexander, Selaru, Florin M., Evert, Katja, Utpatel, Kirsten, Broutier, Laura, Cadamuro, Massimiliano, Huch, Meritxell, Goldin, Robert, Gradilone, Sergio A., and Saito, Yoshimasa

Abstract

Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.

Published
2023

18. Criteria for preclinical models of cholangiocarcinoma:scientific and medical relevance

Author

Calvisi, Diego, Boulter, Luke, Vaquero, Javier, Saborowski, Anna, Fabris, Luca, Rodrigues, Pedro, Coulouarn, Cédric, Castro, Rui, Segatto, Oreste, Raggi, Chiara, van der Laan, Luc, Carpino, Guido, Goeppert, Benjamin, Roessler, Stephanie, Kendall, Timothy, Evert, Matthias, Gonzalez-Sanchez, Ester, Valle, Juan, Vogel, Arndt, Bridgewater, John, Borad, Mitesh, Gores, Gregory, Roberts, Lewis, Marin, Jose, Andersen, Jesper, Alvaro, Domenico, Forner, Alejandro, Banales, Jesus, Cardinale, Vincenzo, Macias, Rocio, Vicent, Silve, Chen, Xin, Braconi, Chiara, Verstegen, Monique, Fouassier, Laura, Scheiter, Alexander, Selaru, Florin, Evert, Katja, Utpatel, Kirsten, Broutier, Laura, Cadamuro, Massimiliano, Huch, Meritxell, Goldin, Robert, Gradilone, Sergio, Saito, Yoshimasa, University of Regensburg, University of Edinburgh, Instituto de Salud Carlos III [Madrid] (ISC), Hannover Medical School [Hannover] (MHH), Yale School of Medicine [New Haven, Connecticut] (YSM), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Universidade de Lisboa, Università degli Studi di Firenze = University of Florence (UniFI), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Università degli Studi di Roma 'Foro Italico', Heidelberg University Hospital [Heidelberg], University of Barcelona, Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), The Christie NHS Foundation Trust [Manchester, Royaume-Uni], University of Manchester [Manchester], University College of London [London] (UCL), Mayo Clinic, Mayo Clinic [Rochester], Universidad de Salamanca, University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Glasgow, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), The authors thank the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and the European H2020 COST Action CA18122. The authors also acknowledge the valuable contributions of the external advisory panel. C.C. is supported by Inserm, Université de Rennes 1 and by a grant from the French Ministry of Health and the French National Cancer Institute (PRT-K20-136), CHU Rennes, CLCC Eugène Marquis, Rennes. M.M.A.V. and L.J.W.v.d.L. are supported by Medical Delta Regenerative Medicine 4D (Generating complex tissues with stem cells and printing technology) and TKI-LSH grant EMC-LSH19002. S.R. is supported by the German Research Foundation (DFG, project no. 314905040 and no. 493697503) and by German Cancer Aid (Deutsche Krebshilfe, project no. 70113922). S.V. is supported by Ministerio de Ciencia, Innovación y Universidades, Convocatoria 2019 para incentivar la Incorporación Estable de Doctores (IED2019-001007-I), by FEDER/Ministerio de Ciencia, Innovación y Universidades – Agencia Estatal de Investigación (PID2020‐116344‐RB‐100) and by the Government of Navarra-Health Research Department (58, and 2018). J.V. is funded by Ministerio de Ciencia e Innovación, part of Agencia Estatal de Investigación (AEI), through the Retos Investigación grant number PID2019-108651RJ-I00/DOI 10.13039/501100011033. The authors thank CERCA Programme/Generalitat de Catalunya for institutional support. R.I.R.M. and J.J.G.M. are supported by Instituto de Salud Carlos III, Spain (PI20/00189, PI19/00819) co-funded by the European Union. L. Fouassier belongs to a team supported by the Fondation pour la Recherche Médicale (Equipe FRM 2020 no. EQU202003010517) and is supported by Inserm and Sorbonne Université, INCa and ITMO Cancer of Aviesan within the framework of the 2021–2030 Cancer Control Strategy, on funds administered by Inserm.

Subjects
Hepatology, [SDV]Life Sciences [q-bio], Gastroenterology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Abstract

International audience; Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.

Published
2023

20. New case of syncytial giant-cell variant of hepatocellular carcinoma in a pediatric patient withHNF1Bdeficiency: does it fit with the syndrome?

Author

Pinon, Michele, primary, Gambella, Alessandro, additional, Giugliano, Laura, additional, Chiadò, Cristina, additional, Kalantari, Silvia, additional, Bracciamà, Valeria, additional, Deaglio, Silvia, additional, Tinti, Davide, additional, Peruzzi, Licia, additional, Cotti, Roberta, additional, Catalano, Silvia, additional, Cadamuro, Massimiliano, additional, Fabris, Luca, additional, Calvo, Pier Luigi, additional, and Romagnoli, Renato, additional

Published
2022
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24. Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry

Author

Medicina, Medikuntza, Izquierdo Sánchez, Laura, Lamarca, Angela, La Casta, Adelaida, Buettner, Stefan, Utpatel, Kirsten, Klümpen, Heinz-Josef, Adeva, Jorge, Vogel, Arndt, Lleo, Ana, Fabris, Luca, Ponz-Sarvise, Mariano, Brustia, Raffaele, Cardinale, Vincenzo, Braconi, Chiara, Vidili, Gianpaolo, Jamieson, Nigel B., Macias, Rocio IR., Jonas, Jan Philipp, Marzioni, Marco, Hołówko, Wacław, Folseraas, Trine, Kupčinskas, Juozas, Sparchez, Zeno, Krawczyk, Marcin, Krupa, Łukasz, Scripcariu, Viorel, Grazi, Gian Luca, Landa Magdalena, Ana, Ijzermans, Jan NM., Evert, Katja, Erdmann, Joris I., López-López, Flora, Saborowski, Anna, Scheiter, Alexander, Santos Laso, Álvaro, Carpino, Guido, Andersen, Jesper B., Marin, Jose JG., Alvaro, Domenico, Bujanda Fernández de Pierola, Luis, Forner, Alejandro, Valle, Juan W., Koerkamp, Bas Groot, Bañales Asurmendi, Jesús María, Medicina, Medikuntza, Izquierdo Sánchez, Laura, Lamarca, Angela, La Casta, Adelaida, Buettner, Stefan, Utpatel, Kirsten, Klümpen, Heinz-Josef, Adeva, Jorge, Vogel, Arndt, Lleo, Ana, Fabris, Luca, Ponz-Sarvise, Mariano, Brustia, Raffaele, Cardinale, Vincenzo, Braconi, Chiara, Vidili, Gianpaolo, Jamieson, Nigel B., Macias, Rocio IR., Jonas, Jan Philipp, Marzioni, Marco, Hołówko, Wacław, Folseraas, Trine, Kupčinskas, Juozas, Sparchez, Zeno, Krawczyk, Marcin, Krupa, Łukasz, Scripcariu, Viorel, Grazi, Gian Luca, Landa Magdalena, Ana, Ijzermans, Jan NM., Evert, Katja, Erdmann, Joris I., López-López, Flora, Saborowski, Anna, Scheiter, Alexander, Santos Laso, Álvaro, Carpino, Guido, Andersen, Jesper B., Marin, Jose JG., Alvaro, Domenico, Bujanda Fernández de Pierola, Luis, Forner, Alejandro, Valle, Juan W., Koerkamp, Bas Groot, and Bañales Asurmendi, Jesús María

Abstract

Background & Aims: Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. Methods: The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. Results: Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/ obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA199 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. Conclusion: CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therap

Published
2022

25. Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models.

Author

Fisiología, Fisiologia, Olaizola Rebe, Paula, Lee-Law, Pui Y., García Fernández de Barrena, Maite, Álvarez Asiain, Laura, Cadamuro, Massimiliano, Azkargorta, Mikel, O’Rourke, Colm J., Caballero Camino, Francisco Javier, Olaizola, Irene, Rodríguez Macías, Rocío Isabel, García Marín, Jose Juan, Serrano Maciá, Marina, Martinez Chantar, Maria Luz, Avila, Matias, Aspichueta Celaá, Patricia, CALVISI, Diego Francesco, Evert, Matthias, Fabris, Luca, Castro, Rui, Elortza, Felix, Andersen, Jesper B., Bujanda Fernández de Pierola, Luis, Rodrigues, Pedro M., Perugorria, Maria Jesus, Bañales Asurmendi, Jesús María, Fisiología, Fisiologia, Olaizola Rebe, Paula, Lee-Law, Pui Y., García Fernández de Barrena, Maite, Álvarez Asiain, Laura, Cadamuro, Massimiliano, Azkargorta, Mikel, O’Rourke, Colm J., Caballero Camino, Francisco Javier, Olaizola, Irene, Rodríguez Macías, Rocío Isabel, García Marín, Jose Juan, Serrano Maciá, Marina, Martinez Chantar, Maria Luz, Avila, Matias, Aspichueta Celaá, Patricia, CALVISI, Diego Francesco, Evert, Matthias, Fabris, Luca, Castro, Rui, Elortza, Felix, Andersen, Jesper B., Bujanda Fernández de Pierola, Luis, Rodrigues, Pedro M., Perugorria, Maria Jesus, and Bañales Asurmendi, Jesús María

Abstract

[EN] BACKGROUND & AIMS: Cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant tumors associated with dismal prognosis. Alterations in post-translational modifications (PTMs), including NEDDylation, result in abnormal protein dynamics, cell disturbances and disease. Herein, we investigate the role of NEDDylation in CCA development and progression. METHODS: Levels and functions of NEDDylation, together with response to pevonedistat (NEDDylation inhibitor) or CRISPR/Cas9 against NAE1 were evaluated invitro, invivo and/or in patients with CCA. The development of preneoplastic lesions in Nae1+/- mice was investigated using an oncogene-driven CCA model. The impact of NEDDylation in CCA cells on tumor-stroma crosstalk was assessed using CCA-derived cancer-associated fibroblasts (CAFs). Proteomic analyses were carried out by mass-spectrometry. RESULTS: The NEDDylation machinery was found overexpressed and overactivated in human CCA cells and tumors. Most NEDDylated proteins found upregulated in CCA cells, after NEDD8-immunoprecipitation and further proteomics, participate in the cell cycle, proliferation or survival. Genetic (CRISPR/Cas9-NAE1) and pharmacological (pevonedistat) inhibition of NEDDylation reduced CCA cell proliferation and impeded colony formation invitro. NEDDylation depletion (pevonedistat or Nae1+/- mice) halted tumorigenesis in subcutaneous, orthotopic, and oncogene-driven models of CCA invivo. Moreover, pevonedistat potentiated chemotherapy-induced cell death in CCA cells invitro. Mechanistically, impaired NEDDylation triggered the accumulation of both cullin RING ligase and NEDD8 substrates, inducing DNA damage and cell cycle arrest. Furthermore, impaired NEDDylation in CCA cells reduced the secretion of proteins involved in fibroblast activation, angiogenesis, and oncogenic pathways, ultimately hampering CAF proliferation and migration. CONCLUSION: Aberrant protein NEDDylation contributes to cholangiocarcinogenesis by promoting cell sur

Published
2022

26. 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, Gervai, 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, Bara, Julie, Horowitz, Manuel A R, Ferreira, Dylan, Sun, David E, Jone, Steven, Flack, Ann, Spicer, Victoria L, Mulcahy, Jinyoung, Byun, Younghun, Han, Richard N, Sandford, Konstantinos N, Lazaridi, Christopher I, Amo, Gideon M, Hirschfield, Michael F, Seldin, Pietro, Invernizzi, Katherine A, Siminovitch, Xiong, Ma, Minoru, Nakamura, George F, Mell, Siminovitch, Katherine A., Hirschfield, Gideon M., Mason, Andrew, Vincent, Catherine, Xie, Gang, Zhang, Jinyi, Tang, Ruqi, Ma, Xiong, Li, Zhiqiang, Shi, Yongyong, Affronti, Andrea, Almasio, Piero L., Alvaro, Domenico, Andreone, Pietro, Andriulli, Angelo, Azzaroli, Francesco, Battezzati, Pier Maria, Benedetti, Antonio, Bragazzi, Maria Consiglia, Brunetto, Maurizia, Bruno, Savino, Calvaruso, Vincenza, Cardinale, Vincenzo, Casella, Giovanni, Cazzagon, Nora, Ciaccio, Antonio, Coco, Barbara, Colli, Agostino, Colloredo, Guido, Colombo, Massimo, Colombo, Silvia, Cristoferi, Laura, Cursaro, Carmela, Saveria Crocè, Lory, Crosignani, Andrea, D’Amato, Daphne, Donato, Francesca, Elia, Gianfranco, Fabris, Luca, Fagiuoli, Stefano, Ferrari, Carlo, Floreani, Annarosa, Galli, Andrea, Giannini, Edoardo, Grattagliano, Ignazio, Lampertico, Pietro, Lleo, Ana, Malinverno, Federica, Mancuso, Clara, Marra, Fabio, Marzioni, Marco, Massironi, Sara, Mattalia, Alberto, Miele, Luca, Milani, Chiara, Morini, Lorenzo, Morisco, Filomena, Muratori, Luigi, Muratori, Paolo, Niro, Grazia A., O’Donnell, Sarah, Picciotto, Antonio, Portincasa, Piero, Rigamonti, Cristina, Ronca, Vincenzo, Rosina, Floriano, Spinzi, Giancarlo, Strazzabosco, Mario, Tarocchi, Mirko, Tiribelli, Claudio, Toniutto, Pierluigi, Valenti, Luca, Vinci, Maria, Zuin, Massimo, Consortium, Japan-PBC-GWAS, PBC Consortium, U, Consortium, UK-PBC, Luca, Miele (ORCID:0000-0003-3464-0068), Heather J, Cordell, James J, Fryett, Kazuko, Ueno, Rebecca, Darlay, Yoshihiro, Aiba, Yuki, Hitomi, Minae, Kawashima, Nao, Nishida, Seik-Soon, Khor, Olivier, Gervai, 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, Bara, Julie, Horowitz, Manuel A R, Ferreira, Dylan, Sun, David E, Jone, Steven, Flack, Ann, Spicer, Victoria L, Mulcahy, Jinyoung, Byun, Younghun, Han, Richard N, Sandford, Konstantinos N, Lazaridi, Christopher I, Amo, Gideon M, Hirschfield, Michael F, Seldin, Pietro, Invernizzi, Katherine A, Siminovitch, Xiong, Ma, Minoru, Nakamura, George F, Mell, Siminovitch, Katherine A., Hirschfield, Gideon M., Mason, Andrew, Vincent, Catherine, Xie, Gang, Zhang, Jinyi, Tang, Ruqi, Ma, Xiong, Li, Zhiqiang, Shi, Yongyong, Affronti, Andrea, Almasio, Piero L., Alvaro, Domenico, Andreone, Pietro, Andriulli, Angelo, Azzaroli, Francesco, Battezzati, Pier Maria, Benedetti, Antonio, Bragazzi, Maria Consiglia, Brunetto, Maurizia, Bruno, Savino, Calvaruso, Vincenza, Cardinale, Vincenzo, Casella, Giovanni, Cazzagon, Nora, Ciaccio, Antonio, Coco, Barbara, Colli, Agostino, Colloredo, Guido, Colombo, Massimo, Colombo, Silvia, Cristoferi, Laura, Cursaro, Carmela, Saveria Crocè, Lory, Crosignani, Andrea, D’Amato, Daphne, Donato, Francesca, Elia, Gianfranco, Fabris, Luca, Fagiuoli, Stefano, Ferrari, Carlo, Floreani, Annarosa, Galli, Andrea, Giannini, Edoardo, Grattagliano, Ignazio, Lampertico, Pietro, Lleo, Ana, Malinverno, Federica, Mancuso, Clara, Marra, Fabio, Marzioni, Marco, Massironi, Sara, Mattalia, Alberto, Miele, Luca, Milani, Chiara, Morini, Lorenzo, Morisco, Filomena, Muratori, Luigi, Muratori, Paolo, Niro, Grazia A., O’Donnell, Sarah, Picciotto, Antonio, Portincasa, Piero, Rigamonti, Cristina, Ronca, Vincenzo, Rosina, Floriano, Spinzi, Giancarlo, Strazzabosco, Mario, Tarocchi, Mirko, Tiribelli, Claudio, Toniutto, Pierluigi, Valenti, Luca, Vinci, Maria, Zuin, Massimo, Consortium, Japan-PBC-GWAS, PBC Consortium, U, Consortium, UK-PBC, and Luca, Miele (ORCID:0000-0003-3464-0068)

Abstract

N/A

Published
2022

27. Cholangiocarcinoma landscape in Europe:Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry

Author

Izquierdo-Sanchez, Laura, Lamarca, Angela, La Casta, Adelaida, Buettner, Stefan, Utpatel, Kirsten, Klümpen, Heinz Josef, Adeva, Jorge, Vogel, Arndt, Lleo, Ana, Fabris, Luca, Ponz-Sarvise, Mariano, Brustia, Raffaele, Cardinale, Vincenzo, Braconi, Chiara, Vidili, Gianpaolo, Jamieson, Nigel B., Macias, Rocio IR, Jonas, Jan Philipp, Marzioni, Marco, Hołówko, Wacław, Folseraas, Trine, Kupčinskas, Juozas, Sparchez, Zeno, Krawczyk, Marcin, Krupa, Łukasz, Scripcariu, Viorel, Grazi, Gian Luca, Landa-Magdalena, Ana, IJzermans, Jan N.M., Evert, Katja, Erdmann, Joris I., López-López, Flora, Saborowski, Anna, Scheiter, Alexander, Santos-Laso, Alvaro, Carpino, Guido, Andersen, Jesper B., Marin, Jose JG, Alvaro, Domenico, Bujanda, Luis, Forner, Alejandro, Valle, Juan W., Koerkamp, Bas Groot, Banales, Jesus M., Izquierdo-Sanchez, Laura, Lamarca, Angela, La Casta, Adelaida, Buettner, Stefan, Utpatel, Kirsten, Klümpen, Heinz Josef, Adeva, Jorge, Vogel, Arndt, Lleo, Ana, Fabris, Luca, Ponz-Sarvise, Mariano, Brustia, Raffaele, Cardinale, Vincenzo, Braconi, Chiara, Vidili, Gianpaolo, Jamieson, Nigel B., Macias, Rocio IR, Jonas, Jan Philipp, Marzioni, Marco, Hołówko, Wacław, Folseraas, Trine, Kupčinskas, Juozas, Sparchez, Zeno, Krawczyk, Marcin, Krupa, Łukasz, Scripcariu, Viorel, Grazi, Gian Luca, Landa-Magdalena, Ana, IJzermans, Jan N.M., Evert, Katja, Erdmann, Joris I., López-López, Flora, Saborowski, Anna, Scheiter, Alexander, Santos-Laso, Alvaro, Carpino, Guido, Andersen, Jesper B., Marin, Jose JG, Alvaro, Domenico, Bujanda, Luis, Forner, Alejandro, Valle, Juan W., Koerkamp, Bas Groot, and Banales, Jesus M.

Abstract

Background & Aims: Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. Methods: The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. Results: Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. Conclusion: CCA is frequently diagnosed at an advanced stage, a proportion of patients fai

Published
2022

28. Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models

Author

Olaizola, Paula, Lee-Law, Pui Yuen, Fernandez-Barrena, Maite G, Alvarez, Laura, Cadamuro, Massimiliano, Azkargorta, Mikel, O'Rourke, Colm J, Caballero-Camino, Francisco J, Olaizola, Irene, Macias, Rocio I R, Marin, Jose J G, Serrano-Maciá, Marina, Martinez-Chantar, Maria L, Avila, Matias A, Aspichueta, Patricia, Calvisi, Diego F, Evert, Matthias, Fabris, Luca, Castro, Rui E, Elortza, Felix, Andersen, Jesper B, Bujanda, Luis, Rodrigues, Pedro M, Perugorria, Maria J, Banales, Jesus M, Olaizola, Paula, Lee-Law, Pui Yuen, Fernandez-Barrena, Maite G, Alvarez, Laura, Cadamuro, Massimiliano, Azkargorta, Mikel, O'Rourke, Colm J, Caballero-Camino, Francisco J, Olaizola, Irene, Macias, Rocio I R, Marin, Jose J G, Serrano-Maciá, Marina, Martinez-Chantar, Maria L, Avila, Matias A, Aspichueta, Patricia, Calvisi, Diego F, Evert, Matthias, Fabris, Luca, Castro, Rui E, Elortza, Felix, Andersen, Jesper B, Bujanda, Luis, Rodrigues, Pedro M, Perugorria, Maria J, and Banales, Jesus M

Abstract

BACKGROUND AND AIMS: cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant tumors with dismal prognosis. Alterations in post-translational modifications (PTMs), including NEDDylation, result in abnormal protein dynamics, cell disturbances and disease. Here, we investigate the role of NEDDylation in CCA development and progression.METHODS: levels and function of NEDDylation, together with response to pevonedistat (NEDDylation inhibitor) or CRISPR/Cas9 against NAE1 were evaluated in vitro, in vivo and/or in patients with CCA. Development of preneoplastic lesions in Nae1 +/- mice was investigated using an oncogene-driven CCA model. The impact of NEDDylation in CCA cells on tumor-stroma crosstalk was assessed using CCA-derived cancer-associated fibroblasts (CAFs). Proteomic analyses were carried out by mass-spectrometry. RESULTS: NEDDylation machinery was found overexpressed and overactivated in human CCA cells and tumors. Most NEDDylated proteins found upregulated in CCA cells, after NEDD8-immunoprecipitation and further proteomics, participate in cell cycle, proliferation or survival. Genetic (CRISPR/Cas9-NAE1) and pharmacological (pevonedistat) inhibition of NEDDylation reduced CCA cell proliferation and impeded colony formation in vitro. NEDDylation depletion (pevonedistat or Nae1 +/- mice) halted tumorigenesis in subcutaneous, orthotopic, and oncogene-driven models of CCA in vivo. Moreover, pevonedistat potentiated chemotherapy-induced cell death in CCA cells in vitro. Mechanistically, impaired NEDDylation triggered the accumulation of both cullin RING ligase and NEDD8 substrates, inducing DNA damage and cell cycle arrest. Furthermore, NEDDylation impairment in CCA cells reduced the secretion of proteins involved in fibroblast activation, angiogenesis, and oncogenic pathways, ultimately hampering CAF proliferation and migration. CONCLUSION: aberrant protein NEDDylation contributes to cholangiocarcinogenesis by promoting cell

Published
2022

29. Urban Voids After the Pandemic. A New Chance for Greenway

Author

Labriola, Valentina, Fabris, Luca Maria Francesco, Balzarotti, Riccardo Maria, Semprebon, Gerardo, and Camerin, Federico

Subjects
Ciudades, COVID 19, Urbanismo
Abstract

Producción Científica, Our proposal deals with the meaning of urban voids in the post-COVID-19 period to suggest new understandings of how urban green corridors can positively affect design for healthier and more sustainable cities. According to Secchi (1986), planning through the void involves a profound revision of the way we think about the city, reversing the points of interest, proposing as polarities the spaces that do not usually emerge. The void thus becomes an opportunity, a chance to improve the structure of our urban landscape (Lopez-Pineiro, 2020). A city is a powerful place, always in motion and transformation. It has an artificial spirit full of surprises and vague limits. It is the scene of remarkable transformations that in their wildness are partially ungovernable by the designers themselves. The desire to control them leaves a series of abandoned and unfinished spaces, “holes” that live from their discontinuity with the surroundings (Labriola, 2021). During a period of crisis, like the one that we are still living with COVID-19 (Fabris et al, 2020), it is common to re-think our cities to create better places for the community. After the long period of forced distance that we lived, an evolution of public space is recommended. During the pandemic, the emptiness of our cities permitted Nature to re-appropriate its spaces. Following this trend and thinking about a new kind of public space where Nature and its inside processes are the protagonists, it is possible to intervene in our cities. The porosity of the urban fabric in towns without humans, blocked at home by the never-ending lockdowns, became a new green corridor that revealed the presence of wildlife (both fauna and flora) as part of a forgotten urban layer that turned visible again. The preservation of this new asset should be possible. The spaces to allow this change can be the abandoned and empty areas present in the contemporary city’s sick body that we can finally heal. The so-called wastelands, voids, or terrain vague, have a significant value independent from the environment in which they are inserted, showing a relationship with the contemporary city extraneous to its rhythms. For this reason, they are the perfect place for experimentation in terms of greenways, a possible starting point to re-think how green can be part of the urban texture and how to conceive public and open spaces after the nowadays crisis. The paper considers the Metropolitan City of Milan as a remarkable case study to understand the pivotal role played by urban voids in the formation of greenways and their capacity of reshaping the environmental, aesthetic and healthy dimensions of urban landscapes.

Published
2022

33. Reply to 'Does multiple intrahepatic cholangiocarcinoma worsen prognosis as 'M1' stage?'; multiple primaries vs liver metastases

Author

Lamarca, Angela, Santos‐Laso, Alvaro, Utpatel, Kirsten, La Casta, Adelaida, Stock, Simone, Forner, Alejandro, Adeva, Jorge, Folseraas, Trine, Fabris, Luca, Macias, Rocio IR, Krawczyk, Marcin, Krawczyk, Marek, Cardinale, Vincenzo, Braconi, Chiara, Alvaro, Domenico, Evert, Matthias, Banales, Jesus M., and Valle, Juan W

Abstract

We thank Zhang and colleagues for their Letter to the Editor (1) regarding our work (2). Our manuscript (“Liver Metastases of Intrahepatic Cholangiocarcinoma: Implications for an Updated Staging System”(2)), suggested changes to the American Joint Committee on Cancer (AJCC) staging classification for intrahepatic cholangiocarcinoma (iCCA), by classifying “liver metastases” as stage IV rather than stage II/III in the absence/presence of lymph node metastases, respectively, as per AJCC v.8 (3).

Published
2021

34. Benign biliary neoplasms and biliary tumor precursors

Author

Sarcognato, Samantha, primary, Sacchi, Diana, additional, Fassan, Matteo, additional, Fabris, Luca, additional, Cadamuro, Massimiliano, additional, Zanus, Giacomo, additional, Cataldo, Ivana, additional, Covelli, Claudia, additional, Capelli, Paola, additional, Furlanetto, Alberto, additional, and Guido, Maria, additional

Published
2021
Full Text
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36. Cholangiocarcinoma

Author

Sarcognato, Samantha, primary, Sacchi, Diana, additional, Fassan, Matteo, additional, Fabris, Luca, additional, Cadamuro, Massimiliano, additional, Zanus, Giacomo, additional, Cataldo, Ivana, additional, Capelli, Paola, additional, Baciorri, Francesca, additional, Cacciatore, Matilde, additional, and Guido, Maria, additional

Published
2021
Full Text
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37. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Author

Asselta, Rosanna, primary, Paraboschi, Elvezia M., additional, Gerussi, Alessio, additional, Cordell, Heather J., additional, Mells, George F., additional, Sandford, Richard N., additional, Jones, David E., additional, Nakamura, Minoru, additional, Ueno, Kazuko, additional, Hitomi, Yuki, additional, Kawashima, Minae, additional, Nishida, Nao, additional, Tokunaga, Katsushi, additional, Nagasaki, Masao, additional, Tanaka, Atsushi, additional, Tang, Ruqi, additional, Li, Zhiqiang, additional, Shi, Yongyong, additional, Liu, Xiangdong, additional, Xiong, Ma, additional, Hirschfield, Gideon, additional, Siminovitch, Katherine A., additional, Carbone, Marco, additional, Cardamone, Giulia, additional, Duga, Stefano, additional, Gershwin, M. Eric, additional, Seldin, Michael F., additional, Invernizzi, Pietro, additional, Walker, Erin, additional, Xie, Gang, additional, Mason, Andy, additional, Myers, Robert, additional, Peltekian, Kevork, additional, Ghent, Cameron, additional, Atkinson, Elizabeth, additional, Juran, Bruce, additional, Lazaridis, Kostas, additional, Lu, Yue, additional, Gu, Xiangjun, additional, Jing, Kaiyan, additional, Amos, Chris, additional, Affronti, Andrea, additional, Brunetto, Maurizia, additional, Coco, Barbara, additional, Spinzi, Giancarlo, additional, Elia, Gianfranco, additional, Ferrari, Carlo, additional, Lleo, Ana, additional, Muratori, Luigi, additional, Muratori, Paolo, additional, Portincasa, Piero, additional, Colli, Agostino, additional, Bruno, Savino, additional, Colloredo, Guido, additional, Azzaroli, Francesco, additional, Andreone, Pietro, additional, Bragazzi, MariaConsiglia, additional, Alvaro, Domenico, additional, Cardinale, Vincenzo, additional, Cazzagon, Nora, additional, Rigamonti, Cristina, additional, Floreani, Annarosa, additional, Rosina, Floriano, additional, Ciaccio, Antonio, additional, Cristoferi, Laura, additional, D’Amato, Daphne, additional, Malinverno, Federica, additional, Mancuso, Clara, additional, Massironi, Sara, additional, Milani, Chiara, additional, O’Donnell, Sarah E., additional, Ronca, Vincenzo, additional, Barisani, Donatella, additional, Lampertico, Pietro, additional, Donato, Francesca, additional, Fagiuoli, Stefano, additional, Almasio, Piero L., additional, Giannini, Edoardo, additional, Cursaro, Carmela, additional, Colombo, Massimo, additional, Valenti, Luca, additional, Miele, Luca, additional, Andriulli, Angelo, additional, Niro, Grazia A., additional, Grattagliano, Ignazio, additional, Morini, Lorenzo, additional, Casella, Giovanni, additional, Vinci, Maria, additional, Battezzati, Pier Maria, additional, Crosignani, Andrea, additional, Zuin, Massimo, additional, Mattalia, Alberto, additional, Calvaruso, Vincenza, additional, Colombo, Silvia, additional, Benedetti, Antonio, additional, Marzioni, Marco, additional, Galli, Andrea, additional, Marra, Fabio, additional, Tarocchi, Mirko, additional, Picciotto, Antonio, additional, Morisco, Filomena, additional, Fabris, Luca, additional, Crocè, Lory Saveria, additional, Tiribelli, Claudio, additional, Toniutto, Pierluigi, additional, Strazzabosco, Mario, additional, Ch’ng, Chin Lye, additional, Rahman, Mesbah, additional, Yapp, Tom, additional, Sturgess, Richard, additional, Healey, Christopher, additional, Czajkowski, Marek, additional, Gunasekera, Anton, additional, Gyawali, Pranab, additional, Premchand, Purushothaman, additional, Kapur, Kapil, additional, Marley, Richard, additional, Foster, Graham, additional, Watson, Alan, additional, Dias, Aruna, additional, Subhani, Javaid, additional, Harvey, Rory, additional, McCorry, Roger, additional, Ramanaden, David, additional, Gasem, Jaber, additional, Evans, Richard, additional, Mathialahan, Thiriloganathan, additional, Shorrock, Christopher, additional, Lipscomb, George, additional, Southern, Paul, additional, Tibble, Jeremy, additional, Gorard, David, additional, Palegwala, Altaf, additional, Jones, Susan, additional, Dawwas, Mohamed, additional, Alexander, Graeme, additional, Dolwani, Sunil, additional, Prince, Martin, additional, Foxton, Matthew, additional, Elphick, David, additional, Mitchison, Harriet, additional, Gooding, Ian, additional, Karmo, Mazn, additional, Saksena, Sushma, additional, Mendall, Mike, additional, Patel, Minesh, additional, Ede, Roland, additional, Austin, Andrew, additional, Sayer, Joanna, additional, Hankey, Lorraine, additional, Hovell, Christopher, additional, Fisher, Neil, additional, Carter, Martyn, additional, Koss, Konrad, additional, Piotrowicz, Andrzej, additional, Grimley, Charles, additional, Neal, David, additional, Lim, Guan, additional, Levi, Sass, additional, Ala, Aftab, additional, Broad, Andrea, additional, Saeed, Athar, additional, Wood, Gordon, additional, Brown, Jonathan, additional, Wilkinson, Mark, additional, Gordon, Harriet, additional, Ramage, John, additional, Ridpath, Jo, additional, Ngatchu, Theodore, additional, Grover, Bob, additional, Shaukat, Syed, additional, Shidrawi, Ray, additional, Abouda, George, additional, Ali, Faiz, additional, Rees, Ian, additional, Salam, Imroz, additional, Narain, Mark, additional, Brown, Ashley, additional, Taylor-Robinson, Simon, additional, Williams, Simon, additional, Grellier, Leonie, additional, Banim, Paul, additional, Das, Debasish, additional, Chilton, Andrew, additional, Heneghan, Michael, additional, Curtis, Howard, additional, Gess, Markus, additional, Drake, Ian, additional, Aldersley, Mark, additional, Davies, Mervyn, additional, Jones, Rebecca, additional, McNair, Alastair, additional, Srirajaskanthan, Raj, additional, Pitcher, Maxton, additional, Sen, Sambit, additional, Bird, George, additional, Barnardo, Adrian, additional, Kitchen, Paul, additional, Yoong, Kevin, additional, Chirag, Oza, additional, Sivaramakrishnan, Nurani, additional, MacFaul, George, additional, Jones, David, additional, Shah, Amir, additional, Evans, Chris, additional, Saha, Subrata, additional, Pollock, Katharine, additional, Bramley, Peter, additional, Mukhopadhya, Ashis, additional, Fraser, Andrew, additional, Mills, Peter, additional, Shallcross, Christopher, additional, Campbell, Stewart, additional, Bathgate, Andrew, additional, Shepherd, Alan, additional, Dillon, John, additional, Rushbrook, Simon, additional, Przemioslo, Robert, additional, Macdonald, Christopher, additional, Metcalf, Jane, additional, Shmueli, Udi, additional, Davis, Andrew, additional, Naqvi, Asifabbas, additional, Lee, Tom, additional, Ryder, Stephen D., additional, Collier, Jane, additional, Klass, Howard, additional, Ninkovic, Mary, additional, Cramp, Matthew, additional, Sharer, Nicholas, additional, Aspinall, Richard, additional, Goggin, Patrick, additional, Ghosh, Deb, additional, Douds, Andrew, additional, Hoeroldt, Barbara, additional, Booth, Jonathan, additional, Williams, Earl, additional, Hussaini, Hyder, additional, Stableforth, William, additional, Ayres, Reuben, additional, Thorburn, Douglas, additional, Marshall, Eileen, additional, Burroughs, Andrew, additional, Mann, Steven, additional, Lombard, Martin, additional, Richardson, Paul, additional, Patanwala, Imran, additional, Maltby, Julia, additional, Brookes, Matthew, additional, Mathew, Ray, additional, Vyas, Samir, additional, Singhal, Saket, additional, Gleeson, Dermot, additional, Misra, Sharat, additional, Butterworth, Jeff, additional, George, Keith, additional, Harding, Tim, additional, Douglass, Andrew, additional, Panter, Simon, additional, Shearman, Jeremy, additional, Bray, Gary, additional, Butcher, Graham, additional, Forton, Daniel, additional, Mclindon, John, additional, Cowan, Matthew, additional, Whatley, Gregory, additional, Mandal, Aditya, additional, Gupta, Hemant, additional, Sanghi, Pradeep, additional, Jain, Sanjiv, additional, Pereira, Steve, additional, Prasad, Geeta, additional, Watts, Gill, additional, Wright, Mark, additional, Neuberger, James, additional, Gordon, Fiona, additional, Unitt, Esther, additional, Grant, Allister, additional, Delahooke, Toby, additional, Higham, Andrew, additional, Brind, Alison, additional, Cox, Mark, additional, Ramakrishnan, Subramaniam, additional, King, Alistair, additional, Collins, Carole, additional, Whalley, Simon, additional, Li, Andy, additional, Fraser, Jocelyn, additional, Bell, Andrew, additional, Wong, Voi Shim, additional, Singhal, Amit, additional, Gee, Ian, additional, Ang, Yeng, additional, Ransford, Rupert, additional, Gotto, James, additional, Millson, Charles, additional, Bowles, Jane, additional, Thomas, Caradog, additional, Harrison, Melanie, additional, Galaska, Roman, additional, Kendall, Jennie, additional, Whiteman, Jessica, additional, Lawlor, Caroline, additional, Gray, Catherine, additional, Elliott, Keith, additional, Mulvaney-Jones, Caroline, additional, Hobson, Lucie, additional, Van Duyvenvoorde, Greta, additional, Loftus, Alison, additional, Seward, Katie, additional, Penn, Ruth, additional, Maiden, Jane, additional, Damant, Rose, additional, Hails, Janeane, additional, Cloudsdale, Rebecca, additional, Silvestre, Valeria, additional, Glenn, Sue, additional, Dungca, Eleanor, additional, Wheatley, Natalie, additional, Doyle, Helen, additional, Kent, Melanie, additional, Hamilton, Caroline, additional, Braim, Delyth, additional, Wooldridge, Helen, additional, Abrahams, Rachel, additional, Paton, Alison, additional, Lancaster, Nicola, additional, Gibbins, Andrew, additional, Hogben, Karen, additional, Desousa, Phillipa, additional, Muscariu, Florin, additional, Musselwhite, Janine, additional, McKay, Alexandra, additional, Tan, LaiTing, additional, Foale, Carole, additional, Brighton, Jacqueline, additional, Flahive, Kerry, additional, Nambela, Estelle, additional, Townshend, Paula, additional, Ford, Chris, additional, Holder, Sophie, additional, Palmer, Caroline, additional, Featherstone, James, additional, Nasseri, Mariam, additional, Sadeghian, Joy, additional, Williams, Bronwen, additional, Thomas, Carol, additional, Rolls, Sally-Ann, additional, Hynes, Abigail, additional, Duggan, Claire, additional, Jones, Sarah, additional, Crossey, Mary, additional, Stansfield, Glynis, additional, MacNicol, Carolyn, additional, Wilkins, Joy, additional, Wilhelmsen, Elva, additional, Raymode, Parizade, additional, Lee, Hye-Jeong, additional, Durant, Emma, additional, Bishop, Rebecca, additional, Ncube, Noma, additional, Tripoli, Sherill, additional, Casey, Rebecca, additional, Cowley, Caroline, additional, Miller, Richard, additional, Houghton, Kathryn, additional, Ducker, Samantha, additional, Wright, Fiona, additional, Bird, Bridget, additional, Baxter, Gwen, additional, Keggans, Janie, additional, Hughes, Maggie, additional, Grieve, Emma, additional, Young, Karin, additional, Williams, D., additional, Ocker, Kate, additional, Hines, Frances, additional, Martin, Kirsty, additional, Innes, Caron, additional, Valliani, Talal, additional, Fairlamb, Helen, additional, Thornthwaite, Sarah, additional, Eastick, Anne, additional, Tanqueray, Elizabeth, additional, Morrison, Jennifer, additional, Holbrook, Becky, additional, Browning, Julie, additional, Walker, Kirsten, additional, Congreave, Susan, additional, Verheyden, Juliette, additional, Slininger, Susan, additional, Stafford, Lizzie, additional, O’Donnell, Denise, additional, Ainsworth, Mark, additional, Lord, Susan, additional, Kent, Linda, additional, March, Linda, additional, Dickson, Christine, additional, Simpson, Diane, additional, Longhurst, Beverley, additional, Hayes, Maria, additional, Shpuza, Ervin, additional, White, Nikki, additional, Besley, Sarah, additional, Pearson, Sallyanne, additional, Wright, Alice, additional, Jones, Linda, additional, Gunter, Emma, additional, Dewhurst, Hannah, additional, Fouracres, Anna, additional, Farrington, Liz, additional, Graves, Lyn, additional, Marriott, Suzie, additional, Leoni, Marina, additional, Tyrer, David, additional, Martin, Kate, additional, Dali-kemmery, Lola, additional, Lambourne, Victoria, additional, Green, Marie, additional, Sirdefield, Dawn, additional, Amor, Kelly, additional, Colley, Julie, additional, Shinder, Bal, additional, Jones, Jayne, additional, Mills, Marisa, additional, Carnahan, Mandy, additional, Taylor, Natalie, additional, Boulton, Kerenza, additional, Tregonning, Julie, additional, Brown, Carly, additional, Clifford, Gayle, additional, Archer, Emily, additional, Hamilton, Maria, additional, Curtis, Janette, additional, Shewan, Tracey, additional, Walsh, Sue, additional, Warner, Karen, additional, Netherton, Kimberley, additional, Mupudzi, Mcdonald, additional, Gunson, Bridget, additional, Gitahi, Jane, additional, Gocher, Denise, additional, Batham, Sally, additional, Pateman, Hilary, additional, Desmennu, Senayon, additional, Conder, Jill, additional, Clement, Darren, additional, Gallagher, Susan, additional, Orpe, Jacky, additional, Chan, PuiChing, additional, Currie, Lynn, additional, O’Donohoe, Lynn, additional, Oblak, Metod, additional, Morgan, Lisa, additional, Quinn, Marie, additional, Amey, Isobel, additional, Baird, Yolanda, additional, Cotterill, Donna, additional, Cumlat, Lourdes, additional, Winter, Louise, additional, Greer, Sandra, additional, Spurdle, Katie, additional, Allison, Joanna, additional, Dyer, Simon, additional, Sweeting, Helen, additional, Kordula, Jean, additional, Aiba, Yoshihiro, additional, Nakamura, Hitomi, additional, Abiru, Seigo, additional, Nagaoka, Shinya, additional, Komori, Atsumasa, additional, Yatsuhashi, Hiroshi, additional, Ishibashi, Hiromi, additional, Ito, Masahiro, additional, Kawai, Yosuke, additional, Kohn, Seik-Soon, additional, Gervais, Olivier, additional, Migita, Kiyoshi, additional, Katsushima, Shinji, additional, Naganuma, Atsushi, additional, Sugi, Kazuhiro, additional, Komatsu, Tatsuji, additional, Mannami, Tomohiko, additional, Matsushita, Kouki, additional, Yoshizawa, Kaname, additional, Makita, Fujio, additional, Nikami, Toshiki, additional, Nishimura, Hideo, additional, Kouno, Hiroshi, additional, Kouno, Hirotaka, additional, Ota, Hajime, additional, Komura, Takuya, additional, Nakamura, Yoko, additional, Shimada, Masaaki, additional, Hirashima, Noboru, additional, Komeda, Toshiki, additional, Ario, Keisuke, additional, Nakamuta, Makoto, additional, Yamashita, Tsutomu, additional, Furuta, Kiyoshi, additional, Kikuchi, Masahiro, additional, Naeshiro, Noriaki, additional, Takahashi, Hironao, additional, Mano, Yutaka, additional, Tsunematsu, Seiji, additional, Yabuuchi, Iwao, additional, Shimada, Yusuke, additional, Yamauchi, Kazuhiko, additional, Sugimoto, Rie, additional, Sakai, Hironori, additional, Mita, Eiji, additional, Koda, Masaharu, additional, Tsuruta, Satoru, additional, Kamitsukasa, Hiroshi, additional, Sato, Takeaki, additional, Masaki, Naohiko, additional, Kobata, Tatsuro, additional, Fukushima, Nobuyoshi, additional, Higuchi, Nobito, additional, Ohara, Yukio, additional, Muro, Toyokichi, additional, Takesaki, Eiichi, additional, Takaki, Hitoshi, additional, Yamamoto, Tetsuo, additional, Kato, Michio, additional, Nagaoki, Yuko, additional, Hayashi, Shigeki, additional, Ishida, Jinya, additional, Watanabe, Yukio, additional, Kobayashi, Masakazu, additional, Koga, Michiaki, additional, Saoshiro, Takeo, additional, Yagura, Michiyasu, additional, Hirata, Keisuke, additional, Takikawa, Hajime, additional, Ohira, Hiromasa, additional, Zeniya, Mikio, additional, Abe, Masanori, additional, Onji, Morikazu, additional, Kaneko, Shuichi, additional, Honda, Masao, additional, Arai, Kuniaki, additional, Arinaga-Hino, Teruko, additional, Hashimoto, Etsuko, additional, Taniai, Makiko, additional, Umemura, Takeji, additional, Joshita, Satoru, additional, Nakao, Kazuhiko, additional, Ichikawa, Tatsuki, additional, Shibata, Hidetaka, additional, Yamagiwa, Satoshi, additional, Seike, Masataka, additional, Honda, Koichi, additional, Sakisaka, Shotaro, additional, Takeyama, Yasuaki, additional, Harada, Masaru, additional, Senju, Michio, additional, Yokosuka, Osamu, additional, Kanda, Tatsuo, additional, Ueno, Yoshiyuki, additional, Kikuchi, Kentaro, additional, Ebinuma, Hirotoshi, additional, Himoto, Takashi, additional, Yasunami, Michio, additional, Murata, Kazumoto, additional, Mizokami, Masashi, additional, Shimoda, Shinji, additional, Miyake, Yasuhiro, additional, Takaki, Akinobu, additional, Yamamoto, Kazuhide, additional, Hirano, Katsuji, additional, Ichida, Takafumi, additional, Ido, Akio, additional, Tsubouchi, Hirohito, additional, Chayama, Kazuaki, additional, Harada, Kenichi, additional, Nakanuma, Yasuni, additional, Maehara, Yoshihiko, additional, Taketomi, Akinobu, additional, Shirabe, Ken, additional, Soejima, Yuji, additional, Mori, Akira, additional, Yagi, Shintaro, additional, Uemoto, Shinji, additional, Tanaka, Tomohiro, additional, Yamashiki, Noriyo, additional, Tamura, Sumito, additional, Sugawara, Yasuhiro, additional, and Kokudo, Norihiro, additional

Published
2021
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38. Cover Image

Author

Milosa, Fabiola, primary, Critelli, Rosina Maria, additional, Lasagni, Simone, additional, Pivetti, Alessandra, additional, Di Marco, Lorenza, additional, Romagnoli, Dante, additional, Carulli, Lucia, additional, Dituri, Francesco, additional, Mancarella, Serena, additional, Giannelli, Gianluigi, additional, Martinez‐Chantar, Maria‐Luz, additional, Fabris, Luca, additional, and Villa, Erica, additional

Published
2021
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39. Prognostic significance of hypoxic and metabolic gene profiling in hepatocellular carcinoma

Author

Milosa, Fabiola, primary, Critelli, Rosina Maria, additional, Lasagni, Simone, additional, Pivetti, Alessandra, additional, Di Marco, Lorenza, additional, Romagnoli, Dante, additional, Carulli, Lucia, additional, Dituri, Francesco, additional, Mancarella, Serena, additional, Giannelli, Gianluigi, additional, Martinez‐Chantar, Maria‐Luz, additional, Fabris, Luca, additional, and Villa, Erica, additional

Published
2021
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41. Liver metastases of intrahepatic Cholangiocarcinoma: implications for an updated staging system

Author

Fisiología, Fisiologia, Lamarca, Angela, Santos Laso, Álvaro, Utpatel, Kirsten, La Casta, Adelaida, Stock, Simone, Forner, Alejandro, Adeva, Jorge, Folseraas, Trine, Fabris, Luca, Macias, Rocio I. R., Krawczyk, Marcin, Krawczyk, Marek, Cardinale, Vincenzo, Braconi, Chiara, Alvaro, Domenico, Evert, Matthias, Bañales Asurmendi, Jesús María, Valle, Juan W., European Network for the Study of Cholangiocarcinoma (ENS-CCA), Fisiología, Fisiologia, Lamarca, Angela, Santos Laso, Álvaro, Utpatel, Kirsten, La Casta, Adelaida, Stock, Simone, Forner, Alejandro, Adeva, Jorge, Folseraas, Trine, Fabris, Luca, Macias, Rocio I. R., Krawczyk, Marcin, Krawczyk, Marek, Cardinale, Vincenzo, Braconi, Chiara, Alvaro, Domenico, Evert, Matthias, Bañales Asurmendi, Jesús María, Valle, Juan W., and European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Abstract

[EN] BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (iCCA) with liver metastases is perceived to have a poor prognosis, but the American Joint Committee on Cancer (AJCC) classifies them as early stage in the absence of lymph nodes or extrahepatic spread. APP ROA CH AND RESULT S: Patients with iCCA from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and Surveillance, Epidemiology, and End Results (SEER) registries with survival/staging (AJCC v.7) data were eligible. Modified staging was used (mAJCC v.7): group A: stages I-III (excluding T2bN0); group B: stage IVa (excluding T2bN1M0); group C: liver metastases (T2bN0/1); and group D: stage IVb (extrahepatic metastases). Survival analysis (Kaplan-Meier and Cox regression) was performed in an ENS-CCA training cohort (TC) and findings internally (ENS-CCA iVC) and externally (SEER) validated. The aim was to assess whether liver metastases (group C) had a shorter survival compared to other early stages (group A) to propose a modified version of AJCC v.8 (mAJCC v.8). A total of 574 and 4,171 patients from the ENS-CCA and SEER registries were included. Following the new classification, 19.86% and 17.31% of patients from the ENS-CCA and SEER registries were reclassified into group C, respectively. In the ENS-CCA TC, multivariable Cox regression was adjusted for obesity (p = 0.026) and performance status (P < 0.001); patients in group C (HR, 2.53; 95% CI, 1.18-5.42; P = 0.017) had a higher risk of death (vs. group A). Findings were validated in the ENS-CCA iVC (HR, 2.93; 95% CI, 2.04-4.19; P < 0.001) and in the SEER registry (HR, 1.88; 95% CI, 1.68-2.09; P < 0.001). CONCLUSIONS: iCCA with liver metastases has a worse outcome than other early stages of iCCA. Given that AJCC v.8 does not take this into consideration, a modification of AJCC v.8 (mAJCC v.8), including “liver metastases: multiple liver lesions, with or without vascular invasion” as an “M1a stage,” is suggested. (Hepatology 2021;73:2311-232

Published
2021

42. An EU Common Training Framework for Landscape Architecture addressing the current needs of society

Author

Cipriani, L. (author), de Vries, Jeroen (author), Stauskis, Gintaras (author), Auweck, Fritz (author), Triboi, Roxana (author), Andreucci, Maria Beatrice (author), Cervera Alonso de Medina, Marina (author), Cancela d’ Abreu, Margarida (author), Freire, Maria (author), Carapinha, Aurora (author), a Conceição Castro, Maria (author), Del Pozo, Cristina (author), Deveikienė, Vaiva (author), Gunnlaugsson, Hermann Georg (author), Fekete, Albert (author), Fetzer, Ellen (author), Fabris, Luca (author), Fingerova, Radmila (author), Gazvoda, Davorin (author), Gkoltsiou, Aikaterini (author), Harmanescu, Mihaela (author), Kamenecki, Monika (author), Koscak Miocic-Stosic, Vesna (author), Melone, Antonella (author), Mertens, Elke (author), Meeres, Sophia (author), Ortacesme, Veli (author), Noortman, Adrian (author), Sárospataki, Máté (author), Stiles, Richard (author), Trolf, Norbert (author), Tóth, Attila (author), Tomic Reljic, Dora (author), Tudora, Ioana (author), Valdés Tejera, Esther (author), Valánszki, István (author), Weckman, Emilia (author), Williams, Tony (author), Tutundzic, Andreja (author), Lambertini, Anna (author), Mihova, Katinka (author), Muru, Toomas (author), Dam, Torben (author), Teqja, Zydi (author), Cipriani, L. (author), de Vries, Jeroen (author), Stauskis, Gintaras (author), Auweck, Fritz (author), Triboi, Roxana (author), Andreucci, Maria Beatrice (author), Cervera Alonso de Medina, Marina (author), Cancela d’ Abreu, Margarida (author), Freire, Maria (author), Carapinha, Aurora (author), a Conceição Castro, Maria (author), Del Pozo, Cristina (author), Deveikienė, Vaiva (author), Gunnlaugsson, Hermann Georg (author), Fekete, Albert (author), Fetzer, Ellen (author), Fabris, Luca (author), Fingerova, Radmila (author), Gazvoda, Davorin (author), Gkoltsiou, Aikaterini (author), Harmanescu, Mihaela (author), Kamenecki, Monika (author), Koscak Miocic-Stosic, Vesna (author), Melone, Antonella (author), Mertens, Elke (author), Meeres, Sophia (author), Ortacesme, Veli (author), Noortman, Adrian (author), Sárospataki, Máté (author), Stiles, Richard (author), Trolf, Norbert (author), Tóth, Attila (author), Tomic Reljic, Dora (author), Tudora, Ioana (author), Valdés Tejera, Esther (author), Valánszki, István (author), Weckman, Emilia (author), Williams, Tony (author), Tutundzic, Andreja (author), Lambertini, Anna (author), Mihova, Katinka (author), Muru, Toomas (author), Dam, Torben (author), and Teqja, Zydi (author)

Abstract

Landscape Architecture

Published
2021

43. The tumour microenvironment and immune milieu of cholangiocarcinoma

Author

Fabris, Luca, Perugorria, María J, Mertens, Joachim, Björkström, Niklas K, Cramer, Thorsten, Lleo, Ana, Solinas, Antonio, Sänger, Hanna, Lukacs-Kornek, Veronika, Moncsek, Anja, Siebenhüner, Alexander, Strazzabosco, Mario, University of Zurich, and Fabris, Luca

Subjects
10219 Clinic for Gastroenterology and Hepatology, 10032 Clinic for Oncology and Hematology, 610 Medicine & health, 2721 Hepatology
Published
2019

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

Author

Medicina, Medikuntza, Bañales Asurmendi, Jesús María, García Marín, Jose Juan, Lamarca, Angela, Rodrigues, Pedro M., Khan, Shahid A., Roberts, Lewis R., Cardinale, Vincenzo, Carpino, Guido, Andersen, Jesper B., Braconi, Chiara, Calvisi, Diego, Perugorria Montiel, María Jesús, Fabris, Luca, Boulter, Luke, Macias, Rocio I. R., Gaudio, Eugenio, Alvaro, Domenico, Gradilone, Sergio A., Strazzabosco, Mario, Marzioni, Marco, Coulouarn, Cédric, Fouassier, Laura, Raggi, Chiara, Invernizzi, Pietro, Mertens, Joachim C., Moncsek, Anja, Rizvi, Sumera, Heimbach, Julie, Groot Koerkamp, Bas, Bruix, Jordi, Forner, Alejandro, Bridgewater, John, Valle, Juan W., Gores, Gregory J., Medicina, Medikuntza, Bañales Asurmendi, Jesús María, García Marín, Jose Juan, Lamarca, Angela, Rodrigues, Pedro M., Khan, Shahid A., Roberts, Lewis R., Cardinale, Vincenzo, Carpino, Guido, Andersen, Jesper B., Braconi, Chiara, Calvisi, Diego, Perugorria Montiel, María Jesús, Fabris, Luca, Boulter, Luke, Macias, Rocio I. R., Gaudio, Eugenio, Alvaro, Domenico, Gradilone, Sergio A., Strazzabosco, Mario, Marzioni, Marco, Coulouarn, Cédric, Fouassier, Laura, Raggi, Chiara, Invernizzi, Pietro, Mertens, Joachim C., Moncsek, Anja, Rizvi, Sumera, Heimbach, Julie, Groot Koerkamp, Bas, Bruix, Jordi, Forner, Alejandro, Bridgewater, John, Valle, Juan W., and Gores, Gregory J.

Abstract

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

Published
2020

47. New Healthy Settlements Responding to Pandemic Outbreaks: Approaches from (and for) the Global City

Author

Fabris, Luca Maria Francesco and Fabris, Luca Maria Francesco

Abstract

Producción Científica, El artículo aborda de forma crítica varias soluciones y estrategias para abordar las desigualdades urbanas con el fin de defender el reciente paradigma espacial del “derecho a la ciudad saludable”. El artículo reflexiona críticamente sobre la aplicación de los conceptos de “Supermanzana”, “Urbanismo Táctico” y “Ciudad de los 15 minutos”, ilustrando y comparando su aplicación en tres ciudades globales (respectivamente Barcelona, Pekín y Milán). El objetivo es demostrar que estas prácticas pueden ser aplicadas de forma eficaz para diferentes contextos, proponiendo estrategias exitosas para superar los problemas de salud, medio ambiente y movilidad en todas las ciudades globales contemporáneas, Proyecto UrbanHist, Programa de Investigación Horizon 2020 de la UE, Acuerdo de subvención Marie Skłodowska-Curie n. 721933

Published
2020

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

Author

Banales, Jesus M, Marin, Jose J G, Lamarca, Angela, Rodrigues, Pedro M, Khan, Shahid A, Roberts, Lewis R, Cardinale, Vincenzo, Carpino, Guido, Andersen, Jesper B, Braconi, Chiara, Calvisi, Diego F, Perugorria, Maria J, Fabris, Luca, Boulter, Luke, Macias, Rocio I R, Gaudio, Eugenio, Alvaro, Domenico, Gradilone, Sergio A, Strazzabosco, Mario, Marzioni, Marco, Coulouarn, Cédric, Fouassier, Laura, Raggi, Chiara, Invernizzi, Pietro, Mertens, Joachim C, Moncsek, Anja, Rizvi, Sumera, Heimbach, Julie, Koerkamp, Bas Groot, Bruix, Jordi, Forner, Alejandro, Bridgewater, John, Valle, Juan W, Gores, Gregory J, Banales, Jesus M, Marin, Jose J G, Lamarca, Angela, Rodrigues, Pedro M, Khan, Shahid A, Roberts, Lewis R, Cardinale, Vincenzo, Carpino, Guido, Andersen, Jesper B, Braconi, Chiara, Calvisi, Diego F, Perugorria, Maria J, Fabris, Luca, Boulter, Luke, Macias, Rocio I R, Gaudio, Eugenio, Alvaro, Domenico, Gradilone, Sergio A, Strazzabosco, Mario, Marzioni, Marco, Coulouarn, Cédric, Fouassier, Laura, Raggi, Chiara, Invernizzi, Pietro, Mertens, Joachim C, Moncsek, Anja, Rizvi, Sumera, Heimbach, Julie, Koerkamp, Bas Groot, Bruix, Jordi, Forner, Alejandro, Bridgewater, John, Valle, Juan W, and Gores, Gregory J

Abstract

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

Published
2020

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