Indicaxanthin Induces Autophagy in Intestinal Epithelial Cancer Cells by Epigenetic Mechanisms Involving DNA Methylation

Autophagy is an evolutionarily conserved process critical in maintaining cellular homeostasis. Recently, the anticancer potential of autophagy inducers, including phytochemicals, was suggested. Indicaxanthin is a betalain pigment found in prickly pear fruit with antiproliferative and pro-apoptotic activities in colorectal cancer cells associated with epigenetic changes in selected methylation-silenced oncosuppressor genes. Here, we demonstrate that indicaxanthin induces the up-regulation of the autophagic markers LC3-II and Beclin1, and increases autophagolysosome production in Caco-2 cells. Methylomic studies showed that the indicaxanthin-induced pro-autophagic activity was associated with epigenetic changes. In addition to acting as a hypermethylating agent at the genomic level, indicaxanthin also induced significant differential methylation in 39 out of 47 autophagy-related genes, particularly those involved in the late stages of autophagy. Furthermore, in silico molecular modelling studies suggested a direct interaction of indicaxanthin with Bcl-2, which, in turn, influenced the function of Beclin1, a key autophagy regulator. External effectors, including food components, may modulate the epigenetic signature of cancer cells. This study demonstrates, for the first time, the pro-autophagic potential of indicaxanthin in human colorectal cancer cells associated with epigenetic changes and contributes to outlining its potential healthy effect in the pathophysiology of the gastrointestinal tract

An In Vitro Model of Glioma Development

Gliomas are the prevalent forms of brain cancer and derive from glial cells. Among them, astrocytomas are the most frequent. Astrocytes are fundamental for most brain functions, as they contribute to neuronal metabolism and neurotransmission. When they acquire cancer properties, their functions are altered, and, in addition, they start invading the brain parenchyma. Thus, a better knowledge of transformed astrocyte molecular properties is essential. With this aim, we previously developed rat astrocyte clones with increasing cancer properties. In this study, we used proteomic analysis to compare the most transformed clone (A-FC6) with normal primary astrocytes. We found that 154 proteins are downregulated and 101 upregulated in the clone. Moreover, 46 proteins are only expressed in the clone and 82 only in the normal cells. Notably, only 11 upregulated/unique proteins are encoded in the duplicated q arm of isochromosome 8 (i(8q)), which cytogenetically characterizes the clone. Since both normal and transformed brain cells release extracellular vesicles (EVs), which might induce epigenetic modifications in the neighboring cells, we also compared EVs released from transformed and normal astrocytes. Interestingly, we found that the clone releases EVs containing proteins, such as matrix metalloproteinase 3 (MMP3), that can modify the extracellular matrix, thus allowing invasion

Nutritional epigenomic and DNA-damage modulation effect of natural stilbenoids

Abstract The aim of the present work is the evaluation of biological effects of natural stilbenoids found in Vitis vinifera, with a focus on their activity as epigenetic modulators. In the present study, resveratrol, pterostilbene and for the first time their dimers (±)-trans-δ-viniferin, (±)-trans-pterostilbene dehydrodimer were evaluated in Caco-2 and HepG-2 cell lines as potential epigenetic modulators. Stilbenoids were added in a Caco-2 cell culture as a model of the intestinal epithelial barrier and in the HepG-2 as a model of hepatic environment, to verify their dose-dependent toxicity, ability to interact with DNA, and epigenomic action. Resveratrol, pterostilbene, and (±)-trans-pterostilbene dehydrodimer were found to have no toxic effects at tested concentration and were effective in reversing arsenic damage in Caco-2 cell lines. (±)-trans-δ-viniferin showed epigenomic activity, but further studies are needed to clarify its mode of action

Delisting HCV-infected liver transplant candidates who improved after viral eradication: Outcome 2 years after delisting

International audienceBACKGROUNDS & AIMS: Treating patients with decompensated cirrhosis with direct-acting antiviral (DAA) therapy while on the waiting list for liver transplantation results in substantial improvement of liver function allowing 1 in 4 patients to be removed from the waiting list or delisted, as reported in a previous study promoted by the European Liver and Intestine Transplant Association (ELITA). The aim of this study was to report on clinical outcomes of delisted patients, including mortality risk, hepatocellular carcinoma development and clinical decompensation requiring relisting. METHODS: One hundred and forty-two HCV-positive patients on the liver transplant waiting list for decompensated cirrhosis, negative for hepatocellular carcinoma, between February 2014 and June 2015 were treated with DAA therapy and were prospectively followed up. RESULTS: Forty-four patients (30.9%) were delisted following clinical improvement. This percentage was higher than in the original study because of a number of patients being delisted long after starting DAAs. The median Child-Pugh and MELD score of delisted patients was 5.5 and 9 respectively. Four patients were relisted, because of HCC diagnosis in 1 case and 3 patients developed ascites. One further patient died (2.4%) because of rapidly progressing hepatocellular carcinoma twenty-two months after delisting. Of the 70 patients who received a liver graft, 9 died (13%). CONCLUSIONS: Antiviral therapy allows for a long-term improvement of liver function and the delisting of one-third of treated patients with risk of liver-related complications after delisting being very low

Economic Impact of European Liver and Intestine Transplantation Association (ELITA) Recommendations for Hepatitis B Prophylaxis After Liver Transplantation

The European Liver and Intestine Transplant Association, ELITA, promoted a Consensus Conference involving 20 experts across the world which generated updated guidelines on HBV prophylaxis in liver transplant candidates and recipients. This study explores the economic impact associated with the implementation of the new ELITA guidelines. To this aim, a condition-specific cohort simulation model has been developed to compare new and historical prophylaxis, including only pharmaceutical cost and using the European perspective. The target population simulated in the model included both prevalent and incident cases, and consisted of 6,133 patients after the first year, that increased to 7,442 and 8,743 patents after 5 and 10 years from its implementation. The ELITA protocols allowed a cost saving of around € 235.65 million after 5 years and € 540.73 million after 10 years; which was mainly due to early HIBG withdrawal either after the first 4 weeks or after the first year post Liver Transplantation (LT) depending on the virological risk at transplantation. Results were confirmed by sensitivity analyses. The money saved by the implementation of the ELITA guidelines would allow healthcare decision makers and budget holders to understand where costs could be reduced and resources re-allocated to different needs

Location and allocation: inequity of access to liver transplantation for patients with severe acute-on-chronic liver failure in Europe

BACKGROUND: There is growing evidence that liver transplantation (LT) is the most effective treatment for acute-on-chronic liver failure grade-3 (ACLF-3). This study examines whether and how this evidence translates into practice by analyzing the variability in intensive care unit (ICU) admissions, listing strategies and LT activity for ACLF-3 patients across transplant centers in Europe. METHODS: Consecutive patients who were admitted to the ICU with ACLF-3, whether or not they were listed and/or transplanted with ACLF-3 between 2018 and 2019 were included across 20 transplantation centers. RESULTS: 351 patients with ACLF-3 were included: 33 had been listed prior to developing ACLF-3 and 318 had not been listed at the time of admission to the ICU. There was no correlation between the number of unlisted ACLF-3 patients admitted to the ICU and the number listed or transplanted whilst in ACLF-3 across centers. In contrast, there was a correlation between the number of patients listed and the number transplanted whilst in ACLF-3. 21% of patients who were listed whilst in ACLF-3 died on the waiting list or were delisted. The percentage of LT for ACLF-3 patients varied from 0%-29% of patients transplanted with decompensated cirrhosis across centers (average = 8%), with an I2 index of 68% (95% CI: 49%-80%), showing substantial heterogeneity among centers. The one-year survival for all patients with ACLF-3 was significantly higher in centers that listed and transplanted more ACLF-3 patients (>10 patients) than in centers that listed and transplanted fewer: respectively 36% vs. 20%, p = 0.012. CONCLUSION: Patients with ACLF-3 face inequity of access to LT across Europe. Wait-listing strategies for ACLF-3 patients influence their access to LT and, ultimately, their survival

Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: results of the ELITA/EF-CLIF collaborative study (ECLIS)

Liver transplantation (LT) has been proposed to be an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to address the current clinical practice and outcomes of ACLF patients wait listed (WL) for LT in Europe

Location and allocation: Inequity of access to liver transplantation for patients with severe acute-on-chronic liver failure in Europe

There is growing evidence that liver transplantation (LT) is the most effective treatment for acute-on-chronic liver failure grade-3 (ACLF-3). This study examines whether and how this evidence translates into practice by analyzing the variability in intensive care unit (ICU) admissions, listing strategies, and LT activity for patients with ACLF-3 across transplantation centers in Europe. Consecutive patients who were admitted to the ICU with ACLF-3, whether or not they were listed and/or transplanted with ACLF-3, between 2018 and 2019 were included across 20 transplantation centers. A total of 351 patients with ACLF-3 were included: 33 had been listed prior to developing ACLF-3 and 318 had not been listed at the time of admission to the ICU. There was no correlation between the number of unlisted patients with ACLF-3 admitted to the ICU and the number listed or transplanted while in ACLF-3 across centers. By contrast, there was a correlation between the number of patients listed and the number transplanted while in ACLF-3. About 21% of patients who were listed while in ACLF-3 died on the waiting list or were delisted. The percentage of LT for patients with ACLF-3 varied from 0% to 29% for those transplanted with decompensated cirrhosis across centers (average = 8%), with an I(2) index of 68% (95% confidence interval, 49%-80%), showing substantial heterogeneity among centers. The 1-year survival for all patients with ACLF-3 was significantly higher in centers that listed and transplanted more patients with ACLF-3 (>10 patients) than in centers that listed and transplanted fewer: 36% versus 20%, respectively (p = 0.012). Patients with ACLF-3 face inequity of access to LT across Europe. Waitlisting strategies for patients with ACLF-3 influence their access to LT and, ultimately, their survival

Location and allocation: inequity of access to liver transplantation for patients with severe acute-on-chronic liver failure in Europe

none43There is growing evidence that liver transplantation (LT) is the most effective treatment for acute-on-chronic liver failure grade-3 (ACLF-3). This study examines whether and how this evidence translates into practice by analyzing the variability in intensive care unit (ICU) admissions, listing strategies and LT activity for ACLF-3 patients across transplant centers in Europe.Artzner, Thierry; Bernal, William; Belli, Luca S; Conti, Sara; Cortesi, Paolo A; Sacleux, Sophie-Caroline; Pageaux, George-Philippe; Radenne, Sylvie; Trebicka, Jonel; Fernandez, Javier; Perricone, Giovanni; Piano, Salvatore; Nadalin, Silvio; Morelli, Maria C; Martini, Silvia; Polak, Wojciech G; Zieniewicz, Krzysztof; Toso, Christian; Berenguer, Marina; Iegri, Claudia; Invernizzi, Federica; Volpes, Riccardo; Karam, Vincent; Adam, René; Faitot, François; Rabinowich, Liane; Saliba, Faouzi; Meunier, Lucy; Lesurtel, Mickael; Uschner, Frank E; Michard, Baptiste; Coilly, Audrey; Meszaros, Magdalena; Poinsot, Domitille; Besch, Camille; Schnitzbauer, Andreas; De Carlis, Luciano G; Fumagalli, Roberto; Angeli, Paolo; Arroyo, Vincente; Fondevila, Constantino; Duvoux, Christophe; Jalan, RajivArtzner, Thierry; Bernal, William; Belli, Luca S; Conti, Sara; Cortesi, Paolo A; Sacleux, Sophie-Caroline; Pageaux, George-Philippe; Radenne, Sylvie; Trebicka, Jonel; Fernandez, Javier; Perricone, Giovanni; Piano, Salvatore; Nadalin, Silvio; Morelli, Maria C; Martini, Silvia; Polak, Wojciech G; Zieniewicz, Krzysztof; Toso, Christian; Berenguer, Marina; Iegri, Claudia; Invernizzi, Federica; Volpes, Riccardo; Karam, Vincent; Adam, René; Faitot, François; Rabinowich, Liane; Saliba, Faouzi; Meunier, Lucy; Lesurtel, Mickael; Uschner, Frank E; Michard, Baptiste; Coilly, Audrey; Meszaros, Magdalena; Poinsot, Domitille; Besch, Camille; Schnitzbauer, Andreas; De Carlis, Luciano G; Fumagalli, Roberto; Angeli, Paolo; Arroyo, Vincente; Fondevila, Constantino; Duvoux, Christophe; Jalan, Raji

Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: Results of the ELITA/EF-CLIF collaborative study (ECLIS)

International audienceLiver transplantation (LT) has been proposed as an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to assess the current clinical practice and outcomes of patients with ACLF who are wait-listed for LT in Europe.Methods: This was a retrospective study including 308 consecutive patients with ACLF, listed in 20 centres across 8 European countries, from January 2018 to June 2019.Results: A total of 2,677 patients received a LT: 1,216 (45.4%) for decompensated cirrhosis. Of these, 234 (19.2%) had ACLF at LT: 58 (4.8%) had ACLF-1, 78 (6.4%) had ACLF-2, and 98 (8.1%) had ACLF-3. Wide variations were observed amongst countries: France and Germany had high rates of ACLF-2/3 (27-41%); Italy, Switzerland, Poland and the Netherlands had medium rates (9-15%); and the United Kingdom and Spain had low rates (3-5%) (p 4 mmol/L (hazard ratio [HR] 3.14; 95% CI 1.37-7.19), recent infection from multidrug resistant organisms (HR 3.67; 95% CI 1.63-8.28), and renal replacement therapy (HR 2.74; 95% CI 1.37-5.51) were independent predictors of post-LT mortality. During the same period, 74 patients with ACLF died on the waiting list. In an intention-to-treat analysis, 1-year survival of patients with ACLF on the LT waiting list was 73% for ACLF-1 or -2 and 50% for ACLF-3.Conclusion: The results reveal wide variations in the listing of patients with ACLF in Europe despite favourable post-LT survival. Risk factors for mortality were identified, enabling a more precise prognostic assessment of patients with ACLF