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2. Opportunities and barriers in omics-based biomarker discovery for steatotic liver diseases

Author

Hansen, Torben, Mann, Matthias, Matthijnssens, Jelle, Krag, Aleksander, Bork, Peer, Arumugam, Manimozhiyan, Trebicka, Jonel, Karsdal, Morten, Anastasiadou, Ema, Israelsen, Hans, Melberg, Hans Olav, Legido-Quigley, Cristina, Thiele, Maja, Villesen, Ida Falk, Niu, Lili, Johansen, Stine, Sulek, Karolina, Nishijima, Suguru, Espen, Lore Van, Keller, Marisa, Israelsen, Mads, Suvitaival, Tommi, Zawadzki, Andressa de, Juel, Helene Bæk, Brol, Maximilian Joseph, Stinson, Sara Elizabeth, Huang, Yun, Silva, Maria Camilla Alvarez, Kuhn, Michael, Leeming, Diana Julie, Dalgaard, Louise Torp, and Jensen, Lars Juhl

Published
2024
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4. Infections increase the risk of decompensation and death in patients with early alcohol-related liver disease

Author

Anastasiadou, Ema, Arumugam, Manimozhian, Bork, Peer, Hansen, Torben, Presto, Jenny, Israelsen, Hans, Karsdal, Morten, Legido-Quigley, Cristina, Melberg, Hans Olav, Thiele, Maja, Trebicka, Jonel, Krag, Aleksander, Mann, Mathias, Matthijnssens, Jelle, Johansen, Stine, Langkjær, Simon, Rasmussen, Ditlev Nytoft, Israelsen, Mads, Torp, Nikolaj, Lindvig, Katrine, Kjærgaard, Maria, Hansen, Johanne Kragh, Hansen, Camilla Dalby, Thorhauge, Katrine, Andersen, Peter, Detlefsen, Sönke, Juel, Helene Bæk, and Justesen, Ulrik Stenz

Published
2024
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5. Rifaximin-α for liver fibrosis in patients with alcohol-related liver disease (GALA-RIF): a randomised, double-blind, placebo-controlled, phase 2 trial

Author

Anastasiadou, Ema, Arumugam, Manimozhian, Bork, Peer, Hansen, Torben, Henrar, Roland, Israelsen, Hans, Karsdal, Morten, Legido-Quigley, Cristina, Melberg, Hans Olav, Thiele, Maja, Trebicka, Jonel, Krag, Aleksander, Mann, Mathias, Matthijnssens, Jelle, Israelsen, Mads, Madsen, Bjørn Stæhr, Torp, Nikolaj, Johansen, Stine, Hansen, Camilla Dalby, Detlefsen, Sönke, Andersen, Peter, Hansen, Johanne Kragh, Lindvig, Katrine Prier, Rasmussen, Ditlev Nytoft, Thorhauge, Katrine Holtz, Kjærgaard, Maria, and Arumugam, Manimozhiyan

Published
2023
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6. Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis

Author

Bork, Peer, Mann, Mathias, Matthijnssens, Jelle, Krag, Aleksander, Hansen, Torben, Anastasiadou, Ema, Arumugam, Manimozhiyan, Henrar, Roland, Israelsen, Hans, Karsdal, Morten, Legido-Quigley, Cristina, Melberg, Hans Olav, Thiele, Maja, Trebicka, Jonel, Suvitaival, Tommi, Trošt, Kajetan, Kim, Min, de Zawadzki, Andressa, Kjaergaard, Maria, Rasmussen, Ditlev Nytoft, Lindvig, Katrine Prier, Israelsen, Mads, Detlefsen, Sönke, Andersen, Peter, Juel, Helene Bæk, Nielsen, Trine, Georgiou, Stella, Filippa, Vicky, Kuhn, Michael, Nishijima, Suguru, Moitinho-Silva, Lucas, and Rossing, Peter

Published
2023
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7. Review: Opportunities and barriers for omics-based biomarker discovery in steatotic liver diseases

Author

Thiele, Maja, primary, Villesen, Ida Falk, additional, Niu, Lili, additional, Johansen, Stine, additional, Sulek, Karolina, additional, Nishijima, Suguru, additional, Van Espen, Lore, additional, Keller, Marisa, additional, Israelsen, Mads, additional, Suvitaival, Tommi, additional, de Zawadzki, Andressa, additional, Juel, Helene Bæk, additional, Brol, Maximilian Joseph, additional, Stinson, Sara Elisabeth, additional, Huang, Yun, additional, Alvarez Silva, Maria Camilla, additional, Kuhn, Michael, additional, Anastasiadou, Ema, additional, Leeming, Diana Julie, additional, Karsdal, Morten, additional, Matthijnssens, Jelle, additional, Arumugam, Manimozhiyan, additional, Dalgaard, Louise Torp, additional, Legido-Quigley, Cristina, additional, Mann, Mathias, additional, Trebicka, Jonel, additional, Bork, Peer, additional, Jensen, Lars Juhl, additional, Hansen, Torben, additional, Krag, Aleksander, additional, Israelsen, Hans, additional, Melberg, Hans Olav, additional, Thiele, Maja, additional, and Mann, Matthias, additional

Published
2024
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9. Infections Increase The Risk Of Decompensation And Death In Patients With Early Alcohol-Related Liver Disease

Author

Johansen, Stine, primary, Langkjær, Simon, additional, Rasmussen, Ditlev Nytoft, additional, Israelsen, Mads, additional, Torp, Nikolaj, additional, Lindvig, Katrine, additional, Kjærgaard, Maria, additional, Hansen, Johanne Kragh, additional, Hansen, Camilla Dalby, additional, Thorhauge, Katrine, additional, Andersen, Peter, additional, Detlefsen, Sönke, additional, Juel, Helene Bæk, additional, Justesen, Ulrik Stenz, additional, Hansen, Torben, additional, Krag, Aleksander, additional, Thiele, Maja, additional, Anastasiadou, Ema, additional, Arumugam, Manimozhian, additional, Bork, Peer, additional, Presto, Jenny, additional, Israelsen, Hans, additional, Karsdal, Morten, additional, Legido-Quigley, Cristina, additional, Melberg, Hans Olav, additional, Trebicka, Jonel, additional, Mann, Mathias, additional, and Matthijnssens, Jelle, additional

Published
2024
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11. α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Cav3.2 calcium signaling in astrocytes.

Author

Leandrou, Emmanouela, Chalatsa, Ioanna, Anagnostou, Dimitrios, Machalia, Christina, Semitekolou, Maria, Filippa, Vicky, Makridakis, Manousos, Vlahou, Antonia, Anastasiadou, Ema, Vekrellis, Kostas, and Emmanouilidou, Evangelia

Subjects
ALPHA-synuclein, ASTROCYTES, OLIGOMERS, PERIPHERAL nervous system, PARKINSON'S disease, MOVEMENT disorders
Abstract

Background: It is now realized that Parkinson's disease (PD) pathology extends beyond the substantia nigra, affecting both central and peripheral nervous systems, and exhibits a variety of non-motor symptoms often preceding motor features. Neuroinflammation induced by activated microglia and astrocytes is thought to underlie these manifestations. α-Synuclein aggregation has been linked with sustained neuroinflammation in PD, aggravating neuronal degeneration; however, there is still a lack of critical information about the structural identity of the α-synuclein conformers that activate microglia and/or astrocytes and the molecular pathways involved. Methods: To investigate the role of α-synuclein conformers in the development and maintenance of neuroinflammation, we used primary quiescent microglia and astrocytes, post-mortem brain tissues from PD patients and A53T α-synuclein transgenic mice that recapitulate key features of PD-related inflammatory responses in the absence of cell death, i.e., increased levels of pro-inflammatory cytokines and complement proteins. Biochemical and -omics techniques including RNAseq and secretomic analyses, combined with 3D reconstruction of individual astrocytes and live calcium imaging, were used to uncover the molecular mechanisms underlying glial responses in the presence of α-synuclein oligomers in vivo and in vitro. Results: We found that the presence of SDS-resistant hyper-phosphorylated α-synuclein oligomers, but not monomers, was correlated with sustained inflammatory responses, such as elevated levels of endogenous antibodies and cytokines and microglial activation. Similar oligomeric α-synuclein species were found in post-mortem human brain samples of PD patients but not control individuals. Detailed analysis revealed a decrease in Iba1Low/CD68Low microglia and robust alterations in astrocyte number and morphology including process retraction. Our data indicated an activation of the p38/ATF2 signaling pathway mostly in microglia and a sustained induction of the NF-κB pathway in astrocytes of A53T mice. The sustained NF-κB activity triggered the upregulation of astrocytic T-type Cav3.2 Ca2+ channels, altering the astrocytic secretome and promoting the secretion of IGFBPL1, an IGF-1 binding protein with anti-inflammatory and neuroprotective potential. Conclusions: Our work supports a causative link between the neuron-produced α-synuclein oligomers and sustained neuroinflammation in vivo and maps the signaling pathways that are stimulated in microglia and astrocytes. It also highlights the recruitment of astrocytic Cav3.2 channels as a potential neuroprotective mediator against the α-synuclein-induced neuroinflammation. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Microtubule Dynamics Deregulation Induces Apoptosis in Human Urothelial Bladder Cancer Cells via a p53-independent Pathway

Author

Drosos, Yiannis, primary, Konstantakou, Eumorphia G., additional, Bassogianni, Aggeliki-Stefania, additional, Nikolakopoulos, Konstantinos-Stylianos, additional, Koumoundourou, Dimitra G., additional, Markaki, Sophia P., additional, Tsitsilonis, Ourania E., additional, Voutsinas, Gerassimos E., additional, Valakos, Dimitrios, additional, Anastasiadou, Ema, additional, Thanos, Dimitris, additional, Velentzas, Athanassios D., additional, and Stravopodis, Dimitrios J., additional

Published
2023
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14. Rifaximin-α for liver fibrosis in patients with alcohol-related liver disease (GALA-RIF): a randomised, double-blind, placebo-controlled, phase 2 trial

Author

Israelsen, Mads, primary, Madsen, Bjørn Stæhr, additional, Torp, Nikolaj, additional, Johansen, Stine, additional, Hansen, Camilla Dalby, additional, Detlefsen, Sönke, additional, Andersen, Peter, additional, Hansen, Johanne Kragh, additional, Lindvig, Katrine Prier, additional, Rasmussen, Ditlev Nytoft, additional, Thorhauge, Katrine Holtz, additional, Kjærgaard, Maria, additional, Karsdal, Morten, additional, Hansen, Torben, additional, Arumugam, Manimozhiyan, additional, Trebicka, Jonel, additional, Thiele, Maja, additional, Krag, Aleksander, additional, Anastasiadou, Ema, additional, Arumugam, Manimozhian, additional, Bork, Peer, additional, Henrar, Roland, additional, Israelsen, Hans, additional, Legido-Quigley, Cristina, additional, Melberg, Hans Olav, additional, Mann, Mathias, additional, and Matthijnssens, Jelle, additional

Published
2023
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18. SPHINGOLIPIDS ARE DEPLETED IN ALCOHOL-RELATED LIVER FIBROSIS

Author

Thiele, Maja, primary, Suvitaival, Tommi, additional, Trošt, Kajetan, additional, Kim, Min, additional, de Zawadzki, Andressa, additional, Kjaergaard, Maria, additional, Rasmussen, Ditlev Nytoft, additional, Lindvig, Katrine Prier, additional, Israelsen, Mads, additional, Detlefsen, Sönke, additional, Andersen, Peter, additional, Juel, Helene Bæk, additional, Nielsen, Trine, additional, Georgiou, Stella, additional, Filippa, Vicky, additional, Kuhn, Michael, additional, Nishijima, Suguru, additional, Moitinho-Silva, Lucas, additional, Rossing, Peter, additional, Trebicka, Jonel, additional, Anastasiadou, Ema, additional, Bork, Peer, additional, Hansen, Torben, additional, Quigley, Cristina Legido, additional, and Krag, Aleksander, additional

Published
2023
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19. Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis

Author

Thiele, Maja, Suvitaival, Tommi, Trošt, Kajetan, Kim, Min, de Zawadzki, Andressa, Kjaergaard, Maria, Rasmussen, Ditlev Nytoft, Lindvig, Katrine Prier, Israelsen, Mads, Detlefsen, Sönke, Andersen, Peter, Juel, Helene Bæk, Nielsen, Trine, Georgiou, Stella, Filippa, Vicky, Kuhn, Michael, Nishijima, Suguru, Moitinho-Silva, Lucas, Rossing, Peter, Trebicka, Jonel, Anastasiadou, Ema, Bork, Peer, Hansen, Torben, Legido-Quigley, Cristina, Krag, Aleksander, Mann, Mathias, Matthijnssens, Jelle, Arumugam, Manimozhiyan, Henrar, Roland, Israelsen, Hans, Karsdal, Morten, Melberg, Hans Olav, Thiele, Maja, Suvitaival, Tommi, Trošt, Kajetan, Kim, Min, de Zawadzki, Andressa, Kjaergaard, Maria, Rasmussen, Ditlev Nytoft, Lindvig, Katrine Prier, Israelsen, Mads, Detlefsen, Sönke, Andersen, Peter, Juel, Helene Bæk, Nielsen, Trine, Georgiou, Stella, Filippa, Vicky, Kuhn, Michael, Nishijima, Suguru, Moitinho-Silva, Lucas, Rossing, Peter, Trebicka, Jonel, Anastasiadou, Ema, Bork, Peer, Hansen, Torben, Legido-Quigley, Cristina, Krag, Aleksander, Mann, Mathias, Matthijnssens, Jelle, Arumugam, Manimozhiyan, Henrar, Roland, Israelsen, Hans, Karsdal, Morten, and Melberg, Hans Olav

Abstract

Background & Aims: Alcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in alcohol-related liver disease (ALD) is unclear. In this biopsy-controlled, prospective, observational study, we characterized the liver and plasma lipidomes in patients with early ALD. Methods: We performed mass spectrometry–based lipidomics of paired liver and plasma samples from 315 patients with ALD and of plasma from 51 matched healthy controls. We associated lipid levels with histologic fibrosis, inflammation, and steatosis with correction for multiple testing and adjustment for confounders. We further investigated sphingolipid regulation by means of quantitative real-time polymerase chain reaction sequencing of microRNA, prediction of liver-related events, and tested causality with Mendelian randomization. Results: We detected 198 lipids in the liver and 236 lipids in the circulation from 18 lipid classes. Most sphingolipids (sphingomyelins and ceramides) and phosphocholines were co–down-regulated in both liver and plasma, where lower abundance correlated with higher fibrosis stage. Sphingomyelins showed the most pronounced negative correlation to fibrosis, mirrored by negative correlations in both liver and plasma with hepatic inflammation. Reduced sphingomyelins predicted future liver-related events. This seemed to be characteristic of “pure ALD,” as sphingomyelin levels were higher in patients with concomitant metabolic syndrome and ALD/nonalcoholic fatty liver disease overlap. Mendelian randomization in FinnGen and UK Biobanks indicated ALD as the cause of low sphingomyelins, and alcohol use disorder did not correlate with genetic susceptibility to low sphingomyelin levels. Conclusions: Alcohol-related liver fibrosis is characterized by selective and progressive lipid depletion in liver and blood, particularly sphingomyelins, which also associates with progression to liver-related events.

Published
2023

20. Microtubule Dynamics Deregulation Induces Apoptosis in Human Urothelial Bladder Cancer Cells via a p53-Independent Pathway.

Author

Drosos, Yiannis, Konstantakou, Eumorphia G., Bassogianni, Aggeliki-Stefania, Nikolakopoulos, Konstantinos-Stylianos, Koumoundourou, Dimitra G., Markaki, Sophia P., Tsitsilonis, Ourania E., Voutsinas, Gerassimos E., Valakos, Dimitrios, Anastasiadou, Ema, Thanos, Dimitris, Velentzas, Athanassios D., and Stravopodis, Dimitrios J.

Subjects
BLADDER tumors, DNA, COMBINATION drug therapy, ONCOGENES, APOPTOSIS, ANTINEOPLASTIC agents, CELLULAR signal transduction, TREATMENT effectiveness, TUMOR suppressor genes, GENE expression profiling, CELL lines, PACLITAXEL, CYTOPLASM, EPIGENOMICS, PHARMACODYNAMICS
Abstract

Simple Summary: Bladder cancer (BLCA) is considered as a highly prevalent disease that is strongly associated with elevated morbidity, mortality, and cost. Strategies designed to be targeting critical components and processes orchestrating BLCA cells' evolutionary trajectories, towards metastasis and chemoresistance, are necessitated to be promptly developed, and successfully pass the proof-of-principle tests in pre-clinical models and clinical trials. To this direction, DepMap and PRISM project-derived findings, combined with transcriptomics and epigenetic data analysis, have herein unveiled the cardinal roles of microtubule dynamics in the survival and growth of BLCA cells. Most importantly, they can foresee the therapeutic promise of pathway's targeted perturbation, with paclitaxel single scheme and paclitaxel-containing drug-cocktails opening new therapeutic windows for the disease. Bladder cancer (BLCA) is the sixth most common type of cancer and has a dismal prognosis if diagnosed late. To identify treatment options for BLCA, we systematically evaluated data from the Broad Institute DepMap project. We found that urothelial BLCA cell lines are among the most sensitive to microtubule assembly inhibition by paclitaxel treatment. Strikingly, we revealed that the top dependencies in BLCA cell lines include genes encoding proteins involved in microtubule assembly. This highlights the importance of microtubule network dynamics as a major vulnerability in human BLCA. In cancers such as ovarian and breast, where paclitaxel is the gold standard of care, resistance to paclitaxel treatment has been linked to p53-inactivating mutations. To study the response of BLCA to microtubule assembly inhibition and its mechanistic link with the mutational status of the p53 protein, we treated a collection of BLCA cell lines with a dose range of paclitaxel and performed a detailed characterization of the response. We discovered that BLCA cell lines are significantly sensitive to low concentrations of paclitaxel, independently of their p53 status. Paclitaxel induced a G2/M cell cycle arrest and growth inhibition, followed by robust activation of apoptosis. Most importantly, we revealed that paclitaxel triggered a robust DNA-damage response and apoptosis program without activating the p53 pathway. Integration of transcriptomics, epigenetic, and dependency data demonstrated that the response of BLCA to paclitaxel is independent of p53 mutational signatures but strongly depends on the expression of DNA repair genes. Our work highlights urothelial BLCA as an exceptional candidate for paclitaxel treatment. It paves the way for the rational use of a combination of paclitaxel and DNA repair inhibitors as an effective, novel therapeutic strategy. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Validation of scores of PRO‐C3 to predict liver‐related events in alcohol‐related liver disease.

Author

Johansen, Stine, Israelsen, Mads, Villesen, Ida F., Torp, Nikolaj, Nielsen, Mette J., Kjærgaard, Maria, Lindvig, Katrine P., Hansen, Camilla D., Andersen, Peter, Rasmussen, Ditlev N., Detlefsen, Sönke, Leeming, Diana J., Thiele, Maja, Karsdal, Morten, Krag, Aleksander, Anastasiadou, Ema, Arumugam, Manimozhian, Bork, Peer, Hansen, Torben, and Henrar, Roland

Subjects
ALCOHOL-induced disorders, LIVER diseases, HEPATIC fibrosis, LIVER disease diagnosis, SECONDARY care (Medicine)
Abstract

Background and Aims: Risk prediction in alcohol‐related liver disease (ArLD) is an unmet need. We aimed to assess PRO‐C3 models to predict liver‐related events (LRE) in patients with a history of excessive alcohol use without an established diagnosis of chronic liver disease. Methods: A prospective cohort study of 462 patients with ArLD, split into a derivation cohort of 221 secondary care patients and a validation cohort of 241 primary care patients. Baseline variables, including fibrogenesis marker PRO‐C3, were used to develop a prediction model. Prognostic accuracy was compared to enhanced liver fibrosis (ELF), fibrosis‐4‐index (FIB‐4), transient elastography (TE) and ADAPT. Results: In the derivation and validation cohorts, 67 (30%) and 19 (8%) experienced an LRE during a median follow‐up of 5.2 years (IQR: 3.2‐6.8) and 4.0 years (IQR: 2.7‐5.6). On top of PRO‐C3 and ADAPT score, we generated a model (ALPACA) of independent predictors of LREs (PRO‐C3, AST/ALT, platelets). ALPACA had high prognostic accuracy with a C‐statistic of 0.85 in the derivation cohort, comparable to ELF (0.83) and TE (0.84) and significantly higher than FIB‐4 (0.78), PRO‐C3 (0.80) and ADAPT (0.81). In the validation cohort, all tests had comparable C‐statistics. Compared to low‐risk patients (ALPACA ≤11), high‐risk patients (>11) had a subhazard ratio for LREs of 12.6 (95% CI 5.9‐26.8, p <.001) and higher cumulative incidence (57% vs. 7%, p <.001; derivation cohort). We observed similar subhazard ratio in the validation cohort. Conclusions: PRO‐C3‐based scores are reliable tools to predict LREs in ArLD patients and are suitable for risk stratification in primary and secondary care. [ABSTRACT FROM AUTHOR]

Published
2023
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24. Prognostic performance of 7 biomarkers compared to liver biopsy in early alcohol-related liver disease

Author

Rasmussen, Ditlev Nytoft, primary, Thiele, Maja, additional, Johansen, Stine, additional, Kjærgaard, Maria, additional, Lindvig, Katrine Prier, additional, Israelsen, Mads, additional, Antonsen, Steen, additional, Detlefsen, Sönke, additional, Krag, Aleksander, additional, Anastasiadou, Ema, additional, Arumugam, Manimozhian, additional, Bork, Peer, additional, Hansen, Torben, additional, Hartoft, Christina, additional, Israelsen, Hans, additional, Karsdal, Morten, additional, Legido-Quigley, Cristina, additional, Melberg, Hans Olav, additional, Trebicka, Jonel, additional, Mann, Mathias, additional, and Matthijnssens, Jelle, additional

Published
2021
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25. Effects of Ethanol Feeding in Early-Stage NAFLD Mice Induced by Western Diet

Author

Brol, Maximilian Joseph, Georgiou, Stella, Rasmussen, Ditlev Nytoft, Ortiz, Cristina, Klein, Sabine, Schierwagen, Robert, Uschner, Frank Erhard, Eberle, Larissa, Detlefsen, Sönke, Pantazopoulou, Vasiliki I., Thiele, Maja, Filippa, Vasiliki, Torres, Sandra, Anastasiadou, Ema, Krag, Aleksander, and Trebicka, Jonel

Subjects
liver steatosis, ALD, metabolic liver disease, NAFLD, animal model, NASH, ddc:610, mouse
Abstract

Background: The prevalence of metabolic liver diseases is increasing and approved pharmacological treatments are still missing. Many animal models of nonalcoholic fatty liver disease (NAFLD) show a full spectrum of fibrosis, inflammation and steatosis, which does not reflect the human situation since only up to one third of the patients develop fibrosis and nonalcoholic steatohepatitis (NASH). Methods: Seven week old C57Bl/J mice were treated with ethanol, Western diet (WD) or both. The animals’ liver phenotypes were determined through histology, immunohistochemistry, Western blotting, hepatic triglyceride content and gene expression levels. In a human cohort of 80 patients stratified by current alcohol misuse and body mass index, liver histology and gene expression analysis were performed. Results: WD diet and ethanol-treated animals showed severe steatosis, with high hepatic triglyceride content and upregulation of fatty acid synthesis. Mild fibrosis was revealed using Sirius-red stains and gene expression levels of collagen. Inflammation was detected using histology, immunohistochemistry and upregulation of proinflammatory genes. The human cohort of obese drinkers showed similar upregulation in genes related to steatosis, fibrosis and inflammation. Conclusions: We provide a novel murine model for early-stage fatty liver disease suitable for drug testing and investigation of pathophysiology.

Published
2021

26. Association of the Liver and Plasma Lipidomes with the Histological Stage of Alcohol-Related Liver Disease

Author

Thiele, Maja, primary, Suvitaival, Tommi, additional, Trošt, Kajetan, additional, Kim, Min, additional, de Zewadzki, Andressa, additional, Kjaergaard, Maria, additional, Rasmussen, Ditlev Nytoft, additional, Lindvig, Katrine Prier, additional, Israelsen, Mads, additional, Detlefsen, Sönke, additional, Andersen, Peter, additional, Bæk Juel, Helene, additional, Nielsen, Trine, additional, Georgiou, Stella, additional, Filippa, Vicky, additional, Kuhn, Michael, additional, Nishijima, Suguru, additional, Moitinho-Silva, Lucas, additional, Rossing, Peter, additional, Trebicka, Jonel, additional, Anastasiadou, Ema, additional, Bork, Peer, additional, Hansen, Torben, additional, Quigley, Cristina Legido, additional, and Krag, Aleksander, additional

Published
2021
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27. AGO2 localizes to cytokinetic protrusions in a p38-dependent manner and is needed for accurate cell division

Author

Pantazopoulou, Vasiliki I. Delis, Anastasios D. Georgiou, Stella and Pagakis, Stamatis N. Filippa, Vicky Dragona, Eleni and Kloukina, Ismini Chatzitheodoridis, Elias Trebicka, Jonel and Velentzas, Athanassios D. Thiele, Maja Gagos, Sarantis and Thanos, Dimitris Tseleni-Balafouta, Sofia Stravopodis, Dimitrios J. Anastasiadou, Ema

Abstract

Argonaute 2 (AGO2) is an indispensable component of the RNA-induced silencing complex, operating at the translational or posttranscriptional level. It is compartmentalized into structures such as GW- and P-bodies, stress granules and adherens junctions as well as the midbody. Here we show using immunofluorescence, image and bioinformatic analysis and cytogenetics that AGO2 also resides in membrane protrusions such as open- and close-ended tubes. The latter are cytokinetic bridges where AGO2 colocalizes at the midbody arms with cytoskeletal components such as alpha-Tau ubulin and Aurora B, and various kinases. AGO2, phosphorylated on serine 387, is located together with Dicer at the midbody ring in a manner dependent on p38 MAPK activity. We further show that AGO2 is stress sensitive and important to ensure the proper chromosome segregation and cytokinetic fidelity. We suggest that AGO2 is part of a regulatory mechanism triggered by cytokinetic stress to generate the appropriate micro-environment for local transcript homeostasis. Pantazopoulou et al. find that AGO2 resides in open-ended tunneling nanotubes and close-ended cytokinetic bridges. At the latter location, AGO2 colocalizes with cell division components and the authors show that AGO2 depletion impairs cell division fidelity.

Published
2021

28. Prognostic performance of 7 biomarkers compared to liver biopsy in early alcohol-related liver disease

Author

Rasmussen, Ditlev Nytoft, Thiele, Maja, Johansen, Stine, Kjærgaard, Maria, Lindvig, Katrine Prier, Israelsen, Mads, Antonsen, Steen, Detlefsen, Sönke, Krag, Aleksander, Anastasiadou, Ema, Arumugam, Manimozhian, Bork, Peer, Hansen, Torben, Hartoft, Christina, Israelsen, Hans, Karsdal, Morten, Legido-Quigley, Cristina, Melberg, Hans Olav, Trebicka, Jonel, Mann, Mathias, Matthijnssens, Jelle, Rasmussen, Ditlev Nytoft, Thiele, Maja, Johansen, Stine, Kjærgaard, Maria, Lindvig, Katrine Prier, Israelsen, Mads, Antonsen, Steen, Detlefsen, Sönke, Krag, Aleksander, Anastasiadou, Ema, Arumugam, Manimozhian, Bork, Peer, Hansen, Torben, Hartoft, Christina, Israelsen, Hans, Karsdal, Morten, Legido-Quigley, Cristina, Melberg, Hans Olav, Trebicka, Jonel, Mann, Mathias, and Matthijnssens, Jelle

Abstract

Background & Aims: Alcohol is the most common cause of liver-related mortality and morbidity. We therefore aimed to assess and compare the prognostic performance of elastography and blood-based markers to predict time to the first liver-related event, severe infection, and all-cause mortality in patients with a history of excess drinking. Methods: We performed a prospective cohort study in patients with early, compensated alcohol-related liver disease. At baseline, we obtained a liver biopsy, transient elastography (TE), 2-dimensional shear-wave elastography (2D-SWE), enhanced liver fibrosis test (ELF), FibroTest, fibrosis-4 index (FIB-4), non-alcoholic fatty liver fibrosis score (NFS) and Forns index. We compared C-statistics and time-dependent AUC for prognostication. We used validated cut-off points to create 3 risk groups for each test: low, intermediate and high risk. Results: We followed 462 patients for a median of 49 months (IQR 31–70). Median age was 57 years, 76% were males, 20% had advanced fibrosis. Eighty-four patients (18%) developed a liver-related event after a median of 18 months (7-34). TE had the highest prognostic accuracy, with a C-statistic of 0.876, and time-dependent AUC at 5 years of 0.889, comparable to 2D-SWE and ELF. TE, ELF and 2D-SWE outperformed FibroTest, FIB4, NFS, Forns index and biopsy-verified fibrosis stage. Compared to patients with TE <10 kPa, the hazard ratios for liver-related events for TE 10–15 kPa were 8.1 (3.2–20.4), and 27.9 (13.8–56.8) for TE >15 kPa. Periods of excessive drinking during follow-up increased the risk of progressing to liver-related events, except for patients in the low-risk groups. Conclusion: TE, ELF and 2D-SWE are highly accurate prognostic markers in patients with alcohol-related liver disease. Easy-to-use cut-offs can distinguish between substantially different risk profiles. Lay summary: Alcohol is the leading cause of death and illness due to liver disease. In this study, we assessed

Published
2021

29. Effects of ethanol feeding in early-stage NAFLD mice induced by western diet

Author

Brol, Maximilian, Georgiou, Stella, Rasmussen, Ditlev Nytoft, Ortiz, Cristina, Klein, Sabine, Schierwagen, Robert, Uschner, Frank Erhard, Eberle, Larissa, Detlefsen, Sönke, Pantazopoulou, Vasiliki I., Thiele, Maja, Filippa, Vasiliki, Torres Núñez, Sandra, Anastasiadou, Ema, Krag, Aleksander, Trebicka, Jonel, Brol, Maximilian, Georgiou, Stella, Rasmussen, Ditlev Nytoft, Ortiz, Cristina, Klein, Sabine, Schierwagen, Robert, Uschner, Frank Erhard, Eberle, Larissa, Detlefsen, Sönke, Pantazopoulou, Vasiliki I., Thiele, Maja, Filippa, Vasiliki, Torres Núñez, Sandra, Anastasiadou, Ema, Krag, Aleksander, and Trebicka, Jonel

Abstract

Background: The prevalence of metabolic liver diseases is increasing and approved pharmacological treatments are still missing. Many animal models of nonalcoholic fatty liver disease (NAFLD) show a full spectrum of fibrosis, inflammation and steatosis, which does not reflect the human situation since only up to one third of the patients develop fibrosis and nonalcoholic steatohepatitis (NASH). Methods: Seven week old C57Bl/J mice were treated with ethanol, Western diet (WD) or both. The animals’ liver phenotypes were determined through histology, immunohistochemistry, Western blotting, hepatic triglyceride content and gene expression levels. In a human cohort of 80 patients stratified by current alcohol misuse and body mass index, liver histology and gene expression analysis were performed. Results: WD diet and ethanol-treated animals showed severe steatosis, with high hepatic triglyceride content and upregulation of fatty acid synthesis. Mild fibrosis was revealed using Sirius-red stains and gene expression levels of collagen. Inflammation was detected using histology, immunohistochemistry and upregulation of proinflammatory genes. The human cohort of obese drinkers showed similar upregulation in genes related to steatosis, fibrosis and inflammation. Conclusions: We provide a novel murine model for early-stage fatty liver disease suitable for drug testing and investigation of pathophysiology.

Published
2021

31. From Proteomic Mapping to Invasion-Metastasis-Cascade Systemic Biomarkering and Targeted Drugging of Mutant BRAF-Dependent Human Cutaneous Melanomagenesis

Author

Giannopoulou, Aikaterini F., primary, Velentzas, Athanassios D., additional, Anagnostopoulos, Athanasios K., additional, Agalou, Adamantia, additional, Papandreou, Nikos C., additional, Katarachia, Stamatia A., additional, Koumoundourou, Dimitra G., additional, Konstantakou, Eumorphia G., additional, Pantazopoulou, Vasiliki I., additional, Delis, Anastasios, additional, Michailidi, Maria T., additional, Valakos, Dimitrios, additional, Chatzopoulos, Dimitris, additional, Syntichaki, Popi, additional, Iconomidou, Vassiliki A., additional, Tsitsilonis, Ourania E., additional, Papassideri, Issidora S., additional, Voutsinas, Gerassimos E., additional, Hatzopoulos, Polydefkis, additional, Thanos, Dimitris, additional, Beis, Dimitris, additional, Anastasiadou, Ema, additional, Tsangaris, George Th., additional, and Stravopodis, Dimitrios J., additional

Published
2021
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32. Effects of Ethanol Feeding in Early-Stage NAFLD Mice Induced by Western Diet

Author

Brol, Maximilian Joseph, primary, Georgiou, Stella, additional, Rasmussen, Ditlev Nytoft, additional, Ortiz, Cristina, additional, Klein, Sabine, additional, Schierwagen, Robert, additional, Uschner, Frank Erhard, additional, Eberle, Larissa, additional, Detlefsen, Sönke, additional, Pantazopoulou, Vasiliki I., additional, Thiele, Maja, additional, Filippa, Vasiliki, additional, Torres, Sandra, additional, Anastasiadou, Ema, additional, Krag, Aleksander, additional, and Trebicka, Jonel, additional

Published
2021
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39. Progressive alcohol‐related liver fibrosis is characterised by imbalanced collagen formation and degradation.

Author

Thiele, Maja, Johansen, Stine, Gudmann, Natasja S., Madsen, Bjørn, Kjærgaard, Maria, Nielsen, Mette Juul, Leeming, Diana J., Jacobsen, Suganya, Bendtsen, Flemming, Møller, Søren, Detlefsen, Sönke, Karsdal, Morten, Krag, Aleksander, Arumugam, Manimozhian, Bork, Peer, Hansen, Torben, Anastasiadou, Ema, Hartoft, Christina, Israelsen, Hans, and Legido‐Quigley, Cristina

Subjects
FIBROSIS, BASAL lamina, ALCOHOL-induced disorders, EXTRACELLULAR matrix, LIVER diseases, COLLAGEN
Abstract

Summary: Background: Liver fibrosis accumulation is considered a turnover disease, with formation exceeding degradation, although this hypothesis has never been tested in humans. Aims: To investigate extracellular matrix (ECM) remodelling in a biopsy‐controlled study of alcohol‐related liver disease (ALD) patients. Methods: We evaluated the relationship between formation and degradation of four collagens as a function of histological fibrosis, inflammation and steatosis in 281 patients with ALD and 50 matched healthy controls. Post hoc, we tested the findings in a cohort of patients with alcohol‐related cirrhosis and assessed the collagens' prognostic accuracy. We assessed the fibrillar collagens type III (PRO‐C3/C3M) and V (PRO‐C5/C5M), the basement membrane collagen IV (PRO‐C4/C4M), and the microfilament interface collagen VI (PRO‐C6/C6M). Results: Mean age was 54 ± 6 years, 74% male, fibrosis stage F0/1/2/3/4 = 33/98/84/18/48. Compared to controls, patients with ALD had higher levels of type III collagen formation and degradation, with the highest concentrations in those with cirrhosis (PRO‐C3 = 8.2 ± 1.7 ng/mL in controls, 14.6 ± 13.5 in ALD, 34.8 ± 23.1 in cirrhosis; C3M 7.4 ± 1.9 in controls, 9.3 ± 4.4 in ALD, 14.0 ± 5 in cirrhosis). ECM remodelling became increasingly imbalanced in higher stages of liver fibrosis, with formation progressively superseding degradation. This was particularly pronounced for type III collagen. We observed similar imbalance for inflammatory severity, but not steatosis. Conclusions: ALD is characterised by both elevated collagen formation and degradation, which becomes increasingly imbalanced with more severe disease. Net increase in fibrillar collagens contributes to fibrosis progression. This has important implications for monitoring and very early identification of patients at highest risk of progressing to cirrhosis. [ABSTRACT FROM AUTHOR]

Published
2021
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42. Revisiting Histone Deacetylases in Human Tumorigenesis: The Paradigm of Urothelial Bladder Cancer

Author

Giannopoulou, Aikaterini, primary, Velentzas, Athanassios, additional, Konstantakou, Eumorphia, additional, Avgeris, Margaritis, additional, Katarachia, Stamatia, additional, Papandreou, Nikos, additional, Kalavros, Nikolas, additional, Mpakou, Vassiliki, additional, Iconomidou, Vassiliki, additional, Anastasiadou, Ema, additional, Kostakis, Ioannis, additional, Papassideri, Issidora, additional, Voutsinas, Gerassimos, additional, Scorilas, Andreas, additional, and Stravopodis, Dimitrios, additional

Published
2019
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43. Gene-Specific Intron Retention Serves as Molecular Signature that Distinguishes Melanoma from Non-Melanoma Cancer Cells in Greek Patients

Author

Giannopoulou, Aikaterini, primary, Konstantakou, Eumorphia, additional, Velentzas, Athanassios, additional, Avgeris, Socratis, additional, Avgeris, Margaritis, additional, Papandreou, Nikos, additional, Zoi, Ilianna, additional, Filippa, Vicky, additional, Katarachia, Stamatia, additional, Lampidonis, Antonis, additional, Prombona, Anastasia, additional, Syntichaki, Popi, additional, Piperi, Christina, additional, Basdra, Efthimia, additional, Iconomidou, Vassiliki, additional, Papadavid, Evangelia, additional, Anastasiadou, Ema, additional, Papassideri, Issidora, additional, Papavassiliou, Athanasios, additional, Voutsinas, Gerassimos, additional, Scorilas, Andreas, additional, and Stravopodis, Dimitrios, additional

Published
2019
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44. Targeting of copper-trafficking chaperones causes gene-specific systemic pathology inDrosophila melanogaster: prospective expansion of mutational landscapes that regulate tumor resistance to cisplatin

Author

Theotoki, Eleni I., primary, Velentzas, Athanassios D., additional, Katarachia, Stamatia A., additional, Papandreou, Nikos C., additional, Kalavros, Nikolas I., additional, Pasadaki, Sofia N., additional, Giannopoulou, Aikaterini F., additional, Giannios, Panagiotis, additional, Iconomidou, Vassiliki, additional, Konstantakou, Eumorphia G., additional, Anastasiadou, Ema, additional, Papassideri, Issidora S., additional, and Stravopodis, Dimitrios J., additional

Published
2019
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45. H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor β gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22)

Author

Schwaller, Juerg, Anastasiadou, Ema, Cain, Danielle, Kutok, Jeff, Wojiski, Sarah, Williams, Ifor R., LaStarza, Roberta, Crescenzi, Barbara, Sternberg, David W., Andreasson, Patrick, Schiavo, Roberta, Siena, Salvatore, Mecucci, Cristina, and Gilliland, D. Gary

Published
2001
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48. A High-Resolution Proteomic Landscaping of Primary Human Dental Stem Cells: Identification of SHED- and PDLSC-Specific Biomarkers

Author

Taraslia, Vasiliki, primary, Lymperi, Stefania, additional, Pantazopoulou, Vasiliki, additional, Anagnostopoulos, Athanasios, additional, Papassideri, Issidora, additional, Basdra, Efthimia, additional, Bei, Marianna, additional, Kontakiotis, Evangelos, additional, Tsangaris, George, additional, Stravopodis, Dimitrios, additional, and Anastasiadou, Ema, additional

Published
2018
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49. Deep-proteome mapping of WM-266-4 human metastatic melanoma cells: From oncogenic addiction to druggable targets

Author

Konstantakou, Eumorphia G., primary, Velentzas, Athanassios D., additional, Anagnostopoulos, Athanasios K., additional, Litou, Zoi I., additional, Konstandi, Ourania A., additional, Giannopoulou, Aikaterini F., additional, Anastasiadou, Ema, additional, Voutsinas, Gerassimos E., additional, Tsangaris, George Th., additional, and Stravopodis, Dimitrios J., additional

Published
2017
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