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1. Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication

Author

Liu, Kaijing, Wehling, Lilija, Wan, Shan, Weiler, Sofia M. E., Tóth, Marcell, Ibberson, David, Marhenke, Silke, Ali, Adnan, Lam, Macrina, Guo, Te, Pinna, Federico, Pedrini, Fabiola, Damle-Vartak, Amruta, Dropmann, Anne, Rose, Fabian, Colucci, Silvia, Cheng, Wenxiang, Bissinger, Michaela, Schmitt, Jennifer, Birner, Patrizia, Poth, Tanja, Angel, Peter, Dooley, Steven, Muckenthaler, Martina U., Longerich, Thomas, Vogel, Arndt, Heikenwälder, Mathias, Schirmacher, Peter, and Breuhahn, Kai

Published
2024
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4. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis

Author

Stickel, Felix, Buch, Stephan, Nischalke, Hans Dieter, Weiss, Karl Heinz, Gotthardt, Daniel, Fischer, Janett, Rosendahl, Jonas, Marot, Astrid, Elamly, Mona, Casper, Markus, Lammert, Frank, McQuillin, Andrew, Zopf, Steffen, Spengler, Ulrich, Marhenke, Silke, Kirstein, Martha M., Vogel, Arndt, Eyer, Florian, von Felden, Johann, Wege, Henning, Buch, Thorsten, Schafmayer, Clemens, Braun, Felix, Deltenre, Pierre, Berg, Thomas, Morgan, Marsha Y., and Hampe, Jochen

Published
2018
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6. Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: Results from a genome-wide case-control study

Author

Buch, Stephan, Innes, Hamish, Lutz, Philipp Ludwig, Nischalke, Hans Dieter, Marquardt, Jens U, Fischer, Janett, Weiss, Karl Heinz, Rosendahl, Jonas, Marot, Astrid, Krawczyk, Marcin, Casper, Markus, Lammert, Frank, Eyer, Florian, Vogel, Arndt, Marhenke, Silke, Von Felden, Johann, Sharma, Rohini, Atkinson, Stephen Rahul, McQuillin, Andrew, Nattermann, Jacob, Schafmayer, Clemens, Franke, Andre, Strassburg, Christian, Rietschel, Marcella, Altmann, Heidi, Sulk, Stefan, Thangapandi, Veera Raghavan, Brosch, Mario, Lackner, Carolin, Stauber, Rudolf E, Canbay, Ali, Link, Alexander, Reiberger, Thomas, Mandorfer, Mattias, Semmler, Georg, Scheiner, Bernhard, Datz, Christian, Romeo, Stefano, Ginanni Corradini, Stefano, Irving, William Lucien, Morling, Joanne R., Guha, Indra Neil, Barnes, Eleanor, Ansari, M. Azim, Quistrebert, Jocelyn, Valenti, Luca, Morgan, Marsha Yvonne, Trebicka, Jonel, Berg, Thomas, Deltenre, Pierre, Mueller, Sebastian, Hampe, Jochen, and Stickel, Felix

Subjects
Gastroenterology
Abstract

Objective: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. Design: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). Results: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-Analysis, at genome-wide significance (p=6.41×10-9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10-5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10-44). Conclusion: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

Published
2022

7. Genetic variation inTERTmodifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study

Author

Buch, Stephan, primary, Innes, Hamish, additional, Lutz, Philipp Ludwig, additional, Nischalke, Hans Dieter, additional, Marquardt, Jens U, additional, Fischer, Janett, additional, Weiss, Karl Heinz, additional, Rosendahl, Jonas, additional, Marot, Astrid, additional, Krawczyk, Marcin, additional, Casper, Markus, additional, Lammert, Frank, additional, Eyer, Florian, additional, Vogel, Arndt, additional, Marhenke, Silke, additional, von Felden, Johann, additional, Sharma, Rohini, additional, Atkinson, Stephen Rahul, additional, McQuillin, Andrew, additional, Nattermann, Jacob, additional, Schafmayer, Clemens, additional, Franke, Andre, additional, Strassburg, Christian, additional, Rietschel, Marcella, additional, Altmann, Heidi, additional, Sulk, Stefan, additional, Thangapandi, Veera Raghavan, additional, Brosch, Mario, additional, Lackner, Carolin, additional, Stauber, Rudolf E, additional, Canbay, Ali, additional, Link, Alexander, additional, Reiberger, Thomas, additional, Mandorfer, Mattias, additional, Semmler, Georg, additional, Scheiner, Bernhard, additional, Datz, Christian, additional, Romeo, Stefano, additional, Ginanni Corradini, Stefano, additional, Irving, William Lucien, additional, Morling, Joanne R, additional, Guha, Indra Neil, additional, Barnes, Eleanor, additional, Ansari, M Azim, additional, Quistrebert, Jocelyn, additional, Valenti, Luca, additional, Müller, Sascha A, additional, Morgan, Marsha Yvonne, additional, Dufour, Jean-François, additional, Trebicka, Jonel, additional, Berg, Thomas, additional, Deltenre, Pierre, additional, Mueller, Sebastian, additional, Hampe, Jochen, additional, and Stickel, Felix, additional

Published
2022
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9. Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results form a genome-wide case-control study

Author

Buch, Stephan, primary, Innes, Hamish, additional, Lutz, Philipp, additional, Nischalke, Hans Dieter, additional, Nattermann, Jacob, additional, Marquardt, Jens U., additional, Fischer, Janett, additional, Weiss, Karl Heinz, additional, Rosendahl, Jonas, additional, Marot, Astrid, additional, Krawczyk, Marcin, additional, Casper, Markus, additional, Lammert, Frank, additional, Eyer, Florian, additional, Vogel, Arndt, additional, Marhenke, Silke, additional, von Felden, Johann, additional, Sharma, Rohini, additional, Atkinson, Stephen, additional, McQuillin, Andrew, additional, Schafmayer, Clemens, additional, Strassburg, Christian, additional, Altmann, Heidi, additional, Sulk, Stefan, additional, Thangapandi, Veera Raghavan, additional, Brosch, Mario, additional, Lackner, Carolin, additional, Stauber, Rudolf E., additional, Canbay, Ali, additional, Link, Alexander, additional, Reiberger, Thomas, additional, Mandorfer, Mattias, additional, Semmler, Georg, additional, Scheiner, Bernhard, additional, Datz, Christian, additional, Romeo, Stefano, additional, Corradini, Stefano Ginanni, additional, Valenti, Luca, additional, Müller, Sascha, additional, Morgan, Marsha, additional, Dufour, Jean-Francois, additional, Trebicka, Jonel, additional, Berg, Thomas, additional, Deltenre, Pierre, additional, Mueller, Sebastian, additional, Hampe, Jochen, additional, and Stickel, Felix, additional

Published
2022
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10. Genetic variation in modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.

Author

UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de gastro-entérologie, Buch, Stephan, Innes, Hamish, Lutz, Philipp Ludwig, Nischalke, Hans Dieter, Marquardt, Jens U, Fischer, Janett, Weiss, Karl Heinz, Rosendahl, Jonas, Marot, Astrid, Krawczyk, Marcin, Casper, Markus, Lammert, Frank, Eyer, Florian, Vogel, Arndt, Marhenke, Silke, von Felden, Johann, Sharma, Rohini, Atkinson, Stephen Rahul, McQuillin, Andrew, Nattermann, Jacob, Schafmayer, Clemens, Franke, Andre, Strassburg, Christian, Rietschel, Marcella, Altmann, Heidi, Sulk, Stefan, Thangapandi, Veera Raghavan, Brosch, Mario, Lackner, Carolin, Stauber, Rudolf E, Canbay, Ali, Link, Alexander, Reiberger, Thomas, Mandorfer, Mattias, Semmler, Georg, Scheiner, Bernhard, Datz, Christian, Romeo, Stefano, Ginanni Corradini, Stefano, Irving, William Lucien, Morling, Joanne R, Guha, Indra Neil, Barnes, Eleanor, Ansari, M Azim, Quistrebert, Jocelyn, Valenti, Luca, Müller, Sascha A, Morgan, Marsha Yvonne, Dufour, Jean-François, Trebicka, Jonel, Berg, Thomas, Deltenre, Pierre, Mueller, Sebastian, Hampe, Jochen, Stickel, Felix, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de gastro-entérologie, Buch, Stephan, Innes, Hamish, Lutz, Philipp Ludwig, Nischalke, Hans Dieter, Marquardt, Jens U, Fischer, Janett, Weiss, Karl Heinz, Rosendahl, Jonas, Marot, Astrid, Krawczyk, Marcin, Casper, Markus, Lammert, Frank, Eyer, Florian, Vogel, Arndt, Marhenke, Silke, von Felden, Johann, Sharma, Rohini, Atkinson, Stephen Rahul, McQuillin, Andrew, Nattermann, Jacob, Schafmayer, Clemens, Franke, Andre, Strassburg, Christian, Rietschel, Marcella, Altmann, Heidi, Sulk, Stefan, Thangapandi, Veera Raghavan, Brosch, Mario, Lackner, Carolin, Stauber, Rudolf E, Canbay, Ali, Link, Alexander, Reiberger, Thomas, Mandorfer, Mattias, Semmler, Georg, Scheiner, Bernhard, Datz, Christian, Romeo, Stefano, Ginanni Corradini, Stefano, Irving, William Lucien, Morling, Joanne R, Guha, Indra Neil, Barnes, Eleanor, Ansari, M Azim, Quistrebert, Jocelyn, Valenti, Luca, Müller, Sascha A, Morgan, Marsha Yvonne, Dufour, Jean-François, Trebicka, Jonel, Berg, Thomas, Deltenre, Pierre, Mueller, Sebastian, Hampe, Jochen, and Stickel, Felix

Abstract

Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). Associations with variants rs738409 in and rs58542926 in previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in was associated with an increased leucocyte telomere length (p=2.12×10). This study identifies rs2242652 in as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

Published
2022

11. Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol- related cirrhosis: results from a genome- wide case- control study.

Author

Buch, Stephan, Innes, Hamish, Nischalke, Philipp Ludwig Lutz Hans Dieter, Marquardt, Jens U., Fischer, Janett, Weiss, Karl Heinz, Rosendahl, Jonas, Marot, Astrid, Krawczyk, Marcin, Casper, Markus, Lammert, Frank, Eyer, Florian, Vogel, Arndt, Marhenke, Silke, von Felden, Johann, Sharma, Rohini, and Atkinson, Stephen Rahul

Subjects
GENETIC variation, HEPATOCELLULAR carcinoma, FATTY liver, PROSTATE cancer, CIRRHOSIS of the liver, MOLECULAR biology, GENETIC epidemiology
Published
2023
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12. The Co‐mutational Spectrum Determines the Therapeutic Response in Murine FGFR2 Fusion‐Driven Cholangiocarcinoma

Author

Kendre, Gajanan, primary, Marhenke, Silke, additional, Lorz, Georgina, additional, Becker, Diana, additional, Reineke‐Plaaß, Tanja, additional, Poth, Tanja, additional, Murugesan, Karthikeyan, additional, Kühnel, Florian, additional, Woller, Norman, additional, Wirtz, Ralph M., additional, Pich, Andreas, additional, Marquardt, Jens U., additional, Saborowski, Michael, additional, Vogel, Arndt, additional, and Saborowski, Anna, additional

Published
2021
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13. Correction: Genetic Variants in PNPLA3 and TM6SF2 Predispose to the Development of Hepatocellular Carcinoma in Individuals With Alcohol-Related Cirrhosis

Author

Stickel, Felix, Buch, Stephan, Nischalke, Hans Dieter, Weiss, Karl Heinz, Gotthardt, Daniel, Fischer, Janett, Rosendahl, Jonas, Marot, Astrid, Elamly, Mona, Casper, Markus, Lammert, Frank, McQuillin, Andrew, Zopf, Steffen, Spengler, Ulrich, Marhenke, Silke, Kirstein, Martha M., Vogel, Arndt, Eyer, Florian, von Felden, Johann, Wege, Henning, Buch, Thorsten, Schafmayer, Clemens, Braun, Felix, Deltenre, Pierre, Berg, Thomas, Morgan, Marsha Y., and Hampe, Jochen

Published
2018
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16. The TNFR1 Antagonist Atrosimab Is Therapeutic in Mouse Models of Acute and Chronic Inflammation

Author

Richter, Fabian, primary, Williams, Sarah K., additional, John, Katharina, additional, Huber, Carina, additional, Vaslin, Camille, additional, Zanker, Henri, additional, Fairless, Richard, additional, Pichi, Kira, additional, Marhenke, Silke, additional, Vogel, Arndt, additional, Dhaen, Marie-Ann, additional, Herrmann, Stefanie, additional, Herrmann, Andreas, additional, Pfizenmaier, Klaus, additional, Bantel, Heike, additional, Diem, Ricarda, additional, Kontermann, Roland E., additional, and Fischer, Roman, additional

Published
2021
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17. p21 promotes sustained liver regeneration and hepatocarcinogenesis in chronic cholestatic liver injury

Author

Marhenke, Silke, Buitrago-Molina, Laura Elisa, Endig, Jessica, Orlik, Johanna, Schweitzer, Nora, Klett, Stephanie, Longerich, Thomas, Geffers, Robert, Sánchez Muñoz, Aránzazu, Dorrell, Craig, Katz, Sarah-Fee, Lechel, André, Weng, Honglei, Krech, Till, Lehmann, Ulrich, Dooley, Steven, Rudolph, Karl Lenhard, Manns, Michael P, and Vogel, Arndt

Published
2014
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18. Genetic variation in TERTmodifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study

Author

Buch, Stephan, Innes, Hamish, Lutz, Philipp Ludwig, Nischalke, Hans Dieter, Marquardt, Jens U, Fischer, Janett, Weiss, Karl Heinz, Rosendahl, Jonas, Marot, Astrid, Krawczyk, Marcin, Casper, Markus, Lammert, Frank, Eyer, Florian, Vogel, Arndt, Marhenke, Silke, von Felden, Johann, Sharma, Rohini, Atkinson, Stephen Rahul, McQuillin, Andrew, Nattermann, Jacob, Schafmayer, Clemens, Franke, Andre, Strassburg, Christian, Rietschel, Marcella, Altmann, Heidi, Sulk, Stefan, Thangapandi, Veera Raghavan, Brosch, Mario, Lackner, Carolin, Stauber, Rudolf E, Canbay, Ali, Link, Alexander, Reiberger, Thomas, Mandorfer, Mattias, Semmler, Georg, Scheiner, Bernhard, Datz, Christian, Romeo, Stefano, Ginanni Corradini, Stefano, Irving, William Lucien, Morling, Joanne R, Guha, Indra Neil, Barnes, Eleanor, Ansari, M Azim, Quistrebert, Jocelyn, Valenti, Luca, Mu¨ller, Sascha A, Morgan, Marsha Yvonne, Dufour, Jean-Francois, Trebicka, Jonel, Berg, Thomas, Deltenre, Pierre, Mueller, Sebastian, Hampe, Jochen, and Stickel, Felix

Abstract

ObjectiveHepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis.DesignPatients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina).ResultsAssociations with variants rs738409 in PNPLA3and rs58542926 in TM6SF2previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT(telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10−9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10−5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERTwas associated with an increased leucocyte telomere length (p=2.12×10−44).ConclusionThis study identifies rs2242652 in TERTas a novel protective factor for HCC in patients with alcohol-related cirrhosis.

Published
2023
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22. Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers

Author

Stickel, Felix, primary, Lutz, Philipp, additional, Buch, Stephan, additional, Nischalke, Hans Dieter, additional, Silva, Ines, additional, Rausch, Vanessa, additional, Fischer, Janett, additional, Weiss, Karl Heinz, additional, Gotthardt, Daniel, additional, Rosendahl, Jonas, additional, Marot, Astrid, additional, Elamly, Mona, additional, Krawczyk, Marcin, additional, Casper, Markus, additional, Lammert, Frank, additional, Buckley, Thomas W. M., additional, McQuillin, Andrew, additional, Spengler, Ulrich, additional, Eyer, Florian, additional, Vogel, Arndt, additional, Marhenke, Silke, additional, von Felden, Johann, additional, Wege, Henning, additional, Sharma, Rohini, additional, Atkinson, Stephen, additional, Franke, Andre, additional, Nehring, Sophie, additional, Moser, Vincent, additional, Schafmayer, Clemens, additional, Spahr, Laurent, additional, Lackner, Carolin, additional, Stauber, Rudolf E., additional, Canbay, Ali, additional, Link, Alexander, additional, Valenti, Luca, additional, Grove, Jane I., additional, Aithal, Guruprasad P., additional, Marquardt, Jens U., additional, Fateen, Waleed, additional, Zopf, Steffen, additional, Dufour, Jean‐Francois, additional, Trebicka, Jonel, additional, Datz, Christian, additional, Deltenre, Pierre, additional, Mueller, Sebastian, additional, Berg, Thomas, additional, Hampe, Jochen, additional, and Morgan, Marsha Y., additional

Published
2020
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24. Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury

Author

Römermann, Dorothee, primary, Ansari, Nadiea, additional, Schultz‐Moreira, Adriana Rita, additional, Michael, Alina, additional, Marhenke, Silke, additional, Hardtke‐Wolenski, Matthias, additional, Longerich, Thomas, additional, Manns, Michael P., additional, Wedemeyer, Heiner, additional, Vogel, Arndt, additional, and Buitrago‐Molina, Laura Elisa, additional

Published
2020
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25. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Author

Strnad, Pavel, Buch, Stephan, Hamesch, Karim, Fischer, Janett, Rosendahl, Jonas, Schmelz, Renate, Brueckner, Stefan, Brosch, Mario, Heimes, Carolin V., Woditsch, Vivien, Scholten, David, Nischalke, Hans Dieter, Janciauskiene, Sabina, Mandorfer, Mattias, Trauner, Michael, Way, Michael J., McQuillin, Andrew, Reichert, Matthias C., Krawczyk, Marcin, Casper, Markus, Lammert, Frank, von Schoenfels, Witigo, Hinz, Sebastian, Burmeister, Greta, Hellerbrand, Claus, Teufel, Andreas, Feldman, Alexandra, Schattenberg, Joern M., Bantel, Heike, Pathil, Anita, Demir, Muenevver, Kluwe, Johannes, Boettler, Tobias, Ridinger, Monika, Wodarz, Norbert, Soyka, Michael, Rietschel, Marcella, Kiefer, Falk, Weber, Thomas, Marhenke, Silke, Vogel, Arndt, Hinrichsen, Holger, Canbay, Ali, Schlattjan, Martin, Sosnowsky, Katharina, Sarrazin, Christoph, von Felden, Johann, Geier, Andreas, Deltenre, Pierre, Sipos, Bence, Schafmayer, Clemens, Nothnagel, Michael, Aigner, Elmar, Datz, Christian, Stickel, Felix, Morgan, Marsha Yvonne, Hampe, Jochen, Berg, Thomas, Trautwein, Christian, Strnad, Pavel, Buch, Stephan, Hamesch, Karim, Fischer, Janett, Rosendahl, Jonas, Schmelz, Renate, Brueckner, Stefan, Brosch, Mario, Heimes, Carolin V., Woditsch, Vivien, Scholten, David, Nischalke, Hans Dieter, Janciauskiene, Sabina, Mandorfer, Mattias, Trauner, Michael, Way, Michael J., McQuillin, Andrew, Reichert, Matthias C., Krawczyk, Marcin, Casper, Markus, Lammert, Frank, von Schoenfels, Witigo, Hinz, Sebastian, Burmeister, Greta, Hellerbrand, Claus, Teufel, Andreas, Feldman, Alexandra, Schattenberg, Joern M., Bantel, Heike, Pathil, Anita, Demir, Muenevver, Kluwe, Johannes, Boettler, Tobias, Ridinger, Monika, Wodarz, Norbert, Soyka, Michael, Rietschel, Marcella, Kiefer, Falk, Weber, Thomas, Marhenke, Silke, Vogel, Arndt, Hinrichsen, Holger, Canbay, Ali, Schlattjan, Martin, Sosnowsky, Katharina, Sarrazin, Christoph, von Felden, Johann, Geier, Andreas, Deltenre, Pierre, Sipos, Bence, Schafmayer, Clemens, Nothnagel, Michael, Aigner, Elmar, Datz, Christian, Stickel, Felix, Morgan, Marsha Yvonne, Hampe, Jochen, Berg, Thomas, and Trautwein, Christian

Abstract

Objective Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (' Pi* Z' and ' Pi* S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. Design We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi* Z and Pi* S variants was performed. Results T he Pi* Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p< 0.0001). Accordingly, the Pi* Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi* Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p< 0.0001). Correspondingly, alcohol misusers carrying the Pi* Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi* S variant was not associated with NAFLDrelated cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). Conclusion T he Pi* Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi* S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi* Z carriers, this finding should be considered in genetic counselling of affected individuals.

Published
2019

26. Hepatocyte-specific S100a8 and S100a9 transgene expression in mice causes Cxcl1 induction and systemic neutrophil enrichment

Author

Wiechert Lars, Németh Julia, Pusterla Tobias, Bauer Christine, De Ponti Aurora, Manthey Sandra, Marhenke Silke, Vogel Arndt, Klingmüller Ursula, Hess Jochen, and Angel Peter

Subjects
Calgranulins, Calprotectin, Hepatocytes, Neutrophils, Chemokines, Immune cell mobilization, Medicine, Cytology, QH573-671
Abstract

Abstract Background Calprotectin consists of the Ca2+-binding proteins S100a8 and S100a9 that are induced in epithelial cells in response to tissue damage and infection. Both proteins are also secreted by activated innate immune cells and numerous studies demonstrate their crucial role in pathological conditions of acute and chronic inflammation. Results Here, we established a conditional mouse model with simultaneous S100a8 and S100a9 transgene expression in hepatocytes (TgS100a8a9hep) under the control of doxycycline to unravel the role of epithelial-derived Calprotectin on tissue homeostasis and inflammation. TgS100a8a9hep mice displayed a significant enrichment of neutrophils in peripheral blood and tissues with high blood content. Interestingly, Cxcl1 transcription was significantly induced in the liver of TgS100a8a9hep mice and primary hepatocytes derived thereof as compared to Control mice, accompanied by an increase of Cxcl1 serum levels. However, expression of other chemokines with a known function in neutrophil mobilization from the bone marrow, e.g. Csf3 and Cxcl2, was not altered. Doxycycline treatment of TgS100a8a9hep mice reduced Cxcl1 expression in the liver and resulted in normal numbers of neutrophils. Conclusion In summary, our data demonstrate for the first time that hepatocyte-specific S100a8 and S100a9 expression induces a systemic mobilization of neutrophils by a specific activation of Cxcl1 transcription in the liver.

Published
2012
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27. PS-177-HSD17B13 rs72613567 TA is associated with a reduced risk for developing hepatocellular carcinoma in patients with alcohol-related cirrhosis

Author

Stickel, Felix, primary, Lutz, Philipp, additional, Buch, Stephan, additional, Fischer, Janett, additional, Rausch, Vanessa, additional, Silva, Ines, additional, Rosendahl, Jonas, additional, Nischalke, Hans Dieter, additional, Krawczyk, Marcin, additional, Lammert, Frank, additional, Casper, Markus, additional, Zopf, Steffen, additional, Marhenke, Silke, additional, Vogel, Arndt, additional, Eyer, Florian, additional, Felden, Johann von, additional, Gotthardt, Daniel, additional, Weiss, Karl Heinz, additional, Spengler, Ulrich, additional, Mueller, Sebastian, additional, Canbay, Ali, additional, Baselli, Guido Alessandro, additional, Valenti, Luca, additional, McQuillin, Andrew, additional, Berg, Thomas, additional, Hampe, Jochen, additional, and Morgan, Marsha, additional

Published
2019
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29. Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma

Author

Schulte, Lena, primary, Scheiner, Bernhard, additional, Voigtländer, Torsten, additional, Koch, Sandra, additional, Schweitzer, Nora, additional, Marhenke, Silke, additional, Ivanyi, Philipp, additional, Manns, Michael P., additional, Rodt, Thomas, additional, Hinrichs, Jan B., additional, Weinmann, Arndt, additional, Pinter, Matthias, additional, Vogel, Arndt, additional, and Kirstein, Martha M., additional

Published
2019
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30. Murine Liver Organoids as a Genetically Flexible System to Study Liver Cancer In Vivo and In Vitro

Author

Saborowski, Anna, primary, Wolff, Katharina, additional, Spielberg, Steffi, additional, Beer, Benedikt, additional, Hartleben, Björn, additional, Erlangga, Zulrahman, additional, Becker, Diana, additional, Dow, Lukas E., additional, Marhenke, Silke, additional, Woller, Norman, additional, Unger, Kristian, additional, Schirmacher, Peter, additional, Manns, Michael P., additional, Marquardt, Jens U., additional, Vogel, Arndt, additional, and Saborowski, Michael, additional

Published
2019
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31. Correction: Genetic Variants in PNPLA3 and TM6SF2 Predispose to the Development of Hepatocellular Carcinoma in Individuals With Alcohol-Related Cirrhosis.

Author

UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de gastro-entérologie, Stickel, Felix, Buch, Stephan, Nischalke, Hans Dieter, Weiss, Karl Heinz, Gotthardt, Daniel, Fischer, Janett, Rosendahl, Jonas, Marot, Astrid, Elamly, Mona, Casper, Markus, Lammert, Frank, McQuillin, Andrew, Zopf, Steffen, Spengler, Ulrich, Marhenke, Silke, Kirstein, Martha M, Vogel, Arndt, Eyer, Florian, von Felden, Johann, Wege, Henning, Buch, Thorsten, Schafmayer, Clemens, Braun, Felix, Deltenre, Pierre, Berg, Thomas, Morgan, Marsha Y, Hampe, Jochen, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de gastro-entérologie, Stickel, Felix, Buch, Stephan, Nischalke, Hans Dieter, Weiss, Karl Heinz, Gotthardt, Daniel, Fischer, Janett, Rosendahl, Jonas, Marot, Astrid, Elamly, Mona, Casper, Markus, Lammert, Frank, McQuillin, Andrew, Zopf, Steffen, Spengler, Ulrich, Marhenke, Silke, Kirstein, Martha M, Vogel, Arndt, Eyer, Florian, von Felden, Johann, Wege, Henning, Buch, Thorsten, Schafmayer, Clemens, Braun, Felix, Deltenre, Pierre, Berg, Thomas, Morgan, Marsha Y, and Hampe, Jochen

Abstract

Author Pierre Deltenre, MD should appear in the author list in position 25, between Felix Braun and Thomas Berg. He should also have a PhD degree added to his name.

Published
2018

32. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Author

Strnad, Pavel, primary, Buch, Stephan, additional, Hamesch, Karim, additional, Fischer, Janett, additional, Rosendahl, Jonas, additional, Schmelz, Renate, additional, Brueckner, Stefan, additional, Brosch, Mario, additional, Heimes, Carolin V, additional, Woditsch, Vivien, additional, Scholten, David, additional, Nischalke, Hans Dieter, additional, Janciauskiene, Sabina, additional, Mandorfer, Mattias, additional, Trauner, Michael, additional, Way, Michael J, additional, McQuillin, Andrew, additional, Reichert, Matthias C, additional, Krawczyk, Marcin, additional, Casper, Markus, additional, Lammert, Frank, additional, Braun, Felix, additional, von Schönfels, Witigo, additional, Hinz, Sebastian, additional, Burmeister, Greta, additional, Hellerbrand, Claus, additional, Teufel, Andreas, additional, Feldman, Alexandra, additional, Schattenberg, Joern M, additional, Bantel, Heike, additional, Pathil, Anita, additional, Demir, Muenevver, additional, Kluwe, Johannes, additional, Boettler, Tobias, additional, Ridinger, Monika, additional, Wodarz, Norbert, additional, Soyka, Michael, additional, Rietschel, Marcella, additional, Kiefer, Falk, additional, Weber, Thomas, additional, Marhenke, Silke, additional, Vogel, Arndt, additional, Hinrichsen, Holger, additional, Canbay, Ali, additional, Schlattjan, Martin, additional, Sosnowsky, Katharina, additional, Sarrazin, Christoph, additional, von Felden, Johann, additional, Geier, Andreas, additional, Deltenre, Pierre, additional, Sipos, Bence, additional, Schafmayer, Clemens, additional, Nothnagel, Michael, additional, Aigner, Elmar, additional, Datz, Christian, additional, Stickel, Felix, additional, Morgan, Marsha Yvonne, additional, Hampe, Jochen, additional, Berg, Thomas, additional, and Trautwein, Christian, additional

Published
2018
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34. Murine Liver Organoids as a Genetically Flexible System to Study Liver Cancer InVivo and In Vitro.

Author

Saborowski, Anna, Wolff, Katharina, Spielberg, Steffi, Beer, Benedikt, Hartleben, Björn, Erlangga, Zulrahman, Becker, Diana, Dow, Lukas E., Marhenke, Silke, Woller, Norman, Unger, Kristian, Schirmacher, Peter, Manns, Michael P., Marquardt, Jens U., Vogel, Arndt, and Saborowski, Michael

Subjects
LIVER cancer, ORGANOIDS, LABORATORY mice
Abstract

The rising incidence of cholangiocarcinoma (CCA) coupled with a low 5‐year survival rate that remains below 10% delineates the urgent need for more effective treatment strategies. Although several recent studies provided detailed information on the genetic landscape of this fatal malignancy, versatile model systems to functionally dissect the immediate clinical relevance of the identified genetic alterations are still missing. To enhance our understanding of CCA pathophysiology and facilitate rapid functional annotation of putative CCA driver and tumor maintenance genes, we developed a tractable murine CCA model by combining the cyclization recombination (Cre)‐lox system, RNA interference, and clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology with liver organoids, followed by subsequent transplantation into immunocompetent, syngeneic mice. Histologically, resulting tumors displayed cytokeratin 19–positive ductal structures surrounded by a desmoplastic stroma—hallmark features of human CCAs. Despite their initial biliary phenotype in vitro, organoids retained the plasticity to induce a broader differentiation spectrum of primary liver cancers following transplantation into recipient mice, depending on their genetic context. Thus, the organoid system combines the advantage of using nontransformed, premalignant cells to recapitulate liver tumorigenesis as a multistep process, with the advantage of a reproducible and expandable cell culture system that abrogates the need for recurrent isolations of primary cells. Conclusion: Genetically modified liver organoids are able to transform into histologically accurate CCAs. Depending on the oncogenic context, they are also able to give rise to liver cancers that show features of hepatocellular carcinomas. The model can be used to functionally explore candidate cancer genes of primary liver cancers in immunocompetent animals and evaluate novel treatment regimens. Genetically modified liver organoids are able to transform into histologically accurate cholangiocarcinomas. Depending on the oncogenic context, they are also able to give rise to liver cancers that show features of hepatocellular carcinomas. This organoid‐based model can be used to functionally explore candidate cancer genes of primary liver cancers in immunocompetent animals and evaluate novel treatment regimens. [ABSTRACT FROM AUTHOR]

Published
2019
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35. Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development

Author

Endig, Jessica, primary, Buitrago-Molina, Laura Elisa, additional, Marhenke, Silke, additional, Reisinger, Florian, additional, Saborowski, Anna, additional, Schütt, Jutta, additional, Limbourg, Florian, additional, Könecke, Christian, additional, Schreder, Alina, additional, Michael, Alina, additional, Misslitz, Ana Clara, additional, Healy, Marc Eammonn, additional, Geffers, Robert, additional, Clavel, Thomas, additional, Haller, Dirk, additional, Unger, Kristian, additional, Finegold, Milton, additional, Weber, Achim, additional, Manns, Michael P., additional, Longerich, Thomas, additional, Heikenwälder, Mathias, additional, and Vogel, Arndt, additional

Published
2016
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36. Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma

Author

Feng, Teng, primary, Dzieran, Johanna, additional, Gu, Xing, additional, Marhenke, Silke, additional, Vogel, Arndt, additional, Machida, Keigo, additional, Weiss, Thomas S., additional, Ruemmele, Petra, additional, Kollmar, Otto, additional, Hoffmann, Patrick, additional, Grässer, Friedrich, additional, Allgayer, Heike, additional, Fabian, Jasmin, additional, Weng, Hong Lei, additional, Teufel, Andreas, additional, Maass, Thorsten, additional, Meyer, Christoph, additional, Lehmann, Ulrich, additional, Zhu, Cheng, additional, Mertens, Peter R., additional, Gao, Chun Fang, additional, Dooley, Steven, additional, and Meindl-Beinker, Nadja M., additional

Published
2015
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39. p21 promotes sustained liver regeneration and hepatocarcinogenesis in chronic cholestatic liver injury

Author

Marhenke, Silke, primary, Buitrago-Molina, Laura Elisa, additional, Endig, Jessica, additional, Orlik, Johanna, additional, Schweitzer, Nora, additional, Klett, Stephanie, additional, Longerich, Thomas, additional, Geffers, Robert, additional, Sánchez Muñoz, Aránzazu, additional, Dorrell, Craig, additional, Katz, Sarah-Fee, additional, Lechel, André, additional, Weng, Honglei, additional, Krech, Till, additional, Lehmann, Ulrich, additional, Dooley, Steven, additional, Rudolph, Karl Lenhard, additional, Manns, Michael P, additional, and Vogel, Arndt, additional

Published
2013
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41. Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development

Author

Marhenke, Silke, primary, Lamlé, Jutta, additional, Buitrago-Molina, Laura Elisa, additional, Cañón, José Manuel Fernández, additional, Geffers, Robert, additional, Finegold, Milton, additional, Sporn, Michael, additional, Yamamoto, Masayuki, additional, Manns, Michael P., additional, Grompe, Markus, additional, and Vogel, Arndt, additional

Published
2008
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44. Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma.

Author

Teng Feng, Johanna, Dzieran, Xing Gu, Marhenke, Silke, Vogel, Arndt, Machida, Keigo, Weiss, Thomas S., Ruemmele, Petra, Kollmar, Otto, Hoffmann, Patrick, Grässer, Friedrich, Allgayer, Heike, Fabian, Jasmin, Hong Lei Weng, Teufel, Andreas, Maass, Thorsten, Meyer, Christoph, Lehmann, Ulrich, Cheng Zhu, and Mertens, Peter R.

Subjects
SMAD proteins, LIVER cells, CELL proliferation, LABORATORY mice, LIVER cancer, TRANSFORMING growth factors-beta
Abstract

Transforming growth factor β (TGF-β) is cytostatic towards damage-induced compensatory hepatocyte proliferation. This function is frequently lost during hepatocarcinogenesis, thereby switching the TGF-β role from tumour suppressor to tumour promoter. In the present study, we investigate Smad7 overexpression as a pathophysiological mechanism for cytostatic TGF-β inhibition in liver damage and hepatocellular carcinoma (HCC). Transgenic hepatocyte-specific Smad7 overexpression in damaged liver of fumarylacetoacetate hydrolase (FAH)-deficient mice increased compensatory proliferation of hepatocytes. Similarly, modulation of Smad7 expression changed the sensitivity of Huh7, FLC-4, HLE and HLF HCC cell lines for cytostatic TGF-β effects. In our cohort of 140 HCC patients, Smad7 transcripts were elevated in 41.4% of HCC samples as compared with adjacent tissue, with significant positive correlation to tumour size, whereas low Smad7 expression levels were significantly associated with worse clinical outcome. Univariate and multivariate analyses indicate Smad7 levels as an independent predictor for overall (P<0.001) and disease-free survival (P=0.0123). Delineating a mechanism for Smad7 transcriptional regulation in HCC, we identified cold-shock Y-box protein-1 (YB-1), a multifunctional transcription factor. YB-1 RNAi reduced TGF-β-induced and endogenous Smad7 expression in Huh7 and FLC-4 cells respectively. YB-1 and Smad7 mRNA expression levels correlated positively (P<0.0001). Furthermore, nuclear co-localization of Smad7 and YB-1 proteins was present in cancer cells of those patients. In summary, the present study provides a YB-1/Smad7-mediated mechanism that interferes with anti-proliferative/tumour-suppressive TGF-β actions in a subgroup of HCC cells that may facilitate aspects of tumour progression. [ABSTRACT FROM AUTHOR]

Published
2015
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46. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Author

Strnad P, Buch S, Hamesch K, Fischer J, Rosendahl J, Schmelz R, Brueckner S, Brosch M, Heimes CV, Woditsch V, Scholten D, Nischalke HD, Janciauskiene S, Mandorfer M, Trauner M, Way MJ, McQuillin A, Reichert MC, Krawczyk M, Casper M, Lammert F, Braun F, von Schönfels W, Hinz S, Burmeister G, Hellerbrand C, Teufel A, Feldman A, Schattenberg JM, Bantel H, Pathil A, Demir M, Kluwe J, Boettler T, Ridinger M, Wodarz N, Soyka M, Rietschel M, Kiefer F, Weber T, Marhenke S, Vogel A, Hinrichsen H, Canbay A, Schlattjan M, Sosnowsky K, Sarrazin C, von Felden J, Geier A, Deltenre P, Sipos B, Schafmayer C, Nothnagel M, Aigner E, Datz C, Stickel F, Morgan MY, Hampe J, Berg T, and Trautwein C

Subjects
Age Distribution, Austria, Biopsy, Needle, Case-Control Studies, Confidence Intervals, Female, Genetic Carrier Screening, Genetic Variation, Germany, Humans, Immunohistochemistry, Incidence, Liver Cirrhosis, Alcoholic epidemiology, Liver Cirrhosis, Alcoholic pathology, Male, Non-alcoholic Fatty Liver Disease epidemiology, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease pathology, Odds Ratio, Polymorphism, Single Nucleotide, Prognosis, Risk Assessment, Sex Distribution, Genetic Predisposition to Disease epidemiology, Heterozygote, Liver Cirrhosis, Alcoholic genetics, alpha 1-Antitrypsin genetics
Abstract

Objective: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse., Design: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed., Results: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19))., Conclusion: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2019
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