Forschung

 

Die enge Verzahnung aus experimenteller, translationaler und klinischer Forschung hat in den letzten Jahrzehnten zu einem enormen Wissenszuwachs in der Medizin geführt und den Alltag für unsere Patienten und Patientinnen relevant und nachhaltig positiv beeinflusst.

Auf diesen Seiten erhalten Sie einen Einblick in die aktuellen Forschungsschwerpunkte und -vorhaben unserer Klinik.

Eine Übersicht über die aktuellen klinischen Studien erhalten Sie über diesen Link zu unserer Studienambulanz, eine aktuelle Liste all unserer Publikationen finden Sie hier.

Zurück zur Homepage

Sektion "Hereditary Colon Cancer & Gut in Acute-on-Chronic Liver Failure (ACLF)" (Prof. Dr. A. Brieger)

Research Group "Hereditary Colon Cancer & Gut in Acute-on-Chronic Liver Failure (ACLF)"

Zurück zur Homepage

Research Overview and Projects

The research group basically deals with colon cancer and pathological changes of the colon.

 

One main research focus lies on the identification of molecular mechanisms responsible for the development of tumors in a hereditary form of colorectal cancer (CRC) called Lynch syndrome. Lynch syndrome is caused by germline mutations in genes of the DNA mismatch repair (MMR) system which lead to MMR deficiency and the accumulation of mutations in the genome. Although patients with Lynch syndrome have a better prognosis compared to patients with sporadic colon cancer, associated tumors often show resistance to common chemotherapeutical treatment. In the long term, our research projects intend to facilitate diagnostics and to contribute to an improved individualized therapy of patients with Lynch syndrome / MMR deficiency.

A new research focus of our group aims to identify molecular patterns or changes in the microbiome responsible for the increased intestinal permeability, which occur in many patients during the development of a very serious disease of the liver - the acute-on-chronic liver failure (ACLF). The reasons for the development of ACLF are still largely unknown, but increased intestinal permeability can significantly trigger the progression of the disease.

Current projects

Phosphorylation of the human DNA mismatch repair protein MLH1 - What is the significance of this modification for DNA mismatch repair function?

15%-20% of all colon tumours exhibit defective MMR and show a significantly poorer response to common chemotherapies than MMR-proficient carcinomas. The most common cause of MMR loss is a defect in the MMR protein MLH1, which is involved not only in MMR but also in important MMR-independent signalling pathways, such as apoptosis. Recently, we identified an amino acid position in MLH1 that is phosphorylated by casein kinase II (CK2) and by which MMR function is blocked. This phosphorylation might govern a poor response to therapy in patients with colorectal carcinomas and is subject of current investigations.

Potential link between homologous recombination and mismatch repair pathways in colorectal carcinoma

Other germline mutations have been found in CRC patients within genes in the homologous recombination (HR) pathway which can lead to HR deficiency (HRD). A previous study showed that of 52,436 solid tumors assessed from 21 different cancer lineages, 17.4% showed HR mutations while 15% of the CRCs alone exhibited these mutations. When HRD occurs, the non-homologous end joining pathway (NHEJ) compensates and corrects DNA damage. In a study using a DNA-PKcs inhibitor to suppress the NHEJ pathway, HR-deficient cancer cells could be identified through catastrophic double strand break repair. This screen also identified cells with mutations in the MSH3 gene as particularly sensitive to NHEJ abrogation. Our group showed that MSH3 as well as MLH1 deficiency made cells sensitive to NHEJ inhibition after induced DNA damage in several CRC cell lines. This suggests that there may be a link between MMR deficiency and HR deficiency in CRC.

Characterization of MLH1- and SPTAN1-dependent signaling pathways as mediators of tumor progression in colon carcinoma

Compared to sporadic CRCs, MMR-deficient tumors show decreased metastatic behavior and respond altered to standard therapies and immune checkpoint inhibitors. We demonstrated that decreased MLH1 expression is associated with a reduction in cytoskeleton-associated Spectrin alpha II (SPTAN1) and leads to impaired migratory capacity. This project will characterize MLH1- and SPTAN1-dependent tumor-promoting genes and signaling pathways that lead to specific tumor progression of CRC and Lynch syndrome which might serve as biomarkers for personalized therapies.

Identification of triggers for dysfunctional intestinal barrier in acute-on-chronic liver failure


ACLF occurs in a background of chronic liver dysfunction and is associated with multiorgan failure and significant short-term mortality. Correlated with ACLF in some patients is an increased intestinal permeability which leads to serious bacterial infection and rapid death of these patients. The aim of this project is to identify alterations of proteins within damaged intestinal epithelial cells as potential triggers and to define therapeutically useful targets. 

Funding

LOEWE, Wilhelm Sander Foundation, Frankfurt Research Funding, Foundation funds

Lab Head

Prof. Dr. Angela Brieger, PhD 
a.brieger@em.uni-frankfurt.de
Tel.: +49 69 6301 6218

Address:
Universitätsklinikum Frankfurt
Medizinische Klinik 1
Biomedizinisches Forschungslabor
Haus 11, EG, Zimmer 28
Theodor-Stern-Kai 7
60590 Frankfurt

Postdoc

Dr. rer. nat. Sarah Overby
Overby@med.uni-frankfurt.de
Tel.: +49 6301 87666

Postdoc

Dr. rer. nat. Olaf Tyc
tyc@med.uni-frankfurt.de
Tel.: +49 6301 80464

Postdoc / Resident Physician

Dr. med. Christopher Schrecker
Christopher.Schrecker@unimedizin-ffm.de
Tel.: +49 69 6301 4245

PhD Student

Clara Meier, M. Sc. 
clmeier@med.uni-frankfurt.de
Tel.: +49 69 6301 87665

PhD Student

Nikolai Leinz
Nikolai.Leinz@unimedizin-ffm.de
Tel.: +49 69 6301 4245

PhD Student

M. Sc. Julia Bous
Bous@med.uni-frankfurt.de
Tel.: +49 69 6301 4837

MD Student

Celine Lehr
Tel.: +49 69 6301 4245

MD Student

Gianluca La Rocca
Tel.: +49 69 6301 6232

MD Student

Philipp Osterroth
Tel.: +49 69 6301 6232

Technician

Babithra Yoganathan-Kugarajan
Yoganathan-Kugarajan@med.uni-frankfurt.de
Tel: +49 6301 6232

Technician

Virginia Nawrot
Virginia.Nawrot@unimedizin-ffm.de
Tel: +49 6301 87662

Selected Publications (last 6 years):    

  • Meier C, La Rocca G, Nawrot V, Fißlthaler B, Overby SJ, Hourfar K, Plotz G, Seidl C, Ziegler P, Wild P, Zeuzem S, Brieger J, Jäger E, Battmann A, Brieger A. Erk Inhibition as a Promising Therapeutic Strategy for High IL-8-Secreting and Low SPTAN1-Expressing Colorectal Cancer. Int J Mol Sci. 2024 May 23;25(11):5658.
  • Mücke MM, El Bali N, Schwarzkopf KM, Uschner FE, Kraus N, Eberle L, Mücke VT, Bein J, Beyer S, Wild PJ, Schierwagen R, Klein S, Zeuzem S, Welsch C, Trebicka J, Brieger A. The Role of Hypoxia-Inducible Factor 1 Alpha in Acute-on-Chronic Liver Failure. Int J Mol Sci. 2024 Jan 26;25(3):1542.
  • Firnau MB, Plotz G, Zeuzem S, Brieger A. Key role of phosphorylation sites in ATPase domain and Linker region of MLH1 for DNA binding and functionality of MutLα. Sci Rep. 2023 Aug 2;13(1):12503.
  • Wolf K, Kosinski J, Gibson TJ, Wesch N, Dötsch V, Genuardi M, Cordisco EL, Zeuzem S, Brieger A, Plotz G. A conserved motif in the disordered linker of human MLH1 is vital for DNA mismatch repair and its function is diminished by a cancer family mutation. Nucleic Acids Res. 2023 May 24:gkad418
  • Mahdouani M, Ben Ahmed S, Hmila F, Rais H, Ben Sghaier R, Saad H, Ben Said M, Masmoudi S, Hmida D, Brieger A., Zeuzem S, Saad A, Gribaa M, Plotz G. Functional characterization of MLH1 missense variants unveils mechanisms of pathogenicity and clarifies role in cancer. PLoS One. 2022 Dec 1;17(12):e0278283.
  • Firnau MB, Brieger A. CK2 and the Hallmarks of Cancer. Biomedicines. 2022 Aug 16;10(8):1987.
  • Ulreich K, Firnau MB, Tagscherer N, Beyer S, Ackermann A, Plotz G, Brieger A. High Expression of Casein Kinase 2 Alpha Is Responsible for Enhanced Phosphorylation of DNA Mismatch Repair Protein MLH1 and Increased Tumor Mutation Rates in Colorectal Cancer.Cancers (Basel). 2022 Mar 18;14(6):1553.
  • Schrecker C, Behrens S, Schönherr R, Ackermann A, Pauli D, Plotz G, Zeuzem S, Brieger A. SPTAN1 Expression Predicts Treatment and Survival Outcomes in Colorectal Cancer. Cancers (Basel). 2021 Jul 20;13(14):3638.
  • Höflich C, Brieger A, Zeuzem S, Plotz G. Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations. Sci Rep. 2021 Apr 7;11(1):7674.
  • Plotz G, Lopez-Garcia LA, Brieger A, Zeuzem S, Biondi RM. Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region. PLoS One. 2020 Nov 30;15(11):e0242819.
  • Ackermann A, Lafferton B, Plotz G, Zeuzem S, Brieger A. Expression and secretion of the pro-inflammatory cytokine IL-8 is increased in colorectal cancer cells with reduced non-erythroid spectrin αII expression. Int J Oncol. 2020 Jun;56(6):1551-1564.
  • Ackermann A and Brieger A. The Role of Nonerythroid Spectrin II in Cancer. J Oncol. 2019 May 2;2019:7079604.
  • Ackermann A, Schrecker C, Bon D, Friedrichs N, Bankov K, Wild P, Plotz G, Zeuzem S, Herrmann E, Hansmann ML, Brieger A. Downregulation of SPTAN1 is related to MLH1 deficiency and metastasis in colorectal cancer. PLoS One. 2019 Mar 11;14(3):e0213411.
  • Köger N, Brieger A, Hinrichsen IM, Zeuzem S, Plotz G. Analysis of MUTYH alternative transcript expression, promoter function, and the effect of human genetic variants. Hum Mutat. 2019 Apr;40(4):472-482.
  • Weßbecher IM and Brieger A. Phosphorylation meets DNA mismatch repair. DNA Repair (Amst). 2018 Dec;72:107-114.
  • Weßbecher IM, Hinrichsen I, Funke S, Oellerich T, Plotz G, Zeuzem S, Grus FH, Biondi RM, Brieger A. DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477). Mol Carcinog. 2018 Dec;57(12):1723-1734.
  • Köger N, Paulsen L, López-Kostner F, Della Valle A, Vaccaro CA, Palmero EI, Alvarez K, Sarroca C, Neffa F, Kalfayan PG, Gonzalez ML, Rossi BM, Reis RM, Brieger A, Zeuzem S, Hinrichsen I, Dominguez-Valentin M, Plotz G. Evaluation of MLH1 variants of unclear significance. Genes Chromosomes Cancer. 2018 Jul;57(7):350-358.
     

Zurück zur Homepage

Sektion "Gastrointestinal Oncology" (PD Dr. med. C. Koch)

Research Group "Gastrointestinal Oncology"

Zurück zur Homepage

Research Overview and Projects

  • Heterogeneity in neuroendocrine tumors (cooperation with Prof. P. Wild, Senckenberg Institute for Pathology)
  • Sinusoidal obstruction syndrome in patients with colorectal liver metastases (cooperation with PD Dr. Schreckenbach, Dept. of Surgery)
  • Immune infiltrate in patients with upper GI cancer (joint project with IKF Frankfurt, Prof. Al-Batran, and Edinger Institute, Prof. Plate)

Lab Members

Lab Head

PD Dr. med. Christine Koch
christine.koch@unimedizin-ffm.de

Staff

Doctoral students: Sharanya Pareek, Mira Hüttenschmidt, Nina Jungblut

Funding

MSNZ Frankfurt

Selected Publications:   

  • Koch C, Bambey C, Filmann N, Stanke M, Waidmann O, Husmann G, Bojunga J. Survival According to Therapy Regimen for Small Intestinal Neuroendocrine Tumors. J Clin Med. 2022 Apr 22;11(9):2358. doi: 10.3390/jcm11092358.
  • Koch C, Koca E, Filmann N, Husmann G, Bojunga J Time from first tumor manifestation to diagnosis in patients with GEP-NET: Results from a large German tertiary referral center Medicine (Baltimore). 2021 Sep 17;100(37):e27276. doi: 10.1097/MD.0000000000027276.
  • Koch C, Göller M, Schott E, Waidmann O, Op den Winkel M, Paprottka P, Zangos S, Vogl T, Bechstein WO, Zeuzem S, Kolligs FT, Trojan J. Combination of Sorafenib and Transarterial Chemoembolization in Selected Patients with Advanced-Stage Hepatocellular Carcinoma: A Retrospective Cohort Study at Three German Liver Centers. Cancers (Basel). 2021 Apr 28;13(9):2121. doi: 10.3390/cancers13092121.
  • Koch C, Bette T, Waidmann O, et al. AFP ratio predicts HCC recurrence after liver transplantation. PLoS One. 2020;15(7):e0235576. Published 2020 Jul 2. doi:10.1371/journal.pone.0235576
  • Koch C, Franzke C, Bechstein WO, et al. Poor Prognosis of Advanced Cholangiocarcinoma: Real-World Data from a Tertiary Referral Center. Digestion. 2020;101(4):458-465. doi:10.1159/000500894
  • Koch C, Reitz C, Schreckenbach T, et al. Sarcopenia as a prognostic factor for survival in patients with locally advanced gastroesophageal adenocarcinoma. PLoS One. 2019;14(10):e0223613. Published 2019 Oct 22. doi: 10.1371/ journal.pone.0223613
  • Schreckenbach T, Hübert H, Koch C, Bojunga J, Schnitzbauer AA, Bechstein WO, Holzer K. Surgical resection of neuroendocrine tumor liver metastases as part of multimodal treatment strategies: A propensity score matching analysis. Eur J Surg Oncol. 2018 Dec 28. pii: S0748-7983(18)32044-4.
  • Koch C, Schmidt N, Winkelmann R, Eichler K, Pession U, Bechstein WO, Zeuzem S, Waidmann O, Trojan J. Anti-EGF Receptor-Based Conversion Chemotherapy in RAS Wild-Type Colorectal Cancer Patients: Impact on Survival and Resection Rates. Digestion. 2018;98(4):263-269.
  • Walter D, Harter PN, Battke F, Winkelmann R, Schneider M, Holzer K, Koch C, Bojunga J, Zeuzem S, Hansmann ML, Peveling-Oberhag J, Waidmann O. Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors. Sci Rep. 2018 Feb 28;8(1):3811.
  • Koch C, Schwing AM, Herrmann E, Borner M, Diaz-Rubio E, Dotan E, Feliu J, Okita N, Souglakos J, Arkenau HT, Porschen R, Koopman M, Punt CJA, de Gramont A, Tournigand C, Zeuzem S, Trojan J. Bevacizumab-based first-line chemotherapy in elderly patients with metastatic colorectal cancer: an individual patient data based meta-analysis. Oncotarget. 2017 Dec 20;9(12):10272-10283.
  • Koch C, Kim Y, Zöller T, Born C, Steinle A. Chronic NKG2D Engagement In Vivo Differentially Impacts NK Cell Responsiveness by Activating NK Receptors. Front Immunol. 2017 Nov 3;8:1466.

Zurück zur Homepage

Sektion "Infections/multidrug-resistance in liver disease and ACLF" (PD Dr. med. M. Mücke)

Research Group "Infections/multidrug-resistance in liver disease and ACLF"

Zurück zur Homepage

Research Overview and Projects

Infections and Infectious diseases constitute a major health problem in the field of hepatology. While earlier efforts of our Group focused on the handling of patients with viral hepatitis – especially with chronic hepatitis C – our latest efforts focus on the role, prevention and treatment of infections in patients with chronic liver disease (CLD) leading to acute decompensation (AD) and acute and chronic liver failure (ACLF).

Infections in CLD causing AD or ACLF: Infections in patients with CLD are the most frequent cause of AD and ACLF in the western world. ACLF, an AD characterized by concomitant organ failure is associated with extreme high short-term mortality (up to 70-90% with 90 days). Over the last decade, the number of multidrug-resistant bacteria (MDRO) isolated from cultures of patients with cirrhosis and infection has drawn the attention of clinicians and the hepatology community. Our group focuses on infections in patients with cirrhosis, the role of MDRO isolated identified in the patients (colonization and/or infection) and its influence on antibiotics used for treatment and infection prophylaxis.

Infections in liver disease: Another interest of our research group is the clinical impact of different viral and bacterial infections possibly causing acute or acute-on-chronic deterioration of liver function.

Chronic hepatitis C:  Chronic hepatitis C virus (cHCV) infection is still a major global health problem resulting in significant morbidity and mortality. The introduction of direct acting antivirals (DAA) has revolutionized HCV treatment and eradication can now be obtained in most patients. However, physicians are faced with an increasing number of patients with cHCV infection the are considered difficult-to-treat. Our group tackled several important questions of daily clinical routine including the handling and treatment of patients with HBV coinfection, elderly patients and patients with drug-abuse.

Lab Members

Lab Head

PD Dr. med. Marcus M. Mücke
marcusmaximilian.muecke@unimedizin-ffm.de

University Hospital Frankfurt
Haus 11, 3. OG
Goethe University
Theodor-Stern-Kai 7
60590 Frankfurt am Main

Staff

Postdocs und Physicians: Dr. med. Carla Cremonese, Dr. med. Myriam Heilani, Dr. Peter Hunyady
Doctoral students: Laura Altepeter, Nihad El Bahli, Malte Jans, Toska Wiedemann
Technicians: Dikra Zouiten

Funding

Frankfurter Forschungsförderung of the Goethe University – Nachwuchsforscher; Project: The role of  Hypoxia inducible Factor 1 alpha (HIF-1α) in the pathogenesis of liver cirrhosis and acute-on-chronic liver disease

Gilead Förderprogramm Infektiologie; Project: Spontanous bacterial peritonitis and the role of antibiotic prophylaxis on patients stool microbiom

Selected Publications  

  • Hunyady P, Streller L, Rüther DF, Groba SR, Bettinger D, Fitting D, Hamesch K, Marquardt JU, Mücke VT, Finkelmeier F, Sekandarzad A, Wengenmayer T, Bounidane A, Weiss F, Peiffer KH, Schlevogt B, Zeuzem S, Waidmann O, Hollenbach M, Kirstein MM, Kluwe J, Kütting F, Mücke MM. Secondary sclerosing cholangitis following COVID-19 disease: a multicenter retrospective study. Clin Infect Dis. 2023 Feb 8;76(3):e179-e187              
  • Mücke MM, Bruns T, Canbay A, Matzdorff A, Tacke F, Tiede A, Trebicka J, Wedemeyer H, Zacharowski K, Zeuzem S, Lange CM. Use of Thrombopoetin-Receptor-Agonists (TPO-RA) in patients with liver cirrhosis before invasive procedures. Z Gastroenterol. 2022 Nov 14
  • Prado V*, Hernández-Tejero M*, Mücke MM*, Marco F, Gu W, Amoros A, Toapanta D, Reverter E, Peña-Ramirez C, Altenpeter L, Bassegoda O, Mezzano G, Aziz F, Juanola A, Rodríguez-Tajes S, Chamorro V, López D, Reyes M, Hogardt M, Kempf VAJ, Ferstl PG, Zeuzem S, Martínez JA, Vila J, Arroyo V, Trebicka J, Fernandez J. Rectal colonization by resistant bacteria increases the risk of infection by the colonizing strain in critically ill patients with cirrhosis. J Hepatol. 2022 May;76(5):1079-1089.    
  • Mücke MM, Zeuzem S. The recent outbreak of acute severe hepatitis in children of unknown origin - what is known so far. J Hepatol. 2022;77(1):237-242. 
  • Mücke VT, Peiffer KH, Kessel J, Schwarzkopf KM, Bojunga J, Zeuzem S, Finkelmeier F, Mücke MM. Impact of colonization with multidrug-resistant organisms on antibiotic prophylaxis in patients with cirrhosis and variceal bleeding. PLoS One. 2022; May 24;17(5):e0268638                           
  • Basic M, Kubesch A, Kuhnhenn L, Görgülü E, Finkelmeier F, Dietz J, Knabe M, Mücke VT, Mücke MM, Berger A, Zeuzem S, Sarrazin C, Hildt E, Peiffer KH. Not uncommon: HBV genotype G co-infections among healthy European HBV carriers with genotype A and E infection. Liver Int. 2021 Jun;41(6):1278-1289.                                                             
  • Ferstl PG, Filmann N, Heilgenthal EM, Schnitzbauzer AA, Bechstein WO, Kempf VAJ, Villinger D, Schultze TG, Hogardt M, Stephan C, Mutlak H, Weiler N, Mücke MM, Trebicka J, Zeuzem S, Waidmann O, Welker MW.  Colonization with multidrug-resistant organisms is associated with increased mortality in liver tranplant candidates. PLoS One. 2021; 16(1):e0245091.                                            
  • Mücke MM, Rüschenbaum S, Mayer, Amelie, Mücke VT, Schwarzkopf KM, Zeuzem S, Kehrmann J, Scholtysik R, Lange CM. Stool and sputum microbiome during quinolone prophylaxis of spontaneous bacterial peritonitis: an exploratory study. Gut Pathog. 2020 Oct 30;12(1):51.                                         
  • Mücke MM, Mücke VT, Graf C, Schwarzkopf KM, Ferstl PG, Fernandez J, Zeuzem S, Trebicka J, Lange CM, Herrmann E.  Efficacy of Norfloxacin Prophylaxis to Prevent Spontaneous Bacterial Peritonitis: A Systematic Review and Meta-Analysis.  Clin Transl. Gastronenterol. 2020 11(8):e00223.                        
  • Hernandez Sempere L, Vermehren J, Mücke VT, Graf C, Peiffer KH, Dultz G, Zeuzem S, Waidmann O, Filmann N, Bojunga J, Sarrazin C, Frieedrich-Rust M, Mücke MM.  Point Shear-Wave Elastorgraphy Using Acoutstic Rediation Force Impulse Imaging for the Prediction of Liver-Related Events in Patients With Chronic Viral Hepatitis.  Hepatol Commun. 2020; 5(1):112-121.                                    
  • Cheng X, Uchida T, Xia Y, Umarova R, Liu CJ, Chen PJ, Gaggar A, Suri V, Mücke MM, Vermehren J, Zeuzem S, Teraoka Y, Osawa M, Aikata H, Tsuji K, Mori N, Hige S, Karino Y, Imamura M, Chayama K, Liang TJ.  Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection.  J Clin Invest. 2020;130(6):3205-3220.                                   
  • Graf G, Mücke MM, Dultz G, Peiffer KH, Kubesch A, Ingiliz P, Zeuzem S, Herrmann E, Vermehren J..  Efficacy of direct-acting antivirals for chronic hepatitis C virus infection in people who inject drugs or receive opioid substitution therapy: a systematic review and meta-analysis. Clin Infect Dis. 2020;70(11):2355-2365.                                          
  • Mücke MM, Mayer A, Kessel J, Mücke VT, Bon D, Schwarzkopf K, Rüschenbaum S, Queck A, Göttig S, Vermehren A, Weiler N, Welker MW, Reinheimer C, Hogardt M, Vermehren J, Herrmann E, Kempf AJK, Zeuzem S, Lange CM. Quinolone- and multidrug-resistance predict failure of antibiotic prophylaxis of spontaneous bacterial peritonitis.  Clin Infect Dis. 2020.70(9):1916–24.                                       
  • Mücke MM, Hermmann E, Mücke VT, Graf C, Zeuzem S, Vermehren J.  Efficacy and safety of direct-acting antivirals for hepatitis C in the elderly: a systematic review and meta-analysis.  Liver Int. 2019; 39(9):1652-1660.
  • Mücke MM, Backus LI, Mücke VT, Coppola N, Preda CM, Yeh ML, Tang LSY, Belperio PS, Wilson EM, Yu ML, Zeuzem S, Hermann E, Vermehren J.  Hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C: a systematic review and meta-analysis.  Lancet Gastroenterol Hepatol. 2018; 3(3):172-180.                       
  • Mücke MM, Rumyantseva T, Mücke VT, Schwarzkopf K, Joshi S, Kempf VAJ, Welsch C, Zeuzem S, Lange CM.  Bacterial infection-triggered acute-on-chronic liver failure is associated with increased mortality.  Liver Int. 2018; 38(4):645-653.                                                             
  • Mücke MM, Kessel J, Mücke VT, Sosnowsky K, Hogardt M, Stephan C, Zeuzem S, Kempf VAJ, Lange CM.  The role of Enterococcus spp. and multidrug-resistant bacteria causing pyogenic liver abscesses. BMC Infect Dis. 2017; 17(1): 450.                                                        
  • Mücke VT#, Mücke MM#, Peiffer KH, Weiler N, Welzel TM, Sarrazin C, Zeuzem S, Berger A, Vermehren J. No evidence of hepatitis B virus reactivation in patients with resolved infection treated with direct acting antivirals for hepatitis C in a large real-world cohort.  Aliment Pharmacol Ther. 2017; 46(4): 432-439.                                 

Zurück zur Homepage

Sektion "Hepatocellular Carcinoma & Non-Alcoholic Steatohepatitis" (Prof. Dr. A. Piiper, Prof. Dr. med. F. Finkelmeier)

Research Group "Hepatocellular Carcinoma & Non-Alcoholic Steatohepatitis"

Zurück zur Homepage

Research Overview and Projects

1) Chronic liver damage and liver cirrhosis caused by viral hepatitis B and C or alcoholic or non-alcoholic steatohepatitis (NASH) lead to development of hepatocelluar carcinoma (HCC). The majority of HCC develop as a result of chronic tissue damage caused by chronic hepatic inflammation.

In our research group we use transgenic, knock-out and chemical induced cancer mouse models and HCC cell spheroids to develop new strategies for the treatment of liver cancer, including new tumor-specific targeting by innovative viral vectors designed to specifically target HCC, and tumor-specific peptides tumor homing peptides. This enables tumor-specific targeting/delivery, thereby increasing therapeutic effectiveness of systemically administered drugs, with a particular focus on the current immune checkpoint inhibitors.

Early detection of malignant tumors such as HCC is crucial for application of potentially curative therapeutic options like resection or liver transplantation. We investigate a new strategy to improve the detection of small/early HCC by blood-based markers using cultured cells and mouse models of HCC.

2) Non-alcoholic steatohepatitis (NASH) is a major and still growing cause of liver fibrosis/cirrhosis and thus cirrhosis-related mortality. No drug therapy of NASH is yet available. We exploit the yet incompletely understood role of autophagy-related mechanisms in NASH and of a repurposed drug showing anti-NASH activity in a mouse model of NASH.

3) The mortality from tumor diseases is critically determined by therapy resistance, invasion of neighboring tissues, and metastasis. These events are governed by a molecular program termed epithelial-mesenchymal trans differentiation (EMT). Hypoxia is an important trigger of EMT. We investigate the role of miRNA in hypoxia-induced EMT in HCC using a panel of different techniques.

4) In a collaboration with the Department of Medicine 2 (Director: Prof. I. Dikic), we investigate the role of ER-phagy and other cell protective mechanisms in NASH and Acute-on-chronic liver failure (ACLF) using transgenic mice and patient samples using a panel of different methods.

All projects are supported by strong collaborations.

Lab Members

Lab Heads

Prof. Dr. Albrecht Piiper
piiper@med.uni-frankfurt.de
+49 (0) 69 - 6301 - 87667

Prof. Dr. med. Fabian Finkelmeier
Fabian.Finkelmeier@unimedizin-ffm.de
+49 (0) 69 - 6301 - 5122

Staff

Physicians: Dr. med. Antonia Mondorf, Meryem Melis Onay
Doctoral students: Alcober-Boquet, M. Sc., Jan Henrik Klug, M. Sc., Daniel Kalina, M. Sc., Emilie Breithäcker, MD student

Funding

LOEWE-ACLF, Nachwuchsforscher der Frankfurter Forschungsförderung

Selected Publications

Experimental studies

  • Meumann N, Cabanes-Creus M, Ertelt M, Navarro RG, Lucifora J, Yuan Q, Huber K, Abdelrahman A, Zhang LA, Franke AC, Schmithals C, Piiper A, Vogt A, Gonzalez-Carmona M, Frueh JT, Ullrich E, Meulemann P, Talbot SR, Odenthal M, Ott M, Seifried E, Schoeder CT, Schwäble J, Lisowski L, Büning H. Adeno-associated virus (AAV) capsid variants for improved liver-directed gene therapy. Hepatology 2023;77:802-815
  • Järveläinen HA, Schmithals C, von Harten M, Kakoschky B, Vogl TJ, Harris S, Henson C, Bullen-Clerkson G, Piiper A.. Assessment of the pharmacokinetics, disposition, and duration of action of the tumour-targeting peptide CEND-1. Int J Mol Sci 2023;24:5700
  • Ibrahim AA, Schmithals C, Kowarz E, Köberle V, Kakoschky B, Pleli T, Kollmar O, Nitsch S, Waidmann O, Finkelmeier F, Zeuzem S, Korf HW, Schmid T, Weigert A, Kronenberger B, Marschalek R, Piiper A. Hypoxia causes down-regulation of Dicer in hepatocellular carcinoma, which is required for up-regulation of hypoxia inducible factor 1α and epithelial-mesenchymal transition. Clin Cancer Res 2017;23:3896-3905
  • Schmithals C, Köberle V, Korkusuz H, Pleli T, Kakoschky B, Augusto EA, Ibrahim AA, Arencibia J, Vafaizadeh V, Groner B, Kronenberger B, Zeuzem S, Korf HW, Vogl TJ, Waidmann O, Piiper A. Improving drug tumor penetrability with iRGD leverages the therapeutic response to sorafenib and doxorubicin in hepatocellular carcinoma. Cancer Res 2015;75:3147-3154
  • Kakoschky B, Pleli T, Schmithals C, Zeuzem S, Brüne B, Vogl TJ, Korf HW, Weigert A, Piiper A. Selective targeting of M2-polarized tumor associated macrophages in different tumor models. PLoS ONE 2018;13:e0193015
  • Pleli T, Mondorf A, Ferreiros N, Thomas D, Dvorak K, Biondi RM, Meyer zu Heringdorf D, Zeuzem S, Geisslinger G, Zimmermann H, Waidmann O, Piiper A. Activation of adenylyl cyclase causes stimulation of adenosine receptors. Cell Physiol Biochem 2018;45:2516-2528
  • Finkelmeier F, Canli Ö, Peiffer, KH, Walter D, Tal A, Koch C, Pession U, Vermehren J, Trojan J, Zeuzem S, Piiper A, Greten FR, Grammatikos G, Waidmann O. Circulating hypoxia marker carbonic anhydrase IX (CA9) in patients with hepatocellular carcinoma and patients with cirrhosis. PLoS ONE 2018;13:e0200855
  • Feczkó T, Piiper A, Ansar S, Blixt FW, Mukul A, Schiffmann S, Ulshöfer, T, Parnham MG, Israel LL, Yifat, H, Lellouche JP, Wacker MG. Stimulating brain recovery after stroke using theranostic albumin nanocarriers loaded with nerve growth factor in combination therapy. J Control Release 2019;293:63–72
  • Feczkó T, Piiper A, Pleli T, Schmithals C, Denk D, Hehlgans S, Rödel F, Vogl T, Wacker MG. Theranostic polymeric nanocarriers modified by enhanced gadolinium conjugation techniques. Pharmaceutics 2019;11:489
  • Dropmann A, Dooley S, Dewidar B, Dediulia T, Werle D, Hartwig V, Ghafoory S, Korhonen H, Janicot M, Wosikowski K, Nittka S, Piiper A, Gaiser T, Brain JG, Jones DEJ, Weiss TS, Itzel T, Zanger UM, Ebert MP, Meindl-Beinker NM. TGF-β2 silencing to target biliary derived liver diseases. Gut 2020;69:1677–1690
  • Waidmann O, Pleli T, Weigert A, Imelmann E, Kakoschky B, Döring C, Frank M, Longerich T, Köberle V, Hansmann ML, Zeuzem S, Piiper A, Dikic I. Tax1BP1 limits hepatic inflammation and reduces tumor formation in a chemical induced hepatocellular carcinoma model. Sci Rep 2020;10:16264
  • Hassan SAH, Schmithals C, von Harten M, Piiper A, Korf HW, von Gall C. Time-dependent changes in proliferation, DNA damage and clock gene expression in hepatocellular carcinoma and normal liver of a transgenic mouse model. Int J Cancer 2021;148:226–237
  • Meumann N, Schmithals C, Elenschneider L, Hansen T, Balakrishnan A, Hu Q, Hook S, Schmitz J, Bräsen JH, Franke AC, Olarewaju O, Brandenberger C, Talbot CR, Fangmann J, Hacker UT, Odenthal M, Ott M, Piiper A, Büning H. Hepatocellular carcinoma is a natural target for adeno-associated virus (AAV) 2 vectors. Cancers 2022;14:427
  • Meumann N, Cabanes-Creus M, Ertelt M, Navarro RG, Lucifora J, Yuan Q, Huber K, Abdelrahman A, Zhang LA, Franke AC, Schmithals C, Piiper A, Vogt A, Gonzalez-Carmona M, Frueh JT, Ullrich E, Meulemann P, Talbot SR, Odenthal M, Ott M, Seifried E, Schoeder CT, Schwäble J, Lisowski L, Büning H. Adeno-associated virus (AAV) capsid variants for improved liver-directed gene therapy. Hepatology 2023;77:802-815
  • Järveläinen HA, Schmithals C, von Harten M, Vogl TJ, Harris S, Henson C, Bullen-Clerkson G, Piiper A.. Assessment of the pharmacokinetics, disposition, and duration of action of the tumour-targeting peptide CEND-1. Int J Mol Sci 2023;24:5700
  • Conche C*, Finkelmeier F*, Pešić M, Nicolas AM, Böttger TW, Kennel KB, Denk D, Ceteci F, Mohs K, Engel E, Canli Ö, Dabiri Y, Peiffer KH, Zeuzem S, Salinas G, Longerich T, Yang H, Greten FR. Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade. Gut 2023 Jan 27:gutjnl-2022-327909. doi: 10.1136/gutjnl-2022-327909. Online ahead of print (*equal contribution)
  • Canli Ö, Nicolas AM*, Gupta J*, Finkelmeier F*, Goncharova O, Pesic M, Neumann T, Horst D, Löwer M, Sahin U, Greten FR. Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis. Cancer Cell 2017;32:869-883. (*equal contribution)
  • Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, Gupta R, Qiu M, Deczkowska A, Weiner A, Müller F, Sinha A, Friebel E, Engleitner T, Lenggenhager D, Moncsek A, Heide D, Stirm K, Kosla J, Kotsiliti E, Leone V, Dudek M, Yousuf S, Inverso D, Singh I, Teijeiro A, Castet F, Montironi C, Haber PK, Tiniakos D, Bedossa P, Cockell S, Younes R, Vacca M, Marra F, Schattenberg JM, Allison M, Bugianesi E, Ratziu V, Pressiani T, D'Alessio A, Personeni N, Rimassa L, Daly AK, Scheiner B, Pomej K, Kirstein MM, Vogel A, Peck-Radosavljevic M, Hucke F, Finkelmeier F, Waidmann O, Trojan J, Schulze K, Wege H, Koch S, Weinmann A, Bueter M, Rössler F, Siebenhüner A, De Dosso S, Mallm JP, Umansky V, Jugold M, Luedde T, Schietinger A, Schirmacher P, Emu B, Augustin HG, Billeter A, Müller-Stich B, Kikuchi H, Duda DG, Kütting F, Waldschmidt DT, Ebert MP, Rahbari N, Mei HE, Schulz AR, Ringelhan M, Malek N, Spahn S, Bitzer M, Ruiz de Galarreta M, Lujambio A, Dufour JF, Marron TU, Kaseb A, Kudo M, Huang YH, Djouder N, Wolter K, Zender L, Marche PN, Decaens T, Pinato DJ, Rad R, Mertens JC, Weber A, Unger K, Meissner F, Roth S, Jilkova ZM, Claassen M, Anstee QM, Amit I, Knolle P, Becher B,… NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021;592:450-456
  • von Knethen A, Schäfer A, Kuchler L, Knape T, Christen U, Hintermann E, Fißlthaler B, Schröder K, Brandes RP, Genz B, Abshagen K, Pützer BM, Sha LK, Weigert A, Syed SN, Schulz M, Shah AM, Ernst A, Putyrski M, Finkelmeier F, Pesic M, Greten F, Hogardt M, Kempf VAJ, Gunne S, Parnham MJ, Brüne B. Tolerizing CTL by Sustained Hepatic PD-L1 Expression Provides a New Therapy Approach in Mouse Sepsis. Theranostics. 2019;9:2003-2016
  • Depner C, Zum Buttel H, Böğürcü N, Cuesta AM, Aburto MR, Seidel S, Finkelmeier F, Foss F, Hofmann J, Kaulich K, Barbus S, Segarra M, Reifenberger G, Garvalov BK, Acker T, Acker-Palmer A. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance. Nat Commun 2016;7:12329
  • Fuhrmann DC, Mondorf A, Beifuß J, Jung M, Brüne B. Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis. Redox Biol 2020;36:101670

Clinical publications

Reviews

Zurück zur Homepage

 

Sektion "Molecular Mechanisms in Hereditary Diseases" (PD Dr. G. Plotz)

Research Group "Molecular Mechanisms in Hereditary Diseases"

Zurück zur Homepage

Click the image to see the publication

Research Overview and Projects

Genetic variations underlie many hereditary disorders, but a significant problem is to clarify if a given genetic variant identified in an affected patient is indeed causative for the patient’s condition or must be considered an innocuous bystander, a so-called “neutral variant”.

The research focuses on the generation of laboratory tools to find answers to this kind of question, therefore the topics are translational and situated between “bench and bedside”.

Major topics include genetic variants observed in context with Lynch syndrome, a hereditary cancer predisposition affecting predominantly the colorectum and the endometrium.

Lynch syndrome is caused by a loss of a vital, evolutionary conserved DNA fidelity system called Mismatch Repair (MMR). The major players of MMR are two heterodimeric protein complexes formed by the products of the genes MLH1, MSH2, PMS2 and MSH6.

Using bioinformatics tools and laboratory functional testing, we evaluate the fitness of variant proteins and – at the same time – unveil mechanisms of the MMR reaction and the mode of function of the proteins since these are incompletely understood.

Besides Lynch syndrome, other hereditary diseases of the gastrointestinal track are also investigated, mainly:

  • MUTYH-associated Polyposis coli (MAP), caused by loss of a DNA repair system for oxidative damage
  • Wilson disease, caused by a defect of a hepatobiliary transporter (ATP7B)

Lab Members

Lab Head

PD Dr. Guido Plotz
Phone: +49 69 6301 87668
E-Mail: plotz@med.uni-frankfurt.de

Adress:
Universitätsklinik Frankfurt – Goethe-Universität
Medizinische Klinik 1
Biomedizinisches Forschungslabor
Haus 11, 2.OG, Zimmer 28
Theodor-Stern-Kai 7
60590 Frankfurt

Funding

DFG, Sander-Stiftung, Deutsche Krebshilfe

Selected Publications

Wolf K, Kosinski J, Gibson TJ, Wesch N, Dötsch V, Genuardi M, Lucci Cofrdisco E, Zeuzem S, Brieger A, Plotz G: A conserved motif in the disordered linker of human MLH1 is vital for DNA mismatch repair and its function is diminished by a cancer family mutation. Nucleic Acids Res. 2023 May 24. PMID 37224528

Höflich C, Brieger A, Zeuzem S, Plotz G. Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations. Sci Rep. 2021; 11(1):7674.PMID 33828154

González-Acosta M, Hinrichsen I, Fernández A, Lázaro C, Pineda M, Plotz G*, Capellá G.*. Validation of an in Vitro Mismatch Repair Assay Used in the Functional Characterization of Mismatch Repair Variants. J Mol Diagn. 2020 Mar;22(3):376-385. PMID 31881334

Köger N, Brieger A, Hinrichsen IM, Zeuzem S, Plotz G. Analysis of MUTYH alternative transcript expression, promoter function and the effect of human genetic variants. Human Mutation 2019. PMID 30653782

Köger N, Paulsen L, López-Kostner F, Della Valle A, Vaccaro CA, Palmero EI, Alvarez K, Sarroca C, Neffa F, Kalfayan PG, Gonzalez ML, Rossi BM, Reis RM, Brieger A, Zeuzem S, Hinrichsen I, Dominguez-Valentin M*, Plotz G.*. Evaluation of MLH1 variants of unclear significance. Genes Chromosomes Cancer. 2018 Jul;57(7):350-358. PMID 29520894

Hinrichsen I, Schäfer D, Langer D, Köger N, Wittmann M, Aretz S, Steinke V, Holzapfel S, Trojan J, König R, Zeuzem S, Brieger A, Plotz G.: Functional testing strategy for coding genetic variants of unclear significance in MLH1 in Lynch syndrome diagnosis. Carcinogenesis. 2015 Feb;36(2):202-11. PMID 25477341

Seguí N, Navarro M, Pineda M, Köger N, Bellido F, González S, Campos O, Iglesias S, Valdés-Mas R, López-Doriga A, Gut M, Blanco I, Lázaro C, Capellá G, Puente XS, Plotz G*, Valle L.*: Exome sequencing identifies MUTYH mutations in a family with colorectal cancer and an atypical phenotype. Gut. 2015 Feb;64(2):355-6. PMID 24691292

Hinrichsen I, Brieger A, Trojan J, Zeuzem S, Nilbert M, Plotz G. Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis. Clin Cancer Res. 2013 May 1;19(9):2432-41. PMID 23403630

Plotz G., Casper M., Raedle J., Hinrichsen I., Heckel V., Brieger A., Trojan J., Zeuzem S. MUTYH gene expression and alternative splicing in controls and polyposis patients. Hum Mutat. 2012. PMID 22473953

Kosinski J., Hinrichsen I., Bujnicki J.M., Friedhoff P., Plotz G. Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair. Hum Mutat. 31(8):975-82, 2010 PMID 20533529

Plotz G, Welsch C, Giron-Monzon L, Friedhoff P, Albrecht M, Piiper A, Biondi RM, Lengauer T, Zeuzem S und Raedle J. Mutations in the MutSalpha interaction interface of MLH1 can abolish DNA mismatch repair. Nucleic Acids Res 34: 6574-6586, 2006. PMID 17135187

Zurück zur Homepage

Sektion "Respiratory Infections in Chronic Lung Diseases" (Univ.-Prof. Dr. med. G. Rohde)

Research Group "Respiratory Infections in Chronic Lung Diseases"

Zurück zur Homepage

Research Overview and Projects

Bacterial-viral interactions in the respiratory tract

Chronic bacterial infections in the lung are common in diseases like COPD or cystic fibrosis. They can shape local immunity and inflammation in the lung and thereby not only change the microenvironment in the lower respiratory tract, but also affect susceptibility to heterologous infections and their course. Relevant mechanisms include the increase of viral entry receptors on the cell surface (Gulraiz et al., 2015), modulation of the production of pro-inflammatory mediators (Bellinghausen et al., 2016), and active degradation of cytokines through bacterial proteases (Endres et al., 2022). In our current projects, we aim to identify determinants of the interplay between bacteria, viruses, and the host, and study consequences of such interactions in vitro and in observational clinical studies.

Respiratory microbiota in chronic lung diseases: Towards clinical applicability of bacterial community profiling

Shifts in the respiratory microbiota are observed in multiple diseases of the respiratory tract. Frequently, chronic pulmonary diseases are associated with a loss of bacterial diversity, and an outgrowth of potential pathogenic bacteria. These changes in turn are hypothesised to further aggravate chronic inflammation and pathological changes in the lung. Intraindividual dynamics in microbiota composition might be an early indicator of acute deteriorations in diseases like COPD, however, large scale studies and longitudinal data are scarce. Using bacterial community profiling techniques, we are longitudinally analysing the respiratory microbiota of patients with COPD. Using these data in conjunction with clinical data and additional laboratory parameters, we aim to improve individual risk assessment for the development of COPD exacerbations. Ultimately, we thereby hope to enable more personalised preventive measures and treatments.

Exogenous type I IFNs for therapy and prophylaxis of respiratory viral infections

Type I IFNs are important antiviral mediators of the innate immune system. By triggering the expression of interferon-stimulated genes (ISGs) with potent antiviral functions, type I IFNs are crucial in establishing early antiviral immunity in a variety of tissues. As pharmacotherapy, systemic application of type I IFNs has been established for multiple sclerosis and chronic hepatitis. However, considerable side effects prohibit systemic application for treatment of prophylaxis of respiratory infections. To circumvent undesired effects and at the same time increase deposition in the lung, local application of exogenous type I IFNs (e.g. through inhalation) has been the focus of recent developments. Next to improving the understanding of antiviral activities exhibited by IFNs, our group is interested in the effects of type I IFN signalling on epithelial barrier function and during bacterial superinfections in the lung. Moreover, together with collaborators, we are working on the improvement of formulation and delivery of inhaled exogenous type I IFN.

Pulmonary infections in acute-on-chronic liver failure (ACLF)

Respiratory infections can be a trigger and are a major complication in acute-on-chronic liver failure (ACLF). As part of the LOEWE Initiative ACLF-I, together with the Institute of Medical Virology (Research Group Toptan) we aim to characterise respiratory infections as precipitating event in ACLF and decipher underlying mechanisms. In experimental models, we investigate the interaction between liver and lung, in order to identify relevant pathways and mediators that contribute to the development of ACLF. Moreover, we study how hepatic damage affects the susceptibility and outcome of respiratory infections. In a clinical cohort established by the ACLF-I consortium, we additionally determine the occurrence of respiratory viruses and their association with clinical outcomes.

Clinical research:

Respiratory infections are also central to many clinical research projects of our group.

As part of the German Competence Network Community Acquired Pneumonia (CAPNETZ), we recruit patients for the network’s studies and conduct research projects with particular focus on the influence of co-morbidities on CAP outcomes, and on the influence of CAP on pre-existing extrapulmonary co-morbidities.

Within the CCHROMO study (COVID-19 Chronic Morbidity), we study the long-term effects of COVID19 on lung function, systemic inflammation, and symptom persistence.

Next to these projects, the department is actively participating in clinical trials and patient registries. The Christiane Herzog CF centre actively contributes to the German Cystic Fibrosis Registry MUKO.web. MUKO.web enables easy documentation of data from CF patients treated at the centre. Visualisations of the centre’s own data set allows to easily analyse patient-specific data on the course of the disease in real time. Participation in the register as part of a benchmarking project moreover aims to compare participating centres and supports their quality assurance.

In other clinical projects, the group analyses risk factors for the development of respiratory failure, especially in patients with structural lung diseases. To this end,  data on the clinical course and outcome of patients with hypoxemic or hypercapnic failure are evaluated. The aim of these projects is to improve the preclinical and clinical treatment of these patients to increase patient safety.

Central to the project “Machine Learning to Machine Teaching (ML2MT)” in collaboration with Prof. Dr. Oliver Hinz (Chair for Business Informatics and Information Management at Goethe University Frankfurt) is the concept of Explainable AI. The goal of the project is to obtain more insight into the „black-box“ nature of machine learning algorithms such that users have a better understanding of how the output of these methods occur.

 

Lab Members

Lab Head

Univ.-Prof. Dr. med. Gernot Rohde
gernot.rohde@unimedizin-ffm.de
+49 (0) 69 - 6301 6336

Staff

Carla Bellinghausen, PhD
c.bellinghausen@med.uni-frankfurt.de
Phone: +49 (0)69-6301 4591

Postdocs: Dr. rer. nat. Helena Boland, Jeremy de Carvalho de Sousa, PhD,
Physicians: Dr. med. Wolfgang Gleiber, Dr. med. Achim Grünewaldt, Khader Musleh, Dr. med. Alexander Seeger, Dr. med. Christina SmacznyDr. med. Adrian Endres (MD/PhD candidate)
Clinical Researcher: Carlo Frigerio
Doctoral Students & Research Assistants: Tara Azem (medical student), Wenhan Du (medical student), Arda Güler (PhD candidate), Leonie Haas (medical student), Cornelius Lask (medical student), Paul Mennig (BSc Biochemistry, research assistant), Jakob Seitz (medical student)

We regularly offer projects for BSc/MSc theses and medical doctorates. If you are interested in joining our group, please send a letter of motivation and CV to carla.bellinghausen@unimedizin-ffm.de.

Funding

BMBF/Eurostars, BMWK, Mukoviszidose e.V., Gilead Sciences, Volkswagenstiftung, Goethe Corona Fonds, Pandemienetzwerk Hessen (HMWK)

Selected Publications:   

  • Endres A, Hügel C, Boland H, Hogardt M, Schubert R, Jonigk D, Braubach P, Rohde G, Bellinghausen C. <i>Pseudomonas aeruginosa</i> Affects Airway Epithelial Response and Barrier Function During Rhinovirus Infection. Front Cell Infect Microbiol. 2022 Feb 21;12:846828. doi: 10.3389/fcimb.2022.846828. PMID: 35265536; PMCID: PMC8899922.
  • Bellinghausen C, Pletz MW, Rupp J, Witzenrath M, Welsch C, Zeuzem S, Trebicka J, Rohde GGU; Members of the CAPNETZ study group. Chronic liver disease negatively affects outcome in hospitalised patients with community-acquired pneumonia. Gut. 2021 Jan;70(1):221-222. doi: 10.1136/gutjnl-2020-320876. Epub 2020 Apr 6. PMID: 32253260.
  • Schierwagen R, Gu W, Brieger A, Brüne B, Ciesek S, Đikić I, Dimmeler S, Geisslinger G, Greten FR, Hermann E, Hildt E, Kempf VAJ, Klein S, Koch I, Mühl H, Müller V, Peiffer KH, Kestner RI, Piiper A, Rohde G, Scholich K, Schulz MH, Storf H, Toptan T, Vasa-Nicotera M, Vehreschild MJGT, Weigert A, Wild PJ, Zeuzem S, Engelmann C; ACLF-I Investigators,; Schaefer L, Welsch C, Trebicka J. Pathogenetic mechanisms and therapeutic approaches of acute-to-chronic liver failure. Am J Physiol Cell Physiol. 2023 Jul 1;325(1):C129-C140. doi: 10.1152/ajpcell.00101.2023. Epub 2023 Jun 5. PMID: 37273239.
  • Schulz MS, Mengers J, Gu W, Drolz A, Ferstl PG, Amoros A, Uschner FE, Ackermann N, Guttenberg G, Queck A, Brol MJ, Graf C, Stoffers P, de la Vera AL, Cremonese C, Erasmus HP, Welker MW, Grünewaldt A, Arroyo V, Bojunga J, Fernandez J, Zeuzem S, Kluwe J, Peiffer KH, Welsch C, Fuhrmann V, Rohde G, Trebicka J. Pulmonary impairment independently determines mortality in critically ill patients with acute-on-chronic liver failure. Liver Int. 2023 Jan;43(1):180-193. doi: 10.1111/liv.15343. Epub 2022 Aug 25. PMID: 35727853.
  • Pletz MW, Jensen AV, Bahrs C, Davenport C, Rupp J, Witzenrath M, Barten- Neiner G, Kolditz M, Dettmer S, Chalmers JD, Stolz D, Suttorp N, Aliberti S, Kuebler WM, Rohde G. Unmet needs in pneumonia research: a comprehensive approach by the CAPNETZ study group. Respir Res. 2022 Sep 10;23(1):239. doi: 10.1186/s12931-022-02117-3. PMID: 36088316; PMCID: PMC9463667.
  • Grünewaldt A, Fritsch N, Rohde G. Hypercapnic Failure in Acute Exacerbated COPD Patients: Severe Airflow Limitation as an Early Warning Signal. J Clin Med. 2022 Dec 29;12(1):258. doi: 10.3390/jcm12010258. PMID: 36615058; PMCID: PMC9821585.
  • Sprooten RTM, Lenaerts K, Braeken DCW, Grimbergen I, Rutten EP, Wouters EFM, Rohde GGU. Increased Small Intestinal Permeability during Severe Acute Exacerbations of COPD. Respiration. 2018;95(5):334-342. doi: 10.1159/000485935. Epub 2018 Jan 25. PMID: 29393240; PMCID: PMC5985742.
  • Wolf A, Stratmann JA, Shaid S, Niklas N, Calleja A, Ubhi H, Munro R, Waldenberger D, Carroll R, Daumont MJ, Penrod JR, Lacoin L, Rohde G. Evolution of treatment patterns and survival outcomes in patients with advanced non-small cell lung cancer treated at Frankfurt University Hospital in 2012-2018. BMC Pulm Med. 2023 Jan 13;23(1):16. doi: 10.1186/s12890-022-02288-1. PMID: 36639770; PMCID: PMC9838033.
  • Further Publications

Zurück zur Homepage

Sektion "Molecular Pathology of Biliary Tract Cancer & Clinical Research on Biliary Strictures" (PD Dr. med. D. Walter)

Research Group "Molecular Pathology of Biliary Tract Cancer & Clinical Research on Biliary Strictures"

Zurück zur Homepage

Research Overview and Projects

  • Intratumoral heterogeneity and subtyping of biliary tract cancer
  • Endoscopic management of biliary strictures
  • Antibiotic treatment of cholangitis after endoscopic treatment

Lab Members

Lab Head

PD Dr. med. Dirk Walter
dirk.walter@unimedizin-ffm.de

University Hospital Frankfurt
Haus 11, 3. OG
Goethe University
Theodor-Stern-Kai 7
60590 Frankfurt am Main

Staff
  • Postdocs and Physicians: Dr. Maximilian Kinzler, Dr. Vera Himmelsbach, Dr. Philip Ferstl, Dr. Alica Kubesch, Dr. Peter Hunyady
  • Doctoral students: Dr. Fabian Görnert, cand. med. Katharina Bremer, cand. med. Alexander Schütz, Imad Osman, cand. med. Lars Holzheimer, cand. med. Christina Klasen

Funding

Junior Clinician Scientist-Programm (Walter, Kinzler)
Stiftungsmittel

Selected Publications  

Originalarbeiten (ab 2017):

2017
Eosinophilic cholangitis is a potentially underdiagnosed etiology in indeterminate biliary stricture.
Walter D, Hartmann S, Herrmann E, Peveling-Oberhag J, Bechstein WO, Zeuzem S, Hansmann ML, Friedrich-Rust M, Albert JG.World J Gastroenterol. 2017 Feb 14;23(6):1044-1050. doi: 10.3748/wjg.v23.i6.1044.PMID: 28246478 

PD-L1 expression in extrahepatic cholangiocarcinoma.
Walter D, Herrmann E, Schnitzbauer AA, Zeuzem S, Hansmann ML, Peveling-Oberhag J, Hartmann S.Histopathology. 2017 Sep;71(3):383-392. doi: 10.1111/his.13238. Epub 2017 Jun 23.

Intratumoral heterogeneity of intrahepatic cholangiocarcinoma.
Walter D, Döring C, Feldhahn M, Battke F, Hartmann S, Winkelmann R, Schneider M, Bankov K, Schnitzbauer A, Zeuzem S, Hansmann ML, Peveling-Oberhag J.Oncotarget. 2017 Feb 28;8(9):14957-14968. doi: 10.18632/oncotarget.14844.

 

2018

Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors.
Walter D, Harter PN, Battke F, Winkelmann R, Schneider M, Holzer K, Koch C, Bojunga J, Zeuzem S, Hansmann ML, Peveling-Oberhag J, Waidmann O. Sci Rep. 2018 Feb 28;8(1):3811. doi: 10.1038/s41598-018-22115-0.

Microsatellite Instability Occurs Rarely in Patients with Cholangiocarcinoma: A Retrospective Study from a German Tertiary Care Hospital.
Winkelmann R, Schneider M, Hartmann S, Schnitzbauer AA, Zeuzem S, Peveling-Oberhag J, Hansmann ML, Walter D.Int J Mol Sci. 2018 May 9;19(5):1421. doi: 10.3390/ijms19051421.

Sequencing of intraductal biopsies is feasible and potentially impacts clinical management of patients with indeterminate biliary stricture and cholangiocarcinoma.
Bankov K, Döring C, Schneider M, Hartmann S, Winkelmann R, Albert JG, Bechstein WO, Zeuzem S, Hansmann ML, Peveling-Oberhag J, Walter D.Clin Transl Gastroenterol. 2018 Apr 30;9(4):151. doi: 10.1038/s41424-018-0015-6.

 

2019

Cholangiocarcinoma in Germany: Epidemiologic trends and impact of misclassification.
Walter D, Ferstl P, Waidmann O, Trojan J, Hartmann S, Schnitzbauer AA, Zeuzem S, Kraywinkel K.Liver Int. 2019 Feb;39(2):316-323. doi: 10.1111/liv.13954. Epub 2018 Oct 8.

 

2022

Impact of small duct- and large duct type on survival in patients with intrahepatic cholangiocarcinoma: Results from a German tertiary center.
Kinzler MN, Schulze F, Bankov K, Gretser S, Becker N, Leichner R, Stehle A, Abedin N, Trojan J, Zeuzem S, Schnitzbauer AA, Wild PJ, Walter D.Pathol Res Pract. 2022 Sep 16;238:154126. doi: 10.1016/j.prp.2022.154126.

Impact of Liver Fibrosis on Survival of Patients with Intrahepatic Cholangiocarcinoma Receiving Gemcitabine-Based Chemotherapy.
Kinzler MN, Klasen C, Schulze F, Herrmann E, Schnitzbauer AA, Trojan J, Zeuzem S, Wild PJ, Walter D.J Clin Med. 2022 Apr 6;11(7):2057. doi: 10.3390/jcm11072057.

Impact of Liver Fibrosis on Survival of Patients with Intrahepatic Cholangiocarcinoma Receiving Gemcitabine-Based Chemotherapy.
Kinzler MN, Klasen C, Schulze F, Herrmann E, Schnitzbauer AA, Trojan J, Zeuzem S, Wild PJ, Walter D.J Clin Med. 2022 Apr 6;11(7):2057. doi: 10.3390/jcm11072057.

Comparison of short-course antibiotic therapy of 6 or less days with a longer treatment in patients with cholangitis after liver transplantation.
Ferstl PG, Queck A, Bremer K, Filmann N, Weiler N, Welker MW, Waidmann O, Knabe M, Bechstein WO, Hogardt M, Kempf VAJ, Zeuzem S, Trebicka J, Friedrich-Rust M, Walter D.Transpl Infect Dis. 2022 Aug;24(4):e13868. doi: 10.1111/tid.13868. Epub 2022 Jun 6.

Impact of a shorter replacement interval of plastic stents on premature stent exchange rate in benign and malignant biliary strictures.
Kubesch A, Görnert F, Filmann N, Bojunga J, Zeuzem S, Jung M, Friedrich-Rust M, Walter D.J Gastroenterol Hepatol. 2022 Jun;37(6):1076-1082. doi: 10.1111/jgh.15824. Epub 2022 Mar 17.

 

2023
Colonization with multidrug-resistant organisms is associated with impaired survival of patients with surgically resected cholangiocarcinoma.
Kinzler MN, Stehle A, Schulze F, Hogardt M, Wichelhaus TA, Kempf VAJ, Finkelmeier F, Trojan J, Zeuzem S, Schnitzbauer AA, Bechstein WO, Wild PJ, Walter D. Liver Int. 2023 Feb;43(2):490-499. doi: 10.1111/liv.15485. Epub 2022 Dec 7.

Impact of IDH1 mutation on clinical course of patients with intrahepatic cholangiocarcinoma: a retrospective analysis from a German tertiary center.
Kinzler MN, Jeroch J, Klasen C, Himmelsbach V, Koch C, Finkelmeier F, Trojan J, Zeuzem S, Pession U, Reis H, Demes MC, Wild PJ, Walter D. J Cancer Res Clin Oncol. 2023 Feb 9. doi: 10.1007/s00432-023-04603-7. Online ahead of print.

 

Übersichtsarbeiten:

Update on cholangiocarcinoma: potential impact of genomic studies on clinical management.
Walter D, Hartmann S, Waidmann O.Z Gastroenterol. 2017 Jun;55(6):575-581. doi: 10.1055/s-0043-102581. Epub 2017 Apr 4.

[The endoscopic approach to indeterminate biliary stricture: current practice and future perspective].
Walter D, Albert J, Jung M, Friedrich-Rust M.Z Gastroenterol. 2020 Feb;58(2):152-159. doi: 10.1055/a-1013-4331. Epub 2019 Dec 20.

[Systemic Chemotherapy of gallbladder carcinoma - simply the same as for cholangiocarcinoma?].
Walter D, Trojan J, Waidmann O.Z Gastroenterol. 2020 Jun;58(6):583-589. doi: 10.1055/a-1161-3985. Epub 2020 Jun 16.

Anomalien im pankreatikobiliären System; Walter D, Jung M. Die Gastroenterologie | Ausgabe 4/2019

Zurück zur Homepage

Sektion "Molecular Hepatology & Inflammation Research" (Prof. Dr. med. C. Welsch)

Lab Head

Prof. Dr. med. Christoph Welsch

Zurück zur Homepage

Contact data:
christoph.welsch@unimedizin-ffm.de
Tel.: +49 69 6301 4840

Address:
Universitätsklinikum Frankfurt
Medizinische Klinik 1
Haus 11, 3. OG
Theodor-Stern-Kai 7
60590 Frankfurt

Research Group “Key Transmission Sites in (Liver) Inflammation”

Research Overview and Projects

We aim in identifying key transmission sites in the liver that control the transition from favorable to unfavorable inflammatory tissue and organ damage in chronic liver disease and acute-on-chronic liver failure (ACLF). Local control of inflammatory processes is achieved through the fidelity of immunological responses and their adaptation to tissue-specific conditions. Specific cell populations within the liver (“relay” stations) integrate complex information from inflammatory mediators into cell-cell communication and play a critical role in the balance between pro- and anti-inflammatory processes at the tissue level. Using high-resolution multiplexed tissue analysis of mouse and human liver, small animal models and cell culture, we aim to temporally and spatially resolve cellular interaction patterns at the RNA and protein level to identify key sites and processes for immunomodulatory intervention. In collaboration with partners from Computer Science and Molecular Bioinformatics and the Dr. Senckenberg Institute of Pathology (SIP), we use machine learning and quantitative image analysis to link morphological features in liver sections with the spatial context of transcriptional activity in liver disease progression from cirrhosis to ACLF.

Staff:

Group leader: Dr. Cristina Ortiz, Nico Kraus
Doctoral Students: Toska Wiedemann, Magdalena Ohngemach
Technicians: Dikra Zouiten

Funding:

LOEWE-SP ACLF-I, EnABLE Cluster

Selected Publications:   

  • Dorochow E*, Kraus N*, Chenaux-Repond N, Pierre S, Kolbinger A, Geisslinger G, Ortiz C, Welsch C, Trebicka J, Gurke R, Hahnefeld L, Klein S, Scholich K. Differential lipidomics, metabolomics, and immunological analysis of alcoholic and non-alcoholic steatohepatitis in mice. Int J Mol Sci. 2023 in press.
  • Ortiz C, Klein S, Reul WH, Magdaleno F, Gröschl S, Dietrich P, Schierwagen R, Uschner FE, Torres S, Hieber C, Meier C, Kraus N, Tyc O, Brol M, Zeuzem S, Welsch C, Poglitsch M, Hellerbrand C, Alfonso-Prieto M, Mira F, Keller UAD, Tetzner A, Moore A, Walther T, Trebicka J. Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1. Cell Rep. 2023 Jan 31;42(2):112059. doi: 10.1016/j.celrep.2023.112059.
  • Torres S*, Ortiz C*, Bachtler N, Gu W, Grünewald LD, Kraus N, Schierwagen R, Hieber C, Meier C, Tyc O, Joseph Brol M, Uschner FE, Nijmeijer B, Welsch C, Berres ML, Garcia-Ruiz C, Fernandez-Checa JC, Trautwein C, Vogl TJ, Zeuzem S, Trebicka J, Klein S. Janus kinase 2 inhibition by pacritinib as potential therapeutic target for liver fibrosis. Hepatology. 2023 Apr 1;77(4):1228-1240. doi: 10.1002/hep.32746.
  • Niu L, Geyer PE, Gupta R, Santos A, Meier F, Doll S, Wewer Albrechtsen NJ, Klein S, Ortiz C, Uschner FE, Schierwagen R, Trebicka J, Mann M. Dynamic human liver proteome atlas reveals functional insights into disease pathways. Mol Syst Biol. 2022 May;18(5):e10947. doi: 10.15252/msb.202210947.
  • Monteiro S, Grandt J, Uschner FE, Kimer N, Madsen JL, Schierwagen R, Klein S, Welsch C, Schäfer L, Jansen C, Claria J, Alcaraz-Quiles J, Arroyo V, Moreau R, Fernandez J, Bendtsen F, Mehta G, Gluud LL, Møller S, Praktiknjo M, Trebicka J. Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation. Gut. 2021 Feb;70(2):379-387. doi: 10.1136/gutjnl-2019-320170.
  • Schierwagen R, Uschner FE, Ortiz C, Torres S, Brol MJ, Tyc O, Gu W, Grimm C, Zeuzem S, Plamper A, Pfeifer P, Zimmer S, Welsch C, Schaefer L, Rheinwalt KP, Clària J, Arroyo V, Trebicka J, Klein S. The Role of Macrophage-Inducible C-Type Lectin in Different Stages of Chronic Liver Disease. Front Immunol. 2020 Jul 7;11:1352. doi: 10.3389/fimmu.2020.01352.

    *Equal contribution

Research Group “Cytokine Signaling at the Nanoscale”

Research Overview and Projects

We address the role of interleukins in cellular homeostasis and inflammation, including barrier function and regeneration, and the resulting therapeutic potential in chronic liver disease and acute-on-chronic liver failure (ACLF). Signal transduction of various cytokines occurs via lipid rafts and is dependent on the lipid environment in the cell membrane and rafts. Specific and nonspecific lipid-receptor interactions can have modulatory effects on receptor assembly and function and offer potential for targeted interventions (druggable sites). Using cell culture systems and primary cells, artificial membrane systems and liposome models with purified cytokine receptors, we aim to develop mechanistic models of cytokine receptor signaling at the nanoscale. Together with our collaborative partners at the Institute of Clinical Pharmacology and Toxicology and the Frankfurt Institute of Advanced Studies (FIAS), we focus on the mechanisms of lipid sensing and modulation of cytokine transduction cascades at the membrane level, using theoretical models, computer simulation methods and artificial intelligence to better understand the dynamic organization of these complex biological systems.

Staff:

Group leader: Dr. Claudia Stroß, Dr. Rebecca M. Richter
Physicians: Dr. Katharina M. Schwarzkopf
Doctoral Students: Hyun-Chun Choi, Alicia Reißenberger, Alexander Faynblat
Technicians: Dikra Zouiten

Funding:

LOEWE-SP ACLF-I, LOEWE-Zentrum TMP, Else Kröner-Fresenius-Stiftung (TRIP-Kolleg), Deutsche Forschungsgemeinschaft (DFG WE 4388/10-1)

Selected Publications:

  • Rueschenbaum S, Cai C, Schmidt M, Schwarzkopf K, Dittmer U, Zeuzem S, Welsch C, Lange CM. Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity. Front Immunol. 2021 Jan 14;11:581352. doi: 10.3389/fimmu.2020.581352.
  • Schwarzkopf KM, Eberle L, Uschner FE, Klein S, Schierwagen R, Mücke MM, Schaefer L, Clària J, Zeuzem S, Hintermann E, Christen U, Lange CM, Trebicka J, Welsch C. Interleukin-22 in acute-on-chronic liver failure: A matter of ineffective levels, receptor dysregulation or defective signalling? J Hepatol. 2020 Oct;73(4):980-982. doi: 10.1016/j.jhep.2020.05.012.
  • Schwarzkopf K, Rüschenbaum S, Barat S, Cai C, Mücke MM, Fitting D, Weigert A, Brüne B, Zeuzem S, Welsch C, Lange CM. IL-22 and IL-22-Binding Protein Are Associated With Development of and Mortality From Acute-on-Chronic Liver Failure. Hepatol Commun. 2019 Jan 17;3(3):392-405. doi: 10.1002/hep4.1303.

 

Research Group “Molecular Evolution and Adaptation”

Our studies focus on functional and structural biology of membrane-associated proteins of hepatotropic viruses in their natural membrane context. We are particularly interested in specific lipid-protein interactions and their role in viral fitness and immune escape mechanisms, in the mode of action of antiviral drugs targeting these proteins and related resistance mechanisms. Our projects rely on synthetic biology, biochemistry and biophysics methods, in particular, on work with purified proteins in artificial membrane systems. Our goal is to understand the molecular mechanics of membrane-associated viral proteins as a function of lipid composition in their cellular/subcellular context. We are working on these projects together with partners at the Riedberg Campus in Frankfurt (the Goethe University and the Max Planck Institute for Biophysics), the University of Texas Medical Branch in Galveston, the Tokyo Metropolitan Institute of Medical Science and Kanazawa University in Japan, as well as the Max Delbrück Center for Molecular Medicine in Berlin.

Staff:

Group leader: Dr. Anna V. Bulankina
Physicians: PD Dr. Georg Dultz
Doctoral Students: Mia König, Jonas Hermann, Hanaa Charif

Funding:

Deutsche Forschungsgemeinschaft (DFG WE 4388/8-1), National Institutes of Health (NIH R01-Grant), Gilead Sciences Intl. Research Scholars Program

Selected Publications:

  • Bulankina AV, Richter RM, Welsch C. Regulatory Role of Phospholipids in Hepatitis C Virus Replication and Protein Function. Pathogens. 2022 Jan 15;11(1):102. doi: 10.3390/pathogens11010102.
  • Dultz G, Srikakulam SK, Konetschnik M, Shimakami T, Doncheva NT, Dietz J, Sarrazin C, Biondi RM, Zeuzem S, Tampé R, Kalinina OV, Welsch C. Epistatic interactions promote persistence of NS3-Q80K in HCV infection by compensating for protein folding instability. J Biol Chem. 2021 Sep;297(3):101031. doi: 10.1016/j.jbc.2021.101031.
  • Dultz G, Shimakami T, Schneider M, Murai K, Yamane D, Marion A, Zeitler TM, Stross C, Grimm C, Richter RM, Bäumer K, Yi M, Biondi RM, Zeuzem S, Tampé R, Antes I, Lange CM, Welsch C. Extended interaction networks with HCV protease NS3-4A substrates explain the lack of adaptive capability against protease inhibitors. J Biol Chem. 2020 Oct 2;295(40):13862-13874. doi: 10.1074/jbc.RA120.013898.
  • Shanmugam S, Nichols AK, Saravanabalaji D, Welsch C, Yi M. HCV NS5A dimer interface residues regulate HCV replication by controlling its self-interaction, hyperphosphorylation, subcellular localization and interaction with cyclophilin A. PLoS Pathog. 2018 Jul 23;14(7):e1007177. doi: 10.1371/journal.ppat.1007177.
  • Welsch C, Haselow K, Gouttenoire J, Schneider M, Morikawa K, Martinez Y, Susser S, Sarrazin C, Zeuzem S, Antes I, Moradpour D, Lange CM. Hepatitis C virus variants resistant to macrocyclic NS3-4A inhibitors subvert IFN-β induction by efficient MAVS cleavage. J Hepatol. 2015 Apr;62(4):779-84. doi: 10.1016/j.jhep.2014.11.009.
  • Yamane D, McGivern DR, Wauthier E, Yi M, Madden VJ, Welsch C, Antes I, Wen Y, Chugh PE, McGee CE, Widman DG, Misumi I, Bandyopadhyay S, Kim S, Shimakami T, Oikawa T, Whitmire JK, Heise MT, Dittmer DP, Kao CC, Pitson SM, Merrill AH Jr, Reid LM, Lemon SM. Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation. Nat Med. 2014 Aug;20(8):927-35. doi: 10.1038/nm.3610.

Zurück zur Homepage

MENÜ