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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  125. Kongress der Deutschen Gesellschaft für Chirurgie; 20080422-20080425; Berlin; DOC08dgch9433 /20080416/
    Publication Date: 2008-04-14
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
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    German Medical Science; Düsseldorf, Köln
    In:  123. Kongress der Deutschen Gesellschaft für Chirurgie; 20060502-20060505; Berlin; DOC06dgch5039 /20060502/
    Publication Date: 2006-05-09
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; GROWTH-FACTOR ; proliferation ; CELL ; Germany ; IN-VIVO ; liver ; PROTEIN ; DIFFERENTIATION ; MICE ; ACTIVATION ; MECHANISM ; FAMILY ; T cells ; MEMBERS ; SUSCEPTIBILITY ; antibody ; DELETION ; MOUSE ; RATES ; DAMAGE ; B-CELLS ; INJURY ; FAMILIES ; development ; FULMINANT HEPATIC-FAILURE ; HUMAN HEPATOCELLULAR-CARCINOMA ; MCL-1 ; MAINTENANCE ; GROWTH-FACTORS ; OCCURS ; 33 ; ANTI-FAS ; BCL-2 PROTEINS
    Abstract: Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. It interacts with proapoptotic Bcl-2 family members, thereby inhibiting mitochondrial activation and induction of apoptosis. Mcl-1 is essential for embryonal development and the maintenance of B cells, T cells, and hematopoietic stem cells. We have recently shown that induction of Mcl-1 by growth factors rescues primary human hepatocy-tes from CD95-mediated apoptosis. This prompted us to further analyze the relevance of Mcl-1 for hepatocellular homeostasis. Therefore, we generated a hepatocyte-specific Mcl-1 knockout mouse (Mcl-1(flox/flox)-AlbCre). Deletion of Mcl-1 in hepatocytes results in liver cell damage caused by spontaneous induction of apoptosis. Livers of Mcl-1(flox/flox)-AlbCre mice are smaller compared to control littermates, due to higher apoptosis rates. As a compensatory mechanism, proliferation of hepatocytes is enhanced in the absence of Mcl-1. Importantly, hepatic pericellular fibrosis occurs in Mcl-1 negative livers in response to chronic liver damage. Furthermore, Mcl-1(flox/flox)-AlbCre mice are more susceptible to hepatocellular damage induced by agonistic anti-CD95 antibodies or concanavalin A. Conclusion: The present study provides in vivo evidence that Mcl-1 is a crucial antiapoptotic factor for the liver, contributing to hepatocellular homeostasis and protecting hepatocytes from apoptosis induction. (HEPATOLOGY 2009;49:627-636.)
    Type of Publication: Journal article published
    PubMed ID: 19127517
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  • 4
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; proliferation ; SURVIVAL ; tumor ; carcinoma ; CELL ; Germany ; IN-VIVO ; PATHWAY ; VIVO ; DEATH ; DISEASE ; HEPATOCELLULAR-CARCINOMA ; liver ; PROTEIN ; TUMORS ; MICE ; MECHANISM ; FAMILY ; MARKER ; CARCINOGENESIS ; DELETION ; hepatocellular carcinoma ; CELL-DEATH ; AGE ; DAMAGE ; REGULATOR ; MITOSIS ; Bcl-2 ; INJURY ; HUMAN CANCER ; SURVIVIN ; cell death ; CANCERS ; HOMEOSTASIS ; HUMAN HEPATOCELLULAR-CARCINOMA ; MCL-1 ; LIVER-REGENERATION
    Abstract: Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes toward apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and nonresponsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the antiapoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1(Delta hep)), spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in 〉50% of Mcl-1(Delta hep) mice already by the age of 8 months, whereas 12-month-old wild-type (wt) and heterozygous Mcl-1(flox/wt) mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1(Delta hep) mice was paralleled by markedly increased levels of Survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers. Conclusion: This study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases. (HEPATOLOGY 2010;51:1226-1236.)
    Type of Publication: Journal article published
    PubMed ID: 20099303
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  • 5
    Abstract: GOALS: The aim of this study was to analyze clinical presentation, course of disease, and management of patients with hepatocellular carcinoma (HCC) in a German referral center between 1998 and 2009. BACKGROUND: HCC is a rare tumor in Germany, but its incidence has increased over the last 30 years. New therapies such as chemoembolization with drug-eluting beads, selective internal radiotherapy, and sorafenib were introduced recently; however, the impact on clinical management and overall survival (OS) is unclear. STUDY: In this retrospective analysis, 1066 patients with HCC, separated into two 6-year periods (n=385; 1998 to 2003 and n=681; 2004 to 2009) were evaluated. RESULTS: The number of patients presenting each year (64 vs. 114 per year), with an age over 80 years or with nonalcoholic steatohepatitis increased significantly between periods. The main risk factors were alcoholic liver disease in 51.7%, chronic hepatitis C virus in 28.2%, and chronic hepatitis B virus in 13.4% of patients with liver cirrhosis and HCC. Patients presented with more advanced tumor stages and with worse liver function in period 2. The majority (61.6%) of patients received local treatment over a spectrum of Barcelona Clinic Liver-Cancer (BCLC) stages, whereas systemic therapy was offered to a minority (8.8%) and limited to BCLC stage C patients only. OS decreased in BCLC stage A and D and improved in BCLC stage B and C and decreased for all patients from 16.5 to 15.3 months between periods. CONCLUSIONS: No improvement of OS was observed when comparing time periods, partly because of the more advanced stage of HCC and because of the increasing age in the second time period. Improved and new therapeutic options and the intensification of surveillance programs are likely to increase survival of HCC patients in the future.
    Type of Publication: Journal article published
    PubMed ID: 24045276
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  • 6
    Abstract: GOALS:: The aim of this study was to assess the long-term outcome of primary biliary cirrhosis (PBC) patients and to test the clinical value of various outcome models, such as the Mayo Risk Score (MRS), in a large single-center cohort in Germany. BACKGROUND:: PBC is a chronic autoimmune liver disease with a female sex predominance and a peak incidence in the fifth decade of life. PBC is characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts in liver histology and the presence of antimitochondrial antibodies in the serum of nearly 95% of patients. In 5% to 20% of patients an overlap syndrome with autoimmune hepatitis (AIH) is diagnosed. Ursodeoxycholic acid is widely accepted as the standard medical treatment. STUDY:: A total of 204 patients with PBC or PBC/AIH were retrospectively analyzed with regard to their clinical, biochemical, serological, and histologic features. PBC was diagnosed on the basis of the American Association for the Study of Liver Diseases criteria. Specific PBC scores, such as the MRS, the European and the Yale model, as well as nonspecific scores such as the Child-Pugh, the Model for End-stage Liver Disease, and Aspartate Aminotransferase to Platelet Ratio Index score were analyzed for their utility to predict the clinical outcome of patients. RESULTS:: One hundred eighty-four patients with PBC alone and 20 with primary biliary cirrhosis/autoimmune hepatitis overlap were followed up for an average of 7.0 (range, 0.5 to 33.2) years. Importantly, baseline values of serum bilirubin, alkaline phosphatase, immunoglobulin M (IgM) and IgG, as well as antimitochondrial antibodies titers did not allow in properly predicting patient's outcome. The MRS proved clinical applicability. Patients with an R-value 〈6 did not develop liver-related complications. The Aspartate Aminotransferase to Platelet Ratio Index score had a significant correlation with the histologic degree of liver fibrosis, with limited value of scores between 1.0 and 1.5. Patients with a Model for End-stage Liver Disease score 〉/=8 (n=17) had a significantly higher risk to undergo liver transplantation or liver-related death. Outcome was less favorable than predicted by the European model. All scores showed low positive predictive values, limiting their applicability in clinical practice. CONCLUSIONS:: Herein, we demonstrate that clinical risk scores in PBC should be interpreted with care. The MRS proved to be helpful to predict a favorable outcome. Novel approaches to predict outcome are needed to identify patients who may benefit from alternative, intensified treatment regimens.
    Type of Publication: Journal article published
    PubMed ID: 25014239
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  • 7
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  132. Kongress der Deutschen Gesellschaft für Chirurgie; 20150428-20150501; München; DOC15dgch637 /20150424/
    Publication Date: 2015-04-25
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 8
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; SURVIVAL ; carcinoma ; CELL ; Germany ; human ; KINASE ; PATHWAY ; THERAPY ; DISEASE ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; DRUG ; cell line ; TISSUE ; LINES ; PATIENT ; FAMILY ; prognosis ; INDUCTION ; hepatocytes ; CELL-LINES ; DOWN-REGULATION ; MEMBER ; MEMBERS ; treatment ; TARGET ; hepatocellular carcinoma ; resistance ; CELL-LINE ; LINE ; SIGNALING PATHWAY ; CANCER-CELLS ; sensitization ; cell lines ; protein expression ; Bcl-2 ; EPIDERMAL-GROWTH-FACTOR ; signaling ; ONCOLOGY ; FAMILIES ; HUMAN CANCER ; TUMORIGENESIS ; GRADE ; KINASE INHIBITORS ; LEVEL ; CHEMOTHERAPEUTIC DRUGS ; DRUGS ; RELEVANCE ; DEFECT ; KINASE INHIBITOR ; epidermal growth factor ; ADJACENT ; BCL-XL ; CHOLANGIOCARCINOMA CELLS ; HEPATOCYTE GROWTH-FACTOR ; INHIBITOR BAY-43-9006 ; MCL-1
    Abstract: Defects in apoptosis signaling in hepatocytes contribute to tumorigenesis in hepatocellular carcinoma (HCC). In addition, treatment with chemotherapeutic drugs is often ineffective in HCC patients due to the apoptosis resistance of cancer cells. Anti-apoptotic members of the Bcl-2 family, including myeloid cell leukemia-1 (Mcl-1), which regulate intrinsic apoptosis induction at the mitochondrial level, are often overexpressed in human cancer, and are implicated with disease grade and prognosis. Yet, little is known about the role of Mcl-1 in HCC. In this study, we analyzed the relevance of Mcl-1 expression for the apoptosis resistance of human HCC. Mcl-1 protein expression was considerably enhanced in human HCC tissue compared to adjacent non-tumor tissue. In addition, Mcl-1 was prominently expressed in various HCC cell lines. Mcl-1 basal expression is dependent on a functional phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway; treatment of the cells with a specific PI3 kinase inhibitor led to both decreased Mcl-1 expression and a sensitization towards chemotherapeutic drug-induced apoptosis. Furthermore, the hepatocyte growth factor and epidermal growth factor induced Mcl-1 expression in an Akt- and ERK-dependent manner. Finally, specific upregulation of Mcl-1 in HCC cells inhibited chemotherapeutic drug-induced apoptosis. Our data suggest that Mcl-1 is an important factor for the apoptosis resistance of human HCC, and constitutes an interesting target for HCC therapy
    Type of Publication: Journal article published
    PubMed ID: 16327976
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  • 9
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; SURVIVAL ; AGENTS ; carcinoma ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; THERAPY ; VITRO ; HEPATOCELLULAR-CARCINOMA ; MORTALITY ; PROTEIN ; RNA ; DRUG ; TISSUE ; LINES ; ACTIVATION ; FAMILY ; IMPACT ; LIVER-TRANSPLANTATION ; PROTEIN FAMILY ; INDUCTION ; TISSUES ; FLOW ; CELL-LINES ; MEMBER ; treatment ; hepatocellular carcinoma ; resistance ; CARCINOMA CELLS ; RATES ; CELL-LINE ; chemotherapy ; LINE ; PCR ; CARCINOMA-CELLS ; sensitization ; sensitivity ; FLOW-CYTOMETRY ; real-time PCR ; cell lines ; Bcl-2 ; TRAIL-INDUCED APOPTOSIS ; ANTISENSE THERAPY ; CASPASE ; INHIBITORS ; signaling ; WORLDWIDE ; FAMILIES ; INTERFERENCE ; HUMAN-MELANOMA ; RNA INTERFERENCE ; KINASE INHIBITORS ; CHEMOTHERAPEUTIC DRUGS ; downregulation ; EPIRUBICIN ; DRUGS ; RESISTANT ; CANCERS ; EXTENT ; DEFECT ; KINASE INHIBITOR ; MCL-1 ; RAF ; mTOR ; MEDIATED MITOCHONDRIAL APOPTOSIS
    Abstract: Background: Hepatocelluar carcinoma ( HCC) is one of the most common cancers worldwide and a major cause of cancer-related mortality. HCC is highly resistant to currently available chemotherapeutic drugs. Defects in apoptosis signaling contribute to this resistance. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 protein family which interferes with mitochondrial activation. In a previous study we have shown that Mcl-1 is highly expressed in tissues of human HCC. In this study, we manipulated expression of the Mcl-1 protein in HCC cells by RNA interference and analyzed its impact on apoptosis sensitivity of HCC cells in vitro. Methods: RNA interference was performed by transfecting siRNA to specifically knock down Mcl-1 expression in HCC cells. Mcl-1 expression was measured by quantitative real-time PCR and Western blot. Induction of apoptosis and caspase activity after treatment with chemotherapeutic drugs and different targeted therapies were measured by flow cytometry and fluorometric analysis, respectively. Results: Here we demonstrate that Mcl-1 expressing HCC cell lines show low sensitivity towards treatment with a panel of chemotherapeutic drugs. However, treatment with the anthracycline derivative epirubicin resulted in comparatively high apoptosis rates in HCC cells. Inhibition of the kinase PI3K significantly increased apoptosis induction by chemotherapy. RNA interference efficiently downregulated Mcl-1 expression in HCC cells. Mcl-1 downregulation sensitized HCC cells to different chemotherapeutic agents. Sensitization was accompanied by profound activation of caspase-3 and -9. In addition, Mcl-1 downregulation also increased apoptosis rates after treatment with PI3K inhibitors and, to a lower extent, after treatment with mTOR, Raf I and VEGF/PDGF kinase inhibitors. TRAIL-induced apoptosis did not markedly respond to Mcl-1 knockdown. Additionally, knockdown of Mcl-1 efficiently enhanced apoptosis sensitivity towards combined treatment modalities: Mcl-1 knockdown significantly augmented apoptosis sensitivity of HCC cells towards chemotherapy combined with PI3K inhibition. Conclusion: Our data suggest that specific downregulation of Mcl-1 by RNA interference is a promising approach to sensitize HCC cells towards chemotherapy and molecularly targeted therapies
    Type of Publication: Journal article published
    PubMed ID: 17014711
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  • 10
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  128. Kongress der Deutschen Gesellschaft für Chirurgie; 20110503-20110506; München; DOC11dgch257 /20110520/
    Publication Date: 2011-05-20
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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