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Cyclosporine versus tacrolimus in patients with HCV infection after liver transplantation:Effects on virus replication and recurrent hepatitis

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World Journal of Gastroenterology 2006年第5期12卷 697-702页

作者： Philip Hilgard Alisan Kahraman Nils Lehmann Cornelia Seltmann Susanne Beckebaum R Stefan Ross Hideo A Baba Massimo Malago Christoph E Broelsch guido gerken Department of Gastroenterology and Hepatology University Hospital EssenHufelandstrasse 5545122 Essen Germany Institute for Medical Informatics Biometry and EpidemiologyUniversity Hospital EssenHufelandstrasse 5545122 EssenGermany Department of General Surgery and Transplantation University Hospital EssenHufelandstrasse 5545122 EssenGermany Institute for Virology University Hospital EssenHufelandstrasse 5545122 EssenGermany Institute for Pathology University Hospital EssenHufelandstrasse 5545122 EssenGermany

瞄准：决定 calcineurin 禁止者， cyclosporine 和 tacrolimus 的效果，在丙肝上，在病人的周期性的丙肝的病毒(HCV ) 复制和活动张贴肝移植。方法：在我们的中心为在 1999 和 2003 之间的联系 HCV 的肝肝硬化收到了肝移植的 107 个病... 详细信息

瞄准：决定 calcineurin 禁止者， cyclosporine 和 tacrolimus 的效果，在丙肝上，在病人的周期性的丙肝的病毒(HCV ) 复制和活动张贴肝移植。方法：在我们的中心为在 1999 和 2003 之间的联系 HCV 的肝肝硬化收到了肝移植的 107 个病人的一个队的数据回顾地被分析。浆液 HCV-RNA 的水平和周期性的肝炎的活动在作为主要抑制免疫力的代理人和没在移植以后在开始的 12 瞬间以内导致胆汁的复杂并发症的不那样类似的抑制免疫力的政体收到了 cyclosporine 或 tacrolimus 的 47 个病人之间被比较。结果：HCV-RNA 在移植以后在 3 瞬间以内增加了，但是 cyclosporine 组和 tacrolimus 组之间的差别是不足道的(在 12 瞬间的 P=0.49 ) 。另外，由浆液 transaminases 决定了的周期性的肝炎并且门发炎和纤维变性的组织学的分级没在 12 瞬间(P=0.34 ) 以后显示出有效差量。结论：一个主要抑制免疫力的代理人不在肝移植以后在感染 HCV 的病人影响周期性的肝炎的正式就职或严厉的 Cyclosporine 或 tacrolimus。

关键词：环孢霉素丙型肝炎病毒肝移植病毒复制

Bcl-2 degradation is an additional pro-apoptotic effect of polo-like kinase inhibition in cholangiocarcinoma cells

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World Journal of Gastroenterology 2017年第22期23卷 4007-4015页

作者： Svenja Sydor Sami Jafoui Lena Wingerter Sandra Swoboda Joachim C Mertens guido gerken Ali Canbay Andreas Paul Christian D Fingas Department of Gastroenterology and Hepatology University Hospital EssenUniversity Duisburg-Essen Department for General Visceral and Transplantation SurgeryUniversity Hospital EssenUniversity Duisburg-Essen Division of Gastroenterology and Hepatology University Hospital Zurich

AIM To examine the influence on apoptotic mechanisms following inhibition of polo-like kinases as therapeuticallyapproach for cholangiocellular cancer treatment. METHODS As most cholangiocarcinomas are chemotherapyresistant due to mechanisms preventing tumor cell death, we investigated the effect of Cisplatin on cholangiocellular carcinoma(CCA) cell lines KMCH-1 and Mz-Ch-1. Polo-like kinases(PLK) are important regulators of the cell cycle and their inhibition is discussed as a potential therapy while PLK inhibition can regulate apoptotic mediators. Here, cells were treated with PLK inhibitor BI6727(Volasertib), Cisplatin, and in combination of both compounds. Cell viability was assessed by MTT; apoptosis was measured by DAPI staining and caspase-3/-7 assay. Western blot and q RT-PCR were used to measure expression levels of apoptosis-related molecules Bax and Bcl-2. RESULTS The cell viability in the CCA cell lines KMCH-1 and Mz-Ch-1 was reduced in all treatment conditions compared to vehicle-treated cells. Co-treatment with BI6727 and cisplatin could even enhance the cytotoxic effect of cisplatin single treatment. Thus, co-treatment of cisplatin with BI6727 could slightly enhance the cytotoxic effect of the cisplatin in both cell lines whereas there was evidence of increased apoptosis induction solely in Mz-Ch-1 as compared to KMCH-1. Moreover, PLK inhibition decreases protein levels of Bcl-2; an effect that can be reversed by the proteasomal degradation inhibitor MG-132. In contrast, protein levels of Bax were not found to be altered by PLK inhibition. These findings indicate that cytotoxic effects of Cisplatin in Mz-Ch-1 cells can be enhanced by co-treatment with *** In conclusion, BI6727 treatment can sensitize CCA cells to cisplatin-induced apoptosis with proteasomal Bcl-2 degradation as an additional pro-apoptotic effect.

关键词：肿瘤坏死因素相关的导致 apoptosis ligand Myeloid 房间 leukemia-1 刺猬小径 Cisplatin 化疗抵抗

Potential triggering factors of acute liver failure as a first manifestation of autoimmune hepatitis-a single center experience of 52 adult patients

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World Journal of Gastroenterology 2018年第13期24卷 1410-1418页

作者： Matthias Buechter Paul Manka Falko Markus Heinemann Monika Lindemann Hideo Andreas Baba Martin Schlattjan Ali Canbay guido gerken Alisan Kahraman Department of Gastroenterology and Hepatology University Clinic of Essen Division of Transplantation Immunology and Mucosal Biology King’s CollegeLondon Institute of Transfusion Medicine University Clinic of Essen Institute of Pathology University Clinic of Essen Department of Gastroenterology Hepatology and Infectious Diseases Otto-von-Guericke University

AIM To investigate potential triggering factors leading to acute liver failure(ALF) as the initial presentation of autoimmune hepatitis(AIH).METHODS A total of 565 patients treated at our Department between 2005 and 2017 for histologically-proven AIH were retrospectively analyzed. However, 52 patients(9.2%) fulfilled the criteria for ALF defined by the "American Association for the Study of the Liver(AASLD)". According to this definition, patients with "acute-on-chronic" or "acute-on-cirrhosis" liver failure were excluded. Following parameters with focus on potential triggering factors were evaluated: Patients' demographics, causation of liver failure, laboratory data(liver enzymes, MELD-score, autoimmune markers, virus serology), liver histology, immunosuppressive regime, and finally, outcome of our *** The majority of patients with ALF were female(84.6%) and mean age was 43.6 ± 14.9 years. Interestingly, none of the patients with ALF was positive for antiliver kidney microsomal antibody(LKM). We could identify potential triggering factors in 26/52(50.0%) of previously healthy patients presenting ALF as their first manifestation of AIH. These were drug-induced ALF(57.7%), virus-induced ALF(30.8%), and preceding surgery in general anesthesia(11.5%), respectively. Unfortunately, 6 out of 52 patients(11.5%) did not survive ALF and 3 patients(5.7%) underwent liver transplantation(LT). Comparing data of survivors and patients with non-recovery following treatment, MELDscore(P < 0.001), age(P < 0.05), creatinine(P < 0.01), and finally, ALT-values(P < 0.05) reached statistical significance. CONCLUSION Drugs, viral infections, and previous surgery may trigger ALF as the initial presentation of AIH. Advanced age and high MELD-score were associated with lethal outcome.

关键词： Acute liver failure Autoimmune hepatitis Drug-induced liver injury Triggering factors MELD-score

Hepatitis C-associated liver carcinogenesis:Role of PML nuclear bodies

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World Journal of Gastroenterology 2014年第35期20卷 12367-12371页

作者： Kerstin Herzer guido gerken Thomas G Hofmann Department for Gastroenterology and Hepatology University Hospital Essen Department of General- Visceral- und Transplantation SurgeryUniversity Hospital Essen Cellular Senescence Group DKFZ-ZMBH AllianceDeutsches Krebsforschungszentrum (dkfz.)

Successful escape from immune response characterises chronic hepatitis C virus(HCV) infection,which results in persistence of infection in about 80% of the *** deleterious consequences are cirrhosis and hepatocellular *** accounts the most frequent cause for hepatocellular carcinoma(HCC) and liver transplantation(LT) in the western *** underlying molecular mechanisms how HCV promotes tumor development are largely *** is some in vitro and in vivo evidence that HCV interferes with the tumor suppressor PML and may thereby importantly contribute to the HCV-associated pathogenesis with respect to the development of *** tumor suppressor protein "promyelocytic leukemia"(PML) has been implicated in the regulation of important cellular processes like differentiation and *** cancer biology,PML and its associated nuclear bodies(NBs) have initially attracted intense interest due to its role in the pathogenesis of acute promyelocytic leukemia(APL).More recently,loss of PML has been implicated in human cancers of various histologic ***,number and intensity of PML-NBs increase in response to interferons(IFNs) and there is evidence that PML-NBs may represent preferential targets in viral ***,PML could not only play a role in the mechanisms of the antiviral action of IFNs but may also be involved in a direct oncogenic effect of the HCV on *** review aims to summarise current knowledge about HCV-related liver carcinogenesis and to discuss a potential role of the nuclear body protein PML for this this hard-to-treat cancer.

关键词： Hepatitis C virus Promyelocytic leukemia Nuclear b

Hepatitis C virus reinfection after liver transplant: New chances and new challenges in the era of direct-acting antiviral agents

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World Journal of Hepatology 2015年第3期7卷 532-538页

作者： Kerstin Herzer guido gerken Department of Gastroenterology and Hepatology University Hospital Essen Department of General Visceral and Transp-lantation Surgery University Hospital Essen

The first interferon-free regimens have been approved for the treatment of patients with chronic hepatitis C virus(HCV). In the liver transplant(LT) setting, these regimens are expected to have an important effect, because graft loss due to HCV recurrence is a serious problem after LT. The response to the hitherto conventional treatment with pegylated interferon and ribavirin is poor. The significantly better responserates achieved with boceprevir-based and telaprevirbased triple therapy have led to better graft and patient survival rates, but severe drug interactions with immunosuppressants limit the feasibility of this therapy for LT patients. With the approval of sofosbuvir in January 2014, of simeprevir in May 2014, and of daclatasvir in August 2014, three antiviral agents are now available and promise to be applicable without relevant adverse effects or negative interactions with immunosuppressants. Thus, 2014 marks the beginning of a new era of treatment options for HCV recurrence after LT. Although safety and efficacy studies of several interferon-free regimens for patients with HCV recurrence after LT have achieved good preliminary results, reports of clinical experiences with LT patients are scarce. The lack of randomized studies, the small number of enrolled and carefully selected patients, and the heterogeneity of these studies make the results questionable. Real-life experiences are eagerly awaited so that clinicians can estimate the usefulness and the pitfalls of these new regimens. Additionally, the high costs of these agents may limit their accessibility for many patients. The aim of this review is to summarize the current experience with and the expectations of the new direct-acting antiviral agents for LT patients.

关键词： Hepatitis C virus Liver transplant Interferon Sofosbuvir Simeprevir Daclatasvir

Successful photodynamic therapy for biliary papillomatosis:A case report

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World Journal of Gastroenterology 2008年第26期14卷 4234-4237页

作者： Lars P Bechmann Philip Hilgard Andrea Frilling Brigitte Schumacher Hideo A Baba guido gerken Thomas Zoepf Department of Gastroenterology and Hepatology University Hospital EssenEssen D-45122Germany Department of General- Visceral- and Transplant Surgery University Hospital EssenEssen D-45122Germany Department of Internal Medicine Evangelisches KrankenhausDuesseldorf D-40217Germany Department of Pathology University Hospital EssenEssen D-45122Germany

Papillomatosis of the bile duct is a rare disease with a high risk of malignant transformation. Therapeutical options include partial hepatectomy and liver transplantation. A previously healthy 65-years old male developed jaundice and right upper abdominal quadrant pain in 1996. A villous adenoma of the distal bile duct was diagnosed. A Whipple procedure was performed. In 2002 the patient turned symptomatic again. Another adenoma was found in the right hepatic duct resulting in a right hepatectomy. Two years later the patient again developed cholestasis. After drainage of the left hepatic duct with a percutaneous transhepatic cholangial drainage (PTCD) catheter, a recurrent biliary adenomatosis was diagnosed by cholangioscopy. As there was no surgical option left, the patient received photodynamic therapy (PDT) for the recurrent biliary papillomatosis. Three mo after he received further photodynamic therapies, the bile duct epithelium appeared normal and the patient had no signs of adenomatosis, both macroscopically and histologically. The follow-up cholangioscopy in late 2005 revealed only a small papilloma without the need for intervention. In early 2006, the patient died of multi organ failure without signs of extrahepatic cholestasis or cholangitis at the age of 75, 10 years after the diagnosis of biliary papillomatosis was established. The patient exceeded the average life expectancy of patients with biliary papillomatosis by far. Thus, PDT might be a sufficient therapeutic option for recurrent papillomatosis patients with no significant side effects.

关键词：胆汁多发性乳头瘤病胆管光力学治疗病例研究

Interferon-α response in chronic hepatitis B-transfected HepG2.2.15 cells is partially restored by lamivudine treatment

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World Journal of Gastroenterology 2007年第2期13卷 228-235页

作者： Shi-He Guan Mengji Lu Petra Grünewald Michael Roggendorf guido gerken Joerg F Schlaak Department of Gastroenterology and Hcpatology University Hospital of Esscn Esscn Germany Institute of Virology University Hospital of Essen Essen Germany Department of Laboratory Medicine the first Affiliated Hospital of Anhui Medical University China

AIM: To characterize the IFN-response and its modul- ation by the antiviral compound lamivudine in HBV- transfected HepG2.2.15 cells. METHODS: HepG2.2.15 and HepG2 cells were stimulated with various concentrations of IFN-a2a in the presence or absence of lamivudine. Then, total RNA was extracted and analysed by customised cDNA arrays and northern blot for interferon-inducible genes (ISGs). In addition, cellular proteins were extracted for EMSA and western blot. HBV replication was assessed by southern blot or ELISAs for HBsAg and HBeAg. RESULTS: Two genes (MxA, Cig5) with completely abolished and 4 genes (IFITM1, -2, -3, and 6-16) with partially reduced IFN-responses were identified in HepG2.2.15 cells. In 2 genes (IFITM1, 6-16), the response to IFN-a could be restored by treatment with lamivudine. This effect could not be explained by a direct modulation of the Jak/Stat signalling pathway since EMSA and western blot experiments revealed no suppression of Stat1 activation and ISGF3 formation after stimulation with IFN-a in HepG2.2.15 compared to HepG2 cells. CONCLUSION: These results are consistent with the assumption that chronic hepatitis B may specifically modulate the cellular response to IFN by a selective blockage of some ISGs. Antiviral treatment with lamivudine may partially restore ISG expression by reducing HBV gene expression and replication.

关键词：慢性乙型肝炎治疗方法表面抗原 e抗原

FibroSURE^(TM) and FibroScan~ in relation to treatment response in chronic hepatitis C virus

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World Journal of Gastroenterology 2011年第41期17卷 4581-4589页

作者： Keyur Patel Mireen Friedrich-Rust Yoav Lurie Mircea Grigorescu Carol Stanciu Chuan-Mo Lee Eugene R Schiff Dieter Hussinger Michael P Manns guido gerken Isabelle Colle Michael Torbenson Erik Pulkstenis G Mani Subramanian John G McHutchison Stefan Zeuzem Department of Gastroenterology and Hepatology Duke Clinical Research Institute Department of Gastroenterology and Hepatology J.W.Goethe University Hospital Department of Gastroenterology and Hepatology Tel Aviv Sourasky Medical Center Department of Clinical Infectious Disease Spitalul Clinic de Urgenta Department of Gastroenterology and Hepatology Institutul de Gastroenterologie si Hepatologie Department of Gastroenterology Chang Gung Memorial Hospital-Kaohsiung Medical CenterChang Gung University College of Medicine Departments of Gastroenterology and Internal Medicine University of Miami Department of Gastroenterology and Hepatology Universittsklinik Department of Gastroenterology and Hepatology Department of Gastroenterology and Hepatology Ghent University Hospital Department of Pathology Johns Hopkins University School of Medicine Department of Biostatistics Human Genome Sciences Department of Clinical Research Human Genome Sciences

AIM:To compare histological endpoint assessment using noninvasive alternatives to biopsy during treatment in a chronic hepatitis C virus(HCV)***:Patients with chronic HCV were randomized to receive interferon-based therapy for 24(genotypes 2/3)or 48(genotype 1)***～TM(FS)was assessed at baseline and at week-12 post-treatment *** biopsy for METAVIR was assessed by a single ***～ transient elastogra-phy(TE)was performed during treatment in a patient ***:Two thousand and sixty patients(n = 253 in Asia)were classif ied as METAVIR F0-1(n = 1682)or F2-4(n = 378).For F2-4,FS(n = 2055)had sensitiv-ity and specif icity of 0.87 and 0.61,respectively,with area under the receiver-operating curve of 0.82;corre-sponding values for TE(n = 214)and combined FS/TE(n = 209)were 0.77,0.88 and 0.88,and 0.93,0.68 and *** FS/TE agreement for F2-4 was 71%(κ = 0.41)and higher in Asians vs non-Asians(κ = 0.86 vs 0.35;P < 0.001).Combined FS/TE had 97% accuracy in Asians(n = 33).Baseline FS(0.38 vs 0.51,P < 0.001)and TE(8.0 kPa vs 11.9 kPa,P = 0.006)scores were lower in patients with sustained virological response than in nonresponders,and were maintained through ***:FS and TE may reliably differentiate mild from moderate-advanced disease,with a potential for high diagnostic accuracy in Asians with chronic HCV.

关键词：丙型肝炎病毒治疗慢性 TM 评估基准亚洲人工作曲线 TE

Cyclosporine A, FK-506, 40-0-[2-hydroxyethyl]rapamycin and mycophenolate mofetil inhibit proliferation of human intrahepatic biliary epithelial cells in vitro

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World Journal of Gastroenterology 2005年第48期11卷 7602-7606页

作者： Chao Liu Thomas Schreiter Andrea Frilling Uta Dahmen Christoph E Broelsch guido gerken Ulrich Treichel Department of Gastroenterology and Hepatology University Hospital Essen Germany Department of General Surgery and Transplantation University Hospital Essen Germany

瞄准：调查 cyclosporine 的效果 A (CsA )(MMF ) ， FK-506，和 mycophenolate mofetil 和 40-0-[2-hydroxyethyl ] 人的肝内的增长上的 rapamycin (RAD ) 胆汁的上皮细胞(BEC ) 在试管内。方法：BEC 与免疫从六个人的肝织物标本被孤... 详细信息

瞄准：调查 cyclosporine 的效果 A (CsA )(MMF ) ， FK-506，和 mycophenolate mofetil 和 40-0-[2-hydroxyethyl ] 人的肝内的增长上的 rapamycin (RAD ) 胆汁的上皮细胞(BEC ) 在试管内。方法：BEC 与免疫从六个人的肝织物标本被孤立磁性的分离方法并且与 CsA， FK-506， RAD，和 MMF 在试管内的不同集中对待。房间的增长被 MTT 试金分别地在 24 和 48 h 术后疗法测量。变化的单程的分析被用来分析结果。在 BEC 的 CK 19 的表示被流动血细胞计数和西方的污点监视。结果：BEC 的六根线被建立。他们为 4-18 wk 在试管内幸存。流动血细胞计数分析证明这些房间总是表示了 CK19。CsA， FK-506， RAD，和 MMF 以一种剂量依赖者方式禁止了 BEC 的增长。禁止 BEC (P<0.05 ) 的增长的 CsA， FK-506， RAD，和 MMF 的最低集中分别地是 500， 100， 0.25，和 100 mug/L。然而，由 BEC 的 CK19 的表示没被改变。结论：CsA， FK-506， RAD，和 MMF 在人的肝内 BEC 在试管内上有 antiproliferative 效果，当 RAD 有最强壮的生长禁止的效果时。他们在 transplant 病人的肝新生和胆汁管损害上的可能的效果应该进一步被调查。

关键词：环孢霉素A FK-506 40-0-[2-羟乙基] 雷帕霉素细胞增生上皮细胞