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Hepatocellular carcinoma in patients with autoimmune hepatitis

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World Journal of Gastroenterology 2009年第5期15卷 578-582页

作者： Andreas Teufel Arndt Weinmann Catherine Centner Anja Piendl Ansgar W Lohse peter r galle Stephan Kanzler Department of Medicine I Johannes Gutenberg University Mainz 55101 Germany Department of Medicine I University of Hamburg Hamburg 22527 Germany

AIM: To evaluate and confirm the low incidence of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH). At present only very few cases of HCC in patients with AIH and definite exclusion of chronic viral hepatitis have been published, suggesting that HCC due to AIH is rare. METHODS: In order to further investigate the incidence of HCC in patients with AIH, we reviewed our large cohort of 278 patients with AIH. rESULTS: Eighty-nine patients (32%) were diagnosed with liver cirrhosis, a preneoplastic condition for HCC. We studied a total of 431 patient years of cirrhosis in these patients, an average 4.8 years per patient. During this period none of the patients of our own study cohort developed HCC. However, three patients with HCC due to AIH associated liver cirrhosis were referred to our department for further treatment of HCC. In all three patients chronic viral hepatitis was excluded. CONCLUSION: We conclude that HCC may under rare circumstances develop due to chronic AIH dependent liver cirrhosis. Compared to other causes of liver cirrhosis such as chronic viral hepatitis, alcohol, or hemochromatosis, the incidence of HCC is significantly lower. Pathophysiological differences between AIH and chronic viral hepatitis responsible for differences in the incidence of HCC are yet to be further characterized and may lead to new therapeutic concepts in prevention and treatment of liver cancer.

关键词：肝炎自体免疫组织 B病毒 C病毒肝细胞

Characterization of human gene encoding SLA/LP autoantigen and its conserved homologs in mouse,fish,fly,and worm

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World Journal of Gastroenterology 2006年第6期12卷 902-907页

作者： Chun-Xia Wang Andreas Teufel Uta Cheruti Joachim Groetzinger peter r galle Ansgar W Lohse Johannes Herkel I. Department of Medicine University Medical Centre Hamburg-Eppendorf Hamburg Germany Shandong University Shandong Provincial Hospital Jinan Shandong Province China I. Department ofMedicine Johannes Gutenberg University Mainz Germany Institute of Biochemistry Christian-Albretchts-University Kiel Germany

瞄准：来临逃犯 SLA/LP 分子的功能，我们在各种各样的种类描绘了 genomic 组织和遗传因子的主要的反和 SLA/LP 分子的功能的性质的保存。方法：借助于计算生物学，我们在人，老鼠，斑马鱼，苍蝇，和蠕虫描绘了完全的 SLA/LP 基因， mr... 详细信息

瞄准：来临逃犯 SLA/LP 分子的功能，我们在各种各样的种类描绘了 genomic 组织和遗传因子的主要的反和 SLA/LP 分子的功能的性质的保存。方法：借助于计算生物学，我们在人，老鼠，斑马鱼，苍蝇，和蠕虫描绘了完全的 SLA/LP 基因， mrNA 和推出的蛋白质序列。结果：约 39 kb 的人的 SLA/LP 基因顺序，印射到染色体 4p15.2，在 11 前 ons， 10 或 11 被翻译被组织，取决于 splice 变体。相应分子在几个生物模型有机体被识别。各种各样的相应蛋白质序列显示出类似或相同的高度，尤其是在功能的重要性的那些残余。与相应序列缺乏重要相同的人的蛋白质顺序的唯一的领域是遗传因子的 epitope 从自体免疫的肝炎(AIH ) 由自身抗体认出了的主要的反病人。结论：SLA/LP 分子和它的机能上地相关的残余高度在整个进化被保存了，建议分子的不可缺少的功能。发现那个唯一的非保存的领域是人的 SLA/LP 的遗传因子的 epitope 定序的主导的反，建议 SLA/LP 汽车免疫是驾驶 autoantigen 的而非被分子的模仿驾驶。

关键词：基因编码同系物老鼠鱼苍蝇生物信息学

High mir-196a levels promote the oncogenic phenotype of colorectal cancer cells

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World Journal of Gastroenterology 2009年第17期15卷 2089-2096页

作者： Carl Christoph Schimanski Kirsten Frerichs Fareed rahman Martin Berger Hauke Lang peter r galle Markus Moehler Ines Gockel First Department of Internal Medicine Johannes Gutenberg University of Mainz 55131 Mainz Germany Unit of Toxicology and Chemotherapy GermanCancer Research Centre 69120 Heidelberg Germany Department of General and Abdominal Surgery Johannes Gutenberg University of Mainz 55131 Mainz Germany

AIM: To analyze the relevance of the microrNA mir-196a for colorectal oncogenesis. METHODS: The impact of mir-196a on the restriction targets HoxA7, HoxB8, HoxC8 and HoxD8 was analyzed by reverse transcription polymerase chain reaction (rT-PCr) after transient transfection of SW480 cancer cells. The mir-196a transcription profile in colorectal cancer samples, mucosa samples and diverse cancer cell lines was quantifi ed by rT-PCr. Transiently mir-196a-transfected colorectal cancer cells were used for diverse functional assays in vitro and for a xenograft lung metastasis model in vivo. rESULTS: HoxA7, HoxB8, HoxC8 and HoxD8 were restricted by mir-196a in a dose-dependent and gene-specific manner. High levels of mir-196a activated the AKT signaling pathway as indicated by increased phosphorylation of AKT. In addition, high levels of mir-196a promoted cancer cell detachment,migration, invasion and chemosensitivity towards platin derivatives but did not impact on proliferation or apoptosis. Furthermore, mir-196a increased the development of lung metastases in mice after tail vein injection. CONCLUSION: mir-196a exerts a pro-oncogenic influence in colorectal cancer.

关键词：大肠癌细胞逆转录聚合酶链反应 AKT信号通路 microrNA 表型致癌 SW480 转移模型

TrAIL-induced apoptosis of hepatocellular carcinoma cells is augmented by targeted therapies

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World Journal of Gastroenterology 2009年第47期15卷 5924-5935页

作者： Bruno Christian Koehler Toni Urbanik Binje Vick regina Johanna Boger Steffen Heeger peter r galle Marcus Schuchmann Henning Schulze-Bergkamen First Department of Medicine Johannes Gutenberg-University Mainz55101 MainzGermany Steffen HeegerMerck KGaAMS-D Global Clinical Development Unit-Oncology64293 DarmstadtGermany National Center of Tumor Diseases Department of Medical OncologyUniversity Clinic of Heidelberg69120 HeidelbergGermany

AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TrAIL),on overcoming TrAIL resistance in hepatocellular carcinoma(HCC)and to study the efficacy of agonistic TrAIL antibodies,as well as the commitment of antiapoptotic BCL-2 proteins, in TrAIL-induced apoptosis. METHODS:Surface expression of TrAIL receptors (TrAIL-r1-4)and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting,respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering *** cellswere treated with kinase inhibitors and chemotherapeutic *** induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. rESULTS:TrAIL-r1 and-r2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However,treatment of Huh7 and Hep-G2 with TrAIL and agonistic antibodies only induced minor apoptosis *** resistance towards TrAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002[inhibition of phosphoinositol- 3-kinase(PI3K)],AG1478(epidermal growth factor receptor kinase),PD98059(MEK1),rapamycin(mam- malian target of rapamycin)and the multi-kinase inhibitor ***,the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TrAIL resistance:knock-down by rNA interference increased TrAIL-induced apoptosis of HCC ***, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and ***:Our data identify the blockage of survival kinases,combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TrAIL resistance in

关键词：肿瘤坏死因子相关凋亡诱导配体细胞凋亡基因 TrAIL PD98059 受体激酶流式细胞仪 rNA干扰酶抑制剂

Genetic association of autoimmune hepatitis and human leucocyte antigen in German patients

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World Journal of Gastroenterology 2006年第34期12卷 5513-5516页

作者： Andreas Teufel Markus Wrns Arndt Weinmann Catherine Centner Anja Piendl Ansgar W Lohse peter r galle Stephan Kanzler Department of Medicine I Johannes Gutenberg University Mainz Germany Department of Medicine I University of Hamburg Germany

AIM: To report on our large German collective and updated data of 142 patients with autoimmune hepatitis (AIH) type 1. METHODS: Key investigations performed were liver biopsy, serum autoantibodies as well as serum markers such as IgG and elevated transaminases. Antinuclear antigen (ANA) and smooth muscle antigen (SMA) autoantibodies characterized type 1 AIH. Type 3 (AIH) was solely characterized by the occurrence of soluble liver antigen/liver-pancreas antigen (SLA/LP) autoantibodies either with or without ANA or SMA autoantibodies. rESULTS: Most prevalent HLAs were A2 (68 patients, 48%), B8 (63 patients, 44%), C7 (90 patients, 63%), Dr3 (49 patients, 38%), Dr4 (49 patients, 38%) and DQ2 (42 patients, 30%). Compared to the Italian and North American patients, we found fewer patients with a DQ2 subtype. Furthermore, the B8-Dr3-DQ2 human leucocyte antigen (HLA) was also less prominent compared to the North American patients. However, prevalences of B8, Dr3, Dr4, Dr7, Dr11 and Dr13 were comparable to the Italian and North American patients. Furthermore, we report on an additional subgroup of patients with SLA/LP positive AIH. Generally, in this subgroup of patients the same HLA subtypes were favoured as the AIH type 1. CONCLUSION: Although HLA subtypes were comparable between these three collectives, the German patients were distinct from the Italian and North American patients with respect to DQ2 and from the North American patients with respect to B8-Dr3-DQ2HLA. A clinical correlation, e.g. difference in severity or treatability of AIH type 1, has yet to be determined.

关键词：遗传因素自体免疫肝炎白血球抗原德国

Treatment of nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2006年第14期12卷 2161-2167页

作者： Juergen Siebler peter r galle Department of Internal Medicine University Hospital of Mainz Langenbeckstr.155131 MainzGermany

不含酒精的脂肝疾病(NAFLD ) 是为在发达国家的提高的肝酶的最普通的原因。在因为超重孩子的增加的数字，具有特别兴趣的预防节目以外，处理应该集中于最重要的风险因素，肥胖和抗胰岛素性。作为阐明的后果 NAFLD 的 pathomechanisms，... 详细信息

不含酒精的脂肝疾病(NAFLD ) 是为在发达国家的提高的肝酶的最普通的原因。在因为超重孩子的增加的数字，具有特别兴趣的预防节目以外，处理应该集中于最重要的风险因素，肥胖和抗胰岛素性。作为阐明的后果 NAFLD 的 pathomechanisms，潜在的治疗学的选择的数字增加了。然而，调查治疗学的效果的许多研究在至少一个下列点显示出缺点：连续的肝活体检视，治疗的短术语和包括的病人的有限数字的缺乏。第二产生胰岛素抗体 pioglitazone 和 rosiglitazone 为注意在 NAFLD，而是重量获得和潜在的 hepatotoxicity 电话显示出最有希望的改进。在结论，为特定的药的应用程序的一个一般建议不能被给。在肥胖的病人改进胰岛素敏感度的而且控制的临床的试用，体重减轻和物理活动应该是优先级目的。

关键词：非酒精性脂肪肝治疗病理机制临床表现

Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients

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World Journal of Gastroenterology 2009年第4期15卷 449-456页

作者： Markus Moehler Martin F Sprinzl Murad Abdelfattah Carl C Schimanski Bernd Adami Werner Godderz Klaus Majer Dimitri Flieger Andreas Teufel Juergen Siebler Thomas Hoehler peter r galle Stephan Kanzler 1st Medical Department Johannes Gutenberg-University Outpatient Clinic Outpatient Clinic of City Hospital Outpatient Clinic of 1st Medical Department Outpatient Clinic of 2nd Medical Department Leopoldina Krankenhaus

AIM:To investigate the efficacy and safety of capecitabine plus irinotecan±bevacizumab in advanced or metastatic colorectal cancer patients. METHODS:Forty six patients with previously untreated,locally-advanced or metastatic colorectal cancer(mCrC) were recruited between 2001-2006 in a prospective open-label phaseⅡtrial,in German community-based outpatient *** received a standard capecitabine plus irinotecan(CAPIrI) or CAPIrI plus bevacizumab(CAPIrI-BEV) regimen every 3 wk. Dose reductions were mandatory from the first cycle in cases of>grade 2 *** treatment choice of bevacizumab was at the discretion of the *** endpoints were response and toxicity and secondary endpoints included progression-free survival and overall survival. rESULTS:In the CAPIrI group vs the CAPrI-Bev group there were more female than male patients(47% vs 24%) ,and more patients had colon as the primary tumor site(58.8%vs 48.2%) with fewer patients having sigmoid colon as primary tumor site(5.9%vs 20.7%) .Grade 3/4 toxicity was higher with CAPIrI than CAPIrI-Bev:82%vs 58.6%.Partial response rates were 29.4%and 34.5%,and tumor control rates were 70.6%and 75.9%,*** complete responses were *** median progression-free survival was 11.4 mo and 12.8 mo for CAPIrI and CAPIrI-Bev,*** median overall survival for CAPIrI was 15 mo(458 d) and for CAPIrI-Bev 24 mo(733 d) .These differences were not statistically *** the CAPIrI-Bev,group,two patients underwent a full secondary tumor resection after treatment,whereas in the CAPIrI group no cases underwent this procedure. CONCLUSION:Both regimens were well tolerated and offered effective tumor growth control in this outpatient *** gastrointestinal toxicities and thromboembolic events were rare and if observed were never fatal.

关键词：肠癌结肠癌直肠癌老年人化疗疗效

Chemokine receptor CXCr4-prognostic factor for gastrointestinal tumors

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World Journal of Gastroenterology 2008年第30期14卷 4721-4724页

作者： Carl C Schimanski peter r galle Markus Moehler First Department of Internal Medicine of Johannes Gutenberg University of Mainz

To review the implication of CXCr4 for gastrointestinal cancer, a "Pubmed" analysis was performed in order to evaluate the relevance of CXCr4 and its ligands for gastrointestinal cancers. Search terms applied were "cancer, malignoma, esophageal, gastric, colon, colorectal, hepatic, pancreatic, CXCr4, SDF-1α, and SDF-1b". CXCr4 expression correlated with dissemination of diverse gastrointestinal malignomas. The CXCr4 ligand SDF-1α might act as "chemorepellent" while SDF-1b might act as "chemorepellent" for CTLs, inducing tumor rejection. The paracrine expression of SDF-1α was furthermore closely associated with neoangiogenesis. CXCr4 and its ligands influence the dissemination, immune rejection, and neoangiogenesis of human gastrointestinal cancers. Inhibition of CXCr4 might be an interesting therapeutic option.

关键词：胃肠肿瘤消化道疾病 CXCr4 CXCL12 癌症

Stable diffusion gradients in microfluidic conduits bounded by fluid walls

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Microsystems & Nanoengineering 2024年第3期10卷 357-367页

作者： Federico Nebuloni Cyril Deroy peter r.Cook Edmond J.Walsh Department of Engineering Science Osney Thermo-Fluids InstituteUniversity of OxfordOxford OX20ESUK Sir William Dunn School of Pathology University of OxfordOxford OX13REUK

Assays mimicking in vitro the concentration gradients triggering biological responses like those involved in fighting infections and blood clotting are essential for biomedical *** assays prove especially attractive as they allow precise control of gradient shape allied to a reduction in *** microfluidic devices are fabricated using solid plastics that prevent direct access to responding ***-walled microfluidics allows the manufacture of circuits on standard Petri dishes in seconds,coupled to simple operating methods;cell-culture medium sitting in a standard dish is confined to circuits by fluid walls made of an immiscible *** develop and experimentally validate an analytical model of diffusion between two or more aqueous streams flowing at different rates into a fluid-walled conduit with the cross-section of a circular *** solid walls,fluid walls morph during flows as pressures fall,with wall shape changing down the *** model is validated experimentally for Fourier numbersrescein diffusing between laminar *** enables a priori prediction of concentration gradients throughout a conduit,so allowing rapid circuit design as well as providing bioscientists with an accurate way of predicting local concentrations of bioactive molecules around responsive and nonresponsive cells.

关键词： walls diffusion attractive