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Utilizing zebrafish and okadaic acid to study Alzheimer's disease

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Neural Regeneration Research 2018年第9期13卷 1538-1541页

作者： Daniel koehler Frederick E.Williams Department of Pharmacology and Experimental Therapeutics University of Toledo

Despite the many years of extensive research using rodent models to study Alzheimer＇s disease （AD）, no cure or disease halting drug exists. An increasing number of people are suffering from the disease and a therapeutic intervention is needed. Therefore, it is necessary to have complementary models to aid in the drug discovery. The zebrafish animal model is emerging as a valuable model for the investigation of AD and neurodegenerative drug discovery. The main genes involved in human AD have homologous counter- parts in zebrafish and have conserved function. The basic brain structure of the zebrafish is also conserved when compared to the mammalian brain. Recently an AD model was established by administering okadaic acid to zebrafish. It was used to test the efficacy of a novel drug, lanthionine ketimine-5-ethyl ester, and to elucidate its mechanism of action. This demonstrated the ability of the okadaic acid-induced AD zebrafish model to be implemented in the drug discovery process for therapeutics against AD.

关键词： Alzheimer's disease Zebrafish okadaic acid protein phosphatase 2A learning and memory lanthionine ketimine-5-ethyl ester

Integration of Chinese Medicine and Western Medicine in Clinical Practice(Patient Care):Past,Present,and A Proposed Model for the Future

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Chinese Journal of Integrative Medicine 2013年第2期19卷 83-85页

作者： Ian Tsang Simon Huang Barry koehler Division of Rheumatology Department of MedicineUniversity of British ColumbiaVancouverBCCanada

Historic Background Chinese medicine （CM） has over 2,000 years of history in China and was the only health care system providing care for Chinese prior to the introduction of Western medicine （WM） into China. WM was slowly introduced into China by missionaries from the middle 17th century to the beginning of the 19th century. By 1840, WM began to take root in China. Western hospitals, clinics, medical schools and nursing schools spread rapidly throughout the country. At that time, with the might and power portrayed by Western countries,

关键词： Patient Care Past,Present,and A Proposed Model for the Future WM

Targeting cell death signaling in colorectal cancer:Current strategies and future perspectives

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World Journal of Gastroenterology 2014年第8期20卷 1923-1934页

作者： Bruno Christian koehler Dirk Jger Henning Schulze-Bergkamen National Center for Tumor Diseases University Hospitals Heidelberg69120 HeidelbergGermany

The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. However, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the “druggability” of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use.

关键词： Colorectal cancer Apoptosis Necroptosis Autophagy Clinical trial Bcl-2 proteins BH-3 mimetics Inflammatory bowel disease

Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease

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World Journal of Gastroenterology 2010年第4期16卷 453-457页

作者： Roger Klein Moreira Frank Revetta Elizabeth koehler Mary Kay Washington Department of Pathology Columbia University College of Physicians & SurgeonsNew YorkNY 10038United States Department of Pathology Vanderbilt UniversityNashvilleTN 37232United States Department of Biostatistics Vanderbilt UniversityNashvilleTN 37232United States

AIM:To assess the role of IgM and IgG immunohistochemistry(IHC) in the evaluation of autoimmune liver conditions-autoimmune hepatitis(AIH),primary biliary cirrhosis(PBC),and primary sclerosing cholangitis(PSC).METHODS:Forty one biopsies from untreated patients diagnosed with autoimmune liver disease(AIH,n = 20;PBC,n = 13;PSC,n = 8) and fourteen biopsies of patients with chronic hepatitis C were *** and IgG-positive plasma cells were counted in each ***:A predominance of IgG-positive plasma cells was seen in AIH(90% of cases),PSC(75% of cases),and chronic hepatitis C(100% of cases),while IgMpositive plasma cells predominated in PBC(92.8% ofcases).The IgM /IgG ratio(< 1 or ≥ 1) accurately distinguished PBC from AIH in 90.9% of cases(sensitivity = 92.3%,specificity = 90%),and PBC from either AIH or PSC in 87.8% of cases(sensitivity = 92.3%,specificity = 85.7%).CONCLUSION:Plasmacytic infiltrates expressing predominantly IgM are characteristic of PBC,while other forms of liver disease analyzed in this study,including AIH,typically show an IgG-predominant plasma cell *** data indicate that IgM and IgG IHC may be a useful tool when PBC is a diagnostic consideration.

关键词： Autoimmune hepatitis Primary sclerosing cholangitis Primary biliary cirrhosis Immunoglobulin Immunohistochemistry

Down-regulation of IL-8 expression in human airway epithelial cells through helper-dependent adenoviral-mediated RNA interference

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Cell Research 2005年第2期15卷 111-119页

作者： Bernard MARTIN,David R.koehler,Pamela L.ZEITLIN,A.Keith TANAWELL,Jim HU Programme in Lung Biology Research and the Canadian Institutes of Health Research Group in Lung Development Hospitalfor Sick Children Toronto Canada M5G 1X8 Programme in Lung Biology Research and the Canadian Institutes of Health Research Group in Lung Development Hospitalfor Sick Children Toronto Canada M5G 1X8 Laboratory Medicine and Pathobiology University of Toronto Toronto Canada M5S 1A1 Departments of Pediatrics The Johns Hopkins University School of Medicine Baltimore MD 21287 USA. Programme in Lung Biology Research and the Canadian Institutes of Health Research Group in Lung Development Hospitalfor Sick Children Toronto Canada M5G 1X8Department of Paediatrics University of Toronto Toronto Canada M5S 1A1 Department of Physiology University of Toronto Toronto Canada M5S 1A1 Programme in Lung Biology Research and the Canadian Institutes of Health Research Group in Lung Development Hospitalfor Sick Children Toronto Canada M5G 1X8Department of Paediatrics University of Toronto Toronto Canada M5S 1A1 Laboratory Medicine and Pathobiology University of Toronto Toronto Canada M5S 1A1

Interleukin (IL)-8 is a potent neutrophil chemotactic factor and a crucial mediator in neutrophil-dependent *** cell types produce IL-8, either in response to external stimuli such as cytokines or bacterial infection, or aftermalignant transformation. Anti-IL-8 strategies have been considered for anti-inflammatory therapy. In this paper wedemonstrate that the RNA interference technique can be used to efficiently down-regulate IL-8 protein expression inairway epithelial cells. We used a helper-dependent adenoviral vector to express a small hairpin (sh)RNA targetinghuman IL-8 in cultured airway epithelial cells (IB3-1, Cftr-/-; C38, Cftr-corrected) stimulated with TNF-α, IL-1β orheat-inactivated Burkholderia cenocepacia. Stimulated IL-8 expression in IB3-1 and C38 cells was significantly reducedby shRNA expression. The shRNA targeting IL-8 had no effect on the activation of NF-κB, or on the protein levels ofIκB or IL-6, suggesting that this anti-IL-8 strategy was highly specific, and therefore may offer potential for thetreatment of inflammatory diseases.

关键词： Interleukin-8 RNA interference helper-dependent adenoviral vector inflammation chemokine neutrophil cystic fibrosis.

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： Hepatocellular carcinoma Apoptosis Tumor necrosis factor-related apoptosis inducing ligand BCL-xL MCL-1 5-fluorouracil Doxorubicin Sorafenib Phosphoinositol-3-kinase (Mitogen-activated protein kinase)/(extracellular signal regulated kinase) kinase c-Jun N-terminal kinase

Development of a Test Apparatus for Measurement of Hydraulic Fluid Efficiency

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润滑油 2011年第5期26卷 28-33页

作者： Matt Jackson Brian koehler Southwest Research Institute

With increasing demand for nonrenewable resources,energy conservation is *** gains allow more work to be performed while maintaining or even decreasing the energy expended in the *** the energy consumed by a system results in favorable economic and environmental *** apparatus has been developed to measure hydraulic fluid efficiency in a stationary *** system can be used to develop more efficient fluids,leading to increased work output or decreased energy consumption.

关键词： mechanical and volumetric efficiency test pump test procedure

Experiences and Challenges of Clinical Research in Traditional Medicines

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World Journal of Integrated Traditional and Western Medicine 2019年第4期5卷 55-56页

作者： Stephan koehler Clinical Research and Pharmacovigilance Division Schwabel Group

Thank you for your introduction,thank DIA inviting me to come to this *** knowing so many data,I am very happy to learn some details about traditional Chinese medicine (TCM),including China's efforts in TCM,and what has been done in Europe.I would like to tell you about some of the challenges of TCM from the perspective of the European Union (EU).Many of them are mentioned by previous *** fact,there are ways to allow herbs to enter the European *** herbal products have been *** there is a full market ***,it is necessary to ensure their medicinal efficacy and *** trials are not necessary for every circumstance,but 10 years of use history within the EU is *** is the process of full *** USA and Europe have a similar situation: 3 of the 4 phases are required before the marketing *** are 3 examples: a newly developed drug in Europe,it is from gentian roots,primrose,sorrel and other drugs,mainly for rhinitis;this is from Switzerland,which is from an extract of coltsfoot flowers;Schwabe's is from lavender,used for anxiety,and this is its name in Australia.

关键词： Experiences Challenges Clinical Research Traditional Medicines

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数字化图书馆和WWW站点及其页面的持续性

现代图书情报技术 2000年第6期 75-79页

作者： Wallace koehler 张莹(译) 美国俄克拉荷马大学图书情报学院

依据 Web页面和 Web站点可以被搜集和分类 ,文章探讨的主题是 :WWW构成图书馆。结论是 :Web不是数字化图书馆 ,但是图书馆可以从 Web中选择搜集材料。 Web文献有两种变化形式。第一种变化形式是本文所谈论的“持续性”;第二种变化形式是... 详细信息

依据 Web页面和 Web站点可以被搜集和分类 ,文章探讨的主题是 :WWW构成图书馆。结论是 :Web不是数字化图书馆 ,但是图书馆可以从 Web中选择搜集材料。 Web文献有两种变化形式。第一种变化形式是本文所谈论的“持续性”;第二种变化形式是 Web页面或 Web站点信息的变化。本文力求更进一步认识 Web页面和 Web站点的生存期 ,生存期的变化会影响具有 Web信息的图书馆的完整性和有效性 ,然而如果能够认识这些变化就可以进行控制和管理。

关键词： WebLibrary 持续性信息管理生存期