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Characterization of the Stem Cell Fraction in Pancreatobiliary Carcinomas: The Notch Signaling Pathway as a Potential Therapeutic Target

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Journal of Cancer Therapy 2018年第6期9卷 480-502页

作者： Elisabeth Seidel Cynthia de Carvalho Fischer christopher neumann Anja Reutzel-Selke Andreas Andreou Joseph Gassner Julia Gogolok Peter Tang Anja Schirmeier Fritz Klein Igor M. Sauer Johann Pratschke Marcus Bahra Rosa B. Schmuck Charité—Universitatsmedizin Berlin Corporate Member of Freie Universitat Berlin Humboldt-Universitatzu Berlin and Berlin Institute of Health Institute of Surgery Augustenburger Platz 1 Berlin Germany

Pancreatic adenocarcinoma (PDAC) and extrahepatic cholangiocarcinoma (ECC) are highly lethal malignancies with limited treatment options. Both a small subpopulation of cancer stem cells (CSC) and the deregulation of the notch pathway have been considered potential sources of tumor formation. In this study, flow cytometry (FCM) was conducted to identify the CSC population and Notch-associated proteins in ECC and PDAC cell lines. Additionally, the treatment effect of Gemcitabine and the specific notch-inhibitor DAPT on ECC and PDAC cell lines was evaluated. Our results show that the amount of SP cells in ECC cell lines is significantly higher than in PDAC cell lines, and that SP-ECC cells show a higher sensitivity to therapy. In conclusion, inhibition of Notch signaling with DAPT may be of therapeutic value in ECC, but seems to show no effect on more aggressive PDAC. As it could be essential for the improvement in outcomes of the ECC patients, other trials are needed to determine the role of further Notch components.

关键词： Notch Pathway Cancer Stem Cells Pancreatic Adenocarcinoma Extrahepatic Cholangiocarcinoma Targeted Therapy

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Performance of silver nanoparticles in the catalysis of the oxygen reduction reaction in neutral media： Efficiency limitation due to hydrogen peroxide escape

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Nano Research 2013年第7期6卷 511-524页

作者： christopher C. M. neumann Eduardo Laborda Kristina Tschulik Kristopher R. Ward Richard G. Compton Department of Chemistry Physical and Theoretical Chemistry Laboratory Oxford University South Parks Road Oxford OXl 3QZUnited Kingdom

The electrocatalytic activity for oxygen reduction reaction （ORR） at neutral pH of citrate-capped silver nanoparticles （diameter = 18 nm） supported on glassy carbon （GC） is investigated voltammetrically. Novelly, the modification of the substrate by nanoparticles sticking to form a random nanoparticle array and the voltammetric experiments are carried out simultaneously by immersion of the GC electrode in an air-saturated 0.1 M NaC104 solution （pH = 5.8） containing chemically-synthesized nanoparticles. The experimental voltammograms of the resulting nanoparticle array are simulated with homemade programs according to the two-proton, two-electron reduction of oxygen to hydrogen peroxide where the first electron transfer is rate determining. In the case of silver electrodes, the hydrogen peroxide generated is partially further reduced to water via heterogeneous decomposition. Comparison of the results obtained on a silver macroelectrode and silver nanoparticles indicates that, for the silver nanoparticles and particle coverages （0.035%-0.457%） employed in this study, the ORR electrode kinetics is slower and the production of hydrogen peroxide larger on the glassy carbon-supported nanoparticles than on bulk silver.

关键词： oxygen reduction reaction silver nanoparticles nanoelectrocatalysis hydrogen peroxide escape fuel cells

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Tumor–stromal cross-talk modulating the therapeutic response in pancreatic cancer

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Hepatobiliary & Pancreatic Diseases International 2018年第5期17卷 461-472页

作者： christopher C.M.neumann Ellen von Horschelmann Anja Reutzel-Selke Elisabeth Seidel Igor Maximilian Sauer Johann Pratschke Marcus Bahra Rosa Bianca Schmuck Department of Surgery Campus Charité Mitte Campus Virchow-KlinikumExperimental SurgeryCharité-Universitatsmedizin BerlinBerlinGermany Berlin Institute of Health Department of SurgeryCampus CharitéMitte and Campus Virchow-KlinikumAugustenburger Platz 113353 BerlinGermany

Background: Pancreatic ductal adenocarcinoma(PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor’s high chemoresistance. Cancer associated fibroblasts(CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor–stromal interactions when exposed to three well-known chemotherapeutic agents. Methods: Monocultures, indirect and direct co-cultures of two PDAC cell lines(AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the γ-secretaseinhibitor(GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed. Results: On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma(CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co-cultures of cancer cells with CAFs. A change in the morphology of direct co-cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor–stromal interaction more complex. Conclusions: CAFs are highly chemoresistant. Direct cell–cell contact and high levels of IL-6 correlate with a high chemoresistance.

关键词： Pancreatic cancer Tumor microenvironment Cancer associated fibroblasts Cancer–stroma co-culture Atroma targeted therapy

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Ex vivo evaluation of IVUS-VH imaging and the role of plaque structure on peripheral artery disease

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Medicine in Novel Technology and Devices 2020年第4期8卷 22-30页

作者： christopher Noble Kent Carlson Erica neumann Bradley Lewis Dan Dragomir-Daescu Amir Lerman Ahmet Erdemir Melissa Young Department of Cardiovascular Medicine Mayo ClinicRochesterMNUSA Department of Physiology and Biomedical Engineering Mayo ClinicRochesterMNUSA Department of Biomedical Engineering and Computational Biomodeling(CoBi)Core Lerner Research InstituteCleveland ClinicClevelandOHUSA Division of Biomedical Statistics and Informatics Mayo ClinicRochesterMNUSA

Peripheral artery disease(PAD)results from the buildup of atherosclerotic plaque in the arterial wall,can progress to severe ischemia and lead to tissue necrosis and limb *** evaluated a means of assessing PAD mechanics ex vivo using ten human peripheral arteries with ***-inflation testing was performed at six physiological pressure intervals ranging from 10 to 200 *** vessels were imaged with IVUS-VH to determine plaque composition and change in vessel structure with *** analysis was performed to determine which plaque structures and distributions of these structures had the greatest influence on wall *** found that fibrous plaque,necrotic core,and calcification had a statistically significant effect on all variables(p<0.05).The presence of large concentrations of fibrous plaque was linked to reduced vessel compliance and ellipticity,which could lead to stent fractures and *** the plaque distribution we found that clustered necrotic core increased overall compliance while clustered calcification decreased overall *** effect of plaque distribution on vessel wall deformation must be considered equally important to plaque concentration.

关键词： Intrasvascular ultrasound Virtual histology Peripheral artery disease Pressure-inflation testing Atherosclerosis

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