190 results on '"Zechner, Dietmar"'
Search Results
2. Effects of triggers of senescence and senolysis in murine pancreatic cancer cells
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Revskij, Denis, Woitas, Aline, Kölle, Bianca, Umstätter, Camilla, Zechner, Dietmar, Khan, Faiz M, Fuellen, Georg, and Jaster, Robert
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- 2024
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3. Uncoupling protein 2 deficiency of non-cancerous tissues inhibits the progression of pancreatic cancer in mice
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Revskij, Denis, Runst, Jakob, Umstätter, Camilla, Ehlers, Luise, Rohde, Sarah, Zechner, Dietmar, Bastian, Manuela, Müller-Hilke, Brigitte, Fuellen, Georg, Henze, Larissa, Murua Escobar, Hugo, Junghanss, Christian, Kowald, Axel, Walter, Uwe, Köhling, Rüdiger, Wolkenhauer, Olaf, and Jaster, Robert
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- 2023
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4. 3D-printed lightweight dorsal skin fold chambers from PEEK reduce chamber-related animal distress
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Xie, Wentao, Lorenz, Matthias, Poosch, Friederike, Palme, Rupert, Zechner, Dietmar, Vollmar, Brigitte, Grambow, Eberhard, and Strüder, Daniel
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- 2022
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5. GSK805 inhibits alpha‐smooth muscle expression and modulates liver inflammation without impairing the well‐being of mice.
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Nierath, Wiebke‐Felicitas, Leitner, Emily, Reimann, Sabrina, Schwarz, Rico, Hinz, Burkhard, Bleich, André, Vollmar, Brigitte, and Zechner, Dietmar
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- 2024
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6. Comparing animal well-being between bile duct ligation models.
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Tang, Guanglin, Nierath, Wiebke-Felicitas, Leitner, Emily, Xie, Wentao, Revskij, Denis, Seume, Nico, Zhang, Xianbin, Ehlers, Luise, Vollmar, Brigitte, and Zechner, Dietmar
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ANIMAL welfare ,BILE ducts ,GLUTAMATE dehydrogenase ,ASPARTATE aminotransferase ,ANIMAL burrowing ,LIVER enzymes - Abstract
A prevailing animal model currently used to study severe human diseases like obstructive cholestasis, primary biliary or sclerosing cholangitis, biliary atresia, and acute liver injury is the common bile duct ligation (cBDL). Modifications of this model include ligation of the left hepatic bile duct (pBDL) or ligation of the left bile duct with the corresponding left hepatic artery (pBDL+pAL). Both modifications induce cholestasis only in the left liver lobe. After induction of total or partial cholestasis in mice, the well-being of these animals was evaluated by assessing burrowing behavior, body weight, and a distress score. To compare the pathological features of these animal models, plasma levels of liver enzymes, bile acids, bilirubin, and within the liver tissue, necrosis, fibrosis, inflammation, as well as expression of genes involved in the synthesis or transport of bile acids were assessed. The survival rate of the animals and their well-being was comparable between pBDL+pAL and pBDL. However, surgical intervention by pBDL+pAL caused confluent necrosis and collagen depositions at the edge of necrotic tissue, whereas pBDL caused focal necrosis and fibrosis in between portal areas. Interestingly, pBDL animals had a higher survival rate and their well-being was significantly improved compared to cBDL animals. On day 14 after cBDL liver aspartate, as well as alanine aminotransferase, alkaline phosphatase, glutamate dehydrogenase, bile acids, and bilirubin were significantly elevated, but only glutamate dehydrogenase activity was increased after pBDL. Thus, pBDL may be primarily used to evaluate local features such as inflammation and fibrosis or regulation of genes involved in bile acid synthesis or transport but does not allow to study all systemic features of cholestasis. The pBDL model also has the advantage that fewer mice are needed, because of its high survival rate, and that the well-being of the animals is improved compared to the cBDL animal model. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Evidence-Based Severity Assessment of Animal Models for Pancreatic Cancer.
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Schreiber, Tim, Koopmann, Ingo, Brandstetter, Jakob, Talbot, Steven R., Goldstein, Lea, Hoffmann, Lisa, Schildt, Anna, Joksch, Markus, Krause, Bernd, Jaster, Robert, Palme, Rupert, Zechner, Dietmar, Vollmar, Brigitte, and Kumstel, Simone
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PANCREATIC cancer ,NEST building ,PSYCHOLOGICAL distress ,ANIMAL experimentation ,INTRAVENOUS injections - Abstract
Animal models are crucial to preclinical oncological research and drug development. Animal experiments must be performed in accordance with the 3R principles of replacement and reduction, if possible, and refinement where these procedures remain crucial. In addition, European Union legislations demand a continuous refinement approach, as well as pro- and retrospective severity assessment. In this study, an objective databased severity assessment was performed in murine models for pancreatic cancer induced by orthotopic, subcutaneous, or intravenous injection of Panc02 cells. Parameters such as body weight change, distress score, perianal temperature, mouse grimace scale, burrowing, nesting behavior, and the concentration of corticosterone in plasma and its metabolites in feces were monitored during tumor progression. The most important parameters were combined into a score and mapped against a reference data set by the Relative Severity Assessment procedure (RELSA) to obtain the maximum achieved severity for each animal (RELSA
max ). This scoring revealed a significantly higher RELSAmax for the orthotopic model than for the subcutaneous and intravenous models. However, compared to animal models such as pancreatitis and bile duct ligation, the pancreatic cancer models are shown to be less severe. Data-based animal welfare assessment proved to be a valuable tool for comparing the severity of differently induced cancer models. [ABSTRACT FROM AUTHOR]- Published
- 2024
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8. Pharmaceutical immunoglobulin G impairs anti-carcinoma activity of oxaliplatin in colon cancer cells
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Shang, Yuru, Zhang, Xianbin, Lu, Lili, Jiang, Ke, Krohn, Mathias, Matschos, Stephanie, Mullins, Christina Susanne, Vollmar, Brigitte, Zechner, Dietmar, Gong, Peng, and Linnebacher, Michael
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- 2021
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9. Sex Matters–Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer.
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Schulz, Benjamin, Leitner, Emily, Schreiber, Tim, Lindner, Tobias, Schwarz, Rico, Aboutara, Nadine, Ma, Yixuan, Escobar, Hugo Murua, Palme, Rupert, Hinz, Burkhard, Vollmar, Brigitte, and Zechner, Dietmar
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BIOLOGICAL models ,RESEARCH funding ,SEX distribution ,IN vivo studies ,CELLULAR signal transduction ,PANCREATIC tumors ,MICE ,SMALL molecules ,DRUG efficacy ,ANIMAL experimentation ,DUCTAL carcinoma ,LUNG tumors ,TRANSFERASES - Abstract
Simple Summary: Pancreatic ductal adenocarcinoma continues to be one of the deadliest cancers worldwide. Preclinical studies involving animals rarely include sex as a major biological variable in testing the efficacy of new drugs. In an animal model of pancreatic cancer, we analyzed the impact of sex on the pathological features of the disease and on an experimental small molecule-based therapy tested in vivo for the first time. While the therapy shows potential, the obtained results are confounded by sex-specific effects. This study, therefore, highlights the importance of sex-inclusive research while simultaneously providing a basis for further studies of the therapy tested. Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease as well as on the efficacy and possible adverse side effects of a novel, small molecule-based therapy inhibiting KRAS:SOS1, MEK1/2 and PI3K signaling in male and female C57BL/6J mice. Male mice had less tumor infiltration of CD8-positive cells, developed bigger tumors, had more lung metastasis and a lower probability of survival compared to female mice. These more severe pathological features in male animals were accompanied by higher distress at the end of the experiment. The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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10. Benefits of non-invasive methods compared to telemetry for distress analysis in a murine model of pancreatic cancer
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Kumstel, Simone, Vasudevan, Praveen, Palme, Rupert, Zhang, Xianbin, Wendt, Edgar Heinz Uwe, David, Robert, Vollmar, Brigitte, and Zechner, Dietmar
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- 2020
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11. LW6 enhances chemosensitivity to gemcitabine and inhibits autophagic flux in pancreatic cancer
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Zhang, Xianbin, Kumstel, Simone, Jiang, Ke, Meng, Songshu, Gong, Peng, Vollmar, Brigitte, and Zechner, Dietmar
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- 2019
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12. Comparing distress of mouse models for liver damage
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Tang, Guanglin, Seume, Nico, Häger, Christine, Kumstel, Simone, Abshagen, Kerstin, Bleich, André, Vollmar, Brigitte, Talbot, Steven R., Zhang, Xianbin, and Zechner, Dietmar
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- 2020
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13. MicroRNAs as systemic biomarkers to assess distress in animal models for gastrointestinal diseases
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Kumstel, Simone, Janssen-Peters, Heike, Abdelrahman, Ahmed, Tang, Guanglin, Xiao, Ke, Ernst, Nicole, Wendt, Edgar Heinz Uwe, Palme, Rupert, Seume, Nico, Vollmar, Brigitte, Thum, Thomas, and Zechner, Dietmar
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- 2020
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14. A novel multi-parametric analysis of non-invasive methods to assess animal distress during chronic pancreatitis
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Abdelrahman, Ahmed, Kumstel, Simone, Zhang, Xianbin, Liebig, Marie, Wendt, Edgar Heinz Uwe, Eichberg, Johanna, Palme, Rupert, Thum, Thomas, Vollmar, Brigitte, and Zechner, Dietmar
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- 2019
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15. Essential Role of Gab1 for Signaling by the c-Met Receptor in Vivo
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Sachs, Martin, Brohmann, Henning, Zechner, Dietmar, Müller, Thomas, Hülsken, Jörg, Walther, Ingrid, Schaeper, Ute, Birchmeier, Carmen, and Birchmeier, Walter
- Published
- 2000
16. A Role for the p38 Mitogen-Activated Protein Kinase Pathway in Myocardial Cell Growth, Sarcomeric Organization, and Cardiac-Specific Gene Expression
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Zechner, Dietmar, Thuerauf, Donna J., Hanford, Deanna S., McDonough, Patrick M., and Glembotski, Christopher C.
- Published
- 1997
17. Towards substitution of invasive telemetry: An integrated home cage concept for unobtrusive monitoring of objective physiological parameters in rodents.
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Mösch, Lucas, Kunczik, Janosch, Breuer, Lukas, Merhof, Dorit, Gass, Peter, Potschka, Heidrun, Zechner, Dietmar, Vollmar, Brigitte, Tolba, René, Häger, Christine, Bleich, André, Czaplik, Michael, and Pereira, Carina Barbosa
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HOME (The concept) ,PATIENT monitoring ,TELEMETRY ,IMAGING systems ,HEART beat ,HEART rate monitors ,RATS - Abstract
This study presents a novel concept for a smart home cage design, tools, and software used to monitor the physiological parameters of mice and rats in animal-based experiments. The proposed system focuses on monitoring key clinical parameters, including heart rate, respiratory rate, and body temperature, and can also assess activity and circadian rhythm. As the basis of the smart home cage system, an in-depth analysis of the requirements was performed, including camera positioning, imaging system types, resolution, frame rates, external illumination, video acquisition, data storage, and synchronization. Two different camera perspectives were considered, and specific camera models, including two near-infrared and two thermal cameras, were selected to meet the requirements. The developed specifications, hardware models, and software are freely available via GitHub. During the first testing phase, the system demonstrated the potential of extracting vital parameters such as respiratory and heart rate. This technology has the potential to reduce the need for implantable sensors while providing reliable and accurate physiological data, leading to refinement and improvement in laboratory animal care. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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18. Risk Factors for Pancreatic Ductal Adenocarcinoma Specifically Stimulate Pancreatic Duct Glands in Mice
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Bobrowski, Alexej, Spitzner, Marie, Bethge, Stefanie, Mueller-Graf, Fabian, Vollmar, Brigitte, and Zechner, Dietmar
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- 2013
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19. Erythropoietin improves skin wound healing and activates the TGF-β signaling pathway
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Siebert, Nikolai, Xu, Weiguo, Grambow, Eberhard, Zechner, Dietmar, and Vollmar, Brigitte
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- 2011
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20. Diagnostic Ability of Methods Depicting Distress of Tumor-Bearing Mice
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Xie, Wentao, Kordt, Marcel, Palme, Rupert, Grambow, Eberhard, Vollmar, Brigitte, and Zechner, Dietmar
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in vivo ,QL1-991 ,animal model ,Veterinary medicine ,SF600-1100 ,xenograft models ,Zoology ,Article ,animal welfare ,3Rs - Abstract
Subcutaneous tumor models in mice are the most commonly used experimental animal models in cancer research. To improve animal welfare and the quality of scientific studies, the distress of experimental animals needs to be minimized. For this purpose, one must assess the diagnostic ability of readout parameters to evaluate distress. In this study, we evaluated different noninvasive readout parameters such as body weight change, adjusted body weight change, faecal corticosterone metabolites concentration, burrowing activity and a distress score by utilising receiver operating characteristic curves. Eighteen immunocompromised NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice were used for this study, half were subcutaneously injected with A-375 cells (human malignant melanoma cells) that resulted in large tumors. The remaining mice were inoculated with SCL-2 cells (cutaneous squamous cell carcinoma cells), which resulted in small tumors. The adjusted body weight and faecal corticosterone metabolites concentration had a high diagnostic ability in distinguishing between mice before cancer cell injection and mice bearing large tumors. All other readout parameters had a low diagnostic ability. These results suggest that adjusted body weight and faecal corticosterone metabolites are useful to depict the distress of mice bearing large subcutaneous tumors.
- Published
- 2021
21. Generalizability, Robustness and Replicability When Evaluating Wellbeing of Laboratory Mice with Various Methods.
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Zechner, Dietmar, Schulz, Benjamin, Tang, Guanglin, Abdelrahman, Ahmed, Kumstel, Simone, Seume, Nico, Palme, Rupert, and Vollmar, Brigitte
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LABORATORY mice , *RECEIVER operating characteristic curves , *MICE , *PSYCHOLOGICAL distress , *WELL-being , *GASTROINTESTINAL diseases , *NEST building - Abstract
Simple Summary: It is in the interest of the general public as well as the scientific community to optimize the wellbeing of animals during scientific research. To reach this goal, methods need to be defined which can reliably evaluate the wellbeing of animals. In this study, we assessed whether various methods, such as measuring body weight, burrowing activity, nesting behavior, a distress score and fecal corticosterone metabolites can differentiate between healthy mice and mice after surgical intervention or during the progression of a gastrointestinal disease. The ability of each method to differentiate between these two states of wellbeing was different between distinct surgical interventions and gastrointestinal diseases. These data suggest that scientists cannot rely on a single method, but have to combine many methods when assessing the wellbeing of animals. An essential basis for objectively improving the status of animals during in vivo research is the ability to measure the wellbeing of animals in a reliable and scientific manner. Several non-invasive methods such as assessing body weight, burrowing activity, nesting behavior, a distress score and fecal corticosterone metabolites were evaluated in healthy mice and after three surgical interventions or during the progression of four gastrointestinal diseases. The performance of each method in differentiating between healthy and diseased animals was assessed using receiver operating characteristic curves. The ability to differentiate between these two states differed between distinct surgical interventions and distinct gastrointestinal diseases. Thus, the generalizability of these methods for assessing animal wellbeing was low. However, the robustness of these methods when assessing wellbeing in one gastrointestinal disease was high since the same methods were often capable of differentiating between healthy and diseased animals independent of applied drugs. Moreover, the replicability when assessing two distinct cohorts with an identical surgical intervention was also high. These data suggest that scientists can reach valid conclusions about animal wellbeing when using these methods within one specific animal model. This might be important when optimizing methodological aspects for improving animal wellbeing. The lack of generalizability, however, suggests that comparing animal models by using single methods might lead to incorrect conclusions. Thus, these data support the concept of using a combination of several methods when assessing animal welfare. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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22. Effects of Bile Duct Ligation and Ghrelin Treatment on the Colonic Barrier and Microbiome of Mice.
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Ehlers, Luise, Netz, Leonard Andreas Wolfgang, Reiner, Johannes, Berlin, Peggy, Bannert, Karen, Bastian, Manuela, Zechner, Dietmar, Lamprecht, Georg, and Jaster, Robert
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BILE ducts ,GHRELIN ,OCCLUDINS ,PEPTIDE hormones ,WEIGHT loss ,GENE expression ,LABORATORY mice ,METAGENOMICS ,MICE - Abstract
Introduction: Cholestatic liver disease (CLD) is associated with intestinal barrier dysfunction. The peptide hormone ghrelin may exert both hepatoprotective and barrier-strengthening effects. Here, we have evaluated these effects under the conditions of experimental cholestasis. Methods: C57BL/6J mice with bile duct ligation (BDL) or sham surgery were treated with ghrelin or solvent for 9 days. Liver injury was assessed by histological and laboratory analyses. Paracellular macromolecule permeability and transmural electrical resistance (TMER) of colonic tissues were measured using a Ussing chamber. Expression of tight junction (TJ) genes was quantified by real-time PCR. Amplicon metagenomic sequencing was employed to analyze bacterial 16S rRNA from colonic stool samples. Results: Mice with BDL exhibited weight loss and signs of severe liver injury. These changes were unaffected by ghrelin treatment. FITC-4-kDa-dextran flux was increased and TMER decreased after BDL. Treatment with ghrelin tended to reduce these effects. Furthermore, application of ghrelin was associated with higher mRNA levels of claudin-4, occludin, and ZO-1 in colonic tissues of mice with BDL. Reduced alpha-diversity of the microbiome was observed in solvent-treated mice with BDL but not in ghrelin-treated animals. Conclusion: Ghrelin treatment did not improve weight loss and liver damage but increased gene expression of colonic TJ proteins and restored the alpha-diversity of the microbiome. Since protective effects of ghrelin might be masked by the severity of the model, we suggest follow-up studies in models of milder CLD. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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23. Senescence-dependent impact of anti-RAGE antibody on endotoxemic liver failure
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Kuhla, Angela, Hauke, Mandy, Sempert, Kai, Vollmar, Brigitte, and Zechner, Dietmar
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- 2013
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24. Darbepoetin-α inhibits the perpetuation of necro-inflammation and delays the progression of cholestatic fibrosis in mice
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Sigal, Michael, Siebert, Nikolai, Zechner, Dietmar, Menschikow, Elena, Abshagen, Kerstin, Vollmar, Brigitte, and Eipel, Christian
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- 2010
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25. Inhibition of KRAS, MEK and PI3K Demonstrate Synergistic Anti-Tumor Effects in Pancreatic Ductal Adenocarcinoma Cell Lines.
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Ma, Yixuan, Schulz, Benjamin, Trakooljul, Nares, Al Ammar, Moosheer, Sekora, Anett, Sender, Sina, Hadlich, Frieder, Zechner, Dietmar, Weiss, Frank Ulrich, Lerch, Markus M., Jaster, Robert, Junhanss, Christian, and Murua Escobar, Hugo
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THERAPEUTIC use of antineoplastic agents ,PANCREATIC tumors ,ADENOCARCINOMA ,DISEASE progression ,DRUG efficacy ,CYTOKINES ,GENETIC mutation ,PHOSPHOTRANSFERASES ,IMMUNE system ,CELL physiology ,DUCTAL carcinoma ,CELL survival ,CELLULAR signal transduction ,DRUG synergism ,GENE expression profiling ,CELL migration inhibition ,CELL lines - Published
- 2022
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26. Diabetes increases pancreatitis induced systemic inflammation but has little effect on inflammation and cell death in the lung
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Zechner, Dietmar, Spitzner, Marie, Müller-Graff, Tassilo, and Vollmar, Brigitte
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- 2014
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27. Targeting pancreatic cancer with combinatorial treatment of CPI-613 and inhibitors of lactate metabolism.
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Kumstel, Simone, Schreiber, Tim, Goldstein, Lea, Stenzel, Jan, Lindner, Tobias, Joksch, Markus, Zhang, Xianbin, Wendt, Edgar Heinz Uwe, Schönrogge, Maria, Krause, Bernd, Vollmar, Brigitte, and Zechner, Dietmar
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MONOCARBOXYLATE transporters ,PANCREATIC cancer ,KREBS cycle ,CANCER cell proliferation ,PANCREATIC tumors ,CANCER treatment - Abstract
Pancreatic cancer is the fourth leading cause of cancer death, with a 5-year survival rate of 10%. A stagnant high mortality rate over the last decades highlights the need for innovative therapeutic approaches. Pancreatic tumors pursue an altered metabolism in order to maintain energy generation under low nutrient influx and hypoxic conditions. Targeting these metabolic strategies might therefore be a reasonable therapeutic approach for pancreatic cancer. One promising agent is CPI- 613, a potent inhibitor of two enzymes of the tricarboxylic acid cycle. The present study evaluated the anti-cancerous efficacy of CPI-613 in combination with galloflavin, a lactate dehydrogenase inhibitor or with alpha-cyano-4-hydroxycinnamic acid, an inhibitor of monocarboxylate transporters. The efficacy of both combination therapies was tested in vitro on one human and two murine pancreatic cancer cell lines and in vivo in an orthotopic pancreatic cancer model. Tumor progression was evaluated by MRI and
18 F-FDG PET-CT. Both combinatorial treatments demonstrated in vitro a significant inhibition of pancreatic cancer cell proliferation and induction of cell death. In contrast to the in vitro results, both combination therapies did not significantly reduce tumor growth in vivo. The in vitro results suggest that a combined inhibition of different metabolic pathways might be a promising approach for cancer therapy. However, the in vivo experiments indicate that applying a higher dosage or using other drugs targeting these metabolic pathways might be more promising. [ABSTRACT FROM AUTHOR]- Published
- 2022
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28. Inhibitory Response to CK II Inhibitor Silmitasertib and CDKs Inhibitor Dinaciclib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines.
- Author
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Ma, Yixuan, Sender, Sina, Sekora, Anett, Kong, Weibo, Bauer, Peter, Ameziane, Najim, Krake, Susann, Radefeldt, Mandy, Al-Ali, Ruslan, Weiss, Frank Ulrich, Lerch, Markus M., Parveen, Alisha, Zechner, Dietmar, Junghanss, Christian, and Murua Escobar, Hugo
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CELL death ,PANCREATIC duct ,RAS oncogenes ,CELL lines ,CYCLIN-dependent kinases ,TUMOR proteins ,PROTEIN kinase CK2 - Abstract
Casein kinase II (CK2) and cyclin-dependent kinases (CDKs) frequently interact within multiple pathways in pancreatic ductal adenocarcinoma (PDAC). Application of CK2- and CDK-inhibitors have been considered as a therapeutic option, but are currently not part of routine chemotherapy regimens. We investigated ten PDAC cell lines exposed to increasing concentrations of silmitasertib and dinaciclib. Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated, and bioinformatic clustering was used to classify cell lines into sensitive groups based on their response to inhibitors. Furthermore, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) was conducted to assess recurrent mutations and the expression profile of inhibitor targets and genes frequently mutated in PDAC, respectively. Dinaciclib and silmitasertib demonstrated pronounced and limited cell line specific effects in cell death induction, respectively. WES revealed no genomic variants causing changes in the primary structure of the corresponding inhibitor target proteins. RNA-Seq demonstrated that the expression of all inhibitor target genes was higher in the PDAC cell lines compared to non-neoplastic pancreatic tissue. The observed differences in PDAC cell line sensitivity to silmitasertib or dinaciclib did not depend on target gene expression or the identified gene variants. For the PDAC hotspot genes kirsten rat sarcoma virus (KRAS) and tumor protein p53 (TP53), three and eight variants were identified, respectively. In conclusion, both inhibitors demonstrated in vitro efficacy on the PDAC cell lines. However, aberrations and expression of inhibitor target genes did not appear to affect the efficacy of the corresponding inhibitors. In addition, specific aberrations in TP53 and KRAS affected the efficacy of both inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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29. The Inhibitory Response to PI3K/AKT Pathway Inhibitors MK-2206 and Buparlisib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines.
- Author
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Ma, Yixuan, Sender, Sina, Sekora, Anett, Kong, Weibo, Bauer, Peter, Ameziane, Najim, Al-Ali, Ruslan, Krake, Susann, Radefeldt, Mandy, Weiss, Frank Ulrich, Lerch, Markus M., Parveen, Alisha, Zechner, Dietmar, Junghanss, Christian, and Murua Escobar, Hugo
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PI3K/AKT pathway ,PANCREATIC duct ,CELL lines ,CELL death ,P53 protein ,PROTEIN kinase B ,TUMOR proteins - Abstract
The aberrant activation of the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) pathway is common in pancreatic ductal adenocarcinomas (PDAC). The application of inhibitors against PI3K and AKT has been considered as a therapeutic option. We investigated PDAC cell lines exposed to increasing concentrations of MK-2206 (an AKT1/2/3 inhibitor) and Buparlisib (a pan-PI3K inhibitor). Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated. Further, whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were performed to analyze the recurrent aberrations and expression profiles of the inhibitor target genes and the genes frequently mutated in PDAC (Kirsten rat sarcoma virus (KRAS), Tumor protein p53 (TP53)). MK-2206 and Buparlisib demonstrated pronounced cytotoxic effects and limited cell-line-specific effects in cell death induction. WES revealed two sequence variants within the direct target genes (PIK3CA c.1143C > G in Colo357 and PIK3CD c.2480C > G in Capan-1), but a direct link to the Buparlisib response was not observed. RNA-seq demonstrated that the expression level of the inhibitor target genes did not affect the efficacy of the corresponding inhibitors. Moreover, increased resistance to MK-2206 was observed in the analyzed cell lines carrying a KRAS variant. Further, increased resistance to both inhibitors was observed in SU.86.86 carrying two TP53 missense variants. Additionally, the presence of the PIK3CA c.1143C > G in KRAS-variant-carrying cell lines was observed to correlate with increased sensitivity to Buparlisib. In conclusion, the present study reveals the distinct antitumor effects of PI3K/AKT pathway inhibitors against PDAC cell lines. Aberrations in specific target genes, as well as KRAS and TP53, individually or together, affect the efficacy of the two PI3K/AKT pathway inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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30. [beta]-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system
- Author
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Zechner, Dietmar, Fujita, Yasuyuki, Hulsken, Jorg, Muller, Thomas, Walther, Ingrid, Taketo, Makoto M., Crenshaw, E. Bryan, III, Birchmeier, Walter, and Birchmeier, Carmen
- Subjects
Cell differentiation -- Research ,Developmental biology -- Research ,Nervous system -- Research ,Biological sciences - Abstract
[beta]-Catenin is an essential component of the canonical Wnt signaling system that controls decisive steps in development. We employed here two conditional/3-catenin mutant alleles to alter [beta]-catenin signaling in the central nervous system of mice: one allele to ablate [beta]-catenin and the second allele to express a constitutively active [beta]-catenin. The tissue mass of the spinal cord and brain is reduced after ablation of [beta]-catenin, and the neuronal precursor population is not maintained. In contrast, the spinal cord and brain of mice that express activated [beta]-catenin is much enlarged in mass, and the neuronal precursor population is increased in size. [beta]-Catenin signals are thus essential for the maintenance of proliferation of neuronal progenitors, controlling the size of the progenitor pool, and impinging on the decision of neuronal progenitors to proliferate or to differentiate. Keywords: Wnt signaling; [beta]-Catenin; Neural stem cells; Neuronal progenitors; Progenitor pool; Proliferation versus differentiation
- Published
- 2003
31. Establishment and Characterization of FusionRed Stable Transfected Canine Prostate Adenocarcinoma and Transitional Cell Carcinoma Cells.
- Author
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ALNAJJAR, SUHAYLA, NOLTE, INGO, SCHILLE, JAN TORBEN, SENDER, SINA, TRAKOOLJU, NARES, PEREZ, SIMON VILLA, ZECHNER, DIETMAR, VOLLMAR, BRIGITTE, JUNGHANSS, CHRISTIAN, and ESCOBAR, HUGO MURUA
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TRANSITIONAL cell carcinoma ,PROSTATE cancer ,CANCER cells ,CELL lines ,RNA sequencing - Abstract
Background/Aim: Cancer cell inoculation is routinely used to evaluate novel therapeutic approaches in vivo. However, without reporter genes enabling deep tissue imaging, study of early tumor progression and therapeutic responses is often limited. We describe the establishment and characterization of two canine cancer cell lines stably expressing red fluorescence proteins as tools for later in vivo imaging. Materials and Methods: Two red fluorescence cell lines were generated by plasmid transfection. Fluorescence protein expression was confirmed by flow cytometry and microscopy. Deep tissue imaging was demonstrated in mice using a NightOWL LB 983. Gene expression changes after transfection were analyzed by RNAseq. Results: Both cell lines were detectable in vivo by subcutaneous injection of 1×10
6 cells. RNAseq revealed up to 2005 transfection-induced differentially expressed genes but no significant changes in cellular key pathways. Conclusion: The fluorescent cell lines provide a solid basis for future in vivo studies on canine cancer. [ABSTRACT FROM AUTHOR]- Published
- 2022
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32. Melatonin restores muscle regeneration and enhances muscle function after crush injury in rats
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Stratos, Ioannis, Richter, Nils, Rotter, Robert, Li, Zhengdong, Zechner, Dietmar, Mittlmeier, Thomas, and Vollmar, Brigitte
- Published
- 2012
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33. Voluntary wheel running behaviour as a tool to assess the severity in a mouse pancreatic cancer model.
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Weegh, Nora, Zentrich, Eva, Zechner, Dietmar, Struve, Birgitta, Wassermann, Laura, Talbot, Steven Roger, Kumstel, Simone, Heider, Miriam, Vollmar, Brigitte, Bleich, André, and Häger, Christine
- Subjects
PANCREATIC cancer ,INTRAPERITONEAL injections ,WEIGHT loss ,BODY weight ,LABORATORY animals ,MICE ,ARTIFICIAL pancreases - Abstract
Laboratory animals frequently undergo routine experimental procedures such as handling, restraining and injections. However, as a known source of stress, these procedures potentially impact study outcome and data quality. In the present study, we, therefore, performed an evidence-based severity assessment of experimental procedures used in a pancreatic cancer model including surgical tumour induction and subsequent chemotherapeutic treatment via repeated intraperitoneal injections. Cancer cell injection into the pancreas was performed during a laparotomy under general anaesthesia. After a four-day recovery phase, mice received either drug treatment (galloflavin and metformin) or the respective vehicle substances via daily intraperitoneal injections. In addition to clinical scoring, an automated home-cage monitoring system was used to assess voluntary wheel running (VWR) behaviour as an indicator of impaired well-being. After surgery, slightly elevated clinical scores and minimal body weight reductions, but significantly decreased VWR behaviour were observed. During therapy, body weight declined in response to chemotherapy, but not after vehicle substance injection, while VWR activity was decreased in both cases. VWR behaviour differed between treatment groups and revealed altered nightly activity patterns. In summary, by monitoring VWR a high impact of repeated injections on the well-being of mice was revealed and substance effects on well-being were distinguishable. However, no differences in tumour growth between treatment groups were observed. This might be due to the severity of the procedures uncovered in this study, as exaggerated stress responses are potentially confounding factors in preclinical studies. Finally, VWR was a more sensitive indicator of impairment than clinical scoring in this model. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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34. Analysis of Pain and Analgesia Protocols in Acute Cerulein-Induced Pancreatitis in Male C57BL/6 Mice.
- Author
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Durst, Mattea, Graf, Theresia Reding, Graf, Rolf, Kron, Mareike, Arras, Margarete, Zechner, Dietmar, Palme, Rupert, Talbot, Steven R., and Jirkof, Paulin
- Subjects
LABORATORY mice ,CHRONIC pancreatitis ,PANCREATITIS ,PAIN management ,ANIMAL burrowing ,SALINE injections - Abstract
Pancreatitis is known to be painful in humans and companion animals. However, the extent of pain in experimental mouse models of acute pancreatitis is unknown. Consequently, the severity classification of acute pancreatitis in mice is controversially discussed and standardized pain management is missing. In this study, we investigated acute Cerulein-induced pancreatitis with pain-specific and well-being orientated parameters to detect its impact on mice. Male C57BL/6J male mice were injected with Cerulein; animals that received saline injections served as control group. The animals were observed for weight change and water intake. To assess pain, behaviors like stretch-and-press and reduced rearing, the Mouse Grimace Scale, and von Frey hypersensitivity were assessed. Fecal corticosterone metabolites and burrowing behavior were assessed to detect changes in the animal's well-being. Pancreatitis severity was evaluated with amylase and lipase in the blood and pancreas histology. To investigate whether different analgesics can alleviate signs of pain, and if they influence pancreas inflammation, animals received Buprenorphine, Paracetamol in combination with Tramadol, or Metamizole in the drinking water. The calculated intake of these analgesics via drinking reached values stated to be efficient for pain alleviation. While pancreatitis did not seem to be painful, we detected acute pain from Cerulein injections that could not be alleviated by analgesics. The number of inflammatory cells in the pancreas did not differ with the analgesic administered. In conclusion: (1) Cerulein injections appear to be acutely painful but pain could not be alleviated by the tested analgesics, (2) acute pancreatitis induced by our protocol did not induce obvious signs of pain, (3) analgesic substances had no detectable influence on inflammation. Nevertheless, protocols inducing more severe or even chronic pancreatitis might evoke more pain and analgesic treatment might become imperative. Considering our results, we recommend the use of Buprenorphine via drinking water in these protocols. Further studies to search for efficient analgesics that can alleviate the acute pain induced by Cerulein injections are needed. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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35. Blocking Autophagy in Cancer-Associated Fibroblasts Supports Chemotherapy of Pancreatic Cancer Cells
- Author
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Zhang, Xianbin, Schönrogge, Maria, Eichberg, Johanna, Wendt, Edgar Heinz Uwe, Kumstel, Simone, Stenzel, Jan, Lindner, Tobias, Jaster, Robert, Krause, Bernd Joachim, Vollmar, Brigitte, and Zechner, Dietmar
- Subjects
autophagy ,Oncology ,α-cyano-4-hydroxycinnamate ,pancreatic cancer ,gemcitabine ,metformin ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,cancer-associated fibroblasts ,lcsh:RC254-282 ,Original Research - Abstract
In this study we evaluated the interaction of pancreatic cancer cells, cancer-associated fibroblasts, and distinct drugs such as α-cyano-4-hydroxycinnamate, metformin, and gemcitabine. We observed that α-cyano-4-hydroxycinnamate as monotherapy or in combination with metformin could significantly induce collagen I deposition within the stromal reaction. Subsequently, we demonstrated that cancer-associated fibroblasts impaired the anti-proliferation efficacy of α-cyano-4-hydroxycinnamate, metformin and gemcitabine. Interestingly, inhibition of autophagy in these fibroblasts can augment the anti-proliferation effect of these chemotherapeutics in vitro and can reduce the tumor weight in a syngeneic pancreatic cancer model. These results suggest that inhibiting autophagy in cancer-associated fibroblasts may contribute to strategies targeting cancer.
- Published
- 2018
36. The Ambivalent Function of YAP in Apoptosis and Cancer
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Zhang, Xianbin, Abdelrahman, Ahmed, Vollmar, Brigitte, and Zechner, Dietmar
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signaling pathway ,autophagy ,p73 ,Apoptosis ,Cell Cycle Proteins ,Review ,Protein Serine-Threonine Kinases ,lcsh:Chemistry ,Hippo ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Animals ,Humans ,cancer ,Hippo Signaling Pathway ,Molecular Targeted Therapy ,lcsh:QH301-705.5 ,therapy ,Nuclear Proteins ,cell death ,Gene Expression Regulation ,lcsh:Biology (General) ,lcsh:QD1-999 ,YAP ,Apoptosis Regulatory Proteins ,Glycolysis ,Protein Binding ,Signal Transduction ,Transcription Factors - Abstract
Yes-associated protein, a core regulator of the Hippo-YAP signaling pathway, plays a vital role in inhibiting apoptosis. Thus, several studies and reviews suggest that yes-associated protein is a good target for treating cancer. Unfortunately, more and more evidence demonstrates that this protein is also an essential contributor of p73-mediated apoptosis. This questions the concept that yes-associated protein is always a good target for developing novel anti-cancer drugs. Thus, the aim of this review was to evaluate the clinical relevance of yes-associated protein for cancer pathophysiology. This review also summarized the molecules, processes and drugs, which regulate Hippo-YAP signaling and discusses their effect on apoptosis. In addition, issues are defined, which should be addressed in the future in order to provide a solid basis for targeting the Hippo-YAP signaling pathway in clinical trials.
- Published
- 2018
37. Development and Validation of a Score for Screening Suicide of Patients With Neuroendocrine Neoplasms.
- Author
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Lu, Lili, Shang, Yuru, Zechner, Dietmar, Mullins, Christina Susanne, Linnebacher, Michael, Zhang, Xianbin, and Gong, Peng
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SUICIDE ,RECEIVER operating characteristic curves ,SUICIDE prevention ,QUALITY of life ,SUICIDE victims - Abstract
Background: If the diagnosis of neuroendocrine neoplasm (NEN) increases the risk of patients to commit suicide has not been investigated so far. Identifying NEN patients at risk to commit suicide is important to increase their life quality and life expectancy. Methods and findings: Cancer cases were extracted from the Surveillance, Epidemiology, and End Results program and were divided into the NEN and the non-NEN cohorts. Subsequently, the NEN patients were randomly split into a training data set and a validation data set. Analyzing the training data set, we developed a score for assessing the risk to commit suicide for patients with NEN. In addition, we validated the score using the validation data set and evaluated, if this score could also be applied to other cancer entities by using the test data set, a non-NEN cohort. The odds ratio (OR) of suicide between NEN and non-NEN patients was determined. Moreover, the performance of a score was evaluated by the receiver operating characteristic curve and the area under the curve (AUC). Compared to non-NEN, NEN significantly increased the risk of suicide to 1.8-fold (NEN vs. non-NEN; OR, 1.832; P < 0.001). In addition, we observed that age, gender, race, marital status, tumor stage, histologic grade, surgery, and chemotherapy were associated with suicide among NEN patients; and a synthesized score based on these factors could significantly distinguish suicide individuals from non-suicide individuals in the training data set (AUC, 0.829; P < 0.001) and in the validation data set (AUC, 0.735; P < 0.001). This score also had a good performance when it was assessed by the test data set (AUC, 0.690; P < 0.001). This demonstrates that the score might also be applicable to other cancer entities. Conclusions: This population-based study suggests that NEN patients have a higher risk of suicide than non-NEN patients. In addition, this study provided a score, which can identify NEN patients at high-risk of committing suicide. Thus, this score in combination with current screening and prevention strategies for suicide may improve life quality and life expectancy of NEN patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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38. Tumor Necrosis Factor Alpha-induced Apoptosis in Cardiac Myocytes: Involvement of the Sphingolipid Signaling Cascade in Cardiac Cell Death
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Krown, Kevin A., Page, M. Trevor, Nguyen, Cuong, Zechner, Dietmar, Gutierrez, Veronica, Comstock, Kevyn L., Glembotski, Christopher C., Quintana, Penelope J.E., and Sabbadini, Roger A.
- Published
- 1996
39. Grading animal distress and side effects of therapies.
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Kumstel, Simone, Wendt, Edgar H. U., Eichberg, Johanna, Talbot, Steven R., Häger, Christine, Zhang, Xianbin, Abdelrahman, Ahmed, Schönrogge, Maria, Palme, Rupert, Bleich, André, Vollmar, Brigitte, and Zechner, Dietmar
- Subjects
DRUG side effects ,METFORMIN ,PANCREATIC cancer ,BODY weight ,ANIMAL experimentation ,LOGISTIC regression analysis - Abstract
In order to combine high‐quality research with minimal harm to animals, a prospective severity assessment for animal experiments is legally required in many countries. In addition, an assessment of the evidence‐based severity level might allow realistic harm–benefit analysis and the appraisal of refinement methods. However, only a few examples describe the distress of animals by simple, cost‐efficient, and noninvasive methods. We, therefore, evaluated the severity of an orthotopic mouse model for pancreatic cancer using C57BL/6J mice when pursuing two different chemotherapies. We assessed fecal corticosterone metabolites, body weight, distress score, and burrowing, as well as nesting activity. Moreover, we established a multifactorial model using multivariate logistic regression to describe animal distress. This multifactorial analysis revealed that metformin + galloflavin treatment caused higher distress than metformin + α‐cyano‐4‐hydroxycinnamate therapy. Similar results were obtained by using the best cutoff calculated by Youden's J index when using only single parameters, such as burrowing activity or fecal corticosterone metabolite concentration. Thus, the present study revealed that single readout parameters, as well as multivariate analysis, can help to assess the severity of animal experiments and detect side effects of therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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40. A Rational Approach of Early Humane Endpoint Determination in a Murine Model for Cholestasis.
- Author
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Xianbin Zhang, Kumstel, Simone, Guanglin Tang, Talbot, Steven R., Seume, Nico, Abshagen, Kerstin, Vollmar, Brigitte, and Zechner, Dietmar
- Abstract
Reduction of animal suffering during in vivo experiments is usually ensured by continuously monitoring the health status using a score sheet and by applying humane endpoints. However, most studies do not evaluate the plausibility of score sheets and do not attempt to reduce the suffering of animals by determining earlier and, therefore, more humane endpoints. The present study uses data from BALB/cANCrl mice after bile duct ligation to retrospectively analyze which score sheet criteria are informative to determine humane endpoints. The performance of each single as well as combinations of multiple animal welfare parameters was analyzed by a Cox proportional-hazards model followed by Harrell’s concordance index. The addition of behavioral parameters, such as burrowing activity, helped to define a more humane early endpoint for euthanizing these animals. Using this approach, we determined that a body weight loss of 10-20% combined with a reduction of burrowing activity by more than 79.4% was able to predict that these animals would die within two days. Thus, this approach successfully determined an earlier humane endpoint and will reduce the suffering of animals in future experiments. Application of such an approach or similar methods can contribute to the refinement of various animal experiments. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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41. A safe bet? Inter-laboratory variability in behaviour-based severity assessment.
- Author
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Jirkof, Paulin, Abdelrahman, Ahmed, Bleich, André, Durst, Mattea, Keubler, Lydia, Potschka, Heidrun, Struve, Birgitta, Talbot, Steven R, Vollmar, Brigitte, Zechner, Dietmar, and Häger, Christine
- Subjects
VETERINARY hospitals ,ANIMAL welfare ,NEEDS assessment ,BODY weight ,ANIMAL experimentation ,WEIGHT loss ,TREATMENT effectiveness - Abstract
Evidence-based severity assessment is essential as a basis for ethical evaluation in animal experimentation to ensure animal welfare, legal compliance and scientific quality. To fulfil these tasks scientists, animal care and veterinary personnel need assessment tools that provide species-relevant measurements of the animals' physical and affective state. In a three-centre study inter-laboratory robustness of body weight monitoring, mouse grimace scale (MGS) and burrowing test were evaluated. The parameters were assessed in naïve and tramadol treated female C57BL/6J mice. During tramadol treatment a body weight loss followed by an increase, when treatment was terminated, was observed in all laboratories. Tramadol treatment did not affect the MGS or burrowing performance. Results were qualitatively comparable between the laboratories, but quantitatively significantly different (inter-laboratory analysis). Burrowing behaviour seems to be highly sensitive to inter-laboratory differences in testing protocol. All locations obtained comparable information regarding the qualitative effect of tramadol treatment in C57BL/6J mice, however, datasets differed as a result of differences in test and housing conditions. In conclusion, our study confirms that results of behavioural testing can be affected by many factors and may differ between laboratories. Nevertheless, the evaluated parameters appeared relatively robust even when conditions were not harmonized extensively and present useful tools for severity assessment. However, analgesia-related side effects on parameters have to be considered carefully. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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42. Where are we heading? Challenges in evidence-based severity assessment.
- Author
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Keubler, Lydia M, Hoppe, Nils, Potschka, Heidrun, Talbot, Steven R, Vollmar, Brigitte, Zechner, Dietmar, Häger, Christine, and Bleich, André
- Subjects
LABORATORY animals ,ANIMAL experimentation - Abstract
Evidence-based severity assessment in laboratory animals is, apart from the ethical responsibility, imperative to generate reproducible, standardized and valid data. However, the path towards a valid study design determining the degree of pain, distress and suffering experienced by the animal is lined with pitfalls and obstacles as we will elucidate in this review. Furthermore, we will ponder on the genesis of a holistic concept relying on multifactorial composite scales. These have to combine robust and reliable parameters to measure the multidimensional aspects that define the severity of animal experiments, generating a basis for the substantiation of the refinement principle. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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43. Genetic interaction between Wnt/beta-catenin and BMP receptor signaling during formation of the AER and the dorsal-ventral axis in the limb
- Author
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Soshnikova, Natalia, Zechner, Dietmar, Huelsken, Joerg, Mishina, Yuji, Behringer, Richard R., Taketo, Makoto M., Crenshaw, E. Bryan, III, and Birchmeier, Walter
- Subjects
Genetic regulation -- Physiological aspects ,Developmental biology -- Genetic aspects ,Ectoderm -- Genetic aspects ,Genetic research -- Analysis ,Biological sciences - Abstract
Research has been conducted on beta-catenin. The authors report that beta-catenin is a regulator of apical ectodermal ridge and limb dorsal-ventral axis formations.
- Published
- 2003
44. Characterisation of novel ductal pancreatic adenocarcinoma cell lines in vitro as well as in diabetic mice
- Author
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Radecke, Tobias, Bürtin, Florian, Partecke, Ivo, Vollmar, Brigitte, and Zechner, Dietmar
- Subjects
ddc: 610 ,education ,610 Medical sciences ,Medicine - Abstract
Introduction The incidence of pancreatic ductal adenocarcinoma (PDA) is nearly equal to mortality with a 5-year survival rate of only 5 %. Diabetes type II is a well known risk factor for the development of PDA. However, little information exists if this risk factor only increases the rate of tumor[for full text, please go to the a.m. URL], 130. Kongress der Deutschen Gesellschaft für Chirurgie
- Published
- 2013
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45. Binding versus Conventional Pancreaticojejunostomy in Preventing Postoperative Pancreatic Fistula: A Systematic Review and Meta-Analysis.
- Author
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Zhang, Xianbin, Dong, Xin, Liu, Peng, Yan, Yumei, Wei, Yushan, Zechner, Dietmar, Gong, Peng, and Vollmar, Brigitte
- Subjects
PANCREATIC fistula ,PANCREATIC diseases - Abstract
Background: The aim of this study was to compare the safety and efficacy of a new technology, binding pancreaticojejunostomy (BPJ), with conventional pancreaticojejunostomy (CPJ) after pancreaticoduodenectomy in preventing postoperative pancreatic fistula (POPF). Methods: Randomized controlled trials and observational studies were retrieved from literature searches. Pooled OR with 95% CI for dichotomous variables and weighted mean difference with 95% CI for continuous variables were calculated. Fixed-effect and random-effect models as well as subgroup analysis were used for sensitivity analysis. Results: No statistically significant differences were found in the incidence of POPF, delayed gastric emptying, postpancreatectomy hemorrhage, reoperation, morbidity, mortality, operation time, intraoperative blood loss, blood transfusion, and hospital stay between 2 groups. However, the total costs of hospitalization and ordinary stay were higher in BPJ group (€10,513 ± €6,536 vs. €8,238 ± €4,687, p = 0.002; €7,946 ± €5,023 vs. €5,700 ± €2,902, p = 0.015, respectively). Conclusions: Our study showed BPJ was as safe as CPJ. However, no significant superiority was found in BPJ group regarding the incidence of POPF. The total costs of hospital stay were higher for patients undergoing BPJ. Surgeons can prefer to perform the digestive tract reconstruction of their choice. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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46. Analysis of Axin2 expression and function in murine models for pancreatic cancer.
- Author
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Zechner, Dietmar, Kroemer, Tim, Albert, Ann-Christin, Schönrogge, Maria, Radecke, Tobias, and Vollmar, Brigitte
- Subjects
- *
PANCREATIC cancer genetics , *AXIN , *WNT signal transduction - Abstract
Background: The involvement of Wnt in carcinogenesis and progression of pancreatic cancer is currently intensely discussed. We evaluated activation of the Wnt signaling pathway by using a Wnt reporter mouse strain expressing β-galactosidase under the control of the Axin2 promotor during pancreatitis induced formation of precancerous lesions. We also evaluated activation of Wnt signaling during interaction of pancreatic cancer with the tumor stroma. Results: Activation of Wnt signaling was observed during acinar-to-ductal metaplasia after chronic as well as acute pancreatitis. Activation of Wnt signaling was also noticed during growth of pancreatic cancer in an orthotopic syngeneic pancreas cancer model. Activation of Wnt signaling was, however, not observed in carcinoma associated fibroblasts, but was detected in few cell clusters inside the tumor. Genetic ablation of Axin2 significantly reduced body weight without having a major impact on blood glucose concentration. However, ablation of Axin2 had no influence on the observed β-galactosidase positive cell clusters or on tumor weight. Conclusion: These data demonstrate that the Wnt signaling pathway is activated during acinar-to-ductal metaplasia after injury to the pancreas. However these data do not support a major role of Wnt signaling or of Axin2 in carcinoma associated fibroblasts and tumor growth. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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47. Differential impact of diabetes type II and chronic inflammation on pancreatic cancer
- Author
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Zechner, Dietmar, Radecke, Tobias, Amme, Jonas, Bürtin, Florian, Albert, Ann-Christin, Partecke, Lars Ivo, and Vollmar, Brigitte
- Published
- 2015
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48. Specific impact of hyperglycaemia on the course of two different forms of chronic pancreatitis
- Author
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Müller-Graff, Tassilo, Knapp, Niklas, Fitzner, Brit, Jaster, Robert, Vollmar, Brigitte, and Zechner, Dietmar
- Published
- 2015
- Full Text
- View/download PDF
49. Characterization of novel carcinoma cell lines for the analysis of therapeutical strategies fighting pancreatic cancer.
- Author
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Zechner, Dietmar, Bürtin, Florian, Amme, Jonas, Lindner, Tobias, Radecke, Tobias, Hadlich, Stefan, Kühn, Jens-Peter, and Vollmar, Brigitte
- Subjects
- *
ANIMAL models in research , *PANCREATIC cancer , *ADENOCARCINOMA , *CELL lines , *IMMUNE system , *METASTASIS - Abstract
Background: Preclinical evaluations of chemotherapies depend on clinically relevant animal models for pancreatic cancer. The injection of syngeneic murine adenocarcinoma cells is one efficient option to generate carcinomas in mice with an intact immune system. However, this option is constrained by the paucity of appropriate cell lines. Results: The murine pancreatic adenocarcinoma cell lines 6606PDA and 7265PDA were compared to the 6606l cell line isolated from a liver metastasis from mice suffering from pancreatic cancer. In tissue culture 6606PDA and 6606l proliferated faster than 7265PDA. 7265PDA cells were, however, significantly more sensitive to gemcitabine as assessed by BrdU-incorporation and trypan blue exclusion assays in vitro. Within 1 week after injection of either one of these three cell lines into the pancreas of C57BL/6J mice, carcinomas were observed by T2 weighted magnetic resonance imaging and histology. Three weeks after injecting 6606PDA or 6606l cells large carcinomas could be characterized, which were surrounded by extensive desmoplastic reaction. After injection of 7265PDA cells, however, remission of cancer was observed between the first and the third week. Compared to 6606PDA cell derived carcinomas a higher apparent diffusion coefficient was quantified by diffusion weighted magnetic resonance imaging in these tumors. This correlated with reduced cancer cell density observed on histological sections. Conclusion: All three cell lines can be used in vitro for testing combinatorial therapies with gemcitabine. The 6606PDA and 6606l cell lines but not the 7265PDA cell line can be used for evaluating distinct therapies in a syngeneic carcinoma model using C57BL/6J mice. Diffusion-weighted MRI proved to be an appropriate method to predict tumor remission. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
50. Impact of diabetes type II and chronic inflammation on pancreatic cancer.
- Author
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Zechner, Dietmar, Radecke, Tobias, Amme, Jonas, Bürtin, Florian, Albert, Ann-Christin, Partecke, Lars Ivo, and Vollmar, Brigitte
- Abstract
Background: We explored if known risk factors for pancreatic cancer such as type II diabetes and chronic inflammation, influence the pathophysiology of an established primary tumor in the pancreas and if administration of metformin has an impact on tumor growth. Methods: Pancreatic carcinomas were assessed in a syngeneic orthotopic pancreas adenocarcinoma model after injection of 6606PDA cells in the pancreas head of either B6.V-Lepob/ob mice exhibiting a type II diabetes-like syndrome or normoglycemic mice. Chronic pancreatitis was then induced by repetitive administration of cerulein. Cell proliferation, cell death, inflammation and the expression of cancer stem cell markers within the carcinomas was evaluated by immunohistochemistry. In addition, the impact of the antidiabetic drug, metformin, on the pathophysiology of the tumor was assessed. Results: Diabetic mice developed pancreatic ductal adenocarcinomas with significantly increased tumor weight when compared to normoglycemic littermates. Diabetes caused increased proliferation of cancer cells, but did not inhibit cancer cell necrosis or apoptosis. Diabetes also reduced the number of Aldh1 expressing cancer cells and moderately decreased the number of tumor infiltrating chloracetate esterase positive granulocytes. The administration of metformin reduced tumor weight as well as cancer cell proliferation. Chronic pancreatitis significantly diminished the pancreas weight and increased lipase activity in the blood, but only moderately increased tumor weight. Conclusion: We conclude that diabetes type II has a fundamental influence on pancreatic ductal adenocarcinoma by stimulating cancer cell proliferation, while metformin inhibits cancer cell proliferation. Chronic inflammation had only a minor effect on the pathophysiology of an established adenocarcinoma. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
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