@article{BriestGrassSeddingetal.2017,
  author    = {Briest, Franziska and Grass, Irina and Sedding, Dagmar and Moebs, Markus and Christen, Friederike and Benecke, Joana and Fuchs, Karolin and Mende, Stefanie and Kaemmerer, Daniel and S{\"a}nger, J{\"o}rg and Kunze, Almut and Geisler, Christina and Freitag, Helma and Lewens, Florentine and Worpenberg, Lina and Iwaszkiewicz, Sara and Siegmund, Britta and Walther, Wolfgang and Hummel, Michael and Grabowski, Patricia},
  title     = {Mechanisms of Targeting the MDM2-p53-FOXM1 Axis in Well-Differentiated Intestinal Neuroendocrine Tumors},
  series = {Neuroendocrinology : international journal for basic and clinical studies on neuroendocrine relationships},
  volume    = {107},
  journal   = {Neuroendocrinology : international journal for basic and clinical studies on neuroendocrine relationships},
  number    = {1},
  publisher = {Karger},
  address   = {Basel},
  issn      = {0028-3835},
  doi       = {10.1159/000481506},
  pages     = {1 -- 23},
  year      = {2017},
  abstract  = {Background/Aims: The tumor suppressor p53 is rarely mutated in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) but they frequently show a strong expression of negative regulators of p53, rendering these tumors excellent targets for a p53 recovery therapy. Therefore, we analyzed the mechanisms of a p53 recovery therapy on intestinal neuroendocrine tumors in vitro and in vivo. Methods: By Western blot and immunohistochemistry, we found that in GEP-NEN biopsy material overexpression of MDM2 was present in intestinal NEN. Therefore, we analyzed the effect of a small-molecule inhibitor, nutlin-3a, in p53 wild-type and mutant GEP-NEN cell lines by proliferation assay, flow cytometry, immunofluorescence, Western blot, and by multiplex gene expression analysis. Finally, we analyzed the antitumor effect of nutlin-3a in a xenograft mouse model in vivo. During the study, the tumor volume was determined. Results: The midgut wild-type cell line KRJ-I responded to the treatment with cell cycle arrest and apoptosis. By gene expression analysis, we could demonstrate that nutlins reactivated an antiproliferative p53 response. KRJ-I-derived xenograft tumors showed a significantly decreased tumor growth upon treatment with nutlin-3a in vivo. Furthermore, our data suggest that MDM2 also influences the expression of the oncogene FOXM1 in a p53-independent manner. Subsequently, a combined treatment of nutlin-3a and cisplatin (as chemoresistance model) resulted in synergistically enhanced antiproliferative effects. Conclusion: In summary, MDM2 overexpression is a frequent event in p53 wild-type intestinal neuroendocrine neoplasms and therefore recovery of a p53 response might be a novel personalized treatment approach in these tumors. (c) 2017 S. Karger AG, Basel},
  language  = {en}
}
@misc{RodriguezSillkeSteinhoffBojarskietal.2019,
  author    = {Rodriguez-Sillke, Yasmina and Steinhoff, U. and Bojarski, Christian and Lissner, Donata and Schumann, Michael and Branchi, F. and Siegmund, Britta and Glauben, Rainer},
  title     = {Deep immune profiling of human Peyer´s Patches in patients of inflammatory bowel diseases},
  series = {European journal of immunology},
  volume    = {49},
  journal   = {European journal of immunology},
  publisher = {Wiley},
  address   = {Weinheim},
  issn      = {0014-2980},
  doi       = {10.1002/eji.201970300},
  pages     = {203 -- 204},
  year      = {2019},
  language  = {en}
}
@article{WuHanRodriguezSillkeetal.2019,
  author    = {Wu, Hao and Han, Yijie and Rodriguez Sillke, Yasmina and Deng, Hongzhang and Siddiqui, Sophiya and Treese, Christoph and Schmidt, Franziska and Friedrich, Marie and Keye, Jacqueline and Wan, Jiajia and Qin, Yue and K{\"u}hl, Anja A. and Qin, Zhihai and Siegmund, Britta and Glauben, Rainer},
  title     = {Lipid droplet-dependent fatty acid metabolism controls the immune suppressive phenotype of tumor-associated macrophages},
  series = {EMBO molecular medicine},
  volume    = {11},
  journal   = {EMBO molecular medicine},
  number    = {11},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {1757-4676},
  doi       = {10.15252/emmm.201910698},
  pages     = {17},
  year      = {2019},
  abstract  = {Tumor-associated macrophages (TAMs) promote tumor growth and metastasis by suppressing tumor immune surveillance. Herein, we provide evidence that the immunosuppressive phenotype of TAMs is controlled by long-chain fatty acid metabolism, specifically unsaturated fatty acids, here exemplified by oleate. Consequently, en-route enriched lipid droplets were identified as essential organelles, which represent effective targets for chemical inhibitors to block in vitro polarization of TAMs and tumor growth in vivo. In line, analysis of human tumors revealed that myeloid cells infiltrating colon cancer but not gastric cancer tissue indeed accumulate lipid droplets. Mechanistically, our data indicate that oleate-induced polarization of myeloid cells depends on the mammalian target of the rapamycin pathway. Thus, our findings reveal an alternative therapeutic strategy by targeting the pro-tumoral myeloid cells on a metabolic level.},
  language  = {en}
}
@misc{RodriguezSillkeSchumannLissneretal.2020,
  author    = {Rodr{\´i}guez Sillke, Yasmina and Schumann, Michael and Lissner, Donata and Branchi, Frederica and Glauben, Rainer and Siegmund, Britta},
  title     = {Small intestinal inflammation but not colitis drives pro-inflammatory nutritional antigen-specific T-cell response},
  series = {Journal of Crohn's and Colitis},
  volume    = {14},
  journal   = {Journal of Crohn's and Colitis},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {1873-9946},
  doi       = {10.1093/ecco-jcc/jjz203.172},
  pages     = {S154 -- S155},
  year      = {2020},
  abstract  = {Background: Inflammatory bowel disease (IBD) represents a dysregulation of the mucosal immune system. The pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) is linked to the loss of intestinal tolerance and barrier function. The healthy mucosal immune system has previously been shown to be inert against food antigens. Since the small intestine is the main contact surface for antigens and therefore the immunological response, the present study served to analyse food-antigen-specific T cells in the peripheral blood of IBD patients. Methods: Peripheral blood mononuclear cells of CD, with an affected small intestine, and UC (colitis) patients, either active or in remission, were stimulated with the following food antigens: gluten, soybean, peanut and ovalbumin. Healthy controls and celiac disease patients were included as controls. Antigen-activated CD4+ T cells in the peripheral blood were analysed by a magnetic enrichment of CD154+ effector T cells and a cytometric antigen-reactive T-cell analysis ('ARTE' technology) followed by characterisation of the ef- fector response. Results: The effector T-cell response of antigen-specific T cells were compared between CD with small intestinal inflammation and UC where inflammation was restricted to the colon. Among all tested food antigens, the highest frequency of antigen-specific T cells (CD4+CD154+) was found for gluten. Celiac disease patients were included as control, since gluten has been identified as the disease- causing antigen. The highest frequency of gluten antigen-specific T cells was revealed in active CD when compared with UC, celiac disease on a gluten-free diet (GFD) and healthy controls. Ovalbuminspecific T cells were almost undetectable, whereas the reaction to soybean and peanut was slightly higher. But again, the strong- est reaction was observed in CD with small intestinal involvement compared with UC. Remarkably, in celiac disease on a GFD only antigen-specific cells for gluten were detected. These gluten-specific T cells were characterised by up-regulation of the pro-inflammatory cytokines IFN-γ, IL-17A and TNF-α. IFN-g was exclusively elevated in CD patients with active disease. Gluten-specific T-cells expressing IL-17A were increased in all IBD patients. Furthermore, T cells of CD patients, independent of disease activity, revealed a high expression of the pro-inflammatory cytokine TNF-α. Conclusion: The 'ARTE'-technique allows to analyse and quantify food antigen specific T cells in the peripheral blood of IBD patients indicating a potential therapeutic insight. These data provide evidence that small intestinal inflammation in CD is key for the development of a systemic pro-inflammatory effector T-cell response driven by food antigens.},
  language  = {en}
}