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Berlin Brandenburg

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  • 1
    In: Pancreas, 2001, Vol.23(1), pp.72-79
    Description: BACKGROUND AND AIMS: Programmed cell death via the Fas receptor/Fas Ligand and DR4, DR5/TRAIL plays a major role in tumor escape and elimination mechanisms. It also promises to be an effective therapy alternative for aggressive tumors, as has been recently shown for colon, breast, and lung cancer cells. We attempted to clarify the role of these molecules in aggressivity of pancreatic carcinomas and to identify possible pathways as targets for therapy. METHODS: Five pancreatic cell lines were investigated for the expression of FasL/Fas, DcR3, DR4, DR5/TRAIL, DcR1, DcR2, and other death pathways related molecules such as Bax, bcl-xL, bcl-2, FADD, and caspase-3 by flow cytometry, immunoblotting, and RT/PCR, both semiquantitative and real time (TaqMan). The susceptibility of these cell lines to apoptosis mediated by recombinant TRAIL was investigated. The effect of therapeutic agents (gemcitabine) on their susceptibility to TRAIL induced apoptosis was studied as well. RESULTS: Pancreatic adenocarcinomas expressed high levels of apoptosis-inducing receptors and ligands. They showed differential susceptibility to cell death induced by TRAIL, despite expressing intact receptors and signaling machineries. Treatment with commonly used therapeutic agents did not augment their susceptibility to apoptosis. This could be explained by the fact that they expressed differentially high levels of decoy receptors, as well as molecules known as inhibitors of apoptosis. CONCLUSIONS: The data suggest that pancreatic carcinoma cells have developed different mechanisms to evade the immune system. One is the expression of nonfunctional receptors, decoy receptors, and molecules that block cell death, such as bcl2 and bcl-xL. The second is the expression of apoptosis-inducing ligands, such as TRAIL, that could induce cell death of immune cells. The success in treating malignant tumors by recombinant TRAIL might apply to some but not all pancreatic tumors because of their differential resistance to TRAIL-induced cell death.
    Keywords: Adenocarcinoma–Chemistry ; Antimetabolites, Antineoplastic–Pathology ; Apoptosis–Pharmacology ; Apoptosis Regulatory Proteins–Drug Effects ; Arabidopsis Proteins–Physiology ; Blotting, Western–Analysis ; Caspase 3–Analogs & Derivatives ; Caspases–Pharmacology ; Computer Systems–Analysis ; Deoxycytidine–Chemistry ; Fas Ligand Protein–Pathology ; Fatty Acid Desaturases–Chemistry ; Flow Cytometry–Pathology ; Gpi-Linked Proteins–Analysis ; Hela Cells–Pharmacology ; Humans–Physiology ; Jurkat Cells–Analysis ; Membrane Glycoproteins–Chemistry ; Neoplasm Proteins–Pathology ; Pancreatic Neoplasms–Analysis ; Proto-Oncogene Proteins–Analysis ; Proto-Oncogene Proteins C-Bcl-2–Analysis ; Receptors, Cell Surface–Analysis ; Receptors, Tnf-Related Apoptosis-Inducing Ligand–Pharmacology ; Receptors, Tumor Necrosis Factor–Chemistry ; Receptors, Tumor Necrosis Factor, Member 10c–Drug Effects ; Receptors, Tumor Necrosis Factor, Member 6b–Pathology ; Recombinant Proteins–Analysis ; Reverse Transcriptase Polymerase Chain Reaction–Pharmacology ; Tnf-Related Apoptosis-Inducing Ligand–Physiology ; Tumor Cells, Cultured–Analysis ; Tumor Necrosis Factor Decoy Receptors–Analysis ; Tumor Necrosis Factor-Alpha–Analysis ; Bcl-2-Associated X Protein–Analysis ; Bcl-X Protein–Analysis ; Fas Receptor–Analysis ; Antimetabolites, Antineoplastic ; Apoptosis Regulatory Proteins ; Arabidopsis Proteins ; Bax Protein, Human ; Bcl2l1 Protein, Human ; Faslg Protein, Human ; Fas Ligand Protein ; Gpi-Linked Proteins ; Membrane Glycoproteins ; Neoplasm Proteins ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins C-Bcl-2 ; Receptors, Cell Surface ; Receptors, Tnf-Related Apoptosis-Inducing Ligand ; Receptors, Tumor Necrosis Factor ; Receptors, Tumor Necrosis Factor, Member 10c ; Receptors, Tumor Necrosis Factor, Member 6b ; Recombinant Proteins ; Tnf-Related Apoptosis-Inducing Ligand ; Tnfrsf10a Protein, Human ; Tnfrsf10b Protein, Human ; Tnfrsf10c Protein, Human ; Tnfrsf6b Protein, Human ; Tnfsf10 Protein, Human ; Tumor Necrosis Factor Decoy Receptors ; Tumor Necrosis Factor-Alpha ; Bcl-2-Associated X Protein ; Bcl-X Protein ; Fas Receptor ; Deoxycytidine ; Gemcitabine ; Fatty Acid Desaturases ; Fad7 Protein, Arabidopsis ; Casp3 Protein, Human ; Caspase 3 ; Caspases;
    ISSN: 0885-3177
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  • 2
  • 3
    In: American Journal of Gastroenterology, 2010, Vol.105(9), pp.2060-2071
    Description: OBJECTIVES:: METHODS:: RESULTS:: Expression profiling showed 272 upregulated genes, including those encoding for immunoglobulins, chemokines and their receptors, and 86 downregulated genes, including those for pancreatic proteases such as three trypsinogen isoforms. Protein profiling showed that the expression of trypsinogens and other pancreatic enzymes was greatly reduced. Immunohistochemistry showed a near-loss of trypsin-positive acinar cells, which was also confirmed by western blotting. The serum of AIP patients contained high titers of autoantibodies against the trypsinogens PRSS1 and PRSS2 but not against PRSS3. In addition, there were autoantibodies against the trypsin inhibitor PSTI (the product of the SPINK1 gene). In the pancreas of AIP animals, we found similar protein patterns and a reduction in trypsinogen. CONCLUSIONS::
    Keywords: Medicine;
    ISSN: 0002-9270
    E-ISSN: 15720241
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  • 4
    Language: English
    In: Journal of the National Cancer Institute, Jan 6, 2010, Vol.102(1), p.127(7)
    Description: Metastases are responsible for cancer deaths, but the molecular alterations leading to tumor progression are unclear. Overexpression of the E2F1 transcription factor is common in high-grade tumors that are associated with poor patient survival. To investigate the association of enhanced E2F1 activity with aggressive phenotype, we performed a gene-specific silencing approach in a metastatic melanoma model. Knockdown of endogenous E2F1 via E2F1 small hairpin RNA (shRNA) expression increased E-cadherin expression of metastatic SK-Mel-147 melanoma cells and reduced their invasive potential but not their proliferative activity. Although growth rates of SK-Mel-147 and SK-Mel-103 xenograft tumors expressing E2F1 shRNA or control shRNA were similar, mice implanted with cells expressing E2F1 shRNA had a smaller area of metastases per lung than control mice (n=3 mice per group; 5% vs 46%, difference=41%, 95% confidence interval=15% to 67%; P = .01; one-way analysis of variance). We identified epidermal growth factor receptor as a direct target of E2F1 and demonstrated that inhibition of receptor signaling abrogates E2F1-induced invasiveness, emphasizing the importance of the E2F1-epidermal growth factor receptor interaction as a driving force in melanoma progression that may serve as a paradigm for E2F1-induced metastasis in other human cancers. DOI: 10.1093/jnci/djp458
    Keywords: Cancer Metastasis -- Genetic Aspects ; Cancer Metastasis -- Research ; Melanoma -- Research ; Melanoma -- Development And Progression ; Melanoma -- Genetic Aspects ; Epidermal Growth Factor Receptors -- Physiological Aspects ; Epidermal Growth Factor Receptors -- Genetic Aspects ; Epidermal Growth Factor Receptors -- Research
    ISSN: 0027-8874
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  • 5
    Language: English
    In: Cellular & Molecular Biology Letters, 2011, Vol.16(4), pp.515-538
    Description: ReNcell VM is an immortalized human neural progenitor cell line with the ability to differentiate in vitro into astrocytes and neurons, in which the Wnt/β-catenin pathway is known to be involved. However, little is known about kinetic changes of this pathway in human neural progenitor cell differentiation. In the present study, we provide a quantitative profile of Wnt/β-catenin pathway dynamics showing its spatio-temporal regulation during ReNcell VM cell differentiation. We show first that T-cell factor dependent transcription can be activated by stabilized β-catenin. Furthermore, endogenous Wnt ligands, pathway receptors and signaling molecules are temporally controlled, demonstrating changes related to differentiation stages. During the first three hours of differentiation the signaling molecules LRP6, Dvl2 and β-catenin are spatio-temporally regulated between distinct cellular compartments. From 24 h onward, components of the Wnt/β-catenin pathway are strongly activated and regulated as shown by mRNA up-regulation of Wnt ligands (Wnt5a and Wnt7a), receptors including Frizzled-2, -3, -6, -7, and -9, and co-receptors, and target genes including Axin2. This detailed temporal profile of the Wnt/β-catenin pathway is a first step to understand, control and to orientate, in vitro , human neural progenitor cell differentiation.
    Keywords: Wnt/β-catenin pathway ; Spatio-temporal dynamics ; Quantitative kinetics
    ISSN: 1425-8153
    E-ISSN: 1689-1392
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  • 6
    Language: English
    In: Clinical & Experimental Metastasis, 2010, Vol.27(3), pp.133-140
    Description: A large-scale gene expression study of melanoma metastases was performed to identify genes involved in late-stage tumor progression. Overall 248 genes, out of more than 47,000 tested, are differentially expressed when comparing peripheral areas (invasion front) with central tumor areas of melanoma metastases. As determined by gene ontology analysis, members of the STAT signaling pathway show significant enrichment. In particular, Stat1 is highly expressed in peripheral compared with central tumor areas. In line with this, stable knockdown of STAT1 in metastatic melanoma cells significantly impairs their migratory and invasive capacity in wounding and matrigel assays. Moreover, STAT1 knockdown affects the metastatic behavior of melanoma cells in a mouse model of melanoma metastasis. Taken together, these data suggest that Stat1 might play a role in late-stage melanoma progression. Interference with the Stat1 pathway could have therapeutic implications for late-stage melanoma patients.
    Keywords: Genomics ; Carcinogenesis ; Cell migration ; Mouse models
    ISSN: 0262-0898
    E-ISSN: 1573-7276
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  • 7
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(8), p.e70626
    Description: Interferon-β is an established treatment for patients with multiple sclerosis (MS) but its mechanisms of action are not well understood. Viral infections are a known trigger of MS relapses. Toll-like receptors (TLRs) are key components of the innate immune system, which sense conserved structures of viruses and other pathogens. Effects of interferon-β on mRNA levels of all known human TLRs (TLR1-10) and the TLR adaptor molecule MyD88 were analyzed in peripheral blood mononuclear cells (PBMCs) of healthy donors by quantitative real-time PCR and by transcriptome analysis in PBMCs of 25 interferon-β-treated patients with relapsing-remitting MS. Regulation of TLR protein expression by interferon-β was investigated by flow cytometry of leukocyte subsets of healthy subjects and of untreated, interferon-β-, or glatiramer acetate-treated patients with MS. Interferon-β specifically upregulated mRNA expression of TLR3, TLR7, and MyD88 and downregulated TLR9 mRNA in PBMCs of healthy donors as well as in PBMCs of patients with MS. Plasmacytoid dendritic cells (pDCs) were identified as the major cell type responding to interferon-β with increased expression of TLR7 and MyD88 protein. In line with this, expression of TLR7 protein was increased in pDCs of interferon-β-treated, but not untreated or glatiramer acetate-treated patients with MS. Interferon-β-induced upregulation of TLR7 in pDCs is of functional relevance since pre-treatment of PBMCs with interferon-β resulted in a strongly increased production of interferon-α upon stimulation with the TLR7 agonist loxoribine. Flow cytometry confirmed pDCs as the cellular source of interferon-α production induced by activation of TLR7. Thus, upregulation of TLR7 in pDCs and a consequently increased activation of pDCs by TLR7 ligands represents a novel immunoregulatory mechanism of interferon-β. We hypothesize that this mechanism could contribute to a reduction of virus-triggered relapses in patients with MS.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    In: Bioinformatics, 2005, Vol.21(8), pp.1737-1738
    Description: Summary: Genetic linkage and association studies define quantitative trait loci (QTLs) and susceptibility loci (SLs) that influence the phenotype of polygenic traits. A web-accessible application was created to identify intergenomic consensuses to fine map QTLs and SLs in silico and select particularly promising candidate genes for such traits. Furthermore, this approach offers an empirical evaluation of animal models for their applicability to the study of human traits. Availability: http://qtl.pzr.uni-rostock.de/qtlmix.php Contact: serrano@pzr.uni-rostock.de
    Keywords: Biology;
    ISSN: 1367-4803
    E-ISSN: 1460-2059
    E-ISSN: 13674811
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  • 9
    Language: English
    In: Cellular Immunology, 2005, Vol.237(2), pp.123-130
    Description: Experimental autoimmune encephalomyelitis (EAE) is widely regarded as an animal model of the human disease multiple sclerosis. A multitude of studies has investigated the neuroantigen-specific T-cell mediated cytokine pattern present in animals with EAE. In particular, the role of the so-called Th1- and Th2-cytokines has been addressed. In a recent study, it has been demonstrated that IL-23 rather than IL-12 is critical for modulating the character of the developing immune response towards a proinflammatory response and leading to EAE. IL-17 is a crucial effector cytokine, whose production is specifically triggered by IL-23, and it has been shown to be an essential inflammatory mediator in other autoimmune diseases and inflammatory conditions. This led us to investigate the role of IL-17 in EAE. Strong antigen-specific production of IL-17 was demonstrated both in peripheral immune organs and in the CNS in acute and chronic EAE, as demonstrated by ELISPOT and RT-PCR analysis. Therapeutic neutralization of IL-17 with IL-17-receptor-Fc-protein in acute EAE ameliorated clinical symptoms. Neutralization of IL-17 with a monoclonal antibody also ameliorated the disease course. We conclude that IL-17 is crucially involved in the cytokine network as an effector cytokine in EAE.
    Keywords: Eae ; Interleukin-17 ; Cytokines ; Myelin Oligodendrocyte Glycoprotein ; Autoimmune T-Cell Regulation ; Multiples Sclerosis ; Immunotherapy ; Medicine ; Biology
    ISSN: 0008-8749
    E-ISSN: 1090-2163
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  • 10
    Language: English
    In: BMC Genomics, 01 November 2017, Vol.18(1), pp.1-19
    Description: Abstract Background Many genes important for reproductive performance are shared by both sexes. However, fecundity indices are primarily based on female parameters such as litter size. We examined a fertility mouse line (FL2), which has a considerably increased number of offspring and a total litter weight of 180% compared to a randomly bred control line (Ctrl) after more than 170 generations of breeding. In the present study, we investigated whether there might be a parallel evolution in males after more than 40 years of breeding in this outbred mouse model. Results Males of the fertility mouse line FL2 showed reduced sperm motility performance in a 5 h thermal stress experiment and reduced birth rate in the outbred mouse line. Transcriptional analysis of the FL2 testis showed the differential expression of genes associated with steroid metabolic processes (Cyp1b1, Cyp19a1, Hsd3b6, and Cyp21a1) and female fecundity (Gdf9), accompanied by 150% elevated serum progesterone levels in the FL2 males. Cluster analysis revealed the downregulation of genes of the kallikrein-related peptidases (KLK) cluster located on chromosome 7 in addition to alterations in gene expression with serine peptidase activity, e.g., angiotensinogen (Agt), of the renin-angiotensin system essential for ovulation. Although a majority of functional annotations map to female reproduction and ovulation, these genes are differentially expressed in FL2 testis. Conclusions These data indicate that selection for primary female traits of increased litter size not only affects sperm characteristics but also manifests as transcriptional alterations of the male side likely with direct long-term consequences for the reproductive performance of the mouse line.
    Keywords: Long-Term Selection Mouse Lines ; Outbred Mouse Model ; High-Fertility ; Fecundity ; Testis ; Reproductive Fitness ; Biology
    E-ISSN: 1471-2164
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