References of "Hamdorf, Matthias 50001933"
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See detailModulation of the IL-6 signaling pathway in liver cells by miRNAs targeting gp130, JAK1 and/or STAT3
Servais, Florence UL; Kirchmeyer, Mélanie UL; Hamdorf, Matthias UL et al

in Molecular Therapy: Nucleic Acids (2019), 16

Interleukin-6 (IL-6)-type cytokines share the common receptor glycoprotein 130 (gp130), which activates a signaling cascade involving Janus kinases (JAKs) and signal transducer and activator of ... [more ▼]

Interleukin-6 (IL-6)-type cytokines share the common receptor glycoprotein 130 (gp130), which activates a signaling cascade involving Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) transcription factors. IL-6 and/or its signaling pathway is often deregulated in diseases, such as chronic liver diseases and cancer. Thus, the identification of compounds inhibiting this pathway is of interest for future targeted therapies. We established novel cellular screening systems based on a STAT-responsive reporter gene (Cypridina luciferase). Of a library containing 538 microRNA (miRNA) mimics, several miRNAs affected hyper-IL-6-induced luciferase activities. When focusing on candidate miRNAs specifically targeting 3' UTRs of signaling molecules of this pathway, we identified, e.g., miR-3677-5p as a novel miRNA affecting protein expression of both STAT3 and JAK1, whereas miR-16-1-3p, miR-4473, and miR-520f-3p reduced gp130 surface expression. Interestingly, combination treatment with 2 or 3 miRNAs targeting gp130 or different signaling molecules of the pathway did not increase the inhibitory effects on phospho-STAT3 levels and STAT3 target gene expression compared to treatment with single mimics. Taken together, we identified a set of miRNAs of potential therapeutic value for cancer and inflammatory diseases, which directly target the expression of molecules within the IL-6-signaling pathway and can dampen inflammatory signal transduction. [less ▲]

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See detailMiR-128 represses L1 retrotransposition by binding directly to L1 RNA
Hamdorf, Matthias UL; Idica, A.; Zisoulis, D. G. et al

in Nature Structural and Molecular Biology (2015), 22(10), 824-831

Long interspersed element 1 (LINE-1 or L1) retrotransposons compose 17% of the human genome. Active L1 elements are capable of replicative transposition (mobilization) and can act as drivers of genetic ... [more ▼]

Long interspersed element 1 (LINE-1 or L1) retrotransposons compose 17% of the human genome. Active L1 elements are capable of replicative transposition (mobilization) and can act as drivers of genetic diversity. However, this mobilization is mutagenic and may be detrimental to the host, and therefore it is under strict control. Somatic cells usually silence L1 activity by DNA methylation of the L1 promoter. In hypomethylated cells, such as cancer cells and induced pluripotent stem cells (iPSCs), a window of opportunity for L1 reactivation emerges, and with it comes an increased risk of genomic instability and tumorigenesis. Here we show that miR-128 represses new retrotransposition events in human cancer cells and iPSCs by binding directly to L1 RNA. Thus, we have identified and characterized a new function of microRNAs: mediating genomic stability by suppressing the mobility of endogenous retrotransposons. © 2015 Nature America, Inc. All rights reserved. [less ▲]

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See detailThe non-autonomous retrotransposon SVA is trans-mobilized by the human LINE-1 protein machinery
Raiz, J.; Damert, A.; Chira, S. et al

in Nucleic Acids Research (2012), 40(4), 1666-1683

SINE-VNTR-Alu (SVA) elements are non-autonomous, hominid-specific non-LTR retrotransposons and distinguished by their organization as composite mobile elements. They represent the evolutionarily youngest ... [more ▼]

SINE-VNTR-Alu (SVA) elements are non-autonomous, hominid-specific non-LTR retrotransposons and distinguished by their organization as composite mobile elements. They represent the evolutionarily youngest, currently active family of human non-LTR retrotransposons, and sporadically generate disease-causing insertions. Since preexisting, genomic SVA sequences are characterized by structural hallmarks of Long Interspersed Elements 1 (LINE-1, L1)-mediated retrotransposition, it has been hypothesized for several years that SVA elements are mobilized by the L1 protein machinery in trans. To test this hypothesis, we developed an SVA retrotransposition reporter assay in cell culture using three different human-specific SVA reporter elements. We demonstrate that SVA elements are mobilized in HeLa cells only in the presence of both L1-encoded proteins, ORF1p and ORF2p. SVA trans-mobilization rates exceeded pseudogene formation frequencies by 12-to 300-fold in HeLa-HA cells, indicating that SVA elements represent a preferred substrate for L1 proteins. Acquisition of an AluSp element increased the trans-mobilization frequency of the SVA reporter element by ∼25-fold. Deletion of (CCCTCT)n repeats and Alu-like region of a canonical SVA reporter element caused significant attenuation of the SVA trans-mobilization rate. SVA de novo insertions were predominantly full-length, occurred preferentially in G+C-rich regions, and displayed all features of L1-mediated retrotransposition which are also observed in preexisting genomic SVA insertions. © 2012 The Author(s). [less ▲]

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See detailEmploying live microbes for vaccine delivery
Loessner, Holger; Schwantes, Astrid; Hamdorf, Matthias UL et al

in Development of Novel Vaccines: Skills, Knowledge and Translational Technologies (2012)

The employment of live attenuated vaccines has a long-standing record in human and veterinary medicine. Most of the vaccines in current use were empirically developed during the last century. Today, due ... [more ▼]

The employment of live attenuated vaccines has a long-standing record in human and veterinary medicine. Most of the vaccines in current use were empirically developed during the last century. Today, due to the great advances in fields such as immunology and bioengineering, the rational development of live attenuated vaccines becomes increasingly feasible. Moreover, live vaccines can be used as carrier systems for heterologous antigens or therapeutic factors. In each case, the development of a recombinant live attenuated vaccine is a complex task where properties such as targeting specificity, antigen synthesis, antigen release, and safety aspects have to be integrated. A range of such recombinant vaccine candidates have successfully been tested in the clinics, but very few have been approved so far. In many cases, further optimization of such vaccines is necessary with regard to their efficacy and safety profiles. In the present chapter, we focus on current strategies which are employed for the development of new and the optimization of first generation recombinant live vaccines based on bacteria and viruses. © 2012 Springer-Verlag Wien. [less ▲]

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