TY - JOUR A1 - Zwink, Nadine A1 - Jenetzky, Ekkehart A1 - Schmiedeke, Eberhard A1 - Schmidt, Dominik A1 - Märzheuser, Schmidt A1 - Grasshoff-Derr, Sabine A1 - Holland-Cunz, Stefan A1 - Weih, Sandra A1 - Hosie, Stuart A1 - Reifferscheid, Peter A1 - Ameis, Helen A1 - Kujath, Christina A1 - Rissmann, Anke A1 - Obermayr, Florian A1 - Schwarzer, Nicole A1 - Bartels, Enrika A1 - Reutter, Heiko A1 - Brenner, Hermann T1 - Assisted reproductive techniques and the risk of anorectal malformations: a German case-control study JF - Orphanet Journal of Rare Diseases N2 - Background: The use of assisted reproductive techniques (ART) for treatment of infertility is increasing rapidly worldwide. However, various health effects have been reported including a higher risk of congenital malformations. Therefore, we assessed the risk of anorectal malformations (ARM) after in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Methods: Data of the German Network for Congenital Uro-REctal malformations (CURE-Net) were compared to nationwide data of the German IVF register and the Federal Statistical Office (DESTATIS). Odds ratios (95% confidence intervals) were determined to quantify associations using multivariable logistic regression accounting for potential confounding or interaction by plurality of births. Results: In total, 295 ARM patients born between 1997 and 2011 in Germany, who were recruited through participating pediatric surgeries from all over Germany and the German self-help organisation SoMA, were included. Controls were all German live-births (n = 10,069,986) born between 1997 and 2010. Overall, 30 cases (10%) and 129,982 controls (1%) were born after IVF or ICSI, which translates to an odds ratio (95% confidence interval) of 8.7 (5.9-12.6) between ART and ARM in bivariate analyses. Separate analyses showed a significantly increased risk for ARM after IVF (OR, 10.9; 95% CI, 6.2-19.0; P < 0.0001) as well as after ICSI (OR, 7.5; 95% CI, 4.6-12.2; P < 0.0001). Furthermore, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed strong associations with ART (ORs 4.9, 11.9 and 7.9, respectively). After stratification for plurality of birth, the corresponding odds ratios (95% confidence intervals) were 7.7 (4.6-12.7) for singletons and 4.9 (2.4-10.1) for multiple births. Conclusions: There is a strongly increased risk for ARM among children born after ART. Elevations of risk were seen after both IVF and ICSI. Further, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed increased risks in each group. An increased risk of ARM was also seen among both singletons and multiple births. KW - metaanalysis KW - in-vitro fertilization KW - reproductive medicine KW - anal atresia KW - imperforate anus KW - anorectal malformation KW - birth defects KW - prevalence KW - assisted reproductive techniques KW - congenital malformations KW - descriptive epidemiology KW - infants born KW - children born KW - IVF-methods KW - technology Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134036 VL - 7 IS - 65 ER - TY - JOUR A1 - Zaitseva, Olena A1 - Hoffmann, Annett A1 - Otto, Christoph A1 - Wajant, Harald T1 - Targeting fibroblast growth factor (FGF)-inducible 14 (Fn14) for tumor therapy JF - Frontiers in Pharmacology N2 - Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) and is activated by its ligand TNF-like weak inducer of apoptosis (TWEAK). The latter occurs as a homotrimeric molecule in a soluble and a membrane-bound form. Soluble TWEAK (sTWEAK) activates the weakly inflammatory alternative NF-κB pathway and sensitizes for TNF-induced cell death while membrane TWEAK (memTWEAK) triggers additionally robust activation of the classical NF-κB pathway and various MAP kinase cascades. Fn14 expression is limited in adult organisms but becomes strongly induced in non-hematopoietic cells by a variety of growth factors, cytokines and physical stressors (e.g., hypoxia, irradiation). Since all these Fn14-inducing factors are frequently also present in the tumor microenvironment, Fn14 is regularly found to be expressed by non-hematopoietic cells of the tumor microenvironment and most solid tumor cells. In general, there are three possibilities how the tumor-Fn14 linkage could be taken into consideration for tumor therapy. First, by exploitation of the cancer associated expression of Fn14 to direct cytotoxic activities (antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxic payloads, CAR T-cells) to the tumor, second by blockade of potential protumoral activities of the TWEAK/Fn14 system, and third, by stimulation of Fn14 which not only triggers proinflammtory activities but also sensitizes cells for apoptotic and necroptotic cell death. Based on a brief description of the biology of the TWEAK/Fn14 system and Fn14 signaling, we discuss the features of the most relevant Fn14-targeting biologicals and review the preclinical data obtained with these reagents. In particular, we address problems and limitations which became evident in the preclinical studies with Fn14-targeting biologicals and debate possibilities how they could be overcome. KW - agonistic antibodies KW - cell death KW - Fn14 KW - NFκB KW - TNF KW - TWEAK Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290238 SN - 1663-9812 VL - 13 ER - TY - JOUR A1 - Zaitseva, Olena A1 - Hoffmann, Annett A1 - Löst, Margaretha A1 - Anany, Mohamed A. A1 - Zhang, Tengyu A1 - Kucka, Kirstin A1 - Wiegering, Armin A1 - Otto, Christoph A1 - Wajant, Harald T1 - Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity JF - Frontiers in Immunology N2 - Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK. KW - agonistic antibodies KW - cell death KW - FcγR KW - Fn14 KW - NFκB KW - TNF receptor superfamily KW - TWEAK Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323116 VL - 14 ER - TY - JOUR A1 - Wollborn, Jakob A1 - Wunder, Christian A1 - Stix, Jana A1 - Neuhaus, Winfried A1 - Bruno, Rapahel R. A1 - Baar, Wolfgang A1 - Flemming, Sven A1 - Roewer, Norbert A1 - Schlegel, Nicolas A1 - Schick, Martin A. T1 - Phosphodiesterase-4 inhibition with rolipram attenuates hepatocellular injury in hyperinflammation in vivo and in vitro without influencing inflammation and HO-1 expression JF - Journal of Pharmacology and Pharmacotherapeutics N2 - Objective: To investigate the impact of the phophodiesterase-4 inhibition (PD-4-I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation. Materials and Methods: Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF-α) and LPS with or without PD-4-I. Results: Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-α and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I. Conclusion: Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation. KW - acute liver failure KW - endotoxemia KW - phosphodiesterase KW - rolipram KW - sepsis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149336 VL - 6 IS - 1 ER - TY - JOUR A1 - Winoto-Morbach, Supandi A1 - Ulrichs, Karin A1 - Leyhausen, Gaby A1 - Müller-Ruchholtz, Wolfgang T1 - New principle for large-scale preparation of purified human pancreas islets N2 - Because successful human islet transplantation requires large quantities of viable islets that must be separated from the highly immunogenic exocrine tissue and because handpicking is too time-consuming and laborious to be clinically relevant, a new approach for solving this problem has been established in rat models. It is based on the principle that magnetic microspheres (MMSs) coupled to lectins with binding specificity for the exocrine tissue portion are trapped in an electromagnetic field, thus providing effluent islets of a high degree of purity. In this study our aim was to adapt this princip'le to human islet preparations. In this context our prime interest was focused on a lectin suitable for human pancreatic tissue. Of 19 different lectins tested, only 1, Wisteria floribunda agglutinin (WFA), is suitable, as shown by immunofluorescence, MMS-Iectin binding, and magnetic separation KW - Immunbiologie Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45600 ER - TY - CHAP A1 - Winoto-Morbach, S. A1 - Ulrichs, Karin A1 - Müller-Ruchholtz, W. T1 - New Developments in Biodegradable Microspheres For Magnetic Separation Techniques N2 - No abstract available KW - Immunbiologie Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45712 ER - TY - JOUR A1 - Winoto-Morbach, S. A1 - Ulrichs, Karin A1 - Hering, BJ A1 - Leyhausen, G. A1 - Müller-Ruchholtz, W. T1 - Lectins for electromagnetic purification of islets from humans and large mammals N2 - No abstract available KW - Chirurgie Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45430 ER - TY - JOUR A1 - Winoto-Morbach, S. A1 - Leyhausen, G. A1 - Schünke, M. A1 - Ulrichs, Karin A1 - Müller-Buchholtz, W. T1 - Magnetic microspheres (MMS) coupled to selective lectins: a new tool for large-scale extraction and purification of human pancreatic islets N2 - No abstract available KW - Chirurgie Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-44789 ER - TY - JOUR A1 - Winoto-Morbach, S. A1 - Leyhausen, G. A1 - Müller-Ruchholtz, W. A1 - Ulrichs, Karin T1 - The Electromagnetic Separation Principle: A Basis for Human Pancreatic Islet Transplantation N2 - No abstract available KW - Allergie Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-82520 ER - TY - JOUR A1 - Winoto-Morbach, S. A1 - Krout, OS A1 - Heiser, A. A1 - Ulrichs, Karin A1 - Müller-Ruchholtz, W. T1 - Lectin binding to acinar tissue for complete magnetophoretic purification of porcine pancreatic islets depends on the composition and pH of the incubation medium N2 - No abstract available KW - Chirurgie Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45183 ER -