TY - THES A1 - Roth, Patrick T1 - Metalltricarbonyl-basierte CO-releasing molecules (CORMs): Variation der Freisetzungskinetik und Biokonjugation T1 - Metal tricarbonyl-based CO-releasing molecules (CORMs): Bioconjugation and modulation of CO-release kinetics N2 - Kohlenstoffmonoxid ist ein wichtiges kleines Signalmolekül das im menschlichen Körper durch die enzymatische Wirkung von Häm-Oxygenase (HO) auf Häm produziert wird. Für eine thera-peutische Anwendung werden Metallcarbonyl-Komplexe als CO-releasing molecules (CORMs) untersucht, die eine kontrollierte Freisetzung in biologischen Zielstrukturen erlauben. Dafür wird entweder die Ligandenperipherie ("drug sphere") modifiziert oder die CORMs an bio-molekulare Trägersysteme konjugiert. Im Rahmen dieser Arbeit stand dabei die lichtinduzierte Freisetzung von Kohlenstoffmonoxid aus Mangan(I)tricarbonyl-Komplexen im Vordergrund. Die oktaedrische Koordinationssphäre des Metallzentrums wurde dabei durch verschiedene faciale tridentate Liganden komplettiert, welche außerdem eine einfache und modulare Verknüpfung mit biologischen Träger-molekülen ermöglichen sollten. Als Chelatoren wurden Derivate von N,N-Bis(pyridin-2-ylmethyl)amin (bpa) ausgewählt, in denen das zentrale Stickstoffatom mit Alkylaminen unterschiedlicher Kettenlänge funktionalisiert ist, welche über Amid-Bindungen mit Carboxylat-modifizierten Trägermolekülen verknüpft werden können. Diesen bpa-Liganden sollte ein neuartiges Ligandensystem auf der Basis von N-(Phenanthridin-6-ylmethyl)-N-(chinolin-2-ylmethyl)ethan-1,2-diamin (pqen) gegenübergestellt werden, in denen die Phenanthridin-Gruppe interessante photophysikalische und photochemische Eigenschaften erwarten lässt. Die CO-releasing molecules sollten zudem mit den isostrukturellen Rhenium(I)tricarbonyl-Komplexen verglichen werden, die als Marker für die Fluoreszenz-mikroskopie dienen. N2 - In many organisms, carbon monoxide is generated in a controlled fashion by the degradation of heme by heme oxygenase (HO) enzymes. This small signaling molecule is involved in the control of blood pressure and possess anti-inflammatory, anti-apoptotic, and cytoprotective properties. However, a key issue is the tissue-specific delivery of carbon monoxide without concomitant formation of elevated toxic levels of CO in blood. In that context, metal carbonyl complexes show great potential for a safe CO delivery in a spatially and temporally well-controlled manner. Such CO-releasing molecules (CORMs) are composed of an inner "CORM sphere", which determines the CO release kinetics, and an outer "drug sphere", which controls bioavailability and tissue-specific uptake. In the context of this work, a series of photoactivatable CO-releasing molecules based on manganese(I) tricarbonyl groups was synthesized. In these systems, the octahedral coordination sphere of the metal center is completed by a variety of facial tridentate N^N^N ligands. Derivatives of bis(2-pyridylmethyl)amine (bpa) were selected as the chelator, in which the central tertiary nitrogen atom is functionalized with alkylamines of different chain lengths that can be linked to carboxylate-modified biological carrier molecules via amide bonds. The series of bpa ligands was contrasted with a novel ligand system based on N-(phenanthridin-6-ylmethyl)-N-(quinolin-2-ylmethyl)ethane-1,2-diamine (pqen), in which the phenanthridine group possesses interesting photophysical and photochemical properties. The series of CO-releasing molecules was complemented with the isostructural rhenium(I) tricarbonyl complexes, which might serve as markers for fluorescence microscopy. KW - Metallcarbonyle KW - Lumineszenz KW - Biomolekül KW - Organische Synthese KW - Reaktionskinetik KW - CO-releasing molecule KW - CORM KW - Magan(I)-Carbonylkomplexe KW - Rhenium(I)-Carbonylkomplexe KW - Biokonjugation KW - tissue targeting Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240171 ER - TY - JOUR A1 - Wobser, Marion A1 - Schummer, Patrick A1 - Appenzeller, Silke A1 - Kneitz, Hermann A1 - Roth, Sabine A1 - Goebeler, Matthias A1 - Geissinger, Eva A1 - Rosenwald, Andreas A1 - Maurus, Katja T1 - Panel sequencing of primary cutaneous B-cell lymphoma JF - Cancers N2 - Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin’s lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low propensity for systemic dissemination or fatal outcome. Up to now, only few studies have investigated underlying molecular alterations of PCFBCL with respect to somatic mutations. Objectives: Our aim was to gain deeper insight into the pathogenesis of PCFBCL and to delineate discriminatory molecular features of this lymphoma subtype. Methods: We performed hybridization-based panel sequencing of 40 lymphoma-associated genes of 10 cases of well-characterized PCFBCL. In addition, we included two further ambiguous cases of atypical B-cell-rich lymphoid infiltrate/B-cell lymphoma of the skin for which definite subtype attribution had not been possible by routine investigations. Results: In 10 out of 12 analyzed cases, we identified genetic alterations within 15 of the selected 40 target genes. The most frequently detected alterations in PCFBCL affected the TNFRSF14, CREBBP, STAT6 and TP53 genes. Our analysis unrevealed novel mutations of the BCL2 gene in PCFBCL. All patients exhibited an indolent clinical course. Both the included arbitrary cases of atypical B-cell-rich cutaneous infiltrates showed somatic mutations within the FAS gene. As these mutations have previously been designated as subtype-specific recurrent alterations in primary cutaneous marginal zone lymphoma (PCMZL), we finally favored the diagnosis of PCMZL in these two cases based on these molecular findings. Conclusions: To conclude, our molecular data support that PCFBCL shows distinct somatic mutations which may aid to differentiate PCFBCL from pseudo-lymphoma as well as from other indolent and aggressive cutaneous B-cell lymphomas. While the detected genetic alterations of PCFBCL did not turn out to harbor any prognostic value in our cohort, our molecular data may add adjunctive discriminatory features for diagnostic purposes on a molecular level. KW - B-cell lymphoma KW - primary cutaneous follicular B-cell lymphoma KW - targeted sequencing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290330 SN - 2072-6694 VL - 14 IS - 21 ER - TY - JOUR A1 - Guth, Sabine A1 - Hüser, Stephanie A1 - Roth, Angelika A1 - Degen, Gisela A1 - Diel, Patrick A1 - Edlund, Karolina A1 - Eisenbrand, Gerhard A1 - Engel, Karl-Heinz A1 - Epe, Bernd A1 - Grune, Tilman A1 - Heinz, Volker A1 - Henle, Thomas A1 - Humpf, Hans-Ulrich A1 - Jäger, Henry A1 - Joost, Hans-Georg A1 - Kulling, Sabine E. A1 - Lampen, Alfonso A1 - Mally, Angela A1 - Marchan, Rosemarie A1 - Marko, Doris A1 - Mühle, Eva A1 - Nitsche, Michael A. A1 - Röhrdanz, Elke A1 - Stadler, Richard A1 - van Thriel, Christoph A1 - Vieths, Stefan A1 - Vogel, Rudi F. A1 - Wascher, Edmund A1 - Watzl, Carsten A1 - Nöthlings, Ute A1 - Hengstler, Jan G. T1 - Contribution to the ongoing discussion on fluoride toxicity JF - Archives of Toxicology N2 - Since the addition of fluoride to drinking water in the 1940s, there have been frequent and sometimes heated discussions regarding its benefits and risks. In a recently published review, we addressed the question if current exposure levels in Europe represent a risk to human health. This review was discussed in an editorial asking why we did not calculate benchmark doses (BMD) of fluoride neurotoxicity for humans. Here, we address the question, why it is problematic to calculate BMDs based on the currently available data. Briefly, the conclusions of the available studies are not homogeneous, reporting negative as well as positive results; moreover, the positive studies lack control of confounding factors such as the influence of well-known neurotoxicants. We also discuss the limitations of several further epidemiological studies that did not meet the inclusion criteria of our review. Finally, it is important to not only focus on epidemiological studies. Rather, risk analysis should consider all available data, including epidemiological, animal, as well as in vitro studies. Despite remaining uncertainties, the totality of evidence does not support the notion that fluoride should be considered a human developmental neurotoxicant at current exposure levels in European countries. KW - pharmacology/toxicology KW - occupational medicine/industrial medicine KW - environmental health KW - biomedicine, general Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307161 SN - 0340-5761 SN - 1432-0738 VL - 95 IS - 7 ER -