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Therapiepräferenzen in der Adjuvanz des malignen Melanoms: eine qualitative Analyse
Get PDFDie adjuvante Behandlung des malignen Melanoms hat sich im letzten Jahrzehnt deutlich weiterentwickelt, insbesondere durch Immuncheckpointinhibitoren und zielgerichtete Substanzen. Sie erfolgt nach operativer Resektion und ist angezeigt, wenn eine Metastasierung nicht ausgeschlossen werden kann. Sie verlängert das Überleben und senkt das Rückfallrisiko, birgt jedoch potenziell schwere Nebenwirkungen. Daher ist eine sorgfältige Abwägung von Chancen und Risiken erforderlich, unter Einbezug medizinischer Faktoren und individueller Präferenzen. Voraussetzung dafür ist eine vertrauensvolle Arzt-Patienten-Kommunikation. Im Rahmen der GERMELATOX-Studie wurden Patientenpräferenzen zur adjuvanten Therapie qualitativ untersucht. Aufbauend auf einer quantitativen Befragung wurden 17 semistrukturierte Interviews geführt und nach Mayring ausgewertet. Die Ergebnisse lassen sich in vier thematische Cluster gliedern: Therapieform und -ablauf, Lebensgestaltung, Gefühle und Empfinden sowie methodisches Vorgehen. Die Erfolgsaussicht war der wichtigste Entscheidungsfaktor. Rezidivfreies Überleben wurde oft dem Gesamtüberleben gleichgesetzt. Es bestanden klare Präferenzen hinsichtlich oraler oder intravenöser Gabe. Mit zunehmenden Nebenwirkungen sank die empfundene Erträglichkeit, während Erwartungen an die Wirksamkeit stiegen. Ängste vor Organschäden oder Rückfällen prägten das Erleben stark. Der Wunsch nach Selbstbestimmung und hoher Lebensqualität war zentral. Ältere Patienten waren zurückhaltender, besonders bei geringer Erfolgserwartung. Frühere Erfahrungen mit Krebstherapien beeinflussten die Einstellung ebenfalls. Die Ergebnisse zeigen eine hohe, aber abwägende Therapiebereitschaft. Die Einbindung individueller Präferenzen ist entscheidend für eine passende, vertrauensvolle Therapieentscheidung
The Direct Pd-Catalyzed γ-Lactonization of Aliphatic Carboxylic Acids
Get PDFA direct palladium-catalyzed γ-lactonization of free carboxylic acids via C–O reductive elimination as a key step is described. Notable aspects of this protocol include the use of convenient and easily available sodium percarbonate as an oxidant and the development of a highly efficient β-alanine-derived ligand. The reported method enables the functionalization of a wide range of aliphatic acids including previously inaccessible β-non-quaternary acids. The regioselectivity and consequently substrate scope of this protocol proved complementary to established routes for the direct lactonization of aliphatic carboxylic acids. Through this report, a valuable compound library of γ-lactones with potential applications in various fields has become available
SOX10-Mediated Regulation of Enteric Glial Phenotype in vitro and its Relevance for Neuroinflammatory Disorders
Get PDFThe transcription factor SOX10 is a key regulator of myelinated glial cell phenotype and function, with a known role in multiple sclerosis (MS). SOX10 is also expressed in enteric glial cells (EGC) within the gut, yet its regulatory functions in EGC remain poorly understood. This study aimed to identify SOX10 target genes that influence EGC phenotype and may have implications for MS. An EGC cell line was established for doxycycline-inducible SOX10 overexpression. Impact of SOX10 overexpression on EGC phenotype was assessed by genome-wide expression analysis and results were validated via RT-qPCR and western blot. Data were compared with SOX10 ChIP-seq and transcriptomic datasets from MS patients to identify pan-glial SOX10 target genes potentially linked to neuroinflammatory disorders. SOX10 overexpression was associated with ectopic upregulation of genes related to myelin regulation and glial differentiation, as evidenced by increased PLP1 expression at mRNA and protein levels. Comparison to ChIP-seq and MS datasets highlight SOX10 target genes, including PLP1, RNF130, NES and APOD potentially involved in central and peripheral manifestations of MS pathology. Our findings support a cell-specific regulation of EGC phenotype through SOX10 expression level and identify SOX10-regulated genes relevant to EGC function. This research advances the understanding of EGC diversity and provide information about glial cells targeting in neuroinflammatory disorders
Physikalische Gasphasenabscheidung von Eisen(II)-Komplexen auf Basis von Azolat-Liganden
No full textIn this work, several new spin-crossover complexes, mostly based on azolate ligands, were designed and synthesised. An important part of the design of new spin-crossover compounds is the prediction of the spin transition temperature of a designed complex. The quantum mechanical calculations performed in this work follow a protocol divised by FLÖSER in previous works, which is shortly presented in the beginning of this work. The following three chapters describe the design processes, synthetic approaches and modifications of various complexes ordered by their constitution, starting with complexes based on three bidentate ligands. Here, a new complex based on a substituted pyridyl pyrrolide was found to show a profound difference in its spin state behaviour depending on whether it is investigated in the bulk material or in thin films. Afterwards, multiple modifications in the form of alternate substituents and heterocycles and their influence on the spin-crossover behaviour of the complexes are discussed. Tridentate ligands, which offer higher stability and synthetic advantages, are the focus of the fifth chapter. As an exception to the general rule, it starts with two studies on a complex based on a pyrazolyl borate ligand, which was supported by quantum mechanical calculations by the author of this work, before proceeding to the design, synthesis, investigation and modification of tridentate pyridyl azolate ligands. Based on these investigations, the development of complexes that show light-induced spincrossover at relatively high temperatures may be within reach. Finally, as an outlook to future research, some general principles as well as some first attempts to design and synthesise coordination polymers are described in the sixth chapter of this work. The goal of this work is to obtain spin-crossover complexes on surfaces that retain the desirable properties that are typically only observed in the solid state
Cysteine-Directed Isobaric Labeling Combined with GeLC-FAIMS-MS for Quantitative Top-Down Proteomics
Get PDFThe quantification of proteoforms, i.e., all molecular forms in which proteins can be present, by top-down proteomics provides essential insights into biological processes at the molecular level. Isobaric labeling-based quantification strategies are suitable for multidimensional separation strategies and allow for multiplexing of the samples. Here, we investigated cysteine-directed isobaric labeling by iodoTMT in combination with a gel- and gas-phase fractionation (GeLC-FAIMS-MS) for in-depth quantitative proteoform analysis. We optimized the acquisition workflow (i.e., the FAIMS compensation voltages, isolation windows, acquisition strategy, and fragmentation method) using a two-proteome mix to increase the number of quantified proteoforms and reduce ratio compression. Additionally, we implemented a mass feature-based quantification strategy in the widely used deconvolution algorithm FLASHDeconv, which improves and facilitates data analysis. The optimized iodoTMT GeLC-FAIMS-MS workflow was applied to quantitatively analyze the proteome of Escherichia coli grown under glucose or acetate as the sole carbon source, resulting in the identification of 726 differentially abundant proteoforms
Gut microbiota and type 2 diabetes associations: a meta-analysis of 16S studies and their methodological challenges
Get PDFDiabetes mellitus is a prevalent chronic non-communicable disease, and recent studies have explored the link between gut microbiota and its development. Despite some evidence suggesting an association, the influence of gut microbiota on type 2 diabetes (T2D) remains unclear. A systematic search of PubMed (January 2016– December 2023) using the keywords “16S” and “diabetes” or “DM2” or “T2DM” or “T2D” and “gut microbiota” and “diabetes” or “DM2” or “T2DM” or “T2D”. The studies included compared gut microbiome diversity between diabetic and non-diabetic adults using 16S rRNA sequencing, excluding children, interventions, and type 1 diabetes. Alpha diversity indices and bacterial mean abundance were analyzed, with statistical assessments using a random-effects model and I2 for heterogeneity. Thirteen studies met the criteria, with the Shannon index being the most commonly used measure. Results showed significant heterogeneity (I2 > 75%) and no notable differences between diabetic and non-diabetic groups. Other indices, such as Chao1 and phylogenetic whole tree, similarly showed no consistent differences. Taxonomic analysis also failed to find phyla consistently correlated with T2D, with variability across studies. The relationship between gut microbiota and diabetes remains uncertain due to technical and biological factors that are often overlooked. The inconsistencies across studies highlight the low reproducibility common in microbiota research
Zur Implementierung eines digitalen Lernprogramms im Fach Mathematik: Determinanten des Übungsverhaltens und Effekte auf Leistung, Selbstkonzept und Angst
No full textAcquiring mathematical competencies is essential for students’ successful participation in modern society. In light of declining mathematic performance and increasing achievement disparities in countries such as Germany, digital learning programs have been discussed as cost-effective and easily implementable solutions. However, empirical studies have yielded mixed and often disappointing results. One explanation may be that previous research focused mainly on program provision, without considering students’ actual practice behavior or effects beyond performance, such as on affect and motivation. This dissertation addresses these gaps by pursuing two objectives: (1) to investigate whether individual student characteristics—such as prior mathematic knowledge, personality traits, affective-motivational factors, and family background—predict practice behavior in a digital mathematic learning program; and (2) to examine how this behavior relates to academic performance, mathematic self-concept, and mathematic anxiety. Three empirical studies and two replication analyses were conducted using data from two program implementation periods (Math Garden; 22—45 weeks), involving up to 829 fifth-grade students. Practice behavior was objectively measured using process data from the program. Results indicate that students with higher levels of mathematic anxiety and those with a migration background practiced significantly less. Performance improvements were not linked to program provision per se, but rather to the actual amount of practice. In contrast, positive effects on students’ mathematic self-concept were observed independently of their practice behavior, while no significant effects on mathematic anxiety were found. Overall, the findings highlight the importance of sustained engagement with digital programs and the need for pedagogical support—particularly for students at risk of disengagement
Proteolytic regulation and functional repertoire of soluble ADAM17
Get PDFADAM17 is a membrane-bound zinc metalloprotease. It is one of the major sheddases that plays a key role in cellular events like tumorigenesis, inflammation, and cell homeostasis by cleaving ectodomains of membrane-bound proteins such as Tumor necrosis factor-α, Interleukin-6 receptor, and Epidermal growth factor receptor ligands. The inactivated rhomboid proteins (iRhoms) 1 and 2 are indispensable for the trafficking and maturation of ADAM17. Additionally, iRhom1 and 2 are involved in substrate recruitment and specificity on the cell surface for membrane-bound ADAM17. Intriguingly, the proteolytic release of the ADAM17 ectodomain (sADAM17) has recently been addressed, with ADAM8 identified as its sheddase. In this thesis, the proteolytic release of sADAM17 was analyzed via in vitro experiments for endogenous and overexpressed, human and murine ADAM17. Further, the role of iRhom1/2 was explored in ADAM17 shedding and its subsequent maturation and activation. In contrast to membrane-bound ADAM17, sADAM17 matures and activates independently of iRhoms, attaining necessary PTMs. The second part of the thesis addressed functional aspects of sADAM17. A persisting shedding capacity of sADAM17 was detected in vitro against EGFR ligands in a substrate-dependent manner, compared to its membrane-bound counterpart. The shedding of AREG and HB-EGF by sADAM17 appeared to be independent of iRhom1/2, unlike that by membrane-bound ADAM17. Finally, the application of N-terminomics in TNBC cells revealed further substrates and potential roles of sADAM17 in extracellular matrix remodeling and subsequent invasion and metastasis. These findings indicate a novel regulatory mechanism of sADAM17, demonstrating its ability to process substrates near the plasma membrane and beyond. These insights enhance understanding of the molecular mechanisms underlying sADAM17-mediated cellular functions and disease pathways, while highlighting its part-time sheddase properties
Crahmer und Planert in Sápmi: Eine Archivrecherche zu den Akteuren hinter der sámischen Sammlung am Museum Europäischer Kulturen
Get PDFDas Museum Europäischer Kulturen (MEK) in Berlin besitzt eine der bedeutendsten sámischen Sammlungen außerhalb Nordeuropas. Einen wesentlichen Teil dieser Sammlung erwarben Wilhelm Crahmer und Wilhelm Planert im Jahr 1912, als sie 108 Objekte aus Sápmi nach Berlin brachten. Trotz ihrer kulturhistorischen Relevanz ist die Sammlung bislang kaum dokumentiert. Die vorliegende Arbeit untersucht anhand bislang unbeachteter Archivquellen die Hintergründe und Motive der beiden Sammler. Entgegen früherer Annahmen zeigt sich, dass es sich bei Crahmer und Planert nicht um ausgewiesene Experten, sondern um junge Museumsassistenten mit begrenzter Erfahrung handelte, deren Sammelaktivitäten stark von persönlichem Ehrgeiz geprägt waren. Die Arbeit reflektiert zudem die Rolle nicht-indigener Forschender in der Auseinandersetzung mit indigener materieller Kultur und beleuchtet die ethischen Herausforderungen der Provenienzforschung im kolonialen Kontext. Durch die Rekonstruktion der Erwerbungsgeschichte leistet die Studie einen Beitrag zur Provenienzaufarbeitung der Sammlung und bietet eine Grundlage für zukünftige Diskussionen über Rückgaben. Die Ergebnisse unterstreichen die Notwendigkeit enger Zusammenarbeit mit sámischen Partner*innen für weiterführende Forschungen.The Museum Europäischer Kulturen (MEK) in Berlin holds one of the most important Sámi collections outside Northern Europe. A significant part of this collection was acquired in 1912 by Wilhelm Crahmer and Wilhelm Planert, who brought 108 artefacts from Sápmi to Berlin. Despite the collection’s historical and cultural relevance, it remains largely undocumented. This thesis examines the backgrounds and motivations of Crahmer and Planert, drawing on overlooked archival sources. Contrary to earlier assumptions of their expertise, the research reveals that both were young museum assistants lacking significant field experience. Their collecting activities were driven more by personal ambition than scholarly commitment. The study also reflects on the role of non-Indigenous researchers working with Indigenous heritage and discusses the ethical challenges of provenance research in colonial contexts. By shedding light on the institutional history and acquisition context, this work contributes to a better understanding of the collection’s provenance and offers a basis for future repatriation discussions. The findings underscore the necessity of collaborative research with Sámi partners for any further in-depth study of the collection
Plasmaproteinbindung und Prostatakarzinomzell-Uptake der Radiopharmaka 68Ga-PSMA-11 und 177Lu-PSMA-617 in Abhängigkeit von der Konzentration des kalten Präkursors
Get PDFDas Prostatakarzinom ist die am häufigsten diagnostizierte Krebserkrankung bei Männern. Die Positronen-Emissions-Tomographie (PET) und die Radioligandentherapie haben hierbei einen zunehmenden Stellenwert. Für die Diagnostik wird 68Gallium mit PSMA-11 und für die Therapie 177Lutetium mit PSMA-617 synthetisiert. Ziel dieser Arbeit war es, die Abhängigkeit der Plasmaproteinbindung und des Prostatakarzinomzell-Uptakes der Radiopharmaka von der Präkursor-Konzentration zu untersuchen. Die Plasmaproteinbindung der jeweiligen Radiopharmaka wurde mittels Ultrafiltration an Humanplasma bestimmt. Die zelluläre Aufnahme der Radiopharmaka wurde an kultivierten, PSMA-positiven LNCaP-Zellen sowie zusätzlich an PSMA‑negativen PC-3-Zellen untersucht. Die in-vitro Plasmaproteinbindung von 68Ga -PSMA-11 lag bei PSMA-11-Konzentrationen zwischen 7,5 und 100 µg/GBq im annähernd gleichen Bereich (42,0 – 42,6 %). Erst bei sehr hohen Präkursor-Konzentrationen (≥ 500 µg/GBq) zeigte sich eine geringe, jedoch nicht signifikante Abnahme. Der Zell-Uptake sank hingegen mit steigender Konzentration signifikant. Die Plasmaproteinbindung von 177Lu-PSMA-617 lag bei den untersuchten Präkursor-Konzentrationen im gleichen Bereich ohne signifikante Änderungen (78 – 79 %). Niedrige PSMA-11-Konzentrationen zwischen 7,5 und 15 µg/GBq zeigten das höchste Verhältnis von Zell-Uptake zu Plasmaproteinbindung und damit die theoretisch günstigsten in-vitro-Eigenschaften für die PET-Diagnostik des Prostatakarzinoms. Die Veränderung der Präkursor-Konzentration ist anhand der Untersuchungen keine effektive Möglichkeit, um die Plasmaproteinbindung zu erhöhen und damit die therapeutische Wirksamkeit der Radioligandentherapie mit 177Lu-PSMA-617 zu steigern