TY - THES A1 - Berberich, Oliver T1 - Lateral Cartilage Tissue Integration - Evaluation of Bonding Strength and Tissue Integration \(in\) \(vitro\) Utilizing Biomaterials and Adhesives T1 - Laterale Knorpelintegration - Beurteilung der Adhäsionskraft und der Gewebeintegration \(in\) \(vitro\) unter Verwendung verschiedener Biomaterialien und Gewebekleber N2 - Articular cartilage defects represent one of the most challenging clinical problem for orthopedic surgeons and cartilage damage after trauma can result in debilitating joint pain, functional impairment and in the long-term development of osteoarthritis. The lateral cartilage-cartilage integration is crucial for the long-term success and to prevent further tissue degeneration. Tissue adhesives and sealants are becoming increasingly more popular and can be a beneficial approach in fostering tissue integration, particularly in tissues like cartilage where alternative techniques, such as suturing, would instead introduce further damage. However, adhesive materials still require optimization regarding the maximization of adhesion strength on the one hand and long-term tissue integration on the other hand. In vitro models can be a valuable support in the investigation of potential candidates and their functional mechanisms. For the conducted experiments within this work, an in vitro disc/ring model obtained from porcine articular cartilage tissue was established. In addition to qualitative evaluation of regeneration, this model facilitates the implementation of biomechanical tests to quantify cartilage integration strength. Construct harvesting for histology and other evaluation methods could be standardized and is ethically less questionable compared to in vivo testing. The opportunity of cell culture technique application for the in vitro model allowed a better understanding of cartilage integration processes. Tissue bonding requires chemical or physical interaction of the adhesive material and the substrate. Adhesive hydrogels can bind to the defect interface and simultaneously fill the gap of irregularly shaped defect voids. Fibrin gels are derived from the physiological blood-clot formation and are clinically applied for wound closure. Within this work, comparisons of different fibrin glue formulations with the commercial BioGlue® were assessed, which highlighted the need for good biocompatibility when applied on cartilage tissue in order to achieve satisfying long-term integration. Fibrin gel formulations can be adapted with regard to their long-term stability and when applied on cartilage disc/ring constructs improved integrative repair is observable. The kinetic of repairing processes was investigated in fibrin-treated cartilage composites as part of this work. After three days in vitro cultivation, deposited extracellular matrix (ECM) was obvious at the glued interface that increased further over time. Interfacial cell invasion from the surrounding native cartilage was detected from day ten of tissue culture. The ECM formation relies on molecular factors, e.g., as was shown representatively for ascorbic acid, and contributes to increasing integration strengths over time. The experiments performed with fibrin revealed that the treatment with a biocompatible adhesive that allows cartilage neosynthesis favors lateral cartilage integration in the long term. However, fibrin has limited immediate bonding strength, which is disadvantageous for use on articular cartilage that is subject to high mechanical stress. The continuing aim of this thesis was to further develop adhesive mechanisms and new adhesive hydrogels that retain the positive properties of fibrin but have an increased immediate bonding strength. Two different photochemical approaches with the advantage of on-demand bonding were tested. Such treatment potentially eases the application for the professional user. First, an UV light induced crosslinking mechanism was transferred to fibrin glue to provide additional bonding strength. For this, the cartilage surface was functionalized with highly reactive light-sensitive diazirine groups, which allowed additional covalent bonds to the fibrin matrix and thus increased the adhesive strength. However, the disadvantages of this approach were the multi-step bonding reactions, the need for enzymatic pretreatment of the cartilage, expensive reagents, potential UV-light damage, and potential toxicity hazards. Due to the mentioned disadvantages, no further experiments, including long-term culture, were carried out. A second photosensitive approach focused on blue light induced crosslinking of fibrinogen (RuFib) via a photoinitiator molecule instead of using thrombin as a crosslinking mediator like in normal fibrin glue. The used ruthenium complex allowed inter- and intramolecular dityrosine binding of fibrinogen molecules. The advantage of this method is a one-step curing of fibrinogen via visible light that further achieved higher adhesive strengths than fibrin. In contrast to diazirine functionalization of cartilage, the ruthenium complex is of less toxicological concern. However, after in vitro cultivation of the disc/ring constructs, there was a decrease in integration strength. Compared to fibrin, a reduced cartilage synthesis was observed at the defect. It is also disadvantageous that a direct adjustment of the adhesive can only be made via protein concentration, since fibrinogen is a natural protein that has a fixed number of tyrosine binding sites without chemical modification. An additional cartilage adhesive was developed that is based on a mussel-inspired adhesive mechanism in which reactivity to a variety of substrates is enabled via free DOPA amino acids. DOPA-based adhesion is known to function in moist environments, a major advantage for application on water-rich cartilage tissue surrounded by synovial liquid. Reactive DOPA groups were synthetically attached to a polymer, here POx, to allow easy chemical modifiability, e.g. insertion of hydrolyzable ester motifs for tunable degradation. The possibility of preparing an adhesive hybrid hydrogel of POx in combination with fibrinogen led to good cell compatibility as was similarly observed with fibrin, but with increased immediate adhesive strength. Degradation could be adjusted by the amount of ester linkages on the POx and a direct influence of degradation rates on the development of integration in the in vitro model could be shown. Hydrogels are well suited to fill defect gaps and immediate integration can be achieved via adhesive properties. The results obtained show that for the success of long-term integration, a good ability of the adhesive to take up synthesized ECM components and cells to enable regeneration is required. The degradation kinetics of the adhesive must match the remodeling process to avoid intermediate loss of integration power and to allow long-term firm adhesion to the native tissue. Hydrogels are not only important as adhesives for smaller lesions, but also for filling large defect volumes and populating them with cells to produce tissue engineered cartilage. Many different hydrogel types suitable for cartilage synthesis are reported in the literature. A long-term stable fibrin formulation was tested in this work not only as an adhesive but also as a bulk hydrogel construct. Agarose is also a material widely used in cartilage tissue engineering that has shown good cartilage neosynthesis and was included in integration assessment. In addition, a synthetic hyaluronic acid-based hydrogel (HA SH/P(AGE/G)) was used. The disc/ring construct was adapted for such experiments and the inner lumen of the cartilage ring was filled with the respective hydrogel. In contrast to agarose, fibrin and HA-SH/P(AGE/G) gels have a crosslink mechanism that led to immediate bonding upon contact with cartilage during curing. The enhanced cartilage neosynthesis in agarose compared to the other hydrogel types resulted in improved integration during in vitro culture. This shows that for the long-term success of a treatment, remodeling of the hydrogel into functional cartilage tissue is a very high priority. In order to successfully treat larger cartilage defects with hydrogels, new materials with these properties in combination with chemical modifiability and a direct adhesion mechanism are one of the most promising approaches. N2 - Gelenkknorpeldefekte stellen eines der größten klinischen Probleme für orthopädische Chirurgen dar, und Knorpelschäden nach einem Trauma können zu starken Gelenkschmerzen, Funktionseinschränkungen und langfristig zur Entwicklung von Arthrose führen. Die laterale Knorpel-Knorpel-Integration ist entscheidend für den langfristigen Behandlungserfolg, um eine weitere Degeneration des Gewebes zu verhindern. Gewebekleber und -versiegelungen erfreuen sich zunehmender Beliebtheit und können einen vorteilhaften Ansatz zur Förderung der Gewebeintegration darstellen. Insbesondere bei einem avaskulären Gewebe wie Knorpel können alternative Fixierungstechniken wie Nähte eher zu weiteren Schäden führen. Aktuelle Klebstoffe bedürfen jedoch noch der Optimierung im Hinblick auf die Maximierung der Klebekraft einerseits und der langfristigen Gewebsintegration andererseits. In vitro Modelle können eine wertvolle Unterstützung bei der Untersuchung potenzieller Kleber-Kandidaten und derer Funktionsmechanismen sein. Für die im Rahmen dieser Arbeit durchgeführten Experimente wurde ein in vitro Disc/Ring-Modell aus porcinem Gelenkknorpel hergestellt. Neben der qualitativen Bewertung der Regeneration erleichtert dieses Modell die Durchführung biomechanischer Tests zur Quantifizierung der Knorpelintegrationskraft. Die Herstellung von Konstrukten für die Histologie und anderer analytischer Verfahren ist standardisierbar und ist im Vergleich zu in vivo Versuchen ethisch weniger bedenklich. Die Möglichkeit der Anwendung von Zellkulturtechniken mit dem in vitro Modell ermöglicht eine bessere Untersuchung von Knorpelintegrationsprozessen. Das Verkleben von Gewebe erfordert eine chemische oder physikalische Wechselwirkung zwischen dem Klebstoff und dem Substrat. Adhäsive Hydrogele können sich an die Defektoberfläche binden und gleichzeitig die Lücke unregelmäßig geformter Defekthohlräume füllen. Fibrin-Gele sind von der physiologischen Blutgerinnung abgeleitet und werden seit langem klinisch zum Wundverschluss eingesetzt. Innerhalb dieser Arbeit wurden Vergleiche verschiedener Fibrinkleberformulierungen mit dem kommerziellen BioGlue® durchgeführt, welche gezeigt haben, dass bei der Anwendung auf Knorpelgewebe eine gute Biokompatibilität erforderlich ist, um eine zufriedenstellende Langzeitintegration zu erreichen. Fibrinformulierungen können im Hinblick auf ihre Langzeitstabilität angepasst werden, und bei der Anwendung auf Knorpel Disc/Ring-Konstrukten ist eine verbesserte integrative Reparatur zu beobachten. Im Rahmen dieser Arbeit wurde die Kinetik der Reparaturprozesse in fibrinbehandelten Knorpelkompositen untersucht. Nach dreitägiger in vitro-Kultivierung war eine Ablagerung von extrazellulärer Matrix (ECM) an der verklebten Grenzfläche zu erkennen, welche mit der Zeit weiter zunahm. Ab dem zehnten Tag der Gewebekultur wurde das Einwandern von Zellen aus dem umgebenden nativen Knorpel an der Grenzfläche festgestellt. Die ECM-Bildung hängt von Stoffwechselfaktoren ab, wie es beispielhaft für Ascorbinsäure gezeigt wurde. Dabei trug neue ECM zu einer mit der Zeit zunehmenden Integrationsstärke bei. Die mit Fibrin durchgeführten Experimente haben gezeigt, dass der Ansatz mit einem biokompatiblen Klebstoff und dem Potenzial zur Knorpelneosynthese die laterale Knorpelintegration langfristig begünstigt. Allerdings hatte Fibrin nur eine begrenzte anfängliche Klebekraft, was für den Einsatz auf mechanisch stark belastetem Gelenkknorpel nachteilig ist. Das weiterführende Ziel dieser Arbeit war es unter anderem Haftmechanismen und neue adhäsive Hydrogele zu entwickeln, welche die positiven Eigenschaften von Fibrin beibehalten, aber eine höhere Klebekraft aufweisen. Es wurden zwei verschiedene photochemische Ansätze getestet, die den Vorteil einer zeitlich festlegbaren Verklebung haben und somit dem Anwender eine einfache Applizierung ermöglichen. Zunächst wurde ein UV-Licht-induzierter Vernetzungsmechanismus zur Bereitstellung zusätzlicher Klebestellen zum Fibrinkleber entwickelt. Die Knorpeloberfläche wurde dabei mit hochreaktiven, lichtempfindlichen Diazirin-Molekülen funktionalisiert, die zusätzliche kovalente Bindungen an die Fibrinmatrix ermöglichten und damit die direkte Adhäsionskraft erhöhten. Die Nachteile dieses Ansatzes waren jedoch die mehrstufigen Vernetzungsreaktionen, die Notwendigkeit einer enzymatischen Vorbehandlung des Knorpels, teure Reagenzien, eine mögliche Schädigung durch UV-Licht und potentielle toxikologische Risiken. Wegen den erwähnten Nachteilen wurde auf zusätzliche Untersuchungen verzichtet und der Fokus auf die Alternativenfindung gelegt. Ein weiterer Ansatz konzentrierte sich auf die Vernetzung von Fibrinogen durch blaues Licht (RuFib) mittels eines Photoinitiaor-Moleküls statt über Thrombinzugabe wie bei gewöhnlichen Fibrinklebern. Der verwendete Rutheniumkomplex ermöglichte die inter- und intramolekulare Dityrosinbindung von Fibrinogenmolekülen. Der Vorteil war dabei die einstufige lichtinduzierte Vernetzung von Fibrinogen mit höheren Haftkräften als bei Fibrin. Im Gegensatz zur Diazirin-Funktionalisierung von Knorpel ist der Rutheniumkomplex auch toxikologisch weniger bedenklich. Nach in vitro Kultivierung der RuFib geklebten Disc/Ring-Konstruktes kam es jedoch zu einer Abnahme der Integrationskraft. Im Vergleich zu Fibrin wurde eine verminderte Knorpelsynthese am Defekt beobachtet. Nachteilig ist auch, dass eine Modifizierung des Klebers einzig über die Proteinkonzentration erfolgen kann, da Fibrinogen als natürliches Protein eine feste Anzahl von Tyrosin-Bindungsstellen hat und alternativ chemisch verändert werden müsste. Ein zusätzlich entwickelter Klebstoff basiert auf einem von Muscheln inspirierten Haftmechanismus, bei dem die Reaktivität zu einer Vielzahl von Substraten über freie DOPA-Aminosäuren ermöglicht wird. Es ist bekannt, dass die DOPA-basierte Adhäsion in einer feuchten Umgebung funktioniert, ein großer Vorteil für die Anwendung auf stark wasserhaltigem Knorpelgewebe und im feuchten Synovium. Reaktive DOPA-Gruppen wurden synthetisch an ein Polymer, in diesem Fall POx, gebunden, um eine einfache chemische Modifizierbarkeit zu ermöglichen. Mögliche Anpassungen sind z.B. das Einfügen von hydrolysierbaren Esterbindungen um veränderte Degradationsraten zu erreichen. Die Möglichkeit der Herstellung eines adhäsiven Hybridhydrogels aus POx in Kombination mit Fibrinogen führte zu einer erhöhten Zellkompatibilität, wie sie bereits bei Fibrin beobachtet wurde, jedoch mit erhöhter direkter Klebekraft. Die angepasste Degradationskinetik über die Menge an Esterbindungen am POx hatte einen direkten Einfluss auf die Entwicklung der Integration im in vitro Modell gezeigt. Hydrogele sind gut geeignet, um Defektlücken zu füllen. Bei intrinsischen Adhäsionseigenschaften kann eine gewisse sofortige Integration erreicht werden. Die erzielten Ergebnisse zeigen, dass für den Erfolg einer langfristigen Integration eine gute Fähigkeit des Klebstoffs zur Aufnahme von synthetisierten ECM-Komponenten und Zellen erforderlich ist. Die Abbaukinetik des Klebstoffs muss dabei mit dem Umbauprozess im Gleichgewicht sein, um einen zwischenzeitlichen Verlust der Integrationskraft zu vermeiden und eine langfristige feste Adhäsion an das native Gewebe zu ermöglichen. Hydrogele sind nicht nur als Klebstoffe für kleinere Defekte wichtig, sondern auch als Tissue-Engineering Material um große Defektvolumina aufzufüllen und mit Zellen zu besiedeln. In der Literatur werden verschiedene Hydrogelarten für die Knorpelsynthese berichtet. Eine langzeitstabile Fibrinformulierung wurde in dieser Arbeit nicht nur als Klebstoff, sondern auch als größeres Hydrogelkonstrukt getestet. Agarose ist ebenfalls ein im Knorpel-Tissue-Engineering häufig verwendetes Material, das bereits eine gute Knorpelneosynthese gezeigt hat. Darüber hinaus wurde ein synthetisches Hyaluronsäure-basiertes Hydrogel (HA-SH/P(AGE/G)) untersucht. In durchgeführten Experimenten wurde das Disc/Ring Modell adaptiert und das innere Lumen des Knorpelrings mit dem jeweiligen Hydrogel gefüllt. Im Gegensatz zu Agarose verfügen Fibrin und das HA-SH/P(AGE/G)-Gel über einen Vernetzungsmechanismus, der beim Kontakt mit dem Knorpel während der Aushärtung zu einer sofortigen Bindung führte. Die verstärkte Knorpelneosynthese in Agarose im Vergleich zu den anderen Hydrogeltypen führte zu einer erhöhten Integration während der in vitro Kultur. Dies zeigt, dass für den langfristigen Erfolg eines Therapieansatzes der Umbau des Hydrogels in funktionelles Knorpelgewebe eine sehr hohe Priorität hat. Um größere Knorpeldefekte erfolgreich mit Hydrogelen behandeln zu können, sind neue Materialien mit diesen Eigenschaften in Kombination mit chemischer Modifizierbarkeit und einem direkten Adhäsionsmechanismus einer der vielversprechendsten Ansätze. KW - Knorpel KW - Hyaliner Knorpel KW - Gelenkknorpel KW - Arthrose KW - Kniegelenkarthrose KW - Cartiage Integration KW - Adhesive Hydrogels KW - in vitro Testmodell KW - Cartilage defect KW - Biomechanics KW - Tissue Engineering Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-346028 ER - TY - THES A1 - Etter, Sonja T1 - Einfluss von beruflicher \(Aspergillus\) \(fumigatus\)-Exposition auf die adaptive Immunantwort via ELISpot und Western Blot T1 - Effect of chronic occupational mold exposure on adaptive immune response via ELISpot and Western Blot N2 - Bereits in Vorstudien konnte dargelegt werden, dass eine signifikante Korrelation zwischen der T-Zell-Zytokin-Antwort und der berufs- bzw. umweltbedingten Schimmelpilzbelastung besteht. Ziel der vorliegenden Studie war, eine mögliche Kombination von Biomarkern ausfindig zu machen, die veränderte T-Zell-Antworten auf A. fumigatus- Antigene bei beruflich Exponierten im Vergleich zu Kontrollprobanden/-innen vorhersagen kann. Um geeignete Marker für das Bio-Monitoring zu finden, wurden zur T-Zell-Aktivierung ein myzeliales A. fumigatus - Lysat und 12 proteinogene Antigene in ELISpot-Versuchen für die Signaturzytokine IFN-γ (TH1), IL-5 (TH2) und IL-17A (TH17) der Haupt-TH-Subpopulationen getestet. Es zeigten sich bei den Biolandwirten/-innen erwartungsgemäß erhöhte TH1- und TH2-Antworten auf die Mehrzahl der verwendeten spezifischen A. fumigatus-Antigene, die möglicherweise eine Schimmelpilzbelastung serologisch nachweisbar machen. Insbesondere die spezifischen A. fumigatus-Antigene Aspf22, CatB und CipC konnten eine Trennschärfe zwischen den beiden Kohorten hinsichtlich ihrer IFN-γ- und IL-5-Zytokinantwort erzielen. Unterschiede in der TH17-Antwort aufgrund chronischer beruflicher Sporenbelastung ohne Krankheitskorrelat konnten nicht explizit festgestellt werden. Weiterhin ergab sich, dass erhöhte TH2-Immunreaktionen, sofern sie mit einer adäquaten TH1-gerichteten Immunantwort einhergehen und damit eine ausgeglichene TH2/TH1-Balance besteht, nicht zwangsläufig zu Hypersensitivitätserkrankungen führen. Im Vergleich zu Langzeitexponierten wurden teilweise überlappende TH-Zellfrequenzen bei beruflich exponierten Biolandwirten/-innen ermittelt. Welche entscheidende Rolle Treg-Zellen bei der Eindämmung überschießender Immunantworten einnehmen, kann hieraus erahnt werden. N2 - Preliminary studies have already set out a significant correlation between T-cell-cytokine-responses and professional and/or environmental mold contaminations. This study aimed for a possible combination of biomarkers to predict altered T-cell-responses to A. fumigatus- antigens in a defined professionally exposed cohort in comparison with controls. To find out suitable markers for the biomonitoring, T-cell-activation was performed with a mycelial A. fumigatus- lysate and 12 proteinaceous antigens in ELISpot assays with look at the main signature cytokines of T-helper cell subsets IFN-γ (TH1), IL-5 (TH2) and IL-17A (TH17). As immunoglobulins play an important role in pathophysiology and diagnostic of allergies, sera of the subjects were examined regarding IgE-specific antibodies against mycelial A. fumigatus - lysate and 12 proteinaceous antigens in Western Blot-technique. As expected, increased levels of TH1- and TH2-cytokine responses were found for a majority of examined specific A. fumigatus-antigens, which may help to verify mold exposure in a serological way. Differences in TH17-immune response in agricultural workers without a hypersensitivity disease has not been found. Furthermore, increased TH2-immune responses don’t necessarily lead to a pathologic value since it is followed by an adequate TH1-answer for upholding the TH2/TH1-balance. TH-frequencies of not occupational exposed individuals partly show overlaps with those of agricultural workers. Therefore, the important role of Treg-cells in containing extensive immune responses is conceivable. The specific A. fumigatus-antigens Aspf22, CatB and CipC are (in contrast to Aspergillus-lysate) able to drag selectivity in-between the two cohorts regarding their IFN- - and IL-5-cytokine response. Even though further investigations must be made, specific antigens are more suitable for exposition-analysis and, eventually, for the depiction of associated hypersensitivity diseases. The discrimination based on B-cell-triggered IgE- immune responses remains difficult, conceivably by reason of the subclinical status of the subjects. Solely Aspf3, which is already established in the Immuno-CAP-analysis, shows differential power. KW - Schimmelpilzallergie KW - Aspergillus fumigatus KW - Immunoblot KW - Hypersensitivität KW - Immunreaktion KW - ELISpot KW - adaptive Immunantwort KW - chronische berufliche Exposition KW - Hypersensitivitätsreaktion KW - T-Helfer-Zellen Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-348582 ER - TY - THES A1 - Leonhardt, Jonas S. T1 - Entwicklung von Gesundheitskompetenz zur Unterstützung der Lebensqualität - Eine Fragebogen basierte Analyse zur Erfassung des subjektiven Beratungsbedarfs sowie der Motivationslage krebskranker Patienten im Hinblick auf die Etablierung eines tagesklinischen Therapie- und Schulungsangebotes (KOI Tagesklinik) an der Universitätsklinik Würzburg T1 - Establishing health-promoting behaviour to support quality of life - A questionnaire-based study on the needs and motivation of cancer patients for a day clinic programme (KOI Day Clinic) at the University Hospital of Würzburg, Germany N2 - Komplementärmedizinische Angebote in der Onkologie erleben eine hohe Nachfrage. Diese Studie sollte klären, ob bei Patienten ein Mehrbedarf an ganzheitlichen, tagesklinischen Angeboten besteht. Im Rahmen dieser Fragebogen-basierten Analyse sollten Zielgruppen identifiziert werden, die besonders hiervon profitieren könnten. Mithilfe eines Fragebogens wurden zwischen 08/2019 und 10/2020 294 ambulant behandelte onkologische Patienten des Comprehensive Cancer Centers Mainfranken an der Universitätsklinik Würzburg befragt. Der Fragebogen ist angelehnt an das etablierte Curriculum Mind-Body-Medizin der Kliniken Essen-Mitte und umfasst zehn Untergruppen. Statistisch signifikante Zusammenhänge wurden durch Anwendung des Chi-Quadrat Tests ermittelt. In allen untersuchten Lebensbereichen fanden sich Hinweise auf einen Mehrbedarf an komplementärmedizinischen Angeboten. Ein Drittel der Patienten gab an, aus eigener Kraft keine überdauernden Lebensstiländerungen herbeiführen zu können. Das höchste Gesundheitsbewusstsein zeigte sich in den Bereichen Ernährung, Bewegung und Entspannung. Trotzdem führte ein Großteil der Befragten empfohlene Maßnahmen nicht durch. Insbesondere die Bereiche Schlaf, Energielevel und psychische Belastung wiesen das größte Verbesserungspotential auf. Defizite in diesen Bereichen beeinflussten sich gegenseitig und konnten mit Unzufriedenheit und negativen Gedanken sowie geringer Veränderungsmotivation in Verbindung gebracht werden. Besonders betroffen waren erwerbstätige Patienten im Alter zwischen 40-65 Jahren. Frauen zeigten sich deutlich motivierter als Männer komplementärmedizinische Angebote zu nutzen. Gemäß unseren Ergebnissen und evidenzbasierten Empfehlungen der S3-Leitlinie Komplementärmedizin ergibt sich ein Mehrbedarf nach folgenden Angeboten: Supervidierte Sportprogramme, MBSR, Tai Chi/ Qigong, individuelle Ernährungsberatung und Selbsthilfegruppen für Angehörige. Durch Vermittlung von Gesundheitsbewusstsein sollten insbesondere Patientengruppen motiviert werden, die aus eigener Kraft ihre Situation nicht verbessern können. Um den Erfolg von gesundheitsfördernden Lebensstiländerungen überdauernd zu sichern, ist weitere Unterstützung nötig. N2 - There has been a sustained interest in complementary medicine in oncology over the recent years. We assessed patients demands for a day care program providing integrative counseling and treatment at the Comprehensive Cancer Center of the University Hospital of Wuerzburg. Furthermore, we aimed to identify target groups of particular interest. We used a questionnaire based on a Mind–Body-Medicine Day Care Clinic program, first published in 2013, covering ten different lifestyle subgroups. A total of 294 patients undergoing oncological therapy at the Comprehensive Cancer Center Mainfranken were surveyed. Statistically significant correlations were determined by applying the chi-square test. The significance level was p<0.05. The results indicated increased demand for complementary medicine in all lifestyle subgroups. One-third of patients reported being unable to maintain lifestyle changes without assistance. Patients demonstrated high levels of health consciousness in nutrition, physical activity, and relaxation. Nevertheless, a majority did not follow recommended concepts. The subgroups sleep, perceived energy level and psychological distress showed great potential for improvement. Deficits influenced each other and were associated with dissatisfaction and negative thoughts as well as low motivation to change. This was seen particularly in patients following a regular job at the age of 40-65. Women were more likely to use concepts of complementary medicine than men. Combining the results of this dissertation with current guidelines for complementary medicine in oncology we suggest that there is an increased need for the following programs: supervised physical activity, MBSR, Tai Chi/ Qigong, nutritional counseling and self-help groups for relatives. In particular, patients who are unable to make lifestyle changes on their own seem relevant. To ensure the success of health-promoting lifestyle changes, more support is required. KW - Onkologie KW - Lebensqualität KW - Bedürfnis KW - integrative Onkologie KW - Komplementärmedizin KW - Alternative Medizin Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357139 ER - TY - THES A1 - Peña Mosca, María Josefina T1 - Local regulation of T-cell immunity in the intestinal mucosa T1 - Lokale Regulation der T-Zell-Immunität in der Darmschleimhaut N2 - After priming in Peyer's patches (PPs) and mesenteric lymph nodes (mLN) T- cells infiltrate the intestine through lymphatic draining and homing through the bloodstream. However, we found that in mouse models of acute graft-versus-host disease (GvHD), a subset of alloreactive T-cells directly migrates from PPs to the adjacent intestinal lamina propria (LP), bypassing the normal lymphatic drainage and vascular trafficking routes. Notably, this direct migration occurred in irradiated and unirradiated GvHD models, indicating that irradiation is not a prerequisite for this observed behavior. Next, we established a method termed serial intravascular staining (SIVS) in mouse models to systematically investigate the trafficking and migration of donor T- cells in the early stages of acute GvHD initiation. We found that the direct migration of T-cells from PPs to LP resulted in faster recruitment of cells after allogeneic hematopoietic cell transplantation (allo-HCT). These directly migrating T-cells were found to be in an activated and proliferative state, exhibiting a TH1/TH17-like phenotype and producing cytokines such as IFN-γ and TNF-α. Furthermore, we observed that the directly migrating alloreactive T-cells expressed specific integrins (α4+, αE+) and chemokine receptors (CxCR3+, CCR5+, and CCR9+). Surprisingly, blocking these integrins and chemokine-coupled receptors did not hinder the direct migration of T- cells from PPs to LP, suggesting the involvement of alternative mechanisms. Previous experiments ruled out the involvement of S1PR1 and topographical features of macrophages, leading us to hypothesize that mediators of cytoskeleton reorganization, such as Coro1a, Dock2, or Cdc42, may play a role in this unique migration process. Additionally, we observed that directly migrating T-cells created a local inflammatory microenvironment, which attracts circulating T-cells. Histological analysis confirmed that alloreactive PPs-derived T-cells and bloodborne T-cells colocalized. We employed two experimental approaches, including either photoconversion of T-cells in PPs or direct transfer of activated T-cells into the vasculature, to demonstrate this colocalization. We hypothesize that cytokines released by migrating T-cells, such as IFN-γ and TNF-α, may play a role in recruiting T-cells from the vasculature, as inhibiting chemokine-coupled receptors did not impair recruitment. N2 - Nach der Priming-Phase in den Peyer-Plaques (PPs) und mesenterialen Lymphknoten (mLN) migrieren T-Zellen über die lymphatische Drainage und den Blutkreislauf die Darmschleimhaut. Allerdings haben wir festgestellt, dass in Mausmodellen der akuten Graft-versus-Host Erkrankung (GvHD) eine Untergruppe alloreaktiver T-Zellen direkt von den Peyer-Plaques in das benachbarte intestinale Lamina propria (LP) migriert, ohne lymphatische Drainage- oder vaskuläre Transportwege zu nutzen. Bemerkenswert ist, dass diese direkte Migration sowohl in bestrahlten als auch in nicht bestrahlten GvHD-Modellen auftrat, was darauf hindeutet, dass Gewebeschaden durch ionisierende Strahlung keine Voraussetzung für dieses beobachtete T-Zell-Migrationsverhalten ist. Anschließend haben wir die Methode der "serielle intravaskulären Zellmarkierung" (SIVS) für Mausmodelle etabliert, um systematisch das Migrationsverhalten von alloreaktiven Spender-T-Zellen in den frühen Stadien der akuten GvHD-Initiierung zu untersuchen. Wir beobachteten, dass die direkte Migration von T-Zellen von PPs zu LP zu einer schnelleren Rekrutierung von Zellen nach allogener hämatopoetischer Zelltransplantation (allo-HCT) führte. Diese direkt migrierenden T-Zellen befanden sich in einem aktivierten und proliferativen Zustand, wiesen einen TH1-/TH17- ähnlichen Phänotyp auf und produzierten Zytokine wie IFN- γ und TNF-α. Darüber hinaus beobachteten wir, dass die direkt migrierenden alloreaktiven T-Zellen spezifische Integrine (α4+, αE+) und Chemokinrezeptoren (CxCR3+, CCR5+ und CCR9+) exprimierten. Überraschenderweise verhinderte die Blockierung dieser Integrine und Chemokinrezeptoren nicht die direkte Migration von T-Zellen aus PPs in LP, was auf die Beteiligung alternativer T- Zellmigrationsmechanismen schließen lässt. Vorangegangene Experimente schlossen die Beteiligung von S1PR1 und topografischer Merkmale gewebeständiger Makrophagen aus, was uns zu der Hypothese führte, dass Mediatoren der Zytoskelett- Reorganisation wie Coro1a, Dock2 oder Cdc42 eine Rolle in diesem einzigartigen Migrationsprozess spielen könnten. Zusätzlich beobachteten wir, dass direkt migrierende T-Zellen in der Darmschleimhaut ein lokales entzündliches Mikromilieu schaffen, welches zirkulierende T-Zellen anzieht. Die histologische Analyse bestätigte die Kolokalisation von direkt aus PP stammenden T-Zellen und T Zellen, welche über die Blutbahn in die Darmmukosa einwanderten. Um die direkte T-Zellmigration eindeutig zu bestätigen, wählten wir zwei experimentelle Ansätze: Die Photokonversion von T-Zellen in PPs während der Priming-Phase sowie den direkten Transfer aktivierter T-Zellen in das Gefäßsystem, um eine T-Zellkolokalisierung nachzuweisen. Aufbauend auf den Ergebnissen vermuten wir, dass Zytokine, die von migrierenden T-Zellen freigesetzt werden, wie zum Beispiel IFN-γ und TNF-α, möglicherweise eine Rolle bei der Rekrutierung von T-Zellen aus dem Gefäßsystem spielen, da die Hemmung von G- Protein-gekoppelter Rezeptoren (und somit aller Chemokinrezeptoren) die T-Zell- Rekrutierung nicht beeinträchtigte. KW - T-Lymphozyt KW - Transplantat-Wirt-Reaktion KW - Zellmigration KW - Darm KW - Peyer's patch KW - Graft versus Host disease KW - T-cell KW - Cell migration KW - Small intestine KW - Bone marrow transplantation Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-352665 ER - TY - THES A1 - Dereser, Katharina T1 - Real world M³P Panel-Sequenzierung für die personalisierte Therapie des Multiplen Myeloms T1 - Real world M³P panel sequencing for the personalized therapy of multiple myleoma N2 - Obwohl es in den letzten 10-15 Jahren gelang, multiple MM-Genome mittels NGS auf eine kosteneffiziente Art und mit geringem Zeit- und Materialaufwand zu sequenzieren und hierdurch zum Teil bahnbrechende Erkenntnisse gewonnen werden konnten, sind molekulargenetische Untersuchungen im diagnostischen Workflow des MMs bisher nicht ausreichend implementiert, um eine personalisierte Therapieentscheidung zu ermöglichen. Vor diesem Hintergrund wurde in der vorliegenden Arbeit eine Gruppe an Patienten mit NDMM und RRMM anhand klinischer Parameter charakterisiert und durch Verwendung des M³P-Panels auf das Vorliegen bestimmter molekulargenetischer Veränderungen untersucht. Zusammenfassend lässt sich sagen, dass unsere Analyse die bisher veröffentliche M³P-Prävalenz in MM-Tumorproben bestätigt. Zu den am häufigsten mutierten Genen gehörten KRAS, NRAS, DIS3, ATM und BRAF. In der Gruppe der Patienten mit NRAS-Mutation oder del17p war die Zahl der relevanten Mutationen deutlich höher als ohne Vorliegen der entsprechenden Veränderung. Der Nachweis eines Double-Hit-Myeloms war erwartungsgemäß der stärkste ungünstige Faktor in unserer Kohorte. Unter den Patienten mit CRBN-Mutation waren alle IMiD-vorbehandelt und zeigten im Verlauf eine Refraktärität gegenüber dieser Substanzgruppe auf. Bezüglich der Überlebensanalysen bestätigten unsere Ergebnisse bereits bekannte prognostische Risikofaktoren wie Hochrisikozytogenetik, insbesondere del17p und gain1q, eine TP53-Mutation sowie ISS- und R-ISS-Stadium III. Die Ergebnisse der Mutationsanalysen dieser Arbeit verdeutlichen den großen wissenschaftlichen und therapeutischen Nutzen, der von molekulargenetischen Untersuchungen ausgeht. Zukünftig werden auch beim MM Therapieentscheidungen auf Grundlage genetischer Diagnostik getroffen werden, mit dem Ziel die Behandlung für MM-Patienten weiter zu verbessern. N2 - Although it has been possible in the last 10-15 years to sequence multiple MM genomes using NGS in a cost-efficient manner and with little time and material expenditure, which has led to some groundbreaking findings, molecular genetic examinations have not yet been sufficiently implemented in the diagnostic workflow of MM to enable a personalized therapy decision. Against this background, the present study characterized a group of patients with NDMM and RRMM on the basis of clinical parameters and examined them for the presence of certain molecular genetic alterations using the M³P panel. In summary, our analysis confirms the previously published M³P prevalence in MM tumor samples. The most frequently mutated genes included KRAS, NRAS, DIS3, ATM and BRAF. In the group of patients with NRAS mutation or del17p, the number of relevant mutations was significantly higher than without the corresponding mutation. As expected, the detection of a double-hit myeloma was the strongest unfavorable factor in our cohort. Among the patients with CRBN mutation, all were pretreated with IMiD and showed refractoriness to this drug group over time. With regard to survival analyses, our results confirmed already known prognostic risk factors such as high-risk cytogenetics, in particular del17p and gain1q, a TP53 mutation as well as ISS and R-ISS stage III. The results of the mutation analyses in this study illustrate the great scientific and therapeutic benefits of molecular genetic testing.In future, treatment decisions for MM will also be made on the basis of genetic diagnostics, with the aim of further improving treatment for MM patients. KW - Multiples Myelom KW - Panel-Sequenzierung KW - Plasmozytom KW - Molekulargenetik Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-352644 ER - TY - THES A1 - Werner, Andrea T1 - Körperpsychotherapie: Grundlagen - Konzepte - Anwendungsgebiete T1 - Bodypsychotherapy: Basics - Concepts - Fields of Application N2 - Körperpsychotherapie etabliert sich zunehmend und ist keine neue Entdeckung. Bereits vor über 120 Jahren war bekannt, dass über den Körper die Psyche erreicht werden kann und damit die verbale Psychotherapie effektiver und gegebenenfalls erst möglich wurde. Wissenschaftliche Untersuchungen sprechen dafür, dass Körperpsychotherapie heute als fünfte Säule der allgemein anerkannten psychotherapeutischen Verfahren (PA, TP, VT, ST) angesehen werden kann. Sie hat sich aus der atemtherapeutischen und der Bewegung der Gymnastik sowie der Verwendung in der Psychoanalyse entwickelt. Sie ist weitestgehend in die tiefenpsychologische und verhaltenstherapeutische Psychotherapie integriert und kann zu den humanistischen Verfahren gezählt werden. Anwendung findet die Körperpsychotherapie beispielsweise in der Psychosomatischen Medizin sowie auf verschiedenen Gebieten der Psychotherapie. Laut den hier vorgelegten Befunden erreicht die Arbeit am Körper nonverbal Verarbeitetes, das sich tief in das implizite Körpergedächtnis eingegraben hat, lange bevor ein junger Mensch das Sprechen erlernte. Eine Möglichkeit, dies konzeptuell einzuordnen und therapeutisch nutzbar zu machen, ist das Modell der „verkörperten Selbstwahrnehmung“ nach Fogel, das Teile des Körperschemas beinhaltet. In der Bindungsbeziehung nicht adäquates Eingehen auf die kindlichen Bedürfnisse hat weitreichende Folgen auf das weitere Leben. In Untersuchungen konnte gezeigt werden, wie sich Störungen in der Entwicklung eines Kindes in Form von Körperschemastörungen und Körperdissoziationen, in Emotionsregulations- und als Entwicklungstraumastörung manifestieren können. Diese sind weit verbreitet und Teil einer Gesellschaft, die auf Leistung und Effizienz ausgerichtet ist und in Zusammenhang mit chronischem Stress stehen. Evolutionsgeschichtlich begründete Überlebensmuster werden durch chronischen Stress aktiviert und sind Ursache zahlreicher Erkrankungen. Hierfür liefert Porges mit seiner Polyvagal-Theorie einen neuen neurobiologischen Erklärungsansatz. Durch eine Imbalance stressauslösender und entspannender Faktoren zugunsten des Stresses werden körpereigene Selbstheilungskräfte der Selbstregulation verhindert und die Resilienzfähigkeit eingeschränkt. Selbstregulation und Resilienz sind vorhanden, wenn das Ruhe- und Bindungssystem dominiert im Gegensatz zur Kampf-, Flucht- und Erstarrungsreaktion. In seiner Hypothese zeigt Porges auf, wie das autonome Nervensystem Verhaltensweisen beeinflusst und wie diesen begegnet werden kann. Durch den sympathischen Zweig wird die An- und Verspannungsreaktion auf körperlicher Seite mit den auch auf der psychischen Seite verbundenen Reaktionen vermittelt. Diesem kann durch die parasympathisch vermittelte Oxytocin-Freisetzung begegnet werden. Durch eine Balance dieser beiden Waagschalen kann körperliche und seelische Gesundheit sowie Resilienzfähigkeit gefördert werden. Die Körperpsychotherapie bietet auch aus meiner Sicht eine noch unterschätzte Möglichkeit, die Balance wieder herzustellen. Eine Methode, die positive durch Oxytocin vermittelte heilsame Reaktionen in Gang zu setzt, stellt die berührende Körperarbeit dar wie sie beispielsweise nach der Rosen-Methode praktiziert wird. Körperpsychotherapie im Allgemeinen kann in der Behandlung von Depressionen, Angst- und psychosomatischen Störungen hilfreich sein. Sie ist empirisch in einer umfassenden Theorie begründet und fundiert auf neurobiologischen und neurowissenschaftlichen Erkenntnissen. Aus Sicht der Autorin handelt es sich bei der Körperpsychotherapie angesichts der vorliegenden Befunde und theoretischen Wirkkonzepte um einen therapeutischen Ansatz, der wesentlich dazu beitragen kann, die Behandlung psychischer Störungen kosteneffizienter und wirksamer zu gestalten. Um differenzierter zwischen theoretischem Potential und tatsächlich nachweisbaren Effekten körperpsychotherapeutischer Methoden unterscheiden zu können, ist es aus meiner Sicht dringend zu empfehlen, körperpsychotherapeutische Arbeitsansätze exakter zu erforschen. Beispielsweise wäre es lang- oder mittelfristig auch wünschenswert, Forschungsdaten für eine präzisere Indikationsstellung zur Verfügung zu haben. Dabei wäre beispielweise zu klären, welche Verfahren für welche Störungsbilder, in welchem Behandlungssetting und für welche Behandlungsdauer in Frage kommen. Auch fehlen hinsichtlich der Kontraindikationen belastbare Forschungsdaten zu den oben benannten Empfehlungen diverser Vertreter der Körperpsychotherapie. Aufgrund des hohen Erklärungspotentials für das individuelle Erleben psychisch beeinträchtigter Personen, das beispielsweise die Polyvagal-Theorie nach Porges oder die verkörperte Selbstwahrnehmung nach Fogel bieten, erscheint mir auch die Forderung nach einer Berücksichtigung körperpsychotherapeutischer Theorien und Methoden in der Ausbildung von Ärzten und Psychologen nachvollziehbar und sinnvoll. Aufgrund der in dieser Arbeit zusammengetragenen Ergebnisse halte ich es für dringend empfehlenswert, die Körperpsychotherapie als eigenständiges Behandlungselement in die fachgerechte Versorgung psychisch Erkrankter aufzunehmen, sofern keine der erwähnten Kontraindikationen dem widersprechen. N2 - Bodypsychotherapy is becoming increasingly established and is not a new discovery. It was already known more than 120 years ago that the psyche can be reached via the body and that this made verbal psychotherapy more effective and, if necessary, possible in the first place. This dissertation aims to provide a systematic overview of the topic of "bodypsychotherapy" in the field of psychosomatics by means of a literature research. The aim is to work out the effectiveness, mode of action, hypotheses and areas of application of bodypsychotherapy. KW - Körperpsychotherapie KW - Psychotherapie KW - Körpertherapie KW - Rosen-Methode KW - Körperarbeit Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265161 ER - TY - THES A1 - Grohmann, Christoph T1 - Kognitive Leistungsfähigkeit und Lebensqualität bei minimaler hepatischer Enzephalopathie - eine Pilotstudie zum Patient Reported Outcome in der Verlaufsdiagnostik T1 - Cognitive performance and quality of life in minimal hepatic encephalopathy - a pilot study of Patient Reported Outcome in follow-up N2 - Die WHO definiert Gesundheit als völliges körperliches, geistiges und soziales Wohlbefinden. Während diese ganzheitliche Betrachtungsweise seit Menschengedenken nahezu weltweit das Gesundheitswesen prägt, hat die Medizin in Europa mit der naturwissenschaftlichen Erkenntnisrevolution einen Sonderweg eingeschlagen. Hier wird der kranke Organismus in erster Linie als defekter Apparat gesehen, der mit ausgeklügelter Technik zu reparieren ist. Aber auch präziseste Qualitätsarbeit stößt dabei oft an Leistungsgrenzen, weil sie als seelenlos erlebt wird. Daher sehen heute viele Fachgebiete die Notwendigkeit, ihre Behandlungskonzepte zu beseelen und ihre Behandlungserfolge auch anhand der subjektiv von Patienten empfundenen Lebensqualität zu beurteilen. Für die Ermittlung dieses PRO kommen etablierte psychometrische Testverfahren in Frage, die sich auch für routinemäßige Verlaufskontrollen eignen. In der vorliegenden Arbeit wurde am Beispiel der mHE geprüft, welchen Nutzen eine PRO-Bestimmung bei der Verlaufskontrolle haben kann. Dazu wurde eine prospektive Studie mit anfänglich 75 Patienten durchgeführt. Alle hatten eine mHE und waren entweder alkoholbedingt oder aus anderen Gründen schwer leberkrank. An vier Terminen im Abstand von sechs Monaten wurden die kognitive Leistungsfähigkeit und der emotionale Status überprüft. Die Patienten zeigten anfänglich kognitive Einschränkungen, die sich im Verlauf der individuell abgestimmten Behandlung deutlich verbesserten oder ganz verschwanden. Die globale Testung mit dem MoCA ergab eine hochsignifikante Normalisierung im ersten Behandlungsjahr. Die MoCA-Werte am Studienanfang und -ende waren von der Erkrankungsursache unabhängig. Dieser Befund differenzierte sich in den Spezialtests TMT, PHES und NHPT. Hier zeigten die alkoholbedingt Erkrankten durchweg schlechtere Leistungen als die nicht-alkoholbedingt Erkrankten, erholten sich aber in der Regel auch deutlicher. Die seelische Gestimmtheit gemäß BDI-II und die mit dem SF-36 MCS ermittelte psychosoziale Befindlichkeit waren in beiden Patientengruppen von Anfang an vergleichsweise günstig. Dabei hatten die alkoholbedingt Erkrankten die besseren Werte, speziell der BDI-II zeigte bei ihnen nach einem halben Jahr eine zusätzliche und bleibende Stimmungsaufhellung an. Der SF-36 PCS zum Körpererleben zeigte hingegen, dass sich die alkoholbedingt Erkrankten zu Studienbeginn in einer deutlich schlechteren Verfassung befanden. Diese verbesserte sich aber kontinuierlich, sodass nach 1,5 Jahren kein Unterschied mehr zu den nicht-alkoholbedingt Erkrankten bestand. Aus diesen Befunden und dem reichhaltigen Erfahrungsgut zur Alkoholkrankheit wird geschlossen, dass der Genesungsprozess bei alkoholbedingtem Leberversagen viel komplexer ist als bei nicht-alkoholbedingtem Leberversagen. Er könnte wesentlich mehr Zeit erfordern und wird offensichtlich anders erlebt. Dieser Patientengruppe könnten besondere physio- und gesprächstherapeutische Angebote eine große Hilfe sein. Die Arbeit zeigt, dass es möglich ist, mit wenig Aufwand komplementär zu den klinischen Verlaufsbefunden einen informativen PRO-Bericht zu erhalten. Er hilft Angehörigen und medizinischem Personal, die persönlichen Nöte und Hoffnungen der Patienten besser zu verstehen und gegebenenfalls einen Korrekturbedarf im Umgang zu erkennen. Hinzu kam im vorliegenden Fall die Erkenntnis, dass die alkoholbedingt Erkrankten in ihrem Kranksein anders betroffen waren. Die Gründe dafür sind im Nachhinein plausibel, der Sachverhalt als solcher wäre aber ohne diese Spezialuntersuchung wohl nicht erkannt worden. Das Beispiel der PRO-Ermittlung bei der mHE macht den praktischen Wert einer Berücksichtigung des gesamtheitlichen Gesundheitskonzepts der WHO auch in der technikzentrierten „westlichen Medizin“ deutlich. N2 - The WHO defines health as complete physical, mental and social well-being. While this holistic approach has characterized health care almost worldwide since time immemorial, medicine in Europe has taken a special path with the scientific knowledge revolution. Here, the sick organism is seen primarily as a defective apparatus that can be repaired with sophisticated technology. But even the most precise quality work often comes up against performance limits, because it is experienced as soulless. For this reason, many specialties today see the need to soul their treatment concepts and to assess their treatment successes also on the basis of the quality of life subjectively perceived by patients. Established psychometric test procedures can be used to determine this PRO, which are also suitable for routine progress monitoring. In the present study, we used the example of mHE to examine the potential benefits of PRO assessment in follow-up. For this purpose, a prospective study with initially 75 patients was performed. All had mHE and were either alcohol-related or severely liver diseased for other reasons. Cognitive performance and emotional status were assessed at four appointments six months apart. Patients initially showed cognitive impairment, which improved significantly or disappeared completely during the course of individually tailored treatment. Global testing with the MoCA showed highly significant normalization in the first year of treatment. MoCA scores at baseline and end of study were independent of disease cause. This finding was differentiated in the special tests TMT, PHES and NHPT. Here, the alcohol-related ill persons consistently performed worse than the non-alcohol-related ill persons, but generally also recovered more clearly. The mental mood according to the BDI-II and the psychosocial well-being measured with the SF-36 MCS were comparatively favorable in both patient groups from the beginning. The alcohol-related patients had the better values, especially the BDI-II showed an additional and lasting improvement of their mood after half a year. The SF-36 PCS on body experience, on the other hand, showed that the alcohol-dependent patients were in a significantly worse condition at the beginning of the study. However, this improved continuously, so that after 1.5 years there was no longer any difference to the non-alcohol-related sufferers. From these findings and the rich body of experience on alcohol-related disease, it is concluded that the recovery process in alcohol-related liver failure is much more complex than in non-alcohol-related liver failure. It could require much more time and is obviously experienced differently. This group of patients could be greatly helped by special physical and talk therapy services. The work shows that it is possible to obtain an informative PRO report complementary to the clinical course findings with little effort. It helps relatives and medical staff to better understand the personal needs and hopes of patients and, if necessary, to recognize a need for corrective action. In addition, in the present case there was the realization that the alcohol-related patients were affected differently in their being ill. The reasons for this are plausible in retrospect, but the facts as such would probably not have been recognized without this special investigation. The example of the PRO investigation in mHE makes clear the practical value of taking into account the holistic health concept of the WHO even in technology-centered "Western medicine". KW - Patient Reported Outcome KW - Lebensqualität bei mHE KW - Kognition bei mHE KW - Encephalopathia hepatica KW - Hepatische Enzephalopathie Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305375 ER - TY - THES A1 - Brückner, Anne Sophie T1 - Biomarker bei Immuntherapie: eine nicht-interventionelle klinische Studie zur Analyse von verschiedenen immunologischen Serumbiomarkern bei Patienten mit fortgeschrittenen malignen Tumorerkrankungen T1 - Biomarker for immunotherapy: a non interventional clinical study of analyzing different immune mediated serum biomarkers in patients with advanced solid tumors under treatment with immune checkpoint inhibition N2 - Ziel der Studie war es, potentielle Serumbiomarker für das Therapieansprechen auf Immuncheckpoint-Inhibition zu detektieren. Patienten, die der Gruppe Responder zugeordnet werden konnten, hatten ein deutlich längeres PFS. Hinzu kommt, dass im Fall der Gruppe Responder Median und Mittelwert der gemessenen Serumparameter Granzym A und B, Interferon Gamma und Perforin von BL zur 1. Messung post treatment ansteigen. Zusätzlich zeigt sich, dass IL-8 Potential als negativ prognostischer Marker hat. Trotz des kleinen und heterogenen Patientenkollektivs lassen sich Trends ableiten, die das Potential der untersuchten Mediatoren zytotoxischer T-Zellen als Serumbiomarker unterstreichen. N2 - Aim of the study was the detection of potential serum biomarkers for measuring therapy response under immune checkpoint inhibition. Patients assigned to group responder had a clearly extended PFS. Additionally patients of this group had an increase of median and mean value of granzyme A and B, interferon gamma and perforin from BL to first measure post treatment. In this study is shown, that IL-8 has potential to become a negative prognostic marker. Despite of the small and heterogeneous patient collective you can record interesting trends from the results. That underlines the potential of the tested mediators of cytotoxic T-cells to serve as serum biomarkers in future. KW - Serumbiomarker KW - Immuncheckpointinhibition Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305385 ER - TY - THES A1 - Weiß, Ronja T1 - Untersuchungen zur Kreuzreaktivität von Cytomegalievirus-spezifischen T-Lymphozyten und Tumorassoziierten Antigenen T1 - Functional analysis of cross reactivity of cytomegalovirus specific T cells and tumor associated antigens N2 - Bei Patienten mit Erkrankungen des blutbildenden Systems ist die hämatopoetische Stammzelltransplantation (HSZT) eine häufig eingesetzte kurative Therapie. Im Rahmen dieser Transplantation werden nicht nur vom Spender gewonnene hämatopoetische Stammzellen auf den Empfänger übertragen, sondern immer auch im peripheren Blut vorhandene T-Zellen. Dies kann zum einen einen positiven Effekt zum anderen aber auch negative Folgen für den transplantierten Patienten mit sich bringen. Eine negative Auswirkung wäre die sogenannte Graft-vesus-Host Disease (GvHD), bei der die T-Zellen des Spenders Zellen des Empfängers als fremd erkennen und angreifen. Klinisch manifestiert sich dies vor allem an Leber, Haut und Darm mit Ikterus, Dermatitiden und Diarrhoen. Einen gewünschten Effekt, den die übertragenen T-Zellen vor allem bei Patienten mit akuter myeloischer Leukämie (AML) mit sich bringen können, ist der sogenannte Graft-versus-Leukemia (GvL) Effekt. Dabei richten sich vom Spender stammende Immunzellen gegen die Tumorzellen des Empfängers und senken damit das Rezidivrisiko der Leukämie. In verschiedenen Studien konnte eine positive Korrelation von CMV-Reaktivierung nach HSZT und einem niedrigerem Rezidivrisiko der hämatopoetischen Grunderkrankung gezeigt werden. Diese Doktorarbeit widmet sich auf Grundlage dessen der Frage, ob Cytomegalievirus (CMV)-spezifische cytotoxische T-Zellen (CTL) direkt durch Kreuzreaktivität zum GvL-Effekt beitragen. Zunächst wurden periphere mononukleäre Zellen (PBMC) aus dem Blut neun gesunder Spender isoliert, die als CMV-seropositiv ausgetestet wurden. Diese wurden mit dem CMVpp65-(NLVPMVATV)-Einzelpeptid stimuliert und in Kultur angereichert. Zusätzlich wurden die expandierten CMV-spezifischen CTL durch eine spezifische Selektion über den Aktivierungsmarker CD137 weiter angereichert. Nach Expansion und Anreicherung zeigten jeweils 75% (Spender 1), 67% (Spender 2), 74% (Spender 3), 86% (Spender 4), 81% (Spender5), 80% (Spender 6), 84% (Spender 7), 51% (Spender 8) und 69% (Spender 9) der CD3+/CD8+-T-Zellen eine IFN-γ-Produktion und CD107a-Expression nach Stimulation mit dem CMVpp65-Einzelpeptid. IFN-γ als Effektormolekül der zytotoxischen Granula der CTL und CD107a als Degranulationsmarker beweisen die spezifische Zytotoxizität. Somit konnte die erfolgreiche Anreicherung funktionsfähiger CMVpp65-spezifischer CTL gezeigt werden. Um zu untersuchen, ob diese nun kreuzreaktiv tumorassoziierte Antigene (TAA) erkennen, wurden sie ebenfalls mit folgenden TAA stimuliert: WT1, Proteinase 3, PRAME, NY-ESO, Muc1 und Bcl-2. Die Stimulation erfolgte entweder über die direkte Zugabe von Einzelpeptiden bzw. Peptidpools oder über die Beladung und Präsentation dieser Peptide bzw. Peptidpools über dendritische Zellen (DC). Die DC wurden aus Monozyten des jeweiligen Spenders generiert. Im Falle von drei Spendern zeigt sich ebenfalls eine deutliche zytotoxische Funktion nach Stimulation mit dem WT1-(DFKDCERRF)-Einzelpeptid durch IFN-γ-Produktion und CD107a-Expression bei 75% (Spender 1), 35% (Spender 4) und 33% (Spender 7) der CD3+/CD8+-T-Zellen. Wie zuvor erwähnt lag der Anteil der CD3+/CD8+-T-Zellen mit spezifischer Zytotoxizität nach Stimulation mit dem CMVpp65-(NLVPMVATV)-Einzelpeptid bei diesen drei besagten Spendern bei 74% (Spender1), 86% (Spender 4) und 84% (Spender7). So ergab sich für diese drei Spender eine gemeinsame Schnittmenge von 48,92% (Spender 1), 21,07% (Spender 4) und 17,45% (Spender 7) derjenigen Zellen, die sowohl nach Stimulation mit CMVpp65-(NLVPMVATV)-Einzelpeptid und WT-(DFKDCERRF)-Einzelpeptid eine zytotoxische Funktion zeigten, sodass von einer kreuzreaktiven Erkennung dieser beiden Peptide in diesen drei Spendern ausgegangen werden muss. Die für diese Spender gezeigte kreuzreaktive Erkennung könnte zum GvL-Effekt bei Leukämie/Myelom-Patienten nach HSZT beitragen. N2 - Patients who suffer a disease affecting the hematopoietic system can be treated with allogenic hematopoietic stem cell transplantation (HSCT). One positive effect which can go along with the HSCT is the so-called graft versus leukemia (GvL) effect. This phenomenon describes a process where donor immune cells attack tumor cells of the recipient organism an thereby lower the relapse risk of the treated disease. Different studies showed a positive correlation between Cytomegalovirus (CMV) reactivation in patients after HSCT and a lower relapse risk of the treated hematopoietic disease. This thesis is devoted to the question whether CMV-specific T cells cause a GvL effect through their cross reactivity. Therefore, peripheral blood mononuclear cells (PBMC) were isolated from 50 healthy CMV-positive donors. In nine cases CMV-specific T cells were successfully generated and expanded by culturing PBMC in the presence of CMVpp65-( NLVPMVATV)- single peptide to perform the final analysis: testing the cytotoxicity by measuring IFN-ɣ-production and expression of CD107a after presentation of CMVpp65-( NLVPMVATV)- single peptide, CMVpp65 peptide pool and different tumor associated antigens (WT1, Proteinase 3, PRAME, NY-ESO, Muc1 und Bcl-2). As key result in cases of three donors the final analysis demonstrated evidence of cytotoxicity of CMV-specific T cells following presentation of both CMVpp65-(NLVPMVATV)- single peptide and WT1-( (DFKDCERRF)- single peptide. The common intersection of cytotoxic T cells is valued at 74%, 86% and 84%. Thus, we can assume cross reactive recognition of the two peptides in cases of these three donors. This demonstrable cross reactive recognition could possibly have an impact on GvL effect in patients after HSCT who suffered from Leukemia or Myeloma. KW - Kreuzreaktion KW - Cytomegalie-Virus KW - kreuzreaktive T-Zellen KW - virusspezifische T-Zellen KW - hämatopoetische Stammzelltransplantation KW - Graft versus Leukemia KW - CMV-Reaktivierung Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-303405 ER - TY - THES A1 - Läsker, Katharina T1 - The influence of the short-chain fatty acid butyrate on "Signal transducer and activator of transcription 3" (STAT3) and selected inflammatory genes in the colon carcinoma cell line CACO-2 cultured in 2D and 3D T1 - Der Einfluss der kurzkettigen Fettsäure Butyrat auf "Signal Übermittler und Aktivator der Transkription 3" (STAT3) und ausgewählte an der Entzündung beteiligte Gene in der Dickdarmkrebszelllinie CACO-2 im 2D- und 3D Modell N2 - A disturbance in the symbiotic mutualism between the intestinal microbiome and the human host’s organism (syn. dysbiosis) accompanies the development of a variety of inflammatory and metabolic diseases that comprise the Metabolic Syndrome, chronic inflammatory gut diseases like Crohn’s disease, Non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases, among others. The changed uptake and effectiveness of short chain fatty acids (SCFAs) as well as an increase of the intestinal permeability are common, interdependent disease elements in this regard. Short chain fatty acids are end-products of intestinal bacterial fermentation and affect the mucosal barrier integrity via numerous molecular mechanisms. There is evidence to suggest, that SCFAs have a modulating influence on Signal transducer and activator of transcription 3 (STAT3) in intestinal epithelial cells. STAT3 is a central gene-transcription factor in signaling pathways of proliferation and inflammation. It can be activated by growth factors and other intercellular signaling molecules like the cytokine Oncostatin M (OSM). The mode of STAT3’s activation exhibits, finally, a decisive influence on the immunological balance at the intestinal mucosa. Therefore, the posttranslational modification of STAT3 under the influence of SCFAs is likely to be a very important factor within the development and -progression of dysbiosis-associated diseases. In this study, a clear positive in vitro-effect of the short chain fatty acid butyrate on the posttranslational serine727-phosphorylation of STAT3 and its total protein amount in the human adenocarcinoma cell line CACO2 is verified. Moreover, an increased gene expression of the OSM-receptor subunit OSMRβ can be observed after butyrate incubation. Histone deacetylase inhibition is shown to have a predominant role in these effects. Furthermore, a subsequent p38 MAPK-activation by Butyrate is found to be a key molecular mechanism regarding the STAT3-phosphorylation at serine727-residues. To consider the portion of butyrate receptor signaling in this context in future assays, a CACO-2 cell 3D-culture model is introduced in which an improvement of the GPR109A-receptor expression in CACO-2 cells is accomplished. N2 - Eine Störung der symbiotischen Wechselbeziehung zwischen dem Darmmikrobiom und dem Wirtsorganismus (syn. Dysbiose) begleitet die Entwicklung vieler verschiedener entzündlicher und metabolischer Erkrankungen. Zu ihnen zählen unter anderem das Metabolische Syndrom, chronisch entzündliche Darmerkrankungen wie M. Crohn, die Nicht-alkoholische Fettlebererkrankung (NAFLD) und kardiovaskuläre Erkrankungen. Eine veränderte Aufnahme und Wirkung von kurzkettigen Fettsäuren (Short-chain fatty acids = SCFAs) und eine Schwächung der Darmbarriere bedingen sich in diesem Zusammenhang gegenseitig. Kurzkettige Fettsäuren sind Endprodukte des bakteriellen Stoffwechsels und beeinflussen die Integrität der Darmbarriere über eine Vielzahl molekularer Mechanismen. Es gibt Hinweise darauf, dass kurzkettige Fettsäuren einen modulierenden Einfluss auf „Signal transducer and activator of transcription 3“ (STAT3) in intestinalen epithelialen Zellen ausüben. STAT3 ist hier ein zentraler Gentranskriptionsfaktor in proliferations- und entzündungsregulierenden Zellsignalwegen. Er kann durch Wachstumsfaktoren und andere interzelluläre Botenstoffe, wie beispielsweise das Zytokin Oncostatin M (OSM), aktiviert werden. Die Art der Aktivierung von STAT3 wirkt sich nicht zuletzt entscheidend auf die immunologische Balance an der Darmbarriere aus. Die Modifikation von STAT3 durch kurzkettige Fettsäuren ist aufgrund dessen mit hoher Wahrscheinlichkeit ein sehr wichtiger Faktor im Hinblick auf Entstehung und Progression der im Zusammenhang mit einer Dysbiose stehenden Erkrankungen. In dieser Arbeit kann eine klare Steigerung der posttranslationalen Phosphorylierung von STAT3 an den Serin-Molekülendungen der Position 727 sowie eine Steigerung der Gesamtproteinmenge von STAT3 in der humanen Karzinomzellline CACO2 in vitro durch Butyrat-Inkubation gezeigt werden. Weiterhin wird unter Butyrat-Einfluss auch die Genexpression der OSM-Rezeptor-Untereinheit OSMRβ gesteigert. Diese Effekte können größtenteils auf den Mechanismus der Histondeacetylase-Hemmung durch Butyrat zurückgeführt werden. Die in der Folge erhöhte P38 MAPK-Phosphorylierung durch Butyrat ist in Bezug auf die Serin727-Phosphorylierung an STAT3 entscheidend beteiligt. Um in künftigen Assays auch den möglichen Einfluss der Butyrat-Rezeptor-Wirkung in diesem Zusammenhang besser zu erfassen, wird ein 3D-Zellkultur Ansatz getestet und in diesem eine verbesserte Expression des Butyrat-Rezeptors GPR109A in CACO-2-Zellen erreicht. KW - Butyrate KW - Signaltransduktion KW - Darmepithel KW - Cytokine KW - MAP-Kinase KW - butyrate KW - signal transduction KW - p38 MAPK KW - STAT3 KW - intestinal barrier KW - 3 dimensional cell culture model KW - CACO-2 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300389 ER - TY - THES A1 - Heinemann, Hannes T1 - Lebensqualität und Coping beim Multiplen Myelom T1 - Quality of Life and Coping with Multiple Myeloma N2 - Einführung: Beim Multiplen Myleom handelt es sich um eine bösartige Proliferation der Plasmazellen, wenn es auch nur 1% aller bösartigen Erkrankungen ausmacht, muss angesichts der steigenden Lebenserwartung von einer Zunahme der Fälle ausgegangen werden. Methoden: Diese Dissertation soll als Übersichtsarbeit zur QoL und Coping bei MM-Patienten und deren Angehörigen dienen. Es konnten 101 relevante Studien in der Literaturrecherche gefunden werden. Resultate: In allen Bereichen lag bei MM-Patienten, abgesehen von frühen Stadien oder bei Patienten mit CR, eine schlechtere QoL als bei der Referenzpopulation vor. Diese Ergebnisse waren unabhängig vom verwendeten QoL-Erhebungsinstrument. Vor allem die Tatsache, dass Multiples Myleom unheilbar ist, ist für die Patienten sehr belastend. Es lagen die unterschiedlichsten Coping-Mechanismen bei den Patienten und deren Angehörigen vor. Soziale Unterstützung war meistens der QoL förderlich, wenn es auch problematische Formen gab. Es konnten diverse, teils widersprüchliche Korrelationen von QoL und demographischen Faktoren, wie Alter und Geschlecht gefunden werden. Diskussion: Auch wenn in den letzten Jahren vermehrt in diesem Gebiet geforscht wurde, gestaltete es sich als schwierig Studien zu dem Thema zu finden und es bleibt zu hoffen, dass zukünftig ein größerer Fokus hier gelegt wird. N2 - Introduction: Multiple myeloma (MM) is a malignant proliferation of plasma cells, although it accounts for only 1% of all malignancies, with increasing life expectancy the number of cases is expected to increase. Methods: This dissertation is intended to serve as a review of quality of life (QoL) and coping in MM patients and their families. In the search in pubmed 101 relevant studies could be found. Results: In all areas, apart from early stages or patients with complete response, MM patients had a poorer QoL than the reference population. These results were independent of the QoL survey instrument used. Above all, the fact that MM is incurable is very stressful for patients. There were different coping mechanisms of the patients and their relatives. Social support was mostly conducive to QoL, although there were problematic forms. Various, sometimes contradictory correlations of QoL and demographic factors such as age and gender were found. Discussion: Even though in recent years there has been increased research in this area, it has proved difficult to find studies on the subject and it is to be hoped that there will be a greater focus here in the future. KW - Plasmozytom KW - QoL KW - Multiple Myeloma KW - review KW - coping KW - symptoms Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313227 ER - TY - THES A1 - Peschka, Melissa Edith Renate T1 - Der Einfluss der Wnt-Modulatoren Quercetin und Lithiumchlorid auf die Expression von Somatostatinrezeptoren und CXCR4 in Zelllinien neuroendokriner Tumoren T1 - The influence of wnt-signaling modulators quercetin and lithiumchloride on the expression of somatostatin receptors and cxcr4 in cell lines of neuroendocrine tumors N2 - In den letzten Jahrzehnten haben Inzidenz und Prävalenz von GEP NET deutlich zugenommen (Yao et al. 2008). Den SSTR kommt eine entscheidende Rolle bei zahlreichen etablierten Therapieverfahren zu. Allerdings stoßen die meisten Therapien bei G3 Tumoren oder bei langfristigem Einsatz an ihre Grenzen, was die Etablierung neuer, molekular zielgerichteter Therapien notwendig macht. Die Inhibition des Wnt-Signalweges stellt einen möglichen Ansatzpunkt für Therapien dar. Ziel dieser Arbeit war es die Wirkung der Wnt-Modulatoren Quercetin und Lithiumchlorid auf die Wnt-Aktivität sowie die Expression von Somatostatinrezeptoren und CXCR4 in den neuroendokrinen Tumorzelllinien QGP-1 und BON-1 zu untersuchen. Durch Real-Time PCR, Western Blots und Immunhistochemie wurden die Effekte auf RNA-, und Proteinebene sowie morphologisch analysiert und ausgewertet. An den verwendeten Zelllinien konnte gezeigt werden, dass Quercetin die Wnt-Signalgebung inhibierte, die SSTR-Expression steigerte und die CXCR4-Expression senkte. Lithiumchlorid bewirkte eine Wnt-Aktivierung und konnte über diesen Weg eine gesteigerte Expression von CXCR4 erzielen. Es konnte gezeigt werden, dass ein Zusammenhang zwischen der Aktivität des Wnt- Signalwegs und der Befähigung der GEP-NET Zelllinien zur SSTR- und CXCR4-Expression bestand. Die Wnt-Inhibierung kann über den Effekt der Steigerung von SSTR Teil neuer Therapiestrategien sein. So ist z.B. eine „add-on“ Therapie von Wnt-Inhibitoren wie Quercetin zusammen mit der PRRT denkbar. N2 - In the last few centuries there is a rising incidence and prevalence on GEP NET noticed (Yao et al. 2008). SSTR are important for established therapy procedures. But there is limitation for most therapies among G3 tumors and in long-term use. So new therapy strategies are needed. Wnt-signaling inhibitors are a potential agent. Aim of this work was to investigate the influence of wnt-signaling modulators quercetin and lithiumchloride on the expression of SSTR and CXCR4 in neuroendocrine tumor cell lines QGP-1 and BON-1. A real-time PCR, western blot and immunohistochemistry were performed. The used cell lines showed that quercetin inhibits wnt-signaling, increases SSTR expression and decreases CXCR4 expression. Lithiumchloride activated Wnt signalling and increased CXCR4 expression. It was shown that there is an association between activated wnt-signaling and the ability of GEP NET cell lines to express SSTR and CXCR4. Wnt inhibition could be part of new strategies for therapy by the effect of increased SSTR expression. For example, an “add on” therapy with wnt inhibitor quercetin in PRRT is a opportunity. KW - Quercetin KW - Neuroendokriner Tumor KW - Wnt KW - GEP-NET Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-327386 ER - TY - THES A1 - Ullmann, Monika Anna T1 - Clostridioides difficile Infektionen im Klinikum Aschaffenburg-Alzenau - Retrospektive Analyse des Zeitraums 01/2013-05/2015 - T1 - Clostridioides difficile infections at the Aschaffenburg-Alzenau Hospital - Retrospective analysis of the period 01/2013-05/2015 - N2 - Die CDI ist weltweit die häufigste Ursache der antibiotikaassoziierten nosokomialen Diarrhoe. Sie geht mit steigender Inzidenz, Hospitalisierung und hohen Behandlungskosten in Milliardenhöhe einher. Auch im ambulanten Sektor werden steigende Infektionszahlen gemeldet, die nicht nur ein Problem für die Krankenhäuser, sondern auch für die Pflegeeinrichtungen darstellen. Ziel dieser Arbeit war es, retrospektiv die CDI-Fälle des Klinikums Aschaffenburg-Alzenau (ausgenommen Kinderklinik) im Zeitraum 01.01.2013 - 25.05.2015 zu erfassen und die antibiotische Initialtherapie zu ermitteln. Für die Diagnose einer CDI wurde ein positiver Toxinnachweis in der Stuhlkultur vorausgesetzt. Im weiteren Fokus standen die Rezidivhäufigkeit, die antibiotische Folgetherapie, die Komplikationen bis hin zu den Todesursachen sowie Präventionsmaßnahmen. Im o.g. Zeitraum waren 299 Patienten und Patientinnen mit einer CDI hospitalisiert. Das mittlere Alter lag bei 73,8 Jahren. Es handelte sich in der Mehrzahl um multimorbide und immunsupprimierte Patienten und Patientinnen. 61% waren antibiotisch vorbehandelt. Am häufigsten verwendet wurden Breitbandpenicilline (36%), Cephalosporine der 3. Generation (12%) und Fluorchinolone (10%). Über 1/3 der Patienten und Patientinnen wurde mit Mehrfachkombinationen behandelt und bei 2% war eine zytostatische Behandlung vorausgegangen. In der Initialtherapie der CDI kam bei fast der Hälfte Erkrankten (47%) Metronidazol zur Anwendung. Die Rezidivrate lag bei 20%, Mehrfachrezidive traten bei 5,7% auf. Die antibiotische Folgetherapie der CDI erfolgte bei 39% der Patienten und Patientinnen mit Vancomycin oder Fidaxomicin entsprechend den damals geltenden Empfehlungen leitlinienkonform. Rund ¼ aller Erkrankten verstarben, davon 17% CDI-assoziiert. Der fäkale Stuhltransfer, der ab dem 2. Rezidiv empfohlen wird, und die Genotypisierung bei Mehrfachrezidiven wurde in keinem Fall durchgeführt. 2021 wurde die CDI-Behandlungsleitlinie der ESCMID aktualisiert. Statt dem Einsatz von Metronidazol werden nun Fidaxomicin oder Vancomycin, in Rezidivsituationen die Standardantibiose um den Antikörper Bezlotoxumab ergänzt. 06/2023 erschien die Konsultationsfassung der S2k-Leitlinie “Gastrointestinale Infektionen und Morbus Whipple” der DGVS. Die Empfehlungen gleichen sich. Es kann festgehalten werden, dass die CDI auch im Klinikum Aschaffenburg-Alzenau ein ernstes Problem darstellt, das Präventionsmaßnahmen bedarf. Die Rezidiv- und Todesraten sind hoch. In dieser Arbeit konnte bestätigt werden, dass der unbedachte Einsatz von Antibiotika ein wichtiger Hauptrisikofaktor für die Entstehung einer CDI ist. Daher sollte die Indikation für eine antibiotische Therapie streng gestellt werden. Die Daten zeigen ferner, dass die Umsetzung aktueller Leitlinienempfehlungen nicht oder zeitlich verzögert erfolgte. Seit der Etablierung und Umsetzung des ABS 2017 am Klinikum Aschaffenburg-Alzenau konnte ein Rückgang der CDI um 21% verzeichnet werden. Ein ABS ist eine Möglichkeit die konsequente Anwendung aktueller Empfehlungen im klinischen Alltag umzusetzen und so zu einer höheren Erfolgsrate der Behandlung und einer niedrigeren Rezidivrate beizutragen. Die Umsetzung einer gezielten frühen Diagnostik, Schutz- und Isoliermaßnahmen, Surveillance und regelmäßige Fort- und Weiterbildung der Mitarbeiter*innen sind weitere wichtige Bausteine, die zur Prävention der CDI beitragen. N2 - CDI is the most common cause of antibiotic-associated nosocomial diarrhea worldwide. It is accompanied by rising incidence, hospitalization and high treatment costs in the billions. Rising numbers of infections are also reported in the outpatient sector, posing a problem not only for hospitals, but also for care facilities. The aim of this study was to retrospectively record the CDI cases of the Aschaffenburg-Alzenau Hospital (except for the Children's Hospital) in the period 01.01.2013 - 25.05.2015 and to determine the initial antibiotic therapy. For the diagnosis of CDI, a positive toxin detection in the stool culture was required. The focus was also on the frequency of recurrence, antibiotic follow-up therapy, complications and causes of death, and preventive measures. In the above-mentioned period, 299 patients with CDI were hospitalized. The median age was 73.8 years. The majority of them were multimorbid and immunosuppressed patients. 61% were pre-treated with antibiotics. The most commonly used antibiotics were broad-spectrum penicillins (36%), 3rd generation cephalosporins (12%) and fluoroquinolones (10%). In the initial therapy of CDI, metronidazole was used in almost half of the patients (47%). The recurrence rate was 20%, multiple recurrences occurred at 5.7%. Follow-up antibiotic therapy of CDI was carried out in 39% of patients with vancomycin or fidaxomicin in accordance with the guidelines in force at the time. About 1/4 of all patients died, 17% of them CDI-associated. Fecal microbiota transplantation, which is recommended from the 2nd recurrence, and genotyping in case of multiple recurrences was not performed in any case. In 2021, ESCMID's CDI treatment guideline, was updated. Instead of the use of metronidazole, fidaxomicin or vancomycin are now supplemented, and in relapse situations, the standard antibiosis is supplemented by the antibody bezlotoxumab. 06/2023, the consultation version of the S2k guideline "Gastrointestinal Infections and Whipple's Disease" of the DGVS was published. The recommendations are similar. It can be stated that CDI is also a serious problem at the Aschaffenburg-Alzenau Hospital, which requires preventive measures. The recurrence and Death rates are high. This study confirmed that the careless use of antibiotics is an important main risk factor for the development of CDI. Therefore, the indication for antibiotic therapy should be set strictly. The data also show that the implementation of current guideline recommendations did not take place or was delayed. Since the establishment and implementation of the ABS in 2017 at the Aschaffenburg-Alzenau Hospital, a 21% decline in CDI has been recorded. An ABS is a way to implement the consistent application of current recommendations in everyday clinical practice and thus contribute to a higher success rate of treatment and a lower recurrence rate. The implementation of targeted early diagnostics, protective and isolation measures, surveillance and regular further education and training of employees are further important building blocks that contribute to the prevention of CDI. KW - Clostridium-difficile-Infektion KW - CDI KW - Rezidiv KW - Antibiotic stewardship Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-328085 ER - TY - THES A1 - Gotthardt [geb. Schubert], Sonja T1 - Einfluss von Oncostatin M auf die Pathogenese der Nicht-alkoholischen Fettlebererkrankung T1 - Influence of Oncostatin M on the pathogenesis of non-alcoholic fatty liver disease N2 - Die Nicht-alkoholische Fettlebererkrankung (NAFLD) ist eine der häufigsten chronischen Lebererkrankungen der westlichen Welt. Die Pathogenese der Erkrankung ist noch nicht vollständig erforscht und wirksame medikamentöse Therapien sind bisher nicht zugelassen. Wachsende Evidenz zeigt, dass das Interleukin-6-Typ-Zytokin Oncostatin M (OSM) eine wichtige Rolle in der Pathogenese der NAFLD spielt. Die japanische Arbeitsgruppe um Komori et al. zeigte an OSM-Rezeptor-β-defizienten (Osmr-KO-) Mäusen sowie durch OSM-Behandlung von genetisch und ernährungsbedingt adipösen Mäusen, dass OSM vor einer hepatischen Steatose und metabolischer Komorbidität schützen kann. Andere Publikationen suggerieren, dass OSM an NAFLD-Entwicklung und -Progression beteiligt ist, indem es die Expression von Genen der β-Oxidation und Very-Low-Density-Lipoprotein (VLDL-) Sekretion reprimiert und die Expression profibrogenetischer Gene fördert. Low-Density-Lipoprotein-Rezeptor-defiziente- (Ldlr-KO-) Mäuse sind seit Langem als Atherosklerose-Modell etabliert und wurden zuletzt auch als physiologisches Modell für NAFLD identifiziert. Um die Rolle von OSM in der NAFLD-Pathogenese zu beleuchten, wurden Osmr-KO-Mäuse auf Wildtyp- (WT-) und Ldlr-KO-Hintergrund untersucht, die über 12 Wochen eine fett- und cholesterinreiche Western Diet erhielten und anschließend für die Organentnahme geopfert wurden. Im Vorfeld dieser Arbeit wurden Körpergewicht, Blutglukose, Serum-Cholesterin und Lebergewicht der Tiere gemessen. Hierbei zeigte sich ein erhöhtes Körpergewicht, unveränderte Blutglukose, erhöhtes Serum-Cholesterin sowie ein erhöhtes Lebergewicht in Osmr-KO- gegenüber WT-Mäusen. Andersherum waren Körpergewicht, Blutglukose, Serum-Cholesterin und Lebergewicht in Ldlr-Osmr-KO- gegenüber Ldlr-KO-Mäusen vermindert. Im Rahmen der vorliegenden Arbeit erfolgte die histologische Untersuchung des Lebergewebes, die Messung von Serum-Triglyzeriden und Fettsäuren sowie die Untersuchung der hepatischen Genexpression. An kultivierten Zellen der humanen Hepatom-Zelllinie HepG2 wurde eine mögliche Regulation der CYP7A1-Genexpression durch OSM untersucht. CYP7A1 ist als Schrittmacherenzym der Gallensäuresynthese an der hepatischen Cholesterin-Clearance beteiligt. Osmr-KO-Mäuse zeigten gegenüber WT-Mäusen histologisch eine verstärkte hepatische Steatose. Bei der Untersuchung der mRNA-Expression von Genen mit Beteiligung an der hepatischen Lipidhomöostase zeigte sich eine Minderexpression von Ldlr in Osmr-KO-Mäusen. Weiterhin zeigte sich eine etwas geringere Expression von Cyp7a1 in Osmr-KO-Mäusen. Die Expression aller anderen untersuchten Gene, die an Fettsäuresynthese, Cholesterintransport und –metabolismus beteiligt sind, lieferten keine Erklärung für eine erhöhte hepatische Lipidakkumulation in Osmr-KO-Mäusen. Ldlr-Osmr-KO-Mäuse hatten gegenüber Ldlr-KO-Mäusen eine geringer ausgeprägte hepatische Steatose. Die mRNA-Expression von Genen der Fettsäuresynthese, der Cholesterinbiosynthese und des Cholesterintransports waren in Ldlr-Osmr-KO- gegenüber Ldlr-KO-Mäusen nicht wesentlich verändert. Allerdings fiel eine deutliche Hochregulation von Cyp7a1 in Ldlr-Osmr-KO-Mäusen auf. Darüber hinaus war Osm in Ldlr-KO-Mäusen gegenüber WT-Mäusen stärker exprimiert. Um eine Regulation von CYP7A1 durch OSM nachzuweisen, wurde die Genexpression in HepG2-Zellen nach Stimulation mit OSM untersucht. Hierbei zeigte sich, dass OSM die mRNA-Expression von CYP7A1 supprimierte. Dieser Effekt war durch die Zugabe von Inhibitoren der Januskinasen (JAK), Mitogen Activated Protein Kinase/ERK-Kinase (MEK) und Extracellular-signal Regulated Kinase ½ (ERK1/2) reversibel. Die CYP7A1-Suppression durch OSM ging mit einer verminderten Expression des Transkriptionsfaktor-Gens HNF4A einher. Osmr-KO-Mäuse zeigten gegenüber WT-Mäusen nach 12 Wochen Western Diet verstärkte Adipositas, Dyslipidämie sowie eine hepatische Steatose. Die Analyse der hepatischen mRNA-Expression legt nahe, dass die Minderexpression von Ldlr in Osmr-KO-Mäusen im Vergleich zu WT-Mäusen zur Verstärkung der Dyslipidämie und hepatischen Steatose beigetragen hat. Weiterhin kann die geringere Expression von Cyp7a1 in Osmr-KO-Mäusen durch daraus resultierende Akkumulation von Cholesterin zur erhöhten hepatischen Lipidakkumulation in diesen Mäusen beigetragen haben. Ldlr-KO-Mäuse zeigten nach 12 Wochen Western Diet ebenfalls eine hepatische Steatose. Diese war in Ldlr-Osmr-KO-Mäusen gegenüber Ldlr-KO-Mäusen geringer ausgeprägt. Die erhöhte Expression von Cyp7a1 in Ldlr-Osmr-KO-Mäusen kann die Verbesserung von hepatischer Lipidakkumulation und Dyslipidämie durch erhöhte Cholesterinmetabolisierung zu Gallensäuren erklären. Übereinstimmend mit der Cyp7a1-Regulation in LDLR-defizienten Mäusen zeigte sich in vitro, dass OSM die Expression von CYP7A1 in HepG2-Zellen vermindert und sich so negativ auf die hepatische Lipidhomöostase auswirken kann. Insgesamt implizieren diese Ergebnisse eine divergierende Rolle von OSM bei der Entwicklung einer hepatischen Steatose abhängig vom genetischen Hintergrund. OSM scheint bei WT-Mäusen für die Erhaltung der metabolischen Gesundheit wichtig zu sein. Bei Ldlr-KO-Mäusen hingegen scheint OSM die Entwicklung von Adipositas, Dyslipidämie und hepatischer Steatose zu fördern. Die differenzielle Rolle in WT- und Ldlr-KO-Mäusen könnte durch unterschiedliche Osm-Expressionsspiegel zustande kommen: Während basale OSMRβ-Signaltransduktion durch geringe OSM-Spiegel in WT-Mäusen für die Lipidhomöostase essenziell zu sein scheint, könnte erhöhte oder prolongierte OSMRβ-Signaltransduktion durch höhere OSM-Spiegel in Ldlr-KO-Mäusen das Fortschreiten der hepatischen Steatose fördern. Dies stellt OSM als mögliches NAFLD-Therapeutikum in Frage. Um die Hypothese zu überprüfen, dass OSM abhängig von der Höhe und Kinetik der Spiegel günstige oder ungünstige Effekte auf die NAFLD-Entwicklung hat, sollte in zukünftigen Experimenten der Einfluss kurz- und langfristiger Behandlung von WT-Mäusen mit OSM unterschiedlicher Konzentrationen auf die Entwicklung einer hepatischen Steatose untersucht werden. N2 - Non-alcoholic fatty liver disease (NAFLD) is among the most common chronic liver diseases in Western societies. Pathogenetic mechanisms are not fully elucidated and to date there is no approved drug therapy available. There is mounting evidence that the Interleukin-6-type-cytokine Oncostatin M (OSM) plays a crucial role in the pathogenesis of NAFLD. The Japanese working group of Komori et al. had shown that OSM has favorable effects on metabolism und protects against hepatic steatosis using OSM-receptor-β-deficient (Osmr-KO-) mice as well as OSM treatment of genetically or diet-induced obese mice. Other publications suggest that OSM contributes to the pathogenesis and progression of NAFLD by reducing the expression of genes involved in β-oxidation and Very-Low-Density-Lipoprotein (VLDL) secretion and inducing the expression of genes involved in fibrogenesis. Recently Low-Density-Lipoprotein-Receptor-deficient (Ldlr-KO-) mice, which are a well-established model for atherosclerosis, have also been considered a physiological model for NAFLD. To further investigate the role of OSM in NAFLD pathogenesis Osmr-KO mice on either wild type- (WT-) or Ldlr-KO-background were fed a high-fat and high-cholesterol Western diet for 12 weeks and were then sacrificed for tissue collection. Prior to the present thesis body weight, blood glucose levels, serum cholesterol and liver weight of the mice were measured. Osmr-KO mice showed increased body weight, serum cholesterol levels and liver weight compared to WT mice, whereas blood glucose levels did not differ. On the contrary, Ldlr-Osmr-KO mice showed decreased values in all parameters compared to Ldlr-KO mice, including body weight, blood glucose levels, serum cholesterol levels and liver weight. In the present thesis a histological examination of the liver tissue was made, serum levels of triglycerides and fatty acids were measured, and hepatic gene expression was analyzed. In cultured cells of the human hepatoma cell line HepG2 a potential regulation of CYP7A1 gene expression by OSM was examined. CYP7A1 is the rate limiting enzyme of bile acid synthesis and is therefore involved in hepatic cholesterol clearance. Osmr-KO mice showed enhanced hepatic steatosis compared to WT mice. Examination of gene expression involved in hepatic lipid homeostasis revealed reduced Ldlr expression levels in Osmr-KO mice. Furthermore, a slightly decreased Cyp7a1 expression was observed. The expression of other genes involved in fatty acid synthesis, cholesterol transport and cholesterol metabolism did not explain the enhanced hepatic lipid accumulation in Osmr-KO mice. In Ldlr-Osmr-KO mice hepatic steatosis was reduced compared to Ldlr-KO mice. The expression of genes involved in fatty acid synthesis, cholesterol synthesis and cholesterol transport was not considerably altered in Ldlr-Osmr-KO compared to Ldlr-KO mice. However, Cyp7a1 was markedly upregulated in Ldlr-Osmr-KO mice. In addition, Osm expression was increased in Ldlr-KO mice compared to WT mice. To prove the regulation of CYP7A1 by OSM, gene expression was determined in OSM-treated HepG2 cells. The results show that OSM attenuated CYP7A1 expression. This effect was reversed by the addition of inhibitors of either januskinases (JAK), mitogen-activated protein kinase/ERK-kinase (MEK) or extracellular-signal regulated kinase 1/2 (ERK1/2). CYP7A1-suppression by OSM was accompanied by reduced expression levels of the transcription factor gene HNF4A. After 12 weeks of Western diet Osmr-KO mice showed enhanced obesity, dyslipidemia and hepatic steatosis compared to WT mice. Determination of hepatic gene expression suggests that decreased expression of Ldlr in Osmr-KO mice compared to WT mice contributes to dyslipidemia and hepatic steatosis. Furthermore, the decreased expression of Cyp7a1 in Osmr-KO mice may contribute to cholesterol accumulation and accordingly to hepatic lipid accumulation in these mice. Ldlr-KO mice also showed hepatic steatosis after 12 weeks of Western diet. In comparison, hepatic steatosis was markedly reduced in Ldlr-Osmr-KO mice. Increased expression levels of Cyp7a1 and hence enhanced metabolization of cholesterol to bile acids in Ldlr-Osmr-KO mice can explain improved hepatic lipid accumulation and dyslipidemia in these mice compared to Ldlr-KO mice. Consistent with the discovered Cyp7a1 regulation in LDLR-deficient mice, OSM decreased the expression of CYP7A1 in HepG2 cells and therefore may have detrimental effects on hepatic lipid homeostasis. Altogether the results implicate a diverging role of OSM in the pathogenesis of hepatic steatosis depending on the genetic background. In WT mice OSM seems to convey protective effects on lipid homeostasis, whereas in Ldlr-KO mice OSM seems to promote the development of obesity, dyslipidemia and hepatic steatosis. The differential role of OSM in WT and Ldlr-KO mice might be caused by diverging Osm expression levels: Basal OSMRβ signal transduction caused by low OSM levels seems to be essential for lipid homeostasis, whereas enhanced or prolonged OSMRβ signal transduction caused by higher OSM levels might foster the progression of hepatic steatosis. These findings question OSM as a putative therapeutic agent for NAFLD. To test the hypothesis that OSM has beneficial or detrimental effects on NAFLD pathogenesis depending on OSM levels and kinetics, future studies should examine the effect of short- and long-term administration of OSM in different concentrations on the development of hepatic steatosis in WT mice. KW - Fettleber KW - Interleukin 6 KW - Leukaemia-inhibitory factor KW - Cholesterinstoffwechsel KW - Fettsäurestoffwechsel KW - NAFLD KW - Oncostatin M KW - Osmr-Knockout KW - Ldlr-Knockout KW - CYP7A1 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281312 ER - TY - THES A1 - Fischer, Julia Katrin T1 - Evaluation der Lebensqualität von Patienten mit Multiplem Myelom mittels standardisierter Fragebögen der EORTC T1 - Evaluation of health-related quality of life in patients with multiple myeloma by using standardized questionnaires of the EORTC N2 - Im Rahmen dieser Studie wurde die Lebensqualität (QoL) von Patienten mit Multiplem Myelom zu verschiedenen Therapiezeitpunkten untersucht. Dabei erwies sich die erstmals im Rahmen einer Studie mit Myelompatienten angewandte Kombination aus PHQ-4, EORTC QLQ-C30 und dem spezifischen -MY20 Fragebogen als geeignetes Instrument zur validen Erfassung von Ängstlichkeit/Depressivität und Lebensqualität. Insgesamt schätzten Erstlinienpatienten, Männer und jüngere Patienten vor, während und nach der Therapie ihre Lebensqualität positiver ein, sodass insbesondere Rezidivpatienten, Frauen und ältere Patienten von einer intensivierten therapiebegleitenden supportiven Betreuung profitieren könnten. Es sollte bei der Therapiewahl berücksichtigt werden, dass Erstlinienpatienten zum einen über eine insgesamt bessere allgemeine QoL und geringere Schmerzen als Rezidivpatienten berichteten und zum anderen es durch die systemische Therapie bei diesen zu einer weiteren Verbesserung kommen kann. Unabhängig hiervon korrelierte der ECOG-Status signifikant mit der QoL und sollte daher regelmäßig erhoben werden. Während der Therapie kam es bei Myelompatienten v.a. zu einer negativeren Wahrnehmung des eigenen Körperbilds, einer Abnahme der kognitiven Funktion und einer Zunahme der Therapienebenwirkungen, sodass interdisziplinäre Behandlerteams neben einem optimalen Nebenwirkungsmanagement auch in der klinischen Routine noch nicht so fest etablierte Ressourcen berücksichtigen sollten, wie z.B. psychoedukative Interventionen, Entspannungsverfahren oder auch kognitives Training. Eine der wichtigsten Erkenntnisse der Studie war die signifikant reduzierte Lebensqualität bei Patienten mit vermehrter Ängstlichkeit/Depressivität, die die Notwendigkeit eines regelmäßigen Screenings in der klinischen Routine aufzeigt, um Risikopatienten entsprechend zu identifizieren. Trotz der vermuteten Lebensqualitätsbeeinflussung durch die intensivere, längere Therapie, zeigten sich bei Tandemtransplantierten nicht mehr Lebensqualitätsvariablen signifikant negativ beeinflusst als beim Gesamtkollektiv, sodass diese Beobachtung eine wertvolle Entscheidungshilfe für Patienten sein könnte, die aus Sorge vor einer reduzierten Lebensqualität transplantationsbasierten Konzepten zurückhaltend gegenüberstehen. Unter Berücksichtigung der o.g. Limitationen, konnte zusätzlich eine deutliche positive Beeinflussung der Lebensqualität durch Teilnahme an klinischen Therapiestudien aufgezeigt werden, sodass Patienten evtl. von einer noch intensiveren multiprofessionellen Begleitung wie sie in Studiensettings gegeben ist profitieren könnten. N2 - Background: Multiple myeloma (MM) is an incurable hematologic malignancy with increasing importance and incidence due to an aging population. Currently, it’s the third most common haematological cancer worldwide. A multitude of therapeutic options for the treatment of MM is available. Each has a different range of adverse events and dependent on this, a varying influence on the health-related quality of life (HRQoL). As of yet, little is known about the impact of the different therapeutic options, especially during and after treatment on HRQoL, so this should be investigated. Also, this study aims to show the influences on the HRQoL of some other patient characteristics like anxiety/depression, gender, age etc. Additionally, the influence of participation in a clinical trial on HRQoL should be examined. The aim of this study is to identify patients with MM at a higher risk for decreased HRQoL under therapy to provide a basis for the consideration of those results in clinical decisions. Methods: In this prospective observational study, the HRQoL of MM patients with different therapies (first-line and higher-treatment-lines) was quantified by standardized questionnaires (EORTC QLQ-C30 and -MY20) in the context of individual depressiveness (PHQ-4), sociodemographic data, and a selected number of symptoms and clinical parameters. In case of treatment without stem cell transplantation, there was a baseline assessment before the start of therapy and two following assessments after the end of the treatment. In case of autologous/allogeneic/tandem-stem cell transplantation, in addition to the baseline assessment, there were two or three following assessments to measure the HRQoL during and after treatment. Results: In total, 70 patients were included in the study. Global health status was significantly higher in patients with first-line treatment and with less anxiety/depression. HRQoL decreased significantly after start of chemotherapy in the parameters body image, side effects of treatment and cognitive functioning. There was no impairment in further HRQoL parameters in patients with tandem-stem cell transplantation in comparison to the whole sample. After start of the therapy there was an increasing global health status and a decreasing pain level in patients with first-line, in contrast of both in patients with a treatment of a recurrent disease. In case of treatment as part of clinical trials, most aspects of HRQoL were indicated better, too. HRQoL scales were especially influenced by gender, age, Eastern Cooperative Oncology Group (ECOG) performance status and bone symptoms with better assessment of men, younger patients, lower ECOG index and less bone symptoms. Conclusion: Anxiety and depression, male gender, older age, higher ECOG status and bone symptoms can be early indicators for a reduced HRQoL of patients undergoing a therapy for MM. Especially patients with a higher-treatment-line need psycho-oncological support during chemotherapy. Additionally, because of the better HRQoL in most parameters, a treatment as part of clinical trials should be contemplated. However, due to inclusion criteria for clinical trials, it might be difficult to compare them with patients treated within standard therapy concepts. KW - Lebensqualität KW - Plasmozytom KW - Depressivität KW - PHQ-4 KW - Ängstlichkeit/Depressivität KW - Multiples Myelom KW - Prospektive klinische Verlaufsstudie KW - EORTC Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-316628 N1 - Teile der Ergebnisse der Diss. sind bereits in einem Zeitschriftenaufsatz veröffentlicht worden (Zeitschrift BMC Cancer): https://bmccancer.biomedcentral.com/articles/10.1186/s12885-022-10101-9 ER - TY - THES A1 - Geis, Maria T1 - Identifizierung von Zielmolekülen und Herstellung zweigeteilter trivalenter T-Zell-aktivierender Antikörperderivate zur immuntherapeutischen Behandlung von Multiplen Myelom T1 - Target identification and generation of trivalent T-cell activating antibody derivatives for multiple myeloma immunotherapy N2 - T-Zell-aktivierende Formate, wie BiTE (bispecific T-cell engagers) Antikörper und CAR T Zellen haben in den vergangen Jahren die Therapiemöglichkeiten für Tumorpatienten erweitert. Diese Therapeutika verknüpfen T-Zellen mit malignen Zellen über je ein spezifisches Oberflächenmolekül und initiieren, über eine T-Zell-vermittelte Immunantwort, die Lyse der Tumorzelle. Tumorspezifische Antigene sind jedoch selten. Häufig werden Proteine adressiert, die neben den Tumorzellen auch auf gesunden Zellen exprimiert werden. Die Folgen sind toxische Effekte abseits der Tumorzellen auf Antigen-positiven gesunden Zellen (on target/off tumor), welche nicht nur die Dosis des Therapeutikums und dessen Effektivität limitieren, sondern zu geringen bis letalen Begleiterscheinungen führen können. Der Bedarf an effektiven Therapieformen mit geringen Nebenwirkungen ist folglich immer noch sehr hoch. Diese Lücke soll durch ein neues Antikörperformat, sogenannten Hemibodies, geschlossen werden. Hemibodies sind eine neue Klasse von T-Zell-aktivierenden Antikörpern, die sich gegen eine Antigenkombination und nicht einzelne Antigene auf Tumorzellen richten. Sie bestehen aus zwei komplementären Molekülen mit je einer Antigen-bindenden Sequenz, die entweder mit der leichten (VL) oder der schweren (VH) Kette eines T-Zell-aktivierenden anti CD3 Antikörpers fusioniert ist. Nur wenn beide Hemibody-Fragmente gleichzeitig in unmittelbarer Nähe an ihr jeweiliges Antigenepitop auf der Tumorzelle binden, komplementieren die beiden Antikörperkonstrukte über das geteilte anti-CD3 und bilden einen trivalenten T Zell aktivierenden Komplex aus. Diese funktionale Einheit rekrutiert T-Zellen zur Tumorzelle und induzierte die T-Zell-vermittelte Lyse der malignen Zelle. Im Rahmen der vorliegenden Arbeit wurden geeignete Antigenkombinationen identifiziert und die erste effektive und spezifische Hemibody-basierte Immuntherapie gegen das Multiple Myelom (MM), ohne Nebenwirkungen auf Antigen-einfach-positiven gesunden Zellen, entwickelt. Basierend auf einer umfangreichen Analyse von Kandidaten-Antigenen wurden Kombinationen aus bekannten MM Zielmolekülen, wie BCMA, CD38, CD138, CD229 und SLAMF7, und für das MM unbekannte Oberflächenmolekülen, wie CHRM5 und LAX1, untersucht. Gegen die vielversprechendsten Antigene wurden Hemibodies entwickelt und produziert. Im Zusammenhang mit Analysen zur Produzierbarkeit sowie biochemischen und funktionalen Charakterisierungen, konnte aus 75 initialen Hemibody-Kombinationen drei Kombinationen mit geeigneten Eigenschaften identifiziert werden. Die Bindung von zwei Hemibody-Partnern auf der Oberfläche der MM Zelle führte zur Ausbildung eines trivalenten T-Zell-rekrutierenden Komplexes. Dieser initiierte nachfolgend über eine T-Zell-vermittelte Immunantwort die spezifische Lyse der malignen Zellen, ohne die Viabilität von Antigen-einfach-positiven gesunden Körper- oder Effektor-Zellen zu beeinflussen. Zusätzlich führte eine Hemibody-Therapie in vivo in einem NOD SCID MM-Mausmodel innerhalb von 7 Tagen zur kompletten Remission der MM Zellen. Diese Daten zeigten Hemibodies als ein neues, sehr vielversprechendes Antikörperformat für eine effektive und tumorspezifische Immuntherapie mit potentiell geringen Nebenwirkungen. N2 - T-cell activating therapies such as BiTEs (bispecific T-cell engagers) and CAR-T-cells have broadened the treatment options for cancer patients in the past years. These therapeutics induce a T-cell mediated immune response by linking T-cells with malignant cells by a specific target on the tumor cell. Tumor-specific antigens are rare and often antigens expressed on malignant and healthy tissues are addressed. Consequently, dosage and efficacy are limited by on-target/off-tumor toxicities, which can cause severe side effects. Efficient therapies with no side effects are still needed. To overcome these limitations and fill the gap of existing cancer immunotherapies, our novel strategy, coined hemibodies, targets an aberrant antigen signature uniquely expressed on tumor cells. Hemibodies are a new class of T-cell engaging antibodies consisting of two complementing molecules. Each hemibody molecule can bind one specific target on a tumor cell using a scFv fused to either the variable heavy (VH) or light (VL) chain domain of a T-cell activating anti-CD3 antibody. When both hemibodies simultaneously bind their specific target, the VL- and the VH-domain reconstitute and form a functional anti-CD3 domain, enabling T-cell recruitment for tumor cell lysis. This way, hemibodies form a trivalent protein complex only on tumor cells for safe cancer immunotherapy. The following work presents target combinations and the first hemibody-based immunotherapy for a precise multiple myeloma (MM) treatment, without side effects, on target-single-positiv cells. Besides combinations of known and often reported MM targets like CD138, CD38, BCMA and SLAMF7, new targets including CHRM5 and LAX1 are described. Moreover, three hemibody combinations out of 75 promising target combinations were identified that displayed favorable production and purification data as well as biochemical and functional characteristics. We demonstrated that hemibodies are able to recognize and bind MM cells on their specific targets and form a functional trivalent T-cell activating complex for tumor cell lysis. In contrast to BiTE antibodies, hemibody-fragments alone and in combination had no/low effects on the viability of target-single positive cells or on T-cells in the absence of tumor cells. Only in the presence of MM cells, hemibodies recruit T-cells to the tumor site and induce tumor specific lysis. In addition, human T-lymphocytes rejected MM cells after treatment with a hemibody combination for seven days in a murine NOD SCID model. In aggregate, the data reported here identified hemibodies as a promising therapeutic protein format for effective and safe cancer immunotherapy. KW - zweigeteilte trivalente T-Zell-aktivierende Antikörperderivate KW - Hemibodies Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186906 ER - TY - THES A1 - Muhr, Christiane T1 - Optimierung eines molekularen Verfahrens zur Quantifizierung des Chimärismus nach allogener Stammzelltransplantation T1 - Optimization of a molecular method for the quantification of chimerism after allogeneic stem cell transplantation N2 - Die molekulare Chimärismusdiagnostik stellt einen essenziellen Teil der Therapieüberwachung nach allogener HSZT dar. In der Uniklinik Würzburg wird hierbei mittels qPCR eines Panels von 21 Allelen eine Informativität von 95 % und eine Sensitivität von 0,1-0,01 % erreicht. Ziel der Arbeit war eine Optimierung dieser in unserem Labor angewandten Methode zur Chimärismusanalyse in puncto Sensitivität und Informativität. Es wurde untersucht, ob durch Steigerung des DNA-Inputs in die qPCR eine Sensitivitätserhöhung erzielt werden kann, ohne dass PCR-Inhibition auftritt. Dabei erwies sich ein DNA-Input von 250 ng als ideal für eine verlässlichere Detektion von 0,01 % Empfängerzellen. PCR-Inhibition trat nicht auf. Zur Deckung des damit einhergehendem erhöhten DNA-Bedarf wurden verschiedene Elutionsmethoden der DNA-Extraktion verglichen, wobei durch Extraktion mit dem QIAamp DNA Blood Midi-Kit und Elution mit 2 x 200 μl AE-Puffer der höchste DNA-Ertrag gewonnen wurde. Zur Erhöhung der Informativität wurde die Anwendbarkeit eines Primersets für qPCR des SNP rs713753 evaluiert. Hierbei zeigte sich eine mäßige Eignung: Beide Allele des SNP gemeinsam ergaben eine gute Informativität für Empfängerdiskriminierung von 37,5 %. Die qPCR-Effizienzen der lokusspezifischen Referenz und des Allels C waren nahezu optimal, die des Allels T lag lediglich bei 0,87. Die Sensitivität der spezifischen Allele lag bei max. 0,1 %. Sofern auch hier eine Sensitivitätssteigerung durch Erhöhung des DNA-Inputs in die qPCR ohne Auftreten unspezifischer Amplifikation möglich ist, wäre eine Integration der qPCR des SNP rs713753 in die Routinediagnostik denkbar. Zusammenfassend ist eine Optimierung der in unserem Labor angewandten Methode zur Chimärismusdiagnostik hinsichtlich Sensitivität und Informativität durchaus möglich. Eine Erhöhung des DNA-Inputs ist dabei am simpelsten umsetzbar; zur Etablierung weiterer Allele bedarf es zusätzlicher Experimente. N2 - The monitoring of molecular chimerism is an essential part of the follow-up after allogeneic hematopoietic stem cell transplantation. At the University Hospital of Würzburg, a qPCR panel consisting of 21 alleles achieves an informativity of 95 % and a sensitivity of 0.1-0.01 %. The aim of this study was the optimization of the chimerism analysis method used in our laboratory in terms of sensitivity and informativity. It was investigated whether an increase in sensitivity could be achieved by increasing the DNA input to qPCR without causing PCR inhibition. A DNA input of 250 ng was found to be ideal for a more reliable detection of 0.01 % recipient cells. No PCR inhibition occurred. In order to meet the increased demand for DNA, different elution methods for DNA extraction were compared, with the highest DNA yield achieved by extraction using the QIAamp DNA Blood Midi Kit and elution with 2 x 200 µl AE buffer. To increase informativity, the practicality of a qPCR primer set for the SNP “rs713753” was evaluated. This was found to be moderately suitable: both alleles of the SNP taken together resulted in a good informativity of 37.5 % for recipient discrimination. The qPCR efficiencies of the locus-specific reference and the C allele were close to optimal values, while that of the T allele was only 0.87. The sensitivity of the specific alleles was max. 0.1 %. If it is possible to increase the sensitivity by increasing the DNA input into the qPCR without the occurrence of non-specific amplification, the integration of qPCR of the SNP rs713753 into daily diagnostics would be conceivable. In conclusion, it is possible to optimize the sensitivity and informativity of the chimerism analysis method used in our laboratory. Increasing the DNA input is the easiest to implement, whereas additional experiments are needed to establish additional alleles. KW - Real time quantitative PCR KW - Chimäre DNS KW - Periphere Stammzellentransplantation KW - Chimärismusdiagnostik KW - ARMS-PCR Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321277 ER - TY - JOUR A1 - Solimando, Antonio G. A1 - Bittrich, Max A1 - Shahini, Endrit A1 - Albanese, Federica A1 - Fritz, Georg A1 - Krebs, Markus T1 - Determinants of COVID-19 disease severity – lessons from primary and secondary immune disorders including cancer JF - International Journal of Molecular Sciences N2 - At the beginning of the COVID-19 pandemic, patients with primary and secondary immune disorders — including patients suffering from cancer — were generally regarded as a high-risk population in terms of COVID-19 disease severity and mortality. By now, scientific evidence indicates that there is substantial heterogeneity regarding the vulnerability towards COVID-19 in patients with immune disorders. In this review, we aimed to summarize the current knowledge about the effect of coexistent immune disorders on COVID-19 disease severity and vaccination response. In this context, we also regarded cancer as a secondary immune disorder. While patients with hematological malignancies displayed lower seroconversion rates after vaccination in some studies, a majority of cancer patients’ risk factors for severe COVID-19 disease were either inherent (such as metastatic or progressive disease) or comparable to the general population (age, male gender and comorbidities such as kidney or liver disease). A deeper understanding is needed to better define patient subgroups at a higher risk for severe COVID-19 disease courses. At the same time, immune disorders as functional disease models offer further insights into the role of specific immune cells and cytokines when orchestrating the immune response towards SARS-CoV-2 infection. Longitudinal serological studies are urgently needed to determine the extent and the duration of SARS-CoV-2 immunity in the general population, as well as immune-compromised and oncological patients. KW - COVID-19 KW - SARS-CoV-2 KW - disorder of immunity KW - cancer Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319412 SN - 1422-0067 VL - 24 IS - 10 ER - TY - JOUR A1 - Luu, Maik A1 - Schütz, Burkhard A1 - Lauth, Matthias A1 - Visekruna, Alexander T1 - The impact of gut microbiota-derived metabolites on the tumor immune microenvironment JF - Cancers N2 - Prevention of the effectiveness of anti-tumor immune responses is one of the canonical cancer hallmarks. The competition for crucial nutrients within the tumor microenvironment (TME) between cancer cells and immune cells creates a complex interplay characterized by metabolic deprivation. Extensive efforts have recently been made to understand better the dynamic interactions between cancer cells and surrounding immune cells. Paradoxically, both cancer cells and activated T cells are metabolically dependent on glycolysis, even in the presence of oxygen, a metabolic process known as the Warburg effect. The intestinal microbial community delivers various types of small molecules that can potentially augment the functional capabilities of the host immune system. Currently, several studies are trying to explore the complex functional relationship between the metabolites secreted by the human microbiome and anti-tumor immunity. Recently, it has been shown that a diverse array of commensal bacteria synthetizes bioactive molecules that enhance the efficacy of cancer immunotherapy, including immune checkpoint inhibitor (ICI) treatment and adoptive cell therapy with chimeric antigen receptor (CAR) T cells. In this review, we highlight the importance of commensal bacteria, particularly of the gut microbiota-derived metabolites that are capable of shaping metabolic, transcriptional and epigenetic processes within the TME in a therapeutically meaningful way. KW - tumor microenvironment (TME) KW - commensal bacteria KW - intratumoral microbiota KW - oncobiome KW - microbiota-derived metabolites KW - cancer immunotherapy Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311005 SN - 2072-6694 VL - 15 IS - 5 ER - TY - THES A1 - Lauruschkat, Chris David T1 - Entwicklung funktioneller Immunassays zur Detektion der humanen Immunantwort auf das opportunistische Pathogen \(Aspergillus\) \(fumigatus\) T1 - Development of functional immunoassays to study human host responses to the opportunistic pathogen \(Aspergillus\) \(fumigatus\) N2 - Aspergillus fumigatus ist ein opportunistisches fungales Humanpathogen, das ein breites Erkrankungsspektrum von der invasiven Aspergillose (IA) in immunkompromittierten Patienten bis zu einer Reihe von Hypersensitivitätserkrankungen in immunkompetenten Individuen hervorrufen kann. Die Diagnostik für A. fumigatus assoziierte Krankheitsbilder beruht auf mehreren diagnostischen Tests, die auch in ihrer Kombination oft zu späten und unzuverlässigen Diagnosen führen, was wiederum zu einer suboptimalen Patientenversorgung, erhöhter Mortalität und gesteigerten Kosten für das Gesundheitssystem führt. Es besteht daher die unbedingte Notwendigkeit, neue und bessere diagnostische Tests zur Detektion von A. fumigatus zu entwickeln. T Zell Assays sind vielversprechende, innovative diagnostische Tests, die bereits für andere Infektionskrankheiten in der Routinediagnostik eingesetzt werden. Erste Versuche wurden bereits unternommen, diese Assays auch für A. fumigatus assoziierte Erkrankungen einzusetzen. Die gängigsten, auf mononukleären Zellen des peripheren Blutes (PBMC)-basierten T Zell Assays sind der Enzyme-linked Immunosorbent Assay (ELISA), Enzyme-linked Immuno Spot Assay (ELISPOT) und die Durchflusszytometrie. Das Ziel dieser Dissertation war die Entwicklung eines klinisch einsetzbaren T-Zell-Assays für A. fumigatus assoziierte Erkrankungen. Die in der Literatur beschriebenen Assays zeigten in unseren Experimenten bei der Anwendung für mykologische Fragestellungen eine hohe Suszeptibilität gegenüber bereits kurzen präanalytischen Lagerzeiten und Krykonservierung, was einen klinischen Einsatz erschwerte. Wir entwickelten deshalb einen Vollblut basierten ELISA (VB-ELISA) mit dualer Kostimulation (α-CD28 und α-CD49d), hoher Reproduzierbarkeit und verbesserter Robustheit gegenüber präanalytischen Einflussfaktoren. Der VB ELISA konnte hohe Differenzen zwischen Typ 1 T Helferzellen (Th1) , Th2 und Th17 Zytokinkonzentrationen bei Patienten mit Aspergillus assoziierten Hypersensitivitätskrankheitsbildern und Kontrollpatienten feststellen. Um zu testen, ob dieser Anstieg auf die Erkrankung zurückzuführen ist oder auch bei hoher Aspergillus-Umweltexposition vorzufinden ist, wurde der Assay in Aspergillus exponierten gesunden ökologischen Landwirten getestet. In dieser Gruppe fanden wir ebenfalls eine erhöhte Th1 und Th2 Expansion und Zytokinsekretion gegenüber gesunden Kontrollspendern, jedoch wurde nur ein geringer Anstieg des Th17 Signalzytokines IL-17 detektiert. Die Detektion von IL-17 im VB-ELISA in Kombination mit anderen Zytokinmarkern ist daher ein vielversprechender Biomarker für die Diagnose von A. fumigatus assoziierten Hypersensitivitätserkrankungen. Neben diesen Hypersensitivitätserkrankungen haben wir den VB-ELISA auch in immunkompromittierten Patienten nach allogener Stammzelltransplantation (alloSZT), einer Hochrisikogruppe für die IA und die durch das humane Cytomegalovirus (HCMV) ausgelöste Zytomegalie, evaluiert. Während in unserer monozentrischen Pilotstudie aufgrund der geringen Inzidenz keine Evaluation an IA-Patienten erfolgen konnte, wurde mittels VB-ELISA eine hohe Konkordanz der HCMV-spezifischen T Zell Antwort mit der HCMV Serologie sowie eine vergleichbare Leistung zum ELISPOT, dem am häufigsten eingestetzen Assay für diese Fragestellung, festgestellt. Zusammenfassend haben wir mit dem VB ELISA einen vielversprechenden und breitflächig im Spektrum A. fumigatus assoziierter Erkrankungen einsetzbaren T Zell Assay entwickelt, der in der Zukunft in großen Studien mit klar definierten Patientenkohorten getestet werden sollte. Auf Grund von Daten aus Folgestudien, die auf dieser Arbeit basieren, ist des Weiteren davon auszugehen, dass der VB-ELISA auf Grund seiner Stärken potenziell in einer Vielzahl von Anwendungsgebieten und Pathogenen (eine Folgestudie mit SARS-CoV-2 wurde vor kurzem veröffentlicht) universell eingesetzt werden kann. Neben der Immundiagnostik für diverse Infektionserkrankungen könnte der Assay außerdem für T Zell Antworten auf Vakzinierungen und Immuntherapien, in vivo Experimente und in vitro Toxizitätstests verwendet werden. N2 - Aspergillus fumigatus is an opportunistic human pathogen, which is the cause of a wide disease spectrum. The spectrum ranges from invasive Aspergillosis (IA) in immunocompromised patients to diverse hypersensitivity diseases in immunocompetent individuals. Diagnostic assays of A. fumigatus have to be combined for efficient detection and still lead to unreliable and late diagnosis, resulting in suboptimal patient care, increased mortality and public health costs. There is, therefore, a great need to develop novel diagnostics for the detection of A. fumigatus. T-cell assays are promising, innovative diagnostic assays, which are used in routine diagnostics for certain infectious diseases. First affords have been made to adapt T-cell assays for the diagnosis of A. fumigatus-associated diseases. The most common T-cell assays are based on the isolation and stimulation of peripheral blood mononuclear cell (PBMC) and relay on Enzyme-linked Immunosorbent Assay (ELISA), Enzyme-Linked Immuno Spot Assay (ELISPOT) and flow cytometry as their read-out platforms. The aim of this dissertation was to develop a clinically feasible T-cell assay for A. fumigatus-associated diseases. We were able to demonstrate that all of these assays have high susceptibility towards pre-analytic factors like cryopreservation and shortly extended pre-analytic blood storage periods, hampering clinical feasibility. Thus, we developed a whole blood based ELISA (WB-ELISA) with dual co-stimulation (α-CD28 and α-CD49d), which showed high reproducibility, increased robustness towards pre-analytic factors and increased cytokine read-outs. The WB-ELISA was able to quantify large differences of T helper cell 1 (Th1), Th2 and Th17 cytokine concentrations in patients suffering from Aspergillus-associated hypersensitivity diseases compared to healthy controls. To analyze, whether these increased cytokine concentrations were the result of the pathology or could also be found in heavily Aspergillus-exposed individuals, we examined cytokine concentration in heavily Aspergillus-exposed organic farmers. We quantified increased Th1 and Th2 cytokine concentrations, however, we only found a minimal increase in the Th17 signal cytokine IL-17. Interleukin (IL)-17 (most likely in combination with other cytokines) is therefore a promising potential biomarker for the diagnosis of Aspergillus-associated hypersensitivity diseases. In addition to Aspergillus-associated hypersensitivity diseases, we tested the feasibility of the WB ELISA in immunocompromised patients after allogeneic stem cell transplantation (alloSCT). These patients are at high-risk for infections like IA as well as cytomegalovirus (CMV) disease, which is caused by CMV. Although, IA-specific evaluation could not be conducted, due to the low IA-incidence in these patients, the WB-ELISA showed high concordance of HCMV-specific T-cell responses with HCMV-serology as well as comparable performance to the ELISPOT, a commonly used T-cell assay for HCMV, in alloSCT patients. In conclusion, the successful development of the WB-ELISA has led to a promising and widely applicable T-cell assay for Aspergillus-associated diseases. In the future, the WB-ELISA should be evaluated in larger, multi-centric studies in well-defined patient cohorts suffering from Aspergillus-associated diseases. Furthermore, the WB-ELISA might be useful for a wide range of areas and pathogens (a follow-up study in COVID-19 patients was recently published). Besides the use in the immune diagnostics of infectious diseases, the WB-ELISA might also be applicable in the quantification of T-cell responses in vaccination- and immune therapy studies, in-vivo experiments and in-vitro toxicity testing. KW - Immunzellassays KW - Immunology KW - Infectious diseases KW - Immune cell assays KW - Immunologie KW - Infektiologie KW - Aspergillus fumigatus Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319835 ER - TY - THES A1 - Müller-Zentis, Ariane T1 - Auswirkungen von Distress auf den Transplantationsverlauf bei Patienten mit Multiplen Myelom während der autologen Stammzelltransplantation. Subanalyse von Zusammenhängen zwischen posttraumatischen Symptomen und klinischen Variablen T1 - Impacts of distress on the transplantation course in patients with multiple myeloma during autologous stem cell transplantation. Subanalysis of correlations between post-traumatic symptoms and clinical variables N2 - Ziel dieser Arbeit war es, den Einfluss psychosozialer Belastungsfaktoren auf den Verlauf einer Stammzelltransplantation zu untersuchen. Die primäre Fragestellung war, ob sich das Vorliegen einer posttraumatischen Belastungsstörung (PTSD) auf die Dauer der Immunrekonstitution, gemessen an der Aplasiezeit, auswirkt. Der Untersuchung liegen Daten aus der Medizinischen Klinik und Poliklinik II des Universitätsklinikums Würzburg zugrunde, die im Rahmen einer monozentrischen Querschnittsstudie erhoben wurden. An der Studie nahmen 50 Patienten mit der Diagnose eines Multiplen Myeloms teil, die am Tag ihrer ersten autologen Stammzelltransplantation befragt wurden. Anhand von Fragebögen konnten die Patienten Angaben zu ihrer individuellen psychischen Belastung machen. Für die statistische Auswertung wurden die Angaben aus dem NCCN-Distress-Thermometer und dem PCL-C ausgewertet. N2 - The aim of this study was to investigate the influence of psychosocial stress factors on the course of stem cell transplantation. The primary research question was whether the presence of post-traumatic stress disorder (PTSD) affects the duration of immune reconstitution, measured by the aplasia period. The study is based on data from the Medical Clinic and Polyclinic II of the University Hospital Würzburg, collected as part of a monocentric cross-sectional study. Fifty patients diagnosed with multiple myeloma, who were interviewed on the day of their first autologous stem cell transplantation, participated in the study. Using questionnaires, patients provided information about their individual psychological stress. The data from the NCCN Distress Thermometer and the PCL-C were analyzed for statistical evaluation KW - Distress KW - Psychoneuroimmunologie Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-345032 ER - TY - JOUR A1 - Stephan, Marlene A1 - Tascilar, Koray A1 - Yalcin-Mutlu, Melek A1 - Hagen, Melanie A1 - Haschka, Judith A1 - Reiser, Michaela A1 - Hartmann, Fabian A1 - Kleyer, Arnd A1 - Hueber, Axel J. A1 - Manger, Bernhard A1 - Figueiredo, Camille A1 - Cobra, Jayme Fogagnolo A1 - Tony, Hans-Peter A1 - Finzel, Stephanie A1 - Kleinert, Stefan A1 - Wendler, Jörg A1 - Schuch, Florian A1 - Ronneberger, Monika A1 - Feuchtenberger, Martin A1 - Fleck, Martin A1 - Manger, Karin A1 - Ochs, Wolfgang A1 - Schmitt-Haendle, Matthias A1 - Lorenz, Hannes Martin A1 - Nüsslein, Hubert A1 - Alten, Rieke A1 - Henes, Joerg A1 - Krüger, Klaus A1 - Schett, Georg A1 - Rech, Jürgen T1 - Physical function of RA patients tapering treatment — a post hoc analysis of the randomized controlled RETRO trial JF - Journal of Clinical Medicine N2 - Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline. KW - HAQ KW - Rheumatoid Arthritis KW - PROM’s KW - DMARD KW - DAS28 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319349 SN - 2077-0383 VL - 12 IS - 11 ER - TY - JOUR A1 - Sudarevic, Boban A1 - Troya, Joel A1 - Fuchs, Karl-Hermann A1 - Hann, Alexander A1 - Vereczkei, Andras A1 - Meining, Alexander T1 - Design and development of a flexible 3D-printed endoscopic grasping instrument JF - Applied Sciences N2 - (1) Background: Interventional endoscopic procedures are growing more popular, requiring innovative instruments and novel techniques. Three-dimensional printing has demonstrated great potential for the rapid development of prototypes that can be used for the early assessment of various concepts. In this work, we present the development of a flexible endoscopic instrument and explore its potential benefits. (2) Methods: The properties of the instrument, such as its maneuverability, flexibility, and bending force, were evaluated in a series of bench tests. Additionally, the effectiveness of the instrument was evaluated in an ex vivo porcine model by medical experts, who graded its properties and performance. Furthermore, the time necessary to complete various interventional endoscopic tasks was recorded. (3) Results: The instrument achieved bending angles of ±216° while achieving a bending force of 7.85 (±0.53) Newtons. The time needed to reach the operating region was 120 s median, while it took 70 s median to insert an object in a cavity. Furthermore, it took 220 s median to insert the instrument and remove an object from the cavity. (4) Conclusions: This study presents the development of a flexible endoscopic instrument using three-dimensional printing technology and its evaluation. The instrument demonstrated high bending angles and forces, and superior properties compared to the current state of the art. Furthermore, it was able to complete various interventional endoscopic tasks in minimal time, thus potentially leading to the improved safety and effectiveness of interventional endoscopic procedures in the future. KW - endoscopy KW - endoscopic intervention KW - 3D printing KW - endoscopic instruments KW - minimally invasive surgery KW - rapid prototyping Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319186 SN - 2076-3417 VL - 13 IS - 9 ER - TY - JOUR A1 - Gelbrich, Götz A1 - Morbach, Caroline A1 - Deutschbein, Timo A1 - Fassnacht, Martin A1 - Störk, Stefan A1 - Heuschmann, Peter U. T1 - The population comparison index: an intuitive measure to calibrate the extent of impairments in patient cohorts in relation to healthy and diseased populations JF - International Journal of Environmental Research and Public Health N2 - We assume that a specific health constraint, e.g., a certain aspect of bodily function or quality of life that is measured by a variable X, is absent (or irrelevant) in a healthy reference population (Ref0), and it is materially present and precisely measured in a diseased reference population (Ref1). We further assume that some amount of this constraint of interest is suspected to be present in a population under study (SP). In order to quantify this issue, we propose the introduction of an intuitive measure, the population comparison index (PCI), that relates the mean value of X in population SP to the mean values of X in populations Ref0 and Ref1. This measure is defined as PCI[X] = (mean[X|SP] − mean[X|Ref0])/(mean[X|Ref1] − mean[X|Ref0]) × 100[%], where mean[X|.] is the average value of X in the respective group of individuals. For interpretation, PCI[X] ≈ 0 indicates that the values of X in the population SP are similar to those in population Ref0, and hence, the impairment measured by X is not materially present in the individuals in population SP. On the other hand, PCI[X] ≈ 100 means that the individuals in SP exhibit values of X comparable to those occurring in Ref1, i.e., the constraint of interest is equally present in populations SP and Ref1. A value of 0 < PCI[X] < 100 indicates that a certain percentage of the constraint is present in SP, and it is more than in Ref0 but less than in Ref1. A value of PCI[X] > 100 means that population SP is even more affected by the constraint than population Ref1. KW - reference data KW - normal values KW - disease severity KW - disease score KW - comparability Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304933 SN - 1660-4601 VL - 20 IS - 3 ER - TY - JOUR A1 - Meier, Johannes P. A1 - Möbus, Selina A1 - Heigl, Florian A1 - Asbach-Nitzsche, Alexandra A1 - Niller, Hans Helmut A1 - Plentz, Annelie A1 - Avsar, Korkut A1 - Heiß-Neumann, Marion A1 - Schaaf, Bernhard A1 - Cassens, Uwe A1 - Seese, Bernd A1 - Teschner, Daniel A1 - Handzhiev, Sabin A1 - Graf, Uwe A1 - Lübbert, Christoph A1 - Steinmaurer, Monika A1 - Kontogianni, Konstantina A1 - Berg, Christoph A1 - Maieron, Andreas A1 - Blaas, Stefan H. A1 - Wagner, Ralf A1 - Deml, Ludwig A1 - Barabas, Sascha T1 - Performance of T-Track\(^®\) TB, a novel dual marker RT-qPCR-based whole-blood test for improved detection of active tuberculosis JF - Diagnostics N2 - Tuberculosis (TB) is one of the leading causes of death by an infectious disease. It remains a major health burden worldwide, in part due to misdiagnosis. Therefore, improved diagnostic tests allowing the faster and more reliable diagnosis of patients with active TB are urgently needed. This prospective study examined the performance of the new molecular whole-blood test T-Track\(^®\) TB, which relies on the combined evaluation of IFNG and CXCL10 mRNA levels, and compared it to that of the QuantiFERON\(^®\)-TB Gold Plus (QFT-Plus) enzyme-linked immunosorbent assay (ELISA). Diagnostic accuracy and agreement analyses were conducted on the whole blood of 181 active TB patients and 163 non-TB controls. T-Track\(^®\) TB presented sensitivity of 94.9% and specificity of 93.8% for the detection of active TB vs. non-TB controls. In comparison, the QFT-Plus ELISA showed sensitivity of 84.3%. The sensitivity of T-Track\(^®\) TB was significantly higher (p < 0.001) than that of QFT-Plus. The overall agreement of T-Track\(^®\) TB with QFT-Plus to diagnose active TB was 87.9%. Out of 21 samples with discordant results, 19 were correctly classified by T-Track\(^®\) TB while misclassified by QFT-Plus (T-Track\(^®\) TB-positive/QFT-Plus-negative), and two samples were misclassified by T-Track\(^®\) TB while correctly classified by QFT-Plus (T-Track\(^®\) TB-negative/QFT-Plus-positive). Our results demonstrate the excellent performance of the T-Track\(^®\) TB molecular assay and its suitability to accurately detect TB infection and discriminate active TB patients from non-infected controls. KW - tuberculosis KW - TB KW - active TB KW - infection detection KW - T-Track\(^®\) TB KW - QuantiFERON\(^®\)-TB Gold Plus KW - mRNA KW - RT-qPCR KW - CXCL10 KW - IFNG Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304113 SN - 2075-4418 VL - 13 IS - 4 ER - TY - JOUR A1 - Haertle, Larissa A1 - Buenache, Natalia A1 - Cuesta Hernández, Hipólito Nicolás A1 - Simicek, Michal A1 - Snaurova, Renata A1 - Rapado, Inmaculada A1 - Martinez, Nerea A1 - López-Muñoz, Nieves A1 - Sánchez-Pina, José María A1 - Munawar, Umair A1 - Han, Seungbin A1 - Ruiz-Heredia, Yanira A1 - Colmenares, Rafael A1 - Gallardo, Miguel A1 - Sanchez-Beato, Margarita A1 - Piris, Miguel Angel A1 - Samur, Mehmet Kemal A1 - Munshi, Nikhil C. A1 - Ayala, Rosa A1 - Kortüm, Klaus Martin A1 - Barrio, Santiago A1 - Martínez-López, Joaquín T1 - Genetic alterations in members of the proteasome 26S subunit, AAA-ATPase (PSMC) gene family in the light of proteasome inhibitor resistance in multiple myeloma JF - Cancers N2 - For the treatment of Multiple Myeloma, proteasome inhibitors are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients. The proteasome is a large and complex machinery. Here, we focus on the AAA ATPases of the 19S proteasome regulator (PSMC1-6) and their implication in PI resistance. As an example of cancer evolution and the acquisition of resistance, we conducted an in-depth analysis of an index patient by applying FISH, WES, and immunoglobulin-rearrangement sequencing in serial samples, starting from MGUS to newly diagnosed Multiple Myeloma to a PI-resistant relapse. The WES analysis uncovered an acquired PSMC2 Y429S mutation at the relapse after intensive bortezomib-containing therapy, which was functionally confirmed to mediate PI resistance. A meta-analysis comprising 1499 newly diagnosed and 447 progressed patients revealed a total of 36 SNVs over all six PSMC genes that were structurally accumulated in regulatory sites for activity such as the ADP/ATP binding pocket. Other alterations impact the interaction between different PSMC subunits or the intrinsic conformation of an individual subunit, consequently affecting the folding and function of the complex. Interestingly, several mutations were clustered in the central channel of the ATPase ring, where the unfolded substrates enter the 20S core. Our results indicate that PSMC SNVs play a role in PI resistance in MM. KW - Multiple Myeloma KW - drug resistance KW - proteasome inhibitors KW - immunoglobulin rearrangement KW - ATPase activity KW - PSMC2 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305013 SN - 2072-6694 VL - 15 IS - 2 ER - TY - THES A1 - Gotthard, Hannes T1 - Targeting Colorectal Cancer Stem Cells with Hemibodies T1 - Eliminierung von Krebsstammzellen des kolorektalen Karzinoms mithilfe von Hemibodies N2 - The cancer stem cell hypothesis is a cancer development model which elicited great interest in the last decades stating that cancer heterogeneity arises from a stem cell through asymmetrical division. The Cancer Stem Cell subset is described as the only population to be tumorigenic and having the potential to renew. Conventional therapy often fails to eradicate CSC resulting in tumor relapse. Consequently, it is of great inter-est to eliminate this subset of cells to provide the best patient outcome. In the last years several approaches to target CSC were developed, one of them being immunotherapeu-tic targeting with antibodies. Since markers associated with CSC are also expressed on normal stem cells or healthy adjacent tissue in colorectal cancer, dual targeting strate-gies are preferred over targeting only a single antigen. Subsequently, the idea of dual targeting two CSC markers in parallel by a newly developed split T cell-engaging anti-body format termed as Hemibodies emerged. In a preliminary single cell RNA sequenc-ing analysis of colorectal cancer cells CD133, CD24, CD166 and CEA were identified as suitable targets for the combinatorial targeting strategy. Therefore, this study focused on trispecific and trivalent Hemibodies comprising a split binding moiety against CD3 and a binding moiety against either CD133, CD24, CD166 or CEA to overcome the occurrence of resistance and to efficiently eradicate all tumor cells including the CSC compartment. The study showed that the Hemibody combinations CD133xCD24, CD133xCD166 and CD133xCEA are able to eliminate double positive CHO cells with high efficacy while having a high specificity indicated by no killing of single antigen positive cells. A thera-peutic window ranging between one to two log levels could be achieved for all combina-tions mentioned above. The combinations CD133xCD24 and CD133xCD166 further-more proved its efficacy and specificity on established colorectal cancer cell lines. Be-sides the evaluation of specificity and efficacy the already introduced 1st generation of Hemibodies could be improved into a 2nd generation Hemibody format with increased half-life, stability and production yield. In future experiments the applicability of above-mentioned Hemibodies will be proven on patient-derived micro tumors to also include variables like tumor microenvironment and infiltration. N2 - In den letzten Jahrzenten wurde neben der klonalen Evolution ein weiteres Modell zur Krebsentstehung und dessen Heterogenität entwickelt: die Krebsstammzellhypothe-se. Diese Hypothese besagt, dass die Heterogenität eines Tumors durch asymmetri-sche Teilung von sogenannten Krebsstammzellen entsteht. Nur diese sind tumorigen und in der Lage Metastasen zu bilden. Außerdem werden Krebsstammzellen als re-sistent gegen konventionelle Therapien beschrieben, weshalb es nach einer anfängli-chen Tumorregression oft zu einem Rezidiv durch erneutes Auswachsen von zurück-bleibenden Krebsstammzellen kommt. Deshalb ist es von großem Interesse genau diese Population abzutöten, um eine erfolgreiche Therapie zu gewährleisten. In den letzten Jahren wurden zahlreiche Medikationen entwickelt, um Krebsstammzellen ge-zielt anzugreifen. Ein vielversprechender Ansatz ist hierbei die immuntherapeutische Adressierung mittels Antikörpern gegen Krebsstammzellmarkern. Einzelne Marker sind allerdings auch auf normalen Stammzellen und gesundem Gewebe exprimiert, weshalb Therapien, die auf mindestens zwei verschiedene Oberflächenproteine ab-zielen, erfolgsversprechender sind. In dieser Arbeit wurde ein neues T-Zell rekrutie-rendes Antikörperformat entwickelt, sogenannte Hemibodies. Hierbei handelt es sich um ein trispezifisches und trivalentes Format, bestehend aus jeweils zwei Fragmen-ten. Jedes Fragment besteht aus einer Bindedomäne gegen ein Krebsstammzellmar-ker und einer geteilten Bindedomäne gegen CD3. Durch Bindung beider Fragmente an einen Stammzellmarker kommt es zur Komplementierung der geteilten anti-CD3 Domäne und zur T-Zellrekrutierung. Der erste Teil der Arbeit befasst sich mit der bioin-formatischen Analyse von Einzelzell-RNA-Daten des kolorektalen Karzinoms (KRK) zur Identifizierung von potentiellen Krebsstammzellmarkern. Dabei konnten die Ober-flächenproteine CD24, CD133, CD166 und CEA und besonders deren Kombination als geeignete Zielstrukturen identifiziert werden. Die gegen oben genannte Antigene gerichteten Hemibodies zeigten in den Kombinationen CD133xCD24, CD133xCD166 und CD133xCEA auf doppelt positiven CHO-Zellen eine hohe Effektivität. Außerdem konnte die Spezifität durch ein Ausbleiben von Zelltod auf einzel-positiven CHO Zellen bewiesen werden. Die Kombinationen CD133xCD24 und CD133xCD166 konnten Effektivität und Spezifität auch auf etablierten Krebszellen zeigen. Die oben genann-ten Kombinationen waren in einem therapeutischen Fenster von ein bis zwei Logstu-fen funktional. Neben der Testung verschiedener Hemibody-Kombinationen konnten die bereits publizierten Hemibodies der ersten Generation in ein neues Format der zweiten Generation weiterentwickelt werden. Das neue Format zeigte eine verbesser-te Halbwertszeit, Stabilität und Produzierbarkeit. In zukünftigen Experimenten werden die in der Thesis benutzten Hemibodies auf Mikrotumoren getestet, um weitere Vari-ablen, die die Effektivität und Spezifität beeinflussen zu ermitteln. KW - Monoklonaler bispezifischer Antikörper KW - Antikörper KW - T-Lymphozyt KW - Immunreaktion KW - Dickdarmkrebs KW - Hemibody KW - Hemibodies KW - Colorectal Cancer KW - trispecific KW - T-cell engager KW - dual targeting KW - Bispecific T-cell engager KW - stem cells KW - Kolorektales Karzinom Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-303090 ER - TY - JOUR A1 - Zacher, Magdalena A1 - Wollanka, Nele A1 - Sauer, Christina A1 - Haßtenteufel, Kathrin A1 - Wallwiener, Stephanie A1 - Wallwiener, Markus A1 - Maatouk, Imad T1 - Prenatal paternal depression, anxiety, and somatic symptom burden in different risk samples: an explorative study JF - Archives of Gynecology and Obstetrics N2 - Purpose Growing evidence implies that transition to parenthood triggers symptoms of mental burden not only in women but likewise in men, especially in high-risk pregnancies. This is the first study that examined and compared the prevalence rates of depression, anxiety, and somatic symptom burden of expectant fathers who face different risk situations during pregnancy. Methods Prevalence rates of paternal depression (Edinburgh postnatal depression scale), anxiety (generalized anxiety disorder seven), and somatic symptom burden (somatic symptom scale eight) were examined in two risk samples and one control group in the third trimester of their partners’ pregnancy: risk sample I (n = 41) consist of expectant fathers whose partners were prenatally hospitalized due to medical complications; risk sample II (n = 52) are fathers whose partners were prenatally mentally distressed; and control group (n = 70) are those non-risk pregnancies. Results On a purely descriptive level, the data display a trend of higher symptom burden of depression, anxiety, and somatic symptoms in the two risk samples, indicating that expectant fathers, whose pregnant partners were hospitalized or suffered prenatal depression, were more prenatally distressed. Exploratory testing of group differences revealed an almost three times higher prevalence rate of anxiety in fathers whose partner was hospitalized (12.2%) compared to those non-risks (4.3%). Conclusion Results underline the need for screening implementations for paternal prenatal psychological distress, as well as specific prevention and treatment programs, especially for fathers in risk situations, such as their pregnant partners’ prenatal hospitalization. The study was registered with the German clinical trials register (DRKS00020131) on 2019/12/09. KW - prenatal paternal depression KW - anxiety KW - somatic symptom burden KW - risk pregnancy KW - hospitalization Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324465 VL - 307 IS - 4 ER - TY - JOUR A1 - Helaß, Madeleine A1 - Haag, Georg Martin A1 - Bankstahl, Ulli Simone A1 - Gencer, Deniz A1 - Maatouk, Imad T1 - Burnout among German oncologists: a cross-sectional study in cooperation with the Arbeitsgemeinschaft Internistische Onkologie Quality of Life Working Group JF - Journal of Cancer Research and Clinical Oncology N2 - Purpose Oncologists are at an increased risk of developing burnout, leading to negative consequences in patient care and in professional satisfaction and quality of life. This study was designed to investigate exhaustion and disengagement among German oncologists and assess the prevalence of burnout among oncologists within different professional settings. Furthermore, we wanted to examine possible relations between sociodemographic factors, the oncological setting, professional experience and different aspects of burnout. Methods In a cross-sectional study design, an Internet-based survey was conducted with 121 oncologists between April and July 2020 using the Oldenburg Burnout Inventory, which contains items on exhaustion, disengagement, and burnout. Furthermore, sociodemographic data of the participants were assessed. The participants were members of the Working Group Medical Oncology (Arbeitsgemeinschaft Internistische Onkologie) within the German Cancer Society. Results The survey showed a burnout prevalence of 43.8%, which correlated with age and professional experience; that is, the prevalence is particularly high among younger oncologists. Exhaustion is closely related to employment status; that is, it was significantly higher among employed oncologists. There were remarkably low levels of disengagement among oncologists, highlighting the own demand to fulfil job requirements despite imminent or actual overburdening in daily work. Conclusion More support is necessary to mitigate the professional stressors in the healthcare system. To ensure quality medical care, employees should be offered preventive mental health services early in their careers. KW - burnout KW - exhaustion KW - disengagement KW - Oldenburg burnout inventory KW - oncologist KW - prevalence Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324446 VL - 149 IS - 2 ER - TY - JOUR A1 - Guggenberger, Konstanze V. A1 - Vogt, Marius L. A1 - Song, Jae W. A1 - Weng, Andreas M. A1 - Fröhlich, Matthias A1 - Schmalzing, Marc A1 - Venhoff, Nils A1 - Hillenkamp, Jost A1 - Pham, Mirko A1 - Meckel, Stephan A1 - Bley, Thorsten A. T1 - Intraorbital findings in giant cell arteritis on black blood MRI JF - European Radiology N2 - Objective Blindness is a feared complication of giant cell arteritis (GCA). However, the spectrum of pathologic orbital imaging findings on magnetic resonance imaging (MRI) in GCA is not well understood. In this study, we assess inflammatory changes of intraorbital structures on black blood MRI (BB-MRI) in patients with GCA compared to age-matched controls. Methods In this multicenter case-control study, 106 subjects underwent BB-MRI. Fifty-six patients with clinically or histologically diagnosed GCA and 50 age-matched controls without clinical or laboratory evidence of vasculitis were included. All individuals were imaged on a 3-T MR scanner with a post-contrast compressed-sensing (CS) T1-weighted sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) BB-MRI sequence. Imaging results were correlated with available clinical symptoms. Results Eighteen of 56 GCA patients (32%) showed inflammatory changes of at least one of the intraorbital structures. The most common finding was enhancement of at least one of the optic nerve sheaths (N = 13, 72%). Vessel wall enhancement of the ophthalmic artery was unilateral in 8 and bilateral in 3 patients. Enhancement of the optic nerve was observed in one patient. There was no significant correlation between imaging features of inflammation and clinically reported orbital symptoms (p = 0.10). None of the age-matched control patients showed any inflammatory changes of intraorbital structures. Conclusions BB-MRI revealed inflammatory findings in the orbits in up to 32% of patients with GCA. Optic nerve sheath enhancement was the most common intraorbital inflammatory change on BB-MRI. MRI findings were independent of clinically reported orbital symptoms. Key Points • Up to 32% of GCA patients shows signs of inflammation of intraorbital structures on BB-MRI. • Enhancement of the optic nerve sheath is the most common intraorbital finding in GCA patients on BB-MRI. • Features of inflammation of intraorbital structures are independent of clinically reported symptoms. KW - giant cell arteritis KW - magnetic resonance imaging KW - orbit KW - ophthalmic artery KW - optic nerve Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324978 VL - 33 IS - 4 ER - TY - JOUR A1 - Nickl, Vera A1 - Eck, Juliana A1 - Goedert, Nicolas A1 - Hübner, Julian A1 - Nerreter, Thomas A1 - Hagemann, Carsten A1 - Ernestus, Ralf-Ingo A1 - Schulz, Tim A1 - Nickl, Robert Carl A1 - Keßler, Almuth Friederike A1 - Löhr, Mario A1 - Rosenwald, Andreas A1 - Breun, Maria A1 - Monoranu, Camelia Maria T1 - Characterization and optimization of the tumor microenvironment in patient-derived organotypic slices and organoid models of glioblastoma JF - Cancers N2 - While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future. KW - glioblastoma KW - organoids KW - slice culture KW - tumormicroenvironment Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319249 SN - 2072-6694 VL - 15 IS - 10 ER - TY - JOUR A1 - McFleder, Rhonda L. A1 - Makhotkina, Anastasiia A1 - Groh, Janos A1 - Keber, Ursula A1 - Imdahl, Fabian A1 - Peña Mosca, Josefina A1 - Peteranderl, Alina A1 - Wu, Jingjing A1 - Tabuchi, Sawako A1 - Hoffmann, Jan A1 - Karl, Ann-Kathrin A1 - Pagenstecher, Axel A1 - Vogel, Jörg A1 - Beilhack, Andreas A1 - Koprich, James B. A1 - Brotchie, Jonathan M. A1 - Saliba, Antoine-Emmanuel A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Brain-to-gut trafficking of alpha-synuclein by CD11c\(^+\) cells in a mouse model of Parkinson’s disease JF - Nature Communications N2 - Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson’s disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate αSyn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal αSyn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c\(^+\) cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c\(^+\) cells traffic from the brain to the ileum. Together these data provide a mechanism of αSyn trafficking between the brain and gut. KW - antigen-presenting cells KW - neuroimmunology KW - Parkinson's disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357696 VL - 14 ER - TY - JOUR A1 - Häder, Antje A1 - Schäuble, Sascha A1 - Gehlen, Jan A1 - Thielemann, Nadja A1 - Buerfent, Benedikt C. A1 - Schüller, Vitalia A1 - Hess, Timo A1 - Wolf, Thomas A1 - Schröder, Julia A1 - Weber, Michael A1 - Hünniger, Kerstin A1 - Löffler, Jürgen A1 - Vylkova, Slavena A1 - Panagiotou, Gianni A1 - Schumacher, Johannes A1 - Kurzai, Oliver T1 - Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity JF - Nature Communications N2 - Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases. KW - antimicrobial responses KW - immunogenetics Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357441 VL - 14 ER - TY - JOUR A1 - Maichl, Daniela Simone A1 - Kirner, Julius Arthur A1 - Beck, Susanne A1 - Cheng, Wen-Hui A1 - Krug, Melanie A1 - Kuric, Martin A1 - Ade, Carsten Patrick A1 - Bischler, Thorsten A1 - Jakob, Franz A1 - Hose, Dirk A1 - Seckinger, Anja A1 - Ebert, Regina A1 - Jundt, Franziska T1 - Identification of NOTCH-driven matrisome-associated genes as prognostic indicators of multiple myeloma patient survival JF - Blood Cancer Journal N2 - No abstract available. KW - cancer microenvironment KW - myeloma Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357598 VL - 13 ER - TY - JOUR A1 - Haake, Markus A1 - Haack, Beatrice A1 - Schäfer, Tina A1 - Harter, Patrick N. A1 - Mattavelli, Greta A1 - Eiring, Patrick A1 - Vashist, Neha A1 - Wedekink, Florian A1 - Genssler, Sabrina A1 - Fischer, Birgitt A1 - Dahlhoff, Julia A1 - Mokhtari, Fatemeh A1 - Kuzkina, Anastasia A1 - Welters, Marij J. P. A1 - Benz, Tamara M. A1 - Sorger, Lena A1 - Thiemann, Vincent A1 - Almanzar, Giovanni A1 - Selle, Martina A1 - Thein, Klara A1 - Späth, Jacob A1 - Gonzalez, Maria Cecilia A1 - Reitinger, Carmen A1 - Ipsen-Escobedo, Andrea A1 - Wistuba-Hamprecht, Kilian A1 - Eichler, Kristin A1 - Filipski, Katharina A1 - Zeiner, Pia S. A1 - Beschorner, Rudi A1 - Goedemans, Renske A1 - Gogolla, Falk Hagen A1 - Hackl, Hubert A1 - Rooswinkel, Rogier W. A1 - Thiem, Alexander A1 - Romer Roche, Paula A1 - Joshi, Hemant A1 - Pühringer, Dirk A1 - Wöckel, Achim A1 - Diessner, Joachim E. A1 - Rüdiger, Manfred A1 - Leo, Eugen A1 - Cheng, Phil F. A1 - Levesque, Mitchell P. A1 - Goebeler, Matthias A1 - Sauer, Markus A1 - Nimmerjahn, Falk A1 - Schuberth-Wagner, Christine A1 - Felten, Stefanie von A1 - Mittelbronn, Michel A1 - Mehling, Matthias A1 - Beilhack, Andreas A1 - van der Burg, Sjoerd H. A1 - Riedel, Angela A1 - Weide, Benjamin A1 - Dummer, Reinhard A1 - Wischhusen, Jörg T1 - Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment JF - Nature Communications N2 - Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development. KW - cancer microenvironment KW - immunotherapy KW - T cells KW - tumour immunology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357333 VL - 14 ER - TY - JOUR A1 - Krenzer, Adrian A1 - Banck, Michael A1 - Makowski, Kevin A1 - Hekalo, Amar A1 - Fitting, Daniel A1 - Troya, Joel A1 - Sudarevic, Boban A1 - Zoller, Wolfgang G. A1 - Hann, Alexander A1 - Puppe, Frank T1 - A real-time polyp-detection system with clinical application in colonoscopy using deep convolutional neural networks JF - Journal of Imaging N2 - Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. The best method to prevent CRC is with a colonoscopy. During this procedure, the gastroenterologist searches for polyps. However, there is a potential risk of polyps being missed by the gastroenterologist. Automated detection of polyps helps to assist the gastroenterologist during a colonoscopy. There are already publications examining the problem of polyp detection in the literature. Nevertheless, most of these systems are only used in the research context and are not implemented for clinical application. Therefore, we introduce the first fully open-source automated polyp-detection system scoring best on current benchmark data and implementing it ready for clinical application. To create the polyp-detection system (ENDOMIND-Advanced), we combined our own collected data from different hospitals and practices in Germany with open-source datasets to create a dataset with over 500,000 annotated images. ENDOMIND-Advanced leverages a post-processing technique based on video detection to work in real-time with a stream of images. It is integrated into a prototype ready for application in clinical interventions. We achieve better performance compared to the best system in the literature and score a F1-score of 90.24% on the open-source CVC-VideoClinicDB benchmark. KW - machine learning KW - deep learning KW - endoscopy KW - gastroenterology KW - automation KW - object detection KW - video object detection KW - real-time Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304454 SN - 2313-433X VL - 9 IS - 2 ER - TY - JOUR A1 - Herrmann, Johannes A1 - Müller, Kerstin A1 - Notz, Quirin A1 - Hübsch, Martha A1 - Haas, Kirsten A1 - Horn, Anna A1 - Schmidt, Julia A1 - Heuschmann, Peter A1 - Maschmann, Jens A1 - Frosch, Matthias A1 - Deckert, Jürgen A1 - Einsele, Hermann A1 - Ertl, Georg A1 - Frantz, Stefan A1 - Meybohm, Patrick A1 - Lotz, Christopher T1 - Prospective single-center study of health-related quality of life after COVID-19 in ICU and non-ICU patients JF - Scientific Reports N2 - Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87% and 80% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24% of non-ICU and 3% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5% of non-ICU and 10% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19. KW - health care KW - public health KW - quality of life Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357174 VL - 13 ER - TY - JOUR A1 - Karunakaran, Mohindar M. A1 - Subramanian, Hariharan A1 - Jin, Yiming A1 - Mohammed, Fiyaz A1 - Kimmel, Brigitte A1 - Juraske, Claudia A1 - Starick, Lisa A1 - Nöhren, Anna A1 - Länder, Nora A1 - Willcox, Carrie R. A1 - Singh, Rohit A1 - Schamel, Wolfgang W. A1 - Nikolaev, Viacheslav O. A1 - Kunzmann, Volker A1 - Wiemer, Andrew J. A1 - Willcox, Benjamin E. A1 - Herrmann, Thomas T1 - A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing JF - Nature Communications N2 - Butyrophilin (BTN)–3A and BTN2A1 molecules control the activation of human Vγ9Vδ2 T cells during T cell receptor (TCR)-mediated sensing of phosphoantigens (PAg) derived from microbes and tumors. However, the molecular rules governing PAg sensing remain largely unknown. Here, we establish three mechanistic principles of PAg-mediated γδ T cell activation. First, in humans, following PAg binding to the intracellular BTN3A1-B30.2 domain, Vγ9Vδ2 TCR triggering involves the extracellular V-domain of BTN3A2/BTN3A3. Moreover, the localization of both protein domains on different chains of the BTN3A homo-or heteromers is essential for efficient PAg-mediated activation. Second, the formation of BTN3A homo-or heteromers, which differ in intracellular trafficking and conformation, is controlled by molecular interactions between the juxtamembrane regions of the BTN3A chains. Finally, the ability of PAg not simply to bind BTN3A-B30.2, but to promote its subsequent interaction with the BTN2A1-B30.2 domain, is essential for T-cell activation. Defining these determinants of cooperation and the division of labor in BTN proteins improves our understanding of PAg sensing and elucidates a mode of action that may apply to other BTN family members. KW - gammadelta T cells KW - immunosurveillance Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358179 VL - 14 ER - TY - JOUR A1 - Leonhardt, Jonas A1 - Winkler, Marcela A1 - Kollikowski, Anne A1 - Schiffmann, Lisa A1 - Quenzer, Anne A1 - Einsele, Hermann A1 - Löffler, Claudia T1 - Mind–body-medicine in oncology—from patient needs to tailored programs and interventions BT - a cross-sectional study JF - Frontiers in Psychology N2 - Introduction: National and international guidelines recommend early integration of evidence-based multimodal interventions and programs, especially with a focus on relaxation techniques and other Mind–Body-based methods to maintain the quality of life of oncology patients, improve treatment tolerability, and promote healthy lifestyle behaviors. Consequently, we aim to understand what drives patients and how they navigate integrative medicine to best advise them. This study aimed to detect possible topics of particular interest to patients and identify the patient groups that could benefit most from further programs. Furthermore, we aimed to investigate if patients are open-minded toward integrative oncology concepts and learn about their motivational level to maintain or change behavior. Methods: Between August 2019 and October 2020 we surveyed patients undergoing oncological therapy in a university oncological outpatient center using a custom-developed questionnaire based on established Mind–Body Medicine concepts. Results: We included 294 patients with various cancers. More than half reported problems sleeping through (61%) and 42% felt stressed frequently, invariably rating this as detrimental to their health. Moreover, a slight majority (52%) felt physically limited due to their disease and only 30% performed defined exercise programs. Women were significantly more likely to feel stressed and reported with alarming frequency that they often feel “everything was up to them.” The 40–65-year-olds reported significantly less restful sleep, more stress and were more dissatisfied with their situation. However, this group already used natural remedies most frequently and was most often motivated to use relaxation techniques in the next 6 months. The lower the perceived individual energy level (EL), the less frequently patients did sport, the more frequently they felt their disease impaired their activity, mostly feeling stressed and tense. We also found significant associations between negative emotions/thoughts and the variables “sleep,” “use of relaxation techniques,” “personal stress perception,” and “successful lifestyle modification.” Conclusion: Mind–Body programs that focus on patient’s individual resources, with tools to explore impairing patterns of self-perception and cognitive biases, can be a valuable resource for oncology patients and should therefore be part of an integrative medical treatment concept. KW - lifestyle habits KW - symptom burden KW - individual mind state KW - motivational level KW - stress Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321970 SN - 1664-1078 VL - 14 ER - TY - JOUR A1 - Schanbacher, Constanze A1 - Hermanns, Heike M. A1 - Lorenz, Kristina A1 - Wajant, Harald A1 - Lang, Isabell T1 - Complement 1q/tumor necrosis factor-related proteins (CTRPs): structure, receptors and signaling JF - Biomedicines N2 - Adiponectin and the other 15 members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of an N-terminal variable domain followed by a stalk region and a characteristic C-terminal trimerizing globular C1q (gC1q) domain originally identified in the subunits of the complement protein C1q. We performed a basic PubMed literature search for articles mentioning the various CTRPs or their receptors in the abstract or title. In this narrative review, we briefly summarize the biology of CTRPs and focus then on the structure, receptors and major signaling pathways of CTRPs. Analyses of CTRP knockout mice and CTRP transgenic mice gave overwhelming evidence for the relevance of the anti-inflammatory and insulin-sensitizing effects of CTRPs in autoimmune diseases, obesity, atherosclerosis and cardiac dysfunction. CTRPs form homo- and heterotypic trimers and oligomers which can have different activities. The receptors of some CTRPs are unknown and some receptors are redundantly targeted by several CTRPs. The way in which CTRPs activate their receptors to trigger downstream signaling pathways is largely unknown. CTRPs and their receptors are considered as promising therapeutic targets but their translational usage is still hampered by the limited knowledge of CTRP redundancy and CTRP signal transduction. KW - adiponectin KW - AMPK KW - C1q/TNF related protein (CTRP) KW - inflammation KW - metabolism Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304136 SN - 2227-9059 VL - 11 IS - 2 ER - TY - JOUR A1 - Munawar, Umair A1 - Zhou, Xiang A1 - Prommersberger, Sabrina A1 - Nerreter, Silvia A1 - Vogt, Cornelia A1 - Steinhardt, Maximilian J. A1 - Truger, Marietta A1 - Mersi, Julia A1 - Teufel, Eva A1 - Han, Seungbin A1 - Haertle, Larissa A1 - Banholzer, Nicole A1 - Eiring, Patrick A1 - Danhof, Sophia A1 - Navarro-Aguadero, Miguel Angel A1 - Fernandez-Martin, Adrian A1 - Ortiz-Ruiz, Alejandra A1 - Barrio, Santiago A1 - Gallardo, Miguel A1 - Valeri, Antonio A1 - Castellano, Eva A1 - Raab, Peter A1 - Rudert, Maximilian A1 - Haferlach, Claudia A1 - Sauer, Markus A1 - Hudecek, Michael A1 - Martinez-Lopez, J. A1 - Waldschmidt, Johannes A1 - Einsele, Hermann A1 - Rasche, Leo A1 - Kortüm, K. Martin T1 - Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma JF - Communications Biology N2 - The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM. KW - immunotherapy KW - translational research Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357609 VL - 6 ER - TY - THES A1 - Wallstabe, Lars T1 - Development and preclinical evaluation of tumour-reactive T cells expressing a chemically programmable chimeric antigen receptor T1 - Entwicklung und präklinische Evaluierung tumorreaktiver T- Zellen, die einen chemisch programmierbaren chimären Antigenrezeptor exprimieren N2 - The genetic modification of T cells for the expression a chimeric antigen receptor (CAR) endows them with a new specificity for an antigen. Adoptive immunotherapy with CD19-CAR T cells has achieved high rates of sustained complete remissions in B cell malignancies. However, the downregulation or loss of the targeted antigen after mono-specific CAR T cell therapy, e.g. against CD19 or CD22, has been reported. Targeting multiple antigens on tumour cells, sequentially or simultaneously, could overcome this limitation. Additionally, targeting multiple antigens with CAR T cells could drive the translation from hematologic malignancies to prevalent solid cancers, which often express tumour-associated antigens heterogeneously. We hypothesised that expression of a universal CAR, which can be programmed with hapten-like molecules, could endow T cells with specificities for multiple antigens. In this study we introduce a novel chemically programmable CAR (cpCAR) based on monoclonal antibody h38C2. Our data show, that cpCARs form a reversible chemical bond to molecules containing a diketone-group and therefore can be programmed to acquire multiple specificities. We programmed cpCAR T cells with hapten-like compounds against integrins αvβ3 and α4β1 as well as the folate receptor. We observed tumour cell lysis, IFN ɣ and IL-2 production and proliferation of programmed cpCAR T cells against tumour cells expressing the respective target antigen in vitro. As a reference to cpCARs programmed against αvβ3, we further introduced novel conventional αvβ3-CARs. These CARs, based on humanised variants of monoclonal antibody LM609 (hLM609), directly bind to integrin αvβ3 via their scFv. The four αvβ3-CAR constructs comprised either an scFv with higher affinity (hLM609v7) or lower affinity (hLM609v11) against αvβ3 integrin and either a long (IgG4 hinge, CH2, CH3) or short (IgG4 hinge) extracellular spacer. We selected the hLM609v7-CAR with short spacer, which showed potent anti-tumour reactivity both in vitro and in a murine xenograft model, for comparison with the cpCAR programmed against αvβ3. Our data show specific lysis of αvβ3-positive tumour cells, cytokine production and proliferation of both hLM609-CAR T cells and cpCAR T cells in vitro. However, conventional hLM609-CAR T cells mediated stronger anti-tumour effects compared to cpCAR T cells in the same amount of time. In line with the in vitro data, complete destruction of tumour lesions in a murine melanoma xenograft model was only observed for mice treated with conventional αvβ3-CAR T cells. Collectively, we introduce a cpCAR, which can be programmed against multiple tumour antigens, and hLM609-CARs specific for the integrin αvβ3. The cpCAR technology bears the potential to counteract current limitations, e.g. antigen loss, of current monospecific CAR T cell therapy. Targeting αvβ3 integrin with CAR T cells could have clinical applications in the treatment of solid malignancies, because αvβ3 is not only expressed on a variety of solid malignancies, but also on tumour-associated vasculature and fibroblast. N2 - T Zellen können durch genetische Modifizierung zur Expression eines chimären Antigen-Rezeptors (CAR) neue Antigenspezifität erhalten. Durch adoptive Immuntherapie mit CD19-CAR T Zellen können hohe Raten von anhaltenden vollständigen Remissionen bei Patienten mit malignen B-Zell-Erkrankungen erzielt werden. In klinischen Studien mit mono-spezifischen CAR T Zellen wurden allerdings der Verlust oder eine verringerte Expression der Ziel-Antigene, z.B. CD19 oder CD22, auf Tumor-Zellen beobachtet. Außerdem sind bei soliden Krebserkrankungen tumor¬assoziierte Antigene häufig unterschiedlich stark auf Krebszellen exprimiert. Wir haben die Hypothese aufgestellt, dass CARs, die mit einem hapten-ähnlichen Molekül programmiert werden können, es ermöglichen, mehrere Antigene mit einer T-Zelle anzugreifen. In dieser Arbeit stellen wir einen neuartigen chemisch programmierbaren CAR (cpCAR) auf Basis des monoklonalen Antikörpers h38C2 vor. Unsere Daten zeigen, dass cpCARs eine reversible chemische Bindung zu Molekülen mit einer Diketongruppe bilden und daher so programmiert werden können, dass sie mehrere Spezifitäten aufweisen. Wir haben cpCAR T Zellen mit hapten-ähnlichen Molekülen gegen die Integrine αvβ3 und α4β1 sowie den Folat-Rezeptor programmiert. In vitro beobachteten wir sowohl die spezifische Lyse von Tumorzellen als auch T-Zell-Proliferation und Sekretion von IFN ɣ und IL-2 durch programmierte cpCAR T Zellen als Reaktion auf Antigen positive Tumorzellen. Als Referenz zu cpCARs, die gegen αvβ3 programmiert wurden, haben wir in dieser Arbeit zudem neue konventionelle αvβ3-CARs vorgestellt. Diese basieren auf humanisierten Varianten des monoklonalen Antikörpers LM609 (hLM609) und binden mittels ihres scFv direkt an Integrin αvβ3. Die vier αvβ3-CAR-Konstrukte enthielten entweder ein scFv mit höherer Affinität (hLM609v7) oder niedrigerer Affinität (hLM609v11) gegenüber αvβ3 und entweder einem langen (IgG4-Hinge, CH2, CH3) oder einem kurzen (IgG4-Hinge) extrazellulären „Spacer“. Für den Vergleich von konventionellem CAR und cpCAR wählten wir den hLM609v7-CAR mit kurzem „Spacer“. T Zellen, die diesen CAR exprimierten, vermittelten eine starke Anti-Tumor Reaktion sowohl in vitro als auch in einem Maus-Xenograft Modell. Unsere in vitro Daten zeigen spezifische Lyse von αvβ3-positiven Tumorzellen, Sekretion von Zytokinen und Proliferation sowohl durch hLM609-CAR T-Zellen als auch durch cpCAR T-Zellen. Konventionelle hLM609-CAR T Zellen vermittelten jedoch in gleicher Zeit eine stärkere Anti-Tumorwirkung als cpCAR T-Zellen. Zusammengefasst präsentieren wir in dieser Arbeit einen cpCAR, der gegen mehrere Tumorantigene programmiert werden kann, und hLM609-CARs, die spezifisch für das Integrin αvβ3 sind. Die cpCAR-Technologie birgt das Potenzial, aktuellen Limitationen der mono-spezifischen CAR-T-Zelltherapie, z.B. dem Antigen¬verlust, entgegenzuwirken. Zudem könnte das Integrin αvβ3 klinische Anwendung bei der Behandlung von soliden Tumoren finden, da es nicht nur auf einer Reihe von Tumor-Entitäten, sondern auch auf Tumor-assoziiertem Gewebe zu finden ist. KW - Tumorimmunologie KW - chimeric antigen receptor Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179071 ER - TY - THES A1 - Pauschinger, Christoph Johannes T1 - Charakterisierung bi- und trispezifischer anti-CD40 Antikörper-Fusionsproteine T1 - Characterization of bi- and trispecific antiCD40 antibody fusion proteins N2 - Das Immunsystem zu aktivieren, um eine körpereigene Immunantwort gegen Tumorzellen hervorzurufen, ist ein innovativer Therapieansatz. Eine vielversprechende Zielstruktur hierfür ist CD40, ein Mitglied der TNFRSF- Familie und starker Stimulator Antigen-präsentierender Zellen. Die TNFRSF-Rezeptor Aktivierung ist abhängig von der Bildung oligomerer (TNFSF3-TNFRSF3)2 Komplexe, was insbesondere durch entsprechende räumliche Ausrichtung membranständiger Liganden und deren hohe lokale Konzentration im Zell-Zell-Kontakt gewährleistet wird. Im Rahmen dieser Arbeit wurde die (TNFSF3-TNFRSF3)2 Komplexbildung mittels membranständiger Liganden durch die Generierung von CD40-spezifischen Antikörper-Fusions- proteinen imitiert, die über zusätzliche Bindedomänen, single chain fragment variable (scFvs), für zellständige Zielstrukturen (CD70, BCMA, PDL1) verfügen. Dazu wurden die schweren und/oder leichten anti-CD40 Antikörperketten C-terminal mit einem scFv-Fragment verknüpft und dadurch verschiedene CD40-spezifische Antikörper-Fusionsproteine mit scFv-Fragmenten generiert. Die Funktionalität dieser besonderen Antikörper-Fusionsproteine wurde hinsichtlich ihrer Bindungsfähigkeit mittels Gaussia princeps Luciferaseassay und hinsichtlich ihres Agonismus über den Nachweis der Interleukin-8 Induktion per ELISA analysiert. Dabei zeigte sich, dass die CD40-Aktivierung durch die an den Antikörper-Fusionsproteinen verankerten scFv-Domänen bei einem Großteil potenziert werden konnte, wenn diese die entsprechenden Zielantigene CD70, BCMA, PDL1 binden. Des Weiteren waren hinsichtlich ihres Agonimsus die Antikörper-Fusionsproteine mit einer scFv-Domäne an der schweren oder an der leichten Antikörperkette den Antikörper-Fusionsproteinen überlegen, die scFv-Domänen an beiden Antikörperketten aufwiesen. Dennoch stellen auch letztere eine vielversprechende Therapievariante dar, da sie aufgrund ihrer breiteren Spezifität verschiedene Tumorantigene binden können. Die in dieser Arbeit produzierten und charakterisierten CD40-spezifischen Antikörper-Fusionsproteine aktivieren das Immunsystem gezielter in dem Gewebe, in dem vermehrt spezifische Tumorantigene exprimiert werden. Dadurch eröffnen sie neue Möglichkeiten in der Tumortherapie. N2 - Activating the immune system to induce an endogenous immune response against tumor cells is an innovative therapeutic approach. A promising target structure for this is CD40, a member of the TNFRSF family and potent stimulator of antigen-presenting cells. TNFRSF receptor activation is dependent on the formation of oligomeric (TNFSF3-TNFRSF3)2 complexes, which is particularly ensured by appropriate spatial targeting of membrane-bound ligands and their high local concentration in cell-cell interaction. In this work, (TNFSF3-TNFRSF3)2 complex formation using membrane-bound ligands was mimicked by the generation of CD40-specific antibody fusion proteins possessing additional binding domains, single chain fragment variables (scFvs), for cell-bound targets (CD70, BCMA, PDL1). For this purpose, anti-CD40 antibody heavy and/or light chains were C-terminally linked to a scFv fragment, thereby generating different CD40-specific antibody fusion proteins with scFv fragments. The functionality of these particular antibody fusion proteins was analyzed with respect to their binding ability by Gaussia princeps luciferase assay and to their agonism via detection of interleukin-8 induction by ELISA. This showed that CD40 activation could be potentiated by the scFv domains anchored to the antibody fusion proteins in a large proportion when these bind the corresponding target antigens CD70, BCMA, PDL1. Furthermore, in terms of agonimus, antibody fusion proteins with an scFv domain on the heavy or on the light antibody chain were superior to antibody fusion proteins that had scFv domains on both antibody chains. Nevertheless, the latter also represent a promising therapeutic option, as they can bind various tumor antigens due to their broader specificity. The CD40-specific antibody fusion proteins produced and characterized in this work activate the immune system in a more targeted manner in the tissue where specific tumor antigens are increasingly expressed. Thus, they open up new possibilities in tumor therapy. KW - Fusionsprotein KW - Monoklonaler Antikörper KW - Monoklonaler bispezifischer Antikörper KW - CD 40 KW - Immunotherapie KW - Tumornekrosefaktor Rezeptor Superfamilie KW - Tumornekrosefaktor Liganden Superfamilie KW - CD40-spezifische Antikörperfusionsproteine Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260184 ER - TY - THES A1 - Aehnlich, Flora T1 - Untersuchungen zur Präsentation kryptischer und kanonischer Peptide über den MHC-Klasse-I-Komplex in Patienten mit akuter myeloischer Leukämie T1 - Investigation about the presentation of cryptic and canonical peptides on the MHC-class-I-complex in patients with acute myeloid leukemia N2 - Die AML stellt mit einem Anteil von 80 % an den akuten Leukämien bei Erwachsenen eine bedeutende Erkrankung für die Gesellschaft dar. Aufgrund fehlender durchbrechender Erfolge in der Therapieentwicklung liegt die durchschnittliche Fünfjahresüberlebensrate dennoch nur bei etwa 25 %. Der Blick auf die Kraft des Graft-versus-Leukämie-Effekts nach allogener Stammzelltransplantation, eine Langzeitremission der AML erzielen zu können, weist jedoch auf die Immunogenität und Eignung der Erkrankung für neue immuntherapeutische Ansätze hin. Anhand der Kartierung der in-vivo präsentierten MHC-Klasse-I-Peptidome auf AML-Blasten sollten in dieser Arbeit potenziell geeignete Therapietargets identifiziert werden, um eine breitere Anwendung immuntherapeutischer Strategien bei AML-Patienten zu ermöglichen. Auf primären Patientenmaterialien, Zelllinien und benignen Zellen wurden hierzu über eine Immunoaffinitätschromatographie mit nachfolgenden Purifizierungsschritten die MHC-präsentierten Peptide massenspekrometrisch-basiert identifiziert. Zusätzlich erfolgte eine Quantifizierung der Oberflächen- und intrazellulären MHC-Klasse-I-Moleküle der verwendeten Proben durch einen indirekten Immunfluoreszenz-Assay. Unter der Gesamtheit von 17.750 identifizierten nicht-redundanten MHC-Klasse- I-präsentierten Peptiden konnte eine Vielzahl von 5.626 Peptiden mit Präsentationsfrequenzen bis zu 72 % als AML-exklusiv beschrieben werden. Hierunter wurden 240 kryptische Peptide vermeintlich nicht-codierenden Ursprungs identifiziert. Zudem wurden mehrere potenziell CMV-kreuzreaktive AML-Peptide erfasst, die zu der reduzierten Rezidivrate bei CMV-Infektion nach allogener Stammzelltransplantation führen könnten. Bei der MHC-Quantifizierung wiesen die AML-Blasten keine verminderte MHC-Expression auf und stellten sich somit als geeignete Target-Zellen für eine T-Zell-Immuntherapie dar. N2 - AML is a disease with huge society impacts since it represents 80 % of all acute leukemia in adults. However, due to the lack of breakthroughs in the development of new therapies, the average five-year survival rate is only around 25%. The Graft-versus-Leukemia-Effect after allogeneic stem cell transplantation, which can achieve long-term remission in AML-patients, provides evidence for the immunogenicity and therefore suitability of the disease for new immunotherapeutic approaches. The aim of this these is to enable a broader application of immunotherapeutic strategies in AML patients by mapping the in-vivo presented peptidomes of the MHC-class-I-pathway. For this purpose, primary patient materials, cell lines and benign cells were analyzed using immunoaffinity chromatography with several subsequential purification steps and mass-spectrometric-based identification. In addition, the surface and intracellular MHC-class-I-molecules of the samples used were quantified by an indirect immunofluorescence assay. Among the total of 17,750 identified non-redundant MHC-class-I-presented peptides, a large number of 5,626 peptides with presentation frequencies of up to 72% could be described as AML-exclusive. Among them, 240 cryptic peptides of supposedly non-coding origin were identified. In addition, several potentially CMV-cross-reactive AML-peptides were identified. Such a cross reactivity could explain the reduced recurrence rate through CMV infection after allogeneic stem cell transplantation. The MHC-class-I-quantification of the AML-blasts did not show any reduced MHC-expression and would therefore be suitable target cells for T-cell-immunotherapy. KW - Akute myeloische Leukämie KW - Immuntherapie KW - MHC KW - Cytomegalie-Virus KW - Kreuzreaktion KW - Kartierung KW - MHC-Klasse-I-Peptidom Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270036 ER - TY - THES A1 - Köchel, Christoph T1 - Einfluss des Tyrosinkinase-Inhibitors Dasatinib auf Endozytose, Präsentation costimulatorischer Oberflächenmarker und Zytokinproduktion dendritischer Zellen T1 - Effects of tyrosine kinase inhibitor dasatinib on endocytosis, presentation of co-stimulatory molecules and cytokine production of dendritic cells N2 - Die Einführung der Tyrosinkinaseinhibitoren (TKIs) stellt einen Meilenstein der Hämatoonkologie im 21. Jahrhundert dar. Im Kontext der chronisch myeloischen Leukämie (CML) konnte das BCR-Abl-Fusionstranskript als pathognomonisches Korrelat identifiziert werden. Dessen pharmakologische Hemmung über bestimmte TKIs korrelierte nicht nur mit hervorragenden Remissionsraten, sondern auch mit einer deutlich besseren Verträglichkeit. Dasatinib verfügt als Zweitgenerations-TKI neben einer hohen Bindungsaffinität zum BCR-Abl-Fusionstranskript als Multi-TKI auch über weitere Zielstrukturen, zu welchen u.a. die Kinasen der Src-Familie (SFKs) gehören. Diese übernehmen bei verschiedenen Immunzellen wichtige regulatorische Funktionen. Bei einem Teil der CML-Patienten kann die TKI-Therapie unterbrochen werden und es findet sich eine anhaltende Remission. Hierfür wurden immunmodulatorische Effekte der TKIs angenommen. Für Dasatinib konnten in vitro und in vivo immunmodulatorische Effekte, u.a. auf T- und NK-Zellen nachgewiesen werden. Im Rahmen dieser Arbeit sollten mögliche immunmodulatorische Effekte auf dendritische Zellen monozytärer Abstammung (moDZ) in vitro untersucht werden. Die Generierung von moDZs erfolgte mittels Zugabe von IL-4 und GM-CSF aus Monozyten gesunder Blutspender. Dasatinib wurde in klinisch relevanten Konzentrationen (10-50 nM) ab Beginn der DZ-Generierung zugegeben, für ausgewählte Experimente auch kurz vor Reifung mit LPS. Dabei wurde der Einfluss von Dasatinib auf die Generierung von moDZs sowie wichtige Funktionen unreifer (Endozytose) und reifer DZs (Expression von zellulären und humoralen Effektorfunktionen) analysiert. Dasatinib bewirkte in einer Konzentration von 50 nM eine verminderte Generierung von moDZs aus Monozyten. Phänotypisch zeigte sich dabei eine verminderte Expression des DZ-typischen Markers CD1a bei einer persistierenden Expression des monozytären Markers CD14. Parallel fand sich auch eine Population CD1a/CD14-koexprimierender Zellen. Daneben konnte auch eine Apoptosesteigerung unter Dasatinib nachgewiesen werden. In Bezug auf die Makropinozytose FITC-konjugierter Dextranpartikel wurde keine relevante Modulation beschrieben. Nach Reifung mit LPS bewirkte Dasatinib 50 nM eine verminderte Expression der costimulatorischen Oberflächenmarker CD80 und CD86, sowie eine verminderte Sekretion von IL-12. Zusammenfassend zeigen unter Dasatinib generierte moDZs Eigenschaften, welche auch bei regulatorischen DZs beschrieben wurden. Eine Behandlung mit Dasatinib könnte folglich Immunantworten negativ modulieren. N2 - The introduction of tyrosine kinase inhibitors (TKIs) represents a hallmark of hemato-oncology in the 21st century. The BCR-Abl fusion transcript was identified as the pathognomonic correlate of the chronic myeloid leukemia (CML). Therapy with TKIs correlated with excellent remission rates as well as a good tolerability. As a second-generation TKI, dasatinib has a high affinity to the BCR-Abl fusion transcript and addresses as a multi-TKI several other targets, including the Src-family-kinases (SFKs). SFKs play an important role in regulating various immune cells. In some CML patients, TKI therapy can be interrupted and sustained remission is found. In this respect immunomodulatory effects of the TKIs were assumed. For dasatinib, immunomodulatory effects, e.g. on T and NK cells, have been demonstrated in vitro and in vivo. Within the scope of this work, possible immunomodulatory effects on monocyte-derived dendritic cells (moDCs) were investigated in vitro. MoDCs were generated from monocytes of healthy blood donors by addition of IL-4 and GM-CSF. Dasatinib was added in clinically relevant concentrations (10-50 nM) from the beginning of DC generation and for selected experiments just before maturation with LPS. Possible effects of dasatinib on the generation of moDCs as well as important functions of immature (endocytosis) and mature DCs (expression of cellular and humoral effector functions) were then analyzed. Dasatinib hampered the generation of moDCs at a concentration of 50 nM. Phenotypically, a reduced expression of the DC marker CD1a was shown with a persistent expression of the monocytic marker CD14. Simultaneously a population of CD1a/CD14-coexpressing cells was found. Additionally an increase in apoptosis was demonstrated with dasatinib treatment. Dasatinib treatment did not affect macropinocytosis of FITC-conjugated dextran particles. Dasatinib 50 nM hampered the expression of CD80 and CD86, as well the secretion of IL-12 in LPS-matured moDCs. In summary, moDCs generated during dasatinib treatment show properties that have also been described in regulatory DCs. Treatment with dasatinib could therefore negatively modulate immune responses. KW - Dendritische Zelle KW - dendritische Zellen KW - Dasatinib KW - Immunmodulation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254210 ER - TY - THES A1 - Großhans, Lukas Friedrich T1 - Funktionelle Validierung von seltenen KRas-Mutationen in Zelllinien des Multiplen Myeloms T1 - Functional Validation of rare KRas-mutations in myeloma cell lines N2 - Das Multiple Myelom (MM) ist eine seltene, maligne Störung der Plasmazellen, welche trotz gehöriger Therapiefortschritte in den letzten Jahrzehnten nach wie vor als unheilbare Erkrankung betrachtet werden muss. Obwohl eine sehr große intra- und interindividuelle Heterogenität beim Multiplen Myelom beobachtet werden kann, gibt es verschiedene Mutationen, die mit höherer Frequenz in Myelompatientinnen und -patienten gefunden werden. Eines dieser häufiger betroffenen Proteine ist KRas mit Mutationen in etwa 20% der Fälle. Da die Ras-Proteine und somit auch ihre Isoform KRas zu Beginn der Ras/Raf/Mek/Erk-Signalkaskade stehen und dementsprechend einen großen Einfluss auf die Übermittlung von Wachstums- und Überlebenssignalen in Zellen besitzen, ist eine nähere funktionelle Analyse verschiedener KRas-Mutationen von großer Relevanz. Während für einige Mutationen von KRas bereits funktionelle Analysen existieren, wurden die häufig auftretende Exon 2-Mutation KRasp.G12A, sowie die beiden seltenen Exon 4-Mutationen KRasp.A146T und KRasp.A146V bisher in ihrer funktionellen Rolle im MM noch nicht näher charakterisiert. Um die funktionellen Aspekte dieser genannten Mutationen von KRas näher zu untersuchen, kamen im Rahmen meiner Versuchsreihe Sleeping Beauty Transposon System basierte Expressionsvektoren zur transienten und dauerhaften Proteinexpression in verschiedenen Myelomzelllinien zum Einsatz. Durch Transfektion dieser Plasmide in die KRas-Wildtyp tragenden Zellen mit nachfolgender Transposition in die genomische DNA konnte gezielt die Überexpression der verschiedenen Mutationen realisiert werden. So konnte durch die funktionelle Proteinauslese mittels der Anfertigung von Western Blots gezeigt werden, dass jede der drei getesteten Mutationen zu einer verstärkten Phosphorylierung und damit Aktivierung von KRas-nachgeschalteten Proteinen wie z.B. Erk führt. Zusätzlich wurde für die KRas-Mutationen auch ein aktivierender Effekt auf den PI3K/Akt-Signalweg anhand einer erhöhten Phosphorylierung des Proteins Akt nachgewiesen. Ebenso wie andere bereits besser charakterisierte KRas-Mutationen haben demnach auch die getesteten KRas-Mutationen KRasp.G12A, KRasp.A146T und KRasp.A146V einen positiven Einfluss auf die intrazellulären Überlebenssignale und könnten daher eine elementare Rolle in der Entwicklung des Multiplen Myeloms bei Patientinnen und Patienten spielen. Es gilt daher, die drei in dieser Arbeit untersuchten KRas-Mutationen, zukünftig in die Wirkstoffsuche KRas-spezifischer Therapeutika miteinzubeziehen. N2 - Multiple Myeloma (MM) is a rare, malignant disorder of plasma cells, which despite the progress in therapy over the last decades, must still be considered an incurable disease. Although a very large intra- and interindividual heterogeneity can be observed in multiple myeloma, there are various mutations that are found at higher frequencies in myeloma patients. One of these more common proteins affected by mutations in myeloma patients is KRas, with mutations in about 20% of cases. Since the Ras proteins and thus also their KRas isoform are at the beginning of the Ras/Raf/Mek/Erk signaling cascade and therefore have a major influence on the transmission of survival signals in cells, a closer functional analysis of various KRas mutations is of great relevance. While functional analyses already exist for some KRas mutations, the frequently occurring exon 2 mutation KRasp.G12A and the two rare exon 4 mutations KRasp.A146T and KRasp.A146V have not yet been characterized in their functional role in MM. To further investigate the functional aspects of these KRas mutations, I used protein expression vectors based on the Sleeping Beauty Transposon System for transient and sustained protein expression in different myeloma cell lines. By transfection of these plasmids into KRas wild-type cells the overexpression of the different mutations could be realized. By functional protein readout using Western blots it could be shown that each of the three tested mutations leads to increased phosphorylation and thus activation of KRas downstream proteins such as Erk. In addition, an activating effect on the PI3K/Akt signaling pathway could be demonstrated for the KRas mutations by showing an increased phosphorylation of the Akt protein. As with other KRas mutations that have already been better characterized, the KRas mutations KRasp.G12A, KRasp.A146T and KRasp.A146V have a positive influence on intracellular survival signals and could therefore play a fundamental role in the development of multiple myeloma in patients. It is therefore important to include the three KRas mutations investigated in this work in the drug discovery process for KRas-specific therapeutics in the future. KW - Plasmozytom KW - K-ras KW - KRas KW - Multiples Myelom KW - Funktionelle Validierung Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-292974 ER - TY - THES A1 - Page, Lukas T1 - Entwicklung und präklinische Evaluation immunologischer und nuklearmedizinischer diagnostischer Tests für Schimmelpilz-assoziierte Hypersensitivität und invasive Mykosen T1 - Development and preclinical evaluation of immunological and nuclear medical diagnostic assays for mould-associated hypersensitivity and invasive mycoses N2 - Schimmelpilze können in Abhängigkeit des Immunstatus und der Vorerkrankungen betroffener Patienten unterschiedliche Krankheitsbilder wie Hypersensitivitäts-erkrankungen oder lebensbedrohliche invasive Infektionen hervorrufen. Da die Diagnosestellung dieser Erkrankungen mitunter komplex und insensitiv ist, sollten im Rahmen dieser Arbeit unterschiedliche Ansätze neuer diagnostischer Assays untersucht werden. In den letzten Jahren wurden Assays entwickelt, die auf Basis durchflusszytometrisch quantifizierter Pilz-spezifischer T-Zellen aus peripherem Blut einen supportiven Biomarker zur Diagnostik invasiver Mykosen liefern könnten. Da die hierfür isolierten T-Zellen anfällig gegenüber präanalytischer Lagerzeiten und immunsuppressiver Medikation sind, wurden hier Protokolloptimierungen vorgenommen, um anhand eines Vollblut-basierten Assays mit zusätzlicher CD49d-Kostimulation diesen Limitationen entgegen zu wirken. In einer Studie an gesunden Probanden konnte dabei gezeigt werden, dass die Kombination der Durchflusszytometrie mit ausgewählten Zytokin-Messungen (IL-5, IL-10 und IL-17) zu einer verbesserten Erkennung vermehrt Schimmelpilz-exponierter Personen beitragen könnte. Neben Infektionen könnten dabei im umwelt- und arbeitsmedizinischen Kontext Polarisationen der T-Zell-Populationen detektiert werden, welche mit Sensibilisierungen und Hypersensitivität assoziiert werden. Zusätzlich wurde ein in vitro Transwell® Alveolarmodell zur Simulation pulmonaler Pilzinfektionen für Erreger der Ordnung Mucorales adaptiert, durch Reproduktion wichtiger Merkmale der Pathogenese von Mucormykosen validiert, und für Untersuchungen der Immunpathologie und Erreger-Invasion verwendet. Das Modell wurde anschließend zur in vitro Evaluation von radioaktiv markiertem Amphotericin B mit 99mTc oder 68Ga als nuklearmedizinischen Tracer verwendet. Die untersuchten Schimmelpilze zeigten dabei eine zeit- und dosis-abhängige Aufnahme der Tracer, während bakteriell infizierte Proben nicht detektiert wurden. Die erhobenen Daten dokumentieren ein vielversprechendes Potenzial von Amphotericin B-basierten Tracer, das in zukünftigen in vivo Studien weiter evaluiert werden sollte. N2 - Depending on the immune constitution and predisposing illnesses, moulds can cause a variety of diseases ranging from hypersensitivity syndromes to life-threatening invasive infections. As the diagnosis of mould-associated diseases remains challenging, this work aimed to refine immunological assays and to develop molecular imaging protocols for pulmonary mould infections. Recently, a flow cytometric assay for mould specific T cell quantification has been proposed as a novel supportive biomarker to diagnose invasive mycoses. As these assays are susceptible to pre-analytic delays and immunosuppressive drugs, a whole blood-based protocol with enhanced CD28 plus CD49d co-stimulation was developed and was shown to be less prone to these limitations. In addition, a study on healthy volunteers demonstrated the applicability of flow cytometric antigen-reactive T cell quantification as a surrogate of environmental mould exposure, especially when combined with T-cellular cytokine measurements (specifically, IL-5, IL-10, and IL-17). Therefore, these assays could potentially be used to detect polarizations of T-cell populations associated with sensitization and hypersensitivity, e. g. in allergology and occupational medicine. Moreover, an in vitro Transwell® alveolar model of invasive pulmonary mould infections has been adapted to study mucormycoses, validated by recapitulation of known pathogenicity factors, and used to characterize the immunopathology and epithelial invasion of Mucorales. The Transwell® model was subsequently used to evaluate radioactively labelled Amphotericin B with either 99mTc or 68Ga as a potential nuclear medical tracer. Time- and dose-dependent enrichment of the tracers was found in both Aspergillus and Mucorales, whereas samples infected with bacteria showed negligible uptake. These in vitro data document a promising potential of radiolabeled amphotericin B for molecular imaging of invasive mycoses and encourage further evaluation in animal models. KW - Schimmelpilze KW - Diagnostik KW - Biomarker KW - Tracer KW - Zellkultur KW - Antimykotika KW - Mucorales KW - Aspergillus KW - T-Zellen KW - Immunsuppressiva KW - Antifungal KW - Mucormycosis KW - Aspergillosis KW - T cells KW - Immunosuppressant Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252459 ER - TY - JOUR A1 - Kosmala, Aleksander A1 - Serfling, Sebastian E. A1 - Dreher, Niklas A1 - Lindner, Thomas A1 - Schirbel, Andreas A1 - Lapa, Constantin A1 - Higuchi, Takahiro A1 - Buck, Andreas K. A1 - Weich, Alexander A1 - Werner, Rudolf A. T1 - Associations between normal organs and tumor burden in patients imaged with fibroblast activation protein inhibitor-directed positron emission tomography JF - Cancers N2 - (1) Background: We aimed to quantitatively investigate [\(^{68}\)Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [\(^{68}\)Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA = TV × SUV\(_{mean}\)). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman's rank correlation coefficient. (3) Results: Median SUV\(_{mean}\) values were 2.15 in the pancreas (range, 1.05–9.91), 1.42 in the right (range, 0.57–3.06) and 1.41 in the left kidney (range, 0.73–2.97), 1.2 in the heart (range, 0.46–2.59), 0.86 in the spleen (range, 0.55–1.58), 0.65 in the liver (range, 0.31–2.11), and 0.57 in the bone marrow (range, 0.26–0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUV\(_{max}\) (ρ = 0.29, p = 0.07) and TV (ρ = −0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUV\(_{max}\) (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUV\(_{max}\) (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [\(^{68}\)Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs. KW - PET KW - [\(^{68}\)Ga]Ga-FAPI KW - theranostics KW - radioligand therapy KW - fibroblast activation protein Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275154 SN - 2072-6694 VL - 14 IS - 11 ER - TY - THES A1 - Dombrowski, Dorothea T1 - GDF-15 im Zusammenhang mit Therapieerfolg einer Immuncheckpointblockade: eine Pilotstudie mit fortgeschrittenen soliden Tumorerkrankungen T1 - Connection of GDF-15 with success of an immune checkpoint blockade therapy: a pilot study with progressed solid tumors N2 - Kurzzusammenfassung: Dank der Einführung von Immuncheckpointinhibitoren hat sich die Therapie fortgeschrittener onkologischer Erkrankungen in den letzten Jahren dramatisch verändert. Trotz außergewöhnlicher Erfolge profitieren viele Patienten jedoch weder akut noch langfristig von einer Behandlung, tragen aber alle ihre Risiken. Ein besseres Verständnis davon, bei welchen Patienten diese Therapieform wirkt, sowie prädiktive Marker werden daher dringend benötigt. Growth Differentiation Factor 15 (GDF-15) ist Teil der Transforming Growth Factor-β Superfamilie, weist in pathologischen Situationen wie Entzündungen und insbesondere bei Krebs sehr hohe Spiegel auf und besitzt in verschiedenen, auch onkologischen Erkrankungen einen starken prognostischen Wert. Möglicherweise könnte GDF-15 durch seine immunmodulierenden Eigenschaften dazu beitragen, dass Krebszellen im Körper nicht angegriffen werden, und die Wirksamkeit einer Immuncheckpointblockade (ICB) dadurch vermindern. Ziel der vorliegenden Pilotstudie war es zu untersuchen, ob ein Zusammenhang zwischen dem GDF-15-Spiegel und dem Erfolg einer ICB besteht. Hierfür wurden 37 Patienten verschiedener onkologischer Entitäten vor Beginn einer ICB auf ihre GDF-15-Spiegel untersucht, sowie nach zwölf bzw. bei Progressive Disease zum Teil auch nach vier Wochen Therapie. Die Bewertung des Therapieergebnisses erfolgte anhand der RECIST sowie der klinischen Präsentation. Ein Therapieerfolg wurde ab Erreichen einer Stable Disease klassifiziert. Die Rekrutierungszeit betrug 23 Monate ab Januar 2017. Die Untersuchungen zeigten vor Therapiebeginn einer ICB einen geringen Unterschied der GDF-15-Spiegel zwischen Patienten mit Therapieerfolg und Therapieversagen (Median des Therapieerfolgs: 0,63 ng/ml versus Median des Therapieversagens: 0,92 ng/ml). Dieser Unterschied war statistisch nicht signifikant. Dagegen zeigte sich ein signifikanter Zusammenhang zwischen einem Anstieg des GDF-15-Spiegels unter Therapie und dem Therapieversagen einer ICB. Bei Therapieerfolg sank oder stagnierte der GDF-15-Spiegel im Median um - 0,01 ng/ml. Dagegen stieg er bei Therapieversagen im Median um + 0,7 ng/ml an (p < 0,01 r = 0,43). Auch die Höhe des GDF-15-Spiegels unter Therapie zeigte einen signifikanten Zusammenhang mit dem Therapieergebnis. Der GDF-15-Spiegel unter Therapie lag im Median bei Patienten mit Therapieerfolg bei 0,72 ng/ml, dagegen bei Patienten mit Therapieversagen bei 1,85 ng/ml (p < 0,01 r = 0,47). Ob der GDF-15-Spiegel vor Therapiebeginn die Wirksamkeit einer ICB vorhersagen kann, bleibt unklar, da in dieser Studie nur eine Tendenz aufgezeigt werden konnte, die in Folgestudien mit größeren Kohorten in den verschiedenen Entitäten untersucht werden sollte. Unsere Daten zeigen jedoch einen Zusammenhang zwischen einem steigenden bzw. erhöhten GDF-15-Spiegel unter Therapie mit dem Therapieergebnis einer ICB. Dieser Zusammenhang fügt sich gut in das Bild gegenwärtiger Diskussionen über immunmodulierende Eigenschaften von GDF-15 und seiner Rolle bei der Tumorprogression. Zugleich bestärkt das Studienergebnis die Annahme, in GDF-15 auch ein vielversprechendes Angriffsziel therapeutischer Ansätze gefunden zu haben. N2 - Abstract: Thanks to the introduction of immune checkpoint inhibitors, therapy of progressed oncological diseases has changed dramatically in recent years. However, many patients benefit neither acutely nor in the long term from the treatment but bear all its risks. A better understanding of which patients profit from this therapy as well as predictive markers are therefore urgently needed. Growth Differentiation Factor 15 (GDF-15) is part of the Transforming Growth Factor-β superfamily. It shows raised levels in pathological situations such as inflammation and reaches especially in cancer remarkably high levels. It has a strong prognostic value in various, also oncological diseases. Possibly, GDF-15 helps cancer cells not to be attacked by the immune system and could thereby reduce the effectiveness of an immune checkpoint blockade (ICB). The aim of the presented pilot study was investigating whether there is a connection between the GDF-15 level and the success of an ICB. For this purpose, the GDF-15 level of 37 patients of different oncological entities were examined before the start of an ICB, as well as after twelve weeks of therapy, or in the case of progressive disease, after four weeks of therapy. The evaluation of the therapy results was based on RECIST and the clinical presentation. The time of recruitment was 23 months since January 2017. For the GDF-15 level before start of an ICB therapy, the investigations showed a small difference between patients with therapy success and therapy failure (median when success of the therapy: 0.63 ng/ml versus median when treatment failure: 0.92 ng/ml). But this difference was not statistically significant. In contrast, during therapy there was a significant connection between an increase in the GDF-15 level and therapy failure of the ICB. In case of successful therapy, the GDF-15 level fell or stagnated with a median of -0.01 ng/ml. In contrast, the GDF-15 level rose with a median of +0.7 ng/ml in case of therapy failure (p<0.01 r=0.43). Also, the absolute height of the GDF-15 level during therapy showed a significant connection with the therapy result. The median of the GDF-15 level during therapy of patients with therapy success was 0.72 ng/ml, but of patients with treatment failure was 1.85 ng/ml (p<0.01 r = 0.47). Whether the GDF-15 level can predict the effectiveness of an ICB before the start of therapy remains unclear, since this study could only show a trend that follow-up studies with larger cohorts for the different entities should further examine. However, our data show a correlation between increasing and increased GDF-15 levels under therapy with the therapy result of an ICB. This correlation fits well with current discussions about immunomodulating properties of GDF-15 and its role in tumor progression. Simultaneously, the study result confirms the assumption of GDF-15 being a promising target of new therapeutic approaches. KW - Immun-Checkpoint KW - Growth-differentiation Factor 15 KW - GDF 15 KW - Immuncheckpointblockade KW - Immuncheckpointinhibitor Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286461 ER - TY - JOUR A1 - Rau, Monika A1 - Buggisch, Peter A1 - Mauss, Stefan A1 - Boeker, Klaus H. W. A1 - Klinker, Hartwig A1 - Müller, Tobias A1 - Stoehr, Albrecht A1 - Schattenberg, Jörn M. A1 - Geier, Andreas T1 - Prognostic impact of steatosis in the clinical course of chronic HCV infection-Results from the German Hepatitis C-Registry JF - PLoS ONE N2 - Background Liver steatosis is often observed in chronic HCV infection and associated to genotype or comorbidities. NAFLD is an important risk factor for end-stage liver disease. We aimed to analyse the course of NAFLD as a concomitant disease in a cohort of HCV patients. Methods The German Hepatitis C-Registry is a national multicenter real-world cohort. In the current analysis, 8789 HCV patients were included and separated based on the presence of steatosis on ultrasound and/or histology. Fibrosis progression was assessed by transient elastography (TE), ultrasound or non-invasive surrogate scores. Results At the time of study inclusion 12.3% (n = 962) of HCV patients presented with steatosis (+S) (higher rate in GT-3). Diabetes mellitus was more frequent in GT-1 patients. HCV patients without steatosis (-S) had a slightly higher rate of fibrosis progression (FP) over time (30.3%) in contrast to HCV patients +S (26%). This effect was mainly observed in GT-3 patients (34.4% vs. 20.6%). A larger decrease of ALT, AST and GGT from baseline to FU-1 (4–24 weeks after EOT) was found in HCV patients (without FP) +S compared to -S. HCV patients -S and with FP presented more often metabolic comorbidities with a significantly higher BMI (+0.58kg/m\(^{2}\)) compared to patients -S without FP. This was particularly pronounced in patients with abnormal ALT. Conclusion Clinically diagnosed steatosis in HCV patients does not seem to contribute to significant FP in this unique cohort. The low prevalence of steatosis could reflect a lower awareness of fatty liver in HCV patients, as patients -S and with FP presented more metabolic risk factors. KW - steatosis KW - HCV infection KW - liver Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300549 VL - 17 IS - 6 ER - TY - JOUR A1 - Reimer, Stanislaus A1 - Lock, Johan F. A1 - Flemming, Sven A1 - Weich, Alexander A1 - Widder, Anna A1 - Plaßmeier, Lars A1 - Döring, Anna A1 - Hering, Ilona A1 - Hankir, Mohammed K. A1 - Meining, Alexander A1 - Germer, Christoph-Thomas A1 - Groneberg, Kaja A1 - Seyfried, Florian T1 - Endoscopic management of large leakages after upper gastrointestinal surgery JF - Frontiers in Surgery N2 - Background Endoscopic vacuum therapy (EVT) is an evidence-based option to treat anastomotic leakages of the upper gastrointestinal (GI) tract, but the technical challenges and clinical outcomes of patients with large defects remain poorly described. Methods All patients with leakages of the upper GI tract that were treated with endoscopic negative pressure therapy at our institution from 2012–2021 were analyzed. Patients with large defects (>30 mm) as an indicator of complex treatment were compared to patients with smaller defects (control group). Results Ninety-two patients with postoperative anastomotic or staplerline leakages were identified, of whom 20 (21.7%) had large defects. Compared to the control group, these patients required prolonged therapy (42 vs. 14 days, p < 0.001) and hospital stay (63 vs. 26 days, p < 0.001) and developed significantly more septic complications (40 vs. 17.6%, p = 0.027.) which often necessitated additional endoscopic and/or surgical/interventional treatments (45 vs. 17.4%, p = 0.007.) Nevertheless, a resolution of leakages was achieved in 80% of patients with large defects, which was similar compared to the control group (p = 0.42). Multiple leakages, especially on the opposite side, along with other local unfavorable conditions, such as foreign material mass, limited access to the defect or extensive necrosis occurred significantly more often in cases with large defects (p < 0.001). Conclusions Overall, our study confirms that EVT for leakages even from large defects of the upper GI tract is feasible in most cases but comes with significant technical challenges. KW - anastomotic leakage KW - endoluminal KW - vacuum-assisted closure KW - negative pressure KW - endoscopic Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-274044 SN - 2296-875X VL - 9 ER - TY - THES A1 - Engelmann, Bernhard T1 - Einfluss von Ganzkörpervibrationstraining auf die Knochenstruktur und den Knochenstoffwechsel bei Personen mit monoklonaler Gammopathie unklarer Signifikanz T1 - Influence of whole-body vibration training on bone structure and bone metabolism in subjects with monoclonal gammopathy of undetermined significance N2 - Der Nachweis einer monoklonalen Gammopathie unklarer Signifikanz (MGUS) im Serum ist ein Risikofaktor für eine Mikroarchitekturstörung des Knochens [3, 81], für Frakturen [10, 11] sowie für die Entstehung einer Osteoporose [12], die auf einen gestörten Knochenstoffwechsel zurückgeführt werden können. Derzeit wird Training mit Vibrationsgeräten bereits erfolgreich gegen Muskelatrophie und Knochenschwund bei bettlägerigen Patienten angewandt [199] [198]. Das Ziel der durchgeführten Studie sowie dieser Dissertationsarbeit war herauszufinden, ob bei Patienten und Patientinnen mit MGUS beziehungsweise SMM ein Training unter Ganzkörpervibration diese gestörten Prozesse beeinflussen kann. Um diese Theorie zu überprüfen, wurde ein dreimonatiges Training mit Vibrationsplatten unter Supervision durchgeführt, mit einer optionalen Verlängerung um weitere drei Monate. Die Dauer des Trainings belief sich auf circa 30-45 Minuten, bei durchschnittlich zwei Einheiten pro Woche. Dabei wurden Trainingsübungen auf den Vibrationsplatten durchgeführt, um die Trainingseinheiten noch effektiver zu gestalten. Die Veränderungen wurden anschließend an zwei Zeiträumen nach drei sowie sechs Monaten zusätzlich zur Baseline Erhebung dokumentiert und ausgewertet. Ermittelt wurde mittels pQCT Strukturparameter des tibialen Knochens in der Bildgebung, der Knochenstoffwechsel mittels Biomarker sowie hämatologische Veränderungen mittels Laborwerten. Als Ergebnisse wurden bei 15 Probanden und Probandinnen mit einer MGUS (Durchschnittsalter 62 Jahre, neun Frauen, sechs Männer) eine Erhöhung der kortikalen Tibia bei den der Frauen (p=0.015) gemessen. Des Weiteren kam es zu einer Änderung des Knochenumbaus, welcher sich an einer Änderung der Marker für die Knochenregulation betreffend DKK1 sowie Sclerostin und den Markern für die Knochenresorption NTX sowie TRAP5b im Blut zeigte. Die hämatologischen Laboruntersuchungen zeigten keinen konsistenten Trend. Das Training wies bei einer Adhärenz im Mittel von 97 % über sechs Monate eine hohe Teilnahme auf. Vibrationsplattentraining ist gut durchführbar und sicher. Als Rückschluss kann auf eine regulatorische Wirkung des Ganzkörpervibrationstrainings geschlossen werden. Dies zeigen die Veränderungen der Knochenumsatzmarker sowie des Knochendichte zuwachses in der Bildgebung. Groß angelegte multizentrische Studien könnten durch- geführt werden, um positive Effekte auf eine Tumorprogression bei einem Multiplen Myelom beziehungsweise bei deren Knochenerkrankung festzustellen. N2 - The detection of a monoclonal gammopathy of undetermined significance (MGUS) in the serum is a risk factor for a microarchitectural disorder of the bone [3, 81], for fractures [10, 11] and for the development of osteoporosis [12], which are attributed to a disturbed bone metabolism. Currently, training with vibration devices is already being used successfully against muscle atrophy and bone loss in bedridden patients [199], [198]. The aim of the study carried out and of this dissertation was to find out whether training under whole-body vibration can influence these disturbed processes in patients with MGUS or SMM. To test this theory, a three-month supervised training session with vibrating plates was conducted, with an optional extension for a further three months. The duration of the training was around 30-45 minutes, with an average of two units per week. Training exercises were carried out on the vibration plates to make the training sessions even more effective. The changes were then documented and evaluated at two periods after three and six months in addition to the baseline survey. Structural parameters of the tibial bone were determined with pQCT in imaging, bone metabolism using biomarkers and hematological changes using laboratory values. The results measured an elevation of the cortical tibia in women (p=0.015) in 15 subjects with MGUS (mean age 62 years, nine women, six men). Furthermore, there was a change in bone remodeling, which was reflected in a change in the markers for bone regulation relating to DKK1 and sclerostin and the markers for bone resorption NTX and TRAP5b in the blood. The hematological laboratory investigations did not show a consistent trend. The training showed a high participation rate with an average adherence of 97% over six months. Vibration plate training is easy to carry out and safe. As a conclusion, a regulatory effect of whole-body vibration training can be concluded. This is shown by the changes in bone turnover markers and the increase in bone density in imaging. Large-scale, multi-centre studies could be carried out to determine positive effects on tumor progression in multiple myeloma or its bone disease. KW - Myelom KW - Vibrationplattsntraining KW - MGUS KW - WBV Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266458 ER - TY - THES A1 - Streit, Anne T1 - Prävalenz von medikamentenassoziierten Kiefernekrosen und deren Risikofaktoren bei Patienten mit Erkrankungen aus dem rheumatischen Formenkreis T1 - Prevalence of osteonecrosis of the jaw in patients with inflammatory rheumatic diseases and Osteoporosis therapy N2 - Einleitung: Das Ziel dieser Studie war die Einschätzung der Prävalenz der medikamentenassoziierten Kieferosteonekrose (MRONJ) in einem Kollektiv von Patienten mit Osteoporose und rheumatischer Grunderkrankung. Zudem wurden Risikofaktoren sowie präventive Maßnahmen betrachtet. Methoden: Insgesamt wurden 198 Patienten in der Rheumatologischen Ambulanz in Zusammenarbeit mit der Mund-Kiefer-Gesichtschirurgie (MKG) des Universitätsklinikums in Würzburg in einem Zeitraum von 14 Monaten rekrutiert. Es wurden Telefoninterviews mit allen Patienten geführt. Auffällige Patienten wurden in der MKG untersucht, zahnärztliche Unterlagen wurden angefordert und evaluiert. Zusätzlich erfolgte eine retrospektive Analyse der elektronischen Patientenakten. Ergebnisse: Die Prävalenz der MRONJ betrug in unserem Patientenkollektiv 1,5 % (n=3). Alle Patientinnen mit MRONJ bekamen das Bisphosponat (BP) oral, eine Patientin bekam es zusätzlich intravenös und eine weitere Patientin bekam zusätzlich Denosumab. Die Patientengruppe mit Kieferosteonekrose hatte im Vergleich zu den Patienten ohne Kieferosteonekrose innerhalb des Kollektivs eine statistisch signifikant höhere Gesamttherapiedauer der Osteoporose (p≤0,0001), einen niedrigeren durchschnittlichen FFbH (p=.031) und eine niedrigere Knochendichte (Femur) (p=.009). Nur 38,4 % der Patienten im Gesamtkollektiv fühlten sich über das Risiko einer MRONJ aufgeklärt. Nur 25,3 % der Patienten gaben an, zu Beginn der BP-Therapie bei einer zahnärztlichen Kontrolluntersuchung gewesen zu sein. Schlussfolgerung: Die Prävalenz von 1,5 % für diese dramatische unerwünschte Arztneimittelwirkung unterstreicht das hohe Risiko rheumatologisch erkrankter Patienten. Ein prospektives Register zur Erfassung von MRONJ bei diesem besonderen Risikokollektiv wäre empfehlenswert. Die Daten zur Prävention der MRONJ zeigen, dass die geforderten Maßnahmen zur Vermeidung einer MRONJ bisher nur unzureichend umgesetzt werden. N2 - Introduction: The aim of this study was to assess the prevalence of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients suffering from inflammatory rheumatic diseases, as well as to evaluate risk factors and preventive measures for MRONJ. Methods: A total of 198 patients with inflammatory rheumatic diseases and osteoporosis therapy were recruited from a tertiary rheumatological/immunological referral center in a period of 14 months. Telephone interviews were conducted with all patients. A maxillofacial surgeon later examined patients complaining of possible symptoms of osteonecrosis. Dental records were requested and evaluated as needed. In addition, a retrospective analysis of the patient files was carried out. Results: The prevalence of MRONJ in our patient collective was 1.5% (n=3). All patients with MRONJ had been treated orally with bisphosphonates (BP), one was given bisphoshonates intravenously and another was treated with denosumab. Long anti-osteoporotic treatment duration (p≤.0001), low functional status (p=.031), and low bone density of the femur (p=.009) were significantly associated with MRONJ development. Only 38.8% of the patients in the total collective felt informed about the risk of MRONJ. Only 25.3% of the patients stated that they had been to a dental check-up at the beginning of the BP therapy. Conclusion: The prevalence of 1.5% underlines the high risk for patients with inflammatory rheumatic diseases. A prospective registry to record MRONJ in this risk collective is advisable. The measures required to avoid MRONJ have been implemented inadequately at the point of this study. KW - Osteoporose KW - MRONJ KW - BONJ KW - Rheumapatient KW - Kieferosteonekrose Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-280267 ER - TY - THES A1 - Jendretzki, Julia Bianca T1 - Ernährungsberatung in der Onkologie – Eine Fragebogen-basierte Analyse zur Erfassung des subjektiven und medizinischen Beratungsbedarfs von krebskranken Patienten am Comprehensive Cancer Center der Uniklinik Würzburg T1 - Nutritional counseling in oncology - A questionnaire-based analysis to assess the subjective and medical counseling needs of patients with cancer at the Comprehensive Cancer Center of Würzburg University Hospital N2 - Hintergrund Mangelernährung bleibt im klinischen Alltag noch oft unerkannt und wird häufig unterschätzt. Die durchgeführte Studie hatte das Ziel, die Häufigkeit eines Ernährungsrisikos sowie die Patientengruppen, welche am meisten von einer Ernährungsberatung profitieren würden, zu ermitteln. Methode Ambulant versorgte Patienten mit Tumorerkrankungen des Universitätsklinikums Würzburgs wurden mittels eines vom Ernährungsteam des Comprehensive Cancer Centers erstellten Fragebogens zwischen Mai 2017 und Januar 2018 befragt. Es wurden insbesondere Fragen zum Ernährungszustand und Ernährungsproblemen gestellt. Zudem wurde das Risiko für das Entstehen einer Mangelernährung mittels des validierten Screening-Fragebogens Malnutrition Universal Screening Tool (MUST) erfasst. Ergebnisse In der vorliegenden Studie wurden 311 Patienten befragt. Im MUST-Screening zeigte sich bei 16,4 % ein mittleres und bei 20,3 % ein hohes Risiko für eine Mangelernährung, wobei die Punktevergabe in 94,8 % der Fälle durch einen ungewollten Gewichtsverlust erfolgte. Insbesondere Patienten der Gastroenterologie sowie Patienten > 65 Jahre wiesen ein hohes Risiko auf. Es zeigte sich ein signifikanter Zusammenhang zwischen stattgehabter Chemotherapie und einem MUST-Score ≥ 2 (OR = 3,6). Als besondere Risikofaktoren ließen sich zudem Geschmackveränderungen, Schluckbeschwerden, Ekelempfinden und Appetitlosigkeit feststellen (OR = 2,3 – 3,2). Interesse am Thema „Ernährung bei Krebs“ zeigten vor allem junge, weibliche und normalgewichtige Patienten. Ein Gespräch mit dem behandelten Arzt hierzu fand nur bei 38 % aller Patienten statt. Schlussfolgerungen Jeder fünfte Patient unterlag einem hohen Ernährungsrisiko, nur ein Bruchteil wäre durch Erhebung des Body Mass Index aufgefallen. Ein valides Screeningverfahren mit aussagekräftigen Parametern sollte Einzug in den klinischen Alltag ambulant versorgter Krebspatienten finden und gemeinsam mit einer Ernährungsberatung standardisiert bei Diagnosestellung sowie in regelmäßigen Abständen im Verlauf stattfinden. N2 - Background Malnutrition still often remains unrecognized in clinical practice and is frequently underestimated. The aim of this study was to determine the frequency of nutritional risk and the patient groups that would benefit most from nutritional counseling. Methods Outpatients with tumor diseases at the University Hospital of Würzburg were surveyed using a questionnaire prepared by the Comprehensive Cancer Center's nutrition team between May 2017 and January 2018. In particular, questions were asked about nutritional status and nutritional problems. In addition, the risk of developing malnutrition was assessed using the validated screening questionnaire Malnutrition Universal Screening Tool (MUST). Results In the present study, 311 patients were interviewed. MUST screening showed 16.4% to be at moderate risk of malnutrition and 20.3% to be at high risk of malnutrition, with scoring by unintentional weight loss in 94.8% of cases. Gastroenterology patients and patients > 65 years of age were at particularly high risk. There was a significant association between chemotherapy given and a MUST score ≥ 2 (OR = 3.6). In addition, changes in taste, difficulty swallowing, disgust, and loss of appetite could be identified as particular risk factors (OR = 2.3 - 3.2). Interest in the topic of "nutrition in cancer" was mainly shown by young, female and normal-weight patients. A discussion with the treating physician on this topic took place in only 38% of all patients. Conclusions One in five patients was at high nutritional risk, only a fraction would have been detected by body mass index. A valid screening procedure with meaningful parameters should be introduced into the clinical routine of outpatient cancer patients and, together with nutritional counseling, should take place in a standardized manner at the time of diagnosis and at regular intervals during the course of treatment. Translated with www.DeepL.com/Translator (free version) KW - Ernährungsberatung KW - Mangelernährung KW - Onkologie KW - Ambulante Patienten KW - MUST-Score KW - Nutritional Counseling KW - Oncology KW - Outpatients KW - MUST-Score KW - Malnutrition Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-283495 ER - TY - JOUR A1 - Strunz, Patrick-Pascal A1 - Vuille-Dit-Bille, Raphael N. A1 - Fox, Mark R. A1 - Geier, Andreas A1 - Maggiorini, Marco A1 - Gassmann, Max A1 - Fruehauf, Heiko A1 - Lutz, Thomas A. A1 - Goetze, Oliver T1 - Effect of high altitude on human postprandial \(^{13}\)C-octanoate metabolism, intermediary metabolites, gastrointestinal peptides, and visceral perception JF - Neurogastroenterology and Motility N2 - Objective At high altitude (HA), acute mountain sickness (AMS) is accompanied by neurologic and upper gastrointestinal symptoms (UGS). The primary aim of this study was to test the hypothesis that delayed gastric emptying (GE), assessed by \(^{13}\)C-octanoate breath testing (OBT), causes UGS in AMS. The secondary aim was to assess post-gastric mechanisms of OBT, which could confound results under these conditions, by determination of intermediary metabolites, gastrointestinal peptides, and basal metabolic rate. Methods A prospective trial was performed in 25 healthy participants (15 male) at 4559 m (HA) and at 490 m (Zurich). GE was assessed by OBT (428 kcal solid meal) and UGS by visual analogue scales (VAS). Blood sampling of metabolites (glucose, free fatty acids (FFA), triglycerides (TG), beta-hydroxyl butyrate (BHB), L-lactate) and gastrointestinal peptides (insulin, amylin, PYY, etc.) was performed as well as blood gas analysis and spirometry. Statistical analysis: variance analyses, bivariate correlation, and multilinear regression analysis. Results After 24 h under hypoxic conditions at HA, participants developed AMS (p < 0.001). \(^{13}\)CO\(_{2}\) exhalation kinetics increased (p < 0.05) resulting in reduced estimates of gastric half-emptying times (p < 0.01). However, median resting respiratory quotients and plasma profiles of TG indicated that augmented beta-oxidation was the main predictor of accelerated \(^{13}\)CO\(_{2}\)-generation under these conditions. Conclusion Quantification of \(^{13}\)C-octanoate oxidation by a breath test is sensitive to variation in metabolic (liver) function under hypoxic conditions. \(^{13}\)C-breath testing using short-chain fatty acids is not reliable for measurement of gastric function at HA and should be considered critically in other severe hypoxic conditions, like sepsis or chronic lung disease. KW - acute hypobaric hypoxia KW - beta-oxidation KW - gastric emptying KW - stable isotope breath tests Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259611 VL - 34 IS - 3 ER - TY - JOUR A1 - Krenzer, Adrian A1 - Makowski, Kevin A1 - Hekalo, Amar A1 - Fitting, Daniel A1 - Troya, Joel A1 - Zoller, Wolfram G. A1 - Hann, Alexander A1 - Puppe, Frank T1 - Fast machine learning annotation in the medical domain: a semi-automated video annotation tool for gastroenterologists JF - BioMedical Engineering OnLine N2 - Background Machine learning, especially deep learning, is becoming more and more relevant in research and development in the medical domain. For all the supervised deep learning applications, data is the most critical factor in securing successful implementation and sustaining the progress of the machine learning model. Especially gastroenterological data, which often involves endoscopic videos, are cumbersome to annotate. Domain experts are needed to interpret and annotate the videos. To support those domain experts, we generated a framework. With this framework, instead of annotating every frame in the video sequence, experts are just performing key annotations at the beginning and the end of sequences with pathologies, e.g., visible polyps. Subsequently, non-expert annotators supported by machine learning add the missing annotations for the frames in-between. Methods In our framework, an expert reviews the video and annotates a few video frames to verify the object’s annotations for the non-expert. In a second step, a non-expert has visual confirmation of the given object and can annotate all following and preceding frames with AI assistance. After the expert has finished, relevant frames will be selected and passed on to an AI model. This information allows the AI model to detect and mark the desired object on all following and preceding frames with an annotation. Therefore, the non-expert can adjust and modify the AI predictions and export the results, which can then be used to train the AI model. Results Using this framework, we were able to reduce workload of domain experts on average by a factor of 20 on our data. This is primarily due to the structure of the framework, which is designed to minimize the workload of the domain expert. Pairing this framework with a state-of-the-art semi-automated AI model enhances the annotation speed further. Through a prospective study with 10 participants, we show that semi-automated annotation using our tool doubles the annotation speed of non-expert annotators compared to a well-known state-of-the-art annotation tool. Conclusion In summary, we introduce a framework for fast expert annotation for gastroenterologists, which reduces the workload of the domain expert considerably while maintaining a very high annotation quality. The framework incorporates a semi-automated annotation system utilizing trained object detection models. The software and framework are open-source. KW - object detection KW - machine learning KW - deep learning KW - annotation KW - endoscopy KW - gastroenterology KW - automation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300231 VL - 21 IS - 1 ER - TY - JOUR A1 - White, P. Lewis A1 - Springer, Jan A1 - Wise, Matt P. A1 - Einsele, Hermann A1 - Löffler, Claudia A1 - Seif, Michelle A1 - Prommersberger, Sabrina A1 - Backx, Matthijs A1 - Löffler, Jürgen T1 - A clinical case of COVID-19-associated pulmonary aspergillosis (CAPA), illustrating the challenges in diagnosis (despite overwhelming mycological evidence) JF - Journal of Fungi N2 - The COVID-19 pandemic has resulted in large numbers of patients requiring critical care management. With the established association between severe respiratory virus infection and invasive pulmonary aspergillosis (7.6% for COVID-19-associated pulmonary aspergillosis (CAPA)), the pandemic places a significant number of patients at potential risk from secondary invasive fungal disease. We described a case of CAPA with substantial supporting mycological evidence, highlighting the need to employ strategic diagnostic algorithms and weighted definitions to improve the accuracy in diagnosing CAPA. KW - COVID-19 KW - CAPA KW - diagnostics KW - Aspergillus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-302438 SN - 2309-608X VL - 8 IS - 1 ER - TY - THES A1 - Paukstat, Katrin T1 - Die Rolle der Einzelnukleotid-Polymorphismen rs10754558 und rs35829419 des NLRP3-Inflammasoms bei der nichtalkoholischen Fettlebererkrankung T1 - The role of the single nucleotide polymorphisms rs10754558 and rs35829419 of the NLRP3 inflammasome in non-alcoholic fatty liver disease N2 - Die vorliegende Dissertation hat sich mit der Fragestellung beschäftigt, inwiefern die Einzelnukleotid-Polymorphismen (kurz SNP) rs10754558 und rs35829419 des NLRP3-Gens mit einer Suszeptibilität für eine NAFL und/oder NASH assoziiert sind. Die Studienkohorte bestand aus 202 Teilnehmern der Würzburger NAFLD-Kohorte der Universitätsklinik Würzburg, 159 NAFLD-Patienten, die im Rahmen der Fettlebersprechstunde der Universitätsklinik Würzburg behandelt wurden und 43 gesunde Kontrollen. Voraussetzung für die Aufnahme in das Patientenkollektiv der durch die Ethikkomission genehmigten Studie war zuallererst die Aufklärung und Zustimmung des Patienten, außerdem eine klinisch oder histologisch diagnostizierte Fettlebererkrankung. Sekundäre Ursachen einer Fettleber oder andere Lebererkrankungen waren Ausschlusskriterien. Alle Teilnehmer erhielten eine Blutentnahme, 97 NAFLD-Patienten eine Leberbiopsie, davon 10 perkutan und 87 subkapsulär im Zuge einer bariatrischen OP. Die Genotypisierung übernahm das Labor der Universitätsklinik Homburg, die weiteren Analysen der Blutwerte, der peripheren und intrahepatischen Immunzellen und die Begutachtung der Leber-Histologie fanden an der Universitätsklinik Würzburg im Rahmen eines vorherigen Forschungsvorhabens statt (Rau et al., 2016). Für beide SNPs war das Hardy-Weinberg-Equilibrium im Studien- sowie Patientenkollektiv erfüllt. Zwischen den einzelnen Genotypen und dem Vorliegen einer NAFL und/oder NASH fanden sich für beide SNPs keine signifikanten Zusammenhänge. Für den Wildtyp CC des SNP rs10754558 ergaben sich in der Studienkohorte signifikant höhere AST-Mediane (p=0,018) und häufiger hochnormale (in den oberen 20 % des Normbereichs) ALT-Werte (p=0,02) im Vergleich zu den Genotypen CG und GG. Hier lässt sich über eine protektive Rolle des Minor Allels in Bezug auf Leberwerterhöhungen spekulieren. Da bisher die Funktion von rs10754558 im NLRP3-Gen noch nicht ausreichend erforscht ist, sollten Untersuchungen auf transkriptioneller Ebene folgen und Studien mit anderen Polymorphismen des NLRP3-Gens und mit NAFLD-assoziierter Gene durchgeführt werden, um eine mögliche Assoziation mit anderen für die Entwicklung der NAFLD relevanten SNPs nicht zu übersehen. In der Analyse mit den Entzündungswerten zeigten sich für die Genotypen CG und GG signifikant erhöhte Frequenzen von Th1-Zellen im peripheren Blut (p=0,003). Zusätzlich lässt sich das vermehrte Vorkommen von Th1-Zellen auch im Rahmen der bestehenden Adipositas bzw. des metabolischen Syndroms im Sinne einer low grade inflammation interpretieren (s. Diskussion). Immerhin sind 95 % der NAFLD-Patienten der Studienkohorte von Adipositas betroffen. Die Ergebnisse zu SNP rs35829419, einer gain-of-function Variante im NLRP3-Gen, waren nur eingeschränkt beurteilbar, da keine homozygoten Allel-A-Träger vorlagen und die Stichprobenzahl für die Analyse der intrahepatischen Immunzellen viel zu gering war, um aussagekräftig sein zu können. In der gesamten Kohorte stellte sich ein signifikanter Zusammenhang zwischen dem heterozygoten Genotyp von rs35829419 und einer erhöhten Frequenz an Th2-Zellen (p=0,024) im peripheren Blut heraus. Innerhalb der NAFLD gingen frühere Studien bisher eher von einer Th1-dominierten Immunantwort aus (Bertola et al., 2010), wenn nicht gar einer Th2-Defizienz (Guebre-Xabier et al., 2000). Das hier vorliegende Ergebnis könnte immerhin auf eine höhere entzündliche Aktivität bei Minor-Allelträgern hindeuten. Die weitere Untersuchung mit größeren Stichproben und weiteren Polymorphismen, die in der NAFLD-Pathogenese bekanntermaßen eine Rolle spielen, erscheint auch für den SNP rs35829419 sinnvoll. Im Hinblick auf die zunehmende Prävalenz der NAFLD als Volkskrankheit der westlichen Welt wird die personalisierte Medizin, inklusive Prävention, Diagnostik und Therapie immer mehr an Bedeutung zunehmen. Die Identifizierung von genetischen Risikovarianten, die an der Pathogenese der NAFLD beteiligt sind, ist ein erster Schritt auf dem Weg hin zu besseren Therapiemöglichkeiten. N2 - This dissertation has dealt with the question of the extent to which the single nucleotide polymorphisms (SNP) rs10754558 and rs35829419 of the NLRP3 gene are associated with susceptibility to NAFL and/or NASH. The study cohort consisted of 202 participants of the Würzburg NAFLD cohort of the University Hospital Würzburg, 159 NAFLD patients who were treated during the fatty liver consultation hours of the University Hospital Würzburg and 43 healthy controls. The prerequisite for inclusion in the patient population of the study approved by the ethics committee was first and foremost the information and consent of the patient, as well as a clinically or histologically diagnosed fatty liver disease. Secondary causes of fatty liver or other liver diseases were exclusion criteria. All participants received a blood sample, 97 NAFLD patients a liver biopsy, of which 10 percutaneously and 87 subcapsular in the course of bariatric surgery. The genotyping was carried out by the laboratory of the University Hospital Homburg, the further analyses of the blood values, the peripheral and intrahepatic immune cells and the assessment of the liver histology took place at the University Hospital Würzburg as part of a previous research project (Rau et al., 2016). For both SNPs, the Hardy Weinberg equilibrium was fulfilled in the study and patient collective. There were no significant associations between the individual genotypes and the presence of NAFL and/or NASH for either SNP. For the wild type CC of SNP rs10754558, significantly higher AST medians (p=0.018) and more frequently highly normal (in the upper 20% of the normal range) ALT values (p=0.02) were found in the study cohort compared to the genotypes CG and GG. Here one can now speculate about a protective role of the minor allele with regard to liver value increases. Since the function of rs10754558 in the NLRP3 gene has not yet been sufficiently researched, studies at the transcriptional level should follow and studies with other polymorphisms of the NLRP3 gene and with NAFLD-associated genes should be carried out in order not to overlook a possible association with other SNPs relevant for the development of NAFLD. The analysis with the inflammation values showed significantly increased frequencies of Th1 cells in peripheral blood for the genotypes CG and GG (p=0.003). In addition, the increased occurrence of Th1 cells can also be interpreted in the context of existing obesity or metabolic syndrome in the sense of low-grade inflammation (see discussion). After all, 95% of NAFLD patients in the study cohort are affected by obesity. The results for SNP rs35829419, a gain-of-function variant in the NLRP3 gene, could only be assessed to a limited extent because there were no homozygous allele A carriers and the sample number for the analysis of intrahepatic immune cells was far too small to be meaningful. Throughout the cohort, there was a significant association between the heterozygous genotype of rs35829419 and an increased frequency of Th2 cells (p=0.024) in peripheral blood. Within NAFLD, previous studies have tended to assume a Th1-dominated immune response (Bertola et al., 2010 ), if not Th2 deficiency (Guebre-Xabier et al., 2000). The present result could at least indicate a higher inflammatory activity in minor allele carriers. Further investigation with larger samples and other polymorphisms, which are known to play a role in NAFLD pathogenesis, would also be useful for SNP rs35829419. In view of the increasing prevalence of NAFLD as a widespread disease in the Western world, personalized medicine, including prevention, diagnostics, and therapy, will become increasingly important. The identification of genetic risk variants involved in the pathogenesis of NAFLD is a first step towards better treatment options. KW - Nichtalkoholische Fettleberhepatitis KW - Fettleber KW - Inflammasom KW - SNP KW - Polymorphismus KW - NLRP3 Inflammasom KW - rs10754558 KW - rs35829419 KW - NAFLD KW - SNP KW - nichtalkoholische Fettlebererkrankung Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290788 ER - TY - JOUR A1 - Zoran, Tamara A1 - Seelbinder, Bastian A1 - White, Philip Lewis A1 - Price, Jessica Sarah A1 - Kraus, Sabrina A1 - Kurzai, Oliver A1 - Linde, Joerg A1 - Häder, Antje A1 - Loeffler, Claudia A1 - Grigoleit, Goetz Ulrich A1 - Einsele, Hermann A1 - Panagiotou, Gianni A1 - Loeffler, Juergen A1 - Schäuble, Sascha T1 - Molecular profiling reveals characteristic and decisive signatures in patients after allogeneic stem cell transplantation suffering from invasive pulmonary aspergillosis JF - Journal of Fungi N2 - Despite available diagnostic tests and recent advances, diagnosis of pulmonary invasive aspergillosis (IPA) remains challenging. We performed a longitudinal case-control pilot study to identify host-specific, novel, and immune-relevant molecular candidates indicating IPA in patients post allogeneic stem cell transplantation (alloSCT). Supported by differential gene expression analysis of six relevant in vitro studies, we conducted RNA sequencing of three alloSCT patients categorized as probable IPA cases and their matched controls without Aspergillus infection (66 samples in total). We additionally performed immunoassay analysis for all patient samples to gain a multi-omics perspective. Profiling analysis suggested LGALS2, MMP1, IL-8, and caspase-3 as potential host molecular candidates indicating IPA in investigated alloSCT patients. MMP1, IL-8, and caspase-3 were evaluated further in alloSCT patients for their potential to differentiate possible IPA cases and patients suffering from COVID-19-associated pulmonary aspergillosis (CAPA) and appropriate control patients. Possible IPA cases showed differences in IL-8 and caspase-3 serum levels compared with matched controls. Furthermore, we observed significant differences in IL-8 and caspase-3 levels among CAPA patients compared with control patients. With our conceptual work, we demonstrate the potential value of considering the human immune response during Aspergillus infection to identify immune-relevant molecular candidates indicating IPA in alloSCT patients. These human host candidates together with already established fungal biomarkers might improve the accuracy of IPA diagnostic tools. KW - host response KW - invasive pulmonary aspergillosis KW - alloSCT patients KW - galectin-2 KW - caspase-3 KW - matrix metallopeptidase-1 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262105 SN - 2309-608X VL - 8 IS - 2 ER - TY - JOUR A1 - Grapp, Miriam A1 - Ell, Johanna A1 - Kiermeier, Senta A1 - Haun, Markus W. A1 - Kübler, Andrea A1 - Friederich, Hans-Christoph A1 - Maatouk, Imad T1 - Feasibility study of a self-guided internet-based intervention for family caregivers of patients with cancer (OAse) JF - Scientific Reports N2 - Despite high levels of distress, family caregivers of patients with cancer rarely seek psychosocial support and Internet-based interventions (IBIs) are a promising approach to reduce some access barriers. Therefore, we developed a self-guided IBI for family caregivers of patients with cancer (OAse), which, in addition to patients' spouses, also addresses other family members (e.g., adult children, parents). This study aimed to determine the feasibility of OAse (recruitment, dropout, adherence, participant satisfaction). Secondary outcomes were caregivers’ self-efficacy, emotional state, and supportive care needs. N = 41 family caregivers participated in the study (female: 65%), mostly spouses (71%), followed by children (20%), parents (7%), and friends (2%). Recruitment (47%), retention (68%), and adherence rates (76% completed at least 4 of 6 lessons) support the feasibility of OAse. Overall, the results showed a high degree of overall participant satisfaction (96%). There were no significant pre-post differences in secondary outcome criteria, but a trend toward improvement in managing difficult interactions/emotions (p = .06) and depression/anxiety (p = .06). Although the efficacy of the intervention remains to be investigated, our results suggest that OAse can be well implemented in caregivers’ daily lives and has the potential to improve family caregivers’ coping strategies. KW - cancer KW - oncology KW - psychology Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300537 VL - 12 ER - TY - THES A1 - Freiherr von Rotenhan, Stefan T1 - Herstellung und Charakterisierung von anti-CD40- und anti-41BB-Fusionsproteinen mit PDL1-abhängiger agonistischer Aktivität T1 - Production and characterization of anti-CD40 and anti-41BB fusion proteins with PDL1-dependent agonistic activity N2 - In this work, bispecific antibodies were produced by coupling TNFR-specific antibodies with checkpoint inhibitors, tested for their functionality and compared with each other. This combination should enable a targeted TNFR activation in tumor tissue, where a high PDL1 expression is frequent and therefore the formation of oligomeric transactivating (TNFSF3-TNFRSF3)2 complexes should only occur there by binding to PDL1-expressing cells. These receptor-ligand complexes are a prerequisite for the agonistic activity of the antibodies. N2 - In dieser Arbeit wurden bispezifische Antikörper durch Kopplung von TNFR-spezifischen Antikörpern mit Checkpoint-Inhibitoren hergestellt, auf ihre Funktionalität getestet und miteinander verglichen. Diese Kombination sollte eine gezielte TNFR-Aktivierung im Tumorgewebe ermöglichen, wo eine hohe PDL1-Expression häufig ist und daher die Bildung oligomerer transaktivierender (TNFSF3-TNFRSF3)2-Komplexe nur dort durch Bindung an PDL1-exprimierende Zellen erfolgen sollte. Diese Rezeptor-Liganden-Komplexe sind eine Voraussetzung für die agonistische Aktivität der Antikörper. KW - Immun-Checkpoint KW - Antigen CD40 KW - Tumor-Nekrose-Faktor KW - Immuntherapie KW - Monoklonaler bispezifischer Antikörper KW - Biotechnologie KW - Spezifisch Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288794 ER - TY - JOUR A1 - Cornberg, Markus A1 - Stoehr, Albrecht A1 - Naumann, Uwe A1 - Teuber, Gerlinde A1 - Klinker, Hartwig A1 - Lutz, Thomas A1 - Möller, Hjördis A1 - Hidde, Dennis A1 - Lohmann, Kristina A1 - Simon, Karl-Georg T1 - Real-world safety, effectiveness, and patient-reported outcomes in patients with chronic hepatitis C virus infection treated with glecaprevir/pibrentasvir: updated data from the German Hepatitis C-Registry (DHC-R) JF - Viruses N2 - Using data from the German Hepatitis C-Registry (Deutsche Hepatitis C-Register, DHC-R), we report the real-world safety and effectiveness of glecaprevir/pibrentasvir (GLE/PIB) treatment and its impact on patient-reported outcomes (PROs) in underserved populations who are not typically included in clinical trials, yet who will be crucial for achieving hepatitis C virus (HCV) elimination. The DHC-R is an ongoing, non-interventional, multicenter, prospective, observational cohort study on patients treated for chronic HCV infection in Germany. The data cutoff was 17 January 2021. The primary effectiveness endpoint was sustained virologic response at post-treatment Week 12 (SVR12). Safety outcomes were assessed in all patients receiving GLE/PIB. PROs were assessed using the SF-36 survey. Of 2354 patients, 1964 had valid SVR12 data (intention-to-treat analysis). Of these, 1905 (97.0%) achieved SVR12 with rates similar across the comorbidities analyzed, except for people who actively use drugs (PWUD (active)) (86.4%). Excluding those who discontinued treatment and did not achieve SVR12, or were reinfected with HCV, the rate was 99.3%, with similar results regardless of comorbidity. PWUD (active) and those with psychiatric disorders had the most meaningful improvements in PROs. Adverse events (AEs) occurred in 631/2354 patients (26.8%), and serious AEs in 44 patients (1.9%). GLE/PIB was highly effective and well tolerated in this real-world study of patient groups key to HCV elimination. KW - direct-acting antiviral KW - glecaprevir/pibrentasvir KW - hepatitis C virus KW - real world evidence KW - German Hepatitis C-Registry Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281939 SN - 1999-4915 VL - 14 IS - 7 ER - TY - THES A1 - Nelke, Johannes T1 - Entwicklung multi‐funktioneller TNFRSF Rezeptorspezifischer Antikörper‐Fusionsproteine mit FcγR‐unabhängiger Aktivität T1 - Development of multi‐functional TNFRSF receptor‐specific antibody fusion proteins with FcγR‐independent activity N2 - Antikörper, die gegen eine klinisch relevante Gruppe von Rezeptoren innerhalb der Tumornekrosefaktor-Rezeptor-Superfamilie (TNFRSF) gerichtet sind, darunter CD40 und CD95 (Fas/Apo-1), benötigen ebenfalls eine Bindung an Fc-Gamma-Rezeptoren (FcγRs), um eine starke agonistische Wirkung zu entfalten. Diese FcγR-Abhängigkeit beruht weitgehend auf der bloßen zellulären Verankerung durch die Fc-Domäne des Antikörpers und benötigt dabei kein FcγR-Signalling. Ziel dieser Doktorarbeit war es, das agonistische Potenzial von αCD40- und αCD95-Antikörpern unabhängig von der Bindung an FcγRs durch die Verankerung an Myelomzellen zu entfalten. Zu diesem Zweck wurden verschiedene Antikörpervarianten (IgG1, IgG1-N297A, Fab2) gegen die TNFRSF-Mitglieder CD40 und CD95 genetisch mit einem einzelkettig kodierten B-Zell-aktivierenden Faktor (scBaff) Trimer als C-terminale myelom-spezifische Verankerungsdomäne fusioniert, welche die Fc-Domäne-vermittelte FcγR-Bindung ersetzt. Diese bispezifischen Antikörper-scBaff-Fusionsproteine wurden in Bindungsstudien und funktionellen Assays mit Tumorzelllinien untersucht, die einen oder mehrere der drei Baff-Rezeptoren exprimieren: BaffR, Transmembran-Aktivator und CAML-Interaktor (TACI) und B-Zell-Reifungsantigen (BCMA). Zelluläre Bindungsstudien zeigten, dass die Bindungseigenschaften der verschiedenen Domänen innerhalb der Antikörper-scBaff-Fusionen gegenüber der Zielantigene vollständig intakt blieben. In Ko-Kulturversuchen von CD40- und CD95-responsiven Zellen mit BaffR-, BCMA- oder TACI-exprimierenden Verankerungszellen zeigten die Antikörper-Fusionsproteine einen starken Agonismus, während in Ko-Kulturen mit Zellen ohne Expression von Baff-interagierenden Rezeptoren nur eine geringe Rezeptorstimulation beobachtet wurde. Die hier vorgestellten αCD40- und αCD95-Antikörper-scBaff-Fusionsproteine zeigen also Myelom-spezifische Aktivität und versprechen im Vergleich zu herkömmlichen CD40- und CD95-Agonisten geringere systemische Nebenwirkungen. N2 - Antibodies that target a clinically relevant group of receptors within the tumor necrosis factor receptor superfamily (TNFRSF), including CD40 and CD95 (Fas/Apo-1), also require binding to Fc gamma receptors (FcγRs) to elicit a strong agonistic activity. This FcγR dependency largely relies on the mere cellular anchoring through the antibody's Fc domain and does not involve the engagement of FcγR signaling. The aim of this doctoral thesis was to elicit agonistic activity from αCD40 and αCD95 antibodies in a myeloma cell anchoring-controlled FcγR-independent manner. For this purpose, various antibody variants (IgG1, IgG1-N297A, Fab2) against the TNFRSF members CD40 and CD95 were genetically fused to a single-chain-encoded B-cell activating factor (scBaff) trimer as a C-terminal myeloma-specific anchoring domain substituting for Fc domain-mediated FcγR binding. These bispecific antibody-scBaff fusion proteins were evaluated in binding studies and functional assays using tumor cell lines expressing one or more of the three receptors of Baff: BaffR, transmembrane activator and CAML interactor (TACI) and B-cell maturation antigen (BCMA). Cellular binding studies showed that the binding properties of the different domains within the fusion proteins remained fully intact in the antibody-scBaff fusion proteins. In co-culture assays of CD40- and CD95-responsive cells with BaffR, BCMA or TACI expressing anchoring cells, the antibody fusion proteins displayed strong agonism while only minor receptor stimulation was observed in co-cultures with cells without expression of Baff-interacting receptors. Thus, the herein presented αCD40 and αCD95 antibody fusion proteins display myeloma cell-dependent activity and promise reduced systemic side effects compared to conventional CD40 and CD95 agonists. KW - Antigen CD40 KW - Monoklonaler bispezifischer Antikörper KW - Antigen CD95 KW - Immunreaktion KW - B-Zell-Lymphom KW - BCMA KW - FcgR KW - Antikörper KW - bispezifisch KW - Antibody KW - bispecific KW - Multiple Myeloma KW - Baff Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-279855 ER - TY - JOUR A1 - Bertram, Ralph A1 - Bartsch, Vanessa A1 - Sodmann, Johanna A1 - Hennig, Luca A1 - Müjde, Engin A1 - Stock, Jonathan A1 - Ruedig, Vivienne A1 - Sodmann, Philipp A1 - Todt, Daniel A1 - Steinmann, Eike A1 - Hitzl, Wolfgang A1 - Steinmann, Joerg T1 - Risk stratification of SARS-CoV-2 breakthrough infections based on an outbreak at a student festive event JF - Vaccines N2 - In early 2022, the Coronavirus disease 2019 (COVID-19) remains a global challenge. COVID-19 is caused by an increasing number of variants of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we report an outbreak of SARS-CoV-2 breakthrough infections related to a student festive event with 100 mostly vaccinated guests, which took place in Northern Bavaria, Germany, in October 2021. The data were obtained by retrospective guest interviews. In total, 95 students participated in the study, with 94 being fully vaccinated and 24 reporting infection by the delta variant. Correlation analyses among 15 examined variables revealed that time spent at the event, conversation with the supposed index person, and a homologous viral vector vaccination regime were significant risk factors for infection. Non-significant observations related to higher rates of infection included time since last vaccination, shared use of drinking vessels, and number of individual person-to-person contacts at the event. Our data suggest that a high rate of breakthrough infections with the delta variant occurs if no preventive measures are practiced. To limit infection risk, high-quality testing of participants should be considered a mandatory measure at gatherings, irrespective of the participants' vaccination status. KW - COVID-19 KW - SARS-CoV-2 KW - outbreak KW - breakthrough infection Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267270 SN - 2076-393X VL - 10 IS - 3 ER - TY - JOUR A1 - Dahlhoff, Julia A1 - Manz, Hannah A1 - Steinfatt, Tim A1 - Delgado-Tascon, Julia A1 - Seebacher, Elena A1 - Schneider, Theresa A1 - Wilnit, Amy A1 - Mokhtari, Zeinab A1 - Tabares, Paula A1 - Böckle, David A1 - Rasche, Leo A1 - Martin Kortüm, K. A1 - Lutz, Manfred B. A1 - Einsele, Hermann A1 - Brandl, Andreas A1 - Beilhack, Andreas T1 - Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression JF - Leukemia N2 - Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4\(^{+}\)FoxP3\(^{+}\) regulatory T cells (Tregs) are highly abundant amongst CD4\(^{+}\) T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma. KW - Multiple myeloma KW - transient regulatory T-cell targeting KW - immune control Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271787 SN - 1476-5551 VL - 36 IS - 3 ER - TY - THES A1 - Zoran, Tamara T1 - Multilevel analysis of the human immune response to \(Aspergillus\) \(fumigatus\) infection: Characteristic molecular signatures and individual risk factors T1 - Analysen der humanen Immunantwort auf eine Infektion mit \(Aspergillus\) \(fumigatus\): Charakteristische molekulare Signaturen und individuelle Risikofaktoren N2 - Although the field of fungal infections advanced tremendously, diagnosis of invasive pulmonary aspergillosis (IPA) in immunocompromised patients continues to be a challenge. Since IPA is a multifactorial disease, investigation from different aspects may provide new insights, helpful for improving IPA diagnosis. This work aimed to characterize the human immune response to Aspergillus fumigatus in a multilevel manner to identify characteristic molecular candidates and risk factors indicating IPA, which may in the future support already established diagnostic assays. We combined in vitro studies using myeloid cells infected with A. fumigatus and longitudinal case-control studies investigating patients post allogeneic stem cell transplantation (alloSCT) suffering from IPA and their match controls. Characteristic miRNA and mRNA signatures indicating A. fumigatus-infected monocyte-derived dendritic cells (moDCs) demonstrated the potential to differentiate between A. fumigatus and Escherichia coli infection. Transcriptome and protein profiling of alloSCT patients suffering from IPA and their matched controls revealed a distinctive IPA signature consisting of MMP1 induction and LGAL2 repression in combination with elevated IL-8 and caspase-3 levels. Both, in vitro and case-control studies, suggested cytokines, matrix-metallopeptidases and galectins are important in the immune response to A. fumigatus. Identified IPA characteristic molecular candidates are involved in numerous processes, thus a combination of these in a distinctive signature may increase the specificity. Finally, low monocyte counts, severe GvHD of the gut (grade ≥ 2) and etanercept administration were significantly associated with IPA diagnosis post alloSCT. Etanercept in monocyte-derived macrophages (MDM) infected with A. fumigatus downregulates genes involved in the NF-κB and TNF-α pathway and affects the secretion of CXCL10. Taken together, identified characteristic molecular signatures and risk factors indicating IPA may in the future in combination with established fungal biomarkers overcome current diagnostic challenges and help to establish tailored antifungal therapy. Therefore, further multicentre studies are encouraged to evaluate reported findings. N2 - Obwohl im Bereich der Erforschung invasiver Pilzinfektionen aktuell enorme Fortschritte erzielt wurden, stellt die Diagnose der Invasiven Pulmonalen Aspergillose (IPA) bei immunsupprimierten Patienten weiterhin eine grosse Herausforderung dar. Da es sich bei der IPA um eine multifaktorielle Erkrankung handelt, können Untersuchungen unter verschiedenen Fragestellungen neue Erkenntnisse liefern, die zur Verbesserung der IPA Diagnose beitragen. In dieser Arbeit wurde die humane Immunantwort auf Aspergillus fumigatus auf mehreren Ebenen untersucht, um charakteristische molekulare Kandidaten und Risikofaktoren zu identifizieren, die auf eine IPA hinweisen um so in Zukunft bereits etablierte diagnostische Tests unterstützen zu können. Wir kombinierten in vitro Studien mit A. fumigatus infizierten, myeloischen Zellen mit longitudinalen Case-Control-Studien, in denen an IPA erkrankte Patienten und ihre passenden Kontrollpatienten nach allogener Stammzelltransplantation (alloSZT) untersucht wurden. Charakteristische miRNA und mRNA Signaturen von A. fumigatus-infizierten Monozyten-abgeleiteten dendritischen Zellen (moDCs) zeigten das Potenzial, zwischen A. fumigatus und Escherichia coli Infektionen zu unterscheiden. Transkriptom- und Protein- Analysen von alloSZT Patienten, die an einer IPA erkrankten, und den passenden Kontrollpatienten ergaben charakteristische IPA Signaturen, bestehend aus einer MMP1 Induktion und einer LGALS2 Repression, in Kombination mit erhöhten IL-8 und Caspase-3 Konzentrationen. Sowohl die in vitro Daten als auch die Fall-Kontroll- Studien zeigten, dass Zytokine, Matrix-Metallopeptidasen und Galectine eine wichtige Rolle bei der Immunantwort auf A. fumigatus spielen. Die in IPA identifizierten charakteristischen molekularen Kandidaten sind an mehreren Prozessen beteiligt, so dass eine Kombination dieser molekularen Kandidaten die Spezifität mittels charakteristischer Signatur erhöhen könnte. Schließlich waren niedrige Monozytenzahlen, eine schwere GvHD des Darms (Grad ≥ 2) und die Anwendung von Etanercept signifikant mit einer IPA Diagnose nach alloSZT assoziiert. Etanercept in Makrophagen, die mit A. fumigatus ko-kultiviert wurden, reguliert Gene herunter, die am NF-κB- und TNF-α-Signalweg beteiligt sind, und beeinflusst die Sekretion von CXCL10. Zusammenfassend lässt sich festhalten, dass die identifizierten charakteristischen molekularen Signaturen und Risikofaktoren, die auf eine IPA hinweisen, in Zukunft in Kombination mit etablierten Pilz-Biomarkern die derzeitigen diagnostischen Limitationen überwinden könnten und dazu beitragen könnten, eine patientenindividuelle antimykotische Therapie zu etablieren. Es werden jedoch weitere multizentrische Studien notwendig sein, um diese Ergebnisse umfassend zu bewerten. KW - Aspergillus fumigatus KW - Immunantwort KW - Risikofaktoren KW - invasive pulmonary aspergillosis KW - immune response KW - risk factors KW - transcriptome profiling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-298512 ER - TY - THES A1 - Hellmann, Anna-Maria T1 - Vergleichende Untersuchung der Interaktion humaner und muriner Immunzellen mit \(Aspergillus\) \(fumigatus\) T1 - Comparative analysis of the in vitro interaction of human and murine innate immune cell populations with \(Aspergillus\) \(fumigatus\) N2 - Aspergillus fumigatus (A. fumigatus) ist der häufigste Erreger der invasiven Aspergillose, welche vornehmlich immunsupprimierte Patientinnen und Patienten betrifft und mit einer hohen Letalität einhergeht. Zur Entwicklung neuer diagnostischer sowie therapeutischer Ansätze ist ein besseres Verständnis der Interaktion von A. fumigatus mit dem humanen Immunsystem zwingend erforderlich. Zur Erforschung dieser Interaktion werden häufig Mausmodelle herangezogen, welche aufgrund der unterschiedlichen Biologie des Wirts jedoch nicht direkt übertragbar sind. Ziel dieser Studie war es, einen funktionellen in vitro Vergleich zwischen humanen und murinen Makrophagen, neutrophilen Granulozyten (PMNs) und dendritischen Zellen (DCs) in ihrer Interaktion mit A. fumigatus Konidien, Keimschläuchen sowie depletiertem Zymosan zu erstellen, um eine bessere Beurteilung und Übertragbarkeit des Mausmodells bei der invasiven Aspergillose zu ermöglichen. Dabei wurden die verschiedenen Zellen des Immunsystems auf standardisierte und reproduzierbare Weise generiert und Stimulationsversuche durchgeführt. Hierbei zeigten humane und murine Zellen in vitro eine unterschiedliche Antwort auf die Stimulation mit A. fumigatus: Murine Makrophagen und neutrophile Granulozyten zeigten im Vergleich zu den humanen Zellen eine stärkere primäre Immunantwort mit einer vermehrten Ausschüttung reaktiver Sauerstoffspezies (ROS). Humane DCs hingegen, welche als Bindeglied zwischen angeborenem und adaptivem Immunsystem fungieren, zeigten nach Stimulation mit A. fumigatus eine vermehrte Oberflächenexpression von Maturationsmarkern sowie eine höhere Phagozytoserate als die murinen DCs. Weiterhin konnte eine inverse Dectin-1-Expression auf humanen und murinen DCs nach Stimulation mit A. fumigatus nachgewiesen werden. Es konnte gezeigt werden, dass es für alle untersuchten Zelltypen Unterschiede zwischen humanen und murinen Zellen in der basalen und der Zytokinausschüttung nach Stimulation mit A. fumigatus gab. In Zusammenschau der Ergebnisse dieser Arbeit zeigt das murine Immunsystem eine stärkere angeborene Immunantwort mit vermehrter ROS-Ausschüttung, jedoch auch eine anti-inflammatorische Zytokinantwort, um möglicherweise eine überschießende Inflammation zu verhindern. Dies könnte durch die stärkere Exposition der Maus gegenüber A. fumigatus durch den bodennahen Lebensraum sowie ihrer kurzen Lebensdauer bedingt sein. Im humanen System kommt hingegen der Aktivierung des adaptiven Immunsystems über die DCs eine übergeordnete Rolle zu. So zeigen beide Spezies distinkte Unterschiede in ihrer in vitro Immunantwort gegenüber A. fumigatus, welche bei der Übertragung von experimentellen Daten von der Maus auf den Menschen beachtet werden sollten. N2 - Aspergillus fumigatus (A. fumigatus) is the main causative organism of invasive aspergillosis which occurs almost exclusively in immunocompromised patients and is still associated with a high lethality. For the development of new diagnostic and therapeutical approaches a better understanding of the in vitro interaction of human and murine innate immune cell populations with A. fumigatus is urgently needed. To study host-pathogen interactions mice are frequently used as infection model. However, little is known about functional differences in the innate immune response of human and murine cell populations in the pathogenesis of invasive aspergillosis. Therefore, the aim of our study was to conduct a functional and highly standardized comparison of human and murine macrophages, polymorphonuclear cells (PMNs) and dendritic cells (DCs) regarding their interaction with A. fumigatus conidia, germtubes and depleted zymosan to improve extrapolation from data achieved in mice experiments. Human and murine innate immune cells displayed a differential behavior after the exposure to A. fumigatus. Murine macrophages and PMNs exhibited a significantly stronger release of reactive oxygen species (ROS) after exposure to A. fumigatus. Human DCs, which function as an important link between the innate and adaptive immune system, displayed a stronger cell surface expression of maturation markers after stimulation with A. fumigatus as well as a higher phagocytosis rate than their murine counterparts. Furthermore, human and murine DCs showed an inverse Dectin-1 surface expression after stimulation with A. fumigatus. Human and murine innate immune cells showed a differential basal as well as stimulated cytokine release. Our data indicate that the murine immune system may have a stronger innate immune response after stimulation with A. fumigatus with an increased release of ROS. However, murine cells also showed a strong anti-inflammatory cytokine release to potentially inhibit excessive inflammation. This effect in mice might be due to the higher exposure to A. fumigatus caused by near-ground habitat as well as the shorter life span. In humans the activation of the adaptive immune system by activation of DCs seems to predominate. To summarize, immune cells of both species display distinct differences in their in vitro immune response after stimulation with A. fumigatus, which should be considered when conducting host-pathogen interaction studies in mice. KW - Aspergillus fumigatus KW - Aspergillose KW - Interaktionsanalyse Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265642 ER - TY - THES A1 - Dresselhaus, Lena Katharina T1 - Die Rolle der gp130 Endozytose für die Homöostase der B- und T-Zellen T1 - The role of gp130 endocytosis in B and T cell homeostasis N2 - IL-6 spielt eine wichtige Rolle bei der Immunantwort, Entzündung und Hämatopoese. Das Glykoprotein 130 (gp130) wird ubiquitär exprimiert und bildet als Dimer die signaltransduzierende Rezeptoreinheit für das IL-6 Signal. Die biologische Wirkung des IL-6 ist abhängig von der Dauer und Stärke des induzierten Signals. Die gp130 Rezeptorexpression stellt einen bedeutenden Faktor zur Beeinflussung des IL-6 Signals dar. Die im Rahmen dieser Arbeit untersuchte gp130LLAA Maus weist eine Punktmutation im gp130 Rezeptor auf, bei der das Dileucin-Motiv (L874, L785) im zytoplasmatischen Bereich von gp130 zu Dialanin verändert wurde. Für die Endozytose ist das intrazelluläre Dileucin-Motiv erforderlich, da das Adapterprotein AP-2 an dieses Motiv bindet und dadurch den Transport mittels Clathrin-umhüllter Vesikel begünstigt. Die beschriebene Punktmutation hat zur Folge, dass die veränderte Form von gp130 resistent gegenüber der Liganden- und crosstalk-vermittelten Endozytose ist. Da IL-6 generell eine wichtige Rolle bei der Differenzierung hämatopoetischer Zellen spielt, so auch bei T- und B-Zellen, wurde der Einfluss der gp130LLAA Mutation auf die Homöostase dieser lymphoiden Zellen untersucht. Für die Versuche wurden sowohl B- und T-Zellen und jeweilige Subpopulationen aus der Milz von WT Mäusen und gp130LLAA Mäusen untersucht. N2 - IL-6 plays an important role in immune response, inflammation and hematopoiesis. Glycoprotein 130 (gp130) is ubiquitously expressed and forms the signal transducing receptor moiety for IL-6 signaling as a dimer. The biological effect of IL-6 is dependent on the duration and strength of the induced signal. The gp130 receptor expression represents a significant factor influencing the IL-6 signal. The gp130LLAA mouse studied in this work has a point mutation in the gp130 receptor in which the dileucine motif (L874, L785) in the cytoplasmic region of gp130 has been changed to dialanine. The intracellular dileucine motif is required for endocytosis because the adaptor protein AP-2 binds to this motif, thereby promoting transport by clathrin-coated vesicles. The described point mutation results in the altered form of gp130 being resistant to ligand- and crosstalk-mediated endocytosis. Because IL-6 generally plays an important role in the differentiation of hematopoietic cells, including T and B cells, the effect of the gp130LLAA mutation on the homeostasis of these lymphoid cells was investigated. For the experiments, both B and T cells and respective subpopulations from the spleens of WT mice and gp130LLAA mice were examined. KW - Endocytose KW - gp KW - bcells KW - tcells KW - gp130 KW - Endozytose Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-289025 ER - TY - THES A1 - Katz, Beverly Vanessa T1 - Rolle der gammadelta T-Zellen in der Immunantwort bei Patienten mit gastrointestinalen Tumoren T1 - Role of gammadelta T cells in the immune response in patients with gastrointestinal tumors N2 - Zusammenfassend konnte im Rahmen der vorliegenden Arbeit die Frage nach der Fähigkeit der selektiven Stimulierung mittels des Phosphorantigens HMBPP und den beiden BTN3 Antikörpern bestätigt werden. Es konnte zudem wie erwartet hierbei ein Unterschied zwischen den beiden Kohorten detektiert werden. Dabei zeigte die Kohorte der Normalspender erwartungsgemäß eine stärkere Aktivierungs- sowie Proliferations-fähigkeit. Normalspender ließen sich signifikant besser mit HMBPP aktivieren und bei bestimmter Konzentration signifikant besser proliferieren, bei BTN3A und sc20.1 konnten keine signifikanten Unterschiede ermittelt werden, allerdings anhand der Mittelwerte eine deutlich stärkere Aktivierung und Proliferation aufgezeigt werden. Außerdem konnten interessante interindividuelle Unterschiede detektiert werden, die neue Erkenntnisse brachten. Mit Hilfe der untersuchten Oberflächenmoleküle CD45RA und CD27 und der Einteilung der gammadelta T-Zellen in unterschiedliche Subgruppen konnten so mögliche Erklärungen für die Unterschiede zwischen den Kohorten aufgezeigt werden. Normalspender zeigten signifikant höhere Anteile an naiven gammadelta T-Zellen und nicht signifikant höhere Anteile an central memory T-Zellen, demnach eine deutliche Verschiebung in Richtung nicht differenzierter Subsets, wohingegen die Tumorkohorte signifikant höhere effector memory T-Zellen aufwiesen und somit eine deutliche Verschiebung in Richtung differenzierter Subsets. Dadurch kann erklärt werden, weshalb Normalspender besser aktiviert werden und besser proliferieren können. Auch die Einteilung in unterschiedliche Profile 1-6 anhand CD28, CD27 und CD16 lieferte Gründe für den Unterschied zwischen den Kohorten, wobei Normalspender der Gruppe 1 und 2, Tumorpatienten der Gruppe 3 und 4 angehörten. Durch Ermittlung weiterer signifikanter Änderungen einiger exprimierter Oberflächenmoleküle CD39, CD161 und PD1 wurde mit Hilfe der vorliegenden Arbeit bekräftigt, dass einige Faktoren betrachtet werden müssen, die die Proliferation und Aktivierung der gammadelta T-Zellen positiv und negativ beeinflussen können. Es konnte jedoch auch erneut verdeutlicht werden, wie komplex und weitgreifend der Aktivierungsmechanismus, die damit verbundene Expansion und die Auslösung der einzelnen Effektorfunktionen ist. N2 - In summary, the present thesis confirmed the ability of the antigen HMBPP and the two BTN3 antibodies to stimulate selectively. Moreover, as expected, a difference between the two cohorts could be detected. As expected, the cohort of normal donors showed a stronger activation and proliferation ability. Normal donors were significantly better activated with HMBPP and significantly better proliferated at certain concentrations. No significant differences could be determined for BTN3A and sc20.1, but a significantly stronger activation and proliferation could be shown on the basis of the mean values. In addition, interesting interindividual differences could be detected, which provided new insights. With the help of the investigated surface molecules CD45RA and CD27 and the classification of the T cells into different subgroups, possible explanations for the differences between the cohorts could be revealed. Normal donors showed significantly higher proportions of naïve T cells and non-significantly higher proportions of central memory T cells, thus a clear shift towards non-differentiated subsets, whereas the tumor cohort showed significantly higher effector memory T cells and thus a clear shift towards differentiated subsets. This may explain why normal donors are better activated and better able to proliferate. Also, classification into different profiles 1-6 based on CD28, CD27, and CD16 provided reasons for the difference between the cohorts, with normal donors belonging to groups 1 and 2, and tumor patients to groups 3 and 4. By identifying further significant changes in some expressed surface molecules CD39, CD161 and PD1, the present work affirmed the need to consider some factors that may positively and negatively influence T cell proliferation and activation. However, it was also possible to illustrate once again how complex and far-reaching the activation mechanism, the associated expansion and the triggering of the individual effector functions are. KW - T-Lymphozyt KW - Immunsystem KW - Immunmodulation KW - Gammadelta T Zellen KW - gastrointestinale Tumore KW - Immunreaktion KW - T cells KW - Immunreaction KW - immune response Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290140 ER - TY - JOUR A1 - Metzner, Valentin A1 - Herzog, Gloria A1 - Heckel, Tobias A1 - Bischler, Thorsten A1 - Hasinger, Julia A1 - Otto, Christoph A1 - Fassnacht, Martin A1 - Geier, Andreas A1 - Seyfried, Florian A1 - Dischinger, Ulrich T1 - Liraglutide + PYY\(_{3-36}\) combination therapy mimics effects of Roux-en-Y bypass on early NAFLD whilst lacking-behind in metabolic improvements JF - Journal of Clinical Medicine N2 - Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY\(_{3-36}\) (0.1 mg/kg/day), liraglutide+PYY\(_{3-36}\), and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY\(_{3-36}\) induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY\(_{3-36}\)- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY\(_{3-36}\) partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB. KW - liraglutide KW - GLP-1 KW - peptide tyrosine tyrosine (PYY) KW - peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) KW - RYGB KW - gastric bypass KW - obesity KW - NASH KW - NAFLD Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255244 SN - 2077-0383 VL - 11 IS - 3 ER - TY - JOUR A1 - Steinhardt, Maximilian J. A1 - Krummenast, Franziska C. A1 - Rosenwald, Andreas A1 - Gerhard-Hartmann, Elena A1 - Heidemeier, Anke A1 - Einsele, Hermann A1 - Topp, Max S. A1 - Duell, Johannes T1 - R-CHOP intensification with mid-cycle methotrexate and consolidating AraC/TT with BCNU/aHSCT in primary aggressive lymphoma with CNS involvement JF - Journal of Cancer Research and Clinical Oncology N2 - Purpose Patients suffering from aggressive systemic peripheral lymphoma with primary central nervous system involvement (PCL) are a rare and sparsely investigated population. Recommended treatment regimens include a combination of intrathecal and systemic chemotherapy as well as whole brain radiotherapy while offering relatively poor survival. Methods We conducted a single-center retrospective study that analyzed safety and outcome of 4 + 4 cycles Rituximab (R)-CHOP and R-high-dose Methotrexate (HD-MTX) for newly diagnosed, transplant-eligible patients ("Ping-Pong"), followed by Cytarabine (AraC)/Thiotepa (TT), BCNU/TT, and autologous hematologic stem cell transplantation (aHSCT). We retrospectively analyzed a set of 16 patients with high-intermediate or high-risk IPI status. Results Overall response rate to Ping-Pong was 100% measured by CT/MRI, including 93.75% complete remissions after BCNU/TT followed by PBSCT. One patient failed to qualify for high-dose chemotherapy due to progression when receiving Cytarabine/TT. All patients experienced grade III adverse events, 3 of them a grade IV adverse event. Estimated progression-free survival is 93.75% after a 4.8-year follow-up currently. Conclusion Our study suggests high effectivity of R-CHOP with mid-cycle MTX with aHSCT consolidation towards acceptable OS results in this challenging patient population. KW - lymphoma KW - HD KW - MTX KW - R-CHOP Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267731 SN - 1432-1335 VL - 148 IS - 1 ER - TY - JOUR A1 - Gernert, Michael A1 - Schmalzing, Marc A1 - Tony, Hans-Peter A1 - Strunz, Patrick-Pascal A1 - Schwaneck, Eva Christina A1 - Fröhlich, Matthias T1 - Calprotectin (S100A8/S100A9) detects inflammatory activity in rheumatoid arthritis patients receiving tocilizumab therapy JF - Arthritis Research & Therapy N2 - Background Assessing serological inflammation is difficult in tocilizumab (TCZ)-treated rheumatoid arthritis (RA) patients, as standard inflammation parameters, like erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are influenced by interleukin-6-receptor inhibition. Calprotectin in the serum, also named S100A8/S100A9, might be a more useful inflammation parameter in TCZ-treated patients. Methods Sixty-nine RA patients taking TCZ were included. Serum-calprotectin levels were assessed, as well as ESR, CRP, need for a change in disease-modifying anti-rheumatic drugs due to RA activity (= active RA), and the RA clinical disease activity score (CDAI). Forty-five RA patients taking tumor-necrosis factor-inhibitors (TNFi) were investigated for the same parameters. Results TCZ-treated patients with active RA had higher calprotectin values than not active RA patients (4155.5 [inter quartile range 1865.3–6068.3] vs 1040.0 [676.0–1638.0] ng/ml, P < 0.001). A calprotectin cut-off value of 1916.5 ng/ml resulted in a sensitivity and specificity of 80.0 %, respectively, for the detection of RA disease activity. Calprotectin values correlated with CDAI-scores (r = 0.228; P = 0.011). ESR and CRP were less suitable to detect RA activity in TCZ-treated patients. Also TNFi-treated patients with active RA had higher calprotectin values compared to not active RA (5422.0 [3749.0–8150.8] vs 1845.0 [832.0–2569.0] ng/ml, P < 0.001). The calprotectin value with the best sensitivity and specificity for detecting RA activity was 3690.5 ng/ml among TNFi-treated patients. Conclusion Calprotectin in the serum can be a useful inflammation parameter despite TCZ-treatment. KW - calprotectin KW - inflammation marker KW - c-reactive protein KW - tocilizumab KW - rheumatoid arthritis KW - S100A8/S100A9 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300523 VL - 24 IS - 1 ER - TY - JOUR A1 - Zhou, Xiang A1 - Ruckdeschel, Anna A1 - Peter, Jessica A1 - Böckle, David A1 - Hornburger, Hannah A1 - Danhof, Sophia A1 - Steinhardt, Maximilian Johannes A1 - Heimeshoff, Larissa A1 - Einsele, Hermann A1 - Kortüm, Klaus Martin A1 - Rasche, Leo T1 - Salvage therapy with "Dara-KDT-P(A)CE" in heavily pretreated, high-risk, proliferative, relapsed/refractory multiple myeloma JF - Hematological Oncology N2 - The multi-agent therapy “VDT-PACE” represents an established regimen in relapsed/refractory multiple myeloma (RRMM). Here, we report on our experience with a “modified VDT-PACE” incorporating new generation anti-MM agents daratumumab and carfilzomib (“Dara-KDT-P(A)CE”). We retrospectively analyzed 38 patients with RRMM treated with “Dara-KDT-P(A)CE”. The median age was 62 (range 45–82) years, and the patients were heavily pretreated with a median of 5 (range 2–12) prior lines of therapy. Twenty-one (55%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81%) patients. The patients received a median of 2 (range 1–10) cycles of this therapy, and the overall response rate (ORR) was 70%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65% and 79%, respectively. The median progression-free survival (PFS) and overall survival were 4.1 (95% CI 2.7–5.4) and 8.4 (95% CI 6.7–10.0) months, respectively. Patients with lactate dehydrogenase >250 IU/L showed significantly shorter PFS in comparison with others patients (p = 0.006). We used this regimen as bridging therapy prior to chimeric antigen receptor T-cell infusion in four patients. In conclusion, “Dara-KDT-P(A)CE” is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options. KW - Dara-KDT-P(A)CE KW - multiple myeloma KW - refractory KW - salvage Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257495 VL - 40 IS - 2 ER - TY - JOUR A1 - Solimando, Antonio Giovanni A1 - Da Vià, Matteo Claudio A1 - Bolli, Niccolò A1 - Steinbrunn, Torsten T1 - The route of the malignant plasma cell in its survival niche: exploring “Multiple Myelomas” JF - Cancers N2 - Growing evidence points to multiple myeloma (MM) and its stromal microenvironment using several mechanisms to subvert effective immune and anti-tumor responses. Recent advances have uncovered the tumor-stromal cell influence in regulating the immune-microenvironment and have envisioned targeting these suppressive pathways to improve therapeutic outcomes. Nevertheless, some subgroups of patients include those with particularly unfavorable prognoses. Biological stratification can be used to categorize patient-, disease- or therapy-related factors, or alternatively, these biological determinants can be included in a dynamic model that customizes a given treatment to a specific patient. Genetic heterogeneity and current knowledge enforce a systematic and comprehensive bench-to-bedside approach. Given the increasing role of cancer stem cells (CSCs) in better characterizing the pathogenesis of solid and hematological malignancies, disease relapse, and drug resistance, identifying and describing CSCs is of paramount importance in the management of MM. Even though the function of CSCs is well-known in other cancer types, their role in MM remains elusive. With this review, we aim to provide an update on MM homing and resilience in the bone marrow micro milieu. These data are particularly interesting for clinicians facing unmet medical needs while designing novel treatment approaches for MM. KW - multiple myeloma KW - cell of origin KW - cancer stem cells KW - bone marrow homing KW - adhesion molecule KW - bone marrow immune-microenvironment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281728 SN - 2072-6694 VL - 14 IS - 13 ER - TY - JOUR A1 - John, Katharina A1 - Franck, Martin A1 - Al Aoua, Sherin A1 - Rau, Monika A1 - Huber, Yvonne A1 - Schattenberg, Joern M. A1 - Geier, Andreas A1 - Bahr, Matthias J. A1 - Wedemeyer, Heiner A1 - Schulze-Osthoff, Klaus A1 - Bantel, Heike T1 - Non-invasive detection of fibrotic NASH in NAFLD patients with low or intermediate FIB-4 JF - Journal of Clinical Medicine N2 - Background: Non-alcoholic steatohepatitis (NASH) and fibrosis are the main prognostic factors in non-alcoholic fatty liver disease (NAFLD). The FIB-4 score has been suggested as an initial test for the exclusion of progressed fibrosis. However, increasing evidence suggests that also NASH patients with earlier fibrosis stages are at risk of disease progression, emphasizing the need for improved non-invasive risk stratification. Methods: We evaluated whether the apoptosis biomarker M30 can identify patients with fibrotic NASH despite low or intermediate FIB-4 values. Serum M30 levels were assessed by ELISA, and FIB-4 was calculated in an exploration (n = 103) and validation (n = 100) cohort of patients with histologically confirmed NAFLD. Results: The majority of patients with low FIB-4 (cut-off value < 1.3) in the exploration cohort revealed increased M30 levels (>200 U/L) and more than 80% of them had NASH, mostly with fibrosis. NASH was also detected in all patients with intermediate FIB-4 (1.3 to 2.67) and elevated M30, from which ~80% showed fibrosis. Importantly, in the absence of elevated M30, most patients with FIB-4 < 1.3 and NASH showed also no fibrosis. Similar results were obtained in the validation cohort. Conclusions: The combination of FIB-4 with M30 enables a more reliable identification of patients at risk for progressed NAFLD and might, therefore, improve patient stratification. KW - apoptosis KW - biomarker KW - fibrosis KW - FIB-4 KW - NAFLD KW - NASH KW - keratin-18 KW - M30 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281824 SN - 2077-0383 VL - 11 IS - 15 ER - TY - JOUR A1 - Reiter, Theresa A1 - Demirbas, Senem A1 - Schmalzing, Marc A1 - Voelker, Wolfram A1 - Bauer, Wolfgang R. A1 - Güder, Gülmisal T1 - CMR detects extensive intracavitary thrombi as solitary clinical presentation of Antiphospholipid Syndrome: A case report JF - Clinical Case Reports N2 - Intracavitary thrombi are an important differential diagnosis of cardiac masses. Cardiac magnetic resonance imaging (CMR) allows their non-invasive characterization. This case highlights extensive cardiac thrombi detected by CMR as solitary presentation of antiphospholipid syndrome. KW - antiphospholipid syndrome KW - cardiac thrombi KW - CMR Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312766 SN - 2050-0904 VL - 10 IS - 11 ER - TY - JOUR A1 - Gernert, Michael A1 - Tony, Hans-Peter A1 - Schwanek, Eva Christina A1 - Gadeholt, Ottar A1 - Fröhlich, Matthias A1 - Portegys, Jan A1 - Strunz, Patrick-Pascal A1 - Schmalzing, Marc T1 - Lymphocyte subsets in the peripheral blood are disturbed in systemic sclerosis patients and can be changed by immunosuppressive medication JF - Rheumatology International N2 - Systemic sclerosis (SSc) is a severe chronic disease with a broad spectrum of clinical manifestations. SSc displays disturbed lymphocyte homeostasis. Immunosuppressive medications targeting T or B cells can improve disease manifestations. SSc clinical manifestations and immunosuppressive medication in itself can cause changes in lymphocyte subsets. The aim of this study was to investigate peripheral lymphocyte homeostasis in SSc with regards to the immunosuppression and to major organ involvement. 44 SSc patients and 19 healthy donors (HD) were included. Immunophenotyping of peripheral whole blood by fluorescence-activated cell sorting was performed. Cytokine secretions of stimulated B cell cultures were measured. SSc patients without immunosuppression compared to HD displayed lower γδ T cells, lower T helper cells (CD3+/CD4+), lower transitional B cells (CD19+/CD38++/CD10+/IgD+), lower pre-switched memory B cells (CD19+/CD27+/IgD+), and lower post-switched memory B cells (CD19+/CD27+/IgD-). There was no difference in the cytokine production of whole B cell cultures between SSc and HD. Within the SSc cohort, mycophenolate intake was associated with lower T helper cells and lower NK cells (CD56+/CD3-). The described differences in peripheral lymphocyte subsets between SSc and HD generate further insight in SSc pathogenesis. Lymphocyte changes under effective immunosuppression indicate how lymphocyte homeostasis in SSc might be restored. KW - mycophenolate KW - systemic sclerosis KW - scleroderma KW - memory B cells KW - B cell culture KW - cytokines KW - γδ T cells KW - immunophenotyping Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266482 SN - 1437-160X VL - 42 IS - 8 ER - TY - JOUR A1 - Tappe, Beeke A1 - Lauruschkat, Chris D. A1 - Strobel, Lea A1 - Pantaleón García, Jezreel A1 - Kurzai, Oliver A1 - Rebhan, Silke A1 - Kraus, Sabrina A1 - Pfeuffer-Jovic, Elena A1 - Bussemer, Lydia A1 - Possler, Lotte A1 - Held, Matthias A1 - Hünniger, Kerstin A1 - Kniemeyer, Olaf A1 - Schäuble, Sascha A1 - Brakhage, Axel A. A1 - Panagiotou, Gianni A1 - White, P. Lewis A1 - Einsele, Hermann A1 - Löffler, Jürgen A1 - Wurster, Sebastian T1 - COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds JF - Frontiers in Immunology N2 - Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients. KW - COVID-19 KW - immune impairment KW - T cells KW - granulocytes KW - Aspergillus KW - Rhizopus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-283558 SN - 1664-3224 VL - 13 ER - TY - JOUR A1 - Kessel, Johanna A1 - Hogardt, Michael A1 - Aspacher, Lukas A1 - Wichelhaus, Thomas A. A1 - Gerkrath, Jasmin A1 - Rosenow, Emely A1 - Springer, Jan A1 - Rickerts, Volker T1 - Exclusion of Mucorales co-infection in a patient with Aspergillus flavus sinusitis by fluorescence in situ hybridization (FISH) JF - Journal of Fungi N2 - Invasive fungal infections are associated with increased mortality in hematological patients. Despite considerable advances in antifungal therapy, the evaluation of suspected treatment failure is a common clinical challenge requiring extensive diagnostic testing to rule out potential causes, such as mixed infections. We present a 64-year-old patient with secondary AML, diabetes mellitus, febrile neutropenia, and sinusitis. While cultures from nasal tissue grew Aspergillus flavus, a microscopic examination of the tissue was suggestive of concomitant mucormycosis. However, fluorescence in situ hybridization (FISH) using specific probes targeting Aspergillus and Mucorales species ruled out mixed infection. This was confirmed by specific qPCR assays amplifying the DNA of Aspergillus, but not of Mucorales. These results provided a rational basis for step-down targeted therapy, i.e., the patient received posaconazole after seven days of calculated dual therapy with liposomal amphotericin B and posaconazole. Despite clinical response to the antifungal therapy, he died due to the progression of the underlying disease within two weeks after diagnosis of fungal infection. Molecular diagnostics applied to tissue blocks may reveal useful information on the etiology of invasive fungal infections, including challenging situations, such as with mixed infections. A thorough understanding of fungal etiology facilitates targeted therapy that may improve therapeutic success while limiting side effects. KW - invasive fungal infection KW - fluorescence in situ hybridization (FISH) KW - fungal sinusitis KW - mixed infection KW - Aspergillus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267208 SN - 2309-608X VL - 8 IS - 3 ER - TY - JOUR A1 - Vargas, Juan Gamboa A1 - Wagner, Jennifer A1 - Shaikh, Haroon A1 - Lang, Isabell A1 - Medler, Juliane A1 - Anany, Mohamed A1 - Steinfatt, Tim A1 - Mosca, Josefina Peña A1 - Haack, Stephanie A1 - Dahlhoff, Julia A1 - Büttner-Herold, Maike A1 - Graf, Carolin A1 - Viera, Estibaliz Arellano A1 - Einsele, Hermann A1 - Wajant, Harald A1 - Beilhack, Andreas T1 - A TNFR2-Specific TNF fusion protein with improved in vivo activity JF - Frontiers in Immunology N2 - Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity. Methods Single-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation which avoids/minimizes interaction with Fcγ-receptors (FcγRs). The fusion protein obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based agonist of TNF receptor 2), was analyzed with respect to activity, productivity, serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or selective TNF-based agonist of TNF receptor 2), a well-established highly active nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in various in vitro and in vivo systems. Results STAR2 (TNC-sc(mu)TNF80) and NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The novel domain architecture of NewSTAR2 significantly improved serum retention compared to STAR2, which correlated with efficient binding to FcRn. A single injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and increased Treg numbers by > 300% in vivo 5 days after treatment. Treg numbers remained as high as 200% for about 10 days. Furthermore, a single in vivo treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) proliferation and expression of activation markers in vitro. Finally, singular preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell transplantation (allo-HCT) protected mice from acute GvHD. Conclusions NewSTAR2 represents a next generation ligand-based TNFR2 agonist, which is efficiently produced, exhibits improved pharmacokinetic properties and high serum retention with superior in vivo activity exerting powerful protective effects against acute GvHD. KW - agonist KW - GvHD KW - regulatory T cells KW - serum retention KW - TNF KW - TNFR2 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-277436 SN - 1664-3224 VL - 13 ER - TY - JOUR A1 - Zimny, Sebastian A1 - Koob, Dennis A1 - Li, Jingguo A1 - Wimmer, Ralf A1 - Schiergens, Tobias A1 - Nagel, Jutta A1 - Reiter, Florian Paul A1 - Denk, Gerald A1 - Hohenester, Simon T1 - Hydrophobic bile salts induce pro-fibrogenic proliferation of hepatic stellate cells through PI3K p110 alpha signaling JF - Cells N2 - Bile salts accumulating during cholestatic liver disease are believed to promote liver fibrosis. We have recently shown that chenodeoxycholate (CDC) induces expansion of hepatic stellate cells (HSCs) in vivo, thereby promoting liver fibrosis. Mechanisms underlying bile salt-induced fibrogenesis remain elusive. We aimed to characterize the effects of different bile salts on HSC biology and investigated underlying signaling pathways. Murine HSCs (mHSCs) were stimulated with hydrophilic and hydrophobic bile salts. Proliferation, cell mass, collagen deposition, and activation of signaling pathways were determined. Activation of the human HSC cell line LX 2 was assessed by quantification of α-smooth muscle actin (αSMA) expression. Phosphatidyl-inositol-3-kinase (PI3K)-dependent signaling was inhibited both pharmacologically and by siRNA. CDC, the most abundant bile salt accumulating in human cholestasis, but no other bile salt tested, induced Protein kinase B (PKB) phosphorylation and promoted HSC proliferation and subsequent collagen deposition. Pharmacological inhibition of the upstream target PI3K-inhibited activation of PKB and pro-fibrogenic proliferation of HSCs. The PI3K p110α-specific inhibitor Alpelisib and siRNA-mediated knockdown of p110α ameliorated pro-fibrogenic activation of mHSC and LX 2 cells, respectively. In summary, pro-fibrogenic signaling in mHSCs is selectively induced by CDC. PI3K p110α may be a potential therapeutic target for the inhibition of bile salt-induced fibrogenesis in cholestasis. KW - cholestasis KW - HSC KW - myofibroblast KW - chenodeoxycholate KW - phosphatidyl-inositol-3-kinase p110 alpha KW - Alpelisib KW - liver fibrosis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281806 SN - 2073-4409 VL - 11 IS - 15 ER - TY - JOUR A1 - Fischer, Julia A1 - Knop, Stefan A1 - Danhof, Sophia A1 - Einsele, Hermann A1 - Keller, Daniela A1 - Löffler, Claudia T1 - The influence of baseline characteristics, treatment and depression on health-related quality of life in patients with multiple myeloma: a prospective observational study JF - BMC Cancer N2 - Background Multiple myeloma (MM) is the third most common hematologic malignancy with increasing importance due to improving treatment strategies and long-term outcomes in an aging population. This study aims to analyse influencing factors on health-related quality of life (HRQoL), such as treatment strategies, participation in a clinical trial and patient characteristics like anxiety, depression, gender, and age. A better understanding of the individual factors in context with HRQoL could provide a helpful instrument for clinical decisions. Methods In this prospective observational study, the HRQoL of MM patients with different therapies (first-line and relapse) was quantified by standardized questionnaires (EORTC QLQ-C30 and -MY20) in the context of sociodemographic data, individual anxiety and depressiveness (PHQ-4), and a selected number of clinical parameters and symptoms at defined time-points before, during, and after therapy. Results In total, 70 patients were included in the study. The median age of the study cohort was 62 years. 44% were female and 56% were male patients. More than half of the patients were fully active with an ECOG 0. Global health status was significantly higher in patients with first-line treatment and even increased after start of therapy, while the pain level decreased. In contrast, patients with relapsed MM reported a decreasing global health status and increasing pain. Additionally, there was a higher global health status in less anxious/depressive patients. HRQoL decreased significantly after start of chemotherapy in the parameters body image, side effects of treatment, and cognitive functioning. Tandem stem-cell transplantation was not found to be a risk factor for higher impairment of HRQoL. Participation in a clinical study led to an improvement of most aspects of HRQoL. Among others, increased anxiety and depression, female gender, older age, impaired performance status, and recurrent disease can be early indicators for a reduced HRQoL. Conclusion This study showed the importance of regular longitudinal assessments of patient reported outcomes (PROs) in routine clinical care. For the first time, to our knowledge, we were able to demonstrate a potential impact between participation in clinical trials and HRQoL. However, due to frequently restrictive inclusion criteria for clinical trials, these MM patients might not be directly comparable with patients treated within standard therapy concepts. Further studies are needed to clarify the relevance of this preliminary data in order to develop an individualized, patient-centred, therapy concept. KW - multiple myeloma KW - quality of life KW - participation in clinical trials KW - depression KW - observational Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300435 VL - 22 ER - TY - JOUR A1 - Fuhr, Viktoria A1 - Heidenreich, Shanice A1 - Srivastava, Mugdha A1 - Riedel, Angela A1 - Düll, Johannes A1 - Gerhard-Hartmann, Elena A1 - Rosenwald, Andreas A1 - Rauert-Wunderlich, Hilka T1 - CD52 and OXPHOS-potential targets in ibrutinib-treated mantle cell lymphoma JF - Cell Death Discovery N2 - Altered features of tumor cells acquired across therapy can result in the survival of treatment-resistant clones that may cause minimal residual disease (MRD). Despite the efficacy of ibrutinib in treating relapsed/refractory mantle cell lymphoma, the obstacle of residual cells contributes to relapses of this mature B-cell neoplasm, and the disease remains incurable. RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line following ibrutinib incubation of up to 4 d, corroborated our previously postulated resistance mechanism of a metabolic switch to reliance on oxidative phosphorylation (OXPHOS) in surviving cells. Besides, we had shown that treatment-persisting cells were characterized by increased CD52 expression. Therefore, we hypothesized that combining ibrutinib with another agent targeting these potential escape mechanisms could minimize the risk of survival of ibrutinib-resistant cells. Concomitant use of ibrutinib with OXPHOS-inhibitor IACS-010759 increased toxicity compared to ibrutinib alone. Targeting CD52 was even more efficient, as addition of CD52 mAb in combination with human serum following ibrutinib pretreatment led to rapid complement-dependent-cytotoxicity in an ibrutinib-sensitive cell line. In primary mantle cell lymphoma cells, a higher toxic effect with CD52 mAb was obtained, when cells were pretreated with ibrutinib, but only in an ibrutinib-sensitive cohort. Given the challenge of treating multi-resistant mantle cell lymphoma patients, this work highlights the potential use of anti-CD52 therapy as consolidation after ibrutinib treatment in patients who responded to the BTK inhibitor to achieve MRD negativity and prolong progression-free survival. KW - cancer metabolism KW - cell death KW - target validation KW - targeted therapies Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300817 SN - 2058-7716 VL - 8 ER - TY - JOUR A1 - Brosinsky, Paulin A1 - Leister, Hanna A1 - Cheng, Nan A1 - Varelas, Xaralabos A1 - Visekruna, Alexander A1 - Luu, Maik T1 - Verteporfin protects against Th17 cell‐mediated EAE independently of YAP inhibition JF - European Journal of Immunology N2 - The known YAP inhibitor verteporfin is capable of repressing IL‐17A production in Th17 cells. However, this effect is mediated independently of YAP and can ameliorate Th17‐mediated experimental autoimmune encephalomyelitis (EAE) upon in vivo administration. The data suggest verteprofin's mode of action for the design of novel therapeutic autoimmune disease intervention. KW - Hippo signaling KW - YAP KW - verteporfin KW - Th17 cells KW - EAE Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-287234 VL - 52 IS - 9 SP - 1523 EP - 1526 ER - TY - JOUR A1 - Haussmann, Alexander A1 - Schmidt, Martina E. A1 - Illmann, Mona L. A1 - Schröter, Marleen A1 - Hielscher, Thomas A1 - Cramer, Holger A1 - Maatouk, Imad A1 - Horneber, Markus A1 - Steindorf, Karen T1 - Meta-analysis of randomized controlled trials on yoga, psychosocial, and mindfulness-based interventions for cancer-related fatigue: What intervention characteristics are related to higher efficacy? JF - Cancers N2 - Cancer-related fatigue (CRF) is a burdensome sequela of cancer treatments. Besides exercise, recommended therapies for CRF include yoga, psychosocial, and mindfulness-based interventions. However, interventions conducted vary widely, and not all show a significant effect. This meta-analysis aimed to explore intervention characteristics related to greater reductions in CRF. We included randomized controlled trials published before October 2021. Standardized mean differences were used to assess intervention efficacy for CRF and multimodel inference to explore intervention characteristics associated with higher efficacy. For the meta-analysis, we included 70 interventions (24 yoga interventions, 31 psychosocial interventions, and 15 mindfulness-based interventions) with 6387 participants. The results showed a significant effect of yoga, psychosocial, and mindfulness-based interventions on CRF but with high heterogeneity between studies. For yoga and mindfulness-based interventions, no particular intervention characteristic was identified to be advantageous for reducing CRF. Regarding psychosocial interventions, a group setting and work on cognition were related to higher intervention effects on CRF. The results of this meta-analysis suggest options to maximize the intervention effects of psychosocial interventions for CRF. The effects of yoga and mindfulness-based interventions for CRF appear to be independent of their design, although the limited number of studies points to the need for further research. KW - fatigue KW - cancer KW - psychosocial KW - mindfulness KW - yoga KW - quality of life KW - patient-reported outcomes Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270753 SN - 2072-6694 VL - 14 IS - 8 ER - TY - JOUR A1 - Leyh, Catherine A1 - Ehmer, Ursula A1 - Roessler, Daniel A1 - Philipp, Alexander B. A1 - Reiter, Florian P. A1 - Jeliazkova, Petia A1 - Jochheim, Leonie S. A1 - Jeschke, Matthias A1 - Hammig, Janina A1 - Ludwig, Johannes M. A1 - Theysohn, Jens M. A1 - Geier, Andreas A1 - Lange, Christian M. T1 - Sorafenib versus lenvatinib-based sequential systemic therapy for advanced hepatocellular carcinoma: a real-world analysis JF - Cancers N2 - The optimal treatment sequence of tyrosine kinase inhibitor (TKI)-based therapy in patients with hepatocellular carcinoma (HCC) remains unclear. Therefore, sequential systemic therapy after first-line therapy with sorafenib or lenvatinib was compared in a retrospective real-world cohort. In total, 164 patients with HCC were included. Child B cirrhosis was present in 26 patients (16.5%), whereas 132 patients (83.5%) had preserved liver function. In total, 72 patients (44%) discontinued systemic therapy after first-line therapy while 51 (31%) and 31 (19%) patients received 2 or more treatment lines. Most notably, median overall survival (mOS) was influenced by liver functional status and patient performance status at the beginning of first-line therapy. Patients receiving a sequential therapy regimen had significantly longer mOS compared to patients that discontinued systemic therapy after omitting first-line treatment. The choice of the initial TKI did not impact mOS. A clear deterioration of liver function could be observed during the course of TKI-based treatment. KW - hepatocellular carcinoma KW - systemic therapy KW - tyrosine-kinase inhibitor Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270765 SN - 2072-6694 VL - 14 IS - 8 ER - TY - JOUR A1 - Brand, Markus A1 - Troya, Joel A1 - Krenzer, Adrian A1 - Saßmannshausen, Zita A1 - Zoller, Wolfram G. A1 - Meining, Alexander A1 - Lux, Thomas J. A1 - Hann, Alexander T1 - Development and evaluation of a deep learning model to improve the usability of polyp detection systems during interventions JF - United European Gastroenterology Journal N2 - Background The efficiency of artificial intelligence as computer-aided detection (CADe) systems for colorectal polyps has been demonstrated in several randomized trials. However, CADe systems generate many distracting detections, especially during interventions such as polypectomies. Those distracting CADe detections are often induced by the introduction of snares or biopsy forceps as the systems have not been trained for such situations. In addition, there are a significant number of non-false but not relevant detections, since the polyp has already been previously detected. All these detections have the potential to disturb the examiner's work. Objectives Development and evaluation of a convolutional neuronal network that recognizes instruments in the endoscopic image, suppresses distracting CADe detections, and reliably detects endoscopic interventions. Methods A total of 580 different examination videos from 9 different centers using 4 different processor types were screened for instruments and represented the training dataset (519,856 images in total, 144,217 contained a visible instrument). The test dataset included 10 full-colonoscopy videos that were analyzed for the recognition of visible instruments and detections by a commercially available CADe system (GI Genius, Medtronic). Results The test dataset contained 153,623 images, 8.84% of those presented visible instruments (12 interventions, 19 instruments used). The convolutional neuronal network reached an overall accuracy in the detection of visible instruments of 98.59%. Sensitivity and specificity were 98.55% and 98.92%, respectively. A mean of 462.8 frames containing distracting CADe detections per colonoscopy were avoided using the convolutional neuronal network. This accounted for 95.6% of all distracting CADe detections. Conclusions Detection of endoscopic instruments in colonoscopy using artificial intelligence technology is reliable and achieves high sensitivity and specificity. Accordingly, the new convolutional neuronal network could be used to reduce distracting CADe detections during endoscopic procedures. Thus, our study demonstrates the great potential of artificial intelligence technology beyond mucosal assessment. KW - CADe KW - colonoscopy KW - deep learning KW - instrument KW - intervention Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312708 VL - 10 IS - 5 ER - TY - JOUR A1 - Gernert, Michael A1 - Tony, Hans-Peter A1 - Fröhlich, Matthias A1 - Schwaneck, Eva Christina A1 - Schmalzing, Marc T1 - Immunosuppressive therapy after autologous hematopoietic stem cell transplantation in systemic sclerosis patients — high efficacy of Rituximab JF - Frontiers in Immunology N2 - Background Systemic sclerosis (SSc) patients often need immunosuppressive medication (IS) for disease control. If SSc is progressive despite IS, autologous hematopoietic stem cell transplantation (aHSCT) is a treatment option for selected SSc patients. aHSCT is effective with good available evidence, but not all patients achieve a treatment-free remission after aHSCT. Thus far, data about the need of IS after aHSCT in SSc is not published. The aim of this study was to investigate the use of IS after aHSCT, its efficacy, and the occurrence of severe adverse events (SAEs). Methods Twenty-seven patients with SSc who had undergone aHSCT were included in this single-center retrospective cohort study. Clinical data, including IS, SAEs, and lung function data, were collected. Results Sixteen of 27 (59.3%) patients received IS after aHSCT. Methotrexate, rituximab, mycophenolate, cyclophosphamide, and hydroxychloroquine were most commonly used. The main reason for starting IS was SSc progress. Nine patients received rituximab after aHSCT and showed an improvement in modified Rodnan skin score and a stabilization of lung function 2 years after rituximab. SAEs in patients with IS after aHSCT (50.0%) were not more common than in patients without IS (54.6%). SAEs were mostly due to SSc progress, secondary autoimmune diseases, or infections. Two deaths after aHSCT were transplantation related and three during long-term follow-up due to pulmonary arterial hypertension. Conclusion Disease progression and secondary autoimmune diseases may necessitate IS after aHSCT in SSc. Rituximab seems to be an efficacious treatment option in this setting. Long-term data on the safety of aHSCT is reassuring. KW - systemic sclerosis KW - scleroderma KW - autologous hematopoietic stem cell transplantation KW - immunosuppression KW - adverse events KW - rituximab Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254345 SN - 1664-3224 VL - 12 ER - TY - JOUR A1 - Siegmund, Daniela A1 - Wagner, Jennifer A1 - Wajant, Harald T1 - TNF receptor associated factor 2 (TRAF2) signaling in cancer JF - Cancers N2 - Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) has been originally identified as a protein interacting with TNF receptor 2 (TNFR2) but also binds to several other receptors of the TNF receptor superfamily (TNFRSF). TRAF2, often in concert with other members of the TRAF protein family, is involved in the activation of the classical NFκB pathway and the stimulation of various mitogen-activated protein (MAP) kinase cascades by TNFRSF receptors (TNFRs), but is also required to inhibit the alternative NFκB pathway. TRAF2 has also been implicated in endoplasmic reticulum (ER) stress signaling, the regulation of autophagy, and the control of cell death programs. TRAF2 fulfills its functions by acting as a scaffold, bringing together the E3 ligase cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 with their substrates and various regulatory proteins, e.g., deubiquitinases. Furthermore, TRAF2 can act as an E3 ligase by help of its N-terminal really interesting new gene (RING) domain. The finding that TRAF2 (but also several other members of the TRAF family) interacts with the latent membrane protein 1 (LMP1) oncogene of the Epstein–Barr virus (EBV) indicated early on that TRAF2 could play a role in the oncogenesis of B-cell malignancies and EBV-associated non-keratinizing nasopharyngeal carcinoma (NPC). TRAF2 can also act as an oncogene in solid tumors, e.g., in colon cancer by promoting Wnt/β-catenin signaling. Moreover, tumor cell-expressed TRAF2 has been identified as a major factor-limiting cancer cell killing by cytotoxic T-cells after immune checkpoint blockade. However, TRAF2 can also be context-dependent as a tumor suppressor, presumably by virtue of its inhibitory effect on the alternative NFκB pathway. For example, inactivating mutations of TRAF2 have been associated with tumor development, e.g., in multiple myeloma and mantle cell lymphoma. In this review, we summarize the various TRAF2-related signaling pathways and their relevance for the oncogenic and tumor suppressive activities of TRAF2. Particularly, we discuss currently emerging concepts to target TRAF2 for therapeutic purposes. KW - apoptosis KW - autophagy KW - B-cell lymphoma KW - cellular inhibitor of apoptosis 1/2 (cIAP1/2) KW - necroptosis KW - nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NFκB) KW - tumor necrosis factor (TNF) KW - TNF receptor associated factor 2 (TRAF2) Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286073 SN - 2072-6694 VL - 14 IS - 16 ER - TY - JOUR A1 - Isberner, Nora A1 - Gesierich, Anja A1 - Balakirouchenane, David A1 - Schilling, Bastian A1 - Aghai-Trommeschlaeger, Fatemeh A1 - Zimmermann, Sebastian A1 - Kurlbaum, Max A1 - Puszkiel, Alicja A1 - Blanchet, Benoit A1 - Klinker, Hartwig A1 - Scherf-Clavel, Oliver T1 - Monitoring of dabrafenib and trametinib in serum and self-sampled capillary blood in patients with BRAFV600-mutant melanoma JF - Cancers N2 - Simple Summary In melanoma patients treated with dabrafenib and trametinib, dose reductions and treatment discontinuations related to adverse events (AE) occur frequently. However, the associations between patient characteristics, AE, and exposure are unclear. Our prospective study analyzed serum (hydroxy-)dabrafenib and trametinib exposure and investigated its association with toxicity and patient characteristics. Additionally, the feasibility of at-home sampling of capillary blood was assessed, and a model to convert capillary blood concentrations to serum concentrations was developed. (Hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or AE. Co-medication with P-glycoprotein inducers was associated with lower trough concentrations of trametinib but not (hydroxy-)dabrafenib. The applicability of the self-sampling of capillary blood was demonstrated. Our conversion model was adequate for estimating serum exposure from micro-samples. The monitoring of dabrafenib and trametinib may be useful for dose modification and can be optimized by at-home sampling and our new conversion model. Abstract Patients treated with dabrafenib and trametinib for BRAF\(^{V600}\)-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters. KW - dabrafenib KW - trametinib KW - hydroxy-dabrafenib KW - melanoma KW - BRAF mutation KW - volumetric absorptive micro-sampling (VAMS) KW - at-home sampling KW - drug monitoring KW - population pharmacokinetics Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288109 SN - 2072-6694 VL - 14 IS - 19 ER - TY - JOUR A1 - Jendretzki, Julia A1 - Henniger, Dorothea A1 - Schiffmann, Lisa A1 - Wolz, Constanze A1 - Kollikowski, Anne A1 - Meining, Alexander A1 - Einsele, Hermann A1 - Winkler, Marcela A1 - Löffler, Claudia T1 - Every fifth patient suffered a high nutritional risk — Results of a prospective patient survey in an oncological outpatient center JF - Frontiers in Nutrition N2 - Introduction Malnutrition in cancer patients often remains undetected and underestimated in clinical practice despite studies revealing prevalences from 20 to 70%. Therefore, this study aimed to identify patient groups exposed to an increased nutritional risk in a university oncological outpatient center. Methods Between May 2017 and January 2018 we screened oncological patients there using the malnutrition universal screening tool (MUST). Qualitative data were collected by a questionnaire to learn about patients’ individual information needs and changes in patients’ diets and stressful personal nutrition restrictions. Results We included 311 patients with various cancers. 20.3% (n = 63) were found to be at high risk of malnutrition, 16.4% (n = 51) at moderate risk despite a mean body mass index (BMI) of 26.5 ± 4.7 kg/m2. The average age was 62.7 (± 11.8) with equal gender distribution (52% women, n = 162). In 94.8% (n = 295) unintended weight loss led to MUST scoring. Patients with gastrointestinal tumors (25%, n = 78) and patients >65 years (22%, n = 68) were at higher risk. Furthermore, there was a significant association between surgery or chemotherapy within six months before survey and a MUST score ≥2 (OR = 3.6). Taste changes, dysphagia, and appetite loss were also particular risk factors (OR = 2.3–3.2). Young, female and normal-weight patients showed most interest in nutrition in cancer. However, only 38% (n = 118) had a nutritional counseling. Conclusion This study confirms that using the MUST score is a valid screening procedure to identify outpatients at risk of developing malnutrition. Here one in five was at high risk, but only 1% would have been detected by BMI alone. Therefore, an ongoing screening procedure with meaningful parameters should be urgently implemented into the clinical routine of cancer outpatients as recommended in international guidelines. KW - nutritional risk screening KW - malnutrition KW - nutritional counseling KW - oncology outpatients KW - MUST-Score KW - nutritional medical needs Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311284 SN - 2296-861X VL - 9 ER - TY - JOUR A1 - Solimando, Antonio Giovanni A1 - Krebs, Markus A1 - Bittrich, Max A1 - Einsele, Hermann T1 - The urgent need for precision medicine in cancer and its microenvironment: the paradigmatic case of multiple myeloma JF - Journal of Clinical Medicine N2 - No abstract available KW - precision medicine KW - multiple myeloma Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288164 SN - 2077-0383 VL - 11 IS - 18 ER - TY - JOUR A1 - Gerner, Bettina A1 - Aghai-Trommeschlaeger, Fatemeh A1 - Kraus, Sabrina A1 - Grigoleit, Götz Ulrich A1 - Zimmermann, Sebastian A1 - Kurlbaum, Max A1 - Klinker, Hartwig A1 - Isberner, Nora A1 - Scherf-Clavel, Oliver T1 - A physiologically-based pharmacokinetic model of ruxolitinib and posaconazole to predict CYP3A4-mediated drug–drug interaction frequently observed in graft versus host disease patients JF - Pharmaceutics N2 - Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug–drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim\(^®\) Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (C\(_{max}\)) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes. KW - physiologically based pharmacokinetic (PBPK) modeling KW - ruxolitinib KW - posaconazole KW - drug–drug interactions (DDIs) KW - graft versus host disease KW - cytochrome P450 3A4 (CYP3A4) KW - pharmacokinetics Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297261 SN - 1999-4923 VL - 14 IS - 12 ER - TY - JOUR A1 - Kelm, Matthias A1 - Reibetanz, Joachim A1 - Kim, Mia A1 - Schoettker, Kathrin A1 - Brand, Markus A1 - Meining, Alexander A1 - Germer, Christoph-Thomas A1 - Flemming, Sven T1 - Kono-S anastomosis in Crohn’s disease: A retrospective study on postoperative morbidity and disease recurrence in comparison to the conventional side-to-side anastomosis JF - Journal of Clinical Medicine N2 - Introduction: The rates of postoperative recurrence following ileocecal resection due to Crohn’s disease remain highly relevant. Despite this fact, while the Kono-S anastomosis technique initially demonstrated promising results, robust evidence is still lacking. This study aimed to analyze the short- and long-term outcomes of the Kono-S versus side-to-side anastomosis. Methods: A retrospective single-center study was performed including all patients who received an ileocecal resection between 1 January 2019 and 31 December 2021 at the Department of Surgery at the University Hospital of Wuerzburg. Patients who underwent conventional a side-to-side anastomosis were compared to those who received a Kono-S anastomosis. The short- and long-term outcomes were analyzed for all patients. Results: Here, 29 patients who underwent a conventional side-to-side anastomosis and 22 patients who underwent a Kono-S anastomosis were included. No differences were observed regarding short-term postoperative outcomes. The disease recurrence rate postoperatively was numerically lower following the Kono-S anastomosis (median Rutgeert score of 1.7 versus 2.5), with a relevantly increased rate of patients in remission (17.2% versus 31.8%); however, neither of these results reached statistical significance. Conclusion: The Kono-S anastomosis method is safe and feasible and potentially decreases the severity of postoperative disease remission. KW - Crohn’s disease KW - surgical therapy KW - ileocecal resection KW - Kono-S anastomosis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297334 SN - 2077-0383 VL - 11 IS - 23 ER - TY - JOUR A1 - Ben Khaled, Najib A1 - Hammer, Katharina A1 - Ye, Liangtao A1 - Alnatsha, Ahmed A1 - Widholz, Sebastian A. A1 - Piseddu, Ignazio A1 - Sirtl, Simon A1 - Schneider, Julia A1 - Munker, Stefan A1 - Mahajan, Ujjwal Mukund A1 - Montero, Juan José A1 - Griger, Joscha A1 - Mayerle, Julia A1 - Reiter, Florian P. A1 - De Toni, Enrico N. T1 - TRAIL receptor targeting agents potentiate PARP inhibitor efficacy in pancreatic cancer independently of BRCA2 mutation status JF - Cancers N2 - Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists. KW - apoptosis KW - DNA damage KW - pancreatic neoplasms KW - poly(ADP-ribose) polymerase inhibitors KW - TNF-related apoptosis-inducing ligand Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290884 SN - 2072-6694 VL - 14 IS - 21 ER - TY - JOUR A1 - Grünwald, Viktor A1 - Pink, Daniel A1 - Egerer, Gerlinde A1 - Schalk, Enrico A1 - Augustin, Marinela A1 - Deinzer, Christoph K. W. A1 - Kob, Viola A1 - Reichert, Dietmar A1 - Kebenko, Maxim A1 - Brandl, Stephan A1 - Hahn, Dennis A1 - Lindner, Lars H. A1 - Hoiczyk, Mathias A1 - Ringsdorf, Uta A1 - Hanker, Lars C. A1 - Hempel, Dirk A1 - De Rivas, Beatriz A1 - Wismann, Tobias A1 - Ivanyi, Philipp T1 - Trabectedin for patients with advanced soft tissue sarcoma: a non-interventional, prospective, multicenter, phase IV trial JF - Cancers N2 - This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23–84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3–6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6–21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile. KW - trabectedin KW - STS KW - sarcoma KW - non-interventional KW - prospective Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290898 SN - 2072-6694 VL - 14 IS - 21 ER - TY - JOUR A1 - Solimando, Antonio G. A1 - Palumbo, Carmen A1 - Pragnell, Mary Victoria A1 - Bittrich, Max A1 - Argentiero, Antonella A1 - Krebs, Markus T1 - Aplastic anemia as a roadmap for bone marrow failure: an overview and a clinical workflow JF - International Journal of Molecular Sciences N2 - In recent years, it has become increasingly apparent that bone marrow (BM) failures and myeloid malignancy predisposition syndromes are characterized by a wide phenotypic spectrum and that these diseases must be considered in the differential diagnosis of children and adults with unexplained hematopoiesis defects. Clinically, hypocellular BM failure still represents a challenge in pathobiology-guided treatment. There are three fundamental topics that emerged from our review of the existing data. An exogenous stressor, an immune defect, and a constitutional genetic defect fuel a vicious cycle of hematopoietic stem cells, immune niches, and stroma compartments. A wide phenotypic spectrum exists for inherited and acquired BM failures and predispositions to myeloid malignancies. In order to effectively manage patients, it is crucial to establish the right diagnosis. New theragnostic windows can be revealed by exploring BM failure pathomechanisms. KW - hematopoietic stem cells KW - bone marrow immune-microenvironment KW - bone marrow failure KW - cytopenia KW - aplastic anemia Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290440 SN - 1422-0067 VL - 23 IS - 19 ER - TY - JOUR A1 - Anger, Friedrich A1 - Lock, Johan Friso A1 - Klein, Ingo A1 - Hartlapp, Ingo A1 - Wiegering, Armin A1 - Germer, Christoph-Thomas A1 - Kunzmann, Volker A1 - Löb, Stefan T1 - Does concurrent cholestasis alter the prognostic value of preoperatively elevated CA19-9 serum levels in patients with pancreatic head adenocarcinoma? JF - Annals of Surgical Oncology N2 - Background Pancreatic adenocarcinoma (PDAC) patients with preoperative carbohydrate antigen 19-9 (CA19-9) serum levels higher than 500 U/ml are classified as biologically borderline resectable (BR-B). To date, the impact of cholestasis on preoperative CA19-9 serum levels in these patients has remained unquantified. Methods Data on 3079 oncologic pancreatic resections due to PDAC that were prospectively acquired by the German Study, Documentation and Quality (StuDoQ) registry were analyzed in relation to preoperative CA19-9 and bilirubin serum values. Preoperative CA19-9 values were adjusted according to the results of a multivariable linear regression analysis of pathologic parameters, bilirubin, and CA19-9 values. Results Of 1703 PDAC patients with tumor located in the pancreatic head, 420 (24.5 %) presented with a preoperative CA19-9 level higher than 500 U/ml. Although receiver operating characteristics (ROC) analysis failed to determine exact CA19-9 cut-off values for prognostic indicators (R and N status), the T, N, and G status; the UICC stage; and the number of simultaneous vein resections increased with the level of preoperative CA19-9, independently of concurrent cholestasis. After adjustment of preoperative CA19-9 values, 18.5 % of patients initially staged as BR-B showed CA19-9 values below 500 U/ml. However, the postoperative pathologic results for these patients did not change compared with the patients who had CA19-9 levels higher than 500 U/ml after bilirubin adjustment. Conclusions In this multicenter dataset of PDAC patients, elevation of preoperative CA19-9 correlated with well-defined prognostic pathologic parameters. Bilirubin adjustment of CA19-9 is feasible but does not affect the prognostic value of CA19-9 in jaundiced patients. KW - pancreatic adenocarcinoma (PDAC) KW - CA19-9 KW - cholestasis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323854 VL - 29 IS - 13 ER - TY - JOUR A1 - Reimer, Stanislaus A1 - Seyfried, Florian A1 - Flemming, Sven A1 - Brand, Markus A1 - Weich, Alexander A1 - Widder, Anna A1 - Plaßmeier, Lars A1 - Kraus, Peter A1 - Döring, Anna A1 - Hering, Ilona A1 - Hankir, Mohammed K. A1 - Meining, Alexander A1 - Germer, Christoph-Thomas A1 - Lock, Johan F. A1 - Groneberg, Kaja T1 - Evolution of endoscopic vacuum therapy for upper gastrointestinal leakage over a 10-year period: a quality improvement study JF - Surgical Endoscopy N2 - Background Endoscopic vacuum therapy (EVT) is an effective treatment option for leakage of the upper gastrointestinal (UGI) tract. The aim of this study was to evaluate the clinical impact of quality improvements in EVT management on patients’ outcome. Methods All patients treated by EVT at our center during 2012–2021 were divided into two consecutive and equal-sized cohorts (period 1 vs. period 2). Over time several quality improvement strategies were implemented including the earlier diagnosis and EVT treatment and technical optimization of endoscopy. The primary endpoint was defined as the composite score MTL30 (mortality, transfer, length-of-stay > 30 days). Secondary endpoints included EVT efficacy, complications, in-hospital mortality, length-of-stay (LOS) and nutrition status at discharge. Results A total of 156 patients were analyzed. During the latter period the primary endpoint MTL30 decreased from 60.8 to 39.0% (P = .006). EVT efficacy increased from 80 to 91% (P = .049). Further, the need for additional procedures for leakage management decreased from 49.9 to 29.9% (P = .013) and reoperations became less frequent (38.0% vs.15.6%; P = .001). The duration of leakage therapy and LOS were shortened from 25 to 14 days (P = .003) and 38 days to 25 days (P = .006), respectively. Morbidity (as determined by the comprehensive complication index) decreased from 54.6 to 46.5 (P = .034). More patients could be discharged on oral nutrition (70.9% vs. 84.4%, P = .043). Conclusions Our experience confirms the efficacy of EVT for the successful management of UGI leakage. Our quality improvement analysis demonstrates significant changes in EVT management resulting in accelerated recovery, fewer complications and improved functional outcome. KW - anastomotic leak KW - gastrointestinal perforation KW - esophageal perforation KW - endoluminal KW - vacuum-assisted closure KW - negative pressure Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323953 VL - 36 IS - 12 ER - TY - JOUR A1 - Nees, Juliane A1 - Kiermeier, Senta A1 - Struewe, Farina A1 - Keymling, Myriam A1 - Maatouk, Imad A1 - Kratz, Christian P. A1 - Schott, Sarah T1 - Health behavior and cancer prevention among adults with Li-Fraumeni syndrome and relatives in Germany — a cohort description JF - Current Oncology N2 - Li-Fraumeni-syndrome (LFS) is a rare, highly penetrant cancer predisposition syndrome (CPS) caused by pathogenic variants (PVs) in TP53. Physical activity (PA) and a Mediterranean diet lead to cancer reduction or survival benefits and increased quality of life (QoL), but this is yet unstudied among LFS. TP53 PV carriers (PVC) and their relatives were questioned on dietary patterns (Mediterranean Diet Adherence Screener), PA (Freiburg Questionnaire), QoL (Short-form-Health-Survey-12), smoking, alcohol consumption and perception of cancer risk in a German bi-centric study from March 2020–June 2021. The study enrolled 70 PVC and 43 relatives. Women compared to men (6.49 vs. 5.38, p = 0.005) and PVC to relatives (6.59 vs. 5.51; p = 0.006) showed a healthier diet, associated with participation in surveillance (p = 0.04) and education (diet p = 0.02 smoking p = 0.0003). Women smoked less (2.91 vs. 5.91 packyears; p = 0.03), psychological well-being was higher among men (SF-12: males 48.06 vs. females 41.94; p = 0.004). PVC rated their own cancer risk statistically higher than relatives (72% vs. 38%, p < 0.001) however, cancer risk of the general population was rated lower (38% vs. 70%, p < 0.001). A relative’s cancer-related death increased the estimated personal cancer risk (p = 0.01). The possibilities of reducing cancer through self-determined health behavior among PVC and relatives has not yet been exhausted. Educating families with a CPS on cancer-preventive behavior requires further investigation with regard to acceptance and real-life implementation. KW - pathogenic TP53 germline variant KW - Li-Fraumeni syndrome KW - cancer prevention KW - physical activity KW - cancer predisposition KW - SF-12 KW - MEDAS Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290432 SN - 1718-7729 VL - 29 IS - 10 SP - 7768 EP - 7778 ER -