TY - THES A1 - Hohaus, Andreas T1 - Intranasale versus intraperitoneale Applikation eines IL-4/IL-13-Antagonisten am murinen Asthmamodell T1 - Intranasal versus intraperitoneal application of an IL-4/IL-13-Antagonist in a mouse model for allergic asthma N2 - Asthma bronchiale ist eine chronische, entzündliche Erkrankung der Atemwege, charakterisiert durch bronchiale Hyperreaktivität und variable Atemwegs-obstruktion. Die Interleukine 4 und 13 sind entscheidend an den pathophysiologischen Vor-gängen beim allergischen Asthma bronchiale beteiligt. IL-4 gilt als spezifisches Zytokin für die Differenzierung von nativen T-Helferzellen zu TH2-Zellen. Gemeinsam mit IL-13 führt es zum Immunglobulinklassenswitch der B-Zellen. Ziel dieser Arbeit war es, in einem etablierten Mausmodell für allergisches Asthma verschiedene Applikationsformen des IL-4/IL-13-Antagonisten QY in ihrer Wirkung während der allergischen Sensibilisierung zu vergleichen. Dazu wurden Balb/c-Mäuse über einen Zeitraum von 6 Wochen wöchentlich mit 50µg OVA sensibilisiert. In zwei Therapiegruppen wurden zu jeder Sensibilisierung jeweils 10µg QY intranasal bzw. intraperitoneal verabreicht. Wöchentlich wurde das Serum der Versuchstiere auf allergenspezifische Antikörper untersucht. Nach sechs Wochen wurde eine bronchoalveoläre Lavage durchgeführt, um den Zytokingehalt und die allergeninduzierte Eosinophilie zu bestimmen. Sowohl die intranasale als auch die intraperitoneale Gabe von QY resultierte in einer signifikanten Abnahme allergenspezifischer IgE-Antikörper im Serum der Versuchstiere. Ebenso konnten die Zahl der inflammativen eosinophilen Granu-lozyten und der IL-5-Spiegel in der BAL signifikant gesenkt werden. Zusammenfassend wurde gezeigt, dass die prophylaktische Behandlung mit dem IL-4/IL-13-Antagonisten QY zuverlässig eine allergische Sensibilisierung der Versuchstiere verhindert. Die intranasale und intraperitoneale Applikation unterscheiden sich hierbei praktisch nicht in ihrer Wirksamkeit. N2 - IL-4 and IL-13 are considered as key regulators for the development of allergic asthma. This study compares intranasal versus intraperitoneal application of an IL-4/IL-13-Antagonist in a murine model for allergic asthma. In summary there is no significant difference between intranasal or intraperitoneal application. KW - Allergie KW - Asthma KW - Interleukin 4 KW - Interleukin 13 KW - Interleukinantagonist QY KW - allergy KW - asthma KW - interleukin 4 KW - interleukin 13 KW - interleukin antagonist Y1 - 2006 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-21533 ER - TY - THES A1 - Toksoy, Atiye T1 - Die Expression von Chemokinen bei entzündlichen Reaktionen der Haut T1 - The expression of chemokines in inflammatory skin diseases N2 - Für das Verständnis der Pathogenese entzündlicher Hauterkrankungen ist die Zusammensetzung des zellulären Entzündungsinfiltrates und die Verteilung der Entzündungszellen von wesentlicher Bedeutung. In Anbetracht der chemotaktischen Funktion der Chemokine liegt die Annahme nahe, dass das zelluläre Infiltrationsmuster in entzündlichen Hauterkrankungen das Expressionsmuster von Chemokinen und umgekehrt widerspiegelt. Die Infiltrationsroute der Leukozyten in die Haut erfolgt immer vom Lumen dermaler Gefäße in das dermale Milieu und ggf. weiter in das epidermale Kompartiment (sog. Epidermotropismus). Die Migration inflammatorischer Zellen über die Grenzen unterschiedlicher Hautkompartimente hinweg ist einzigartig und präsentiert ein ideales Modell, um die chemotaktischen Cytokin- bzw. Chemokinfunktionen zu evaluieren. Anhand verschiedener ausgewählter Hautdermatosen (Wundheilung, Psoriasis, Alopecia areata) wurden die unterschiedlichen Expressionsmuster einer Auswahl von Chemokinen untersucht. Dabei nehmen Chemokine, die von Endothelzellen exprimiert bzw. sezerniert werden, eine zentrale Rolle ein, da sie eine „Pförtnerfunktion“ ausführen. Diese Funktion ist entscheidend bei der Rekrutierung und Akkumulation der für das Erkrankungsbild und bei reparativen Vorgängen der Wundheilung spezifischen Leukozytensubpopulation ins dermale bzw. epidermale Gewebe N2 - The composition of the cellular inflammatory infiltrates and the distribution of inflammatory cells is essential for the understanding of the pathogenesis of inflammatory skin diseases. In view of the chemotactic function of chemokines we assume that the cellular infiltration pattern in inflammatory skin diseases reflects the expression patterns of chemokines and vice versa. The route of leukocyte infiltration into the skin is always directed from the lumen of dermal vessels in the dermal milieu and in some cases further into the epidermal compartment (so-called epidermotropism). The migration of inflammatory cells across the borders of different skin compartments is unique and represents an ideal model to evaluate the chemotactic function of cytokines or chemokines. In various representative dermatoses (wound healing, psoriasis, alopecia areata) we investigated the different expression patterns of selected chemokines. Chemokines, expressed or secreted by endothelial cells, play an important role because they exert a "gatekeeper function". This is crucial in the recruitment and accumulation pattern of the disease and repair processes of wound-specific leukocyte subpopulation, which invade the dermal and epidermal compartment. KW - Schuppenflechte KW - Wundheilung KW - Alopecia areata KW - Chemokine KW - CXCL12 KW - CXCR$ KW - psoriasis KW - wound healing KW - alopecia areata KW - chemokines Y1 - 2008 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-34692 ER - TY - THES A1 - Dotterweich, Barbara T1 - Untersuchungen zur Pathogenität von Antikörpern bei der Epidermolysis bullosa acquisita N2 - Erstellung eines Tiermodells für die EBA mittels passiven Transfers von Kaninchenantikörpern gegen Typ VII Kollagen in Mäuse. Immunologische Untersuchungen der EBA im Modell. N2 - To study the pathogenic relevance of antibodies specific to type VII collagen in vivo, we generated and characterized rabbit antibodies specific to a murine form of this antigen and passively transferred them into BALB/c mice. Immune rabbit IgG bound to the lamina densa of murine skin and immunoblotted type VII collagen. Mice injected with purified IgG specific to type VII collagen, in contrast to control mice, developed subepidermal skin blisters, reproducing the human disease at the clinical, histological, electron microscopical, and immunopathological levels. KW - EBA KW - Autoimmunität KW - Tiermodell KW - passiver Transfer KW - EBA KW - passive transfer of antibodies Y1 - 2005 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-20707 ER - TY - THES A1 - Brookman-Amissah, Sabine T1 - Untersuchung der Interaktionskinetik naiver humaner T-Zellen und dendritischer Zellen in dreidimensionaler Kollagenmatrix und Erfassung der T-Zell-Aktivierung und -Proliferation unter Oxidative Mitogenese-Bedingungen T1 - Evaluation of interactions of human naive t-cells with dentritic cells in three-dimensional collagen matrix and assessment of t-cell activation and proliferation under terms of oxidative mitogenesis N2 - Hintergrund:Die Aktivierung naiver T-Zellen ist Folge eines Kontaktes zu Antigen präsentierenden Zellen (APC), die auf ihrer Oberfläche Antigene im MHC-Peptid-Komplex präsentieren. Bisherige Daten zur Kontaktdauer und -dynamik sowie zur nachfolgenden Aktivierung und Proliferation naiver T-Zellen beruhen meist auf Ergebnissen von Experimenten, die in Flüssigkulturmodellen gemacht wurden. Aus diesen resultierte die Beschreibung des sog. statischen Interaktionskonzeptes. Die T-Zell-Aktivierung wird überwiegend als Folge eines einzelnen lang dauernden und statischen Kontaktes zwischen T-Zelle und APC beschrieben (single encounter model), der zu einer kontinuierlichen Stimulation des T-Zell-Rezeptors über mehrere Stunden führt. Dem gegenüber steht das Konzept dynamischer Interaktionen, in dem T-Zell-Aktivierung und -Proliferation als Folge dynamischer, kurz dauernder und sequentieller Kontakte zu einer oder zu verschiedenen DC beschrieben werden (serielles Kontaktmodell). Methode: Da Flüssigkeitskulturen jedoch nicht annähernd das dreidimensionale Netzwerk lymphatischer Organe widerspiegeln, in dem der Kontakt zwischen T-Zellen und APC in vivo stattfindet, sollten in der vorliegenden Arbeit naive T-Zellen und dendritische Zellen (DC) in einer dreidimensionalen (3D) Umgebung kokultiviert und auf Interaktionsdynamik und Mitoseaktivität untersucht werden. Im Verlauf der oxidativen Mitogenese mit autologen DC in einer 3D Kollagenmatrix über 56 Stunden wurden humane naive T-Zellen auf Dauer und Dynamik der Zell-Zell-Interaktionen videomikroskopisch sowie die nachfolgende Aktivierung und Proliferation mittels Durchflusszytometrie untersucht. Ergebnisse: Sowohl während der Oxidativen Mitogenese als auch in nicht stimulierten Kontrollkulturen wurden bei naiven T-Zellen fast ausschließlich kurz dauernde, wenige Minuten anhaltende Kontakte zwischen T-Zellen und DC beobachtet. Die mediane Dauer der Kontakte der Kontroll-T-Zellen zu DC war dagegen während aller Beobachtungsintervalle kürzer als die der naiven T-Zellen unter Oxidative Mitogenese-Bedingungen. Es ergaben sich in der Gesamtpopulation der naiven T-Zellen in allen Beobachtungszeiträumen signifikante Unterschiede bezüglich der medianen Interaktionszeiten unter Oxidative Mitogenese-Bedingungen und Kontrollbedingungen Die mediane Interaktionszeit unter Oxidative Mitogenese-Bedingungen lag in allen Beobachtungszeiträumen bei über fünf bis zehn Minuten, unter Kontrollbedingungen jeweils zwischen drei und sechs Minuten (p jeweils < 0,001). Lediglich in der Gruppe der anfangs DC adhärenten T-Zellen nach 24 – 32 Stunden konnten keine signifikanten Unterschiede bezüglich der Dauer der Kontakte festgestellt werden (p = 0,461). Sowohl die Oxidative Mitogenese - wie auch die Kontrollkulturen zeigten nahezu ausschließlich dynamische und serielle Kontakte zu DC, multizelluläre Aggregate und statische Kontakte traten dagegen nur sehr selten auf. Infolge der Oxidativen Mitogenese, nicht jedoch in Kontrollkulturen, traten 40 %der T-Zellen in den Zellzyklus und durchliefen bis zu sechs Mitosen innerhalb von 96 h. Ausblick: Die Oxidative Mitogenese ist ein suffizientes Modell der vollständigen Aktivierung humaner peripherer naiver T-Lymphozyten in Kokultivierung mit DC. Passend zu in vivo Befunden sowie in vitro Daten muriner TCR-transgener T-Zellen erfolgt die Aktivierung und nachfolgende Proliferation überwiegend durch dynamische und kurzlebige Interaktionen. Die vorliegende Arbeit bestätigt das serielle Kontaktmodell für die Aktivierung naiver humaner T-Zellen. N2 - The activation of humane naive t-cells is a consequence of a contact to antigen presenting cells (APC)that present molecules in the MHC-peptide-complex. Until now we consider a long-lasting contact lastging over several hours to be essential for activation and proliferation of naive t-cells. Beside this concept (single encounter model) with a continuous signaling between both cell types as a condition for activation there is also one more hypothesis regarding contact and duration of t-cell-APC-interactions, the serial encounter model. We assessed the duration and type of interactions between naive humane t-cells and dendritic cells in a three-dimensional collagen matrix under terms of oxidative mitogenesis and recognized activation and also proliferation of naive t-cells after one single or several contacts to dentritic cells lasting only a few minutes to a few hours. Long-lasting contacts we found very rare. Hence activation and proliferation of naive t-cells can result from short and serial interactions to APC as the serial encounter model predicts. KW - dendritische Zellen KW - oxidative Mitogenese KW - naive T-Zellen KW - Aktivierung KW - Proliferation KW - dendritische Zellen KW - oxidative Mitogenese KW - naive T-Zellen KW - Aktivierung KW - Proliferation KW - dendrtic cells KW - naive t-cells KW - oxidative mitogenesis KW - activation KW - proliferation Y1 - 2007 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-27742 ER - TY - THES A1 - Wienrich, Bernd Gregor T1 - Expression von LEEP-CAM (Lymphocyte Endothelial EPithelial-Cell Adhesion Molecule) in Haut und Hoden - funktionelle Implikationen für die Immunevasion epithelialer Hauttumoren und Entzündungen immunprivilegierter Gewebe T1 - Expression of LEEP-CAM (Lymphocyte Endpthelial EPithelial-Cell Adhesion Molecule) in Skin and testis –functional implication of immunevasion in epithelial skincancer and inflammation in immunologically privileged tissue N2 - Der Schutz vor der Einwanderung von Immunzellen ist einerseits unter physiologischen Bedingungen wichtig für die Integrität immunprivilegierter Organe, andererseits aber auch (mit)entscheidend für die Pathogenese maligner Tumoren. Vor diesem Hintergrund wurde LEEP-CAM (Lymphocyte Endothelial EPithelial-Cell Adhesion Molecule) untersucht, ein Adhäsionsmolekül, welches in der Epidermis und den dermalen Blutgefäßen in normaler Haut konstitutiv exprimiert wird. Durch immunhistochemische Untersuchungen wurde im ersten Teil der Arbeit gezeigt, dass LEEP-CAM in Basalzellkarzinomen, Plattenepithelkarzinomen und Keratoakanthomen der Haut deutlich vermindert oder gar nicht exprimiert wird. Die verminderte Expression war mit fehlender Infiltration von T-Lymphozyten in das Tumorgewebe assoziiert, was insbesondere durch zwei hinsichtlich ihrer LEEP-CAM-Expression unterschiedenen Populationen von Keratoakanthomen nahe gelegt wurde. Die Hypothese, dass LEEP-CAM in die epidermale Rekrutierung aktivierter T-Zellen involviert ist, wurde durch funktionelle Stamper-Woodruff-Experimente (Adhäsion aktivierter T-Lymphozyten an Gewebe-Gefrierschnitte) mit Basalzellkarzinomen und psoriatischer Haut gestützt. Durch metabolische Markierung mit 35(S)-Methionin und anschließende Radioimmunpräzipitation sowie durch durchflusszytometrische Untersuchungen an kultivierten Zellen wurde gezeigt, dass LEEPCAM in transformierten Keratinozyten im Vergleich zu normalen Keratinozyten deutlich vermindert synthetisiert und exprimiert wird. In zwei komplementären murinen Karzinogenese-Modellen wurde die Assoziation der verminderten LEEP-CAM-Expression mit Entdifferenzierung und invasivem Wachstum der Tumorzellen untermauert. Insgesamt kann experimentelle Evidenz für die Hypothese, dass die Herabregulation der LEEP-CAM-Expression ein (Teil)-Mechanismus ist, durch welchen sich invasiv wachsende Tumoren den Angriffen des Immunsystems entziehen können, präsentiert werden. Im Weiteren wurde die Expression und Funktion von LEEPCAM im Keimepithel des Hodens (als ein Beispiel für ein immunprivilegiertes Gewebe) untersucht. Durch immunhistochemische Untersuchungen wurde die konstitutive Expression von LEEP-CAM in den Sertoli-Zellen des Keimepithels nachgewiesen. Mittels Immun-Elektronenmikroskopie wurde dann die Lokalisation an desmosomalen Strukturen sowie entlang der Zellmembran gezeigt. Im Hinblick auf die Funktion von LEEP-CAM wurde in modifizierten Stamper-Woodruff-Experimenten erstmals gezeigt, dass aktivierte T-Lymphozyten an das Keimepithel des Hodens binden können und dass diese Adhäsion durch LEEP-CAM-gerichtete Antikörper inhibiert werden kann. Damit ist LEEP-CAM das erste Molekül, für welches direkte experimentelle Evidenz eine mögliche Rolle bei der testikulären Lymphozyten-Rekrutierung belegt. Dies könnte Relevanz für die Pathogenese von Orchitiden, den häufigsten Ursachen männlicher Infertilität, haben. N2 - Under physiologic conditions protection of invading immune cells is on one hand important for integrity of immune-privileged organs and on the other hand crucial for the pathogenesis of malignant tumors. In the current thesis LEEP-CAM (Lymphocyte Endothelial Epithelial-Cell Adhesion Molecule), an adhesion molecule which is expressed in the epidermis and dermal blood vessels was investigated. In immunohistochemical stains LEEP-CAM expression was dramatically reduced or absent in basal cell carcinoma, squamous cell carcinoma or keratoacanthoma. Reduced expression was associated with lack of infiltrating T-lymphocytes in the tumor tissue, which was especially obvious in keratoacanthoma. The hypothesis that LEEP-CAM is involved in epidermal recruiting of activated T cells was verified by functional Stamper-Woodruff experiments (adhesion of activated T lymphocytes to frozen tissue sections) for basal cell carcinoma and psoriasis. By metabolic labeling with 35-S-methionin and subsequent radioimmuno-precipitation and additional FACS analysis we could demonstrate, that LEEP-CAM synthesis and expression was reduced in transformed keratinocytes in comparison to primary keratinocytes. The association of reduced LEEP-CAM expression with differentiation and invasive tumor growth was confirmed in two complementary murine carcinogenesis models. In summary, reduced expression of LEEP-CAM may be a mechanism by which invasive tumors are capable of escaping the immune surveillance. In the second part of the thesis, expression and function of LEEP-CAM in the testis was investigated. Constitutive expression of LEEP-CAM was identified immunhistochemically in Sertoli cells. By immunoelectron microscopy LEEP-CAM was localized to desmosomal structures and along the cell membrane. Functional analysis by modified Stamper-Woodruff experiments demonstrated the capability of activated T-lymphocytes to bind to germinal tissue of human testis. This adhesion could be blocked by anti-LEEP-CAM-antibodies. Our studies suggest that LEEP-CAM may the first molecule which is involved in lymphocyte testicular recruitment. This may be relevant for the pathogenesis of orchtitis. KW - Zell-Adhesionsmolekül KW - Hoden KW - Haut KW - Hauttumor KW - Hautkrebs KW - Basaliom KW - Epitheliom KW - Spinaliom KW - Endothel KW - Epithel KW - Keimepithel KW - Plattenepithel KW - Keratoakant KW - LEEP-CAM KW - adhesion molecule KW - inflammation KW - human testis KW - LEEP-CAM KW - adhesion molecule KW - inflammation KW - human testis Y1 - 2006 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-27872 ER - TY - THES A1 - Hahn, Christian T1 - Die Rolle von IL-4 und IL-13 in Maus-Modellen für allergische Erkrankungen T1 - The role of IL-4 and IL-13 in mouse models for allergic diseases N2 - IL-4 und IL-13 sind wichtige Faktoren bei der Entwicklung allergischer Erkrankungen. In dieser Arbeit wird die Rolle von IL-4 und IL-13 in einem Maus-Modell für allergisches Asthma während der allergischen Sensibilisierung und in einer etablierten asthmatischen Erkrankung untersucht. Weiterhin wird die Rolle von IL-4 und IL-13 in frühen Stadien der atopischen Dermatitis in einem Maus-Modell betrachtet. In einem Maus-Modell für allergisches Asthma mit anhaltender IgE-Synthese und einer persistierenden allergischen Atemwegspathologie konnte gezeigt werden, dass die Inhibition des IL-4/IL-13 Systems während der allergischen Sensibilisierung zu einer dosisabhängigen Reduktion der allergen-spezifischen IgE-Titer, zur Inhibition der Atemwegseosinophilie, zur Reduktion der IL-5-Spiegel in der BAL und zu einer gesenkten Anzahl von IL-4 sezernierenden CD4+ T-Zellen. Weiterhin konnte durch die Inhibition des IL-4/IL-13 Systems die Becherzellmetaplasie signifikant gesenkt werden. Die Inhibition des IL-4/IL-13 Systems nach der Entwicklung der allergischen Atemwegspathologie führte hingegen nicht zu einer signifikanten Reduktion der gemessenen Allergie-Parameter. Daraus lässt sich schließen, dass IL-4 und IL-13 nur eine untergeordnete Rolle in einer etablierten Allergie spielt. Diese Ergebnisse sind insbesondere wichtig, wenn man über das Verwendungspotential eines IL-4/IL-13-Inhibitors in der Allergie-Therapie bei asthmatischen Patienten spekuliert. Weiterhin konnte in dieser Arbeit gezeigt werden, dass die NC/Nga-Maus ein Modell für die humane atopische Dermatitis darstellt. NC/Nga Mäuse, die unter konventionellen Bedingungen gehalten wurden, entwickeln makroskopische und histologische Hautpathologien, die der humanen atopischen Dermatitis sehr ähneln. Weiterhin entwickeln unter konventionellen Bedingungen gehaltenen NC/Nga Mäuse hohe IgE-Titer im Serum, die mit einer erhöhten Produktion an Th2-Zytokinen verbunden war. Die Inhibition des IL-4/IL-13-Systems führte in diesem Modell jedoch nicht zu einer Reduktion von Symptomen und Pathologien der humanen atopischen Dermatitis. Deswegen kann man spekulieren, dass die Inhibition des IL-4/IL-13-Systems zu einem zu späten Zeitpunkt erfolgte. Des Weiteren kann eine nicht-standardisierte Sensibilisierung bei Mäusen, die in einer konventionellen Tierhaltung gehalten werden, zu einem sehr unterschiedlichen Ausbruch der Dermatitis führen. Deshalb werden weitere Tierversuche mit einer höheren Anzahl von Tieren, die zwischen den Würfen randomisiert werden, nötig sein, um die Rolle von IL-4 und IL-13 in der atopischen Dermatitis zu klären. N2 - IL-4 and IL-13 are considered as key regulators for the development of atopic diseases. This study addresses the role of IL-4 and IL-13 in a murine asthma model during allergic sensitization and in established disease. In addition we describe the role of IL-4 and IL-13 in early stages of atopic dermatitis in a mouse model. In a murine asthma model with ongoing IgE synthesis and persistent allergic airway pathology we could show that the inhibition of the IL-4/IL-13 system during allergic sensitization resulted in a dose dependent reduction of OVA specific IgEs, inhibition of airway eosinophilia together with decreased IL-5 levels and decreased numbers of IL-4 secreting CD4+ T cells. Moreover, goblet cell metaplasia could be reduced significantly by the IL-4/IL-13 inhibitor. However, the inhibition of the IL-4/IL-13 system after the development of allergic airway pathology did not reveal any significant reduction of all measured allergic parameters. These findings are important to estimate the therapeutic potential of allergy therapy with IL-4/IL-13 inhibitors in asthmatic patients. In addition we demonstrated that the NC/Nga mouse represents a model for human atopic dermatitis. NC/Nga mice kept under conventional conditions, developed macroscopic and histological skin symptoms which resemble human AD. In addition NC/Nga mice kept under conventional conditions developed high serum IgE titers combined with an increased production of Th2 cytokines by in vitro stimulated splenic T- cells. However, the inhibition of the IL-4/IL-13 system did not lead in any significant reduction of symptoms and pathology which might be a problem of the time point of administration of the inhibitor. In addition non standardized sensitization conditions in mice kept in a conventional animal facility may result in different outcomes of the dermatitis. Therefore further animal experiments with a higher number of mice within the groups, which are randomized between the litters, would be necessary to clarify of IL-4 and IL-13 for the pathogenesis of AD. KW - Immunologie KW - Allergie KW - Asthma KW - Atopische Dermatitis KW - Maus-Modell KW - Immunology KW - Allergy KW - Asthma KW - Atopic Dermatitis KW - Mouse model Y1 - 2003 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-8493 ER - TY - THES A1 - Wolf, Katarina T1 - Migration of tumor cells and leukocytes in extracellular matrix : proteolytic and nonproteolytic strategies for overcoming tissue barriers T1 - Migration von Tumorzellen und Leukozyten in extrazellulärer Matrix : proteolytische und nicht-proteolytische Strategien zur Überwindung von Gewebsbarrieren N2 - The extracellular matrix within connective tissues represents a structural scaffold as well as a barrier for motile cells, such as invading tumor cells or passenger leukocytes. It remains unclear how different cell types utilize matrix-degrading enzymes for proteolytic migration strategies and, on the other hand, non-proteolytic strategies to overcome 3D fibrillar matrix networks. To monitor cell migration, a 3D collagen model in vitro or the mouse dermis in vivo were used, in combination with time-lapse video-, confocal- or intravital multiphoton-microscopy, and computer-assisted cell tracking. Expression of proteases, including several MMPs, ADAMs, serine proteases and cathepsins, was shown by flow cytometry, Western blot, zymography, and RT-PCR. Protease activity by migrating HT-1080 fibrosarcoma cells resulting in collagenolysis in situ and generation of tube-like matrix defects was detected by three newly developed techniques:(i) quantitative FITC-release from FITC-labelled collagen, (ii) structural alteration of the pyhsical matrix structure (macroscopically and microscopically), and (iii) the visualization of focal in situ cleavage of individual collagen fibers. The results show that highly invasive ollagenolytic cells utilized a spindle-shaped "mesenchymal" migration strategy, which involved beta1 integrindependent interaction with fibers, coclustering of beta1 integrins and matrix metalloproteinases (MMPs) at fiber bundling sites, and the proteolytic generation of a tube-like matrix-defect by MMPs and additional proteases. In contrast to tumor cells, activated T cells migrated through the collagen fiber network by flexible "amoeboid" crawling including a roundish, elliptoid shape and morphological adaptation along collagen fibers, which was independent of collagenase function and fiber degradation. Abrogation of collagenolysis in tumor cells was achieved by a cocktail of broad-spectrum protease inhibitors at non-toxic conditions blocking collagenolysis by up to 95%. While in T cells protease inhibition induced neither morphodynamic changes nor reduced migration rates, in tumor cells a time-dependent conversion was obtained from proteolytic mesenchymal to non-proteolytic amoeboid migration in collagen lattices in vitro as well as the mouse dermis in vivo monitored by intravital microscopy. Tumor cells vigorously squeezed through matrix gaps and formed constriction rings in regions of narrow space, while the matrix structure remained intact. MMPs were excluded from fiber binding sites and beta1 integrin distribution was non-clustered linear. Besides for fibrosarcoma cells, this mesenchymal-toameboid transition (MAT) was confirmed for epithelial MDA-MB-231 breast carcinoma cells. In conclusion, cells of different origin exhibit significant diversity as well as plasticity of protease function in migration. In tumor cells, MAT could respresent a functionally important cellular and molecular escape pathway in tumor invasion and migration. N2 - Die extrazelluläre Matrix (EZM) des Bindegewebes stellt sowohl ein strukturelles Gerüst als auch eine Barriere für migrierende Zellen dar, wie z.B. invadierende Tumorzellen oder zirkulierende Leukozyten. Es ist bisher unklar, wie diese verschiedenen Zelltypen matrix-degradierende Enzyme für eine proteolytische Migrationsstrategie benutzen bzw. ob und wie sie ohne deren Hilfe durch das Gewebe gelangen. Um Zellmigration in EZM zu untersuchen, wurde ein dreidimensionales Kollagenmodell in vitro wie auch Maus-Dermis in vivo eingesetzt und Zellmigration mittels Zeitraffer-Video-, Konfokal- und Multiphoton-Mikroskopie sowie computer-gestützter Zelltracking-Analyse dargestellt. Expression von Proteasen verschiedener Klassen, wie der MMPs, ADAMs, Serinproteasen und Cathepsine, wurde mittels Durchfluss-Zytometrie, Western blot, Zymographie oder RT-PCR detektiert. Gegen Kollagen gerichtete zelluläre Protease-Aktivität wurde mit Hilfe drei neu entwickelter Techniken dargestellt: (i)quantitative Messung von löslichem FITC aus FITC-markiertem fibrillären Kollagen, (ii) mikro-und makroskopische Reorganisation der physikalischen Matrix-Struktur, und (iii) Visualisierung der Topologie fokaler Degradation von Matrixfasern. Die Ergebnisse zeigen, dass hochinvasive spindelförmige HT-1080 Fibrosarkomzellen eine sogenannte "mesenchymale" Migrationsstrategie mit folgenden Charakteristika entwickelten: (i) beta1 Integrin-abhängige Interaktion mit Kollagenfasern, (ii) das "Co-clustering" von beta1 Integrinen und Matrix-Metalloproteinasen an Faserzugstellen und (iii) eine röhrenförmige, durch Proteasen verursachte Matrixdefektbildung. Im Gegensatz zu proteolytischen Tumorzellen migrierten T-Zellen rundlich-elliptoid mittels flexibler Morphodynamik, ähnlich wie Amöben, durch das Kollagennetzwerk und orientierten sich entlang Kollagenfasern, wobei sie keine biochemisch und strukturell detektierbare Faserdegradation zeigten. Um Tumorzell-vermittelte Kollagenolyse zu hemmen, wurde ein Cocktail, bestehend aus Breitspektrum-Protease-Inhibitioren, etabliert, der die Kollagenolyse unter nicht-toxischen Bedingungen um bis zu 98% blockierte. Während in T-Zellen keine morphodynamischen Veränderungen detektiert wurden, entwickelten Tumorzellen eine Verschiebung von proteolytisch mesenchymaler zu unverminderter nicht-proteolytisch amöboider Migration (mesenchymale-amöboide Transition - MAT) aus, sowohl in Kollagenmatrices in vitro als auch in Maus-Dermis in vivo, dargestellt mittels Intravital-Multiphoton-Mikroskopie. Die Tumorzellen "quetschten" sich dabei durch Lücken in der Matrix und bildeten sogenannte Konstriktionsringe aus, während die Matrixstruktur intakt blieb. MMPs lokalisierten nicht mehr an Faser-Kontakstellen auf der Zelloberfläche, und beta1 Integrine lagen nicht mehr geclustert vor. Neben HT-1080 Fibrosarkomzellen wurde MAT auch für MDA-MB-231 Brustkrebszellen epithelialer Herkunft nach Protease-Blockade detektiert. Somit entwickeln migrierende Zellen verschiedener Herkunft eine signifikante Diversität wie auch Plastizität bei der Migration durch EZM aus, resultierend aus der Funktionalität von Matrix-Proteasen. In Tumorzellen könnte MAT einen funktionell wichtigen zellulären und molekularen Anpassungsmechanismus für die Tumorinvasion und -migration darstellen. KW - Zellmigration KW - Grundsubstanz KW - Tumorzelle KW - Leukozyt KW - Zellmigration KW - Invasion KW - Karzinomzellen KW - Leukozyten KW - Matrixproteasen KW - Kollagenasen KW - Proteaseinhibitoren KW - cell migration KW - invasion KW - carcinoma cells KW - leukozytes KW - matrix proteases KW - collagenases KW - protease inhibitors Y1 - 2002 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-5670 ER - TY - THES A1 - Alb, Miriam T1 - Tumorstroma-Immuntherapie und spontane Immunsuppression im Grm1-transgenen Melanom-Modell T1 - Tumor stroma immunotherapy and spontaneous immunosuppression in Grm1 transgenic murine melanoma N2 - 5.1 Immuntherapie mit vom Tumorstroma abgeleiteten Peptiden Tumore bestehen nicht nur aus Tumorzellen, sondern auch aus der sie umgebenden extrazellulären Matrix (EZM), und Stromazellen wie Fibroblasten (cancer-associated fibroblast; CAF) und Endothelzellen (tumor endothelial cell; TEC). Diese Stromazellen haben durch die Ausschüttung von Zytokinen, proteolytischen Enzymen, Wachstums- und Angiogenesefaktoren einen entscheidenden Einfluss auf die Tumorprogression. Sie unterscheiden sich von den Stromazellen der normalen Gewebe durch die Expression von sogenannten Tumorstroma-assoziierten Antigenen (TSAA). Damit sollten Therapien, die auf TSAA abzielen, universell einsetzbar und weniger anfällig gegenüber Resistenzentwicklungen (immune escape Mechanismen) sein, da Stromazellen im Gegensatz zu neoplastischen Zellen genetisch relativ stabil sind. Für eine Immuntherapie mit vom Tumorstroma abgeleiteten Peptiden wählten wir die TSAA Endoglin und Fap, welche während der Wundheilung und im Tumorstroma induziert werden. Dabei sollte überprüft werden, ob prophylaktische Vakzinierungen in C57Bl/6j Mäusen Peptid-reaktive T-Zellen induzieren können, und das Wachstum von transplantieren Grm1-transgenen Tumoren reduziert werden kann. In der Tat konnten wir sowohl bei Endoglin- als auch bei Fap Peptid vakzinierten Tieren in vivo Peptid-reaktive Lymphozyten im Blut und zu einem geringeren Anteil auch in der Milz nachweisen, welche Peptid-gepulste syngene Milzzellen lysieren konnten. Allerdings konnte in beiden Fällen keine Reduktion des Tumorwachstums gegenüber der Kontrollgruppe beobachtet werden. Bei der Fap-Peptid-vakzinierten Gruppe war das Tumorwachstum gegenüber der Kontrollgruppe sogar gesteigert. Dies könnte darauf hindeuten, dass die Induktion Fap-Peptid-reaktiver T-Zellen tumorpromovierend wirkt. Möglicherweise könnte aber durch eine Modifikation des Vakzinierungsprotokolls bzw. durch eine Kombination mit anderen Immuntherapeutika ein verbessertes Ansprechen auf eine Endoglin bzw. Fap basierte Immuntherapie erzielt werden. 5.2 Immunsuppressive Mechanismen im Grm1-transgenen Melanom-Modell Grm1-transgene Mäuse entwickeln spontan kutane Melanome. Dieses Modell erlaubte es uns in der vorliegenden Arbeit spontane Immunantworten im Laufe der Melanomentstehung zu untersuchen. Hierfür analysierten wir sowohl ex vivo als auch in vitro aus Milz und Lymphknoten gewonnene Lymphozyten von Mäusen, welche keine Tumorläsionen bzw. eine niedrige oder hohe Tumorlast aufwiesen. Dabei konnten wir ex vivo einen Anstieg der Frequenz aktivierter CD4+ und CD8+ Lymphozyten mit zunehmender Tumorlast zeigen. Bei tumortragenden Tieren exprimierten jedoch hauptsächlich CD4+ T-Zellen Aktivierungsmarker nach in vitro Stimulation. Interessanterweise waren diese Zellen tumortragender Tiere auch funktionell beeinträchtigt, was sich in einer verminderten Proliferationskapazität nach in vitro Stimulation zeigte. Weitere Analysen ergaben, dass die erhöhte Frequenz regulatorischer T Zellen bei tumortragenden Tieren ein frühes Ereignis im Laufe der Tumorentstehung ist. Gleichzeitig konnte auch ein starker Anstieg der immunsupprimierenden Zytokine Tgf-β1 und Il-10 sowohl in den Lymphknoten als auch im Tumorgewebe beobachtet werden. Dabei war die Tgf-β1-Expression sowohl im Tumor als auch im tumor-drainierenden Lymphknoten erhöht, während Il-10 im Tumor nur moderat exprimiert wurde, was eine komplexere Regulation der Il-10-Expression nahe legt. Dies bedeutet, dass in Grm1-transgenen Mäusen ähnlich wie auch bei Melanompatienten zelluläre und zytokinabhängige Mechanismen zur Tumorentstehung beitragen und dieses Modell daher geeignet ist, um präklinisch immunmodulierende Therapieansätze zu testen. N2 - 6.1 Immunotherapy with peptides derived from tumor stroma-associated antigens Tumors do not only comprise tumor cells but also stromal cells like fibroblasts (cancer associated fibroblast; CAF) and endothelial cells (tumor endothelial cell; TEC) and the surrounding extracellular matrix (ECM). These stromal cells impact on progression and invasion of tumors through release of cytokines, ECM-degrading enzymes, growth factors, and angiogenic factors. They differ from their normal counterparts through expression of so called tumor stroma-associated antigens (TSAA). Therefore, therapies targeting the tumor stroma should be universally applicable. Furthermore, such therapies should be less prone to resistance mechanisms as stromal cells are genetically more stable than neoplastic cells. We selected the TSAA Endoglin and Fap, which are both specifically induced during wound healing and in the tumor stroma, to test if vaccination with peptides derived from these TSAA induced peptide-reactive T cells, and could reduce the growth of transplanted Grm1 transgenic tumors in C57Bl/6j mice in a prophylactic setting. In mice vaccinated with Endoglin- and Fap-peptides, respectively, peptide-reactive lymphocytes from peripheral blood and spleen were able to lyse peptide-loaded syngeneic splenocytes in vivo. However, vaccination with Endoglin- and Fap-peptides, respectively, did not affect the growth of transplanted Grm1-transgenic tumors. In fact, tumor growth was enhanced in Fap peptide vaccinated mice compared to the control group. This suggests that Fap peptide reactive T cells promote tumor progression. Modification of the vaccination protocol or a combination with an immune-modulatory therapy could, however, increase the efficacy of an anti-Endoglin or anti-Fap therapy, respectively. 6.2 Immunosuppressive mechanisms of Grm1-transgenic murine melanoma Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increased frequency of activated CD4+ and CD8+ T lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4+ T cells, which could constitute both T helper as well as immune suppressive regulatory T cells, but not CD8+ T cells expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines Tgf-β1 and Il-10 became more evident with increased tumor burden. Notably, Tgf-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas Il-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of Il-10. Thus, similar to the situation in melanoma patients both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immune suppressed state of tumor-bearing Grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immune-modulatory therapies. KW - Stroma KW - Melanom KW - Immunsuppression KW - tumor KW - stroma KW - melanoma KW - immunosuppression KW - Tumorstroma Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78890 ER - TY - THES A1 - Willmes, Christoph T1 - Therapie kutaner Tumoren : Identifizierung molekularer Biomarker der ex vivo Chemosensitivität des malignen Melanoms und Evaluierung der Wirkungsweise von Interferonen und Artemisininen auf das Merkelzellkarzinom T1 - Treatment of cutaneous tumors N2 - Für Patienten mit malignem Melanom im Stadium der Fernmetastasierung gibt es bis heute lediglich Therapieoptionen mit sehr eingeschränkten Erfolgsaussichten. Diese Tatsache bestätigt die Notwendigkeit von Biomarkern zur Vorhersage des Erfolgs verschiedener Therapien. Der ATP-basierende ex vivo Chemosensitivitätsassay hat sich als erfolgreiche Methode zur individuellen Vorhersage eines Chemotherapieerfolgs herausgestellt. Tatsächlich zeigte der Assay ein heterogenes Sensitivitätsprofil gegen verschiedene Chemotherapeutika und ließ in getesteten Patienten ein ex vivo wirksames Chemotherapieregime identifizieren, das anschließend auch klinische Therapieerfolge bei Verwendung der Therapie mit dem besten individuellen Chemosensitivitätsindex(BICSI) zeigte. Um diesen sehr aufwendigen Assay zukünftig zu umgehen, sollten in der vorliegenden Arbeit prädiktive molekulare Biomarker der Chemosensitivität identifiziert werden. Hierfür wurden im Voraus durch einen Microarray die Kandidaten Secernin 1 (SCRN1), Lysyl oxidaselike 1 (LOXL1), Thymosin beta 4 X-linked (TMSB4X), Vesicle-associated membrane protein 5 (VAMP5) und Serine protease inhibitor B1 (SERPINB1) als differentiell exprimierte Gene in chemosensitivem gegenüber chemoresistentem Gewebe identifiziert. Die relative Expression dieser Kandidatengene wurde daraufhin in bis zu 128 verschiedenen Melanomgeweben mit dem Chemosensitivitätsindex verschiedener Chemotherapeutika korreliert. Hierbei konnte eine signifikante Korrelation zwischen SerpinB1 mit der Chemosensitivität gegenüber der Therapiekombination mit Paclitaxel und Cisplatin auf Gen- aber nicht auf Proteinebene identifiziert werden. Weiterhin konnte eine differentielle Expression ebenfalls in chemosensitiven und -resistenten Melanomzelllinien nachgewiesen werden, die allerdings im Vergleich mit dem analysierten Gewebe in gegensätzlicher Richtung verlief. Zusammenfassend lässt sich sagen, dass SerpinB1 ein vielversprechender Marker für die Chemosensitivität gegenüber Paclitaxel und Cisplatin ist, dessen funktionelle Bedeutung aber unklar bleibt. Das Merkelzellkarzinom (MCC) ist ein seltener und hoch aggressiver Tumor der mit dem Merkelzellpolyomavirus (MCV) in Zusammenhang steht. Da MCC Zelllinien zur Aufrechterhaltung ihrer Viabilität die MCV T-Antigene benötigen, könnte der Einsatz von Interferonen (IFN) ein möglicher therapeutischer Ansatz zur Behandlung dieser Krebserkrankung sein. In der vorliegenden Arbeit haben wir daher die Effekte von IFNs auf MCC Zelllinien, mit besonderer Berücksichtigung der MCV+ Linien, untersucht. IFNs vom Typ I (hier Multiferon, ein Mix verschiedener IFN α Subtypen, und IFN β) wirkten stark inhibierend auf die zelluläre Viabilität. Die Zellzyklusanalyse zeigte eine Erhöhung des sub-G Anteils der Zellen nach Behandlung mit IFN, was auf Apoptose als ausschlagebenden Grund schließen ließ. Diese Effekte waren für die Behandlung mit IFN β weniger stark ausgeprägt. Der inhibitorische Effekt von Typ I IFNs auf MCV+ MCC Zelllinien war assoziiert mit einer verringerten Expression des viralen großen T-Antigens (LTA) und einer Erhöhung in der Expression von promyelocytic leukemia protein (PML), das dafür bekannt ist, die Funktion des LTA störend zu beeinflussen. Zusätzlich führte die intratumorale Anwendung von Multiferon in vivo zu einer Regression im Wachstum von MCV+, aber nicht MCV- MCC Xenotransplantaten. Die Ergebnisse zeigen das Typ I IFNs einen starken antitumoralen Effekt haben, der zum Teil durch die Regulierung des LTA herbeigeführt wird. Neben diesen direkten Effekten der IFNs auf die Zellproliferation induzieren diese auch die Expression von MHC Klasse I Molekülen in MCC Zelllinien. Die Durchflusszytometrie zeigte eine Induktion der MHC Klasse I Expression in drei MHC I negativen MCC Zelllinien und eine Erhöhung der Expression, die vor der Behandlung eine geringe Menge an MHC I aufwiesen. Diese Effekte konnten auch in den in vivo Xenotransplantaten beobachtet werden. Die Ergebnisse zeigen, dass die Behandlung mit IFN sowohl direkte als auch indirekte Effekte auf das MCC hat und eine breite Anwendung in Patienten mit MCV+ und MCV- Tumoren finden kann. Neben IFNs sind auch Artemisinin und seine Derivate bekannt für ihre antitumoralen und antiviralen Eigenschaften. Daher haben wir den Effekt des Artemisininderivats Artesunate auf MCV+ und MCV- MCC Zelllinien getestet. Tatsächlich konnten wir auch hier einen antiproliferativen Effekt des Stoffes nachweisen, der stärker auf MCV+ als auf MCV- Zelllinien wirkte und bei ersteren wiederum mit einer reduzierten LTA Expression einherging. Im Vergleich dazu blieben Fibroblasten von der Behandlung unbeeinflusst. Das verringerte Tumorwachstum konnte ebenfalls für in vivo Xenotransplantationsmodelle gezeigt werden. Auf Grundlage dieser Erkenntnis sollte eine genauere Untersuchung dieses alten Naturheilstoffes für die Behandlung von MCC Patienten in Betracht gezogen werden. N2 - For melanoma patients with distant metastases all available therapeutic options demonstrate only very limited efficacy up to date. This fact substantiates the need of predictive markers for therapy response. For example, ex-vivo chemosensitivity testing by an ATP-based luminescence assay is a promising tool to predict the individual outcome of different chemotherapy regimens. Indeed, this assay demonstrates a heterogeneous chemosensitivity against different cytotoxic drugs which correlates with chemotherapy outcome in terms of therapy response and overall survival; for the treatment of the patient the drug with the best individual chemosensitivity index(BICSI) is used. To circumvent this elaborate assay in the future, we want to identify and characterize predictive molecular biomarkers of specific chemosensitivity. Initially, predictive biomarker aspirants were identified by a microarray comparing chemosensitive and chemoresistant melanoma cell lines. To this end, we found Secernin 1 (SCRN1), Lysyl oxidaselike 1 (LoxL1), Thymosin beta 4 X-linked (TMSB4X), Vesicleassociated membrane protein 5 (Vamp 5) and Serine protease inhibitor B1 (SerpinB1) as differential expressed in chemosensitive versus chemoresistant melanoma cells. Furthermore, we correlated the relative expression of our candidates with the chemosensitivity index of different chemotherapy regimes in up to 128 melanoma tissues so far. Importantly, we found a significant correlation between SerpinB1 gene but not protein expression and chemosensitivity towards Paclitaxel and Platin. Moreover, we also detected a differential expression of SerpinB1 in melanoma cell lines which however was running in reverse direction compared to the analyzed tissues. In conclusion, SerpinB1 seems to be a promising biomarker for prediction of Paclitaxel and Platin chemosensitivity. Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer associated with the Merkel cell polyomavirus (MCV). As MCC cell lines demonstrate oncogene addiction to the MCV T-antigens, pharmacological interference of the large T-antigen(LTA) may represent an effective therapeutic approach for this deadly cancer. In this study, we investigated the effects of interferons (IFNs) on MCC cell lines, especially on MCV positive (MCV+) lines. Type I IFNs (i.e. Multiferon, a mix of different IFN α subtypes, and IFN β) strongly inhibited the cellular viability. Cell cycle analysis demonstrated increased sub-G fractions for these cells upon IFN treatment indicating apoptotic cell deathν these effects were less pronounced for IFN β. Notably, this inhibitory effect of type I IFNs on MCV+ MCC cell lines was associated with a reduced expression of the MCV LTA as well as an increased expression of promyelocytic leukemia protein (PML), which is known to interfere with the function of the LTA. In addition, the intra-tumoural application of multiferon resulted in a regression of MCV+ but not MCV- MCCs in vivo. Together, our findings demonstrate that type I IFNs have a strong antitumour effect, which is at least in part explained by modulation of the virally encoded LTA. Moreover, in addition to directly affecting MCC cell proliferation, IFNs strongly reinduce MHC class I expression in MCC cells. Flowcytometry demonstrated a re-induction of MHC class I expression upon IFN treatment in three MHC class I- MCV+ cell lines and an increase in MHC class I expression in cell lines that were characterized by a weak expression prior to treatment. Importantly, the increase or induction of MHC class I expression could also be demonstrated in vivo in xenotransplantation models. These results imply that IFN treatment has both a direct and an indirect effect in MCC and should be applicable in a general manner, i.e. irrespective of the MCV status of the patient. Beside IFN, Artemisinins are also known for their antitumoral and antiviral properties. In consequence, we tested the effect of Artesunate, i.e., an Artemisinin drivate, on MCV+ and MCV- MCC cell lines. In this regard, we could demonstrate an antiproliferative effect which was stronger on MCV+ cell lines, and which was associated with a reduced expression of the viral LTA. In contrast, fibroblasts were uneffected by Artenusate treatment. The reduced tumor growth could also be shown in vivo by intra-tumoral injection of Artesunate in MCV+ xenotransplantation models. According to these findings, a more detailed investigation of this ancient natural drug for the treatment of MCC patients should be considered. KW - Interferon KW - Melanom KW - Qinghaosu KW - Chemosensitivität KW - Merkelzellkarzinom KW - Chemosensitivity KW - Merkel cell carcinoma KW - Merkel-Zellkarzinom Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-83470 ER - TY - JOUR A1 - Anders, Diana A1 - Trautmann, Axel T1 - Allergic anaphylaxis due to subcutaneously injected heparin JF - Allergy, Asthma & Clinical Immunology N2 - Heparins are one of the most used class of anticoagulants in daily clinical practice. Despite their widespread application immune-mediated hypersensitivity reactions to heparins are rare. Among these, the delayed-type reactions to s.c. injected heparins are well-known usually presenting as circumscribed eczematous plaques at the injection sites. In contrast, potentially life-threatening systemic immediate-type anaphylactic reactions to heparins are extremely rare. Recently, some cases of non-allergic anaphylaxis could be attributed to undesirable heparin contaminants. A 43-year-old patient developed severe anaphylaxis symptoms within 5–10 minutes after s.c. injection of enoxaparin. Titrated skin prick testing with wheal and flare responses up to an enoxaparin dilution of 1:10.000 indicated a probable allergic mechanism of the enoxaparin-induced anaphylaxis. The basophil activation test as an additional in-vitro test method was negative. Furthermore, skin prick testing showed rather broad cross-reactivity among different heparin preparations tested. In the presented case, history, symptoms, and results of skin testing strongly suggested an IgE-mediated allergic hypersensitivity against different heparins. Therefore, as safe alternative anticoagulants the patient could receive beneath coumarins the hirudins or direct thrombin inhibitors. Because these compounds have a completely different molecular structure compared with the heparin-polysaccharides. KW - Anaphylaxis KW - Allergy KW - Basophil activation test KW - Enoxaparin KW - Heparin KW - Hypersensitivity KW - Immunoglobulin E KW - Immediate-type Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96214 UR - http://www.aacijournal.com/content/9/1/1 ER - TY - JOUR A1 - Schmitt, T. A1 - Egu, D.T. A1 - Walter, E. A1 - Sigmund, A.M. A1 - Eichkorn, R. A1 - Yazdi, A. A1 - Schmidt, E. A1 - Sárdy, M. A1 - Eming, R. A1 - Goebeler, M. A1 - Waschke, J. T1 - Ca\(^{2+}\) signalling is critical for autoantibody‐induced blistering of human epidermis in pemphigus JF - British Journal of Dermatology N2 - Background Pemphigus is a severe bullous autoimmune skin disease. Pemphigus foliaceus (PF) is characterized by antidesmoglein (Dsg) 1 IgG causing epidermal blistering; mucosal pemphigus vulgaris (mPV) by anti‐Dsg3 IgG inducing erosions in the mucosa; and mucocutaneous pemphigus vulgaris (PV) by affecting both, with autoantibodies targeting Dsg1 and Dsg3. Objectives To characterize the Ca\(^{2+}\) flux pathway and delineate its importance in pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles. Methods Immunoprecipitation, Ca\(^{2+}\) flux analysis, Western blotting, immunofluorescence staining, dissociation assays and a human skin ex vivo model were used. Results PV IgG and PF IgG, but neither Dsg3‐specific monoclonal antibody (AK23) nor mPV IgG, caused Ca\(^{2+}\) influx in primary human keratinocytes. Phosphatidylinositol 4‐kinase α interacts with Dsg1 but not with Dsg3. Its downstream target – phospholipase‐C‐γ1 (PLC) – was activated by PV IgG and PF IgG but not AK23 or mPV IgG. PLC releases inositol 1,4,5‐trisphosphate (IP3) causing IP3 receptor (IP3R) activation and Ca2+ flux from the endoplasmic reticulum into the cytosol, which stimulates Ca2+ release‐activated channels (CRAC)‐mediated Ca\(^{2+}\) influx. Inhibitors against PLC, IP3R and CRAC effectively blocked PV IgG and PF IgG‐induced Ca\(^{2+}\) influx; ameliorated alterations of Dsg1 and Dsg3 localization, and reorganization of keratin and actin filaments; and inhibited loss of cell adhesion in vitro. Finally, inhibiting PLC or IP3R was protective against PV IgG‐induced blister formation and redistribution of Dsg1 and Dsg3 in human skin ex vivo. Conclusions Ca2+‐mediated signalling is important for epidermal blistering and dependent on the autoantibody profile, which indicates different roles for signalling complexes organized by Dsg1 and Dsg3. Interfering with PLC and Ca\(^{2+}\) signalling may be a promising approach to treat epidermal manifestations of pemphigus. KW - pemphigus KW - epidermis KW - Ca\(^{2+}\) signalling Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262810 VL - 185 IS - 3 SP - 595 EP - 604 ER - TY - THES A1 - Wons, Annette Marie T1 - Retrospektive Analyse von 108 Patienten mit leukozytoklastischer Vaskulitis aus den Jahren 2001-2007: Diagnose, Prognose und Therapie T1 - Retrospective analysis of 108 patients with Leukocytoclastic Vascultitis from 2001-2007: diagnosis, prognosis and therapy N2 - Diese Arbeit umfasst eine retrospektive Analyse von 108 Patienten mit leukozytoklastischer Vaskulitis (LcV), welche an der Universitätshautklinik Würzburg in den Jahren 2001-2007 behandelt wurden. Zunächst wurde eine Auswertung aller Patienten unter demographischen, labordiagnostischen wie auch therapeutischen Gesichtspunkten durchgeführt. Zusätzlich erfolgte eine Analyse von Patienten mit schwerem Krankheitsverlauf in fünf Patientengruppen (hämorrhagisch-nekrotisierende Vaskulitis (n=42), Vaskulitis oberhalb der Gürtellinie (n=62), Nierenbeteiligung (n=36), Rezidiv (n=19), prästationärer Krankheitsverlauf über drei Wochen (n=39)). Ziel dieser Arbeit war, Risikofaktoren für einen schwerwiegenden oder chronischen Verlauf der Erkrankung aufzuzeigen. Zusätzlich wurde ein weiterer Schwerpunkt auf die Analyse möglicher Auslöser einer LcV gelegt. Die Auswertung zeigte am häufigsten Infekte (68,3%) als Ursache einer LcV. Eher selten schienen maligne Erkrankungen (6,7%), Kollagenosen (5,8%) oder Medikamente (6,7%) an der Entwicklung der LcV beteiligt zu sein. In 12,5% der Fälle konnte trotz intensiver Focus-Suche und ausgedehnter Labordiagnostik keine Ursache für die Entstehung einer LcV gefunden werden. Die Ergebnisse widerlegen Angaben älterer Studien, die Medikamente als primären Auslöser einer LcV postulieren. Bei 21,74% der Patienten mit Rezidiv konnte keine Ursache für die LcV gefunden werden, im Vergleich zu 9,26% der Patienten ohne Rezidiv (p=0,075). So konnte gezeigt werden, dass eine intensive Infektfocussuche und deren anschließende Sanierung das Auftreten von Rezidiven der LcV reduziert. Risikofaktoren für einen schwerwiegenden oder chronischen Verlauf einer LcV werden in der Literatur bisher kontrovers diskutiert. In der vorliegenden Studie konnten folgende Korrelationen aufgezeigt werden: Patienten mit nekrotisierender Vaskulitis litten hoch signifikant (p=0,0001) und Patienten mit Nierenbeteiligung signifikant (p=0,016) häufiger an Diabetes mellitus. Zudem war bei Patienten mit systemischer Beteiligung der LcV (p=0,005) und schwerwiegendem Hautbefall (p=0,008) signifikant häufiger IgA im Serum erhöht. Als Risikofaktoren für einen schwerwiegenden Krankheitsverlauf wie für eine systemische Beteiligung der LcV konnten somit folgende Parameter erhoben werden: Diabetes mellitus (RR=1:1,95 (1,17-3,25)) und IgA-Erhöhung im Serum (RR=1:2,11 (1,28-3,48)). Bei Patienten mit chronischem Krankheitsverlauf waren signifikant häufiger B-Symptome (RR=1: 3,19 (1,27-3,19)), der Nachweis von Kryoglobulinen (RR=1: 4,12 (1,65-10,24)), eine Komplement-Erhöhung von C3/C4 (RR=1:4,88 (2,36-10,05)), ein prästationärer Verlauf von über 3 Wochen (RR=1:6,64 (2,37-18,60)) sowie eine Urtikaria-Vaskulitis (RR=1:3,33 (1,44-7,68)) zu beobachten. Die in dieser Arbeit ermittelten Risikofaktoren für einen schwerwiegenden oder chronisch-rezidivierenden Verlauf einer LcV könnten in Zukunft dazu beitragen, früher einen bestimmten Krankheitsverlauf abschätzen zu können und entsprechende Therapieoptionen einzuleiten. N2 - This paper includes a retrospective analysis of 108 patients with leukocytoclastic vasculitis, who have been seen at the university department of dermatology in Würzburg in the years form 2001-2007. We analysed data from all patients under demographic, laboratory diagnostic and therapeutic aspects. In addition an extra evaluation of patients with an severe course of disease in 5 subgroups was accomplished. The aim of this paper was to recognize riskfactors for an acute or chronic course of disease. Another focus lied on the analysis of potential trigger for the leukocytoclastic vascultis. KW - Leukozytoklastische Vaskulitis KW - renale Mitbeteiligung KW - Risikofaktoren KW - Leukozytoklastische Vaskulitis KW - renale Mitbeteiligung KW - leukocytoclastic vasculitis KW - renal outcome Y1 - 2009 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42270 ER - TY - THES A1 - Roth, Nadine T1 - Hyperhidrose bei Acne inversa T1 - Hidradenitis Suppurativa: Absence of Hyperhidrosis but Presence of a Proinflammatory Signature in Patients’ Sweat N2 - Trotz der ursprünglichen Bezeichnung der Acne inversa als "hidrosadénite phlegmoneuse", die eine inflammatorische Fehlfunktion der apokrinen Schweißdrüsen impliziert, geriet die Rolle der Schweißdrüsen hinsichtlich der Pathogenese der AI in Vergessenheit. Ziel dieser Studie war die Evaluierung der Rolle der Schweißdrüsen im Hinblick auf die für die AI charakteristischen proinflammatorischen Mediatoren. Zu diesem Zweck wurden gravimetrische Schweißmessungen, Multiplex-Zytokin-Assays von Schweißproben, sowie immunfluoreszenzoptische Zytokin-/Chemokin-Untersuchungen von läsionaler AI-Haut durchgeführt. Die gravimetrische Untersuchung von 17 AI-Patienten zeigte, dass AI nicht mit Hyperhidrose assoziiert ist. Allerdings scheinen sich AI-Patienten durch ihr Schwitzen im Vergleich zu einer gesunden Kontrollgruppe subjektiv stärker beeinträchtigt zu fühlen. Unsere Daten zeigen eine komplexe proinflammatorische Signatur im AI-Schweiß, die durch eine signifikant erhöhte Konzentration von Monozyten-Chemoattraktant-Protein-1 (MCP-1), Interleukin-8 (CXCL8) und Interferon-γ gekennzeichnet ist. Passend dazu konnten wir eine erhöhte Expression dieser Mediatoren in apokrinen Schweißdrüsen läsionaler AI-Haut nachweisen. Diese Ergebnisse werfen ein neues Licht auf die proinflammatorische Kapazität apokriner Schweißdrüsen bei AI, was zu einem Überdenken der Rolle der Schweißdrüsen im Hinblick auf die Pathogenese der AI führen kann. N2 - The role of sweat glands in hidradenitis suppurativa has been largely neglected, despite the fact that its original designation, as “hidrosadénite phlegmoneuse”, implied an inflammatory malfunction of the apocrine sweat glands as the underlying pathogenic driver. The aim of this study was to evaluate the role of apocrine sweat glands with respect to the proinflammatory environment of hidradenitis suppurativa. Therefore, gravimetric assessment and multiplex cytokine assays from sweat obtained from patients with hidradenitis suppurativa along with immunofluorescence cytokine/chemokine analysis of lesional apocrine glands-bearing hidradenitis suppurativa skin were performed. Gravimetric assessment of 17 patients with hidradenitis suppurativa revealed that the condition is not associated with hyperhidrosis. However, patients seem to be more affected by subjective sweating. The current data identified a complex proinflammatory signature in hidradenitis suppurativa sweat characterized by a significant upregulation of monocyte chemoattractant protein-1, interleukin-8 (CXCL8), and interferon-γ. In agreement with this, a strong in situ expression of these mediators could be observed in apocrine glands of lesional hidradenitis suppurativa skin. These data shed new light on the proinflammatory capacity of apocrine sweat glands in hidradenitis suppurativa, which may lead to reconsideration of the role of sweat glands in hidradenitis suppurativa pathology. KW - Hidradenitis suppurativa KW - Acne inversa KW - Hyperhidrose KW - Hyperhidrosis KW - Hiperhidrosis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305779 ER - TY - JOUR A1 - Stoevesandt, Johanna A1 - Trautmann, Axel T1 - Risk factors in bee and Vespula venom allergy: state of the art JF - Allergo Journal International N2 - Background Correct recognition of risk factors enables individualized management and treatment of venom allergic patients. Methods Systematic research and review of current literature regarding the risk of (1) severe sting-induced anaphylaxis, (2) anaphylactic adverse event during venom immunotherapy (VIT), and (3) treatment failure. Results and discussion (1) Mastocytosis is the most important risk factor for severe sting-induced anaphylaxis. Hereditary α‑tryptasemia was recently identified as a genetic predictor of severe reactions. Older age is clearly associated with an increased risk; the respective impact of defined cardiovascular comorbidities has yet to be determined. Recent data do not support an aggravation of venom-induced anaphylaxis by intake of β‑blockers or angiotensin-converting enzyme (ACE) inhibitors. A higher risk in men can be attributed to more intensive exposure to stinging insects. (2) Anaphylactic side effects of VIT are most common during the buildup phase, particularly in the course of (ultra-)rush protocols involving a high number of injections and high cumulative daily doses. They are significantly more frequent during honeybee compared to Vespula VIT. Data supporting a negative effect of mastocytosis on the tolerability of VIT are scarce. Older age and cardiovascular medication are not associated with a higher incidence of VIT-induced anaphylaxis. (3) Relapsing anaphylactic reactions to both field and challenge stings are significantly more common during and after honeybee compared to Vespula VIT. Reports of severe field-sting reactions in mastocytosis patients suggest an increased risk of treatment failure which may be overcome by higher maintenance doses and longer duration of VIT. KW - mastocytosis KW - ACE inhibitor KW - age KW - Beta-blocker KW - hereditary alpha-tryptasemia KW - immunotherapy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270498 SN - 2197-0378 VL - 31 IS - 1 ER - TY - JOUR A1 - Wobser, Marion A1 - Siedel, Claudia A1 - Kneitz, Hermann A1 - Bröcker, Eva-Bettina A1 - Goebeler, Mathias A1 - Houben, Roland A1 - Geissinger, Eva T1 - Microvessel Density and Expression of Vascular Endothelial Growth Factor and its Receptors in Different Subtypes of Primary Cutaneous B-cell Lymphoma JF - Acta Dermato-Venereologica N2 - A proangiogenic micromilieu is associated with a worse prognosis in systemic lymphoma. Hence, targeting the tumour microenvironment and its vasculature has evolved as a promising novel treatment strategy. The role of tumour neoangiogenesis in cutaneous B-cell lymphoma, however, has not yet been elucidated. Therefore, we examined the expression of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2, as well as microvessel density by immunohistochemistry in paraffin-embedded specimens of different subtypes of primary cutaneous B-cell lymphomas, systemic diffuse large B-cell lymphoma, and cutaneous B-cell pseudolymphoma. Primary cutaneous large B-cell lymphoma (PCLBCL) were characterized by significantly higher intratumoral expression levels of VEGF and its receptors in comparison with the indolent lymphoma subtypes. Moreover, PCLBCL exhibited significantly higher intratumoral microvessel counts. Our study provides evidence that the most aggressive subtype of cutaneous B-cell lymphoma, PCLBCL, is characterized by a proangiogenic micromilieu. KW - microvessel density KW - vascular endothelial growth KW - B-cell lymphoma KW - subtypes Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128608 VL - 93 IS - 6 ER - TY - JOUR A1 - Poppe, Lidia M. A1 - Bröcker, Eva-Bettina A1 - Trautmann, Axel T1 - The One-nail Brown Band: Macro- and Micro-morphology JF - Acta Dermato-Venereologica N2 - No abstract available. KW - brown band KW - macro-morphology KW - micro-morphology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128566 VL - 93 IS - 4 ER - TY - JOUR A1 - Lodde, Georg A1 - Forschner, Andrea A1 - Hassel, Jessica A1 - Wulfken, Lena M. A1 - Meier, Friedegund A1 - Mohr, Peter A1 - Kähler, Katharina A1 - Schilling, Bastian A1 - Loquai, Carmen A1 - Berking, Carola A1 - Hüning, Svea A1 - Schatton, Kerstin A1 - Gebhardt, Christoffer A1 - Eckardt, Julia A1 - Gutzmer, Ralf A1 - Reinhardt, Lydia A1 - Glutsch, Valerie A1 - Nikfarjam, Ulrike A1 - Erdmann, Michael A1 - Stang, Andreas A1 - Kowall, Bernd A1 - Roesch, Alexander A1 - Ugurel, Selma A1 - Zimmer, Lisa A1 - Schadendorf, Dirk A1 - Livingstone, Elisabeth T1 - Factors influencing the adjuvant therapy decision: results of a real-world multicenter data analysis of 904 melanoma patients JF - Cancers N2 - Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74–80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68–80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24–38), and fear of adverse events (21.1%, 95% CI 16–28) and impaired quality of life (11.9%, 95% CI 7–16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47–59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI. KW - melanoma KW - adjuvant treatment KW - checkpoint blocker KW - targeted therapy KW - BRAF KW - PD-1 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239583 SN - 2072-6694 VL - 13 IS - 10 ER - TY - JOUR A1 - Sarma, Bhavishya A1 - Willmes, Christoph A1 - Angerer, Laura A1 - Adam, Christian A1 - Becker, Jürgen C. A1 - Kervarrec, Thibault A1 - Schrama, David A1 - Houben, Roland T1 - Artesunate affects T antigen expression and survival of virus-positive Merkel cell carcinoma JF - Cancers N2 - Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer with frequent viral etiology. Indeed, in about 80% of cases, there is an association with Merkel cell polyomavirus (MCPyV); the expression of viral T antigens is crucial for growth of virus-positive tumor cells. Since artesunate — a drug used to treat malaria — has been reported to possess additional anti-tumor as well as anti-viral activity, we sought to evaluate pre-clinically the effect of artesunate on MCC. We found that artesunate repressed growth and survival of MCPyV-positive MCC cells in vitro. This effect was accompanied by reduced large T antigen (LT) expression. Notably, however, it was even more efficient than shRNA-mediated downregulation of LT expression. Interestingly, in one MCC cell line (WaGa), T antigen knockdown rendered cells less sensitive to artesunate, while for two other MCC cell lines, we could not substantiate such a relation. Mechanistically, artesunate predominantly induces ferroptosis in MCPyV-positive MCC cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and β-mercaptoethanol reduced artesunate-induced death. Finally, application of artesunate in xenotransplanted mice demonstrated that growth of established MCC tumors can be significantly suppressed in vivo. In conclusion, our results revealed a highly anti-proliferative effect of the approved and generally well-tolerated anti-malaria compound artesunate on MCPyV-positive MCC cells, suggesting its potential usage for MCC therapy. KW - artesunate KW - Merkel cell carcinoma KW - MCC KW - polyomavirus KW - ferroptosis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203851 SN - 2072-6694 VL - 12 IS - 4 ER - TY - JOUR A1 - Kolb-Mäurer, Annette A1 - Goebeler, Matthias A1 - Mäurer, Mathias T1 - Cutaneous adverse events associated with interferon-\(\beta\) treatment of multiple sclerosis JF - International Journal of Molecular Sciences N2 - Interferons are widely used platform therapies as disease-modifying treatment of patients with multiple sclerosis. Although interferons are usually safe and well tolerated, they frequently cause dermatological side effects. Here, we present a multiple sclerosis (MS) patient treated with interferon-\(\beta\) who developed new-onset psoriasis. Both her MS as well as her psoriasis finally responded to treatment with fumarates. This case illustrates that interferons not only cause local but also systemic adverse events of the skin. These systemic side effects might indicate that the Th17/IL-17 axis plays a prominent role in the immunopathogenesis of this individual case and that the autoimmune process might be deteriorated by further administration of interferons. In conclusion, we think that neurologists should be aware of systemic cutaneous side effects and have a closer look on interferon-associated skin lesions. Detection of psoriasiform lesions might indicate that interferons are probably not beneficial in the individual situation. We suggest that skin lesions may serve as biomarkers to allocate MS patients to adequate disease-modifying drugs. KW - autoimmune diseases KW - psoriasis KW - cutaneous adverse events KW - utaneous adverse events KW - interferon-\(\beta\) KW - multiple sclerosis KW - lesions KW - therapy KW - experience KW - skin reactions KW - improvement Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148451 VL - 16 ER - TY - JOUR A1 - Glatzel, Caroline Maria A1 - Patzkó, Ágnes A1 - Matlach, Juliane A1 - Grehn, Franz T1 - Ergebnisse der filtrierenden Trabekulotomie (FTO) im Vergleich zur konventionellen Trabekulektomie (TE) – eine gematchte Fall-Kontroll-Studie JF - Der Ophthalmologe N2 - Ziel Ziel dieser Studie war es, die 2‑Jahres-Ergebnisse der filtrierenden Trabekulotomie (FTO) im Vergleich zur konventionellen Trabekulektomie (TE) bei primärem Offenwinkelglaukom, Pseudoexfoliationsglaukom und Pigmentglaukom zu untersuchen. Patienten und Methoden Es wurden 30 konsekutive Patienten nach FTO und 87 Patienten nach TE nach intraokularem Druck (IOD) und Alter im Verhältnis 1:3 gematcht. Primärer Endpunkt war das Erreichen des Zieldrucks nach 2 Jahren. Als vollständiger Erfolg wurde ein IOD ohne Medikamente von ≤ 18 mm Hg bei gleichzeitiger IOD-Reduktion um ≥ 30 % definiert, als qualifizierter Erfolg, wenn hierfür zusätzlich Medikamente erforderlich waren. Sekundäre Endpunkte waren mittlere Drucksenkung, resultierende Sehschärfe, Komplikationen und nachfolgende Operationen. Die Operationstechnik der filtrierenden Trabekulotomie ist als Video zu diesem Beitrag abrufbar. Ergebnisse Zwei-Jahres-Daten konnten von 27 Patienten aus der FTO-Gruppe und 68 Patienten aus der TE-Gruppe erhoben werden. Die Patienten beider Gruppen wurden vor Beginn der Studie bezüglich Alter und IOD gematcht, waren aber auch bezüglich Sehschärfe, Geschlecht und Medikation nicht unterschiedlich. Der Median des präoperativen IOD unter Therapie betrug in beiden Gruppen 23,0 mm Hg. Nach den oben genannten Kriterien wurde ein qualifizierter 2‑Jahres-Erfolg bei 70,4 % der FTO-Gruppe und bei 77,6 % der TE-Gruppe erzielt (p = 0,60), ein vollständiger 2‑Jahres-Erfolg bei 33,3 % der FTO-Gruppe und bei 56,7 % der TE-Gruppe (p = 0,07). Beide Operationsmethoden senkten den Augeninnendruck nach 24 Monaten signifikant (p < 0,001), und zwar auf 12,8 mm Hg in der FTO-Gruppe und 11,0 mm Hg in der TE-Gruppe. Die Sehschärfe war postoperativ bei beiden Gruppen etwas verringert, unterschied sich jedoch nicht signifikant zwischen beiden Gruppen. Komplikations- und Reoperationsrate waren gering und unterschieden sich nicht zwischen den Gruppen. Schlussfolgerung FTO und TE sind nach 2 Jahren weitgehend gleichwertig bezüglich Zieldruck, IOD-Senkung, Sehschärfe und Komplikationen. KW - Filtrierende Trabekulotomie (FTO) KW - Konventionelle Trabekulektomie (TE) KW - Glaukom Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266542 VL - 118 IS - 5 ER - TY - JOUR A1 - Schummer, Patrick A1 - Schilling, Bastian T1 - How representative are data from global trials on programmed death-1 blockade in melanoma? JF - The British Journal of Dermatology KW - programmed cell death receptor-1 KW - melanoma KW - therapy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318406 VL - 187 IS - 3 SP - 283 EP - 284 ER - TY - JOUR A1 - Martin, Eva A1 - Mauer, Isabell A1 - Malzahn, Uwe A1 - Heuschmann, Peter Ulrich A1 - Goebeler, Matthias A1 - Benoit, Sandrine T1 - Comorbid diseases among bullous pemphigoid patients in Germany: new insights from a case-control study JF - Journal der Deutschen Dermatologischen Gesellschaft N2 - Background and objectives Bullous pemphigoid (BP) is associated with neuropsychiatric disorders. Other comorbid diseases are discussed controversially. We evaluated the prevalence of comorbidity in BP patients in a representative area of Germany. Patients and methods Medical files of all BP patients treated at the Department of Dermatology, University Hospital Würzburg, Germany, between June 2002 and May 2013 were retrospectively reviewed. Bullous pemphigoid was diagnosed based on established criteria. For each patient, two controls were individually matched. Records were evaluated for age, sex, laboratory values, concomitant medication and comorbidity. Conditional logistic regression, multivariable regression analysis and complex regression models were performed to compare results. Results 300 BP patients were identified and compared to 583 controls. Bullous pemphigoid was associated with neuropsychiatric disorders as well as laboratory abnormalities including leukocytosis and eosinophilia. Importantly, a highly significant association of BP with anemia (OR 2.127; 95 % CI 1.532–2.953) and renal impairment (OR 2.218; 95 % CI 1.643–2.993) was identified. No association was found with malignancy and arterial hypertension. Conclusions Our data revealed an increased frequency of anemia and renal impairment in BP patients. In accordance with previous studies the strong association for neuropsychiatric disorders was confirmed (p < 0.0005). KW - bullous pemphigoid KW - comorbid diseases KW - Germany Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318395 VL - 20 IS - 6 SP - 798 EP - 805 ER - TY - JOUR A1 - Jessen, Christina A1 - Kreß, Julia K. C. A1 - Baluapuri, Apoorva A1 - Hufnagel, Anita A1 - Schmitz, Werner A1 - Kneitz, Susanne A1 - Roth, Sabine A1 - Marquardt, André A1 - Appenzeller, Silke A1 - Ade, Casten P. A1 - Glutsch, Valerie A1 - Wobser, Marion A1 - Friedmann-Angeli, José Pedro A1 - Mosteo, Laura A1 - Goding, Colin R. A1 - Schilling, Bastian A1 - Geissinger, Eva A1 - Wolf, Elmar A1 - Meierjohann, Svenja T1 - The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression JF - Oncogene N2 - The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H\(_2\)O\(_2\) or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma. KW - NRF2 KW - melanoma malignancy KW - COX2 expression Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235064 SN - 0950-9232 VL - 39 ER - TY - JOUR A1 - Kneitz, Hermann A1 - Rose, Christian A1 - Glutsch, Valerie A1 - Goebeler, Matthias T1 - Recurrence of a cellular blue nevus with satellitosis — a diagnostic pitfall with clinical consequences JF - Dermatopathology N2 - Blue nevus is a benign melanocytic lesion, typically asymptomatic and of unknown etiology. Several histologic and clinical variants have been distinguished, the most frequent being common blue nevus, cellular blue nevus, and combined blue nevus. Although melanocytic nevi with a satellite lesion are usually suggestive of locally advanced malignant melanoma, very few cases of blue nevi with satellite lesions have been reported. The diagnosis of common or cellular blue nevi is generally straightforward; however, the presence of structures such as irregular edges or satellitosis are highly suggestive for malignancy, and differential diagnoses such as locally advanced malignant melanoma and malignant blue nevus should be considered. Recurrent blue nevi can display atypical features not seen in the primary lesion, such as pleomorphism and mitotic activity. They usually tend to follow a benign course; however, in some cases, recurrence may indicate malignant transformation. We here report the unique case of a 64-year-old woman with a recurrent cellular blue nevus accompanied by satellite lesions. Such a biological behavior resulting in a clinical presentation as a melanoma-like lesion is a rarity in blue nevus and has not been described before. KW - common blue nevus KW - cell rich blue nevus KW - satellitosis KW - immunohistochemistry KW - skin Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297436 SN - 2296-3529 VL - 9 IS - 4 SP - 361 EP - 367 ER - TY - JOUR A1 - Houben, Roland A1 - Alimova, Pamela A1 - Sarma, Bhavishya A1 - Hesbacher, Sonja A1 - Schulte, Carolin A1 - Sarosi, Eva-Maria A1 - Adam, Christian A1 - Kervarrec, Thibault A1 - Schrama, David T1 - 4-[(5-methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone inhibits MCPyV T antigen expression in Merkel cell carcinoma independent of Aurora kinase A JF - Cancers N2 - Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV), and MCPyV-positive tumor cells depend on expression of the virus-encoded T antigens (TA). Here, we identify 4-[(5-methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone (PHT) — a reported inhibitor of Aurora kinase A — as a compound inhibiting growth of MCC cells by repressing noncoding control region (NCCR)-controlled TA transcription. Surprisingly, we find that TA repression is not caused by inhibition of Aurora kinase A. However, we demonstrate that β-catenin — a transcription factor repressed by active glycogen synthase kinase 3 (GSK3) — is activated by PHT, suggesting that PHT bears a hitherto unreported inhibitory activity against GSK3, a kinase known to function in promoting TA transcription. Indeed, applying an in vitro kinase assay, we demonstrate that PHT directly targets GSK3. Finally, we demonstrate that PHT exhibits in vivo antitumor activity in an MCC xenograft mouse model, suggesting a potential use in future therapeutic settings for MCC. KW - Merkel cell carcinoma KW - polyomavirus KW - large T antigen KW - phthalazinone pyrazole KW - glycogen synthase kinase 3 KW - GSK3 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313547 SN - 2072-6694 VL - 15 IS - 9 ER - TY - JOUR A1 - Rak, Katrin A1 - Hamm, Henning A1 - Kerstan, Andreas A1 - Kolb-Mäurer, Annette A1 - Goebeler, Matthias T1 - Severe and prolonged liver damage in pityriasis rubra pilaris treated with acitretin: a case report JF - SN Comprehensive Clinical Medicine N2 - Acitretin is a systemic retinoid that is used in dermatology for treatment of various inflammatory and especially hyperkeratotic diseases. Elevation of liver enzymes may occur occasionally but normally resolves spontaneously, at the latest after termination of acitretin. However, it can very rarely develop into a life-threatening adverse event including drug-induced liver injury (DILI). A 45-year-old man with classical pityriasis rubra pilaris, a frequently severe, inflammatory skin disease, was started on acitretin. After a seemingly harmless elevation of transaminases, a few weeks after initiation of acitretin, the patient experienced a dramatic course of liver injury with hepatic jaundice though acitretin was stopped immediately. Eventually, laboratory values recovered upon high-dose oral prednisolone therapy. Prescribing physicians should keep in mind that acitretin might induce severe liver injury. Even after termination of acitretin laboratory values should be monitored for a while in order to recognize symptomless but harmful drug-induced liver injury in time. KW - acitretin KW - pityriasis rubra pilaris KW - drug-induced liver injury (DILI) KW - adverse event Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323982 VL - 4 IS - 1 ER - TY - JOUR A1 - Wobser, Marion A1 - Schummer, Patrick A1 - Appenzeller, Silke A1 - Kneitz, Hermann A1 - Roth, Sabine A1 - Goebeler, Matthias A1 - Geissinger, Eva A1 - Rosenwald, Andreas A1 - Maurus, Katja T1 - Panel sequencing of primary cutaneous B-cell lymphoma JF - Cancers N2 - Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin’s lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low propensity for systemic dissemination or fatal outcome. Up to now, only few studies have investigated underlying molecular alterations of PCFBCL with respect to somatic mutations. Objectives: Our aim was to gain deeper insight into the pathogenesis of PCFBCL and to delineate discriminatory molecular features of this lymphoma subtype. Methods: We performed hybridization-based panel sequencing of 40 lymphoma-associated genes of 10 cases of well-characterized PCFBCL. In addition, we included two further ambiguous cases of atypical B-cell-rich lymphoid infiltrate/B-cell lymphoma of the skin for which definite subtype attribution had not been possible by routine investigations. Results: In 10 out of 12 analyzed cases, we identified genetic alterations within 15 of the selected 40 target genes. The most frequently detected alterations in PCFBCL affected the TNFRSF14, CREBBP, STAT6 and TP53 genes. Our analysis unrevealed novel mutations of the BCL2 gene in PCFBCL. All patients exhibited an indolent clinical course. Both the included arbitrary cases of atypical B-cell-rich cutaneous infiltrates showed somatic mutations within the FAS gene. As these mutations have previously been designated as subtype-specific recurrent alterations in primary cutaneous marginal zone lymphoma (PCMZL), we finally favored the diagnosis of PCMZL in these two cases based on these molecular findings. Conclusions: To conclude, our molecular data support that PCFBCL shows distinct somatic mutations which may aid to differentiate PCFBCL from pseudo-lymphoma as well as from other indolent and aggressive cutaneous B-cell lymphomas. While the detected genetic alterations of PCFBCL did not turn out to harbor any prognostic value in our cohort, our molecular data may add adjunctive discriminatory features for diagnostic purposes on a molecular level. KW - B-cell lymphoma KW - primary cutaneous follicular B-cell lymphoma KW - targeted sequencing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290330 SN - 2072-6694 VL - 14 IS - 21 ER - TY - JOUR A1 - Haist, Maximilian A1 - Stege, Henner A1 - Lang, Berenice Mareen A1 - Tsochataridou, Aikaterini A1 - Salzmann, Martin A1 - Mohr, Peter A1 - Schadendorf, Dirk A1 - Ugurel, Selma A1 - Placke, Jan-Malte A1 - Weichenthal, Michael A1 - Gutzmer, Ralf A1 - Leiter, Ulrike A1 - Kaatz, Martin A1 - Haferkamp, Sebastian A1 - Berking, Carola A1 - Heppt, Markus A1 - Tschechne, Barbara A1 - Schummer, Patrick A1 - Gebhardt, Christoffer A1 - Grabbe, Stephan A1 - Loquai, Carmen T1 - Response to first-line treatment with immune-checkpoint inhibitors in patients with advanced cutaneous squamous cell carcinoma: a multicenter, retrospective analysis from the German ADOReg registry JF - Cancers N2 - Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates. KW - advanced cutaneous squamous cell carcinoma KW - checkpoint inhibitor therapy KW - cemiplimab KW - immunosuppression KW - response durability KW - real-world data Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297506 SN - 2072-6694 VL - 14 IS - 22 ER - TY - THES A1 - Fusi, Lorenza T1 - Crosstalk between the MEK5/ERK5 and PKB/FoxO pathways: underlying mechanism and its relevance for vasoprotection and tumorigenesis T1 - Interaktion zwischen dem MEK5/ERK5-Signalweg und der PKB/FoxO Signalkaskade: zugrunde liegender Mechanismus und seine Relevanz für Gefäßerhalt und Tumorgenese N2 - Forkhead box O transcription factors are a family of proteins involved in cellular processes downstream of the Insulin-PI3K-PKB pathway. In response to extra- or intracellular stresses, for example starvation or oxidative stress, FoxOs are required to direct cell cycle progression and apoptosis. In endothelial cells, they induce apoptosis, and their deregulation is linked to diseases involving the insulin pathway, such as diabetes. FoxOs also exhibit a complex role in tumour transformation: here their main function is to suppress tumorigenesis. In both physiological and cancer contexts, FoxO activation leads to the transcription of some general targets, such as p27kip1 or IGFBP1. The FoxOs can also induce tissue-specific genes, as ANGPT2 and BIM in the endothelium. In endothelial cells, another pathway with a pivotal function is the MEK5/ERK5 MAPK signalling way. Its activation promotes cell survival and proliferation in stressful conditions, e.g., when blood vessels are exposed to the shear forces exerted by the blood stream. Furthermore, recent data described ERK5 as a kinase directing tumour resistance upon therapy-induced stress. Comparing their reported roles in various tumours and in the endothelium, FoxO proteins and the MEK5/ERK5 MAPK cascade appear to exert opposite functions. First non-published data confirmed the hypothesis that FoxO factors are subject to a negative modulation by the MEK5/ERK5 pathway. Hence, one goal of this PhD project was to further characterise this crosstalk at molecular level. The major mechanism of FoxO regulation is the balance among several post translational modifications, such as phosphorylation, acetylation, and ubiquitination. Most importantly, the PKB dependent phosphorylation of FoxOs negatively controls their activity, and it is critical for their subcellular localization. Therefore, the regulation of FoxO localization as mechanism of ERK5 dependent suppression was studied, but the results presented in this thesis argue against this hypothesis. However, additional experiments are required to explore the impact of ERK5 activity on FoxO post-translational modifications. FoxO activity can also be modulated by the interaction with other proteins, which in turn could explain general- and tissue-specific gene expression. Thus, another objective of this work was to investigate FoxO3-interactome in endothelial cells and the impact of MEK5/ERK5 activation on it. As published in (Fusi et al. 2022) and presented here, this analysis unveiled TRRAP as new FoxO bound protein in several cell types. Moreover, the interaction did not rely on the capacity of the FoxOs to bind their consensus DNA sequences at the promoter of target genes. Functional data demonstrated that TRRAP is required for FoxO-dependent gene transcription in endothelial and osteosarcoma cells. In addition, TRRAP expression in the endothelium is important for FoxO induced apoptosis. In summary, the interaction between FoxO factors and TRRAP revealed a new regulatory mechanism of FoxO-dependent gene transcription. It remains to be analysed whether the MEK5/ERK5 cascade may exert its suppressive effect on FoxO activity by interfering with their binding to TRRAP and whether such a mechanism may be relevant for tumorigenesis. N2 - Forkhead-Box-O-Proteine sind eine Familie von Transkriptionsfaktoren, die an verschiedenen zellulären Prozessen stromabwärts des Insulin-PI3K-PKB-Signalwegs beteiligt sind. Als Reaktion auf extra- oder intrazelluläre Stressfaktoren, wie Wachstumsfaktorentzug oder oxidativen Stress, werden die FoxOs benötigt, um Zellzyklusprogression und Apoptose zu regulieren. In Endothelzellen induzieren sie Apoptose und ihre Fehlregulation ist mit Krankheiten, bei denen der Insulinsignalweg involviert ist, wie etwa Diabetes mellitus, verbunden. FoxOs spielen auch eine komplexe Rolle bei der Tumortransformation: Hier besteht ihre Hauptfunktion darin, die Tumorentstehung zu unterdrücken. Sowohl im physiologischen als auch im Kontext von Krebs führt die FoxO-Aktivierung zur Transkription verschiedener allgemeiner Zielgene, wie p27kip1, BIM oder IGFBP1. Die FoxOs können aber auch gewebespezifische Gene, wie zum Beispiel ANGPT2 im Endothel, induzieren. Ein weiterer Signalweg mit wichtiger Funktion in Endothelzellen ist der MEK5/ERK5-MAPK Signalweg. Seine Aktivierung fördert das Überleben und Wachstum von Zellen unter Stressbedingungen, wie z. B. wenn Blutgefäße durch den Blutstrom Schubspannungskräften ausgesetzt sind. Darüber hinaus zeigen neuere Daten, dass ERK5 auch an der Tumorresistenzentwicklung unter therapieinduziertem Stress beteiligt ist. Ein Vergleich der bekannten Rolle beider Signalwege im Endothel und bei der Tumorgenese, impliziert eine mutmaßlich gegensätzliche Funktion von FoxO Proteinen und der MEK5/ERK5-MAPK Kaskade. Erste unveröffentlichte Daten stützen die Hypothese, dass FoxO Faktoren einer Negativregulation durch MEK5/ERK5 unterliegen. Ein Ziel dieses Promotionsprojekts, war es daher diesen Zusammenhang auf molekularer Ebene näher zu charakterisieren. Die FoxO-Regulierung ist primär das Zusammenspiel mehrerer posttranslationaler Modifikationen wie Phosphorylierung, Acetylierung und Ubiquitinierung. Der wichtigste Regulationsmechanismus ist dabei die inhibitorische Phosphorylierung durch die Kinase PKB, welche die transkriptionelle FoxO-Aktivität hemmt und deren subzelluläre Lokalisierung ins Zytoplama fördert. Daher wurde zunächst der Einfluss von ERK5 auf die FoxO-Lokalisierung untersucht. Die Daten dieser Arbeit sprechen gegen einen Einfluss von der ERK5 Aktivität auf FoxO Lokalisation, doch sind zusätzliche Experimente erforderlich, um dessen Wirkung auf das Muster der posttranslationalen Modifikation der FoxOs zu klären. FoxO-Aktivität kann auch durch die Interaktion mit anderen Proteinen moduliert werden, die wiederum auch die allgemeine und gewebespezifische Genexpression steuern könnten. Ein weiteres Ziel dieser Arbeit war es daher, das FoxO3-Interaktom in Endothelzellen und den Einfluss forcierter MEK5/ERK5-Aktivierung darauf zu untersuchen. Wie in (Fusi et al. 2022) gezeigt und hier vorgestellt, führte diese Analyse zur Identifikation von TRRAP als neuem generellen FoxO Bindepartner. Die zelltypunabhängige Interaktion beider Proteine beruhte dabei nicht auf der Fähigkeit der FoxOs direkt an ihre Konsensus-DNA-Sequenzen in den Promotoren ihrer Zielgene zu binden. Funktionelle Daten zeigten nachfolgend, dass TRRAP entscheidend zur FoxO abhängigen Gentranskription in Endothel- und Osteosarkomzellen beiträgt. Darüber hinaus ist TRRAP im Endothel für die effiziente Apoptoseinduktion durch FoxOs wichtig. Zusammenfassend offenbarte die Interaktion zwischen FoxO-Faktoren und TRRAP einen neuen Regulationsmechanismus der FoxO-abhängigen Gentranskription. Es bleibt zu prüfen, ob die MEK5/ERK5 Kaskade FoxOs dadurch hemmt, dass sie die Bindungsfähigkeit von FoxO an TRRAP stört, und ob die beobachtete FoxO-TRRAP Interaktion auch im Kontext der Tumorgenese von Bedeutung ist. KW - Endothel KW - MAP-Kinase KW - Apoptosis KW - FoxO transcription factors KW - MEK5/ERK5 cascade KW - TRRAP KW - Crosstalk KW - Forkhead-Box-Proteine KW - Endothelium KW - Forkhead Transcription Factors Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-296769 ER - TY - JOUR A1 - Schön, Michael P. A1 - Berking, Carola A1 - Biedermann, Tilo A1 - Buhl, Timo A1 - Erpenbeck, Luise A1 - Eyerich, Kilian A1 - Eyerich, Stefanie A1 - Ghoreschi, Kamran A1 - Goebeler, Matthias A1 - Ludwig, Ralf J. A1 - Schäkel, Knut A1 - Schilling, Bastian A1 - Schlapbach, Christoph A1 - Stary, Georg A1 - von Stebut, Esther A1 - Steinbrink, Kerstin T1 - COVID‐19 and immunological regulations – from basic and translational aspects to clinical implications JF - JDDG: Journal der Deutschen Dermatologischen Gesellschaft N2 - The COVID‐19 pandemic caused by SARS‐CoV‐2 has far‐reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS‐CoV‐2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS‐CoV‐2/COVID‐19 with mediators of the acute phase of inflammation (TNF, IL‐1, IL‐6), type 1 and type 17 immune responses (IL‐12, IL‐23, IL‐17, IL‐36), type 2 immune reactions (IL‐4, IL‐13, IL‐5, IL‐31, IgE), B‐cell immunity, checkpoint regulators (PD‐1, PD‐L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non‐specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte‐mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS‐CoV‐2/COVID‐19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID‐19 pandemic; some even appear to alleviate COVID‐19. KW - COVID-19 KW - SARS-CoV-2 KW - immunology Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218205 VL - 18 IS - 8 SP - 795 EP - 807 ER - TY - JOUR A1 - Baur, Johannes A1 - Mathe, Katrin A1 - Gesierich, Anja A1 - Weyandt, Gerhard A1 - Wiegering, Armin A1 - Germer, Christoph-Thomas A1 - Gasser, Martin A1 - Pelz, Jörg O. W. T1 - Morbidity and oncologic outcome after saphenous vein-sparing inguinal lymphadenectomy in melanoma patients JF - World Journal of Surgical Oncology N2 - Background: Inguinal lymph node dissection (LND) is a surgical procedure with a high morbidity rate. Variations in surgical procedure, such as sparing of the saphenous vein, have been proposed to reduce surgical morbidity. While sparing of the saphenous vein has shown promising results in earlier studies, data for this procedure in melanoma patients are rare. In this retrospective study, we report 10-year findings on the effects of saphenous vein-sparing LND on surgical morbidity and oncologic outcomes in melanoma patients. Methods: A retrospective analysis of melanoma patients receiving inguinal LND in our facility between 2003 and 2013 was performed. Patients were divided into two groups: the saphenous vein resection group and the vein sparing group. Surgical morbidity, including wound infection, lymphatic fistula, severe bleeding, neurological complications, and chronic lymphedema, as well as regional recurrence-free survival were investigated. Results: A total of 106 patients were included in this study; of these, the saphenous vein was spared in 41 patients (38.7%). The rate of lymphatic fistula was 51.6 vs. 48.8%, wound infection occurred in 31.3 vs. 24.4%, and patients suffered from chronic lymphedema in 30.0 vs. 26.5% in V. saphena magna resection vs. sparing group. Differences observed, however, were not significant. No difference in regional recurrence-free survival between the two study groups was detected. Conclusions: The results of our retrospective analysis could not confirm the promising results reported in earlier studies. Thus, sparing of the saphenous vein appears to be optional. KW - malignant melanoma KW - inguinal lymph node dissection KW - regional recurrence KW - V. saphena magna Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157687 VL - 15 IS - 99 ER - TY - JOUR A1 - Wendlinger, Simone A1 - Wohlfarth, Jonas A1 - Kreft, Sophia A1 - Siedel, Claudia A1 - Kilian, Teresa A1 - Dischinger, Ulrich A1 - Heppt, Markus V. A1 - Wistuba-Hamprecht, Kilian A1 - Meier, Friedegund A1 - Goebeler, Matthias A1 - Schadendorf, Dirk A1 - Gesierich, Anja A1 - Kosnopfel, Corinna A1 - Schilling, Bastian T1 - Blood eosinophils are associated with efficacy of targeted therapy in patients with advanced melanoma JF - Cancers N2 - Background: Eosinophils appear to contribute to the efficacy of immunotherapy and their frequency was suggested as a predictive biomarker. Whether this observation could be transferred to patients treated with targeted therapy remains unknown. Methods: Blood and serum samples of healthy controls and 216 patients with advanced melanoma were prospectively and retrospectively collected. Freshly isolated eosinophils were phenotypically characterized by flow cytometry and co-cultured in vitro with melanoma cells to assess cytotoxicity. Soluble serum markers and peripheral blood counts were used for correlative studies. Results: Eosinophil-mediated cytotoxicity towards melanoma cells, as well as phenotypic characteristics, were similar when comparing healthy donors and patients. However, high relative pre-treatment eosinophil counts were significantly associated with response to MAPKi (p = 0.013). Eosinophil-mediated cytotoxicity towards melanoma cells is dose-dependent and requires proximity of eosinophils and their target in vitro. Treatment with targeted therapy in the presence of eosinophils results in an additive tumoricidal effect. Additionally, melanoma cells affected eosinophil phenotype upon co-culture. Conclusion: High pre-treatment eosinophil counts in advanced melanoma patients were associated with a significantly improved response to MAPKi. Functionally, eosinophils show potent cytotoxicity towards melanoma cells, which can be reinforced by MAPKi. Further studies are needed to unravel the molecular mechanisms of our observations. KW - melanoma KW - eosinophils KW - biomarker Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275137 SN - 2072-6694 VL - 14 IS - 9 ER - TY - JOUR A1 - Køllgaard, Tania A1 - Ugurel-Becker, Selma A1 - Idorn, Manja A1 - Andersen, Mads Hald A1 - Becker, Jürgen C. A1 - Straten, Per thor T1 - Pre-Vaccination Frequencies of Th17 Cells Correlate with Vaccine-Induced T-Cell Responses to Survivin-Derived Peptide Epitopes JF - PLoS One N2 - Various subsets of immune regulatory cells are suggested to influence the outcome of therapeutic antigen-specific anti-tumor vaccinations. We performed an exploratory analysis of a possible correlation of pre-vaccination Th17 cells, MDSCs, and Tregs with both vaccination-induced T-cell responses as well as clinical outcome in metastatic melanoma patients vaccinated with survivin-derived peptides. Notably, we observed dysfunctional Th1 and cytotoxic T cells, i.e. down-regulation of the CD3\(\zeta\)chain (p=0.001) and an impaired IFN\(\gamma\)-production (p=0.001) in patients compared to healthy donors, suggesting an altered activity of immune regulatory cells. Moreover, the frequencies of Th17 cells (p=0.03) and Tregs (p=0.02) were elevated as compared to healthy donors. IL-17-secreting CD4\(^{+}\) T cells displayed an impact on the immunological and clinical effects of vaccination: Patients characterized by high frequencies of Th17 cells at pre-vaccination were more likely to develop survivin-specific T-cell reactivity post-vaccination (p=0.03). Furthermore, the frequency of Th17 (p=0.09) and Th17/IFN\(\gamma\)\(^{+}\) (p=0.19) cells associated with patient survival after vaccination. In summary, our explorative, hypothesis-generating study demonstrated that immune regulatory cells, in particular Th17 cells, play a relevant role for generation of the vaccine-induced anti-tumor immunity in cancer patients, hence warranting further investigation to test for validity as predictive biomarkers. KW - suppressor cells KW - melanoma patients KW - patient survival KW - cancer patients KW - Th17 KW - tumor immunity KW - blood Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151509 VL - 10 IS - 7 ER - TY - JOUR A1 - Buhl, Timo A1 - Beissert, Stefan A1 - Gaffal, Evelyn A1 - Goebeler, Matthias A1 - Hertl, Michael A1 - Mauch, Cornelia A1 - Reich, Kristian A1 - Schmidt, Enno A1 - Schön, Michael P. A1 - Sticherling, Michael A1 - Sunderkötter, Cord A1 - Traidl‐Hoffmann, Claudia A1 - Werfel, Thomas A1 - Wilsman‐Theis, Dagmar A1 - Worm, Margitta T1 - COVID‐19 and implications for dermatological and allergological diseases JF - JDDG: Journal der Deutschen Dermatologischen Gesellschaft N2 - COVID‐19, caused by the coronavirus SARS‐CoV‐2, has become pandemic. A further level of complexity opens up as soon as we look at diseases whose pathogenesis and therapy involve different immunological signaling pathways, which are potentially affected by COVID‐19. Medical treatments must often be reassessed and questioned in connection with this infection. This article summarizes the current knowledge of COVID‐19 in the light of major dermatological and allergological diseases. It identifies medical areas lacking sufficient data and draws conclusions for the management of our patients during the pandemic. We focus on common chronic inflammatory skin diseases with complex immunological pathogenesis: psoriasis, eczema including atopic dermatitis, type I allergies, autoimmune blistering and inflammatory connective tissue diseases, vasculitis, and skin cancers. Since several other inflammatory skin diseases display related or comparable immunological reactions, clustering of the various inflammatory dermatoses into different disease patterns may help with therapeutic decisions. Thus, following these patterns of skin inflammation, our review may supply treatment recommendations and thoughtful considerations for disease management even beyond the most frequent diseases discussed here. KW - COVID-19 KW - dermatology KW - allergies Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-217860 VL - 18 IS - 8 SP - 815 EP - 824 ER - TY - JOUR A1 - Glutsch, Valerie A1 - Amaral, Teresa A1 - Garbe, Claus A1 - Thoms, Kai-Martin A1 - Mohr, Peter A1 - Hauschild, Axel A1 - Schilling, Bastian T1 - Indirect Comparison of Combined BRAF and MEK Inhibition in Melanoma Patients with Elevated Baseline Lactate Dehydrogenase JF - Acta Dermato-Venereologica N2 - The approval of BRAF and MEK inhibitors has signifi-cantly improved treatment outcomes for patients with BRAF-mutated metastatic melanoma. The 3 first-line targeted therapy trials have provided similar results, and thus the identification of predictive biomarkers may generate a more precise basis for clinical deci-sion-making. Elevated baseline lactate dehydrogenase (LDH) has already been determined as a strong prog-nostic factor. Therefore, this indirect analysis compa-red subgroups with elevated baseline LDH across the pivotal targeted therapy trials co-BRIM, COMBI-v and COLUMBUS part 1. The Bucher method was used to compare progression-free survival, objective response rate and overall survival indirectly. The results show a non-significant risk reduction for progression in the subgroup with elevated baseline LDH receiving vemu-rafenib plus cobimetinib compared with dabrafenib plus trametinib and encorafenib plus binimetinib. Al-though an indirect comparison, these data might pro-vide some guidance for treatment recommendations in melanoma patients with elevated LDH. KW - melanoma KW - BRAF KW - lactate dehydrogenase Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230190 VL - 100 ER - TY - JOUR A1 - Benoit, Sandrine A1 - Scheurlen, Michael A1 - Goebeler, Matthias A1 - Stoevesandt, Johanna T1 - Structured diagnostic approach and risk assessment in mucous membrane pemphigoid with oesophageal involvement JF - Acta Dermato-Venereologica N2 - Oesophageal involvement in mucous membrane pemphigoid is considered rare, but it may be underdiagnosed. To assess the incidence of oesophageal involvement in a group of patients with newly diagnosed mucous membrane pemphigoid we retrospectively analysed the medical records of 30 consecutive patients with mucous membrane pemphigoid diagnosed between 2006 and 2016 at the Department of Dermatology, University Hospital Würzburg. Twenty-one patients (70%) reported symptoms indicative of oesophageal mucous membrane pemphigoid. Twelve patients (40%) underwent oesophagogastroduodenoscopy, and oesophageal pathology compatible with mucous membrane pemphigoid was endoscopically found in 9 cases (30%). In all patients indirect and direct immunofluorescence were performed. Patients with and without oesophageal involvement did not differ with regard to the results of indirect immunofluorescence on salt-split human skin and monkey oesophagus. Study results demonstrate the necessity of a standardized diagnostic work-up, including adequate tissue samples for direct immunofluorescence, to prevent underdiagnosis of oesophageal mucous membrane pemphigoid. KW - cicatricial pemphigoid KW - mucous membrane pemphigoid KW - oesophagogastroduodenoscopy KW - laminin 332 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176191 VL - 98 ER - TY - JOUR A1 - Halfmann, Marie A1 - Castioni, Noah A1 - Wetzel, Lea A1 - Koopmann, Anne A1 - König, Sarah A1 - Schmieder, Astrid T1 - Effects of the COVID-19 pandemic on the mental health of medical students and young physicians in Germany: Gender-specific results of an online survey JF - Heliyon N2 - Background Healthcare workers and medical students faced new challenges during the COVID-19 pandemic. Processes within many hospitals were completely disrupted. In addition, the face to face teaching of medical students was drastically reduced. Those at risk of developing mental health problems appear to be younger health care workers and women. Objective To investigate potential COVID-19 pandemic-related gender differences in psychological distress among medical students and physicians in their first years of practice. Design and setting An anonymous survey was carried out online between December 1, 2021, and March 31, 2022, at the Mannheim Medical Faculty and the Würzburg Medical Faculty, Germany, after obtaining informed consent. Primary outcome measures were changes in anxiety and depression symptoms using the Hospital Anxiety and Depression Scale (HADS), and changes in participants' current quality of life using the WHO Quality of Life BREF. Results The results show wave-like courses for perceived anxiety and burden overlapping with the course of the COVID-19 incidence. In comparison to men, women showed a significant higher increase in HADS (p = 0.005) and a reduced life quality (p = 0.007) after COVID-19. Both sexes showed different frequencies of the factors influencing quality of life, with the presence of a previous mental illness and mean anxiety having a significant higher negative impact in women. Conclusion Future and young female physicians reported a disproportionate higher burden during COVID-19 compared to their male colleges. These observations suggest an increased need for support and prevention efforts especially in this vulnerable population. KW - mental health KW - Covid-19 KW - medical students KW - sex differences Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350502 SN - 2405-8440 VL - 10 IS - 1 ER - TY - JOUR A1 - Houben, Roland T1 - Reduced frequency of migraine attacks following coronavirus disease 2019: a case report JF - Journal of Medical Case Reports N2 - Background Severe acute respiratory syndrome coronavirus 2 is a virus affecting different organs and causing a wide variety and severity of symptoms. Headache as well as loss of smell and taste are the most frequently reported neurological manifestations of coronavirus disease 2019 induced by severe acute respiratory syndrome coronavirus 2. Here we report on a patient with chronic migraine and medication overuse headache, who experienced remarkable mitigation of migraine following coronavirus disease 2019. Case presentation For many years prior to the severe acute respiratory syndrome coronavirus 2 infection, a 57-year-old Caucasian male suffered from very frequent migraine attacks and for control of headaches he had been taking triptans almost daily. In the 16-month period before the outbreak of coronavirus disease 2019, triptan was taken 98% of the days with only a 21-day prednisolone-supported triptan holiday, which, however, had no longer-lasting consequences on migraine frequency. Upon severe acute respiratory syndrome coronavirus 2 infection, the patient developed only mild symptoms including fever, fatigue, and headache. Directly following recovery from coronavirus disease 2019, the patient surprisingly experienced a period with largely reduced frequency and severity of migraine attacks. Indeed, during 80 days following coronavirus disease 2019, migraine as well as triptan usage were restricted to only 25% of the days, no longer fulfilling criteria of a chronic migraine and medication overuse headache. Conclusion Severe acute respiratory syndrome coronavirus 2 infection might be capable of triggering mitigation of migraine. KW - migraine KW - triptan KW - severe acute respiratory syndrome coronavirus 2 KW - coronavirus disease 2019 KW - case report Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357327 VL - 17 ER - TY - JOUR A1 - Huttelmaier, Johanna A1 - Benoit, Sandra A1 - Goebeler, Matthias T1 - Comorbidity in bullous pemphigoid: up-date and clinical implications JF - Frontiers in Immunology N2 - Bullous pemphigoid is the most common autoimmune blistering disease in industrialized countries and particularly affects the elderly. In this patient population, comorbid diseases are frequent and may complicate management and treatment of bullous pemphigoid. A better understanding why distinct diseases are more frequent in bullous pemphigoid patients may lead to new pathophysiological insights and - as a consequence - result in better patient care. The association of bullous pemphigoid with neurological and psychiatric diseases is well known and confirmed by several case-control studies. Association with further diseases such as malignancy and metabolic diseases are still discussed controversially. In recent years new relationships between bullous pemphigoid and autoimmune as well as inflammatory skin diseases have been reported. This review provides a systematic overview on studies addressing comorbidity in bullous pemphigoid patients. Increasing the awareness of both, common and rare comorbid diseases, may enable clinicians to optimize patient support and individualized treatment of bullous pemphigoid. KW - bullous pemphigoid KW - autoimmune skin blistering disease KW - comorbidity KW - neurologic disease KW - metabolic disease KW - malignancy KW - inflammatory disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321671 VL - 14 ER - TY - JOUR A1 - Goebeler, M. A1 - Bata-Csörgő, Z. A1 - Simone, C. de A1 - Didona, B. A1 - Remenyik, E. A1 - Reznichenko, N. A1 - Stoevesandt, J. A1 - Ward, E. S. A1 - Parys, W. A1 - Haard, H. de A1 - Dupuy, P. A1 - Verheesen, P. A1 - Schmidt, E. A1 - Joly, P. T1 - Treatment of pemphigus vulgaris and foliaceus with efgartigimod, a neonatal Fc receptor inhibitor: a phase II multicentre, open-label feasibility trial JF - British Journal of Dermatology N2 - Background Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. Objectives To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus. Methods Thirty-four patients with mild-to-moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase II adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg kg\(^{-1}\) intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. The study is registered at ClinicalTrials.gov (identifier NCT03334058). Results Adverse events were mostly mild and were reported by 16 of 19 (84%) patients receiving efgartigimod 10 mg kg\(^{-1}\) and 13 of 15 (87%) patients receiving 25 mg kg−1, with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0·26 mg \(^{-1}\) per day (range 0·06–0·48) led to complete clinical remission in 14 of 22 (64%) patients within 2–41 weeks. Conclusions Efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus. KW - pemphigus vulgaris KW - efgartigimod KW - pemphigus foliaceus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258328 VL - 186 IS - 3 ER - TY - JOUR A1 - Paudel, Rupesh A1 - Fusi, Lorenza A1 - Schmidt, Marc T1 - The MEK5/ERK5 pathway in health and disease JF - International Journal of Molecular Sciences N2 - The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway. KW - atherosclerosis KW - bone KW - cartilage KW - endothelium KW - extracellular-regulated kinase 5 KW - Krüppel-like factor KW - mechanotransduction KW - mitogen-activated protein kinase KW - stress signaling KW - tumor Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261638 SN - 1422-0067 VL - 22 IS - 14 ER - TY - JOUR A1 - Frings, Verena Gerlinde A1 - Schöffski, Oliver A1 - Goebeler, Matthias A1 - Presser, Dagmar T1 - Economic analysis of the costs associated with Hidradenitis suppurativa at a German University Hospital JF - PLoS One N2 - Background and objectives Hidradenitis suppurativa (HS) significantly affects the patient`s quality of life and leads to multiple medical consultations. Aim of this study was to assess the utilization of medical care of HS patients. Patients and methods All patients presenting in 2017 for an outpatient, day patient and / or inpatient treatment with leading claim type HS at the Department of Dermatology, University Hospital Würzburg, were included. Primary outcome was the economic burden of HS patients, measured by resource utilization in €. Results The largest share of the direct medical costs for HS were the inpatient costs with a leading surgical diagnosis-related group (DRG). Antiseptics were the predominant topical prescription. While doxycycline was the most frequently prescribed systemic therapy, adalimumab was the main cost driver. The difference between in-patient (€ 110.25) and outpatient (€ 26.34) direct non-medical costs was statistically significant (p < 0.001). With regards to indirect medical costs, a statistically significantly higher loss of gross value added (inpatient mean € 1,827.00; outpatient mean € 203.00) and loss of production (inpatient mean € 1,026.00; outpatient mean € 228.00) could be noted (p < 0.001), respectively. Conclusions The present study on disease-specific costs of HS confirms that the hospital care of patients with this disease is cost-intensive. However, the primary goal of physicians is not and should not be to save costs regarding their patients`treatment, but rather the premise to utilize the existing resources as efficient as possible. Reducing the use of costly therapeutics and inpatient stays therefore requires more effective therapy options with an improved cost-benefit profile. KW - inpatients KW - outpatients KW - health insurance KW - dermatology KW - surgical and invasive medical procedures KW - health economics KW - psoriasis KW - indirect costs Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261668 VL - 16 IS - 8 ER - TY - JOUR A1 - Glutsch, Valerie A1 - Wobser, Marion A1 - Schilling, Bastian A1 - Gesierich, Anja A1 - Goebeler, Matthias A1 - Kneitz, Hermann T1 - PRAME expression as helpful immunohistochemical marker in rhabdoid melanoma JF - Dermatopathology N2 - Background: Rhabdoid melanoma is a rare variant of malignant melanoma with characteristic cytomorphologic features. Due to the potential loss of conventional melanocytic markers, histopathologic diagnosis is often challenging. We hypothesize that immunostaining for PReferentially expressed Antigen in MElanoma (PRAME) might have the potential to uncover the melanocytic origin of these dedifferentiated tumors. Methods: Four cases of rhabdoid primary melanomas were assessed by immunohistochemistry for expression of PRAME and conventional melanocytic markers. Immunohistochemical expression patterns were analyzed in the rhabdoid primaries and, if available, associated metastases. Results: All four cases of rhabdoid primary melanomas showed a strong nuclear positivity for PRAME, while the expression of conventional melanocytic markers S100, MART-1, SOX-10 and HMB-45 was variable between the analyzed cases. Conclusions: In summary, we report four cases of rhabdoid primary melanoma with high to intermediate expression of PRAME despite the partial and variable loss of other melanocytic markers. Hence, PRAME might facilitate the recognition of this highly aggressive entity to avoid misdiagnosis due to histopathologic pitfalls. KW - PRAME KW - rhabdoid differentiation KW - rhabdoid melanoma KW - immunohistochemistry KW - melanocytic markers Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284115 SN - 2296-3529 VL - 9 IS - 2 SP - 148 EP - 157 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 - Wobser, Marion A1 - Goebeler, Matthias T1 - Special Issue “Cutaneous Lymphomas” JF - Cancers N2 - No abstract available KW - cutaneous lymphomas Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304180 SN - 2072-6694 VL - 15 IS - 5 ER - TY - JOUR A1 - Houben, Roland A1 - Celikdemir, Büke A1 - Kervarrec, Thibault A1 - Schrama, David T1 - Merkel cell polyomavirus: infection, genome, transcripts and its role in development of Merkel cell carcinoma JF - Cancers N2 - The best characterized polyomavirus family member, i.e., simian virus 40 (SV40), can cause different tumors in hamsters and can transform murine and human cells in vitro. Hence, the SV40 contamination of millions of polio vaccine doses administered from 1955–1963 raised fears that this may cause increased tumor incidence in the vaccinated population. This is, however, not the case. Indeed, up to now, the only polyomavirus family member known to be the most important cause of a specific human tumor entity is Merkel cell polyomavirus (MCPyV) in Merkel cell carcinoma (MCC). MCC is a highly deadly form of skin cancer for which the cellular origin is still uncertain, and which appears as two clinically very similar but molecularly highly different variants. While approximately 80% of cases are found to be associated with MCPyV the remaining MCCs carry a high mutational load. Here, we present an overview of the multitude of molecular functions described for the MCPyV encoded oncoproteins and non-coding RNAs, present the available MCC mouse models and discuss the increasing evidence that both, virus-negative and -positive MCC constitute epithelial tumors. KW - Merkel cell carcinoma KW - polyomavirus KW - T antigen Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305021 SN - 2072-6694 VL - 15 IS - 2 ER - TY - JOUR A1 - Marquardt, André A1 - Hartrampf, Philipp A1 - Kollmannsberger, Philip A1 - Solimando, Antonio G. A1 - Meierjohann, Svenja A1 - Kübler, Hubert A1 - Bargou, Ralf A1 - Schilling, Bastian A1 - Serfling, Sebastian E. A1 - Buck, Andreas A1 - Werner, Rudolf A. A1 - Lapa, Constantin A1 - Krebs, Markus T1 - Predicting microenvironment in CXCR4- and FAP-positive solid tumors — a pan-cancer machine learning workflow for theranostic target structures JF - Cancers N2 - (1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database — representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets. KW - machine learning KW - tumor microenvironment KW - immune infiltration KW - angiogenesis KW - mRNA KW - miRNA KW - transcriptome Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305036 SN - 2072-6694 VL - 15 IS - 2 ER - TY - THES A1 - Demeter, Eran T1 - Retrospektive Untersuchung zur Häufigkeit von unerwünschten immunvermittelten Ereignissen unter Immuntherapie mit Nivolumab oder Pembrolizumab bei älteren und jüngeren Patient*innen T1 - Incidence of Immune-Related Adverse Events in Older and Younger Patients Receiving Immunotherapy with Nivolumab or Pembrolizumab: A Retrospective Analysis N2 - ICIs sind inzwischen integrales Therapiemittel vieler Tumoren, selbst in nicht metastasierten Stadien. Das Management von dabei eventuell entstehenden Nebenwirkungen bleibt wichtiger Bestandteil der Therapie vor allem im fortgeschrittenen Alter. Retrospektive Untersuchungen wie unsere tragen dazu bei, das in vielen klinischen Studien unterrepräsentierte Patientenkollektiv älterer Patienten in den klinischen Alltag sowie in Therapieentscheidungen und -planungen zu integrieren. Der primäre Studienendpunkt unserer Arbeit unterstützt wichtige Erkenntnisse anderer Studien, dass irAEs insgesamt unter älteren Patienten nicht häufiger auftreten. Zwischen allen drei Altersklassen von ~55, ~70 und ~80 Jahren zeigten sich keine signifikanten Unterschiede im Auftreten von irAEs aller Grade, wobei irAEs Grad III/IV etwas häufiger bei ~80-Jährigen auftraten. In unserem Fall stellten wir fest, dass auftretende irAEs im Alter häufiger behandelt wurden, und dass die Immuntherapie häufiger pausiert oder abgebrochen wurde. Zudem war der Anteil an Therapieabbrüchen unter den älteren Patienten wegen bestimmter Ereignisse wie TRAEs und dem Einsatz von Glukokortikoiden höher als bei jüngeren Patienten. Die Ergebnisse unserer Studie deuten außerdem darauf hin, dass selbst unter Polypharmazie und Multimorbidität irAEs nicht häufiger bei Älteren auftraten. Ebenso können wir die interessante Beobachtung verzeichnen, dass Patienten mit >5 Medikamenten und gleichzeitig >5 Erkrankungen signifikant mehr irAEs Grad III/IV aufwiesen oder mehr Patienten Glukokortikoide verabreicht bekommen haben. Auch der Anteil an Interventionsbedarf oder Therapieabbruch war hier in allen Altersklassen höher. Es stellt sich die Frage, inwiefern hohes Alter, Komorbidität und Polypharmazie Risikofaktoren für Interventionsbedarf oder Therapieabbruch in der Immuntherapie sind, und ob ihnen eher besondere Gewichtung als Risikofaktor zukommt als dem Alter selbst. N2 - ICIs are now an important part of the treatment of many tumors, even in the non-metastatic stage. Managing potential side effects is a significant aspect of treatment, particularly for elderly patients. Retrospective studies, such as the one presented here, help to integrate the underrepresented elderly patient population in many clinical trials into clinical practice, as well as into treatment decisions and planning. The primary outcome of this study supports the important findings of previous studies showing there is no overall increased incidence of irAEs in elderly patients. There were no significant differences in the occurrence of irAEs among the three age groups (~55, ~70, and ~80 years), although irAEs grade III/IV occurred slightly more frequently in patients aged ~80 years. In our study, we found that older patients who experienced irAEs required more medical intervention and that immunotherapy was interrupted or discontinued more frequently. Additionally, older patients experienced a higher incidence of treatment discontinuation due to events such as treatment-related adverse events (TRAEs) and the use of glucocorticoids when compared to younger patients. The study findings indicate that elderly patients do not have a higher incidence of irAEs, even in cases of polypharmacy and multimorbidity. However, patients of all age groups who were taking more than five medications and had more than five comorbidities experienced a higher incidence of irAEs grade III/IV. Additionally, more patients were administered glucocorticoids and had higher treatment discontinuation rates. The question arises as to whether advanced age, comorbidity and polypharmacy are more significant risk factors for discontinuing immunotherapy or medical intervention than age alone. KW - Immuntherapie KW - Ältere Patienten KW - Unerwünschte immunvermittelte Ereignisse KW - IrAEs Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-352586 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 - Wobser, Marion A1 - Weber, Alexandra A1 - Glunz, Amelie A1 - Tauch, Saskia A1 - Seitz, Kristina A1 - Butelmann, Tobias A1 - Hesbacher, Sonja A1 - Goebeler, Matthias A1 - Bartz, René A1 - Kohlhof, Hella A1 - Schrama, David A1 - Houben, Roland T1 - Elucidating the mechanism of action of domatinostat (4SC-202) in cutaneous T cell lymphoma cells JF - Journal of Hematology & Oncology N2 - Background Targeting epigenetic modifiers is effective in cutaneous T cell lymphoma (CTCL). However, there is a need for further improvement of this therapeutic approach. Here, we compared the mode of action of romidepsin (FK228), an established class I histone deacetylase inhibitor, and domatinostat (4SC-202), a novel inhibitor of class I HDACs, which has been reported to also target the lysine-specific histone demethylase 1A (LSD1). Methods We performed MTS assays and flow cytometric analyses of propidium iodide or annexin V-stained cells to assess drug impact on cellular proliferation, cell cycle distribution, and survival. Histone acetylation and methylation as well as caspase activation was analyzed by immunoblot. Gene expression analysis was performed using NanosString technology. Knockdown and knockout of LSD1 was achieved with shRNA and CRISPR/Cas9, respectively, while the CRISPR/Cas9 synergistic activation mediator system was used to induce expression of endogenous HDACs and LSD1. Furthermore, time-lapse fluorescence microscopy and an in vitro tubulin polymerization assay were applied. Results While FK228 as well as 4SC-202 potently induced cell death in six different CTCL cell lines, only in the case of 4SC-202 death was preceded by an accumulation of cells in the G2/M phase of the cell cycle. Surprisingly, apoptosis and accumulation of cells with double DNA content occurred already at 4SC-202 concentrations hardly affecting histone acetylation and methylation, and provoking significantly less changes in gene expression compared to biologically equivalent doses of FK228. Indeed, we provide evidence that the 4SC-202-induced G2/M arrest in CTCL cells is independent of de novo transcription. Furthermore, neither enforced expression of HDAC1 nor knockdown or knockout of LSD1 affected the 4SC-202-induced effects. Since time-lapse microscopy revealed that 4SC-202 could affect mitotic spindle formation, we performed an in vitro tubulin polymerization assay revealing that 4SC-202 can directly inhibit microtubule formation. Conclusions We demonstrate that 4SC-202, a drug currently tested in clinical trials, effectively inhibits growth of CTCL cells. The anti-cancer cell activity of 4SC-202 is however not limited to LSD1-inhibition, modulation of histone modifications, and consecutive alteration of gene expression. Indeed, the compound is also a potent microtubule-destabilizing agent. KW - Cutaneous lymphoma KW - Epigenetic regulation KW - Histone deacetylase KW - HDAC KW - Lysine-specific methylase KW - LSD1 KW - Tubulin Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200703 VL - 12 ER -