TY - JOUR A1 - Heller, Bianca A1 - Reiter, Florian P. A1 - Leicht, Hans Benno A1 - Fiessler, Cornelia A1 - Bergheim, Ina A1 - Heuschmann, Peter U. A1 - Geier, Andreas A1 - Rau, Monika T1 - Salt-intake-related behavior varies between sexes and is strongly associated with daily salt consumption in obese patients at high risk for MASLD JF - Nutrients N2 - Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) imposes a significant burden on Westernized regions. The Western diet, high in salt intake, significantly contributes to disease development. However, there are a lack of data on salt literacy and salt intake among MASLD patients in Germany. Our study aims to analyze daily salt intake and salt-intake-related behavior in MASLD patients. Methods: 234 MASLD patients were prospectively included. Daily salt intake and salt-intake-related behavior were assessed via a food frequency questionnaire (FFQ—DEGS) and a salt questionnaire (SINU). Statistical analyses were performed using SPSS. Results: Mean daily salt intake was higher in men than in women (7.3 ± 5 g/d vs. 5.3 ± 4 g/d; p < 0.001). There was significant agreement between increased daily salt intake (6 g/d) and the behavioral salt index (SI) (p < 0.001). Men exhibited higher SI scores compared to women, indicating lower awareness of salt in everyday life. Multivariate analysis identified specific salt-intake-related behaviors impacting daily salt consumption. Conclusions: Our study reveals a strong link between daily salt intake and salt-intake-related behavior, highlighting sex-specific differences in an MASLD cohort. To enhance patient care in high-cardiovascular-risk populations, specific behavioral approaches may be considered, including salt awareness, to improve adherence to lifestyle changes, particularly in male patients. KW - MASLD KW - steatotic liver disease KW - salt consumption KW - salt-intake-related behavior Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363107 SN - 2072-6643 VL - 15 IS - 18 ER - TY - JOUR A1 - Grunz, Jan-Peter A1 - Kunz, Andreas Steven A1 - Baumann, Freerk T. A1 - Hasenclever, Dirk A1 - Sieren, Malte Maria A1 - Heldmann, Stefan A1 - Bley, Thorsten Alexander A1 - Einsele, Hermann A1 - Knop, Stefan A1 - Jundt, Franziska T1 - Assessing osteolytic lesion size on sequential CT scans is a reliable study endpoint for bone remineralization in newly diagnosed multiple myeloma JF - Cancers N2 - Multiple myeloma (MM) frequently induces persisting osteolytic manifestations despite hematologic treatment response. This study aimed to establish a biometrically valid study endpoint for bone remineralization through quantitative and qualitative analyses in sequential CT scans. Twenty patients (seven women, 58 ± 8 years) with newly diagnosed MM received standardized induction therapy comprising the anti-SLAMF7 antibody elotuzumab, carfilzomib, lenalidomide, and dexamethasone (E-KRd). All patients underwent whole-body low-dose CT scans before and after six cycles of E-KRd. Two radiologists independently recorded osteolytic lesion sizes, as well as the presence of cortical destruction, pathologic fractures, rim and trabecular sclerosis. Bland–Altman analyses and Krippendorff’s α were employed to assess inter-reader reliability, which was high for lesion size measurement (standard error 1.2 mm) and all qualitative criteria assessed (α ≥ 0.74). After six cycles of E-KRd induction, osteolytic lesion size decreased by 22% (p < 0.001). While lesion size response did not correlate with the initial lesion size at baseline imaging (Pearson’s r = 0.144), logistic regression analysis revealed that the majority of responding osteolyses exhibited trabecular sclerosis (p < 0.001). The sum of osteolytic lesion sizes on sequential CT scans defines a reliable study endpoint to characterize bone remineralization. Patient level response is strongly associated with the presence of trabecular sclerosis. KW - multiple myeloma KW - bone remineralization KW - computed tomography KW - whole-body imaging Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-362526 SN - 2072-6694 VL - 15 IS - 15 ER - TY - JOUR A1 - Göpfert, Dennis A1 - Traub, Jan A1 - Sell, Roxane A1 - Homola, György A. A1 - Vogt, Marius A1 - Pham, Mirko A1 - Frantz, Stefan A1 - Störk, Stefan A1 - Stoll, Guido A1 - Frey, Anna T1 - Profiles of cognitive impairment in chronic heart failure—A cluster analytic approach JF - Frontiers in Human Neuroscience N2 - Background Cognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits. Methods The prospective cohort study “Cognition.Matters-HF” recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing. Results Dendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4%). A third cluster with 50 patients (34.0%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the “global deficits” cluster and the “no deficits” group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048). Conclusion Apart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition. KW - chronic heart failure KW - cluster analysis KW - cognitive impairment KW - intensity of attention KW - glial fibrillary acidic protein Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313429 VL - 17 ER - TY - JOUR A1 - Froehlich, Matthias A1 - Zahner, Antonia A1 - Schmalzing, Marc A1 - Gernert, Michael A1 - Strunz, Patrick-Pascal A1 - Hueper, Sebastian A1 - Portegys, Jan A1 - Schwaneck, Eva Christina A1 - Gadeholt, Ottar A1 - Kübler, Andrea A1 - Hewig, Johannes A1 - Ziebell, Philipp T1 - Patient-reported outcomes provide evidence for increased depressive symptoms and increased mental impairment in giant cell arteritis JF - Frontiers in Medicine N2 - Objectives The spectrum of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) represents highly inflammatory rheumatic diseases. Patients mostly report severe physical impairment. Possible consequences for mental health have been scarcely studied. The aim of this study was to investigate psychological well-being in the context of GCA and PMR. Methods Cross-sectional study with N = 100 patients with GCA and/or PMR (GCA-PMR). Patient-reported outcomes (PROs) were measured using the Short Form 36 Version 2 (SF-36v2) and visual analog scale (VAS) assessment. Moreover, the Patient Health Questionnaire 9 (PHQ-9) was used in 35 of 100 patients to detect depression. To compare PROs with physician assessment, VAS was also rated from physician perspective. To assess a possible association with inflammation itself, serological parameters of inflammation (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]) were included. Results In all scales of the SF-36v2 except General Health (GH) and in the physical and mental sum score (PCS, MCS), a significant impairment compared to the German reference collective was evident (MCS: d = 0.533, p < 0.001). In the PHQ-9 categorization, 14 of the 35 (40%) showed evidence of major depression disorder. VAS Patient correlated significantly with PHQ-9 and SF-36 in all categories, while VAS Physician showed only correlations to physical categories and not in the mental dimensions. Regarding inflammatory parameters, linear regression showed CRP to be a complementary significant positive predictor of mental health subscale score, independent of pain. Conclusion PRO show a relevant impairment of mental health up to symptoms of major depression disorder. The degree of depressive symptoms is also distinctly associated with the serological inflammatory marker CRP. KW - giant cell arteritis KW - PRO KW - depression KW - mental impairment KW - SF-36 KW - PHQ-9 KW - VAS KW - polymyalgia rheumatica Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319761 VL - 10 ER - TY - JOUR A1 - Elgheznawy, Amro A1 - Öftering, Patricia A1 - Englert, Maximilian A1 - Mott, Kristina A1 - Kaiser, Friederike A1 - Kusch, Charly A1 - Gbureck, Uwe A1 - Bösl, Michael R. A1 - Schulze, Harald A1 - Nieswandt, Bernhard A1 - Vögtle, Timo A1 - Hermanns, Heike M. T1 - Loss of zinc transporters ZIP1 and ZIP3 augments platelet reactivity in response to thrombin and accelerates thrombus formation in vivo JF - Frontiers in Immunology N2 - Zinc (Zn2+) is considered as important mediator of immune cell function, thrombosis and haemostasis. However, our understanding of the transport mechanisms that regulate Zn2+ homeostasis in platelets is limited. Zn2+ transporters, ZIPs and ZnTs, are widely expressed in eukaryotic cells. Using mice globally lacking ZIP1 and ZIP3 (ZIP1/3 DKO), our aim was to explore the potential role of these Zn2+ transporters in maintaining platelet Zn2+ homeostasis and in the regulation of platelet function. While ICP-MS measurements indicated unaltered overall Zn2+ concentrations in platelets of ZIP1/3 DKO mice, we observed a significantly increased content of FluoZin3-stainable free Zn2+, which, however, appears to be released less efficiently upon thrombin-stimulated platelet activation. On the functional level, ZIP1/3 DKO platelets exhibited a hyperactive response towards threshold concentrations of G protein-coupled receptor (GPCR) agonists, while immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptor agonist signalling was unaffected. This resulted in enhanced platelet aggregation towards thrombin, bigger thrombus volume under flow ex vivo and faster in vivo thrombus formation in ZIP1/3 DKO mice. Molecularly, augmented GPCR responses were accompanied by enhanced Ca2+ and PKC, CamKII and ERK1/2 signalling. The current study thereby identifies ZIP1 and ZIP3 as important regulators for the maintenance of platelet Zn2+ homeostasis and function. KW - platelets KW - zinc KW - ZIP KW - thrombin KW - signaling KW - thrombosis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320154 VL - 14 ER - TY - JOUR A1 - Zaitseva, Olena A1 - Hoffmann, Annett A1 - Löst, Margaretha A1 - Anany, Mohamed A. A1 - Zhang, Tengyu A1 - Kucka, Kirstin A1 - Wiegering, Armin A1 - Otto, Christoph A1 - Wajant, Harald T1 - Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity JF - Frontiers in Immunology N2 - Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK. KW - agonistic antibodies KW - cell death KW - FcγR KW - Fn14 KW - NFκB KW - TNF receptor superfamily KW - TWEAK Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323116 VL - 14 ER - TY - JOUR A1 - Lauruschkat, Chris David A1 - Muchsin, Ihsan A1 - Rein, Alice A1 - Erhard, Florian A1 - Grathwohl, Denise A1 - Dölken, Lars A1 - Köchel, Carolin A1 - Falk, Christine Susanne A1 - Einsele, Hermann A1 - Wurster, Sebastian A1 - Grigoleit, Götz Ulrich A1 - Kraus, Sabrina T1 - CD4+ T cells are the major predictor of HCMV control in allogeneic stem cell transplant recipients on letermovir prophylaxis JF - Frontiers in Immunology N2 - Introduction Human cytomegalovirus (HCMV) causes significant morbidity and mortality in allogeneic stem cell transplant (alloSCT) recipients. Recently, antiviral letermovir prophylaxis during the first 100 days after alloSCT replaced PCR-guided preemptive therapy as the primary standard of care for HCMV reactivations. Here, we compared NK-cell and T-cell reconstitution in alloSCT recipients receiving preemptive therapy or letermovir prophylaxis in order to identify potential biomarkers predicting prolonged and symptomatic HCMV reactivation. Methods To that end, the NK-cell and T-cell repertoire of alloSCT recipients managed with preemptive therapy (n=32) or letermovir prophylaxis (n=24) was characterized by flow cytometry on days +30, +60, +90 and +120 after alloSCT. Additionally, background-corrected HCMV-specific T-helper (CD4+IFNγ+) and cytotoxic (CD8+IFNγ+CD107a+) T cells were quantified after pp65 stimulation. Results Compared to preemptive therapy, letermovir prophylaxis prevented HCMV reactivation and decreased HCMV peak viral loads until days +120 and +365. Letermovir prophylaxis resulted in decreased T-cell numbers but increased NK-cell numbers. Interestingly, despite the inhibition of HCMV, we found high numbers of “memory-like” (CD56dimFcεRIγ- and/or CD159c+) NK cells and an expansion of HCMV-specific CD4+ and CD8+ T cells in letermovir recipients. We further compared immunological readouts in patients on letermovir prophylaxis with non/short-term HCMV reactivation (NSTR) and prolonged/symptomatic HCMV reactivation (long-term HCMV reactivation, LTR). Median HCMV-specific CD4+ T-cell frequencies were significantly higher in NSTR patients (day +60, 0.35 % vs. 0.00 % CD4+IFNγ+/CD4+ cells, p=0.018) than in patients with LTR, whereas patients with LTR had significantly higher median regulatory T-cell (Treg) frequencies (day +90, 2.2 % vs. 6.2 % CD4+CD25+CD127dim/CD4+ cells, p=0.019). ROC analysis confirmed low HCMV specific CD4+ (AUC on day +60: 0.813, p=0.019) and high Treg frequencies (AUC on day +90: 0.847, p=0.021) as significant predictors of prolonged and symptomatic HCMV reactivation. Discussion Taken together, letermovir prophylaxis delays HCMV reactivation and alters NK- and T-cell reconstitution. High numbers of HCMV-specific CD4+ T cells and low numbers of Tregs seem to be pivotal to suppress post-alloSCT HCMV reactivation during letermovir prophylaxis. Administration of more advanced immunoassays that include Treg signature cytokines might contribute to the identification of patients at high-risk for long-term and symptomatic HCMV reactivation who might benefit from prolonged administration of letermovir. KW - human cytomegalovirus (HCMV) KW - viral infection KW - allogeneic stem cell transplantation KW - T cells KW - NK cells Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-316982 VL - 14 ER - TY - JOUR A1 - Zaitseva, Olena A1 - Anany, Mohamed A1 - Wajant, Harald A1 - Lang, Isabell T1 - Basic characterization of antibodies targeting receptors of the tumor necrosis factor receptor superfamily JF - Frontiers in Immunology N2 - Many new immunotherapeutic approaches aim on the stimulatory targeting of receptors of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) using antibodies with intrinsic or conditional agonism. There is an initial need to characterize corresponding TNFRSF receptor (TNFR)-targeting antibodies with respect to affinity, ligand binding, receptor activation and the epitope recognized. Here, we report a collection of simple and matched protocols enabling the detailed investigation of these aspects by help of Gaussia princeps luciferase (GpL) fusion proteins and analysis of interleukin-8 (IL8) production as an easily measurable readout of TNFR activation. In a first step, the antibodies and antibody variants of interest are transiently expressed in human embryonal kidney 293 cells, either in non-modified form or as fusion proteins with GpL as a reporter domain. The supernatants containing the antibody-GpL fusion proteins can then be used without further purification in cell-free and/or cellular binding studies to determine affinity. Similarly, binding studies with mutated TNFR variants enable the characterization of the antibody binding site within the TNFR ectodomain. Furthermore, in cellular binding studies with GpL fusion proteins of soluble TNFL molecules, the ability of the non-modified antibody variants to interfere with TNFL-TNFR interaction can be analyzed. Last but not least, we describe a protocol to determine the intrinsic and the Fc gamma receptor (FcγR)-dependent agonism of anti-TNFR antibodies which exploits i) the capability of TNFRs to trigger IL8 production in tumor cell lines lacking expression of FcγRs and ii) vector- and FcγR-transfected cells, which produce no or only very low amounts of human IL8. The presented protocols only require standard molecular biological equipment, eukaryotic cell culture and plate readers for the quantification of luminescent and colorimetric signals. KW - affinity KW - agonism KW - antibody KW - FcγR KW - Gaussia princeps luciferase (GpL) KW - immunotherapy KW - TNF receptor superfamily Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311407 VL - 14 ER - TY - JOUR A1 - Staudt, Sarah A1 - Ziegler-Martin, Kai A1 - Visekruna, Alexander A1 - Slingerland, John A1 - Shouval, Roni A1 - Hudecek, Michael A1 - Van den Brink, Marcel A1 - Luu, Maik T1 - Learning from the microbes: exploiting the microbiome to enforce T cell immunotherapy JF - Frontiers in Immunology N2 - The opportunities genetic engineering has created in the field of adoptive cellular therapy for cancer are accelerating the development of novel treatment strategies using chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells. The great success in the context of hematologic malignancies has made especially CAR T cell therapy a promising approach capable of achieving long-lasting remission. However, the causalities involved in mediating resistance to treatment or relapse are still barely investigated. Research on T cell exhaustion and dysfunction has drawn attention to host-derived factors that define both the immune and tumor microenvironment (TME) crucially influencing efficacy and toxicity of cellular immunotherapy. The microbiome, as one of the most complex host factors, has become a central topic of investigations due to its ability to impact on health and disease. Recent findings support the hypothesis that commensal bacteria and particularly microbiota-derived metabolites educate and modulate host immunity and TME, thereby contributing to the response to cancer immunotherapy. Hence, the composition of microbial strains as well as their soluble messengers are considered to have predictive value regarding CAR T cell efficacy and toxicity. The diversity of mechanisms underlying both beneficial and detrimental effects of microbiota comprise various epigenetic, metabolic and signaling-related pathways that have the potential to be exploited for the improvement of CAR T cell function. In this review, we will discuss the recent findings in the field of microbiome-cancer interaction, especially with respect to new trajectories that commensal factors can offer to advance cellular immunotherapy. KW - microbiome KW - immunotherapy KW - immunology KW - cancer immune cell therapy KW - CAR T cell Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-328019 VL - 14 ER - TY - JOUR A1 - Munawar, Umair A1 - Zhou, Xiang A1 - Prommersberger, Sabrina A1 - Nerreter, Silvia A1 - Vogt, Cornelia A1 - Steinhardt, Maximilian J. A1 - Truger, Marietta A1 - Mersi, Julia A1 - Teufel, Eva A1 - Han, Seungbin A1 - Haertle, Larissa A1 - Banholzer, Nicole A1 - Eiring, Patrick A1 - Danhof, Sophia A1 - Navarro-Aguadero, Miguel Angel A1 - Fernandez-Martin, Adrian A1 - Ortiz-Ruiz, Alejandra A1 - Barrio, Santiago A1 - Gallardo, Miguel A1 - Valeri, Antonio A1 - Castellano, Eva A1 - Raab, Peter A1 - Rudert, Maximilian A1 - Haferlach, Claudia A1 - Sauer, Markus A1 - Hudecek, Michael A1 - Martinez-Lopez, J. A1 - Waldschmidt, Johannes A1 - Einsele, Hermann A1 - Rasche, Leo A1 - Kortüm, K. Martin T1 - Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma JF - Communications Biology N2 - The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM. KW - immunotherapy KW - translational research Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357609 VL - 6 ER - TY - JOUR A1 - Leonhardt, Jonas A1 - Winkler, Marcela A1 - Kollikowski, Anne A1 - Schiffmann, Lisa A1 - Quenzer, Anne A1 - Einsele, Hermann A1 - Löffler, Claudia T1 - Mind–body-medicine in oncology—from patient needs to tailored programs and interventions BT - a cross-sectional study JF - Frontiers in Psychology N2 - Introduction: National and international guidelines recommend early integration of evidence-based multimodal interventions and programs, especially with a focus on relaxation techniques and other Mind–Body-based methods to maintain the quality of life of oncology patients, improve treatment tolerability, and promote healthy lifestyle behaviors. Consequently, we aim to understand what drives patients and how they navigate integrative medicine to best advise them. This study aimed to detect possible topics of particular interest to patients and identify the patient groups that could benefit most from further programs. Furthermore, we aimed to investigate if patients are open-minded toward integrative oncology concepts and learn about their motivational level to maintain or change behavior. Methods: Between August 2019 and October 2020 we surveyed patients undergoing oncological therapy in a university oncological outpatient center using a custom-developed questionnaire based on established Mind–Body Medicine concepts. Results: We included 294 patients with various cancers. More than half reported problems sleeping through (61%) and 42% felt stressed frequently, invariably rating this as detrimental to their health. Moreover, a slight majority (52%) felt physically limited due to their disease and only 30% performed defined exercise programs. Women were significantly more likely to feel stressed and reported with alarming frequency that they often feel “everything was up to them.” The 40–65-year-olds reported significantly less restful sleep, more stress and were more dissatisfied with their situation. However, this group already used natural remedies most frequently and was most often motivated to use relaxation techniques in the next 6 months. The lower the perceived individual energy level (EL), the less frequently patients did sport, the more frequently they felt their disease impaired their activity, mostly feeling stressed and tense. We also found significant associations between negative emotions/thoughts and the variables “sleep,” “use of relaxation techniques,” “personal stress perception,” and “successful lifestyle modification.” Conclusion: Mind–Body programs that focus on patient’s individual resources, with tools to explore impairing patterns of self-perception and cognitive biases, can be a valuable resource for oncology patients and should therefore be part of an integrative medical treatment concept. KW - lifestyle habits KW - symptom burden KW - individual mind state KW - motivational level KW - stress Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321970 SN - 1664-1078 VL - 14 ER - TY - JOUR A1 - Karunakaran, Mohindar M. A1 - Subramanian, Hariharan A1 - Jin, Yiming A1 - Mohammed, Fiyaz A1 - Kimmel, Brigitte A1 - Juraske, Claudia A1 - Starick, Lisa A1 - Nöhren, Anna A1 - Länder, Nora A1 - Willcox, Carrie R. A1 - Singh, Rohit A1 - Schamel, Wolfgang W. A1 - Nikolaev, Viacheslav O. A1 - Kunzmann, Volker A1 - Wiemer, Andrew J. A1 - Willcox, Benjamin E. A1 - Herrmann, Thomas T1 - A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing JF - Nature Communications N2 - Butyrophilin (BTN)–3A and BTN2A1 molecules control the activation of human Vγ9Vδ2 T cells during T cell receptor (TCR)-mediated sensing of phosphoantigens (PAg) derived from microbes and tumors. However, the molecular rules governing PAg sensing remain largely unknown. Here, we establish three mechanistic principles of PAg-mediated γδ T cell activation. First, in humans, following PAg binding to the intracellular BTN3A1-B30.2 domain, Vγ9Vδ2 TCR triggering involves the extracellular V-domain of BTN3A2/BTN3A3. Moreover, the localization of both protein domains on different chains of the BTN3A homo-or heteromers is essential for efficient PAg-mediated activation. Second, the formation of BTN3A homo-or heteromers, which differ in intracellular trafficking and conformation, is controlled by molecular interactions between the juxtamembrane regions of the BTN3A chains. Finally, the ability of PAg not simply to bind BTN3A-B30.2, but to promote its subsequent interaction with the BTN2A1-B30.2 domain, is essential for T-cell activation. Defining these determinants of cooperation and the division of labor in BTN proteins improves our understanding of PAg sensing and elucidates a mode of action that may apply to other BTN family members. KW - gammadelta T cells KW - immunosurveillance Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358179 VL - 14 ER - TY - JOUR A1 - 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 - Herrmann, Johannes A1 - Müller, Kerstin A1 - Notz, Quirin A1 - Hübsch, Martha A1 - Haas, Kirsten A1 - Horn, Anna A1 - Schmidt, Julia A1 - Heuschmann, Peter A1 - Maschmann, Jens A1 - Frosch, Matthias A1 - Deckert, Jürgen A1 - Einsele, Hermann A1 - Ertl, Georg A1 - Frantz, Stefan A1 - Meybohm, Patrick A1 - Lotz, Christopher T1 - Prospective single-center study of health-related quality of life after COVID-19 in ICU and non-ICU patients JF - Scientific Reports N2 - Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87% and 80% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24% of non-ICU and 3% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5% of non-ICU and 10% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19. KW - health care KW - public health KW - quality of life Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357174 VL - 13 ER - TY - JOUR A1 - McFleder, Rhonda L. A1 - Makhotkina, Anastasiia A1 - Groh, Janos A1 - Keber, Ursula A1 - Imdahl, Fabian A1 - Peña Mosca, Josefina A1 - Peteranderl, Alina A1 - Wu, Jingjing A1 - Tabuchi, Sawako A1 - Hoffmann, Jan A1 - Karl, Ann-Kathrin A1 - Pagenstecher, Axel A1 - Vogel, Jörg A1 - Beilhack, Andreas A1 - Koprich, James B. A1 - Brotchie, Jonathan M. A1 - Saliba, Antoine-Emmanuel A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Brain-to-gut trafficking of alpha-synuclein by CD11c\(^+\) cells in a mouse model of Parkinson’s disease JF - Nature Communications N2 - Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson’s disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate αSyn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal αSyn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c\(^+\) cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c\(^+\) cells traffic from the brain to the ileum. Together these data provide a mechanism of αSyn trafficking between the brain and gut. KW - antigen-presenting cells KW - neuroimmunology KW - Parkinson's disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357696 VL - 14 ER - TY - JOUR A1 - Häder, Antje A1 - Schäuble, Sascha A1 - Gehlen, Jan A1 - Thielemann, Nadja A1 - Buerfent, Benedikt C. A1 - Schüller, Vitalia A1 - Hess, Timo A1 - Wolf, Thomas A1 - Schröder, Julia A1 - Weber, Michael A1 - Hünniger, Kerstin A1 - Löffler, Jürgen A1 - Vylkova, Slavena A1 - Panagiotou, Gianni A1 - Schumacher, Johannes A1 - Kurzai, Oliver T1 - Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity JF - Nature Communications N2 - Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases. KW - antimicrobial responses KW - immunogenetics Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357441 VL - 14 ER - TY - JOUR A1 - Maichl, Daniela Simone A1 - Kirner, Julius Arthur A1 - Beck, Susanne A1 - Cheng, Wen-Hui A1 - Krug, Melanie A1 - Kuric, Martin A1 - Ade, Carsten Patrick A1 - Bischler, Thorsten A1 - Jakob, Franz A1 - Hose, Dirk A1 - Seckinger, Anja A1 - Ebert, Regina A1 - Jundt, Franziska T1 - Identification of NOTCH-driven matrisome-associated genes as prognostic indicators of multiple myeloma patient survival JF - Blood Cancer Journal N2 - No abstract available. KW - cancer microenvironment KW - myeloma Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357598 VL - 13 ER - TY - JOUR A1 - Helaß, Madeleine A1 - Haag, Georg Martin A1 - Bankstahl, Ulli Simone A1 - Gencer, Deniz A1 - Maatouk, Imad T1 - Burnout among German oncologists: a cross-sectional study in cooperation with the Arbeitsgemeinschaft Internistische Onkologie Quality of Life Working Group JF - Journal of Cancer Research and Clinical Oncology N2 - Purpose Oncologists are at an increased risk of developing burnout, leading to negative consequences in patient care and in professional satisfaction and quality of life. This study was designed to investigate exhaustion and disengagement among German oncologists and assess the prevalence of burnout among oncologists within different professional settings. Furthermore, we wanted to examine possible relations between sociodemographic factors, the oncological setting, professional experience and different aspects of burnout. Methods In a cross-sectional study design, an Internet-based survey was conducted with 121 oncologists between April and July 2020 using the Oldenburg Burnout Inventory, which contains items on exhaustion, disengagement, and burnout. Furthermore, sociodemographic data of the participants were assessed. The participants were members of the Working Group Medical Oncology (Arbeitsgemeinschaft Internistische Onkologie) within the German Cancer Society. Results The survey showed a burnout prevalence of 43.8%, which correlated with age and professional experience; that is, the prevalence is particularly high among younger oncologists. Exhaustion is closely related to employment status; that is, it was significantly higher among employed oncologists. There were remarkably low levels of disengagement among oncologists, highlighting the own demand to fulfil job requirements despite imminent or actual overburdening in daily work. Conclusion More support is necessary to mitigate the professional stressors in the healthcare system. To ensure quality medical care, employees should be offered preventive mental health services early in their careers. KW - burnout KW - exhaustion KW - disengagement KW - Oldenburg burnout inventory KW - oncologist KW - prevalence Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324446 VL - 149 IS - 2 ER - TY - JOUR A1 - Guggenberger, Konstanze V. A1 - Vogt, Marius L. A1 - Song, Jae W. A1 - Weng, Andreas M. A1 - Fröhlich, Matthias A1 - Schmalzing, Marc A1 - Venhoff, Nils A1 - Hillenkamp, Jost A1 - Pham, Mirko A1 - Meckel, Stephan A1 - Bley, Thorsten A. T1 - Intraorbital findings in giant cell arteritis on black blood MRI JF - European Radiology N2 - Objective Blindness is a feared complication of giant cell arteritis (GCA). However, the spectrum of pathologic orbital imaging findings on magnetic resonance imaging (MRI) in GCA is not well understood. In this study, we assess inflammatory changes of intraorbital structures on black blood MRI (BB-MRI) in patients with GCA compared to age-matched controls. Methods In this multicenter case-control study, 106 subjects underwent BB-MRI. Fifty-six patients with clinically or histologically diagnosed GCA and 50 age-matched controls without clinical or laboratory evidence of vasculitis were included. All individuals were imaged on a 3-T MR scanner with a post-contrast compressed-sensing (CS) T1-weighted sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) BB-MRI sequence. Imaging results were correlated with available clinical symptoms. Results Eighteen of 56 GCA patients (32%) showed inflammatory changes of at least one of the intraorbital structures. The most common finding was enhancement of at least one of the optic nerve sheaths (N = 13, 72%). Vessel wall enhancement of the ophthalmic artery was unilateral in 8 and bilateral in 3 patients. Enhancement of the optic nerve was observed in one patient. There was no significant correlation between imaging features of inflammation and clinically reported orbital symptoms (p = 0.10). None of the age-matched control patients showed any inflammatory changes of intraorbital structures. Conclusions BB-MRI revealed inflammatory findings in the orbits in up to 32% of patients with GCA. Optic nerve sheath enhancement was the most common intraorbital inflammatory change on BB-MRI. MRI findings were independent of clinically reported orbital symptoms. Key Points • Up to 32% of GCA patients shows signs of inflammation of intraorbital structures on BB-MRI. • Enhancement of the optic nerve sheath is the most common intraorbital finding in GCA patients on BB-MRI. • Features of inflammation of intraorbital structures are independent of clinically reported symptoms. KW - giant cell arteritis KW - magnetic resonance imaging KW - orbit KW - ophthalmic artery KW - optic nerve Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324978 VL - 33 IS - 4 ER - TY - JOUR A1 - Zacher, Magdalena A1 - Wollanka, Nele A1 - Sauer, Christina A1 - Haßtenteufel, Kathrin A1 - Wallwiener, Stephanie A1 - Wallwiener, Markus A1 - Maatouk, Imad T1 - Prenatal paternal depression, anxiety, and somatic symptom burden in different risk samples: an explorative study JF - Archives of Gynecology and Obstetrics N2 - Purpose Growing evidence implies that transition to parenthood triggers symptoms of mental burden not only in women but likewise in men, especially in high-risk pregnancies. This is the first study that examined and compared the prevalence rates of depression, anxiety, and somatic symptom burden of expectant fathers who face different risk situations during pregnancy. Methods Prevalence rates of paternal depression (Edinburgh postnatal depression scale), anxiety (generalized anxiety disorder seven), and somatic symptom burden (somatic symptom scale eight) were examined in two risk samples and one control group in the third trimester of their partners’ pregnancy: risk sample I (n = 41) consist of expectant fathers whose partners were prenatally hospitalized due to medical complications; risk sample II (n = 52) are fathers whose partners were prenatally mentally distressed; and control group (n = 70) are those non-risk pregnancies. Results On a purely descriptive level, the data display a trend of higher symptom burden of depression, anxiety, and somatic symptoms in the two risk samples, indicating that expectant fathers, whose pregnant partners were hospitalized or suffered prenatal depression, were more prenatally distressed. Exploratory testing of group differences revealed an almost three times higher prevalence rate of anxiety in fathers whose partner was hospitalized (12.2%) compared to those non-risks (4.3%). Conclusion Results underline the need for screening implementations for paternal prenatal psychological distress, as well as specific prevention and treatment programs, especially for fathers in risk situations, such as their pregnant partners’ prenatal hospitalization. The study was registered with the German clinical trials register (DRKS00020131) on 2019/12/09. KW - prenatal paternal depression KW - anxiety KW - somatic symptom burden KW - risk pregnancy KW - hospitalization Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324465 VL - 307 IS - 4 ER - TY - JOUR A1 - Haertle, Larissa A1 - Buenache, Natalia A1 - Cuesta Hernández, Hipólito Nicolás A1 - Simicek, Michal A1 - Snaurova, Renata A1 - Rapado, Inmaculada A1 - Martinez, Nerea A1 - López-Muñoz, Nieves A1 - Sánchez-Pina, José María A1 - Munawar, Umair A1 - Han, Seungbin A1 - Ruiz-Heredia, Yanira A1 - Colmenares, Rafael A1 - Gallardo, Miguel A1 - Sanchez-Beato, Margarita A1 - Piris, Miguel Angel A1 - Samur, Mehmet Kemal A1 - Munshi, Nikhil C. A1 - Ayala, Rosa A1 - Kortüm, Klaus Martin A1 - Barrio, Santiago A1 - Martínez-López, Joaquín T1 - Genetic alterations in members of the proteasome 26S subunit, AAA-ATPase (PSMC) gene family in the light of proteasome inhibitor resistance in multiple myeloma JF - Cancers N2 - For the treatment of Multiple Myeloma, proteasome inhibitors are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients. The proteasome is a large and complex machinery. Here, we focus on the AAA ATPases of the 19S proteasome regulator (PSMC1-6) and their implication in PI resistance. As an example of cancer evolution and the acquisition of resistance, we conducted an in-depth analysis of an index patient by applying FISH, WES, and immunoglobulin-rearrangement sequencing in serial samples, starting from MGUS to newly diagnosed Multiple Myeloma to a PI-resistant relapse. The WES analysis uncovered an acquired PSMC2 Y429S mutation at the relapse after intensive bortezomib-containing therapy, which was functionally confirmed to mediate PI resistance. A meta-analysis comprising 1499 newly diagnosed and 447 progressed patients revealed a total of 36 SNVs over all six PSMC genes that were structurally accumulated in regulatory sites for activity such as the ADP/ATP binding pocket. Other alterations impact the interaction between different PSMC subunits or the intrinsic conformation of an individual subunit, consequently affecting the folding and function of the complex. Interestingly, several mutations were clustered in the central channel of the ATPase ring, where the unfolded substrates enter the 20S core. Our results indicate that PSMC SNVs play a role in PI resistance in MM. KW - Multiple Myeloma KW - drug resistance KW - proteasome inhibitors KW - immunoglobulin rearrangement KW - ATPase activity KW - PSMC2 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305013 SN - 2072-6694 VL - 15 IS - 2 ER - TY - JOUR A1 - Sudarevic, Boban A1 - Troya, Joel A1 - Fuchs, Karl-Hermann A1 - Hann, Alexander A1 - Vereczkei, Andras A1 - Meining, Alexander T1 - Design and development of a flexible 3D-printed endoscopic grasping instrument JF - Applied Sciences N2 - (1) Background: Interventional endoscopic procedures are growing more popular, requiring innovative instruments and novel techniques. Three-dimensional printing has demonstrated great potential for the rapid development of prototypes that can be used for the early assessment of various concepts. In this work, we present the development of a flexible endoscopic instrument and explore its potential benefits. (2) Methods: The properties of the instrument, such as its maneuverability, flexibility, and bending force, were evaluated in a series of bench tests. Additionally, the effectiveness of the instrument was evaluated in an ex vivo porcine model by medical experts, who graded its properties and performance. Furthermore, the time necessary to complete various interventional endoscopic tasks was recorded. (3) Results: The instrument achieved bending angles of ±216° while achieving a bending force of 7.85 (±0.53) Newtons. The time needed to reach the operating region was 120 s median, while it took 70 s median to insert an object in a cavity. Furthermore, it took 220 s median to insert the instrument and remove an object from the cavity. (4) Conclusions: This study presents the development of a flexible endoscopic instrument using three-dimensional printing technology and its evaluation. The instrument demonstrated high bending angles and forces, and superior properties compared to the current state of the art. Furthermore, it was able to complete various interventional endoscopic tasks in minimal time, thus potentially leading to the improved safety and effectiveness of interventional endoscopic procedures in the future. KW - endoscopy KW - endoscopic intervention KW - 3D printing KW - endoscopic instruments KW - minimally invasive surgery KW - rapid prototyping Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319186 SN - 2076-3417 VL - 13 IS - 9 ER - TY - JOUR A1 - Meier, Johannes P. A1 - Möbus, Selina A1 - Heigl, Florian A1 - Asbach-Nitzsche, Alexandra A1 - Niller, Hans Helmut A1 - Plentz, Annelie A1 - Avsar, Korkut A1 - Heiß-Neumann, Marion A1 - Schaaf, Bernhard A1 - Cassens, Uwe A1 - Seese, Bernd A1 - Teschner, Daniel A1 - Handzhiev, Sabin A1 - Graf, Uwe A1 - Lübbert, Christoph A1 - Steinmaurer, Monika A1 - Kontogianni, Konstantina A1 - Berg, Christoph A1 - Maieron, Andreas A1 - Blaas, Stefan H. A1 - Wagner, Ralf A1 - Deml, Ludwig A1 - Barabas, Sascha T1 - Performance of T-Track\(^®\) TB, a novel dual marker RT-qPCR-based whole-blood test for improved detection of active tuberculosis JF - Diagnostics N2 - Tuberculosis (TB) is one of the leading causes of death by an infectious disease. It remains a major health burden worldwide, in part due to misdiagnosis. Therefore, improved diagnostic tests allowing the faster and more reliable diagnosis of patients with active TB are urgently needed. This prospective study examined the performance of the new molecular whole-blood test T-Track\(^®\) TB, which relies on the combined evaluation of IFNG and CXCL10 mRNA levels, and compared it to that of the QuantiFERON\(^®\)-TB Gold Plus (QFT-Plus) enzyme-linked immunosorbent assay (ELISA). Diagnostic accuracy and agreement analyses were conducted on the whole blood of 181 active TB patients and 163 non-TB controls. T-Track\(^®\) TB presented sensitivity of 94.9% and specificity of 93.8% for the detection of active TB vs. non-TB controls. In comparison, the QFT-Plus ELISA showed sensitivity of 84.3%. The sensitivity of T-Track\(^®\) TB was significantly higher (p < 0.001) than that of QFT-Plus. The overall agreement of T-Track\(^®\) TB with QFT-Plus to diagnose active TB was 87.9%. Out of 21 samples with discordant results, 19 were correctly classified by T-Track\(^®\) TB while misclassified by QFT-Plus (T-Track\(^®\) TB-positive/QFT-Plus-negative), and two samples were misclassified by T-Track\(^®\) TB while correctly classified by QFT-Plus (T-Track\(^®\) TB-negative/QFT-Plus-positive). Our results demonstrate the excellent performance of the T-Track\(^®\) TB molecular assay and its suitability to accurately detect TB infection and discriminate active TB patients from non-infected controls. KW - tuberculosis KW - TB KW - active TB KW - infection detection KW - T-Track\(^®\) TB KW - QuantiFERON\(^®\)-TB Gold Plus KW - mRNA KW - RT-qPCR KW - CXCL10 KW - IFNG Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304113 SN - 2075-4418 VL - 13 IS - 4 ER - TY - JOUR A1 - Gelbrich, Götz A1 - Morbach, Caroline A1 - Deutschbein, Timo A1 - Fassnacht, Martin A1 - Störk, Stefan A1 - Heuschmann, Peter U. T1 - The population comparison index: an intuitive measure to calibrate the extent of impairments in patient cohorts in relation to healthy and diseased populations JF - International Journal of Environmental Research and Public Health N2 - We assume that a specific health constraint, e.g., a certain aspect of bodily function or quality of life that is measured by a variable X, is absent (or irrelevant) in a healthy reference population (Ref0), and it is materially present and precisely measured in a diseased reference population (Ref1). We further assume that some amount of this constraint of interest is suspected to be present in a population under study (SP). In order to quantify this issue, we propose the introduction of an intuitive measure, the population comparison index (PCI), that relates the mean value of X in population SP to the mean values of X in populations Ref0 and Ref1. This measure is defined as PCI[X] = (mean[X|SP] − mean[X|Ref0])/(mean[X|Ref1] − mean[X|Ref0]) × 100[%], where mean[X|.] is the average value of X in the respective group of individuals. For interpretation, PCI[X] ≈ 0 indicates that the values of X in the population SP are similar to those in population Ref0, and hence, the impairment measured by X is not materially present in the individuals in population SP. On the other hand, PCI[X] ≈ 100 means that the individuals in SP exhibit values of X comparable to those occurring in Ref1, i.e., the constraint of interest is equally present in populations SP and Ref1. A value of 0 < PCI[X] < 100 indicates that a certain percentage of the constraint is present in SP, and it is more than in Ref0 but less than in Ref1. A value of PCI[X] > 100 means that population SP is even more affected by the constraint than population Ref1. KW - reference data KW - normal values KW - disease severity KW - disease score KW - comparability Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304933 SN - 1660-4601 VL - 20 IS - 3 ER - TY - JOUR A1 - Stephan, Marlene A1 - Tascilar, Koray A1 - Yalcin-Mutlu, Melek A1 - Hagen, Melanie A1 - Haschka, Judith A1 - Reiser, Michaela A1 - Hartmann, Fabian A1 - Kleyer, Arnd A1 - Hueber, Axel J. A1 - Manger, Bernhard A1 - Figueiredo, Camille A1 - Cobra, Jayme Fogagnolo A1 - Tony, Hans-Peter A1 - Finzel, Stephanie A1 - Kleinert, Stefan A1 - Wendler, Jörg A1 - Schuch, Florian A1 - Ronneberger, Monika A1 - Feuchtenberger, Martin A1 - Fleck, Martin A1 - Manger, Karin A1 - Ochs, Wolfgang A1 - Schmitt-Haendle, Matthias A1 - Lorenz, Hannes Martin A1 - Nüsslein, Hubert A1 - Alten, Rieke A1 - Henes, Joerg A1 - Krüger, Klaus A1 - Schett, Georg A1 - Rech, Jürgen T1 - Physical function of RA patients tapering treatment — a post hoc analysis of the randomized controlled RETRO trial JF - Journal of Clinical Medicine N2 - Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline. KW - HAQ KW - Rheumatoid Arthritis KW - PROM’s KW - DMARD KW - DAS28 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319349 SN - 2077-0383 VL - 12 IS - 11 ER - TY - JOUR A1 - Nickl, Vera A1 - Eck, Juliana A1 - Goedert, Nicolas A1 - Hübner, Julian A1 - Nerreter, Thomas A1 - Hagemann, Carsten A1 - Ernestus, Ralf-Ingo A1 - Schulz, Tim A1 - Nickl, Robert Carl A1 - Keßler, Almuth Friederike A1 - Löhr, Mario A1 - Rosenwald, Andreas A1 - Breun, Maria A1 - Monoranu, Camelia Maria T1 - Characterization and optimization of the tumor microenvironment in patient-derived organotypic slices and organoid models of glioblastoma JF - Cancers N2 - While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future. KW - glioblastoma KW - organoids KW - slice culture KW - tumormicroenvironment Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319249 SN - 2072-6694 VL - 15 IS - 10 ER - TY - JOUR A1 - Luu, Maik A1 - Schütz, Burkhard A1 - Lauth, Matthias A1 - Visekruna, Alexander T1 - The impact of gut microbiota-derived metabolites on the tumor immune microenvironment JF - Cancers N2 - Prevention of the effectiveness of anti-tumor immune responses is one of the canonical cancer hallmarks. The competition for crucial nutrients within the tumor microenvironment (TME) between cancer cells and immune cells creates a complex interplay characterized by metabolic deprivation. Extensive efforts have recently been made to understand better the dynamic interactions between cancer cells and surrounding immune cells. Paradoxically, both cancer cells and activated T cells are metabolically dependent on glycolysis, even in the presence of oxygen, a metabolic process known as the Warburg effect. The intestinal microbial community delivers various types of small molecules that can potentially augment the functional capabilities of the host immune system. Currently, several studies are trying to explore the complex functional relationship between the metabolites secreted by the human microbiome and anti-tumor immunity. Recently, it has been shown that a diverse array of commensal bacteria synthetizes bioactive molecules that enhance the efficacy of cancer immunotherapy, including immune checkpoint inhibitor (ICI) treatment and adoptive cell therapy with chimeric antigen receptor (CAR) T cells. In this review, we highlight the importance of commensal bacteria, particularly of the gut microbiota-derived metabolites that are capable of shaping metabolic, transcriptional and epigenetic processes within the TME in a therapeutically meaningful way. KW - tumor microenvironment (TME) KW - commensal bacteria KW - intratumoral microbiota KW - oncobiome KW - microbiota-derived metabolites KW - cancer immunotherapy Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311005 SN - 2072-6694 VL - 15 IS - 5 ER - TY - THES A1 - Gotthard, Hannes T1 - Targeting Colorectal Cancer Stem Cells with Hemibodies T1 - Eliminierung von Krebsstammzellen des kolorektalen Karzinoms mithilfe von Hemibodies N2 - The cancer stem cell hypothesis is a cancer development model which elicited great interest in the last decades stating that cancer heterogeneity arises from a stem cell through asymmetrical division. The Cancer Stem Cell subset is described as the only population to be tumorigenic and having the potential to renew. Conventional therapy often fails to eradicate CSC resulting in tumor relapse. Consequently, it is of great inter-est to eliminate this subset of cells to provide the best patient outcome. In the last years several approaches to target CSC were developed, one of them being immunotherapeu-tic targeting with antibodies. Since markers associated with CSC are also expressed on normal stem cells or healthy adjacent tissue in colorectal cancer, dual targeting strate-gies are preferred over targeting only a single antigen. Subsequently, the idea of dual targeting two CSC markers in parallel by a newly developed split T cell-engaging anti-body format termed as Hemibodies emerged. In a preliminary single cell RNA sequenc-ing analysis of colorectal cancer cells CD133, CD24, CD166 and CEA were identified as suitable targets for the combinatorial targeting strategy. Therefore, this study focused on trispecific and trivalent Hemibodies comprising a split binding moiety against CD3 and a binding moiety against either CD133, CD24, CD166 or CEA to overcome the occurrence of resistance and to efficiently eradicate all tumor cells including the CSC compartment. The study showed that the Hemibody combinations CD133xCD24, CD133xCD166 and CD133xCEA are able to eliminate double positive CHO cells with high efficacy while having a high specificity indicated by no killing of single antigen positive cells. A thera-peutic window ranging between one to two log levels could be achieved for all combina-tions mentioned above. The combinations CD133xCD24 and CD133xCD166 further-more proved its efficacy and specificity on established colorectal cancer cell lines. Be-sides the evaluation of specificity and efficacy the already introduced 1st generation of Hemibodies could be improved into a 2nd generation Hemibody format with increased half-life, stability and production yield. In future experiments the applicability of above-mentioned Hemibodies will be proven on patient-derived micro tumors to also include variables like tumor microenvironment and infiltration. N2 - In den letzten Jahrzenten wurde neben der klonalen Evolution ein weiteres Modell zur Krebsentstehung und dessen Heterogenität entwickelt: die Krebsstammzellhypothe-se. Diese Hypothese besagt, dass die Heterogenität eines Tumors durch asymmetri-sche Teilung von sogenannten Krebsstammzellen entsteht. Nur diese sind tumorigen und in der Lage Metastasen zu bilden. Außerdem werden Krebsstammzellen als re-sistent gegen konventionelle Therapien beschrieben, weshalb es nach einer anfängli-chen Tumorregression oft zu einem Rezidiv durch erneutes Auswachsen von zurück-bleibenden Krebsstammzellen kommt. Deshalb ist es von großem Interesse genau diese Population abzutöten, um eine erfolgreiche Therapie zu gewährleisten. In den letzten Jahren wurden zahlreiche Medikationen entwickelt, um Krebsstammzellen ge-zielt anzugreifen. Ein vielversprechender Ansatz ist hierbei die immuntherapeutische Adressierung mittels Antikörpern gegen Krebsstammzellmarkern. Einzelne Marker sind allerdings auch auf normalen Stammzellen und gesundem Gewebe exprimiert, weshalb Therapien, die auf mindestens zwei verschiedene Oberflächenproteine ab-zielen, erfolgsversprechender sind. In dieser Arbeit wurde ein neues T-Zell rekrutie-rendes Antikörperformat entwickelt, sogenannte Hemibodies. Hierbei handelt es sich um ein trispezifisches und trivalentes Format, bestehend aus jeweils zwei Fragmen-ten. Jedes Fragment besteht aus einer Bindedomäne gegen ein Krebsstammzellmar-ker und einer geteilten Bindedomäne gegen CD3. Durch Bindung beider Fragmente an einen Stammzellmarker kommt es zur Komplementierung der geteilten anti-CD3 Domäne und zur T-Zellrekrutierung. Der erste Teil der Arbeit befasst sich mit der bioin-formatischen Analyse von Einzelzell-RNA-Daten des kolorektalen Karzinoms (KRK) zur Identifizierung von potentiellen Krebsstammzellmarkern. Dabei konnten die Ober-flächenproteine CD24, CD133, CD166 und CEA und besonders deren Kombination als geeignete Zielstrukturen identifiziert werden. Die gegen oben genannte Antigene gerichteten Hemibodies zeigten in den Kombinationen CD133xCD24, CD133xCD166 und CD133xCEA auf doppelt positiven CHO-Zellen eine hohe Effektivität. Außerdem konnte die Spezifität durch ein Ausbleiben von Zelltod auf einzel-positiven CHO Zellen bewiesen werden. Die Kombinationen CD133xCD24 und CD133xCD166 konnten Effektivität und Spezifität auch auf etablierten Krebszellen zeigen. Die oben genann-ten Kombinationen waren in einem therapeutischen Fenster von ein bis zwei Logstu-fen funktional. Neben der Testung verschiedener Hemibody-Kombinationen konnten die bereits publizierten Hemibodies der ersten Generation in ein neues Format der zweiten Generation weiterentwickelt werden. Das neue Format zeigte eine verbesser-te Halbwertszeit, Stabilität und Produzierbarkeit. In zukünftigen Experimenten werden die in der Thesis benutzten Hemibodies auf Mikrotumoren getestet, um weitere Vari-ablen, die die Effektivität und Spezifität beeinflussen zu ermitteln. KW - Monoklonaler bispezifischer Antikörper KW - Antikörper KW - T-Lymphozyt KW - Immunreaktion KW - Dickdarmkrebs KW - Hemibody KW - Hemibodies KW - Colorectal Cancer KW - trispecific KW - T-cell engager KW - dual targeting KW - Bispecific T-cell engager KW - stem cells KW - Kolorektales Karzinom Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-303090 ER - TY - JOUR A1 - Solimando, Antonio G. A1 - Bittrich, Max A1 - Shahini, Endrit A1 - Albanese, Federica A1 - Fritz, Georg A1 - Krebs, Markus T1 - Determinants of COVID-19 disease severity – lessons from primary and secondary immune disorders including cancer JF - International Journal of Molecular Sciences N2 - At the beginning of the COVID-19 pandemic, patients with primary and secondary immune disorders — including patients suffering from cancer — were generally regarded as a high-risk population in terms of COVID-19 disease severity and mortality. By now, scientific evidence indicates that there is substantial heterogeneity regarding the vulnerability towards COVID-19 in patients with immune disorders. In this review, we aimed to summarize the current knowledge about the effect of coexistent immune disorders on COVID-19 disease severity and vaccination response. In this context, we also regarded cancer as a secondary immune disorder. While patients with hematological malignancies displayed lower seroconversion rates after vaccination in some studies, a majority of cancer patients’ risk factors for severe COVID-19 disease were either inherent (such as metastatic or progressive disease) or comparable to the general population (age, male gender and comorbidities such as kidney or liver disease). A deeper understanding is needed to better define patient subgroups at a higher risk for severe COVID-19 disease courses. At the same time, immune disorders as functional disease models offer further insights into the role of specific immune cells and cytokines when orchestrating the immune response towards SARS-CoV-2 infection. Longitudinal serological studies are urgently needed to determine the extent and the duration of SARS-CoV-2 immunity in the general population, as well as immune-compromised and oncological patients. KW - COVID-19 KW - SARS-CoV-2 KW - disorder of immunity KW - cancer Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319412 SN - 1422-0067 VL - 24 IS - 10 ER - TY - JOUR A1 - Schanbacher, Constanze A1 - Hermanns, Heike M. A1 - Lorenz, Kristina A1 - Wajant, Harald A1 - Lang, Isabell T1 - Complement 1q/tumor necrosis factor-related proteins (CTRPs): structure, receptors and signaling JF - Biomedicines N2 - Adiponectin and the other 15 members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of an N-terminal variable domain followed by a stalk region and a characteristic C-terminal trimerizing globular C1q (gC1q) domain originally identified in the subunits of the complement protein C1q. We performed a basic PubMed literature search for articles mentioning the various CTRPs or their receptors in the abstract or title. In this narrative review, we briefly summarize the biology of CTRPs and focus then on the structure, receptors and major signaling pathways of CTRPs. Analyses of CTRP knockout mice and CTRP transgenic mice gave overwhelming evidence for the relevance of the anti-inflammatory and insulin-sensitizing effects of CTRPs in autoimmune diseases, obesity, atherosclerosis and cardiac dysfunction. CTRPs form homo- and heterotypic trimers and oligomers which can have different activities. The receptors of some CTRPs are unknown and some receptors are redundantly targeted by several CTRPs. The way in which CTRPs activate their receptors to trigger downstream signaling pathways is largely unknown. CTRPs and their receptors are considered as promising therapeutic targets but their translational usage is still hampered by the limited knowledge of CTRP redundancy and CTRP signal transduction. KW - adiponectin KW - AMPK KW - C1q/TNF related protein (CTRP) KW - inflammation KW - metabolism Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304136 SN - 2227-9059 VL - 11 IS - 2 ER - TY - JOUR A1 - Krenzer, Adrian A1 - Banck, Michael A1 - Makowski, Kevin A1 - Hekalo, Amar A1 - Fitting, Daniel A1 - Troya, Joel A1 - Sudarevic, Boban A1 - Zoller, Wolfgang G. A1 - Hann, Alexander A1 - Puppe, Frank T1 - A real-time polyp-detection system with clinical application in colonoscopy using deep convolutional neural networks JF - Journal of Imaging N2 - Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. The best method to prevent CRC is with a colonoscopy. During this procedure, the gastroenterologist searches for polyps. However, there is a potential risk of polyps being missed by the gastroenterologist. Automated detection of polyps helps to assist the gastroenterologist during a colonoscopy. There are already publications examining the problem of polyp detection in the literature. Nevertheless, most of these systems are only used in the research context and are not implemented for clinical application. Therefore, we introduce the first fully open-source automated polyp-detection system scoring best on current benchmark data and implementing it ready for clinical application. To create the polyp-detection system (ENDOMIND-Advanced), we combined our own collected data from different hospitals and practices in Germany with open-source datasets to create a dataset with over 500,000 annotated images. ENDOMIND-Advanced leverages a post-processing technique based on video detection to work in real-time with a stream of images. It is integrated into a prototype ready for application in clinical interventions. We achieve better performance compared to the best system in the literature and score a F1-score of 90.24% on the open-source CVC-VideoClinicDB benchmark. KW - machine learning KW - deep learning KW - endoscopy KW - gastroenterology KW - automation KW - object detection KW - video object detection KW - real-time Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304454 SN - 2313-433X VL - 9 IS - 2 ER - TY - THES A1 - Läsker, Katharina T1 - The influence of the short-chain fatty acid butyrate on "Signal transducer and activator of transcription 3" (STAT3) and selected inflammatory genes in the colon carcinoma cell line CACO-2 cultured in 2D and 3D T1 - Der Einfluss der kurzkettigen Fettsäure Butyrat auf "Signal Übermittler und Aktivator der Transkription 3" (STAT3) und ausgewählte an der Entzündung beteiligte Gene in der Dickdarmkrebszelllinie CACO-2 im 2D- und 3D Modell N2 - A disturbance in the symbiotic mutualism between the intestinal microbiome and the human host’s organism (syn. dysbiosis) accompanies the development of a variety of inflammatory and metabolic diseases that comprise the Metabolic Syndrome, chronic inflammatory gut diseases like Crohn’s disease, Non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases, among others. The changed uptake and effectiveness of short chain fatty acids (SCFAs) as well as an increase of the intestinal permeability are common, interdependent disease elements in this regard. Short chain fatty acids are end-products of intestinal bacterial fermentation and affect the mucosal barrier integrity via numerous molecular mechanisms. There is evidence to suggest, that SCFAs have a modulating influence on Signal transducer and activator of transcription 3 (STAT3) in intestinal epithelial cells. STAT3 is a central gene-transcription factor in signaling pathways of proliferation and inflammation. It can be activated by growth factors and other intercellular signaling molecules like the cytokine Oncostatin M (OSM). The mode of STAT3’s activation exhibits, finally, a decisive influence on the immunological balance at the intestinal mucosa. Therefore, the posttranslational modification of STAT3 under the influence of SCFAs is likely to be a very important factor within the development and -progression of dysbiosis-associated diseases. In this study, a clear positive in vitro-effect of the short chain fatty acid butyrate on the posttranslational serine727-phosphorylation of STAT3 and its total protein amount in the human adenocarcinoma cell line CACO2 is verified. Moreover, an increased gene expression of the OSM-receptor subunit OSMRβ can be observed after butyrate incubation. Histone deacetylase inhibition is shown to have a predominant role in these effects. Furthermore, a subsequent p38 MAPK-activation by Butyrate is found to be a key molecular mechanism regarding the STAT3-phosphorylation at serine727-residues. To consider the portion of butyrate receptor signaling in this context in future assays, a CACO-2 cell 3D-culture model is introduced in which an improvement of the GPR109A-receptor expression in CACO-2 cells is accomplished. N2 - Eine Störung der symbiotischen Wechselbeziehung zwischen dem Darmmikrobiom und dem Wirtsorganismus (syn. Dysbiose) begleitet die Entwicklung vieler verschiedener entzündlicher und metabolischer Erkrankungen. Zu ihnen zählen unter anderem das Metabolische Syndrom, chronisch entzündliche Darmerkrankungen wie M. Crohn, die Nicht-alkoholische Fettlebererkrankung (NAFLD) und kardiovaskuläre Erkrankungen. Eine veränderte Aufnahme und Wirkung von kurzkettigen Fettsäuren (Short-chain fatty acids = SCFAs) und eine Schwächung der Darmbarriere bedingen sich in diesem Zusammenhang gegenseitig. Kurzkettige Fettsäuren sind Endprodukte des bakteriellen Stoffwechsels und beeinflussen die Integrität der Darmbarriere über eine Vielzahl molekularer Mechanismen. Es gibt Hinweise darauf, dass kurzkettige Fettsäuren einen modulierenden Einfluss auf „Signal transducer and activator of transcription 3“ (STAT3) in intestinalen epithelialen Zellen ausüben. STAT3 ist hier ein zentraler Gentranskriptionsfaktor in proliferations- und entzündungsregulierenden Zellsignalwegen. Er kann durch Wachstumsfaktoren und andere interzelluläre Botenstoffe, wie beispielsweise das Zytokin Oncostatin M (OSM), aktiviert werden. Die Art der Aktivierung von STAT3 wirkt sich nicht zuletzt entscheidend auf die immunologische Balance an der Darmbarriere aus. Die Modifikation von STAT3 durch kurzkettige Fettsäuren ist aufgrund dessen mit hoher Wahrscheinlichkeit ein sehr wichtiger Faktor im Hinblick auf Entstehung und Progression der im Zusammenhang mit einer Dysbiose stehenden Erkrankungen. In dieser Arbeit kann eine klare Steigerung der posttranslationalen Phosphorylierung von STAT3 an den Serin-Molekülendungen der Position 727 sowie eine Steigerung der Gesamtproteinmenge von STAT3 in der humanen Karzinomzellline CACO2 in vitro durch Butyrat-Inkubation gezeigt werden. Weiterhin wird unter Butyrat-Einfluss auch die Genexpression der OSM-Rezeptor-Untereinheit OSMRβ gesteigert. Diese Effekte können größtenteils auf den Mechanismus der Histondeacetylase-Hemmung durch Butyrat zurückgeführt werden. Die in der Folge erhöhte P38 MAPK-Phosphorylierung durch Butyrat ist in Bezug auf die Serin727-Phosphorylierung an STAT3 entscheidend beteiligt. Um in künftigen Assays auch den möglichen Einfluss der Butyrat-Rezeptor-Wirkung in diesem Zusammenhang besser zu erfassen, wird ein 3D-Zellkultur Ansatz getestet und in diesem eine verbesserte Expression des Butyrat-Rezeptors GPR109A in CACO-2-Zellen erreicht. KW - Butyrate KW - Signaltransduktion KW - Darmepithel KW - Cytokine KW - MAP-Kinase KW - butyrate KW - signal transduction KW - p38 MAPK KW - STAT3 KW - intestinal barrier KW - 3 dimensional cell culture model KW - CACO-2 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300389 ER -