@article{LangFuellsackWajant2018, author = {Lang, Isabell and F{\"u}llsack, Simone and Wajant, Harald}, title = {Lack of Evidence for a Direct Interaction of Progranulin and Tumor Necrosis Factor Receptor-1 and Tumor Necrosis Factor Receptor-2 From Cellular Binding Studies}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2018.00793}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236373}, year = {2018}, abstract = {Progranulin (PGRN) is a secreted anti-inflammatory protein which can be processed by neutrophil proteases to various granulins. It has been reported that at least a significant portion of the anti-inflammatory effects of PGRN is due to direct high affinity binding to tumor necrosis factor receptor-1 (TNFR1) and TNFR2 and inhibition of tumor necrosis factor (TNF)-induced TNFR1/2 signaling. Two studies failed to reproduce the interaction of TNFR1 and TNFR2 with PGRN, but follow up reports speculated that this was due to varying experimental circumstances and/or the use of PGRN from different sources. However, even under consideration of these speculations, there is still a striking discrepancy in the literature between the concentrations of PGRN needed to inhibit TNF signaling and the concentrations required to block TNF binding to TNFR1 and TNFR2. While signaling events induced by 0.2-2 nM of TNF have been efficiently inhibited by low, near to equimolar concentrations (0.5-2.5 nM) of PGRN in various studies, the reported inhibitory effects of PGRN on TNF-binding to TNFR1/2 required a huge excess of PGRN (100-1,000-fold). Therefore, we investigated the effect of PGRN on TNF binding to TNFR1 and TNFR2 in highly sensitive cellular binding studies. Unlabeled TNF inhibited >95\% of the specific binding of a Gaussia princeps luciferase (GpL) fusion protein of TNF to TNFR1 and TNFR2 and blocked binding of soluble GpL fusion proteins of TNFR1 and TNFR2 to membrane TNF expressing cells to >95\%, too. Purified PGRN, however, showed in both assays no effect on TNF-TNFR1/2 interaction even when applied in huge excess. To rule out that tags and purification- or storage-related effects compromise the potential ability of PGRN to bind TNF receptors, we directly co-expressed PGRN, and as control TNF, in TNFR1- and TNFR2-expressing cells and looked for binding of GpL-TNF. While expression of TNF strongly inhibited binding of GpL-TNF to TNFR1/2, co-expression of PGRN had not effect on the ability of the TNFR1/2-expressing cells to bind TNF.}, language = {en} } @article{WeissZieglerFliesseretal.2018, author = {Weiss, Esther and Ziegler, Sabrina and Fliesser, Mirjam and Schmitt, Anna-Lena and H{\"u}nniger, Kerstin and Kurzai, Oliver and Morton, Charles-Oliver and Einsele, Hermann and Loeffler, Juergen}, title = {First Insights in NK—DC Cross-Talk and the Importance of Soluble Factors During Infection With Aspergillus fumigatus}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {8}, journal = {Frontiers in Cellular and Infection Microbiology}, doi = {10.3389/fcimb.2018.00288}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233565}, year = {2018}, abstract = {Invasive aspergillosis (IA) is an infectious disease caused by the fungal pathogen Aspergillus fumigatus that mainly affects immunocompromised hosts. To investigate immune cell cross-talk during infection with A. fumigatus, we co-cultured natural killer (NK) cells and dendritic cells (DC) after stimulation with whole fungal structures, components of the fungal cell wall, fungal lysate or ligands for distinct fungal receptors. Both cell types showed activation after stimulation with fungal components and were able to transfer activation signals to the counterpart not stimulated cell type. Interestingly, DCs recognized a broader spectrum of fungal components and thereby initiated NK cell activation when those did not recognize fungal structures. These experiments highlighted the supportive function of DCs in NK cell activation. Furthermore, we focused on soluble DC mediated NK cell activation and showed that DCs stimulated with the TLR2/Dectin-1 ligand zymosan could maximally stimulate the expression of CD69 on NK cells. Thus, we investigated the influence of both receptors for zymosan, Dectin-1 and TLR2, which are highly expressed on DCs but show only minimal expression on NK cells. Specific focus was laid on the question whether Dectin-1 or TLR2 signaling in DCs is important for the secretion of soluble factors leading to NK cell activation. Our results show that Dectin-1 and TLR2 are negligible for NK cell activation. We conclude that besides Dectin-1 and TLR2 other receptors on DCs are able to compensate for the missing signal.}, language = {en} } @article{SirtlKnollDieuThuyetal.2018, author = {Sirtl, Simon and Knoll, Gertrud and Dieu Thuy, Trinh and Lang, Isabell and Siegmund, Daniela and Gross, Stefanie and Schuler-Thurner, Beatrice and Neubert, Patrick and Jantsch, Jonathan and Wajant, Harald and Ehrenschwender, Martin}, title = {Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors}, series = {Oncogene}, volume = {37}, journal = {Oncogene}, doi = {10.1038/s41388-018-0265-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238327}, pages = {4122-4136}, year = {2018}, abstract = {Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens.}, language = {en} } @article{SolimandoBrandlMattenheimeretal.2018, author = {Solimando, A G and Brandl, A and Mattenheimer, K and Graf, C and Ritz, M and Ruckdeschel, A and St{\"u}hmer, T and Mokhtari, Z and Rudelius, M and Dotterweich, J and Bittrich, M and Desantis, V and Ebert, R and Trerotoli, P and Frassanito, M A and Rosenwald, A and Vacca, A and Einsele, H and Jakob, F and Beilhack, A}, title = {JAM-A as a prognostic factor and new therapeutic target in multiple myeloma}, series = {Leukemia}, volume = {32}, journal = {Leukemia}, doi = {10.1038/leu.2017.287}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239069}, pages = {736-743}, year = {2018}, abstract = {Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification.}, language = {en} } @article{SiegmundEhrenschwenderWajant2018, author = {Siegmund, Daniela and Ehrenschwender, Martin and Wajant, Harald}, title = {TNFR2 unlocks a RIPK1 kinase activity-dependent mode of proinflammatory TNFR1 signaling}, series = {Cell Death \& Disease}, volume = {9}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-018-0973-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238034}, year = {2018}, abstract = {TNF is not only a major effector molecule of PAMP/DAMP-activated macrophages, but also regulates macrophage function and viability. We recently demonstrated that TNFR2 triggers necroptosis in macrophages with compromised caspase activity by two cooperating mechanisms: induction of endogenous TNF with subsequent stimulation of TNFR1 and depletion of cytosolic TRAF2-cIAP complexes. Here we show that TNFR2 activation in caspase-inhibited macrophages results in the production of endogenous TNF and TNFR1 stimulation followed by upregulation of A20, TRAF1, IL-6, and IL-1β. Surprisingly, TNFR1-mediated induction of IL-6 and IL-1β was clearly evident in response to TNFR2 stimulation but occurred not or only weakly in macrophages selectively and directly stimulated via TNFR1. Moreover, TNFR2-induced TNFR1-mediated gene induction was largely inhibited by necrostatin-1, whereas upregulation of A20 and TRAF1 by direct and exclusive stimulation of TNFR1 remained unaffected by this compound. Thus, treatment with TNFR2/ZVAD enables TNFR1 in macrophages to stimulate gene induction via a pathway requiring RIPK1 kinase activity. TNFR2/ZVAD-induced production of IL-6 and IL-1β was largely blocked in necroptosis-resistant MLKL- and RIPK3-deficient macrophages, whereas induction of A20 and TRAF1 remained unaffected. In sum, our results show that in caspase-inhibited macrophages TNFR2 not only triggers TNF/TNFR1-mediated necroptosis but also TNF/TNFR1-mediated RIPK3/MLKL-dependent and -independent gene induction.}, language = {en} } @article{WentSudSpeedyetal.2018, author = {Went, Molly and Sud, Amit and Speedy, Helen and Sunter, Nicola J. and F{\"o}rsti, Asta and Law, Philip J. and Johnson, David C. and Mirabella, Fabio and Holroyd, Amy and Li, Ni and Orlando, Giulia and Weinhold, Niels and van Duin, Mark and Chen, Bowang and Mitchell, Jonathan S. and Mansouri, Larry and Juliusson, Gunnar and Smedby, Karin E and Jayne, Sandrine and Majid, Aneela and Dearden, Claire and Allsup, David J. and Bailey, James R. and Pratt, Guy and Pepper, Chris and Fegan, Chris and Rosenquist, Richard and Kuiper, Rowan and Stephens, Owen W. and Bertsch, Uta and Broderick, Peter and Einsele, Hermann and Gregory, Walter M. and Hillengass, Jens and Hoffmann, Per and Jackson, Graham H. and J{\"o}ckel, Karl-Heinz and Nickel, Jolanta and N{\"o}then, Markus M. and da Silva Filho, Miguel Inacio and Thomsen, Hauke and Walker, Brian A. and Broyl, Annemiek and Davies, Faith E. and Hansson, Markus and Goldschmidt, Hartmut and Dyer, Martin J. S. and Kaiser, Martin and Sonneveld, Pieter and Morgan, Gareth J. and Hemminki, Kari and Nilsson, Bj{\"o}rn and Catovsky, Daniel and Allan, James M. and Houlston, Richard S.}, title = {Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology}, series = {Blood Cancer Journal}, volume = {9}, journal = {Blood Cancer Journal}, doi = {10.1038/s41408-018-0162-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233627}, year = {2018}, abstract = {The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.}, language = {en} } @article{WalkerMavrommatisWardelletal.2019, author = {Walker, Brian A. and Mavrommatis, Konstantinos and Wardell, Christopher P. and Ashby, T. Cody and Bauer, Michael and Davies, Faith and Rosenthal, Adam and Wang, Hongwei and Qu, Pingping and Hoering, Antje and Samur, Mehmet and Towfic, Fadi and Ortiz, Maria and Flynt, Erin and Yu, Zhinuan and Yang, Zhihong and Rozelle, Dan and Obenauer, John and Trotter, Matthew and Auclair, Daniel and Keats, Jonathan and Bolli, Niccolo and Fulciniti, Mariateresa and Szalat, Raphael and Moreau, Phillipe and Durie, Brian and Stewart, A. Keith and Goldschmidt, Hartmut and Raab, Marc S. and Einsele, Hermann and Sonneveld, Pieter and San Miguel, Jesus and Lonial, Sagar and Jackson, Graham H. and Anderson, Kenneth C. and Avet-Loiseau, Herve and Munshi, Nikhil and Thakurta, Anjan and Morgan, Gareth}, title = {A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis}, series = {Leukemia}, volume = {33}, journal = {Leukemia}, doi = {10.1038/s41375-018-0196-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233299}, pages = {159-170}, year = {2019}, abstract = {Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4\% and 25.2\%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3\% for PFS and 46.5\% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1\% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.}, language = {en} } @article{AnanyKreckelFuellsacketal.2018, author = {Anany, Mohamed A. and Kreckel, Jennifer and F{\"u}llsack, Simone and Rosenthal, Alevtina and Otto, Christoph and Siegmund, Daniela and Wajant, Harald}, title = {Soluble TNF-like weak inducer of apoptosis (TWEAK) enhances poly(I:C)-induced RIPK1-mediated necroptosis}, series = {Cell Death \& Disease}, volume = {9}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-018-1137-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221104}, year = {2018}, abstract = {TNF-like weak inducer of apoptosis (TWEAK) and inhibition of protein synthesis with cycloheximide (CHX) sensitize for poly(I:C)-induced cell death. Notably, although CHX preferentially enhanced poly(I:C)-induced apoptosis, TWEAK enhanced primarily poly(I:C)-induced necroptosis. Both sensitizers of poly(I:C)-induced cell death, however, showed no major effect on proinflammatory poly(I:C) signaling. Analysis of a panel of HeLa-RIPK3 variants lacking TRADD, RIPK1, FADD, or caspase-8 expression revealed furthermore similarities and differences in the way how poly(I:C)/TWEAK, TNF, and TRAIL utilize these molecules for signaling. RIPK1 turned out to be essential for poly(I:C)/TWEAK-induced caspase-8-mediated apoptosis but was dispensable for this response in TNF and TRAIL signaling. TRADD-RIPK1-double deficiency differentially affected poly(I:C)-triggered gene induction but abrogated gene induction by TNF completely. FADD deficiency abrogated TRAIL- but not TNF- and poly(I:C)-induced necroptosis, whereas TRADD elicited protective activity against all three death inducers. A general protective activity against poly(I:C)-, TRAIL-, and TNF-induced cell death was also observed in FLIPL and FLIPS transfectrants.}, language = {en} } @article{LopezKleinheinzAukemaetal.2019, author = {L{\´o}pez, Cristina and Kleinheinz, Kortine and Aukema, Sietse M. and Rohde, Marius and Bernhart, Stephan H. and H{\"u}bschmann, Daniel and Wagener, Rabea and Toprak, Umut H. and Raimondi, Francesco and Kreuz, Markus and Waszak, Sebastian M. and Huang, Zhiqin and Sieverling, Lina and Paramasivam, Nagarajan and Seufert, Julian and Sungalee, Stephanie and Russell, Robert B. and Bausinger, Julia and Kretzmer, Helene and Ammerpohl, Ole and Bergmann, Anke K. and Binder, Hans and Borkhardt, Arndt and Brors, Benedikt and Claviez, Alexander and Doose, Gero and Feuerbach, Lars and Haake, Andrea and Hansmann, Martin-Leo and Hoell, Jessica and Hummel, Michael and Korbel, Jan O. and Lawerenz, Chris and Lenze, Dido and Radlwimmer, Bernhard and Richter, Julia and Rosenstiel, Philip and Rosenwald, Andreas and Schilhabel, Markus B. and Stein, Harald and Stilgenbauer, Stephan and Stadler, Peter F. and Szczepanowski, Monika and Weniger, Marc A. and Zapatka, Marc and Eils, Roland and Lichter, Peter and Loeffler, Markus and M{\"o}ller, Peter and Tr{\"u}mper, Lorenz and Klapper, Wolfram and Hoffmann, Steve and K{\"u}ppers, Ralf and Burkhardt, Birgit and Schlesner, Matthias and Siebert, Reiner}, title = {Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, organization = {ICGC MMML-Seq Consortium}, doi = {10.1038/s41467-019-08578-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237281}, year = {2019}, abstract = {Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.}, language = {en} } @article{MedlerNelkeWeisenbergeretal.2019, author = {Medler, Juliane and Nelke, Johannes and Weisenberger, Daniela and Steinfatt, Tim and Rothaug, Moritz and Berr, Susanne and H{\"u}nig, Thomas and Beilhack, Andreas and Wajant, Harald}, title = {TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity}, series = {Cell Death \& Disease}, volume = {10}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-019-1456-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223948}, year = {2019}, abstract = {Antibodies specific for TNFRSF receptors that bind soluble ligands without getting properly activated generally act as strong agonists upon FcγR binding. Systematic analyses revealed that the FcγR dependency of such antibodies to act as potent agonists is largely independent from isotype, FcγR type, and of the epitope recognized. This suggests that the sole cellular attachment, achieved by Fc domain-FcγR interaction, dominantly determines the agonistic activity of antibodies recognizing TNFRSF receptors poorly responsive to soluble ligands. In accordance with this hypothesis, we demonstrated that antibody fusion proteins harboring domains allowing FcγR-independent cell surface anchoring also act as strong agonist provided they have access to their target. This finding defines a general possibility to generate anti-TNFRSF receptor antibodies with FcγR-independent agonism. Moreover, anti-TNFRSF receptor antibody fusion proteins with an anchoring domain promise superior applicability to conventional systemically active agonists when an anchoring target with localized disease associated expression can be addressed.}, language = {en} } @article{EstesAnsteeAriasLosteetal.2018, author = {Estes, Chris and Anstee, Quentin M. and Arias-Loste, Maria Teresa and Bantel, Heike and Bellentani, Stefano and Caballeria, Joan and Colombo, Massimo and Craxi, Antonio and Crespo, Javier and Day, Christopher P. and Eguchi, Yuichiro and Geier, Andreas and Kondili, Loreta A. and Kroy, Daniela C. and Lazarus, Jeffrey V. and Loomba, Rohit and Manns, Michael P. and Marchesini, Giulio and Nakajima, Atsushi and Negro, Francesco and Petta, Salvatore and Ratziu, Vlad and Romero-Gomez, Manuel and Sanyal, Arun and Schattenberg, J{\"o}rn M. and Tacke, Frank and Tanaka, Junko and Trautwein, Christian and Wei, Lai and Zeuzem, Stefan and Ravazi, Homie}, title = {Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030}, series = {Journal of Hepatology}, volume = {69}, journal = {Journal of Hepatology}, doi = {10.1016/j.jhep.2018.05.036}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227286}, pages = {896-904}, year = {2018}, abstract = {Background \& Aims Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. Methods A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. Results If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30\%), between 2016-2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15-56\%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population. Conclusions NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden. Lay summary Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.}, language = {en} } @phdthesis{Fleissner2024, author = {Fleißner, Janik Frank Hans-Werner}, title = {Die Bedeutung von Oncostatin M f{\"u}r die Lipidhom{\"o}ostase Apoe- und Ldlr-deletierter M{\"a}use}, doi = {10.25972/OPUS-28059}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-280592}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {OSM, ein Vertreter der IL-6-Typ-Zytokine, ist nicht nur f{\"u}r entz{\"u}ndliche, sondern auch f{\"u}r metabolische Prozesse von Bedeutung. Vorarbeiten der Arbeitsgruppe GEIER/HERMANNS und Studien von KOMORI et al. legen protektive Eigenschaften des Zytokins nahe, da M{\"a}use, denen OSMR fehlte, Charakteristika des metabolischen Syndroms aufwiesen. Zur eingehenderen Untersuchung der von OSM vermittelten Wirkung auf den murinen Lipidstoffwechsel wurden zwei f{\"u}r die NAFLD und Atherosklerose anf{\"a}llige Modelle herangezogen und jeweils in Gegenwart und Abwesenheit des Osmr studiert: Weibliche Apoe-/-(Osmr-/-) und Ldlr-/-(Osmr-/-) M{\"a}use wurden {\"u}ber einen Zeitraum von zw{\"o}lf Wochen mit westlicher Di{\"a}t gef{\"u}ttert, w{\"o}chentlich gewogen, am Ende der Di{\"a}t geopfert und geerntet. Wildtypische C57Bl/6-M{\"a}use erfuhren die gleiche Behandlung und dienten als Referenzgruppe. Im Rahmen des Promotionsprojektes wurden Leberfettgehalt, Serumlipidspiegel, Lipoproteinfraktionen und Stuhllipide von Apoe-deletierten M{\"a}usen bestimmt und mit bereits vorhandenen Daten der Ldlr-/-(Osmr-/-) und wildtypischen M{\"a}use in Beziehung gesetzt. Expressionsanalysen von am Lipidstoffwechsel beteiligten Genen in Darm-, Leber- und Fettgewebe trugen dazu bei, OSM-abh{\"a}ngige Regulationen aufzudecken. Ldlr-/- Tiere nahmen unter der Di{\"a}t exzessiv zu, hatten hohe Serumspiegel an Leptin, Gluco-se und Lipiden, eine Lebersteatose und, begleitet von einer Induktion des Vldlr, erh{\"o}hte inflammatorische Marker im visceralen Fettgewebe. Der zus{\"a}tzliche Knockout des Osmr ging mit einer geringeren Vldlr-Expression im Fettgewebe und einer hepatozyt{\"a}ren Induktion von Cyp7a1 einher und resultierte in einem metabolisch g{\"u}nstigeren Ph{\"a}notyp. Apoe-defiziente Tiere unterschieden sich hinsichtlich ihrer Gewichtszunahme nicht von Ldlr-/-Osmr-/- und C57Bl/6-M{\"a}usen. {\"U}berraschenderweise zeigten sich im Serum von Apoe-/-Osmr-/- jedoch gegen{\"u}ber Apoe-/- M{\"a}usen erh{\"o}hte Konzentrationen des Gesamt- und VLDL-Cholesterins, der Triglyceride und freien Fetts{\"a}uren. Obwohl Lebern der Apoe-/-Osmr-/- M{\"a}use geringere Ldlr- und Lrp1-mRNA-Spiegel als die der Apoe-/- M{\"a}use aufwiesen, hatten sie einen h{\"o}heren hepatischen Cholesteringehalt. Bei gesteigerter Cpt1a-Expression fiel der hepatische Tri-glyceridgehalt Apoe-deletierter M{\"a}use geringer aus als in Ldlr-/-(Osmr-/-) und wildtypischen Tieren. Unter Umgehung einer Fettgewebsentz{\"u}ndung pr{\"a}sentierten Apoe-defiziente M{\"a}use Hinweise einer inflammatorischen Lebersch{\"a}digung, die pathogenetisch am ehesten mit einer gest{\"o}rten Cholesterinhom{\"o}ostase in Verbindung zu bringen war. Abh{\"a}ngig vom genetischen Hintergrund des Mausmodells hatte OSM sch{\"u}tzende oder sch{\"a}dliche Effekte auf den Lipidmetabolismus. Die Ergebnisse der vorliegenden Arbeit betonen die entscheidende Bedeutung entz{\"u}ndlicher, von OSM modulierter Prozesse f{\"u}r den Fettstoffwechsel in Leber- und Fettgewebe. Weiterf{\"u}hrende Experimente sind n{\"o}tig, um die den Beobachtungen zugrunde liegenden molekularen Mechanismen zu entschl{\"u}sseln.}, subject = {Apolipoprotein E}, language = {de} } @article{HoeniglOraschFaserletal.2019, author = {Hoenigl, Martin and Orasch, Thomas and Faserl, Klaus and Prattes, Juergen and Loeffler, Juergen and Springer, Jan and Gsaller, Fabio and Reischies, Frederike and Duettmann, Wiebke and Raggam, Reinhard B. and Lindner, Herbert and Haas, Hubertus}, title = {Triacetylfusarinine C: A urine biomarker for diagnosis of invasive aspergillosis}, series = {Journal of Infection}, volume = {78}, journal = {Journal of Infection}, doi = {10.1016/j.jinf.2018.09.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320939}, pages = {150-157}, year = {2019}, abstract = {Objectives Early diagnosis of invasive aspergillosis (IA) remains challenging, with available diagnostics being limited by inadequate sensitivities and specificities. Triacetylfusarinine C, a fungal siderophore that has been shown to accumulate in urine in animal models, is a potential new biomarker for diagnosis of IA. Methods We developed a method allowing absolute and matrix-independent mass spectrometric quantification of TAFC. Urine TAFC, normalized to creatinine, was determined in 44 samples from 24 patients with underlying hematologic malignancies and probable, possible or no IA according to current EORTC/MSG criteria and compared to other established biomarkers measured in urine and same-day blood samples. Results TAFC/creatinine sensitivity, specificity, positive and negative likelihood ratio for probable versus no IA (cut-off ≥ 3) were 0.86, 0.88, 6.86, 0.16 per patient. Conclusion For the first time, we provide proof for the occurrence of TAFC in human urine. TAFC/creatinine index determination in urine showed promising results for diagnosis of IA offering the advantages of non-invasive sampling. Sensitivity and specificity were similar as reported for GM determination in serum and bronchoalveolar lavage, the gold standard mycological criterion for IA diagnosis.}, language = {en} } @article{HeimannPenackHeinzetal.2019, author = {Heimann, Sebastian M. and Penack, Olaf and Heinz, Werner J. and Rachow, Tobias and Egerer, Gerlinde and Kessel, Johanna and Claßen, Annika Y. and Vehreschild, J{\"o}rg Janne}, title = {Intravenous and tablet formulation of posaconazole in antifungal therapy and prophylaxis: A retrospective, non-interventional, multicenter analysis of hematological patients treated in tertiary-care hospitals}, series = {International Journal of Infectious Diseases}, volume = {83}, journal = {International Journal of Infectious Diseases}, doi = {10.1016/j.ijid.2019.04.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319567}, pages = {130-138}, year = {2019}, abstract = {Objectives Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness. Methods We set up a web-based registry on www.ClinicalSurveys.net for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively. Results Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 - 03/2016 were observed. Median age was 58 years (range: 19 - 77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76\%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 μg/L (IQR 573-1,498 μg/L) and 904 μg/L (IQR 728-1,550 μg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6\%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86\%. The median overall duration of POS therapy was 18 days (IQR: 7 - 23 days). Fourteen patients (48\%) had progressive IFD under POS therapy, of these five patients (36\%) died related to or likely related to IFD. Conclusions Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species.}, language = {en} } @article{MuellerJungWinteretal.2018, author = {Mueller, Dolores and Jung, Kathrin and Winter, Manuel and Rogoll, Dorothee and Melcher, Ralph and Kulozik, Ulrich and Schwarz, Karin and Richling, Elke}, title = {Encapsulation of anthocyanins from bilberries - Effects on bioavailability and intestinal accessibility in humans}, series = {Food Chemistry}, volume = {248}, journal = {Food Chemistry}, doi = {10.1016/j.foodchem.2017.12.058}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224247}, pages = {217-224}, year = {2018}, abstract = {Anthocyanins are flavonoids that have been suggested to provide beneficial health effects. The biological activity of anthocyanins is influenced by their pharmacokinetic properties, but anthocyanins are associated with limited bioavailability in humans. In the presented study, we investigated how the encapsulation of bilberry extract (BE), a source of anthocyanins, with either whey protein or citrus pectin influences the bioavailability and intestinal accessibility of anthocyanins in humans. We performed an intervention study that analyzed anthocyanins and their degradation products in the urine, plasma, and ileal effluent of healthy volunteers and ileostomists (subjects without an intact colon). We were able to show, that whey protein encapsulation modulated short-term bioavailability and that citrus pectin encapsulation increased intestinal accessibility during passage through the small intestine and modulated the formation of the degradation product phloroglucinol aldehyde (PGAL) in human plasma.}, language = {en} } @phdthesis{Mueller2024, author = {M{\"u}ller, Nicole}, title = {Modellierung klonaler Evolution beim Multiplen Myelom}, doi = {10.25972/OPUS-37081}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370818}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In dieser Arbeit wurde ein modulares Zelllinienmodell zur Visualisierung klonaler Evolutionsmechanismen etabliert. Hierf{\"u}r wurden unterschiedlich fluoreszierende Proteine (LSSmKate2, EGFP, mTagBFP2) durch Anwendung eines Sleeping Beauty basierten Vektorsystems in unterschiedliche Sublinien der Myelom Zelllinie L363 eingebracht. Diese vier Sublinien beinhalten jeweils eine von drei aus prim{\"a}ren Patientenproben gewonnenen Mutationen in IKZF1 (A152T, E170D, R439H) oder den IKZF1 WT. Die Anwendung von immunmodulatorischen Medikamenten (IMiDs) f{\"u}hrt zu einer Ubiquitinierung des Transkriptionsfaktors IKZF1 durch die E3-Ubiquitin-Protein-Ligase (CRBN-CUL4). Durch Mutationen in IKZF1 kommt es zu St{\"o}rungen in diesem Prozess und damit zu einer {\"U}berexpression von IKZF1. Dies wirkt sich wachstumsf{\"o}rdert auf die Myelomzellen aus. Die Auswirkungen der einzelnen Mutationen in IKZF1 ist aufgrund dessen ein klinisch relevantes Forschungsthema. In dieser Arbeit wurden jeweils zwei Sublinien mit Zellen des IKZF1 WT und Zellen mit einer IKZF1 Mutation mit jeweils unterschiedlich fluoreszierenden Proteinen markiert. Diese wurden gemeinsam unter Behandlung mit verschiedenen Konzentrationen von Lenalidomid inkubiert. Somit konnte das Selektionsverhalten mittels Durchflusszytometrie-Auswertungen visualisiert werden. Es konnte gezeigt werden, dass die IKZF1 Mutation A152T einen deutlichen Selektionsvorteil f{\"u}r die Myelomzellen darstellt. Bei den IKZF1 Mutationen E170D und R439H konnte kein Selektionsvorteil gegen{\"u}ber dem IKZF1 WT beobachtet werden.}, subject = {Lenalidomid}, language = {de} } @phdthesis{Weis2024, author = {Weis, Philipp}, title = {Translationale Untersuchung zur Anwendung der durchflusszytometrischen Bestimmung \(Aspergillus\) \(fumigatus\) spezifischer T-Zellen in der Diagnostik von Aspergillosen}, doi = {10.25972/OPUS-37114}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371145}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Bei Patienten mit invasiver Aspergillose fanden sich gegen{\"u}ber gesunden Probanden deutlich erh{\"o}hte Werte A. fumigatus spezifischer CD154+/CD4+ Zellen. Die Anwendbarkeit dieses Assays im klinischen Routinebetrieb und bei gegen{\"u}ber A. fumigatus epxonierten Probanden und Patienten sollte in dieser translationalen Arbeit untersucht werden. F{\"u}r den vorbeschriebenen Assay zur Bestimmung CD154+/CD4+ Zellen aus aufgereinigten PBMCs zeigt diese Arbeit eine signifikant reduzierte Detektionsrate nach Blutprobenlagerung von {\"u}ber 2 Stunden. In der Literatur beschriebene Verfahren zur verl{\"a}ngerten Lagerungszeit von heparinisierten Blutproben mittels vorhergehender Dilution und Agitation erm{\"o}glichen keine Verl{\"a}ngerung pr{\"a}analytischer Lagerungszeiten {\"u}ber 6 Stunden. Die Kryokonservierung frisch aufbereiteter PBMCs bei -20 C vor Bestimmung A. fumigatus spezifischer T-Zellen wird als Versandm{\"o}glichkeit in einem multizentrischen Setting gezeigt. Um die klinische Anwendbarkeit zu verbessern, wird ein Vollblutprotokoll zur Detektion A. fumigatus spezifischer CD154+/CD4+ Zellen demonstriert, das die Verwendung von bettseitig mit Vollblut beimpften Blutmonovetten mit vorgelegtem A. fumigatus-Lysat erm{\"o}glicht. Die Anwendung des Assays zur Bestimmung A. fumigatus spezifischer T-Zellen wurde bei h{\"a}matoonkologischen Patienten vor und drei Monate nach Stammzelltransplantation untersucht. Insbesondere eine reduzierte Zellzahl der gemessenen Lymphozyten ist hier ein limitierender Faktor der erfolgreichen Messung. Aufgrund der generell nied- rigen Erfolgsrate von 20 \% bzw. 54 \% vor bzw. nach HSCT ist die Anwendbarkeit des Assays in diesem Kollektiv fraglich. Die Erhebung von Expositionsfaktoren gesunder Probanden gegen{\"u}ber A. fumigatus erm{\"o}glicht die Einteilung in eine schwach und stark gegen{\"u}ber A. fumigatus exponierte Gruppe mit signifikant erh{\"o}htem Anteil A. fumigatus spezifischer CD154+/CD4+ Zellen. Hierzu tr{\"a}gt insbesondere das Vorliegen antigenspezifischer T-Ged{\"a}chtniszellen als Korrelat einer langfristigen Exposition bei. Retrospektiv fand sich auch nach kurzfris- tiger beruflicher Exposition ein Anstieg CD154+/CD4+ spezifischer T-Zellen. Dies legt eine Verwendung CD154+/CD4+ spezifischer T-Zellen als Biomarker in Bereichen der umweltmedizinischen Abkl{\"a}rung von Schimmelpilzexposition oder der Diagnostik allergischer Erkrankungen nahe.}, subject = {Aspergillus fumigatus}, language = {de} } @article{KampfReiterBauer2018, author = {Kampf, Thomas and Reiter, Theresa and Bauer, Wolfgang Rudolf}, title = {An analytical model which determines the apparent T1 for Modified Look-Locker Inversion Recovery - Analysis of the longitudinal relaxation under the influence of discontinuous balanced (classical MOLLI) and spoiled gradient echo readouts}, series = {Zeitschrift f{\"u}r Medizinische Physik}, volume = {28}, journal = {Zeitschrift f{\"u}r Medizinische Physik}, doi = {10.1016/j.zemedi.2017.07.004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325498}, pages = {150-157}, year = {2018}, abstract = {Quantitative nuclear magnetic resonance imaging (MRI) shifts more and more into the focus of clinical research. Especially determination of relaxation times without/and with contrast agents becomes the foundation of tissue characterization, e.g. in cardiac MRI for myocardial fibrosis. Techniques which assess longitudinal relaxation times rely on repetitive application of readout modules, which are interrupted by free relaxation periods, e.g. the Modified Look-Locker Inversion Recovery = MOLLI sequence. These discontinuous sequences reveal an apparent relaxation time, and, by techniques extrapolated from continuous readout sequences, a putative real T1 is determined. What is missing is a rigorous analysis of the dependence of the apparent relaxation time on its real partner, readout sequence parameters and biological parameters as heart rate. This is provided in this paper for the discontinuous balanced steady state free precession (bSSFP) and spoiled gradient echo readouts. It turns out that the apparent longitudinal relaxation rate is the time average of the relaxation rates during the readout module, and free relaxation period. Knowing the heart rate our results vice versa allow to determine the real T1 from its measured apparent partner.}, language = {en} } @article{DuellLammersDjureticetal.2019, author = {Duell, Johannes and Lammers, Philip E. and Djuretic, Ivana and Chunyk, Allison G. and Alekar, Shilpa and Jacobs, Ira and Gill, Saar}, title = {Bispecific Antibodies in the Treatment of Hematologic Malignancies}, series = {Clinical Pharmacology \& Therapeutics}, volume = {106}, journal = {Clinical Pharmacology \& Therapeutics}, doi = {10.1002/cpt.1396}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226392}, pages = {781-791}, year = {2019}, abstract = {Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single-agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single-agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients.}, language = {en} } @article{GilesGreenhalghDenesetal.2018, author = {Giles, James A. and Greenhalgh, Andrew D. and Denes, Adam and Nieswandt, Bernhard and Coutts, Graham and McColl, Barry W. and Allan, Stuart M.}, title = {Neutrophil infiltration to the brain is platelet-dependent, and is reversed by blockade of platelet GPIbα}, series = {Immunology}, volume = {154}, journal = {Immunology}, doi = {10.1111/imm.12892}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233048}, pages = {322-328}, year = {2018}, abstract = {Neutrophils are key components of the innate immune response, providing host defence against infection and being recruited to non-microbial injury sites. Platelets act as a trigger for neutrophil extravasation to inflammatory sites but mechanisms and tissue-specific aspects of these interactions are currently unclear. Here, we use bacterial endotoxin in mice to trigger an innate inflammatory response in different tissues and measure neutrophil invasion with or without platelet reduction. We show that platelets are essential for neutrophil infiltration to the brain, peritoneum and skin. Neutrophil numbers do not rise above basal levels in the peritoneum and skin and are decreased (~60\%) in the brain when platelet numbers are reduced. In contrast neutrophil infiltration in the lung is unaffected by platelet reduction, up-regulation of CXCL-1 (2·4-fold) and CCL5 (1·4-fold) acting as a compensatory mechanism in platelet-reduced mice during lung inflammation. In brain inflammation targeting platelet receptor GPIbα results in a significant decrease (44\%) in platelet-mediated neutrophil invasion, while maintaining platelet numbers in the circulation. These results suggest that therapeutic blockade of platelet GPIbα could limit the harmful effects of excessive inflammation while minimizing haemorrhagic complications of platelet reduction in the brain. The data also demonstrate the ability to target damaging brain inflammation in stroke and related disorders without compromising lung immunity and hence risk of pneumonia, a major complication post stroke. In summary, our data reveal an important role for platelets in neutrophil infiltration to various tissues, including the brain, and so implicate platelets as a key, targetable component of cerebrovascular inflammatory disease or injury.}, language = {en} }