IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases - Shen, Ping; Roch, Toralf; Lampropoulou, Vicky; O'Connor, Richard A.; Stervbo, Ulrik; Hilgenberg, Ellen; Ries, Stefanie; Van Duc Dang,; Jaimes, Yarua; Daridon, Capucine; Li, Rui; Jouneau, Luc; et al. (Nature, 2014)
B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.
EVALuna2:1911

IL-36 in chronic inflammation and cancer - Neurath, Markus (Cytokine & Growth Factor Reviews, 2020)
IL-36 belongs to the IL-1 family of cytokines and activates target cells by binding to a specific cytokine receptor (IL-36R) followed by activation of intracellular regulators such as MAP kinases and NF-kappaB. Three subforms of IL-36, denoted IL-36alpha, IL-36beta and IL-36gamma, have been described that require N-terminal cleavage for activation. Functional studies have shown that IL-36 may activate a broad spectrum of immune and non-immune cells such as macrophages, T cells, keratinocytes and epithelial cells in an IL-1-independent fashion and thereby controls various inflammatory or oncogenic processes in the skin, the lung, the kidney, the liver and the intestine, respectively. Based on the presence of mutations of the IL-36RN in patients with generalized pustular psoriasis, successful clinical pilot trials with IL-36R blocking antibodies were conducted in these patients and further studies in patients with autoimmune or chronic inflammatory disorders such as inflammatory bowel diseases are under way. Collectively, these findings highlight a crucial regulatory role of IL-36 signaling in driving various inflammatory disorders that provide a rational basis for clinical targeting of this cytokine.
CRIS-Team Scopus Importer:2020-06-26
Keywords: Cytokines; IL-36; Immune cells; Inflammation

IL-36 in chronic inflammation and fibrosis - bridging the gap? - Elias, Michael; Zhao, Shuai; Le, Hongnga T.; Wang, Jie; Neurath, Markus; Neufert, Clemens; Fiocchi, Claudio; Rieder, Florian (Journal of Clinical Investigation, 2021)
IL-36 is a member of the IL-1 superfamily and consists of three agonists and one receptor antagonist (IL-36Ra). The three endogenous agonists, IL-36α, -β, and -γ, act primarily as proinflammatory cytokines, and their signaling through the IL-36 receptor (IL-36R) promotes immune cell infiltration and secretion of inflammatory and chemotactic molecules. However, IL-36 signaling also fosters secretion of profibrotic soluble mediators, suggesting a role in fibrotic disorders. IL-36 isoforms and IL-36 have been implicated in inflammatory diseases including psoriasis, arthritis, inflammatory bowel diseases, and allergic rhinitis. Moreover, IL-36 has been connected to fibrotic disorders affecting the kidney, lung, and intestines. This review summarizes the expression, cellular source, and function of IL-36 in inflammation and fibrosis in various organs, and proposes that IL-36 modulation may prove valuable in preventing or treating inflammatory and fibrotic diseases and may reveal a mechanistic link between inflammation and fibrosis.
CRIS-Team Scopus Importer:2021-02-05

IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo - Scheibe, Kristina; Backert, Ingo; Wirtz, Stefan; Hueber, Axel; Schett, Georg; Vieth, Michael; Probst, Hans Christian; Bopp, Tobias; Neurath, Markus; Neufert, Clemens (Gut, 2016)
Interleukin (IL)-36R signalling plays a proinflammatory role in different organs including the skin, but the expression of IL-36R ligands and their molecular function in intestinal inflammation are largely unknown.We studied the characteristics of IL-36R ligand expression in IBDs and experimental colitis. The functional role of IL-36R signalling in the intestine was addressed in experimental colitis and wound healing models in vivo by using mice with defective IL-36R signalling (IL-36R-/-) or Myd88, neutralising anti-IL-36R antibodies, recombinant IL-36R ligands and RNA-seq genome expression analysis.Expression of IL-36? and IL-36? was significantly elevated in active human IBD and experimental colitis. While IL-36? was predominantly detected in nuclei of the intestinal epithelium, IL-36? was mainly found in the cytoplasm of CD14(+) inflammatory macrophages. Functional studies showed that defective IL-36R signalling causes high susceptibility to acute dextran sodium sulfate colitis and impairs wound healing. Mechanistically, IL-36R ligands released upon mucosal damage activated IL-36R(+) colonic fibroblasts via Myd88 thereby inducing expression of chemokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-6. Moreover, they induced proliferation of intestinal epithelial cells (IECs) and expression of the antimicrobial protein lipocalin 2. Finally, treatment of experimental intestinal wounds with IL-36R ligands significantly accelerated mucosal healing in vivo.IL-36R signalling is activated upon intestinal damage, stimulates IECs and fibroblasts and drives mucosal healing. Modulation of the IL-36R pathway emerges as a potential therapeutic strategy for induction of mucosal healing in IBD.
EVALuna2:2028

IL-3 drives IL-10-secreting Tr1 cells to counteract experimental colitis - Zundler, Sebastian; Spocinska, M.; Popp, V.; Becker, E.; Atreya, Raja; Neufert, Clemens; Atreya, I.; Weigmann, Benno; Neurath, Markus (2018)
EVALuna2:34113

IL-3 receptor signalling suppresses chronic intestinal inflammation by controlling mechanobiology and tissue egress of regulatory T cells. - Ullrich, Karen; Derdau, Julia; Baltes, Carsten; Battistella, Alice; Rosso, Gonzalo; Uderhardt, Stefan; Schulze, Lisa; Liu, Lijuan; Dedden, Mark; Spocinska, Marta; Kainka, Lucina; Kubánková, Markéta; et al. (Gut, 2023)
IL-3 has been reported to be involved in various inflammatory disorders, but its role in inflammatory bowel disease (IBD) has not been addressed so far. Here, we determined IL-3 expression in samples from patients with IBD and studied the impact of Il3 or Il3r deficiency on T cell-dependent experimental colitis. We explored the mechanical, cytoskeletal and migratory properties of Il3r -/- and Il3r +/+ T cells using real-time deformability cytometry, atomic force microscopy, scanning electron microscopy, fluorescence recovery after photobleaching and in vitro and in vivo cell trafficking assays. We observed that, in patients with IBD, the levels of IL-3 in the inflamed mucosa were increased. In vivo, experimental chronic colitis on T cell transfer was exacerbated in the absence of Il-3 or Il-3r signalling. This was attributable to Il-3r signalling-induced changes in kinase phosphorylation and actin cytoskeleton structure, resulting in increased mechanical deformability and enhanced egress of Tregs from the inflamed colon mucosa. Similarly, IL-3 controlled mechanobiology in human Tregs and was associated with increased mucosal Treg abundance in patients with IBD. Collectively, our data reveal that IL-3 signaling exerts an important regulatory role at the interface of biophysical and migratory T cell features in intestinal inflammation and suggest that this might be an interesting target for future intervention.
EVALuna2:539503

IL-4 and helminth infection downregulate MINCLE-dependent macrophage response to mycobacteria and Th17 adjuvanticity - Schick, Judith; Altunay, Meltem; Lacorcia, Matthew; Marschner, Nathalie; Westermann, Stefanie; Schluckebier, Julia; Schubart, Christoph; Bodendorfer, Barbara; Christensen, Dennis; Alexander, Christian; Wirtz, Stefan; Vöhringer, David; et al. (eLife, 2023)
The myeloid C-type lectin receptor (CLR) MINCLE senses the mycobacterial cell wall component trehalose-6,6'-dimycolate (TDM). Recently, we found that IL-4 downregulates MINCLE expression in macrophages. IL-4 is a hallmark cytokine in helminth infections, which appear to increase the risk for mycobacterial infection and active tuberculosis. Here, we investigated functional consequences of IL-4 and helminth infection on MINCLE-driven macrophage activation and Th1/Th17 adjuvanticity. IL-4 inhibited MINCLE and cytokine induction after macrophage infection with Mycobacterium bovis bacille Calmette-Guerin (BCG). Infection of mice with BCG upregulated MINCLE on myeloid cells, which was inhibited by IL-4 plasmid injection and by infection with the nematode Nippostrongylus brasiliensis in monocytes. To determine the impact of helminth infection on MINCLE-dependent immune responses, we vaccinated mice with a recombinant protein together with the MINCLE ligand trehalose-6,6-dibehenate (TDB) as adjuvant. Concurrent infection with N. brasiliensis or with Schistosoma mansoni promoted T cell-derived IL-4 production and suppressed Th1/Th17 differentiation in the spleen. In contrast, helminth infection did not reduce Th1/Th17 induction by TDB in draining peripheral lymph nodes, where IL-4 levels were unaltered. Upon use of the TLR4-dependent adjuvant G3D6A, N. brasiliensis infection impaired selectively the induction of splenic antigen-specific Th1 but not of Th17 cells. Inhibition of MINCLE-dependent Th1/Th17 responses in mice infected with N. brasiliensis was dependent on IL-4/IL-13. Thus, helminth infection attenuated the Th17 response to MINCLE-dependent immunization in an organ- and adjuvant-specific manner via the Th2 cytokines IL-4/IL-13. Taken together, our results demonstrate downregulation of MINCLE expression on monocytes and macrophages by IL-4 as a possible mechanism of thwarted Th17 vaccination responses by underlying helminth infection.
CRIS-Team Scopus Importer:2023-02-17
Keywords: C-type lectin receptors; co-infection; immunology; infectious disease; inflammation; microbiology; mouse; mycobacterial cord factor; Nippostrongylus brasiliensis; Schistosoma mansoni; Th cell differentiation

IL-4/IL-13-producing ILC2s are required for timely control of intestinal helminth infection in mice - Varela, Filipa; Symowski, Cornelia; Pollock, Jonathan; Wirtz, Stefan; Vöhringer, David (European Journal of Immunology, 2022)
Infection of mice with Nippostrongylus brasiliensis (Nb) serves as a model for human hookworm infection affecting about 600 million people world-wide. Expulsion of Nb from the intestine requires IL-13-mediated mucus secretion from goblet cells and activation of smooth muscles cells. Type 2 innate lymphoid cells (ILC2s) are a major cellular source of IL-13 but it remains unclear whether IL-13 secretion from ILC2s is required for Nb expulsion. Here, we compared the immune response to Nb infection in mixed bone marrow chimeras with wild-type or IL-4/IL-13-deficient ILC2s. ILC2-derived IL-4/IL-13 was required for recruitment of eosinophils to the lung but had no influence of systemic eosinophil levels. In the small intestine, goblet cell hyperplasia and tuft cell accumulation was largely dependent on IL-4/IL-13 secretion from ILC2s. This further translated to higher eggs counts and impaired worm expulsion in mice with IL-4/IL-13-deficient ILC2s. Overall, we demonstrate that ILC2s constitute a non-redundant source of IL-4/IL-13 required for protective immunity against primary Nb infection.
CRIS-Team Scopus Importer:2022-10-14
Keywords: bone marrow chimeras; eosinophils; IL-4/IL-13; ILC2; intestinal helminth infection

IL-9 and its receptor are predominantly involved in the pathogenesis of UC - Nalleweg, Nancy; Chiriac, Mircea Teodor; Podstawa, Eva; Lehmann, Christian; Rau, Tilman; Atreya, Raja; Krauss, Ekaterina; Hundorfean, Gheorghe; Fichtner-Feigl, Stefan; Hartmann, Arndt; Becker, Christoph; Mudter, Jonas (Gut, 2015)
Several pathogenic roles attributed over the past two decades to either T helper (Th)1 or Th2 cells are increasingly becoming associated with interleukin (IL)-17 and most recently IL-9 signalling. However, the implication of IL-9 in IBD has not been addressed so far.We investigated the expression of IL-9 and IL-9R by using peripheral blood, biopsies and surgical samples. We addressed the functional role of IL-9 signalling by analysis of downstream effector proteins. Using Caco-2 cell monolayers we followed the effect of IL-9 on wound healing.IL-9 mRNA expression was significantly increased in inflamed samples from patients with UC as compared with controls. CD3(+) T cells were major IL-9-expressing cells and some polymorphonuclear leucocytes (PMN) also expressed IL-9. IL-9 was co-localised with the key Th9 transcription factors interferon regulatory factor 4 and PU.1. Systemically, IL-9 was abundantly produced by activated peripheral blood lymphocytes, whereas its receptor was overexpressed on gut resident and circulating PMN. IL-9 stimulation of the latter induced IL-8 production in a dose-dependent manner and rendered PMN resistant to apoptosis suggesting a functional role for IL-9R signalling in the propagation of gut inflammation. Furthermore, IL-9R was overexpressed on gut epithelial cells and IL-9 induced STAT5 activation in these cells. Moreover, IL-9 inhibited the growth of Caco-2 epithelial cell monolayers in wound healing experiments.Our results provide evidence that IL-9 is predominantly involved in the pathogenesis of UC suggesting that targeting IL-9 might become a therapeutic option for patients with UC.
EVALuna2:1839

IL-9 Producing Tumor-Infiltrating Lymphocytes and Treg Subsets Drive Immune Escape of Tumor Cells in Non-Small Cell Lung Cancer - Heim, Lisanne; Yang, Zuqin; Tausche, Patrick; Hohenberger, Katja; Chiriac, Mircea-Teodor; Kölle, Julia; Geppert, Carol-Immanuel; Kachler, Katerina; Miksch, Sarah; Graser, Anna; Friedrich, Juliane; Kharwadkar, Rakshin; et al. (Frontiers in Immunology, 2022)
Although lung cancer is the leading cause of cancer deaths worldwide, the mechanisms how lung cancer cells evade the immune system remain incompletely understood. Here, we discovered IL-9-dependent signaling mechanisms that drive immune evasion in non-small cell lung cancer (NSCLC). We found increased IL-9 and IL-21 production by T cells in the tumoral region of the lung of patients with NSCLC, suggesting the presence of Th9 cells in the lung tumor microenvironment. Moreover, we noted IL-9 producing Tregs in NSCLC. IL-9 target cells in NSCLC consisted of IL-9R+ tumor cells and tumor-infiltrating lymphocytes. In two murine experimental models of NSCLC, and in vitro, IL-9 prevented cell death and controlled growth of lung adenocarcinoma cells. Targeted deletion of IL-9 resulted in successful lung tumor rejection in vivo associated with an induction of IL-21 and reduction of Treg cells. Finally, anti-IL-9 antibody immunotherapy resulted in suppression of tumor development even in established experimental NSCLC and was associated with reduced IL-10 production in the lung. In conclusion, our findings indicate that IL-9 drives immune escape of lung tumor cells via effects on tumor cell survival and tumor infiltrating T cells. Thus, strategies blocking IL-9 emerge as a new approach for clinical therapy of lung cancer.
CRIS-Team Scopus Importer:2022-05-20
Keywords: IL-9; immune escape; NSCLC; TIL; tumor immunotherapy

IL-9 regulates intestinal barrier function in experimental T cell-mediated colitis - Gerlach, Katharina; McKenzie, Andrew N.; Neurath, Markus; Weigmann, Benno (Tissue Barriers, 2015)
As previous studies suggested that IL-9 may control intestinal barrier function, we tested the role of IL-9 in experimental T cell-mediated colitis induced by the hapten reagent 2,4,6-trinitrobenzenesulfonic acid (TNBS). The deficiency of IL-9 suppressed TNBS-induced colitis and led to lower numbers of PU.1 expressing T cells in the lamia propria, suggesting a regulatory role for Th9 cells in the experimental TNBS colitis model. Since IL-9 is known to functionally alter intestinal barrier function in colonic inflammation, we assessed the expression of tight junction molecules in intestinal epithelial cells of TNBS-inflamed mice. Therefore we made real-time PCR analyses for tight junction molecules in the inflamed colon from wild-type and IL-9 KO mice, immunofluorescent stainings and investigated the expression of junctional proteins directly in intestinal epithelial cells of TNBS-inflamed mice by Western blot studies. The results demonstrated that sealing proteins like occludin were up regulated in the colon of inflamed IL-9 KO mice. In contrast, the tight junction protein Claudin1 showed lower expression levels when IL-9 is absent. Surprisingly, the pore-forming molecule Claudin2 revealed equal expression in TNBS-treated wild-type and IL-9-deficient animals. These results illustrate the pleiotropic functions of IL-9 in changing intestinal permeability in experimental colitis. Thus, modulation of IL-9 function emerges as a new approach for regulating barrier function in intestinal inflammation.
EVALuna2:2009

IL-9 signaling as key driver of chronic inflammation in mucosal immunity - Neurath, Markus; Finotto, Susetta (Cytokine & Growth Factor Reviews, 2016)
Recent studies have highlighted a crucial regulatory role of the cytokine IL-9 in driving immune responses in chronic inflammatory and autoimmune diseases at mucosal surfaces. IL-9 activates various types of immune and non-immune cells carrying the membrane bound IL-9R. IL-9 signaling plays a pivotal role in controlling the differentiation and activation of these cells by inducing the Jak/STAT pathway. In particular, IL-9 induces activation of T helper cells and affects the function of various tissue resident cells such as mast cells and epithelial cells in the mucosa. Importantly, recent findings suggest that blockade of IL-9 signaling is effective in treating experimental models of autoimmune and chronic inflammatory diseases such as inflammatory bowel diseases, allergic disorders such as food allergy and asthma. Thus, blockade of IL-9 and IL-9R signaling emerges as potentially novel approach for therapy of inflammatory diseases in the mucosal immune system.
EVALuna2:2054

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure - Schulz-Kuhnt, Anja; Greif, Vicky; Hildner, Kai; Knipfer, Lisa; Döbrönti, Michael; Zirlik, Sabine; Fuchs, Florian; Atreya, Raja; Zundler, Sebastian; Lopez Posadas, Rocío; Neufert, Clemens; Ramming, Andreas; et al. (Frontiers in Immunology, 2020)
Cystic fibrosis patients suffer from a progressive, often fatal lung disease, which is based on a complex interplay between chronic infections, locally accumulating immune cells and pulmonary tissue remodeling. Although group-2 innate lymphoid cells (ILC2s) act as crucial initiators of lung inflammation, our understanding of their involvement in the pathogenesis of cystic fibrosis remains incomplete. Here we report a marked decrease of circulating CCR6+ ILC2s in the blood of cystic fibrosis patients, which significantly correlated with high disease severity and advanced pulmonary failure, strongly implicating increased ILC2 homing from the peripheral blood to the chronically inflamed lung tissue in cystic fibrosis patients. On a functional level, the CCR6 ligand CCL20 was identified as potent promoter of lung-directed ILC2 migration upon inflammatory conditions in vitro and in vivo using a new humanized mouse model with light-sheet fluorescence microscopic visualization of lung-accumulated human ILC2s. In the lung, blood-derived human ILC2s were able to augment local eosinophil and neutrophil accumulation and induced a marked upregulation of pulmonary type-VI collagen expression. Studies in primary human lung fibroblasts additionally revealed ILC2-derived IL-4 and IL-13 as important mediators of this type-VI collagen-inducing effect. Taken together, the here acquired results suggest that pathologically increased CCL20 levels in cystic fibrosis airways induce CCR6-mediated lung homing of circulating human ILC2s. Subsequent ILC2 activation then triggers local production of type-VI collagen and might thereby drive extracellular matrix remodeling potentially influencing pulmonary tissue destruction in cystic fibrosis patients. Thus, modulating the lung homing capacity of circulating ILC2s and their local effector functions opens new therapeutic avenues for cystic fibrosis treatment.
CRIS-Team Scopus Importer:2020-06-02
Keywords: CCR6; cystic fibrosis; group-2 innate lymphoid cells; tissue remodeling; type-VI collagen

ILC2s in infectious diseases and organ-specific fibrosis - Kindermann, Markus; Knipfer, Lisa; Atreya, Imke; Wirtz, Stefan (Seminars in Immunopathology, 2018)
Type 2 immune responses evolved to provide host protection against parasitic infections and to support the repair of infection-induced tissue injury. However, persistent chronic organ damage can result in dysregulated production of critical type 2 cytokines supporting tissue remodeling and fibrosis development. Recently, group 2 innate lymphoid cells (ILC2s) were newly described as central innate mediators of type 2 responses. In particular, by secretion of the cytokines IL-5, IL-9, and IL-13 and the growth factor amphiregulin in response to the release of tissue-derived alarmins, ILC2s have been shown to substantially contribute to both the dismissal of metazoan parasites and the repair of infection-dependent or sterile tissue damage. Conversely, cytokine production by ILC2s emerged as a driving force for tissue remodeling and excessive fibrosis in several organ systems including the lung, liver, and skin. In this review, we discuss how ILC2s are specifically implicated in the body's immune response to different pathogenic infections and how dysregulated ILC2s may promote organ-specific fibrosis.
EVALuna2:35153

ILCs—Crucial Players in Enteric Infectious Diseases - Leupold, Tamara; Wirtz, Stefan (International Journal of Molecular Sciences, 2022)
Research of the last decade has remarkably increased our understanding of innate lymphoid cells (ILCs). ILCs, in analogy to T helper (Th) cells and their cytokine and transcription factor profile, are categorized into three distinct populations: ILC1s express the transcription factor T-bet and secrete IFNγ, ILC2s depend on the expression of GATA-3 and release IL-5 and IL-13, and ILC3s express RORγt and secrete IL-17 and IL-22. Noteworthy, ILCs maintain a level of plasticity, depending on exposed cytokines and environmental stimuli. Furthermore, ILCs are tissue resident cells primarily localized at common entry points for pathogens such as the gut-associated lymphoid tissue (GALT). They have the unique capacity to initiate rapid responses against pathogens, provoked by changes of the cytokine profile of the respective tissue. Moreover, they regulate tissue inflammation and homeostasis. In case of intracellular pathogens entering the mucosal tissue, ILC1s respond by secreting cytokines (e.g., IFNγ) to limit the pathogen spread. Upon infection with helminths, intestinal epithelial cells produce alarmins (e.g., IL-25) and activate ILC2s to secrete IL-13, which induces differentiation of intestinal stem cells into tuft and goblet cells, important for parasite expulsion. Additionally, during bacterial infection ILC3-derived IL-22 is required for bacterial clearance by regulating antimicrobial gene expression in epithelial cells. Thus, ILCs can limit infectious diseases via secretion of inflammatory mediators and interaction with other cell types. In this review, we will address the role of ILCs during enteric infectious diseases.
CRIS-Team Scopus Importer:2022-12-09
Keywords: crosstalk between ILCs and other immune cells; cytokine responses; enteric infections; ILC plasticity; innate lymphoid cells (ILCs); mucosal immunity; tissue homeostasis and ILCs

Ileal and colonic Crohn's disease: Does location makes a difference in therapy efficacy? - Atreya, Raja; Bojarski, Christian; Kühl, Anja A.; Trajanoski, Zlatko; Neurath, Markus; Siegmund, Britta (Current Research in Pharmacology and Drug Discovery, 2022)
Within the IBD entity of Crohn's disease, there is currently no differentiation between ileal and colonic manifestation for recruitment of patients in clinical trials, well-powered analysis of study results or therapeutic decisions in daily clinical practice. However, there is accumulating evidence from epidemiological, genetic, microbial, immunological, and clinical characteristics that clearly indicate that ileal Crohn's disease represents a distinct disease entity, which differentiates itself from colonic Crohn's disease. This is also reflected by lower efficacy of targeted therapies in isolated ileal compared to colonic Crohn's disease. The distinct site-specific mechanisms that drive heightened non-response in ileal disease need to be analysed in-depth in the future, to enable optimized therapy in the individual Crohn's disease patient.
CRIS-Team Scopus Importer:2022-04-08
Keywords: Colonic Crohn's disease; Crohn's disease; Ileal Crohn's disease; Segment; Therapy

Imaging in inflammatory arthritis: progress towards precision medicine - Minopoulou, Ioanna; Kleyer, Arnd; Yalcin-Mutlu, Melek; Fagni, Filippo; Kemenes, Stephan; Schmidkonz, Christian; Atzinger, Armin; Pachowsky, Milena; Engel, Klaus; Folle, Lukas; Roemer, Frank; Waldner, Maximilian; et al. (Nature Reviews Rheumatology, 2023)
Imaging techniques such as ultrasonography and MRI have gained ground in the diagnosis and management of inflammatory arthritis, as these imaging modalities allow a sensitive assessment of musculoskeletal inflammation and damage. However, these techniques cannot discriminate between disease subsets and are currently unable to deliver an accurate prediction of disease progression and therapeutic response in individual patients. This major shortcoming of today’s technology hinders a targeted and personalized patient management approach. Technological advances in the areas of high-resolution imaging (for example, high-resolution peripheral quantitative computed tomography and ultra-high field MRI), functional and molecular-based imaging (such as chemical exchange saturation transfer MRI, positron emission tomography, fluorescence optical imaging, optoacoustic imaging and contrast-enhanced ultrasonography) and artificial intelligence-based data analysis could help to tackle these challenges. These new imaging approaches offer detailed anatomical delineation and an in vivo and non-invasive evaluation of the immunometabolic status of inflammatory reactions, thereby facilitating an in-depth characterization of inflammation. By means of these developments, the aim of earlier diagnosis, enhanced monitoring and, ultimately, a personalized treatment strategy looms closer.
CRIS-Team Scopus Importer:2023-09-29

Imaging of Mucosal Inflammation: Current Technological Developments, Clinical Implications, and Future Perspectives - Waldner, Maximilian; Rath, Timo; Schürmann, Sebastian; Bojarski, Christian; Atreya, Raja (Frontiers in Immunology, 2017)
In recent years, various technological developments markedly improved imaging of mucosal inflammation in patients with inflammatory bowel diseases. Although technological developments such as high-definition-, chromo-, and autofluorescence-endoscopy led to a more precise and detailed assessment of mucosal inflammation during wide-field endoscopy, probe-based and stationary confocal laser microscopy enabled in vivo real-time microscopic imaging of mucosal surfaces within the gastrointestinal tract. Through the use of fluorochromes with specificity against a defined molecular target combined with endoscopic techniques that allow ultrastructural resolution, molecular imaging enables in vivo visualization of single molecules or receptors during endoscopy. Molecular imaging has therefore greatly expanded the clinical utility and applications of modern innovative endoscopy, which include the diagnosis, surveillance, and treatment of disease as well as the prediction of the therapeutic response of individual patients. Furthermore, non-invasive imaging techniques such as computed tomography, magnetic resonance imaging, scintigraphy, and ultrasound provide helpful information as supplement to invasive endoscopic procedures. In this review, we provide an overview on the current status of advanced imaging technologies for the clinical non-invasive and endoscopic evaluation of mucosal inflammation. Furthermore, the value of novel methods such as multiphoton microscopy, optoacoustics, and optical coherence tomography and their possible future implementation into clinical diagnosis and evaluation of mucosal inflammation will be discussed.
EVALuna2:33891

Imaging the Parasinus Region with a Third-Generation Dual-Source CT and the Effect of Tin Filtration on Image Quality and Radiation Dose - Lell, Michael; May, Matthias; Brand, Michael; Eller, A.; Buder, Thomas; Hofmann, Eva Maria; Uder, Michael; Wüst, Wolfgang (American Journal of Neuroradiology, 2015)
CT is the imaging technique of choice in the evaluation of midface trauma or inflammatory disease. We performed a systematic evaluation of scan protocols to optimize image quality and radiation exposure on third-generation dual-source CT.CT protocols with different tube voltage (70-150 kV), current (25-300 reference mAs), prefiltration, pitch value, and rotation time were systematically evaluated. All images were reconstructed with iterative reconstruction (Advanced Modeled Iterative Reconstruction, level 2). To individually compare results with otherwise identical factors, we obtained all scans on a frozen human head. Conebeam CT was performed for image quality and dose comparison with multidetector row CT. Delineation of important anatomic structures and incidental pathologic conditions in the cadaver head was evaluated.One hundred kilovolts with tin prefiltration demonstrated the best compromise between dose and image quality. The most dose-effective combination for trauma imaging was Sn100 kV/250 mAs (volume CT dose index, 2.02 mGy), and for preoperative sinus surgery planning, Sn100 kV/150 mAs (volume CT dose index, 1.22 mGy). "Sn" indicates an additional prefiltration of the x-ray beam with a tin filter to constrict the energy spectrum. Exclusion of sinonasal disease was possible with even a lower dose by using Sn100 kV/25 mAs (volume CT dose index, 0.2 mGy).High image quality at very low dose levels can be achieved by using a Sn100-kV protocol with iterative reconstruction. The effective dose is comparable with that of conventional radiography, and the high image quality at even lower radiation exposure favors multidetector row CT over conebeam CT.
EVALuna2:14481

Immune Cell Circuits in Mucosal Wound Healing: Clinical Implications - Zundler, Sebastian; Tauschek, Verena; Neurath, Markus (Visceral Medicine, 2020)
Background: An intact mucosal barrier is essential for homeostasis in the gastrointestinal tract. Various pathological conditions such as infection or immune-mediated inflammation as well as therapeutic interventions like bowel surgery can result in injury of the intestinal mucosa. To counteract potential negative sequelae and to restore integrity of the tissue, a tightly regulated machinery of mechanisms exists, which crucially depends on the presence and absence of various immune cell subsets in different phases of intestinal wound healing. Cell trafficking is an increasingly acknowledged process that steers the localization of cells in tissues and the circulation. Thus, such cell circuits also crucially impact on the recruitment of immune cells in wound healing. Summary: We performed a selective literature research. In our review, we will shortly delineate some basic principles of intestinal immune cell trafficking before discussing the contribution of different immune cells to wound healing. Finally, we will discuss potential clinical implications of immune cell trafficking and wound healing interactions in inflammatory bowel disease (IBD) and bowel surgery. Key Messages: Intestinal wound healing has immense importance in pathological conditions like IBD, anastomotic healing, and others. Immune cell trafficking is indispensable for the correct temporal and spatial interaction of the cells involved. Further research is required to understand the final consequences of interfering with immune cell trafficking for intestinal wound healing.
CRIS-Team Scopus Importer:2020-04-03
Keywords: Immune cell trafficking; Mucosal healing; Vedolizumab; Wound healing

Immune cell regulation by vitamin D-3 during allogeneic hematopoietic stem cell transplantation (HSCT) - Flamann, Cindy; Zeun, J.; Kremer, Andreas; Peter, K.; Kreutz, M.; Büttner-Herold, Maike; Kellner, C.; Saul, Domenica; Mougiakakos, Dimitrios; Mackensen, Andreas; Bruns, Heiko; Völkl, Simon (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-10-23

Immune cell trafficking and retention in inflammatory bowel disease: Mechanistic insights and therapeutic advances - Zundler, Sebastian; Becker, Elisabeth; Schulze, Lisa; Neurath, Markus (Gut, 2019)
Intestinal immune cell trafficking has been identified as a central event in the pathogenesis of inflammatory bowel diseases (IBD). Intensive research on different aspects of the immune mechanisms controlling and controlled by T cell trafficking and retention has led to the approval of the anti-α4β7 antibody vedolizumab, the ongoing development of a number of further anti-trafficking agents (ATAs) such as the anti-β7 antibody etrolizumab or the anti-MAdCAM-1 antibody ontamalimab and the identification of potential future targets like G-protein coupled receptor 15. However, several aspects of the biology of immune cell trafficking and regarding the mechanism of action of ATAs are still unclear, for example, which impact these compounds have on the trafficking of non-lymphocyte populations like monocytes and how precisely these therapies differ with regard to their effect on immune cell subpopulations. This review will summarise recent advances of basic science in the field of intestinal immune cell trafficking and discuss these findings with regard to different pharmacological approaches from a translational perspective.
CRIS-Team Scopus Importer:2019-06-18
Keywords: cell adhesion; Crohn's disease; inflammatory bowel disease; integrins; ulcerative colitis

Immune-checkpoint inhibitor-associated diabetes compared to other diabetes types - A prospective, matched control study - Tittel, Sascha R.; Laubner, Katharina; Schmid, Sebastian M.; Kress, Stefan; Merger, Sigrun; Karges, Wolfram; Wosch, Frank J.; Altmeier, Marcus; Pavel, Marianne Ellen; Holl, Reinhard W. (Journal of Diabetes, 2021)
Background To describe checkpoint inhibitor-induced diabetes mellitus (CPI-DM) and to compare with regular type 1 (T1DM), type 2 (T2DM), and medication-induced diabetes mellitus (MI-DM). Methods We included 88 177 adult patients from the Diabetes Patient Follow-Up (DPV) registry with diabetes manifestation between 2011 and 2020. Inclusion criteria were T1DM, T2DM, MI-DM, or CPI-DM. Because of the heterogeneity between the groups, we matched patients by age, sex, and diabetes duration using propensity scores. Patient data were aggregated in the respective first documented treatment year. Results The matched cohort consisted of 24 164 patients; T1DM: 29, T2DM: 24000, MI-DM: 120, CPI-DM: 15 patients. Median age at manifestation of CPI-DM patients was 63.6 (57.2-72.8) years (53.3% male). Body mass index in CPI-DM patients was significantly lower (26.8 [23.9-28.1] kg/m(2)) compared with T2DM patients (29.8 [26.2-34.3] kg/m(2), P = 0.02). At manifestation, HbA1c was significantly higher in CPI-DM compared with MI-DM, but there was no difference during follow-up. Diabetic ketoacidosis (DKA) was documented in six CPI-DM patients (T1DM: 0%, T2DM: 0.4%, MI-DM: 0.0%). Fourteen CPI-DM patients were treated with insulin, and three received additional oral antidiabetics. The most common therapy in T2DM was lifestyle modification (38.8%), insulin in MI-DM (52.5%). Concomitant autoimmune thyroid disease was present in four CPI-DM patients (T1DM: 0.0%, T2DM: 1.0%, MI-DM: 0.8%). Conclusions The data from this controlled study show that CPI-DM is characterized by a high prevalence of DKA, autoimmune comorbidity, and metabolic decompensation at onset. Structured diagnostic monitoring is warranted to prevent DKA and other acute endocrine complications in CPI-treated patients.
CRIS-Team WoS Importer:2021-08-13

Immune deficiency vs. immune excess in inflammatory bowel diseases-STAT3 as a rheo-STAT of intestinal homeostasis - Leppkes, Moritz; Neurath, Markus; Herrmann, Martin; Becker, Christoph (Journal of Leukocyte Biology, 2016)
Genome-wide association studies have provided many genetic alterations, conferring susceptibility to multifactorial polygenic diseases, such as inflammatory bowel diseases. Yet, how specific genetic alterations functionally affect intestinal inflammation often remains elusive. It is noteworthy that a large overlap of genes involved in immune deficiencies with those conferring inflammatory bowel disease risk has been noted. This has provided new arguments for the debate on whether inflammatory bowel disease arises from either an excess or a deficiency in the immune system. In this review, we highlight the functional effect of an inflammatory bowel disease-risk allele, which cannot be deduced from genome-wide association studies data alone. As exemplified by the transcription factor signal transducer and activator of transcription 3 (STAT3), we show that a single gene can have a plethora of effects in various cell types of the gut. These effects may individually contribute to the restoration of intestinal homeostasis on the one hand or pave the way for excessive immunopathology on the other, as an inflammatory "rheo-STAT".
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Immune-epithelial crosstalk at the intestinal surface - Wittkopf, Nadine; Neurath, Markus; Becker, Christoph (Journal of Gastroenterology, 2014)
The intestinal tract is one of the most complex organs of the human body. It has to exercise various functions including food and water absorption, as well as barrier and immune regulation. These functions affect not only the gut itself, but influence the overall health of the organism. Diseases involving the gastrointestinal tract such as inflammatory bowel disease and colorectal cancer therefore severely affect the patient's quality of life and can become life-threatening. Intestinal epithelial cells (IECs) play an important role in intestinal inflammation, infection, and cancer development. IECs not only constitute the first barrier in the gut against the lumen, they also constantly signal information about the gut lumen to immune cells, thereby influencing their behaviour. In contrast, by producing various antimicrobial peptides, IECs shape the microbial community within the gut. IECs also respond to cytokines and other mediators of immune cells in the lamina propria. Interactions between epithelial cells and immune cells in the intestine are responsible for gut homeostasis, and modulations of this crosstalk have been reported in studies of gut diseases. This review discusses the wide field of immune-epithelial interactions and shows the importance of immune-epithelial crosstalk in the intestine to gut homeostasis and the overall health status.
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Immune-Epithelial Crosstalk in Inflammatory Bowel Diseases and Mucosal Wound Healing - Leppkes, Moritz; Siegmund, Britta; Becker, Christoph (Frontiers in Immunology, 2018)
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Immune profiling of adipose tissue in murine models of inflammatory bowel disease (IBD) - Letizia, M.; Sillke, Y. Rodriguez; Schmidt, F.; Günther, Claudia; Kunkel, D.; Glauben, R.; Siegmund, B.; Weidinger, C. (JOURNAL OF CROHNS & COLITIS, 2019)
CRIS-Team WoS Importer:2019-03-20

IMMUNOLOGY OF IL-12: AN UPDATE ON FUNCTIONAL ACTIVITIES AND IMPLICATIONS FOR DISEASE - Ullrich, Karen; Schulze, Lisa; Paap, Eva-Maria; Müller, Tanja; Neurath, Markus; Zundler, Sebastian (Excli Journal, 2020)
As its first identified member, Interleukin-12 (IL-12) named a whole family of cytokines. In response to pathogens, the heterodimeric protein, consisting of the two subunits p35 and p40, is secreted by phagocytic cells. Binding of IL-12 to the IL-12 receptor (IL-12R) on T and natural killer (NK) cells leads to signaling via signal transducer and activator of transcription 4 (STAT4) and subsequent interferon gamma (IFN-gamma) production and secretion. Signaling downstream of IFN-gamma includes activation of T-box transcription factor TBX21 (Tbet) and induces pro-inflammatory functions of T helper 1 (T(H)1) cells, thereby linking innate and adaptive immune responses. Initial views on the role of IL-12 and clinical efforts to translate them into therapeutic approaches had to be re-interpreted following the discovery of other members of the IL-12 family, such as IL-23, sharing a subunit with IL-12. However, the importance of IL-12 with regard to immune processes in the context of infection and (auto-) inflammation is still beyond doubt. In this review, we will provide an update on functional activities of IL-12 and their implications for disease. We will begin with a summary on structure and function of the cytokine itself as well as its receptor and outline the signal transduction and the transcriptional regulation of IL-12 secretion. In the second part of the review, we will depict the involvement of IL-12 in immune-mediated diseases and relevant experimental disease models, while also providing an outlook on potential translational approaches.
CRIS-Team WoS Importer:2021-01-15

Immunopathogenesis of IBD: Batf as a Key Driver of Disease Activity - Hildner, Kai; Punkenburg, Elise; Abendroth, Benjamin; Neurath, Markus (Digestive Diseases, 2016)
Inflammatory bowel diseases (IBDs) represent a group of chronic immune-mediated disorders that are influenced by a genetic predisposition and additional environmental triggers. Genome-wide association studies strongly implicate that a number of immune system-related genetic variations are critically contributing to the initiation and promotion of intestinal inflammation. Especially the identification of the strong association of a series of single nucleotide polymorphisms including interleukin (IL)-23R, CCR6, signal transducer and activator of transcription 3 (Stat3) and Stat4 with IBD susceptibility point at a critical involvement of T cells and especially of IL-17a-producing Th17 cells in the immune pathogenesis of IBD. In line with this hypothesis, a series of preclinical studies have unequivocally established that T cells are key drivers of immune-mediated colitis. Interestingly, especially Th17 cells were identified to be highly prevalent in inflamed IBD tissues, a finding that seems to be functionally relevant as genetic inactivation studies in the mouse resulted in almost complete suppression of colitis development.While targeting Th17 cell differentiation regulating transcription factors, as retinoic acid-related orphan receptor gamma t (ROR?t) is effective in preventing murine colitis, one concern of drugs targeting ROR?t in a clinical setting represents the large body of murine data unambiguously demonstrating that additional pathways within and outside the immune system are equally ROR?t-dependent increasing the risk of undesirable side effects. The AP1 transcription factor Batf (B cell-activating transcription factor) appears to exclusively regulate pathways within lymphocytes. Importantly, Batf represents a central regulator of Th17 cell development and is strongly upregulated within IBD-affected tissues. Employing 2 acute colitis models, we demonstrate in this study that Batf-expressing T cells are critical drivers of T cell-mediated colitis while in contrast to Stat3 loss of Batf does not affect intestinal epithelial cell homeostasis ex vivo.Targeting Batf in IBD emerges as an attractive therapeutic approach disabling colitogenic T cell activities while sparing off-target effects in the intestinal epithelial cell compartment.
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Immunopathogenesis of inflammatory bowel diseases: functional role of T cells and T cell homing - Zundler, Sebastian; Neurath, Markus (Clinical and Experimental Rheumatology, 2015)
Inflammatory bowel diseases (IBD) are believed to arise from a complex interplay of environmental factors, genetic susceptibility, epithelial barrier defects and dysregulation of the intestinal immune system. Although the exact mechanisms of contribution and interference of these players are still not clear, significant advances have been achieved in understanding the immunopathogenesis of IBD in recent years resulting in novel and targeted therapeutic strategies. We will begin this review by giving a brief outline of current pathogenetic concepts of IBD and then focus on the description of the present knowledge of T cell function and regulation in the context of IBD. Moreover, we will summarise the progress on the emerging field of gut homing and delineate some implications for future therapeutic approaches.
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Immunoprofiling in Neuroendocrine Neoplasms: Implications for Immunotherapy - Busse, A.; Spenke, C.; Arsenic, R.; Briest, F.; Sipos, B.; Kaemmerer, D.; Pavel, Marianne Ellen; Mochmann, L. H.; Baum, R. P.; Wirtz, R.; Hummel, M.; Grabowski, P. (NEUROENDOCRINOLOGY, 2019)
CRIS-Team WoS Importer:2019-03-26

Immunoprofiling in neuroendocrine neoplasms unveil immunosuppressive microenvironment - Busse, Antonia; Mochmann, Liliana H.; Spenke, Christiane; Arsenic, Ruza; Briest, Franziska; Jöhrens, Korinna; Lammert, Hedwig; Sipos, Bence; Kühl, Anja A.; Wirtz, Ralph; Pavel, Marianne Ellen; Hummel, Michael; et al. (Cancers, 2020)
Checkpoint inhibitors have shown promising results in a variety of tumors; however, in neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), low response rates were reported. We aimed herein to investigate the tumor immune microenvironment in NET/NEC to determine whether checkpoint pathways like programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) might play a role in immune escape and whether other escape mechanisms might need to be targeted to enable a functional antitumor response. Forty-eight NET and thirty NEC samples were analyzed by immunohistochemistry (IHC) and mRNA immunoprofiling including digital spatial profiling. Through IHC, both NET/NEC showed stromal, but less intratumoral CD3+ T cell infiltration, although this was significantly higher in NEC compared to NET. Expression of PD1, PD-L1, and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on immune cells was low or nearly absent. mRNA immunoprofiling revealed low expression of IFNγ inducible genes in NET and NEC without any spatial heterogeneity. However, we observed an increased mRNA expression of chemokines, which attract myeloid cells in NET and NEC, and a high abundance of genes related to immunosuppressive myeloid cells and genes with immunosuppressive functions like CD47 and CD74. In conclusion, NET and NEC lack signs of an activation of the adaptive immune system, but rather show abundance of several immunosuppressive genes that represent potential targets for immunomodulation.
CRIS-Team Scopus Importer:2020-12-04
Keywords: Ileal neuroendocrine tumors; Immunoprofiling; Neuroendocrine carcinoma; Programmed cell death protein 1; Programmed death-ligand 1; Tumor infiltrating lymphocytes; Tumor-associated macrophages

Immunoregulatory role of NFAT-interacting protein (NIP) 45 in adaptive and innate immune responses in allergic asthma - Koch, Sonja; Maeding, N.; Karwot, R.; Mirzakhani, H.; Springel, R.; Mittler, S.; Zimmermann, Theodor; Melichar, V. O.; Knipfer, Lisa; Wirtz, Stefan; Weiss, S. T. (2017)
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Immuntherapie bei neuroendokrinen Tumoren: Zeitpunkt und Zielgruppe - Auernhammer, Christoph J.; Pavel, Marianne Ellen (Die Onkologie, 2022)
Background Neuroendocrine tumors (NET) of the digestive system and lung carcinoids are rare neoplasms. In advanced unresectable disease, various systemic therapies are used. Primary tumor site, pathological classification including grading, tumor slope and tumor burden, as well as expression of somatostatin receptors and functional activity have an impact on treatment choices. Established treatment options include somatostatin analogs (octreotide, lanreotide), peptide receptor radionuclide therapy (PRRT) with Lu-177-DOTA-TATE, molecular targeted therapies (everolimus, sunitinib), and systemic chemotherapy with streptozotocin- or temozolomide-based regimes in well-differentiated NET, or platinum/etoposide in poorly differentiated neuroendocrine carcinoma. There is a high unmet need for novel therapies. Aim Review of the current status of immunotherapy in neuroendocrine neoplasms of the digestive system and of lung carcinoids. Results Immunotherapy with checkpoint inhibitors is a well-established therapy for example in non-small cell lung cancer (NSCLC), melanoma, hepatocellular carcinoma, and Merkel cell carcinoma, and in combination therapy in small cell lung cancer (SCLC). Studies are limited so far and demonstrate absent or low response rates in well-differentiated NET G1/G2. Other subgroups of patients have shown benefit particularly with dual checkpoint inhibitor therapy with 17-44% objective response rates (ORR). These include primarily neuroendocrine carcinomas of gastroenteropancreatic origin, but also atypical lung carcinoids and possibly also more proliferative NET G3, although data for NET G3 are limited.
CRIS-Team WoS Importer:2022-08-12

Impact of acoustic radiation force impulse imaging in clinical practice of patients after orthotopic liver transplantation - Wildner, Dane; Strobel, Deike; Konturek, Peter C.; Görtz, Rüdiger; Croner, Roland S.; Neurath, Markus; Zopf, Steffen (Medical Science Monitor, 2014)
Acoustic radiation force impulse (ARFI) elastography is a reliable diagnostic device for quantitative non-invasive assessment of liver fibrosis in patients with chronic liver disease. The aim of our prospective study was to evaluate the impact of ARFI in patients after orthotopic liver transplantation (OLT). Therefore, we compared ARFI shear wave velocities with clinical features, non-invasive markers, and the histology of patients following OLT.Post-transplant patients underwent a clinical examination and blood samples were taken. B-mode and Doppler ultrasound (US) of the portal vein and the hepatic artery were performed. Subsequently, a minimum of 10 valid ARFI values were measured in the left and right liver lobe. Liver biopsy was performed if indicated.Between May 2012 and May 2014, 58 Patients after OLT were included in the prospective study. Laboratory markers and aspartate aminotransferase-to-platelet ratio index (APRI) correlated with ARFI values (r=0.44, p<0.001). The histological (n=22) fibrosis score (Ludwig) was significantly correlated with the ARFI of the biopsy site (r=0.55, p=0.008). The mean shear-wave velocities were significantly increased in advanced fibrosis (F<=2 1.57±0.57 m/s; F>=3 2.85±0.66 m/s; p<0.001), obstructive cholestasis and active viral hepatitis. The area under the receiver operating characteristic (AUROC) curves for the accuracy of ARFI were 74% (F>=1), 73% (F>=2), 93% (F>=3), and 80% (=F4).ARFI elastography correlates well with laboratory values and with noninvasive and invasive markers of fibrosis in patients after OLT. In this regard, elevated ARFI-velocities should be interpreted with caution in the context of obstructive cholestasis and active viral disease.
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Impact of a reduced dosing interval of lanreotide autogel (LAN) on tumor growth rate (TGR) in patients with progressive neuroendocrine tumors (NETs) in the prospective, single-arm, phase 2 CLARINET FORTE trial - Dromain, C.; Cwikla, J. B.; Lombard-Bohas, C.; Borbath,; Shah, T.; Pape, U. F.; Capdevila, J.; Panzuto, F.; Ruszniewski, P.; Thanh, Truong X. M.; Houchard, A.; Pavel, Marianne Ellen (JOURNAL OF NEUROENDOCRINOLOGY, 2022)
CRIS-Team WoS Importer:2022-04-22

Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort - Simon, David; Tascilar, Koray; Kleyer, Arnd; Fagni, Filippo; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Kliem, Thorsten; Moessner, Johanna; Liphardt, Anna-Maria; Schoenau, Verena; et al. (Arthritis and Rheumatology, 2022)
Objective To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. Results In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). Conclusion IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.
CRIS-Team WoS Importer:2022-04-08

Impact of Epithelial Cell Shedding on Intestinal Homeostasis - Ngo, Phuong A.; Neurath, Markus; Lopez Posadas, Rocío (International Journal of Molecular Sciences, 2022)
The gut barrier acts as a first line of defense in the body, and plays a vital role in nutrition and immunoregulation. A layer of epithelial cells bound together via intercellular junction proteins maintains intestinal barrier integrity. Based on a tight equilibrium between cell extrusion and cell restitution, the renewal of the epithelium (epithelial turnover) permits the preservation of cell numbers. As the last step within the epithelial turnover, cell shedding occurs due to the pressure of cell division and migration from the base of the crypt. During this process, redistribution of tight junction proteins enables the sealing of the epithelial gap left by the extruded cell, and thereby maintains barrier function. Disturbance in cell shedding can create transient gaps (leaky gut) or cell accumulation in the epithelial layer. In fact, numerous studies have described the association between dysregulated cell shedding and infection, inflammation, and cancer; thus epithelial cell extrusion is considered a key defense mechanism. In the gastrointestinal tract, altered cell shedding has been observed in mouse models of intestinal inflammation and appears as a potential cause of barrier loss in human inflammatory bowel disease (IBD). Despite the relevance of this process, there are many unanswered questions regarding cell shedding. The investigation of those mechanisms controlling cell extrusion in the gut will definitely contribute to our understanding of intestinal homeostasis. In this review, we summarized the current knowledge about intestinal cell shedding under both physiological and pathological circumstances.
CRIS-Team Scopus Importer:2022-04-29
Keywords: cell extrusion; colorectal cancer; epithelial cell shedding; inflammatory bowel disease (IBD); leaky gut

Impact of global Fxr deficiency on experimental acute pancreatitis and genetic variation in the FXR locus in human acute pancreatitis - Nijmeijer, Rian M.; Schaap, Frank G.; Smits, Alexander J. J.; Kremer, Andreas; Akkermans, Louis M. A.; Kroese, Alfons B. A.; Rijkers, Ger. T.; Schipper, Marguerite E. I.; Verheem, Andre; Wijmenga, Cisca; Gooszen, Hein G.; Van Erpecum, Karel J. (PLoS ONE, 2014)
Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the pancreas, exhibits anti-inflammatory effects by inhibiting NF-?B activation and is implicated in maintaining intestinal barrier integrity and preventing bacterial overgrowth and translocation. Here we explore, with the aid of complementary animal and human experiments, the potential role of FXR in acute pancreatitis.Experimental acute pancreatitis was induced using the CCK-analogue cerulein in wild-type and Fxr-/- mice. Severity of acute pancreatitis was assessed using histology and a semi-quantitative scoring system. Ileal permeability was analyzed in vitro by Ussing chambers and an in vivo permeability assay. Gene expression of Fxr and Fxr target genes was studied by quantitative RT-PCR. Serum FGF19 levels were determined by ELISA in acute pancreatitis patients and healthy volunteers. A genetic association study in 387 acute pancreatitis patients and 853 controls was performed using 9 tagging single nucleotide polymorphisms (SNPs) covering the complete FXR gene and two additional functional SNPs.In wild-type mice with acute pancreatitis, ileal transepithelial resistance was reduced and ileal mRNA expression of Fxr target genes Fgf15, SHP, and IBABP was decreased. Nevertheless, Fxr-/- mice did not exhibit a more severe acute pancreatitis than wild-type mice. In patients with acute pancreatitis, FGF19 levels were lower than in controls. However, there were no associations of FXR SNPs or haplotypes with susceptibility to acute pancreatitis, or its course, outcome or etiology.We found no evidence for a major role of FXR in acute human or murine pancreatitis. The observed altered Fxr activity during the course of disease may be a secondary phenomenon.
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Impact of High Salt-Intake on a Natural Gut Ecosystem in Wildling Mice - Cardilli, Alessio; Hamad, Ibrahim; Dyczko, Aleksandra; Thijs, Sofie; Vangronsveld, Jaco; Müller, Dominik N.; Rosshart, Stephan Patrick; Kleinewietfeld, Markus (Nutrients, 2023)
The mammalian holobiont harbors a complex and interdependent mutualistic gut bacterial community. Shifts in the composition of this bacterial consortium are known to be a key element in host health, immunity and disease. Among many others, dietary habits are impactful drivers for a potential disruption of the bacteria-host mutualistic interaction. In this context, we previously demonstrated that a high-salt diet (HSD) leads to a dysbiotic condition of murine gut microbiota, characterized by a decrease or depletion of well-known health-promoting gut bacteria. However, due to a controlled and sanitized environment, conventional laboratory mice (CLM) possess a less diverse gut microbiota compared to wild mice, leading to poor translational outcome for gut microbiome studies, since a reduced gut microbiota diversity could fail to depict the complex interdependent networks of the microbiome. Here, we evaluated the HSD effect on gut microbiota in CLM in comparison to wildling mice, which harbor a natural gut ecosystem more closely mimicking the situation in humans. Mice were treated with either control food or HSD and gut microbiota were profiled using amplicon-based methods targeting the 16S ribosomal gene. In line with previous findings, our results revealed that HSD induced significant loss of alpha diversity and extensive modulation of gut microbiota composition in CLM, characterized by the decrease in potentially beneficial bacteria from Firmicutes phylum such as the genera Lactobacillus, Roseburia, Tuzzerella, Anaerovorax and increase in Akkermansia and Parasutterella. However, HSD-treated wildling mice did not show the same changes in terms of alpha diversity and loss of Firmicutes bacteria as CLM, and more generally, wildlings exhibited only minor shifts in the gut microbiota composition upon HSD. In line with this, 16S-based functional analysis suggested only major shifts of gut microbiota ecological functions in CLM compared to wildling mice upon HSD. Our findings indicate that richer and wild-derived gut microbiota is more resistant to dietary interventions such as HSD, compared to gut microbiota of CLM, which may have important implications for future translational microbiome research.
CRIS-Team Scopus Importer:2023-04-21
Keywords: high-salt diet; immunity; microbiome; wildling

Impact of insulin and insulin resistance on brain dopamine signalling and reward processing – An underexplored mechanism in the pathophysiology of depression? - Gruber, Judith; Hanssen, Ruth; Qubad, Mishal; Bouzouina, Aicha; Schack, Vivi; Sochor, Hannah; Schiweck, Carmen; Aichholzer, Mareike; Matura, Silke; Slattery, David A.; Zopf, Yurdagül; Borgland, Stephanie L.; et al. (Neuroscience and Biobehavioral Reviews, 2023)
Type 2 diabetes and major depressive disorder (MDD) are the leading causes of disability worldwide and have a high comorbidity rate with fatal outcomes. Despite the long-established association between these conditions, the underlying molecular mechanisms remain unknown. Since the discovery of insulin receptors in the brain and the brain's reward system, evidence has accumulated indicating that insulin modulates dopaminergic (DA) signalling and reward behaviour. Here, we review the evidence from rodent and human studies, that insulin resistance directly alters central DA pathways, which may result in motivational deficits and depressive symptoms. Specifically, we first elaborate on the differential effects of insulin on DA signalling in the ventral tegmental area (VTA) - the primary DA source region in the midbrain - and the striatum as well as its effects on behaviour. We then focus on the alterations induced by insulin deficiency and resistance. Finally, we review the impact of insulin resistance in DA pathways in promoting depressive symptoms and anhedonia on a molecular and epidemiological level and discuss its relevance for stratified treatment strategies.
CRIS-Team Scopus Importer:2023-04-21
Keywords: Anhedonia; Depression; Diabetes; Dopamine; Insulin; Motivation; Reward; Striatum; Ventral tegmental area

Impact of Microbiome–Brain Communication on Neuroinflammation and Neurodegeneration - Stolzer, Iris; Scherer, Eveline; Süß, Patrick; Rothhammer, Veit; Winner, Beate; Neurath, Markus; Günther, Claudia (International Journal of Molecular Sciences, 2023)
The gut microbiome plays a pivotal role in maintaining human health, with numerous studies demonstrating that alterations in microbial compositions can significantly affect the development and progression of various immune-mediated diseases affecting both the digestive tract and the central nervous system (CNS). This complex interplay between the microbiota, the gut, and the CNS is referred to as the gut–brain axis. The role of the gut microbiota in the pathogenesis of neurodegenerative diseases has gained increasing attention in recent years, and evidence suggests that gut dysbiosis may contribute to disease development and progression. Clinical studies have shown alterations in the composition of the gut microbiota in multiple sclerosis patients, with a decrease in beneficial bacteria and an increase in pro-inflammatory bacteria. Furthermore, changes within the microbial community have been linked to the pathogenesis of Parkinson’s disease and Alzheimer’s disease. Microbiota–gut–brain communication can impact neurodegenerative diseases through various mechanisms, including the regulation of immune function, the production of microbial metabolites, as well as modulation of host-derived soluble factors. This review describes the current literature on the gut–brain axis and highlights novel communication systems that allow cross-talk between the gut microbiota and the host that might influence the pathogenesis of neuroinflammation and neurodegeneration.
CRIS-Team Scopus Importer:2023-11-03
Keywords: gut–brain-axis; microbial dysbiosis; neurodegenerative diseases

Impact of patient characteristics on the clinical efficacy of mongersen (GED-0301), an oral Smad7 antisense oligonucleotide, in active Crohn's disease - Monteleone, G.; Di Sabatino, Antonio; Ardizzone, Sandro; Pallone, F.; Usiskin, K.; Zhan, X.; Rossiter, G.; Neurath, Markus (Alimentary Pharmacology & Therapeutics, 2016)
In a phase 2 study, mongersen, an oral antisense oligonucleotide targeting Smad7, was effective in inducing clinical remission in approximately 60% of patients with active Crohn's disease (CD).In a post hoc analysis to evaluate those patient disease characteristics that may have influenced the efficacy and safety of mongersen therapy.Patients with steroid-dependent/resistant, active CD were randomised to mongersen 10, 40 or 160 mg/day or placebo for 2 weeks; patients were followed for 10 weeks. Clinical remission [Crohn's Disease Activity Index (CDAI) score <150] and clinical response (CDAI score reduction >=100 points) were assessed at weeks 2, 4 and 12 for these subgroups: disease duration <5/>=5 years, human serum C-reactive protein (hsCRP) <3/>=3 mg/L, and CDAI at baseline <=260/>260. Additional patient baseline and disease characteristics were explored.Clinical remission and response rates were significantly higher in patients receiving mongersen 40 and 160 mg/day but not 10 mg/day vs. placebo and independent of disease duration and hsCRP. Patients with baseline CDAI <=260 had significantly higher remission rates with 40 and 160 mg/day. In patients with baseline CDAI >260, remission rates were statistically greater with 160 mg/day and numerically better with 40 mg/day vs. placebo. Adverse event rates were similar across treatment groups. Mongersen was safe and well tolerated.Patients with higher CDAI scores achieved clinical remission most frequently with the highest mongersen dose. Disease duration and baseline human serum C-reactive protein did not appear to significantly impact efficacy of mongersen in this study (EudraCT Number: 2011-002640-27.).
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Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4 - Buzzoni, Roberto; Carnaghi, Carlo; Strosberg, Jonathan; Fazio, Nicola; Singh, Simron; Herbst, Fabian; Ridolfi, Antonia; Pavel, Marianne Ellen; Wolin, Edward M.; Valle, Juan W.; Oh, Do-Youn; Yao, James C.; et al. (Oncotargets and Therapy, 2017)
BACKGROUND: Recently, everolimus was shown to improve median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) tract compared with placebo (HR, 0.48; 95% CI, 0.35-0.67; P<0.00001) in the Phase III, RADIANT-4 study. This post hoc analysis evaluates the impact of prior therapies (somatostatin analogs [SSA], chemotherapy, and radiotherapy) on everolimus activity. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01524783. PATIENTS AND METHODS: Patients were randomized (2:1) to everolimus 10 mg/day or placebo, both with best supportive care. Subgroups of patients who received prior SSA, chemotherapy, or radiotherapy (including peptide receptor radionuclide therapy) were analyzed and reported. RESULTS: A total of 302 patients were enrolled, of whom, 163 (54%) had any prior SSA use (mostly for tumor control), 77 (25%) received chemotherapy, and 63 (21%) were previously exposed to radiotherapy. Patients who received everolimus had longer median PFS compared with placebo, regardless of previous SSA (with SSA: 11.1 vs 4.5 months [HR, 0.56 95% CI, 0.37-0.85]; without SSA: 9.5 vs 3.7 months [0.57 0.36-0.89]), chemotherapy (with chemotherapy: 9.2 vs 2.1 months [0.35 0.19-0.64]; without chemotherapy: 11.2 vs 5.4 months [0.60 0.42-0.86]), or radiotherapy (with radiotherapy: 9.2 vs 3.0 months [0.47 0.24-0.94]; without radiotherapy: 11 vs 5.1 months [0.59 0.42-0.83]) exposure. The most frequent drug-related adverse events included stomatitis (59%-65%), fatigue (27%-35%), and diarrhea (24%-34%) among the subgroups. CONCLUSION: These results suggest that everolimus improves PFS in patients with advanced, progressive lung or GI NET, regardless of prior therapies. Safety findings were consistent with the known safety profile of everolimus in NET.
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Impact on follow-up strategies in patients with primary sclerosing cholangitis - Bergquist, Annika; Weismueller, Tobias J.; Levy, Cynthia; Rupp, Christian; Joshi, Deepak; Nayagam, Jeremy Shanika; Montano-Loza, Aldo J.; Lytvyak, Ellina; Wunsch, Ewa; Milkiewicz, Piotr; Zenouzi, Roman; Schramm, Christoph; et al. (Liver International, 2022)
Background & Aims Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow-up strategies in PSC with the hypothesis that regular imaging improves survival. Methods We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow-up from 1 January 2000, until death or last clinical follow-up alive. The primary endpoint was all-cause mortality. Results A broad variety of different follow-up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow-up, was 0.61 (0.47-0.80) for scheduled imaging with and without ERCP; 0.64 (0.48-0.86) for US/MRI and 0.53 (0.37-0.75) for follow-up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high-grade dysplasia as a time-dependent covariate, HR 0.57 (0.44-0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow-up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed. Conclusions Follow-up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures.
CRIS-Team WoS Importer:2022-06-03

Impairment of gustatory and olfactory senses in plaque psoriasis - Rueter, P.; Gruenthaler, V.; Zopf, Yurdagül; Sticherling, Michael (2017)
EVALuna2:34082

Impairment of Taste and Smell in Psoriasis- another Cause of Impaired Calorie Intake? - Gruenthaler, V.; Rueter, P.; Zopf, Yurdagül; Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Implementation of a national registry for patients with primary biliary cholangitis (PBC): The German PBC cohort - Wiegand, Johannes; Stein, Kerstin; Guenther, Rainer; Naumann, Uwe; Zimny, Sebastian; Reuken, Philipp; Boettler, Tobias; Bantel, Heike; Hofmann, Wolf Peter; Kremer, Andreas; Kautz, Achim; Beuers, Ulrich; et al. (JOURNAL OF HEPATOLOGY, 2021)
CRIS-Team WoS Importer:2021-07-30

Improved cancer diagnostics by different image processing techniques on OCT images - Kanawade, Rajesh; Lengenfelder, Benjamin; Menezes, Tassiana Marini; Hohmann, Martin; Kopfinger, Stefan; Hohmann, Tim; Grabiec, Urszula; Klämpfl, Florian; Menezes, Jean Gonzales; Waldner, Maximilian; Schmidt, Michael (Proceedings of SPIE, 2015)
Optical-coherence tomography (OCT) is a promising non-invasive, high-resolution imaging modality which can be used for cancer diagnosis and its therapeutic assessment. However, speckle noise makes detection of cancer boundaries and image segmentation problematic and unreliable. Therefore, to improve the image analysis for a precise cancer border detection, the performance of different image processing algorithms such as mean, median, hybrid median filter and rotational kernel transformation (RKT) for this task is investigated. This is done on OCT images acquired from an ex-vivo human cancerous mucosa and in vitro by using cultivated tumour applied on organotypical hippocampal slice cultures. The preliminary results confirm that the border between the healthy and the cancer lesions can be identified precisely. The obtained results are verified with fluorescence microscopy. This research can improve cancer diagnosis and the detection of borders between healthy and cancerous tissue. Thus, it could also reduce the number of biopsies required during screening endoscopy by providing better guidance to the physician.

Improvement of clinical management and outcome in hepatocellular carcinoma nowadays compared with historical cohorts - Schellhaas, Barbara; Strobel, Deike; Stumpf, Miriam; Ganslmayer, Marion; Pfeifer, Lukas; Görtz, Rüdiger; Neurath, Markus; Zopf, Steffen (European Journal of Gastroenterology & Hepatology, 2018)
OBJECTIVES: Therapeutic approaches in the treatment of hepatocellular carcinoma (HCC) depend on tumour stage, liver function and patient comorbidities. The aim of this study was to investigate the influence of tumour stage and therapeutic approach on overall survival in HCC. MATERIALS AND METHODS: Two hundred and fourteen patients with HCC diagnosed between December 2012 and May 2017 were assessed retrospectively for tumour stage [Barcelona Clinic Liver Cancer (BCLC)], liver function (Child-Pugh score), therapeutic approach and outcome (mean survival time). The results were compared to two historical cohorts from our centre diagnosed between 1999 and 2013 and 1988 and 1999, respectively. RESULTS: Nowadays, HCC is diagnosed in earlier tumour stages and with better liver function compared with the historical cohorts (P<0.001). Survival times depend on both BCLC stages and liver function for all therapeutic approaches. The 1-year survival rate in the present cohort was 79.4% compared with 58.6% in the historical cohort.In terms of BCLC stages, therapeutic approaches followed HCC guidelines in 43.9% of cases.Whereas the percentage of patients receiving resection or ablation did not change between the historical and the present cohort, there was a tendency towards a decrease in transarterial chemoembolization, with a shift towards selective internal radiotherapy, accompanied by an increase in systemic therapy with sorafenib.Also, the percentage of patients receiving single instead of multiple therapies was significantly higher in the present cohort compared with the historical cohort (P=0.016). In 62/83 patients receiving single therapy (64.7%), tumour remission was maintained during the period of follow-up. CONCLUSION: HCC is increasingly being diagnosed in earlier stages, so that single therapy is often sufficient. Besides BCLC stages, therapy in HCC must consider liver function, tumour location, local expertise and patients' comorbidities and preferences. Further research is needed to evaluate the benefit of early multimodal concepts. Therapeutic approaches in HCC remain individual decisions.
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Increased CD47 expression inhibits phagocytosis of alloreactive donor T cells after allo-HSCT - Flamann, Cindy; Matos, C.; Kreutz, M.; Shaikh, H.; Beilhack, A.; Büttner-Herold, Maike; Lischer, Christopher; Völkl, Simon; Kellner, C.; Zeun, J.; Kremer, Andreas; Bitterer, Katrin; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

Increased Motility and Suppression of Ex Vivo–Expanded Regulatory T Cells Designed for Adoptive Transfer Therapy in Ulcerative Colitis - Müller, Tanja; Liu, Lijuan; Czerwinski, Tina; Wiesinger, Manuel; Dedden, Mark; Paap, Eva-Maria; Ullrich, Karen; Atreya, Imke; Siegmund, Britta; Atreya, Raja; Fabry, Ben; Berking, Carola; et al. (Cellular and Molecular Gastroenterology and Hepatology, 2023)
CRIS-Team Scopus Importer:2023-06-02

Increase of liver stiffness and altered bile acid metabolism after triple CFTR modulator initiation in children and young adults with cystic fibrosis - Schnell, Alexander; Jüngert, Jörg M.; Klett, Daniel; Hober, Hannah; Kaiser, Natalie; Ruppel, Renate; Geppert, Annika; Tremel, Christina; Sobel, Julia; Plattner, Erika; Schmitt-Grohe, Sabina; Zirlik, Sabine; et al. (Liver International, 2023)
Background: Novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies (elexacaftor/tezacaftor/ivacaftor—ETI) promise clinically significant and sustained improvements for patients with cystic fibrosis (CF). In this study, we investigated the impact of ETI therapy on liver stiffness and bile acid metabolism in a cohort of children and young adults with CF. Methods: A prospective observational study (NCT05576324) was conducted from September 2020 to November 2021 enrolling CF patients naive to ETI. Standard laboratory chemistry, sweat test, lung function, share wave velocity (SWV) derived by acoustic radiation force impulse imaging (ARFI) and serum bile acid profiles were assessed before and 6 months after induction of ETI therapy. Results: A total of 20 patients (10 aged <20 years) completed the study. While lung function and BMI improved after ETI therapy, ARFI SWV increased in CF patients <20 years of age (from 1.27 to 1.43 m/s, p = 0.023). Bile acid (BA) profiles revealed a decrease in unconjugated (5.75 vs 1.46, p = 0.007) and increase in glycine-conjugated derivatives (GCDCA) (4.79 vs 6.64 p = 0.016). There was a positive correlation between ARFI SWV values and GCDCA (r = 0.80, p < 0.0001). Glycine-conjugated BA provided high diagnostic accuracy to predict increased ARFI measurements (AUC 0.90) and clinical (Colombo) CFLD grading (AUC 0.97). Conclusions: ARFI SWV and bile acid profiles provide evidence for early increase in liver stiffness and altered bile acid metabolism in young CF patients after initiation of ETI and may serve as synergistic measures for detection of hepatic complications during ETI therapy.
CRIS-Team Scopus Importer:2023-03-17
Keywords: ARFI; bile acids; CFLD; cystic fibrosis

Inducible mouse models of colon cancer for the analysis of sporadic and inflammation-driven tumor progression and lymph node metastasis - Neufert, Clemens; Heichler, Christina; Brabletz, Thomas; Scheibe, Kristina; Boonsanay, Verawan; Greten, Florian R.; Neurath, Markus (Nature Protocols, 2020)
Despite advances in the detection and therapy of colorectal cancer (CRC) in recent years, CRC has remained a major challenge in clinical practice. Although alternative methods for modeling CRC have been developed, animal models of CRC remain helpful when analyzing molecular aspects of pathogenesis and are often used to perform preclinical in vivo studies of potential therapeutics. This protocol updates our protocol published in 2007, which provided an azoxymethane (AOM)-based setup for investigations into sporadic (Step 5A) and, when combined with dextran sodium sulfate (Step 5B), inflammation-associated tumor growth. This update also extends the applications beyond those of the original protocol by including an option in which AOM is serially applied to mice with p53 deficiency in the intestinal epithelium (Step 5C). In this model, the combination of p53 deficiency and AOM promotes tumor development, including growth of invasive cancers and lymph node metastasis. It also provides details on analysis of colorectal tumor growth and metastasis, including analysis of partial epithelial-to-mesenchymal transition, cell isolation and co-culture studies, high-resolution mini-endoscopy, light-sheet fluorescence microscopy and micro-CT imaging in mice. The target audience for our protocol is researchers who plan in vivo studies to address mechanisms influencing sporadic or inflammation-driven tumor development, including the analysis of local invasiveness and lymph node metastasis. It is suitable for preclinical in vivo testing of novel drugs and other interventional strategies for clinical translation, plus the evaluation of emerging imaging devices/modalities. It can be completed within 24 weeks (using Step 5A/C) or 10 weeks (using Step 5B).
CRIS-Team WoS Importer:2021-01-01

Induction of Intestinal Graft-versus-host Disease and Its Mini-endoscopic Assessment in Live Mice - Buchele, Vera; Büttner-Herold, Maike; Vogler, Tina; Neurath, Markus; Hildner, Kai (Journal of Visualized Experiments, 2019)
Acute graft-versus-host disease (GvHD) represents the most severe complication that patients previously undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) face and is frequently associated with a poor clinical outcome. While, for instance, GvHD manifestations of the skin are usually responsive to established immune-suppressive therapies and are, hence, not taking a fatal course, the presence and the intensity of intestinal GvHD, especially of the mid-to-lower parts of the gut, strongly influence the outcome and overall survival of patients with acute GvHD. Therapeutic options are essentially limited to the classic immune-suppressive agents yielding only moderate disease-mitigating effects. Hence, detailed knowledge about the tissue-resident immune cascade, changes in the intestinal microbiota, and the stromal response prior, upon, and after intestinal GvHD onset are urgently needed to understand the events and mechanisms underlying its pathogenesis and to develop innovative therapeutic options. Murine models of GvHD are frequently employed to identify and functionally assess molecules and pathways putatively driving intestinal GvHD. However, means to specifically monitor and evaluate intestinal inflammation over time are essentially lacking since established scores to assess and grade acute GvHD are routinely comprised of various parameters which rather reflect systemic GvHD manifestations. The detailed evaluation of intestinal GvHD has been restricted to studies using euthanized mice, thereby essentially excluding longitudinal (i.e., kinetic) analyses of the colonic compartment under a given experimental condition (e.g., antibody-mediated blockade of a proinflammatory cytokine) in live mice (i.e., in vivo). The mini-endoscopic in situ assessment of the distal colon of alloHCT-treated mice described here allows a) a detailed macroscopic evaluation of different aspects of intestinal inflammation and b) the option to collect tissue samples for downstream analyses at various time points over the course of the observation period. Overall, the mini-endoscopic approach provides a major advance in preclinical noninvasive monitoring and assessment of intestinal GvHD.
CRIS-Team WoS Importer:2019-04-12

Induction of microRNA-124 as a novel therapeutic concept in ulcerative colitis - Atreya, Raja; Neurath, Markus (Lancet Gastroenterology and Hepatology, 2022)
CRIS-Team Scopus Importer:2022-10-21

Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study - Feagan, Brian G.; Sandborn, William J.; D'Haens, Geert; Panes, Julian; Kaser, Arthur; Ferrante, Marc; Louis, Edouard; Franchimont, Denis; Dewit, Olivier; Seidler, Ursula; Kim, Kyung-Jo; Neurath, Markus; et al. (Lancet, 2017)
BACKGROUND: The interleukin-23 pathway is implicated genetically and biologically in the pathogenesis of Crohn's disease. We aimed to assess the efficacy and safety of risankizumab (BI 655066, Boehringer Ingelheim, Ingelheim, Germany), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23, in patients with moderately-to-severely active Crohn's disease. METHODS: In this randomised, double-blind, placebo-controlled phase 2 study, we enrolled patients at 36 referral sites in North America, Europe, and southeast Asia. Eligible patients were aged 18-75 years, with a diagnosis of Crohn's disease for at least 3 months, assessed as moderate-to-severe Crohn's disease at screening, defined as a Crohn's Disease Activity Index (CDAI) of 220-450, with mucosal ulcers in the ileum or colon, or both, and a Crohn's Disease Endoscopic Index of Severity (CDEIS) of at least 7 (≥4 for patients with isolated ileitis) on ileocolonoscopy scored by a masked central reader. Patients were randomised 1:1:1 using an interactive response system to a double-blind investigational product, and stratified by previous exposure to TNF antagonists (yes vs no). Patients received intravenous 200 mg risankizumab, 600 mg risankizumab, or placebo, at weeks 0, 4, and 8. The primary outcome was clinical remission (CDAI <150) at week 12 (intention-to-treat population). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02031276. FINDINGS: Between March, 2014, and September, 2015, 213 patients were screened, and 121 patients randomised. At baseline, 113 patients (93%) had been previously treated with at least one tumour necrosis factor (TNF) antagonist (which had failed in 96 [79%]). At week 12, 25 (31%) of 82 risankizumab patients (pooled 41 patients in 200 mg and 41 patients in 600 mg arms) had clinical remission versus six (15%) of 39 placebo patients (difference vs placebo 15·0%, 95% CI 0·1 to 30·1; p=0·0489). Ten (24%) of 41 patients who received 200 mg risankizumab had clinical remission (9·0%, -8·3 to 26·2; p=0·31) and 15 (37%) of 41 who received the 600 mg dose (20·9%, 2·6 to 39·2; p=0·0252). 95 (79%) patients had adverse events (32 in the placebo group, 32 randomised to 200 mg risankizumab, 31 randomised to 600 mg risankizumab); 18 had severe adverse events (nine, six, three); 12 discontinued (six, five, one); 24 had serious adverse events (12, nine, three). The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohn's disease. No deaths occurred. INTERPRETATION: In this short-term study, risankizumab was more effective than placebo for inducing clinical remission in patients with active Crohn's disease. Therefore, selective blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in Crohn's disease. FUNDING: Boehringer Ingelheim.
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Inflammatory bowel diseases : Crohn's disease and ulcerative colitis - Fischer, Sören; Rath, T.; Neurath, Markus (Internist, 2018)
Inflammatory bowel diseases (IBD) are complex diseases. Epidemiological studies suggest rising incidences in industrialized countries. The article is based on a literature search in PubMed and is oriented on the current guidelines published by the European Crohn's and Colitis Organisation. IBD are characterized by chronic diarrhoea, abdominal pain and peranal haemorrhage. Extraintestinal manifestations commonly affect joints, skin, eyes and bile tracts. Early diagnosis and therapeutic intervention determine individual patient outcome. Medical treatment currently includes aminosalicylates, corticosteroids, thiopurines, calcineurin inhibitors and biologicals. IBDs require anti-inflammatory and if necessary immunosuppressive therapy. Due to extraintestinal complications and the possible need for surgical intervention, an interdisciplinary approach is important.
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Inflammatory Bowel Diseases: Current Medical and Surgical Therapy - Lamprecht, Georg; Atreya, Raja; Kreis, Martin E.; Siegmund, Britta; Stallmach, Andreas (Viszeralmedizin: Gastrointestinal Medicine and Surgery, 2015)
EVALuna2:2166

Inflammatory bowel diseases - therapy update 2022 Chronisch-entzündliche Darmerkrankungen - Atreya, Raja; Neurath, Markus (Deutsche Medizinische Wochenschrift, 2022)
Growing insights into the underlying immunopathogenesis of inflammatory bowel diseases (IBD) have led to the advent of targeted therapies, which selectively target pivotal mediators of the inflammatory process. This has enabled us to define and achieve novel therapeutic outcomes to prevent disease-associated complications and halt the progressive course of disease. In addition to already available treatment options, the selective Janus kinase type 1 inhibitor filgotinib and the selective sphingosine-1-phosphate receptor modulator Ozanimod have recently been approved for the treatment of ulcerative colitis patients. Furthermore, positive phase 2/3 induction and maintenance trial results have been reported for representatives of the class of IL-23p19 inhibitors, which are expected to further increase our therapeutic possibilities. All these agents can be applied as first-line or also subsequent treatment options and recent head-to-head trials have helped us to position these substances in our therapeutic algorithm. Nevertheless, there is still the currently unmet clinical need do establish predictive markers of response to identify the subgroup of IBD patients, that have a heightened probability of response to each therapy. In the following, we will give an overview of the recently approved or in late-stage clinical development tested substances and discuss their positioning in our therapeutic armamentarium.
CRIS-Team Scopus Importer:2022-04-01

Inflammatory bowel diseases: Update 2023 and perspectives Chronisch entzündliche Darmerkrankungen: Stand 2023 und Perspektiven - Zundler, Sebastian; Blumenstein, Irina (Die Gastroenterologie, 2023)
CRIS-Team Scopus Importer:2023-12-22

Influence of cancer and acute inflammatory disease on taste perception: a clinical pilot study - Schalk, Priska; Kohl, M.; Herrmann, H. J.; Schwappacher, R.; Rimmele, Martina; Büttner, Andrea; Neurath, Markus; Zopf, Yurdagül; Siebler, Jürgen (Supportive Care in Cancer, 2018)
Cancer patients are at high risk of malnutrition and tumor cachexia further increasing morbidity and mortality. Reasons for cachexia are not clear yet, but inflammatory processes as well as the occurrence of taste disorders reducing nutrient uptake are discussed to play key roles. The purpose of this study was to gain insight into causative factors of taste disturbance in cancer patients. Does the cancer itself, inflammatory processes or cancer therapy influence taste disorders?To capture an underlying taste disorder patients with cancer (n = 42), acutely hospitalized inflammatory disease patients (n = 57) and healthy controls (n = 39) were examined. To assess the influence of chemotherapy, patients with and without chemotherapy were compared. Taste tests were performed according to DIN ISO 3972:2011. Inflammation was recorded using laboratory parameters. Statistical evaluation was conducted using the Software R.Cancer patients showed significantly increased taste thresholds for sweet, salty, and umami compared to healthy controls. There were no significant differences in taste detection and recognition between patients with former, current, or without chemotherapeutical treatment. Patients with an acute inflammatory disease showed an increased taste threshold for umami compared to healthy controls.It could be shown that cancer patients suffer from taste disorders irrespective of an existing chemotherapeutical treatment. Cancer-related inflammation appears to have a greater impact on taste perception than an acute inflammatory process. Therefore, an adapted dietary adjustment should be carried out at an early stage for cancer patients in order to avoid nutritional disorders caused by a taste disorder.
Keywords: Cancer; Taste disturbance; Inflammatory disease; Cachexia; Malnutrition

Influence of Compression and Network Impairments on the Picture Quality of Video Transmissions in Telemedicine - Naegele-Jackson, Susanne; Holleczek, Peter; Rabenstein, Thomas; Maiß, Jürgen; Hahn, Eckhart Georg; Sackmann, Michael (Proceedings of the 35th Hawaii International Conference of System Sciences (HICSS), 2002)
UnivIS-Import:2015-04-16:Pub.2002.zwiss.rrze.ksys.influe

Influence of low FODMAP and gluten-free diets on disease activity and intestinal microbiota in patients with non-celiac gluten sensitivity - Dieterich, Walburga; Schuppan, Detlef; Schink, Monic; Schwappacher, Raphaela; Wirtz, Stefan; Agaimy, Abbas; Neurath, Markus; Zopf, Yurdagül (Clinical Nutrition, 2019)
Background & aims: Non-celiac gluten sensitivity (NCGS) is characterized by intestinal and extra intestinal symptoms triggered by ingestion of gluten. However, non-gluten triggers have recently been implicated, and a FODMAP (fermentable oligo-, di-, monosaccharides and polyols)-reduced diet can partially improve symptoms in NCGS. Our aim was to analyze the effect of a low FODMAP versus a gluten-free diet (GFD) on clinical symptoms, psychological well-being, intestinal inflammation and integrity, and stool microbiota.
CRIS-Team WoS Importer:2019-05-21

Influence of reviewers' clinical backgrounds on interpretation of confocal laser endomicroscopy findings - Kobayashi, Masakuni; Neumann, Helmut; Hino, Shoryoku; Abe, Seiichiro; Nakai, Yousuke; Nakajima, Kiyokazu; Kiesslich, Ralf; Hirooka, Shinichi; Sumiyama, Kazuki; Vieth, Michael (Endoscopy, 2016)
Substantial differences in endoscopic strategy for gastric cancer exist between Western and Eastern countries, owing to clinicoepidemiological diversity, including differences in the prevalence of gastric cancer. This international multicenter study involved German and Japanese institutions and aimed to evaluate the influence of reviewers' clinical backgrounds on interpreting probe-based confocal laser endomicroscopy (pCLE) findings for diagnosis of superficial gastric lesions.39 reviewers answered questionnaires about their clinical background and then reviewed 30 sets of white light endoscopy (WLE) and pCLE video clips via an online questionnaire. For each set of clips, reviewers were asked to classify lesions as neoplastic or non-neoplastic. RESULTS of video reviews were compared with the final histopathological diagnosis for each lesion. The accuracy of diagnosis based on WLE + pCLE was compared with that based on WLE alone for each aspect of clinical background.The overall accuracy of diagnosis based on WLE + pCLE was higher than that based on WLE alone (73.93 % vs. 65.64 %, P = .0002). Outcomes of expert gastroenterologists were better than those of pathologists (P = .038 for WLE, P = .002 for WLE + pCLE) and outcomes of reviewers at Japanese institutions were better than those of reviewers at German institutions (P = .001 for WLE, P < .001 for WLE + pCLE).Reviewers from Japanese institutions and expert gastroenterologists performed well in the pCLE interpretation. Substantial experience in conventional endoscopy is important for interpreting pCLE images for the diagnosis of gastric cancer.University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; www.umin.ac.jp/ctr/index.htm) number UMIN 000013437).
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Influence of the autotaxin-lysophosphatidic acid axis on cellular function and cytokine expression in different breast cancer cell lines - Hauck, Theresa; Kadam, Sheetal; Heinz, Katharina; Garcia Peraza, Maria; Schmid, Rafael; Kremer, Andreas; Wolf, Katharina; Bauer, Alina; Horch, Raymund E.; Arkudas, Andreas; Kengelbach-Weigand, Annika (Scientific Reports, 2022)
Previous studies provide high evidence that autotaxin (ATX)-lysophosphatidic acid (LPA) signaling through LPA receptors (LPAR) plays an important role in breast cancer initiation, progression, and invasion. However, its specific role in different breast cancer cell lines remains to be fully elucidated to offer improvements in targeted therapies. Within this study, we analyzed in vitro the effect of LPA 18:1 and the LPAR1, LPAR3 (and LPAR2) inhibitor Ki16425 on cellular functions of different human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7, BT-474, SKBR-3) and the human breast epithelial cell line MCF-10A, as well as Interleukin 8 (IL-8), Interleukin 6 (IL-6) and tumor necrosis factor (TNF)-alpha cytokine secretion after LPA-incubation. ATX-LPA signaling showed a dose-dependent stimulatory effect especially on cellular functions of triple-negative and luminal A breast cancer cell lines. Ki16425 inhibited the LPA-induced stimulation of triple-negative breast cancer and luminal A cell lines in variable intensity depending on the functional assay, indicating the interplay of different LPAR in those assays. IL-8, IL-6 and TNF-alpha secretion was induced by LPA in MDA-MB-468 cells. This study provides further evidence about the role of the ATX-LPA axis in different breast cancer cell lines and might contribute to identify subtypes suitable for a future targeted therapy of the ATX-LPA axis.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Cancer; Medical research; Molecular medicine

Influence of therapy on risk of cancer in rheumatoid arthritis. Pathophysiological principles - Waldner, Maximilian; Strangfeld, A.; Aringer, Martin (Zeitschrift für Rheumatologie, 2016)
The increased incidence of certain tumor entities in chronic inflammation and infections as well as the increased tumor risk under immunosuppression, illustrate the multiple and complex influences of the immune system on tumor pathogenesis. It is therefore conceivable that immunomodulatory therapy for rheumatoid arthritis (RA) could also influence the risk of malignancies, apart from treating the underlying disease. Basic scientific research studies have identified various signal transduction pathways that are relevant for tumorigenesis and tumor defense mechanisms. This review presents the current knowledge on the effects of the immune system on the occurrence of cancer and tries, where possible, to relate it to specific treatment options.
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Inherited CDH1 pathogenic variant: is there a place for surveillance of esophageal gastric inlet patch? - Leclercq, Philippe; Jadot, Virginie; Bours, Vincent; Oliveira, Carla; Neumann, Helmut; Bisschops, Raf (Therapeutic Advances in Gastroenterology, 2020)
CRIS-Team Scopus Importer:2020-05-22
Keywords: CDH1; Hereditary diffuse gastric cancer; Signet ring cell carcinoma

Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice with Chronic Intestinal Inflammation - Scheibe, Kristina; Kersten, Christina; Schmied, Anabel; Vieth, Michael; Primbs, Tatjana; Carlé, Birgitta-Elisabeth; Knieling, Ferdinand; Claussen, Jing; Klimowicz, Alexander C.; Zheng, Jie; Baum, Patrick; Meyer, Sebastian; et al. (Gastroenterology, 2018)
BACKGROUND & AIMS: Intestinal fibrosis is a long-term complication in inflammatory bowel diseases (IBD) frequently resulting in functional damage, bowel obstruction, and surgery. Interleukin 36 (IL36) is a group of cytokines in the IL1 family with inflammatory effects. We studied expression of IL36 and its receptor, interleukin 1 receptor like 2 (IL1RL2 or IL36R) in development of intestinal fibrosis in human tissues and mice. METHODS: We obtained intestinal tissues from 92 patients with Crohn´s disease (CD), 48 patients with ulcerative colitis (UC), and 26 patients without inflammatory bowel diseases (controls). Tissues were analyzed by histology to detect fibrosis and immunohistochemistry to determine the distribution of fibroblasts and levels of IL36R ligands. Human and mouse fibroblasts were incubated with IL36 or control medium, and transcriptome-wide RNA sequences were analyzed. Mice were given neutralizing antibodies against IL36R and we studied intestinal tissues from Il1rl2-/- mice; colitis and fibrosis was induced in mice by repetitive administration of DSS or TNBS. Bone marrow cells were transplanted from Il1rl2-/- to irradiated wild-type mice and intestinal tissues were analyzed. Antibodies against IL36R were applied to mice with established chronic colitis and fibrosis and intestinal tissues were studied. RESULTS: Mucosal and submucosal tissues from patients with CD or UC had higher levels of collagens including type VI collagen compared to tissues from controls. In tissues from patients with fibrostenotic CD, significantly higher levels of IL36A were noted, which correlated with high numbers of activated fibroblasts that expressed alpha smooth muscle actin. IL36R activation of mouse and human fibroblasts resulted in expression of genes that regulate fibrosis and tissue remodeling, as well as expression of collagen type VI. Il1rl2-/- mice and mice given injections of an antibody against IL36R developed less severe colitis and fibrosis following administration of DSS or TNBS, but bone marrow cells from Il1rl2-/- mice did not prevent induction of colitis and fibrosis. Injection of antibodies against IL36R significantly reduced established fibrosis in mice with chronic intestinal inflammation. CONCLUSION: We found higher levels of IL36A in fibrotic intestinal tissues from patients with IBD, compared with controls. IL36 induced expression of genes that regulate fibrogenesis in fibroblasts. Inhibition or knockout of the IL36R in mice reduces chronic colitis and intestinal fibrosis. Agents designed to block IL36R signaling could be developed for prevention and treatment of intestinal fibrosis in patients with IBD.
EVALuna2:35123

Inhibiting PGGT1B Disrupts Function of RHOA, Resulting in T-cell Expression of Integrin α4β7 and Development of Colitis in Mice - Lopez Posadas, Rocío; Fastancz, Petra; Martínez-Sánchez, Luz del Carmen; Panteleev-Ivlev, Julia; Thonn, Veronika; Kisseleva, Tatyana; Becker, Lukas S.; Schulz-Kuhnt, Anja; Zundler, Sebastian; Wirtz, Stefan; Atreya, Raja; Carlé, Birgitta-Elisabeth; et al. (Gastroenterology, 2019)
Background & Aims: It is not clear how regulation of T-cell function is altered during development of inflammatory bowel diseases (IBD). We studied the mechanisms by which geranylgeranyltransferase-mediated prenylation controls T-cell localization to the intestine and chronic inflammation. Methods: We generated mice with T-cell–specific disruption of the geranylgeranyltransferase type I, beta subunit gene (Pggt1b), called Pggt1bΔCD4 mice, or the ras homolog family member A gene (Rhoa), called RhoaΔCD4 mice. We also studied mice with knockout of CDC42 or RAC1 and wild-type mice (controls). Intestinal tissues were analyzed by histology, multiphoton and confocal microscopy, and real-time polymerase chain reaction. Activation of CDC42, RAC1, and RHOA were measured with G-LISA, cell fractionation, and immunoblots. T cells and lamina propria mononuclear cells from mice were analyzed by flow cytometry or transferred to Rag1–/– mice. Mice were given injections of antibodies against integrin alpha4beta7 or gavaged with the RORC antagonist GSK805. We obtained peripheral blood and intestinal tissue samples from patients with and without IBD and analyzed them by flow cytometry. Results: Pggt1bΔCD4 mice developed spontaneous colitis, characterized by thickening of the intestinal wall, edema, fibrosis, accumulation of T cells in the colon, and increased expression of inflammatory cytokines. Compared with control CD4+ T cells, PGGT1B-deficient CD4+ T cells expressed significantly higher levels of integrin alpha4beta7, which regulates their localization to the intestine. Inflammation induced by transfer of PGGT1B-deficient CD4+ T cells to Rag1–/– mice was blocked by injection of an antibody against integrin alpha4beta7. Lamina propria of Pggt1bΔCD4 mice had increased numbers of CD4+ T cells that expressed RORC and higher levels of cytokines produced by T-helper 17 cells (granulocyte-macrophage colony-stimulating factor, interleukin [IL]17A, IL17F, IL22, and tumor necrosis factor [TNF]). The RORC inverse agonist GSK805, but not antibodies against IL17A or IL17F, prevented colitis in Pggt1bΔCD4 mice. PGGT1B-deficient CD4+ T cells had decreased activation of RHOA. RhoAΔCD4 mice had a similar phenotype to Pggt1bΔCD4 mice, including development of colitis, increased numbers of CD4+ T cells in colon, increased expression of integrin alpha4beta7 by CD4+ T cells, and increased levels of IL17A and other inflammatory cytokines in lamina propria. T cells isolated from intestinal tissues from patients with IBD had significantly lower levels of PGGT1B than tissues from individuals without IBD. Conclusion: Loss of PGGT1B from T cells in mice impairs RHOA function, increasing CD4+ T-cell expression of integrin alpha4beta7 and localization to colon, resulting in increased expression of inflammatory cytokines and colitis. T cells isolated from gut tissues from patients with IBD have lower levels of PGGT1B than tissues from patients without IBD.
CRIS-Team Scopus Importer:2019-10-08
Keywords: IBD; Immune Regulation; Mouse Models; Prenylation

INHIBITION OF NOTCH1 PROMOTES HEDGEHOG SIGNALING IN A HES1-DEPENDENT MANNER AND EXACERBATES EXPERIMENTAL OSTEOARTHRITIS - Lin, N. Y.; Distler, A.; Beyer, Christian; Philipi-Schobinger, A.; Stock, Michael; Niemeier, A.; Dell'Accio, F.; Schett, Georg; Distler, Jörg (2016)
EVALuna2:13490

Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases - Schulz-Kuhnt, Anja; Neurath, Markus; Wirtz, Stefan; Atreya, Imke (Frontiers in Medicine, 2021)
The occurrence of epithelial defects in the gut relevantly contributes to the pathogenesis of inflammatory bowel diseases (IBD), whereby the impairment of intestinal epithelial barrier integrity seems to represent a primary trigger as well as a disease amplifying consequence of the chronic inflammatory process. Besides epithelial cell intrinsic factors, accumulated and overwhelmingly activated immune cells and their secretome have been identified as critical modulators of the pathologically altered intestinal epithelial cell (IEC) function in IBD. In this context, over the last 10 years increasing levels of attention have been paid to the group of innate lymphoid cells (ILCs). This is in particular due to a preferential location of these rather newly described innate immune cells in close proximity to mucosal barriers, their profound capacity to secrete effector cytokines and their numerical and functional alteration under chronic inflammatory conditions. Aiming on a comprehensive and updated summary of our current understanding of the bidirectional mucosal crosstalk between ILCs and IECs, this review article will in particular focus on the potential capacity of gut infiltrating type-1, type-2, and type-3 helper ILCs (ILC1s, ILC2s, and ILC3s, respectively) to impact on the survival, differentiation, and barrier function of IECs. Based on data acquired in IBD patients or in experimental models of colitis, we will discuss whether the different ILC subgroups could serve as potential therapeutic targets for maintenance of epithelial integrity and/or mucosal healing in IBD.
CRIS-Team Scopus Importer:2021-04-23
Keywords: colitis; cytokines; ILC plasticity; inflammatory bowel diseases; innate lymphoid cells; intestinal epithelium

Innate lymphoid cells contribute to the control of cutaneous leishmaniasis - Lukas, D.; Lorenz, B.; Reibetanz, M.; Koenen-Waisman, S.; Gasteiger, G.; Wirtz, Stefan; Vivier, E.; Yogev, N.; Von Stebut, E. (EXPERIMENTAL DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-14

Innate lymphoid cells in intestinal cancer development - Atreya, Imke; Kindermann, Markus; Wirtz, Stefan (Seminars in Immunology, 2019)
Colorectal cancer (CRC) is a highly prominent cause of cancer-related deaths worldwide. Although the functions of immune cells in the colorectal tumor microenvironment are complex and heterogeneous, dysregulated changes in the composition and activation state of immune cells are believed to represent key events supporting the establishment of pro- or anti-tumorigenic immune states. Recently, innate lymphoid cells (ILCs) emerged as central innate immune mediators during both gastrointestinal homeostasis and inflammatory pathologies. Hence, ILCs might also represent promising targets in the context of cancer therapy and are increasingly recognized as innate immune cells with potent immunomodulatory properties. In this review, we summarize the pleiotropic roles of the different ILC subsets for intestinal homeostasis and discuss the recent evidence on their potential involvement in the development and growth of intestinal cancers.
CRIS-Team Scopus Importer:2019-10-04
Keywords: Colorectal cancer; Gut immune system; ILC1; ILC2; ILC3; Innate lymphoid cells

Innovative Diagnostic Endoscopy in Inflammatory Bowel Diseases: From High-Definition to Molecular Endoscopy - Bojarski, Christian; Waldner, Maximilian; Rath, Timo; Schürmann, Sebastian; Neurath, Markus; Atreya, Raja; Siegmund, Britta (Frontiers in Medicine, 2021)
High-definition endoscopy is one essential step in the initial diagnosis of inflammatory bowel disease (IBD) characterizing the extent and severity of inflammation, as well as discriminating ulcerative colitis (UC) from Crohn's disease (CD). Following general recommendations and national guidelines, individual risk stratification should define the appropriate surveillance strategy, biopsy protocol and frequency of endoscopies. Beside high-definition videoendoscopy the application of dyes applied via a spraying catheter is of additional diagnostic value with a higher detection rate of intraepithelial neoplasia (IEN). Virtual chromoendoscopy techniques (NBI, FICE, I-scan, BLI) should not be recommended as a single surveillance strategy in IBD, although newer data suggest a higher comparability to dye-based chromoendoscopy than previously assumed. First results of oral methylene blue formulation are promising for improving the acceptance rate of classical chromoendoscopy. Confocal laser endomicroscopy (CLE) is still an experimental but highly innovative endoscopic procedure with the potential to contribute to the detection of dysplastic lesions. Molecular endoscopy in IBD has taken application of CLE to a higher level and allows topical application of labeled probes, mainly antibodies, against specific target structures expressed in the tissue to predict response or failure to biological therapies. First pre-clinical and in vivo data from label-free multiphoton microscopy (MPM) are now available to characterize mucosal and submucosal inflammation on endoscopy in more detail. These new techniques now have opened the door to individualized and highly specific molecular imaging in IBD in the future and pave the path to personalized medicine approaches. The quality of evidence was stated according to the Oxford Center of evidence-based medicine (March 2009). For this review a Medline search up to January 2021 was performed using the words “inflammatory bowel disease,” “ulcerative colitis,” “crohn's disease,” “chromoendoscopy,” “high-definition endoscopy,” “confocal laser endomicroscopy,” “confocal laser microscopy,” “molecular imaging,” “multiphoton microscopy.”
CRIS-Team Scopus Importer:2021-08-13
Keywords: chromoendoscopy; confocal laser microscopy; high-definition endoscopy; molecular endoscopy; multiphoton microscopy

Innovative Methods and Applications in Mucoadhesion Research - Mackie, Alan R.; Goycoolea, Francisco M.; Menchicchi, Bianca; Caramella, Carla Marcella; Saporito, Francesca; Lee, Seunghwan; Stephansen, Karen; Chronakis, Ioannis S.; Hiorth, Marianne; Adamczak, Malgorzata; Waldner, Maximilian; Nielsen, Hanne Morck; et al. (Macromolecular Bioscience, 2017)
The present review is aimed at elucidating relatively new aspects of mucoadhesion/mucus interaction and related phenomena that emerged from a Mucoadhesion workshop held in Munster on 2-3 September 2015 as a satellite event of the ICCC 13th-EUCHIS 12th. After a brief outline of the new issues, the focus is on mucus description, purification, and mucus/mucin characterization, all steps that are pivotal to the understanding of mucus related phenomena and the choice of the correct mucosal model for in vitro and ex vivo experiments, alternative bio/mucomimetic materials are also presented. Then a selection of preparative techniques and testing methods are described (at molecular as well as micro and macroscale) that may support the pharmaceutical development of mucus interactive systems and assist formulators in the scale-up and industrialization steps. Recent applications of mucoadhesive systems (including medical devices) intended for different routes of administration (oral, gastrointestinal, vaginal, nasal, ocular, and intravesical) and for the treatment of difficult to treat pathologies or the alleviation of symptoms are described.
EVALuna2:33895

Integrated Safety Analysis of Telotristat Ethyl in Patients With Carcinoid Heart Disease - Lapuerta, Pablo; Kulke, Matthew H.; Pavel, Marianne Ellen; Biran, Talia; Fleming, Rosanna; Zacks, Jerome S.; Hoffmanns, Phillip; Warner, Richard R. P. (2018)
EVALuna2:34107

Integrating Immunologic Signaling Networks: The JAK/STAT Pathway in Colitis and Colitis-Associated Cancer - Zundler, Sebastian; Neurath, Markus (Vaccines, 2016)
Cytokines are believed to be crucial mediators of chronic intestinal inflammation in inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). Many of these cytokines trigger cellular effects and functions through signaling via janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules. In this way, JAK/STAT signaling controls important events like cell differentiation, secretion of cytokines or proliferation and apoptosis in IBD in both adaptive and innate immune cells. Moreover, JAK/STAT signaling, especially via the IL-6/STAT3 axis, is believed to be involved in the transition of inflammatory lesions to tumors leading to colitis-associated cancer (CAC). In this review, we will introduce the main cellular players and cytokines that contribute to pathogenesis of IBD by JAK/STAT signaling, and will highlight the integrative function that JAK/STATs exert in this context as well as their divergent role in different cells and processes. Moreover, we will explain current concepts of the implication of JAK/STAT signaling in CAC and finally discuss present and future therapies for IBD that interfere with JAK/STAT signaling.
EVALuna2:2080

Intensity and longevity of SARS-CoV-2 vaccination response in patients with immune-mediated inflammatory disease: a prospective cohort study. - Simon, David; Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Mößner, Johanna; Taubmann, Jule; Mutlu, Melek Yalcin; Knitza, Johannes; et al. (The Lancet Rheumatology, 2022)
Background: Concerns have been raised about the reduced immunogenicity of vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory diseases and the higher risk of breakthrough infections. The objective of our study was to investigate the intensity and longevity of SARS-CoV-2 vaccination responses in patients with immune-mediated inflammatory diseases, and to assess the effects of diagnosis, treatment, and adapted vaccination schedules. Methods: SARS-CoV-2 IgG antibody response after SARS-CoV-2 vaccination was measured over time in a large prospective cohort of healthy controls and participants with immune-mediated inflammatory diseases (attending or admitted to affiliated centres) between Dec 15, 2020, and Dec 1, 2021. Cohort participants with immune-mediated inflammatory diseases and control participants with no diagnosis of immune-mediated inflammatory diseases, were eligible for this analysis. Demographic data and disease-specific data were collected using a questionnaire. Humoral response was compared across treatment and disease groups, and with respect to the receipt of additional vaccinations. SARS-CoV-2 antibody response was measured by ELISA using optical density ratio units and modelled over time with age and sex adjustment using mixed-effects models. Using these models, marginal mean antibody titres and marginal risks of a poor response (optical density ratio <1·1) were calculated for each week starting from week 8 after the first vaccination to week 40. Findings: Among 5076 individuals registered, 2535 participants with immune-mediated inflammatory diseases (mean age 55·0 [15·2] years; 1494 [58·9%] women and 1041 [41·1%] men) and 1198 healthy controls (mean age 40·7 [13·5] years; 554 [46·2%] women and 644 [53·8%] men) were included in this analysis. Mean antibody titres were higher in healthy controls compared with people with immune-mediated inflammatory diseases at all timepoints, with a peak antibody response in healthy controls (mean optical density ratio 12·48; 95% CI 11·50-13·53) of more than twice that in participants with immune-mediated inflammatory diseases (5·50; 5·23-5·77; mean difference 6·98; 5·92-8·04). A poor response to vaccination was observed in participants with immune-mediated inflammatory diseases who were taking B-cell inhibitors (peak mean difference from healthy controls 11·68; 10·07-13·29) and T-cell inhibitors (peakmean difference from healthy controls 10·43; 8·33-12·53). Mean differences in antibody responses between different immune-mediated inflammatory diseases were small. Participants with immune-mediated inflammatory diseases who were given a third vaccine dose had higher mean antibody titres than did healthy controls vaccinated with two vaccine doses at 40 weeks after the initial vaccination (mean difference 1·34; 0·01-2·69). Interpretation: People with immune-mediated inflammatory diseases show a lower and less durable SARS-CoV-2 vaccination response and are at risk of losing humoral immune protection. Adjusted vaccination schedules with earlier booster doses or more frequent re-doses, or both, could better protect people with immune-mediated inflammatory diseases. Funding: Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Research Council, Innovative Medicine Initiative, Friedrich-Alexander-Universität Erlangen-Nürnberg, Else Kröner-Memorial Foundation.
EVALuna2:506737

Interferon Gamma Counteracts the Angiogenic Switch and Induces Vascular Permeability in Dextran Sulfate Sodium Colitis in Mice - Haep, Lisa; Britzen-Laurent, Nathalie; Weber, Thomas G.; Naschberger, Elisabeth; Schäfer, Amrei; Kremmer, Elisabeth; Försch, Sebastian; Scheuer, Werner; Wirtz, Stefan; Waldner, Maximilian; Stürzl, Michael; Vieth, Michael (Inflammatory Bowel Diseases, 2015)
Interferon (IFN)-? is a central pathogenesis factor in inflammatory bowel disease (IBD) with pleiotropic effects on many different cell types. However, as yet, the immune modulatory functions of IFN-? in IBD have been predominantly investigated. Based on previous studies showing that IFN-? acts antiangiogenic in colorectal carcinoma, we investigated the effects of IFN-? on the vascular system in IBD.Colon tissues of patients with IBD and dextran sulfate sodium-induced colitis in mice were subjected to immunohistochemistry, quantitative real-time polymerase chain reactions, and in situ hybridization to quantify cell activation, angiogenesis, and immune responses. Vascular structure and permeability in mice were analyzed by ultramicroscopy and in vivo confocal laser endomicroscopy.We showed a significantly increased blood vessel density in IBD and dextran sulfate sodium colitis. In mice, this was associated with a disorganized blood vessel structure and profound vascular leakage. As compared with genes associated with angiogenesis, genes associated with inflammatory cell activation including IFN-? were more strongly upregulated in colitis tissues. IFN-? exerted direct effects on endothelial cells in IBD tissues in vivo, as indicated by the expression of IFN-?-induced guanylate binding protein 1 (GBP-1). Neutralization of IFN-? in the acute dextran sulfate sodium colitis model demonstrated that this cytokine exerts endogenous angiostatic activity in IBD and contributes to increased vascular permeability.The dissection of the pleiotropic activities of IFN-? in IBD provides new insights to the pathological functions of this cytokine and may be of high relevance for the optimization of combination therapy approaches.
EVALuna2:1969

Interferon-gamma triggers an anti-tumorigenic chain reaction in the tumor vessels of colorectal carcinoma - Stürzl, Michael; Langer, Victoria; Regensburger, Daniela; Tenkerian, Clara; Klingler, Annika; Waldner, Maximilian; Becker, Christoph; Meniel, Valerie; Grützmann, Robert; Geppert, Carol-Immanuel; Britzen-Laurent, Nathalie; Naschberger, Elisabeth (CANCER RESEARCH, 2018)
CRIS-Team WoS Importer:2019-06-18

Interferon Lambda Promotes Paneth Cell Death Via STAT1 Signaling in Mice and Is Increased in Inflamed Ileal Tissues of Patients With Crohn's Disease - Günther, Claudia; Ruder, Barbara; Stolzer, Iris; Dorner, Heidrun; He, Gui-Wei; Aden, Konrad; Strigli, Anne; Bittel, Miriam; Zeissig, Sebastian; Rosenstiel, Philip; Atreya, Raja; Neurath, Markus; et al. (Gastroenterology, 2019)
BACKGROUND & AIMS: Interferon lambda (IFNL) is expressed at high levels by intestinal epithelial cells (IECs) and mucosal immune cells in response to infection and inflammation. We investigated whether IFNL might contribute to pathogenesis of Crohn's disease (CD). METHODS: We obtained serum samples and terminal ileum biopsies from 47 patients with CD and 16 healthy individuals (controls). We measured levels of IFNL by enzyme-linked immunosorbent assay and immunohistochemistry and location of expression by confocal microscopy. Activation of IFNL signaling via STAT1 was measured in areas of no, mild, moderate, and severe inflammation and correlated with Paneth cell homeostasis and inflammation. IFNL expression and function were studied in wild-type mice and mice with intestinal epithelial cell-specific (Delta IEC) disruption or full-body disruption of specific genes (Mlkl(-/-), Stat1(Delta IEC), Casp8(Delta IEC), Casp8(Delta IEC)Ripk3(-/-), Casp8(Delta IEC)Tnfr(-/-), Casp8(Delta IEC)Mlkl(-/-), and Nod2(-/-) mice). Some mice were given tail vein injections of a vector encoding a secreted form of IFNL. Intestinal tissues were collected from mice and analyzed by immunohistochemistry and immunoblots. We generated 3-dimensional small intestinal organoids from mice and studied the effects of IFNL and inhibitors of STAT-signaling pathway. RESULTS: Patients with CD had significant increases in serum and ileal levels of IFNL compared with controls. Levels of IFNL were highest in ileum tissues with severe inflammation. High levels of IFNL associated with a reduced number of Paneth cells and increased cell death at the crypt bottom in inflamed ileum samples. Intestinal tissues from the ileum of wild-type mice injected with a vector expressing IFNL had reduced numbers of Paneth cells. IFNL-induced death of Paneth cells in mice did not occur via apoptosis, but required Mixed Lineage Kinase Domain Like (MLKL) and activation of Signal transducer and activator of transcription 1 (STAT1). In organoids, inhibitors of Janus kinase (JAK) signaling via STAT1 (glucocorticoids, tofacitinib, or filgotinib) reduced expression of proteins that mediate cell death and prevented Paneth cell death. CONCLUSIONS: Levels of IFNL are increased in serum and inflamed ileal tissues from patients with CD and associated with a loss of Paneth cells. Expression of a secreted form of IFNL in mice results in loss of Paneth cells from intestinal tissues, via STAT1 and MLKL, controlled by caspase 8. Strategies to reduce IFNL or block its effects might be developed for treatment of patients with CD affecting the terminal ileum.
Keywords: Inflammatory Bowel Diseases; Ileitis; Necroptosis; Cytokine

Interferon regulatory factor 1 (IRF-1) promotes intestinal group 3 innate lymphoid responses during Citrobacter rodentium infection - Schmalzl, Angelika; Leupold, Tamara; Kreiß, Lucas; Waldner, Maximilian; Schürmann, Sebastian; Neurath, Markus; Becker, Christoph; Wirtz, Stefan (Nature Communications, 2022)
Group 3 innate lymphoid cells (ILC3s) are crucial mediators of immunity and epithelial barrier function during immune responses against extracellular bacteria. Here, we identify Interferon regulatory factor 1 (IRF-1), a transcription factor previously associated with type 1 immunity, as an essential regulator of intestinal ILC3 accumulation and effector cytokine production. We demonstrate that IRF-1 is upregulated in the context of infection with the enteropathogen Citrobacter rodentium and that its presence is central for anatomical containment and prevention of pathogen dissemination. We furthermore show that IRF-1 is required in order for intestinal ILC3s to produce large amounts of the protective effector cytokine IL-22 early in the course of infection. On a molecular level, our data indicate that IRF-1 controls ILC3 numbers and their activation by direct transcriptional regulation of the IL-12Rβ1 chain, thereby allowing ILCs to physiologically respond to IL-23 stimulation.
CRIS-Team Scopus Importer:2022-10-14

Interferons at the crossroad of cell death pathways during gastrointestinal inflammation and infection - Stolzer, Iris; Ruder, Barbara; Neurath, Markus; Günther, Claudia (International Journal of Medical Microbiology, 2021)
Interferons (IFNs) are pleiotropic immune-modulatory cytokines that are well known for their essential role in host defense against viruses, bacteria, and other pathogenic microorganisms. They can exert both, protective or destructive functions depending on the microorganism, the targeted tissue and the cellular context. Interferon signaling results in the induction of IFN-stimulated genes (ISGs) influencing different cellular pathways including direct anti-viral/anti-bacterial response, immune-modulation or cell death. Multiple pathways leading to host cell death have been described, and it is becoming clear that depending on the cellular context, IFN-induced cell death can be beneficial for both: host and pathogen. Accordingly, activation or repression of corresponding signaling mechanisms occurs during various types of infection but is also an important pathway for gastrointestinal inflammation and tissue damage. In this review, we summarize the role of interferons at the crossroad of various cell death pathways in the gut during inflammation and infection.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Cell death; Gastrointestinal infection; IBD; Interferons

Interleukin-12: Functional activities and implications for disease - Zundler, Sebastian; Neurath, Markus (Cytokine & Growth Factor Reviews, 2015)
Interleukin-12 (IL-12) was the first member of the IL-12 family of cytokines to be identified and has therefore become its eponym. It is a heterodimeric protein of two subunits (p35, p40) secreted by phagocytic cells in response to pathogens and mainly acts through STAT4 to induce IFN-? production in T and NK cells. IFN-? in turn mediates proinflammatory functions and activates T-bet. As IL-12 engages in TH1 development, it is believed to represent an important link between innate and adaptive immunity. Following its identification and the finding of its association to TH1 commitment, great hopes were placed in IL-12 to become a target for therapeutic applications in multiple settings of autoimmunity and cancer. Though, the discovery of the related members of the IL-12 family and several rather disappointing attempts to translate experimental results into clinical practice, have relativized these hopes. Nevertheless, IL-12 remains a cytokine of outstanding importance with lots of unresolved questions. In this review, we will first briefly depict the biochemistry of the cytokine, its receptor and the related signal transduction, before summarizing the regulation of IL-12 production and its biological functions. We will then describe the current knowledge about the implication of IL-12 in different murine disease models as well as in the corresponding human conditions and comment on possible consequences for future clinical applications.
EVALuna2:2016

Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease - Karbach, Susanne; Croxford, Andrew L.; Oelze, Matthias; Schueler, Rebecca; Minwegen, Daniel; Wegner, Joanna; Koukes, Lija; Yogev, Nir; Nikolaev, Alexei; Reissig, Sonja; Ullmann, Alexander; Knorr, Maike; et al. (Arteriosclerosis, Thrombosis, and Vascular Biology, 2014)
Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease.Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A(ind/+) mice), associated with increased reactive oxygen species formation and circulating CD11b(+) inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17A(ind/+) mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) cells accompanied by increased expression of the inducible nitric oxide synthase and the nicotinamide dinucleotide phosphate (NADPH) oxidase, nox2. Neutrophil depletion by anti-GR-1 antibody injections reduced oxidative stress in blood and vessels. Neutralization of tumor necrosis factor-? and IL-6 (both downstream of IL-17A) reduced skin lesions, attenuated oxidative stress in heart and blood, and partially improved endothelial dysfunction in K14-IL-17A(ind/+) mice.Dermal overexpression of IL-17A induces systemic endothelial dysfunction, vascular oxidative stress, arterial hypertension, and increases mortality mainly driven by myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) inflammatory cells. Depletion of the GR-1(+) immune cells or neutralization of IL-17A downstream cytokines by biologicals attenuates the vascular phenotype in K14-IL-17A(ind/+) mice.
EVALuna2:1859

Interleukin 36 receptor-inducible matrix metalloproteinase 13 mediates intestinal fibrosis - Koop, Kristina; Enderle, Karin; Hillmann, Miriam; Ruspeckhofer, Laura; Vieth, Michael; Sturm, Gregor; Trajanoski, Zlatko; Kühl, Anja A.; Atreya, Raja; Leppkes, Moritz; Baum, Patrick; Roy, Janine; et al. (Frontiers in Immunology, 2023)
Background: Fibrostenotic disease is a common complication in Crohn’s disease (CD) patients hallmarked by transmural extracellular matrix (ECM) accumulation in the intestinal wall. The prevention and medical therapy of fibrostenotic CD is an unmet high clinical need. Although targeting IL36R signaling is a promising therapy option, downstream mediators of IL36 during inflammation and fibrosis have been incompletely understood. Candidate molecules include matrix metalloproteinases which mediate ECM turnover and are thereby potential targets for anti-fibrotic treatment. Here, we have focused on understanding the role of MMP13 during intestinal fibrosis. Methods: We performed bulk RNA sequencing of paired colon biopsies taken from non-stenotic and stenotic areas of patients with CD. Corresponding tissue samples from healthy controls and CD patients with stenosis were used for immunofluorescent (IF) staining. MMP13 gene expression was analyzed in cDNA of intestinal biopsies from healthy controls and in subpopulations of patients with CD in the IBDome cohort. In addition, gene regulation on RNA and protein level was studied in colon tissue and primary intestinal fibroblasts from mice upon IL36R activation or blockade. Finally, in vivo studies were performed with MMP13 deficient mice and littermate controls in an experimental model of intestinal fibrosis. Ex vivo tissue analysis included Masson’s Trichrome and Sirius Red staining as well as evaluation of immune cells, fibroblasts and collagen VI by IF analysis. Results: Bulk RNA sequencing revealed high upregulation of MMP13 in colon biopsies from stenotic areas, as compared to non-stenotic regions of patients with CD. IF analysis confirmed higher levels of MMP13 in stenotic tissue sections of CD patients and demonstrated αSMA+ and Pdpn+ fibroblasts as a major source. Mechanistic experiments demonstrated that MMP13 expression was regulated by IL36R signaling. Finally, MMP13 deficient mice, as compared to littermate controls, developed less fibrosis in the chronic DSS model and showed reduced numbers of αSMA+ fibroblasts. These findings are consistent with a model suggesting a molecular axis involving IL36R activation in gut resident fibroblasts and MMP13 expression during the pathogenesis of intestinal fibrosis. Conclusion: Targeting IL36R-inducible MMP13 could evolve as a promising approach to interfere with the development and progression of intestinal fibrosis.
CRIS-Team Scopus Importer:2023-06-02
Keywords: collagen type VI; collagenase 3; extracellular matrix (ECM); IL-36; il36 receptor; intestinal fibrosis; matrix metalloproteinase 13 (MMP13); αSMA+ fibroblasts

Interleukin-36 receptor mediates the crosstalk between plasma cells and synovial fibroblasts - Schmitt, Verena; Hahn, Madelaine; Kästele, Verena; Wagner, Olga; Wiendl, Maximilian; Derer, Anja; Taddeo, Adriano; Hahne, Stefanie; Radbruch, Andreas; Jäck, Hans-Martin; Schuh, Wolfgang; Mielenz, Dirk; et al. (European Journal of Immunology, 2017)
The IL-1 family member IL-36? has proinflammatory and pathogenic properties in psoriasis. IL-36? binds to the IL-36 receptor leading to nuclear factor kappa B/mitogen activated protein kinase mediated cytokine release. The IL-36R antagonist prevents recruitment of IL-1 receptor accessory protein and therefore IL-36-dependent cell activation. In inflamed human tissue, we previously could show that resident B cells and plasma cells (PC) express IL-36?. Further, fibroblast-like synoviocytes (FLS) produced proinflammatory cytokines upon IL-36?-stimulation. We hypothesize an IL-36-specific crosstalk between B cells/PCs and FLS permitting a proinflammatory B cell niche. Here, we firstly demonstrated that B cell lines and B cells from healthy donors express IL-36? and stimulation increased IL-36? in B cells and primary plasmablasts/PCs. Moreover, FLS respond specifically to IL-36? by proliferation and production of matrix metalloproteinases via p38/HSP27 signaling. Importantly, IL-36R-deficiency abrogated IL-36?-induced production of inflammatory mediators in FLS and changed the intrinsic FLS-phenotype. Using an in vitro co-culture system, we could show that IL-36R-deficient FLS had a limited capacity to support PC survival compared to wild-type FLS. Hence, we demonstrated an IL-36R-dependent crosstalk between B cells/PCs and FLS. Our data support the concept of initiation and maintenance of a proinflammatory niche by B cells in the joints. This article is protected by copyright. All rights reserved.
EVALuna2:13406

Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections - Bénard, Alan; Jacobsen, Anne; Brunner, Maximilian; Krautz, Christian; Klösch, Bettina; Swierzy, Izabela; Naschberger, Elisabeth; Podolska, Malgorzata; Kouhestani, Dina; David, Paul; Birkholz, Torsten; Castellanos, Ixchel; et al. (Nature Communications, 2021)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.
CRIS-Team Scopus Importer:2021-03-05

Interleukin-9 protects from early podocyte injury and progressive glomerulosclerosis in Adriamycin-induced nephropathy - Xiong, Tingting; Attar, Madena; Gnirck, Ann Christin; Wunderlich, Malte; Becker, Martina; Rickassel, Constantin; Puelles, Victor G.; Meyer-Schwesinger, Catherine; Wiech, Thorsten; Nies, Jasper F.; Divivier, Mylène; Fuchs, Tobias; et al. (Kidney International, 2020)
A wide spectrum of immunological functions has been attributed to Interleukin 9 (IL-9), including effects on the survival and proliferation of immune and parenchymal cells. In recent years, emerging evidence suggests that IL-9 expression can promote tissue repair in inflammatory conditions. However, data about the involvement of IL-9 in kidney tissue protection is very limited. Here, we investigated the role of IL-9 in Adriamycin-induced nephropathy (AN), a mouse model for proteinuric chronic kidney disease. Compared to wild type mice, IL-9 knockout (Il9−/−) mice with AN displayed accelerated development of proteinuria, aggravated glomerulosclerosis and deterioration of kidney function. At an early stage of disease, the Il9−/− mice already displayed a higher extent of glomerular podocyte injury and loss of podocyte number compared to wild type mice. In the kidney, T cells and innate lymphoid cells produced IL-9. However, selective deficiency of IL-9 in the innate immune system in Il9−/−Rag2−/− mice that lack T and B cells did not alter the outcome of AN, indicating that IL-9 derived from the adaptive immune system was the major driver of tissue protection in this model. Mechanistically, we could show that podocytes expressed the IL-9 receptor in vivo and that IL-9 signaling protects podocytes from Adriamycin-induced apoptosis in vitro. Finally, in vivo treatment with IL-9 effectively protected wild type mice from glomerulosclerosis and kidney failure in the AN model. The detection of increased serum IL-9 levels in patients with primary focal and segmental glomerulosclerosis further suggests that IL-9 production is induced by glomerular injury in humans. Thus, IL-9 confers protection against experimental glomerulosclerosis, identifying the IL-9 pathway as a potential therapeutic target in proteinuric chronic kidney disease.
CRIS-Team Scopus Importer:2020-08-14
Keywords: cytokines; focal segmental glomerulosclerosis; inflammation; lymphocytes

International experience of vedolizumab in primary sclerosis cholangitis and inflammatory bowel disease - Williamson, K.; Lytvyak, E.; Kremer, Andreas; De Krijger, M.; Trivedi, P.; Estes, D.; Yu, L.; Pratt, D.; De Vries, A.; Yimam, K. K.; Daretti, L.; Liu, C. H.; et al. (JOURNAL OF HEPATOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-26

Interobserver Agreement for Contrast-Enhanced Ultrasound (CEUS)-Based Standardized Algorithms for the Diagnosis of Hepatocellular Carcinoma in High-Risk Patients - Schellhaas, Barbara; Pfeifer, Lukas; Kielisch, Christian; Görtz, Rüdiger; Neurath, Markus; Strobel, Deike (Ultraschall in der Medizin, 2018)
OBJECTIVES: This pilot study aimed at assessing interobserver agreement with two contrast-enhanced ultrasound (CEUS) algorithms for the diagnosis of hepatocellular carcinoma (HCC) in high-risk patients. METHODS: Focal liver lesions in 55 high-risk patients were assessed independently by three blinded observers with two standardized CEUS algorithms: ESCULAP (Erlanger Synopsis of Contrast-Enhanced Ultrasound for Liver Lesion Assessment in Patients at risk) and ACR-CEUS-LI-RADSv.2016 (American College of Radiology CEUS-Liver Imaging Reporting and Data System). Lesions were categorized according to size and ultrasound contrast enhancement in the arterial, portal-venous and late phase. Interobserver agreement for assessment of enhancement pattern and categorization was compared between both CEUS algorithms. Additionally, diagnostic accuracy for the definitive diagnosis of HCC was compared. Histology and/or CE-MRI and follow-up served as reference standards. RESULTS: 55 patients were included in the study (male/female, 44/ 11; mean age: 65.9 years). 90.9 % had cirrhosis. Histological findings were available in 39/55 lesions (70.9 %). Reference standard of the 55 lesions revealed 48 HCCs, 2 intrahepatic cholangiocellular carcinomas (ICCs), and 5 non-HCC-non-ICC lesions. Interobserver agreement was moderate to substantial for arterial phase hyperenhancement (ĸ = 0.53 - 0.67), and fair to moderate for contrast washout in the portal-venous or late phase (ĸ = 0.33 - 0.53). Concerning the CEUS-based algorithms, the interreader agreement was substantial for the ESCULAP category (ĸ = 0.64 - 0.68) and fair for the CEUS-LI-RADS® category (ĸ = 0.3 - 0.39). Disagreement between observers was mostly due to different perception of washout. CONCLUSION: Interobserver agreement is better for ESCULAP than for CEUS-LI-RADS®. This is mostly due to the fact that perception of contrast washout varies between different observers. However, interobserver agreement is good for arterial phase hyperenhancement, which is the key diagnostic feature for the diagnosis of HCC with CEUS in the cirrhotic liver.
EVALuna2:35127

Interobserver and intermodality agreement of standardized algorithms for non-invasive diagnosis of hepatocellular carcinoma in high-risk patients: CEUS-LI-RADS versus MRI-LI-RADS - Schellhaas, Barbara; Hammon, Matthias; Strobel, Deike; Pfeifer, Lukas; Kielisch, Christian; Görtz, Rüdiger; Janka, Rolf Matthias; Neurath, Markus; Uder, Michael; Seuß, Hannes; Cavallaro, Alexander Josef (European Radiology, 2018)
OBJECTIVES: We compared the interobserver agreement for the recently introduced contrast-enhanced ultrasound (CEUS)-based algorithm CEUS-LI-RADS (Liver Imaging Reporting and Data System) versus the well-established magnetic resonance imaging (MRI)-LI-RADS for non-invasive diagnosis of hepatocellular carcinoma (HCC) in high-risk patients. METHODS: Focal liver lesions in 50 high-risk patients (mean age 66.2 ± 11.8 years; 39 male) were assessed retrospectively with CEUS and MRI. Two independent observers reviewed CEUS and MRI examinations, separately, classifying observations according to CEUS-LI-RADSv.2016 and MRI-LI-RADSv.2014. Interobserver agreement was assessed with Cohen's kappa. RESULTS: Forty-three lesions were HCCs; two were intrahepatic cholangiocarcinomas; five were benign lesions. Arterial phase hyperenhancement was perceived less frequently with CEUS than with MRI (37/50 / 38/50 lesions = 74%/78% [CEUS; observer 1/observer 2] versus 46/50 / 44/50 lesions = 92%/88% [MRI; observer 1/observer 2]). Washout appearance was observed in 34/50 / 20/50 lesions = 68%/40% with CEUS and 31/50 / 31/50 lesions = 62%/62%) with MRI. Interobserver agreement was moderate for arterial hyperenhancement (ĸ = 0.511/0.565 [CEUS/MRI]) and "washout" (ĸ = 0.490/0.582 [CEUS/MRI]), fair for CEUS-LI-RADS category (ĸ = 0.309) and substantial for MRI-LI-RADS category (ĸ = 0.609). Intermodality agreement was fair for arterial hyperenhancement (ĸ = 0.329), slight to fair for "washout" (ĸ = 0.202) and LI-RADS category (ĸ = 0.218) CONCLUSION: Interobserver agreement is substantial for MRI-LI-RADS and only fair for CEUS-LI-RADS. This is mostly because interobserver agreement in the perception of washout appearance is better in MRI than in CEUS. Further refinement of the LI-RADS algorithms and increasing education and practice may be necessary to improve the concordance between CEUS and MRI for the final LI-RADS categorization. KEY POINTS: • CEUS-LI-RADS and MRI-LIRADS enable standardized non-invasive diagnosis of HCC in high-risk patients. • With CEUS, interobserver agreement is better for arterial hyperenhancement than for "washout". • Interobserver agreement for major features is moderate for both CEUS and MRI. • Interobserver agreement for LI-RADS category is substantial for MRI, and fair for CEUS. • Interobserver-agreement for CEUS-LI-RADS will presumably improve with ongoing use of the algorithm.
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Interplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage fidelity - Wang, Jueqiong; Farkas, Carlos; Benyoucef, Aissa; Carmichael, Catherine; Haigh, Katharina; Wong, Nick; Huylebroeck, Danny; Stemmler, Marc P.; Brabletz, Simone; Brabletz, Thomas; Nefzger, Christian M.; Goossens, Steven; et al. (Plos Biology, 2021)
The ZEB2 transcription factor has been demonstrated to play important roles in hematopoiesis and leukemic transformation. ZEB1 is a close family member of ZEB2 but has remained more enigmatic concerning its roles in hematopoiesis. Here, we show using conditional loss-of-function approaches and bone marrow (BM) reconstitution experiments that ZEB1 plays a cell-autonomous role in hematopoietic lineage differentiation, particularly as a positive regulator of monocyte development in addition to its previously reported important role in T-cell differentiation. Analysis of existing single-cell (sc) RNA sequencing (RNA-seq) data of early hematopoiesis has revealed distinctive expression differences between Zeb1 and Zeb2 in hematopoietic stem and progenitor cell (HSPC) differentiation, with Zeb2 being more highly and broadly expressed than Zeb1 except at a key transition point (short-term HSC [ST-HSC]?MPP1), whereby Zeb1 appears to be the dominantly expressed family member. Inducible genetic inactivation of both Zeb1 and Zeb2 using a tamoxifen-inducible Cre-mediated approach leads to acute BM failure at this transition point with increased long-term and short-term hematopoietic stem cell numbers and an accompanying decrease in all hematopoietic lineage differentiation. Bioinformatics analysis of RNA-seq data has revealed that ZEB2 acts predominantly as a transcriptional repressor involved in restraining mature hematopoietic lineage gene expression programs from being expressed too early in HSPCs. ZEB1 appears to fine-tune this repressive role during hematopoiesis to ensure hematopoietic lineage fidelity. Analysis of Rosa26 locus-based transgenic models has revealed that Zeb1 as well as Zeb2 cDNA-based overexpression within the hematopoietic system can drive extramedullary hematopoiesis/splenomegaly and enhance monocyte development. Finally, inactivation of Zeb2 alone or Zeb1/2 together was found to enhance survival in secondary MLL-AF9 acute myeloid leukemia (AML) models attesting to the oncogenic role of ZEB1/2 in AML.
CRIS-Team WoS Importer:2021-10-01

Interplay of GTPases and Cytoskeleton in Cellular Barrier Defects during Gut Inflammation - Lopez Posadas, Rocío; Stürzl, Michael; Atreya, Imke; Neurath, Markus; Britzen-Laurent, Nathalie (Frontiers in Immunology, 2017)
An essential role of the intestine is to build and maintain a barrier preventing the luminal gut microbiota from invading the host. This involves two coordinated physical and immunological barriers formed by single layers of intestinal epithelial and endothelial cells, which avoid the activation of local immune responses or the systemic dissemination of microbial agents, and preserve tissue homeostasis. Accordingly, alterations of epithelial and endothelial barrier functions have been associated with gut inflammation, for example during inflammatory bowel disease (IBD). The discriminative control of nutriment uptake and sealing toward potentially pathological microorganisms requires a profound regulation of para- and transcellular permeability. On the subcellular level, the cytoskeleton exerts key regulatory functions in the maintenance of cellular barriers. Increased epithelial/endothelial permeability occurs primarily as a result of a reorganization of cytoskeletal-junctional complexes. Pro-inflammatory mediators such as cytokines can induce cytoskeletal rearrangements, causing inflammation-dependent defects in gut barrier function. In this context, small GTPases of the Rho family and large GTPases from the Dynamin superfamily appear as major cellular switches regulating the interaction between intercellular junctions and actomyosin complexes, and in turn cytoskeleton plasticity. Strikingly, some of these proteins, such as RhoA or guanylate-binding protein-1 (GBP-1) have been associated with gut inflammation and IBD. In this review, we will summarize the role of small and large GTPases for cytoskeleton plasticity and epithelial/endothelial barrier in the context of gut inflammation.
EVALuna2:15286

Interrogating host immunity to predict treatment response in inflammatory bowel disease - Digby-Bell, Jonathan L.; Atreya, Raja; Monteleone, Giovanni; Powell, Nick (Nature Reviews Gastroenterology & Hepatology, 2019)
IBD treatment is undergoing a transformation with an expanding repertoire of drugs targeting different aspects of the immune response. Three novel classes of drugs have emerged in the past decade that target leukocyte trafficking to the gut (vedolizumab), neutralize key cytokines with antibodies (ustekinumab) and inhibit cytokine signalling pathways (tofacitinib). In advanced development are other drugs for IBD, including therapies targeting other cytokines such as IL-23 and IL-6. However, all agents tested so far are hampered by primary and secondary loss of response, so it is desirable to develop personalized strategies to identify which patients should be treated with which drugs. Stratification of patients with IBD by clinical parameters alone lacks sensitivity, and alternative modalities are now needed to deliver precision medicine in IBD. High-resolution profiling of immune response networks in individual patients is a promising approach and different technical platforms, including in vivo real-time molecular endoscopy, tissue transcriptomics and germline genetics, are promising tools to help predict responses to specific therapies. However, important challenges remain regarding the clinical utility of these technologies, including their scalability and accessibility. This Review focuses on unravelling some of the complexity of mucosal immune responses in IBD pathogenesis and how current and emerging analytical platforms might be harnessed to effectively stratify and individualise IBD therapy.
CRIS-Team Scopus Importer:2019-12-03

Intestinal Barrier Healing Is Superior to Endoscopic and Histologic Remission for Predicting Major Adverse Outcomes in Inflammatory Bowel Disease: The Prospective ERIca Trial - Rath, Timo; Atreya, Raja; Bodenschatz, Julia; Uter, Wolfgang; Geppert, Carol-Immanuel; Vitali, Francesco; Fischer, Sarah; Waldner, Maximilian; Colombel, Jean Frédéric; Hartmann, Arndt; Neurath, Markus (Gastroenterology, 2023)
Background & Aims: Endoscopic and histologic remission have emerged as key therapeutic goals in the management of inflammatory bowel diseases (IBD) that are associated with favorable long-term disease outcomes. Here, we prospectively compared the predictive value of barrier healing with endoscopic and histologic remission for predicting long-term disease behavior in a large cohort of patients with IBD in clinical remission. Methods: At baseline, patients with IBD in clinical remission underwent ileocolonoscopy with assessment of intestinal barrier function by confocal endomicroscopy. Endoscopic and histologic disease activity, as well as barrier healing, was prospectively assessed along established scores. During subsequent follow-up, patients were closely monitored for clinical disease activity and the occurrence of major adverse outcomes (MAOs): disease flares, IBD-related hospitalization or surgery, and initiation or dose escalation of systemic steroids, immunosuppressants, small molecules, or biological therapy. Results: The final analysis included 181 patients, 100 with Crohn's disease [CD] and 81 with ulcerative colitis (UC). During a mean follow-up of 35 (CD) and 25 (UC) months, 73% of patients with CD and 69% of patients with UC experienced at least 1 MAO. The probability of MAO-free survival was significantly higher in patients with IBD with endoscopic remission compared with endoscopically active disease. In addition, histologic remission predicted MAO-free survival in patients with UC but not CD. Barrier healing on endomicroscopy was superior to endoscopic and histologic remission for predicting MAO-free survival in both UC and CD. Conclusions: Barrier healing is associated with decreased risk of disease progression in patients with clinically remittent IBD, with superior predictive performance compared with endoscopic and histologic remission. Analysis of barrier function might be considered as a future treatment target in clinical trials. ClinicalTrials.gov number, NCT05157750.
CRIS-Team Scopus Importer:2023-01-27
Keywords: Confocal Laser Endomicroscopy; Endoscopy; Histology; Inflammatory Bowel Diseases; Intestinal Barrier

Intestinal epithelial barrier integrity investigated by label-free techniques in ulcerative colitis patients - Quansah, Elsie; Gardey, Elena; Ramoji, Anuradha; Meyer-Zedler, Tobias; Goehrig, Bianca; Heutelbeck, Astrid; Hoeppener, Stephanie; Schmitt, Michael; Waldner, Maximilian; Stallmach, Andreas; Popp, Jürgen (Scientific Reports, 2023)
The intestinal epithelial barrier, among other compartments such as the mucosal immune system, contributes to the maintenance of intestinal homeostasis. Therefore, any disturbance within the epithelial layer could lead to intestinal permeability and promote mucosal inflammation. Considering that disintegration of the intestinal epithelial barrier is a key element in the etiology of ulcerative colitis, further assessment of barrier integrity could contribute to a better understanding of the role of epithelial barrier defects in ulcerative colitis (UC), one major form of chronic inflammatory bowel disease. Herein, we employ fast, non-destructive, and label-free non-linear methods, namely coherent anti-Stokes Raman scattering (CARS), second harmonic generation (SHG), two-photon excited fluorescence (TPEF), and two-photon fluorescence lifetime imaging (2P-FLIM), to assess the morpho-chemical contributions leading to the dysfunction of the epithelial barrier. For the first time, the formation of epithelial barrier gaps was directly visualized, without sophisticated data analysis procedures, by the 3D analysis of the colonic mucosa from severely inflamed UC patients. The results were compared with histopathological and immunofluorescence images and validated using transmission electron microscopy (TEM) to indicate structural alterations of the apical junction complex as the underlying cause for the formation of the epithelial barrier gaps. Our findings suggest the potential advantage of non-linear multimodal imaging is to give precise, detailed, and direct visualization of the epithelial barrier in the gastrointestinal tract, which can be combined with a fiber probe for future endomicroscopy measurements during real-time in vivo imaging.
CRIS-Team Scopus Importer:2023-03-03

Intestinal epithelial Caspase-8 signaling is essential to prevent necroptosis during Salmonella Typhimurium induced enteritis - Hefele, Manuela; Stolzer, Iris; Ruder, Barbara; He, Gui-Wei; Mahapatro, Mousumi; Wirtz, Stefan; Neurath, Markus; Günther, Claudia (Mucosal Immunology, 2018)
Although induction of host cell death is a pivotal step during bacteria-induced gastroenteritis, the molecular regulation remains to be fully characterized. To expand our knowledge, we investigated the role of the central cell death regulator Caspase-8 in response to Salmonella Typhimurium. Here, we uncovered that intestinal salmonellosis was associated with strong upregulation of members of the host cell death machinery in intestinal epithelial cells (IECs) as an early event, suggesting that elimination of infected IECs represents a host defense strategy. Indeed, Casp8∆IEC mice displayed severe tissue damage and high lethality after infection. Additional deletion of Ripk3 or Mlkl rescued epithelial cell death and lethality of Casp8∆IEC mice, demonstrating the crucial role of Caspase-8 as a negative regulator of necroptosis. While Casp8∆IECTnfr1-/- mice showed improved survival after infection, tissue destruction was similar to Casp8∆IEC mice, indicating that necroptosis partially depends on TNF-α signaling. Although there was no impairment in antimicrobial peptide secretion during the early phase of infection, functional Caspase-8 seems to be required to control pathogen colonization. Collectively, these results demonstrate that Caspase-8 is essential to prevent Salmonella Typhimurium induced enteritis and to ensure host survival by two different mechanisms: maintenance of intestinal barrier function and restriction of pathogen colonization.
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Intestinal ex vivo organoid culture reveals altered programmed crypt stem cells in patients with celiac disease - Dieterich, Walburga; Neurath, Markus; Zopf, Yurdagül (Scientific Reports, 2020)
The ex vivo generation of gastrointestinal organoids from crypt stem cells opens up the possibility of new research approaches investigating gastrointestinal diseases. We used this technology to study differences between healthy controls and patients with celiac disease (CD). We noticed distinct dissimilarities in the phenotypes of organoids between our study groups and found considerable variations in their gene expression. Extracellular matrix genes involved in epithelial-mesenchymal transition are expressed most differently. In addition, we demonstrated epigenetic modifications that might be responsible for the different organoid gene expression thus accounting for a deranged crypt/villus axis development in CD. The organoids have proven valuable to demonstrate fundamental differences in duodenal derived organoids between healthy controls and patients with CD and thus are a suitable tool to gain new insights in pathogenesis of CD.
CRIS-Team Scopus Importer:2020-03-10

Intestinal graft-versus-host disease is driven by BATF-dependent IL-7R(hi)GM-CSF+ T cells - Ullrich, Evelyn; Abendroth, Benjamin; Rothamer, Johanna; Huber, Carina; Buettner-Herold, Maike; Kitowski, Vera; Vogler, Tina; Longerich, Thomas; Zundler, Sebastian; Völkl, Simon; Beilhack, Andreas; Rose-John, Stefan; et al. (2018)
EVALuna2:207769

INTESTINAL HIF1 alpha EXPRESSION PROTECTS AGAINST EPITHELIAL CELL DEATH IN ARTHRITIS - Lyu, Pang; Wen, Jinming; Stolzer, Iris; Gießl, Andreas; Song, Rui; Meng, Xiangjun; Cao, Shan; Günther, Claudia; Schett, Georg; Bozec, Aline (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

[Intestinal microbiota - a vital "organ" with manifold functions]. - Konturek, Peter; Konturek, Kathrin; Zopf, Yurdagül; Harsch, Igor A. (MMW Fortschritte der Medizin, 2020)
BACKGROUND: The intestinal microbiota must be seen as an elementary component of our health. METHOD: Review article RESULTS AND CONCLUSIONS: An abnormal gut microbiota (dysbiosis) plays an essential role in the pathogenesis of functional and inflammatory bowel diseases. It is often also associated with diseases outside the intestine. The exact causality remains unclear ("chicken and egg problem"). With the help of prebiotics, probiotics or fecal microbiota therapy, relevant therapeutic effects can be achieved in chronic, dysbiosis-associated diseases. The choice of the preparation depends on the clinical symptoms, the duration of the treatment depends on the particular clinical picture.
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Intestinal Mucosal Wound Healing and Barrier Integrity in IBD–Crosstalk and Trafficking of Cellular Players - Sommer, Katrin; Wiendl, Maximilian; Müller, Tanja; Heidbreder, Karin; Voskens, Caroline; Neurath, Markus; Zundler, Sebastian (Frontiers in Medicine, 2021)
The intestinal epithelial barrier is carrying out two major functions: restricting the entry of potentially harmful substances while on the other hand allowing the selective passage of nutrients. Thus, an intact epithelial barrier is vital to preserve the integrity of the host and to prevent development of disease. Vice versa, an impaired intestinal epithelial barrier function is a hallmark in the development and perpetuation of inflammatory bowel disease (IBD). Besides a multitude of genetic, molecular and cellular alterations predisposing for or driving barrier dysintegrity in IBD, the appearance of intestinal mucosal wounds is a characteristic event of intestinal inflammation apparently inducing breakdown of the intestinal epithelial barrier. Upon injury, the intestinal mucosa undergoes a wound healing process counteracting this breakdown, which is controlled by complex mechanisms such as epithelial restitution, proliferation and differentiation, but also immune cells like macrophages, granulocytes and lymphocytes. Consequently, the repair of mucosal wounds is dependent on a series of events including coordinated trafficking of immune cells to dedicated sites and complex interactions among the cellular players and other mediators involved. Therefore, a better understanding of the crosstalk between epithelial and immune cells as well as cell trafficking during intestinal wound repair is necessary for the development of improved future therapies. In this review, we summarize current concepts on intestinal mucosal wound healing introducing the main cellular mediators and their interplay as well as their trafficking characteristics, before finally discussing the clinical relevance and translational approaches to therapeutically target this process in a clinical setting.
CRIS-Team Scopus Importer:2021-04-16
Keywords: IBD; intestinal epithelial barrier function; intestinal epithelial cells; mucosal healing; wound healing

Intestinal myofibroblast-specific Tpl2-Cox-2-PGE2 pathway links innate sensing to epithelial homeostasis - Roulis, Manolis; Nikolaou, Christoforos; Kotsaki, Elena; Kaffe, Eleanna; Karagianni, Niki; Koliaraki, Vasiliki; Salpea, Klelia; Ragoussis, Jiannis; Aidinis, Vassilis; Martini, Eva; Becker, Christoph; Herschman, Harvey R.; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2014)
Tumor progression locus-2 (Tpl2) kinase is a major inflammatory mediator in immune cell types recently found to be genetically associated with inflammatory bowel diseases (IBDs). Here we show that Tpl2 may exert a dominant homeostatic rather than inflammatory function in the intestine mediated specifically by subepithelial intestinal myofibroblasts (IMFs). Mice with complete or IMF-specific Tpl2 ablation are highly susceptible to epithelial injury-induced colitis showing impaired compensatory proliferation in crypts and extensive ulcerations without significant changes in inflammatory responses. Following epithelial injury, IMFs sense innate or inflammatory signals and activate, via Tpl2, the cyclooxygenase-2 (Cox-2)-prostaglandin E2 (PGE2) pathway, which we show here to be essential for the epithelial homeostatic response. Exogenous PGE2 administration rescues mice with complete or IMF-specific Tpl2 ablation from defects in crypt function and susceptibility to colitis. We also show that Tpl2 expression is decreased in IMFs isolated from the inflamed ileum of IBD patients indicating that Tpl2 function in IMFs may be highly relevant to human disease. The IMF-mediated mechanism we propose also involves the IBD-associated genes IL1R1, MAPK1, and the PGE2 receptor-encoding PTGER4. Our results establish a previously unidentified myofibroblast-specific innate pathway that regulates intestinal homeostasis and may underlie IBD susceptibility in humans.
EVALuna2:1871

Intradermally applied LPA but not bile salts induce itch and pain in humans depending on the mode of application - Kremer, Andreas; Düll, Miriam; Wurm, L.; Ries, V.; Stengel, M.; Reeh, Peter; Fischer, Michael Jochen Marco; Namer, Barbara (2017)
EVALuna2:33355

Intrahepatic Cholestasis of Pregnancy - Jurk, Stanislaw M.; Kremer, Andreas; Schleussner, Ekkehard (Geburtshilfe und Frauenheilkunde, 2021)
Intrahepatic cholestasis of pregnancy (ICP) is a rare but potentially serious complication of pregnancy, the main symptom of which is intense pruritus with elevated serum levels of bile acids. The elevated serum bile acid concentration is regarded as a predictor for poor perinatal outcome including intrauterine death. Ursodeoxycholic acid (UDCA) has become established as the treatment of choice in clinical management to achieve a significant improvement in symptoms and reduce the cholestasis. Pregnant women with severe intrahepatic cholestasis should always be managed in a perinatal centre with close interdisciplinary monitoring and treatment involving perinatologists and hepatologists to minimise the markedly increased perinatal morbidity and mortality as well as maternal symptoms.
CRIS-Team WoS Importer:2021-09-03

Intrahepatic cholestasis of pregnancy : Rare but important - Kremer, Andreas; Wolf, Katharina; Staender, S. (Hautarzt, 2017)
Intrahepatic cholestasis of pregnancy (ICP) is a liver-specific disorder occurring in approximately 0.5-2.0% of all pregnancies with a considerable variation in certain ethnic groups. ICP usually runs a benign course for the mother and is characterized by maternal pruritus mainly in the third trimester, elevated transaminases and fasting total serum bile salts and increased fetal adverse events. The etiology of ICP is only partially understood but seems to be multifactorial. Cholestasis-inducing effects of certain female sex hormones and their metabolites play an important role in genetically susceptible women. The mechanisms resulting in fetal complications such as spontaneous preterm labour, antepartum passage of meconium, asphyxia events, still birth and fetal death are not well understood. Certain sulfated progesterone metabolites are likely to play a role in the pathogenesis of pruritus in ICP. In contrast to pregnancy-related dermatoses, pruritus does not present with primary skin alterations. However, intense scratching may cause secondary skin changes such as abrasions, excoriations and sometimes prurigo nodularis. Treatment is based on ursodeoxycholate treatment to reduce pruritus and hepatic impairment as well as elective delivery between gestation week 37-38 to pre-empt potential stillbirths. This article reviews clinical symptoms, diagnosis, treatment and in particular pathogenesis of pruritus in ICP.
EVALuna2:33922

Intravenous vitamin C in the treatment of allergies: an interim subgroup analysis of a long-term observational study - Vollbracht, Claudia; Raithel, Martin; Krick, Bianka; Kraft, Karin; Hagel, Alexander (Journal of International Medical Research, 2018)
Objective Oxidative stress appears to be a key factor in the pathogenesis of allergic diseases and a potential therapeutic target in allergy treatment. Allergic diseases are reportedly associated with reduced plasma levels of ascorbate, which is a key physiological antioxidant. Ascorbate prevents excessive inflammation without reducing the defensive capacity of the immune system. Methods An interim analysis of a multicenter, prospective, observational study was conducted to investigate the change in disease-specific and nonspecific symptoms (fatigue, sleep disorders, depression, and lack of mental concentration) during adjuvant treatment with intravenous vitamin C (Pascorbin®; Pascoe, Giessen, Germany) in 71 patients with allergy-related respiratory or cutaneous indications. Results Between the start and end of treatment, the mean sum score of three disease-specific symptoms decreased significantly by 4.71 points and that of four nonspecific symptoms decreased significantly by 4.84 points. More than 50% of patients took no other allergy-related medication besides vitamin C. Conclusions Our observations suggest that treatment with intravenous high-dose vitamin C reduces allergy-related symptoms. Our observations form a basis for planning a randomized controlled clinical trial to obtain more definitive evidence of the clinical relevance of our findings. We also obtained evidence of ascorbate deficiency in allergy-related diseases. TRIAL REGISTRATION: Clinical Trials NCT02422901.
EVALuna2:35145

Investigating Intestinal Barrier Breakdown in Living Organoids - Bardenbacher, Marco; Ruder, Barbara; Britzen-Laurent, Nathalie; Naschberger, Elisabeth; Becker, Christoph; Palmisano, Ralf; Stürzl, Michael; Tripal, Philipp (Journal of Visualized Experiments, 2020)
Organoids and three-dimensional (3D) cell cultures allow the investigation of complex biological mechanisms and regulations in vitro, which previously was not possible in classical cell culture monolayers. Moreover, monolayer cell cultures are good in vitro model systems but do not represent the complex cellular differentiation processes and functions that rely on 3D structure. This has so far only been possible in animal experiments, which are laborious, time consuming, and hard to assess by optical techniques. Here we describe an assay to quantitatively determine the barrier integrity over time in living small intestinal mouse organoids. To validate our model, we applied interferon gamma (IFN-gamma) as a positive control for barrier destruction and organoids derived from IFN-gamma receptor 2 knock out mice as a negative control. The assay allowed us to determine the impact of IFN-gamma on the intestinal barrier integrity and the IFN-gamma induced degradation of the tight junction proteins claudin-2, -7, and -15. This assay could also be used to investigate the impact of chemical compounds, proteins, toxins, bacteria, or patient-derived probes on the intestinal barrier integrity.
CRIS-Team WoS Importer:2020-04-17

In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease - Atreya, Raja; Neumann, Helmut; Neufert, Clemens; Waldner, Maximilian; Billmeier, Ulrike; Zopf, Yurdagül; Willma, Marcus; App, Christine; Münster, Tino; Kessler, Hermann; Maas, Stefanie; Gebhardt, Bernd; et al. (Nature Medicine, 2014)
As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn's disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohn's disease led to detection of intestinal mTNF(+) immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF(+) cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF(+) cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn's disease and autoimmune or inflammatory disorders.
EVALuna2:1838

In vivo monitoring of the anti-angiogenic therapeutic effect of the pan-deacetylase inhibitor panobinostat by small animal PET in a mouse model of gastrointestinal cancers - Maschauer, Simone; Gahr, Susanne; Gandesiri, Muktheshwar; Tripal, Philipp; Schneider-Stock, Regine; Kuwert, Torsten; Ocker, Matthias; Prante, Olaf (Nuclear Medicine and Biology, 2016)
Deacetylase inhibitors have recently been established as a novel therapeutic approach to solid and hematologic cancers and have also been demonstrated to possess anti-angiogenic properties. Although these compounds show a good efficacy in vitro and in vivo, no data on monitoring and predicting treatment response are currently available. We therefore investigated the effect of the pan-deacetylase inhibitor panobinostat (LBH589) on gastrointestinal cancer models and the suitability of 2-[(18)F]FGlc-RGD as a specific agent for imaging integrin ?v?3 expression during tumor angiogenesis using small animal positron emission tomography (PET).The effect of panobinostat on cell viability in vitro was assessed with a label-free impedance based real-time analysis. Nude mice bearing HT29 and HepG2 tumors were treated with daily i.p. injections of 10mg/kg panobinostat for 4weeks. During this time, tumor size was determined with a calliper and mice were repeatedly subjected to PET imaging. Tumor tissues were analyzed immunohistochemically with a focus on proliferation and endothelial cell markers (Ki-67, Meca-32) and by Western blot applying specific markers of apoptosis.In vitro, panobinostat inhibited the proliferation of HepG2 and HT29 cells. Contrary to the situation in HepG2 tumors in vivo, where panobinostat treatment is known to reduce proliferation and vascularization resulting in a decreased tumor growth, HT29 tumors did not show any effect on these parameters. We demonstrated by Western blotting, that panobinostat induced apoptosis in HT29 tumors in vivo. Longitudinal PET imaging studies in HepG2 tumor-bearing mice using 2-[(18)F]FGlc-RGD demonstrated that the standard uptake value (SUVmax) in HepG2 tumors was significantly decreased by 39% at day 7 after treatment. The comparative PET study using HT29 tumor-bearing animals did not reveal any response of the tumors to panobinostat treatment.Small-animal PET imaging using 2-[(18)F]FGlc-RGD was successfully applied to the non-invasive monitoring of the HepG2-tumor response to panobinostat in nude mice early after begin of treatment. Thus, PET imaging of angiogenesis using 2-[(18)F]FGlc-RGD could be a valuable tool to monitor panobinostat therapy in further preclinical studies.When successfully translated to the clinical surrounding, PET imaging of angiogenesis could therefore facilitate therapy planning and monitoring of therapy success with panobinostat in hepatocellular carcinoma.
EVALuna2:6737

In vivo multi spectral colonoscopy in mice - Hohmann, Martin; Ganzleben, Ingo; Grünberg, Alexander; Menezes, Jean Gonzales; Klämpfl, Florian; Lengenfelder, Benjamin; Liebing, Eva; Heichler, Christina; Neufert, Clemens; Becker, Christoph; Neurath, Markus; Waldner, Maximilian; et al. (Scientific Reports, 2022)
Multi- and hyperspectral endoscopy are possibilities to improve the endoscopic detection of neoplastic lesions in the colon and rectum during colonoscopy. However, most studies in this context are performed on histological samples/biopsies or ex vivo. This leads to the question if previous results can be transferred to an in vivo setting. Therefore, the current study evaluated the usefulness of multispectral endoscopy in identifying neoplastic lesions in the colon. The data set consists of 25 mice with colonic neoplastic lesions and the data analysis is performed by machine learning. Another question addressed was whether adding additional spatial features based on Gauss-Laguerre polynomials leads to an improved detection rate. As a result, detection of neoplastic lesions was achieved with an MCC of 0.47. Therefore, the classification accuracy of multispectral colonoscopy is comparable with hyperspectral colonoscopy in the same spectral range when additional spatial features are used. Moreover, this paper strongly supports the current path towards the application of multi/hyperspectral endoscopy in clinical settings and shows that the challenges from transferring results from ex vivo to in vivo endoscopy can be solved.
CRIS-Team WoS Importer:2022-06-10

In-vivo multispectral Video Endoscopy towards in-vivo hyperspectral Video Endoscopy - Hohmann, Martin; Kanawade, Rajesh; Klämpfl, Florian; Douplik, Alexandre; Mudter, Jonas; Neurath, Markus; Albrecht, Heinz (Journal of Biophotonics, 2016)

In-vivo multispectral video endoscopy towards in-vivo hyperspectral video endoscopy - Hohmann, Martin; Kanawade, R.; Klämpfl, Florian; Douplik, Alexandre; Mudter, J.; Neurath, Markus; Albrecht, Heinz (Journal of Biophotonics, 2017)
For in-vivo diagnostics of cancer and pre-cancer in the stomach, there is no endoscopic procedure offering both high sensitivity and high specificity. Our data suggest that multispectral or hyperspectral imaging may be helpful to solve this problem. It is successfully applied to the detection and analysis of easily reachable carcinomas, ex-vivo samples of hollow organ mucosal carcinomas and also histological samples. An endoscopy system which allows flexible multispectral videoendoscopy for in-vivo diagnostics has so far been unavailable. To overcome this problem, we modified a standard Olympus endoscopy system to conduct in-vivo multispectral imaging of the upper GI tract. The pilot study is performed on 14 patients with adeno carcinomas in the stomach. For analysis, Support Vector Machine with linear and Gaussian Kernel, AdaBoost, RobustBoost and Random-Forest-walk are used and compared for the data classification with a leave-one-out strategy. The margin of the carcinoma for the training of the classifier is drawn by expert-labeling. The cancer findings are cross-checked by biopsies. We expect that the present study will help to improve the further development of hyperspectral endoscopy and to overcome some of the problems to be faced in this process.
EVALuna2:33820

In vivo real-time assessment of colorectal polyp histology using an optical biopsy forceps system based on laser-induced fluorescence spectroscopy - Rath, Timo; Tontini, Gian E.; Naegel, Andreas; Neurath, Markus; Neumann, Helmut; Vieth, Michael (Endoscopy, 2016)
In order to reduce time, costs, and risks associated with resection of diminutive colorectal polyps, the American Society for Gastrointestinal Endoscopy (ASGE) recently proposed performance thresholds that new technologies should meet for the accurate real-time assessment of histology of colorectal polyps. In this study, we prospectively assessed whether laser-induced fluorescence spectroscopy (LIFS), using the new WavSTAT4 optical biopsy system, can meet the ASGE criteria.27 patients undergoing screening or surveillance colonoscopy were included. The histology of 137 diminutive colorectal polyps was predicted in real time using LIFS and findings were compared with the results of conventional histopathological examination. The accuracy of predicting polyp histology with WavSTAT4 was assessed according to the ASGE criteria.The overall accuracy of LIFS using WavSTAT4 for predicting polyp histology was 84.7 % with sensitivity, specificity, and negative predictive value (NPV) of 81.8 %, 85.2 %, and 96.1 %. When only distal colorectal diminutive polyps were considered, the NPV for excluding adenomatous histology increased to 100 % (accuracy 82.4 %, sensitivity 100 %, specificity 80.6 %). On-site, LIFS correctly predicted the recommended surveillance intervals with an accuracy of 88.9 % (24/27 patients) when compared with histology-based United States guideline recommendations; in the 3 patients for whom LIFS- and histopathology-based recommended surveillance intervals differed, LIFS predicted shorter surveillance intervals.From the data of this pilot study, LIFS using the WavSTAT4 system appears accurate enough to allow distal colorectal polyps to be left in place and nearly reaches the threshold to "resect and discard" them without pathologic assessment. WavSTAT4 therefore has the potential to reduce costs and risks associated with the removal of diminutive colorectal polyps.
EVALuna2:2067

Involvement of Neuro-Immune Interactions in Pruritus With Special Focus on Receptor Expressions - Ruppenstein, Aylin; Limberg, Maren M.; Loser, Karin; Kremer, Andreas; Homey, Bernhard; Raap, Ulrike (Frontiers in Medicine, 2021)
Pruritus is a common, but very challenging symptom with a wide diversity of underlying causes like dermatological, systemic, neurological and psychiatric diseases. In dermatology, pruritus is the most frequent symptom both in its acute and chronic form (over 6 weeks in duration). Treatment of chronic pruritus often remains challenging. Affected patients who suffer from moderate to severe pruritus have a significantly reduced quality of life. The underlying physiology of pruritus is very complex, involving a diverse network of components in the skin including resident cells such as keratinocytes and sensory neurons as well as transiently infiltrating cells such as certain immune cells. Previous research has established that there is a significant crosstalk among the stratum corneum, nerve fibers and various immune cells, such as keratinocytes, T cells, basophils, eosinophils and mast cells. In this regard, interactions between receptors on cutaneous and spinal neurons or on different immune cells play an important role in the processing of signals which are important for the transmission of pruritus. In this review, we discuss the role of various receptors involved in pruritus and inflammation, such as TRPV1 and TRPA1, IL-31RA and OSMR, TSLPR, PAR-2, NK1R, H1R and H4R, MRGPRs as well as TrkA, with a focus on interaction between nerve fibers and different immune cells. Emerging evidence shows that neuro-immune interactions play a pivotal role in mediating pruritus-associated inflammatory skin diseases such as atopic dermatitis, psoriasis or chronic spontaneous urticaria. Targeting these bidirectional neuro-immune interactions and the involved pruritus-specific receptors is likely to contribute to novel insights into the underlying pathogenesis and targeted treatment options of pruritus.
CRIS-Team Scopus Importer:2021-03-19
Keywords: atopic dermatitis (AD); chronic spontaneous urticaria (CSU); inflammation; neuro-immune; pruritus; psoriasis; sensory neurons; skin disease

IRAK-M Expression in Tumor Cells Supports Colorectal Cancer Progression through Reduction of Antimicrobial Defense and Stabilization of STAT3 - Kesselring, Rebecca; Glaesner, Joachim; Hiergeist, Andreas; Naschberger, Elisabeth; Neumann, Helmut; Brunner, Stefan M.; Wege, Anja K.; Seebauer, Caroline; Koehl, Gudrun; Merkl, Susanne; Croner, Roland S.; Hackl, Christina; et al. (Cancer Cell, 2016)
Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity, which facilitates the interaction of the immunological microenvironment with the luminal microbiome, eliciting tumor-supportive inflammation. An important regulator of intestinal inflammatory responses is IRAK-M, a negative regulator of TLR signaling. Here we investigate the compartment-specific impact of IRAK-M on colorectal carcinogenesis using a mouse model. We demonstrate that IRAK-M is expressed in tumor cells due to combined TLR and Wnt activation. Tumor cell-intrinsic IRAK-M is responsible for regulation of microbial colonization of tumors and STAT3 protein stability in tumor cells, leading to tumor cell proliferation. IRAK-M expression in human CRCs is associated with poor prognosis. These results suggest that IRAK-M may be a potential therapeutic target for CRC treatment.
EVALuna2:2089

Iron beats electricity: Resistance training but not whole-body electromyostimulation improves cardiometabolic health in obese metabolic syndrome patients during caloric restriction—a randomized-controlled study - Reljic, Dejan; Herrmann, Hans J.; Neurath, Markus; Zopf, Yurdagül (Nutrients, 2021)
Caloric restriction (CR) and exercise are cornerstones in the treatment of obesity and cardiometabolic disorders. Recently, whole body electromyostimulation (WB-EMS) has emerged as a more time-efficient alternative to traditional resistance training (RT). However, the effects of WB-EMS compared to RT on cardiometabolic health in obese metabolic syndrome (MetS) patients performed during CR are still unclear. In total, 118 obese MetS patients (52.7 ± 11.8 years, BMI: 38.1 ± 6.9 kg/m2 ) undergoing CR over 12 weeks (aim: −500 kcal deficit/day) were randomly allocated to either WB-EMS, single-set RT (1-RT), 3-set RT (3-RT) or an inactive control group (CON). Primary outcome was MetS severity (MetS z-score). Secondary outcomes were body composition, muscle strength and quality of life (QoL). All groups significantly reduced body weight ( 3%) and fat mass ( 2.6 kg) but only 1-RT and 3-RT preserved skeletal muscle mass (SMM). All exercise groups increased muscle strength in major muscle groups (20–103%). However, only the two RT-groups improved MetS z-score (1-RT: −1.34, p = 0.003; 3-RT: −2.06, p < 0.001) and QoL (1-RT: +6%, p = 0.027; 3-RT: +12%, p < 0.001), while WB-EMS and CON had no impact on these outcomes. We conclude that traditional RT has superior effects on cardiometabolic health, SMM and QoL in obese MetS patients undergoing CR than WB-EMS.
CRIS-Team Scopus Importer:2021-05-21
Keywords: Cardiovascular disease; Electrical stimulation; Exercise; Fasting; Hyper-tension; Muscle mass; Muscular strength; Obesity; Psychological health; Strength training

I-scan optical enhancement for the in vivo prediction of diminutive colorectal polyp histology: Results from a prospective three-phased multicentre trial - Klenske, Entcho; Zopf, Steffen; Neufert, Clemens; Naegel, Andreas; Gschossmann, Juergen; Muehldorfer, Steffen; Pfeifer, Lukas; Fischer, Sören; Vitali, Francesco; Iacucci, Marietta; Ghosh, Subrata; Rath, Michelle G.; et al. (PLoS ONE, 2018)
BACKGROUND AND AIMS: Dye-less chromoendoscopy is an emerging technology for colorectal polyp characterization. Herein, we investigated whether the newly introduced I-scan optical enhancement (OE) can accurately predict polyp histology in vivo in real-time. METHODS: In this prospective three-phased study, 84 patients with 230 diminutive colorectal polyps were included. During the first two study phases, five endoscopists assessed whether analysis of polyp colour, surface and vascular pattern under i-scan OE can differentiate in vivo between adenomatous and hyperplastic polyps. Finally, junior and experienced endoscopists (JE, EE, each n = 4) not involved in the prior study phases made a post hoc diagnosis of polyp histology using a static i-scan OE image database. Histopathology was used as a gold-standard in all study phases. RESULTS: The overall accuracy of i-scan OE for histology prediction was 90% with a sensitivity, specificity, positive (PPV) and negative prediction value (NPV) of 91%, 90%, 86% and 94%, respectively. In high confidence predictions, the diagnostic accuracy increased to 93% with sensitivity, specificity, PPV and NPV of 94%, 91%, 89% and 96%. Colonoscopy surveillance intervals were predicted correctly in ≥ 90% of patients. In the post hoc analysis EE predicted polyp histology under i-scan OE with an overall accuracy of 91%. After a single training session, JE achieved a comparable diagnostic performance for predicting polyp histology with i-scan OE. CONCLUSION: The histology of diminutive colorectal polyps can be accurately predicted with i-scan OE in vivo in real-time. Furthermore, polyp differentiation with i-scan OE appears to require only a short learning curve.
EVALuna2:35169

Is COVID-19-associated pulmonary aspergillosis (CAPA) a myth? Frequency of Aspergillus detection from respiratory samples in intensive care unit patients with and without COVID-19 - Kuemmig, T.; Esse, Jan; Herbst, Larissa; Castellanos, I.; Strauss, Richard; Geißdörfer, Walter; Mihai, Sidonia; Rakova, Natalia; Cipa, Franziska; Pflaum, D.; Werblow, M.; Lang, Anne-Katharina; et al. (MYCOSES, 2021)
CRIS-Team WoS Importer:2021-10-08

Is histological healing a feasible endpoint in ulcerative colitis? - Rath, Timo; Atreya, Raja; Neurath, Markus (Expert Review of Gastroenterology and Hepatology, 2021)
Introduction: Currently, treatment goals in ulcerative colitis aim to achieve clinical remission and endoscopic mucosal healing. Emerging evidence suggests that histologic assessment of inflammation is a sensitive marker that can outcompete mucosal healing in predicting the clinical course of disease in patients with ulcerative colitis. Based on this, histologic healing is frequently included as a secondary endpoint in pharmacological trials. Areas covered: We introduce currently used clinical and endoscopic treatment goals, summarize commonly used histologic scoring systems and then provide an overview on the relevance of histologic healing on the outcome in patients with ulcerative colitis. Finally, we review the efficacy of existing UC therapies for inducing histologic remission. Expert opinion: Histologic healing is achievable in a substantial portion of UC patients. Further, histologic healing is, as consolidated by several meta-analyses, associated with better disease outcome compared to clinical remission and/or endoscopic healing. However, before becoming a widely acceptable treatment endpoint, consensus definitions for histologic healing and the technical aspects as well as for the timing for obtaining biopsies are needed. And finally, we need more evidence to show that resolution of microscopic inflammation as a means of therapy change or dose escalation is indeed a superior endpoint.
CRIS-Team Scopus Importer:2021-02-12
Keywords: endoscopic healing; histologic healing; histologic remission; Inflammatory bowel diseases; mucosal healing; ulcerative colitis

Is non-invasive Cytosponge the holy grail for Barrett's neoplasia? - Neurath, Markus; Vieth, Michael (The Lancet. Oncology, 2022)
CRIS-Team Scopus Importer:2022-02-11

Issues in histopathological reporting: A crucial crossroad between surgeons and pathologists after oesophago-gastrectomy - Neurath, Markus; Vieth, Michael (Diseases of the Esophagus, 2021)
CRIS-Team Scopus Importer:2021-09-17

Jejunitis and brown bowel syndrome with multifocal carcinogenesis of the small bowel - Raithel, Martin; Rau, Tilman; Hagel, Alexander; Albrecht, Heinz; De Rossi, Thomas; Kirchner, Thomas; Hahn, Eckhart Georg (World Journal of Gastroenterology, 2015)
This is the first report describing a case where prolonged, severe malabsorption from brown bowel syndrome progressed to multifocally spread small bowel adenocarcinoma. This case involves a female patient who was initially diagnosed with chronic jejunitis associated with primary diffuse lymphangiectasia at the age of 26 years. The course of the disease was clinically, endoscopically, and histologically followed for 21 years until her death at the age 47 due to multifocal, metastasizing adenocarcinoma of the small bowel. Multiple lipofuscin deposits (so-called brown bowel syndrome) and severe jejunitis were observed microscopically, and sections of the small bowel showed dense lymphoplasmacytic infiltration of the lamina propria as well as blocked lymphatic vessels. After several decades, multifocal nests of adenocarcinoma cells and extensive, flat, neoplastic mucosal proliferations were found only in the small bowel, along with a loss of the mismatch repair protein MLH1 as a long-term consequence of chronic jejunitis with malabsorption. No evidence was found for hereditary nonpolyposis colon carcinoma syndrome. This article demonstrates for the first time multifocal carcinogenesis in the small bowel in a malabsorption syndrome in an enteritis-dysplasia-carcinoma sequence.
EVALuna2:1973

K+ Channel Inhibition Differentially Regulates Migration of Intestinal Epithelial Cells in Inflamed vs. Non-Inflamed Conditions in a PI3K/Akt-Mediated Manner - Zundler, Sebastian; Caioni, Massimiliano; Mueller, Martina; Strauch, Ulrike; Kunst, Claudia; Woelfel, Gisela (PLoS ONE, 2016)
Potassium channels have been shown to determine wound healing in different tissues, but their role in intestinal epithelial restitution–the rapid closure of superficial wounds by intestinal epithelial cells (IEC)–remains unclear.In this study, the regulation of IEC migration by potassium channel modulation was explored with and without additional epidermal growth factor (EGF) under baseline and interferon-? (IFN-?)-pretreated conditions in scratch assays and Boyden chamber assays using the intestinal epithelial cell lines IEC-18 and HT-29. To identify possibly involved subcellular pathways, Western Blot (WB)-analysis of ERK and Akt phosphorylation was conducted and PI3K and ERK inhibitors were used in scratch assays. Furthermore, mRNA-levels of the potassium channel KCNN4 were determined in IEC from patients suffering from inflammatory bowel diseases (IBD).Inhibition of Ca(2+)-dependent potassium channels significantly increased intestinal epithelial restitution, which could not be further promoted by additional EGF. In contrast, inhibition of KCNN4 after pretreatment with IFN-? led to decreased or unaffected migration. This effect was abolished by EGF. Changes in Akt, but not in ERK phosphorylation strongly correlated with these findings and PI3K but not ERK inhibition abrogated the effect of KCNN4 inhibition. Levels of KCNN4 mRNA were higher in samples from IBD patients compared with controls.Taken together, we demonstrate that inhibition of KCNN4 differentially regulates IEC migration in IFN-?-pretreated vs. non pretreated conditions. Moreover, our data propose that the PI3K signaling cascade is responsible for this differential regulation. Therefore, we present a cellular model that contributes new aspects to epithelial barrier dysfunction in chronic intestinal inflammation, resulting in propagation of inflammation and symptoms like ulcers or diarrhea.
EVALuna2:2085

Kniffelige Fälle – Wann bringt die Labordiagnostik eine Lösung? - Mettang, T.; Kremer, Andreas (Hautarzt, 2020)
Chronic pruritus is a symptom of many systemic diseases. In contrast to dermatological pruritus, there are no primary changes in skin appearance. Establishing the correct diagnosis in these cases can be quite challenging. In some instances, laboratory tests can be helpful. This report highlights the importance of specific and target-orientated laboratory tests in four patients with chronic pruritus due to systemic diseases.
CRIS-Team Scopus Importer:2020-06-05
Keywords: Itch; Itching; Laboratory test; Pruritus; Systemic diseases

Know your neighbors: microbial recognition at the intestinal barrier and its implications for gut homeostasis and inflammatory bowel disease - Iyer, Krishna; Erkert, Lena; Becker, Christoph (Frontiers in Cell and Developmental Biology, 2023)
Intestinal epithelial cells (IECs) perform several physiological and metabolic functions at the epithelial barrier. IECs also play an important role in defining the overall immune functions at the mucosal region. Pattern recognition receptors (PRRs) on the cell surface and in other cellular compartments enable them to sense the presence of microbes and microbial products in the intestinal lumen. IECs are thus at the crossroads of mediating a bidirectional interaction between the microbial population and the immune cells present at the intestinal mucosa. This communication between the microbial population, the IECs and the underlying immune cells has a profound impact on the overall health of the host. In this review, we focus on the various PRRs present in different cellular compartments of IECs and discuss the recent developments in the understanding of their role in microbial recognition. Microbial recognition and signaling at the epithelial barrier have implications in the maintenance of intestinal homeostasis, epithelial barrier function, maintenance of commensals, and the overall tolerogenic function of PRRs in the gut mucosa. We also highlight the role of an aberrant microbial sensing at the epithelial barrier in the pathogenesis of inflammatory bowel disease (IBD) and the development of colorectal cancer.
CRIS-Team Scopus Importer:2023-10-20
Keywords: inflammatory bowel disease (IBD); intestinal epithelial cells (IECs); intestinal homeostasis; microbiome; mucosal immunity; pattern recognition receptors (PRRs)

Label-free analysis of experimental lung fibrosis using multiphoton microscopy and Raman spectroscopy - Ganzleben, Ingo; Kreiß, Lucas; Mühlberg, Alexander; Friedrich, Oliver; Neurath, Markus; Schürmann, Sebastian; Waldner, Maximilian (EUROPEAN RESPIRATORY JOURNAL, 2021)
CRIS-Team WoS Importer:2022-02-25

Label-free analysis of inflammatory tissue remodeling in murine lung tissue based on multiphoton microscopy, Raman spectroscopy and machine learning - Kreiß, Lucas; Ganzleben, Ingo; Mühlberg, Alexander; Ritter, Paul; Schneidereit, Dominik; Becker, Christoph; Neurath, Markus; Friedrich, Oliver; Schürmann, Sebastian; Waldner, Maximilian (Journal of Biophotonics, 2022)
Inflammatory fibrotic tissue remodeling can lead to severe morbidity. Histopathology grading requires extraction of biopsies and elaborate tissue processing. Label-free optical technologies can provide diagnostic readout without preparation and artificial stainings and show potential for in vivo applications. Here, we present an integration of Raman spectroscopy (RS) and multiphoton microscopy for joint investigation of the bio-chemical composition and morphological features related to cellular components and connective tissue. Both modalities show that collagen signatures were significantly increased in a murine fibrosis model. Furthermore, autofluorescence signatures assigned to immune cells show high correlation with disease severity. RS indicates increased levels of elastin and lipids. Further, we investigated the effect of joint data sets on prediction performance in machine learning models. Although binary classification did not benefit from adding more features, multi-class classification was improved by integrated data sets.
CRIS-Team WoS Importer:2022-07-08

Label-Free Characterization and Quantification of Mucosal Inflammation in Common Murine Colitis Models With Multiphoton Imaging - Kreiß, Lucas; Thoma, Oana-Maria; Lemire, Sarah; Lechner, Kristina; Carlé, Birgitta-Elisabeth; Dilipkumar, Ashwathama; Kunert, Timo; Scheibe, Kristina; Heichler, Christina; Merten, Anna-Lena; Weigmann, Benno; Neufert, Clemens; et al. (Inflammatory Bowel Diseases, 2022)
Background Clinical challenges in inflammatory bowel diseases require microscopic in vivo evaluation of inflammation. Here, label-free imaging holds great potential, and recently, our group demonstrated the advantage of using in vivo multiphoton endomicroscopy for longitudinal animal studies. This article extends our previous work by in-depth analysis of label-free tissue features in common colitis models quantified by the multiphoton colitis score (MCS). Methods Fresh mucosal tissues were evaluated from acute and chronic dextran sulfate sodium (DSS), TNBS, oxazolone, and transfer colitis. Label-free imaging was performed by using second harmonic generation and natural autofluorescence. Morphological changes in mucosal crypts, collagen fibers, and cellularity in the stroma were analyzed and graded. Results Our approach discriminated between healthy (mean MCS = 2.5) and inflamed tissue (mean MCS > 5) in all models, and the MCS was validated by hematoxylin and eosin scoring of the same samples (85.2% agreement). Moreover, specific characteristics of each phenotype were identified. While TNBS, oxazolone, and transfer colitis showed high cellularity in stroma, epithelial damage seemed specific for chronic, acute DSS and transfer colitis. Crypt deformations were mostly observed in acute DSS. Conclusions Quantification of label-free imaging is promising for in vivo endoscopy. In the future, this could be valuable for monitoring of inflammatory pathways in murine models, which is highly relevant for the development of new inflammatory bowel disease therapeutics.
CRIS-Team WoS Importer:2022-10-07

Label-free imaging of inflammatory bowel disease using multiphoton microscopy. - Schürmann, Sebastian; Försch, Sebastian; Atreya, Raja; Neumann, Helmut; Friedrich, Oliver; Neurath, Markus; Waldner, Maximilian (Gastroenterology, 2013)
Multiphoton microscopy (MPM) became one of the most important optical in vivo imaging techniques for basic research during recent years. In comparison with single photon excitation during confocal microscopy, MPM provides a superior effective resolution in thick tissue samples and an increased penetration depth.1 Because of the effects of nonlinear optics, various molecular components can be discriminated with MPM in vivo and in vitro without the need to apply fluorophores. The detection of these molecules is based on specific autofluorescence or second harmonic generation (SHG) signals generated by multiphoton excitation.

Label-Free In Vivo Histopathology of Experimental Colitis via 3-Channel Multiphoton Endomicroscopy - Kreiß, Lucas; Thoma, Oana Maria; Dilipkumar, Ashwathama; Carlé, Birgitta-Elisabeth; Longequeue, Pascal; Kunert, Timo; Rath, Timo; Hildner, Kai; Neufert, Clemens; Neurath, Markus; Friedrich, Oliver; Schürmann, Sebastian; et al. (Gastroenterology, 2020)
CRIS-Team Scopus Importer:2020-08-28

Label-Free Multiphoton Endomicroscopy for Minimally Invasive In Vivo Imaging - Dilipkumar, Ashwathama; Al-Shemmary, Alaa; Kreiß, Lucas; Cvecek, Kristian; Carlé, Birgitta-Elisabeth; Knieling, Ferdinand; Menezes, Jean Gonzales; Thoma, Oana-Maria; Schmidt, Michael; Neurath, Markus; Waldner, Maximilian; Friedrich, Oliver; et al. (Advanced Science, 2019)
Multiphoton microscopy of cellular autofluorescence and second harmonic generation from collagen facilitates imaging of living cells and tissues without the need for additional fluorescent labels. Here, a compact multiphoton endomicroscope for label-free in vivo imaging in small animals via side-viewing needle objectives is presented. Minimal invasive imaging at cellular resolution is performed in colonoscopy of mice without surgical measures and without fluorescent dyes as a contrast agent. The colon mucosa is imaged repeatedly in the same animal in a mouse model of acute intestinal inflammation to study the process of inflammation at the tissue level within a time period of ten days, demonstrating the capabilities of label-free endomicroscopy for longitudinal studies for the first time.
CRIS-Team Scopus Importer:2019-05-02
Keywords: endoscopy; inflammatory bowel disease; multiphoton microscopy; optical imaging

Lack of antibodies against seasonal coronavirus OC43 nucleocapsid protein identifies patients at risk of critical COVID-19 - Dugas, Martin; Grote-Westrick, Tanja; Merle, Uta; Fontenay, Michaela; Kremer, Andreas; Hanses, Frank; Vollenberg, Richard; Lorentzen, Eva; Tiwari-Heckler, Shilpa; Duchemin, Jérôme; Ellouze, Syrine; Vetter, Marcel; et al. (Journal of Clinical Virology, 2021)
Background: The vast majority of COVID-19 patients experience a mild disease. However, a minority suffers from critical disease with substantial morbidity and mortality. Objectives: To identify individuals at risk of critical COVID-19, the relevance of a seroreactivity against seasonal human coronaviruses was analyzed. Methods: We conducted a multi-center non-interventional study comprising 296 patients with confirmed SARS-CoV-2 infections from four tertiary care referral centers in Germany and France. The ICU group comprised more males, whereas the outpatient group contained a higher percentage of females. For each patient, the serum or plasma sample obtained closest after symptom onset was examined by immunoblot regarding IgG antibodies against the nucleocapsid protein (NP) of HCoV 229E, NL63, OC43 and HKU1. Results: Median age was 60 years (range 18-96). Patients with critical disease (n=106) had significantly lower levels of anti-HCoV OC43 nucleocapsid protein (NP)-specific antibodies compared to other COVID-19 inpatients (p=0.007). In multivariate analysis (adjusted for age, sex and BMI), OC43 negative inpatients had an increased risk of critical disease (adjusted odds ratio (AOR) 2.68 [95% CI 1.09 - 7.05]), higher than the risk by increased age or BMI, and lower than the risk by male sex. A risk stratification based on sex and OC43 serostatus was derived from this analysis. Conclusions: Our results suggest that prior infections with seasonal human coronaviruses can protect against a severe course of COVID-19. Therefore, anti-OC43 antibodies should be measured for COVID-19 inpatients and considered as part of the risk assessment for each patient. Hence, we expect individuals tested negative for anti-OC43 antibodies to particularly benefit from vaccination against SARS-CoV-2, especially with other risk factors prevailing.
CRIS-Team Scopus Importer:2021-05-21
Keywords: COVID-19; Critical disease; OC43; SARS-CoV-2; Seasonal coronavirus

Lack of intestinal epithelial atg7 affects paneth cell granule formation but does not compromise immune homeostasis in the gut. - Günther, Claudia; Martini, Eva; Waldner, Maximilian; Amann, Kerstin Ute; Neurath, Markus; Becker, Christoph; et al. (Clinical & Developmental Immunology, 2012)
Genetic polymorphisms of autophagy-related genes have been associated with an increased risk to develop inflammatory bowel disease (IBD). Autophagy is an elementary process participating in several cellular events such as cellular clearance and nonapoptotic programmed cell death. Furthermore, autophagy may be involved in intestinal immune homeostasis due to its participation in the digestion of intracellular pathogens and in antigen presentation. In the present study, the role of autophagy in the intestinal epithelial layer was investigated. The intestinal epithelium is essential to maintain gut homeostasis, and defects within this barrier have been associated with the pathogenesis of IBD. Therefore, mice with intestinal epithelial deletion of Atg7 were generated and investigated in different mouse models. Knockout mice showed reduced size of granules and decreased levels of lysozyme in Paneth cells. However, this was dispensable for gut immune homeostasis and had no effect on susceptibility in mouse models of experimentally induced colitis.

Lanreotide autogel/depot in advanced enteropancreatic neuroendocrine tumours: final results of the CLARINET open-label extension study - Caplin, Martyn E.; Pavel, Marianne Ellen; Phan, Alexandria T.; Cwikla, Jaroslaw B.; Sedlackova, Eva; Thanh, Xuan-Mai Truong; Wolin, Edward M.; Ruszniewski, Philippe (Endocrine, 2020)
Purpose: In the phase III CLARINET study (NCT00353496), lanreotide autogel/depot (lanreotide) significantly improved progression-free survival (PFS) vs placebo in patients with non-functioning intestinal or pancreatic neuroendocrine tumours (NETs). The aim of CLARINET open-label extension (OLE) (NCT00842348) was to evaluate long-term safety and efficacy of lanreotide in these patients. Methods: Patients from the CLARINET study were eligible for the OLE if they had stable disease (irrespective of treatment group) or progressive disease (PD) (placebo-treated patients only). All patients in the OLE received lanreotide 120 mg every 28 days. Computed tomography or magnetic resonance imaging scans were conducted every 6 months and assessed locally for PD (the final scan was also assessed centrally). Results: Overall, 89 patients took part in the OLE (lanreotide, n = 42; placebo, n = 47). Median (range) exposure to lanreotide in patients who received lanreotide in the core study and OLE (LAN–LAN group) was 59.0 (26.0–102.3) months. In this group, the overall incidences of adverse events (AEs) and treatment-related AEs were lower in the OLE than in the core study. Median [95% CI] PFS in the LAN–LAN group was 38.5 [30.9; 59.4] months. In placebo-treated patients with PD at the end of the core study, time to death or subsequent PD during the OLE was 19 [10.1; 26.7] months. Conclusions: This study provides new evidence on the long-term safety profile and sustained anti-tumour effects of lanreotide autogel/depot in indolent and progressive metastatic intestinal or pancreatic NETs.
CRIS-Team Scopus Importer:2020-10-23
Keywords: Lanreotide autogel; Lanreotide depot; Neuroendocrine tumours; Progression-free survival; Safety

Lanreotide Autogel (LAN) 120 mg Every 14 Days in Progressive Pancreatic Neuroendocrine Tumors (panNETs): CLARINET FORTE Study - Pavel, Marianne Ellen; Cwikla, J.; Lombard-Bohas, C.; Borbath, I.; Shah, T.; Pape, U. -F.; Thanh, X. -M. Truong; Houchard, A.; Ruszniewski, P. (PANCREAS, 2021)
CRIS-Team WoS Importer:2021-05-21

Laser-Induced Breakdown Spectroscopy (LIBS): An immerging modality for revealing elemental distribution in tissues - Mehari, Fanuel; Lengenfelder, Benjamin; Späth, Moritz; Klämpfl, Florian; Waldner, Maximilian; Schmidt, Michael (International Conference on Advanced Optical Technologies, 2019)
A Laser-Induced Breakdown Spectroscopy (LIBS) based 2-dimensional elemental mapping of tissue slices is demonstrated. The technique allows obtaining multi-elemental information from each point making it attractive for micro characterization of patho-physiological processes of diseasessuch as cance

Learning curve of virtual chromoendoscopy for the prediction of hyperplastic and adenomatous colorectal lesions: A prospective 2-center study - Neumann, Helmut; Fry, Lucia C.; Günther, Claudia; Atreya, Raja; Neurath, Markus; Moenkemueller, Klaus; Vieth, Michael (Gastrointestinal Endoscopy, 2013)
Background: Computed virtual chromoendoscopy (CVC) enables high-definition imaging of mucosal lesions with improved tissue contrast. Previous studies have shown that CVC yields an improved detection rate of colorectal lesions. However, the learning curve for interpretation of CVC images is unknown. Objective: To examine the learning curve of correctly identifying hyperplastic and adenomatous colorectal lesions by using CVC. Design: Prospective, 2-center study. Patients: Consecutive patients undergoing screening colonoscopy were included. CVC images were analyzed by using corresponding polypectomies as the reference standard followed by a prospective, double-blind review of i-scan images. Methods: A training set containing 20 images with known histology was reviewed to standardize image interpretation, followed by a blind review of 110 unknown images. Overall, 4 endoscopists from 2 different endoscopy centers evaluated the images, which were obtained by 1 endoscopist using high-definition endoscopy with CVC. Results: Patients were included in a prospective fashion. Seventy-seven of 110 colorectal lesions were adenomas and 33 were hyperplastic lesions. Mean diameter of colonic polyps was 4 mm (range, 2-20 mm). Overall accuracy for the group was 73.9% for lesions 1 to 22, 79.6% for lesions 23 to 44, 84.1% for lesions 45 to 66, 87.5% for lesions 67 to 88, and 94.3% for lesions 89 to 110. Accuracy of i-scan for prediction of polyp histology was not dependent on polyp size (≤5 mm, 6-10 mm, or > 10 mm). The ability to obtain high-quality images was stable over time, and high-quality images were constantly produced. Limitation: Post-hoc assessment. Conclusion: Accurate interpretation of CVC images for prediction of hyperplastic and adenomatous colorectal lesions follows a learning curve but can be learned rapidly. © 2013 American Society for Gastrointestinal Endoscopy.
CRIS-Team Scopus Importer:2020-10-28
Keywords: computed virtual chromoendoscopy; CVC; FICE; Fuji intelligent color enhancement; PIVI; Preservation and Incorporation of Valuable Endoscopic Innovations

Leitliniengerechte Therapie des Morbus Crohn: Aktuelle Handlungsempfehlungen - Fischer, Sören; Neurath, Markus (Gastroenterologe, 2019)
Background: Crohn’s disease is a complex condition with rising incidence worldwide. The approval of multiple new therapeutic options results in growing challenges for physicians and guidelines. Objectives: The aim of this paper is to describe a plausible algorithm for the treatment of Crohn’s disease based on the current scientific knowledge. Materials and methods: We refer to the current guidelines of the German Gastroenterology Organization (DGVS), the European Crohn’s and Colitis Organization (ECCO), the American College of Gastroenterology (ACG) as well as the drug professional information. Results: The therapy of Crohn’s disease depends on the affected tract regions, severity of inflammation, individual patient characteristics, previous therapies, and the patient’s preferences. Conclusions: The therapeutic options in Crohn’s disease are constantly evolving. The prediction of therapy response is a continued challenge for medical science. In the principle of participatory medicine, shared decision-making of patient and physician leads to better adherence to the therapy.
CRIS-Team Scopus Importer:2019-11-19
Keywords: Biologicals; Colorectal surgery; Drug therapy; Glucocorticoids; Inflammatory bowel diseases

Letter to the Editor on "LI-RADS-CEUS - Proposal for a Contrast-Enhanced Ultrasound Algorithm for the Diagnosis of Hepatocellular Carcinoma in High-Risk Populations". Ultraschall in Med 2016; 37: 627-634 - Strobel, Deike; Schellhaas, Barbara (Ultraschall in der Medizin, 2017)
EVALuna2:34093

Lifestyle im Management chronisch-entzündlicher Darmerkrankungen – Teil 1: Ernährung - Weber, Linda; Dieterich, Walburga; Herrmann, Hans Joachim; Zopf, Yurdagül (Die Gastroenterologie, 2023)
Background: Patients suffering from chronic inflammatory bowel disease (IBD) are a heterogenous patient group with varying symptoms and complications. Concerning disease activity, one has to differentiate between acute flare-ups and remission phases. Aim: The present publication describes the practice of nutritional therapy in IBD patients, focusing on aspects that have to be considered during this treatment. In addition, the potential positive impact of exercise and physical activity on the course of disease in IBD patients is addressed in part 2 of this article. Materials and methods: In this publication, we describe how the nutritional status of IBD patients is evaluated at the beginning of the nutritional therapy and how we then proceed with nutritional therapy, based on this evaluation and adapted to the actual disease progress. The recommendations given in the latest guidelines are presented, considering IBD-associated symptoms and complications. Results and conclusion: We recommend anti-inflammatory nutrition, based on a Mediterranean diet, for IBD patients. Specific nutritional concepts for the respective disease phases have to be adapted to the individual nutritional status of the patient. Diagnosis of nutritional deficiencies, concomitant symptoms, or food intolerances should be checked before starting nutritional therapy. The individual treatment has to consider these results and select appropriate dietetic recommendations for each patient.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Individualized medicine; Inflammatory bowel disease; Mediterranean diet; Nutrition therapy; Nutritional status

Light and sound - emerging imaging techniques for inflammatory bowel disease - Knieling, Ferdinand; Waldner, Maximilian (World Journal of Gastroenterology, 2016)
Patients with inflammatory bowel disease are known to have a high demand of recurrent evaluation for therapy and disease activity. Further, the risk of developing cancer during the disease progression is increasing from year to year. New, mostly non-radiant, quick to perform and quantitative methods are challenging, conventional endoscopy with biopsy as gold standard. Especially, new physical imaging approaches utilizing light and sound waves have facilitated the development of advanced functional and molecular modalities. Besides these advantages they hold the promise to predict personalized therapeutic responses and to spare frequent invasive procedures. Within this article we highlight their potential for initial diagnosis, assessment of disease activity and surveillance of cancer development in established techniques and recent advances such as wide-view full-spectrum endoscopy, chromoendoscopy, autofluorescence endoscopy, endocytoscopy, confocal laser endoscopy, multiphoton endoscopy, molecular imaging endoscopy, B-mode and Doppler ultrasound, contrast-enhanced ultrasound, ultrasound molecular imaging, and elastography.
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Limitation of TCA Cycle Intermediates Represents an Oxygen-Independent Nutritional Antibacterial Effector Mechanism of Macrophages - Hayek, Inaya; Fischer, Fabian; Schulze-Luehrmann, Jan; Dettmer, Katja; Sobotta, Katharina; Schatz, Valentin; Kohl, Lisa; Boden, Katharina; Lang, Roland; Oefner, Peter J.; Wirtz, Stefan; Jantsch, Jonathan; et al. (Cell Reports, 2019)
In hypoxic and inflamed tissues, oxygen (O-2)-dependent antimicrobial defenses are impaired due to a shortage of O-2. To gain insight into the mechanisms that control bacterial infection under hypoxic conditions, we infected macrophages with the obligate intracellular pathogen Coxiella burnetii, the causative agent of Q fever. Our experiments revealed that hypoxia impeded C. burnetii replication in a hypoxia-inducible factor (HIF) 1 alpha-dependent manner. Mechanistically, under hypoxia, HIF1 alpha impaired the activity of STAT3, which in turn reduced the intracellular level of TCA cycle intermediates, including citrate, and impeded C. burnetii replication in macrophages. However, bacterial viability was maintained, allowing the persistence of C. burnetii, which is a prerequisite for the development of chronic Q fever. This knowledge will open future research avenues on the pathogenesis of chronic Q fever. In addition, the regulation of TCA cycle metabolites by HIF1 alpha represents a previously unappreciated mechanism of host defense against intracellular pathogens.
CRIS-Team WoS Importer:2019-04-09

Limited Dose-Dependent Effects of Vedolizumab on Various Leukocyte Subsets - Becker, Emily; Schweda, Anna; Ullrich, Karen; Voskens, Caroline; Atreya, Raja; Müller, Tanja; Atreya, Imke; Neurath, Markus; Zundler, Sebastian (Clinical and Translational Gastroenterology, 2022)
OBJECTIVES: The anti-α4β7 integrin antibody vedolizumab (VDZ) is successfully used for the treatment of inflammatory bowel diseases. However, only a subgroup of patients respond to therapy. VDZ is administered at a fixed dose, leading to a wide range of serum concentrations in patients. Previous work from our group showed a dose-dependent preferential binding of VDZ to effector compared with regulatory CD4 + T cells. Therefore, we aimed to determine the dose-dependent binding profile of VDZ to other leukocyte subsets. METHODS: We characterized α4β7 integrin expression on CD8 + T cells, CD19 + B cells, CD14 + monocytes, natural killer cells, and eosinophils from patients with inflammatory bowel disease and healthy controls. We studied the binding of VDZ to these cells at different concentrations and investigated the functional consequences for dynamic adhesion and transmigration in vitro . RESULTS: The expression of α4β7 differed between the analyzed leukocyte subsets and was significantly higher on eosinophils from inflammatory bowel disease patients compared with controls. Almost all α4β7-expressing cells from these subsets were bound by VDZ at a concentration of 10 μg/mL. Dynamic cell adhesion was significantly impaired in all subsets, but there were no dose-dependent differences in the inhibition of adhesion. DISCUSSION: Our data suggest that α4β7-expressing CD8 + T cells, CD19 + B cells, CD14 + monocytes, natural killer cells, and eosinophils are a target of VDZ. However, there do not seem to be concentration-dependent differences, regarding the effects on these cells in the clinically relevant range. Thus, the reported exposure-efficacy characteristic of VDZ can probably mainly be attributed to CD4 + T-cell subsets.
CRIS-Team Scopus Importer:2022-07-08

LI-RADS-CEUS - Proposal for a Contrast-Enhanced Ultrasound Algorithm for the Diagnosis of Hepatocellular Carcinoma in High-Risk Populations - Schellhaas, B.; Wildner, Dane; Pfeifer, Lukas; Görtz, Rüdiger; Hagel, Alexander; Neurath, Markus; Strobel, Deike (Ultraschall in der Medizin, 2016)
Purpose: To develop a contrast-enhanced ultrasound algorithm (LI-RADS-CEUS = liver imaging reporting and data system with contrast-enhanced ultrasound) for the diagnosis of hepatocellular carcinoma (HCC) in patients at risk. Materials and Methods: A CEUS algorithm (LI-RADS-CEUS) was designed analogously to CT- and MRI-based LI-RADS. LI-RADS-CEUS was evaluated retrospectively in 50 patients at risk with confirmed HCC or non-HCC lesions (test group) with subsequent validation in a prospective cohort of 50 patients (validation group). Results were compared to histology, CE-CT and CE-MRI as reference standards. Results: Tumor diagnosis in the test group/validation group (n = 50/50) were 46/41 HCCs, 3/3 intrahepatic cholangiocellular carcinomas (ICCs) and 1/6 benign lesions. The diagnostic accuracy of LI-RADS-CEUS for HCC, ICC and non-HCC-non-ICC-lesions was 89 %. For the diagnosis of HCC, the diagnostic accuracy was 93.5 % (43/46 cases) in the test group and 95.1 % (39/41 cases) in the validation group. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 94.3 %, 66.6 %, 94.3 % and 66.6 %, respectively (mean values from both cohorts). Histological findings of HCC were available in 40 versus 23 cases (in total: G1 / G2/G3: 15/35/13). Arterial hyperenhancement was seen in 68/87 (78.2 %) of HCCs. Arterial hyperenhancement with subsequent portal venous or late phase hypoenhancement was seen in 66 % of HCCs. Conclusion: LI-RADS-CEUS offers a CEUS algorithm for standardized assessment and reporting of focal liver lesions in patients at risk for HCC. Arterial hyperenhancement in CEUS is the key feature for the diagnosis of HCC in patients at risk, whereas washout is not a necessary prerequisite.
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Liver stiffness assessed by acoustic radiation force impulse (ARFI) technology is considerably increased in patients with cholestasis - Pfeifer, Lukas; Strobel, Deike; Neurath, Markus; Wildner, D. (Ultraschall in der Medizin, 2014)
To explore the impact of cholestasis on liver stiffness assessed by acoustic radiation force impulse (ARFI) technology.Over a period of four months, patients with sonographic cholestasis and increased cholestatic blood values (Bilirubin, ?GT, AP > 2 times ULN) scheduled for endoscopic therapy were recruited. Exclusion criteria were: known liver disease; signs of cirrhosis at ultrasound (irregular liver veins and/or surface); heart insufficiency (NYHA III-VI). ARFI (Siemens S2000), ultrasound and blood examinations were performed before and in a subgroup after successful biliary drainage.In total, 21 patients with cholestasis were included in the study. ARFI measurements were above the cut-off for cirrhosis (1.8 m/s) in all patients with a mean of 2.91 m/s ± 0.89 m/s without a history or signs of cirrhosis. Bilirubin, ?GT and AP were elevated on average to 9.7 ± 5.3 mg/dl, 1192 ± 960 U/l and 730 ± 389 U/l. A subgroup of 10 patients was measured after successful drainage. ARFI measurements declined in all patients of that subgroup on average by 0.76 m/s at a mean time interval of 4.5 days (p < 0.001).Cholestasis significantly increases liver stiffness assessed by ARFI. Therefore, it is important to exclude profound cholestasis when using ARFI for evaluating patients for liver fibrosis.
EVALuna2:1875

Location is important: differentiation between ileal and colonic Crohn’s disease - Atreya, Raja; Siegmund, Britta (Nature Reviews Gastroenterology & Hepatology, 2021)
Crohn’s disease can affect any part of the gastrointestinal tract; however, current European and national guidelines worldwide do not differentiate between small-intestinal and colonic Crohn’s disease for medical treatment. Data from the past decade provide evidence that ileal Crohn’s disease is distinct from colonic Crohn’s disease in several intestinal layers. Remarkably, colonic Crohn’s disease shows an overlap with regard to disease behaviour with ulcerative colitis, underlining the fact that there is more to inflammatory bowel disease than just Crohn’s disease and ulcerative colitis, and that subtypes, possibly defined by location and shared pathophysiology, are also important. This Review provides a structured overview of the differentiation between ileal and colonic Crohn’s disease using data in the context of epidemiology, genetics, macroscopic differences such as creeping fat and histological findings, as well as differences in regard to the intestinal barrier including gut microbiota, mucus layer, epithelial cells and infiltrating immune cell populations. We also discuss the translation of these basic findings to the clinic, emphasizing the important role of treatment decisions. Thus, this Review provides a conceptual outlook on a new mechanism-driven classification of Crohn’s disease.
CRIS-Team Scopus Importer:2021-03-26

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation - Szewczykowski, Charlotte; Mardin, Christian; Lucio, Marianna; Wallukat, Gerd; Hoffmanns, Jakob; Schröder, Tim; Raith, Franziska; Rogge, Lennart; Heltmann, Felix; Moritz, Michael; Beitlich, Lorenz; Schottenhamml, Julia; et al. (International Journal of Molecular Sciences, 2022)
Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation. The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT–angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.
CRIS-Team Scopus Importer:2022-07-15
Keywords: chronic fatigue syndrome; COVID-19; functionally GPCR autoantibodies; glaucoma; Long-COVID syndrome; OCT–angiography

Long-term Combination Therapy with Anti-TNF plus Vedolizumab Induces and Maintains Remission in Therapy-refractory Ulcerative Colitis - Fischer, Sören; Rath, Timo; Geppert, Carol-Immanuel; Manger, Bernhard; Schett, Georg; Neurath, Markus; Atreya, Raja (American Journal of Gastroenterology, 2017)
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Long-term control with chemoradiation of initially metastatic mixed adenoneuroendocrine carcinoma of the rectum: A case report - Semrau, S.; Agaimy, Abbas; Pavel, Marianne Ellen; Lubgan, Dorota; Schmidt, Daniela; Golcher, H.; Grützmann, Robert; Fietkau, Rainer; Cavallaro, Alexander Josef (Journal of Medical Case Reports, 2019)
Background: Mixed adenoneuroendocrine carcinomas are highly malignant tumors with both adenocarcinomatous and neuroendocrine components. They can originate in any organ but are more common in the rectum. Due to their rarity, current treatment recommendations for mixed adenoneuroendocrine carcinoma are based on limited data and follow general guidelines for the management of adenocarcinomas and neuroendocrine neoplasms. Uncertainty regarding the efficacy of the available local and systemic treatment strategies is a compounding issue. Even those patients with locally limited disease have a relatively short life expectancy. In this report, we describe a case of deep rectal mixed adenoneuroendocrine carcinoma with long survival after chemoradiation. Case presentation: A 48-year-old Caucasian woman was diagnosed with a grade 3 rectal adenocarcinoma combined with a poorly differentiated large cell neuroendocrine carcinoma component and synchronous metastases (cT3cN1cM1) in both lobes of the liver in 2012. She received concomitant chemoradiotherapy followed by four additional cycles of cisplatin plus irinotecan. Initial treatment induced complete remission of the rectal tumor and liver metastases. Consequently, it was not necessary to surgically resect the primary tumor or any of the metastases. Three months after the end of treatment, one metastasis in the first segment of the liver showed regrowth, and stereotactic body radiotherapy of the metastasis and chemotherapy resulted in a clinical complete response. The patient has been recurrence-free for more than 5 years. Conclusions: Extended long-term control of a poorly differentiated metastatic (stage IV) mixed adenoneuroendocrine carcinoma is rare. The multimodal first- and second-line regimens of radiotherapy and chemotherapy described in this case report represent a new therapeutic approach. Encouraged by the results in this case, we compiled a review of the literature on mixed adenoneuroendocrine carcinoma.
CRIS-Team Scopus Importer:2019-05-14
Keywords: Chemoradiation; MANEC; Rectum; SBRT

Long-term effectiveness, safety and immunogenicity of the biosimilar SB2 in inflammatory bowel disease patients after switching from originator infliximab - Fischer, Sören; Cohnen, Sarah; Klenske, Entcho; Schmitt, Heike; Vitali, Francesco; Hirschmann, Simon; Ramming, Andreas; Zundler, Sebastian; Rath, Timo; Krebs, Sabine; Dörje, Frank; Uter, Wolfgang; et al. (Therapeutic Advances in Gastroenterology, 2021)
Background: Long-term data on inflammatory bowel disease (IBD) patients switched from originator to biosimilar infliximab SB2 are lacking. The aim of the conducted study was to investigate the effectiveness, immunogenicity and safety of a large prospectively followed-up IBD patient cohort that was entirely switched from originator infliximab to biosimilar SB2 treatment. Methods: This was a prospective, single-center, longitudinal, observational study describing clinical outcomes in IBD patients, over an 80-week period following switch from originator infliximab to SB2. Primary outcome measures were change of disease activity [Harvey-Bradshaw Index for Crohn’s disease (CD), partial Mayo Score for ulcerative colitis (UC)], C-reactive protein (CRP), infliximab trough levels (TLs), anti-drug antibodies (ADAs) and adverse events. Results: One hundred and forty-four IBD patients (94 CD, 50 UC), with median duration of 30.5 months’ (range 2–110) treatment with originator infliximab were evaluated. Mean change of disease activity compared with baseline was −0.9 (SD 2.6), –0.4 (2.2) and –0.4 (2.0) in CD; 0.1 (1.1), 0.1 (1.1) and 0.1 (1.3) in UC patients at weeks 24, 48 and 72. Median infliximab TLs were 6.2 µg/ml (interquartile range 2.3–12.2), 5.0 µg/ml (2.7–10.0), 6.6 µg/ml (3.5–12.4) and 5.1 µg/ml (2.7–10.9) at baseline and weeks 24, 48 and 72. Median CRP levels were within normal ranges throughout the study. After the switch, 9.8% of the patients developed new ADAs. Persistence on SB2 was 90% (95% confidence interval 0.85–0.95), 79% (0.72–0.86), 72% (0.64–0.80) at weeks 26, 52 and 78. Serious adverse events occurred in 11 patients. Conclusion: Over the individual patient follow-up of 80 weeks, switch to biosimilar SB2 from originator infliximab does not result in increased disease activity or changed immunogenicity patterns. The switch to SB2 was well tolerated.
CRIS-Team Scopus Importer:2021-02-05
Keywords: biosimilar; inflammatory bowel diseases; infliximab; SB2; switch

LONG-TERM EFFICACY AND SAFETY OF OBETICHOLIC ACID IN PATIENTS WITH PBC FROM THE POISE TRIAL GROUPED BIOCHEMICALLY BY RISK OF DISEASE PROGRESSION - Bowlus, Christopher L.; Trauner, Michael H.; Kremer, Andreas; Liberman, Alexander; Malecha, Elizabeth Smoot; Macconell, Leigh; Nevens, Frederik (HEPATOLOGY, 2020)
CRIS-Team WoS Importer:2020-11-06

LONG-TERM EFFICACY AND SAFETY OF OBETICHOLIC ACID IN PRIMARY BILIARY CHOLANGITIS: RESPONDER ANALYSIS OF OVER 5 YEARS OF TREATMENT IN THE POISE TRIAL - Hansen, Bettina E.; Jones, David; Carbone, Marco; Bowlus, Christopher L.; Nevens, Frederik; Kremer, Andreas; Liberman, Alexander; Macconell, Leigh; Hirschfield, Gideon M. (HEPATOLOGY, 2020)
CRIS-Team WoS Importer:2020-11-06

Long-Term Follow Up of Patients With Carcinoid Syndrome Diarrhea Treated With Telotristat Ethyl: A Pooled Analysis of Phase 2 and 3 Trials - Anthony, Lowell; Kulke, Matthew; Caplin, Martyn; Bergsland, Emily; Oberg, Kjell; Pavel, Marianne Ellen; Horsch, Dieter; O'Dorisio, Thomas; Dillon, Joseph; Lapuerta, Pablo; Kassler-Taub, Kenneth; Jiang, Wenjun (PANCREAS, 2019)
CRIS-Team WoS Importer:2019-04-12

Long term follow up of through-the-scope balloon dilation as compared to strictureplasty and bowel resection of intestinal strictures in crohn's disease - Krauss, Ekaterina; Agaimy, Abbas; Gottfried, Angelina; Maiss, Juergen; Weidinger, Thomas; Albrecht, Heinz; Hartmann, Arndt; Hohenberger, Werner; Neurath, Markus; Kessler, Hermann; Mudter, Jonas (International Journal of Clinical and Experimental Pathology, 2014)
Ileo-colonic strictures are common complication of Crohn's disease (CD), and may result in repeated endoscopic or surgical therapy with a risk of further complications, such as perforation or short bowel syndrome. Strictures develop as a consequence of tissue remodelling and fibrosis due to chronic inflammation. This study compares the outcome of CD patients undergoing primarily endoscopic treatment with those undergoing surgery at an university hospital.In this study we retrospectively included 88 CD patients with intestinal strictures (37 males, 51 females, mean age 40 years, range 19-65 years) of both our medical and our surgical department, who underwent either surgical or endoscopic therapy between January 2002 and January 2006 with prospective, controlled follow-up, extended till January 2010 (mean follow-up period: 5 years; range 4-8 years). The primary end-point was operation- and symptom-free time. Patients were primarily divided into four groups: only surgical therapy, only endoscopic therapy, endoscopy with subsequent surgery, and initial surgical therapy followed by endoscopic dilations.53% of all patients remained surgery-free with mean follow-up of 49 months; a single endoscopic dilation was sufficient enough in 9 patients to achieve a surgery-free time of 51 months, other patients required up to 5 dilations. The average interval between first and second dilation was 6.5 months, between second and third 10.5 months. In the group of patients with only endoscopic therapy, surgery- and symptom-free time was shorter, as compared to the group of only surgical therapy. We found that stenoses in the surgical group with an average length of 6.5 cm were as expected longer, as compared to the endoscopic group (3 cm, ranging from 2-4 cm). The surgery-free time was 49 months (42-71 months, P = 0.723) with a symptom-free time of 12 months (4.5-46 months, P = 0.921). In the group of only surgically treated patients, 68.4% of the patients had only one stenosis, 18.4% had 2-3 stenoses and 13.2% more than 3 stenoses. In all patients the surgery- and symptoms- free time was 69 months (57-83 months, P = 0.850 and 0.908). The other two groups showed similar results. We found no significant effect of characteristic of stenosis (length, inflammation, the number of stenoses), injection of prednisolone, disease activity at the time of dilation and medication at the time of dilation on the long-term outcome. Importantly, the success of symptom free time correlated with the diameter of the balloon.Endoscopic dilation should be considered as a first-line therapy for short, accessible, fibrotic strictures. Careful patient selection and proper diagnostic imaging pre-procedure are essential requirements for safe and successful treatment. The balloon diameter seems to correlate positively with the long term outcome of dilation. However, at ever shorter intervals between endoscopic interventions, surgery should be discussed as an option for further treatment.
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LONG-TERM HUMORAL RESPONSE TO SARS-COV-2 VACCINATION IN PATIENTS WITH IMMUNE-MEDIATED INFLAMMATORY DISEASE - Tascilar, Koray; Simon, David; Kleyer, Arnd; Fagni, Filippo; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Kliem, Thorsten; Moessner, J.; Liphardt, Anna-Maria; Schönau, Verena; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Long-Term Obeticholic Acid (OCA) treatment associated with reversal or stabilization of fibrosis/cirrhosis in patients with Primary Biliary Cholangitis (PBC) - Bowlus, C.; Pockros, P.; Kremer, Andreas; Pares, A.; Forman, L.; Drenth, J. P.; Ryder, S.; Malecha, E. S.; Pencek, R.; Iloeje, U.; Macconell, L.; Shapiro, D.; et al. (JOURNAL OF HEPATOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-26

Long-Term Obeticholic Acid Therapy Improves Histological Endpoints in Patients With Primary Biliary Cholangitis - Bowlus, Christopher L.; Pockros, Paul J.; Kremer, Andreas; Parés, Albert; Forman, Lisa M.; Drenth, Joost P.H.; Ryder, Stephen D.; Terracciano, Luigi; Jin, Yuying; Liberman, Alexander; Pencek, Richard; Iloeje, Uche; et al. (Clinical Gastroenterology and Hepatology, 2020)
Background & Aims: Primary biliary cholangitis (PBC) is an autoimmune disease characterized by bile duct destruction that can progress to cirrhosis. A liver biopsy substudy was conducted in the PBC obeticholic acid (OCA) International Study of Efficacy (POISE) to determine the long-term effects of OCA on liver damage and fibrosis in patients with PBC. POISE is a phase 3, double-blind, placebo-controlled, randomized trial with a 5-year open-label extension that evaluated 5 to 10 mg OCA daily in patients who were intolerant or unresponsive to ursodeoxycholic acid. Methods: Liver biopsy specimens were collected from 17 patients at time of enrollment in the double-blind phase and after 3 years of OCA treatment. Histologic evaluations were performed by 2 pathologists in a blinded, randomized fashion to determine the effects of OCA on fibrosis and other histologic parameters. Collagen morphometry assessments were performed by automated second harmonic generation and 2-photon excitation microscopy to observe quantitative measures of fibrosis. Results: From the time of enrollment until 3 years of treatment, most patients had improvements or stabilization in fibrosis (71%), bile duct loss (76%), ductopenia (82%), ductular reaction (82%), interface hepatitis (100%), and lobular hepatitis (94%). Over the 3-year period, we found significant reductions in collagen area ratio (median, –2.1; first quartile, –4.6, third quartile, –0.3; P =.013), collagen fiber density (median, –0.8; first quartile, –2.5; third quartile, 0; P =.021), collagen reticulation index (median, –0.1; first quartile, –0.3; third quartile, 0; P =.008), and fibrosis composite score (median, –1.0; first quartile, –2.5; third quartile, –0.5; P =.002). Conclusions: A subanalysis of data from the POISE study showed that long-term OCA treatment in patients with PBC is associated with improvements or stabilization of disease features, including ductular injury, fibrosis, and collagen morphometry features (ClinicalTrials.gov no: NCT01473524 and EudraCT no: 2011-004728-36).
CRIS-Team Scopus Importer:2020-03-27
Keywords: Farnesoid X Receptor Agonist; FXR Agonist; Hepatic; Liver Disease

Long-term obeticholic acid treatment is associated with improvements in collagen morphometry in patients with primary biliary cholangitis - Kremer, Andreas; Bowlus, Christopher; Bedossa, Pierre; Pares, Albert; Forman, Lisa; Drenth, Joost Ph; Ryder, Stephen; Terracciano, Luigi Maria; Jin, Yuying; Liberman, Alexander; Pencek, Richard; Macconell, Leigh; et al. (JOURNAL OF HEPATOLOGY, 2019)
CRIS-Team WoS Importer:2019-05-07

Long-term outcomes of cyclosporin induction and ustekinumab maintenance combination therapy in patients with steroid-refractory acute severe ulcerative colitis - Vitali, Francesco; Rath, Timo; Klenske, Entcho; Vögele, Anna-Lena; Ganzleben, Ingo; Zundler, Sebastian; Strobel, Deike; Geppert, Carol-Immanuel; Hartmann, Arndt; Neurath, Markus; Atreya, Raja (Therapeutic Advances in Gastroenterology, 2024)
Background: Effective management of patients with acute severe ulcerative colitis (ASUC) is a major challenge and there remains a paucity of available maintenance treatment options after efficacious cyclosporin induction therapy. Objectives: We investigated the long-term effectiveness and safety of cyclosporin and ustekinumab combination therapy in patients with steroid refractory ASUC. Design: Monocentric, prospective study. Methods: We included patients with steroid refractory ASUC with multiple failed prior advanced therapies, who were treated with cyclosporin and ustekinumab combination therapy. Results: Among the 11 included patients, 10 had prior failure to infliximab and 8 failed at least three previous biological therapies. The mean baseline Mayo and Lichtiger scores were 10.9 (9–12) and 13.3 (11–14), respectively. Ustekinumab was initiated 3.2 weeks (1–8) after initiation of cyclosporin treatment and combination therapy was continued for a mean of 11.5 (4–20) weeks. Clinical response was achieved in six patients at week 16 and clinical steroid-free clinical remission in five patients at week 48. Endoscopic remission was achieved in five patients at week 16 and together with histological remission in five patients at week 52. Intestinal ultrasound demonstrated mean bowel wall thickening in the sigmoid colon of 5.5 mm at baseline and 3.5 mm at week 52, respectively. Two patients had to undergo colectomy (mean 4.5 months, range 3–6) and three stopped ustekinumab therapy due to ineffectiveness. Overall, combination therapy was well tolerated. Conclusion: Combination of cyclosporin and ustekinumab therapy allowed nearly half of ASUC patients to reach clinical and endoscopic remission after 52 weeks, warranting further studies. Trial registration: Not applicable.
CRIS-Team Scopus Importer:2024-01-19
Keywords: cyclosporin; proctocolectomy; severe ulcerative colitis; sonography; ustekinumab

Long-term results of teduglutide treatment for chronic intestinal failure – Insights from a national, multi-centric patient home-care service program - Greif, Sophie; Maasberg, Sebastian; Wehkamp, Jan; Fusco, Stefano; Zopf, Yurdagül; Herrmann, Hans Joachim; Lamprecht, Georg; Jacob, Torid; Schiefke, Ingolf; von Websky, Martin W.; Büttner, Janine; Blüthner, Elisabeth; et al. (Clinical Nutrition ESPEN, 2022)
Background & aims: Teduglutide is a Glucagon-like peptide-2 (GLP-2) agonist indicated for the treatment of patients with parenteral support (PS) dependent short bowel syndrome (SBS) with chronic intestinal failure (cIF). Its application is accompanied by a structured nation-wide home-care service program in Germany. We investigated care characteristics and outcome parameters in a clinical real-world observational setting. Methods: Data generated within a therapy-accompanying home-care service program for adult SBS-cIF patients were analyzed retrospectively for patients treated up to 1 year (data cut: April 2020). Results: In total, 52 teduglutide-treated patients were included by 6 German cIF centers. At teduglutide administration start, 49/52 patients were on PS, 3 of them without macronutrients. The majority of patients received individualized parenteral nutrition (PN) (n = 32/46), while 13/46 were on commercial premixed bags. PS application was done by patients themselves (37%), home-care nurses (19%), relatives (8%) or by a combination of those (16%). In patients with PS dependency at baseline and available follow-up data (n = 40–44), teduglutide treatment resulted in significantly reduced PN days, caloric needs, infusion time, and infusion volume after 6 and 12 months. After 1 year, reduction of infusion time was positively correlated with a reduction of PN calories and volume; 30 patients (68%) were responders (PS-volume reduction ≥20%), and 6 patients (14%) were completely weaned off PS. Sleep disturbances per night were significantly reduced after 3 months of treatment and stool characteristics improved in consistency and significantly in frequency, while meal frequency remained stable. Conclusions: Teduglutide treatment associated reduction in PS volume and calories was accompanied by reduced infusion days, infusion times, sleep disturbances, stable oral intake surrogates, and improved stool characteristics, all of these potential parameters for improving quality of life. Furthermore, analyzed care characteristics reflect SBS-cIF treatment as a complex, resource-intensive and demanding task for both, healthcare system and patients.
CRIS-Team Scopus Importer:2022-10-14
Keywords: Home parenteral support; Infusion time; Intestinal failure; Quality of life; Sleep disturbances; Teduglutide

Long-term safety of adalimumab in patients with moderate-to-severe ulcerative colitis: Interim results of a non-interventional registry, LEGACY - Bossuyt, P.; Atreya, Raja; Taxonera, C.; Hebuterne, X.; Isaacs, K.; Higgins, P. D.; Lindsay, J.; Heap, G.; Arikan, D.; Kuehnl, V.; Petersson, J.; Robinson, A. M.; et al. (2018)
EVALuna2:35191

Loss of IFN-gamma pathway gene expression in tumor cells as mechanism of immune escape of colorectal carcinoma - Britzen-Laurent, Nathalie; Straube, Julia; Waldner, Maximilian; Becker, Christoph; Croner, Roland; Pilarsky, Christian; Merkel, Susanne; Stürzl, Michael (CANCER RESEARCH, 2018)
CRIS-Team WoS Importer:2019-06-18

Loss of Survivin in Intestinal Epithelial Progenitor Cells Leads to Mitotic Catastrophe and Breakdown of Gut Immune Homeostasis - Martini, Eva; Wittkopf, Nadine; Günther, Claudia; Leppkes, Moritz; Okada, Hitoshi; Watson, Alastair J.; Podstawa, Eva; Backert, Ingo; Amann, Kerstin Ute; Neurath, Markus; Becker, Christoph (Cell Reports, 2016)
A tightly regulated balance of proliferation and cell death of intestinal epithelial cells (IECs) is essential for maintenance of gut homeostasis. Survivin is highly expressed during embryogenesis and in several cancer types, but little is known about its role in adult gut tissue. Here, we show that Survivin is specifically expressed in transit-amplifying cells and Lgr5(+) stem cells. Genetic loss of Survivin in IECs resulted in destruction of intestinal integrity, mucosal inflammation, and death of the animals. Survivin deletion was associated with decreased epithelial proliferation due to defective chromosomal segregation. Moreover, Survivin-deficient animals showed induced phosphorylation of p53 and H2AX and increased levels of cell-intrinsic apoptosis in IECs. Consequently, induced deletion of Survivin in Lgr5(+) stem cells led to cell death. In summary, Survivin is a key regulator of gut tissue integrity by regulating epithelial homeostasis in the stem cell niche.
EVALuna2:2058

Low Pretreatment Acoustic Radiation Force Impulse Imaging (ARFI) Values Predict Sustained Virological Response in Antiviral Hepatitis C Virus (HCV) Therapy - Zopf, Steffen; Rösch, Lara; Konturek, Peter; Görtz, Rüdiger; Neurath, Markus; Strobel, Deike (Medical Science Monitor, 2016)
BACKGROUND Non-invasive procedures such as acoustic radiation force impulse imaging (ARFI) shear-wave elastography are currently used for the assessment of liver fibrosis. In the course of chronic hepatitis C, significant liver fibrosis or cirrhosis develops in approximately 25% of patients, which is a negative predictor of antiviral treatment response. Cirrhosis can be prevented by successful virus elimination. In this prospective study, a pretreatment ARFI cutoff value of 1.5 m/s was evaluated in relation to sustained virological response to anti-HCV therapy. MATERIAL AND METHODS In 23 patients with chronic hepatitis C, liver stiffness was examined with ARFI at defined times before and under antiviral triple therapy (peginterferon, ribavirin in combination with a first-generation protease inhibitor, and telaprevir or boceprevir). Patients were stratified into 2 groups based on pretreatment ARFI values (<1.5 m/s and >=1.5 m/s) for the assessment of virological response. RESULTS The liver stiffness at baseline for all patients was 1.57±0.79 m/s (ARFI median ± standard deviation; margin: 0.81 m/s to 3.45 m/s). At week 4 of triple therapy, patients with low pretreatment ARFI values had higher rates of HCV-RNA negativity (69% vs. 43%), reflecting an early rapid virological response (eRVR). Sustained virological response (SVR) was found in 75% (12/16) of patients with an ARFI value <1.5 m/s and only 57% (4/7) of patients with ARFI value >=1.5 m/s. CONCLUSIONS Patients with chronic hepatitis C and pretreatment ARFI <1.5 m/s showed earlier virus elimination and better response to treatment.
EVALuna2:2192

Low-volume high-intensity interval training improves cardiometabolic health, work ability and well-being in severely obese individuals: a randomized-controlled trial sub-study - Reljic, Dejan; Frenk, Fabienne; Herrmann, Hans J.; Neurath, Markus; Zopf, Yurdagül (Journal of Translational Medicine, 2020)
Background: Obesity is associated with impaired health and lower work ability. Increased physical activity is a cornerstone in the treatment of obesity and related risk factors. Recently, high-intensity interval training (HIIT) has emerged as a popular exercise option. However, data regarding the effects on cardiometabolic health, perceived work ability and well-being in severely obese individuals are lacking. Methods: Sixty-five obese individuals with sedentary occupation (48.7 ± 9.9 years, BMI: 39.6 ± 7.1 kg/m2) were randomly allocated to an extremely time-efficient HIIT (5 × 1 min at 80–95% maximal heart rate on cycle ergometers, 2×/week for 12 weeks) or an inactive control group (CON). Both groups received nutritional counseling to support weight loss. Primary outcome was maximal oxygen uptake (VO2max), secondary outcomes were cardiometabolic risk indices, body composition, work ability index (WAI), quality of life (QoL, EQ-5D-5L-questionnaire) and perceived stress (PSQ-questionnaire). Results: Mean body weight reduction was 5.3 kg [95% confidence interval (95% CI) − 7.3 to − 3.3 kg] in the HIIT group (P < 0.001) and 3.7 kg (95% CI − 5.3 to − 2.1 kg) in CON (P < 0.001), respectively. Only the HIIT group showed significant (P < 0.001) changes in VO2max [+ 3.5 mL/kg/min (95% CI 2.5 to 4.6 mL/kg/min)], waist circumference [–7.5 cm (95% CI − 9.8 to − 5.1 kg)], mean arterial blood pressure [− 11 mmHg (95% CI − 14 to − 8 mmHg)], WAI [+ 3.0 points (95% CI 1.7 to 4.3 points)] and QoL [+ 10% (95% CI 5 to 16%)]. In CON, none of these parameters improved significantly. Conclusions: Low-volume HIIT may induce significant improvements in cardiometabolic health, especially VO2max, WAI and well-being in obese individuals after only 12 weeks. Our results underpin the wide range of benefits on health and subjective measures through exercise that go well beyond simple weight loss through dietary restriction alone. Trial registration: ClinicalTrials.gov Id: NCT03306069. Registered 10 October 2017, https://clinicaltrials.gov/ct2/show/NCT03306069.
CRIS-Team Scopus Importer:2020-11-13
Keywords: Aerobic exercise; Cardiorespiratory fitness; High-intensity interval training; Metabolic syndrome; Obesity; Psychological health; Weight loss; Work ability

LPA receptor 1 (LPAR1) is a novel interaction partner of Filamin A that promotes Filamin A phosphorylation, MRTF-A transcriptional activity and oncogene-induced senescence - Konopa, Andreas; Meier, Melanie; Franz, Miriam; Bernardinelli, Emanuele; Vögele, Anna-Lena; Atreya, Raja; Ribback, Silvia; Roessler, Stephanie; Aigner, Achim; Singer, Kerstin; Singer, Stephan; Sarikas, Antonio; et al. (Oncogenesis, 2022)
Myocardin-related transcription factors A and B (MRTFs) are coactivators of Serum Response Factor (SRF), which controls fundamental biological processes such as cell growth, migration, and differentiation. MRTF and SRF transcriptional activity play an important role in hepatocellular carcinoma (HCC) growth, which represents the second leading cause of cancer-related mortality in humans worldwide. We, therefore, searched for druggable targets in HCC that regulate MRTF/SRF transcriptional activity and can be exploited therapeutically for HCC therapy. We identified the G protein-coupled lysophosphatidic acid receptor 1 (LPAR1) as a novel interaction partner of MRTF-A and Filamin A (FLNA) using fluorescence resonance energy transfer-(FRET) and proximity ligation assay (PLA) in vitro in HCC cells and in vivo in organoids. We found that LPAR1 promotes FLNA phosphorylation at S2152 which enhances the complex formation of FLNA and MRTF-A, actin polymerization, and MRTF transcriptional activity. Pharmacological blockade or depletion of LPAR1 prevents FLNA phosphorylation and complex formation with MRTF-A, resulting in reduced MRTF/SRF target gene expression and oncogene-induced senescence. Thus, inhibition of the LPAR1-FLNA-MRTF-A interaction represents a promising strategy for HCC therapy.
CRIS-Team WoS Importer:2023-01-13

Lu-177-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial - Strosberg, Jonathan R.; Caplin, Martyn E.; Kunz, Pamela L.; Ruszniewski, Philippe B.; Bodei, Lisa; Hendifar, Andrew; Mittra, Erik; Wolin, Edward M.; Yao, James C.; Pavel, Marianne Ellen; Grande, Enrique; Van Cutsem, Eric; et al. (Lancet Oncology, 2021)
Background The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with Lu-177-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results.
CRIS-Team WoS Importer:2021-12-31

[Lu-177]Lu-DOTA-TATE as First-line Therapy for Patients With Grade 2 and 3 Advanced Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): The NETTER-2 Study - Singh, Simron; Pavel, Marianne Ellen; Kunz, Pamela L.; De Herder, Wouter; Herrmann, Ken; D'Amelio, Anthony M.; Santoro, Paola; Folitar, Ilya; Ferone, Diego (PANCREAS, 2022)
CRIS-Team WoS Importer:2022-07-15

Luminal application of a GATA3-specific DNAzyme ameliorates mucosal inflammation in a randomised trial with active ulcerative colitis patients - Atreya, Raja; Kuehbacher, T.; Schmitt, H.; Hirschmann, S.; Waldner, Maximilian; Drvarov, O.; Fischer, Sven Moritz; Vetter, Marcel; Weigmann, Benno; Turowska, A.; Muhl, T.; Homburg, U.; et al. (2018)
EVALuna2:34074

Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆ - Baudin, E.; Caplin, M.; Garcia-Carbonero, R.; Fazio, N.; Ferolla, P.; Filosso, P. L.; Frilling, A.; de Herder, W. W.; Hörsch, D.; Knigge, U.; Korse, C. M.; Lim, E.; et al. (Annals of Oncology, 2021)
CRIS-Team Scopus Importer:2021-03-05
Keywords: characterisation; diagnosis; lung carcinoids; prognosis; therapy; thymic carcinoids

Lung cancer presenting with central nervous system metastasis: Clinicopathological and molecular analysis of 171 cases - Demleitner, Madeleine; Erlenbach-Wünsch, Katharina; Coras, Roland; Erber, Ramona; Polifka, Iris; Eyüpoglu, Ilker Yasin; Fuchs, Florian; Hartmann, Arndt; Agaimy, Abbas (Annals of Diagnostic Pathology, 2023)
A subset of lung carcinoma presents initially with brain metastasis. Precise subtyping is mandatory for optimized treatment of these advanced aggressive carcinomas. We herein analyzed surgical biopsies from 171 Patients (99 males and 72 females aged 48–96; mean, 72), who presented with brain metastasis of lung cancer. In addition to conventional subtyping, we applied an extended immunohistochemistry (IHC) panel and performed several molecular tests looking for potential therapeutic targets other than EGFR mutations. Non-small cell carcinoma (NSCLC) comprised 157 (91.8 %) of cases: 109 (63.7 %) adenocarcinomas, 27 (15.8 %) squamous cell (SCC), 18 (10.5 %) large cell undifferentiated, 1 (0.6 %) adenosquamous and 2 (1.2 %) unclassified carcinomas. Of the adenocarcinomas, 81.7 % were TTF1+. Notably, 45 % of those TTF1-negative cases expressed HepPar1. SMARCA4 and SMARCA2 loss was observed in 13/171 (7.6 %) and 32/163 (19.6 %) cases, respectively; mainly TTF1- (40.0 %) and HepPar1+ (38.1 %) adenocarcinomas were affected by SMARCA2/4 loss. Loss of at least one mismatch repair (MMR) protein was observed in 3/156 (1.9 %) cases (2 adenocarcinomas and 1 large cell neuroendocrine carcinoma/LCNEC). Limited available data on mutation testing showed a frequency of EGFR mutations of 4.3% and of KRAS mutations of 57%. HER2 expression (2+/3+) was found in 45/166 (27.1 %) of cases with amplification verified by CISH in 18/38 (47.4 % of immunopositive cases and 10.5 % of the whole cohort); all but one were adenocarcinomas. Other genetic abnormalities detected included EML4::ALK rearrangements in 3 (1.8 %; 2 TTF1+ adenocarcinomas and 1 LCNEC) and RET rearrangements in one SCNEC. Variable subsets of tumors revealed amplifications of several potentially therapeutically targetable genes including MYC (30.0 %), MET (10.1 %), HER2 (10 %), FGFR1 (9.6 %), FGFR3 (4.6 %), and FGFR2 (3.4 %). This study highlights a highly heterogeneous molecular background in lung cancer presenting with CNS metastases. These findings highlight the need for individualized tumor testing strategies looking for potential therapeutic targets for this aggressive disease.
CRIS-Team Scopus Importer:2023-01-27
Keywords: ALK; Central nervous system metastasis; Immune therapy; Microsatellite instability; NSCLC; SMARCA4

LUTATHERA (R) in first line therapy of G2 and G3 GEP-NETs (the NETTER-2 study) - Ferone, D.; Pavel, Marianne Ellen; Kunz, P.; De Herder, W.; Santoro, P.; Wegener, A.; Broberg, P.; Ravasi, L.; Singh, S. (EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 2019)
CRIS-Team WoS Importer:2019-11-19

Lysophosphatidic acid activates nociceptors and causes pain or itch depending on the application mode in human skin - Düll, Miriam; Stengel, Martina; Ries, Vivien; Strupf, Marion; Reeh, Peter; Kremer, Andreas; Namer, Barbara (Pain, 2022)
ABSTRACT: Lysophosphatidic acid (LPA) is involved in the pathophysiology of cholestatic pruritus and neuropathic pain. Slowly conducting peripheral afferent C-nerve fibers are crucial in the sensations of itch and pain. In animal studies, specialized neurons ("pruriceptors") have been described, expressing specific receptors, eg, from the Mas-related G-protein-coupled receptor family. Human nerve fibers involved in pain signaling ("nociceptors") can elicit itch if activated by focalized stimuli such as cowhage spicules. In this study, we scrutinized the effects of LPA in humans by 2 different application modes on the level of psychophysics and single nerve fiber recordings (microneurography). In healthy human subjects, intracutaneous LPA microinjections elicited burning pain, whereas LPA application through inactivated cowhage spicules evoked a moderate itch sensation. Lysophosphatidic acid microinjections induced heat hyperalgesia and hypersensitivity to higher electrical stimulus frequencies. Pharmacological blockade of transient receptor potential channel A1 or transient receptor potential channel vanilloid 1 reduced heat hyperalgesia, but not acute chemical pain. Microneurography revealed an application mode-dependent differential activation of mechanosensitive (CM) and mechanoinsensitive C (CMi) fibers. Lysophosphatidic acid microinjections activated a greater proportion of CMi fibers and more strongly than CM fibers; spicule application of LPA activated CM and CMi fibers to a similar extent but excited CM fibers more and CMi fibers less intensely than microinjections. In conclusion, we show for the first time in humans that LPA can cause pain as well as itch dependent on the mode of application and activates afferent human C fibers. Itch may arise from focal activation of few nerve fibers with distinct spatial contrast to unexcited surrounding afferents and a specific combination of activated fiber subclasses might contribute.
CRIS-Team Scopus Importer:2022-02-25

Lysophosphatidic acid activates peripheral glia cells via LPA receptor 1 - Wolf, Katharina; Gebhardt, L.; Robering, J.; Fischer, M.; Kremer, Andreas (JOURNAL OF HEPATOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-26

Lysophosphatidic acid activates peripheral glial cells - Gebhardt, Lisa; Robering, J; Ciotu, C.; Wolf, Katharina; Kühn, Helen; Kremer, Andreas; Fischer, M. (GLIA, 2019)
CRIS-Team WoS Importer:2020-01-10

Lysophosphatidic acid activates satellite glia cells and Schwann cells - Robering, Jan Willem; Gebhardt, Lisa; Wolf, Katharina; Kühn, Helen; Kremer, Andreas; Fischer, Michael Jochen Marco (Glia, 2019)
Pruritus is a common and disabling symptom in patients with hepatobiliary disorders, particularly in those with cholestatic features. Serum levels of lysophosphatidic acid (LPA) and its forming enzyme autotaxin were increased in patients suffering from hepatic pruritus, correlated with itch severity and response to treatment. Here we show that in a culture of dorsal root ganglia LPA 18:1 surprisingly activated a large fraction of satellite glia cells, and responses to LPA 18:1 correlated inversely with responses to neuronal expressed transient receptor potential channels. LPA 18:1 caused only a marginal activation of heterologously expressed TRPV1, and responses in dorsal root ganglion cultures from TRPV1-deficient mice were similar to controls. LPA 18:1 desensitized subsequent responsiveness to chloroquine and TGR5 agonist INT-777. The LPA 18:1-induced increase in cytoplasmatic calcium stems from the endoplasmatic reticulum. LPA receptor expression in dorsal root ganglia and Schwann cells, LPAR1 immunohistochemistry, and pharmacological results indicate a signaling pathway through LPA receptor 1. Peripheral rat Schwann cells, which are of glial lineage as the satellite glia cells, were also responsive to LPA 18:1. Summarizing, LPA 18:1 primarily activates rather glial cells than neurons, which may subsequently modulate neuronal responsiveness and sensory sensations such as itch and pain.
CRIS-Team WoS Importer:2019-04-04

LYSOPHOSPHATIDIC ACID INDUCES ITCH AND PAIN IN HUMANS DEPENDING ON THE MODE OF APPLICATION - Düll, Miriam; Wurm, Lina; Ries, Vivien; Stengel, Martina; Reeh, Peter; Fischer, Michael J.; Namer, Barbara; Kremer, Andreas (2017)
EVALuna2:33336

Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever - Kohl, Lisa; Siddique, Md Nur A Alam; Bodendorfer, Barbara; Berger, Raffaela; Preikschat, Annica; Daniel, Christoph; Ölke, Martha; Liebler-Tenorio, Elisabeth; Schulze-Lührmann, Jan; Mauermeir, Michael; Yang, Kai-Ting; Hayek, Inaya; et al. (Embo Molecular Medicine, 2022)
Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis-aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti-microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1−/− mice caused increased C. burnetii burden, weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1−/− mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1−/− mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1-derived itaconate is a key factor in the macrophage-mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.
CRIS-Team Scopus Importer:2022-12-16
Keywords: Cis-aconitate decarboxylase 1; Coxiella burnetii; Immune responsive gene 1; immunometabolism; itaconate

Magnification endoscopy with optical chromoendoscopy for in vivo assessment of histological inflammation in patients with inflammatory bowel disease - Klenske, E.; Atreya, Raja; Hartmann, Arndt; Fischer, Sören; Hirschmann, Simon; Zundler, Sebastian; Iacucci, M.; Neurath, Markus; Rath, Timo (JOURNAL OF CROHNS & COLITIS, 2019)
CRIS-Team WoS Importer:2019-03-20

Magnification endoscopy with optical chromoendoscopy shows strong correlation with histologic inflammation in patients with inflammatory bowel disease - Klenske, Entcho; Atreya, Raja; Hartmann, Arndt; Fischer, Sören; Hirschmann, Simon; Zundler, Sebastian; Iaccuci, Marietta; Neurath, Markus; Rath, Timo (Endoscopy International Open, 2019)
Background and study aims Apart from mucosal healing as an established treatment goal in inflammatory bowel diseases (IBD), recent evidence suggests that histologic healing may become another key prognostic parameter in IBD patients. We aimed to evaluate whether magnification endoscopy with optical chromoendoscopy can accurately assess histologic inflammation in IBD patients.
CRIS-Team WoS Importer:2019-09-13

Malnutrition in Hospitals: It Was, Is Now, and Must Not Remain a Problem! - Konturek, Peter C.; Herrmann, Hans J.; Schink, Kristin; Neurath, Markus; Zopf, Yurdagül (Medical Science Monitor, 2015)
BACKGROUND Malnutrition is an under-recognized problem in hospitalized patients. Despite systematic screening, the prevalence of malnutrition in the hospital did not decrease in the last few decades. The aim of our study was to evaluate the prevalence of malnutrition and to determine the explicit daily calorie intake of hospitalized patients, to identify the risk factors of developing malnutrition during hospitalization and the effect on the financial reimbursement according to the German DRG-system. MATERIAL AND METHODS 815 hospitalized patients were included in this study. The detection of malnutrition was based on the nutritional-risk-screening (NRS) and subjective-global-assessment (SGA) scores. A trained investigator recorded the daily calorie and fluid intake of each patient. Furthermore, clinical parameters, and the financial reimbursement were evaluated. RESULTS The prevalence of malnutrition was 53.6% according to the SGA and 44.6% according the NRS. During hospitalization, patients received on average 759.9±546.8 kcal/day. The prevalence of malnutrition was increased in patients with hepatic and gastrointestinal disease and with depression or dementia. The most important risk factors for malnutrition were bed rest and immobility (OR=5.88, 95% CI 2.25-15.4). In 84.5% of patient records, malnutrition was not correctly coded, leading to increased financial losses according to the DRG-system (94.908 Euros). CONCLUSIONS Hospitalized patients suffer from inadequate nutritional therapy and the risk for developing malnutrition rises during the hospital stay. The early screening of patients for malnutrition would not only improve management of nutritional therapy but also, with adequate coding, improve financial reimbursement according to the DRG-system.
EVALuna2:1991

Management of Chronic Hepatic Itch - Düll, Miriam; Kremer, Andreas (Dermatologic Clinics, 2018)
Hepatic itch remains among the most agonizing symptoms for affected patients and a major clinical challenge for physicians. Pruritus may occur in almost all liver diseases, particularly those with cholestatic features. Hepatic itch arises irrespective of the severity of the underlying liver disease or extent of cholestasis. Antihistamines are ineffective in hepatic itch. Therapeutic recommendations consist of a guideline-based stepwise approach, starting with the anion exchange resin cholestyramine, followed by rifampicin, naltrexone, and sertraline. Bezafibrate and ileal bile acid transporter inhibitors are promising future treatment options. Experimental and invasive procedures should be reserved for refractory pruritus.
EVALuna2:35154

Management of pruritus in patients with cholestatic liver disease - Kremer, Andreas; Kraus, M. R. (MMW Fortschritte der Medizin, 2016)
EVALuna2:2221

Manual cell selection in single cell transcriptomics using scSELpy supports the analysis of immune cell subsets - Dedden, Mark; Wiendl, Maximilian; Müller, Tanja; Neurath, Markus; Zundler, Sebastian (Frontiers in Immunology, 2023)
Introduction: Single cell RNA sequencing plays an increasing and indispensable role in immunological research such as in the field of inflammatory bowel diseases (IBD). Professional pipelines are complex, but tools for the manual selection and further downstream analysis of single cell populations are missing so far. Methods: We developed a tool called scSELpy, which can easily be integrated into Scanpy-based pipelines, allowing the manual selection of cells on single cell transcriptomic datasets by drawing polygons on various data representations. The tool further supports the downstream analysis of the selected cells and the plotting of results. Results: Taking advantage of two previously published single cell RNA sequencing datasets we show that this tool is useful for the positive and negative selection of T cell subsets implicated in IBD beyond standard clustering. We further demonstrate the feasibility for subphenotyping T cell subsets and use scSELpy to corroborate earlier conclusions drawn from the dataset. Moreover, we also show its usefulness in the context of T cell receptor sequencing. Discussion: Collectively, scSELpy is a promising additive tool fulfilling a so far unmet need in the field of single cell transcriptomic analysis that might support future immunological research.
CRIS-Team Scopus Importer:2023-05-26
Keywords: chronic inflammation; gut homing; inflammatory bowel disease; single cell RNA sequencing; transcriptomics

Markers of Systemic Inflammation in Neuroendocrine Tumors: A Pooled Analysis of the RADIANT-3 and RADIANT-4 Studies - Chan, David L.; Yao, James C.; Carnaghi, Carlo; Buzzoni, Roberto; Herbst, Fabian; Ridolfi, Antonia; Strosberg, Jonathan; Kulke, Matthew H.; Pavel, Marianne Ellen; Singh, Simron (Pancreas, 2021)
OBJECTIVE: The aim of the study was to assess the impact of systemic markers of inflammation on the outcomes in patients with neuroendocrine tumors (NETs) treated with everolimus or placebo (as measured by baseline neutrophil-to-lymphocyte ratio [NLR] and lymphocyte-to-monocyte ratio [LMR]). METHODS: Patient data (gastrointestinal, pancreatic, and lung NETs) from 2 large phase 3 studies, RADIANT-3 (n = 410) and RADIANT-4 (n = 302), were pooled and analyzed. The primary end point was centrally assessed progression-free survival (PFS) as estimated by the Kaplan-Meier method. RESULTS: In the pooled population, elevated LMR (median PFS, 11.1 months; 95% confidence interval, 9.3-13.7; hazard ratio, 0.69; P < 0.001) and reduced NLR (median PFS, 10.8 months; 95% confidence interval, 9.2-11.7; hazard ratio, 0.75; P = 0.0060) correlated with longer PFS among all patients. These markers were also found to be prognostic in the everolimus- and placebo-treated subgroups. CONCLUSIONS: Data from this study suggest that LMR and NLR are robust prognostic markers for NETs and could potentially be used to identify patients who may receive or are receiving the most benefit from targeted therapies. As both are derived from a complete blood count, they can be routinely used in clinical practice, providing valuable information to clinicians and patients alike.
CRIS-Team Scopus Importer:2021-03-05

Mas-related G protein–coupled receptor X2 and its activators in dermatologic allergies - Kühn, Helen; Kolkhir, Pavel; Babina, Magda; Düll, Miriam; Frischbutter, Stefan; Fok, Jie Shen; Jiao, Qingqing; Metz, Martin; Scheffel, Jörg; Wolf, Katharina; Kremer, Andreas; Maurer, Marcus (Journal of Allergy and Clinical Immunology, 2020)
The Mas-related G protein–coupled receptor X2 (MRGPRX2) is a multiligand receptor responding to various exogenous and endogenous stimuli. Being highly expressed on skin mast cells, MRGPRX2 triggers their degranulation and release of proinflammatory mediators, and it promotes multicellular signaling cascades, such as itch induction and transmission in sensory neurons. The expression of MRGPRX2 by skin mast cells and the levels of the MRGPRX2 agonists (eg, substance P, major basic protein, eosinophil peroxidase) are upregulated in the serum and/or skin of patients with inflammatory and pruritic skin diseases, such as chronic spontaneous urticaria or atopic dermatitis. Therefore, MRGPRX2 and its agonists might be potential biomarkers for the progression of cutaneous inflammatory diseases and the response to treatment. In addition, they may represent promising targets for prevention and treatment of signs and symptoms in patients with skin diseases or drug reactions. To assess this possibility, this review explores the role and relevance of MRGPRX2 and its activators in cutaneous inflammatory disorders and chronic pruritus.
CRIS-Team Scopus Importer:2020-10-23
Keywords: agonists; antimicrobial peptides; atopic dermatitis; chronic spontaneous urticaria; eosinophil granule proteins; itch; MRGPRX2; MRGX2; neuropeptides; pruritus; substance P

Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options - Molderings, G. J.; Homann, J.; Brettner, S.; Raithel, M.; Frieling, T. (Deutsche Medizinische Wochenschrift, 2014)
In the present paper clinical phenotypes, pathogenetic relationships, and diagnostic algorithms as well as therapeutic concepts of/for systemic mast cell activation disease are reviewed. The reader should be able to recognize and diagnose a systemic mast cell activation disease, as well as to counsel a personalized drug therapy. In the case of chronic multisystem polymorbidity systemic mast cell activation disease should be considered as a differential diagnosis at an early stage. In most cases, specific, little invasive investigations allow diagnosing the disease and, hence, an appropriate therapy can be initiated.
EVALuna2:1887

Mast cell activation disease: An underappreciated cause of neurologic and psychiatric symptoms and diseases - Afrin, Lawrence B.; Poehlau, Dieter; Raithel, Martin; Haenisch, Britta; Dumoulin, Franz L.; Homann, Juergen; Mauer, Uwe M.; Harzer, Sabrina; Molderings, Gerhard J. (Brain Behavior and Immunity, 2015)
Neurologists and psychiatrists frequently encounter patients whose central and/or peripheral neurologic and/or psychiatric symptoms (NPS) are accompanied by other symptoms for which investigation finds no unifying cause and for which empiric therapy often provides little to no benefit. Systemic mast cell activation disease (MCAD) has rarely been considered in the differential diagnosis in such situations. Traditionally, MCAD has been considered as just one rare (neoplastic) disease, mastocytosis, generally focusing on the mast cell (MC) mediators tryptase and histamine and the suggestive, blatant symptoms of flushing and anaphylaxis. Recently another form of MCAD, MC activation syndrome (MC), has been recognized, featuring inappropriate MC activation with little to no neoplasia and likely much more heterogeneously clonal and far more prevalent than mastocytosis. There also has developed greater appreciation for the truly very large menagerie of MC mediators and their complex patterns of release, engendering complex, nebulous presentations of chronic and acute illness best characterized as multisystem polymorbidity of generally inflammatory±allergic themes - including very wide arrays of central and peripheral NPS. Significantly helpful treatment - including for neuropsychiatric issues - usually can be identified once MCAD is accurately diagnosed. We describe MCAD's pathogenesis, presentation (focusing on NPS), and therapy, especially vis-à-vis neuropsychotropes. Since MCAD patients often present NPS, neurologists and psychiatrists have the opportunity, in recognizing the diagnostic possibility of MCAD, to short-circuit the often decades-long delay in establishing the correct diagnosis required to identify optimal therapy.
EVALuna2:2030

Master regulator of intestinal disease: IL-6 in chronic inflammation and cancer development - Waldner, Maximilian; Neurath, Markus (Seminars in Immunology, 2014)
IL-6 signaling is of central importance for the maintenance of chronic intestinal inflammation in inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. IL-6 regulates T cell differentiation, activation and resistance against apoptosis and thereby controls the balance between pro-inflammatory T cell subsets such as Th1 or Th17 cells and immunosuppressive regulatory T cells. Furthermore, IL-6 has been implicated in the pathogenesis of colorectal cancer (CRC). In fact, IL-6 directly promotes tumor cell proliferation and survival through STAT3 activation. Due to its role in both types of diseases, IL-6 has been proposed as a missing link between inflammation and tumor development. During recent years, several therapeutics targeting IL-6 dependent pathways have been developed. Although clinical data about anti-IL-6 treatment in intestinal diseases are currently scarce, targeting this pathway might be a promising strategy in IBD and CRC.
EVALuna2:1873

Matching-adjusted indirect treatment comparison of [177Lu]Lu-DOTA-TATE, everolimus and sunitinib in advanced, unresectable gastroenteropancreatic neuroendocrine tumours: Relative effectiveness of [177Lu]Lu-DOTA-TATE in gastroenteropancreatic neuroendocrine tumours - Khan, Mohid S.; Stamp, Elaine; Sammon, Cormac; Brabander, Tessa; de Herder, Wouter W.; Pavel, Marianne Ellen (Ejc Supplements, 2021)
Head-to-head comparisons of the efficacy of treatments for gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have not yet been reported. This study used a series of matching-adjusted indirect comparisons to indirectly compare the effectiveness of [177Lu]Lu-DOTA-TATE to everolimus, sunitinib and best supportive care (BSC) for extending progression-free survival and overall survival in patients with advanced, unresectable gastrointestinal (GI)-NETs and P-NETs. The results of the main analysis suggest that after accounting for differences in key prognostic variables, the hazard of progression was 62% (hazard ratio [HR], 0.38; confidence interval [CI]95 0.25–0.58) and 65% (HR 0.35 CI95 0.21–0.59) lower in patients with GI-NETs treated with [177Lu]Lu-DOTA-TATE than in those treated with everolimus and BSC, respectively. Similarly, the hazard of progression was 64% (HR 0.36 CI95 0.18–0.70), 54% (HR 0.46 CI95 0.30–0.71) and 79–87% (HR 0.21 CI95 0.13–0.32; HR 0.13 CI95 0.08–0.22) lower in patients with P-NET treated with [177Lu]Lu-DOTA-TATE than in those treated with sunitinib, everolimus and BSC, respectively. The hazard of death was 58% (HR 0.42 CI95 0.25–0.72), 47% (HR 0.53 CI95 0.33–0.87) and 44–64% (HR 0.56 CI95 0.36–0.90; HR 0.34 CI95 0.20–0.57) lower in P-patients with NET treated with [177Lu]Lu-DOTA-TATE than in those treated with sunitinib, everolimus and BSC, respectively. While our results must be interpreted with caution given the non-randomised nature of the comparisons and the potential for residual confounding, the magnitude of the effect sizes we observe and their consistency across comparators suggest that [177Lu]Lu-DOTA-TATE may be a more effective treatment option than everolimus, sunitinib and BSC in advanced, unresectable GEP-NETs.
CRIS-Team Scopus Importer:2021-12-03
Keywords: Best supportive care; Comparative effectiveness; Overall survival; Progression-free survival

Matricellular Protein SPARCL1 Regulates Blood Vessel Integrity and Antagonizes Inflammatory Bowel Disease - Regensburger, Daniela; Tenkerian, Clara; Pürzer, Victoria; Schmid, Benjamin; Wohlfahrt, Thomas; Stolzer, Iris; Lopez Posadas, Rocío; Günther, Claudia; Waldner, Maximilian; Becker, Christoph; Sticht, Heinrich; Petter, Katja; et al. (Inflammatory Bowel Diseases, 2021)
Background The understanding of vascular plasticity is key to defining the role of blood vessels in physiologic and pathogenic processes. In the present study, the impact of the vascular quiescence marker SPARCL1 on angiogenesis, capillary morphogenesis, and vessel integrity was evaluated. Methods Angiogenesis was studied using the metatarsal test, an ex vivo model of sprouting angiogenesis. In addition, acute and chronic dextran sodium sulfate colitis models with SPARCL1 knockout mice were applied. Results This approach indicated that SPARCL1 inhibits angiogenesis and supports vessel morphogenesis and integrity. Evidence was provided that SPARCL1-mediated stabilization of vessel integrity counteracts vessel permeability and inflammation in acute and chronic dextran sodium sulfate colitis models. Structure-function analyses of purified SPARCL1 identified the acidic domain of the protein necessary for its anti-angiogenic activity. Conclusions Our findings inaugurate SPARCL1 as a blood vessel–derived anti-angiogenic molecule required for vessel morphogenesis and integrity. SPARCL1 opens new perspectives as a vascular marker of susceptibility to colitis and as a therapeutic molecule to support blood vessel stability in this disease. <br
Keywords: angiogenesis; blood vessel; DSS colitis; endothelial cell; inflammatory bowel disease; permeability; SPARCL1

Maximizing the diagnostic information from biopsies in chronic inflammatory bowel diseases: recommendations from the Erlangen International Consensus Conference on Inflammatory Bowel Diseases and presentation of the IBD-DCA score as a proposal for a new index for histologic activity assessment in ulcerative colitis and Crohn's disease - Lang-Schwarz, Corinna; Agaimy, Abbas; Atreya, Raja; Becker, Christoph; Danese, Silvio; Flejou, Jean-Francois; Gassler, Nikolaus; Grabsch, Heike I.; Hartmann, Arndt; Kamaradova, Katerina; Kuehl, Anja A.; Lauwers, Gregory Y.; et al. (Virchows Archiv, 2020)
CRIS-Team WoS Importer:2021-01-22

Maximum Heart Rate- and Lactate Threshold-Based Low-Volume High-Intensity Interval Training Prescriptions Provide Similar Health Benefits in Metabolic Syndrome Patients - Reljic, Dejan; Frenk, Fabienne; Herrmann, Hans Joachim; Neurath, Markus; Zopf, Yurdagül (Healthcare, 2023)
Exercise is an integral part of metabolic syndrome (MetS) treatment. Recently, low-volume high-intensity interval training (LOW-HIIT) has emerged as a time-efficient approach to improving cardiometabolic health. Intensity prescriptions for LOW-HIIT are typically based on maximum heart rate (HRmax) percentages. However, HRmax determination requires maximal effort during exercise testing, which may not always be feasible/safe for MetS patients. This trial compared the effects of a 12-week LOW-HIIT program based on: (a) HRmax (HIIT-HR), or (b) submaximal lactate threshold (HIIT-LT), on cardiometabolic health and quality of life (QoL) in MetS patients. Seventy-five patients were randomized to HIIT-HR (5 × 1 min at 80–95% HRmax), HIIT-LT (5 × 1 min at 95–105% LT) groups, both performed twice weekly on cycle ergometers, or a control group (CON). All patients received nutritional weight loss consultation. All groups reduced their body weight (HIIT-HR: −3.9 kg, p < 0.001; HTT-LT: −5.6 kg, p < 0.001; CON: −2.6 kg, p = 0.003). The HIIT-HR and HIIT-LT groups similarly, improved their maximal oxygen uptake (+3.6 and +3.7 mL/kg/min, p < 0.001), glycohemoglobin (−0.2%, p = 0.005, and −0.3%, p < 0.001), homeostasis model assessment index (−1.3 units, p = 0.005, and −1.0 units, p = 0.014), MetS z-score (−1.9 and −2.5 units, p < 0.001) and QoL (+10 points, p = 0.029, and +11 points, p = 0.002), while the CON did not experience changes in these variables. We conclude that HIIT-LT is a viable alternative to HIIT-HR for patients who are not able/willing to undergo maximal exercise testing.
CRIS-Team Scopus Importer:2023-03-23
Keywords: cardiometabolic health; cardiorespiratory fitness; exercise prescription; glycemic control; heart rate; interval training; lactate; maximal oxygen uptake; obesity; quality of life

M cell maturation and cDC activation determine the onset of adaptive immune priming in the neonatal Peyer's patch - Torow, Natalia; Li, Ronghui; Hitch, Thomas Charles Adrian; Mingels, Clemens; Al Bounny, Shahed; van Best, Niels; Stange, Eva Lena; Simons, Britta; Maié, Tiago; Rüttger, Lennart; Gubbi, Narasimha Murthy Keshava Prasad; Abbott, Darryl Adelaide; et al. (Immunity, 2023)
Early-life immune development is critical to long-term host health. However, the mechanisms that determine the pace of postnatal immune maturation are not fully resolved. Here, we analyzed mononuclear phagocytes (MNPs) in small intestinal Peyer's patches (PPs), the primary inductive site of intestinal immunity. Conventional type 1 and 2 dendritic cells (cDC1 and cDC2) and RORgt+ antigen-presenting cells (RORgt+ APC) exhibited significant age-dependent changes in subset composition, tissue distribution, and reduced cell maturation, subsequently resulting in a lack in CD4+ T cell priming during the postnatal period. Microbial cues contributed but could not fully explain the discrepancies in MNP maturation. Type I interferon (IFN) accelerated MNP maturation but IFN signaling did not represent the physiological stimulus. Instead, follicle-associated epithelium (FAE) M cell differentiation was required and sufficient to drive postweaning PP MNP maturation. Together, our results highlight the role of FAE M cell differentiation and MNP maturation in postnatal immune development.
CRIS-Team Scopus Importer:2023-06-23
Keywords: cDC2; dendritic cell; M cell; microbiota; neonatal immunology; Peyer's patch; post-natal establishment of intestinal homeostasis; RORgt

Mechanism-based treatment strategies for IBD: Cytokines, cell adhesion molecules, JAK inhibitors, gut flora, and more - Schreiner, Philipp; Neurath, Markus; Ng, Siew C.; El-Omar, Emad M.; Sharara, Ala I.; Kobayashi, Taku; Hisamatsu, Tadakazu; Hibi, Toshifumi; Rogler, Gerhard (Inflammatory Intestinal Diseases, 2019)
Background: Although TNF inhibitors revolutionized the therapy of inflammatory bowel disease (IBD), we have been reaching a point where other therapies with different mechanisms of action are necessary. A rising number of elderly IBD patients with contraindications to established therapies and a growing group of patients losing response to anti-TNF therapy compel us to find safer, better-tolerated, and, ideally, personalized treatment options. However, in order to choose the right drug to fit a patient, it is indispensable to understand the pathomechanism involved in IBD. Summary: The aim of this review is to explain the inflammatory signaling pathways in IBD and how to inhibit them with current and future therapeutic approaches. Next to biologic agents targeting inflammatory cytokines (anti-TNF agents, anti-IL-12/-23 agents, and specific inhibitors of IL-23), biologics blocking leukocyte trafficking to the gut (anti-integrin antibodies) are available nowadays. More recently, small molecules inhibiting the JAK-STAT pathway (JAK inhibitors) or preventing lymphocyte trafficking (sphingosine-1-phosphate modulators) have been approved or are under investigation. Furthermore, modifying the microbiota has potential therapeutic effects on IBD, and autologous hematopoietic or mesenchymal stem cell transplantation may be considered for a highly selected group of IBD patients. Key Message: Physicians should understand the different mechanisms of action of the potential therapies for IBD to select the right drug for the right patient.
CRIS-Team Scopus Importer:2023-03-23
Keywords: Biologics; Crohn's disease; Inflammatory bowel disease; Small molecules; Ulcerative colitis

Mechanisms of molecular resistance and predictors of response to biological therapy in inflammatory bowel disease - Atreya, Raja; Neurath, Markus (Lancet Gastroenterology and Hepatology, 2018)
Biological therapy has led to marked improvements in treatment of patients with inflammatory bowel disease, and an increasing number of drugs has been approved for treatment. However, only a subgroup of patients responds to therapy, highlighting the need to identify biomarkers for therapeutic response to allow personalised medicine in inflammatory bowel disease. Potential markers of response to biological therapy have been identified; however, studies also suggest that changes in the composition of immune cell infiltrates in response to therapeutic pressure lead to molecular resistance to these drugs. For instance, the cytokine interleukin 23 has been identified as a driver of evasion of apoptosis in response to anti-tumour necrosis factor drugs in patients with Crohn's disease, leading to expansion of apoptosis-resistant T cells and drug resistance. In this Review, we examine the concept of molecular resistance to biological therapy and discuss implications for future therapy.
EVALuna2:35134

Medication safety in patients treated with new oral antitumor agents: A prospective, randomized investigation on the impact of intensified clinical pharmaceutical/clinical pharmacological care on patient safety, patient knowledge and patient well-being (AMBORA). Supported by the German Cancer Aid within the Comprehensive Cancer Center Erlangen-EMN - Schlichtig, Katja; Lechner, P.; Grafe, Carolin; Ferstl, B.; Fuchs, F.; Hein, Alexander; Meidenbauer, N.; Sell, C.; Semrau, S.; Pavel, Marianne Ellen; Wullich, Bernd; Neurath, Markus; et al. (2018)
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