Efficacy and Safety of Seladelpar, a Selective Peroxisome Proliferator-Activated Receptor Delta Agonist, in Primary Biliary Cholangitis: 52-Week Analysis of an Ongoing International, Randomized, Dose Ranging Phase 2 Study - Bowlus, Christopher L.; Neff, Guy W.; Aspinall, Richard; Galambos, Michael R.; Goel, Aparna; Hirschfield, Gideon; Kremer, Andreas; Mayo, Marlyn J.; Swain, Mark Gordon; Borg, Brian; Doerffel, Yvonne; Gordon, Stuart C.; et al. (2018)
EVALuna2:207767

Efficacy and Safety of Telotristat Ethyl in Patients With Carcinoid Syndrome Inadequately Controlled by Somatostatin Analogs: Analysis of the Completed TELESTAR Extension Period - Hoersch, Dieter; Kulke, Matthew H.; Caplin, Martyn E.; Anthony, Lowell B.; Bergsland, Emily; Oberg, Kjell; Warner, Richard R. P.; Kunz, Pamela L.; Grande, Enrique; Valle, Juan W.; Dillon, Joseph S.; Lapuerta, Pablo; et al. (2018)
EVALuna2:34106

Efficacy and Toxicity of 5-Fluorouracil-Oxaliplatin in Gastroenteropancreatic Neuroendocrine Neoplasms - Merola, Elettra; Dal Buono, Arianna; Denecke, Timm; Arsenic, Ruza; Pape, Ulrich Frank; Jann, Henning; Wiedenmann, Bertram; Pavel, Marianne Ellen (Pancreas, 2020)
OBJECTIVES: The objective of this study was to investigate the efficacy and tolerability of 5-fluorouracil-oxaliplatin (FOLFOX) in advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). METHODS: Retrospective analysis of consecutive 72 advanced GEP-NENs treated with FOLFOX between 2005 and 2016 at a single German referral center for NENs was performed. We assessed treatment response by response evaluation criteria in solid tumors 1.0 criteria, progression-free survival by Kaplan-Meyer method, and risk factor analysis by Cox-regression model. RESULTS: Patients were 44.5% G1/G2, 55.5% G3, receiving a median of 7 treatment cycles (range, 2-21), and had a median of 18 months of follow-up (range, 3-111 months). Disease control was achieved in 75.0% of cases but 91.3% in the 23 patients receiving FOLFOX as first line (P = 0.04). Median progression-free survival of the overall population was 8 months. A better outcome was significantly related to treatment duration (P = 0.02) and grade of histological differentiation for G3 patients (well differentiated vs poorly differentiated, P = 0.03). Adverse events occurred in 88.8% of patients, mostly grade 1 and 2 hematotoxicity and chemotherapy-induced peripheral sensory neuropathy (84.1% and 50.0% of patients, respectively). CONCLUSIONS: Our results support FOLFOX as therapeutic option in advanced GEP-NENs with poor prognosis, either at first or further therapy line. Longer duration of therapy was associated with a more durable benefit.
CRIS-Team Scopus Importer:2020-07-31

Efficacy of GKT831 in patients with primary biliary cholangitis and inadequate response to ursodeoxycholic acid: Interim efficacy results of a phase 2 clinical trial - Dalekos, George; Invernizzi, Pietro; Nevens, Frederik; Hans, Van Vlierberghe; Zigmond, Ehud; Andrade, Raul J.; Ben Ari, Ziv; Heneghan, Michael; Huang, Jonathan; Harrison, Stephen; Minuk, Gerald; Joern, Schattenberg; et al. (JOURNAL OF HEPATOLOGY, 2019)
CRIS-Team WoS Importer:2019-05-07

EFFICACY OF HEMOSPRAY AND ENDOCLOT IN THE TREATMENT OF GASTROINTESTINAL BLEEDING: RESULTS FROM A TERTIARY REFFERAL CENTER - Vitali, Francesco; Naegel, Andreas; Neurath, Markus; Rath, Timo; Siebler, Jürgen (2018)
EVALuna2:35162

Efficacy of risankizumab rescue therapy in patients with moderately to severely active Crohn's Disease and inadequate response to risankizumab maintenance therapy - Baert, F. J.; Atreya, Raja; Kakuta, Y.; Long, M.; Roblin, X.; Neimark, E.; Song, A.; Wallace, K.; Kingys, K.; Mallick, M.; Liao, X.; Lim, A. (JOURNAL OF CROHNS & COLITIS, 2022)
Background The efficacy and safety of 12 weeks of induction and 52 weeks of maintenance treatment with risankizumab (RZB), an interleukin 23 p19 inhibitor, in patients with moderately to severely active Crohn’s disease (CD) was previously demonstrated in 3 phase 3 trials (ADVANCE, MOTIVATE, and FORTIFY). We investigated outcomes in patients with inadequate response to subcutaneous (SC) RZB or SC placebo (PBO) treatment and required RZB rescue therapy during maintenance. Methods In FORTIFY, a phase 3, double-blind, re-randomised responder withdrawal, maintenance study (NCT03105102), patients that responded to 12 weeks of RZB IV induction received RZB 180 mg SC, RZB 360 mg SC, or PBO (ie, withdrawal) every 8 weeks for 52 weeks. Starting at week 16, patients with inadequate response, defined as average daily stool frequency [SF] ≥ 3.3 and/or average daily abdominal pain score [APS] ≥ 1.5 as well as high-sensitivity C-reactive protein ≥ 5 mg/L and/or faecal calprotectin ≥ 250 μg/g; or Simple Endoscopic Score for CD (SES-CD) ≥ 6 (≥ 4 for isolated ileal disease), excluding the narrowing component as scored by the site Investigator, were eligible to receive open-label rescue therapy (1 dose of intravenous [IV] RZB 1200 mg, followed by RZB 360 mg SC every 8 weeks). Up to 2 rescue therapy visits ≥ 16 weeks apart were permitted. Efficacy at week 52 was assessed in the intent-to-treat population using nonresponder imputation for missing data. Patients were also considered nonresponders when maximum equivalent steroid dose exceeded the dose used at baseline or if patients initiated any new steroids. Safety was assessed throughout the study. Results In the maintenance study, a greater proportion of patients in the withdrawal (PBO SC) arm (40.2% [66/164]) were administered RZB rescue therapy vs RZB 180 mg SC (24.2% [38/157]) and RZB 360 mg SC (21.3% [30/141]; Figure A); most patients (71.1%–81.8%) required 1 rescue visit, and 16.7%–26.3% required 2 visits. Median time to first RZB rescue therapy was 178 days for the withdrawal (PBO SC) group, 179 days for the RZB 180 mg SC group, and 154 days for the RZB 360 mg SC group. At week 52, 52.5%–75.0% of patients who received RZB rescue therapy achieved SF/APS clinical response (Figure B), and 20.0–36.4% of patients who received rescue therapy achieved clinical remission (per CDAI or SF/APS) and/or endoscopic response (Figures C-E). The safety profile of RZB in CD has previously been reporte
CRIS-Team WoS Importer:2022-05-13

Efficacy of Upadacitinib Dose Escalation in a Phase 3 Long-Term Extension Ulcerative Colitis Study - Panaccione, Remo; Long, Millie; Ran, Zhihua; Atreya, Raja; Nakase, Hiroshi; Zhou, Wen; Yao, Xuan; Ilo, Dapo; D'Haens, Geert (AMERICAN JOURNAL OF GASTROENTEROLOGY, 2022)
CRIS-Team WoS Importer:2023-03-10

Efficacy, safety, and pharmacokinetics after switching from infliximab originator to biosimilar SB2 in inflammatory bowel disease patients: A long-term observational, prospective cohort study - Fischer, Sören; Mesfin, Sarah Ellen; Klenske, E.; Schmitt, Heike; Vitali, Francesco; Hirschmann, Simon; Ramming, A.; Zundler, Sebastian; Rath, Timo; Krebs, Sabine; Dörje, Frank; Uter, Wolfgang; et al. (JOURNAL OF CROHNS & COLITIS, 2020)
CRIS-Team WoS Importer:2020-04-10

Efficacy, safety and quality of life (QoL) with Lanreotide Autogel (LAN) 120 mg every 14 days in progressive pancreatic or midgut neuroendocrine tumors (NETs): CLARINET FORTE study results - Pavel, Marianne Ellen; Cwikla, J. B.; Lombard-Bohas, C.; Borbath,; Shah, T.; Pape, U. F.; Thanh, Truong X. M.; Houchard, A.; Ruszniewski, P. (JOURNAL OF NEUROENDOCRINOLOGY, 2021)
CRIS-Team WoS Importer:2021-03-12

Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome - Koumarianou, Anna; Daskalakis, Kosmas; Tsoli, Marina; Kaltsas, Gregory; Pavel, Marianne Ellen (Journal of Neuroendocrinology, 2022)
This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient. Although dose escalation of SSA remains an unapproved option, it is clinically implemented to alleviate symptoms in refractory carcinoid syndrome and supported by the most recent guidelines. The side effects associated with the increased dose are in general mild and consistent with standard dose of SSA. Telotristat ethyl, an oral inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, represents a rather novel innovative treatment option in patients with carcinoid syndrome suffering from diarrhea and complements the standard therapy of SSA. Given the low toxicity profile, TE may be considered an early add-on treatment to SSA in patients with uncontrolled carcinoid syndrome. However, further prolonged follow-up of patients treated with TE may be needed to exclude potential AEs, such as liver toxicity or depressed mood, in patients with long–term treatment. Interferon alpha is a cytokine with direct inhibitory effect on hormone secretion and tumor cell proliferation and an approved therapy in carcinoid syndrome but is associated with significant AEs in the majority of the patients requiring frequently dose reduction. The finding of a more favorable tolerability of pegylated interferon needs to be confirmed in a prospective study.
CRIS-Team Scopus Importer:2022-07-15
Keywords: alpha-interferon; carcinoid syndrome; medical therapy; neuroendocrine tumors; somatostatin analogues

Efficiency and Toxicity of Lenvatinib in Advanced HCC in Later Treatment Lines - Jefremow, Andre; Wiesmüller, Marco; Rouse, Rachel Amanda; Dietrich, Peter; Kremer, Andreas; Waldner, Maximilian; Neurath, Markus; Siebler, Jürgen (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Efficient and Easy Conversion of Human iPSCs into Functional Induced Microglia-like Cells - Lanfer, Jonas; Winner, Beate; Kaindl, Johanna; Krumm, Laura; Acera, Miguel Gonzalez; Neurath, Markus; Regensburger, Martin; Krach, Florian (International Journal of Molecular Sciences, 2022)
Current protocols converting human induced pluripotent stem cells (iPSCs) into induced microglia-like cells (iMGL) are either dependent on overexpression of transcription factors or require substantial experience in stem-cell technologies. Here, we developed an easy-to-use two-step protocol to convert iPSCs into functional iMGL via: (1) highly efficient differentiation of hematopoietic progenitor cells (HPCs) from iPSCs, and (2) optimized maturation of HPCs to iMGL. A sequential harvesting approach led to an increased HPC yield. The protocol implemented a freezing step, thus allowing HPC biobanking and flexible timing of differentiation into iMGL. Our iMGL responded adequately to the inflammatory stimuli LPS, and iMGL RNAseq analysis matched those of other frequently used protocols. Comparing three different coating modalities, we increased the iMGL yield by culturing on uncoated glass surfaces, thereby retaining differentiation efficiency and functional hallmarks of iMGL. In summary, we provide a high-quality, easy-to-use protocol, rendering generation and functional studies on iMGL an accessible lab resource.
CRIS-Team Scopus Importer:2022-04-29
Keywords: cell differentiation; immunology; microglia; neurology; pluripotent stem cells

EFSUMB Guidelines and Recommendations on the Clinical Use of Liver Ultrasound Elastography, Update 2017 (Short Version) - Dietrich, Christoph F.; Bamber, Jeffrey; Berzigotti, Annalisa; Bota, Simona; Cantisani, Vito; Castera, Laurent; Cosgrove, David; Ferraioli, Giovanna; Friedrich-Rust, Mireen; Gilja, Odd Helge; Görtz, Rüdiger; Karlas, Thomas; et al. (Ultraschall in der Medizin, 2017)
We present here the first update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use of elastography with a focus on the assessment of diffuse liver disease. The short version provides clinical information about the practical use of elastography equipment and interpretation of results in the assessment of diffuse liver disease and analyzes the main findings based on published studies, stressing the evidence from meta-analyses. The role of elastography in different etiologies of liver disease and in several clinical scenarios is also discussed. All of the recommendations are judged with regard to their evidence-based strength according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. This updated document is intended to act as a reference and to provide a practical guide for both beginners and advanced clinical users.
EVALuna2:34087

Einflussfaktoren auf die medizinisch-diagnostische Beurteilbarkeit des endoskopischen Videobildes bei digitaler real-time Datenübertragung (Gigabit Testbed Sued, Teilprojekt 1.15) - Maiß, Jürgen; Rabenstein, Thomas; Naegele-Jackson, Susanne; Radespiel-Tröger, Martin; Hengstenberg, Thomas; Holleczek, Peter; Hahn, Eckhart Georg; Sackmann, Michael (Endoskopie heute 2002, Thema Abstracts XXXII. Kongress der Deutschen Gesellschaft fuer Endoskopie, 2002)
UnivIS-Import:2015-04-14:Pub.2002.zwiss.rrze.ksys.einflu

Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis - Reissig, Sonja; Tang, Yilang; Nikolaev, Alexei; Gerlach, Katharina; Wolf, Christine; Davari, Kathrin; Gallus, Christian; Masri, Joumana; Mufazalov, Ilgiz A.; Neurath, Markus; Wunderlich, F. Thomas; Schattenberg, Joern M.; et al. (Nature Communications, 2017)
Bcl-3 is an atypical NF-κB family member that regulates NF-κB-dependent gene expression in effector T cells, but a cell-intrinsic function in regulatory T (Treg) cells and colitis is not clear. Here we show that Bcl-3 expression levels in colonic T cells correlate with disease manifestation in patients with inflammatory bowel disease. Mice with T-cell-specific overexpression of Bcl-3 develop severe colitis that can be attributed to defective Treg cell development and function, leading to the infiltration of immune cells such as pro-inflammatory γδT cells, but not αβ T cells. In Treg cells, Bcl-3 associates directly with NF-κB p50 to inhibit DNA binding of p50/p50 and p50/p65 NF-κB dimers, thereby regulating NF-κB-mediated gene expression. This study thus reveals intrinsic functions of Bcl-3 in Treg cells, identifies Bcl-3 as a potential prognostic marker for colitis and illustrates the mechanism by which Bcl-3 regulates NF-κB activity in Tregs to prevent colitis.
EVALuna2:33818

ElevatION: NET-201 A Phase II Study to Evaluate the Efficacy and Safety of PDR001 in Patients with Metastatic, Well-Differentiated NET of Pancreatic/GI/Thoracic Origin or Poorly-Differentiated GEP NEC Who Have Progressed on Prior Treatment - Yao, J. C.; Fazio, N.; Li, D.; Pavel, Marianne Ellen; Strosberg, J.; Bergsland, E.; Ruszniewski, P.; Voi, M.; Wu, C.; Degtyarev, E.; Aimone, P.; Singh, S. (2018)
EVALuna2:34122

Elexacaftor – Tezacaftor – Ivacaftor treatment improves systemic infection parameters and Pseudomonas aeruginosa colonization rate in patients with cystic fibrosis a monocentric observational study - Schnell, Alexander; Hober, Hannah; Kaiser, Natalie; Ruppel, Renate; Geppert, Annika; Tremel, Christina; Sobel, Julia; Plattner, Erika; Wölfle, Joachim; Hörning, André (Heliyon, 2023)
Background & aims: The CFTR-modulating therapy Elexaftor – Tezacaftor - Ivacaftor (ETI) has been widely prescribed since its approval in 2020 in the European Union. The aim of this study was to methodically evaluate the effects of an ETI treatment on clinical, biochemical data and Pseudomonas colonization in order to demonstrate its efficacy. Methods: This prospective monocentric study comprised 69 patients diagnosed with cystic fibrosis aged at least 12 years and treated with ETI between September 2020 and November 2021. Clinical and laboratory data of each patient and study visit were collected before and after 24 weeks of ETI treatment. Follow-up status of Pseudomonas aeruginosa (PsA) colonization was assessed after one year of therapy by regularly determined sputum or throat swab samples. Results: Marked improvements biochemical markers of systemic inflammation as white blood cell count, levels of immunoglobulins A, G and M and albumin within 24 weeks of therapy were observed. ETI treatment proved to be effective as seen by amelioration of lung function and sweat chloride concentration. Assessment of PsA colonization status revealed a conversion from a positive to negative detection in 36% of the cases after one year of therapy. Conclusions: ETI treatment effectively improves systemic inflammation parameters and shows promising results in PsA status conversion.
CRIS-Team Scopus Importer:2023-06-02
Keywords: CFTR modulator; Clinical data; Cystic fibrosis; Elexacaftor; ETI; Inflammation markers; Ivacaftor; Kaftrio; Tezacaftor

Emerging Histopathological and Genetic Parameters of Pituitary Adenomas: Clinical Impact and Recommendation for Future WHO Classification - Saeger, W.; Petersenn, S.; Schöfl, Christof; Knappe, U. J.; Theodoropoulou, M.; Buslei, R.; Honegger, J. (Endocrine Pathology, 2016)
The review assesses immunohistochemical findings of somatostatin receptors and of metalloproteinases in different pituitary adenoma types and the significance of molecular genetic data. Current evidence does not support routine immunohistochemical assessment of somatostatin or dopamine receptor subtype expression on hormone-secreting or nonfunctioning pituitary adenomas. Further prospective studies are needed to define its role for clinical decision making. Until then we suggest to restrict membrane receptor profiling to individual cases or for study purposes. The problems of adenoma expansion and invasion are discussed. Despite partially contradictory publications, proteases clearly play a major role in permission of infiltrative growth of pituitary adenomas. Therefore, detection of at least MMP-2, MMP-9, TIMP-2, and uPA seems to be justified. Molecular characterization is important for familial adenomas, adenomas in MEN, Carney complex, and McCune-Albright syndrome and can gain insight into pathogenesis of sporadic adenomas.
EVALuna2:7324

Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges - Vetter, Marcel; Neurath, Markus (Therapeutic Advances in Gastroenterology, 2017)
To improve quality of life and prevent long-term risks in patients with inflammatory bowel diseases (IBDs: Crohn's disease, ulcerative colitis), it is essential to suppress inflammatory activity adequately. However, corticosteroids are only suitable for therapy of acute flares and the evidence for positive effects of immunosuppressive substances like azathioprine or 6-mercapropurine is mainly limited to maintenance of remission. In addition, only subgroups of patients benefit from biologicals targeting tumour necrosis factor α or α4β7 integrins. In summary, until now the disease activity is not sufficiently controlled in a relevant fraction of the patients with IBD. Thus, there is an urge for the development of new substances in the therapy of ulcerative colitis and Crohn's disease. Fortunately, new oral and parenteral substances are in the pipeline. This review will focus on oral substances, which have already passed phase II studies successfully at this stage. In this article, we summarize data regarding AJM300, phosphatidylcholine (LT-02), mongersen, ozanimod, filgotinib and tofacitinib. AJM300 and ozanimod were tested in patients with ulcerative colitis and target lymphocyte trafficking through inhibition of the α subunit of integrin, respectively binding to the sphingosine-1-phosphate receptor (subtypes 1 and 5) on lymphocytes. Mongersen was utilized in patients with Crohn's disease and accelerates the degradation of SMAD7 mRNA, which consequently strengthens the mainly anti-inflammatory signalling pathway of transforming growth factor β1. Various Janus kinase (JAK) inhibitors were developed, which inhibit the intracellular signalling pathway of cytokines. For example, the JAK1 blocker filgotinib was tested in Crohn's disease, whereas the JAK1/3 inhibitor tofacitinib was tested in clinical trials for both Crohn's disease and ulcerative colitis. A different therapeutic approach is the substitution of phosphatidylcholine (LT-02), which might recover the colonic mucus. Taken together, clinical trials with these new agents have opened avenues for further clinical studies and it can be expected that at least some of these agents will be finally approved for clinical therapy.
EVALuna2:33802

Endocytoscopy for assessing histologic inflammation in ulcerative colitis: development and prospective validation of the ELECT (ErLangen Endocytoscopy in ColiTis) score (with videos) - Vitali, Francesco; Morgenstern, Nadine; Eckstein, Markus; Atreya, Raja; Waldner, Maximilian; Hartmann, Arndt; Neurath, Markus; Rath, Timo (Gastrointestinal Endoscopy, 2022)
Background and Aims: Apart from endoscopic healing as an established treatment goal in patients with inflammatory bowel disease (IBD), histologic remission is an emerging endpoint that might even better predict disease outcome, especially in ulcerative colitis (UC). Within this study, we aimed to evaluate whether endocytoscopy (EC) as an in vivo contact microscopy technology can accurately assess histologic inflammation and predict the further course of disease in UC patients. Methods: Initially, a new and intuitive EC score reflecting the entire spectrum of microscopic disease activity in UC was consensually developed. Subsequently, this score was independently validated in 46 patients with UC who underwent close-meshed follow-up during which major adverse outcomes (MAOs; defined as disease flare, IBD-related hospitalization, IBD-related surgery, necessity for initiation or escalation therapy) were recorded. Results of EC grading of inflammatory activity were compared against 2 validated histologic scores in UC. Diagnostic performance of endoscopic remission under white-light endoscopy (Mayo Endoscopic Score and Ulcerative Colitis Endoscopic Index of Severity), EC, and histology were compared for the prediction of MAOs. Results: Endocytoscopic assessment of inflammatory activity in UC based on the newly developed ErLangen Endocytoscopy in ColiTis score showed strong correlation with histopathologic scoring (Robarts Histopathology Index, r = .70; Nancy Histologic Index, r = .73) and was superior to white-light endoscopy for grading of microscopic disease activity, with a sensitivity of 88%, specificity of 95.2%, and area under the curve of .916. Furthermore, EC exhibited a high interobserver agreement for in vivo grading of microscopic inflammation and was comparably accurate as histopathology for forecasting the occurrence of MAOs in UC. Conclusions: Endocytoscopic grading of inflammatory activity along a newly developed scoring system enabled real-time histology in UC patients and better predicted clinical outcome in UC patients than endoscopic remission.
CRIS-Team Scopus Importer:2022-12-16

Endogenous Opioid Levels Do Not Correlate With Itch Intensity and Therapeutic Interventions in Hepatic Pruritus - Düll, Miriam; Wolf, Katharina; Vetter, Marcel; Dietrich, Peter; Neurath, Markus; Kremer, Andreas (Frontiers in Medicine, 2021)
Background: Chronic pruritus affects up to 70% of patients with immune-mediated hepatobiliary disorders. Antagonists of the μ-opioid receptor (MOR) and agonists of the κ-opioid receptor (KOR) are used to treat hepatic itch, albeit with limited success. An imbalance between ligands of MOR and KOR receptors has recently been suggested as a potential mechanism of hepatic pruritus. In this study, we therefore investigated systemic levels of important endogenous opioids such as β-endorphin, dynorphin A, Leu- and Met-enkephalin in plasma of a large cohort of well-characterized patients with immune-mediated cholestatic disorders, including patients with liver cirrhosis, and during effective anti-pruritic therapy. Methods: Plasma samples and clinical data were prospectively collected from well-characterized patients with primary/secondary sclerosing cholangitis (PSC/SSC), primary biliary cholangitis (PBC) and overlap syndromes suffering from pruritus (n = 29) and age-, gender- and disease-matched controls without pruritus (n = 27) as well as healthy controls (n = 20). General laboratory testing for hepatobiliary and renal function was performed. Levels of β-endorphin, dynorphin A, Leu- and Met-enkephalin were quantified in plasma by ELISA. Intensity of pruritus over the last week was evaluated using a visual analog scale (VAS, 0–10). Results: PBC and PSC patients with or without pruritus did neither differ in disease entity, disease stage, nor in the presence of cirrhosis. While both dynorphin A and β-endorphin concentrations were lower in pruritic patients compared to those without pruritus and healthy controls, the MOR/KOR ligand ratio was unaltered. No significant differences were observed for Leu- and Met-enkephalin concentrations. Opioid levels correlated with neither itch intensity nor stage of disease. Cirrhotic patients displayed higher concentrations of MOR agonist Leu-enkephalin and KOR agonist dynorphin A. Endogenous opioid levels remained largely unchanged after successful treatment with the potent anti-pruritic drugs rifampicin and bezafibrate. Conclusions: Endogenous opioid levels and the MOR/KOR ligand ratio neither correlate with itch intensity nor differentiate pruritic from non-pruritic patients with immune-mediated liver diseases. Thus, endogenous opioids may modulate signaling pathways involved in hepatic pruritus, but are unlikely to represent the major pruritogens in liver disease.
CRIS-Team Scopus Importer:2021-05-14
Keywords: bezafibrate; cholestasis; dynorphin; endorphin; enkephalin; liver; rifampicin; therapy

Endoscopic classification for colorectal tumors using narrow-band imaging - Tontini, Gian Eugenio; Neumann, Helmut (Digestive Endoscopy, 2016)
EVALuna2:2159

ENDOSCOPIC FULL-THICKNESS RESECTION IN THE COLORECTUM USING THE FTRD: RESULTS FROM A UNIVERSITY TERTIARY REFERRAL CENTER - Vitali, Francesco; Naegel, Andreas; Neurath, Markus; Rath, Timo; Siebler, Jürgen (2018)
EVALuna2:35163

Endoscopic management of buried bumper syndrome using a novel grasping-type scissor forceps - Rath, Timo; Vitali, Francesco; Naegel, Andreas; Neurath, Markus (Endoscopy, 2021)
CRIS-Team WoS Importer:2021-01-29

Endoscopic recanalization of complete esophageal obstruction - Vitali, Francesco; Naegel, Andreas; Pfeifer, Lukas; Goetz, Martin; Neurath, Markus; Rath, Timo; Siebler, Jürgen (Surgical Endoscopy, 2021)
Background and aims Complete esophageal obstruction (CEO) is a rare complication after radiochemotherapy that dramatically impairs quality of life. Within this study, we assessed the outcome of two different endoscopic techniques for lumen restoration in patients with CEO.
CRIS-Team WoS Importer:2021-02-26

Endoscopic remission assessed with PICaSSO virtual electronic chromendoscopy accurately predicts clinical outcomes in ulcerative colitis - Nardone, Olga Maria; Bazarova, Alina; Bhandari, Pradeep; Cannatelli, Rosanna; Daperno, Marco; Ferraz, Jose; Goetz, Martin; Gui, Xianyong; Hayee, Bu; De Hertogh, Gert; Lazarev, Mark; Li, Ji; et al. (United European Gastroenterology Journal, 2022)
Background and Aims: A composite endoscopic-histologic remission is increasingly explored as an important endpoint in ulcerative colitis (UC). We investigated combined endoscopic-histologic remission for predicting clinical outcomes at 12 months compared with endoscopic remission alone using the high definition virtual chromoendoscopy (VCE) Paddington International virtual ChromoendoScopy ScOre (PICaSSO) and histology scores. Methods: Ulcerative colitis patients, prospectively enrolled from 11 international centres, underwent VCE with targeted biopsies and followed up for 12 months. Endoscopic activity was assessed by Mayo Endoscopic Score (MES), Ulcerative Colitis Endoscopic Index Severity (UCEIS) followed by VCE-PICaSSO. Robarts Histopathological Index|Robarts Histological index≤3 without neutrophils in mucosa, and Nancy Histological index (NHI)≤ 1 were used to define histologic remission. Combined endoscopic-histologic remission was compared with endoscopic remission alone by Cox proportional hazards model and by two- and three-proportion analysis using pre-specified clinical outcomes. Results: 307 patients were recruited and 302 analysed. There was no difference in survival without specified clinical outcomes between PICaSSO defined endoscopic remission alone and endoscopic plus histologic remission in the rectum (HR 0.42, 95%CI 0.16-1.11 and HR 1.03, 95%CI 0.42-2.52 for Robarts Histological index and NHI respectively) at 12 months. There was however a significant survival advantage without specified clinical outcome events for UCEIS combined with histology compared with UCEIS alone (HR 0.30, 95%CI 0.12-0.75, p = 0.02) at 12 months (but not combined with NHI). For MES there was no advantage for predicting specified clinical outcomes at 12 months for endoscopy alone versus endoscopy plus histology, but there were differences in two and three proportion analysis at 6 months. Conclusion: Endoscopic remission by VCE-PICaSSO alone was similar to combined endoscopic and histologic remission for predicting specified clinical outcomes at 12 months. Larger studies with specific therapeutic interventions are required to further confirm the findings.
CRIS-Team Scopus Importer:2022-03-04
Keywords: endoscopic remission; histological remission; mucosal healing; ulcerative colitis; virtual electronic chromoendoscopy - PICaSSO – clinical outcomes – prediction

Endoscopic scoring systems for inflammatory bowel disease: pros and cons - Tontini, Gian Eugenio; Bisschops, Raf; Neumann, Helmut (Expert Review of Gastroenterology and Hepatology, 2014)
Endoscopy plays a pivotal role for diagnosis and assessment of disease activity and extent in patients with inflammatory bowel diseases. International guidelines recommend the use of endoscopic scoring systems for evaluation of the prognosis and efficacy of medical treatments. Ideal scoring systems are easy to use, reproducible, reliable, responsive to changes, and validated in different clinical settings in order to guide therapeutic strategies. However, currently available endoscopic scoring systems often appear as complex for routine endoscopy and suffer from insufficient interobserver agreement and lack of formal validation which often limit their use in clinical trials. Here, we describe the role of endoscopic scoring systems in inflammatory bowel diseases focusing on pros and cons in the era of advanced endoscopic imaging and mucosal healing.
EVALuna2:1894

Endoscopic Submucosal Dissection in the distal Anorectum: Effectiveness, Safety and unexpected Side Effects, and the Need for comprehensive Patient Information - Raithel, Martin; Hagel, Alexander; Anneken, Andrea; Albrecht, Heinz; Vitali, Francesco; Bruetting, Alfred (INTERNIST, 2019)
CRIS-Team WoS Importer:2019-05-17

Endoscopic therapy of Zenker's diverticulum using a novel endoscopic scissor - the Clutch Cutter device - Neumann, Helmut; Loeffler, Silke; Rieger, Stefanie; Kretschmer, Claudia; Naegel, Andreas (Endoscopy, 2015)
EVALuna2:2014

Endoscopic Ultrasound in Pancreatology: Focus on Inflammatory Diseases and Interventions - Vitali, Francesco; Zundler, Sebastian; Jesper, Daniel; Strobel, Deike; Wildner, Dane; De Pretis, Nicoló; Frulloni, Luca; Crinó, Stefano Francesco; Neurath, Markus (Visceral Medicine, 2023)
Background: Endoscopic ultrasound (EUS) is a main tool in pancreatology for both diagnosis and therapy. It allows minimally invasive differentiation of various diseases, with a minimal degree of inflammation or anatomic variations. EUS also enables interventional direct access to the pancreatic parenchyma and the retroperitoneal space, the pancreatic duct, the pancreatic masses, cysts, vascular structures for diagnostic and therapeutic purposes. Summary: This review aimed to summarize the new developments of EUS in the field of pancreatology, with special interest on inflammation and interventions. EUS enables way to perform pseudocyst drainage, necrosectomy, transenteral drainage and transenteric access of the main pancreatic duct, or the direct visualization or therapy of vascular structures adjacent to the pancreas. Key Messages: EUS has a deep impact on pancreatology, and the development of new diagnostic and interventional approaches to the retroperitoneal space and the pancreas has increased in the last years exponentially, allowing minimal invasive diagnostics and therapy and avoiding surgery and percutaneous therapy.
CRIS-Team Scopus Importer:2023-09-29
Keywords: Endoscopic ultrasound; Endoscopic ultrasound-guided biopsy; Endoscopic ultrasound-guided drainage; Pancreatic cancer; Pancreatitis

Endoscopy as a Diagnostic Tool for Personalized Therapy in IBD: Prediction of Response to Biological Therapy - Atreya, Raja (Drug Research, 2021)
CRIS-Team WoS Importer:2021-12-03

Endoscopy: Chromoendoscopy in IBD: indispensable in real-life screening - Atreya, Raja; Neurath, Markus (Nature Reviews Gastroenterology & Hepatology, 2016)
Long-standing IBD is associated with an increased risk of neoplasia. Chromoendoscopy was proven to be the most sensitive modality for dysplasia detection in several clinical trials, but a new study has now shown ityto be an effective screening strategy in a routine clinical setting, further warranting its implementation into real-world practice.
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ENETS consensus guidelines for synoptic reporting of radiology studies - Dromain, Clarisse; Vullierme, Marie-Pierre; Hicks, Rodney J.; Prasad, Vikas; O'Toole, Dermot; De Herder, Wouter W.; Pavel, Marianne Ellen; Faggiano, Antongiulio; Kos-Kudla, Beata; Oberg, Kjell; Krejs, Guenter J.; Grande, Enrique; et al. (Journal of Neuroendocrinology, 2021)
This expert consensus document represents an initiative by the European Neuroendocrine Tumor Society (ENETS) to provide guidance for synoptic reporting of radiological examinations critical to the diagnosis, grading, staging and treatment of neuroendocrine neoplasms (NENs). Template drafts for initial tumor staging and follow-up by computed tomography (CT) and magnetic resonance imaging (MRI) were established, based on existing institutional and organisational reporting templates relevant for NEN imaging, and applying the RadLex lexicon of radiological information (Radiological Society of North America), for consistency regarding the radiological terms. During the ENETS Scientific Advisory Board meeting 2018, the template drafts were subject to iterative interdisciplinary discussions among experts in imaging, surgery, gastroenterology, oncology and pathology. Members of the imaging group stated a strong preference for a combination of limited and standardised options by way of drop-down menus. Separate templates were produced for the initial work-up and for follow-up, respectively. To provide a detailed description of the radiological findings of the primary tumor and its local extension and spread, different templates were developed for bronchial, pancreatic and gastrointestinal NENs for CT and MRI, respectively. Each template was structured in 10 sections: clinical details, comparative imaging modality, acquisition technique, primary tumor findings, regional lymph node metastases, distant metastases, TNM classification, reference lesions according to RECIST 1.1, additional findings and conclusion. Two templates were developed for follow-up, for CT and MRI, respectively, and were specifically focused on assessment of therapy response. These included a qualitative response assessment, such as decrease of vascularisation and presence of necrosis, and a quantitative assessment according to RECIST 1.1 and the modified RECIST (mRECIST) for assessing tumor response following transarterial chemoembolisation.
CRIS-Team Scopus Importer:2021-11-05
Keywords: CT; MRI; neuroendocrine neoplasia; synoptic reporting

Enteroendocrine cells are a potential source of serum autotaxin in men - Bolier, Ruth; Tolenaars, Dagmar; Kremer, Andreas; Saris, Job; Pares, Albert; Verheij, Joanne; Bosma, Piter J.; Beuers, Ulrich; Elferink, Ronald P. J. Oude (BBA - Biochimica et Biophysica Acta, 2016)
Serum autotaxin (ATX) activity is significantly increased in cholestatic patients. Our study aimed to unravel the source(s) of ATX in cholestasis.ATX activity and protein were measured in sera of healthy (n=33) and cholestatic patients (n=152), including women with intrahepatic cholestasis of pregnancy. ATX mRNA and protein expression were analyzed in various tissues from mice and men. Induction of ATX activity was assessed in mouse models of extrahepatic (bile duct ligation) and intrahepatic cholestasis (Atp8b1(G308V/G308V), 0.1% cholate-supplemented diet). ATX clearance in cholestatic and control mice was assessed after intravenous injection of recombinant ATX. Human hepatic clearance was estimated by comparing ATX activity in portal and hepatic vein serum.Serum ATX activity and ATX protein concentration tightly correlated under all conditions in patients and controls (p<0.0001). In humans Atx mRNA was highly expressed in small intestine, whereas in mice Atx was expressed mainly in brain and placenta but not in small intestine. Extensive ATX protein expression was identified in human, but not murine intestinal enteroendocrine cells. In murine models of cholestasis and cholestatic pregnancy plasma ATX activity was only mildly elevated (up to 2.1-fold). Atx tissue expression and rATX clearance after parenteral administration did not differ between cholestatic and control mice.Serum ATX activity during cholestasis and itch is enhanced by increased protein concentration rather than enzymatic induction. In mice, clearance of ATX is not affected by cholestasis. Small intestinal ATX expression by enteroendocrine cells might represent an important source of cholestasis-induced serum ATX activity in men.
EVALuna2:2087

Environmental Microbial Factors Determine the Pattern of Inflammatory Lesions in a Murine Model of Crohn's Disease-Like Inflammation - Stolzer, Iris; Kaden-Volynets, Valentina; Ruder, Barbara; Letizia, Marilena; Bittel, Miriam; Rausch, Philipp; Basic, Marijana; Bleich, André; Baines, John F.; Neurath, Markus; Wirtz, Stefan; Weidinger, Carl; et al. (Inflammatory Bowel Diseases, 2019)
Crohn's disease (CD) patients can be grouped into patients suffering from ileitis, ileocolitis, jejunoileitis, and colitis. The pathophysiological mechanism underlying this regional inflammation is still unknown. Although most murine models of inflammatory bowel disease (IBD) develop inflammation in the colon, there is an unmet need for novel models that recapitulate the spontaneous and fluctuating nature of inflammation as seen in CD. Recently, mice with an intestinal epithelial cell-specific deletion for Caspase-8 (Casp8ΔIEC mice), which are characterized by cell death-driven ileitis and disrupted Paneth cell homeostasis, have been identified as a novel model of CD-like ileitis. Here we uncovered that genetic susceptibility alone is sufficient to drive ileitis in Casp8ΔIEC mice. In sharp contrast, environmental factors, such as a disease-relevant microbial flora, determine colonic inflammation. Accordingly, depending on the microbial environment, isogenic Casp8ΔIEC mice either exclusively developed ileitis or suffered from pathologies in several parts of the gastrointestinal tract. Colitis in these mice was characterized by massive epithelial cell death, leading to spread of commensal gut microbes to the extra-intestinal space and hence an aberrant activation of the systemic immunity. We further uncovered that Casp8ΔIEC mice show qualitative and quantitative changes in the intestinal microbiome associated with an altered mucosal and systemic immune response. In summary, we identified that inflammation in this murine model of CD-like inflammation is characterized by an immune reaction, presumably directed against a disease-relevant microbiota in a genetically susceptible host, with impaired mucosal barrier function and bacterial clearance at the epithelial interface.
Keywords: Crohn’s disease; Paneth cells; cell death; colitis; ileitis; microflora

Environmental triggers in IBD: a review of progress and evidence - Ananthakrishnan, Ashwin N.; Bernstein, Charles N.; Iliopoulos, Dimitrios; Macpherson, Andrew; Neurath, Markus; Ali, Raja A. Raja; Vavricka, Stephan R.; Fiocchi, Claudio (Nature Reviews Gastroenterology & Hepatology, 2018)
A number of environmental factors have been associated with the development of IBD. Alteration of the gut microbiota, or dysbiosis, is closely linked to initiation or progression of IBD, but whether dysbiosis is a primary or secondary event is unclear. Nevertheless, early-life events such as birth, breastfeeding and exposure to antibiotics, as well as later childhood events, are considered potential risk factors for IBD. Air pollution, a consequence of the progressive contamination of the environment by countless compounds, is another factor associated with IBD, as particulate matter or other components can alter the host's mucosal defences and trigger immune responses. Hypoxia associated with high altitude is also a factor under investigation as a potential new trigger of IBD flares. A key issue is how to translate environmental factors into mechanisms of IBD, and systems biology is increasingly recognized as a strategic tool to unravel the molecular alterations leading to IBD. Environmental factors add a substantial level of complexity to the understanding of IBD pathogenesis but also promote the fundamental notion that complex diseases such as IBD require complex therapies that go well beyond the current single-agent treatment approach. This Review describes the current conceptualization, evidence, progress and direction surrounding the association of environmental factors with IBD.
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Eosinophilic gastroenteritis with refractory ulcer disease and gastrointestinal bleeding as a rare manifestation of seronegative gastrointestinal food allergy - Raithel, Martin; Hahn, Markus; Donhuijsen, Konrad; Hagel, Alexander; Nagel, Andreas; Rieker, Ralf J.; Neurath, Markus; Reinshagen, Max (Nutrition Journal, 2014)
Gastrointestinal bleeding and iron deficiency anaemia may cause severe symptoms and may require extensive diagnostics and substantial amounts of health resources.This case report focuses on the clinical presentation of a 22 year old patient with recurrent gastrointestinal bleeding from multilocular non-healing ulcers of the stomach, duodenum and jejunum over a period of four years. Extensive gastroenterological and allergological standard diagnostic procedures showed benign ulcerative lesions with tissue eosinophilia, but no conclusive diagnosis. Multiple diagnostic procedures were performed, until finally, endoscopically guided segmental gut lavage identified locally produced, intestinal IgE antibodies by fluoro-enzyme-immunoassay.IgE antibody concentrations at the intestinal level were found to be more-fold increased for total IgE and food-specific IgE against nuts, rye flour, wheat flour, pork, beef and egg yolk compared with healthy controls.Thus, a diet eliminating these allergens was introduced along with antihistamines and administration of a hypoallergenic formula, which resulted in complete healing of the multilocular ulcers with resolution of gastrointestinal bleeding. All gastrointestinal lesions disappeared and total serum IgE levels dropped to normal within 9 months. The patient has been in remission now for more than two years.Eosinophilic gastroenteritis (EG) is well known to induce refractory ulcer disease. In this case, the mechanisms for intestinal damage and gastrointestinal bleeding were identified as local gastrointestinal type I allergy. Therefore, future diagnostics in EG should also be focused on the intestinal level as identification of causative food-specific IgE antibodies proved to be effective to induce remission in this patient.
EVALuna2:1913

Epithelial Cell Detection in Endomicroscopy Images of the Vocal Folds - Mualla, Firas; Schöll, Simon; Bohr, Christopher; Neumann, Helmut; Maier, Andreas (Springer Proceedings in Physics 154, Proceedings of InterM, 2014)
UnivIS-Import:2015-04-16:Pub.2014.tech.IMMD.IMMD5.epithe

Epithelial HIF2 alpha expression induces intestinal barrier dysfunction and exacerbation of arthritis - Wen, Jinming; Lyu, Pang; Stolzer, Iris; Xu, Jin; Gießl, Andreas; Lin, Zhen; Andreev, Darja; Kachler, Katerina; Song, Rui; Meng, Xianyi; Cao, Shan; Guggino, Giuliana; et al. (Annals of the Rheumatic Diseases, 2022)
To investigate how the mucosal barrier in the intestine influences the development of arthritis, considering that metabolic changes in the intestinal epithelium influence its barrier function. Intestinal HIF2α expression peaked at onset of experimental arthritis and RA. Conditionally, deletion of HIF2α in gut epithelial cells inhibited arthritis and was associated with improved intestinal barrier function and less intestinal and lymphatic Th1 and Th17 activation. Mechanistically, HIF2α induced the transcription of the pore-forming claudin (CLDN)-15, which inhibits intestinal barrier integrity. Furthermore, treatment with HIF2α inhibitor decreased claudin-15 expression in epithelial cells and inhibited arthritis and littermate control mice. The gut intestinal HIF2α target genes were delineated by chromatin immunoprecipitation and luciferase experiments. Furthermore, pharmacological HIF2α inhibitor PT2977 was used for inhibition of arthritis. These findings show that the HIF2α-CLDN15 axis is critical for the breakdown of intestinal barrier function at onset of arthritis, highlighting the functional link between intestinal homeostasis and arthritis.
CRIS-Team WoS Importer:2022-07-01
Keywords: Arthritis; Arthritis; Experimental; Inflammation.

Epithelial presenilin-1 drives colorectal tumour growth by controlling EGFR-COX2 signalling - Gámez Belmonte, Maria de los Reyes; Mahapatro, Mousumi; Erkert, Lena; Gonzalez Acera, Miguel; Naschberger, Elisabeth; Yu, Yuqiang; Tena-Garitaonaindia, Mireia; Patankar, Jay; Wagner, Yara; Podstawa, Eva; Schoedel, Lena; Bubeck, Marvin; et al. (Gut, 2022)
Objective Psen1 was previously characterised as a crucial factor in the pathogenesis of neurodegeneration in patients with Alzheimer's disease. Little, if any, is known about its function in the gut. Here, we uncovered an unexpected functional role of Psen1 in gut epithelial cells during intestinal tumourigenesis. Design Human colorectal cancer (CRC) and control samples were investigated for PSEN1 and proteins of the gamma-secretase complex. Tumour formation was analysed in the AOM-DSS and Apc (min/+) mouse models using newly generated epithelial-specific Psen1 deficient mice. Psen1 deficient human CRC cells were studied in a xenograft tumour model. Tumour-derived organoids were analysed for growth and RNA-Seq was performed to identify Psen1-regulated pathways. Tumouroids were generated to study EGFR activation and evaluation of the influence of prostanoids. Results PSEN1 is expressed in the intestinal epithelium and its level is increased in human CRC. Psen1-deficient mice developed only small tumours and human cancer cell lines deficient in Psen1 had a reduced tumourigenicity. Tumouroids derived from Psen1-deficient Apc (min/+) mice exhibited stunted growth and reduced cell proliferation. On a molecular level, PSEN1 potentiated tumour cell proliferation via enhanced EGFR signalling and COX-2 production. Exogenous administration of PGE(2) reversed the slow growth of PSEN1 deficient tumour cells via PGE(2) receptor 4 (EP4) receptor signalling. Conclusions Psen1 drives tumour development by increasing EGFR signalling via NOTCH1 processing, and by activating the COX-2-PGE(2) pathway. PSEN1 inhibition could be a useful strategy in treatment of CRC.
CRIS-Team WoS Importer:2022-11-04

Epithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammation - Martínez Sánchez, Luz del Carmen; Phuong Anh Ngo,; Pradhan, Rashmita; Becker, Lukas S; Böhringer, David; Soteriou, Despina; Kubankova, Marketa; Schweitzer, Christine; Koch, Tatyana; Thonn, Veronika; Erkert, Lena; Stolzer, Iris; et al. (Gut, 2022)
Objective Increased apoptotic shedding has been linked to intestinal barrier dysfunction and development of inflammatory bowel diseases (IBD). In contrast, physiological cell shedding allows the renewal of the epithelial monolayer without compromising the barrier function. Here, we investigated the role of live cell extrusion in epithelial barrier alterations in IBD. Design Taking advantage of conditional GGTase and RAC1 knockout mice in intestinal epithelial cells (Pggt1b (i Delta IEC) and Rac1 (i Delta IEC) mice), intravital microscopy, immunostaining, mechanobiology, organoid techniques and RNA sequencing, we analysed cell shedding alterations within the intestinal epithelium. Moreover, we examined human gut tissue and intestinal organoids from patients with IBD for cell shedding alterations and RAC1 function. Results Epithelial Pggt1b deletion led to cytoskeleton rearrangement and tight junction redistribution, causing cell overcrowding due to arresting of cell shedding that finally resulted in epithelial leakage and spontaneous mucosal inflammation in the small and to a lesser extent in the large intestine. Both in vivo and in vitro studies (knockout mice, organoids) identified RAC1 as a GGTase target critically involved in prenylation-dependent cytoskeleton dynamics, cell mechanics and epithelial cell shedding. Moreover, inflamed areas of gut tissue from patients with IBD exhibited funnel-like structures, signs of arrested cell shedding and impaired RAC1 function. RAC1 inhibition in human intestinal organoids caused actin alterations compatible with arresting of cell shedding. Conclusion Impaired epithelial RAC1 function causes cell overcrowding and epithelial leakage thus inducing chronic intestinal inflammation. Epithelial RAC1 emerges as key regulator of cytoskeletal dynamics, cell mechanics and intestinal cell shedding. Modulation of RAC1 might be exploited for restoration of epithelial integrity in the gut of patients with IBD.
CRIS-Team WoS Importer:2022-03-25

Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine - Chen, Yong; Wang, Zi Long; Yeo, Michele; Zhang, Qiao Juan; López-Romero, Ana E.; Ding, Hui Ping; Zhang, Xin; Zeng, Qian; Morales-Lázaro, Sara L.; Moore, Carlene; Jin, Ying Ai; Yang, Huang He; et al. (Gastroenterology, 2021)
Background & Aims: Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of antipruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus. Methods: Pruritogenicity of lysophosphatidylcholine (LPC), LPA's precursor, was examined in naïve mice, cholestatic mice, and nonhuman primates. LPC's pruritogenicity involving keratinocyte TRPV4 was studied using genetic and pharmacologic approaches, cultured keratinocytes, ion channel physiology, and structural computational modeling. Activation of pruriceptor sensory neurons by microRNA-146a (miR-146a), secreted from keratinocytes, was identified by in vitro and ex vivo Ca2+ imaging assays. Sera from patients with primary biliary cholangitis were used for measuring the levels of LPC and miR-146a. Results: LPC was robustly pruritic in mice. TRPV4 in skin keratinocytes was essential for LPC-induced itch and itch in mice with cholestasis. Three-dimensional structural modeling, site-directed mutagenesis, and channel function analysis suggested a TRPV4 C-terminal motif for LPC binding and channel activation. In keratinocytes, TRPV4 activation by LPC induced extracellular release of miR-146a, which activated TRPV1+ sensory neurons to cause itch. LPC and miR-146a levels were both elevated in sera of patients with primary biliary cholangitis with itch and correlated with itch intensity. Moreover, LPC and miR-146a were also increased in sera of cholestatic mice and elicited itch in nonhuman primates. Conclusions: We identified LPC as a novel cholestatic pruritogen that induces itch through epithelia-sensory neuron cross talk, whereby it directly activates skin keratinocyte TRPV4, which rapidly releases miR-146a to activate skin-innervating TRPV1+ pruriceptor sensory neurons. Our findings support the new concept of the skin, as a sensory organ, playing a critical role in cholestatic itch, beyond liver, peripheral sensory neurons, and central neural pathways supporting pruriception.
CRIS-Team Scopus Importer:2021-07-02
Keywords: Cholestatic Itch; Keratinocyte TRPV4; Lysophosphatidylcholine; miR-146a; TRPV1 Pruriceptor

ERCP with the overtube-assisted enteroscopy technique: a systematic review - Skinner, Matthew; Popa, Daniel; Neumann, Helmut; Wilcox, C. Mel; Moenkemueller, Klaus (Endoscopy, 2014)
Overtube-assisted enteroscopy (OAE) techniques have increased the ability to perform endoscopic retrograde cholangiopancreatography (ERCP) in patients with altered upper gastrointestinal anatomy, such as Roux-en-Y gastric bypass. The aim of this study was to compare the efficacy and safety of OAE-ERCP in patients with different configurations of upper gastrointestinal anatomy.A systematic review was performed following a literature search for papers published between 1966 and August 2013. The following databases were searched: MEDLINE (via PubMed), Embase, Cochrane library, and Scopus. The following end points were analyzed: diagnostic and therapeutic success rates, cannulation success rate, ERCP success rate, type of enteroscopy, types of intervention, complications.A total of 23 relevant reports on OAE procedures, including single-balloon, double-balloon, and spiral enteroscopy, were analyzed. Studies included a total of 945 procedures in 679 patients (age 2 - 91 years) who had a variety of postsurgical upper gastrointestinal anatomical configurations. Among patients who underwent Roux-en-Y with gastric bypass, endoscopic success was 80 % and ERCP success was 70 %. In patients who had undergone a Roux-en-Y with either a pancreaticoduodenectomy, pylorus-preserving pancreaticoduodenectomy, or hepaticojejunostomy, endoscopic success was 85 % and ERCP success was 76 %. In patients who had undergone a Billroth II procedure, endoscopic success was 96 % and ERCP success was 90 %. In patients with native papilla who underwent successful endoscopy, cannulation was successful in 90 % of patients compared with 92 % in patients with an anastomosis. Overall ERCP success for all attempts was approximately 74 %. Interventions included sphincterotomy, pre-cut papillotomy, anastomotic stricturoplasty, stone removal, stent insertion, stent replacement, and balloon dilation of stenotic anastomosis. There were 32 major complications among the 945 procedures (3.4 %).Both endoscopic and ERCP success rates were highest in patients with Billroth II anatomy, followed by those with pancreaticoduodenectomy and Roux-en-Y hepaticojejunostomy; the lowest success rates were in patients with Roux-en-Y gastric bypass. Cannulation rates appeared to be equivalent in patients with both native papilla and biliary-enteric or pancreaticoenteric anastomoses. The diagnostic and therapeutic potential of balloon-assisted ERCP were high and the adverse event rate was low.
EVALuna2:1892

Erratum: August 2019 - AWMF-Registriernummer: 021-009 (Zeitschrift fur Gastroenterologie (2019) 57 (1321-1405) DOI: 10.1055/a-1015-7265) Erratum: Aktualisierte S3-Leitlinie Colitis ulcerosa (Zeitschrift fur Gastroenterologie (2019) 57 (1321-1405) DOI: 10.1055/a-1015-7265) - Kucharzik, Torsten; Dignass, Axel U.; Atreya, Raja; Bokemeyer, Bernd; Esters, Philip; Herrlinger, Klaus; Kannengieβer, Klaus; Kienle, Peter; Langhorst, Jost; Lügering, Andreas; Schreiber, Stefan; Stallmach, Andreas; et al. (Zeitschrift für Gastroenterologie, 2019)
CRIS-Team Scopus Importer:2021-04-20

Erratum: Contrast-Enhanced Ultrasound Algorithms (CEUS-LIRADS/ESCULAP) for the Noninvasive Diagnosis of Hepatocellular Carcinoma-A Prospective Multicenter DEGUM Study (Ultraschall in Med (2020) DOI: 10.1055/a-1198-4874) - Schellhaas, Barbara; Bernatik, Thomas; Bohle, Wolfram; Borowitzka, Fanny; Chang, Johannes; Dietrich, Christoph F.; Dirks, Klaus; Donoval, Robert; Drube, Kristine; Friedrich-Rust, Mireen; Gall, Christine; Gittinger, Fleur; et al. (Ultraschall in der Medizin, 2020)
In the above article, the affiliations of two co-authors were indicated incorrectly. Correct: Albrecht Neesse, Golo Petzold Klinik für Gastroenterologie, gastrointestinale Onkologie und Endokrinologie, Universitätsmedizin Göttingen, Göttingen, Germany
CRIS-Team Scopus Importer:2020-11-20

Esophageal epithelial resistance - Günther, Claudia; Neumann, Helmut; Vieth, Michael (Digestive Diseases, 2014)
Besides its important role of digestion and absorption, esophageal tissue has an essential role as a major barrier against intraluminal pathogens like hostile microorganisms and toxins. This barrier function is achieved via various mechanical, chemical, and immunological mechanisms which are typically altered in inflammatory diseases, thereby causing subsequent damage of the mucosa. In this review we will focus on the main structural and functional barriers of host defense within the esophageal mucosa, including the epithelial layer, membrane-bound and secretory mucins, and different types of defensins. In addition, we will discuss the relevance of biofilm on esophageal tissue and will illustrate the importance of different regulators of intestinal permeability like zonulin and desmosomal components.
EVALuna2:1884

Esophageal post-inflammatory polyposis in extensive and severe Crohn's disease treated with anti-tumor necrosis factor alpha - Soriani, Paola; Tontini, Gian Eugenio; Neumann, Helmut; Ishaq, Sauid; Annunziata, Maria Laura; Pastorelli, Luca; Vecchi, Maurizio (Endoscopy, 2016)
EVALuna2:2199

Ethanol consumption decreases autoantibody titers by blocking IL-21 secretion of Tfh cells during the development of arthritis - Azizov, Vugar; Dietel, K.; Kolenbrander, A.; Seubert, S.; Steffen, F.; Meidenbauer, J.; Steffen, Ulrike; Hofmann, Jörg; Nimmerjahn, Falk; Linker, R.; Wirtz, Stefan; Sarter-Zaiss, Kerstin; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Ethanol consumption inhibits TFH cell responses and the development of autoimmune arthritis - Azizov, Vugar; Dietel, Katharina; Steffen, Franziska; Dürholz, Kerstin; Meidenbauer, Julia; Lucas, Sébastien; Frech, Michael; Omata, Yasunori; Tajik, Narges; Knipfer, Lisa; Kolenbrander, Anne; Seubert, Silvia; et al. (Nature Communications, 2020)
Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by TFH cells, preventing proper spatial organization of TFH cells to form TFH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption.
CRIS-Team Scopus Importer:2020-05-05

Ethanol consumption inhibits the development of autoimmunity by blocking IL-21 secretion in T-FH cells - Azizov, Vugar; Dietel, K.; Kolenbrander, A.; Seubert, S.; Steffen, F.; Meidenbauer, J.; Steffen, Ulrike; Hofmann, J.; Nimmerjahn, Falk; Linker, R.; Wirtz, Stefan; Herrmann, Martin; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-05

Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn's disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial - Sandborn, William J.; Panés, Julian; Danese, Silvio; Sharafali, Zaineb; Hassanali, Azra; Jacob-Moffatt, Rhian; Eden, Christopher; Daperno, Marco; Valentine, John F.; Laharie, David; Baía, Carolina; Atreya, Raja; et al. (Lancet Gastroenterology and Hepatology, 2022)
Background: Etrolizumab is a gut-targeted anti-β7 monoclonal antibody targeting α4β7 and αEβ7 integrins. We aimed to compare the safety and efficacy of two doses of etrolizumab with placebo in patients with Crohn's disease. Methods: BERGAMOT was a randomised, placebo-controlled, double-blind, phase 3 study done at 326 treatment centres worldwide. We included patients aged 18–80 years with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220–480, and a mean daily stool frequency score of ≥6 or a mean daily stool frequency score of >3, and a mean daily abdominal pain score of >1, as well as the presence of active inflammation on screening ileocolonoscopy) who had intolerance, inadequate response, or no response to one or more of corticosteroids, immunosuppressants, or anti-TNF therapy within the past 5 years. BERGAMOT consisted of three induction cohorts (a placebo-controlled, double-blind exploratory cohort [cohort 1]; an active treatment cohort not containing a placebo control [cohort 2]; and a placebo-controlled, double-blind pivotal cohort [cohort 3]) and one maintenance cohort. In induction cohort 3, during the 14-week induction, patients were randomly assigned (2:3:3) to receive matched placebo, 105 mg etrolizumab subcutaneously every 4 weeks (at weeks 0, 4, 8, and 12) or 210 mg etrolizumab subcutaneously (at weeks 0, 2, 4, 8, and 12), stratified by concomitant treatment with oral corticosteroids, concomitant treatment with immunosuppressants, baseline disease activity, and previous exposure to anti-TNF therapy. To preserve masking, all patients received two injections at weeks 0, 4, 8, and 12 and one injection at week 2. Week 14 etrolizumab responders from all cohorts were re-randomly assigned (1:1) to receive 105 mg etrolizumab (etrolizumab maintenance group) or placebo (placebo maintenance group) every 4 weeks for 52 weeks; patients in the induction placebo group underwent a sham re-randomisation to preserve masking. During maintenance, randomisation was stratified by CDAI remission status, concomitant treatment with oral corticosteroids, induction dose regimen, and previous exposure to anti-TNF therapy. All participants and study site personnel were masked to treatment assignment for both induction and maintenance. Co-primary induction endpoints at week 14 (placebo vs 210 mg etrolizumab) were clinical remission (mean stool frequency ≤3 and mean abdominal pain ≤1, with no worsening) and endoscopic improvement (≥50% reduction in Simple Endoscopic Score for Crohn's Disease [SES-CD]). Co-primary maintenance endpoints at week 66 (placebo vs etrolizumab) were clinical remission and endoscopic improvement. Efficacy was analysed using a modified intention-to-treat (mITT) population, defined as all randomised patients who received at least one dose of study drug (induction) and as all patients re-randomised into maintenance who received at least one dose of study drug in the maintenance phase (maintenance). Safety analyses included all patients who received at least one dose of study drug. Maintenance safety analyses include all adverse events occurring in both induction and maintenance. This trial is registered with ClinicalTrials.gov, NCT02394028, and is closed to recruitment. Findings: Between March 20, 2015, and Sept 7, 2021, 385 patients (209 [54%] male and 326 [85%] white) were randomly assigned in induction cohort 3 to receive placebo (n=97), 105 mg etrolizumab (n=143), or 210 mg etrolizumab (n=145). 487 patients had a CDAI-70 response in any of the induction cohorts and were enrolled into the maintenance cohort, of whom 434 had a response to etrolizumab and were randomly assigned to placebo (n=217) or 105 mg etrolizumab (n=217). At week 14, 48 (33%) of 145 patients in the 210 mg induction etrolizumab group versus 28 (29%) of 96 patients in the placebo induction group were in clinical remission (adjusted treatment difference 3·8% [95% CI –8·3 to 15·3]; p=0·52), and 40 (27%) versus 21 (22%) showed endoscopic improvement (5·8% [–5·4 to 17·1]; p=0·32). At week 66, a significantly higher proportion of patients receiving etrolizumab than those receiving placebo had clinical remission (76 [35%] of 217 vs 52 [24%] of 217; adjusted treatment difference 11·3% [95% CI 2·7–19·7]; p=0·0088) and endoscopic improvement (51 [24%] vs 26 [12%]; 11·5% [4·1–18·8]; p=0·0026). Similar proportions of patients reported one or more adverse events during induction (95 [66%] of 143 in the 105 mg etrolizumab group, 85 [59%] of 145 in the 210 mg etrolizumab group, and 51 [53%] of 96 in the placebo group) and maintenance (189 [87%] of 217 in the etrolizumab group and 190 [88%] of 217 in the placebo group). During induction, the most common treatment-related adverse events were injection site erythema (six [4%] of 143 in the 105 mg etrolizumab group, four [3%] of 145 in the 210 mg etrolizumab group, and none of 96 in the placebo group), and arthralgia (two [1%], one [1%], and four [4%]). In the maintenance cohort, the most common treatment-related adverse events were injection site erythema (six [3%] of 217 in the etrolizumab group vs 14 [6%] of 217 in the placebo: group), arthralgia (five [2%] vs eight [4%]), and headache (five [2%] vs seven [3%]). The most common serious adverse event was exacerbation of Crohn's disease (14 [6%] of 217 patients taking placebo and four [2%] of 217 patients taking 105 mg etrolizumab in the maintenance cohort). Interpretation: A significantly higher proportion of patients with moderately to severely active Crohn's disease achieved clinical remission and endoscopic improvement with etrolizumab than placebo during maintenance, but not during induction. Funding: F Hoffmann-La Roche.
CRIS-Team Scopus Importer:2022-11-11

Etrolizumab-s Does Not Induce Residual Trafficking of Regulatory T Cells - Schweda, Anna; Becker, Emily; Wiendl, Maximilian; Atreya, Raja; Atreya, Imke; Müller, Tanja; Neurath, Markus; Zundler, Sebastian (Inflammatory Bowel Diseases, 2022)
Background Blocking immune cell gut homing via α4β7 integrin with the monoclonal antibody vedolizumab is an established therapeutic strategy in inflammatory bowel disease. However, despite promising preclinical and phase 2 clinical data, the anti-β7 antibody etrolizumab yielded disappointing results in a large phase 3 trial program in UC. Mechanistic explanations are still lacking. We have recently shown that vedolizumab is associated with residual homing of regulatory T (Treg) cells in a certain exposure range and aimed to investigate whether a similar mechanism applies for etrolizumab. Methods We used flow cytometry, competitive dynamic adhesion, and transmigration assays to assess binding of the etrolizumab surrogate (etrolizumab-s) antibody FIB504 to Treg and effector T cells (Teff) and to explore the impact on cell trafficking. Results We observed only minimal differences in the binding of etrolizumab-s to Treg and Teff cells. Dynamic adhesion and transmigration of Treg and Teff cells was not substantially differentially affected at relevant concentrations. The β1+ and PI16+ Treg cells were only resistant to etrolizumab-s at low concentrations. Conclusions Etrolizumab does not seem to induce notable residual trafficking of Treg cells. Thus, the Teff overweight in the inflamed gut might persist despite reduced overall T cell recruitment. This might be one piece of the puzzle to explain recent clinical results in phase 3.
CRIS-Team WoS Importer:2022-07-22

Etrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells - Wiendl, Maximilian; Dedden, Mark; Liu, Lijuan; Schweda, Anna; Paap, Eva-Maria; Ullrich, Karen; Hartmann, Leonie; Wieser, Luisa; Vitali, Francesco; Atreya, Imke; Müller, Tanja; Günther, Claudia; et al. (Nature Communications, 2024)
Despite promising preclinical and earlier clinical data, a recent phase III trial on the anti-β7 integrin antibody etrolizumab in Crohn’s disease (CD) did not reach its primary endpoint. The mechanisms leading to this outcome are not well understood. Here we characterize the β7+ T cell compartment from patients with CD in comparison to cells from individuals without inflammatory bowel disease. By flow cytometric, transcriptomic and functional profiling of circulating T cells, we find that triple-integrin-expressing (α4+β7+β1hi) T cells have the potential to home to the gut despite α4β7 blockade and have a specific cytotoxic signature. A subset of triple-integrin-expressing cells readily acquires αE expression and could be co-stimulated via E-Cadherin-αEβ7 interactions in vitro. Etrolizumab-s fails to block such αEβ7 signalling at high levels of T cell stimulation. Consistently, in CD patients treated with etrolizumab, T cell activation correlates with cytotoxic signatures. Collectively, our findings might add one important piece to the puzzle to explain phase III trial results with etrolizumab, while they also highlight that αEβ7 remains an interesting target for future therapeutic approaches in inflammatory bowel disease.
CRIS-Team Scopus Importer:2024-02-16

E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis - Patankar, Jay; Muller, Tanja M.; Kantham, Srinivas; Acera, Miguel Gonzalez; Mascia, Fabrizio; Scheibe, Kristina; Mahapatro, Mousumi; Heichler, Christina; Yu, Yuqiang; Li, Wei; Ruder, Barbara; Günther, Claudia; et al. (Nature Cell Biology, 2021)
Inflammatory bowel diseases present with elevated levels of intestinal epithelial cell (IEC) death, which compromises the gut barrier, activating immune cells and triggering more IEC death. The endogenous signals that prevent IEC death and break this vicious cycle, allowing resolution of intestinal inflammation, remain largely unknown. Here we show that prostaglandin E2 signalling via the E-type prostanoid receptor 4 (EP4) on IECs represses epithelial necroptosis and induces resolution of colitis. We found that EP4 expression correlates with an improved IBD outcome and that EP4 activation induces a transcriptional signature consistent with resolution of intestinal inflammation. We further show that dysregulated necroptosis prevents resolution, and EP4 agonism suppresses necroptosis in human and mouse IECs. Mechanistically, EP4 signalling on IECs converges on receptor-interacting protein kinase 1 to suppress tumour necrosis factor-induced activation and membrane translocation of the necroptosis effector mixed-lineage kinase domain-like pseudokinase. In summary, our study indicates that EP4 promotes the resolution of colitis by suppressing IEC necroptosis.
CRIS-Team WoS Importer:2021-07-23

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma - Sorbye, Halfdan; Grande, Enrique; Pavel, Marianne Ellen; Tesselaar, Margot; Fazio, Nicola; Reed, Nicholas Simon; Knigge, Ulrich; Christ, Emanuel; Ambrosini, Valentina; Couvelard, Anne; Tiensuu Janson, Eva (Journal of Neuroendocrinology, 2023)
This ENETS guidance paper, developed by a multidisciplinary working group, provides up-to-date and practical advice on the diagnosis and management of digestive neuroendocrine carcinoma, based on recent developments and study results. These recommendations aim to pave the road for more standardized care for our patients resulting in improved outcomes. Prognosis is generally poor for digestive NEC, most are advanced at diagnosis and median survival in metastatic disease is 11-12 months. Surgery can be of benefit for localized disease after extensive preoperative imaging. Carboplatin in combination with etoposide is recommended as first-line treatment for metastatic disease. Irinotecan with fluoropyrimidines has the best evidence as second-line treatment. Immunotherapy plays a minor role in biomarker-unselected patients. Molecular profiling if available is encouraged to identify new targets. More prospective clinical trials are highly needed to fulfil the unmet needs in this field, especially on new predictive and prognostic biomarkers and to improve survival of patients with advanced disease.
CRIS-Team WoS Importer:2023-04-07

Evaluation and Management of Pruritus in Primary Biliary Cholangitis - Düll, Miriam; Kremer, Andreas E. (CLIN LIVER DIS, 2022)
CRIS-Team Scopus Importer:2022-11-04
Keywords: Bezafibrate; Gabapentinoids; IBAT; Opioid receptors; Therapy; UVB

EVALUATION OF A REAL-TIME ARTIFICIAL INTELLIGENCE SYSTEM USING A DEEP NEURAL NETWORK FOR POLYP DETECTION AND LOCALIZATION IN THE LOWER GASTROINTESTINAL TRACT - Seibt, Hannes; Beyer, Albert; Hafner, Michael; Eggert, Christian; Huber, Harald; Rath, Timo (GASTROINTESTINAL ENDOSCOPY, 2020)
CRIS-Team WoS Importer:2021-02-19

Evaluation of meaningful change in bowel move frequency for patients with carcinoid syndrome - Pavel, Marianne Ellen; Gable, J.; Kulke, M. H.; Bergsland, E.; Anthony, L. B.; Caplin, M. E.; Oberg, K. E.; Banks, P.; Yang, Q. M.; Lapuerta, P.; Hudgens, S. (2017)
EVALuna2:34128

Evaluation of meaningful change in bowel movement frequency for patients with carcinoid syndrome - Hudgens, Stacie; Ramage, John; Kulke, Matthew; Bergsland, Emily; Anthony, Lowell; Caplin, Martyn; Öberg, Kjell; Pavel, Marianne Ellen; Gable, Jonathon; Banks, Phillip; Yang, Qi Melissa; Lapuerta, Pablo (Journal of Patient-Reported Outcomes, 2019)
Background: Carcinoid syndrome is associated with a reduced quality of life that can be attributed to symptoms such as diarrhea and fatigue as well as social and financial issues. This study was conducted to psychometrically assess meaningful change in bowel movement frequency among carcinoid syndrome patients using data from the TELESTAR clinical study. Methods: An anchor-based approach for deriving meaningful change thresholds consisted of mapping change from baseline bowel movement frequency to other patient-reported assessments of change. These included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core Questionnaire (QLQ-C30) Diarrhea Symptom responders, the EORTC Gastrointestinal NET questionnaire (GI.NET21) GI Symptom responders, and reported adequate relief at Week 12 (≥ 10-point score decrease from Day 1 to Week 12). Parameters included within-group mean change from baseline to Week 12, t-tests of the change (Wilcoxon rank sum for adequate relief), and effect size. Results: There were 135 carcinoid syndrome patients with a mean baseline frequency of 5.7 bowel movements a day. A distribution-based method yielded meaningful change estimates of 0.62 bowel movements a day for overall frequency and 0.83 bowel movements a day at Week 12. Anchor-based analysis indicated a large effect size among patients who reported adequate relief at Week 12 (− 1.58; n = 18; P = 0.014), the QLQ-C30 Diarrhea domain responders (− 1.24; n = 40; P < 0.001), and the GI.NET21 GI Symptoms Domain responders (− 1.49; n = 25; P = 0.005). Exit interview data for meaningful change yielded effect size estimates of − 1.57 for overall change during the Double-blind Treatment Period and − 1.97 for change between Baseline and Week 12. Conclusions: Meaningful change derivation is critical to interpret patient outcomes for evaluating treatment efficacy. In this study, carcinoid syndrome patients experienced clinically meaningful reductions in bowel movement frequency of ≥30% over 12 weeks with telotristat ethyl treatment. Trial registration: NCT01677910.
CRIS-Team Scopus Importer:2020-02-21
Keywords: Bowel movement frequency; Carcinoid syndrome; Meaningful change

Evaluation of multidisciplinary team decisions in neuroendocrine neoplasms: Impact of expert centres - Zandee, Wouter T.; Merola, Elettra; Poczkaj, Karolina; de Mestier, Louis; Klümpen, Heinz Josef; Geboes, Karen; de Herder, Wouter W.; Munir, Alia (European Journal of Cancer Care, 2022)
Objective: To evaluate the impact of multidisciplinary team (MDT) meetings on the management of patients with neuroendocrine neoplasms (NENs). Methods: All newly referred gastro-entero-pancreatic (GEP)-NEN patients discussed from 1 April to 1 October 2017 in the MDT of seven European expert centres were prospectively included. The impact on patients' management was defined as a change in diagnosis, grade, stage or treatment. Results: A total of 292 patients were included, mainly small intestinal (siNENs) (32%) and pancreatic NENs (28%), with distant metastases in 51%. Patients had received prior surgery in 43% of cases and prior medical treatment in 32%. A significant change occurred in 61% of NENs: 7% changes in diagnosis, 8% in grade and 16% in stage. The MDT recommended a new treatment for 51% of patients, mainly surgery (9%) or somatostatin analogues (20%). A significant change was most frequently observed in patients with Stage IV disease (hazard ratio [HR] 3.6, 95% confidence interval [CI]: 1.9–6.9 vs. Stage I) and G2 NENs (vs. G1, HR 2.1 95% CI: 1.2–3.8). Conclusion: NEN-dedicated MDT discussion in expert centres yields significant management changes in over 60% of patients and thus represents the gold standard for the management of these patients.
CRIS-Team Scopus Importer:2022-07-01
Keywords: expert centres; impact; management changes; multidisciplinary team; neuroendocrine neoplasms

Everolimus-induced pneumonitis in neuroendocrine neoplasms: correlation of CT findings and clinical signs - Fehrenbach, Uli; Rodríguez-Laval, Víctor; Jann, Henning; Fernández, Carmen M.Pérez; Pavel, Marianne Ellen; Denecke, Timm (Acta Radiologica, 2020)
Background: Everolimus, a mammalian target of rapamycin (mTOR)-inhibitor, is approved for the treatment of advanced neuroendocrine neoplasms (NEN). A rare major adverse event is the occurrence of drug-induced pneumonitis. Purpose: To evaluate the correlation between clinical signs and computed tomography (CT) findings in everolimus-induced pneumonitis in patients with NEN. Material and Methods: Ninety patients with NEN treated with everolimus were retrospectively enrolled (approved by our Institutional Review Board). All patients received chest CTs before the initiation of everolimus and during the treatment along with physical examinations. Clinical signs of pneumonitis were scored (symptomatic score) according to CTCAE v5.0. Pulmonary function tests (PFT) were evaluated if available. CT images were analyzed based on the severity of interstitial lung disease (ILD), the overall pneumonitis extent (PnE), and regarding presence of typical lung opacification patterns. Follow-up examinations of patients with pneumonitis were analyzed. Results: Pneumonitis was diagnosed in 18 (20%) patients. There was no significant correlation between symptomatic score or PFT and ILD score or PnE. In case of a cryptogenic organizing pneumonia pattern (n = 14), symptomatic scores were significantly lower (P = 0.035) than in case of other opacification patterns (n = 4). In the follow-up analysis, we could identify four different clinical courses. Conclusion: CT detects everolimus-induced pneumonitis at a subclinical stage. In this setting, CT findings, clinical severity, and PFT do not clearly correlate. Opacification pattern analysis seems to be of importance when assessing the severity of CT findings. Asymptomatic patients with positive CT findings should be closely monitored to timely initiate specific treatment.
CRIS-Team Scopus Importer:2020-08-28
Keywords: Computed tomography; everolimus; neuroendocrine neoplasms; pneumonitis; toxicity

Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level - Heinrichs, Sophie K. M.; Hess, Timo; Becker, Jessica; Hamann, Lutz; Vashist, Yogesh K.; Butterbach, Katja; Schmidt, Thomas; Alakus, Hakan; Krasniuk, Iurii; Hoeblinger, Aksana; Lingohr, Philipp; Ludwig, Monika; et al. (Cancer Medicine, 2018)
Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10 ) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10 ). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10 ). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10 ). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10 ). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.
EVALuna2:91838

Excretion of urinary histamine and N-tele methylhistamine in patients with gastrointestinal food allergy compared to non-allergic controls during an unrestricted diet and a hypoallergenic diet - Raithel, Martin; Hagel, Alexander; Albrecht, Heinz; Zopf, Yurdagül; Naegel, Andreas; Baenkler, Hanns-Wolf; Buchwald, Fred; Schultis, Hans-Wolfgang; Kressel, Juergen; Hahn, Eckhart Georg; Konturek, Peter (BMC Gastroenterology, 2015)
Patients with gastrointestinal food allergy are characterised by increased production of mast cell derived mediators upon allergen contact and present often with unspecific symptoms. The aim of this study was to evaluate urinary histamine and methylhistamine excretion in patients with food allergy and to compare their values with food-tolerant controls.In a retrospective case control study the urinary excretion parameters were analysed from 56 patients (40.9, 19 - 58 years) in whom later food challenge tests confirmed food allergy. During their diagnostic work-up urine was collected during a 12-h period under an unrestricted diet with staple foods and a hypoallergenic potato-rice-diet (each 2 days). Healthy controls underwent the same diet types to define normal excretion parameters. Urinary histamine and n-methylhistamine were determined by ELISA or tandem mass spectrometry, respectively, and were expressed as median (25 - 75% range, ?g/mmol creatinine x m(2)BSA).During unrestricted diet urinary histamine was significantly higher in gastrointestinal food allergy than healthy controls (1.42, 0.9 - 2.7 vs 0.87, 0.4 - 1.3; p < 0.0001), while the difference between both groups became marginal during potato-rice diet (1.30, 0.7 - 2.1 vs 1.05, 0.5 - 1.5; p = 0.02). N-methylhistamine was found to be significantly elevated in gastrointestinal food allergy both during unrestricted diet (7.1, 5.0 - 11.2) and potato-rice diet (5.7, 3.7 - 8.7) compared to controls (p < 0.0001). Interestingly, urinary methylhistamine excretion (p < 0.004) and clinical symptom score (p < 0.02) fell significantly when the diet was switched from unrestricted to hypoallergenic food, but was not correlated with symptom scores.In gastrointestinal food allergy significantly higher levels of urine histamine and methylhistamine excretion were found under unrestricted diet, reflecting an increased secretion of histamine due to offending foods. Measurement of urinary n-methylhistamine levels may help to find out patients with increased histamine production and/or food-allergen induced clinical symptoms, respectively.
EVALuna2:2029

Exosomal lncRNA PCAT-1 promotes Kras-associated chemoresistance via immunosuppressive miR-182/miR-217 signaling and p27/CDK6 regulation - Domvri, Kalliopi; Petanidis, Savvas; Anestakis, Doxakis; Porpodis, Konstantinos; Bai, Chong; Zarogoulidis, Paul; Freitag, Lutz; Hohenforst-Schmidt, Wolfgang; Katopodi, Theodora (Oncotarget, 2020)
Immunosuppressive chemoresistance is a major burden in lung cancer. Recent data reveal that long noncoding RNAs (lncRNAs) present in the lung tumor microenvironment are implicated in chemoresistant-related immune deregulation, and metastasis but their exact pathogenic role is still unknown. In this study, we investigate the role of lncRNA PCAT-1 in chemoresistant immunosuppression and its involvement in tumor stroma remodeling. Findings reveal PCAT-1 to regulate Kras-related lung chemoresistance through increased expression of the immunosuppressive micrornas miR-182/miR217 in lung tissues, thus promoting a pre-metastatic niche formation and a subsequent increase in lung metastatic burden. Elevated expression of PCAT-1 negative regulates p27/CDK6 expression by inducing G0/G1 cell cycle arrest through AMPK augmentation, contributing to a tumor-promoting status. Furthermore, PCAT-1 triggered fibroblast differentiation followed by CAF/myofibroblast secretion in TME triggering a CD133/SOX2-related stem cell phenotype. Subsequent PCAT-1 knockdown impaired CAF-mediated stromal activation, and reversed chemoresistance and tumor growth in vivo. Overall, these findings demonstrate the versatile roles of PCAT-1 in sustaining lung immunosuppressive neoplasia through tumor microenvironment remodeling and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.
CRIS-Team Scopus Importer:2020-08-28
Keywords: Immunosuppression; Kras; MiR-182; MiR-217; PCAT-1

Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease - Schmitt, Heike; Billmeier, Ulrike; Dieterich, Walburga; Rath, Timo; Sonnewald, Sophia; Reid, Stephen; Hirschmann, Simon; Hildner, Kai; Waldner, Maximilian; Mudter, Jonas; Hartmann, Arndt; Grützmann, Robert; et al. (Gut, 2018)
OBJECTIVE: Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn's disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy. DESIGN: Mucosal and blood cells were isolated from patients with Crohn's disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS. RESULTS: Responders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4β7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R- cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23. CONCLUSIONS: Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn's disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn's disease refractory to anti-TNF therapy.
EVALuna2:34305

Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy - Denk, Dominic; Petrocelli, Valentina; Conche, Claire; Drachsler, Moritz; Ziegler, Paul K.; Braun, Angela; Kress, Alena; Nicolas, Adele M.; Mohs, Kathleen; Becker, Christoph; Neurath, Markus; Farin, Henner F.; et al. (Immunity, 2022)
T memory stem cells (TSCM) display increased self-renewal and prolonged survival capabilities, thus preventing T cell exhaustion and promoting effective anti-tumor T cell responses. TSCM cells can be expanded by Urolithin A (UA), which is produced by the commensal gut microbiome from foods rich in ellagitannins and is known to improve mitochondrial health. Oral UA administration to tumor-bearing mice conferred strong anti-tumor CD8+ T cell immunity, whereas ex vivo UA pre-treated T cells displayed improved anti-tumor function upon adoptive cell transfer. UA-induced TSCM formation depended on Pink1-mediated mitophagy triggering cytosolic release of the mitochondrial phosphatase Pgam5. Cytosolic Pgam5 dephosphorylated β-catenin, which drove Wnt signaling and compensatory mitochondrial biogenesis. Collectively, we unravel a critical signaling pathway linking mitophagy to TSCM formation and suggest that the well-tolerated metabolic compound UA represents an attractive option to improve immune therapy.
CRIS-Team Scopus Importer:2022-11-25
Keywords: anti-tumor immunity; mitophagy; T

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps - Kienhofer, Deborah; Hahn, Jonas; Stoof, Julia; Csepregi, Janka Zsofia; Reinwald, Christiane; Urbonaviciute, Vilma; Johnsson, Caroline; Maueröder, Christian; Podolska, Malgorzata; Biermann, Mona; Leppkes, Moritz; Harrer, Thomas; et al. (JCI Insight, 2017)
Many effector mechanisms of neutrophils have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) have been assigned a particularly detrimental role. Here we investigated the functional impact of neutrophils and NETs on a mouse model of lupus triggered by intraperitoneal injection of the cell death-inducing alkane pristane. Pristane-induced lupus (PIL) was aggravated in 2 mouse strains with impaired induction of NET formation, i.e., NOX2-deficient (Ncf1-mutated) and peptidyl arginine deiminase 4-deficient (PAD4-deficient) mice, as seen from elevated levels of antinuclear autoantibodies (ANAs) and exacerbated glomerulonephritis. We observed a dramatically reduced ability to form pristane-induced NETs in vivo in both Ncf1-mutated and PAD4-deficient mice, accompanied by higher levels of inflammatory mediators in the peritoneum. Similarly, neutropenic Mcl-1ΔMyelo mice exhibited higher levels of ANAs, which indicates a regulatory function in lupus of NETs and neutrophils. Blood neutrophils from Ncf1-mutated and human individuals with SLE exhibited exuberant spontaneous NET formation. Treatment with specific chemical NOX2 activators induced NET formation and ameliorated PIL. Our findings suggest that aberrant NET is one of the factors promoting experimental lupus-like autoimmunity by uncontrolled release of inflammatory mediators.
EVALuna2:1833

EXPERT CONSENSUS CRITERIA AND PRACTICAL RECOMMENDATIONS FOR PBC CARE IN THE COVID-19 ERA AND BEYOND - Berenguer, Marina; Kremer, Andreas; Hirschfield, Gideon; Jones, David; Leroy, Vincent; Adekunle, Femi; Carbone, Marco (HEPATOLOGY, 2021)
CRIS-Team WoS Importer:2021-12-03

Exploring the interrelationship between the skin microbiome and skin volatiles: A pilot study - Härtl, Tobias; Owsienko, Diana; Schwinn, Leo; Hirsch, Cathrin; Eskofier, Björn; Lang, Roland; Wirtz, Stefan; Loos, Helene (Frontiers in Ecology and Evolution, 2023)
Unravelling the interplay between a human’s microbiome and physiology is a relevant task for understanding the principles underlying human health and disease. With regard to human chemical communication, it is of interest to elucidate the role of the microbiome in shaping or generating volatiles emitted from the human body. In this study, we characterized the microbiome and volatile organic compounds (VOCs) sampled from the neck and axilla of ten participants (five male, five female) on two sampling days, by applying different methodological approaches. Volatiles emitted from the respective skin site were collected for 20 min using textile sampling material and analyzed on two analytical columns with varying polarity of the stationary phase. Microbiome samples were analyzed by a culture approach coupled with MALDI-TOF-MS analysis and a 16S ribosomal RNA gene (16S RNA) sequencing approach. Statistical and advanced data analysis methods revealed that classification of body sites was possible by using VOC and microbiome data sets. Higher classification accuracy was achieved by combination of both data pools. Cutibacterium, Staphylococcus, Micrococcus, Streptococcus, Lawsonella, Anaerococcus, and Corynebacterium species were found to contribute to classification of the body sites by the microbiome. Alkanes, esters, ethers, ketones, aldehydes and cyclic structures were used by the classifier when VOC data were considered. The interdisciplinary methodological platform developed here will enable further investigations of skin microbiome and skin VOCs alterations in physiological and pathological conditions.
CRIS-Team Scopus Importer:2023-02-17
Keywords: axilla; body odor; chemical communication; gas chromatography–mass spectrometry; multi-omic analyses; neck

Expression and function of α4β7 integrin predict the success of vedolizumab treatment in inflammatory bowel disease - Schneider, Ines; Allner, Clarissa; Mühl, Laura; Melde, Michaela; Lissner, Donata; Mantzivi, Eleni; Glauben, Rainer; Vitali, Francesco; Becker, Emily; Atreya, Imke; Müller, Tanja; Atreya, Raja; et al. (Translational Research, 2022)
Inflammatory bowel diseases are medically intractable and require constant therapy in many cases. While a growing number of biologicals and small molecules is available for treatment, a substantial portion of patients experiences primary non-response to these compounds and head-to-head evidence for therapy selection is scarce. Thus, approaches to predict treatment success in individual patients are a huge unmet need. We had previously suggested that the expression and function of α4β7 integrin on T cells in the peripheral blood correlate to outcomes of therapy with the anti-α4β7 integrin antibody vedolizumab. Here, we conducted a translational multicenter trial to prospectively evaluate this hypothesis. In a cohort of 89 patients with inflammatory bowel disease undergoing regular therapy with vedolizumab, lower baseline expression of α4β7 was associated with short-term clinical response. Consistently, low α4β7 expression in patients achieving remission predicted sustained remission in week 30. Moreover, high dynamic adhesion of CD4+ T cells to MAdCAM-1 and high reduction of adhesion by vedolizumab in vitro at baseline were associated with clinical remission. These data substantiate the potential of α4β7 integrin function and expression to forecast outcomes of vedolizumab therapy. Further translational efforts are necessary to improve the performance of the assays and to implement the concept in clinical practice.
CRIS-Team Scopus Importer:2023-01-31

Expression of inflammatory mediators in biofilm samples and clinical association in inflammatory bowel disease patients—a preliminary study - Buchbender, Mayte; Fehlhofer, Jakob Paul; Proff, Peter; Möst, Tobias; Ries, Jutta; Hannig, Matthias; Neurath, Markus; Gund, Madline; Atreya, Raja; Kesting, Marco Rainer (Clinical Oral Investigations, 2021)
Objectives: Inflammatory bowel disease (IBD) has multiple impacts on soft and hard tissues in the oral cavity. The aim of this study was to analyze the expression of cytokines in biofilm samples from patients suffering from IBD and compare them to healthy patients. It was hypothesized that different cytokine expression levels and clinical associations might be drawn. Material and methods: A total of 56 biofilm samples from three different patient cohorts (group 0 = healthy, HC n = 30; group 1 = Crohn’s disease, CD, n = 19; group 2 = ulcerative colitis, UC, n = 7) were examined for the expression levels of the cytokine interleukins IL-2, -6, and -10; matrix metalloproteinases 7 and 9; and surface antigens CD90/CD11a by quantitative real-time PCR and according to clinical parameters (plaque index, BOP, PD, DMFT, CAL). Relative gene expression was determined using the ∆∆CT method. Results: The mean BOP values (p = 0.001) and PD (p = 0.000) were significantly higher in the CD group compared to controls. Expression of IL-10 was significantly higher in the CD (p = 0.004) and UC groups (p = 0.022). Expression of MMP-7 was significantly higher in the CD group (p = 0.032). IBD patients treated with TNF inhibitors (p = 0.007) or other immunosuppressants (p = 0.014) showed significant overexpression of IL-10 compared to controls. Conclusion: Different expression levels of IL-10 and MMP-7 were detected in plaque samples from IBD patients. As only BOP was significantly increased, we conclude that no clinical impairment of periodontal tissue occurred in IBD patients. Clinical relevance: With the worldwide increasing incidence of IBD, it is important to obtain insights into the effects of the disease on the oral cavity. The study was registered (01.09.2020) at the German clinical trial registry (DRKS00022956). Clinical trial registration: The study is registered at the German clinical trial registry (DRKS00022956).
CRIS-Team Scopus Importer:2021-08-20
Keywords: Crohn’s disease; Cytokine expression; Oral biofilm; Periodontitis; Ulcerative colitis

Extension study to the open-label, multi-center, expanded access study of everolimus in patients with advanced neuroendocrine tumors - Doerffel, Y.; Kullmann, F.; Lammert, F.; Quietzsch, D.; Schöfl, Christof; Schuppert, F.; Weber, M.; Baum, V.; Berndt, I.; Weiss, C.; Lahner, H. (2017)
EVALuna2:33894

Extensive small-bowel Crohn's disease detected by the newly introduced 360° panoramic viewing capsule endoscopy system - Tontini, Gian Eugenio; Cavallaro, Flaminia; Neumann, Helmut; Pastorelli, Luca; Neurath, Markus; Spina, Luisa; Vecchi, Maurizio (Endoscopy, 2014)
EVALuna2:1893

Extent of Mucosal Inflammation in Ulcerative Colitis Influences the Clinical Remission Induced by Vedolizumab - Scarozza, Patrizio; Marafini, Irene; Laudisi, Federica; Troncone, Edoardo; Schmitt, Heike; Lenti, Marco Vincenzo; Costa, Stefania; Rocchetti, Irene; De Cristofaro, Elena; Salvatori, Silvia; Frezzati, Ludovica; Di Sabatino, Antonio; et al. (Journal of Clinical Medicine, 2020)
Randomized controlled clinical trials and real-life observations indicate that less than 50% of patients with Crohn's disease (CD) or ulcerative colitis (UC) respond to vedolizumab, a humanized monoclonal antibody that blocks the alpha 4 beta 7 integrin. Since alpha 4 beta 7-expressing lymphocytes mainly infiltrate the left colon, we assessed whether localization of CD and UC influences vedolizumab-induced remission. One hundred and eighty-one patients (74 CD and 107 UC) receiving vedolizumab in 3 referral centers were retrospectively evaluated for clinical remission at week 14. Demographic and clinical characteristics were compared between remitters and non-responders, and multivariable multinomial analysis was performed to identify predictors of remission. Remission was achieved in 17 CD (23%) and 34 UC (32%) patients, respectively. In CD, localization of the lesions did not influence clinical remission. In UC, the remitters had more frequently a distal/left-sided colitis (21/34, 62%) as compared to the non-responders (9/47, 19%), and extensive colitis was more frequent in the non-responders (38/47, 81%) than in the remitters (13/34, 38%). The multivariable multinomial analysis showed that distal/left-sided colitis was associated with a higher probability of clinical remission while extensive colitis was inversely associated with induction of remission. Data indicate that UC patients with distal or left-sided colitis are more likely to achieve remission than patients with extensive colitis following vedolizumab treatment.
CRIS-Team WoS Importer:2020-03-24

Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis - Leppkes, Moritz; Maueröder, Christian; Hirth, Sebastian; Nowecki, Stefanie; Günther, Claudia; Billmeier, Ulrike; Paulus, Susanne; Biermann, Mona; Munoz, Luis Enrique; Hoffmann, Markus; Wildner, Dane; Croxford, Andrew L.; et al. (Nature Communications, 2016)
Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and mice occluding pancreatic ducts and thereby driving pancreatic inflammation. Experimental models indicate that PADI4 is critical for intraductal aggregate formation and that PADI4-deficiency abrogates disease progression. Mechanistically, we identify the pancreatic juice as a strong instigator of neutrophil chromatin extrusion. Characteristic single components of pancreatic juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with relevance in a plethora of inflammatory conditions involving secretory ducts.
EVALuna2:2052

Extremely time-efficient Interval Endurance Training improves cardiometabolic Risk Profile and Inflammation Status for Obese Patient with increased risk of Metabolic Syndrome: A randomized-controlled Pilot Study - Reljic, Dejan; Frenk, Fabienne; Tobschall, Maike; Klaussner, Melanie; Herrmann, Hans Joachim; Neurath, Markus; Zopf, Yurdagül (INTERNIST, 2019)
CRIS-Team WoS Importer:2019-05-17

Ex-vivo, remote photoacoustic sensing using speckle-analysis - Lengenfelder, Benjamin; Hohmann, Martin; Klämpfl, Florian; Waldner, Maximilian; Zalevsky, Zeev; Schmidt, Michael (International Conference on Advanced Optical Technologies, 2019)

Facts, myths and hypotheses on the zoonotic nature of Mycobacterium avium subspecies paratuberculosis - Atreya, Raja; Buelte, Michael; Gerlach, Gerald-F.; Goethe, Ralph; Hornef, Mathias W.; Koehler, Heike; Meens, Jochen; Moebius, Petra; Roeb, Elke; Weiss, Siegfried (International Journal of Medical Microbiology, 2014)
Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of paratuberculosis (Johne's disease [JD]), a chronic granulomatous enteritis in ruminants. JD is one of the most widespread bacterial diseases of domestic animals with significant economic impact. The histopathological picture of JD resembles that of Crohn's disease (CD), a human chronic inflammatory bowel disease of still unresolved aetiology. An aetiological relevance of MAP for CD has been proposed. This and the ambiguity of other published epidemiological findings raise the question whether MAP represents a zoonotic agent. In this review, we will discuss evidence that MAP has zoonotic capacity.
EVALuna2:1904

Faecal Microbiota Therapy as a Treatment Option for a Clostridium difficile-induced toxic Megacolon - Konturek, Peter; Dieterich, Walburga; Hess, Thomas; Neurath, Markus; Zopf, Yurdagül (2018)
EVALuna2:35183

Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy - Dietz, Julia; Di Maio, Velia Chiara; de Salazar, Adolfo; Merino, Dolores; Vermehren, Johannes; Paolucci, Stefania; Kremer, Andreas; Lara, Magdalena; Pardo, Maria Rodriguez; Zoller, Heinz; Degasperi, Elisabetta; Peiffer, Kai Henrik; et al. (Journal of Hepatology, 2021)
Background & Aims: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. Methods: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. Results: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 15/19 (79%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. Conclusions: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. Lay summary: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (79%).
CRIS-Team Scopus Importer:2021-03-05
Keywords: DAA; Direct-acting antivirals; HCV; Hepatitis C virus; Rescue therapy; Resistance-associated substitutions; Voxilaprevir/velpatasvir/sofosbuvir

Failure to achieve disease control in acromegaly: cause analysis by a registry-based survey - Schöfl, Christof; Grussendorf, Martin; Honegger, Juergen; Toenjes, Anke; Thyroke-Gronostay, Daniel; Mayr, Bernhard; Schopohl, Jochen (European Journal of Endocrinology, 2015)
Disease control is a prime target in acromegaly treatment. This should be achievable in the vast majority of patients by available treatment options. For unknown reasons, however, a significant number of patients do not achieve disease control.To investigate reasons for failure to achieve disease control in long-standing acromegaly.Survey based on the German Acromegaly Registry database (1755 patients in 57 centres). Questionnaires were sent to 47 centres treating 178 patients with elevated disease markers (IGF1 and GH) at the last documented database visit out of 1528 patients with a diagnosis dated back >=2 years. Thirty-three centres returned anonymised information for 120 patients (recall rate 67.4%).Median age of the 120 patients (58 females) was 57 years (range 17-84). Ninety-four patients had at least one operation, 29 had received radiotherapy and 71 had been previously treated medically. Comorbidities were reported in 67 patients. In 61 patients, disease activity had been controlled since the last documented database visit, while 59 patients still had biochemically active disease. Reasons were patients' denial to escalate therapy (23.3%), non-compliance (20.6%), fluctuating insulin-like growth factor 1 (IGF-1) and growth hormone (GH) levels with normal values at previous visits (23.3%) and modifications in pharmacotherapy (15.1%). Therapy resistance (9.6%), drug side effects (4.1%) and economic considerations (4.1%) were rare reasons.Main reasons for long-standing active acromegaly were patients' lack of motivation to agree to therapeutic recommendations and non-compliance with medical therapy. Development of patient education programmes could improve long-term control and thus prognosis of acromegalic patients.
EVALuna2:1995

FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex-driven autoimmunity - Hubbard, Jonathan J.; Pyzik, Michal; Rath, Timo; Kozicky, Lisa K.; Sand, Kine M. K.; Gandhi, Amit K.; Grevys, Algirdas; Foss, Stian; Menzies, Susan C.; Glickman, Jonathan N.; Fiebiger, Edda; Roopenian, Derry C.; et al. (Journal of Experimental Medicine, 2020)
IgG immune complexes (ICs) promote autoimmunity through binding fragment crystallizable (Fc) gamma-receptors (FcyRs). Of these, the highly prevalent FcyRIIa (CD32a(H)) histidine (H)-131 variant (CD32(H)) is strongly linked to human autoimmune diseases through unclear mechanisms. We show that, relative to the CD32a arginine (R)-131 (CD32a(R)) variant, CD32a(H) more avidly bound human (h) IgG' IC and formed a ternary complex with the neonatal Fc receptor (FcRn) under acidic conditions. In primary human and mouse cells, both CD32a variants required FcRn to induce innate and adaptive immune responses to hIgG1 ICs, which were augmented in the setting of CD32a(H). Conversely, FcRn induced responses to IgG IC independently of classical FcyR, but optimal responses required FcRn and FcyR. Finally, FcRn blockade decreased inflammation in a rheumatoid arthritis model without reducing circulating autoantibody levels, providing support for FcRn's direct role in IgG IC-associated inflammation. Thus, CD32a and FcRn coregulate IgG IC-mediated immunity in a manner favoring the CD32a(H) variant, providing a novel mechanism for its disease association.
CRIS-Team WoS Importer:2020-11-13

Feasibility and Efficacy of high intensity Interval Endurance Exercise (HIIT) in Tumor Patients: A systematic Overview with Meta-Analysis - Reljic, Dejan; Herrmann, Hans Joachim; Neurath, Markus; Zopf, Yurdagül (2018)
EVALuna2:35186

Feasibility of Respiratory-gated High-pitch Spiral CT:: Free-breathing Inspiratory Image Quality - Lell, Michael; Scharf, Michael; Eller, Achim; Wüst, Wolfgang; Allmendinger, Thomas; Fuchs, Florian; Achenbach, Stephan; Uder, Michael; May, Matthias (Academic Radiology, 2016)
This study aimed to develop and implement a respiratory-gated setup for dual-source computed tomography (CT) at high pitch to examine patients in a reproducible inspiratory phase.Twenty-one patients underwent free-breathing respiratory-gated chest CT using a high-pitch scan mode no more than 6 months after inspiratory breath-held nongated CT, which serves as reference. Scan parameters were as follows: pitch = 3.4, 128 × 0.6 mm collimation, 0.28 s gantry rotation time, and 150 ref.mAs per tube at 120 kV. The examinations were triggered using the tidal wave provided by a respiratory-gating system as input signal. Image quality was assessed focusing on artifacts and delineation of the anatomical and pathological structures. Lung volumes were measured on both free-breathing and reference examinations.All examinations were performed without complications. Image quality was high with both protocols. Significantly less motion artifacts were recorded with the high-pitch mode compared to the reference (P = 0.02). Most of the artifacts were located in the peripheral parts of the lower lobes for the study group and in the central part of the left lower lobe for the reference. Average total lung volume was 4.5 ± 1.5 L in respiratory-gated examinations and 5.8 ± 0.9 L in examinations with breath-hold in inspiration.High-pitch chest CT scanning during free breathing minimizes motion artifacts, improving image quality in patients with limited breath-holding abilities. To assure scanning in an inspiratory phase, data acquisition should be triggered with a respiratory-gating system.
EVALuna2:12027

Feasibility, Safety, and Preliminary Efficacy of Very Low-Volume Interval Training in Advanced Cancer Patients - Reljic, Dejan; Herrmann, Hans J.; Jakobs, Benedikt; Dieterich, Walburga; Mougiakakos, Dimitrios; Neurath, Markus; Zopf, Yurdagül (Medicine and science in sports and exercise, 2022)
Purpose High-intensity interval training (HIIT) has been shown to improve cardiorespiratory fitness (CRF) and health-related outcomes in various chronic diseases, including cancer. However, data on feasibility and efficacy of HIIT in advanced cancer patients are still sparse, presumably because of safety concerns, like suspected immunosuppression after vigorous exercise. This randomized, sham-intervention controlled study aimed to investigate feasibility, safety, and preliminary efficacy of very low-volume HIIT (LOW-HIIT) in advanced cancer patients. Methods Twenty-seven patients (55.4 ± 13.2 yr) with different advanced cancers (Union for International Cancer Control [UICC] III/IV) were randomly allocated to LOW-HIIT (n = 13), consisting of 5 × 1 min cycle ergometer intervals (14 min per session total duration) at 80% to 95% HRpeak (two sessions per week for 12 wk), or a sham intervention (n = 14) performing light physical mobilization exercises (SHAM). Primary outcomes were attrition and attendance rates, with values of ≤25% and ≥80%, respectively, considered acceptable. Secondary outcomes were safety, protocol fidelity, physiological (including CRF measures) and patient-reported outcomes (including fatigue and quality of life). Results One of 13 patients (8%) receiving LOW-HIIT dropped out. Mean attendance rate was 93%. The prescribed minimum exercise intensity was consistently reached by all patients. Low-volume HIIT was well tolerated and not associated with any serious adverse event nor with increased infection susceptibility. There were no biochemical signs of acute immunosuppression after LOW-HIIT. Contrarily, differentiation and degranulation of natural killer cells was acutely increased postexercise. Low-volume HIIT improved CRF measures including peak oxygen uptake, self-reported fatigue, physical, and social functioning. No significant changes occurred in the SHAM group. Conclusions Low-volume HIIT can be regarded as feasible and safe in advanced cancer patients. Our preliminary data indicate favorable acute effects on NK-cells and beneficial chronic adaptations in CRF, fatigue, and aspects of quality of life.
CRIS-Team Scopus Importer:2022-10-28
Keywords: AEROBIC EXERCISE; CARDIOPULMONARY FITNESS; HIIT; NK CELLS; ONCOLOGY; SUPPORTIVE CARE

Fecal and Urinary Adipokines as Disease Biomarkers - Tews, Hauke C.; Elger, Tanja; Grewal, Thomas; Weidlich, Simon; Vitali, Francesco; Buechler, Christa (Biomedicines, 2023)
The use of biomarkers is of great clinical value for the diagnosis and prognosis of disease and the assessment of treatment efficacy. In this context, adipokines secreted from adipose tissue are of interest, as their elevated circulating levels are associated with a range of metabolic dysfunctions, inflammation, renal and hepatic diseases and cancers. In addition to serum, adipokines can also be detected in the urine and feces, and current experimental evidence on the analysis of fecal and urinary adipokine levels points to their potential as disease biomarkers. This includes increased urinary adiponectin, lipocalin-2, leptin and interleukin-6 (IL-6) levels in renal diseases and an association of elevated urinary chemerin as well as urinary and fecal lipocalin-2 levels with active inflammatory bowel diseases. Urinary IL-6 levels are also upregulated in rheumatoid arthritis and may become an early marker for kidney transplant rejection, while fecal IL-6 levels are increased in decompensated liver cirrhosis and acute gastroenteritis. In addition, galectin-3 levels in urine and stool may emerge as a biomarker for several cancers. With the analysis of urine and feces from patients being cost-efficient and non-invasive, the identification and utilization of adipokine levels as urinary and fecal biomarkers could become a great advantage for disease diagnosis and predicting treatment outcomes. This review article highlights data on the abundance of selected adipokines in urine and feces, underscoring their potential to serve as diagnostic and prognostic biomarkers.
CRIS-Team Scopus Importer:2023-05-05
Keywords: adiponectin; biomarker; chemerin; galectin-3; inflammatory bowel disease; interleukin-6; kidney; leptin; lipocalin-2; liver

Fever of unknown origin following allogeneic stem cell transplantation - an unusual case - Meintker, Lisa; Kremer, Andreas; Brandt, Adrian; Spoerl, S.; Slanikova, A.; Mackensen, Andreas; Winkler, Julia; Rösler, Wolf (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-10-23

Final analysis of time to subsequent disease progression/death in patients with metastatic enteropancreatic neuroendocrine tumours progressing under placebo and switched to lanreotide autogel/depot 120mg in the CLARINET open-label extension - Cwikla, J. B.; Wolin, E. M.; Pavel, Marianne Ellen; Phan, A. T.; Raderer, M.; Sedlackova, E.; Cadiot, G.; Capdevila, J.; Rindi, G.; Lombard-Bohas, C.; Liyanage, N.; Thanh, X-M. Truong; et al. (2017)
EVALuna2:34126

Final analysis of time to subsequent disease progression/death in patients with metastatic enteropancreatic neuroendocrine tumours progressing under placebo and switched to lanreotide Autogel/depot 120mg in the CLARINET open-label extension - Pavel, Marianne Ellen; Cwikla, J.; Wolin, E.; Phan, A.; Raderer, M.; Sedlackova, E.; Cadiot, G.; Capdevila, J.; Rindi, G.; Lombard-Bohas, C.; Liyanage, N.; Thanh, Truong X. -M; et al. (2018)
EVALuna2:35198

Final Progression-Free Survival Analyses for Lanreotide Autogel/Depot 120 mg in Metastatic Enteropancreatic Neuroendocrine Tumors: The CLARINET Extension Study - Wolin, Edward M.; Pavel, Marianne Ellen; Cwikla, Jaroslaw B.; Phan, Alexandria T.; Raderer, Markus; Sedlackova, Eva; Cadiot, Guillaume; Capdevila, Jaume; Wall, Lucy; Rindi, Guido; Lombard-Bohas, Catherine; Liyanage, Nilani; et al. (2018)
EVALuna2:34104

First case report of exacerbated ulcerative colitis after anti-interleukin-6R salvage therapy - Atreya, Raja; Billmeier, Ulrike; Rath, Timo; Mudter, Jonas; Neumann, Helmut; Neurath, Markus; Vieth, Michael (World Journal of Gastroenterology, 2015)
We present the case of a 53-year-old woman with long-standing ulcerative colitis and severe, steroid-dependent disease course unresponsive to treatment with azathioprine, methotrexate, anti-TNF antibodies (infliximab, adalimumab) and tacrolimus, who refused colectomy as a therapeutic option. As the pro-inflammatory cytokine interleukin-6 (IL-6) had been identified as a crucial regulator in the immunopathogenesis of inflammatory bowel diseases, we treated the patient with biweekly intravenous infusions of an anti-IL-6R antibody (tocilizumab) for 12 wk. However, no clinical improvement of disease activity was noted. In fact, endoscopic, histological and endomicroscopic assessment demonstrated exacerbation of mucosal inflammation and ulcer formation upon anti-IL-6R therapy. Mechanistic studies revealed that tocilizumab treatment failed to suppress intestinal IL-6 production, impaired epithelial barrier function and induced production of pro-inflammatory cytokines such as TNF, IL-21 and IFN-?. Inhibition of IL-6 by tocilizumab had no clinical benefit in this patient with intractable ulcerative colitis and even led to exacerbation of mucosal inflammation. Our findings suggest that anti-IL-6R antibody therapy may lead to aggravation of anti-TNF resistant ulcerative colitis. When targeting IL-6, the differential responsiveness of target cells has to be taken into account, as IL-6 on the one side promotes acute and chronic mucosal inflammation via soluble IL-6R signaling but on the other side also strongly contributes to epithelial cell survival via membrane bound IL-6R signaling.
EVALuna2:2079

First Patient Survey about Tumor - Associated Fatigue in NEN - Banz, S.; Mellar, K.; Letsch, A.; Scheibenbogen, C.; Pavel, Marianne Ellen; Grabowski, P. (2018)
EVALuna2:34114

First results of the “Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS)” - Jakob, Carolin E.M.; Borgmann, Stefan; Duygu, Fazilet; Behrends, Uta; Hower, Martin; Merle, Uta; Friedrichs, Anette; Tometten, Lukas; Hanses, Frank; Jung, Norma; Rieg, Siegbert; Wille, Kai; et al. (Infection, 2020)
Purpose: Knowledge regarding patients’ clinical condition at severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is sparse. Data in the international, multicenter Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort study may enhance the understanding of COVID-19. Methods: Sociodemographic and clinical characteristics of SARS-CoV-2-infected patients, enrolled in the LEOSS cohort study between March 16, 2020, and May 14, 2020, were analyzed. Associations between baseline characteristics and clinical stages at diagnosis (uncomplicated vs. complicated) were assessed using logistic regression models. Results: We included 2155 patients, 59.7% (1,287/2,155) were male; the most common age category was 66–85 years (39.6%; 500/2,155). The primary COVID-19 diagnosis was made in 35.0% (755/2,155) during complicated clinical stages. A significant univariate association between age; sex; body mass index; smoking; diabetes; cardiovascular, pulmonary, neurological, and kidney diseases; ACE inhibitor therapy; statin intake and an increased risk for complicated clinical stages of COVID-19 at diagnosis was found. Multivariable analysis revealed that advanced age [46–65 years: adjusted odds ratio (aOR): 1.73, 95% CI 1.25–2.42, p = 0.001; 66–85 years: aOR 1.93, 95% CI 1.36–2.74, p < 0.001; > 85 years: aOR 2.38, 95% CI 1.49–3.81, p < 0.001 vs. individuals aged 26–45 years], male sex (aOR 1.23, 95% CI 1.01–1.50, p = 0.040), cardiovascular disease (aOR 1.37, 95% CI 1.09–1.72, p = 0.007), and diabetes (aOR 1.33, 95% CI 1.04–1.69, p = 0.023) were associated with complicated stages of COVID-19 at diagnosis. Conclusion: The LEOSS cohort identified age, cardiovascular disease, diabetes and male sex as risk factors for complicated disease stages at SARS-CoV-2 diagnosis, thus confirming previous data. Further data regarding outcomes of the natural course of COVID-19 and the influence of treatment are required.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Cohort study; COVID-19; LEOSS; SARS-CoV-2

FLAMINGO SET FOR THE ENDOSCOPIC TREATMENT OF BURIED BUMPER SYNDROME: MULTICENTRE, RETROSPECTIVE, COHORT STUDY - Costa, D.; Despott, E. J.; Woodward, J.; Kohout, P.; Rath, Timo; Scovell, L.; Gee, I.; Hindryckx, P.; Forrest, E.; Jordan, D.; Hollywood, C.; Hearing, S.; et al. (DIGESTIVE AND LIVER DISEASE, 2020)
CRIS-Team WoS Importer:2020-11-27

Food Intolerance of Unknown Origin: Caused by Mucosal Inflammation? A Pilot Study - Dieterich, Walburga; Tietz, Esther; Kohl, Matthias; Konturek, Peter C.; Rath, Timo; Neurath, Markus; Zopf, Yurdagül (Clinical and Translational Gastroenterology, 2021)
INTRODUCTION: The prevalence of patients with food intolerance (FI) has increased significantly. Immunoglobulin (Ig)E-mediated food allergies (FAs) are detected by determining IgE antibodies and skin prick test. Carbohydrate malabsorptions are clarified with breath tests. However, these diagnostic measures cannot capture all intolerances and have limitations in case of gut-mediated FI. The aims of this pilot study were to evaluate different methods to determine intestinal mucosal IgE in patients with FA and to characterize the intestinal mucosa in patients with FI of unknown origin (FH). METHODS: Patients with FA and FH were compared with healthy controls. To determine the IgE antibodies and the cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ of the intestinal mucosal, a lavage was performed as part of an ileocolonoscopy and samples were taken using the cytobrush and biopsy forceps. In a subgroup, mucosal samples were also taken from the duodenum. RESULTS: Data in homogenates of intestinal mucosal samples yielded the highest sensitivity for IgE antibody titers compared with lavage and cytobrush. Patients with FA presented increased intestinal TNF-α and low IFN-γ values. This was in contrast to FH patients, who showed low intestinal IgE antibodies and TNF-α levels, but increased IFN-γ values. DISCUSSION: The determination of IgE antibodies to diagnose intestinal IgE-mediated FA is most reliable in intestinal mucosal samples. Increased TNF-α and low IFN-γ levels in patients with FA characterize an allergic reaction. Decreased TNF-α and increased IFN-γ levels in patients with FH indicate an inflammation-related intolerance reaction (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/CTG/A520).
CRIS-Team Scopus Importer:2021-04-16

Free-Breathing Low-Field MRI of the Lungs Detects Functional Alterations Associated With Persistent Symptoms After COVID-19 Infection. - Levy, Simon; Heiß, Rafael; Grimm, Robert; Grodzki, David; Hadler, Dominique; Voskrebenzev, Andreas; Vogel-Claussen, Jens; Fuchs, Florian; Strauss, Richard; Achenbach, Susanne; Hinsen, Maximilian; Klett, Daniel; et al. (Investigative Radiology, 2022)
OBJECTIVES: With the COVID-19 pandemic, repetitive lung examinations have become necessary to follow-up symptoms and associated alterations. Low-field MRI, benefiting from reduced susceptibility effects, is a promising alternative for lung imaging to limit radiations absorbed by patients during CT examinations, which also have limited capability to assess functional alterations. The aim of this investigative study was to explore the functional abnormalities that free-breathing 0.55 T MRI in combination with the phase-resolved functional lung (PREFUL) analysis could identify in patients with persistent symptoms after COVID-19 infection. MATERIALS AND METHODS: Seventy-four COVID-19 patients and 8 healthy volunteers were prospectively scanned in free-breathing with a balanced steady-state free-precession sequence optimized at 0.55 T, 5 months postinfection on average. Normalized perfusion (Q), fractional ventilation (FV), and flow-volume loop correlation (FVLc) maps were extracted with the PREFUL technique. Q, FV, and FVLc defects as well as defect overlaps between these metrics were quantified. Morphological turbo-spin-echo images were also acquired, and the extent of abnormalities was scored by a board-certified radiologist. To investigate the functional correlates of persistent symptoms, a recursive feature elimination algorithm was applied to find the most informative variables to detect the presence of persistent symptoms with a logistic regression model and a cross-validation strategy. All MRI metrics, sex, age, body mass index, and the presence of preexisting lung conditions were included. RESULTS: The most informative variables to detect persistent symptoms were the percentage of concurrent Q and FVLc defects and of areas free of those defects. A detection accuracy of 71.4% was obtained with these 2 variables when fitting the model on the entire dataset. Although none of the single variables differed between patients with and without persistent symptoms ( P > 0.05), the combined score of these 2 variables did ( P < 0.02). This score also showed a consistent increase from healthy volunteers (7.7) to patients without persistent symptoms (8.2) and with persistent symptoms (8.6). The morphological abnormality score showed poor correlation with the functional parameters. CONCLUSIONS: Functional pulmonary examinations using free-breathing 0.55 T MRI with PREFUL analysis revealed potential quantitative markers of impaired lung function in patients with persistent symptoms after COVID-19 infection, potentially complementing morphologic imaging. Future work is needed to explore the translational relevance and clinical implication of these findings.
EVALuna2:506323

Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study - Schöfl, Christof; Honegger, Juergen; Droste, Michael; Grussendorf, Martin; Finke, Reinhard; Ploeckinger, Ursula; Berg, Christian; Willenberg, Holger S.; Lammert, Alexander; Klingmueller, Dietrich; Jaursch-Hancke, Cornelia; Toenjes, Anke; et al. (Journal of Clinical Endocrinology and Metabolism, 2014)
Familial and sporadic GH-secreting pituitary adenomas are associated with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. Patients with an AIP mutation (AIPmut) tend to have more aggressive tumors occurring at a younger age.The objective of the study was to investigate the frequency of AIPmut in patients diagnosed at 30 years of age or younger.The German Acromegaly Registry database (1795 patients in 58 centers) was screened for patients diagnosed with acromegaly at 30 years of age or younger (329 patients). Sixteen centers participated and 91 patients consented to AIPmut analysis.DNA was analyzed by direct sequencing and multiplex ligation dependent probe amplification Main outcome Measures: The number of patients with AIPmut was measured.Five patients had either a mutation (c.490C>T, c.844C>T, and c.911G>A, three males) or gross deletions of exons 1 and 2 of the AIP gene (n = 2, one female). The overall frequency of an AIPmut was 5.5%, and 2.3% or 2.4% in patients with an apparently sporadic adenoma or macroadenoma, respectively. By contrast, three of four patients (75%) with a positive family history were tested positive for an AIPmut. Except for a positive family history, there were no significant differences between patients with and without an AIPmut.The frequency of AIPmut in this registry-based cohort of young patients with acromegaly is lower than previously reported. Patients with a positive family history should be tested for an AIPmut, whereas young patients without an apparent family history should be screened, depending on the individual cost to benefit ratio.
EVALuna2:2017

Frequent Follow-Up of Delisted Liver Transplant Candidates Is Necessary: An Observational Study about Characteristics and Outcomes of Delisted Liver Transplant Candidates - Payani, Elnaz; Koliogiannis, Dionysios; Schoenberg, Markus Bo; Koch, Dominik; Eser-Valeri, Daniela; Denk, Gerald; Rehm, Markus; Schäfer, Simon; Ehmer, Ursula; Kremer, Andreas; Meiser, Bruno; Werner, Jens; et al. (Journal of Clinical Medicine, 2023)
This observational study focuses on the characteristics and survival of patients taken off of the liver transplant waiting list. Assessment of post-delisting survival and a frequent follow-up of patients after delisting are important keys to improve the survival rate of patients with liver failure after being delisted. Within this study, delisted liver transplant candidates were divided into the following groups: (1) “too good” (54%) or (2) “too sick” (22%) for transplantation, (3) adherence issues (12%) or (4) therapy goal changed (11%). The 5-year survival after delisting within these groups was 84%, 9%, 50%, and 68%, respectively. Less than 3% of the delisted patients had to be relisted again. The clinical expert decision of the multidisciplinary transplant team was sufficiently accurate to differentiate between patients requiring liver transplantation and those who were delisted after a stable recovery of liver function. The assessment of post-delisting survival may serve as a complementary metric to assess differences in center practices and to estimate cumulative post-delisting mortality risk.
CRIS-Team Scopus Importer:2023-10-06
Keywords: delisting; liver transplant waiting list; liver transplantation; transplant conference

Friend or Foe? The Ambiguous Role of Innate Lymphoid Cells in Cancer Development - Mattner, Jochen; Wirtz, Stefan (Trends in Immunology, 2017)
The development of immunotherapies represents a major advance towards the effective eradication of malignant tumors. So far, therapeutic approaches have largely focused on T lymphocytes, but the innate arm of the immune system might be similarly important. Innate lymphoid cells (ILCs) are rapidly-responding cells that are functionally analogous to diverse T cell subsets. In recent years these cells have attracted enormous attention owing to their pleiotropic effects in early host defense to infection and organ pathologies. ILCs might also represent promising targets in the context of cancer therapy because they are an innate immune cell population endowed with potent immunomodulatory properties. In this review we discuss the impact of the three ILC subsets and the signature cytokines they release on cancer development and tumor growth.
EVALuna2:7741

From bench to bedside: molecular imaging in inflammatory bowel diseases - Atreya, Raja; Neurath, Markus (Current Opinion in Gastroenterology, 2016)
Standard structural imaging procedures such as endoscopy, ultrasonography, or MRI are an integral part of the rational management of patients with inflammatory bowel diseases (IBDs). There is nevertheless the need for further refined imaging approaches that are able to overcome the limitations of currently used formats. The advent of molecular imaging modalities that allow real-time visualization of cellular processes not only in the preclinical setting but also in clinical trials has demonstrated its ability to improve current therapeutic strategies. The purpose of this review is to present and discuss advancements in the field of molecular imaging approaches in the IBD field.Recent preclinical and clinical studies have addressed the applicability of molecular imaging for improving the differentiation between benign and malignant mucosal alterations, increasing the detection of dysplastic intestinal lesions, and predicting individual responses to biological therapies.Molecular imaging in IBD represents an exciting and evolving field that has the potential to impact on current diagnostic and therapeutic algorithms in the treatment of IBD patients by analyzing and visualizing the molecular mechanisms that drive mucosal inflammation. It might enable us to base individualized therapeutic decisions on preceded molecular level analysis by suitable imaging modalities.
EVALuna2:2091

From physiology to disease and targeted therapy: interleukin-6 in inflammation and inflammation-associated carcinogenesis - Rath, Timo; Billmeier, Ulrike; Waldner, Maximilian; Atreya, Raja; Neurath, Markus (Archives of Toxicology, 2015)
Since its discovery in 1986, originally as B cell stimulating factor 2, the knowledge on IL-6 for immune homeostasis and its pathophysiological implications has rapidly increased. It is now clear that IL-6, alone or in combination with other cytokines, is an architect for shaping and generating immune responses which exerts profound activities on the induction of acute-phase reactions, the differentiation of B lymphocytes, the modulation of T cell apoptosis, the activation of T helper cells and the balance between regulatory T cells and Th17 cells. In parallel to the identification of these physiologic functions, IL-6 has emerged as a critical mediator for perpetuating chronic inflammation and autoimmunity and is increasingly recognized as a key cytokine for linking chronic inflammation to cancer development. In this review, we begin by briefly summarizing the molecular events of IL-6 regulation and signaling and then describe the role of IL-6 in orchestrating innate and adaptive immune responses and its immunopathological relevance for chronic inflammatory diseases. We further outline how IL-6 links chronic inflammation and cancer development and finally provide an outlook on novel therapeutic strategies targeting IL-6 signaling for the treatment of chronic inflammatory diseases and cancer.
EVALuna2:1974

From the surface to the single cell: Novel endoscopic approaches in inflammatory bowel disease - Rath, Timo; Tontini, Gian Eugenio; Neurath, Markus; Neumann, Helmut (World Journal of Gastroenterology, 2015)
Inflammatory bowel diseases (IBD) comprise the two major entities Crohn's disease and ulcerative colitis and endoscopic imaging of the gastrointestinal tract has always been an integral and central part in the management of IBD patients. Within the recent years, mucosal healing emerged as a key treatment goal in IBD that substantially decides about the clinical outcome of IBD patients, thereby demanding for a precise, timely and detailed endoscopic assessment of the mucosal inflammation associated with IBD. Further, molecular imaging has tremendously expanded the clinical utility and applications of modern endoscopy, now encompassing not only diagnosis, surveillance, and treatment but also the prediction of individual therapy response. Within this review we describe novel endoscopic approaches and advanced endoscopic imaging methods for the diagnosis, treatment and surveillance of IBD patients. We begin by providing an overview over novel and advanced imaging techniques such as magnification endoscopy and dye-based and dye-less chromoendoscopy, endomicroscopy and endocytoscopy. We then describe how these techniques can be utilized for the precise and ultrastructural assessment of mucosal inflammation and dysplasia development associated with IBD and outline how they have enabled the endoscopist to gain insight onto the cellular level in real-time. Finally, we provide an outlook on how molecular imaging has rapidly evolved in the recent past and can be used to make individual predictions about the therapeutic response towards biological treatment.
EVALuna2:2011

Full Length Interleukin 33 Aggravates Radiation-Induced Skin Reaction - Kurow, Olga; Frey, Benjamin; Schuster, Louis; Schmitt, Verena; Adam, Susanne; Hahn, Madelaine; Gilchrist, Derek; Mcinnes, Iain B.; Wirtz, Stefan; Gaipl, Udo; Krönke, Gerhard; Schett, Georg; et al. (Frontiers in Immunology, 2017)
The interleukin (IL)-1 family member IL-33 has been described as intracellular alarmin with broad roles in wound healing, skin inflammation but also autoimmunity. Its dichotomy between full length (fl) IL-33 and the mature (m) form of IL-33 and its release by necrosis is still not fully understood. Here, we compare functional consequences of both forms in the skin in vivo, and therefore generated two lines of transgenic mice which selectively overexpress mmIL-33 and flmIL-33 in basal keratinocytes. Transgene mRNA was expressed at high level in skin of both lines but not in organs due to the specific K14 promoter. We could demonstrate that transgenic overexpression of mmIL-33 in murine keratinocytes leads to a spontaneous skin inflammation as opposed to flmIL-33. K14-mmIL-33 mice synthesize and secrete high amounts of mmIL-33 along with massive cutaneous manifestations, like increased epidermis and dermis thickness, infiltration of mast cells in the epidermis and dermis layers and marked hyperkeratosis. Using skin inflammation models such as IL-23 administration, imiquimod treatment, or mechanical irritation did not lead to exacerbated inflammation in the K14-flmIL-33 strain. As radiation induces a strong dermatitis due to apoptosis and necrosis, we determined the effect of fractionated radiation (12 Gy, 4 times). In comparison to wild-type mice, an increase in ear thickness in flmIL-33 transgenic mice was observed 25 days after irradiation. Macroscopic examination showed more severe skin symptoms in irradiated ears compared to controls. In summary, secreted mmIL-33 itself has a potent capacity in skin inflammation whereas fl IL-33 is limited due to its intracellular retention. During tissue damage, fl IL-33 exacerbated radiation-induced skin reaction.
EVALuna2:13432

Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer - Plattner, Christina; Lamberti, Giorgia; Blattmann, Peter; Kirchmair, Alexander; Rieder, Dietmar; Loncova, Zuzana; Sturm, Gregor; Scheidl, Stefan; Ijsselsteijn, Marieke; Fotakis, Georgios; Noureen, Asma; Lisandrelli, Rebecca; et al. (iScience, 2023)
Precision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology—a strategy that is based on perturbing primary tumor cells from cancer patients—could provide a road forward to personalize treatment. We extend this paradigm to measuring proteome activity landscapes by acquiring quantitative phosphoproteomic data from patient-derived organoids (PDOs). We show that kinase inhibitors induce inhibitor- and patient-specific off-target effects and pathway crosstalk. Reconstruction of the kinase networks revealed that the signaling rewiring is modestly affected by mutations. We show non-genetic heterogeneity of the PDOs and upregulation of stemness and differentiation genes by kinase inhibitors. Using imaging mass-cytometry-based profiling of the primary tumors, we characterize the tumor microenvironment (TME) and determine spatial heterocellular crosstalk and tumor-immune cell interactions. Collectively, we provide a framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno-) oncology in CRC.
CRIS-Team Scopus Importer:2023-12-01
Keywords: Cancer; Cancer systems biology; Proteomics

Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms - Wallukat, Gerd; Hohberger, Bettina; Wenzel, Katrin; Fürst, Julia; Schulze-Rothe, Sarah; Wallukat, Anne; Hönicke, Anne Sophie; Müller, Johannes (Journal of Translational Autoimmunity, 2021)
Impairment of health after overcoming the acute phase of COVID-19 is being observed more and more frequently. Here different symptoms of neurological and/or cardiological origin have been reported. With symptoms, which are very similar to the ones reported but are not caused by SARS-CoV-2, the occurrence of functionally active autoantibodies (fAABs) targeting G-protein coupled receptors (GPCR-fAABs) has been discussed to be involved. We, therefore investigated, whether GPCR-fAABs are detectable in 31 patients suffering from different Long-COVID-19 symptoms after recovery from the acute phase of the disease. The spectrum of symptoms was mostly of neurological origin (29/31 patients), including post-COVID-19 fatigue, alopecia, attention deficit, tremor and others. Combined neurological and cardiovascular disorders were reported in 17 of the 31 patients. Two recovered COVID-19 patients were free of follow-up symptoms. All 31 former COVID-19 patients had between 2 and 7 different GPCR-fAABs that acted as receptor agonists. Some of those GPCR-fAABs activate their target receptors which cause a positive chronotropic effect in neonatal rat cardiomyocytes, the read-out in the test system for their detection (bioassay for GPCR-fAAB detection). Other GPCR-fAABs, in opposite, cause a negative chronotropic effect on those cells. The positive chronotropic GPCR-fAABs identified in the blood of Long-COVID patients targeted the β2-adrenoceptor (β2-fAAB), the α1-adrenoceptor (α1-fAAB), the angiotensin II AT1-receptor (AT1-fAAB), and the nociceptin—like opioid receptor (NOC-fAAB). The negative chronotropic GPCR-fAABs identified targeted the muscarinic M2-receptor (M2-fAAB), the MAS-receptor (MAS-fAAB), and the ETA-receptor (ETA-fAAB). It was analysed which of the extracellular receptor loops was targeted by the autoantibodies.
CRIS-Team Scopus Importer:2021-05-07
Keywords: Autoantibody; Autoimmunity; COVID-19; Fatigue; Long-COVID; Post-covid-19 symptom

Functional Brain Changes Due to Chronic Abdominal Pain in Inflammatory Bowel Disease: A Case-Control Magnetic Resonance Imaging Study - Prüß, Magdalena S.; Bayer, Arian; Bayer, Kian Elias; Schumann, Michael; Atreya, Raja; Mekle, Ralf; Fiebach, Jochen B.; Siegmund, Britta; Neeb, Lars (Clinical and Translational Gastroenterology, 2022)
INTRODUCTION: Various chronic pain conditions go along with functional and structural brain changes. This study aimed to investigate functional and structural brain changes by magnetic resonance imaging (MRI) in inflammatory bowel disease (IBD) patients with chronic abdominal pain. METHODS: Sixty-four subjects were included in the final analysis (32 IBD patients with chronic abdominal pain; 32 age-matched and sex-matched controls). All patients suffered from chronic abdominal pain, defined as a score of ≥3/10 on the visual analog scale for at least 3 months in the past 6 months. Besides structural MRI, resting state functional MRI was used to compare functional connectivity of 10 networks between groups. RESULTS: Patients with IBD showed no structural brain alterations but a significantly increased resting state functional connectivity of the secondary somatosensory cortex within the salience network. DISCUSSION: Because the secondary somatosensory cortex saves sensory stimuli and compares novel information with latter experiences, these functions may be maladaptive in IBD patients with abdominal pain.
CRIS-Team Scopus Importer:2022-03-04

Functional Brain Imaging Reveals Rapid Blockade of Abdominal Pain Response Upon Anti-TNF Therapy in Crohn's Disease - Heß, Andreas; Roesch, Julie; Saake, Marc; Sergeeva, Marina; Hirschmann, Simon; Neumann, Helmut; Dörfler, Arnd; Neurath, Markus; Atreya, Raja (Gastroenterology, 2015)
EVALuna2:2003

Functional connectivity reveals altered activation of distinct brain areas in pruritus of cholestasis - Kremer, Andreas; Buchwald, Theresa; Vetter, Marcel; Dörfler, Arnd; Forster, Clemens (JOURNAL OF HEPATOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-26

Functional Contribution and Targeted Migration of Group-2 Innate Lymphoid Cells in Inflammatory Lung Diseases: Being at the Right Place at the Right Time - Wirtz, Stefan; Schulz-Kuhnt, Anja; Neurath, Markus; Atreya, Imke (Frontiers in Immunology, 2021)
During the last decade, group-2 innate lymphoid cells (ILC2s) have been discovered and successfully established as crucial mediators of lung allergy, airway inflammation and fibrosis, thus affecting the pathogenesis and clinical course of many respiratory diseases, like for instance asthma, cystic fibrosis and chronic rhinosinusitis. As an important regulatory component in this context, the local pulmonary milieu at inflammatory tissue sites does not only determine the activation status of lung-infiltrating ILC2s, but also influences their motility and migratory behavior. In general, many data collected in recent murine and human studies argued against the former concept of a very strict tissue residency of innate lymphoid cells (ILCs) and instead pointed to a context-dependent homing capacity of peripheral blood ILC precursors and the inflammation-dependent capacity of specific ILC subsets for interorgan trafficking. In this review article, we provide a comprehensive overview of the so far described molecular mechanisms underlying the pulmonary migration of ILC2s and thereby the numeric regulation of local ILC2 pools at inflamed or fibrotic pulmonary tissue sites and discuss their potential to serve as innovative therapeutic targets in the treatment of inflammatory lung diseases.
CRIS-Team WoS Importer:2021-07-09

Functional molecular network analysis enables prediction of response to vedolizumab therapy in anti-TNF refractory IBD patients - Breidert, Matthias; Eftekhari, Pierre; Louis, François; Rotoiu, Claudia; Rath, Timo; Neurath, Markus; Atreya, Raja (Crohn's & Colitis 360, 2020)
Background: We applied for the first time 2 label-free technologies, physiological intermolecular modulation spectroscopy (PIMS) and nematic protein organization technic (NPOT) in anti-tumor necrosis factor (TNF) refractory inflammatory bowel disease (IBD) patients to identify clinical responders to vedolizumab therapy and elucidate their underlying functional molecular network. Methods: PIMS analysis was performed in peripheral blood taken prior to the first vedolizumab application in 20 IBD patients (Crohn disease n = 13; ulcerative colitis n = 7) refractory to at least 1 previous anti-TNF agent therapy. Peripheral blood taken from clinical responders and nonresponders at week 14 of vedolizumab therapy were additionally subjected to NPOT analysis. Response to therapy was assessed by respective clinical disease activity scores (partial Mayo Score and Harvey-Bradshaw Index). Results: Clinical response to vedolizumab treatment was observed in 7 of 13 Crohn disease and 4 of 7 ulcerative colitis patients at week 14. Response to therapy was accurately predicted by PIMS blood analysis in 100% of ulcerative colitis and 77% of Crohn disease patients. Overall prediction of clinical response with PIMS blood analysis was achieved with a 89% positive predictive value and a 82% negative predictive value. NPOT analysis revealed the heightened expression of the proteins ITGB7, ITGAV, ITG3, PF4, and ASGH in the peripheral blood of vedolizumab responders compared to nonresponders. Conclusions: PIMS analysis of the blood of anti-TNF refractory IBD patients was able to stratify responders to vedolizumab therapy with high accuracy and specificity. NPOT technology could decipher underling molecular networks in the blood of responders, enabling subsequent personalized therapeutic approaches in IBD.
CRIS-Team Scopus Importer:2021-04-19
Keywords: Anti-TNF antibody; Inflammatory bowel disease; Nematic protein organization technic (NPOT); Physiological intermolecular modification spectroscopy (PIMS); Responder interactors; Vedolizumab

Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients - Mlecnik, Bernhard; Bindea, Gabriela; Angell, Helen K.; Sasso, Maria Stella; Obenauf, Anna C.; Fredriksen, Tessa; Lafontaine, Lucie; Bilocq, Amelie M.; Kirilovsky, Amos; Tosolini, Marie; Waldner, Maximilian; Berger, Anne; et al. (Science Translational Medicine, 2014)
The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local expression for 13 cytokines were shown. Metastatic patients exhibited an increased frequency of deletions of cytokines from chromosome 4. Interleukin 15 (IL15) deletion corresponded with decreased IL15 expression, a higher risk of tumor recurrence, and reduced patient survival. Decreased IL15 expression affected the local proliferation of B and T lymphocytes. Patients with proliferating B and T cells at the invasive margin and within the tumor center had significantly prolonged disease-free survival. These results delineate chromosomal instability as a mechanism of modulating local cytokine expression in human tumors and underline the major role of IL15. Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumor, and the importance of local active lymphocyte proliferation for patient survival.
EVALuna2:1872

Functional role of the Tec kinase ITK in the pathogenesis of inflammatory bowel disease - Lechner, K.; Neurath, Markus; Weigmann, Benno (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Functional Role of Transient Receptor Potential Channels in Immune Cells and Epithelia - Khalil, Mohammad; Alliger, Korina; Weidinger, Carl; Yerinde, Cansu; Wirtz, Stefan; Becker, Christoph; Engel, Matthias (Frontiers in Immunology, 2018)
Transient receptor potential (TRP) ion channels are widely expressed in several tissues throughout the mammalian organism. Originally, TRP channel physiology was focusing on its fundamental meaning in sensory neuronal function. Today, it is known that activation of several TRP ion channels in peptidergic neurons does not only result in neuropeptide release and consecutive neurogenic inflammation. Growing evidence demonstrates functional extra-neuronal TRP channel expression in immune and epithelial cells with important implications for mucosal immunology. TRP channels maintain intracellular calcium homeostasis to regulate various functions in the respective cells such as nociception, production and release of inflammatory mediators, phagocytosis, and cell migration. In this review, we provide an overview about TRP-mediated effects in immune and epithelial cells with an emphasis on mucosal immunology of the gut. Crosstalk between neurons, epithelial cells, and immune cells induced by activation of TRP channels orchestrates the immunologic response. Understanding of its molecular mechanisms paves the way to novel clinical approaches for the treatment of various inflammatory disorders including IBD.
EVALuna2:33883

Further efficacy and safety data for maintenance upadacitinib in ulcerative colitis - Atreya, Raja; Neurath, Markus (Lancet Gastroenterology and Hepatology, 2023)
CRIS-Team Scopus Importer:2023-10-06

Gastric hyperplastic polyps (hyperplasiogenic polyps): a constant debate! - Neurath, Markus; Vieth, Michael (Endoscopy, 2021)
CRIS-Team WoS Importer:2021-01-29

Gastric neuroendocrine neoplasias: manifestations and comparative outcomes - Felder, S.; Jann, H.; Arsenic, R.; Denecke, T.; Prasad,; Knappe-Drzikova, B.; Maasberg, S.; Wiedenmann, B.; Pavel, Marianne Ellen; Pascher, A.; Pape, U. F. (Endocrine-Related Cancer, 2019)
Although gastric neuroendocrine neoplasias (gNEN) are an orphan disease, their incidence is rising. The heterogeneous clinical course powers the ongoing discussion of the most appropriate classification system and management. Prognostic relevance of proposed classifications was retrospectively analysed in 142 patients from a single tertiary referral centre. Baseline, management and survival data were acquired for statistical analyses. The distribution according to the clinicopathological typification was gNEN-1 (n = 86/60.6%), gNEN-2 (n = 7/4.9%), gNEN-3 (n = 24/16.9%) and gNEN-4 (n = 25/17.6%), while hypergastrinemia-associated gNEN-1 and -2 were all low-grade tumours (NET-G1/2), formerly termed sporadic gNEN-3 could be subdivided into gNEN-3 with grade 1 or 2 and gNEN-4 with grade 3 (NEC-G3). During follow-up 36 patients died (25%). The mean overall survival (OS) of all gNEN was 14.2 years. The OS differed statistically significant across all subgroups with either classification system. According to UICC 2017 TNM classification, OS differed for early and advanced stages, while WHO grading indicated poorer prognosis for NEC-G3. Cox regression analysis confirmed the independent prognostic validity of either classification system for survival. Particularly careful analysis of the clinical course of gNEN-1 (ECLomas, gastric carcinoids) confirmed their mostly benign, but recurrent and extremely slowly progressive behaviour with low risk of metastasis (7%) and an efficient long-term control by repetitive endoscopic procedures. Our study provides evidence for the validity of current classifications focusing on typing, grading and staging. These are crucial tools for risk stratification, especially to differentiate gNEN-1 as well as sporadic gNET and gNEC (gNEN-3 vs -4).
CRIS-Team WoS Importer:2019-08-30

Gastric neuroendocrine neoplasms - Lamberti, Giuseppe; Panzuto, Francesco; Pavel, Marianne Ellen; O’Toole, Dermot; Ambrosini, Valentina; Falconi, Massimo; Garcia-Carbonero, Rocio; Riechelmann, Rachel P.; Rindi, Guido; Campana, Davide (2024)
Gastric neuroendocrine neoplasms (gNENs) display peculiar site-specific features among all NENs. Their incidence and prevalence have been rising in the past few decades. gNENs comprise gastric neuroendocrine carcinomas (gNECs) and gastric neuroendocrine tumours (gNETs), the latter further classified into three types. Type I anatype II gNETs are gastrin-dependent and develop in chronic atrophic gastritis and as part of Zollinger–Ellison syndrome within a multiple endocrine neoplasia type 1 syndrome (MEN1), respectively. Type III or sporadic gNETs develop in the absence of hypergastrinaemia and in the context of a near-normal or inflamed gastric mucosa. gNECs can also develop in the context of variable atrophic, relatively normal or inflamed gastric mucosa. Each gNEN type has different clinical characteristics and requires a different multidisciplinary approach in expert dedicated centres. Type I gNETs are managed mainly by endoscopy or surgery, whereas the treatment of type II gNETs largely depends on the management of the concomitant MEN1. Type III gNETs may require both locoregional approaches and systemic treatments; NECs are often metastatic and therefore require systemic treatment. Specific data regarding the systemic treatment of gNENs are lacking and are derived from the treatment of intestinal NETs and NECs. An enhanced understanding of molecular and clinical pathophysiology is needed to improve the management and outcomes of patients’ gNETs.
CRIS-Team Scopus Importer:2024-04-26

GastroDigitalShirt: A smart shirt for digestion acoustics monitoring - Baronetto, Annalisa; Graf, Luisa; Fischer, Sören; Neurath, Markus; Amft, Oliver (Proceedings - International Symposium on Wearable Computers, ISWC, 2020)
We present the GastroDigitalShirt, a smart T-Shirt for capturing abdominal sounds produced during digestion. The garment prototype embeds an array of eight miniaturised microphones connected to a low-power wearable computer and is designed for long-term recording. We present the microphone integration and shirt wiring layout. With the GastroDigitalShirt we monitored the different digestion phases over six hours in four healthy participants with no prior gastro-intestinal diseases. The collected data were annotated by two independent raters to mark Bowel Sounds (BS) instances. The interrater agreement was substantial, with Cohen's Kappa of 0.7, confirming a consistent labeling approach. Overall 3046 BS instances were individually annotated. The extracted BS were structured by Hierarchical Agglomerative Clustering. The analysis highlighted the presence of 4 BS types. The results show that our prototype can capture the main BS types reported in literature.
CRIS-Team Scopus Importer:2020-11-13
Keywords: bowel sounds; smart garments; wearable sensors

Gastroduodenal neuroendocrine neoplasms including gastrinoma - Update of the diagnostic and therapeutic guidelines (recommended by the Polish Network of Neuroendocrine Tumours) - Rydzewska, Grazyna; Strzelczyk, Janusz; Bednarczuk, Tomasz; Bolanowski, Marek; Borowska, Malgorzata; Chmielik, Ewa; Cwikla, Jaroslaw B.; Foltyn, Wanda; Gisterek, Iwona; Handkiewicz-Junak, Daria; Hubalewska-Dydejczyk, Alicja; Janas, Ksenia; et al. (Endokrynologia Polska, 2022)
After another meeting of experts of the Polish Network of Neuroendocrine Tumours, updated recommendations for the management of patients with gastric and duodenal neuroendocrine neoplasms (GNENs and DNENs), including gastrinoma, have been issued. As before, the epidemiology, pathogenesis, and clinical symptoms of these neoplasms have been discussed, as well as the principles of diagnostic procedures, including biochemical and histopathological diagnostics and tumour localisation, highlighting the changes introduced in the recommendations. Updated principles of therapeutic management have also been presented, including endoscopic and surgical treatment, and the options of pharmacological and radioisotope treatment. The importance of monitoring patients with GNENs and DNENs, including gastrinoma, has also been emphasised.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Diagnostics; duodenum; gastrinoma; neuroendocrine neoplasms; recommendations; stomach; therapy

Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up† - Pavel, Marianne Ellen; Öberg, K.; Falconi, M.; Krenning, E. P.; Sundin, A.; Perren, A.; Berruti, A. (Annals of Oncology, 2020)
CRIS-Team Scopus Importer:2020-06-09
Keywords: Clinical Practice Guidelines; diagnosis; gastroenteropancreatic neuroendocrine neoplasms; GEP-NENs; GEP-NETs; Pan-NENs; SI-NETs; treatment and follow-up

Gastrointestinal microbiome in Parkinson's disease in a Bavarian cohort - Marxreiter, Franz; Cosma-Grigorov, Alexandra; Gaßner, Heiko; Meixner, Holger; Kohl, Zacharias; Neurath, Markus; Wirtz, Stefan; Winkler, Jürgen (2019)
EVALuna2:209001

GBP-1 acts as a tumor suppressor in colorectal cancer cells - Britzen-Laurent, Nathalie; Lipnik, Karoline; Ocker, Matthias; Naschberger, Elisabeth; Schellerer, Vera; Croner, Roland S.; Vieth, Michael; Waldner, Maximilian; Steinberg, Pablo; Hohenadl, Christine; Stürzl, Michael (Carcinogenesis, 2013)
The human guanylate-binding protein 1 (GBP-1) is among the proteins the most highly induced by interferon-γ (IFN-γ) in every cell type investigated as yet. In vivo, GBP-1 expression is associated with the presence of inflammation and has been observed in autoimmune diseases, inflammatory bowel diseases (IBD) and cancer. In colorectal carcinoma (CRC), the expression of GBP-1 in the desmoplastic stroma has been previously reported to correlate with the presence of an IFN-γ-dominated T helper type 1 (Th1) micromilieu and with an increased cancer-related 5-year survival. In the present study, the analysis of GBP-1 expression in a series of 185 CRCs by immunohistochemistry confirmed that GBP-1 is expressed in stroma cells of CRCs and revealed a significantly less frequent expression in tumor cells, which was contradictory with the broad inducibility of GBP-1. Furthermore, three of six CRC cell lines treated with IFN-γ were unable to express GBP-1 indicating that colorectal tumor cells tend to downregulate GBP-1. On the contrary, non-transformed colon epithelial cells strongly expressed GBP-1 in vitro in presence of IFN-γ and in vivo in inflammatory bowel diseases. Reconstitution of GBP-1 expression in a negative CRC cell line inhibited cell proliferation, migration and invasion. Using RNA interference, we showed that GBP-1 mediates the antitumorigenic effects of IFN-γ in CRC cells. In addition, GBP-1 was able to inhibit tumor growth in vivo. Altogether, these results suggested that GBP-1 acts directly as a tumor suppressor in CRC and the loss of GBP-1 expression might indicate tumor evasion from the IFN-γ-dominated Th1 immune response. © The Author 2012. Published by Oxford University Press. All rights reserved.
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Gene fusions are frequent in ACTH-secreting neuroendocrine neoplasms of the pancreas, but not in their non-pancreatic counterparts - Agaimy, Abbas; Kasajima, Atsuko; Stöhr, Robert; Haller, Florian; Schubart, Christoph; Tögel, Lars; Pfarr, Nicole; von Werder, Alexander; Pavel, Marianne Ellen; Sessa, Fausto; Uccella, Silvia; La Rosa, Stefano; et al. (Virchows Archiv, 2023)
Ectopic Cushing syndrome is a rare clinical disorder resulting from excessive adrenocorticotrophic hormone (ACTH) produced by non-pituitary neoplasms, mainly neuroendocrine neoplasms (NENs) of the lung, pancreas, and gastrointestinal tract, and other less common sites. The genetic background of ACTH-producing NENs has not been well studied. Inspired by an index case of ACTH-producing pancreatic NEN carrying a gene fusion, we postulated that ACTH-producing NENs might be enriched for gene fusions. We herein examined 21 ACTH-secreting NENs of the pancreas (10), lung (9), thymus (1), and kidney (1) using targeted RNA sequencing. The tumors were classified according to the most recent WHO classification as NET-G1/typical carcinoid (n = 4), NETG-2/atypical carcinoid (n = 14), and NET-G3 (n = 3). Overall, targeted RNA sequencing was successful in 11 cases (4 of 10 pancreatic tumors, 5 of 9 pulmonary tumors, and in the one renal and one thymic tumor). All four successfully tested pancreatic tumors revealed a gene fusion: two had a EWSR1::BEND2 and one case each had a KMT2A::BCOR and a TFG::ADGRG7 fusion, respectively. EWSR1 rearrangements were confirmed in both tumors with a EWSR1::BEND2 by FISH. Gene fusions were mutually exclusive with ATRX, DAXX, and MEN1 mutations (the most frequently mutated genes in NETs) in all four cases. Using RNA-based variant assessment (n = 16) or via the TSO500 panel (n = 5), no pathogenic BCOR mutations were detected in any of the cases. Taken together, gene fusions were detected in 4/4 (100%) pancreatic versus 0/7 (0%) non-pancreatic tumors, respectively. These results suggest a potential role for gene fusions in triggering the ACTH production in pancreatic NENs presenting with ectopic Cushing syndrome. While the exact mechanisms responsible for the ectopic ACTH secretion are beyond the scope of this study, overexpressed fusion proteins might be involved in promoter-mediated overexpression of pre-ACTH precursors in analogy to the mechanisms postulated for EWSR1::CREB1-mediated paraneoplastic phenomena in certain mesenchymal neoplasms. The genetic background of the ACTH-producing non-pancreatic NENs remains to be further studied.
CRIS-Team Scopus Importer:2023-02-03
Keywords: ACTH; Neuroendocrine tumor; NET; ectopic Cushing; EWSR1; BCOR fusion; BEND2 fusion; KMT2A

Generalized resistance to pruritogen-induced scratching in the C3H/HeJ strain - Zhang, Yanbin; Richter, Nicole; König, Christine; Kremer, Andreas; Zimmermann, Katharina (Frontiers in Molecular Neuroscience, 2022)
Previously the effect of the pruritogens, such as histamine and chloroquine, was tested in 11 inbred mouse strains, and this study aimed to identify resistant and sensitive strains, consistent with the observation that underlies the large variability in human populations. In the present study, we used the low responder C3H/HeJ (C3H) and the more sensitive C57BL/6J (C57) strain to find out if resistance and sensitivity to develop pruritus is restricted to only histamine and chloroquine or extends to other known pruritogens as well. We tested five additional commonly known pruritogens. We established dose-response relationships by injecting four concentrations of the pruritogens in the range of 0.3, 1, 3, and ten-fold in the nuchal fold. Then we assessed the scratching behavior for 30 min after injection with an automated custom-designed device based on the bilateral implantation of mini-magnets in the hind paws and on single cages placed within a magnetic coil. We found that the resistance to pruritogens is a general phenotype of the C3H strain and extends to all pruritogens tested, including not only histamine and chloroquine, but also endothelin, trypsin, 5-HT (serotonin), the short peptide SLIGRL, and Lysophosphatidic acid (LPA). C57 was more sensitive to all pruritogens and, in contrast to C3H, dose-response relationships were evident for some of the pruritogens. In general, comparable peak scratch responses were observed for the 0.3-fold concentrations of the pruritogens in C57 whereas C3H required at least the ten-fold concentration and still displayed only between 5 and 33% of the scratch responses observed in C57 for the respective pruritogen. The general resistance to pruritogens and the low level of scratching behavior found in the C3H strain is an interesting trait and represents a model for the study of the heritability of itch. It is accompanied in C3H with a higher sensitivity in assays of nociception.
CRIS-Team Scopus Importer:2022-11-04
Keywords: C57BL/6J; heritability; inbred mouse strains; itch; pruritus; scratching behavior

Generation and characterization of an endogenously tagged SPG11-human iPSC line by CRISPR/Cas9 mediated knock-in - Winner, Beate; Krumm, Laura; Pozner, Tatyana; Kaindl, Johanna; Regensburger, Martin; Günther, Claudia; Turan, Sören; Asadollahi, Reza; Rauch, Anita (Stem Cell Research, 2021)
Pathogenic bi-allelic variants in the SPG11 gene result in rare motor neuron disorders such as Hereditary Spastic Paraplegia type 11, Charcot-Marie Tooth, and Juvenile Amyotrophic Lateral Sclerosis-5. The main challenge in SPG11-linked disease research is the lack of antibodies against SPG11 encoded spatacsin. Here, we describe the CRISPR/Cas9 mediated generation and validation of an endogenously tagged SPG11- human iPSC line that contains an HA tag at the C-terminus of SPG11. The line exhibits multi-lineage differentiation potential and holds promise for studying the role of spatacsin and for the elucidation of SPG11-associated pathogenesis. Resource Table.

Genetically Single Generation and characterization of an endogenously tagged SPG11-human iPSC line by CRISPR/Cas9 mediated knock-in - Krumm, Laura; Pozner, Tatyana; Kaindl, Johanna; Regensburger, Martin; Günther, Claudia; Turan, Sören; Asadollahi, Reza; Rauch, Anita; Winner, Beate (Stem Cell Research, 2021)
Pathogenic bi-allelic variants in the SPG11 gene result in rare motor neuron disorders such as Hereditary Spastic Paraplegia type 11, Charcot-Marie Tooth, and Juvenile Amyotrophic Lateral Sclerosis-5. The main challenge in SPG11-linked disease research is the lack of antibodies against SPG11 encoded spatacsin. Here, we describe the CRISPR/Cas9 mediated generation and validation of an endogenously tagged SPG11- human iPSC line that contains an HA tag at the C-terminus of SPG11. The line exhibits multi-lineage differentiation potential and holds promise for studying the role of spatacsin and for the elucidation of SPG11-associated pathogenesis.
CRIS-Team Scopus Importer:2021-09-10

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts - Mayr, Bernhard; Schnabel, Dirk; Dörr, Helmuth-Günther; Schöfl, Christof (European Journal of Endocrinology, 2016)
The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper- and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.
EVALuna2:2068

Genomic profiling of NETs: a comprehensive analysis of the RADIANT trials - Yao, James; Garg, Abhishek; Chen, David; Capdevila, Jaume; Engstrom, Paul; Pommier, Rodney; Van Cutsem, Eric; Singh, Simron; Fazio, Nicola; He, Wei; Riester, Markus; Patel, Parul; et al. (Endocrine-Related Cancer, 2019)
Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.
CRIS-Team WoS Importer:2019-03-15

Giardia duodenalis and its secreted ppib trigger inflammasome activation and pyroptosis in macrophages through TLR4-induced ROS signaling and A20-mediated NLRP3 deubiquitination - Liu, Lin; Yang, Yongwu; Fang, Rui; Zhu, Weining; Wu, Jingxue; Li, Xiaoyun; Patankar, Jay; Li, Wei (Cells, 2021)
The extracellular protozoan parasite Giardia duodenalis is a well-known and important causative agent of diarrhea on a global scale. Macrophage pyroptosis has been recognized as an important innate immune effector mechanism against intracellular pathogens. Yet, the effects of noninvasive Giardia infection on macrophage pyroptosis and the associated molecular triggers and regulators remain poorly defined. Here we initially observed that NLRP3 inflammasome-mediated pyroptosis was activated in Giardia-treated macrophages, and inhibition of ROS, NLRP3, or caspase-1 could block GSDMD cleavage, IL-1β, IL-18 and LDH release, and the cell viability reduction. We also confirmed that Giardia-induced NLRP3 inflammasome activation was involved in its K63 deubiquitination. Thus, six candidate deubiquitinases were screened, among which A20 was identified as an effective regulator. We then screened TLRs on macrophage membranes and found that upon stimulation TLR4 was tightly correlated to ROS enhancement, A20-mediated NLRP3 deubiquitination, and pyroptotic signaling. In addition, several Giardia-secreted proteins were predicted as trigger factors via secretome analysis, of which peptidyl-prolyl cis-trans isomerase B (PPIB) independently induced macrophage pyroptosis. This was similar to the findings from the trophozoite treatment, and also led to the TLR4-mediated activation of NLRP3 through K63 deubiquitination by A20. Collectively, the results of this study have significant implications for expanding our understanding of host defense mechanisms after infection with G. duodenalis.
CRIS-Team Scopus Importer:2021-12-31
Keywords: A20; Giardia duodenalis; Macrophage pyroptosis; NLRP3 deubiquitination; PPIB; TLR4

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus - Levy, Cynthia; Kendrick, Stuart; Bowlus, Christopher L.; Tanaka, Atsushi; Jones, David; Kremer, Andreas; Mayo, Marlyn J.; Haque, Nazneen; von Maltzahn, Robyn; Allinder, Matthew; Swift, Brandon; McLaughlin, Megan M.; et al. (Clinical Gastroenterology and Hepatology, 2023)
Background & Aims: GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC). Methods: GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0–10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (3:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changes in mean worst daily itch (MWDI) score. Results: One hundred forty-seven patients received placebo (n = 36) or linerixibat (once daily: 20 mg, n = 16; 90 mg, n = 23; 180 mg, n = 27; twice daily: 40 mg, n = 23; 90 mg, n = 22). Linerixibat groups exhibited ≥2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P = .0424), 40 mg twice daily (P = .0105), and 90 mg twice daily (P = .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P = .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. Conclusions: Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. ClinicalTrials.gov ID: NCT02966834.
CRIS-Team Scopus Importer:2023-01-20
Keywords: Bile Acids; Cholestatic Pruritus; Clinical Trial; IBAT Inhibitor; Patient-Reported Outcomes

Global challenges in access to diagnostics and treatment for neuroendocrine tumor (NET) patients - Dureja, Sugandha; McDonnell, Mark; Van Genechten, Dirk; Bouvier, Catherine; Kolarova, Teodora; O'Toole, Dermot; Singh, Harjit; Chen, Jie; Howe, James; Singh, Simron; Rodien-Louw, Christine; Leyden, Simone; et al. (Journal of Neuroendocrinology, 2023)
SCAN, an online survey, measured access to diagnosis, treatments and monitoring of neuroendocrine tumor (NET) patients globally. Between September and November 2019, NET patients and healthcare professionals (HCPs) completed an online, semi-standardized survey with 54 patient questions and 33 HCP questions. A total of 2359 patients with NETs and 436 HCPs responded. Misdiagnosis was common (44% [1043/2359]). Mean time to diagnosis was 4.8 years (standard deviation [SD], 6.2). Compared with global figures (60% [1407/2359]), the availability of 68Ga-DOTA positron emission tomography (PET)/computed tomography (CT) was significantly lower in Asia (45% [126/280]) and higher in Oceania (86% [171/200]). HCPs reported that 68Ga-DOTA PET/CT was free/affordable to fewer patients in Emerging and Developing Economies (EDE) than Advanced Economies (AE; 17% [26/150] and 59% [84/142], respectively). Compared with global data (52% [1234/2359]), patient-reported availability of peptide receptor radionuclide therapy (PRRT) was significantly lower in Asia (31% [88/280]) and higher in Oceania (61% [122/200]). Significant differences were observed in average annual NET specialist costs between AE and EDE (1081 and 2915, respectively). Compared with AE, patients in EDE traveled further for NET specialists (1032 [SD, 1578] and 181 [SD, 496] km, respectively). Patients and HCPs both recommended referral to HCPs that were more knowledgeable in the field of NETs and had better access to NET experts/specialist centers. National care pathways, enhancing HCP NET knowledge and ensuring effective diagnostics and access to appropriate treatments are crucial to improving patient survival and NET care worldwide.
CRIS-Team Scopus Importer:2023-07-07
Keywords: access to diagnostics; global challenges; healthcare provider survey; neuroendocrine tumor; patient survey

Glucocorticoid-induced relapse of COVID-19 in a patient with sarcoidosis - Györfi, Andrea-Hermina; Kopp, Markus; May, Matthias; Vetter, Marcel; Uder, Michael; Kremer, Andreas; Schett, Georg; Harrer, Thomas; Distler, Jörg (Annals of the Rheumatic Diseases, 2020)
CRIS-Team Scopus Importer:2020-11-20

Glucose-Restricted Diet Regulates the Tumor Immune Microenvironment and Prevents Tumor Growth in Lung Adenocarcinoma - Gähler, Alexander; Trufa, Denis; Chiriac, Mircea-Teodor; Tausche, Patrick; Hohenberger, Katja; Brunst, Ann-Kathrin; Rauh, Manfred; Geppert, Carol-Immanuel; Rieker, Ralf; Krammer, Susanne; Leberle, Anna; Neurath, Markus; et al. (Frontiers in Oncology, 2022)
BackgroundLung cancer is the second common cancer type in western countries and has a high mortality. During the development and progression of the tumor, the nutrients in its environment play a central role. The tumor cells depend crucially on glucose metabolism and uptake. Tumor cell metabolism is dominated by the Warburg effect, where tumor cells produce large amounts of lactate from pyruvate under aerobic conditions. We thus reasoned that, reducing carbohydrates in the diet might support anti-tumoral effects of current immunotherapy and additionally target tumor immune escape. ObjectivesThe link between reducing carbohydrates to improve current immunotherapy is not clear. We thus aimed at analyzing the effects of different glucose levels on the tumor development, progression and the anti-tumoral immune response. MethodsWe correlated the clinical parameters of our LUAD cohort with different metabolic markers. Additionally, we performed cell culture experiments with A549 tumor cell line under different glucose levels. Lastly, we investigated the effect of low and high carbohydrate diet in an experimental murine model of lung cancer on the tumor progression and different immune subsets. ResultsHere we found a positive correlation between the body mass index (BMI), blood glucose levels, reduced overall survival (OS) and the expression of Insulin-like growth factor-1 receptor (IGF1R) in the lung tumoral region of patients with lung adenocarcinoma (LUAD). Furthermore, increasing extracellular glucose induced IGF1R expression in A549 LUAD cells. Functional studies in a murine model of LUAD demonstrated that, glucose restricted diet resulted in decreased tumor load in vivo. This finding was associated with increased presence of lung infiltrating cytotoxic CD8+ T effector memory (TEM), tissue resident memory T (TRM) and natural killer cells as well as reduced IGFR mRNA expression, suggesting that glucose restriction regulates lung immunity in the tumor microenvironment. ConclusionsThese results indicate that, glucose restricted diet improves lung immune responses of the host and suppresses tumor growth in experimental lung adenocarcinoma. As glucose levels in LUAD patients were negatively correlated to postoperative survival rates, glucose-restricted diet emerges as therapeutic avenue for patients with LUAD.
CRIS-Team WoS Importer:2022-05-27

Gluten and FODMAPS-sense of a restriction/when is restriction necessary? - Dieterich, Walburga; Zopf, Yurdagül (Nutrients, 2019)
Gluten-free diet (GFD) is enjoying increasingly popularity, although gluten-free products are considerably more expensive. GFD is absolutely necessary for patients with celiac disease, as in this case even minor amounts of gluten can lead to the destruction of the intestinal mucosa. In addition, GFD is currently the best therapy to improve clinical symptoms of patients with non-celiac gluten sensitivity (NCGS), although the diet may not be as strict as that for patients with celiac disease. Beside gluten, other wheat components such as oligosaccharides and amylase trypsin inhibitors are discussed as triggers of NCGS in this review. An overlap between gastrointestinal symptoms in NCGS and irritable bowel syndrome (IBS) is described. Patients with NCGS attribute their symptoms to the consumption of gluten, while patients with IBS rarely describe gluten as a trigger. Recently, several studies have demonstrated that the introduction of a low FODMAP (fermentable oligo-, di-, monosaccharides, and polyols) diet reduced gastrointestinal symptoms in patients with IBS and this diet is suggested as the first choice of therapy in IBS. However, a low FODMAP diet also eliminates prebiotica and may negatively influence the gut microbiota. For this reason, the diet should be liberalized after symptom improvement. There is no evidence that a GFD is healthier than the standard diet. In contrast, GFD often is accompanied by nutritional deficiencies, mainly minerals and vitamins. Therefore, GFD and low FODMAP diets are not recommended for healthy subjects. Since wheat contains fructans belonging to FODMAPs), a GFD is not only gluten-free but also has less FODMAPs. Thus, symptom improvement cannot be correctly correlated with the reduction of either one or the other.
CRIS-Team Scopus Importer:2019-09-17
Keywords: Celiac disease; Gluten-free diet (GFD); Irritable bowel syndrome (IBS); Low fodmap diet; Non-celiac gluten sensitivity (NCGS)

Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis - Hohenester, Simon; Kanitz, Veronika; Kremer, Andreas; Paulusma, Coen C.; Wimmer, Ralf; Kühn, Helen; Denk, Gerald; Horst, David; Elferink, Ronald Oude; Beuers, Ulrich (Cells, 2020)
Hydrophobic bile salts are considered to promote liver fibrosis in cholestasis. However, evidence for this widely accepted hypothesis remains scarce. In established animal models of cholestasis, e.g., by Mdr2 knockout, cholestasis and fibrosis are both secondary to biliary damage. Therefore, to test the specific contribution of accumulating bile salts to liver fibrosis in cholestatic disease, we applied the unique model of inducible hepatocellular cholestasis in cholate-fed Atp8b1(G308V/G308V) mice. Glycochenodeoxycholate (GCDCA) was supplemented to humanize the murine bile salt pool, as confirmed by HPLC. Biomarkers of cholestasis and liver fibrosis were quantified. Hepatic stellate cells (HSC) isolated from wild-type mice were stimulated with bile salts. Proliferation, cell accumulation, and collagen deposition of HSC were determined. In cholestatic Atp8b1(G308V/G308V) mice, increased hepatic expression of alpha SMA and collagen1a mRNA and excess hepatic collagen deposition indicated development of liver fibrosis only upon GCDCA supplementation. In vitro, numbers of myofibroblasts and deposition of collagen were increased after incubation with hydrophobic but not hydrophilic bile salts, and associated with EGFR and MEK1/2 activation. We concluded that chronic hepatocellular cholestasis alone, independently of biliary damage, induces liver fibrosis in mice in presence of the human bile salt GCDCA. Bile salts may have direct pro-fibrotic effects on HSC, putatively involving EGFR and MEK1/2 signaling.
CRIS-Team WoS Importer:2020-04-21

Good Manufacturing Practice-Compliant Production and Lot-Release ofEx VivoExpanded Regulatory T Cells As Basis for Treatment of Patients with Autoimmune and Inflammatory Disorders - Wiesinger, Manuel; Stoica, Diane; Roessner, Susanne; Lorenz, Carmen; Fischer, Anika; Atreya, Raja; Neufert, Clemens; Atreya, Imke; Scheffold, Alexander; Schuler-Thurner, Beatrice; Neurath, Markus; Schuler, Gerold; et al. (Frontiers in Immunology, 2017)
In recent years, the exploration of regulatory T cell (Treg)-based cellular therapy has become an attractive strategy to ameliorate inflammation and autoimmunity in various clinical settings. The main obstacle to the clinical application of Treg in human is their low number circulating in peripheral blood. Therefore,ex vivoexpansion is inevitable. Moreover, isolation of Treg bears the risk of concurrent isolation of unwanted effector cells, which may trigger or deteriorate inflammation upon adoptive Treg transfer. Here, we present a protocol for the GMP-compliant production, lot-release and validation ofex vivoexpanded Tregs for treatment of patients with autoimmune and inflammatory disorders. In the presented production protocol, large numbers of Treg, previously enriched from a leukapheresis product by using the CliniMACS®system, areex vivoexpanded in the presence of anti-CD3/anti-CD28 expander beads, exogenous IL-2 and rapamycin during 21 days. The expanded Treg drug product passed predefined lot-release criteria. These criteria include (i) sterility testing, (ii) assessment of Treg phenotype, (iii) assessment of non-Treg cellular impurities, (iv) confirmation of successful anti-CD3/anti-CD28 expander bead removal after expansion, and (v) confirmation of the biological function of the Treg product. Furthermore, the Treg drug product was shown to retain its stability and suppressive function for at least 1 year after freezing and thawing. Also, dilution of the Treg drug product in 0.9% physiological saline did not affect Treg phenotype and Treg function for up to 90 min. These data indicate that these cells are ready to use in a clinical setting in which a cell infusion time of up to 90 min can be expected. The presented production process has recently undergone on site GMP-conform evaluation and received GMP certification from the Bavarian authorities in Germany. This protocol can now be used for Treg-based therapy of various inflammatory and autoimmune disorders.
EVALuna2:33800

Gp96 Peptide Antagonist gp96-II Confers Therapeutic Effects in Murine Intestinal Inflammation - Nold-Petry, Claudia A.; Nold, Marcel F.; Levy, Ofer; Kliger, Yossef; Oren, Anat; Borukhov, Itamar; Becker, Christoph; Wirtz, Stefan; Sandhu, Manjeet K.; Neurath, Markus; Dinarello, Charles A. (Frontiers in Immunology, 2017)
Background: The expression of heat shock protein gp96 is strongly correlated with the degree of tissue inflammation in ulcerative colitis and Crohn's disease, thereby leading us to the hypothesis that inhibition of expression via gp96-II peptide prevents intestinal inflammation. Methods: We employed daily injections of gp96-II peptide in two murine models of intestinal inflammation, the first resulting from five daily injections of IL-12/IL-18, the second via a single intrarectal application of TNBS (2,4,6-trinitrobenzenesulfonic acid). We also assessed the effectiveness of gp96-II peptide in murine and human primary cell culture. Results: In the IL-12/IL-18 model, all gp96-II peptide-treated animals survived until day 5, whereas 80% of placebo-injected animals died. gp96-II peptide reduced IL-12/IL-18-induced plasma IFNγ by 89%, IL-1β by 63%, IL-6 by 43% and tumor necrosis factor (TNF) by 70% compared to controls. The clinical assessment Disease Activity Index of intestinal inflammation severity was found to be significantly lower in the gp96-II-treated animals when compared to vehicle-injected mice. gp96-II peptide treatment in the TNBS model limited weight loss to 5% on day 7 compared with prednisolone treatment, whereas placebo-treated animals suffered a 20% weight loss. Histological disease severity was reduced equally by prednisolone (by 40%) and gp96-II peptide (35%). Mice treated with either gp96-II peptide or prednisolone exhibited improved endoscopic scores compared with vehicle-treated control mice: vascularity, fibrin, granularity, and translucency scores were reduced by up to 49% by prednisolone and by up to 30% by gp96-II peptide. In vitro, gp96-II peptide reduced TLR2-, TLR4- and IL-12/IL-18-induced cytokine expression in murine splenocytes, with declines in constitutive IL-6 (54%), lipopolysaccharide-induced TNF (48%), IL-6 (81%) and in Staphylococcus epidermidis-induced TNF (67%) and IL-6 (81%), as well as IL-12/IL-18-induced IFNγ (75%). gp96-II peptide reduced IL-1β, IL-6, TNF and GM-CSF in human peripheral blood mononuclear cells to a similar degree without affecting cell viability, whereas RANTES, IL-25 and MIF were twofold to threefold increased. Conclusion: gp96-II peptide protects against murine intestinal inflammation by regulating inflammation in vivo and in vitro, pointing to its promise as a novel treatment for inflammatory bowel disease.
EVALuna2:33887

Grehlin concentrations correlate with hunger and craving ratings following oral ingestion of macronutrients - Thürauf, Norbert; Bachlechner, Stephan; Denzer-Lippmann, Melanie; Wielopolski, Jan; Fischer, Marie; Büttner, Andrea; Dörfler, Arnd; Schöfl, Christof; Muench, Gerald; Kornhuber, Johannes (CHEMICAL SENSES, 2019)
CRIS-Team WoS Importer:2019-03-26

Group 2 Innate Lymphoid Cells Attenuate Inflammatory Arthritis and Protect from Bone Destruction in Mice - Omata, Yasunori; Frech, Michael; Primbs, Tatjana; Lucas, Sebastien; Andreev, Darja; Scholtysek, Carina; Sarter-Zaiss, Kerstin; Kindermann, Markus; Yeremenko, Nataliya; Baeten, Dominique L.; Andreas, Nico; Kamradt, Thomas; et al. (Cell Reports, 2018)
Group 2 innate lymphoid cells (ILC2s) were detected in the peripheral blood and the joints of rheumatoid arthritis (RA) patients, serum-induced arthritis (SIA), and collagen-induced arthritis (CIA) using flow cytometry. Circulating ILC2s were significantly increased in RA patients compared with healthy controls and inversely correlated with disease activity. Induction of arthritis in mice led to a fast increase in ILC2 number. To elucidate the role of ILC2 in arthritis, loss- and gain-of-function mouse models for ILC2 were subjected to arthritis. Reduction of ILC2 numbers in RORαcre/GATA3fl/fl and Tie2cre/RORαfl/fl mice significantly exacerbated arthritis. Increasing ILC2 numbers in mice by IL-25/IL-33 mini-circles or IL-2/IL-2 antibody complex and the adoptive transfer of wild-type (WT) ILC2s significantly attenuated arthritis by affecting the initiation phase. In addition, adoptive transfer of IL-4/13-competent WT but not IL-4/13-/- ILC2s and decreased cytokine secretion by macrophages. These data show that ILC2s have immune-regulatory functions in arthritis.
EVALuna2:34467

Group 2 Innate Lymphoid Cells (ILC2) Suppress Beneficial Type 1 Immune Responses During Pulmonary Cryptococcosis - Kindermann, Markus; Knipfer, Lisa; Obermeyer, Stephanie; Müller, Uwe; Alber, Gottfried; Bogdan, Christian; Schleicher, Ulrike; Neurath, Markus; Wirtz, Stefan (Frontiers in Immunology, 2020)
Cryptococcus neoformans is an opportunistic fungal pathogen preferentially causing disease in immunocompromised individuals such as organ-transplant-recipients, patients receiving immunosuppressive medications or, in particular, individuals suffering from HIV infection. Numerous studies clearly indicated that the control of C. neoformans infections is strongly dependent on a prototypic type 1 immune response and classical macrophage activation, whereas type 2-biased immunity and alternative activation of macrophages has been rather implicated in disease progression and detrimental outcomes. However, little is known about regulatory pathways modulating and balancing immune responses during early phases of pulmonary cryptococcosis. Here, we analyzed the role of group 2 innate lymphoid cells (ILC2s) for the control of C. neoformans infection. Using an intranasal infection model with a highly virulent C. neoformans strain, we found that ILC2 numbers were strongly increased in C. neoformans-infected lungs along with induction of a type 2 response. Mice lacking ILC2s due to conditional deficiency of the transcription factor RAR-related orphan receptor alpha (Rora) displayed a massive downregulation of features of type 2 immunity as reflected by reduced levels of the type 2 signature cytokines IL-4, IL-5, and IL-13 at 14 days post-infection. Moreover, ILC2 deficiency was accompanied with increased type 1 immunity and classical macrophage activation, while the pulmonary numbers of eosinophils and alternatively activated macrophages were reduced in these mice. Importantly, this shift in pulmonary macrophage polarization in ILC2-deficient mice correlated with improved fungal control and prolonged survival of infected mice. Conversely, adoptive transfer of ILC2s was associated with a type 2 bias associated with less efficient anti-fungal immunity in lungs of recipient mice. Collectively, our date indicate a non-redundant role of ILC2 in orchestrating myeloid anti-cryptococcal immune responses toward a disease exacerbating phenotype.
CRIS-Team Scopus Importer:2020-03-10
Keywords: fungi (Candida; Cryptococcus); ILC2; innate immunity; lung infection; type 2 immune response

Growth in thyroid disorders in childhood and adolescence. Thyroid dysfunction and growth - Bettendorf, M.; Binder, G.; Hauffa, B. P.; Pohlenz, J.; Rohrer, T. R.; Schöfl, Christof; Dörr, Helmuth-Günther (Monatsschrift Kinderheilkunde, 2016)
Disorders of the thyroid function of mother and child can not only irreversibly inhibit maturation of the central nervous system, but may also affect growth and puberty. Review of the consequences of thyroid function disorders on the growth of children and adolescents and the relevance of adequate treatment. This article summarises the current literature concerning the effect of thyroid hormone disorders of mother and child and their therapy on growth. Every untreated manifestation of congenital or acquired hypothyroidism is associated with a delay of growth and skeletal maturation. In children presenting with acquired hyperthyroidism, height is shifted towards higher values and skeletal maturation is accelerated. Approximately 20 % of children and adolescents with Down syndrome develop primary hypothyroidism, frequently manifesting within the first months of life (approximately 5.5 %). Adequate treatment of the thyroid disorder can normalise growth disorders. About 6 % of children with growth hormone deficiency develop abnormally low free thyroxin (fT4) levels in serum during growth hormone treatment due to increased conversion of T4 to T3. There is no indication for treatment after excluding secondary hypothyroidism. Early diagnosis and timely, adequate treatment of thyroid function disorders of mother and child are essential to achieving growth that is as age-appropriate as possible in affected children and adolescents.
EVALuna2:33874

Gut as viral reservoir: Lessons from gut viromes, HIV and COVID-19 - Neurath, Markus; Überla, Klaus; Ng, Siew C. (Gut, 2021)
CRIS-Team Scopus Importer:2021-05-07
Keywords: immunology

Gut immune cell trafficking: inter-organ communication and immune-mediated inflammation - Zundler, Sebastian; Günther, Claudia; Kremer, Andreas E.; Rothhammer, Veit; Neurath, Markus; Zaiss, Mario (Nature Reviews Gastroenterology & Hepatology, 2022)
Immune cell trafficking is a complex and tightly regulated process that is indispensable for the body’s fight against pathogens. However, it is also increasingly acknowledged that dysregulation of cell trafficking contributes to the pathogenesis of immune-mediated inflammatory diseases (IMIDs) in gastroenterology and hepatology, such as inflammatory bowel disease and primary sclerosing cholangitis. Moreover, altered cell trafficking has also been implicated as a crucial step in the immunopathogenesis of other IMIDs, such as rheumatoid arthritis and multiple sclerosis. Over the past few years, a central role of the gut in mediating these disorders has progressively emerged, and the partly microbiota-driven imprinting of particular cell trafficking phenotypes in the intestine seems to be crucially involved. Therefore, this Review highlights achievements in understanding immune cell trafficking to, within and from the intestine and delineates its consequences for immune-mediated pathology along the gut–liver, gut–joint and gut–brain axes. We also discuss implications for current and future therapeutic approaches that specifically interfere with homing, retention, egress and recirculation of immune cells.
CRIS-Team Scopus Importer:2022-08-26

Gut⁻Liver Axis: How Do Gut Bacteria Influence the Liver? - Konturek, Peter Christopher; Harsch, Igor Alexander; Konturek, Kathrin; Schink, Monic; Konturek, Thomas; Neurath, Markus; Zopf, Yurdagül (Medical Sciences, 2018)
Chronic liver diseases are a major cause of morbidity and mortality worldwide. Recently, gut dysbiosis was identified as an important factor in the pathogenesis of liver diseases. The relationship between gut microbiota and the liver is still not well understood; however, dysfunction of the gut mucosal barrier ("leaky gut") and increased bacterial translocation into the liver via the gut⁻liver axis probably play crucial roles in liver disease development and progression. The liver is an important immunological organ, and, after exposure to gut-derived bacteria via portal circulation, it responds with activation of the innate and adaptive immune system, leading to hepatic injury. A better understanding of the pathophysiological links among gut dysbiosis, the integrity of the gut barrier, and the hepatic immune response to gut-derived factors is essential for the development of new therapies to treat chronic liver diseases.
CRIS-Team Scopus Importer:2023-03-23
Keywords: chronic liver diseases; dysbiosis; gut microbiota

Gut-to-brain spreading of pathology in synucleinopathies: A focus on molecular signalling mediators - Schmitt, Verena; Masanetz, Rebecca Katharina; Weidenfeller, Martin; Ebbinghaus, Lara Savannah; Süß, Patrick; Rosshart, Stephan Patrick; von Hörsten, Stephan; Zunke, Friederike; Winkler, Jürgen; Xiang, Wei (Behavioural Brain Research, 2023)
Synucleinopathies are a group of neurodegenerative disorders, classically characterized by the accumulation of aggregated alpha synuclein (aSyn) in the central nervous system. Parkinson's disease (PD) and multiple system atrophy (MSA) are the two prominent members of this family. Current treatment options mainly focus on the motor symptoms of these diseases. However, non-motor symptoms, including gastrointestinal (GI) symptoms, have recently gained particular attention, as they are frequently associated with synucleinopathies and often arise before motor symptoms. The gut-origin hypothesis has been proposed based on evidence of an ascending spreading pattern of aggregated aSyn from the gut to the brain, as well as the comorbidity of inflammatory bowel disease and synucleinopathies. Recent advances have shed light on the mechanisms underlying the progression of synucleinopathies along the gut-brain axis. Given the rapidly expanding pace of research in the field, this review presents a summary of the latest findings on the gut-to-brain spreading of pathology and potential pathology-reinforcing mediators in synucleinopathies. Here, we focus on 1) gut-to-brain communication pathways, including neuronal pathways and blood circulation, and 2) potential molecular signalling mediators, including bacterial amyloid proteins, microbiota dysbiosis-induced alterations in gut metabolites, as well as host-derived effectors, including gut-derived peptides and hormones. We highlight the clinical relevance and implications of these molecular mediators and their possible mechanisms in synucleinopathies. Moreover, we discuss their potential as diagnostic markers in distinguishing the subtypes of synucleinopathies and other neurodegenerative diseases, as well as for developing novel individualized therapeutic options for synucleinopathies.
CRIS-Team Scopus Importer:2023-08-25
Keywords: Alpha synuclein; Gut-to-brain communication; Inflammatory bowel disease; Multiple system atrophy; Parkinson's disease

HCCs lacking arterial phase hyperenhancement (APHE) on contrast-enhanced ultrasound (CEUS) - a diagnostic challenge. Findings from the prospective multicenter DEGUM CEUS HCC trial - Strobel, Deike; Agaimy, Abbas; Jesper, Daniel; Zundler, Sebastian; Schellhaas, Barbara (Ultraschall in der Medizin, 2023)
Objectives Hepatocellular carcinoma (HCC) upon contrast-enhanced ultrasound (CEUS) typically shows arterial phase hyperenhancement (APHE), followed by late (> 60 seconds) and mild contrast washout (WO). Although APHE is considered as the hallmark of HCC, it can be absent in some HCCs. Thus, we explored which sonomorphological and histopathological features of HCC are associated with a lack of APHE upon CEUS.Methods Focal liver lesions in high-risk patients for HCC were assessed with CEUS following a standardized protocol in a prospective multi-center real-life setting. CEUS patterns in HCC were assessed, and tumour and patient characteristics were compared for HCCs with and without APHE.Results 316 patients with HCC were recruited (cirrhosis, 76.9%). APHE occurred in 271/316 HCCs (85.8%). A lack of APHE was associated with portal vein thrombosis, tumour infiltration of the liver vessels (p<0.001), larger size, multilocularity, and higher depth location upon ultrasound (p<0.01). Histological grading did not differ between HCCs with and without APHE (p=0.39). Histopathological features of HCCs without APHE included cirrhotic stromal reaction, marked tumour cell steatosis and absence of the typical surrounding dilated sinusoidal vascular channels.Conclusion Correlation with histopathological findings support the fact that HCCs with a lack of APHE in CEUS are a heterogeneous group. The examiner has to be aware that particularly HCCs with portal vein thrombosis or macro-invasion of the liver vessels may lack APHE.
CRIS-Team WoS Importer:2023-04-21

Healing of the epithelial barrier in the ileum is superior to endoscopic and histologic remission for predicting major adverse outcomes in ulcerative colitis - Rath, Timo; Atreya, Raja; Bodenschatz, Julia; Uter, Wolfgang; Geppert, Carol-Immanuel; Vitali, Francesco; Zundler, Sebastian; Waldner, Maximilian; Hartmann, Arndt; Neurath, Markus (Frontiers in Medicine, 2023)
Background: Achieving endoscopic remission is a key therapeutic goal in patients with ulcerative colitis (UC) that is associated with favorable long-term disease outcomes. Here, we prospectively compared the predictive value of endoscopic and/or histologic remission against ileal barrier healing for predicting long-term disease behavior in a large cohort of UC patients in clinical remission. Methods: At baseline, UC patients in clinical remission underwent ileocolonoscopy with assessment of ileal barrier function by confocal endomicroscopy. Endoscopic and histologic disease activity and ileal barrier healing were scored using validated scores. During subsequent follow-up (FU), patients were closely monitored for clinical disease activity and occurrence of major adverse outcomes (MAO) defined as the following: disease relapse; UC-related hospitalization; UC-related surgery; necessity for initiation or dose escalation of systemic steroids, immunosuppressants, small molecules or biological therapy. Results: Of the 73 UC patients included, 67% experienced MAO during a mean FU of 25 months. The probability of MAO-free survival was significantly higher in UC patients with endoscopic and/or histologic remission compared to patients with endoscopically and/or histologically active disease. Ileal barrier healing on endomicroscopy was highly accurate for predicting the further course of UC and outcompeted endoscopic and histologic remission for predicting MAO-free survival. Conclusion: Ileal barrier healing in clinically remittent UC patients can accurately predict future MAO development and is superior in its predictive capabilities than endoscopic and histologic remission. Ileal barrier healing therefore represents a novel and superior surrogate parameter for stratification of UC patients according to their risk for development of complicated disease behavior. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT05157750, identifier NCT05157750.
CRIS-Team Scopus Importer:2023-11-03
Keywords: endoscopy; histology; inflammatory bowel diseases; intestinal barrier; ulcerative colitis

Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial - Pavel, Marianne Ellen; Singh, Simron; Strosberg, Jonathan R.; Bubuteishvili-Pacaud, Lida; Degtyarev, Evgeny; Neary, Maureen P.; Carnaghi, Carlo; Tomasek, Jiri; Wolin, Edward; Raderer, Markus; Lahner, Harald; Valle, Juan W.; et al. (Lancet Oncology, 2017)
BACKGROUND: In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint. METHODS: RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (± 1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (≥7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783. FINDINGS: Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months (95% CI 9·27-19·35) with everolimus and 9·23 months (5·52-not estimable) with placebo (adjusted hazard ratio 0·81, 95% CI 0·55-1·21; log-rank p=0·31). INTERPRETATION: HRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer. FUNDING: Novartis Pharmaceuticals.
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Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1–2 cm in size: a retrospective, Europe-wide, pooled cohort study - Nesti, Cédric; Bräutigam, Konstantin; Benavent, Marta; Bernal, Laura; Boharoon, Hessa; Botling, Johan; Bouroumeau, Antonin; Brcic, Iva; Brunner, Maximilian; Cadiot, Guillaume; Camara, Maria; Christ, Emanuel; et al. (The Lancet. Oncology, 2023)
Background: Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1–2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1–2 cm in size in patients with or without right-sided hemicolectomy. Methods: In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1–2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. Findings: 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1–2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0–15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 –21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36–2·17]; p=0·71). Interpretation: This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1–2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort. Funding: Swiss Cancer Research foundation.
CRIS-Team Scopus Importer:2023-02-10

Hepatobiliary malignancy surveillance strategies in primary sclerosing cholangitis associate with reduced mortality - Bergquist, Annika M.; Weismueller, Tobias; Levy, Cynthia; Rupp, Christian; Joshi, Deepak; Nayagam, Jeremy; Montano-Loza, Aldo J.; Lytvyak, Ellina; Wunsch, Ewa; Milkiewicz, Piotr; Zenouzi, Roman; Schramm, Christoph; et al. (JOURNAL OF HEPATOLOGY, 2021)
CRIS-Team WoS Importer:2021-07-30

Heterogeneity of tertiary lymphoid structures in cancer - You, Xin; Koop, Kristina; Weigert, Andreas (Frontiers in Immunology, 2023)
The success of immunotherapy approaches, such as immune checkpoint blockade and cellular immunotherapy with genetically modified lymphocytes, has firmly embedded the immune system in the roadmap for combating cancer. Unfortunately, the majority of cancer patients do not yet benefit from these therapeutic approaches, even when the prognostic relevance of the immune response in their tumor entity has been demonstrated. Therefore, there is a justified need to explore new strategies for inducing anti-tumor immunity. The recent connection between the formation of ectopic lymphoid aggregates at tumor sites and patient prognosis, along with an effective anti-tumor response, suggests that manipulating the occurrence of these tertiary lymphoid structures (TLS) may play a critical role in activating the immune system against a growing tumor. However, mechanisms governing TLS formation and a clear understanding of their substantial heterogeneity are still lacking. Here, we briefly summarize the current state of knowledge regarding the mechanisms driving TLS development, outline the impact of TLS heterogeneity on clinical outcomes in cancer patients, and discuss appropriate systems for modeling TLS heterogeneity that may help identify new strategies for inducing protective TLS formation in cancer patients.
CRIS-Team Scopus Importer:2023-12-29
Keywords: antigens; cancer; immunity; mouse models; tertiary lymphoid structures

Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype - Glaudo, Markus; Letz, Saskia; Quinkler, Marcus; Bogner, Ulrich; Elbelt, Ulf; Strasburger, Christian J.; Schnabel, Dirk; Lankes, Erwin; Scheel, Sandra; Feldkamp, Joachim; Haag, Christine; Schulze, Egbert; et al. (European Journal of Endocrinology, 2016)
Homozygous inactivating mutations of the calcium-sensing receptor (CaSR) lead to neonatal severe hyperparathyroidism (NSHPT), whereas heterozygous inactivating mutations result in familial hypocalciuric hypercalcemia (FHH). It is unknown why in some cases heterozygous CaSR mutations cause neonatal hyperparathyroidism (NHPT) clinically similar to NSHPT but with only moderately elevated serum calcium.A literature survey was conducted to identify patients with heterozygous CaSR mutations and NHPT. The common NHPT CaSR mutants R185Q and R227L were compared with 15 mutants causing only FHH in the heterozygous state. We studied in vitro calcium signaling including the functional consequences of co-expression of mutant and wild-type (wt) CaSR, patients' phenotype, age of disease manifestation and mode of inheritance.All inactivating CaSR mutants impaired calcium signaling of wt-CaSR regardless of the patients' clinical phenotype. The absolute intracellular calcium signaling response to physiologic extracellular calcium concentrations in vitro showed a high correlation with patients' serum calcium concentrations in vivo, which is similar in NHPT and FHH patients with the same genotype. Pedigrees of FHH families revealed that paternal inheritance per se does not necessarily lead to NHPT but may only cause FHH.There is a significant correlation between in vitro functional impairment of the CaSR at physiologic calcium concentrations and the severity of alterations in calcium homeostasis in patients. Whether a particular genotype leads to NHPT or FHH appears to depend on additional predisposing genetic or environmental factors. An individual therapeutic approach appears to be warranted for NHPT patients.
EVALuna2:2211

HiatoGast 1: An exploring, semiblinded trial establishing a new endoscopical categorisation of axial hiatal hernias - Eckhardt, Daniel; Engel, Matthias; Golcher, Henriette; Krautz, Christian; Grützmann, Robert; Elshafei, Moustafa (BMJ Global Health, 2019)
Introduction Axial hiatal hernias are a common incidental finding in endoscopical examinations, but reflux symptoms do not necessarily correspond to the presence of hiatal hernias. Diagnosing a reflux disease is difficult due to a leak of existing distinct criteria, especially in order to evaluate a surgical indication. Also a preoperative measurement of the hernia is necessary to choose between surgical options. Methods and analysis We planned a semiblinded trial including a questionnaire and an oesophagogastroduodenoscopy afterwards. While the endoscopy is done, the hiatus oesophagi should be measured in inversion technique under maximum insufflation including length, width and herniated volume. A sample of 210 participants until December 2020 is determined to evaluate the primary endpoint: we look forward to evaluate the anatomical parameters of reflux and non-reflux participants. Ethics and Dissemination The study has been approved by the local ethics committee on 12th February 2019, the data will bei published after closure of inclusion. Trial registration number German Clinical Trials Register (DRKS00016863).
CRIS-Team Scopus Importer:2019-07-02
Keywords: endoscopical technique; gastroscopy; hiatal hernia; reflux

High-definition endoscopy with digital chromoendoscopy for histologic prediction of distal colorectal polyps - Rath, Timo; Tontini, Gian E.; Naegel, Andreas; Zopf, Steffen; Günther, Claudia; Hoffman, Arthur; Neurath, Markus; Neumann, Helmut; Vieth, Michael (BMC Gastroenterology, 2015)
Distal diminutive colorectal polyps are common and accurate endoscopic prediction of hyperplastic or adenomatous polyp histology could reduce procedural time, costs and potential risks associated with the resection. Within this study we assessed whether digital chromoendoscopy can accurately predict the histology of distal diminutive colorectal polyps according to the ASGE PIVI statement.In this prospective cohort study, 224 consecutive patients undergoing screening or surveillance colonoscopy were included. Real time histology of 121 diminutive distal colorectal polyps was evaluated using high-definition endoscopy with digital chromoendoscopy and the accuracy of predicting histology with digital chromoendoscopy was assessed.The overall accuracy of digital chromoendoscopy for prediction of adenomatous polyp histology was 90.1 %. Sensitivity, specificity, positive and negative predictive values were 93.3, 88.7, 88.7, and 93.2 %, respectively. In high-confidence predictions, the accuracy increased to 96.3 % while sensitivity, specificity, positive and negative predictive values were calculated as 98.1, 94.4, 94.5, and 98.1 %, respectively. Surveillance intervals with digital chromoendoscopy were correctly predicted with >90 % accuracy.High-definition endoscopy in combination with digital chromoendoscopy allowed real-time in vivo prediction of distal colorectal polyp histology and is accurate enough to leave distal colorectal polyps in place without resection or to resect and discard them without pathologic assessment. This approach has the potential to reduce costs and risks associated with the redundant removal of diminutive colorectal polyps.ClinicalTrials NCT02217449 .
EVALuna2:1977

High-definition endoscopy with iScan and Lugol's solution for the detection of inflammation in patients with nonerosive reflux disease: histologic evaluation in comparison with a control group - Rey, J. W.; Deris, N.; Marquardt, J. U.; Thomaidis, T.; Moehler, M.; Kittner, J. M.; Nguyen-Tat, M.; Duemcke, S.; Tresch, A.; Biesterfeld, S.; Goetz, M.; Mudter, J.; et al. (Diseases of the Esophagus, 2016)
Nonerosive reflux disease (NERD) is commonly diagnosed in patients with symptoms of reflux. The aim of the present study was to determine whether high-definition endoscopy (HD) plus equipped with the iScan function or chromoendoscopy with Lugol's solution might permit the differentiation of NERD patients from those without reflux symptoms, proven by targeted biopsies of endoscopic lesions. A total of 100 patients without regular intake of proton pump inhibitors and with a normal conventional upper endoscopy were prospectively divided into NERD patients and controls. A second upper endoscopy was performed using HD+ with additional iScan function and then Lugol's solution was applied. Biopsy specimens were taken from the gastroesophageal junction in all patients. A total of 65 patients with reflux symptoms and 27 controls were included. HD(+) endoscopy with iScan revealed subtle mucosal breaks in 52 patients; the subsequent biopsies confirmed esophagitis in all cases. After Lugol's solution, 58 patients showed mucosal breaks. Sensitivity for the iScan procedure was 82.5%, whereas that for Lugol's solution was 92.06%. Excellent positive predictive values of 100% and 98.3%, respectively, were noted. The present study suggests that the majority of patients with NERD and typical symptoms of reflux disease can be identified by iScan or Lugol's chromoendoscopy as minimal erosive reflux disease (ERD) patients.
EVALuna2:2096

High-fat-diet-associated intestinal microbiota exacerbates psoriasis-like inflammation by enhancing systemic γδ T cell IL-17 production - Sonomoto, Koshiro; Song, Rui; Eriksson, Daniel; Hahn, Anne Maria; Meng, Xianyi; Lyu, Pang; Cao, Shan; Liu, Ning; Taudte, Verena; Wirtz, Stefan; Tanaka, Yoshiya; Winkler, Thomas; et al. (Cell Reports, 2023)
Although it is known that psoriasis is strongly associated with obesity, the mechanistic connection between diet and skin lesions is not well established. Herein, we showed that only dietary fat, not carbohydrates or proteins, exacerbates psoriatic disease. Enhanced psoriatic skin inflammation was associated with changes in the intestinal mucus layer and microbiota composition by high-fat diet (HFD). Change of intestinal microbiota by vancomycin treatment effectively blocked activation of psoriatic skin inflammation by HFD, inhibited the systemic interleukin-17 (IL-17) response, and led to increased mucophilic bacterial species such as Akkermansia muciniphila. By using IL-17 reporter mice, we could show that HFD facilitates IL-17-mediated γδ T cell response in the spleen. Notably, oral gavage with live or heat-killed A. muciniphila effectively inhibited HFD-induced enhancement of psoriatic disease. In conclusion, HFD exacerbates psoriatic skin inflammation through changing the mucus barrier and the intestine microbial composition, which leads to an enhanced systemic IL-17 response.
CRIS-Team Scopus Importer:2023-07-28
Keywords: CP: Immunology; CP: Microbiology; high-fat diet; psoriasis; γδT cell

High level of EPA is associated with lower perivascular coronary attenuation as measured by coronary CTA - Bittner, D. O.; Göller, Markus; Zopf, Yurdagül; Achenbach, Stephan; Marwan, Mohamed (EUROPEAN HEART JOURNAL, 2019)
CRIS-Team WoS Importer:2020-02-04

High levels of eicosapentaenoic acid are associated with lower pericoronary adipose tissue attenuation as measured by coronary CTA - Bittner, Daniel O.; Göller, Markus; Dey, Damini; Zopf, Yurdagül; Achenbach, Stephan; Marwan, Mohamed (Atherosclerosis, 2020)
Background and aims: Higher pericoronary adipose tissue (PCAT) attenuation, a novel marker of inflammation in coronary CT angiography (CTA), has been shown to indicate increased cardiac mortality. Supplementation of eicosapentaenoic acid (EPA) has been shown to decrease cardiovascular death. Whether blood levels of n-3 fatty acids are associated with differences in PCAT attenuation is unknown. Methods: This is a cross-sectional analysis including 64 symptomatic patients who underwent coronary CTA. PCAT attenuation was measured in Hounsfield Units (HU) around the proximal 40 mm of the right coronary artery using semi-automated software. Erythrocyte membrane fatty acid composition was analyzed using gas chromatography. Individual fatty acids were expressed as a percentage of total identified fatty acids. Results: The patient cohort was divided into two groups using the median PCAT attenuation of −78.1 HU (each n = 32). No differences were seen in age, sex, BMI or traditional cardiovascular risk factors (CVRF) between groups (all p > 0.05). In univariable analysis, significantly higher values of EPA (1.00% [0.78; 1.26] vs. 0.78% [0.63; 0.99]; p = 0.02) were seen in patients with lower PCAT attenuation. All other fatty acids showed no differences (all p > 0.05). Moreover, a significant negative correlation was seen between PCAT attenuation and EPA (CC: 0.38; p = 0.002). In multivariable analysis, an inverse association of EPA with PCAT attenuation existed (ß = −0.31, p = 0.017), independent of age, gender, BMI and number of CVRF (all p > 0.1). Conclusions: High levels of EPA are associated with lower PCAT attenuation on coronary CTA. This may indicate a different composition of pericoronary adipose tissue, potentially caused by a lower degree of coronary inflammation.
CRIS-Team Scopus Importer:2020-11-06
Keywords: Coronary CT-Angiography; Eicosapentaenoic acid; Omega-3 fatty acids; Perivascular coronary inflammation

High-protein Nutrition and Whole-body Electromyostimulation in Hematologic-oncological Patients: Is a new Option? - Reljic, Dejan; Herrmann, Hans Joachim; Neurath, Markus; Zopf, Yurdagül (2018)
EVALuna2:35185

High rate of Ki-67 increase in entero-pancreatic NET relapses after surgery with curative intent - Merola, Elettra; Perren, Aurel; Rinke, Anja; Zerbi, Alessandro; Mcnamara, Mairead G.; Arsenic, Ruza; Fazio, Nicola; De Herder, Wouter; Valle, Juan W.; Gress, Thomas M.; Wiedenmann, Bertram; Pascher, Andreas; et al. (Journal of Neuroendocrinology, 2022)
Neuroendocrine neoplasms (NENs) present with advanced disease at diagnosis in up to 28% of cases, precluding the possibility of curative-intent surgery. Histopathological heterogeneity of this disease can be observed inter-individually as well as intra-individually during disease course. The present study aimed to assess the frequency of Ki-67 change after radical surgery, in a series of patients with radically resected entero-pancreatic neuroendocrine tumors (EP-NETs). We present the analysis of a multicenter, retrospective, series of EP-NETs G1-G2 recurring after radical resection and with histological re-evaluation at disease recurrence (DR). The primary endpoint was the description of Ki-67 change at DR compared to time of surgery. The secondary endpoint was assessment of recurrence-free survival (RFS) rates. In total, 47 patients had a second histological evaluation and could be included in the present study. Median Ki-67 at surgery was 3% (range 1-15%) but, at DR, a significant increase in the value was observed (7%, range 1-30%; p < .01) and involved 66.0% of cases, with a corresponding increase in tumor grading in 34.0% (p = .05). Median RFS of the overall population was 40 months, and was worse when Ki-67 increased at DR vs. stable Ki-67 value (36 vs. 61 months, respectively; p = .02). In conclusion, in more than half of the cases with relapse after radical surgery, a higher proliferative index with a potentially more aggressive potential was observed. Therefore, histological reassessment should be considered on DR because tailored therapeutic strategies may be required for these patients.
CRIS-Team WoS Importer:2022-09-02

High-resolution quantitative computed tomography demonstrates structural defects in cortical and trabecular bone in IBD patients. - Haschka, Judith; Hirschmann, Simon; Kleyer, Arnd; Englbrecht, Matthias; Faustini, Francesca; Simon, David; Figueiredo, Camille P; Schuster, Louis; Muschitz, Christian; Kocijan, Roland; Resch, Heinrich; Atreya, Raja; et al. (Journal of Crohns & Colitis, 2016)
Background and Aims To investigate the macro- and microstructural changes of bone in patients with inflammatory bowel disease (IBD) and to define the factors associated with bone loss in IBDMethods A total of148 subjects, 59 with Crohn's Disease (CD), 39 with Ulcerative Colitis (UC) and 50 healthy controls were assessed for the geometric, volumetric and microstructural properties of bone using high-resolution peripheral quantitative computed tomography. In addition, demographic and disease-specific characteristics of IBD patients were recorded.Results IBD patients and controls were comparable in age, sex and body mass index. Total (p=0.001), cortical (p<0.001) and trabecular volumetric BMD (p=0.03) were significantly reduced in IBD patients compared to healthy controls. Geometric and microstructure analysis revealed significantly lower cortical area (p=0.001) and cortical thickness (p<0.001) without differences in cortical porosity, pore volume or pore diameter. CD showed a more severe bone phenotype than UC: While cortical bone loss was observed in both diseases, CD additionally showed profound trabecular bone loss with reduced trabecular BMD (p=0.008), bone volume (p=0.008) and trabecular thickness (p=0.009).Multivariate regression models identified the diagnosis of CD, female sex, lower body mass index and the lack of remission as factors independently associated with bone loss in IBD.Conclusion IBD patients develop significant cortical bone loss impairing bone strength. Trabecular bone loss is limited to CD patients, which exhibits a more severe bone phenotype compared to UC patients.
EVALuna2:2046

High-throughput Raman spectroscopy allows ex vivo characterization of murine small intestinal intra-epithelial lymphocytes (IEL) - Guliev, Rustam R. R.; Vogler, Tina; Arend, Natalie; Eiserloh, Simone; Wiede, Alexander; Kunert, Timo; Dinkel, Martin; Popp, Juergen; Schie, Iwan W. W.; Hildner, Kai; Neugebauer, Ute (Analyst, 2023)
T cells are considered to be critical drivers of intestinal inflammation in mice and people. The so called intra-epithelial lymphocyte (IEL) compartment largely consist of T cells. Interestingly, the specific regulation and contribution of IELs in the context of inflammatory bowel disease remains poorly understood, in part due to the lack of appropriate analysis tools. Powerful, label-free methods could ultimately provide access to this cell population and hence give valuable insight into IEL biology and even more to their disease-related functionalities. Raman spectroscopy has demonstrated over the last few years its potential for reliable cell characterization and differentiation, but its utility in regard to IEL exploration remains unknown. To address this question experimentally, we utilized a murine, T cell-driven experimental model system which is accepted to model human gut inflammation. Here, we repopulated the small intestinal IEL compartment (SI IELs) of Rag1-deficient mice endogenously lacking T cells by transferring naïve CD4+ T helper cells intraperitoneally. Using multivariate statistical analysis, high-throughput Raman spectroscopy managed to define a cell subpopulation ex vivo within the SI IEL pool of mice previously receiving T cells in vivo that displayed characteristic spectral features of lymphocytes. Raman data sets matched flow cytometry analyses with the latter identifying T cell receptor (TCR)αβ+ CD4+ T cell population in SI IELs from T cell-transferred mice, but not from control mice, in an abundance comparable to the one detected by Raman spectroscopy. Hence, in this study, we provide experimental evidence for high-throughput Raman spectroscopy to be a novel, future tool to reliably identify and potentially further characterize the T cell pool of small intestinal IELs ex vivo.
CRIS-Team Scopus Importer:2023-04-20

“HIIT the Inflammation”: Comparative Effects of Low-Volume Interval Training and Resistance Exercises on Inflammatory Indices in Obese Metabolic Syndrome Patients Undergoing Caloric Restriction - Reljic, Dejan; Dieterich, Walburga; Herrmann, Hans J.; Neurath, Markus; Zopf, Yurdagül (Nutrients, 2022)
Exercise is a cornerstone in metabolic syndrome (MetS) treatment. However, the effects of low-volume exercise modalities on MetS-associated low-grade inflammation are unclear. A total of 106 MetS patients (53.7 ± 11.4 years) were randomized to low-volume high-intensity interval training (LOW-HIIT, 14 min/session), single-set resistance training (1-RT, 15 min/session), whole-body electromyostimulation (WB-EMS, 20 min/session), three-set resistance training (3-RT, 50 min/session), each performed 2 ×/week for 12 weeks, or a control group (CON). All groups received nutritional counseling for weight loss. Inflammatory and cardiometabolic indices were analyzed pre-and post-intervention. All groups significantly reduced body weight by an average of 3.6%. Only LOW-HIIT reduced C-reactive protein (CRP) (−1.6 mg/L, p = 0.001) and interleukin-6 (−1.1 pg/mL, p = 0.020). High-sensitivity CRP and lipopolysaccharide-binding protein decreased following LOW-HIIT (−1.4 mg/L, p = 0.001 and −2.1 ng/mL, p = 0.004) and 3-RT (−0.6 mg/L, p = 0.044 and −2.0 ng/mL, p < 0.001). MetS severity score improved with LOW-HIIT (−1.8 units, p < 0.001), 1-RT (−1.6 units, p = 0.005), and 3-RT (−2.3 units, p < 0.001). Despite similar effects on body weight, low-volume exercise modalities have different impact on inflammatory and cardiometabolic outcomes in MetS patients. LOW-HIIT has superior efficacy for improving inflammation compared to 1-RT and WB-EMS. Resistance-based exercise appears to require a higher volume to promote beneficial impact on inflammation.
CRIS-Team Scopus Importer:2022-05-20
Keywords: cardiometabolic health; CRP; high-intensity interval training; obesity; single-set resistance training; whole-body electromyostimulation

Histamine in atrial fibrillation (AF)–is there any connection? Results from an unselected population - Layritz, C. M.; Hagel, Alexander; Graf, V.; Reiser, C.; Klinghammer, Lutz; Ropers, Dieter; Achenbach, Susanne; Raithel, M. (International Journal of Cardiology, 2014)
EVALuna2:1903

Histamine intolerance: Causes, diagnosis and therapy - Schink, Monic; Tietz, E.; Zopf, Yurdagül (Allergologie, 2018)
At present, histamine intolerance (HIT) represents a controversial condition. An impaired degradation of orally supplied histamine due to diamine oxidase (DAO) deficiency is assumed to be the leading cause. Histamine-rich or -liberating foods as well as DAO-inhibiting drugs are discussed as exogenous sources. Endogenously, histamine is produced by mast cells, basophils, or enterochromaffin cells. Because of a broad range of gastrointestinal (diarrhea, nausea, vomiting) and extra-intestinal symptoms (headache, flush, rash) as well as an unclear diagnostic approach, diagnosis is difficult at present. The exclusion of other differential diagnoses, including carbohydrate malabsorption or mastocytosis, plays an important role. Therapeutically, a histamine-reduced diet seems to be the first choice, adjusted to the individual tolerance threshold and supported by a professional dietician.
EVALuna2:35157

Histopathological Revision for Gastroenteropancreatic Neuroendocrine Neoplasms in Expert Centers: Does It Make the Difference? - Merola, E.; Zandee, W.; De Mestier, L.; Klumpen, H. J.; Geboes, K. P.; Poczkaj, K.; W, De Herder; Munir, A. (2018)
EVALuna2:34080

HLA-DO: a possible switch between GvHD and GvL effect - Zeun, J.; Neubeck, S.; Lang, Vanessa; Flamann, Cindy; Nagel, L.; Kunert, Timo; Vogler, T.; Brey, Stefanie; Hildner, Kai; Bäuerle, Tobias; Büttner-Herold, Maike; Winkler, Thomas; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Hobit- and Blimp-1-driven CD4(+) tissue-resident memory T cells control chronic intestinal inflammation - Zundler, Sebastian; Becker, Emily; Spocinska, Marta; Slawik, Monique; Parga-Vidal, Loreto; Stark, Regina; Wiendl, Maximilian; Atreya, Raja; Rath, Timo; Leppkes, Moritz; Hildner, Kai; Lopez Posadas, Rocío; et al. (Nature Immunology, 2019)
Although tissue-resident memory T cells (T-RM cells) have been shown to regulate host protection in infectious disorders, their function in inflammatory bowel disease (IBD) remains to be investigated. Here we characterized T-RM cells in human IBD and in experimental models of intestinal inflammation. Pro-inflammatory T-RM cells accumulated in the mucosa of patients with IBD, and the presence of CD4(+)CD69(+)CD103(+) T-RM cells was predictive of the development of flares. In vivo, functional impairment of T-RM cells in mice with double knockout of the T-RM-cell-associated transcription factors Hobit and Blimp-1 attenuated disease in several models of colitis, due to impaired cross-talk between the adaptive and innate immune system. Finally, depletion of T-RM cells led to a suppression of colitis activity. Together, our data demonstrate a central role for T-RM cells in the pathogenesis of chronic intestinal inflammation and suggest that these cells could be targets for future therapeutic approaches in IBD.
CRIS-Team WoS Importer:2019-03-06

Hobit- and Blimp1-driven tissue resident memory T cells critically control chronic intestinal inflammation - Zundler, Sebastian; Becker, E.; Spocinska, M.; Parga-Vidal, L.; Stark, R.; Atreya, Raja; Rath, T.; Leppkes, Moritz; Neufert, Clemens; Atreya, I.; Van Gisbergen, K.; Neurath, Markus (2018)
EVALuna2:34078

Host and microbiota interactions are critical for development of murine Crohn's-like ileitis - Roulis, M.; Bongers, Gerold; Armaka, M.; Salviano, T.; He, Z.; Singh, A.; Seidler, U.; Becker, Christoph; Demengeot, Jocelyne; Furtado, G. C.; Lira, S. A.; Kollias, George (Mucosal Immunology, 2016)
Deregulation of host-microbiota interactions in the gut is a pivotal characteristic of Crohn's disease. It remains unclear, however, whether commensals and/or the dysbiotic microbiota associated with pathology in humans are causally involved in Crohn's pathogenesis. Here, we show that Crohn's-like ileitis in Tnf(?ARE/+) mice is microbiota-dependent. Germ-free Tnf(?ARE/+) mice are disease-free and the microbiota and its innate recognition through Myd88 are indispensable for tumor necrosis factor (TNF) overexpression and disease initiation in this model. The epithelium of diseased mice shows no major defects in mucus barrier and paracellular permeability. However, Tnf(?ARE/+) ileitis associates with the reduction of lysozyme-expressing Paneth cells, mediated by adaptive immune effectors. Furthermore, we show that established but not early ileitis in Tnf(?ARE/+) mice involves defective expression of antimicrobials and dysbiosis, characterized by Firmicutes expansion, including epithelial-attaching segmented filamentous bacteria, and decreased abundance of Bacteroidetes. Microbiota modulation by antibiotic treatment at an early disease stage rescues ileitis. Our results suggest that the indigenous microbiota is sufficient to drive TNF overexpression and Crohn's ileitis in the genetically susceptible Tnf(?ARE/+) hosts, whereas dysbiosis in this model results from disease-associated alterations including loss of lysozyme-expressing Paneth cells.
EVALuna2:2174

Host–microbiota interactions in inflammatory bowel disease - Neurath, Markus (Nature Reviews Gastroenterology & Hepatology, 2019)
CRIS-Team Scopus Importer:2019-12-31

How Much Liver Tissue Is Required for Sufficient Histological Staging in Patients with Primary Biliary Cholangitis? - Vetter, Marcel; Kremer, Andreas; Agaimy, Abbas; Pfeifer, Lukas; Neurath, Markus; Zopf, Steffen; Siebler, Jürgen (Digestion, 2020)
Introduction: Histological alterations in primary biliary cholangitis (PBC) are heterogeneously distributed throughout the liver. Thus, the quality of histological staging is probably dependent on the available amount of liver tissue. The goals of this study were to test this hypothesis and to define biopsy conditions for obtaining sufficient tissue. Methods: In this retrospective analysis, we investigated 34 patient cases who fulfilled the criteria of the European Association for the Study of the Liver (EASL) for PBC and underwent a mini-laparoscopic liver biopsy between 2011 and 2018 using 16 or 18G needles. For histological assessment of fibrosis, we used the Ishak score, and the amount of tissue was measured by the number of portal fields. Histological staging was compared with the macroscopic mini-laparoscopic fibrosis score (MLFS), and non-invasive liver stiffness measurements using acoustic radiation force impulse (ARFI) imaging and the FIB-4 score. Results: Biopsy was successful in 33 of 34 patients (97%). Fibrosis assessment by MLFS and ARFI correlated strongly with each other (r = 0.7088, p = 0.000017). However, the correlation of both methods with the histological staging was weaker (MLFS vs. histology: r = 0.4231, p = 0.0142; ARFI vs. histology: r = 0.3564, p = 0.0577). The correlation of ARFI and MLFS with the histological staging was better in the subgroup of biopsies with at least 10 portal fields (= SG≥10PF) (MLFS vs. histology: r = 0.6369, p = 0.006; ARFI vs. histology: r = 0.7538, p = 0.0012). FIB-4 correlated weakly with the histological staging, which was statistically not significant (all samples: r = 0.2693, p = 0.1296; SG≥10PF: r = 0.2244, p = 0.3866). The number of portal fields correlated well with the length of the samples (r = 0.6436, p = 0.00012). The probability to attain at least 10 portal fields depended on the needle diameter and number of samples (1 × 16G or 18G [n = 10]: 30.0%; 2 × 18G [n = 15]: 53.3%; 2 × 16G [n = 5]: 100%; p = 0.0414). Conclusion: ARFI and MLFS are probably well suited for the assessment of liver fibrosis in patients with PBC. A minimum of 10 portal fields could improve the histological assessment in PBC and can probably be achieved by obtaining two 16G biopsies.
CRIS-Team Scopus Importer:2020-06-19

How the Tumor Micromilieu Modulates the Recruitment and Activation of Colorectal Cancer-Infiltrating Lymphocytes - Atreya, Imke; Neurath, Markus (Biomedicines, 2022)
The successful treatment of advanced colorectal cancer disease still represents an insufficiently solved clinical challenge, which is further complicated by the fact that the majority of malignant colon tumors show only relatively low immunogenicity and therefore have only limited responsiveness to immunotherapeutic approaches, such as, for instance, the use of checkpoint inhibitors. As it has been well established over the past two decades that the local tumor microenvironment and, in particular, the quantity, quality, and activation status of intratumoral immune cells critically influence the clinical prognosis of patients diagnosed with colorectal cancer and their individual benefits from immunotherapy, the enhancement of the intratumoral accumulation of cytolytic effector T lymphocytes and other cellular mediators of the antitumor immune response has emerged as a targeted objective. For the future identification and clinical validation of novel therapeutic target structures, it will thus be essential to further decipher the molecular mechanisms and cellular interactions in the intestinal tumor microenvironment, which are crucially involved in immune cell recruitment and activation. In this context, our review article aims at providing an overview of the key chemokines and cytokines whose presence in the tumor micromilieu relevantly modulates the numeric composition and antitumor capacity of tumor-infiltrating lymphocytes.
CRIS-Team WoS Importer:2022-12-23

How will new and future therapies change our treatment of IBD? - Zundler, Sebastian; Neurath, Markus (Expert Review of Clinical Immunology, 2016)
Fundamental insights into the pathogenesis of inflammatory bowel diseases (IBD) have led to the development of new therapies and lots of experimental compounds in the pipeline. Our treatment of IBD is therefore constantly evolving. In this editorial, we postulate that bi- or even polyspecific therapy will be an important mainstay of future IBD treatment. Moreover, we highlight some promising new therapeutic concepts currently under investigation and point at the outstanding and growing importance of personalized medicine to assign drugs from the increasing pool of options to the individual patient.
EVALuna2:2069

Human CD4+ T cells specific for dominant epitopes of SARS-CoV-2 Spike and Nucleocapsid proteins with therapeutic potential - Verhagen, Johan; van der Meijden, Edith; Lang, Vanessa; Kremer, Andreas; Völkl, Simon; Mackensen, Andreas; Aigner, Michael; Kremer, Anita (Clinical and Experimental Immunology, 2021)
Since December 2019, Coronavirus disease-19 (COVID-19) has spread rapidly throughout the world, leading to a global effort to develop vaccines and treatments. Despite extensive progress, there remains a need for treatments to bolster the immune responses in infected immunocompromised individuals, such as cancer patients who recently underwent a haematopoietic stem cell transplantation. Immunological protection against COVID-19 is mediated by both short-lived neutralizing antibodies and long-lasting virus-reactive T cells. Therefore, we propose that T cell therapy may augment efficacy of current treatments. For the greatest efficacy with minimal adverse effects, it is important that any cellular therapy is designed to be as specific and directed as possible. Here, we identify T cells from COVID-19 patients with a potentially protective response to two major antigens of the SARS-CoV-2 virus, Spike and Nucleocapsid protein. By generating clones of highly virus-reactive CD4+ T cells, we were able to confirm a set of nine immunodominant epitopes and characterize T cell responses against these. Accordingly, the sensitivity of T cell clones for their specific epitope, as well as the extent and focus of their cytokine response was examined. Moreover, using an advanced T cell receptor (TCR) sequencing approach, we determined the paired TCR-αβ sequences of clones of interest. While these data on a limited population require further expansion for universal application, the results presented here form a crucial first step towards TCR-transgenic CD4+ T cell therapy of COVID-19.
CRIS-Team Scopus Importer:2021-07-09
Keywords: COVID-19; epitope; SARS-CoV-2; T cell; T cell receptor

Human Double-Negative Regulatory T-Cells Induce a Metabolic and Functional Switch in Effector T-Cells by Suppressing mTOR Activity - Haug, Tabea; Aigner, Michael; Peuser, Moritz M.; Strobl, Carolin; Hildner, Kai; Mougiakakos, Dimitrios; Bruns, Heiko; Mackensen, Andreas; Völkl, Simon (Frontiers in Immunology, 2019)
The recently discovered population of TCR alpha b + CD4-/CD8-(double-negative, DN) T-cells are highly potent suppressor cells in mice and humans. In preclinical transplantation models, adoptive transfer of DN T-cells specifically inhibits alloreactive T-cells and prevents transplant rejection or graft-vs.-host disease (GvHD). Interestingly, clinical studies in patients who underwent allogeneic stem cell transplantation reveal an inverse correlation between the frequency of circulating DN T-cells and the severity of GvHD, suggesting a therapeutic potential of human DN T-cells. However, their exact mode of action has not been elucidated yet. Investigating the impact of DN T-cells on conventional T-cells, we found that human DN T-cells selectively inhibit mTOR signaling in CD4 T-cells. Given that mTOR is a critical regulator of cellular metabolism, we further determined the impact of DN T-cells on the metabolic framework of T-cells. Intriguingly, DN T-cells diminished expression of glucose transporters and glucose uptake, whereas fatty acid uptake was not modified, indicating that DN T-cells prevent metabolic adaptation of CD4 T-cells upon activation (i.e., glycolytic switch) thereby contributing to their suppression. Further analyses demonstrated that CD4 T-cells also do not upregulate homing receptors associated with inflammatory processes. In contrast, expression of central memory-cell associated cell surface markers and transcription factors were increased by DN T-cells. Moreover, CD4 T-cells failed to produce inflammatory cytokines after co-culture with DN T-cells, whereas IL-2 secretion was enhanced. Taken together DN T-cells impair metabolic reprogramming of conventional CD4 T-cells by abrogating mTOR signaling, thereby modulating CD4 T-cell functionality. These results uncover a new mechanism of DN T-cell-mediated suppression, pointing out that DN T-cells could serve as cell-based therapy to limit alloreactive immune response.
CRIS-Team WoS Importer:2019-05-03

Human resident liver myeloid cells protect against metabolic stress in obesity - Barreby, Emelie; Strunz, Benedikt; Nock, Sebastian; Naudet, Léa; Shen, Joanne X.; Johansson, Helene; Sönnerborg, Isabella; Ma, Junjie; Urgard, Egon; Pallett, Laura J.; Hu, Yizhou; Fardellas, Achilleas; et al. (Nature Metabolism, 2023)
Although multiple populations of macrophages have been described in the human liver, their function and turnover in patients with obesity at high risk of developing non-alcoholic fatty liver disease (NAFLD) and cirrhosis are currently unknown. Herein, we identify a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation, we find that liver myeloid cell turnover differs between humans and mice. Using single-cell techniques and flow cytometry, we determine that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures reveal that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD.
CRIS-Team Scopus Importer:2023-07-21

Human T cells loaded with superparamagnetic iron oxide nanoparticles retain antigen-specific TCR functionality. - Pfister, Felix; Dörrie, Jan; Schaft, Niels; Buchele, Vera; Unterweger, Harald; Carnell, Lucas R.; Schreier, Patrick; Stein, René; Kubánková, Markéta; Guck, Jochen; Hackstein, Holger; Alexiou, Christoph; et al. (Frontiers in Immunology, 2023)
BACKGROUND: Immunotherapy of cancer is an emerging field with the potential to improve long-term survival. Thus far, adoptive transfer of tumor-specific T cells represents an effective treatment option for tumors of the hematological system such as lymphoma, leukemia or myeloma. However, in solid tumors, treatment efficacy is low owing to the immunosuppressive microenvironment, on-target/off-tumor toxicity, limited extravasation out of the blood vessel, or ineffective trafficking of T cells into the tumor region. Superparamagnetic iron oxide nanoparticles (SPIONs) can make cells magnetically controllable for the site-specific enrichment. METHODS: In this study, we investigated the influence of SPION-loading on primary human T cells for the magnetically targeted adoptive T cell therapy. For this, we analyzed cellular mechanics and the T cell response after stimulation via an exogenous T cell receptor (TCR) specific for the melanoma antigen MelanA or the endogenous TCR specific for the cytomegalovirus antigen pp65 and compared them to T cells that had not received SPIONs. RESULTS: SPION-loading of human T cells showed no influence on cellular mechanics, therefore retaining their ability to deform to external pressure. Additionally, SPION-loading did not impair the T cell proliferation, expression of activation markers, cytokine secretion, and tumor cell killing after antigen-specific activation mediated by the TCR. CONCLUSION: In summary, we demonstrated that SPION-loading of T cells did not affect cellular mechanics or the functionality of the endogenous or an exogenous TCR, which allows future approaches using SPIONs for the magnetically enrichment of T cells in solid tumors.
EVALuna2:539766
Keywords: Adoptive T cell therapy; superparamagnetic iron oxide nanoparticles (SPIONs); antigen-specific T cell response; targeted immune therapy; cell deformability

Human α-Defensin 51–9 and Human β-Defensin 2 Improve Metabolic Parameters and Gut Barrier Function in Mice Fed a Western-Style Diet - Filipe Rosa, Louisa; Rings, Andreas; Stolzer, Iris; Koeninger, Louis; Wehkamp, Jan; Beisner, Julia; Günther, Claudia; Nordkild, Peter; Jensen, Benjamin A.H.; Bischoff, Stephan C. (International Journal of Molecular Sciences, 2023)
Obesity and metabolic comorbidities are associated with gut permeability. While high-fructose and Western-style diet (WSD) disrupt intestinal barrier function, oral administration of human α-defensin 5 (HD5) and β-defensin 2 (hBD2) is believed to improve intestinal integrity and metabolic disorders. Eighty-four male C57BL/6J mice were fed a WSD or a control diet (CD) ± fructose (F) for 18 weeks. In week 13, mice were randomly divided into three intervention groups, receiving defensin fragment HD51–9, full-length hBD2, or bovine serum albumin (BSA)-control for six weeks. Subsequently, parameters of hepatic steatosis, glucose metabolism, and gut barrier function were assessed. WSDF increased body weight and hepatic steatosis (p < 0.01) compared to CD-fed mice, whereas peptide intervention decreased liver fat (p < 0.05) and number of hepatic lipid droplets (p < 0.01) compared to BSA-control. In addition, both peptides attenuated glucose intolerance by reducing blood glucose curves in WSDF-fed mice. Evaluation of gut barrier function revealed that HD51–9 and hBD2 improve intestinal integrity by upregulating tight junction and mucin expression. Moreover, peptide treatment restored ileal host defense peptides (HDP) expression, likely by modulating the Wnt, Myd88, p38, and Jak/STAT pathways. These findings strongly suggest that α- and β-defensin treatment improve hepatic steatosis, glucose metabolism, and gut barrier function.
CRIS-Team Scopus Importer:2023-11-03
Keywords: antimicrobial peptides; glucose metabolism; gut barrier; hBD2; HD5 fragments; host defense peptides; NAFLD; obesity

Hybrid reflected-ultrasound computed tomography versus B-mode-ultrasound for muscle scoring in spinal muscular atrophy - Danko, Vera; Jüngert, Jörg M.; Schüssler, Stephanie; Bühler, Adrian; Klett, Daniel; Federle, Anna; Roos, Andreas; Lochmüller, Hanns; Neurath, Markus; Wölfle, Joachim; Trollmann, Regina; Waldner, Maximilian; et al. (Journal of Neuroimaging, 2023)
Background and Purpose: Novel light- and sound-based technologies like multispectral optoacoustic tomography (MSOT) with co-registered reflected-ultrasound computed tomography (RUCT) could add additional value to conventional ultrasound (US) for disease phenotyping in pediatric spinal muscular atrophy (SMA). The aim of this study was to investigate the quality of RUCT compared to US for qualitative and quantitative assessment of imaging neuromuscular disorders. Methods: Subanalyzing the MSOT SMA study, 288 RUCT and 276 US images from 10 SMA patients (mean age 9.0 ± 3.7) and 10 gender- and age-matched healthy volunteers (HV; mean age 8.7 ± 4.3) were analyzed for quantitative (grayscale levels [GSLs]) and qualitative (echogenicity, distribution pattern, Heckmatt scale, and muscle texture) muscle changes. RUCT and US measures were further correlated with clinical standard motor outcomes. Results: Quantitative agreement using GSLs revealed significantly higher GSLs in muscles of SMA patients compared to healthy muscles in both techniques (US mean GSL [SD] SMA vs. HV: 110.70 [27.8] vs. 68.85 [19.2], p <.0001; RUCT mean GSL [SD] SMA vs. HV: 91.81 [21.8] vs. 59.86 [8.2], p <.0001) with good correlation with motor outcome tests, respectively. Qualitative agreement between methods for muscle composition was excellent for differentiation of pathological versus healthy muscles, echogenicity, and distribution pattern, moderate for Heckmatt scale, and poor for muscle texture. Conclusions: The data suggest that RUCT may allow the assessment of basic qualitative and quantitative measures for muscular diseases with comparable results to conventional US.
CRIS-Team Scopus Importer:2023-01-20
Keywords: neuromuscular disorders; optoacoustics; photoacoustics; spinal muscular atrophy; ultrasound

Hybrid ultrasound and single wavelength optoacoustic imaging reveals muscle degeneration in peripheral artery disease - Träger, Anna P.; Günther, Josefine; Raming, Roman; Paulus, Lars-Philip; Lang, Werner; Meyer, Alexander; Kempf, Julius; Caranovic, Milenko; Li, Yi; Wagner, Alexandra; Tan, Lina; Danko, Vera; et al. (Photoacoustics, 2024)
Peripheral arterial disease (PAD) leads to chronic vascular occlusion and results in end organ damage in critically perfused limbs. There are currently no clinical methods available to determine the muscular damage induced by chronic mal-perfusion. This monocentric prospective cross-sectional study investigated n = 193 adults, healthy to severe PAD, in order to quantify the degree of calf muscle degeneration caused by PAD using a non-invasive hybrid ultrasound and single wavelength optoacoustic imaging (US/SWL-OAI) approach. While US provides morphologic information, SWL-OAI visualizes the absorption of pulsed laser light and the resulting sound waves from molecules undergoing thermoelastic expansion. US/SWL-OAI was compared to multispectral data, clinical disease severity, angiographic findings, phantom experiments, and histological examinations from calf muscle biopsies. We were able to show that synergistic use of US/SWL-OAI is most likely to map clinical degeneration of the muscle and progressive PAD.
CRIS-Team Scopus Importer:2023-12-15
Keywords: Muscle degeneration; Muscle imaging; Optoacoustics; Peripheral artery disease; Photoacoustics

IBD IN 2017 Development of therapy for and prediction of IBD - getting personal - Atreya, Raja; Siegmund, Britta (Nature Reviews Gastroenterology & Hepatology, 2018)
The central studies published in 2017 address novel IBD therapeutic strategies and prediction of the future disease course or response to a distinct therapy. Together, these studies contribute to the understanding of the regulation of mucosal homeostasis and at the same time serve to develop novel personalized treatment algorithms in patients in whom a severe disease course can be predicted.
EVALuna2:33885

IBD pathogenesis in 2014: Molecular pathways controlling barrier function in IBD - Atreya, Raja; Neurath, Markus (Nature Reviews Gastroenterology & Hepatology, 2015)
Several key studies published in 2014 have shed light on the pathogenesis of IBD by investigating the molecular mechanisms controlling mucosal homeostasis and intestinal barrier function. These studies revealed that alterations of intestinal homeostasis drive chronic intestinal inflammation. Here, we describe these findings and discuss future directions for translational research in IBD.
EVALuna2:2013

„Ich habe Durchfall und Erbrechen“ - Fischer, Sarah; Neurath, Markus (MMW Fortschritte der Medizin, 2020)
CRIS-Team Scopus Importer:2020-02-07
Keywords: Diarrhea; endoscopy; epidemiology; gastrointestinal infection; vomiting

Identification and characterization of the specific murine NK cell subset supporting graft-versus-leukemia- and reducing graft-versus-host-effects - Meinhardt, Kathrin; Kroeger, Irena; Bauer, Ruth; Ganss, Franziska; Ovsiy, Ilja; Rothamer, Johanna; Büttner, Maike; Atreya, Imke; Waldner, Maximilian; Bittrich, Max; Lehmann, Christian; Rieger, Michael A.; et al. (OncoImmunology, 2015)
Clinical studies investigating the impact of natural killer (NK) cells in allogeneic hematopoietic stem cell transplantation settings have yielded promising results. However, NK cells are a functionally and phenotypically heterogeneous population. Therefore, we addressed the functional relevance of specific NK cell subsets distinguished by expression of CD117, CD27 and CD11b surface markers in graft-versus-leukemia (GVL)-reaction and graft-versus-host-disease (GVHD). Our results clearly demonstrate that the subset of c-Kit(-)CD27(-)CD11b(+) NK cells expressed multiple cytotoxic pathway genes and provided optimal graft-versus-leukemia-effects, while significantly reducing T cell proliferation induced by allogeneic dendritic cells. Furthermore, these NK cells migrated to inflamed intestinal tissues where graft-versus-host-colitis was efficiently mitigated. For the first time, we identified the c-Kit(-)CD27(-)CD11b(+) NK cell population as the specific effector NK cell subset capable of significantly diminishing GVHD in fully mismatched bone marrow transplantation settings. In conclusion, the subset of c-Kit(-)CD27(-)CD11b(+) NK cells not only supports GVL, but also plays a unique role in the protection against GVHD by migrating to the peripheral GVHD target organs where they exert efficient immunoregulatory activities. These new insights demonstrate the importance of selecting the optimal NK cell subset for cellular immunotherapy following allogeneic hematopoietic stem cell transplantation.
EVALuna2:1965

Identification of Bronchoalveolar Lavage Components Applying Confocal Laser Endomicroscopy - Zirlik, Sabine; Neurath, Markus; Meidenbauer, Norbert; Fuchs, Florian; Vieth, Michael (Medical Science Monitor, 2018)
BACKGROUND In many studies, confocal laser endomicroscopy (CLE) has proven to be a useful tool in pulmonology; nevertheless, the application in this field is still experimental. By contrast, CLE is almost a standard technique in gastroenterology. The aim of the present study was to demonstrate the identification of bronchoalveolar lavage (BAL) components applying CLE, using a dye. MATERIAL AND METHODS In 21 patients with various underlying diseases a bronchoscopy with BAL was performed. As in routine clinical practice common, BAL fluid (BALF) was analyzed in terms of cytologic, virologic, and microbiologic aspects. To one fraction of BALF, we added acriflavine. After centrifugation CLE was applied and the video sequences were analyzed by an experienced investigator. RESULTS Using CLE, BALF components (such as alveolar macrophages or leucocytes) could be easily identified. A further subdivision of leucocytes (neutrophilic, eosinophilic granulocytes, and lymphocytes) was not possible. Analogous to conventional cytology, a precise distinction of lymphocyte subpopulation (cd 4/cd 8 ratio) was not feasible. In terms of quantification, this is still the application field of flow cytometry and immunohistochemistry. CONCLUSIONS Using CLE, alveolar macrophages and leucocytes in stained BALF can be differentiated independent of smoking status. Further studies should be initiated in order to subclassify leucocytes in eosinophilic, neutrophilic granulocytes, and lymphocytes, which is important for routine clinical practice.
EVALuna2:34445

Identification of human CD4(+) T cells specific for dominant epitopes of SARS-CoV-2 Spike and Nucleocapsid proteins with therapeutic potential - Verhagen, Johan; van der Meijden, Edith; Lang, Vanessa; Kremer, Andreas; Völkl, Simon; Mackensen, Andreas; Aigner, Michael; Kremer, Anita (ONCOLOGY RESEARCH AND TREATMENT, 2021)
Since December 2019, Coronavirus disease-19 (COVID-19) has spread rapidly throughout the world, leading to a global effort to develop vaccines and treatments. Despite extensive progress, there remains a need for treatments to bolster the immune responses in infected immunocompromised individuals, such as cancer patients who recently underwent a haematopoietic stem cell transplantation. Immunological protection against COVID-19 is mediated by both short-lived neutralizing antibodies and long-lasting virus-reactive T cells. Therefore, we propose that T cell therapy may augment efficacy of current treatments. For the greatest efficacy with minimal adverse effects, it is important that any cellular therapy is designed to be as specific and directed as possible. Here, we identify T cells from COVID-19 patients with a potentially protective response to two major antigens of the SARS-CoV-2 virus, Spike and Nucleocapsid protein. By generating clones of highly virus-reactive CD4+ T cells, we were able to confirm a set of nine immunodominant epitopes and characterize T cell responses against these. Accordingly, the sensitivity of T cell clones for their specific epitope, as well as the extent and focus of their cytokine response was examined. Moreover, using an advanced T cell receptor (TCR) sequencing approach, we determined the paired TCR-αβ sequences of clones of interest. While these data on a limited population require further expansion for universal application, the results presented here form a crucial first step towards TCR-transgenic CD4+ T cell therapy of COVID-19.<br
CRIS-Team WoS Importer:2022-03-25
Keywords: COVID-19; SARS-CoV-2; T cell; T cell receptor; epitope

Identification of novel MRGX2-agonists triggering mast cell degranulation and potentially mediating drug-induced pruritus - Kühn, Helen; Wolf, Katharina; Boehm, F.; Glaudo, Markus; Gebhardt, Lisa; Ectors, Philipp; Agelopoulos, K.; Zahn, Dirk; Staender, S.; Kremer, Andreas (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

IFN-α in advanced well-differentiated neuroendocrine tumors: the neglected drug? - Amoroso, Vito; Pavel, Marianne Ellen; Claps, Melanie; Roca, Elisa; Ravanelli, Marco; Maroldi, Roberto; Oberg, Kjell; Berruti, Alfredo (Future Oncology, 2018)
EVALuna2:35190

IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin-directed vascular barrier disruption. - Langer, Victoria; Vivi, Eugenia; Regensburger, Daniela; Winkler, Thomas; Waldner, Maximilian; Rath, Timo; Schmid, Benjamin; Skottke, Lisa; Lee, Somin; Jeon, Noo Li; Wohlfahrt, Thomas; Kramer, Viktoria; et al. (Journal of Clinical Investigation, 2019)
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact of the vasculature in IBD and the underlying regulatory mechanisms remain largely unknown. IFN-γ is a major cytokine in IBD pathogenesis, but in the context of the disease, it is almost exclusively its immune-modulatory and epithelial cell-directed functions that have been considered. Recent studies by our group demonstrated that IFN-γ also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-γ and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-γ response in vessels by endothelial-specific knockout of IFN-γ receptor 2 ameliorates experimentally induced colitis in mice. IFN-γ acts pathogenic by causing a breakdown of the vascular barrier through disruption of the adherens junction protein VE-cadherin. Notably, intestinal vascular barrier dysfunction was also confirmed in human IBD patients, supporting the clinical relevance of our findings. Treatment with imatinib restored VE-cadherin/adherens junctions, inhibited vascular permeability, and significantly reduced colonic inflammation in experimental colitis. Our findings inaugurate the pathogenic impact of IFN-γ-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease.

IgA2 Antibodies against SARS-CoV-2 Correlate with NET Formation and Fatal Outcome in Severely Diseased COVID-19 Patients - Staats, Leonie A. N.; Pfeiffer, Hella; Knopf, Jasmin; Lindemann, Aylin; Fürst, Julia; Kremer, Andreas; Hackstein, Holger; Neurath, Markus; Munoz, Luis Enrique; Achenbach, Susanne; Leppkes, Moritz; Herrmann, Martin; et al. (Cells, 2020)
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to an adaptive immune response in the host and the formation of anti-SARS-CoV-2 specific antibodies. While IgG responses against SARS-CoV-2 have been characterized quite well, less is known about IgA. IgA2 activates immune cells and induces inflammation and neutrophil extracellular trap (NET) formation which may contribute to organ injury and fatal outcome in SARS-CoV-2-infected patients. SARS-CoV-2 spike protein specific antibody levels were measured in plasma samples of 15 noninfected controls and 82 SARS-CoV-2-infected patients with no or mild symptoms, moderate symptoms (hospitalization) or severe disease (intensive care unit, ICU). Antibody levels were compared to levels of C-reactive protein (CRP) and circulating extracellular DNA (ecDNA) as markers for general inflammation and NET formation, respectively. While levels of SARS-CoV-2-specific IgG were similar in all patient groups, IgA2 antibodies were restricted to severe disease and showed the strongest discrimination between nonfatal and fatal outcome in patients with severe SARS-CoV-2 infection. While anti-SARS-CoV-2 IgG and IgA2 levels correlated with CRP levels in severely diseased patients, only anti-SARS-CoV-2 IgA2 correlated with ecDNA. These data suggest that the formation of anti-SARS-CoV-2 IgA2 during SARS-CoV-2 infection is a marker for more severe disease related to NET formation and poor outcome.
CRIS-Team WoS Importer:2021-01-15

IL-10 induction properties of the TLR-9 agonist cobitolimod - a candidate for treatment of active ulcerative colitis in late stage of clinical development - Admyre, C.; Zargari, A.; Atreya, Raja; Knittel, T. (2017)
EVALuna2:33920

IL-12 and IL-23 pathway inhibition in inflammatory bowel disease - Verstockt, Bram; Salas, Azucena; Sands, Bruce E.; Abraham, Clara; Leibovitzh, Haim; Neurath, Markus; Vande Casteele, Niels (Nature Reviews Gastroenterology & Hepatology, 2023)
Interleukin-12 (IL-12) and interleukin-23 (IL-23), which belong to the IL-12 family of cytokines, have a key role in intestinal homeostasis and inflammation and are implicated in the pathogenesis of inflammatory bowel disease. Upon their secretion by antigen-presenting cells, they exert both pro-inflammatory and anti-inflammatory receptor-mediated effects. An increased understanding of these biological effects, particularly the pro-inflammatory effects mediated by IL-12 and IL-23, has led to the development of monoclonal antibodies that target a subunit common to IL-12 and IL-23 (p40; targeted by ustekinumab and briakinumab), or the IL-23-specific subunit (p19; targeted by risankizumab, guselkumab, brazikumab and mirikizumab). This Review provides a summary of the biology of the IL-12 family cytokines IL-12 and IL-23, discusses the role of these cytokines in intestinal homeostasis and inflammation, and highlights IL-12- and IL-23-directed drug development for the treatment of Crohn's disease and ulcerative colitis.
CRIS-Team WoS Importer:2023-05-26

IL-13 as Target to Reduce Cholestasis and Dysbiosis in Abcb4 Knockout Mice - Hahn, Luisa; Helmrich, Nora; Herebian, Diran; Mayatepek, Ertan; Drebber, Uta; Domann, Eugen; Olejniczak, Stefan; Weigel, Markus; Hain, Torsten; Rath, Timo; Wirtz, Stefan; Mollenkopf, Hans Joachim; et al. (Cells, 2020)
The Th2 cytokine IL-13 is involved in biliary epithelial injury and liver fibrosis in patients as well as in animal models. The aim of this study was to investigate IL-13 as a therapeutic target during short term and chronic intrahepatic cholestasis in an Abcb4-knockout mouse model (Abcb4-/-). Lack of IL-13 protected Abcb4-/- mice transiently from cholestasis. This decrease in serum bile acids was accompanied by an enhanced excretion of bile acids and a normalization of fecal bile acid composition. In Abcb4-/-/IL-13-/- double knockout mice, bacterial translocation to the liver was significantly reduced and the intestinal microbiome resembled the commensal composition in wild type animals. In addition, 52-week-old Abcb4-/-IL-13-/- mice showed significantly reduced hepatic fibrosis. Abcb4-/- mice devoid of IL-13 transiently improved cholestasis and converted the composition of the gut microbiota towards healthy conditions. This highlights IL-13 as a potential therapeutic target in biliary diseases.
CRIS-Team Scopus Importer:2020-09-25
Keywords: bacterial translocation; bile acid; intestinal microbiome; liver fibrosis; Th2; tight junction

IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling - Chiriac, Mircea-Teodor; Hracsko, Zsuzsanna; Günther, Claudia; Gonzalez Acera, Miguel; Atreya, Raja; Stolzer, Iris; Wittner, Leonie; Dressel, Anja; Schickedanz, Laura; Gámez Belmonte, Maria de los Reyes; Erkert, Lena; Hundorfean, Gheorghe; et al. (Gut, 2023)
Objective: We sought to investigate the role of interleukin (IL)-20 in IBD and experimental colitis. Design: Experimental colitis was induced in mice deficient in components of the IL-20 and signal transducer and activator of transcription (STAT)2 signalling pathways. In vivo imaging, high-resolution mini-endoscopy and histology were used to assess intestinal inflammation. We further used RNA-sequencing (RNA-Seq), RNAScope and Gene Ontology analysis, western blot analysis and co-immunoprecipitation, confocal microscopy and intestinal epithelial cell (IEC)-derived three-dimensional organoids to investigate the underlying molecular mechanisms. Results were validated using samples from patients with IBD and non-IBD control subjects by a combination of RNA-Seq, organoids and immunostainings. Results: In IBD, IL20 levels were induced during remission and were significantly higher in antitumour necrosis factor responders versus non-responders. IL-20RA and IL-20RB were present on IECs from patients with IBD and IL-20-induced STAT3 and suppressed interferon (IFN)-STAT2 signalling in these cells. In IBD, experimental dextran sulfate sodium (DSS)-induced colitis and mucosal healing, IECs were the main producers of IL-20. Compared with wildtype controls, Il20-/-, Il20ra-/- and Il20rb-/- mice were more susceptible to experimental DSS-induced colitis. IL-20 deficiency was associated with increased IFN/STAT2 activity in mice and IFN/STAT2-induced necroptotic cell death in IEC-derived organoids could be markedly blocked by IL-20. Moreover, newly generated Stat2ΔIEC mice, lacking STAT2 in IECs, were less susceptible to experimental colitis compared with wildtype controls and the administration of IL-20 suppressed colitis activity in wildtype animals. Conclusion: IL-20 controls colitis and mucosal healing by interfering with the IFN/STAT2 death signalling pathway in IECs. These results indicate new directions for suppressing gut inflammation by modulating IL-20-controlled STAT2 signals.
CRIS-Team Scopus Importer:2023-11-17
Keywords: experimental colitis; inflammatory bowel disease; interferon; interleukins; signal transduction

IL-23 Blockade in Anti-TNF Refractory IBD: From Mechanisms to Clinical Reality - Atreya, Raja; Neurath, Markus (Journal of Crohns & Colitis, 2022)
Increasing insights into the immunopathogenesis of inflammatory bowel diseases [IBD] have led to the advent of targeted therapies that inhibit crucial mediators of the inflammatory process, thereby widening our available therapeutic armamentarium. Anti-tumour necrosis factor (anti-TNF) agents are still a mainstay of our therapeutic endeavours and the introduction of corresponding biosimilars has further widened their use. Nevertheless, only a subgroup of treated patients benefit from the initiated treatment and there is secondary non-response in the course of therapy. Initiation of subsequent therapy often poses a challenge to the treating physician, as non-response to primary anti-TNF treatment generally characterizes a patient group that is more treatment-resistant, which may be due to the immunological impregnation by prior anti-TNF exposure. At present, there is currently no guidance for the most appropriate second-line therapy after anti-TNF failure. Here, we review the efficacy of secondary biological therapy in anti-TNF-treated patients. We focus on and assess available clinical trial data of the emerging substance class of IL-23p19 inhibitors, which have demonstrated remarkable efficacy not only in anti-TNF-nalve but also refractory patients. We present molecular mechanisms that drive IL-23-mediated resistance to ongoing anti-TNF therapy and discuss the dynamic fluidity of the mucosal cytokine network in the course of therapy that perpetuates the mucosal inflammatory reaction. Translation of these findings into clinical practice might finally lead to initiation of the most appropriate therapy at the right time of the individual disease course, which would have important implications for the patient's probability of response to treatment.
CRIS-Team WoS Importer:2022-05-27

IL-23 in inflammatory bowel diseases and colon cancer - Neurath, Markus (Cytokine & Growth Factor Reviews, 2019)
Studies in recent years have identified a pivotal role of the cytokine IL-23 in the pathogenesis of inflammatory bowel diseases (IBD: Crohn's disease, ulcerative colitis) and colitis-associated colon cancer. Genetic studies revealed that subgroups of IBD patients have single nucleotide polymorphisms in the IL-23R gene suggesting that IL-23R signaling affects disease susceptibility. Furthermore, increased production of IL-23 by macrophages, dendritic cells or granulocytes has been observed in various mouse models of colitis, colitis-associated cancer and IBD patients. Moreover, in several murine models of colitis, suppression of IL-12/IL-23 p40, IL-23 p19 or IL-23R function led to marked suppression of gut inflammation. This finding was associated with reduced activation of IL-23 target cells such as T helper 17 cells, innate lymphoid cells type 3, granulocytes and natural killer cells as well as with impaired production of proinflammatory cytokines. Based on these findings, targeting of IL-23 emerges as important concept for suppression of gut inflammation and inflammation-associated cancer growth. Consistently, neutralizing antibodies against IL-12/IL-23 p40 and IL-23 p19 have been successfully used in clinical trials for therapy of Crohn's disease and pilot studies in ulcerative colitis are ongoing. These findings underline the crucial regulatory role of IL-23 in chronic intestinal inflammation and colitis-associated cancer and indicate that therapeutic strategies aiming at IL-23 blockade may be of key relevance for future therapy of IBD patients.
CRIS-Team WoS Importer:2019-03-20

IL-23 is centrally involved in mediating molecular resistance to anti-TNF therapy in Crohn's disease patients - Schmitt, H.; Billmeier, Ulrike; Dieterich, Walburga; Rath, T.; Sonnewald, Sophia; Reid, Stephen; Hirschmann, S.; Hildner, Kai; Waldner, Maximilian; Mudter, J.; Hartmann, Arndt; Grützmann, Robert; et al. (2018)
EVALuna2:34077

IL-27 suppresses type 2 immune responses in vivo via direct effects on group 2 innate lymphoid cells - Mchedlidze, T.; Kindermann, M.; Neves, A. T.; Vöhringer, David; Neurath, Markus; Wirtz, Stefan (Mucosal Immunology, 2016)
Group 2 innate lymphoid cells (ILC2) were recently characterized by their ability to produce significant amounts of type-2 signature cytokines and drive central beneficial and pathological features of type-2 immune responses. Although factors such as IL-33 and IL-25 were shown to have ILC2 activating capacity, it is not well understood, how ILC2 responses are regulated in vivo. Here we provide compelling evidence that IL-27-signalling directly inhibits ILC2 responses and reveal a novel mechanism for negative regulation of the innate arm of type-2 immunity. We demonstrate that IL-27-deficiency is linked to increased mucosal presence of ILC2 in a model of inflammatory lung disease. Moreover, IL-27-treatment inhibited ILC2 proliferation and cytokine production and significantly reduced their accumulation in vivo. During helminth infection, regulation of ILC2 by IL-27 directly impacted anti-parasitic immunity. Thus, therapeutic modulation of the IL-27/IL-27R axis may be relevant in a number of inflammatory conditions associated with dysregulated type-2 responses.
EVALuna2:2062

IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation - Faas, Maria; Ipseiz, Natacha; Ackermann, Jochen; Culemann, Stephan; Grüneboom, Anika; Schröder, Fenja; Rothe, Tobias; Scholtysek, Carina; Eberhardt, Martin; Böttcher, Martin; Kirchner, Philipp; Stoll, Cornelia; et al. (Immunity, 2021)
Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.
CRIS-Team Scopus Importer:2021-11-19
Keywords: alternatively activated macrophage; GATA3; interleukin-33; itaconate; mitochondrial rewiring; resolution of inlammation; UCP2; uncoupling