(1 -> 3)-beta-D-glucan and mannan guided early termination of antifungal therapy in ICU patients: a prospective randomized intervention study (REDUCE-AM) - Erb, T.; Mihai, Sidonia; Cipa, Franziska; Herbst, Larissa; Strauss, Richard; Castellanos, Ixchel; Lang, K.; Ganslmayer, Marion; Willam, Carsten; Rath, Anca; Diesch, Katharina; Held, Jürgen (MYCOSES, 2020)
CRIS-Team WoS Importer:2020-10-02

3Dscript: animating 3D/4D microscopy data using a natural-language-based syntax - Schmid, Benjamin; Tripal, Philipp; Fraaß, Tina; Kersten, Christina; Ruder, Barbara; Grüneboom, Anika; Huisken, Jan; Palmisano, Ralf (Nature Methods, 2019)
CRIS-Team WoS Importer:2019-04-09

Ablation of CD8?(+) dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice - Legein, Bart; Janssen, Edith M.; Theelen, Thomas L.; Gijbels, Marion J.; Walraven, Joep; Klarquist, Jared S.; Hennies, Cassandra M.; Wouters, Kristiaan; Seijkens, Tom T. P.; Wijnands, Erwin; Sluimer, Judith C.; Lutgens, Esther; et al. (Scientific Reports, 2015)
Clinical complications of atherosclerosis are almost exclusively linked to destabilization of the atherosclerotic plaque. Batf3-dependent dendritic cells specialize in cross-presentation of necrotic tissue-derived epitopes to directly activate cytolytic CD8 Tcells. The mature plaque (necrotic, containing dendritic cells and CD8 Tcells) could offer the ideal environment for cross-presentation, resulting in cytotoxic immunity and plaque destabilization. Ldlr(-/-) mice were transplanted with batf3(-/-) or wt bone marrow and put on a western type diet. Hematopoietic batf3 deficiency sharply decreased CD8?(+) DC numbers in spleen and lymph nodes (>80%; P < 0,001). Concordantly, batf3(-/-) chimeras had a 75% reduction in OT-I cross-priming capacity in vivo. Batf3(-/-) chimeric mice did not show lower Tcell or other leukocyte subset numbers. Despite dampened cross-presentation capacity, batf3(-/-) chimeras had equal atherosclerosis burden in aortic arch and root. Likewise, batf3(-/-) chimeras and wt mice revealed no differences in parameters of plaque stability: plaque Tcell infiltration, cell death, collagen composition, and macrophage and vascular smooth muscle cell content were unchanged. These results show that CD8?(+) DC loss in hyperlipidemic mice profoundly reduces cross-priming ability, nevertheless it does not influence lesion development. Taken together, we clearly demonstrate that CD8?(+) DC-mediated cross-presentation does not significantly contribute to atherosclerotic plaque formation and stability.
EVALuna2:1982

Acceptable risks of treatments to prevent rheumatoid arthritis among first-degree relatives: demographic and psychological predictors of risk tolerance - Simons, Gwenda; Janssen, Ellen M.; Veldwijk, Jorien; Disantostefano, Rachael L.; Englbrecht, Matthias; Radawski, Christine; Valor-Mendez, Larissa; Humphreys, Jennifer H.; Bruce, Ian N.; Hauber, Brett; Raza, Karim; Falahee, Marie (RMD Open, 2022)
ObjectivesTo quantify tolerance to risks of preventive treatments among first-degree relatives (FDRs) of patients with rheumatoid arthritis (RA).MethodsPreventive treatments for RA are under investigation. In a preference survey, adult FDRs assumed a 60% chance of developing RA within 2 years and made choices between no treatment and hypothetical preventive treatment options with a fixed level of benefit (reduction in chance of developing RA from 60% to 20%) and varying levels of risks. Using a probabilistic threshold technique, each risk was increased or decreased until participants switched their choice. Perceived risk of RA, health literacy, numeracy, Brief Illness Perception Questionnaire and Beliefs about Medicines Questionnaire-General were also assessed. Maximum acceptable risk (MAR) was summarised using descriptive statistics. Associations between MARs and participants' characteristics were assessed using interval regression with effects coding.Results289 FDRs (80 male) responded. The mean MAR for a 40% reduction in chance of developing RA was 29.08% risk of mild side effects, 9.09% risk of serious infection and 0.85% risk of a serious side effect. Participants aged over 60 years were less tolerant of serious infection risk (mean MAR +/- 2.06%) than younger participants. Risk of mild side effects was less acceptable to participants who perceived higher likelihood of developing RA (mean MAR +/- 3.34%) and more acceptable to those believing that if they developed RA it would last for a long time (mean MAR +/- 4.44%).ConclusionsAge, perceived chance of developing RA and perceived duration of RA were associated with tolerance to some risks of preventive RA therapy.
CRIS-Team WoS Importer:2023-01-20

A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2-mediated inflammation - Knipfer, Lisa; Schulz-Kuhnt, Anja; Kindermann, Markus; Greif, Vicky; Symowski, Cornelia; Vöhringer, David; Neurath, Markus; Atreya, Imke; Wirtz, Stefan (Journal of Experimental Medicine, 2019)
Group 2 innate lymphoid cells (ILC2s) possess indispensable roles during type 2-mediated inflammatory diseases. Although their physiological and detrimental immune functions seem to depend on the anatomical compartment they reside, their tissue tropism and the molecular and immunological processes regulating the self-renewal of the local pool of ILC2s in the context of inflammation or infection are incompletely understood. Here, we analyzed the role of the CC-chemokine receptor CCR8 for the biological functions of ILC2s. In vitro and in vivo experiments indicated that CCR8 is in comparison to the related molecule CCR4 less important for migration of these cells. However, we found that activated mouse and human ILC2s produce the CCR8 ligand CCL1 and are a major source of CCL1 in vivo. CCL1 signaling to ILC2s regulates their proliferation and supports their capacity to protect against helminthic infections. In summary, we identify a novel chemokine receptor-dependent mechanism by which ILC2s are regulated during type 2 responses.
CRIS-Team Scopus Importer:2019-12-13

Acetaminophen-induced liver injury is mediated by the ion channel TRPV4 - Echtermeyer, Frank; Eberhardt, Mirjam; Risser, Linus; Herzog, Christine; Gueler, Faikah; Khalil, Mohammad; Engel, Matthias; Vondran, Florian; Leffler, Andreas (The FASEB Journal, 2019)
Overdosing of the analgesic acetaminophen (APAP) is one of the most common causes for acute liver failure in modern countries. Although the exact molecular mechanisms mediating hepatocellular necrosis are still elusive, it is preceded by oxidative stress triggered by excessive levels of the metabolite N-acetyl-para-benzoquinone imine (NAPQI). Here, we describe the role of the redox-sensitive transient receptor potential (TRP) ion channel TRP vanilloid 4 (TRPV4) for APAP-induced hepatoxicity. Both pharmacological inhibition and genetic deletion of TRPV4 ameliorate APAP-induced necrosis in mouse and human hepatocytes in vitro. Liver injury caused by a systemic overdose of APAP is reduced in TRPV4-deficient mice and in wild-type mice treated with a TRPV4 inhibitor. The reduction of hepatotoxicity accomplished by systemic TRPV4 inhibition is comparable to the protective effects of the antioxidant N-acetyl-cysteine. Although TRPV4 does not modulate intrahepatic levels of glutathione, both its inhibition and genetic deletion attenuate APAP-induced oxidative and nitrosative stress as well as mitochondrial membrane depolarization. NAPQI evokes a calcium influx by activating heterologously expressed TRPV4 channels and endogenous TRPV4 channels in hepatoma cells but not in primary mouse hepatocytes. Taken together, our data suggest that TRPV4 mediates APAP-induced hepatotoxicity and thus may be a suitable target for treatment of this critical side effect.-Echtermeyer, F., Eberhardt, M., Risser, L., Herzog, C., Gueler, F., Khalil, M., Engel, M., Vondran, F., Leffler, A. Acetaminophen-induced liver injury is mediated by the ion channel TRPV4.
CRIS-Team WoS Importer:2019-09-10

Achievement of treatment goals for secondary prevention of myocardial infarction or stroke in 29,325 patients with type 2 diabetes: a German/Austrian DPV-multicenter analysis - Bohn, Barbara; Schöfl, Christof; Zimmer, Vincent; Hummel, Michael; Heise, Nikolai; Siegel, Erhard; Karges, Wolfram; Riedl, Michaela; Holl, Reinhard W. (Cardiovascular Diabetology, 2016)
To analyze whether medical care is in accordance with guidelines for secondary prevention of myocardial infarction (MI), or stroke in patients with type 2 diabetes from Germany and Austria.29,325 patients (>= 20 years of age) with type 2 diabetes and MI, or stroke, documented between 2006 and 2015 were selected from the Diabetes-Patienten-Verlaufsdokumentation database. We analyzed medication, clinical characteristics, and lifestyle factors according to national secondary prevention guidelines in patients with MI, or stroke, separately.HbA1C <7.5 % was achieved in 64.9 % (MI), and in 61.1 % (stroke) of patients. LDL <100 mg/dl was documented in 56.2 % (MI), and in 42.2 % (stroke). Non-smoking was reported in 92.0 % (MI), and in 93.1 % (stroke), physical activity in 9.6 % (MI), and 5.5 % (stroke). Target values of blood pressure (<130/80 mmHg in MI, 120/70-140/90 in stroke) were reached in 67.0 % (MI), and in 89.9 % (stroke). Prescription prevalence of inhibitors of platelet aggregation (IPA) was 50.7 % (MI), and 31.7 % (stroke). 57.0 % (MI), and 40.1 % (stroke) used statins, 65.1 % (MI), and 65.8 % (stroke) used any type of antihypertensives, and ACE inhibitors were prescribed in 49.7 % (MI), and 41.3 % (stroke). A body mass index (BMI) <27 kg/m(2) and the use of beta blockers were only recommended in subjects with MI. Of the patients with MI, 32.0 % had a BMI <27 kg/m(2), and 59.5 % used beta blockers.Achievement of treatment goals in secondary prevention of MI, or stroke in subjects with type 2 diabetes needs improvement. Target goals were met more frequently in patients with MI compared to subjects with stroke. Especially the use of IPA was very low in patients with stroke. There remains great potential to reduce the risk of repeated macrovascular events and premature death, as well as to increase patients' quality of life.
EVALuna2:2090

Acidified nitrite contributes to the antitumor effect of cold atmospheric plasma on melanoma cells - Zimmermann, Tom; Gebhardt, Lisa; Kreiß, Lucas; Schneider, Christin; Arndt, Stephanie; Karrer, Sigrid; Friedrich, Oliver; Fischer, Michael Jochen Marco; Boßerhoff, Anja Katrin (International Journal of Molecular Sciences, 2021)
Cold atmospheric plasma (CAP) is partially ionized gas near room temperature with previously reported antitumor effects. Despite extensive research and growing interest in this technol-ogy, active components and molecular mechanisms of CAP are not fully understood to date. We used Raman spectroscopy and colorimetric assays to determine elevated nitrite and nitrate levels after treatment with a MiniFlatPlaster CAP device. Previously, we demonstrated CAP-induced acidification. Cellular effects of nitrite and strong extracellular acidification were assessed using live-cell imaging of intracellular Ca2+ levels, cell viability analysis as well as quantification of p21 and DNA damage. We further characterized these observations by analyzing established molecular effects of CAP treatment. A synergistic effect of nitrite and acidification was found, leading to strong cytotoxicity in melanoma cells. Interestingly, protein nitration and membrane damage were absent after treatment with acidified nitrite, thereby challenging their contribution to CAP-induced cyto-toxicity. Further, phosphorylation of ERK1/2 was increased after treatment with both acidified ni-trite and indirect CAP. This study characterizes the impact of acidified nitrite on melanoma cells and supports the importance of RNS during CAP treatment. Further, it defines and evaluates im-portant molecular mechanisms that are involved in the cancer cell response to CAP.
CRIS-Team Scopus Importer:2021-04-16
Keywords: Acidification; Acidified nitrite; Cold atmospheric plasma; Malignant melanoma; Membrane damage; Nitration; Nitrite

A comparative analysis of articular bone in large cohort of patients with chronic inflammatory diseases of the joints, the gut and the skin - Simon, David; Kleyer, Arnd; Englbrecht, Matthias; Stemmler, Fabian; Simon, Christoph; Berlin, Andreas; Kocijan, Roland; Haschka, Judith; Hirschmann, Simon; Atreya, Raja; Neurath, Markus; Sticherling, Michael; et al. (Bone, 2018)
Chronic inflammatory diseases are associated with bone loss. While the occurrence of systemic bone loss is well described in chronic inflammatory diseases, the impact of these conditions on articular bone has not been systematically investigated. Recent refinements in high-resolution CT assessment of the joints now allow the accurate measure of articular bone composition. In this study 476 subjects comprising healthy individuals and patients with anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA), ACPA-negative RA, Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO) and psoriatic arthritis (PsA) were subjected to high-resolution quantitative computed tomography (HR-pQCT) of the hand. Metacarpal heads were assessed for total, trabecular and cortical volumetric bone mineral density (vBMD). Only ACPA+RA, but not the remaining inflammatory diseases (ACPA-RA, CD, UC, PsO, PsA) showed significant (p < 0.001) loss of articular bone affecting both the trabecular and the cortical compartments. Age and body mass index were also associated with articular bone changes, the former with lower, the latter with higher articular bone mass. In multivariate models, presence of ACPA+RA was an independent factor for articular bone loss. Among chronic inflammatory diseases ACPA+RA is the most potent precipitator for articular bone loss pointing out the role of autoimmunity in the development of articular bone disease in the context of chronic inflammatory disease.
EVALuna2:34480

A comparative efficacy and safety analysis of subcutaneous infliximab and vedolizumab in patients with Crohn's Disease and Ulcerative Colitis - Peyrin-Biroulet, L.; Arkkila, P.; Armuzzi, A.; Atreya, Raja; Danese, S.; Ferrante, M.; Guardiola, J.; Jahnsen, J.; Louis, E.; Lukas, M.; Reinisch, W.; Roblin, X.; et al. (JOURNAL OF CROHNS & COLITIS, 2022)
CRIS-Team WoS Importer:2022-05-13

Acoustic radiation force impulse (ARFI) and high-frequency ultrasound of the liver surface for the diagnosis of compensated liver cirrhosis - Pfeifer, Lukas; Görtz, Rüdiger; Sturm, Jörg; Wachter, David; Riener, M. O.; Schwitulla, Judith; Bernatik, T.; Neurath, Markus; Strobel, Deike (Ultraschall in der Medizin, 2014)
To evaluate the diagnostic value of acoustic radiation force impulse (ARFI) and high-frequency ultrasound of the liver surface, using histology as a gold standard for the diagnosis of compensated liver cirrhosis.73 patients without ascites undergoing liver biopsy were included in the study. The left and right liver lobes were examined with ARFI and high-frequency ultrasound. Liver surface irregularity was quantified using image analysis software to calculate the difference between the real surface and the approximated physiological surface through a 20 mm standardized line.There is a significant difference between cirrhotic and non-cirrhotic patients for both quantified liver surface (QLS) and ARFI (p < 0.001). The mean values for QLS of the left lobe were 0.71 ± 0.24 mm and 1.17 ± 0.80 mm, of the right lobe 0.56 ± 0.26 mm and 0.87 ± 0.26 mm for non-cirrhotic and cirrhotic patients, respectively. The mean values of ARFI measurements of the left lobe were 2.04 ± 0.76 m/s and 2.85 ± 0.81 m/s, of the right lobe 1.65 ± 0.61 m/s and 3.02 ± 0.77 m/s for non-cirrhotic and cirrhotic patients, respectively. Diagnostic accuracy (AUROC) was 0.78/0.80 for QLS and 0.77/0.91 for ARFI of the left/right lobe, respectively. ARFI of the right lobe is significantly better than ARFI of the left (p = 0.023) or QLS of the left (p = 0.025)/right (p = 0.046) lobe of the liver.Assessment of liver surface irregularity by high-frequency ultrasound (QLS) is a useful diagnostic test for the assessment of compensated liver cirrhosis. ARFI of the right liver lobe is significantly better than high-frequency ultrasound (QLS of the left/right lobe of the liver) and ARFI of the left lobe of the liver.
EVALuna2:1858

Acoustic Radiation Force Impulse (ARFI) Elastography in Autoimmune and Cholestatic Liver Diseases - Görtz, Rüdiger; Gassmann, Luise; Strobel, Deike; Wildner, Dane; Schellhaas, Barbara; Neurath, Markus; Pfeifer, Lukas (Annals of Hepatology, 2019)
Introduction. Acoustic Radiation Force Impulse (ARFI) elastography evaluates hepatic fibrosis non-invasively and has been mainly validated in viral hepatitis. Data on rare liver diseases such as autoimmune hepatitis (AIH), overlap syndrome, primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) are sparse. Material and methods. 85 patients (including 31 AIH, 26 PBC, 16 PSC and 3 PSC- and 9 PBC-AIH-overlap syndromes) were retrospectively analysed pointing at ARFI elastography of the liver and the correlation with histologic Ishak fibrosis score (F0-6). Results of shear wave velocities (m/s) were expressed as mean +/- standard deviation. Results. The mean shear wave velocity of all 85 patients showed 1.80 +/- 0.84 m/s (0.74-3.98). The ARFI elastography values correlated with the degree of fibrosis in all patients overall and in patients with AIH, overlap syndrome and PSC, respectively. The subgroup of 26 patients with PBC (only with Ishak F <= 3) revealed no correlation between ARFI and these early fibrosis stages (r = 0.019, p = 0.927). ARFI elastography correlated with bilirubin, AST, but not with patient age, body mass index or measurement depth. The cut-off of 2.04 m/s for detecting cirrhosis (Ishak F >= 5) leads to a sensitivity of 90.0% and specificity of 74.7% (AUROC 87.2%). Conclusion. ARFI elastography can evaluate fibrosis in AIH, PSC and PSC-/PBC-AIH-overlap syndrome with good accuracy for the detection of hepatic cirrhosis. Shear wave velocities in PBC should be interpreted with caution in early stages of fibrosis.
CRIS-Team WoS Importer:2019-03-20

Acoustic radiation force impulse (ARFI) elastography of the bowel wall as a possible marker of inflammatory activity in patients with Crohn's disease - Görtz, Rüdiger; Lueke, C.; Wildner, Dane; Vitali, Francesco; Neurath, Markus; Strobel, Deike (Clinical Radiology, 2018)
AIM: To evaluate acoustic radiation force impulse (ARFI) shear-wave velocities of the bowel wall in patients with Crohn's disease (CD). MATERIAL AND METHODS: ARFI shear-wave elastography was analysed within the wall of the stomach, terminal ileum, and sigmoid, and correlated with ultrasound signs of activity in CD patients both retrospectively and in a prospective cohort. RESULTS: A total of 77 retrospective and 21 prospective CD patients were included. ARFI elastography in the stomach, the normal ileum, and sigmoid was lower than in ileitis or sigmoiditis. Retrospectively, the ARFI values correlated with the bowel wall thickness and Limberg vascularisation score. Prospectively, there was no correlation between ARFI and bowel wall thickness, Limberg score, clinical activity, or C-reactive protein. A cut-off analysis of 105 ileal ARFI measurements showed a cut-off value of 1.92 m/s for the diagnosis of ileal inflammation with 75.3% sensitivity and 87.5% specificity. CONCLUSION: In patients with CD, ARFI shear-wave velocities show a trend to higher values in inflamed bowel wall thickening on B-mode ultrasound; however, the differences appear small and may not be clinically significant. The factors influencing ARFI measurements of the bowel wall require further investigation.
EVALuna2:35159

Acoustic radiation force impulse (ARFI) shear wave elastography of the bowel wall in healthy volunteers and in ulcerative colitis - Görtz, Rüdiger; Lueke, Christian; Schellhaas, Barbara; Pfeifer, Lukas; Wildner, Dane; Neurath, Markus; Strobel, Deike (Acta Radiologica Open, 2019)
Background Acoustic radiation force impulse (ARFI) elastography is a non-invasive, ultrasound-based approach of evaluation of tissue elasticity. It has not yet been systematically applied to the bowel wall. Purpose To perform ARFI elastography of the bowel wall in healthy volunteers and patients with ulcerative colitis (UC). Material and Methods A high-frequency ultrasound (with bowel wall thickness and vascularization score) and an ARFI elastography of the bowel wall were performed in 20 patients with UC and 13 healthy volunteers. At least 10 ARFI measurements were obtained within the terminal ileum and the ascending, transverse, descending, and sigmoid colon and correlated with results of high-frequency ultrasound. Results The UC group had mostly moderate disease activity. All patients had signs of inflammation upon B-mode ultrasound. Eight patients showed an ulcerative (ileo)pancolitis. Overall, ARFI elastography values and wall thickness were higher in the UC group than in the group of healthy volunteers (P = 0.021 and P < 0.001, respectively). ARFI velocities of the separate segments were significantly higher in the transverse (P = 0.045) and sigmoid colon (P = 0.032) in case of UC. Conclusion ARFI elastography of the bowel wall of the colonic frame and the terminal ileum is feasible but shows high standard deviation. ARFI shear wave velocities appear to be slightly higher in patients with UC than in healthy volunteers, particularly in the sigmoid and transverse colon. Further studies are needed.
CRIS-Team WoS Importer:2019-04-30

Acoustic radiation force impulse elastography: comparison and combination with other noninvasive tests for the diagnosis of compensated liver cirrhosis - Pfeifer, Lukas; Adler, Werner; Zopf, Steffen; Wildner, Dane; Görtz, Rüdiger; Schellhaas, Barbara; Neurath, Markus; Strobel, Deike; Siebler, Jürgen (European Journal of Gastroenterology & Hepatology, 2017)
BACKGROUND AND AIMS: The aim of this study was to compare acoustic radiation force impulse (ARFI) elastography with other noninvasive tests and to develop a new score for the assessment of liver fibrosis/cirrhosis. MATERIALS AND METHODS: B-mode ultrasound (including high-frequency liver surface evaluation), routine blood tests, ARFI quantification, and mini-laparoscopic liver evaluation were obtained in compensated patients scheduled for mini-laparoscopic biopsy. Our new cirrhosis score (CS) for the assessment of liver cirrhosis, based on a linear combination of ARFI, platelet (PLT), liver surface, and prothrombin index (PI), was calculated by linear discriminant analysis. Its performance was compared with ARFI-elastography, APRI, FIB-4, alanine aminotransferase (ALT)/aspartate aminotransferase (AST)-ratio, PLT, and PI. For the diagnosis of cirrhosis, a combined gold standard (cirrhosis at histology and/or at macroscopic liver evaluation) was used. RESULTS: In total, 171 patients, of whom 38 had compensated cirrhosis, were included. The CS was significantly better for the diagnosis of cirrhosis compared with ARFI (P=0.028), APRI (P=0.012), PLTs (P=0.013), PI (P=0.025), and ALT/AST ratio (P=0.001), but not the FIB-4 score (P=0.207), with an area under the receiver operating characteristic curve of 0.92 [95% confidence interval (CI): 0.87-0.97], 0.86 (95% CI:0.79-0.93), 0.80 (95% CI: 0.72-0.87), 0.79 (95% CI: 0.7-0.87), 0.81 (95% CI: 0.73-0.89), 0.72 (95% CI:0.64-0.81), and 0.86 (95% CI: 0.8-0.93), respectively. Sensitivity, specificity, positive predictive value, and negative predictive value for CS were 87%, 86%, 63%, and 96%, respectively. The FIB-4 score was significantly superior to the APRI score (P=0.041) and the ALT/AST ratio (P=0.011), with no significant difference from ARFI elastography (P=0.88) for the diagnosis of cirrhosis. CONCLUSION: Combining ARFI elastography with other noninvasive tests that are used routinely in the workup of patients with suspected liver disease can improve diagnostic accuracy for compensated liver cirrhosis as compared with ARFI elastography alone. The FIB-4 score showed an overall comparable diagnostic accuracy to ARFI-elastography for compensated cirrhosis.
EVALuna2:33816

Acoustic radiation force impulse shear wave elastography (ARFI) of acute and chronic pancreatitis and pancreatic tumor - Görtz, Rüdiger; Schuderer, Johanna; Strobel, Deike; Pfeifer, Lukas; Neurath, Markus; Wildner, Dane (European Journal of Radiology, 2016)
Acoustic Radiation Force Impulse (ARFI) elastography evaluates tissue stiffness non-invasively and has rarely been applied to pancreas examinations so far. In a prospective and retrospective analysis, ARFI shear wave velocities of healthy parenchyma, pancreatic lipomatosis, acute and chronic pancreatitis, adenocarcinoma and neuroendocrine tumor (NET) of the pancreas were evaluated and compared.In 95 patients ARFI elastography of the pancreatic head, and also of the tail for a specific group, was analysed retrospectively. Additionally, prospectively in 100 patients ARFI was performed in the head and tail of the pancreas.A total of 195 patients were included in the study. Healthy parenchyma (n=21) and lipomatosis (n=30) showed similar shear wave velocities of about 1.3m/s. Acute pancreatitis (n=35), chronic pancreatitis (n=53) and adenocarcinoma (n=52) showed consecutively increasing ARFI values, respectively. NET (n=4) revealed the highest shear wave velocities amounting to 3.62m/s. ARFI elastography showed relevant differences between acute pancreatitis and chronic pancreatitis or adenocarcinoma. With a cut-off value of 1.74m/s for the diagnosis of a malignant disease the sensitivity was 91.1% whereas the specificity amounted to 60.4%.ARFI shear wave velocities present differences in various pathologies of the pancreas. Acute and chronic pancreatitis as well as neoplastic lesions show high ARFI values. Very high elasticity values may indicate malignant disease of the pancreas. However, there is a considerable overlap between the entities.
EVALuna2:2188

Acoustic radiation force impulse tissue characterization of the anterior talofibular ligament: a promising noninvasive approach in ankle imaging - Hotfiel, Thilo; Heiß, Rafael; Janka, Rolf Matthias; Forst, Raimund; Raithel, Martin; Lutter, Christoph; Gelse, Kolja; Pachowsky, Milena; Golditz, Tobias (The physician and sportsmedicine, 2018)
OBJECTIVES: The anterior talofibular ligament (ATFL) is the most frequently injured ligament during inversion strains of the ankle. The purpose of this study was to evaluate the feasibility of acoustic radiation force impulse (ARFI) elastography and to determine the in vivo mechanical properties of the ATFL in healthy athletes. METHODS: Sixty healthy athletes (32 female, 28 male; 28.9 ± 2.1 years) were recruited from the medical and sports faculty. ARFI values, represented as shear wave velocities (SWVs) as well as conventional ultrasound were obtained for the ATFL in neutral ankle position. A clinical assessment was performed in which the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Score and the functional ankle ability measure (FAAM) were collected. Interobserver and intraobserver reliability (repeated sessions and repeated days) were assessed using an intra class correlation coefficient (ICC) and typical error (TE) calculation in absolute (TE) and relative units as coefficient of the variation (CV). RESULTS: SWV values of the ATFL had an average velocity of 1.79 ± 0.20 m/s for all participants, with an average of 1.72 ± 0.36 m/s for females and 1.85 ± 0.31 m/s for males. The interobserver and intraobserver reliability revealed an ICC of 0.902 and 0.933 (TE of 0.67 (CV: 5.2%) and 0.52 (CV: 3.84%)), respectively. FAAM and AOFAS revealed the best possible scores. CONCLUSION: ARFI seems to be a valuable diagnostic modality and represents a promising imaging marker for the assessment and monitoring of ankle ligaments in the context of acute and chronic ankle instabilities; ARFI could also be used to investigate loading or sport dependent adaptions.
EVALuna2:36110

Activating Calcium-Sensing Receptor Mutations: Prospects for Future Treatment with Calcilytics - Mayr, Bernhard; Glaudo, Markus; Schöfl, Christof (Trends in Endocrinology and Metabolism, 2016)
Activating mutations of the G protein-coupled receptor, calcium-sensing receptor (CaSR), cause autosomal dominant hypocalcemia and Bartter syndrome type 5. These mutations lower the set-point for extracellular calcium sensing, thereby causing decreased parathyroid hormone secretion and disturbed renal calcium handling with hypercalciuria. Available therapies increase serum calcium levels but raise the risk of complications in affected patients. Symptom relief and the prevention of adverse outcome is currently very difficult to achieve. Calcilytics act as CaSR antagonists that attenuate its activity, thereby correcting the molecular defect of activating CaSR proteins in vitro and elevating serum calcium in mice and humans in vivo, and have emerged as the most promising therapeutics for the treatment of these rare and difficult to treat diseases.
EVALuna2:2214

Activation of Epithelial Signal Transducer and Activator of Transcription 1 by Interleukin 28 Controls Mucosal Healing in Mice With Colitis and Is Increased in Mucosa of Patients With Inflammatory Bowel Disease. - Chiriac, Mircea-Teodor; Buchen, Barbara; Wandersee, Alexandra; Hundorfean, Gheorghe; Günther, Claudia; Bourjau, Yvonne; Doyle, Sean E.; Frey, Benjamin; Ekici, Arif Bülent; Büttner, Christian; Weigmann, Benno; Atreya, Raja; et al. (Gastroenterology, 2017)
We investigated the roles of interleukin 28A (also called IL28A or interferon λ2) in intestinal epithelial cell (IEC) activation, studying its effects in mouse models of inflammatory bowel diseases (IBD) and intestinal mucosal healing. and Stat1IEC-KO mice also developed more severe colitis in response to oxazolone than control mice. We found IL28 to induce phosphorylation (activation) of STAT1 in epithelial cells, leading to their proliferation in organoid culture. Administration of IL28 to mice with induced colonic wounds promoted mucosal healing. ). We used high-resolution mini-endoscopy and in vivo imaging methods to assess colitis progression. We used 3-dimensional small intestine and colon organoids, along with RNA-Seq and gene ontology methods, to characterize the effects of IL28 on primary IECs. We studied the effects of IL28 on the human intestinal cancer cell line Caco-2 in a wound-healing assay, and in mice colon wounds. Colonic biopsies and resected tissue from patients with IBD (n = 62) and patients without colon inflammation (controls, n = 23) were analyzed by quantitative polymerase chain rection to measure expression of IL28A, IL28RA, and other related cytokines; biopsy samples were also analyzed by immunofluorescence to identify sources of IL28 production. IECs were isolated from patient tissues and incubated with IL28; signal transducer and activator of transcription 1 (STAT1) phosphorylation was measured by immunoblots and confocal imaging. IL28 controls proliferation of IECs in mice with colitis and accelerates mucosal healing by activating STAT1. IL28 might be developed as a therapeutic agent for patients with IBD. BACKGROUND & AIMS RESULTS METHODS CONCLUSIONS
Keywords: Crohn’s Disease; Interferon λ; Ulcerative Colitis; Wound Healing

Activation of Epithelial Signal Transducer and Activator of Transcription 1 by Interleukin 28 Controls Mucosal Healing in Mice With Colitis and Is Increased in Mucosa of Patients With Inflammatory Bowel Disease - Chiriac, Mircea-Teodor; Buchen, Barbara; Wandersee, Alexandra; Hundorfean, Gheorghe; Günther, Claudia; Bourjau, Yvonne; Doyle, Sean E.; Frey, Benjamin; Ekici, Arif Bülent; Büttner, Christian; Weigmann, Benno; Atreya, Raja; et al. (Gastroenterology, 2017)
We investigated the roles of interleukin 28A (also called IL28A or interferon λ2) in intestinal epithelial cell (IEC) activation, studying its effects in mouse models of inflammatory bowel diseases (IBD) and intestinal mucosal healing. and Stat1IEC-KO mice also developed more severe colitis in response to oxazolone than control mice. We found IL28 to induce phosphorylation (activation) of STAT1 in epithelial cells, leading to their proliferation in organoid culture. Administration of IL28 to mice with induced colonic wounds promoted mucosal healing. ). We used high-resolution mini-endoscopy and in vivo imaging methods to assess colitis progression. We used 3-dimensional small intestine and colon organoids, along with RNA-Seq and gene ontology methods, to characterize the effects of IL28 on primary IECs. We studied the effects of IL28 on the human intestinal cancer cell line Caco-2 in a wound-healing assay, and in mice colon wounds. Colonic biopsies and resected tissue from patients with IBD (n = 62) and patients without colon inflammation (controls, n = 23) were analyzed by quantitative polymerase chain rection to measure expression of IL28A, IL28RA, and other related cytokines; biopsy samples were also analyzed by immunofluorescence to identify sources of IL28 production. IECs were isolated from patient tissues and incubated with IL28; signal transducer and activator of transcription 1 (STAT1) phosphorylation was measured by immunoblots and confocal imaging. IL28 controls proliferation of IECs in mice with colitis and accelerates mucosal healing by activating STAT1. IL28 might be developed as a therapeutic agent for patients with IBD. BACKGROUND & AIMS RESULTS METHODS CONCLUSIONS
Keywords: Crohn’s Disease; Interferon λ; Ulcerative Colitis; Wound Healing

Activation of Epithelial Signal Transducer and Activator of Transcription 1 by Interleukin 28 Controls Mucosal Healing in Mice With Colitis and Is Increased in Mucosa of Patients With Inflammatory Bowel Disease - Chiriac, Mircea T.; Buchen, Barbara; Wandersee, Alexandra; Hundorfean, Gheorghe; Günther, Claudia; Bourjau, Yvonne; Doyle, Sean E.; Frey, Benjamin; Ekici, Arif Bülent; Büttner, Christian; Weigmann, Benno; Atreya, Raja; et al. (Gastroenterology, 2017)
We investigated the roles of interleukin 28A (also called IL28A or interferon ?2) in intestinal epithelial cell (IEC) activation, studying its effects in mouse models of inflammatory bowel diseases (IBD) and intestinal mucosal healing.Colitis was induced in C57BL/6JCrl mice (controls), mice with IEC-specific disruption of Stat1 (Stat1IEC-KO), mice with disruption of the interferon ? receptor 1 gene (Il28ra(-/-)), and mice with disruption of the interferon regulatory factor 3 gene (Irf3(-/-)), with or without disruption of Irf7 (Irf7(-/-)). We used high-resolution mini-endoscopy and in vivo imaging methods to assess colitis progression. We used 3-dimensional small intestine and colon organoids, along with RNA-Seq and gene ontology methods, to characterize the effects of IL28 on primary IECs. We studied the effects of IL28 on the human intestinal cancer cell line Caco-2 in a wound-healing assay, and in mice colon wounds. Colonic biopsies and resected tissue from patients with IBD (n = 62) and patients without colon inflammation (controls, n = 23) were analyzed by quantitative polymerase chain rection to measure expression of IL28A, IL28RA, and other related cytokines; biopsy samples were also analyzed by immunofluorescence to identify sources of IL28 production. IECs were isolated from patient tissues and incubated with IL28; signal transducer and activator of transcription 1 (STAT1) phosphorylation was measured by immunoblots and confocal imaging.Lamina propria cells in colon tissues of patients with IBD, and mice with colitis, had increased expression of IL28 compared with controls; levels of IL28R were increased in the colonic epithelium of patients with IBD and mice with colitis. Administration of IL28 induced phosphorylation of STAT1 in primary human and mouse IECs, increasing with dose. Il28ra(-/-), Irf3(-/-), Irf3(-/-)Irf7(-/-), as well as Stat1IEC-KO mice, developed more severe colitis after administration of dextran sulfate sodium than control mice, with reduced epithelial restitution. Il28ra(-/-) and Stat1IEC-KO mice also developed more severe colitis in response to oxazolone than control mice. We found IL28 to induce phosphorylation (activation) of STAT1 in epithelial cells, leading to their proliferation in organoid culture. Administration of IL28 to mice with induced colonic wounds promoted mucosal healing.IL28 controls proliferation of IECs in mice with colitis and accelerates mucosal healing by activating STAT1. IL28 might be developed as a therapeutic agent for patients with IBD.
EVALuna2:9356

Activation of human C-Fibers by Lysophosphatidic Acid - Düll, Miriam; Stengel, M.; Wurm, L.; Ries, V.; Kremer, Andreas; Namer, Barbara (2017)
EVALuna2:33350

Activation of human C-fibres by lysophosphatidic acid - Düll, Miriam; Stengel, M.; Wurm, L.; Ries, V.; Kremer, Andreas; Namer, Barbara (2017)
EVALuna2:33347

Activation of intestinal epithelial Stat3 orchestrates tissue defense during gastrointestinal infection - Wittkopf, Nadine; Pickert, Geethanjali; Billmeier, Ulrike; Mahapatro, Mousumi; Wirtz, Stefan; Martini, Eva; Leppkes, Moritz; Neurath, Markus; Becker, Christoph (PLoS ONE, 2015)
Gastrointestinal infections with EHEC and EPEC are responsible for outbreaks of diarrheal diseases and represent a global health problem. Innate first-line-defense mechanisms such as production of mucus and antimicrobial peptides by intestinal epithelial cells are of utmost importance for host control of gastrointestinal infections. For the first time, we directly demonstrate a critical role for Stat3 activation in intestinal epithelial cells upon infection of mice with Citrobacter rodentium - a murine pathogen that mimics human infections with attaching and effacing Escherichia coli. C. rodentium induced transcription of IL-6 and IL-22 in gut samples of mice and was associated with activation of the transcription factor Stat3 in intestinal epithelial cells. C. rodentium infection induced expression of several antimicrobial peptides such as RegIII? and Pla2g2a in the intestine which was critically dependent on Stat3 activation. Consequently, mice with specific deletion of Stat3 in intestinal epithelial cells showed increased susceptibility to C. rodentium infection as indicated by high bacterial load, severe gut inflammation, pronounced intestinal epithelial cell death and dissemination of bacteria to distant organs. Together, our data implicate an essential role for Stat3 activation in intestinal epithelial cells during C. rodentium infection. Stat3 concerts the host response to bacterial infection by controlling bacterial growth and suppression of apoptosis to maintain intestinal epithelial barrier function.
EVALuna2:1990

Activity & safety of spartalizumab (PDR001) in patients (pts) with advanced neuroendocrine tumors (NET) of pancreatic (Pan), gastrointestinal (GI), or thoracic (T) origin, & gastroenteropancreatic neuroendocrine carcinoma (GEP NEC) who have progressed on prior treatment (Tx) - Yao, J. C.; Strosberg, J.; Fazio, N.; Pavel, Marianne Ellen; Ruszniewski, P.; Bergsland, E.; Li, D.; Tafuto, S.; Raj, N.; Campana, D.; Hijioka, S.; Raderer, M.; et al. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

Addiction in IBD patients: more than just smoke? - Hirschmann, Simon; Koehnen, J.; Schuster, B.; Atreya, Raja; Krauss, N.; Mudter, J.; Dauer, M.; Hagel, A.; Neurath, Markus; Albrecht, Heinz (JOURNAL OF CROHNS & COLITIS, 2019)
CRIS-Team WoS Importer:2019-03-20

Additive antitumour response to the rabbit VX2 hepatoma by combined radio frequency ablation and toll like receptor 9 stimulation - Behm, Barbara; Di Fazio, Pietro; Michl, Patrick; Neureiter, Daniel; Kemmerling, Ralf; Hahn, Eckhart Georg; Strobel, Deike; Gress, Thomas; Schuppan, Detlef; Wissniowski, Thaddaeus Till (Gut, 2016)
Radiofrequency ablation (RFA), a palliative therapeutic option for solid hepatic tumours, stimulates localised and systemic antitumour cytotoxic T cells. We studied how far addition of CpG B oligonucleotides, toll like receptor (TLR) 9 agonists, would increase the antitumoural T cell response of RFA in the highly aggressive VX2 hepatoma.Rabbits were randomised to receive RFA, CpG B, their combination or no therapy. The antitumour efficacy of RFA alone or in combination with CpG B was further tested by rechallenging a separate group with intravenously injected VX2 tumour cells after 120 days. Animals were assessed for survival, tumour size and spread, and tumour and immune related histological markers after 120 days. Peripheral blood mononuclear cells were tested for tumour-specific T cell activation and cytotoxicity. Immune modulatory cytokines tumour necrosis factor ?, interleukin (IL)-2/IL-8/IL-10/IL-12 and interferon ?, and vascular endothelial growth factor were measured in serum.Mean survival of untreated animals was 36 days, as compared with 97, 78 and 114 days for RFA, CpG and combination therapy, respectively. Compared with untreated controls, antitumour T cell stimulation/cytotoxicity increased 26/16-fold, 32/17-fold and 50/38-fold 2 weeks after RFA, CpG and combination treatments, respectively. The combination inhibited tumour spread to lungs and peritoneum significantly and prohibited new tumour growth in animals receiving a secondary systemic tumour cell injection. RFA alone induced a Th1 cytokine pattern, while IL-8 and IL-10 were only upregulated in CpG treated animals and controls.The combination of TLR9 stimulation with RFA resulted in a potentiated antitumour T cell response and cytotoxicity in the VX2 tumour model. Only this combination prevented subsequent tumour spread and resulted in a significantly improved survival, justifying the need for further exploration of the combination of ablative therapies and TLR9 agonists in liver cancer.
EVALuna2:2070

Adhesion GPCR Gpr126 (Adgrg6) Expression Profiling in Zebrafish, Mouse, and Human Kidney. - Cazorla-Vázquez, Salvador; Kösters, Peter; Bertz, Simone; Pfister, Frederick; Daniel, Christoph; Dedden, Mark; Zundler, Sebastian; Jobst-Schwan, Tilman; Amann, Kerstin Ute; Engel, Felix (Cells, 2023)
Adhesion G protein-coupled receptors (aGPCRs) comprise the second-largest class of GPCRs, the most common target for approved pharmacological therapies. aGPCRs play an important role in development and disease and have recently been associated with the kidney. Several aGPCRs are expressed in the kidney and some aGPCRs are either required for kidney development or their expression level is altered in diseased kidneys. Yet, general aGPCR function and their physiological role in the kidney are poorly understood. Here, we characterize in detail Gpr126 (Adgrg6) expression based on RNAscope® technology in zebrafish, mice, and humans during kidney development in adults. Gpr126 expression is enriched in the epithelial linage during nephrogenesis and persists in the adult kidney in parietal epithelial cells, collecting ducts, and urothelium. Single-cell RNAseq analysis shows that gpr126 expression is detected in zebrafish in a distinct ionocyte sub-population. It is co-detected selectively with slc9a3.2, slc4a4a, and trpv6, known to be involved in apical acid secretion, buffering blood or intracellular pH, and to maintain high cytoplasmic Ca2+ concentration, respectively. Furthermore, gpr126-expressing cells were enriched in the expression of potassium transporter kcnj1a.1 and gcm2, which regulate the expression of a calcium sensor receptor. Notably, the expression patterns of Trpv6, Kcnj1a.1, and Gpr126 in mouse kidneys are highly similar. Collectively, our approach permits a detailed insight into the spatio-temporal expression of Gpr126 and provides a basis to elucidate a possible role of Gpr126 in kidney physiology.
EVALuna2:539836
Keywords: adhesion GPCR; kidney development; Gpr126; parietal epithelial cell; collecting duct; urothelium; ionocytes; zebrafish; RNAscope

ADSCs and adipocytes are the main producers in the autotaxin-lysophosphatidic acid axis of breast cancer and healthy mammary tissue in vitro - Schmid, Rafael; Wolf, Katharina; Robering, Jan Willem; Strauss, Selina; Strissel, Pamela; Strick, Reiner; Rübner, Matthias; Fasching, Peter; Horch, Raymund E.; Kremer, Andreas; Boos, Anja; Weigand, Annika (BMC Cancer, 2018)
BACKGROUND: Breast cancer is the most common malignancy in women affecting one out of eight females throughout their lives. Autotaxin (ATX) is upregulated in breast cancer which results in increased lysophosphatidic acid (LPA) formation within the tumor. This study's aim was to identify the role of different mammary cell populations within the ATX-LPA axis. METHODS: Epithelial-cell-adhesion-molecule-positive (EpCAM) and -negative cells from breast tumors, adipose-derived stem cells (ADSCs) of tumor-adjacent and tumor-distant mammary fat were isolated and compared to healthy ADSCs, mammary epithelial cells (HMECs), and mesenchymal cells (MES) of healthy mammary tissue (n = 4 each) and further to well-established breast (cancer) cell lines. RESULTS: mRNA expression analyses revealed that ADSCs and MES largely expressed LPA receptor 1 (LPAR1) while epithelial cells mainly expressed LPAR6. LPA 18:1 activated all the cell populations and cell lines by rise in cytosolic free calcium concentrations. MES and ADSCs expressed ATX whereas epithelial cells did not. ADSCs revealed the highest expression in ATX with a significant decline after adipogenic differentiation in healthy ADSCs, whereas ATX expression increased in ADSCs from tumor patients. Breast (cancer) cell lines did not express ATX. Transmigration of MES was stimulated by LPA whereas an inhibitory effect was observed in epithelial cells with no differences between tumors and healthy cells. Triple-negative breast cancer (TNBC) cell lines were also stimulated and the transmigration partly inhibited using the LPA receptor antagonist Ki16425. CONCLUSIONS: We here show that each mammary cell population plays a different role in the ATX-LPA axis with ADSCs and adipocytes being the main source of ATX in tumor patients in our experimental setting. Inhibitors of this axis may therefore present a valuable target for pharmacological therapies.
EVALuna2:35125

A Dual Role for TNF-Producing T Cells in the Fetal Intestine - Leppkes, Moritz; Neurath, Markus (Immunity, 2019)
The role of tumor necrosis factor (TNF) in the fetal intestine is poorly understood. In this issue of Immunity, Schreurs et al. (2019) identify important roles of TNF-producing T cells as both regulators of gut development and potential inducers of colitis.
CRIS-Team WoS Importer:2019-03-06

A dual role for UCMA in osteoarthritis-Inhibition of aggrecanases and promotion of bone turnover - Stock, Michael; Menges, Stefanie; Eitzinger, Nicole; Gesslein, Maria; Botschner, Renate; Wormser, Laura; Distler, Alfiya; Schlötzer-Schrehardt, Ursula; Dietel, Katharina; Distler, Jörg; Beyer, Christian; Gelse, Kolja; et al. (Arthritis and Rheumatology, 2017)
Cartilage damage and subchondral bone changes are closely connected in osteoarthritis. How these processes are interlinked is however incompletely understood to date. Here, we investigate the mechanistic role of the cartilage-derived protein UCMA in osteoarthritis-related cartilage and bone changes.UCMA expression was assessed in healthy and osteoarthritic human and mouse cartilage. DMM-induced osteoarthritis was performed in WT and Ucma-deficient mice analysing cartilage and bone changes. UCMA-collagen interactions, effect of UCMA on aggrecanase activity and the impact of recombinant UCMA on osteoclast differentiation were studied in vitro.UCMA was found overexpressed in human and mouse osteoarthritic cartilage. DMM-triggered cartilage changes were aggravated in Ucma-deficient mice compared to WT littermates, showing increased structural damage, proteoglycan loss and chondrocyte cell death indicating chondroprotective effects of UCMA. Moreover, UCMA inhibited ADAMTS-dependent aggrecanase activity and directly interacted with cartilage-specific collagen types. In contrast, osteoarthritis-related bone changes were significantly reduced in Ucma-deficient mice, showing less pronounced osteophyte formation and subchondral bone sclerosis. Mechanistically, UCMA directly promoted osteoclast differentiation in vitro.UCMA links cartilage with bone changes in osteoarthritis, supporting cartilage integrity as an endogenous inhibitor of aggrecanases on the one hand, and promoting osteoclastogenesis and subchondral bone turnover on the other hand. Hence, UCMA represents an important link between cartilage and bone in osteoarthritis. This article is protected by copyright. All rights reserved.
EVALuna2:10230

A dual-targeting triplebody mediates preferential redirected lysis of antigen double-positive over single-positive leukemic cells - Schubert, Ingo; Saul, Domenica; Nowecki, Stefanie; Mackensen, Andreas; Fey, Georg; Oduncu, Fuat S. (Mabs, 2014)
The single-chain triplebody HLA-ds16-hu19 consists of three single-chain Fv (scFv) antibody fragments connected in a single polypeptide chain. This protein with dual-targeting capacity mediated preferential lysis of antigen double-positive (dp) over single-positive (sp) leukemic cells by recruitment of natural killer (NK) cells as effectors. The two distal scFv modules were specific for the histocompatibility protein HLA-DR and the lymphoid antigen CD19, the central one for the Fc gamma receptor CD16. In antibody-dependent cellular cytotoxicity (ADCC) experiments with a mixture of leukemic target cells comprising both HLA-DR sp HuT-78 or Kasumi-1 cells and (HLA-DR plus CD19) dp SEM cells, the triplebody mediated preferential lysis of the dp cells even when the sp cells were present in <=20-fold numerical excess. The triplebody promoted equal lysis of SEM cells at 2.5-fold and 19.5-fold lower concentrations than the parental antibodies specific for HLA-DR and CD19, respectively. Finally, the triplebody also eliminated primary leukemic cells at lower concentrations than an equimolar mixture of bispecific single-chain Fv fragments (bsscFvs) separately addressing each target antigen (hu19-ds16 and HLA-ds16). The increased selectivity of targeting and the preferential lysis of dp over sp cells achieved by dual-targeting open attractive new perspectives for the use of dual-targeting agents in cancer therapy.
EVALuna2:1718

Advanced colonoscopic imaging using endocytoscopy - Neumann, Helmut; Kudo, Shin-Ei; Kiesslich, Ralf; Neurath, Markus (Digestive Endoscopy, 2015)
Optical biopsy techniques were recently introduced to luminal gastrointestinal endoscopy. These include confocal laser endomicroscopy, spectroscopic imaging techniques and endocytoscopy. Optical biopsy techniques allow on demand in vivo histology during ongoing endoscopy, thereby potentially accelerating clinical diagnosis and specific therapy. In the present review, we focus on endocytoscopy as one of the rapidly emerging optical biopsy techniques. We provide technical details of currently available endocytoscopy systems and give tips on their use in clinical practice. We also summarize applications of endocytoscopy for colorectal pathologies.
EVALuna2:2024

Advanced endoscopic imaging for diagnosis of Crohn's disease - Neumann, Helmut; Moenkemueller, Klaus; Günther, Claudia; Atreya, Raja; Neurath, Markus; Vieth, Michael (Gastroenterology Research and Practice, 2012)
Endoscopy in IBD has tremendous importance to diagnose inflammatory activity, to evaluate therapeutic success and for the surveillance of colitis associated cancer. Thus it becomes obvious that there is a need for new and more advanced endoscopic imaging techniques for better characterization of mucosal inflammation and early neoplasia detection in IBD. This paper describes the concept of advanced endoscopic imaging for the diagnosis and characterization of Crohn's disease, including magnification endoscopy, chromoendoscopy, balloon-assisted enteroscopy, capsule endoscopy, confocal laser endomicroscopy, and endocytoscopy. Copyright © 2012 Helmut Neumann et al.
CRIS-Team Scopus Importer:2020-10-28

Advanced Endoscopic Imaging in Colonic Neoplasia - Rath, Timo; Morgenstern, Nadine; Vitali, Francesco; Atreya, Raja; Neurath, Markus (Visceral Medicine, 2020)
Background: Endoscopic imaging is a rapidly evolving field with a constant influx of new concepts and technologies. Since the introduction of video endoscopy and subsequently high-definition imaging as the first revolutions in gastrointestinal endoscopy, several technologies of virtual chromoendoscopy have been developed and brought to the market in the past decade, which have shaped and revolutionized for a second time our approach to endoscopic imaging. In parallel to these developments, microscopic imaging technologies, such as endomicroscopy and endocytoscopy, allow us to examine single cells within the mucosa in real time, thereby enabling histological diagnoses during ongoing endoscopy. Summary: In this review, we provide an overview on the technical background of different technologies of advanced endoscopic imaging, and then review and discuss their role and applications for the diagnosis and management of colorectal neoplasms as well as limitations and challenges that exist despite all technological improvements. Key Messages: Technologies of advanced endoscopic imaging have profound impact not only on our imaging capabilities, they are also about to fundamentally change our approach to managing lesions in the gastrointestinal tract: Not every lesion found during colonoscopy has to be excised or sent for histopathologic evaluation. However, before this becomes widespread reality, major obstacles such as patient acceptance, adoption by less trained endoscopists, and also legal aspects need to carefully addressed. The development of computer-aided diagnosis and artificial intelligence algorithms hold the potential to overcome the obstacles associated with the concept of optical biopsy and will most likely fundamentally facilitate, shape, and change decision making in the management of colorectal lesions.
CRIS-Team Scopus Importer:2020-02-04
Keywords: Colorectal cancer; Colorectal polyps; Endocytoscopy; Endomicroscopy; Endoscopy

Advanced endoscopic imaging techniques in Crohn's disease - Tontini, Gian Eugenio; Vecchi, Maurizio; Neurath, Markus; Neumann, Helmut (Journal of Crohns & Colitis, 2014)
Endoscopy is of pivotal importance in Crohn's disease (CD) patients for diagnosis, surveillance and assessment of disease activity and extent. Device-assisted enteroscopy (DAE) and small-bowel capsule endoscopy (SBCE) have recently changed our endoscopic approach to small-bowel imaging. Furthermore, new advanced endoscopic imaging techniques have been implemented into clinical practice to improve both characterization of mucosal inflammation and detection of dysplastic lesions.To provide readers with a review about the concept of advanced endoscopic imaging for the diagnosis and characterization of CD.A literature search on the use of advanced endoscopy techniques in IBD patients was performed.DAE and SBCE allow for deep enteroscopy with high diagnostic yields and low complication's rate but their collocation in the diagnostic algorithm is still not clearly defined. Dye-based chromoendoscopy (DBC) and magnification chromoendoscopy improved dysplasia's detection in long standing colitis and prediction of inflammatory activity and extent. Dye-less chromoendoscopy (DLC) might offer the potential to replace conventional DBC for surveillance. However, both narrow band imaging and i-scan have already shown to significantly improve activity and extent assessment in comparison to white-light endoscopy. Confocal laser endomicroscopy (CLE) can detect more dysplastic lesions in surveillance colonoscopy and predict neoplastic and inflammatory changes with high accuracy compared to histology. Moreover, CLE-based molecular imaging may anticipate the therapeutic responses to biological therapy. Endocytoscopy can identify in vivo inflammatory mucosal cells harboring a new method to assess the mucosal activity.Recent progresses in small-bowel enteroscopy offer several potential benefits to improve both diagnosis and characterization of CD. New advanced endoscopic imaging techniques can improve detection of dysplasia and refine mucosal healing assessment, even looking beyond the morphological parameters revealed by conventional endoscopic imaging.
EVALuna2:1907

Advanced endoscopic imaging to improve adenoma detection - Neumann, Helmut; Naegel, Andreas; Buda, Andrea (World Journal of Gastrointestinal Endoscopy, 2015)
Advanced endoscopic imaging is revolutionizing our way on how to diagnose and treat colorectal lesions. Within recent years a variety of modern endoscopic imaging techniques was introduced to improve adenoma detection rates. Those include high-definition imaging, dye-less chromoendoscopy techniques and novel, highly flexible endoscopes, some of them equipped with balloons or multiple lenses in order to improve adenoma detection rates. In this review we will focus on the newest developments in the field of colonoscopic imaging to improve adenoma detection rates. Described techniques include high-definition imaging, optical chromoendoscopy techniques, virtual chromoendoscopy techniques, the Third Eye Retroscope and other retroviewing devices, the G-EYE endoscope and the Full Spectrum Endoscopy-system.
EVALuna2:2012

Advanced endoscopy imaging in inflammatory bowel diseases - Kiesslich, Ralf; Neurath, Markus (Gastrointestinal Endoscopy, 2017)
BACKGROUND AND AIMS: Rapid assessment of mucosal inflammation is of crucial importance for the initial diagnosis and the assessment of mucosal healing in inflammatory bowel disease (IBD). Moreover, the identification of intraepithelial neoplasias in IBD is of key relevance for clinical management. Here, we systematically analyzed the utility of advanced endoscopic imaging techniques for optimized diagnosis in IBD. METHODS: PubMed/Medline, Web of Knowledge, and Cochrane library were searched twice for diagnostic studies on advanced endoscopic imaging in IBD. Clinical and technical information was retrieved and subsequently analyzed. Main outcome parameters consisted of the quality of the results, adverse events, and diagnostic yield. RESULTS: Fifty-six clinical studies with a total of 3296 patients were selected for final analysis. Filter technologies permitted a more detailed analysis of mucosal inflammation in IBD. In spite of substantial heterogeneity across studies, dye-based chromoendoscopy with targeted biopsy sampling yielded higher detection rates of intraepithelial neoplasias in ulcerative colitis as compared with white-light endoscopy with random biopsy sampling. Moreover, endocytoscopy and endomicroscopy allowed subsurface imaging of inflamed or neoplastic mucosa in IBD at subcellular resolution. Finally, endomicroscopy-aided molecular imaging enabled the identification of membrane-bound tumor necrosis factor on mucosal cells as a potential driver of disease activity in Crohn's disease. No relevant adverse events were reported. CONCLUSIONS: Advanced endoscopic imaging technologies are feasible, safe, and partially effective tools for detailed diagnosis of mucosal inflammation and detection of neoplasias in IBD. Results obtained from these advanced techniques may provide a rational basis for individualized, optimized therapy for IBD patients.
EVALuna2:33824

Advanced gastrointestinal endoscopic imaging for inflammatory bowel diseases - Tontini, Gian Eugenio; Rath, Timo; Neumann, Helmut (World Journal of Gastroenterology, 2016)
Gastrointestinal luminal endoscopy is of paramount importance for diagnosis, monitoring and dysplasia surveillance in patients with both, Crohn's disease and ulcerative colitis. Moreover, with the recent recognition that mucosal healing is directly linked to the clinical outcome of patients with inflammatory bowel disorders, a growing demand exists for the precise, timely and detailed endoscopic assessment of superficial mucosal layer. Further, the novel field of 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 therapeutic responses. Within this review, we describe how novel endoscopic approaches and advanced endoscopic imaging methods such as high definition and high magnification endoscopy, dye-based and dye-less chromoendoscopy, confocal laser endomicroscopy, endocytoscopy and molecular imaging now allow for the precise and ultrastructural assessment of mucosal inflammation and describe the potential of these techniques for dysplasia detection.
EVALuna2:2109

Advanced Imaging of Lung Homing Human Lymphocytes in an Experimental In Vivo Model of Allergic Inflammation Based on Light-sheet Microscopy - Schulz-Kuhnt, Anja; Zundler, Sebastian; Grüneboom, Anika; Neufert, Clemens; Wirtz, Stefan; Neurath, Markus; Atreya, Imke (Journal of Visualized Experiments, 2019)
Overwhelming tissue accumulation of highly activated immune cells represents a hallmark of various chronic inflammatory diseases and emerged as an attractive therapeutic target in the clinical management of affected patients. In order to further optimize strategies aiming at therapeutic regulation of pathologically imbalanced tissue infiltration of pro-inflammatory immune cells, it will be of particular importance to achieve improved insights into disease- and organ-specific homing properties of peripheral lymphocytes. The here described experimental protocol allows to monitor lung accumulation of fluorescently labeled and adoptively transferred human lymphocytes in the context of papain-induced pulmonary inflammation. In contrast to standard in vitro assays frequently used for the analysis of immune cell migration and chemotaxis, the now introduced in vivo setting takes into account lung-specific aspects of tissue organization and the influence of the complex inflammatory scenario taking place in the living murine organism. Moreover, three-dimensional cross-sectional light-sheet fluorescence microscopic imaging does not only provide quantitative data on infiltrating immune cells, but also depicts the pattern of immune cell localization within the inflamed lung. Overall, we are able to introduce an innovative technique of high value for immunological research in the field of chronic inflammatory lung diseases, which can be easily applied by following the provided step-by-step protocol.
CRIS-Team Scopus Importer:2019-05-24

Advanced small-bowel well-differentiated neuroendocrine tumours: An international survey of practice on 3rd-line treatment - Lamarca, Angela; Cives, Mauro; De Mestier, Louis; Crona, Joakim; Spada, Francesca; Oberg, Kjell; Pavel, Marianne Ellen; Alonso-Gordoa, Teresa (World Journal of Gastroenterology, 2021)
BACKGROUND Somatostatin analogues are an established first-line therapy for well differentiated small bowel neuroendocrine tumours (Wd-SBNETs), while and peptide receptor radionuclide therapy (PRRT) is frequently used as a second-line therapy. Adequate treatment selection of third-line treatment remains challenging due to the limited prospective data currently available on the best therapeutic sequence. AIM To understand current practice and rationale for decision-making by physicians in the 3rd-line setting by building an online survey. METHODS Weighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored. RESULTS Replies from representatives of 28 centers were received (5/8/2020-21/9/2020); medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from European Neuroendocrine Tumor Society (ENETS) Centres of Excellence (57.1%), who followed ENETS guidelines (82.1%). Generally speaking, 3rd-line treatment for Wd-SBNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon-alpha (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%), or personal experience (22.2%). EVE was most likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3rd-line setting (WA 3.23/4); regardless of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was mainly utilised only if rapid progression (within 6 mo) (WA 3.35/4), Ki-67 10%-20% (WA 2.77/4), negative somatostatin receptor imaging (WA 2.65/4) or high tumour burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-fluorouracil (5-FU) (57.7%), FOLFOX (5-FU combined with oxaliplatin) (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4). CONCLUSION Everolimus was the most frequently used therapeutic option in the third-line setting. The most important factors for decision-making included Ki-67, rate of progression, functionality and tumour burden; since this decision is based on multiple factors, it highlights the need for a multidisciplinary assessment.
CRIS-Team Scopus Importer:2021-03-26
Keywords: Advanced; Neuroendocrine tumour; Practice; Small bowel; Survey; Third-line

Advanced small intestine well-differentiated neuroendocrine tumors (WD-SiNET): A survey of practice on 3rd line treatment - Lamarca, A.; Cives, M.; De Mestier, L.; Crona, J.; Spada, F.; Oberg, K.; Pavel, Marianne Ellen; Alonso-Gordoa, T. (JOURNAL OF NEUROENDOCRINOLOGY, 2021)
CRIS-Team WoS Importer:2021-03-12

Advances in detection and management of dysplasia in inflammatory bowel disease: Is endoscopic submucosal dissection ready for prime time in inflammatory bowel disease? - Kiesslich, Ralf; Neurath, Markus (Gastrointestinal Endoscopy, 2015)
EVALuna2:1981

Advances in endoscopic imaging in ulcerative colitis - Tontini, Gian Eugenio; Pastorelli, Luca; Ishaq, Sauid; Neumann, Helmut (Expert Review of Gastroenterology and Hepatology, 2015)
Modern strategies for the treatment of ulcerative colitis require more accurate tools for gastrointestinal imaging to better assess mucosal disease activity and long-term prognostic clinical outcomes. Recent advances in gastrointestinal luminal endoscopy are radically changing the role of endoscopy in every-day clinical practice and research trials. Advanced endoscopic imaging techniques including high-definition endoscopes, optical magnification endoscopy, and various chromoendoscopy techniques have remarkably improved endoscopic assessment of ulcerative colitis. More recently, optical biopsy techniques with either endocytoscopy or confocal laser endomicroscopy have shown great potential in predicting several histological changes in real time during ongoing endoscopy. Here, we review current applications of advanced endoscopic imaging techniques in ulcerative colitis and present the most promising upcoming headways in this field.
EVALuna2:1984

Advances in hepatitis C therapy: What is the current state - what come's next? - Zopf, Steffen; Kremer, Andreas; Neurath, Markus; Siebler, Jürgen (World Journal of Hepatology, 2016)
Chronic hepatitis C virus (HCV) infection affects 80-160 million people worldwide and is one of the leading causes of chronic liver disease. It is only a few years ago that standard treatment regimes were based on pegylated interferon alpha and ribavirin. However, treatment of HCV has undergone a revolutionary change in recent years. The admission of the nucleotide polymerase inhibitor Sofosbuvir enabled an interferon-free regimen with direct antiviral agents (DAA). Meanwhile seven DAAs are available and can be applied in several combinations for 8 to 24 wk depending on HCV genotype and patient characteristics such as cirrhosis and chronic renal failure. High rates of sustained virological response (SVR) rates can be achieved with these novel drugs. Even in difficult to treat populations such as patients with liver cirrhosis, HCV-human immunodeficiency virus co-infections, after liver transplantion, or with chronic kidney disease comparable high rates of SVR can be achieved. The anticipated 2(nd) generation DAAs are strikingly effective in patients so far classified as difficult to treat including decompensated liver cirrhosis or post-transplant patients. These 2(nd) generations DAAs will have higher resistance barriers, higher antiviral effects and a pan-genotypic spectrum. This review highlights the current state of the art of antiviral treatment in hepatitis C and gives an outlook for upcoming therapies.
EVALuna2:2078

Advances in imaging to allow personalized medicine in Crohn's disease - Neurath, Markus (Current Opinion in Pharmacology, 2015)
Crohn's disease is a destructive inflammatory bowel disease of unknown origin that may lead to various complications such as strictures, stenosis, fistulas and colitis-associated neoplasias. However, the course of the disease varies substantially among patients and disease behaviour may also change with time. At diagnosis behaviour is inflammatory in the majority of patients, while penetrating or structuring behaviour become more prominent at later time points. Thus, medication in Crohn's disease needs frequent optimization over time. Therefore, new strategies for prediction of response to therapy are urgently needed. Here, recent advantages in imaging techniques for personalized medicine in Crohn's disease are reviewed. Such advantages include ultrasonography, computed tomography, magnetic resonance imaging and new endoscopic approaches such as molecular endoscopy. It is expected that these novel techniques will lead to marked improvements in the assessment of disease behaviour and the prediction of response to clinical therapy with biologicals.
EVALuna2:1980

Advances in pathogenesis and management of pruritus in cholestasis - Kremer, Andreas; Bolier, Ruth; Van Dijk, Remco; Elferink, Ronald P. J. Oude; Beuers, Ulrich (Digestive Diseases, 2014)
Chronic pruritus is a burdensome feature of numerous hepatobiliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy. Bile salts, ?-opioids, serotonin, histamine and steroids have been controversially discussed in the pathogenesis of cholestatic pruritus. However, for these substances neither a correlation with itch severity nor a causative link has ever been established. Recent findings indicate that the potent neuronal activator lysophosphatidic acid and autotaxin, the enzyme forming lysophosphatidic acid, may play a key element in the pathogenesis of cholestatic pruritus. Serum activity of autotaxin correlated with itch intensity and response to antipruritic treatment in patients with cholestatic pruritus, but not other forms of pruritus. Autotaxin activity thereby represents the first biomarker for pruritus and had a positive predictive value of 70% in differentiating cholestatic pruritus from other forms of pruritus. Treatment options for patients with cholestatic pruritus include the anion exchange resin colestyramine, the PXR agonist rifampicin, the ?-opioid antagonist naltrexone, and the serotonin reuptake inhibitor sertraline. These drugs are recommended by evidence-based guidelines as a stepwise therapeutic approach. Patients unresponsive to these drugs should be referred to specialized centers to receive experimental approaches such as UVB phototherapy, albumin dialysis, plasmapheresis or nasobiliary drainage. This review discusses pruritogen candidates in cholestasis, gives novel insights into the neuronal signaling pathway of pruritus and summarizes evidence-based treatment options for patients suffering from pruritus in cholestasis.
EVALuna2:1863

Affected differentiation and function of innate lymphoid cells type 2 in the absence of the Th2-and Th1-associated transcription factor NIP45 - Koch, Sonja; Springel, R.; Knipfer, Lisa; Wirtz, Stefan; Finotto, Susetta (2018)
EVALuna2:207770

Aggregated neutrophil extracellular traps occlude Meibomian glands during ocular surface inflammation - Mahajan, Aparna; Hasíková, Lenka; Hampel, Ulrike; Grüneboom, Anika; Shan, Xiaomei; Herrmann, Irmgard; Garreis, Fabian; Bock, Felix; Knopf, Jasmin; Singh, Jeeshan; Mahajan, Siddharth; Leppkes, Moritz; et al. (Ocular Surface, 2021)
Purpose: Obstructive Meibomian gland dysfunction (MGD) is one of the leading causes of evaporative dry eye disease. Meibomian glands at the eyelid secrete lipids that prevent evaporation of the aqueous tear film. The pathogenesis of obstructive MGD is incompletely understood to date. Herein, we aim to investigate the pathogenesis of obstructive MGD using murine and human samples with various forms of ocular surface inflammation. Method: The presence of Neutrophil extracellular Traps (NETs) was detected with immunofluorescence analysis of ocular surface discharge and biopsy samples from patients with blepharitis. Tear fluid from patients with MGD and blepharitis were evaluated for the presence of inflammatory mediators using bead based immunoassay. Murine model of allergic eye disease (AED) was performed to investigate the role of NETs in MG occlusion. Results: we show that the ocular discharge from patients with blepharitis contains aggregated neutrophil extracellular traps (aggNETs). Furthermore, the ducts of human Meibomian glands affected by blepharitis were largely congested by aggNETs. Tear fluid from patients with MGD showed elevated neutrophil chemoattractants (C5a, IL6, IL8 and IL18). C5a and IL8 correlated with the degree of deficiency of tear fluid. In the murine model of allergic eye disease (AED), aggNETs accumulated in the MG leading to occlusion of their ducts and the retrograde pent-up of the fluid followed by acinar atrophy. Constraining aggNET formation by genetic or pharmacological inhibition of peptidyl arginine deiminase type 4 (PADI4) effectively reduced MG damage. Conclusion: We conclude that aggNETs occlude MG causing MGD after ocular surface inflammation.
CRIS-Team Scopus Importer:2021-01-15
Keywords: Blepharitis; Meibomian gland dysfunction (MGD); Neutrophil extracellular traps (NETs); Occlusion

A group of cationic amphiphilic drugs activates MRGPRX2 and induces scratching behavior in mice - Wolf, Katharina; Kühn, Helen; Boehm, Felicitas; Gebhardt, Lisa; Glaudo, Markus; Agelopoulos, Konstantin; Ständer, Sonja; Ectors, Philipp; Zahn, Dirk; Riedel, Yvonne K.; Thimm, Dominik; Müller, Christa E.; et al. (Journal of Allergy and Clinical Immunology, 2021)
Background: Mas gene–related G protein–coupled receptors (MRGPRs) are a G protein–coupled receptor family responsive to various exogenous and endogenous agonists, playing a fundamental role in pain and itch sensation. The primate-specific family member MRGPRX2 and its murine orthologue MRGPRB2 are expressed by mast cells mediating IgE-independent signaling and pseudoallergic drug reactions. Objectives: Our aim was to increase knowledge about the function and regulation of MRGPRX2/MRGPRB2, which is of major importance in prevention of drug hypersensitivity reactions and drug-induced pruritus. Methods: To identify novel MRGPR (ant)agonists, we screened a library of pharmacologically active compounds by utilizing a high-throughput calcium mobilization assay. The identified hit compounds were analyzed for their pseudoallergic and pruritogenic effects in mice and human. Results: We found a class of commonly used drugs activating MRGPRX2 that, to a large extent, consists of antidepressants, antiallergic drugs, and antipsychotics. Three-dimensional pharmacophore modeling revealed structural similarities of the identified agonists, classifying them as cationic amphiphilic drugs. Mast cell activation was investigated by using the 3 representatively selected antidepressants clomipramine, paroxetine, and desipramine. Indeed, we were able to show a concentration-dependent activation and MRGPRX2-dependent degranulation of the human mast cell line LAD2 (Laboratory of Allergic Diseases-2). Furthermore, clomipramine, paroxetine, and desipramine were able to induce degranulation of human skin and murine peritoneal mast cells. These substances elicited dose-dependent scratching behavior following intradermal injection into C57BL/6 mice but less so in MRGPRB2-mutant mice, as well as wheal-and-flare reactions following intradermal injections in humans. Conclusion: Our results contribute to the characterization of structure-activity relationships and functionality of MRGPRX2 ligands and facilitate prediction of adverse reactions such as drug-induced pruritus to prevent severe drug hypersensitivity reactions.
CRIS-Team Scopus Importer:2021-04-19
Keywords: (drug-induced) pruritus; Mas gene–related G protein–coupled receptors; mast cells; pseudoallergic drug reactions

A High-Calorie Diet Aggravates Mitochondrial Dysfunction and Triggers Severe Liver Damage in Wilson Disease Rats - Einer, Claudia; Leitzinger, Christin; Lichtmannegger, Josef; Eberhagen, Carola; Rieder, Tamara; Borchard, Sabine; Wimmer, Ralf; Denk, Gerald; Popper, Bastian; Neff, Frauke; Polishchuk, Elena; Polishchuk, Roman S.; et al. (Cellular and Molecular Gastroenterology and Hepatology, 2019)
BACKGROUND & AIMS: In Wilson disease, ATP7B mutations impair copper excretion into bile. Hepatic copper accumulation may induce mild to moderate chronic liver damage or even acute liver failure. Etiologic factors for this heterogeneous phenotype remain enigmatic. Liver steatosis is a frequent finding in Wilson disease patients, suggesting that impaired copper homeostasis is linked with liver steatosis. Hepatic mitochondrial function is affected negatively both by copper overload and steatosis. Therefore, we addressed the question of whether a steatosis-promoting high-calorie diet aggravates liver damage in Wilson disease via amplified mitochondrial damage.
CRIS-Team WoS Importer:2019-05-03

A homozygous CaSR mutation causing a FHH phenotype completely masked by vitamin D deficiency presenting as rickets - Szczawinska, Dorothea; Schnabel, Dirk; Letz, Saskia; Schöfl, Christof (Journal of Clinical Endocrinology and Metabolism, 2014)
Heterozygous inactivating calcium-sensing receptor (CaSR) mutations lead to familial hypocalciuric hypercalcemia (FHH), whereas homozygous mutations usually cause neonatal severe hyperparathyroidism.The objective of the study was to investigate the pathophysiological mechanisms of a homozygous inactivating CaSR mutation identified in a 16-year-old female.Clinical, biochemical, and genetic analyses of the index patient and her family were performed. Functional capacity of CaSRQ459R and CaSR mutants causing FHH (Q27R, P39A, S417C) or neonatal severe hyperparathyroidism (W718X) was assessed. Activation of the cytosolic calcium pathway and inhibition of PTH-induced cAMP signaling were measured.A 16-year-old girl presented with adolescent rickets, vitamin D deficiency, and secondary hyperparathyroidism. Vitamin D treatment unmasked features resembling FHH, and genetic testing revealed a homozygous CaSRQ459R mutation. Two apparently healthy siblings were homozygous for CaSRQ459R and had asymptomatic hypercalcemia and hypocalciuria. The CaSRQ459R mutation leads to mild functional inactivation in vitro, which explains the FHH-like phenotype in homozygous family members and the grossly exaggerated PTH response to vitamin D deficiency in the index case. The patient's parents and two other siblings were heterozygous, had normal serum calcium and PTH, but had marked hypocalciuria, which appeared to be associated with impaired in vitro activation of the calcium signaling pathway by CaSRQ459R. The Q459R mutation responded well to calcimimetic treatment in vitro.CaSR mutations causing mild functional impairment can lead to FHH, even in homozygous patients. The skeletal deformities in the index case were mainly due to severe vitamin D deficiency, and the CaSR mutation did not appear to have played a major independent role in the skeletal phenotype.
EVALuna2:1905

A key regulatory role for Vav1 in controlling lipopolysaccharide endotoxemia via macrophage-derived IL-6 - Zenker, Stefanie; Panteleev-Ivlev, Julia; Wirtz, Stefan; Kishimoto, Tadamitsu; Waldner, Maximilian; Ksionda, Olga; Tybulewicz, Victor L. J.; Neurath, Markus; Atreya, Imke (Journal of Immunology, 2014)
Macrophages are centrally involved in the pathogenesis of acute inflammatory diseases, peritonitis, endotoxemia, and septic shock. However, the molecular mechanisms controlling such macrophage activation are incompletely understood. In this article, we provide evidence that Vav1, a member of the RhoGEF family, plays a crucial role in macrophage activation and septic endotoxemia. Vav1-deficient mice demonstrated a significantly increased susceptibility for LPS endotoxemia that could be abrogated by anti-IL-6R Ab treatment. Subsequent studies showed that Vav1-deficient macrophages display augmented production of the proinflammatory cytokine IL-6. Nuclear Vav1 was identified as a key negative regulator of macrophage-derived IL-6 production. In fact, Vav1 formed a nuclear DNA-binding complex with heat shock transcription factor 1 at the HSE2 region of the IL-6 promoter to suppress IL-6 gene transcription in macrophages. These findings provide new insights into the pathogenesis of endotoxemia and suggest new avenues for therapy.
EVALuna2:1870

Aktualisierte S3-Leitlinie Colitis ulcerosa - Kucharzik, Torsten; Dignass, Axel U.; Atreya, Raja; Bokemeyer, Bernd; Esters, Philip; Herrlinger, Klaus; Kannengießer, Klaus; Kienle, Peter; Langhorst, Jost; Lügering, Andreas; Schreiber, Stefan; Stallmach, Andreas; et al. (Zeitschrift für Gastroenterologie, 2019)
CRIS-Team Scopus Importer:2019-11-29

Aktualisierte S3-Leitlinie Colitis ulcerosa-Living Guideline-August 2020-AWMF-Registriernummer: 021-009 - 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, 2020)
CRIS-Team Scopus Importer:2020-12-25

Aktualisierte S3-Leitlinie Colitis ulcerosa (Version 6.1) - Februar 2023 - AWMF-Registriernummer: 021-009 - Kucharzik, T.; Dignass, A.; Atreya, Raja; Bokemeyer, B.; Esters, P.; Herrlinger, K.; Kannengiesser, K.; Kienle, P.; Langhorst, J.; Lügering, A.; Schreiber, S.; Stallmach, A.; et al. (Zeitschrift für Gastroenterologie, 2023)
CRIS-Team Scopus Importer:2023-09-08

Aktualisierte S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“ der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) – August 2021 – AWMF-Registernummer: 021-004 - Sturm, Andreas; Atreya, Raja; Bettenworth, Dominik; Bokemeyer, Bernd; Dignaß, Axel; Ehehalt, Robert; Germer, Christoph; Grunert, Philip C.; Helwig, Ulf; Herrlinger, Klaus; Kienle, Peter; Kreis, Martin E.; et al. (Zeitschrift für Gastroenterologie, 2022)
CRIS-Team Scopus Importer:2022-03-25

A large cohort of patients with hepatocellular carcinoma in a single European centre: aetiology and prognosis now and in a historical cohort - Ganslmayer, Marion; Hagel, Alexander; Dauth, Wolfgang; Zopf, Steffen; Strobel, Deike; Mueller, Volker; Uder, Michael; Neurath, Markus; Siebler, Jürgen (Swiss Medical Weekly, 2014)
The incidence of hepatocellular carcinoma is rising. However, this is occurring not only in developing nations, but in industrial countries as well. Surveillance programmes, classification systems and therapeutic options have improved, but there is a lack of data regarding their impact on the prognosis of this difficult-to-treat cancer.We evaluated 484 patients and reported on disease stage, therapeutic procedures and survival time. Data were compared with a historical cohort treated in the same centre 10 years before.In this cohort, the main reason for liver disease was alcoholism, although hepatitis B remains the leading cause of hepatocellular carcinoma worldwide. Now, most patients have compensated liver function and hepatocellular carcinoma is diagnosed in the early tumour stages (it was diagnosed in the advanced disease stages in the previous cohort). Overall, median survival time was 62.4 weeks, 1-year survival was 58.6% and 3-year survival was 23.2%. Survival time correlated with the stage of liver disease, tumour stage and with therapeutic options.Surveillance programmes lead to diagnosis in earlier tumour stages. Differentiated classification systems allow individualised therapeutic approaches. Earlier cancer stage and compensated liver function allow combination or sequential therapy, which was nearly impossible some years ago but is an option for most now. Primary liver cancer remains a difficult-to-treat malignancy, but the prognosis has improved remarkably, at least in the western world.
EVALuna2:1851

All are Equal, Some are More Equal: Targeting IL 12 and 23 in IBD - A Clinical Perspective - Jefremow, Andre; Neurath, Markus (ImmunoTargets and Therapy, 2020)
Chronic inflammatory diseases like inflammatory bowel diseases (IBD) or psoriasis represents a worldwide health burden. Researchers provided great achievements in understanding the origin of these diseases leading to improved therapeutic options. The discovery of cytokines like tumor necrosis factor-a or transforming growth factor-beta are examples for these efforts. Interleukin 12 (IL 12) and interleukin 23 (IL 23) represent different important cytokines in this regard. They both belong to the interleukin 12 family and are related by sharing the subunit p40. Ustekinumab is an antibody that blocks p40 and thereby interleukins 12 and 23. Trials showed promising results in treating IBD patients with this drug. Consequently, new questions arose about the distinct features of IL 12 and 23. This review focuses on these interleukins regarding their functions in the healthy and inflamed gut and provides an overview about the results from in vitro and in vivo studies as well as clinical trials.
CRIS-Team WoS Importer:2021-01-22

Alpha1-antitrypsin impacts innate host–pathogen interactions with Candida albicans by stimulating fungal filamentation - Jaeger, Martin; Dietschmann, Axel; Austermeier, Sophie; Dinçer, Sude; Porschitz, Pauline; Vornholz, Larsen; Maas, Ralph J.A.; Sprenkeler, Evelien G.G.; Ruland, Jürgen; Wirtz, Stefan; Azam, Tania; Joosten, Leo A.B.; et al. (Virulence, 2024)
Our immune system possesses sophisticated mechanisms to cope with invading microorganisms, while pathogens evolve strategies to deal with threats imposed by host immunity. Human plasma protein α1-antitrypsin (AAT) exhibits pleiotropic immune-modulating properties by both preventing immunopathology and improving antimicrobial host defence. Genetic associations suggested a role for AAT in candidemia, the most frequent fungal blood stream infection in intensive care units, yet little is known about how AAT influences interactions between Candida albicans and the immune system. Here, we show that AAT differentially impacts fungal killing by innate phagocytes. We observed that AAT induces fungal transcriptional reprogramming, associated with cell wall remodelling and downregulation of filamentation repressors. At low concentrations, the cell-wall remodelling induced by AAT increased immunogenic β-glucan exposure and consequently improved fungal clearance by monocytes. Contrastingly, higher AAT concentrations led to excessive C. albicans filamentation and thus promoted fungal immune escape from monocytes and macrophages. This underscores that fungal adaptations to the host protein AAT can differentially define the outcome of encounters with innate immune cells, either contributing to improved immune recognition or fungal immune escape.
CRIS-Team Scopus Importer:2024-04-19
Keywords: cell wall remodelling; filamentous growth; fungal adaptation; host–pathogen interactions; Immune escape; immune evasion

Alpha 4 beta 7 Integrin-dependent gut homing of non-classical monocytes is essential for intestinal wound healing mediated by M2 macrophages - Schleier, L.; Wiendl, Maximilian; Binder, M. -T.; Atreya, Raja; Watson, A.; Neufert, Clemens; Atreya, I.; Neurath, Markus; Zundler, Sebastian (2018)
EVALuna2:34111

Altered Diversity and Composition of the Microbiome in Patients with Primary Untreated Colorectal Cancer - Langheinrich, Melanie; Wirtz, Stefan; Weber, Klaus; Grützmann, Robert; Kersting, Stephan (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Alternative Splice Forms of CYLD Mediate Ubiquitination of SMAD7 to Prevent TGFB Signaling and Promote Colitis - Tang, Yilang; Reissig, Sonja; Glasmacher, Elke; Regen, Tommy; Wanke, Florian; Nikolaev, Alexei; Gerlach, Katharina; Popp, Vanessa; Karram, Khalad; Fantini, Massimo C.; Schattenberg, Jam M.; Galle, Peter R.; et al. (Gastroenterology, 2019)
BACKGROUND & AIMS: The CYLD lysine 63 deubiquitinase gene (CYLD) encodes tumor suppressor protein that is mutated in familial cylindromatosus, and variants have been associated with Crohn disease (CD). Splice forms of CYLD that lack exons 7 and 8 regulate transcription factors and functions of immune cells. We examined the expression of splice forms of CYLD in colon tissues from patients with CD and their effects in mice. METHODS: We performed immunohistochemical analyses of colon tissues from patients with untreated CD and patients without inflammatory bowel diseases (controls). We obtained mice that expressed splice forms of CYLD (sCYLD mice) without or with SMAD7 (sCYLD/SMAD7 mice) from transgenes and CYLD-knockout mice (with or without transgenic expression of SMAD7) and performed endoscopic analyses. Colitis was induced in Rag1(-/-) mice by transfer of CD4(+) CD62L(+) T cells from C57/Bl6 or transgenic mice. T cells were isolated from mice and analyzed by flow cytometry and quantitative realtime polymerase chain reaction and intestinal tissues were analyzed by histology and immunohistochemistry. CYLD forms were expressed in mouse embryonic fibroblasts, primary T cells, and HEK293T cells, which were analyzed by immunoblot, mobility shift, and immunoprecipitation assays. RESULTS: The colonic lamina propria from patients with CD was infiltrated by T cells and had higher levels of sCYLD (but not full-length CYLD) and SMAD7 than tissues from controls. Incubation of mouse embryonic fibroblasts and T cells with transforming growth factor b increased their production of sCYLD and decreased full-length CYLD. Transgenic expression of sCYLD and SMAD7 in T cells prevented the differentiation of regulatory T cells and T-helper type 17 cells and increased the differentiation of T-helper type 1 cells. The same effects were observed in colon tissues from sCYLD/SMAD7 mice but not in those from CYLD-knockout SMAD7 mice. The sCYLD mice had significant increases in the numbers of T-helper type 1 cells and CD44high CD62Llow memory-effector CD4(+) T cells in the spleen and mesenteric lymph nodes compared with wild-type mice; sCYLD/SMAD7 mice had even larger increases. The sCYLD/ SMAD7 mice spontaneously developed severe colitis, with infiltration of the colon by dendritic cells, neutrophils, macrophages, and CD4(+) T cells and increased levels of Ifng, Il6, Il12a, Il23a, and Tnf mRNAs. Co-transfer of regulatory T cells from wild-type, but not from sCYLD/SMAD7, mice prevented the induction of colitis in Rag1(-/-) mice by CD4(+) T cells. We found increased levels of poly-ubiquitinated SMAD7 in sCYLD CD4(+)T cells. CYLD formed a nuclear complex with SMAD3, whereas sCYLD recruited SMAD7 to the nucleus, which inhibited the expression of genes regulated by SMAD3 and SMAD4. We found that sCYLD mediated lysine 63-linked ubiquitination of SMAD7. The sCYLD-SMAD7 complex inhibited transforming growth factor beta signaling in CD4(+)T cells. CONCLUSIONS: Levels of the spliced form of CYLD are increased in colon tissues from patients with CD. sCYLD mediates ubiquitination and nuclear translocation of SMAD7 and thereby decreases transforming growth factor beta signaling in T cells. This prevents immune regulatory mechanisms and leads to colitis in mice.
CRIS-Team WoS Importer:2019-02-21

Amino Alcohol- (NPS-2143) and Quinazolinone-Derived Calcilytics (ATF936 and AXT914) Differentially Mitigate Excessive Signalling of Calcium-Sensing Receptor Mutants Causing Bartter Syndrome Type 5 and Autosomal Dominant Hypocalcemia - Letz, Saskia; Haag, Christine; Schulze, Egbert; Frank-Raue, Karin; Raue, Friedhelm; Hofner, Benjamin; Mayr, Bernhard; Schöfl, Christof (PLoS ONE, 2014)
Activating calcium sensing receptor (CaSR) mutations cause autosomal dominant hypocalcemia (ADH) characterized by low serum calcium, inappropriately low PTH and relative hypercalciuria. Four activating CaSR mutations cause additional renal wasting of sodium, chloride and other salts, a condition called Bartter syndrome (BS) type 5. Until today there is no specific medical treatment for BS type 5 and ADH. We investigated the effects of different allosteric CaSR antagonists (calcilytics) on activating CaSR mutants.All 4 known mutations causing BS type 5 and five ADH mutations were expressed in HEK 293T cells and receptor signalling was studied by measurement of intracellular free calcium in response to extracellular calcium ([Ca2+]o). To investigate the effect of calcilytics, cells were stimulated with 3 mM [Ca2+]o in the presence or absence of NPS-2143, ATF936 or AXT914.All BS type 5 and ADH mutants showed enhanced signalling activity to [Ca2+]o with left shifted dose response curves. In contrast to the amino alcohol NPS-2143, which was only partially effective, the quinazolinone calcilytics ATF936 and AXT914 significantly mitigated excessive cytosolic calcium signalling of all BS type 5 and ADH mutants studied. When these mutants were co-expressed with wild-type CaSR to approximate heterozygosity in patients, ATF936 and AXT914 were also effective on all mutants.The calcilytics ATF936 and AXT914 are capable of attenuating enhanced cytosolic calcium signalling activity of CaSR mutations causing BS type 5 and ADH. Quinazolinone calcilytics might therefore offer a novel treatment option for patients with activating CaSR mutations.
EVALuna2:1857

A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes - Serr, Isabelle; Scherm, Martin G.; Zahm, Adam M.; Schug, Jonathan; Flynn, Victoria K.; Hippich, Markus; Kaelin, Stefanie; Becker, Maike; Achenbach, Peter; Nikolaev, Alexei; Gerlach, Katharina; Liebsch, Nicole; et al. (Science Translational Medicine, 2018)
Molecular checkpoints that trigger the onset of islet autoimmunity or progression to human type 1 diabetes (T1D) are incompletely understood. Using T cells from children at an early stage of islet autoimmunity without clinical T1D, we find that a microRNA181a (miRNA181a)-mediated increase in signal strength of stimulation and costimulation links nuclear factor of activated T cells 5 (NFAT5) with impaired tolerance induction and autoimmune activation. We show that enhancing miRNA181a activity increases NFAT5 expression while inhibiting FOXP3+ regulatory T cell (T-reg) induction in vitro. Accordingly, Treg induction is improved using T cells from NFAT5 knockout (NFAT5ko) animals, whereas altering miRNA181a activity does not affect T-reg induction in NFAT5ko T cells. Moreover, high costimulatory signals result in phosphoinositide 3-kinase (PI3K)-mediated NFAT5, which interferes with FoxP(3+) Treg induction. Blocking miRNA181a or NFAT5 increases Treg induction in murine and humanized models and reduces murine islet autoimmunity in vivo. These findings suggest targeting miRNA181a and/or NFAT5 signaling for the development of innovative personalized medicines to limit islet autoimmunity.
EVALuna2:33886

A mutation within the SH2 domain of slp-76 regulates the tissue distribution and cytokine production of iNKT cells in mice - Danzer, Claudia Agnes; Koller, Anna; Baier, Julia; Arnold, Harald; Giessler, Claudia; Opoka, Robert; Schmidt, Stephanie; Willers, Maike; Mihai, Sidonia; Parsch, Hans; Wirtz, Stefan; Daniel, Christoph; et al. (European Journal of Immunology, 2016)
TCR ligation is critical for the selection, activation, and integrin expression of T lymphocytes. Here, we explored the role of the TCR adaptor protein slp-76 on iNKT-cell biology. Compared to B6 controls, slp-76(ace/ace) mice carrying a missense mutation (Thr428Ile) within the SH2-domain of slp-76 showed an increase in iNKT cells in the thymus and lymph nodes, but a decrease in iNKT cells in spleens and livers, along with reduced ADAP expression and cytokine response. A comparable reduction in iNKT cells was observed in the livers and spleens of ADAP-deficient mice. Like ADAP(-/-) iNKT cells, slp-76(ace/ace) iNKT cells were characterized by enhanced CD11b expression, correlating with an impaired induction of the TCR immediate-early gene Nur77 and a decreased adhesion to ICAM-1. Furthermore, CD11b-intrinsic effects inhibited cytokine release, concanavalin A-mediated inflammation, and iNKT-cell accumulation in the liver. Unlike B6 and ADAP(-/-) mice, the expression of the transcription factors Id3 and PLZF was reduced, whereas NP-1-expression was enhanced in slp-76(ace/ace) mice. Blockade of NP-1 decreased the recovery of iNKT cells from peripheral lymph nodes, identifying NP-1 as an iNKT-cell-specific adhesion factor. Thus, slp-76 contributes to the regulation of the tissue distribution, PLZF, and cytokine expression of iNKT cells via ADAP-dependent and -independent mechanisms.
EVALuna2:2050

An algorithm for differentiating food antigen-related gastrointestinal symptoms - Rostami, Kamran; Bold, Justine; Ali, Jafer Ismail; Parr, Alison; Dieterich, Walburga; Zopf, Yurdagül; Htoo, Aung; Rostami-Nejad, Mohammad; Danciu, Mihai (Gastroenterology and Hepatology From Bed to Bench, 2021)
Aim: The aim of this clinical audit was to assess patient-reported outcomes on the effect of dietary intervention, to enhance our understanding of possible treatment options in irritable bowel syndrome (IBS). Background: A large number of food-related gastro-intestinal disorders have been attributed to IBS for decades. Methods: Patient-reported outcomes from the records of 149 IBS patients treated at secondary and tertiary Gastroenterology outpatients in two UK hospitals between January 2014 and July 2016 were audited. Patients all presented with symptoms fulfilling Rome III-IV criteria for IBS had negative coeliac serology and did not have other gastrointestinal (GI) conditions. A modified version of a low FODMAP diet had been recommended (gluten and lactose free diet (G/LFD)) and was implemented for 6 weeks. Outcomes and dietary adherence were recorded during outpatient's consultations. Results: A total of 134 patients complied with the diet optimally. The majority had an improvement rate >70% and continued with the diet. Fifty-three percent became completely or almost asymptomatic, while 27.6% had a poor response to the diet (scoring < 30%) to G/LFD. The improvement was excellent in patients with normal BMI and good in overweight and obese and where BMI <18. Over 50% did not require any follow-up within 12 months. Conclusion: Although it is unclear whether symptoms are triggered by gluten, fructans or lactose, elimination of gluten and lactose proved to be an effective treatment in patients with IBS. Multidisciplinary team management and implementation of detailed nutrition therapy using the audit algorithm might prove to be both cost effective and efficacious a treatment option in IBS.
CRIS-Team Scopus Importer:2021-04-16
Keywords: Amylase trypsin inhibitors; FODMAP; Fructans; Gluten; Irritable bowel syndrome; Lactose intolerance; NCGS

Analysis of factors contributing to variation in the C57BL/6J fecal microbiota across German animal facilities. - Günther, Claudia; Rausch, Philipp; Basic, Marijana; Batra, Arvind; Bischoff, Stephan C.; Blauth, Michael; Clavel, Thomas; Glaesner, Joachim; Gopalakrishnan, Shreya; Grassl, Guntram A.; Haller, Dirk; Hirose, Misa; et al. (International Journal of Medical Microbiology, 2016)
The intestinal microbiota is involved in many physiological processes and it is increasingly recognized that differences in community composition can influence the outcome of a variety of murine models used in biomedical research. In an effort to describe and account for the variation in intestinal microbiota composition across the animal facilities of participating members of the DFG Priority Program 1656 "Intestinal Microbiota", we performed a survey of C57BL/6J mice from 21 different mouse rooms/facilities located at 13 different institutions across Germany. Fresh feces was sampled from five mice per room/facility using standardized procedures, followed by extraction and 16S rRNA gene profiling (V1-V2 region, Illumina MiSeq) at both the DNA and RNA (reverse transcribed to cDNA) level. In order to determine the variables contributing to bacterial community differences, we collected detailed questionnaires of animal husbandry practices and incorporated this information into our analyses. We identified considerable variation in a number of descriptive aspects including the proportions of major phyla, alpha- and beta diversity, all of which displayed significant associations to specific aspects of husbandry. Salient findings include a reduction in alpha diversity with the use of irradiated chow, an increase in inter-individual variability (beta diversity) with respect to barrier access and open cages and an increase in bacterial community divergence with time since importing from a vendor. We further observe a high degree of facility-level individuality, which is likely due to each facility harboring its own unique combination of multiple varying attributes of animal husbandry. While it is important to account and control for such differences between facilities, the documentation of such diversity may also serve as a valuable future resource for investigating the origins of microbial-driven host phenotypes.
Keywords: 16S rRNA gene; C57BL/6J; Gut microbiota; Mouse husbandry

Analysis of factors contributing to variation in the C57BL/6J fecal microbiota across German animal facilities - Günther, Claudia; Rausch, Philipp; Basic, Marijana; Batra, Arvind; Bischoff, Stephan C.; Blaut, Michael; Clavel, Thomas; Gläsner, Joachim; Gopalakrishnan, Shreya; Grassl, Guntram A.; Haller, Dirk; Hirose, Misa; et al. (International Journal of Medical Microbiology, 2016)
The intestinal microbiota is involved in many physiological processes and it is increasingly recognized that differences in community composition can influence the outcome of a variety of murine models used in biomedical research. In an effort to describe and account for the variation in intestinal microbiota composition across the animal facilities of participating members of the DFG Priority Program 1656 "Intestinal Microbiota", we performed a survey of C57BL/6J mice from 21 different mouse rooms/facilities located at 13 different institutions across Germany. Fresh feces was sampled from five mice per room/facility using standardized procedures, followed by extraction and 16S rRNA gene profiling (V1-V2 region, Illumina MiSeq) at both the DNA and RNA (reverse transcribed to cDNA) level. In order to determine the variables contributing to bacterial community differences, we collected detailed questionnaires of animal husbandry practices and incorporated this information into our analyses. We identified considerable variation in a number of descriptive aspects including the proportions of major phyla, alpha- and beta diversity, all of which displayed significant associations to specific aspects of husbandry. Salient findings include a reduction in alpha diversity with the use of irradiated chow, an increase in inter-individual variability (beta diversity) with respect to barrier access and open cages and an increase in bacterial community divergence with time since importing from a vendor. We further observe a high degree of facility-level individuality, which is likely due to each facility harboring its own unique combination of multiple varying attributes of animal husbandry. While it is important to account and control for such differences between facilities, the documentation of such diversity may also serve as a valuable future resource for investigating the origins of microbial-driven host phenotypes.
Keywords: 16S rRNA gene; C57BL/6J; Gut microbiota; Mouse husbandry

Analysis of factors contributing to variation in the C57BL/6J fecal microbiota across German animal facilities - Rausch, Philipp; Basic, Marijana; Batra, Arvind; Bischoff, Stephan C.; Blaut, Michael; Clavel, Thomas; Glaesner, Joachim; Gopalakrishnan, Shreya; Grass, Guntram A.; Günther, Claudia; Haller, Dirk; Hirose, Misa; et al. (International Journal of Medical Microbiology, 2016)
The intestinal microbiota is involved in many physiological processes and it is increasingly recognized that differences in community composition can influence the outcome of a variety of murine models used in biomedical research. In an effort to describe and account for the variation in intestinal microbiota composition across the animal facilities of participating members of the DFG Priority Program 1656 "Intestinal Microbiota", we performed a survey of C57BL/6J mice from 21 different mouse rooms/facilities located at 13 different institutions across Germany. Fresh feces was sampled from five mice per room/facility using standardized procedures, followed by extraction and 16S rRNA gene profiling (V1-V2 region, Illumina MiSeq) at both the DNA and RNA (reverse transcribed to cDNA) level. In order to determine the variables contributing to bacterial community differences, we collected detailed questionnaires of animal husbandry practices and incorporated this information into our analyses. We identified considerable variation in a number of descriptive aspects including the proportions of major phyla, alpha- and beta diversity, all of which displayed significant associations to specific aspects of husbandry. Salient findings include a reduction in alpha diversity with the use of irradiated chow, an increase in inter-individual variability (beta diversity) with respect to barrier access and open cages and an increase in bacterial community divergence with time since importing from a vendor. We further observe a high degree of facility-level individuality, which is likely due to each facility harboring its own unique combination of multiple varying attributes of animal husbandry. While it is important to account and control for such differences between facilities, the documentation of such diversity may also serve as a valuable future resource for investigating the origins of microbial-driven host phenotypes.
EVALuna2:2061

Analysis of shear wave elastography and serum autotaxin as novel non-invasive markers of liver fibrosis in patients with autoimmune hepatitis - a prospective study - Janik, M. K.; Kruk, B.; Kostrzewa, K.; Raszeja-Wyszomirska, J.; Wolf, Katharina; Lammert, F.; Kremer, Andreas; Krawczyk, M.; Milkiewicz, P. (2017)
EVALuna2:33925

Analysis of the interferon-γ-induced secretome of intestinal endothelial cells: putative impact on epithelial barrier dysfunction in IBD - Naschberger, Elisabeth; Flierl, Christian; Huang, Jinghao; Erkert, Lena; Gámez Belmonte, Maria de los Reyes; Gonzalez Acera, Miguel; Bober, Magdalena; Mehnert, Martin; Becker, Christoph; Schellerer, Vera S.; Britzen-Laurent, Nathalie; Stürzl, Michael (Frontiers in Cell and Developmental Biology, 2023)
The development of inflammatory bowel diseases (IBD) involves the breakdown of two barriers: the epithelial barrier and the gut-vascular barrier (GVB). The destabilization of each barrier can promote initiation and progression of the disease. Interestingly, first evidence is available that both barriers are communicating through secreted factors that may accordingly serve as targets for therapeutic modulation of barrier functions. Interferon (IFN)-γ is among the major pathogenesis factors in IBD and can severely impair both barriers. In order to identify factors transmitting signals from the GVB to the epithelial cell barrier, we analyzed the secretome of IFN-γ-treated human intestinal endothelial cells (HIEC). To this goal, HIEC were isolated in high purity from normal colon tissues. HIEC were either untreated or stimulated with IFN-γ (10 U/mL). After 48 h, conditioned media (CM) were harvested and subjected to comparative hyper reaction monitoring mass spectrometry (HRM™ MS). In total, 1,084 human proteins were detected in the HIEC-CM. Among these, 43 proteins were present in significantly different concentrations between the CM of IFN-γ- and control-stimulated HIEC. Several of these proteins were also differentially expressed in various murine colitis models as compared to healthy animals supporting the relevance of these proteins secreted by inflammatory activated HIEC in the inter-barrier communication in IBD. The angiocrine pathogenic impact of these differentially secreted HIEC proteins on the epithelial cell barrier and their perspectives as targets to treat IBD by modulation of trans-barrier communication is discussed in detail.
CRIS-Team Scopus Importer:2023-09-08
Keywords: angiocrine; barrier; cytokines; endothelial; IBD-inflammatory bowel disease; interferon; paracrine; secretion

Anatomical location of the vocal cords in relation to cervical vertebrae: A new predictor of difficult laryngoscopy? - Münster, Tino; Hoffmann, Melanie; Schlaffer, Sven-Martin; Ihmsen, Harald; Schmitt, Heike; Tzabazis, Alexander (European Journal of Anaesthesiology, 2016)
Several anatomical factors, such as prognathism, sex, short thyromental distance and others are known to make direct laryngoscopy difficult.We investigated the hypothesis that the anatomical position of the vocal cords in relation to the cervical vertebrae correlates with difficult laryngoscopy. Existing MRI was used to identify the position of the vocal cords relative to the cervical spine in patients with and without difficult laryngoscopy.Observational study with adaptive enrichment.University hospital.A total of 142 adult patients, 91 with easy (Cormack-Lehane class 1 or 2) and 51 with difficult (Cormack-Lehane class 3 or 4) laryngoscopy.Position of the vocal cords relative to cervical vertebrae in patients with easy vs. difficult laryngoscopy.In patients with difficult laryngoscopy, we found a higher incidence of cranial position of the vocal cords in relation to the cervical spine compared with patients with easy laryngoscopy (P < 0.001).Anaesthesiologists should take advantage of existing imaging of the cervical spine when assessing the patient's airway.
EVALuna2:16726

Anchoring of self-expanding metal stents using the over-the-scope clip, and a technique for subsequent removal - Mudumbi, Sandhya; Velazquez-Avina, Jacobo; Neumann, Helmut; Baig, K. R. Kyanam Kabir; Moenkemueller, Klaus (Endoscopy, 2014)
Standard clips do not consistently prevent the migration of covered self-expanding metal stents (SEMS). The aims of this study were to assess the efficacy and safety of the over-the-scope clip (OTSC) system for anchoring SEMS to the esophagus, and to evaluate a novel OTSC removal technique.This was a single-center, retrospective, cohort study of consecutive patients undergoing SEMS anchoring with OTSC. Removal of the OTSC was accomplished using an inject-and-resect technique.A total of 12 patients were included. The indications for endoscopic stenting were: tracheo-esophageal fistula (n = 7), postoperative leak or fistula (n = 4), perforation (n = 1). Successful application of the OTSC system was accomplished in all patients (100 %). Stent migration during follow-up (mean 3 weeks, range 2 - 4 weeks) occurred in two patients (16.7 %). After healing of the underlying condition, the stent was removed in six patients (50.0 %). In four patients (33.3 %), the anchored stent was left indefinitely in order to treat the underlying condition. There were no complications associated with deployment of the OTSC or SEMS removal.Although endoscopic anchoring of fully covered SEMS with the OTSC was feasible, easy to accomplish, safe, and prevented stent migration in most cases, larger studies are needed to confirm these encouraging early findings. The inject-and-resect technique was safe and efficient for OTSC and stent removal in all cases in which it was attempted.
EVALuna2:1890

An easily expandable multi-drug LC-MS assay for the simultaneous quantification of 57 oral antitumor drugs in human plasma - Kehl, Niklas; Schlichtig, Katja; Dürr, Pauline; Bellut, Laura; Dörje, Frank; Fietkau, Rainer; Pavel, Marianne Ellen; Mackensen, Andreas; Wullich, Bernd; Maas, Renke; Fromm, Martin; Geßner, Arne; et al. (Cancers, 2021)
Oral anticancer drugs have led to significant improvements in the treatment of multiple tumor entities. However, in patients undergoing oral antitumor therapy, plasma concentrations are highly variable, resulting in risks of reduced therapeutic effects or an increase in side effects. One important tool to reduce this variability is therapeutic drug monitoring. In this work we describe a method to simultaneously quantify the plasma concentrations of 57 oral antitumor agents. Quantification of these drugs was achieved using liquid chromatography coupled to an Orbitrap mass spectrometer. The method was fully validated according to the FDA guidelines and constitutes a simple and robust way for exposure monitoring of a wide variety of oral anticancer drugs. Applicability to clinical routine was demonstrated by the analysis of 71 plasma samples taken from 39 patients. In summary, this new multi-drug method allows simultaneous quantification of 57 oral antitumor drugs, which can be applied to exposure monitoring in clinical studies, taking into account the broad variety of oral antitumor drugs prescribed in clinical routine.
CRIS-Team Scopus Importer:2021-12-24
Keywords: Exposure measurement; Kinase inhibitors; Liquid chromatography mass spectrometry; Oral antitumor drug; Orbitrap mass spectrometer

A New Immortalized Human Lacrimal Gland Cell Line - Gleixner, Sophie; Zahn, Ingrid; Dietrich, Jana; Singh, Swati; Drobny, Alice; Schneider, Yanni; Schwendner, Raphael; Socher, Eileen; Blavet, Nicolas; Bräuer, Lars; Gostian, Antoniu-Oreste; Balk, Matthias; et al. (Cells, 2024)
The lacrimal gland is crucial for maintaining ocular health by producing the aqueous component of the tear film, which hydrates and nourishes the ocular surface. Decreased production of this component results in dry eye disease, a condition affecting over 250 million people worldwide. However, the scarcity of primary human material for studying its underlying mechanisms and the absence of a cell model for human lacrimal gland epithelial cells present significant challenges. Here, we describe the generation of immortalized human lacrimal gland cell lines through the introduction of an SV40 antigen. We successfully isolated and characterized three cell clones from a female lacrimal gland donor, confirming their epithelial identity through genomic and protein analyses, including PCR, RNAseq, immunofluorescence and cultivation in a 3D spheroid model. Our findings represent a significant advancement, providing improved accessibility to investigate the molecular pathogenesis mechanisms of dry eye disease and potential therapeutic interventions. We identified the expression of typical epithelial cell marker genes and demonstrated the cells’ capability to form 2D cell sheets and 3D spheroids. This establishment of immortalized human lacrimal gland cells with epithelial characteristics holds promise for future comprehensive studies, contributing to a deeper understanding of dry eye disease and its cellular mechanisms.<br
Keywords: lacrimal gland; epithelial cells; immortalized; cell line; dry eye; tears; tear secretion

A new simplified histology artificial intelligence system for accurate assessment of remission in Ulcerative Colitis - Villanacci, V.; Parigi, T. L.; Del Amor, R.; Esbri, P. Mesguer; Gui, X.; Bazarova, A.; Bhandari, P.; Bisschops, R.; Danese, S.; De Hertogh, G.; Ferraz, J. G.; Goetz, M.; et al. (JOURNAL OF CROHNS & COLITIS, 2022)
CRIS-Team WoS Importer:2022-05-13

Angiostatic immune reaction in colorectal carcinoma: Impact on survival and perspectives for antiangiogenic therapy - Naschberger, Elisabeth; Croner, Roland S.; Merkel, Susanne; Dimmler, Arno; Tripal, Philipp; Amann, Kerstin Ute; Kremmer, Elisabeth; Brueckl, Wolfgang M.; Papadopoulos, Thomas; Hohenadl, Christine; Hohenberger, Werner; Stürzl, Michael (International Journal of Cancer, 2008)
Angiogenesis and inflammation are the 2 major stroma reactions in colorectal carcinoma (CRC). Guanylate binding protein-1 (GBP-1) is a key mediator of angiostatic effects of inflammation. Therefore, we hypothesized that GBP-1 may be a biomarker of intrinsic angiostasis associated with an improved outcome in CRC patients. GBP-1 was strongly expressed in endothelial cells and immune cells in the desmoplastic stroma of 32% of CRC as determined by immunohistochemical investigation of 388 sporadic CRC. Cancer-related 5-year survival was highly significant (p < 0.001) increased (16.2%) in patients with GBP-1-positive CRC. Multivariate analysis showed that GBP-1 is an independent prognostic factor indicating a reduction of the relative risk of cancer-related death by the half (p = 0.032). A comparative transcriptome analysis (22,215 probe sets) of GBP-1-positive (n = 12) and -negative (n = 12) tumors showed that particularly IFN-γ-induced genes including the major antiangiogenic chemokines CXCL9, CXCL10 and CXCL11 were coexpressed with GBP-1. Altogether our findings indicated that GBP-1 may be a novel biomarker and an active component of a Th-1-like angiostatic immune reaction in CRC. This reaction may affect patient's response to antiangiogenic therapy and the identification of such tumors may provide a novel criterion for patient selection. Moreover, the induction of a Th-1-like angiostatic immune reaction may be a promising approach for the clinical treatment of CRC. © 2008 Wiley-Liss, Inc.
Created from Fastlane, Scopus look-up
Keywords: Angiogenesis; Colorectal carcinoma; Guanylate binding protein-1; Inflammation; Interferon-γ

An IFN-STAT1-MLKL axis drives programmed necrosis of Paneth cells in Crohn's ileitis - Hartmann, Leonie; Siegmund, B.; Weidinger, C.; Becker, Christoph; Neurath, Markus; Günther, Claudia (JOURNAL OF CROHNS & COLITIS, 2020)
CRIS-Team WoS Importer:2020-04-10

An IFN-STAT Axis Augments Tissue Damage and Inflammation in a Mouse Model of Crohn's Disease - Stolzer, Iris; Dressel, Anja; Neurath, Markus; Günther, Claudia; Chiriac, Mircea-Teodor (Frontiers in Medicine, 2021)
Blocking interferon-function by therapeutic intervention of the JAK-STAT-axis is a novel promising treatment option for inflammatory bowel disease (IBD). Although JAK inhibitors have proven efficacy in patients with active ulcerative colitis (UC), they failed to induce clinical remission in patients with Crohn's disease (CD). This finding strongly implicates a differential contribution of JAK signaling in both entities. Here, we dissected the contribution of different STAT members downstream of JAK to inflammation and barrier dysfunction in a mouse model of Crohn's disease like ileitis and colitis (Casp8ΔIEC mice). Deletion of STAT1 in Casp8ΔIEC mice was associated with reduced cell death and a partial rescue of Paneth cell function in the small intestine. Likewise, organoids derived from the small intestine of these mice were less sensitive to cell death triggered by IBD-key cytokines such as TNFα or IFNs. Further functional in vitro and in vivo analyses revealed the impairment of MLKL-mediated necrosis as a result of deficient STAT1 function, which was in turn associated with improved cell survival. However, a decrease in inflammatory cell death was still associated with mild inflammation in the small intestine. The impact of STAT1 signaling on gastrointestinal inflammation dependent on the localization of inflammation, as STAT1 is essential for intestinal epithelial cell death regulation in the small intestine, whereas it is not the key factor for intestinal epithelial cell death in the context of colitis. Of note, additional deletion of STAT2 was not sufficient to restore Paneth cell function but strongly ameliorated ileitis. In summary, we provide here compelling molecular evidence that STAT1 and STAT2, both contribute to intestinal homeostasis, but have non-redundant functions. Our results further demonstrate that STATs individually affect the distinct pathophysiology of inflammation in the ileum and colon, respectively, which might explain the diverse outcome of JAK inhibitors on inflammatory bowel diseases.
CRIS-Team Scopus Importer:2021-06-25
Keywords: cell death; inflammation; inflammatory bowel disease; Paneth cells; STAT signaling

(untitled)
Background & Aims: Endoscopic and histologic remission are important goals in the treatment of ulcerative colitis (UC). We investigated the correlation of the recently developed Paddington International Virtual ChromoendoScopy ScOre (PICaSSO) and other established endoscopic scores against multiple histological indices and prospectively assessed outcomes. Methods: In this prospective multicenter international study, inflammatory activity was assessed with high-definition and virtual chromoendoscopy in the rectum and sigmoid using the Mayo Endoscopic Score (MES), UC Endoscopic Index of Severity (UCEIS), and PICaSSO. Targeted biopsies were taken for assessment using Robarts Histological Index (RHI), Nancy Histological index (NHI), ECAP (Extent, Chronicity, Activity, Plus score), Geboes, and Villanacci. Follow-up data were obtained at 6 and 12 months after colonoscopy. Results: A total of 307 patients were recruited. There was strong correlation between PICaSSO and histology scores, significantly superior to correlation coefficients of MES and UCEIS with histology scores. A PICaSSO score of ≤3 detected histologic remission by RHI (≤3 + absence of neutrophils) with area under the receiver operating characteristic curve (AUROC) 0.90 (95% confidence interval [CI] 0.86–0.94) and NHI (≤1) AUROC 0.82 (95% CI 0.77–0.87). The interobserver agreement for PICaSSO was 0.88 (95% CI 0.83–0.92). At 6- and 12-months follow-up, PICaSSO score ≤3 predicted better outcomes than PICaSSO >3 (hazard ratio [HR] 0.19 [0.11–0.33] and 0.22 [0.13–0.34], respectively),

An intravital microscopy-based approach to assess intestinal permeability and epithelial cell shedding performance - Martínez Sánchez, Luz del Carmen; Pradhan, Rashmita; Ngo, Phuong A.; Erkert, Lena; Becker, Lea; Watson, Alastair J.; Atreya, Imke; Neurath, Markus; Lopez Posadas, Rocío (Journal of Visualized Experiments, 2020)
Intravital microscopy of the gut using confocal imaging allows real time observation of epithelial cell shedding and barrier leakage in living animals. Therefore, the intestinal mucosa of anesthetized mice is topically stained with unspecific staining (acriflavine) and a fluorescent tracer (rhodamine-B dextran), mounted on a saline solution-rinsed plate and directly imaged using a confocal microscope. This technique can complement other non-invasive techniques to identify leakage of intestinal permeability, such as transmucosal passage of orally administered tracers. Besides this, the approach presented here allows the direct observation of cell shedding events at real-time. In combination with appropriate fluorescent reporter mice, this approach is suitable for shedding light into cellular and molecular mechanisms controlling intestinal epithelial cell extrusion, as well as to other biological processes. In the last decades, interesting studies using intravital microscopy have contributed to knowledge on endothelial permeability, immune cell gut homing, immune-epithelial communication and invasion of luminal components, among others. Together, the protocol presented here would not only help increase the understanding of mechanisms controlling epithelial cell extrusion, but could also be the basis for the developmental of other approaches to be used as instruments to visualize other highly dynamic cellular process, even in other tissues. Among technical limitations, optical properties of the specific tissue, as well as the selected imaging technology and microscope configuration, would in turn, determine the imaging working distance, and resolution of acquired images.
CRIS-Team Scopus Importer:2020-12-25

An in vivo gene delivery approach for the isolation of reasonable numbers of type 2 innate lymphoid cells - Frech, Michael; Knipfer, Lisa; Wirtz, Stefan; Zaiss, Mario (MethodsX, 2020)
Group 2 innate lymphoid cells (ILC2s) are a recently recognized subset of innate lymphocytes with crucial role in mucosal immunity and tissue homeostasis. Over the past decade, substantial advances in our understanding of ILC2 biology have established them as an essential element in innate and adaptive immunity. However, their relatively low abundance and laborious purification from mucosal tissues make their study difficult. Moreover, due to a lack of an ILC2-specific Cre mouse-line, adoptive transfer of ILC2s into ILC-deficient hosts is inevitable. Herein we describe an in-depth protocol for the induction, isolation, and expansion of murine ILC2s. By combining an in vivo gene delivery approach to boost ILC2 numbers and a cell culture strategy to expand isolated cells, large quantities of highly pure ILC2s can be obtained. The isolated cells maintain their phenotype and can be used for subsequent cell transfer or in vitro studies. In comparison to previous protocols, this approach is cost-effective and efficient with potential yield of more than 20 million ILC2s isolated per mouse. • Group 2 innate lymphoid cells (ILC2s) are extensively studied in mouse models and humans in recent years. • Low abundance of ILC2s and current lack of specific ILC2 knockout mice makes in vivo research challenging. • This method allows high and pure ILC2 numbers for in vitro or adoptive in vivo transfer experiments.
CRIS-Team Scopus Importer:2020-09-25
Keywords: Cell culture; Cytokines; Fluorescent activated cell sorting; Group 2 innate lymphoid cells; Isolation and expansion of murine ILC2s

A Novel Mobile Phone App (OncoFood) to Record and Optimize the Dietary Behavior of Oncologic Patients: Pilot Study - Orlemann, Till; Reljic, Dejan; Zenker, Björn; Meyers, Julia; Eskofier, Björn; Thiemt, Jana; Herrmann, Hans Joachim; Neurath, Markus; Zopf, Yurdagül (JMIR Cancer, 2018)
BACKGROUND: Catabolism and tumor-specific therapy lead to reduced nutrient intake and weight loss in cancer patients. Maintaining a specific individualized diet can be challenging for the patient as the nutritional counseling options are limited. Monitoring of nutrient intake and frequent feedback are, however, vital for successful nutritional therapy because they support the patient's compliance and realization of dietary therapeutic goals. OBJECTIVE: This study aimed at investigating the feasibility and applicability of a novel mobile phone app to assess and evaluate dietary behaviors in oncologic patients. METHODS: To determine dietary habits and food preferences in oncologic patients, initially 1400 nutritional records were evaluated and analyzed. The results provided the basis for creating a nutritional mobile phone app. Key requirements for the app included simple handling, recording the daily intake, and a comparison of nutrient targets and current status. In total, 39 cancer patients were recruited for the study; 15 patients dropped out prior to the study. All patients received a nutritional anamnesis, nutritional analysis, and nutritional counseling. Individual energy and nutrient aims were defined. The intervention group (n=12) additionally used the app. Weight and body composition of each group were evaluated after 4 weeks. RESULTS: The app group gained significantly more weight (P=.045; mean weight 1.03 kg vs -1.46 kg). Also, skeletal muscle mass showed a significant increase in the app group (P=.009; mean skeletal muscle mass 0.58 kg vs -0.61 kg) compared with the control group. There was no significant difference between groups relating to the daily protein intake (P=.06). Additionally, there was a decrease in macronutrient intake during the study period in the control group. CONCLUSIONS: Our study indicates that patients who track their daily dietary habits using a mobile phone app are more likely to reach their nutritional goals than the control patients. Further large-scale studies are needed to confirm these initial findings and test the applicability on a broader basis.
EVALuna2:208323

Anti-Adhesion Therapies in Inflammatory Bowel Disease-Molecular and Clinical Aspects - Zundler, Sebastian; Becker, Emily; Weidinger, Carl; Siegmund, Britta (Frontiers in Immunology, 2017)
The number of biologicals for the therapy of immunologically mediated diseases is constantly growing. In contrast to other agents that were previously introduced in rheumatologic or dermatologic diseases and only later adopted for the treatment of inflammatory bowel diseases (IBDs), the field of IBD was ground breaking for the concept of anti-adhesion blockade. Anti-adhesion antibodies selectively target integrins controlling cell homing to the intestine, which leads to reduction of inflammatory infiltration to the gut in chronic intestinal inflammation. Currently, the anti-α4β7-antibody vedolizumab is successfully used for both Crohn's disease and ulcerative colitis worldwide. In this mini-review, we will summarize the fundamental basis of intestinal T cell homing and explain the molecular groundwork underlying current and potential future anti-adhesion therapies. Finally, we will comment on noteworthy clinical aspects of anti-adhesion therapy and give an outlook to the future of anti-integrin antibodies and inhibitors.
EVALuna2:34129

Anti-beta 7 integrin treatment impedes the recruitment on non-classical monocytes to the gut and delays macrophage-mediated intestinal wound healing - Sommer, Katrin; Heidbreder, Karin; Kreiß, Lucas; Dedden, Mark; Paap, Eva-Maria; Wiendl, Maximilian; Becker, Emily; Atreya, Raja; Müller, Tanja; Atreya, Imke; Waldner, Maximilian; Schürmann, Sebastian; et al. (Clinical and Translational Medicine, 2023)
BackgroundClosing mucosal defects to reach mucosal healing is an important goal of therapy in inflammatory bowel disease (IBD). Among other cells, monocyte-derived macrophages are centrally involved in such intestinal wound healing. We had previously demonstrated that the anti-alpha 4 beta 7 integrin antibody vedolizumab blocks the recruitment of non-classical monocytes as biased progenitors of wound healing macrophages to the gut and delays wound healing. However, although important for the interpretation of disappointing results in recent phase III trials in IBD, the effects of the anti-beta 7 antibody etrolizumab on wound healing are unclear so far. MethodsWe analyzed the expression of etrolizumab targets on human and mouse monocyte subsets by flow cytometry and assessed their function in adhesion and homing assays. We explored wound-associated monocyte recruitment dynamics with multi-photon microscopy and compared the effects of etrolizumab and vedolizumab surrogate (-s) antibodies on experimental wound healing and wound-associated macrophage abundance. Finally, we investigated wound healing macrophage signatures in the large intestinal transcriptome of patients with Crohn's disease treated with etrolizumab. ResultsHuman and mouse non-classical monocytes expressed more alpha E beta 7 integrin than classical monocytes and were a target of etrolizumab-s, which blocked non-classical monocyte adhesion to MAdCAM-1 and E-Cadherin as well as gut homing in vivo. Intestinal wound healing was delayed on treatment with etrolizumab-s along with a reduction of peri-lesional wound healing macrophages. Wound healing macrophage signatures in the colon of patients with Crohn's disease were substantially down-regulated on treatment with etrolizumab, but not with placebo. ConclusionsCombined blockade of alpha E beta 7 and alpha 4 beta 7 with etrolizumab seems to exceed the effect of anti-alpha 4 beta 7 treatment on intestinal wound healing, which might help to inform further investigations to understand the recent observations in the etrolizumab phase III trial program.
CRIS-Team WoS Importer:2023-05-05

ANTICOAGULANT-RELATED GASTROINTESTINAL BLEEDING: A REAL-LIFE DATA ANALYSIS ON BLEEDING PROFILES, FREQUENCY AND ETIOLOGY OF PATIENTS RECEIVING DIRECT ORAL ANTICOAGULANTS VERSUS VITAMIN K ANTAGONISTS - Albrecht, Heinz; Maass, L. S.; Hagel, Alexander; Neurath, Markus; Konturek, P. C.; Raithel, M. (Journal of Physiology and Pharmacology, 2019)
Vitamin K antagonists (VKA) continue to be the standard of long-term anticoagulation. Direct oral anticoagulants (DOAC) are increasingly used. In many trials DOAC were at least as effective as VKA. In this study we evaluate the bleeding profiles, frequencies and etiologies of patients receiving DOAC versus VKA in a real-life setting. All patients presenting with suspected gastrointestinal bleeding (GIB) in the emergency department of the University Hospital Erlangen in one year were enrolled in this study. They were looked up for the intake of either DOAC (dabigatran, rivaroxaban and apixaban) or VKA. The results showed that 406 patients with suspected GIB were admitted to the emergency unit of the University Hospital Erlangen. In 228 of those patients GIB could be verified (56.2%). Fifty four of those patients (23.7%) were administered either VKA or DOAC. In 35 of those 54 patients (64.8%) GIB was classified as 'major bleeding'. In 27 patients with administration of VKA upper GIB was recorded and lower GIB was detected four times. In 16 patients with administration of DOAC upper GIB was found and lower GIB was found in 7 patients. The presented data do not show higher GIB rates for DOAC (mainly dabigatran and rivaroxaban), but do also not indicate a significantly higher safety of DOAC concerning GIB than VKA. This finding represents a clear contrast to the reduced bleeding rates of DOAC for intracerebral bleeding and other non-GIB events. According to our study, the absolute number of DOAC-associated GIB events is lower than in the VKA group.
CRIS-Team WoS Importer:2020-04-28

Antiproliferative Systemic Therapies for Metastatic Small Bowel Neuroendocrine Tumours - Dawod, Mohammed; Gordoa, Teresa Alonso; Cives, Mauro; De Mestier, Louis; Crona, Joakim; Spada, Francesca; Oberg, Kjel; Pavel, Marianne; Lamarca, Angela (Current Treatment Options in Oncology, 2021)
Opinion statement Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies with rising incidence and prevalence. Outcome and therapy of small bowel neuroendocrine tumours (SBNETs) is variable, depending on the grade, differentiation, tumour burden, as well as the site of the tumour origin. Because of this, multidisciplinary approach is essential. Large randomized clinical trials, with somatostatin analogues (PROMID, CLARINET) or with peptide receptor radionuclide therapy (PRRT) with 177-lutetium (NETTER-1 trial) as well as the mammalian target of rapamycin inhibitor (mTOR) everolimus (RADIANT trials), represent milestones for the medical management of unresectable grade 1 and 2 SBNETS over the last decade. Novel therapies, such as tyrosine kinase inhibitors (TKI), are on the cutting edge. However, multiple unsolved questions remain. This review provides a comprehensive review of the main systemic therapeutic options for advanced SBNETs and discusses the latest guideline recommendations for palliative treatment.
CRIS-Team WoS Importer:2021-07-16

Antipruritic effect of bezafibrate and serum autotaxin measures in patients with primary biliary cholangitis - Kremer, Andreas; Le Cleac'H, Aline; Lemoinne, Sara; Wolf, Katharina; De Chaisemartin, Luc; Chollet-Martin, Sylvie; Humbert, Lydie; Rainteau, Dominique; Poupon, Raoul; Rousseau, Alexandra; Chazouilleres, Olivier; Corpechot, Christophe (Gut, 2019)
CRIS-Team WoS Importer:2019-11-29

Anti-TNF Antibodies and Autophagy: A Hidden Nexus for a Successful Therapeutic Response? - Genua, Marco; Becker, Christoph; Vetrano, Stefania (Journal of Crohns & Colitis, 2016)
EVALuna2:2104

Anti-TNF biosimilars in Crohn's Disease: a patient-centric interdisciplinary approach - Peyrin-Biroulet, Laurent; Danese, Silvio; Cummings, Fraser; Atreya, Raja; Greveson, Kay; Pieper, Burkhard; Kang, Taegyun (Expert Review of Gastroenterology and Hepatology, 2019)
Introduction: The purpose of this review is to highlight the role of biosimilars in early treatment in IBD and introduce ways to facilitate a patient-centric switching process through multidisciplinary approach. Areas covered: We summarize existing scientific literature related to the role of biosimilars in inflammatory bowel disease in terms of early treatment and cost-saving and implementing switching process. Expert opinion: Use of anti-TNF biosimilars in patients has the potential for large drug-acquisition cost-saving, which can be reinvested into early treatment. Managed switched programs for adalimumab can add further benefits in the future.
CRIS-Team WoS Importer:2019-08-23

Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis - Lankes, Katharina; Hundorfean, Gheorghe; Harrer, Thomas; Pommer, Ansgar J.; Agaimy, Abbas; Angelovska, Irena; Tajmir-Riahi, Azadeh; Göhl, Jonas; Schuler, Gerold; Neurath, Markus; Hohenberger, Werner; Heinzerling, Lucie (OncoImmunology, 2016)
Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics.
EVALuna2:2063

Anti-trafficking agents in the treatment of inflammatory bowel disease - Zundler, Sebastian; Wiendl, Maximilian; Neurath, Markus (Current Opinion in Gastroenterology, 2019)
Purpose of review To describe the latest developments in the field of anti-trafficking agents (ATAs), a class of therapeutics with growing importance in the field of inflammatory bowel diseases (IBDs) that specifically inhibit steps of immune cell trafficking. Recent findings Several translational and clinical studies have further shaped the knowledge about the mechanisms and effects of the anti-α4β7 integrin antibody vedolizumab. In parallel, new ATAs like the anti-β7 integrin antibody etrolizumab and the anti-MAdCAM-1 antibody ontamalimab are investigated in phase III clinical trials and might soon increase the therapeutic armamentarium in IBD. Summary ATAs have unique mechanisms of action and can meanwhile be considered an indispensable column of IBD therapy. Further efforts are necessary to elucidate complex mechanistic aspects, to exactly define their role in relation to other therapeutic approaches and to identify novel treatment targets as well as biomarkers for personalized medicine.
CRIS-Team Scopus Importer:2019-10-01
Keywords: etrolizumab; gut homing; ontamalimab; trafficking; vedolizumab

A Phase 2 Study of Galunisertib (TGF-beta 1 Receptor Type I Inhibitor) and Sorafenib in Patients With Advanced Hepatocellular Carcinoma - Kelley, R. K.; Gane, E.; Assenat, E.; Galle, P. R.; Merle, P.; Hourmand, I. O.; Cleverly, A.; Zhao, Y.; Gueorguieva,; Lahn, M.; Faivre, S.; Benhadji, K. A.; et al. (Clinical and Translational Gastroenterology, 2019)
INTRODUCTION: Inhibition of tumor growth factor-beta (TGF-beta) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-beta 1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment.
CRIS-Team WoS Importer:2019-08-16

A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis - Bowlus, Christopher L.; Galambos, Michael R.; Aspinall, Richard J.; Hirschfield, Gideon M.; Jones, David E.J.; Dörffel, Yvonne; Gordon, Stuart C.; Harrison, Stephen A.; Kremer, Andreas; Mayo, Marlyn J.; Thuluvath, Paul J.; Levy, Cynthia; et al. (Journal of Hepatology, 2022)
Background & Aims: We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid. Methods: In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8. Results: Mean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events. Conclusions: Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus. ClinicalTrials.gov Number: NCT02955602 Clinicaltrialsregister.eu Number: 2016-002996-91 Lay summary: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10 mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores.
CRIS-Team Scopus Importer:2022-05-13
Keywords: Clinical study; Primary biliary cholangitis; Seladelpar

Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. - Günther, Claudia; Neumann, Helmut; Neurath, Markus; Becker, Christoph (Gut, 2013)
Intestinal epithelial cells (IEC) are organised as a single cell layer which covers the intestine. Their primary task is to absorb nutrients present in the intestinal lumen. However, IEC also play an important role in the immune defence of our body by building a barrier that separates the bowel wall from potentially hazardous bacteria present in the gut lumen. The life cycle of IEC is determined by the time span in which cells migrate from their place of origin at the crypt base to the villus tip, from where they are shed into the lumen. Cell death in the intestinal epithelium has to be tightly regulated and irregularities might cause pathologies. Excessive cell death has been associated with chronic inflammation as seen in patients with Crohn's disease and ulcerative colitis. While until recently apoptosis was discussed as being essential for epithelial turnover and tissue homeostasis in the intestinal epithelium, recent data using gene deficient mice have challenged this concept. Moreover, an apoptosis-independent mode of programmed cell death, termed necroptosis, has been identified and described in the intestinal epithelium. The following article reviews previous studies on cell death regulation in IEC and a potential role of necroptosis for gut homeostasis.
Keywords: Cell death; Paneth cells; RIP; bacterial translocation; caspase-8; cytokines; endoscopy; epithelial cells; gene expression; inflammatory bowel disease; necroptosis; signal transduction.

Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. - Günther, Claudia; Neumann, Helmut; Neurath, Markus; Becker, Christoph (Gut, 2013)
Intestinal epithelial cells (IEC) are organised as a single cell layer which covers the intestine. Their primary task is to absorb nutrients present in the intestinal lumen. However, IEC also play an important role in the immune defence of our body by building a barrier that separates the bowel wall from potentially hazardous bacteria present in the gut lumen. The life cycle of IEC is determined by the time span in which cells migrate from their place of origin at the crypt base to the villus tip, from where they are shed into the lumen. Cell death in the intestinal epithelium has to be tightly regulated and irregularities might cause pathologies. Excessive cell death has been associated with chronic inflammation as seen in patients with Crohn's disease and ulcerative colitis. While until recently apoptosis was discussed as being essential for epithelial turnover and tissue homeostasis in the intestinal epithelium, recent data using gene deficient mice have challenged this concept. Moreover, an apoptosis-independent mode of programmed cell death, termed necroptosis, has been identified and described in the intestinal epithelium. The following article reviews previous studies on cell death regulation in IEC and a potential role of necroptosis for gut homeostasis.
Keywords: Cell death; Paneth cells; RIP; bacterial translocation; caspase-8; cytokines; endoscopy; epithelial cells; gene expression; inflammatory bowel disease; necroptosis; signal transduction

Apoptotic cell death in disease—Current understanding of the NCCD 2023 - Vitale, Ilio; Pietrocola, Federico; Guilbaud, Emma; Aaronson, Stuart A.; Abrams, John M.; Adam, Dieter; Agostini, Massimiliano; Agostinis, Patrizia; Alnemri, Emad S.; Altucci, Lucia; Amelio, Ivano; Andrews, David W.; et al. (Cell Death and Differentiation, 2023)
Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
CRIS-Team Scopus Importer:2023-05-05

A Possible Distinct Molecular Subtype (Quintuple-Wildtype) of Metastatic Colorectal Cancer in First-Line Anti-EGFR Therapy with Cetuximab Plus FOLFIRI - Palliative Precision Therapy and a Multidisciplinary Treatment Approach: Interim Analysis of the IVOPAK II Trial with Early Results - Wein, Axel; Stöhr, Robert; Kersting, Stephan; Siebler, Jürgen; Merkel, Susanne; Busse, Daniel; Wolff, Kerstin; Ostermeier, Nicola; Neufert, Clemens; Vitali, Francesco; Eckstein, Markus; Roth, Jan-Peter; et al. (Oncology, 2021)
Objective: The study aimed to prospectively evaluate a new molecular biomarker panel (KRAS, NRAS, BRAF, PIK3CA, and ERBB2) for palliative first-line treatment of colorectal cancer (CRC), including a multidisciplinary treatment approach. The rate of secondary metastasis resections was assessed. Patients and Methods: A total of 40 patients with definitively nonresectable metastatic CRC were enrolled from 10 centers before the interim analysis (June 2019) of the IVOPAK II trial (Interdisciplinary Care with Quality Control in Palliative Treatment of Colorectal Cancer). After determination of 5 molecular biomarkers in the tumor (KRAS, exons 2-4; NRAS, exons 2-4; BRAF V600E; PIK3CA; and ERBB2), patients in the IVOPAK II study received FOLFIRI plus cetuximab for all-RAS/quintuple-wildtype disease and FOLFIRI plus bevacizumab in the case of RAS mutations. The current article presents the early description of the clinical outcome of the interim analysis of IVOPAK II comparing the all-RAS/quintuple-wildtype and RAS-mutations populations, including a multidisciplinary-treated case report of a quintuple-wildtype patient. Results: The quintuple-wildtype population treated with FOLFIRI plus cetuximab in first-line exhibited a significantly higher response rate and enhanced early tumor shrinkage in the interim analysis than the RAS-mutations population, as well as a high rate of secondary metastatic resections. Conclusion: Initial results of this new biomarker panel (quintuple-wildtype) are promising for anti-EGFR therapy with cetuximab plus doublet chemotherapy (FOLFIRI) in first-line treatment of metastatic CRC. These results warrant confirmation with higher case numbers in the IVOPAK II trial.
CRIS-Team WoS Importer:2021-11-05

Application of machine learning algorithms for multiparametric MRI-based evaluation of murine colitis - Ellmann, Stephan; Langer, Victoria; Britzen-Laurent, Nathalie; Hildner, Kai; Huber, Carina; Tripal, Philipp; Seyler, Lisa; Waldner, Maximilian; Uder, Michael; Stürzl, Michael; Bäuerle, Tobias (PLoS ONE, 2018)
Magnetic resonance imaging (MRI) allows non-invasive evaluation of inflammatory bowel disease (IBD) by assessing pathologically altered gut. Besides morphological changes, relaxation times and diffusion capacity of involved bowel segments can be obtained by MRI. The aim of this study was to assess the use of multiparametric MRI in the diagnosis of experimentally induced colitis in mice, and evaluate the diagnostic benefit of parameter combinations using machine learning. This study relied on colitis induction by Dextran Sodium Sulfate (DSS) and investigated the colon of mice in vivo as well as ex vivo. Receiver Operating Characteristics were used to calculate sensitivity, specificity, positive- and negative-predictive values (PPV and NPV) of these single values in detecting DSS-treatment as a reference condition. A Model Averaged Neural Network (avNNet) was trained on the multiparametric combination of the measured values, and its predictive capacity was compared to those of the single parameters using exact binomial tests. Within the in vivo subgroup (n = 19), the avNNet featured a sensitivity of 91.3% (95% CI: 86.6-96.0%), specificity of 92.3% (95% CI: 85.1-99.6%), PPV of 96.9% (94.0-99.9%) and NPV of 80.0% (95% CI: 69.9-90.1%), significantly outperforming all single parameters in at least 2 accuracy measures (p < 0.003) and performing significantly worse compared to none of the single values. Within the ex vivo subgroup (n = 30), the avNNet featured a sensitivity of 87.4% (95% CI: 82.6-92.2%), specificity of 82.9% (95% CI: 76.1-89.7%), PPV of 88.9% (84.3-93.5%) and NPV of 80.8% (95% CI: 73.8-87.9%), significantly outperforming all single parameters in at least 2 accuracy measures (p < 0.015), exceeded by none of the single parameters. In experimental mouse colitis, multiparametric MRI and the combination of several single measured values to an avNNet can significantly increase diagnostic accuracy compared to the single parameters alone. This pilot study will provide new avenues for the development of an MR-derived colitis score for optimized diagnosis and surveillance of inflammatory bowel disease.
EVALuna2:35135

Application of the BIA: Case studies from the University of Erlangen - Reljic, Dejan; Herrmann, Hans Joachim; Neurath, Markus; Zopf, Yurdagül (Ernährungsumschau, 2019)
CRIS-Team Scopus Importer:2021-04-20

Application of the BIA Case Studies from the University of Erlangen - Reljic, Dejan; Herrmann, Hans Joachim; Neurath, Markus; Zopf, Yurdagül (Ernährungsumschau, 2019)
CRIS-Team WoS Importer:2019-10-04

Apremilast for active ulcerative colitis: a phase 2, randomised, double-blind, placebo-controlled induction study - Danese, S.; Neurath, Markus; Kopon, A.; Zakko, S.; Simmons, T.; Fogel, R.; Maccarone, J.; Zhan, X.; Usiskin, K.; Chitkara, D. (2018)
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Apremilast Prevents Intestinal Inflammation in Colitis Models via Influencing Epithelial Barrier - Weigmann, Benno; Popp, Vanessa; Neurath, Markus; Horan, Gerald; Schafer, Peter (2017)
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A randomized trial of a transglutaminase 2 inhibitor for celiac disease - Schuppan, Detlef; Mäki, Markku; Lundin, Knut E.A.; Isola, Jorma; Friesing-Sosnik, Tina; Taavela, Juha; Popp, Alina; Koskenpato, Jari; Langhorst, Jost; Hovde, Øistein; Lähdeaho, Marja Leena; Fusco, Stefano; et al. (New England Journal of Medicine, 2021)
BACKGROUND In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease. METHODS In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life). RESULTS Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P=0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group. CONCLUSIONS In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease.
CRIS-Team Scopus Importer:2021-07-16

Are Guideline Recommendations on Supportive Nutrition and Exercise Therapy for Cancer Patients Implemented in Clinical Routine? A National Survey with Real-Life Data - Hardt, Luisa; Herrmann, Hans J.; Reljic, Dejan; Jaensch, Peter; Zerth, Jürgen; Neurath, Markus; Zopf, Yurdagül (Nutrients, 2023)
Malnutrition and cancer cachexia are highly prevalent comorbidities of cancer, limiting patients’ quality of life and being relevant to prognosis. International and national clinical guidelines recommend supportive nutrition and exercise therapy for cancer patients. However, there is little current epidemiological evidence on the implementation of these guideline recommendations in clinical routine. To close this data gap, a national survey in Germany using an online questionnaire was conducted. There were 261 of a total of 5074 contacted hospitals and medical offices who participated in the survey (5.1% response rate). The data indicated that nutrition and exercise therapy for cancer patients is so far inadequately implemented, with 59% of the respondents reporting nutrition therapy as an integral part of oncological treatment, 66.7% having a nutrition specialist/team, and 65.1% routinely conducting a screening for nutritional status. Only half of the participants stated that there are defined goals in nutrition therapy. The majority of respondents (85.8%) generally recommend exercise therapy, but only a few of them provide specific offers at their own institution (19.6%) or at cooperation partners (31.7%). In order to implement the recommended combined nutrition and exercise therapy as part of regular care, there is a need for nationwide availability of multidisciplinary nutrition teams and targeted offers of individualized exercise therapy. Health policy support would be important to create the structural, financial, and staff conditions for appropriate guideline implementation in order to achieve the optimal treatment of cancer patients.
CRIS-Team Scopus Importer:2023-08-11
Keywords: cancer patients; exercise therapy; healthcare research; nutrition therapy; supportive cancer therapy; tumor cachexia

Arginase 1 functions as anti-resolvin in inflammatory bowel disease - Nuese, B.; Gänsbauer, Maximilian; Baier, J.; Mattner, Jochen; Gerlach, Roman; Wirtz, Stefan; Rauh, Manfred (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Arginase expression impedes the resolution of intestinal inflammation by altering the fecal microbiome and the metabolome - Baier, Julia; Gänsbauer, Maximilian; Giessler, Claudia; Arnold, Harald; Muske, Mercedes; Schleicher, Ulrike; Lukassen, Sören; Ekici, Arif Bülent; Rauh, Manfred; Daniel, Christoph; Hartmann, Arndt; Schmid, Benjamin; et al. (Journal of Clinical Investigation, 2020)
Arginase 1 (Arg1), which converts L-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. However, the function of Arg1 in inflammatory bowel disease (IBD) remains poorly characterized. Here, we found that Arg1 expression correlated with the degree of inflammation in intestinal tissues from IBD patients. In mice, Arg1 was upregulated in an IL-4-/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre+/-Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from experimental colitis than Arg1-expressing littermates. This correlated with decreased vessel density, compositional changes in intestinal microbiota, diminished infiltration by myeloid cells and an accumulation of intraluminal polyamines that promote epithelial healing. The pro-resolving effect of Arg1-deletion was reduced by an L-arginine-free diet, but rescued by simultaneous deletion of other L-arginine-metabolizing enzymes such as Arg2 or Nos2, demonstrating that protection from colitis requires L-arginine. Fecal microbiota transfers from Tie2-Cre+/-Arg1fl/fl mice into wild-type recipients ameliorated intestinal inflammation while transfers from wild-type littermates into Arg1-deficient mice prevented an advanced recovery from colitis. Thus, an increased availability of L-arginine as well as altered intestinal microbiota and metabolic products account for the accelerated resolution from colitis in the absence of Arg1. Consequently, the metabolism of L-arginine may serve as target for clinical intervention in IBD patients.<br

Artificial Intelligence Enabled Histological Prediction of Remission or Activity and Clinical Outcomes in Ulcerative Colitis - Iacucci, Marietta; Parigi, Tommaso Lorenzo; Del Amor, Rocio; Meseguer, Pablo; Mandelli, Giulio; Bozzola, Anna; Bazarova, Alina; Bhandari, Pradeep; Bisschops, Raf; Danese, Silvio; De Hertogh, Gert; Ferraz, Jose G.; et al. (Gastroenterology, 2023)
Background & Aims: Microscopic inflammation has significant prognostic value in ulcerative colitis (UC); however, its assessment is complex with high interobserver variability. We aimed to develop and validate an artificial intelligence (AI) computer-aided diagnosis system to evaluate UC biopsies and predict prognosis. Methods: A total of 535 digitalized biopsies (273 patients) were graded according to the PICaSSO Histologic Remission Index (PHRI), Robarts, and Nancy Histological Index. A convolutional neural network classifier was trained to distinguish remission from activity on a subset of 118 biopsies, calibrated on 42 and tested on 375. The model was additionally tested to predict the corresponding endoscopic assessment and occurrence of flares at 12 months. The system output was compared with human assessment. Diagnostic performance was reported as sensitivity, specificity, prognostic prediction through Kaplan-Meier, and hazard ratios of flares between active and remission groups. We externally validated the model in 154 biopsies (58 patients) with similar characteristics but more histologically active patients. Results: The system distinguished histological activity/remission with sensitivity and specificity of 89% and 85% (PHRI), 94% and 76% (Robarts Histological Index), and 89% and 79% (Nancy Histological Index). The model predicted the corresponding endoscopic remission/activity with 79% and 82% accuracy for UC endoscopic index of severity and Paddington International virtual ChromoendoScopy ScOre, respectively. The hazard ratio for disease flare-up between histological activity/remission groups according to pathologist-assessed PHRI was 3.56, and 4.64 for AI-assessed PHRI. Both histology and outcome prediction were confirmed in the external validation cohort. Conclusion: We developed and validated an AI model that distinguishes histologic remission/activity in biopsies of UC and predicts flare-ups. This can expedite, standardize, and enhance histologic assessment in practice and trials.
CRIS-Team Scopus Importer:2023-04-28
Keywords: Computer-aided Diagnosis; Convolutional Neural Network; PICaSSO Histologic Remission Index; Robarts Histopathology Index; Ulcerative Colitis

Artificial intelligence for the classification of focal liver lesions in ultrasound - a systematic review. - Vetter, Marcel; Waldner, Maximilian; Zundler, Sebastian; Klett, Daniel; Bocklitz, Thomas; Neurath, Markus; Adler, Werner; Jesper, Daniel (Ultraschall in der Medizin, 2023)
Focal liver lesions are detected in about 15% of abdominal ultrasound examinations. The diagnosis of frequent benign lesions can be determined reliably based on the characteristic B-mode appearance of cysts, hemangiomas, or typical focal fatty changes. In the case of focal liver lesions which remain unclear on B-mode ultrasound, contrast-enhanced ultrasound (CEUS) increases diagnostic accuracy for the distinction between benign and malignant liver lesions. Artificial intelligence describes applications that try to emulate human intelligence, at least in subfields such as the classification of images. Since ultrasound is considered to be a particularly examiner-dependent technique, the application of artificial intelligence could be an interesting approach for an objective and accurate diagnosis. In this systematic review we analyzed how artificial intelligence can be used to classify the benign or malignant nature and entity of focal liver lesions on the basis of B-mode or CEUS data. In a structured search on Scopus, Web of Science, PubMed, and IEEE, we found 52 studies that met the inclusion criteria. Studies showed good diagnostic performance for both the classification as benign or malignant and the differentiation of individual tumor entities. The results could be improved by inclusion of clinical parameters and were comparable to those of experienced investigators in terms of diagnostic accuracy. However, due to the limited spectrum of lesions included in the studies and a lack of independent validation cohorts, the transfer of the results into clinical practice is limited.
EVALuna2:550718

A Severe Case of Tuberculosis Radiologically and Endoscopically Mimicking Colorectal Cancer with Peritoneal Carcinomatosis - Rath, Timo; Atreya, Raja; Geissdorfer, Walter; Lang, Roland; Nägel, Andreas; Neurath, Markus (Case Reports in Gastrointestinal Medicine, 2017)
Although generally rising in incidence, intestinal tuberculosis is still rare in western countries and due to unspecific manifestations mainly as ulcerations on endoscopy, diagnosis of intestinal tuberculosis is challenging. Within this report, we describe a case of severe intestinal tuberculosis radiologically and endoscopically masquerading as colorectal cancer with peritoneal carcinomatosis. Our case exemplifies that intestinal tuberculosis needs to be considered as a differential diagnosis in patients at risk and that undelayed and sensitive diagnosis of intestinal tuberculosis is of central importance for avoiding unfavorable disease outcome.
EVALuna2:33728

ASO Author Reflection: Risk of Recurrence After Radical Resection in Entero-Pancreatic Neuroendocrine Tumors - Merola, Elettra (Annals of Surgical Oncology, 2022)
CRIS-Team WoS Importer:2022-06-03

ASO Visual Abstract: Radical Resection in Enteropancreatic Neuroendocrine Tumors-Recurrence-Free Survival Rate and Definition of a Risk Score for Recurrence - Merola, Elettra; Pascher, A.; Rinke, A.; Bartsch, D. K.; Zerbi, A.; Nappo, G.; Carnaghi, C.; Ciola, M.; Mcnamara, M. G.; Zandee, W.; Bertani, E.; Marcucci, S.; et al. (Annals of Surgical Oncology, 2022)
CRIS-Team WoS Importer:2022-07-15

Aspergillosis: Emerging risk groups in critically ill patients - Kluge, Stefan; Strauss, Richard; Kochanek, Matthias; Weigand, Markus A.; Rohde, Holger; Lahmer, Tobias (Medical Mycology, 2021)
Information on invasive aspergillosis (IA) and other invasive filamentous fungal infections is limited in non-neutropenic patients admitted to the intensive care unit (ICU) and presenting with no classic IA risk factors. This review is based on the critical appraisal of relevant literature, on the authors' own experience and on discussions that took place at a consensus conference. It aims to review risk factors favoring aspergillosis in ICU patients, with a special emphasis on often overlooked or neglected conditions. In the ICU patients, corticosteroid use to treat underlying conditions such as chronic obstructive pulmonary disease (COPD), sepsis, or severe COVID-19, represents a cardinal risk factor for IA. Important additional host risk factors are COPD, decompensated cirrhosis, liver failure, and severe viral pneumonia (influenza, COVID-19). Clinical observations indicate that patients admitted to the ICU because of sepsis or acute respiratory distress syndrome are more likely to develop probable or proven IA, suggesting that sepsis could also be a possible direct risk factor for IA, as could small molecule inhibitors used in oncology. There are no recommendations for prophylaxis in ICU patients; posaconazole mold-active primary prophylaxis is used in some centers according to guidelines for other patient populations and IA treatment in critically ill patients is basically the same as in other patient populations. A combined evaluation of clinical signs and imaging, classical biomarkers such as the GM assay, and fungal cultures examination, remain the best option to assess response to treatment.
CRIS-Team WoS Importer:2022-03-25

A spotlight on intestinal permeability and inflammatory bowel diseases - Rath, Timo; Atreya, Raja; Neurath, Markus (Expert Review of Gastroenterology and Hepatology, 2023)
Introduction: The intestinal barrier is a multi-faced structure lining the surface of the intestinal mucosa of the GI tract. To exert its main functions as a physical and immunological defense barrier, several components of the intestinal barrier act in a concerted and cooperative manner. Areas covered: Herein, we first introduce to the basic organization of the intestinal barrier and then summarize different methods to assess barrier function in and ex vivo. Finally, we provide an in-depth overview of the relevance of intestinal barrier dysfunction in inflammatory bowel diseases. Expert opinion: In parallel to a more fundamental understanding of the intestinal barrier as a key component for intestinal integrity is the notion that intestinal barrier defects are associated with a variety of diseases such as inflammatory bowel diseases. Recent research has fueled and perpetuated the concept that barrier defects are critical components of disease development, disease behavior, and potentially also an area of therapeutic intervention in IBD patients. Although being far away from standard, new technologies can be used to easily assess barrier healing in IBD and to derive clinical consequences from these findings such as more accurate forecasting of future disease behavior or the identification of novel therapeutic targets.
CRIS-Team Scopus Importer:2023-11-24
Keywords: confocal laser endomicroscopy; Crohn’s disease; inflammatory bowel diseases; Intestinal barrier; intestinal permeability; leaky gut; ulcerative colitis

Assessing cachexia in older patients: Different definitions – But which one is the most practical for clinical routine? - Zopf, Yurdagül; Schink, Kristin; Reljic, Dejan; Herrmann, Hans J.; Dieterich, Walburga; Kießwetter, Eva; Sieber, Cornel; Neurath, Markus; Volkert, Dorothee (Archives of gerontology and geriatrics, 2020)
Objective: Patients with chronic inflammatory diseases and malignant tumors have an increased risk of cachexia. No consistent definition exists to rapidly identify cachexia in older patients with and without cancer. Methods: One-hundred patients (53% male) aged 70 + years were included in the study by a university hospital. In addition to the detection of malnutrition and determination of body composition by bioelectrical impedance analysis, cachexia was assessed according to the well-established definitions of Evans (weight loss ≥ 5% within the last 12 months plus additional clinical parameters), Fearon (weight loss > 5% in 6 months) and Bozzetti (weight loss ≥ 10% of habitual weight). After a follow-up of 3.5 years, the mortality rate was recorded. Results: Thirty-three patients had a malignant tumor disease. The patients with a non-malignant underlying disease did not differ in their mental state, physical condition and state of health compared to patients with cancer. A higher percentage of patients with underlying malignancy had cachexia. There were significant differences in the body composition between the patients with or without cachexia. Cachectic patients exhibited a significantly lower skeletal muscle mass and fat mass. The risk of death was increased in cachectic patients of all three cachexia definitions. Conclusion: For clinical daily routine, the assessments by a weight loss according to Fearon and Bozzetti are suggested to be practicable methods to detect cachexia in older patients with and without cancer.
CRIS-Team Scopus Importer:2019-10-01
Keywords: Body composition; Cachexia; Cancer; Malnutrition; Muscle mass; Weight loss

Assessment of gait parameters and physical function in patients with advanced cancer participating in a 12-week exercise and nutrition programme: A controlled clinical trial - Schink, Kristin; Gaßner, Heiko; Reljic, Dejan; Herrmann, Hans J.; Kemmler, Wolfgang; Schwappacher, Raphaela; Meyer, Julia; Eskofier, Björn; Winkler, Jürgen; Neurath, Markus; Klucken, Jochen; Zopf, Yurdagül (European Journal of Cancer Care, 2019)
Objective: Gait is a sensitive marker for functional declines commonly seen in patients treated for advanced cancer. We tested the effect of a combined exercise and nutrition programme on gait parameters of advanced-stage cancer patients using a novel wearable gait analysis system. Methods: Eighty patients were allocated to a control group with nutritional support or to an intervention group additionally receiving whole-body electromyostimulation (WB-EMS) training (2×/week). At baseline and after 12 weeks, physical function was assessed by a biosensor-based gait analysis during a six-minute walk test, a 30-s sit-to-stand test, a hand grip strength test, the Karnofsky Index and EORTC QLQ–C30 questionnaire. Body composition was measured by bioelectrical impedance analysis and inflammation by blood analysis. Results: Final analysis included 41 patients (56.1% male; 60.0 ± 13.0 years). After 12 weeks, the WB-EMS group showed higher stride length, gait velocity (p <.05), six-minute walking distance (p <.01), bodyweight and skeletal muscle mass, and emotional functioning (p <.05) compared with controls. Correlations between changes in gait and in body composition, physical function and inflammation were detected. Conclusion: Whole-body electromyostimulation combined with nutrition may help to improve gait and functional status of cancer patients. Sensor-based mobile gait analysis objectively reflects patients’ physical status and could support treatment decisions.
CRIS-Team Scopus Importer:2019-12-24
Keywords: cancer; exercise; gait; nutrition; physical function; whole-body electromyostimulation

Assessment of pathologic increase in liver stiffness enables earlier diagnosis of CFLD: Results from a prospective longitudinal cohort study - Klotter, Victoria; Gunchick, Caroline; Siemers, Enno; Rath, Timo; Hudel, Helge; Naehrlich, Lutz; Roderfeld, Martin; Roeb, Elke (PLoS ONE, 2017)
About 30% of patients with Cystic Fibrosis (CF) develop CF-associated liver disease (CFLD). Recent studies have shown that transient elastography (TE), as a method to quantify liver stiffness, allows non-invasive diagnosis of CFLD in adults and children with CF. Within this study we aimed to prospectively identify patients at risk for development of CFLD by longitudinal analysis of liver stiffness and fibrosis scores in a 5-year follow-up. 36 pediatric and 16 adult patients with initial liver stiffness below the cut-off value indicative of CFLD (6.3 kPa) were examined by transient elastography for 4-5 years. TE, APRI-, and FIB-4-scores were assessed and compared by Kruskal-Wallis test and receiver operating characteristic (ROC)-analysis. Frequencies were compared by Chi2-test. Among the 36 patients participating in this study, a subgroup of 9 patients developed liver stiffness >6.3 kPa after 4-5 years with an increase of ΔTE >0.38 kPa/a (the group with increasing liver stiffness was labelled TEinc). APRI- and FIB-4 scores confirmed the rationale for grouping. The frequency of CFLD assessed by conventional diagnosis was significantly higher in TEinc-group compared to the control group (TEnorm). None of the adult CF patients matched criteria for TEinc-group. For the first time it was shown that the non-invasive longitudinal assessment of TE allows identification of patients with progression of CFLD in a subgroup of juvenile but not in adult CF patients. Comparing TE to conventional fibrosis-scores underlined the strength of the continuous assessment of liver stiffness for the exact diagnosis of progressive CFLD. The newly described cut-off for pathologic increase of liver stiffness, ΔTEcutoff = 0.38kPa/a, might enable to detect developing CFLD using consequent follow up TE measurements before reaching the level of stiffness indicating established CFLD. Nevertheless, the limited size of the analyzed cohort should encourage a prospective, multi-center, long term follow up study to confirm the suggested cut-off for the rise in liver stiffness.
EVALuna2:34089

Assessment of sorafenib induced changes in tumor perfusion of uveal melanoma metastases with dynamic contrast-enhanced ultrasound (DCE-US) - Wildner, Dane; Heinzerling, Lucie; Scheulen, Max E.; Kämpgen, Eckhart; Schuler, Gerold; Strobel, Deike; Janka, Rolf Matthias; Neurath, Markus; Sturm, Jörg; Knieling, Ferdinand (Journal of Cancer Research and Clinical Oncology, 2021)
Purpose Dynamic contrast-enhanced ultrasound (DCE-US) was used to monitor early response to sorafenib therapy in patients with liver metastases from uveal melanoma. Methods In total, 21 patients with liver metastases were recruited within a prospective trial and underwent daily sorafenib therapy. DCE-US of a target lesion was performed before initiation of treatment, on day 15 and 56. Two independent blinded investigators performed software analysis for DCE-US parameters and inter-observer-correlation was calculated. Response to treatment was evaluated on day 56. DCE-US parameters were correlated with clinical response and RECIST1.1 criteria. Results Inter-observer-correlation (r) of DCE-US parameters [time-to-peak (TTP), mean-transit-time (MTT), peak intensity (PI), regional blood volume (RBV), regional blood flow (RBF)] at baseline, day 15, and day 56 was highly significant (r-range 0.73-0.97, all p < 0.001). Out of 17 evaluable patients, 12 patients survived day 56 (clinical responders, cRE), whereas, five patients died before day 56 and were classified as non-responders (cNR). TTP values significantly increased in the cRE group 15 days after initiation of treatment for investigator 1 (p = 0.034) and at day 56 for both investigators (p = 0.028/0.028). MTT had increased significantly in the cRE group on day 56 (p = 0.037/0.022). In the cNR group changes for TTP and MTT remained insignificant. Thus, increase of the DCE-US parameters TTP and MTT are associated with response to treatment and prognosis. Conclusion An increase of TTP and MTT at frequent intervals could serve as a surrogate marker for early response evaluation to anti-angiogenic treatment of metastatic uveal melanoma.
CRIS-Team WoS Importer:2021-06-04

Assessment of tumor development and wound healing using endoscopic techniques in mice - Günther, Claudia; Neurath, Markus; Waldner, Maximilian; Neufert, Clemens; Wirtz, Stefan; Becker, Christoph; et al. (Gastroenterology, 2010)
Mouse models of intestinal inflammation and colon cancer are valuable tools to gain insights into the pathogenesis of the corresponding human diseases. Recently, in vivo mouse endoscopy has been developed, allowing not only the high-resolution monitoring and scoring of experimental disease development, but also enables the investigator to perform manipulations, including local injection of reagents or the taking of biopsies for molecular and histopathologic analyses. Chromoendoscopic staining with methylene blue enables visualization of the crypt structure and allows discrimination between inflammatory and neoplastic changes. The development of endoscopic techniques in live mice opened new options for the investigation of disease mechanisms in the gut and for the preclinical testing of potential therapeutic effects of drug candidates. Finally, mouse endoscopy can help to reduce animal numbers needed to gain significant experimental data.

Association of C-reactive Protein and Partial Mayo Score With Response to Tofacitinib Induction Therapy: Results From the Ulcerative Colitis Clinical Program - Dubinsky, Marla C.; Magro, Fernando; Steinwurz, Flavio; Hudesman, David P.; Kinnucan, Jami A.; Ungaro, Ryan C.; Neurath, Markus; Kulisek, Nicole; Paulissen, Jerome; Su, Chinyu; De Leon, Dario Ponce; Regueiro, Miguel (Inflammatory Bowel Diseases, 2022)
Lay Summary Early decreases in partial Mayo score and C-reactive protein were found to be associated with achieving efficacy outcomes following tofacitinib 10 mg twice daily induction therapy in the ulcerative colitis clinical program.
CRIS-Team WoS Importer:2022-04-29

A Stat6/Pten Axis Links Regulatory T Cells with Adipose Tissue Function - Kaelin, Stefanie; Becker, Maike; Ott, Verena B.; Serr, Isabelle; Hosp, Fabian; Mollah, Mohammad M. H.; Keipert, Susanne; Lamp, Daniel; Rohner-Jeanrenaud, Francoise; Flynn, Victoria K.; Scherm, Martin G.; Nascimento, Lucas F. R.; et al. (Cell Metabolism, 2017)
Obesity and type 2 diabetes are associated with metabolic defects and adipose tissue inflammation. Foxp3+ regulatory T cells (Tregs) control tissue homeostasis by counteracting local inflammation. However, if and how T cells interlink environmental influences with adipocyte function remains unknown. Here, we report that enhancing sympathetic tone by cold exposure, beta3-adrenergic receptor (ADRB3) stimulation or a short-term high-calorie diet enhances Treg induction in vitro and in vivo. CD4+ T cell proteomes revealed higher expression of Foxp3 regulatory networks in response to cold or ADRB3 stimulation in vivo reflecting Treg induction. Specifically, Ragulator-interacting protein C17orf59, which limits mTORC1 activity, was upregulated in CD4+ T cells by either ADRB3 stimulation or cold exposure, suggesting contribution to Treg induction. By loss- and gain-of-function studies, including Treg depletion and transfers in vivo, we demonstrated that a T cell-specific Stat6/Pten axis links cold exposure or ADRB3 stimulation with Foxp3+ Treg induction and adipose tissue function. Our findings offer a new mechanistic model in which tissue-specific Tregs maintain adipose tissue function.
EVALuna2:33893

A Systematic Review on Infliximab Biosimilar SB2: From Pre-Clinical Data to Real-World Evidence - Macaluso, Fabio Salvatore; Cummings, JR Fraser; Atreya, Raja; Choi, Jaeyun; Orlando, Ambrogio (Expert Opinion on Biological Therapy, 2021)
Introduction: The infliximab biosimilar SB2 was approved in the EU (2016, Flixabi®) and the US (2017, Renflexis®) for the same indications as the reference product (Remicade®) based on a robust analytical and clinical data package. Areas covered: This systematic literature review summarizes available analytical and clinical data on SB2, including randomized controlled clinical trials and real-world evidence studies. Overall, 184 articles and congress abstracts were identified (excluding duplicates), whereof 5 reports on analytical data, four reports on two randomized controlled trials and 13 reports of real-world evidence studies were included. Expert opinion: The available analytical and clinical data support the equivalence of SB2 to the reference product across approved indications. This is further supported by emerging real-world evidence, particularly in extrapolated indications such as inflammatory bowel disease for both infliximab-naïve patients and patients already established on infliximab switching to SB2. Switching from originator or biosimilar infliximab to SB2 including both single and multiple switches was not associated with an increased risk of loss of treatment response or any safety or immunogenicity concerns. Overall, the approved infliximab biosimilar SB2 is safe and effective in clinical practice across licensed indications.
CRIS-Team Scopus Importer:2021-08-27
Keywords: Ankylosing spondylitis; inflammatory bowel disease; infliximab biosimilar; psoriasis; psoriatic arthritis; real-world evidence; rheumatoid arthritis; SB2; switching

ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2 - Hübner, Kerstin; Erlenbach-Wünsch, Katharina; Prochazka, Jan; Sheraj, Ilir; Hampel, Chuanpit; Mrazkova, Blanka; Michalcikova, Tereza; Tureckova, Jolana; Iatsiuk, Veronika; Weissmann, Anne; Ferrazzi, Fulvia; Kunze, Philipp; et al. (Cellular and Molecular Life Sciences, 2022)
In cancer, the activating transcription factor 2 (ATF2) has pleiotropic functions in cellular responses to growth stimuli, damage, or inflammation. Due to only limited studies, the significance of ATF2 in colorectal cancer (CRC) is not well understood. We report that low ATF2 levels correlated with worse prognosis and tumor aggressiveness in CRC patients. NanoString gene expression and ChIP analysis confirmed trophoblast cell surface antigen 2 (TROP2) as a novel inhibitory ATF2 target gene. This inverse correlation was further observed in primary human tumor tissues. Immunostainings revealed that high intratumoral heterogeneity for ATF2 and TROP2 expression was sustained also in liver metastasis. Mechanistically, our in vitro data of CRISPR/Cas9-generated ATF2 knockout (KO) clones revealed that high TROP2 levels were critical for cell de-adhesion and increased cell migration without triggering EMT. TROP2 was enriched in filopodia and displaced Paxillin from adherens junctions. In vivo imaging, micro-computer tomography, and immunostainings verified that an ATF2(KO)/TROP2(high) status triggered tumor invasiveness in in vivo mouse and chicken xenograft models. In silico analysis provided direct support that ATF2(low)/TROP2(high) expression status defined high-risk CRC patients. Finally, our data demonstrate that ATF2 acts as a tumor suppressor by inhibiting the cancer driver TROP2. Therapeutic TROP2 targeting might prevent particularly the first steps in metastasis, i.e., the de-adhesion and invasion of colon cancer cells.
CRIS-Team WoS Importer:2022-07-29

A true vascular aneurysm of the hepatic artery proper as a rare cause of nonmalignant painless jaundice - Raithel, Martin; Ganzleben, Ingo; Gschossmann, Juergen; Hagel, Alexander; Neurath, Markus; Görtz, Rüdiger (Endoscopy, 2014)
EVALuna2:2006

Attenuation of visible and near-infrared light signals in murine cortical bone - Bittermann, Lennart Martin; Campbell, Graeme; Glueer, Claus-Christian; Schmalzl, Angelika (JOURNAL OF BONE AND MINERAL RESEARCH, 2019)
CRIS-Team WoS Importer:2020-02-07

At the Forefront of the Mucosal Barrier: The Role of Macrophages in the Intestine - Ruder, Barbara; Becker, Christoph (Cells, 2020)
Macrophages are part of the innate immunity and are key players for the maintenance of intestinal homeostasis. They belong to the group of mononuclear phagocytes, which exert bactericidal functions and help to clear apoptotic cells. Moreover, they play essential roles for the maintenance of epithelial integrity and tissue remodeling during wound healing processes and might be implicated in intestinal tumor development. Macrophages are antigen-presenting cells and secrete immune-modulatory factors, like chemokines and cytokines, which are necessary to activate other intestinal immune cells and therefore to shape immune responses in the gut. However, overwhelming activation or increased secretion of pro-inflammatory cytokines might also contribute to the pathogenesis of inflammatory bowel disease. Presently, intestinal macrophages are in the center of intense studies, which might help to develop new therapeutic strategies to counteract the development or treat already existing inflammatory diseases in the gut. In this review, we focus on the origin of intestinal macrophages and, based on current knowledge, discuss their role in the gut during homeostasis and inflammation, as well as during intestinal wound healing and tumor development.
CRIS-Team Scopus Importer:2020-10-16
Keywords: IBD; inflammation; intestine; macrophages; phagocytosis

Auswirkungen eines verkurzten Dosierungsintervalls von Lanreotid-Autogel (LAN) auf die Tumorwachstumsrate ( TGR) bei Patienten mit fortgeschrittenen Neuroendokrinen Tumoren (NETs) in der prospektiven, einarmigen, Phase 2 Studie CLARINET FORTE - Pape, U. -F; Dromain, C.; Cwikla, J. B.; Lombard-Bohas, C.; Borbath, I.; Shah, T.; Capdevilla, J.; Panzuto, F.; Ruszniewski, P.; Truong Thanh, X. -M; Houchard, A.; Pavel, Marianne Ellen (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

Autoimmune Colitis and Subsequent CMV-induced Hepatitis After Treatment With Ipilimumab - Uslu, Ugur; Agaimy, Abbas; Hundorfean, Gheorghe; Harrer, Thomas; Schuler, Gerold; Heinzerling, Lucie (Journal of Immunotherapy, 2015)
Ipilimumab, a humanized CTLA-4 antibody, improves overall survival in patients with metastatic melanoma. However, immune-related adverse effects occur in about 65% of ipilimumab-treated patients and have to be adequately managed. A 55-year-old patient developed grade 3 autoimmune colitis 7 weeks after initiation of ipilimumab treatment and subsequently hepatitis with grade 3 elevation of transaminases and ?-glutamyl transferase. Colitis manifested with up to 18 watery and bloody stools per day and severe attacks of abdominal pain. After exclusion of infectious causes, immunosuppression with corticosteroids was initiated. Because of recurrent abdominal pain, spontaneous perforation of the colon had to be excluded. Elevated liver function tests (grade 3 CTCAE) occurred and differential diagnosis included immune-mediated, toxic, and viral hepatitis. It is interesting to note that, not an immune-mediated but a cytomegalovirus-induced hepatitis was diagnosed by serum blood tests and liver biopsy and was subsequently successfully treated. Careful elaboration of the patient under immunotherapy was essential as further immunosuppression mandatory for autoimmune hepatitis would have worsened the viral hepatitis. In conclusion, cytomegalovirus reactivation should be included in the differential in patients under immunotherapy with checkpoint inhibitors and has to be considered as a cause for morbidity.
EVALuna2:1966

Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis - Voskens, Caroline; Stoica, Diane; Rosenberg, Marita; Vitali, Francesco; Zundler, Sebastian; Ganslmayer, Marion; Knott, Heike; Wiesinger, Manuel; Wunder, Jutta; Kummer, Mirko; Siegmund, Britta; Schnoy, Elisabeth; et al. (Gut, 2022)
Objective Ulcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available.
CRIS-Team WoS Importer:2022-04-29

Automated quantitative morphometry of vertebral heights on spinal radiographs: comparison of a clinical workflow tool with standard 6-point morphometry - Engelke, Klaus; Stampa, B.; Steiger, P.; Fuerst, T.; Genant, H. K. (Archives of Osteoporosis, 2019)
A workflow tool for measurements of vertebral heights on lateral spine radiographs based on automated placements of 6 points per vertebra was evaluated. The tool helps to standardize point placement among operators. Its success rate is very good in normal vertebrae but lower in vertebrae with more severe fractures. Manual corrections were required in 192 of 1257 analyzed vertebrae.IntroductionTo evaluate a new workflow tool (SA) for the automated measurements of vertebral heights on lateral spine radiographs.MethodologyLateral radiographs from 200 postmenopausal women were evaluated at two visits. Genant's semi-quantitative fracture assessment (SQ) and manual quantitative morphometry (QM) results were available from prior analyses. Vertebral heights from point placements using SA were compared with manual 6-point placement QM. Differences were quantified as RMS coefficient of variations (rmsCV) and standard deviations (rmsSD).Results and conclusionsSA required manual corrections in 192 of 1257 vertebrae. SA heights were larger than QM ones by 2.2-3.6%. Correlations (r(2)>0.92) between SA and QM were very high. Differences between QM and SA were higher for fractured (SQ=2; rmsCV% 14.5%) than for unfractured vertebrae (rmsCV% 4.2-4.7%). rmsCV% for QM varied between 3 and 6% and for SA between 2.5 and 7.5%. For SA, highest rmsCV% was obtained for T4 and L4. Manual correction mostly affected the end vertebrae T4 and L4. SA helps to standardize point placement among operators. The algorithm success rate is very good in normal vertebrae but lower in vertebrae with more severe fractures, which are of greater clinical interest but are more readily recognized without morphometric measurements.
CRIS-Team WoS Importer:2019-02-21

Automatic Classification and Pathological Staging of Confocal Laser Endomicroscopic Images of the Vocal Cords - Vo, Kim; Jaremenko, Christian; Bohr, Christopher; Neumann, Helmut; Maier, Andreas (Bildverarbeitung für die Medizin 2017 Algorithmen Systeme Anwendungen, 2017)
Confocal laser endomicroscopy is a novel imaging technique which provides real-time in vivo examination and histological analysis of tissue during an ongoing endoscopy. We present an automatic classification system that is able to differentiate between healthy and cancerous tissue of the vocal cords. Textural as well as CNN features are encoded using Fisher vectors and vector of locally aggregated descriptors while the classification is performed using random forests and support vector machines. Two experiments are investigated following a leave-one-sequence-out cross-validation and a fixed training and test set approach. Classification rates reach up to 87.6 % and 81.5 %, respectively.
UnivIS-Import:2017-12-18:Pub.2017.tech.IMMD.IMMD5.automa_7

Autophagy in cancer therapy—molecular mechanisms and current clinical advances - Ganzleben, Ingo; Neurath, Markus; Becker, Christoph (Cancers, 2021)
Autophagy is a crucial general survival tactic of mammalian cells. It describes the capability of cells to disassemble and partially recycle cellular components (e.g., mitochondria) in case they are damaged and pose a risk to cell survival or simply if their resources are urgently needed elsewhere at the time. Autophagy-associated pathomechanisms have been increasingly recognized as important disease mechanisms in non-malignant (neurodegeneration, diffuse parenchymal lung disease) and malignant conditions alike. However, the overall consequences of autophagy for the organism depend particularly on the greater context in which autophagy occurs, such as the cell type or whether the cell is proliferating. In cancer, autophagy sustains cancer cell survival under challenging, i.e., resource-depleted, conditions. However, this leads to situations in which cancer cells are completely dependent on autophagy. Accordingly, autophagy represents a promising yet complex target in cancer treatment with therapeutically induced increase and decrease of autophagic flux as important therapeutic principles.
CRIS-Team Scopus Importer:2021-11-12
Keywords: Autophagy; Cancer; Glutamine; Hydroxychloroquine; Mitophagy; Reverse Warburg effect

Autophagy regulates TNFα-mediated joint destruction in experimental arthritis - Lin, Neng-Yu; Beyer, Christian; Gießl, Andreas; Kireva, Trayana; Scholtysek, Carina; Uderhardt, Stefan; Munoz, Luis Enrique; Dees, Clara; Distler, Alfiya; Wirtz, Stefan; Krönke, Gerhard; Spencer, Brian; et al. (Annals of the Rheumatic Diseases, 2013)
Objectives: Autophagy is a homeostatic process to recycle dispensable and damaged cell organelles. Dysregulation of autophagic pathways has recently been implicated in the pathogenesis of various diseases. Here, we investigated the role of autophagy during joint destruction in arthritis. Methods: Autophagy in osteoclasts was analysed in vitro and ex vivo by transmission electron microscopy, Western blotting and immunohistochemistry for Beclin1 and Atg7. Small molecule inhibitors, LysMCre-mediated knockout of Atg7 and lentiviral overexpression of Beclin1 were used to modulate autophagy in vitro and in vivo. Osteoclast differentiation markers were quantified by realtime PCR. The extent of bone and cartilage destruction was analysed in human tumour necrosis factor α transgenic (hTNFα tg) mice after adoptive transfer with myeloid specific Atg7-deficient bone marrow. Results: Autophagy was activated in osteoclasts of human rheumatoid arthritis (RA) showing increased expression of Beclin1 and Atg7. TNFα potently induced the expression of autophagy-related genes and activated autophagy in vitro and in vivo. Activation of autophagy by overexpression of Beclin1-induced osteoclastogenesis and enhanced the resorptive capacity of cultured osteoclasts, whereas pharmacologic or genetic inactivation of autophagy prevented osteoclast differentiation. Arthritic hTNFα tg mice transplanted with Atg7fl/fl×LysMCre+ bone marrow cells (BMC) showed reduced numbers of osteoclasts and were protected from TNFα-induced bone erosion, proteoglycan loss and chondrocyte death. Conclusions: These findings demonstrate that autophagy is activated in RA in a TNFα-dependent manner and regulates osteoclast differentiation and bone resorption. We thus provide evidence for a central role of autophagy in joint destruction in RA.
CRIS-Team Scopus Importer:2020-11-20

Autotaxin activity has a high accuracy to diagnose intrahepatic cholestasis of pregnancy - Kremer, Andreas; Bolier, Ruth; Dixon, Peter H.; Geenes, Victoria; Chambers, Jenny; Tolenaars, Dagmar; Ris-Stalpers, Carrie; Kaess, Bernhard M.; Rust, Christian; Van Der Post, Joris A.; Williamson, Catherine; Beuers, Ulrich; et al. (Journal of Hepatology, 2015)
Intrahepatic cholestasis of pregnancy (ICP) is defined by pruritus, elevated total fasting serum bile salts (TBS) and transaminases, and an increased risk of adverse fetal outcome. An accurate diagnostic marker is needed. Increased serum autotaxin correlates with cholestasis-associated pruritus. We aimed at unraveling the diagnostic accuracy of autotaxin in ICP.Serum samples and placental tissue were collected from 44 women with uncomplicated pregnancies and 105 with pruritus and/or elevated serum transaminases. Autotaxin serum levels were quantified enzymatically and by Western blotting, autotaxin gene expression by quantitative PCR.Serum autotaxin was increased in ICP (mean ± SD: 43.5 ± 18.2 nmol ml(-1)min(-1), n=55, p<0.0001) compared to other pruritic disorders of pregnancy (16.8 ± 6.7 nmol ml(-1)min(-1), n=33), pre-eclampsia complicated by HELLP-syndrome (16.8 ± 8.9 nmol ml(-1)min(-1), n=17), and pregnant controls (19.6 ± 5.7 nmol ml(-1)min(-1), n=44). Longitudinal analysis during pregnancy revealed a marked rise in serum autotaxin with onset of ICP-related pruritus. Serum autotaxin was increased in women taking oral contraceptives. Increased serum autotaxin during ICP was not associated with increased autotaxin mRNA in placenta. With a cut-off value of 27.0 nmol ml(-1)min(-1), autotaxin had an excellent sensitivity and specificity in distinguishing ICP from other pruritic disorders or pre-eclampsia/HELLP-syndrome. Serum autotaxin displayed no circadian rhythm and was not influenced by food intake.Increased serum autotaxin activity represents a highly sensitive, specific and robust diagnostic marker of ICP, distinguishing ICP from other pruritic disorders of pregnancy and pregnancy-related liver diseases. Pregnancy and oral contraception increase serum autotaxin to a much lesser extent than ICP.
EVALuna2:2015

Autotaxin activity predicts transplant-free survival in primary sclerosing cholangitis - Dhillon, Amandeep K.; Kremer, Andreas; Kummen, Martin; Boberg, Kirsten M.; Elferink, Ronald P.Oude; Karlsen, Tom H.; Beuers, Ulrich; Vesterhus, Mette; Hov, Johannes R. (Scientific Reports, 2019)
Autotaxin has been associated with liver disease severity and transplant-free survival. This study aimed to validate autotaxin as a biomarker in two cohorts of Norwegian large-duct PSC patients, one discovery panel (n = 165) and one validation panel (n = 87). Serum activity of autotaxin was measured in diluted sera by a fluorometric enzymatic assay. Patients reaching an end-point, liver transplantation or death, (discovery panel: n = 118 [71.5%]; validation panel: n = 35 [40.2%]), showed higher autotaxin activity compared with the other patients, P < 0.001 and P = 0.004, respectively. Kaplan-Meier survival analyses showed a strong association between increasing autotaxin activity and shorter liver transplant-free survival (discovery panel: P < 0.001, validation panel: P = 0.001). There was no relationship between autotaxin activity and the presence of inflammatory bowel disease or occurrence of hepatobiliary malignancy. In a multivariable analysis, high autotaxin activity was associated with an increased risk of liver transplantation or death (hazard ratio 2.03 (95% confidence interval 1.21–3.40), P < 0.01), independent from Mayo risk score, an in-house enhanced liver fibrosis score and interleukin-8 in serum. In conclusion, increased serum autotaxin activity is associated with reduced liver transplant-free survival independent from Mayo risk score and markers of inflammation and fibrosis.
CRIS-Team Scopus Importer:2019-06-21

Band-Pass Filter Design by Segmentation in Frequency Domain for Detection of Epithelial Cells in Endomicroscope Images - Bier, Bastian; Mualla, Firas; Steidl, Stefan; Bohr, Christopher; Neumann, Helmut; Maier, Andreas; Hornegger, Joachim (Bildverarbeitung für die Medizin 2015 - Algorithmen, Systeme, Anwendungen, 2015)
Voice hoarseness can have various reasons, one of them is a change of the vocal fold mucus. This change can be examined with micro endoscopes. Cell detection in these images is a difficult task, due to bad image quality, caused by noise and illumination variations. In previous works, it was observed that the repetitive pattern of the cell walls cause an elliptical shape in the Fourier domain [1, 2]. A manual segmentation and back transformation of this shape results in filtered images, where the cell detection is much easier [3]. The goal of this work is to automatically segment the elliptical shape in Fourier domain. Two different approaches are developed to get a suitable band-pass filter: a thresholding and an active contour method. After the band-pass filter is applied, the achieved results are superior to the manual segmentation case.
UnivIS-Import:2018-09-11:Pub.2015.tech.IMMD.IMMD5.bandpa_5
Keywords: medizinische Bildverarbeitung; Zelldetektion

Barrett's Esophagus: Today's Mistakes and Tomorrow's Wisdom - Pouw, Roos E.; Pech, Oliver; Haidry, Rehan; Bisschops, Raf; Rath, Timo; Gisbertz, Suzanne (Visceral Medicine, 2022)
CRIS-Team WoS Importer:2022-06-03

Barrett's neoplasia: where is the problem? - Krugmann, J.; Vieth, M.; Neumann, Helmut (Zentralblatt für Chirurgie, 2014)
The Barrett mucosa is characterised by metaplastic transformation in the distal oesophagus from squamous epithelium into columnar-lined cells and shows an increased risk for progression into adenocarcinoma. Up to date an international definition of Barrett's oesophagus is still lacking and it is also difficult to separate low-grade dysplasia/intraepithelial neoplasia from high-grade dysplasia/intraepithelial neoplasia. The present review describes the criteria for the histological diagnosis, discusses the possibilities of endoscopic diagnosis and highlights the biomarkers of the Barrett mucosa.
EVALuna2:1917

Baseline characteristics from CLARINET FORTE: Evaluating lanreotide autogel (LAN) 120mg every 14 days in patients with progressive pancreatic or midgut neuroendocrine tumours during a standard first-line LAN regimen - Ruszniewski, P.; Cwikla, J.; Lombard-Bohas, C.; Borbath, I.; Shah, T.; Pape, U-F.; Thanh, X-M. Truong; Houchard, A.; Pavel, Marianne Ellen (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

Baseline characteristics of Crohn's disease patients in the vedolizumab PASS study: a cohort study assessing the safety and effectiveness of vedolizumab compared to other biologic agents (02) - Siegel, C. A.; Lichtenstein, G.; Siegmund, Britta; Lewis, J. D.; Wolf, D.; Louis, E.; Sebastian, S.; Hebuterne, X.; Bell, A.; Soderman, C.; Schubert, S.; Atreya, Raja; et al. (2017)
EVALuna2:33921

Baseline levels of dynamic CD4+ T cell adhesion to MAdCAM-1 correlate with clinical response to vedolizumab treatment in ulcerative colitis: a cohort study - Allner, Clarissa; Melde, Michaela; Becker, Elisabeth; Fuchs, Friederike; Mühl, Laura; Klenske, Entcho; Müller, Lisa; Morgenstern, Nadine; Fietkau, Konstantin; Hirschmann, Simon; Atreya, Raja; Atreya, Imke; et al. (BMC Gastroenterology, 2020)
BACKGROUND: While the number of therapeutic options for treating inflammatory bowel diseases (IBD) is increasing, evidence for rational treatment decisions is scarce in many cases. In particular, appropriate biomarkers to predict the response to the anti-α4β7 integrin antibody vedolizumab are currently lacking. METHODS: We performed a cohort study with 21 patients suffering from ulcerative colitis (UC), in which first-time treatment with vedolizumab was initiated. CD4+ T cells were isolated from the peripheral blood and dynamic adhesion to recombinant mucosal vascular addressin cell adhesion molecule (MAdCAM-)1 in vitro as well as the effect of vedolizumab on such adhesion in vitro was determined. The expression of α4β1 integrin on peripheral blood CD4+ T cells was quantified by flow cytometry. Electronic patient records were reviewed to determine clinical response to vedolizumab. RESULTS: Dynamic adhesion of peripheral blood CD4+ T cells to MAdCAM-1 and the reduction of adhesion following vedolizumab treatment in vitro were higher and the change in α4β1 expression on CD4+ T cells was different in vedolizumab responders and non-responders. Responders could be identified with high specificity and positive-predictive value. CONCLUSIONS: Determining dynamic adhesion of CD4+ T cells to MAdCAM-1 and the in vitro response to vedolizumab before treatment initiation or dynamic integrin regulation in the early course of treatment seem to be promising tools to predict the clinical response to vedolizumab therapy. Larger prospective studies are warranted.
CRIS-Team Scopus Importer:2020-04-28
Keywords: Adhesion; Gut homing; Inflammatory bowel diseases; T cells; Vedolizumab

Batf3 deficiency proves the pivotal role of CD8?(+) dendritic cells in protection induced by vaccination with attenuated Plasmodium sporozoites - Montagna, G. N.; Biswas, A.; Hildner, Kai; Matuschewski, K.; Dunay, I. R. (Parasite Immunology, 2015)
Increasing evidence indicates that hepatic CD8?(+) dendritic cells (DCs) are important antigen cross-presenting cells (APC) involved in the priming of protective CD8(+) T cell responses induced by live-attenuated Plasmodium sporozoites. Experimental proof for a critical role of CD8?(+) DCs in protective pre-erythrocytic malaria immunizations has pivotal implications for vaccine development, including improved vectored subunit vaccines. Employing Batf3(-/-) mice, which lack functional CD8?(+) DCs, we demonstrate that deficiency of these particular APCs completely abolishes protection and corresponding signatures of vaccine-induced immunity. We show that in wild-type, but not in Batf3(-/-) , mice CD8?(+) DCs accumulate in the liver after immunization with live irradiation-attenuated P. berghei sporozoites. IFN-? production by Plasmodium antigen-specific CD8(+) T cells is dependent on functional Batf3. In addition, our results demonstrate that the dysfunctional cDC-CD8+ T cell axis correlates with MHC class II upregulation on splenic CD8?(-) DCs. Collectively, these findings underscore the essential role of CD8?(+) DCs in robust protection induced by experimental live-attenuated malaria vaccines. This article is protected by copyright. All rights reserved.
EVALuna:32558

BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease - Ullrich, Evelyn; Abendroth, Benjamin; Rothamer, Johanna; Huber, Carina; Büttner-Herold, Maike; Buchele, Vera; Vogler, Tina; Longerich, Thomas; Zundler, Sebastian; Völkl, Simon; Beilhack, Andreas; Rose-John, Stefan; et al. (Journal of Clinical Investigation, 2018)
Acute graft-versus-host disease (GVHD) represents a severe, T cell-driven inflammatory complication following allogeneic hematopoietic cell transplantation (allo-HCT). GVHD often affects the intestine and is associated with a poor prognosis. Although frequently detectable, proinflammatory mechanisms exerted by intestinal tissue-infiltrating Th cell subsets remain to be fully elucidated. Here, we show that the Th17-defining transcription factor basic leucine zipper transcription factor ATF-like (BATF) was strongly regulated across human and mouse intestinal GVHD tissues. Studies in complete MHC-mismatched and minor histocompatibility-mismatched (miHA-mismatched) GVHD models revealed that BATF-expressing T cells were functionally indispensable for intestinal GVHD manifestation. Mechanistically, BATF controlled the formation of colon-infiltrating, IL-7 receptor-positive (IL-7R+), granulocyte-macrophage colony-stimulating factor-positive (GM-CSF+), donor T effector memory (Tem) cells. This T cell subset was sufficient to promote intestinal GVHD, while its occurrence was largely dependent on T cell-intrinsic BATF expression, required IL-7-IL-7R interaction, and was enhanced by GM-CSF. Thus, this study identifies BATF-dependent pathogenic GM-CSF+ effector T cells as critical promoters of intestinal inflammation in GVHD and hence putatively provides mechanistic insight into inflammatory processes previously assumed to be selectively Th17 drive
EVALuna2:25783

Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer - Punkenburg, Elise; Vogler, Tina; Büttner, Maike; Amann, Kerstin Ute; Waldner, Maximilian; Atreya, Raja; Abendroth, Benjamin; Mudter, Jonas; Merkel, Susanne; Gallmeier, Eike; Rose-John, Stefan; Neurath, Markus; et al. (Gut, 2016)
IBDs have an increased risk for development of colorectal cancer (CRC). Here, we aimed at the characterisation of the functional role of Th17-associated transcription factors in sporadic and colitis-associated colon cancer in vivo.We used mice deficient or transgenic for the activating protein 1 family member basic leucine zipper transcription factor ATF-like (Batf) to evaluate the role of Th17 cells during sporadic and inflammation-induced colon carcinogenesis. We also studied the expression of Batf and ROR?t in patients with IBD and CRC.Batf but not retinoic acid-related orphan receptor ?t(ROR?t) expression was significantly increased together with interleukin (IL) 23 expression in UC but not in Crohn's disease (CD) tissue samples. In CRC also Batf but not ROR?t expression was increased and its expression correlated with the IL-23 and IL-23 receptor (IL-23R) expression. Finally, Batf but not ROR?t was coexpressed with IL-17a, IL-23R and IL-6 within CRC-infiltrating CD4(+) T cells. Functional studies in mice revealed that Batf-dependent T cells are crucial regulators of sporadic and inflammation-induced CRC. Colitis-associated Batf(-/-) tumours lacked IL-17a(+)IL-23R(+)IL-6(+)CD4(+) T cells, hence displaying characteristics reminiscent of human CRC-infiltrating CD4(+) T cells. Strikingly, Batf(-/-) tumours contained low IL-23 but high IL-17a expression levels. Tumour formation and intratumoral IL-23 expression could be restored by administration of Hyper-IL-6 consisting of IL-6 and soluble IL-6 receptor.Batf-dependent IL-23R(+)IL-6(+)CD4(+) Th17 cells critically control IL-23 driven colitis-associated tumour formation and the progression of sporadic colon tumours. Batf-dependent IL-23R(+) T cells represent a potential future therapeutic target limiting CRC progression.
EVALuna2:2026

Beyond endoscopic assessment in inflammatory bowel disease: real-time histology of disease activity by non-linear multimodal imaging. - Chernavskaia, Olga; Heuke, Sandro; Friedrich, Oliver; Schürmann, Sebastian; Atreya, Raja; Stallmach, Andreas; Neurath, Markus; Waldner, Maximilian; Petersen, Iver; Schmitt, Michael; Bocklitz, Thomas; Popp, Juergen; et al. (Scientific Reports, 2016)
Assessing disease activity is a prerequisite for an adequate treatment of inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. In addition to endoscopic mucosal healing, histologic remission poses a promising end-point of IBD therapy. However, evaluating histological remission harbors the risk for complications due to the acquisition of biopsies and results in a delay of diagnosis because of tissue processing procedures. In this regard, non-linear multimodal imaging techniques might serve as an unparalleled technique that allows the real-time evaluation of microscopic IBD activity in the endoscopy unit. In this study, tissue sections were investigated using the non-linear multimodal microscopy combination of coherent anti-Stokes Raman scattering (CARS), two-photon excited auto fluorescence (TPEF) and second-harmonic generation (SHG). After the measurement a gold-standard assessment of histological indexes was carried out based on a conventional H&E stain. Subsequently, various geometry and intensity related features were extracted from the multimodal images. An optimized feature set was utilized to predict histological index levels based on a linear classifier. Based on the automated prediction, the diagnosis time interval is decreased. Therefore, non-linear multimodal imaging may provide a real-time diagnosis of IBD activity suited to assist clinical decision making within the endoscopy unit.

Beyond the border: The use of lenvatinib in advanced hepatocellular carcinoma after different treatment lines: A retrospective analysis - Jefremow, Andre; Wiesmüller, Marco; Rouse, R. A.; Dietrich, Peter; Kremer, Andreas; Waldner, Maximilian; Neurath, Markus; Siebler, Jürgen (Journal of Physiology and Pharmacology, 2020)
The systemic treatment of unresectable hepatocellular carcinoma (HCC) has been improved throughout the past years. Different tyrosine kinase inhibitors (TKI) and checkpoint inhibitors have approval for first-and second-line treatment. Still, data are missing about the choice for the right agent and senseful therapy sequences. Between 2017 and 2019 we treated 149 HCC patients. From those, we identified the patients, who received lenvatinib either as a first-line treatment or in a later treatment line. We investigated seven patients retrospectively, who received lenvatinib in second, third, or fourth treatment line regarding efficacy and safety. Besides that, we compared those patients with 13 patients, who received lenvatinib as a first-line treatment regarding duration of therapy, overall survivial (OS), side effects and best response to treatment. We discovered remission (PR) showed 4/7, stable disease (SD) 2/7 and 1/7 mixed response with an overall tolerable safety profile in patients with a later line lenvatinib treatment. The duration and overall survival for therapy is similar in first-and later treatment lines with comparable results. Most side effects are moderate in each treatment line. Remarkably, on patient diagnoses with HCC (the Barcelona Clinic Liver Cancer C algorithm), who received lenvatinib in fourth line reached 67 months OD since diagnosis. We conclude, that lenvatinib could be considered as a treatment option of HCC for later treatment lines.
CRIS-Team Scopus Importer:2021-04-19
Keywords: Advanced hepatocellular carcinoma; Lenvatinib; Liver cancer; Sequence therapy; Systemic treatment; Treatment lines; Tyrosine kinase inhibitors

Bile salt subspecies activate MRGX4 expressed on sensory neurons and cause itching in humans - Wolf, Katharina; Kühn, Helen; Leibl, Victoria; Gebhardt, Lisa; Glaudo, Markus; Reeh, Peter; Fischer, Michael J. M.; Neurath, Markus; Namer, Barbara; Kremer, Andreas (HEPATOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-25

BIOCHEMICAL RESPONSES IN SYMPTOMATIC AND ASYMPTOMATIC PATIENTS WITH NEUROENDOCRINE TUMORS: POOLED ANALYSIS OF 2 PHASE 3 TRIALS - Mirakhur, Beloo; Pavel, Marianne Ellen; Pommier, Rodney F.; Fisher, George A.; Phan, Alexandria T.; Massien, Christine; Liyanage, Nilani; Lowenthal, Susan Pitman; Vinik, Aaron (Endocrine Practice, 2018)
OBJECTIVE: Neuroendocrine tumors (NETs) are associated with elevated 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A (CgA) levels. This study aimed to analyze relationships between urinary 5-HIAA and plasma CgA levels and clinical outcomes. METHODS: Centrally assessed biomarker levels and correlations with progression-free survival (PFS) and carcinoid syndrome (CS) symptom control were evaluated in a pooled analysis of CLARINET (96-week randomized, double-blind, placebo-controlled) and ELECT (16-week randomized, double-blind, placebo-controlled, 32-week initial open label and ≥2 year long-term extension open label) studies of adults with NETs, with (ELECT) or without (CLARINET) CS at 97 institutions. Patients were treated with subcutaneous lanreotide depot 120 mg monthly. RESULTS: Of 319 pooled patients, 86% and 95% had baseline 5-HIAA and CgA data, respectively, with 47% and 74% having levels greater than the upper limit of normal (ULN). PFS was longer among patients who experienced a decrease in biomarker levels at week 12, with statistical significance reached in the CgA cohort (not reached vs. 14.4 months; P<.0001). A large proportion (87%) of patients without symptoms of CS in the CLARINET study had detectable levels of 5-HIAA (48% >ULN). In ELECT, patients with CS who received lanreotide and experienced a biochemical response (≥50% decrease from baseline) achieved greater symptom control. CONCLUSION: This pooled analysis of two randomized, placebo-controlled trials demonstrated that 5-HIAA and CgA are secreted as biochemical biomarkers in many patients with NETs, regardless of clinical syndromes. Significant biochemical response was associated with improved clinical outcomes, as measured by improved PFS or improved CS symptom control. ABBREVIATIONS: 5-HIAA = 5-hydroxyindoleacetic acid; CgA = chromogranin A; CI = confidence interval; CLARINET = Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors; CS = carcinoid syndrome; ELECT = Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment; HR = hazard ratio; ITT = intention-to-treat; NET = neuroendocrine tumor; PanNET = pancreatic NET; PFS = progression-free survival; PPI = proton pump inhibitor; SSA = somatostatin analogue; ULN = upper limit of normal.
EVALuna2:35132

Bioelectrical Impedance Analysis (BIA) Basics and Application - Reljic, Dejan; Herrmann, Hans Joachim; Neurath, Markus; Zopf, Yurdagül (Ernährungsumschau, 2019)
CRIS-Team WoS Importer:2019-10-04

Bioelektrische Impedanzanalyse (BIA): Grundlagen und Anwendung - Reljic, Dejan; Herrmann, Hans Joachim; Neurath, Markus; Zopf, Yurdagül (Ernährungsumschau, 2019)
CRIS-Team Scopus Importer:2021-04-20

Biomimetic Magnetic Particles for the Removal of Gram-Positive Bacteria and Lipoteichoic Acid. - Friedrich, Bernhard; Eichermüller, Julia; Bogdan, Christian; Cunningham, Sarah; Hackstein, Holger; Strauss, Richard; Alexiou, Christoph; Lyer, Stefan; Tietze, Rainer (Pharmaceutics, 2022)
Gram+ bacteria are very common in clinical medicine and responsible for a large number of infectious diseases. For example, Gram+ bacteria play a major role in causing bloodstream infections and sepsis. Therefore, the detection of Gram+ bacteria is of great importance for the diagnosis and treatment of infectious diseases. Furthermore, these bacteria are often present in biofilms that cover implants. Recent research work has mainly focused on the biologic activity and removal of Gram-negative bacteria or bacterial components such as lipopolysaccharides (LPS). In contrast, the effects of lipoteichoic acid (LTA) have been less well studied so the relevance of their removal from body fluids is possibly underestimated. To address this topic, we evaluated superparamagnetic iron oxide particles (SPION) carrying different peptides derived from the innate immune receptor (GP-340) for their ability to bind and remove Gram+ bacteria and LTA from different media. Our results show that, beyond S. aureus, effective agglutinating and removing of S. pneumoniae was possible. Furthermore, we were able to show for the first time that this was possible with LTA alone and that the magnetic removal of bacteria was also efficient under flow conditions. We also found that this method was able to capture Stapyhylococcus aureus from platelet concentrates, which can help to enhance the sensitivity of microbiological diagnostics, quality control measures, and blood product safety.
EVALuna2:508460

Biosimilars in inflammatory bowel disease - Siegmund, B.; Atreya, Raja; Bokemeyer, B.; Kruis, W.; Mudter, J.; Sander, C.; Schreiber, S.; Reindl, W.; Zeissig, Sebastian; Kucharzik, T. (Zeitschrift für Gastroenterologie, 2016)
After the expiry date of the patent protection for Infliximab in 2013, the biosimilar CT-P13 was approved for indications in Crohn's disease and ulcerative colitis in adults as well as in children. The approval has been based on two randomized clinical studies indicating equivalence for the biosimilar with regard to pharmacokinetics, efficacy, as well as side-effects. The clinical experience since, in addition to multiple non-randomized studies, indicate a comparable efficacy and immunogenicity of the Infliximab biosimilar CT-P13 in inflammatory bowel disease. Thus, the introduction of the biosimilar as primary therapy seems to be justified. Tight monitoring of the safety of biosimilars with regard to efficacy and side effects has to be ensured.
EVALuna2:2203

Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo - Zundler, Sebastian; Schillinger, Daniela; Fischer, Anika; Atreya, Raja; Lopez Posadas, Rocío; Watson, Alastair; Neufert, Clemens; Atreya, Imke; Neurath, Markus (Gut, 2016)
Objective Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of antiadhesion compounds are incompletely understood. We investigated the role of αEβ7 and α4β7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut. Design We explored integrin expression in patients with IBD by flow cytometry and immunohistochemistry, while regulation of integrins was studied in T cell cultures. The functional relevance of integrins was assessed by adhesion assays and a recently established humanised mouse model in dextran sodium sulfate-treated immunodeficient mice. Results High expression of αEβ7 was noted on CD8+ and CD4+ Th9 cells, while α4β7 was expressed on CD8+, Th2 and Th17 cells. T cell receptor stimulation and transforming growth factor β were key inducers of αEβ7 on human T cells, while butyric acid suppressed αEβ7. In comparison to α4β7 blockade via vedolizumab, blockade of β7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8+ and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AEβ7 expression was higher on CD8+ T cells from patients with IBD under vedolizumab therapy. Conclusions AEβ7 is of key relevance for gut trafficking of IBD CD8+ T cells and CD4+ Th9 cells in vivo and mainly retention might account for this effect. These findings indicate that blockade of αEβ7 in addition to α4β7 may be particularly effective in intestinal disorders with expansion of CD8+ and Th9 cells such as IBD.
EVALuna2:2222

Bowel wall thickening and hyperemia assessed by high-frequency ultrasound indicate histological inflammation in Crohn's ileitis - Görtz, Rüdiger; Hensel, Stefanie; Wildner, Dane; Neurath, Markus; Strobel, Deike (Abdominal Radiology, 2020)
Purpose We evaluated ileal bowel wall thickness and semiquantitative vascularization by ultrasound in correlation with the presence or absence of histopathological inflammation in patients with Crohn's disease (CD). Methods We conducted a retrospective analysis of 221 ultrasound examinations of the terminal ileum or neoterminal ileum in CD patients with biopsies of the ileum during colonoscopies within 8 weeks of the ultrasound. Ultrasound data were obtained from an inflammatory bowel disease ultrasound register from 2011 to 2017. Bowel wall ultrasound was performed by a high-frequency, linear transducer (7-12 MHz). Presence of bowel wall thickening (> 3 mm), vascularization by the Limberg score, and presence of ileal histopathological inflammation were analyzed. Results In 221 bowel wall ultrasound examinations of CD patients (128 female, 93 male, mean age 37.5 years), a thickened bowel wall was found in 140 (63.3%) and hypervascularization (corresponding to a Limberg score >= 2) in 96 (43.4%) cases. In 187 (84.6%) cases, ileal inflammation was confirmed by histopathology and in 34 (15.4%) cases no inflammation was shown. Bowel wall thickening showed a sensitivity of 70.1%, a negative predictive value (NPV) of 30.9%, a specificity of 73.5% and a positive predictive value (PPV) of 93.6% for the detection of histopathological ileal inflammation. Hypervasularization had a low sensitivity (49.7%) and NPV (24.8%), but high specificity (91.2%) and PPV (96.9%). Conclusion In this CD subcohort of an ultrasound register, pathologic ultrasound findings were quite common. Bowel wall thickening (> 3 mm) and hypervascularization are good predictors of histopathological inflammation within the terminal ileum or neoterminal ileum. Normal ultrasound findings without bowel wall thickening and without hypervascularization do not rule out histopathological inflammation.
CRIS-Team WoS Importer:2021-01-08

Breaking bad: necroptosis in the pathogenesis of gastrointestinal diseases - Patankar, Jay; Bubeck, Marvin; Gonzalez Acera, Miguel; Becker, Christoph (Frontiers in Immunology, 2023)
A delicate balance between programmed cell death and proliferation of intestinal epithelial cells (IEC) exists in the gut to maintain homeostasis. Homeostatic cell death programs such as anoikis and apoptosis ensure the replacement of dead epithelia without overt immune activation. In infectious and chronic inflammatory diseases of the gut, this balance is invariably disturbed by increased levels of pathologic cell death. Pathological forms of cell death such as necroptosis trigger immune activation barrier dysfunction, and perpetuation of inflammation. A leaky and inflamed gut can thus become a cause of persistent low-grade inflammation and cell death in other organs of the gastrointestinal (GI) tract, such as the liver and the pancreas. In this review, we focus on the advances in the molecular and cellular understanding of programmed necrosis (necroptosis) in tissues of the GI tract. In this review, we will first introduce the reader to the basic molecular aspects of the necroptosis machinery and discuss the pathways leading to necroptosis in the GI system. We then highlight the clinical significance of the preclinical findings and finally evaluate the different therapeutic approaches that attempt to target necroptosis against various GI diseases. Finally, we review the recent advances in understanding the biological functions of the molecules involved in necroptosis and the potential side effects that may occur due to their systemic inhibition. This review is intended to introduce the reader to the core concepts of pathological necroptotic cell death, the signaling pathways involved, its immuno-pathological implications, and its relevance to GI diseases. Further advances in our ability to control the extent of pathological necroptosis will provide better therapeutic opportunities against currently intractable GI and other diseases.
CRIS-Team Scopus Importer:2023-08-25
Keywords: caspase 8; inflammatory bowel disease; MLKL; necroptosis; RIPK3; therapeutic

Brown bowel syndrome: a rare complication in diseases associated with long-standing malabsorption - Albrecht, Heinz; Hagel, Alexander; De Rossi, Thomas; Rau, Tilman; Kirchner, Thomas; Neurath, Markus; Raithel, Martin (Digestion, 2014)
Longtime chronic malabsorption may among other things cause a lack of liposoluble vitamins. Vitamin E deficiency can lead to formation of lipofuscin aggregates. Its deficiency is also associated with an increased lipofuscinosis of the bowel, i.e. brown bowel syndrome.Systematic research via Medline on brown bowel syndrome, lipofuscinosis, and vitamin E deficiency was performed. We combined our own clinical experience and a review of the literature for this paper. Its goal is to inform about the possible consequences of severe malabsorption and brown bowel syndrome.Systematic data about the occurrence of severe malabsorption and brown bowel syndrome are rare. Only about 27 scientific reports can be found on this subject. Brown bowel syndrome is found mostly in conjunction with vitamin E deficiency and lipofuscinosis of the bowel. The clinical findings are caused by both malabsorption and lipofuscinosis. Case reports show a therapeutic effect of vitamin E.Vitamin deficiency caused by longtime chronic malabsorption can lead to the development of brown bowel syndrome, which is seen as the expression of lipofuscinosis of the bowel, and can cause further clinical disorders. Patients with malabsorption should therefore be monitored regarding their vitamin E levels.
EVALuna2:1837

Btn2a2 Regulates ILC2-T Cell Cross Talk in Type 2 Immune Responses - Frech, Michael; Omata, Yasunori; Schmalzl, Angelika; Wirtz, Stefan; Taher, Leila; Schett, Georg; Zaiss, Mario; Sarter, Kerstin (Frontiers in Immunology, 2022)
Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. In vitro and in vivo experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. In vivo transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2-T cell interactions.
CRIS-Team WoS Importer:2022-02-18

Budesonide loaded nanoparticles with pH-sensitive coating for improved mucosal targeting in mouse models of inflammatory bowel diseases - Ali, H.; Weigmann, Benno; Neurath, Markus; Collnot, E. M.; Windbergs, M.; Lehr, C. -M. (Journal of Controlled Release, 2014)
The purpose of this study was to investigate the therapeutic potential of budesonide loaded nanocarriers for the treatment of inflammatory bowel disease (IBD). First, budesonide was encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles by an oil in water (O/W) emulsion technique. A second batch of the same nanoparticles was additionally coated with a pH-sensitive methyl-methacrylate-copolymer. The particle sizes of the plain and the coated PLGA were 200±10.1nm and 240±14.7nm, respectively. As could be shown in vitro, the pH-sensitive coating prevented premature drug release at acidic pH and only releases the drug at neutral to slightly alkaline pH. The efficacy of both coated and plain nanoparticle formulations was assessed in different acute and chronic colitis mouse models, also in comparison to an aqueous solution of the drug. The dose was always the same (0.168mg/kg). It was found that delivery by coated PLGA nanoparticles alleviated the induced colitis significantly better than by plain PLGA particles, which was already more effective than treatment with the same dose of the free drug. These data further corroborate the potential of polymeric nanocarriers for targeted drug delivery to the inflamed intestinal mucosa, and that this concept can still be further improved regarding the oral route of administration by implementing pH-dependent drug release characteristics.
EVALuna2:1906

Burden of bowel urgency across specific treatment groups among Ulcerative Colitis patients - real world global study analyses - Atreya, Raja; Redondo, I.; Hill, J.; Streit, P.; Hartz, S.; Knight, H.; Barlow, S.; Hennessy, F.; Hunter, T. (JOURNAL OF CROHNS & COLITIS, 2022)
CRIS-Team WoS Importer:2022-05-13

Can genetic testing guide the therapy of cholestatic pruritus? A case of benign recurrent intrahepatic cholestasis type 2 with severe nasobiliary drainage-refractory itch - Holz, Robert; Kremer, Andreas; Luetjohann, Dieter; Wasmuth, Hermann E.; Lammert, Frank; Krawczyk, Marcin (Hepatology Communications, 2018)
Benign recurrent intrahepatic cholestasis (BRIC) is a peculiar familial disease caused by mutations of the genes encoding hepatocanalicular flippase for phosphatidylserine (ATP8B1; BRIC type 1) or the bile salt export pump (ABCB11; BRIC type 2). Here, we report on a patient with nasobiliary drainage-refractory BRIC type 2 who improved under plasma separation and anion absorption therapy. We also suggest that nasobiliary drainage might be an ineffective approach in carriers of severe loss-of-function mutations of the bile salt export pump ABCB11. (Hepatology Communications 2018;2:152-154).
EVALuna2:208322

Can Serum Proteomic Profiling Annunciate Individual Disease Progression in Newly Diagnosed Inflammatory Bowel Disease Patients? - Atreya, Raja; Neurath, Markus (Journal of Crohns & Colitis, 2021)
CRIS-Team Scopus Importer:2021-06-04

Cap polyposis in children: case report and literature review - Brunner, Maximilian; Agaimy, Abbas; Atreya, Raja; Grützmann, Robert; Matzel, Klaus E. (International Journal of Colorectal Disease, 2019)
PURPOSE: Cap polyposis is a benign disease of the colon, characterized by inflammatory polyps with a "cap" of inflammatory granulation tissue. Its prevalence is very low, especially in children. METHODS AND RESULTS: A 16-year-old girl presented with frequent bowel movements with mucous discharge and bloody stool, leading to the initial suspicion of chronic inflammatory bowel disease. Results of further investigation by endoscopy and histological examination were consistent with a diagnosis of cap polyposis. Treatment with systemic steroids resulted in symptom improvement. CONCLUSION: A review of the literature shows that cap polyposis can occur at any age, including childhood, with a slight predilection for the male gender. Rectal bleeding and rectal polyps are consistent features in all reported cases. Other typical symptoms include constipation, diarrhea, and abdominal pain. Symptoms may be very similar to those of chronic inflammatory bowel disease, the most important differential diagnosis. The cause of cap polyposis is still unclear, and specific therapy has not as yet been established. Conservative therapeutic measures should be preferred, especially in children.
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Carbohydrate intake and insulin requirement in children, adolescents and young adults with cystic fibrosis-related diabetes: A multicenter comparison to type 1 diabetes - Scheuing, Nicole; Thon, Angelika; Konrad, Katja; Bauer, Maria; Karsten, Claudia; Meissner, Thomas; Seufert, Jochen; Schoenau, Eckhard; Schöfl, Christof; Woelfle, Joachim; Holl, Reinhard W. (Clinical Nutrition, 2015)
In cystic fibrosis-related diabetes (CFRD), energy needs differ from type 1 (T1D) or type 2 diabetes, and endogenous insulin secretion is not totally absent. We analyzed whether daily carbohydrate intake, its diurnal distribution and insulin requirement per 11 g of carbohydrate differ between CFRD and T1D.Anonymized data of 223 CFRD and 36,780 T1D patients aged from 10 to <30 years from the multicenter diabetes registry DPV were studied. Carbohydrate intake and insulin requirement were analyzed using multivariable regression modeling with adjustment for age and sex. Moreover, carbohydrate intake was compared to the respective recommendations (CFRD: energy intake 130% of general population with 45% carbohydrates; T1D: carbohydrate intake 50% of total energy).After demographic adjustment, carbohydrate intake (238 ± 4 vs. 191 ± 1 g/d, p < 0.001) and meal-related insulin (0.52 ± 0.02 vs. 0.47 ± 0.004 IU/kg*d, p = 0.001) were higher in CFRD, whereas basal insulin (0.27 ± 0.01 vs. 0.38 ± 0.004 IU/kg*d, p < 0.001) and total insulin requirement per 11 g of carbohydrate (1.15 ± 0.06 vs. 1.70 ± 0.01 IU/d, p < 0.001) were lower compared to T1D. CFRD patients achieved 62% [Q1;Q3: 47; 77] of recommended carbohydrate intake and T1D patients 60% [51; 71] of age- and gender-specific recommended intake (p < 0.001). CFRD and T1D patients had a carbohydrate intake below healthy peers (79% [58; 100] and 62% [52; 74], p < 0.001). The circadian rhythm of insulin sensitivity persisted in CFRD and the diurnal distribution of carbohydrates was comparable between groups.In pediatric and young adult patients, carbohydrate intake and insulin requirement differ clearly between CFRD and T1D. However, both CFRD and T1D patients seem to restrict carbohydrates.
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Cardivascular Risk Profile in Patients with Diabetes and Acromegaly or Cushing's Disease - Analysis from the DPV Database - Warncke, Katharina; Kummer, Sebastian; Kann, Peter Herbert; Bergis, Dominik; Bollow, Esther; Hummel, Michael; Zoicas, Flavius; Wernert, Sebastian; Holl, Reinhard W. (Experimental and Clinical Endocrinology and Diabetes, 2020)
BACKGROUND: Although diabetes is a common complication of acromegaly or Cushing´s disease, there are only few detailed studies with a focus on cardiovascular risk, metabolic control or diabetes therapy. Here, we provide a comprehensive characterization from the longitudinal DPV (Diabetes Patienten Verlaufsdokumentation) registry. METHODS: Patients from the registry≥18 years of age with diabetes and acromegaly or Cushing´s disease were compared to patients with type 1 diabetes or type 2 diabetes using the statistical software SAS 9.4. RESULTS: Patients with diabetes and acromegaly (n=52) or Cushing's disease (n=15) were significantly younger at diabetes onset (median age 50.1 and 45.0 vs. 59.0 years in type 2 diabetes; both p<0.05). Dyslipidemia was common in both diseases (71.0% and 88.9% vs. 71.8% in type 2 diabetes; n.s.), while hypertension was most frequent in acromegaly (56.8% vs. 20.9% in type 1 diabetes, p<0.00001). 36.5% of patients with acromegaly and 46.7% with Cushing´s disease receive insulin, compared to 50.4% with type 2 diabetes. Oral antidiabetic drugs were used in 36.5% of patients with acromegaly and 40% with Cushing´s disease, with a predominance of biguanides and dipeptidyl peptidase-4 inhibitors. HbA1c was well controlled in both groups (median 7.0% and 6.5%; vs. 7.2% in type 2 diabetes). CONCLUSION: Patients with acromegaly are at a high risk for cardiovascular disease, reflected by dyslipidemia and hypertension. A high proportion of patients with diabetes in acromegaly or Cushing´s disease receives insulin. Based on a multicenter register, a sufficient number of patients with rare forms of diabetes can be analyzed.
CRIS-Team Scopus Importer:2020-02-11

Care for neuroendocrine tumor patients, monitored by medical oncologists: Comparative data Europe vs North America - Kolarova, T.; Mcdonnell, M.; Bouvier, C. V.; Pavel, Marianne Ellen; Singh, H.; Howe, J.; Singh, S.; O'Toole, D.; Chen, J.; Leyden, S.; Gellerman, E.; Dureja, S.; et al. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-10-15

Case Report: IBD-like colitis following CAR T cell therapy for diffuse large B cell lymphoma - Zundler, Sebastian; Vitali, Francesco; Kharboutli, Soraya; Völkl, Simon; Polifka, Iris; Mackensen, Andreas; Atreya, Raja; Neurath, Markus; Mougiakakos, Dimitrios (Frontiers in Oncology, 2023)
Chimeric antigen receptor (CAR) T cell therapy has become a new mainstay in the treatment of several hematologic malignancies, but the spectrum of associated complications is still incompletely defined. Here, we report the case of a 70-year-old female patient treated with tisagenlecleucel for diffuse large B cell lymphoma (DLBCL), who developed chronic diarrhea with characteristics of inflammatory bowel disease (IBD)-like colitis. CAR T cells were substantially enriched in the colon lamina propria and other diagnoses were ruled out. Thus, we conclude that IBD-like colitis in this patient was associated to CAR T cell therapy and needs to be considered as a rare potential complication.
CRIS-Team Scopus Importer:2023-06-16
Keywords: CAR T cells; case report; diffuse large B cell lymphoma; inflammatory bowel disease (IBD); tisagenlecleucel

Case report of severe constrictive perimyocarditis and ischemic hepatitis in a Crohn’s disease patient upon infliximab-induced lupus-like syndrome - Hirschmann, Simon; Fischer, Sarah; Klenske, Entcho; Dechant, Katharina; Distler, Jörg; Treutlein, Christoph; Neurath, Markus; Atreya, Raja (Therapeutic Advances in Gastroenterology, 2021)
Anti-tumor necrosis factor (TNF) antibodies have become an indispensable part in the therapeutic landscape of treating inflammatory bowel disease (IBD) patients. Nevertheless, they can be associated with the occurrence of severe systemic side effects. Here, we report the case of a 23-year-old patient with ileocolonic Crohn’s disease in endoscopic remission under ongoing anti-TNF infliximab therapy with occurrence of novel generalized arthralgia, pleuritic chest pain, and dyspnea. Clinical, laboratory, and imaging diagnostic workup in an extended clinical routine setting at the University Hospital of Erlangen, Germany, was used by a multidisciplinary team consisting of gastroenterologists, radiologists, cardiologists, and rheumatologists to investigate the underlying cause of the clinical symptoms in the patient. The results received using the aforementioned diagnostic setup led to the diagnosis of severe constrictive perimyocarditis due to infliximab-induced lupus-like syndrome with distinct ANA reactivity and elevated anti-dsDNA levels. Furthermore, pronounced ischemic hepatitis was diagnosed. Infliximab treatment was immediately stopped, and initiated corticosteroid pulse therapy only led to partial response as it had to be reduced due to pronounced psychiatric side effects. Persistent signs of pericarditis required additional ibuprofen therapy, which led to subsequent resolution of cardial symptoms. Formerly elevated liver enzymes returned to normal, and there were no clinical signs of recurrence of Crohn’s disease activity over 18 months of follow-up. The patient was subsequently switched to ustekinumab therapy for further treatment of underlying Crohn’s disease. This case report describes for the first time severe infliximab-induced lupus-like syndrome in an IBD patient, concurrently mimicking ST-elevation myocardial infarction with MRI visualization of pericarditis, occurrence of ischemic hepatitis, and pronounced signs of systemic inflammation.
CRIS-Team Scopus Importer:2021-10-15
Keywords: anti-TNF antibody; case report; Crohn’s disease; infliximab; lupus-like syndrome

Case report: persistent fever after SARS-CoV-2 infection Fallbericht: Persistierendes Fieber nach SARS-CoV-2-Infektion - Kliem, Thorsten; Strobel, Deike; Heinke, Fabian; Pavel, Marianne Ellen; Neurath, Markus; Neufert, Clemens (Internist, 2022)
A 44-year-old man had persistent fever following a severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Because of progressive sinus tachycardia, thyroid hormones were measured which showed hyperthyroidism. Thyroid sonography revealed enlargement of the thyroid gland with hypoechoic areas with blurred margins. We diagnosed subacute granulomatous thyroiditis associated with SARS-CoV‑2 infection and initiated therapy with prednisolone. This therapy resulted in rapid improvement of the patient’s clinical condition and complete remission after three months.
CRIS-Team Scopus Importer:2022-04-01
Keywords: COVID-19; De Quervain’s thyroiditis; Diagnostic ultrasound; Subacute granulomatous thyroiditis; Tachycardia

Caspase-8 controls the gut response to microbial challenges by Tnf-?-dependent and independent pathways - Günther, Claudia; Buchen, Barbara; He, Gui-Wei; Hornef, Mathias; Torow, Natalia; Neumann, Helmut; Wittkopf, Nadine; Martini, Eva; Basic, Marijana; Bleich, Andre; Watson, Alastair J. M.; Neurath, Markus; et al. (Gut, 2015)
Intestinal epithelial cells (IEC) express toll-like receptors (TLR) that facilitate microbial recognition. Stimulation of TLR ligands induces a transient increase in epithelial cell shedding, a mechanism that serves the antibacterial and antiviral host defence of the epithelium and promotes elimination of intracellular pathogens. Although activation of the extrinsic apoptosis pathway has been described during inflammatory shedding, its functional involvement is currently unclear.We investigated the functional involvement of caspase-8 signalling in microbial-induced intestinal cell shedding by injecting Lipopolysaccharide (LPS) to mimic bacterial pathogens and poly(I:C) as a probe for RNA viruses in vivo.TLR stimulation of IEC was associated with a rapid activation of caspase-8 and increased epithelial cell shedding. In mice with an epithelial cell-specific deletion of caspase-8 TLR stimulation caused Rip3-dependent epithelial necroptosis instead of apoptosis. Mortality and tissue damage were more severe in mice in which IECs died by necroptosis than apoptosis. Inhibition of receptor-interacting protein (Rip) kinases rescued the epithelium from TLR-induced gut damage. TLR3-induced necroptosis was directly mediated via TRIF-dependent pathways, independent of Tnf-? and type III interferons, whereas TLR4-induced tissue damage was critically dependent on Tnf-?.Together, our data demonstrate an essential role for caspase-8 in maintaining the gut barrier in response to mucosal pathogens by permitting inflammatory shedding and preventing necroptosis of infected cells. These data suggest that therapeutic strategies targeting the cell death machinery represent a promising new option for the treatment of inflammatory and infective enteropathies.
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Caspase-8 controls the gut response to microbial challenges by Tnf-α-dependent and independent pathways. - Günther, Claudia; Buchen, Barbara; He, Guiwei; Hornef, Mathias W.; Torow, Natalia; Neumann, Helmut; Martini, Eva; Basic, Marijana; Bleich, André; Watson, Alastair J.M.; Neurath, Markus; Becker, Christoph; et al. (Gut, 2015)
Together, our data demonstrate an essential role for caspase-8 in maintaining the gut barrier in response to mucosal pathogens by permitting inflammatory shedding and preventing necroptosis of infected cells. These data suggest that therapeutic strategies targeting the cell death machinery represent a promising new option for the treatment of inflammatory and infective enteropathies. TLR stimulation of IEC was associated with a rapid activation of caspase-8 and increased epithelial cell shedding. In mice with an epithelial cell-specific deletion of caspase-8 TLR stimulation caused Rip3-dependent epithelial necroptosis instead of apoptosis. Mortality and tissue damage were more severe in mice in which IECs died by necroptosis than apoptosis. Inhibition of receptor-interacting protein (Rip) kinases rescued the epithelium from TLR-induced gut damage. TLR3-induced necroptosis was directly mediated via TRIF-dependent pathways, independent of Tnf-α and type III interferons, whereas TLR4-induced tissue damage was critically dependent on Tnf-α. Intestinal epithelial cells (IEC) express toll-like receptors (TLR) that facilitate microbial recognition. Stimulation of TLR ligands induces a transient increase in epithelial cell shedding, a mechanism that serves the antibacterial and antiviral host defence of the epithelium and promotes elimination of intracellular pathogens. Although activation of the extrinsic apoptosis pathway has been described during inflammatory shedding, its functional involvement is currently unclear. We investigated the functional involvement of caspase-8 signalling in microbial-induced intestinal cell shedding by injecting Lipopolysaccharide (LPS) to mimic bacterial pathogens and poly(I:C) as a probe for RNA viruses in vivo. CONCLUSIONS RESULTS OBJECTIVES DESIGN
Keywords: Apoptosis; Cell Biology; Cell Death; Intestinal Epithelium; TNF

Caspase-8 controls the gut response to microbial challenges by Tnf-α-dependent and independent pathways - Günther, Claudia; Buchen, Barbara; Hornef, Mathias; Torow, Natalia; Neumann, Helmut; Martini, Eva; Basic, Marijana; Bleich, Andre; Watson, Alastair; Neurath, Markus; Becker, Christoph; et al. (Gut, 2015)
Together, our data demonstrate an essential role for caspase-8 in maintaining the gut barrier in response to mucosal pathogens by permitting inflammatory shedding and preventing necroptosis of infected cells. These data suggest that therapeutic strategies targeting the cell death machinery represent a promising new option for the treatment of inflammatory and infective enteropathies. TLR stimulation of IEC was associated with a rapid activation of caspase-8 and increased epithelial cell shedding. In mice with an epithelial cell-specific deletion of caspase-8 TLR stimulation caused Rip3-dependent epithelial necroptosis instead of apoptosis. Mortality and tissue damage were more severe in mice in which IECs died by necroptosis than apoptosis. Inhibition of receptor-interacting protein (Rip) kinases rescued the epithelium from TLR-induced gut damage. TLR3-induced necroptosis was directly mediated via TRIF-dependent pathways, independent of Tnf-α and type III interferons, whereas TLR4-induced tissue damage was critically dependent on Tnf-α. Intestinal epithelial cells (IEC) express toll-like receptors (TLR) that facilitate microbial recognition. Stimulation of TLR ligands induces a transient increase in epithelial cell shedding, a mechanism that serves the antibacterial and antiviral host defence of the epithelium and promotes elimination of intracellular pathogens. Although activation of the extrinsic apoptosis pathway has been described during inflammatory shedding, its functional involvement is currently unclear. We investigated the functional involvement of caspase-8 signalling in microbial-induced intestinal cell shedding by injecting Lipopolysaccharide (LPS) to mimic bacterial pathogens and poly(I:C) as a probe for RNA viruses in vivo. CONCLUSIONS RESULTS OBJECTIVES DESIGN
Keywords: Apoptosis; Cell Biology; Cell Death; Intestinal Epithelium; TNF

Caspase-8 in endothelial cells maintains gut homeostasis and prevents small bowel inflammation in mice - Tisch, Nathalie; Mogler, Carolin; Stojanovic, Ana; Luck, Robert; Korhonen, Emilia A.; Ellerkmann, Alexander; Adler, Heike; Singhal, Mahak; Schermann, Geza; Erkert, Lena; Patankar, Jay; Karakatsani, Andromachi; et al. (Embo Molecular Medicine, 2022)
The gut has a specific vascular barrier that controls trafficking of antigens and microbiota into the bloodstream. However, the molecular mechanisms regulating the maintenance of this vascular barrier remain elusive. Here, we identified Caspase-8 as a pro-survival factor in mature intestinal endothelial cells that is required to actively maintain vascular homeostasis in the small intestine in an organ-specific manner. In particular, we find that deletion of Caspase-8 in endothelial cells results in small intestinal hemorrhages and bowel inflammation, while all other organs remained unaffected. We also show that Caspase-8 seems to be particularly needed in lymphatic endothelial cells to maintain gut homeostasis. Our work demonstrates that endothelial cell dysfunction, leading to the breakdown of the gut-vascular barrier, is an active driver of chronic small intestinal inflammation, highlighting the role of the intestinal vasculature as a safeguard of organ function.
CRIS-Team Scopus Importer:2022-05-13
Keywords: caspase-8; chronic intestinal inflammation; endothelium; necroptosis; vascular homeostasis

Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis - Günther, Claudia; Martini, Eva; Amann, Kerstin Ute; Weigmann, Benno; Neumann, Helmut; Waldner, Maximilian; Tenzer, Stefan; Neurath, Markus; Becker, Christoph; et al. (Nature, 2011)
Dysfunction of the intestinal epithelium is believed to result in the excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease, an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum. In healthy individuals, the intestinal epithelium maintains a physical barrier, established by the tight contact of cells. Moreover, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides, which hamper access and survival of bacteria adjacent to the epithelium. Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a possible pathogenic mechanism driving Crohn's disease in humans. However, the regulation of epithelial cell death and its role in intestinal homeostasis remain poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IECs) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8(ΔIEC)) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8(ΔIEC) mice lacked Paneth cells and showed reduced numbers of goblet cells, indicating dysregulated antimicrobial immune cell functions of the intestinal epithelium. Casp8(ΔIEC) mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumour necrosis factor (TNF)-α, was associated with increased expression of receptor-interacting protein 3 (Rip3; also known as Ripk3) and could be inhibited on blockade of necroptosis. Lastly, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IECs from TNF-α-induced necroptotic cell death.

Catheter-based distal sciatic nerve block in patients with Charcot-Marie-Tooth disease - Schmitt, Heike; Huberth, Sandra; Huber, Horst; Münster, Tino (BMC Anesthesiology, 2014)
The use of peripheral nerve blocks in patients with Charcot-Marie-Tooth (CMT) disease is scarcely reported; however, when performed it has proven to be effective for postoperative pain control.A distal catheter-based sciatic nerve block for postoperative pain control was offered to 27 consecutive CMT patients scheduled for elective foot surgery. 18 of the 27 CMT patients consented to the offered sciatic nerve block. Localization of the sciatic nerve was guided by a nerve stimulator. The threshold current required to generate a motor response was assessed and a catheter inserted. Postoperative pain was assessed by recording the dose of analgesics to maintain visual analog score < 3 the next 48 hours. On demand patients received boluses of ropivacaine (2 mg/mL) via the catheter and/or analgesics in case of insufficient pain relief. Total postoperative ropivacaine dosage and analgesic consumption were recorded. About one year after the block patients were contacted to report their actual status by self-assessment.In 17 patients a catheter could be placed. In 7 patients placement of the catheter was difficult (several attempts, high electrical impedance). Patients with nerve block had lower analgesics consumption compared to patients without a block. Surprisingly, the 7 patients with "difficult" catheter-placement had the overall lowest ropivacaine and analgesics consumption compared to all other patients with or without peripheral block. No anesthesia related complications were reported by the questionnaire.In our small series catheter-based distal sciatic block within CMT patients had safely been used for pain relief up to three days. The infusion of local anesthetics via a catheter was not associated with any complication.
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CCR8 Signaling via CCL1 Regulates Responses of Intestinal IFN-γ Producing Innate Lymphoid CelIs and Protects From Experimental Colitis - Kang, Le; Schmalzl, Angelika; Leupold, Tamara; Gonzalez-Acera, Miguel; Atreya, Raja; Neurath, Markus; Becker, Christoph; Wirtz, Stefan (Frontiers in Immunology, 2021)
A diverse spectrum of immune cells populates the intestinal mucosa reflecting the continuous stimulation by luminal antigens. In lesions of patients with inflammatory bowel disease, an aberrant inflammatory process is characterized by a very prominent infiltrate of activated immune cells producing cytokines and chemokines. These mediators perpetuate intestinal inflammation or may contribute to mucosal protection depending on the cellular context. In order to further characterize this complex immune cell network in intestinal inflammation, we investigated the contribution of the chemokine receptor CCR8 to development of colitis using a mouse model of experimental inflammation. We found that CCR8−/− mice compared to wildtype controls developed strong weight loss accompanied by increased histological and endoscopic signs of mucosal damage. Further experiments revealed that this gut protective function of CCR8 seems to be selectively mediated by the chemotactic ligand CCL1, which was particularly produced by intestinal macrophages during colitis. Moreover, we newly identified CCR8 expression on a subgroup of intestinal innate lymphoid cells producing IFN-γ and linked a functional CCL1/CCR8 axis with their abundance in the gut. Our data therefore suggest that this pathway supports tissue-specific ILC functions important for intestinal homeostasis. Modulation of this regulatory circuit may represent a new strategy to treat inflammatory bowel disease in humans.
CRIS-Team Scopus Importer:2021-03-05
Keywords: CCR8; chemokines; cytokines; inflammatory bowel disease; innate immunity; innate lymphoid cell

CD101 inhibits the expansion of colitogenic T cells - Schey, Regina; Dornhoff, H.; Baier, J. L. C.; Purtak, M.; Opoka, R.; Koller, A. K.; Atreya, Raja; Rau, Tilman; Daniel, Christoph; Amann, Kerstin Ute; Bogdan, Christian; Mattner, Jochen (Mucosal Immunology, 2016)
CD101 exerts negative-costimulatory effects in vitro, but its function in vivo remains poorly defined. CD101 is abundantly expressed on lymphoid and myeloid cells in intestinal tissues, but absent from naïve splenic T cells. Here, we assessed the impact of CD101 on the course of inflammatory bowel disease (IBD). Using a T-cell transfer model of chronic colitis, we found that in recipients of naïve T cells from CD101(+/+) donors up to 30% of the recovered lymphocytes expressed CD101, correlating with an increased interleukin (IL)-2-mediated FoxP3 expression. Transfer of CD101(-/-) T cells caused more severe colitis and was associated with an expansion of IL-17-producing T cells and an enhanced expression of IL-2R?/? independently of FoxP3. The co-transfer of naïve and regulatory T cells (Treg) protected most effectively from colitis, when both donor and recipient mice expressed CD101. Although the expression of CD101 on T cells was sufficient for Treg-function and the inhibition of T-cell proliferation, sustained IL-10 production required additional CD101 expression by myeloid cells. Finally, in patients with IBD a reduced CD101 expression on peripheral and intestinal monocytes and CD4(+) T cells correlated with enhanced IL-17 production and disease activity. Thus, CD101 deficiency is a novel marker for progressive colitis and potential target for therapeutic intervention.
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CD14 Plays a Protective Role in Experimental Inflammatory Bowel Disease by Enhancing Intestinal Barrier Function - Buchheister, Stephanie; Buettner, Manuela; Basic, Marijana; Noack, Andreas; Breves, Gerhard; Buchen, Barbara; Keubler, Lydia M.; Becker, Christoph; Bleich, Andre (American Journal of Pathology, 2017)
Intestinal homeostasis disturbance through intestinal barrier disruption presumably plays a key role in inflammatory bowel disease (IBD) development. Genetic and candidate gene analyses in an Il10-deficient IBD mouse model system identified Cd14 as a potentially protective candidate gene. The role of Cd14 in colitis development was determined using dextran sulfate sodium (DSS)-induced acute and an Il10-deficiency-induced chronic model of intestinal inflammation. Intestinal permeability was investigated by fluorescein isothiocyanate-dextran uptake assay, quantitative RT-PCR analysis of tight junction proteins, myosin light chain kinase, and proinflammatory cytokine expression. Immunohistological staining of occludin, Ki-67, NF-κB-p65, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay was performed, and intestinal inflammation severity was evaluated histologically. Untreated B6-Cd14-/- mice and wild-type controls did not differ in intestinal barrier function. However, DSS-treated Cd14-deficient and B6-Il10-/-Cd14-/- mice exhibited more severe intestinal barrier disruption, with increased histological scores and proinflammatory cytokine expression, compared to controls. Therefore, Cd14 deficiency did not influence epithelial integrity under steady-state conditions but caused intestinal barrier dysfunction under inflammation. As expected, CD14 overexpression increased barrier integrity. No difference in intestinal epithelial NF-κB translocation was observed between the investigated groups. Intestinal myosin light chain kinase expression decreased in Cd14-deficient mice under steady-state conditions and in the chronic model, whereas no difference was detected in the DSS models. Thus, CD14 plays a protective role in IBD development by enhancing intestinal barrier function.
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CD4 T cells with identical TCR clonotypes show functional plasticity in a mouse model of relapsing-remitting colitis - De Albuquerque, Juliana Barreto; Chung, Cheong Kc Kwong; Von Werdt, Diego; Limenitakis, Julien P.; Keller, Irene; Gungor, Bilgi; Zundler, Sebastian; Van Gisbergen, Klaas Pjm; Macpherson, Andrew J.; Corazza, Nadia; Mueller, Christoph (EUROPEAN JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

CD83 expression is essential for Treg cell differentiation and stability - Döbbeler, Marina; Koenig, Christina; Krzyzak, Lena; Seitz, Christine; Wild, Andreas; Ulas, Thomas; Bassler, Kevin; Kopelyanskiy, Dmitry; Butterhof, Alina; Kuhnt, Christine; Kreiser, Simon; Stich, Lena; et al. (JCI Insight, 2018)
Foxp3-positive regulatory T cells (Tregs) are crucial for the maintenance of immune homeostasis and keep immune responses in check. Upon activation, Tregs are transferred into an effector state expressing transcripts essential for their suppressive activity, migration, and survival. However, it is not completely understood how different intrinsic and environmental factors control differentiation. Here, we present for the first time to our knowledge data suggesting that Treg-intrinsic expression of CD83 is essential for Treg differentiation upon activation. Interestingly, mice with Treg-intrinsic CD83 deficiency are characterized by a proinflammatory phenotype. Furthermore, the loss of CD83 expression by Tregs leads to the downregulation of Treg-specific differentiation markers and the induction of an inflammatory profile. In addition, Treg-specific conditional knockout mice showed aggravated autoimmunity and an impaired resolution of inflammation. Altogether, our results show that CD83 expression in Tregs is an essential factor for the development and function of effector Tregs upon activation. Since Tregs play a crucial role in the maintenance of immune tolerance and thus prevention of autoimmune disorders, our findings are also clinically relevant.
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CED per Sono erkennen und überwachen - Klett, Daniel (MMW Fortschritte der Medizin, 2019)
CRIS-Team Scopus Importer:2019-07-09
Keywords: Crohn’s disease; IBD; intestinal wall; sonography; ulcerative colitis

Cell death inhibition by KSHV - Murtadak, Vinay; Becker, Christoph; Stürzl, Michael (Aging-Us, 2015)
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Cell death in the gut epithelium and implications for chronic inflammation - Patankar, Jay V.; Becker, Christoph (Nature Reviews Gastroenterology & Hepatology, 2020)
The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. As the transit-amplifying progenitors of the intestinal epithelium generate 300 cells per crypt every day, regulated cell death and sloughing at the apical surface keeps the overall cell number in check. An aberrant increase in the rate of intestinal epithelial cell (IEC) death underlies instances of extensive epithelial erosion, which is characteristic of several intestinal diseases such as inflammatory bowel disease and infectious colitis. Emerging evidence points to a crucial role of necroptosis, autophagy and pyroptosis as important modes of programmed cell death in the intestine in addition to apoptosis. The mode of cell death affects tissue restitution responses and ultimately the long-term risks of intestinal fibrosis and colorectal cancer. A vicious cycle of intestinal barrier breach, misregulated cell death and subsequent inflammation is at the heart of chronic inflammatory and infectious gastrointestinal diseases. This Review discusses the underlying molecular and cellular underpinnings that control programmed cell death in IECs, which emerge during intestinal diseases. Translational aspects of cell death modulation for the development of novel therapeutic alternatives for inflammatory bowel diseases and colorectal cancer are also discussed.
CRIS-Team Scopus Importer:2020-07-24

Cell Migration as a therapeutic Target Process - Zundler, Sebastian (Drug Research, 2021)
CRIS-Team WoS Importer:2021-12-03

Cellular and humoral immune responses to SARS-CoV-2 vaccination in patients after CD19.CAR T-cell therapy - Reimann, Hannah; Kremer, Anita; Blumenberg, Viktoria; Schmidt, Katja; Aigner, Michael; Jacobs, Benedikt; Eisenhauer, Nina; Kämpf, Alina; Rösler, Wolf; Kharboutli, Soraya; Mougiakakos, Dimitrios; Lang, Vanessa; et al. (Blood Advances, 2023)
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Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8. - Günther, Claudia; Martini, Eva; He, Guiwei; Amann, Kerstin Ute; He, You-Wen; Neurath, Markus; Becker, Christoph; et al. (Gastroenterology, 2013)
The intestinal epithelium generates a barrier that protects mammals from potentially harmful intestinal contents, such as pathogenic bacteria. Dysregulation of epithelial cell death has been implicated in barrier dysfunction and in the pathogenesis of intestinal inflammation. We investigated mechanisms of cell-death regulation in the intestinal epithelium of mice. Conditional knockout mice (either inducible or permanent) with deletion of cellular FLICE-inhibitory protein (cFlip) or caspase-8 in the intestinal epithelium were analyzed by histology and high-resolution endoscopy. We assessed the effects of cFlip or caspase-8 deficiency on intestinal homeostasis. Expression of cFlip in the intestinal epithelium was required for constitutive activation of caspase-8 under steady-state conditions. Intestinal expression of cFlip was required for development; disruption of the gene encoding cFlip from the intestinal epithelium (cFlip(fl/fl) VillinCre(+) mice) resulted in embryonic lethality. When cFlip was deleted from the intestinal epithelium of adult mice (cFlip(iΔIEC) mice), the animals died within a few days from severe tissue destruction, epithelial cell death, and intestinal inflammation. Death of cFlip-depleted intestinal epithelial cells was regulated extrinsically and required the presence of death receptor ligands, such as tumor necrosis factor-α and CD95 ligand, but was independent of receptor-interacting protein 3. cFlip deficiency was associated with strong up-regulation of caspase-8 and caspase-3 activity and excessive apoptosis in intestinal crypts. cFlip is required for intestinal tissue homeostasis in mice. It controls the level of activation of caspase-8 to promote survival of intestinal epithelial cells. BACKGROUND & AIMS METHODS RESULTS CONCLUSIONS
Keywords: CASP8; CFLAR; Fadd; Fadd-Like Apoptosis Regulator; Fas-associated protein with death domain; IEC; NEMO; NF-κB essential modulator; Rip; TNF; TUNEL; cFLIP; cellular FLICE-like inhibitory protein; intestinal epithelial cell; receptor interacting protein; terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling; tumor necrosis factor

Cellular Mechanisms of Etrolizumab Treatment in Inflammatory Bowel Disease - Lichnog, Charlotte; Klabunde, Sha; Becker, Emily; Fuh, Franklin; Tripal, Philipp; Atreya, Raja; Klenske, Entcho; Erickson, Rich; Chiu, Henry; Reed, Chae; Chung, Shan; Neufert, Clemens; et al. (Frontiers in Pharmacology, 2019)
Background: Anti-integrin therapy is a new frontline strategy in the treatment of inflammatory bowel diseases (IBD). The anti-beta 7 integrin antibody etrolizumab is currently being investigated for safety and efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in several phase III trials. Mechanistically, etrolizumab is known to block beta 7 integrin ligand binding and reduces intestinal trafficking of beta 7-expressing cells. Etrolizumab blocks beta 7 integrin ligand binding and reduces beta 7-positive lymphocyte migration and retention in the inflamed gut mucosa, but the exact mechanisms by which this inhibition occurs are not fully understood.
CRIS-Team WoS Importer:2019-02-21

CELLULAR SENESCENCE OF CD4+T CELLS IN THE ADAPTIVE IMMUNE RESPONSE AGAINST COLORECTAL CANCER - Thoma, Oana-Maria; Neurath, Markus; Waldner, Maximilian (2019)
EVALuna2:209000

Cetuximab-Induced Aseptic Meningitis in a Patient with Colorectal Cancer: A Case Report and Review of Literature - Jäger, Jakob; Sprügel, Maximilian; Brunner, Tamara; Uhl, Martin; Schwab, Stefan; Vitali, Francesco; Wein, Axel; Volbers, Bastian (Case Reports in Neurology, 2022)
Cetuximab is a chimeric IgG1 monoclonal antibody against epidermal growth factor receptor. It is approved by the European medical agency for the treatment of RAS wild-type metastatic colorectal cancer and metastatic squamous cell cancer of the head and neck. Few cases of aseptic meningitis, primarily associated with the first administration of cetuximab in patients with squamous cell cancer, have been reported. So far, there was only 1 case in a patient with metastatic colorectal cancer. We report on a 50-year-old Caucasian patient with metastatic rectum carcinoma who suffered from headache, fever, and neck stiffness 3 h after the first administration of cetuximab (400 mg/m(2)). CSF examination revealed an excessive pleocytosis with a white blood cell count of 2,433/mu L. He was diagnosed with cetuximab-induced aseptic meningitis since clinical symptoms and CSF pleocytosis resolved within days, and further diagnostic workup revealed no infectious cause. Cetuximab-induced aseptic meningitis is a rare and severe drug reaction with predominance in treating squamous cell cancer of the head and neck. Clinical presentation and CSF findings suggest acute meningoencephalitis. In all reported cases, the course of the disease was benign and self-limited. Empiric antimicrobial and antiviral therapy are suggested until infectious causes can be ruled out. A lower dosage of cetuximab and a premedication including antihistamines and glucocorticosteroids may lower the risk of a re-occurrence if cetuximab therapy is continued.
CRIS-Team WoS Importer:2023-01-27

CEUS in hepatocellular carcinoma and intrahepatic cholangiocellular carcinoma in 320 patients - early or late washout matters: a subanalysis of the DEGUM multicenter trial - Wildner, Dane; Bernatik, T.; Greis, C.; Seitz, K.; Neurath, Markus; Strobel, Deike (Ultraschall in der Medizin, 2015)
The aim of the study was the comparison of tumor vascularization and contrast enhancement in contrast-enhanced ultrasound (CEUS) for the characterization of hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (ICC). We present data of the subpopulations HCC and ICC examined in the DEGUM multicenter trial for the characterization of focal liver lesions in clinical practice.Based on the data of the DEGUM multicenter trial (1349 patients), all patients with histologically proven HCC (n = 278) and ICC (n = 42) were analyzed. The vascularity pattern and contrast enhancement pattern during the arterial, portal-venous and late phase were compared.An underlying liver cirrhosis was found in 214/278 patients with HCC (76.9 %) and 7/42 patients with ICC (16.7 %). In CEUS, HCC showed a global arterial hyperenhancement compared to ICC (HCC: tumor center: 60.3 %; tumor periphery: 75 %; ICC: tumor center: 16.7 %; tumor periphery: 40.5 %). ICC showed an initial contrast enhancement primarily at the tumor periphery (ICC: 85.7 % vs. HCC: 61 %) followed by an early portal-venous contrast washout in the tumor center (ICC: 85.8 % vs. HCC: 49.8 %) and tumor periphery (ICC: 66.7 % vs. HCC: 32.6 %). HCC showed a delayed contrast washout (late phase hypoenhancement: HCC: 75 % vs. ICC: 92.9 %).ICCs are rare in cirrhotic livers. CEUS can demonstrate differences in the vascularization patterns between HCC and ICC. HCC showed an arterial global hyperenhancement and delayed contrast washout in the late phase. ICCs are characterized by an arterial contrast enhancement at the tumor periphery with early contrast washout of the vascularized parts of the lesions in the portal-venous and late phase.
EVALuna2:1988

Challenges for the crosstalk between endoscopists and pathologists - Neurath, Markus; Vieth, Michael (Endoscopy, 2019)
CRIS-Team WoS Importer:2019-03-15

Challenging a Preconception: Optoacoustic Spectrum Differs from the Optical Absorption Spectrum of Proteins and Dyes for Molecular Imaging - Werner, Juan Pablo Fuenzalida; Huang, Yuanhui; Mishra, Kanuj; Janowski, Robert; Vetschera, Paul; Heichler, Christina; Chmyrov, Andriy; Neufert, Clemens; Niessing, Dierk; Ntziachristos, Vasilis; Stiel, Andre C. (Analytical Chemistry, 2020)
Optoacoustic (photoacoustic) imaging has seen marked advances in detection and data analysis, but there is less progress in understanding the photophysics of common optoacoustic contrast agents. This gap blocks the development of novel agents and the accurate analysis and interpretation of multispectral optoacoustic images. To close it, we developed a multimodal laser spectrometer (MLS) to enable the simultaneous measurement of optoacoustic, absorbance, and fluorescence spectra. Herein, we employ MLS to analyze contrast agents (methylene blue, rhodamine 800, Alexa Fluor 750, IRDye 800CW, and indocyanine green) and proteins (sfGFP, mCherry, mKate, HcRed, iRFP720, and smURFP). We found that the optical absorption spectrum does not correlate with the optoacoustic spectrum for the majority of the analytes. We determined that for dyes, the transition underlying an aggregation state has more optoacoustic signal generation efficiency than the monomer transition. For proteins we found a favored optoacoustic relaxation that stems from the neutral or zwitterionic chromophores and unreported photoswitching behavior of tdTomato and HcRed. We then crystalized HcRed in its photoswitch optoacoustic state, confirming structurally the change in isomerization with respect to HcReds' fluorescence state. Finally, on the example of the widely used label tdTomato and the dye indocyanine green, we show the importance of correct photophysical (e.g., spectral and kinetic) information as a prerequisite for spectral-unmixing for in vivo imaging.
CRIS-Team WoS Importer:2020-08-28

Changes in Gastrointestinal Microbiome Composition in PD: A Pivotal Role of Covariates - Cosma-Grigorov, Alexandra; Meixner, Holger; Mrochen, Anne; Wirtz, Stefan; Winkler, Jürgen; Marxreiter, Franz (Frontiers in Neurology, 2020)
Altered gut microbiota may trigger or accelerate alpha-synuclein aggregation in the enteric nervous system in Parkinson's disease (PD). While several previous studies observed gut microbiota alterations in PD, findings like diversity indices, and altered bacterial taxa itself show a considerable heterogeneity across studies. We recruited 179 participants, of whom 101 fulfilled stringent inclusion criteria. Subsequently, the composition of the gut microbiota in 71 PD patients and 30 healthy controls was analyzed, sequencing V3–V4 regions of the bacterial 16S ribosomal RNA gene in fecal samples. Our goal was (1) to evaluate whether gut microbiota are altered in a southern German PD cohort, (2) to delineate the influence of disease duration, stage, and motor impairment, and (3) to investigate the influence of PD associated covariates like constipation and coffee consumption. Aiming to control for a large variety of covariates, strict inclusion criteria were applied. Finally, propensity score matching was performed to correct for, and to delineate the effect of remaining covariates (non-motor symptom (NMS) burden, constipation, and coffee consumption) on microbiota composition. Prior to matching altered abundances of distinct bacterial classes, orders, families, and genera were observed. Both, disease duration, and stage influenced microbiome composition. Interestingly, levodopa equivalent dose influenced the correlation of taxa with disease duration, while motor impairment did not. Applying different statistical tests, and after propensity score matching to control for NMS burden, constipation and coffee consumption, Faecalibacterium and Ruminococcus were most consistently reduced in PD compared to controls. Taken together, similar to previous studies, alterations of several taxa were observed in PD. Yet, further controlling for PD associated covariates such as constipation and coffee consumption revealed a pivotal role of these covariates. Our data highlight the impact of these PD associated covariates on microbiota composition in PD. This suggests that altered microbiota may mediate the protective effect of i.e., coffee consumption and the negative effect of constipation in PD.
CRIS-Team Scopus Importer:2020-10-16
Keywords: biomarker; constipation; covariates; gut; microbiome; non-motor symptoms; Parkinson's disease

Changes in HbA(1c), BMI and rates of severe hypoglycaemia in 4,113 adults with type 1 or type 2 diabetes using continuous glucose monitoring systems - Lanzinger, S.; Best, F.; Bergmann, Tanja; Laimer, M.; Lipovsky, B.; Danne, T.; Zimny, S.; Bramlage, P.; Holl, R. W. (DIABETOLOGIA, 2021)
CRIS-Team WoS Importer:2021-10-01

Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome - Weickert, Martin O.; Kaltsas, Gregory; Hoersch, Dieter; Lapuerta, Pablo; Pavel, Marianne Ellen; Valle, Juan W.; Caplin, Martyn E.; Bergsland, Emily; Kunz, Pamela L.; Anthony, Lowell B.; Grande, Enrique; Oberg, Kjell; et al. (Clinical Therapeutics, 2018)
PURPOSE: In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m2) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival. METHODS: Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan. FINDINGS: In 120 patients with weight data available, weight gain ≥3% was observed in 2 of 39 patients (5.1%) taking placebo TID, 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss ≥3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status. IMPLICATIONS: Up to 32.5% of patients treated with telotristat ethyl experienced significant, dose-dependent weight gain, associated with reduced diarrhea severity and improved biochemical and metabolic parameters. Improved nutritional status could be an additional aspect of telotristat ethyl efficacy among patients with functioning metastatic neuroendocrine tumors. ClinicalTrials.gov identifier: NCT01677910.
EVALuna2:208002

Characterization and Expansion of Autologous GMP-ready Regulatory T Cells for TREG-based Cell Therapy in Patients with Ulcerative Colitis - Voskens, Caroline J.; Fischer, Anika; Roessner, Susanne; Lorenz, Carmen; Hirschmann, Simon; Atreya, Raja; Neufert, Clemens; Atreya, Imke; Neurath, Markus; Schuler, Gerold (Inflammatory Bowel Diseases, 2017)
BACKGROUND: A local imbalance between regulatory (Treg) and effector T cells is believed to play a major role in gut-specific inflammation, including ulcerative colitis (UC). Restoration of this balance through an adoptive Treg transfer is an attractive new treatment approach in patients who are refractory to current standard therapies. It was our goal to develop a Good Manufacturing Practices (GMP)-conform protocol for expansion of UC Treg cells as a rational backbone for future studies on Treg therapy in UC. METHODS: CD25 blood T cells derived from patients with UC were ex vivo expanded in the presence of IL-2, rapamycin, and anti-CD3/anti-CD28 expander beads using a GMP-conform protocol. Cells were subsequently assessed for stability and function. RESULTS: Patient-derived ex vivo rapamycin-expanded GMP-ready CD25 cells were polyclonal, hypomethylated at intron 1 of the FoxP3 locus, and suppressive in carboxyfluorescein succinimidyl ester-dilution assays against autologous peripheral blood-derived and allogeneic colon-derived responder cells. Function was mediated by soluble factors, including toxic granules. In addition to CD4 T cells, suppressive hypermethylated CD8 T-cell subsets were also induced during the expansion process. CONCLUSIONS: Patient-derived rapamycin-expanded CD25 cells are stable and functional, and as such, ready to serve in a phase I dose-escalation safety study in UC.
EVALuna2:33805

Characterization and treatment of persistent hepatocellular secretory failure - Van Dijk, Remco; Kremer, Andreas; Smit, Wouter; Van Den Elzen, Bram; Van Gulik, Thomas; Gouma, Dirk; Lameris, Johan S.; Bikker, Hennie; Enemuo, Valentine; Stokkers, Pieter C. F.; Feist, Mark; Bosma, Piter; et al. (Liver International, 2015)
Hepatocellular secretory failure induced by drugs, toxins or transient biliary obstruction may sometimes persist for months after removal of the initiating factor and may then be fatal without liver transplantation. We characterized patients with severe persistent hepatocellular secretory failure (PHSF) and treated them with the pregnane X receptor (PXR) agonist, rifampicin. We also studied the effect of rifampicin on PXR-dependent expression of genes involved in biotransformation and secretion in vitro.Thirteen patients (age 18-81 years, 6 male) with hepatocellular secretory failure that persisted after removal of the inducing factor (drugs/toxin: 9) or biliary obstruction (4) were identified over 6 years. Six of these patients were screened for ATP8B1 or ABCB11 mutations. All were treated with rifampicin (300 mg daily) for 1-10 weeks. Expression of genes involved in biotransformation and secretion was determined by rtPCR in human hepatocytes and intestinal cells incubated with rifampicin (10 ?mol/L).Serum bilirubin of patients with PHSF ranged from 264 to 755 ?mol/L. Normal ?GT was found in 10/13 patients of whom 3/6 tested positive for ATP8B1/ABCB11 mutations. Serum bilirubin declined to <33 ?mol/L after 1-10 weeks of rifampicin treatment. In vitro, rifampicin PXR-dependently upregulated biotransformation phase 1 (CYP3A4), phase 2 (UGT1A1) and phase 3 (MRP2) enzymes/carriers as well as the basolateral bile salt exporter OST?.Persistent hepatocellular secretory failure may develop in carriers of transporter gene mutations. In severe cases, rifampicin may represent an effective therapeutic option of PHSF. PXR-dependent induction of CYP3A4, UGT1A1, MRP2 and OST? could contribute to the anticholestatic effect of rifampicin in PHSF.
EVALuna2:1999

Characterization of CD4+ T cells primed and boosted by MHCII primary uveal melanoma cell-based vaccines. - Kittler, Julia; Sommer, Jonas; Fischer, Anika; Britting, Sabine; Karg, Margarete; Bock, Barbara; Atreya, Imke; Heindl, Ludwig M.; Mackensen, Andreas; Bosch, Jacobus J. (Oncotarget, 2019)
Uveal melanoma is the most common primary malignancy of the eye in adults. Despite significant improvements in treatment of the primary tumor, to date none of these therapies prevent metastatic disease or improve overall survival. We are exploring immunotherapeutic options for metastatic uveal melanoma using MHC II uveal melanoma cell-based vaccines that target the activation of tumor-reactive CD4+ T cells. Previously, we showed that these uveal melanoma cell-based vaccines activate CD4+ T cells within total peripheral blood lymphocytes (PBMC). Since PBMC include professional antigen presenting cells, we now demonstrate that Mel202/DR1/CD80 vaccine cells directly activate a diverse repertoire of purified, naïve CD4+ T cells. The activated CD4+ T cells proliferated, secreted high amounts of interferon gamma (IFNγ) and produced a heterogeneous profile of Th1, Th2 and Th17 cytokines. Analysis of the TCR-Vβ-repertoire showed that a polyclonal T cell response was induced, suggesting the capacity of vaccine-activated CD4+ T cells to target multiple tumor (neo)antigens. In addition, a subset of the responding CD4+ T cells expressed forkhead box protein P3 (FoxP3), indicating that although a regulatory component of the vaccine-activated CD4+ T cell response was induced, the anti-tumor vaccine response was not limited by these regulatory CD4+ T cells. Finally, Mel202/DR1/CD80 uveal melanoma vaccine cells expressed the intercellular adhesion molecule 1 (ICAM-1) that was pivotal for CD4+ T cell activation via lymphocyte function-associated antigen 1(LFA-1). In conclusion, MHC II uveal melanoma vaccines activate purified CD4+ T cells and may serve as a novel immunotherapy for uveal melanoma patients.
EVALuna2:184245
Keywords: uveal melanoma; tumor immunity; T cell activation; CD4+ T cells; ICAM-1

Characterization of CD4+ T cells primed and boosted by MHCII primary uveal melanoma cell-based vaccines - Kittler, Julia; Sommer, Jonas; Fischer, Anika; Britting, Sabine; Karg, Margarete; Bock, Barbara; Atreya, Imke; Heindl, Ludwig M.; Mackensen, Andreas; Bosch, Jacobus J. (Oncotarget, 2019)
Uveal melanoma is the most common primary malignancy of the eye in adults. Despite significant improvements in treatment of the primary tumor, to date none of these therapies prevent metastatic disease or improve overall survival. We are exploring immunotherapeutic options for metastatic uveal melanoma using MHC II uveal melanoma cell-based vaccines that target the activation of tumor-reactive CD4+ T cells. Previously, we showed that these uveal melanoma cell-based vaccines activate CD4+ T cells within total peripheral blood lymphocytes (PBMC). Since PBMC include professional antigen presenting cells, we now demonstrate that Mel202/ DR1/CD80 vaccine cells directly activate a diverse repertoire of purified, naïve CD4+ T cells. The activated CD4+ T cells proliferated, secreted high amounts of interferon gamma (IFNγ) and produced a heterogeneous profile of Th1, Th2 and Th17 cytokines. Analysis of the TCR-Vβ-repertoire showed that a polyclonal T cell response was induced, suggesting the capacity of vaccine-activated CD4+ T cells to target multiple tumor (neo)antigens. In addition, a subset of the responding CD4+ T cells expressed forkhead box protein P3 (FoxP3), indicating that although a regulatory component of the vaccine-activated CD4+ T cell response was induced, the anti-tumor vaccine response was not limited by these regulatory CD4+ T cells. Finally, Mel202/DR1/CD80 uveal melanoma vaccine cells expressed the intercellular adhesion molecule 1 (ICAM-1) that was pivotal for CD4+ T cell activation via lymphocyte function-associated antigen 1(LFA-1). In conclusion, MHC II uveal melanoma vaccines activate purified CD4+ T cells and may serve as a novel immunotherapy for uveal melanoma patients.
CRIS-Team Scopus Importer:2019-06-07
Keywords: CD4+ T cells; ICAM-1; T cell activation; Tumor immunity; Uveal melanoma

Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy - Angelova, Mihaela; Charoentong, Pornpimol; Hackl, Hubert; Fischer, Maria L.; Snajder, Rene; Krogsdam, Anne M.; Waldner, Maximilian; Bindea, Gabriela; Mlecnik, Bernhard; Galon, Jerome; Trajanoski, Zlatko (Genome biology, 2015)
While large-scale cancer genomic projects are comprehensively characterizing the mutational spectrum of various cancers, so far little attention has been devoted to either define the antigenicity of these mutations or to characterize the immune responses they elicit. Here we present a strategy to characterize the immunophenotypes and the antigen-ome of human colorectal cancer.We apply our strategy to a large colorectal cancer cohort (n = 598) and show that subpopulations of tumor-infiltrating lymphocytes are associated with distinct molecular phenotypes. The characterization of the antigenome shows that a large number of cancer-germline antigens are expressed in all patients. In contrast, neo-antigens are rarely shared between patients, indicating that cancer vaccination requires individualized strategy. Analysis of the genetic basis of the tumors reveals distinct tumor escape mechanisms for the patient subgroups. Hypermutated tumors are depleted of immunosuppressive cells and show upregulation of immunoinhibitory molecules. Non-hypermutated tumors are enriched with immunosuppressive cells, and the expression of immunoinhibitors and MHC molecules is downregulated. Reconstruction of the interaction network of tumor-infiltrating lymphocytes and immunomodulatory molecules followed by a validation with 11 independent cohorts (n = 1,945) identifies BCMA as a novel druggable target. Finally, linear regression modeling identifies major determinants of tumor immunogenicity, which include well-characterized modulators as well as a novel candidate, CCR8, which is then tested in an orthologous immunodeficient mouse model.The immunophenotypes of the tumors and the cancer antigenome remain widely unexplored, and our findings represent a step toward the development of personalized cancer immunotherapies.
EVALuna2:2007