Teleendoskopie im Gigabit Testbed Süd (Teilprojekt 1.15): Eine prospektive Anwendungsstudie - Rabenstein, Thomas; Maiß, Jürgen; Naegele-Jackson, Susanne; Liebl, Kersten; Radespiel-Tröger, Martin; Rosette, R.; Holleczek, Peter; Hahn, Eckhart Georg; Sackmann, Michael (Biomedizinische Technik 2001, 2001)
UnivIS-Import:2015-04-16:Pub.2001.zwiss.rrze.ksys.teleen

Teleendoskopie im Gigabit Testbed Süd (Teilprojekt 1.15): Einfluß von Datenkomprimierung, Bandbreite und Bildstörungen auf die medizinisch-diagnostische Beurteilbarkeit des endoskopischen Videobildes - Rabenstein, Thomas; Maiß, Jürgen; Naegele-Jackson, Susanne; Liebl, Kersten; Radespiel-Tröger, Martin; Rosette, R.; Holleczek, Peter; Hahn, Eckhart Georg; Sackmann, Michael (Biomedizinische Technik. Biomedical engineering, 2001)

Teleendoskopie im Gigabit Testbed Süd (Teilprojekt 1.15): Einfluss von Datenkomprimierung, Bandbreite und Bildstörungen auf die medizinisch-diagnostische Beurteilbarkeit des endoskopischen Videobildes - Rabenstein, Thomas; Maiß, Jürgen; Naegele-Jackson, Susanne; Liebl, Kersten; Radespiel-Tröger, Martin; Rosette, R.; Holleczek, Peter; Hahn, Eckhart; Sackmann, Michael (Biomedizinische Technik 2001, 2001)
UnivIS-Import:2017-12-18:Pub.2001.zwiss.rrze.ksys.einflu

Telomerase deficiency reflects age-associated changes in CD4+T cells - Matthe, Diana; Thoma, Oana-Maria; Sperka, Tobias; Neurath, Markus; Waldner, Maximilian (Immunity & Ageing, 2022)
Background Amongst other systemic changes, aging leads to an immune dysfunction. On the molecular level, a hallmark of aging is telomere shortening. The functional relevance of telomerase, an enzyme capable of elongating telomeres in T cells upon antigen stimulation, is not fully understood. Studying the impact of telomere shortening on CD4+ T cells and especially Th1 effector function can provide a better understanding on immune dysfunctions in elderly. Results We investigated T cell numbers and differentiation in telomerase-deficient (mTerc-/-) mice under steady-state conditions and the functional role of telomerase in CD4+ T cells using in vitro stimulation and Th1 polarization protocols by comparing T cells from mTerc-/- and control mice. We report reduced relative CD4+ T cell numbers in blood and secondary lymphoid organs and a relative decline in the naive T cell population in thymus, blood and spleen of mTerc-/- mice compared to control mice. Importantly, after in vitro polarization, mTerc-/- G3 CD4+ T cells showed higher numbers of IFN gamma-producing cells and reduced expression of CD28. Notably, telomerase-deficient T cells were more susceptible to inhibition of Th1 polarization by IL-6 in vitro. These results demonstrate that telomerase deficiency recapitulates several changes of CD4+ T cells seen in aged humans regarding the naive T cell population, expression of CD28 and cytokine production. Conclusion Our data suggest that telomere shortening could play a key role in the aging of T cell immunity, with clinical implications for immune diseases and tumor development and that mTerc-/- mice are a suitable model to study aging-related defects of adaptive immunity.
CRIS-Team WoS Importer:2022-04-08

Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial - Pavel, Marianne Ellen; Gross, David J.; Benavent, Marta; Perros, Petros; Srirajaskanthan, Raj; Warner, Richard R. P.; Kulke, Matthew H.; Anthony, Lowell B.; Kunz, Pamela L.; Hoersch, Dieter; Weickert, Martin O.; Lapuerta, Pablo; et al. (Endocrine-Related Cancer, 2018)
Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients (N = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges-Lehmann estimators of median treatment differences from placebo of -54.0% (95% confidence limits, -85.0%, -25.1%, P < 0.001) and -89.7% (95% confidence limits, -113.1%, -63.9%, P < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659).
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Temporally Distinct Functions of the Cytokines IL-12 and IL-23 Drive Chronic Colon Inflammation in Response to Intestinal Barrier Impairment - Eftychi, Christina; Schwarzer, Robin; Vlantis, Katerina; Wachsmuth, Laurens; Basic, Marijana; Wagle, Prerana; Neurath, Markus; Becker, Christoph; Bleich, André; Pasparakis, Manolis (Immunity, 2019)
Epithelial barrier defects are implicated in the pathogenesis of inflammatory bowel disease (IBD); however, the role of microbiome dysbiosis and the cytokine networks orchestrating chronic intestinal inflammation in response to barrier impairment remain poorly understood. Here, we showed that altered Schaedler flora (ASF), a benign minimal microbiota, was sufficient to trigger colitis in a mouse model of intestinal barrier impairment. Colitis development required myeloid-cell-specific adaptor protein MyD88 signaling and was orchestrated by the cytokines IL-12, IL-23, and IFN-γ. Colon inflammation was driven by IL-12 during the early stages of the disease, but as the mice aged, the pathology shifted toward an IL-23-dependent inflammatory response driving disease chronicity. These findings reveal that IL-12 and IL-23 act in a temporally distinct, biphasic manner to induce microbiota-driven chronic intestinal inflammation. Similar mechanisms might contribute to the pathogenesis of IBD particularly in patients with underlying intestinal barrier defects.
CRIS-Team Scopus Importer:2019-08-23
Keywords: altered Schaedler flora; dysbiosis; IFN-γ; IL-12; IL-23; inflammatory bowel disease; intestinal barrier impairment; intestinal inflammation; microbiota; MyD88

Teufelskreis aus Jucken und Kratzen - Kremer, Andreas (Pharmazeutische Zeitung, 2019)
CRIS-Team Scopus Importer:2019-11-12

TGF beta-Dependent Upregulation of XIAP Fosters Fibroblast Activation and Tissue Fibrosis By Promoting Canonical Wnt Signaling - Bergmann, Christina; Hallenberger, Ludwig; Brandt, Adrian; Merlevede, Benita; Dees, Clara; Chen, Chih-Wei; Beyer, Christian; Distler, Oliver; Schett, Georg; Distler, Jörg (2017)
EVALuna2:33427

TGFβ and the Tumor Microenvironment in Colorectal Cancer - Waldner, Maximilian; Neurath, Markus (Cells, 2023)
Growing evidence supports an important role of the tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC). Resident cells such as fibroblasts or immune cells infiltrating into the TME maintain continuous crosstalk with cancer cells and thereby regulate CRC progression. One of the most important molecules involved is the immunoregulatory cytokine transforming growth factor-β (TGFβ). TGFβ is released by various cells in the TME, including macrophages and fibroblasts, and it modulates cancer cell growth, differentiation, and cell death. Mutations in components of the TGF pathway, including TGFβ receptor type 2 or SMAD4, are among the most frequently detected mutations in CRC and have been associated with the clinical course of disease. Within this review, we will discuss our current understanding about the role of TGFβ in the pathogenesis of CRC. This includes novel data on the molecular mechanisms of TGFβ signaling in TME, as well as possible strategies for CRC therapy targeting the TGFβ pathway, including potential combinations with immune checkpoint inhibitors.
CRIS-Team Scopus Importer:2023-05-12
Keywords: colorectal cancer; immune response; SMAD4; TGFβ; tumor microenvironment

Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell-Extrinsic Manner - Buchele, Vera; Konein, Patrick; Vogler, Tina; Kunert, Timo; Enderle, Karin; Khan, Hanif; Büttner-Herold, Maike; Lehmann, Christian; Amon, Lukas; Wirtz, Stefan; Dudziak, Diana; Neurath, Markus; et al. (Frontiers in Immunology, 2021)
Inflammatory bowel diseases (IBDs) are characterized by chronic, inflammatory gastrointestinal lesions and often require life-long treatment with immunosuppressants and repetitive surgical interventions. Despite progress in respect to the characterization of molecular mechanisms e.g. exerted by TNF-alpha, currently clinically approved therapeutics fail to provide long-term disease control for most patients. The transcription factor interferon regulatory factor 4 (IRF4) has been shown to play important developmental as well as functional roles within multiple immune cells. In the context of colitis, a T cell-intrinsic role of IRF4 in driving immune-mediated gut pathology is established. Here, we conversely addressed the impact of IRF4 inactivation in non-T cells on T cell driven colitis in vivo. Employing the CD4+CD25− naïve T cell transfer model, we found that T cells fail to elicit colitis in IRF4-deficient compared to IRF4-proficient Rag1−/− mice. Reduced colitis activity in the absence of IRF4 was accompanied by hampered T cell expansion both within the mesenteric lymph node (MLN) and colonic lamina propria (cLP). Furthermore, the influx of various myeloids, presumably inflammation-promoting cells was abrogated overall leading to a less disrupted intestinal barrier. Mechanistically, gene profiling experiments revealed a Th17 response dominated molecular expression signature in colon tissues of IRF4-proficient, colitic Rag1−/− but not in colitis-protected Rag1−/−Irf4−/− mice. Colitis mitigation in Rag1−/−Irf4−/− T cell recipients resulted in reduced frequencies and absolute numbers of IL-17a-producing T cell subsets in MLN and cLP possibly due to a regulation of conventional dendritic cell subset 2 (cDC2) known to impact Th17 differentiation. Together, extending the T cell-intrinsic role for IRF4 in the context of Th17 cell driven colitis, the provided data demonstrate a Th17-inducing and thereby colitis-promoting role of IRF4 through a T cell-extrinsic mechanism highlighting IRF4 as a putative molecular master switch among transcriptional regulators driving immune-mediated intestinal inflammation through both T cell-intrinsic and T cell-extrinsic mechanisms. Future studies need to further dissect IRF4 controlled pathways within distinct IRF4-expressing myeloid cell types, especially cDC2s, to elucidate the precise mechanisms accounting for hampered Th17 formation and, according to our data, the predominant mechanism of colitis protection in Rag1−/−Irf4−/− T cell receiving mice.
CRIS-Team Scopus Importer:2021-02-26
Keywords: inflammatory bowel disease (IBD); interferon regulatory factor 4 (IRF4); intestinal inflammation; myeloid cells; Th17

Th2-dependent disappearance and phenotypic conversion of mouse alveolar macrophages - Dietschmann, Axel; Ruhl, Andreas; Murray, Peter J.; Günther, Claudia; Becker, Christoph; Fallon, Padraic; Vöhringer, David (European Journal of Immunology, 2023)
Alveolar macrophages (alvMs) play an important role for maintenance of lung function by constant removal of cellular debris in the alveolar space. They further contribute to defense against microbial or viral infections and limit tissue damage during acute lung injury. alvMs arise from embryonic progenitor cells, seed the alveoli before birth, and have life-long self-renewing capacity. However, recruited monocytes may also help to restore the alvM population after depletion caused by toxins or influenza virus infection. At present, the population dynamics and cellular plasticity of alvMs during allergic lung inflammation is poorly defined. To address this point, we used a mouse model of Aspergillus fumigatus-induced allergic lung inflammation and observed that Th2-derived IL-4 and IL-13 caused almost complete disappearance of alvMs. This effect required STAT6 expression in alvMs and also occurred in various other settings of type 2 immunity-mediated lung inflammation or administration of IL-4 complexes to the lung. In addition, Th2 cells promoted conversion of alvMs to alternatively activated macrophages and multinucleated giant cells. Given the well-established role of alvMs for maintenance of lung function, this process may have implications for resolution of inflammation and tissue homeostasis in allergic asthma.
CRIS-Team Scopus Importer:2023-11-03
Keywords: Allergic asthma; Alternatively activated macrophages; Alveolar macrophages; Aspergillus; Multinucleated giant cells; STAT6

Th9 cells in immunity and immunopathological diseases - Neurath, Markus; Kaplan, Mark H. (Seminars in Immunopathology, 2017)
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Th9 cells in inflammatory bowel diseases - Weigmann, Benno; Neurath, Markus (Seminars in Immunopathology, 2017)
Inflammatory bowel diseases are chronic, relapsing, immunologically mediated disorders of the gastrointestinal tract. Emerging evidence suggests a critical functional role of transcription factors and T cell-related cytokines in ulcerative colitis and Crohn's disease. Gut-residing T cells from patients with inflammatory bowel disease produce high amounts of IL-9. Experimental models of colitis highlighted that IL-9-producing T cells critically interfered with an intact barrier function of the intestinal epithelium by impacting cellular proliferation and tight junction molecules. The blockade of IL-9 was suited to significantly ameliorate the disease activity and severity in experimental models of inflammatory bowel disease thereby suggesting that targeting IL-9 might function as a novel targeted approach for therapy.
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TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells - Gerlach, Katharina; Hwang, Youyi; Nikolaev, Alexej; Atreya, Raja; Dornhoff, Heike; Steiner, Stefanie; Lehr, Hans-Anton; Wirtz, Stefan; Waisinan, Ari; Rosenbauer, Frank; Mckenzie, Andrew N. J.; Weigmann, Benno; et al. (Nature Immunology, 2014)
The molecular checkpoints that drive inflammatory bowel diseases are incompletely understood. Here we found more T cells expressing the transcription factor PU.1 and interleukin 9 (IL-9) in patients with ulcerative colitis. In an animal model, citrine reporter mice had more IL-9-expressing mucosal T cells in experimental oxazolone-induced colitis. IL-9 deficiency suppressed acute and chronic colitis. Mice with PU.1 deficiency in T cells were protected from colitis, whereas treatment with antibody to IL-9 suppressed colitis. Functionally, IL-9 impaired intestinal barrier function and prevented mucosal wound healing in vivo. Thus, our findings suggest that the TH9 subset of helper T cells serves an important role in driving ulcerative colitis by regulating intestinal epithelial cells and that TH9 cells represent a likely target for the treatment of chronic intestinal inflammation.
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The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF-like (BATF), regulates lymphocyte- and mast cell-driven immune responses in the setting of allergic asthma - Ubel, Caroline; Sopel, Nina; Graser, Anna; Hildner, Kai; Reinhardt, Cornelia; Zimmermann, Theodor; Rieker, Ralf Joachim; Maier, Anja; Neurath, Markus; Murphy, Kenneth M.; Finotto, Susetta (Journal of Allergy and Clinical Immunology, 2014)
Mice without the basic leucine zipper transcription factor, ATF-like (BATF) gene (Batf(-/-)) lack TH17 and follicular helper T cells, which demonstrates that Batf is a transcription factor important for T- and B-cell differentiation.In this study we examined whether BATF expression would influence allergic asthma.In a cohort of preschool control children and children with asthma, we analyzed BATF mRNA expression using real-time PCR in PBMCs. In a murine model of allergic asthma, we analyzed differences in this allergic disease between wild-type, Batf transgenic, and Batf(-/-) mice.In the absence of corticosteroid treatment, children with recurrent asthma have a significant increase in BATF mRNA expression in their PBMCs. Batf(-/-) mice display a significant reduction in the pathophysiologic responses seen in asthmatic wild-type littermates. Moreover, we discovered a decrease in IL-3 production and IL-3-dependent mast cell development in Batf(-/-) mice. By contrast, IFN-? was induced in lung CD4(+) and CD8(+) T cells. Intranasal delivery of anti-IFN-? antibodies induced airway hyperresponsiveness and inflammation in wild-type but not in Batf(-/-) mice. Transgenic overexpression of Batf under the control of the CD2 promoter/enhancer augmented lung inflammation and IgE levels in the setting of experimental asthma.BATF is increased in non-steroid-treated asthmatic children. Targeting BATF expression resulted in amelioration of the pathophysiologic responses seen in children with allergic asthma, and BATF has emerged as a novel target for antiasthma interventions.
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The adrenal gland: between diagnostics and conservative or surgical therapy Die Nebenniere: zwischen Diagnostik, konservativer und operativer Therapie - Bergmann, Tanja (Journal für Urologie und Urogynäkologie, 2022)
The adrenal glands play a central role in the regulation of several functions in the body. Hydrocortisone is the most essential hormone in the body and is also produced in the adrenal glands. On the one hand, diseases of the adrenal glands can present with symptoms of hormonal overproduction or insufficiency. On the other hand, incidentally detected tumors of the adrenal glands can be a challenge not only for endocrinologists but also for other medical disciplines and require special diagnostic and therapeutic measures. The latest European guidelines provide good practical advice on the topic of adrenal incidentalomas. In many cases after completion of the diagnostic cascade, a multidisciplinary decision-making team is needed for planning of the definitive therapeutic algorithm.
CRIS-Team Scopus Importer:2022-12-09
Keywords: Adrenal adenoma; Adrenal carcinoma; Adrenal incidentaloma; Adrenalectomy; Hormonal activity

THE AMOUNT OF LIVER TISSUE IS ESSENTIAL FOR ACCURATE HISTOLOGICAL STAGING IN PATIENTS WITH AUTOIMMUNE HEPATITIS - Vetter, Marcel; Kremer, Andreas; Agaimy, Abbas; Konturek, P. C.; Pfeifer, L.; Neurath, Markus; Zopf, Steffen; Siebler, Jürgen (Journal of Physiology and Pharmacology, 2021)
The gold standard for the evaluation of liver fibrosis is histology. However, the heterogenous distribution of fibrosis limits the sensitivity of histology. The collection of two samples with a 16G needle is therefore recommended to reduce the risk of sampling error. The aim of this study was to investigate whether this standard is also applicable to patients with autoimmune hepatitis (AIH). This retrospective study included patients with AIH, who underwent mini-laparoscopic biopsy at our center between 2011 and 2020 (n = 32). Diagnosis was verified by usage of the simplified AIH score (>= 6). Patients were categorized into three groups, based on the number of portal fields (PF) in the collected liver tissue (< 10 PF, 10 - 19 PF, >= 20 PF). We correlated the histological staging for these groups with the mini-laparoscopic fibrosis score (MLFS). Furthermore, non-invasive methods for the assessment of fibrosis were correlated with the histological staging (acoustic radiation force impulse (ARFI) and FIB-4 score). MLFS correlated well with histological staging (r = 0.649, p = 0.0001). The correlation between MLFS and histology improved with higher numbers of histologically analyzed portal fields (< 10 PF: r = 0.400, p = 0.378; 10 - 19 PF: r = 0.5467, p = 0.023; >= 20 PF: r = 0.956, p = 0.0002). The probability of collecting at least 10 or 20 portal fields was dependent on the number and diameter of the samples. For all patients with at least two 16G biopsies, 10 or more PF were available. With three 16G biopsies, at least 20 PF were obtained for all patients. ARFI correlated with MLFS and histological staging only in patients with low/moderate-grade inflammation as defined by ALT < 10xULN (upper limit of normal) (MLFS: r = 0.723; p = 0.004; histology: r = 0.619, p = 0.018). FIB-4 did not correlate with histological staging. The amount of liver tissue obtained by liver biopsy is crucial to minimalize the risk of sampling error and thus underestimation of fibrosis. This study was the first to investigate the amount of liver tissue required for histological staging in AIH. Our data suggest that diagnostic accuracy is likely to be higher with 20 PF compared to the generally recommended 10 PF. We therefore recommend to perform three biopsies with a 16G needle in (suspected) AIH patients. ARFI correlated well with histological staging unless inflammatory activity is high.
CRIS-Team WoS Importer:2021-10-29

The anticonvulsive Phenhydan® suppresses extrinsic cell death - Moerke, Caroline; Jaco, Isabel; Dewitz, Christin; Müller, Tammo; Jacobsen, Annette V.; Gautheron, Jérémie; Fritsch, Jürgen; Schmitz, Jessica; Bräsen, Jan Hinrich; Günther, Claudia; Murphy, James M.; Kunzendorf, Ulrich; et al. (Cell Death and Differentiation, 2019)
Different forms of regulated cell death-like apoptosis and necroptosis contribute to the pathophysiology of clinical conditions including ischemia-reperfusion injury, myocardial infarction, sepsis, and multiple sclerosis. In particular, the kinase activity of the receptor-interacting serine/threonine protein kinase 1 (RIPK1) is crucial for cell fate in inflammation and cell death. However, despite its involvement in pathological conditions, no pharmacologic inhibitor of RIPK1-mediated cell death is currently in clinical use. Herein, we screened a collection of clinical compounds to assess their ability to modulate RIPK1-mediated cell death. Our small-scale screen identified the anti-epilepsy drug Phenhydan® as a potent inhibitor of death receptor-induced necroptosis and apoptosis. Accordingly, Phenhydan® blocked activation of necrosome formation/activation as well as death receptor-induced NF-κB signaling by influencing the membrane function of cells, such as lipid raft formation, thus exerting an inhibitory effect on pathophysiologic cell death processes. By targeting death receptor signaling, the already FDA-approved Phenhydan® may provide new therapeutic strategies for inflammation-driven diseases caused by aberrant cell death.
CRIS-Team Scopus Importer:2019-08-16

The Application of Hemospray in Gastrointestinal Bleeding during Emergency Endoscopy - Hagel, Alexander; Albrecht, Heinz; Naegel, Andreas; Vitali, Francesco; Vetter, Marcel; Dauth, Christine; Neurath, Markus; Raithel, Martin (Gastroenterology Research and Practice, 2017)
Introduction . Gastrointestinal bleeding represents the main indication for emergency endoscopy (EE). Lately, several hemostatic powders have been released to facilitate EE.Methods. We evaluated all EE in which Hemospray was used as primary or salvage therapy, with regard to short- and long-term hemostasis and complications.Results. We conducted 677 EE in 474 patients (488 examinations in 344 patients were upper GI endoscopies). Hemospray was applied during 35 examinations in 27 patients (19 males), 33 during upper and 2 during lower endoscopy. It was used after previous treatment in 21 examinations (60%) and in 14 (40%) as salvage therapy. Short-term success was reached in 34 of 35 applications (97.1%), while long-term success occurred in 23 applications (65.7%). Similar long-term results were found after primary application (64,3%) or salvage therapy (66,7%). Rebleeding was found in malignant and extended ulcers. One major adverse event (2.8%) occurred with gastric perforation after Hemospray application.Discussion. Hemospray achieved short-term hemostasis in virtually all cases. The long-term effect is mainly determined by the type of bleeding source, but not whether it was applied as first line or salvage therapy. But, even in the failures, patients had benefit from hemodynamic stabilization and consecutive interventions in optimized conditions.
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The Bisphosphonate Pamidronate is an Intestinal Antiinflammatory Agent in Rat and Mouse Experimental Colitis - Lopez Posadas, Rocío; Mascaraque, Cristina; Gonzalez, Raquel; Suarez, Maria D.; Zarzuelo, Antonio; Martinez-Augustin, Olga; Sanchez De Medina, Fermin (Inflammatory Bowel Diseases, 2016)
Statins have antiinflammatory effects at the cardiovascular level because of inhibition of prenylation, which also probably underlies their therapeutic effects in preclinical models of inflammatory bowel disease. Another inhibitor of prenylation, namely alendronate, reduces colitis in rodents. In this study, we aim to explore the therapeutic potential of second-generation, nitrogen-containing bisphosphonates in 3 preclinical models of colitis.The trinitrobenzenesulfonic acid and dextran sulfate sodium models of rat colitis and the adoptive lymphocyte transfer model of colitis in mice were used. Pamidronate, alendronate, and ibandronate were tested. Treatments were administered in equimolar doses through the oral or intraperitoneal route. The effect of pamidronate on prenylation and cytokine release was assessed in vivo and in vitro.Pretreatment with pamidronate, but not with ibandronate or alendronate, improves chemically induced trinitrobenzenesulfonic acid and dextran sulfate sodium colitis in rats. Moreover, this beneficial effect is extended to lymphocyte transfer colitis. Pamidronate has no effect on intestinal epithelial cells in vitro in terms of cytokine/chemokine release, but enhances IFN-?, IL-6, and IL-10 production by T cells in coculture. Pamidronate also exerts a direct immunomodulatory effect on T cells, favoring Th1 differentiation and impairing Th17 polarization.Pamidronate presents antiinflammatory and immunomodulatory properties in 3 different models of experimental colitis in rodents. This effect requires oral administration and may involve T cells in the gut mucosa, although the exact mechanism is unclear.
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The Clinical Research Group 257, "CEDER" Molecular Pathogenesis and Optimized Therapy of Chronic inflammatory Bowel Diseases - Becker, Christoph; Neurath, Markus (Zeitschrift für Gastroenterologie, 2017)
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The dichotomous function of interleukin-9 in cancer diseases - Gerlach, Katharina; Weigmann, Benno (Journal of Molecular Medicine, 2019)
The pleiotropic function of the cytokine IL-9 is so far described in many inflammation processes and autoimmune diseases. But its role in cancer immunology is rather diverse as it can have a pro-tumorigenic function as well as anti-tumorigenic characteristics. In various disease models of cancer, this cytokine is involved in different signaling pathways triggering the expression of proteins involved in cell growth, migration, and transformation or repressing cells from the adaptive immune system to reject tumor growth. Additionally, there are even therapeutic approaches for IL-9 in cancer development. This review will give an overview of the various roles of IL-9 in different immune organs and cells and provide an insight in the current state of research in the IL-9-dependent cancer area.
CRIS-Team Scopus Importer:2019-08-16
Keywords: Anti-tumorigenic role; IL-9; Pro-tumorigenic role; Therapy

The Effects of a Normal Rate versus a Slow Intervalled Rate of Oral Nutrient Intake and Intravenous Low Rate Macronutrient Application on Psychophysical Function - Two Pilot Studies - Denzer-Lippmann, Melanie; Bachlechner, Stephan; Wielopolski, Jan; Fischer, Marie; Büttner, Andrea; Dörfler, Arnd; Schöfl, Christof; Muench, Gerald; Kornhuber, Johannes; Thürauf, Norbert (Frontiers in Psychology, 2017)
Stomach distension and energy per time are factors influencing satiety. Moreover, different rates of nutrient intake induce different stomach distension. The goal of our studies was to elucidate the influence of different oral rates of nutrient intake (normal rate versus slow intervalled rate; study I) and intravenous low rate macronutrient application (protein, carbohydrate, fat) or placebo (study II) on psychophysical function. The pilot studies investigated the effects of 1) study I: a mixed nutrient solution (1/3 protein, 1/3 fat, 1/3 carbohydrates) 2) study II: intravenous macronutrient infusions (protein, carbohydrate, fat) or placebo on psychophysical function (mood, hunger, food craving, alertness, smell intensity ratings and hedonic ratings) in human subjects. In study I 10 male subjects (age range: 21-30 years) completed the study protocol participating in both test conditions and in study II 20 male subjects (age range: 19-41 years) completed the study protocol participating in all test conditions. Additionally, metabolic function was analyzed and cognitive and olfactory tests were conducted twice starting 100 min before the beginning of the intervention and 240 min after. Psychophysical (mood, hunger, fat-, protein-, carbohydrate-, sweets- and vegetable-craving), alertness and metabolic function tests were performed seven times on each examination day. Greater effects on hunger and food cravings were observed for normal rate of intake compared to slow intervalled rate of intake and intravenous low rate macronutrient application. Our findings potentially confirm that volume of the food ingested and a higher rate of energy per time contribute to satiety during normal rate of food intake, while slow intervalled rate of food intake and intravenous low rate macronutrient application showed no effects on satiation. Our results motivate the view that a certain amount of volume of the food ingested and a certain energy per time ratio are necessary to reduce hunger and food craving.
EVALuna2:33741
Keywords: food ingestion; food intake; rate of food intake; psychophysical function; food craving; parenteral food administration; parenteral food intake

The Effects of Different Isocaloric Oral Nutrient Solutions on Psychophysical, Metabolic, Cognitive, and Olfactory Function in Young Male Subjects - Bachlechner, Stephan; Denzer-Lippmann, Melanie Y.; Wielopolski, Jan; Fischer, Marie; Büttner, Andrea; Dörfler, Arnd; Schöfl, Christof; Muench, Gerald; Kornhuber, Johannes; Thürauf, Norbert (Frontiers in Psychology, 2017)
Food intake influences human cognition, olfaction, hunger, and food craving. However, little research has been done in this field to elucidate the effects of different nutrients. Thus, the goal of our study was to investigate the effects of oral ingestion of different nutrient solutions on olfactory, cognitive, metabolic and psychophysical function. Twenty healthy men participated in our study employing a double-blind, cross-over, repeated measurement design. Participants were tested on four different study days. Each day participants received, in randomized order, one of three isocaloric (protein, carbohydrate or fat 600 kcal, 1,500mL) solutions or a placebo. Olfactory and cognitive tests (monitoring only) were conducted three times, i.e., 60min before the beginning of nutrient intake, following oral ingestion of the solution and 60, and 240min after. Psychophysical and metabolic function tests (active grehlin, desacyl ghrelin, insulin, glucagon, glucose, triglyceride, urea) were performed 7 times on each examination day (observation period: -60min, 0 = solution intake, +60, +120, +180, +240, and +300min). Ratings of hunger and food craving significantly differed over the observation period with lowest ratings following application of the protein solution. Highest ratings of craving were found following placebo intake. We further observed a significant positive correlation of active grehlin with hunger and fat, protein and sweets craving for each nutrient solution. Active grehlin significantly correlated with carbohydrate craving for carbohydrate and fat solution and with vegetable craving for fat solution only. Hunger hormone levels, hunger and food craving ratings demonstrated that the hierarchical order that appears in satiating efficiencies of isovolumetric-isocaloric ingested macronutrients is protein > fat > carbohydrate. Our study reveals that the type of nutrient exerts a significant influence on metabolic parameters, hunger and food craving.
Keywords: food ingestion; food intake; oral intake; olfaction; psychophysical function

The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer - Krebs, Angela M.; Mitschke, Julia; Losada, Maria Lasierra; Schmalhofer, Otto; Boerries, Melanie; Busch, Hauke; Böttcher, Martin; Mougiakakos, Dimitrios; Reichardt, Wilfried; Bronsert, Peter; Brunton, Valerie G.; Pilarsky, Christian; et al. (Nature Cell Biology, 2017)
Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis. Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects. Accordingly, we conclude that different EMT-TFs have complementary subfunctions in driving pancreatic tumour metastasis. Therapeutic strategies should consider these potential specificities of EMT-TFs to target these factors simultaneously.

THE FIRST REAL-LIFE MULTICENTRE, INTERNATIONAL, PROSPECTIVE VALIDATION STUDY OF THE ELECTRONIC CHROMOENDOSCOPY SCORING SYSTEM (PICASSO-THE PADDINGTON INTERNATIONAL VIRTUAL CHROMOENDOSCOPY SCORE) AND ITS OUTCOME IN ULCERATIVE COLITIS PATIENTS - Iacucci, Marietta; Smith, Samuel C.; Bazarova, Alina; Shivaji, Uday N.; Bhandari, Pradeep; Cannatelli, Rosanna; Daperno, Marco; Ferraz, Jose G.; Goetz, Martin; Gui, Sean X.; Hayee, Bu; De Hertogh, Gert; et al. (GASTROINTESTINAL ENDOSCOPY, 2020)
CRIS-Team WoS Importer:2021-02-19

The first real-life multicentre prospective validation study of the electronic chromoendoscopy score (Paddington International Virtual ChromoendoScopy ScOre) and its outcome in ulcerative colitis - Iacucci, M.; Smith, S. C.; Bazarova, A.; Shivaji, U. N.; Bhandari, P.; Cannatelli, R.; Daperno, M.; Ferraz, J. G.; Goetz, M.; Gui, X.; Hayee, B.; De Hertogh, G.; et al. (JOURNAL OF CROHNS & COLITIS, 2020)
CRIS-Team WoS Importer:2020-04-10

The first virtual chromoendoscopy artificial intelligence system to detect endoscopic and histologic remission in Ulcerative Colitis - Iacucci, M.; Cannatelli, R.; Parigi, T. L.; Buda, A.; Labarile, N.; Nardone, O. M.; Tontini, G. E.; Rimondi, A.; Bazarova, A.; Bhandari, P.; Bisschops, R.; De Hertogh, G.; et al. (JOURNAL OF CROHNS & COLITIS, 2022)
CRIS-Team WoS Importer:2022-05-13

The G protein-coupled receptor MRGX4 is a novel receptor for bile salts expressed on sensory neurons - Wolf, Katharina; Kühn, Helen; Leibl, Victoria; Gebhardt, Lisa; Glaudo, Markus; Reeh, Peter; Fischer, Michael J. M.; Neurath, Markus; Namer, Barbara; Kremer, Andreas (SWISS MEDICAL WEEKLY, 2021)
CRIS-Team WoS Importer:2022-03-11

The gut-brain axis in inflammatory bowel disease—current and future perspectives - Günther, Claudia; Rothhammer, Veit; Karow, Marisa; Neurath, Markus; Winner, Beate (International Journal of Molecular Sciences, 2021)
The gut–brain axis is a bidirectional communication system driven by neural, hormonal, metabolic, immunological, and microbial signals. Signaling events from the gut can modulate brain function and recent evidence suggests that the gut–brain axis may play a pivotal role in linking gastrointestinal and neurological diseases. Accordingly, accumulating evidence has suggested a link between inflammatory bowel diseases (IBDs) and neurodegenerative, as well as neuroinflammatory diseases. In this context, clinical, epidemiological and experimental data have demonstrated that IBD predisposes a person to pathologies of the central nervous system (CNS). Likewise, a number of neurological disorders are associated with changes in the intestinal environment, which are indicative for disease-mediated gut–brain inter-organ communication. Although this axis was identified more than 20 years ago, the sequence of events and underlying molecular mechanisms are poorly defined. The emergence of precision medicine has uncovered the need to take into account non-intestinal symptoms in the context of IBD that could offer the opportunity to tailor therapies to individual patients. The aim of this review is to highlight recent findings supporting the clinical and biological link between the gut and brain, as well as its clinical significance for IBD as well as neurodegeneration and neuroinflammation. Finally, we focus on novel human-specific preclinical models that will help uncover disease mechanisms to better understand and modulate the function of this complex system.
CRIS-Team Scopus Importer:2021-08-27
Keywords: Ex vivo organ models; Gut-brain axis; IBD; MS; PD

The Gut–Immune–Brain Axis: An Important Route for Neuropsychiatric Morbidity in Inflammatory Bowel Disease - Masanetz, Rebecca Katharina; Winkler, Jürgen; Winner, Beate; Günther, Claudia; Süß, Patrick (International Journal of Molecular Sciences, 2022)
Inflammatory bowel disease (IBD) comprises Crohn’s disease (CD) and ulcerative colitis (UC) and is associated with neuropsychiatric symptoms like anxiety and depression. Both conditions strongly worsen IBD disease burden. In the present review, we summarize the current understanding of the pathogenesis of depression and anxiety in IBD. We present a stepwise cascade along a gut–immune–brain axis initiated by evasion of chronic intestinal inflammation to pass the epithelial and vascular barrier in the gut and cause systemic inflammation. We then summarize different anatomical transmission routes of gut-derived peripheral inflammation into the central nervous system (CNS) and highlight the current knowledge on neuroinflammatory changes in the CNS of preclinical IBD mouse models with a focus on microglia, the brain-resident macrophages. Subsequently, we discuss how neuroinflammation in IBD can alter neuronal circuitry to trigger symptoms like depression and anxiety. Finally, the role of intestinal microbiota in the gut–immune–brain axis in IBD will be reviewed. A more comprehensive understanding of the interaction between the gastrointestinal tract, the immune system and the CNS accounting for the similarities and differences between UC and CD will pave the path for improved prediction and treatment of neuropsychiatric comorbidities in IBD and other inflammatory diseases.
Created from Fastlane, Scopus look-up
Keywords: Crohn’s disease; depression; gut microbiota; gut-brain axis; inflammatory bowel disease; neuroinflammation; systemic inflammation; ulcerative colitis

The immunological role of adipose tissue in inflammatory bowel disease - Letizia, M.; Boettcher, C.; Sillke, Y. Rodriguez; Schmidt, F.; Günther, Claudia; Kunkel, D.; Glauben, R.; Siegmund, B.; Weidinger, C. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

The impact of COVID-19 on the management of neuroendocrine tumors (NETS): An international NET CONNECT survey of NET patients and healthcare professionals treating net patients - Cives, Mauro; Hernando, Jorge; Lamarca, Angela; Bouvier, Catherine; Caplin, Martyn; Pavel, Marianne Ellen (Journal of Neuroendocrinology, 2022)
The COVID-19 outbreak has added complexity in the management of patients with neuroendocrine tumors (NETs). Little information is currently available regarding the real impact of the pandemic in current practice. The present study aimed to capture patients' and healthcare professionals' experiences on how the NET management has changed during the pandemic and how it should be modified in a foreseeable post-pandemic environment. Physicians and nurses working in ENETS Centers of Excellence or other hospitals with high volume of NET patients (n = 48), as well as NET patients residing worldwide (n = 353), were asked to respond to two online anonymous surveys addressing different aspects of NET care. Deferred diagnoses, delayed surveillance procedures and postponed elective surgeries were among the main negative consequences of the COVID-19 outbreak according to 40%, 54% and 46% of healthcare professionals (HPs) respectively. Somatostatin analogs were increasingly used as bridging strategy for delaying surgery based on the views of 31% of HPs and were self-injected or delivered by home care services more frequently than before the initiation of the pandemic (53% of patients during the pandemic vs. 44% before the pandemic). Multidisciplinary tumor boards kept their usual schedule according to 58% of HPs, but were held virtually in the 77% of cases. The contact with healthcare professionals was maintained by remote methods more often than in the past (69% of patients), but only 34% of patients (59% among subjects < 41 years) would prefer telemedicine to face-to-face consultations in the future. New health policy measures should guarantee the highest standard of treatment to NET patients, regardless of the trajectory followed by the COVID-19 pandemic in the next months. Pros and cons of telemedicine should be carefully weighted before systematic implementation.
CRIS-Team Scopus Importer:2022-09-16
Keywords: carcinoids; SARS-CoV-2; telemedicine; vaccination

The impact of hospitalization on the performance of capsule endoscopy (CE) - Albrecht, Heinz; Vetter, Marcel; Dauth, Wolfgang; Zoicas, Flavius; Neurath, Markus; Hagel, Alexander (Digestive and Liver Disease, 2017)
BACKGROUND: For proper evaluation of capsule endoscopy (CE), a complete examination is necessary. AIM: We evaluated risk factors of an incomplete CE with focus on patient hospitalization. METHODS: We retrospectively evaluated 161 consecutive patients who underwent CE between 01.07.2013 and 13.03.2016. Main indications were active bleeding, iron deficiency anemia (IDA), inflammatory bowel disease (IBD), abdominal pain, and familial adenomatous polyposis (FAP). RESULTS: We report the results of 103 in-patients and 56 out-patients. Eighty-two patients were male, average age was 58.9 years (range 18-90). Indications for CE were active bleeding (103 patients), IDA and IBD (16 patients), and FAP, abdominal pain and others (eight examinations each). All FAP patients were out-patients, but showed the longest small bowel transit time (SBTT) of 443.6min (p=0.0001). The shortest SBTT was found in out-patients without FAP (267.5min, p<0.05). In the in-patient group, nine endoscopies did not record the entire small bowel (8.7%) due to battery depletion, compared with only one incomplete examination in the out-patients (1.8%, p=0.036). We found pathologic lesions in the last 30min of the SBTT in 43 patients, and this indicates the necessity for complete examination. Thirteen of these 43 patients showed major lesions such as ulcers or angiodysplasia in this last region alone. CONCLUSION: In-patients might require special treatment to ensure complete examination, since a considerable amount of pathologies can only be found in the ileum.
EVALuna2:33812

The Impact of the Cellular Environment and Aging on Modeling Alzheimer's Disease in 3D Cell Culture Models - Hebisch, Matthias; Klostermeier, Stefanie; Wolf, Katharina; Boccaccini, Aldo R.; Wolf, Stephan; Tanzi, Rudolph E.; Kim, Doo Yeon (Advanced Science, 2023)
Creating a cellular model of Alzheimer's disease (AD) that accurately recapitulates disease pathology has been a longstanding challenge. Recent studies showed that human AD neural cells, integrated into three-dimensional (3D) hydrogel matrix, display key features of AD neuropathology. Like in the human brain, the extracellular matrix (ECM) plays a critical role in determining the rate of neuropathogenesis in hydrogel-based 3D cellular models. Aging, the greatest risk factor for AD, significantly alters brain ECM properties. Therefore, it is important to understand how age-associated changes in ECM affect accumulation of pathogenic molecules, neuroinflammation, and neurodegeneration in AD patients and in vitro models. In this review, mechanistic hypotheses is presented to address the impact of the ECM properties and their changes with aging on AD and AD-related dementias. Altered ECM characteristics in aged brains, including matrix stiffness, pore size, and composition, will contribute to disease pathogenesis by modulating the accumulation, propagation, and spreading of pathogenic molecules of AD. Emerging hydrogel-based disease models with differing ECM properties provide an exciting opportunity to study the impact of brain ECM aging on AD pathogenesis, providing novel mechanistic insights. Understanding the role of ECM aging in AD pathogenesis should also improve modeling AD in 3D hydrogel systems.
CRIS-Team Scopus Importer:2023-01-27
Keywords: Alzheimer; hydrogel; neurodegeneration; nonclassical crystallization; synthetic extracellular matrix

The importance of pancreatic inflammation in endosonographic diagnostics of solid pancreatic masses - Vitali, Francesco; Strobel, Deike; Frulloni, Luca; Heinrich, Marc Christopher; Pfeifer, Lukas; Görtz, Rüdiger; Hundorfean, Gheorghe; Wachter, David Lukas; Wachter, David; Grützmann, Robert; Bernatik, Thomas; Neurath, Markus; et al. (Medical Ultrasonography, 2018)
AIMS: Endosonography (EUS) is one of the main diagnostic tools for the differential diagnosis of pancreatic masses. The aim of our study was to describe the value of this technique in the work-up of solid pancreatic lesions, considering the influence of the morphological evidence of pancreatic inflammation in the diagnostic process. MATERIAL AND METHODS: Retrospective analysis of prospectively collected data in our tertiary University center. From March 2007 to October 2015, 218 patients underwent EUS for a suspected solid pancreatic neoplasm (based on previous cross-sectional imaging results, idiopatic acute pancreatitis, weight loss, pancreatic hyperenzymemia, painless jaundice or elevated Ca 19-9 values). RESULTS: Malignant lesions were diagnosed in 98 (45%) patients. Sensitivity of EUS for malignancy was 91% and specificity 89.2%. Signs of pancreatic inflammation in the surrounding pancreatic parenchyma around the focal lesion were present in 97 patients (44.4%)(more often in men, smokers and drinkers, and the most common etiology was focal chronic pancreatitis) and in these patients the sensitivity and sensibility dropped to 44% and 87.1%, respectively. In patients without signs of pancreatic inflammation, the pancreatic focal lesions were adenocarcinoma, neuroendocrine tumor, ventral/dorsal split, non-pancreatic pathology, pancreatic lipomatosis and autoimmune pancreatitis. CONCLUSION: Pancreatic inflammation (either focal or involving the whole gland) lowers the diagnostic sensibility of EUS in the work- up of pancreatic masses suspected for cancer, requiring further invasive diagnostic methods. Focal autoimmune pancreatitis and paraduodenal pancreatitis are still confused with pancreatic cancer, even in the absence of pancreatic inflammation.
EVALuna2:35194

The Incidence of Cancer Among Acromegaly Patients: Results From the German Acromegaly Registry - Petroff, David; Tönjes, Anke; Grussendorf, Martin; Droste, Michael; Dimopoulou, Christina; Stalla, Günter; Jaursch-Hancke, Cornelia; Mai, Manuel; Schopohl, Jochen; Schöfl, Christof (Journal of Clinical Endocrinology and Metabolism, 2015)
Acromegaly is a rare disease characterized by high serum levels of GH and IGF-1. Animal studies have demonstrated links between these hormones and cancer, but data regarding cancer incidence among acromegaly patients are inconsistent. Moreover, therapy options have changed considerably since many of the aforementioned data were collected.The objective was to determine whether the overall and site-specific incidence of cancer is comparable to that of the general population.Data from the German Acromegaly Registry for 446 patients (6656 person-years from diagnosis) treated in seven specialized endocrine centers were analyzed.Standard incidence ratios (SIRs) were calculated as compared to the general population.Overall cancer incidence was slightly but not significantly lower than in the general population (SIR, 0.75; 95% confidence interval, 0.55 to 1.00; P = .051) and was not significantly higher for colorectal, breast, thyroid, prostate, and lung cancers. The SIRs of those with GH in the ranges <1, 1-2.5, and >=2.5 ng/mL were 0.75, 0.44, and 0.92, respectively (P = .94). There was not a significant dependence on normal vs elevated IGF-1 (P = .87), radiation therapy (P = .45), disease duration (P = .96), age at diagnosis (P = .15), or during a period of high GH and IGF-1 from 8 years before to 2 years after diagnosis of acromegaly (P = .41).Cancer screening strategies need to take incidence into account, which does not seem to be substantially higher in treated acromegaly patients than in the general population for any site of cancer.
EVALuna2:1998

The influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome - Lenk, Christian; Meßbacher, Maria-Elena; Abel, Judith; Mueller, Sarina K.; Mantsopoulos, Konstantinos; Gostian, Antoniu-Oreste; Sievert, Matti; Wirtz, Stefan; Marxreiter, Franz; Winkler, Jürgen; Iro, Heinrich; Traxdorf, Maximilian (European Review for Medical and Pharmacological Sciences, 2023)
OBJECTIVE: The aim of this study was to investigate the influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome. PATIENTS AND METHODS: Endonasal swabs from the olfactory groove of 22 patients with moderate and severe obstructive sleep apnea (OSA) and a control group of 17 healthy controls were obtained at the Department of Otorhinolaryngology of the Friedrich-Alexander-Universität Erlangen-Nürnberg. 16S rRNA gene sequencing was performed to further evaluate the endonasal microbiome. In a second step, the longitudinal influence of continuous positive airway pressure (CPAP) therapy on the nasal microbiome was investigated (3-6 and 6-9 months). RESULTS: Analysis of the bacterial load and β-diversity showed no significant differences between the groups, although patients with severe OSA showed increased α-diversity compared to the control group, while those with moderate OSA showed decreased α-diversity. The evaluation of longitudinal changes in the nasal microbiota during CPAP treatment showed no significant difference in α- or β-diversity. However, the number of bacteria for which a significant difference between moderate and severe OSA was found in the linear discriminant analysis decreased during CPAP treatment. CONCLUSIONS: Long-term CPAP treatment showed an alignment of the composition of the nasal microbiome in patients with moderate and severe OSA as well as an alignment of biodiversity with that of the healthy control group. This change in the composition of the microbiome could be both part of the therapeutic effect in CPAP therapy and a promoting factor of the adverse side effects of the therapy. Further studies are needed to investigate whether the endonasal microbiome is related to CPAP compliance and whether CPAP compliance can be positively influenced in the future by therapeutic modification of the microbiome.
CRIS-Team WoS Importer:2023-05-26

The Intestinal Microbiota in Inflammatory Bowel Disease - Becker, Christoph; Neurath, Markus; Wirtz, Stefan (IlAR Journal, 2015)
The intestinal microbiota has important metabolic and host-protective functions. Conversely to these beneficial functions, the intestinal microbiota is thought to play a central role in the etiopathogenesis of inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), a chronic inflammation of the gut mucosa. Genetic screens and studies in experimental mouse models have clearly demonstrated that IBD can develop due to excessive translocation of bacteria into the bowel wall or dysregulated handling of bacteria in genetically susceptible hosts. In healthy individuals, the microbiota is efficiently separated from the mucosal immune system of the gut by the gut barrier, a single layer of highly specialized epithelial cells, some of which are equipped with innate immune functions to prevent or control access of bacterial antigens to the mucosal immune cells. It is currently unclear whether the composition of the microbial flora or individual bacterial strains or pathogens induces or supports the pathogenesis of IBD. Further research will be necessary to carefully dissect the contribution of individual bacterial species to this disease and to ascertain whether specific modulation of the intestinal microbiome may represent a valuable further option for future therapeutic strategies.
EVALuna2:2000

The Intratumoral and Intestinal Microbiome in Pancreatic Cancer - Langheinrich, Melanie; Wirtz, Stefan; Grützmann, Robert; Kersting, Stephan; Weber, Georg (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

The JAK1/3 Inhibitor to Tofacitinib Suppresses T Cell Homing and Activation in Chronic Intestinal Inflammation - Gerlach, Katharina; Lechner, Kristina; Popp, Vanessa; Offensperger, Laura; Zundler, Sebastian; Wiendl, Maximilian; Becker, Emily; Atreya, Raja; Rath, Timo; Neurath, Markus; Weigmann, Benno (Journal of Crohns & Colitis, 2021)
Background and Aims: The molecular mechanism of action of the Janus kinase [JAK] inhibitor tofacitinib is poorly understood. Methods: Here we analysed the inhibitory effect of tofacitinib on mucosal and blood T cells from patients with ulcerative colitis [UC]. Furthermore, tofacitinib treatment was analysed in experimental colitis models and wound healing. Additionally, tofacitinib effects were analysed in bioassays. Results: Tofacitinib significantly reduced T cell-derived inflammatory cytokine production [Th2, Th9, Th17] in patients with active UC. Additionally, impaired expression of the homing receptors alpha4/beta1 and alpha4/beta7, as well as reduced gut homing capacity of T cells in a humanised mouse model of colitis, were observed. Tofacitinib suppressed acute and chronic oxazolone colitis, compared with untreated wild-type mice, associated with downregulation of cytokines produced by Th2, Th9, and Th17 cells. Functionally, tofacitinib induced apoptosis of intestinal epithelial cells and prevented mucosal wound healing in vivo at higher concentration. Thus, our findings suggest that tofacitinib is quite effective in protecting from colitis, by inhibition of a bundle of T cell-derived cytokines like IL-5, IL-6, IL-9, IL-13, and IL-17A. Conclusions: Application of tofacitinib emerges as an attractive concept for treatment of chronic intestinal inflammation at lower concentrations, whereas higher concentrations require attention due to prolonged wound healing.
CRIS-Team Scopus Importer:2021-05-07
Keywords: cytokines; inflammatory bowel disease; T cells; Tofacitinib; wound healing

The Memory T Cell “Communication Web” in Context with Gastrointestinal Disorders—How Memory T Cells Affect Their Surroundings and How They Are Influenced by It - Knauß, Annkathrin; Gabel, Michael; Neurath, Markus; Weigmann, Benno (Cells, 2022)
Gut-related diseases like ulcerative colitis, Crohn’s disease, or colorectal cancer affect millions of people worldwide. It is an ongoing process finding causes leading to the development and manifestation of those disorders. This is highly relevant since understanding molecular processes and signalling pathways offers new opportunities in finding novel ways to interfere with and apply new pharmaceuticals. Memory T cells (mT cells) and their pro-inflammatory properties have been proven to play an important role in gastrointestinal diseases and are therefore increasingly spotlighted. This review focuses on mT cells and their subsets in the context of disease pathogenesis and maintenance. It illustrates the network of regulatory proteins and metabolites connecting mT cells with other cell types and tissue compartments. Furthermore, the crosstalk with various microbes will be a subject of discussion. Characterizing mT cell interactions will help to further elucidate the sophisticated molecular and cellular networking system in the intestine and may present new ideas for future research approaches to control gut-related diseases.
CRIS-Team Scopus Importer:2022-10-07
Keywords: colorectal cancer; Crohn’s disease; etrolizumab; IBD; immune cells; interactions; memory T cells; metabolites; microbiota; ozanimod; ulcerative colitis; vedolizumab

The Microbiome in Visceral Medicine: Inflammatory Bowel Disease, Obesity and Beyond - Chiriac, Mircea T.; Mahapatro, Mousumi; Neurath, Markus; Becker, Christoph (Visceral Medicine, 2017)
It has become increasingly evident over the past two decades that the microbiota plays a nurturing role in the development of the immune system. This appears to be important since the amplitude of immune responses has a crucial regulatory function in homeostasis and the prevention of unwanted inflammation. Hence, a malfunctioning gut flora has been shown to play a key role in visceral medicine. Strong evidence demonstrates for example that intestinal inflammation can develop as a result of a dysregulated microbiota, deficient antimicrobial responses, and aberrant bacterial translocation into the bowel wall. In healthy individuals, the bacterial translocation is blocked by a single layer of highly specialized intestinal epithelial cells which forms a strong barrier that lines the gut wall. This structure is responsible for an efficient absorption of nutrients while keeping the luminal flora at bay. In susceptible individuals, for yet incompletely understood reasons, either defective epithelial barrier function or dysregulated microbial composition or microbial pathogens drive intestinal inflammation. Many therapeutic strategies focusing on the modulation of the microbiota have been proposed recently but future research including prospective human studies and gnotobiotic mouse models are still needed to evaluate the contribution and potential therapeutic value of individual bacteria to human health.
EVALuna2:35240

The non-neuronal cyclin-dependent kinase 5 is a fibrotic mediator potentially implicated in systemic sclerosis and a novel therapeutic target - Wei, Jun; Marangoni, Roberta G.; Fang, Feng; Wang, Wenxia; Huang, Jingang; Distler, Jörg; Varga, John (Oncotarget, 2018)
The mechanisms underlying persistent fibroblast activation and myofibroblast phenoconversion in underlying multi-organ fibrosis in systemic sclerosis (SSc) remain incompletely understood, hindering effective therapies to slow or reverse the process. Cyclin-dependent kinase 5 (CDK5) is a pleiotropic member of the CDK family originally identified in neuronal cells. In contrast to other CDKs, CDK5 activity depends on its CDK5R1 subunit p35. Here we demonstrate that expression of p35 and CDK5 activity are induced by TGF-ß in fibroblasts and adipocytic cell types. Levels of p35 are markedly elevated in both SSc skin biopsies and explanted SSc fibroblasts, as well as in fibrotic skin in mice. Ectopic p35 and CDK5 suppressed adipogenic markers while stimulating collagen production and myofibroblast markers, whereas RNAi-mediated CDK5 knockdown abrogated TGF-β fibrotic responses in a Smad-independent manner. Pharmacological inhibitors of CDK5 likewise prevented and reversed TGF-β responses in fibroblast monolayers and in ex vivo human skin organ cultures, ameliorated collagen overproduction in SSc fibroblasts, and prevented and reversed skin fibrosis in two distinct mouse models of SSc. Together, these results reveal a previously unrecognized key function for p35/CDK5 as a mediator of mesenchymal cell fibrotic responses. The results suggest a potential pathogenic role for elevated p35 expression and CDK5 activity in SSc, and raise the possibility that their selective pharmacological targeting might represent a novel treatment approach in fibrosis.
EVALuna2:215886

THE NOX1/4 INHIBITOR GKT831 ACHIEVES CLINICALLY MEANINGFUL REDUCTIONS IN LIVER STIFFNESS, ATTENUATES CHOLESTASIS, AND IMPROVES QUALITY OF LIFE IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS - Huang, Jonathan C.; Invernizzi, Pietro; Dalekos, George N.; Nevens, Frederik; Van Vlierberghe, Hans; Zigmond, Ehud; Andrade, Raul J.; Ben-Ari, Ziv; Heneghan, Michael A.; Harrison, Stephen A.; Minuk, Gerald Y.; Schattenberg, Joern; et al. (HEPATOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-25

The Ominous Ouzo Party - A Case Series of Four Patients with Accidental Alkali Ingestion - Vetter, Marcel; Rath, Timo; Siebler, Jürgen; Waldner, Maximilian; Neurath, Markus; Pfeifer, Lukas (Clinical and Experimental Gastroenterology, 2021)
Background: Ingestion of alkaline fluids is a common problem, which can lead to perforations, strictures and malignancy. We present a rare case series of several patients who accidentally ingested the same alkaline substance in different doses.
CRIS-Team WoS Importer:2021-07-30

The outcome of patients with inflammatory bowel disease-associated colorectal cancer is not worse than that of patients with sporadic colorectal cancer-a matched-pair analysis of survival - Vitali, Francesco; Wein, Axel; Rath, Timo; Eckstein, Markus; Neufert, Clemens; Siebler, Jürgen; Atreya, Raja; Hartmann, Arndt; Hohenberger, Werner; Weber, Klaus; Neurath, Markus; Grützmann, Robert; et al. (International Journal of Colorectal Disease, 2021)
Purpose Patients with inflammatory bowel disease (IBD) have an increased risk for colorectal cancer (CRC). In IBD patients, cancer is often diagnosed in advanced stages and conflicting data on survival compared to sporadic CRC have been reported. The aim of this study was to directly compare clinical characteristics and prognosis of patients with IBD-CRC and sporadic CRC. Methods The clinical and pathological data of 63 patients with IBD-CRC and 3710 patients with sporadic CRC treated at the University Hospital of Erlangen between 1995 and 2015 were compared. Forty-seven M0 patients with IBD were matched with sporadic CRC patients after curative resection (R0) according to tumor localization, stage, sex, and year of treatment. Overall and disease-free survival were compared. Results Sixty-three patients presented IBD-CRC. Fifty were affected with ulcerative colitis (UC) and 13 with Crohn's disease (CD). CRC was diagnosed within 1.45 years since last endoscopic surveillance. Twelve patients (19%) had a diagnosis of primary sclerosing cholangitis. In matched analysis, IBD patients were diagnosed with CRC at younger age compared to sporadic CRC and were more likely to have right-sided CRC (40% versus 23.3%) and rare histological subtypes (19% versus 9.2%). No differences in 5-year overall (78.7 versus 80.9 months) and 5-year disease-free survival (74.5 versus 70.2 months) were noted. Conclusion IBD-CRC patients were younger and more frequently had right-sided carcinomas compared to sporadic CRC. CRC in IBD patients did not show survival difference compared to matched-pair sporadic CRC patients without distant metastases after curative resection. Surveillance might be important for early detection of CRC in IBD patients.
CRIS-Team WoS Importer:2021-12-17

The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update - Catassi, Carlo; Alaedini, Armin; Bojarski, Christian; Bonaz, Bruno; Bouma, Gerd; Carroccio, Antonio; Castillejo, Gemma; De Magistris, Laura; Dieterich, Walburga; Di Liberto, Diana; Elli, Luca; Fasano, Alessio; et al. (Nutrients, 2017)
Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion.
EVALuna2:33889

The pan-deacetylase inhibitor panobinostat affects angiogenesis in hepatocellular carcinoma models via modulation of CTGF expression - Gahr, Susanne; Mayr, Christian; Kiesslich, Tobias; Illig, Romana; Neureiter, Daniel; Alinger, Beate; Ganslmayer, Marion; Wissniowski, Till; Di Fazio, Pietro; Montalbano, Roberta; Ficker, Joachim H.; Ocker, Matthias; et al. (International Journal of Oncology, 2015)
Post-translational modifications of chromatin components are significantly involved in the regulation of tumor suppressor gene and oncogene expression. Connective tissue growth factor (CTGF) is an epigenetically regulated growth factor with functions in angiogenesis and cell-matrix interactions and plays a pivotal role in hepatocellular carcinoma (HCC). The pharmacologic inhibition of histone and protein deacetylases represents a new approach to interfere with pathways of apoptosis and angiogenesis. We investigated the effect of the pan-deacetylase inhibitor panobinostat (LBH589) on human HCC cell lines HepG2 (p53wt) and Hep3B (p53null) and in a subcutaneous xenograft model and explored the influence on angiogenesis. Specimens were characterized by quantitative real-time PCR. Protein was separated for western blotting against CTGF, VEGF, VEGF receptor-1 (VEGFR-1/FLT-1), VEGF receptor-2 (VEGFR-2/KDR), MAPK and phospho-MAPK. In vivo, HepG2 cells were xenografted to NMRI mice and treated with daily i.p. injections of 10 mg/kg panobinostat. After 1, 7 and 28 days, real-time PCR was performed. Immunohistochemistry and western blotting were examined after 28 days. An increased significant expression of CTGF was only seen after 24 h treatment with 0.1 µM panobinostat in HepG2 cells and Hep3B cells, whereas after 72 h treatment CTGF expression clearly decreased. In the xenografts, treatment with panobinostat showed a minimal CTGF expression after 1 day and 4 weeks, respectively. In vitro as well as in vivo, VEGF was not affected by panobinostat treatment at any time. In conclusion, panobinostat influences extracellular signaling cascades via CTGF-dependent pathways.
EVALuna2:2025

The Phase 3 NETTER-1 Study of [Lu-177]Lu-DOTA-TATE in Patients with Midgut Neuroendocrine Tumours: Final Overall Survival and Long-Term Renal Safety - Kunz, P.; Caplin, M. E.; Ruszniewski, P. B.; Bodei, L.; Hendifar, A.; Mittra, E.; Wolin, E. M.; Yao, J. C.; Pavel, Marianne Ellen; Grande, E.; Van Cutsem, E.; Seregni, E.; et al. (EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 2021)
CRIS-Team WoS Importer:2022-01-07

The phase III NETTER-1 study of 177Lu-DOTATATE in patients with midgut neuroendocrine tumours: Further survival analyses - Ruszniewski, P. B.; Caplin, M. E.; Kunz, P. L.; Bodei, L.; Hendifar, A. E.; Mittra, E.; Wolin, E. M.; Yao, J. C.; Pavel, Marianne Ellen; Grande, E.; Van Cutsem, E.; Seregni, E.; et al. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-10-15

The place of new oral anticoagulants in travel medicine - Ringwald, Juergen; Grauer, Martin; Eckstein, Reinhold; Jelinek, Tomas (Travel Medicine and Infectious Disease, 2014)
New oral anticoagulants are increasingly used instead of vitamin K antagonists or low molecular weight heparins. Hence, more individuals treated with new oral anticoagulants will seek travel medicine advice. Travel medicine experts should therefore become familiar with new oral anticoagulants and with their impact and role in travel medicine. This review summarizes pharmacological characteristics and approved indications of dabigatran, rivaroxaban and apixaban, and highlights their relevance for travellers on permanent oral anticoagulation and for the prophylaxis of travellers' thrombosis. Compared to vitamin K antagonists, the new oral anticoagulants have many advantages: they do not have interactions with food, they have lower potential for drug-drug interactions and do not require regularly performed laboratory tests. The oral administration, obviating the need to carry needles and syringes during travel may give the new oral anticoagulants a further advantage over low molecular weight heparins. Clinical experience with the new oral anticoagulants, however, is still rather limited and there is concern regarding the clinical management of patients treated with new oral anticoagulants who suffer from severe bleeding or who need urgent invasive procedures. Overall, it remains an individual decision based on a risk/benefit analysis as to whether or not patients on long-term treatment with vitamin K antagonists should be switched to new oral anticoagulants for intended travel. Further caution is also indicated so that the availability of orally administered new anticoagulants should not lead to undifferentiated and unjustified prescription of anticoagulants for the prophylaxis of traveller's thrombosis.
EVALuna2:15976

The Positive Rate of Pulmonary Embolism by CT Pulmonary Angiography Is High in an Emergency Department, even in Low-Risk or Young Patients - Al-Zaher, Nizam; Vitali, Francesco; Neurath, Markus; Görtz, Rüdiger (Medical Principles and Practice, 2021)
Objective: The clinical presentation of pulmonary embolism (PE) can be various and misleading. We analyzed patients with suspicion of PE and subsequently performed computed tomography pulmonary angiography (CTPA) in an emergency department of Internal Medicine, focusing on patient groups in which PE might be underestimated in the emergency setting, such as young patients and patients with low clinical probability. Material and Methods: In 2016 and 2017, all patients receiving a CTPA for investigation of PE were retrospectively evaluated for clinical parameters (age, symptoms, and vital parameters) and D-dimers. The Wells score was calculated. Results: CTPA was performed in 323 patients (158 female and 165 male; mean age 62 years). The leading symptoms for admission were dyspnea or chest pain; 62% showed intermediate or high risk for PE, calculated by applying the Wells score. In 123 (38%) of all patients, a PE was proved and pathologic age-Adjusted D-dimers were found in 97.6%. Thirty of 121 (25%) patients with low risk according to Wells score had a PE. Deep vein thrombosis was verified in 67/123 (55%) patients; 43% (15/35) of all suspicions for PE in patients <40 years were positive with 4/15 (26%), showing a central PE. Younger patients (<40 years) with PE presented more often with tachycardia or tachypnea and chest pain or dyspnea than elderly patients with PE. Conclusion: CTPA frequently proves a PE in patients with suspicion of PE in an emergency department of Internal Medicine. If PE is suspected and CTPA performed accordingly, the presence of PE is quite common even in low-risk patient groups (Wells score) or in young patients <40 years with chest pain or dyspnea.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Chest pain; CT pulmonary angiography; Dyspnea; Emergency; Pulmonary embolisms

The potential of omics technologies for the treatment of immune‐mediated inflammatory diseases - Anchang, Charles Gwellem; Xu, Cong; Raimondo, Maria Gabriella; Atreya, Raja; Maier, Andreas; Schett, Georg; Zaburdaev, Vasily; Rauber, Simon; Ramming, Andreas (International Journal of Molecular Sciences, 2021)
Immune‐mediated inflammatory diseases (IMIDs), such as inflammatory bowel diseases and inflammatory arthritis (e.g., rheumatoid arthritis, psoriatic arthritis), are marked by increasing worldwide incidence rates. Apart from irreversible damage of the affected tissue, the systemic nature of these diseases heightens the incidence of cardiovascular insults and colitis‐associated neo-plasia. Only 40–60% of patients respond to currently used standard‐of‐care immunotherapies. In addition to this limited long‐term effectiveness, all current therapies have to be given on a lifelong basis as they are unable to specifically reprogram the inflammatory process and thus achieve a true cure of the disease. On the other hand, the development of various OMICs technologies is consid-ered as “the great hope” for improving the treatment of IMIDs. This review sheds light on the pro-gressive development and the numerous approaches from basic science that gradually lead to the transfer from “bench to bedside” and the implementation into general patient care procedures.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Advanced imaging technologies; Immune‐mediated inflammatory diseases (IMIDs); Single‐cell RNA sequencing; Spatial sequencing

The PPARα Agonist Fenofibrate Prevents Formation of Protein Aggregates (Mallory-Denk bodies) in a Murine Model of Steatohepatitis-like Hepatotoxicity - Nikam, Aniket; Patankar, Jay; Somlapura, Meghana; Lahiri, Pooja; Sachdev, Vinay; Kratky, Dagmar; Denk, Helmut; Zatloukal, Kurt; Abuja, Peter M. (Scientific Reports, 2018)
Chronic intoxication of mice with the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) leads to morphological and metabolic changes closely resembling steatohepatitis, a severe form of metabolic liver disease in humans. Since human steatohepatitis (both the alcoholic and non-alcoholic type) is characterized by reduced expression of PPARα and disturbed lipid metabolism we investigated the role of this ligand-activated receptor in the development of DDC-induced liver injury. Acute DDC-intoxication was accompanied by early significant downregulation of Pparα mRNA expression along with PPARα-controlled stress-response and lipid metabolism genes that persisted in the chronic stage. Administration of the specific PPARα agonist fenofibrate together with DDC prevented the downregulation of PPARα-associated genes and also improved the stress response of Nrf2-dependent redox-regulating genes. Moreover, oxidative stress and inflammation were strongly reduced by DDC/fenofibrate co-treatment. In addition, fenofibrate prevented the disruption of hepatocyte intermediate filament cytoskeleton and the formation of Mallory-Denk bodies at late stages of DDC intoxication. Our findings show that, like in human steatohepatitis, PPARα is downregulated in the DDC model of steatohepatitis-like hepatocellular damage. Its downregulation and the pathomorphologic features of steatohepatitis are prevented by co-administration of fenofibrate.
Created from Fastlane, Scopus look-up

The prognostic significance of respiratory rate in patients with pneumonia: a retrospective analysis of data from 705,928 hospitalized patients in Germany from 2010-2012 - Strauss, Richard; Ewig, Santiago; Richter, Klaus; Koenig, Thomas; Heller, Guenther; Bauer, Torsten T. (Deutsches Ärzteblatt international, 2014)
Measurement of the respiratory rate is an important instrument for assessing the severity of acute disease. The respiratory rate is often not measured in routine practice because its clinical utility is inadequately appreciated. In Germany, documentation of the respiratory rate is obligatory when a patient with pneumonia is hospitalized. This fact has enabled us to study the prognostic significance of the respiratory rate in reference to a large medical database.We retrospectively analyzed data from the external quality-assurance program for community-acquired pneumonia for the years 2010-2012. All patients aged 18 years or older who were not mechanically ventilated on admission were included in the analysis. Logistic regression was used to determine the significance of the respiratory rate as a risk factor for in-hospital mortality.705,928 patients were admitted to the hospital with community-acquired pneumonia (incidence: 3.5 cases per 1000 adults per year). The in-hospital mortality of these patients was 13.1% (92 227 persons). The plot of mortality as a function of respiratory rate on admission was U-shaped and slanted to the right, with the lowest mortality at a respiratory rate of 20/min on admission. If patients with a respiratory rate of 12-20/min are used as a baseline for comparison, patients with a respiratory rate of 27-33/min had an odds ratio (OR) of 1.72 for in-hospital death, and those with a respiratory rate above 33/min had an OR of 2.55. Further independent risk factors for in-hospital death were age, admission from a nursing home, hospital, or rehabilitation facility, chronic bedridden state, disorientation, systolic blood pressure, and pulse pressure.Respiratory rate is an independent risk marker for in-hospital mortality in community-acquired pneumonia. It should be measured when patients are admitted to the hospital with pneumonia and other acute conditions.
EVALuna2:1886

The Proteomic Signature of Tissue Remodeling in Chronic Intestinal Inflammation - Neurath, Markus (Cellular and Molecular Gastroenterology and Hepatology, 2024)
CRIS-Team Scopus Importer:2024-03-22

The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis - Lopez Posadas, Rocío; Becker, Christoph; Günther, Claudia; Tenzer, Stefan; Amann, Kerstin Ute; Billmeier, Ulrike; Atreya, Raja; Fiorino, Gionata; Vetrano, Stefania; Danese, Silvio; Ekici, Arif Bülent; Wirtz, Stefan; et al. (Journal of Clinical Investigation, 2016)
Although necrosis and necroinflammation are central features of many liver diseases, the role of programmed necrosis in the context of inflammation-dependent hepatocellular death remains to be fully determined. Here, we have demonstrated that the pseudokinase mixed lineage kinase domain-like protein (MLKL), which plays a key role in the execution of receptor-interacting protein (RIP) kinase-dependent necroptosis, is upregulated and activated in human autoimmune hepatitis and in a murine model of inflammation-dependent hepatitis. Using genetic and pharmacologic approaches, we determined that hepatocellular necrosis in experimental hepatitis is driven by an MLKL-dependent pathway that occurs independently of RIPK3. Moreover, we have provided evidence that the cytotoxic activity of the proinflammatory cytokine IFN-? in hepatic inflammation is strongly connected to induction of MLKL expression via activation of the transcription factor STAT1. In summary, our results reveal a pathway for MLKL-dependent programmed necrosis that is executed in the absence of RIPK3 and potentially drives the pathogenesis of severe liver diseases.
EVALuna2:2178

The Quest for Anti-α-Synuclein Antibody Specificity—Lessons Learnt From Flow Cytometry Analysis - Leupold, Lukas; Sigutova, Veronika; Gerasimova, Elizaveta; Regensburger, Martin; Zundler, Sebastian; Zunke, Friederike; Xiang, Wei; Winner, Beate; Prots, Iryna (Frontiers in Neurology, 2022)
The accumulation of alpha-synuclein (aSyn) is the hallmark of a group of neurodegenerative conditions termed synucleopathies. Physiological functions of aSyn, including those outside of the CNS, remain elusive. However, a reliable and reproducible evaluation of aSyn protein expression in different cell types and especially in low-expressing cells is impeded by the existence of a huge variety of poorly characterized anti-aSyn antibodies and a lack of a routinely used sensitive detection methods. Here, we developed a robust flow cytometry-based workflow for aSyn detection and antibody validation. We test our workflow using three commercially available antibodies (MJFR1, LB509, and 2A7) in a variety of human cell types, including induced pluripotent stem cells, T lymphocytes, and fibroblasts, and provide a cell- and antibody-specific map for aSyn expression. Strikingly, we demonstrate a previously unobserved unspecificity of the LB509 antibody, while the MJFR1 clone revealed specific aSyn binding however with low sensitivity. On the other hand, we identified an aSyn-specific antibody clone 2A7 with an optimal sensitivity for detecting aSyn in a range of cell types, including those with low aSyn expression. We further utilize our workflow to demonstrate the ability of the 2A7 antibody to distinguish between physiological differences in aSyn expression in neuronal and non-neuronal cells from the cortical organoids, and in neural progenitors and midbrain dopaminergic neurons from healthy controls and in patients with Parkinson's disease who have aSyn gene locus duplication. Our results provide a proof of principle for the use of high-throughput flow cytometry-based analysis of aSyn and highlight the necessity of rigorous aSyn antibody validation to facilitate the research of aSyn physiology and patholog
Keywords: alpha-synuclein; antibodies; synuclein antibodies; T cell; antibody specificity; flow cytometry; α-synuclein expression

The Randomized AMBORA Trial: Impact of Pharmacological/Pharmaceutical Care on Medication Safety and Patient-Reported Outcomes During Treatment With New Oral Anticancer Agents - Dürr, Pauline; Schlichtig, Katja; Kelz, Carolin; Deutsch, Birgit; Maas, Renke; Eckart, Michael J.; Wilke, Jochen; Wagner, Harald; Wolff, Kerstin; Preuß, Caroline; Brückl, Valeska; Meidenbauer, Norbert; et al. (Journal of Clinical Oncology, 2021)
PURPOSE: Oral anticancer drugs (eg, kinase inhibitors) play an important role in cancer therapy. However, considerable challenges regarding medication safety of oral anticancer drugs have been reported. Randomized, controlled, multicenter studies on the impact of intensified clinical pharmacological/pharmaceutical care on patient safety and patient treatment perception are lacking. METHODS: Patients were eligible for the randomized, multicenter AMBORA study, if they were newly started on any of the oral anticancer drugs approved in 2001 or later without restriction to certain tumor entities. Patients were randomly assigned to receive either standard of care (control group) or an additional, intensified clinical pharmacological/pharmaceutical care, which included medication management and structured patient counseling, over a period of 12 weeks (intervention group). Primary end points were the number of antitumor drug-related problems (ie, side effects and unresolved medication errors) and patient treatment satisfaction with the oral anticancer therapy after 12 weeks measured with the Treatment Satisfaction Questionnaire for Medication, category convenience. RESULTS: Two hundred two patients were included. Antitumor drug-related problems were significantly lower in the intervention compared with the control group (3.85 v 5.81 [mean], P < .001). Patient treatment satisfaction was higher in the intervention group (Treatment Satisfaction Questionnaire for Medication, convenience; 91.6 v 74.4 [mean], P < .001). The hazard ratio for the combined end point of severe side effects (Common Terminology Criteria for Adverse Events ≥ 3), treatment discontinuation, unscheduled hospital admission, and death was 0.48 (95% CI, 0.32 to 0.71, P < .001) in favor of the intervention group. CONCLUSION: Treatment with oral anticancer drugs is associated with a broad range of medication errors and side effects. An intensified clinical pharmacological/pharmaceutical care has considerable, positive effects on the number of medication errors, patient treatment perception, and severe side effects.
CRIS-Team Scopus Importer:2021-07-02

Therapeutic modulation of the bile acid pool by cyp8b1 knockdown protects against nonalcoholic fatty liver disease in mice - Chevre, Raphael; Trigueros-Motos, Laia; Castano, David; Chua, Tricia; Corliano, Maria; Patankar, Jay; Sng, Lareina; Sim, Lauren; Juin, Tan Liang; Carissimo, Guillaume; Ng, Lisa F. P.; Yi, Cheryl Neo Jia; et al. (The FASEB Journal, 2018)
Bile acids (BAs) are surfactant molecules that regulate the intestinal absorption of lipids. Thus, the modulation of BAs represents a potential therapy for nonalcoholic fatty liver disease (NAFLD), which is characterized by hepatic accumulation of fat and is a major cause of liver disease worldwide. Cyp8b1 is a critical modulator of the hydrophobicity index of the BA pool. As a therapeutic proof of concept, we aimed to determine the impact of Cyp8b1 inhibition in vivo on BA pool composition and as protection against NAFLD. Inhibition of Cyp8b1 expression in mice led to a remodeling of the BA pool, which altered its signaling properties and decreased intestinal fat absorption. In a model of cholesterol-induced NAFLD, Cyp8b1 knockdown significantly decreased steatosis and hepatic lipid content, which has been associated with an increase in fecal lipid and BA excretion. Moreover, inhibition of Cyp8b1 not only decreased hepatic lipid accumulation, but also resulted in the clearance of previously accumulated hepatic cholesterol, which led to a regression in hepatic steatosis. Taken together, our data demonstrate that Cyp8b1 inhibition is a viable therapeutic target of crucial interest for metabolic diseases, such as NAFLD.—Chevre, R., Trigueros-Motos, L., Castaño, D., Chua, T., Corlianò, M., Patankar, J. V., Sng, L., Sim, L., Juin, T. L., Carissimo, G., Ng, L. F. P., Yi, C. N. J., Eliathamby, C. C., Groen, A. K., Hayden, M. R., Singaraja, R. R. Therapeutic modulation of the bile acid pool by Cyp8b1 knockdown protects against nonalcoholic fatty liver disease in mice.
Created from Fastlane, Scopus look-up
Keywords: Intestinal cholesterol absorption; Liver targeting; NAFLD therapeutics; SiRNA delivery; Steatosis

Therapy adaption by dose titration of obeticholic acid in a 57-year-old female patient with PBC and advanced liver fibrosis - Vetter, Marcel; Dietrich, Peter; Kremer, Andreas (SWISS MEDICAL WEEKLY, 2021)
CRIS-Team WoS Importer:2022-03-11

The Regulation of Intestinal Inflammation and Cancer Development by Type 2 Immune Responses - Gamez-Belmonte, Reyes; Erkert, Lena; Wirtz, Stefan; Becker, Christoph (International Journal of Molecular Sciences, 2020)
The gut is among the most complex organs of the human body. It has to exert several functions including food and water absorption while setting up an efficient barrier to the outside world. Dysfunction of the gut can be life-threatening. Diseases of the gastrointestinal tract such as inflammatory bowel disease, infections, or colorectal cancer, therefore, pose substantial challenges to clinical care. The intestinal epithelium plays an important role in intestinal disease development. It not only establishes an important barrier against the gut lumen but also constantly signals information about the gut lumen and its composition to immune cells in the bowel wall. Such signaling across the epithelial barrier also occurs in the other direction. Intestinal epithelial cells respond to cytokines and other mediators of immune cells in the lamina propria and shape the microbial community within the gut by producing various antimicrobial peptides. Thus, the epithelium can be considered as an interpreter between the microbiota and the mucosal immune system, safeguarding and moderating communication to the benefit of the host. Type 2 immune responses play important roles in immune-epithelial communication. They contribute to gut tissue homeostasis and protect the host against infections with helminths. However, they are also involved in pathogenic pathways in inflammatory bowel disease and colorectal cancer. The current review provides an overview of current concepts regarding type 2 immune responses in intestinal physiology and pathophysiology.
CRIS-Team WoS Importer:2021-01-15

The relevance of cancer related fatigue in neuroendocrine neoplasia patients - Banz, S.; Mellar, K.; Letsch, A.; Scheibenbogen, C.; Pavel, Marianne Ellen; Grabowski, P. (ONCOLOGY RESEARCH AND TREATMENT, 2019)
CRIS-Team WoS Importer:2020-10-02

The role of interferon type I and type III receptors in rhinovirus induced allergic asthma - Krug, J.; Kölle, Julia; Kiefer, Alexander; Vuorinen, T.; Xepapadaki, P.; Stanic, B.; Akdis, M.; Zimmermann, Theodor; Papadopoulos, N. G.; Finotto, Susetta; Chiriac, Mircea-Teodor (ALLERGY, 2020)
CRIS-Team WoS Importer:2020-10-02

The role of IRF-1 during pathogen-induced intestinal Inflammation - Schmalzl, Angelika; Neurath, Markus; Wirtz, Stefan (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

The role of Krueppel-like factor 2 in B cell activation and plasma cell homeostasis - Schubert, T.; Knipfer, Lisa; Wallrapp, Antonia; Wittner, Jens; Jäck, Hans-Martin; Schuh, Wolfgang (2017)
EVALuna2:13652

The role of midkine in health and disease - Neumaier, Emely; Rothhammer, Veit; Linnerbauer, Mathias (Frontiers in Immunology, 2023)
Midkine (MDK) is a neurotrophic growth factor highly expressed during embryogenesis with important functions related to growth, proliferation, survival, migration, angiogenesis, reproduction, and repair. Recent research has indicated that MDK functions as a key player in autoimmune disorders of the central nervous system (CNS), such as Multiple Sclerosis (MS) and is a promising therapeutic target for the treatment of brain tumors, acute injuries, and other CNS disorders. This review summarizes the modes of action and immunological functions of MDK both in the peripheral immune compartment and in the CNS, particularly in the context of traumatic brain injury, brain tumors, neuroinflammation, and neurodegeneration. Moreover, we discuss the role of MDK as a central mediator of neuro-immune crosstalk, focusing on the interactions between CNS-infiltrating and -resident cells such as astrocytes, microglia, and oligodendrocytes. Finally, we highlight the therapeutic potential of MDK and discuss potential therapeutic approaches for the treatment of neurological disorders.
CRIS-Team Scopus Importer:2023-12-22
Keywords: CNS; inflammation; injury; malignancy; midkine

The Role of Programmed Necrosis in Colorectal Cancer - Yu, Yidong; Gámez Belmonte, Maria de los Reyes; Patankar, Jay; Liebing, Eva; Becker, Christoph (Cancers, 2022)
Simple Summary Necrosis is a type of cell death characterized by plasma membrane rupture and the induction of inflammation. This review focuses on colorectal cancer and outlines the role of programmed necrosis in tumor development. Potential strategies for anti-tumor treatment via targeting programmed necrosis are also discussed. For quite a long time, necrosis was considered a chaotic and unorganized form of cell death. However, studies conducted during the past few decades unveiled multiple types of programmed necrosis, such as necroptosis, pyroptosis and ferroptosis. These types of programmed necrosis have been shown to play crucial roles in mediating pathological processes, including tumorigenesis. Almost all key mediators, such as RIPK3 and MLKL in necroptosis, GSDMD and caspase 1/11 in pyroptosis and GPX4 in ferroptosis, are highly expressed in intestinal epithelial cells (IECs). An aberrant increase or decrease in programmed necrosis in IECs has been connected to intestinal disorders. Here, we review the pathways of programmed necrosis and the specific consequences of regulated necrosis in colorectal cancer (CRC) development. Translational aspects of programmed necrosis induction as a novel therapeutic alternative against CRC are also discussed.
CRIS-Team WoS Importer:2022-09-16

The role of the chemokine receptor CCR8 in migration and effector function of innate lymphoid cells type 2 - Knipfer, Lisa; Schulz-Kuhnt, Anja; Symowski, Cornelia; Vöhringer, David; Neurath, Markus; Atreya, I.; Wirtz, Stefan (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study - Hegade, V. S.; Krawczyk, M.; Kremer, Andreas; Kuczka, Judith; Gaouar, F.; Kuiper, E. M. M.; Van Buuren, H. R.; Lammert, F.; Corpechot, C.; Jones, D. E. J. (Alimentary Pharmacology & Therapeutics, 2016)
Pruritus is a common symptom associated with cholestatic liver diseases. To date only small single centre case series have suggested efficacy of nasobiliary drainage in relieving cholestatic pruritus.To perform a multicentre study to evaluate the safety and efficacy of nasobiliary drainage in cholestatic pruritus.This was a retrospective study of all patients treated with nasobiliary drainage for refractory cholestatic pruritus between 2006 and 2015 at five European centres. Pruritus was quantified using a visual analogue scale (VAS) and liver enzymes, serum bilirubin and total serum bile salts (TBS) were measured before (pre-NBD) and after nasobiliary drainage (post-NBD). We analysed the duration of treatment response and associated complications.In total, 27 patients (59% females) underwent 29 nasobiliary drainage procedures. The median duration of NBD was 7 days. NBD decreased pruritus in 89.6% of cases (VAS from 10.0 to 0.3, P < 0.0001). The median percentage decline in pruritus VAS was 94% and 33% of patients were free of pruritus within 24 h of starting drainage. The duration of treatment response was independent of duration of drainage (P = 0.12) and bile output. Significant improvements were seen in the median levels of serum alkaline phosphatase (P = 0.001) and serum bilirubin (P = 0.03) but not in serum TBS (P = 0.07). Mild post-endoscopic retrograde cholangiopancreatography pancreatitis (31%) was the most frequent complication.Nasobiliary drainage is effective in relieving cholestatic pruritus in most patients and has favourable effect on biomarkers of cholestasis. Nasobiliary drainage may be associated with high risk of adverse events, especially pancreatitis. Prospective studies are needed to confirm our findings.
EVALuna2:2039

The sphingosine-1-phosphate receptor agonist etrasimod in ulcerative colitis - Atreya, Raja; Neurath, Markus (Lancet, 2023)
CRIS-Team Scopus Importer:2023-03-23

The TLR9 agonist cobitolimod induces anti-inflammatory effects and balances the Th17/T-reg cell response in ulcerative colitis - Schmitt, H.; Billmeier, Ulrike; Ulmschneider, J.; Admyre, C.; Knittel, T.; Zargari, A.; Neurath, Markus; Atreya, Raja (2018)
EVALuna2:34112

The TLR9 agonist cobitolimod induces IL10 producing wound healing macrophages and regulatory T cells in ulcerative colitis - Schmitt, Heike; Ulmschneider, Julia; Billmeier, Ulrike; Scarozza, Patrizio; Sonnewald, Sophia; Reid, Stephen; Atreya, Imke; Rath, Timo; Zundler, Sebastian; Langheinrich, Melanie; Schüttler, Jürgen; Hartmann, Arndt; et al. (Journal of Crohns & Colitis, 2020)
BACKGROUND AND AIMS: The topically applied Toll-like receptor 9 (TLR9) agonist cobitolimod is a first-in-class DNA-based oligonucleotide that demonstrated therapeutic efficacy in clinical trials with ulcerative colitis (UC) patients. We here characterized its anti-inflammatory mechanism in UC. METHODS: Luminal cobitolimod administration was evaluated in an experimental DSS-induced colitis model. Cultured blood and mucosal cells from UC patients were treated with cobitolimod and analyzed via microarray, qRT-PCR, ELISA and flow cytometry. Intestinal slides of cobitolimod treated UC patients were analyzed by immunohistochemistry. RESULTS: Cobitolimod administration markedly suppressed experimental colitis activity and microarrays analyses demonstrated mucosal IL10 upregulation and suppression of IL17 signaling pathways. Cobitolimod treatment was associated with significant induction of mucosal IL10+ Tr1 and Treg cells and suppression of Th17 cells. TLR9 knockout mice indicated that cobitolimod requires TLR9 signaling for IL10 induction. In UC patients, mucosal TLR9 levels correlated with severity of inflammation. Cobitolimod inhibited IL17A and IL17F, but increased IL10 and FoxP3 expression in cultured intestinal UC T cells. Cobitolimod-mediated suppression of intestinal IL17+ T cells was abrogated by IL10 blockade. Furthermore, cobitolimod led to heightened IL10 production by wound healing macrophages. Immunohistochemistry in intestinal biopsies of cobitolimod treated UC patients indicated increased presence of IL10+ mononuclear and regulatory T cells, as well as reduction of IL17+ cells. CONCLUSION: Our studies suggest that activation of TLR9 via cobitolimod might represent a novel therapeutic approach in UC, as it suppresses Th17 cells and induces anti-inflammatory IL10+ macrophages and regulatory T cells, thereby modifying the dysregulated intestinal cytokine balance.
EVALuna2:212910
Keywords: Ulcerative colitis; TLR9; cobitolimod

The transcription factor NFATc3 promotes intestinal inflammation by suppression of regulatory T cells - Gerlach, Katharina; Popp, Vanessa; Neurath, Markus; Weigmann, Benno (2017)
EVALuna2:33799

The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis - Mlecnik, Bernhard; Bindea, Gabriela; Kirilovsky, Amos; Angell, Helen K.; Obenauf, Anna C.; Tosolini, Marie; Church, Sarah E.; Maby, Pauline; Vasaturo, Angela; Angelova, Mihaela; Fredriksen, Tessa; Mauger, Stephanie; et al. (Science Translational Medicine, 2016)
Although distant metastases account for most of the deaths in cancer patients, fundamental questions regarding mechanisms that promote or inhibit metastasis remain unanswered. We show the impact of mutations, genomic instability, lymphatic and blood vascularization, and the immune contexture of the tumor microenvironment on synchronous metastases in large cohorts of colorectal cancer patients. We observed large genetic heterogeneity among primary tumors, but no major differences in chromosomal instability or key cancer-associated mutations. Similar patterns of cancer-related gene expression levels were observed between patients. No cancer-associated genes or pathways were associated with M stage. Instead, mutations of FBXW7 were associated with the absence of metastasis and correlated with increased expression of T cell proliferation and antigen presentation functions. Analyzing the tumor microenvironment, we observed two hallmarks of the metastatic process: decreased presence of lymphatic vessels and reduced immune cytotoxicity. These events could be the initiating factors driving both synchronous and metachronous metastases. Our data demonstrate the protective impact of the Immunoscore, a cytotoxic immune signature, and increased marginal lymphatic vessels, against the generation of distant metastases, regardless of genomic instability.
EVALuna2:2107

The use of deep learning models to predict progression-free survival in patients with neuroendocrine tumors - Pavel, Marianne Ellen; Dromain, Clarisse; Ronot, Maxime; Schaefer, Niklaus; Mandair, Dalvinder; Gueguen, Delphine; Elvira, David; Jégou, Simon; Balazard, Félix; Dehaene, Olivier; Schutte, Kathryn (Future Oncology, 2023)
Aim: The RAISE project assessed whether deep learning could improve early progression-free survival (PFS) prediction in patients with neuroendocrine tumors. Patients & methods: Deep learning models extracted features from CT scans from patients in CLARINET (NCT00353496) (n = 138/204). A Cox model assessed PFS prediction when combining deep learning with the sum of longest diameter ratio (SLDr) and logarithmically transformed CgA concentration (logCgA), versus SLDr and logCgA alone. Results: Deep learning models extracted features other than lesion shape to predict PFS at week 72. No increase in performance was achieved with deep learning versus SLDr and logCgA models alone. Conclusion: Deep learning models extracted relevant features to predict PFS, but did not improve early prediction based on SLDr and logCgA.
CRIS-Team Scopus Importer:2023-11-10
Keywords: artificial intelligence; deep learning; neuroendocrine tumors; progression-free survival; RECIST

The use of deep learning models to predict progression-free survival in patients with neuroendocrine tumors: Results from phase 3 of the RAISE project - Pavel, Marianne Ellen; Dromain, C.; Ronot, M.; Schaefer, N.; Mandair, D.; Gueguen, D.; Elvira, D.; Balazard, F.; Dehaene, O.; Schutte, K. (JOURNAL OF NEUROENDOCRINOLOGY, 2021)
CRIS-Team WoS Importer:2021-03-12

The validation of estrogen receptor 1 mRNA expression as a predictor of outcome in patients with metastatic non-small cell lung cancer - Atmaca, Akin; Al-Batran, Salah-Eddin; Wirtz, Ralph Markus; Werner, Dominique; Zirlik, Sabine; Wiest, Gunther; Eschbach, Corinna; Claas, Silke; Hartmann, Arndt; Ficker, Joachim Hans; Jaeger, Elke; Brueckl, Wolfgang Michael (International Journal of Cancer, 2014)
The prognostic role of estrogen receptors in lung cancer is not validated. Results from patients with early stage non-small lung cancer patients indicate a prognostic role of estrogen receptor 1 (ESR1) mRNA expression in these patients. Automated RNA extraction from paraffin and RT-quantitative PCR was used for evaluation of tumoral ESR1 and progesterone receptor (PGR) mRNA expression. The test cohort consisted of 31 patients with advanced or metastatic non-small cell lung cancer (NSCLC) patients, treated in a first-line registry trial. For validation, 53 patients from a randomized multicentre first-line study with eligible tumor samples were evaluated. There was no significant correlation of ESR1 expression with clinical characteristics. ESR1 high expression was of significant positive prognostic value in the training set with a median overall survival (OS) of 15.9 versus 6.2 months for high versus low ESR1 expression patients (p = 0.0498, HR 0.39). This could be confirmed in the validation cohort with a median OS of 10.9 versus 5.0 months in ESR1 high versus low patients, respectively (p = 0.0321, HR 0.51). In the multivariate analysis adjusted for histological subtype, gender, age and performance status, ESR1 expression remained an independent prognostic parameter for survival in both cohorts. In contrast to ESR1, PGR expression was not able to separate prognostic groups or to predict outcome significantly (for OS; p = 0.94). Our study shows that ESR1 mRNA as assessed by qPCR represents a reliable method for detecting ESR1 expression in NSCLC and that ESR1 expression is an independent prognostic factor in metastatic NSCLC.
EVALuna2:1901

The yin and yang of B cells in a constant state of battle: intestinal inflammation and inflammatory bowel disease - Zogorean, Roxana; Wirtz, Stefan (Frontiers in Immunology, 2023)
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, defined by a clinical relapse-remitting course. Affecting people worldwide, the origin of IBD is still undefined, arising as a consequence of the interaction between genes, environment, and microbiota. Although the root cause is difficult to identify, data clearly indicate that dysbiosis and pathogenic microbial taxa are connected with the establishment and clinical course of IBD. The composition of the microbiota is shaped by plasma cell IgA secretion and binding, while cytokines such as IL10 or IFN-γ are important fine-tuners of the immune response in the gastrointestinal environment. B cells may also influence the course of inflammation by promoting either an anti-inflammatory or a pro-inflammatory milieu. Here, we discuss IgA-producing B regulatory cells as an anti-inflammatory factor in intestinal inflammation. Moreover, we specify the context of IgA and IgG as players that can potentially participate in mucosal inflammation. Finally, we discuss the role of B cells in mouse infection models where IL10, IgA, or IgG contribute to the outcome of the infection.
CRIS-Team Scopus Importer:2023-10-27
Keywords: IBD; IgA; IgG; intestinal inflammation; microbiota; plasma cells; regulatory B cells (Bregs)

The α4β1 Homing Pathway Is Essential for Ileal Homing of Crohn's Disease Effector T Cells In Vivo - Zundler, Sebastian; Fischer, Anika; Schillinger, Daniela; Binder, Marie-Theres; Atreya, Raja; Rath, Timo; Lopez Posadas, Rocío; Voskens, Caroline J.; Watson, Alastair; Atreya, Imke; Neufert, Clemens; Neurath, Markus (Inflammatory Bowel Diseases, 2017)
BACKGROUND: The precise mechanisms controlling homing of T effector (Teff) cells to the inflamed gut in Crohn's disease (CD) are still unclear, and clinical outcome data from patients with inflammatory bowel disease treated with the anti-α4β7 integrin antibody vedolizumab suggest differences between ulcerative colitis and CD. METHODS: Expression of homing molecules was studied with flow cytometry and immunohistochemistry. Their functional role was investigated in in vitro adhesion assays and in a humanized mouse model of T cell homing to the inflamed gut in vivo. RESULTS: Despite in vitro blockade of CD Teff adhesion to mucosal vascular addressin cell adhesion molecule-1 (MadCAM-1) and in contrast to previous observations in ulcerative colitis, anti-α4β7 treatment did not result in reduced Teff cell homing to the colon in vivo. However, the integrin α4β1 was expressed in higher levels on Teffs from patients with CD compared with controls, while its expression in the peripheral blood declined, and its expression in the intestine increased during the course of clinical vedolizumab treatment. Consistently, adhesion of CD Teffs to vascular cell adhesion molecule-1 (VCAM-1) was blocked by inhibition of α4 and α4β1 in vitro. Moreover, in vivo homing of CD Teffs to the ileum was reduced by inhibition of α4 and α4β1 integrins, but not α4β7 integrins. CONCLUSIONS: Our findings suggest that Teff cell homing to the ileum through the axis α4β1-VCAM-1 is an essential and nonredundant pathway in CD in vivo, possibly affecting efficacy of clinical treatment with antiadhesion compounds.
EVALuna2:33825

Thiopurines in Inflammatory Bowel Disease: New Findings and Perspectives - De Boer, Nanne K. H.; Peyrin-Biroulet, Laurent; Jharap, Bindia; Sanderson, Jeremy D.; Meijer, Berrie; Atreya, Imke; Barclay, Murray L.; Colombel, Jean-Frederic; Lopez, Anthony; Beaugerie, Laurent; Marinaki, Anthony M.; Van Bodegraven, Adriaan A.; et al. (Journal of Crohns & Colitis, 2018)
Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the available literature, as assessed by several experts in the field of thiopurine treatment and research in inflammatory bowel disease.
EVALuna2:35180

Three-Dimensional Cross-Sectional Light-Sheet Microscopy Imaging of the Inflamed Mouse Gut - Zundler, Sebastian; Klingberg, Anika; Schillinger, Daniela; Fischer, Sören; Neufert, Clemens; Atreya, Imke; Gunzer, Matthias; Neurath, Markus (Gastroenterology, 2017)
EVALuna2:33801

Three years of obeticholic Acid (OCA) therapy results in histological improvements in patients with primary biliary cholangitis: further analysis of the POISE Biopsy substudy - Bowlus, C. L.; Pockros, P. J.; Kremer, Andreas; Pares, A.; Forman, L. M.; Drenth, J. P. H.; Ryder, S.; Terracciano, L.; Floreani, A.; Jin, Y.; Lieberman, A.; Pencek, R.; et al. (DIGESTIVE AND LIVER DISEASE, 2019)
CRIS-Team WoS Importer:2019-03-01

Thumb sucking or nail biting in childhood and adolescence is associated with an increased risk of Crohn’s disease: results from a large case–control study - Teich, Niels; Mohl, Wolfgang; Primas, Christian; Novacek, Gottfried; Gauss, Annika; Walldorf, Jens; Felten, Gisela; Atreya, Raja; Kruis, Wolfgang; Bettenworth, Dominik; Roznowski, Artur Bartosz; Langhorst, Jost; et al. (Scandinavian Journal of Gastroenterology, 2020)
Background: The hygiene hypothesis suggests that a reduction in microbial exposure contributes to an impaired immune response later in life and increases the incidence of immune-mediated diseases such as inflammatory bowel diseases (IBD). Thumb sucking and nail biting are two early habits that modulate the oral microbiota composition and antigen load. Objective: We hypothesized a lower risk of Crohn’s disease (CD) and ulcerative colitis (UC) in adults with prior thumb sucking and nail biting. Methods: 918 IBD cases and their 918 siblings without IBD were asked to fill out a survey containing 32 questions on environmental factors in childhood and early adulthood. Prevalence of thumb sucking and/or nail biting at the usually well-remembered time of (1) school enrollment and (2) coming-of-age ceremonies was the predefined combined risk factor of this study. Results: 65% of the patients were female and 57% suffered from CD. About 49% of IBD patients but only 44% of their siblings reported thumb sucking/nail biting at the time of school enrollment or coming-of-age (p =.007). Sensitivity analysis revealed that this difference was observed in patients with CD (50% versus 41%; RR= 1.22; 95% CI 1.09–1.37, p =.001) but not in patients with UC (49% versus 48%; RR= 1.02; 95% CI 0.90–1.17; p =.83). Conclusion: Contrary to our expectation and challenging the hygiene hypothesis, we found that common oral habits are not protective against IBD. Instead, nail biting at the time of school enrollment and coming-of-age was a statistically significant risk factor for CD in our cohort. Key summary Evidence available before this study: The hygiene hypothesis suggests that a reduction in microbial exposure due to improved health activities has contributed to an immunological imbalance in the intestine and an increased incidence of allergic and autoimmune diseases. A population-based birth cohort study has demonstrated that thumb-sucking and nail biting in children lead to a reduction of the risk of atopic sensitization, asthma, and hay fever. Added value of this study: Contrary to the hypothesis, thumb sucking and nail biting were not associated with a reduced risk of IBD. Instead, thumb sucking and/or nail biting at the usually well-remembered points in time of school enrollment and of religious or secular coming-of-age ceremonies was associated with a higher risk of Crohn’s disease but not of ulcerative colitis. Our data did not support the hygiene hypothesis, one pathogenic concept in the context of IBD.
CRIS-Team Scopus Importer:2020-08-07
Keywords: Crohn’s disease; gut microbiota; hygiene hypothesis; nail biting; thumb sucking; ulcerative colitis

Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome - Dillon, Joseph S.; Kulke, Matthew H.; Hörsch, Dieter; Anthony, Lowell B.; Warner, Richard R.P.; Bergsland, Emily; Welin, Staffan; O’Dorisio, Thomas M.; Kunz, Pamela L.; McKee, Chad; Lapuerta, Pablo; Banks, Phillip; et al. (Journal of Gastrointestinal Cancer, 2020)
Background: Telotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analogs. In TELESTAR and TELECAST phase III studies, patients with carcinoid syndrome received telotristat ethyl 250 or 500 mg 3 times per day (tid) or placebo tid in addition to somatostatin analogs. The aim of this prespecified analysis was to examine the time to reductions in bowel movements (BMs) in the TELESTAR and TELECAST studies using survival analysis methods. Methods: First occurrence of sustained response was defined as the time to the first day of 2 consecutive weeks with a mean BM frequency improvement of ≥ 30% from baseline during the 12-week double-blind treatment periods. Time to first ≥ 30% worsening in BM frequency was also measured. Treatments were compared with the log-rank test; Cox regression models provided point and confidence interval estimates of the hazard ratios for each trial. Results: In TELESTAR and TELECAST, majority of patients (69%) on telotristat ethyl experienced a sustained ≥ 30% improvement in BM frequency. The median time to sustained reduction of at least 30% in BM frequency was significantly faster (fewer days to onset) for telotristat ethyl compared with placebo in both TELESTAR (250 mg, HR = 2.3 [95% CI, 1.3–4.1, P = 0.004]; 500 mg, HR = 2.2 [95% CI, 1.2–3.9, P = 0.009]) and TELECAST (250 mg, HR = 3.9 [95% CI, 1.6–11.1, P = 0.003]; 500 mg, HR = 4.2 [95% CI, 1.7–11.7, P = 0.002]). In TELECAST, 42% of patients on placebo experienced sustained worsening in BM frequency compared with 20% on telotristat ethyl; no significant difference was observed in TELESTAR. Conclusion: The time of onset of sustained BM frequency improvement mean and range are important when considering use of telotristat ethyl in patients with carcinoid syndrome diarrhea. Telotristat ethyl may also reduce sustained worsening in BM frequency. Trial Registration: ClinicalTrials.gov Identifiers: NCT01677910, NCT02063659
CRIS-Team Scopus Importer:2020-03-27
Keywords: Diarrhea; Malignant carcinoid syndrome; Neuroendocrine tumors; Serotonin; Telotristat ethyl; Tryptophan hydroxylase

Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Two Phase 3 Studies in Carcinoid Syndrome - Dillon, J.; Kulke, M.; Warner, R.; Bergsland, E.; Welin, S.; O'Dorisio, T.; Mckee, C.; Lapuerta, P.; Pavel, Marianne Ellen (2018)
EVALuna2:34123

Time to Sustained Improvement in Bowel Movement Frequency With Telotristat Ethyl: Analysis of the Phase 3 TELESTAR Study - Dillon, Joseph S.; Kulke, Matthew H.; Pavel, Marianne Ellen; Horsch, Dieter; Anthony, Lowell B.; Warner, Richard R. P.; Bergsland, Emily; Welin, Staffan; O'Dorisio, Thomas M.; Patel, Nilay; Lapuerta, Pablo (2018)
EVALuna2:34105

Tips and Tricks in Contrast-Enhanced Ultrasound (CEUS) for the Characterization and Detection of Liver Malignancies - Schellhaas, Barbara; Strobel, Deike (Ultraschall in der Medizin, 2019)
Contrast-enhanced ultrasound (CEUS) has a high diagnostic accuracy in the assessment of focal liver lesions. Clinical context (presence of liver cirrhosis, history of other malignancy versus incidental finding) is crucial for the correct interpretation of CEUS findings. CEUS has to be preceded by structured anamnesis and clinical examination as well as accurate B-mode sonography. Metastases are the most common malignant liver lesions in a non-cirrhotic liver. According to their contrast enhancement in the arterial phase, metastases are categorized as hyper- and hypo-vascular metastases. A common feature of all metastatic lesions is washout of the contrast agent in the portal venous or late phase. In the context of liver cirrhosis, > 95 % of focal liver lesions are hepatocellular carcinomas (HCCs). HCCs typically show arterial phase hyperenhancement, followed by mild and gradual contrast washout occurring very late in the late phase. For intrahepatic cholangiocellular carcinoma (ICC), the pattern of contrast enhancement in the arterial phase can vary. However, all ICCs typically show early and pronounced washout. Other liver malignancies like lymphoma, angiosarcoma, epithelioid hemangioendothelioma and others are very rare. Except for the contrast washout seen in all liver malignancies, they do not display pathognomonic enhancement patterns upon CEUS. Thus, biopsy is indispensable for definite diagnosis of the tumor entity. Furthermore, CEUS is used for the detection of metastases and therapeutic monitoring after local ablative procedures. The examination procedure differs slightly depending on the specific indication (characterization, detection).
CRIS-Team Scopus Importer:2019-08-16

TLR7/8 regulates type I and type III interferon signalling in rhinovirus 1b-induced allergic asthma - Krug, Jasmin; Kiefer, Alexander; Kölle, Julia; Vuorinen, Tytti; Xepapadaki, Paraskevi; Stanic, Barbara; Chiriac, Mircea-Teodor; Akdis, Muebeccel; Zimmermann, Theodor; Papadopoulos, Nikolaos G.; Finotto, Susetta (European Respiratory Journal, 2021)
Introduction: Interferon (IFN) responses have been reported to be defective in rhinovirus (RV)-induced asthma. The heterodimeric receptor of type I IFN (IFN-α/β) is composed of IFN-αR1 and IFN-αR2. Ligand binding to the IFN-α/β receptor complex activates signal transducer and activator of transcription (STAT) proteins STAT1 and STAT2 intracellularly. Although type III IFN (IFN-λ) binds to a different receptor containing IFN-λR1 and interleukin-10R2, its triggering leads to activation of the same downstream transcription factors. Here, we analysed the effects of RV on IFN type I and III receptors, and asked about possible Toll-like receptor 7/8 (TLR7/8) agonist R848-mediated IFN-αR1 and IFN-λR1 regulation. Methods: We measured IFN-α, IFN-β and IFN-λ and their receptor levels in peripheral blood mononuclear cell (PBMC) supernatants and cell pellets stimulated with RV1b and R848 in two cohorts of children with and without asthma recruited at pre-school age (PreDicta) and at primary school age (AGENDAS) as well as in cell supernatants from total lung cells isolated from mice. Results: We observed that R848 induced IFN-λR mRNA expression in PBMCs of healthy and asthmatic children, but suppressed IFN-αR mRNA levels. In murine lung cells, RV1b alone and together with R848 suppressed IFN-αR protein in T-cells compared with controls and in total lung IFN-λR mRNA compared with RV1b infection alone. Conclusions: In PBMCs from pre-school age children, IFN-αR mRNA was reduced and IFN-λR1 mRNA was induced upon treatment with the TLR7/8 agonist R848, thus suggesting new avenues for induction of antiviral immune responses in paediatric asthma.
CRIS-Team Scopus Importer:2021-06-04

Top-down approach to biological therapy of Crohn's disease - Hirschmann, Simon; Neurath, Markus (Expert Opinion on Biological Therapy, 2017)
INTRODUCTION: Crohn's disease (CD) is a chronic, immune-mediated condition with a potentially disabling and destructive course. Despite growing data on when to use a therapeutic 'top-down' strategy, clinical management of this complex disorder is still challenging. Currently, the discussion of 'top-down' strategy in CD mostly includes biological therapy alone or in combination. Areas covered: This article is based on a review of existing literature regarding the use of biological therapy in a 'top-down' approach for the treatment of Crohn's disease. The authors reviewed all the major databases including MEDLINE as well as DDW and ECCO abstracts, respectively. Expert opinion: A 'top-down' therapeutic approach in Crohn's disease is strongly supported by existing data in patients with several risk factors for a severe course of disease. Moreover, there is an increasing amount of published data recommending a more individualised therapeutic strategy to identify candidates for 'top-down' treatment, based on enhanced diagnostics using biomarkers. Emerging therapeutic approaches besides existing therapy concepts using biologicals may possibly redefine the 'top-down' therapeutic strategy for Crohn's disease in the future.
EVALuna2:33823

Topical application of Chlorin e6-PVP (Ce6-PVP) for improved endoscopic detection of neoplastic lesions in a murine colitis-associated cancer model - Ganzleben, Ingo; Hohmann, Martin; Grünberg, Alexander; Menezes, Jean Gonzales; Liebing, Eva; Günther, Claudia; Thonn, Veronika; Beß, Daniel; Becker, Christoph; Schmidt, Michael; Neurath, Markus; Waldner, Maximilian; et al. (Scientific Reports, 2020)
Screening colonoscopy is crucial in reducing the mortality of colorectal cancer. However, detecting adenomas against the backdrop of an inflamed mucosa (e.g. in ulcerative colitis) remains exceedingly difficult. Therefore, we aimed to improve neoplastic lesion detection by employing a fluorescence-based endoscopic approach. We used the well-established murine AOM/DSS model to induce inflammation-driven carcinogenesis in the colon. In our diagnostic approach, we evaluated Chlorin e6 polyvinylpyrrolidone (Ce6-PVP)-based fluorescence endoscopy in comparison to standard white-light endoscopy. A specialized pathologist then analyzed the histology of the detected lesions. Complementary in vitro studies were performed using human cell lines and a murine organoid system. Ce6-PVP-based fluorescence endoscopy had an improved detection rate of 100% (8/8) in detecting high-grade dysplasias and carcinomas over white-light detection alone with 75% (6/8). Trade-off for this superior detection rate was an increased rate of false positive lesions with an increase in the false discovery rate from 45% for white-light endoscopy to 81% for fluorescence endoscopy. We demonstrate in a proof-of-concept study that Ce6-PVP-based fluorescence endoscopy is a highly sensitive red flag technology to identify biopsy-worthy lesions in the colon.
CRIS-Team Scopus Importer:2020-08-14

Total bile acids in the maternal and fetal compartment in relation to placental ABCG2 expression in preeclamptic pregnancies complicated by HELLP syndrome - Jebbink, Jiska; Veenboer, Geertruda; Boussata, Souad; Keijser, Remco; Kremer, Andreas; Elferink, Ronald Oude; Van Der Post, Joris; Afink, Gijs; Ris-Stalpers, Carrie (BBA - Biochimica et Biophysica Acta, 2015)
To investigate total bile acid (TBA) levels in maternal (MB) and umbilical cord blood (UCB) in normotensive, preeclamptic (PE), and PE pregnancies complicated by hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in the context of ABCG2 placental gene expression levels, a recently reported placental bile acid transporter.TBA levels were determined in 83 paired MB and UCB samples of normotensive, PE and PE/HELLP pregnancies and in 22 paired arterial and venous UCB samples from uncomplicated term pregnancies. ABCG2 gene expression was measured in 104 human placentas by reverse transcriptase quantitative polymerase chain reaction.Overall, TBA levels in MB are higher compared to levels in UCB (p<0.0001), but this comparison looses statistical significance for the 11 PE/HELLP cases. TBA levels in maternal blood are increased in PE/HELLP compared to PE pregnancies (p=0.016). TBA levels in arterial and venous UCB from 22 normotensive pregnancies are not statistically different. ABCG2 expression is reduced in pregnancies where preeclampsia is further complicated by HELLP syndrome. ABCG2 expression in human placenta is not correlated with TBA levels in either the maternal or fetal compartment.Increased maternal TBA levels in PE/HELLP pregnancies indicate a relation between bile acids in the maternal circulation and HELLP syndrome. As overall TBA levels in maternal blood are increased compared to UCB, we conclude that the placenta partly protects the fetus from increased maternal TBA levels. This consistent difference in TBA levels between the maternal and fetal compartment is unrelated to the placental expression of ABCG2.
EVALuna2:1976

Total Recall: Intestinal T-RM Cells in Health and Disease - Paap, Eva-Maria; Müller, Tanja; Sommer, Katrin; Neurath, Markus; Zundler, Sebastian (Frontiers in Immunology, 2021)
Tissue-resident memory T cells (T-RM cells) have crucial functions in host defense in mucosal tissues. They provide local adaptive immune surveillance and allow the fast initiation of targeted adaptive immune responses in case of antigen re-exposure. Recently, an aberrant activation in the case of immunologically mediated diseases has been increasingly acknowledged. As the organ with the largest interface to the environment, the gastrointestinal tract faces billions of antigens every day. Tightly balanced processes are necessary to ensure tolerance towards non-hazardous antigens, but to set up a powerful immune response against potentially dangerous ones. In this complex nexus of immune cells and their mediators, T-RM cells play a central role and have been shown to promote both physiological and pathological events. In this review, we will summarize the current knowledge on the homeostatic functions of T-RM cells and delineate their implication in infection control in the gut. Moreover, we will outline their commitment in immune dysregulation in gastrointestinal chronic inflammatory conditions and shed light on T-RM cells as current and potential future therapeutic targets.
CRIS-Team WoS Importer:2021-02-19

Towards a Computable Data Corpus of Temporal Correlations between Drug Administration and Lab Value Changes - Newe, Axel; Wimmer, Stefan; Neubert, Antje; Becker, Linda; Prokosch, Hans-Ulrich; Beckmann, Matthias; Fietkau, Rainer; Forster, Christian; Neurath, Markus; Schett, Georg; Ganslandt, Thomas (PLoS ONE, 2015)
Background The analysis of electronic health records for an automated detection of adverse drug reactions is an approach to solve the problems that arise from traditional methods like spontaneous reporting or manual chart review. Algorithms addressing this task should be modeled on the criteria for a standardized case causality assessment defined by the World Health Organization. One of these criteria is the temporal relationship between drug intake and the occurrence of a reaction or a laboratory test abnormality. Appropriate data that would allow for developing or validating related algorithms is not publicly available, though. Methods In order to provide such data, retrospective routine data of drug administrations and temporally corresponding laboratory observations from a university clinic were extracted, transformed and evaluated by experts in terms of a reasonable time relationship between drug administration and lab value alteration. Result The result is a data corpus of 400 episodes of normalized laboratory parameter values in temporal context with drug administrations. Each episode has been manually classified whether it contains data that might indicate a temporal correlation between the drug administration and the change of the lab value course, whether such a change is not observable or whether a decision between those two options is not possible due to the data. In addition, each episode has been assigned a concordance value which indicates how difficult it is to assess. This is the first open data corpus of a computable ground truth of temporal correlations between drug administration and lab value alterations. Discussion The main purpose of this data corpus is the provision of data for further research and the provision of a ground truth which allows for comparing the outcome of other assessments of this data with the outcome of assessments made by human experts. It can serve as a contribution towards systematic, computerized ADR detection in retrospective data. With this lab value curve data as a basis, algorithms for detecting temporal relationships can be developed, and with the classification made by human experts, these algorithms can immediately be validated. Due to the normalization of the lab value data, it allows for a generic approach rather than for specific or solitary drug/lab value combination

Towards shifted position-diffuse reflectance imaging of anatomically correctly scaled human microvasculature - Späth, Moritz; Hohmann, Martin; Roider, Clemens; Lengenfelder, Benjamin; Stelzle, Florian; Wirtz, Stefan; Klämpfl, Florian (Scientific Reports, 2020)
Due to significant advantages, the trend in the field of medical technology is moving towards minimally or even non-invasive examination methods. In this respect, optical methods offer inherent benefits, as does diffuse reflectance imaging (DRI). The present study attempts to prove the suitability of DRI—when implemented alongside a suitable setup and data evaluation algorithm—to derive information from anatomically correctly scaled human capillaries (diameter: 10μm, length: 45μm) by conducting extensive Monte–Carlo simulations and by verifying the findings through laboratory experiments. As a result, the method of shifted position-diffuse reflectance imaging (SP-DRI) is established by which average signal modulations of up to 5% could be generated with an illumination wavelength of λ=424nm and a core diameter of the illumination fiber of 50μm. No reference image is needed for this technique. The present study reveals that the diffuse reflectance data in combination with the SP-DRI normalization are suitable to localize human capillaries within turbid media.<br

Toxic megacolon - Leppkes, M.; Ganslmayer, M.; Strauss, R.; Neurath, Markus (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2015)
Toxic megacolon constitutes a feared, life-threatening complication of severe intestinal inflammation and is a challenge for interdisciplinary medical care.Specific aspects of conservative treatment based on current scientific evidence derived from guidelines, qualified reviews, and scientific studies are presented, which provide a rational approach and maximize therapeutic success.This work is based on a selective literature review and the authors' experience of many years in gastroenterology and intensive care.Toxic megacolon requires a rapid interdisciplinary assessment. Depending on the underlying etiology, an individual treatment concept needs to be developed. If an infectious or inflammatory cause is probable, a conservative approach can reduce perioperative morbidity and mortality. A step-wise approach with controlled reevaluations of the response to therapy after 72 h and 7 days avoids uncontrolled delay of surgical options further ensuring patient safety.Despite a decreasing incidence of toxic megacolon, it remains an interdisciplinary therapeutic challenge.
EVALuna2:2018

Transabdominal ultrasonography for confirmation of accurate percutaneous endoscopic gastrostomy tube placement: analysis of patient- and procedure-related complications - Wildner, Dane; Pfeifer, Lukas; Vitali, Francesco; Neurath, Markus; Albrecht, Heinz (Medical Ultrasonography, 2022)
Aims: Technique-related factors, patient-related factors, and localization determine the risk for complications in percutaneous endoscopic gastrostomy (PEG) tube placement. The objective of this study was to identify patient characteristics and ultrasonographic parameters after PEG tube placement concerning localization, which correlate with complications. Material and methods: Patients undergoing PEG-tube placement were examined by abdominal ultrasound after dismissal from the endoscopic recovery room. Patient demographics, PEG characteristics, ultrasonographic parameters and complications were retrospectively analyzed. Results: Of 64 enrolled patients, 59.4% were male and the mean age was 62.3 years. A significant negative correlation between complications at PEG placement and Body-Mass-Index (BMI; kg/m(2)) was observed (Spearman's Rho: -0.382; p=0.002). A low BMI <18 tended to be more frequent in the group with complication-related PEG removal compared to patients without (18.2% vs. 1.9%). Further descriptive analysis revealed that 4 patients (36.4% of N=11) with and 5 patients (9.4% of N=53) without PEG removal due to complications already had complications at the time of PEG placement. Of the patients with complications during follow-up, those with a peritoneal course (N=10) in ultrasound tended to have a lower BMI (mean +/- standard deviation: 22.5 +/- 6.5 vs. 26.8 +/- 5.9) compared to those without (N=5). In all 4 patients with a triad of follow-up complications, peritoneal course, and complications at PEG placement, the tube was removed due to complications. Conclusions: Post-PEG-placement ultrasonography can help to determine complications in specific procedure-related conditions. A low BMI was found to be a relevant predictor of PEG-related complications, substantiating the need for early intervention in potentially PEG-relevant indications.
CRIS-Team WoS Importer:2023-03-03

Transcriptomes of MPO-deficient patients with generalized pustular psoriasis reveals expansion of CD4+cytotoxic T cells and an involvement of complement system and interferon pathways - Hüffmeier, Ulrike; Frey, Benjamin; Becker, Ina; Atreya, Imke; Berking, Carola; Moessner, R.; Wilsmann-Theis, D.; Uebe, Steffen; Kirchner, P.; Haskamp, Stefan (JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-11-05

Transcriptomes of MPO-Deficient Patients with Generalized Pustular Psoriasis Reveals Expansion of CD4+ Cytotoxic T Cells and an Involvement of the Complement System - Haskamp, Stefan; Frey, Benjamin; Becker, Ina; Schulz-Kuhnt, Anja; Atreya, Imke; Berking, Carola; Pauli, David; Ekici, Arif Bülent; Berges, Johannes; Mößner, Rotraut; Wilsmann-Theis, Dagmar; Sticherling, Michael; et al. (Journal of Investigative Dermatology, 2022)
Generalized pustular psoriasis is a severe psoriatic subtype characterized by epidermal neutrophil infiltration. Although variants in IL36RN and MPO have been shown to affect immune cells, a systematic analysis of neutrophils and PBMC subsets and their differential gene expression dependent on MPO genotypes was not performed yet. We assessed the transcriptomes of MPO-deficient patients using single-cell RNA sequencing of PBMCs and RNA sequencing of neutrophils in a stable disease state. Cell-type annotation by multimodal reference mapping of single-cell RNA-sequencing data was verified by flow cytometry of surface and intracellular markers; the proportions of CD4+ cytotoxic T lymphocytes and other CD4+ effector cells were increased in generalized pustular psoriasis, whereas the frequencies of naïve CD4+ T cells were significantly lower. The expression of FGFBP2 marking CD4+ cytotoxic T lymphocytes and CD8+ effector memory T cells was elevated in patients with generalized pustular psoriasis with disease-contributing variants compared with that in noncarriers (P = 0.0015). In neutrophils, differentially expressed genes were significantly enriched in genes of the classical complement activation pathway. Future studies assessing affected cell types and pathways will show their contribution to generalized pustular psoriasis's pathogenesis and indicate whether findings can be transferred to the acute epidermal situation and whether depletion or inactivation of CD4+ cytotoxic T lymphocytes may be a reasonable therapeutic approach.
CRIS-Team Scopus Importer:2022-07-08

Transient receptor potential melastatin 8 ion channel in macrophages modulates colitis through a balance-shift in TNF-alpha and interleukin-10 production - Khalil, Mohammad; Babes, Alexandru; Lakra, R.; Försch, Sebastian; Reeh, Peter; Wirtz, Stefan; Becker, Christoph; Neurath, Markus; Engel, Matthias (Mucosal Immunology, 2016)
The transient receptor potential (TRP) ion channel family is well characterized in sensory neurons; however, little is known about its role in the immune system. Here we show that the cold-sensing TRPM8 has an unexpected role in innate immunity. TRPM8 expression and function in macrophages were demonstrated in vitro using molecular techniques and calcium imaging. In addition, adoptive macrophage transfer and systemic interleukin (IL)-10 overexpression were performed in experimental colitis. TRPM8 activation induced calcium-transients in murine peritoneal macrophages (PM) and bone marrow-derived macrophages of wild-type (WT) but not TRPM8-deficient mice. TRPM8-deficient PM exhibited defective phagocytosis and increased motility compared with those in WT, whereas the opposite effects of TRPM8 activation were induced in WT PM. TRPM8 activation or blockage/genetic deletion induced a anti- or pro-inflammatory macrophage cytokine profile, respectively. WT mice treated with repeated menthol (TRPM8 agonist) enemas were consistently protected from experimental colitis, whereas TRPM8-deficient mice showed increased colitis susceptibility. Adoptive transfer of TRPM8-deficient macrophages aggravated colitis, whereas systemic IL-10 overexpression rescued this phenotype. TRPM8 activation in peptidergic sensory neurons did not affect neuropeptide release from the inflamed colon. TRPM8 in macrophages determines pro- or anti-inflammatory actions by regulating tumor necrosis factor-? and interleukin-10 production. These findings suggest novel TRPM8-based options for immunomodulatory intervention.
EVALuna2:2053

Transrectal Absorber Guide Raster-Scanning Optoacoustic Mesoscopy for Label-Free In Vivo Assessment of Colitis - Bühler, Adrian; Brown, Emma; Paulus, Lars-Philip; Eckstein, Markus; Thoma, Oana-Maria; Oraiopoulou, Mariam-Eleni; Rother, Ulrich; Hörning, André; Hartmann, Arndt; Neurath, Markus; Wölfle, Joachim; Friedrich, Oliver; et al. (Advanced Science, 2023)
Optoacoustic imaging (OAI) enables microscale imaging of endogenous chromophores such as hemoglobin at significantly higher penetration depths compared to other optical imaging technologies. Raster-scanning optoacoustic mesoscopy (RSOM) has recently been shown to identify superficial microvascular changes associated with human skin pathologies. In animal models, the imaging depth afforded by RSOM can enable entirely new capabilities for noninvasive imaging of vascular structures in the gastrointestinal tract, but exact localization of intra-abdominal organs is still elusive. Herein the development and application of a novel transrectal absorber guide for RSOM (TAG-RSOM) is presented to enable accurate transabdominal localization and assessment of colonic vascular networks in vivo. The potential of TAG-RSOM is demonstrated through application during mild and severe acute colitis in mice. TAG-RSOM enables visualization of transmural vascular networks, with changes in colon wall thickness, blood volume, and OAI signal intensities corresponding to colitis-associated inflammatory changes. These findings suggest TAG-RSOM can provide a novel monitoring tool in preclinical IBD models, refining animal procedures and underlines the capabilities of such technologies to address inflammatory bowel diseases in humans.
CRIS-Team WoS Importer:2023-05-12

Transtracheal single-point stent fixation in posttracheotomy tracheomalacia under cone-beam computer tomography guidance by transmural suturing with the Berci needle - a perspective on a new tool to avoid stent migration of Dumon stents - Hohenforst-Schmidt, Wolfgang; Linsmeier, Bernd; Zarogoulidis, Paul; Freitag, Lutz; Darwiche, Kaid; Browning, Robert; Turner, J. Francis; Huang, Haidong; Li, Qiang; Vogl, Thomas; Zarogoulidis, Konstantinos; Brachmann, Johannes; et al. (Therapeutics and Clinical Risk Management, 2015)
Tracheomalacia or tracheobronchomalacia (TM or TBM) is a common problem especially for elderly patients often unfit for surgical techniques. Several surgical or minimally invasive techniques have already been described. Stenting is one option but in general long-time stenting is accompanied by a high complication rate. Stent removal is more difficult in case of self-expandable nitinol stents or metallic stents in general in comparison to silicone stents. The main disadvantage of silicone stents in comparison to uncovered metallic stents is migration and plugging. We compared the operation time and in particular the duration of a sufficient Dumon stent fixation with different techniques in a patient with severe posttracheotomy TM and strongly reduced mobility of the vocal cords due to Parkinson's disease. The combined approach with simultaneous Dumon stenting and endoluminal transtracheal externalized suture under cone-beam computer tomography guidance with the Berci needle was by far the fastest approach compared to a (not performed) surgical intervention, or even purely endoluminal suturing through the rigid bronchoscope. The duration of the endoluminal transtracheal externalized suture was between 5 minutes and 9 minutes with the Berci needle; the pure endoluminal approach needed 51 minutes. The alternative of tracheobronchoplasty was refused by the patient. In general, 180 minutes for this surgical approach is calculated. The costs of the different approaches are supposed to vary widely due to the fact that in Germany 1 minute in an operation room costs on average approximately 50-60EUR inclusive of taxes. In our own hospital (tertiary level), it is nearly 30EUR per minute in an operation room for a surgical approach. Calculating an additional 15 minutes for patient preparation and transfer to wake-up room, therefore a total duration inside the investigation room of 30 minutes, the cost per flexible bronchoscopy is per minute on average less than 6EUR. Although the Dumon stenting requires a set-up with more expensive anesthesiology accompaniment, which takes longer than a flexible investigation estimated at 1 hour in an operation room, still without calculation of the costs of the materials and specialized staff that the surgical approach would consume at least 3,000EUR more than a minimally invasive approach performed with the Berci needle. This difference is due to the longer time of the surgical intervention which is calculated at approximately 180 minutes in comparison to the achieved non-surgical approach of 60 minutes in the operation suite.
EVALuna2:12091

Treatment efficacyand safety of seladelpar, a selective peroxisome proliferator-activated receptor delta agonist, in primary biliary cholangitis patients: 12-and 26-week analysis from an ongoing international, randomized, dose raging phase 2 study - Hirschfield, G.; Boudes, P.; Bowlus, C.; Gitlin, N.; Michael, G.; Harrison, S.; Gordon, S. C.; Aspinall, R.; Doerffel, Y.; Kremer, Andreas; Sheridan, D.; Bacon, B.; et al. (JOURNAL OF HEPATOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-26

Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine? - Rinke, Anja; Auernhammer, Christoph J.; Bodei, Lisa; Kidd, Mark; Krug, Sebastian; Lawlor, Rita; Marinoni, Ilaria; Perren, Aurel; Scarpa, Aldo; Sorbye, Halfdan; Pavel, Marianne Ellen; Weber, Matthias M.; et al. (Gut, 2021)
Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. 'Targeted' treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options. The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour. This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.
CRIS-Team Scopus Importer:2021-03-26
Keywords: cancer genetics; chemotherapy; immunotherapy; molecular oncology; neuroendocrine tumors

Treatment of chronic itch in systemic disease : Current standards - Mettang, T.; Staender, S.; Kremer, Andreas (Internist, 2015)
Chronic itch (CI) is a frequent and sometimes tormenting symptom in many skin and systemic diseases. In systemic diseases, it mostly appears on primarily unaffected skin. As a sequelae of intense scratching, secondary skin lesions such as excoriations, scars, and prurigo nodularis may occur. Due to the lack of valid pathogenetic concepts and good clinical trials, the therapy of CI remains mostly symptomatic. In Europe almost all drugs used to treat CI are not approved for this indication. CI is frequent in patients with chronic kidney diseases in advanced stages. Gabapentin and pregabalin, anticonvulsants, and centrally acting calcium channel blockers have been shown to exert a profound effect in CI. Furthermore, UVB phototherapy has been proven to attenuate pruritus in uremic patients. Randomized controlled studies have recently shown that nalfurafine, a ?-opioid receptor agonist, is able to ameliorate itch in patients with uremic itch. In patients suffering from cholestatic itch, the anion exchange resin colestyramine and rifampicin are effective antipruritic drugs. Furthermore, µ-opioid receptor antagonists and sertraline may be used to alleviate CI in hepatic diseases. In refractory cases, naso-biliary drainage or albumin dialysis are effective invasive procedures. For the treatment of chronic itch in hematological diseases no controlled trials have been performed so far. The mainstay in these cases is to treat the underlying disease.
EVALuna2:1848

Treatment of Pruritus Secondary to Liver Disease - Düll, Miriam; Kremer, Andreas (Current Gastroenterology Reports, 2019)
Purpose of Review: Pruritus is a common extrahepatic symptom in various liver disorders, in particularly those with cholestatic features. This review summarizes epidemiology, pathophysiology, evidence-based therapeutic recommendations and currently investigated drugs for pruritus in hepatobiliary disorders. Recent Findings: Recent epidemiological data suggest pruritus as a common and relevant symptom in immune-mediated liver diseases, i.e., primary biliary cholangitis (PBC) with over 70% affected patients, up to 56% suffering from chronic pruritus. The better pathophysiological understanding of hepatic pruritus has led to the identification of novel therapeutic targets, addressed in drug trials using KOR agonists, PPAR agonists, and ileal bile acid transporter inhibitors. Summary: Hepatic itch remains among the most agonizing symptoms for affected patients and a clinical challenge for physicians. Therapeutic recommendations include a guideline-based stepwise approach starting with cholestyramine, followed by rifampicin, naltrexone, and sertraline. Bezafibrate and ileal bile acid transporter inhibitors represent promising future anti-pruritic treatment options.
CRIS-Team Scopus Importer:2019-08-06
Keywords: Autotaxin; Bile salt; Cholestasis; Liver; Lysophosphatidic acid; Pruritus

Treatment outcomes of advanced digestive well-differentiated grade 3 NETs - de Mestier, Louis; Lamarca, Angela; Hernando, Jorge; Zandee, Wouter; Alonso-Gordoa, Teresa; Perrier, Marine; Walenkamp, Annemiek Me; Chakrabarty, Bipasha; Landolfi, Stefania; Van Velthuysen, Marie Louise F.; Kats-Ugurlu, Gursah; Caminoa, Alejandra; et al. (Endocrine-Related Cancer, 2021)
There is no standardized treatment for grade 3 neuroendocrine tumors (G3 NETs). We aimed to describe the treatments received in patients with advanced G3 NETs and compare their efficacy. Patients with advanced digestive G3 NETs treated between 2010 and 2018 in seven expert centers were retrospectively studied. Pathological samples were centrally reviewed, and radiological data were locally reviewed. We analyzed RECIST-defined objective response (OR), tumor growth rate (TGR) and progression-free survival (PFS) obtained with first- (L1) or second-line (L2) treatments. We included 74 patients with advanced G3 NETs, mostly from the duodenal or pancreatic origin (71.6%), with median Ki-67 of 30%. The 126 treatments (L1 = 74; L2 = 52) included alkylating-based (n = 32), etoposide-platinum (n = 22) or adenocarcinoma-like (n = 20) chemotherapy, somatostatin analogs (n = 21), targeted therapies (n = 22) and liver-directed therapies (n = 7). Alkylating-based chemotherapy achieved the highest OR rate (37.9%) compared to other treatments (multivariable OR 4.22, 95% CI (1.5-12.2); P = 0.008). Adenocarcinoma-like and alkylating-based chemotherapies showed the highest reductions in 3-month TGR (P < 0.001 and P = 0.008, respectively). The longest median PFS was obtained with adenocarcinoma-like chemotherapy (16.5 months (9.0-24.0)) and targeted therapies (12.0 months (8.2-15.8)), while the shortest PFS was observed with somatostatin analogs (6.2 months (3.8-8.5)) and etoposide-platinum chemotherapy (7.2 months (5.2-9.1)). Etoposide-platinum CT achieved shorter PFS than adenocarcinoma-like (multivariable HR 3.69 (1.61-8.44), P = 0.002) and alkylating-based chemotherapies (multivariable HR 1.95 (1.01-3.78), P = 0.049). Overall, adenocarcinoma-like and alkylating-based chemotherapies may be the most effective treatments for patients with advanced G3 NETs regarding OR and PFS. Etoposide-platinum chemotherapy has poor efficacy in this setting.
CRIS-Team Scopus Importer:2021-07-16
Keywords: grade 3; neuroendocrine tumors; prognosis; treatment

Treatment Perspectives in Crohn's Disease - Vetter, Marcel; Neurath, Markus (Digestion, 2018)
BACKGROUND: Crohn's disease (CD) is a chronic immune-mediated disorder of the gastrointestinal tract. The pathophysiological understanding of this disease is limited and no curative therapy is available so far. Therefore, most patients require long-lasting or even life-long immunosuppressive therapies for the suppression of symptoms to improve quality of life and reduction of long-term risks. However, in a relevant subgroup of patients, these therapeutic goals cannot be sufficiently attained. SUMMARY: Clinically established therapies in active CD comprise corticosteroids and immunosuppressants such as azathioprine. After the introduction of anti-TNFα (Tumor necrosis factor alpha) antibodies, other biologicals (e.g., vedolizumab and ustekinumab) have also been approved. New drugs in the pipeline like filgotinib, upadacitinib, risankizumab or rifaximin could improve the therapy of CD in the near future. Thus, an individualized therapy management, based on optimal selection of therapeutic agents will become more important. Additionally, the local application of mesenchymal stem cells might be helpful in the management of fistulas. Key Messages: The targeted biological therapeutic agents (anti-TNFα antibodies, vedolizumab, ustekinumab) are well established for therapy in CD. There are several new substances in the pipeline with promising results in phase II trials (filgotinib, rifaximin, risankizumab, upadacitinib). The upcoming extension of the therapeutic arsenal will require methods for an optimized selection of substances, thus enabling a more individualized therapy.
EVALuna2:35196

Treatment preferences for preventive interventions for rheumatoid arthritis: Protocol of a mixed methods case study for the Innovative Medicines Initiative PREFER project - Falahee, Marie; Simons, Gwenda; Disantostefano, Rachael L.; Valor Méndez, Larissa; Radawski, Christine; Englbrecht, Matthias; Schölin Bywall, Karin; Tcherny-Lessenot, Stephanie; Kihlbom, Ulrik; Hauber, Brett; Veldwijk, Jorien; Raza, Karim (BMJ Open, 2021)
Introduction Amidst growing consensus that stakeholder decision-making during drug development should be informed by an understanding of patient preferences, the Innovative Medicines Initiative project â € Patient Preferences in Benefit-Risk Assessments during the Drug Life Cycle' (PREFER) is developing evidence-based recommendations about how and when patient preferences should be integrated into the drug life cycle. This protocol describes a PREFER clinical case study which compares two preference elicitation methodologies across several populations and provides information about benefit-risk trade-offs by those at risk of rheumatoid arthritis (RA) for preventive interventions. Methods and analysis This mixed methods study will be conducted in three countries (UK, Germany, Romania) to assess preferences of (1) first-degree relatives (FDRs) of patients with RA and (2) members of the public. Focus groups using nominal group techniques (UK) and ranking surveys (Germany and Romania) will identify and rank key treatment attributes. Focus group transcripts will be analysed thematically using the framework method and average rank orders calculated. These results will inform the treatment attributes to be assessed in a survey including a discrete choice experiment (DCE) and a probabilistic threshold technique (PTT). The survey will also include measures of sociodemographic variables, health literacy, numeracy, illness perceptions and beliefs about medicines. The survey will be administered to (1) 400 FDRs of patients with RA (UK); (2) 100 FDRs of patients with RA (Germany); and (3) 1000 members of the public in each of UK, Germany and Romania. Logit-based approaches will be used to analyse the DCE and imputation and interval regression for the PTT. Ethics and dissemination This study has been approved by the London-Hampstead Research Ethics Committee (19/LO/0407) and the Ethics Committee of the Friedrich-Alexander-Universität Erlangen-Nürnberg (92_17 B). The protocol has been approved by the PREFER expert review board. The results will be disseminated widely and will inform the PREFER recommendations.
CRIS-Team Scopus Importer:2021-04-19
Keywords: preventive medicine; public health; rheumatology

Treatment Strategies Derived from Comprehensive Genomic and Transcriptomic Analysis in Patients with Advanced-Stage Neuroendocrine Neoplasms: Results from the MASTER Trial of the German Cancer Consortium - Apostolidis, L.; Kreutzfeldt, S.; Oles, M.; Heining, C.; Hutter, B.; Gieldon, L.; Lamping, M.; Pape, U. F.; Stenzinger, A.; Wiedenmann, B.; Pavel, Marianne Ellen; Froehling, S. (NEUROENDOCRINOLOGY, 2019)
CRIS-Team WoS Importer:2019-03-26

Treatment Strategies in Inflammatory Bowel Diseases - Stallmach, Andreas; Atreya, Raja; Grunert, Philip C.; Stallhofer, Johannes; de Laffolie, Jan; Schmidt, Carsten (Deutsches Ärzteblatt international, 2023)
BACKGROUND: The prevalence of inflammatory bowel disease (IBD) is rising globally. In Germany, these conditions affect 0.7% of the population, or approximately 600 000 patients. Treatment strategies have become more diversified as a result of an improved understanding of disease pathogenesis. It remains unclear how the currently available drugs should best be used in each individual patient. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, with special attention to phase III and IV trials and to the German and European guidelines on the treatment of IBD. RESULTS: An improved understanding of the immunological mechanisms of disease underlies the current treatment strategies in patients with IBD. For those with a complex clinical course, monoclonal antibodies against pro-inflammatory cytokines (TNF, IL-12/IL-23, IL-23) and cell adhesion molecules (α4β7) are of established therapeutic value, along with "small molecules" such as JAK inhibitors and sphingosine-1-phosphate receptor modulators. The numerous studies that have been performed, only a few of which have been head-to-head comparison trials, and the (network) meta-analyses that have been published to date do not imply that any single one of these drugs can be considered the universal, primary treatment for all patients with IBD. In this review, we discuss the available substances and certain important differential-therapeutic aspects of the treatment of IBD. CONCLUSION: The treatment of a patient with IBD must take his or her prior treatment(s) and comorbidities into account, along with individual patient characteristics and treatment goals. Rational decision-making is required on the basis of the mechanism of action and the side-effect profile of the various drugs that are now available for use.
CRIS-Team Scopus Importer:2023-12-15

Treatment strategy by radioiodine refractory differentiated thyroid cancer - Mantsopoulos, Konstantinos; Mueller, Sarina K.; Pavel, Marianne Ellen; Kuwert, Torsten; Meidenbauer, Norbert; Fietkau, Rainer; Sievert, Matti; Iro, Heinrich (Laryngo-Rhino-Otologie, 2021)
Zusammenfassung Traditionell besteht das multimodale Therapiekonzept bei den differenzierten Schilddrusenkarzinomen in der Thyreoidektomie mit Neck-Dissection (bei cN+-Halsstatus) und adjuvanten Radiojodablation mit abschlie ss ender risikoadaptierter TSH-Suppression. Das Ausma ss der Radiojodaufnahme beim metastasierten Schilddrusenkarzinom spielt eine signifikante Rolle bei der Einschatzung der Prognose. Das fehlende Jodspeicherungsvermogen einer Lasion in Zusammenschau mit dem fehlenden Abfall des Tumormarkers Thyreoglobulin sowie radiologische Zeichen einer Tumorprogression charakterisieren den Radiojod-refraktaren Patienten. Aufgrund des meistens uber einen langen Zeitraum indolenten Verlaufs erscheint in den meisten Fallen ein abwartendes Verhalten in Kombination mit lokaler Metastasenbehandlung sowie Symptomlinderung primar sinnvoll zu sein. Der Nachweis einer Veranderung der Tumordynamik ist der Zeitpunkt, um eine Systemtherapie zu evaluieren. Diese beruht auf Multi-Tyrosinkinase-Inhibitoren (Sorafenib, Lenvatinib). Diese Substanzen sind gro ss tenteils mit einem ungunstigen Nebenwirkungsprofil assoziiert (Diarrho, Hautauschlage, arterielle Hypertonie mit hypertensiver Entgleisung, lokale Wundheilungsstorungen), welches zu einer nicht vernachlassigbaren Rate einer therapieassoziierten Morbiditat sowie einer hohen Anzahl an Therapieunterbrechungen fuhrt. Daher sind im Jahr 2020 2 selektive RET-Inhibitoren (Selpercatinib, Pralsetinib) fur die differenzierten Schilddrusenkarzinome von der FDA zugelassen worden. Eine neue Perspektive fur die Zukunft waren die unterschiedlichen Redifferenzierungsstrategien, welche auf die Steigerung der Sensitivitat der Tumorzellen auf Radiojod abzielen.
CRIS-Team WoS Importer:2021-10-08

TRPA1 and substance P mediate colitis in mice - Engel, Matthias; Leffler, Andreas; Niedermirtl, Florian; Babes, Alexandru; Zimmermann, Katharina; Filipovic, Milos; Izydorczyk, Iwona; Eberhardt, Mirjam; Kichko, Tetyana; Müller-Tribbensee, Sonja; Khalil, Mohammad; Siklosi, Norbert; et al. (Gastroenterology, 2011)

Tumor growth rate as a metric of progression, response, and prognosis in pancreatic and intestinal neuroendocrine tumors - Dromain, Clarisse; Pavel, Marianne Ellen; Ruszniewski, Philippe; Langley, Alison; Massien, Christine; Baudin, Eric; Caplin, Martyn E. (BMC Cancer, 2019)
Background: Lanreotide depot/autogel antitumor activity in intestinal/pancreatic neuroendocrine tumors (NETs) was demonstrated in the phase-3 CLARINET study (NCT00353496), based on significantly prolonged progression-free survival (PFS) versus placebo. Methods: During CLARINET, patients with metastatic intestinal/pancreatic NETs received lanreotide depot/autogel 120 mg or placebo every 4 weeks for 96 weeks. Imaging data (response evaluation criteria in solid tumors [RECIST] v1.0, centrally reviewed) were re-evaluated in this post hoc analysis of tumor growth rate (TGR) in NETs. TGR (%/month) was calculated from two imaging scans during relevant periods: pre-treatment (TGR 0 ); 12-24 weeks before randomization versus baseline; each treatment visit versus baseline (TGR Tx-0 ); between consecutive treatment visits (TGR Tx-Tx ). To assess TGR as a measure of prognosis, PFS was compared for TGR 0 subgroups stratified by optimum TGR 0 cut-off; a multivariate analysis was conducted to identify prognostic factors for PFS. Results: TGR 0 revealed tumors growing during pre-treatment (median [interquartile range] TGR 0 : lanreotide 2.1%/month [0.2; 6.1]; placebo 2.7%/month [0.15; 6.8]), contrary to RECIST status. TGR was significantly reduced by 12 weeks with lanreotide versus placebo (difference in least-square mean TGR 0-12 of - 2.9 [- 5.1, - 0.8], p = 0.008), a difference that was maintained at most subsequent visits. TGR 0 > 4%/month had greater risk of progression/death than ≤4%/month (hazard ratio 4.1; [95% CI 2.5-6.5]; p < 0.001); multivariate analysis revealed lanreotide treatment, progression at baseline, TGR 0 , hepatic tumor load, and primary tumor type were independently associated with PFS. Conclusions: TGR provides valuable information on tumor activity and prognosis in patients with metastatic intestinal/pancreatic NETs, and identifies early lanreotide depot/autogel antitumor activity. Trial registration: Retrospective registration, 18 July 2006; EudraCT: 2005-004904-35; ClinicalTrials.gov: NCT00353496.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Lanreotide; Neuroendocrine tumor; Prognostic factor; RECIST; Tumor growth rate

Tumor growth rate as a validated early radiological biomarker able to reflect treatment-induced changes in neuroendocrine tumors: The GREPONET-2 study - Lamarca, Angela; Ronot, Maxime; Moalla, Salma; Crona, Joakim; Opalinska, Marta; Lopez, Carlos Lopez; Pezzutti, Daniela; Najran, Pavan; Carvhalo, Luciana; Bezerra, Regis Otaviano Franca; Borg, Philip; Violi, Naik Vietti; et al. (Clinical Cancer Research, 2019)
Purpose: Tumor growth rate (TGR) represents the percentage change in tumor volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR3m) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in neuroendocrine tumors (NET). Experimental Design: Patients from 7 centers with advanced grade (G) 1/2 NETs from the pancreas (P)/small bowel (SB) initiating ST/WW were eligible. Computed tomography (CT)/MRI performed at prebaseline, baseline, and 3 (±1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (DTGR3mBL; paired T test), and Aim-2: validate TGR3m (<0.8%/m vs. ≥0.8%/m) as an early biomarker in an independent cohort (Kaplan–Meier/Cox regression). Results: Of 785 patients screened, 127 were eligible. Mean (SD) TGR0 and TGR3m were 5.4%/m (14.9) and -1.4%/m (11.8), respectively. Mean (SD) DTGR3m-BL paired-difference was -6.8%/m (19.3; P < 0.001). Most marked DTGR3m-BL [mean (SD)] were identified with targeted therapies [-11.3%/m (4.7); P ¼ 0.0237] and chemotherapy [-7.9%/m (3.4); P ¼ 0.0261]. Multivariable analysis confirmed the absence of previous treatment (OR ¼ 4.65; 95% CI, 1.31–16.52; P ¼ 0.018) and low TGR3m (continuous variable; OR 1.09; 95% CI, 1.01–1.19; P ¼ 0.042) to be independent predictors of radiologic objective response. When the multivariable survival analysis for PFS (Cox regression) was adjusted to grade (P ¼ 0.004) and stage (P ¼ 0.017), TGR3m ≥ 0.8 (vs. <0.8) maintained its significance as a prognostic factor (P < 0.001), whereas TGR0 and DTGR3m-BL did not. TGR3m ≥ 0.8%/m was confirmed as an independent prognostic factor for PFS [external validation; Aim-2; multivariable HR 2.21 (95% CI, 1.21–3.70; P ¼ 0.003)]. Conclusions: TGR has a role as a biomarker for monitoring response to therapy for early identification of treatment-induced changes and for early prediction of PFS and radiologic objective response.
CRIS-Team Scopus Importer:2019-11-26

Tumor Growth Rate to Predict the Outcome of Patients with Neuroendocrine Tumors: Performance and Sources of Variability - Dromain, Clarisse; Sundin, Anders; Najran, Pavan; Vidal Trueba, Hector; Dioguardi Burgio, Marco; Crona, Joakim; Opalinska, Marta; Carvalho, Luciana; Franca, Regis; Borg, Philip; Vietti Violi, Naik; Schaefer, Niklaus; et al. (Neuroendocrinology, 2021)
Introduction: Tumor growth rate (TGR), percentage of change in tumor volume/month, has been previously identified as an early radiological biomarker for treatment monitoring in neuroendocrine tumor (NET) patients. We assessed the performance and reproducibility of TGR at 3 months (TGR3m) as a predictor factor of progression-free survival (PFS), including the impact of imaging method and reader variability. Methods: Baseline and 3-month (±1 month) CT/MRI images from patients with advanced, grade 1-2 NETs were retrospectively reviewed by 2 readers. Influence of number of targets, tumor burden, and location of lesion on the performance of TGR3m to predict PFS was assessed by uni/multivariable Cox regression analysis. Agreement between readers was assessed by Lin's concordance coefficient (LCC) and kappa coefficient (KC). Results: A total of 790 lesions were measured in 222 patients. Median PFS was 22.9 months. On univariable analysis, number of lesions (
CRIS-Team Scopus Importer:2021-09-03
Keywords: Biomarkers; Neuroendocrine tumors; Prognosis; Reproducibility of results

Tumor immunoevasion by high glycolytic tumors through an acidosis-dependent induction of noninflammatory tumor-associated macrophages - Bohn, T.; Rapp, S.; Pektor, S.; Gerlach, Katharina; Weigmann, Benno; Lueckel, C.; Truong, N.; Von Stebut, E.; Schild, H.; Bopp, T. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages - Bohn, Toszka; Rapp, Steffen; Luther, Natascha; Klein, Matthias; Bruehl, Till-Julius; Kojima, Nobuhiko; Lopez, Pamela Aranda; Hahlbrock, Jennifer; Muth, Sabine; Endo, Shogo; Pektor, Stefanie; Brand, Almut; et al. (Nature Immunology, 2018)
Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein-coupled receptor-dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system.
EVALuna2:113934

Tumor microenvironment-dependent epigenetic imprinting in the vasculature predicts colon cancer outcome - Naschberger, Elisabeth; Fuchs, Maximilian; Dickel, Nicholas; Kunz, Meik; Popp, Bernt; Anchang, Charles Gwellem; Demmler, Richard; Lyu, Yanmin; Uebe, Steffen; Ekici, Arif Bülent; Geppert, Carol-Immanuel; Hartmann, Arndt; et al. (Cancer Communications, 2023)
CRIS-Team Scopus Importer:2023-10-27

Tumor Necrosis of Primary Malignancy Affects Survival and Outcome in Patients with Liver Metastases from Neuroendocrine Tumors - Atanasov, G.; Tsvetkova,; Struecker, B.; Andreou, A.; Bahra, M.; Prasad,; Denecke, T.; Pavel, Marianne Ellen; Wiedenmann, B.; Pratschke, J.; Pape, U. F.; Pascher, A. (2018)
EVALuna2:34115

Tumour Growth Rate (TGR) in Neuroendocrine Tumours (NETs): Changes Following Systemic Treatment; the GREPONET-2 Study - Lamarca, A.; Ronot, M.; Moall, S.; Crona, J.; Opalinska, M.; Lopez, C.; Pezzutti, D.; Baudin, E.; Sundin, A.; Costa, F.; Pavel, Marianne Ellen; Dromain, C. (NEUROENDOCRINOLOGY, 2019)
CRIS-Team WoS Importer:2019-03-26

Tumour Necrosis Factor Alpha in Intestinal Homeostasis and Gut Related Diseases - Ruder, Barbara; Atreya, Raja; Becker, Christoph (International Journal of Molecular Sciences, 2019)
The intestinal epithelium constitutes an indispensable single-layered barrier to protect the body from invading pathogens, antigens or toxins. At the same time, beneficial nutrients and water have to be absorbed by the epithelium. To prevent development of intestinal inflammation or tumour formation, intestinal homeostasis has to be tightly controlled and therefore a strict balance between cell death and proliferation has to be maintained. The proinflammatory cytokine tumour necrosis factor alpha (TNFα) was shown to play a striking role for the regulation of this balance in the gut. Depending on the cellular conditions, on the one hand TNFα is able to mediate cell survival by activating NFκB signalling. On the other hand, TNFα might trigger cell death, in particular caspase-dependent apoptosis but also caspase-independent programmed necrosis. By regulating these cell death and survival mechanisms, TNFα exerts a variety of beneficial functions in the intestine. However, TNFα signalling is also supposed to play a critical role for the pathogenesis of inflammatory bowel disease (IBD), infectious diseases, intestinal wound healing and tumour formation. Here we review the literature about the physiological and pathophysiological role of TNFα signalling for the maintenance of intestinal homeostasis and the benefits and difficulties of anti-TNFα treatment during IBD.
CRIS-Team Scopus Importer:2019-05-14
Keywords: anti-TNFα treatment; cell death; IBD; infectious disease; intestinal epithelium; tumour necrosis factor

Two-dimensional shear-wave elastography: a new method comparable to acoustic radiation force impulse imaging? - Schellhaas, Barbara; Strobel, Deike; Wildner, Dane; Görtz, Rüdiger; Neurath, Markus; Pfeifer, Lukas (European Journal of Gastroenterology & Hepatology, 2017)
OBJECTIVES: Two-dimensional shear-wave elastography (2D-SWE) is an ultrasound-based technique for the noninvasive assessment of tissue stiffness. In contrast to the well-established point-shear-wave elastography (pSWE) method acoustic radiation force impulse imaging, there is little evidence on the performance and usefulness of 2D-SWE in the assessment of liver stiffness. Thus, the aim of our study was to compare 2D-SWE versus pSWE. MATERIALS AND METHODS: 2D-SWE and pSWE were performed in 20 cirrhotic patients, 20 healthy individuals and an elasticity phantom. Stiffness values, examination time and number of measurements were compared. For 2D-SWE, the influence of size of the region of interest (ROI) was assessed. RESULTS: Elastography values in healthy individuals were slightly higher for 2D-SWE versus pSWE (1.4 m/s, range: 1.21-1.68 vs. 1.23 m/s, range: 1.07-1.39). In cirrhotic patients, there were no significant differences (3.06 m/s, range: 1.83-5.35 vs. 3 m/s, range: 1.67-4.37 m/s). Examination times were significantly longer for 2D-SWE in both patient groups (mean values for healthy/cirrhotic patients: 129.6/157.1 vs. 75/71.6 s). For 2D-SWE, variation of ROI size (5, 10, 20 mm) produced comparable results. After eight measurements, 90% of cirrhotic patients showed less than 5% of deviation from the results after the gold standard of 10 measurements; for healthy individuals, this was observed after six measurements. CONCLUSION: 2D-SWE seems to be comparable to pSWE (acoustic radiation force impulse-imaging) in cirrhotic patients, with slightly higher values in healthy individuals. 2D-SWE measurements require considerably more time. For 2D-SWE, ROI size seems to be of minor importance; multiple measurements should be obtained as single measurements differ. These preliminary results should be confirmed in larger patient collectives with histology as the reference standard.
EVALuna2:33813

Type 1 Autoimmune Pancreatitis in Europe: Clinical Profile and Response to Treatment - Overbeek, Kasper A.; Poulsen, Jakob L.; Lanzillotta, Marco; Vinge-Holmquist, Olof; Macinga, Peter; Demirci, A. Fatih; Sindhunata, Daniko P.; Backhus, Johanna; Algül, Hana; Buijs, Jorie; Levy, Philippe; Kiriukova, Mariia; et al. (Clinical Gastroenterology and Hepatology, 2024)
Background & Aims: Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens. Methods: We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP. Results: We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (<0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054–3.387) and neither was a starting dose duration >2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818–1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427–0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose. Conclusions: Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens.
CRIS-Team Scopus Importer:2024-02-23
Keywords: Autoimmune Pancreatitis; IgG4-Related Disease; IgG4-Related Pancreatitis

Type 2 innate lymphoid cells inhibit the differentiation of osteoclasts and protect from ovariectomy-induced bone loss - Omata, Yasunori; Frech, Michael; Lucas, Sébastien; Primbs, Tatjana; Knipfer, Lisa; Wirtz, Stefan; Kadono, Yuho; Saito, Taku; Tanaka, Sakae; Sarter, Kerstin; Schett, Georg; Zaiss, Mario (Bone, 2020)
While the role of T cells in the regulation of bone homeostasis is well defined, little is known about the role of innate lymphoid cells (ILCs) on bone. ILCs are innate immune cells that share cytokine expression patterns with T cells but lack the T cell receptor. In this study we show that type 2 ILCs (ILC2) potently inhibit the generation of bone resorbing osteoclasts in vitro as well as favorably influence bone homeostasis under steady state conditions in vivo using loss and gain of function models. Furthermore, adoptive transfer of ILC2 completely abrogated ovariectomy-induced bone loss by significantly down-regulating osteoclast numbers in vivo. The suppressive effects of ILC2s on osteoclasts in vitro and in vivo as well as the protection from ovariectomy-induced bone loss were linked to their expression of IL-4 and IL-13 as well as STAT6 activation on the myeloid target cell, since deletion of IL-4/IL-13 in ILC2s or STAT6 in osteoclast precursors abrogated the anti-osteoclastogenic effect of ILC2s. Taken together, these findings show that ILC2 have to be considered as potent regulators of bone homeostasis.
CRIS-Team Scopus Importer:2020-04-14
Keywords: Bone loss; Cytokines; ILC2; Osteoclasts; Osteoimmunology; Type 2 innate lymphoid cells type

Ultra-long-term human salt balance studies reveal interrelations between sodium, potassium, and chloride intake and excretion - Birukov, Anna; Rakova, Natalia; Lerchl, Kathrin; Engberink, Rik H. G. Olde; Johannes, Bernd; Wabel, Peter; Moissl, Ulrich; Rauh, Manfred; Luft, Friedrich C.; Titze, Jens (American Journal of Clinical Nutrition, 2016)
BACKGROUND: The intake of sodium, chloride, and potassium is considered important to healthy nutrition and cardiovascular disease risk. Estimating the intake of these electrolytes is difficult and usually predicated on urine collections, commonly for 24 h, which are considered the gold standard. We reported on data earlier for sodium but not for potassium or chloride. OBJECTIVE: We were able to test the value of 24-h urine collections in a unique, ultra-long-term balance study conducted during a simulated trip to Mars. DESIGN: Four healthy men were observed while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, while their potassium intake was maintained at 4 g/d for 105 d. Six healthy men were studied while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, with a re-exposure of 12 g/d, while their potassium intake was maintained at 4 g/d for 205 d. Food intake and other constituents were recorded every day for each subject. All urine output was collected daily. RESULTS: Long-term urine recovery rates for all 3 electrolytes were very high. Rather than the expected constant daily excretion related to daily intake, we observed remarkable daily variation in excretion, with a 7-d infradian rhythm at a relatively constant intake. We monitored 24-h aldosterone excretion in these studies and found that aldosterone appeared to be the regulator for all 3 electrolytes. We report Bland-Altman analyses on the value of urine collections to estimate intake. CONCLUSIONS: A single 24-h urine collection cannot predict sodium, potassium, or chloride intake; thus, multiple collections are necessary. This information is important when assessing electrolyte intake in individuals.
EVALuna2:33935

Ultraschallelastographie - Görtz, Rüdiger (Radiologe, 2015)
Noninvasive, ultrasound-based methods for visualizing and measuring tissue elasticity are becoming more and more common in routine practice. Using hepatic shear wave elastography, cut-off levels can help to detect the degree of relevant fibrosis (F >= 2) with a diagnostic accuracy using the area under the reader operating characteristic (AUROC) of 87 % and cirrhosis (F = 4, AUROC 93 %). Normal values virtually exclude liver cirrhosis (negative predictive value up to 97 %) and high shear wave velocities predict complications in the course of primary sclerosing cholangitis, liver cirrhosis and chronic hepatitis B or C. Elastography is of no relevant help in the differentiation of the dignity of hepatic lesions. Concerning thyroid or breast lesions, low shear wave velocities are indicative of benign lesions and in contrast, high velocities of malignant lesions. A differentiation between benign and malignant thyroid nodules is performed by elastography with a sensitivity of 89 % and a specificity of 82 %. In breast lesions a differentiation of nodes can be improved with elastography compared to B-mode ultrasound alone with a sensitivity of 97 % and a specificity of 83 %. Invasive biopsy punctures can therefore be specifically performed or can be omitted. Due to several influencing factors, in particular during liver elastography, the measurements need to be interpreted in the clinical context. In summary, ultrasound-based elastography provides helpful information for the detection of hepatic fibrosis and for further characterization of thyroid or breast lesions in addition to classical techniques, such as B-mode imaging and color Doppler.
EVALuna2:2034

Ultrasensitive molecular imaging of intestinal mucosal inflammation using leukocyte-mimicking particles targeted to MAdCAM-1 in mice - Fournier, Antoine P.; De Lizarrondo, Sara Martinez; Rateau, Adrien; Gerard-Brisou, Axel; Waldner, Maximilian; Neurath, Markus; Vivien, Denis; Docagne, Fabian; Gauberti, Maxime (Science Translational Medicine, 2020)
Mucosal tissues play critical roles in health and disease as the primary barrier between the external world and the inner body, lining the digestive, respiratory, urinary, mammary, and reproductive tracts. Clinical evaluation of mucosal tissues is currently performed using endoscopy, such as ileocolonoscopy for the intestinal mucosa, which causes substantial patient discomfort and can lead to organ damage. Here, we developed a contrast agent for molecular magnetic resonance imaging (MRI) that is targeted to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), an adhesion molecule overexpressed by inflamed mucosal tissues. We investigated the diagnostic performance of molecular MRI of MAdCAM-1 to detect mucosal inflammation in several models of acute and chronic intestinal inflammation in mice. We demonstrated that molecular MRI of MAdCAM-1 reveals disease activity and can evaluate the response to inflammatory treatments along the whole intestinal mucosa in clinically relevant models of inflammatory bowel diseases. We also provide evidence that this technique can detect low, subclinical mucosal inflammation. Molecular MRI of MAdCAM-1 has potential applications in early diagnosis, longitudinal follow-up, and therapeutic response monitoring in diseases affecting mucosal tissues, such as inflammatory bowel diseases.
CRIS-Team WoS Importer:2020-09-25

Ultrasound-Based Attenuation Imaging for the Non-Invasive Quantification of Liver Fat-A Pilot Study on Feasibility and Inter-Observer Variability - Jesper, Daniel; Klett, Daniel; Schellhaas, Barbara; Pfeifer, Lukas; Leppkes, Moritz; Waldner, Maximilian; Neurath, Markus; Strobel, Deike (IEEE Journal of Translational Engineering in Health and Medicine, 2020)
Attenuation imaging is a novel, ultrasound-based technique to objectively detect and quantify liver steatosis. In this study, we evaluated the performance and inter-observer variability of attenuation imaging and compared it to a known quantification method of liver fat, the hepatorenal index (HRI). Two observers measured attenuation coefficients (AC) in an attenuation phantom, 20 healthy volunteers and 27 patients scheduled for biopsy for suspected diffuse liver disease. Results were compared with the HRI and histological findings. Both observers were blinded to the results of the biopsy and the measurements of the other observer. Our results showed that patients with moderate (S2, 33-66%) and severe fatty infiltration of the liver (S3, >66%) showed significantly higher ACs in comparison to patients with a liver fat fraction of less than 33% (S0/1). There was no significant difference in AC-values of patients with fatty infiltration of less than 5% (S0) and 5-32% (S1). In the Receiver Operating Characteristic (ROC)-analysis, the area under the curve (AUC)-values for the detection of moderate and severe steatosis were excellent at 0.98. Cut-off values were 0.64 dB/cm/MHz for the detection of S2- A nd 0.68 dB/cm/MHz for the detection of S3-steatosis. The inter-observer agreement of attenuation imaging was very good with an intraclass correlation coefficient (ICC) of 0.92 in patient and 0.96 in phantom measurements. The ICC decreased with depth in the phantom measurements. In summary, attenuation imaging showed very good inter-observer agreement and is a promising tool for the detection and quantification of moderate and severe hepatic steatosis.
CRIS-Team Scopus Importer:2020-07-31
Keywords: Attenuation imaging; fatty liver; hepatic fat; hepatic steatosis; hepatorenal index; inter-observer; liver steatosis; NAFLD; NASH; ultrasound

Undertreatment of cardiovascular risk factors in the type 1 diabetes exchange clinic network (United States) and the prospective diabetes follow-up (Germany/Austria) registries - Shah, Viral N.; Grimsmann, Julia M.; Foster, Nicole C.; Dost, Axel; Miller, Kellee M.; Pavel, Marianne Ellen; Weinstock, Ruth S.; Karges, Wolfram; Maahs, David M.; Holl, Reinhard W. (Diabetes Obesity & Metabolism, 2020)
Aim To examine the control of cardiovascular risk factors in type 1 diabetes (T1D) registries from the United States and Germany/Austria.
CRIS-Team WoS Importer:2020-05-29

United European Gastroenterology Week review: Endoscopy and inflammatory bowel disease - Neumann, Helmut; Vieth, Michael (Digestive Endoscopy, 2016)
EVALuna2:2157

Upadacitinib improves steroid-free clinical and endoscopic endpoints in patients with Crohn's disease: Data from the CELEST study - Panaccione, R.; Atreya, Raja; Ferrante, M.; Dubinsky, M. C.; Sands, B. E.; Abreu, M. T.; Cataldi, F.; Enejosa, J. V.; Zhou, Q.; Huang, B.; Lacerda, A. P.; Pangan, A. L. (2018)
EVALuna2:35192

Update: chronisch entzündliche Darmerkrankungen - Atreya, Raja; Neumann, Helmut; Neurath, Markus (Deutsche Medizinische Wochenschrift, 2015)
Crohn's disease and ulcerative colitis are the major entities of inflammatory bowel diseases (IBD). IBD is a clinical diagnosis, which is supported by endoscopic, histologic, radiologic, sonographic and laboratory findings. IBD are not restricted to the GI-tract but are instead systemic diseases that often involve extra-intestinal manifestations. Aim of the rational medical therapy is the induction and maintenance of a steroid-free remission. The medical therapy depends on the severity, activity and extent of disease as well as the disease course of the patient. There is the dire necessity for an individualized therapeutic concept as the natural disease course differs between the patients.
EVALuna2:1989

Updated S3-Guideline Ulcerative Colitis. German Society for Digestive and Metabolic Diseases (DGVS): AWMF Registry 021/009 - Kucharzik, Torsten; Dignass, Axel U.; Atreya, Raja; Bokemeyer, Bernd; Esters, Philip; Herrlinger, Klaus; Kannengiesser, Klaus; Kienle, Peter; Langhorst, Jost; Luegering, Andreas; Schreiber, Stefan; Stallmach, Andreas; et al. (Zeitschrift für Gastroenterologie, 2019)
This guideline provides evidence-based key recommendations for diagnosis and treatment of ulcerative colitis and upgrades the 2011 version. The guideline was developed by an interdisciplinary team of gastroenterologists, surgeons, pathologists, nutrition experts, and patient support groups under the auspice of the German Society for Gastroenterology and Metabolic Diseases. The guideline used structural S3 consensus-based methodology and includes statements on clinical practice, prevention, infectiological problems, surgery and nutrition.
CRIS-Team WoS Importer:2019-03-12

Update of the diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours) - Kos-Kudła, Beata; Foltyn, Wanda; Malczewska, Anna; Bednarczuk, Tomasz; Bolanowski, Marek; Borowska, Małgorzata; Chmielik, Ewa; Ćwikla, Jaroslaw B.; Gisterek, Iwona; Handkiewicz-Junak, Daria; Hubalewska-Dydejczyk, Alicja; Jarząb, Barbara; et al. (Endokrynologia Polska, 2022)
Continuous progress in the diagnostics and treatment of neuroendocrine neoplasms (NENs), the emerging results of new clinical trials, and the new guidelines issued by medical societies have prompted experts from the Polish Network of Neuroendocrine Tumours to update the 2017 recommendations regarding the management of neuroendocrine neoplasms. This article presents the general recommendations for the management of NENs, resulting from the findings of the experts participating in the Fourth Round Table Conference, entitled "Polish Guidelines for the Diagnostics and Treatment of Neuroendocrine Neoplasms of the gastrointestinal tract, Zelechów, June 2021". Drawing from the extensive experience of centres treating these cancers, we hope that we have managed to formulate the optimal method of treating patients with NENs, applying the latest reports and achievements in the field of medicine, which can be effectively implemented in our country. The respective parts of this work present the approach to the management of: NENs of the stomach and duodenum (including gastrinoma), pancreas, small intestine, and appendix, as well as large intestine.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Diagnostics; gastro-entero-pancreatic neuroendocrine neoplasms; treatment

Update on Nephrolithiasis: Core Curriculum 2016 - Pfau, Anja; Knauf, Felix (American Journal of Kidney Diseases, 2016)
EVALuna2:3931

Upregulation of CCR4 in activated CD8(+) T cells indicates enhanced lung homing in patients with severe acute SARS-CoV-2 infection - Spoerl, Silvia; Kremer, Anita; Aigner, Michael; Eisenhauer, Nina; Koch, Pauline; Meretuk, Lina; Loeffler, Patrick; Tenbusch, Matthias; Maier, Clara; Überla, Klaus; Heinzerling, Lucie; Frey, Benjamin; et al. (European Journal of Immunology, 2021)
COVID-19 is a life-threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood.
CRIS-Team WoS Importer:2021-05-07

Uremic pruritus - Mettang, Thomas; Kremer, Andreas (Kidney International, 2015)
Uremic pruritus or chronic kidney disease-associated pruritus (CKD-aP) remains a frequent and compromising symptom in patients with advanced or end-stage renal disease, strongly reducing the patient's quality of life. More than 40% of patients undergoing hemodialysis suffer from chronic pruritus; half of them complain about generalized pruritus. The pathogenesis of CKD-aP remains obscure. Parathormone and histamine as well as calcium and magnesium salts have been suspected as pathogenetic factors. Newer hypotheses are focusing on opioid-receptor derangements and microinflammation as possible causes of CKD-aP, although until now this could not be proven. Pruritus may be extremely difficult to control, as therapeutic options are limited. The most consequential approaches to treatment are: topical treatment with or without anti-inflammatory compounds or systemic treatment with (a) gabapentin, (b) ?-opioid receptor antagonists and ?-agonists, (c) drugs with an anti-inflammatory action, (d) phototherapy, or (e) acupuncture. A stepwise approach is suggested starting with emollients and gabapentin or phototherapy as first-line treatments. In refractory cases, more experimental options as ?-opioid-receptor-antagonists (i.e., naltrexone) or ?-opioid-receptor agonist (nalfurafine) may be chosen. In desperate cases, patients suitable for transplantation might be set on 'high urgency'-status, as successful kidney transplantation will relieve patients from CKD-aP.
EVALuna2:1996

Use and perceived utility of [18F]FDG PET/CT in neuroendocrine neoplasms: A consensus report from the European Neuroendocrine Tumor Society (ENETS) Advisory Board Meeting 2022 - Ambrosini, Valentina; Caplin, Martyn; Castaño, Justo P.; Christ, Emanuel; Denecke, Timm; Deroose, Christophe M.; Dromain, Clarisse; Falconi, Massimo; Grozinsky-Glasberg, Simona; Hicks, Rodney J.; Hofland, Johannes; Kjaer, Andreas; et al. (Journal of Neuroendocrinology, 2023)
Somatostatin receptor (SST) PET/CT is the gold standard for well-differentiated neuroendocrine tumours (NET) imaging. Higher grades of neuroendocrine neoplasms (NEN) show preferential [18F]FDG (FDG) uptake, and even low-grade NET may de-differentiate over time. FDG PET/CT's prognostic role is widely accepted; however, its impact on clinical decision-making remains controversial and its use varies widely. A questionnaire-based survey on FDG PET/CT use and perceived decision-making utility in NEN was submitted to the ENETS Advisory Board Meeting attendees (November 2022, response rate = 70%). In 3/15 statements, agreement was higher than 75%: (i) FDG was considered useful in NET, irrespective of grade, in case of mis-matched lesions (detectable on diagnostic CT but negative/faintly positive on SST PET/CT), especially if PRRT is contemplated (80%); (ii) in NET G3 if curative surgery is considered (82%); and (iii) in NEC prior to surgery with curative intent (98%). FDG use in NET G3, even in the presence of matched lesions, as a baseline for response assessment was favoured by 74%. Four statements obtained more than 60% consensus: (i) FDG use in NET G3 if locoregional therapy is considered (65%); (ii) in neuroendocrine carcinoma before initiating active therapy as a baseline for response assessment (61%); (iii) biopsy to re-assess tumour grade prior to a change in therapeutic management (68%) upon detection of FDG-positivity on the background of a prior G1-2 NET; (iv) 67% were in favour to reconsider PRRT to treat residual SST-positive lesions after achieving complete remission on FDG of the SST-negative disease component. Multidisciplinary opinion broadly supports the use of FDG PET/CT for characterisation of disease biology and to guide treatment selection across a range of indications, despite the lack of full consensus in many situations. This may reflect existing clinical access due to lack of reimbursement or experience with this investigation, which should be addressed by further research.
CRIS-Team Scopus Importer:2023-12-22
Keywords: FDG; neuroendocrine neoplasms; neuroendocrine tumours; PET/CT

Usefulness of recombinant ?-gliadin 1 for identifying patients with celiac disease and monitoring adherence to a gluten-free diet - Srinivasan, Bharani; Focke-Tejkl, Margarete; Weber, Milena; Pahr, Sandra; Baar, Alexandra; Atreya, Raja; Neurath, Markus; Vogelsang, Harald; Huber, Wolf-Dietrich; Valenta, Rudolf (Journal of Allergy and Clinical Immunology, 2015)
Celiac disease (CD) is an inflammatory disease of the small intestine caused by an immunologic hypersensitivity reaction to dietary wheat gluten.We sought to clone, express, and perform IgA epitope mapping of a CD-specific wheat antigen and to study its usefulness for identifying patients with CD and monitoring adherence to a gluten-free diet.A synthetic gene coding for ?-gliadin 1 (GG1) was expressed in Escherichia coli. Recombinant ?-gliadin 1 (rGG1) was purified and characterized biochemically, structurally, and immunologically by using sera from patients with CD and control subjects. Overlapping GG1 peptides were synthesized for IgA and IgG epitope mapping. GG1 and peptide-specific antibodies were raised for tracing GG1 in cereals and dietary wheat products and to study its resistance to digestion.rGG1 was expressed and purified. rGG1-based IgA ELISAs performed in populations of patients with CD and control subjects showed a specificity of 92.9%, which was higher than that of gliadin extract (e). Furthermore, it allowed monitoring of adherence to a gluten-free diet in patients. A 26-amino-acid peptide from the proline-glutamine-rich repetitive N-terminal region was identified as the immunodominant IgA epitope. GG1-related antigens were found in rye, barley, and spelt but not in oat, rice, or maize. GG1 was detected in dietary wheat products after baking, and in particular, the major IgA epitope-containing region was resistant against digestion.rGG1 and its epitope might be useful for identifying patients with CD, monitoring treatment, and studying the pathomechanisms of CD and development of preventive and therapeutic strategies.
EVALuna2:2102

Use of an over-the-scope clip for endoscopic sealing of anastomotic dehiscence after anterior resection for rectal cancer - Soriani, Paola; Tontini, Gian Eugenio; Pastorelli, Luca; Mauri, Massimo; Neumann, Helmut; Vecchi, Maurizio; Lagoussis, Pavlos (Endoscopy, 2015)
EVALuna2:1987

Use of Fluorescent Dyes in Endoscopy and Diagnostic Investigation - Hoffman, Arthur; Atreya, Raja; Rath, Timo; Neurath, Markus (Visceral Medicine, 2020)
Background: The advancement of innovative endoscopic technology in terms of improving the visualization of the mucosa has been of significant benefit. Summary: Advancements in image resolution, software processing, and optical filter technology have resulted in several techniques complemental to traditional white light endoscopy. These new techniques provide a real-time optical diagnosis as well as virtual histology of detected lesions. Optical molecular imaging permits a functional assessment within cells. Key Message: Optical molecular imaging provides an understanding of cellular processes and permits validation of the specificity of fluorescent tracers and the possibility of quantifying the signal.
CRIS-Team Scopus Importer:2020-04-07

Use of probe-based confocal laser endomicroscopy (pCLE) in gastrointestinal applications. A consensus report based on clinical evidence - Wang, Kenneth K.; Carr-Locke, David L.; Singh, Satish K.; Neumann, Helmut; Bertani, Helga; Galmiche, Jean-Paul; Arsenescu, Razvan I.; Caillol, Fabrice; Chang, Kenneth J.; Chaussade, Stanislas; Coron, Emmanuel; Costamagna, Guido; et al. (United European Gastroenterology Journal, 2015)
Probe-based confocal laser endomicroscopy (pCLE) provides microscopic imaging during an endoscopic procedure. Its introduction as a standard modality in gastroenterology has brought significant progress in management strategies, affecting many aspects of clinical care and requiring standardisation of practice and training.This study aimed to provide guidance on the standardisation of its practice and training in Barrett's oesophagus, biliary strictures, colorectal lesions and inflammatory bowel diseases.Initial statements were developed by five group leaders, based on the available clinical evidence. These statements were then voted and edited by the 26 participants, using a modified Delphi approach. After two rounds of votes, statements were validated if the threshold of agreement was higher than 75%.Twenty-six experts participated and, among a total of 77 statements, 61 were adopted (79%) and 16 were rejected (21%). The adoption of each statement was justified by the grade of evidence.pCLE should be used to enhance the diagnostic arsenal in the evaluation of these indications, by providing microscopic information which improves the diagnostic performance of the physician. In order actually to implement this technology in the clinical routine, and to ensure good practice, standardised initial and continuing institutional training programmes should be established.
EVALuna2:2019

Utilization of Diagnostic Imaging and Ionizing Radiation Exposure-Has the Tide Already Turned? - Zundler, Sebastian (Inflammatory Bowel Diseases, 2020)
Inflammatory bowel diseases require repetitive abdominal imaging for diagnosis, follow-up, or management of complications. This editorial comments on the large incident-based case-control study on utilization of diagnostic imaging and ionizing radiation exposure by Nguyen and colleagues published in this issue.
CRIS-Team Scopus Importer:2020-05-22

Validation of the 'Inflammatory Bowel Disease-Distribution, Chronicity, Activity [IBD-DCA] Score' for Ulcerative Colitis and Crohn ' s Disease - Lang-Schwarz, Corinna; Angeloni, Miriam; Agaimy, Abbas; Atreya, Raja; Becker, Christoph; Dregelies, Theresa; Danese, Silvio; Flejou, Jean-Francois; Gassler, Nikolaus; Grabsch, Heike; Hartmann, Arndt; Kamaradova, Katerina; et al. (Journal of Crohns & Colitis, 2021)
Background and Aims: Histological scoring plays a key role in the assessment of disease activity in ulcerative colitis [UC] and is also important in Crohns disease [CD]. Currently, there is no common scoring available for UC and CD. We aimed to validate the Inflammatory Bowel Disease [IBD]-Distribution [D], Chronicity [C], Activity [A] score [IBD-DCA score] for histological disease activity assessment in IBD.
CRIS-Team WoS Importer:2021-11-12

Value of Tumor Growth Rate (TGR) as an Early Biomarker Predictor of Patients’ Outcome in Neuroendocrine Tumors (NET)—The GREPONET Study - Lamarca, Angela; Crona, Joakim; Ronot, Maxime; Opalinska, Marta; Lopez Lopez, Carlos; Pezzutti, Daniela; Najran, Pavan; Carvhalo, Luciana; Franca Bezerra, Regis Otaviano; Borg, Philip; Vietti Violi, Naik; Vidal Trueba, Hector; et al. (Oncologist, 2019)
Introduction: Tumor growth rate (TGR; percent size change per month [%/m]) is postulated to be an early radiological biomarker to overcome limitations of RECIST. This study aimed to assess the impact of TGR in neuroendocrine tumors (NETs) and potential clinical and therapeutic applications. Materials and Methods: Patients (pts) with advanced grade (G) 1/2 NETs from the pancreas or small bowel initiating systemic treatment (ST) or watch and wait (WW) were eligible. Baseline and follow-up scans were retrospectively reviewed to calculate TGR at pretreatment (TGR 0 ), first follow-up (TGR first ), and 3(±1) months of study entry (TGR 3m ). Results: Out of 905 pts screened, 222 were eligible. Best TGR first (222 pts) cutoff was 0.8 (area under the curve, 0.74). When applied to TGR 3m (103 pts), pts with TGR 3m <0.8 (66.9%) versus TGR 3m ≥ 0.8 (33.1%) had longer median progression-free survival (PFS; 26.3 m; 95% confidence interval [CI] 19.5–32.4 vs. 9.3 m; 95% CI, 6.1–22.9) and lower progression rate at 12 months (7.3% vs. 56.8%; p =.001). WW (vs. ST) and TGR 3m ≥ 0.8 (hazard ratio [HR], 3.75; 95% CI, 2.21–6.34; p <.001) were retained as factors associated with a shorter PFS in multivariable Cox regression. TGR 3m (HR, 3.62; 95% CI, 1.97–6.64; p <.001) was also an independent factor related to shorter PFS when analysis was limited to pts with stable disease (81 pts). Out of the 60 pts with TGR 0 data available, 60% of pts had TGR 0 < 4%/month. TGR 0 ≥ 4 %/month (HR, 2.22; 95% CI, 1.15–4.31; p =.018) was also an independent factor related to shorter PFS. Conclusion: TGR is an early radiological biomarker able to predict PFS and to identify patients with advanced NETs who may require closer radiological follow-up. Implications for Practice: Tumor growth rate at 3 months (TGR 3m ) is an early radiological biomarker able to predict progression-free survival and to identify patients with advanced neuroendocrine tumors who may require closer radiological follow-up. It is feasible to calculate TGR 3m in clinical practice and it could be a useful tool for guiding patient management. This biomarker could also be implemented in future clinical trials to assess response to therapy.
CRIS-Team Scopus Importer:2019-06-07
Keywords: NET; Neuroendocrine tumor; Progression-free survival; TGR; Tumor growth rate

Value of Tumor Growth Rate (TGR) as an Early Predictor of Patients' Outcome in Patients Diagnosed with Well-Differentiated Neuroendocrine Tumors (NETs): The GREPONET Study - Lamarca, A.; Crona, J.; Ronot, M.; Opalinska, M.; Lopez Lopez, C.; Pezzutti, D.; Najran, P.; Franca, R.; Scaefer, N.; Sundin, A.; Pavel, Marianne Ellen; Dromain, C. (2018)
EVALuna2:34119

Vascular occlusion by neutrophil extracellular traps in COVID-19 - Leppkes, Moritz; Knopf, Jasmin; Naschberger, Elisabeth; Lindemann, Aylin; Singh, Jeeshan; Herrmann, Irmgard; Stürzl, Michael; Staats, Léonie; Mahajan, Aparna; Kremer, Anita; Amann, Kerstin Ute; Evert, Katja; et al. (EBioMedicine, 2020)
Background: Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood. Methods: Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry. Patient findings: Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage. Interpretation: These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage. Funding: Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung
CRIS-Team Scopus Importer:2020-08-14
Keywords: Aggregated neutrophil extracellular traps; Coagulopathy; Endothelialitis; Immunothrombosis; SARS-CoV-2

Vedolizumab-associated enthesitis: correlation or causality? - Vitali, Francesco; Simon, David; Neurath, Markus; Schett, Georg; Zundler, Sebastian (Rheumatology, 2021)
CRIS-Team WoS Importer:2022-02-04

Vedolizumab blocks alpha 4 beta 7 integrin-mediated T cell adhesion to MAdCAM-1 in microscopic colitis - Besendorf, Laura; Müller, Tanja; Geppert, Carol-Immanuel; Schneider, Ines; Mühl, Laura; Atreya, Imke; Vitali, Francesco; Atreya, Raja; Neurath, Markus; Zundler, Sebastian (Therapeutic Advances in Gastroenterology, 2022)
Background: In Crohn's disease and ulcerative colitis, the anti-alpha 4 beta 7 integrin antibody vedolizumab has demonstrated efficacy in phase III trials and has been successfully used under real-world conditions. Occasionally, it has also been used in other forms of inflammatory bowel disease (IBD) such as microscopic colitis (MC). However, the mechanisms of vedolizumab in MC have not been studied to date. Therefore, we aimed to investigate the expression and functional role of gut-homing integrins and in particular alpha 4 beta 7 integrin in a cohort study in MC.
CRIS-Team WoS Importer:2022-07-08
Keywords: α4β7 integrin; microscopic colitis; T cell trafficking; vedolizumab

Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease - a prospective multicenter observational study - Stallmach, A.; Langbein, C.; Atreya, Raja; Bruns, T.; Dignass, A.; Ende, K.; Hampe, J.; Hartmann, F.; Neurath, Markus; Maul, J.; Preiss, J. C.; Schmelz, R.; et al. (Alimentary Pharmacology & Therapeutics, 2016)
Vedolizumab, a monoclonal antibody targeting the ?4?7-integrin, is effective in inducing and maintaining clinical remission in Crohn's disease and ulcerative colitis according to randomised clinical trials.To determine the long-term effectiveness of vedolizumab in a real-world clinical setting.This observational registry assessed the clinical outcome in patients treated with vedolizumab for clinically active Crohn's disease (n = 67) or ulcerative colitis (n = 60). Primary endpoint was clinical remission (HBI <= 4/pMayo <= 1) at week 54. Secondary endpoints included clinical response rates (HBI/pMayo score drop >=3) and steroid-free clinical remission at weeks 30 and 54.Vedolizumab was stopped in 69/127 (56%) patients after a median time of 18 weeks (range 2-49) predominantly owing to lack or loss of response. Using nonresponder imputation analysis, clinical remission and steroid-free remission rates were 21% and 15% in Crohn's disease and 25% and 22% in ulcerative colitis, respectively. Lack of clinical remission was associated with prior treatment with anti-TNF or with steroids for more than 3 months in the last 6 months in ulcerative colitis. At week 14, the absence of remission in Crohn's disease or nonresponse in ulcerative colitis indicated a low likelihood of clinical remission at week 54 [2/31 (7%) in Crohn's disease, 4/41 (10%) in ulcerative colitis]. Accordingly, declining C-reactive protein in inflammatory bowel disease and/or lower faecal calprotectin in ulcerative colitis at week 14 predicted remission at week 54.Among patients who started vedolizumab for active inflammatory bowel disease, clinical remission rates are 21-25% after 54 weeks.
EVALuna2:2185

VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis - Försch, Sebastian; Sperka, Tobias; Lindner, Christina; Taut, Astrid; Rudolph, Karl L.; Breier, Georg; Boxberger, Frank; Rau, Tilman; Hartmann, Arndt; Stürzl, Michael; Wittkopf, Nadine; Haep, Lisa; et al. (Gastroenterology, 2015)
Senescence prevents cellular transformation. We investigated whether vascular endothelial growth factor (VEGF) signaling via its receptor, VEGFR2, regulates senescence and proliferation of tumor cells in mice with colitis-associated cancer (CAC).CAC was induced in VEGFR2(?IEC) mice, which do not express VEGFR2 in the intestinal epithelium, and VEGFR2(fl/fl) mice (controls) by administration of azoxymethane followed by dextran sodium sulfate. Tumor development and inflammation were determined by endoscopy. Colorectal tissues were collected for immunoblot, immunohistochemical, and quantitative polymerase chain reaction analyses. Findings from mouse tissues were confirmed in human HCT116 colorectal cancer cells. We analyzed colorectal tumor samples from patients before and after treatment with bevacizumab.After colitis induction, VEGFR2(?IEC) mice developed significantly fewer tumors than control mice. A greater number of intestinal tumor cells from VEGFR2(?IEC) mice were in senescence than tumor cells from control mice. We found VEGFR2 to activate phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT, resulting in inactivation of p21 in HCT116 cells. Inhibitors of VEGFR2 and AKT induced senescence in HCT116 cells. Tumor cell senescence promoted an anti-tumor immune response by CD8(+) T cells in mice. Patients whose tumor samples showed an increase in the proportion of senescent cells after treatment with bevacizumab had longer progression-free survival than patients in which the proportion of senescent tumor cells did not change before and after treatment.Inhibition of VEGFR2 signaling leads to senescence of human and mouse colorectal cancer cells. VEGFR2 interacts with phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT to inactivate p21. Colorectal tumor senescence and p21 level correlate with patient survival during treatment with bevacizumab.
EVALuna2:1356

Very Low-Volume, High-Intensity Interval Training Mitigates Negative Health Impacts of COVID-19 Pandemic-Induced Physical Inactivity - Reljic, Dejan; Eichhorn, Annalena; Herrmann, Hans J.; Neurath, Markus; Zopf, Yurdagül (International Journal of Environmental Research and Public Health, 2022)
Initially, we aimed to investigate the impact of a one-year worksite low-volume, high-intensity interval training (LOW-HIIT) on cardiometabolic health in 114 sedentary office workers. Due to the COVID-19 pandemic outbreak, LOW-HIIT was discontinued after 6 months and participants were followed up for 6 months to analyze physical activity/exercise behavior and outcome changes during lockdown. Health examinations, including cardiopulmonary exercise testing and the assessment of cardiometabolic markers were performed baseline (T-1), after 6 months (T-2, termination of worksite LOW-HIIT) and 12 months (T-3, follow-up). Cycle ergometer LOW-HIIT (5 x 1 min at 85-95% HRmax) was performed 2x/week. For follow-up analyses, participants were classified into three groups: HIIT-group (continued home-based LOW-HIIT), EX-group (continued other home-based exercises), and NO-EX-group (discontinued LOW-HIIT/exercise). At T-2, VO2max (+1.5 mL/kg/min, p = 0.002), mean arterial blood pressure (MAB, -4 mmHg, p < 0.001), HbA(1c) (-0.2%, p = 0.005) and self-reported quality of life (QoL, +5 points, p < 0.001) were improved. At T-3, HIIT-group maintained VO2max and QoL and further improved MAB. EX-group maintained MAB and QoL but experienced a VO2max decrease. In NON-EX, VO2max, MAB and QoL deteriorated. We conclude that LOW-HIIT can be considered a promising option to improve cardiometabolic health in real-life conditions and to mitigate physical inactivity-related negative health impacts during lockdowns.
CRIS-Team WoS Importer:2022-10-21

VERY LOW-VOLUME INTERVAL TRAINING IMPROVES NONALCOHOLIC FATTY LIVER DISEASE FIBROSIS SCORE AND CARDIOMETABOLIC HEALTH IN ADULTS WITH OBESITY AND METABOLIC SYNDROME - Reljic, Dejan; Konturek, P. C.; Herrmann, H. J.; Siebler, Jürgen; Neurath, Markus; Zopf, Yurdagül (Journal of Physiology and Pharmacology, 2021)
Non-alcoholic fatty liver disease (NAFLD) and cardiometabolic disorders are highly prevalent in obese individuals. Physical exercise is an important element in obesity and metabolic syndrome (MetS) treatment. However, the vast majority of individuals with obesity do not meet the general physical activity recommendations (i.e. 150 min of moderate activity per week). The present study aimed to investigate the impact of a highly time-saving high-intensity interval training (HIIT) protocol (28 min time requirement per week) on NAFLD fibrosis (NFS) and cardiometabolic risk scores in obese patients with MetS and elevated NFS values. Twenty-nine patients performed HIIT on cycle ergometers (5 x 1 min at an intensity of 80 - 95% maximal heart rate) twice weekly for 12 weeks and were compared to a control group without exercise (CON, n = 17). Nutritional counseling for weight loss was provided to both groups. NFS, cardiometabolic risk indices, MetS z-score, cardiorespiratory fitness (VO2max) and body composition were assessed before and after intervention. The HIIT (-4.3 kg, P < 0.001) and CON (-2.3 kg, P = 0.003) group significantly reduced body weight. There were no significant group differences in relative weight reduction (HIIT: -3.5%, CON: -2.4%). However, only the HIIT group improved NFS (-0.52 units, P = 0.003), MetS z-score (-2.0 units, P < 0.001), glycemic control (HbA1c: -0.20%, P = 0.014) and VO2max (+3.1 mL/kg/min, P < 0.001). Decreases in NFS (-0.50 units, P = 0.025) and MetS z-score (-1.4 units, P = 0.007) and the increment in VO2max (3.3 mL/kg/min, P < 0.001) were significantly larger in the HIIT than in the CON group. In conclusion, only 28 min of HIIT per week can elicit significant improvements in NFS and a several cardiometabolic health indices in obese MetS patients with increased NFS grades. Our results underscore the importance of exercise in NAFLD and MetS treatment and suggest that our low-volume HIIT protocol can be regarded as viable alternative to more time-consuming exercise programs.
CRIS-Team WoS Importer:2022-05-13
Keywords: obesity; interval training; non-alcoholic fatty liver disease; physical activity; metabolic syndrome; cardiopulmonary exercise test; blood pressure; liver fibrosis

VEXAS syndrome mimicking lupus-like disease - Valor-Mendez, Larissa; Sticherling, Michael; Zeschick, Martin; Atreya, Raja; Schmidt, Daniela; Waldfahrer, Frank; Saake, Marc; Hüffmeier, Ulrike; Schett, Georg; Rech, Jürgen (Rheumatology, 2023)
CRIS-Team WoS Importer:2023-03-17

Viral FLIP blocks Caspase-8 driven apoptosis in the gut in vivo - Ruder, Barbara; Günther, Claudia; Stürzl, Michael; Neurath, Markus; Cesarman, Ethel; Ballon, Gianna; Becker, Christoph (PLoS ONE, 2020)
A strict cell death control in the intestinal epithelium is indispensable to maintain barrier integrity and homeostasis. In order to achieve a balance between cell proliferation and cell death, a tight regulation of Caspase-8, which is a key player in controlling apoptosis, is required. Caspase-8 activity is regulated by cellular FLIP proteins. These proteins are expressed in different isoforms (cFLIPlong and cFLIPshort) which determine cell death and survival. Interestingly, several viruses encode FLIP proteins, homologous to cFLIPshort, which are described to regulate Caspase-8 and the host cell death machinery. In the current study a mouse model was generated to show the impact of viral FLIP (vFLIP) from Kaposi's Sarcoma-associated Herpesvirus (KSHV)/ Human Herpesvirus-8 (HHV-8) on cell death regulation in the gut. Our results demonstrate that expression of vFlip in intestinal epithelial cells suppressed cFlip expression, but protected mice from lethality, tissue damage and excessive apoptotic cell death induced by genetic cFlip deletion. Finally, our model shows that vFlip expression decreases cFlip mediated Caspase-8 activation in intestinal epithelial cells. In conclusion, our data suggests that viral FLIP neutralizes and compensates for cellular FLIP, efficiently counteracting host cell death induction and facilitating further propagation in the host organism.
CRIS-Team Scopus Importer:2020-02-11

Virtual chromoendoscopy for prediction of severity and disease extent in patients with inflammatory bowel disease: A randomized controlled study - Neumann, Helmut; Günther, Claudia; Neufert, Clemens; Kiesslich, Ralf; Grauer, Martin; Atreya, Raja; Neurath, Markus; Vieth, Michael (Inflammatory Bowel Diseases, 2013)
Background: Increased vascular permeability and angiogenesis play a crucial role in the pathogenesis of inflammatory bowel disease (IBD). Aim was to determine whether computed virtual chromoendoscopy has the potential to enhance assessment of disease severity and extent in patients with mild or inactive IBD in comparison to high-definition white-light endoscopy. Methods: Consecutive patients with IBD were randomly assigned at a 1:1 ratio to undergo colonoscopy with high-definition white light (group A) or computed virtual chromoendoscopy (group B). The mucosal vascular pattern and any mucosal abnormalities were recorded. Subsequent to endoscopic characterization targeted, biopsies were obtained from every segment for subsequent histopathological analysis of disease activity. Results: Overall, 100 patients were screened to participate in this study of whom 78 patients (high-definition white light, n = 39; computed virtual chromoendoscopy, n = 39) completed the study protocol thereby matching the previously calculated sample size. Average duration of the examination was 18 minutes in group A and 20.5 minutes in group B that was not statistically significant. When comparing the endoscopic prediction of inflammatory extent and activity with the histological results, an overall agreement of 48.71% and 53.85% (group A) and 92.31% and 89.74% (group B) was found, respectively. These differences were statistically significant (P = 0.0009 and P = 0.066). Conclusions: This study indicates that computed virtual chromoendoscopy significantly improves the diagnosis of the severity and extent of mucosal inflammation in patients with IBD. This newly developed imaging technique may therefore have important implications for therapeutic interventions in patients with IBD. Copyright © 2013 Crohn's & Colitis Foundation of America, Inc.
CRIS-Team Scopus Importer:2020-10-28
Keywords: Advanced imaging; Chromoendoscopy; Endocytoscopy; Endomicroscopy; FICE; I-scan; IBD; Mucosal healing; Prediction

Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe-host-communication in vivo - Bittel, Miriam; Reichert, Patrick; Sarfati, Ilann; Dressel, Anja; Leikam, Stefanie; Uderhardt, Stefan; Stolzer, Iris; Phu, Tuan Anh; Ng, Martin; Vu, Ngan K.; Tenzer, Stefan; Distler, Ute; et al. (Journal of Extracellular Vesicles, 2021)
The intestinal microbiota influences mammalian host physiology in health and disease locally in the gut but also in organs devoid of direct contact with bacteria such as the liver and brain. Extracellular vesicles (EVs) or outer membrane vesicles (OMVs) released by microbes are increasingly recognized for their potential role as biological shuttle systems for inter-kingdom communication. However, physiologically relevant evidence for the transfer of functional biomolecules from the intestinal microbiota to individual host cells by OMVs in vivo is scarce. By introducing Escherichia coli engineered to express Cre-recombinase (E. coliCre) into mice with a Rosa26.tdTomato-reporter background, we leveraged the Cre-LoxP system to report the transfer of bacterial OMVs to recipient cells in vivo. Colonizing the intestine of these mice with E. coliCre, resulted in Cre-recombinase induced fluorescent reporter gene-expression in cells along the intestinal epithelium, including intestinal stem cells as well as mucosal immune cells such as macrophages. Furthermore, even far beyond the gut, bacterial-derived Cre induced extended marker gene expression in a wide range of host tissues, including the heart, liver, kidney, spleen, and brain. Together, our findings provide a method and proof of principle that OMVs can serve as a biological shuttle system for the horizontal transfer of functional biomolecules between bacteria and mammalian host cells.
CRIS-Team Scopus Importer:2021-10-29
Keywords: Cre-Loxp; extracellular vesicles; inflammation; intestinal stem cells; microbiome; outer membrane vesicles

Vitamin A- and D-Deficient Diets Disrupt Intestinal Antimicrobial Peptide Defense Involving Wnt and STAT5 Signaling Pathways in Mice - Filipe Rosa, Louisa; Petersen, Patricia P.; Görtz, Lisa F.; Stolzer, Iris; Kaden-Volynets, Valentina; Günther, Claudia; Bischoff, Stephan C. (Nutrients, 2023)
Vitamin A and D deficiencies are associated with immune modulatory effects and intestinal barrier impairment. However, the underlying mechanisms remain unclear. C57BL/6J mice were fed either a diet lacking in vitamin A (VAd), vitamin D (VDd) or a control diet (CD) for 12 weeks. Gut barrier function, antimicrobial peptide (AMP) defense and regulatory pathways were assessed. VAd mice compared to CD mice showed a reduced villus length in the ileum (p < 0.01) and decreased crypt depth in the colon (p < 0.05). In both VAd- and VDd-fed mice, ileal α-defensin 5 (p < 0.05/p < 0.0001 for VAd/VDd) and lysozyme protein levels (p < 0.001/p < 0.0001) were decreased. Moreover, mRNA expression of lysozyme (p < 0.05/p < 0.05) and total cryptdins (p < 0.001/p < 0.01) were reduced compared to controls. Furthermore, matrix metalloproteinase-7 (Mmp7) mRNA (p < 0.0001/p < 0.001) as well as components of the Wnt signaling pathway were decreased. VAd- and VDd-fed mice, compared to control mice, exhibited increased expression of pro-inflammatory markers and β-defensins in the colon. Organoid cell culture confirmed that vitamins A and D regulate AMP expression, likely through the Jak/STAT5 signaling pathway. In conclusion, our data show that vitamin A and D regulate intestinal antimicrobial peptide defense through Wnt and STAT5 signaling pathways.
CRIS-Team Scopus Importer:2023-02-03
Keywords: antimicrobial peptides; gut barrier; Jak/STAT; MAPk; vitamin A; vitamin D; Wnt signaling pathway

Washout appearance of hepatocellular carcinomas using standardized contrast-enhanced ultrasound (CEUS) including an extended late phase observation - Real-world data from the prospective multicentre DEGUM study - Meitner-Schellhaas, Barbara; Jesper, Daniel; Görtz, Rüdiger; Zundler, Sebastian; Strobel, Deike (Clinical hemorheology and microcirculation, 2023)
BACKGROUND: Non-invasive diagnosis of hepatocellular carcinoma (HCC) in contrast-enhanced ultrasound (CEUS) is based on the combination of arterial phase hyperenhancement (APHE) and subsequent late (>60 seconds) and mild contrast washout (WO). Whereas APHE is seen in the majority of HCC, wash-out pattern may vary in onset and intensity. In some HCC lesions, even no washout is seen at all. OBJECTIVE: Our prospective multicentre DEGUM HCC CEUS study aimed at identifying typical and atypical washout appearance of HCC in a real-life setting. METHODS: High-risked patients for HCC with focal liver lesions upon B-mode ultrasound were recruited prospectively. In a multicentre real-life setting, a standardised CEUS examination including an extended late phase up to 6 minutes was performed. CEUS patterns of HCC were recorded, and onset and intensity of washout appearance were assessed with respect to patient and tumour characteristics. Histological findings served as reference standard. RESULTS: In 230/316 HCC (72.8%), a CEUS pattern of APHE followed by WO was observed. In 158 cases (68.7%), WO was typical (onset > 60 seconds, mild intensity). 72 cases (31.3%) showed marked and / or early WO, whereas in 41 HCCs (13%), APHE was followed by sustained isoenhancement.Atypical WO upon CEUS was associated with macroinvasion of the liver vessels, portal vein thrombosis and diffuse growth pattern, but not tumour size and histological grading. CONCLUSIONS: In a prospective multicentre real-life setting, APHE is followed by atypical washout appearance or no washout at all in almost half of the HCCs with APHE. The examiner has to bear in mind that in spite of a characteristic APHE in HCCs, washout appearance can be atypical in CEUS, especially in HCCs with macrovascular invasion or diffuse growth pattern.
CRIS-Team Scopus Importer:2023-10-06
Keywords: CEUS LI-RADS® (Contrast Enhanced UltraSound Liver Imaging Reporting And Data System); contrast-enhanced ultrasound (CEUS); ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk); Hepatocellular carcinoma; liver cirrhosis; prospective multicentre study; standardized ultrasound examination

Water assisted colonoscopy: A promising new technique - Ishaq, Sauid; Neumann, Helmut (Digestive and Liver Disease, 2016)
EVALuna2:2095

Weekly High-dose 5-Fluorouracil as 24-hour Infusion Combined with Sodium Folinic Acid (AIO regimen) Plus Irinotecan in Second-line and Sequential Therapy of Metastatic Colorectal Cancer (CRC) - Wein, Axel; Wolff, Kerstin; Ostermeier, Nicola; Busse, Daniel; Hagel, Alexander; Koch, Franz; Merx, Kirsten; Neurath, Markus; Hofheinz, Ralf-Dieter; Siebler, Jürgen (Anticancer Research, 2017)
BACKGROUND/AIM: The aim of this work was to evaluate the efficacy and safety of second-line treatment with weekly high-dose 5-fluorouracil (5-FU) as a 24-hour infusion (24-h inf.) combined with sodium folinic acid (FA) (AIO-regimen) plus irinotecan (Iri.) after pretreatment with AIO-regimen plus oxaliplatin (L-OHP). PATIENTS AND METHODS: Patients with non-resectable distant CRC metastases were enrolled in a prospective phase II study for palliative second-line treatment after previous progression of first-line treatment in accordance with the AIO-regimen plus oxaliplatin. On an outpatient basis, the patients received a treatment regimen comprising of weekly 80 mg/m2 irinotecan in the form of a 1-hour i.v. infusion and 2,000 mg/m2 5-FU combined with 500 mg/m2 sodium folinic acid administered as a 24-h infusion i.v. once weekly. RESULTS: During second-line treatment, a total of 59 patients received 520 chemotherapy applications. As the main higher-grade symptom of toxicity, diarrhea (NCI-CTC-toxicity grade 3) presented in 8 patients (13.6%, 95%CI=5.1-23.7), followed by leukocytopenia (CTC grade 3) in 3 patients (5.1%, 95%CI=0-11.9), followed by thrombocytopenia (CTC grade 3) in 1 patient (1.7%, 95%CI=0-5.1). Fifty-nine patients were evaluable for treatment response. The remission data can be summarized as follows: complete remission (CR); n=0; partial remission (PR); n=6 (10%; 95%CI=3.4-18.6); stable disease (SD); n=31 (53%; 95%CI=39.0-64.4); progressive disease (PD); n=19 (33%; 95%CI=20.3-44.1). The median progression-free survival (PFS) rate (n=59) was 4.2 months (range=3.8-5.8 months). The median survival time counted from the start of second-line treatment (n=59) 14.2 months (range 8.2-17.3 months) and the median survival time counted from the start of first-line therapy (n=59) 25 months (range 19-27 months). CONCLUSION: Palliative second-line treatment according to the AIO regimen plus irinotecan offers both a favourable toxicity profile and promising efficacy in second-line and palliative sequential therapy.
EVALuna2:33808

Weight Change 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. (Pancreas, 2018)
EVALuna2:34109

Weight Maintenance up to 48 Weeks in Patients With Carcinoid Syndrome Treated With Telotristat Ethyl: Pooled Data From the Open-Label Extensions of the Phase III Clinical Trials TELESTAR and TELECAST - Srirajaskanthan, Rajaventhan; Pavel, Marianne Ellen; Kulke, Matthew; Clement, Dominique; Houchard, Aude; Keeber, Lucie; Weickert, Martin O. (Clinical Therapeutics, 2021)
Reported incidences of neuroendocrine tumors (NETs) appear to be increasing, possibly due to greater disease awareness and increased accuracy of diagnosis. Approximately 20% of patients with NETs develop carcinoid syndrome (CS), which arises from elevated secretion of bioactive compounds, including serotonin, from NETs. This leads to symptoms including diarrhea and flushing, which result in weight loss and are associated with considerable negative impact on patients’ quality of life. We previously reported significant weight gain and improved nutritional status in patients with NETs who were treated with telotristat ethyl (TE) for 12 weeks. In this follow-up analysis, using pooled data from the 36-week open-label extensions of the TELESTAR (NCT01677910) and TELECAST (NCT02063659) phase III trials, we demonstrate that improvements in weight and nutritional parameters were sustained or further improved in patients with CS through to week 48 of treatment with TE. At week 48/end of study, 68.7% of all patients maintained a stable weight or had weight gain and the mean changes from baseline in cholesterol and albumin levels in patients treated with TE were +0.41 mmol/L and -0.34 g/L, respectively. These results indicate that TE, alongside routine clinical practice, may provide long-term benefits in nutritional intake and weight evolution in patients with CS.
CRIS-Team Scopus Importer:2021-12-03
Keywords: carcinoid syndrome; carcinoid syndrome diarrhea; malnutrition; neuroendocrine tumor; telotristat ethyl; weight

What are new treatment concepts in systemic itch? - Kremer, Andreas (Experimental Dermatology, 2019)
Chronic pruritus is a relevant symptom burden in various systemic diseases. It is most commonly observed in patients with chronic kidney disease, hepatobiliary and hematological disorders as well as adverse drug reaction. Recent basic research has unravelled novel treatment targets which are currently in preclinical phases, clinical trials or have already been licensed. While mu-opioid receptor antagonists have been used since decades mainly in cholestatic pruritus, the k-opioid receptor agonist nalfurafine has been licensed in Japan for chronic kidney disease-associated pruritus (CKDaP) as well as cholestatic pruritus. Further kappa-opioid receptor agonists are currently investigated in various clinical trials including CKDaP. In recent years, the calcium channel blockers gabapentin and pregabalin have also been recognized as effective anti-pruritus therapy in several internal diseases with the best evidence in chronic kidney disease-associated pruritus. Neurokinin-1 receptor antagonists have been investigated with variable benefit in CKDaP, solid tumors and lymphoproliferative disorders such as cutaneous T-cell lymphoma, Sezary syndrome. Inhibitors of the ileal bile acid transporter (IBAT) represent a selective interruption of the enterohepatic circulation and are currently investigated in various hepatobiliary disorders associated with pruritus. The current development and testing of novel drugs in clinical trials offers hope to struggling physicians and suffering patients.
CRIS-Team WoS Importer:2019-10-01

What Gastroenterologists and Hepatologists should know about organoids in 2019 - Günther, Claudia; Brevini, Teresa; Sampaziotis, Fotios; Neurath, Markus (Digestive and Liver Disease, 2019)
Most of the research behind new medical advances is carried out using either animal models or cancer cells, which both have their disadvantage in particular with regard to medical applications such as personalized medicine and novel therapeutic approaches. However, recent advances in stem cell biology have enabled long-term culturing of organotypic intestinal or hepatic tissues derived from tissue resident or pluripotent stem cells. These 3D structures, denoted as organoids, represent a substantial advance in structural and functional complexity over traditional in vitro cell culture models that are often non-physiological and transformed. They can recapitulate the in vivo architecture, functionality and genetic signature of the corresponding tissue. The opportunity to model epithelial cell biology, epithelial turnover, barrier dynamics, immune-epithelial communication and host-microbe interaction more efficiently than previous culture systems, greatly enhance the translational potential of organotypic hepato-gastrointestinal culture systems. Thus there is increasing interest in using such cultured cells as a source for tissue engineering, regenerative medicine and personalized medicine. This review will highlight some of the established and also some exciting novel perspectives on organoids in the fields of gastroenterology and hepatology.
CRIS-Team Scopus Importer:2019-06-04
Keywords: Gastroenterology; Hepatology; Organoids

What rheumatologists can learn from gastroenterologists - Fischer, Sören; Beyer, Christian; Neurath, Markus (Zeitschrift für Rheumatologie, 2018)
BACKGROUND: Chronic inflammatory diseases are complex disorders, which due to their multitude of manifestations require interdisciplinary treatment. OBJECTIVE: The aim of this article is to provide a brief overview of current strategies and innovations for chronic inflammatory bowel diseases. METHODS: A literature search was carried out in PubMed. RESULTS: Shared pathophysiological pathways in chronic inflammatory diseases sometimes lead to common targets in treatment; however, there are also relevant specific differences with respect to treatment. CONCLUSION: Due to the many extraintestinal organ manifestations, chronic inflammatory bowel diseases require interdisciplinary treatment.
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Wheat Consumption Aggravates Colitis in Mice via Amylase Trypsin Inhibitor–mediated Dysbiosis - Pickert, Geethanjali; Wirtz, Stefan; Matzner, Johannes; Ashfaq-Khan, Muhammad; Heck, Rosario; Rosigkeit, Sebastian; Thies, Dorothe; Surabattula, Rambabu; Ehmann, Dirk; Wehkamp, Jan; Aslam, Misbah; He, Guiwei; et al. (Gastroenterology, 2020)
Background & Aims: Wheat has become the world's major staple and its consumption correlates with prevalence of noncommunicable disorders such as inflammatory bowel diseases. Amylase trypsin inhibitors (ATIs), a component of wheat, activate the intestine's innate immune response via toll-like receptor 4 (TLR4). We investigated the effects of wheat and ATIs on severity of colitis and fecal microbiota in mice. Methods: C57BL/6 wild-type and Tlr4–/– mice were fed wheat- or ATI-containing diets or a wheat-free (control) diet and then given dextran sodium sulfate to induce colitis; we also studied Il10–/– mice, which develop spontaneous colitis. Changes in fecal bacteria were assessed by taxa-specific quantitative polymerase chain reaction and 16S ribosomal RNA metagenomic sequencing. Feces were collected from mice on wheat-containing, ATI-containing, control diets and transplanted to intestines of mice with and without colitis on control or on ATI-containing diets. Intestinal tissues were collected and analyzed by histology, immunohistochemistry, and flow cytometry. Bacteria with reported immunomodulatory effects were incubated with ATIs and analyzed in radial diffusion assays. Results: The wheat- or ATI-containing diets equally increased inflammation in intestinal tissues of C57BL/6 mice with colitis, compared with mice on control diets. The ATI-containing diet promoted expansion of taxa associated with development of colitis comparable to the wheat-containing diet. ATIs inhibited proliferation of specific human commensal bacteria in radial diffusion assays. Transplantation of microbiota from feces of mice fed the wheat- or ATI-containing diets to intestines of mice on control diets increased the severity of colitis in these mice. The ATI-containing diet did not increase the severity of colitis in Tlr4–/– mice. Conclusions: Consumption of wheat or wheat ATIs increases intestinal inflammation in mice with colitis, via TLR4, and alters their fecal microbiota. Wheat-based, ATI-containing diets therefore activate TLR4 signaling and promote intestinal dysbiosis.
CRIS-Team Scopus Importer:2020-07-31
Keywords: Inflammatory bowel diseases; microbiome; mouse model; wheat sensitivity

Whole-Body Electromyostimulation Combined With Individualized Nutritional Support Improves Body Composition in Patients With Hematological Malignancies - A Pilot Study - Schink, Kristin; Relijic, Dejan; Herrmann, Hans J.; Meyer, Julia; Mackensen, Andreas; Neurath, Markus; Zopf, Yurdagül (Frontiers in Physiology, 2018)
Patients undergoing the complex treatment for hematological malignancies are exposed to a high physiological and psychological distress inducing fatigue and physical inactivity. In line with cancer-related metabolic changes patients are predisposed for skeletal muscle mass loss that leads to a functional decline, affects therapeutic success, and quality of life. Benefits of physical exercise and nutritional interventions on muscle maintenance are observed in solid cancer patients, but marginally investigated in patients with hematological cancer. We here studied the effects of a combined supportive exercise and nutrition intervention using whole-body electromyostimulation (WB-EMS) training and individualized nutritional support in patients actively treated for hematological malignancy. In a controlled pilot trial, 31 patients (67.7% male; 58.0 +/- 16.7 years) with various hematological cancers were allocated to a control group (n = 9) receiving nutritional support of usual care regarding a high protein intake (> 1.0 g/kg/d) or to a physical exercise group (n = 22) additionally performing WB-EMS training twice weekly for 12 weeks. Bodyweight and body composition assessed by bioelectrical impedance analysis were measured every 4 weeks. Physical function, blood parameters, quality of life and fatigue were assessed at baseline and after 12 weeks. No WB-EMS-related adverse effects occurred. Patients attending the exercise program presented a higher skeletal muscle mass than controls after 12-weeks (1.51 kg [0.41, 2.60]; p = 0.008). In contrast, patients of the control group showed a higher fat mass percentage than patients of the WB-EMS group (-4.46% [-7.15, -1.77]; p = 0.001) that was accompanied by an increase in serum triglycerides in contrast to a decrease in the WB-EMS group (change +/- SD, control 36.3 +/- 50.6 mg/dl; WB-EMS -31.8 +/- 68.7 mg/dl; p = 0.064). No significant group differences for lower limb strength, quality of life, and fatigue were detected. However, compared to controls the WB-EMS group significantly improved in physical functioning indicated by a higher increase in the 6-min-walking distance (p = 0.046). A combined therapeutic intervention of WB-EMS and protein-rich nutritional support seems to be safe and effective in improving skeletal muscle mass and body composition in hematological cancer patients during active oncological treatment.
EVALuna2:35109

Whole-Body Electromyostimulation combined with personalized Nutritional Support improves the Body Composition of Patients with advanced Cancer - Schink, Kristin; Herrmann, Hans Joachim; Schwappacher, Raphaela; Orlemann, Till; Meyer, Julia; Waldmann, Elisabeth; Wullich, Bernd; Kahlmeyer, Andreas; Fietkau, Rainer; Lubgan, Dorota; Beckmann, Matthias; Hack, Carolin; et al. (2018)
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Whole-Body Electrostimulation in Combination with protein-rich Nutrition in Patients with metastatic or advanced Stage gynecological Cancer: An innovative Therapy Concept - Zopf, Yurdagül; Herrmann, Hans Joachim; Neurath, Markus; Reljic, Dejan (2018)
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Wireless capsule endoscopy of the small intestine: a review with future directions - Neumann, Helmut; Fry, Lucia C.; Naegel, Andreas; Neurath, Markus (Current Opinion in Gastroenterology, 2014)
Here, we review the clinical applications of small bowel capsule endoscopy. Moreover, we provide an outlook on the exceptional future developments of small bowel capsule endoscopy. We discuss clinical algorithms for diagnosis of small bowel diseases. Multiple studies have shown the potential of capsule endoscopy for identification of the bleeding source located in the small bowel and the increased diagnostic yield over radiographic studies. Capsule endoscopy could detect villous atrophy and severe complications in patients with nonresponsive celiac disease. In addition, small bowel capsule endoscopy was proven as a valid tool to diagnose polyps and tumors and Crohn's disease.Major current clinical indications of capsule endoscopy in the small bowel include evaluation of obscure gastrointestinal bleeding, diagnosis and surveillance of small bowel polyps and tumors, celiac disease and Crohn's disease. Recent developments have also passed the way for small bowel capsule endoscopy to become a therapeutic instrument.
EVALuna2:1880

WNT5A Promotes Tissue Fibrosis By Wnt/PCP-Dependent Activation of Latent TGF-beta - Chen, Chih-Wei; Thuong Trinh-Minh,; Lin, Neng-Yu; Zhang, Yun; Groeber, Florian; Beyer, Christian; Schett, Georg; Distler, Jörg (2017)
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α4β7 integrin-dependent adhesion of T cells to MAdCAM-1 is blocked by vedolizumab in patients with chronic refractory pouchitis - Melde, Michaela; Müller, Tanja; Schneider, Ignaz Hans Friedrich; Geppert, Carol-Immanuel; Mühl, Laura; Besendorf, Laura; Allner, Clarissa; Becker, Emily; Atreya, Imke; Vitali, Francesco; Atreya, Raja; Neurath, Markus; et al. (Therapeutic Advances in Gastroenterology, 2021)
Background: The anti-α4β7 integrin antibody vedolizumab is an established therapeutic option for the treatment of inflammatory bowel disease (IBD). It has also been successfully used in patients with chronic antibiotic-refractory pouchitis following proctocolectomey with ileal pouch-anal anastomosis. However, the expression and function of gut-homing markers as well as strategies to predict the response to vedolizumab in pouchitis are understudied so far. Methods: We used flow cytometry and dynamic adhesion assays to study the expression and function of gut-homing integrins on T cells from patients with pouchitis and controls as well as longitudinally during therapy of pouchitis with vedolizumab. Moreover, we describe clinical effects of vedolizumab in a cohort of patients with pouchitis. Results: T cells from patients with pouchitis express a specific profile of gut-homing integrins. Integrin α4β7 on T cells from patients with pouchitis mediates adhesion to mucosal addressin cell adhesion molecule (MAdCAM)-1, which can be blocked by vedolizumab in vitro. Vedolizumab efficiently treats pouchitis in a portion of patients and response correlates with dynamic adhesion profiles to MAdCAM-1. Conclusion: Our data suggest that T cell trafficking seems to be important for the pathogenesis of pouchitis and support the therapeutic use of vedolizumab. Integrin function might serve as a biomarker to predict response to vedolizumab.
CRIS-Team Scopus Importer:2021-12-17
Keywords: ileal pouch-anal anastomosis; pouchitis; proctocolectomy; T cells trafficking; vedolizumab

β-(1→3)-D-glucan- and mannan-guided early termination of antifungal therapy in ICU patients: a randomized controlled study - Erb, Timothy; Mihai, Sidonia; Strauss, Richard; Herbst, Larissa; Castellanos, Ixchel; Diesch, Katharina; Cipa, Franziska; Bihlmaier, Karl; Lang, Anne-Katharina; Ganslmayer, Marion; Willam, Carsten; Bremer, Frank Felix; et al. (Antimicrobial Agents and Chemotherapy, 2023)
Candida spp. are frequently encountered in specimens from ICUs. However, most of these detections represent colonization. Nevertheless, clinical practice shows that a considerable proportion of these patients will receive antifungal therapy (AT). β-(1→3)-D-glucan (BDG) and mannan are fungal biomarkers with high negative predictive values. We aimed to examine whether biomarker-guided discontinuation of AT can reduce the antifungal consumption. Therefore, we conducted a prospective, randomized intervention study between 1 April 2019 and 31 March 2020. All adult ICU patients with a newly started systemic AT but without fungal infection were eligible for inclusion. Enrolled patients were randomized into an intervention and a control group. In both groups, serum BDG and mannan were determined on days 1 and 2 of AT. If all measurements were negative, AT was discontinued in the intervention group. The primary endpoint was antifungal use. The study was terminated after 12 months. Until this time-point, 41 patients had been included. In the intervention group (n = 19), AT was stopped in only two patients because all others showed either positive BDG and∕or mannan levels. One of these two patients developed candidemia and AT had to be restarted. There was no significant difference in the primary and secondary endpoints. In summary, the strategy of using two negative BDG and mannan levels to stop AT failed to reduce antifungal consumption in our cohort. Indeed, there will inevitably be patients with invasive candidiasis in whom necessary AT is discontinued. The optimal patient population, biomarker set, and termination criteria are critical to the success of biomarker-based termination strategies.
CRIS-Team Scopus Importer:2023-12-15
Keywords: antibiotic stewardship; antifungal therapy; biomarker; Candida infection; candidemia; candidosis; discontinuation; fungal infection

A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis - Buch, Stephan; Stickel, Felix; Trepo, Eric; Way, Michael; Herrmann, Alexander; Nischalke, Hans Dieter; Brosch, Mario; Rosendahl, Jonas; Berg, Thomas; Ridinger, Monika; Rietschel, Marcella; Mcquillin, Andrew; et al. (Nature Genetics, 2015)
Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.
EVALuna2:2033

Alteration of contrast enhanced ultrasound (CEUS) of hepatocellular carcinoma in patients with cirrhosis and transjugular intrahepatic portosystemic shunt (TIPS) - Chang, Johannes; Dumitrache, Alexia; Böhling, Nina; Abu-Omar, Jasmin; Meyer, Carsten; Strobel, Deike; Luetkens, Julian; Luu, Andreas Minh; Rockstroh, Jürgen; Strassburg, Christian P.; Trebicka, Jonel; Gonzalez-Carmona, Maria A.; et al. (Scientific Reports, 2020)
Transjugular intrahepatic portosystemic shunt (TIPS) can treat portal hypertensive complications and modifies hepatic hemodynamics. Modification of liver perfusion can alter contrast enhancement dynamics of liver nodules. This study investigated the diagnostic performance of contrast-enhanced ultrasound (CEUS) to diagnose hepatocellular carcinoma (HCC) in cirrhosis with TIPS. In this prospective monocentric observational study, CEUS was used to characterize focal liver lesions in patients at risk for HCC with and without TIPS. Times of arterial phase hyperenhancement (APHE) und washout were quantified. Perfusion-index (PI) and resistance-index (RI) of hepatic artery and portal venous flow parameters were measured via doppler ultrasonography. Diagnostic gold standard was MRI/CT or histology. This study included 49 liver lesions [23 TIPS (11 HCC), 26 no TIPS (15 HCC)]. 26 were diagnosed as HCC by gold standard. Sensitivity and specificity of CEUS to diagnose HCC with and without TIPS were 93.3% and 100% vs. 90.9% and 93.3%, respectively. APHE appeared significantly earlier in patients with TIPS compared to patients without TIPS. TIPS significantly accentuates APHE of HCC in CEUS. CEUS has good diagnostic performance for diagnosis of HCC in patients with TIPS.
CRIS-Team Scopus Importer:2020-12-04

Benefit of Contrast-Enhanced Ultrasound (CEUS) in the Follow-Up Care of Patients with Colon Cancer: A Prospective Multicenter Study - Bernatik, T.; Schuler, A.; Kunze, G.; Mauch, M.; Dietrich, C. F.; Dirks, K.; Pachmann, C.; Boerner, N.; Fellermann, K.; Menzel, J.; Strobel, Deike (Ultraschall in der Medizin, 2015)
According to the German guidelines on colorectal cancer, unenhanced ultrasound is recommended for follow-up. On the other hand, ultrasound and radiology societies specify the use of contrast-enhanced ultrasound for ruling out liver metastases. Studies focusing on the follow-up of cancer patients are lacking. The goal of this multicenter study initiated by the German Ultrasound Society (DEGUM) was to determine the potential benefit of contrast-enhanced ultrasound in the follow-up of patients with colon cancer.Follow-up patients with colon cancer (UICC > IIa) were investigated. As scheduled according to the German guidelines, unenhanced ultrasound was performed followed by contrast-enhanced ultrasound. All liver lesions were recorded. In case of additional metastases detected on contrast-enhanced ultrasound, contrast-enhanced CT, MRI or biopsy was performed to confirm additional liver metastases.A total of 45 liver metastases were detected in 26/290 patients (= 9 %) using unenhanced ultrasound. A further 28 metastases were detected on contrast-enhanced ultrasound in these 26 patients. In 18 patients showing no liver metastases, 40 additional metastases were detected on unenhanced ultrasound. This means that 44 patients with a total of 113 liver metastases were detected on contrast-enhanced ultrasound (p = 0.0006).Contrast-enhanced ultrasound should be recommended in the follow-up of patients with colon cancer in addition to unenhanced ultrasound - the up-to-date standard.
EVALuna2:2082

Budesonide Loaded PLGA Nanoparticles for Targeting the Inflamed Intestinal Mucosa-Pharmaceutical Characterization and Fluorescence Imaging - Ali, Hussain; Weigmann, Benno; Collnot, Eva-Maria; Khan, Saeed Ahmad; Windbergs, Maike; Lehr, Claus-Michael (Pharmaceutical Research, 2016)
The purpose of this study was to evaluate the specifically targeted efficiency of budesonide loaded PLGA nanoparticles for the treatment of inflammatory bowel disease (IBD).The nanoparticles were prepared by an oil/water (O/W) emulsion evaporation technique. The nanoparticles were characterized for their size, shape and in vitro drug release profile. Solid state characterization was carried out by differential scanning calorimetry (DSC) and X-ray Power diffraction (XPRD). In order to evaluate the targeted efficiency of nanoparticles, a particle localization study in the healthy and in the inflamed colon was determined in vivo. These data were complemented by cryo-sections.Nanoparticles were 200 ± 05 nm in size with a smooth and spherical shape. The encapsulation efficiency was around 85 ± 3.5%, which was find-out by both, direct and indirect methods. Release of budesonide from the nanoparticles showed a biphasic release profile with an initial burst followed by sustained release. XPRD data revealed that the drug in the polymer matrix existed in crystalline state. Nanoparticles accumulation in inflamed tissues was evaluated by in-vivo imaging system and it was found that particles are accumulated in abundance at the site of inflammation when compared to the healthy group.The study demonstrates that the budesonide loaded PLGA nanoparticles are an efficient delivery system for targeted drug delivery to the inflamed intestinal mucosa.
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Clinical course and predictive risk factors for fatal outcome of SARS-CoV-2 infection in patients with chronic kidney disease - Pilgram, Lisa; Eberwein, Lukas; Wille, Kai; Koehler, Felix C.; Stecher, Melanie; Rieg, Siegbert; Kielstein, Jan T.; Jakob, Carolin E. M.; Ruthrich, Maria; Burst, Volker; Prasser, Fabian; Borgmann, Stefan; et al. (Infection, 2021)
Purpose: The ongoing pandemic caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) has stressed health systems worldwide. Patients with chronic kidney disease (CKD) seem to be more prone to a severe course of coronavirus disease (COVID-19) due to comorbidities and an altered immune system. The study’s aim was to identify factors predicting mortality among SARS-CoV-2-infected patients with CKD. Methods: We analyzed 2817 SARS-CoV-2-infected patients enrolled in the Lean European Open Survey on SARS-CoV-2-infected patients and identified 426 patients with pre-existing CKD. Group comparisons were performed via Chi-squared test. Using univariate and multivariable logistic regression, predictive factors for mortality were identified. Results: Comparative analyses to patients without CKD revealed a higher mortality (140/426, 32.9% versus 354/2391, 14.8%). Higher age could be confirmed as a demographic predictor for mortality in CKD patients (> 85 years compared to 15–65 years, adjusted odds ratio (aOR) 6.49, 95% CI 1.27–33.20, p = 0.025). We further identified markedly elevated lactate dehydrogenase (> 2 × upper limit of normal, aOR 23.21, 95% CI 3.66–147.11, p < 0.001), thrombocytopenia (< 120,000/µl, aOR 11.66, 95% CI 2.49–54.70, p = 0.002), anemia (Hb < 10 g/dl, aOR 3.21, 95% CI 1.17–8.82, p = 0.024), and C-reactive protein (≥ 30 mg/l, aOR 3.44, 95% CI 1.13–10.45, p = 0.029) as predictors, while renal replacement therapy was not related to mortality (aOR 1.15, 95% CI 0.68–1.93, p = 0.611). Conclusion: The identified predictors include routinely measured and universally available parameters. Their assessment might facilitate risk stratification in this highly vulnerable cohort as early as at initial medical evaluation for SARS-CoV-2.
CRIS-Team Scopus Importer:2021-08-27
Keywords: Chronic kidney disease; COVID-19; LEOSS; Predictive factor; SARS-CoV-2

Depletion of CD56+CD3+ invariant natural killer T cells prevents allergen-induced inflammation in humanized mice - Ose, Robert; Weigmann, Benno; Schuppan, Detlef; Waisman, Ari; Saloga, Joachim; Bellinghausen, Iris (Journal of Allergy and Clinical Immunology, 2021)
Background: CD56-expressing natural killer (NK) cells as well as invariant NK T (iNKT) cells have been shown to either promote or inhibit allergic immune responses. Objective: The aim of the present study was to investigate the impact of these cells in a recently developed humanized mouse model of allergen-induced IgE-dependent gut and lung inflammation. Methods: Nonobese diabetic–severe combined immunodeficiency γ-chain knockout mice were injected intraperitoneally with human PBMCs or CD56-depleted (CD56neg) PBMCs from highly sensitized donors with birch or grass pollen allergy together with the respective allergen or with NaCl as a control. Three weeks later, the mice were challenged with the allergen rectally and gut inflammation was monitored by video miniendoscopy and by histology. Furthermore, airway inflammation was measured after an additional intranasal allergen challenge. Results: Allergen-specific human IgE in mouse sera, detectable only after coinjection of the respective allergen, was reduced in mice being injected with CD56neg PBMCs compared with in mice receiving nondepleted PBMCs. Consequently, allergen-induced IgE-dependent colitis, airway hyperreactivity, and mucus-producing goblet cells were significantly inhibited in these mice. Interestingly, reconstitution of CD56neg PBMCs with nondepleted CD56+ cells and with CD56+CD3+ iNKT cells restored gut as well as lung inflammation, whereas addition of CD3–depleted CD56+ cells did not. Conclusion: These results demonstrate that allergen-specific gut and lung inflammation in PBMC-engrafted humanized mice is promoted by CD56+CD3+ iNKT cells, which opens new possibilities of therapeutic intervention in allergic diseases.
CRIS-Team Scopus Importer:2021-06-18
Keywords: allergy; colon; Humanized mice; IgE; invariant natural killer T cells; lung; natural killer cells

Diagnostic ultrasound performed by a physician as a dialog - Strobel, Deike; Meng, Stefan (Ultraschall in der Medizin, 2018)
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Diminished allergen-induced intestinal and airway inflammation in humanized mice by depletion of natural killer cells prior to PBMC engraftment - Ose, R.; Weigmann, Benno; Maxeiner, J.; Schuster, P.; Saloga, J.; Bellinghausen, I. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part I - General Aspects (long Version) - Lorentzen, T.; Nolsoe, C. P.; Ewertsen, C.; Nielsen, M. B.; Leen, E.; Havre, R. F.; Gritzmann, N.; Brkljacic, Boris; Nuernberg, D.; Kabaalioglu, A.; Strobel, Deike; Jenssen, C.; et al. (Ultraschall in der Medizin, 2015)
This is the first part of the Guidelines on Interventional Ultrasound of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) and covers all general aspects of ultrasound-guided procedures (long version).
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EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part I - General Aspects (Short Version) - Lorentzen, T.; Nolsoe, C. P.; Ewertsen, C.; Nielsen, M. B.; Leen, E.; Havre, R. F.; Gritzmann, N.; Brkljacic, Boris; Nuernberg, D.; Kabaalioglu, Adnan; Strobel, Deike; Jenssen, C.; et al. (Ultraschall in der Medizin, 2015)
This is the first part of the Guidelines on Interventional Ultrasound of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) and covers all general aspects of ultrasound-guided procedures (short version; the long version is published online).
EVALuna2:2037

Exacerbation of allergic lung and gut inflammation in pbmc-engrafted humanized mice by nutritional wheat alpha-amylase/ trypsin inhibitors is mediated by human ige and by toll-like receptor 4 - Bellinghausen,; Weigmann, Benno; Maxeiner, J.; Schuster, P.; Zevallos,; Waisman, A.; Schuppan, D.; Saloga, J. (2018)
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Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis - Stickel, Felix; Buch, Stephan; Nischalke, Hans Dieter; Weiss, Karl Heinz; Gotthardt, Daniel; Fischer, Janett; Rosendahl, Jonas; Marot, Astrid; Elamly, Mona; Casper, Markus; Lammert, Frank; Mcquillin, Andrew; et al. (American Journal of Gastroenterology, 2018)
OBJECTIVES: Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC. METHODS: Risk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol-related cirrhosis and HCC and in 1165 controls with alcohol-related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression. RESULTS: The development of HCC was independently associated with PNPLA3 rs738409 (ORadjusted 1.84 [95% CI 1.55-2.18], p = 1.85 × 10-12) and TM6SF2 rs58542926 (ORadjusted 1.66 [1.30-2.13], p = 5.13 × 10-05), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (ORadjusted 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined. CONCLUSIONS: Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk-stratification of patients with alcohol-related cirrhosis, and genotype-guided screening algorithms would optimize patient care.
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Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers - Stickel, Felix; Lutz, Philipp; Buch, Stephan; Nischalke, Hans Dieter; Silva, Ines; Rausch, Vanessa; Fischer, Janett; Weiss, Karl Heinz; Gotthardt, Daniel; Rosendahl, Jonas; Marot, Astrid; Elamly, Mona; et al. (Hepatology, 2020)
Background and Aims Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC.
CRIS-Team WoS Importer:2020-06-02

Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury - Pyzik, Michal; Rath, Timo; Kuo, Timothy T.; Win, Sanda; Baker, Kristi; Hubbard, Jonathan J.; Grenha, Rosa; Gandhi, Amit; Kraemer, Thomas D.; Mezo, Adam R.; Taylor, Zachary S.; Mcdonnell, Kevin; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2017)
The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood. Here we demonstrate that mice with global or liver-specific FcRn deletion exhibit hypoalbuminemia, albumin loss into the bile, and increased albumin levels in the hepatocyte. In vitro models with polarized cells illustrate that FcRn mediates basal recycling and bidirectional transcytosis of albumin and uniquely determines the physiologic release of newly synthesized albumin into the basal milieu. These properties allow hepatic FcRn to mediate albumin delivery and maintenance in the circulation, but they also enhance sensitivity to the albumin-bound hepatotoxin, acetaminophen (APAP). As such, global or liver-specific deletion of FcRn results in resistance to APAP-induced liver injury through increased albumin loss into the bile and increased intracellular albumin scavenging of reactive oxygen species. Further, protection from injury is achieved by pharmacologic blockade of FcRn-albumin interactions with monoclonal antibodies or peptide mimetics, which cause hypoalbuminemia, biliary loss of albumin, and increased intracellular accumulation of albumin in the hepatocyte. Together, these studies demonstrate that the main function of hepatic FcRn is to direct albumin into the circulation, thereby also increasing hepatocyte sensitivity to toxicity.
EVALuna2:34090

Incidence of bleeding in 8172 percutaneous ultrasound-guided intraabdominal diagnostic and therapeutic interventions - results of the prospective multicenter DEGUM interventional ultrasound study (PIUS study) - Strobel, Deike; Bernatik, T.; Blank, W.; Will, U.; Reichel, A.; Wuestner, M.; Keim, V.; Schacherer, D.; Barreiros, A. P.; Kunze, G.; Nuernberg, D.; Ignee, A.; et al. (Ultraschall in der Medizin, 2015)
To analyse the incidence of bleeding after percutaneous ultrasound guided diagnostic and therapeutic intraabdominal interventions in a prospective multicentre study (DEGUM percutaneous interventional ultrasound study).Within a time period of 2 years diagnostic and therapeutic intraabdominal interventions (with the exclusion of ascites paracentesis) performed percutaneously under continuous ultrasound (US) guidance were prospectively assessed using a pseudonymized standardized web site entry form. Number and type of intervention, operator experience, patient characteristics, medication, lab data as well as technical aspects of the procedure and bleeding complications were analysed according to the interventional radiology standards.8172 US-guided intraabdominal interventions (liver n = 5903; pancreas n = 501, kidney n = 434, lymph node = 272, biliary system n = 153, spleen n = 63, other abdominal organs and extra-organic targets n = 999) were analysed in 30 hospitals. The majority were diagnostic biopsies including 1780 liver parenchyma, 3400 focal liver lesions and 404 pancreatic lesions. 7525 interventions (92.1 %) were performed in hospitalized patients (mean age 62.6 years). Most operators were highly experienced in US-guided interventions (> 500 interventions prior to the study n = 5729; 70.1 %). Sedation was administered in 1131 patients (13.8 %). Needle diameter was >= 1 mm in 7162 punctures (87.9 %) with main focus on core needle biopsies (18 G, n = 4185). Clinically relevant bleeding complications with need of transfusion (0.4 %), surgical bleeding control (0.1 %) and radiological coiling (0.05 %) were very rare. Bleeding complications with fatal outcome occurred in four patients (0.05 %). The frequency of major bleeding complications was significantly higher in patients with an INR > 1.5 (p < 0.001) and patients taking a medication potentially interfering with platelet function or plasmatic coagulation (p < 0.0333).This prospective multicentre study confirms the broad spectrum of percutaneous US-guided intraabdominal interventions. However diagnostic liver biopsies dominate with the use of core needle biopsies (18 G). Percutaneous US-guided interventions performed by experienced sonographers are associated with a low bleeding risk. Major bleeding complications are very rare. A pre-interventional INR < 1.5 and individual medication risk assessment are recommended.
EVALuna2:2035

Infusion of ex-vivo expanded human TCR-αβ+ double-negative regulatory T cells delays onset of xenogeneic graft-versus-host disease - Achita, P.; Dervovic, D.; Ly, D.; Lee, J. B.; Haug, T.; Joe, B.; Hirano, N.; Zhang, L. (Clinical and Experimental Immunology, 2018)
Despite the demonstration of potent immunosuppressive function of T cell receptor (TCR)-αβ+ double-negative regulatory T cells (DN Tregs ), scarce numbers and lack of effective expansion method limit their clinical applications. Here we describe an approach that allows for ∼3500-fold ex-vivo expansion of human DN Tregs within 3 weeks with > 97% purity. Ex-vivo-expanded DN Tregs suppress proliferation of polyclonally stimulated autologous T and B cells in vitro through direct cell-to-cell contact. In vivo, we demonstrate for the first time that infusion of human DN Tregs delayed an onset of xenogeneic graft-versus-host disease (GVHD) significantly in a humanized mouse model. Furthermore, preincubation of ex-vivo-expanded DN Tregs with a mechanistic target of rapamycin (mTOR) inhibitor rapamycin enhanced their immune regulatory function further. Taken together, this study demonstrates that human DN Tregs can be expanded ex vivo to therapeutic numbers. The expanded DN Tregs can suppress proliferation of T and B cells and attenuate GVHD, highlighting the potential clinical use of DN Tregs to mitigate GVHD.
EVALuna2:34645

Monitoring of Chemically Induced Colitis - Reissig, Sonja; Weigmann, Benno (Methods in Molecular Biology, 2017)
Inflammation is a common symptom of inflammatory bowel disease (IBD). Actually, many experimental models of colitis exist and try to mimic the human situation in order to understand the pathogenesis of Crohn's disease and ulcerative colitis. These experimental models of inflammation can be characterized by specific parameters, which illustrate the proceeding inflammatory process. By use of these models potentially new reagents for improved therapeutic approaches can be analyzed. Here, we describe the TNBS-mediated colitis model and specify different parameters for the detailed characterization of the inflammatory process in experimental colitis models.
EVALuna2:35245

Prevention and Management of CMV Infections after Liver Transplantation: Current Practice in German Transplant Centers - Engelmann, Cornelius; Sterneck, Martina; Weiss, Karl Heinz; Templin, Silke; Zopf, Steffen; Denk, Gerald; Eurich, Dennis; Pratschke, Johann; Weiss, Johannes; Braun, Felix; Welker, Martin-Walter; Zimmermann, Tim; et al. (Journal of Clinical Medicine, 2020)
Human cytomegalovirus (CMV) remains a major cause of mortality and morbidity in human liver transplant recipients. Anti-CMV therapeutics can be used to prevent or treat CMV in liver transplant recipients, but their toxicity needs to be balanced against the benefits. The choice of prevention strategy (prophylaxis or preemptive treatment) depends on the donor/recipient sero-status but may vary between institutions. We conducted a series of consultations and roundtable discussions with German liver transplant center representatives. Based on 20 out of 22 centers, we herein summarize the current approaches to CMV prevention and treatment in the context of liver transplantation in Germany. In 90% of centers, transient prophylaxis with ganciclovir or valganciclovir was standard of care in high-risk (donor CMV positive, recipient CMV naive) settings, while preemptive therapy (based on CMV viremia detected during (bi) weekly PCR testing for circulating CMV-DNA) was preferred in moderate- and low-risk settings. Duration of prophylaxis or intense surveillance was 3-6 months. In the case of CMV infection, immunosuppression was adapted. In most centers, antiviral treatment was initiated based on PCR results (median threshold value of 1000 copies/mL) with or without symptoms. Therefore, German transplant centers report similar approaches to the prevention and management of CMV infection in liver transplantation.
CRIS-Team WoS Importer:2020-09-25

Risk Factors for Pancreatic Cancer in Patients with New-Onset Diabetes: A Systematic Review and Meta-Analysis - Mellenthin, Claudia; Balaban, Vasile Daniel; Dugic, Ana; Cullati, Stephane (Cancers, 2022)
(1) Background: Patients with new-onset diabetes (NOD) are at risk of pancreatic ductal adenocarcinoma (PDAC), but the most relevant additional risk factors and clinical characteristics are not well established. (2) Objectives: To compare the risk for PDAC in NOD patients to persons without diabetes. Identify risk factors of PDAC among NOD patients. (3) Methods: Medline, Embase, and Google Scholar were last searched in June 2022 for observational studies on NOD patients and assessing risk factors for developing PDAC. Data were extracted, and Meta-Analysis was performed. Pooled effect sizes with 95% confidence intervals (CI) were estimated with DerSimonian & Laird random effects models. (4) Findings: Twenty-two studies were included, and 576,210 patients with NOD contributed to the analysis, of which 3560 had PDAC. PDAC cases were older than controls by 6.14 years (CI 3.64–8.65, 11 studies). The highest risk of PDAC involved a family history of PDAC (3.78, CI 2.03–7.05, 4 studies), pancreatitis (5.66, CI 2.75–11.66, 9 studies), cholecystitis (2.5, CI 1.4–4.45, 4 studies), weight loss (2.49, CI 1.47–4.22, 4 studies), and high/rapidly increasing glycemia (2.33, CI 1.85–2.95, 4 studies) leading to more insulin use (4.91, CI 1.62–14.86, 5 studies). Smoking (ES 1.20, CI 1.03–1.41, 9 studies) and alcohol (ES 1.23, CI 1.09–1.38, 9 studies) have a smaller effect. (5) Conclusion: Important risk factors for PDAC among NOD patients are age, family history, and gallstones/pancreatitis. Symptoms are weight loss and rapid increase in glycemia. The identified risk factors could be used to develop a diagnostic model to screen NOD patients.
CRIS-Team Scopus Importer:2022-10-28
Keywords: cancer screening; meta-analysis; new onset diabetes; pancreatic cancer; risk factors

Short-term cold exposure supports human Treg induction in vivo - Becker, M.; Serr, Isabelle; Salb, Victoria K.; Ott, Verena B.; Mengel, L.; Blüher, Matthias; Weigmann, Benno; Hauner, Hans; Tschöp, Matthias H.; Daniel, Carolin (Molecular Metabolism, 2019)
Objective: Obesity and type-2 diabetes (T2D) are metabolic diseases that represent a critical health problem worldwide. Metabolic disease is differentially associated with fat distribution, while visceral white adipose tissue (VAT) is particularly prone to obesity-associated inflammation. Next to their canonical function of immune suppression, regulatory T cells (Tregs) are key in controlling adipose tissue homeostasis. Towards understanding the molecular underpinnings of metabolic disease, we focus on how environmental-metabolic stimuli impinge on the functional interplay between Tregs and adipose tissue. Here, cold exposure or beta3-adrenergic signaling are a promising tool to increase energy expenditure by activating brown adipose tissue, as well as by reducing local inflammation within fat depots by supporting immunosuppressive Tregs. However, in humans, the underlying mechanisms that enable the environmental-immune crosstalk in the periphery and in the respective tissue remain currently unknown. Methods: We used combinatorial approaches of next generation humanized mouse models and in vitro and in vivo experiments together with beta3-adrenergic stimulation to dissect the underlying mechanisms of human Treg induction exposed to environmental stimuli such as cold. To test the translational relevance of our findings, we analyzed samples from the FREECE study in which human subjects were exposed to individualized cooling protocols. Samples were analyzed ex vivo and after in vitro Treg induction using qRT-PCR, immunofluorescence, as well as with multicolor flow cytometry and cell sorting. Results: In vivo application of the beta3-adrenergic receptor agonist mirabegron in humanized mice induced thermogenesis and improved the Treg induction capacity of naïve T cells isolated from these animals. Using samples from the human FREECE study, we demonstrate that a short-term cold stimulus supports human Treg induction in vitro and in vivo. Mechanistically, we identify BORCS6 encoding the Ragulator-interacting protein C17orf59 to be significantly induced in human CD4+ T cells upon short-term cold exposure. Strong mTOR signaling is known to limit successful Treg induction and thus likely by interfering with mTOR activation at lysosomal surfaces, C17orf59 improves the Treg induction capacity of human naïve T cells upon cold exposure. Conclusions: These novel insights into the molecular underpinnings of human Treg induction suggest an important role of Tregs in linking environmental stimuli with adipose tissue function and metabolic diseases. Moreover, these discoveries shed new light on potential approaches towards tailored anti-inflammatory concepts that support human adipose tissue homeostasis by enabling Tregs.
CRIS-Team Scopus Importer:2019-08-23
Keywords: Beta3-adrenergic stimulation; Human adipose tissue; Humanized mice; Immunometabolism; Mirabegron; Regulatory T cell

Using contrast-enhanced ultrasound in the diagnosis of hepatocellular carcinoma – what we have and have not achieved - Strobel, Deike (Ultraschall in der Medizin, 2021)
CRIS-Team Scopus Importer:2021-04-23

Wheat amylase-trypsin inhibitors exacerbate intestinal and airway allergic immune responses in humanized mice - Bellinghausen, Iris; Weigmann, Benno; Zevallos, Victor; Maxeiner, Joachim; Reissig, Sonja; Waisman, Ari; Schuppan, Detlef; Saloga, Joachim (Journal of Allergy and Clinical Immunology, 2019)
Background: Amylase-trypsin inhibitors (ATIs) in wheat and related cereals are potent activators of myeloid innate immune cells via engagement of TLR4. Furthermore, ATIs have been shown to serve as adjuvants in experimental intestinal inflammatory diseases. Objective: The aim of this study was to analyze whether ATIs are also modifiers of allergic inflammation. Methods: Therefore, CD4+ T cells from donors sensitized to grass or birch pollen were stimulated with autologous allergen-pulsed dendritic cells in the presence or absence of ATIs or the control storage protein zein from corn. To analyze allergen-induced gut and lung inflammation, immunodeficient mice were engrafted with PBMCs from these allergic donors plus the respective allergen, and fed with selected diets. Three weeks later, inflammation was induced by rectal or intranasal allergen challenge and monitored by mini endoscopy or airway hyperreactivity, respectively. Results: Allergen-specific T-cell proliferation and cytokine production was significantly exacerbated by ATIs and not by zein. In vivo, allergen-specific human IgE level was strongly elevated in sera of mice receiving an ATI-containing diet compared with mice that were fed gluten-free and thus ATI-free diet. Importantly, allergen-induced IgE-dependent colitis and airway hyperreactivity were also enhanced in ATI-fed mice. Gut inflammation was further increased in mice receiving an additional ATI injection and even detectable in the absence of the aeroallergen, whereas zein had no such effect. Injection of anti-human TLR4 mAbs or the anti-human IgE mAb omalizumab completely abolished ATI-induced allergic inflammation. Conclusions: These results underline that wheat ATIs are important nutritional activators and adjuvants of allergy, which might be exploited for nutritional therapeutic strategies.
CRIS-Team Scopus Importer:2019-11-22
Keywords: allergen; amylase-trypsin inhibitors; celiac disease; colon; gluten; Humanized mice; IgE; lung; wheat sensitivity