Ménage-à-Trois: The Ratio of Bicarbonate to CO2 and the pH Regulate the Capacity of Neutrophils to Form NETs - Maueröder, Christian; Mahajan, Aparna; Paulus, Susanne; Goesswein, Stefanie; Hahn, Jonas; Kienhoefer, Deborah; Biermann, Mona H.; Tripal, Philipp; Friedrich, Ralf P.; Munoz Becerra, Luis; Neurath, Markus; Becker, Christoph; et al. (Frontiers in Immunology, 2016)
In this study, we identified and characterized the potential of a high ratio of bicarbonate to CO2 and a moderately alkaline pH to render neutrophils prone to undergo neutrophil extracellular trap (NET) formation. Both experimental settings increased the rate of spontaneous NET release and potentiated the NET-inducing capacity of phorbol esters (phorbol-2-myristate-13-acetate), ionomycin, monosodium urate, and LPS. In contrast, an acidic environment impaired NET formation both spontaneous and induced. Our findings indicate that intracellular alkalinization of neutrophils in response to an alkaline environment leads to an increase of intracellular calcium and neutrophil activation. We further found that the anion channel blocker DIDS strongly reduced NET formation induced by bicarbonate. This finding suggests that the effects observed are due to a molecular program that renders neutrophils susceptible to NET formation. Inflammatory foci may be characterized by an acidic environment. Our data indicate that NET formation is favored by the higher pH at the border regions of inflamed areas. Moreover, our findings highlight the necessity for strict pH control during assays of NET formation.
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Mend Your Fences: The Epithelial Barrier and its Relationship With Mucosal Immunity in Inflammatory Bowel Disease - Martini, Eva; Krug, Susanne M.; Siegmund, Britta; Neurath, Markus; Becker, Christoph (Cellular and Molecular Gastroenterology and Hepatology, 2017)
The intestinal epithelium can be easily disrupted during gut inflammation as seen in inflammatory bowel disease (IBD), such as ulcerative colitis or Crohn's disease. For a long time, research into the pathophysiology of IBD has been focused on immune cell-mediated mechanisms. Recent evidence, however, suggests that the intestinal epithelium might play a major role in the development and perpetuation of IBD. It is now clear that IBD can be triggered by disturbances in epithelial barrier integrity via dysfunctions in intestinal epithelial cell-intrinsic molecular circuits that control the homeostasis, renewal, and repair of intestinal epithelial cells. The intestinal epithelium in the healthy individual represents a semi-permeable physical barrier shielding the interior of the body from invasions of pathogens on the one hand and allowing selective passage of nutrients on the other hand. However, the intestinal epithelium must be considered much more than a simple physical barrier. Instead, the epithelium is a highly dynamic tissue that responds to a plenitude of signals including the intestinal microbiota and signals from the immune system. This epithelial response to these signals regulates barrier function, the composition of the microbiota, and mucosal immune homeostasis within the lamina propria. The epithelium can thus be regarded as a translator between the microbiota and the immune system and aberrant signal transduction between the epithelium and adjacent immune cells might promote immune dysregulation in IBD. This review summarizes the important cellular and molecular barrier components of the intestinal epithelium and emphasizes the mechanisms leading to barrier dysfunction during intestinal inflammation.
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Menthacarin attenuates experimental colitis - Alliger, Korina; Khalil, Mohammad; König, Beatrix; Weisenburger, Sabrina; Koch, Egon; Engel, Matthias (Phytomedicine, 2020)
Background: Peppermint oil and caraway oil are established remedies in gastroenterological medicine because of their spasmolytic/analgesic effects. Purpose: We investigated whether Menthacarin, a combination of both oils, exerted anti-inflammatory effects in a dextran sodium sulphate (DSS, 2%) murine model of colitis. Study Design and Methods: C57BL/6 mice were orally administered Menthacarin in doses of 10, 30, 60, and 120 µg/g body weight (BW), and control mice received 0.2% agar, 10 µl/g BW, during 8 days of DSS-induced colitis. Colitis was monitored by BW measurements and colonoscopies. Colons of euthanised mice were excised for histological staining and ELISA measurements of the cytokines TNFα, IL-6, IL-10, IL-1β, and TGF-β. Results: Menthacarin-treated mice compared to controls showed improved macroscopical and microscopical parameters and lower BW loss during the course of colitis. Menthacarin changed the colonic cytokine profile towards a regulatory/anti-inflammatory phenotype. Conclusion: Menthacarin attenuates experimental colitis and may be a promising add-on therapy for the treatment of IBD.
CRIS-Team Scopus Importer:2020-08-07
Keywords: Caraway; Inflammatory bowel disease; Menthacarin; Peppermint; TRPA1; TRPM8

Menthacarin induces calcium ion influx in sensory neurons, macrophages and colonic organoids of mice - Zhang, Zehua; Engel, Matthias; Koch, E.; Reeh, Peter; Khalil, Mohammad (Life Sciences, 2021)
Aims: Menthacarin is a herbal combination that is clinically used for the treatment of functional gastrointestinal disorders (FGIDs). In several clinical studies, Menthacarin reduced visceral hypersensitivity-related symptoms. Pathogenesis of visceral hypersensitivity is multifactorial. This involves several cell types and different transient receptor potential ion channels (TRPs); these ion channels are highly conductive for calcium ions. Since transient changes in cytosolic calcium levels are crucial for many functions of living cells, we investigated if Menthacarin can induce calcium influx in sensory, largely nociceptive, neurons from dorsal root ganglia (DRG), peritoneal macrophages (PMs) and colonic organoids. Main methods: We employed the calcium imaging technique on sensory neurons from DRG, PMs and colonic organoids isolated from mice. All cells were superfused by Menthacarin at several concentrations (600, 1200, 1800 μg/ml) during the experiments, followed by calcium ionophor ionomycin (Iono., 1 μM) as a positive control. Key findings: Menthacarin induced concentration-dependent calcium ion influx in all investigated cell types. Furthermore, repeated applications of Menthacarin induced tachyphylaxis (desensitisation) of calcium responses in sensory neurons and colonic organoids. Significance: Menthacarin-induced calcium influx into sensory neurons, macrophages and colonic organoids is probably related to its clinical desensitising effects in patients with FGIDs.
CRIS-Team Scopus Importer:2020-12-25
Keywords: Caraway oil; Menthacarin; Nociception; Peppermint oil; Visceral hypersensitivity

Metabolic and molecular imaging in inflammatory arthritis - de Sousa, Rita Noversa; Tascilar, Koray; Corte, Giulia; Atzinger, Armin; Minopoulou, Ioanna; Ohrndorf, Sarah; Waldner, Maximilian; Schmidkonz, Christian; Kuwert, Torsten; Knieling, Ferdinand; Kleyer, Arnd; Ramming, Andreas; et al. (RMD Open, 2024)
It is known that metabolic shifts and tissue remodelling precede the development of visible inflammation and structural organ damage in inflammatory rheumatic diseases such as the inflammatory arthritides. As such, visualising and measuring metabolic tissue activity could be useful to identify biomarkers of disease activity already in a very early phase. Recent advances in imaging have led to the development of so-called ‘metabolic imaging’ tools that can detect these changes in metabolism in an increasingly accurate manner and non-invasively. Nuclear imaging techniques such as 18F-D-glucose and fibroblast activation protein inhibitor-labelled positron emission tomography are increasingly used and have yielded impressing results in the visualisation (including whole-body staging) of inflammatory changes in both early and established arthritis. Furthermore, optical imaging-based bedside techniques such as multispectral optoacoustic tomography and fluorescence optical imaging are advancing our understanding of arthritis by identifying intra-articular metabolic changes that correlate with the onset of inflammation with high precision and without the need of ionising radiation. Metabolic imaging holds great potential for improving the management of patients with inflammatory arthritis by contributing to early disease interception and improving diagnostic accuracy, thereby paving the way for a more personalised approach to therapy strategies including preventive strategies. In this narrative review, we discuss state-of-the-art metabolic imaging methods used in the assessment of arthritis and inflammation, and we advocate for more extensive research endeavours to elucidate their full field of application in rheumatology.
CRIS-Team Scopus Importer:2024-02-23

Met amplification in non‐small cell lung cancer (Nsclc)— a consecutive evaluation using next‐generation sequencing (ngs) in a real‐world setting - Schubart, Christoph; Stöhr, Robert; Tögel, Lars; Fuchs, Florian; Sirbu, Horia; Seitz, Gerhard; Seggewiss‐bernhardt, Ruth; Leistner, Rumo; Sterlacci, William; Seidl, Christoph; Mugler, Michael; Kapp, Markus; et al. (Cancers, 2021)
In non‐small cell lung cancer (NSCLC), approximately 1–3% of cases harbor an increased gene copy number (GCN) of the MET gene. This alteration can be due to de novo amplification of the MET gene or can represent a secondary resistance mechanism in response to targeted therapies. To date, the gold standard method to evaluate the GCN of MET is fluorescence in situ hybridization (FISH). However, next‐generation sequencing (NGS) is becoming more relevant to optimize therapy by revealing the mutational profile of each NSCLC. Using evaluable n = 205 NSCLC cases of a consecutive cohort, this study addressed the question of whether an amplicon based NGS assay can completely replace the FISH method regarding the classification of MET GCN status. Out of the 205 evaluable cases, only n = 9 cases (43.7%) of n = 16 high‐level MET amplified cases assessed by FISH were classified as amplified by NGS. Cases harboring a MET GCN >10 showed the best concordance when comparing FISH versus NGS (80%). This study confirms that an amplicon‐based NGS assessment of the MET GCN detects high‐level MET amplified cases harboring a MET GCN >10 but fails to detect the various facets of MET gene amplification in the context of a therapy‐induced resistance mechanism.
CRIS-Team Scopus Importer:2021-10-22
Keywords: Amplification; Fluorescence in situ hybridization; MET; MET inhibitor; Next‐generation sequencing; NSCLC; Precision medicine; Resistance mechanism

Metastatic adenocarcinomas of the stomach or esophagogastric junction (UICC stage IV) are not always a palliative situation: a retrospective analysis - Schildberg, Claus W.; Weidinger, Thomas; Hohenberger, Werner; Wein, Axel; Langheinrich, Melanie; Neurath, Markus; Boxberger, Frank (World Journal of Surgery, 2014)
Gastric cancer is one of the most common cancers. Unfortunately, it is often diagnosed at the advanced stage International Union Against Cancer stage IV. This induced us to carry out an interdisciplinary analysis of this patient group with the Department of Internal Medicine 1. Our aim was to discuss cancers classified initially as unresectable in a meeting of the interdisciplinary tumor board after palliative chemotherapy, and to refer selected patients for surgery after establishing resectability. The outcome of the chemotherapy, operation method, complication rate, and long-term survival were analyzed.From 1999 to 2008, 76 patients with metastatic gastric cancer or carcinoma of the esophagogastric junction were discussed by the interdisciplinary tumor board of the University of Erlangen and classified initially as unresectable. The patients then received palliative chemotherapy according to the AIO regimen (weekly high-dose 5-fluorouracil/folinic acid [FU/FA] in a 24 h infusion), plus irinotecan. If the tumor was subsequently classified as resectable, the patient underwent either gastric resection or gastrectomy with DII-III dissection. Metastases were resected depending on their location (liver). Peritoneal carcinomatosis was treated additionally by HIPEC. Statistical analysis was with SPSSS version 20.Surgical and general complications and hospital mortality were acceptable. There were no cases of anastomotic leak, but one patient died of fulminant pneumonia. The R0 resection rate was 69 %, and four patients had long-term survival of more than 60 months. There were significant survival advantages.Metastatic gastric cancer or carcinoma of the esophagogastric junction can become resectable after downsizing the tumor with palliative chemotherapy. Long-term survival is achieved in some cases. Therefore, every patient with this type of cancer should be discussed by the interdisciplinary tumour board after palliative chemotherapy to provide him with a chance of cure after re-evaluation.
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Methotrexate Hampers Immunogenicity to BNT162b2 mRNA COVID-19 Vaccine in Immune-Mediated Inflammatory Disease - Haberman, Rebecca; Herati, Ramin; Simon, David; Samanovic, Marie; Tuen, Michael; Blank, Rebecca; Koralov, Sergei; Atreya, Raja; Tascilar, Koray; Allen, Joseph; Castillo, Rochelle; Cornelius, Amber; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease - Haberman, Rebecca H.; Herati, Ramin Sedaghat; Simon, David; Samanovic, Marie; Blank, Rebecca B.; Tuen, Michael; Koralov, Sergei B.; Atreya, Raja; Tascilar, Koray; Allen, Joseph R.; Castillo, Rochelle; Cornelius, Amber R.; et al. (Annals of the Rheumatic Diseases, 2021)
Objective To investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.
CRIS-Team WoS Importer:2021-10-08

Microbial patterns in patients with histamine intolerance - Schink, Monic; Konturek, P. C.; Tietz, E.; Dieterich, Walburga; Pinzer, T. C.; Wirtz, Stefan; Neurath, Markus; Zopf, Yurdagül (Journal of Physiology and Pharmacology, 2018)
Histamine intolerance represents a controversially discussed disorder. Besides an impaired degradation of orally supplied histamine due to diamine oxidase (DAO) deficiency, a deranged gut flora may also contribute to elevated histamine levels. Our aim was to determine the intestinal bacterial composition in patients with proven histamine intolerance in comparison to other food intolerances and healthy controls. A total of 64 participants were included in the study, encompassing 8 patients with histamine intolerance (HIT), 25 with food hypersensitivity (FH), 21 with food allergy and 10 healthy controls (HC). All participants underwent blood testing for total and food-specific immunoglobulin E, plasma histamine and DAO serum activity. Stool samples were used to analyze stool histamine and zonulin levels and bacterial composition by 16s rRNA sequencing. No significant differences in stool histamine levels were observed, but HIT patients showed elevated levels of stool zonulin. Microbiota analysis revealed increased levels of Proteobacteria (5.4%) and a significantly reduced alpha-diversity in the HIT group (P = 0.019). On family level, HC showed a significantly higher abundance of Bifidobacteriaceae compared to other study groups (P = 0.005), with lowest levels in the HIT group (P = 0.036). Also significantly reduced abundances of the genera Butyricimonas (P = 0.026) and Hespellia (P = 0.025) were observed in the HIT patients, whereas Roseburia were significantly elevated (P = 0.021). We concluded that the altered occurrence of Proteobacteria and Bifidobacteriaceae, reduced alpha-diversity as well as elevated stool zonulin levels suggest a dysbiosis and intestinal barrier dysfunction in histamine intolerant patients, which in turn may play an important role in driving disease pathogenesis.
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Microbiome and gut immunity: The epithelium - Günther, Claudia (The Gut Microbiome in Health and Disease, 2018)
The intestinal epithelium not only plays a fundamental role in negotiating a homeostatic host-microbial relation but also represents the first line of defense against pathogenic microbes and microbial agents. As a consequence intestinal epithelial cells have developed a variety of mechanisms to respond to commensal and non-commensal microbes. Accordingly intestinal epithelial cells can physically restrict the translocation of potentially harmful microorganisms from the intestinal tract into the surrounding tissue by providing a physical barrier but also release antimicrobial peptides and mucus that control microbial composition and location. Despite its barrier function, the intestinal epithelium has an important function in translating luminal signals from the barrier surface to the underlying mucosal immune system. Defects in one of these functions can have tremendous effects on intestinal homeostasis and have been identified as key factors in the pathogenesis of intestinal inflammation. In this chapter we will discuss the role of the intestinal epithelium during host-microbe interactions.
CRIS-Team Scopus Importer:2020-10-28

Microbiome Patterns in Matched Bile, Duodenal, Pancreatic Tumor Tissue, Drainage, and Stool Samples: Association with Preoperative Stenting and Postoperative Pancreatic Fistula Development - Langheinrich, Melanie; Wirtz, Stefan; Kneis, Barbara; Gittler, Matthias M.; Tyc, Olaf; Schierwagen, Robert; Brunner, Maximilian; Krautz, Christian; Pilarsky, Christian; Trebicka, Jonel; Agaimy, Abbas; Grützmann, Robert; et al. (Journal of Clinical Medicine, 2020)
Postoperative complications after pancreatic surgery are still a significant problem in clinical practice. The aim of this study was to characterize and compare the microbiomes of different body compartments (bile duct, duodenal mucosa, pancreatic tumor lesion, postoperative drainage fluid, and stool samples; preoperative and postoperative) in patients undergoing pancreatic surgery for suspected pancreatic cancer, and their association with relevant clinical factors (stent placement, pancreatic fistula, and gland texture). For this, solid (duodenal mucosa, pancreatic tumor tissue, stool) and liquid (bile, drainage fluid) biopsy samples of 10 patients were analyzed using 16s rRNA gene next-generation sequencing. Our analysis revealed: (i) a distinct microbiome in the different compartments, (ii) markedly higher abundance of Enterococcus in patients undergoing preoperative stent placement in the common bile duct, (iii) significant differences in the beta diversity between patients who developed a postoperative pancreatic fistula (POPF B/C), (iv) patients with POPF B/C were more likely to have bacteria belonging to the genus Enterococcus, and (v) differences in microbiome composition with regard to the pancreatic gland texture. The structure of the microbiome is distinctive in different compartments, and can be associated with the development of a postoperative pancreatic fistula.
CRIS-Team WoS Importer:2020-11-06

Microbiota from Obese Mice Regulate Hematopoietic Stem Cell Differentiation by Altering the Bone Niche - Luo, Yubin; Chen, Guangliang; Hannemann, Nicole; Ipseiz, Natacha; Krönke, Gerhard; Bäuerle, Tobias; Munos, Luis; Wirtz, Stefan; Schett, Georg; Bozec, Aline (Cell Metabolism, 2015)
The effect of metabolic stress on the bone marrow microenvironment is poorly defined. We show that high-fat diet (HFD) decreased long-term Lin(-)Sca-1(+)c-Kit(+) (LSK) stem cells and shifted lymphoid to myeloid cell differentiation. Bone marrow niche function was impaired after HFD as shown by poor reconstitution of hematopoietic stem cells. HFD led to robust activation of PPAR?2, which impaired osteoblastogenesis while enhancing bone marrow adipogenesis. At the same time, expression of genes such as Jag-1, SDF-1, and IL-7 forming the bone marrow niche was highly suppressed after HFD. Moreover, structural changes of microbiota were associated to HFD-induced bone marrow changes. Antibiotic treatment partially rescued HFD-mediated effects on the bone marrow niche, while transplantation of stools from HFD mice could transfer the effect to normal mice. These findings show that metabolic stress affects the bone marrow niche by alterations of gut microbiota and osteoblast-adipocyte homeostasis.
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Microbiota: relevant player in thiopurine metabolisation? - Atreya, Imke; Neurath, Markus (Gut, 2017)
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MicroRNA-622 is a novel mediator of tumorigenicity in melanoma by targeting Kirsten rat sarcoma - Dietrich, Peter; Kuphal, Silke; Spruss, Thilo; Hellerbrand, Claus; Boßerhoff, Anja Katrin (Pigment Cell & Melanoma Research, 2018)
The network of molecular players is similar when comparing neural crest-derived, actively migrating melanoblasts to melanoma cells. However, melanoblasts are sensitive to differentiation-initiating signals at their target site (epidermis), while melanoma cells maintain migratory and undifferentiated features. We aimed at identifying downregulated genes in melanoma that are particularly upregulated in melanoblasts. Loss of such genes could contribute to stabilization of a dedifferentiated, malignant phenotype in melanoma. We determined that microRNA-622 (miR-622) expression was strongly downregulated in melanoma cells and tissues compared to melanocytes and melanoblast-related cells. miR-622 expression correlated with survival of patients with melanoma. miR-622 re-expression inhibited clonogenicity, proliferation, and migration in melanoma. Inhibition of miR-622 in melanocytes induced enhanced migration. Kirsten rat sarcoma (KRAS) was identified as a major functional target of miR-622 in melanoma. We conclude that miR-622 is a novel tumor suppressor in melanoma and identify the miR-622-KRAS axis as potential therapeutic target.
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Microscopic colitis and colorectal neoplastic lesion rate in chronic nonbloody diarrhea: a prospective, multicenter study - Tontini, Gian Eugenio; Pastorelli, Luca; Spina, Luisa; Fabris, Federica; Bruni, Barbara; Clemente, Claudio; De Nucci, Germana; Cavallaro, Flaminia; Marconi, Stefano; Neurath, Markus; Neumann, Helmut; Tacconi, Milena; et al. (Inflammatory Bowel Diseases, 2014)
Lymphocytic and collagenous colitis are emerging as common findings in subjects undergoing colonoscopy for chronic non-bloody diarrhea (CNBD). Data concerning microscopic colitis (MC) are still limited and affected by controversial epidemiological evidences. Recent converging lines of evidence suggest that MC correlates a lower risk of colorectal neoplasia. Accordingly, we prospectively assessed MC prevalence in a multicenter cohort of subjects submitted to colonoscopy for CNBD, thereby defining whether MC influences the risk of colorectal neoplasia.Consecutive patients with CNBD of unknown origin underwent pan-colonoscopy with multiple biopsies. The prevalence of neoplastic patients in MC was compared with that observed in negative CNBD subjects.Among 8006 colonoscopy, 305 subjects were enrolled for CNBD. Patients with CNBD were more likely to be women than men (odds ratio = 1.5; P = 0.001). Histopathology detected high prevalence of MC (16%) with a clear predominance of collagenous colitis (70%). A striking age-dependent rise in MC-associated risk was observed, depicting outstanding differences among varying age groups, as in the number needed to screen 1 new case. Gender distribution was balanced within MC patients (Female/Male = 1.5/1), especially among lymphocytic colitis (Female/Male = 1.2/1). MC patients were negatively associated with the risk of neoplastic polyps compared with negative CNBD subjects (odds ratio = 0.22; P = 0.035).MC is the first cause of CNBD in subjects submitted to colonoscopy. Multiple biopsies are strongly recommended, even in the case of uneventful endoscopic inspection, especially for age >=40 years. MC has a reduced risk of colorectal neoplasia, suggesting that this model of chronic inflammation plays a protective effect against colorectal carcinogenesis.
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Mild COVID-19 Symptoms in an Infliximab-Treated Ulcerative Colitis Patient: Can Ongoing Anti-TNF Therapy Protect against the Viral Hyperinflammatory Response and Avoid Aggravated Outcomes? - Abdullah, Abdullah; Neurath, Markus; Atreya, Raja (Visceral Medicine, 2020)
The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, represents a potentially major challenge to patients with immune-mediated inflammatory diseases who are treated with immunomodulatory therapies. We report the case of an 18-year-old ulcerative colitis patient in sustained clinical remission who 4 days after application of her ongoing therapy with the anti-TNF antibody infliximab developed mild respiratory and abdominal symptoms. The patient was subsequently diagnosed with COVID-19 but did not need hospitalization. The clinical symptoms completely resolved within 1 week after onset and there was no change in ulcerative colitis activity. The recently applied anti-TNF therapy did not lead to exacerbation of the infectious symptoms. Current recommendations strongly favor continuation of effective maintenance anti-TNF therapy in inflammatory bowel disease patients, as there is no evidence for aggravated CO-VID-19 upon infection. It is unclear whether anti-TNF treatment might even have assisted in preventing worsening of COVID-19 and improving outcome. Further data in the group of immune-mediated inflammatory disease patients under anti-TNF therapy are urgently needed.
CRIS-Team Scopus Importer:2020-06-19

miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes - Scherm, Martin G.; Serr, Isabelle; Zahm, Adam M.; Schug, Jonathan; Bellusci, Saverio; Manfredini, Rossella; Salb, Victoria K.; Gerlach, Katharina; Weigmann, Benno; Ziegler, Anette Gabriele; Kaestner, Klaus H.; Daniel, Carolin (Nature Communications, 2019)
In type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.
CRIS-Team Scopus Importer:2019-12-20

Missed lesions and artificial intelligence during colonoscopy: the tireless working expert in the room - Rath, Timo (Endoscopy, 2021)
CRIS-Team WoS Importer:2021-12-24

Modern Endoscopic Imaging in Diagnosis and Surveillance of Inflammatory Bowel Disease Patients - Hundorfean, Gheorghe; Pereira, Stephen P.; Karstensen, John G.; Vilmann, Peter; Saftoiu, Adrian (Gastroenterology Research and Practice, 2018)
Endoscopy remains the most important diagnostic and monitoring modality in the management of inflammatory bowel disease. Advances in imaging have progressively added new tools into the armamentarium of endoscopists with the goal of more accurate, sensitive, and accessible visual diagnoses for the benefit of patients with gastrointestinal diseases. Here, we review the relevant literature regarding commonly used endoscopic techniques (dye-based and digital chromoendoscopy, high-definition endoscopy, capsule endoscopy, and endosonography), as well as advanced and experimental technologies (full-spectrum endoscopy, endocytoscopy, autofluorescence, laser endoscopy, and endomicroscopy, including molecular imaging), applicable to inflammatory bowel diseases and emerging for implementation into everyday practice. Additionally, we discuss future directions and techniques as candidates for a superior inflammation imaging in the diagnosis and prediction of therapeutic response.
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Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure - Bittel, Miriam; Kremer, Andreas; Stürzl, Michael; Wirtz, Stefan; Stolzer, Iris; Neurath, Markus; Ballon, Gianna; Günther, Claudia (Cell Death & Disease, 2019)
During viral infections viruses express molecules that interfere with the host-cell death machinery and thus inhibit cell death responses. For example the viral FLIP (vFLIP) encoded by Kaposi’s sarcoma-associated herpesvirus interacts and inhibits the central cell death effector, Caspase-8. In order to analyze the impact of anti-apoptotic viral proteins, like vFlip, on liver physiology in vivo, mice expressing vFlip constitutively in hepatocytes (vFlipAlbCre+) were generated. Transgenic expression of vFlip caused severe liver tissue injury accompanied by massive hepatocellular necrosis and inflammation that finally culminated in early postnatal death of mice. On a molecular level, hepatocellular death was mediated by RIPK1-MLKL necroptosis driven by an autocrine TNF production. The loss of hepatocytes was accompanied by impaired bile acid production and disruption of the bile duct structure with impact on the liver-gut axis. Notably, embryonic development and tissue homeostasis were unaffected by vFlip expression. In summary our data uncovered that transgenic expression of vFlip can cause severe liver injury in mice, culminating in multiple organ insufficiency and death. These results demonstrate that viral cell death regulatory molecules exhibit different facets of activities beyond the inhibition of cell death that may merit more sophisticated in vitro and in vivo analysis.
CRIS-Team Scopus Importer:2019-12-03

Molecular Communication Between Neuronal Networks and Intestinal Epithelial Cells in Gut Inflammation and Parkinson's Disease - Drobny, Alice; Ngo, Phuong A.; Neurath, Markus; Zunke, Friederike; Lopez-Posadas, Rocio (Frontiers in Medicine, 2021)
Intestinal symptoms, such as nausea, vomiting, and constipation, are common in Parkinson's disease patients. These clinical signs normally appear years before the diagnosis of the neurodegenerative disease, preceding the occurrence of motor manifestations. Moreover, it is postulated that Parkinson's disease might originate in the gut, due to a response against the intestinal microbiota leading to alterations in alpha-synuclein in the intestinal autonomic nervous system. Transmission of this protein to the central nervous system is mediated potentially via the vagus nerve. Thus, deposition of aggregated alpha-synuclein in the gastrointestinal tract has been suggested as a potential prodromal diagnostic marker for Parkinson's disease. Interestingly, hallmarks of chronic intestinal inflammation in inflammatory bowel disease, such as dysbiosis and increased intestinal permeability, are also observed in Parkinson's disease patients. Additionally, alpha-synuclein accumulations were detected in the gut of Crohn's disease patients. Despite a solid association between neurodegenerative diseases and gut inflammation, it is not clear whether intestinal alterations represent cause or consequence of neuroinflammation in the central nervous system. In this review, we summarize the bidirectional communication between the brain and the gut in the context of Parkinson's disease and intestinal dysfunction/inflammation as present in inflammatory bowel disease. Further, we focus on the contribution of intestinal epithelium, the communication between intestinal epithelial cells, microbiota, immune and neuronal cells, as well as mechanisms causing alterations of epithelial integrity.
CRIS-Team WoS Importer:2021-09-03

Molecular cross-talk between Y5-receptor and neuropeptide Y drives liver cancer - Dietrich, Peter; Wormser, Laura; Fritz, Valerie; Seitz, Tatjana; de Maria, Monica; Schambony, Alexandra; Kremer, Andreas; Günther, Claudia; Itzel, Timo; Thasler, Wolfgang E.; Teufel, Andreas; Trebicka, Jonel; et al. (Journal of Clinical Investigation, 2020)
Hepatocellular carcinoma (HCC) is clearly age-related and represents one of the deadliest cancer types worldwide. Due to globally increasing risk factors including metabolic disorders, the incidence rates of HCC are still rising. However, the molecular hallmarks of HCC remain poorly understood. Neuropeptide Y (NPY) and NPY-receptors represent a highly conserved, stress-activated system which is involved in diverse cancer-related hallmarks including aging and metabolic alterations, but its impact on liver cancer had been unclear. Here, we observed increased NPY5-receptor (Y5R) expression in HCC which correlated with tumor growth and survival. Furthermore, we found that its ligand NPY was secreted by peri-tumorous hepatocytes. Hepatocyte-derived NPY promoted HCC progression by Y5R-activation. Transforming growth factor beta 1 (TGFβ1) was identified as a regulator of NPY in hepatocytes and induced Y5R in invasive cancer cells. Moreover, NPY-conversion by dipeptidylpeptidase 4 (DPP4) augmented Y5R-activation and function in liver cancer. The TGFβ-NPY-Y5R-axis and DPP4 represent attractive therapeutic targets for controlling liver cancer progression.
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Keywords: Aging; Cancer; Hepatology

Molecular Endoscopic Imaging in Cancer - Rath, Timo; Neurath, Markus; Atreya, Raja (Elsevier, 2021)
Through the combination of administration of fluorescently labeled molecular dyes that specifically bind to defined molecular targets and their subsequent visualization with endoscopic devices, molecular endoscopic imaging enables in vivo real-time imaging of single molecules or receptors.
CRIS-Team Scopus Importer:2023-03-23
Keywords: Barrett’s esophagus; Cancer; Colorectal cancer; Endoscopy; Gastric cancer; Molecular imaging

Molecular Endoscopy and in vivo Imaging in Inflammatory Bowel Diseases - Neurath, Markus (Digestive Diseases, 2015)
Studies in recent years have shown that standard imaging modalities such as endoscopy, ultrasonography or MRI are essential for assessment of gut inflammation in patients with inflammatory bowel diseases (IBDs). In addition, endoscopy plays a pivotal role in the analysis of mucosal healing in these disorders. However, these techniques do not allow a detailed analysis of the molecular pathways driving gut inflammation in IBD patients. Here, we discuss the role of new techniques for the molecular imaging of gut inflammation in IBD with special reference to the prediction of responses to therapy using antibodies to tumor necrosis factor (anti-TNF). Key Messages: Several in vivo imaging studies have been performed in IBD patients before and after anti-TNF therapy. In one study, (99m)Technetium-labeled annexin V was given to patients with active Crohn's disease before and after anti-TNF therapy with infliximab. Subsequently, single-photon emission CT (SPECT) was performed to study the effect of anti-TNF treatment on apoptosis in the intestine during active colitis. This study showed enrichment of technetium signals in the gut of patients who responded to anti-TNF therapy. The findings suggested that anti-TNF treatment induces T-cell apoptosis in vivo and that SPECT imaging can be used for prediction of response to anti-TNF therapy. In another study, fluorescent anti-TNF antibodies (fluorescent adalimumab) were chosen for molecular imaging during confocal laser endomicroscopy in patients with active Crohn's disease. This study revealed that an increase of membrane-bound TNF expressing mucosal immune cells predicts response to subsequent adalimumab therapy.Molecular in vivo imaging is an exciting new field in patients with IBD. It is expected that this field will allow new insights into the pathophysiology of IBD and may be used for personalized medicine in the future.
EVALuna2:2170

Molecular Endoscopy for the Diagnosis and Therapeutic Monitoring of Colorectal Cancer - Waldner, Maximilian; Neurath, Markus (Frontiers in Oncology, 2022)
Colorectal cancer (CRC) is one of the leading causes of cancer related death in the western world. Its successful treatment requires early detection and removal of precursor lesions as well as individualized treatment of advanced disease. During recent years, molecular imaging techniques have shown promising results to improve current clinical practice. For instance, molecular endoscopy resulted in higher detection rates of precursors in comparison to conventional endoscopy in preclinical and clinical studies. Molecular confocal endomicroscopy allowed a further classification of suspect lesions as well as the prediction and monitoring of the therapeutic response. In this review, we summarize recent achievements for molecular imaging of CRC in preclinical studies, initial clinical trials and the remaining challenges for future translation into clinical practice.
CRIS-Team Scopus Importer:2022-03-25
Keywords: adenoma; colorectal cancer; confocal endomicroscopy; endoscopy; fluorescence; molecular imaging; near-infrared imaging; Raman

Molecular Imaging and its Applications in Selected GI Diseases - Rath, Timo; Neurath, Markus; Atreya, Raja (Techniques and Innovations in Gastrointestinal Endoscopy, 2021)
During the past decade, molecular imaging has emerged as a new and innovative field combining clinical endoscopy with methods prior used in basic science. Through the labeling of cellular targets with certain molecular probes and their subsequent detection with dedicated endoscopic devices, molecular imaging enables the visualization of single molecules or receptors during ongoing endoscopy. Early studies in the field have provided proof-of-principle that molecular imaging can improve visualization, or even unmask, previously unrecognized early dysplasia or cancer. Building on this, further studies then used molecular imaging for grading and detecting inflammation and inflammation associated cancer. Most recently, molecular imaging has been used to phenotype the expression of single receptors and targets of biological therapy and thereby enables molecular tissue profile in vivo. With this live molecular fingerprinting, molecular imaging can be used to guide expression-tailored individualized therapy, and due to the diversification of biological therapy in both cancer and intestinal inflammation, it can be expected that molecular imaging will gain further traction in the foreseeable future. Within this review, we first summarize the technical components commonly used for molecular imaging and then review preclinical and clinical studies and possible and evolving clinical applications on molecular imaging within the entire the GI tract.
CRIS-Team Scopus Importer:2021-04-02
Keywords: Barretts esophagus; Colorectal cancer; Endoscopy; Inflammatory bowel disease; Molecular imaging

Molecular imaging in gastroenterology: A route for personalized endoscopy - Klenske, Entcho; Neurath, Markus; Atreya, Raja; Rath, Timo (Digestive and Liver Disease, 2018)
With the rapid expansion and diversification of the repertoire of biological agents utilized in inflammatory bowel diseases and cancer and the increase in oncological patients in gastroenterology, visualization of single receptor or molecular target expression and the subsequent initiation of expression tailored therapy are gaining increasing attention. Through the combination of utilizing fluorescently labeled probes with high specificity towards defined molecular targets and their subsequent detection and visualization with endoscopic devices, molecular imaging is a new emerging field focusing on the receptor expression within the mucosa on a cellular level rather than on macroscopic changes. In the past years various new technological and molecular probes have been successfully utilized for molecular imaging. Within this review, we summarize different technologies as well as molecular probes applied in molecular imaging and review current and past approaches for functional imaging with molecular endoscopy within the GI Tract and resulting clinical applications. It can be expected that molecular imaging allows for individualized diagnostic approaches and patient tailored medicine in the future.
EVALuna2:35144

Molecular imaging in inflammatory bowel disease - Rath, Timo; Neurath, Markus; Atreya, Raja (Elsevier, 2020)
Recent advances in biological therapy in inflammatory bowel diseases (IBDs) and early detection of colitis-associated neoplasia have increased the popularity of molecular endoscopy with visualization of single receptor or molecular target expression and the subsequent initiation of expression tailored therapy. Molecular imaging is an emerging field in the receptor expression within the mucosa on a cellular level rather than on macroscopic changes. Various new technological and molecular probes have been utilized for molecular imaging. These new technologies have found their applications in diagnosis, disease monitoring, and assessment of treatment response in IBD. They may also play a role in the detection of colitis-associated neoplasia.
CRIS-Team Scopus Importer:2023-03-23
Keywords: Biological therapy; Crohn’s disease; endomicroscopy; inflammation; therapeutic response; ulcerative colitis

Molecular Imaging of alpha 4 beta 7 Integrin Expression by Confocal Laser Endomicroscopy With Fluorescent Vedolizumab in Crohn's Disease - Rath, Timo; Bojarski, Christian; Neurath, Markus; Atreya, Raja (2017)
EVALuna2:33904

Molecular imaging of mucosal α4β7 integrin expression with the fluorescent anti-adhesion antibody vedolizumab in Crohn's disease - Rath, Timo; Bojarski, Christian; Neurath, Markus; Atreya, Raja (Gastrointestinal Endoscopy, 2017)
EVALuna2:33806

Molecular imaging within the lower gastrointestinal tract: From feasibility to future - Rath, Timo; Kiesslich, Ralf; Neurath, Markus; Atreya, Raja (Digestive Endoscopy, 2018)
Molecular imaging is based on the labelling of defined molecular targets through the utilization of fluorescently linked probes and their subsequent detection with high-resolution endoscopic devices, thereby enabling visualization of single molecules including receptors. Whereas early studies have used molecular imaging for improved visualization and detection of early dysplasia and cancer as well as for assessing intestinal inflammation and inflammation-associated cancer within the gastrointestinal (GI) tract, more recent studies have impressively demonstrated that molecular imaging can also be used to characterize and visualize the molecular fingerprint of cancer and inflammation in vivo and in real time. With this, molecular imaging can be used to guide expression-tailored individualized therapy. With the rapid expansion and diversification of the repertoire of biological agents utilized in inflammatory bowel disease and cancer, this approach is gaining increasing attention. Within this review, we first summarize the technical components commonly used for molecular imaging and then review preclinical and clinical studies and evolving clinical applications on molecular imaging within the lower GI tract. Molecular imaging has the potential to significantly change endoscopic diagnosis and subsequent targeted therapy of gastrointestinal cancer and chronic gastrointestinal diseases.
EVALuna2:35133

Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases - Billmeier, Ulrike; Dieterich, Walburga; Neurath, Markus; Atreya, Raja (World Journal of Gastroenterology, 2016)
Anti-tumor necrosis factor (TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases (IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn's disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each anti-TNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membrane-bound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with anti-TNF antibodies in chronic intestinal inflammation, by predicting response to therapy.
EVALuna2:2196

Molecular pathways driving disease-specific alterations of intestinal epithelial cells - Lopez Posadas, Rocío; Neurath, Markus; Atreya, Imke (Cellular and Molecular Life Sciences, 2017)
Due to the fact that chronic inflammation as well as tumorigenesis in the gut is crucially impacted by the fate of intestinal epithelial cells, our article provides a comprehensive overview of the composition, function, regulation and homeostasis of the gut epithelium. In particular, we focus on those aspects which were found to be altered in the context of inflammatory bowel diseases or colorectal cancer and also discuss potential molecular targets for a disease-specific therapeutic intervention.
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Molecular signature for lymphatic metastasis in colorectal carcinomas. - Croner, Roland S.; Förtsch, Thomas; Brueckl, Wolfgang M.; Roedel, Franz; Roedel, Claus; Papadopoulos, Thomas; Brabletz, Thomas; Kirchner, Thomas; Sachs, Martin; Behrens, Jürgen; Klein-Hitpass, Ludger; Stürzl, Michael; et al. (Annals of Surgery, 2008)
Fifty differently expressed genes between stage UICC I, II versus III CRC were identified respecting the selection criteria by allowing for multiple testing. The data validation by the independent clinical study confirmed our results. In comparison to MC, the genes were over- or underexpressed. They belong to various functional groups such as cellular adhesion, transporters, signaling, metabolism, protein synthesis, gene control, and immune system. Forty tumor samples of stage UICC I, II CRC, 40 samples of stage III CRC, and 25 biopsies of healthy mucosa (MC) were shock frozen in liquid nitrogen and underwent cryotomy after manual dissection for tumor tissue or MC enrichment. Isolated RNA was hybridized to GeneChips (HG-U133A, Affymetrix). Preprocessing of the microarray results was done by the robust multichip average method, and differentially expressed genes were selected by the maximum Wilcoxon statistic over 22,215 probe sets. The results were validated at an independent clinical study. Our large patient cohort and the data validation on an independent study identified 50 differentially expressed genes between CRC of different histopathologic stages. These findings indicate that molecular staging of CRC may be possible, which could help to guide individual CRC treatment before surgery. TNM-staging of colorectal carcinomas (CRC) relies on the histopathologic workup of the surgically removed specimen. If valid preoperative staging methods existed, patients could be selected for adequate individual therapy before surgery. Microarray techniques provide a promising tool to identify stage-specific molecular signatures on primary tumor biopsies. RESULTS MATERIAL AND METHODS CONCLUSION PURPOSE

Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease - Monteleone, Giovanni; Neurath, Markus; Ardizzone, Sandro; Di Sabatino, Antonio; Fantini, Massimo C.; Castiglione, Fabiana; Scribano, Maria L.; Armuzzi, Alessandro; Caprioli, Flavio; Sturniolo, Giacomo C.; Rogai, Francesca; Vecchi, Maurizio; et al. (New England Journal of Medicine, 2015)
Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor ?1 (TGF-?1) due to high levels of SMAD7, an inhibitor of TGF-?1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7.In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28.The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease.We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).
EVALuna2:2001

Moonlighting chromatin: when DNA escapes nuclear control - Singh, Jeeshan; Boettcher, Michael; Dölling, Maximilian; Heuer, Annika; Hohberger, Bettina; Leppkes, Moritz; Naschberger, Elisabeth; Schapher, Mirco; Schauer, Christine; Schoen, Janina; Stürzl, Michael; Vitkov, Ljubomir; et al. (Cell Death and Differentiation, 2023)
Extracellular chromatin, for example in the form of neutrophil extracellular traps (NETs), is an important element that propels the pathological progression of a plethora of diseases. DNA drives the interferon system, serves as autoantigen, and forms the extracellular scaffold for proteins of the innate immune system. An insufficient clearance of extruded chromatin after the release of DNA from the nucleus into the extracellular milieu can perform a secret task of moonlighting in immune-inflammatory and occlusive disorders. Here, we discuss (I) the cellular events involved in the extracellular release of chromatin and NET formation, (II) the devastating consequence of a dysregulated NET formation, and (III) the imbalance between NET formation and clearance. We include the role of NET formation in the occlusion of vessels and ducts, in lung disease, in autoimmune diseases, in chronic oral disorders, in cancer, in the formation of adhesions, and in traumatic spinal cord injury. To develop effective therapies, it is of utmost importance to target pathways that cause decondensation of chromatin during exaggerated NET formation and aggregation. Alternatively, therapies that support the clearance of extracellular chromatin are conceivable. [Figure not available: see fulltext.].
CRIS-Team Scopus Importer:2023-02-17

Morbus Crohn und Colitis ulcerosa in der Hausarztpraxis - Baer, Eva; Jesper, Daniel; Neurath, Markus; Atreya, Raja (MMW Fortschritte der Medizin, 2020)
CRIS-Team Scopus Importer:2020-11-20

Morphometric Assessment of Confocal Laser Endomicroscopy for Pancreatic Ductal Adenocarcinoma, an Ex-Vivo Pilot Study - Ungureanu, Bogdan Silviu; Pirici, Daniel; Dima, Simona Olimpia; Popescu, Irinel; Hundorfean, Gheorghe; Surlin, Valeriu; Saftoiu, Adrian (Diagnostics, 2020)
Ex-vivo freshly surgical removed pancreatic ductal adenocarcinoma (PDAC) specimens were assessed using pCLE and then processed for paraffin embeding and histopathological diagnostic in an endeavour to find putative image analysis algorithms that might recognise adenocarcinoma. Methods: Twelve patients diagnosed with PDAC on endoscopic ultrasound and FNA confirmation underwent surgery. Removed samples were sprayed with acriflavine as contrast agent, underwent pCLE with an experimental probe and compared with previous recordings of normal pancreatic tissue. Subsequently, all samples were subjected to cross-sectional histopathology, including surgical resection margins for controls. pCLE records, as well as corespondant cytokeratin-targeted immunohistochemistry images were processed using the same morphological classifiers in the Image ProPlus AMS image analysis software. Specific morphometric classifiers were automatically generated on all images: Area, Hole Area (HA), Perimeter, Roundness, Integrated Optical Density (IOD), Fractal Dimension (FD), Ferret max (Fmax), Ferret mean (Fmean), Heterogeneity and Clumpiness. Results: After histopathological confirmation of adenocarcinoma areas, we have found that the same morphological classifiers could clearly differentiate between tumor and non-tumor areas on both pathology and correspondand pCLE (area, roundness, IOD, ferret and heterogeneity (p < 0.001), perimeter and hole area (p < 0.05). Conclusions: This pilot study proves that classical morphometrical classifiers can clearly differentiate adenocarcimoma on pCLE data, and the implementation in a live image-analysis algorithm might help in improving the specificity of pCLE in vivo diagnostic.
CRIS-Team WoS Importer:2020-12-11

Motorized spiral enteroscopy: Results of an international multicenter prospective observational clinical study in patients with normal and altered gastrointestinal anatomy - Beyna, Torsten; Moreels, Tom; Arvanitakis, Marianna; Pioche, Mathieu; Saurin, Jean-Christophe; May, Andrea; Knabe, Mate; Agnholt, Jorgen Steen; Bjerregaard, Niels Christian; Puustinen, Lauri; Schlag, Christoph; Aabakken, Lars; et al. (Endoscopy, 2022)
Background Motorized spiral enteroscopy (MSE) has been shown to be safe and effective for deep enteroscopy in studies performed at expert centers with limited numbers of patients without previous abdominal surgery. This study aimed to investigate the safety, efficacy, and learning curve associated with MSE in a real-life scenario, with the inclusion of patients after abdominal surgery and with altered anatomy. Methods Patients with indications for deep enteroscopy were enrolled in a prospective observational multicenter study. The primary objective was the serious adverse event (SAE) rate; secondary objectives were the diagnostic and therapeutic yield, procedural success, time, and insertion depth. Data analysis was subdivided into training and core (post-training) study phases at centers with different levels of MSE experience. Results 298 patients (120 women; median age 68, range 19-92) were enrolled. In the post-training phase, 21.5 % (n = 54) had previous abdominal surgery, 10.0 % (n = 25) had surgically altered anatomy. Overall, SAEs occurred in 2.3 % (7/298; 95 %CI 0.9 %-4.8 %). The SAE rate was 2.0 % (5/251) in the core group and 4.3 % (2/47) in the training group, and was not increased after abdominal surgery (1.9 %). Total enteroscopy was achieved in half of the patients (n = 42) undergoing planned total enteroscopy. In 295/337 procedures (87.5 %), the anatomical region of interest could be reached. Conclusions This prospective multicenter study showed that MSE was feasible and safe in a large cohort of patients in a real-life setting, after a short learning curve. MSE was shown to be feasible in postsurgical patients, including those with altered anatomy, without an increase in the SAE rate.
CRIS-Team Scopus Importer:2022-07-22

Mucosal Biofilms Are an Endoscopic Feature of Irritable Bowel Syndrome and Ulcerative Colitis - Baumgartner, Maximilian; Lang, Michaela; Holley, Hunter; Crepaz, Daniel; Hausmann, Bela; Pjevac, Petra; Moser, Doris; Haller, Felix; Hof, Fabian; Beer, Andrea; Orgler, Elisabeth; Frick, Adrian; et al. (Gastroenterology, 2021)
Background & Aims: Irritable bowel syndrome (IBS) and inflammatory bowel diseases result in a substantial reduction in quality of life and a considerable socioeconomic impact. In IBS, diagnosis and treatment options are limited, but evidence for involvement of the gut microbiome in disease pathophysiology is emerging. Here we analyzed the prevalence of endoscopically visible mucosal biofilms in gastrointestinal disease and associated changes in microbiome composition and metabolism. Methods: The presence of mucosal biofilms was assessed in 1426 patients at 2 European university-based endoscopy centers. One-hundred and seventeen patients were selected for in-depth molecular and microscopic analysis using 16S ribosomal RNA gene amplicon-sequencing of colonic biopsies and fecal samples, confocal microscopy with deep learning–based image analysis, scanning electron microscopy, metabolomics, and in vitro biofilm formation assays. Results: Biofilms were present in 57% of patients with IBS and 34% of patients with ulcerative colitis compared with 6% of controls (P < .001). These yellow-green adherent layers of the ileum and right-sided colon were microscopically confirmed to be dense bacterial biofilms. 16S-sequencing links the presence of biofilms to a dysbiotic gut microbiome, including overgrowth of Escherichia coli and Ruminococcus gnavus. R. gnavus isolates cultivated from patient biofilms also formed biofilms in vitro. Metabolomic analysis found an accumulation of bile acids within biofilms that correlated with fecal bile acid excretion, linking this phenotype with a mechanism of diarrhea. Conclusions: The presence of mucosal biofilms is an endoscopic feature in a subgroup of IBS and ulcerative colitis with disrupted bile acid metabolism and bacterial dysbiosis. They provide novel insight into the pathophysiology of IBS and ulcerative colitis, illustrating that biofilm can be seen as a tipping point in the development of dysbiosis and disease.
CRIS-Team Scopus Importer:2021-09-24
Keywords: Bacterial–Epithelial Interaction; Endoscopy; Functional Gastrointestinal Disorders; Microbiota

MULTICENTER ANALYSIS OF ENDOCLOT AS HEMOSTATIC POWDER IN DIFFERENT ENDOSCOPIC SETTINGS OF THE UPPER GASTROINTESTINAL TRACT - Hagel, Alexander; Raithel, M.; Hempen, P.; Preclik, G.; Dauth, W.; Neurath, Markus; Gschossmann, J.; Konturek, P. C.; Albrecht, Heinz (Journal of Physiology and Pharmacology, 2020)
Gastrointestinal bleeding (GIB) still presents a demanding situation with high morbidity and mortality rates; thus hemostatic powders such as EndoClot (EC) have been developed to improve endoscopic armament. The aim of the present study was to determine which indications triggered the application of EC and to assess resulting hemostasis rates. Forty three patients undergoing endoscopical procedures in three hospitals; two tertiary care and one university hospital, were included. EC was applied in 48 endoscopies in 43 patients (27 male, age 65.5 years, range 28 - 92 years) following four different indications. EC was used in active GIB as rescue or first-line therapy giving a short-term and long-term hemostasis in 13/17 patients (76.5%). In the setting of non-active GIB, following conventionally achieved hemostasis or endoscopic interventions, EC was found to prevent bleeding in 19/21 patients (90.4%). EC induced hemostasis in 8/10 patients (80%) with impaired coagulation. EC failures resulted from tumor bleeding, Forrest I lesions or perforated duodenal ulcers. No major adverse events were recorded and one technical failure (2.1%) occurred. EC was applied as first line or salvage treatment in ongoing bleedings with promising results. Furthermore, EC was used after successful hemostasis or following endoscopic interventions to further reduce re-bleeding rates. We saw promising results in all indications, albeit lacking a control group.
CRIS-Team WoS Importer:2021-02-19

Multicenter Analysis of Treatment Outcomes for Systemic Therapy in Well Differentiated Grade 3 Neuroendocrine Tumors (NET G3) - Apostolidis, Leonidas; Dal Buono, Arianna; Merola, Elettra; Jann, Henning; Jaeger, Dirk; Wiedenmann, Bertram; Winkler, Eva Caroline; Pavel, Marianne Ellen (Cancers, 2021)
Simple Summary
CRIS-Team WoS Importer:2021-05-14

Multicenter cohort study of patients with buried bumper syndrome treated endoscopically with a novel, dedicated device - Costa, Deborah; Despott, Edward J.; Lazaridis, Nikolaos; Woodward, Jeremy; Kohout, Pavel; Rath, Timo; Scovell, Louise; Gee, Ian; Hindryckx, Pieter; Forrest, Ewan; Hollywood, Coral; Hearing, Stephen; et al. (Gastrointestinal Endoscopy, 2021)
Background and Aims: Buried bumper syndrome (BBS) is a rare adverse event of percutaneous endoscopic gastrostomy (PEG) placement in which the internal bumper migrates through the stomal tract to become embedded within the gastric wall. Excessive tension between the internal and external bumpers, causing ischemic necrosis of the gastric wall, is believed to be the main etiologic factor. Several techniques for endoscopic management of BBS have been described using off-label devices. The Flamingo set is a novel, sphincterotome-like device specifically designed for BBS management. We aimed to evaluate the effectiveness of the Flamingo device in a large, homogeneous cohort of patients with BBS. Methods: A guidewire was inserted through the external access of the PEG tube into the gastric lumen. The Flamingo device was then introduced into the stomach over the guidewire. This dedicated tool can be flexed by 180 degrees, exposing a sphincterotome-like cutting wire, which is used to incise the overgrown tissue until the PEG bumper is exposed. A retrospective, international, multicenter cohort study was conducted on 54 patients between December 2016 and February 2019. Results: The buried bumper was successfully removed in 53 of 55 procedures (96.4%). The median time for the endoscopic removal of the buried bumper was 22 minutes (range, 5-60). Periprocedural endoscopic adverse events occurred in 7 procedures (12.7%) and were successfully managed endoscopically. A median follow-up of 150 days (range, 33-593) was performed in 29 patients (52.7%), during which no significant adverse events occurred. Conclusions: Through our experience, we found this dedicated novel device to be safe, quick, and effective for minimally invasive, endoscopic management of BBS.
CRIS-Team Scopus Importer:2021-02-12

Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Neuroendocrine Tumors in Routine Clinical Practice in Germany and Austria - Rinke, Anja; Maintz, Christoph; Muller, Lothar; Weber, Matthias M.; Lahner, Harald; Pavel, Marianne Ellen; Saeger, Wolfgang; Houchard, Aude; Ungewiss, Hanna; Petersenn, Stephan (Experimental and Clinical Endocrinology and Diabetes, 2021)
Background The long-acting somatostatin analog lanreotide autogel is effective in the treatment of patients with neuroendocrine tumors. Objective To evaluate the long-term treatment response in patients with neuroendocrine tumors receiving lanreotide autogel in routine clinical practice. Methods Non-interventional, 24-month study in patients with neuroendocrine tumors treated with lanreotide autogel (NCT01840449). Results Patients (n=80) from 26 centers in Germany and Austria were enrolled. Neuroendocrine tumors were mainly grade 1/2, metastasized, intestinal, and associated with carcinoid syndrome; 88.9% had received previous neuroendocrine tumor treatment. Of those, 84.4% had previous surgery, 18.7% had received octreotide. The primary endpoint, defined by a <50% chromogranin A increase at month 12 compared with the lowest value between baseline and month 3 was achieved by 89.5% patients. Stable disease according to Response Evaluation Criteria in Solid Tumors 1.1 was observed in 76.9 and 75.0% patients at months 12 and 24 of lanreotide treatment, respectively. Mean change of chromogranin A levels from baseline to month 24 was -0.12 × upper limit of normal (95% CI, -0.22; -0.45). In a post hoc analysis, 38.5% of the subgroup of patients with carcinoid syndrome had daily diarrhea at baseline vs. 21.4% at month 24. At baseline, 27.8% of patients received lanreotide 120 mg every 4 weeks vs. 56.7% at month 24. Quality of life data were heterogeneous. No new safety issues arose and/or required further investigation. Conclusions Our study reflects routine lanreotide autogel use in patients with advanced/metastatic neuroendocrine tumors. This analysis shows effectiveness with stabilization of disease-related symptoms and good tolerability of lanreotide autogel in clinical practice.
CRIS-Team Scopus Importer:2021-08-06
Keywords: carcinoid syndrome; chromogranin A; diarrhea; flushing; quality of life

Multiple Endocrine Neoplasia Type 1 and the Pancreas: Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement - Niederle, Bruno; Selberherr, Andreas; Bartsch, Detlef K.; Brandi, Maria L.; Doherty, Gerard M.; Falconi, Massimo; Goudet, Pierre; Halfdanarson, Thorvardur R.; Ito, Tetsuhide; Jensen, Robert T.; Larghi, Alberto; Lee, Lingaku; et al. (Neuroendocrinology, 2021)
The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook"for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies.
CRIS-Team Scopus Importer:2021-07-09
Keywords: Consensus statement; Diagnosis; Multiple endocrine neoplasia type 1; Neuroendocrine pancreatic tumors; Treatment

Multispectral optoacoustic tomography enables assessment of disease activity in paediatric inflammatory bowel disease - Regensburger, Adrian; Eckstein, Markus; Wetzl, Matthias; Raming, Roman; Paulus, Lars-Philip; Bühler, Adrian; Nedoschill, Emmanuel; Danko, Vera; Jüngert, Jörg; Wagner, Alexandra; Schnell, Alexander; Rückel, Aline; et al. (Photoacoustics, 2024)
Multispectral optoacoustic tomography (MSOT) allows non-invasive molecular disease activity assessment in adults with inflammatory bowel disease (IBD). In this prospective pilot-study, we investigated, whether increased levels of MSOT haemoglobin parameters corresponded to inflammatory activity in paediatric IBD patients, too. 23 children with suspected IBD underwent MSOT of the terminal ileum and sigmoid colon with standard validation (e.g. endoscopy). In Crohn‘s disease (CD) and ulcerative colitis (UC) patients with endoscopically confirmed disease activity, MSOT total haemoglobin (HbT) signals were increased in the terminal ileum of CD (72.1 ± 13.0 a.u. vs. 32.9 ± 15.4 a.u., p = 0.0049) and in the sigmoid colon of UC patients (62.9 ± 13.8 a.u. vs. 35.1 ± 16.3 a.u., p = 0.0311) as compared to controls, respectively. Furthermore, MSOT haemoglobin parameters correlated well with standard disease activity assessment (e.g. SES-CD and MSOT HbT (rs =0.69, p = 0.0075). Summarizing, MSOT is a novel technology for non-invasive molecular disease activity assessment in paediatric patients with inflammatory bowel disease.
CRIS-Team Scopus Importer:2023-12-15
Keywords: Multispectral optoacoustic tomography; Optoacoustic imaging; Paediatric inflammatory bowel disease

Multispectral Optoacoustic Tomography for Assessment of Crohn's Disease Activity - Knieling, Ferdinand; Neufert, Clemens; Hartmann, Arndt; Claussen, Jing; Urich, Alexander; Egger, Cornelia; Vetter, Marcel; Fischer, Sarah; Pfeifer, Lukas; Hagel, Alexander; Kielisch, Christian; Görtz, Rüdiger; et al. (New England Journal of Medicine, 2017)
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Multispectral optoacoustic tomography for non-invasive disease phenotyping in pediatric spinal muscular atrophy patients - Regensburger, Adrian; Wagner, Alexandra; Danko, Vera; Jüngert, Jörg M.; Federle, Anna; Klett, Daniel; Schüssler, Stephanie; Buehler, Adrian; Neurath, Markus; Roos, Andreas; Lochmüller, Hanns; Wölfle, Joachim; et al. (Photoacoustics, 2022)
Proximal spinal muscular atrophy (SMA) is a rare progressive, life limiting genetic motor neuron disease. While promising causal therapies are available, meaningful prognostic biomarkers for therapeutic monitoring are missing. We demonstrate handheld Multispectral Optoacoustic Tomography (MSOT) as a novel non-invasive imaging approach to visualize and quantify muscle wasting in pediatric SMA. While MSOT signals were distributed homogeneously in muscles of healthy volunteers (HVs), SMA patients showed moth-eaten optoacoustic signal patterns. Further signal quantification revealed greatest differences between groups at the isosbestic point for hemoglobin (SWL 800 nm). The SWL 800 nm signal intensities further correlated with clinical phenotype tested by standard motor outcome measures. Therefore, handheld MSOT could enable non-invasive assessment of disease burden in SMA patients.
CRIS-Team Scopus Importer:2021-11-26
Keywords: Multispectral optoacoustic tomography; Optoacoustics; Photoacoustics; Spinal muscular atrophie

Multispectral optoacoustic tomography for the non-invasive identification of patients with severe anemia in vivo - Ganzleben, Ingo; Klett, Daniel; Hartz, Wiebke; Götzfried, Lisa; Vitali, Francesco; Neurath, Markus; Waldner, Maximilian (Photoacoustics, 2022)
The immediate diagnosis of severe anemia is crucial for patient outcome. However, reliable non-invasive point-of-care diagnostic tools for e.g., ICU monitoring are currently lacking. Using an advanced Multispectral Optoacoustic Tomography (MSOT) research device, we first substantiated a strong positive correlation of MSOT-signal and absolute hemoglobin concentration ex vivo in blood samples. In a clinical exploratory proof-of-concept study, we then evaluated 19 patients with different severities of anemia and controls by non-invasive in vivo measurement of hemoglobin in the radial artery. Our approach proved excellent in identifying patients with severe anemia triggering RBC transfusion based on a strong positive correlation of MSOT-signal intensity and hemoglobin concentration for 700 nm single wavelength and HbR unmixed MSOT-parameter analysis. In conclusion, our study lays the foundation to further develop MSOT-based real-time quantitative perfusion analyses in follow-up preclinical and clinical imaging studies and as a promising diagnostic tool to improve patient care in the future. DRKS00021442
CRIS-Team Scopus Importer:2022-10-28
Keywords: Anemia; Clinical study; Hemoglobin; Optoacoustic imaging

Multispectral Optoacoustic Tomography in Crohn's disease - A First-in-human Diagnostic Clinical Trial - Knieling, Ferdinand; Hartmann, Arndt; Uter, Wolfgang; Urich, Alexander; Claussen, Jing; Atreya, Raja; Rascher, Wolfgang; Waldner, Maximilian (2017)
EVALuna2:33902

Multispectral Optoacoustic Tomography in Crohn's Disease: Noninvasive Imaging of Disease Activity - Waldner, Maximilian; Knieling, Ferdinand; Egger, Cornelia; Morscher, Stefan; Claussen, Jing; Vetter, Marcel; Kielisch, Christian; Fischer, Sören; Pfeifer, Lukas; Hagel, Alexander; Görtz, Rüdiger; Wildner, Dane; et al. (Gastroenterology, 2016)
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Multispectral Optoacoustic Tomography in Ulcerative Colitis - A First-in-human Diagnostic Clinical Trial - Knieling, Ferdinand; Hartmann, Arndt; Claussen, Jing; Urich, Alexander; Atreya, Raja; Rascher, Wolfgang; Waldner, Maximilian (2017)
EVALuna2:33901

Multispectral optoacoustic tomography of the human intestine – temporal precision and the influence of postprandial gastrointestinal blood flow - Paulus, Lars-Philip; Wagner, Alexandra; Buehler, Adrian; Raming, Roman; Jüngert, Jörg; Simon, David; Tascilar, Koray; Schnell, Alexander; Günther, Josefine; Rother, Ulrich; Lang, Werner; Hörning, André; et al. (Photoacoustics, 2023)
Multispectral optoacoustic tomography (MSOT) holds great promise as a non-invasive diagnostic tool for inflammatory bowel diseases. Yet, reliability and the impact of physiological processes during fasting and after food intake on optoacoustic signals have not been studied. In the present investigator initiated trial (NCT05160077) the intestines of ten healthy subjects were examined by MSOT at eight timepoints on two days, one fasting and one after food intake. While within-timepoint and within-day reproducibility were good for single wavelength 800 nm and total hemoglobin (ICC 0.722–0.956), between-day reproducibility was inferior (ICC −0.137 to 0.438). However, temporal variability was smaller than variation between individuals (coefficients of variation 8.9%−33.7% vs. 17.0%−48.5%). After food intake and consecutive increased intestinal circulation, indicated by reduced resistance index of simultaneous Doppler ultrasound, optoacoustic signals did not alter significantly. In summary, this study demonstrates high reliability and temporal stability of MSOT for imaging the human intestine during fasting and after food intake.
CRIS-Team Scopus Importer:2023-02-24
Keywords: Gut; Inflammatory bowel disease; Intestinal blood flow; Multispectral optoacoustic imaging; Optoacoustic; Photoacoustic; Postprandial; Reliability; Reproducibility

Murine CD83-positive T cells mediate suppressor functions in vitro and in vivo - Kreiser, Simon; Eckhardt, Jenny; Kuhnt, Christine; Stein, Marcello F.; Krzyzak, Lena; Seitz, Christine; Tucher, Christine; Knippertz, Ilka; Becker, Christoph; Günther, Claudia; Steinkasserer, Alexander; Lechmann, Matthias (Immunobiology, 2015)
The CD83 molecule (CD83) is a well-known surface marker present on mature dendritic cells (mDC). In this study, we show that CD83 is also expressed on a subset of T cells which mediate regulatory T cell (Treg)-like suppressor functions in vitro and in vivo. Treg-associated molecules including CD25, cytotoxic T lymphocyte antigen-4 (CTLA-4), glucocorticoid-induced TNFR family-related gene (GITR), Helios and neuropilin-1 (NRP-1) as well as forkhead box protein 3 (FOXP3) were specifically expressed by these CD83(+) T cells. In contrast, CD83(-) T cells showed a naive T cell phenotype with effector T cell properties upon activation. Noteworthy, CD83(-) T cells were not able to upregulate CD83 despite activation. Furthermore, CD83(+) T cells suppressed the proliferation and inflammatory cytokine release of CD83(-) T cells in vitro. Strikingly, stimulated CD83(+) T cells released soluble CD83 (sCD83), which has been reported to possess immunosuppressive properties. In vivo, using the murine transfer colitis model we could show that CD83(+) T cells were able to suppress colitis symptoms while CD83(-) T cells possessed effector functions. In addition, this CD83 expression is also conserved on expanded human Treg. Thus, from these studies we conclude that CD83(+) T cells share important features with regulatory T cells, identifying CD83 as a novel lineage marker to discriminate between different T cell populations.
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Muscle‐derived cytokines reduce growth, viability and migratory activity of pancreatic cancer cells - Schwappacher, Raphaela; Dieterich, Walburga; Reljic, Dejan; Pilarsky, Christian; Mukhopadhyay, Debabrata; Chang, David K.; Biankin, Andrew; Siebler, Jürgen; Herrmann, Hans J.; Neurath, Markus; Zopf, Yurdagül (Cancers, 2021)
The evidence that regular physical exercise reduces the risk of developing cancer is well described. However, the interaction between physical exercise and cancer is not fully clarified yet. Several myokines released by skeletal muscle appear to have a direct anti‐tumour function. There are few data on myokine secretion after exercise in patients with advanced tumours. Pancreatic cancer (PC) is a very aggressive and usually fatal cancer. To investigate the effects of exercise in PC, the blood of advanced‐stage PC patients was analysed after 12 weeks of resistance training using whole‐body electromyostimulation. After the 12‐week training period, the patient serum inhibited the proliferation and the motility of PC cells and enhanced PC cell apoptosis. The impact of exercise training was also investigated in an exercise‐mimicking in vitro model using electric pulse stimulation of human myotubes and revealed similar anti‐tumour effects on PC cells, clearly indicating direct cancer‐protective properties of activated skeletal muscle. Protein and gene expression analyses in plasma from exercise‐trained patients and in myotube cultures after in vitro exercise showed that interleukin 10 (IL10), C‐X‐C motif ligand 1 (CXCL1) and C‐C motif chemokine ligand 4 (CCL4) are myokines released from activated skeletal muscle. In accordance with the effects of serum from exercise‐trained patients, the supplementation with recombinant IL10, CXCL1 and CCL4 impaired growth and migration of PC cells. Treatment of PC cells with these myokines upregulated caspase 3/7 expression and the cleavage of poly(ADP‐ribose) polymerase, leading to enhanced PC cell death. The identification of myokines with anti‐tumour properties in advanced‐stage PC patients after exercise opens a new perspective in supportive therapy with sports and exercise for cancer patients.
CRIS-Team Scopus Importer:2021-08-13
Keywords: Apoptosis; Electric pulse stimulation; Exercise; Migration; Myokine; Pancreatic cancer; Physical activity; Proliferation; Whole‐body electromyostimulation

Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-γ towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1 - Huber, Alexandra; Killy, Barbara; Grummel, Nadine; Bodendorfer, Barbara; Paul, Sushmita; Wiesmann, Veit; Naschberger, Elisabeth; Zimmer, Jana; Wirtz, Stefan; Schleicher, Ulrike; Vera, Julio; Ekici, Arif Bülent; et al. (Journal of Immunology, 2020)
Mycobacteria survive in macrophages despite triggering pattern recognition receptors and T cell-derived IFN-γ production. Mycobacterial cord factor trehalose-6,6-dimycolate (TDM) binds the C-type lectin receptor MINCLE and induces inflammatory gene expression. However, the impact of TDM on IFN-γ-induced macrophage activation is not known. In this study, we have investigated the cross-regulation of the mouse macrophage transcriptome by IFN-γ and by TDM or its synthetic analogue trehalose-6,6-dibehenate (TDB). As expected, IFN-γ induced genes involved in Ag presentation and antimicrobial defense. Transcriptional programs induced by TDM and TDB were highly similar but clearly distinct from the response to IFN-γ. The glycolipids enhanced expression of a subset of IFN-γ-induced genes associated with inflammation. In contrast, TDM/TDB exerted delayed inhibition of IFN-γ-induced genes, including pattern recognition receptors, MHC class II genes, and IFN-γ-induced GTPases, with antimicrobial function. TDM downregulated MHC class II cell surface expression and impaired T cell activation by peptide-pulsed macrophages. Inhibition of the IFN-γ-induced GTPase GBP1 occurred at the level of transcription by a partially MINCLE-dependent mechanism that may target IRF1 activity. Although activation of STAT1 was unaltered, deletion of Socs1 relieved inhibition of GBP1 expression by TDM. Nonnuclear Socs1 was sufficient for inhibition, suggesting a noncanonical, cytoplasmic mechanism. Taken together, unbiased analysis of transcriptional reprogramming revealed a significant degree of negative regulation of IFN-γ-induced Ag presentation and antimicrobial gene expression by the mycobacterial cord factor that may contribute to mycobacterial persistence.
CRIS-Team Scopus Importer:2020-09-18

Myeloid Cell-Derived HIF-1? Promotes Control of Leishmania major - Schatz, Valentin; Strussmann, Yannic; Mahnke, Alexander; Schley, Gunnar; Waldner, Maximilian; Ritter, Uwe; Wild, Jens; Willam, Carsten; Dehne, Nathalie; Brune, Bernhard; Mcniff, Jennifer M.; Colegio, Oscar R.; et al. (Journal of Immunology, 2016)
Hypoxia-inducible factor-1? (HIF-1?), which accumulates in mammalian host organisms during infection, supports the defense against microbial pathogens. However, whether and to what extent HIF-1? expressed by myeloid cells contributes to the innate immune response against Leishmania major parasites is unknown. We observed that Leishmania-infected humans and L. major-infected C57BL/6 mice exhibited substantial amounts of HIF-1? in acute cutaneous lesions. In vitro, HIF-1? was required for leishmanicidal activity and high-level NO production by IFN-?/LPS-activated macrophages. Mice deficient for HIF-1? in their myeloid cell compartment had a more severe clinical course of infection and increased parasite burden in the skin lesions compared with wild-type controls. These findings were paralleled by reduced expression of type 2 NO synthase by lesional CD11b(+) cells. Together, these data illustrate that HIF-1? is required for optimal innate leishmanicidal immune responses and, thereby, contributes to the cure of cutaneous leishmaniasis.
EVALuna2:2181

Naldemedine versus placebo in opioid-induced constipation: a meta-analysis - Wobbe, Bastian; Gerner, Maximilian; Koehne, Claus-Henning (BMJ Supportive & Palliative Care, 2022)
ObjectiveOpioid-induced constipation (OIC) is a frequent adverse event among patients receiving chronic pain therapy that is requiring opioids. Naldemedine was approved by the Food and Drug Administration to treat OIC and appears to be more efficient than any other peripherally acting mu-opioid receptor antagonist. This meta-analysis aimed at assessing the available data on naldemedine in terms of efficacy. MethodsWe searched the Cochrane Library, PubMed and ClinicalTrials on 24 May 2022 to identify randomised controlled trials (RCTs) comparing naldemedine to placebo among patients reporting OIC. ResultsEvaluation of 6 RCTs enrolling 2769 participants showed significantly greater respondence to treatment (OR=2.48; 95% CI: 2.02 to 3.06; p<0.00001), change in weekly spontaneous bowel movements (SBMs) (mean difference=1.45; 95% CI: 1.14 to 1.76; p<0.00001), complete SBMs (mean difference=0.89; 95% CI: 0.62 to 1.17; p<0.00001) and SBMs without straining (mean difference=0.89; 95% CI: 0.61 to 1.17; p<0.00001) for patients treated with naldemedine. We found no difference in numeric pain rating scales after one (mean difference=0.05; 95% CI: -0.22 to 0.31; p=0.73) and two weeks of treatment (mean difference= -0.04; 95% CI: -0.31 to 0.22; p=0.75). Funding and clinical diversity were possible risks of bias. ConclusionsNaldemedine improves a variety of bowel function parameters while preserving analgesia, confirming its efficacy for patients with OIC. However, head-to-head trials are needed to establish naldemedine as treatment of first choice for laxative-refractory OIC. PROSPERO registration numberCRD42022281353.
CRIS-Team WoS Importer:2023-01-13

Nanoparticles in Gastrooncology - Jefremow, André; Neurath, Markus (Visceral Medicine, 2020)
Background: Gastrointestinal malignancies have the greatest incidence and cancer-associated death rates worldwide. Routine therapeutic modalities include surgery, chemotherapy and radiation but they often fail to reach the goal of cancer-free survival. Summary: In the light of this urgent medical need for the treatment of GI tumors, nanotech-nology-based approaches, i.e. nanomedicine, promise new therapeutic options. Using nanoparticles instead of classically designed drugs, targeting anticancer agents directly to the tumor site may revolutionize both diagnostic and therapeutic tools thereby facilitating the identification and elimination of malignant cells. Importantly, diagnostic insight and therapeutic effects can be achieved simultaneously through the same nanoparticle. Additionally, a nanoparticle may be loaded with more than one agent, thereby further increasing the value and power of the nanotechnology approach in oncologic therapeutic concepts. Although most insight into mechanisms of nanomedicine has been gained from in vitro and preclinical in vivo models, few clinical trials have been conducted, and nanomedicine-based concepts are already part of standard treatment algorithms. However, despite substantial progress it remains a challenge to design nanoparticles that feature all desirable characteristics at the same time. Key Messages: This review seeks to provide substantial insight into the current status of nanomedicine-based approaches employed for diagnostic and/or therapeutic purposes in the field of gastrointestinal cancers by highlighting achievements and pointing out unresolved issues that need to be further addressed by future research attempts.
CRIS-Team Scopus Importer:2020-04-03
Keywords: Gastrointestinal tumors; Gastrooncology; Nanomedicine; Nanoparticles

Natural NADH and FAD Autofluorescence as Label-Free Biomarkers for Discriminating Subtypes and Functional States of Immune Cells - Lemire, Sarah; Thoma, Oana-Maria; Kreiß, Lucas; Völkl, Simon; Friedrich, Oliver; Neurath, Markus; Schürmann, Sebastian; Waldner, Maximilian (International Journal of Molecular Sciences, 2022)
Immune cell activity is a major factor for disease progression in inflammatory bowel diseases (IBD). Classifying the type and functional state of immune cells is therefore crucial in clinical diagnostics of IBD. Label-free optical technologies exploiting NADH and FAD autofluorescence, such as multiphoton microscopy, have been used to describe tissue morphology in healthy and inflamed colon samples. Nevertheless, a strategy for the identification of single immune cell subtypes within the tissue is yet to be developed. This work aims to initiate an understanding of autofluorescence changes depending on immune cell type and activation state. For this, NADH and FAD autofluorescence signals of different murine immune cell subtypes under native conditions, as well as upon in vitro stimulation and cell death, have been evaluated. Autofluorescence was assessed using flow cytometry and multiphoton microscopy. Our results reveal significantly increased NADH and FAD signals in innate immune cells compared to adaptive immune cells. This allowed identification of relative amounts of neutrophils and CD4+ T cells in mixed cell suspensions, by using NADH signals as a differentiation marker. Furthermore, in vitro stimulation significantly increased NADH and FAD autofluorescence in adaptive immune cells and macrophages. Cell death induced a significant drop in NADH autofluorescence, while FAD signals were hardly affected. Taken together, these results demonstrate the value of autofluorescence as a tool to characterize immune cells in different functional states, paving the way to the label-free clinical classification of IBD in the future.
CRIS-Team Scopus Importer:2022-03-11
Keywords: Cell autofluorescence; FAD; Flow cytometry; Immune cells; Inflammatory bowel diseases; Multiphoton microscopy; NADH

Neuroblastoma RAS Viral Oncogene Homolog (NRAS) Is a Novel Prognostic Marker and Contributes to Sorafenib Resistance in Hepatocellular Carcinoma - Dietrich, Peter; Gaza, Anne; Wormser, Laura; Fritz, Valerie; Hellerbrand, Claus; Boßerhoff, Anja Katrin (Neoplasia, 2019)
Inhibition of the RAS-RAF-ERK-pathway using sorafenib as a first-line and regorafenib as a second-line treatment approach is the only effective therapeutic strategy for advanced hepatocellular carcinoma (HCC). Recent studies suggest that wild-type KRAS and HRAS isoforms could majorly contribute to HCC progression and sorafenib resistance. In contrast, the role of neuroblastoma RAS viral oncogene homolog (NRAS) in HCC remained elusive. In this study, wild-type NRAS was found to be overexpressed in HCC cell lines, preclinical HCC models, and human HCC tissues. Moreover, NRAS overexpression correlated with poor survival and proliferation in vivo. However, siRNA-pool-mediated NRAS knockdown showed only slight effects on HCC proliferation, clonogenicity, and AKT activity. We determined that KRAS upregulation served as a functional compensatory mechanism in the absence of NRAS, which was overcome by combined inhibition of NRAS and KRAS in HCC cells. Furthermore, NRAS expression was elevated in sorafenib-resistant compared to nonresistant HCC cells, and NRAS knockdown enhanced sorafenib efficacy in resistant cells. In summary, NRAS appears to be a prognostic marker in HCC and contributes to sorafenib resistance. Regarding potential therapeutic strategies, NRAS inhibition in HCC should be combined with KRAS inhibition to prevent KRAS-mediated rescue effects.
CRIS-Team WoS Importer:2019-03-20

Neuroendocrine neoplasms of the small intestine and the appendix - Update of the diagnostic and therapeutic guidelines (recommended by the Polish Network of Neuroendocrine Tumours) Nowotwory neuroendokrynne jelita cienkiego i wyrostka robaczkowego - uaktualnione zasady diagnostyki i leczenia (rekomendowane przez Polską Sieć Guzów Neuroendokrynnych) - Bednarczuk, Tomasz; Zemczak, Anna; Bolanowski, Marek; Borowska, Malgorzata; Chmielik, Ewa; Cwikla, Jaroslaw B.; Foltyn, Wanda; Gisterek, Iwona; Handkiewicz-Junak, Daria; Hubalewska-Dydejczyk, Alicja; Jarzab, Michal; Junik, Roman; et al. (Endokrynologia Polska, 2022)
Updated Polish recommendations for the management of patients with neuroendocrine neoplasms (NENs) of the small intestine (SINENs) and of the appendix (ANENs) are presented herein. The small intestine, and especially the ileum, is one of the most common locations for these neoplasms. Most of them are well-differentiated and slow-growing tumours; uncommonly - neuroendocrine carcinomas. Their symptoms may be untypical, and their diagnosis may be delayed or accidental. Most often, the first manifestation of ANEN is their acute inflammation. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of SINENs patients with distant metastases. In laboratory diagnostics, it is most useful to determine the concentration of chromogranin A (CgA) and assessment of urinary or plasma the 5-hydroxyindoleacetic acid concentration is helpful in the diagnosis of carcinoid syndrome. The most commonly used imaging methods are ultrasound (US) examination, computed tomography (CT), magnetic resonance imaging (MRI), colonoscopy, and somatostatin receptor imaging (SRI). Histopathological examination is crucial for the proper diagnosis and treatment of patients with SINENs and ANENs. The treatment of choice is a surgical procedure, either radical or palliative. Long-acting somatostatin analogues (SSAs) are essential in the medical treatment of functional and non-functional SINENs. In patients with SINENs, at the stage of dissemination with progression during SSAs treatment, with high expression of somatostatin receptors on functional imaging, radioligand therapy should be considered first followed by targeted therapies - everolimus. Recommendations for patient monitoring are also presented.
CRIS-Team Scopus Importer:2022-08-05
Keywords: appendix; carcinoid syndrome; neuroendocrine neoplasms; neuroendocrine tumours; radioligand therapy; recommendations; small intestine; somatostatin analogues; targeted therapies

Neuroendocrine Tumors and Peptide Receptor Radionuclide Therapy: When Is the Right Time? - Hope, Thomas A.; Pavel, Marianne Ellen; Bergsland, Emily K. (Journal of Clinical Oncology, 2022)
Since its approval in 2018 by the US Food and Drug Administration, peptide receptor radionuclide therapy (PRRT) has become a mainstay in the treatment of neuroendocrine tumors. Lutetium-177-DOTATATE, the only approved agent, is indicated for the treatment of gastroenteropancreatic-neuroendocrine tumors. Although patient selection appears straightforward with somatostatin receptor-positron emission tomography, there is considerable complexity when deciding which patients to treat and when to start PRRT. Herein, we review the many factors that affect patient selection, focusing on the optimal patients to treat. Although significant effort has been expended to determine which patients benefit the most from PRRT, a validated predictive biomarker remains elusive. Although PRRT has been used for more than 2 decades in Europe and standards of care exist for safe treatment, there remain numerous questions regarding when PRRT should be used relative to other treatments. It is important to remember that multidisciplinary discussions are essential. Currently, there are a number of ongoing studies looking to assess the efficacy of PRRT compared with other treatment options and to optimize treatment through combination therapy, different dosing strategies, or use of different radionuclides and radioligands.
CRIS-Team WoS Importer:2022-08-26

Neuroendocrine Tumor Treatments and Follow-up Disease Management: Comparative Perspective (US and Canada vs Global) - Kolarova, Teodora; Hollander, Ron; Mcdonnell, Mark; Bouvier, Catherine; Pavel, Marianne Ellen; Singh, Harjit; Howe, James; O'Toole, Dermot; Chen, Jie; Leyden, Simone; Gellerman, Elyse; Dureja, Sugandha; et al. (PANCREAS, 2022)
CRIS-Team WoS Importer:2022-07-15

Neuro-Immune Networks in Gastrointestinal Disorders - Khalil, Mohammad; Zhang, Zehua; Engel, Matthias (Visceral Medicine, 2019)
Tissue homeostasis is controlled by multilateral cell interactions. Established in autoimmune diseases of the central nervous system, growing evidence shows a fundamental role of bidirectional communication between the nervous and immune systems in various gastrointestinal disorders. Primarily the primary sensory nervous system seems to play an important role in this cross talk because of its ability for transducing inflammatory signals and to convey them to the central nervous system, which in turn responds in an efferent manner (gut-brain axis vs. brain-gut axis). Moreover, sensory neurons that play a central role in pain processing immediately respond to inflammatory stimuli through releasing a myriad of immunomodulatory neuropeptides and neurotransmitters whose receptors are expressed in different immune cell populations. Thus, a better understanding of neuro-immune networks will pave the way to novel therapeutic strategies in inflammatory as well as functional gastrointestinal disorders. (C) 2019 S. Karger AG, Basel
CRIS-Team WoS Importer:2019-05-14

Neuropathy in paediatric type 1 diabetes mellitus - Clinical characterization and analysis of risk factors in the diabetes prospective follow-up registry DPV (Diabetes-Patienten-Verlaufsdokumentation)-registry - Pappa, Angeliki; Haeusler, Martin G.; Tittel, Sascha R.; Boettcher, Claudia; Hilgard, Doerte; Knauer-Fischer, Sabine; Pavel, Marianne Ellen; Wölfle, Joachim; Holl, Reinhard W. (Journal of Pediatric Endocrinology & Metabolism, 2023)
Objectives: Data on the prevalence, clinical features and risk factors associated with paediatric diabetic neuropathy (DN) are scarce. Methods: We retrospectively analysed data from the DPV registry, including patients under 20years of age, treated for type 1 diabetes mellitus (T1D) between 2005 and 2021. Patients with non-diabetic neuropathy were excluded. Data came from centres in Austria, Germany, Luxembourg and Switzerland. Results: 1,121 of the 84,390 patients included had been diagnosed with DN. Univariate analysis showed patients with DN to be older and predominantly female, with a longer duration of T1D, higher insulin dosages per kg and day, lower rates of insulin pump therapy, higher postprandial glucose-, higher HbA1c-and higher cholesterol levels, and higher diastolic and systolic blood pressure values. There was also a larger proportion of smokers and higher prevalence of diabetic retinopathy. Median duration of diabetes at diagnosis of DN was 8.3years. Multivariable analysis, adjusted for demographics revealed an increased risk for DN among female patients and those who were older, underweight (BMI-SDS), smoked cigarettes or had a longer duration of T1D or higher levels of HbA1c and postprandial blood glucose. The presence of retinopathy and higher cholesterol levels were also linked to increased risk while not-using insulin pump therapy was not. Conclusions: DN can develop after just a short duration of T1D. Prevention may be achieved by a lowering of HbA1c-and postprandial glucose levels through improved glycaemic control. This warrants further investigation. The slight female predominance suggests further hormonal and genetic etiological factors.
CRIS-Team Scopus Importer:2023-07-07
Keywords: autonomic dysfunction; childhood diabetes; diabetic neuropathy; DPV; small fiber neuropathy; type 1 diabetes mellitus

Neutralizing monoclonal antibodies against SARS-CoV-2 for COVID-19 pneumonia in a rituximab treated patient with systemic sclerosis-A case report and literature review - Yalcin Mutlu, Melek; Taubmann, Jule; Wacker, Jochen; Tascilar, Koray; Fagni, Filippo; Gerner, Maximilian; Klett, Daniel; Schett, Georg; Manger, Bernhard; Simon, David (Frontiers in Medicine, 2022)
Patients with immune-mediated diseases (IMID) such as systemic sclerosis (SSc), who are treated with B cell depleting treatments, are at risk for developing severe COVID-19 due to inadequate humoral immune response. During B cell depletion, therapeutic substitution of neutralizing monoclonal antibodies against the SARS-CoV-2 spike protein (mAbs) might be helpful to prevent severe COVID-19. It has been shown, that in non-IMID patients mABs reduce SARS-CoV-2 viral load and lower the risk of COVID-19 associated hospitalization or death. However, there are limited data on the effect of mAbs in IMID patients after exposure, especially in patients treated with B cell depleting agents. Herein, we report a case of a rituximab treated SSc patient who developed COVID-19 and was successfully treated with a combination of mAbs (casirivimab/imdevimab). With this case we show that IMID patients may benefit from post-exposure administration of mAbs. In our case treatment with neutralizing autoantibodies was safe and a possible contributor in protecting the patient from mechanical ventilation and eventually death. We frame this case within the current evidence from the literature and provide a perspective on the future potential role of mAbs for treating IMID patients suffering from COVID-19.
CRIS-Team WoS Importer:2022-08-26

Neutrophil extracellular traps and DNases orchestrate formation of peritoneal adhesions. - Elrod, Julia; Heuer, Annika; Knopf, Jasmin; Schoen, Janina; Schönfeld, Lavinia; Trochimiuk, Magdalena; Stiel, Carolin; Appl, Birgit; Raluy, Laia Pagerols; Saygi, Ceren; Zlatar, Leticija; Hosari, Sami; et al. (iScience, 2023)
Peritoneal adhesions are poorly understood but highly prevalent conditions that can cause intestinal obstruction and pelvic pain requiring surgery. While there is consensus that stress-induced inflammation triggers peritoneal adhesions, the molecular processes of their formation still remain elusive. We performed murine models and analyzed human samples to monitor the formation of adhesions and the treatment with DNases. Various molecular analyses were used to evaluate the adhesions. The experimental peritoneal adhesions of the murine models and biopsy material from humans are largely based on neutrophil extracellular traps (NETs). Treatment with DNASE1 (Dornase alfa) and the human DNASE1L3 analog (NTR-10), significantly reduced peritoneal adhesions in experimental models. We conclude that NETs serve as essential scaffold for the formation of adhesions; DNases interfere with this process. Herein, we show that therapeutic application of DNases can be employed to prevent the formation of murine peritoneal adhesions. If this can be translated into the human situation requires clinical studies.
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Neutrophil extracellular traps drive epithelial‐mesenchymal transition of human colon cancer - Stehr, Antonia; Wang, Guangxia; Demmler, Richard; Stemmler, Marc; Straube, Julia; Tripal, Philipp; Schmid, Benjamin; Geppert, Carol-Immanuel; Hartmann, Arndt; Munoz, Luis Enrique; Schoen, Janina; Völkl, Simon; et al. (Journal of Pathology, 2021)
Neutrophil extracellular traps (NETs) are extracellular structures, composed of nuclear DNA and various proteins released from neutrophils. Evidence is growing that NETs exert manifold functions in infection, immunity, and cancer. Recently, NETs have been detected in colorectal cancer (CRC) tissues but their association with disease progression and putative functional impact on tumourigenesis remained elusive. Using high-resolution stimulated emission depletion (STED) microscopy we showed that citrullinated histone H3 (H3cit) is sufficient to specifically detect citrullinated NETs in colon cancer tissues. Among other evidence this was supported by the close association of H3cit with de-condensed extracellular DNA, the hallmark of NETs. Extracellular DNA was reliably differentiated from nuclear condensed DNA by staining with an anti-DNA-antibody providing a novel and valuable tool to detect NETs in FFPE tissues. Using these markers, the clinical association of NETs has been investigated in a cohort of 85 patients with colon cancer. NETs were frequently detected (n = 37/n = 85, 44%) in colon cancer tissue sections and preferentially localized either only in the tumour centre or both, in the tumour centre and the invasive front. Of note, citrullinated NETs were significantly associated with high histopathologic tumour grades and lymph node metastasis. In vitro, purified NETs induced filopodia formation and cell motility in CRC cell lines. This was associated with increased expression of mesenchymal marker mRNAs (vimentin [VIM], fibronectin [FN1]) and epithelial- mesenchymal transition (EMT) promoting transcription factors (ZEB1 and Slug [SNAI2]) as well as decreased expression of the epithelial markers E-cadherin (CDH1) and EpCAM (EPCAM). These findings indicated that NETs activate an EMT-like process in CRC cells and may contribute to the metastatic progression of CRC.

Neutrophil Extracellular Traps Form a Barrier between Necrotic and Viable Areas in Acute Abdominal Inflammation - Bilyy, Rostyslav; Fedorov, Volodymyr; Vovk, Volodymyr; Leppkes, Moritz; Dumych, Tetiana; Chopyak, Valentyna; Schett, Georg; Herrmann, Martin (Frontiers in Immunology, 2016)
Neutrophils form neutrophil extracellular traps (NETs) of decondensed DNA and histones that trap and immobilize particulate matter and microbial pathogens like bacteria. NET aggregates reportedly surround and isolate large objects like monosodium urate crystals, which cannot be sufficiently cleared from tissues. In the setting of acute necrotizing pancreatitis, massive tissue necrosis occurs, which is organized as pancreatic pseudocysts (1). In contrast to regular cysts, these pseudocysts are not surrounded by epithelial layers. We hypothesize that, instead, the necrotic areas observed in necrotizing pancreatitis are isolated from the surrounding healthy tissues by aggregated NETs. These may form an alternative, putatively transient barrier, separating necrotic areas from viable tissue. To test this hypothesis, we investigated histological samples from the necropsy material of internal organs of two patients with necrotizing pancreatitis and peritonitis accompanied by multiple organ failure. Tissues including the inflammatory zone were stained with hematoxylin and eosin and evaluated for signs of inflammation. Infiltrating neutrophils and NETs were detected by immunohistochemistry for DNA, neutrophil elastase (NE), and citrullinated histone H3. Interestingly, in severely affected areas of pancreatic necrosis or peritonitis, chromatin stained positive for NE and citrullinated histone H3, and may, therefore, be considered NET-derived. These NET structures formed a layer, which separated the necrotic core from the areas of viable tissue remains. A condensed layer of aggregated NETs, thus, spatially shields and isolates the site of necrosis, thereby limiting the spread of necrosis-associated proinflammatory mediators. We propose that necrotic debris may initiate and/or facilitate the formation of the NET-based surrogate barrier.
EVALuna2:2179

Neutrophil Extracellular Traps Initiate Gallstone Formation - Munoz, Luis Enrique; Boeltz, Sebastian; Bilyy, Rostyslav; Schauer, Christine; Mahajan, Aparna; Widulin, Navena; Grüneboom, Anika; Herrmann, Irmgard; Boada, Edgyda; Rauh, Manfred; Krenn, Veit; Biermann, Mona H.C.; et al. (Immunity, 2019)
The presence of gallstones (cholelithiasis) is a highly prevalent and severe disease and one of the leading causes of hospital admissions worldwide. Due to its substantial health impact, we investigated the biological mechanisms that lead to the formation and growth of gallstones. We show that gallstone assembly essentially requires neutrophil extracellular traps (NETs). We found consistent evidence for the presence of NETs in human and murine gallstones and describe an immune-mediated process requiring activation of the innate immune system for the formation and growth of gallstones. Targeting NET formation via inhibition of peptidyl arginine deiminase type 4 or abrogation of reactive oxygen species (ROS) production, as well as damping of neutrophils by metoprolol, effectively inhibit gallstone formation in vivo. Our results show that after the physicochemical process of crystal formation, NETs foster their assembly into larger aggregates and finally gallstones. These insights provide a feasible therapeutic concept to prevent cholelithiasis in patients at risk.
CRIS-Team Scopus Importer:2019-09-17
Keywords: calcium carbonate crystals; cholesterol crystals; gallstone growth; gallstones; lisosomal leakage; lithogenic diet; neutrophil extracellular traps; neutrophils; NOX2; PADi4

Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones - Schapher, Mirco; Koch, Michael; Weidner, Daniela; Scholz, Michael; Wirtz, Stefan; Mahajan, Aparna; Herrmann, Irmgard; Singh, Jeeshan; Knopf, Jasmin; Leppkes, Moritz; Grüneboom, Anika; Alexiou, Christoph; et al. (Cells, 2020)
Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth.
CRIS-Team Scopus Importer:2020-10-09
Keywords: lithogenesis; neutrophil extracellular traps; neutrophils; salivary glands; salivary stones; sialadenitis; sialolithiasis; stone development; stone growth

Neutrophils and neutrophil extracellular traps orchestrate initiation and resolution of inflammation - Hahn, Jonas; Knopf, Jasmin; Maueröder, Christian; Kienhoefer, D.; Leppkes, M.; Herrmann, Martin (Clinical and Experimental Rheumatology, 2016)
Neutrophils, the most abundant leukocytes in the human body, are considered to be the first line of defense in the fight against microorganisms. In this fight neutrophils employ weaponry such as reactive oxygen species produced via the NADPH oxidase complex 2 together with the release of intracellular granules containing antimicrobial agents. The discovery that activated neutrophils release decondensed chromatin as DNase-sensitive neutrophil extracellular traps (NETs) lead to a renewed interest in these leukocytes and the function of NETs in vivo. In this review, we will focus on desirable as well as detrimental features of NETs by the example of gout and pancreatitis. In our models we observed that neutrophils drive the initiation of inflammation and are required for the resolution of inflammation.
EVALuna2:2175

Neutrophils prevent rectal bleeding in ulcerative colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis - Leppkes, Moritz; Lindemann, Aylin; Goesswein, Stefanie; Paulus, Susanne; Roth, Dominik; Hartung, Anne; Liebing, Eva; Zundler, Sebastian; Gonzalez-Acera, Miguel; Patankar, Jay; Mascia, Fabrizio; Scheibe, Kristina; et al. (Gut, 2021)
Objective Bleeding ulcers and erosions are hallmarks of active ulcerative colitis (UC). However, the mechanisms controlling bleeding and mucosal haemostasis remain elusive. Design We used high-resolution endoscopy and colon tissue samples of active UC (n = 36) as well as experimental models of physical and chemical mucosal damage in mice deficient for peptidyl-arginine deiminase-4 (PAD4), gnotobiotic mice and controls. We employed endoscopy, histochemistry, live-cell microscopy and flow cytometry to study eroded mucosal surfaces during mucosal haemostasis. Results Erosions and ulcerations in UC were covered by fresh blood, haematin or fibrin visible by endoscopy. Fibrin layers rather than fresh blood or haematin on erosions were inversely correlated with rectal bleeding in UC. Fibrin layers contained ample amounts of neutrophils coaggregated with neutrophil extracellular traps (NETs) with detectable activity of PAD. Transcriptome analyses showed significantly elevated PAD4 expression in active UC. In experimentally inflicted wounds, we found that neutrophils underwent NET formation in a PAD4-dependent manner hours after formation of primary blood clots, and remodelled clots to immunothrombi containing citrullinated histones, even in the absence of microbiota. PAD4-deficient mice experienced an exacerbated course of dextrane sodium sulfate-induced colitis with markedly increased rectal bleeding (96 % vs 10 %) as compared with controls. PAD4-deficient mice failed to remodel blood clots on mucosal wounds eliciting impaired healing. Thus, NET-associated immunothrombi are protective in acute colitis, while insufficient immunothrombosis is associated with rectal bleeding. Conclusion Our findings uncover that neutrophils induce secondary immunothrombosis by PAD4-dependent mechanisms. Insufficient immunothrombosis may favour rectal bleeding in UC.
CRIS-Team WoS Importer:2021-12-17

Neutrophils prevent rectal bleeding in Ulcerative Colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis - Leppkes, Moritz; Lindemann, Aylin; Goesswein, S.; Paulus, S.; Roth, Dominik; Hartung, A.; Liebing, Eva; Zundler, Sebastian; Gonzalez Acera, Miguel; Patankar, Jay; Mascia, Fabrizio; Scheibe, Kristina; et al. (JOURNAL OF CROHNS & COLITIS, 2022)
CRIS-Team WoS Importer:2022-05-13

New agents for immunosuppression - Jefremow, André; Neurath, Markus (Best Practice & Research in Clinical Gastroenterology, 2021)
The human abdomen harbors organs that the host's immune system can attack easily. This immunological storm front leads to diseases like Crohn's Disease, Ulcerative Colitis or Autoimmune Hepatitis. Serious symptoms like pain, diarrhea, fatigue, or malnutrition accompany these diseases. Moreover, many patients have an increased risk for developing special kind of malignancies and some autoimmune disease can show a high mortality. The key to treat them consists of a deep understanding of their pathophysiology. In vitro and especially in vivo basic research laid the foundation for our increasing knowledge about it during the past years. This enabled the development of new therapeutic approaches that interact directly with cytokines or immune cells instead of building the treatment on a total immunosuppression. Different kind of antibodies, kinase inhibitors, and regulatory T cells build the base for these approaches. This review shows new therapeutical approaches in gastrointestinal autoimmune diseases in context to their pathophysiological basis.
CRIS-Team Scopus Importer:2021-09-10
Keywords: AIH; Autoimmune diseases; Autoimmune hepatitis; CD; Coeliac disease; Crohn's disease; Immunosuppressive therapy; PBC; PSC; UC; Ulcerative colitis

New findings regarding the neurobiology of pruritus - Pereira, M. P.; Agelopoulos, K.; Kremer, Andreas; Schmelz, M. (Hautarzt, 2018)
Chronic pruritus may arise from different conditions, including dermatological, systemic, neurologic, psychiatric, and psychosomatic diseases, leading to a substantial decrease in the quality of life of affected patients. The neurobiological mechanisms involved in chronic pruritus are not yet fully understood. However, in recent years important achievements have been made in this regard. This article aims to provide an overview of the current understanding of these mechanisms. The complex network of neurons, keratinocytes, inflammatory cells, cytokines, and neurotrophic factors which play a role in the development and maintenance of chronic pruritus are highlighted, as well as the pruritogens involved in pruritic diseases in humans. Additionally, the importance of neuropathy and scratch-induced changes for the pathophysiology of chronic pruritus are discussed. The new findings on the neurobiological mechanisms underlying chronic pruritus have already led to the development of novel therapies, e. g., monoclonal antibodies against specific interleukins, which are important for pruritus transmission. A deeper understanding of the neurobiological mechanisms is necessary in order to develop specifically targeted therapeutic options and thus provide better care for affected patients.
EVALuna2:35152

New targets for mucosal healing and therapy in inflammatory bowel diseases - Neurath, Markus (Mucosal Immunology, 2014)
Healing of the inflamed mucosa (mucosal healing) is an emerging new goal for therapy and predicts clinical remission and resection-free survival in inflammatory bowel diseases (IBDs). The era of antitumor necrosis factor (TNF) antibody therapy was a remarkable progress in IBD therapy and anti-TNF agents led to mucosal healing in a subgroup of IBD patients; however, many patients do not respond to anti-TNF treatment highlighting the relevance of finding new targets for therapy of IBD. In particular, current studies are addressing the role of other anticytokine agents including antibodies against interleukin (IL)-6R, IL-13, and IL-12/IL-23 as well as new anti-inflammatory concepts (regulatory T cell therapy, Smad7 antisense, Jak inhibition, Toll-like receptor 9 stimulation, worm eggs). In addition, blockade of T-cell homing via the integrins ?4?7 and the addressin mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) emerges as a promising new approach for IBD therapy. Here, new approaches for achieving mucosal healing are discussed as well as their implications for future therapy of IBD.
EVALuna2:1787

N-glycosylation Regulates Intrinsic IFN-γ Resistance in Colorectal Cancer: Implications for Immunotherapy - Krug, Julia; Rodrian, Gabriele; Petter, Katja; Yang, Hai; Khoziainova, Svetlana; Guo, Wei; Benard, Alan; Merkel, Susanne; Gellert, Susan; Maschauer, Simone; Spermann, Monika; Waldner, Maximilian; et al. (Gastroenterology, 2023)
Background & AIMS: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored. Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines. Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling. Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC.
CRIS-Team Scopus Importer:2023-02-10
Keywords: Colon Cancer; IFNGR1; Immune Evasion

NLRP3 Inhibition Leads to Impaired Mucosal Fibroblast Function in Patients with Inflammatory Bowel Diseases - Weber, Simone; Sitte, Selina; Vögele, Anna-Lena; Sologub, Ludmilla; Wilfer, Angelika; Rath, Timo; Nägel, Andreas; Zundler, Sebastian; Franchi, Luigi; Opipari, Anthony W.; Sonnewald, Sophia; Reid, Stephen; et al. (Journal of Crohns & Colitis, 2023)
Background and Aims: Inflammatory bowel diseases (IBD) are characterized by mucosal inflammation and sequential fibrosis formation, but the exact role of the hyperactive NLRP3 inflammasome in these processes is unclear. Thus, we studied the expression and function of the NLRP3 inflammasome in the context of inflammation and fibrosis in IBD. Methods: We analysed intestinal NLRP3 expression in mucosal immune cells and fibroblasts from IBD patients and NLRP3-associated gene expression via single-cell RNA sequencing and microarray analyses. Furthermore, cytokine secretion of NLRP3 inhibitor treated blood and mucosal cells, as well as proliferation, collagen production, and cell death of NLRP3 inhibitor treated intestinal fibroblasts from IBD patients were studied. Results: We found increased NLRP3 expression in the inflamed mucosa of IBD patients and NLRP3 inhibition led to reduced IL-1β and IL-18 production in blood cells and diminished the bioactive form of mucosal IL-1β. Single cell analysis identified overlapping expression patterns of NLRP3 and IL-1β in classically activated intestinal macrophages and we also detected NLRP3 expression in CD163+ macrophages. In addition, NLRP3 expression was also found in intestinal fibroblasts from IBD patients. Inhibition of NLRP3 led to reduced proliferation of intestinal fibroblasts, which was associated with a marked decrease in production of collagen type I and type VI in IBD patients. Moreover, NLRP3 inhibition in intestinal fibroblasts induced autophagy, a cellular process involved in collagen degradation. Conclusions: In the presented study, we demonstrate that inhibiting NLRP3 might pave the way for novel therapeutic approaches in IBD, especially to prevent the severe complication of intestinal fibrosis formation.
CRIS-Team Scopus Importer:2023-11-17
Keywords: fibroblasts; fibrosis; IL-18; IL-1β; Inflammatory bowel diseases; mucosal immune system; NLRP3 inflammasome; small molecule inhibitor

Non-celiac disease non-wheat allergy wheat sensitivity - Zopf, Yurdagül; Dieterich, Walburga (Deutsche Medizinische Wochenschrift, 2015)
Non-celiac non-wheat allergy wheat sensitivity is regarded as discrete glutensensitivity diagnosed after the exclusion of celiac disease and wheat allergy. Due to the absence of reliable biomarkers no exact prevalence rates are known and estimations range between 0,5-6 %. Soon after ingestion of wheat, patients complain of intestinal symptoms mainly bloating, abdominal pain, diarrhea or nausea which improve fast under glutenfree diet. Often extraintestinal manifestation as tiredness, muscle or joint pain, headache and depression are reported. Actually, there are no serological markers and no intestinal mucosal damage was found in patients. The underlying mechanism of the disease is completely unknown and beside of gluten other wheat proteins as well as amylase-trypsin-inhibitor or short chain sugars are discussed as triggers. In addition, the involvement of the intestinal microbiome in pathology of glutensensitivity must be considered.
EVALuna2:2023

Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing - Schleier, Lena; Wiendl, Maximilian; Heidbreder, Karin; Binder, Marie Theres; Atreya, Raja; Rath, Timo; Becker, Elisabeth; Schulz-Kuhnt, Anja; Stahl, Annette; Schulze, Lisa; Ullrich, Karen; Merz, Simon F.; et al. (Gut, 2019)
Objective: To study the role of α4β7 integrin for gut homing of monocytes and to explore the biological consequences of therapeutic α4β7 inhibition with regard to intestinal wound healing. Design: We studied the expression of homing markers on monocyte subsets in the peripheral blood and on macrophage subsets in the gut of patients with IBD and controls with flow cytometry and immunohistochemistry. Integrin function was addressed with dynamic adhesion assays and in vivo gut homing assays. In vivo wound healing was studied in mice deficient for or depleted of α4β7 integrin. Results: Classical and non-classical monocytes were clearly dichotomous regarding homing marker expression including relevant expression of α4β7 integrin on human and mouse non-classical monocytes but not on classical monocytes. Monocyte-expressed α4β7 integrin was functionally important for dynamic adhesion to mucosal vascular addressin cell adhesion molecule 1 and in vivo gut homing. Impaired α4β7-dependent gut homing was associated with reduced (effect size about 20%) and delayed wound healing and suppressed perilesional presence of wound healing macrophages. Non-classical monocytes in the peripheral blood were increased in patients with IBD under clinical treatment with vedolizumab. Conclusion: In addition to reported effects on lymphocytes, anti-α4β7 therapy in IBD also targets non-classical monocytes. Impaired gut homing of such monocytes might lead to a reduction of wound healing macrophages and could potentially explain increased rates of postoperative complications in vedolizumab-treated patients, which have been observed in some studies.
CRIS-Team Scopus Importer:2019-05-28
Keywords: Crohn's disease; gut immunology; inflammatory bowel disease; surgery for IBD; ulcerative colitis

Non-dermatological challenges of chronic itch - Kremer, Andreas; Mettang, Thomas; Weisshaar, Elke (Acta Dermato-Venereologica, 2020)
Chronic itch occurs in many skin diseases, but also in a variety of systemic, neurological, and psychogenic/ psychosomatic disorders, or is caused by drug intake. When several diseases or causes co-exist, chronic itch is categorized as “mixed origin”. These patients present with unaltered skin or with chronic scratch lesions including chronic prurigo. Precise diagnostics are necessary to evaluate the underlying aetiology, to enable identification of the best treatment available, and to improve patients’ quality of life. This is of particular relevance in elderly people in whom chronic itch is often of systemic or mixed origin. Xerosis cutis is a frequent cofactor contributing to chronic itch of non-dermatological origin. Treatment is frequently multi-modal, considering age, comorbidities, current drug intake, quality and intensity of itch. With regard to the demographic situation of the population, characterized by increasing life expectancy and polypharmacy, itch of non-dermatological origin will represent an increasing medical challenge in the future.
CRIS-Team Scopus Importer:2020-01-24
Keywords: Cholestasis; Chronic kidney disease; Liver; Pruritus; Systemic disease; Uraemic itch

Non-invasive assessment of intestinal inflammatory activity in Ulcerative Colitis by Multispectral Optoacoustic Tomography (MSOT) - Klett, Daniel; Jesper, D.; Vitali, Francesco; Federle, Anna; Atreya, Raja; Strobel, Deike; Leppkes, Moritz; Neufert, Clemens; Rath, Timo; Neurath, Markus; Waldner, Maximilian (JOURNAL OF CROHNS & COLITIS, 2022)
CRIS-Team WoS Importer:2022-05-13

NON-INVASIVE IN VIVO METABOLIC PROFILING OF INFLAMMATION IN JOINTS AND ENTHESES BY OPTOACOUSTIC IMAGING - Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Bayat, Sara; Heidemann, Robert; Steiger, F.; Krönke, Gerhard; Bohr, D.; Ramming, Andreas; Hartmann, F.; Klett, Daniel; Federle, Anna; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Non-invasive metabolic profiling of inflammation in joints and entheses by multispectral optoacoustic tomography - Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Bayat, Sara; Heidemann, Robert; Steiger, Florian; Krönke, Gerhard; Bohr, Daniela; Ramming, Andreas; Hartmann, Fabian; Klett, Daniel; Federle, Anna; et al. (Rheumatology, 2022)
Objective To explore the metabolic characteristics of arthritis and enthesitis using multispectral opto-acoustic tomography (MSOT), a technology using near-infrared multispectral laser to stimulate tissues and detect the emitted acoustic energy, enabling non-invasive quantification of tissue components in vivo based on differential absorbance at multiple wavelengths. Methods We performed a cross-sectional study in patients with RA or PsA and healthy controls (HCs). Participants underwent clinical, ultrasonographic and MSOT examination of MCP and wrist joints as well as the entheses of the common extensor tendon at the lateral humeral epicondyles and of the patellar, quadriceps and Achilles tendon. MSOT-measured haemoglobin (Hb), oxygen saturation, collagen and lipid levels were quantified and scaled mean differences between affected and unaffected joints and entheses were calculated as defined by clinical examination or ultrasonography using linear mixed effects models. Results We obtained 1535 MSOT and 982 ultrasonography scans from 87 participants (34 PsA, 17 RA, 36 HCs). Entheseal tenderness was not associated with significant metabolic changes, whereas enthesitis-related sonographic changes were associated with increased total Hb, oxygen saturation and collagen content. In contrast, the presence of arthritis-related clinical and sonographic findings showed increased Hb levels, reduced oxygen saturation and reduced collagen content. Synovial hypertrophy was associated with increased lipid content in the joints. Conclusion MSOT allows determination of distinct metabolic differences between arthritis and enthesitis in a non-invasive setting in humans in vivo.
CRIS-Team WoS Importer:2022-07-22

Non-professional phagocytosis: a general feature of normal tissue cells - Seeberg, Jacob; Loibl, Monika; Moser, Fabian; Schwegler, Manuela; Büttner-Herold, Maike; Daniel, Christoph; Engel, Felix; Hartmann, Arndt; Schlötzer-Schrehardt, Ursula; Goppelt-Strübe, Margarete; Schellerer, Vera; Naschberger, Elisabeth; et al. (Scientific Reports, 2019)
Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells.
CRIS-Team Scopus Importer:2019-08-27

Normalisation of biomarkers and improvement in clinical outcomes in patients with Crohn's Disease treated with risankizumab in the phase 3 ADVANCE, MOTIVATE, and FORTIFY studies - Atreya, Raja; Feagan, B.; Shchukina, O.; Jairath, V.; Rieder, F.; Hisamatsu, T.; Siegmund, B.; Rizzo, J.; Kligys, K.; Neimark, E.; Song, A.; Zambrano, J.; et al. (JOURNAL OF CROHNS & COLITIS, 2022)
CRIS-Team WoS Importer:2022-05-13

Normal values for body composition in adults are better represented by continuous reference ranges dependent on age and BMI - Enderle, Janna; Reljic, Dejan; Jensen, Björn; Peine, Sven; Zopf, Yurdagül; Bosy-Westphal, Anja (Clinical Nutrition, 2023)
Background & aims: Reference values for body composition parameters like skeletal muscle mass index (SMI) depend on age and BMI. To ensure reference intervals reflect these changes, they have traditionally been separated into groups of young adults based on sex and BMI. However, this static stratification oversimplifies the dynamic and gradual changes of body composition with increasing age and BMI. The aim was therefore to provide continuous reference ranges for body composition parameters. Methods: Cross-sectional data of 1958 healthy men and women with an age between 18 and 97 years and a BMI between 17.1 und 45.6 kg/m2 were obtained between 2011 and 2019. Multiple regression analyses stratified by sex with age, age2 and BMI as independent variables were conducted to predict fat mass index (FMI), visceral adipose tissue (VAT), SMI, appendicular lean soft tissue index (ALSTI) and the ratio between extracellular to total body water (ECW/TBW). Results: The regression models explained between 61 (VAT in women and ALSTI in men) and 93% of the variance in the respective body composition parameters (FMI in women). Age had only a minor impact (2–16%) whereas BMI substantially increased the explained variance of reference models for FMI, VAT and ALSTI (total explained variance 61–93%). In SMI, age is a major determinant of the explained variance (36% in men and 38% in women) with BMI equally contributing to the explained variance (total explained variance 72% in men and 75% in women). For ECW/TBW-ratio, age nearly completely explained the variance (79% in men and 74% in women) whereas BMI added only 2–3% to the explained variance. Conclusions: In conclusion, the derived continuous reference ranges are expected to improve body composition evaluation especially in very overweight and very old persons. Future studies applying these reference equations need to validate these assumptions. Study registration, clinicaltrials.gov: NCT01368640, NCT01481285, NCT03779932, NCT 04028648.
CRIS-Team Scopus Importer:2023-03-24
Keywords: Age; Bioelectrical impedance analysis; BMI; Body composition; Reference ranges

Norovirus triggered microbiota-driven mucosal inflammation in interleukin 10-deficient mice - Basic, Marijana; Keubler, Lydia M.; Buettner, Manuela; Achard, Marcel; Breves, Gerhard; Schroeder, Bernd; Smoczek, Anna; Joerns, Anne; Wedekind, Dirk; Zschemisch, Nils H.; Günther, Claudia; Neumann, Detlef; et al. (Inflammatory Bowel Diseases, 2014)
Infection may trigger clinically overt mucosal inflammation in patients with predisposition for inflammatory bowel disease. However, the impact of particular enteropathogenic microorganisms is ill-defined. In this study, the influence of murine norovirus (MNV) infection on clinical, histopathological, and immunological features of mucosal inflammation in the IL10-deficient (Il10) mouse model of inflammatory bowel disease was examined.C57BL/6J and C3H/HeJBir wild-type and Il10 mice kept under special pathogen-free conditions and devoid of clinical and histopathological signs of mucosal inflammation were monitored after MNV infection for structural and functional intestinal barrier changes by in situ MNV reverse transcription PCR, transgene reporter gene technology, histology, flux measurements, quantitative real-time PCR, immunohistology, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. In addition, the influence of the enteric microbiota was analyzed in MNV-infected germfree Il10 mice.Although MNV-infected wild-type mice remained asymptomatic, mucosal inflammation was noted in previously healthy Il10 mice 2 to 4 weeks after infection. MNV-induced changes in Il10 mice included increased paracellular permeability indicated by increased mucosal mannitol flux, reduced gene expression of tight junction molecules, and an enhanced rate of epithelial apoptosis. MNV-induced reduction of tight junction protein expression and inflammatory lesions were absent in germfree Il10 mice, whereas epithelial apoptosis was still observed.Despite its subclinical course in wild-type animals, MNV causes epithelial barrier disruption in Il10 animals representing a potent colitogenic stimulus that largely depends on the presence of the enteric microbiota. MNV might thus trigger overt clinical disease in individuals with a nonsymptomatic predisposition for inflammatory bowel disease by impairment of the intestinal mucosa.
EVALuna2:1852

norUrsodeoxycholic acid (norUDCA) improves non-alcoholic fatty liver disease (NAFLD): Results from a randomized placebo-controlled, double-blind phase IIa study - Traussnigg, Stefan; Schattenberg, Jorn M.; Demir, Muenevver; Wiegand, Johannes; Geier, Andreas; Teuber, Gerlinde; Hofmann, Wolf Peter; Kremer, Andreas; Spreda, Frank; Kluwe, Johannes; Petersen, Joerg; Boettler, Tobias; et al. (2017)
EVALuna2:33892

Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial - Traussnigg, Stefan; Schattenberg, Jörn M.; Demir, Münevver; Wiegand, Johannes; Geier, Andreas; Teuber, Gerlinde; Hofmann, Wolf Peter; Kremer, Andreas; Spreda, Frank; Kluwe, Johannes; Petersen, Jörg; Boettler, Tobias; et al. (Lancet Gastroenterology and Hepatology, 2019)
Background: Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease. Methods: We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial in tertiary referral hospitals and medical centres in Austria (n=6) and Germany (n=23) for patients with non-alcoholic fatty liver disease with or without diabetes. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and serum alanine aminotransferase (ALT) concentrations of more than 0·8 times the upper limit of normal were randomly assigned (1:1:1) using a computer-generated central randomisation. Patients were randomly assigned to receive either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks with a subsequent 4-week follow-up period. All individuals involved in the trial were masked to treatment allocation. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment assessed in the intention-to-treat population. This trial is registered with EudraCT, number 2013-004605-38. Findings: Between March 30, 2015, and Sept 20, 2016, of 198 individuals included in the analysis, 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. 112 treatment-emergent adverse events occurred in the 1500 mg group, 99 in the 500 mg group, and 103 in the placebo group. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis). Interpretation: Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated encouraging further studies. Funding: Dr Falk Pharma GmbH.
CRIS-Team Scopus Importer:2019-08-02

Novel imaging modalities for immune cell monitoring in the intestine - Atreya, Raja; Neurath, Markus (Current Opinion in Gastroenterology, 2014)
The introduction of novel molecular imaging modalities that can not only define disease states on the basis of structural changes and morphology, but also allow in-vivo visualization and characterization of molecular and biochemical alterations on a cellular level add a new dimension to our current diagnostic possibilities. The advents of innovative endoscopic devices coupled with the introduction of novel targeting ligands contribute to the recent advances made in the field of molecular imaging. The purpose of this review is to present and discuss the concepts and the potential of novel endoscopic imaging modalities for immune cell monitoring in the intestine.Recent progress concerning molecular imaging studies in animals and human patients implicates that this approach can be used to improve detection of mucosal lesions in wide-field imaging and for in-vivo characterization of the mucosa with the ultimate goal of assessing the likelihood of response to targeted therapy with biological agents. In particular, molecular endomicroscopy for assessment of mucosal immune responses ('immunoendoscopy') emerges as a novel approach for optimized endoscopic diagnosis and individualized therapy.Molecular imaging modalities in the intestine have the immediate potential to have an impact on current clinical practice and could therefore open new frontiers for clinical endoscopy and give hope for improved diagnosis and targeted therapies.
EVALuna2:1881

Novel Insights into the Mechanisms of Gut Homing and Antiadhesion Therapies in Inflammatory Bowel Diseases - Zundler, Sebastian; Neurath, Markus (Inflammatory Bowel Diseases, 2017)
Therapeutic compounds interfering with T cell trafficking are a new column of inflammatory bowel disease (IBD) treatment. Currently, the anti-α4β7 integrin antibody vedolizumab is successfully used in the clinic and further drugs are likely to follow. Despite these clinical advances, the precise mechanistic background of their action is only gradually elucidated and still a matter of intensive research. Only recently, advances made with the help of new in vivo models and human studies have contributed to shape our concept of T cell trafficking in IBD by deciphering some important and so far unanswered questions. At the same time, basic and clinical data have generated new issues to be addressed on the way toward a clear perception of trafficking mechanisms and toward elucidation of the action of compounds interfering with this process. In this review, we will give a comprehensive outline of all components of T cell trafficking in regard to IBD before discussing the current knowledge concerning targeted interference with integrins in this complex network. Moreover, we will summarize remaining ambiguity and give an outlook on potential future targets.
EVALuna2:33819

Novel Small Molecules in IBD: Current State and Future Perspectives - Jefremow, André; Neurath, Markus (Cells, 2023)
Biologicals have dominated the therapeutic scenery in inflammatory bowel diseases (IBDs), namely ulcerative colitis (UC) and Crohn’s disease (CD), for the past 20 years. The development of tofacitinib was the starting point for an era of small molecules after the era of biologicals. These new agents may challenge the use of biological agents in the future. They share properties that appeal to both patients and physicians. Low production costs, a lack of immunogenicity, and ease of use are only some of their benefits. On the other hand, patients and their physicians must manage the potential side effects of small molecules such as JAK inhibitors or S1P1R modulators. Here, we present agents that have already entered the clinical routine and those that are still being investigated in clinical trials.
CRIS-Team Scopus Importer:2023-07-28
Keywords: Crohn’s; inflammatory bowel diseases; JAK; small molecular drugs; small molecules; ulcerative colitis

Novel T cell/organoid culture system allows ex vivo modeling of intestinal graft-versus-host disease - Matthe, Diana; Dinkel, Martin; Schmid, Benjamin; Vogler, Tina; Neurath, Markus; Poeck, Hendrik; Neufert, Clemens; Büttner-Herold, Maike; Hildner, Kai (Frontiers in Immunology, 2023)
Acute graft-versus-host disease (GvHD) remains the biggest clinical challenge and prognosis-determining complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Donor T cells are acceptedly key mediators of alloreactivity against host tissues and here especially the gut. In support of previous studies, we found that the intestinal intra-epithelial lymphocyte (IEL) compartment was dynamically regulated in the course of MHC class I full mismatch allo-HSCT. However, while intestinal epithelial cell (IEC) damage endangers the integrity of the intestinal barrier and is a core signature of intestinal GvHD, the question whether and to what degree IELs are contributing to IEC dysregulation is poorly understood. To study lymphoepithelial interaction, we employed a novel ex vivo T cell/organoid co-culture model system. Here, allogeneic intra-epithelial T cells were superior in inducing IEC death compared to syngeneic IEL and allogeneic non-IEL T cells. The ability to induce IEC death was predominately confined to TCRβ+ T cells and was executed in a largely IFNγ-dependent manner. Alloreactivity required a diverse T cell receptor (TCR) repertoire since IELs genetically modified to express a TCR restricted to a single, non-endogenous antigen failed to mediate IEC pathology. Interestingly, minor histocompatibility antigen (miHA) mismatch was sufficient to elicit IEL-driven IEC damage. Finally, advanced live cell imaging analyses uncovered that alloreactive IELs patrolled smaller areas within intestinal organoids compared to syngeneic controls, indicating their unique migratory properties within allogeneic IECs. Together, we provide here experimental evidence for the utility of a co-culture system to model the cellular and molecular characteristics of the crosstalk between IELs and IEC in an allogeneic setting ex vivo. In the light of the emerging concept of dysregulated immune-epithelial homeostasis as a core aspect of intestinal GvHD, this approach represents a novel experimental system to e.g. screen therapeutic strategies for their potential to normalize T cell/IEC- interaction. Hence, analyses in pre-clinical in vivo allo-HSCT model systems may be restricted to hereby positively selected, promising approaches.
CRIS-Team Scopus Importer:2023-09-22
Keywords: allogeneic hematopoietic stem cell transplantation; alloreactive T cell; epithelial cell death; ex vivo model; graft-versus-host disease; GvHD; intestinal organoids; intraepithelial lymphocytes

Novel therapeutic approaches in inflammatory bowel diseases - Atreya, Raja; Neurath, Markus (Deutsche Medizinische Wochenschrift, 2016)
Increasing knowledge regarding the immunopathogenesis of IBD has led to the development or approval of novel therapeutic agents for the treatment of Crohn's disease or ulcerative colitis. The new substances for example include antibodies against IL-12 / 23, anti-adhesion molecules and antisense oligonucleotides. The increase of therapeutic options will lead to a change of currently used therapeutic algorithms. Biomarkers to ensure a more individualized therapeutic approach are urgently needed to improve an efficient therapy of IBD patients.
EVALuna2:2198

Nr4a1-dependent non-classical monocytes are important for macrophage-mediated wound healing in the large intestine - Heidbreder, Karin; Sommer, Katrin; Wiendl, Maximilian; Müller, Tanja; Atreya, Imke; Hildner, Kai; Neurath, Markus; Zundler, Sebastian (Frontiers in Immunology, 2023)
Introduction: Macrophages play an important role in intestinal wound healing. However, the trajectories from circulating monocytes to gut macrophages are incompletely understood. Methods: Taking advantage of mice depleted for non-classical monocytes due to deficiency for the transcription factor Nr4a1, we addressed the relevance of non-classical monocytes for large intestinal wound healing using flow cytometry, in vivo wound healing assays and immunofluorescence. Results: We show that wound healing in Nr4a1-deficient mice is substantially delayed and associated with reduced peri-lesional presence of macrophages with a wound healing phenotype. Discussion: Our data suggest that non-classical monocytes are biased towards wound healing macrophages. These insights might help to understand, how targeting monocyte recruitment to the intestine can be used to modulate intestinal macrophage functions.
CRIS-Team Scopus Importer:2023-02-10
Keywords: gut homing; intestinal wound healing; macrophages; monocytes; Nr4a1 (Nur77)

Nuclear factor of activated T cells - a transcription factor family as critical regulator in lung and colon cancer - Daniel, Carolin; Gerlach, Katharina; Vaeth, Martin; Neurath, Markus; Weigmann, Benno (International Journal of Cancer, 2014)
Nuclear factor of activated T cells (NFAT) was first identified as a transcription factor which is activated upon T cell stimulation. Subsequent studies uncovered that a whole family of individual NFAT proteins exists with pleiotropic functions not only in immune but also in nonimmune cells. However, dysregulation of NFAT thereby favors malignant growth and cancer. Summarizing the recent advances in understanding how individual NFAT factors regulate the immune system, this review gives new insights into the critical role of NFAT in cancer development with special focus on inflammation-associated colorectal cancer.
EVALuna2:1902

Nutritional Status and Body Composition of Patients with Glioblastomas - Reljic, Dejan; Herrmann, Joachim; Neurath, Markus; Zopf, Yurdagül (INTERNIST, 2019)
CRIS-Team WoS Importer:2019-05-17

Nutrition and sports in cancer - What should we consider? - Zopf, Yurdagül; Herrmann, Hans Joachim; Neurath, Markus; Reljic, Dejan (gynäkologische praxis, 2019)
In cancer, various inflammatory and disease-related processes typically lead to muscle mass loss. Muscle wasting is associated with a reduction in physical performance and quality of life and may affect the tolerability of anticancer therapy. In order to compensate the increased protein turnover and to counteract the progression of muscle breakdown or to reactivate muscle building, respectively, a high-protein diet is recommended. Physical exercise is another crucial component in the multimodal treatment of cancer cachexia with the aim of improving muscle mass, physical performance, and metabolism. The additional anabolic stimulus provided by physical exercise, especially strength training, can effectively support the maintenance of muscle mass and functional capacity during oncologic therapy. Time-efficient exercise interventions are recommended because they can be better integrated into the overall oncologic therapy regimen and thus increase patient compliance. In sum, current data suggest that the combination of an individualized, protein-rich nutritional therapy and targeted physical exercise can have synergistic effects on stabilizing or improving nutritional and performance status. This can positively affect the quality of life of patients.
CRIS-Team Scopus Importer:2021-04-20
Keywords: Cancer cachexia; Exercise; Inflammation; Muscle wasting; Nutrition; Protein intake; Supportive cancer therapy

OBETICHOLIC ACID TREATMENT IS ASSOCIATED WITH IMPROVED COLLAGEN MORPHOMETRY IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS - Kremer, Andreas; Bowlus, Christopher L.; Bedossa, Pierre; Pares, Albert; Forman, Lisa M.; Drenth, Joost P. H.; Ryder, Stephen; Terracciano, Luigi; Jin, Yuying; Liberman, Alexander; Pencek, Richard; Macconell, Leigh; et al. (GUT, 2019)
CRIS-Team WoS Importer:2020-04-14

Octreotide SC depot in patients with acromegaly and functioning neuroendocrine tumors: a phase 2, multicenter study - Pavel, Marianne Ellen; Borson-Chazot, Francoise; Cailleux, Anne; Hoersch, Dieter; Lahner, Harald; Pivonello, Rosario; Tauchmanova, Libuse; Darstein, Christelle; Olsson, Hakan; Tiberg, Fredrik; Ferone, Diego (Cancer Chemotherapy and Pharmacology, 2019)
PurposeOctreotide SC depot is a novel, ready-to-use formulation administered via a thin needle. In a phase 1 study in healthy volunteers, this formulation provided higher bioavailability of octreotide with faster onset and stronger suppression of IGF-1 in healthy volunteers versus long-acting intramuscular (IM) octreotide. This phase 2 study evaluated the pharmacokinetics, efficacy, and safety of octreotide SC depot in patients with acromegaly and functioning NETs, previously treated with octreotide IM.MethodsAdult patients with acromegaly or functioning NETs treated for 2 months with octreotide IM [10/20/30mg every 4 weeks (q4w)] received the last dose of octreotide IM treatment in study period 0 and were randomized 28 days later to receive octreotide SC depot 10mg q2w, or 20mg q4w for 3 months (period 1). The primary objective was to characterize the PK profile of octreotide SC depot after each injection vs PK for octreotide IM (period 0).ResultsTwelve patients were randomized to receive octreotide SC depot 10mg q2w (acromegaly n=3; NET n=1) or 20mg q4w (acromegaly n=4; NET n=4). Plasma levels of octreotide were higher with octreotide SC depot as compared to octreotide IM. Adverse events were reported in 6 and 8 patients during period 0 and period 1, respectively; most common in period 1 were gastrointestinal disorders.ConclusionOctreotide SC depot provided higher exposure (AUC) than octreotide IM, maintained biochemical control in patients with acromegaly and symptom control in patients with functioning NETs, and was well tolerated with a safety profile consistent with octreotide IM.ClinicalTrials.gov identifierNCT02299089.
CRIS-Team WoS Importer:2019-03-08

Oligonucleotides-A Novel Promising Therapeutic Option for IBD - Scarozza, Patrizio; Schmitt, Heike; Monteleone, Giovanni; Neurath, Markus; Atreya, Raja (Frontiers in Pharmacology, 2019)
Inflammatory Bowel Diseases (IBD), whose denomination comprehends Crohn's Disease (CD) and Ulcerative Colitis (UC), are intestinal chronic diseases that often require lifelong medical therapy. In the last two decades monoclonal antibodies against the cytokine TNF have become integral parts in the treatment of IBD patients, however there are unwanted side-effects and one third of patients show primary non-response while another subgroup loses response over time. Finding novel drugs which could act as therapies against precise pro-inflammatory molecular targets to avoid unwanted systemic side effects and additionally the process of immunization, represents an important aim for subsequent therapeutic approaches. Oligonucleotide based therapies represent a promising novel concept for the treatment of IBD. The molecular action of oligonucleotides ranges from inhibition of the translational process of mRNA transcripts of pro-inflammatory molecules, to mimicking bacterial DNA which can activate cellular targets for immunomodulation. Alicaforsen, selectively targets ICAM-1 mRNA. ICAM-1 is an adhesion molecule which is upregulated on endothelial cells during IBD, thereby mediating the adhesion and migration of leucocytes from blood to sites of active inflammation. In CD parenteral application of alicaforsen did not show therapeutic efficacy in phase II trials, but it demonstrated an improved efficacy as a topical enema in distal UC. Topical application of alicaforsen might represent a therapeutic perspective for refractory pouchitis as well. SMAD7 is a protein that inhibits the signaling of TGF beta, which is the mainstay of a regulatory counterpart in cellular immune responses. An antisense oligonucleotide against SMAD7 mRNA (mongersen) demonstrated pre-clinical and phase II efficacy in CD, but a phase III clinical trial was stopped due to lack of efficacy. Cobitolimod is a single strand oligonucleotide, which mimics bacterial DNA as its CpG dinucleotide sequences can be recognized by the Toll-like receptor 9 on different immune cells thereby causing induction of different cytokines, for example IL10 and IFN alpha. Topical application of cobitolimod was studied in UC patients. We will also discuss two other novel oligonucleotides which act on the GATA3 transcription factor (SB012) and on carbohydrate sulfotransferase 15 (STNM01), which could both represent novel promising therapeutic options for the treatment of UC.
CRIS-Team WoS Importer:2019-05-09

Optical diagnosis of colorectal polyps with Blue Light Imaging using a new international classification - Subramaniam, Sharmila; Hayee, Bu; Aepli, Patrick; Schoon, Erik; Stefanovic, Milan; Kandiah, Kesavan; Thayalasekaran, Sreedhari; Alkandari, Asma; Bassett, Paul; Coron, Emmanuel; Pech, Oliver; Hassan, Cesare; et al. (United European Gastroenterology Journal, 2019)
Background Blue Light Imaging (BLI) is a new imaging technology that enhances mucosal surface and vessel patterns. A specific BLI classification was recently developed to enable better characterisation of colorectal polyps (BLI Adenoma Serrated International Classification (BASIC)). The aim of this study was to validate the diagnostic performance of BASIC in predicting polyp histology in experienced and trainee endoscopists. Methods Five experienced and five trainee endoscopists evaluated high-definition white light (HDWL) and BLI images from 45 small polyps to assess baseline accuracy, sensitivity, specificity, and positive and negative predictive values (NPVs) of polyp histology. Each endoscopist was trained with the BLI classification before repeating the exercise. Results were compared pre- and post-training. Results The overall pre-training accuracy improved from 87% to 94%. The sensitivity and NPV of adenoma diagnosis also improved significantly from 79% to 96% and 81% to 95% with BASIC training. This improvement was noted in both groups. The interobserver level of agreement was very good (K = 0.90) in the experienced cohort and good (K = 0.66) in the trainee group post-training. Conclusions BLI is a useful tool for optical diagnosis, and the use of BASIC with adequate training can significantly improve the accuracy, sensitivity and NPV of adenoma diagnosis.
CRIS-Team WoS Importer:2019-03-20

Optimized imaging of the lower abdomen and pelvic region in hepatocyte-specific MRI: evaluation of a whole-abdomen first-pass shuttle protocol in patients with neuroendocrine neoplasms - Fehrenbach, Uli; Kahn, Johannes; Fahlenkamp, Ute; Baur, Alexander; Pavel, Marianne Ellen; Geisel, Dominik; Denecke, Timm (Acta Radiologica, 2019)
Background Gadoxetic acid (Gd-EOB) has shown its advantages in hepatic tumor evaluation besides its disadvantages in extrahepatic staging due to its short hemodynamic interval. This results in the dilemma of which contrast agent to choose for whole abdominal magnetic resonance imaging (MRI). Purpose To evaluate the achievable contrast of a shuttle protocol for Gd-EOB MRI with accelerated 3D-T1-weighted sequences enabling complete dynamic liver imaging plus first-pass pelvic imaging. Material and Methods Seventy-four patients with abdominal neuroendocrine neoplasms were scanned with a protocol including a first-pass pelvic (pelvic(FP)) sequence in Gd-EOB MRI. Acquisition of this pelvic(FP) sequence was between portal venous and venous liver phase. Pelvic vessel and tissue enhancement was compared to a commonly acquired late/transitional phase sequence. In the same patients, liver enhancement was compared to a standard Gd-EOB protocol (n = 55) as well as to vessel contrast in previously acquired MRI with extracellular contrast medium (ECCM) (n = 14). Results Pelvic vessel and lymph node enhancement showed significantly higher signal intensities (SI) in pelvic(FP) than in late phase sequences with Gd-EOB (P < 0.001). Liver enhancement showed no significant differences compared to the standard protocol. Vessel enhancement in Gd-EOB pelvic(FP) showed significantly higher SI than an equilibrium phase sequence with ECCM (P = 0.003-0.04). Conclusion Including a pelvic(FP) sequence between portal venous and venous liver phases is technically feasible and achieves improved contrast in the pelvis in Gd-EOB MRI. There was no quality loss in liver enhancement compared to a regular Gd-EOB liver examination. Gd-EOB pelvic(FP) vessel enhancement was not inferior to an equilibrium phase with ECCM.
CRIS-Team WoS Importer:2019-08-27

Optoacoustic Imaging in Inflammation - Regensburger, Adrian; Brown, Emma; Krönke, Gerhard; Waldner, Maximilian; Knieling, Ferdinand (Biomedicines, 2021)
Optoacoustic or photoacoustic imaging (OAI/PAI) is a technology which enables non-invasive visualization of laser-illuminated tissue by the detection of acoustic signals. The combination of "light in" and "sound out" offers unprecedented scalability with a high penetration depth and resolution. The wide range of biomedical applications makes this technology a versatile tool for preclinical and clinical research. Particularly when imaging inflammation, the technology offers advantages over current clinical methods to diagnose, stage, and monitor physiological and pathophysiological processes. This review discusses the clinical perspective of using OAI in the context of imaging inflammation as well as in current and emerging translational applications.
CRIS-Team WoS Importer:2021-06-04

Organoids in gastrointestinal diseases: from experimental models to clinical translation - Günther, Claudia; Winner, Beate; Neurath, Markus; Stappenbeck, Thaddeus S. (Gut, 2022)
We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct therapies. We predict that the most valuable data will be produced by systems that are highly dynamic in both time and space. Three-dimensional (3D) organoids are poised to be such a highly valuable system for a variety of gastrointestinal (GI) diseases. In the lab, organoids have emerged as powerful systems to model molecular and cellular processes orchestrating natural and pathophysiological human tissue formation in remarkable detail. Preclinical studies have impressively demonstrated that these organs-in-a-dish can be used to model immunological, neoplastic, metabolic or infectious GI disorders by taking advantage of patient-derived material. Technological breakthroughs now allow to study cellular communication and molecular mechanisms of interorgan cross-talk in health and disease including communication along for example, the gut-brain axis or gut-liver axis. Despite considerable success in culturing classical 3D organoids from various parts of the GI tract, some challenges remain to develop these systems to best help patients. Novel platforms such as organ-on-a-chip, engineered biomimetic systems including engineered organoids, micromanufacturing, bioprinting and enhanced rigour and reproducibility will open improved avenues for tissue engineering, as well as regenerative and personalised medicine. This review will highlight some of the established methods and also some exciting novel perspectives on organoids in the fields of gastroenterology. At present, this field is poised to move forward and impact many currently intractable GI diseases in the form of novel diagnostics and therapeutics.
CRIS-Team WoS Importer:2022-06-17
Keywords: gastrointestinal pathology; gastrointestinal physiology; intestinal stem cell; stem cells

Osteonecrosis of the jaw in a Crohn's disease patient following a course of Bisphosphonate and Adalimumab therapy: a case report - Preidl, Raimund; Ebker, Tobias; Raithel, Martin; Wehrhan, Falk; Neukam, Friedrich Wilhelm; Stockmann, Philipp (BMC Gastroenterology, 2014)
Bisphosphonates have a widespread indication for osteoporosis and are also applied in cancer patients with skeletal-related conditions. Bisphosphonate-associated osteonecrosis of the jaw (BRONJ) is a feared side effect which is hard to treat and often affects patient´s quality of life in an extensive manner. Adalimumab (Humira®), a fully human recombinant antibody specific for tumor necrosis factor- ?, is approved for treatment in patients with Inflammatory Bowel Disease like ulcerative colitis or Crohn's disease.In March 2013, a 36-year-old female presented with right-sided perimandibular swelling, recurrent facial pain and exposed necrotic bone after previous extraction of tooth 47. She had the medical history of Crohn's disease for more than one decade with chronic active enterocolitis, fistula disease as well as previous oral manifestation and was currently treated with Adalimumab since September 2008. Due to steroid-induced osteoporosis, diagnosed in 2004, she received oral Bisphosphonates (Risedronate) from 2004 until 2007 followed by two infusions of Zoledronic acid in 2008 and 2009.This patient with a medical history of Crohn's disease and gastrointestinal remission under Adalimumab therapy presented with osteonecrosis of the jaw after suspended oral and intravenous Bisphosphonate therapy implicating that the biologic therapy with an anti-TNF-? antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity.
EVALuna2:1730

Outcome analysis of liver stiffness by ARFI (acoustic radiation force impulse) elastometry in patients with chronic viral hepatitis B and C - Görtz, Rüdiger; Sturm, Jörg; Zopf, Steffen; Wildner, D.; Neurath, Markus; Strobel, Deike (Clinical Radiology, 2014)
To evaluate the association between liver stiffness measured by acoustic radiation force impulse (ARFI) elastometry and the outcome of antiviral treatment in patients with chronic viral hepatitis B and C.Thirty-eight patients with chronic viral hepatitis B (n = 16) or hepatitis C (n = 22) underwent liver biopsy and ARFI elastometry of the right hepatic lobe. A follow-up assessment using ARFI was performed a mean of 2.3 years after the baseline evaluation. The patients with favourable outcome were classified in group S and those receiving no treatment, showing no response to treatment, or experiencing a relapse were classified in group N.The 38 patients had an initial mean ARFI value of 1.56 ± 0.62 m/s as compared with 1.54 ± 0.64 m/s in the follow-up evaluation. Group S showed a significant decline in ARFI values (1.55 ± 0.60 m/s versus 1.34 ± 0.47 m/s; p < 0.05) and included 16 (64%) patients with lower shear wave velocities at follow-up. In group N, liver stiffness values showed a slight but not significant increase (1.57 ± 0.70 m/s versus 1.93 ± 0.77 m/s).Changes in liver stiffness during antiviral therapy can be assessed by ARFI reflecting response or no response. ARFI elastometry is an additional, useful tool for the follow-up assessment of treatment outcome in patients with chronic viral hepatitis B or C infection.
EVALuna2:1862

Outcome and complications of endoscopic balloon dilatations in various types of ileocaecal and colonic stenosis in patients with Crohn's disease - Hagel, Alexander; Hahn, Anna; Dauth, Wolfgang; Matzel, Klaus; Konturek, Peter C.; Neurath, Markus; Raithel, Martin (Surgical Endoscopy, 2014)
We examined the outcome and the complications of endoscopic balloon dilatation (EBD) of ileocaecal and colonic strictures due to Crohn's disease.We examined 237 dilatation procedures in 77 patients with symptomatic ileocaecal and colonic stenosis regarding outcome, individual perforation risk, the need for further interventions, and other complications within a 10 years observation period.In 50 of 77 patients (64.9%), endoscopic dilatation procedures were successful within a median follow-up period of 24 months (25th and 75th percentile 10-38.5 months). Thirty five patients (45.5%) were successfully dilated with only one endoscopic procedure, while the remaining patients required two or more EBDs. Albeit the EBD, 27 patients of the whole cohort (35.1%) underwent surgical repair of the stenosis in due course. Overall complication rate was 7.6%, with postdilatation bleeding in 1.7% and abdominal pain longer than 24 h in 4.2%. Perforation occurred in 4 of 77 patients (5.2%), resulting in a perforation rate of 1.7% per intervention, or, more importantly, for the individual patient in a long-term perforation rate of 5.2% per patient, respectively.Endoscopic balloon dilatation (EBD) is a safe and effective approach to ileocaecal and colonic stenosis in approximately 65% of Crohn's disease patients. Even in case of recurrence, further endoscopic treatments can be undertaken. The perforation rate depending on the number of interventions is low, but for the individual patient a cumulative per patient perforation risk of 5.2% in the long-term should be considered during patient information and decisions for or against surgical interventions.
EVALuna2:1834

Outcome, comorbidity, hospitalization and 30-day mortality after closure of acute perforations and postoperative anastomotic leaks by the over-the-scope clip (OTSC) in an unselected cohort of patients - Raithel, M.; Albrecht, H.; Scheppach, W.; Farnbacher, M.; Haupt, Werner; Hagel, Alexander; Schellerer, Vera; Vitali, Francesco; Neurath, Markus; Schneider, H. T. (Surgical Endoscopy, 2016)
Acute gastrointestinal (GI) wall defects contain a high risk of morbidity and mortality and may be closed endoscopically by a full-thickness over-the-scope clip (OTSC).Unselected consecutive patients presenting with acute non-surgical perforations or postoperative anastomotic leaks or perforations underwent attempted OTSC placement as primary closure method after interdisciplinary consensus in three tertiary referral centres. Their clinical data and intervention characteristics were evaluated in an intention to treat analysis during a 24-month period to assess closure rates, 30-day mortality, hospitalization and comorbidity.In total, 34 patients (16 females, 18 males, 69.5 years) were included with 22 non-surgical perforations and 12 postoperative anastomotic leaks or perforations. Definitive closure of the perforations and leaks was achieved in 26/34 patients (76.5 %). Successful closure of the GI wall defect resulted in a significantly shorter hospital stay (8 days, p = 0.03) and was significantly correlated with comorbidity (r = 0.56, p = 0.005). In the group with OTSC failure, hospitalization was 18 days and 6 of 8 patients (75 %) required immediate surgery. Three deaths occurred in the group with successful OTSC closure due to comorbidity, while one death in the OTSC failure group was related to a refractory perforation. Favourable indications and locations for a successful OTSC procedure were identified as PEG complications, endoscopic or postoperative leaks of stomach, colon or rectum, respectively.In unselected patients, OTSC was effective for closure of acute GI wall defects in more than 75 % of all patients. Clinical success and short hospitalization were best achieved in patients without comorbidity, but closure of the perforation or the anastomotic leak was found to be not the only parameter relevant for patient outcome and mortality.
EVALuna2:2224

Out-of-hospital cardiac arrest and percutaneous coronary intervention for ST-elevation myocardial infarction: Long-term survival and neurological outcome - Zimmermann, Stefan; Flachskampf, Frank A.; Alff, Anna; Schneider, Reinhard; Dechant, Katharina; Klinghammer, Lutz; Stumpf, Christian; Zopf, Yurdagül; Loehr, Thomas; Brand, Georg; Ludwig, Josef; Daniel, Werner; et al. (International Journal of Cardiology, 2013)
Background: Predictors of long-term outcome after ST-elevation myocardial infarction (STEMI) complicated by out-of-hospital cardiac arrest (OHCA) are incompletely understood, including the influence of successful coronary reperfusion. Methods: We analysed clinical and procedural data as well as 1-year outcome of 72 consecutive patients who underwent primary coronary intervention (PCI) after witnessed OHCA and STEMI and compared the results with 695 patients with STEMI and PCI, but without OHCA. Neurological recovery after OHCA was assessed using the Cerebral Performance Category (CPC) scale. Results: PCI was successful in 83.3% after OHCA vs. 84.3% in the non-OHCA group (p = 0.87). One-year mortality was 34.7% vs. 9.5% (p < 0.001). 58.3% of the OHCA-patients showed complete neurological recovery (CPC 1) or moderate neurological disability (CPC 2). Another 6.9% showed severe cerebral disability (CPC 3) or permanent vegetative status (CPC 4). Delay from collapse until start of Advanced Cardiopulmonary Life Support (ACLS) was shorter for survivors with CPC status ≤ 2 (median 1 min, range 0-11 min) compared to non-survivors or survivors with CPC status > 2 (median 8 min, range 0-13 min), p < 0.0001. Age-adjusted multivariate analysis identified 'unsuccessful PCI', 'vasopressors on admission' and 'start of ACLS after > 6 min' as independent predictors of negative long-term outcome (death or CPC > 2). Conclusions: Mortality is high in patients with STEMI complicated by OHCA - even though PCI was performed with the same success rate as in patients without OHCA. The majority of survivors had favourable neurological outcomes at 1 year, especially if advanced life support had been started within ≤ 6 min and PCI was successful. © 2011 Elsevier Ireland Ltd.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Cardiac arrest; Outcome; Primary coronary intervention; Prognosis; Resuscitation; ST-elevation myocardial infarction

Over-the-scope clip-assisted endoscopic full-thickness resection after incomplete resection of rectal adenocarcinoma - Lagoussis, Pavlos; Soriani, Paola; Tontini, Gian Eugenio; Neumann, Helmut; Pastorelli, Luca; De Nucci, Germana; Vecchi, Maurizio (Endoscopy, 2016)
EVALuna2:2098

Over-the-scope-clipping in colonic perforation caused small-bowel fixation and pneumoperitoneum requiring surgical repair - Albrecht, Heinz; Naegel, Andreas; Hagel, Alexander; Rösler, Wolf; Förtsch, Thomas; Neurath, Markus; Atreya, Raja; Raithel, Martin (Endoscopy, 2014)
EVALuna2:1835

Oxazolone-Induced Colitis as a Model of Th2 Immune Responses in the Intestinal Mucosa - Weigmann, Benno; Neurath, Markus (Methods in Molecular Biology, 2016)
Murine models of intestinal inflammation have been widely used in biomedical research. Similarities in anatomy and physiology between such murine models and patients with inflammatory bowel diseases may allow a better understanding of the pathogenesis of Crohn's disease and ulcerative colitis. Additionally, models of intestinal inflammation may be used for the analysis of potentially new therapeutic agents. One key class of models consists of chemically induced inflammation models. Within this group, colitis induced by the haptenizing agent oxazolone is an important model that results in induction of acute or chronic inflammation of the large bowel. Here, we describe the induction and the analysis of this experimental colitis model.
EVALuna2:2163

p21 Prevents the Exhaustion of CD4+ T Cells Within the Antitumor Immune Response Against Colorectal Cancer - Thoma, Oana-Maria; Naschberger, Elisabeth; Kubánková, Markéta; Larafa, Imen; Kramer, Viktoria; Menchicchi, Bianca; Merkel, Susanne; Britzen-Laurent, Nathalie; Jefremow, André; Grützmann, Robert; Koop, Kristina; Neufert, Clemens; et al. (Gastroenterology, 2024)
Background & Aims: T cells are crucial for the antitumor response against colorectal cancer (CRC). T-cell reactivity to CRC is nevertheless limited by T-cell exhaustion. However, molecular mechanisms regulating T-cell exhaustion are only poorly understood. Methods: We investigated the functional role of cyclin-dependent kinase 1a (Cdkn1a or p21) in cluster of differentiation (CD) 4+ T cells using murine CRC models. Furthermore, we evaluated the expression of p21 in patients with stage I to IV CRC. In vitro coculture models were used to understand the effector function of p21-deficient CD4+ T cells. Results: We observed that the activation of cell cycle regulator p21 is crucial for CD4+ T-cell cytotoxic function and that p21 deficiency in type 1 helper T cells (Th1) leads to increased tumor growth in murine CRC. Similarly, low p21 expression in CD4+ T cells infiltrated into tumors of CRC patients is associated with reduced cancer-related survival. In mouse models of CRC, p21-deficient Th1 cells show signs of exhaustion, where an accumulation of effector/effector memory T cells and CD27/CD28 loss are predominant. Immune reconstitution of tumor-bearing Rag1−/− mice using ex vivo-treated p21-deficient T cells with palbociclib, an inhibitor of cyclin-dependent kinase 4/6, restored cytotoxic function and prevented exhaustion of p21-deficient CD4+ T cells as a possible concept for future immunotherapy of human disease. Conclusions: Our data reveal the importance of p21 in controlling the cell cycle and preventing exhaustion of Th1 cells. Furthermore, we unveil the therapeutic potential of cyclin-dependent kinase inhibitors such as palbociclib to reduce T-cell exhaustion for future treatment of patients with colorectal cancer.
CRIS-Team Scopus Importer:2024-01-19
Keywords: CD4; Colorectal Cancer; p21; Palbociclib

Palliative CT Brachytherapy in Hepatic Metastatic NET - Feldhaus, F.; Jann, H.; Jonczyk, M.; Boening, G.; Wieners, G.; Geisel, D.; Pavel, Marianne Ellen; Gebauer, B.; Wiedenmann, B.; Fehrenbach, U.; Denecke, T. (NEUROENDOCRINOLOGY, 2020)
CRIS-Team WoS Importer:2020-04-10

Palliative treatment of colorectal cancer in Germany: cost of care and quality of life - Emmert, Martin; Pohl-Dernick, Katharina; Wein, Axel; Dörje, Frank; Merkel, Susanne; Boxberger, Frank; Männlein, Gudrun; Joost, Robert; Harich, Hans-Detlev; Lamberti, Christof; Neurath, Markus; Hohenberger, Werner; et al. (European Journal of Health Economics, 2012)
<div class="AbstractSection" id="ASec1" style="border: 0px; font-stretch: inherit; font-size: 13px; line-height: 13px; font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; margin: 0.3em 0px 0px; padding: 0px; vertical-align: baseline; outline: 0px; color: rgb(51, 51, 51);"> <h3 class="Heading" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: 400; font-stretch: inherit; font-size: 1.2em; line-height: inherit; font-family: inherit; margin: 0.7em 0px 0.3em; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> Introduction <p class="Para" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: inherit; font-stretch: inherit; font-size: inherit; line-height: 1.6; font-family: inherit; margin: 0px; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> To estimate the costs of palliative care for colorectal cancer (CRC) from the perspective of German statutory health insurance and to measure the patients’ quality of life (QoL) for a 2-year time period. <div class="AbstractSection" id="ASec2" style="border: 0px; font-stretch: inherit; font-size: 13px; line-height: 13px; font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; margin: 0.3em 0px 0px; padding: 0px; vertical-align: baseline; outline: 0px; color: rgb(51, 51, 51);"> <h3 class="Heading" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: 400; font-stretch: inherit; font-size: 1.2em; line-height: inherit; font-family: inherit; margin: 0.7em 0px 0.3em; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> Methods <p class="Para" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: inherit; font-stretch: inherit; font-size: inherit; line-height: 1.6; font-family: inherit; margin: 0px; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> A prospective observational multicentre study was carried out to estimate the direct costs of care over a 2-year period. Case report forms, medical records, and claims data were all applied to document medical and resource usage data in real-world settings. QoL was measured by using the Short Form-12 Health Survey. <div class="AbstractSection" id="ASec3" style="border: 0px; font-stretch: inherit; font-size: 13px; line-height: 13px; font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; margin: 0.3em 0px 0px; padding: 0px; vertical-align: baseline; outline: 0px; color: rgb(51, 51, 51);"> <h3 class="Heading" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: 400; font-stretch: inherit; font-size: 1.2em; line-height: inherit; font-family: inherit; margin: 0.7em 0px 0.3em; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> Results <p class="Para" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: inherit; font-stretch: inherit; font-size: inherit; line-height: 1.6; font-family: inherit; margin: 0px; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> In total 101 patients (mean age 67.09 ± 11.13 years, 68 % male) from 12 different settings were included. The mean costs per patient during the 1st and 2nd years were calculated to be 42,361€ and 32,023€, respectively. Highest mean costs were calculated for the second quarter, which reached an amount of 12,900€ (95 % CI: 11,127€–14,673€). Mean physical summary scores and mean mental summary scores were 41.8 and 49.7, respectively. <div class="AbstractSection" id="ASec4" style="border: 0px; font-stretch: inherit; font-size: 13px; line-height: 13px; font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; margin: 0.3em 0px 0px; padding: 0px; vertical-align: baseline; outline: 0px; color: rgb(51, 51, 51);"> <h3 class="Heading" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: 400; font-stretch: inherit; font-size: 1.2em; line-height: inherit; font-family: inherit; margin: 0.7em 0px 0.3em; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> Discussion <p class="Para" style="border: 0px; font-style: inherit; font-variant: inherit; font-weight: inherit; font-stretch: inherit; font-size: inherit; line-height: 1.6; font-family: inherit; margin: 0px; padding: 0px; vertical-align: baseline; outline: 0px; width: 580px;"> This is the first study assessing the costs of palliative care and the quality of life of patients with CRC in real-world health-care delivery in Germany. It could be shown that CRC treatment represents an enormous economic burden to the German health-care system. Increased efforts in promoting effective and efficient treatment options, or performance-based medication reimbursement schemes, might be helpful in reducing the costs.
WiSo-Import:2015-03-26:4180
Keywords: Colorectal cancer; Palliative care; Cost of care Health service research; Quality of life; SF-12

Palliative Treatment of Colorectal Cancer with Secondary Metastasis Resection in Germany - Impact of the Multidisciplinary Treatment Approach on Prognosis and Cost: The Northern Bavaria IVOPAK I Project - Wein, Axel; Emmert, Martin; Merkel, Susanne; Harich, Hans-Detlev; Thiemann, Roland; Lamberti, Christof; Göttler, Bernhard; Fries, Stefan; Kiani, Alexander; Schlag, Rudolf; Grüner, Marcus; Steinbild, Simone; et al. (Oncology, 2015)
Purpose The aim of this study was to evaluate the quality of care and interdisciplinary cooperation in the palliative treatment of colorectal cancer (CRC), including the associated costs. Patients and Methods 103 patients were enrolled from 13 institutions to reflect the existing clinical treatment reality and costs of palliative CRC treatment. We present the clinical outcome of the patients and compare the results obtained in the 3 centers with double-figure recruitment numbers (centers A, B, and C). Results First-line treatment with 5-fluorouracil monotherapy was applied in exceptional cases. The regular treatment method comprised either an irinotecan- (30%) or an oxaliplatin-based regimen (32%). Biological agents were added to the treatment of 33 patients (32%). The median overall survival (OS) of the total patient collective was 25 months. The OS differed significantly in 2 out of the 3 centers, ranging between 27 and 11 months. Secondary metastasis resections were performed in 26% of the total patient collective. The center with the most favorable outcome results also had the lowest costs for palliative treatment and care, including the lowest drug costs. Conclusion A combined chemotherapy treatment was the rule. Concerning biological agents, a significant lack of their application in first-line treatment and the quality of interdisciplinary cooperation have to be addresse
Keywords: Interdisciplinary cooperation; Costs; Colorectal cancer; Palliative treatment results

Pancreas morphogenesis and homeostasis depends on tightly regulated Zeb1 levels in epithelial cells - Losada, Maria Lasierra; Pauler, Melissa; Vandamme, Niels; Goossens, Steven; Berx, Geert; Leppkes, Moritz; Schuhwerk, Harald; Brabletz, Simone; Brabletz, Thomas; Stemmler, Marc (Cell Death Discovery, 2021)
The pancreas is comprised of exocrine and endocrine compartments releasing digestive enzymes into the duodenum and regulating blood glucose levels by insulin and glucagon release. Tissue homeostasis is depending on transcription factor networks, involving Ptf1α, Ngn3, Nkx6.1, and Sox9, which are already activated during organogenesis. However, proper organ function is challenged by diets of high sugar and fat content, increasing the risk of type 2 diabetes and other disorders. A detailed understanding of processes that are important for homeostasis and are impaired during type 2 diabetes is lacking. Here, we show that Zeb1—a transcription factor known for its pivotal role in epithelial-mesenchymal transition, cell plasticity, and metastasis in cancer—is expressed at low levels in epithelial cells of the pancreas and is crucial for organogenesis and pancreas function. Loss of Zeb1 in these cells result in an increase of islet mass, impaired glucose tolerance, and sensitizes to develop liver and pancreas steatosis during diabetes and obesity. Interestingly, moderate overexpression of Zeb1 results in severe pancreas agenesis and lethality after birth, due to islet insufficiency and lack of acinar structures. We show that Zeb1 induction interferes with proper differentiation, cell survival, and proliferation during pancreas formation, due to deregulated expression of endocrine-specific transcription factors. In summary, our analysis suggests a novel role of Zeb1 for homeostasis in epithelial cells that is indispensable for pancreas morphogenesis and proper organ function involving a tight regulation of Zeb1 expression.
CRIS-Team Scopus Importer:2021-06-18

Pancreatic neuroendocrine neoplasms - Update of the diagnostic and therapeutic guidelines (recommended by the Polish Network of Neuroendocrine Tumours) - Kos-Kudła, Beata; Rosiek, Violetta; Borowska, Małgorzata; Bednarczuk, Tomasz; Bolanowski, Marek; Chmielik, Ewa; Ćwikla, Jarosław B.; Foltyn, Wanda; Gisterek, Iwona; Handkiewicz-Junak, Daria; Hubalewska-Dydejczyk, Alicja; Jarząb, Michal; et al. (Endokrynologia Polska, 2022)
In this paper, we present the current guidelines for the diagnostics and management of pancreatic neuroendocrine neoplasms (PanNENs) developed by Polish experts providing care for these patients in everyday clinical practice. In oncological diagnostics, in addition to biochemical tests, molecular identification with the use of NETest liquid biopsy and circulating microRNAs is gaining importance. Both anatomical and functional examinations (including new radiopharmaceuticals) are used in imaging diagnostics. Histopathological diagnosis along with immunohistochemical examination still constitute the basis for therapeutic decisions. Whenever possible, surgical procedure is the treatment of choice. Pharmacological management including biotherapy, radioisotope therapy, targeted molecular therapy, and chemotherapy are important methods of systemic therapy. Treatment of PanNENs requires a multidisciplinary team of specialists in the field of neuroendocrine neoplasms.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Diagnostics; functional; non-functional; pancreatic neuroendocrine neoplasms; recommendations; therapy

Pancreatic Panniculitis and Polyarthritis - Zundler, Sebastian; Strobel, Deike; Manger, Bernhard; Neurath, Markus; Wildner, Dane (Current Rheumatology Reports, 2017)
Polyarthritis can have numerous reasons and may thus constitute a challenge for differential diagnosis. One rare potential reason for sterile polyarthritis is underlying pancreatic disease with systemic hyperlipasemia, most often accompanied by painful skin lesions caused by a subcutaneous inflammatory process known as panniculitis. Systematic evidence on pancreatic panniculitis and polyarthritis is limited, particularly regarding its feature as facultative paraneoplasia with underlying intra- or even extra-pancreatic malignancy. Therefore, we will summarize the current knowledge about this orphan disease including epidemiological, pathophysiological, diagnostic, and treatment aspects in the present review.Although direct evidence is lacking, it is highly probable that pancreatic polyarthritis and panniculitis are caused by peripheral lipolytic activity of lipase systemically circulating due to benign (e.g., acute or chronic pancreatitis) or malign (e.g., acinar cell carcinoma (ACC) or adenocarcinoma) pancreatic disease. In the latter case, pancreatic polyarthritis and panniculitis are associated with poor outcome. Pancreatic polyarthritis and panniculitis should always be included into diagnostic considerations, and once suspected, a thorough work-up to identify the underlying disease has to be performed.
EVALuna2:13446

Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver–case report and review of literature - Zundler, Sebastian; Erber, Ramona; Agaimy, Abbas; Hartmann, Arndt; Kiesewetter, Franklin; Strobel, Deike; Neurath, Markus; Wildner, Dane (BMC Cancer, 2016)
Pancreatic panniculitis is a rare condition, which has only been described in relation with pancreatic diseases up to now. It is characterized by necrotizing subcutaneous inflammation and is thought to be triggered by adipocyte necrosis due to systemic release of pancreatic enzymes with consecutive infiltration of neutrophils. We present the first case of a patient with pancreatic panniculitis caused by pancreatic-type primary acinar cell carcinoma (ACC) of the liver and without underlying pancreatic disease.A 73-year old Caucasian female patient was referred to our department with painful cutaneous nodules persisting for eight weeks and with marked lipasemia ( 15000 U/l; normal range <60 U/l). Four weeks prior, several liver lesions had been detected. Empiric treatment with steroids did not show any effect. A biopsy of the skin nodules revealed "pancreatic" panniculitis, while abdominal imaging with ultrasound, computed tomography and magnetic resonance imaging detected no abnormal pancreatic findings. Ultrasound-guided biopsy of the liver lesions showed infiltrates of an ACC. The patient died soon thereafter. Autopsy failed to reveal any other primary for the ACC, so that a pancreatic-type ACC of the liver was diagnosed by exclusion. One hundred thirty cases of pancreatic panniculitis published within the last 20 years are reviewed. ACC of the pancreas is the most common underlying neoplastic condition. Patients with associated neoplasm are significantly older, take longer to be diagnosed and have higher lipase levels than patients with underlying pancreatitis. Extrapancreatic pancreatic-type ACC is very rare, but shows the same biological features as ACC of the pancreas. It is believed to develop from metaplastic or ectopic pancreatic tissue. Up to now, no pancreatic panniculitis in extrapancreatic ACC has been described.Pancreatic panniculitis should always be included in the differential diagnosis of lipolytic panniculitic lesions. It can be regarded as a facultative paraneoplastic phenomenon. When suspected, a thorough work-up for identification of the underlying disease is mandatory and extrapancreatic lesions (e.g. liver) should also be considered. While administration of octreotide or steroids can sometimes alleviate symptoms, immediate treatment of the associated condition is the only effective management option.
EVALuna2:2057

Participation of the intestinal microbiota in the mechanism of beneficial effect of treatment with synbiotic syngut on experimental colitis under stress conditions - Konturek, P. C.; Konturek, K.; Brzozowski, T.; Wojcik, D.; Magierowski, M.; Targosz, A.; Krzysiek-Maczka, G.; Sliwowski, Z.; Strzalka, M.; Magierowska, K.; Szczyrk, U.; Kwiecien, S.; et al. (Journal of Physiology and Pharmacology, 2020)
Gut-brain axis plays a central role in the regulation of stress related diseases such as irritable bowel syndrome (iBs) or inflammatory bowel disease (iBD). it is increasingly recognized that stress modulates gut microbiota community structure and activity and represents an important causal factor in dysbiosis. this study was designed to determine the effect of daily treatment with synbiotic (syngut) containing inulin, Lactobacillus acidophilus, Bifidobacterium lactisw51, Lactobacillus plantarumw21 and Lactococcus lactis applied i.g. at a dose of 50 mg/kg i.g. on the colonic damage and colonic mucosal blood flow in rats with experimentally induced tnBs-colitis that were additionally exposed or not to acute stress (episodes of cold restraint stress every other day before colitis induction). Control rats received daily treatment with vehicle (saline, i.g.) or mesalazine (50 mg/kg-d i.g.), the standard drug recommended in therapy of iBD. at the termination of tnBs colitis, the histologic evaluation of colonic mucosa, mucosal malonyldialdehyde (MDa) level and plasma concentrations of proinflammatory cytokines (tnf-α, iL-1β) and adipokine adiponectin were assessed. the samples of colonic mucosa not involving colonic lesions and surrounding the flared mucosa were excised for the determination of mrna expression for proinflammatory biomarkers tnf-α, iL-1β, iL-10 and Cox-2 as well as antioxidazing factors soD-1 and soD-2. finally, the gut microbial profiles were analyzed by 16s rrna sequencing at phylum, family and genus level. episodes of cold stress significantly aggravated the course of tnBs colitis, and significantly increased the release of proinflammatory cytokines as well as the significant increase in the MDa concentration has been observed as compared with non-stressed tnBs rats. these changes were followed by the significant fall in the CBf and plasma adiponectin levels and by the overexpression of mrna of proinflammatory biomarkers. synbiotic treatment with syngut significantly reduced the area of colonic lesions observed macroscopically and microscopically in rats with tnBs colitis with or without exposure to cold stress, significantly increased the CBf, normalized plasma adiponectin levels and significantly attenuated the release and colonic expression of proinflammatory cytokines and biomarkers. the analysis of the gut microbiota showed a significant reduction of microbial diversity (shannon index) in rats with tnBs colitis with or without exposure to stress. the therapy with syngut failed to significantly affect the alpha diversity. at the phylum level, the significant rise in Proteobacteria has been observed in stressed rats with tnBs colitis and this effects was attenuated by treatment with syngut. at family level, tnBs colitis alone or in combination with stress led to a significant decrease of sCfa producing bacterial taxa such as Ruminococaceae and Lachnospiraceae and syngut counteracted this effect. we conclude that: 1) cold stress exacerbates the gastrointestinal inflammation in experimental colitis; 2) the synbiotic therapy with syngut ameliorates the gut inflammation in rats with tnBs colitis combined with cold stress; 3) the beneficial effect of syngut is accompanied by increase of anti-inflammatory taxa such as Ruminococaceae and Lachnospiraceae, and 4) the modulation of gut microbiota with syngut alleviates stressrelated intestinal inflammation suggesting a potential usefulness of synbiotic therapy in intestinal disorders accompanied by stress in patients with iBD.
CRIS-Team Scopus Importer:2020-10-16
Keywords: Adiponectin; Bacterial diversity; Colonic blood flow; Experimental colitis; Malonyldialdehyde; Microbiota; Oxidative stress; Proinflammatory cytokines; Stress; Synbiotic Syngut

Pathogenesis and Management of Pruritus in PBC and PSC - Kremer, Andreas; Namer, Barbara; Bolier, Ruth; Fischer, Michael; Elferink, Ronald P. Oude; Beuers, Ulrich (Digestive Diseases, 2015)
Pruritus is a preeminent symptom in patients with chronic cholestatic liver disorders such as primary biliary cirrhosis and primary sclerosing cholangitis. More than two-thirds of these patients experience itching during the course of their disease. This symptom is also frequently observed in patients with other causes of cholestasis such as cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy, but may accompany almost any other liver disease. The pathogenesis of pruritus of cholestasis remains largely elusive. Increased concentrations of bile salts, histamine, serotonin, progesterone metabolites and endogenous opioids have been controversially discussed as potential pruritogens. However, for these molecules, neither a correlation with itch intensity nor a causative link could be established. The G protein-coupled receptor for bile salts, TGR5, has been shown to be expressed in dorsal root ganglia and give rise to itch in rodents, albeit upon stimuli with suprapathological concentrations of bile salts. The potent neuronal activator lysophosphatidic acid (LPA) and its forming enzyme, autotaxin (ATX), could be identified in the serum of patients with cholestatic pruritus. ATX activity correlated with itch severity and effectiveness of several anti-pruritic therapeutic interventions in cholestatic patients. Thus, the ATX-LPA-axis may represent a key element in the pathogenesis of this agonizing symptom. Treatment options for pruritus of cholestasis remain limited to a few evidence-based and several experimental medical and interventional therapies. The current guideline-based recommendations include the anion exchange resins colestyramine, the pregnane X receptor-agonist and enzyme inducer rifampicin, the ?-opioid antagonist naltrexone, and the selective serotonin reuptake inhibitors sertraline. Still, a considerable part of patients is unresponsive to these drugs and requires experimental approaches including phototherapy, plasmapheresis, albumin dialysis or nasobiliary drainage. This review outlines the current knowledge on pathogenesis of cholestatic pruritus and summarizes evidence-based and experimental therapeutic interventions for cholestatic patients with itch.
EVALuna2:1849

Pathogenic T cell subsets in allergic and chronic inflammatory bowel disorders - Zundler, Sebastian; Neurath, Markus (Immunological Reviews, 2017)
Homeostasis in the gastrointestinal tract relies on a sensitive equilibrium between permissive and protective functions. This is closely reflected in the regulation of the intestinal immune system and especially T cells in the gut. This balance, however, is susceptible to disturbances as demonstrated by pathological conditions like food allergy, celiac disease, or inflammatory bowel disease. In these allergic and chronic inflammatory bowel disorders, luminal antigens get access to the lamina propria where they trigger a dysregulated immune response with crucial involvement of different T cell subsets. We will begin this review with some comprehensive remarks on current concepts on the pathogenesis of these diseases before taking a closer look at the life cycle of intestinal T cells consisting of priming, homing, differentiation and proliferation and apoptosis respectively. Subsequently we will discuss the specific implication of distinct T cell subsets in allergic and chronic inflammatory conditions of the gastrointestinal tract in detail and comment on current and future approaches to targeted therapy in this context.
EVALuna2:33809

Patients Receiving Cytokine Inhibitors Have Low Prevalence of SARS-CoV-2 Infection - Simon, David; Tascilar, Koray; Krönke, Gerhard; Kleyer, Arnd; Zaiss, Mario; Heppt, Franz; Meder, Christine; Atreya, Raja; Klenske, Entcho; Dietrich, Peter; Abdullah, Abdullah; Kliem, Thorsten; et al. (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Patients with COVID-19: in the dark-NETs of neutrophils - Ackermann, Maximilian; Anders, Hans-Joachim; Bilyy, Rostyslav; Bowlin, Gary L.; Daniel, Christoph; De Lorenzo, Rebecca; Egeblad, Mikala; Henneck, Timo; Hidalgo, Andres; Hoffmann, Markus; Hohberger, Bettina; Kanthi, Yogendra; et al. (Cell Death and Differentiation, 2021)
SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.
CRIS-Team Scopus Importer:2021-06-04

PATIENTS WITH IMMUNE MEDIATED INFLAMMATORY DISEASES ARE OVERREPRESENTED IN LOW-FREQUENCY VIRAL SYMPTOM CLUSTERS - Tascilar, Koray; Simon, David; Krönke, Gerhard; Kleyer, Arnd; Ramming, Andreas; Atreya, Raja; Tenbusch, Matthias; Überla, Klaus; Berking, Carola; Sticherling, Michael; Neurath, Markus; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion - Simon, David; Tascilar, Koray; Krönke, Gerhard; Kleyer, Arnd; Zaiss, Mario; Heppt, Franz; Meder, Christine; Atreya, Raja; Klenske, Entcho; Dietrich, Peter; Abdullah, Abdullah; Kliem, Thorsten; et al. (Nature Communications, 2020)
Immune-mediated inflammatory diseases (IMIDs) of the joints, gut and skin are treated with inhibitors of inflammatory cytokines. These cytokines are involved in the pathogenesis of coronavirus disease 2019 (COVID-19). Investigating anti-SARS-CoV-2 antibody responses in IMIDs we observe a reduced incidence of SARS-CoV-2 seroconversion in IMID patients treated with cytokine inhibitors compared to patients receiving no such inhibitors and two healthy control populations, despite similar social exposure. Hence, cytokine inhibitors seem to at least partially protect from SARS-CoV-2 infection.
CRIS-Team Scopus Importer:2020-08-07

Pearls & Oy-sters: Moyamoya Vasculopathy and Its Association With Congenital Heart Disease - Osterloh, Justus; Heim, Christian; Siedler, Gabriela; Engelhorn, Tobias; Dörfler, Arnd; Schwab, Stefan; Kallmünzer, Bernd (Neurology, 2021)
CRIS-Team Scopus Importer:2021-06-25

Pearls & Oy-sters: SARS-CoV-2 Infection of the CNS in a Patient With Meningeosis Carcinomatosa - Steininger, Philipp; Seifert, Frank; Balk, Stefanie; Kuramatsu, Joji; Kremer, Andreas; Coras, Roland; Engelhorn, Tobias; Maier, Clara; Tenbusch, Matthias; Korn, Klaus; Enßer, Armin (Neurology, 2021)
CRIS-Team Scopus Importer:2021-03-26

People without Celiac disease: Gluten Abandonment do not bring any Benefit for the Heart - Zopf, Yurdagül (Deutsche Medizinische Wochenschrift, 2017)
EVALuna2:34086

Peptide Receptor Radionuclide Therapy During the COVID-19 Pandemic: Are There Any Concerns? - Bodei, Lisa; Bergsland, Emily; de Herder, Wouter W.; Ferone, Diego; Hicks, Rodney J.; Hope, Thomas A.; Kunikowska, Jolanta; Pavel, Marianne Ellen; Reidy-Lagunes, Diane; Siveke, Jens; Strosberg, Jonathan; Dittmer, Ulf; et al. (Journal of Nuclear Medicine, 2020)
CRIS-Team Scopus Importer:2020-08-14

Perceived distress, personality characteristics, coping strategies and psychosocial impairments in a national German multicenter cohort of patients with Crohn's disease and ulcerative colitis - Petruo, Vanessa A.; Krauss, Ekaterina; Kleist, Anika; Hardt, Juliane; Hake, Karsten; Peirano, Julia; Krause, Thomas; Ehehalt, Robert; De La Perriere, Philipp Von Arnauld; Buening, Juergen; Treml, Oliver; Krauss, Norbert; et al. (Zeitschrift für Gastroenterologie, 2019)
BACKGROUND AND AIMS: This study examined differences in personality, psychological distress, and stress coping in inflammatory bowel disease (IBD) depending on type of disease and disease activity. We compared patients suffering from Crohn's disease (CD) and ulcerative colitis (UC) with controls. While the literature is replete with distinctive features of the pathogenesis of IBD, the specific differences in psychological impairments are not well studied. METHODS: In this German national multicenter study, participants were recruited from 32 centers. Two hundred ninety-seven questionnaires were included, delivering vast information on disease status and psychological well-being based on validated instruments with a total of 285 variables. RESULTS: CD patients were more affected by psychological impairments than patients suffering from UC or controls. Importantly, patients with active CD scored higher in neuroticism (p < 0.01), psychological distress (p < 0.001) and maladaptive stress coping (escape, p = 0.03; rumination, p < 0.03), but less need for social support (p = 0.001) than controls. In contrast, patients suffering from active UC showed psychological distress (p < 0.04) and maladaptive coping (avoidance, p < 0.03; escape, p = 0.01). Patients in remission seemed to be less affected. In particular, patients with UC in remission were not inflicted by psychological impairments. The group of CD patients in remission however, showed insecurity (p < 0.01) and paranoid ideation (p = 0.04). CONCLUSIONS: We identified specific aspects of psychological impairment in IBD depending on disease and disease activity. Our results underscore the need for psychological support and treatment particularly in active CD.
EVALuna2:209006

Perforations after routine biopsy in IBD patients, their management and potential risk reductions by microscopic imaging with endocytoscopy - Klenske, Entcho; Hartmann, Arndt; Atreya, Raja; Neurath, Markus; Rath, Timo (Journal of Gastrointestinal and Liver Diseases, 2020)
CRIS-Team Scopus Importer:2020-09-25

Peripheral Sensitization and Loss of Descending Inhibition Is a Hallmark of Chronic Pruritus - Pogatzki-Zahn, Esther M.; Pereira, Manuel P.; Cremer, Alexander; Zeidler, Claudia; Dreyer, Tim; Riepe, Claudia; Wempe, Carola; Lotts, Tobias; Segelcke, Daniel; Ringkamp, Matthias; Kremer, Andreas; Agelopoulos, Konstantin; et al. (Journal of Investigative Dermatology, 2019)
Neurophysiological mechanisms leading to chronicity of pruritus are not yet fully understood and it is not known whether these mechanisms diverge between different underlying diseases of chronic pruritus (CP). This study aimed to detect such mechanisms in CP of various origins. A total of 120 patients with CP of inflammatory origin (atopic dermatitis), neuropathic origin (brachioradial pruritus), and chronic prurigo of nodular type, the latter as a model for chronic scratching, as well as 40 matched healthy controls participated in this study. Stimulation with cowhage induced a more intensive itch sensation compared with stimulation with other substances in all patient groups but not in healthy controls, arguing for sensitization of cutaneous mechano- and heat-sensitive C-fibers in CP. All patient groups showed a decreased intraepidermal nerve fiber density compared with controls. A decreased condition pain modulation effect was observed in all patient groups compared with controls, suggesting a reduced descending inhibitory system in CP. In sum, CP of different etiologies showed a mixed peripheral and central pattern of neuronal alterations, which might contribute to the chronicity of pruritus with no differences between pruritus entities. Our findings may contribute to the development of future treatment strategies targeting these pathomechanisms.
CRIS-Team Scopus Importer:2019-09-17

Peritoneal Carcinomatosis in Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: Clinical Impact and Effectiveness of the Available Therapeutic Options - Merola, Elettra; Prasad, Vikas; Pascher, Andreas; Pape, Ulrich Frank; Arsenic, Ruza; Denecke, Timm; Fehrenbach, Uli; Wiedenmann, Bertram; Pavel, Marianne Ellen (Neuroendocrinology, 2020)
BACKGROUND: Peritoneal carcinomatosis (PC) can affect the quality of life of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Peritoneal disease control by medical therapies in these patients has been poorly investigated Objectives: To describe, in a consecutive series of GEP-NENs, the clinical impact of PC and to report the effectiveness of available treatments in PC control. METHODS: A retrospective, monocenter analysis was performed of 135 GEP-NENs (1993-2016) with at least a 12-month follow-up. Peritoneal disease progression was defined as detection of a significant increase in size or appearance of new implants by imaging. RESULTS: A total of 62.9% of cases had diffuse PC (involving at least 2 abdominal quadrants). According to WHO 2017 classification, cases were 42.3% neuroendocrine tumors NET-G1, 45.5% NET-G2, 6.5% NET-G3, 4.9% neuroendocrine carcinomas NEC-G3, and 0.8% mixed neuroendocrine-nonneuroendocrine neoplasms. Bowel obstruction occurred in 30 (22.2%) patients mainly depending on size of peritoneal implants (HR: 1.10; 95% CI: 1.02-1.20; p = 0.01). Patients with diffuse PC treated with peptide receptor radionuclide therapy (PRRT) showed peritoneal progression in 37.5% of cases, and bowel obstruction or ascites in 28.1%. Better peritoneal disease control was observed in cases receiving somatostatin analogs at first-line therapy, probably due to a less aggressive disease behavior for these patients. CONCLUSIONS: Bowel obstruction is not uncommon in GEP-NENs with PC. PRRT should be adopted with caution in GEP-NENs with diffuse PC, but larger series are needed to confirm these data.
CRIS-Team Scopus Importer:2020-06-02
Keywords: Bowel obstruction; Disease control; Neuroendocrine neoplasms; Peptide receptor radionuclide therapy; Peritoneal carcinomatosis

Permeability analyses and three dimensional imaging of interferon gamma-induced barrier disintegration in intestinal organoids - Bardenbacher, Marco; Ruder, Barbara; Britzen-Laurent, Nathalie; Schmid, Benjamin; Waldner, Maximilian; Naschberger, Elisabeth; Scharl, Michael; Mueller, Werner; Günther, Claudia; Becker, Christoph; Stürzl, Michael; Tripal, Philipp (Stem Cell Research, 2019)
The aberrant regulation of the epithelial barrier integrity is involved in many diseases of the digestive tract, including inflammatory bowel diseases and colorectal cancer. Intestinal epithelial cell organoid cultures provide new perspectives for analyses of the intestinal barrier in vitro. However, established methods of barrier function analyses from two dimensional cultures have to be adjusted to the analysis of three dimensional organoid structures. Here we describe the methodology for analysis of epithelial barrier function and molecular regulation in intestinal organoids. Barrier responses to interferon-y of intestinal organoids with and without epithelial cellspecific deletion of the interferon-y-receptor 2 gene were used as a model system. The established method allowed monitoring of the kinetics of interferon-y-induced permeability changes in living organoids. Proteolytic degradation and altered localization of the tight junction proteins claudin-2, -7, and - 15 was detected using confocal spinning disc microscopy with 3D reconstruction. Hessian analysis was used for quantification of relocalization of claudins. In summary, we provide a novel methodologic approach for quantitative analyses of intestinal epithelial barrier functions in the 3D organoid model.
CRIS-Team WoS Importer:2019-03-12

Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF? - Atreya, Raja; Neurath, Markus; Siegmund, Britta (Frontiers in Medicine, 2020)
The advent of anti-TNF agents as the first approved targeted therapy in the treatment of inflammatory bowel disease (IBD) patients has made a major impact on our existing therapeutic algorithms. They have not only been approved for induction and maintenance treatment in IBD patients, but have also enabled us to define and achieve novel therapeutic outcomes, such as combination of clinical symptom control and endoscopic remission, as well as mucosal healing. Nevertheless, approximately one third of treated patients do not respond to initiated anti-TNF therapy and these treatments are associated with sometimes severe systemic side-effects. There is therefore the currently unmet clinical need do establish predictive markers of response to identify the subgroup of IBD patients, that have a heightened probability of response. There have so far been approaches from different fields of IBD research, to descry markers that would empower us to apply TNF-inhibitors in a more rational manner. These markers encompass findings from disease-related and clinical factors, pharmacokinetics, biochemical markers, blood and stool derived parameters, pharmacogenomics, microbial species, metabolic compounds, and mucosal factors. Furthermore, changes in the intestinal immune cell composition in response to therapeutic pressure of anti-TNF treatment have recently been implicated in the process of molecular resistance to these drugs. Insights into factors that determine resistance to anti-TNF therapy give reasonable hope, that a more targeted approach can then be utilized in these non-responders. Here, IL-23 could be identified as one of the key factors determining resistance to TNF-inhibitors. Growing insights into the molecular mechanism of action of TNF-inhibitors might also enable us to derive critical molecular markers that not only mediate the clinical effects of anti-TNF therapy, but which level of expression might also correlate with its therapeutic efficacy. In this narrative review, we present an overview of currently identified possible predictive markers for successful anti-TNF therapy and discuss identified molecular pathways that drive resistance to these substances. We will also point out the necessity and difficulty of developing and validating a diagnostic marker concerning clinically relevant outcome parameters, before they can finally enter daily clinical practice and enable a more personalized therapeutic approach.
CRIS-Team Scopus Importer:2020-09-25
Keywords: anti-TNF; inflammatory bowel diseases; personalized medicine; prediction; response

Perspectives, potentials and trends of ex vivo and in vivo optical molecular pathology - Krafft, Christoph; Von Eggeling, Ferdinand; Guntinas-Lichius, Orlando; Hartmann, Arndt; Waldner, Maximilian; Neurath, Markus; Popp, Juergen (Journal of Biophotonics, 2018)
It is pivotal for medical applications, such as noninvasive histopathologic characterization of tissue, to realize label-free and molecule-specific representation of morphologic and biochemical composition in real-time with subcellular spatial resolution. This unmet clinical need requires new approaches for rapid and reliable real-time assessment of pathologies to complement established diagnostic tools. Photonic imaging combined with digitalization offers the potential to provide the clinician the requested information both under in vivo and ex vivo conditions. This report summarizes photonic approaches and their use in combination with image processing, machine learning and augmented virtual reality that might solve current challenges in modern medicine. Details are given for pathology, intraoperative diagnosis in head and neck cancer and endoscopic diagnosis in gastroenterology.
EVALuna2:33796

PGAM5 acts as a key mediator of lung fibrosis by disrupting mitochondrial homeostasis - Ganzleben, Ingo; He, Gui-Wei; Günther, Claudia; Prigge, Elena-Sophie; Richter, Karsten; Rieker, Ralf; Mougiakakos, Dimitrios; Neurath, Markus; Becker, Christoph (EUROPEAN RESPIRATORY JOURNAL, 2019)
CRIS-Team WoS Importer:2020-02-04

PGAM5 is a key driver of mitochondrial dysfunction in experimental lung fibrosis - Ganzleben, Ingo; He, Gui Wei; Günther, Claudia; Prigge, Elena Sophie; Richter, Karsten; Rieker, Ralf; Mougiakakos, Dimitrios; Neurath, Markus; Becker, Christoph (Cellular and Molecular Life Sciences, 2019)
Rationale: Mitochondrial homeostasis has recently emerged as a focal point in the pathophysiology of idiopathic pulmonary fibrosis (IPF), but conflicting data have been reported regarding its regulation. We speculated that phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein at the intersection of multiple cell death and mitochondrial turnover pathways, might be involved in the pathogenesis of IPF. Methods: PGAM5-deficient mice and human pulmonary epithelial cells were analyzed comparatively with PGAM5-proficient controls in a bleomycin-based model of pulmonary fibrogenesis. Mitochondria were visualized by confocal and transmission electron microscopy. Mitochondrial homeostasis was assessed using JC1 (ΔΨ) and flow cytometry. Results: PGAM5 plays an important role in pulmonary fibrogenesis. Pgam5−/− mice displayed significantly attenuated lung fibrosis compared to controls. Complementary, in vitro studies demonstrated that PGAM5 impaired mitochondrial integrity on a functional and structural level independently of mtROS-production. On a molecular level, reduced mitophagy caused by PGAM5 deficiency improved mitochondrial homeostasis. Conclusions: Our study identifies PGAM5 as an important regulator of mitochondrial homeostasis in pulmonary fibrosis. Our data further indicate PGAM5-mediated mitophagy itself as a pivotal gateway event in the mediation of self-sustaining mitochondrial damage and membrane depolarization. Our work hereby highlights the importance of mitochondrial dynamics and identifies a potential therapeutic target that warrants further studies. Graphical abstract: Toxic agents lead to mitochondrial damage resulting in depolarization of the mitochondrial membrane potential (ΔΨ) which is a gateway event for the initiation of PGAM5-mediated mitophagy. PGAM5-mediated mitophagy in turn leads to a self-perpetuating escalation of ΔΨ depolarization. Loss of the mitophagy-based damage-enhancing loop under PGAM5-deficient conditions breaks this vicious cycle, leading to improved mitochondrial homeostasis.[Figure not available: see fulltext.].
CRIS-Team Scopus Importer:2019-06-21
Keywords: Bleomycin; IPF; Mitophagy

PGAM5-MAVS interaction regulates TBK1/ IRF3 dependent antiviral responses - Yu, Yidong; Zielinska, Marta; Li, Wei; Bernkopf, Dominic; Heilingloh, Christiane; Neurath, Markus; Becker, Christoph (Scientific Reports, 2020)
Viral infections trigger host innate immune responses, characterized by the production of type-I interferons (IFN) including IFNβ. IFNβ induces cellular antiviral defense mechanisms and thereby contributes to pathogen clearance. Accumulating evidence suggests that mitochondria constitute a crucial platform for the induction of antiviral immunity. Here we demonstrate that the mitochondrial protein phosphoglycerate mutase family member 5 (PGAM5) is important for the antiviral cellular response. Following challenge of HeLa cells with the dsRNA-analog poly(I:C), PGAM5 oligomers and high levels of PGAM5 were found in mitochondrial aggregates. Using immunoprecipitation, a direct interaction of PGAM5 with the mitochondrial antiviral-signaling protein (MAVS) was demonstrated. In addition, PGAM5 deficient cells showed diminished expression of IFNβ and IFNβ target genes as compared to WT cells. Moreover, PGAM5 deficient mouse embryonic fibroblasts (MEFs) exhibited decreased phosphorylation levels of IRF3 and TBK1 when challenged with poly(I:C) intracellularly. Finally, PGAM5 deficient MEFs, upon infection with vesicular stomatitis virus (VSV), revealed diminished IFNβ expression and increased VSV replication. Collectively, our study highlights PGAM5 as an important regulator for IFNβ production mediated via the TBK1/IRF3 signaling pathway in response to viral infection.
CRIS-Team Scopus Importer:2020-06-02

PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury - He, Gui-Wei; Günther, Claudia; Kremer, Andreas; Thonn, Veronika; Amann, Kerstin Ute; Poremba, Christopher; Neurath, Markus; Wirtz, Stefan; Becker, Christoph (Gut, 2016)
Autoimmune hepatitis (AIH) is a severe necroinflammatory liver disease associated with significant mortality. Although loss of hepatocytes is generally recognised as a key trigger of liver inflammation and liver failure, the regulation of hepatic cell death causing AIH remains poorly understood. The aim of this study was to identify molecular mechanisms that drive hepatocyte cell death in the pathogenesis of acute liver injury.Acute liver injury was modelled in mice by intravenous administration of concanavalin A (ConA). Liver injury was demonstrated by serum transaminases and histological assessment of liver sections. PGAM5-deficient mice (PGAM5-/-) were used to determine its role in experimental hepatitis. Mdivi-1 was used as an inhibitor of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Mitochondrial fission and the expression of PGAM5 were compared between liver biopsies derived from patients with AIH and control patients.PGAM5 was highly expressed in hepatocytes of patients with AIH and in mice with ConA-induced experimental hepatitis. Deficiency of PGAM5 protected mice from ConA-induced hepatocellular death and liver injury. PGAM5 regulated ConA-induced mitochondrial fission in hepatocytes. Administration of the Drp1-inhibitor Mdivi-1 blocked mitochondrial fission, diminished hepatocyte cell death and attenuated liver tissue damage induced by ConA.Our data demonstrate for the first time that PGAM5 plays an indispensable role in the pathogenesis of ConA-induced liver injury. Downstream of PGAM5, Drp1-mediated mitochondrial fission is an obligatory step that drives the execution of hepatic necrosis and tissue damage. Our data highlight the PGAM5-Drp1 axis as a potential therapeutic target for acute immune-mediated liver injury.
EVALuna2:2219

Phase 1 Clinical Study of siRNA Targeting Carbohydrate Sulphotransferase 15 in Crohn's Disease Patients with Active Mucosal Lesions - Suzuki, Kenji; Yokoyama, Junji; Kawauchi, Yusuke; Honda, Yutaka; Sato, Hiroki; Aoyagi, Yutaka; Terai, Shuji; Okazaki, Kazuichi; Suzuki, Yasuo; Sameshima, Yukinori; Fukushima, Tsuneo; Sugahara, Kazuyuki; et al. (Journal of Crohns & Colitis, 2017)
BACKGROUND AND AIMS: Carbohydrate sulphotransferase 15 [CHST15] is a specific enzyme biosynthesizing chondroitin sulphate E that binds various pathogenic mediators and is known to create local fibrotic lesions. We evaluated the safety of STNM01, a synthetic double-stranded RNA oligonucleotide directed against CHST15, in Crohn's disease [CD] patients whose mucosal lesions were refractory to conventional therapy. METHODS: This was a randomized, double-blind, placebo-controlled, concentration-escalation study of STNM01 by a single-dose endoscopic submucosal injection in 18 CD patients. Cohorts of increasing concentration of STNM01 were enrolled sequentially as 2.5nM [n = 3], 25nM [n = 3], and 250nM [n = 3] were applied. A cohort of placebo [n = 3] was included in each concentration. Safety was monitored for 30 days. Pharmacokinetics was monitored for 24h. The changes from baseline in the segmental Simple Endoscopic Score for CD [SES-CD] as well as the histological fibrosis score were evaluated. RESULTS: STNM01 was well tolerated and showed no drug-related adverse effects in any cohort of treated patients. There were no detectable plasma concentrations of STNM01 at all measured time points in all treatment groups. Seven of nine subjects who received STNM01 showed reduction in segmental SES-CD at Day 30, when compared with those who received placebo. Histological analyses of biopsy specimens revealed that STNM01 reduced the extent of fibrosis. CONCLUSION: Local application of STNM01 is safe and well tolerated in CD patients with active mucosal lesions.
EVALuna2:33828

Phase angle and vector analysis from multifrequency segmental bioelectrical impedance analysis: New reference data for older adults - Reljic, Dejan; Zarafat, Daniel; Jensen, B.; Herrmann, H. J.; Neurath, Markus; Konturek, P. C.; Zopf, Yurdagül (Journal of Physiology and Pharmacology, 2020)
Phase angle (PA) and bioelectrical impedance vector analysis (BIVA) have been recommended as useful prognostic markers in various clinical settings. However, reference data for older adults measured by the novel segmental multifrequency bioelectrical impedance analysis (SMF-BIA) technique are currently lacking. This study examined 567 (286 men, 281 women) healthy older adults (65 – 97 years) and new SMF-BIA-based PA and BIVA reference values were generated stratified according to gender and 3 age groups (65 – 75 years, 76 – 85 years, > 85 years). Mean PA-values (women: 4.30 ± 0.6°, men: 4.77 ± 0.7°) were significantly lower than those previously reported for a younger reference population. Age and gender were significant determinants of PA and BIVA. PA showed a significant decrease with increasing age in both genders. The greatest changes occurred in the age group > 85 years. Men had higher PAs compared to women (except for the oldest age group), but showed a substantially steeper decline in PA, possibly due to a more pronounced reduction of muscle mass. Compared to published reference data for younger adults, there was a clear downward migration of the BIVA vector points in older adults, indicating an age-related reduction of body cell mass. Accordingly, the equation for the BIVA chart generation was modified by adding the factor age. In conclusion, this is the first study to present SMF-BIA-determined PA and BIVA reference data for healthy subjects aged ³ 65 years. These data can be used for clinical purposes to identify individuals at increased risk for adverse health events or to monitor treatment responses.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Age and gender stratification; Bioimpedance analysis; Body composition; Geriatric medicine; Health risk diagnostic and prediction; Nutrition status monitoring

Physical activity and advanced cancer: evidence of exercise-sensitive genes regulating prostate cancer cell proliferation and apoptosis - Schwappacher, Raphaela; Schink, Kristin; Sologub, Svetlana; Dieterich, Walburga; Reljic, Dejan; Friedrich, Oliver; Herrmann, Hans J.; Neurath, Markus; Zopf, Yurdagül (The Journal of Physiology, 2020)
Key points: Physical activity is known to protect against cancer. The resistance exercise method whole-body electromyostimulation (WB-EMS) has a significant anti-cancer effect. WB-EMS-conditioned serum from advanced prostate cancer patients decreased human prostate carcinoma cell growth and viability in vitro. Multiplex analysis revealed that genes associated with human prostate cancer cell proliferation and apoptosis are sensitive for exercise. Feasible exercise should be part of multimodal anti-cancer therapies, also for physically weakened patients. Abstract: Regular physical activity is known to protect against cancer development. In cancer survivors, exercise reduces the risk of cancer recurrence and mortality. However, the link between exercise and decreased cancer risk and improved survival is still not well understood. Serum from exercising healthy individuals inhibits proliferation and activates apoptosis in various cancer cells, suggesting that mechanisms regulating cancer cell growth are affected by exercise. For the first time, we analysed serum from advanced-stage cancer patients with prostate (exercise group n = 8; control group n = 10) or colorectal (exercise n = 6; control n = 6) cancer, after a 12-week whole-body electromyostimulation training (20 min/session, 2×/week; frequency 85 Hz; pulse width 350 µs; 6 s stimulation, 4 s rest), a tolerable, yet effective, resistance exercise for physically weakened patients. We report that serum from these advanced cancer patients inhibits proliferation and enhances apoptosis of human prostate and colon cancer cells in vitro using cell growth and death assays (5-bromo-2′-deoxyuridine incorporation, cell counting, DNA fragmentation). Exercise-mimicking electric pulse stimulation of human primary myotubes showed that electric pulse stimulation-conditioned myotube medium also impairs human cancer cell viability. Gene expression analysis using a multiplex array of cancer-associated genes and subsequent quantitative RT-PCR revealed the presence of exercise-sensitive genes in human prostate cancer cells that potentially participate in the exercise-mediated regulation of malignant cell growth and apoptosis. Our data document the strong efficiency of the anti-oncogenic effects of physical activity and will further support the application of regular therapeutic exercise during cancer disease.
CRIS-Team Scopus Importer:2020-08-07
Keywords: apoptosis; cancer cells; colorectal cancer; electric pulse stimulation; exercise; gene expression; physical activity; proliferation; prostate cancer; whole-body electromyostimulation

Physical phenotype of blood cells is altered in COVID-19 - Kubankova, Marketa; Hohberger, Bettina; Hoffmanns, Jakob; Fürst, Julia; Herrmann, Martin; Guck, Jochen; Kraeter, Martin (Biophysical Journal, 2021)
Clinical syndrome coronavirus disease 2019 (COVID-19) induced by severe acute respiratory syndrome coronavirus 2 is characterized by rapid spreading and high mortality worldwide. Although the pathology is not yet fully understood, hyperinflammatory response and coagulation disorders leading to congestions of microvessels are considered to be key drivers of the still-increasing death toll. Until now, physical changes of blood cells have not been considered to play a role in COVID-19 related vascular occlusion and organ damage. Here, we report an evaluation of multiple physical parameters including the mechanical features of five frequent blood cell types, namely erythrocytes, lymphocytes, monocytes, neutrophils, and eosinophils. More than four million blood cells of 17 COVID-19 patients at different levels of severity, 24 volunteers free from infectious or inflammatory diseases, and 14 recovered COVID-19 patients were analyzed. We found significant changes in lymphocyte stiffness, monocyte size, neutrophil size and deformability, and heterogeneity of erythrocyte deformation and size. Although some of these changes recovered to normal values after hospitalization, others persisted for months after hospital discharge, evidencing the long-term imprint of COVID-19 on the body.
CRIS-Team Scopus Importer:2021-07-30

Physiological intermolecular modification spectroscopy for the prediction of response to anti-tumor necrosis factor therapy in patients with inflammatory bowel diseases - Eftekhari, Pierre; Glaubitz, Lisa; Breidert, Matthias; Neurath, Markus; Atreya, Raja (Digestive Diseases, 2014)
Anti-tumor necrosis factor (TNF) antibodies have clinical efficiency only in a subgroup of patients with inflammatory bowel diseases (IBD). Prediction of clinical response is a critical clinical problem. Physiological intermolecular modification spectroscopy (PIMS) is a label-free technology performed in physiological conditions. PIMS enables real-time monitoring of dynamic molecular resonance of entire proteins and macromolecules of an individual. The aim of this study was to explore the capacity of PIMS to discriminate IBD patients regarding response to anti-TNF treatment.Protein extracts of peripheral blood mononuclear cells (PBMC) from 30 outpatients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD) and treated with infliximab were subjected to PIMS analysis in a blinded transversal study. Total protein from each patient's PBMCs was challenged with infliximab. Dynamic changes in macromolecular interaction were registered while the temperature rose from -37 to 37°C. Individual macromolecular volume and molecular elasticity were determined for each patient.Clinical data revealed that 67% of UC and 79% of CD patients responded to infliximab therapy during the 3-month study period based on their respective clinical activity score. These results confirm that PIMS data predicted response to anti-TNF therapy with an accuracy of 96%.PIMS stratified IBD patients into two groups, responders and nonresponders, which correlated with the clinical efficacy of anti-TNF therapy. PIMS seems to be a powerful technology to adapt IBD treatment to the individual patient. Further studies with PIMS might enable to predict clinical response to biological treatment in IBD patients before the therapy is initiated.
EVALuna2:1885

PICaSSO Histologic Remission Index (PHRI) in ulcerative colitis: development of a novel simplified histological score for monitoring mucosal healing and predicting clinical outcomes and its applicability in an artificial intelligence system - Gui, Xianyong; Bazarova, Alina; Del Amor, Rocio; De Hertogh, Gert; Villanacci, Vincenzo; Zardo, Davide; Parigi, Tommaso Lorenzo; Royset, Elin Synnove; Shivaji, Uday N.; Monica, Melissa Anna Teresa; Mandelli, Giulio; Bhandari, Pradeep; et al. (Gut, 2022)
Histological remission is evolving as an important treatment target in UC. We aimed to develop a simple histological index, aligned to endoscopy, correlated with clinical outcomes, and suited to apply to an artificial intelligence (AI) system to evaluate inflammatory activity. Methods Using a set of 614 biopsies from 307 patients with UC enrolled into a prospective multicentre study, we developed the Paddington International virtual ChromoendoScopy ScOre (PICaSSO) Histologic Remission Index (PHRI). Agreement with multiple other histological indices and validation for inter-reader reproducibility were assessed. Finally, to implement PHRI into a computer-aided diagnosis system, we trained and tested a novel deep learning strategy based on a CNN architecture to detect neutrophils, calculate PHRI and identify active from quiescent UC using a subset of 138 biopsies. Results PHRI is strongly correlated with endoscopic scores (Mayo Endoscopic Score and UC Endoscopic Index of Severity and PICaSSO) and with clinical outcomes (hospitalisation, colectomy and initiation or changes in medical therapy due to UC flare-up). A PHRI score of 1 could accurately stratify patients' risk of adverse outcomes (hospitalisation, colectomy and treatment optimisation due to flare-up) within 12 months. Our inter-reader agreement was high (intraclass correlation 0.84). Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity and 86% accuracy. Conclusions PHRI is a simple histological index in UC, and it exhibits the highest correlation with endoscopic activity and clinical outcomes. A PHRI-based AI system was accurate in predicting histological remission.
CRIS-Team WoS Importer:2022-03-04

Pig models for Duchenne muscular dystrophy – from disease mechanisms to validation of new diagnostic and therapeutic concepts - Stirm, Michael; Fonteyne, Lina Marie; Shashikadze, Bachuki; Stöckl, Jan B.; Kurome, Mayuko; Keßler, Barbara; Zakhartchenko, Valeri; Kemter, Elisabeth; Blum, Helmut; Arnold, Georg J.; Matiasek, Kaspar; Wanke, Rüdiger; et al. (Neuromuscular Disorders, 2022)
Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the DMD gene, leading to complete absence of dystrophin and progressive degeneration of skeletal muscles and heart. Animal models are essential for preclinical evaluation of novel diagnostic procedures and treatment strategies. Gene targeting/editing offers the possibility of developing tailored pig models for monogenic diseases. The first porcine DMD model was generated by deletion of DMD exon 52 (DMDΔ52) in cultured kidney cells, which were used for somatic cell nuclear transfer to produce DMDΔ52 offspring. The animals resembled clinical, biochemical, and pathological hallmarks of DMD, but died before sexual maturity, thus preventing their propagation by breeding. This limitation was overcome by the generation of female heterozygous DMDΔ52 carrier pigs, which allowed the establishment of a large breeding colony. In this overview, we summarize how porcine DMD models have been used for dissecting disease mechanisms, for validating multispectral optoacoustic tomography as an imaging modality for monitoring fibrosis, and for preclinical testing of a CRISPR/Cas9 based approach to restore an intact DMD reading frame. Particular advantages of porcine DMD models include their targeted design and the rapid disease progression with early cardiac involvement, facilitating translational studies in reasonable time frames.
CRIS-Team Scopus Importer:2022-07-01
Keywords: Duchenne muscular dystrophy; Gene editing; Optoacoustic imaging; Pig model

Pivotal Role of Carbohydrate Sulfotransferase 15 in Fibrosis and Mucosal Healing in Mouse Colitis - Suzuki, Kenji; Arumugam, Somasundaram; Yokoyama, Junji; Kawauchi, Yusuke; Honda, Yutaka; Sato, Hiroki; Aoyagi, Yutaka; Terai, Shuji; Okazaki, Kazuichi; Suzuki, Yasuo; Mizumoto, Shuji; Sugahara, Kazuyuki; et al. (PLoS ONE, 2016)
Induction of mucosal healing (MH) is an important treatment goal in inflammatory bowel disease (IBD). Although the molecular mechanisms underlying MH in IBD is not fully explored, local fibrosis would contribute to interfere mucosal repair. Carbohydrate sulfotransferase 15 (CHST15), which catalyzes sulfation of chondroitin sulfate to produce rare E-disaccharide units, is a novel mediator to create local fibrosis. Here we have used siRNA-based approach of silencing CHST15 in dextran sulfate sodium (DSS) induced colitis in mice, human colon fibroblasts and cancer cell lines. In a DSS-induced acute colitis model, CHST15 siRNA reduced CHST15 mRNA in the colon, serum IL-6, disease activity index (DAI) and accumulation of F4/80+ macrophages and ER-TR7+ fibroblasts, while increased Ki-67+ epithelial cells. In DSS-induced chronic colitis models, CHST15 siRNA reduced CHST15 mRNA in the colon, DAI, alpha-smooth muscle actin+ fibroblasts and collagen deposition, while enhanced MH as evidenced by reduced histological and endoscopic scores. We also found that endoscopic submucosal injection achieved effective pancolonic delivery of CHST15 siRNA in mice. In human CCD-18 Co cells, CHST15 siRNA inhibited the expression of CHST15 mRNA and selectively reduced E-units, a specific product biosynthesized by CHST15, in the culture supernatant. CHST15 siRNA significantly suppressed vimentin in both TGF-ß-stimulated CCD18-Co cells and HCT116 cells while up-regulated BMP7 and E-cadherin in HCT116 cells. The present study demonstrated that blockade CHST15 represses colonic fibrosis and enhances MH partly though reversing EMT pathway, illustrating a novel therapeutic opportunity to refractory and fibrotic lesions in IBD.
EVALuna2:2164

Plasma concentrations of ascorbic acid in a cross section of the German population - Hagel, Alexander; Albrecht, Heinz; Dauth, Wolfgang; Hagel, Wolfgang; Vitali, Francesco; Ganzleben, Ingo; Schultis, Hans W.; Konturek, Peter C.; Stein, Juergen; Neurath, Markus; Raithel, Martin (Journal of International Medical Research, 2018)
Objectives Vitamin C deficiency is considered extremely rare in modern industrialized countries. This study was performed to assess vitamin C concentrations in the German population. Methods As part of a consultant-patient seminar on nutrition and food intolerances, patients were asked to participate in this study on a voluntary basis. Blood samples were taken for analysis of serum vitamin C concentrations, and all patients were asked to complete a questionnaire. The vitamin C concentration was determined by high-performance liquid chromatography. Results Of approximately 300 patients attending the seminar, 188 (62.6%) consented to vitamin C blood sample analysis and 178 (59.3%) answered the questionnaire. The mean vitamin C concentration was 7.98 mg/L (range, 0.50-17.40; reference range, 5-15 mg/L). A low plasma level with vitamin C insufficiency (<5 mg/L) was found in 31 patients (17.4%), and a potential scorbutogenic deficiency (<1.5 mg/L) was found in 6 (3.3%). Conclusions Potential vitamin C insufficiency and deficiency is common. It is therefore possible, even in modern developed populations, that certain individuals may require a higher intake of vitamin C.
EVALuna2:33798

Plasma histamine and tumour necrosis factor-alpha levels in Crohn's disease and ulcerative colitis at various stages of disease - Hagel, Alexander; De Rossi, T.; Konturek, Peter; Albrecht, H.; Walker, Stefanie Elke; Hahn, Eckhart Georg; Raithel, M. (Journal of Physiology and Pharmacology, 2015)
Mast cells secrete numerous mediators and this study investigated plasma levels of histamine, and tumor necrosis factor alpha (TNF-?) in chronic inflammatory bowel disease (IBD). Plasma levels of histamine were determined in 68 patients with Crohn's disease (CD), 22 with ulcerative colitis (UC) and 13 controls. TNF-? levels were assessed in 29 CD patients, 11 UC patients, and in 11 controls. Plasma histamine levels in the control group were 0.25 ng (0.14 - 0.33) and showed no difference to CD (0.19 ng, 0.09 - 0.35) or UC (0.23 ng, 0.11 - 0.60). Significantly lower histamine levels were only found in CD patients on 5-aminosalicylic acid treatment (P <= 0.04). Plasma TNF-? levels in the control group were significantly lower 0.44 ml/m(2) (0 - 1.15) than in CD patients (4.62 ml/m(2), 1.82 - 9.22, P = 0.005) or UC (3.14 ml/m(2); 0.08 - 11.34, P = 0.01). In CD disease activity, fistula, and extraintestinal manifestations (EM) were associated with significantly higher plasma TNF-? values, but not the type of treatment. We concluded that in contrast to TNF-?, histamine levels were normal in CD and UC. There is no correlation with histamine and thus the proportion of TNF-? secreted from mast cells in the plasma in patients with IBD is less important.
EVALuna2:2032

Pleiotropic functions of TNF-? in the regulation of the intestinal epithelial response to inflammation - Leppkes, Moritz; Roulis, Manolis; Neurath, Markus; Kollias, George; Becker, Christoph (International Immunology, 2014)
An important function of intestinal epithelial cells (IECs) is to maintain the integrity of the mucosal barrier. Inflammation challenges the integrity of the mucosal barrier and the intestinal epithelium needs to adapt to a multitude of signals in order to perform the complex process of maintenance and restitution of its barrier function. Dysfunctions in epithelial barrier integrity and restoration contribute to the pathogenesis of inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis. Mucosal healing has developed to a significant treatment goal in IBD. In this review, we would like to highlight physiologic and pathologic adaptations of the intestinal epithelium to inflammation, exemplified by its responses to TNF-?. A large body of literature exists that highlights the diverse effects of this cytokine on IECs. TNF-? modulates intestinal mucus secretion and constitution. TNF-? stimulation modulates paracellular flow via tight junctional control. TNF-? induces intracellular signaling cascades that determine significant cell fate decisions such as survival, cell death or proliferation. TNF-? impacts epithelial wound healing in ErbB- and Wnt-dependent pathways while also importantly guiding immune cell attraction and function. We selected important studies from recent years with a focus on functional in vivo data providing crucial insights into the complex process of intestinal homeostasis.
EVALuna2:1867

Point of Care detection of anti-infliximab antibodies in inflammatory bowel disease patients treated with the biosimilar SB2: performance comparison with ELISA - Atreya, Raja; Schmitt, H.; Fischer, Sven Moritz; Neurath, Markus; Rekalde, X.; Nagore, D.; Ametzazurra, A. (JOURNAL OF CROHNS & COLITIS, 2019)
CRIS-Team WoS Importer:2019-03-20

Polycystic Ovary Syndrome (PCOS) in Juvenile and Adult Type 1 Diabetes in a German/Austrian Cohort - Reinauer, Christina; Bollow, Esther; Froehlich-Reiterer, Elke; Laubner, Katharina; Bergis, Dominik; Schöfl, Christof; Kempe, Hans-Peter; Hummel, Michael; Hennes, Pia; Gollisch, Katja; Haberland, Holger; Datz, Nicolin; et al. (Experimental and Clinical Endocrinology and Diabetes, 2017)
Context While an association between PCOS and type 2 diabetes is well established, to date there have been few data on clinical care of type 1 diabetes (T1D) patients with PCOS. Objective The aim of our study was to characterize T1D patients with the comorbidity of PCOS within the DPV cohort with regard to diabetes phenotype, therapy and metabolic control. Design and Setting Clinical data from the prospective German/Austrian DPV cohort on patients with T1D and documented PCOS (n=76) were compared to female T1D controls (n=32,566) in reproductive age. Results The age at T1D manifestation in PCOS patients was later than in the control group (14.9±8.2 vs. 11.8±7.0 years, p<0.001). PCOS patients had higher BMI-SDS (0.92±0.11 vs. 0.38±0.01, p<0.001), metformin and oral contraceptives were used more frequently (p<0.001). A1c levels were significantly lower (7.92 +/- 0.23% vs. 8.43±0.01%, p<0.05) despite of lower insulin requirements (0.76±0.04 IU/kg/d vs. 0.84±0.00 IU/kg/d, p<0.05). In the PCOS group, higher rates of dyslipidemia (63.4 vs. 48.7%, p =0.032) and thyroid disorders (42.2% vs. 21.2%, p<0.001) were present. Discussion While patients with T1D and comorbid PCOS showed features of a "type 1.5 diabetes" phenotype, insulin requirements per kg body weight were not higher and metabolic control was better, which could be explained only partially by additional metformin therapy. A more precise genetic and metabolic characterisation of these patients is needed to answer open questions on the underlying autoimmune process and residual ß-cell function.
EVALuna2:33890

Polyol pathway links glucose metabolism to the aggressiveness of cancer cells - Schwab, Annemarie; Siddiqui, Aarif; Vazakidou, Maria Eleni; Napoli, Francesca; Böttcher, Martin; Menchicchi, Bianca; Raza, Umar; Saatci, Ozge; Krebs, Angela; Ferrazzi, Fulvia; Rapa, Ida; Dettmer-Wilde, Katja; et al. (Cancer Research, 2018)
Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGF-? signature genes. Excess glucose was found to promote EMT through autocrine TGF-? stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target.
EVALuna2:10237

Poor agreement between endoscopists and gastrointestinal pathologists for the interpretation of probe-based confocal laser endomicroscopy findings - Peter, Shajan; Council, Leona; Bang, Ji Young; Neumann, Helmut; Moenkemueller, Klaus; Varadarajulu, Shyam; Wilcox, Charles Melbern (World Journal of Gastroenterology, 2014)
To compare the interpretation of probe-based confocal laser endomicroscopy (pCLE) findings between endoscopists and gastrointestinal (GI)-pathologists.All pCLE procedures were undertaken and the endoscopist rendered assessment. The same pCLE videos were then viewed offline by an expert GI pathologist. Histopathology was considered the gold standard for definitive diagnosis. The sensitivity, specificity and accuracy for diagnosis of dysplastic/ neoplastic GI lesions and interobserver agreement between endoscopists and experienced gastrointestinal pathologist for pCLE findings were analyzed.Of the 66 included patients, 40 (60.6%) had lesions in the esophagus, 7 (10.6%) in the stomach, 15 (22.7%) in the biliary tract, 3 (4.5%) in the ampulla and 1 (1.5%) in the colon. The overall sensitivity, specificity and accuracy for diagnosing dysplastic/neoplastic lesions using pCLE were higher for endoscopists than pathologist at 87.0% vs 69.6%, 80.0% vs 40.0% and 84.8% vs 60.6% (P = 0.0003), respectively. Area under the ROC curve (AUC) was greater for endoscopists than the pathologist (0.83 vs 0.55, P = 0.0001). Overall agreement between endoscopists and pathologist was moderate for all GI lesions (K = 0.43; 95%CI: 0.26-0.61), luminal lesions (K = 0.40; 95%CI: 0.20-0.60) and those of dysplastic/neoplastic pathology (K = 0.55; 95%CI: 0.37-0.72), the agreement was poor for benign (K = 0.13; 95%CI: -0.097-0.36) and pancreaticobiliary lesions (K = 0.19; 95%CI: -0.26-0.63).There is a wide discrepancy in the interpretation of pCLE findings between endoscopists and pathologist, particularly for benign and malignant pancreaticobiliary lesions. Further studies are needed to identify the cause of this poor agreement.
EVALuna2:1916

Portal Vein Thrombosis due to Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT) after Covid Vaccination with ChAdOx1 nCoV-19 - Strobel, Deike; Haberkamp, Sophie; Zundler, Sebastian (Ultraschall in der Medizin, 2021)
CRIS-Team Scopus Importer:2021-10-22

Positionspapier „Universitäre Karrierewege“ - Staudacher, Jonas J.; Backes, Moritz; Bettinger, Dominik; Blüthner, Elisabeth; Dietz-Fricke, Christopher; Dugic, Ana; Fusco, Stefano; Garbe, Jakob; Goeser, Felix; Guliyeva, Sura; Hamesch, Karim; Hollenbach, Marcus; et al. (Zeitschrift für Gastroenterologie, 2023)
CRIS-Team Scopus Importer:2023-08-25

Positionspapier zur Befunderhebung von Darmultraschallbefunden bei chronisch entzündlichen Darmerkrankungen - Kucharzik, Torsten; Atreya, Raja; Bachmann, Oliver; Baumgart, Daniel C.; Daebritz, Jan; Helwig, Ulf; Janschek, Johannes; Kienle, Peter; Langhorst, Jost; Mudter, Jonas; Schmidt, Carsten; Schreyer, Andreas G.; et al. (Zeitschrift für Gastroenterologie, 2022)
Background Intestinal ultrasound is increasingly used for primary diagnosis, detection of complications and monitoring of patients with Crohn's disease and ulcerative colitis. Standardization of reporting is relevant to ensure quality of the methodology and to improve communication between different specialties. The current manuscript describes the features required for optimized reporting of intestinal ultrasound findings in inflammatory bowel disease (IBD). Methods An expert consensus panel of gastroenterologists, radiologists, pathologists, paediatric gastroenterologists and surgeons conducted a systematic literature search. In a Delphi- process members of the Kompetenznetz Darmerkrankungen in collaboration with members of the German Society for Radiology (DRG) voted on relevant criteria for reporting of findings in intestinal ultrasound. Based on the voting results statements were agreed by expert consensus. Results Clinically relevant aspects of intestinal ultrasound (IUS) findings have been defined to optimize reporting and to standardize terminology. Minimal requirements for standardized reporting are suggested. The statements focus on description of disease activity as well as on complications of IBD. Attributes of intestinal inflammation are described and illustrated by exemplary images. Conclusion The current manuscript provides practical recommendations on how to standardize documentation and reporting from intestinal ultrasound findings in patients with IBD.
CRIS-Team Scopus Importer:2022-06-17
Keywords: cross sectional imaging; IBD; intestinal ultrasound; reporting

Positionspapier zur Befunderstellung endoskopischer Untersuchungen bei Patienten mit chronisch-entzündlichen Darmerkrankungen - Schmidt, Carsten; Bachmann, Oliver; Baumgart, Daniel C.; Goetz, Martin; Drvarov, Oliver; Kucharzik, Torsten F.; Kuehbacher, Tanja; Langhorst, Jost; Maul, Jochen; Mohl, Wolfgang; Mudter, Jonas; Repp, Michael; et al. (Zeitschrift für Gastroenterologie, 2021)
The complete and reliable documentation of endoscopic findings make up the crucial foundation for the treatment of patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. These findings are, on the one hand, a prerequisite for therapeutic decisions and, on the other hand, important as a tool for assessing the response to ongoing treatments. Endoscopic reports should, therefore, be recorded according to standardized criteria to ensure that the findings of different endoscopists can be adequately compared and that changes in the course of the disease can be traced back. In consideration of these necessities, fifteen members of the Imaging Working Group of the German Kompetenznetz Darmerkrankungen have created a position paper proposing a structure and specifications for the documentation of endoscopic exams. In addition to the formal report structure, the recommendations address a large number of attributes of acute and chronic inflammatory alterations as well as endoscopically detectable complications, which are explained in detail and illustrated using exemplary images. In addition, more frequently used endoscopic activity indices are presented and their use in everyday clinical practice is discussed.
CRIS-Team Scopus Importer:2021-08-06
Keywords: colonoscopy; Crohn's disease; Endoscopy; enteroscopy; gastroscopy; IBD; terminology; ulcerative colitis; video capsule endoscopy

Post-COVID-19 Syndrome: Retinal Microcirculation as a Potential Marker for Chronic Fatigue - Schlick, Sarah; Lucio, Marianna; Wallukat, Gerd; Bartsch, Alexander; Skornia, Adam; Hoffmanns, Jakob; Szewczykowski, Charlotte; Schröder, Thora; Raith, Franziska; Rogge, Lennart; Heltmann, Felix; Moritz, Michael; et al. (International Journal of Molecular Sciences, 2022)
Post-COVID-19 syndrome (PCS) is characterized by persisting sequelae after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PCS can affect patients with all COVID-19 disease severities. As previous studies have revealed impaired blood flow as a provoking factor triggering PCS, it was the aim of the present study to investigate the potential association between self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker. A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT angiography (OCT-A) and quantified using the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic fatigue (CF) was assessed according to the variables of Bell’s score, age and gender. VDs in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed, considering the repetitions (12 times). Seropositivity for autoantibodies targeting G protein-coupled receptors (GPCR-AAbs) was determined by an established cardiomyocyte bioassay. Taking account of the repetitions, a mixed model was performed to detect possible differences in the least square means between the different groups included in the analysis. An age effect in relation to VD was observed between patients and controls (p < 0.0001). Gender analysis showed that women with PCS showed lower VD levels in the SVP compared to male patients (p = 0.0015). The PCS patients showed significantly lower VDs in the ICP as compared to the controls (p = 0.0001 (CI: 0.32; 1)). Moreover, considering PCS patients, the mixed model revealed a significant difference between those with chronic fatigue (CF) and those without CF with respect to VDs in the SVP (p = 0.0033 (CI: −4.5; −0.92)). The model included variables of age, gender and Bell’s score, representing a subjective marker for CF. Consequently, retinal microcirculation might serve as an objective biomarker in subjectively reported chronic fatigue in patients with PCS.
CRIS-Team Scopus Importer:2022-12-09
Keywords: chronic fatigue; chronic fatigue syndrome; COVID-19; functional GPCR autoantibodies; long COVID syndrome; OCT angiography; post-COVID-19 syndrome; retinal microcirculation

Postictal agitation after electroconvulsive therapy - Tzabazis, Alexander Z.; Schmitt, Heike; Münster, Tino (Journal of Ect, 2014)
EVALuna2:16664

Postinterventional pain and complications of sonographically guided interventions in the liver and pancreas - Lindner, A.; Frieser, M.; Heide, R.; Wildner, D.; Neurath, Markus; Dauth, W.; Bernatik, T.; Strobel, Deike (Ultraschall in der Medizin, 2014)
Sonographically guided interventions in abdominal organs are routine procedures with rare severe complications. However, potential patient discomfort or pain is frequently not addressed in the literature.In a prospective 1-year study, the peri- and postinterventional pain of patients undergoing sonographically guided punctures of the liver and pancreas was analyzed. Data acquisition was done with a standardized questionnaire. This included three numeric rating scales (NRS) ranging from "0" to "10" to be answered at puncture and 1 hour and 4 hours later. Data concerning complications and administered analgesic medication was acquired from the patients' charts.223/274 patients could be analyzed (83 %). 91 women (40.8 %) and 132 men (59.2 %) were included. The mean age was 56.0 yrs. Overall the average level of pain was 2.98 at puncture, 1.21 after 1 hour and 0.71 after 4 hours. In patients with diagnostic biopsies, the pain levels were 3.37(0 h)/1.33(1 h)/0.71(4 h) for liver parenchyma, 2.64(0 h)/0.95(1 h)/0.65(4 h) for focal liver lesions and 3.1(0 h)/1.9(1 h)/1.1(4 h) for pancreatic punctures. The pain levels at therapeutic interventions were 3.00(0 h)/2.00(1 h)/0.50(4 h). Female and younger (< 50 yrs) patients had statistically significantly more pain at puncture and 1 hour postintervention. Only minor complications occurred (0.9 %).Severe pain after sonographically guided interventions is rare. Most patients suffer only from mild pain postinterventionally.
EVALuna2:1874

Practical recommendations for the management of patients with gastroenteropancreatic and thoracic (carcinoid) neuroendocrine neoplasms in the COVID-19 era - Rodriguez-Freixinos, Víctor; Capdevila, Jaume; Pavel, Marianne Ellen; Thawer, Alia; Baudin, Eric; O'Toole, Dermot; Herrmann, Ken; Welin, Staffan; Grozinsky-Glasberg, Simona; de Herder, Wouter W.; Valle, Juan W.; Herman, Jackie; et al. (European Journal of Cancer, 2021)
Neuroendocrine neoplasms (NENs) are a heterogeneous family of uncommon tumours with challenging diagnosis, clinical management and unique needs that almost always requires a multidisciplinary approach. In the absence of guidance from the scientific literature, along with the rapidly changing data available on the effect of COVID-19, we report how 12 high-volume NEN centres of expertise in 10 countries at different stages of the evolving COVID-19 global pandemic along with members of international neuroendocrine cancer patient societies have suggested to preserve high standards of care for patients with NENs. We review the multidisciplinary management of neuroendocrine neoplasms during the COVID-19 pandemic, and we suggest potential strategies to reduce risk and aid multidisciplinary treatment decision-making. By sharing our joint experiences, we aim to generate recommendations for proceeding to other institutions facing the same challenges.
CRIS-Team Scopus Importer:2021-02-12
Keywords: Carcinoid tumours; COVID-19; Gastroenteropancreatic neuroendocrine tumour; Lung neuroendocrine tumours; Neuroendocrine tumours

Prebiotic Inulin and Sodium Butyrate Attenuate Obesity-Induced Intestinal Barrier Dysfunction by Induction of Antimicrobial Peptides - Beisner, Julia; Filipe Rosa, Louisa; Kaden-Volynets, Valentina; Stolzer, Iris; Günther, Claudia; Bischoff, Stephan C. (Frontiers in Immunology, 2021)
Defects in the mucosal barrier have been associated with metabolic diseases such as obesity and non-alcoholic fatty liver disease (NAFLD). Mice fed a Western-style diet (WSD) develop obesity and are characterized by a diet-induced intestinal barrier dysfunction, bacterial endotoxin translocation and subsequent liver steatosis. To examine whether inulin or sodium butyrate could improve gut barrier dysfunction, C57BL/6 mice were fed a control diet or a WSD ± fructose supplemented with either 10% inulin or 5% sodium butyrate for 12 weeks respectively. Inulin and sodium butyrate attenuated hepatosteatitis in the WSD-induced obesity mouse model by reducing weight gain, liver weight, plasma and hepatic triglyceride level. Furthermore, supplementation with inulin or sodium butyrate induced expression of Paneth cell α-defensins and matrix metalloproteinase-7 (MMP7), which was impaired by the WSD and particularly the fructose-added WSD. Effects on antimicrobial peptide function in the ileum were accompanied by induction of β-defensin-1 and tight junction genes in the colon resulting in improved intestinal permeability and endotoxemia. Organoid culture of small intestinal crypts revealed that the short chain fatty acids (SCFA) butyrate, propionate and acetate, fermentation products of inulin, induce Paneth cell α-defensin expression in vitro, and that histone deacetylation and STAT3 might play a role in butyrate-mediated induction of α-defensins. In summary, inulin and sodium butyrate attenuate diet-induced barrier dysfunction and induce expression of Paneth cell antimicrobials. The administration of prebiotic fiber or sodium butyrate could be an interesting therapeutic approach to improve diet-induced obesity.
CRIS-Team Scopus Importer:2021-07-09
Keywords: antimicrobial peptides; butyrate; defensin; innate immunity; inulin; NAFLD; obesity

Precision Medicine in Inflammatory Bowel Diseases - Fischer, Sören; Neurath, Markus (Clinical Pharmacology & Therapeutics, 2017)
Inflammatory bowel diseases (IBDs) are a lifelong condition of chronic, recurrent inflammation in the gut. The introduction of immunomodulators and biologic agents markedly improved the treatment of IBDs. Therefore, the use of biologics became an essential element in the rational therapy of IBDs. Various substances are currently evaluated in clinical trials, addressing different target structures and offering further approaches in the field of IBD. Regarding the growing number of treatment options, the need for prediction of therapy response became a necessity and is the subject of the present research.
EVALuna2:33803

Precision of handheld multispectral optoacoustic tomography for muscle imaging - Wagner, Anna; Danko, Vera; Federle, Anna; Klett, Daniel; Simon, David; Heiß, Rafael; Jüngert, Jörg M.; Uder, Michael; Schett, Georg; Neurath, Markus; Wölfle, Joachim; Waldner, Maximilian; et al. (Photoacoustics, 2021)
Photo-or optoacoustic imaging (OAI) allows quantitative imaging of target tissues. Using multi-wavelength illumination with subsequent ultrasound detection, it may visualize a variety of different chromophores at centimeter depth. Despite its non-invasive, label-free advantages, the precision of repeated measurements for clinical applications is still elusive. We present a multilayer analysis of n = 1920 imaging datasets obtained from a prospective clinical trial (NCT03979157) in n = 10 healthy adult volunteers. All datasets were analyzed for 13 single wavelengths (SWL) between 660 nm–1210 nm and five MSOT-parameters (deoxygenated/oxygenated/total hemoglobin, collagen and lipid) by a semi-automated batch mode software. Intraclass correlation coefficients (ICC) were good to excellent for intrarater (SWL: 0.82–0.92; MSOT-parameter: 0.72−0.92) and interrater reproducibility (SWL: 0.79−0.87; MSOT-parameter: 0.78−0.86), with the exception for MSOT-parameter lipid (interrater ICC: 0.56). Results were stable over time, but exercise-related effects as well as inter-and intramuscular variability were observed. The findings of this study provide a framework for further clinical OAI implementation.
CRIS-Team Scopus Importer:2020-12-25
Keywords: MSOT; Multispectral optoacoustic tomography; Muscle imaging; Optoacoustics; Photoacoustics

Predicting Therapeutic Response by in vivo Molecular Imaging in Inflammatory Bowel Diseases - Atreya, Raja; Neurath, Markus (Digestive Diseases, 2016)
Different invasive and non-invasive imaging modalities are indispensable tools in the management of inflammatory bowel disease (IBD) patients. Standard imaging procedures like white light endoscopy or MRI are used to define gut inflammation based on structural changes and altered morphology of the mucosa. Nevertheless, it has thus far not been possible to analyse biological processes at the cellular level, which drive intestinal inflammation in IBD patients. The recent advent of molecular imaging in the field of IBD has opened new promising avenues to allow personalized medicine approaches based on in vivo-detected molecular findings.Recent clinical studies have attempted to address the issue of predicting therapeutic response to anti-tumor necrosis factor (TNF) treatment in IBD patients based on the molecular mechanism of action of these agents and corresponding in vivo assessment of mucosal immune responses. Several experimental studies have indicated that one of the main functions of efficacious anti-TNF therapy in IBD is the induction of intestinal cell apoptosis. Fittingly, a corresponding molecular-imaging study using single-photon emission CT for the localization and quantification of cell apoptosis, demonstrated that induction of mucosal T-cell apoptosis correlated with the therapeutic response to anti-TNF therapy in Crohn's disease patients. There was moreover a predictive capacity regarding therapeutic efficacy. As the main biological properties of anti-TNF antibodies in IBD are mediated through binding to membrane-bound TNF (mTNF) expressing intestinal cells, another study used molecular imaging for in vivo visualization of these cells via fluorescent anti-TNF antibodies to predict therapeutic efficacy of these agents. It could be shown that patients with high amounts of mTNF positive cells showed significantly better response rates compared to patients with low amounts of mTNF positive cells.In vivo molecular imaging in IBD has the potential to have an impact on our current treatment approaches and may allow us to individualize specific therapies based on molecular level analysis.
EVALuna2:2092

Prediction of clinical outcomes in Crohn's disease by using confocal laser endomicroscopy: results from a prospective multicenter study - Tontini, Gian Eugenio; Mudter, Jonas; Günther, Claudia; Milani, Valentina; Atreya, Raja; Rath, Timo; Nagel, Andreas; Hatem, Giorgia; Sturniolo, Giacomo Carlo; Vecchi, Maurizio; Neurath, Markus; Galle, Peter R.; et al. (Gastrointestinal Endoscopy, 2018)
BACKGROUND AND AIMS: Assessment of prognostic factors in patients with Crohn's disease (CD) is of pivotal importance for early intervention and "treat-to-target" strategies. Confocal laser endomicroscopy (CLE) enables on-demand in vivo characterization of mucosal inflammatory and architectural changes during endoscopy. We prospectively assessed the value of CLE for prediction of clinical outcome parameters in CD. METHODS: Consecutive patients with CD undergoing colonoscopy were included in a multicenter study. Confocal imaging focused on 2 highly reproducible histologic hallmarks of active colonic inflammation: focal cryptitis and crypt architectural abnormality. We evaluated whether CLE, CD endoscopic index of severity (CDEIS), serum C-reactive protein (CRP), and CD activity index (CDAI) were associated with the risk of medical treatment escalation, transmural adverse events, and CD-related hospitalization or surgery during a 4-year follow-up. RESULTS: Among 49 patients (53% men, median age, 39 years), baseline CRP was ≥5 mg/L in 47%, CDEIS ≥3 in 75%, and CDAI >150 in 51%. Focal cryptitis and crypt architectural abnormality were observed in 63% (CLE+ group). CLE+ patients showed an increased incidence of medical treatment escalation (P < .001; relative risk [RR] = 3.27) and transmural lesions (P = .025; RR = 1.70), whereas patients with CRP ≥5 mg/L had increased CD-related hospitalization and surgery (P = .020, RR = 2.71) at 1-year follow-up. No further association with prognostic clinical outcomes was found over the 1-year follow-up as well as for CDEIS and CDAI at any time. CONCLUSIONS: CLE reveals CD-related features of mucosal inflammation and allows for early prediction of relevant clinical outcomes. Further studies should now address whether this promising prognostic tool could refine the timing of treatment strategies in patients with CD.
EVALuna2:35166

Prediction of COVID-19 deterioration in high-risk patients at diagnosis: an early warning score for advanced COVID-19 developed by machine learning - Jakob, Carolin E. M.; Mahajan, Ujjwal Mukund; Oswald, Marcus; Stecher, Melanie; Schons, Maximilian; Mayerle, Julia; Rieg, Siegbert; Pletz, Mathias; Merle, Uta; Wille, Kai; Borgmann, Stefan; Spinner, Christoph D.; et al. (Infection, 2021)
Purpose While more advanced COVID-19 necessitates medical interventions and hospitalization, patients with mild COVID-19 do not require this. Identifying patients at risk of progressing to advanced COVID-19 might guide treatment decisions, particularly for better prioritizing patients in need for hospitalization. Methods We developed a machine learning-based predictor for deriving a clinical score identifying patients with asymptomatic/mild COVID-19 at risk of progressing to advanced COVID-19. Clinical data from SARS-CoV-2 positive patients from the multicenter Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) were used for discovery (2020-03-16 to 2020-07-14) and validation (data from 2020-07-15 to 2021-02-16). Results The LEOSS dataset contains 473 baseline patient parameters measured at the first patient contact. After training the predictor model on a training dataset comprising 1233 patients, 20 of the 473 parameters were selected for the predictor model. From the predictor model, we delineated a composite predictive score (SACOV-19, Score for the prediction of an Advanced stage of COVID-19) with eleven variables. In the validation cohort (n = 2264 patients), we observed good prediction performance with an area under the curve (AUC) of 0.73 +/- 0.01. Besides temperature, age, body mass index and smoking habit, variables indicating pulmonary involvement (respiration rate, oxygen saturation, dyspnea), inflammation (CRP, LDH, lymphocyte counts), and acute kidney injury at diagnosis were identified. For better interpretability, the predictor was translated into a web interface. Conclusion We present a machine learning-based predictor model and a clinical score for identifying patients at risk of developing advanced COVID-19.
CRIS-Team WoS Importer:2021-07-30

Prediction of disease progression and treatment success: Importance of individualized treatment approaches Prädiktion von Krankheitsverlauf und Therapieerfolg: Stellenwert individualisierter Therapieansätze - Atreya, Raja (Die Gastroenterologie, 2023)
Background: Although the introduction of targeted therapies has led to a significant improvement in the care of patients with inflammatory bowel diseases (IBD), only a subgroup of the treated patients benefit from the initiated treatments. Furthermore, the individual disease course in patients with IBD is often unclear. Objectives: To what extent are currently available predictive biomarkers able to predict treatment response and disease progression in IBD patients? Materials and methods: Evaluation of available studies that have characterized potential biomarkers to evaluate treatment response and disease progression. Results: Substantial progress has been made in various areas of biomarker studies to identify relevant biomarkers, yet their use in clinical practice is still not foreseeable. Conclusion: Potential biomarkers must be validated in independent cohorts with comparable endpoints before they can be used in daily clinical practice.
CRIS-Team Scopus Importer:2023-12-22
Keywords: Biologicals; Biomarkers; Infliximab; Precision medicine; Therapy resistance

Predictors of Delayed Response to Tofacitinib: Results of the OCTAVE Open Study for Delayed Responders - Regueiro, Miguel; Kinnucan, Jami A.; Ungaro, Ryan; Quirk, Daniel; Su, Chinyu; Lawendy, Nervin; Fan, Haiyun; Woodworth, Deborah A.; Neurath, Markus (AMERICAN JOURNAL OF GASTROENTEROLOGY, 2019)
CRIS-Team WoS Importer:2020-02-28

Preliminary results for hyperspectral videoendoscopy diagnostics on the phantoms of normal and abnormal tissues: towards gastrointestinal diagnostics - Hohmann, Martin; Douplik, Alexandre; Varadhachari, Janani; Nasution, Aulia; Mudter, Jonas; Neurath, Markus; Schmidt, Michael (mudter jonas, 2011)

Pre-Treatment Tumor Growth Rate (TGR0) in Patients Diagnosed with Well-Differentiated Neuroendocrine Tumors (NETs) Treated with Systemic Therapies: Subgroup Analysis of the GREPONET Study - Crona, J.; Lamarca, A.; Ronot, M.; Opalinska, M.; Lopez Lopez, C.; Pezzutti, D.; Vidal Trueba, H.; Carvhalo, L.; De Mestier, L.; Najran, P.; Pavel, Marianne Ellen; Dromain, C. (2018)
EVALuna2:34117

PREVALENCE AND CHARACTERISTICS OF SPONDYLOARTHRITIS ACCORDING TO ASAS CRITERIA IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE - RESULTS FROM THE SPICE COHORT - Haschka, J.; Hirschmann, S.; Kleyer, Arnd; Englbrecht, Matthias; Zimmermann, Julia; Faustini, F.; Simon, David; Figueiredo, C. P.; Muschitz, C.; Kocijan, R.; Resch, H.; Atreya, Raja; et al. (2017)
EVALuna2:33811

Prevalence and overlap of sarcopenia, frailty, cachexia and malnutrition in older medical inpatients - Gingrich, Anne; Volkert, Dorothee; Kießwetter, Eva; Thomanek, Marta; Bach, Svenja; Sieber, Cornel; Zopf, Yurdagül (BMC Geriatrics, 2019)
Background: Sarcopenia, frailty, cachexia and malnutrition are widespread syndromes in older people, characterized by loss of body tissue and related to poor outcome. The aim of the present cross-sectional study was to assess the prevalence of these syndromes and their overlap in older medical inpatients. Methods: Patients aged 70 years or older who had been admitted to the internal medical department of a German university hospital were recruited. Sarcopenia, frailty, cachexia and malnutrition were assessed in a standardized manner according to current consensus definitions. Prevalence rates of these syndromes and their constituents and the concurrent occurrence of the syndromes (overlap) were calculated. Results: One hundred patients (48 female) aged 76.5 ± 4.7 years with a BMI of 27.6 ± 5.5 kg/m 2 were included. The main diagnoses were gastroenterological (33%) and oncological diseases (31%). Sarcopenia was present in 42%, frailty in 33%, cachexia in 32% and malnutrition in 15% of the patients. 63% had at least one syndrome: 32% one, 11% two, 12% three and 8% all four. All four syndromes are characterized by significant weight loss during the last 12 months, which was most pronounced in malnourished patients and least pronounced in frail patients, and by significantly reduced physical performance. All syndromes were significantly pairwise related, except malnutrition and frailty. In 19% of patients sarcopenia and frailty occurred concurrently, in 20% frailty and cachexia and in 22% sarcopenia and cachexia with or without additional other syndromes. All malnourished patients except one were also cachectic (93%) and 80% of malnourished patients were also sarcopenic. 53% of malnourished patients were in addition frail, and these patients were affected by all four syndromes. Conclusions: Nearly two thirds of older medical inpatients had at least one of the tissue loss syndromes sarcopenia, frailty, cachexia and malnutrition. The syndromes overlapped partly and were interrelated. Future studies with larger patient groups and longitudinal design are required to clarify the significance of single and concurrent occurrence of these syndromes for clinical outcome and successful therapy.
CRIS-Team Scopus Importer:2019-05-17
Keywords: Cachexia; Frailty; Malnutrition; Sarcopenia; Weight loss

Prevalence and predictors of dropout from high-intensity interval training in sedentary individuals: A meta-analysis - Reljic, Dejan; Lampe, David; Wolf, Franziska; Zopf, Yurdagül; Herrmann, Hans Joachim; Fischer, Joachim (Scandinavian journal of medicine & science in sports, 2019)
Recent evidence suggests that high-intensity interval training (HIIT) is an effective method to improve fitness and various health markers. However, the tolerability and acceptability of HIIT among sedentary individuals is currently controversially discussed. Therefore, our objective was to investigate the prevalence and predictors of dropout among sedentary individuals in HIIT-based exercise interventions. MEDLINE/PubMed, SPORTDiscus, and Web of Science were searched systematically for relevant articles until 06/2018. Studies included were required to (a) be written in English, (b) include sedentary healthy adults, (c) use some form of HIIT without any complementary intervention, (d) last ≥4 weeks, (e) report detailed description of the applied HIIT protocol, and (f) report data that allow calculation of a dropout rate. Fifty-five studies reporting results from 67 HIIT interventions with 1318 participants met the eligibility criteria. The trim and fill adjusted pooled dropout rate across all interventions was 17.6% (95% confidence interval 14.2-21.5%). Dropout rates were significantly lower in cycling-based interventions compared with studies using running/walking as exercise modality (P < 0.001). Longer session time (β = 0.02, P < 0.05), higher time effort/week (β = 0.005, P < 0.05), and overall time effort/intervention (β = 0.0003, P < 0.05) predicted greater dropout. Exercise intensity was not related to dropout. Our data suggest that HIIT-based interventions are tolerable and acceptable for previously sedentary individuals, exhibiting generally lower dropout rates than commonly reported for traditional exercise programs. Given the association between HIIT volume and dropouts, future studies should further focus on identifying the minimally effective dose of practical HIIT for improving health status. Such efforts would be important to increase implementation and public health impact of HIIT.
CRIS-Team Scopus Importer:2019-06-18
Keywords: cardiorespiratory fitness; exercise adherence; feasibility; health promotion; public health; sprint interval training

Primary aortoduodenal fistula - Overlooked because of guidelines? - Wiesmüller, Felix; Neufert, Clemens; Croner, Roland; Lang, Werner; Grützmann, Robert; Siebler, Jürgen (Innovative Surgical Science, 2020)
Primary aortoduodenal fistula is an uncommon yet mostly lethal finding. We present a case of a 63 year-old male who exhibited significant upper gastrointestinal bleeding and hemorrhagic shock. Repeated endoscopies did not detect any source of bleeding. Emergency laparotomy disclosed an aortoduodenal fistula. Despite intense medical efforts for several months the patient did not fully recover and treatment was limited to palliative care. In light of the substantial mortality associated with this condition, computed tomography imaging should be performed in case of doubt to prevent delayed diagnosis.
CRIS-Team Scopus Importer:2020-11-20
Keywords: aortoduodenal fistula; aortoenteric fistula; gastrointestinal bleeding; PADF; primary aortoduodenal fistula

Primary biliary cholangitis-established and novel therapies - Vetter, Marcel; Kremer, Andreas (Internist, 2018)
BACKGROUND: Patients with primary biliary cholangitis (PBC, formerly primary biliary cirrhosis) and insufficient treatment response or risk factors exhibit a remarkably increased risk for disease progression and associated complications. Furthermore, extrahepatic manifestations may considerably reduce quality of life in affected patients. OBJECTIVES: This article presents an overview on standard therapy with ursodeoxycholic acid (UDCA) and further therapeutic options in patients with insufficient treatment response. In addition, symptom-orientated therapies will be presented in a practical and compact way. METHODS: The current European and German guidelines from 2017 in addition to several research papers and expert opinions are the basis for this review. RESULTS: Every PBC patient should be treated with UDCA life-long. In case of insufficient response to UDCA, obeticholic acid (OCA) has been approved as second line therapy since 2016. Fibrates and budesonide present off-label options for certain patient subpopulations. Pruritus should initially be treated with colestyramine. In case of insufficient efficacy or intolerance, rifampicin represents the most effective off-label option. If fatigue is present, differential diagnoses shall be excluded and coping strategies combined with regular physical activity can have a positive effect. CONCLUSION: UDCA and OCA are effective and approved drugs for treating PBC. Patients with insufficient treatment response or risk factors have to be treated consequently. Due to the improved anti-cholestatic treatment options, therapies to reduce fatigue and pruritus are increasingly important.
EVALuna2:35165

Primary Manifestation of Inflammatory Bowel Disease Following Subcutaneous Autovaccination - Raithel, Martin; Weidenhiller, Michael; Hahn, Markus; Hagel, Alexander; Bechthold, Caroline; Neurath, Markus; Rieker, Ralf J.; Stein, Juergen (Journal of Crohns & Colitis, 2015)
Onset of inflammatory bowel disease [IBD] is nowadays seen as an interplay or a combination of genetic susceptibility, disturbed intestinal immunity, and environmental factors including gut microbiome. However, the initiation of inflammation and progression to IBD pathogenesis in a given individual is poorly understood. In this case report we describe the clinical course of a 17-year-old female patient developing symptoms suggestive of IBD after 'autovaccine therapy', in which sterilised samples of the patient's own stool were injected subcutaneously for improvement of her general immunity. The patient presented with a severe onset of disease, which was first suspected to be ulcerative colitis on outpatient examination and was later corrected to IBD with Crohn's-like features due to high systemic inflammation, mixed lymphocytic-granulocytic infiltrates in gastric biopsies, and further characteristics suggestive of Crohn's disease. A prolonged and complicated course was seen with intermittent steroid dependency in the long term. Numerous publications postulate that [auto-]immune reactions against resident bacterial stool flora may play a role in IBD. It is possible that in this patient tolerance to endogenous bacteria was disrupted by systemic pro-inflammatory mechanisms induced by autovaccination.
EVALuna2:1971

Probe based confocal laser endomicroscopy of the pancreatobiliary system - Almadi, Majid A.; Neumann, Helmut (World Journal of Gastroenterology, 2015)
To review applications of confocal laser endomicroscopy (CLE) in pancreatobiliary lesions and studies that assessed training and interpretation of images.A computerized literature search was performed using OVID MEDLINE, EMBASE, Cochrane library, and the ISI Web of Knowledge from 1980 to October 2014. We also searched abstracts from major meetings that included the Digestive Disease Week, Canadian Digestive Disease Week and the United European Gastroenterology Week using a combination of controlled vocabulary and text words related to pCLE, confocal, endomicroscopy, probe-based confocal laser endomicroscopy, and bile duct to identify reports of trials. In addition, recursive searches and cross-referencing was performed, and manual searches of articles identified after the initial search was also completed. We included fully published articles and those in abstract form. Given the relatively recent introduction of CLE we included randomized trials and cohort studies.In the evaluation of indeterminate pancreatobiliary strictures CLE with ERCP compared to ERCP alone can increase the detection of cancerous strictures with a sensitivity of (98% vs 45%) and has a negative predictive value (97% vs 69%), but decreased the specificity (67% vs 100%) and the positive predictive value (71% vs 100%) when compared to index pathology. Modifications in the classification systems in indeterminate biliary strictures have increased the specificity of pCLE from 67% to 73%. In pancreatic cystic lesions there is a need to develop similar systems to interpret and characterize lesions based on CLE images obtained. The presence of superficial vascular network predicts serous cystadenomas accurately. Also training in acquiring and interpretation of images is feasible in those without any prior knowledge in CLE in a relatively simple manner and computer-aided diagnosis software is a promising innovation.The role of pCLE in the evaluation of pancreatobiliary disorders might be better suited for those with an intermediate and low probability.
EVALuna2:2108

Prognosis and Management of Advanced Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors (G3 NETs): A NET-CONNECT Study Performed in Four Expert Centers - De Mestier, L.; Lamarca, A.; Hernando-Cubero, J.; Alonso Gordoa, T.; Cros, J.; Chakrabarty, B.; Landolfi, S.; Palacios, J.; Thomlinson, V.; Pavel, Marianne Ellen; Capdevila, J. (NEUROENDOCRINOLOGY, 2020)
CRIS-Team WoS Importer:2020-04-10

Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum - Abu-Hayyeh, Shadi; Ovadia, Caroline; Lieu, Tinamarie; Jensen, Dane D.; Chambers, Jenny; Dixon, Peter H.; Lövgren-Sandblom, Anita; Bolier, Ruth; Tolenaars, Dagmar; Kremer, Andreas; Syngelaki, Argyro; Noori, Muna; et al. (Hepatology, 2015)
A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP), or due to benign pruritus gravidarum (PG). ICP is characterised by raised serum bile acids, and complicated by spontaneous preterm labour and stillbirth. A biomarker for ICP would be invaluable for the early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n=35/80, uncomplicated pregnancy=29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from PG (group 2: ICP n=41, PG n=14). In a third group of first trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n=54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice.Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP. This article is protected by copyright. All rights reserved.
EVALuna2:2027

Prognostic Significance of Somatostatin Receptor Heterogeneity in Progressive Neuroendocrine Tumor Treated with Lu-177 DOTATOC or Lu-177 DOTATATE - Graf, Josephine; Pape, Ulrich Frank; Jann, Henning; Denecke, Timm; Arsenic, Ruza; Brenner, Winfried; Pavel, Marianne Ellen; Prasad, Vikas (European Journal of Nuclear Medicine and Molecular Imaging, 2019)
Aim: One of the primary prerequisites for peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine tumors (NET) is the presence of somatostatin receptors (SSTR) on NET cells. NET are highly heterogeneous and an individual patient as well as separate metastases can harbor cells with different clones, which influence the SSTR expression on NET cells. With this background we looked into our institutional database to assess the prognostic significance of quality of SSTR expression on SSTR PET/CT imaging in patients treated with at least two cycles of Lu-177 DOTATOC or Lu-177 DOTATATE. Method: Clinical reports and images from 65 (25 females, 40 males; 65 ± 11 years old) patients with progressive grade 1 or grade 2 NET with 2–5 therapy cycles of PRRT with an average administered dose of 6.6 ± 0.97 GBq Lu-177 DOTATOC or Lu-177 DOTATATE were analyzed. All patients were examined with baseline Ga-68 DOTATATE or Ga-68 DOTATOC PET/CT (PET). Quality of SSTR expression as a measure of heterogeneity on indexed lesions was assessed visually. Patients were followed for a median duration of 25 months after the first PRRT (range 5–77 months). Results: A total of 70% of the patients received three or more therapy cycles. Twenty-six patients (40%) were treated with PRRT as first or second line while 39 (60%) as third line or more. SSTR expression was heterogeneous in 28 (44.4%) and homogeneous in 35 (55.6%) patients. Disease stabilization could be achieved in 23 patients (35.4%), whereas 17 (26.1%) showed partial remission and 25 patients (38.5%) had disease progression. Median OS was not reached. The 24-month survival rate of the whole study cohort was 83%. In univariate analyses, factors influencing OS were carcinoid heart disease, carcinoid syndrome and quality of SSTR expression (p < 0.05). Patients with heterogeneous SSTR expression on target lesions had a significantly lower OS (p = 0.01). Median time to progression in total patient population was found to be 40 months. Patients with heterogeneous SSTR expression on target lesions had significantly lower TTP (26 months vs 54 months log Rank p = 0.013). By multivariate analyses, quality of SSTR was found to be the only prognostic factor for OS (p = 0.04; HR = 3.68) and also for TTP (p = 0.03; HR = 3.09). Conclusion: Visual assessment of SSTR heterogeneity has both predictive and prognostic value in progressive grade 1 or grade 2 NET patients undergoing PRRT.
CRIS-Team Scopus Importer:2019-08-30
Keywords: Heterogeneity; NET; PET; PRRT; SSTR

Prognostic value of the neutrophil/lymphocyte ratio in enteropancreatic neuroendocrine tumors - Grenader, Tal; Pavel, Marianne Ellen; Ruszniewski, Philippe B.; Ćwikła, Jarosław B.; Phan, Alexandria T.; Raderer, Markus; Sedláčková, Eva; Cadiot, Guillaume; Wolin, Edward M.; Capdevila, Jaume; Wall, Lucy; Rindi, Guido; et al. (Anti-Cancer Drugs, 2020)
Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1-2, Ki-67 < 10%). The exploratory post-hoc analyses presented here evaluated the prognostic value of NLR in the CLARINET study cohort, in the context of and independently from treatment. Kaplan-Meier PFS plots were generated for patients with available NLR data, in subgroups based on NLR values, and 24-month survival rates were calculated. P values and hazard ratios for prognostic effects were generated using Cox models. 31216222 Baseline characteristics were balanced between lanreotide autogel/depot 120 mg (n = 100) and placebo (n = 101) arms. Irrespective of treatment, raw 24-month PFS rates were comparable across subgroups based on NLR tertiles [37.3% (low), 38.8% (middle), 38.8% (high); n = 67 per group] and NLR cutoff of 4 [38.1% (NLR ≤ 4; n = 176), 40.0% (NLR > 4; n = 25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/depot 120 mg was independent of NLRs (P > 0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis.
CRIS-Team Scopus Importer:2020-02-21

Programming of Intestinal Epithelial Differentiation by IL-33 Derived from Pericryptal Fibroblasts in Response to Systemic Infection - Mahapatro, Mousumi; Försch, Sebastian; Hefele, Manuela; He, Gui-Wei; Giner-Ventura, Elisa; Mchedlidze, Tamar; Kindermann, Markus; Vetrano, Stefania; Danese, Silvio; Günther, Claudia; Neurath, Markus; Wirtz, Stefan; et al. (Cell Reports, 2016)
The intestinal epithelium constitutes an efficient barrier against the microbial flora. Here, we demonstrate an unexpected function of IL-33 as a regulator of epithelial barrier functions. Mice lacking IL-33 showed decreased Paneth cell numbers and lethal systemic infection in response to Salmonella typhimurium. IL-33 was produced upon microbial challenge by a distinct population of pericryptal fibroblasts neighboring the intestinal stem cell niche. IL-33 programmed the differentiation of epithelial progenitors toward secretory IEC including Paneth and goblet cells. Finally, IL-33 suppressed Notch signaling in epithelial cells and induced expression of transcription factors governing differentiation into secretory IEC. In summary, we demonstrate that gut pericryptal fibroblasts release IL-33 to translate bacterial infection into an epithelial response to promote antimicrobial defense.
EVALuna2:2065

Proposal for a new M1 subclassification in colorectal carcinoma - Merkel, Susanne; Weber, K.; Croner, R.; Golcher, H.; Göhl, Jonas; Agaimy, Abbas; Semrau, S.; Wein, Axel; Hohenberger, Werner; Wittekind, C.; Siebler, Jürgen (2016)
EVALuna2:2176

Prospective Evaluation of Acoustic Radiation Force Impulse (ARFI) Elastography and High-Frequency B-Mode Ultrasound in Compensated Patients for the Diagnosis of Liver Fibrosis/Cirrhosis in Comparison to Mini-Laparoscopic Biopsy - Pfeifer, Lukas; Zopf, Steffen; Schwitulla, Judith; Wildner, Dane; Wachter, David; Neurath, Markus; Strobel, Deike; Siebler, Jürgen (Ultraschall in der Medizin, 2015)
Purpose: Ultrasound is a well-established noninvasive test for assessing patients with liver disease. This study aims to prospectively compare ultrasound to the new technique elastography (ARFI) for the assessment of liver fibrosis/cirrhosis. Materials and Methods: High-frequency B-mode ultrasound (liver surface/vein irregularity, liver homogeneity, spleen size), ARFI quantification, mini-laparoscopic liver evaluation including biopsy were prospectively obtained in compensated patients scheduled for liver biopsy. For the diagnosis of cirrhosis, a combined gold standard (cirrhosis at histology and/or at macroscopic liver evaluation) was used. Results: Out of 157 patients, 35 patients were diagnosed cirrhotic. Ultrasound (combination of liver vein and/or surface irregularity) showed no significant difference compared to ARFI quantification for the diagnosis of significant liver fibrosis (Ishak> = 3) and cirrhosis. Diagnosis of cirrhosis had a sensitivity/specificity/PPV/NPV of 83 %(± 12) / 82 %(± 7) / 57 %(± 14) / 94 %(± 4), respectively, with ultrasound and 86 %(± 12) / 81 %(± 7) / 57 %(± 13) / 95 %(± 4), respectively, with ARFI quantification. The sensitivity/specificity/PPV/NPV for the detection of significant fibrosis were 68 %(± 13) / 86 %(± 7) / 71 %(± 13) / 84 %(± 7), respectively, for ultrasound and 70 %(± 12) / 84 %(± 7) / 69 %(± 12) / 84 %(± 7), respectively, for ARFI quantification. Conclusion: ARFI elastography and high-frequency B-mode ultrasound show similar and good results for the diagnosis of compensated liver cirrhosis and high-grade fibrosis. A key benefit of both methods is the high NPV suggesting them as noninvasive exclusion tests.
EVALuna2:2049

Prospective genome and transcriptome sequencing in advanced-stage neuroendocrine neoplasms - Apostolidis, L.; Kreutzfeldt, S.; Oles, M.; Gieldon, L.; Heining, C.; Horak, P.; Hutter, B.; Froehlich, M.; Klink, B.; Lamping, M.; Uhrig, S.; Stenzinger, A.; et al. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

Prospective long-term assessment of sedation-related adverse events and patient satisfaction for upper endoscopy and colonoscopy - Kilgert, Beate; Rybizki, Lydia; Grottke, Michael; Neurath, Markus; Neumann, Helmut (Digestion, 2014)
Fear of pain and sedation-related adverse events are impediments for patients to attend endoscopic screening or surveillance programs.To investigate the long-term effect of different sedation protocols in patients undergoing screening or surveillance endoscopy. Moreover, motivation of patients to decline endoscopic procedures was evaluated by focusing on the patient's satisfaction, fear and pain in relation to type of sedation used.A prospective, double-blind controlled trial data collection was performed by using a standardized clinical questionnaire followed by a telephone interview 3-4 weeks after the initial endoscopic procedure.The study was conducted at the Department of Medicine I at the University Hospital of Erlangen-Nuremberg. Data collection was performed during June 2012 till April 2013.Overall, 307 patients were prospectively evaluated (44.3% female, mean age 51 ± 17.4 years; mean BMI 25.5 ± 5.7). 247 patients (80.5%) were outpatients, 60 inpatients (19.5%).Endoscopic procedures were divided into five groups: (i) procedures in the upper gastrointestinal tract, (ii) complete colonoscopies, (iii) ileocolonoscopies, (iv) incomplete colonoscopies, and (v) other procedures.Patient satisfaction, fear and pain were measured in a structured and standardized clinical interview using a 6-point numerical rating scale, where 1 was 'very satisfied/no pain' and 6 was 'very unsatisfied/unsupportable pain'.Different types of sedation were assessed: propofol in monosedation (6.5%), combination of propofol + meperidine (41.0%), combination of midazolam + meperidine (48.5%) and other combinations (3.9%). Patient satisfaction was significantly reduced regarding fear and pain during the endoscopic procedure (p = 0.001 and p = 0.0001, respectively). All patients receiving propofol monosedation indicated significantly less pain in comparison to other sedation groups (p < 0.0001). Moreover, sedation with midazolam + meperidine increased the fear during the procedure significantly in comparison to monosedation with propofol (p = 0.082). Propofol/meperidine in combination and midazolam/meperidine increased the probability for cardiovascular events in comparison to monosedation with propofol (p = 0.005; p = 0.039). Finally, we observed significantly lower doses of propofol when used in monosedation than propofol in combination with meperidine (p = 0.066).Single-center study at a tertiary referral center.Propofol in monosedation should preferably be used for patient sedation in screening and surveillance endoscopies. Whether this approach could also improve participation rates in screening and surveillance endoscopies requires further investigations.
EVALuna2:1882

Protection of Batf3-deficient mice from experimental cerebral malaria correlates with impaired cytotoxic T-cell responses and immune regulation - Kuehlwein, Janina M.; Borsche, Max; Korir, Patricia J.; Risch, Frederic; Mueller, Ann-Kristin; Huebner, Marc P.; Hildner, Kai; Hoerauf, Achim; Dunay, Ildiko Rita; Schumak, Beatrix (Immunology, 2019)
Excessive inflammatory immune responses during infections with Plasmodium parasites are responsible for severe complications such as cerebral malaria (CM) that can be studied experimentally in mice. Dendritic cells (DCs) activate cytotoxic CD8+ T-cells and initiate immune responses against the parasites. Batf3−/− mice lack a DC subset, which efficiently induces strong CD8 T-cell responses by cross-presentation of exogenous antigens. Here we show that Batf3−/− mice infected with Plasmodium berghei ANKA (PbA) were protected from experimental CM (ECM), characterized by a stable blood−brain barrier (BBB) and significantly less infiltrated peripheral immune cells in the brain. Importantly, the absence of ECM in Batf3−/− mice correlated with attenuated responses of cytotoxic T-cells, as their parasite-specific lytic activity as well as the production of interferon gamma and granzyme B were significantly decreased. Remarkably, spleens of ECM-protected Batf3−/− mice had elevated levels of regulatory immune cells and interleukin 10. Thus, protection from ECM in PbA-infected Batf3−/− mice was associated with the absence of strong CD8+ T-cell activity and induction of immunoregulatory mediators and cells.
CRIS-Team Scopus Importer:2019-11-26
Keywords: dendritic cells; experimental cerebral malaria; inflammation; Plasmodium; T-cells

Protective effect of the novel calcineurin inhibitor voclosporin in experimental colitis - Lindemann, Aylin; Roth, Dominik; Koop, Kristina; Neufert, Clemens; Zundler, Sebastian; Atreya, Raja; Neurath, Markus; Leppkes, Moritz (Frontiers in Medicine, 2023)
Background and aims: Acute severe steroid-refractory ulcerative colitis remains a medically challenging condition with frequent need of surgery. It can be treated with the calcineurin inhibitor cyclosporine A with the need for therapeutic drug monitoring and significant toxicity. Recently, a novel calcineurin inhibitor, voclosporin, has been approved for the treatment of lupus nephritis with no need for therapeutic drug monitoring and an improved long-term safety profile. However, the therapeutic effect of voclosporin in acute severe steroid-refractory ulcerative colitis is still uncertain. We aimed to assess the therapeutic potential of voclosporin to ameliorate inflammation in an experimental model of colitis. Methods: We used the dextran sodium sulfate-induced model of colitis in C57BL/6 J wildtype mice treated with either cyclosporine A, voclosporin or solvent control. We employed endoscopy, histochemistry, immunofluorescence, bead-based multiplex immunoassays and flow cytometry to study the therapeutic effect of calcineurin inhibitors in a preventive setting. Results: Acute colitis was induced by dextran sodium sulfate characterized by weight loss, diarrhea, mucosal erosions and rectal bleeding. Both cyclosporine A and voclosporin strongly ameliorated the course of disease and reduced colitis severity in a similar manner. Conclusion: Voclosporin was identified as biologically effective in a preclinical model of colitis and may be a potential therapeutic option in treating acute severe steroid-refractory ulcerative colitis.
CRIS-Team Scopus Importer:2023-07-28
Keywords: calcineurin inhibitors; IBD; steroid refractory colitis; ulcerative colitis; voclosporin

Proteins from Modern and Ancient Wheat Cultivars: Impact on Immune Cells of Healthy Individuals and Patients with NCGS - Dieterich, Walburga; Schuster, Charlotte; Gundel, Paulina; Scherf, Katharina A.; Pronin, Darina; Geisslitz, Sabrina; Boerner, Andreas; Neurath, Markus; Zopf, Yurdagül (Nutrients, 2022)
In non-celiac gluten sensitivity (NCGS), the elimination of wheat results in a clear symptom improvement, but gluten has still not been proven as (the sole) trigger. Due to the increase in the prevalence of gluten-related diseases, the breeding of high-performance wheat cultivars is discussed as a trigger. To analyze the immune stimulation and signal pathways, the immune cells of healthy subjects and patients with NCGS were stimulated with gliadins from wheat, and the expression and secretion of interleukin 1ss (IL1ss) and interleukin 6 (IL6) were studied. To determine the impact of wheat breeding, the monocyte cell line THP1 and human immune cells were stimulated with gliadin, glutenin, and albumin/globulin fractions of ancient and modern cereals, and expression of inflammatory molecules was checked. Immune cells of patients with NCGS showed an increased expression of IL1ss and IL6 after stimulation with gliadins compared to immune cells of healthy controls. Gliadins caused a strong activation of P-STAT3 in immune cells of healthy controls, and inhibitors of JAK and NF kappa B pathways considerably reduced this response. In addition to gliadins, we further showed that glutenins and albumin/globulins from all wheat cultivars from the last century, and especially from einkorn and spelt, also markedly induced the expression of inflammatory genes in THP1 and human immune cells. There was no correlation between enhanced immune stimulation and ancient or modern cultivars. This does not support the hypothesis that modern wheat breeding is responsible for the increase in gluten-related diseases. An altered immune situation is suggested in patients with NCGS.
CRIS-Team WoS Importer:2022-11-11

Protein Supplementation Does Not Maximize Adaptations to Low-Volume High-Intensity Interval Training in Sedentary, Healthy Adults: A Placebo-Controlled Double-Blind Randomized Study - Reljic, Dejan; Zieseniss, Nilas; Herrmann, Hans J.; Neurath, Markus; Zopf, Yurdagül (Nutrients, 2022)
There is ample evidence that specific nutritional strategies can enhance adaptions to resistance and endurance training. However, it is still unclear whether post-session protein supplementation may increase the effects of low-volume high-intensity interval training (LOW-HIIT). We examined the impact of LOW-HIIT combined with protein vs. placebo supplementation on cardiometabolic health indices in sedentary healthy individuals. Forty-seven participants (31.1 ± 8.0 yrs) performed cycle ergometer LOW-HIIT (5–10x1 min at 80–95% maximum heart rate) for eight weeks and randomly received double-blinded 40 g of whey protein (PRO-HIIT, N = 24) or an isocaloric placebo (maltodextrin, PLA-HIIT, N = 23) after each session. The maximum oxygen uptake (VO2max, primary outcome) and several secondary cardiometabolic outcomes were determined pre-/post-intervention. VO2max increased in PRO-HIIT (+2.8 mL/kg/min, p = 0.003) and PLA-HIIT (+3.5 mL/kg/min, p < 0.001). Systolic and diastolic blood pressure decreased in PRO-HIIT (−7/3 mmHg, p < 0.05) and PLA-HIIT (−8/5 mmHg, p < 0.001). Gamma glutamyl transferase (−2 U/L, p = 0.003) decreased in PRO-HIIT and alanine aminotransferase (−3 U/L, p = 0.014) in PLA-HIIT. There were no significant between-group differences in any of the outcome changes. In conclusion, LOW-HIIT improved VO2max and other cardiometabolic markers irrespective of the supplementation condition. Post-session protein supplementation does not seem to provide any additional benefit to LOW-HIIT in improving cardiometabolic health in sedentary healthy individuals.
CRIS-Team Scopus Importer:2022-10-28
Keywords: cardiometabolic health; cardiorespiratory fitness; HIIT; whey protein