Publications by authors named "Markus F Neurath"

581 Publications

A Possible Distinct Molecular Subtype (Quintuple-Wildtype) of Metastatic Colorectal Cancer in First-Line Anti-EGFR Therapy with Cetuximab Plus FOLFIRI - Palliative Precision Therapy and a Multidisciplinary Treatment Approach: Interim Analysis of the IVOPAK II Trial with Early Results.

Oncology 2021 Oct 20:1-11. Epub 2021 Oct 20.

Department of Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

Objective: The study aimed to prospectively evaluate a new molecular biomarker panel (KRAS, NRAS, BRAF, PIK3CA, and ERBB2) for palliative first-line treatment of colorectal cancer (CRC), including a multidisciplinary treatment approach. The rate of secondary metastasis resections was assessed.

Patients And Methods: A total of 40 patients with definitively nonresectable metastatic CRC were enrolled from 10 centers before the interim analysis (June 2019) of the IVOPAK II trial (Interdisciplinary Care with Quality Control in Palliative Treatment of Colorectal Cancer). After determination of 5 molecular biomarkers in the tumor (KRAS, exons 2-4; NRAS, exons 2-4; BRAF V600E; PIK3CA; and ERBB2), patients in the IVOPAK II study received FOLFIRI plus cetuximab for all-RAS/quintuple-wildtype disease and FOLFIRI plus bevacizumab in the case of RAS mutations. The current article presents the early description of the clinical outcome of the interim analysis of IVOPAK II comparing the all-RAS/quintuple-wildtype and RAS-mutations populations, including a multidisciplinary-treated case report of a quintuple-wildtype patient.

Results: The quintuple-wildtype population treated with FOLFIRI plus cetuximab in first-line exhibited a significantly higher response rate and enhanced early tumor shrinkage in the interim analysis than the RAS-mutations population, as well as a high rate of secondary metastatic resections.

Conclusion: Initial results of this new biomarker panel (quintuple-wildtype) are promising for anti-EGFR therapy with cetuximab plus doublet chemotherapy (FOLFIRI) in first-line treatment of metastatic CRC. These results warrant confirmation with higher case numbers in the IVOPAK II trial.
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http://dx.doi.org/10.1159/000519252DOI Listing
October 2021

Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe-host-communication in vivo.

J Extracell Vesicles 2021 Oct;10(12):e12159

Institute of Neurology (Edinger Institute), Goethe University, Frankfurt am Main, Germany.

The intestinal microbiota influences mammalian host physiology in health and disease locally in the gut but also in organs devoid of direct contact with bacteria such as the liver and brain. Extracellular vesicles (EVs) or outer membrane vesicles (OMVs) released by microbes are increasingly recognized for their potential role as biological shuttle systems for inter-kingdom communication. However, physiologically relevant evidence for the transfer of functional biomolecules from the intestinal microbiota to individual host cells by OMVs in vivo is scarce. By introducing Escherichia coli engineered to express Cre-recombinase (E. coli ) into mice with a Rosa26.tdTomato-reporter background, we leveraged the Cre-LoxP system to report the transfer of bacterial OMVs to recipient cells in vivo. Colonizing the intestine of these mice with E. coli , resulted in Cre-recombinase induced fluorescent reporter gene-expression in cells along the intestinal epithelium, including intestinal stem cells as well as mucosal immune cells such as macrophages. Furthermore, even far beyond the gut, bacterial-derived Cre induced extended marker gene expression in a wide range of host tissues, including the heart, liver, kidney, spleen, and brain. Together, our findings provide a method and proof of principle that OMVs can serve as a biological shuttle system for the horizontal transfer of functional biomolecules between bacteria and mammalian host cells.
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http://dx.doi.org/10.1002/jev2.12159DOI Listing
October 2021

Case report of severe constrictive perimyocarditis and ischemic hepatitis in a Crohn's disease patient upon infliximab-induced lupus-like syndrome.

Therap Adv Gastroenterol 2021 29;14:17562848211044033. Epub 2021 Sep 29.

Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.

Anti-tumor necrosis factor (TNF) antibodies have become an indispensable part in the therapeutic landscape of treating inflammatory bowel disease (IBD) patients. Nevertheless, they can be associated with the occurrence of severe systemic side effects. Here, we report the case of a 23-year-old patient with ileocolonic Crohn's disease in endoscopic remission under ongoing anti-TNF infliximab therapy with occurrence of novel generalized arthralgia, pleuritic chest pain, and dyspnea. Clinical, laboratory, and imaging diagnostic workup in an extended clinical routine setting at the University Hospital of Erlangen, Germany, was used by a multidisciplinary team consisting of gastroenterologists, radiologists, cardiologists, and rheumatologists to investigate the underlying cause of the clinical symptoms in the patient. The results received using the aforementioned diagnostic setup led to the diagnosis of severe constrictive perimyocarditis due to infliximab-induced lupus-like syndrome with distinct ANA reactivity and elevated anti-dsDNA levels. Furthermore, pronounced ischemic hepatitis was diagnosed. Infliximab treatment was immediately stopped, and initiated corticosteroid pulse therapy only led to partial response as it had to be reduced due to pronounced psychiatric side effects. Persistent signs of pericarditis required additional ibuprofen therapy, which led to subsequent resolution of cardial symptoms. Formerly elevated liver enzymes returned to normal, and there were no clinical signs of recurrence of Crohn's disease activity over 18 months of follow-up. The patient was subsequently switched to ustekinumab therapy for further treatment of underlying Crohn's disease. This case report describes for the first time severe infliximab-induced lupus-like syndrome in an IBD patient, concurrently mimicking ST-elevation myocardial infarction with MRI visualization of pericarditis, occurrence of ischemic hepatitis, and pronounced signs of systemic inflammation.
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http://dx.doi.org/10.1177/17562848211044033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488501PMC
September 2021

Shear Wave Dispersion Imaging for the Characterization of Focal Liver Lesions - A Pilot study.

Ultraschall Med 2021 Oct 6. Epub 2021 Oct 6.

Department of Internal Medicine 1, Erlangen University Hospital Department of Medicine 1 Gastroenterology Endocrinology and Pneumology, Erlangen, Germany.

Purpose: Shear wave dispersion imaging is a novel ultrasound-based technique, which analyzes the speed of different shear wave components depending on their frequency. The dispersion of shear wave speed correlates with the viscosity of the liver parenchyma. The aim of this prospective study was to evaluate the use of shear wave dispersion imaging in focal liver lesions in the non-cirrhotic liver.

Methods: Patients with unclear focal liver lesions in B-mode ultrasound were prospectively assigned to shear wave dispersion imaging (m/s/kHz). Measurements were conducted within the lesion and in the liver parenchyma of the right liver lobe using an intercostal window. Histology and contrast-enhanced ultrasound served as the reference for the characterization of the lesions.

Results: Out of 46 patients included in this study, 24 had liver metastases and 22 had benign liver lesions. Benign lesions consisted mostly of hemangiomas (n=12) and focal nodular hyperplasia (n=8). Malignant lesions showed significantly lower shear wave dispersion (13.0±2.45 m/s/kHz) compared to benign tumors (15.2±2.74 m/s/kHz, p<0.01). In further subgroup analysis, the difference was significant for hemangiomas (15.32±2.42 m/s/kHz, p=0.04) but not for FNHs (14.98±3.36 m/s/kHz, p=0.38). The dispersion of reference liver parenchyma did not differ significantly between the groups (p=0.54).

Conclusion: The quantification of viscosity by shear wave dispersion is a new parameter for the characterization of focal liver lesions with higher dispersion values in hemangiomas and lower dispersion values in metastases. However, it cannot differentiate reliably between benign and malignant lesions.
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http://dx.doi.org/10.1055/a-1610-9171DOI Listing
October 2021

Dynamic, Transient, and Robust Increase in the Innervation of the Inflamed Mucosa in Inflammatory Bowel Diseases.

Cells 2021 Aug 30;10(9). Epub 2021 Aug 30.

Department of Medicine 1, University of Erlangen-Nuremberg, 91052 Erlangen, Germany.

Inflammatory bowel diseases (IBD) are characterized by chronic dysregulation of immune homeostasis, epithelial demise, immune cell activation, and microbial translocation. Each of these processes leads to proinflammatory changes via the release of cytokines, damage-associated molecular patterns (DAMPs), and pathogen-associated molecular patterns (PAMPs), respectively. The impact of these noxious agents on the survival and function of the enteric nervous system (ENS) is poorly understood. Here, we show that in contrast to an expected decrease, experimental as well as clinical colitis causes an increase in the transcript levels of enteric neuronal and glial genes. Immunostaining revealed an elevated neuronal innervation of the inflamed regions of the gut mucosa. The increase was seen in models with overt damage to epithelial cells and models of T cell-induced colitis. Transcriptomic data from treatment naïve pediatric IBD patients also confirmed the increase in the neuroglial genes and were replicated on an independent adult IBD dataset. This induction in the neuroglial genes was transient as levels returned to normal upon the induction of remission in both mouse models as well as colitis patients. Our data highlight the dynamic and robust nature of the enteric nervous system in colitis and open novel questions on its regulation.
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http://dx.doi.org/10.3390/cells10092253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471820PMC
August 2021

STAT1 coordinates intestinal epithelial cell death during gastrointestinal infection upstream of Caspase-8.

Mucosal Immunol 2021 Sep 8. Epub 2021 Sep 8.

Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU), Erlangen, Germany.

Intestinal homeostasis and the maintenance of the intestinal epithelial barrier are essential components of host defense during gastrointestinal Salmonella Typhimurium infection. Both require a strict regulation of cell death. However, the molecular pathways regulating epithelial cell death have not been completely understood. Here, we elucidated the contribution of central mechanisms of regulated cell death and upstream regulatory components during gastrointestinal infection. Mice lacking Caspase-8 in the intestinal epithelium are highly sensitive towards bacterial induced enteritis and intestinal inflammation, resulting in an enhanced lethality of these mice. This phenotype was associated with an increased STAT1 activation during Salmonella infection. Cell death, barrier breakdown and systemic infection were abrogated by an additional deletion of STAT1 in Casp8 mice. In the absence of epithelial STAT1, loss of epithelial cells was abolished which was accompanied by a reduced Caspase-8 activation. Mechanistically, we demonstrate that epithelial STAT1 acts upstream of Caspase-8-dependent as well as -independent cell death and thus might play a major role at the crossroad of several central cell death pathways in the intestinal epithelium. In summary, we uncovered that transcriptional control of STAT1 is an essential host response mechanism that is required for the maintenance of intestinal barrier function and host survival.
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http://dx.doi.org/10.1038/s41385-021-00450-2DOI Listing
September 2021

COVID-19 and immune-mediated inflammatory diseases: effect of disease and treatment on COVID-19 outcomes and vaccine responses.

Lancet Rheumatol 2021 Oct 27;3(10):e724-e736. Epub 2021 Aug 27.

Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuermberg, Erlangen, Germany.

At the beginning of the COVID-19 pandemic, patients with immune-mediated inflammatory diseases were considered to be at high risk for SARS-CoV-2 infection and the development of severe COVID-19. Data collected over the past year, however, suggest that a diagnosis of inflammatory arthritis, psoriasis, or inflammatory bowel diseases does not increase risk for SARS-CoV-2 infection or severe COVID-19 compared with people without these diseases. Furthermore, substantial data suggest that certain medications frequently used in patients with immune-mediated inflammatory diseases, in particular cytokine inhibitors, might even lower the risk for severe COVID-19. Conversely, glucocorticoids and potentially B-cell-depleting treatments seem to worsen COVID-19 outcomes. Additionally, the first data on SARS-CoV-2 vaccination in patients with these diseases suggest that tolerability of vaccination in patients with immune-mediated inflammatory diseases is good, although the immune response to vaccination can be somewhat reduced in this patient group, particularly those taking methotrexate or CD20-targeted treatment.
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http://dx.doi.org/10.1016/S2665-9913(21)00247-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397302PMC
October 2021

Residual homing of α4β7-expressing β1PI16 regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab.

Gut 2021 Aug 30. Epub 2021 Aug 30.

Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany

Objective: The anti-α4β7 integrin antibody vedolizumab is administered at a fixed dose for the treatment of IBDs. This leads to a wide range of serum concentrations in patients and previous studies had suggested that highest exposure levels are associated with suboptimal clinical response. We aimed to determine the mechanisms underlying these non-linear exposure-efficacy characteristics of vedolizumab.

Design: We characterised over 500 samples from more than 300 subjects. We studied the binding of vedolizumab to T cells and investigated the functional consequences for dynamic adhesion, transmigration, gut homing and free binding sites in vivo. Employing single-cell RNA sequencing, we characterised α4β7 integrin-expressing T cell populations 'resistant' to vedolizumab and validated our findings in vitro and in samples from vedolizumab-treated patients with IBD. We also correlated our findings with a post-hoc analysis of the Gemini II and III studies.

Results: Regulatory T (T) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (T) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional α4β7 on T cells in vivo was higher than that of/on T cells. We identified a vedolizumab-'resistant' α4β7-expressing β1PI16 T cell subset with pronounced regulatory properties as the substrate for this effect. Our observations correlated with exposure-efficacy data from Gemini II and III trials.

Conclusion: Completely blocking T cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful T cells in an optimal 'therapeutic window' based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.
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http://dx.doi.org/10.1136/gutjnl-2021-324868DOI Listing
August 2021

Expression of inflammatory mediators in biofilm samples and clinical association in inflammatory bowel disease patients-a preliminary study.

Clin Oral Investig 2021 Aug 12. Epub 2021 Aug 12.

Department of Oral and Maxillofacial Surgery, University of Erlangen- Nuremberg, Glückstrasse 11, 91054, Erlangen, Germany.

Objectives: Inflammatory bowel disease (IBD) has multiple impacts on soft and hard tissues in the oral cavity. The aim of this study was to analyze the expression of cytokines in biofilm samples from patients suffering from IBD and compare them to healthy patients. It was hypothesized that different cytokine expression levels and clinical associations might be drawn.

Material And Methods: A total of 56 biofilm samples from three different patient cohorts (group 0 = healthy, HC n = 30; group 1 = Crohn's disease, CD, n = 19; group 2 = ulcerative colitis, UC, n = 7) were examined for the expression levels of the cytokine interleukins IL-2, -6, and -10; matrix metalloproteinases 7 and 9; and surface antigens CD90/CD11a by quantitative real-time PCR and according to clinical parameters (plaque index, BOP, PD, DMFT, CAL). Relative gene expression was determined using the ∆∆CT method.

Results: The mean BOP values (p = 0.001) and PD (p = 0.000) were significantly higher in the CD group compared to controls. Expression of IL-10 was significantly higher in the CD (p = 0.004) and UC groups (p = 0.022). Expression of MMP-7 was significantly higher in the CD group (p = 0.032). IBD patients treated with TNF inhibitors (p = 0.007) or other immunosuppressants (p = 0.014) showed significant overexpression of IL-10 compared to controls.

Conclusion: Different expression levels of IL-10 and MMP-7 were detected in plaque samples from IBD patients. As only BOP was significantly increased, we conclude that no clinical impairment of periodontal tissue occurred in IBD patients.

Clinical Relevance: With the worldwide increasing incidence of IBD, it is important to obtain insights into the effects of the disease on the oral cavity. The study was registered (01.09.2020) at the German clinical trial registry (DRKS00022956).

Clinical Trial Registration: The study is registered at the German clinical trial registry (DRKS00022956).
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http://dx.doi.org/10.1007/s00784-021-04093-2DOI Listing
August 2021

Reframing Immune-Mediated Inflammatory Diseases through Signature Cytokine Hubs.

N Engl J Med 2021 08;385(7):628-639

From the Departments of Medicine 3 (G.S.) and Medicine 1 (M.F.N.) and Deutsches Zentrum Immuntherapie (G.S., M.F.N.), Friedrich Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany; and the College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (I.B.M.).

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http://dx.doi.org/10.1056/NEJMra1909094DOI Listing
August 2021

Innovative Diagnostic Endoscopy in Inflammatory Bowel Diseases: From High-Definition to Molecular Endoscopy.

Front Med (Lausanne) 2021 21;8:655404. Epub 2021 Jul 21.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany.

High-definition endoscopy is one essential step in the initial diagnosis of inflammatory bowel disease (IBD) characterizing the extent and severity of inflammation, as well as discriminating ulcerative colitis (UC) from Crohn's disease (CD). Following general recommendations and national guidelines, individual risk stratification should define the appropriate surveillance strategy, biopsy protocol and frequency of endoscopies. Beside high-definition videoendoscopy the application of dyes applied via a spraying catheter is of additional diagnostic value with a higher detection rate of intraepithelial neoplasia (IEN). Virtual chromoendoscopy techniques (NBI, FICE, I-scan, BLI) should not be recommended as a single surveillance strategy in IBD, although newer data suggest a higher comparability to dye-based chromoendoscopy than previously assumed. First results of oral methylene blue formulation are promising for improving the acceptance rate of classical chromoendoscopy. Confocal laser endomicroscopy (CLE) is still an experimental but highly innovative endoscopic procedure with the potential to contribute to the detection of dysplastic lesions. Molecular endoscopy in IBD has taken application of CLE to a higher level and allows topical application of labeled probes, mainly antibodies, against specific target structures expressed in the tissue to predict response or failure to biological therapies. First pre-clinical and data from label-free multiphoton microscopy (MPM) are now available to characterize mucosal and submucosal inflammation on endoscopy in more detail. These new techniques now have opened the door to individualized and highly specific molecular imaging in IBD in the future and pave the path to personalized medicine approaches. The quality of evidence was stated according to the Oxford Center of evidence-based medicine (March 2009). For this review a Medline search up to January 2021 was performed using the words "inflammatory bowel disease," "ulcerative colitis," "crohn's disease," "chromoendoscopy," "high-definition endoscopy," "confocal laser endomicroscopy," "confocal laser microscopy," "molecular imaging," "multiphoton microscopy."
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http://dx.doi.org/10.3389/fmed.2021.655404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333704PMC
July 2021

Molecular Communication Between Neuronal Networks and Intestinal Epithelial Cells in Gut Inflammation and Parkinson's Disease.

Front Med (Lausanne) 2021 22;8:655123. Epub 2021 Jul 22.

Medicine 1, University Hospital Erlangen, Erlangen, Germany.

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.
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http://dx.doi.org/10.3389/fmed.2021.655123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339315PMC
July 2021

Muscle-Derived Cytokines Reduce Growth, Viability and Migratory Activity of Pancreatic Cancer Cells.

Cancers (Basel) 2021 Jul 29;13(15). Epub 2021 Jul 29.

Medical Department 1, Friedrich-Alexander University Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.

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.
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http://dx.doi.org/10.3390/cancers13153820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345221PMC
July 2021

Successful treatment of COVID-19 infection with convalescent plasma in B-cell-depleted patients may promote cellular immunity.

Eur J Immunol 2021 10 3;51(10):2478-2484. Epub 2021 Sep 3.

Department of Transfusion Medicine and Haemostaseology, University Hospital Erlangen and Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

Treatment with convalescent plasma has been shown to be safe in coronavirus disease in 2019 (COVID-19) infection, although efficacy reported in immunocompetent patients varies. Nevertheless, neutralizing antibodies are a key requisite in the fight against viral infections. Patients depleted of antibody-producing B cells, such as those treated with rituximab (anti-CD20) for hematological malignancies, lack a fundamental part of their adaptive immunity. Treatment with convalescent plasma appears to be of general benefit in this particularly vulnerable cohort. We analyzed clinical course and inflammation markers of three B-cell-depleted patients suffering from COVID-19 who were treated with convalescent plasma. In addition, we measured serum antibody levels as well as peripheral blood CD38/HLA-DR-positive T-cells ex vivo and CD137-positive T-cells after in vitro stimulation with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides in these patients. We observed that therapy with convalescent plasma was effective in all three patients and analysis of CD137-positive T-cells after stimulation with SARS-CoV-2 peptides showed an increase in peptide-specific T-cells after application of convalescent plasma. In conclusion, we here demonstrate efficacy of convalescent plasma therapy in three B-cell-depleted patients and present data that suggest that while application of convalescent plasma elevates systemic antibody levels only transiently, it may also boost specific T-cell responses.
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http://dx.doi.org/10.1002/eji.202149277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420096PMC
October 2021

The Ominous Ouzo Party - A Case Series of Four Patients with Accidental Alkali Ingestion.

Clin Exp Gastroenterol 2021 13;14:303-308. Epub 2021 Jul 13.

Department of Gastroenterology and Interventional Endoscopy, Krankenhaus Barmherzige Brüder, Regensburg, Germany.

Background: Ingestion of alkaline fluids is a common problem, which can lead to perforations, strictures and malignancy. We present a rare case series of several patients who accidentally ingested the same alkaline substance in different doses.

Methods: We investigated four patients with accidental ingestion of dishwashing liquid. All patients underwent gastroscopy within 24h after inpatient admission. Gastroesophageal lesions were classified according to the Zargar classification for corrosive ingestions.

Results: Esophagogastric lesions were predominantly found at the distal esophagus and the small curvature of the stomach. The severity of these lesions ranged from mild erosions (Zargar 2A) to marked necrosis (Zargar 3A). Our data suggest that the degree of these lesions correlated with the amount of ingested toxin and duration of the inpatient stay. However, a low symptom severity or inconspicuous otolaryngologic examination did not exclude severe gastroesophageal lesions.

Conclusion: Our data suggest that the severity of gastroesophageal lesions correlates with the amount of ingested alkaline substance. Symptom burden and an otolaryngologic examination are not sufficiently predictive for the severity of gastroesophageal lesions. The composition and quantity of the swallowed liquid should be determined.
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http://dx.doi.org/10.2147/CEG.S320047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286424PMC
July 2021

E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis.

Nat Cell Biol 2021 07 8;23(7):796-807. Epub 2021 Jul 8.

Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.

Inflammatory bowel diseases present with elevated levels of intestinal epithelial cell (IEC) death, which compromises the gut barrier, activating immune cells and triggering more IEC death. The endogenous signals that prevent IEC death and break this vicious cycle, allowing resolution of intestinal inflammation, remain largely unknown. Here we show that prostaglandin E2 signalling via the E-type prostanoid receptor 4 (EP4) on IECs represses epithelial necroptosis and induces resolution of colitis. We found that EP4 expression correlates with an improved IBD outcome and that EP4 activation induces a transcriptional signature consistent with resolution of intestinal inflammation. We further show that dysregulated necroptosis prevents resolution, and EP4 agonism suppresses necroptosis in human and mouse IECs. Mechanistically, EP4 signalling on IECs converges on receptor-interacting protein kinase 1 to suppress tumour necrosis factor-induced activation and membrane translocation of the necroptosis effector mixed-lineage kinase domain-like pseudokinase. In summary, our study indicates that EP4 promotes the resolution of colitis by suppressing IEC necroptosis.
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http://dx.doi.org/10.1038/s41556-021-00708-8DOI Listing
July 2021

Targeting of the Tec Kinase ITK Drives Resolution of T Cell-Mediated Colitis and Emerges as Potential Therapeutic Option in Ulcerative Colitis.

Gastroenterology 2021 Oct 3;161(4):1270-1287.e19. Epub 2021 Jul 3.

Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Erlangen, Germany. Electronic address:

Background & Aims: The molecular checkpoints driving T cell activation and cytokine responses in ulcerative colitis (UC) are incompletely understood. Here, we studied the Tec kinase ITK in UC.

Methods: We analyzed patients with inflammatory bowel disease (n = 223) and evaluated ITK activity as well as the functional effects of cyclosporine-A (CsA). In addition, 3 independent murine colitis models were used to investigate the functional role of ITK. Finally, the activity of ITK was blocked via pharmacological inhibitors and genetically engineered mice. Readout parameters were mini-endoscopy, histopathology, mucosal T cell apoptosis, and cytokine production.

Results: We found an expansion of pITK-expressing mucosal CD4 T cells in UC rather than Crohn's disease that correlated with disease severity. CsA suppressed activation of ITK in cultured CD4 T cells and calcineurin-containing microclusters adjacent to the T cell receptor signaling complex. Functionally, the capacity of CsA to suppress activity of experimental colitis was critically dependent on ITK. Genetic inactivation of Itk via gene targeting or induction of allele-sensitive Itk mutants prevented experimental colitis in 3 colitis models, and treatment with pharmacological ITK blockers suppressed established colitis. In addition, ITK controlled apoptosis and activation of mucosal Th2 and Th17 lymphocytes via NFATc2 signaling pathways.

Conclusions: ITK activation was detected in UC and could be down-regulated in cultured T cells by CsA administration. Selective targeting of ITK emerges as an attractive approach for treatment of chronic intestinal inflammation and potentially UC by driving resolution of mucosal inflammation.
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http://dx.doi.org/10.1053/j.gastro.2021.06.072DOI Listing
October 2021

COVID-19: biologic and immunosuppressive therapy in gastroenterology and hepatology.

Authors:
Markus F Neurath

Nat Rev Gastroenterol Hepatol 2021 10 29;18(10):705-715. Epub 2021 Jun 29.

Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany.

The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health crisis causing major challenges for clinical care in patients with gastrointestinal diseases. Although triggering of anti-viral immune responses is essential for clearance of infection, some patients have severe lung inflammation and multiorgan failure due to marked immune cell dysregulation and cytokine storm syndrome. Importantly, the activation of cytotoxic follicular helper T cells and a reduction of regulatory T cells have a crucial, negative prognostic role. These findings lead to the question of whether immunosuppressive and biologic therapies for gastrointestinal diseases affect the incidence or prognosis of COVID-19 and, thus, whether they should be adjusted to prevent or affect the course of the disease. In this Review, data on the use of such therapies are discussed with a primary focus on inflammatory bowel disease, autoimmune hepatitis and liver transplantation. In particular, the roles of corticosteroids, classic immunosuppressive agents (such as thiopurines and mycophenolate mofetil), small molecules (such as Janus kinase (JAK) inhibitors), and biologic agents (such as tumour necrosis factor (TNF) blockers, vedolizumab and ustekinumab) are reviewed. Finally, the use of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines for the prevention of infection in patients with gastrointestinal diseases and concomitant immunosuppressive or biologic therapy will be discussed.
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http://dx.doi.org/10.1038/s41575-021-00480-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239481PMC
October 2021

Functional Contribution and Targeted Migration of Group-2 Innate Lymphoid Cells in Inflammatory Lung Diseases: Being at the Right Place at the Right Time.

Front Immunol 2021 10;12:688879. Epub 2021 Jun 10.

Department of Medicine 1, University Hospital of Erlangen, Erlangen, Germany.

During the last decade, group-2 innate lymphoid cells (ILC2s) have been discovered and successfully established as crucial mediators of lung allergy, airway inflammation and fibrosis, thus affecting the pathogenesis and clinical course of many respiratory diseases, like for instance asthma, cystic fibrosis and chronic rhinosinusitis. As an important regulatory component in this context, the local pulmonary milieu at inflammatory tissue sites does not only determine the activation status of lung-infiltrating ILC2s, but also influences their motility and migratory behavior. In general, many data collected in recent murine and human studies argued against the former concept of a very strict tissue residency of innate lymphoid cells (ILCs) and instead pointed to a context-dependent homing capacity of peripheral blood ILC precursors and the inflammation-dependent capacity of specific ILC subsets for interorgan trafficking. In this review article, we provide a comprehensive overview of the so far described molecular mechanisms underlying the pulmonary migration of ILC2s and thereby the numeric regulation of local ILC2 pools at inflamed or fibrotic pulmonary tissue sites and discuss their potential to serve as innovative therapeutic targets in the treatment of inflammatory lung diseases.
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http://dx.doi.org/10.3389/fimmu.2021.688879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222800PMC
June 2021

Issues in histopathological reporting: a crucial crossroad between surgeons and pathologists after oesophago-gastrectomy.

Dis Esophagus 2021 08;34(8)

Internal Medicine II, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.

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http://dx.doi.org/10.1093/dote/doab038DOI Listing
August 2021

Mucosal Biofilms Are an Endoscopic Feature of Irritable Bowel Syndrome and Ulcerative Colitis.

Gastroenterology 2021 Oct 17;161(4):1245-1256.e20. Epub 2021 Jun 17.

Division of Gastroenterology and Hepatology, Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria; Loha for Life, Center for Gastroenterlogy and Iron Deficiency, Vienna, Austria. Electronic address:

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.
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http://dx.doi.org/10.1053/j.gastro.2021.06.024DOI Listing
October 2021

An IFN-STAT Axis Augments Tissue Damage and Inflammation in a Mouse Model of Crohn's Disease.

Front Med (Lausanne) 2021 20;8:644244. Epub 2021 May 20.

Medizinische Klinik 1, Universitäts-Klinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Blocking interferon-function by therapeutic intervention of the JAK-STAT-axis is a novel promising treatment option for inflammatory bowel disease (IBD). Although JAK inhibitors have proven efficacy in patients with active ulcerative colitis (UC), they failed to induce clinical remission in patients with Crohn's disease (CD). This finding strongly implicates a differential contribution of JAK signaling in both entities. Here, we dissected the contribution of different STAT members downstream of JAK to inflammation and barrier dysfunction in a mouse model of Crohn's disease like ileitis and colitis ( mice). Deletion of STAT1 in mice was associated with reduced cell death and a partial rescue of Paneth cell function in the small intestine. Likewise, organoids derived from the small intestine of these mice were less sensitive to cell death triggered by IBD-key cytokines such as TNFα or IFNs. Further functional and analyses revealed the impairment of MLKL-mediated necrosis as a result of deficient STAT1 function, which was in turn associated with improved cell survival. However, a decrease in inflammatory cell death was still associated with mild inflammation in the small intestine. The impact of STAT1 signaling on gastrointestinal inflammation dependent on the localization of inflammation, as STAT1 is essential for intestinal epithelial cell death regulation in the small intestine, whereas it is not the key factor for intestinal epithelial cell death in the context of colitis. Of note, additional deletion of STAT2 was not sufficient to restore Paneth cell function but strongly ameliorated ileitis. In summary, we provide here compelling molecular evidence that STAT1 and STAT2, both contribute to intestinal homeostasis, but have non-redundant functions. Our results further demonstrate that STATs individually affect the distinct pathophysiology of inflammation in the ileum and colon, respectively, which might explain the diverse outcome of JAK inhibitors on inflammatory bowel diseases.
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http://dx.doi.org/10.3389/fmed.2021.644244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205542PMC
May 2021

Cross-sectional imaging of intestinal barrier dysfunction by confocal laser endomicroscopy can identify patients with food allergy in vivo with high sensitivity.

Sci Rep 2021 06 17;11(1):12777. Epub 2021 Jun 17.

Department of Gastroenterology, Hector-Center for Nutrition, Exercise and Sports, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuernberg, Erlangen, Germany.

Food allergy (FA) affects approximately 3 to 4% of the adult population in westernized countries. Suspected FA is even more prevalent and requires extensive diagnostic work-up. Within this study, we evaluated whether assessment of the integrity of the epithelial barrier by confocal laser endomicroscopy (CLE) during colonoscopy can be used as a screening tool to identify patients with FA. 60 patients with suspected FA were prospectively included. Serology with total and food-specific IgE, anti-tissue transglutaminase, skin prick testing, food intolerance tests, food intake registration and assessment of clinical complaints were performed. During colonocopy, standardized CLE was performed in the terminal ileum and at two colorectal sites. Analysis of CLE images included functional (i.e. presence of epithelial barrier dysfunction) and quantitative parameters of intestinal architecture. 27 of 60 patients (45%) were diagnosed with FA. Barrier dysfunction was analyzed on 65.837 ileal and on 93.251 colonic images. 96% of patients with FA exhibited functional and structural barrier defects while barrier dysfunction was found in only 33% of patients without FA (p < 0.0001). Visualizing barrier dysfunction with CLE for in vivo diagnosis of FA had a sensitivity and specificity of 96% and 67%, respectively, with a positive and negative prediction of 70% and 96%, respectively. Parameters intrinsic to the crypt architecture including crypt diameter, intercrypt distance, crypt lumen diameter and colonic vasculature were not different between patients with and without FA. CLE-based imaging of the intestinal barrier during colonoscopy might help in stratifying patients with suspected FA for further diagnostic work-up.
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http://dx.doi.org/10.1038/s41598-021-92262-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211682PMC
June 2021

Comparative Transcriptomics of IBD Patients Indicates Induction of Type 2 Immunity Irrespective of the Disease Ideotype.

Front Med (Lausanne) 2021 31;8:664045. Epub 2021 May 31.

Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.

Inflammatory cytokines initiate and sustain the perpetuation of processes leading to chronic inflammatory conditions such as inflammatory bowel diseases (IBD). The nature of the trigger causing an inflammatory reaction decides whether type 1, type 17, or type 2 immune responses, typically characterized by the respective T- helper cell subsets, come into effect. In the intestine, Type 2 responses have been linked with mucosal healing and resolution upon an immune challenge involving parasitic infections. However, type 2 cytokines are frequently elevated in certain types of IBD in particular ulcerative colitis (UC) leading to the assumption that Th2 cells might critically support the pathogenesis of UC raising the question of whether such elevated type 2 responses in IBD are beneficial or detrimental. In line with this, previous studies showed that suppression of IL-13 and other type 2 related molecules in murine models could improve the outcomes of intestinal inflammation. However, therapeutic attempts of neutralizing IL-13 in ulcerative colitis patients have yielded no benefits. Thus, a better understanding of the role of type 2 cytokines in regulating intestinal inflammation is required. Here, we took a comparative transcriptomic approach to address how Th2 responses evolve in different mouse models of colitis and human IBD datasets. Our data show that type 2 immune-related transcripts are induced in the inflamed gut of IBD patients in both Crohn's disease and UC and across widely used mouse models of IBD. Collectively our data implicate that the presence of a type 2 signature rather defines a distinct state of intestinal inflammation than a disease-specific pathomechanism.
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http://dx.doi.org/10.3389/fmed.2021.664045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200538PMC
May 2021

Targeted inhibition of the WEE1 kinase as a novel therapeutic strategy in neuroendocrine neoplasms.

Endocr Relat Cancer 2021 Jul 21;28(9):605-620. Epub 2021 Jul 21.

Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Neuroendocrine neoplasms (NENs) represent a rare and heterogeneous group of malignancies, sharing features of both neural and endocrine cells. NENs G3 appear as a highly aggressive subset with a poor prognosis and limited therapeutic options. The small-molecule inhibitor of the WEE1 tyrosine kinase, adavosertib (AZD1775), has previously demonstrated potent anti-tumor effects on various types of cancer in preclinical and clinical studies. However, the role of adavosertib in NENs G3 had remained elusive. We evaluated the effects of adavosertib on pancreatic (BON-1, QGP-1) and bronchopulmonary (NCI-H720) neuroendocrine tumor cell lines applying 2D and 3D spheroid models. We newly demonstrated that adavosertib is sufficient to reduce cell viability and proliferation in neuroendocrine cell lines with features of high-grade NENs. As underlying mechanisms, we identified adavosertib-mediated DNA double-strand breaks and a G2/M cell cycle checkpoint abrogation leading into mitotic catastrophe and cancer cell apoptosis. Silencing of WEE1 via siRNA transfection resulted in a phenotype similar to adavosertib treatment. Together, inhibition of the WEE1 tyrosine kinase applying adavosertib on NENs G3 outlines a promising novel therapeutic strategy.
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http://dx.doi.org/10.1530/ERC-20-0500DOI Listing
July 2021

Iron Beats Electricity: Resistance Training but Not Whole-Body Electromyostimulation Improves Cardiometabolic Health in Obese Metabolic Syndrome Patients during Caloric Restriction-A Randomized-Controlled Study.

Nutrients 2021 May 13;13(5). Epub 2021 May 13.

Hector-Center for Nutrition, Exercise and Sports, Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.

Caloric restriction (CR) and exercise are cornerstones in the treatment of obesity and cardiometabolic disorders. Recently, whole body electromyostimulation (WB-EMS) has emerged as a more time-efficient alternative to traditional resistance training (RT). However, the effects of WB-EMS compared to RT on cardiometabolic health in obese metabolic syndrome (MetS) patients performed during CR are still unclear. In total, 118 obese MetS patients (52.7 ± 11.8 years, BMI: 38.1 ± 6.9 kg/m) undergoing CR over 12 weeks (aim: -500 kcal deficit/day) were randomly allocated to either WB-EMS, single-set RT (1-RT), 3-set RT (3-RT) or an inactive control group (CON). Primary outcome was MetS severity (MetS z-score). Secondary outcomes were body composition, muscle strength and quality of life (QoL). All groups significantly reduced body weight (~3%) and fat mass (~2.6 kg) but only 1-RT and 3-RT preserved skeletal muscle mass (SMM). All exercise groups increased muscle strength in major muscle groups (20-103%). However, only the two RT-groups improved MetS z-score (1-RT: -1.34, = 0.003; 3-RT: -2.06, < 0.001) and QoL (1-RT: +6%, = 0.027; 3-RT: +12%, < 0.001), while WB-EMS and CON had no impact on these outcomes. We conclude that traditional RT has superior effects on cardiometabolic health, SMM and QoL in obese MetS patients undergoing CR than WB-EMS.
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http://dx.doi.org/10.3390/nu13051640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152778PMC
May 2021

Dynamic Imaging of IEL-IEC Co-Cultures Allows for Quantification of CD103-Dependent T Cell Migration.

Int J Mol Sci 2021 May 13;22(10). Epub 2021 May 13.

Department of Medicine 1, Kussmaul Campus for Medical Research Universitätsklinikum Erlangen, University of Erlangen-Nuremberg, 91052 Erlangen, Germany.

Intraepithelial lymphocytes (IEL) are widely distributed within the small intestinal epithelial cell (IEC) layer and represent one of the largest T cell pools of the body. While implicated in the pathogenesis of intestinal inflammation, detailed insight especially into the cellular cross-talk between IELs and IECs is largely missing in part due to lacking methodologies to monitor this interaction. To overcome this shortcoming, we employed and validated a murine IEL-IEC (organoids) ex vivo co-culture model system. Using livecell imaging we established a protocol to visualize and quantify the spatio-temporal migratory behavior of IELs within organoids over time. Applying this methodology, we found that IELs lacking CD103 (i.e., integrin alpha E, ITGAE) surface expression usually functioning as a retention receptor for IELs through binding to E-cadherin (CD324) expressing IECs displayed aberrant mobility and migration patterns. Specifically, CD103 deficiency affected the ability of IELs to migrate and reduced their speed during crawling within organoids. In summary, we report a new technology to monitor and quantitatively assess especially migratory characteristics of IELs communicating with IEC ex vivo. This approach is hence readily applicable to study the effects of targeted therapeutic interventions on IEL-IEC cross-talk.
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http://dx.doi.org/10.3390/ijms22105148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152227PMC
May 2021

Assessment of sorafenib induced changes in tumor perfusion of uveal melanoma metastases with dynamic contrast-enhanced ultrasound (DCE-US).

J Cancer Res Clin Oncol 2021 May 28. Epub 2021 May 28.

Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Loschgestr. 15, 91054, Erlangen, Germany.

Purpose: Dynamic contrast-enhanced ultrasound (DCE-US) was used to monitor early response to sorafenib therapy in patients with liver metastases from uveal melanoma.

Methods: In total, 21 patients with liver metastases were recruited within a prospective trial and underwent daily sorafenib therapy. DCE-US of a target lesion was performed before initiation of treatment, on day 15 and 56. Two independent blinded investigators performed software analysis for DCE-US parameters and inter-observer-correlation was calculated. Response to treatment was evaluated on day 56. DCE-US parameters were correlated with clinical response and RECIST1.1 criteria.

Results: Inter-observer-correlation (r) of DCE-US parameters [time-to-peak (TTP), mean-transit-time (MTT), peak intensity (PI), regional blood volume (RBV), regional blood flow (RBF)] at baseline, day 15, and day 56 was highly significant (r-range 0.73-0.97, all p < 0.001). Out of 17 evaluable patients, 12 patients survived day 56 (clinical responders, cRE), whereas, five patients died before day 56 and were classified as non-responders (cNR). TTP values significantly increased in the cRE group 15 days after initiation of treatment for investigator 1 (p = 0.034) and at day 56 for both investigators (p = 0.028/0.028). MTT had increased significantly in the cRE group on day 56 (p = 0.037/0.022). In the cNR group changes for TTP and MTT remained insignificant. Thus, increase of the DCE-US parameters TTP and MTT are associated with response to treatment and prognosis.

Conclusion: An increase of TTP and MTT at frequent intervals could serve as a surrogate marker for early response evaluation to anti-angiogenic treatment of metastatic uveal melanoma.
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http://dx.doi.org/10.1007/s00432-021-03666-8DOI Listing
May 2021

Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease.

Ann Rheum Dis 2021 10 25;80(10):1339-1344. Epub 2021 May 25.

Division of Rheumatology, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA

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.

Methods: Established patients at New York University Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunisation. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analysed for humoral response. Cellular immune response to SARS-CoV-2 was further analysed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany, were also analysed for humoral immune response.

Results: Although healthy subjects (n=208) and patients with IMID on biologic treatments (mostly on tumour necrosis factor blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, patients with IMID on methotrexate do not demonstrate an increase in CD8+ T-cell activation after vaccination.

Conclusions: In two independent cohorts of patients with IMID, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut-offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunisation efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines.
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http://dx.doi.org/10.1136/annrheumdis-2021-220597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219484PMC
October 2021

Computer-aided detection of colorectal polyps using a newly generated deep convolutional neural network: from development to first clinical experience.

Eur J Gastroenterol Hepatol 2021 May 21. Epub 2021 May 21.

Department of Internal Medicine 1, Division of Gastroenterology, Ludwig Demling Endoscopy Center of Excellence, Friedrich-Alexander-University, Erlangen-Nuernberg, Germany Department of Gastroenterology, Physiopathology and Endoscopy of the Gastrointestinal Tract, Central Hospital Bolzano, Bolzano, Italy Gastroenterology Outpatient Clinic, Altötting Department of Internal Medicine 3, Division of Gastroenterology, Klinikum Aschaffenburg, Aschaffenburg, Germany Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.

Aim: The use of artificial intelligence represents an objective approach to increase endoscopist's adenoma detection rate (ADR) and limit interoperator variability. In this study, we evaluated a newly developed deep convolutional neural network (DCNN) for automated detection of colorectal polyps ex vivo as well as in a first in-human trial.

Methods: For training of the DCNN, 116 529 colonoscopy images from 278 patients with 788 different polyps were collected. A subset of 10 467 images containing 504 different polyps were manually annotated and treated as the gold standard. An independent set of 45 videos consisting of 15 534 single frames was used for ex vivo performance testing. In vivo real-time detection of colorectal polyps during routine colonoscopy by the DCNN was tested in 42 patients in a back-to-back approach.

Results: When analyzing the test set of 15 534 single frames, the DCNN's sensitivity and specificity for polyp detection and localization within the frame was 90% and 80%, respectively, with an area under the curve of 0.92. In vivo, baseline polyp detection rate and ADR were 38% and 26% and significantly increased to 50% (P = 0.023) and 36% (P = 0.044), respectively, with the use of the DCNN. Of the 13 additionally with the DCNN detected lesions, the majority were diminutive and flat, among them three sessile serrated adenomas.

Conclusion: This newly developed DCNN enables highly sensitive automated detection of colorectal polyps both ex vivo and during first in-human clinical testing and could potentially increase the detection of colorectal polyps during colonoscopy.
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http://dx.doi.org/10.1097/MEG.0000000000002209DOI Listing
May 2021
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