Loss of TRAIL-receptors is a recurrent feature in pancreatic cancer and determines the prognosis of patients with no nodal metastasis after surgery.

Agonistic antibodies targeting TRAIL-receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are being developed as a novel therapeutic approach in cancer therapy including pancreatic cancer. However, the cellular distribution of these receptors in primary pancreatic cancer samples has not been sufficiently investigated and no study has yet addressed the issue of their prognostic significance in this tumor entity. Applying tissue microarray (TMA) analysis, we performed an immunohistochemical assessment of TRAIL-receptors in surgical samples from 84 consecutive patients affected by pancreatic adenocarcinoma and in 26 additional selected specimens from patients with no lymph nodes metastasis at the time of surgery. The prognostic significance of membrane staining and staining intensity for TRAIL-receptors was evaluated. The fraction of pancreatic cancer samples with positive membrane staining for TRAIL-R1 and TRAIL-R2 was lower than that of cells from surrounding non-tumor tissues (TRAIL-R1: p<0.001, TRAIL-R2: p = 0.006). In addition, subgroup analyses showed that loss of membrane staining for TRAIL-R2 was associated with poorer prognosis in patients without nodal metastases (multivariate Cox regression analysis, Hazard Ratio: 0.44 [95% confidence interval: 0.22-0.87]; p = 0.019). In contrast, analysis of decoy receptors TRAIL-R3 and -R4 in tumor samples showed an exclusively cytoplasmatic staining pattern and no prognostic relevance. This is a first report on the prognostic significance of TRAIL-receptors expression in pancreatic cancer showing that TRAIL-R2 might represent a prognostic marker for patients with early stage disease. In addition, our data suggest that loss of membrane-bound TRAIL-receptors could represent a molecular mechanism for therapeutic failure upon administration of TRAIL-receptors-targeting antibodies in pancreatic cancer. This hypothesis should be evaluated in future clinical trials

Inherited multifocal RPE-diseases: mechanisms for local dysfunction in global retinoid cycle gene defects

AbstractAlterations of retinoid cycle genes are known to cause retinal diseases characterized by focal white dot fundus lesions. Fundus appearances reveal circumscribed RPE-changes, although generalized metabolic defects and global functional abnormalities are present. As a possible explanation, topographic inhomogeneities of the human photoreceptor mosaic and the role of a cone specific visual cycle will be discussed. Due to particular characteristics of photoreceptor subtypes as well as different pathways for photopigment regeneration the metabolic demand of individual RPE cells might differ. In “flecked retina diseases” heterogeneity of metabolic demand in individual RPE cells could therefore be responsible for their multifocal appearance

EFEMP1 binds the EGF receptor and activates MAPK and Akt pathways in pancreatic carcinoma cells

The EGF-related protein EFEMP1 (EGF-containing fibulin-like extracellular matrix protein 1) has been shown to promote tumor growth in human adenocarcinoma. To understand the mechanism of this action, the signal transduction activated upon treatment with this protein has been investigated. We show that EFEMP1 binds EGF receptor (EGFR) in a competitive manner relative to epidermal growth factor (EGF), implicating that EFEMP1 and EGF share the same or adjacent binding sites on the EGFR. Treatment of pancreatic carcinoma cells with purified EFEMP1 activates autophosphorylation of EGFR at the positions Tyr-992 and Tyr-1068, but not at the position Tyr-1048. This signal is further transduced to phosphorylation of Akt at position Thr-308 and p44/p42 MAPK (mitogen-activated protein kinase) at positions Thr-202 and Tyr-204. These downstream phosphorylation events can be inhibited by treatment with the EGFR kinase inhibitor PD 153035. The observed signal transduction upon treatment with EFEMP1 can contribute to the enhancement of tumor growth shown in pancreatic carcinoma cells overexpressing EFEMP1

Extrinsic intestinal denervation modulates tumor development in the small intestine of ApcMin/+ mice

Background Innervation interacts with enteric immune responses. Chronic intestinal inflammation is associated with increased risk of colorectal cancer. We aimed to study potential extrinsic neuronal modulation of intestinal tumor development in a mouse model. Methods Experiments were performed with male ApcMin/+ or wild type mice (4 weeks old, body weight approximately 20 g). Subgroups with subdiaphragmatic vagotomy (apcV/wtV), sympathetic denervation of the small intestine (apcS/wtS) or sham operated controls (apcC/wtC) were investigated (n = 6-14 per group). Three months after surgical manipulation, 10 cm of terminal ileum were excised, fixed for 48 h in 4% paraformaldehyde and all tumors were counted and their area determined in mm2 (mean ± standard error of the mean (SEM)). Whole mounts of the muscularis of terminal ileum and duodenum (internal positive control) were also stained for tyrosine hydroxylase to confirm successful sympathetic denervation. Results Tumor count in ApcMin/+ mice was 62 ± 8 (apcC), 46 ± 11 (apcV) and 54 ± 8 (apcS) which was increased compared to wildtype controls with 4 ± 0.5 (wtC), 5 ± 0.5 (wtV) and 5 ± 0.6 (wtS; all p < 0.05). For ApcMin/+ groups, vagotomized animals showed a trend towards decreased tumor counts compared to sham operated ApcMin/+ controls while sympathetic denervation was similar to sham ApcMin/+. Area covered by tumors in ApcMin/+ mice was 55 ± 10 (apcC), 31 ± 8 (apcV) and 42 ± 8 (apcS) mm2, which was generally increased compared to wildtype controls with 7 ± 0.6 (wtC), 7 ± 0.4 (wtV) and 7 ± 0.6 (wtS) mm2 (all p < 0.05). In ApcMin/+ groups, tumor area was decreased in vagotomized animals compared to sham operated controls (p < 0.05) while sympathetically denervated mice showed a minor trend to decreased tumor area compared to controls. Conclusions Extrinsic innervation of the small bowel is likely to modulate tumor development in ApcMin/+ mice. Interrupted vagal innervation, but not sympathetic denervation, seems to inhibit tumor growth

Risk factors for upper and lower type prolonged postoperative ileus following surgery for Crohn’s disease

Purpose: Prolonged postoperative ileus (PPOI) is common after bowel resections, especially in Crohn's disease (CD). The pathophysiology of PPOI is not fully understood. PPOI could affect only the upper or lower gastrointestinal (GI) tract. The aim of this study was to assess risk factors for diverse types of PPOI, particularly to differentiate PPOI of upper and lower GI tract. Methods: A retrospective analysis of 163 patients with CD undergoing ileocecal resection from 2015 to 2020 in a single center was performed. PPOI of the upper GI tract was predefined as the presence of vomiting or use of nasogastric tube longer than the third postoperative day. Lower PPOI was predefined as the absence of defecation for more than three days. Independent risk factors were identified by multivariable logistic regression analysis. Results: Overall incidence of PPOI was 42.7%. PPOI of the upper GI tract was observed in 30.7% and lower PPOI in 20.9% of patients. Independent risk factors for upper PPOI included older age, surgery by a resident surgeon, hand-sewn anastomosis, prolonged opioid analgesia, and reoperation, while for lower PPOI included BMI <= 25 kg/m(2), preoperative anemia, and absence of ileostomy. Conclusion: This study identified different risk factors for upper and lower PPOI after ileocecal resection in patients with CD. A differentiated upper/lower type approach should be considered in future research and clinical practice. High-risk patients for each type of PPOI should be closely monitored, and modifiable risk factors, such as preoperative anemia and opioids, should be avoided if possible

Impact of myopenia and myosteatosis on postoperative outcome and recurrence in Crohn’s disease

PURPOSE: Myopenia and myosteatosis have been proposed to be prognostic factors of surgical outcomes for various diseases, but their exact role in Crohn’s disease (CD) is unknown. The aim of this study is to evaluate their impact on anastomotic leakage, CD recurrence, and postoperative complications after ileocecal resection in patients with CD. METHODS: A retrospective analysis of CD patients undergoing ileocecal resection at our tertiary referral center was performed. To assess myopenia, skeletal muscle index (skeletal muscle area normalized for body height) was measured using an established image analysis method at third lumbar vertebra level on MRI cross-sectional images. Muscle signal intensity was measured to assess myosteatosis index. RESULTS: A total of 347 patients were retrospectively analyzed. An adequate abdominal MRI scan within 12 months prior to surgery was available for 223 patients with median follow-up time of 48.8 months (IQR: 20.0–82.9). Anastomotic leakage rate was not associated with myopenia (SMI: p = 0.363) or myosteatosis index (p = 0.821). Patients with Crohn’s recurrence had a significantly lower SMI (p = 0.047) in univariable analysis, but SMI was not an independent factor for recurrent anastomotic stenosis in multivariable analysis (OR 0.951, 95% CI 0.840–1.078; p = 0.434). Postoperative complications were not associated with myopenia or myosteatosis. CONCLUSION: Based on the largest cohort of its kind with a long follow-up time, we could provide some data that MRI parameters for myopenia and myosteatosis may not be reliable predictors of postoperative outcome or recurrence in patients with Crohn’s disease undergoing ileocecal resection

EFEMP1 binds the EGF receptor and activates MAPK and Akt pathways in pancreatic carcinoma cells

The EGF-related protein EFEMP1 (EGF-containing fibulin-like extracellular matrix protein 1) has been shown to promote tumor growth in human adenocarcinoma. To understand the mechanism of this action, the signal transduction activated upon treatment with this protein has been investigated. We show that EFEMP1 binds EGF receptor (EGFR) in a competitive manner relative to epidermal growth factor (EGF), implicating that EFEMP1 and EGF share the same or adjacent binding sites on the EGFR. Treatment of pancreatic carcinoma cells with purified EFEMP1 activates autophosphorylation of EGFR at the positions Tyr-992 and Tyr-1068, but not at the position Tyr-1048. This signal is further transduced to phosphorylation of Akt at position Thr-308 and p44/p42 MAPK (mitogen-activated protein kinase) at positions Thr-202 and Tyr-204. These downstream phosphorylation events can be inhibited by treatment with the EGFR kinase inhibitor PD 153035. The observed signal transduction upon treatment with EFEMP1 can contribute to the enhancement of tumor growth shown in pancreatic carcinoma cells overexpressing EFEMP1

Correction to: EGFR/Ras-induced CCL20 production modulates the tumour microenvironment

The article ‘EGFR/Ras-induced CCL20 production modulates the tumour microenvironment’, written by Andreas Hippe, Stephan Alexander Braun, Péter Oláh, Peter Arne Gerber, Anne Schorr, Stephan Seeliger, Stephanie Holtz, Katharina Jannasch, Andor Pivarcsi, Bettina Buhren, Holger Schrumpf, Andreas Kislat, Erich Bünemann, Martin Steinhoff, Jens Fischer, Sérgio A. Lira, Petra Boukamp, Peter Hevezi, Nikolas Hendrik Stoecklein, Thomas Hoffmann, Frauke Alves, Jonathan Sleeman, Thomas Bauer, Jörg Klufa, Nicole Amberg, Maria Sibilia, Albert Zlotnik, Anja Müller- Homey and Bernhard Homey, was originally published electronically on the publisher’s internet portal on 30 June 2020 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on 16 September 2021 to © The Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. Open Access funding enabled and organized by Projekt DEAL

Mobility in a Globalised World 2016

The term mobility has different meanings in the following science disciplines. In economics, mobility is the ability of an individual or a group to improve their economic status in relation to income and wealth within their lifetime or between generations. In information systems and computer science, mobility is used for the concept of mobile computing, in which a computer is transported by a person during normal use. Logistics creates by the design of logistics networks the infrastructure for the mobility of people and goods. Electric mobility is one of today’s solutions from engineering perspective to reduce the need of energy resources and environmental impact. Moreover, for urban planning, mobility is the crunch question about how to optimise the different needs for mobility and how to link different transportation systems. In this publication we collected the ideas of practitioners, researchers, and government officials regarding the different modes of mobility in a globalised world, focusing on both domestic and international issues

Mobility in a Globalised World

The term mobility has different meanings in the following academic disciplines. In economics, mobility is the ability of an individual or a group to improve their economic status in relation to income and wealth within their lifetime or between generations. In information systems and computer science, mobility is used for the concept of mobile computing, in which a computer is transported by a person during normal use. Logistics creates, by the design of logistics networks, the infrastructure for the mobility of people and goods. Electric mobility is one of today’s solutions from engineering perspective to reduce the need of energy resources and environmental impact. Moreover, for urban planning, mobility is the crunch question about how to optimize the different needs for mobility and how to link different transportation systems. The conference “Mobility in a Globalised World” took place in Iserlohn, Germany, on September 14th – 15th, 2011. The aim of this conference was to provide an interdisciplinary forum for the exchange of ideas among practitioners, researchers, and government officials regarding the different modes of mobility in a globalised world, focusing on both domestic and international issues. The proceedings at hand document the results of the presentations and ensuing discussions at the conference