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Background. TLR ligands can promote Th1-biased immune responses, mimicking potent stimuli of viruses and bacteria. Aim. To investigate the adjuvant properties of dual TLR2/7 ligands compared to those of the mixture of both single ligands.
Methods. Dual TLR2/7 ligands: CL401, CL413, and CL531, including CL264 (TLR7-ligand) and Pam2CysK4 (TLR2-ligand), were used. Immune-modulatory capacity of the dual ligands with the individual ligands alone or as a mixture in mouse BMmDCs, BMmDC:TC cocultures, or BMCMCs was compared and assessed in naïve mice and in a mouse model of OVA-induced intestinal allergy.
Results. CL413 and CL531 induced BMmDC-derived IL-10 secretion, suppressed rOVA-induced IL-5 secretion from OVA-specific DO11.10 CD4+ TCs, and induced proinflammatory cytokine secretion in vivo. In contrast, CL401 induced considerably less IL-10 secretion and led to IL-17A production in BMmDC:TC cocultures, but not BMCMC IL-6 secretion, or IL-6 or TNF-α production in vivo. No immune-modulating effects were observed with single ligands. All dual TLR2/7 ligands suppressed DNP-induced IgE-and-Ag-specific mast cell degranulation. Compared to vaccination with OVA, vaccination with the mixture CL531 and OVA, significantly suppressed OVA-specific IgE production in the intestinal allergy model.
Conclusions. Based on beneficial immune-modulating properties, CL413 and CL531 may have utility as potential adjuvants for allergy treatment.
This work aims at radar sensors in the frequency band from 57 to 64 GHz that can be embedded in wind turbine blades during manufacturing, enabling non-destructive quality inspection directly after production and structural health monitoring (SHM) during the complete service life of the blade. In this paper, we show the fundamental damage detection capability of this sensor technology during fatigue testing of typical rotor blade materials. Therefore, a frequency modulated continuous wave (FMCW) radar sensor is used for damage diagnostics, and the results are validated by simultaneous camera recordings. Here, we focus on the failure modes delamination, fiber waviness (ondulation), and inter-fiber failure. For each failure mode, three samples have been designed and experimentally investigated during fatigue testing. A damage index has been proposed based on residual, that is, differential, signals exploiting measurements from pristine structural conditions. This study shows that the proposed innovative radar approach is able to detect continuous structural degradation for all failure modes by means of gradual signal changes.
SDF-1/CXCR4 expression in head and neck cancer and outcome after postoperative radiochemotherapy
(2017)
Introduction: Outcome after postoperative radiochemotherapy (RT-CT) for patients with advanced head and neck squamous cell carcinomas (HNSCC) remains unsatisfactory, especially among those with HPV negative tumours. Therefore, new biomarkers are needed to further define subgroups for individualised therapeutic approaches. Preclinical and first clinical observations showed that the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12) play an important role in tumour cell proliferation, survival, cancer progression, metastasis and treatment resistance. However, the data on the prognostic value of SDF-1/CXCR4 expression for HNSCC are conflicting. The aim of our hypothesis-generating study was to retrospectively explore the prognostic potential of SDF-1/CXCR4 in a well-defined cohort of HNSCC patients collected within the multicenter biomarker study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Material and methods: Patients with stage III and IVA HNSCC of the oral cavity, oropharynx and hypopharynx were treated with resection and adjuvant radiotherapy (RT) with ≥60 Gy and concurrent cisplatin-based chemotherapy (CT). Tissue micro-arrays (TMAs) from a total of 221 patients were generated from surgical specimens, 201 evaluated for the SDF-1 and CXCR4 expression by immunofluorescence and correlated with clinico-pathological and outcome data.
Results: In univariate and multivariate analyses intracellular SDF-1 expression was associated with lower loco-regional control (LRC) in the entire patient group as well as in the HPV16 DNA negative subgroup. CXCR4 expression showed a trend for lower LRC in the univariate analysis which was not confirmed in the multivariate analysis. Neither for SDF-1 nor CXCR4 expression associations with distant metastasis free or overall survival were found.
Conclusions: Our exploratory data support the hypothesis that overexpression of intracellular SDF-1 is an independent negative prognostic biomarker for LRC after postoperative RT-CT in high-risk HNSCC. Prospective validation is warranted and further exploration of SDF-1/CXCR4 as a potential therapeutic target to overcome treatment resistance in HNSCC appears promising.
The objective of this study is to determine whether specific industries across countries or within countries are more likely to reach a stage of profitability and make a successful exit. In particular, we assess whether firms in certain industries are more prone to exit via IPO, be acquired, or exit through a leveraged buy-out. We are also interested in analyzing whether substantial differences across industries and countries arise when looking separately at the success’ rate of firms which have received venture funding at the early seed and start-up stages, vis-à-vis firms that received funding at later stages. Our results suggest that, inasmuch as some of the differences in performance can be explained by country-specific factors, there are also important idiosyncratic differences across industries: In particular, firms in the biotech and the medical / health / life science sectors tend to be significantly more likely to have a successful exit via IPO, while firms in the computer industry and communications and media are more prone to exit via merger or acquisition. Key differences across industries also emerge when considering infant versus mature firms, and their preferred exit. JEL Classification: G24, G3 Keywords:
Im nordrhein-westfälischen Teil der Eifel (Nordeifel) ist das Luzulo-Fagetum Meusel 1937 aufgrund der geologischen und edaphischen Gegebenheiten die kennzeichnende Waldgesellschaft der Potentiellen natürlichen Vegetation. Die rezenten Bestände wurden anhand von 130 Aufnahmen nach Braun-Blanquet dokumentiert und differenziert. Demnach sind in diesem Teil der Eifel das Luzulo-Fagetum typicum und das auf reichere Wuchsorte beschränkte Luzulo-Fagetum milietosum anzutreffen. Innerhalb dieser Bestände wird auf sickerfeuchten Standorten eine Variante von Athyrium filix-femina, auf stau- bzw. wechselfeuchten hingegen eine Variante mit Deschampsia cespitosa erkennbar. Luvseitige Aushagerungsstandorte sind durch Avenella flexuosa, leeseitige Anreicherungsstandorte mit dicker Fallaub-Auflage durch Festuca altissima gekennzeichnet. Geographisch können die Bestände der nordmitteleuropäischen Ausbildung der subatlantischen Rasse des Luzulo-Fagetum zugeordnet werden.
Zur Verbreitung und Ökologie von Atriplex sagittata BORKH. (Glanz-Melde) im nördlichen Rheinland
(1994)
Atriplex sagittata BORKH. (Atriplex nitens Schkuhr) wurde schon vor 1850 gelegentlich ins Rheinland eingeschleppt, etablierte sich hier aber erst nach 1945 auf den Trümmern des kriegszerstörten Bonn in größerem Maße, um sich mit dem Wiederaufbau in Randgebiete zurückzuziehen. Heute tritt sie auf Müll-, Kehrricht- und Erdabkippflächen in z.T. ausgedehnten Dominanzbeständen auf, für welche die Bezeichnung Lactuco-Atriplicetum sagittatae als nomen novum vorgeschlagen wird. Im Rheinland kommt vor allem die Typische Subassoziation dieser Gesellschaft vor. In den oftmals deutlich geschichteten Beständen können nur wenige andere Stellarietea mediae-Arten nennenswerte Deckungsanteile erreichen. Für die Ausbreitung der Art und die Bildung ausgedehnter Herden ist vor allem die ausgeprägte Heterokarpie der Glanz-Melde verantwortlich. Daneben werden aber offensichtlich ganz spezifische Ansprüche an den Wuchsort gestellt. Die von uns untersuchten Substrate lassen sich als kalkhaltige, schwach alkalische, meist gut mit Phosphor und Kalium versorgte, schluffige Sande charakterisieren. Da Verwechslungen von Atriplex sagittata mit anderen hochwüchsigen Meldenarten nicht auszuschließen sind, werden in einem eigenen Kapitel wesentliche Unterscheidungsmerkmale vorgestellt.
Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes.
CCR8 leads to eosinophil migration and regulates neutrophil migration in murine allergic enteritis
(2019)
Allergic enteritis (AE) is a gastrointestinal form of food allergy. This study aimed to elucidate cellular and molecular mechanisms of AE using a murine model. To induce AE, BALB/c wild type (WT) mice received intraperitoneal sensitization with ovalbumin (an egg white allergen) plus ALUM and feeding an egg white (EW) diet. Microarray analysis showed enhanced gene expression of CC chemokine receptor (CCR) 8 and its ligand, chemokine CC motif ligand (CCL) 1 in the inflamed jejunum. Histological and FACS analysis showed that CCR8 knock out (KO) mice exhibited slightly less inflammatory features, reduced eosinophil accumulation but accelerated neutrophil accumulation in the jejunums, when compared to WT mice. The concentrations of an eosinophil chemoattractant CCL11 (eotaxin-1), but not of IL-5, were reduced in intestinal homogenates of CCR8KO mice, suggesting an indirect involvement of CCR8 in eosinophil accumulation in AE sites by inducing CCL11 expression. The potential of CCR8 antagonists to treat allergic asthma has been discussed. However, our results suggest that CCR8 blockade may promote neutrophil accumulation in the inflamed intestinal tissues, and not be a suitable therapeutic target for AE, despite the potential to reduce eosinophil accumulation. This study advances our knowledge to establish effective anti-inflammatory strategies in AE treatment.
Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice
(2012)
Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2y/−) or the classical transient receptor potential channel 6 (TRPC6−/−) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE.
Es werden genaue Angaben über Systematik, Morphologie, Verbreitung, Ökologie und Gefährdung von Dryopteris affinis (LOWE) FRASER-JENKINS in der Westeifel gemacht. Die Fundorte werden auf Übersichtskarten dargestellt und in einer ökologischen Tabelle und durch Vegetationsaufnahmen charakterisiert. Es zeigt sich, daß Dryopteris affinis im Untersuchungsgebiet vor allem auf Waldrand-Böschungen, aber auch in naturnahen Fagion-Gesellschaften wächst. Entscheidend für das Vorkommen der Art sind offensichtlich ausreichende Wasserversorgung, hohe Luftfeuchte sowie wintermildes Klima. Daher bevorzugt Dryopteris affinis auch in der Eifel die stärker atlantisch geprägten Gebiete. Dryopteris affinis lässt sich morphologisch relativ leicht von Dryopteris filix-mas unterscheiden. Nachweise von Dryopteris x complexa in der Westeifel fehlen bisher. Die Unterscheidung der Unterarten von Dryopteris affinis anhand rein morphologischer Merkmale gestaltet sich schwierig, jedoch scheinen nur die triploiden Sippen ssp. borreri und ssp. robusta vorzukommen. Unter dem Gesichtspunkt der Erhaltung des genetischen Potentials der von anderen Unterarten schwer zu unterscheidenden diploiden Unterart müssen die Wuchsorte von Dryopteris affinis unbedingt erhalten werden.