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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.
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.
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
The German Cancer Consortium ('Deutsches Konsortium für Translationale Krebsforschung', DKTK) is a long-term cancer consortium, bringing together the German Cancer Research Center (DKFZ), Germany's largest life science research center, and the leading University Medical Center-based Comprehensive Cancer Centers (CCCs) at seven sites across Germany. DKTK was founded in 2012 following international peer review and has positioned itself since then as the leading network for translational cancer research in Germany. DKTK is long term funded by the German Ministry of Research and Education and the federal states of each DKTK partner site. DKTK acts at the interface between basic and clinical cancer research, one major focus being to generate suitable multisite cooperation structures and provide the basis for including higher numbers of patients and facilitate effective collaborative forward and reverse translational cancer research. The consortium addresses areas of high scientific and medical relevance and develops critical infrastructures, for example, for omics technologies, clinical and research big data exchange and analysis, imaging, and clinical grade drug manufacturing. Moreover, DKTK provides a very attractive environment for interdisciplinary and interinstitutional training and career development for clinician and medical scientists.
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.
Zum Cystopteris fragilis-Komplex gehören in Mitteleuropa drei grobmorphologisch nur schwer unterscheidbare Arten (Cystopteris alpina [Lam.] Desv., C. dickieana R. Sim, C. fragilis [L.] Bernh.). Vor allem C. dickieana und C. fragilis sind sehr polymorph und lassen sich lediglich durch die Struktur des Perispors eindeutig voneinander abgrenzen. C. dickieana ist eine in Deutschland sehr seltene Art. Außer einem nur historisch belegten Fund aus der Umgebung von Berchtesgaden war sie bislang lediglich aus dem Südschwarzwald bekannt, konnte aktuell aber auch aus dem Nahegebiet nachgewiesen werden. Da die Art im Gelände nicht von C. fragilis unterschieden werden kann, ist sie möglicherweise häufiger als bisher bekannt. Die beiden aktuellen Vorkommen im Südschwarzwald und an der Nahe werden standortökologisch, populationsbiologisch und pflanzensoziologisch näher charakterisiert. Bei einer cytologischen Überprüfung erwies sich das Vorkommen im Südschwarzwald als tetraploid. Da die Pflanzen aller drei deutschen Herkünfte in ihrer Sporen- und Stomatalänge weitgehend übereinstimmen, kann vermutet werden, daß auch das (historische) bayerische und das rheinland-pfälzische Vorkommen den tetraploiden Cytotyp repräsentieren.
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.
Im nordrhein-westfälischen Teil der Eifel (nördliche Eifel) tritt das Galio odorati-Fagetum Sougnez & Thill 1959 (Waldmeister-Buchenwald) vor allem in Silikat-, seltener auch in Kalkgebieten auf. Seinen Schwerpunkt besitzt es dort, wo unterdevonische Schiefer und Grauwacken von pleistozänen Hochflächenlehmen und Solifluktionsdecken überlagert werden. Die Bestände werden anhand von pflanzensoziologischen Aufnahmen nach BRAUN-BLANQUET dokumentiert und differenziert. Das Galio-Fagetum unterscheidet sich vom Luzulo-Fagetum (Hainsimsen-Buchenwald) durch eine ganze Reihe von Trennarten, größere mittlere Artenzahlen, höhere durchschnittliche Deckungsgrade der Krautschicht und einige feinere floristische Merkmale. Im Untersuchungsgebiet sind zwei Subassoziationen des Galio-Fagetum anzutreffen, das anspruchsvollere Galio-Fagetum typicum und das zum Luzulo-Fagetem überleitende Galio-Fagetum luzuletosum. Diese lassen sich weiter untergliedern in eine leicht verhagerte wechseltrockene Flieracium sylvaticum-Variante, eine frische Typische Variante bzw. Hordelymus europaeus-Variante, eine sickerfeuchte Dryopteris filix-mas-Variante und eine stau- bzw. wechselfeuchte Deschampsia cespitosa-Variante. Anreicherungsstandorte mit dicker Fallaubdecke sind durch Massenbestände von Festuca altissima gekennzeichnet. Ferner läßt sich eine collin-submontane Form mit Rubus fruticosus agg. von einer montanen Form mit Polygonatum verticillatum unterscheiden. Geographisch können die Bestände des Galio-Fagetum innerhalb der subatlantischen Ilexaquifolium-Rasse der nordmitteleuropäischen Melica uniflora-Ausbildung zugeordnet werden.
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.
Comprehensive analysis of tumour sub-volumes for radiomic risk modelling in locally advanced HNSCC
(2020)
Simple Summary: Radiomic risk models are usually based on imaging features, which are extracted from the entire gross tumour volume (GTV entire ). This approach does not explicitly consider the complex biological structure of the tumours. Therefore, in this retrospective study, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma who were treated with primary radio-chemotherapy. The GTV entire was cropped by different margins to define the rim and corresponding core sub-volumes of the tumour. Furthermore, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. As a result, the models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed an improved performance compared to models based on the corresponding tumour core. This indicates that the consideration of tumour sub-volumes may help to improve radiomic risk models.
Abstract: Imaging features for radiomic analyses are commonly calculated from the entire gross tumour volume (GTVentire). However, tumours are biologically complex and the consideration of different tumour regions in radiomic models may lead to an improved outcome prediction. Therefore, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma. The GTVentire was cropped by different margins to define the rim and the corresponding core sub-volumes of the tumour. Subsequently, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. Radiomic risk models were developed and validated using a retrospective cohort consisting of 291 patients in one of the six Partner Sites of the German Cancer Consortium Radiation Oncology Group treated between 2005 and 2013. The validation concordance index (C-index) averaged over all applied learning algorithms and feature selection methods using the GTVentire achieved a moderate prognostic performance for loco-regional tumour control (C-index: 0.61 ± 0.04 (mean ± std)). The models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed higher median performances (C-index: 0.65 ± 0.02 and 0.64 ± 0.05, respectively), while models based on the corresponding tumour core volumes performed less (C-index: 0.59 ± 0.01). The difference in C-index between the 5 mm tumour rim and the corresponding core volume showed a statistical trend (p = 0.10). After additional prospective validation, the consideration of tumour sub-volumes may be a promising way to improve prognostic radiomic risk models.