Die Analyse der Inhibition des Monozyten chemotaktischen Proteins-1 (MCP-1) und der Stimulation durch MCP-1 auf die Koloniebildung und die Zytokinexpression von Plattenepithelkarzinomen der Kopf-Hals-Region im FLAVINO-Assay

Das Monozyten chemotaktische Protein-1 (MCP-1) ist ein CC-Chemokin, das in seiner Rolle als Chemoattraktor auf Monozyten in der Genese von Malignomen eine wesentliche Rolle spielt. Dabei kann es sowohl zur lokalen Tumorabwehr als auch zur Tumorgenese, Tumor-angiogenese und Metastasierung beitragen. Die vorliegende Arbeit untersucht die MCP-1-Inhibition und die Stimulation durch MCP-1 auf die Koloniebildung und die Zytokinexpression von Plattenepithelkarzinomen der Kopf-Hals-Region (HNSCC) im FLAVINO-Assay. Dieser ist ein klonogener, qualitätskontrollierter Ex-vivo-Koloniebildungsassay, der an der Klinik für Hals-Nasen-Ohrenheilkunde der Universität Leipzig etabliert und patentiert wurde und unter flavinschützenden Bedingungen durchgeführt wird. Weiterhin wird die Eignung von MCP-1, Interleukin-6 (IL-6), Interleukin-8 (IL-8) und des Vascular endothelial growth factor (VEGF) als Biomarker in HNSCC, die mithilfe von ELISA in Seren und Kulturüberständen quantifiziert wurden, untersucht. Durch die Stimulation durch MCP-1 und dessen Blockade sowie durch in vivo tolerierbare Konzentrationen von Cisplatin, Docetaxel, Cilengitide und Temsirolimus wurde die Expression der untersuchten Zytokine in den Kulturüberständen der HNSCC unterschiedlich moduliert. Cisplatin und MCP-1 supprimierten die Koloniebildung signifikant, während unter Docetaxel und Temsirolimus eine insignifikante Reduktion und durch Cilengitide eine insignifikante Stimulation der Koloniebildung beobachtet wurde. Die MCP-1-Blockade durch einen Anti-MCP-1-Antikörper führte zu keiner signifikanten Modulation der Koloniebildung. MCP-1 und der Anti-MCP-1-Antikörper senkten die Zytokinexpression, während bis auf Cisplatin alle Zytostatika die Zytokinexpressionen steigerten. Bezüglich der kombinierten Testung der Zytostatika und der MCP-1-Blockade bzw. Stimulation unterschieden sich die Proben, sodass additive, synergistische und antagonistische Effekte resultierten. Da durch MCP-1 gesteuerte tumorassoziierte Makrophagen das Mikromilieu eines Tumors wesentlich beeinflussen, gebührt diesen ebenfalls eine besondere Aufmerksamkeit. In dieser Arbeit wurden unter MCP-1 antitumoröse Effekte beobachtet, sodass weitere klinische Testungen der antitumorösen Wirkung des MCP-1 auf HNSCC lohnenswert erscheinen. Die individuelle Chemoresponse-Testung kann dabei helfen, das biologisch heterogene Verhalten der HNSCC besser zu verstehen. In diesem Sinne wäre die klinische Validierung solcher Testsysteme wertvoll

Wrought Al - Cast Al compound casting based on zincate treatment for aluminum wrought alloy inserts

AbstractThe surface properties of solid inserts are critical to the development of a reaction zone in compound castings. In contrast to prior works (based on Al99.5) the goal of this paper is to apply the zincate treatment to different aluminum wrought alloys. This enables the possibility to create compound structures with enhanced mechanical properties. During zincate treatment the aluminum oxide layers are dissolved and a thin layer of zinc (<500nm) prevents reoxidation. Coating parameters are optimized especially for compound castings: maximum coverage of the surface and high coating adhesion implemented by double zincate treatment. The pretreated inserts are embedded in an aluminum component by high pressure die casting. A sound metallic bonding between both aluminum alloys develops due to diffusion and reaction zones. Mechanical tests confirm a sound metallic bonding. Depending on the integrated wrought alloy enhanced mechanical properties of the compound structure can be achieved. Microprobe and fracture analysis provide detailed information about the interface properties of the compound structure, which can be enhanced by thermal treatment

Associations of Green Spaces and Streets in the Living Environment with Outdoor Activity, Media Use, Overweight/Obesity and Emotional Wellbeing in Children and Adolescents

Aspects of the living environment can affect health and wellbeing of children and adolescents. Whereas most previous studies assessed the more distant residential urban environment, less is known on possible effects of the close environment. The present study investigated associations of the proportion of streets and green spaces in the immediate urban living environment (50, 100 and 400 m around the home) with media use, outdoor activity, overweight/obesity and emotional problems in two samples of younger (age 3–10, n = 395) and older children (age 10–19, n = 405). Independently of socioeconomic parameters, a higher proportion of streets was associated with overweight/obesity (in younger and older children), higher media use (in younger children), less outdoor activity and more emotional problems (in older children). Older children’s outdoor activity in winter increased with increasing proportions of green spaces. The observations suggest that the immediate urban living environment is a factor that can affect leisure behavior and health in children

Yeast Svf1 binds ceramides and contributes to sphingolipid metabolism at the ER cis-Golgi interface

Ceramides are essential precursors of complex sphingolipids and act as potent signaling molecules. Ceramides are synthesized in the endoplasmic reticulum (ER) and receive their head-groups in the Golgi apparatus, yielding complex sphingolipids (SPs). Transport of ceramides between the ER and the Golgi is executed by the essential ceramide transport protein (CERT) in mammalian cells. However, yeast cells lack a CERT homolog, and the mechanism of ER to Golgi ceramide transport remains largely elusive. Here, we identified a role for yeast Svf1 in ceramide transport between the ER and the Golgi. Svf1 is dynamically targeted to membranes via an N-terminal amphipathic helix (AH). Svf1 binds ceramide via a hydrophobic binding pocket that is located in between two lipocalin domains. We showed that Svf1 membrane-targeting is important to maintain flux of ceramides into complex SPs. Together, our results show that Svf1 is a ceramide binding protein that contributes to sphingolipid metabolism at Golgi compartments

Digital twin-enabled collaborative data management for metal additive manufacturing systems

Metal Additive Manufacturing (AM) has been attracting a continuously increasing attention due to its great advantages compared to traditional subtractive manufacturing in terms of higher design flexibility, shorter development time, lower tooling cost, and fewer production wastes. However, the lack of process robustness, stability and repeatability caused by the unsolved complex relationships between material properties, product design, process parameters, process signatures, post AM processes and product quality has significantly impeded its broad acceptance in the industry. To facilitate efficient implementation of advanced data analytics in metal AM, which would support the development of intelligent process monitoring, control and optimisation, this paper proposes a novel Digital Twin (DT)-enabled collaborative data management framework for metal AM systems, where a Cloud DT communicates with distributed Edge DTs in different product lifecycle stages. A metal AM product data model that contains a comprehensive list of specific product lifecycle data is developed to support the collaborative data management. The feasibility and advantages of the proposed framework are validated through the practical implementation in a distributed metal AM system developed in the project MANUELA. A representative application scenario of cloud-based and deep learning-enabled metal AM layer defect analysis is also presented. The proposed DT-enabled collaborative data management has shown great potential in enhancing fundamental understanding of metal AM processes, developing simulation and prediction models, reducing development times and costs, and improving product quality and production efficiency

Grain Structure Evolution of Al−Cu Alloys in Powder Bed Fusion with Laser Beam for Excellent Mechanical Properties

Powder Bed Fusion with Laser Beam of Metals (PBF-LB/M) is one of the fastest growing technology branches. More and more metallic alloys are being qualified, but processing of aluminum wrought alloys without cracks and defects is still challenging. It has already been shown that small parts with low residual porosity can be produced. However, suffering from microscopic hot cracks, the fracture behavior has been rather brittle. In this paper different combinations of temperature gradients and solidification rates are used to achieve specific solidification conditions in order to influence the resulting microstructure, as well as internal stresses. By this approach it could be shown that EN AW-2024, an aluminum-copper wrought alloy, is processable via PBF-LB/M fully dense and crack-free with outstanding material properties, exceeding those reported for commonly manufactured EN AW-2024 after T4 heat treatment

A Syd-1 homologue regulates pre- and postsynaptic maturation in Drosophila

A proteomics approach identifies Drosophila Syd-1 as a Bruchpilot binding partner that controls maturation on both sides of the neuromuscular junction