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Gotze S.,Max Planck Institute of Molecular Physiology | Wolter M.,Heinrich Heine University Düsseldorf | Reifenberger G.,Heinrich Heine University Düsseldorf | Muller O.,Kaiserslautern University of Applied Sciences | Sievers S.,Max Planck Institute of Molecular Physiology
International Journal of Cancer | Year: 2010

Aberrant activation of wingless (Wnt) signaling is involved in the pathogenesis of various cancers. Recent studies suggested a role of Wnt signaling in gliomas, the most common primary brain tumors. We investigated 70 gliomas of different malignancy grades for promoter hypermethylation in 8 genes encoding members of the secreted frizzled-related protein (SFRP1, SFRP2, SFRP4, SFRP5), dickkopf (DKK1, DKK3) and naked (NKD1, NKD2) families of Wnt pathway inhibitors. All tumors were additionally analyzed for mutations in exon 3 of the β-catenin gene (CTNNB1). While none of the tumors carried CTNNB1 mutations, we found frequent promoter hypermethylation of Wnt pathway inhibitor genes, with at least one of these genes being hypermethylated in 6 of 16 diffuse astrocytomas (38%), 4 of 14 anaplastic astrocytomas (29%), 7 of 10 secondary glioblastomas (70%) and 23 of 30 primary glioblastomas (77%). Glioblastomas often demonstrated hypermethylation of 2 or more analyzed genes. Hypermethylation of SFRP1, SFRP2 and NKD2 each occurred in more than 40% of the primary glioblastomas, while DKK1 hypermethylation was found in 50% of secondary glioblastomas. Treatment of SFRP1-, SFRP5-, DKK1-, DKK3-, NKD1- and NKD2-hypermethylated U87-MG glioblastoma cells with 5-aza-2′-deoxycytidine and trichostatin A resulted in increased expression of each gene. Furthermore, SFRP1-hypermethylated gliomas showed significantly lower expression of the respective transcripts when compared with unmethylated tumors. Taken together, our results suggest an important role of epigenetic silencing of Wnt pathway inhibitor genes in astrocytic gliomas, in particular, in glioblastomas, with distinct patterns of hypermethylated genes distinguishing primary from secondary glioblastomas. © 2009 UICC.


Demir I.E.,TU Munich | Schafer K.-H.,Kaiserslautern University of Applied Sciences | Tieftrunk E.,TU Munich | Friess H.,TU Munich | Ceyhan G.O.,TU Munich
Acta Neuropathologica | Year: 2013

Neural plasticity is not only the adaptive response of the central nervous system to learning, structural damage or sensory deprivation, but also an increasingly recognized common feature of the gastrointestinal (GI) nervous system during pathological states. Indeed, nearly all chronic GI disorders exhibit a disease-stage-dependent, structural and functional neuroplasticity. At structural level, GI neuroplasticity usually comprises local tissue hyperinnervation (neural sprouting, neural, and ganglionic hypertrophy) next to hypoinnervated areas, a switch in the neurochemical (neurotransmitter/ neuropeptide) code toward preferential expression of neuropeptides which are frequently present in nociceptive neurons (e.g., substance P/SP, calcitonin-gene-related-peptide/CGRP) and of ion channels (TRPV1, TRPA1, PAR2), and concomitant activation of peripheral neural glia. The functional counterpart of these structural alterations is altered neuronal electric activity, leading to organ dysfunction (e.g., impaired motility and secretion), together with reduced sensory thresholds, resulting in hypersensitivity and pain. The present review underlines that neural plasticity in all GI organs, starting from esophagus, stomach, small and large intestine to liver, gallbladder, and pancreas, actually exhibits common phenotypes and mechanisms. Careful appraisal of these GI neuroplastic alterations reveals that - no matter which etiology, i.e., inflammatory, infectious, neoplastic/malignant, or degenerative - neural plasticity in the GI tract primarily occurs in the presence of chronic tissue- and neuro-inflammation. It seems that studying the abundant trophic and activating signals which are generated during this neuro-immune-crosstalk represents the key to understand the remarkable neuroplasticity of the GI tract. © 2013 Springer-Verlag Berlin Heidelberg.


Susloparova A.,Kaiserslautern University of Applied Sciences | Koppenhofer D.,Kaiserslautern University of Applied Sciences | Vu X.T.,Kaiserslautern University of Applied Sciences | Weil M.,Kaiserslautern University of Applied Sciences | Ingebrandt S.,Kaiserslautern University of Applied Sciences
Biosensors and Bioelectronics | Year: 2013

In this study, impedance spectroscopy measurements of silicon-based open-gate field-effect transistor (FET) devices were utilized to study the adhesion status of cancer cells at a single cell level. We developed a trans-impedance amplifier circuit for the FETs with a higher bandwidth compared to a previously described system. The new system was characterized with a fast lock-in amplifier, which enabled measuring of impedance spectra up to 50. MHz. We studied cellular activities, including cell adhesion and anti-cancer drug induced apoptosis of human embryonic kidney (HEK293) and human lung adenocarcinoma epithelial (H441) cells. A well-known chemotherapeutic drug, topotecan hydrochloride, was used to investigate the effect of this drug to tumor cells cultured on the FET devices. The presence of the drug resulted in a 20% change in the amplitude of the impedance spectra at 200. kHz as a result of the induced apoptosis process. Real-time impedance measurements were performed inside an incubator at a constant frequency. The experimental results can be interpreted with an equivalent electronic circuit to resolve the influence of the system parameters. The developed method could be applied for the analysis of the specificity and efficacy of novel anti-cancer drugs in cancer therapy research on a single cell level in parallelized measurements. © 2012 Elsevier B.V.


Koppenhofer D.,Kaiserslautern University of Applied Sciences | Susloparova A.,Kaiserslautern University of Applied Sciences | Docter D.,University Hospital Freiburg | Stauber R.H.,University Hospital Freiburg | Ingebrandt S.,Kaiserslautern University of Applied Sciences
Biosensors and Bioelectronics | Year: 2013

In this work we propose the use of field-effect transistors (FETs) to examine the reaction of individual tumor cells to treatment with cell death inducing nanoparticles for future use in cancer therapy. For our analysis the human cancer cell line H441 (a human lung adenocarcinoma epithelial cell line) was cultivated on fibronectin coated FETs and treated with various concentrations of silicon nanoparticles. The cell line was cultivated under standard conditions. The reactions of the cells to the nanoparticles were analyzed via transfer function measurements, microscopic examination and standard MTT viability assays. Microscopic examination showed a clear change of morphology to round cells, which accompanies detachment from the surface of the substrate. Cell detachment could also be observed as a signal shift in the transfer function. The results of our study indicate the applicability of FETs for cancer research and analyzing pharmacological effects of new compounds. In addition our results implicate the usefulness of silicon nanoparticle based compounds in cancer therapy. © 2012 Elsevier B.V.


Schmarr H.-G.,German Aerospace Center | Koschinski S.,German Aerospace Center | Sang W.,German Aerospace Center | Sang W.,Kaiserslautern University of Applied Sciences | Slabizki P.,German Aerospace Center
Journal of Chromatography A | Year: 2012

This work describes the development of a trace level (<1ngL -1) analysis of haloanisoles in complex wine matrix. The suggested method involves sample preparation based on solid phase extraction, a clean-up to remove acidic compounds, concentration of the haloanisole fraction and large volume on-column injection into a multidimensional GC-MS system. Mass spectrometric detection in the selected ion mode allowed reliable quantification of 2,4,6-trichloroanisole (TCA) or 2,4,6-tribromoanisole (TBA), via their highly deuterated ([ 2H 5]) isotopologues as internal standards (stable isotope dilution analysis; SIDA), which had prior been synthesized in house. The development of this new method had become necessary, as a one-dimensional HS-SPME-GC-ECD method, routinely applied for analysis of TCA in cork soaks, had to be extended for TeCA and TBA determination, but failed due to co-elutions within wine matrices. The newly developed SPE//MDGC-MS method provided detection limits well below olfactory thresholds of the analytes with 0.05ngL -1 (LOD), 0.19ngL -1 (LOQ) for TCA, 0.06ngL -1 (LOD), 0.21ngL -1 (LOQ) for TeCA, and 0.09ngL -1 (LOD), 0.34ngL -1 (LOQ) for TBA. © 2011 Elsevier B.V.


Obeidat W.M.,University of Sharjah | Schwabe K.,Free University of Berlin | Muller R.H.,Free University of Berlin | Keck C.M.,University Putra Malaysia | Keck C.M.,Kaiserslautern University of Applied Sciences
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2010

Due to their positive features (e.g., increased penetration of actives, re-enforcement of the lipid barrier and increase in skin hydration), nanostructured lipid carriers (NLC) are used in many dermal formulations. These formulations require preservation, and preservatives can impair the physical stability of disperse systems. Therefore, in this study, the influence of preservatives on the physical stability of Q10-loaded NLC was investigated using 11 different preservative mixtures. Whereas for nanosuspensions, only a limited number of preservatives are known from the literature not affecting their physical stability, a surprisingly high number of seven preservatives could be identified to be suitable for the preservation of NLC dispersions. For Q10-loaded NLC, Hydrolite 5 proved to be the best preservative, as it was found surprisingly to stabilize the NLC dispersion. Based on the data, a preservative classification system is suggested and a mechanistic model describing six key parameters affecting the physical stability of NLC could be developed. As most suitable characterization method to screen for suitable preservatives, light microscopy was identified. By being a simple, fast and cost efficient method, even extensive preservative screening studies can be performed very efficiently. © 2010 Elsevier B.V.


Keck C.M.,Free University of Berlin | Keck C.M.,Kaiserslautern University of Applied Sciences | Muller R.H.,Free University of Berlin
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2013

There is an increasing discussion about potential toxicity of nanoparticles (nanotoxicity). A classification system is proposed classifying the nanoparticles in four classes (I to IV) from low/no risk to high risk. It is based on the nanoparticle size (>/<100 nm) and size-related differences in interaction with human cells, and on biodegradability/non-biodegradability in the body. This classification is superimposed by biocompatibility (B) and non-biocompatibility (NB) of the nanoparticle surface, resulting in a total of eight classes from I-B (best tolerated) to IV-NB (highest potential risk). The classification should help as a guideline in pharmaceutical formulation development, but also as a guide for risk assessment in other product areas and environmental exposure. © 2013 Elsevier B.V. All rights reserved.


Patent
Kaiserslautern University of Applied Sciences | Date: 2013-08-21

The invention relates to a micro fluidic system for simulating in vivo-equivalent cell barriers, comprising a container with one or more micro fluidic modules, wherein each module consists of two micro-structured polycarbonate sheets (PC sheets) (1) separated by a polycarbonate membrane (PC membrane) (2), wherein both sides of the PC membrane (2) are co-cultured with different cell types (4). The systems is characterized in that the two PC sheets (1) contain continuous and in parallel arranged micro channels (3), the PC sheets (1) with the micro channels (3) being arranged orthogonally and sealed against each other to induce a cross flow of different media streams through the micro channels (3) at the crossing sites of the micro channels (3).


Grant
Agency: GTR | Branch: EPSRC | Program: | Phase: Research Grant | Award Amount: 1.37M | Year: 2013

In spite of its challenging properties, the utilization of graphene for technical applications still demands considerable efforts in developing dedicated processing methods, which have a potential to be adapted and finally utilized for industrial scale device manufacturing. Among the processes which have been investigated so far, chemical vapour deposition of graphene on copper, where copper acts as a catalyst to facilitate the growth of single layered graphene - appears to be one the most promising approaches. Although extensively studied, there are issues with this process related to quality, reproducibility and yield, which are connected to the lack of control of the interface between copper and graphene. Within the process, which we will be able to tackle these issues in a more controllable way by a combined in-situ deposition system, where copper and other possible metals are deposited within one vacuum system together with the graphene CVD, i.e without exposing the sample to an ambient environment. Like for 2D Ga-Al-As semiconductor heterostructures, the control of the interfaces on an atomic length scale by means of an in-situ multilayer deposition process is expected to be the pathway which will enable the ultilization of graphenes unqiue properties within manufacturable device structures. In spite of this potential, we feel the full integration of graphene into CMOS technology, although being extremely challenging on the long term - still has a very long way to go and may even be impossible without fundamentally different processing approaches. However, sensor technologies as a whole are mostly based on hybrid solutions, where the sensor itself - even chip based in some cases - is still separated from the CMOS digital electronic by flip chip, wire bonding or simple by conventional wiring. A widely used example of high indutrial impact are piezoelectric sensors, where the high processing temperature of the lead-zirconium-titanate ceramics are incompatible with CMOS processing conditions. Based on this philosophy, we believe that the in-situ growing approach for metal-graphene multilayers, as envisaged to be developed within this project, will enable a significant improvement of existing sensor concepts and the realization and manufacturing of new sensor concepts. Based on the expertise of our scientific partners within Imperial College and NPL and our associated partners from industry, we will focus on biosensor applications, where graphene - as carbon based material - is particularly challenging as bio-interface. As - from the point of view of process technology -the most simple approach, graphene coated copper electrodes will have a potential for radiofrequency - microwave - terahertz biosensor, where copper will outperform gold due to lower conduction losses and graphene provides the interface to the biomolecules and cells. As a second step on a scale of increasing complexity of process technology, we believe that a sacrificial layer process for arbitrary shaped free standing graphene membranes and (sub)micro scale flexural beam is a realistic development goal. This technology will enable the development of arrays of nanomechanical sensors, based on the exceptional mechanical properties of graphene. Apart from sensor applications, graphene- based NEMS structures are challenging objects for the refinement and exploration of metrology for nanotechnology and biology, as being pursued by our collaborators from NPL. The recently discovered confined plasmon-polariton excitations - originating from the unique electronic properties of graphene - are currently one of the hottest topic within the graphene research community. We believe, that the tailored free standing structures we will be able to manufacture with this deposition kit, will pave the way to explore and finally utilize this unique optical - infrared properties of graphene for novel sensor applications.


Patent
Kaiserslautern University of Applied Sciences, Fresenius University of Applied Sciences and Saarland University | Date: 2013-06-17

A head-rest of a vehicle seat with a deformable central supporting body which forms an impact zone for the head of a vehicle occupant and into which the kinetic energy of the head in the event of an accident is admitted. On both sides of the impact zone the central supporting bodies are joined by lateral supporting surfaces which are extendable out of the plane of the head-rest in the direction of travel in order to laterally support the head. In order to avoid or at least to reduce the risk of a cervical-spine whiplash injury, it is proposed according to the invention that the head-rest comprises a device for absorbing the energy admitted into the central supporting body and for outputting the absorbed energy in order to activate lateral supporting surfaces.

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