Search

In rheumatoid arthritis (RA), chronic joint inflammation leading to bone and cartilage damage is the major cause of functional impairment. Whereas reduction of synovitis and blockade of joint damage can be successfully achieved by disease modifying antirheumatic therapies, bone repair upon therapeutic interventions has only been rarely reported. The aim of this study was to use fluorodeoxyglucose ([18 F]FDG) and [18 F]fluoride µPET/CT imaging to monitor systemic inflammatory and destructive bone remodeling processes as well as potential bone repair in an established mouse model of chronic inflammatory, erosive polyarthritis. Therefore, human tumor necrosis factor transgenic (hTNFtg) mice were treated with infliximab, an anti-TNF antibody, for 4 weeks. Before and after treatment period, mice received either [18 F]FDG, for detecting inflammatory processes, or [18 F]fluoride, for monitoring bone remodeling processes, for PET scans followed by CT scans. Standardized uptake values (SUVmean ) were analyzed in various joints and histopathological signs of arthritis, joint damage, and repair were assessed. Longitudinal PET/CT scans revealed a significant decrease in [18 F]FDG SUVs in affected joints demonstrating complete remission of inflammatory processes due to TNF blockade. In contrast, [18 F]fluoride SUVs could not discriminate between different severities of bone damage in hTNFtg mice. Repeated in vivo CT images proved a structural reversal of preexisting bone erosions after anti-TNF therapy. Accordingly, histological analysis showed complete resolution of synovial inflammation and healing of bone at sites of former bone erosion. We conclude that in vivo multimodal [18 F]FDG µPET/CT imaging allows to quantify and monitor inflammation-mediated bone damage and reveals not only reversal of synovitis but also bone repair upon TNF blockade in experimental arthritis. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

When setting up the first Social Entrepreneurship Venture Capital Funds in Austria, the institutional investor fair-finance had to find a suitable vehicle for this new form of investment in social enterprises. A valid exit strategy via a social bond ensures the fund is suitable for long-term investors. The declared aim of this initiative, launched jointly with the SME & industry stakeholder group “Senat der Wirtschaft”, is to increase the number of social entrepreneurs and thus also the number of social business cases in Austria and Germany. Investors placing social impact above profit maximisation are to be given the opportunity to invest meaningfully in companies offering a solution for overcoming social challenges—and in return receive a socially sustainable yield.

Resolving the kinetic mechanisms of biomolecular interactions have become increasingly important in early-phase drug development. Since traditional in vitro methods belong to dose-dependent assessments, binding kinetics is usually overlooked. The present study aimed at the establishment of two novel experimental approaches for the assessment of binding affinity of both, radiolabelled and non-labelled compounds targeting the A3R, based on high-resolution real-time data acquisition of radioligand-receptor binding kinetics. A novel time-resolved competition assay was developed and applied to determine the Ki of eight different A3R antagonists, using CHO-K1 cells stably expressing the hA3R. In addition, a new kinetic real-time cell-binding approach was established to quantify the rate constants k on and k off, as well as the dedicated K d of the A3R agonist [125I]-AB-MECA. Furthermore, lipophilicity measurements were conducted to control influences due to physicochemical properties of the used compounds. Two novel real-time cell-binding approaches were successfully developed and established. Both experimental procedures were found to visualize the kinetic binding characteristics with high spatial and temporal resolution, resulting in reliable affinity values, which are in good agreement with values previously reported with traditional methods. Taking into account the lipophilicity of the A3R antagonists, no influences on the experimental performance and the resulting affinity were investigated. Both kinetic binding approaches comprise tracer administration and subsequent binding to living cells, expressing the dedicated target protein. Therefore, the experiments resemble better the true in vivo physiological conditions and provide important markers of cellular feedback and biological response.

Objective To use in vivo multimodal [18F]FDG (fluoro-D-glucose, tracer for inflammation) and [18F]sodium fluoride (bone tracer) positron emission tomography/computed tomography (PET-CT) imaging for the monitoring of systemic inflammatory and bone remodelling processes as well as colocalized bone destructions before and after TNF blockade in human tumour necrosis factor transgenic (hTNFtg) mice, an established mouse model of chronic inflammatory, erosive polyarthritis. Methods 8 week-old hTNFtg mice were treated with anti-TNF antibodies (Infliximab, i.p., 3x times per week, 10 mg/kg body weight) for 4 weeks. Before and after the treatment period isofluran-anaesthetised mice received [18F]FDG or [18F]sodium fluoride (~25 MBq) static PET scans (45 min post injection) followed by whole-body and high resolution leg CT scans (800kV, 500µA, 800 ms, 360 projections) using an Inveon PET/CT/SPECT multimodality system (Siemens Medical Solutions). PET reconstructions were conducted with OSEM3D/MAP, FBP algorithm. Standard uptake values (SUV) were calculated using PMOD software. Joints were fixed in 7% formaldehyde and stored in 70% ethanol for ex vivo high-resolution µCT imaging (Scanco µCT35). Histopathological features were analysed in H and E, TRAP and TB stained joint sections. Tissue regeneration processes were addressed after short-term TNF blockade (2 weeks) in cryo and metacrylate-embedded sections. Results Before therapeutic intervention, we observed an increased accumulation of [18F]FDG but no changes of [18F]sodium fluoride uptake in various joints of hTNFtg mice including knees, ankles and shoulders compared to wt littermates indicating ongoing inflammatory processes. After four weeks, placebo-treated hTNFtg animals showed significantly increased [18F]FDG SUVs and severe progressive bone destructions in those joints. In contrast, TNF-blockade led to a significant decrease in [18F]FDG SUVs supposing complete resolution of inflammatory processes in those individuals. Comparison of repeated in vivoCT images demonstrated a significant reduction and reversal of bone destructions indicating bone regeneration upon TNF blockade. However, we found no changes in [18F]Fluoride SUVs. Short-term TNF blockade demonstrated fibrocartilaginous tissue remodelling and endochondral ossification processes at sites of structural joint damage. Conclusion In vivo small animal multimodal [18F]FDG, but not [18F]sodium fluoride, PET-CT imaging provides an objective, non-invasive imaging tool for the (I) monitoring of reversibility of ongoing inflammatory processes and (II) regeneration of bone damage during therapeutic intervention in TNF-driven experimental arthritis.

Background The melanin-concentrating hormone receptor 1 (MCHR1), which is highly expressed in the lateral hypothalamus, plays a key role in energy homeostasis, obesity and other endocrine diseases. Hence, there is a major interest in in vivo imaging of this receptor. A PET tracer would allow non-invasive in vivo visualization and quantification of the MCHR1. The aim of the study was the ex vivo evaluation of the MCHR1 ligand [18F]FE@SNAP as a potential PET tracer for the MCHR1. Methods [18F]FE@SNAP was injected directly into the jugular vein of awake naïve rats for ex vivo brain autoradiography, biodistribution and additional blood metabolite analysis. Blocking experiments were conducted using the unlabeled MCHR1 ligand SNAP-7941. Results A high uptake of [18F]FE@SNAP was observed in the lateral hypothalamus and the ventricular system. Both regions were significantly blocked by SNAP-7941. Biodistribution evinced the highest uptake in the kidneys, adrenals, lung and duodenum. Specific blocking with SNAP-7941 led to a significant tracer reduction in the heart and adrenals. In plasma samples, 47.73 ± 6.1 % of a hydrophilic radioactive metabolite was found 45 min after tracer injection. Conclusions Since [18F]FE@SNAP uptake was significantly blocked in the lateral hypothalamus, there is strong evidence that [18F]FE@SNAP is a highly suitable agent for specific MCHR1 imaging in the central nervous system. Additionally, this finding is supported by the specific blocking in the ventricular system, where the MCHR1 is expressed in the ependymal cells. These findings suggest that [18F]FE@SNAP could serve as a useful imaging and therapy monitoring tool for MCHR1-related pathologies.

Android is an open software platform for mobile devices with a large market share in the smartphone sector. The openness of the system as well as its wide adoption lead to an increasing amount of malware developed for this platform. ANANAS is an expandable and modular framework for analyzing Android applications. It takes care of common needs for dynamic malware analysis and provides an interface for the development of plugins. Adaptability and expandability have been main design goals during the development process. An abstraction layer for simple user interaction and phone event simulation is also part of the framework. It allows an analyst to script the required user simulation or phone events on demand or adjust the simulation to his needs. Six plugins have been developed for ANANAS. They represent well known techniques for malware analysis, such as system call hooking and network traffic analysis. The focus clearly lies on dynamic analysis, as five of the six plugins are dynamic analysis methods., Paper accepted at First Int. Workshop on Emerging Cyberthreats and Countermeasures ECTCM 2013

The melanin-concentrating hormone (MCH) system is a new target for the treatment of human disorders. Since the knowledge of the MCH system's involvement in a variety of pathologies (obesity, diabetes, and deregulation of metabolic feedback mechanism) is based on in vitro or preclinical studies, a suitable positron emission tomography (PET) tracer needs to be developed. We herein present the preparation and first preclinical evaluation of [(18)F]FE@SNAP - a new PET tracer for MCH receptor-1 (MCHR1). The synthesis was performed using a microfluidic device. Preclinical evaluation included binding affinity, plasma stability, plasma free fraction, stability against the cytochrome P-450 (CYP450) system using liver microsomes, stability against carboxyl-esterase, and methods to assess the penetration of the blood-brain barrier (BBB) such as logD analysis and immobilized artificial membrane (IAM) chromatography. Levels at 374 ± 202 MBq [(18)F]FE@SNAP were obtained after purification. The obtained K d value of [(18)F]FE@SNAP was 2.9 nM. [(18)F]FE@SNAP evinced high stability against carboxylesterase, CYP450 enzymes, and in human plasma. LogD (3.83) and IAM chromatography results (Pm=0.51) were in the same range as for known BBB-penetrating compounds. The synthesis of [(18)F]FE@SNAP was reliable and successful. Due to high binding affinity and stability, [(18)F]FE@SNAP is a promising tracer for MCHR1.

Detecting malicious connection attempts and attacks against web-based applications is one of many approaches to protect the World Wide Web and its users.

Despite extensive research effort, ordinary anomaly detection systems still suffer from serious drawbacks such as high false alarm rates due to the enormous variety of network traffic. Also, increasingly fast network speeds pose performance problems to systems which base upon deep packet inspection. In this paper, we address these problems by proposing a novel inductive network intrusion detection system. The system operates on lightweight network flows and uses One-Class Support Vector Machines for analysis. In contrast to traditional anomaly detection systems, the system is trained with malicious rather than with benign network data. The system is suited for the load of large-scale networks and is less affected by typical problems of ordinary anomaly detection systems. Evaluations brought satisfying results which indicate that the proposed approach is interesting for further research and perfectly complements traditional signature-based intrusion detection systems.

Objective To use in vivo multimodal [ 18 F]FDG (fluoro-D-glucose) positron emission tomography/computed tomography (PET-CT) imaging for the assessment and monitoring of systemic inflammatory processes and its colocalized bone destructions before and after TNF blockade in human tumour necrosis factor transgenic (hTNFtg) mice, an established mouse model of chronic inflammatory, erosive polyarthritis. Methods 8 week old hTNFtg mice were treated with anti-TNF antibodies (i.p., 3x times per week, 10 mg/kg body weight) for 4 weeks. Before and after the treatment period isofluran-anaesthetised hTNFtg mice and their wt littermates were used for [ 18 F]FDG PET-CT scans using an Inveon small animal PET/CT/SPECT multimodality system (Siemens Medical Solutions). Mice received [ 18 F]FDG (˜25 MBq) either by intra-venous injection for dynamic (0–90 min) or by intra-orbital injections for static PET scans (45 min post injection) followed by whole-body and high resolution leg CT scans (800 kV, 500 µA, 800 ms, 360 projections, FOV whole-body: 10 cm or legs: 4 cm, Feldkamp, Ramp filter). PET reconstructions were conducted with OSEM3D/MAP, FBP algorithm using the Inveon Acquisition Workplace software. Joints were subsequently isolated, fixed in 7% formaldehyde for 24 h and stored in 70% ethanol for ex vivo high resolution µCT imaging (Scanco µCT35, energy: 55 kVp; 145 µA, 8 W; FOV/diameter 12.3). Synovial inflammation, bone and cartilage destruction were assessed in hematoxylin-eosin (H&E), tartrate-resistant acid phosphatase (TRAP) and toluidine-blue (TB) stained paraffin-embedded joint sections. Results Before therapeutic interventions we observed an increased accumulation of [ 18 F]FDG in various joints of hTNFtg mice including knees, ankles, shoulders, elbows, wrists, hips, iliosacroiliac and atlanto-axial joints compared to wt littermates. Four weeks after anti-TNF treatment we found a significant decrease in [ 18 F]FDG uptake in the same individuals. Fusion of PET images with CT scans demonstrated intact bone surfaces in anti-TNF-treated animals. In contrast, placebo treated hTNFtg animals showed progressed [ 18 F]FDG uptake and severe bone destructions by CT in the above mentioned joints. Therapeutic effects on synovial inflammation, bone erosion and cartilage damage were also confirmed on histological sections and µCTs. Conclusion In vivo multimodal [ 18 F]FDG PET-CT imaging provides an objective, non-invasive imaging tool for the longitudinal monitoring of inflammatory processes and morphological features of bone destruction during therapeutic interventions in arthritic mice.

Purpose The adenosine A3 receptor (A3R) is involved in cardiovascular, neurological and tumour-related pathologies and serves as an exceptional pharmaceutical target in the clinical setting. A3R antagonists are considered antiinflammatory, antiallergic and anticancer agents, and to have potential for the treatment of asthma, COPD, glaucoma and stroke. Hence, an appropriate A3R PET tracer would be highly beneficial for the diagnosis and therapy monitoring of these diseases. Therefore, in this preclinical in vivo study we evaluated the potential as a PET tracer of the A3R antagonist [18F]FE@SUPPY. Methods Rats were injected with [18F]FE@SUPPY for baseline scans and blocking scans (A3R with MRS1523 or FE@SUPPY, P-gp with tariquidar; three animals each). Additionally, metabolism was studied in plasma and brain. In a preliminary experiment in a mouse xenograft model (mice injected with cells expressing the human A3R; three animals), the animals received [18F]FE@SUPPY and [18F]FDG. Dynamic PET imaging was performed (60 min in rats, 90 min in xenografted mice). In vitro stability of [18F]FE@SUPPY in human and rat plasma was also evaluated. Results [18F]FE@SUPPY showed high uptake in fat-rich regions and low uptake in the brain. Pretreatment with MRS1523 led to a decrease in [18F]FE@SUPPY uptake (p = 0.03), and pretreatment with the P-gp inhibitor tariquidar led to a 1.24-fold increase in [18F]FE@SUPPY uptake (p = 0.09) in rat brain. There was no significant difference in metabolites in plasma and brain in the treatment groups. However, plasma concentrations of [18F]FE@SUPPY were reduced to levels similar to those in rat brain after blocking. In contrast to [18F]FDG uptake (p = 0.12), the xenograft model showed significantly increased uptake of [18F]FE@SUPPY in the tissue masses from CHO cells expressing the human A3R (p = 0.03). [18F]FE@SUPPY was stable in human plasma. Conclusion Selective and significant tracer uptake of [18F]FE@SUPPY was found in xenografted mice injected with cells expressing human A3R. This finding supports the strategy of evaluating [18F]FE@SUPPY in “humanized animal models”. In conclusion, preclinical evaluation points to the suitability of [18F]FE@SUPPY as an A3R PET tracer in humans.