Endothelial damage and dysfunction in acute graft-versus-host disease

Altres ajuts: Deutsche Forschungsgemeinschaft (DFG) TRR221 (B11 Z02), TRR225 (B08)Clinical studies have suggested a potential involvement of endothelial dysfunction and damage in the development and severity of acute graft-versus-host disease (aGvHD). Accordingly, we found an increased percentage of apoptotic caspase 3 positive blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGvHD. In murine experimental aGvHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGvHD target organs. During intestinal aGvHD, colonic vasculature structurally changed, reflected by increased vessel branching and vessel diameter. As recent data demonstrated an association of endothelium-related factors and steroid refractory aGvHD (SR-aGvHD), we analyzed human biopsies and murine tissues from SR-aGvHD. We found extensive tissue damage but low levels of alloreactive T-cell infiltration in target organs, providing the rationale for T-cell independent SR-aGvHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental SR-aGvHD. Our results demonstrate extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Therapeutic intervention by endothelium-protecting agents is an attractive approach for SR-aGvHD complementing current anti-inflammatory treatment options

TRAIL receptor I (DR4) polymorphisms C626G and A683C are associated with an increased risk for hepatocellular carcinoma (HCC) in HCV-infected patients

<p>Abstract</p> <p>Background</p> <p>Tumour surveillance via induction of TRAIL-mediated apoptosis is a key mechanism, how the immune system prevents malignancy. To determine if gene variants in the TRAIL receptor I (<it>DR4</it>) gene affect the risk of hepatitis C virus (HCV)-induced liver cancer (HCC), we analysed <it>DR4 </it>mutations C626G (rs20575) and A683C (rs20576) in HCV-infected patients with and without HCC.</p> <p>Methods</p> <p>Frequencies of <it>DR4 </it>gene polymorphisms were determined by LightSNiP assays in 159 and 234 HCV-infected patients with HCC and without HCC, respectively. 359 healthy controls served as reference population.</p> <p>Results</p> <p>Distribution of C626G and A683C genotypes were not significantly different between healthy controls and HCV-positive patients without HCC. <it>DR4 </it>variants 626C and 683A occurred at increased frequencies in patients with HCC. The risk of HCC was linked to carriage of the 626C allele and the homozygous 683AA genotype, and the simultaneous presence of the two risk variants was confirmed as independent HCC risk factor by Cox regression analysis (Odds ratio 1.975, 95% CI 1.205-3.236; p = 0.007). Furthermore HCV viral loads were significantly increased in patients who simultaneously carried both genetic risk factors (2.69 ± 0.36 × 10⁶ IU/ml vs. 1.81 ± 0.23 × 10⁶ IU/ml, p = 0.049).</p> <p>Conclusions</p> <p>The increased prevalence of patients with a 626C allele and the homozygous 683AA genotype in HCV-infected patients with HCC suggests that these genetic variants are a risk factor for HCC in chronic hepatitis C.</p

Development of a testbed for systems of intelligent load carriers

Im Rahmen dieses Artikels werden aktuelle Forschungsarbeiten zum Einsatz von Energy-Harvesting und Ultra-Low-Power-Geräten in Materialflusssystemen beschrieben. Ein besonderes Augenmerk wird auf die inBin-Plattform, das Energy-Harvesting und deren Auswirkungen auf die Leistungsverfügbarkeit gelegt. Dazu werden die Hardwareplattform und Architektur der inBin-Plattform sowie der Aufbau eines Versuchsfelds detailliert erläutert. Des Weiteren wird ein Ansatz zur Modellierung und Simulation von Systemen mit einer großen Anzahl von inBin-Plattformen vorgestellt. Darüber hinaus werden die Ergebnisse zweier simulierter Szenarien und mögliche Folgen für die Planung zukünftiger Materialflusssysteme betrachtet.This paper provides a description and analysis of research in material handling systems in regard to energy-harvesting, ultra-low-power devices. Particular attention is paid to the inBin smart device, energy-harvesting, and the performance availability of material handling systems. A detailed description of the hardware platform, architecture and testbed is provided and an approach to model systems with a large number of devices is presented. Within the proposed model, two scenarios are simulated and their implications for the architecture of future materials handling systems are discussed

Building Objective 3D Fault Representations in Active Tectonic Settings

Developing 3D representations of active faults is an important step to improve seismic‐hazard assessment. However, the geometries of faults can be difficult to constrain at depth, and building representations is often subjective. We present a new objective workflow to build 3D fault geometries from surface and subsurface data that are generally available in active tectonic environments. We use surface traces, focal mechanism orientations, and relocated hypocenters as geological constraints in an implicit modeling approach. This method enables us to control the weights assigned to the different constraints, increasing the accuracy of the fault model. We evaluate and refine our method by applying it to a well‐known natural case study: the Puente Hills thrust fault, a blind thrust beneath Los Angeles, California, that is imaged by high‐quality seismic reflection data and that generated the 1987 Mw 6.0 Whittier Narrows earthquake. Then, we apply our new workflow to the Xianshuihe–Anninghe left‐lateral strike‐slip fault systems, China. Implementing this workflow allows for the development of improved fault surface representations that can contribute to Community Fault Models and support fault system modeling, rupture simulations, and regional hazard assessments.Published versio

Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases

Synthetic peptide immunogens that mimic the conformation of a target epitope of pathological relevance offer the possibility to precisely control the immune response specificity. Here, we performed conformational analyses using a panel of peptides in order to investigate the key parameters controlling their conformation upon integration into liposomal bilayers. These revealed that the peptide lipidation pattern, the lipid anchor chain length, and the liposome surface charge all significantly alter peptide conformation. Peptide aggregation could also be modulated post-liposome assembly by the addition of distinct small molecule β-sheet breakers. Immunization of both mice and monkeys with a model liposomal vaccine containing β-sheet aggregated lipopeptide (Palm1–15) induced polyclonal IgG antibodies that specifically recognized β-sheet multimers over monomer or non-pathological native protein. The rational design of liposome-bound peptide immunogens with defined conformation opens up the possibility to generate vaccines against a range of protein misfolding diseases, such as Alzheimer disease

Definition of a fluorescence in-situ hybridization score identifies high- and low-level FGFR1 amplification types in squamous cell lung cancer

We recently reported fibroblast growth factor receptor-type 1 (FGFR1) amplification to be associated with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. This makes FGFR1 a novel target for directed therapy in these tumors. To reproducibly identify patients for clinical studies, we developed a standardized reading and evaluation strategy for FGFR1 fluorescence in-situ hybridization (FISH) and propose evaluation criteria, describe different patterns of low- and high-level amplifications and report on the prevalence of FGFR1 amplifications in pulmonary carcinomas. A total of 420 lung cancer patients including 307 squamous carcinomas, 100 adenocarcinomas of the lung and 13 carcinomas of other types were analyzed for FGFR1 amplification using a dual color FISH. We found heterogeneous and different patterns of gene copy numbers. FGFR1 amplifications were observed in 20% of pulmonary squamous carcinomas but not in adenocarcinomas. High-level amplification (as defined by an FGFR1/centromer 8 (CEN8) ratio >= 2.0, or average number of FGFR1 signals per tumor cell nucleus >= 6, or the percentage of tumor cells containing >= 15 FGFR1 signals or large clusters >= 10%) was detected at a frequency of 16% and low-level amplification (as defined by >= 5 FGFR1 signals in >= 50% of tumor cells) at a frequency of 4%. We conclude that FGFR1 amplification is one of the most frequent therapeutically tractable genetic lesions in pulmonary carcinomas. Standardized reporting of FGFR1 amplification in squamous carcinomas of the lung will become increasingly important to correlate therapeutic responses with FGFR1 inhibitors in clinical studies. Thus, our reading and evaluation strategy might serve as a basis for identifying patients for ongoing and upcoming clinical trials. Modern Pathology (2012) 25, 1473-1480; doi: 10.1038/modpathol.2012.102; published online 8 June 201