Pulmonary Delivery of Nanoparticle-Bound Toll-like Receptor 9 Agonist for the Treatment of Metastatic Lung Cancer

CpG oligodeoxynucleotides are potent toll-like receptor (TLR) 9 agonists and have shown promise as anticancer agents in preclinical studies and clinical trials. Binding of CpG to TLR9 initiates a cascade of innate and adaptive immune responses, beginning with activation of dendritic cells and resulting in a range of secondary effects that include the secretion of pro-inflammatory cytokines, activation of natural killer cells, and expansion of T cell populations. Recent literature suggests that local delivery of CpG in tumors results in superior antitumor effects as compared to systemic delivery. In this study, we utilized PRINT (particle replication in nonwetting templates) nanoparticles as a vehicle to deliver CpG into murine lungs through orotracheal instillations. In two murine orthotopic metastasis models of non-small-cell lung cancer-344SQ (lung adenocarcinoma) and KAL-LN2E1 (lung squamous carcinoma), local delivery of PRINT-CpG into the lungs effectively promoted substantial tumor regression and also limited systemic toxicities associated with soluble CpG. Furthermore, cured mice were completely resistant to tumor rechallenge. Additionally, nanodelivery showed extended retention of CpG within the lungs as well as prolonged elevation of antitumor cytokines in the lungs, but no elevated levels of proinflammatory cytokines in the serum. These results demonstrate that PRINT-CpG is a potent nanoplatform for local treatment of lung cancer that has collateral therapeutic effects on systemic disease and an encouraging toxicity profile and may have the potential to treat lung metastasis of other cancer types

Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline

Compelling evidence suggests that epigenetic mechanisms such as DNA methylation play a role in stress regulation and in the etiologic basis of stress related disorders such as Post traumatic Stress Disorder (PTSD). Here we describe the purpose and methods of an international consortium that was developed to study the role of epigenetics in PTSD. Inspired by the approach used in the Psychiatric Genomics Consortium, we brought together investigators representing seven cohorts with a collective sample size of N = 1147 that included detailed information on trauma exposure, PTSD symptoms, and genome-wide DNA methylation data. The objective of this consortium is to increase the analytical sample size by pooling data and combining expertise so that DNA methylation patterns associated with PTSD can be identified. Several quality control and analytical pipelines were evaluated for their control of genomic inflation and technical artifacts with a joint analysis procedure established to derive comparable data over the cohorts for meta-analysis. We propose methods to deal with ancestry population stratification and type I error inflation and discuss the advantages and disadvantages of applying robust error estimates. To evaluate our pipeline, we report results from an epigenome-wide association study (EWAS) of age, which is a well-characterized phenotype with known epigenetic associations. Overall, while EWAS are highly complex and subject to similar challenges as genome-wide association studies (GWAS), we demonstrate that an epigenetic meta-analysis with a relatively modest sample size can be well-powered to identify epigenetic associations. Our pipeline can be used as a framework for consortium efforts for EWAS

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD. PTSD has been associated with DNA methylation of specific loci in the genome, but studies have been limited by small sample sizes. Here, the authors perform a meta-analysis of DNA methylation data from 10 different cohorts and identify CpGs in AHRR that are associated with PTSD.Stress-related psychiatric disorders across the life spa

Charakterisierung von Schichtverbunden aus Aluminiumlegierungen in Kombination mit polymeren Faserverbunden

In der vorliegenden Diplomarbeit wurden die Schichtverbunde ARALL, GLARE und CARE ausfuehrlich untersucht. Die Metall-Laminate setzen sich dabei aus den Aluminiumfolien und den entsprechenden Prepreglagen zusammen, wobei fuer ARALL Aramid-, fuer GLARE Glas- und fuer CARE Kohlenstoffaserprepreg verwendet wird. Durch das Verkleben dieser Prepreglagen mit den Aluminiumfolien erhaelt man einen Werkstoff, der nahezu ideale Eigenschaften fuer den Flugzeugbau aufweist. Zunaechst werden die Schichtverbunde ARALL und GLARE mit denen im Flugzeugbau herkoemmlichen Werkstoffen Aluminium und CFK verglichen. Der Schwerpunkt dieser Untersuchungen liegt auf den statischen und dynamischen Eigenschaften der Werkstoffe. Auf spezielle Gesichtspunkte wie zum Beispiel das Brennverhalten, das Impact-Verhalten oder die mechanische Bearbeitung der Materialien wird ebenfalls eingegangen. Fuer die Schichtverbund ARALL und GLARE werden anschliessend einige Einsatzmoeglichkeiten im Flugzeugbau aufgezeigt. Danach wird insbesondere der neue Schichtverbund CARE behandelt. Hierzu wird rechnerisch die thermomechanische Vertraeglichkeit dieser Werkstoffkombination analysiert. Zum Absenken der hohen Steifigkeitsspruenge zwischen der Aluminium-und der CFK-Schicht, koennen hier Zwischenschichten aus CFK- bzw. GFK-Matten eingelegt werden um damit einen sanften Steifigkeitsuebergang zu ermoeglichen. (orig./RHM)Unter the present thesis, the composite laminates ARALL, GLARE and CARE were subjected to a detailed investigation. Metal laminates are composed of aluminum foils and corresponding prepreg layers, using aramide prepregs in ARALL, glass prepregs in GLARE, and carbon fiber prepregs in CARE. Adhesive bonding of these prepreg layers with the aluminum foils produces a material which has almost ideal properties for aircraft construction. First, the composite laminates ARALL and GLARE are compared with aluminum and CFRP, which are common materials in aircraft construction. This investigation is focused on the static and dynamic characteristics of these materials. Special aspects such as fire behavior, impact behavior or mechanical processing of the materials are also addressed. Then some possible uses of the composite laminates ARALL and CARE in aircraft construction are indicated. After this, in particular the new composite laminate CARE is treated. For this purpose the thermomechanical compatibility of this material combination is analyzed. To reduce the high stiffness leaps between the aluminum and CRFP layers it is possible to insert intermediate layers of CFRP of GFRP mats in order to enable a smooth stiffness transition. (orig./RHM)SIGLEAvailable from TIB Hannover: RN 4165(1993,33) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Stroemungssichtbarmachung an Hubschrauberrotorblaettern mittels Acenaphthen

With 22 figs., 2 tabs., 10 refs.Copy held by FIZ Karlsruhe; available from UB/TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Aeroakustischer Entwurf eines 6-Blatt Propellers Teil des Projektes ''Leises Propellerflugzeug''

The objective of the present study is the new design of a 6-blade propeller for the LFU 205 aircraft of the German Aerospace Research Establishment (DLR). A preceding experimental study has indicated the potential of noise abatement by reducing the blade tip Mach number while maintaining a constant engine speed. Starting from the results of the experimental study and fundamental considerations with regard to noise reduction and aerodynamic quality, a new propeller is designed on the basis of a diameter reduction from 1.93 m to 1.5 m. Besides the design of a 6-blade and a 4-blade propeller, a propeller, measured in the German-Dutch Wind Tunnel (DNW) with a diameter of 2.03, is used both as a reference propeller and to verify the methods applied here. (orig.)Available from TIB Hannover: RO 8051(1995,21) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Numerical investigation on two airfoil analysis codes using the Euler and Navier-Stokes equations in inviscid and viscous flows

Under the framework of the DLG-CAE cooperation topic: 92-16, numerical investigation is carried out on two transonic airfoil analysis/design codes at the Institute of Design Aerodynamics, DLR, Braunschweig. The first is the DLR Airfoil Design Method based on the solutions of the Euler/Navier-Stokes eqs., and the other is the ISES Transonic Airfoil Analysis/Design code of MIT, which uses the Euler eqs. with viscous correction. This report summarizes the analysis part of the investigation where a DLR-2D Euler/Navier-Stokes code, which is the analysis part of the DLR Airfoil Design Method, is compared with ISES, running in direct mode, through numerical computations on several airfoils in inviscid and viscous flow conditions. The investigation suggests that both DLR-2D Euler/Navier-Stokes and the ISES codes are very powerful tools for the analysis of airfoils under subcritical and supercritical flow conditions, even with laminar separation bubbles and turbulent separations. Detailed discussions are made on parametric study, drag estimation, total pressure losses, and the features of different numerical algorithms, meshes and turbulent models involved. Viscous analysis results are compared with experimental data available and the CPU time needed for each code is also compared. (orig.)This work is under the DLR-CAE cooperation topic: 92-16, (Report 1)Available from TIB Hannover: RN 4165(1995,5) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman