Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease

Introduction: CAD106 is designed to stimulate amyloid-β (Aβ)-specific antibody responses while avoiding T-cell autoimmune responses. The CAD106 first-in-human study demonstrated a favorable safety profile and promising antibody response. We investigated long-term safety, tolerability and antibody response after repeated CAD106 injections. Methods: Two phase IIa, 52-week, multicenter, randomized, double-blind, placebo-controlled core studies (2201; 2202) and two 66-week open-label extension studies (2201E; 2202E) were conducted in patients with mild Alzheimer’s disease (AD) aged 40 to 85 years. Patients were randomized to receive 150μg CAD106 or placebo given as three subcutaneous (2201) or subcutaneous/intramuscular (2202) injections, followed by four injections (150 μg CAD106; subcutaneous, 2201E1; intramuscular, 2202E1). Our primary objective was to evaluate the safety and tolerability of repeated injections, including monitoring cerebral magnetic resonance imaging scans, adverse events (AEs) and serious AEs (SAEs). Further objectives were to assess Aβ-specific antibody response in serum and Aβ-specific T-cell response (core only). Comparable Aβ-immunoglobulin G (IgG) exposure across studies supported pooled immune response assessments. Results: Fifty-eight patients were randomized (CAD106, n = 47; placebo, n = 11). Baseline demographics and characteristics were balanced. Forty-five patients entered extension studies. AEs occurred in 74.5% of CAD106-treated patients versus 63.6% of placebo-treated patients (core), and 82.2% experienced AEs during extension studies. Most AEs were mild to moderate in severity, were not study medication-related and did not require discontinuation. SAEs occurred in 19.1% of CAD106-treated patients and 36.4% of placebo-treated patients (core). One patient (CAD106-treated; 2201) reported a possibly study drug-related SAE of intracerebral hemorrhage. Four patients met criteria for amyloid-related imaging abnormalities (ARIA) corresponding to microhemorrhages: one was CAD106-treated (2201), one placebo-treated (2202) and two open-label CAD106-treated. No ARIA corresponded to vasogenic edema. Two patients discontinued extension studies because of SAEs (rectal neoplasm and rapid AD progression, respectively). Thirty CAD106-treated patients (63.8%) were serological responders. Sustained Aβ-IgG titers and prolonged time to decline were observed in extensions versus core studies. Neither Aβ1–6 nor Aβ1–42 induced specific T-cell responses; however, positive control responses were consistently detected with the CAD106 carrier. Conclusions: No unexpected safety findings or Aβ-specific T-cell responses support the CAD106 favorable tolerability profile. Long-term treatment-induced Aβ-specific antibody titers and prolonged time to decline indicate antibody exposure may increase with additional injections. CAD106 may be a valuable therapeutic option in AD

Atomic Carbon in M82: Physical conditions derived from simultaneous observations of the [CI] fine structure submillimeter wave transitions

We report the first extragalactic detection of the neutral carbon [CI] 3P2-3P1 fine structure line at 809 GHz. The line was observed towards M82 simultaneously with the 3P1-3P0 line at 492 GHz, providing a precise measurement of the J=2-1/J=1-0 integrated line ratio of 0.96 (on a [K km s^-1] -scale). This ratio constrains the [CI] emitting gas to have a temperature of at least 50 K and a density of at least 10^4 cm^-3. Already at this minimum temperature and density, the beam averaged CI-column density is large, 2.1 10^18 cm^-2, confirming the high CI/CO abundance ratio of approximately 0.5 estimated earlier from the 492 GHz line alone. We argue that the [CI] emission from M82 most likely arises in clouds of linear size around a few pc with a density of about 10^4 cm^-3 or slightly higher and temperatures of 50 K up to about 100 K.Comment: 4 pages, 2 figures, ApJL in press, postscript also available at ftp://apollo.ph1.uni-koeln.de/pub/stutzki/m82_pap.ps.gz e-mail-contact:[email protected]

Lattice dynamics and correlated atomic motion from the atomic pair distribution function

The mean-square relative displacements (MSRD) of atomic pair motions in crystals are studied as a function of pair distance and temperature using the atomic pair distribution function (PDF). The effects of the lattice vibrations on the PDF peak widths are modelled using both a multi-parameter Born von-Karman (BvK) force model and a single-parameter Debye model. These results are compared to experimentally determined PDFs. We find that the near-neighbor atomic motions are strongly correlated, and that the extent of this correlation depends both on the interatomic interactions and crystal structure. These results suggest that proper account of the lattice vibrational effects on the PDF peak width is important in extracting information on static disorder in a disordered system such as an alloy. Good agreement is obtained between the BvK model calculations of PDF peak widths and the experimentally determined peak widths. The Debye model successfully explains the average, though not detailed, natures of the MSRD of atomic pair motion with just one parameter. Also the temperature dependence of the Debye model largely agrees with the BvK model predictions. Therefore, the Debye model provides a simple description of the effects of lattice vibrations on the PDF peak widths.Comment: 9 pages, 11 figure

Effect of NASA Light-emitting Diode Irradiation on Wound Healing

Objective: The purpose of this study was to assess the effects of hyperbaric oxygen (HBO) and near-infrared light therapy on wound healing. Background Data: Light-emitting diodes (LED), originally developed for NASA plant growth experiments in space show promise for delivering light deep into tissues of the body to promote wound healing and human tissue growth. In this paper, we review and present our new data of LED treatment on cells grown in culture, on ischemic and diabetic wounds in rat models, and on acute and chronic wounds in humans. Materials and Methods: In vitro and in vivo (animal and human) studies utilized a variety of LED wavelength, power intensity, and energy density parameters to begin to identify conditions for each biological tissue that are optimal for biostimulation. Results: LED produced in vitro increases of cell growth of 140–200% in mouse-derived fibroblasts, rat-derived osteoblasts, and rat-derived skeletal muscle cells, and increases in growth of 155–171% of normal human epithelial cells. Wound size decreased up to 36% in conjunction with HBO in ischemic rat models. LED produced improvement of greater than 40% in musculoskeletal training injuries in Navy SEAL team members, and decreased wound healing time in crew members aboard a U.S. Naval submarine. LED produced a 47% reduction in pain of children suffering from oral mucositis. Conclusion: We believe that the use of NASA LED for light therapy alone, and in conjunction with hyperbaric oxygen, will greatly enhance the natural wound healing process, and more quickly return the patient to a preinjury/ illness level of activity. This work is supported and managed through the NASA Marshall Space Flight Center–SBIR Program

Strong Expression of Chemokine Receptor CXCR4 by Renal Cell Carcinoma Correlates with Advanced Disease

Diverse chemokines and their receptors have been associated with tumor growth, tumor dissemination, and local immune escape. In different tumor entities, the level of chemokine receptor CXCR4 expression has been linked with tumor progression and decreased survival. The aim of this study was to evaluate the influence of CXCR4 expression on the progression of human renal cell carcinoma. CXCR4 expression of renal cell carcinoma was assessed by immunohistochemistry in 113 patients. Intensity of CXCR4 expression was correlated with both tumor and patient characteristics. Human renal cell carcinoma revealed variable intensities of CXCR4 expression. Strong CXCR4 expression of renal cell carcinoma was significantly associated with advanced T-status (P = .039), tumor dedifferentiation (P = .0005), and low hemoglobin (P = .039). In summary, strong CXCR4 expression was significantly associated with advanced dedifferentiated renal cell carcinoma

Localization criteria for Anderson models on locally finite graphs

We prove spectral and dynamical localization for Anderson models on locally finite graphs using the fractional moment method. Our theorems extend earlier results on localization for the Anderson model on \ZZ^d. We establish geometric assumptions for the underlying graph such that localization can be proven in the case of sufficiently large disorder

p-BioSPRE-an information and communication technology framework for transnational biomaterial sharing and access

Biobanks represent key resources for clinico-genomic research and are needed to pave the way to personalised medicine. To achieve this goal, it is crucial that scientists can securely access and share high-quality biomaterial and related data. Therefore, there is a growing interest in integrating biobanks into larger biomedical information and communication technology (ICT) infrastructures. The European project p-medicine is currently building an innovative ICT infrastructure to meet this need. This platform provides tools and services for conducting research and clinical trials in personalised medicine. In this paper, we describe one of its main components, the biobank access framework p-BioSPRE (p-medicine Biospecimen Search and Project Request Engine). This generic framework enables and simplifies access to existing biobanks, but also to offer own biomaterial collections to research communities, and to manage biobank specimens and related clinical data over the ObTiMA Trial Biomaterial Manager. p-BioSPRE takes into consideration all relevant ethical and legal standards, e.g., safeguarding donors’ personal rights and enabling biobanks to keep control over the donated material and related data. The framework thus enables secure sharing of biomaterial within open and closed research communities, while flexibly integrating related clinical and omics data. Although the development of the framework is mainly driven by user scenarios from the cancer domain, in this case, acute lymphoblastic leukaemia and Wilms tumour, it can be extended to further disease entities.FP7/2007-2013/27008

Model of C-Axis Resistivity of High-\Tc Cuprates

We propose a simple model which accounts for the major features and systematics of experiments on the $c$-axis resistivity, $\rho_c$, for \lsco, \ybco and \bsco . We argue that the $c$-axis resistivity can be separated into contributions from in-plane dephasing and the $c$-axis ``barrier'' scattering processes, with the low temperature semiconductor-like behavior of $\rho_c$ arising from the suppression of the in-plane density of states measured by in-plane magnetic Knight shift experiments. We report on predictions for $\rho_c$ in impurity-doped \ybco materials.Comment: 10 pages + figures, also see March Meeting J13.1

Shear induced instabilities in layered liquids

Motivated by the experimentally observed shear-induced destabilization and reorientation of smectic A like systems, we consider an extended formulation of smectic A hydrodynamics. We include both, the smectic layering (via the layer displacement u and the layer normal p) and the director n of the underlying nematic order in our macroscopic hydrodynamic description and allow both directions to differ in non equilibrium situations. In an homeotropically aligned sample the nematic director does couple to an applied simple shear, whereas the smectic layering stays unchanged. This difference leads to a finite (but usually small) angle between n and p, which we find to be equivalent to an effective dilatation of the layers. This effective dilatation leads, above a certain threshold, to an undulation instability of the layers. We generalize our earlier approach [Rheol. Acta, vol.39(3), 15] and include the cross couplings with the velocity field and the order parameters for orientational and positional order and show how the order parameters interact with the undulation instability. We explore the influence of various material parameters on the instability. Comparing our results to recent experiments and molecular dynamic simulations, we find a good qualitative agreement.Comment: 15 pages, 12 figures, accepted for publication in PR

CHAMP+ observations of warm gas in M17 SW

Since the main cooling lines of the gas phase are important tracers of the interstellar medium in Galactic and extragalactic sources, proper and detailed understanding of their emission, and the ambient conditions of the emitting gas, is necessary for a robust interpretation of the observations. With high resolution (7"-9") maps (~3x3 pc^2) of mid-J molecular lines we aim to probe the physical conditions and spatial distribution of the warm (50 to few hundred K) and dense gas (n(H_2)>10^5 cm^-3) across the interface region of M17 SW nebula. We have used the dual color multiple pixel receiver CHAMP+ on APEX telescope to obtain a 5'.3x4'.7 map of the J=6-5 and J=7-6 transitions of 12CO, the 13CO J=6-5 line, and the {^3P_2}-{^3P_1} 370 um fine-structure transition of [C I] in M17 SW. LTE and non-LTE radiative transfer models are used to constrain the ambient conditions. The warm gas extends up to a distance of ~2.2 pc from the M17 SW ridge. The 13CO J=6-5 and [C I] 370 um lines have a narrower spatial extent of about 1.3 pc along a strip line at P.A=63 deg. The structure and distribution of the [C I] {^3P_2}-{^3P_1} 370 um map indicate that its emission arises from the interclump medium with densities of the order of 10^3 cm^-3. The warmest gas is located along the ridge of the cloud, close to the ionization front. An LTE approximation indicates that the excitation temperature of the embedded clumps goes up to ~120 K. The non-LTE model suggests that the kinetic temperature at four selected positions cannot exceed 230 K in clumps of density n(H_2)~5x10^5 cm^-3, and that the warm T_k>100 K and dense (n(H_2)>10^4 cm^-3) gas traced by the mid-J 12CO lines represent just about 2% of the bulk of the molecular gas. The clump volume filling factor ranges between 0.04 and 0.11 at these positions.Comment: Accepted for publication in Astronomy and Astrophysics, 12 pages, 10 figures, 1 tabl