Immunogenicity and safety of three consecutive production lots of the non replicating smallpox vaccine MVA: A randomised, double blind, placebo controlled phase III trial

<div><p>Background</p><p>Modified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. A randomised, double-blind, placebo-controlled phase III clinical trial was conducted to demonstrate the humoral immunogenic equivalence of three consecutively manufactured MVA production lots, and to confirm the safety and tolerability of MVA focusing on cardiac readouts.</p><p>Methods</p><p>The trial was conducted at 34 sites in the US. Vaccinia-naïve adults aged 18-40 years were randomly allocated to one of four groups using a 1:1:1:1 randomization scheme. Subjects received either two MVA injections from three consecutive lots (Groups 1-3), or two placebo injections (Group 4), four weeks apart. Everyone except personnel involved in vaccine handling and administration was blinded to treatment. Safety assessment focused on cardiac monitoring throughout the trial. Vaccinia-specific antibody titers were measured using a Plaque Reduction Neutralization Test (PRNT) and an Enzyme-Linked Immunosorbent Assay (ELISA). The primary immunogenicity endpoint was Geometric Mean Titers (GMTs) after two MVA vaccinations measured by PRNT at trial visit 4. This trial is registered with ClinicalTrials.gov, number NCT01144637.</p><p>Results</p><p>Between March 2013 and May 2014, 4005 subjects were enrolled and received at least one injection of MVA (n = 3003) or placebo (n = 1002). The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). Overall, 180 (6·0%) subjects receiving MVA and 29 (2·9%) subjects in the placebo group reported at least one unsolicited Adverse Event (AE) that was considered trial-related. Vaccination was well tolerated without significant safety concerns, particularly regarding cardiac assessment.</p><p>Conclusions</p><p>The neutralizing and total antibody titers induced by each of the three lots were equivalent. No significant safety concerns emerged in this healthy trial population, especially regarding cardiac safety, thus confirming the excellent safety and tolerability profile of MVA.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01144637" target="_blank">NCT01144637</a></p></div

Evaluating the use of amber in palaeoatmospheric reconstructions: The carbon-isotope variability of modern and Cretaceous conifer resins.

Stable carbon-isotope geochemistry of fossilized tree resin (amber) potentially could be a very useful tool to infer the composition of past atmospheres. To test the reliability of amber as a proxy for the atmosphere, we studied the variability of modern resin d13C at both local and global scales. An amber d13C curve was then built for the Cretaceous, a period of abundant resin production, and interpreted in light of data from modern resins. Our data show that hardening changes the pristine d13C value by causing a 13C-depletion in solid resin when compared to fresh liquid-viscous resin, probably due to the loss of 13C-enriched volatiles. Modern resin d13C values vary as a function of physiological and environmental parameters in ways that are similar to those described for leaves and wood. Resin d13C varies between plant species and localities, within the same tree and between different plant tissues by up to 6¿, and in general increases with increasing altitudes of the plant-growing site. We show that, as is the case with modern resin, Cretaceous amber d13C has a high variability, generally higher than that of other fossil material. Despite the high natural variability, amber shows a negative 2.5-3¿ d13C trend from the middle Early Cretaceous to the Maastrichtian that parallels published terrestrial d13C records. This trend mirrors changes in the atmospheric d13C calculated from the d13C and d18O of benthic foraminiferal tests, although the magnitude of the shift is larger in plant material than in the atmosphere. Increasing mean annual precipitation and pO2 could have enhanced plant carbon-isotope fractionation during the Late Cretaceous, whereas changing pCO2 levels seem to have had no effect on plant carbon-isotope fractionation. The results of this study suggest that amber is a powerful fossil plant material for palaeoenvironmental and palaeoclimatic reconstructions. Improvement of the resolution of the existing data coupled with more detailed information about botanical source and environmental growing conditions of the fossil plant material will probably allow a more faithful interpretation of amber d13C records and a wider understanding of the composition of the past atmosphere

Three-dimensional ultrahigh resolution optical coherence tomography of macular pathologies

purpose. To demonstrate a new generation of three-dimensional (3-D) ultrahigh-resolution optical coherence tomography (UHR OCT) technology for visualization of macular diseases. methods. One hundred forty eyes with a distinct disease in each of the posterior pole compartments were examined with 3-D UHR OCT. 3-D imaging was performed with a high axial resolution of 3 ?m with a compact, commercially available, ultra–broad-bandwidth (160 nm) titanium:sapphire laser at a video rate of up to 25 B-scans/s. Each tomogram consisted of 1024 × 1024 pixels, resulting in 25 megavoxels/s. results. 3-D UHR OCT offers high-precision 3-D visualization of macular diseases at all structural levels. The UHR modality allows identification of the contour of the hyaloid membrane, tractive forces of epiretinal membranes, and changes within the inner limiting membrane. The system provides quality 3-D images of the topographic dynamics of traction lines from the retinal surface down to the level of the photoreceptor segments. Intraretinal diseases are identified by their specific location in different layers of the neurosensory ultrastructure. Photoreceptor inner and outer segments are clearly delineated in configuration and size, with a characteristic peak in the subfoveal area. The microarchitecture of choroidal neovascularization is distinctly imaged, related leakage can be identified, and the volume can be quantified. conclusions. High-speed UHR OCT offers unprecedented, realistic, 3-D imaging of ocular diseases at all epi-, intra- and subretinal levels. A complete 3-D data set of the macular layers allows a comprehensive analysis of focal and diffuse diseases, as well as identification of dynamic pathomechanisms

A Search for Selectrons and Squarks at HERA

Data from electron-proton collisions at a center-of-mass energy of 300 GeV are used for a search for selectrons and squarks within the framework of the minimal supersymmetric model. The decays of selectrons and squarks into the lightest supersymmetric particle lead to final states with an electron and hadrons accompanied by large missing energy and transverse momentum. No signal is found and new bounds on the existence of these particles are derived. At 95% confidence level the excluded region extends to 65 GeV for selectron and squark masses, and to 40 GeV for the mass of the lightest supersymmetric particle.Comment: 13 pages, latex, 6 Figure

Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

The β1-subunit of Na+,K+-ATPase was isolated and identified as an androgen down-regulated gene. Expression was observed at high levels in androgen-independent as compared to androgen-dependent (responsive) human prostate cancer cell lines and xenografts when grown in the presence of androgens. Down-regulation of the β1-subunit was initiated at concentrations between 0.01 nM and 0.03 nM of the synthetic androgen R1881 after relatively long incubation times (> 24 h). Using polyclonal antibodies, the concentration of β1-subunit protein, but not of the α1-subunit protein, was markedly reduced in androgen-dependent human prostate cancer cells (LNCaP-FGC) cultured in the presence of androgens. In line with these observations it was found that the protein expression of total Na+,K+-ATPase in the membrane (measured by 3H-ouabain binding) was also markedly decreased. The main function of Na+,K+-ATPase is to maintain sodium and potassium homeostasis in animal cells. The resulting electrochemical gradient is facilitative for transport of several compounds over the cell membrane (for example cisplatin, a chemotherapeutic agent experimentally used in the treatment of hormone-refractory prostate cancer). Here we observed that a ouabain-induced decrease of Na+,K+-ATPase activity in LNCaP-FGC cells results in reduced sensitivity of these cells to cisplatin-treatment. Surprisingly, androgen-induced decrease of Na+,K+-ATPase expression, did not result in significant protection against the chemotherapeutic agent. © 1999 Cancer Research Campaig

Astrophysical constraints from gamma-ray spectroscopy

Gamma-ray lines from cosmic sources provide unique isotopic information, since they originate from energy level transitions in the atomic nucleus. Gamma-ray telescopes explored this astronomical window in the past three decades, detecting radioactive isotopes that have been ejected in interstellar space by cosmic nucleosynthesis events and nuclei that have been excited through collisions with energetic particles. Short-lived radioactivities have been detected in a couple of supernovae (56Co and 57Co in SN1987A, 44Ti in Cas A), the diffuse glow of long-lived 26Al has been mapped along the entire plane of the Galaxy, several excited nuclei have been detected in solar flares, and, last but not least, positron annihilation has been observed in the inner Galaxy since the 70ies. Recent imaging and line shape measurements of e-/e+ annihilation emission from the Galactic bulge can hardly be accounted for by conventional sources of positrons; recent 26Al emission and line width measurement from the inner Galaxy and from the Cygnus region can constrain the properties of the interstellar medium; a diffuse 60Fe gamma-ray line emission appears rather weak, in view of current theoretical predictions. Recent Galactic core-collapse supernovae are studied through 44Ti radioactivity, but, apart from Cas A, no other source has been found. The characteristic signature of 22Na-line emission from a nearby O-Ne-Mg novae is expected to be measured during INTEGRAL's lifetime.Comment: 30 pages, 11 figures; accepted for publication in Nucl.Phys.A, special volume on Nuclear Astrophysics, Eds. K.-H. Langanke, F.-K. Thielemann, M. Wiesche