Clinical and functional characterisation of a novel TNFRSF1A c.605T > A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment.

Objectives: To study the clinical outcome, treatment response, T-cell subsets and functional consequences of a novel tumour necrosis factor (TNF) receptor type 1 (TNFRSF1A) mutation affecting the receptor cleavage site. Methods: Patients with symptoms suggestive of tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and 22 healthy controls (HC) were screened for mutations in the TNFRSF1A gene. Soluble TNFRSF1A and inflammatory cytokines were measured by ELISAs. TNFRSF1A shedding was examined by stimulation of peripheral blood mononuclear cells (PBMCs) with phorbol 12-myristate 13-acetate followed by flow cytometric analysis (FACS). Apoptosis of PBMCs was studied by stimulation with TNFa in the presence of cycloheximide and annexin V staining. T cell phenotypes were monitored by FACS. Results: TNFRSF1A sequencing disclosed a novel V173D/ p.Val202Asp substitution encoded by exon 6 in one family, the c.194–14G.A splice variant in another and the R92Q/p.Arg121Gln substitution in two families. Cardiovascular complications (lethal heart attack and peripheral arterial thrombosis) developed in two V173D patients. Subsequent etanercept treatment of the V173D carriers was highly effective over an 18-month follow-up period. Serum TNFRSF1A levels did not differ between TRAPS patients and HC, while TNFRSF1A cleavage from monocytes was significantly reduced in V173D and R92Q patients. TNFa-induced apoptosis of PBMCs and T-cell senescence were comparable between V173D patients and HC. Conclusions: The TNFRSF1A V173D cleavage site mutation may be associated with an increased risk for cardiovascular complications and shows a strong response to etanercept. T-cell senescence does not seem to have a pathogenetic role in affected patients

Immunomodulatory activity of humanized anti-IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes

BACKGROUND: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. METHODS: Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study. RESULTS: Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T cells. The ratios of Tregs to CD4+ or CD8+ effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti-EBV IgG+ after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. CONCLUSIONS: This trial shows that, at dosages of 1-3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. TRIAL REGISTRATION: NCT02038764. FUNDING: Pfizer Inc

EXTRACTION OF RAILROAD OBJECTS FROM VERY HIGH RESOLUTION HELICOPTER-BORNE LIDAR AND ORTHO-IMAGE DATA

LiDAR (Light Detection and Ranging) sensors and digital aerial camera systems using a slow and low flying aircraft provide a new quality of data for a variety of promising large-scale applications. The main of this study objective is the development of methods for the automated object extraction of railway infrastructure from combined helicopter-based extremely dense laser scanner measurement points and very high resolution digital ortho-imagery. Thus, different existing methods from digital image processing, image segmentation and object recognition have been compared regarding their performance, output quality and level of automation. It turned out that all existing methods are not suitable to meet the requirements (geometrical accuracy of the result, amount of data to be processed etc.). Since original LiDAR point data provides a higher accuracy than derived DTM raster data or ortho-imagery new suited methods for the object extraction from point clouds have been developed. For the extraction of linear features, such as rails and catenaries, two new methods were implemented. The first method sets up on pre-classified laser points as input data. Therefore the RANSAC algorithm was implemented successfully to extract linear objects within the environment of MATLAB and ArcGIS. Second, a knowledge-based classification method was designed to compare a reference profile with the situation along the track using IDL. The results show new prospects to automatically extract railroad objects with a high geometrical accuracy from extremely dense LiDAR data without using aerial imagery. The decision not to use image data was especially caused by the enormous data amount t

Hydrogen Phases on the Surface of a Strongly Magnetized Neutron Star

The outermost layers of some neutron stars are likely to be dominated by hydrogen, as a result of fast gravitational settling of heavier elements. These layers directly mediate thermal radiation from the stars, and determine the characteristics of X-ray/EUV spectra. For a neutron star with surface temperature T\lo 10^6 K and magnetic field B\go 10^{12} G, various forms of hydrogen can be present in the envelope, including atom, poly-molecules, and condensed metal. We study the physical properties of different hydrogen phases on the surface of a strongly magnetized neutron star for a wide range of field strength $B$ and surface temperature $T$. Depending on the values of $B$ and $T$, the outer envelope can be either in a nondegenerate gaseous phase or in a degenerate metallic phase. For T\go 10^5 K and moderately strong magnetic field, B\lo 10^{13} G, the envelope is nondegenerate and the surface material gradually transforms into a degenerate Coulomb plasma as density increases. For higher field strength, $B>> 10^{13}$ G, there exists a first-order phase transition from the nondegenerate gaseous phase to the condensed metallic phase. The column density of saturated vapor above the metallic hydrogen decreases rapidly as the magnetic field increases or/and temperature decreases. Thus the thermal radiation can directly emerge from the degenerate metallic hydrogen surface. The characteristics of surface X-ray/EUV emission for different phases are discussed. A separate study concerning the possibility of magnetic field induced nuclear fusion of hydrogen on the neutron star surface is also presented.Comment: TeX, 35 pages including 6 postscript figures. To be published in Ap

Biomarkers in Urachal Cancer and Adenocarcinomas in the Bladder: A Comprehensive Review Supplemented by Own Data

Urachal cancer (UrC) is a rare but aggressive cancer. Due to overlapping histomorphology, discrimination of urachal from primary bladder adenocarcinomas (PBAC) and adenocarcinomas secondarily involving the bladder (particularly colorectal adenocarcinomas, CRC) can be challenging. Therefore, we aimed to give an overview of helpful (immunohistochemical) biomarkers and clinicopathological factors in addition to survival analyses and included institutional data from 12 urachal adenocarcinomas. A PubMed search yielded 319 suitable studies since 1930 in the English literature with 1984 cases of UrC including 1834 adenocarcinomas (92%) and 150 nonadenocarcinomas (8%). UrC was more common in men (63%), showed a median age at diagnosis of 50.8 years and a median tumor size of 6.0 cm. No associations were noted for overall survival and progression-free survival (PFS) and clinicopathological factors beside a favorable PFS in male patients (p = 0.047). The immunohistochemical markers found to be potentially helpful in the differential diagnostic situation are AMACR and CK34betaE12 (UrC versus CRC and PBAC), CK7, beta-Catenin and CD15 (UrC and PBAC versus CRC), and CEA and GATA3 (UrC and CRC versus PBAC). Serum markers like CEA, CA19-9 and CA125 might additionally be useful in the follow-up and monitoring of UrC

Biological and technical variables affecting immunoassay recovery of cytokines from human serum and simulated vaginal fluid: A multicenter study

The increase of proinflammatory cytokines in vaginal secretions may serve as a surrogate marker of unwanted inflammatory reaction to microbicide products topically applied for the prevention of sexually transmitted diseases, including HIV-1. Interleukin (IL)-1β and IL-6 have been proposed as indicators of inflammation and increased risk of HIV-1 transmission; however, the lack of information regarding detection platforms optimal for vaginal fluids and interlaboratory variation limit their use for microbicide evaluation and other clinical applications. This study examines fluid matrix variants relevant to vaginal sampling techniques and proposes a model for interlaboratory comparisons across current cytokine detection technologies. IL-1β and IL-6 standards were measured by 12 laboratories in four countries, using 14 immunoassays and four detection platforms based on absorbance, chemiluminescence, electrochemiluminescence, and fluorescence. International reference preparations of cytokines with defined biological activity were spiked into (1) a defined medium simulating the composition of human vaginal fluid at pH 4.5 and 7.2, (2) physiologic salt solutions (phosphate-buffered saline and saline) commonly used for vaginal lavage sampling in clinical studies of cytokines, and (3) human blood serum. Assays were assessed for reproducibility, linearity, accuracy, and significantly detectable fold difference in cytokine level. Factors with significant impact on cytokine recovery were determined by Kruskal−Wallis analysis of variance with Dunn’s multiple comparison test and multiple regression models. All assays showed acceptable intra-assay reproducibility; however, most were associated with significant interlaboratory variation. The smallest reliably detectable cytokine differences (P < 0.05) derived from pooled interlaboratory data varied from 1.5- to 26-fold depending on assay, cytokine, and matrix type. IL-6 but not IL-1β determinations were lower in both saline and phosphate-buffered saline as compared to vaginal fluid matrix, with no significant effect of pH. The (electro)chemiluminescence-based assays were most discriminative and consistently detected <2-fold differences within each matrix type. The Luminex-based assays were less discriminative with lower reproducibility between laboratories. These results suggest the need for uniform vaginal sampling techniques and a better understanding of immunoassay platform differences and cross-validation before the biological significance of cytokine variations can be validated in clinical trials. This investigation provides the first standardized analytic approach for assessing differences in mucosal cytokine levels and may improve strategies for monitoring immune responses at the vaginal mucosal interface

Compton Scattering in Ultra-Strong Magnetic Fields: Numerical and Analytical Behavior in the Relativistic Regime

This paper explores the effects of strong magnetic fields on the Compton scattering of relativistic electrons. Recent studies of upscattering and energy loss by relativistic electrons that have used the non-relativistic, magnetic Thomson cross section for resonant scattering or the Klein-Nishina cross section for non-resonant scattering do not account for the relativistic quantum effects of strong fields ($> 4 \times 10^{12}$ G). We have derived a simplified expression for the exact QED scattering cross section for the broadly-applicable case where relativistic electrons move along the magnetic field. To facilitate applications to astrophysical models, we have also developed compact approximate expressions for both the differential and total polarization-dependent cross sections, with the latter representing well the exact total QED cross section even at the high fields believed to be present in environments near the stellar surfaces of Soft Gamma-Ray Repeaters and Anomalous X-Ray Pulsars. We find that strong magnetic fields significantly lower the Compton scattering cross section below and at the resonance, when the incident photon energy exceeds $m_ec^2$ in the electron rest frame. The cross section is strongly dependent on the polarization of the final scattered photon. Below the cyclotron fundamental, mostly photons of perpendicular polarization are produced in scatterings, a situation that also arises above this resonance for sub-critical fields. However, an interesting discovery is that for super-critical fields, a preponderance of photons of parallel polarization results from scatterings above the cyclotron fundamental. This characteristic is both a relativistic and magnetic effect not present in the Thomson or Klein-Nishina limits.Comment: AASTeX format, 31 pages included 7 embedded figures, accepted for publication in The Astrophysical Journa

Corona of Magnetars

We develop a theoretical model that explains the formation of hot coronae around strongly magnetized neutron stars -- magnetars. The starquakes of a magnetar shear its external magnetic field, which becomes non-potential and is threaded by an electric current. Once twisted, the magnetosphere cannot untwist immediately because of its self-induction. The self-induction electric field lifts particles from the stellar surface, accelerates them, and initiates avalanches of pair creation in the magnetosphere. The created plasma corona maintains the electric current demanded by curl(B) and regulates the self-induction e.m.f. by screening. This corona persists in dynamic equilibrium: it is continually lost to the stellar surface on the light-crossing time of 10^{-4} s and replenished with new particles. In essence, the twisted magnetosphere acts as an accelerator that converts the toroidal field energy to particle kinetic energy. Using a direct numerical experiment, we show that the corona self-organizes quickly (on a millisecond timescale) into a quasi-steady state, with voltage ~1 GeV along the magnetic lines. The heating rate of the corona is ~10^{36} erg/s, in agreement with the observed persistent, high-energy output of magnetars. We deduce that a static twist that is suddenly implanted into the magnetosphere will decay on a timescale of 1-10 yrs. The particles accelerated in the corona impact the solid crust, knock out protons, and regulate the column density of the hydrostatic atmosphere of the star. The transition layer between the atmosphere and the corona is the likely source of the observed 100-keV emission from magnetars. The corona emits curvature radiation and can supply the observed IR-optical luminosity. (Abridged)Comment: 70 pages, 14 figures, accepted to Ap