Evaluation of CD46 re-targeted adenoviral vectors for clinical ovarian cancer intraperitoneal therapy

Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralizing antibodies (nAbs) in ascitic fluid were quantified and tumor cells were assessed for the expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of epithelial ovarian cancers (EOCs) by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, Ad35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cance

Cross-sectional area of the paraspinal muscles and its association with muscle strength among fighter pilots : A 5-year follow-up

Background: A small cross sectional area (CSA) of the paraspinal muscles may be related to low back pain among military aviators but previous studies have mainly concentrated on spinal disc degeneration. Therefore, the primary aim of the study was to investigate the changes in muscle CSA and composition of the psoas and paraspinal muscles during a 5-year follow up among Finnish Air Force (FINAF) fighter pilots. Methods: Study population consisted of 26 volunteered FINAF male fighter pilots (age: 20.6 (±0.6) at the baseline). The magnetic resonance imaging (MRI) examinations were collected at baseline and after 5 years of follow-up. CSA and composition of the paraspinal and psoas muscles were obtained at the levels of 3-4 and 4-5 lumbar spine. Maximal isometric strength tests were only performed on one occasion at baseline. Results: The follow-up comparisons indicated that the mean CSA of the paraspinal muscles increased (p <0.01) by 8% at L3-4 level and 7% at L4-5 level during the 5-year period. There was no change in muscle composition during the follow-up period. The paraspinal and psoas muscles' CSA was positively related to overall maximal isometric strength at the baseline. However, there was no association between LBP and muscle composition or CSA. Conclusions: The paraspinal muscles' CSA increased among FINAF fighter pilots during the first 5 years of service. This might be explained by physically demanding work and regular physical activity. However, no associations between muscle composition or CSA and low back pain (LBP) experienced were observed after the five-year follow-up. © 2019 The Author(s).Peer reviewe

Methane production and oxidation potentials along a fen-bog gradient from southern boreal to subarctic peatlands in Finland

Methane (CH4) emissions from northern peatlands are projected to increase due to climate change, primarily because of projected increases in soil temperature. Yet, the rates and temperature responses of the two CH4 emission-related microbial processes (CH4 production by methanogens and oxidation by methanotrophs) are poorly known. Further, peatland sites within a fen-bog gradient are known to differ in the variables that regulate these two mechanisms, yet the interaction between peatland type and temperature lacks quantitative understanding. Here, we investigated potential CH4 production and oxidation rates for 14 peatlands in Finland located between c. 60 and 70 degrees N latitude, representing bogs, poor fens, and rich fens. Potentials were measured at three different temperatures (5, 17.5, and 30celcius) using the laboratory incubation method. We linked CH4 production and oxidation patterns to their methanogen and methanotroph abundance, peat properties, and plant functional types. We found that the rich fen-bog gradient-related nutrient availability and methanogen abundance increased the temperature response of CH4 production, with rich fens exhibiting the greatest production potentials. Oxidation potential showed a steeper temperature response than production, which was explained by aerenchymous plant cover, peat water holding capacity, peat nitrogen, and sulfate content. The steeper temperature response of oxidation suggests that, at higher temperatures, CH4 oxidation might balance increased CH4 production. Predicting net CH4 fluxes as an outcome of the two mechanisms is complicated due to their different controls and temperature responses. The lack of correlation between field CH4 fluxes and production/oxidation potentials, and the positive correlation with aerenchymous plants points toward the essential role of CH4 transport for emissions. The scenario of drying peatlands under climate change, which is likely to promote Sphagnum establishment over brown mosses in many places, will potentially reduce the predicted warming-related increase in CH4 emissions by shifting rich fens to Sphagnum-dominated systems.Peer reviewe

Pc1-Pc2 waves and energetic particle precipitation during and after magnetic storms: superposed epoch analysis and case studies

Magnetic pulsations in the Pc1-Pc2 frequency range (0.1-5 Hz) are often observed on the ground and in the Earth's magnetosphere during the aftermath of geomagnetic storms. Numerous studies have suggested that they may play a role in reducing the fluxes of energetic ions in the ring current; more recent studies suggest they may interact parasitically with radiation belt electrons as well. We report here on observations during 2005 from search coil magnetometers and riometers installed at three Antarctic stations, Halley (-61.84 degrees magnetic latitude, MLAT), South Pole (-74.18 degrees MLAT), and McMurdo (-79.96 degrees MLAT), and from energetic ion detectors on the NOAA Polar-orbiting Operational Environment Satellites (POES). A superposed epoch analysis based on 13 magnetic storms between April and September 2005 as well as case studies confirm several earlier studies that show that narrowband Pc1-Pc2 waves are rarely if ever observed on the ground during the main and early recovery phases of magnetic storms. However, intense broadband Pi1-Pi2 ULF noise, accompanied by strong riometer absorption signatures, does occur during these times. As storm recovery progresses, the occurrence of Pc1-Pc2 waves increases, at first in the daytime and especially afternoon sectors but at essentially all local times later in the recovery phase (typically by days 3 or 4). During the early storm recovery phase the propagation of Pc1-Pc2 waves through the ionospheric waveguide to higher latitudes was more severely attenuated. These observations are consistent with suggestions that Pc1-Pc2 waves occurring during the early recovery phase of magnetic storms are generated in association with plasmaspheric plumes in the noon-to-dusk sector, and these observations provide additional evidence that the propagation of waves to ground stations is inhibited during the early phases of such storms. Analysis of 30- to 250-keV proton data from four POES satellites during the 24-27 August and 18-19 July 2005 storm intervals showed that the location of the inner edge of the ring current matched well with the plasmapause model of O'Brien and Moldwin (2003). However, the POES data showed no evidence of the consequences of electromagnetic ion cyclotron waves (localized proton precipitation) during main and early recovery phase. During later stages of the recovery phase, when such precipitation was observed, it was coincident with intense wave events at Halley, and it occurred at L shells near or up to 1 RE outside the modeled plasmapause but well equatorward of the isotropy boundary

Immunogenicity of subcutaneous TNF inhibitors and its clinical significance in real-life setting in patients with spondyloarthritis

Key messages Considerable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels. Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1-2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients.Peer reviewe

Objects as culture-specific referents of color terms in Russian

The present study is an extension of our analysis of Russian basic color terms (BCTs) elicited in a web-based psycholinguistic experiment. Color samples (N = 600) were approximately uniformly distributed in the Munsell color solid. An unconstrained color-naming method was employed. Native Russian speakers (N = 713; 333 males) participated in the study. Among 1422 elicited unique color words, 698 terms (49%) were derived from object names. Here we explore object-derived non-BCTs, focusing on broad classes of names referred to objects, categories within these, and the inventory of color terms, as well as their frequency, patterns of derivation, and derivational productivity. Six classes of object referents were identified: flora, fauna, inanimate nature, food and beverages, man-made objects, body and bodily products. In detail, 20 most frequent object-derived terms are reported. These are accompanied by analysis of gender differences and representation of the terms' denotata on the Munsell Mercator projection. In addition, Russian object-derived color terms are related to those in English; discussed are differences between the 2 languages in the color term classes, inventories and incidences. We conclude that Russian object-derived color terms follow the generic metonymy pattern, that is, signifying color of objects in the speakers' natural environment. The inventory is also language-specific, reflecting social practices, preferences and views entrenched in the traditional Russian culture. Furthermore, recent extensive development of the inventory signals 2 novel phenomena: marked globalization influence, surfacing as abundant transliteration of English referent loanwords, and noticeable sociolectal diversification that manifests itself by novel evocative color terms, particularly in marketing and advertisement

Efficient intravenous tumor targeting using the αvβ6 integrin-selective precision virotherapy Ad5NULL-A20

We previously developed a refined, tumor-selective adenovirus, Ad5NULL-A20, harboring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20-mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5NULL-A20 for αvβ6-positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 h post intravenous administration. Results: Ad5NULL-A20 vector transduced cells in an αvβ6-selective manner, whilst cell killing mediated by oncolytic Ad5NULL-A20 was αvβ6-selective. Biodistribution analysis following intravenous administration into mice bearing breast cancer xenografts demonstrated that Ad5NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor-to-liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5NULL-A20-based virotherapies efficiently target αvβ6-integrin-positive tumors following intravenous administration, validating the potential of Ad5NULL-A20 for systemic applications, enabling tumor-selective overexpression of virally encoded therapeutic transgenes

High-resolution spatial patterns and drivers of terrestrial ecosystem carbon dioxide, methane, and nitrous oxide fluxes in the tundra

Arctic terrestrial greenhouse gas (GHG) fluxes of carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) play an important role in the global GHG budget. However, these GHG fluxes are rarely studied simultaneously, and our understanding of the conditions controlling them across spatial gradients is limited. Here, we explore the magnitudes and drivers of GHG fluxes across fine-scale terrestrial gradients during the peak growing season (July) in sub-Arctic Finland. We measured chamber-derived GHG fluxes and soil temperature, soil moisture, soil organic carbon and nitrogen stocks, soil pH, soil carbon-to-nitrogen (C/N) ratio, soil dissolved organic carbon content, vascular plant biomass, and vegetation type from 101 plots scattered across a heterogeneous tundra landscape (5 km2). We used these field data together with high-resolution remote sensing data to develop machine learning models for predicting (i.e., upscaling) daytime GHG fluxes across the landscape at 2 m resolution. Our results show that this region was on average a daytime net GHG sink during the growing season. Although our results suggest that this sink was driven by CO2 uptake, it also revealed small but widespread CH4 uptake in upland vegetation types, almost surpassing the high wetland CH4 emissions at the landscape scale. Average N2O fluxes were negligible. CO2 fluxes were controlled primarily by annual average soil temperature and biomass (both increase net sink) and vegetation type, CH4 fluxes by soil moisture (increases net emissions) and vegetation type, and N2O fluxes by soil C/N (lower C/N increases net source). These results demonstrate the potential of high spatial resolution modeling of GHG fluxes in the Arctic. They also reveal the dominant role of CO2 fluxes across the tundra landscape but suggest that CH4 uptake in dry upland soils might play a significant role in the regional GHG budget.</p

Effect of pathology type and severity on the distribution of MRI signal intensities within the degenerated nucleus pulposus: application to idiopathic scoliosis and spondylolisthesis

<p>Abstract</p> <p>Background</p> <p>Disc degeneration is characterized by a loss of cellularity, degradation of the extracellular matrix, and, as a result, morphological changes and biomechanical alterations. We hypothesized that the distribution of the MR signal intensity within the nucleus zone of the intervertebral disc was modified according to the pathology and the severity of the pathology. The objective of this study was to propose new parameters characterizing the distribution of the signal intensity within the nucleus zone of lumbar intervertebral discs, and to quantify these changes in patients suffering from spondylolisthesis or idiopathic scoliosis.</p> <p>Methods</p> <p>A retrospective study had been performed on T2-weighted MR images of twenty nine patients suffering from spondylolisthesis and/or scoliosis. The high intensity zone of the nucleus pulposus was semi-automatically detected. The distance "DX" between the center weighted by the signal intensity and the geometrical center was quantified. The sum of the signal intensity on the axis perpendicular to the longitudinal axis of the disc was plotted for each position of the longitudinal axis allowing defining the maximum sum "SM" and its position "PSM".</p> <p>Results</p> <p>"SM" was clearly higher and "PSM" was more shifted for scoliosis than for spondylolisthesis. A two-way analysis of variance showed that the differences observed on "DX" were not attributed to the pathology nor its severity, the differences observed on "SM" were attributed to the pathology but not to its severity, and the differences observed on "PSM" were attributed to both the pathology and its severity.</p> <p>Conclusions</p> <p>The technique proposed in this study showed significant differences in the distribution of the MR signal intensity within the nucleus zone of intervertebral discs due to the pathology and its severity. The dependence of the "PSM" parameter to the severity of the pathology suggests this parameter as a predictive factor of the pathology progression. This new technique should be useful for the early diagnosis of intervertebral disc pathologies as it highlights abnormal patterns in the MRI signal for low severity of the pathology.</p