An updated version of a gap-free monthly mean zonal mean ozone database

An updated and improved version of a global, vertically resolved, monthly mean zonal mean ozone database has been calculated – hereafter referred to as the BSVertOzone (Bodeker Scientific Vertical Ozone) database. Like its predecessor, it combines measurements from several satellite-based instruments and ozone profile measurements from the global ozonesonde network. Monthly mean zonal mean ozone concentrations in mixing ratio and number density are provided in 5° latitude bins, spanning 70 altitude levels (1 to 70km), or 70 pressure levels that are approximately 1km apart (878.4 to 0.046hPa). Different data sets or “tiers” are provided: Tier 0 is based only on the available measurements and therefore does not completely cover the whole globe or the full vertical range uniformly; the Tier 0.5 monthly mean zonal means are calculated as a filled version of the Tier 0 database where missing monthly mean zonal mean values are estimated from correlations against a total column ozone (TCO) database. The Tier 0.5 data set includes the full range of measurement variability and is created as an intermediate step for the calculation of the Tier 1 data where a least squares regression model is used to attribute variability to various known forcing factors for ozone. Regression model fit coefficients are expanded in Fourier series and Legendre polynomials (to account for seasonality and latitudinal structure, respectively). Four different combinations of contributions from selected regression model basis functions result in four different Tier 1 data sets that can be used for comparisons with chemistry–climate model (CCM) simulations that do not exhibit the same unforced variability as reality (unless they are nudged towards reanalyses). Compared to previous versions of the database, this update includes additional satellite data sources and ozonesonde measurements to extend the database period to 2016. Additional improvements over the previous version of the database include the following: (i) adjustments of measurements to account for biases and drifts between different data sources (using a chemistry-transport model, CTM, simulation as a transfer standard), (ii) a more objective way to determine the optimum number of Fourier and Legendre expansions for the basis function fit coefficients, and (iii) the derivation of methodological and measurement uncertainties on each database value are traced through all data modification steps. Comparisons with the ozone database from SWOOSH (Stratospheric Water and OzOne Satellite Homogenized data set) show good agreement in many regions of the globe. Minor differences are caused by different bias adjustment procedures for the two databases. However, compared to SWOOSH, BSVertOzone additionally covers the troposphere. Version 1.0 of BSVertOzone is publicly available at https://doi.org/http://doi.org/10.5281/zenodo.1217184

Measured greenhouse gas budgets challenge emission savings from palm-oil biodiesel

Special thanks to our field assistants in Indonesia (Basri, Bayu and Darwis) and to Frank Tiedemann, Edgar Tunsch, Dietmar Fellert and Malte Puhan for technical assistance. We thank PTPN VI and the owner of the plantation at Pompa Air for allowing us to conduct our research at their plantation. We would also like to thank the Spanish national project GEISpain (CGL2014-52838-C2-1-R) and the DAAD (scholarship from the programme ‘Research Stays for University Academics and Scientist 2018, ref. no. 91687130)' for partly financing A. Meijide during the preparation of this paper.The potential of palm-oil biofuels to reduce greenhouse gas (GHG) emissions compared with fossil fuels is increasingly questioned. So far, no measurement-based GHG budgets were available, and plantation age was ignored in Life Cycle Analyses (LCA). Here, we conduct LCA based on measured CO2, CH4 and N2O fluxes in young and mature Indonesian oil palm plantations. CO2 dominates the on-site GHG budgets. The young plantation is a carbon source (1012 ± 51 gC m−2 yr−1), the mature plantation a sink (−754 ± 38 gC m−2 yr−1). LCA considering the measured fluxes shows higher GHG emissions for palm-oil biodiesel than traditional LCA assuming carbon neutrality. Plantation rotation-cycle extension and earlier-yielding varieties potentially decrease GHG emissions. Due to the high emissions associated with forest conversion to oil palm, our results indicate that only biodiesel from second rotation-cycle plantations or plantations established on degraded land has the potential for pronounced GHG emission savings.This study was financed by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)— Project-ID 192626868—in the framework of the collaborative German-Indonesian research project CRC990 (subprojects A03, A04 and A05).Spanish national project GEISpain (CGL2014-52838-C2-1-R) and the DAAD (scholarship from the programme ‘Research Stays for University Academics and Scientist 2018, ref. no. 91687130

Androgen-Regulated Expression of Arginase 1, Arginase 2 and Interleukin-8 in Human Prostate Cancer

BACKGROUND: Prostate cancer (PCa) is the most frequently diagnosed cancer in North American men. Androgen-deprivation therapy (ADT) accentuates the infiltration of immune cells within the prostate. However, the immunosuppressive pathways regulated by androgens in PCa are not well characterized. Arginase 2 (ARG2) expression by PCa cells leads to a reduced activation of tumor-specific T cells. Our hypothesis was that androgens could regulate the expression of ARG2 by PCa cells. METHODOLOGY/PRINCIPAL FINDINGS: In this report, we demonstrate that both ARG1 and ARG2 are expressed by hormone-sensitive (HS) and hormone-refractory (HR) PCa cell lines, with the LNCaP cells having the highest arginase activity. In prostate tissue samples, ARG2 was more expressed in normal and non-malignant prostatic tissues compared to tumor tissues. Following androgen stimulation of LNCaP cells with 10 nM R1881, both ARG1 and ARG2 were overexpressed. The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry. Patients treated by ADT prior to surgery had lower ARG2 expression in both non-malignant and malignant tissues. Furthermore, ARG1 and ARG2 were enzymatically active and their decreased expression by siRNA resulted in reduced overall arginase activity and l-arginine metabolism. The decreased ARG1 and ARG2 expression also translated with diminished LNCaP cells cell growth and increased PBMC activation following exposure to LNCaP cells conditioned media. Finally, we found that interleukin-8 (IL-8) was also upregulated following androgen stimulation and that it directly increased the expression of ARG1 and ARG2 in the absence of androgens. CONCLUSION/SIGNIFICANCE: Our data provides the first detailed in vitro and in vivo account of an androgen-regulated immunosuppressive pathway in human PCa through the expression of ARG1, ARG2 and IL-8

The unfolded protein response in immunity and inflammation.

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6

Estimates of ozone return dates from Chemistry-Climate Model Initiative simulations

We analyse simulations performed for the Chemistry-Climate Model Initiative (CCMI) to estimate the return dates of the stratospheric ozone layer from depletion caused by anthropogenic stratospheric chlorine and bromine. We consider a total of 155 simulations from 20 models, including a range of sensitivity studies which examine the impact of climate change on ozone recovery. For the control simulations (unconstrained by nudging towards analysed meteorology) there is a large spread (±20 DU in the global average) in the predictions of the absolute ozone column. Therefore, the model results need to be adjusted for biases against historical data. Also, the interannual variability in the model results need to be smoothed in order to provide a reasonably narrow estimate of the range of ozone return dates. Consistent with previous studies, but here for a Representative Concentration Pathway (RCP) of 6.0, these new CCMI simulations project that global total column ozone will return to 1980 values in 2049 (with a 1σ uncertainty of 2043–2055). At Southern Hemisphere mid-latitudes column ozone is projected to return to 1980 values in 2045 (2039–2050), and at Northern Hemisphere mid-latitudes in 2032 (2020–2044). In the polar regions, the return dates are 2060 (2055–2066) in the Antarctic in October and 2034 (2025–2043) in the Arctic in March. The earlier return dates in the Northern Hemisphere reflect the larger sensitivity to dynamical changes. Our estimates of return dates are later than those presented in the 2014 Ozone Assessment by approximately 5–17 years, depending on the region, with the previous best estimates often falling outside of our uncertainty range. In the tropics only around half the models predict a return of ozone to 1980 values, around 2040, while the other half do not reach the 1980 value. All models show a negative trend in tropical total column ozone towards the end of the 21st century. The CCMI models generally agree in their simulation of the time evolution of stratospheric chlorine and bromine, which are the main drivers of ozone loss and recovery. However, there are a few outliers which show that the multi-model mean results for ozone recovery are not as tightly constrained as possible. Throughout the stratosphere the spread of ozone return dates to 1980 values between models tends to correlate with the spread of the return of inorganic chlorine to 1980 values. In the upper stratosphere, greenhouse gas-induced cooling speeds up the return by about 10–20 years. In the lower stratosphere, and for the column, there is a more direct link in the timing of the return dates of ozone and chlorine, especially for the large Antarctic depletion. Comparisons of total column ozone between the models is affected by different predictions of the evolution of tropospheric ozone within the same scenario, presumably due to differing treatment of tropospheric chemistry. Therefore, for many scenarios, clear conclusions can only be drawn for stratospheric ozone columns rather than the total column. As noted by previous studies, the timing of ozone recovery is affected by the evolution of N2O and CH4. However, quantifying the effect in the simulations analysed here is limited by the few realisations available for these experiments compared to internal model variability. The large increase in N2O given in RCP 6.0 extends the ozone return globally by ∼ 15 years relative to N2O fixed at 1960 abundances, mainly because it allows tropical column ozone to be depleted. The effect in extratropical latitudes is much smaller. The large increase in CH4 given in the RCP 8.5 scenario compared to RCP 6.0 also lengthens ozone return by ∼ 15 years, again mainly through its impact in the tropics. Overall, our estimates of ozone return dates are uncertain due to both uncertainties in future scenarios, in particular those of greenhouse gases, and uncertainties in models. The scenario uncertainty is small in the short term but increases with time, and becomes large by the end of the century. There are still some model–model differences related to well-known processes which affect ozone recovery. Efforts need to continue to ensure that models used for assessment purposes accurately represent stratospheric chemistry and the prescribed scenarios of ozone-depleting substances, and only those models are used to calculate return dates. For future assessments of single forcing or combined effects of CO2, CH4, and N2O on the stratospheric column ozone return dates, this work suggests that it is more important to have multi-member (at least three) ensembles for each scenario from every established participating model, rather than a large number of individual models

RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases - results and lessons learnt

BACKGROUND: Brain metastases occur in up to 75% of patients with advanced melanoma. Most are treated with whole-brain radiotherapy (WBRT), with limited effectiveness. Vandetanib, an inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and rearranged during transfection tyrosine kinases, is a potent radiosensitiser in xenograft models. We compared WBRT with WBRT plus vandetanib in the treatment of patients with melanoma brain metastases. METHODS: In this double-blind, multi-centre, phase 2 trial patients with melanoma brain metastases were randomised to receive WBRT (30 Gy in 10 fractions) plus 3 weeks of concurrent vandetanib 100 mg once daily or placebo. The primary endpoint was progression-free survival in brain (PFS brain). The main study was preceded by a safety run-in phase to confirm tolerability of the combination. A post-hoc analysis and literature review considered barriers to recruiting patients with melanoma brain metastases to clinical trials. RESULTS: Twenty-four patients were recruited, six to the safety phase and 18 to the randomised phase. The study closed early due to poor recruitment. Median PFS brain was 3.3 months (90% confidence interval (CI): 1.6-5.6) in the vandetanib group and 2.5 months (90% CI: 0.2-4.8) in the placebo group (P=0.34). Median overall survival (OS) was 4.6 months (90% CI: 1.6-6.3) and 2.5 months (90% CI: 0.2-7.2), respectively (P=0.54). The most frequent adverse events were fatigue, alopecia, confusion and nausea. The most common barrier to study recruitment was availability of alternative treatments. CONCLUSIONS: The combination of WBRT plus vandetanib was well tolerated. Compared with WBRT alone, there was no significant improvement in PFS brain or OS, although we are unable to provide a definitive result due to poor accrual. A review of barriers to trial accrual identified several factors that affect study recruitment in this difficult disease area

Neuro-arterial relations in the region of the optic canal

WOS: 000084313600008PubMed ID: 10635097In this paper, we present the results of our investigations on the neuro-arterial relations in the region of the optic canal. A thorough knowledge of the microanatomic features of the ophthalmic artery, optic canal and optic nerve is very important for surgeons approaching lesions of this area. We aimed to extend our present knowledge of the origin of the ophthalmic artery and microsurgical anatomy of the optic canal with exposure of the optic nerve. The optic canal walls and width and height of the orbital and cranial apertures, and thickness of the bony roof of the optic canal were measured on the right and left sides of 57 sphenoid bones, 102 skull bases and 58 fixed adult cadaver heads. The ophthalmic artery originated from the rostromedial circumference of the internal carotid artery in 51.8%, from the medial circumference in 26.2% and the laterobasal circumference in 22% of the specimens. The outer diameter of the ophthalmic artery at its origin was 1.81 +/- 0.36 mm on the right and 1.75 +/- 0.37 mm on the left side