Inhibition of all-TRANS-retinoic acid metabolism by R116010 induces antitumour activity

All-trans-retinoic acid is a potent inhibitor of cell proliferation and inducer of differentiation. However, the clinical use of all-trans-retinoic acid in the treatment of cancer is significantly hampered by its toxicity and the prompt emergence of resistance, believed to be caused by increased all-trans-retinoic acid metabolism. Inhibitors of all-trans-retinoic acid metabolism may therefore prove valuable in the treatment of cancer. In this study, we characterize R116010 as a new anticancer drug that is a potent inhibitor of all-trans-retinoic acid metabolism. In vitro, R116010 potently inhibits all-trans-retinoic acid metabolism in intact T47D cells with an IC50-value of 8.7 nM. In addition, R116010 is a selective inhibitor as indicated by its inhibition profile for several other cytochrome P450-mediated reactions. In T47D cell proliferation assays, R116010 by itself has no effect on cell proliferation. However, in combination with all-trans-retinoic acid, R116010 enhances the all-trans-retinoic acid-mediated antiproliferative activity in a concentration-dependent manner. In vivo, the growth of murine oestrogen-independent TA3-Ha mammary tumours is significantly inhibited by R116010 at doses as low as 0.16 mg kg−1. In conclusion, R116010 is a highly potent and selective inhibitor of all-trans-retinoic acid metabolism, which is able to enhance the biological activity of all-trans-retinoic acid, thereby exhibiting antitumour activity. R116010 represents a novel and promising anticancer drug with an unique mechanism of action

Cyp26b1 Regulates Retinoic Acid-Dependent Signals in T Cells and Its Expression Is Inhibited by Transforming Growth Factor-β

The vitamin A metabolite, retinoic acid (RA), plays important roles in the regulation of lymphocyte properties. Dendritic cells in gut-related lymphoid organs can produce RA, thereby imprinting gut-homing specificity on T cells and enhancing transforming growth factor (TGF)-β-dependent induction of Foxp3+ regulatory T cells upon antigen presentation. In general, RA concentrations in cells and tissues are regulated by its degradation as well. However, it remained unclear if T cells could actively catabolize RA.We assessed the expression of known RA-catabolizing enzymes in T cells from mouse lymphoid tissues. Antigen-experienced CD44+ T cells in gut-related lymphoid organs selectively expressed Cyp26b1, a member of the cytochrome P450 family 26. However, T cells in the spleen or skin-draining lymph nodes did not significantly express Cyp26b1. Accordingly, physiological levels of RA (1-10 nM) could induce Cyp26b1 expression in naïve T cells upon activation in vitro, but could not do so in the presence of TGF-β. Overexpression of Cyp26b1 significantly suppressed the RA effect to induce expression of the gut-homing receptor CCR9 on T cells. On the other hand, knocking down Cyp26b1 gene expression with small interfering RNA or inhibiting CYP26 enzymatic activity led to enhancement of the RA-induced CCR9 expression.Our data demonstrate a role for CYP26B1 in regulating RA-dependent signals in activated T cells but not during TGF-β-dependent differentiation to Foxp3+ regulatory T cells. Aberrant expression of CYP26B1 may disturb T cell trafficking and differentiation in the gut and its related lymphoid organs

Early fibrinogen concentrate therapy for major haemorrhage in trauma (E-FIT 1): results from a UK multi-centre, randomised, double blind, placebo-controlled pilot trial.

BACKGROUND: There is increasing interest in the timely administration of concentrated sources of fibrinogen to patients with major traumatic bleeding. Following evaluation of early cryoprecipitate in the CRYOSTAT 1 trial, we explored the use of fibrinogen concentrate, which may have advantages of more rapid administration in acute haemorrhage. The aims of this pragmatic study were to assess the feasibility of fibrinogen concentrate administration within 45 minutes of hospital admission and to quantify efficacy in maintaining fibrinogen levels ≥ 2 g/L during active haemorrhage. METHODS: We conducted a blinded, randomised, placebo-controlled trial at five UK major trauma centres with adult trauma patients with active bleeding who required activation of the major haemorrhage protocol. Participants were randomised to standard major haemorrhage therapy plus 6 g of fibrinogen concentrate or placebo. RESULTS: Twenty-seven of 39 participants (69%; 95% CI, 52-83%) across both arms received the study intervention within 45 minutes of admission. There was some evidence of a difference in the proportion of participants with fibrinogen levels ≥ 2 g/L between arms (p = 0.10). Fibrinogen levels in the fibrinogen concentrate (FgC) arm rose by a mean of 0.9 g/L (SD, 0.5) compared with a reduction of 0.2 g/L (SD, 0.5) in the placebo arm and were significantly higher in the FgC arm (p < 0.0001) at 2 hours. Fibrinogen levels were not different at day 7. Transfusion use and thromboembolic events were similar between arms. All-cause mortality at 28 days was 35.5% (95% CI, 23.8-50.8%) overall, with no difference between arms. CONCLUSIONS: In this trial, early delivery of fibrinogen concentrate within 45 minutes of admission was not feasible. Although evidence points to a key role for fibrinogen in the treatment of major bleeding, researchers need to recognise the challenges of timely delivery in the emergency setting. Future studies must explore barriers to rapid fibrinogen therapy, focusing on methods to reduce time to randomisation, using 'off-the-shelf' fibrinogen therapies (such as extended shelf-life cryoprecipitate held in the emergency department or fibrinogen concentrates with very rapid reconstitution times) and limiting the need for coagulation test-based transfusion triggers. TRIAL REGISTRATION: ISRCTN67540073 . Registered on 5 August 2015

Earnings management and audit quality:stakeholders’ perceptions

This paper examines the perceptions of Libyan Commercial Banks’ (LCBs) stakeholders regarding the role of the external auditor in relation to earnings management (EM). A total of 28 semi-structured interviews were carried out with a range of LCB stakeholders comprising preparers of financial statements, users, regulators and academics. A questionnaire survey of stakeholders which yielded 102 Responses (response rate 53%) was also carried out. A variety of views were held which varied to some extent according to stakeholder group. A widely held perception amongst interviewees was that the auditor has the ability to detect EM practices but may not be able to prevent it. However questionnaire respondents were, in aggregate, more confident of the auditor’s ability to deter EM due to the influence of the audit report. The paper provides insights into stakeholders’ perceptions of the quality of bank audits. The findings are of particular relevance to regulators, and specifically, the Central Bank of Libya. Perceptions of audit quality raise questions about its guidance and regulations especially in connection with audit firm rotation. Perceptions of audit quality, and therefore, of the credibility of financial statements should be of interest to all stakeholders. The importance of the banking sector for society has been amply demonstrated in recent years. A well-functioning audit function is a key component of its regulation. To the best of our knowledge, this paper is the first to examine issues related to banks’ audit quality and audit firm rotation in Libya

How fast do gully headcuts retreat?

© 2016 Elsevier B.V. Gully erosion has important on and off site effects. Therefore, several studies have been conducted over the past decades to quantify gully headcut retreat (GHR) in different environments. Although these led to important site-specific and regional insights, the overall importance of this erosion process or the factors that control it at a global scale remain poorly understood. This study aims to bridge this gap by reviewing research on GHR and conducting a meta-analysis of measured GHR rates worldwide. Through an extensive literature review, GHR rates for 933 individual and actively retreating gullies have been compiled from more than 70 study areas worldwide (comprising a total measuring period of >19 600 years). Each GHR rate was measured through repeated field surveys and/or analyses of aerial photographs over a period of at least one year (maximum: 97 years, median: 17 years). The data show a very large variability, both in terms of gully dimensions (cross-sectional areas ranging between 0.11 and 816 m2 with a median of 4 m2) and volumetric GHR rates (ranging between 0.002 and 47 430 m3 year- 1 with a median of 2.2 m3 year- 1). Linear GHR rates vary between 0.01 and 135 m year- 1 (median: 0.89 m year- 1), while areal GHR rates vary between 0.01 and 3628 m2 year- 1 (median: 3.12 m2 year- 1). An empirical relationship allows estimating volumetric retreat rates from areal retreat rates with acceptable uncertainties. By means of statistical analyses for a subset of 724 gullies with a known contributing area, we explored the factors most relevant in explaining the observed 7 orders of magnitudes of variation in volumetric GHR rates. Results show that measured GHR rates are significantly correlated to the runoff contributing area of the gully (r2 = 0.15) and the rainy day normal (RDN; i.e. the long-term average annual rainfall depth divided by the average number of rainy days; r2 = 0.47). Other factors (e.g. land use or soil type) showed no significant correlation with the observed GHR rates. This may be attributed to the uncertainties associated with accurately quantifying these factors. In addition, available time series data demonstrate that GHR rates are subject to very large year-to-year variations. As a result, average GHR rates measured over short (100%) uncertainties. We integrated our findings into a weighted regression model that simulates the volumetric retreat rate of a gully headcut as a function of upstream drainage area and RDN. When weighing each GHR observation proportional to its measuring period, this model explains 68% of the observed variance in GHR rates at a global scale. For 76% of the monitored gullies, the simulated GHR values deviate less than one order of magnitude from their corresponding observed value. Our model clearly indicates that GHR rates are very sensitive to rainfall intensity. Since these intensities are expected to increase in most areas as a result of climate change, our results suggest that gully erosion worldwide will become more intense and widespread in the following decades. Finally, we discuss research topics that will help to address these challenges

Impact ionization mass spectra of anorthite cosmic dust analogue particles

Anorthite, the Ca-rich end-member of plagioclase feldspar, is a dominant mineral component of the Lunar highlands. Plagioclase feldspar is also found in comets, meteorites and stony asteroids. It is therefore expected to contribute to the population of interplanetary (and circumplanetary) dust grains within the solar system. After coating micron- and submicron-sized grains of Anorthite with a conductive layer of Platinum, the mineral was successfully accelerated to hypervelocity speeds in the Max Planck Institut für Kernphysik’s Van de Graaff accelerator. We present impact ionization mass spectra generated following the impacts of anorthite grains with a prototype mass spectrometer (the Large Area Mass Analyser, LAMA) designed for use in space, and discuss the behavior of the spectra with increasing impact energy. Correlation analysis is used to identify the compositions and sources of cations present in the spectra, enabling the identification of several molecular cations (e.g., CaAlO2, CaSiO2, Ca2AlO3/CaAlSi2O2) which identify anorthite as the progenitor bulk grain material