A population pharmacokinetic model of AT9283 in adults and children to predict the maximum tolerated dose in children with leukaemia

Aims AT9283 is used to treat patients with solid tumours and patients with leukaemia. However, the maximum tolerated dose (MTD) for children with leukaemia remains unknown due to early termination of the Phase I trial. The aim of this study was to develop a population model of AT9283 to describe the pharmacokinetics in adults and children and to estimate the MTD in children with leukaemia. Methods Data from Phase I dose‐escalation studies in adults and children were used to build a population pharmacokinetic model (NONMEM v7.3). Potential covariates investigated included body weight, body surface area (BSA), glomerular filtration rate (GFR), age and sex. Model‐derived area under the concentration–time curve was used to investigate the relationship between dose and exposure in adults and children. Results The plasma concentrations of AT9283 (n = 1770) from 92 patients (53 adults, 39 children) were used to build a two‐compartment model with all pharmacokinetic parameters scaled using body weight. Renal function (GFR), but not BSA, was a significant covariate for the clearance of AT9283. In children with leukaemia (median weight 16 kg), a flat dose of 500 mg 72 h–1 provided similar drug exposures at the MTD as the adult population. The estimated MTD for children with leukaemia, therefore, is 30 mg kg−1 72 h–1. Conclusion For adults, GFR was a significant predictor of clearance, whilst body‐weight based dosing was more useful than BSA in determining the drug exposure in children. The MTD was estimated to be 30 mg kg−1 72 h–1 children with leukaemia

The peculiar debris disk of HD 111520 as resolved by the Gemini Planet Imager

This is the author accepted manuscript. The final version is available from American Astronomical Society / IOP Publishing via the DOI in this record.Using the Gemini Planet Imager, we have resolved the circumstellar debris disk around HD 111520 at a projected range of ∼30-100 AU in both total and polarized H-band intensity. The disk is seen edge-on at a position angle of 165° along the spine of emission. A slight inclination and asymmetric warp are covariant and alter the interpretation of the observed disk emission. We employ three point-spread function subtraction methods to reduce the stellar glare and instrumental artifacts to confirm that there is a roughly 2:1 brightness asymmetry between the NW and SE extension. This specific feature makes HD 111520 the most extreme example of asymmetric debris disks observed in scattered light among similar highly inclined systems, such as HD 15115 and HD 106906. We further identify a tentative localized brightness enhancement and scale height enhancement associated with the disk at ∼40 AU away from the star on the SE extension. We also find that the fractional polarization rises from 10% to 40% from 0.″5 to 0.″8 from the star. The combination of large brightness asymmetry and symmetric polarization fraction leads us to believe that an azimuthal dust density variation is causing the observed asymmetry.Z.H.D. and B.C.M. acknowledge a Discovery Grant and Accelerator Supplement from the Natural Science and Engineering Research Council of Canada. Supported by NSF grants AST-0909188, AST-1313718 (J.R.G., J.J.W., P.G.K.), AST-141378 (G.D., M.F.), and AST-1411868 (K.F., J.L.P., A.R., K.W.D.). Supported by NASA grants NNX15AD95G/NEXSS, NNX14AJ80G, and NNX11AD21G (J.R.G., J.J.W., P.G.K.)

The peculiar debris disk of HD 111520 as resolved by the Gemini Planet Imager

This is the author accepted manuscript. The final version is available from American Astronomical Society / IOP Publishing via the DOI in this record.Using the Gemini Planet Imager, we have resolved the circumstellar debris disk around HD 111520 at a projected range of ∼30-100 AU in both total and polarized H-band intensity. The disk is seen edge-on at a position angle of 165° along the spine of emission. A slight inclination and asymmetric warp are covariant and alter the interpretation of the observed disk emission. We employ three point-spread function subtraction methods to reduce the stellar glare and instrumental artifacts to confirm that there is a roughly 2:1 brightness asymmetry between the NW and SE extension. This specific feature makes HD 111520 the most extreme example of asymmetric debris disks observed in scattered light among similar highly inclined systems, such as HD 15115 and HD 106906. We further identify a tentative localized brightness enhancement and scale height enhancement associated with the disk at ∼40 AU away from the star on the SE extension. We also find that the fractional polarization rises from 10% to 40% from 0.″5 to 0.″8 from the star. The combination of large brightness asymmetry and symmetric polarization fraction leads us to believe that an azimuthal dust density variation is causing the observed asymmetry.Z.H.D. and B.C.M. acknowledge a Discovery Grant and Accelerator Supplement from the Natural Science and Engineering Research Council of Canada. Supported by NSF grants AST-0909188, AST-1313718 (J.R.G., J.J.W., P.G.K.), AST-141378 (G.D., M.F.), and AST-1411868 (K.F., J.L.P., A.R., K.W.D.). Supported by NASA grants NNX15AD95G/NEXSS, NNX14AJ80G, and NNX11AD21G (J.R.G., J.J.W., P.G.K.)

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Plasmodium falciparum Gametocyte Carriage Is Associated with Subsequent Plasmodium vivax Relapse after Treatment

Mixed P. falciparum/P. vivax infections are common in southeast Asia. When patients with P. falciparum malaria are treated and followed for several weeks, a significant proportion will develop P. vivax malaria. In a combined analysis of 243 patients recruited to two malaria treatment trials in western Cambodia, 20/43 (47%) of those with P. falciparum gametocytes on admission developed P. vivax malaria by Day 28 of follow-up. The presence of Pf gametocytes on an initial blood smear was associated with a 3.5-fold greater rate of vivax parasitemia post-treatment (IRR = 3.5, 95% CI 2.0–6.0, p<0.001). The increased rate of post-treatment P. vivax infection persisted when correlates of exposure and immunity such as a history of malaria, male gender, and age were controlled for (IRR = 3.0, 95% CI 1.9–4.7, p<0.001). Polymerase chain reaction (PCR) confirmed that only a low proportion of subjects (5/55 or 9.1%) who developed vivax during follow-up had detectable Pv parasites in the peripheral blood at baseline. Molecular detection of falciparum gametocytes by reverse transcriptase PCR in a subset of patients strengthened the observed association, while PCR detection of Pv parasitemia at follow-up was similar to microscopy results. These findings suggest that the majority of vivax infections arising after treatment of falciparum malaria originate from relapsing liver-stage parasites. In settings such as western Cambodia, the presence of both sexual and asexual forms of P. falciparum on blood smear at presentation with acute falciparum malaria serves as a marker for possible occult P. vivax coinfection and subsequent relapse. These patients may benefit from empiric treatment with an 8-aminoquinolone such as primaquine

Assessment of the effect of betaine on p16 and c-myc DNA methylation and mRNA expression in a chemical induced rat liver cancer model

<p>Abstract</p> <p>Background</p> <p>The development and progression of liver cancer may involve abnormal changes in DNA methylation, which lead to the activation of certain proto-oncogenes, such as <it>c-myc</it>, as well as the inactivation of certain tumor suppressors, such as <it>p16</it>. Betaine, as an active methyl-donor, maintains normal DNA methylation patterns. However, there are few investigations on the protective effect of betaine in hepatocarcinogenesis.</p> <p>Methods</p> <p>Four groups of rats were given diethylinitrosamine (DEN) and fed with AIN-93G diets supplemented with 0, 10, 20 or 40 g betaine/kg (model, 1%, 2%, and 4% betaine, respectively), while the control group, received no DEN, fed with AIN-93G diet. Eight or 15 weeks later, the expression of <it>p16 </it>and <it>c-myc </it>mRNA was examined by Real-time PCR (Q-PCR). The DNA methylation status within the <it>p16 </it>and <it>c-myc </it>promoter was analyzed using methylation-specific PCR.</p> <p>Results</p> <p>Compared with the model group, numbers and areas of glutathione S-transferase placental form (GST-p)-positive foci were decreased in the livers of the rats treated with betaine (<it>P < 0.05</it>). Although the frequency of <it>p16 </it>promoter methylation in livers of the four DEN-fed groups appeared to increase, there is no difference among these groups after 8 or 15 weeks (<it>P > 0.05</it>). Betaine supplementation attenuated the down-regulation of <it>p16 </it>and inhibited the up-regulation of <it>c-myc </it>induced by DEN in a dose-dependent manner (<it>P </it>< 0.01). Meanwhile, increases in levels of malondialdehyde (MDA) and glutathione S-transferase (GST) in model, 2% and 4% betaine groups were observed (<it>P < 0.05</it>). Finally, enhanced antioxidative capacity (T-AOC) was observed in both the 2% and 4% betaine groups.</p> <p>Conclusion</p> <p>Our data suggest that betaine attenuates DEN-induced damage in rat liver and reverses DEN-induced changes in mRNA levels.</p

Pyronaridine-Artesunate versus Chloroquine in Patients with Acute Plasmodium vivax Malaria: A Randomized, Double-Blind, Non-Inferiority Trial

BACKGROUND: New antimalarials are needed for P. vivax and P. falciparum malaria. This study compared the efficacy and safety of pyronaridine-artesunate with that of chloroquine for the treatment of uncomplicated P. vivax malaria. METHODS AND FINDINGS: This phase III randomized, double-blind, non-inferiority trial included five centers across Cambodia, Thailand, India, and Indonesia. In a double-dummy design, patients (aged >3-≤ 60 years) with microscopically confirmed P. vivax mono-infection were randomized (1:1) to receive pyronaridine-artesunate (target dose 7.2:2.4 mg/kg to 13.8:4.6 mg/kg) or chloroquine (standard dose) once daily for three days. Each treatment group included 228 randomized patients. Outcomes for the primary endpoint, Day-14 cure rate in the per-protocol population, were 99.5%, (217/218; 95%CI 97.5, 100) with pyronaridine-artesunate and 100% (209/209; 95%CI 98.3, 100) with chloroquine. Pyronaridine was non-inferior to chloroquine: treatment difference -0.5% (95%CI -2.6, 1.4), i.e., the lower limit of the 2-sided 95%CI for the treatment difference was greater than -10%. Pyronaridine-artesunate cure rates were non-inferior to chloroquine for Days 21, 28, 35 and 42. Parasite clearance time was shorter with pyronaridine-artesunate (median 23.0 h) versus chloroquine (32.0 h; p<0.0001), as was fever clearance time (median 15.9 h and 23.8 h, respectively; p = 0.0017). Kaplan-Meier estimates of post-baseline P. falciparum infection incidence until Day 42 were 2.5% with pyronaridine-artesunate, 6.1% with chloroquine (p = 0.048, log-rank test). Post-baseline P. vivax or P. falciparum infection incidence until Day 42 was 6.8% and 12.4%, respectively (p = 0.022, log rank test). There were no deaths. Adverse events occurred in 92/228 (40.4%) patients with pyronaridine-artesunate and 72/228 (31.6%) with chloroquine. Mild and transient increases in hepatic enzymes were observed for pyronaridine-artesunate. CONCLUSION: Pyronaridine-artesunate efficacy in acute uncomplicated P. vivax malaria was at least that of chloroquine. As pyronaridine-artesunate is also efficacious against P. falciparum malaria, this combination has potential utility as a global antimalarial drug. TRIAL REGISTRATION: Clinicaltrials.gov NCT00440999

CEO Profile and Earnings Quality

This paper introduces the PSCORE, which aggregates nine personal characteristics of chief executive officers (CEOs), to signal the quality of earnings. The PSCORE is a composite score based on publicly available data on CEOs. The study reports strong positive relationships between the PSCORE and two different proxies for earnings quality, (i) discretionary accruals and (ii) financial statement errors, measured by deviations of the first digits of figures reported in financial statements from those expected by Benford’s Law. Further analyses indicate that the relationships between the PSCORE and the proxies for earnings quality become more pronounced when CEOs have high equity-based compensation incentives. The findings have some implications for practitioners