A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Purpose: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials.
Experimental design: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules.
Results: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma.
Conclusions: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.

Mechanisms of Disease: specialized interstitial cells of the urinary tract--an assessment of current knowledge.

Scientists interested in the smooth muscles of the urinary tract, and their control, have recently been studying cells in the interstitium of tissues that express the c-kit antigen (Kit(+) cells). These cells have morphologic features that are reminiscent of the well-described pacemaker cells in the gut, the interstitial cells of Cajal (ICC). The spontaneous contractile behavior of muscles in the urinary tract varies widely, and it is clear that urinary tract Kit(+) interstitial cells cannot be playing an identical role to that played by the ICC in the gut. Nevertheless, there is increasing evidence that they do play a role in modulating the contractile behavior of adjacent smooth muscle, and might also be involved in mediating neural control. This review outlines the properties of ICC in the gut, and gives an account of the discovery of cells in the interstitium of the main components of the urinary tract. The physiologic properties of such cells and the functional implications of their presence are discussed, with particular reference to the bladder. In this organ, Kit(+) cells are found under the lamina propria, where they might interact with the urothelium and with sensory nerves, and also between and within the smooth-muscle bundles. Confocal microscopy and calcium imaging are being used to assess the physiology of ICC and their interactions with smooth muscles. Differences in the numbers of ICC are seen in smooth muscle specimens obtained from patients with various pathologies; in particular, bladder overactivity is associated with increased numbers of these cells.

The Galactic metallicity gradient

We have previously published intermediate to hi,oh resolution spectroscopic observations of approximately 80 early B-type main-sequence stars situated in 19 Galactic open clusters/associations with Galactocentric distances distributed over 6 less than or equal to R-g less than or equal to 18 kpc. This current study collates and re-analyses these equivalent- width datasets using LTE and non-LTE model atmosphere techniques, in order to determine the stellar atmospheric parameters and abundance estimates for C, N, O, Mg, Al and Si. The latter should be representative of the present-day Galactic interstellar medium. Our extensive observational dataset permits the identification of sub-samples of stars with similar atmospheric parameters and of homogeneous subsets of lines. As such, this investigation represents the most extensive and systematic study of its kind to date. We conclude that the distribution of light elements (CI O, Mg & Si) in the Galactic disk can be represented by a linear, radial gradient of -0.07 +/- 0.01 dex kpc(-1) Our results for nitrogen and oxygen viz. (-0.09 +/- 0.01 dex kpc(-1) and -0.067 +/- 0.008 dex kpc(-1)) are in excellent agreement with that found from the study of HII regions. We have also examined our datasets for evidence of an abrupt discontinuity in the metallicity of the Galactic disk near a Galactocentric distance of 10 kpc (see Twarog et al. 1997). However, there is no evidence to suggest that our data would be better fitted with a two-zone model. Moreover, we observe a N/O gradient of -0.04 +/- 0.02 dex kpc(-1) which is consistent with that found for other spiral galaxies (Vila- Costas gr Edmunds 1993).

Investigations on the adsorption of acidic gases using activated dolomite

In this work activated dolomite adsorption was investigated for removal of acidic gaseous pollutants. Charring was found to be an effective method for the activation of dolomite. This thermal processing resulted in partial decomposition, yielding a calcite and magnesium oxide structure. Adsorbents were produced over a range of char temperatures (750, 800 and 850 °C) and char times (1–8 h). The surface properties and the adsorption capability of raw and thermally treated dolomite sorbents were investigated using porosimetry, SEM and XRD. The sorbates individually investigated were CO2 and NO2. Volumetric equilibrium isotherm determinations were produced in order to quantify sorbate capacity on the various sorbents. The equilibrium data were successfully described using the Freundlich isotherm model. Despite relatively low surface area characteristics of the activated dolomite, there was a high capacity for the acidic gas sorbates investigated, showing a maximum of 12.6 mmol/g (554 mg/g) for CO2 adsorption and 9.93 mmol/g (457 mg/g) for NO2 adsorption. Potentially the most cost effective result from the work concerns the adsorptive capacity for the naturally occurring material, which gave a capacity of 9.71 mmol/g (427 mg/g) for CO2 adsorption and 4.18 mmol/g (193 mg/g) for NO2 adsorption. These results indicate that dolomitic sorbents are potentially cost effective materials for acidic gases adsorption.

Stereoselective reductase-catalysed deoxygenation of sulfoxides in aerobic and anaerobic bacteria

Direct and indirect evidence, Of unexpected stereoselective reductase-catalysed deoxygenations of sulfoxides, was found. The deoxygenations proceeded simultaneously, with the expected dioxygenase-catalysed asymmetric sulfoxidation of sulfides, during some biotransformations with the aerobic bacterium Pseudomonas putida UV4. Stereoselective reductase-catalysed asymmetric deoxygenation of racemic alkylaryl, dialkyl and phenolic sulfoxides was observed, without evidence of the reverse sulfoxidation reaction, using anaerobic bacterial strains. A purified dimethyl sulfoxide reductase, obtained from the intact cells of the anaerobic bacterium Citrobacter braakii DMSO 11, yielded, from the corresponding racemates, enantiopure alkylaryl sulfoxide and thiosulfinate samples.

The impact and recovery of asteroid 2008 TC3

In the absence of a firm link between individual meteorites and their asteroidal parent bodies, asteroids are typically characterized only by their light reflection properties, and grouped accordingly into classes. On 6 October 2008, a small asteroid was discovered with a flat reflectance spectrum in the 554-995nm wavelength range, and designated 2008 TC3 (refs 4-6). It subsequently hit the Earth. Because it exploded at 37km altitude, no macroscopic fragments were expected to survive. Here we report that a dedicated search along the approach trajectory recovered 47 meteorites, fragments of a single body named Almahata Sitta, with a total mass of 3.95kg. Analysis of one of these meteorites shows it to be an achondrite, a polymict ureilite, anomalous in its class: ultra-fine-grained and porous, with large carbonaceous grains. The combined asteroid and meteorite reflectance spectra identify the asteroid as F class, now firmly linked to dark carbon-rich anomalous ureilites, a material so fragile it was not previously represented in meteorite collections.

Effect of corrosion of reinforcement on the mechanical behaviour of highly corroded RC beams

This paper describes an experimental investigation of the behaviour of corroded reinforced concrete beams. These have been stored in a chloride environment for a period of 26 years under service loading so as to be representative of real structural and environmental conditions. The configuration and the widths of the cracks in the two seriously corroded short-span beams were depicted carefully, and then the beams were tested until failure by a three-point loading system. Another two beams of the same age but without corrosion were also tested as control specimens. A short span arrangement was chosen to investigate any effect of a reduction in the area and bond strength of the reinforcement on shear capacity. The relationship of load and deflection was recorded so as to better understand the mechanical behaviour of the corroded beams, together with the slip of the tensile bars. The corrosion maps and the loss of area of the tensile bars were also described after having extracted the corroded bars from the concrete beams. Tensile tests of the main longitudinal bars were also carried out. The residual mechanical behaviour of the beams is discussed in terms of the experimental results and the cracking maps. The results show that the corrosion of the reinforcement in the beams induced by chloride has a very important effect on the mechanical behaviour of the short-span beams, as loss of cross-sectional area and bond strength have a very significant effect on the bending capacity.