Chris J. Ottley

A Phase i clinical study of cisplatin-incorporated polymeric micelles (NC-6004) in patients with solid tumours

Background:On the basis of preclinical studies of NC-6004, a cisplatin-incorporated micellar formulation, we hypothesised that NC-6004 could show lower toxicity than cisplatin and show greater anti-tumour activity in phase I study.Methods:A total of 17 patients were recruited in a range of advanced solid tumour types. NC-6004 was administered intravenously (i.v.) every 3 weeks. The dose escalation started at 10 mg m−2 and was increased up to 120 mg m−2 according to the accelerated titration method and modified Fibonacci method.Results:One dose-limiting toxicity (DLT) occurred in a patient who was given 90 mg m−2 of NC-6004, otherwise any significant cisplatin-related toxicity was not observed or generally mild toxicity was observed. Despite the implementation of post-hydration and pre-medication regimen, renal impairment and hypersensitivity reactions still developed at 120 mg m−2, which led to the conclusion that the maximum tolerated dose was 120 mg m−2, and the recommended dose was 90 mg m−2, although DLT was not defined as per protocol. Stable disease was observed in seven patients. The maximum concentration and area under the concentration–time curve of ultrafilterable platinum at 120 mg m−2 NC-6004 were 34-fold smaller and 8.5-fold larger, respectively, than those for cisplatin.Conclusion:The delayed and sustained release of cisplatin after i.v. administration contributes to the low toxicity of NC-6004.

Chemical catalysis of nitrate reduction by iron (II)

Experiments have been conducted to investigate the chemical reduction of nitrate under conditions relevant to the often low organic carbon environment of groundwaters. At pH 8 and 20 ± 2°C, in the presence of Cu(II), NO3− was chemically reduced by Fe(II) to NH4+ with an average stoichiometric liberation of 8 protons. The rate of the reaction systematically increased with pH in the range pH 7–8.5. The half-life for nitrate reduction, t1/2, was inversely related to the total molar copper concentration, [CuT], by the equation log t1/2 = −1.35 log [CuT] −2.616, for all measured values of t1/2 from 23 min to 15 days. At the Cu(II) concentrations used of 7 × 10−6 −10−3 M, Cu was present mainly as a solid phase, either adsorbed to the surfaces of precipitated iron oxides or as a saturated solid. It is this solid phase copper rather than CU2+ in solution which is catalytically active. Neither magnetite, which was formed as a product of the reaction, nor freshly prepared lepidocrocite catalysed the reaction, but goethite did. Although traces of oxygen accelerated the reaction, at higher partial pressures (>0.01 atm) the reduction of nitrate was inhibited, probably due to competition between NO3− and O2 for Fe(II). Appreciable catalytic effects were also observed for solid phase forms of Ag(I), Cd(H), Ni(H), Hg(II), and Pb(II). Mn(II) enhanced the rate slightly, and there was evidence for slow abiotic reduction in the absence of any added metal catalysts. These results suggest that the chemical reduction of nitrate at catalytic concentrations and temperatures appropriate to groundwater conditions is feasible on a timescale of months to years.

The spatial distribution and particle size of some inorganic nitrogen, sulphur and chlorine species over the North Sea

The use of filter packs and a cascade impactor during a series of research cruises in the southern area of the North Sea has yielded detailed spatial distribution patterns of aerosol concentrations, Cl−, NO3−, SO42−1 and NH4+ and gaseous concentrations, HCl, HNO3 and NH3. The overall distribution of the atmospheric concentrations closely parallels published modelled results for metallic species. The chemical transformations of these aerosols and gases are investigated together with their interactions with the seasalt aerosol. Aerosol chloride loss is greatest in the more polluted areas, whilst concentrations products of NH3 with HNO3 and HCl appear insufficient to sustain the existence of NH4NO3 and NH4Cl. Nitrate is associated predominantly with larger particles and appears to be present substantially as a surface coating on marine aerosol. The total dry deposition input for nitrogen species is calculated for the southern sector with extrapolation to the whole of the North Sea, using particle size weighted deposition velocities of 0.63 and 0.21 cm s−1 for NO3−1 and NH4+, respectively, and literature-derived values for the gaseous constituents. Finally the use of air-mass back trajectories illustrates the role of source regions in influencing the chemical composition of the North Sea atmosphere.

Estimation of the net air-sea flux of ammonia over the southern bight of the North Sea

Abstract Measurements of airborne gaseous ammonia and total dissolved ammonium in sea water determined on cruises on the North Sea have been used to calculate net fluxes of ammonia between air and sea. The system is finely balanced with the majority of net fluxes from air to sea, but some periods occur when the sea becomes a net source of ammonia in air. Examination of the field data suggests that the main factor determining the direction of flux is the airborne ammonia concentration, which when elevated causes ammonia deposition to the sea. It is calculated that ammonia deposition to the southern bight of the North Sea (below 56°N) amounts to 7.6 x 103 tonnes N per year, about one-half of an earlier upper limit estimate. Comparison with studies from the Pacific Ocean, in which the sea acts as a source of atmospheric ammonia, reveals that the major differences arise from much higher concentrations of airborne ammonia in the North Sea atmosphere caused by advection from adjacent land.

Lapita migrants in The Pacific's oldest cemetery: isotopic analysis at Teouma, Vanuatu

Teouma, an archaeological site on Efate Island, Vanuatu, features the earliest cemetery yet discovered of the colonizers of Remote Oceania, from the late second millennium B.C. In order to investigate potential migration of seventeen human individuals, we measured isotopes of strontium (87Sr/86Sr), oxygen (δ18O), and carbon (δ13C), as well as barium (Ba) and strontium (Sr) concentrations, in tooth enamel from skeletons excavated in the first two field seasons. The majority of individuals cluster with similar isotope and Ba/Sr ratios, consistent with a diet of marine resources supplemented with plants grown on the local basaltic soils. Four outliers, with distinctive 87Sr/86Sr and δ18O, are probably immigrants, three of which were buried in a distinctive position (supine, with the head to the south) with higher Ba/Sr and δ13C, consistent with a terrestrial, nonlocal diet. Among the probable immigrants was a male buried with the crania of three of the locally raised individuals on his chest.

Curcumin ameliorates oxaliplatin-induced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo†

The aims of this study were to determine potency of oxaliplatin in combination with curcumin in oxaliplatin‐resistant cell lines in vitro and to evaluate the efficacy of a novel curcumin formulation (Meriva®) alone and in combination with oxaliplatin in colorectal tumor‐bearing mice, exploring relevant pharmacodynamic markers in vivo. Oxaliplatin‐resistant HCT116 p53wt and p53−/− cell lines were generated, and the effects of oxaliplatin in combination with curcumin on resistance‐ and proliferation‐associated proteins investigated. Eighty nude mice were implanted with HCT116 p53wt colorectal cancer cells before randomization into the following treatment groups: control; Meriva only; oxaliplatin only; Meriva + oxaliplatin. Tumor volume was assessed, as was the expression of Ki‐67, cleaved caspase‐3 and Notch‐1. Curcumin in combination with oxaliplatin was able to decrease proliferative capacity of oxaliplatin‐resistant p53 wildtype and p53−/− cell lines more effectively than oxaliplatin alone. It also decreased markers associated with proliferation. After 21 days of treatment in the xenograft model, the order of efficacy was combination > Meriva > oxaliplatin > control. The decrease in tumor volume when compared to vehicle‐treated animals was 53, 35 and 16%, respectively. Ki‐67 and Notch‐1 immunoreactivity was decreased by the combination when compared to vehicle‐treated animals, with cleaved caspase‐3 rising by 4.4‐fold. Meriva did not adversely affect the DNA‐platinating ability of oxaliplatin. Curcumin enhanced the cytotoxicity of oxaliplatin in models of oxaliplatin resistance in vitro. In vivo, Meriva greatly enhanced oxaliplatin efficacy, without affecting the mode of action of oxaliplatin. Addition of formulated curcumin to oxaliplatin‐based chemotherapy regimens has the potential for clinical benefit.

Highly saline fluids from a subducting slab as the source for fluid-rich diamonds

The infiltration of fluids into continental lithospheric mantle is a key mechanism for controlling abrupt changes in the chemical and physical properties of the lithospheric root, as well as diamond formation, yet the origin and composition of the fluids involved are still poorly constrained. Such fluids are trapped within diamonds when they form and so diamonds provide a unique means of directly characterizing the fluids that percolate through the deep continental lithospheric mantle. Here we show a clear chemical evolutionary trend, identifying saline fluids as parental to silicic and carbonatitic deep mantle melts, in diamonds from the Northwest Territories, Canada. Fluid–rock interaction along with in situ melting cause compositional transitions, as the saline fluids traverse mixed peridotite–eclogite lithosphere. Moreover, the chemistry of the parental saline fluids—especially their strontium isotopic compositions—and the timing of host diamond formation suggest that a subducting Mesozoic plate under western North America is the source of the fluids. Our results imply a strong association between subduction, mantle metasomatism and fluid-rich diamond formation, emphasizing the importance of subduction-derived fluids in affecting the composition of the deep lithospheric mantle.

A comparison of the predictions of an eulerian atmospheric transport — chemistry model with experimental measurements over the North sea

Abstract A very comprehensive set of airborne concentration measurement for gaseous HNO 3 and NH 3 and particulate NH 4 + , SO 4 2− and NO 3 − collected abroad R.R.S. Challenger over the Southern Bight of the North Sea has been compared with the predictions of an Eulerian atmospheric transport — chemistry model. Comparison of time-averaged concentrations and temporal variations shows generally excellent agreement between measurement and model predictions. It is concluded that, given the difficulties of making airborne concentration measurements over the Sea, the model provides a reliable and cost-effective means of estimating pollutant concentrations.

Sr isotope analysis of bird feathers by TIMS: a tool to trace bird migration paths and breeding sites

Here we present a methodology to analyse 87Sr/86Sr isotope ratios in bird feathers with very low Sr concentration using ultra-low blank ion-exchange chemistry combined with thermal ionisation mass spectrometry. For this study, Sedge Warbler (Acrocephalus schoenobaenus) feathers were used from four different locations within Europe. Prior to analyses, dust particles from the feathers’ surface were removed with nitrogen gas. The shaft and the vane parts of the feather were analysed separately. Generally, the vane had higher trace element abundances compared to the shaft. The vane contained between 3 ng and 12 ng of Sr and the shaft between 0.5 ng and 3 ng of Sr. Due to the small amount of Sr in the feathers, small loads (0.5–12 ng Sr) of international standard NBS 987 were analysed for 87Sr/86Sr isotope ratios giving an average of 0.710263 ± 0.000013 (2σ) (n = 177) and an external reproducibility below 0.002%. The average 88Sr beam intensities for all the shaft analyses were 0.79 V while for the vane analyses it was 2.7 V, consistent with the measured Sr contents of the feather shafts and vanes. The 87Sr/86Sr isotope ratios of the vane were more precise than the shaft with 2 SD internal precision of 0.0026% and 0.053%, respectively. However, the precision was adequate for resolving Sr isotope variations between localities. The 87Sr/86Sr isotope ratios of the cleaned Sedge Warbler feathers varied geographically and were indicative of the different geology in the locations where the feathers were grown.

Atmospheric dry deposition flux of metallic species to the North Sea

Abstract Air sampling on a series of 10 research cruises on the North Sea (south of 56°N) has yielded detailed spatial distributions of atmospheric metal concentrations, Al, Ca, Cd, Cu, Fe, Mg, Na, Pb and Zn which closely parallel the results of earlier published models. Air mass back trajectory analysis demonstrates the strong influence which source region may have upon the elemental composition of the North Sea atmosphere. A cascade impactor designed to collect efficiently large as well as small aerosol has produced detailed size distributions from which mass weighted deposition velocity estimates have been produced (Al, 0.33; Cd, 0.24; Cu, 0.44; Fe, 0.30; Pb, 0.13; Zn, 0.30 cm s −1 ) enabling estimates for the dry deposition flux to the study area to be made. Extrapolation of these data to the whole of the North Sea yields dry deposition flux estimates (Cd, 33; Cu, 350; Pb, 370; Zn, 2640 tonnes yr −1 ) which are in some instances substantially lower than those previously reported, but nevertheless represent a significant pathway for metallic species to enter this marine environment. The size distributions show the clear dominance that large aerosol has upon the overall dry deposition flux. Flux estimates are thus highly sensitive to the sampling of this large aerosol component, and to assumptions made regarding the sea surface as a source of giant trace metal-enriched particles which act only as a means of recycling marine metals.