Degradation and adsorption of synthetic DNA water tracers in environmental matrices.

Synthetic DNA tracers are gaining interest as tools for tracking contamination pathways and hydraulic connections in surface water and groundwater systems. However, few quantitative data exist that describe DNA tracer degradation and adsorption in environmental matrices. We undertook laboratory experiments to quantify the degradation of multiple double-stranded DNA tracers in stream water, groundwater, and domestic and dairy-shed effluent, and adsorption to stream sediments, soils, coastal sand aquifer media and alluvial sandy gravel aquifer media.

Impact of a computerized decision support tool deployed in two intensive care units on acute kidney injury progression and guideline compliance: a prospective observational study.

Background: Acute kidney injury (AKI) affects a large proportion of the critically ill and is associated with worse patient outcomes. Early identification of AKI can lead to earlier initiation of supportive therapy and better management. In this study, we evaluate the impact of computerized AKI decision support tool integrated with the critical care clinical information system (CCIS) on patient outcomes.

A 2-step synthesis of Combretastatin A-4 and derivatives as potent tubulin assembly inhibitors.

A series of combretastatin derivatives were designed and synthesised by a two-step stereoselective synthesis by use of Wittig olefination followed by Suzuki cross-coupling. Interestingly, all new compounds (2a-2i) showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, 2a, 2b and 2e were the most active across three cancer cell lines.

Assessing changes in nitrogen contamination in groundwater using water aging: Waikato River, New Zealand.

Groundwater and surface water contamination by nitrogen can produce serious health issues particularly regarding the contraction of methemoglobinemia in infants; prevention of this disorder is a main reason for regulating drinking water quality in New Zealand. To assist the management of water quality in the Upper Waikato Catchment in the light of growing intensification of nitrogen producing land uses, a regional groundwater flow and contamination transport model was developed to assess probable future nitrogen concentrations. Calibration of the steady state model was achieved with a root mean square error of 4.

Water tracking in surface water, groundwater and soils using free and alginate-chitosan encapsulated synthetic DNA tracers.

Investigating contamination pathways and hydraulic connections in complex hydrological systems will benefit greatly from multi-tracer approaches. The use of non-toxic synthetic DNA tracers is promising, because unlimited numbers of tracers, each with a unique DNA identifier, could be used concurrently and detected at extremely low concentrations. This study aimed to develop multiple synthetic DNA tracers as free molecules and encapsulated within microparticles of biocompatible and biodegradable alginate and chitosan, and to validate their field utility in different systems.

Achieving unbiased predictions of national-scale groundwater redox conditions via data oversampling and statistical learning.

An important policy consideration for integrated land and water management is to understand the spatial distribution of nitrate attenuation in the groundwater system, for which redox condition is the key indicator. This paper proposes a methodology to accommodate the computational demands of large datasets, and presents national-scale predictions of groundwater redox class for New Zealand. Our approach applies statistical learning methods to relate the redox class determined on groundwater samples to spatially varying attributes.

The effects of denitrification parameterization and potential benefits of spatially targeted regulation for the reduction of N-discharges from agriculture.

Diffuse nitrate leaching from agricultural areas is a major environmental problem in many parts of the world. Understanding where in a catchment nitrate is removed is key for designing effective land use management strategies that protect water quality, while minimizing the impact on economic development. In this study we assess the effects of spatially targeted nitrate leaching regulation in a basin with limited knowledge of the complexity of chemical heterogeneity.

A baseline assessment of emerging organic contaminants in New Zealand groundwater.

Emerging organic contaminants (EOCs) are manufactured compounds, used for a range of purposes, that are a rising concern for freshwater quality, human and aquatic health. Their occurrence in groundwater has been demonstrated in several international surveys. We conducted the first baseline survey on EOC occurrence in New Zealand groundwater, using a wide-screening approach (723 compounds) and a novel stratified to mean residence time (MRT) randomised design to inform future monitoring.

Tubulin-binding dibenz[c,e]oxepines: Part 2. Structural variation and biological evaluation as tumour vasculature disrupting agents.

5,7-Dihydro-3,9,10,11-tetramethoxybenz[c,e]oxepin-4-ol 1, prepared from a dibenzyl ether precursor via Pd-catalysed intramolecular direct arylation, possesses broad-spectrum in vitro cytotoxicity towards various tumour cell lines, and induces vascular shutdown, necrosis and growth delay in tumour xenografts in mice at sub-toxic doses. The biological properties of 1 and related compounds can be attributed to their ability to inhibit microtubule assembly at the micromolar level, by binding reversibly to the same site of the tubulin αβ-heterodimer as colchicine 2 and the allocolchinol, N-acetylcolchinol 4.

Rates of organ donation in a UK tertiary cardiac arrest centre following out-of-hospital cardiac arrest.

Aim: To ascertain the rate of successful organ donation (OD) within patients who sustained an out of hospital cardiac arrest (OHCA) with initial return of spontaneous circulation (ROSC) and survival to hospital admission, but whom subsequently do not survive to hospital discharge.

Methods: A retrospective audit of ambulance service and hospital databases from January 2010 to January 2015 was undertaken in a United Kingdom tertiary-referral regional cardiac arrest centre. Crude denominator data for cardiac arrests was obtained from the regional ambulance service; the ICU database was interrogated for OHCA patient admissions and outcomes.

Three-dimensional imaging and uptake of the anticancer drug combretastatin in cell spheroids and photoisomerization in gels with multiphoton excitation.

The uptake of E -combretastatins, potential prodrugs of the anticancer Z -isomers, into multicellular spheroids has been imaged by intrinsic fluorescence in three dimensions using two-photon excited fluorescence lifetime imaging with 625-nm ultrafast femtosecond laser pulses. Uptake is initially observed at the spheroid periphery but extends to the spheroid core within 30 min. Using agarose gels as a three-dimensional model, the conversion of Z(trans)→E(cis) via two-photon photoisomerization is demonstrated and the location of this photochemical process may be precisely selected within the micron scale in all three dimensions at depths up to almost 2 mm.

Anticancer phototherapy using activation of E-combretastatins by two-photon-induced isomerization.

The photoisomerization of relatively nontoxic E-combretastatins to clinically active Z-isomers is shown to occur in solution through both one- and two-photon excitations at 340 and 625 nm, respectively. The photoisomerization is also demonstrated to induce mammalian cell death by a two-photon absorption process at 625 nm. Unlike conventional photodynamic therapy (PDT), the mechanism of photoisomerization is oxygen-independent and active in hypoxic environments such as in tumors.

Novel cyanocombretastatins as potent tubulin polymerisation inhibitors.

A series of novel cyanocombretastatins bearing a 3,4,5-trimethoxyphenyl moiety combined with a variety of substituted phenyl rings, were synthesised and their antitumour activity was evaluated. The Z-cyanocombretastatins were synthesised in a one-step protocol in high purity and yield. Fluoro, bromo, iodo, and derivatives with boronic acid and an ethyne function at meta position of the B ring were synthesised.

Fluorescence lifetime imaging of E-combretastatin uptake and distribution in live mammalian cells.

To investigate within live mammalian cells the uptake and disposition of combretastatins, fluorescence lifetime imaging was used with two-photon excitation (2PE). Combretastatin A4 (CA4) and analogues are potential anticancer drugs due to their ability to inhibit angiogenesis. E(trans)-combretastatins are considerably less active than the Z(cis)-combretastatins proposed for clinical use.

Tubulin-binding dibenz[c,e]oxepines as colchinol analogues for targeting tumour vasculature.

Various methoxy- and hydroxy-substituted dibenz[c,e]oxepines were prepared via the copper(I)-induced coupling of ether-tethered arylstannanes or the dehydrative cyclisation of 1,1'-biphenyl-2,2'-dimethanols, assembled using the Ullmann cross-coupling of ortho-bromoaryl carbonyl compounds. The dibenzoxepines were screened for their ability to inhibit tubulin polymerisation and the in vitro growth of K562 human chronic myelogenous leukemia cells. The most active was 5,7-dihydro-3,9,10,11-tetramethoxydibenz[c,e]oxepin-4-ol, whose tubulin inhibitory and cytotoxicity (IC(50)) values were 1 μM and 40 nM, respectively.

Synthesis and biological evaluation of 2- and 3-aminobenzo[b]thiophene derivatives as antimitotic agents and inhibitors of tubulin polymerization.

Two new series of inhibitors of tubulin polymerization based on the 2-amino-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene molecular skeleton and its 3-amino positional isomer were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell cycle effects. Although many more 3-amino derivatives have been synthesized so far, the most promising compound in this series was 2-amino-6-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene, which inhibits cancer cell growth at subnanomolar concentrations and interacts strongly with tubulin by binding to the colchicine site.

Synthesis and evaluation of double bond substituted combretastatins.

A series of combretastatins substituted with epoxides, amides and small alkyl groups has been synthesised and evaluated for cytotoxicity and their ability to inhibit the assembly of tubulin. The methyl and ethyl substituted phenols 36, 44 have shown potent antimitotic effects whilst exhibiting reduced cytotoxicity.

Functional comparison of annexin V analogues labeled indirectly and directly with iodine-124.

We are interested in imaging cell death in vivo using annexin V radiolabeled with (124)I. In this study, [(124)I]4IB-annexin V and [(124)I]4IB-ovalbumin were made using [(124)I]N-hydroxysuccinimidyl-4-iodobenzoate prepared by iododestannylation of N-hydroxysuccinimidyl-4-(tributylstannyl)benzoate. [(124)I]4IB-annexin V binds to phosphatidylserine-coated microtiter plates and apoptotic Jurkat cells and accumulates in hepatic apoptotic lesions in mice treated with anti-Fas antibody, while [(124)I]4IB-ovalbumin does not.

Hydraulic constraints on the performance of a groundwater denitrification wall for nitrate removal from shallow groundwater.

Denitrification walls are a practical approach for decreasing non-point source pollution of surface waters. They are constructed by digging a trench perpendicular to groundwater flow and mixing the aquifer material with organic matter, such as sawdust, which acts as a carbon source to stimulate denitrification. For efficient functioning, walls need to be permeable to groundwater flow.

Tubulin and microtubules as targets for anticancer drugs.

Microtubules are intracellular organelles formed from the protein tubulin. These organelles have a number of essential cellular functions including chromosome segregation, the maintenance of cell shape, transport, motility, and organelle distribution. Drugs that affect the tubulin-microtubule equilibrium (taxol, vinca alkaloids) are effective anticancer drugs.

The total synthesis of an aurone isolated from Uvaria hamiltonii: aurones and flavones as anticancer agents.

The naturally occurring aurone 1, isolated from Uvaria hamiltonii, and a series of aurones analogues based structurally on known tubulin binding agents were prepared and evaluated for anticancer activity. Aurone 20 was the most active (IC(50) K562 50 nM) and caused significant G2/M cell-cycle arrest.

Structural requirements for the interaction of combretastatins with tubulin: how important is the trimethoxy unit?

A series of combretastatins possessing both a trimethoxy unit and other substituents on ring A has been synthesised and tested for cytotoxicity and their ability to interact with the protein tubulin. All previous studies have indicated that the trimethoxy unit is essential for interaction with tubulin. The studies herein show that molecules possessing functionalities other than trimethoxy can also interact with tubulin.