The HSP90 Inhibitor NVP-AUY922 Radiosensitizes by Abrogation of Homologous Recombination Resulting in Mitotic Entry with Unresolved DNA Damage

Heat shock protein 90 (HSP90) is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies.NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end-point survival (p = <0.0001). NVP-AUY922 was shown to ubiquitously inhibit resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induced a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. Cell cycle analysis indicated that NVP-AUY922 induced aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage due to ubiquitous CHK1 depletion, but resultant downstream cell cycle effects were cell line dependent.These results identify NVP-AUY922 as the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validate it in a clinically relevant in vivo model. Mechanistic analysis at clinically achievable concentrations demonstrated that radiosensitization is mediated by the combinatorial inhibition of cell growth and survival pathways, ubiquitous delay in Rad51-mediated homologous recombination and CHK1-mediated G(2)/M arrest, but that the contribution of cell cycle perturbation to radiosensitization may be cell line specific

Discussion of 'Assessing the Sources of Changes in the Volatility of Real Growth'

business cycles; volatility; inventories; monetary policy; financial innovation; structural policies

Discussion of The Economic Consequences of Oil Shocks: Differences across Countries and Time

oil demand shocks; oil supply shocks; cross-country differences; pass-through; SVAR models

Microstructural and residual stress development due to inertia friction welding in Ti-6246

A thorough investigation has been performed to assess the microstructural properties, mechanical properties (hardness and elastic modulus), and residual stress development in Ti-6Al-2Sn-4Zr-6Mo (Ti-6246) inertia friction welds in the as-welded and postweld heat-treated conditions. It was evident that the thermomechanical deformation in the weld region occurred above the β transus, forming dynamically recrystallized β grains and precipitating acicular α within the β grains, which resulted in a localized hardness increase. In the heat-affected zone, a ghost microstructure of the base metal formed because of the absence of sufficient time for diffusion, resulting in Mo segregation in the prior primary α plates. Energy-dispersive synchrotron X-ray diffraction and neutron diffraction were used to assess the residual stress development in the three principal directions. The variation in the unstrained lattice parameters across the weld regions was established by imposing a stress balance on the axial stress component in the radial direction. It was found that the maximum stresses occurred in the hoop direction, with significantly lower stresses present in the radial and axial directions. The maximum tensile hoop stresses were located at ~4 mm from the weld centerline and not at the dynamically recrystallized β-rich weld zone. This was associated with the α → β phase transformation and the subsequent acicular α precipitation within the region surrounding the weld centerline

Screening a diverse collection of Artemisia annua germplasm accessions for the antimalarial compound, artemisinin

The anti-malarial drug artemisinin is commercially extracted from the medicinal plant Artemisia annua (L.). Here we report the screening of seventy A. annua individuals sourced from around the world, identifying individuals containing > 2% artemisinin, concentrations approximately twice as high as have been previously reported. These extremely high yielding individuals have been maintained as propagational clones, and represent promising parental lines for future A. annua breeding programmes

Enhancement of artemisinin concentration and yield in response to optimization of nitrogen and potassium supply to Artemisia annua

Background and Aims: The resurgence of malaria, particularly in the developing world, is considerable and exacerbated by the development of single-gene multi-drug resistances to chemicals such as chloroquinone. Drug therapies, as recommended by the World Health Organization, now include the use of antimalarial compounds derived from Artemisia annua – in particular, the use of artemisinin-based ingredients. Despite our limited knowledge of its mode of action or biosynthesis there is a need to secure a supply and enhance yields of artemisinin. The present study aims to determine how plant biomass can be enhanced while maximizing artemisinin concentration by understanding the plant’s nutritional requirements for nitrogen and potassium. Methods: Experiments were carried out, the first with differing concentrations of nitrogen, at 6, 31, 56, 106, 206 or 306 mg L21 being applied, while the other differing in potassium concentration (51, 153 or 301 mg L21). Nutrients were supplied in irrigation water to plants in pots and after a growth period biomass production and leaf artemisinin concentration were measured. These data were used to determine optimal nutrient requirements for artemisinin yield. Key Results: Nitrogen nutrition enhanced plant nitrogen concentration and biomass production successively up to 106 mg N L21 for biomass and 206 mg N L21 for leaf nitrogen; further increases in nitrogen had no influence. Artemisinin concentration in dried leaf material, measured by HPLC mass spectroscopy, was maximal at a nitrogen application of 106 mg L21, but declined at higher concentrations. Increasing potassium application from 51 to 153 mg L21 increased total plant biomass, but not at higher applications. Potassium application enhanced leaf potassium concentration, but there was no effect on leaf artemisinin concentration or leaf artemisinin yield. Conclusions: Artemisinin concentration declined beyond an optimal point with increasing plant nitrogen concentration. Maximization of artemisinin yield (amount per plant) requires optimization of plant biomass via control of nitrogen nutrition