Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studies

Background: The mechanisms of action and efficacy of cisplatin and paclitaxel at cell population level are well studied and documented, however the localized spatio-temporal effects of the drugs are less well understood. We explore the emergence of spatially preferential drug efficacy resulting from variations in mechanisms of cell-drug interactions. Methods: 3D spheroids of HeLa-C3 cells were treated with drugs, cisplatin and paclitaxel. This was followed by sectioning and staining of the spheroids to track the spatio-temporal apoptotic effects of the drugs. A mechanistic drug-cell interaction model was developed and simulated to analyse the localized efficacy of these drugs. Results: The outcomes of drug actions on a local cell population was dependant on the interactions between cell repair probability, intracellular drug concentration and cell’s mitosis phase. In spheroids treated with cisplatin, drug induced apoptosis is found to be scattered throughout the volume of the spheroids. In contrast, effect of paclitaxel is found to be preferentially localized along the periphery of the spheroids. Combinatorial treatments of cisplatin and paclitaxel result in varying levels of cell apoptosis based on the scheduling strategy. Conclusions: The preferential action of paclitaxel can be attributed to the cell characteristics of the peripheral population. The model simulations and experimental data show that treatments initiated with paclitaxel are more efficacious due to the cascading of spatial effects of the drugs.Published versio

Geology of the continental margin of Enderby and Mac. Robertson Lands, East Antarctica: Insights from a regional data set

In 2001 and 2002, Australia acquired an integrated geophysical data set over the deep-water continental margin of East Antarctica from west of Enderby Land to offshore from Prydz Bay. The data include approximately 7700 km of high-quality, deep-seismic data with coincident gravity, magnetic and bathymetry data, and 37 non-reversed refraction stations using expendable sonobuoys. Integration of these data with similar quality data recorded by Japan in 1999 allows a new regional interpretation of this sector of the Antarctic margin. This part of the Antarctic continental margin formed during the breakup of the eastern margin of India and East Antarctica, which culminated with the onset of seafloor spreading in the Valanginian. The geology of the Antarctic margin and the adjacent oceanic crust can be divided into distinct east and west sectors by an interpreted crustal boundary at approximately 58° E. Across this boundary, the continent–ocean boundary (COB), defined as the inboard edge of unequivocal oceanic crust, steps outboard from west to east by about 100 km. Structure in the sector west of 58° E is largely controlled by the mixed rift-transform setting. The edge of the onshore Archaean–Proterozoic Napier Complex is downfaulted oceanwards near the shelf edge by at least 6 km and these rocks are interpreted to underlie a rift basin beneath the continental slope. The thickness of rift and pre-rift rocks cannot be accurately determined with the available data, but they appear to be relatively thin. The margin is overlain by a blanket of post-rift sedimentary rocks that are up to 6 km thick beneath the lower continental slope. The COB in this sector is interpreted from the seismic reflection data and potential field modelling to coincide with the base of a basement depression at 8.0–8.5 s two-way time, approximately 170 km oceanwards of the shelf-edge bounding fault system. Oceanic crust in this sector is highly variable in character, from rugged with a relief of more than 1 km over distances of 10–20 km, to rugose with low-amplitude relief set on a long-wavelength undulating basement. The crustal velocity profile appears unusual, with velocities of 7.6–7.95 km s−1 being recorded at several stations at a depth that gives a thickness of crust of only 4 km. If these velocities are from mantle, then the thin crust may be due to the presence of fracture zones. Alternatively, the velocities may be coming from a lower crust that has been heavily altered by the intrusion of mantle rocks. The sector east of 58° E has formed in a normal rifted margin setting, with complexities in the east from the underlying structure of the N–S trending Palaeozoic Lambert Graben. The Napier Complex is downfaulted to depths of 8–10 km beneath the upper continental slope, and the margin rift basin is more than 300 km wide. As in the western sector, the rift-stage rocks are probably relatively thin. This part of the margin is blanketed by post-rift sediments that are up to about 8 km thick. The interpreted COB in the eastern sector is the most prominent boundary in deep water, and typically coincides with a prominent oceanwards step-up in the basement level of up to 1 km. As in the west, the interpretation of this boundary is supported by potential field modelling. The oceanic crust adjacent to the COB in this sector has a highly distinctive character, commonly with (1) a smooth upper surface underlain by short, seaward-dipping flows; (2) a transparent upper crustal layer; (3) a lower crust dominated by dipping high-amplitude reflections that probably reflect intruded or altered shears; (4) a strong reflection Moho, confirmed by seismic refraction modelling; and (5) prominent landward-dipping upper mantle reflections on several adjacent lines. A similar style o f oceanic crust is also found in contemporaneous ocean basins that developed between Greater India and Australia–Antarctica west of Bruce Rise on the Antarctic margin, and along the Cuvier margin of ...H. M. J. Stagg, J. B. Colwel, N. G. Direen, P. E. O’Brien, G. Bernardel, I. Borissova, B. J. Brown, T. Ishirar