Response to mTOR inhibition: activity of eIF4E predicts sensitivity in cell lines and acquired changes in eIF4E regulation in breast cancer.

BACKGROUND: Inhibitors of the kinase mTOR, such as rapamycin and everolimus, have been used as cancer therapeutics with limited success since some tumours are resistant. Efforts to establish predictive markers to allow selection of patients with tumours likely to respond have centred on determining phosphorylation states of mTOR or its targets 4E-BP1 and S6K in cancer cells. In an alternative approach we estimated eIF4E activity, a key effector of mTOR function, and tested the hypothesis that eIF4E activity predicts sensitivity to mTOR inhibition in cell lines and in breast tumours. RESULTS: We found a greater than three fold difference in sensitivity of representative colon, lung and breast cell lines to rapamycin. Using an assay to quantify influences of eIF4E on the translational efficiency specified by structured 5'UTRs, we showed that this estimate of eIF4E activity was a significant predictor of rapamycin sensitivity, with higher eIF4E activities indicative of enhanced sensitivity. Surprisingly, non-transformed cell lines were not less sensitive to rapamycin and did not have lower eIF4E activities than cancer lines, suggesting the mTOR/4E-BP1/eIF4E axis is deregulated in these non-transformed cells. In the context of clinical breast cancers, we estimated eIF4E activity by analysing expression of eIF4E and its functional regulators within tumour cells and combining these scores to reflect inhibitory and activating influences on eIF4E. Estimates of eIF4E activity in cancer biopsies taken at diagnosis did not predict sensitivity to 11-14 days of pre-operative everolimus treatment, as assessed by change in tumour cell proliferation from diagnosis to surgical excision. However, higher pre-treatment eIF4E activity was significantly associated with dramatic post-treatment changes in expression of eIF4E and 4E-binding proteins, suggesting that eIF4E is further deregulated in these tumours in response to mTOR inhibition. CONCLUSIONS: Estimates of eIF4E activity predict sensitivity to mTOR inhibition in cell lines but breast tumours with high estimated eIF4E activity gain changes in eIF4E regulation in order to enhance resistance.

Patterns in flowing sand: understanding the physics of granular flow.

Dense granular flows are often unstable and form inhomogeneous structures. Although significant advances have been recently made in understanding simple flows, instabilities of such flows are often not understood. We present experimental and numerical results that show the formation of longitudinal stripes that arise from instability of the uniform flowing state of granular media on a rough inclined plane. The form of the stripes depends critically on the mean density of the flow with a robust form of stripes at high density that consists of fast sliding pluglike regions (stripes) on top of highly agitated boiling material--a configuration reminiscent of the Leidenfrost effect when a droplet of liquid lifted by its vapor is hovering above a hot surface.

Scaling and dynamics of washboard roads.

Granular surfaces subjected to forces due to rolling wheels develop ripples above a critical speed. The resulting pattern, known as washboard or corrugated road, is common on dry unpaved roads. We investigated this phenomenon theoretically and experimentally using laboratory-scale apparatus and beds of dry sand. A thick layer of sand on a circular track was forced by a rolling wheel on an arm whose weight and moment of inertia could be varied. We compared the ripples made by the rolling wheel to those made using a simple inclined plow blade. We investigated the dependence of the critical speed on various parameters and described a scaling argument that leads to a dimensionless ratio, analogous to the hydrodynamic Froude number, which controls the instability. This represents the crossover between conservative dynamic forces and dissipative static forces. Above onset wheel-driven ripples move in the direction of motion of the wheel, but plow-driven ripples move in the reverse direction for a narrow range of Froude numbers.

Persistent northward North Atlantic tropical cyclone track migration over the past five centuries.

Accurately predicting future tropical cyclone risk requires understanding the fundamental controls on tropical cyclone dynamics. Here we present an annually-resolved 450-year reconstruction of western Caribbean tropical cyclone activity developed using a new coupled carbon and oxygen isotope ratio technique in an exceptionally well-dated stalagmite from Belize. Western Caribbean tropical cyclone activity peaked at 1650 A.D., coincident with maximum Little Ice Age cooling, and decreased gradually until the end of the record in 1983. Considered with other reconstructions, the new record suggests that the mean track of Cape Verde tropical cyclones shifted gradually north-eastward from the western Caribbean toward the North American east coast over the last 450 years. Since ~1870 A.D., these shifts were largely driven by anthropogenic greenhouse gas and sulphate aerosol emissions. Our results strongly suggest that future emission scenarios will result in more frequent tropical cyclone impacts on the financial and population centres of the northeastern United States.

Was millennial scale climate change during the Last Glacial triggered by explosive volcanism?

The mechanisms responsible for millennial scale climate change within glacial time intervals are equivocal. Here we show that all eight known radiometrically-dated Tambora-sized or larger NH eruptions over the interval 30 to 80 ka BP are associated with abrupt Greenland cooling (>95% confidence). Additionally, previous research reported a strong statistical correlation between the timing of Southern Hemisphere volcanism and Dansgaard-Oeschger (DO) events (>99% confidence), but did not identify a causative mechanism. Volcanic aerosol-induced asymmetrical hemispheric cooling over the last few hundred years restructured atmospheric circulation in a similar fashion as that associated with Last Glacial millennial-scale shifts (albeit on a smaller scale). We hypothesise that following both recent and Last Glacial NH eruptions, volcanogenic sulphate injections into the stratosphere cooled the NH preferentially, inducing a hemispheric temperature asymmetry that shifted atmospheric circulation cells southward. This resulted in Greenland cooling, Antarctic warming, and a southward shifted ITCZ. However, during the Last Glacial, the initial eruption-induced climate response was prolonged by NH glacier and sea ice expansion, increased NH albedo, AMOC weakening, more NH cooling, and a consequent positive feedback. Conversely, preferential SH cooling following large SH eruptions shifted atmospheric circulation to the north, resulting in the characteristic features of DO events.

Shallow granular flows.

Many processes in geophysical and industrial settings involve the flow of granular materials down a slope. In order to investigate the granular dynamics, we report a series of laboratory experiments conducted by releasing grains at a steady rate from a localized source on a rough inclined plane. Different types of dense granular flow are observed by varying the flow rate at the source and the slope of the inclined plane. The two cases of steady flow confined by levees and the flow of avalanches down the plane are examined. The width of the steady flow increases linearly with the prescribed flow rate, which does not appreciably affect the characteristic depth or surface velocity of the bulk flow. When the flow rate is just below that required for sustaining the steady flow, avalanches are triggered at regular intervals. The avalanches maintain their shape, size, and speed down the inclined plane. We propose a simple model of steady flow that is consistent with our observations and discuss the challenges associated with the theoretical treatment of avalanche dynamics.

Lift and drag forces on an inclined plow moving over a granular surface.

We studied the drag and lift forces acting on an inclined plate while it is dragged on the surface of a granular media, both in experiment and in numerical simulation. In particular, we investigated the influence of the horizontal velocity of the plate and its angle of attack. We show that a steady wedge of grains is moved in front of the plow and that the lift and drag forces are proportional to the weight of this wedge. These constants of proportionality vary with the angle of attack but not (or only weakly) on the velocity. We found a universal effective friction law that accounts for the dependence on all the above-mentioned parameters. The stress and velocity fields are calculated from the numerical simulations and show the existence of a shear band under the wedge and that the pressure is nonhydrostatic. The strongest gradients in stress and shear occur at the base of the plow where the dissipation rate is therefore highest.

Washboard road: the dynamics of granular ripples formed by rolling wheels.

We report laboratory experiments on rippled granular surfaces formed under rolling wheels. Ripples appear above a critical speed and drift slowly in the driving direction. Ripples coarsen as they saturate and exhibit ripple creation and destruction events. All of these effects are captured qualitatively by 2D soft-particle simulations in which a disk rolls over smaller disks in a periodic box. The simulations show that compaction and segregation are inessential to the ripple phenomenon. We describe a simplified scaling model which gives some insight into the mechanism of the instability.