A View on Drug Development for Cancer Prevention.

Despite some notable successes, there are still relatively few agents approved for cancer prevention. Here we review progress thus far in the development of medicines for cancer prevention, and we outline some key concepts that could further enable or accelerate drug development for cancer prevention in the future. These are summarized under six key themes: (i) unmet clinical need, (ii) patient identification, (iii) risk stratification, (iv) pharmacological intervention, (v) clinical trials, and (vi) health care policy. These concepts, if successfully realized, may help to increase the number of medicines available for cancer prevention. SIGNIFICANCE: The huge potential public health benefits of preventing cancer, combined with recent advances in the availability of novel early detection technologies and new treatment modalities, has caused us to revisit the opportunities and challenges associated with developing medicines to prevent cancer. Here we review progress in the field of developing medicines to prevent cancer to date, and we present a series of ideas that might help in the development of more medicines to prevent cancer in the future.

The microglia response to electrical overstimulation of the retina imaged under a transparent stimulus electrode.

Objective.We investigated using the morphological response of retinal microglia as indicators of tissue damage from electrical overstimulation by imaging them through an optically transparent stimulus electrode.Approach.To track the microglia, we used a transgenic mouse where the microglia expressed a water soluble green fluorescent protein. The clear stimulus electrode was placed epiretinally on the inner limiting membrane and the microglia layers were imaged using time-lapse confocal microscopy. We examined how the microglia responded both temporally and spatially to local overstimulation of the retinal tissue. Using confocal microscope vertical image stacks, the microglia under the electrode were imaged at 2.5 min intervals. The retina was overstimulated for a 5 min period using 1 ms 749µC cm-2ph-1biphasic current pulses and changes in the microglia morphology were followed for 1 h post stimulation. After the imaging period, a label for cellular damage was applied to the retina.Main results.The microglia response to overstimulation depended on their spatial location relative to the electrode lumen and could result in three different morphological responses. Some microglia were severely injured and became a series of immotile ball-like fluorescent processes. Other microglia survived, and reacted rapidly to the injury by extending filopodia oriented toward the damage zone. This response was seen in inner retinal microglia outside the stimulus electrode edge. A third effect, seen with the deeper outer microglia under the electrode, was a fading of their fluorescent image which appeared to be due to optical scatter caused by overstimulation-induced retinal edema.Significance.The microglial morphological responses to electrical overstimulation injury occur rapidly and can show both direct and indirect effects of the stimulus electrode injury. The microglia injury pattern closely follows models of the electric field distribution under thinly insulated disc electrodes.