The Peaks and Valleys of Photon Versus Proton Spatially Fractionated Radiotherapy.

Spatially-fractionated radiotherapy (SFRT) delivers high doses to small areas of tumor while sparing adjacent tissue, including intervening disease. In this review, we explore the evolution of SFRT technological advances, contrasting approaches with photon and proton beam radiotherapy. We discuss unique dosimetric considerations and physical properties of SFRT, as well as review the preclinical literature that provides an emerging understanding of biological mechanisms. We emphasize crucial areas of future study and highlight clinical trials that are underway to assess SFRT's safety and efficacy, with a focus on immunotherapeutic synergies. The review concludes with practical considerations for SFRT's clinical application, advocating for strategies that leverage its unique dosimetric and biological properties for improved patient outcomes.

Origins of an intrinsic hippocampal EEG pattern.

Sharp waves (SPWs) are irregular waves that originate in field CA3 and spread throughout the hippocampus when animals are alert but immobile or as a component of the sleep EEG. The work described here used rat hippocampal slices to investigate the factors that initiate SPWs and govern their frequency. Acute transection of the mossy fibers reduced the amplitude but not the frequency of SPWs, suggesting that activity in the dentate gyrus may enhance, but is not essential for, the CA3 waves. However, selective destruction of the granule cells and mossy fibers by in vivo colchicine injections profoundly depressed SPW frequency. Reducing mossy fiber release with an mGluR2 receptor agonist or enhancing it with forskolin respectively depressed or increased the incidence of SPWs. Collectively, these results indicate that SPWs can be triggered by constitutive release from the mossy fibers. The waves were not followed by large after-hyperpolarizing potentials and their frequency was not strongly affected by blockers of various slow potassium channels. Antagonists of GABA-B mediated IPSCs also had little effect on incidence. It appears from these results that the spacing of SPWs is not dictated by slow potentials. However, modeling work suggests that the frequency and variance of large mEPSCs from the mossy boutons can account for the temporal distribution of the waves. Together, these results indicate that constitutive release from the mossy fiber terminal boutons regulates the incidence of SPWs and their contribution to information processing in hippocampus.

Mechanisms of late-onset cognitive decline after early-life stress.

Progressive cognitive deficits that emerge with aging are a result of complex interactions of genetic and environmental factors. Whereas much has been learned about the genetic underpinnings of these disorders, the nature of "acquired" contributing factors, and the mechanisms by which they promote progressive learning and memory dysfunction, remain largely unknown. Here, we demonstrate that a period of early-life "psychological" stress causes late-onset, selective deterioration of both complex behavior and synaptic plasticity: two forms of memory involving the hippocampus, were severely but selectively impaired in middle-aged, but not young adult, rats exposed to fragmented maternal care during the early postnatal period. At the cellular level, disturbances to hippocampal long-term potentiation paralleled the behavioral changes and were accompanied by dendritic atrophy and mossy fiber expansion. These findings constitute the first evidence that a short period of stress early in life can lead to delayed, progressive impairments of synaptic and behavioral measures of hippocampal function, with potential implications to the basis of age-related cognitive disorders in humans.