The mechanisms linking deposits of insoluble amyloid fibrils to the debilitating neuronal cell death characteristic of neurodegenerative diseases remain enigmatic. Recent findings implicate transiently formed intermediates of mature amyloid fibrils as the principal toxic agent. Hence, determining which intermediate aggregates represent on-pathway precursors or off-pathway side branches is critical for understanding amyloid self-assembly, and for devising therapeutic approaches targeting relevant toxic species. We examined amyloid fibril self-assembly in acidic solutions, using the model protein hen egg-white lysozyme. Combining in situ dynamic light scattering with calibrated atomic-force microscopy, we monitored the nucleation and growth kinetics of multiple transient aggregate species, and characterized both their morphologies and physical dimensions. Upon incubation at elevated temperatures, uniformly sized oligomers formed at a constant rate. After a lag period of several hours, protofibrils spontaneously nucleated. The nucleation kinetics of protofibrils and the tight match of their widths and heights with those of oligomers imply that protofibrils both nucleated and grew via oligomer fusion. After reaching several hundred nanometers in length, protofibrils assembled into mature fibrils. Overall, the amyloid fibril assembly of lysozyme followed a strict hierarchical aggregation pathway, with amyloid monomers, oligomers, and protofibrils forming on-pathway intermediates for assembly into successively more complex structures.
Even for a well-commissioned TPS, comparison metrics show better agreement on average to MGDR than to TPS on the arbitrary-shaped measurable "patient." The method requires no more accelerator time than standard QA, while producing more clinically relevant information. Validation in a heterogeneous thoracic phantom is under way, as is the ultimate application of 4D MGDR to virtual motion studies.
Introduction of the improved calibration methodology, enabled by a robust virtual inclinometer algorithm, improves the accuracy of the dosimeter's absolute dose measurements. With our treatment planning and delivery chain, gamma analysis passing rates for the VMAT plans based on the AAPM TG-119 report are expected to be above 91% and average at about 95% level for γ(3%/3 mm) with the local dose-error normalization. This stringent comparison methodology is more indicative of the true VMAT system commissioning accuracy compared to the often quoted dose-error normalization to a single high value.
MAPCHECK analysis demonstrates high passing rates with the stringent γ(2%/2 mm) and local normalization criteria combination. The geometry of the ARCCHECK array creates a stress test for the FFF TPS model because of the shallow depth of the entrance diodes and large air cavity. Hence, the ARCCHECK γ-analysis passing rates are lower than with the MAPCHECK, while still on par with TG-119.
The 6 MV flattening filter‐free (FFF) beam has been commissioned for use with compensators at our institution. This novel combination promises advantages in mitigating tumor motion due to the reduced treatment time made possible by the greatly increased dose rate of the FFF beam. Given the different energy spectrum of the FFF beam and the beam hardening effect of the compensator, the accuracy of the treatment planning system (TPS) model in the presence of low‐density heterogeneities cannot be assumed. Therefore, inhomogeneity correction factors (ICF) for an FFF beam attenuated by brass slabs were measured and compared to the TPS calculations in this work. The ICF is the ratio of the point dose in the presence of inhomogeneity to the dose in the same point in a homogeneous medium. The ICFs were measured with an ion chamber at a number of points in a flat water‐equivalent slab phantom containing a 7.5 cm deep heterogeneity (air or 0.27 g/cm3 wood). Comparisons for the FFF beam were carried out for the field sizes from 5×5 to 20×20 cm2 with the brass slabs ranging from 0 to 5 cm in thickness. For a low‐density wood heterogeneity in a slab phantom, with the exception of the point 1 cm beyond the proximal buildup interface, the TPS handles the inhomogeneity correction with the brass‐filtered 6 MV FFF beam at the requisite 2% error level. The combinations of field sizes and compensator thicknesses when the error exceeds 2% (2.6% maximum) are not likely to be experienced in clinical practice. In terms of heterogeneity corrections, the beam model is adequate for clinical use.PACS number: 87.56.ng
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