Validation of CARE kV automated tube voltage selection for PET-CT: PET quantification and CT radiation dose reduction in phantoms.

BACKGROUND: Applied tube voltage (kilovolts, kV) and tube current (milliampere seconds, mAs) affect CT radiation dose and image quality and should be optimised for the individual patient. CARE kV determines the kV and mAs providing the lowest dose to the patient, whilst maintaining user-defined reference image quality. Given that kV changes affect CT values which are used to obtain attenuation maps, the aim was to evaluate the effect of kV changes on PET quantification and CT radiation dose using phantoms. METHOD: Four phantoms ('Lungman', 'Lungman plus fat', 'Esser' and 'NEMA image quality' (NEMA IQ)) containing F-18 sources underwent 1 PET and 5 CT scans, with CARE kV on (automatic kV selection and mAs modulation) and in semi mode with specified tube voltages of 140, 120, 100 and 80 kV (mAs modulation only). A CARE kV image quality reference of 120 kV/50 mAs was used. Impact on PET quantification was determined by comparing measured activity concentrations for PET reconstructions from different CT scans with the reconstruction using the 120 kV reference, and dose (DLP, CTDIvol) differences calculated by comparing doses from all kV settings with the 120 kV reference. RESULTS: CARE kV-determined optimal tube voltage and CARE kV 'on' dose (DLP) savings compared with the 120 kV reference were: Lungman, 100 kV, 2.0%; Lungman plus fat, 120 kV, 0%; Esser, 100 kV, 9.3%; NEMA IQ, 100 kV, 3.4%. Using tube voltages in CARE kV 'semi' mode which were not advised by CARE kV 'on' resulted in dose increases ≤ 65% compared with the 120 kV reference (greatest difference Lungman plus fat, 80 kV). Clinically insignificant differences in PET activity quantification of up to 0.7% (Lungman, 100 kV, mean measured activity concentration) were observed when using the optimal tube voltage advised by CARE kV. Differences in PET quantification of up to 4.0% (Lungman, 140 kV, maximum measured activity concentration) were found over the full selection of tube voltages in semi mode, with the greatest differences seen at the most suboptimal kV for each phantom. However, most differences were within 1%. CONCLUSIONS: CARE kV on can provide CT radiation dose savings without concern over changes in PET quantification.

Theory for the stability and regulation of epigenetic landscapes.

Cells can often choose among several stably heritable phenotypes. Examples are the expressions of genes in eukaryotic cells where long chromosomal regions can adopt persistent and heritable silenced or active states that may be associated with positive feedback in dynamic modification of nucleosomes. We generalize this mechanism in terms of bistability associated with valleys in an epigenetic landscape. A transfer matrix method was used to rigorously follow the system through the disruptive process of cell division. This combined treatment of noisy dynamics both between and during cell division provides an efficient way to calculate the stability of alternative states in a broad range of epigenetic systems.

Ultrasensitive gene regulation by positive feedback loops in nucleosome modification.

Eukaryotic transcription involves the synergistic interaction of many different proteins. However, the question remains how eukaryotic promoters achieve ultrasensitive or threshold responses to changes in the concentration or activity of a single transcription factor (TF). We show theoretically that by recruiting a histone-modifying enzyme, a TF binding non-cooperatively to a single site can change the balance between opposing positive feedback loops in histone modification to produce a large change in gene expression in response to a small change in concentration of the TF. This mechanism can also generate bistable promoter responses, allowing a gene to be on in some cells and off in others, despite the cells being in identical conditions. In addition, the system provides a simple means by which the activities of many TFs could be integrated at a promoter.

Theoretical analysis of epigenetic cell memory by nucleosome modification.

Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Such epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of the states are thought to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. We developed a simplified stochastic model for dynamic nucleosome modification based on the silent mating-type region of the yeast Schizosaccharomyces pombe. We show that the mechanism can give strong bistability that is resistant both to high noise due to random gain or loss of nucleosome modifications and to random partitioning upon DNA replication. However, robust bistability required: (1) cooperativity, the activity of more than one modified nucleosome, in the modification reactions and (2) that nucleosomes occasionally stimulate modification beyond their neighbor nucleosomes, arguing against a simple continuous spreading of nucleosome modification.