Abstract
High-frequency ultrasound (~20 MHz) techniques were investigated using in vitro and ex vivo models to determine whether alterations in chromatin structure are responsible for ultrasound backscatter changes in biological samples. Acute myeloid leukemia (AML) cells and their isolated nuclei were exposed to various chromatin altering treatments. These included 10 different ionic environments, DNA cleaving and unfolding agents, as well as DNA condensing agents. Raw radiofrequency (RF) data was used to generate quantitative ultrasound parameters from spectral and form factor analyses. Chromatin structure was evaluated using electron microscopy. Results indicated that trends in quantitative ultrasound parameters mirrored trends in biophysical chromatin structure parameters. In general, higher ordered states of chromatin compaction resulted in increases to ultrasound paramaters of midband fit, spectral intercept, and estimated scatterer concentration, while samples with decondensed forms of chromatin followed an opposite trend. Experiments with isolated nuclei demonstrated that chromatin changes alone were sufficient to account for these observations. Experiments with ex vivo samples indicated similar effects of chromatin structure changes. The results obtained in this research provide a mechanistic explanation for ultrasound investigations studying scattering from cells and tissues undergoing biological processes affecting chromatin.
Highlights
The determination of tumor response to treatment is based on the Response Evaluation Criteria in Solid Tumors (RECIST) parameters
Transmission electron microscopy (TEM) indicated that sodium chloride concentration had a significant effect on the structure of chromatin (Figure 1A)
As ultrasound data was acquired from non-fixed samples, size trends from light microscopy images are more accurate of physiological response
Summary
The determination of tumor response to treatment is based on the Response Evaluation Criteria in Solid Tumors (RECIST) parameters. Several functional imaging techniques have been developed such as PET/CT and MRI to assess tumor response. These modalities are often limited by their cost, repeated use of radioactive material (for PET/CT), and their primary use to measure standard anatomical features. Ultrasound is an imaging technique that does not utilize ionizing radiation, is low cost, label-free, features real-time imaging, and provides relatively high-resolution images. These qualities make it a superb candidate technique for multiple imaging sessions per patient. The term “high-frequency” will refer to the use of ultrasound probes with central frequencies of 20 MHz or greater, as used in previous studies [5, 6]
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