Intracellular Water Lifetime as a Tumor Biomarker to Monitor Doxorubicin Treatment via FFC-Relaxometry in a Breast Cancer Model

This study aims to explore whether the water exchange rate constants in tumor cells can act as a hallmark of pathology status and a reporter of therapeutic outcomes. It has been shown, using 4T1 cell cultures and murine allografts, that an early assessment of the therapeutic effect of doxorubicin can be detected through changes in the cellular water efflux rate constant kio. The latter has been estimated by analyzing the magnetization recovery curve in standard NMR T1 measurements when there is a marked difference in the proton relaxation rate constants (R1) between the intra- and the extra-cellular compartments. In cellular studies, T1 measurements were carried out on a relaxometer working at 0.5 T, and the required difference in R1 between the two compartments was achieved via the addition of a paramagnetic agent into the extracellular compartment. For in-vivo experiments, the large difference in the R1 values of the two-compartments was achieved when the T1 measurements were carried out at low magnetic field strengths. This task was accomplished using a Fast Field Cycling (FFC) relaxometer that was properly modified to host a mouse in its probe head. The decrease in kio upon the administration of doxorubicin is the result of the decreased activity of Na+/K+-ATPase, as shown in an independent test on the cellular uptake of Rb ions. The results reported herein suggest that kio can be considered a non-invasive, early and predictive biomarker for the identification of responsive patients immediately from the first doxorubicin treatment.

Temperature monitoring through nanoparticle-activated proton relaxation for magnetic resonance imaging application

An effect of temperature on the proton relaxation times in aqueous suspensions of solid-state nanoparticles (NPs) is comparatively investigated for the NPs’ composition varied from pure silicon (Si) with natural isotope content to Si with iron impurities as well as for Si NPs enriched with Si-29 isotope. For all types of the investigated NPs both the longitudinal and transverse relaxation times become shorter compared with that for pure water because of the interaction of electron spin centers in those NPs with nuclear spins of the protons in water molecules. The obtained results allow us to evaluate the temperature sensitivity of NP-based systems for their biomedical applications in magnetic resonance imaging (MRI).

Low-Field NMR Relaxometry for Intraoperative Tumour Margin Assessment in Breast-Conserving Surgery

As conserving surgery is routinely applied for the treatment of early-stage breast cancer, the need for new technology to improve intraoperative margin assessment has become increasingly important. In this study, the potential of fast field-cycling 1H-NMR relaxometry as a new diagnostic tool was evaluated. The technique allows the determination of the tissue proton relaxation rates (R1), as a function of the applied magnetic field, which are affected by the changes in the composition of the mammary gland tissue occurring during the development of neoplasia. The study involved 104 small tissue samples obtained from surgical specimens destined for histopathology. It was found that a good accuracy in margin assessment, i.e., a sensitivity of 92% and a specificity of 85%, can be achieved by using two quantifiers, namely (i) the slope of the line joining the R1 values measured at 0.02 and 1 MHz and (ii) the sum of the R1 values measured at 0.39 and 1 MHz. The method is fast, and it does not rely on the expertise of a pathologist or cytologist. The obtained results suggest that a simplified, low-cost, automated instrument might compete well with the currently available tools in margin assessment.

Quantum properties of dielectric losses in nanometer layers of solid dielectrics at ultra-low temperatures

Using the methods of quasi-classical kinetic theory, continuum electrodynamics, and non-relativistic quantum theory, we construct and study the quantum kinetic equation of proton relaxation, which, together with the Poisson operator equation describes the mechanism of diffusion tunneling transport of hydrogen ions (protons) in the potential field of a crystal lattice perturbed by a polarizing field (quantum diffusion polarization) in crystals with hydrogen bonds. Using the apparatus of the density matrix (statistical matrix), by complete quantum-mechanical averaging of the polarization operator, studies are carried out of the experimental value of the polarization of the dielectric, as a function of the parameters of the external electric field (amplitude, frequency of electromotive force) and temperature. When calculating the equilibrium density matrix for an ensemble of basic relaxers (hydrogen ions), the proton-proton and proton-phonon interactions are not taken into account, and the Hamilton operator for the phonon subsystem is assumed to be a numerical constant for a given crystal under given experimental conditions (calculated by computer method as a parameter for comparing the theory with the experiment). The influence of the phonon subsystem on the kinetics of the relaxation process is reduced to a weak spatially homogeneous force field acting on protons moving in the field of the main forces of hydrogen bonds. The Hamilton of the proton subsystem is constructed for the model of an ideal proton gas in equilibrium with the ionic subsystem of the crystal lattice, and the equilibrium statistical operator of the proton subsystem is written using the Boltzmann quantum statistics. Theoretically, the size effects are found to be manifested in shifts of the low-temperature (50–100 K) maxima of the dielectric loss angle tangent towards ultra-low temperatures (4–25 K) with a decrease in the amplitudes of the maxima by 3-4 orders of magnitude, with a reduction in the thickness of the crystal layer from 1–10 microns to 1–10 nm. The effect of anomalous displacements of low-temperature maxima, which is explained by the abnormally high quantum transparency of the potential barrier for protons (0.8-0.9) in thin films of a crystal with hydrogen bonds (1-10 nm), causes, near the temperatures of the shifted maxima of dielectric losses (4–25 K), a quasi-ferroelectric state, which is also characterized by abnormally high values of the real component of the complete dielectric permittivity (2.5–3.5millions).

Synergistic effects in cross-linked blends of ion-conducting PEO-/PPO-based unsaturated polyesters

Ion-conductive unsaturated polyesters (UP) were synthesised from poly(ethylene oxide) (Xn = 9, 13, 22, 90) or poly(propylene oxide) (Xn = 7, 13, 20, 34, 68) and maleic anhydride. Subsequently, the polyesters were doped with LiClO4 and cross-linked with styrene using a redox initiator. For PEO-based polyesters, the minimum resistivity is found at an O/Li+ molar ratio of 50/1. In contrast, more lithium is required to reach the minimum when using PPO (O/Li+ = 10/1). Unlike the PEO-based polyesters, cross-linking of the PPO types gives rise to decreasing resistivities at increasing molecular weight. This correlates well with the transverse proton relaxation time determined by single-sided NMR, which is an indicator of the chain mobility. The cross-linking reaction of these UP with styrene exactly follows the predictions based on the copolymerisation parameters and is, therefore, not dependent on the ratio of styrene to UP double bonds as previously reported. Due to the opposing effects of the molecular weight on the ion conductivity of PEO- and PPO-based UP, 1:1 blends of short-chain PPO and long-chain PEO polyesters were cross-linked with styrene. The resulting networks showed a resistivity of 4 kΩ m (σ = 2.5∙10−4 S∙m−1), which is 5 times lower than the pure PEO and 3 times lower than the pure PPO materials.

Hydrogels for Three-Dimensional Ionizing-Radiation Dosimetry

Radiation-sensitive gels are among the most recent and promising developments for radiation therapy (RT) dosimetry. RT dosimetry has the twofold goal of ensuring the quality of the treatment and the radiation protection of the patient. Benchmark dosimetry for acceptance testing and commissioning of RT systems is still based on ionization chambers. However, even the smallest chambers cannot resolve the steep dose gradients of up to 30–50% per mm generated with the most advanced techniques. While a multitude of systems based, e.g., on luminescence, silicon diodes and radiochromic materials have been developed, they do not allow the truly continuous 3D dose measurements offered by radiation-sensitive gels. The gels are tissue equivalent, so they also serve as phantoms, and their response is largely independent of radiation quality and dose rate. Some of them are infused with ferrous sulfate and rely on the radiation-induced oxidation of ferrous ions to ferric ions (Fricke-gels). Other formulations consist of monomers dispersed in a gelatinous medium (Polyacrylamide gels) and rely on radiation-induced polymerization, which creates a stable polymer structure. In both gel types, irradiation causes changes in proton relaxation rates that are proportional to locally absorbed dose and can be imaged using magnetic resonance imaging (MRI). Changes in color and/or opacification of the gels also occur upon irradiation, allowing the use of optical tomography techniques. In this work, we review both Fricke and polyacrylamide gels with emphasis on their chemical and physical properties and on their applications for radiation dosimetry.

Inspecting Insulin Products Using Water Proton NMR. I. Noninvasive vs Invasive Inspection

Background: There is a clear need to transition from batch-level to vial/syringe/pen-level quality control of biologic drugs, such as insulin. This could be achieved only by noninvasive and quantitative inspection technologies that maintain the integrity of the drug product. Methods: Four insulin products for patient self-injection presented as prefilled pens have been noninvasively and quantitatively inspected using the water proton NMR technology. The inspection output is the water proton relaxation rate R2(1H2O), a continuous numerical variable rather than binary pass/fail. Results: Ten pens of each product were inspected. R2(1H2O) displays insignificant variation among the 10 pens of each product, suggesting good insulin content uniformity in the inspected pens. It is also shown that transferring the insulin solution out of and then back into the insulin pen caused significant change in R2(1H2O), presumably due to exposure to O2 in air. Conclusions: Water proton NMR can noninvasively and quantitatively inspect insulin pens. wNMR can confirm product content uniformity, but not absolute content. Its sensitivity to sample transferring provides a way to detect drug product tampering. This opens the possibility of inspecting every pen/vial/syringe by manufacturers and end-users.

Survey of water proton longitudinal relaxation in liver in vivo

Objective To determine the variability, and preferred values, for normal liver longitudinal water proton relaxation rate R1 in the published literature. Methods Values of mean R1 and between-subject variance were obtained from literature searching. Weighted means were fitted to a heuristic and to a model. Results After exclusions, 116 publications (143 studies) remained, representing apparently normal liver in 3392 humans, 99 mice and 249 rats. Seventeen field strengths were included between 0.04 T and 9.4 T. Older studies tended to report higher between-subject coefficients of variation (CoV), but for studies published since 1992, the median between-subject CoV was 7.4%, and in half of those studies, measured R1 deviated from model by 8.0% or less. Discussion The within-study between-subject CoV incorporates repeatability error and true between-subject variation. Between-study variation also incorporates between-population variation, together with bias from interactions between methodology and physiology. While quantitative relaxometry ultimately requires validation with phantoms and analysis of propagation of errors, this survey allows investigators to compare their own R1 and variability values with the range of existing literature.

Single-sided Time Domain-Nuclear Magnetic Resonance to Study the Effect of Cell Membrane Electroporation on the Water Mobility in Vegetal Tissues

This paper presents the characteristics of potato and apple tissues, with/out electroporation, by Time Domain-Nuclear Magnetic Resonance (TD-NMR). A portable TD-NMR was used to measure the proton relaxation time, T2, and the changes in the cells due to molecular water mobility of potato tubers,-NMR to identify the modifications that occurred at the cell level involving water molecules mobility in potato tubers and apple tissues after the electroporation treatment and compared with non-electroporated ones. The comparisons with normal potato and apple tissue and preliminary measurements in bulk were performed. Samples were also analyzed in terms of conductivity of the tissue and microscopic morphology. The results indicate that the electroporation process effect is identified with a variation of the peak position in T2 distribution, associated with sub-cell modifications.

Cardiac MRI T1 mapping and extracellular volume application in hypertrophic cardiomyopathy

Background Hypertrophic cardiomyopathy (HCM) is one of the commonest inheritable cardiac disorders. Being a global disease with diffuse myocardial fibrosis, it has a wide range of adverse outcomes ending with sudden cardiac death. Cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) has become a reference standard for visualization of focal myocardial fibrosis. In the setting of less severe or more diffuse fibrosis, LGE is unlikely to reveal the presence of abnormal tissue given the lack of normal myocardium as a reference. Direct measurement of myocardial T1 time (T1 mapping) may improve these methodologic problems of LGE CMR in the setting of diffuse retention of gadolinium-based contrast material. So, we aim at this study to evaluate the clinical application of CMRI native and post-contrast T1 relaxation in assessing diffuse myocardial fibrosis non-invasively in hypertrophic cardiomyopathy. Results There was a significant difference between the percent of fibrosis detected by measuring the extracellular volume percent compared to that detected by LGE, with the former detecting fibrosis in 45.1% of the examined cardiac segments while the latter showed fibrosis in 20.9% of the cardiac segments. Also, measuring the native T1 values showed evidence of fibrosis in about 32.2% of the cardiac segments superseding the percent of fibrosis detected using the LGE alone. The ejection fraction percent showed a negative correlation with the left ventricular mass with a correlation coefficient value of − 0.139 where both interstitial and replacement fibrosis play an important role in the pathophysiology of diastolic dysfunction as well as impairing the myocardial contractility. Also, in cases of obstruction, the extracellular volume (ECV) is more likely to increase in the basal anterior and antero-septal segments as well as the basal inferior segment with P values 0.015, 0.013, and 0.045, respectively. Conclusion Diffuse fibrosis was found to be difficult to be distinguished using LGE. The unique ability of CMR to use proton relaxation times provides a quantitative measurement to detect increased interstitial volume in diffuse myocardial fibrosis. Moreover, it showed that in cases of obstruction, the segments exposed to the highest pressure are more vulnerable to the fibrotic process denoting a relationship between the pressure gradient and the adverse myocardial remodeling.