BiTE secretion from in situ-programmed myeloid cells results in tumor-retained pharmacology.

Bispecific T-Cell Engagers (BiTEs) are effective at inducing remission in hematologic cancers, but their use in solid tumors has been challenging due to their extreme potency and on-target, off-tumor toxicities in healthy tissue. Their deployment against solid tumors is further complicated by insufficient drug penetration, a hostile tumor microenvironment, and immune escape. To address these challenges, we developed targeted nanocarriers that can deliver in vitro-transcribed mRNA encoding BiTEs to host myeloid cells - a cell type that is actively recruited into the tumor microenvironment. We demonstrate in an immunocompetent mouse model of ovarian cancer, that infusion of these nanoparticles directs BiTE expression to tumor sites, which reshapes the microenvironment from suppressive to permissive and triggers disease regression without systemic toxicity. In contrast, conventional injections of recombinant BiTE protein at doses required to achieve anti-tumor activity, induced systemic inflammatory responses and severe tissue damage in all treated animals. Implemented in the clinic, this in situ gene therapy could enable physicians - with a single therapeutic - to safely target tumor antigen that would otherwise not be druggable due to the risks of on-target toxicity and, at the same time, reset the tumor milieu to boost key mediators of antitumor immune responses.

Correction to: MRI assessment of the thigh musculature in dermatomyositis and healthy subjects using diffusion tensor imaging, intravoxel incoherent motion and dynamic DTI.

The original version of this article, published on 04 June 2018, unfortunately contained a mistake.

Health-related parental indicators and their association with healthy weight and overweight/obese children's physical activity.

BACKGROUND: Although it is accepted that parents play a key role in forming children's health behaviours, differences in parent-child physical activity (PA) have not previously been analysed simultaneously in random samples of families with non-overweight and overweight to obese preschool and school-aged children. This study answers the question which of the health-related parental indicators (daily step count (SC), screen time (ST), and weight status and participation in organized leisure-time PA) help their children achieve the step count recommendations. METHODS: A nationally representative sample comprising 834 families including 1564 parent-child dyads who wore the Yamax Digiwalker SW-200 pedometer for at least 8 h a day on at least four weekdays and both weekend days and completed a family log book (anthropometric parameters, SC, and ST). Logistic regression analyses were used to investigate whether parental achievement of the daily SC recommendation (10,000 SC/day), non-excessive ST (< 2 h/day), weight status, and active participation in organized PA were associated with children's achievement of their daily SC (11,500 SC/day for pre-schoolers and 13,000/11,000 SC/day for school-aged boys/girls). RESULTS: While living in a family with non-overweight parents helps children achieve the daily SC recommendation (mothers in the model: OR = 3.50, 95% CI = 2.29-5.34, p < 0.001; fathers in the model: OR = 2.41, 95% CI = 1.37-4.26, p < 0.01) regardless of their age category, gender, or ST, for families with overweight/obese children, only the mother's achievement of the SC recommendations and non-excessive ST significantly (p < 0.05) increase the odds of their children reaching the daily SC recommendation. The active participation of children in organized leisure-time PA increases the odds of all children achieving the daily SC recommendations (OR = 1.80-2.85); however, for overweight/obese children this remains non-significant. The participation of parents in organized leisure-time PA does not have a significant relationship to the odds of their overweight/obese or non-overweight children achieving the daily SC recommendations. CONCLUSIONS: The mother's health-related behaviours (PA and ST) significantly affect the level of PA of overweight/obese preschool and school-aged children. PA enhancement programmes for overweight/obese children cannot rely solely on the active participation of children in organized leisure-time PA; they also need to take other family-based PA, especially at weekends, into account.

MRI assessment of the thigh musculature in dermatomyositis and healthy subjects using diffusion tensor imaging, intravoxel incoherent motion and dynamic DTI.

INTRODUCTION: Dermatomyositis (DM) is an idiopathic inflammatory myopathy involving severe debilitation in need of diagnostics. We evaluated the proximal lower extremity musculature with diffusion tensor imaging (DTI), intravoxel incoherent motion (IVIM) and dynamic DTI in DM patients and controls and compared with standard clinical workup. METHODS: In this IRB-approved, HIPAA-compliant study with written informed consent, anatomical, Dixon fat/water and diffusion imaging were collected in bilateral thigh MRI of 22 controls and 27 DM patients in a 3T scanner. Compartments were scored on T1/T2 scales. Single voxel dynamic DTI metrics in quadriceps before and after 3-min leg exercise were measured. Spearman rank correlation and mixed model analysis of variance/covariance (ANOVA/ANCOVA) were used to correlate with T1 and T2 scores and to compare patients with controls. RESULTS: DM patients showed significantly lower pseudo-diffusion and volume in quadriceps than controls. All subjects showed significant correlation between T1 score and signal-weighted fat fraction; tissue diffusion and pseudo-diffusion varied significantly with T1 and T2 score in patients. Radial and mean diffusion exercise response in patients was significantly higher than controls. CONCLUSION: Static and dynamic diffusion imaging metrics show correlation with conventional imaging scores, reveal spatial heterogeneity, and provide means to differentiate dermatomyositis patients from controls. KEY POINTS: • Diffusion imaging shows regional differences between thigh muscles of dermatomyositis patients and controls. • Signal-weighted fat fraction and diffusion metrics correlate with T1/T2 scores of disease severity. • Dermatomyositis patients show significantly higher radial diffusion exercise response than controls.

Spatially resolved kinetics of skeletal muscle exercise response and recovery with multiple echo diffusion tensor imaging (MEDITI): a feasibility study.

OBJECTIVES: We describe measurement of skeletal muscle kinetics with multiple echo diffusion tensor imaging (MEDITI). This approach allows characterization of the microstructural dynamics in healthy and pathologic muscle. MATERIALS AND METHODS: In a Siemens 3-T Skyra scanner, MEDITI was used to collect dynamic DTI with a combination of rapid diffusion encoding, radial imaging, and compressed sensing reconstruction in a multi-compartment agarose gel rotation phantom and within in vivo calf muscle. An MR-compatible ergometer (Ergospect Trispect) was employed to enable in-scanner plantar flexion exercise. In a HIPAA-compliant study with written informed consent, post-exercise recovery of DTI metrics was quantified in eight volunteers. Exercise response of DTI metrics was compared with that of T2-weighted imaging and characterized by a gamma variate model. RESULTS: Phantom results show quantification of diffusivities in each compartment over its full dynamic rotation. In vivo calf imaging results indicate larger radial than axial exercise response and recovery in the plantar flexion-challenged gastrocnemius medialis (fractional response: nT2w = 0.385 ± 0.244, nMD = 0.163 ± 0.130, nλ1 = 0.110 ± 0.093, nλrad = 0.303 ± 0.185). Diffusion and T2-weighted response magnitudes were correlated (e.g., r = 0.792, p = 0.019 for nMD vs. nT2w). CONCLUSION: We have demonstrated the feasibility of MEDITI for capturing spatially resolved diffusion tensor data in dynamic systems including post-exercise skeletal muscle recovery following in-scanner plantar flexion.

Self-reported recurrent pain and medicine use behaviours among 15-year olds: results from the international study.

BACKGROUND: There is considerable variation in adolescent pain prevalence across epidemiological studies, with limited information on pain-related behaviours among adolescents, including medicine use. The aims of this study were (1) to examine the prevalence of recurrent pain among 15-year-old adolescents internationally; (2) to investigate the association between recurrent pain and medicine use behaviours among boys and girls; and (3) to evaluate the consistency of these associations across countries. METHODS: The World Health Organization (WHO) collaborative international Health Behaviour in School-aged Children 2009/2010 study collects data about self-reported aches and medicine use from 36,762 15-year-old adolescents from 22 countries/regions in Europe and the United States. Multi-level multivariate logistic regression, stratified by gender, was used to analyse the association between recurrent pain and medicine use for headache, stomachache, nervousness and difficulties in getting to sleep. RESULTS: More than 30% of adolescents reported recurrent headache, almost 30% recurrent backache and approximately 20% recurrent stomachache. Although pain prevalence and medicine use for aches were much higher for girls, the association between pain and medicine use was similarly strong for both genders. Adolescents with recurrent pain are more likely to use medicines also for non-corresponding pain, nervousness and difficulties in getting to sleep. The association between recurrent pain and medicine use was consistent across countries despite large-country differences in the prevalence of recurrent pain and medicine use. CONCLUSIONS: Recurrent pain in adolescence is common cross-nationally. Adolescents with recurrent pain are more likely to use medicine in general. Recurrent pain and medicine use should be addressed in adolescent health policies.

A better characterization of spinal cord damage in multiple sclerosis: a diffusional kurtosis imaging study.

BACKGROUND AND PURPOSE: The spinal cord is a site of predilection for MS lesions. While diffusion tensor imaging is useful for the study of anisotropic systems such as WM tracts, it is of more limited utility in tissues with more isotropic microstructures (on the length scales studied with diffusion MR imaging) such as gray matter. In contrast, diffusional kurtosis imaging, which measures both Gaussian and non-Gaussian properties of water diffusion, provides more biomarkers of both anisotropic and isotropic structural changes. The aim of this study was to investigate the cervical spinal cord of patients with MS and to characterize lesional and normal-appearing gray matter and WM damage by using diffusional kurtosis imaging. MATERIALS AND METHODS: Nineteen patients (13 women, mean age = 41.1 ± 10.7 years) and 16 controls (7 women, mean age = 35.6 ± 11.2-years) underwent MR imaging of the cervical spinal cord on a 3T scanner (T2 TSE, T1 magnetization-prepared rapid acquisition of gradient echo, diffusional kurtosis imaging, T2 fast low-angle shot). Fractional anisotropy, mean diffusivity, and mean kurtosis were measured on the whole cord and in normal-appearing gray matter and WM. RESULTS: Spinal cord T2-hyperintense lesions were identified in 18 patients. Whole spinal cord fractional anisotropy and mean kurtosis (P = .0009, P = .003), WM fractional anisotropy (P = .01), and gray matter mean kurtosis (P = .006) were significantly decreased, and whole spinal cord mean diffusivity (P = .009) was increased in patients compared with controls. Mean spinal cord area was significantly lower in patients (P = .04). CONCLUSIONS: Diffusional kurtosis imaging of the spinal cord can provide a more comprehensive characterization of lesions and normal-appearing WM and gray matter damage in patients with MS. Diffusional kurtosis imaging can provide additional and complementary information to DTI on spinal cord pathology.

High-resolution human cervical spinal cord imaging at 7 T.

We present high-resolution anatomical imaging of the cervical spinal cord in healthy volunteers at the ultrahigh field of 7 T with a prototype four-channel radiofrequency coil array, in comparison with 3-T imaging of the same subjects. Signal-to-noise ratios at both field strengths were estimated using the rigorous Kellman method. Spinal cord cross-sectional area measurements were performed, including whole-cord measurements at both fields and gray matter segmentation at 7 T. The 7-T array coil showed reduced sagittal coverage, comparable axial coverage and the expected significantly higher signal-to-noise ratio compared with equivalent 3-T protocols. In the cervical spinal cord, the signal-to-noise ratio was found by the Kellman method to be higher by a factor of 3.5 with the 7-T coil than with standard 3-T coils. Cervical spine imaging in healthy volunteers at 7 T revealed not only detailed white/gray matter differentiation, but also structures not visualized at lower fields, such as denticulate ligaments, nerve roots and rostral-caudal blood vessels. Whole-cord cross-sectional area measurements showed good agreement at both field strengths. The measurable gray/white matter cross-sectional areas at 7 T were found to be comparable with reports from histology. These pilot data demonstrate the use of higher signal-to-noise ratios at the ultrahigh field of 7 T for significant improvement in anatomical resolution of the cervical spinal cord, allowing the visualization of structures not seen at lower field strength, particularly for axial imaging.

Intravoxel incoherent motion imaging of tumor microenvironment in locally advanced breast cancer.

Diffusion-weighted imaging plays important roles in cancer diagnosis, monitoring, and treatment. Although most applications measure restricted diffusion by tumor cellularity, diffusion-weighted imaging is also sensitive to vascularity through the intravoxel incoherent motion effect. Hypervascularity can confound apparent diffusion coefficient measurements in breast cancer. We acquired multiple b-value diffusion-weighted imaging at 3 T in a cohort of breast cancer patients and performed biexponential intravoxel incoherent motion analysis to extract tissue diffusivity (D(t)), perfusion fraction (f(p)), and pseudodiffusivity (D(p)). Results indicated significant differences between normal fibroglandular tissue and malignant lesions in apparent diffusion coefficient mean (±standard deviation) values (2.44 ± 0.30 vs. 1.34 ± 0.39 µm(2)/msec, P < 0.01) and D(t) (2.36 ± 0.38 vs. 1.15 ± 0.35 µm(2)/msec, P < 0.01). Lesion diffusion-weighted imaging signals demonstrated biexponential character in comparison to monoexponential normal tissue. There is some differentiation of lesion subtypes (invasive ductal carcinoma vs. other malignant lesions) with f(p) (10.5 ± 5.0% vs. 6.9 ± 2.9%, P = 0.06), but less so with D(t) (1.14 ± 0.32 µm(2)/msec vs. 1.18 ± 0.52 µm(2)/msec, P = 0.88) and D(p) (14.9 ± 11.4 µm(2)/msec vs. 16.1 ± 5.7 µm(2)/msec, P = 0.75). Comparison of intravoxel incoherent motion biomarkers with contrast enhancement suggests moderate correlations. These results suggest the potential of intravoxel incoherent motion vascular and cellular biomarkers for initial grading, progression monitoring, or treatment assessment of breast tumors.

Changes in physical activity in pre-schoolers and first-grade children: longitudinal study in the Czech Republic.

BACKGROUND: The transition from kindergarten to first year at school is associated with a variety of psychosocial changes in children. The aim of this longitudinal study was to identify the changes in children's physical activity (PA) upon entry to first year at school; and to identify the days of the school week that exhibit low PA. METHODS: We monitored the PA levels of 176 children twice: initially in kindergarten and again in first-year classes at school. The age (mean +/- standard deviation) of children at kindergarten was 5.7 +/- 0.5 years and 6.7 +/- 0.5 years at the first year of elementary school. We evaluated PA employing the activity energy expenditure (AEE - kcal/kg/day) from Caltrac accelerometer and daily amount of steps (STEPS) from Yamax pedometer. Participants were monitored over 7 days to include a weekend. RESULTS: The mean AEE was 11.5 in pre-school girls and 12.9 kcal/kg/day in boys; and STEPS were 9923 steps/day in girls and 11 864 in boys on weekdays. At weekends, it was 11.5 kcal/kg/day in girls and 12.7 kcal/kg/day in boys and 10 606 steps/day in girls and 11 182 steps/day in boys. The mean AEE and STEPS in first-grade girls and boys was 9.9 and 9.8 kcal/kg/day respectively, and 7911 and 8252 steps/day respectively on weekdays, and 8.8 and 9.0 kcal/kg/day and 6872 and 7194 steps/day respectively at weekends. First-grade school children had significantly lower PA than pre-school children on weekdays (P < 0.0001) and at weekends (P < 0.0001). Decline in PA on weekdays was during time spent at school (P < 0.0001) and not during after-school children's leisure time. CONCLUSION: The parts of the week when first-grade school children show low PA are the times spent in lessons and in after-school nursery and at weekends. PA needs to be promoted using intervention programmes mainly during the after-school nursery programmes and at weekends.

High-resolution MRI of internal field diffusion-weighting in trabecular bone.

Trabecular bone structure is known to play a crucial role in the overall strength, and thus fracture risk, of such areas of the skeleton as the vertebrae, spine, femur, tibiae, or radius. Several MR methods devoted to probing this structure depend upon the susceptibility difference between the solid bone matrix and the intervening fluid/marrow/fat, usually in the context of a linewidth (1/T(2)') measurement or mapping technique. A recently demonstrated new approach to this system involves using internal gradients to encode diffusion weighting, and extracting structural information (e.g., surface-to-volume ratio) from the resulting signal decay. This contrast method has been demonstrated in bulk measurements on cleaned, water-saturated bovine trabecular bone samples. In the present work, microscopic imaging (0.156 mm in-plane resolution) is performed in order to spatially resolve this contrast on the trabecular level, and confirm its interpretation for the bulk measurements. It is found that the local rate of decay due to diffusion in the internal field (DDIF) is maximal close to the trabecular surfaces. The overall decay rate in a lower resolution scan probes the abundance of these surfaces, and provides contrast beyond that found in conventional proton density weighted or T(1)-weighted imaging. Furthermore, a microscopic calculation of internal field distributions shows a qualitative distinction between the structural sensitivities of DDIF and T(2)'. DDIF contrast is highly localized around trabecular walls than is the internal field itself, making it a less sensitive but more specific measure of such important properties as trabecular number.

Diffusion-based MR methods for bone structure and evolution.

A new approach to MR trabecular bone characterization is presented. This method probes the diffusion of spins through internal magnetic field gradients due to the susceptibility contrast between the bone and water (or marrow) phases. The resulting spin magnetization decay encodes properties of the underlying structure. This method, termed decay due to diffusion in the internal field (DDIF), is well established as a probe of pore size and structure. In the present work its application is shown for in vitro experiments on excised bovine tibiae samples. A comparison with pulsed field gradient (PFG) measurement of restricted diffusion shows a strong correlation of DDIF with the surface-to-volume ratio (SVR) of bones. Calculation of the internal magnetic field within the bone structure also supports this interpretation. These NMR measurements compare well with the image analysis from microscopic computed tomography (muCT). The SVR is not accessible in the clinically standard densitometry measurements, and provides vital information on bone strength and therefore on its fracture risk. The DDIF and PFG methods derive this information from a straightforward pulse sequence that does not employ either high applied field gradients or microimaging, and thus may have clinical potential.

Rapid measurement of three-dimensional diffusion tensor.

In this article, the authors demonstrate a rapid NMR method to measure a full three-dimensional diffusion tensor. This method is based on a multiple modulation multiple echo sequence and utilizes static and pulsed magnetic field gradients to measure diffusion along multiple directions simultaneously. The pulse sequence was optimized using a well-known linear inversion metric (condition number) and successfully tested on both isotropic (water) and anisotropic (asparagus) diffusion systems.

A single-scan method for measuring flow along an arbitrary direction.

In this article, we demonstrate a single-scan method to measure an average flow velocity vector along an arbitrary direction. This method is based on the MMME sequence and utilizes static and pulsed magnetic field gradients along multiple directions for the optimal determination of flow velocity components in three-dimensional space. Experimentally measured average flow velocities from the flow induced phase shift with a single-scan MMME sequence show excellent agreements with the known flow rate, and the signal decay of each echo due to a velocity distribution is also quantitatively verified with known laminar flow patterns.

Stokes-Einstein relation in supercooled aqueous solutions of glycerol.

The diffusion of glycerol molecules decreases with decreasing temperature as its viscosity increases in a manner simply described by the Stokes-Einstein relation. Approaching the glass transition, this relation breaks down as it does with a number of other pure liquid glass formers. We have measured the diffusion coefficient for binary mixtures of glycerol and water and find that the Stokes-Einstein relation is restored with increasing water concentration. Our comparison with theory suggests that adding water postpones the formation of frustration domains.

Fast imaging with the MMME sequence.

The multiple-modulation-multiple-echo sequence, previously used for rapid measurement of diffusion, is extended to a method for single shot imaging. Removing the gradient switching requirement during the application of RF pulses by a constant frequency encoding gradient can shorten experiment time for ultrafast imaging. However, having the gradient on during the pulses gives rise to echo shape variations from off-resonance effects, which make the image reconstruction difficult. In this paper, we propose a simple method to deconvolve the echo shape variation from the true one-dimensional image. This method is extended to two-dimensional imaging by adding phase encoding gradients between echoes during the acquisition period to phase encode each echo separately. Slice selection is achieved by a frequency selective pulse at the beginning of the sequence. Imaging speed is mainly limited by the phase encoding gradients' switching times and echo overlap when echo spacing is very short. This technique can produce a single-shot image of sub-millimeter resolution in 5 ms.

Hole-burning diffusion measurements in high magnetic field gradients.

We describe methods for the measurement of translational diffusion in very large static magnetic field gradients by NMR. The techniques use a "hole-burning" sequence that, with the use of fringe field gradients of 42 T/m, can image diffusion along one dimension on a submicron scale. Two varieties of this method are demonstrated, including a particularly efficient mode called the "hole-comb," in which multiple diffusion times comprising an entire diffusive evolution can be measured within the span of a single detected slice. The advantages and disadvantages of these methods are discussed, as well as their potential for addressing non-Fickian diffusion, diffusion in restricted media, and spatially inhomogeneous diffusion.

Spatially resolved electronic structure inside and outside the vortex cores of a high-temperature superconductor.

Puzzling aspects of high-transition-temperature (high-Tc) superconductors include the prevalence of magnetism in the normal state and the persistence of superconductivity in high magnetic fields. Superconductivity and magnetism generally are thought to be incompatible, based on what is known about conventional superconductors. Recent results, however, indicate that antiferromagnetism can appear in the superconducting state of a high-Tc superconductor in the presence of an applied magnetic field. Magnetic fields penetrate a superconductor in the form of quantized flux lines, each of which represents a vortex of supercurrents. Superconductivity is suppressed in the core of the vortex and it has been suggested that antiferromagnetism might develop there. Here we report the results of a high-field nuclear-magnetic-resonance (NMR) imaging experiment in which we spatially resolve the electronic structure of near-optimally doped YBa2Cu3O7-delta inside and outside vortex cores. Outside the cores, we find strong antiferromagnetic fluctuations, whereas inside we detect electronic states that are rather different from those found in conventional superconductors.

NMR phase noise in bitter magnets.

We have studied the temporal instability of a high field resistive Bitter magnet through nuclear magnetic resonance (NMR). This instability leads to transverse spin decoherence in repeated and accumulated NMR experiments as is normally performed during signal averaging. We demonstrate this effect via Hahn echo and Carr--Purcell--Meiboom--Gill (CPMG) transverse relaxation experiments in a 23-T resistive magnet. Quantitative analysis was found to be consistent with separate measurements of the magnetic field frequency fluctuation spectrum, as well as with independent NMR experiments performed in a magnetic field with a controlled instability. Finally, the CPMG sequence with short pulse delays is shown to be successful in recovering the intrinsic spin--spin relaxation even in the presence of magnetic field temporal instability.