Imaging the transmembrane and transendothelial sodium gradients in gliomas.
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ABSTRACT:
SUBMITTER: Khan MH
PROVIDER: S-EPMC7987982 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of gastrointestinal inflammation, with significant implications for host defense, injury and repair. However, phenotypic and mechanistic aspects of PMN recruitment in inflamed intestines have not been explored in vivo. Using novel epithelial/PMN fluorescence reporter mice, advanced intravital imaging and 3D reconstruction analysis, we mapped the microvasculature architecture across the intestinal layers and determined that in response to Salmonella/endotoxin-induced inflammation, PMN transendothelial migration (TEM) was restricted to submucosal vessels. PMN TEM was not observed in villus or crypt vessels, proximal to the epithelium that underlies the intestinal lumen, and was partially dependent on (C-X-C motif) ligands 1 (CXCL1) and 2 (CXCL2) expression, which was found to be elevated in the submucosa layer. Restricted PMN extravasation at the submucosa and subsequent PMN interstitial migration may serve as a novel regulatory step of PMN effector function and recruitment to the luminal space in inflamed intestines.
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Project description:PurposeThere is limited knowledge about the associations between sodium and proton MRI measurements in brain tumors. The purpose of this study was to quantify intra- and intertumoral correlations between sodium, diffusion, and perfusion MRI in human gliomas.MethodsTwenty glioma patients were prospectively studied on a 3T MRI system with multinuclear capabilities. Three mutually exclusive tumor volumes of interest (VOIs) were segmented: contrast-enhancing tumor (CET), T2/FLAIR hyperintense non-enhancing tumor (NET), and necrosis. Median and voxel-wise associations between apparent diffusion coefficient (ADC), normalized relative cerebral blood volume (nrCBV), and normalized sodium measurements were quantified for each VOI.ResultsBoth relative sodium concentration and ADC were significantly higher in areas of necrosis compared to NET (P = 0.003 and P = 0.008, respectively) and CET (P = 0.02 and P = 0.02). Sodium concentration was higher in CET compared to NET (P = 0.04). Sodium and ADC were higher in treated compared to treatment-naïve gliomas within NET (P = 0.006 and P = 0.01, respectively), and ADC was elevated in CET (P = 0.03). Median ADC and sodium concentration were positively correlated across patients in NET (r = 0.77, P < 0.0001) and CET (r = 0.84, P < 0.0001), but not in areas of necrosis (r = 0.45, P = 0.12). Median nrCBV and sodium concentration were negatively correlated across patients in areas of NET (r=-0.63, P = 0.003). Similar associations were observed when examining voxel-wise correlations within VOIs.ConclusionSodium MRI is positively correlated with proton diffusion MRI measurements in gliomas, likely reflecting extracellular water. Unique areas of multinuclear MRI contrast may be useful in future studies to understand the chemistry of the tumor microenvironment.
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Project description:The position and extent of movement of a charged peptide within a membrane bilayer provides much controversy. In our study, we have examined the nature of the highly charged helix-turn-helix motif (S3b and S4) to address how a highly charged peptide is stabilized within a bilayer in the presence of various transmembrane electrical potentials. Our double-bilayer simulation results show how the variation of the salt concentrations between the inner and outer bath establishes a transmembrane potential. Our results also show that important features of the peptide affected by changes in electrical potential are the center of mass depth, the swivel/kink degrees of conformation, and the hydrogen-bonding patterns. As the voltage gradient across the bilayer increased, the center of mass of the peptide shifted in a direction toward the outer bath. The peptide also has a higher percent helical content and the swivel/kink conformation is more rigid for nonpolarized systems where no voltage drop occurred between salt baths. Our results also provide some suggestions for how this domain may be affected by environmental changes as part of the voltage sensor in a K-channel.
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Project description:INTRODUCTION:Diffuse gliomas are incurable malignancies, which undergo inevitable progression and are associated with seizure in 50-90% of cases. Glutamate has the potential to be an important glioma biomarker of survival and local epileptogenicity if it can be accurately quantified noninvasively. METHODS:We applied the glutamate-weighted imaging method GluCEST (glutamate chemical exchange saturation transfer) and single voxel MRS (magnetic resonance spectroscopy) at 7 Telsa (7 T) to patients with gliomas. GluCEST contrast and MRS metabolite concentrations were quantified within the tumour region and peritumoural rim. Clinical variables of tumour aggressiveness (prior adjuvant therapy and previous radiological progression) and epilepsy (any prior seizures, seizure in last month and drug refractory epilepsy) were correlated with respective glutamate concentrations. Images were separated into post-hoc determined patterns and clinical variables were compared across patterns. RESULTS:Ten adult patients with a histo-molecular (n = 9) or radiological (n = 1) diagnosis of grade II-III diffuse glioma were recruited, 40.3 +/- 12.3 years. Increased tumour GluCEST contrast was associated with prior adjuvant therapy (p = .001), and increased peritumoural GluCEST contrast was associated with both recent seizures (p = .038) and drug refractory epilepsy (p = .029). We distinguished two unique GluCEST contrast patterns with distinct clinical and radiological features. MRS glutamate correlated with GluCEST contrast within the peritumoural voxel (R = 0.89, p = .003) and a positive trend existed in the tumour voxel (R = 0.65, p = .113). CONCLUSION:This study supports the role of glutamate in diffuse glioma biology. It further implicates elevated peritumoural glutamate in epileptogenesis and altered tumour glutamate homeostasis in glioma aggressiveness. Given the ability to non-invasively visualise and quantify glutamate, our findings raise the prospect of 7 T GluCEST selecting patients for individualised therapies directed at the glutamate pathway. Larger studies with prospective follow-up are required.
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Project description:The accuracy of target delineation in radiation treatment (RT) planning of cerebral gliomas is crucial to achieve high tumor control, while minimizing treatment-related toxicity. Conventional magnetic resonance imaging (MRI), including contrast-enhanced T1-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, represents the current standard imaging modality for target volume delineation of gliomas. However, conventional sequences have limited capability to discriminate treatment-related changes from viable tumors, owing to the low specificity of increased blood-brain barrier permeability and peritumoral edema. Advanced physiology-based MRI techniques, such as MR spectroscopy, diffusion MRI and perfusion MRI, have been developed for the biological characterization of gliomas and may circumvent these limitations, providing additional metabolic, structural, and hemodynamic information for treatment planning and monitoring. Radionuclide imaging techniques, such as positron emission tomography (PET) with amino acid radiopharmaceuticals, are also increasingly used in the workup of primary brain tumors, and their integration in RT planning is being evaluated in specialized centers. This review focuses on the basic principles and clinical results of advanced MRI and PET imaging techniques that have promise as a complement to RT planning of gliomas.
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Project description:PurposePrevious studies have shown that diffusion of water through intrinsic susceptibility gradients produces a dispersion of the spin-lattice relaxation rate in the rotating frame (R1 ρ ) over a low range of spin-locking amplitudes (0 < ω1 < 100 Hz), whereas at higher ω1 and high magnetic fields, a second dispersion arises due to chemical exchange. Here, we separated these different effects and evaluated their contributions in tumors.MethodsMaps of R1 ρ and its changes with locking field were acquired on intracranial 9-L tumor models. The R1 ρ changes due to diffusion ( R1ρDiff ) were calculated by subtracting maps of R1 ρ at 100 Hz (R1 ρ [100 Hz]) from those at 0 Hz (R1 ρ [0 Hz]). The R1 ρ changes due to exchange ( R1ρEx ) were calculated by subtracting maps of R1 ρ at 5620 Hz (R1 ρ [5620 Hz]) from those of R1 ρ at 100 Hz (R1 ρ [100 Hz]). Measurements of vascular dimensions and spacing were performed ex vivo using 3D confocal microscopy.ResultsThe R1 ρ changes at low ω1 in tumors (5.24 ± 1.78 s-1 ) are substantially (p = 3.76 ) greater than those in normal tissues (1.36 ± 0.70 s-1 ), which we suggest are due to greater contributions from diffusion through susceptibility gradients. Tumor vessels were larger and spaced less closely compared with normal brain, which may be 1 factor contributing the susceptibility within 9-L tumors. The contrast between tumor and normal tissues for R1ρDiff is larger than for R1ρEx and for the apparent R2w .ConclusionImages that are sensitive to the variations of spin-lock relaxation rates at low ω1 provide a novel form of contrast that reflects the heterogeneous nature of intrinsic variations within tumors.
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Project description:Background23Na MRI correlates with tumor proliferation, and studies in pediatric patients are lacking.The purpose of the study(1) to compare total sodium concentration (TSC) between pediatric glioma and non-neoplastic brain tissue using 23Na MRI; (2) compare tissue conspicuity of bound sodium concentration (BSC) using 23Na MRI dual echo relative to TSC imaging.MethodsTSC was measured in: (1) non-neoplastic brain tissues and (2) three types of manually segmented gliomas (diffuse intrinsic brainstem glioma (DIPG), recurrent supratentorial low-grade glioma (LGG), and high-grade glioma (HGG)). In a subset of patients, serial changes in both TSC and BSC (dual echo 23Na MRI) were assessed.ResultsTwenty-six pediatric patients with gliomas (median age of 12.0 years, range 4.9-23.3 years) were scanned with 23Na MRI. DIPG treated with RT demonstrated higher TSC values than the uninvolved infratentorial tissues (p < 0.001). Recurrent supratentorial LGG and HGG exhibited higher TSC values than the uninvolved white matter (WM) and gray matter (GM) (p < 0.002 for LGG, and p < 0.02 for HGG). The dual echo 23Na MRI suppressed the sodium signal within both CSF and necrotic foci.ConclusionQuantitative 23Na MRI of pediatric gliomas demonstrates a range of values that are higher than non-neoplastic tissues. Dual echo 23Na MRI of BCS improves tissue conspicuity relative to TSC imaging.
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Project description:The adult diffusely infiltrating low-grade gliomas (LGGs) are typically IDH mutant and slow-growing gliomas having moderately increased cellularity generally without mitosis, necrosis, and microvascular proliferation. Supra-total resection of LGG significantly increases the overall survival by delaying malignant transformation compared with a simple debulking so accurate MR diagnosis is crucial for treatment planning. Data from meta-analysis support the addition of diffusion and perfusion-weighted MR imaging and MR spectroscopy in the diagnosis of suspected LGG. Typically, LGG has lower cellularity (ADCmin), angiogenesis (rCBVmax), capillary permeability (Ktrans), and mitotic activity (Cho/Cr ratio) compared to high-grade glioma. The identification of 2-hydroxyglutarate by MR spectroscopy can reflect the IDH status of the tumor. The initial low ADCmin, high rCBVmax, and Ktrans values are consistent with the poor prognosis. The gradual increase in intratumoral Cho/Cr ratio and rCBVmax values are well correlated with tumor progression. Besides MR-based technical artifacts, which are minimized by the voxel-based assessment of data obtained by histogram analysis, the problems derived from the diversity and the analysis of imaging data should be solved by using artificial intelligence techniques. The quantitative multiparametric MR imaging of LGG can either improve the diagnostic accuracy of their differential diagnosis or assess their prognosis.
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