Noninvasive Diagnosis of Kidney Dysfunction Using a Small-Molecule Manganese-Based Magnetic Resonance Imaging Probe.

Contrast-enhanced magnetic resonance imaging (CE-MRI) is a promising approach for the diagnosis of kidney diseases. However, safety concerns, including nephrogenic systemic fibrosis, limit the administration of gadolinium (Gd)-based contrast agents (GBCAs) in patients who suffer from renal impairment. Meanwhile, nanomaterials meet biosafety concerns because of their long-term retention in the body. Herein, we propose a small-molecule manganese-based imaging probe Mn-PhDTA as an alternative to GBCAs to assess renal insufficiency for the first time. Mn-PhDTA was synthesized via a simple three-step reaction with a total yield of up to 33.6%, and a gram-scale synthesis can be realized. Mn-PhDTA has an r1 relaxivity of 2.72 mM-1 s-1 at 3.0 T and superior kinetic inertness over Gd-DTPA and Mn-EDTA with a dissociation time of 60 min in the presence of excess Zn2+. In vivo and in vitro experiments demonstrate their good stability and biocompatibility. In the unilateral ureteral obstruction rats, Mn-PhDTA provided significant MR signal enhancement, enabled distinguishing structure changes between the normal and damaged kidneys, and evaluated the renal function at different injured stages. Mn-PhDTA could act as a potential MRI contrast agent candidate for the replacement of GBCAs in the early detection of kidney dysfunction and analysis of kidney disease progression.

Gold nanoparticles conjugated with epidermal growth factor and gadolinium for precision delivery of contrast agents in magnetic resonance imaging.

The utilization of contrast agents in magnetic resonance imaging (MRI) has become increasingly important in clinical diagnosis. However, the low diagnostic specificity of this technique is a limiting factor for the early detection of tumors. To develop a new contrast agent with a specific target for early stage tumors, we present the synthesis and characterization of a nanocontrast composed of gold nanoparticles (AuNPs), gadopentetic acid (Gd-DTPA), and epidermal growth factor (EGF). Carbodiimide-based chemistry was utilized to modify Gd-DTPA for functionalization with AuNPs. This resulted in the formation of the Au@Gd-EGF nanocontrast. The relaxation rate (1/T1) of the nanocontrast was analyzed using MRI, and cytotoxicity was determined based on cell viability and mitochondrial activity in a human breast adenocarcinoma cell line. Fourier-transform infrared spectroscopy analysis confirmed the effectiveness of carbodiimide in the formation of the Gd-DTPA-cysteamine complex in the presence of bands at 930, 1042, 1232, 1588, and 1716 cm-1. The complexes exhibited good interactions with the AuNPs. However, the signal intensity of the Au@Gd-EGF nanocontrast was lower than that of the commercial contrast agent because the r1/r2 relaxivities of the Gd-DTPA-based contrast agents were lower than those of the gadoversetamide-based molecules. The Au@Gd-EGF nanocontrast agent exhibited good biocompatibility, low cytotoxicity, and high signal intensity in MRI with active targeted delivery, suggesting significant potential for future applications in the early diagnosis of tumors.

MRI Directed Magnevist Effective to Study Toxicity of Gd-Doped Mesoporous Carbon Nanoparticles in Mice Model.

Purpose: Magnetic resonance imaging (MRI) has been a valuable and widely used examination technique in clinical diagnosis and prognostic efficacy evaluation. The introduction of MRI contrast agent (CA) improves its sensitivity obviously, particularly with the development of nano-CA, which presents higher contrast enhancement ability. However, systematical evaluation of their toxicity is still limited, hampering their further translation in clinics. Methods: In this paper, to systematically evaluate the toxicity of nano-CA, Gd-doped mesoporous carbon nanoparticles (Gd-MCNs) prepared by a one-step hard template method were introduced as a model and clinically used MRI CA, Magnevist (Gd-DTPA) as control. Their in vitro blood compatibility, cellular toxicity, DNA damage, oxidative stress, inflammation response as well as in vivo toxicity and MR imaging behaviors were studied and compared. Results: The experimental results showed that compared with Gd-DTPA, Gd-MCNs displayed negligible influence on the red blood cell shape, aggregation, BSA structure, macrophage morphology and mitochondrial function. Meanwhile, limited ROS and inflammatory cytokine production also illustrated the cellular compatibility of Gd-MCNs. For in vivo toxicity evaluation, Gd-MCNs presented acceptable in vivo biosafety even under 12 times injection for 12 weeks. More importantly, at the same concentration of Gd, Gd-MCNs displayed better contrast enhancement of tumor than Gd-DTPA, mainly coming from its high MRI relaxation rate which is nearly 9 times that of Gd-DTPA. Conclusion: In this paper, we focus on the toxicity evaluation of MRI nano-CA, Gd-MCNs from different angles. With Gd-DTPA as control, Gd-MCNs appeared to be highly biocompatible and safe nanoparticles that possessed promising potentials for the use of MRI nano-CA. In the future, more research on the long-term genotoxicity and the fate of nanoparticles after being swallowed should be performed.

Analysis of the elemental species-dependent uptake of lanthanide complexes in Arabidopsis thaliana plants by LA-ICP-MS.

Gadolinium-based contrast agents (GBCAs) are found increasingly in different water bodies, making the investigation of their uptake and distribution behavior in plants a matter of high interest to assess their potential effects on the environment. Depending on the used complexing agent, they are classified into linear or macrocyclic GBCAs, with macrocyclic complexes being more stable. In this study, by using TbCl3, Gd-DTPA-BMA, and Eu-DOTA as model compounds for ionic, linear, and macrocyclic lanthanide species, the elemental species-dependent uptake into leaves of Arabidopsis thaliana under identical biological conditions was studied. After growing for 14 days on medium containing the lanthanide species, the uptake of all studied compounds was confirmed by means of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Furthermore, the uptake rate of TbCl3 and the linear Gd-DTPA-BMA was similar, with Tb and Gd hotspots colocated in the areas of hydathodes and the trichomes of the leaves. In contrast, in the case of the macrocyclic Eu-DOTA, Eu was mainly located in the leaf veins. Additionally, Eu was colocated with Tb and Gd in the hydathode at the tip of the leave. Removal of the lanthanide species from the medium led to a decrease in signal intensities, indicating their subsequent release to some extent. However, seven days after the removal, depositions of Eu, Gd, and Tb were still present in the same areas of the leaves as before, showing that complete elimination was not achieved after this period of time. Overall, more Eu was present in the leaves compared to Gd and Tb, which can be explained by the high stability of the Eu-DOTA complex, potentially leading to a higher transport rate into the leaves, whereas TbCl3 and Gd-DTPA-BMA could interact with the roots, reducing their mobility.

A New OATP-Mediated Hepatobiliary-Specific Mn(II)-Based MRI Contrast Agent for Hepatocellular Carcinoma in Mice: A Comparison With Gd-EOB-DTPA.

BACKGROUND: Growing concerns about the safety of gadolinium (Gd)-based contrast agents have reinforced the need for the development of Gd-free MRI contrast agents (CAs) that are effective in imaging liver tumors. PURPOSE: To evaluate the ability of Mn-BnO-TyEDTA MRI CA to detect hepatocellular carcinoma in a mouse model of implanted liver tumor. STUDY TYPE: Prospective. ANIMAL MODEL: Thirteen orthotopically implanted liver tumor mice. FIELD STRENGTH/SEQUENCE: 3.0 T/precontrast and postcontrast T1-weighted fast spoiled gradient recalled echo and T2-weighted fast recovery fast spin-echo imaging with fat suppression. ASSESSMENT: The relative enhancement ratio was calculated and statistically compared. Lesion detection in postcontrast images was analyzed by calculations of area under the curve (AUC, the increases in liver-to-tumor contrast-to-noise ratio [∆CNR] vs. time curve). Mn or Gd levels were measured in the liver and tumoral tissues by inductively coupled plasma-mass spectrometry. Tumor specimens were stained with hematoxylin and eosin (H&E) and the expression of organic anion transfer peptide (OATP)1B1 was evaluated by immunofluorescence (IF) staining and mean fluorescence intensity (MFI) was calculated. STATISTICAL TESTS: Unpaired t-test and two-tailed paired t-test. P < 0.05 was considered statistical significance. RESULTS: Mn-BnO-TyEDTA and Gd-EOB-DTPA demonstrated nearly identical enhancement patterns in the liver, tumor, and psoas muscle and no difference in lesion detection (AUC10-30, Mn  = 851 ∆CR·min, AUC10-30, Gd  = 823 ∆CR·min). A Significant higher concentration of metal (Mn or Gd) was found in the liver compared to the tumor ([Mn]liver  = 0.88 ± 0.07 µmmol/g, [Mn]tumor  = 0.49 ± 0.05 µmmol/g, [Gd]liver  = 0.65 ± 0.07 µmmol/g, [Gd]tumor  = 0.27 ± 0.04 µmmol/g). IF staining showed significantly decreased expression of OATP1B1 in the tumor core compared to the liver (MFItumor  = 5.28 ± 1.54, MFIliver  = 25.49 ± 3.41). DATA CONCLUSION: Mn-BnO-TyEDTA can provide comparable hepatobiliary tumor contrast enhancement to Gd-EOB-DTPA. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Dual-modal polypeptide-containing contrast agents for magnetic resonance/fluorescence imaging.

Dual-modal magnetic resonance/fluorescent imaging (MRI/FI) attracts moreandmoreattentions in diagnosis of tumors. A corresponding dual-modal imaging agent with sufficient tumor sensitivity and specificity should be matched to improve imaging quality. Tripeptide (RGD) and pentapeptide (YIGSR) were selected as the tumor-targeting groups and attached to gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and rhodamine B (RhB), and then make two novel polypeptide-based derivatives (RGD-Gd-DTPA-RhB and YIGSR-Gd-DTPA-RhB), respectively. These derivatives were further characterized and their properties, such as cell uptake, cell cytotoxicity, MRI and FI assay, were measured. YIGSR-Gd-DTPA-RhB and RGD-Gd-DTPA-RhB had high relaxivity, good tumor-targeting property, low cell cytotoxicity and good red FI in B16F10 melanoma cells. Moreover, YIGSR-Gd-DTPA-RhB and RGD-Gd-DTPA-RhB possessed high uptake to B16F10 melanoma, and then achieve highly enhanced FI and MRI of tumors in mice for a prolonged time. Therefore, YIGSR-Gd-DTPA-RhB and RGD-Gd-DTPA-RhB can be applied as the potential agents for tumor targeted MRI/FI in vivo.

Boosting Vascular Imaging-Performance and Systemic Biosafety of Ultra-Small NaGdF4 Nanoparticles via Surface Engineering with Rationally Designed Novel Hydrophilic Block Co-Polymer.

Revealing the anatomical structures, functions, and distribution of vasculature via contrast agent (CA) enhanced magnetic resonance imaging (MRI) is crucial for precise medical diagnosis and therapy. The clinically used MRI CAs strongly rely on Gd-chelates, which exhibit low T1 relaxivities and high risks of nephrogenic systemic fibrosis (NSF) for patients with renal dysfunction. It is extremely important to develop high-performance and safe CAs for MRI. Herein, it is reported that ultra-small NaGdF4 nanoparticles (UGNs) can serve as an excellent safe MRI CA via surface engineering with rationally designed novel hydrophilic block co-polymer (BPn ). By optimizing the polymer molecular weights, the polymer-functionalized UGNs (i.e., UGNs-BP14 ) are obtained to exhibit remarkably higher relaxivity (11.8 mm-1 s-1 at 3.0 T) than Gd-DTPA (3.6 mm-1 s-1 ) due to their ultracompact and abundant hydrophilic surface coating. The high performance of UGNs-BP14 enables us to sensitively visualize microvasculature with a small diameter of ≈0.17 mm for up to 2 h, which is the thinnest blood vessel and the longest time window for low field (1.0 T) MR angiography ever reported, and cannot be achieved by using the clinically used Gd-DTPA under the same conditions. More importantly, renal clearable UGNs-BP14 show lower risks of inducing NSF in comparison with Gd-DTPA due to their negligible release of Gd3+ ions after modification with the novel hydrophilic block copolymer. The study presents a novel avenue for boosting imaging-performance and systemic biosafety of UGNs as a robust MRI CA with great potential in precise diagnosis of vasculature-related diseases.

Comparison of liver scintigraphy and the liver-spleen contrast in Gd-EOB-DTPA-enhanced MRI on liver function tests.

The liver-spleen contrast (LSC) using hepatobiliary-phase images could replace the receptor index (LHL15) in liver scintigraphy; however, few comparative studies exist. This study aimed to verify the convertibility from LSC into LHL15. In 136 patients, the LSC, not at 20 min, but at 60 min after injecting gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid was compared with the LHL15, albumin-bilirubin (ALBI) score, and the related laboratory parameters. The LHL15 was also compared with their biochemical tests. The correlation coefficients of LSC with LHL15, ALBI score, total bilirubin, and albumin were 0.740, -0.624, -0.606, and 0.523 (P < 0.00001), respectively. The correlation coefficients of LHL15 with ALBI score, total bilirubin, and albumin were -0.647, -0.553, and 0.569 (P < 0.00001), respectively. The linear regression equation on the estimated LHL15 (eLHL15) from LSC was eLHL15 = 0.460 · LSC + 0.727 (P < 0.00001) and the coefficient of determination was 0.548. Regarding a contingency table using imaging-based clinical stage classification, the degree of agreement between eLHL15 and LHL15 was 65.4%, and Cramer's V was 0.568 (P < 0.00001). Therefore, although the LSC may be influenced by high total bilirubin, the eLHL15 can replace the LSC as an index to evaluate liver function.

Grafting of Gd-DTPA onto MOF-808 to enhance MRI performance for guiding photothermal therapy.

Gd(III) chelates are important T1-weighted contrast agents used in clinical magnetic resonance imaging (MRI), but their low longitudinal relaxivity (r1) results in limited imaging efficiency. In this study, we utilize a geometric confinement strategy to restrict a Gd chelate (Gd-DTPA) within the channels of a porous metal-organic framework material (MOF-808) for increasing its r1 relaxivity. Moreover, the Gd-DTPA-grafted MOF-808 nanoparticles were further surface modified with polyaniline (PANI) to construct an MRI-guided photothermal therapy platform. The resulting Gd-DTPA-MOF-808@PANI shows a high r1 relaxivity of 30.1 mM-1 s-1 (0.5 T), which is 5.4 times higher than that of the commercial contrast agent Magnevist. In vivo experiments revealed that Gd-DTPA-MOF-808@PANI has good T1-weighted contrast performance and can effectively guide photothermal ablation of tumors upon 808 nm laser irradiation. This work may shed some light on the design and preparation of high relaxation rate Gd-based contrast agents for theranostic application via utilization of versatile MOF materials.

Organic Anion Transporting Polypeptide 1B1 Is a Potential Reporter for Dual MR and Optical Imaging.

Membrane proteins responsible for transporting magnetic resonance (MR) and fluorescent contrast agents are of particular importance because they are potential reporter proteins in noninvasive molecular imaging. Gadobenate dimeglumine (Gd-BOPTA), a liver-specific MR contrast agent, has been used globally for more than 10 years. However, the corresponding molecular transportation mechanism has not been validated. We previously reported that the organic anion transporting polypeptide (OATP) 1B3 has an uptake capability for both MR agents (Gd-EOB-DTPA) and indocyanine green (ICG), a clinically available near-infrared (NIR) fluorescent dye. This study further evaluated OATP1B1, another polypeptide of the OATP family, to determine its reporter capability. In the OATP1B1 transfected 293T transient expression model, both Gd-BOPTA and Gd-EOB-DTPA uptake were confirmed through 1.5 T MR imaging. In the constant OAPT1B1 and OATP1B3 expression model in the HT-1080 cell line, both HT-1080-OAPT1B1 and HT-1080-OATP1B3 were observed to ingest Gd-BOPTA and Gd-EOB-DTPA. Lastly, we validated the ICG uptake capability of both OATP1B1 and OATP1B3. OAPT1B3 exhibited a superior ICG uptake capability to that of OAPT1B1. We conclude that OATP1B1 is a potential reporter for dual MR and NIR fluorescent molecular imaging, especially in conjunction with Gd-BOPTA.

Highly Efficient Activatable MRI Probe to Sense Myeloperoxidase Activity.

Myeloperoxidase (MPO) is a key component of innate immunity but can damage tissues when secreted abnormally. We developed a new generation of a highly efficient MPO-activatable MRI probe (heMAMP) to report MPO activity. heMAMP has improved Gd stability compared to bis-5-HT-Gd-DTPA (MPO-Gd) and demonstrates no significant cytotoxicity. Importantly, heMAMP is more efficiently activated by MPO compared to MPO-Gd, 5HT-DOTA(Gd), and 5HT-DOTAGA-Gd. Molecular docking simulations revealed that heMAMP has increased rigidity via hydrogen bonding intramolecularly and improved binding affinity to the active site of MPO. In animals with subcutaneous inflammation, activated heMAMP showed a 2-3-fold increased contrast-to-noise ratio (CNR) compared to activated MPO-Gd and 4-10 times higher CNR compared to conventional DOTA-Gd. This increased efficacy was further confirmed in a model of unstable atherosclerotic plaque where heMAMP demonstrated a comparable signal increase and responsiveness to MPO inhibition at a 3-fold lower dosage compared to MPO-Gd, further underscoring heMAMP as a potential translational candidate.

A Contrast Examination of Proinflammatory Effects on Kidney Function for γ-Fe2O3 NP and Gadolinium Dimeglumine.

BACKGROUND: Contrast-enhanced magnetic resonance imaging (MRI) is a powerful diagnostic tool for many diseases. In many situations, the contrasts are repeatedly administrated in order to monitor and assess the disease progression. OBJECTIVE: To investigate and compare the biological effects of γ-Fe2O3 nanoparticle (NP) and gadolinium dimeglumine (Gd-DTPA) with high and multiple doses on the kidney of healthy mice. METHODS: Polydextrose sorbitol carboxymethyl ether coated γ-Fe2O3 NP with hydrodynamic size of 68.2 nm and clinically applied Gd-DTPA were employed on healthy mice with the repeatedly intravenous administration of high doses. The cell viability of human umbilical vein endothelial cells (HUVEC) in high doses of these two contrast agents were measured using the xCELLigence Real-Time Cell Analysis (RTCA) S16 Instrument. The biological effects of γ-Fe2O3 NP and Gd-DTPA on the kidney were obtained using a biochemical automatic analyzer and multiple proinflammatory factor kit on the serum. Histopathological and immunohistochemistry analysis were taken on kidney tissues. RESULTS: It showed that the proinflammatory responses elicited by the γ-Fe2O3 NPs were weaker than that by Gd-DTPA, evidenced by the relatively much lower level of IL-1ß, IL-6, IL-18, TNF-α, C-reactive protein (CRP) and Ferritin. At the same time, the γ-Fe2O3 NPs did not have the biochemical index elevated, while the Gd-DTPA did. CONCLUSION: The γ-Fe2O3 NPs induced weaker proinflammatory effects in reference to the Gd-DTPA, indicating better renal safety. Therefore, it is suggested that γ-Fe2O3 NPs should be safer and optional choice when repeated contrast-enhanced MRI is necessary.

Pilot study of gadoxetate disodium-enhanced mri for localized and metastatic prostate cancers.

OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. Gadoxetate disodium is a substrate of OATP1B3, and its uptake has been shown to correlate with OATP1B3 expression in other cancers. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. A single center open-label non-randomized pilot study recruited men with (1) localized, and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3, NCTP and OATP1B1 was conducted. The mCRPC subgroup (n = 9) demonstrated significant enhancement compared to pre-contrast images at 20-, 40- and 60-min timepoints (p < 0.0078). The localized cancer subgroup (n = 11) demonstrated earlier enhancement compared to the mCRPC group, but no retention over time (p > 0.05). OATP1B3 expression on IHC trended higher contrast enhancement between 20-40 min (p ≤ 0.064) and was associated with contrast enhancement at 60 min (p = 0.0422). OATP1B1 haplotype, with N130D and V174A substitutions, impacted enhancement at 40-60 min (p ≤ 0.038). mCRPC lesions demonstrate enhancement after injection of gadoxetate disodium on MRI and retention over 60 min. As inter-individual variability in OATP1B3 expression and function has both predictive and prognostic significance, gadoxetate disodium has potential as a biomarker in prostate cancer.

Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging-guided risk assessment in living donor liver transplant patients with postoperative complications: a pilot study.

OBJECTIVE: To evaluate whether gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (MRI), the measurements of quantitative and qualitative parameters on hepatobiliary phase images can predict the risk of postoperative complications in patients underwent living donor liver transplantation (LDLT) PATIENTS AND METHODS: We obtained Gd-EOB-DTPA-enhanced 3 Tesla MRI before living donor hepatectomy in donors (donor group; n=30) and after LDLT in their recipients (recipient group; n=30). MRIs were evaluated in terms of quantitative and qualitative variables. Quantitative parameters included relative liver enhancement value, biliary signal intensity value, and muscle signal index value. Qualitative parameters included visual evaluation of the liver and biliary enhancement on hepatobiliary phase images. Patients were followed up for postoperative biliary and vascular complications and divided according to the presence and absence of complications. The relationship between MRI parameters and postoperative complications was statistically analyzed. RESULTS: The mean relative liver enhancement values, mean biliary signal values, and muscle signal index were significantly lower in recipients with postoperative complications than those in donors and recipients without complications (p < 0.001). Visual assessments of liver enhancement and biliary signal were also significantly different in recipients with postoperative complications than that in donors and recipients without complications (p < 0.001). CONCLUSIONS: Quantitative and qualitative MRI parameters obtained by Gd-EOB-DTPA-enhanced MRI on hepatobiliary phase images may potentially become a reliable tool for the assessment of the risk for postoperative complications after LDLT.

Tuning Magnetic Properties of a Carbon Nanotube-Lanthanide Hybrid Molecular Complex through Controlled Functionalization.

Molecular magnets attached to carbon nanotubes (CNT) are being studied as potential candidates for developing spintronic and quantum technologies. However, the functionalization routes used to develop these hybrid systems can drastically affect their respective physiochemical properties. Due to the complexity of this systems, little work has been directed at establishing the correlation between the degree of functionalization and the magnetic character. Here, we demonstrate the chemical functionalization degree associated with molecular magnet loading can be utilized for controlled tuning the magnetic properties of a CNT-lanthanide hybrid complex. CNT functionalization degree was evaluated by interpreting minor Raman phonon modes in relation to the controlled reaction conditions. These findings were exploited in attaching a rare-earth-based molecular magnet (Gd-DTPA) to the CNTs. Inductively coupled plasma mass spectrometry, time-of-flight secondary ion mass spectrometry and super conducting quantum interference device (SQUID) measurements were used to elucidate the variation of magnetic character across the samples. This controlled Gd-DTPA loading on the CNT surface has led to a significant change in the nanotube intrinsic diamagnetism, showing antiferromagnetic coupling with increase in the Weiss temperature with respect to increased loading. This indicates that synthesis of a highly correlated spin system for developing novel spintronic technologies can be realized through a carbon-based hybrid material.

Optimal Combination of Features on Gadoxetate Disodium-enhanced MR Imaging for Non-invasive Differential Diagnosis of Hepatocellular Carcinoma: The JAMP-HCC Study.

PURPOSE: To determine the optimal combination of gadoxetate disodium-enhanced magnetic resonance imaging (MRI) findings for the diagnosis of hepatocellular carcinoma (HCC) and to compare its diagnostic ability to that of dynamic computed tomography (CT) in patients with chronic liver disease. METHODS: This multi-institutional study consisted of two parts: Study 1, a retrospective study to determine the optimal combination of gadoxetate disodium-enhanced MRI findings (decision tree and logistic model) to distinguish HCC (n = 199) from benign (n = 81) or other malignant lesions (n = 95) (375 nodules in 269 patients) and Study 2, a prospective study to compare the diagnostic ability of gadoxetate disodium-enhanced MRI to distinguish HCC (n = 73) from benign (n = 15) or other malignant lesions (n = 12) with that of dynamic CT (100 nodules in 83 patients). Two radiologists independently evaluated the imaging findings (Study 1 and 2) and made a practical diagnosis (Study 2). RESULTS: In Study 1, rim or whole enhancement on arterial phase images, signal intensities on T2-weighted/diffusion-weighted/portal venous/transitional/hepatobiliary phase images, and signal drop on opposed-phase images were independently useful for differential diagnosis. In Study 2, the accuracy, sensitivity, negative predictive value, and negative likelihood ratio of the CT decision tree (reader 2) were higher than those of MRI Model 2 (P = 0.015-0.033). There were no other significant differences in diagnostic ability (P = 0.059-1.000) and radiologist-made practical diagnosis (P = 0.059-1.000) between gadoxetate disodium-enhanced MRI and CT. CONCLUSION: We identified the optimal combination of gadoxetate disodium-enhanced MRI findings for HCC diagnosis. However, its diagnostic ability was not superior to that of dynamic CT.

Gadolinium-based contrast agents: in vitro paraoxonase 1 inhibition, in silico studies.

Medications show their biological effects by interaction with enzymes, which have been known to play an essential role in the pathogenesis of many diseases. Inhibition or induction of drug metabolizing enzymes has an essential place in the drug design for many kinds of diseases including cardiovascular, neurological, metabolic, and cancer. The main goal of the current study is to contribute to this growing drug design field by observing PON1-drug interactions. In recent years, the safety of gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI) has discussed. In the present study, paraoxonase 1 (PON1) enzyme was purified from human serum by simple chromatographic methods with 4095.24 EU mg-1 protein specific activity. The inhibitory activities of gadoteric acid, gadopentetic acid, gadoxetate disodium, and gadodiamide were investigated on PON1 activity of the enzyme. IC50 values were found in the range of 51.28 ± 0.14 to 285.80 ± 0.96 mM. Ki constants were found as 67.95 ± 0.60 mM, 104.97 ± 0.96 mM, 202.33 ± 1.75 mM, and 299.43 ± 2.64 mM for gadoteric acid, gadopentetic acid, gadoxetate disodium, and gadodiamide, respectively. While the inhibition types are determined as competitive of gadoxetate disodium and gadodiamide by the Lineweaver-Burk curves, it was noncompetitive for other compounds. In addition, the molecular docking analyses of gadoxetate disodium and gadodiamide were carried out to understand the binding interactions on the active site of the PON1 enzyme. The structure-activity relationship (SAR) of the drugs was established on the basis of different substituents and their positions in the compounds.

How the Chemical Properties of GBCAs Influence Their Safety Profiles In Vivo.

The extracellular class of gadolinium-based contrast agents (GBCAs) is an essential tool for clinical diagnosis and disease management. In order to better understand the issues associated with GBCA administration and gadolinium retention and deposition in the human brain, the chemical properties of GBCAs such as relative thermodynamic and kinetic stabilities and their likelihood of forming gadolinium deposits in vivo will be reviewed. The chemical form of gadolinium causing the hyperintensity is an open question. On the basis of estimates of total gadolinium concentration present, it is highly unlikely that the intact chelate is causing the T1 hyperintensities observed in the human brain. Although it is possible that there is a water-soluble form of gadolinium that has high relaxitvity present, our experience indicates that the insoluble gadolinium-based agents/salts could have high relaxivities on the surface of the solid due to higher water access. This review assesses the safety of GBCAs from a chemical point of view based on their thermodynamic and kinetic properties, discusses how these properties influence in vivo behavior, and highlights some clinical implications regarding the development of future imaging agents.

Role of Contrast-Enhanced Ultrasound as a Second-Line Diagnostic Modality in Noninvasive Diagnostic Algorithms for Hepatocellular Carcinoma.

OBJECTIVE: To investigate the diagnostic performance of contrast-enhanced ultrasound (CEUS) and its role as a second-line imaging modality after gadoxetate-enhanced MRI (Gd-EOB-MRI) in the diagnosis of hepatocellular carcinoma (HCC) among at risk observations. MATERIALS AND METHODS: We prospectively enrolled participants at risk of HCC with treatment-naïve solid hepatic observations (≥ 1 cm) of Liver Imaging Reporting and Data System (LR)-3/4/5/M during surveillance and performed Gd-EOB-MRI. A total of one hundred and three participants with 103 hepatic observations (mean size, 28.2 ± 24.5 mm; HCCs [n = 79], non-HCC malignancies [n = 15], benign [n = 9]; diagnosed by pathology [n = 57], or noninvasive method [n = 46]) were included in this study. The participants underwent CEUS with sulfur hexafluoride. Arterial phase hyperenhancement (APHE) and washout on Gd-EOB-MRI and CEUS were evaluated. The distinctive washout in CEUS was defined as mild washout 60 seconds after contrast injection. The diagnostic ability of Gd-EOB-MRI and of CEUS as a second-line modality for HCC were determined according to the European Association for the Study of the Liver (EASL) and the Korean Liver Cancer Association and National Cancer Center (KLCA-NCC) guidelines. The diagnostic abilities of both imaging modalities were compared using the McNemar's test. RESULTS: The sensitivity of CEUS (60.8%) was lower than that of Gd-EOB-MRI (72.2%, p = 0.06 by EASL; 86.1%, p < 0.01 by KLCA-NCC); however, the specificity was 100%. By performing CEUS on the inconclusive observations in Gd-EOB-MRI, HCCs without APHE (n = 10) or washout (n = 12) on Gd-EOB-MRI further presented APHE (80.0%, 8/10) or distinctive washout (66.7%, 8/12) on CEUS, and more HCCs were diagnosed than with Gd-EOB-MRI alone (sensitivity: 72.2% vs. 83.5% by EASL, p < 0.01; 86.1% vs. 91.1% by KCLA-NCC, p = 0.04). There were no false-positive cases for HCC on CEUS. CONCLUSION: The addition of CEUS to Gd-EOB-MRI as a second-line diagnostic modality increases the frequency of HCC diagnosis without changing the specificities.

Experimentally based structural model of Yih1 provides insight into its function in controlling the key translational regulator Gcn2.

Yeast impact homolog 1 (Yih1), or IMPACT in mammals, is part of a conserved regulatory module controlling the activity of General Control Nonderepressible 2 (Gcn2), a protein kinase that regulates protein synthesis. Yih1/IMPACT is implicated not only in many essential cellular processes, such as neuronal development, immune system regulation and the cell cycle, but also in cancer. Gcn2 must bind to Gcn1 in order to impair the initiation of protein translation. Yih1 hinders this key Gcn1-Gcn2 interaction by binding to Gcn1, thus preventing Gcn2-mediated inhibition of protein synthesis. Here, we solved the structures of the two domains of Saccharomyces cerevisiae Yih1 separately using Nuclear Magnetic Resonance and determined the relative positions of the two domains using a range of biophysical methods. Our findings support a compact structural model of Yih1 in which the residues required for Gcn1 binding are buried in the interface. This model strongly implies that Yih1 undergoes a large conformational rearrangement from a latent closed state to a primed open state to bind Gcn1. Our study provides structural insight into the interactions of Yih1 with partner molecules.