Chiral coordination polymer nanowires boost radiation-induced in situ tumor vaccination.

Radiation-induced in situ tumor vaccination alone is very weak and insufficient to elicit robust antitumor immune responses. In this work, we address this issue by developing chiral vidarabine monophosphate-gadolinium nanowires (aAGd-NWs) through coordination-driven self-assembly. We elucidate the mechanism of aAGd-NW assembly and characterize their distinct features, which include a negative surface charge, ultrafine topography, and right-handed chirality. Additionally, aAGd-NWs not only enhance X-ray deposition but also inhibit DNA repair, thereby enhancing radiation-induced in situ vaccination. Consequently, the in situ vaccination induced by aAGd-NWs sensitizes radiation enhances CD8+ T-cell-dependent antitumor immunity and synergistically potentiates the efficacy immune checkpoint blockade therapies against both primary and metastatic tumors. The well-established aAGd-NWs exhibit exceptional therapeutic capacity and biocompatibility, offering a promising avenue for the development of radioimmunotherapy approaches.

Scar architecture affects the electrophysiological characteristics of induced ventricular arrhythmias in hypertrophic cardiomyopathy.

AIMS: Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) detects myocardial scarring, a risk factor for ventricular arrhythmias (VAs) in hypertrophic cardiomyopathy (HCM). The LGE-CMR distinguishes core, borderzone (BZ) fibrosis, and BZ channels, crucial components of re-entry circuits. We studied how scar architecture affects inducibility and electrophysiological traits of VA in HCM. METHODS AND RESULTS: We correlated scar composition with programmed ventricular stimulation-inducible VA features using LGE intensity maps. Thirty consecutive patients were enrolled. Thirteen (43%) were non-inducible, 6 (20%) had inducible non-sustained, and 11 (37%) had inducible sustained mono (MMVT)- or polymorphic VT/VF (PVT/VF). Of 17 induced VA, 13 (76%) were MMVT that either ended spontaneously, persisted as sustained monomorphic, or degenerated into PVT/VF. Twenty-seven patients (90%) had LGE. Of these, 17 (57%) had non-sustained or sustained inducible VA. Scar mass significantly increased (P = 0.002) from non-inducible to inducible non-sustained and sustained VA patients in both the BZ and core components. Borderzone channels were found in 23%, 67%, and 91% of non-inducible, inducible non-sustained, and inducible sustained VA patients (P = 0.003). All 13 patients induced with MMVT or monomorphic-initiated PVT/VF had LGE. The origin of 10/13 of these VTs matched scar location, with 8/10 of these LGE regions showing BZ channels. During follow-up (20 months, interquartile range: 7-37), one patient with BZ channels and inducible PVT had an ICD shock for VF. CONCLUSION: Scar architecture determines inducibility and electrophysiological traits of VA in HCM. Larger studies should explore the role of complex LGE patterns in refining risk assessment in HCM patients.

NIR-Light-Triggered Mild-Temperature Hyperthermia to Overcome the Cascade Cisplatin Resistance for Improved Resistant Tumor Therapy.

Currently, cisplatin resistance has been recognized as a multistep cascade process for its clinical chemotherapy failure. Hitherto, it remains challenging to develop a feasible and promising strategy to overcome the cascade drug resistance (CDR) issue for achieving fundamentally improved chemotherapeutic efficacy. Herein, a novel self-assembled nanoagent is proposed, which is constructed by Pt(IV) prodrug, cyanine dye (cypate), and gadolinium ion (Gd3+), for systematically conquering the cisplatin resistance by employing near-infrared (NIR) light activated mild-temperature hyperthermia in tumor targets. The proposed nanoagents exhibit high photostability, GSH/H+-responsive dissociation, preferable photothermal conversion, and enhanced cellular uptake performance. In particular, upon 785-nm NIR light irradiation, the generated mild temperature of ≈ 43 °C overtly improves the cell membrane permeability and drug uptake, accelerates the disruption of intracellular redox balance, and apparently enhances the formation of Pt-DNA adducts, thereby effectively overcoming the CDR issue and achieves highly improved therapeutic efficacy for cisplatin-resistant tumor ablation.

Magnetic Resonance Angiography with Hour-Scale Duration after Single Low-Dose Administration of Biocompatible Gadolinium Oxide Nanoprobe.

Long-term contrast-enhanced angiography offers significant advantages in theranostics for diverse vascular diseases, particularly in terms of real-time dynamic monitoring during acute vascular events; However, achieving vascular imaging with a duration of hours through a single administration of low-dose contrast agent remains challenging. Herein, a hyaluronic acid-templated gadolinium oxide (HA@Gd2O3) nanoprobe-enhanced magnetic resonance angiography (MRA) is proposed to address this bottleneck issue for the first time. The HA@Gd2O3 nanoprobe synthesized from a facile one-pot biomineralization method owns ultrasmall size, good biocompatibility, optimal circulation half-life (≈149 min), and a relatively high T1 relaxivity (r1) under both clinical 3 T (8.215 mM-1s-1) and preclinical 9.4 T (4.023 mM-1s-1) equipment. The HA@Gd2O3 nanoprobe-enhanced MRA highlights major vessels readily with significantly improved contrast, extended imaging duration for at least 2 h, and ultrahigh resolution of 0.15 mm under 9.4 T, while only requiring half clinical dosage of Gd. This technique can enable rapid diagnosis and real-time dynamic monitoring of vascular changes in a model of acute superior mesenteric vein thrombosis with only a single injection of nanoprobe. The HA@Gd2O3 nanoprobe-enhanced MRA provides a sophisticated approach for long-term (hour scale) vascular imaging with ultrahigh resolution and high contrast through single administration of low-dose contrast agent.

Effects of Endohedral Gd-Containing Fullerenols with a Different Number of Oxygen Substituents on Bacterial Bioluminescence.

Gadolinium (Gd)-containing fullerenols are perspective agents for magnetic resonance imaging and cancer research. They combine the unique paramagnetic properties of Gd with solubility in water, low toxicity and antiradical activity of fullerenols. We compared the bioeffects of two Gd-containing fullerenols with a different number of oxygen groups-20 and 42: Gd@C82O20H14 and Gd@C82O42H32. The bioluminescent bacteria-based assay was applied to monitor the toxicity of fullerenols, bioluminescence was applied as a signal physiological parameter, and bacterial enzyme-based assay was used to evaluate the fullerenol effects on enzymatic intracellular processes. Chemiluminescence luminol assay was applied to monitor the content of reactive oxygen species (ROS) in bacterial and enzymatic media. It was shown that Gd@C82O42H32 and Gd@C82O20H14 inhibited bacterial bioluminescence at >10-1 and >10-2 gL-1, respectively, revealing a lower toxicity of Gd@C82O42H32. Low-concentration (10-3-10-1 gL-1) bacterial bioluminescence activation by Gd@C82O42H32 was observed, while this activation was not found under exposure to Gd@C82O20H14. Additional carboxyl groups in the structure of Gd@C82O42H32 were determined by infrared spectroscopy and confirmed by quantum chemical calculations. The groups were supposed to endow Gd@C82O42H32 with higher penetration ability through the cellular membrane, activation ability, lower toxicity, balancing of the ROS content in the bacterial suspensions, and lower aggregation in aqueous media.

Distinguishing metabolic signals of liver tumors from surrounding liver cells using hyperpolarized 13 C MRI and gadoxetate.

PURPOSE: To use the hepatocyte-specific gadolinium-based contrast agent gadoxetate combined with hyperpolarized (HP) [1-13 C]pyruvate MRI to selectively suppress metabolic signals from normal hepatocytes while preserving the signals arising from tumors. METHODS: Simulations were performed to determine the expected changes in HP 13 C MR signal in liver and tumor under the influence of gadoxetate. CC531 colon cancer cells were implanted into the livers of five Wag/Rij rats. Liver and tumor metabolism were imaged at 3 T using HP [1-13 C] pyruvate chemical shift imaging before and 15 min after injection of gadoxetate. Area under the curve for pyruvate and lactate were measured from voxels containing at least 75% of normal-appearing liver or tumor. RESULTS: Numerical simulations predicted a 36% decrease in lactate-to-pyruvate (L/P) ratio in liver and 16% decrease in tumor. In vivo, baseline L/P ratio was 0.44 ± 0.25 in tumors versus 0.21 ± 0.08 in liver (p = 0.09). Following administration of gadoxetate, mean L/P ratio decreased by an average of 0.11 ± 0.06 (p < 0.01) in normal-appearing liver. In tumors, mean L/P ratio post-gadoxetate did not show a statistically significant change from baseline. Compared to baseline levels, the relative decrease in L/P ratio was significantly greater in liver than in tumors (-0.52 ± 0.16 vs. -0.19 ± 0.25, p < 0.05). CONCLUSIONS: The intracellular hepatobiliary contrast agent showed a greater effect suppressing HP 13 C MRI metabolic signals (through T1 shortening) in normal-appearing liver when compared to tumors. The combined use of HP MRI with selective gadolinium contrast agents may allow more selective imaging in HP 13 C MRI.

Effect of late gadolinium enhancement on left atrial impairment in myocarditis patients.

OBJECTIVE: The aims of our study were to investigate the effect of the extent and location of late gadolinium enhancement (LGE) on the left atrium (LA) function in patients with acute myocarditis (AM) using cardiovascular magnetic resonance (CMR). METHOD: This retrospective study performed CMR scans in 113 consecutive patients (89 males, 24 females; mean age 45.8 ± 17.3 years) with AM that met the updated Lake Louise criteria. Reservoir, conduit, and booster LA functions were analyzed by CMR feature tracking using dedicated software. Besides LA strain measurements, myocardial scar location and extent were assigned and quantified by LGE imaging. RESULTS: AM patients with septal LGE had impaired reservoir, conduit, and conduit strain rate function in comparison with AM patients with non-septal LGE (p = 0.001, for all). In fully adjusted multivariable linear regression, reservoir and conduit were significantly associated with left ventricle (LV) LGE location (ß coefficient = 8.205, p = 0.007; ß coefficient = 5.185, p = 0.026; respectively). In addition, LA parameters decreased according to the increase in the extent of LV fibrosis (LGE ≤ 10%; LGE 11-19%; LGE ≥ 20%). After adjustment in multivariable linear regression, the association with LV LGE extent was no longer statistically significant. CONCLUSION: In patients with acute myocarditis, LA function abnormalities are significantly associated with LV LGE location, but not with LGE extent. Septal LGE is paralleled by a deterioration of LA reservoir and conduit function. CLINICAL RELEVANCE STATEMENT: Left atrium dysfunction is associated with the presence of late gadolinium enhancement in the left ventricle septum and can be useful in the clinical prognostication of patients with acute myocarditis, allowing individually tailored treatment. KEY POINTS: • Myocardial fibrosis is related to atrial impairment. • The location of myocardial fibrosis is the main determinant of atrial dysfunction in myocarditis patients. • The quantification of atrial mechanisms may provide more in-depth insight into myocarditis pathophysiology.

Late gadolinium enhanced cardiac MR derived radiomics approach for predicting all-cause mortality in cardiac amyloidosis: a multicenter study.

OBJECTIVES: To evaluate the prognostic value of radiomics features based on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) images in patients with cardiac amyloidosis (CA). METHODS: This retrospective study included 120 CA patients undergoing CMR at three institutions. Radiomics features were extracted from global and three different segments (base, mid-ventricular, and apex) of left ventricular (LV) on short-axis LGE images. Primary endpoint was all-cause mortality. The predictive performance of the radiomics features and semi-quantitative and quantitative LGE parameters were compared by ROC. The AUC was used to observe whether Rad-score had an incremental value for clinical stage. The Kaplan-Meier curve was used to further stratify the risk of CA patients. RESULTS: During a median follow-up of 12.9 months, 30% (40/120) patients died. There was no significant difference in the predictive performance of the radiomics model in different LV sections in the validation set (AUCs of the global, basal, middle, and apical radiomics model were 0.75, 0.77, 0.76, and 0.77, respectively; all p > 0.05). The predictive performance of the Rad-score of the base-LV was better than that of the LGE total enhancement mass (AUC:0.77 vs. 0.54, p < 0.001) and LGE extent (AUC: 0.77 vs. 0.53, p = 0.004). Rad-score combined with Mayo stage had better predictive performance than Mayo stage alone (AUC: 0.86 vs. 0.81, p = 0.03). Rad-score (≥ 0.66) contributed to the risk stratification of all-cause mortality in CA. CONCLUSIONS: Compared to quantitative LGE parameters, radiomics can better predict all-cause mortality in CA, while the combination of radiomics and Mayo stage could provide higher predictive accuracy. CLINICAL RELEVANCE STATEMENT: Radiomics analysis provides incremental value and improved risk stratification for all-cause mortality in patients with cardiac amyloidosis. KEY POINTS: • Radiomics in LV-base was superior to LGE semi-quantitative and quantitative parameters for predicting all-cause mortality in CA. • Rad-score combined with Mayo stage had better predictive performance than Mayo stage alone or radiomics alone. • Rad-score ≥ 0.66 was associated with a significantly increased risk of all-cause mortality in CA patients.

Prognostic Role of the Progression of Late Gadolinium Enhancement in Hypertrophic Cardiomyopathy.

In hypertrophic cardiomyopathy (HCM), late gadolinium enhancement (LGE) extent ≥15% of left ventricular mass is considered a prognostic risk factor. LGE extent increases over time and the clinical role of the progression of LGE over time (LGE rate) was not prospectively evaluated. We sought to evaluate the prognostic role of the LGE rate in HCM. We enrolled 105 patients with HCM who underwent cardiac magnetic resonance (CMR) at baseline (CMR-I) and after ≥2 years of follow-up (CMR-II). LGE rate was defined as the ratio between the increase of LGE extent (grams) and the time interval (months) between examinations. A combined end point of sudden cardiac death, resuscitated cardiac arrest, appropriate Implanted Cardioverter Defibrillator (ICD) intervention, and sustained ventricular tachycardia was used (hard events). The percentage of patients with LGE extent ≥15% increased from 9% to 20% from CMR-I to CMR-II (p = 0.03). During a median follow-up of 52 months, 25 hard events were recorded. The presence of LGE ≥15% at CMR-II allowed a significant reclassification of the risk of patients than at LGE ≥15% at CMR-I (net reclassification improvement 0.21, p = 0.046). On the MaxStat analysis, the optimal prognostic cut point for LGE rate was >0.07 g/month. On the Kaplan-Meier curve, patients with LGE rate >0.07 had worse prognosis than those without (p <0.0001). LGE rate >0.07 allowed a significant reclassification of the risk compared with LGE ≥15% at CMR-I and at CMR-II (net reclassification improvement 0.49, p = 0.003). In the multivariable models, LGE rate >0.07 was the best independent predictor of hard events. In conclusion, CMR should be repeated after 2 years to reclassify the risk for sudden death of those patients. A high LGE rate may be considered a novel prognostic factor in HCM.

Absence of visible infarction on cardiac magnetic resonance imaging despite the established diagnosis of myocardial infarction by 4th Universal Definition of Myocardial Infarction.

AIMS: Myocardial scarring due to acute myocardial infarction (AMI) can be visualized by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging. However, a recent study revealed a group of Type 1 AMI patients with undetectable myocardial injury on LGE. This study aims to describe these cases in detail and explore possible explanations for this new phenomenon. METHODS AND RESULTS: A total of 137 patients diagnosed with either ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (non-STEMI) diagnosed according to the 4th Universal Definition of Myocardial Infarction underwent LGE-CMR after invasive coronary angiography. Fourteen of them (10.2%) showed no LGE and were included in the final study population. Most patients presented with acute chest pain, 3 patients were diagnosed as STEMI, and 11 as non-STEMI. Peak high-sensitive cardiac troponin T ranged from 45 to 1173 ng/L. A culprit lesion was identified in 12 patients. Severe coronary stenoses were found in five patients, while seven patients had subtotal to total coronary artery occlusion. Percutaneous coronary intervention was performed in 10 patients, while 2 patients required coronary artery bypass grafting and no intervention was required in 2 patients. Cardiac magnetic resonance was performed 30 (4-140) days after the initial presentation. Most patients showed preserved left ventricular ejection fraction on CMR. No alternative reasons for the rise/fall of high-sensitive cardiac troponin T were found. CONCLUSION: The absence of LGE on CMR in patients with Type 1 AMI is a new finding. While insufficient spatial resolution of LGE imaging, delayed CMR performance, spontaneous reperfusion, and coronary collaterals may provide some explanations, further investigations are required to fully understand this phenomenon.

Gadolinium-Based Contrast Agents and Free Gadolinium Inhibit Differentiation and Activity of Bone Cell Lineages.

OBJECTIVES: Administration of gadolinium-based contrast agents (GBCA) in magnetic resonance imaging results in the long-term retention of gadolinium (Gd) in tissues and organs, including the bone, and may affect their function and metabolism. This study aims to investigate the effects of Gd and GBCA on the proliferation/survival, differentiation, and function of bone cell lineages. MATERIALS AND METHODS: Primary murine osteoblasts (OB) and osteoclast progenitor cells (OPC) isolated from C57BL/6J mice were used to test the effects of Gd 3+ (12.5-100 µM) and GBCA (100-2000 µM). Cultures were supplemented with the nonionic linear Gd-DTPA-BMA (gadodiamide), ionic linear Gd-DTPA (gadopentetic acid), and macrocyclic Gd-DOTA (gadoteric acid). Cell viability and differentiation were analyzed on days 4-6 of the culture. To assess the resorptive activity of osteoclasts, the cells were grown in OPC cultures and were seeded onto layers of amorphous calcium phosphate with incorporated Gd. RESULTS: Gd 3+ did not affect OB viability, but differentiation was reduced dose-dependently up to 72.4% ± 6.2%-73.0% ± 13.2% (average ± SD) at 100 µM Gd 3+ on days 4-6 of culture as compared with unexposed controls ( P < 0.001). Exposure to GBCA had minor effects on OB viability with a dose-dependent reduction up to 23.3% ± 10.2% for Gd-DTPA-BMA at 2000 µM on day 5 ( P < 0.001). In contrast, all 3 GBCA caused a dose-dependent reduction of differentiation up to 88.3% ± 5.2% for Gd-DTPA-BMA, 49.8% ± 16.0% for Gd-DTPA, and 23.1% ± 8.7% for Gd-DOTA at 2000 µM on day 5 ( P < 0.001). In cultures of OPC, cell viability was not affected by Gd 3+ , whereas differentiation was decreased by 45.3% ± 9.8%-48.5% ± 15.8% at 100 µM Gd 3+ on days 4-6 ( P < 0.05). Exposure of OPC to GBCA resulted in a dose-dependent increase in cell viability of up to 34.1% ± 11.4% at 2000 µM on day 5 of culture ( P < 0.001). However, differentiation of OPC cultures was reduced on day 5 by 24.2% ± 9.4% for Gd-DTPA-BMA, 47.1% ± 14.0% for Gd-DTPA, and 38.2% ± 10.0% for Gd-DOTA ( P < 0.001). The dissolution of amorphous calcium phosphate by mature osteoclasts was reduced by 36.3% ± 5.3% upon incorporation of 4.3% Gd/Ca wt/wt ( P < 0.001). CONCLUSIONS: Gadolinium and GBCA inhibit differentiation and activity of bone cell lineages in vitro. Thus, Gd retention in bone tissue could potentially impair the physiological regulation of bone turnover on a cellular level, leading to pathological changes in bone metabolism.

Evaluation of gadolinium-based contrast agents in juvenile CD-1 mice including behavioral evaluations.

INTRODUCTION: Seven gadolinium-based contrast agents (GBCAs), four linear and three macrocyclic, were evaluated for potential effects on development, including behavior of juvenile CD-1 mice. METHODS: The GBCAs were administered via intravenous injection once daily on postnatal day (PND) 9, 12, 15, 18, and 21 (PND 1 was the day of delivery) at doses up to twice the human equivalent clinical dose (i.e., 0.63 mmol Gd/kg for gadoxetate disodium and 2.5 mmol Gd/kg for the other GBCAs). Mice were bled for evaluation of exposure (plasma) to gadolinium (Gd) on PND 9, 12, and 70. At scheduled euthanasia, the liver, spleen, brain, skin (dorsal surface), bone (left femur), and kidneys were excised from up to six mice/sex/group on PND 10, 22, or 70 for the determination of Gd levels and histopathological analysis. All mice were monitored for toxicity, growth and survival, sexual maturation, and behavior. CONCLUSION: Gd was quantifiable in the brain tissues with levels declining over time. There was no long-term effect on the growth and development for mice exposed to any of the GBCAs. There was no impact on neurodevelopment as assessed by brain histology and validated neurobehavioral tests, including a functional observational battery, motor activity, and learning and memory as evaluated in the Morris water maze. For all GBCAs, the highest dose tested represented the no-observable-adverse-effect level in juvenile mice.

EFFECTIVENESS OF THE PHOTON CAPTURE BEAM TECHNOLOGY AND PHOTODYNAMIC IMPACT ON MALIGNANT HUMAN CELLS ІN A RESTING STATE. / ЕФЕКТИВНІСТЬ ФОТОН/ЗАХВАТНОЇ ПРОМЕНЕВОЇ ТЕХНОЛОГІЇ ТА ФОТОДИНАМІЧНОГО ВПЛИВУ НА ЗЛОЯКІСНІ КЛІТИНИ ЛЮДИНИ, ЩО ЗНАХОДЯТЬСЯ У СТАНІ СПОКОЮ.

OBJECTIVE: to investigate the structural and morphofunctional changes in test system of malignant (cell line A-549) human cells in a resting state exposed to X-rays in the presence of gadolinium-containing photon capture agent «Dotavist¼ and optical light (red spectrum) in combination with «Photolon¼ photosensitizer. METHODS: Passaged malignant human cell culture technology, X-ray and red light exposure, cytological and statistical methods. RESULTS: X-ray exposure at a dose of 10.0 Gy in the presence of photon capture agent «Dotavist¼ (at a 100 µg/ml nutrient medium concentration) led to death of 75-83 % of malignant cells in a resting state on the 6-8th day of cultivation. Photodynamic exposure (630 nm wavelength red light) in the presence of «Photolon¼ photosensitizer (200 µg/ml concentration) resulted in death of 69-73 % of malignant cells, respectively. Combination of the photon-capturing technology and photodynamic exposure resulted in death of 90 % of the malignant cells in a phase of steady-state growth on the 8th day of cultivation. CONCLUSION: Combination of the photon capture technology (X-ray exposure with gadolinium-containing photoncapture agent «Dotavist¼ in cytotoxic concentration) and photodynamic exposure in the presence of «Photolon¼ photosensitizer increased devitalization effectiveness of human non-small cell lung cancer cells (A-549 cell line) being in a steady-state growth phase up to 90 %. Ten percent of cells resistant to the applied technologies retained their proliferative potential, evident as changes in their morphology, genotype and adhesiveness during further cultivation.

Holmium (III)-doped multifunctional nanotheranostic agent for ultra-high-field magnetic resonance imaging-guided chemo-photothermal tumor therapy.

Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Despite being the most commonly used MRI contrast agents, gadolinium chelates perform poorly in high magnetic fields, which significantly weakens their T1 intensity. In comparison, the rare element Holmium (Ho)-based nanoparticles (NPs) have demonstrated great potential as T2-weighted MRI contrast agents in UHF MRI due to their extremely short electron relaxation times (∼ 10-13s). In this study, a multifunctional nanotherapeutic probe was designed for UHF MRI-guided chemotherapy and photothermal therapy. The Ho (III)-doped mesoporous polydopamine (Ho-MPDA, HM) nanosphere was loaded with the chemotherapeutic drug mitoxantrone (MTO) and then coated with 4T1 cell membranes to enhance active targeting delivery to breast cancer. The prepared nanotherapeutic probe MTO@HMM@4T1 (HMM@T) exhibited good biocompatibility, high drug-loading capability and great potential as Ho (III)-based UHF MRI contrast agents. Moreover, the biodegradation of HMM@T in response to the intratumor pH and glutathione (GSH) promotes MTO release. Near-infrared (NIR) light irradiation of HM induced photothermal therapy and further enhanced drug release. Consequently, HMM@T effectively acted as an MRI-guided tumor-targeting chemo-photothermal therapy against 4T1 breast cancer. STATEMENT OF SIGNIFICANCE: Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Although gadolinium chelates are the most commonly used MRI contrast agents in clinical practice, they exhibit a significantly decreased T1 relaxivity at UHF. Holmium exhibits outstanding UHF magnetic resonance capabilities in comparison with gadolinium chelates currently used in clinic. Herein, a theranostic nanodrug (HMM@T) was designed for UHF MRI-guided chemo-photothermal therapy. The nanodrug possessed remarkable UHF T2 MRI properties (r2 = 152.13 mM-1s-1) and high drug loading capability of 18.4 %. The biodegradation of HMM@T NPs under triple stimulations of pH, GSH, and NIR led to an efficient release of MTO in tumor microenvironment. Our results revealed the potential of a novel UHF MRI-guided multifunctional nanosystem in cancer treatment.

Significant cell uptake of Gd(III)-diphenylphosphoryl-diphenylphosphonium complexes: evidence for a new conformationally-dependent tumour cell targeting vector.

The synthesis, characterisation, and tumour cell uptake of six novel Gd(III)-diphenylphosphoryl-diphenylphosphonium complexes are reported. The propyl-linked Gd(III) complexes can accumulate inside human glioma cells at prodigious levels, approaching 1200%, over the parent triphenylphosphonium salts. DFT and quantum chemical topology analyses support a new type of conformationally-dependent tumour cell targeting vector.

Phytoremediation, recovery and toxic effects of ionic gadolinium using the free-floating plant Lemna gibba.

The biosorption and recovery of ionic gadolinium (Gd) from contaminated water by the free-floating duckweed Lemna gibba was studied. The highest non-toxic concentration range was determined as (6.7 mg L-1). The concentration of Gd in the medium and in the plant biomass was monitored and a mass balance was established. Tissue Gd concentration of Lemna increased with increasing Gd concentration of the medium. The bioconcentration factor was up to 1134 and in nontoxic concentrations up to 2.5 g kg-1 Gd tissue concentration was reached. Lemna ash contained 23.2 g Gd kg-1. Gd removal efficiency from the medium was 95%, however, only 17-37% of the initial Gd content of the medium accumulated in Lemna biomass, an average of 5% remained in the water, and 60-79% was calculated as a precipitate. Gadolinium-exposed Lemna plants released ionic Gd into the nutrient solution when they were transferred to a Gd-free medium. The experimental results revealed that in constructed wetlands, L. gibba is able to remove ionic Gd from the water and can be suitable for bioremediation and recovery purposes.

The prognostic value of myocardial salvage index by cardiac magnetic resonance in ST-segment elevation myocardial infarction patients: a systematic review and meta-analysis.

OBJECTIVE: To assess the prognostic value of myocardial salvage index (MSI) by cardiac magnetic resonance (CMR) in ST-segment elevation myocardial infarction (STEMI) patients. METHODS: We systematically searched PubMed, Embase, Web of Science, Cochrane Central, China National Knowledge Infrastructure, and Wanfang Data to identify primary studies reporting MSI in STEMI patients with major adverse cardiovascular events (MACE) comprised of death, myocardial reinfarction, and congestive heart failure. The MSI and MACE rates were pooled. The bias of risk was assessed using the Quality In Prognosis Studies tool. The evidence level was rated based on the meta-analysis of hazard ratio (HR) and 95% confidence interval (CI) of MSI for predicting MACE. RESULTS: Eighteen studies were included covering twelve unique cohorts. Eleven cohorts measured MSI using T2-weighted imaging and T1-weighted late gadolinium enhancement, while one cohort applied T2-mapping and T1-mapping. The pooled MSI (95% CI) was 44% (39 to 49%; 11 studies, 2946 patients), and the pooled MACE rate (95% CI) was 10% (7 to 14%; 12 studies, 311/3011 events/patients). Seven prognostic studies overall showed low risk of bias. The HR (95% CI) per 1% increase of MSI for MACE was 0.95 (0.92 to 0.98; 5 studies, 150/885 events/patients), and HR (95% CI) of MSI < median versus MSI > median for MACE was 5.62 (3.74 to 8.43; 6 studies, 166/1570 events/patients), both rated as weak evidence. CONCLUSIONS: MSI presents potential in predicting MACE in STEMI patients. The prognostic value of MSI using advanced CMR techniques for adverse cardiovascular events needs further investigation. CLINICAL RELEVANCE STATEMENT: Seven studies supported the MSI to serve as a predictor for MACE in STEMI patients, indicating its potential as a risk stratification tool to help manage expectations for these patients in clinical practice. KEY POINTS: • The pooled infarct size (95% CI) and area at risk (95% CI) were 21% (18 to 23%; 11 studies, 2783 patients) and 38% (34 to 43%; 10 studies, 2022 patients), respectively. • The pooled rates (95% CI) of cardiac mortality, myocardial reinfarction, and congestive heart failure were 2% (1 to 3%; 11 studies, 86/2907 events/patients), 4% (3 to 6%; 12 studies, 127/3011 events/patients), and 3% (1 to 5%; 12 studies, 94/3011 events/patients), respectively. • The HRs (95% CI) per 1% increase of MSI for cardiac mortality and congestive heart failure were 0.93 (0.91 to 0.96; 1 study, 14/202 events/patients) and 0.96 (0.93 to 0.99; 1 study, 11/104 events/patients), respectively, but the prognostic value of MSI for myocardial re-infraction has not been measured.

Intracerebral gadolinium deposition following blood-brain barrier disturbance in two different mouse models.

To evaluate the influence of the blood-brain barrier on neuronal gadolinium deposition in a mouse model after multiple intravenous applications of the linear contrast agent gadodiamide. The prospective study held 54 mice divided into three groups: healthy mice (A), mice with iatrogenic induced disturbance of the blood-brain barrier by glioblastoma (B) or cerebral infarction (C). In each group 9 animals received 10 iv-injections of gadodiamide (1.2 mmol/kg) every 48 h followed by plain T1-weighted brain MRI. A final MRI was performed 5 days after the last contrast injection. Remaining mice underwent MRI in the same time intervals without contrast application (control group). Signal intensities of thalamus, pallidum, pons, dentate nucleus, and globus pallidus-to-thalamus and dentate nucleus-to-pons ratios, were determined. Gadodiamide complex and total gadolinium amount were quantified after the last MR examination via LC-MS/MS and ICP-MS. Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios showed no significant increase over time within all mice groups receiving gadodiamide, as well as compared to the control groups at last MR examination. Comparing healthy mice with group B and C after repetitive contrast administration, a significant SI increase could only be detected for glioblastoma mice in globus pallidus-to-thalamus ratio (p = 0.033), infarction mice showed no significant SI alteration. Tissue analysis revealed significantly higher gadolinium levels in glioblastoma group compared to healthy (p = 0.013) and infarction mice (p = 0.029). Multiple application of the linear contrast agent gadodiamide leads to cerebral gadolinium deposition without imaging correlate in MRI.

Long-Term Treatment with Gadopentetic Acid or Gadodiamide Increases TRPC5 Expression and Decreases Adriamycin Nuclear Accumulation in Breast Cancer Cells.

Gadopentetic acid and gadodiamide are paramagnetic gadolinium-based contrast agents (GBCAs) that are routinely used for dynamic contrast-enhanced magnetic resonance imaging (MRI) to monitor disease progression in cancer patients. However, growing evidence indicates that repeated administration of GBCAs may lead to gadolinium (III) cation accumulation in the cortical bone tissue, skin, basal ganglia, and cerebellum, potentially leading to a subsequent slow long-term discharge of Gd3+. Gd3+ is a known activator of the TRPC5 channel that is implicated in breast cancer's resistance to chemotherapy. Herein, we found that gadopentetic acid (Gd-DTPA, 1 mM) potentiated the inward and outward currents through TRPC5 channels, which were exogenously expressed in HEK293 cells. Gd-DTPA (1 mM) also activated the Gd3+-sensitive R593A mutant of TRPC5, which exhibits a reduced sensitivity to GPCR-Gq/11-PLC dependent gating. Conversely, Gd-DTPA had no effect on TRPC5-E543Q, a Gd3+ insensitive TRPC5 mutant. Long-term treatment (28 days) of human breast cancer cells (MCF-7 and SK-BR-3) and adriamycin-resistant MCF-7 cells (MCF-7/ADM) with Gd-DTPA (1 mM) or gadodiamide (GDD, 1 mM) did not affect the IC50 values of ADM. However, treatment with Gd-DTPA or GDD significantly increased TRPC5 expression and decreased the accumulation of ADM in the nuclei of MCF-7 and SK-BR-3 cells, promoting the survival of these two breast cancer cells in the presence of ADM. The antagonist of TRPC5, AC1903 (1 µM), increased ADM nuclear accumulation induced by Gd-DTPA-treatment. These data indicate that prolonged GBCA treatment may lead to increased breast cancer cell survival owing to the upregulation of TRPC5 expression and the increased ADM resistance. We propose that while focusing on providing medical care of the best personalized quality in the clinic, excessive administration of GBCAs should be avoided in patients with metastatic breast cancer to reduce the risk of promoting breast cancer cell drug resistance.

Delayed post gadolinium MRI descriptors for Meniere's disease: a systematic review and meta-analysis.

OBJECTIVES: Delayed post-gadolinium magnetic resonance imaging (MRI) detects changes of endolymphatic hydrops (EH) within the inner ear in Meniere's disease (MD). A systematic review with meta-analysis was conducted to summarise the diagnostic performance of MRI descriptors across the range of MD clinical classifications. MATERIALS AND METHODS: Case-controlled studies documenting the diagnostic performance of MRI descriptors in distinguishing MD ears from asymptomatic ears or ears with other audio-vestibular conditions were identified (MEDLINE, EMBASE, Web of Science, Scopus databases: updated 17/2/2022). Methodological quality was evaluated with Quality Assessment of Diagnostic Accuracy Studies version 2. Results were pooled using a bivariate random-effects model for evaluation of sensitivity, specificity and diagnostic odds ratio (DOR). Meta-regression evaluated sources of heterogeneity, and subgroup analysis for individual clinical classifications was performed. RESULTS: The meta-analysis included 66 unique studies and 3073 ears with MD (mean age 40.2-67.2 years), evaluating 11 MRI descriptors. The combination of increased perilymphatic enhancement (PLE) and EH (3 studies, 122 MD ears) achieved the highest sensitivity (87% (95% CI: 79.92%)) whilst maintaining high specificity (91% (95% CI: 85.95%)). The diagnostic performance of "high grade cochlear EH" and "any EH" descriptors did not significantly differ between monosymptomatic cochlear MD and the latest reference standard for definite MD (p = 0.3; p = 0.09). Potential sources of bias were case-controlled design, unblinded observers and variable reference standard, whilst differing MRI techniques introduced heterogeneity. CONCLUSIONS: The combination of increased PLE and EH optimised sensitivity and specificity for MD, whilst some MRI descriptors also performed well in diagnosing monosymptomatic cochlear MD. KEY POINTS: • A meta-analysis of delayed post-gadolinium magnetic resonance imaging (MRI) for the diagnosis of Meniere's disease is reported for the first time and comprised 66 studies (3073 ears). • Increased enhancement of the perilymphatic space of the inner ear is shown to be a key MRI feature for the diagnosis of Meniere's disease. • MRI diagnosis of Meniere's disease can be usefully applied across a range of clinical classifications including patients with cochlear symptoms alone.