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.

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.

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.

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.

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.

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.

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.

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.

Can gadolinium contrast agents be replaced with saline for direct MR arthrography of the hip? A pilot study with arthroscopic comparison.

OBJECTIVE: To compare image quality and diagnostic performance of preoperative direct hip magnetic resonance arthrography (MRA) performed with gadolinium contrast agent and saline solution. METHODS: IRB-approved retrospective study of 140 age and sex-matched symptomatic patients with femoroacetabular impingement, who either underwent intra-articular injection of 15-20 mL gadopentetate dimeglumine (GBCA), 2.0 mmol/L ("GBCA-MRA" group, n = 70), or 0.9% saline solution ("Saline-MRA" group, n = 70) for preoperative hip MRA and subsequent hip arthroscopy. 1.5 T hip MRA was performed including leg traction. Two readers assessed image quality using a 5-point Likert scale (1-5, excellent-poor), labrum and femoroacetabular cartilage lesions. Arthroscopic diagnosis was used to calculate diagnostic accuracy which was compared between groups with Fisher's exact tests. Image quality was compared with the Mann-Whitney U tests. RESULTS: Mean age was 33 years ± 9, 21% female patients. Image quality was excellent (GBCA-MRA mean range, 1.1-1.3 vs 1.1-1.2 points for Saline-MRA) and not different between groups (all p > 0.05) except for image contrast which was lower for Saline-MRA group (GBCA-MRA 1.1 ± 0.4 vs Saline-MRA 1.8 ± 0.5; p < 0.001). Accuracy was high for both groups for reader 1/reader 2 for labrum (GBCA-MRA 94%/ 96% versus Saline-MRA 96%/93%; p > 0.999/p = 0.904) and acetabular (GBCA-MRA 86%/ 83% versus Saline-MRA 89%/87%; p = 0.902/p = 0.901) and femoral cartilage lesions (GBCA-MRA 97%/ 99% versus Saline-MRA 97%/97%; both p > 0.999). CONCLUSION: Diagnostic accuracy and image quality of Saline-MRA and GBCA-MRA is high in assessing chondrolabral lesions underlining the potential role of non-gadolinium-based hip MRA. KEY POINTS: • Image quality of Saline-MRA and GBCA-MRA was excellent for labrum, acetabular and femoral cartilage, ligamentum teres, and the capsule (all p > 0.18). • The overall image contrast was lower for Saline-MRA (Saline-MRA 1.8 ± 0.5 vs. GBCA-MRA 1.1 ± 0.4; p < 0.001). • Diagnostic accuracy was high for Saline-MRA and GBCA-MRA for labrum (96% vs. 94%; p > 0.999), acetabular cartilage damage (89% vs. 86%; p = 0.902), femoral cartilage damage (97% vs. 97%; p > 0.999), and extensive cartilage damage (97% vs. 93%; p = 0.904).

Validation of the simplified magnetic resonance index of activity by using DWI without gadolinium enhancement to evaluate bowel inflammation in Crohn's disease.

OBJECTIVES: To validate the modified simplified magnetic resonance index of activity (sMARIA) score using DWI on non-contrast magnetic resonance enterography (MRE) to evaluate active inflammation in patients with Crohn's disease (CD), compared to the original sMARIA scoring system, with and without contrast enhancement. METHODS: This retrospective study included 275 bowel segments from 55 CD patients who underwent ileocolonoscopy and MRE within a 2-week period. Two blinded radiologists evaluated original sMARIA on both conventional MRE (CE-sMARIA) and non-contrast MRE (T2-sMARIA). Modified sMARIA was then evaluated using non-contrast MRE, replacing ulcerations with DWI grades. Three scoring systems were compared for diagnostic accuracy of active inflammation, correlation with simple endoscopic score (SES)-CD, and interobserver reproducibility. RESULTS: The AUC of modified sMARIA for detecting active inflammation (0.863, 95% confidence interval [0.803-0.923]) was significantly higher than T2-sMARIA (0.827 [0.773-0.881], p = 0.017), and comparable to CE-sMARIA (0.908 [0.857-0.959], p = 0.122). CE-sMARIA, T2-sMARIA, and modified sMARIA all showed moderate correlation with SES-CD (r = 0.795, 0.722, and 0.777, respectively). Interobserver reproducibility of diffusion restriction (κ, 0.686 [0.602-0.770]) was significantly better than ulcers on conventional MRE (κ, 0.382 [0.212-0.552]; p = 0.001) and T2-weighted image (κ, 0.312 [0.034-0.590]; p = 0.012). CONCLUSIONS: Modified sMARIA using DWI can improve the diagnostic performance of sMARIA on non-contrast MRE, showing comparable performance to sMARIA using contrast-enhanced MRE. KEY POINTS: • DWI can improve the diagnostic performance of non-contrast magnetic resonance enterography (MRE) for assessing active inflammation in patients with Crohn's disease. • Modified simplified magnetic resonance index of activity (sMARIA) using DWI grades in place of ulcers showed comparable diagnostic performance to sMARIA using conventional MRE with contrast-enhanced sequences.

Gadolinium-enhanced MRI visualizing backflow at increasing intra-renal pressure in a porcine model.

INTRODUCTION: Intrarenal backflow (IRB) is known to occur at increased intrarenal pressure (IRP). Irrigation during ureteroscopy increases IRP. Complications such as sepsis is more frequent after prolonged high-pressure ureteroscopy. We evaluated a new method to document and visualize intrarenal backflow as a function of IRP and time in a pig model. METHODS: Studies were performed on five female pigs. A ureteral catheter was placed in the renal pelvis and connected to a Gadolinium/ saline solution 3 ml/L for irrigation. An occlusion balloon-catheter was left inflated at the uretero-pelvic junction and connected to a pressure monitor. Irrigation was successively regulated to maintain steady IRP levels at 10, 20, 30, 40 and 50 mmHg. MRI of the kidneys was performed at 5-minute intervals. PCR and immunoassay analyses were executed on the harvested kidneys to detect potential changes in inflammatory markers. RESULTS: MRI showed backflow of Gadolinium into the kidney cortex in all cases. The mean time to first visual damage was 15 minutes and the mean registered pressure at first visual damage was 21 mmHg. On the final MRI the mean percentage of IRB affected kidney was 66% after irrigation with a mean maximum pressure of 43 mmHg for a mean duration of 70 minutes. Immunoassay analyses showed increased MCP-1 mRNA expression in the treated kidneys compared to contralateral control kidneys. CONCLUSIONS: Gadolinium enhanced MRI provided detailed information about IRB that has not previously been documented. IRB occurs at even very low pressures, and these findings are in conflict with the general consensus that keeping IRP below 30-35 mmHg eliminates the risk of post-operative infection and sepsis. Moreover, the level of IRB was documented to be a function of both IRP and time. The results of this study emphasize the importance of keeping IRP and OR time low during ureteroscopy.

Simultaneous late-gadolinium enhancement and T1 mapping of fibrosis and a novel cell-based combination therapy in hypertensive mice.

Fibrosis is a hallmark of chronic hypertension and disrupts the viability of human bone marrow-derived mesenchymal stromal cells (BM-MSCs) post-transplantation. This study thus, determined whether the anti-fibrotic drug, serelaxin (RLX), could enhance the therapeutic effects of BM-MSCs or BM-MSC-derived exosomes (BM-MSC-EXO) in hypertensive mice. Left ventricular (LV) fibrosis in particular was assessed using conventional histological staining and non-invasive cardiac magnetic resonance imaging (CMRI). CMRI was employed using a novel magnetisation prepared 2 rapid acquisition gradient echo (MP2RAGE) sequence to simultaneously perform late gadolinium enhancement imaging and T1 mapping. Adult male C57BL/6 mice were uninephrectomised, received deoxycorticosterone acetate and saline to drink (1 K/DOCA/salt) for 21 days, whilst control mice were given normal drinking water for the same time-period. On day 14 post-injury, subgroups of 1 K/DOCA/salt-hypertensive mice were treated with RLX alone or in combination with BM-MSCs or BM-MSC-EXO; or the mineralocorticoid receptor antagonist, spironolactone. At day 21 post-injury, LV and kidney histopathology was assessed, whilst LV fibrosis and function were additionally analysed by CMRI and echocardiography. 1 K/DOCA/salt-hypertensive mice developed kidney tubular injury, inflammation, fibrosis, and more moderate LV hypertrophy, fibrosis and diastolic dysfunction. RLX and BM-MSCs combined provided optimal protection against these pathologies and significantly reduced picrosirius red-stained organ fibrosis and MP2RAGE analysis of LV fibrosis. A significant correlation between MP2RAGE analysis and histologically-stained interstitial LV fibrosis was detected. It was concluded that the MP2RAGE sequence enhanced the non-invasive CMRI detection of LV fibrosis. Furthermore, combining RLX and BM-MSCs may represent a promising treatment option for hypertensive cardiorenal syndrome.

Regulatory actions of rare earth elements (La and Gd) on the cell cycle of root tips in rice seedlings (Oryza sativa L.).

The continuous expansion of the application of rare earth elements (REEs) in various fields has attracted attention to their biosafety. At present, the molecular mechanisms underlying the biological effects of REEs are unclear. In this study, the effects of lanthanum (La) and gadolinium (Gd) on cell cycle progression in the root tips of rice seedlings were investigated. Low concentrations of REEs (0.1 mg L-1) induced an increase in the number of cells in the prophase and metaphase, while high concentrations of REEs (10 mg L-1) induced an increase in the number of cells in the late and terminal stages of the cell cycle, and apoptosis or necrosis. Additionally, low concentrations of REEs induced a significant increase in the expression of the cell cycle factors WEE1, CDKA;1, and CYCB1;1, and promoted the G2/M phase and accelerated root tip growth. However, at high REEs concentrations, the DNA damage response sensitized by BRCA1, MRE11, and TP53 could that prevent root tip growth by inhibiting the transcription factor E2F, resulting in obvious G1/S phase transition block and delayed G2/M phase conversion. Furthermore, by comparing the biological effect mechanisms of La and Gd, we found that these two REEs share regulatory actions on the cell cycle of root tips in rice seedlings.

Gadolinium(III) Porphyrinoid Phototheranostics.

Molecular phototheranostics as an emerging field of modern precision medicine has recently attracted increasing research attention owing to non-invasiveness, high precision, and controllable nature of light. In this work, we reported promising gadolinium (Gd3+ ) porphyrinoids as phototheranostic agents for magnetic resonance imaging (MRI) and photodynamic therapy (PDT). The synthesized Gd-1-4-Glu featured with meso-glycosylation and ß-lactonization to endow good biocompatibility and improved photophysical properties. In particular, ß-lactonization of glycosylated Gd3+ porphyrinoids substantially red-shifted Q band absorption to near-infrared (NIR) region and boosted generation of reactive oxygen species including 1 O2 , and some radical species that engaged in both type II and type I PDT pathways. In addition, the number and regioisomerism of ß-oxazolone moieties was observed to play an essential role in improving longitude relaxivity (r1 ) of Gd-1-4-Glu of up to 4.3±0.2 mM-1 s-1 by affecting environmental water exchange. Taking Gd-4-Glu as a promising complex, we further achieved real-time T1 -weighted MRI and PDT on HeLa tumour mice in vivo, revealing the appealing potential of Gd3+ porphyrinoids in phototheranostics.

The Effect of Magnetic Field Gradient and Gadolinium-Based MRI Contrast Agent Dotarem on Mouse Macrophages.

Magnetic resonance imaging (MRI) is widely used in diagnostic medicine. MRI uses the static magnetic field to polarize nuclei spins, fast-switching magnetic field gradients to generate temporal and spatial resolution, and radiofrequency (RF) electromagnetic waves to control the spin orientation. All these forms of magnetic static and electromagnetic RF fields interact with human tissue and cells. However, reports on the MRI technique's effects on the cells and human body are often inconsistent or contradictory. In both research and clinical MRI, recent progress in improving sensitivity and resolution is associated with the increased magnetic field strength of MRI magnets. Additionally, to improve the contrast of the images, the MRI technique often employs contrast agents, such as gadolinium-based Dotarem, with effects on cells and organs that are still disputable and not fully understood. Application of higher magnetic fields requires revisiting previously observed or potentially possible bio-effects. This article focuses on the influence of a static magnetic field gradient with and without a gadolinium-based MRI contrast agent (Dotarem) and the cellular and molecular effects of Dotarem on macrophages.

Iron Oxide Nanoparticles in Mesenchymal Stem Cell Detection and Therapy.

Mesenchymal stem cells (MSCs) exhibit regenerative and reparative properties. However, most MSC-related studies remain to be translated for regular clinical usage, partly due to challenges in pre-transplantation cell labelling and post-transplantation cell tracking. Amidst this, there are growing concerns over the toxicity of commonly used gadolinium-based contrast agents that mediate in-vivo cell detection via MRI. This urges to search for equally effective but less toxic alternatives that would facilitate and enhance MSC detection post-administration and provide therapeutic benefits in-vivo. MSCs labelled with iron oxide nanoparticles (IONPs) have shown promising results in-vitro and in-vivo. Thus, it would be useful to revisit these studies before inventing new labelling approaches. Aiming to inform regenerative medicine and augment clinical applications of IONP-labelled MSCs, this review collates and critically evaluates the utility of IONPs in enhancing MSC detection and therapeutics. It explains the rationale, principle, and advantages of labelling MSCs with IONPs, and describes IONP-induced intracellular alterations and consequent cellular manifestations. By exemplifying clinical pathologies, it examines contextual in-vitro, animal, and clinical studies that used IONP-labelled bone marrow-, umbilical cord-, adipose tissue- and dental pulp-derived MSCs. It compiles and discusses studies involving MSC-labelling of IONPs in combinations with carbohydrates (Venofer, ferumoxytol, dextran, glucosamine), non-carbohydrate polymers [poly(L-lysine), poly(lactide-co-glycolide), poly(L-lactide), polydopamine], elements (ruthenium, selenium, gold, zinc), compounds/stains (silica, polyethylene glycol, fluorophore, rhodamine B, DAPI, Prussian blue), DNA, Fibroblast growth Factor-2 and the drug doxorubicin. Furthermore, IONP-labelling of MSC exosomes is reviewed. Also, limitations of IONP-labelling are addressed and methods of tackling those challenges are suggested.

Identifying early stages of doxorubicin-induced cardiotoxicity in rat model by 7.0 tesla cardiovascular magnetic resonance combining hematological and pathological parameters.

PURPOSE: To identify early doxorubicin-induced cardiotoxicity by applying 7.0 T cardiac magnetic resonance (CMR) combined with creatine kinase isoenzymes (CKMB) from rat models, using pathological results as a reference standard. METHODS: The 48 male rats included in the study were divided into a doxorubicin (DOX) group (n = 32) and a control group (n = 16). Each group was further divided into four subgroups according to the interval weeks between the first administration and CMR examination. DOX group and the controls were injected with DOX (2.5 mg/kg) or physiological saline (2.5 mg/kg) through vena caudalis weekly. The rats in first subgroup received 4 weekly injections and were sacrificed after CMR examination at week 4. Rats in the second, third and fourth DOX or control subgroups underwent 6 weekly injections and were sacrificed after CMR examination at weeks 6, 8 and 10, respectively. The conventional cardiac function parameters, myocardial strain, standardized myocardial T2 value, late gadolinium enhancement, CKMB and pathological results of each rat were analyzed. RESULTS: The LV mass index was reduced and CKMB was increased in the first subgroup (week 4), global circumference strain was decreased and normalized myocardial T2 relaxation time was prolonged in the second subgroup (week 6). At these early point of time, LVEF remained unaffected. Myocardial fibrosis was observed in the third and fourth subgroups (in week 8 and 10, respectively) and the collagen volume fraction was significantly negatively correlated with the LVEF and myocardial strain. CONCLUSIONS: CMR can be used to identify doxorubicin-induced cardiotoxicity at early stage, with the LV mass index, global circumference strain, normalized myocardial T2 relaxation time as the early markers. CKMB can indicate the optimal timing for CMR examination of chemotherapy recipients to improve medical efficiency. Myocardial fibrosis persists in the advanced stage of doxorubicin-induced cardiotoxicity which comprises the main cause of LV dysfunction.

The Molecular Mechanism of Human Voltage-Dependent Anion Channel 1 Blockade by the Metallofullerenol Gd@C82(OH)22: An In Silico Study.

The endohedral metallofullerenol Gd@C82(OH)22 has been identified as a possible antineoplastic agent that can inhibit both the growth and metastasis of cancer cells. Despite these potentially important effects, our understanding of the interactions between Gd@C82(OH)22 and biomacromolecules remains incomplete. Here, we study the interaction between Gd@C82(OH)22 and the human voltage-dependent anion channel 1 (hVDAC1), the most abundant porin embedded in the mitochondrial outer membrane (MOM), and a potential druggable target for novel anticancer therapeutics. Using in silico approaches, we observe that Gd@C82(OH)22 molecules can permeate and form stable interactions with the pore of hVDAC1. Further, this penetration can occur from either side of the MOM to elicit blockage of the pore. The binding between Gd@C82(OH)22 and hVDAC1 is largely driven by long-range electrostatic interactions. Analysis of the binding free energies indicates that it is thermodynamically more favorable for Gd@C82(OH)22 to bind to the hVDAC1 pore when it enters the channel from inside the membrane rather than from the cytoplasmic side of the protein. Multiple factors contribute to the preferential penetration, including the surface electrostatic landscape of hVDAC1 and the unique physicochemical properties of Gd@C82(OH)22. Our findings provide insights into the potential molecular interactions of macromolecular biological systems with the Gd@C82(OH)22 nanodrug.