Structure-Based Rational and General Strategy for Stabilizing Single-Chain T-Cell Receptors to Enhance Affinity.

The T-cell receptor (TCR) is a crucial molecule in cellular immunity. The single-chain T-cell receptor (scTCR) is a potential format in TCR therapeutics because it eliminates the possibility of αß-TCR mispairing. However, its poor stability and solubility impede the in vitro study and manufacturing of therapeutic applications. In this study, some conserved structural motifs are identified in variable domains regardless of germlines and species. Theoretical analysis helps to identify those unfavored factors and leads to a general strategy for stabilizing scTCRs by substituting residues at exact IMGT positions with beneficial propensities on the consensus sequence of germlines. Several representative scTCRs are displayed to achieve stability optimization and retain comparable binding affinities with the corresponding αß-TCRs in the range of µM to pM. These results demonstrate that our strategies for scTCR engineering are capable of providing the affinity-enhanced and specificity-retained format, which are of great value in facilitating the development of TCR-related therapeutics.

Bright white light emission from lanthanide oxide LaGdO3 for LED lighting by Bi3+ to Eu3+ energy transfer.

Phosphors with intrinsic white light emission are of great potential in constructing high-quality white LEDs (WLEDs). In this work, we propose the use of energy transfer from Bi3+ to Eu3+ ions for white light emission. A unique Bi3+-activated phosphor LaGdO3 (LGO):Bi3+ was generated using the conventional high-temperature solid-state process. An energy transfer was established by introducing Eu3+ into the phosphor composition. The emission colour of LGO:Bi3+,Eu3+ phosphors changes from cyan to white to orange-red depending on the Bi3+/Eu3+ doping proportion. The energy transfer between the Bi3+ and Eu3+ ions results from the dipole-dipole interaction. The LGO:Bi3+,Eu3+ phosphors were combined with a near-ultraviolet chip to successfully create a single-component WLED device with a colour-rendering index of 92.4. Our work demonstrates the energy transfer as a route for single-component white light emission and makes LGO:Bi3+,Eu3+ phosphors one of the candidate materials for near-ultraviolet lighting.

MEMS Resonant Beam with Outstanding Uniformity of Sensitivity and Temperature Distribution for Accurate Gas Sensing and On-Chip TGA.

Micromechanical resonators have aroused growing interest as biological and chemical sensors, and microcantilever beams are the main research focus. Recently, a resonant microcantilever with an integrated heater has been applied in on-chip thermogravimetric analysis (TGA). However, there is a strong relationship between the mass sensitivity of a resonant microcantilever and the location of adsorbed masses. Different sampling positions will cause sensitivity differences, which will result in an inaccurate calculation of mass change. Herein, an integrated H-shaped resonant beam with uniform mass sensitivity and temperature distribution is proposed and developed to improve the accuracy of bio/chemical sensing and TGA applications. Experiments verified that the presented resonant beam possesses much better uniformity of sensitivity and temperature distribution compared with resonant microcantilevers. Gas-sensing and TGA experiments utilizing the integrated resonant beam were also carried out and exhibited good measurement accuracy.

Small-molecule targeting PKM2 provides a molecular basis of lactylation-dependent fibroblast-like synoviocytes proliferation inhibition against rheumatoid arthritis.

Fibroblast-like synoviocytes (FLS) play an important role in rheumatoid arthritis (RA)-related swelling and bone damage. Therefore, novel targets for RA therapy in FLS are urgently discovered for improving pathologic phenomenon, especially joint damage and dyskinesia. Here, we suggested that pyruvate kinase M2 (PKM2) in FLS represented a pharmacological target for RA treatment by antimalarial drug artemisinin (ART). We demonstrated that ART selectively inhibited human RA-FLS and rat collagen-induced arthritis (CIA)-FLS proliferation and migration without observed toxic effects. In particular, the identification of targets revealed that PKM2 played a crucial role as a primary regulator of the cell cycle, leading to the heightened proliferation of RA-FLS. ART exhibited a direct interaction with PKM2, resulting in an allosteric modulation that enhances the lactylation modification of PKM2. This interaction further promoted the binding of p300, ultimately preventing the nuclear translocation of PKM2 and inducing cell cycle arrest at the S phase. In vivo, ART obviously suppressed RA-mediated synovial hyperplasia, bone damage and inflammatory response to further improve motor behavior in CIA-rats. Taken together, these findings indicate that directing interventions towards PKM2 in FLS could offer a hopeful avenue for pharmaceutical treatments of RA through the regulation of cell cycle via PKM2 lactylation.

In situcell-scale probing nucleation, growth and evolution of CsPbBr3nanowires by optical absorption spectroscopy.

The growth kinetics of colloidal lead halide perovskite nanomaterials are an integral part of their applications, remains poorly understood due to complex nucleation processes and lack ofin situsize monitoring method. Here we demonstrated that absorption spectra can be used to observein situgrowth processes of ultrathin CsPbBr3nanowires in solution with reference to the effective mass infinite deep square potential well model. By means of this method, we have found that the ultrathin nanowires, fabricated by hot injection method, were firstly formed within one minute. Subsequently, they merge with each other into a thicker structure with increasing reaction time. We revealed that the nucleation, growth, and merging of the CsPbBr3nanowires are determined by the acid concentration and ligand chain length. At lower acidity, the critical nucleation size of the nanowire is smaller, while the shorter the ligand chain length, the faster the merging among the nanowires. Moreover, the merging mode between nanowires changed with their nucleation size. This growth kinetics of CsPbBr3nanowires provides a reference for optimizing the synthesis conditions to obtain the one-dimensional CsPbBr3with desired size, thus enabling accurate control of the nanowire shape.

Differentiation of testicular seminomas from nonseminomas based on multiphase CT radiomics combined with machine learning: A multicenter study.

BACKGROUND: Differentiating seminomas from nonseminomas is crucial for formulating optimal treatment strategies for testicular germ cell tumors (TGCTs). Therefore, our study aimed to develop and validate a clinical-radiomics model for this purpose. METHODS: In this study, 221 patients with TGCTs confirmed by pathology from four hospitals were enrolled and classified into training (n = 126), internal validation (n = 55) and external test (n = 40) cohorts. Radiomics features were extracted from the CT images. After feature selection, we constructed a clinical model, radiomics models and clinical-radiomics model with different machine learning algorithms. The top-performing model was chosen utilizing receiver operating characteristic (ROC) curve analysis. Decision curve analysis (DCA) was also conducted to assess its practical utility. RESULTS: Compared with those of the clinical and radiomics models, the clinical-radiomics model demonstrated the highest discriminatory ability, with AUCs of 0.918 (95 % CI: 0.870 - 0.966), 0.909 (95 % CI: 0.829 - 0.988) and 0.839 (95 % CI: 0.709 - 0.968) in the training, validation and test cohorts, respectively. Moreover, DCA confirmed that the combined model had a greater net benefit in predicting seminomas and nonseminomas. CONCLUSION: The clinical-radiomics model serves as a potential tool for noninvasive differentiation between testicular seminomas and nonseminomas, offering valuable guidance for clinical treatment.

Molten-Salt-Assisted Strategy Enables High-Rate Micron-Sized Single-Crystal Li-Rich, Mn-Based Layered Oxide Cathode Materials.

Li-rich Mn-based layered oxides (LMLOs) are expected to be the most promising high-capacity cathodes for the next generation of lithium-ion batteries (LIBs). However, the poor cycling stability and kinetics performance of polycrystalline LMLOs restrict their practical applications due to the anisotropic lattice stress and crack propagation during cycling. Herein, B-doped micron-sized single-crystal Co-free LMLOs were obtained by molten-salt (LiNO3 and H3BO3)-assisted sintering. The results reveal that the low-melting-point molten salt can serve as liquid-phase media to improve the efficiency of atomic mass transfer and crystal nucleation and growth. The modified single-crystal LMLO cathodes can resist the accumulation of anisotropic stress and strain during the cycling and reduce interface side reactions, thus achieving excellent high-voltage stability and kinetics performance. The reversible specific capacity of the single crystals is 210.8 mAh g-1 at 1C with a voltage decay rate of 1.95 mV/cycle and up to 161.1 mAh g-1 at 10C with a capacity retention of 81.06% after 200 cycles.

Assessment of the Efficacy of the Combination of RNAi of lncRNA DANCR with Chemotherapy to Treat Triple Negative Breast Cancer Using Magnetic Resonance Molecular Imaging.

Long noncoding RNA (lncRNA) differentiation antagonizing noncoding RNA (DANCR) is overexpressed in human triple-negative breast cancer (TNBC) and promotes cell migration and proliferation. TNBC is limited in treatment options relative to hormone-receptor-positive breast cancer and is commonly treated with chemotherapy, which is often compromised by acquired resistance. DANCR has been implicated in the development of chemoresistance across multiple cancer types. Here, we applied magnetic resonance molecular imaging (MRMI) with a targeted contrast agent, MT218, specific to extradomain-B fibronectin (EDB-FN), a marker for epithelial-to-mesenchymal transition, to assess the therapeutic efficacy of the combination of paclitaxel and ZD2-PEG-ECO/siDANCR nanoparticles (ZD2-siDANCR-ELNP) to treat TNBC. The treatment of orthotopic MDA-MB-231 TNBC in mice with paclitaxel significantly suppressed tumor growth but with a significant increase of EDB-FN in the tumor, as revealed by MRMI and immunohistochemistry. Combining ZD2-siDANCR-ELNP with paclitaxel further reduced tumor sizes, along with reduced EDB-FN expression. Interestingly, MT218-MRMI revealed a lower reduction of tumor signal enhancement with the combination treatment than that with the siDANCR treatment alone, which was supported by higher cell density in the tumors treated with the combination therapy, as shown by histochemical analysis. MT218-MRMI clearly revealed the changes of the tumor microenvironment in response to various therapies and is effective to noninvasively assess the response of TNBC tumors to the therapies. Regulating oncogenic lncRNA DANCR is an effective strategy for improving the outcomes of chemotherapy in TNBC.

Intravitreal Delivery of PEGylated-ECO Plasmid DNA Nanoparticles for Gene Therapy of Stargardt Disease.

OBJECTIVE: Current gene therapy of inherited retinal diseases is achieved mainly by subretinal injection, which is invasive with severe adverse effects. Intravitreal injection is a minimally invasive alternative for gene therapy of inherited retinal diseases. This work explores the efficacy of intravitreal delivery of PEGylated ECO (a multifunctional pH-sensitive amphiphilic amino lipid) plasmid DNA (pGRK1-ABCA4-S/MAR) nanoparticles (PEG-ELNP) for gene therapy of Stargardt disease. METHODS: Pigmented Abca4-/- knockout mice received 1 µL of PEG-ELNP solution (200 ng/uL, pDNA concentration) by intravitreal injections at an interval of 1.5 months. The expression of ABCA4 in the retina was determined by RT-PCR and immunohistochemistry at 6 months after the second injection. A2E levels in the treated eyes and untreated controls were determined by HPLC. The safety of treatment was monitored by scanning laser ophthalmoscopy and electroretinogram (ERG). RESULTS: PEG-ELNP resulted in significant ABCA4 expression at both mRNA level and protein level at]6 months after 2 intravitreal injections, and a 40% A2E accumulation reduction compared with non-treated controls. The PEG-ELNP also demonstrated excellent safety as shown by scanning laser ophthalmoscopy, and the eye function evaluation from electroretinogram. CONCLUSIONS: Intravitreal delivery of the PEG-ELNP of pGRK1-ABCA4-S/MAR is a promising approach for gene therapy of Stargardt Disease, which can also be a delivery platform for gene therapy of other inherited retinal diseases.

Integration of Prior Expectations and Suppression of Prediction Errors During Expectancy-Induced Pain Modulation: The Influence of Anxiety and Pleasantness.

Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating.

MiR-186-5p prevents hepatocellular carcinoma progression by targeting methyltransferase-like 3 that regulates m6A-mediated stabilization of follistatin-like 5.

Background: Hepatocellular carcinoma (HCC) is a multistep process involving sophisticated genetic, epigenetic, and transcriptional changes. However, studies on microRNA (miRNA)'s regulatory effects of N6-methyladenosine (m6A) modifications on HCC progression are limited. Methods: Cell Counting Kit-8 (CCK-8), clone formation, and Transwell assays were used to investigate changes in cancer cell proliferation, invasion, and migration. RNA m6A levels were verified using methylated RNA immunoprecipitation. Luciferase reporter assay was used to study the potential binding between miRNAs and mRNA. A mouse tumor transplant model was established to study the changes in tumor progression. Results: Follistatin-like 5 (FSTL5) was significantly downregulated in HCC and inhibited its further progression. Additionally, methyltransferase-like 3 (METTL3) reduced FSTL5 mRNA stability in an m6A-YTH domain family 2(YTHDF2)-dependent manner. Functional experiments revealed that METTL3 downregulation inhibited HCC progression by upregulating FSTL5 in vitro and in vivo. Luciferase reporter assay verified that miR-186-5p directly targets METTL3. Additionally, miR-186-5p inhibits the proliferation, migration, and invasion of HCC cells by downregulating METTL3 expression. Conclusions: The miR-186-5p/METTL3/YTHDF2/FSTL5 axis may offer new directions for targeted HCC therapy.

The prevalence and clinical correlates of suicide attempts in patients with bipolar disorder misdiagnosed with major depressive disorder: Results from a national survey in China.

BACKGROUND AND AIM: Suicide is nearly always associated with underlying mental disorders. Risk factors for suicide attempts (SAs) in patients with bipolar disorder (BD) misdiagnosed with major depressive disorder (MDD) remain unelucidated. This study was to evaluate the prevalence and clinical risk factors of SAs in Chinese patients with BD misdiagnosed with MDD. METHODS: A total of 1487 patients with MDD from 13 mental health institutions in China were enrolled. Mini International Neuropsychiatric Interview (MINI) was used to identify patients with BD who are misdiagnosed as MDD. The general sociodemographic and clinical data of the patients were collected and MINI suicide module was used to identify patients with SAs in these misdiagnosed patients. RESULTS: In China, 20.6% of patients with BD were incorrectly diagnosed as having MDD. Among these misdiagnosed patients, 26.5% had attempted suicide. These patients tended to be older, had a higher number of hospitalizations, and were more likely to experience frequent and seasonal depressive episodes with atypical features, psychotic symptoms, and suicidal thoughts. Frequent depressive episodes and suicidal thoughts during depression were identified as independent risk factors for SAs. Additionally, significant sociodemographic and clinical differences were found between individuals misdiagnosed with MDD in BD and patients with MDD who have attempted suicide. CONCLUSIONS: This study highlights the importance of accurate diagnosis in individuals with BD and provide valuable insights for the targeted identification and intervention of individuals with BD misdiagnosed as having MDD and those with genuine MDD, particularly in relation to suicidal behavior.

Structural and functional changes following brain surgery in pediatric patients with intracranial space-occupying lesions.

We explored the structural and functional changes of the healthy hemisphere of the brain after surgery in children with intracranial space-occupying lesions. We enrolled 32 patients with unilateral intracranial space-occupying lesions for brain imaging and cognitive assessment. Voxel-based morphometry and surface-based morphometry analyses were used to investigate the structural images of the healthy hemisphere. Functional images were analyzed using regional homogeneity, amplitude of low-frequency fluctuations, and fractional-amplitude of low-frequency fluctuations. Voxel-based morphometry and surface-based morphometry analysis used the statistical model built into the CAT 12 toolbox. Paired t-tests were used for functional image and cognitive test scores. For structural image analysis, we used family-wise error correction of peak level (p < 0.05), and for functional image analysis, we use Gaussian random-field theory correction (voxel p < 0.001, cluster p < 0.05). We found an increase in gray matter volume in the healthy hemisphere within six months postoperatively, mainly in the frontal lobe. Regional homogeneity and fractional-amplitude of low-frequency fluctuations also showed greater functional activity in the frontal lobe. The results of cognitive tests showed that psychomotor speed and motor speed decreased significantly after surgery, and reasoning increased significantly after surgery. We concluded that in children with intracranial space-occupying lesions, the healthy hemisphere exhibits compensatory structural and functional effects within six months after surgery. This effect occurs mainly in the frontal lobe and is responsible for some higher cognitive compensation. This may provide some guidance for the rehabilitation of children after brain surgery.

Ultrasound-based deep learning radiomics nomogram for risk stratification of testicular masses: a two-center study.

OBJECTIVE: To develop an ultrasound-driven clinical deep learning radiomics (CDLR) model for stratifying the risk of testicular masses, aiming to guide individualized treatment and minimize unnecessary procedures. METHODS: We retrospectively analyzed 275 patients with confirmed testicular lesions (January 2018 to April 2023) from two hospitals, split into training (158 cases), validation (68 cases), and external test cohorts (49 cases). Radiomics and deep learning (DL) features were extracted from preoperative ultrasound images. Following feature selection, we utilized logistic regression (LR) to establish a deep learning radiomics (DLR) model and subsequently derived its signature. Clinical data underwent univariate and multivariate LR analyses, forming the "clinic signature." By integrating the DLR and clinic signatures using multivariable LR, we formulated the CDLR nomogram for testicular mass risk stratification. The model's efficacy was gauged using the area under the receiver operating characteristic curve (AUC), while its clinical utility was appraised with decision curve analysis(DCA). Additionally, we compared these models with two radiologists' assessments (5-8 years of practice). RESULTS: The CDLR nomogram showcased exceptional precision in distinguishing testicular tumors from non-tumorous lesions, registering AUCs of 0.909 (internal validation) and 0.835 (external validation). It also excelled in discerning malignant from benign testicular masses, posting AUCs of 0.851 (internal validation) and 0.834 (external validation). Notably, CDLR surpassed the clinical model, standalone DLR, and the evaluations of the two radiologists. CONCLUSION: The CDLR nomogram offers a reliable tool for differentiating risks associated with testicular masses. It augments radiological diagnoses, facilitates personalized treatment approaches, and curtails unwarranted medical procedures.

Chemical Constituents from Berchemia polyphylla var. Leioclada.

One previously undescribed naphthoquinone-benzisochromanquinone dimer berpolydiquinone A (1), along with two previously undescribed naphthoquinone-anthraquinone dimers berpolydiquinones B and C (2-3), and one previously undescribed dimeric naphthalene berpolydinaphthalene A (4), were isolated from the stems and leaves of Berchemia polyphylla var. leioclada. The chemical structures of these compounds were determined using high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS), spectroscopic data, the exciton chirality method (ECM), and quantum chemical calculation. Notably, compounds (1-2 and 5) are dimeric quinones that share the same naphthoquinone moiety, specifically identified as 2-methoxystypandron. Compound (4) is a derivative of dimeric naphthalene with a symmetrical structure, which is a new structure type isolated from B. polyphylla var. leioclada for the first time. These findings suggest that B. polyphylla var. leioclada serves as a significant reservoir of structurally diverse phenolic compounds. This study provides a scientific foundation for regarding B. polyphylla var. leioclada as a potential source of "Tiebaojin".

Multifunctional ytterbium oxide buffer for perovskite solar cells.

Perovskite solar cells (PSCs) comprise a solid perovskite absorber sandwiched between several layers of different charge-selective materials, ensuring unidirectional current flow and high voltage output of the devices1,2. A 'buffer material' between the electron-selective layer and the metal electrode in p-type/intrinsic/n-type (p-i-n) PSCs (also known as inverted PSCs) enables electrons to flow from the electron-selective layer to the electrode3-5. Furthermore, it acts as a barrier inhibiting the inter-diffusion of harmful species into or degradation products out of the perovskite absorber6-8. Thus far, evaporable organic molecules9,10 and atomic-layer-deposited metal oxides11,12 have been successful, but each has specific imperfections. Here we report a chemically stable and multifunctional buffer material, ytterbium oxide (YbOx), for p-i-n PSCs by scalable thermal evaporation deposition. We used this YbOx buffer in the p-i-n PSCs with a narrow-bandgap perovskite absorber, yielding a certified power conversion efficiency of more than 25%. We also demonstrate the broad applicability of YbOx in enabling highly efficient PSCs from various types of perovskite absorber layer, delivering state-of-the-art efficiencies of 20.1% for the wide-bandgap perovskite absorber and 22.1% for the mid-bandgap perovskite absorber, respectively. Moreover, when subjected to ISOS-L-3 accelerated ageing, encapsulated devices with YbOx exhibit markedly enhanced device stability.

Remote Control and Noninvasive Detection Enabled by a High-performance NIR pc-LED.

In an increasing manner, near-infrared phosphor-converted light-emitting diodes (NIR pc-LEDs) are considered to be exemplary light sources owing to their notable attributes of elevated output power, economical nature, and exceptional portability. NIR phosphors are critical components of NIR pc-LEDs. Herein, we report a novel blue light excitable NIR phosphor CaLu2ZrScAl3O12:Cr3+ (CLZSA:Cr3+) as a crucial and efficient broadband NIR emitter. The CLZSA:Cr3+ phosphor displays an intense NIR broadband emission peaking at 776 nm and with a full width at half-maximum (fwhm) of 140 nm. The designed material also exhibits superior resistance to thermal quenching, as the intensity of emission at 423 K remains at 80% of that at room temperature. The constructed NIR pc-LED device based on CLZSA:Cr3+ demonstrates a high total output power of 68.4 mW at a drive current of 100 mA, along with a high photoelectric conversion efficiency of 23.0%. Impressively, the high-power NIR pc-LEDs are utilized as light sources for remote control and non-invasive detection, resulting in the excellent performance and remarkable achievement.

Buried-Metal-Grid Electrodes for Efficient Parallel-Connected Perovskite Solar Cells.

The limited conductivity of existing transparent conducting oxide (TCO) greatly restricts the further performance improvement of perovskite solar cells (PSCs), especially for large-area devices. Herein, buried-metal-grid tin-doped indium oxide (BMG ITO) electrodes are developed to minimize the power loss caused by the undesirable high sheet resistance of TCOs. By burying 140-nm-thick metal grids into ITO using a photolithography technique, the sheet resistance of ITO is reduced from 15.0 to 2.7 Ω sq-1 . The metal step of BMG over ITO has a huge impact on the charge carrier transport in PSCs. The PSCs using BMG ITO with a low metal step deliver power conversion efficiencies (PCEs) significantly better than that of their counterparts with higher metal steps. Moreover, compared with the pristine ITO-based PSCs, the BMG ITO-based PSCs show a smaller PCE decrease when scaling up the active area of devices. The parallel-connected large-area PSCs with an active area of 102.8 mm2 reach a PCE of 22.5%. The BMG ITO electrodes are also compatible with the fabrication of inverted-structure PSCs and organic solar cells. The work demonstrates the great efficacy of improving the conductivity of TCO by BMG and opens up a promising avenue for constructing highly efficient large-area PSCs.

Pharmacokinetics and Tolerability of the Cancer-Targeting MRI Contrast Agent MT218 in Healthy Males.

OBJECTIVE: The aim of this study was to evaluate the pharmacokinetics and safety profile of MT218, a peptide-targeted gadolinium-based contrast agent, in healthy males. MATERIALS AND METHODS: This was a double-blind, randomized, placebo-controlled, single-ascending-dose study including 30 healthy male subjects. In each dose group (0.01, 0.02, 0.04, and 0.08 mmol/kg), 4 subjects received MT218 and 2 subjects received placebo (saline) in bolus injections. The highest dose group (0.08 mmol/kg) was assessed in 2 cohorts, 1 fasted and 1 nonfasted. Clinical laboratory tests, vital signs, and electrocardiograms were investigated. Gadolinium concentrations were measured in plasma samples collected before administration and over a 24-hour period postinjection, and in urine specimens collected until 22 days. A noncompartmental model was used for pharmacokinetic analysis. A clinical and biological safety follow-up was carried out for up to 6 months. RESULTS: No clinically significant modifications in biochemistry, hematology, urinalysis, electrocardiogram parameters, or vital signs were reported at any time point for any treatment group. No serious adverse events were observed in any dose group. Transient dizziness, hyperhidrosis, and injection site coldness were the main adverse events reported in both the MT218 and placebo groups. The mean total apparent clearance decreased slightly with increasing dose, and the median plasma t 1/2 ranged from 1.7 hours in the 0.01 mmol/kg group to 2.7 hours in the 0.08 mmol/kg nonfasted group. MT218 was rapidly excreted via renal filtration with 42.9% to 52.8% of the injected dose measured in urine within the first hour after administration, and 92.5% to 117.3% in urine within 24 hours. No Gd was detected by inductively coupled plasma mass spectrometry in urine after 21 days. CONCLUSION: Single intravenous administration of MT218 was safely tolerated in the healthy males. Its pharmacokinetic parameters and safety profile are well aligned with those of other gadolinium-based contrast agents.