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Lenvatinib is a multi-target inhibitor that exerts anti-tumor effects by inhibiting angiogenesis and is now commonly used as a first-line treatment for hepatocellular carcinoma. However, with the widespread use of lenvatinib, the problem of serious and fatal hepatotoxicity has become increasingly prominent. Currently, the mechanism behind this toxicity is not yet understood, and as a result, there is a lack of safe and effective intervention strategies with minimal side effects. Here, we established the model of lenvatinib-induced liver injury in vivo and in vitro and found that lenvatinib caused hepatotoxicity by inducing apoptosis. Further mechanistic studies in cellular models revealed that lenvatinib upregulated death receptor signaling pathway, which activated the downstream effector Caspase-8, and ultimately led to apoptosis. Meanwhile, lenvatinib-induced apoptosis was associated with ROS generation and DNA damage. In addition, after screening marketed drugs and natural products in combination with cellular modeling, we identified a potential co-administered drug, dabrafenib, which could alleviate lenvatinib-induced hepatotoxicity. Further mechanistic studies revealed that dabrafenib attenuated lenvatinib-induced hepatotoxicity by inhibiting the activation of the death receptor signaling pathway. Subsequently, cancer cell proliferation assays confirmed that dabrafenib did not antagonize the antitumor effects of lenvatinib. In conclusion, our results validate that apoptosis caused by the death receptor signaling pathway is the key cause of lenvatinib-induced hepatotoxicity, and dabrafenib alleviates lenvatinib-induced hepatotoxicity by inhibiting this pathway. • Lenvatinib induces apoptosis by activating the death receptor pathway, causing hepatotoxicity in vivo and in vitro. • Lenvatinib upregulates the expression of Fas and TRAIL proteins, which activates the downstream effector Caspase-8. • Hepatotoxicity caused by lenvatinib is associated with ROS generation and DNA damage. • Dabrafenib alleviates lenvatinib-induced liver injury by inhibiting the death receptor signaling pathway. [ABSTRACT FROM AUTHOR]

Aim: The aim of this work is to investigate the influence of leaders' innovation expectation on nurses' innovation behaviour in conjunction with artificial intelligence, as well as explore the chain mediating effect of job control and creative self‐efficacy between leaders' innovation expectation and nurses' innovation behaviour. Background: The nurses' innovation behaviour is crucial in promoting medical artificial intelligence. Thus, clarifying the influencing factors of nurses' innovation behaviour has become a priority. Methods: A cross‐sectional survey was conducted with 263 Chinese nurses from tertiary hospitals and secondary hospitals in Hefei, Anhui province. Results: Leaders' innovation expectation was positively related to nurses' innovation behaviour. Creative self‐efficacy and job control respectively mediated the relationship between leaders' innovation expectation and nurses' innovation behaviour. Furthermore, creative self‐efficacy and job control played a chain mediation role between leaders' innovation expectation and nurses' innovation behaviour. Conclusion: Leaders' innovation expectation helps to enhance nurses' creative self‐efficacy and job control, thereby enhancing nurses' enthusiasm for innovation. Implications for Nursing Management: Hospital managers and leaders formulate intervention measures to increase leaders' innovation expectation, nurses' creative self‐efficacy and job control, and encourage nurses' innovation behaviour. [ABSTRACT FROM AUTHOR]

Mirabegron and vibegron, both newly identified beta-3 adrenergic agonists, have significantly improved the quality of life for patients suffering from overactive bladder. In order to comprehensively assess the plasma exposure levels of these agents, the development of a rapid and highly sensitive bioanalytical method becomes imperative. The primary objective of this study was to establish a robust high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the concurrent quantification of mirabegron and vibegron in human plasma. The analytes were extracted from a 100 μL plasma sample through protein precipitation, employing 300 μL of methanol. Subsequently, samples underwent separation and quantification using a Waters XBridge C 18 column (2.1 × 100 mm, 3.5 µm), with a mobile phase consisting of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The mass analysis was conducted using positive electrospray ionization (ESI+) operated in a multiple reaction monitoring (MRM) mode. The proposed method was meticulously validated in accordance with the guidelines set forth by the U.S. Food and Drug Administration (FDA) for bioanalytical method validation. The regression equations demonstrated exceptional linearity for both mirabegron (r² ≥ 0.994) and vibegron (r² ≥ 0.996) across the concentration range of 0.5 – 200 ng/mL. Furthermore, the assay exhibited accuracy (inter-day relative error ≤ 6.90%) and precision (inter-day coefficient of variation ≤ 8.88%). The average recoveries of the analytes were found to range from 81.94% to 102.02%, with mean matrix effects falling within the range of 89.77% to 110.58%. As a result, this method was deemed highly suitable for the precise determination of the concentrations of both mirabegron and vibegron in the context of therapeutic drug monitoring and bioequivalence studies. ● First simultaneous determination of two beta-3 adrenergic agonists in human plasma. ● A rapid, robust, and sensitive method for the quantification of mirabegron and vibegron by HPLC-MS/MS. ● Simple protein precipitation method with short run time suitable for high-throughput analysis of biological samples. ● The proposed method was successfully implemented for therapeutic drug monitoring in patients with overactive bladder. [ABSTRACT FROM AUTHOR]

The CSs@ZrSiO 4 black inclusion pigments were prepared by calcining the precursor formed by the precipitation of Si 4+ and Zr 4+ on the surface of carbon spheres (CSs), which were synthesized from glucose by hydrothermal process. The as-prepared CSs were amorphous and had plenty of rich oxygen-containing functional groups on their surface with negative charges, which endows the CSs the ability to disperse well in the precursor solution. The amorphous carbon source was carbonized as colorant, which was coated by zircon phase at 1050 ℃ for 2 h in Ar. The results indicated that a dense zirconium silicate coating layer was formed with high encapsulation rate, which protects the inner CSs from oxidation, and enabling the pigment to achieve a deep black hue, as CIE coordination L* = 22.21, a* = 0.14, b* = 2.43 consequently. When the as-prepared inclusion pigment was applied to the transparent glaze at 1100 ℃, it showed a good chromaticity. [ABSTRACT FROM AUTHOR]

ADAMTS18 is a member of a secreted Zn-metalloproteinase ADAMTS family, and has been implicated in development, hemostasis, and various malignancies. It has thus far proven difficult to resolve its post-translational modification status, cleaved forms, and splice variants in living organisms due to the lack of specific antibodies available to characterize this enzyme. In this study, we develop six murine monoclonal antibodies (mAbs) against different functional regions of ADAMTS18 using hybridoma technology. These mAbs exhibit cross-recognition between ADAMTS18 and the homology domain of its family members. Using the tissues from Adamts18 knockout (KO) mice, we find that two of these mAbs (N-3 and C-5) precisely identify five significantly attenuated bands located at 180, 135, 95, 72, and 45 kDa. These bands represent the forms of ADAMTS18 that potentially exist in the tissues. These mAbs will provide a useful tool to investigate the ADAMTS18's biologic significance in the tissues. [ABSTRACT FROM AUTHOR]

Potassium homeostasis plays an essential role in the control of blood pressure. It is unknown, however, whether potassium balance is involved in the gender-associated blood pressure differences. We therefore investigated the possible mechanism of sexual dimorphism in blood pressure regulation by measuring the blood pressure, plasma potassium, renal actions of potassium channels and upstream regulator in male and female mice. Here we found that female mice exhibited lower blood pressure and higher plasma K + level as compared to male littermates. Western blot analyses of mouse kidney extract revealed a significant decrease in renal outer medullary potassium (ROMK) channel expression, while large-conductance Ca 2+ -activated K + (BK) channel and Na-K-2Cl cotransporter (NKCC2) as well as the upstream regulator with-no-lysine kinase 1 (WNK1) enhanced in female mice under normal condition. Surprisingly, both dietary K + loading and K + depletion eliminated the differences in plasma K + and blood pressure between females and males, and the differences of renal K + channels and WNK1 also attenuated in both groups of mice. These findings indicated the existence of a close correlation between K + homeostasis and sex-associated blood pressure. Moreover, the differential regulation of ROMK, BK-α and NKCC2 between female and male mice, at least, were partly mediated via WNK1 pathway, which may contribute to the sexual dimorphism of plasma K + and blood pressure control. [ABSTRACT FROM AUTHOR]

Background/aim: Recently, an increase in the number of asymptomatic rare benign liver tumors (BLTs) has been reported during health check-ups. It is difficult to determine the nature of partial rare BLTs and not easy to distinguish from malignant liver tumors. This study aimed to analysis clinical features, diagnosis and treatment of rare BLTs to reduce misdiagnosis and provide reference for clinical practice. Methods: From January 2012 to January 2021, we treated 112 rare BLTs by hepatectomy, including 54 focal nodular hyperplasias, 14 hepatocellular adenomas, 28 hepatic angiomyolipomas, 3 hepatic granulomas, 2 inflammatory pseudotumors of the liver, 2 nodular regenerative hyperplasia, 2 hepatic lipomas, 1 solitary fibrous tumor of the liver, 1 hepatic schwannoma and 1 hepatic myelolipoma. Results: The majority of patients were middle-aged female and asymptomatic. Single tumors were dominant. The diagnostic accuracies of computed tomography (CT) and magnetic resonance imaging (MRI) were 32.5% and 44.2%, respectively. The majority of tumors were likely to be misdiagnosed as hepatocellular carcinoma (HCC) or difficult to distinguish from HCC. All patients underwent surgical treatment. Postoperative pathological and immunohistochemical examination can confirm the diagnosis. No patients without tumor recurrence or metastasis during follow-up period. Conclusion: Altogether, the clinical symptoms of rare BLTs lack specificity, and their preoperative diagnosis largely depends on imaging examination, with a low diagnostic accuracy rate and high chances of misdiagnosis as HCC. Diagnosis is confirmed by pathological and immunohistochemical examination. Surgical resection for rare BLT is safe and effective, regular postoperative follow-up is necessary. [ABSTRACT FROM AUTHOR]

Graphene nanoribbon is a novel variety of graphene with high length-to-width ratio and straight edges. Herein, we report an improved method for the synthesis of graphene oxide nanoribbons (GONRs) from longitudinal unraveling of multiwalled carbon nanotubes by means of a one-step, one-pot pressurized oxidation reaction. The obtained GONRs were characterized by different techniques. Furthermore, owing to their unique properties such as strong optical absorption and good water dispersibility, we show that GONRs can be used as an excellent matrix or probe in matrix-assisted or surface-enhanced laser desorption/ionization mass spectrometry (MALDI or SELDI MS) for the first time. In MALDI MS, GONRs generated significantly higher signals than conventional organic matrix and other graphene-based matrices in the detection of low-mass compounds. We also demonstrate the use of GONRs as a sensitive SELDI probe for simultaneous detection of multiple small molecules and profiling of small molecules in complex environmental samples, thus revealing its application potential in rapid screening of low-mass pollutants in complex media. [ABSTRACT FROM AUTHOR]

Graphene oxide nanoribbons (GONRs) were covalently functionalized with an antibody using polyethylene glycol (PEG) as a linker to produce a novel probe for surface enhanced laser desorption/ionization mass spectrometry (SELDI MS). This probe provides a highly sensitive and selective platform for enrichment and MS detection of small molecules in complex media. [ABSTRACT FROM AUTHOR]

Highlights: [•] Graphenized pencil lead fiber was prepared by in situ exfoliation of graphite. [•] The exfoliation was achieved by a one-pot, one-step pressurized oxidation reaction. [•] The fiber was used as a highly efficient, low-cost, and robust fiber for SPME. [•] Four bisphenol analogs (BPA, BPS, BPAF and TBBPA) were selected as analytes. [•] The fiber was applied in analysis of tap water and WWTP effluent samples. [ABSTRACT FROM AUTHOR]

To be mild! Mild oxidization of chemically converted graphene with diluted nitric acid produces low‐oxidation and low‐defect acid‐oxidized graphene (AOG) material with excellent water dispersibility (see scheme). In MALDI MS, the AOG matrix yielded significantly higher signals than graphene, graphene oxide, and conventional organic matrices for nonpolar analytes. [ABSTRACT FROM AUTHOR]

[Display omitted] The rational design and synthesis of carbon nanocages with highly complex porous structures are continuously facing challenges in the development of high-performance supercapacitors (SCs). The electrochemical performance characteristics of electrodes rely on their compositions and fabrication methods. Here, we propose a universal and efficient approach for the in-situ synthesis of zeolitic imidazolate framework-8 (ZIF-8) on porous carbonized wood, where the selective utilization of hexacarbonyl molybdenum protects the structural integrity of the ZIF-8 precursor, preventing collapse during thermal treatment. The subsequent pyrolysis process leads to the formation of small-sized molybdenum carbide (MoC) which are embedded in carbon nanocages (CN). The composite electrode consists of MoC/CN embedded in a porous carbonized wood (PCW), and it shows area-specific capacity of 9.7F cm−2 and 9.4 F cm−2 at 5 mA cm−2 and 30 mA cm−2, respectively. Subsequently, the symmetric supercapacitor, with two MoC/CN@PCW electrodes exhibits a areal specific capacitance of 2.7 F cm−2 at 5 mA cm−2. Moreover, this supercapacitor maintains an capacitance retention rate of 98.5 % after 12,000 discharge cycles. The supercapacitor exhibits a power density of 6.5 mW cm−2, resulting in an energy density of 0.864 mWh cm−2. Therefore, the utilization of wood-based electrodes holds promise for energy storage systems. [ABSTRACT FROM AUTHOR]

Background: Cholestasis is a common yet severe complication that occurs during the advancement of liver metastasis. However, how cholestasis impacts the development, treatment, and tumor microenvironment (TME) of liver metastasis remains to be elucidated. Methods: Extrahepatic and intrahepatic cholestatic mouse models with liver metastasis were established to detect the differential expression levels of genes, infiltration of immune cells and change in bile acid-associated metabolites by using RNA-Sequencing, flowcytometry, and liquid chromatography and mass spectrometry. Western blot was applied to neutrophils under the stimulation of primary bile acids (BAs) in vitro to study the mechanism of phenotypic alteration. In vitro coculture of BA-treated neutrophils with CD8+ T cells were performed to study the immune-suppressive effect of phenotypic-altered neutrophils. Clinical samples collected from colorectal cancer patients with liver metastasis and cholestasis were applied to RNA-Seq. Results: Compared to non-cholestatic mice, the progression of liver metastasis of cholestatic mice was significantly accelerated, which was associated with increased neutrophil infiltration and T-cell exclusion. Both neutrophils and T cells expressed higher immunosuppressive markers in the cholestatic mouse model, further indicating that an immunosuppressive tumor microenvironment was induced during cholestasis. Although neutrophils deletion via anti-Ly6G antibody partially hindered liver metastasis progression, it reduced the overall survival of mice. Tauro-β-muricholic acid (Tβ-MCA) and Glycocholic acid (GCA), the two most abundant cholestasis-associated primary BAs, remarkably promoted the expression of Arg1 and iNOS on neutrophils via p38 MAPK signaling pathway. In addition, BAs-pretreated neutrophils significantly suppressed the activation and cytotoxic effects of CD8+ T cells, indicating that the immunosuppressive phenotype of neutrophils was directly induced by BAs. Importantly, targeting BA anabolism with Obeticholic acid (OCA) under cholestasis effectively suppressed liver metastasis progression, enhanced the efficacy of immune checkpoint blockade, and prolonged survival of mice. Conclusions: Our study reveals the TME of cholestasis-associated liver metastasis and proposes a new strategy for such patients by targeting bile acid anabolism. Schematic model depicting the proposed mechanism of cholestasis-mediated progression of colorectal liver metastasis. As cholestasis progresses, excessive primary bile acids that accumulate in the liver intoxicates hepatocytes, which lead to exacerbated release of chemokines, particularly CXCL2 and CXCL5. Neutrophils are then accumulated by CXCL2 and CXCL5 and undergo an immunosuppressive-phenotypic alteration induced by direct stimulation of BAs via activating the p38 MAPK signaling pathway, which eventually led to the dysfunction of T cells and progression of LM. Targeting bile acid anabolism can effectively restore the immune-activated microenvironment and prevent the progression of LM. [ABSTRACT FROM AUTHOR]

Different from the common understanding that crystallization deteriorates the degradation capability of amorphous alloys, we show here that the Fe-based multi-phase nanocrystalline ribbons (Fe-MNRs) exhibit 3 and 17 times higher degradation rate than its amorphous counterpart and the conventional zero valent iron powders, respectively. The formation of multi-phase nanocrystals and nanoporous structure resulted from selective corrosion during degradation is responsible for the high degradation capability of Fe-MNRs. The present results suggest that suitable nano-crystallization annealing treatment could be a novel approach to enhance the degradation capability of Fe-based amorphous alloys. [ABSTRACT FROM AUTHOR]

The construction of advanced nanocomposite structures is a principal strategy to realize the electrical and mechanical functionalities of graphene for flexible electronic applications. Herein, two types of conductive and stretchable networks were fabricated by incorporation of polyurethane and silicone elastomers into highly porous and interconnected graphene gels. The layer-by-layer assembly of the graphene aerogel was solution-processable at room temperature, which offers a wide processing window for the solvent engineering and infiltration of polymers to improve wettability. Effects of graphene-polymer interfacial properties were investigated by their cross-sectional morphologies and viscoelastic analyses to elucidate the packing density, dispersion state, surface chemistry, polymer distribution and chain mobility. The polymer-infiltrated graphene network exhibited a high conductivity of ~100 S/m at a low filler content of 0.8 wt%. Given the excellent structural integrity, the graphene composites demonstrated unique electrical properties under stretching and bending conditions. Particularly, a maximum conductivity of 47 S/m was achieved under 50% tensile strain and the resistance deviation was less than 5% upon 500 bending cycles. The proposed design of graphene architecture and polymer infiltration techniques serve to pave the way for the next-level development of graphene electronics. Image 1 [ABSTRACT FROM AUTHOR]