Malignant melanoma is a highly metastatic and life-threatening cancer. Reactive oxygen species (ROS) play important roles in cancer initiation and progression including metastasis. It has been ...reported that the oxidative stress spontaneously generated in circulating melanoma cells was able to suppress distant metastasis in vivo. However, little is known regarding the effects and mechanism of glutathione reductase (GR) inhibition-induced oxidative stress in regulation of melanoma metastasis. Here, we demonstrate that GR inhibition generates oxidative stress and suppresses lung metastasis and subcutaneous growth of melanoma in vivo. In addition, inhibitory effects by GR activity reduction were observed on cell proliferation, colony formation, cell adhesion, migration and invasion in melanoma cells in vitro. GR inhibition-induced oxidative stress was also found to block epithelial-to-mesenchymal transition (EMT) by decreasing the expression of Vimentin, ERK1/2, transcription factor Snail and increasing the expression of E-cadherin. In addition, actin rearrangement, a key element involved in cell motility, was also affected by GR-mediated oxidative stress possibly through protein S-glutathionylation on actin. In conclusion, this study identifies GR as an effective regulator of oxidative stress that affects the multistep processes of metastasis in melanoma cells, and it becomes a potential target for melanoma therapy.
Display omitted
•Inhibition of GR induced oxidative stress which suppresses melanoma cells lung metastasis and subcutaneous growth in vivo.•GR inhibition-induced oxidative stress reduces melanoma growth, colony formation, adhesion, migration and invasion in vitro.•GR inhibition blocks EMT by decreasing the expression of Snail, Vimentin, ERK1/2 and increasing the expression of E-cadherin.•Actin rearrangement is affected by GR-mediated oxidative stress through protein S-glutathionylation modification.
Background: Acute pancreatitis caused by hyperlipidemia is a severe life-threatening condition. Therefore, it is urgent to develop new therapeutic methods to treat this disease.
Methods: Cell ...viability was determined by the Cell Counting Kit-8 (CCK-8) assay. Western blotting (WB) was used to detect the expression levels of apoptotic and endoribonuclease inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP-1) pathway-associated proteins. The induction of cell apoptosis was determined using flow cytometry. The expression levels of the oxidative stress indicators were measured by an enzyme-linked immunosorbent assay.
Results: WB analysis and the CCK-8 assay demonstrated that trimethylamine-N-oxide (TMAO) decreased cell viability and facilitated apoptosis of MPC-83 cells in a dose-dependent manner. Furthermore, the induction of oxidative stress was assessed by evaluating the levels of specific markers, including hydrogen peroxide, reactive oxygen species, nitric oxide, and superoxide dismutase. The levels of the aforementioned markers were increased in the TMAO-treated group. Subsequently, the IRE1α/XBP-1 pathway-associated proteins were analyzed by WB analysis and the data demonstrated that the regulatory effects of TMAO on MPC-83 cells were meditated by the IRE1α/XBP-1 signaling pathway. Subsequently, rescue experiments were performed to further assess the effects of TMAO.
Conclusion: The present study provides evidence on the application of TMAO as a potential diagnostic and therapeutic strategy for the therapeutic intervention of hyperlipidemic acute pancreatitis.
A new approach is proposed that identifies three different zones of the Si-rich network structure (the cellular structure) in laser powder bed fused (LPBF) AlSi10Mg alloy, based on the variation in ...morphology, grain growth transition, and melt pool solidification conditions. The three identified zones are denoted in the present work as the liquid solidification zone (LSZ), the mushy solidification zone (MSZ), and the heat affected zone (HAZ). The LSZ is the result of liquid-solid transformation, showing small planar growth at the boundary and large cellular growth in the center, while the MSZ is related to a semisolid reaction, and the HAZ arises from a short-time aging process. The boundary between the LSZ and MSZ is identified by the change of grain growth direction and the Si-rich network advancing direction. The boundary between MSZ and HAZ is identified by the start of the breakdown of the Si-rich network. In addition, it is found that the fracture is generated in and propagates along the HAZ during tensile tests.
•A simple and rapid UPLC-MS/MS method was first developed for the analysis of sorafenib, lenvatinib and apatinib in plasma.•The influence of methanol in standard or QC samples and stability in whole ...blood were also evaluated.•This method can be applied to therapeutic drug monitoring in HCC patients successfully.
Sorafenib, lenvatinib, and apatinib, as multi-targeted tyrosine kinase inhibitors with anti-proliferative and anti-angiogenic effects, are widely used for systemic therapy in advanced hepatocellular carcinoma patients. Nevertheless, insufficient efficacy or adverse effects often appear due to the significant inter-individual variability of plasma concentration for these drugs. In order to carry out therapeutic drug monitoring of these drugs and then ensure the effectiveness and safety of the medical treatment, the first method allowing to quantify sorafenib, lenvatinib, and apatinib simultaneously in human plasma was developed in this study. The analysis was performed by UPLC-MS/MS system and the chromatographic separation was achieved on a C18 column using a gradient elution of water-acetonitrile in 3.5 min. This method presented satisfactory results in terms of specificity, precision (coefficient of variation of intra-day and inter-day:1.4–6.6 %), accuracy (92.6–105.4 %), matrix effects (96.9–107.2 %), extraction recovery (90.5–99.4 %), as well as stability in human plasma and even whole blood under certain conditions. This sensitive, rapid and simple method was successfully applied to the analysis of sorafenib, lenvatinib and apatinib for therapeutic drug monitoring in hepatocellular carcinoma patients, and it was expected to be applied to further study about clarifying the concentration- efficacy and concentration-toxic relationship of sorafenib, lenvatinib, and apatinib in hepatocellular carcinoma patients.
Melodic intonation therapy (MIT) is a melodic musical training method that could be combined with language rehabilitation. However, some of the existing literature focuses on theoretical mechanism ...research, while others only focus on clinical behavioral evidence. Few clinical experimental studies can combine the two for behavioral and mechanism analysis. This review aimed at systematizing recent results from studies that have delved explicitly into the MIT effect on non-fluent aphasia by their study design properties, summarizing the findings, and identifying knowledge gaps for future work. MIT clinical trials and case studies were retrieved and teased out the results to explore the validity and relevance of these results. These studies focused on MIT intervention for patients with non-fluent aphasia in stroke recovery period. After retrieving 128 MIT-related articles, 39 valid RCT studies and case reports were provided for analysis. Our summary shows that behavioral measurements at MIT are excessive and provide insufficient evidence of MRI imaging structure. This proves that MIT still needs many MRI studies to determine its clinical evidence and intervention targets. The strengthening of large-scale clinical evidence of imaging observations will result in the clear neural circuit prompts and prediction models proposed for the MIT treatment and its prognosis.
Remote maintenance is the development tendency of library automation management. Related discussion has very good practical significance. This paper introduced some cases about remote maintenance for ...library automation management and the application of TeamViewer software.
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases arising from the bone marrow (BM), and approximately 30% of MDS eventually progress to ...AML, associated with increasingly aggressive neoplastic hematopoietic clones and poor survival. Dysregulated immune microenvironment has been recognized as a key pathogenic driver of MDS and AML, causing high rate of intramedullary apoptosis in lower-risk MDS to immunosuppression in higher-risk MDS and AML. Immune checkpoint molecules, including programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), play important roles in oncogenesis by maintaining an immunosuppressive tumor microenvironment. Recently, both molecules have been examined in MDS and AML. Abnormal inflammatory signaling, genetic and/or epigenetic alterations, interactions between cells, and treatment of patients all have been involved in dysregulating PD-1/PD-L1 signaling in these two diseases. Furthermore, with the PD-1/PD-L1 pathway activated in immune microenvironment, the milieu of BM shift to immunosuppressive, contributing to a clonal evolution of blasts. Nevertheless, numerous preclinical studies have suggested a potential response of patients to PD-1/PD-L1 blocker. Current clinical trials employing these drugs in MDS and AML have reported mixed clinical responses. In this paper, we focus on the recent preclinical advances of the PD-1/PD-L1 signaling in MDS and AML, and available and ongoing outcomes of PD-1/PD-L1 inhibitor in patients. We also discuss the novel PD-1/PD-L1 blocker-based immunotherapeutic strategies and challenges, including identifying reliable biomarkers, determining settings, and exploring optimal combination therapies.
Music therapy has been employed as an alternative treatment modality for the arousal therapy of patients with disorders of consciousness (DOC) in clinical settings. However, due to the absence of ...continuous quantitative measurements and the lack of a non-musical sound control group in most studies, the identification of the specific impact of music on DOC patients remains challenging. In this study, 20 patients diagnosed with minimally consciousness state (MCS) were selected, and a total of 15 patients completed the experiment.
All patients were randomly assigned to three groups: an intervention group (music therapy group,
= 5), a control group (familial auditory stimulation group,
= 5), and a standard care group (no sound stimulation group,
= 5). All three groups received 30 min of therapy five times a week for a total of 4 weeks (20 times per group, 60 times in total). Autonomic nervous system (ANS) measurements, Glasgow Coma Scale (GCS), and functional magnetic resonance-diffusion tensor imaging (fMRI-DTI) were used to measure the peripheral nervous system indicators and brain networks, and to evaluate patients' behavior levels.
The results reveal that PNN50 (
= 0.0004**), TP (
= 0.0003**), VLF (
= 0.0428**), and LF/HF (
= 0.0001**) in the music group were significantly improved compared with the other two groups. Such findings suggest that the ANS of patients with MCS exhibits higher activity levels during music exposure compared to those exposed to family conversation or no auditory stimulation. In fMRI-DTI detection, due to the relative activity of ANS in the music group, the ascending reticular activation system (ARAS) in the brain network also exhibited significant nerve fiber bundle reconstruction, superior temporal gyrus (STG), transverse temporal gyrus (TTG), inferior temporal gyrus (ITG), limbic system, corpus callosum, subcorticospinal trace, thalamus and brainstem regions. In the music group, the reconstructed network topology was directed rostrally to the diencephalon's dorsal nucleus, with the brainstem's medial region serving as the hub. This network was found to be linked with the caudal corticospinal tract and the ascending lateral branch of the sensory nerve within the medulla.
Music therapy, as an emerging treatment for DOC, appears to be integral to the awakening of the peripheral nervous system-central nervous system based on the hypothalamic-brainstem-autonomic nervous system (HBA) axis, and is worthy of clinical promotion. The research was supported by the Beijing Science and Technology Project Foundation of China, No. Z181100001718066, and the National Key R&D Program of China No. 2022YFC3600300, No. 2022YFC3600305.
•Hierarchical spatial correlation models are investigated.•Inverse modeling is used to find parameters for correlation models.•Estimated correlation models provides accurate spatial correlation ...structure.
Outcrop analogs for aquifers allow measurements of permeability with relatively high-resolution and mapping sedimentary unit types. The spatial bivariate structure of permeability is defined by aquifer architecture. The architecture is often organized into a hierarchy of unit types, and associated permeability modes, across different spatial scales. The composite covariance (or semivariogram) is a linear summation of the auto- and cross-covariances (or semivariograms) of unit types defined at smaller scales, weighted by the related proportions and transition probabilities. It is well-known that an appreciable fraction of the composite variance arises from differences in mean permeability across unit types defined at smaller scales. Previous work has shown that the transition probabilities usually define the spatial bivariate correlation structure. The composite spatial bivariate statistics for permeability (covariance or semivariogram) will not be representative unless data locations allow proper definition of the transition probabilities of the units. Quantification of the stratal architecture can be used to better interpret the transition probabilities and thereby improve a model for the sample covariance and semivariogram. In this paper, we use an inverse modeling algorithm to fit the components of the hierarchical model, written as nested functions, in developing a hierarchical spatial correlation models. Specifically, the least-squares criterion along with prior information and other weighted constraints are used as the objective function for the inverse problem, which is solved by the Gauss–Newton–Levenberg–Marquardt method. The estimated covariance and transition probability models provides accurate representation of the spatial correlation structure of permeability for field-measured data from in Española Basin, New Mexico.
The position of the emission zone (EZ) in the active material of a light‐emitting electrochemical cell (LEC) has a profound influence on its performance because of microcavity effects and doping‐ and ...electrode‐induced quenching. Previous attempts of EZ control have focused on the two principal constituents in the active material—the organic semiconductor (OSC) and the mobile ions—but this study demonstrates that it is possible to effectively control the EZ position through the inclusion of an appropriate additive into the active material. More specifically, it is shown that a mere modification of the end group on an added neutral compound, which also functions as an ion transporter, results in a shifted EZ from close to the anode to the center of the active material, which translates into a 60% improvement of the power efficiency. This particular finding is rationalized by a lowering of the effective electron mobility of the OSC through specific additive: OSC interactions, but the more important generic conclusion is that it is possible to control the EZ position, and thereby the LEC performance, by the straightforward inclusion of an easily tuned additive in the active material.
The position of the in situ formed emission zone (EZ) in light‐emitting electrochemical cells has a profound influence on the device performance because of microcavity effects and doping and electrode quenching. This study shows that the inclusion of easily tuned additives can rationally shift the EZ position for improved performance.
PDF
