Serum fibrosis markers for systemic sclerosis (SSc) remain limited. The Enhanced Liver Fibrosis (ELF) score is a collagen marker set consisting of procollagen type III amino terminal propeptide ...(PIIINP), tissue inhibitor of metalloproteinases 1 (TIMP-1), and hyaluronic acid (HA). This longitudinal study aimed to examine the performance of the ELF score and its single analytes as surrogate outcome measures of fibrosis in SSc.
Eighty-five SSc patients fulfilling the 2013 ACR/EULAR criteria with the absence of chronic liver diseases were enrolled. Serum PIIINP, TIMP-1, HA, and the ELF score were measured and correlated with clinical variables including the modified Rodnan skin score (mRSS) and interstitial lung disease (ILD). Twenty SSc patients underwent a follow-up serological testing and mRSS evaluation during treatment with immunosuppressants and/or anti-fibrotic drugs.
Serum PIIINP, TIMP-1, and ELF score were significantly higher in patients with SSc than in healthy controls PIIINP: 10.31 (7.83-14.10) vs. 5.61 (4.69-6.30),
< .001; TIMP-1: 110.73 (66.21-192.45) vs. 61.81 (48.86-85.24),
< .001; ELF: 10.34 (9.91-10.86) vs. 9.68 (9.38-9.99),
< .001. Even higher levels of PIIINP, TIMP-1, and ELF score were found in patients with diffuse cutaneous SSc than those with limited cutaneous SSc. At baseline, both PIIINP and ELF score showed good correlation with mRSS (PIIINP: r = .586,
< .001; ELF: r = .482,
< .001). Longitudinal analysis showed that change in PIIINP positively correlated with change in mRSS (r = 0.701,
= .001), while change in ELF score were not related, in a statistical context, to the change in mRSS (ELF: r = .140,
= .555). Serum TIMP-1 was significantly higher in SSc patients with ILD, compared to the matched group of patients without ILD 109.45 (93.05-200.09) vs. 65.50 (40.57-110.73),
= 0.007.
In patients with SSc, the ELF score well correlates with the extent of skin fibrosis, while serum PIIINP is a sensitive marker for longitudinal changes of skin fibrosis. In the future, circulating collagen metabolites may potentially be used to evaluate therapeutic effects of anti-fibrotic treatments in the disease.
•Icaritin attenuates cigarette smoke-mediated oxidative stress.•Icaritin activates PI3K-AKT and Nrf2 signal pathways.•Inactivation of PI3k and Nrf2 reserves icaritin-induced GCL upregulation.
Icariin ...is the major active ingredient of Herba Epimedii. Icaritin (ICT) is a hydrolytic product of Icariin. In the present study, we investigated the protective role of ICT against cigarette smoke extract (CSE)-mediated oxidative stress in human lung epithelial A549 cells. As demonstrated by the WST-8 assay, exposure to CSE (2.5%, 5%, and 10%) reduced the cell viability of A549 cells (84%, 64% and 53%) in a dose-dependent manner and treatment with ICT 10μM dramatically attenuated CSE induced cytotoxicity (73% and 64%). The MFI data suggested that CSE induced oxidative stress by generating ROS (230) and 10μM ICT treatment attenuated CSE-induced ROS production (90). 10μM ICT treatment resulted in significant AKT activation, Nrf2 nuclear translocation, increased GCL transcription and GSH levels, as compared with CSE exposure alone. However, ICT-mediated upregulation of GCL transcription in CSE-treated cells were lost in Nrf2 siRNA-transfected cells. Furthermore, inhibition of PI3K/AKT signaling by LY294002 partially prevents ICT-induced nuclear translocation of Nrf2 and GCL transcription. These findings suggest that ICT attenuates CS-induced oxidative stress by quenching ROS and also by upregulating GSH via a PI3K-AKT-Nrf2-dependent mechanism. Further studies are required to confirm that a similar protective effect of ICT occurs in the lungs in vivo in response to CS exposure.
Combining the oxidant and coolant flow in an air-cooled proton exchange membrane fuel cell can significantly simplify the fuel cell design. In this paper, an air-cooled PEM fuel cell stack with an ...open cathode flow field, which supplied the oxidant and removed the heat produced in the fuel cell, was fabricated and tested. The influence of different operating parameters on cell voltage performance and the overall cell ohmic resistance, such as cell temperature and airflow rate, was investigated. The cell temperature and the temperature difference between the cell and the hydrogen humidifier were shown to serve important roles in reducing the fuel cell ohmic resistance. The test results also showed a noteworthy temperature gradient between each cell of a 5-cell stack. A hydrophilic treatment of the cathode flow field channels was demonstrated to be an effective way to mitigate water management issues caused at elevated operating temperatures.
Durability issues have been attracting a great deal of attention in hydrogen/air proton exchange membrane (PEM) fuel cell research. In the present work, membrane electrode assembly (MEA) degradation ...under open circuit (OC) conditions was carried out for more than 250
h. By means of several on-line electrochemical measurements, the performance of the fuel cell was analysed at different times during the degradation process. The results indicate that structural changes in the PEM and catalyst layers (CLs) are the main reasons for the decline in performance during OC operation. The results also show that degradation due to platinum oxidation or catalyst contamination can be partially recovered by a subsequent potential cycling process, whereas the same cycling process cannot recover the membrane degradation.
Immune checkpoint inhibitors (ICIs) have shown promising results for the treatment of multiple cancers. ICIs and related therapies may also be useful for the treatment of thyroid cancer (TC). In TC, ...Myc binding protein 2 (MYCBP2) is correlated with inflammatory cell infiltration and cancer prognosis. However, the relationship between MYCBP2 expression and ICI efficacy in TC patients is unclear.
We downloaded data from two TC cohorts, including transcriptomic data and clinical prognosis data. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict the efficacy of ICIs in TC patients. MCPcounter, xCell, and quanTIseq were used to calculate immune cell infiltration scores. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were used to evaluate signaling pathway scores. Immunohistochemical (IHC) analysis and clinical follow up was used to identify the MYCBP2 protein expression status in patients and associated with clinical outcome.
A higher proportion of MYCBP2-high TC patients were predicted ICI responders than MYCBP2-low patients. MYCBP2-high patients also had significantly increased infiltration of CD8+ T cells, cytotoxic lymphocytes (CTLs), B cells, natural killer (NK) cells and dendritic cells (DC)s. Compared with MYCBP2-low patients, MYCBP2-high patients had higher expression of genes associated with B cells, CD8+ T cells, macrophages, plasmacytoid dendritic cells (pDCs), antigen processing and presentation, inflammatory stimulation, and interferon (IFN) responses. GSEA and ssGSEA also showed that MYCBP2-high patients had significantly increased activity of inflammatory factors and signaling pathways associated with immune responses.In addiation, Patients in our local cohort with high MYCBP2 expression always had a better prognosis and greater sensitivity to therapy while compared to patients with low MYCBP2 expression after six months clinic follow up.
In this study, we found that MYCBP2 may be a predictive biomarker for ICI efficacy in TC patients. High MYCBP2 expression was associated with significantly enriched immune cell infiltration. MYCBP2 may also be involved in the regulation of signaling pathways associated with anti-tumor immune responses or the production of inflammatory factors.
3, 5, 7-Trihydroxy-4′-methoxy-8-(3-hydroxy-3-methylbutyl)-flavone (ICT) is a novel derivative of Icariin (ICA), the major active ingredient of Herba Epimedii, a herb used in traditional Chinese and ...alternative medicine. We previously demonstrated its anti-inflammatory effect in murine innate immune cells and activated human PBMCs. We report herein that ICA or ICT treatment reduces the expression of MRP8/MRP14 and toll-like receptor 4 (TLR4) on human PBMCs. Administration of ICA or ICT inhibited tumor growth in 4T1-Neu tumor-bearing mice and considerably decreased MDSC numbers in the spleen of these mice. Further, we saw a restoration of IFN-γ production by CD8+ T cells in tumor bearing mice when treated with ICA or ICT. ICA and ICT significantly decreased the amounts of nitric oxide and reactive oxygen species in MDSC in vivo. When MDSC were treated in vitro with ICT, we saw a significant reduction in the percent of these cells with concomitant differentiation into dendritic cells and macrophages. Concomitant with this cell type conversion was a down-regulation of IL-10, IL-6 and TNF-α production. Decreased expression of S100A8/9 and inhibition of activation of STAT3 and AKT may in part be responsible for the observed results. In conclusion, our results showed that ICA, and more robustly, ICT, directly modulate MDSC signaling and therefore altered the phenotype and function of these cells, in vitro and in vivo.
Most nurses in China have not been trained to take care of end-of-life patients appropriately due to lack of educational resources and insufficient training. A palliative care program was launched by ...the Jiangsu Nursing Association (JNA training program) and to identify gaps in palliative care training. The main aim of this study was to evaluate the training effects of the JNA training program on nurses' knowledge and attitudes to palliative care.
A cross-sectional study was conducted with 10 048 registered nurses in all regions of Jiangsu. All participants completed an online questionnaire using the Chinese version of The Palliative Care Quiz for Nursing (PCQN-C) and the Frommelt Attitude Toward Care of the Dying scale (FATCOD-B-C). A propensity score matched analysis was performed between the nurses who had attended the JNA training program and whose who hadn't.
The average score of PCQN-C among all nurses was 8.79, while the mean score of the FATCOD-B-C was 103.62. Those participants who attended the JNA training program had significantly better scores than those who did not. Propensity score matching analysis showed that the palliative care training program failed to improve nurses' knowledge in psychosocial and spiritual care or their attitudes towards the necessity of family support although there was positive impact on other aspects of palliative care.
Knowledge of palliative care among Chinese nurses remains low. Training programs may improve general knowledge and attitudes to palliative care. However, important aspects of knowledge such as communication skills, family support, and psychosocial aspects of care, are missing. These gaps should be filled in future palliative care training programs targeting nurses with oriental culture background.
► Icariside II potentiates paclitaxel-induced apoptosis in melanoma cells. ► These effects were mediated by inhibiting the activation of the TLR4 signaling. ► Further preclinical evaluation of IS as ...a novel anti-tumor agent is necessary.
Combination therapy of paclitaxel (taxol) with natural anti-tumor agents that are capable of inhibiting survival signals may provide a rational molecular basis for novel chemotherapeutic strategies. Our previous study showed that icariside II (IS), derived from Herba Epimedii, inhibited the proliferation of melanoma cells in vivo and in vitro through the regulation of apoptosis. In this report, the combination effects of paclitaxel and IS were investigated in human melanoma A375 cells. As compared to the treatment with paclitaxel alone, the co-administration of IS and paclitaxel resulted in an enhancement of apoptosis as revealed by WST-8 and PI assays. Meanwhile, Western blot analysis showed that the co-administration of IS and paclitaxel resulted in increases of cleaved caspase-3, one of the terminal pro-apoptotic proteins. In melanoma, IL-8 and VEGF are positively correlated with disease stage and a high probability of progression. We demonstrated that treatment of A375 cells with IS in combination with paclitaxel resulted in a significant decrease in the production of IL-8 and VEGF, compared with paclitaxel alone. Recent studies suggest that TLR4–MyD88–ERK signaling may be a novel target for reversing chemoresistance to paclitaxel. Our flow cytometry and Western blot data showed that paclitaxel activated TLR4–MyD88–ERK signaling and that IS treatment could effectively inhibit this paclitaxel-induced activation of TLR4–MyD88–ERK signaling. In conclusion, this study demonstrated for the first time that IS could potentiate paclitaxel-induced apoptosis in melanoma cells. These effects were mediated, at least in part, by inhibiting the activation of the TLR4 signal transduction pathways. These findings support further preclinical evaluation of IS as a new potential anti-tumor agent.
Melanoma metastasis to the brain is one of the most frequent extracranial brain tumors. Cell surface gangliosides are elevated in melanoma metastasis; however, the metabolic regulatory mechanisms ...that govern these specific changes are poorly understood in melanoma particularly brain metastases (MBM) development. We found ganglioside GD3 levels significantly upregulated in MBM compared to lymph node metastasis (LNM) but not for other melanoma gangliosides. Moreover, we demonstrated an upregulation of ST8SIA1 (GD3 synthase) as melanoma progresses from melanocytes to MBM cells. Using RNA‐ISH on FFPE specimens, we evaluated ST8SIA1 expression in primary melanomas (PRM) (n = 23), LNM and visceral metastasis (n = 45), and MBM (n = 39). ST8SIA1 was significantly enhanced in MBM compared to all other specimens. ST8SIA1 expression was assessed in clinically well‐annotated melanoma patients from multicenters with AJCC stage III B‐D LNM (n = 58) with 14‐year follow‐up. High ST8SIA1 expression was significantly associated with poor overall survival (HR = 3.24; 95% CI, 1.19–8.86, P = 0.02). In a nude mouse human xenograft melanoma brain metastasis model, MBM variants had higher ST8SIA1 expression than their respective cutaneous melanoma variants. Elevated ST8SIA1 expression enhances levels of cell surface GD3, a phenotype that favors MBM development, hence associated with very poor prognosis. Functional assays demonstrated that ST8SIA1 overexpression enhanced cell proliferation and colony formation, whereby ST8SIA1 knockdown had opposite effects. Icaritin a plant‐derived phytoestrogen treatment significantly inhibited cell growth in high GD3‐positive MBM cells through targeting the canonical NFκB pathway. The study demonstrates GD3 phenotype associates with melanoma progression and poor outcome.
We demonstrated the upregulation of a ganglioside synthase, ST8SIA1 and GD3 expression in MBM, which can be suppressed by icaritin treatment. Icaritin inhibits NFκB‐mediated activation of ST8SIA1 by downregulating p50. These findings suggest that ST8SIA1 is a significant factor and potential target to MBM.
The minimum void ratio is a fundamental physical index for evaluating particle properties in soil mechanics, ceramic processing, and concrete mixes. Previous research found that both particle size ...distribution and particle shape characteristics would affect minimum void ratio, while the current research generally uses a linear model to estimate the minimum void ratio of a binary mixture, ignoring quantitative effect of particle shape on the minimum void ratio. Based on a study of binary mixtures of natural sand from three different origins and iron particles of two different shapes, this paper analyzes the influence factors of the minimum void ratio, and a quadratic nonlinear model is proposed for estimating the minimum void ratio of binary mixture. The model contains only one undetermined coefficient, a, the value of which is correlated to the particle sphericity, particle size, and particle size ratio. A theoretical calculation formula for the coefficient a is proposed to quantitatively analyze the effects of these three factors on the size of the parameters. In the end, the model is used to estimate the minimum void ratios of sand and substitute particles from different producing areas; the average difference between the estimated values and the fitted values is about 2.03%, suggesting that the estimated values of the model fit well with the measured data.
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