Andrographolide(ADE) has been demonstrated to inhibit tumor growth through direct cytotoxicity on tumor cells. However, its potential activity on tumor microenvironment (TME) remains unclear. ...Tumor‐associated macrophages (TAMs), composed mainly of M2 macrophages, are the key cells that create an immunosuppressive TME by secretion of cytokines, thus enhancing tumor progression. Re‐polarized subpopulations of macrophages may represent vital new therapeutic alternatives. Our previous studies showed that ADE possessed anti‐metastasis and anoikis‐sensitization effects. Here, we demonstrated that ADE significantly suppressed M2‐like polarization and enhanced M1‐like polarization of macrophages. Moreover, ADE inhibited the migration of M2 and tube formation in HUVECs under M2 stimulation. In vivo studies showed that ADE restrained the growth of MDA‐MB‐231 and HCC1806 human breast tumor xenografts and 4T‐1 mammary gland tumors through TAMs. Wnt5a/β‐catenin pathway and MMPs were particularly associated with ADE's regulatory mechanisms to M2 according to RNA‐seq and bioinformatics analysis. Moreover， western blot also verified the expressions of these proteins were declined with ADE exposure. Among the cytokines released by M2, PDGF‐AA and CCL2 were reduced. Our current findings for the first time elucidated that ADE could modulate macrophage polarization and function through Wnt5a signaling pathway, thereby playing its role in inhibition of triple‐negative breast cancer.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Adoptive immunotherapy is a new potential method of tumour therapy, among which anti‐CD19 chimeric antigen receptor T‐cell therapy (CAR‐T cell), is a typical treatment agent for haematological ...malignancies. Previous clinical trials showed that the quality and phenotype of CAR‐T cells expanded ex vivo would seriously affect the tumour treatment efficacy. Although magnetic beads are currently widely used to expand CAR‐T cells, the optimal expansion steps and methods have not been completely established. In this study, the differences between CAR‐T cells expanded with anti‐CD3/CD28 mAb‐coated beads and those expanded with cell‐based aAPCs expressing CD19/CD64/CD86/CD137L/mIL‐15 counter‐receptors were compared. The results showed that the number of CD19‐specific CAR‐T cells with a 4‐1BB and CD28 co‐stimulatory domain was much greater with stimulation by aAPCs than that with beads. In addition, the expression of memory marker CD45RO was higher, whereas expression of exhausted molecules was lower in CAR‐T cells expanded with aAPCs comparing with the beads. Both CAR‐T cells showed significant targeted tumoricidal effects. The CAR‐T cells stimulated with aAPCs secreted apoptosis‐related cytokines. Moreover, they also possessed marked anti‐tumour effect on NAMALWA xenograft mouse model. The present findings provided evidence on the safety and advantage of two expansion methods for CAR‐T cells genetically modified by piggyBac transposon system.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cytokine-induced killer (CIK) cells have been proved to be an effective method of tumor immunotherapy in numerous preclinical and clinical studies. In our previous study, a new method was developed ...to prime and propagate CIK cells by the combination of IL-2 and IL-15, and this kind of CIK cells had enhanced antitumor effect on lung cancer. For renal cell carcinoma (RCC), immunotherapy plays an important role because of the poor efficacy of radiotherapy and chemotherapy. In this study, we further evaluated the antitumor effects of these enhanced CIK cells against RCC. Enhanced CIK cells were generated by IL-2 combined with IL-15 and identified by flow cytometry. HEK-293 and ACHN cell lines were used to verify the efficiency of CIK cells in vitro, and then the ACHN tumor xenograft model was also employed for in vivo study. In addition, the secreted cytokines including IFN-γ, granzyme B, TNF-α, and perforin, as well as the local microstructure were also studied. Subsequently, 20 patients with RCC were enrolled into our study, and 11 patients were randomly divided into the autologous CIK treatment group for clinical research. The results showed that enhanced CIK cells exert better antitumor effects in RCC in vitro (p<0.01 in HEK-293 and p<0.05 in ACHN）and in vivo (p<0.05). Patients benefit overall survival from enhanced CIK therapy in our clinical study. Our present preclinical and clinical studies for the first time elucidated that these enhanced CIK cells would be used as an effective adjuvant therapy in the treatment of RCC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective To investigate the relationship between the serum levels of leptin, neuron-specific enolase (NSE) and S-100B in patients of stroke and the incidence of post-stroke depression (PSD). Methods ...The clinical data of 121 cases of acute ischemic stroke, admitted to Zhengzhou Central Hospital affiliated to Zhengzhou University from Jun. 2010 to Dec. 2012, were retrospectively analyzed. After six months of follow-up 42 patients were diagnosed as suffering from PSD (Hamilton Depression Scale score ≥8). Another 42 participants with available matching data on onset time, age, gender and lesions of brain were selected. The serum samples were collected from all patients at time of discharge, and the concentrations of serum leptin, NSE and S-100B were analyzed by enzyme-linked immunosorbent assay (ELISA) kit. Correlation and efficiency of diagnosing PSD among them was validated by receptor operator curve (ROC). Results The concentration of serum leptin, NSE, and S-100B in PSD group (25.84±13.80, 2.59±1.48 and 25.0
A cascade oxidation/Pictet-Spengler condensation/annulation process has been developed for the one-pot total synthesis of nitramarine, nitraridine, and their analogues. The procedure proceeded with ...easily available quinolines and tryptophan derivatives. A simple and metal-free approach, wide substrate scope, and functional group tolerance make it applicable for the synthesis of diverse bioactive nitramarine, nitraridine, and their derivatives. Furthermore, the bioactivity evaluation has identified two promising leading compounds 5d and 5e with potent antitumor proliferative activity against breast cancer cells.A cascade oxidation/Pictet-Spengler condensation/annulation process has been developed for the one-pot total synthesis of nitramarine, nitraridine, and their analogues. The procedure proceeded with easily available quinolines and tryptophan derivatives. A simple and metal-free approach, wide substrate scope, and functional group tolerance make it applicable for the synthesis of diverse bioactive nitramarine, nitraridine, and their derivatives. Furthermore, the bioactivity evaluation has identified two promising leading compounds 5d and 5e with potent antitumor proliferative activity against breast cancer cells.
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IJS, KILJ, NUK, PNG, UL, UM
A novel, efficient, and robust synthetic route to ZG1077 with an atropisomer structure for KRAS G12C inhibitors was designed. The critical process parameters were optimized and established to reduce ...or avoid process-related impurities. The formation mechanism, purge pathways, and control strategy for these impurities are discussed. Compared with the medicinal chemistry route, the single atropisomer drug substance was obtained with chiral resolution rather than the supercritical fluid chromatogram purification technique, and it was obtained in 3.01% overall yield with >99.5% purity and 99.8% e.e. in the novel route. However, the overall yield is only 0.56%, and the purity and chiral purity were less than 99.0% in the medicinal chemistry route. The process is suitable to obtain enough active pharmaceutical ingredients for preclinical and clinical studies.
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IJS, KILJ, NUK, PNG, UL, UM
In this paper, the effect of pre-existing discrete fracture network（DFN） connectivity on hydraulic fracturing is numerically investigated in a rock mass subjected to in-situ stress. The simulation ...results show that DFN connectivity has a significant influence on the hydraulic fracture（HF） ＆ DFN interaction and hydraulic fracturing effectiveness, which can be characterized by the total interaction area, stimulated DFN length, stimulated HF length, leak-off ratio, and stimulated total length. In addition, even at the same fluid injection rate, simulation models exhibit different responses that are strongly affected by the DFN connectivity. At a low injection rate, total interaction area decreases with increasing DFN connectivity; at a high injection rate, total interaction area increases with the increase of DFN connectivity. However, for any injection rate, the stimulated DFN length increases and stimulated HF length decreases with the increase of connectivity. Generally, this work shows that the DFN connectivity plays a crucial role in the interaction between hydraulic fractures, the pre-existing natural fractures and hydraulic fracturing effectiveness; in return, these three factors affect treating pressure, created microseismicity and corresponding stimulated volume. This work strongly relates to the production technology and the evaluation of hydraulic fracturing effectiveness. It is helpful for the optimization of hydraulic fracturing simulations in naturally fractured formations.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Amorphous Ni-P coating was plated on AZ31 magnesium alloy via the electroless plating technique, and the plated alloy was subsequently annealed. X-ray dif- fraction （XRD）, scanning electron ...microscopy （SEM）, energy dispersive spectroscopy （EDS）, and differential scanning calorimetry （DSC） were used to characterize the coating. The results show that the hardness of the coating is much higher than that of bare magnesium alloy, which further increases after crystallization. The electrochemical polarization and salt spray tests show that the coating exhibits a much higher corrosion resistance than that of the bare magnesium alloy. Moreover, the crystallized coating still exhibits a much stronger corrosion resistance than that of the bare magnesium alloy, although its corrosion resistance is lower than that of the as-plated one.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We integrate the genomics, proteomics, and phosphoproteomics of 480 clinical tissues from 146 patients in a Chinese colorectal cancer (CRC) cohort, among which 70 had metastatic CRC (mCRC). Proteomic ...profiling differentiates three CRC subtypes characterized by distinct clinical prognosis and molecular signatures. Proteomic and phosphoproteomic profiling of primary tumors alone successfully distinguishes cases with metastasis. Metastatic tissues exhibit high similarities with primary tumors at the genetic but not the proteomic level, and kinase network analysis reveals significant heterogeneity between primary colorectal tumors and their liver metastases. In vivo xenograft-based drug tests using 31 primary and metastatic tumors show personalized responses, which could also be predicted by kinase-substrate network analysis no matter whether tumors carry mutations in the drug-targeted genes. Our study provides a valuable resource for better understanding of mCRC and has potential for clinical application.
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•A large-scale proteogenomics study of metastatic colorectal cancers•Phosphoproteomic pattern distinguishes metastasis and predicts drug response•A workflow from generation of large omics datasets to in vivo drug testing models•Improves the selection of treatment strategies for patients without druggable mutation
Li et al. provide a global proteogenomic landscape for metastatic colorectal cancer in a Chinese cohort. Proteomic and phosphoproteomic profiling of primary tumors successfully distinguishes cases with metastasis and, together with network analysis, accurately reflects the drug responses of primary and metastatic tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Whole genome variants offer sufficient information for genetic prediction of human disease risk, and prediction of animal and plant breeding values. Many sophisticated statistical methods have been ...developed for enhancing the predictive ability. However, each method has its own advantages and disadvantages, so far, no one method can beat others.
We herein propose an Ensemble Learning method for Prediction of Genetic Values (ELPGV), which assembles predictions from several basic methods such as GBLUP, BayesA, BayesB and BayesCπ, to produce more accurate predictions. We validated ELPGV with a variety of well-known datasets and a serious of simulated datasets. All revealed that ELPGV was able to significantly enhance the predictive ability than any basic methods, for instance, the comparison p-value of ELPGV over basic methods were varied from 4.853E-118 to 9.640E-20 for WTCCC dataset.
ELPGV is able to integrate the merit of each method together to produce significantly higher predictive ability than any basic methods and it is simple to implement, fast to run, without using genotype data. is promising for wide application in genetic predictions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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