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Purpose. Treatment outcomes for advanced liver cancer are poor. Immunotherapy is a treatment strategy that has been widely used to treat other cancers. Studies have shown that CD8+ T lymphocytes are essential factors affecting the efficacy of immunotherapy. We used computational biology methods to determine the coexpressed gene network that promotes CD8+ T lymphocyte infiltration. Method. We obtained the liver cancer gene matrix and clinical follow-up information data from TCGA liver hepatocellular carcinoma FPKM. We obtained single nucleotide polymorphism (SNP) data to evaluate the tumor mutation burden. The “estimate” package and the CIBERSORT algorithm were used to evaluate tumor purity and the proportion of CD8+ T lymphocytes in the liver cancer cohort. We used the gene expression matrix of liver cancer and the relative proportion of CD8+ T lymphocytes as input files and performed WGCNA based on this analysis. The weighted coexpression network identified the most CD8+ T lymphocyte-related coexpression modules in liver cancer. Then, we analyzed the biological processes involved in the module. We determined the coexpression module with CD8+ T lymphocyte infiltration in terms of data and function. We then screened the factors in the coexpression module correlated with CD8+ T lymphocyte content greater than 0.4. Finally, the expression levels of these factors were verified at the protein level using immunohistochemistry and single-cell sequencing. Results. We determined the CD8+ T lymphocyte proportions that correlated with coexpression networks. Four coexpressed genes (C1QC, CD3D, GZMA, and PSMB9) were identified as CD8+ T cell coexpression genes that promoted infiltration of CD8+ T cells. Because the factors in the coexpression network often participate in similar biological processes, we found that these factors were most related to antigen processing and presentation of peptide antigen through functional enrichment. In the clinical phenotype analysis, we found that 18 factors can be used as independent prognostic protective factors. We found that these factors were significantly negatively correlated with tumor purity and negatively correlated with M2 macrophages in the immunophenotyping analysis. Using immunohistochemistry and single-cell sequencing analysis, we found that CD3D antibody staining was weaker in tumor tissues than normal tissues and was related to CD8+ T cells. Conclusion. These coexpressed genes were positively related to the high infiltration proportion of CD8+ T lymphocytes in an antigen presentation process. The biological process might provide new directions for patients who are insensitive to immune therapy.

FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity 1and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC50 values for H226 and HCC827 GR were 2.11 μM, and 0.93 μM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.

A series of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives were designed and synthesised as novel fibroblast growth factor receptor-1 (FGFR1) inhibitors. We found that one of the most promising compounds, C9, inhibited five non-small cell lung cancer (NSCLC) cell lines with FGFR1 amplification, including NCI-H520, NCI-H1581, NCI-H226, NCI-H460 and NCI-H1703. Moreover, the IC50 values for the compound C9 were 1.36 ± 0.27 µM, 1.25 ± 0. 23 µM, 2.31 ± 0.41 µM, 2.14 ± 0.36 µM and 1.85 ± 0.32 µM, respectively. The compound C9 arrested the cell cycle at the G2 phase in NSCLC cell lines. The compound C9 also induced cellular apoptosis and inhibited the phosphorylation of FGFR1, PLCγ1 and ERK in a dose-dependent manner. In addition, molecular docking experiments showed that compound C9 binds to FGFR1 to form six hydrogen bonds. Taken together, our data suggested that the compound C9 represented a promising lead compound-targeting FGFR1.

Background: Thienopyrimidinone is a newly designed, selective fibroblast growth factor receptor 1 (FGFR1) inhibitor with an excellent anticancer effect. Objective: The goal of the present study was to design and synthesize better FGFR1 inhibitors through modifications of the lead compound thienopyrimidinone. Methods: In the present study, a series of C-2 substituted derivatives of thienopyrimidinone, namely L1–L16, were synthesized, and their inhibitory effects on FGFR1 were evaluated. The anti-proliferative activities of these compounds were assessed by MTT assay. Results: Among the novel derivatives, L11 was found to exert remarkable FGFR1 inhibitory activity (79.93% at 10 μM) and anti-proliferative activity, with IC50 values of 2.1, 2.5, and 3.5 μM in the FGFR1-overexpressing cell lines, H460, HT-1197, and B16F10, respectively. Conclusion: Our newly synthesized thienopyrimidinone derivatives may be candidate FGFR1 inhibitors for future development as novel anticancer agents.

It is demonstrated that nanoparticles are ubiquitous in subsurface sediments; therefore, investigation of the adsorption and desorption of U(VI) on nanoparticles plays vital role in the understanding of the fate and transport of U(VI) in sub-sediment at their initial sources. The nano-alumina was synthesized by self-assemble method and was characterized by TEM, XRD and potentiometric titration. The characteristic results revealed the presence of nanoscale space confinement effect of nano-alumina. The batch adsorption of U(VI) on nano-alumina was carried out under various water chemistry such as reaction time, pH, ionic strength, initial U(VI) concentration and temperature. The maximum adsorption capacity of nano-alumina and alpha-alumina calculated from Langmuir model at pH 4.5 and T = 298 K are 92.59 and 59.88 mg/g, respectively. Approximately 35% and 5% of U(VI) are desorbed from alpha-alumina and nano-alumina at 48 h in the presence of 0.01 M NaHCO 3 solution, which indicate that the nano-alumina presents the strong chemical affinity for U(VI) as compared to alpha-alumina. This study implies that nano-alumina could be as a promising adsorbent to remove the U(VI) from aqueous solutions.

The nano goethite and nano alumina were synthesized to investigate the effect of nanoscale size on adsorption–desorption of U(VI) from aqueous solution. It was determined that the site densities of nanoparticles are higher than α-alumina and goethite, whereas slight effect of carbonate on adsorption of U(VI) onto nanoparticles was observed. The maximum adsorption capacities of nano alumina and nano goethite were ~151 and 79 mg/g, respectively. The batch desorption indicated stronger binding affinity of U(VI) for nanoparticles as compared to non-nanoparticles, which were consistent with the results of surface complexation modeling assuming weak and strong sites for nanoparticles while weak sites for α-alumina and goethite.

A total of 24 N-substituted 3,5-bis(2-(trifluoromethyl)benzylidene)piperidin-4-one derivatives were synthesized via aldol condensation, and their anti-inflammatory activities were evaluated. These compounds were found to have no significant cytotoxicity against mouse bone marrow cells in vitro. However, some compounds, such as c6 (N-(3-methylbenzoyl)-3,5-bis-(2-(trifluoromethyl)benzylidene)piperidin-4-one) and c10 (N-(2-chlorobenzoyl)-3,5-bis-(2-(trifluoromethyl)benzylidene)piperidin-4-one), displayed potent anti-inflammatory activity by inhibiting lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), IL-1β, prostaglandin E2 (PGE2), and nitric oxide (NO) production in RAW 264.7 cells. Treatment with c6 or c10 at 2.5 or 10 mg kg−1 significantly decreased the paw edema induced by carrageenan in rats, and the anti-inflammatory effects of these compounds were found to be better than those of celecoxib or indomethacin as well as their parent compound C66 (2,6-bis-(2-(trifluoromethyl)benzylidene)cyclohexanone). Pharmacokinetic analysis indicated that c6 has better bioavailability than curcumin. Therefore, these compounds may be valuable leads for the development of new anti-inflammatory drugs.

Surface complexation modeling based on diffuse double layer model (DDLM) has been employed to simulate the leaching behaviors of radionuclides (i.e., 60Co2+, 63Ni2+, 64Cu2+ and UO2 2+) on fly ashes from hospital wastes. The fly ashes were characterized by X-ray diffraction (XRD), potentiometric acid–base titration, and scanning electron microscopy (SEM). The effect of pH, the ratio of solid-to-liquid (RSL), and particle size on the leaching of radionuclides was also conducted under the batch techniques. According to XRD patterns analysis, the main components of fly ashes was determined to be quartz and clay minerals such as kaolinite, illite and smectite. The site density and pHPNZC (pH at point of net zero charge) of fly ashes calculated from potentiometric titration data was found to be 4.53 × 10−4 mol/g and 7.4, respectively. One can see that the small amount of metal oxides attached on the surface of fly ashes by SEM images, corrosion surface of fly ashes was observed after leaching experiments. Results of the batch leaching experiments indicated that the leaching amount of radionuclides in fly ashes significantly depended on pH, the ratio of solid-to-liquid, and particle size. It is found that the leaching amount of radionuclides decreased in the order of 64Cu2+ ≫ 63Ni2+ > 60Co2+ > UO2 2+ under the different pH, the RSL or particle size conditions. In this paper, DDLM has successfully been applied to describe the leaching behaviors of radionuclides from fly ashes. This research provides critical information for application of surface complexation modeling on the simulation of radionuclides leaching from fly ashes, which would clarify the leaching mechanism of radionuclides from fly ashes.

Sequestration of radioactive nickel (63Ni2+) in fly ash coming from hospital wastes incineration plant by incorporating nano-goethite as a function of pH, particle size and the ratio of solid and liquid was investigated under the batch leaching experiments. The synthetic nanogoethite was characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM) and specific surface area (SSA). The admired needle nanogoethite was obtained in terms of XRD, TEM and SSA analysis. Approximate 5% of 63Ni2+ was desorbed from the nanogoethite/fly ash composite under the circum natural pH conditions. The ratio of solid to liquid has little effect on desorption of 63Ni2+ from nanogoethite/fly ash composite. These results indicate that the radioactive nickel in fly ash can be sequestrated by incorporating nanogoethite. The results may play significantly a role in immobilization in situ of trace radionuclides in the natural environment.

Background. Some experimental transplant-tolerance models have shown that the presence of regulatory T cells within grafts is important for the development of tolerance (Tol). , Methods. To determine if the presence of regulatory T cells correlates with graft acceptance in living-donor liver-transplantation tolerance, the expression of Foxp3 mRNA and the presence of CD4 + , CDB + , and Foxp3 + cells were quantified in biopsies from tolerant recipients by real-time polymerase chain reaction and by immunohistochemistry and immunofluorescent staining (Gr-Tol). The results were compared with biopsies from the recipients on maintenance immunosuppression (Gr-IS), grafts removed because of chronic rejection (Gr-CR), or normal liver (Gr-NL). Results. The expression ofFoxp3 mRNA in Gr-Tol was higher than that in Gr-IS (P=0.07) and Gr-NL (P

Background Operational tolerance is defined as long-term acceptance of a transplanted organ after complete cessation of immunosuppression (IS), but may not always protect against antigen-dependent changes in graft morphology. Method IS free patients after living-donor liver transplantation (LDLT) underwent protocol biopsy (tolerance group [Gr-Tol]) and were evaluated for rejection and fibrosis. The degree of fibrosis was compared with those in the patients on maintenance IS group (Gr-IS) and the base line normal liver group (Gr-BS). When bridging fibrosis or progression of fibrosis was observed, IS was reintroduced or increased in Gr-Tol or in the patients in the weaning process. Results Neither acute nor chronic rejection was observed. The degree of fibrosis, however, was significantly greater in Gr-Tol than those in Gr-IS and Gr-BS. In Gr-Tol, the number of graft infiltrating FOXP3 cells was significantly increased, the interval between LDLT and biopsy plus the donor age was significantly longer, and recipient age at LDLT was significantly younger, compared with those in Gr-IS. However, none of these three parameters correlated with the degree of fibrosis. In 7 of 11 patients in whom IS was reintroduced or increased, the improvement of fibrosis was observed by the subsequent biopsy. Conclusion Grafts of operationally tolerant patients after LDLT did not exhibit acute or chronic rejection, but they exhibited fibrosis. It remains elusive whether fibrosis observed in tolerant grafts is antigen dependent. The finding that after [corrected] the reintroduction or the increase of IS fibrosis was improved supported the possibility that fibrosis in operationally tolerant patients was antigen dependent.