Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis). Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer.

Background Choroidal melanoma(CM)is a common form of primary ocular cancer in adults.It is reported that indomethacin has inhibitory effect on many tumor in vitro and in vivo,but whether it can inhibit the growth of CM has not been published. Objective This study was to investigate the anti-tumor activity of indomethacin on the growth of human CM OCM-1 cell xenografts in nude mice. Methods OCM-1 cells were subcutaneously implanted on 24 SPF female BALB/C.nu/nu nude mice to establish ectopic models of human CM.The nude mice with the tumor 5 mm were randomly divided into 4 groups:untreated group,normal saline solution(NS) group,indomethacin 1 ms/kg group,indomethacin 2 ms/kg group.The 1 mS/kg or 2 ms/kg indomethacin was intraperitoneally injected for 14 consecutive days in indomethacin 1 ms/kg group and indomethacin 2 me/kg group respectively.and 0.2 ml of 2%NS-DMSO was used at a same way in the NS group.No any agent was used as the untreated group.The volume and weight of implanted tumor as well as inhibitory rates of indomethaein on tumor were calculated.The expression of ki67 and survivin proteins were measured with immunohistochemistry,and the expression of survivin mRNA in CM was assessed by RT-PCR. ResuIts The tumor of indomethacin treatment group was reduced in volume and weight with a significant difference between treatment group and control group as well as indomethacin 1 ms/ks group and indomethacin 2 ms/kg group(P＜0.05).The inhibitory rate of indomethacin 1 ms/kg and 2 ms/kg for tumor was 22.86%,48.00%respectively.The prolifiration index (PI)of ki67 in these 4 groups were (76.73±3.34)%,(73.30±2.95)%,(55.97±2.24)%,(32.87±2.91)%respectively,and significant difference was found in PI between indomethacin 2 mg/kg group and untreated group or NS group(P＜0.05),but there was not significant difference between indomethacin 1 mg/kg and 2 ms/kg group(P＞0.05).Compared with the control group,the indomethacin treatment groups showed the decreased expression of survivin protein and mRNA,and significant difference was found between indomethaein 2 ms/kg group and untreated group or NS group(P＜0.05),however,no significant difference was found between indomethacin 1 mg/kg and 2 mg/kg group(P＞0.05). Conclusion Indomethacin inhibits the growth of CM in nude mice through inhibiting the expression of survivin in the tumor and accelerating cell apoptosis and inhibiting tumor cell proliferation.

A male patient,39 years old,presented with symptoms of cataract,dwarf,progeria,polydactyly and genu valgum,after the extracapusular cataract extraction and intraocular lens implantation on both eyes,the visual acuity was improved and his fundus examination was normal.As the syndrome is different from any eye syndrome we have ever known,so it maybe a new one.

The results of open-field test,step-through passive avoidance task and radial-arm maze experiment showed that changes of locomotor activity,anxiety-related behaviour and ability of learning and memory were associated with the increased apoptosis of neurons in hippocampus in rats with perinatal hypothyroidism.

Animals ; Aorta ; pathology ; Apolipoproteins E ; deficiency ; Atherosclerosis ; metabolism ; pathology ; Female ; Glycosides ; isolation & purification ; pharmacology ; Intercellular Adhesion Molecule-1 ; metabolism ; Mice ; Plants, Medicinal ; chemistry ; Polygonum ; chemistry ; Vascular Cell Adhesion Molecule-1 ; metabolism

OBJECTIVETo study the effect of Fuzheng Sanjie recipe in regulating tumor-associated macrophages (TAMs) in Lewis lung cancer mice.

METHODEfforts were made to establish the Lewis lung cancer mouse model, weigh tumors and calculate the anti-tumor rate. The immunohistochemical method was used to examine the infiltration degree of CD68 + in tumor tissues in each group. ELISA was used to examine the content of IFN-γ, TGF-β, IL-4, IL-13, IL-6, IL-10, IL-12, TNF-α in mice serum.

RESULTCompared with the tumor-bearing model group, all of the other groups showed higher tumor inhibition rates, i. e. 50.28% for the DDP group, 34.37% for the TCM-preventing group and 66.76% for the Chinese and western medicine group, with statistical difference (P < 0.05), but without statistical difference in the infiltration degree of CD68+. The expressions of the IFN-γ, IL-6, IL-12 in tumor-bearing groups were lower than that in the blank control group, but with higher contents of IL-4, IL-13, TGF-β. Intervened with different drugs, there were significant differences in content among some relevant cytokines (P < 0.05), as well as statistical differences among the TCM prevention group, the Chinese and western medicine group and the tumor-bearing control group (P <0. 05) , but without statistical difference in TNF-α and IL-10 content from the tumor-bearing control group (P < 0.05).

CONCLUSIONFuzheng Sanjie recipe could reverse the immune remodeling effect and control the tumor growth by down-regulating the expressions of IL-4, IL-13, TGF-α in lung cancer immune microenvironment and up-regulating the expression of IFN-γ.

Animals ; Cell Line, Tumor ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Interleukin-10 ; blood ; Interleukin-12 ; blood ; Interleukin-13 ; blood ; Lung Neoplasms ; blood ; drug therapy ; immunology ; Macrophages ; drug effects ; immunology ; Male ; Mice ; Mice, Inbred C57BL ; Transforming Growth Factor beta ; blood ; Tumor Necrosis Factor-alpha ; blood

This study aims to investigate the change of plasma concentration of digoxin (DIG) in rats with ovariectomy. Twelve female SD rats were randomly assigned into ovariectomized group and sham group (n = 6). All rats plasma was collected after a single dose of 2 mg x kg(-1) DIG administrated orally, serum DIG concentration was determined by LC-MS/MS. The level of P-gp in the intestinal was analyzed by Western blotting. Pharmacokinetic calculations were performed on each individual using DAS 2.0 practical pharmacokinetic software. Compared with the sham group, C(max) of ovariectomized group decreased significantly (P < 0.01). There was no significant difference of AUC(0-t), and the level of P-gp was elevated in ovariectomized group. It was found that C(max) of DIG was significantly reduced after ovariectomy, and the change was associated with the decreased level of estrogen, which contributes to the increased level of P-gp.
ATP-Binding Cassette, Sub-Family B, Member 1 ; metabolism ; Animals ; Blotting, Western ; Chromatography, Liquid ; Digoxin ; blood ; pharmacokinetics ; Disease Models, Animal ; Estrogens ; blood ; Female ; Ovariectomy ; Rats ; Rats, Sprague-Dawley ; Tandem Mass Spectrometry

Background Cellular autophagy is a non-apoptosis death form of tumor tissue.Research determined that arsenie trioxide (As2O3) leads to apoptosis of tumor cells.But whether As2O3 induce autophagy of SO-Rb50 cells or not is unclear.Objective This study was to assess the effects of As2O3 on autophagy of SO-Rb50 cells.Methods As2O3 with the concentration of 0,0.5,1.0,2.0,4.0 μmol/L was used to treat the SO-Rb50 cell line for 48 hours,and the growth and proliferation of SO-Rb50 cells were detected using MTT assay (A570).pGFP-LC3,a marker of autophagy,was constructed to transfer SO-Rb50 cells,and the cells were then divided into RPMI-1640 culture group (untreated group),As2O3 + RPMI-1640 culture group (As2O3 treated group) and rapamycin culture group (positive control group).Autophagy of SO-Rb50 cells was examined by laser confocal microscope and monodansylcadaverine (MDC) influorescence staining,respectively,48 hours following cell culture.Ultrastructural features of autophagy were examined with transmission electron microscope (TEM).The percentage of autophagy positive cells in different concentrations of As2O3 treated groups was calculated with flow cytometer.Results The A570 values of SO-Rb50 cells were 2.194±0.066,1.841 ±0.213,1.035±0.046,0.374±0.042 and 0.167±0.019 in 0,0.5,1.0,2.0,4.0 μmol/L As2O3 treated groups,with a significant difference among these 5 groups(F=547.636,P＜0.05),and those of 0.5,1.0,2.0,4.0 μmol/L As2O3 treated groups were significantly reduced in comparison with untreated group (P =0.000).The positive granular spots for GFP-LC3 chimeric protein were seen to aggregate in autophagic vacuoles in the As2O3 treated group and positive control group,but diffuse cytoplasmic signal for GFP-LC3 was found in the untreated group.Normal ultrastructure of SO-Rb50 cells was exhibited in the untreated group,and many double-membrane-like bound vesicles and autlysosomes were documented in the As2O3 treated group and positive control group under the TEM.A lots of MDC fluorescence granule were found in the As2O3 treated group and positive control group rather than the untreated group.Flow cytometry showed that the percentages of SO-Rb50 cells were 0,15.6％,42.7％,57.9％,79.5％ and 89.0％ in the 0,0.5,1.0,2.0,4.0 μmol/L As2O3 groups and positive control group,respectively,showing a As2O3 concentration-dependent increase.Conclusions As2O3 can induce the autophagy of SO-Rb50 cells and inhibit the proliferation of SO-Rb50 cells.Autophagic response of SO-Rb50 cells appears prior to the nuclear change after exposed to As2O3.The degree of autophagy of SO-Rb50 cells is associated with As2O3 dose.

Objective To investigate the state of drinking water defluorination project in Dagang district and study urinary fluoride levels and detect dental fluorosis of children aged 8 to 12, and to provide scientific basis for prevention and control of fluorosis. Methods Five defluorination projects in rural streets (towns) with highfluoride water and 2 urban water supply projects were choosen to investigate the running status in Dagang district Tianjin in 2009. Five rural and 2 urban schools were choosen to select 100 children aged 8 to 12 (for gender, age matched) in each primary school to study urinary fluoride levels and detection of dental fluorosis. Results A total of 66 defluorination projects in 73 villages were surveyed, among which 61 projects actually worked normally with using rate 92.4%(61/66). Water qualification of all projects could not be ensured due to direct project managers'lack of necessary expertise. In 2009, water qualification rate were 39.3%(24/61 )among the project normally used,with highlighted problem of biological pollution. A total of 490 children aged 8 - 12 in 5 rural towns were surveyed,dental fluorosis rate were 90%(441/490), and dental fluorosis index were 1.82. A total of 207 children aged 8 - 12in 2 urban areas were surveyed, the detection rate of dental fluorosis was 49.8%(103/207), and dental fluorosis index were 0.86. The urinary fluoride level of 230 children aged 8 - 12 in the 5 villages were surveyed. The Range of geometric mean of urinary fluoride were 1.82 - 2.70 mg/L. The urinary fluoride of 102 children aged 8 - 12 in the 2 urban area were surveyed. The Range of geometric mean of urinary fluoride were 1.53 - 1.72 mg/L. Conclusions There was phenomenon of high coverage, low utilization rate and less water consumption in the villages of Dagang district, Tianjin drinking water defluoridation projects, thus the health effects of the projects was minimum.Significant health effects is found in the defluorination projects in the urban areas with high coverage and high utilization rate. Studying new water improvment methods and new forms of water supply system is urgent for solving the problems met in the ineffective water defluorination project.

BACKGROUND: Early reperfusion can effectively treat acute myocardial infarction (AMI) and reduce the mortality significantly. This study aimed to compare the role of plasma microRNA-1 (miR-1) and cardiac troponin T (cTnT) in early diagnosis of AMI patients. METHODS: From May 2011 to May 2012, plasma samples were collected from 56 AMI patients and 28 non-AMI controls. The expression of plasma miR-1 was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and the level of plasma cTnT was measured using electrochemiluminescence-based methods on an Elecsys 2010 Immunoassay Analyzer. SPSS 16.0 was used for the statistical analysis of the results. Data were expressed as mean±standard deviation unless otherwise described. The differences about clinical characteristics between the AMI patients and controls were tested using Student'st test or Fisher's exact test. The Mann-WhitneyU test was conducted to compare the expression of microRNAs between the AMI patients and controls. MicroRNAs expression between different intervals of the AMI patients was compared using Wilcoxon's signed-rank test. The receiver operating characteristic (ROC) curve was established to discriminate the AMI patients from the controls. RESULTS: In the present study, the expression of plasma miR-1 was significantly increased in the AMI patients compared with the healthy controls (P<0.01). The plasma miR-1 in the AMI patients decreased to the normal level at 14 days (P>0.05). The expression of plasma miR-1 was not related to the clinical characteristics of the study population (P>0.05). ROC curve analyses demonstrated that miR-1 was specific and sensitive for the early diagnosis of AMI, but not superior to cTnT. CONCLUSION: Plasma miR-1 could be used in the early diagnosis of AMI, but it is similar to cTnT.