Objective To investigate the effects of estradiol replacement therapy on novel-object recognition and extinction of conditioned fear memory in ovariectomized (OVX) rats.Methods Sixty sexually mature (＞90 days) female SD rats weighing 250g-300g were used as subjects.The rats were randomly divided into 7groups as following:OVX with low dose of estradiol replacement (OVX + LD,0.1 mg · kg-1),medium dose (OVX + MD,0.3mg · kg-1) and high dose (OVX + HD,0.9mg · kg-1),estradiol replacement with medium dose at 2 weeks after OVX (MD + 2W) and 4 weeks after OVX (MD + 4W),OVX group and Sham group (SH).According to the different dose and time schedules,each group was administrated estradiol or vehicle via subcutaneous injection on the dorsal side of the rat.Estradiol maintained for one month after the surgery,and then the novel-object recognition and extinction of conditioned fear memory were tested.Results (1) The rats after OVX (5.83 ±4.5)s showed access-dependent impairments on novel-object recognition ((5.83 ± 4.5)s vs(27.14 ± 6.6)s,P ＜0.01) and the estradiol replacement therapy can reverse this impairment,but not in the HD group.There was an increase of the ability on novel-object recognition in group LD and MD + 2W as compared with group OVX,but the difference was not statistically significant (P ＞ 0.05).Moreover,group MD (27.86 ± 2.6)s had a significant difference compared with group OVX (P ＜ 0.05).(2) The conditioned fear memory of rats after OVX (21.67 ± 2.0) ％showed significantly lower than group SH (56.81 ± 4.6) ％ (P ＜ 0.01).Chronic administration with estradiol enhanced acquisition of context fear,respectively (P ＜ 0.01),but except group HD and group MD + 4W.The group HD(18.43 ± 1.1)％ was negatively enhanced and the group MD +4W(25.25 ±2.5)％ was no difference compared with group OVX.(3) On extinction of conditioned fear memory,the OVX rats produced significantly less freezing by fear context (F =3.337,P ＜ 0.01),and estradiol treatment (except group MD + 4W)also facilitated the extinction of conditioned fear memory,respectively (P ＜ 0.01).Conclusion These results demonstrate that estradiol may have a beneficial effect on the cognition function,and the improving effect is better when estradiol replacement is given at once depriving of sex hormone.

【Objective】 To explore the expression of checkpoint kinase 2 (CHEK2) in clear cell renal cell carcinoma (ccRCC), its association with the clinicopathological features and prognosis, and to predict its relevant molecular signaling pathways and biological functions. 【Methods】 The gene expression data, phenotype data, and corresponding survival information of ccRCC patients were downloaded from TCGA database. The optimal cutoff value of CHEK2 was determined with the "survminer" package. The patients were divided into low and high expression groups, and the association between CHEK2 expression and clinicopathological features was analyzed. The correlation between CHEK2 expression and ccRCC prognosis was evaluated with univariate and multivariate Cox proportional hazard models. The changes of cell signaling pathways involved in different CHEK2 expression levels were explored with gene set variation analysis (GSVA). The correlation between CHEK2 and immune cell infiltration as well as immune checkpoint molecular expression was analyzed. 【Results】 CHEK2 expression was significantly higher in ccRCC tissues than in normal tissues (P<0.01). Higher level of CHEK2 was significantly associated with higher T stage of ccRCC (P<0.01). Kaplan-Meier analysis showed overall survival (OS) of patients with high CHEK2 expression were notably decreased (P<0.001). Univariate and multivariate analyses revealed CHEK2 expression as an independent risk factor of survival (HR=1.950, 95%CI: 1.490-2.570, P<0.001; HR=1.588, 95%CI: 1.185-2.127, P=0.002). GSVA showed that CHEK2 was involved in the following pathways: proximal tubule bicarbonate reclamation, propanoate metabolism, limonene and pinene degradation, fatty acid metabolism, primary immunodeficiency, systemic lupus erythematosus, p53 signaling pathway, homologous recombination, DNA replication and mismatch repair. Correlation analysis suggested that CHEK2 was associated with increased infiltration of multiple immune cells in ccRCC and upregulation of various immune checkpoint molecules. 【Conclusion】 The high level of CHEK2 in ccRCC is an independent predicting factor for poor prognosis. It is probably involved in regulating related events of tumor immune infiltration and may become a new target for ccRCC therapy.

OBJECTIVETo synthesize compounds based on imidazo-fused heterocycles and evaluate their anti-tumor activity against breast cancer.

METHODSThe compounds 1a-1e, 2a and 2b were synthesized by aerobic copper-catalyzed halocyclization of methyl N-heteroaromatics with aliphatic amines; 3a and 3b were generated by sonogashira reaction and Suzuki reaction, respectively; the compounds 4a-4c were obtained by Buchwald-Hartwig reaction of the corresponding amines and 1e. The effects of these compounds against breast cancer cells and their nephrotoxicity were determined using MTT assay. Annexin VFITC/PI apoptosis detection kit was used to assess the apoptosis-inducing effects of these compounds in breast cancer cells. With normal saline as the control, the safety and anti-tumor activity of the compound 2a (daily dose of 10 mg/kg for 14 days) was tested in a mouse model bearing human breast cancer xenografts.

RESULTSThe compounds 2a, 4a, 4b and 4c all showed obvious anti-tumor activities. Among these compounds, 2a showed the most potent anti-tumor effect against breast cancer cells with an IC of 9.77 ± 2.32 μmol/L, similar to that of cisplatin (IC=8.96 ± 2.35 μmol/L); 2a also showed a slightly lower nephrotoxicity than cisplatin, and their CC was 10.79±0.87 μmol/L and 8.45±0.68 μmol/L, respectively. 2a obviously promoted apoptosis of breast cancer cells and caused a moderate suppression of the breast cancer growth in the tumor-bearing mouse models without producing serious adverse effects.

CONCLUSIONSFour compounds synthesized based on imidazo-fused heterocycles have anti-tumor activities against breast cancer. The compound 2a is capable of dose-dependently promoting apoptosis of breast cancer cells and has a good safety and a moderate efficacy for suppressing tumor growth in mouse models bearing human breast cancer xenografts.

【Objective】 To investigate the role of solute carrier family 7 member 11 (SLC7A11) in the pathogenesis and progression of clear cell renal cell carcinoma (ccRCC) and its prognostic significance. 【Methods】 Mendelian randomization analysis was employed to identify genes causally associated with the risk of ccRCC.The expression patterns and prognostic relevance of SLC7A11 were assessed using RNA sequencing data and clinical information obtained from the UCSC Xena pan-cancer cohort.Gene set enrichment analysis (GSEA) was conducted using data from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) dataset (training set).A prognostic model based on SLC7A11 was then developed using stepwise Cox regression and validated externally in the E-MTAB-1980 cohort (validation set) . 【Results】 Elevated level of SLC7A11 was associated with an increased risk of ccRCC (HR=1.27, 95%CI: 1.15-1.40, P<0.001).SLC7A11 was overexpressed in various tumors and correlated with higher T stage and poorer survival (P<0.05).GSEA demonstrated that SLC7A11 was enriched in pathways related to proliferation and metastasis, including E2F and epithelial-to-mesenchymal transition signaling pathways.Moreover, the SLC7A11 prognostic model exhibited robust predictive performance in both the training set (1-, 3-, and 5-year AUC=0.78, 0.73, 0.71, respectively) and the external validation set (1-, 3-, and 5-year AUC=0.70, 0.71, 0.72, respectively). 【Conclusion】 SLC7A11 can be a potential biomarker and therapeutic target for ccRCC, offering novel perspectives for precision medicine.