Coagulation factor XIa (FXIa) plays a crucial role in thrombus formation; therefore, the development of potent and safe FXIa inhibitors is of great significance. In this study, compound F22, previously discovered by our group, was selected as the lead compound. Based on the principles of bioisosterism and fragment-based drug design, four series comprising 14 novel Asundexian derivatives not previously reported in the literature were designed and synthesized. The structures of the target compounds were confirmed by 1H NMR and HRMS, and their inhibitory activities against FXIa were evaluated using chromogenic substrate assay. Results showed that compound FD-1 exhibited the most potent activity, with an IC50 value of 2.8 nmol/L, which was superior to that of the lead compound F22 (IC50 = 4.5 nmol/L) and the reference drug Asundexian (IC50 = 5.0 nmol/L). Furthermore, in the activated partial thromboplastin time (aPTT) assay, compound FD-1 demonstrated excellent anticoagulant activity, outperforming Asundexian, showing no significant effect on prothrombin time (PT). These findings provide valuable insights for further structural optimization and rational design of small-molecule FXIa inhibitors.

Objective To establish a human luminal breast cancer stem cell(BCSC)model and investigate the inhibitory effects of astragaloside Ⅳ(AS-Ⅳ)on BCSC growth.Methods MCF-7 breast cancer cells were cultured in stem cell-specific medium to induce BCSC formation.The BCSCs were then divided into a blank control group and an AS-Ⅳ treatment group,both groups were given PBS or AS-Ⅳ treatment.Morphological changes were observed after intervention.The therapeutic efficacy of AS-Ⅳ was evaluated using 3D spheroid formation and cell viability assays.Transcriptomic profiling and gene expression analysis were performed to elucidate the underlying mechanisms.Results Compared with the MCF7 breast cancer cells,MCF7 breast cancer stem cell mammospheres exhibited accelerated growth(P＜0.01)and significantly increased expression of the stemness marker ALDH1A1(P＜0.01).Further comparison with the blank control group revealed that astragaloside Ⅳ(AS-Ⅳ)treatment significantly inhibited MCF7 breast cancer stem cell proliferation(P＜0.001)and slowed mammosphere growth(P＜0.01).Transcriptomic analysis demonstrated that differentially expressed genes(DEGs)induced by stem cell modeling and AS-Ⅳ intervention were enriched in the cellular senescence signaling pathway.AS-Ⅳ intervention substantially increased the number of SA-β-gal-positive cells(P＜0.01).RT-PCR analysis confirmed that AS-Ⅳsignificantly upregulated mRNA expression of IL-1α(P＜0.01),P21(P＜0.001),and P53(P＜0.05)in MCF7 breast cancer stem cells.Conclusion Astragaloside Ⅳ suppresses the growth of human luminal breast cancer stem cells by inducing cellular senescence.

Objective To observe the international obstetric services model to reduce the incidence of hypoxic ischemic encephalopathy( HIE) in natural childbirth neonatal. Methods A total of 360 maternals from February 2012 to May 2014 were selected, according to production inspection manual number, odd as the study group and even as the control group, 180 cases in each group. The study group adopts the scheme of new international obstetrics service mode, the control group used traditional obstetric services model. Rate of maternal natural childbirth, maternal satisfaction and incidence of HIE were compared between the two groups. Results The rate of childbirth maternal natural and satisfaction of the observation group were 88. 5%, 96. 0%, which were significantly higher than that of the control group (χ2 =6. 632, 4. 114,P<0. 05). Incidence of HIE in the observation group was 4. 19%, which was significantly lower than 10. 14% in the control group, the difference was statistically significant (χ2 =4. 267,P <0. 05). Conclusions International obstetric service mode can reduce the incidence of HIE in natural childbirth neonatal, which has a high value of popularization.

Objecteve To study the relation between the enhanced CT image parameters and metastasis, type of peripheral lung cancer. Methods The enhanced CT image parameters of 138 peripheral lung cancers confirmed by pathology were analyed retrospectively. Both plane scan and contrast-enhanced CT were performed in all the patients, and boundary CT value of each lung cancer was measured. Results Contrast-enhanced CT showed that peripheral lung cancer had big and bent peripheral vessels, and the peripheral density of tumor mass was correlated with its metastasis. The frequency of adenocarcinoma metastasis was higher than that of squamous carcinoma. Conclusion Contrast-enhanced CT was helpful for predicting the latent possibility of peripheral lung cancer metastasis.