Discovery of 1,3,4-oxadiazole derivatives as potential antitumor agents inhibiting the programmed cell death-1/programmed cell death-ligand 1 interaction.

Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction by small-molecule inhibitors is emerging cancer immunotherapy. A series of novel 1,3,4-oxadiazole derivatives were designed, synthesized, and evaluated for their activities in vitro and vivo to find potent inhibitors of the PD-1/PD-L1 interaction. Among them, compoundⅡ-14exhibited outstanding biochemical activity, with an IC50of 0.0380 µM. Importantly, compound II-14, with a TGI value of 35.74 %, had more potent efficacy in a mouse tumor model compared to that in the control group. Surprisingly, when compound II-14 combined with 5-FU in a mouse tumor model having a TGI value of 64.59 %, which showed potential anti-tumor synergistic effects. Furthermore, immunohistochemistry analysis demonstrated thatcompound II-14 activated the immune microenvironment by promoting the infiltration of CD4+ T cells into tumor tissues. These results indicate that compound II-14 is a promising lead compound for further development of small-molecule PD-1/PD-L1 inhibitors for cancer therapy.

3-Hydroxyisoindolin-1-one derivates: Synthesis by palladium-catalyzed CH activation as BRD4 inhibitors against human acute myeloid leukemia (AML) cells.

Bromodomain protein 4 (BRD4) is a member of the bromodomain and extra-terminal domain (BET) protein family, which plays a key role in transcriptional regulation. Recent biological and pharmacological studies have enabled linking of the BET bromodomains with diseases, including inflammation and cancer, suggesting that bromodomains are druggable targets. In this study, we made further structural modifications of our previously reported BRD4 inhibitors, to develop new chemical scaffold 3-Hydroxyisoindolin-1-One. Then a series of compounds (10a-q) were synthesized via palladium-catalyzed CH activation and BRD4-inhibitory activities and anti-proliferative effects of these compounds were evaluated. Compound 10e exhibited excellent BRD4-inhibitory activity with IC50 value of 80 nM and anti-proliferation potency with IC50 value of 365 nM in HL-60 (humanpromyelocytic leukemia) cancer cell lines. We have demonstrated compound 10e modulated the intrinsic apoptotic pathway. In conclusion, these results suggested that compound 10e could be utilized as a BRD4 inhibitor for further leukemia treatment.

[An epidemiological study on domestic violence in Hunan, China].

OBJECTIVE: To investigate the prevalence of domestic violence (DV) in Hunan. METHODS: Using a multi-stage sampling strategy, 9451 households involving 32 720 persons in urban, rural and industrial areas in Hunan, China were studied. Multiform clue investigation and face-to-face interviews were combined to investigate the prevalence of DV. RESULTS: A lifetime prevalence of DV was reported by 1533 households (16.2%). A total of 1098 households (11.6%) reported at least one incident of DV in the previous year. Both lifetime and 12-month prevalence of DV varied significantly by geographic setting (P < 0.01). The lifetime prevalence abuse rates were: spousal 10.2%, child abuse 7.8%, and elder 1.5%. With regard to household structure, the lifetime prevalence of DV was highest among those remarried families (21.0%), followed by married couples with one child and extended families with several generations living together (20.1% and 20.0%, respectively). The highest rate of spousal abuse was found among remarried families (14.7%), while child and elder abuse was most prevalent among extended families (12.4% and 4.1%, respectively). CONCLUSIONS: The findings suggested that although the prevalence of DV in Hunan was modest compared to Western countries, it remained a serious public health problem affecting over 1 in 10 households. Furthermore, the prevalence of various types of DV varied by geographic setting and family structure, suggesting that diverse geographic setting and family constellations carried different risk and protective features.