Objective To investigate the role of endometrial thickness,uterine artery and spiral artery blood flow parameters,endometrial and subendometrial blood flow on pregnancy outcome in vitro fertilization-embryo transfer (IVF-ET) cycle,compare the difference of the endometrial and subendometrial blood flow typing between the superb micro-vascular imaging (SMI) and power doppler ultrasound (PDUS). Methods Forty-one patients undergoing IVF-ET cycles in our hospital were recruited in this study. Transvaginal color Doppler ultrasound was performed to determine and record endometrial thickness,peak systolic velocity(PSV),end diastolic velocity(EDV),pulse index(PI),resistance index(RI), systolic diastolic ratio(S/D) of uterine artery and spiral artery,and degree endometrial and subendometrial blood flow signals were showed under the two blood flow modes of PDUS and SMI respectively on the day of human chorionic gonadotropin(HCG) injection.The degree of the endometrial and subendometrial blood flow was scored using Applehau classification method.According to the pregnancy outcome,patients were divided into pregnancy group and nonpregnancy group,the difference of the above indicators between the two groups were compared,and the degree of endometrial and subendometrial blood flow under two kinds of blood flow mode were observed.Results ①On the day of HCG injection,patients in pregnancy group had lower RI,PI,S/D of spiral artery than those in the nonpregnancy group (P< 0.05). There were no significant difference between the pregnant group and nonpregnant group in endometrial thickness and the blood flow parameters of uterine artery ( P >0.05). ②On the day of HCG injection,there was significant difference between the pregnant group and nonpregnant group in endometrial and subendometrial blood flow degree with SMI mode ( P =0.005).The patients with type Ⅲ in pregnancy group were most (50% ). ③The endometrial and subendometrial blood flow typing (β= 1.085,OR= 1.085,95% CI=1.040 -8.421, P=0.042) of pregnancy group under SMI mode have an independent predictive value.With increased blood flow typing under endometrial and subendometrial blood flow,the higher the possibility of pregnancy in patients.The ROC curve analysis showed that the area under ROC endometrial and subendometrial blood flow typing SMI mode on the HCG day was 0.746( P =0.008).Conclusions SMI is a new and effective type of Doppler ultrasound technique to evaluate the endometrial and subendometrial blood flow in IVF-ET cycle.On the day of HCG injection,the endometrial and subendometrial blood flow typing in SMI mode may predict pregnancy outcomes in IVF-ET cycles,and guide to choose the best embryo transfer time.

Nicotinamide phosphoribosyl transferase (NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation. However, therapeutic benefit of NAMPT enzymatic inhibitors appears very limited, likely due to the failure to intervene non-enzymatic functions of NAMPT. Herein, we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells (MDSCs) via a mechanism independent of its enzymatic activity. Using proteolysis-targeting chimera (PROTAC) technology, PROTAC A7 is identified as a potent and selective degrader of NAMPT, which degrades intracellular NAMPT (iNAMPT) via the ubiquitin-proteasome system, and in turn decreases the secretion of extracellular NAMPT (eNAMPT), the major player of the non-enzymatic activity of NAMPT. In vivo, PROTAC A7 efficiently degrades NAMPT, inhibits tumor infiltrating MDSCs, and boosts antitumor efficacy. Of note, the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs. Together, our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment, and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT, pointing out a new direction for the development of NAMPT-targeted therapies.