Erratum: Author correction to 'Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA' Acta Pharmaceutica Sinica B 13 (2023) 2585-2600

[This corrects the article DOI: 10.1016/j.apsb.2023.04.002.].

Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA

Mevalonate metabolism plays an important role in regulating tumor growth and progression; however, its role in immune evasion and immune checkpoint modulation remains unclear. Here, we found that non-small cell lung cancer (NSCLC) patients with higher plasma mevalonate response better to anti-PD-(L)1 therapy, as indicated by prolonged progression-free survival and overall survival. Plasma mevalonate levels were positively correlated with programmed death ligand-1 (PD-L1) expression in tumor tissues. In NSCLC cell lines and patient-derived cells, supplementation of mevalonate significantly up-regulated the expression of PD-L1, whereas deprivation of mevalonate reduced PD-L1 expression. Mevalonate increased CD274 mRNA level but did not affect CD274 transcription. Further, we confirmed that mevalonate improved CD274 mRNA stability. Mevalonate promoted the affinity of the AU-rich element-binding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA. By in vivo study, we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1, increased the infiltration of CD8+ T cells, and improved cytotoxic function of T cells. Collectively, our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody, and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.

The impact of lipids on the cancer-immunity cycle and strategies for modulating lipid metabolism to improve cancer immunotherapy

Lipids have been found to modulate tumor biology, including proliferation, survival, and metastasis. With the new understanding of tumor immune escape that has developed in recent years, the influence of lipids on the cancer-immunity cycle has also been gradually discovered. First, regarding antigen presentation, cholesterol prevents tumor antigens from being identified by antigen presenting cells. Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells, impairing antigen presentation to T cells. Prostaglandin E2 (PGE2) reduce the accumulation of tumor-infiltrating dendritic cells. Regarding T-cell priming and activation, cholesterol destroys the structure of the T-cell receptor and reduces immunodetection. In contrast, cholesterol also promotes T-cell receptor clustering and relative signal transduction. PGE2 represses T-cell proliferation. Finally, regarding T-cell killing of cancer cells, PGE2 and cholesterol weaken granule-dependent cytotoxicity. Moreover, fatty acids, cholesterol, and PGE2 can improve the activity of immunosuppressive cells, increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines. Given the regulatory role of lipids in the cancer-immunity cycle, drugs that modulate fatty acids, cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy. These strategies have been studied in both preclinical and clinical studies.

Inhibitory effect of adenosine on adaptive antitumor immunity and intervention strategies / 浙江大学学报·医学版

Tumors in which the microenvironment is characterized by lack of immune cell infiltration are referred as "cold tumors" and typically exhibit low responsiveness to immune therapy. Targeting the factors contributing to "cold tumors" formation and converting them into "hot tumors" is a novel strategy for improving the efficacy of immunotherapy. Adenosine, a hydrolysis product of ATP, accumulates with a significantly higher concentration in the tumor microenvironments compared with normal tissue and exerts inhibitory effects on tumor-specific adaptive immunity. Tumor cells, dendritic cells, macrophages, and T cells express abundant adenosine receptors on their surfaces. The binding of adenosine to these receptors initiates downstream signaling pathways that suppress tumor antigen presentation and immune cell activation, consequently dampening adaptive immune responses against tumors. Adenosine down-regulates the expression of major histocompatibility complex Ⅱ and co-stimulatory factors on dendritic cells and macrophages, thereby inhibiting antigen presentation to T cells. Adenosine also inhibits ligand-receptor binding and transmembrane signaling on T cells, concomitantly suppressing the secretion of anti-tumor cytokines and impairing T cell activation. Furthermore, adenosine hinders effector T cell trafficking to tumor sites and infiltration by inhibiting chemokine secretion and KCa3.1 channels. Additionally, adenosine promotes the secretion of immunosuppressive cytokines, increases immune checkpoint protein expression, and enhances the activity of immunosuppressive cells, collectively curbing cytotoxic T cell-mediated tumor cell killing. Given the immunosuppressive role of adenosine in adaptive antitumor immunity, several inhibitors targeting adenosine generation or adenosine receptor blockade are currently in preclinical or clinical development with the aim of enhancing the effectiveness of immunotherapies. This review provides an overview of the inhibitory effects of adenosine on adaptive antitumor immunity, elucidate the molecular mechanisms involved, and summarizes the latest advances in application of adenosine inhibition strategies for antitumor immunotherapy.

Study on quality standard for Xuanxi Rongjin powder / 药学实践杂志

Objective To revise the qualitative and quantitative determination methods of Xuanxi Rongjin powder. Methods TLC was used to qualitatively identify Chuanxiong and Chuanshanlong. The content of cinnamaldehyde in the preparation was determined by HPLC with KR100-5C18 column (250 mm×4.6 mm, 5μm). The mobile phase was acetonitrile-water (35:65) and the detection wavelength was 290 nm. Results TLC can qualitatively identify Chuanxiong and Chuanshanlong. Cinnamaldehyde has a good linear relationship in the range of 0.0489~0.3260 µg/ml (r=1.00), The average recovery was 95.71% (RSD=1.78%). Conclusion The method has high sensitivity, good specificity, simple operation and good reproducibility.

Efficiency of preeclampsia screening based on biomarkers of aneuploidy screening in first trimester / 中华围产医学杂志

Objective:To evaluate the performance of biomarkers in aneuploidy screening in the first trimester-pregnancy associated plasma protein A(PAPP-A) combined with Fetal Medicine Foundation (FMF)'s competing risk model in screening preeclampsia among our population.Methods:This study was based on a prospective cohort of singleton pregnant women who underwent aneuploidy screening in the first trimester in Nanjing Drum Tower Hospital from January 2017 to September 2020. Mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), and PAPP-A were converted into multiples of median (MoM) using the algorithm disclosed on the website of the FMF (fetalmedicine.org). The predictive outcomes of maternal factors alone or in combination with MAP, UtA-PI, and PAPP-A (alone or in combination) were calculated. Chi-square test, Fisher's exact test or rank sum test were used for comparison among groups and Bonferroni method for pairwise comparisons. Receiver operating characteristic (ROC) curve was used to evaluate the screening efficiency and to calculate the sensitivities of predicting preeclampsia, term and preterm preeclampsia at false-positive rates of 5% and 10%. The predictive performance of this model was further compared to the screening strategy that was recommended in Diagnosis and treatment of hypertension and pre-eclampsia in pregnancy: a clinical practice guideline in China (2020). Results:Among the 5 144 singleton pregnancy women who were recruited in the cohort, 4 919 cases were included and analyzed in this study. A total of 223 cases were diagnosed as preeclampsia (4.5%), including 55 preterm (1.1%) and 168 term preeclampsia (3.4%). The median of MoM values of MAP, UtA-PI, and PAPP-A in the non-preeclampsia group were around 1.0±0.1. Statistical significance was observed in the difference of MAP, UtA-PI, and PAPP-A Mom between women with preterm preeclampsia and those without preeclampsia [1.061 (0.999-1.150) vs 0.985 (0.935-4.043), 1.115 (0.873-1.432) vs 1.039 (0.864-1.236), 0.820 (0.493-1.066) vs 1.078 (0.756-1.508)], which was also seen in the difference of MAP and PAPP-A Mom between women with term preeclampsia and those without preeclampsia [1.065 (1.002-1.133) vs 0.985 (0.935-4.043), 1.007 (0.624-1.393) vs 1.078 (0.756-1.508)] (all P<0.025). The combination screening with maternal factors+MAP+UtA-PI+PAPP-A was noted for the best efficiency. In predicting preeclampsia preterm and term preeclampsia at the false-positive rate of 10%, the sensitivity of the model was 53.0%, 76.4% and 44.6% respectively. Using the screening method recommended in Diagnosis and treatment of hypertension and pre-eclampsia in pregnancy: a clinical practice guideline in China(2020), the proportion of people at high risk of preeclampsia was 5.9% (290/4 919), and the sensitivity for predicting preterm preeclampsia was 25.5% (14/55), which was significantly lower than the combination screening with maternal factors+MAP+UtA-PI+PAPP-A [65.5% (36/55)] when using the same proportion of high-risk population. Conclusion:The preeclampsia screening model based on aneuploidy screening biomarkers in the first trimester--PAPP-A in combination with materral factors, MAP, UtA-PI, can effectively screen preterm preeclampsia in the local population without increasing the laboratory costs.

Association between gestational blood pressure and pregnancy induced hypertension or pre-eclampsia / 中华妇产科杂志

Objective:To construct the gestational‐age‐specific blood pressure curve and percentile blood pressure values of pregnant women in Jiangsu Province, and to explore the clinic significance of the blood pressure changes in women whose blood pressure was less than 140/90 mmHg (1 mmHg=0.133 kPa) in each trimester and eventually developed pregnancy induced hypertension (PIH) or pre-eclampsia (PE).Methods:A prospective longitudinal cohort during pregnancy was built. Singleton pregnant women in the first trimester (11-13 +6 weeks) were recruited from July 2017 to September 2020 in Nanjing Drum Tower Hospital, and were followed up in the second trimester (19-23 +6 weeks), the third trimester (30-33 +6 weeks) and approaching the expected date of delivery (35-38 +6 weeks). The Viewpoint 6.0 software was used to record pregnancy-related information. The blood pressure was measured by standard methods in our clinic. Least mean square (LMS) function was performed to fit the gestational-age-specific blood pressure curve and percentile blood pressure values were calculated at every follow‐up time point. Logistic regression was applied to calculate the OR for the groups with blood pressure ≥95th percentile ( P95). Results:There were 3 728 singleton pregnant women invited in this study, including 3 490 normal pregnant women (93.62%, 3 490/3 728), and 238 pregnant women with PIH or PE (6.38%, 238/3 728). Gestational-age-specific blood pressure curve showed that systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) decreased in the second trimester, compared with those in the first and the third trimester, however the fluctuation of blood pressure was low, but regardless of the gestational age, P95 of SBP, DBP and MAP increased by 14, 11 and 11 mmHg respectively, compared with 50th percentile ( P50). In the first trimester, the risk of developing PIH or PE finally in pregnant women with blood pressure ≥ P95 was 4.36-fold (95% CI: 2.99-6.35) for SBP than women with SBP< P95, 5.22-fold (95% CI: 3.65-7.46) for DBP and 5.14-fold (95% CI: 3.61-7.32) for MAP. When approaching the expected date of delivery, the corresponding risks of the women with blood pressure ≥ P95 were 16.76 times, 27.45 and 27.31 times respectively than those of the women with blood pressure < P95. In the first trimester, every 1 mmHg elevation of SBP the risk developing PIH or PE increased by 24% ( OR=1.24, 95% CI: 1.15-1.33), 44% ( OR=1.44, 95% CI: 1.31-1.59) for DBP and 47% ( OR=1.47, 95% CI: 1.33-1.61) for MAP, respectively. The risk in the second trimester was similar to that in the first trimester, and in the third trimester, the risk was further increased. When approaching the expected date of delivery, DBP or MAP increased by 1 mmHg, the risk developing PIH or PE was double; while SBP increased by 1 mmHg, the risk increased by 58%. The areas under the receiver operator characteristic curves of SBP, DBP and MAP were similar for predicting PIH or PE, and the predictive efficiency were all poor. Conclusions:Construction of percentile blood pressure values for pregnant women is helpful in identification of high-risk women of developing PIH or PE. The risk of PIH or PE in pregnant women with blood pressure ≥ P95 but <140/90 mmHg has significantly increased compared with women with blood pressure < P95.

Effects of gestational weight gain at different stages on pregnancy complications / 中华围产医学杂志

Objective:To investigate the effects of gestational weight gain (GWG) at different stages on pregnancy complications such as preeclampsia, gestational hypertension, gestational diabetes mellitus(GDM), small for gestational age (SGA), and large for gestational age (LGA).Methods:This was a prospective longitudinal cohort study. Singleton pregnancies at 11-13 +6 weeks of gestation in the Affiliated Drum Tower Hospital, Medical School of Nanjing University from January 2017 to November 2019 were recruited. The maternal height, weight, blood pressure, and fetal ultrasonic parameters were measured at 19-23 +6, 29-34 +6, and 35-40 +6 weeks of gestation by face-to-face interview and the pregnancy outcomes were followed up. All participants were grouped by body mass index (BMI) in the first trimester, with <18.50 kg/m 2 as underweight group, 18.50-23.99 kg/m 2 as normal group, ≥24.00 kg/m 2 as overweight/obesity group. Chi-square test and rank-sum test were adopted for comparison among groups. Weekly weight gain was converted into Z scores, and insufficient, appropriate, and excessive weight gain were respectively defined when Z<-1, -1≤ Z≤1, and Z>1. The effect of weekly weight gain at different gestational trimesters on pregnancy complications was analyzed by binary logistic regression. Results:Totally, 4 143 pregnant women entered the cohort. After excluding 327 cases, 3 816 were finally included in the analysis, with 394 in underweight group, 2 668 in normal group, and 754 in overweight/obesity group. Excessive weekly weight gain in the early second trimester was a risk factor for LGA( aOR=1.78, 95% CI:1.31-2.42, P<0.001), and in the later second trimester it was associated with preterm preeclampsia ( aOR=3.00, 95% CI: 1.26-7.10, P=0.013), gestational hypertension ( aOR=2.38, 95% CI: 1.44-3.94, P=0.001), and LGA ( aOR=1.59, 95% CI: 1.15-2.22, P=0.005). In the third trimester, excessive weekly weight gain was associated with higher risks of term preeclampsia ( aOR=2.70, 95% CI: 1.61-4.54, P<0.001) and gestational hypertension ( aOR=1.84, 95% CI: 1.05-3.21, P=0.033); while insufficient weekly weight gain was a risk factor for SGA ( aOR=1.58, 95% CI: 1.01-2.48, P=0.045), but a protective factor for term preeclampsia ( aOR=0.37, 95% CI: 0.14-0.97, P=0.041). Insufficient and excessive weekly weight gain in the early second trimester were not related to GDM (both P>0.05). Conclusions:GWG at different stages has different effects on pregnancy complications. A more relaxed control of GWG in the early second trimester combined with strict control in both the later second trimester and the third trimester may be a reasonable strategy to reduce the risk of preeclampsia without increasing the risk of SGA.

Prospective cohort study of fetal nuchal translucency in first-trimester and pregnancy outcome / 中华妇产科杂志

Objective@#To explore the relationship between fetal nuchal translucency (NT) in the first trimester and pregnancy outcome.@*Methods@#A prospective cohort study was conducted in Nanjjing Drum Tower Hospital from December 2015 to December 2018, 4 958 singleton pregnant women were enrolled to screen fetal ultrasound structure and serology in the first trimester, ultrasound in the second trimester and neonatus physical examination 28 days after birth. According to the results of NT, 167 cases of fetus with increased NT (≥3.0 mm) and 4 791 cases of normal NT were divided, moreover, 86 cases with isolate increased NT and 81 cases of increased NT combined with structural abnormality. The prognosis of fetuses with different NT thickness was analyzed, and the pregnancy outcome of fetuses with isolate increased NT or combined with structural abnormality were analyzed. In the first trimester, if the fetal structure was abnormal or the serological screening result was high risk, the chromosomal microarray analysis (CMA) would be performed by chorionic villus sampling to determine the prenatal diagnosis.@*Results@#(1) The pregnancy outcome for fetus of normal NT: there were 4 791 cases with normal NT. Totally, 4 726 cases with normal NT and no structural abnormalities were screened out in the firsttrimester. In this group, 5 cases of aneuploidies were diagnosed based on high risk of maternal serum biomarkers and 83 cases of structural abnormalities were screened out in the subsequent ultrasound scan and the neonatal examination. Another 65 cases with normal NT present complicated with structural anomalies were screened out in the first trimester and 4 cases were diagnosed as aneuploidies. (2) The pregnancy outcome for fetus of isolate increased NT: 66 (76.7%, 66/86) cases of isolated increased NT were performed CMA, 3 cases were diagnosed as trisomy 21 and terminated pregnancy. Another 4 cases were terminated pregnancy privately without cytogenetic diagnosis. No further anomalies were found in 79 cases till 6 to 21 months postnatally. (3) The pregnancy outcome for fetus of increased NT with structural anomalies: increased NT present with structural anomalies were screened out by detailed anomaly scan in the first trimester and 32 of them were confirmed as aneuploidies. In this group, 70 cases terminated pregnancy, 2 cases had spontaneous miscarriages and 9 cases had liveborns (1 newborn was found ventricular septal defect). (4) The pregnancy outcome for fetus of increased NT with or without structural anomalies: the percentage of aneuploidies in fetuses with isolated increased NT (3.5%, 3/86) was significantly lower than those with structural abnormalities (39.5%,32/81). The healthy survival rate in fetuses with isolated increased NT (91.9%,79/86) was significantly higher than those with structural abnormalities (9.9%, 8/81).@*Conclusions@#A detailed first-trimester anomaly scan could improve prenatal screening efficiency of birth defects. Compared to the fetuses with increased NT combined with structural abnormalities, the healthy survival rate of fetuses with isolated increased NT based on detailed first-trimester anomaly scan is higher and the percentage of fetal aneuploidies is lower.

Prospective cohort study of fetal nuchal translucency in first-trimester and pregnancy outcome / 中华妇产科杂志

Objective:To explore the relationship between fetal nuchal translucency (NT) in the first trimester and pregnancy outcome.Methods:A prospective cohort study was conducted in Nanjjing Drum Tower Hospital from December 2015 to December 2018, 4 958 singleton pregnant women were enrolled to screen fetal ultrasound structure and serology in the first trimester, ultrasound in the second trimester and neonatus physical examination 28 days after birth. According to the results of NT, 167 cases of fetus with increased NT (≥3.0 mm) and 4 791 cases of normal NT were divided, moreover, 86 cases with isolate increased NT and 81 cases of increased NT combined with structural abnormality. The prognosis of fetuses with different NT thickness was analyzed, and the pregnancy outcome of fetuses with isolate increased NT or combined with structural abnormality were analyzed. In the first trimester, if the fetal structure was abnormal or the serological screening result was high risk, the chromosomal microarray analysis (CMA) would be performed by chorionic villus sampling to determine the prenatal diagnosis.Results:(1) The pregnancy outcome for fetus of normal NT: there were 4 791 cases with normal NT. Totally, 4 726 cases with normal NT and no structural abnormalities were screened out in the firsttrimester. In this group, 5 cases of aneuploidies were diagnosed based on high risk of maternal serum biomarkers and 83 cases of structural abnormalities were screened out in the subsequent ultrasound scan and the neonatal examination. Another 65 cases with normal NT present complicated with structural anomalies were screened out in the first trimester and 4 cases were diagnosed as aneuploidies. (2) The pregnancy outcome for fetus of isolate increased NT: 66 (76.7%, 66/86) cases of isolated increased NT were performed CMA, 3 cases were diagnosed as trisomy 21 and terminated pregnancy. Another 4 cases were terminated pregnancy privately without cytogenetic diagnosis. No further anomalies were found in 79 cases till 6 to 21 months postnatally. (3) The pregnancy outcome for fetus of increased NT with structural anomalies: increased NT present with structural anomalies were screened out by detailed anomaly scan in the first trimester and 32 of them were confirmed as aneuploidies. In this group, 70 cases terminated pregnancy, 2 cases had spontaneous miscarriages and 9 cases had liveborns (1 newborn was found ventricular septal defect). (4) The pregnancy outcome for fetus of increased NT with or without structural anomalies: the percentage of aneuploidies in fetuses with isolated increased NT (3.5%, 3/86) was significantly lower than those with structural abnormalities (39.5%,32/81). The healthy survival rate in fetuses with isolated increased NT (91.9%,79/86) was significantly higher than those with structural abnormalities (9.9%, 8/81).Conclusions:A detailed first-trimester anomaly scan could improve prenatal screening efficiency of birth defects. Compared to the fetuses with increased NT combined with structural abnormalities, the healthy survival rate of fetuses with isolated increased NT based on detailed first-trimester anomaly scan is higher and the percentage of fetal aneuploidies is lower.

Effects and potential mechanisms of bradykinin B2 receptor on growth and biological function of human extravillous trophoblast cells / 中华围产医学杂志

Objective To investigate the effects and its mechanisms of bradykinin B2 receptor (B2R) on the growth and function of human extravillous trophoblast cells (HTR-8/SVneo cells).Methods B2R expression plasmid (pcDNA3.1-B2R) was constructed and B2R-specific small interfering RNA (siRNA) was synthesized.HTR-8/SVneo cells were divided into four groups and transfected with pcDNA-3.1 (blank plasmid group),pcDNA3.1-B2R (B2R expression plasmid group),siRNA negative control and B2R-specific siRNA,respectively.Quantitative real-time reverse transcription-polymerase chain reaction and Western blot were used to detect the changes in the expression of B2R,matrix metalloproteinase-2,matrix metalloproteinase-9,cyclin D1 and vascular endothelial growth factor-A at both mRNA and protein levels in HTR-8/SVneo cells.Cell counting kit-8 and flow cytometry were used to detect cell activity and cell cycle,respectively.Cell migration assay and cell invasion assay were used to detect cell migration and invasion,respectively.Tube formation assay was used to evaluate the tube formation abilities of HTR-8/SVneo cells.All data were analyzed with t test.Results (1) Compared with the blank plasmid group,expression of B2R in HTR-8/SVneo cells in the B2R expression plasmid group were significantly increased at both mRNA (5.06±0.49 vs 1.00±0.28,t=7.226,P=0.002) and protein levels (1.34 ± 0.07 vs 1.00± 0.05,t=3.727,P=0.006).And the expression of B2R in HTR 8/SVneo cells transfected with B2R-specific siRNA were significantly reduced at both mRNA (0.34±0.05 vs 1.00±0.17,t=3.667,P=0.021) and protein levels (0.74±0.03 vs 1.00±0.05,t=4.097,P=0.006) comparing with the siRNA negative control group.(2) Compared with the blank plasmid group,HTR-8/SVneo cells being transfected with B2R expression plasmid showed a higher proliferation activity (1.50 ±0.03 vs 1.34± 0.04) promoting G0/G1 to S phase transition;compared with the siRNA negative control group,B2R-specific siRNA inhibited the proliferation of HTR-8/SVneo cells (1.06 ± 0.04 vs 1.20± 0.02) and arrested the cell cycle at G0/G 1 phase (all P＜0.05).(3) Compared with the blank plasmid group,B2R expression plasmid significantly increased the HTR-8/SVneo cell migration distance [(80.67±0.33) vs (41.33±5.24) μm],the number of cells penetrating matrigel gel (360.70 ±12.33 vs 268.70 ±14.45) and the number of cells having tube-like structures (28.20 ± 2.47 vs 14.00± 1.67),while significantly decrease was shown in these three parameters in B2R-specific siRNA group comparing with the siRNA negative control group [HTR-8/SVneo cell migration distance:(56.00±3.51) vs (87.00±1.53) μ m,number of cells penetrating matrigel gel:143.30± 12.91 vs 252.30± 17.07;number of tube-like structures:6.25±1.49 vs 15.75 ±2.02;all P＜0.05].(4) Expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 at mRNA level,and expression of cyclin D1 and vascular endothelial growth factor-A increased in the B2R expression plasmid group than in the blank plasmid group,and decreased in the B2R-specific siRNA group than in the siRNA negative control group at both mRNA and protein levels (all P＜0.05).Conclusions B2R might enhance the activity,migration,invasion and tube formation ability of human extravillous trophoblast cells through promoting the expression of matrix metalloproteinase-2,matrix metalloproteinase-9,cyclin D1 and vascular endothelial growth factor-A.

Associated factors and pregnancy outcomes of trial of labor after cesarean: a prospective cohort study / 中华围产医学杂志

Objective To investigate the safety of trial of labor after cesarean (TOLAC) and clinical factors associated with successful TOLAC and to compare TOLAC with elective repeat caesarean section (ERCS) in terms of obstetric and neonatal outcomes.Methods A prospective cohort study was conducted among gravidas who had a history of lower segment cesarean section and were hospitalized in the Department of Obstetrics and Gynecology,the Affiliated Drum Tower Hospital of Medical School of Nanjing University from January to December 2014.Exclusion criteria included indications for caesarean section (such as placenta previa,placenta accreta,twin pregnancy,breech presentation and severe preeclampsia),serious maternal complications after cesarean section,lower uterine segment thinner than 3 mm and poor healing of uterine incision.Totally,287 gravidas were enrolled.Among them,142 chose TOLAC and the other 145 requested ERCS.Clinical data of those gravidas were collected and statistically analyzed by t-test,Log-rank test,Chi-square or Fisher's exact test.Results (1) The success rate of TOLAC was 90.8％ (129/142).There was no significant difference in maternal age,gestational age,thickness of lower uterine segment,interval between the two deliveries and neonatal birth weight and asphyxia rate between the successful (n=129) and unsuccessful (n=13) groups (all P＞0.05).Although the two groups had no significant difference in postpartum hemorrhage (PPH) rate,the gravidas who failed in TOLAC lost more blood than those who succeeded [425 (195-675) vs 200 (50-1 400) ml,P＜0.05].Moreover,higher amniotic fluid contamination rate was observed in the unsuccessful group [6/13 vs 17.1％ (22/129),P＜0.05].In the TOLAC group,99.3％ (141/142) were under continuous fetal heart rate monitoring.Incomplete uterine rupture occurred in one women without serious maternal or neonatal outcomes.The reasons for 13 failed TOLAC cases were unbearable pain during labor,abnormal labor,fetal distress and threatened rupture of uterus.(2) Compared with the ERCS group,the TOLAC group showed shorter interval from last cesarean section to the indexed delivery[5 (2-18) vs 6 (2-19) years],younger maternal age [(31±4) vs (33 ±4) years old] and less blood loss [200 (50-1 400) vs 300 (100-1 500) ml] (all P＜0.05).Conclusion Our study shows that,those who preferred TOLAC were younger,or had shorter pregnancy interval from last cesarean section.The success rate of TOLAC is high for women undergoing systematic prenatal assessment and close management during labor with less blood loss and non-serious maternal and neonatal complications compared with ERCS.

First-trimester screening for fetal structural and chromosomal anomalies by detailed early anomaly scan / 中华围产医学杂志

Objectives To assess the performance of first trimester ultrasound screening for fetal structural and chromosomal anomalies based on a detailed anomaly and nuchal translucency (NT) scan at 11-13+6 weeks' gestation.Methods A prospective cohort study was conducted at Nanjing Drum Tower Hospital.Fetuses with a crown-rump length (CRL) between 45 mm and 84 mm scanned during December 2015 to March 2016 were enrolled in this study.After a detailed first-trimester anomaly scan followed the protocol of systematic standardized scan plans,fetuses with congenital abnormalities were screened out.Second trimester ultrasound screening and postnatal examination were performed for further examination of fetal anomalies.Cytogenetic analysis was performed on the fetuses with informed consent.Results (1) A total of 1 154 fetuses were enrolled in this study and among them,36 (3.1％) cases of fetal abnormalities were diagnosed through prenatal examination (35 cases) and postnatal examination (one case).(2) Twenty-one (58.3％) out of the 36 cases with structural and chromosomal anomalies were screened out by using the first-trimester scan,including eight cases of congenital cardiac defect (two cases of atrioventricular septal defect,one case of tricuspid atresia,one case of tetralogy of tetralogy,one case of right ventricle aneurysms and one cases of hypoplastic left heart syndrome combined with cystic hygroma with one case combined with polydactyly),four cases of central nervous system anomaly (three cases of exencephaly and one case of anencephaly combined with double outlet right ventricle),two cases of cleft palate/lip with one case combined with double outlet right ventricle,two cases of exomphalos,one case of amniotic band syndrome,one case of spinal bifida combined with megacystis,one case of umbilical cyst,one case of polydactyly and one case of cystic hygroma.One case of twin pregnancy chose selective fetocide to the fetus with exencephaly and 16 cases terminated pregnancy.The other four cases were confirmed by second trimester ultrasound screening and postnatal examination.Fourteen (38.9％,14/36) new cases of structural and chromosomal anomalies were detected by the second-trimester scan,six of which terminated the pregnancies and the rest were confirmed at term.One (2.8％,1/36) case of polydactyly was detected postnatally.(3) Chromosomal microarray analysis was performed on 28 cases,seven of which were identified as having chromosomal abnormalities including five cases detected in the first trimester and two cases detected in the second trimester.(4) Out of the 20 fetuses with abnormal NT in early trimester,which accounted for 1.7％ of all enrolled fetuses,nine were indentified with major structural or chromosomal abnormalies,a quarter of all abnormal fetus.Conclusions Detailed anomaly scan and NT scan in the first-trimester can increase the detection rate of fetal structural and chromosomal anomalies as compared with the traditional NT scan and provide earlier detection of severe fetal abnormalities as compared with second trimester anomaly scan.

Induction of preeclamptic rat model by injection of ultra-low-dose lipopolysaccharide in early pregnancy / 中华围产医学杂志

Objective To establish an animal model of preeclampsia by injecting ultra-low-dose lipopolysaccharide (LPS) to rats in early pregnancy,and to lay the foundation for further study on mechanisms of preeclampsia.Methods Twenty-four pregnant rats were divided into six groups according to the random number table and were injected with LPS 0.3,0.5,0.7,1.0,2.0 μg/kg or saline 2 ml respectively through tail veins on day 5 of pregnancy.The differences in blood pressure,urinary protein and pathological changes in placenta among groups were compared to confirm the suitable dose of LPS for establishing preeclamptic model.Then another 19 pregnant rats were injected with the chosen dose of LPS slowly through tail veins on day 5 of pregnancy; 15 of which were chosen as model group; the other four were chosen as postpartum group.Three non-pregnant rats were as non-pregnant group.Besides,another 15 pregnant rats were injected with saline as pregnant control group.Systolic blood pressure,urinary protein excretion,placental weight,fetal weight,serum white blood cell counts,blood platelet counts,plasma anti-thrombin-Ⅲ content,D-dimer content were examined and compared among groups with one way analysis of variance; histopathologic studies were also done on the placentas,kidneys and aortas of the rats.Results (1) Placental weight of LPS 0.3 μg/kg group increased compared with control group.One pregnant rats(1/4) in LPS 1.0 μg/kg group and LPS 2.0 μg/kg group died on day 16 of pregnancy as a result of vaginal bleeding.Systolic blood pressure of LPS 0.5 μg/kg group rose steadily,while no significant changes were found in other groups.Urinary protein increased in all LPS groups,while urinary protein of LPS 0.7 μg/kg group and LPS 1.0 μg/kg group peaked on day 12 of pregnancy and then decreased; urinary protein of LPS 0.5 μg/kg group increased most significantly,and fetus in LPS 0.5,0.7 and 2.0 μg/kg groups had lighter body weight.So LPS 0.5 μg/kg was chosen as the suitable dose to establish preeclamptic model.(2)Compared with pregnant control group,model group had higher systolic blood pressure [(124.89±1.79) mm Hg vs (119.02±1.80) mm Hg,LSD test,P=0.03] from day 6 of pregnancy,more urinary protein [(2.02±0.29) mg vs (1.11±0.18) mg,LSD test,P=0.00] from day 9 of pregnancy,more absorbed embryos [3.6％ (7/194) vs 0.0％ (0/200),Fisher exact test,P=0.01] at day 20 of pregnancy,higher incidence of placenta bleeding [4.1％ (8/194) vs 0.0％ (0/200),Fisher exact test,P=0.00] and fetal growth restriction [13.9％ (27/194) vs 6.0％ (12/200),X2=6.92,Fisher exacttest,P=0.01].Model group showed more inflammatory cells infiltration in the placenta,more glomerular mesangial cells,swelling and desquamated of renal tubular epithelial cells compared to control group.Blood pressure and urinary protein of the model group recovered to the baseline at the sixth day of postpartum,and no changes in blood pressure and urinary protein were found in non-pregnant rats.Conclusions Injection of LPS 0.5 μg/kg on day 5 of pregnancy through tail veins could induce the clinical symptoms of preeclampsia in rats,which might be an ideal model for further preeclampsia research.

Trans-cervical Foley catheter balloon versus vaginal prostaglandin E2 suppository for cervical ripening and induction of labor: a prospective randomized controlled trial / 中华围产医学杂志

Objective To compare the effectiveness and safety of Foley catheter(FC)and vaginal prostaglandin E2 suppository(PGE2,Propess)for cervical ripening and labor induction in fullterm pregnant women with unfavorable cervix.Methods A prospective randomized controlled trial was conducted.Women with a term or post-term,live,singleton fetus in cephalic presentation,intact membranes,Bishop score＜6,not in labor,medically indicated for labor induction from June 2009 to December 2009 in Drum Tower Hospital of Nanjing University Medical School were randomly divided into two groups:FC group(n=64)and Propess group(n=62).In FC group,a 16-F Foley catheter was inserted into patient's cervical canal; once past the internal os,the balloon was inflated with 80 ml saline.Intravenous oxytocin was initiated after the balloon was spontaneously extruded from the cervix or after 24 hours.In Propess group,vaginal Propess was used.x2 or Fisher's exact test and t test were used to compare the outcomes,delivery mode and induction success rate between the two groups.Results There were no significant differences in gestational weeks,Bishop score,indication of induction,improvement of Bishop score,success rate of induction,rate of vaginal delivery,total duration of labor and volume of postpartum hemorrhage between the two groups(P ＞ 0.05,respectively).Propess group had a higher rate of vaginal birth within 24 hours[56.5％(35/62)vs 28.1％(18/64),t=10.37,P＜0.05],a higher risk for excessively frequent and hard uterine contraction[17.7％(11/62)vs 0.0％(0/64),P＜0.05]and lower incidence of oxytocin induction/augmentation during labor[21.0％(13/62)vs 87.5％(56/64),x2 =56.27,P＜0.05]than those of FC group.There were no differences in neonatal Apgar score,meconium staining and neonatal birth weight between the two groups.Puerperal infection occured in neither group.Conclusions Under strict control of indication and aseptic manipulation,Foley catheter was as effective and safe as Propess for cervical ripening with lower risk of excessive uterine activity.It is suggested that Foley catheter could be used for cervical ripening,especially in patients with economic difficulty.