The effect of intrapartum prolonged oxygen exposure on fetal metabolic status: secondary analysis from a randomized controlled trial.

Objective: The aim of the study is to assess the effect of maternal prolonged oxygen exposure during labor on fetal acid-base status, fetal heart rate tracings, and umbilical cord arterial metabolites. Design: The study was conducted as a secondary analysis. Settings: The study was set in three tertiary teaching hospitals in Beijing, China. Participants: Approximately 140 women in the latent phase of labor with no complications participated in the study. Intervention: Participants were randomly allocated in a 1:1 ratio to receive either 10 L of oxygen per minute in a tight-fitting simple facemask until delivery or room air only. Main outcome measures: The primary outcome was the umbilical cord arterial lactate. Results: Baseline demographics and labor outcomes were similar between the oxygen and room air groups; the time from randomization to delivery was 322 ± 147 min. There were no differences between the two groups in the umbilical cord arterial lactate (mean difference 0.3 mmol/L, 95% confidence interval -0.2 to 0.9), the number of participants with high-risk category II fetal heart rate tracings (relative risk 0.94, 95% confidence interval 0.68 to 1.32), or the duration of those high-risk tracings (mean difference 3.6 min, 95% confidence interval -9.3 to 16.4). Prolonged oxygen exposure significantly altered 91 umbilical cord arterial metabolites, and these alterations did not appear to be related to oxidative stress. Conclusion: Maternal prolonged oxygen exposure during labor did not affect either the umbilical cord arterial lactate or high-risk category II fetal heart rate tracings but might result in alterations to the umbilical cord arterial metabolic profile. Clinical trial registration: www.clinicaltrials.gov, identifier NCT03764696.

3CLpro inhibitors: DEL-based molecular generation.

Molecular generation (MG) via machine learning (ML) has speeded drug structural optimization, especially for targets with a large amount of reported bioactivity data. However, molecular generation for structural optimization is often powerless for new targets. DNA-encoded library (DEL) can generate systematic, target-specific activity data, including novel targets with few or unknown activity data. Therefore, this study aims to overcome the limitation of molecular generation in the structural optimization for the new target. Firstly, we generated molecules using the structure-affinity data (2.96 million samples) for 3C-like protease (3CLpro) from our own-built DEL platform to get rid of using public databases (e.g., CHEMBL and ZINC). Subsequently, to analyze the effect of transfer learning on the positive rate of the molecule generation model, molecular docking and affinity model based on DEL data were applied to explore the enhanced impact of transfer learning on molecule generation. In addition, the generated molecules are subjected to multiple filtering, including physicochemical properties, drug-like properties, and pharmacophore evaluation, molecular docking to determine the molecules for further study and verified by molecular dynamics simulation.

Effect of long-duration oxygen vs room air during labor on umbilical cord venous partial pressure of oxygen: a randomized controlled trial.

BACKGROUND: There are limited data to guide the duration and dose of oxygen supplementation for pregnant women undergoing labor. OBJECTIVE: To assess the effect of maternal long-duration high-concentration oxygen administration during labor on umbilical cord venous partial pressure of oxygen. STUDY DESIGN: This randomized clinical trial was conducted between January and October of 2021 in the obstetrics wards of 3 tertiary teaching hospitals in Beijing, China. Women undergoing the latent phase of labor with no existing medical conditions or obstetrical complications who were admitted for delivery were eligible. The women who met inclusion criteria with category I fetal heart rate tracings in labor were randomized in a 1:1 ratio to oxygen or room air. The oxygen group received 10 L of oxygen per minute by simple, tight-fitting face mask until delivery. The room-air group received room air only, without a face mask. The primary outcome was the umbilical cord venous partial pressure of oxygen. RESULTS: A total of 661 women were screened, and 521 were excluded; 140 participants with category I fetal heart rate tracings were enrolled and randomized to oxygen (N=70) or room air (N=70). A total of 135 women with valid paired umbilical cord venous and arterial gas values were included in the umbilical cord venous partial pressure of oxygen and arterial pH analyses. All 140 women were included in the fetal heart rate tracings analysis. Baseline characteristics were similar between the oxygen and room-air groups. The duration of oxygen exposure was approximately 322±147 minutes. There were no differences between the oxygen and room-air groups in the umbilical cord venous partial pressure of oxygen (mean difference, 1.1 mm Hg; 95% confidence interval, -1.0 to 3.2; P=.318) or the proportion of participants with category II fetal heart rate tracings (81.4% vs 78.6%; relative risk, 1.04; 95% confidence interval, 0.88-1.22; P=.672). However, the umbilical cord arterial pH was significantly lower in the oxygen group than in the room-air group (median, 7.23; interquartile range, 7.20-7.27 vs median 7.27; interquartile range, 7.20-7.30; P=.005). CONCLUSION: Maternal long-duration high-concentration oxygen administration during labor did not affect either the umbilical cord venous partial pressure of oxygen or fetal heart rate pattern distribution but resulted in a deterioration of the umbilical cord arterial pH at birth.

Sesamol Augments Paclitaxel-Induced Apoptosis in Human Cervical Cancer Cell Lines.

Natural medicinal compounds have gained increasing attention as adjuvants during cancer chemotherapy. The present study demonstrated the chemosensitizing effect of sesamol, a natural phenolic compound, in HeLa cell lines In Vitro. Sesamol-pretreated (10 µM) HeLa cells were exposed to 7.5 nM paclitaxel. The chemosensitization was estimated by MTT-based metabolic assay. Further, oxidative DNA damage, alterations in mitochondrial membrane potential (MMP), and apoptotic morphological changes were analyzed. Sesamol treatment before paclitaxel treatment significantly decreased the IC50 value of paclitaxel (7.5 nM) in a concentration-dependent manner. Further, Sesamol treatment before paclitaxel increased the intracellular ROS levels and enhanced apoptosis through MMP alterations. Moreover, there was an increased % of tail DNA in sesamol + paclitaxel-treated cervical cancer cells compared to paclitaxel alone treatment. The frequency of apoptotic cells were also increased during sesamol + paclitaxel treatment cells compared to paclitaxel alone treatment. Thus, Sesamol treatment before paclitaxel exposure enhanced the apoptotic cell death in the HeLa cell lines. The results of the present study were in support of the usage of natural medicinal compounds for clinical chemotherapy after systematic animal experimentations.

Uterine decidual niche modulates the progressive dedifferentiation of spiral artery vascular smooth muscle cells during human pregnancy†.

Uterine spiral artery (SPA) remodeling is a crucial event during pregnancy to provide enough blood supply to maternal-fetal interface and meet the demands of the growing fetus. Along this process, the dynamic change and the fate of spiral artery vascular smooth muscle cells (SPA-VSMCs) have long been debatable. In the present study, we analyzed the cell features of SPA-VSMCs at different stages of vascular remodeling in human early pregnancy, and we demonstrated the progressively morphological change of SPA-VSMCs at un-remodeled (Un-Rem), remodeling, and fully remodeled (Fully-Rem) stages, indicating the extravillous trophoblast (EVT)-independent and EVT-dependent phases of SPA-VSMC dedifferentiation. In vitro experiments in VSMC cell line revealed the efficient roles of decidual stromal cells, decidual natural killer cells (dNK), decidual macrophages, and EVTs in inducing VSMCs dedifferentiation. Importantly, the potential transformation of VSMC toward CD56+ dNKs was displayed by immunofluorescence-DNA in-situ hybridization-proximity ligation and chromatin immunoprecipitation assays for H3K4dime modification in the myosin heavy chain 11 (MYH11) promoter region. The findings clearly illustrate a cascade regulation of the progressive dedifferentiation of SPA-VSMCs by multiple cell types in uterine decidual niche and provide new evidences to reveal the destination of SPA-VSMCs during vascular remodeling.

Placental endovascular extravillous trophoblasts (enEVTs) educate maternal T-cell differentiation along the maternal-placental circulation.

OBJECTIVES: During human pregnancy, the endothelial cells of the uterine spiral arteries (SPA) are extensively replaced by a subtype of placental trophoblasts, endovascular extravillous trophoblasts (enEVTs), thus establishing a placental-maternal circulation. On this pathway, foetus-derived placental villi and enEVTs bath into the maternal blood that perfuses along SPA being not attacked by the maternal lymphocytes. We aimed to reveal the underlying mechanism of such immune tolerance. METHODS: In situ hybridization, immunofluorescence, ELISA and FCM assay were performed to examine TGF-ß1 expression and distribution of regulatory T cells (Tregs) along the placental-maternal circulation route. The primary enEVTs, interstitial extravillous trophoblasts (iEVTs) and decidual endothelial cells (dECs) were purified by FACS, and their conditioned media were collected to treat naïve CD4+ T cells. Treg differentiation was measured by FLOW and CFSE assays. RESULTS: We found that enEVTs but not iEVTs or dECs actively produced TGF-ß1. The primary enEVTs significantly promoted naïve CD4+ T-cell differentiation into immunosuppressive FOXP3+ Tregs, and this effect was dependent on TGF-ß1. In recurrent spontaneous abortion (RSA) patients, an evidently reduced proportion of TGF-ß1-producing enEVTs and their ability to educate Tregs differentiation were observed. CONCLUSIONS: Our findings demonstrate a unique immune-regulatory characteristic of placental enEVTs to develop immune tolerance along the placental-maternal circulation. New insights into the pathogenesis of RSA are also suggested.

Prediction of candidate RNA signatures for recurrent ovarian cancer prognosis by the construction of an integrated competing endogenous RNA network.

Tumor recurrence hinders treatment of ovarian cancer. The present study aimed to identify potential biomarkers for ovarian cancer recurrence prognosis and explore relevant mechanisms. RNA­sequencing of data from the TCGA database and GSE17260 dataset was carried out. Samples of the data were grouped according to tumor recurrence information. Following data normalization, differentially expressed genes/micro RNAs (miRNAs)/long non­coding (lncRNAs) (DEGs/DEMs/DELs) were selected between recurrent and non­recurrent samples. Their correlations with clinical information were analyzed to identify prognostic RNAs. A support vector machine classifier was used to find the optimal gene set with feature genes that could conclusively distinguish different samples. A protein­protein interaction (PPI) network was established for DEGs using relevant protein databases. An integrated 'lncRNA/miRNA/mRNA' competing endogenous RNA (ceRNA) network was constructed to reveal potential regulatory relationships among different RNAs. We identified 36 feature genes (e.g. TP53 and RBPMS) for the classification of recurrent and non­recurrent ovarian cancer samples. Prediction with this gene set had a high accuracy (91.8%). Three DELs (WT1­AS, NBR2 and ZNF883) were highly associated with the prognosis of recurrent ovarian cancer. Predominant DEMs with their targets were hsa­miR­375 (target: RBPMS), hsa­miR­141 (target: RBPMS), and hsa­miR­27b (target: TP53). Highlighted interactions in the ceRNA network were 'WT1­AS­hsa­miR­375­RBPMS' and 'WT1­AS­-hsa­miR­27b­TP53'. TP53, RBPMS, hsa­miR­375, hsa­miR­141, hsa­miR­27b, and WT1­AS may be biomarkers for recurrent ovarian cancer. The interactions of 'WT1­AS­hsa­-miR­375­RBPMS' and 'WT1­AS­hsa­miR­27b­TP53' may be potential regulatory mechanisms during cancer recurrence.

MiR-195 modulates oxidative stress-induced apoptosis and mitochondrial energy production in human trophoblasts via flavin adenine dinucleotide-dependent oxidoreductase domain-containing protein 1 and pyruvate dehydrogenase phosphatase regulatory subunit.

OBJECTIVE: Preeclampsia is a severe pregnancy-specific syndrome defined as newly onset hypertension and proteinuria. Abnormal placental development has been generally accepted as the initial cause of the disorder. Recently, miR-195 was identified as one of the downregulated small RNAs in preeclamptic placentas. METHODS: The potential targets of miR-195 in human trophoblast cells were screened by isobaric tags for relative and absolute quantification-based mass spectrum analysis. Localization of miR-195 and its targets was examined by in-situ hybridization and immunohistochemistry in human placenta. Real-time PCR, western blotting and luciferase assay were used for target validation. Apoptosis was accessed by Annexin V/PI costaining, whereas mitochondrial function by ATP measurement and tetramethylrhodamine ethyl ester fluorescence. RESULTS: Two mitochondria-associated proteins, flavin adenine dinucleotide-dependent oxidoreductase domain-containing protein 1 (FOXRED1) and pyruvate dehydrogenase phosphatase regulatory subunit (PDPR), were identified as targets of miR-195. Overexpression of miR-195 in HTR8/SVneo cells resulted in enhanced apoptosis, decreased mitochondrial membrane potential and cellular ATP content upon hydrogen peroxide stimulation. The effects could be partially rescued by FOXRED1 or PDPR. In preeclamptic patients, lowered circulating level of miR-195 were found at early-to-mid gestation and term pregnancy, and marked increase in FOXRED1 and PDPR expression were observed in the placenta when compared with gestational week-matched controls. In addition, chronic hydrogen peroxide stimuli suppressed miR-195 expression in trophoblast cells. CONCLUSION: MiR-195 could suppress mitochondrial energy production via targeting FOXRED1 and PDPR, and lead to trophoblast cell apoptosis under oxidative stress. In preeclamptic placenta, lowered level of miR-195 might be induced by chorionic oxidative stress and subsequently form a compensation mechanism to defend the disturbed energy production and cell apoptosis upon oxidative stress.

A network-pathway based module identification for predicting the prognosis of ovarian cancer patients.

BACKGROUND: This study aimed to screen multiple genes biomarkers based on gene expression data for predicting the survival of ovarian cancer patients. METHODS: Two microarray data of ovarian cancer samples were collected from The Cancer Genome Atlas (TCGA) database. The data in the training set were used to construct Reactome functional interactions network, which then underwent Markov clustering, supervised principal components, Cox proportional hazard model to screen significantly prognosis related modules. The distinguishing ability of each module for survival was further evaluated by the testing set. Gene Ontology (GO) functional and pathway annotations were performed to identify the roles of genes in each module for ovarian cancer. RESULTS: The network based approach identified two 7-gene functional interaction modules (31: DCLRE1A, EXO1, KIAA0101, KIN, PCNA, POLD3, POLD2; 35: DKK3, FABP3, IRF1, AIM2, GBP1, GBP2, IRF2) that are associated with prognosis of ovarian cancer patients. These network modules are related to DNA repair, replication, immune and cytokine mediated signaling pathways. CONCLUSIONS: The two 7-gene expression signatures may be accurate predictors of clinical outcome in patients with ovarian cancer and has the potential to develop new therapeutic strategies for ovarian cancer patients.

Conclusiveness of the Cochrane reviews in gynaecological cancer: A systematic analysis.

OBJECTIVE: To assess the conclusiveness of Cochrane reviews in the field of gynaecological cancer. METHODS: The Cochrane Library was searched for reviews regarding gynaecological cancer published between 1 January 2000 and 1 November 2014. Data were extracted from each paper and the conclusiveness of each review was assessed. RESULTS: The study included 66 reviews, 41 (62.1%) of which were conclusive. Of these, 58 included randomized controlled trials (RCTs), 37 (63.8%) of which were conclusive. Conclusive reviews of RCTs included significantly more patients than inconclusive reviews, but there was no difference in the number of included studies. Of the eight reviews of nonrandomized studies, four (50.0%) were conclusive. The majority of reviews recognized the need for additional studies. CONCLUSIONS: In the field of gynaecological cancer, reviews are more likely to be conclusive when they include RCTs, as well as large numbers of patients.

Expression of ATP-sensitive potassium channels in human pregnant myometrium.

BACKGROUND: Potassium channels play critical roles in the regulation of cell membrane potential, which is central to the excitability of myometrium. The ATP-sensitive potassium (KATP) channel is one of the most abundant potassium channels in myometrium. The objectives of this study were to investigate the protein expression of KATP channel in human myometrium and determine the levels of KATP channel in lower and upper segmental myometrium before and after onset of labour. METHODS: Both lower segmental (LS) and upper segmental (US) myometrial biopsies were collected at cesarean section from pregnant women not-in-labour (TNL) or in-labour (TL) at term. Protein expression level and cellular localization of four KATP channel subunits in US and LS myometrium were determined by Western blot analysis and immunohistochemistry, respectively. The contractile activity of myometrial strip was measured under isometric conditions. RESULTS: Four KATP channel subunits, namely Kir6.1, Kir6.2, SUR1 and SUR2B were identified in pregnant myometrium. While found in vascular myocytes, these subunits appear to be preferentially expressed in myometrial myocytes. Diazoxide, a KATP channel opener, inhibited the spontaneous contractility of pregnant myometrium, suggesting that the KATP channels are functional in human pregnant myometrium. Diazoxide was less potent in TL strips than that in TNL strips. Interestingly, expression of SUR1 was greater in TL than TNL tissues, although no differences were found for SUR2B in these two tissues. For both lower and upper segmental myometrium, Kir6.1 and Kir6.2 were less in TL compared with TNL tissues. CONCLUSIONS: Functional KATP channels are expressed in human pregnant myometrium. Down-regulation of Kir6.1 and Kir6.2 expression in myometrium may contribute to the enhanced uterine contractility associated with the onset of labour.

Association of obestatin with blood pressure in the third trimesters of pregnancy.

Obestatin is a recently discovered 23-amino acid peptide encoded by the same gene that encodes ghrelin. It has been reported that there is a significant negative correlation between the plasma ghrelin concentration and systemic blood pressure in patients with pregnancy-induced hypertension. We investigated the plasma concentration of obestatin in 18 non-pregnant women, 18 normal pregnant women, and 15 patients with pregnancy-induced hypertension. The plasma concentrations of obestatin in these 3 groups of women were 63.4+/-9.5pg/ml, 38.1+/-6.3pg/ml, and 46.0+/-9.3pg/ml, respectively. In non-pregnant women, there was no correlation between the plasma obestatin concentration and the mean arterial pressure. However, there was a positive correlation between the plasma obestatin concentration and the mean arterial pressure in normal pregnant women and pregnant women with pregnancy-induced hypertension. These results suggest that obestatin may have some potential role in the regulation of blood pressure in normal pregnant women and women with pregnancy-induced hypertension.

Reduced expression of CRH receptor type 1 in upper segment human myometrium during labour.

BACKGROUND: Corticotropin-releasing hormone (CRH) and CRH-related peptide are shown to modulate uterine contractility through two CRH receptor subtype, CRH-R1 and CRH-R2 during pregnancy. Through different signaling pathways, CRH-R1 maintains myometrial quiescence whereas CRH-R2 promotes smooth muscle contractility. We hypothesized that the expression of CRH receptors in myometrium might be changed during pregnancy and labour. METHOD: Immunohistochemistry, Western blot and RT-PCR were used to quantify the cellular localization, the protein levels and the mRNA variants of both CRH-R1 and CRH-R2 in upper segment (US) and lower segment (LS) myometrium from nonpregnant and pregnant women at term before or after labour. RESULTS: CRH-R1 and CRH-R2 were predominately localized to myometrial smooth muscle cells in US and LS. The protein level of CRH-R1 in US was significantly down-regulated in pregnancy, with a further decrease at the onset of labour. However, the expression of CRH-R1 in LS remained unchanged during pregnancy and labour. No significant changes in CRH-R2 expression were observed in US or LS. Six variants of CRH-R1, CRH-R1alpha,-R1beta,-R1c, -R1e,-R1f and -R1g, were identified in nonpregnant and pregnant myometrium. CRH-R2alpha was identified in pregnant myometrium, whereas CRH-R2beta was identified in nonpregnant myometrium CONCLUSION: CRH-R1 and CRH-R2 are expressed in nonpregnant and pregnant US and LS myometrium. Changed expression of CRH receptors during labour may underlie the initiation of uterine contractility during parturition.

Expression of the calcium-activated potassium channel in upper and lower segment human myometrium during pregnancy and parturition.

BACKGROUND: Large conductance calcium-activated potassium channel (BKCa) plays an important role in the control of uterine contractility during pregnancy. The change from uterine quiescence to enhanced contractile activity may be associated with the spatial and temporal expression of BKCa within myometrium. The objectives of this study were to examine the expression of BKCa alpha- and beta-subunit in upper segment (US) and lower segment (LS) regions of uterus, and to investigate for the possibly differential expression of these proteins in US and LS myometrium obtained from three functional states: (1) non-pregnant (NP); (2) term pregnant not in labour (TNL) and (3) term pregnant in labour (TL). METHODS: Myometrial biopsies were collected from non-pregnant women at hysterectomy and pregnant women at either elective caesarean section or emergency caesarean section. Protein expression level and cellular localization of BKCa alpha- and beta-subunit in US and LS myometrium were determined by Western blot analysis and immunohistochemistry, respectively. RESULTS: BKCa alpha- and beta-subunit were predominantly localized to myometrial smooth muscle in both US and LS myometrium obtained from non-pregnant and pregnant patients. The level of BKCa alpha-subunit in US but not in LS was significantly higher in NP myometrium than those measured in myometrium obtained during pregnancy. Lower expression of BKCa alpha-subunit in both US and LS was found in TL than in TNL biopsies. Expression of beta-subunit in both US and LS myometrium was significantly reduced in TL group compared with those measured in TNL group. There was no significant difference in BKCa beta-subunit expression in either US or LS between NP and TNL group. CONCLUSION: Our results suggest that expression of BKCa alpha- and beta-subunit in pregnant myometrium is reduced during labour, which is consistent with the myometrial activity at the onset of parturition.

Corticotropin-releasing hormone acts on CRH-R1 to inhibit the spontaneous contractility of non-labouring human myometrium at term.

AIMS: Corticotropin-releasing hormone (CRH) has been implicated in the mechanisms controlling human parturition. The aims of the present study were to explore effects of CRH on contractility of human term myometrium and compare these effects in labouring and non-labouring myometrial strips. MAIN METHODS: The cumulative effects of CRH (10(-10) to 10(-7) mol/l) on the spontaneous contractility of labouring and non-labouring myometrial samples were evaluated using isometric tension recordings. KEY FINDINGS: CRH exhibited a concentration-dependent relaxant effect on spontaneous contractions in non-labouring term myometrium. This effect was mediated principally via a reduction in the amplitude rather than any changes in the frequency of contractions. The CRH-induced inhibitory effect on contractility could be blocked by pre-treatment with a CRH-R1 antagonist antalarmin, but not by pre-treatment with the CRH-R2 antagonist astressin 2B. CRH had no effect on spontaneous contractions in the labouring myometrium, as no change in either the amplitude or the frequency was observed. SIGNIFICANCE: Our findings indicate that CRH acts on CRH-R1 to inhibit spontaneous contractions in term myometrium from women who were not undergoing labour, but not those who were undergoing labour, supporting the hypothesis that CRH exerts dual effect on myometrium during pregnancy.