Structural and Mechanistic Insights into the C-C Bond-Forming Rearrangement Reaction Catalyzed by Heterodimeric Hinokiresinol Synthase.

Hinokiresinol synthase (HRS) from Asparagus officinalis consists of two subunits, α and ß, and catalyzes an unusual decarboxylative rearrangement reaction of 4-coumaryl 4-coumarate to generate (Z)-hinokiresinol with complete stereoselectivity. Herein, we describe the mechanism of rearrangement catalysis and the role played by the heterodimeric HRS, through structural and computational analyses. Our results suggest that the HRS reaction is unlikely to proceed via the previously hypothesized Claisen rearrangement mechanism. Instead, we propose that the 4-coumaryl 4-coumarate substrate is first cleaved into coumarate and an extended p-quinone methide, which then recombine to generate a new C-C bond. These processes are facilitated by proton transfers mediated by the basic residues (α-Lys164, α-Arg169, ß-Lys168, and ß-Arg173) in the cavity at the heterodimer interface. The active site residues, α-Asp165, ß-Asp169, ß-Trp17, ß-Met136, and ß-Ala171, play crucial roles in controlling the regioselectivity of the coupling between the fragmented intermediates as well as the stereoselectivity of the decarboxylation step, leading to the formation of the (Z)-hinokiresinol product.

A real-world disproportionality analysis of Rucaparib: Post-marketing Pharmacovigilance Data.

BACKGROUND: Rucaparib has been approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. However, the long-term safety of rucaparib in large sample population was unknown. The presented study aimed to evaluate rucaparib-associated adverse events (AEs) according to the real-world pharmacovigilance database. METHODS: Disproportionality analysis was conducted to assess the association between rucaparib and its AEs. Data were collected from the international pharmacovigilance database of US FDA Adverse Event Reporting System (FAERS) between January 2017 and June 2022. The characteristics of rucaparib-related AEs, and the onset time were further analyzed. RESULTS: A total of 9,296,694 AE reports were recorded in the FAERS during the study period, among which 7,087 reports were associated with rucaparib. About 135 rucaparib-related AE signals in 15 system organ class (SOCs) were identified. The most common AEs included anaemia, thrombocytopenia, nausea, vomiting, fatigue, blood creatinine increase, alanine aminotransferase increase, and aspartate aminotransferase increase, which were listed in the label for rucaparib. Of note, 21 new and unexpected significant AEs that off-label were also found in our study, such as preferred term (PTs) of intestinal obstruction, gastrooesophageal reflux disease, blood iron decreased, dehydration, and hypersomnia. The median onset time of rucaparib-related AEs was 12 days (interquartile range [IQR] 1-62 days), and had early failure types. CONCLUSION: Our study demonstrated potential new AEs of rucaparib, and further studies were expected to confirm the results.

Diagnostic signature composed of seven genes in HIF-1 signaling pathway for preeclampsia.

PURPOSE: In this study, we explored the relationship of genes in HIF-1 signaling pathway with preeclampsia and establish a logistic regression model for diagnose preeclampsia using bioinformatics analysis. METHOD: Two microarray datasets GSE75010 and GSE35574 were downloaded from the Gene Expression Omnibus database, which was using for differential expression analysis. DEGs were performed the Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene set enrichment analysis (GSEA). Then we performed unsupervised consensus clustering analysis using genes in HIF-1 signaling pathway, and clinical features and immune cell infiltration were compared between these clusters, as well as the least absolute shrinkage and selection operator (LASSO) method to screened out key genes to constructed logistic regression model, and receiver operating characteristic (ROC) curve was plotted to evaluate the accuracy of the model. RESULTS: 57 DEGs were identified, of which GO, KEGG and analysis GSEA showed DEGs were mostly involved in HIF-1 signaling pathway. Two subtypes were identified of preeclampsia and 7 genes in HIF1-signaling pathway were screened out to establish the logistic regression model for discrimination preeclampsia from controls, of which the AUC are 0.923 and 0.845 in training and validation datasets respectively. CONCLUSION: Seven genes (including MKNK1, ARNT, FLT1, SERPINE1, ENO3, LDHA, BCL2) were screen out to build potential diagnostic model of preeclampsia.

Evaluation of triage strategies for high-risk human papillomavirus-positive women in cervical cancer screening: A multicenter randomized controlled trial in different resource settings in China.

Objective: We aimed to evaluate the effectiveness of different triage strategies for high-risk human papillomavirus (hrHPV)-positive women in primary healthcare settings in China. Methods: This study was undertaken in 11 rural and 9 urban sites. Women aged 35-64 years old were enrolled. HrHPV-positive women were randomly allocated to liquid-based cytology (LBC), visual inspection with acetic acid and Lugol's iodine (VIA/VILI) (rural only) triage, or directly referred to colposcopy (direct COLP). At 24 months, hrHPV testing, LBC and VIA/VILI were conducted for combined screening. Results: In rural sites, 1,949 hrHPV-positive women were analyzed. A total of 852, 218 and 480 women were randomly assigned to direct COLP, LBC and VIA/VILI. At baseline, colposcopy referral rates of LBC or VIA/VILI triage could be reduced by 70%-80%. LBC (n=3 and n=7) or VIA/VILI (n=8 and n=26) could significantly decrease the number of colposcopies needed to detect one cervical intraepithelial neoplasia (CIN) 2 or worse and CIN3+ compared with direct COLP (n=14 and n=23). For the 24-month cumulative detection rate of CIN2+, VIA/VILI triage was 0.50-fold compared with LBC triage and 0.46-fold with the direct COLP. When stratified by age, baseline LBC triage+ performed best (P<0.001), peaking among women aged 35-44 years (Ptrend=0.002). In urban sites, 1,728 women were hrHPV genotyping test positive. A total of 408, 571 and 568 women were randomly assigned to direct COLP for HPV16/18+, direct COLP for other hrHPV subtypes+, and LBC triage for other hrHPV subtypes+. LBC (n=12 and n=31) significantly decreased the number of colposcopies needed to detect one CIN2+ and CIN3+ compared with direct COLP (n=14 and n=44). HPV16/18+ increased the 24-month cumulative detection rate of CIN2+ (17.89%, P<0.001). Conclusions: LBC triage for hrHPV-positive women in rural settings and direct COLP for HPV16/18+ women and LBC triage for other hrHPV subtype+ women in urban settings might be feasible strategies.

Diagnosis, management, and neurodevelopmental outcomes of fetal hydrocephalus: an observational prospective study.

The etiology of fetal hydrocephalus is complex, and the outcome of fetal neurodevelopment after birth is also different. The purpose of this study is to conduct anti-infection of hydrocephalus fetuses with non-specific infection, and observe their neurodevelopment after birth, so as to provide clinical basis for further guidance and management of fetal hydrocephalus. Eighteen single pregnant women with fetal hydrocephalus confirmed by intrapartum ultrasonography in the Second Xiangya Hospital between July 1, 2019, and December 1, 2020, were included. Pelvis MRI, NITP, amniotic fluid/umbilical cord blood puncture, infection index, TORCH, and other examinations were completed during pregnancy. If the patient's infection index is elevated, the second-generation cephalosporin will be used for anti-infection therapy, and the development of fetal hydrocephalus, growth, and neurodevelopment after birth will be observed. Fetal hydrocephalus subsided in 3 cases (25%, 95% CI [0%, 53.7%]) remained stable in 6 cases (50%, 95% CI [16.8%, 83.2%]), progressed in 2 cases (16.7%, 95% CI [0%, 41.4%]), and terminated pregnancy in 1 case (8.7% [0%, 26.7%]). Of the 6 untreated patients, pregnancy was terminated in 3 (50%), hydrocephalus remained stable in 2 (33.3%), and spontaneous resolution in 1 case (16.7%). Fourteen patients delivered successfully, including 11 children with no obvious abnormalities in growth and development, 1 with mild growth retardation and 2 with moderate growth retardation. Anti-infective therapy in the case of non-specific infection or maternal infection can partially prevent the progression of hydrocephalus.

Early diagnostic test for acute fatty liver of pregnancy: a retrospective case control study.

BACKGROUND: Early diagnosis is important to lower the mortality rate of acute fatty liver of pregnancy (AFLP). The Swansea criteria is commonly used to diagnose AFLP, but some terms could only be reached when symptoms and signs have progressed, or are not efficient in clinical practice. Therefore, it is necessary to select cost effective tests to simplify and facilitate early suspicion of acute fatty liver of pregnancy. METHODS: This is a retrospective study of 28,800 medical records at the Second Xiangya Hospital from 2009 to 2015, including 41 patients with AFLP and 172 other diseases that could show similar symptoms to AFLP. The evaluated variables included past history of liver diseases, blood pressure, gastrointestinal symptoms, blood count, liver function test, coagulation function test and blood sugar test. The sensitivity, specificity, positive predict value and negative predict value were calculated for models in diagnosing AFLP. RESULTS: The significant variables associated with AFLP included gastrointestinal symptoms, blood pressure > 140/90 mmHg, aminotransferase> 42 IU/l, total bilirubin> 0.8 mg/dl, total bilirubin acid> 10.0 µmol/L, activated partial prothrombin time(APTT) > 34 s, prothrombin time(PT) > 14 s, white blood cells> 11 *106/l and blood sugar< 72 mg/dl. Gastrointestinal symptoms +aminotransferase +bilirubin +bile acid +APTT/PT showed 97.6% sensitivity and 97.1% specificity to diagnose AFLP. Adding blood pressure, blood sugar or white blood cells decreased the accuracy of the statistical model. CONCLUSIONS: Application of a statistical model including maternal symptoms, biochemical and haematological parameters has high diagnostic accuracy for earlier identification of AFLP. However, this finding needs to be tested in another cohort to determine whether this statistical model has the same performance.

Serum prolactin levels across pregnancy and the establishment of reference intervals.

BACKGROUND: Reference intervals (RIs) play key roles in clinical diagnosis, treatment and prognosis. However, RIs for clinical testing tend to be confined to the general population, and RIs for pregnant women are not very comprehensive. In this study, we establish RIs for prolactin (PRL) in healthy pregnant and postpartum women in the Chinese population. METHODS: Healthy pregnant women (n=378) were divided into groups according to whether they were in the first, second or third trimester of pregnancy. Healthy postpartum women (n=493) were separated into four groups according to mode of delivery as follows: postvaginal (24 and 48 h) or postcesarean (24 and 48 h). Healthy, non-pregnant women (n=123) were enrolled as a control group. Serum PRL levels were measured by electrochemiluminescence immunoassay, and RIs were established for each group. RESULTS: The RIs for PRL were as follows: healthy non-pregnant women, 178.89-757.52 µIU/mL; first trimester, 621.20-3584.00 µIU/mL; second trimester, 1432.00-5349.68 µIU/mL; third trimester, 4087.33-9733.65 µIU/mL; 24 and 48 h postvaginal delivery (combined), 7865.36-10998.86 µIU/mL; and 24 and 48 h postcesarean delivery, 4556.41-7675.99 and 6578.45-9980.45 µIU/mL, respectively. CONCLUSIONS: PRL RIs for pregnant women were established according to trimester, days postpartum and mode of delivery, thus providing a clinical reference for medical staff.

Nestin Improves Preeclampsia-Like Symptoms by Inhibiting Activity of Cyclin-Dependent Kinase 5.

BACKGROUND/AIMS: Preeclampsia (PE) is a pregnancy-specific hypertensive disorder that is characterised by a high incidence of hypertension and proteinuria. Podocytes are involved in the formation of a split membrane, which is the last barrier preventing the leakage of protein into the urine. Nestin, a cytoskeleton protein, is expressed stably in podocytes. However, the association between the Nestin concentration in urine and the progression of PE and the role of Nestin in PE remains unclear. METHODS: In the present study, a mouse podocyte cell line, PE-like animal model and PE patients' urine samples were used. Eilsa kits were used to detect the levels of proteins expression in urine samples from patients and animal models. Western Blotting and immunofluorescence were used to detect proteins expression levels in cell samples and animal tissue samples. Flow cytometry was used to detect the level of apoptosis in cells. Tunel assay was used to detect the levels of apoptosis in animal tissue samples. RESULTS: Nestin levels were significantly increased in PE patients than in hypertensive patients and healthy subjects, and positively correlated with proteinuria and podocalyxin. Ang II treatment decreased the expression of Nestin and Podocin in a time- and dose- dependent manner in podocytes. Restoration of the Nestin levels could reverse Ang II-induced F-actin degradation and attenuate Ang II-mediated podocyte apoptosis, while knockdown of the Nestin level exhibited the opposite. Moreover, the protective role of Nestin on podocytes is mediated by inhibition of the kinase activity of CDK5. In PE-like animal model induced by L-NAME injection, restoration of Nestin lowered the pressure and proteinuria concentration, attenuated the loss of podocytes, and decreased the expression of p35, p53 and the activity of CDK5 kinase, as compared with the control. CONCLUSIONS: Our findings suggest that Nestin could improve preeclampsia-like symptoms by inhibiting the activity of CDK5, and Nestin may become a new prognostic factor and a potential therapy target for PE.

Akt-mTOR Signaling Mediates Abnormalities in the Proliferation and Apoptosis of Ovarian Granulosa Cells in Patients with Polycystic Ovary Syndrome.

BACKGROUND/AIMS: Abnormal apoptosis of granulosa cells (GCs) is thought to involve in the pathogenesis of polycystic ovary syndrome (PCOS); however, the associated cellular and molecular mechanisms remain unclear. METHODS: Primary GCs were obtained from healthy women and women with PCOS. The cell proliferation and apoptosis were analyzed in insulin-stimulated and insulin receptor gene (INSR) siRNA-transfected GCs. The protein expression of Akt-mTOR-S6K1 signal molecules was measured by Western blot. RESULTS: This study showed that 1 nM of insulin significantly stimulated cell proliferation, induced cell apoptosis, and decreased the telomerase activity in GCs from both the healthy women and PCOS patients (p < 0.001), but silencing of INSR expression blocked the effects of insulin. Insulin induced significantly more apoptosis in GCs from PCOS patients than from healthy women (p < 0.01). Insulin significantly increased the ratio of p-Akt/Akt, the expression of mTOR protein, and the ratio of p-S6K1/S6K1 in GCs from normal control than in cells from PCOS patients (p < 0.001). CONCLUSION: Insulin-induced apoptosis of GCs, less activation of Akt-mTOR signaling, and reduction of telomerase activity may be associated with the pathogenesis of PCOS.

Efficacy of Chinese herbal medicine Zengru Gao to promote breastfeeding: a multicenter randomized controlled trial.

BACKGROUND: Breastfeeding is recommended worldwide but not fully practiced. The first week after childbirth is regarded as a critical period for increasing breast milk production. The aim of the study was to investigate whether Chinese herbal medicine Zengru Gao would result in more women breastfeeding in the first week after childbirth. METHODS: A multicenter randomized controlled trial was conducted of 588 mothers considering breastfeeding in China. Among the mothers of the intervention group, the intervention included Chinese herbal medicine Zengru Gao; among those of the control group, it did not. Primary outcomes were the percentages of fully and partially breastfeeding mothers. Secondary outcome was baby's daily formula intake. RESULTS: At 3 d and 7 d after delivery, significant differences were found in favour of Zengru Gao group on the percentage of full/ partial breastfeeding (Z = - 3.0037, p = 0.0027). At day 7, the percentage of full/ partial breastfeeding of the active group increased to 71.48%/20.70% versus 58.67%/30.26% in the control group, the differences remained significant (Z = - 3.0037, p = 0.0027). No statistically significant differences were detected on primary measures at 1 d. While intake of formula differed between groups at 1 d and 3 d, this difference did not achieve statistical significance, but this difference was apparent by 7 d (55.45 ± 115.39 ml/day vs 90.66 ± 153.89 ml/day). CONCLUSION: In conclusion, Chinese Herbal medicine Zengru Gao enhanced breastfeeding success during one week postpartum. The approach is acceptable to participants and merits further evaluation. TRIAL REGISTRATION: ChiCTR-IPR-15007376 , December 11, 2015.

Gold nanoparticle enhanced hybridization chain reaction as a method for signal amplification. Application to electrochemical immunodetection of the ovarian cancer biomarker carbohydrate antigen 125.

The authors describe a method for enhancing the hybridization chain reaction (HCR) by using gold nanoparticles (AuNPs). This can considerably improve the sensitivity of electrochemical immunoassays as demonstrated for the carbohydrate antigen 125 (CA125), a biomarker for ovarian cancer. Compared to previous HCR based assays, the DNA acting as fuel strands were immobilized onto AuNPs, so that dendrimeric like chains were formed on the electrode after HCR. The improved signal is due to the reaction of DNA on the electrode. Specifically, the reaction of the phosphate groups of DNA with molybdate forms redox-active molybdophosphate, and this generates a strong electrochemical current. The immunosensor was prepared by sequential capturing, on the electrode, (a) antibody against CA125, (b) analyte (CA125), and (c) an aptamer against CA125 to form a sandwich structure. The primer on the aptamer sequence initiates HCR by annealing to one strand of DNA on the AuNPs and to another DNA in solution. The increased loading of DNA molecules onto the electrode increases the amount of phosphate groups and subsequently increases the electrical signal. The sensitivity of the assay is found to be significantly improved compared to assays without HCR and when using conventional HCR. The immunosensor was successfully applied to the determination of CA125 in human serum samples. The detection limit (based on an S/N ratio of 3) is 50 µU.mL-1. This indicates that this signal amplification strategy has a large potential in terms of clinical applications. It may be modified such that it also can be applied to the determination of other analytes for which proper aptamers are available. Graphical abstract Gold nanoparticle (AuNP) enhanced hybridization chain reaction is reported to improve the sensitivity of electrochemical immunosensor. Hybridization chain reaction is carried out by annealing of H1 DNA strand immobilized on AuNP to the sticky end primer sequence of the aptamer and H2 strand to the complementary sequence of H1.

Intrauterine infection with plasmid-free Chlamydia muridarum reveals a critical role of the plasmid in chlamydial ascension and establishes a model for evaluating plasmid-independent pathogenicity.

Intravaginal infection with plasmid-competent but not plasmid-free Chlamydia muridarum induces hydrosalpinx in mouse upper genital tract, indicating a critical role of the plasmid in chlamydial pathogenicity. To evaluate the contribution of the plasmid to chlamydial ascension and activation of tubal inflammation, we delivered plasmid-free C. muridarum directly into the endometrium by intrauterine inoculation. We found that three of the six mouse strains tested, including CBA/J, C3H/HeJ, and C57BL/6J, developed significant hydrosalpinges when 1 × 10(7) inclusion-forming units (IFU) of plasmid-free C. muridarum were intrauterinally inoculated. Even when the inoculum was reduced to 1 × 10(4) IFU, the CBA/J mice still developed robust hydrosalpinx. The hydrosalpinx development in CBA/J mice correlated with increased organism ascension to the oviduct following the intrauterine inoculation. The CBA/J mice intravaginally infected with the same plasmid-free C. muridarum strain displayed reduced ascending infection and failed to develop hydrosalpinx. These observations have demonstrated a critical role of the plasmid in chlamydial ascending infection. The intrauterine inoculation of the CBA/J mice with plasmid-free C. muridarum not only resulted in more infection in the oviduct but also stimulated more inflammatory infiltration and cytokine production in the oviduct than the intravaginal inoculation, suggesting that the oviduct inflammation can be induced by plasmid-independent factors, which makes the hydrosalpinx induction in CBA/J mice by intrauterine infection with plasmid-free C. muridarum a suitable model for investigating plasmid-independent pathogenic mechanisms.

Nexrutine inhibits cancer cell growth as a consequence of mitochondrial damage and mitophagy.

BACKGROUND/AIMS: Nexrutine is an herbal extract of Phellodendron amurense and has been used as nutrient supplement in China as well as America. Potential protection effect of Nexrutine has been reported. METHODS: To investigate the mechanism of Nexrutine, we used the HeLa, U2OS and HCT116 as a model. Based on the acidification of cell culture media, we examined the lactate, mitochondria damage as well as mitophagy status by corresponding assay. RESULTS: Our data suggest that Nexrutine alters the cellular glucose metabolism to promote lactate production. This effect is caused by mitochondrial damage, not an alteration to lactate dehydrogenase activity. As a result of the mitochondrial damage, cell proliferation was inhibited and was associated with an elevation in p21/p27 proteins, which are both important cell cycle inhibitors. As another consequence of the mitochondrial damage, mitophagy was highly activated in Nexrutine-treated cells in a dose-dependent manner. When the autophagy pathway was blocked by siRNAs against BECN1 or ATG7, the growth inhibition caused by Nexrutine was reversed. CONCLUSION: Our study revealed that autophagy plays an important role in the inhibition of cancer cell proliferation by Nexrutine.

Serum screening in first trimester to predict pre-eclampsia, small for gestational age and preterm delivery: systematic review and meta-analysis.

BACKGROUND: Early assessment before the establishment of placental dysfunction has the potential to improve treatment and prognosis for clinical practice.The objective of the study is to investigate the accuracy of serum biochemical markers(Pregnancy- Associated Plasma Protein-A (PAPP-A), human Chorionic Gonadotropin (hCG), Placental Growth Factor (PlGF), Placental Protein 13 (PP13) used in first trimester serum screening in predicting preelampsia, small for gestational age (SGA) and preterm delivery. METHODS: The data sources included Medline, Embase, Cochrane library, Medion, hand searching of relevant journals, reference list checking of included articles and contact with experts. Two reviewers independently selected the articles. Two authors independently extracted data on study characteristics, quality and results. RESULTS: The results showed low predictive accuracy overall. For preeclampsia, the best predictor was PlGF; LR + 4.01 (3.74, 4.28), LR-(0.67, 0.64, 0.69). The predictive value of serum markers for early preeclampsia was better than that of late preeclampsia. For SGA the best predictor was PP13; LR+ 3.70 (3.39, 4.03), LR- 0.70 (0.67, 0.73). For preterm delivery, the best predictor was PP13; LR+ 4.16 (2.72, 5.61), LR- 0.56 (0.45, 0.67). CONCLUSION: First trimester screening analytes have low predictive accuracy for pre-eclampsia, small for gestational age and preterm delivery. However, the predict value of first trimester analytes is not worse than that of the second trimester markers.

Exploration of the successful treatment algorithms used in 23 cases of early live cesarean scar pregnancy.

Without timely discovery and treatment, early live cesarean scar pregnancy (CSP) can cause hemorrhage, uterine rupture or excision, and in extreme cases, loss of fertility or death. This study explored the significance of early diagnosis and treatment algorithms for early live CSP. Twenty-three patients with early live CSP who were hospitalized at the Second Xiangya Hospital of Central South University from June 2012 to July 2013 were retrospectively analyzed. The patients were selected according to the number of days since the last menstrual period, the color Doppler ultrasound results, the ß-HCG values, and the thickness of the lower uterine myometrium. Ultrasound-guided evacuation and Foley balloon compression hemostasis were conducted directly in the lower uterine segment to stop the bleeding. All 23 patients were cured, and their uteri and fertility were conserved. Timely and proper treatment algorithms can yield satisfactory outcomes in the treatment of CSP.

Reduced live organism recovery and lack of hydrosalpinx in mice infected with plasmid-free Chlamydia muridarum.

Plasmid-free Chlamydia trachomatis and Chlamydia muridarum fail to induce severe pathology. To evaluate whether the attenuated pathogenicity is due to insufficient infection or inability of the plasmidless chlamydial organisms to trigger pathological responses, we compared plasmid-competent and plasmid-free C. muridarum infections in 5 different strains of mice. All 5 strains developed hydrosalpinx following intravaginal inoculation with plasmid-competent, but not inoculation with plasmid-free, C. muridarum. The lack of hydrosalpinx induction by plasmid-free C. muridarum correlated with significantly reduced live organism recovery from the lower genital tract and shortened infection in the upper genital tract. The plasmid-free C. muridarum organisms failed to induce hydrosalpinx even when the organisms were directly inoculated into the oviduct via an intrabursal injection, which was accompanied by significantly reduced survival of the plasmidless organisms in the genital tracts. Furthermore, plasmid-competent C. muridarum organisms after UV inactivation were no longer able to induce hydrosalpinx even when directly delivered into the oviduct at a high dose. Together, these observations suggest that decreased survival of and shortened infection with plasmid-free C. muridarum may contribute significantly to its attenuated pathogenicity. We conclude that adequate live chlamydial infection in the oviduct may be necessary to induce hydrosalpinx.

Elevated serum chemerin in Chinese women with hyperandrogenic PCOS.

OBJECTIVES: To compare serum chemerin levels between women with classic hyperandrogenic PCOS, euandrogenic PCOS and matched control subjects. RESEARCH DESIGN AND METHODS: This study was carried out at the Second XiangYa Hospital between July 2012 and April 2013. Sixty-seven women with PCOS and 20 controls were included. Blood pressure, body mass index (BMI), waist to hip ratio (WHR), fasting insulin, fasting plasma glucose and blood serum hormone and blood lipid were measured. Transvaginal ultrasound was performed. Serum chemerin was measured by ELISA. RESULTS: Serum chemerin was significantly higher in classic hyperandrogenic PCOS compared with euandrogenic PCOS and controls (311.07 ± 141.87 ng/mL versus 228.03 ± 119.66 ng/mL and 225.87 ± 86.44 ng/mL, p < 0.05). Serum chemerin was positively related to follicle count, ovarian volume, the level of testosterone, luteinizing hormone/follicle-stimulating hormone, low-density lipoprotein, triglycerides, fasting blood insulin, insulin resistance by homeostasis model assessment, WHR and BMI, while negatively related to the level of high-density lipoprotein. Multiple linear regression analyses revealed ovarian volumes and WHR were the significant influencing factors of chemerin (p < 0.05). The area under the receiver operating characteristic curve for chemerin reached a value of 0.684 (0.572-0.796, 95% confidence interval). The best compromise between sensitivity (80.0%) and specificity (47.6%) was obtained with a cutoff value of 200.94 ng/mL. CONCLUSIONS: Serum chemerin level was increased in Chinese women with classic hyperandrogenic PCOS. Serum chemerin measurement offers a relatively moderate diagnostic potency with a sensitivity of 80.0% and a specificity of 47.6% at 200.94 ng/mL. This suggested that chemerin may be involved in the development of the metabolic syndrome of classic PCOS.

Impaired fetal myocardial deformation in intrahepatic cholestasis of pregnancy.

OBJECTIVES: To investigate changes in fetal myocardial deformation in intrahepatic cholestasis of pregnancy. METHODS: Patients with intrahepatic cholestasis of pregnancy were divided into 2 groups according to the total maternal serum bile acid concentration: mild cholestasis (10-40 µmol/L) and severe cholestasis (>40 µmol/L). Fetal echocardiography and velocity vector imaging were performed on women with cholestasis and control patients. The left ventricular global longitudinal strain and strain rate were measured. Clinical characteristics, maternal serum bile acid levels, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in umbilical vein blood were compared between groups. The relationships among fetal myocardial deformation, maternal total bile acids, and cord NT-proBNP were analyzed. RESULTS: Twenty women with mild cholestasis, 20 with severe cholestasis, and 40 control patients were enrolled. There were no significant differences in maternal and gestational ages between the case and control groups. Maternal bile acids and NT-proBNP were significantly higher in fetuses of mothers with cholestasis than control fetuses. The left ventricular longitudinal strain (-10.56% ± 1.83% versus -18.36% ± 1.11%; P < .01), systolic strain rate (-1.63 ± 0.18 versus -2.04 ± 0.18 secondsz(-1); P < .01), and diastolic strain rate (1.37 ± 0.18 versus 1.83 ± 0.14 seconds(-1); P < .01) were significantly decreased in fetuses with severe cholestasis compared with control fetuses. There were positive correlations between fetal myocardial deformation and maternal total bile acids (r = 0.705, 0.643, and 0.690, respectively; P < .01) and between myocardial deformation and NT-proBNP (r = 0.672, 0.643, and 0.647; P < .01). CONCLUSIONS: Fetal myocardial deformation is impaired in severe intrahepatic cholestasis of pregnancy. Further investigation is needed to determine whether fetal echocardiography and velocity vector imaging can help predict which fetuses of mothers with cholestasis are likely to have poor outcomes.

Post-marketing safety concerns of sotorasib: A disproportionality analysis based on FDA adverse event reporting system.

Background: Sotorasib has been approved for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Due to the limitations of clinical trials, potential adverse events (AEs) and long-term safety issues cannot be detected. The presented study aimed to evaluate sotorasib-associated AEs using the FDA Adverse Event Reporting System (FAERS) database. Methods: Post-marketing AE reports of sotorasib in the database were collected for analysis. Disproportionality analyses, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC) and empirical bayes geometric mean (EBGM) algorithms, were performed to mine the signals of sotorasib-associated AEs. The median duration, quartiles and the Weibull shape parameter (WSP) test were used to assess the onset time data. Results: The database contained 1538 cases of sotorasib as primary suspect (PS), with 27 signals detected, scattering in 5 SOCs. The SOC of hepatobiliary disorders (182, ROR 4.48, PRR 4.07, IC 2.02, EBGM 4.07) met the four methodological thresholds. The median onset time of sotorasib-associated AEs was 42 days (interquartile range [IQR] 14-86.75 days). Different SOCs had different types of risk over time. Conclusion: After obtaining marketing authorization, the study identified all potentially relevant adverse event (AE) signals expected to have a reporting frequency higher than anticipated and characterized them during sotorasib treatment.

[Effect of corticotrophin-releasing hormone on connexin-43 phosphorylation and gap junction intercellular communication in human myometrial smooth muscle cells].

OBJECTIVE: To determine the effect of human corticotrophin-releasing hormone (CRH) on the expression of connexin-43 phosphate (P-Cx43) in human myometrial smooth muscle cells (SMCs) and the function of cell gap junction intercellular communication in SMCs. METHODS: Human non-conceive myometial SMCs were cultured with different concentrations of CRH (0, 5.85, 58.5, 585 and 5850 pmol/L). Western blot was used to test P-Cx43 and Cx43 non-phosphate (NP-Cx43) of protein expression. Cell scratch was used to test cell gap junction intercellular communication opening status in human myometrial SMCs. RESULTS: Compared with the control group, the expression of P-Cx43 was higher in the CRH groups (P<0.01), and was concentration-dependent. There was no significant difference in NPCx43 between the control group and the CRH groups (P>0.05). The transmission of cell layers in the CRH groups was higher than that in the control group (P<0.01), and as the concentration of CRH increased, the time was concentration-dependent (P<0.01). CONCLUSION: CRH can enhance the expression of P-Cx43 and the function of gap junction intercellular communication in the primary cultured myometrial SMCs.