Comprehensive machine learning-based preoperative blood features predict the prognosis for ovarian cancer.

PURPOSE: Significant advancements in improving ovarian cancer (OC) outcomes have been limited over the past decade. To predict prognosis and improve outcomes of OC, we plan to develop and validate a robust prognosis signature based on blood features. METHODS: We screened age and 33 blood features from 331 OC patients. Using ten machine learning algorithms, 88 combinations were generated, from which one was selected to construct a blood risk score (BRS) according to the highest C-index in the test dataset. RESULTS: Stepcox (both) and Enet (alpha = 0.7) performed the best in the test dataset with a C-index of 0.711. Meanwhile, the low RBS group possessed observably prolonged survival in this model. Compared to traditional prognostic-related features such as age, stage, grade, and CA125, our combined model had the highest AUC values at 3, 5, and 7 years. According to the results of the model, BRS can provide accurate predictions of OC prognosis. BRS was also capable of identifying various prognostic stratifications in different stages and grades. Importantly, developing the nomogram may improve performance by combining BRS and stage. CONCLUSION: This study provides a valuable combined machine-learning model that can be used for predicting the individualized prognosis of OC patients.

Isolation and proteomic profiling of urinary exosomes from patients with colorectal cancer.

Exosomes in the body fluid are effective cell-derived membranous structures transferring various molecules to mediate intercellular communication. The expression of protein in the urinary exosomes from the colorectal cancer (CRC) patients could reflect the characteristics of tumorigenesis. The urinary exosomes with globular membrane structure, the size of 30 ~ 100 nm and positive expression of CD9, CD63 and CD81 were successfully isolated from 9 CRC patients and 3 heathy adults using the density gradient ultracentrifugation. Proteome profiles revealed by label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) indicated that several proteins were differentially expressed among different stages of CRC. Compared with normal controls, 67 proteins in CRC urinary exosomes were upregulated and 74 proteins were downregulated. The bioinformatics analysis revealed the decreased proteins were related to ESCRT III complex disassembly. The CHMP family was further determined to be the hub of interaction network of proteins enriched in ESCRT signaling. The significant decrease of CHMP4A, CHMP4B, CHMP2A, CHMP2B and CHMP1B were respectively found in the total CRC group and distant metastasis group compared with NC group. Moreover, the CEACAM family also showed significant aberrant changes in the urinary exosomes of CRC patients. The CEACAM7 and CEACAM1 were increased in the CRC patients compared with healthy individuals (P < 0.05). Significant changes of proteomic profile could be found in the urinary exosomes in the CRC patients. The differential expressed urinary exosomes derived proteins showed potential usage in diagnosis and prognosis of CRC.

Effect of low dose aspirin application during pregnancy on fetal congenital anomalies.

BACKGROUND: With the extensive use of aspirin in obstetrics and reproductive medicine, concerns of potentially related congenital anomalies have been raised in previous studies. However, there is a lack of evidence concerning the safety of application of aspirin during pregnancy in Chinese population, especially during the first trimester. PATIENTS AND METHODS: We retrospectively included a total of 2,763 patients with 2,856 fetuses (2670 singleton births and 93 pairs of twins), among whom 1,684 took low dose aspirin (LDA) during pregnancy (the LDA group) and the other 1,079 were not exposed to LDA (the control group). The primary outcome was the rate of fetal congenital anomalies, and was compared between the LDA group and the control group. We also conducted logistic regression to examine the potential risk factors of congenital abnormalities. RESULTS: The average daily dose of LDA taken was 67.6 mg. The rate of congenital anomalies was comparable between the two groups, suggesting low teratogenicity of LDA application during pregnancy (3.3% vs. 2.8%; P = 0.421). The duration of LDA exposure and the time of LDA exposure showed no association with congenital anomalies. A previous history of fetal congenital anomalies was associated with an increased risk of the recurrence of congenital anomalies in the siblings (adjusted OR = 3.00, 95% CI: 1.00-8.60; P = 0.041). CONCLUSION: Exposure to LDA during pregnancy did not increase the risk of congenital anomalies in the fetus, suggesting that it was safe to apply LDA during pregnancy. A history of previous fetal abnormalities was found to be an independent risk factor of congenital anomalies. Our study suggests that LDA can be safely applied during pregnancy without increasing risks of congenital anomalies.

Effect of early inflammatory reaction on ovarian reserve after laparoscopic cystectomy for ovarian endometriomas.

This study aimed to investigate the effect of early inflammatory reaction on ovarian reserve of patients with ovarian endometriomas after laparoscopic cystectomy. Our retrospective case series included 112 patients with ovarian endometriomas that underwent the laparoendoscopic single-site cystectomy. Interleukin-6 (IL-6), hs-CRP, tumour necrosis factor-α (TNF-α), interleukin-17A (IL-17A) and AMH level were detected during perioperative and postoperative period. In our study, ovarian endometriomas with low AMH group were found having higher level of IL-6 than the normal AMH group in the preoperative status. On the 3rd day after operation, the change of AMH level was inversely proportional to the IL-6 level. During the follow-up within one year, it was found that the bilateral nature of the cyst and the postoperative IL-6 increased level were the risk factors for AMH not returning to baseline level. Our results suggested that inflammatory reaction is indeed involved in the damage of ovarian reserve during laparoscopic cystectomy. Hence, the negative impact of inflammatory injury should be fully considered before operation, especially young women with bilateral ovarian endometriomas.Impact StatementWhat is already known on this subject? Ovarian reserve in women always was reduced after the laparoscopic cystectomy. It is reported that it may be related to the use of energy instruments, haemostatic methods or the size of cysts in minimally invasive surgery.What do the results of this study add? Inflammatory reaction is indeed involved in the damage of ovarian reserve during LESS cystectomy. Interleukin-6 (IL-6) may act as the most main inflammatory factor aggravating damage of the ovarian reserve. Moreover, increased IL-6 level after surgery and bilateral cyst burden are the two risk factors for AMH not returning to baseline level within one year after surgery.What are the implications of these findings for clinical practice and/or further research? In clinic, the negative impact of inflammatory injury on ovarian reserve should be fully considered before operation, especially young women with bilateral ovarian endometriomas. Moreover, this is also the clinical basis for further study on the mechanism of inflammatory ovarian injury or the method of blocking the inflammatory response to reduce the damage of ovarian reserve after surgery.

Estrogen-induced FOS-like 1 regulates matrix metalloproteinase expression and the motility of human endometrial and decidual stromal cells.

The regulation mechanisms involved in matrix metalloproteinase (MMP) expression and the motility of human endometrial and decidual stromal cells (ESCs and DSCs, respectively) during decidualization remain unclear. DSCs show significant increased cell motility and expression of FOS-like 1 (FOSL1) and MMP1, MMP2, and MMP9 compared with ESCs, whereas lack of decidualization inducers leads to a rapid decrease in FOSL1 and MMP1 and MMP9 expression in DSCs in vitro Therefore, we hypothesized that a link exists between decidualization inducers and FOSL1 in up-regulation of motility during decidualization. Based on the response of ESCs/DSCs to different decidualization systems in vitro, we found that progesterone (P4) alone had no significant effect and that 17ß-estradiol (E2) significantly increased cell motility and FOSL1 and MMP1 and MMP9 expression at the mRNA and protein levels, whereas 8-bromo-cAMP significantly decreased cell motility and FOSL1 and MMP9 expression in the presence of P4. In addition, we showed that E2 triggered phosphorylation of estrogen receptor 1 (ESR1), which could directly bind to the promoter of FOSL1 in ESCs/DSCs. Additionally, we also revealed silencing of ESR1 expression by siRNA abrogated E2-induced FOSL1 expression at the transcript and protein levels. Moreover, silencing of FOSL1 expression by siRNA was able to block E2-induced MMP1 and MMP9 expression and cell motility in ESCs/DSCs. Taken together, our data suggest that, in addition to its enhancement of secretory function, the change in MMP expression and cell motility is another component of the decidualization of ESCs/DSCs, including estrogen-dependent MMP1 and MMP9 expression mediated by E2-ESR1-FOSL1 signaling.

Effect of low-molecular-weight heparins on anti-Xa peak levels and adverse reactions in Chinese patients with recurrent spontaneous abortion: a single-center, observational study.

OBJECTIVE: To compare three commonly used low-molecular-weight heparins (LWMHs) in the treatment of recurrent spontaneous abortion (RSA) by evaluating the anti-Xa peak levels and adverse reactions. METHODS: In this single-center, observational study, we enrolled 310 patients with RSA in whom anti-Xa levels were measured during pregnancy. Patients were divided into three groups according to the LMWH they used: the nadroparin group, enoxaparin group and dalteparin group. We compared the peak anti-Xa levels and the coagulation status of each group, and analyzed the incidence of adverse reactions, including local allergy, liver and renal dysfunction, and the impact on platelet. RESULTS: Patients in the enoxaparin group had a higher anti-Xa peak level than those in the nadroparin group (0.80 ± 0.22 IU/ml vs. 0.61 ± 0.24 IU/ml; P <  0.0001), although most patients in the three groups reached the target concentration of anti-Xa. Furthermore, patients in the enoxaparin group had a more stable anti-Xa levels during pregnancy. In addition, patients in the nadroparin group had a higher rate of local allergy than those in the enoxaparin group (60.5% vs. 42.5%; P = 0.004) and those in the dalteparin group (60.5% vs. 33.3%; P = 0.002). Further examination by the type of local allergy indicated a dramatic difference in pruritus and induration between the nadroparin group and the other two groups. No difference was found in the incidence of liver and renal dysfunction and thrombocytopenia. CONCLUSION: Compared with nadroparin and daltepatin, enoxaparin showed a better performance regarding anti-Xa levels and the incidence of adverse reactions in the treatment of RSA.

The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3.

The B7-CD28 family of ligands and receptors play important roles in T-cell co-stimulation and co-inhibition. Phylogenetically they can be divided into three groups. The recent discovery of the new molecules (B7-H3 [CD276], B7x [B7-H4/B7S1], and HHLA2 [B7H7/B7-H5]/TMIGD2 [IGPR-1/CD28H]) of the group III has expanded therapeutic possibilities for the treatment of human diseases. In this review, we describe the discovery, structure, and function of B7-H3, B7x, HHLA2, and TMIGD2 in immune regulation. We also discuss their roles in important pathological states such as cancers, autoimmune diseases, transplantation, and infection. Various immunotherapeutical approaches are emerging including antagonistic monoclonal antibodies and agonistic fusion proteins to inhibit or potentiate these molecules and pathways in cancers and autoimmune diseases.

Decidua-derived granulocyte macrophage colony-stimulating factor induces polymorphonuclear myeloid-derived suppressor cells from circulating CD15+ neutrophils.

STUDY QUESTION: Do decidua-derived factors stimulate the conversion of circulating neutrophils to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in early human pregnancy? SUMMARY ANSWER: Circulating neutrophils can acquire PMN-MDSC-like phenotypes and function via phosphorylated signal transducer and activator of transcription 5/programmed death ligand 2 (pSTAT5/PD-L2) signalling after stimulation with decidua-derived granulocyte macrophage colony-stimulating factor (GM-CSF). WHAT IS KNOWN ALREADY: PMN-MDSCs are an important immunoregulatory cell type in early pregnancy. Neutrophils are of high heterogeneity and plasticity and can polarize to immunosuppressive PMN-MDSCs upon stimulation. STUDY DESIGN, SIZE, DURATION: For analysis of myeloid-derived suppressor cell (MDSC) subset proportions, 12 endometrium tissues and 12 peripheral blood samples were collected from non-pregnant women, and 40 decidua tissues and 16 peripheral blood samples were obtained from women with normal early pregnancy undergoing elective surgical pregnancy termination for nonmedical reasons with gestation age of 6-10 weeks. Twenty-nine decidua tissues were collected for isolation of CD15+ PMN-MDSCs. Twenty endometrium tissues and 30 decidua tissues were collected for cytokine analysis, immunohistochemistry or neutrophil stimulation. Peripheral blood samples were obtained from 36 healthy donors for isolation of CD3+ T cells and CD15+ neutrophils. PARTICIPANTS/MATERIALS, SETTING, METHODS: The proportion of MDSC subsets in the decidua and peripheral blood of normal early pregnancy, endometrium and peripheral blood of non-pregnant women was analysed by flow cytometry. The phenotypes and function of decidual PMN-MDSCs and circulating neutrophils were compared by flow cytometry. Circulating neutrophils were stimulated with decidual explant supernatant (DES) and the phenotypes were measured by flow cytometry and immunofluorescence. The suppressive capacity of decidual PMN-MDSCs and DES-conditioned neutrophils was analysed by flow cytometry with or without anti-programmed cell death-1 (PD-1) antibody. Cytokines from DES and endometrial explant supernatant (EES) were detected by a Luminex assay. GM-CSF expression was determined by ELISA and immunohistochemistry. Neutrophils were stimulated with DES, EES, DES with anti-GM-CSF antibody or EES with GM-CSF. CD11b, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), PD-L2 and pSTAT5 expression were measured by flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE: The frequency of PMN-MDSCs was significantly increased in the decidua of early pregnancy compared with peripheral blood of non-pregnant women, the endometrium of non-pregnant women or peripheral blood during early pregnancy. Decidual PMN-MDSCs suppressed T-cell proliferation and cytokine production. Phenotypes of decidual PMN-MDSCs were similar to mature activated neutrophils. DES-induced CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation in neutrophils. The PD-L2 expression in neutrophils was dependent on STAT5 phosphorylation. Both decidual PMN-MDSCs and DES-conditioned neutrophils suppressed T-cell proliferation via PD-1 signalling. GM-CSF was up-regulated in the decidua and induced CD11b, LOX-1 and PD-L2 expression on neutrophils. DES significantly induced CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation. Anti-GM-CSF antibody remarkably blocked such stimulation in neutrophils. EES did not induce CD11b, LOX-1, PD-L2 expression or STAT5 phosphorylation, while GM-CSF treatment sufficiently stimulated CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation in neutrophils. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The study was based on in vitro experiments and we were not able to evaluate neutrophils differentiation to PMN-MDSCs in other sites before entering the maternal-foetal interface due to the limited availability of human samples. This needs to be explored using murine models. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study demonstrating that decidual PMN-MDSCs are a group of immunoregulatory cells with mature status, and that neutrophils can be induced to a PMN-MDSC-like phenotype with decidua-derived GM-CSF via pSTAT5/PD-L2 signalling. This study indicates that GM-CSF can facilitate immune tolerance of early pregnancy through regulating PMN-MDSCs and further provides a potential role of GM-CSF in prevention and treatment for pregnancy complications. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (81671481) and National Natural Science Foundation of China (81871179). All authors have no competing interests to declare.

Application value of Caprini risk assessment model and elevated tumor-specific D-dimer level in predicting postoperative venous thromboembolism for patients undergoing surgery of gynecologic malignancies.

AIM: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in gynecologic malignant patients after surgery. We aimed to validate the Caprini risk assessment model (RAM) and elevated tumor-specific D-dimer as predictive marker of postoperative VTE for patients undergoing surgery of gynecologic malignancies. METHODS: Inpatients were divided into five groups (low: score = 0-1; moderate: score = 2; high: score = 3-4; higher: score = 5-7; sup-high: score > 7) and treated according to their risk level after the surgery during the hospitalization according to the Caprini RAM. D-dimer level was detected during the perioperative period. If D-dimer did not fall to normal reference range on the seventh day after operation, the use of low-molecular-weight heparin was prolonged to 28 days after surgery. RESULTS: The majority (853/974, 87.6%) of the patients was in the Caprini score ≥5, with an overall VTE incidence of 1.75%. The VTE group had significantly higher Caprini score, CA125, vascular invasion rate and lymph node metastasis rate. If 1.5 µg/mL was used as the D-dimer cut-off value to predicting VTE, the sensitivity was 87.5%, the specificity was 93.8% and the negative predictive value was 99.2%. The D-dimer level was a marker for prolonging the anticoagulants use during the perioperative period, especially for the sup-high group. CONCLUSION: The Caprini RAM is an effective and reliable VTE risk prediction tool for patients undergoing gynecological malignant tumor surgery. The group (score ≥ 5) can be divided into two subgroups (higher: score = 5-7 and sup-high: score > 7), which may better predict the occurrence of VTE for malignant tumor patients. Great than 1.5 µg/mL D-dimer before operation should be given more attention for the presence of VTE.

Prevalence of depression and anxiety in women with recurrent pregnancy loss and the associated risk factors.

OBJECTIVE: To investigate the prevalence and explore potential risk factors of depression and anxiety in patients with recurrent pregnancy loss (RPL). METHODS: 1138 non-pregnant women aged 20-40 years old who attempted to conceive were invited to complete a questionnaire, including basic information, Self-Rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS). RESULTS: 782 RPL women, 218 women with one pregnancy loss and 138 women with no history of pregnancy loss were included in this study. We found that both RPL patients and women with one pregnancy loss had significantly higher SDS and SAS scores than the control group (P = 0.006, 0.003). Furthermore, in RPL patients, those with lower education level (lower than university), lower household income (< 10,000 yuan) and history of induced abortion had significantly higher levels of depression and anxiety. Women with multiple pregnancy losses ( ≥ 3) and no live birth had significantly higher SDS scores. Women who had been married for 3 years or more had a significantly higher SAS score. Logistic regression revealed that lower education level (lower than university) was an independent risk factor for depression (adjusted OR = 1.75, 95% CI 1.10-2.77, P = 0.018) and anxiety (adjusted OR = 1.80, 95% CI 1.04-3.13, P = 0.037), and women with three or more pregnancy losses had increased odds of depression than those with two pregnancy losses (adjusted OR = 1.82, 95% CI 1.15-2.88, P = 0.012). CONCLUSION: RPL patients are more likely to develop depression and anxiety than women with no history of pregnancy loss. Lower education level and multiple pregnancy losses (≥ 3) appear to be two independent risk factors of depression and anxiety in women with RPL. Women with one pregnancy loss also show a significant higher level for depression and anxiety. Appropriate psychological intervention can be considered for such patients.

Study on the Association between the Fibroblast Growth Factor Receptor 4 Expression and High-Risk Human Papillomavirus Infection in Cervical Cancer and Precancerous Lesions.

AIMS: To discuss the correlation between the expression of fibroblast growth factor receptor 4 (FGFR4) and human papillomavirus (HPV) infection in cervical cancer and precancerous lesions. METHODS: One hundred and sixty four cases of cervical lesions tissue samples were collected (60 cases of cervical cancer, 38 cases of cervical intraepithelial neoplasia [CIN] stage I, 32 cases of CIN II, 34 cases of CIN III). HPV infection status and expression strength of FGFR4 of all samples were detected and compared among different groups. The correlation between the HPV infection and the expression strength of FGFR4 was analyzed. RESULTS: There were differences of the HPV infection status and type distribution and FGFR4 expression strength among the 4 groups; The infection rate of high-risk HPV in cervical cancer group was higher than that of the 3 CIN groups. The FGFR4 positive expression rate of the cervical cancer group was also obviously higher than that of the 3 CIN groups; HPV infection was correlated with the FGFR4 expression strength and the FGFR4 expression was stronger when infected with high-risk type HPV. CONCLUSION: The expression of FGFR4 in the cervical cancer and CIN tissues was correlated with the HPV infection and the FGFR4 may be involved in the development of the HPV-infected cervical lesions.

Aryl hydrocarbon receptor and unexplained miscarriage.

AIM: The aim of this study was to carry out a preliminary investigation of the expression of aryl hydrocarbon receptor (AhR) in decidua and villus and the relationship between AhR and unexplained miscarriage. METHODS: The expression of AhR mRNA and protein from decidua and villus were measured using real-time reverse transcription-polymerase chain reaction, western blot and immunohistochemistry in 34 patients with unexplained miscarriage (miscarriage group) and 38 women with normal early pregnancy (control group). RESULTS: The AhR mRNA and protein expression was increased significantly in the villus in both groups compared with decidua (P < 0.05, P < 0.05). In decidua, AhR mRNA and protein expression in the miscarriage group was increased significantly compared with the control group (P < 0.05, P < 0.05). In villus, AhR mRNA and protein expression in the miscarriage group was increased significantly compared with the control group (P < 0.05, P < 0.05). AhR is expressed mostly in the cytoplasm of syncytiotrophoblasts in villus, and also in the cytoplasm of decidual cells. CONCLUSIONS: AhR was expressed more in the villus than in the decidua, and the upregulation of AhR mRNA and protein expression is associated with the pathogenesis of unexplained miscarriage.

Macrophage depletion and TNF-α inhibition prevent resorption in CBA/J × DBA/2 model of CpG-induced abortion.

OBJECTIVE: To elucidate the mechanism by which embryo-resorption was enhanced by pathogenic CpG ODN motif in abortion-prone CBA/J × DBA/2 model and to develop a counter strategy for normal pregnancy outcome. METHODS: This is an animal model-based study. Abortion-prone model is established by CBA/J × DBA/2. An infection was mimicked by CpG ODN injection. RESULTS: Embryo-resorption was readily induced by CpG ODN in low doses of CpG ODN (∼25 µg/dam) when intraperitoneally (IP) injected on gestational day(gd) 6.5 in male DBA/2 mated CBA/J female mice. A more modest decline in Progesterone(P4), but not Estrogen(E2) was observed after exposure to CpG ODN in the model. P4 supplement fail to improve pregnancy outcomes, even at pharmocology dose. CpG ODN-induced fetal resorption is prevented by the treatment of anti-F4/80 or by that of anti-TNFα.In the implantation sites, the treatment of anti-F4/80 inhibits the increase both of F4/80(+) macrophage proportion and TNF-αexpression level which are induced by CpG ODN. The anti-TNFαtreatment also recovers CpG ODN-induced reduction of CD4(+)Foxp3(+) T cells. CONCLUSION: Circulating P4 is not responsible for the process by which CpG ODN-induced embryonic resorption in an abortion-prone mice. Macrophage depletion and TNF-α inhibition are really noteworthy for CpG ODN-induced pregnancy disruption.

Granulocytic myeloid-derived suppressor cells maintain feto-maternal tolerance by inducing Foxp3 expression in CD4+CD25-T cells by activation of the TGF-ß/ß-catenin pathway.

STUDY HYPOTHESIS: The transforming growth factor (TGF)-ß/ß-catenin pathway is involved in granulocytic myeloid-derived suppressor cell (G-MDSCs)-induced Foxp3 expression in CD4(+)CD25(-)T cells, which plays an essential role in maintaining feto-maternal tolerance. STUDY FINDING: Decidual G-MDSCs play an important role in promoting Foxp3 induction in CD4(+)CD25(-)T cells, which is dependent on TGF-ß/ß-catenin pathway. WHAT IS KNOWN ALREADY: MDSCs contribute to the observed increase in regulatory T cells in animal cancer models. The TGF-ß/ß-catenin pathway is required for T cell development and survival. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: MDSC levels in deciduas from patients undergoing elective termination of pregnancy or spontaneous abortion were assessed by flow-cytometric analysis. The best characterized markers of G-MDSCs cells were examined by immunocytochemistry and flow-cytometric analysis. In vivo, fetus resorption and proportion of decidual immune cells were evaluated after depletion of G-MDSCs. In vitro, we established an antigen-non-specific (CD3/CD28) CD4(+)CD25(-)T and G-MDSC co-culture system and added TGF-ß, anti-TGFß, TGF-ß plus anti-TGFß or ß-catenin inhibitor ICG001 to the system. Protein levels were measured by western blot. MAIN RESULTS AND THE ROLE OF CHANCE: G-MDSCs showed a significant decrease in spontaneous abortion compared with elective abortion in women with normal pregnancy (P < 0.01), whereas the numbers of monocytic MDSCs remained unchanged. The dynamics of G-MDSCs in mice revealed that few G-MDSCs were present in non-pregnant uteri. G-MDSCs expanded rapidly in CBA/J×BALB/c mice with normal pregnancy and decreased in CBA/J×DBA/2 mice with abortion-prone pregnancy. G-MDSCs were characterized by the expression of CD115, CD117, CD135, CD62L, CCR2, MHCII, CD80, Arginase I and iNOS, and a lack of F4/80 or CD11c expression. Specifically, depletion of G-MDSCs-induced severe embryo resorption and decreased the percentage of CD4(+)CD25(+)Foxp3(+)T cells. In vitro, G-MDSCs had an important role in promoting Foxp3 induction in CD4(+)CD25(-)T cells, dependent on TGF-ß/ß-catenin pathway. LIMITATIONS, REASONS FOR CAUTION: It is not sufficient to examine the role of G-MDSCs in the maintenance of maternal-fetal tolerance by depleting G-MDSCs using neutralizing antibody. Further studies are needed to establish an animal model of G-MDSCs in order to elucidate their exact role at the maternal-fetal tolerance. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide novel insights into a new function and mechanism of action for G-MDSCs in mediating feto-maternal immune tolerance. LARGE-SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: This research was supported by the National Natural Science Foundation of China (Grant No. 81270715; 91442113). The authors have nothing to disclose.

Effect of Low-Dose Aspirin on Midluteal Phase Uterine Artery Blood Flow in Patients With Recurrent Pregnancy Loss.

OBJECTIVES: The purpose of this study was to evaluate differences in uterine artery blood flow parameters and pregnancy outcomes, if any. An investigation was conducted to determine the effects of low-dose aspirin on uterine artery blood flow indices in patients with recurrent pregnancy loss. METHODS: This observational study included 353 Chinese women with a history of recurrent pregnancy loss and 85 women without a history of recurrent pregnancy loss (control group) from Ren Ji Hospital. All patients were scanned transvaginally with transvaginal Doppler sonography 6 to 8 days after ovulation to measure the pulsatility index (PI), resistive index (RI), and systolic-to-diastolic ratio (S/D) of the left and right main uterine arteries. Low-dose aspirin at a dose of 50 mg/d was administered orally in patients with recurrent pregnancy loss for 2 months, and the blood flow indices were measured subsequently. The Student t test was used for analysis of the results, P < .05 was considered significant. RESULTS: The mean PI and S/D of the uterine arteries in the recurrent pregnancy loss group were significantly higher than in the control group. Although not statistically significant, the RI was higher in the recurrent pregnancy loss group than the control group. Moreover, the PI and S/D increased as the number of pregnancy losses increased. Significant enhancements of the PI and S/D were observed in patients with 4 or more consecutive abortions. After low-dose aspirin supplementation, patients with recurrent pregnancy loss showed a highly significant reduction in the PI and S/D. CONCLUSIONS: Uterine blood flow decreased during the luteal phase in patients with recurrent pregnancy loss. Low-dose aspirin induced a reversible increase in uterine blood flow and may be of therapeutic value.

HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function.

T-cell costimulation and coinhibition generated by engagement of the B7 family and their receptor CD28 family are of central importance in regulating the T-cell response, making these pathways very attractive therapeutic targets. Here we describe HERV-H LTR-associating protein 2 (HHLA2) as a member of the B7 family that shares 10-18% amino acid identity and 23-33% similarity to other human B7 proteins and phylogenetically forms a subfamily with B7x and B7-H3 within the family. HHLA2 is expressed in humans but not in mice, which is unique within the B7 and CD28 families. HHLA2 protein is constitutively expressed on the surface of human monocytes and is induced on B cells after stimulation with LPS and IFN-γ. HHLA2 does not interact with other known members of the CD28 family or the B7 family, but does bind a putative receptor that is constitutively expressed not only on resting and activated CD4 and CD8 T cells but also on antigen-presenting cells. HHLA2 inhibits proliferation of both CD4 and CD8 T cells in the presence of T-cell receptor signaling. In addition, HHLA2 significantly reduces cytokine production by T cells including IFN-γ, TNF-α, IL-5, IL-10, IL-13, IL-17A, and IL-22. Thus, we have identified a unique B7 pathway that is able to inhibit human CD4 and CD8 T-cell proliferation and cytokine production. This unique human T-cell coinhibitory pathway may afford unique strategies for the treatment of human cancers, autoimmune disorders, infection, and transplant rejection and may help to design better vaccines.

Ovarian hyperstimulation syndrome in a spontaneous pregnancy with invasive mole.

Spontaneous ovarian hyperstimulation syndrome (sOHSS) is an extremely rare event. Herein, we report a case of severe sOHSS with invasive mole in a 29-year-old woman. In this case the full-blown OHSS developed after evacuation when the serum ß-hCG value was declining. Also noticeable was a very high level of cancer antigen-125. Molecular biology study of the follicle-stimulating hormone (FSHR) gene did not detect exonic mutations, but revealed the presence of c.-29G>A (rs1394205) in the 5'-non-coding region of exon 1. The A307T and S680N polymorphisms of exon 10 of FSHR was Thr307 Asn680. Although sOHSS is a rare entity, clinicians must bear the differential diagnosis of sOHSS in mind if a patient presents with gross ascites and other symptoms of ovarian cancer, which also may be signs of OHSS. Whether the single nucleotide polymorphism rs1394205 affects the level of transcriptional activity of the FSHR gene needs to be studied in the future.

Female third party lymphocytes are effective for immunotherapy of patients with unexplained primary recurrent spontaneous abortion: A retrospective analysis of outcomes.

OBJECTIVES: Allogeneic lymphocytes of paternal origin or supplied by a male third party have been used for the treatment of recurrent spontaneous abortion. Few studies, however, have examined the use of female third party lymphocytes. Our purpose was to determine whether female third party lymphocytes could be used for immunotherapy of women with recurrent spontaneous abortion. METHODS: In this retrospective non-randomised cohort-controlled study, the medical records of patients with three or more spontaneous abortions who received immunotherapy with lymphocytes from their partner, a male third party or a female third party, as well as those who received no immunotherapy, from 1996 to 2012 were reviewed. All patients were negative for mixed lymphocyte culture reaction (MLR)-blocking antibodies. Immunotherapy was performed in 302 patients in two courses, while 53 patients received no immunotherapy. RESULTS: The pregnancy rates in patients who received lymphocytes from their partners, a male third party or a female third party, and in those not immunised, were 85.6%, 87.3%, 89.7%, and 79.3%, respectively (p = 0.523);the live birth rates were 87.3%, 75.8%, 84.6%, and 40.5%, respectively (p < 0.001). CONCLUSIONS: We conclude that female third party lymphocytes can be used for immunotherapy in patients with recurrent spontaneous abortion.

Combined laparoscopy and hysteroscopy vs. uterine curettage in the uterine artery embolization-based management of cesarean scar pregnancy: a retrospective cohort study.

BACKGROUND: The number of cesarean scar pregnancy (CSP) has significantly increased in the recent decade. Although uterine artery embolization (UAE) has been adopted to minimize the blood loss during uterine curettage removing of CSP, massive bleeding and uterine rupture can still be frequently encountered. The aim of this study was to compare the efficacy and safety of a novel combined laparoscopy and hysteroscopy technique with the traditional curettage in removing the conceptus and repairing the incision defect following the UAE management of CSP. METHODS: The CSP patients (n = 58) diagnosed between March 1, 2005 and March 1, 2010 were enrolled in three medical centers in Shanghai, China. All of these patients have undergone intra-arterial methotrexate, UAE and one of the following treatments: combined laparoscopy and hysteroscopy (study group, n = 25) and uterine curettage (control group, n = 33). Their medical records and 2-year outcomes were reviewed. The CSP removal rate, amount of blood loss during the treatment, incision repair rate (note: the post-curettage healing process of the incision defect was seen as a form of natural incision repairing, i.e., the self-repair mode), hospital stay, ß-hCG regression time and postoperative sequelae were compared between two groups. RESULTS: The CSP removal rate in the study group (100%) was significantly higher than that (79%) in the control group (p = 0.024). The average blood loss was 78.0 mL in the study group, which was much less than the 258.5 mL (p = 0.004) in the control group. A satisfactory incision repair rate (96%) was achieved in the study group, while it was 25% (p < 0.001) in the control group. Moreover, the study group had significantly shorter hospital stays (p = 0.043) and ß-hCG regression times (p = 0.033), lower rates of postoperative abdominal pain (p = 0.035) and menstruation abnormalities (p = 0.043). CONCLUSIONS: Combined laparoscopy and hysteroscopy is much safer and more effective than uterine curettage as a supplementary measure to remove the conceptus and repair the cesarean incision following the UAE management of CSP.

Decidual stromal cell-derived exosomes deliver miR-22-5p_R-1 to suppress trophoblast metabolic switching from mitochondrial respiration to glycolysis by targeting PDK4 in unexplained recurrent spontaneous abortion.

INTRODUCTION: Studies have shown that EMT (epithelial-mesenchymal transition) and energy metabolism influence each other, and it is unclear whether the trophoblast energy metabolism phenotype is dominated by glycolysis or mitochondrial respiration, and the relationship between trophoblast energy metabolism and EMT is still unclear. METHODS: Exosomes were isolated from the DSC of URSA patients and their miRNA profile was characterized by miRNA sequencing. Wound healing assays and transwell assays were used to assess the invasion and migration ability of trophoblasts. Mitochondrial stress and glycolysis stress test were used to evaluate energy metabolism phenotype of trophoblast. Luciferase reporter assays, qRT-PCR and WB were conducted to uncover the underlying mechanism. Finally, animal experiments were employed to explore the effect of DSC-exos on embryo absorption in mice. RESULTS: Our results showed that URSA-DSC-exos suppressed trophoblast EMT to reduce their migration and invasion, miR-22-5p_R-1 was the most upregulated miRNAs. URSA-DSC-exos can suppress trophoblast MGS (metabolic switch from mitochondrial respiration to glycolysis) and inhibit trophoblast migration and invasion by transferring miR-22-5p_R-1. Mechanistically, miR-22-5p_R-1 suppress trophoblast MGS and inhibit trophoblast EMT by directly suppressing PDK4 expression at the post-transcriptional level. Furthermore, in vivo experiment suggested that URSA-DSC-exos aggravated embryo absorption in mice. Clinically, PDK4 and EMT molecule were aberrant in villous of URSA patients, and negative correlations were found between miR-22-5p_R-1 and PDK4. DISCUSSION: Our findings indicated that URSA-DSC-exos induced MGS obstacle playing an important role in intercellular communication between trophoblast and DSC, illuminating a novel mechanism in DSC regulation of trophoblasts and their role in URSA.