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Objective Studies about the epidemiology and risk factors of late onset of sepsis (LOS) in preterm very low birth weight (PVLBW) infants of developing countries are limited and variable. The objective of this study was to explore the epidemiology, risk factors and pathogens of LOS in VLBW infants in a Chinese tertiary hospital. Methods Data concerning demographies, pathogens, risk factors and outcomes of LOS were collected in a cohort of 710 VLBW infants discharged from January 2012 to December 2018. Chi-square, t-test and multivariable logistic regression analysis were used to identify risk factors. Results The overall incidence of LOS was 24.08% and blood culture-proven sepsis was 19.58%. Gram-negative bacteria accounted for 57.93%, and 32.41% of the isolates were Klebsiella pneumoniae. LOS led to a longer hospital stay, higher hospitalization cost and higher mortality compared to infants without LOS. Mortality in Gram-negative or fungi LOS was higher than in Gram-positive LOS. The factor of PVLBW infants with registered permanent residence (PR) was associated with 80% lower likelihood of LOS compared to those without registered PR (P = 0.000, 95% CI 0.096–0.420). Infants with thrombocytopenia had 2.5 times LOS of control (P = 0.014, CI 1.210–5.132). Duration of parenteral nutrition was a risk of LOS (P = 0.009, CI 1.010–1.069). Conclusion Gram-negative bacteria, especially Klebsiella pneumonia, were the dominant pathogens in this study. Social factors might be a risk of LOS in PVLBW infants in developing countries. Taking measures to reduce the duration of parenteral nutrition may be helpful in decreasing the incidence of LOS. Awareness of thrombocytopenia may help to recognized diagnosis of LOS.

STUDY QUESTION What is the mechanism of Tim-3+ regulatory T (Treg)-cell accumulation in the decidua during early pregnancy and is its disruption associated with recurrent pregnancy loss (RPL)? SUMMARY ANSWER IL-27 and Gal-9 secreted by trophoblasts activate the Tim-3 signaling pathway in CD4+ T cells and Treg cells and so promote accumulation of Tim-3+ Treg cells, the abnormal expression of IL-27 and Gal-9 is associated with impaired immunologic tolerance in RPL patients. WHAT IS KNOWN ALREADY Tim-3+ Treg cells are better suppressors of Teff cell proliferation, and display higher proliferative activity than Tim-3− Treg cells. Tim-3+ Treg cells are tissue-specific promoters of T-cell dysfunction in many tumors. These cells express a unique factor that influences and shapes the tumor microenvironment. STUDY DESIGN, SIZE, DURATION The animal study included 80 normal pregnant mice. In human study, decidua tissues in the first trimester for flow cytometry analysis were collected from 32 normal pregnant women and 23 RPL patients. Placenta tissues for immunohistochemistry analysis were collected from 15 normal pregnant women. Placenta tissues for western blot analysis were collected from 5 normal pregnant women, 5 RPL patients and 5 women who have experienced one miscarriage. Blood samples for in vitro experiments were collected from 30 normal pregnant women. This study was performed between January 2017 and March 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS In this study, we investigated the kinetics of Tim-3+ CD4+ T-cell accumulation, and the proportions of Tim-3+ Treg cells throughout murine pregnancies using flow cytometry. We compared Tim-3 expression on decidual CD4+ T cells and Treg cells during normal pregnancies with expression on the same cell populations in women suffering from RPL. IL-27 and Gal-9 transcription and protein expression in the placenta were determined by RT-PCR and western blot, respectively. An in vitro co-culture model consisting of peripheral CD4+ T cells and primary trophoblasts from early pregnancy was used to mimic the maternal–fetal environment. MAIN RESULTS AND THE ROLE OF CHANCE The percentage of Tim-3+ Treg cells present in mouse uteri fluctuates as gestation proceeds but does not change in the spleen. Levels of Tim3+ Treg cells in uteri peaked at pregnancy Day 6.5 (E 6.5), then progressively diminished, and fell to non-pregnant levels by E18.5. In pregnant mice, Tim-3+ Treg cells constituted 40–70% of Treg cells in uteri but were present at much lower abundance in spleens. About 60% of decidual Treg cells were Tim-3 positive at E6.5. Of these decidual Tim3+ Treg cells, nearly 90% were PD-1 positive. However, only about 16% of Tim3− Treg cells expressed PD-1. Blocking the Tim-3 signaling pathway decreased the proportion of Treg cells and led to embryo resorption. Moreover, much lower Tim-3 expression was observed on CD4+ T cells and Treg cells in women who had suffered from RPL at 6–9 gestational weeks compared with those who had normal pregnancies at matched gestations. In a normal pregnancy, Tim-3 expression on decidual CD4+ T cells is induced initially by IL-27. Then Gal-9-Tim-3 interaction promotes differentiation of decidual Tim-3+ CD4+ T cells into Treg cells. IL-27 and Gal-9 cooperatively induced Tim-3+ Treg cells in vitro. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION We did not investigate the kinetics of human decidual Tim-3+ CD4+ T and Tim-3+ Treg cell populations throughout pregnancy due to limited availability of second and third trimester decidua. In addition, functional suppressive data on the decidual Tim-3+ Treg cells are lacking due to limited and low quantities of these cells in decidua. WIDER IMPLICATIONS OF THE FINDINGS These findings might have therapeutic clinical implications in RPL. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by research grants from the National Natural Science Foundation of China (No. 81871186) and National Key Research & Developmental Program of China (2018YFC1003900, 2018YFC1003904). The authors declare no conflict of interest.

Introduction The limited cell number of primary trophoblasts and contamination of trophoblast cell lines promote us to develop a novel stable trophoblast cell line. Method of study Primary trophoblast cells were isolated from first-trimester placenta and telomerase-induced immortalization was used to immortalize these cells. Subsets of cells were then evaluated by flow cytometry using CK7, HLA-G, CD45 and CD14, specific markers for trophoblast cells, extra-villous trophoblast, pan leucocyte and monocyte/macrophage, respectively. Immunofluorescence staining and immunocytochemistry were used to detect CK7 expression in trophoblast cells. The level of secreted human Chorionic Gonadotropin (hCG) was measured by electrochemiluminescence (ECL). The Bio-Plex MAGPIX System was used to analyze the cytokines and chemokines produced by AL07 cell line. Results We were able to isolate primary trophoblast cells from several first-trimester placentas. One clone, AL07 trophoblast cells, isolated from a week 7 placenta, was morphologically stable and positive for the expression of CK7 by immunofluorescence and immunocytochemistry staining. Characterization of AL07 cells reveled that they are CD45 or CD14 negative and had constitutive secretion of hCG and low HLA-G expression. Furthermore, clone AL07 secret high levels of several cytokines and chemokines, including IL-6, IL-8 and VEGF, and moderately secreted MCP-1 IP-10 and RANTES. Discussion We report the successful isolation, immortalization and characterization of AL07 cells, a novel cell clone isolated from first trimester human placenta. The clone is free of contamination of immune cells, and exhibits similar cytokine profile as other trophoblast cell lines. This new cytotrophoblast-like AL07 cell, can be a valuable tool for in-vitro trophoblast studies in the future.

Mounting studies demonstrated both chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infection might be associated not only with an increased risk of hepatocellular carcinoma but also extrahepatic malignancies, i.e., gastric cancer (GC). However, a quantitative result addressing the association between HBV/HCV infection and GC development is scarce. A systematic search to identify the eligible studies was performed in four databases, including MEDLINE, EMBASE, Cochrane Library, and the PsychINFO. The relationship between HBV/HCV infection and the risk of GC was quantified by calculating the hazard ratio (HR) with a 95% confidence interval (CI). More methodologies of this study were available in the PROSPERO (ID: CRD42021243719). Thirteen included studies involving 7,027,546 individuals (mean age, 42.6-71.9 years) were enrolled in the pooled analyses. Two articles provided the clinical data of both HBV and HCV infections. The proportion of high methodological quality studies was 76.9% (10/13). Synthetic results from 10 eligible studies of HBV showed that HBV infection was associated with a significantly higher risk of GC when compared with the healthy controls without HBV infection (pooled HR, 1.26; 95% CI, 1.08–1.47; P = 0.003; heterogeneity, I2 = 89.3%; P< 0.001). In line with this finding, the combined effect derived from five included studies of HCV also supported a significant positive association between chronic HBV infection and GC development (pooled HR, 1.88; 95% CI, 1.28–2.76; P = 0.001; heterogeneity, I2 = 74.7%; P = 0.003). In conclusion, both chronic HBV and HCV infections were related to a high risk of GC. The plausible mechanisms underlying such association might be correlated to HBV/HCV infection-induced persistent inflammation, immune dysfunction, and cirrhosis.Systematic Review RegistrationPROSPERO (http://www.crd.york.ac.uk/PROSPERO), identifier (CRD42021243719).

During pregnancy, the maternal immune system undergoes major adaptive modifications that are necessary for the acceptance and protection of the fetus. It has been postulated that these modifications are temporary and limited to the time of pregnancy. Growing evidence suggests that pregnancy has a long-term impact on maternal health, especially among women with pregnancy complications, such as preeclampsia (PE). In addition, the presence of multiple immunological-associated changes in women that remain long after delivery has been reported. To explain these long-term modifications, we hypothesized that pregnancy induces long-term immunological memory with effects on maternal well-being. To test this hypothesis, we evaluated the immunological phenotype of circulating immune cells in women at least 1 year after a normal pregnancy and after pregnancy complicated by PE. Using multiparameter flow cytometry (FCM) and whole-genome bisulfite sequencing (WGBS), we demonstrate that pregnancy has a long-term effect on the maternal immune cell populations and that this effect differs between normal pregnancy and pregnancy complicated by PE; furthermore, these modifications are due to changes in the maternal methylation status of genes that are associated with T cell and NK cell differentiation and function. We propose the existence of an “immunological memory of pregnancy (IMOP)” as an evolutionary advantage for the success of future pregnancies and the proper adaptation to the microchimeric status established during pregnancy. Our findings demonstrate that the type of immune cell populations modified during pregnancy may have an impact on subsequent pregnancy and future maternal health.

To investigate the predictive value of AMH level for pregnancy outcomes in different age groups of IVF/ICSI patients. The study was a cohort study that included 11,484 patients that had their first IVF/ICSI procedure between 2016 and 2019. All patients who met the inclusion and exclusion criteria were divided into 6 groups according to 5-year age intervals, namely, Group 1: 20–24 years (n = 725); Group 2: 25–29 years (n = 4019); Group 3: 30–34 years (n = 3600); Group 4: 35–39 years (n = 1915); Group 5: 40–44 years (n = 1006); and Group 6: ≥ 45 years (n = 219). Receiver operating characteristic (ROC) curve analysis revealed that AMH level could only predict the outcome of live birth in Group 3 and Group 4 (p

The coronavirus disease 2019 (COVID-19) pandemic has been raging around the world since January 2020. Pregnancy places the women in a unique immune scenario which may allow severe COVID‐19 disease. In this regard, the potential unknown effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on mothers and fetuses have attracted considerable attention. There is no clear consistent evidence of the changes in the immune status of pregnant women after recovery from COVID-19. In this study, we use multiparameter flow cytometry and Luminex assay to determine the immune cell subsets and cytokines, respectively, in the peripheral blood and umbilical cord blood from pregnant women recovering from COVID-19 about 3 months (n=5). Our results showed decreased percentages of Tc2, Tfh17, memory B cells, virus-specific NK cells, and increased percentages of naive B cells in the peripheral blood. Serum levels of IL-1ra and MCP-1 showed a decreased tendency in late recovery stage (LRS) patients. Meanwhile, there was no significant difference in immune cell subsets in the umbilical cord blood. The placentas from LRS patients showed increased CD68+ macrophages infiltration and mild hypoxic features. The inflammatory damage of the placenta may be related to the antiviral response. Since the receptors, ACE2 and TMPRSS2, utilized by SARS-CoV-2 are not co-expressed in the placenta, so it is extremely rare for SARS-CoV-2 to cause infection through this route and the impact on the fetus is negligible.

Purpose: Accumulative studies suggest the Glasgow prognostic score (GPS) and modified Glasgow prognostic score (mGPS) to be potential biomarkers; however, their prognostic value remains debatable. Our meta-analysis focused on assessing the accurate prognostic value of GPS and mGPS in patients with renal cell carcinoma (RCC) in addition to their effectiveness. Methods: To investigate the relationship between mGPS/GPS and prognostic value in patients with RCC, we performed a comprehensive retrieval of relevant articles from databases such as PubMed, Embase, Web of Science, and Medline up to February 1, 2020. STATA 15.0 software was used to obtain pooled hazard ratios (HRs) and their 95% confidence intervals for survival outcome, including overall survival (OS), recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS). A formal meta-analysis of these outcomes was performed. Results: In total, 2,691 patients with RCC were enrolled from 15 cohort studies. Higher GPS/mGPS (GPS/mGPS of 2) indicated poorer OS, CSS, PFS, and RFS in patients with RCC. Similarly, medium GPS/mGPS (GPS/mGPS of 1) also had a significant association with poorer OS, CSS, PFS, and RFS but superior than higher GPS/mGPS in these patients. Conclusion: GPS and mGPS are effective biomarkers for predicting prognosis in patients with RCC, and higher GPS and mGPS are closely related to inferior survival outcomes. More randomized controlled trials are needed to investigate the promising value of GPS/mGPS in the future.

High mobility group box 3 (HMGB3) is strongly involved in oncogenesis in a variety of cancers. In the present study, we have explored the role of HMGB3 in glioblastoma multiforme (GBM) tumorigenesis and have identified the microRNAs (miRNAs) miR-200b-3p and miR-200c-3p as negative regulators of HMGB3 expression. We began by determining that endogenous HMGB3 expression levels were significantly elevated in GBM tissues and in 3 GBM cell lines. To study the function of HMGB3 in GBM, we transfected a small-interfering RNA (siRNA) against HMGB3 into GBM cell lines U251 and LN229. MTT and tumour sphere assays demonstrated that HMGB3 knockdown significantly inhibited cell proliferation. Wound healing and transwell assays determined that HMGB3 knockdown substantially suppressed GBM cell migration and invasion. We evaluated the effects of HMGB3 knockdown on MAPK phosphorylation and target gene expression, finding that HMGB3 knockdown significantly reduced MAPK phosphorylation (p-ERK (1/2), p-p38, and p-JNK). We then used the biologic prediction algorithm TargetScan to identify the 3' untranslated region (3'-UTR) of HMGB3 as a target of miR-200b-3p and miR-200c-3p. Luciferase, qRT-PCR, and western blot assays confirmed that miR-200b-3p and miR-200c-3p bind and inhibit HMGB3 expression. Finally, Pearson correlation analyses demonstrated a negative correlation between relative HMGB3 mRNA and miR-200b/c-3p expression levels in GBM tissue samples. Overall, the present study strongly suggests that HMGB3 promotes GBM oncogenesis through the MAPK signalling pathway while miR-200b-3p and miR-200c-3p inhibit its expression.

Gene expression data using retrieved ovarian cancer (OC) samples were used to identify genes of interest and a support vector machine (SVM) classifier was subsequently established to predict the recurrence of OC. Three datasets (GSE17260, GSE44104 and GSE51088) investigating OC gene expression were downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) in samples from patients with non‑recurrent and recurrent OC were revealed via a homogeneity test and quality control analysis. A protein‑protein interaction (PPI) network was subsequently established for the DEGs using data from Biological General Repository for Interaction Datasets, Human Protein Reference Database and Database of Interacting Proteins. Degrees of interaction and betweenness centrality (BC) scores were calculated for each node in the PPI network. The top 100 genes ranked by BC scores were selected to identify feature genes via recursive feature elimination using the GSE17260 dataset. Following this, a SVM classifier was constructed and further validated using the GSE44104 and GSE51088 datasets and independent gene expression data obtained from the Cancer Genome Atlas (TCGA). A total of 639 DEGs were identified from the three gene expression datasets, and a PPI network including 249 nodes and 354 edges was constructed. A SVM classifier consisting of 39 feature genes (including cullin 3, mouse double minute 2 homolog, aurora kinase A, WW domain containing oxidoreducatase, large tumor suppressor kinase 2, sirtuin 6, staphylococcal nuclease and tudor domain containing 1, leucine rich repeats and immunoglobulin like domains 1 and aurora kinase 1 interacting protein 1) was subsequently constructed. The prediction accuracies of the SVM classifier for GSE17260, GSE44104 and GSE51088 datasets as well as data downloaded from TCGA were revealed to be 92.7, 93.3, 96.6 and 90.4%, respectively. Furthermore, the results of the present study revealed that patients with predicted non‑recurrent OC survived significantly longer compared with the patients with predicted recurrent OC (P=6.598x10‑6). A SVM classifier consisting of 39 feature genes was established for predicting the recurrence and prognosis of OC. Therefore, the results of the present study suggested that the 39 feature genes may serve important roles in the development of OC and may represent therapeutic biomarkers of OC.

Fructus Corni, the dried ripe sarcocarp of Cornus officinalis Sieb.et Zucc (Cornaceae), is widely used in traditional medicine. Pharmacological studies to date have attributed many biological effects to the high-polarity components. However, current quality control methods focus on only several iridoid glycoside components, and, of note, there is no comprehensive method available to simultaneously quantify the high-polarity components in Fructus Corni. Here, a simple, sensitive and robust liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed to simultaneously determine 11 high-polarity constituents (5-hydroxymethyl-2-furfural, gallic acid, sweroside, cornin, loganin, morroniside, 7α-O-methylmorroniside, 7β-O-methylmorroniside, 7α-O-ethylmorroniside and 7β-O-ethylmorroniside, cornuside) of Fructus Corni. This method showed good specificity, linearity (r2 ≥ 0.9907), repeatability (RSD < 5.98%) and recovery (93.24 ~ 112.92%, RSD < 9.06%). This validated method was successfully employed to assess the component variation of crude Fructus Corni of three regional origins as well as after processing. In particular, the iridoid isomers were, for the first time, included as the quality markers for Fructus Corni. We propose that this method may provide a new and powerful tool for achieving comprehensive quality control of Fructus Corni.

Background: Birth hypoxia causes neonatal mortality and morbidity. Hypoxia/ischemia can facilitate brain damage, causing various kinds of diseases, such as ischemic stroke. It is necessary to understand the potential underlying mechanisms of ischemic stroke. Previous studies revealed the involvement of thousand and one kinase 1 (TAOK1) in many cellular processes. Methods: Herein, middle cerebral artery (MCA) occlusion (MCAO) was performed in rats to establish ischemic stroke in the animal model, and cortical neural stem cells from rats were treated with oxygen-glucose deprivation (OGD) to induce ischemic stroke cell model. The animal model of ischemic stroke was validated by Bederson and Zea-Longa neurological deficit scores and rotarod test. TAOK1 expression was examined by quantitative real-time PCR (qRT-PCR), Western blot, and immunofluorescent staining both in vivo and in vitro. Result: Compared with sham animals, the MCAO rats showed a significant increase in the neurological scores, and obvious motor behavioral deficits. Meanwhile, there was increased apoptosis and inflammatory response in the model group. TAOK1 overexpression reversed the OGD-induced cell injury, while TAOK1 knockdown exhibited the opposing effects. On the mechanism, the OGD-induced suppression of PI3K/AKT, and activation of mitogen-activated protein kinase (MAPK) signaling pathways were abolished by TAOK1 overexpression, and aggravated by TAOK1 knockdown in vitro. Moreover, we proved that the inhibitory effect of TAOK1 on OGD-induced apoptosis was dependent on the intracellular kinase activity. Conclusion: TAOK1 protected MCAO-induced cerebral ischemic stroke by decreasing the pro-inflammatory factors and apoptosis via PI3K/AKT and MAPK signaling pathways.

Methylophiopogonanone B (MO-B), which belongs to a group of homoisoflavonoids, present in Ophiopogon japonicus, has been identified as an active component with antioxidative and anti-tumor properties. The present study investigated whether MO-B may exert protective effects on human umbilical vein endothelial cells (HUVECs) against H2O2-induced injury in vitro, and whether the MO-B effects may be modulated by the NADPH pathway. HUVECs were treated with MO-B in the presence or absence of H2O2. Malondialdehyde (MDA), reactive oxygen species (ROS) levels, and superoxide dismutase (SOD) activity were analyzed to evaluate cell injury and the antioxidative potential of MO-B. The results revealed that MO-B inhibited the production of MDA and ROS, but enhanced SOD activity. Furthermore, MO-B could alleviate H2O2-induced apoptosis in HUVECs, which is consistent with the expression of apoptosis-associated genes and proteins in cells, including Bax/Bcl-2 and caspase-3. To explore the potential mechanism, the present study investigated the effects of MO-B on NADPH-related signaling via the analysis of neutrophil cytochrome b light chain (p22phox) expression, which is the membrane-associated subunit of NADPH oxidase. MO-B could improve the survival of endothelial cells and therefore may be a potential drug in the treatment of cardiovascular diseases.

Background Studies have shown that the effects of maternal nutrition exposure during gestation influence metabolic risk in early life through an epigenetic mechanism. Low glycaemic index (GI) diets benefit both maternal and neonatal gestational outcomes. We hypothesize that maternal dietary GI or glycaemic load (GL) changes during pregnancy impact placental DNA methylation, especially in insulin resistance-related genes. Methods From a clinical trial of overweight pregnant women, 12 subjects who successfully reduced their GI and another 12 whose GI increased despite the intervention were selected. A genome-wide differential methylation analysis of placental tissue DNA was conducted, followed by bioinformatic annotation and validation analysis. The distribution of genome-wide differentially methylated regions (DMRs) and CpG sites was described. Six CpG sites in regulatory regions of four insulin-related genes (PLIN1, CPT1B, SSTR4, and CIDEA) were selectively validated by pyrosequencing. Pairwise Spearman correlation analysis was performed to test methylation–phenotype association in an additional 153 subjects from the same trial. Correlation between methylation of significant sites and placental mRNA expression of SSTR4 was also analysed. Results Dietary GI decreased by 24.3 (26.2–20.1) in the group who responded appropriately to the intervention and increased by 19.6 (15.2–29.1) in the comparison group. Epigenome-wide analysis identified 108 DMRs and 365 CpG sites with P

Dysfunction of decidual macrophages (DMs) is considered a critical event in the pathogenesis of pre-eclampsia (PE). T cell immunoglobulin mucin 3 (Tim-3) is an important negative regulatory molecule that induces immune tolerance by interacting with its ligand Galectin-9 (Gal-9) and thus modulating function of various immune cells, including macrophages. However, the regulatory effects of Tim-3/Gal-9 signaling on DMs polarization and its role in PE remain unclear. In this study, we established a PE-like rat model by administering 1.0 μg/kg lipopolysaccharide (LPS) to normal pregnant Sprague-Dawley rats via the tail vein at embryonic day 5 (E5). Apart from the pre-eclamptic manifestations, increased M1 subtype and decreased M2 subtype were observed at the maternal-fetal interface, as well as increased pro-inflammatory cytokines (TNF-α and IL-1β) and reduced anti-inflammatory cytokines (TGF-β and IL-10). Moreover, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were reduced. After administration of recombinant Galectin-9 (rGal-9) protein, we found that liver and renal injuries and maternofetal placental functional deficiency, including inadequate trophoblast cells invasion, impaired spiral artery remodeling and fetal capillary development, were reversed. In addition, the polarization of DMs was inclined to M2 subtype, which was similar to the polarization of DMs in the control rats but contrary to the PE-like rats. Interestingly, at E9, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were significantly increased in the rGal-9 protein intervention group. Taken together, our findings show that administration of rGal-9 protein can alleviate the PE-like rat manifestations induced by LPS. This finding may be related to the activation of the Tim-3/Gal-9 signaling pathway, which promotes DMs polarization dominantly shifting to M2 subtype. Moreover, upregulation of Tim-3 in DMs and Gal-9 at the maternal-fetal interface at E9 suggests that Tim-3/Gal-9 pathway may play some important roles in early pregnancy and even embryo development.

Autoimmune thyroiditis (AIT) is a common organ-specific autoimmune disease with a high incidence among women of childbearing age. Recent studies have reported that women with AIT are more susceptible to infertility, miscarriage and preterm birth. It has been investigated that abnormal changes in maternal immune system and maternal-fetal interface can dampen the immune tolerance between mother and fetus, which underlie the pathogenesis of adverse pregnancy outcomes. Hence, we summarize the immunological changes related to adverse reproductive outcomes in AIT and highlight the respective contributions of both humoral and cellular immune dysfunctions to pregnancy failures. Moreover, the direct impacts of AIT on maternal-fetal immune activation and biological influences to trophoblasts are discussed as well. All these associations require confirmation in larger studies, and the pathogenic mechanisms need to be better understood, which might provide useful information for clinical diagnosis and therapy of AIT.

Glioblastoma multiforme (GBM) is one of the most common primary malignant adult brain tumors. It is characterized by aggressive progression and poor prognosis. There is significant need to understand the mechanism of GBM malignancy and develop improved therapeutic options for GBM patients. We systematically studied the function of PTP4A3 in the malignancy of GBM. We found that PTP4A3 was upregulated in GBM tissues and cells. Knockdown of PTP4A3 expression in GBM cells inhibited cell proliferation, migration, and invasion. PTP4A3 knockdown modulated the activity of the Akt/mTOR signaling pathway by inducing de-phosphorylation of Akt and mTOR. We identified PTP4A3 as a direct target of miR-137. MiR-137 has been reported as a tumor suppressor in GBM development. In this study, overexpression of miR-137 in GBM cells also inhibited cell proliferation, migration, and invasion. Finally, restoration of PTP4A3 expression in miR-137 overexpressing cells partially reversed the inhibition of GBM cell malignancy, and the de-phosphorylation of Akt and mTOR. We identified that PTP4A3 regulated GBM via miR-137-mediated Akt/mTOR signaling pathway.

PROBLEM This study aims to determine the expression and localization of programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) in the testes of mice at different developmental stages. METHOD OF STUDY By means of RT-qPCR, Western blot and immunofluorescence, the expression and localization of PD-1 and PD-L1 were detected in the testicular tissues of mice at different postnatal times: P7, P14, P21, P28, P35, and adulthood. Meanwhile, the level of soluble PD-L1 (sPD-L1) was evaluated by ELISA in the testicular interstitial fluid (IF) of the adult mice, culture supernatants of TM4 cell lines (Sertoli cells lines), and primary Sertoli cells at P14. RESULTS Pd-1 mRNA levels were unexpectedly low. From P7 to P21, there was limited PD-1 protein detected while PD-1 was evident at P28 and afterward at significantly higher levels than at P14 and P21 (P

Ovarian cancer (OC) is associated with a poor prognosis due to difficulties in early detection. The aims of the present study were to construct a recurrence risk prediction model and to reveal important OC genes or pathways. RNA sequencing data was obtained for 307 OC samples, and the corresponding clinical data were downloaded from The Cancer Genome Atlas database. Additionally, two validation datasets, {"type":"entrez-geo","attrs":{"text":"GSE44104","term_id":"44104"}}GSE44104 (20 recurrent and 40 non-recurrent OC samples) and {"type":"entrez-geo","attrs":{"text":"GSE49997","term_id":"49997"}}GSE49997 (204 OC samples), were obtained from the Gene Expression Omnibus database. Differentially expressed genes were screened using the differential expression via distance synthesis algorithm, followed by gene ontology enrichment analysis and weighted gene coexpression network analysis (WGCNA). Furthermore, subnetwork analysis was conducted for the protein-protein interaction (PPI) network using the BioNet package. Finally, a random forest classifier was constructed based on the subnetwork nodes, and its reliability was validated using the {"type":"entrez-geo","attrs":{"text":"GSE44104","term_id":"44104"}}GSE44104 and {"type":"entrez-geo","attrs":{"text":"GSE49997","term_id":"49997"}}GSE49997 validation datasets. A total of 44 upregulated and 117 downregulated genes were identified in the recurrent samples. Enrichment analysis indicated that cytochrome P450 family 17 subfamily A member 1 (CYP17A1) was associated with ‘positive regulation of steroid hormone biosynthetic processes’. WGCNA identified turquoise and grey modules that were significantly correlated with status and prognosis. A significant PPI subnetwork containing 16 nodes was also identified, including: Transcription factor GATA-4; fibroblast growth factor 9; aromatase; 3β-hydroxysteroid dehydrogenase/δ5-4-isomerase type 2; corticosteroid 11β-dehydrogenase isozyme 1; CYP17A1; pituitary homeobox 2; left-right determination factor 1; homeobox protein ARX; estrogen receptor β; steroidogenic factor 1; forkhead box protein L2; myocardin; steroidogenic acute regulatory protein mitochondrial; vesicular inhibitory amino acid transporter; and twist-related protein 1. A random forest classifier was constructed using the subnetwork nodes as feature genes, which exhibited a 92% true positive rate when classifying recurrent and non-recurrent OC samples. The classifying efficiency of the random forest classifier was validated using the two other independent datasets. Overall, 44 upregulated and 117 downregulated genes associated with OC recurrence were identified. Furthermore, the 16 subnetwork node genes that were identified may be important molecules in OC recurrence.

Due to early detection and effective treatment, quality of sexual life of patients with gynaecological malignancies has become an important issue. However, the morbidity of sexual dysfunction and the proportion of different kinds of sexual dysfunction after radical hysterectomy are unclear. The aim of the current study was to assess the morbidity of sexual dysfunction and to conduct multivariate logistic regression analysis of patients’ sexual dysfunction. Between July 2007 and December 2012, 125 women underwent radical hysterectomy, modified radical hysterectomy, and nerve-sparing radical hysterectomy were administered a self-reported sexual function questionnaire. The preoperative, and 1- and 2-year postoperative sexual dysfunction rates were 50.5% (50/99), 86.9% (93/107), and 92.3% (72/78), respectively. The incidence rates of sexual desire disorders before operation, at postoperative year 1, and at postoperative year 2 were 14.7% (14/95), 42.1% (45/107), and 51.9% (40/77), respectively. The preoperative incidence rates of sexual arousal disorders, orgasmic disorders, and sexual pain disorders were 18.4% (18/98), 51.1% (48/94), and 10.9% (11/101), respectively. At postoperative years 1 and 2, these were 38.8% (31/80), 81.0% (64/79), and 24.4% (20/82), and 49.1% (26/53), 84.6% (44/52), and 30.2% (16/53), respectively. Multivariable regression analysis revealed that age, preserved ovary, preserved posterior vaginal wall length, preoperative stage, radiotherapy, and education background were risk factors associated with sexual dysfunction. The patients following radical hysterectomy had a high incidence of sexual dysfunction, which plateaued in postoperative years 1 and 2.

RATIONALE Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is caused by mutations in GPC3 or in both GPC3 and GPC4. Physical manifestations of SGBS1 include fetal overgrowth and macrostomia, macroglossia. Subclinical hypothyroidism has never been reported in SGBS1 cases. PATIENT CONCERNS An 8-days-old boy was referred to our hospital with persistent hypoglycemia and special facies. And the infant showed elevated levels of thyroid-stimulating hormone (TSH). Free T4 and free T3 were normal. DIAGNOSES Definitive diagnosis of SGBS1 depends on clinical features and genetic testing. A nonsense mutation (c.1515C > A, p. Cys505*) was tested by whole-exome sequencing. INTERVENTIONS Normal blood glucose levels were maintained with glucose infusions. Levothyroxine was given to the patient for treating subclinical hypothyroidism. OUTCOMES The parents decided to abandon the treatment of the patient. We learned that the patient died of a lung infection by a telephone follow-up. LESSONS Subclinical hypothyroidism could be added to the known clinical manifestations of SGBS1.

Objective. To develop a quantitative analysis of multicomponents by single-marker (QAMS) method for the simultaneous determination of polar active components inFructus Corni.Methods. Loganin was selected as the internal reference, and the relative correction factors (RCFs) of gallic acid, 5-hydroxymethyl-2-furfural, morroniside, sweroside, cornin, 7α-O-methylmorroniside, 7β-O-methylmorroniside, 7α-O-ethylmorroniside, 7β-O-ethylmorroniside, and cornuside were established. The contents of multicomponents were then calculated based on their RCFs, respectively. Contents of the 11 components were also calculated by external standard method and compared with those of the QAMS method.Results.The contents of the 11 components in 21 crude and 10 processedFructus Corniproducts were measured. No significant difference was found in the quantitative results of the QAMS and external standard methods.Conclusion. QAMS could serve as an accurate and convenient method in determining the polar and active components inFructus Corniand its processed products.

The PD-1/PD-L1 pathway plays a vital role in the maintenance of peripheral tolerance, promoting the development and function of regulatory T cells, and maintaining the quiescence of autoreactive T cells. Abnormalities in this inhibitory pathway are involved in the pathogenesis of some disorders such as tumours, autoimmune diseases, pregnancy complications, and transplantation rejection. Immune privilege represents a special immunological condition, where foreign antigens can be tolerated and do not elicit an immune response. The anterior chamber of the eye, central nervous system, testis, pregnant uterus, and hair follicles are all regarded as immune-privileged sites in humans. Numerous studies show that the PD-1/PD-L1 pathway contributes to the maintenance of the immune-privileged microenvironment. In this review, we will mainly focus on the roles of the PD-1/PD-L1 pathway in the anterior chamber of the eye, brain and testis, as well as further investigations in testis.