Unraveling the role of sulfiredoxin-1 in early-onset preeclampsia: A key player in trophoblast ferroptosis.

Preeclampsia (PE) significantly contributes to obstetric complications and maternal mortality, yet its pathogenesis and mechanisms are not well understood. Sulfiredoxin-1 (SRXN1) is known for its antioxidant activity and its role in defending against oxidative stress; it is also linked to various cancers. However, the role of SRXN1 in PE remains unclear. Our study found a significant decrease in SRXN1 levels in the serum and placental tissues of patients with early-onset preeclampsia (EOPE). Similarly, a PE-like mouse model showed reduced SRXN1 expression. Our in vitro experiments showed that reducing SRXN1 impaired trophoblast viability, decreased invasion and migration, and led to cell death, primarily through ferroptosis. These results are consistent with analyses of placental tissues from EOPE patients. In summary, lower SRXN1 levels during pregnancy contribute to trophoblast ferroptosis, potentially affecting the development and progression of EOPE.

Overexpressed Trophoblast Glycoprotein Contributes to Preeclampsia Development by Inducing Abnormal Trophoblast Migration and Invasion Toward the Uterine Spiral Artery.

BACKGROUND: Preeclampsia is a significant pregnancy disorder with an unknown cause, mainly attributed to impaired spiral arterial remodeling. METHODS: Using RNA sequencing, we identified key genes in placental tissues from healthy individuals and preeclampsia patients. Placenta and plasma samples from pregnant women were collected to detect the expression of TPBG (trophoblast glycoprotein). Pregnant rats were injected with TPBG-carrying adenovirus to detect preeclamptic features. HTR-8/SVneo cells transfected with a TPBG overexpression lentiviral vector were used in cell function experiments. The downstream molecular mechanisms of TPBG were explored using RNA sequencing and single-cell RNA sequencing data. TPBG expression was knocked down in the lipopolysaccharide-induced preeclampsia-like rat model to rescue the preeclampsia features. We also assessed TPBG's potential as an early preeclampsia predictor using clinical plasma samples. RESULTS: TPBG emerged as a crucial differentially expressed gene, expressed specifically in syncytiotrophoblasts and extravillous trophoblasts. Subsequently, we established a rat model with preeclampsia-like phenotypes by intravenously injecting TPBG-expressing adenoviruses, observing impaired spiral arterial remodeling, thus indicating a causal correlation between TPBG overexpression and preeclampsia. Studies with HTR-8/SVneo cells, chorionic villous explants, and transwell assays showed TPBG overexpression disrupts trophoblast/extravillous trophoblast migration/invasion and chemotaxis. Notably, TPBG knockdown alleviated the lipopolysaccharide-induced preeclampsia-like rat model. We enhanced preeclampsia risk prediction in early gestation by combining TPBG expression with established clinical predictors. CONCLUSIONS: These findings are the first to show that TPBG overexpression contributes to preeclampsia development by affecting uterine spiral artery remodeling. We propose TPBG levels in maternal blood as a predictor of preeclampsia risk. The proposed mechanism by which TPBG overexpression contributes to the occurrence of preeclampsia via its disruptive effect on trophoblast and extravillous trophoblast migration/invasion on uterine spiral artery remodeling, thereby increasing the risk of preeclampsia.

Bioinformatics analysis identifies potential autophagy key genes and immune infiltration in preeclampsia.

BACKGROUND: Preeclampsia (PE) is a disease that seriously threatens maternal and fetal health. Appropriate autophagy can shield the placenta from oxidative stress, but its role in PE is unclear. OBJECTIVE: To identify potential autophagy-related genes in PE. METHODS: Microarray datasets from the Gene Expression Omnibus database, compassing the test dataset GSE10588, along with validation datasets GSE4707 and GSE60438 GPL10558, were utilized. Differentially expressed genes (DEGs) were identified using the limma R package, intersected with autophagy-related genes. Hub genes were obtained using the Cytoscape software and analyzed via gene set enrichment analysis (GSEA). The diagnostic capability of hub genes was evaluated using receiver operating characteristic (ROC) curve analysis. Analysis of immune cell infiltration was conducted using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT methods. Placental tissues were collected from 10 normal pregnant women and 10 preeclamptic pregnant women, and the expression of hub genes was validated through immunohistochemistry and western blot analysis. RESULTS: Analysis of the microarray data identified 2224 DEGs, among which 26 were autophagy-related DEGs identified through intersection with autophagy genes. Ten hub genes were identified. Immune cell infiltration analysis suggested the potential involvement of T regulatory cells (Tregs), natural killer cells, neutrophils, and T follicular helper cells in the pathogenesis of PE. ROC curve analysis indicated promising diagnostic capabilities for EGFR and TP53. Additionally, levels of EGFR and TP53 were significantly higher in placental tissue from PE pregnancies compared to normal pregnancies. CONCLUSION: EGFR and TP53 may play a role in PE by influencing autophagy.

Association between serum iron and liver transaminases based on a large adult women population.

BACKGROUND: Studies are being focused on the potential roles of iron in various diseases, but remain unclear for the association between serum iron and liver injury, especially in adult women. METHODS: Based on the National Health and Nutrition Examination Survey, we investigated the relationship between serum iron and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) among 19,185 adult women. RESULTS: Using weighted multivariate regression analyses, subgroup analyses, and threshold effect analyses, we found that serum iron was independently and positively correlated with ALT and AST. These associations differed in various age or race. Additionally, we found turning points in the curves of the relationship between serum iron and ALT in all women and the non-pregnant women. Using sensitivity analyses, we further found that the associations between serum iron and the liver transaminases remained positive in the non-pregnant women after adjusting for various covariates, but not in pregnant women. Besides, the positive associations between them kept present after excluding the women with high blood pressure, diabetes, and chronic kidney disease. CONCLUSION: The present study indicated a positive association between serum iron and liver transaminases, indicating that serum iron may be a potential biomarker of liver function.

Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis.

BACKGROUND: Pre-eclampsia (PE) is one of the leading causes of maternal and fetal morbidity/mortality during pregnancy, and alpha-2-macroglobulin (A2M) is associated with inflammatory signaling; however, the pathophysiological mechanism by which A2M is involved in PE development is not yet understood. METHODS: Human placenta samples, serum, and corresponding clinical data of the participants were collected to study the pathophysiologic mechanism underlying PE. Pregnant Sprague-Dawley rats were intravenously injected with an adenovirus vector carrying A2M via the tail vein on gestational day (GD) 8.5. Human umbilical artery smooth muscle cells (HUASMCs), human umbilical vein endothelial cells (HUVECs), and HTR-8/SVneo cells were transfected with A2M-expressing adenovirus vectors. RESULTS: In this study, we demonstrated that A2M levels were significantly increased in PE patient serum, uterine spiral arteries, and feto-placental vasculature. The A2M-overexpression rat model closely mimicked the characteristics of PE (i.e., hypertension in mid-to-late gestation, histological and ultrastructural signs of renal damage, proteinuria, and fetal growth restriction). Compared to the normal group, A2M overexpression significantly enhanced uterine artery vascular resistance and impaired uterine spiral artery remodeling in both pregnant women with early-onset PE and in pregnant rats. We found that A2M overexpression was positively associated with HUASMC proliferation and negatively correlated with cell apoptosis. In addition, the results demonstrated that transforming growth factor beta 1 (TGFß1) signaling regulated the effects of A2M on vascular muscle cell proliferation described above. Meanwhile, A2M overexpression regressed rat placental vascularization and reduced the expression of angiogenesis-related genes. In addition, A2M overexpression reduced HUVEC migration, filopodia number/length, and tube formation. Furthermore, HIF-1α expression was positively related to A2M, and the secretion of sFLT-1 and PIGF of placental origin was closely related to PE during pregnancy or A2M overexpression in rats. CONCLUSIONS: Our data showed that gestational A2M overexpression can be considered a contributing factor leading to PE, causing detective uterine spiral artery remodeling and aberrant placental vascularization.

A Retrospective Evaluation of Pregnancy Outcomes Following Bariatric Surgery: A Single-Center Experience.

Background: Bariatric and metabolic surgery (BMS) is an effective treatment for obesity and its complications, but its effect on pregnancy outcomes is inconclusive. The present study aimed to investigate women's pregnancy status and outcomes as well as the impact of pregnancy intervals after BMS. Methods: The menstrual cycle and fertility status of women who underwent BMS in our centre between July 2010 and January 2021 were retrospectively analyzed and followed up until one-year post-delivery. The pregnancy outcomes after BMS were observed, including changes in weight, pregnancy interval, pregnancy complications, weight and health status of the newborn (premature birth, admission to neonatology, or deformity). Results: We identified 31 women who were successfully conceived after BMS. There were statistical differences in weight and menstrual status before and post-operation (P < 0.05), and 77.97% of them had remission or recovery of obesity-related comorbidities. Eighteen patients delivered successfully after BMS, but there were still 12 cases of spontaneous abortion and 1 case of induced abortion. The abortion rate in pregnancy intervals less than 2 years was higher than those ≥2 years (P = 0.045). Of the women who delivered successfully, 5 had pregnancy-specific complications, including gestational diabetes mellitus and hypertensive disorder of pregnancy. However, the growth and development of the newborn are normal since the birth follow-up. Conclusion: The present results suggest that the abortion rate in pregnancy intervals less than 2 years was higher than those ≥2 years. It is recommended that postoperative patients avoid pregnancy until their weight is stable to reduce the risk of adverse pregnancy outcomes.

Ferritin light chain deficiency-induced ferroptosis is involved in preeclampsia pathophysiology by disturbing uterine spiral artery remodelling.

The proteomic analysis from samples of patients with preeclampsia (PE) displayed a low level of ferritin light chains (FTL), but we do not know what the significance of reduced FTL in PE pathophysiology is. To address this question, we first demonstrated that FTL was expressed in first- and third-trimester cytotrophoblasts, including extravillous trophoblasts (EVTs), of the human placenta. Furthermore, a pregnant rat model of FTL knockdown was successfully established by intravenously injecting adenoviruses expressing shRNA targeting FTL. In pregnant rats with downregulated FTL, we observed PE-like phenotypes and impaired spiral arterial remodelling, implying a causal relationship between FTL downregulation and PE. Blocking ferroptosis with ferrostatin-1 (Fer-1) significantly rescued the above PE-like phenotypes in pregnant rats with FTL knockdown. Furthermore, using trophoblast cell line and chorionic villous explant culture assays, we showed that FTL downregulation induced cell death, especially ferroptosis, resulting in defective uterine spiral artery remodelling. Eventually, this conclusion from the animal model was verified in PE patients' placental tissues. Taken together, this study revealed for the first time that FTL reduction during pregnancy triggered ferroptosis and then caused defective uterine spiral artery remodelling, thereby leading to PE.

Plasma Olink Proteomics Identifies CCL20 as a Novel Predictive and Diagnostic Inflammatory Marker for Preeclampsia.

Inflammation is generally thought to be involved in the occurrence and development of preeclampsia (PE), but its specific effect on PE remains unclear. In the present study, the expression levels of 92 inflammation-related proteins were measured in the late pregnancy maternal plasma from patients with PE (n = 15) and normal pregnant controls (n = 15) using the Olink inflammation panel based on the highly sensitive and specific proximity extension assay technology. A total of 28 inflammation-related markers differed between the PE and control groups. Among them, fibroblast growth factor 21 (FGF-21) and cysteine-cysteine motif chemokine ligand 20 (CCL20) had the largest fold changes. We further validated the levels of CCL20 in the late (43 with PE and 44 controls) and early (37 with PE and 37 controls) pregnancy maternal plasma using enzyme-linked immunosorbent assay (ELISA). To the best of our knowledge, for the first time, CCL20 was found to be upregulated in the late and early pregnancy plasma of patients with PE and had an area under the curve (AUC) of 0.753 and 0.668, respectively. In conclusion, patients with PE had increased levels of most inflammatory markers, and CCL20 might be a novel potential predictive and diagnostic biomarker for PE.

The impact of antibiotic use on clinical features and survival outcomes of cancer patients treated with immune checkpoint inhibitors.

Background: Nowadays, immune checkpoint inhibitors (ICIs) have become one of the essential immunotherapies for cancer patients. However, the impact of antibiotic (ATB) use on cancer patients treated with ICIs remains controversial. Methods: Our research included retrospective studies and a randomized clinical trial (RCT) with cancer patients treated with ICIs and ATB, from the public database of PubMed, Web of Science, Embase, Cochrane, clinical trials, and JAMA. The survival outcomes included progression-free survival (PFS) and overall survival (OS). Meanwhile, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated, and subgroup analyses were performed to determine the concrete association between ATB use and the prognosis of cancer patients treated in ICIs. Results: Our results revealed that ATB use was associated with poor survival outcomes, including OS (HR: 1.94, 95% CI: 1.68-2.25, p <0.001) and PFS (HR: 1.83, 95% CI: 1.53-2.19, p <0.001). The subgroup analysis learned about the association between ATB use and the prognosis of cancer patients with ICI treatment, including 5 cancer types, 3 kinds of ICI, 5 different ATP windows, broad-spectrum ATB class, and ECOG score. ATB treatment was associated with poor OS of non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), esophageal cancer (EC), and melanoma (MEL) in patients treated in ICIs, while non-small-cell lung cancer (NSCLC) and renal cell carcinoma (RCC) were associated with poor PFS. Meanwhile, it was strongly related to the ICI type and ATB window. Furthermore, it is firstly mentioned that the use of broad-spectrum ATB class was strongly associated with poor PFS. Conclusion: In conclusion, our meta-analysis indicated that ATB use was significantly associated with poor OS and PFS of cancer patients treated with ICI immunotherapy, especially for patients with ATB use in the period of (-60 days; +30 days) near the initiation of ICI treatment. Also, different cancer types and the ICI type can also impact the survival outcome. This first reveals the strong relationship between the broad-spectrum ATB class and poor PFS. Still, more studies are needed for further study.

WASF2 Serves as a Potential Biomarker and Therapeutic Target in Ovarian Cancer: A Pan-Cancer Analysis.

Background: Wiskott-Aldrich syndrome protein family member 2 (WASF2) has been shown to play an important role in many types of cancer. Therefore, it is worthwhile to further study expression profile of WASF2 in human cancer, which provides new molecular clues about the pathogenesis of ovarian cancer. Methods: We used a series of bioinformatics methods to comprehensively analyze the relationship between WASF2 and prognosis, tumor microenvironment (TME), immune infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), and tried to find the potential biological processes of WASF2 in ovarian cancer. Biological behaviors of ovarian cancer cells were investigated through CCK8 assay, scratch test and transwell assay. We also compared WASF2 expression between epithelial ovarian cancer tissues and normal ovarian tissues by using immunohistochemical staining. Results: In the present study, we found that WASF2 was abnormally expressed across the diverse cancer and significantly correlated with overall survival (OS) and progression-free interval (PFI). More importantly, the WASF2 expression level also significantly related to the TME. Our results also showed that the expression of WASF2 was closely related to immune infiltration and immune-related genes. In addition, WASF2 expression was associated with TMB, MSI, and antitumor drugs sensitivity across various cancer types. Functional bioinformatics analysis demonstrated that the WASF2 might be involved in several signaling pathways and biological processes of ovarian cancer. A risk factor model was found to be predictive for OS in ovarian cancer based on the expression of WASF2. Moreover, in vitro experiments, it was demonstrated that the proliferative, migratory and invasive capacity of ovarian cancer cells was significantly inhibited due to WASF2 knockdown. Finally, the immunohistochemistry data confirmed that WASF2 were highly expressed in ovarian cancer. Conclusions: Our study demonstrated that WASF2 expression was associated with a poor prognosis and may be involved in the development of ovarian cancer, which might be explored as a potential prognostic marker and new targeted treatments.

Identify a DNA Damage Repair Gene Signature for Predicting Prognosis and Immunotherapy Response in Cervical Squamous Cell Carcinoma.

The DNA damage repair (DDR) genes are increasingly gaining attention as potential therapeutic targets in cancers. In this study, we identified the DDR genes associated with the tumor mutation burden (TMB) and prognosis of cervical squamous cell carcinoma (CESC) based on The Cancer Genome Atlas (TCGA) database. Through LASSO Cox regression, the prognostic signature involving five DDR genes (ACTR2, TEX12, UBE2V1, HSF1, and FBXO6) was established, and the risk score was identified as an independent risk factor for CESC. The nomogram consisting of the five genes accurately predicted the overall survival (OS) and the immunotherapeutic response of CESC patients. Finally, the loss of the copies of the transcription factor (TF) SP140 in CESC patients may decrease the expression of FBXO6, improve DNA repair function, and reduce the diversity of neoantigens, thereby lowering the response to immunotherapies. Therefore, the DDR gene signature is a novel prognostic model and a biomarker for immunotherapies in CESC patients.

Placental and plasma early predictive biomarkers for gestational diabetes mellitus.

PURPOSE: Gestational diabetes mellitus (GDM) is a common disease that can give rise to adverse obstetric outcomes. For successful early intervention, more studies on novel predictive biomarkers for GDM are required. EXPERIMENTAL DESIGN: The protein expression profiles of placental tissue from patients with GDM and normal pregnant women were investigated using data-independent acquisition proteomics with five biological replicates. Early pregnancy maternal plasma samples from the GDM (n = 79) and control (n = 81) groups were used for further validation of candidate biomarkers. RESULTS: We identified 37 differentially expressed proteins between the two groups. CD109 antigen (CD109) and endosialin (CD248) were identified as hub proteins. In the validation experiments, CD109 expression was lower in the early pregnancy maternal plasma of patients with GDM compared with that in normal pregnant women, and CD248 expression was higher in the GDM group. The area under the curve of CD109, CD248, and their combination as indicators in early pregnancy maternal plasma was 0.681, 0.609, and 0.695, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The present study is the first to obtain preliminary evidence that CD109 and CD248 can predict GDM during early pregnancy, as well as providing proteome-level insights into this disease's pathological mechanisms.

Second-Trimester Cervical Shear Wave Elastography Combined With Cervical Length for the Prediction of Spontaneous Preterm Birth.

The goal of this study was to explore the value of shear wave elastography (SWE) combined with cervical length (CL) in the prediction of spontaneous preterm birth (sPTB) between 18 and 24 weeks of gestation. In this study, SWE was used to evaluate four regions of the cervix: the external and anterior lip (region A1), the external and posterior lip (region A2), the internal and anterior lip (region A3) and the internal and posterior lip (region A4). The cervical Young's modulus (YM) was compared between women who spontaneously delivered prematurely (<37 wk) and those who delivered full term. Finally, the predictive power of SWE was evaluated using receiver operating characteristic analysis. Overall, 773 patients were included in this study, of whom 60 (7.8%) had a sPTB. In the univariate analysis, prior sPTB, history of spontaneous abortion, history of cervical surgery, CL and YM at the anterior portion of both the internal and external os and the posterior portion of the internal os were associated with sPTB (p < 0.05). Multiple regression analyses were performed to develop the prediction probability for sPTB. YM and CL were independent predictors of sPTB in asymptomatic women, and the combination of YM and CL improved the ability to predict sPTB (area under the receiver operating characteristic curve = 0.98, 95% confidence interval: 0.97-0.99, p < 0.001). The interventions had relatively little impact on the outcome indicators measured. Cervical YM added to the CL may improve the predictive performance of second-trimester transvaginal ultrasound for sPTB.

Machine learning-based prediction of postpartum hemorrhage after vaginal delivery: combining bleeding high risk factors and uterine contraction curve.

PURPOSE: This work used a machine learning model to improve the accuracy of predicting postpartum hemorrhage in vaginal delivery. METHODS: Among the 25,098 deliveries in the obstetrics department of the First Hospital of Jinan University recorded from 2016 to 2020, 10,520 were vaginal deliveries with complete study data. Further review selected 850 cases of postpartum hemorrhage (amount of bleeding > 500 mL) and 54 cases of severe postpartum hemorrhage (amount of bleeding > 1000 mL). Indicators of clinical risk factors for postpartum hemorrhage were retrieved from electronic medical records. Features of the uterine contraction curve were extracted 2 h prior to vaginal delivery and modeled using a 49-variable machine learning with 90% of study cases used in the training set and 10% of study cases used in the test set. Accuracy was compared among the assessment table, classical statistical models, and machine learning models used to predict postpartum hemorrhage to assess their clinical use. The assessment table contained 16 high-risk factor scores to predict postpartum hemorrhage. The classical statistical model used was Logistic Regression (LR). The machine learning models were Random Forest (RF), K Nearest Neighbor (KNN), and the one integrated with Lightgbm (LGB) and LR. The effect of model prediction was evaluated by area under the receiver operating characteristic curve (AUC), namely, C-static, calibration curve Brier score, decision curve, F-measure, sensitivity (SE), and specificity (SP). RESULTS: 1: Among the tested tools, the machine learning model LGB + LR has the best performance in predicting postpartum hemorrhage. Its Brier, AUC, and F-measure scores are better than those of other models in each group, and its SE and SP reach 0.694 and 0.800, respectively. The predictive performance of the classical statistical model LR is AUC: 0.729, 95%CI [0.702-0.756]). 2: Verification on the testing set reveals that the features of uterine contraction contribute to the improved accuracy of the model prediction. 3: LGB + LR model suggested that among the 49 indicators for predicting severe postpartum hemorrhage, the importance of the first 10 characteristics in descending order is as follows: hematocrit (%), shock index, frequency of contractions (min-1), white blood cell count, gestational hypertension, neonatal weight (kg), time of second labor (min), mean area of contractions (mmHg s), total amniotic fluid (mL), and body mass index (BMI). The prediction effect is close to that of the model after training with all 49 features. The predictive effect was close to that of the model after training using all 49 features. 4: Contraction frequency and intensity Mean_Area (representing effective contractions) have a high predictive value for severe postpartum hemorrhage. 5: Blood loss amount within 2 h has a high warning effect on postpartum hemorrhage, and the increase in AUC to 0.95 indicates that postpartum bleeding mostly occurs within 2 h after delivery. CONCLUSION: Machine learning models incorporated with uterine contraction features can further improve the accuracy of postpartum hemorrhage prediction in vaginal delivery and provide a reference for clinicians to intervene early and reduce adverse pregnancy outcomes.

Giant Congenital Melanocytic Nevus in a Chinese Newborn.

Giant congenital melanocytic nevus (GCMN) is a rare birthmark disorder that reportedly affects 1 in 20,000-500,000 live births. Here, we present a case of GCMN in a 1-day-old newborn that covered the entire abdomen, reaching the thigh and chest, and laterally toward the backward aspect of the trunk to involve the entire back and buttocks. We discuss the diagnostic and treatment approach.

Dissection of the potential pharmacological function of neohesperidin dihydrochalcone - a food additive - by in vivo substances profiling and network pharmacology.

Food additives are widely used in our daily life, and the side-effects caused by them have gained extensive attention around the world. Notably, constituent-oriented metabolites, in some sense, always contribute to pharmacological changes, inducing toxicity, therapeutic effects, etc. Characterization of the metabolites and their potential functions is of great importance to the practical applications. In this work, an integrated strategy by combining metabolite profiling and network pharmacology was applied to characterize the metabolic features and reveal pharmacological changes of neohesperidin dihydrochalcone (NHDC) in vivo to demonstrate its pharmacological mechanism and potential functions. As a result, a total of 19 metabolites (3 in plasma, 19 in urine, 8 in feces, 3 in heart, 5 in liver, 0 in spleen, 1 in lung, 2 in kidneys and 2 in brain) were screened and 18 of them were characterized for the first time. Phase I metabolic reactions of hydrolysis and phase II reactions of glucuronidation, sulfation, glutamylation, N-butyryl glycylation and lactylation were the main metabolic reactions of NHDC in vivo. Moreover, the results analyzed by network pharmacology revealed that, in addition to common pathways (steroid hormone biosynthesis) of NHDC, metabolites' targets were involved in pathways in cancer, ovarian steroidogenesis, proteoglycans in cancer, PI3K-Akt signaling pathway and progesterone-mediated oocyte maturation, indicating that these functional changes might result in potential novel functions or other side-effects, such as a disorder of steroid hormones. Our work provided the metabolic features and functional modifications of NHDC in vivo for the first time, and meaningful information for further pharmacological validations or potential functions is supplied.

Prognostic value of an autophagy-related long-noncoding-RNA signature for endometrial cancer.

This study retrieved the transcriptome profiling data of 552 endometrial cancer (EC) patients from the TCGA (The Cancer Genome Atlas) database, and identified 1297 lncRNAs (long noncoding RNAs) related to autophagy genes using Pearson correlation analysis. Univariate Cox regression analysis of the training data set revealed that 14 autophagy-related lncRNAs had significantly prognostic value for endometrial cancer (P < 0.01). Multivariate Cox regression analysis of these autophagy-related lncRNAs established the following autophagy-related lncRNA prognosis signature for endometrial cancer: PI = (0.255 × AC005229.4 expression) + (0.405 × BX322234.1 expression) + (0.169 × FIRRE expression value) + (-0.122 × RAB11B-AS1 expression) + (-0.338 × AC003102.1 expression). This signature was validated in both the testing data set and the entire data set. The areas under the receiver operating characteristics curves for the 1-, 3-, and 5-year overall survival rates in the entire data set were 0.772, 0.733, and 0.714, respectively. In addition, a gene set enrichment analysis confirmed that cancer-related and autophagy-related pathways were significantly up-regulated in the high-risk group. In summary, this study has demonstrated that a signature comprising five autophagy-related lncRNAs has potential as an independent prognostic indicator of endometrial cancer, and also that these lncRNAs may play a key role in the development of endometrial cancer.

ZBTB7A, a potential biomarker for prognosis and immune infiltrates, inhibits progression of endometrial cancer based on bioinformatics analysis and experiments.

BACKGROUD: ZBTB protein is an important member of the C2H2 zinc finger protein family. As a transcription factor, it is widely involved in the transcriptional regulation of genes, cell proliferation, differentiation, and apoptosis. The ZBTB7A has been largely linked to different kinds of tumors due to its diverse function. However, the value for ZBTB7A in uterine corpus endometrial carcinoma (UCEC) is unclear. METHODS: In our work, we assessed the importance of ZBTB7A in UCEC. Firstly, Using Oncomine and Tumor Immunoassay Resource (TIMER) databases to evaluate the expression of ZBTB7A. Secondly, we explored the co-expression network of ZBTB7A through the cBioPortal online tool, Metascape, and LinkedOmics. TIMER was also used to explore the relationship between ZBTB7A and tumor immune invasion, and to detect the correlation between the ZBTB7A and the marker genes related to immune infiltration. Finally, CCK8, migration, ChIP assays were introduced to partly validate ZBTB7A function in endometrial cancer cells. RESULTS: We found the ZBTB7A expression in TIMER was associated with various cancers, especially UCEC. The decreased expression of ZBTB7A was markedly related to the stage and prognosis of UCEC. Furthermore, ZBTB7A was also related to the expression of various immune markers such as Neutrophils, Dendritic cell, T cell (general), Th1, Th2, and Treg. Finally, we verified that ZBTB7A repressed E2F4 transcription and inhibited cells proliferation and migration. These results indicate that ZBTB7A may play a vital role in regulating immune cell infiltration in UCEC, and is a valuable prognostic marker. CONCLUSIONS: In summary, we demonstrate that ZBTB7A is notably downregulated in UCEC, plays a vital role in regulating immune cell infiltration, possesses diagnostic and prognostic values and attenuates E2F4 transcription and cell proliferation, migration in vitro.

RNF183 Is a Prognostic Biomarker and Correlates With Tumor Purity, Immune Infiltrates in Uterine Corpus Endometrial Carcinoma.

RNF183, a member of the E3 ubiquitin ligase, has been shown to involve in carcinogenesis and proposed as one of the biomarkers in Uterine Corpus Endometrial Carcinoma (UCEC). However, no research focused on the role of RNF183 in UCEC. We analyzed the expression and immune infiltration of RNF183 in UCEC. TIMER, UALCAN, and GEPIA were used to analyze the gene expression of RNF183. We emplored Kaplan-Meier Plotter to examine the overall survival and progression-free survival of RNF183, and applied GeneMANIA to identify RNF183-related functional networks. LinkedOmics was helpful to identify the differential gene expression of RNF183, and to further analyze gene ontology and the genome pathways in the Kyoto Protocol. Finally, we used TIMER to investigate the immune infiltration of RNF183 in UCEC. Otherwise, we partly verified the results of bioinformatics analysis that RNF183 controlled ERα expression in ERα-positive Ishikawa cells dependent on its RING finger domain. We also found that ERα increased the stability of RNF183 through the post-translational mechanism. Together, patients with a high level of RNF183 harbor favorable overall and progression-free survival. High expression of RNF183 was associated with a low stage, endometrioid, and TP53 Non-Mutant status in endometrial cancer. The RNF183 expression was greater at higher expression and the tumor stage was greater at the lower level. On the side of immunization, high level of RNF183 in UCEC is negatively related to tumor purity, infiltrating levels of CD4 + T cells, neutrophils, and dendritic cells. Besides, the expression of RNF183 in UCEC is significantly correlated with the expression of several immune cell markers, including B cell, M1 macrophage marker, M2 Macrophage, Dendritic cell, Th1 markers, Th2 markers, Treg markers, and T cell exhaustion markers, indicating its role in regulating tumor immunity. These results suggested that RNF183 may be considered as a novel prognostic factor in endometrial cancer and an early diagnostic indicator for patients with UCEC.

Gestational diabetes mellitus in women increased the risk of neonatal infection via inflammation and autophagy in the placenta.

BACKGROUND: Gestational diabetes mellitus (GDM) produces numerous problems for maternal and fetal outcomes. However, the precise molecular mechanisms of GDM are not clear. METHODS: In our study, we randomly assigned 22 pregnant women with fasting glucose concentrations, 1 hour oral glucose tolerance test (1H-OGTT) and 2 hour oral glucose tolerance test (2H-OGTT), different than 28 normal pregnant women from a sample of 107 pregnant women at the First Affiliated Hospital of Jinan University in China. Lipopolysaccharide (LPS), interleukin 1 alpha (IL-1α), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) were measured from blood plasma of pregnant women and umbilical arteries using ultraviolet spectrophotometry. Hematoxylin & Eosin (H&E), Periodic acid-Schiff (PAS) or Masson staining were performed to examine whether diabetes mellitus altered the morphology of placenta. Quantitative PCR (Q-PCR), western blotting and immunofluorescent staining were performed to examine whether diabetes mellitus and autophagy altered the gene expressions of the placental tissue. RESULTS: We found that women with GDM exhibited increased placental weight and risk of neonatal infection. The concentrations of IL-6 protein and IL-8 protein in GDM were increased in both maternal and umbilical arterial blood. H&E, Masson and PAS staining results showed an increased number of placental villi and glycogen deposition in patients with GDM, but no placental sclerosis was found. Q-PCR results suggested that the expression levels of HIF-1α and the toll like receptor 4 (TLR4)/ myeloid differential protein-88 (MyD88)/ nuclear factor kappa-B (NF-κB) pathway were increased in the GDM placenta. Through Western Blotting, we found that the expression of NF-kappa-B inhibitor alpha (IKBα) and Nuclear factor-κB p65 (NF-κB p65) in GDM placenta was significantly enhanced. We also showed that the key autophagy-related genes, autophagy-related 7 (ATG7) and microtubule-associated protein 1A/1B-light chain 3 (LC3), were increased in GDM compared with normal pregnant women. CONCLUSIONS: Our results suggest that women with GDM exhibit an increased risk of neonatal infection via inflammation and autophagy in the placenta.