Rosiglitazone alleviates LPS-induced endometritis via suppression of TLR4-mediated NF-κB activation.

OBJECTIVE: The aim of this study was to investigate the anti-inflammatory effect of Rosiglitazone (RGZ) on lipopolysaccharide (LPS) -induced Endometritis and explore its possible mechanism. METHODS: The preventive and therapeutic effects of RGZ on Endometritis were studied in vivo and in vitro. A total of 40 female C57BL/6 mice were randomly divided into the following 4 groups: RGZ+LPS, RGZ control, LPS and DMSO control. The mice uterine tissue sections were performed with HE and immunohistochemical staining. Human endometrial stromal cells (HESCs) were cultured, and different concentrations of LPS stimulation groups and RGZ and/or a TLR4 signaling inhibitor TAK-242 pretreatment +LPS groups were established to further elucidate the underlying mechanisms of this protective effect of RGZ. RESULTS: The HE results in mice showed that RGZ+LPS group had less tissue loss than LPS group. Immunohistochemical staining (IHC) results showed that the expression of TLR4 after RGZ treatment was significantly lower than that in LPS group. These findings suggested that RGZ effectively improves the pathological changes associated with LPS-induced endometritis by inhibiting TLR4. Reverse transcription-polymerase chain reaction and western blot analysis demonstrated that RGZ pretreatment suppresses the expression of Toll-like receptor 4 (TLR4) and its downstream activation of nuclear factor-κB (NF-κB). In vitro, RGZ inhibited LPS-stimulated expression of proinflammatory cytokines in a dose-dependent manner and also downregulated LPS induced toll-like receptor 4 (TLR4) expression and inhibited phosphorylation of LPS-induced nuclear transcription factor-kappa B (NF-κB) P65 protein. CONCLUSIONS: These results suggest that RGZ may inhibit LPS-induced endometritis through the TLR4-mediated NF-κB pathway.

Regioselectivity Switch of α-Amino Acid-Derived Esters and MBH Carbonates for the Synthesis of Allyl-Substituted Azlactones.

Allylic azlactones are greatly significant in terms of potential bioactivities and synthetic applications. Owing to the burgeoning interest of the pharmaceutical industry in α-amino acid derivatives, discovering strategies for the synthesis of allylic azlactones is important. Herein, we establish a transition-metal-free regioselectivity switch of α-amino acid-derived esters and MBH carbonates, which exhibits broad reaction scope and good reaction yields. Control reactions indicate that both base and solvent are important for regioselectivity.

Increasing expression of STING by ERα antagonizes LCN2 downregulation during chronic endometritis.

Chronic endometritis has a high incidence in infertile women, which is caused by endometrial microbiome infection. In response to microbial infection, the role of defensins during chronic endometritis need explored. Besides, the expression of estrogen and its receptors vary in different menstrual cycles, but their roles in chronic endometritis are still unclear. In this study, we used the human endometrial tissues to examine the expression of antimicrobial peptides (AMPs) α-defensin hNP-1 and ß-defensins hBD-1, hBD-2, hBD-3, hBD-4 and LCN2. We found the expression of hBD-1 and LCN2 were downregulated in endometritis tissues, while the expressions of hBD-2, hBD-3, hBD-4, hNP-1, and estrogen and ERα were upregulated in chronic endometritis tissues compared to normal tissues. The expression and phosphorylation of STING, which is a crucial mediator of mammalian innate immunity in response to pathogens, was regulated with the treatment of ERα inhibitor raloxifene (Rx). Furthermore, using with the estrogen receptor inhibitor Rx and STING inhibitor H-151 significantly decreases the LCN2 expression. Taken together, these results suggested ERα was upregulated to modulate STING expression inducing LCN2 antimicrobial peptide expression to modulate the mucosal immunity during chronic endometritis.

Upregulated RPA2 in endometrial tissues of repeated implantation failure patients impairs the endometrial decidualization.

PURPOSE: To investigate the expression and underlying mechanism of RPA2 in endometrium of patients with repeated implantation failure (RIF). METHODS: In this study, we retrieved the expression profiles from GEO databases and filtered the differentially expressed genes between RIF and the fertile control group. Ultimately, RPA2 was confirmed as a target gene. RPA2 expression in endometrial tissues of RIF patients, the control group, and different phases was detected by RT-qPCR, immunohistochemistry, and Western blotting. The role of RPA2 in endometrial decidualization was performed by in vitro decidualization inducing by 8-Br-cAMP and MPA. Furthermore, RT-qPCR was used to detect changes in the decidual biomarkers after transfection of RPA2 overexpression vector in human endometrium stromal cell (HESC). RESULTS: RPA2 was significantly upregulated in the mid-secretory endometrium of patients with RIF. As a proliferation-related gene, RPA2 was obviously higher expressed at proliferative phase during the normal menstrual cycles. Moreover, the downregulation of RPA2 was discovered during decidualization of HESC. Furthermore, RPA2 overexpression impaired decidualization by inhibiting the expression of prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1). CONCLUSIONS: Our finding indicated that aberrant upregulation of RPA2 attenuated decidualization of HESC in RIF women and provided new potential therapeutic targets.

Death associated protein­3 (DAP3) and DAP3 binding cell death enhancer­1 (DELE1) in human colorectal cancer, and their impacts on clinical outcome and chemoresistance.

Death associated protein­3 (DAP3) was identified as a responsive protein to interferon­gamma­induced cell death which possibly exerts this regulation by interacting with DAP3 binding cell Death enhancer­1 (DELE1), a newly discovered mitochondrial stress protein in response to cell stress signals. Whilst DAP3 has been shown to be aberrantly expressed in several cancer types (i.e. breast cancer), little is known about the relationship between DAP3 and DELE1 in cancers. The present study examined the expression levels of both DAP3 and DELE1 in clinical colorectal cancers (CRCs), as well as their implication on chemoresistance and mechanism behind the action. Firstly, transcript levels of both DAP3 and DELE1 were quantitatively assessed in a clinical cohort of CRC (n=94). Tumour tissues had significantly higher levels of DAP3, but not DELE1 compared with normal tissues. Levels of DAP3 and DELE1 had a significant association with patient's clinical outcomes and local recurrence. DAP3 and DELE1 significantly correlated in normal colorectal tissues but not in tumour tissues. Secondly, the protein levels of DAP3 and DELE1 were evaluated in both normal and tumour colon tissues which showed that both proteins were highly aberrant in CRC tissues. In addition, both DAP3 and DELE1 at transcript and protein levels were identified as prognostic factors for patient's clinical outcomes. Furthermore, in in vitro assays, knocking down DAP3 or DELE1, and in particular both DAP3 and DELE1 together rendered the CRC cells more sensitive to chemotherapy drugs, consistent with clinical findings of the TCGA­COAD datasets. The acquisition of drug sensitivity following the genetic knockdown was independent of the mitochondrial metabolism, as neither DAP3 knockdown nor DELE1 knockdown showed a significant change. In summary, DAP3 and DELE1 are highly aberrant in CRCs, and both molecules are prognostic factors for patient's clinical outcomes and local recurrence, and are indicators for chemoresistance.

The Clinical Efficacy of Personalized Embryo Transfer Guided by the Endometrial Receptivity Array/Analysis on IVF/ICSI Outcomes: A Systematic Review and Meta-Analysis.

Objective: To assess the prevalence of displaced window of implantation (WOI) in infertile women, and the clinical utility of personalized embryo transfer (pET) guided by the endometrial receptivity array/analysis (ERA) on IVF/ICSI outcomes. Methods: The protocol was registered at Prospero: CRD42020204237. We systematically searched all published English literature related to the prevalence of WOI displacement and ongoing pregnancy rate/live birth rate in the overall good-prognosis infertile patients (GPP) and/or repeated implantation failure (RIF) patients undergoing IVF/ICSI-ET cycles after ERA test until August 2021. Result(s): 11 published studies were enrolled in the final analysis. The estimate of the incidence of WOI displacement based on ERA was 38% (95%CI 19-57%) in GPP and 34% (95%CI 24-43%) in RIF, respectively. There was no difference in OPR/LBR between patients undergoing routine ET without ERA test and those who following pET with ERA (39.5 vs. 53.7%, OR 1.28, p = 0.49, 95%CI 0.92-1.77, I 2 = 0%) in relative GPP. Notably, the meta-analysis revealed that OPR/LBR of patients with RIF undergoing pET who had non-receptive ERA increased to the level of to those undergoing sET with receptive ERA (40.7 vs.49.6%, OR 0.94, p = 0.85, 95%CI 0.70-1.26, I 2 = 0%). Conclusion: Considering the approximately one third of infertile women could suffered from displaced WOI, the ERA test emerged as a promising tool. Although the present meta-analysis demonstrates that patients with general good-prognosis may not benefit from ERA, pET guided by ERA significantly increases the chances of pregnancy for non-receptive patients with RIF of endometrial origin.

Higher Chronic Endometritis Incidences within Infertile Polycystic Ovary Syndrome Clinical Cases.

Background: Clinical cases of a polycystic ovarian syndrome (PCOS) have prolonged subclinical inflammation. Hysteroscopy has revealed worsened chronic endometritis (CE), particularly endometrial diffuse hyperemia, in PCOS patients. However, the possible relationships between PCOS and CE remain largely unexplored. Methods: This retrospective-based investigation was conducted on 3336 infertile patients. The PCOS group consisted of 508 patients, while the non-POCS group consisted of 2828 individuals with normal ovarian function. Their clinical features and CE prevalence diagnosed with hysteroscopy were compared. The risk factors affecting the incidence of diffuse endometrial hyperemia were analyzed by binary logistic regression. Results: The PCOS cohort and the non-PCOS cohort showed marked variations in age, body mass index (BMI), infertility (primary, secondary), basal hormone level (bFSH, bLH, bT, and PRL), anti-Müllerian hormone (AMH), and CA125 (P < 0.05). The prevalence of CE in PCOS women was 41.73% (212/508), markedly higher than the 28.50% in the non-PCOS cohort (806/2828). Variations within diffuse endometrial hyperemia prevalence were especially marked (P < 0.05). Furthermore, we found that the variables of BMI, bLH, bT, and AMH correlated with diffuse endometrial hyperemia. Conclusions: CE prevalence was elevated in clinical cases of infertility associated with PCOS, and diffuse endometrial hyperemia was prevalent, as indicated by hysteroscopy. Furthermore, increased BMI, bLH, bT, and AMH levels all contribute to the risk of diffuse endometrial hyperemia.

Identification and verification of immune-related gene prognostic signature based on ssGSEA for breast cancer.

Introduction: Breast cancer (BC) is the most common cancer in women worldwide and has a high mortality rate. The fact that the tumor microenvironment affects clinical outcomes of all types of cancers underlines the involvement of various immune-related genes (IRGs). Therefore, this study aimed to establish an IRGs-based signature for the prognosis of BC patients. Material and methods: In this study, 12 immune cell infiltrating degrees in 1,102 BC cases from The Cancer Genome Atlas (TCGA) database were assessed, and RNA-sequencing (RNA-seq) data of these samples were analyzed by single-sample gene set enrichment analysis (ssGSEA). Based on the results, high, low, and middle immune infiltrating clusters were constructed. A total of 138 overlapped differentially expressed genes (DEGs) were identified in the high and low infiltrating clusters, as well as in normal and BC samples. Univariate Cox regression and LASSO analyses were also performed. Furthermore, GSEA suggested some highly enriched pathways in the different immune infiltrating clusters, leading to a better understanding of potential mechanisms of immune infiltration in BC. Results: Finally, 19 immune-related genes were identified that could be utilized as a potential prognostic biomarker for BC. Kaplan-Meier plot and ROC curve, univariate as well as multivariate Cox analyses were carried out, which suggested that the 19-IRG-based signature is a significant prognosis factor independent of clinical features. Based on the analysis of protein-protein interactions (PPI), the three hub genes were identified. Conclusions: These results provide a new method to predict the prognosis and survival of BC based on the three genes' features.

Integrated transcriptome and network analysis identifies EZH2/CCNB1/PPARG as prognostic factors in breast cancer.

Breast cancer (BC) has high morbidity, with significant relapse and mortality rates in women worldwide. Therefore, further exploration of its pathogenesis is of great significance. This study selected therapy genes and possible biomarkers to predict BC using bioinformatic methods. To this end, the study examined 21 healthy breasts along with 457 BC tissues in two Gene Expression Omnibus (GEO) datasets and then identified differentially expressed genes (DEGs). Survival-associated DEGs were screened using the Kaplan-Meier curve. Based on Gene Ontology (GO) annotation, survival-associated DEGs were mostly associated with cell division and cellular response to hormone stimulus. The enriched Kyoto Encyclopedia of Gene and Genome (KEGG) pathway was mostly correlated with cell cycle and tyrosine metabolism. Using overlapped survival-associated DEGs, a survival-associated PPI network was constructed. PPI analysis revealed three hub genes (EZH2, CCNB1, and PPARG) by their degree of connection. These hub genes were confirmed using The Cancer Genome Atlas (TCGA)-BRCA dataset and BC tissue samples. Through Gene Set Enrichment Analysis (GSEA), the molecular mechanism of the potential therapy and prognostic genes were evaluated. Thus, hub genes were shown to be associated with KEGG_CELL_CYCLE and VANTVEER_BREAST_CANCER_POOR_PROGNOSIS gene sets. Finally, based on integrated bioinformatics analysis, this study identified three hub genes as possible prognostic biomarkers and therapeutic targets for BC. The results obtained further understanding of the underground molecular mechanisms related to BC occurrence and prognostic outcomes.

Efficacy of the depot gonadotropin-releasing hormone agonist protocol on in vitro fertilization outcomes in young poor ovarian responders from POSEIDON group 3.

OBJECTIVE: To investigate whether the depot gonadotropin-releasing hormone (GnRH) agonist protocol could improve in vitro fertilization (IVF) outcomes for young poor responders from POSEIDON group 3. METHODS: This retrospective cohort study was carried out from June 2017 to June 2020. A total of 451 patients were assigned to three groups depending on the ovarian stimulation protocols. The outcome parameters of IVF were compared in each group. RESULTS: Patients who received the depot GnRH agonist had significantly higher cumulative clinical pregnancy rates (50.88%, 32.02%, and 31.88%, respectively; P = 0.009 and P = 0.007) and cumulative live birth rate (48.25%, 26.97%, and 28.99%, respectively; P = 0.004 and P = 0.009) compared with mild ovarian stimulation protocol and GnRH antagonist protocol. They also had higher live birth rate per fresh embryo transfer cycle (47.78%, 32.35%, and 36.62%, respectively), but these differences were not statistically significant. Moreover, duration of stimulation, total dose of gonadotropins and endometrial thickness were significantly higher among women who received the depot GnRH agonist (P < 0.001). However, they had lower embryo transfer cancellation rate, and abnormal endometrium rate (P < 0.001). CONCLUSION: The depot GnRH agonist protocol may improve cumulative clinical pregnancy rate and cumulative live birth rate for young women with poor ovarian response from POSEIDON group 3.

Dyslipidemia Is Negatively Associated With the Cumulative Live-Birth Rate in Patients Without PCOS Following IVF/ICSI.

Objective: To evaluate the effect of dyslipidemia on the cumulative live-birth rate (cLBR) in patients without polycystic ovary syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) cycles. Methods: A total of 1,132 patients from the Yantai Yuhuangding Hospital Affiliated to Qingdao University from January 2016 to December 2017 were retrospectively included. The subjects were distributed into two groups based on their lipid profiles, namely, dyslipidemia group (n = 195) and control group (n = 937). The clinical and laboratory parameters of the two groups were analyzed, and a multivariate logistic regression analysis of the cLBR was conducted. In addition, subgroup analysis was carried out to avoid deviation according to the body mass index (BMI). Results: Patients with dyslipidemia had significantly greater BMI and longer duration of infertility, as well as lower antral follicle count and basal follicle-stimulating hormone level compared with patients without dyslipidemia. Stratified analysis showed that dyslipidemia was associated with a significantly higher total gonadotrophin dosage required for ovarian stimulation as well as lower number of oocytes retrieved, independent of obesity. The live-birth rate in fresh cycle and cLBR were higher in the control group, although the difference between the groups was not significant (54.9% vs. 47.3%, p = 0.116; 67.6% vs. 62.1%, p = 0.138). However, multivariate logistic regression analysis adjusting for potential confounders showed that dyslipidemia was negatively associated with cLBR (OR, 0.702, 95% CI, 0.533-0.881, p = 0.044). Conclusion: Our findings demonstrate for the first time that dyslipidemia has a deleterious impact on cLBR, independent of obesity, in non-PCOS population considered to have good prognosis. Assessment of serum lipid profiles as well as the provision of nutritional counseling is essential for increasing successful outcomes in assisted reproductive techniques.

Identification of candidate biomarkers correlated with poor prognosis of breast cancer based on bioinformatics analysis.

Breast cancer (BC) is a malignancy with high incidence among women in the world. This study aims to screen key genes and potential prognostic biomarkers for BC using bioinformatics analysis. Total 58 normal tissues and 203 cancer tissues were collected from three Gene Expression Omnibus (GEO) gene expression profiles, and then the differential expressed genes (DEGs) were identified. Subsequently, the Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway were analyzed to investigate the biological function of DEGs. Additionally, hub genes were screened by constructing a protein-protein interaction (PPI) network. Then, we explored the prognostic value and molecular mechanism of these hub genes using Kaplan-Meier (KM) curve and Gene Set Enrichment Analysis (GSEA). As a result, 42 up-regulated and 82 down-regulated DEGs were screened out from GEO datasets. The DEGs were mainly related to cell cycles and cell proliferation by GO and KEGG pathway analysis. Furthermore, 12 hub genes (FN1, AURKA, CCNB1, BUB1B, PRC1, TPX2, NUSAP1, TOP2A, KIF20A, KIF2C, RRM2, ASPM) with a high degree were identified initially, among which, 11 hub genes were significantly correlated with the prognosis of BC patients based on the Kaplan-Meier-plotter. GSEA reviewed that these hub genes correlated with KEGG_CELL_CYCLE and HALLMARK_P53_PATHWAY. In conclusion, this study identified 11 key genes as BC potential prognosis biomarkers on the basis of integrated bioinformatics analysis. This finding will improve our knowledge of the BC progress and mechanisms.

Hsa_circ_0038383-mediated competitive endogenous RNA network in recurrent implantation failure.

BACKGROUND: Inadequate endometrial receptivity contributes to recurrent implantation failure (RIF) during IVF-embryo transfer. Though multiple circRNAs have been confirmed differentially expression in RIF, the potential function of novel circRNAs needed to be detected. RESULTS: The top ten DEcircRNAs were selected as initial candidates. A ceRNA network was conducted on the basis of circRNA-miRNA-mRNA potential interaction, consisting of 10 DEcircRNAs, 28 DEmiRNAs and 59 DEmRNAs. Three down-regulation circRNAs with high degree of connectivity were verified by RT-qPCR, and results suggested that only hsa_circ_0038383 was significantly downregulation in RIF compared with control group. Subsequently, three hub genes (HOXA3, HOXA9 and PBX1) were identified as hub genes. Ultimately, a subnetwork was determined based on one DEcircRNA (hsa_circ_0038383), two DEmiRNAs (has-miR-196b-5p and has-miR-424-5p), and three DEmRNAs (HOXA3, HOXA9 and PBX1). Following verification, hsa_circ_0038383/miR-196b-5p/HOXA9 axis may be a key pathway in affecting RIF. CONCLUSION: In summary, a hsa_circ_0038383-mediated ceRNA network related to RIF was proposed. This network provided new insight into exploring potential biomarkers for diagnosis and clinical treatment of RIF. METHODS: We retrieved the expression profiles of RIF from GEO databases (circRNA, microRNA and mRNA) and constructed a competing endogenous RNAs (ceRNA) network based on predicted circRNA-miRNA and miRNA-mRNA pairs. The expression levels of three hub DEcircRNAs identified by cytoscape were validated by RT-qPCR.

DEPDC1 upregulation promotes cell proliferation and predicts poor prognosis in patients with gastric cancer.

BACKGROUND: Previous studies revealed that DEP domain containing 1 (DEPDC1) is involved in the carcinogenesis and progression of several types of human cancer. However the role of DEPDC1 in gastric cancer has not been studied. OBJECTIVE: The objective of this study was to study the expression and pathophysiological function of DEPDC1 in gastric cancer. METHODS: DEPDC1 expression in gastric adenocarcinoma cells was examined with Western blot and qRT-PCR. Clinical pathological features of patients were determined by immunohistochemistry. The effect of DEPDC1 expression on cell proliferation was studied by in vitro cell proliferation assay; and cell cycle influence was assessed by flow cytometry. Survival curves were plotted using Kaplan-Meier. RESULTS: DEPDC1 was overexpressed in gastric adenocarcinoma tissues compared with the paired adjacent normal gastric tissues, in accordance with mRNA level downloaded from GEPIA database. DEPDC1 expression level was significantly associated with cancer metastasis and differentiation. DEPDC1 upregulation caused cell cycle accelerating from G1 to S phase, and it was correlated with poorer overall survival. CONCLUSION: Therefore, DEPDC1 upregulation in gastric adenocarcinoma is associated with tumor development and poor clinical outcomes of the patients, implying DEPDC1 might be a potential therapeutic target against gastric cancer.

Assisted Oocyte Activation With Calcium Ionophore Improves Pregnancy Outcomes and Offspring Safety in Infertile Patients: A Systematic Review and Meta-Analysis.

This study aimed to evaluate the efficacy and safety of calcium ionophore during assisted oocyte activation (AOA). This meta-analysis contained randomized controlled trials and prospective observational and retrospective trials. The summary odds ratio (OR) with 95% confidence intervals (CIs) was calculated for clinical pregnancy rate and live birth rate. Both fixed and random effects models were applied. A total of 22 studies were included into this meta-analysis. Seventeen of the included studies showed that calcium ionophore increased the clinical pregnancy rate (OR, 2.14; 95% CI, 1.38-3.31). Similarly, 14 studies indicated that AOA with calcium ionophore during intracytoplasmic sperm injection (ICSI) improved the live birth rate considerably (OR, 2.65; 95% CI, 1.53-4.60). Moreover, fertilization, blastocyst formation, and implantation rate were higher after using AOA with calcium ionophore combined with ICSI. In addition, calcium ionophore did not increase top-quality embryo rate, cleavage rate, miscarriage rate, congenital birth defects, and neonatal sex ratio. Therefore, calcium ionophore followed by ICSI not only significantly improved live birth and overall pregnancy, but also did not affect the incidence of miscarriage, congenital birth defects, and neonatal sex ratio. This meta-analysis indicated that using calcium ionophore to activate oocytes was beneficial for couples with poor fertilization rates following ICSI.

Analysis of pharmacological mechanisms of Yinyanghuo as treatment of erectile dysfunction with network pharmacology-based strategy.

Erectile dysfunction is considered an important health problem that impacts the quality of life of men. Yinyanghuo, also called Epimedium or Horny Goat Weed, is a frequently used Chinese traditional herbal medicine, commonly used in treating erectile dysfunction in China. A network pharmacology method was performed systematically, at a molecular level, to analyse the pharmacological mechanism of Yinyanghuo as erectile dysfunction therapy. The network pharmacology method used in this study primarily includes prescreening of the active compounds, prediction of targets, network analysis and gene enrichment analysis. This network analysis proved that 4 targets (AR, NR3C2, PDE5A and BMP2) could be the targets of Yinyanghuo therapy on erectile dysfunction. Besides, gene enrichment analysis predicted that Yinyanghuo might have a role in erectile dysfunction by regulating 10 molecular functions, 8 cellular components, 10 biological processes and 36 possible targets related to 10 signalling pathways. Our study demonstrated the molecular and pharmacological mechanisms of Yinyanghuo against erectile dysfunction with a holistic approach and demonstrated a powerful method for analysing pharmacological mechanisms and rational utilisation of Traditional Chinese Medicine clinically.

Effect of upregulation of DD3 on early detection and prognosis in prostate cancer.

BACKGROUND: Expression of prostate cancer antigen 3 (PCA3 OR DD3) in the blood has been reported to be significantly higher in prostate cancer (PCa) than in benign prostate hyperplasia (BPH). To confirm whether DD3 expression is significantly different between PCa and BPH tissues, DD3 expression was tested in the blood both preoperatively and postoperatively and in the paired tissues of PCa patients. METHODS: Expression levels of DD3 mRNA in the blood of patients who did not undergo surgery (PCa, n=102; BPH, n=53), those underwent surgery (preoperative, n=35; postoperative, n=35), and in PCa tissue specimens (tumor, n=41; adjacent normal, n=21) were determined by real-time quantitative PCR. Sensitivity and specificity for DD3 in PCa patients were validated by receiver operating characteristic (ROC) curve analysis. RESULTS: Our data suggest that expression level of DD3 in blood samples was significantly higher in PCa patients than in BPH patients (P=0.005). Expression of DD3 mRNA was also significantly elevated in PCa tissues compared with adjacent normal tissues (P=0.013). The increase in DD3 expression in PCa patients was further validated using a dataset from The Cancer Genome Atlas (n=549). Postoperative DD3 expression decreased following surgical intervention (P<0.001). Moreover, low DD3 expression was associated with improved overall survival (OS). Using gene set enrichment analysis, DD3 expression was correlated with specific PCa target genes including carcinogenesis-related and cancer proliferation-related genes. CONCLUSIONS: This study demonstrated that expression of DD3 was upregulated in blood and PCa tumor tissues and was associated with prognosis. The oncogenic role of DD3 was further validated in the TCGA database, indicating that DD3 is a potential therapeutic target for PCa. Furthermore, this study suggests that DD3 expression could be considered as a prognostic biomarker for PCa.

PD-L1 Expression in Glioblastoma, the Clinical and Prognostic Significance: A Systematic Literature Review and Meta-Analysis.

Background: The clinical and prognostic value of programmed death-ligand 1, PD-L1, in glioblastoma remains controversial. The present study aimed to identify the expression of PD-L1 for its prognostic value in glioblastoma. Methods: A comprehensive literature search was performed using the PubMed and CNKI databases. The overall survival (OS) and disease-free survival (DFS) of GBM was analyzed based on Hazard ratios (HRs) and 95% confidence intervals (CIs). Furthermore, Odds ratios (ORs) and 95% CIs were summarized for clinicopathological parameters. The statistical analysis was using RevMan 5.3 software. Results: The meta-analysis was performed by using total nine studies including 806 patients who had glioblastoma. The pooled results indicated that PD-L1 expression in tumor tissues was significantly related to a poor OS (HR = 1.63, 95%CI: 1.19-2.24, P = 0.003, random effects model) with heterogeneity (I 2 = 51%). In subgroup analyses, PD-L1 positivity was significantly associated with a worse OS for patients of American and Asian regions, but not for those of European regions. Moreover, PD-L1 expression implied a trend toward the mutation status of the IDH1 gene [coding the Isocitrate Dehydrogenase (NADP(+))-1 protein] (HR = 9.92, 95%CI: 1.85-53.08, P = 0.007, fixed effects model). However, the prediction overall survival (OS) of the patients showed that PD-L1 expression was independent from other clinicopathological features, such as gender and age. Conclusions: Our analyses indicated that high expression of PD-L1 in glioblastoma tumor tissues is associated with poor survival of patients, and PD-L1 may act as a prognostic predictor and an effective therapeutic target for glioblastoma.

Identification of biomarkers correlated with diagnosis and prognosis of endometrial cancer using bioinformatics analysis.

Endometrial cancer (EC) is one of the most common malignancies in the female genital system, characterized by high mortality and recurrence rates. This study attempted to screen key genes and potential prognostic biomarkers for EC using bioinformatics analysis. Twenty-seven normal endometrial tissues and 135 EC samples were collected from four Gene Expression Omnibus (GEO) databases, then we identified the differentially expressed genes (DEGs) and conducted downstream analyses. Moreover, we screened hub genes by constructing a protein-protein interaction (PPI) network. Finally, we assessed the prognostic values and molecular mechanism of the potential prognostic genes using the Kaplan-Meier curve and Gene Set Enrichment Analysis (GSEA). As a result, 28 upregulated and 94 downregulated genes were determined after gene integration of these four GEO data sets. Gene Ontology analysis indicated that DEGs were mainly involved in transcriptional regulation and cell proliferation. The Kyoto Encyclopedia of Gene and Genome pathway analysis primarily related to transcriptional misregulation and apoptosis. Moreover, the PPI analysis revealed 10 hub genes (JUN, UBE2I, GATA2, WT1, PIAS1, FOXL2, RUNXI, EZR, TCF4, and NR2F2) with a high degree of connectivity, among them, the expression tendency of nine genes except UBE2I were consistent with messenger RNA level from The Cancer Genome Atlas data. Furthermore, only FOXL2, TCF4, and NR2F2 were significantly correlated with prognosis of EC patients, and their low expression associated biological pathways were enriched in the cell cycle and fatty acid metabolism. In conclusion, this study identified three key genes as biomarkers and potential therapeutic targets of EC on the basis of integrated bioinformatics analysis. The findings will improve our comprehension of the molecular mechanisms underlying the pathogenesis and prognosis of EC.

Up-regulation of miR-145 may contribute to repeated implantation failure after IVF-embryo transfer by targeting PAI-1.

RESEARCH QUESTION: Repeated implantation failure (RIF) is a major limiting factor in assisted reproductive technology. As miR-145 (also known as MIR145) is up-regulated in patients with RIF, this study asked, what is the molecular mechanism underlying the affect of miR-145 on embryo implantation in RIF? DESIGN: Ishikawa cells were infected with lentivirus containing miR-145 and miR-145 NC. Massive transcriptome data analyses and bioinformatics analysis were used to search for a potential candidate target of miR-145. The expression of the potential candidate target was detected using quantitative reverse transcription PCR (qRT-PCR) and western blotting in the Ishikawa cells infected with lentivirus containing miR-145 or miR-145 NC. Subsequently, a dual luciferase reporter assay was performed to verify whether the potential candidate target was a novel direct target of miR-145. In addition, expression of PAI-1 (plasminogen activator inhibitor 1, also known as SERPINE1) in endometrial tissue from women with RIF and in control endometrial tissue was examined using qRT-PCR and immunohistochemistry. RESULTS: Based on massive transcriptome data analyses and bioinformatics analysis, PAI-1 was regarded as a potential candidate target of miR-145. miR-145 overexpression was achieved in Ishikawa cells. PAI-1 was confirmed as a direct target of miR-145 by bioinformatic analysis, qRT-PCR, western blotting and dual luciferase reporter assay. Further, results from the clinical sample indicated that at both the mRNA and protein levels, PAI-1 expression was down-regulated in endometrial tissues from women with RIF compared with control group women, and this was negatively related to miR-145 expression. CONCLUSIONS: The study results suggests that miR-145 may target and down-regulate PAI-1 expression and influence embryo implantation in women with RIF who are undergoing IVF.