Causal effects between gut microbiota and endometriosis: a two-sample Mendelian randomisation study.

BACKGROUND: Previous observational evidence has indicated the potential involvement of the gut microbiota (GM) in the development of endometriosis. However, the causal relationship of the association remains to be investigated. METHOD: Genome-wide association study (GWAS) data of GM was obtained from the MiBioGen consortium, and GWAS for endometriosis data was from the FinnGen consortium. Initially, a two-sample Mendelian randomisation (MR) analysis was performed to identify specific bacteria associated with endometriosis. Inverse variance-weighted (IVW) was used as the main MR analysis to infer causal relationships. The other four popular MR methods including MR-Egger regression, weighted mode, weighted median, and simple mode were used for secondary confirmation. Subsequently, these selected bacteria were employed as exposure to investigate their causal effects on six sub-types of endometriosis. Furthermore, reverse MR analysis was implemented to evaluate the reverse causal effects. Cochran's Q statistics was used to test the heterogeneity of instrumental variables (IVs); MR-Egger regression was used to test horizontal pleiotropy; MR-PRESSO and leave-one-out sensitivity analysis were applied to find significant outliers. RESULT: A total of 1131 single nucleotide polymorphisms (SNPs) were collected as IVs for 196 GM taxa with endometriosis as the outcome. We identified 12 causal relationships between endometriosis and GM taxa including 1 phylum, 3 families, 2 orders, and 6 genera (Rikenellaceae RC9 gut group, Eubacterium ruminantium group, Faecalibacterium, Peptococcus, Clostridium sensu stricto 1, and Ruminococcaceae UCG005). Utilizing the Bonferroni method, we identified phylum Cyanobacteria as the strongest associated GM taxa. Subsequently, 6 significant causal effects were uncovered between the 12 selected specific GM and 6 sub-types of endometriosis. Meanwhile, no reverse causal relationship was found. Further, no horizontal pleiotropy and no significant outliers were detected in the sensitive analysis. CONCLUSIONS: This MR analysis revealed significant causal effects between GM and endometriosis and phylum Cyanobacteria had the strongest association.

The imbalance of gut microbiota (GM) is suggested to be involved in the development of endometriosis while the causal relationship between GM and endometriosis remains undetermined. This two-sample mendelian randomisation analysis firstly demonstrated the potential association between GM and the risk of endometriosis including 6 sub-types. We revealed 12 causal relationships between endometriosis and GM taxa including 1 phylum, 3 families, 2 orders, and 6 genera while Phylum Cyanobacteria was the strongest associated GM taxa by using Bonferroni method. Meanwhile, we identified 6 significant causal effects between 12 selected specific GM and 6 sub-types of endometriosis. Meanwhile, the result from reverse MR analysis showed that there was no causal effect of endometriosis on the identified specific GM taxa. Thus, we revealed the causal relationship between GM and endometriosis. It is necessary to further study its potential mechanism, which may contribute to the prevention and treatment of Endometriosis.

Rational of topical photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) for treatment of endocervical canal low-grade squamous intraepithelial lesion with high-risk human papillomavirus infection.

BACKGROUND: The detection and continuous monitoring of low-grade squamous intraepithelial lesions (LSIL) within the endocervical canal pose considerable challenges, and the effectiveness of ablation treatment is also constrained. In this context, the potential efficacy of 5-aminolevulinic acid photodynamic therapy (5-ALA PDT) in targeting these concealed lesions merits exploration. The present study undertakes a comprehensive analysis of the clinical effectiveness and safety aspects associated with the utilization of 5-ALA PDT. METHODS: A retrospective analysis was conducted on a cohort of 13 patients who were diagnosed with LSIL within the endocervical canal, concomitant with high-risk human papillomavirus (hrHPV) infection. These patients were subjected to treatment with 5-ALA PDT and subsequently monitored over a period of 3-6 months following the intervention. RESULTS: The study cohort comprised 13 patients, among whom 4 presented with isolated lesions within the endocervical canal, 5 exhibited LSIL involving both the endocervical canal and the cervix vaginal portion, 3 displayed LSIL within the endocervical canal in conjunction with vaginal involvement, and 1 patient demonstrated lesions across all three of these anatomical sites. All identified lesions underwent therapeutic intervention via 5-ALA PDT. Before treatment initiation, 9 patients returned positive results in the liquid-based cytologic test (LBC), 4 displayed concurrent multiple hrHPV infections, and 5 manifested infections specifically with HPV 16/18. Subsequent to the application of 5-ALA PDT, regression was observed in the LBC results of all patients, with only 3 individuals retaining a singular type of hrHPV infection. Adverse reactions following treatment encompassed mild aberrant vaginal secretions and mild to moderately pronounced distending abdominal discomfort, all of which were remitted within a span of 7 days. CONCLUSIONS: Within the context of LSIL within the endocervical canal in association with hrHPV infection, the findings affirm the efficacy and safety of 5-ALA PDT as a viable therapeutic modality.

The comparative analysis of laparoscopic or transvaginal cerclage in pregnancies with cervical insufficiency: a retrospective cohort study.

OBJECTIVE: To evaluate the efficacy and safety of prophylactic cervical cerclage by laparoscopy in pregnant women versus transvaginal way. DESIGN: Retrospective, monocentric cohort study was performed. SETTING: The First Affiliated Hospital of Sun Yat-sen University. PATIENTS: Cases with cervical insufficiency (defined by previous history of painless second or early third trimester pregnancy loss/losses) were selected. INTERVENTIONS: Laparoscopic or transvaginal cerclage were conducted. The maternal information and the neonatal data were collected and compared. The pregnancy outcomes including the incidence of full-term labor and gestational weeks at delivery were defined as the primary outcomes. Neonatal survival and birth weight, neonatal complications were evaluated as the secondary outcomes. MEASUREMENTS AND MAIN RESULTS: Totally 36 twin pregnant cases and 82 singleton pregnant cases were managed with cerclage, either trans-laparoscopy (totally 78 cases) or transvaginal (totally 40 cases). Demographic characteristics showed no significant differences. Cases in laparoscopic group had a prolonged gestational age at delivery (36.43 ± 0.93 weeks and 33.60 ± 2.78 weeks, respectively, P < 0.001), a higher incidence of full-term labor (60.26% vs 42.50%, P = 0.05) with no significant difference of perinatal mortality (P = 0.661). Meanwhile, higher incidence of normal birth weight infants (88.46% vs 67.50%, P = 0.007) was shown in laparoscopic group with no more complications such as the cases of neonatal with Apgar < 7 (P = 0.296), and the incidence of NICU admission (P = 0.237). Besides, LTC showed good efficiency on VTC in the incidence of full-term labor: HR 0.24 (95% CI 0.070-0.85), P < 0.001. While LSC showed the similar efficiency on VSC: HR 0.734 (95% CI 0.36-1.49), P = 0.857, showing that cases with twin pregnancy may benefit more from laparoscopic cerclage. CONCLUSIONS: The comparative effect between laparoscopic and transvaginal cerclage in pregnant women showed that laparoscopic cerclage may be a relatively effective and safety prophylactic way for cervical insufficiency. This would be an acceptable and safe replace for traditional transvaginal cervical cerclage.

H19/TET1 axis promotes TGF-ß signaling linked to endothelial-to-mesenchymal transition.

While emerging evidence suggests the link between endothelial activation of TGF-ß signaling, induction of endothelial-to-mesenchymal transition (EndMT), and cardiovascular disease (CVD), the molecular underpinning of this connection remains enigmatic. Here, we report aberrant expression of H19 lncRNA and TET1 in endothelial cells (ECs) of human atherosclerotic coronary arteries. Using primary human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells (HAoECs) we show that TNF-α, a known risk factor for endothelial dysfunction and CVD, induces H19 expression which in turn activates TGF-ß signaling and EndMT via a TET1-dependent epigenetic mechanism. We also show that H19 regulates TET1 expression at the posttranscriptional level. Further, we provide evidence that this H19/TET1-mediated regulation of TGF-ß signaling and EndMT occurs in mouse pulmonary microvascular ECs in vivo under hyperglycemic conditions. We propose that endothelial activation of the H19/TET1 axis may play an important role in EndMT and perhaps CVD.

Characterization of the Sperm Proteome and Reproductive Outcomes with in Vitro, Fertilization after a Reduction in Male Ejaculatory Abstinence Period.

Semen samples from men after a short ejaculatory abstinence show improved sperm quality and result in increased pregnancy rates, but the underlying mechanisms remain unclear. Herein, we report that ejaculates from short (1-3 h) compared with long (3-7 days) periods of abstinence showed increases in motile sperm count, sperm vitality, normal sperm morphology, acrosome reaction capacity, total antioxidant capacity, sperm mitochondrial membrane potential, high DNA stainability, and a decrease in the sperm DNA fragmentation index (p, < 0.05). Sperm proteomic analysis showed 322 differentially expressed proteins (minimal fold change of ±1.5 or greater and p, < 0.05), with 224 upregulated and 98 downregulated. These differentially expressed proteins are profoundly involved in specific cellular processes, such as motility and capacitation, oxidative stress, and metabolism. Interestingly, protein trimethyllysine modification was increased, and butyryllysine, propionyllysine, and malonyllysine modifications were decreased in ejaculates from a short versus, long abstinence (p, < 0.05). Finally, the rates of implantation, clinical pregnancy, and live births from in vitro, fertilization treatments were significantly increased in semen samples after a short abstinence. Our study provides preliminary mechanistic insights into improved sperm quality and pregnancy outcomes associated with spermatozoa retrieved after a short ejaculatory abstinence.

Characterization of long non-coding RNA and messenger RNA profiles in follicular fluid from mature and immature ovarian follicles of healthy women and women with polycystic ovary syndrome.

STUDY QUESTION: Do long non-coding RNA (lncRNA) and messenger RNA (mRNA) profiles in follicular fluid from mature and immature ovarian follicles differ between healthy women and women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: lncRNA and mRNA profiles in follicular fluid from both mature and immature ovarian follicles differed significantly between healthy women and PCOS patients. WHAT IS KNOWN ALREADY: Unlike microRNAs, which have been extensively studied, lncRNAs present in follicular fluid have never been sequenced and the biological associations of lncRNAs in healthy follicles and follicles in women who develop PCOS remain largely unknown. STUDY DESIGN, SIZE, DURATION: A total of 18 subjects (8 controls and 10 PCOS patients) were recruited to participate in this study. Recruitment took place from May 2016 to September 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: The follicular fluid donors underwent their first round of in-vitro fertilization treatment. Follicle size was determined based on the average follicular diameter, and follicular fluid samples were collected from mature follicles (17-22 mm) and matched-immature follicles (8-13 mm). RNA sequencing was performed on follicular fluids from mature and immature follicles of healthy women and PCOS patients. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1583 novel lncRNAs were identified in 36 human follicular fluid samples and some were expressed differently in healthy and PCOS women. lncRNAs associated with the metabolic process were highly enriched in the follicular fluid of mature follicles from the PCOS group versus the healthy group. In the PCOS group, nervous system process lncRNAs were highly enriched in the follicular fluid of mature versus immature follicles, whereas in the healthy group, lncRNAs associated with junction adhesion and communication-related processes were highly enriched in the follicular fluid of mature versus immature follicles. In addition, differentially expressed mRNAs were principally linked to olfactory transduction pathways. Consistent results from Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) indicated that telomere maintenance and MAPK and Wnt pathways may be conserved processes, active in follicular development, and monosaccharide biosynthesis might provide possible pathway markers to distinguish between normal and PCOS follicles. We constructed gene co-expression networks that identified many co-regulatory relationships among follicular fluid lncRNAs, mRNAs, and PCOS phenotypes. Weighted Gene Co-expression Network Analysis (WGCNA) revealed lncRNAs and mRNAs that were core and others associated with the PCOS phenotype. LIMITATIONS, REASONS FOR CAUTION: It remains unclear whether these differential transcripts contribute directly to follicular development or the pathogenesis of PCOS, or are merely biomarkers. WIDER IMPLICATIONS OF THE FINDINGS: It will be important in the future for investigators to ascertain the biologic mechanisms underlying the development of both normal and PCOS follicles. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (No. 81671423, No. 81402130 and No. 81501247), the Fok Ying Tung Education Foundation (No. 151039), and Distinguished Talent Program of Shengjing Hospital (No. ME76). No competing interests declared.

Injectable cartilage microtissues based on 3D culture using porous gelatin microcarriers for cartilage defect treatment.

Cartilage tissues possess an extremely limited capacity for self-repair, and current clinical surgical approaches for treating articular cartilage defects can only provide short-term relief. Despite significant advances in the field of cartilage tissue engineering, avoiding secondary damage caused by invasive surgical procedures remains a challenge. In this study, injectable cartilage microtissues were developed through 3D culture of rat bone marrow mesenchymal stem cells (BMSCs) within porous gelatin microcarriers (GMs) and induced differentiation. These microtissues were then injected for the purpose of treating cartilage defects in vivo, via a minimally invasive approach. GMs were found to be noncytotoxic and favorable for cell attachment, proliferation and migration evaluated with BMSCs. Moreover, cartilage microtissues with a considerable number of cells and abundant extracellular matrix components were obtained from BMSC-laden GMs after induction differentiation culture for 28 days. Notably, ATDC5 cells were complementally tested to verify that the GMs were conducive to cell attachment, proliferation, migration and chondrogenic differentiation. The microtissues obtained from BMSC-laden GMs were then injected into articular cartilage defect areas in rats and achieved superior performance in alleviating inflammation and repairing cartilage. These findings suggest that the use of injectable cartilage microtissues in this study may hold promise for enhancing the long-term outcomes of cartilage defect treatments while minimizing the risk of secondary damage associated with traditional surgical techniques.

Engineered biomechanical microenvironment of articular chondrocytes based on heterogeneous GelMA hydrogel composites and dynamic mechanical compression.

Tissue-engineered articular cartilage constructs are currently not able to equal native tissues in terms of mechanical and biological properties. A major cause lies in the deficiency in engineering the biomechanical microenvironment (BMME) of articular chondrocytes. In this work, to engineer the BMME of articular chondrocytes, heterogeneous hydrogel structures of gelatin methacrylated (GelMA) containing differential-stiffness domains were first fabricated, and then periodic dynamic mechanical stimulations were applied to the hydrogel structures. The chondrocyte phenotype of ATDC5 cells was enhanced as the spatial differentiation in stiffness was increased in the hydrogel structures and was further strengthened by dynamic mechanical stimulation. It was speculated that the mechanical signals generated by the engineered BMME were sensed by the cells through the integrin ß1-FAK signaling pathway. This study revealed the key role of the combined effects of differential and dynamic BMME on the chondrocyte phenotype, which could provide theoretical guidance for highly active tissue-engineered articular cartilage.

Biomimetic cell culture for cell adhesive propagation for tissue engineering strategies.

Biomimetic cell culture, which involves creating a biomimetic microenvironment for cells in vitro by engineering approaches, has aroused increasing interest given that it maintains the normal cellular phenotype, genotype and functions displayed in vivo. Therefore, it can provide a more precise platform for disease modelling, drug development and regenerative medicine than the conventional plate cell culture. In this review, initially, we discuss the principle of biomimetic cell culture in terms of the spatial microenvironment, chemical microenvironment, and physical microenvironment. Then, the main strategies of biomimetic cell culture and their state-of-the-art progress are summarized. To create a biomimetic microenvironment for cells, a variety of strategies has been developed, ranging from conventional scaffold strategies, such as macroscopic scaffolds, microcarriers, and microgels, to emerging scaffold-free strategies, such as spheroids, organoids, and assembloids, to simulate the native cellular microenvironment. Recently, 3D bioprinting and microfluidic chip technology have been applied as integrative platforms to obtain more complex biomimetic structures. Finally, the challenges in this area are discussed and future directions are discussed to shed some light on the community.

EGCG-LYS Fibrils-Mediated CircMAP2K2 Silencing Decreases the Proliferation and Metastasis Ability of Gastric Cancer Cells in Vitro and in Vivo.

Aberrant expression of circular RNAs (circRNAs) has been reported to play an important biological regulatory role in gastric cancer (GC). For the purpose of silencing cancer-related genes, a new approach for cancer treatment using nanocarriers to deliver siRNA has been proposed. In this study, abundantly expressed circMAP2K2 (hsa_circRNA_102415) is identified in GC cells. CircMAP2K2 regulates the PCBP1/GPX1 axis through proteasome-mediated degradation, which further mediates the activation of the AKT/GSK3ß/epithelial-to-mesenchymal transition (EMT) signaling pathway and enhances the proliferation and metastatic ability of GC cells. To establish novel GC treatment, epigallocatechin-3-gallate-lysozyme (EGCG-LYS) fibrils are synthesized, and in vitro experiments demonstrate that EGCG-LYS has a higher siRNA delivery efficiency than Lipofectamine 2000 (lipo2000), which effectively silences the expression of circMAP2K2. Further studies show that EGCG-LYS carrying siRNA can successfully achieve lysosome escape, which allows it to be located in the cytoplasm to achieve post-transcriptional gene silencing. In addition, EGCG-LYS carrying si-circMAP2K2 has good circulating stability, excellent biosafety and antitumor ability in vivo. The EGCG-LYS fibrils delivery system provides a new tool and approach for the treatment of GC.

Identification of fatty acid signature to predict prognosis and guide clinical therapy in patients with ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is a heterogeneous cancer characterized by high relapse rate. Approximately 80% of women are diagnosed with late-stage disease, and 15-25% of patients experience primary treatment resistance. Ovarian cancer brings tremendous suffering and is the most malignant type in all gynecologic malignancies. Metabolic reprogramming in tumor microenvironment (TME), especially fatty acid metabolism, has been identified to play a crucial role in cancer prognosis. Yet, the underlying mechanism of fatty acid metabolism on ovarian cancer progression is severely understudied. Recently, studies have demonstrated the role of fatty acid metabolism reprogramming in immune cells, but their roles on cancer cell metastasis and cancer immunotherapy response are poorly characterized. Here, we reported that the fatty acid-related genes are aberrantly varied between ovarian cancer and normal samples. Using samples in publicly databases and bio-informatic analyses with fatty acid-related genes, we disentangled that cancer cases can be classified into high- and low-risk groups related with prognosis. Furthermore, the nomogram model was constructed to predict the overall survival. Additionally, we reported that different immune cells infiltration was presented between groups, and immunotherapy response differed in two groups. Results showed that our signature may have good prediction value on immunotherapy efficacy, especially for anti-PD-1 and anti-CTLA-4. Our study systematically marked the critical association between cancer immunity in TME and fatty acid metabolism, and bridged immune phenotype and metabolism programming in tumors, thereby constructed the metabolic-related prognostic model and help to understand the underlying mechanism of immunotherapy response.

Development of a multi-gene-based immune prognostic signature in ovarian Cancer.

BACKGROUND: Various components of the immune system play a critical role in the prognosis and treatment response in ovarian cancer (OC). Immunotherapy has been recognized as a hallmark of cancer but the effect is contradictional. Reliable immune gene-based prognostic biomarkers or regulatory factors are necessary to be systematically explored to develop an individualized prediction signature. METHODS: This study systematically explored the gene expression profiles in patients with ovarian cancer from RNA-seq data set for The Cancer Genome Atlas (TCGA). Differentially expressed immune genes and transcription factors (TFs) were identified using the collected immune genes from ImmPort dataset and TFs from Cistoma database. Survival associated immune genes and TFs were identified in terms of overall survival. The prognostic signature was developed based on survival associated immune genes with LASSO (Least absolute shrinkage and selection operator) Cox regression analysis. Further, we performed network analysis to uncover the potential regulators of immune-related genes with the help of computational biology. RESULTS: The prognostic signature, a weighted combination of the 21 immune-related genes, performed moderately in survival prediction with AUC was 0.746, 0.735, and 0.749 for 1, 3, and 5 year overall survival, respectively. Network analysis uncovered the regulatory role of TFs in immune genes. Intriguingly, the prognostic signature reflected the immune cells landscape and infiltration of some immune cell subtypes. CONCLUSIONS: We first constructed a signature with 21 immune genes of clinical significance, which showed promising predictive value in the surveillance, and prognosis of OC patients.

Upregulated Circular RNA hsa_circ_0008433 Regulates Pathogenesis in Endometriosis Via miRNA.

circRNAs (circular RNAs) play important roles in the development of endometriosis. This study aimed to explore the functions of circRNAs on endometriosis. Two ectopic, two paired eutopic, and two normal endometrial tissue samples were collected for RNA-seq to obtain circRNA profiles and construct a circRNA-miRNA-mRNA network. The validation of 9 circRNAs in 15 patients was assessed by qRT-PCR. We selected hsa_circ_0008433 as the potential biomarker, followed by examining cell proliferation, colony formation, migration, angiopoiesis, cell cycle, and apoptosis. Furthermore, the expression of apoptosis-related proteins was detected using immunofluorescence (IF) and Western blotting. Bioinformatic analysis was used to select the potential target miRNA and genes of hsa_circ_0008433. A total of 209 upregulated and 117 downregulated differentially expressed circRNAs were identified from the eutopic and ectopic endometrial tissue samples. Eight circRNA levels were significantly increased in ectopic endometrial tissue sample compared with eutopic endometrial tissue. The hsa_circ_0008433 knockdown inhibited endometrial stromal cell proliferation, migration, colony formation, and angiopoiesis; promoted cell apoptosis; and downregulated Ki67 and PCNA expression levels. Moreover, the hsa_circ_0008433 knockdown increased Bax and E-CAD expression and decreased Bcl2, CDKN1B, and CyclinD1 levels. Ten potential target miRNAs of hsa_circ_0008433 were selected, and six of them occur significantly aberrant in hsa_circ_0008433-expressing cells. Increased hsa_circ_0008433 levels regulate epithelial mesenchymal transition (EMT) in endometriosis through the circRNA-miRNA-mRNA axis.

A Positive Feedback Loop of TET3 and TGF-ß1 Promotes Liver Fibrosis.

Pathological activation of TGF-ß signaling is universal in fibrosis. Aberrant TGF-ß signaling in conjunction with transdifferentiation of hepatic stellate cells (HSCs) into fibrogenic myofibroblasts plays a central role in liver fibrosis. Here we report that the DNA demethylase TET3 is anomalously upregulated in fibrotic livers in both humans and mice. We demonstrate that in human HSCs, TET3 promotes profibrotic gene expression by upregulation of multiple key TGF-ß pathway genes, including TGFB1. TET3 binds to target gene promoters, inducing demethylation, which in turn facilitates chromatin remodeling and transcription. We also reveal a positive feedback loop between TGF-ß1 and TET3 in both HSCs and hepatocytes. Furthermore, TET3 knockdown ameliorates liver fibrosis in mice. Our results uncover a TET3/TGF-ß1 positive feedback loop as a crucial determinant of liver fibrosis and suggest that inhibiting TET3 may represent a therapeutic strategy for liver fibrosis and perhaps other fibrotic diseases.

Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform.

Precise control of hepatic glucose production (HGP) is pivotal to maintain systemic glucose homeostasis. HNF4α functions to stimulate transcription of key gluconeogenic genes. HNF4α harbors two promoters (P2 and P1) thought to be primarily active in fetal and adult livers, respectively. Here we report that the fetal version of HNF4α is required for HGP in the adult liver. This isoform is acutely induced upon fasting and chronically increased in type-2 diabetes (T2D). P2 isoform induction occurs in response to glucagon-stimulated upregulation of TET3, not previously shown to be involved in HGP. TET3 is recruited to the P2 promoter by FOXA2, leading to promoter demethylation and increased transcription. While TET3 overexpression augments HGP, knockdown of either TET3 or the P2 isoform alone in the liver improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies unmask an unanticipated, conserved regulatory mechanism in HGP and offer potential therapeutic targets for T2D.

PRMT6 promotes endometrial cancer via AKT/mTOR signaling and indicates poor prognosis.

Arginine methylation plays essential roles in post-transcriptional modification and signal transduction. Dysregulation of protein arginine methyltransferases (PRMTs) has been reported in human cancers, yet the expression and biological function of PRMT6 in endometrial cancer (EMC) remains unclear. Here, we show that PRMT6 is upregulated in EMC and exhibits oncogenic activities via activation of AKT/mTOR pathway. The expression of PRMT6 in EMC is much higher than that in the adjacent nontumorous tissues. Elevated PRMT6 expression is significantly associated with higher histological tumor grade and unfavorable prognosis in two independent cohorts consisting of a total of 564 patients with EMC. In vitro data demonstrate that PRMT6 expression was identified as a downstream target of miR-372-3p. Ectopic expression of miR-372-3p downregulates PRMT6. Overexpression of PRMT6 promotes EMC cell proliferation and migration, whereas knockdown of PRMT6 leads to opposite phenotypes. Mechanistically, PRMT6 induces the phosphorylation of AKT and mTOR in EMC cells. Inhibition of AKT/mTOR signaling by MK2206 or rapamycin attenuates the PRMT6-mediated EMC progression. In clinical samples, high expression of PRMT6 was correlated to low expression of miR-372-3p and high expression of phosphorylated AKT. Collectively, our findings suggest PRMT6 may function as an oncogene to promote tumor progression, and be of prognostic value to predict disease-free survival of patients with EMC. The newly identified miR-372-3p/PRMT6/AKT/mTOR axis represents a new promising target for EMC management.

Increased expression of TET3 predicts unfavorable prognosis in patients with ovarian cancer-a bioinformatics integrative analysis.

Ovarian carcinoma is a lethal gynecological malignancy. Women with ovarian cancer (OC) are highly recurrent and typically diagnosed at late stage. Ten-eleven translocation protein 3 (TET3) belongs to the family of ten-eleven translocations (TETs) which induce DNA demethylation and gene regulation in epigenetic level by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Previous studies indicated that TET3 is overexpressed in ovarian cancer tissues. However, the clinic-pathological functions and prognostic values of TET3 remain unclear. Here we performed an integrative study to identify the role of TET3 by bioinformatics analysis. The TET3 expression in ovarian cancer was assessed with Oncomine database, and validated with TCGA and GTEx database. The correlation of TET3 gene alteration and clinic-pathological functions was addressed by integrative analysis of GEO datasets. Then we showed mainly TET3 gain and diploid but less deletion in ovarian cancer by copy number alteration (CNA) or mutation analysis with cBioPortal. Furthermore, by using Kaplan-Meier plotter (K-M plotter), we evaluated that high TET3 level was associated with poor survival in ovarian cancer patients, which was validated with analysis by PrognoScan database and gene differential analyses with TCGA and GTEx. This is the first study demonstrated that elevated expression of TET3 is associated with poor clinic-pathological functions, poor prognosis, wherein TET3, which presents epigenetic changes or methylation changes, might be served as a diagnostic marker or therapeutic target for ovarian cancer.

H19 lncRNA identified as a master regulator of genes that drive uterine leiomyomas.

Uterine leiomyomas or fibroids (UFs) are benign tumors characterized by hyperplastic smooth muscle cells and excessive deposition of extracellular matrix (ECM). Afflicting ~80% of women, and symptomatic in 25%, UFs bring tremendous suffering and are an economic burden worldwide; they cause severe pain and bleeding, and are the leading cause of hysterectomy. Yet, UFs are severely understudied with few effective treatment options available; those that are available frequently have significant side effects such as menopausal symptoms. Recently, integrated genome-scale studies have revealed mutations and fibroid subtype-specific expression changes in key driver genes, with MED12 and HMGA2 together contributing to nearly 90% of all UFs, but their regulation of expression is poorly characterized. Here we report that the expression of H19 long noncoding RNA (lncRNA) is aberrantly increased in UFs. Using cell culture and genome-wide transcriptome and methylation profiling analyses, we demonstrate that H19 promotes expression of MED12, HMGA2, and key ECM-remodeling genes via multiple mechanisms including a new class of epigenetic modification by TET3. Our results mark the first example of an evolutionarily conserved lncRNA in pathogenesis of UFs and regulation of TET expression. Given the link between a H19 single-nucleotide polymorphism (SNP) and increased risk and tumor size of UFs, and the existence of multiple fibroid subtypes driven by key pathway genes regulated by H19, we propose a unifying mechanism for pathogenesis of uterine fibroids mediated by H19 and identify a pathway for future exploration of novel target therapies for uterine leiomyomas.

Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemia.

Excessive hepatic glucose production (HGP) contributes significantly to the hyperglycemia of type 2 diabetes; however, the molecular mechanism underlying this dysregulation remains poorly understood. Here, we show that fasting temporally increases the expression of H19 long noncoding RNA (lncRNA) in nondiabetic mouse liver, whereas its level is chronically elevated in diet-induced diabetic mice, consistent with the previously reported chronic hepatic H19 increase in diabetic patients. Importantly, liver-specific H19 overexpression promotes HGP, hyperglycemia, and insulin resistance, while H19 depletion enhances insulin-dependent suppression of HGP. Using genome-wide methylation and transcriptome analyses, we demonstrate that H19 knockdown in hepatic cells alters promoter methylation and expression of Hnf4a, a master gluconeogenic transcription factor, and that this regulation is recapitulated in vivo. Our findings offer a mechanistic explanation of lncRNA H19's role in the pathogenesis of diabetic hyperglycemia and suggest that targeting hepatic H19 may hold the potential of new treatment for this disease.

Neoadjuvant chemotherapy followed by conization to spare fertility in cases of locally advanced cervical cancer: A case report and review of the literature.

The average age when cervical cancer is diagnosed is decreasing, resulting in a larger proportion of patients seeking fertility preservation. Therefore, a less radical approach that aims to preserve the potential for fertility during the treatment of cervical carcinoma is crucial. The present study reported a case of a patient with stage IB2 cervical cancer who exhibited pathological complete regression to neoadjuvant chemotherapy (NACT). This patient underwent deep cervical conization and laparoscopic lymphadenectomy to preserve her fertility. The patient gave birth at 29 weeks of gestation and exhibited no recurrent disease until May 2016 (72 months after surgery). This is the first, to the best of our knowledge, IB2 case treatment by NACT, followed by conization plus lymphadenectomy, producing favorable oncological and obstetrical outcome. The present study, together with data from a limited number of published articles, offers a new perspective in the preservation of fertility in young women with cervical cancer. Additional studies are required in a selected population.