Exploration and prognostic analysis of two types of high-risk ovarian cancers: clear cell vs. serous carcinoma: a population-based study.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is a rare pathological histotype in ovarian cancer, while the survival rate of advanced OCCC (Stage III-IV) is substantially lower than that of the advanced serous ovarian cancer (OSC), which is the most common histotype. The goal of this study was to identify high-risk OCCC by comparing OSC and OCCC, with investigating potential risk and prognosis markers. METHODS: Patients diagnosed with ovarian cancer from 2009 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) Program. Logistic and Cox regression models were used to identify risk and prognostic factors in high-risk OCCC patients. Cancer-specific survival (CSS) and overall survival (OS) were assessed using Kaplan-Meier curves. Furthermore, Cox analysis was employed to build a nomogram model. The performance evaluation results were displayed using the C-index, calibration plots, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). Immunohistochemically approach was used to identify the expression of the novel target (GPC3). RESULTS: In the Cox analysis for advanced OCCC, age (45-65 years), tumor numbers (total number of in situ/malignant tumors for patient), T3-stage, bilateral tumors, and liver metastases could be defined as prognostic variables. Nomogram showed good predictive power and clinical practicality. Compared with OSC, liver metastases had a stronger impact on the prognosis of patients with OCCC. T3-stage, positive distant lymph nodes metastases, and lung metastases were risk factors for developing liver metastases. Chemotherapy was an independent prognostic factor for patient with advanced OCCC, but had no effect on CSS in patients with liver metastases (p = 0.0656), while surgery was significantly related with better CSS in these patients (p < 0.0001) (p = 0.0041). GPC3 expression was detected in all tissue sections, and GPC3 staining was predominantly found in the cytoplasm and membranes. CONCLUSION: Advanced OCCC and OCCC with liver metastases are two types of high-risk OCCC. The constructed nomogram exhibited a satisfactory survival prediction for patients with advanced OCCC. GPC3 immunohistochemistry is expected to accumulate preclinical evidence to support the inclusion of GPC3 in OCCC targeted therapy.

Day 4 and day 0 neutrophil-to-lymphocyte ratios as predictors of treatment failure with single-dose methotrexate for ectopic pregnancies.

OBJECTIVE: To evaluate changes in the neutrophil-to-lymphocyte ratio (NLR) between day 4 and day 0 in ectopic pregnancy (EP) patients treated with single-dose methotrexate (MTX) and investigate its predictive value for treatment outcome. METHODS: A total of 406 EP patients receiving single-dose MTX therapy at Shanghai First Maternity and Infant Hospital from January 10, 2013 to September 30, 2019 were studied. A multivariate model was constructed to predict treatment outcome. RESULTS: Among the 406 patients, 281 were treated successfully. Treatment success declined significantly when NLR decreased by less than 23% (74.8% vs 58.5%, P = 0.004). Multivariate regression analysis identified NLR reduction of less than 23% on day 4 (odds ratio [OR] 2.09, 95% confidence interval [CI] 1.27-3.44), a human chorionic gonadotropin (hCG) decrease of 15% or less (OR 3.17, 95% CI 1.62-6.34), and an hCG increase of more than 15% on day 4 (OR 5.47, 95% CI 3.05-10.22) as independent risk factors for single-dose MTX treatment failure. The final predictive model had a sensitivity of 0.768 and a specificity of 0.569, using a cut-off value of 3. The area under the receiver operating characteristic curve was 0.712. Patients with a predictive score of ≥3 were more likely to fail single-dose MTX therapy. CONCLUSION: The present study concluded that an NLR decrease of less than 23% on day 4, a plateau or increase in serum hCG on day 4, and an hCG value greater than 1000 mIU/mL on day 0 were predictors of single-dose MTX treatment failure in EP patients.

Efficacy and safety of Qiangli Dingxuan tablet combined with amlodipine besylate for essential hypertension: a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial.

Background: Hypertension, a major cardiovascular risk factor, severely impacts patients' quality of life. Qiangli Dingxuan tablet (QDT) is a formally approved Chinese patent medicine, which has been widely used as an adjunctive treatment for hypertension. This study aimed to investigate the antihypertensive efficacy and safety of QDT combined with amlodipine besylate in patients with essential hypertension. Methods: In this randomized, double-blind, placebo-controlled, parallel-group, multicenter trial conducted in China, patients diagnosed with grade 1 to 2 essential hypertension were randomly assigned in a 1:1 to the treatment of QDT or placebo for 12 weeks, alongside their ongoing treatment with amlodipine besylate. The primary outcome was the change in office blood pressure (BP) from baseline to 12 weeks. In addition, safety analysis included the assessment of vital signs and laboratory values. Results: At baseline, 269 patients were randomly assigned to the QDT group (n = 133) or the placebo group (n = 136), and there were no significant differences in baseline characteristics between the two groups. The primary outcome based on the full analysis set from baseline to 12 weeks showed that the mean difference in the change of office systolic BP reduction between the two groups was 6.86 mmHg (95%CI, 4.84 to 8.88, p < 0.0001), for office diastolic BP, the mean difference in the change of office diastolic BP reduction between the two groups was 4.64 mmHg (95%CI, 3.10 to 6.18, p < 0.0001). In addition, traditional Chinese medicine symptom scores were significantly decreased in the QDT group compared with the placebo group. No severe adverse events attributable to QDT were reported. Conclusion: The combination of QDT and amlodipine besylate demonstrates superior efficacy compared to amlodipine besylate monotherapy in the management of essential hypertension. QDT shows potential as an adjunctive treatment for essential hypertension. However, further rigorous clinical trials are warranted to validate these findings. Clinical Trial Registration: [https://clinicaltrials.gov/study/NCT05521282?cond=NCT05521282&rank=1]; Identifier: [NCT05521282].

San Jie Tong Mai Fang Protects Against Atherosclerosis Progression by Regulating Macroautophagy through the PI3K/AKT/mTOR Signaling Pathway.

ABSTRACT: Many studies have confirmed that macrophage autophagy injury negatively impacts the pathogenesis of atherosclerosis (AS). Meanwhile, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway affects AS progression by regulating macrophage autophagy. We previously reported that the herbal formula San Jie Tong Mai Fang (SJTMF) elicits lipid regulatory and anti-inflammatory properties. Hence, the current study used an ApoE -/- high-fat diet-fed mouse model to determine whether SJTMF elicits protective effects against AS progression by means of the regulation of macrophage autophagy through the PI3K/AKT/mTOR signaling pathway. Our results show that SJTMF reduced the number of atherosclerotic plaques, foam cell formation, and intimal thickness in mouse aorta. In addition, SJTMF improved blood lipid metabolism and inflammatory levels in mice. We also observed that SJTMF caused macrophages to be polarized toward the M2 phenotype through the inhibition of the PI3K/AKT/mTOR signaling pathway. In addition, the abundances of LC3-II/I and beclin1 proteins-key autophagy molecules-were increased, whereas that of p62 was decreased, resulting in the promotion of macrophage autophagy. Taken together, these findings indicate that SJTMF may regulate the polarization of macrophages by inhibiting the PI3K/AKT/mTOR signaling pathway, thereby reducing atherosclerotic plaque damage in ApoE -/- mice, thereby promoting macrophage autophagy and eliciting a significant antiarteriosclerosis effect. Hence, SJTMF may represent a promising new candidate drug for the treatment of AS.

Evaluation of pretreatment and early treatment changes in serum ß-hCG with methotrexate.

BACKGROUND: Serum beta-human chorionic gonadotropin (ß-hCG) is an important biomarker for the detection of ectopic pregnancies (EPs). The ß-hCG levels between days 1 and 4 after methotrexate (MTX) treatment as an indicator of the success of the MTX in EP have been the focus of research. OBJECTIVES: To determine whether the change in the ß-hCG levels at day 1 and 4 and pretreatment at 48-hour increments can predict early treatment failure of single-dose MTX in EP. MATERIAL AND METHODS: This was a retrospective study of 1120 EPs treated with a single dose of MTX. Treatment failure was defined as an obligation to proceed to surgery or the need for additional doses of MTX. RESULTS: A total 722 out of 1120 EPs had an increase in ß-hCG on day 4 after MTX treatment. The logistic regression analysis indicated that 3 dependents were significantly associated with treatment failure: 1) a pretreatment 48-hour increase in ß-hCG (odds ratio (OR): 1.249, 95% confidence interval (95% CI): 1.008-2.049, p < 0.001); 2) a change in ß-hCG between day 1 and 4 (OR: 1.384, 95% CI: 1.097-2.198, p < 0.001); and 3) a history of EP (OR: 1.208, 95% CI: 1.041- 2.011, p < 0.001). The optimal cutoff point for the prediction of treatment failure was an increase of more than 19% in the 48 h before the treatment, and an increase of more than 36% between day 1 and day 4 in ß-hCG concentrations. Patients with an increase in ß-hCG levels of less than 36% on day 4 experienced MTX treatment failure in 4.2% (n = 25), compared to 74.5% (n = 88) of the patients with an increase above 36%. CONCLUSIONS: A serum ß-hCG increase of more than 36% on day 4 after the administration of MTX alongside a more than 19% increase in ß-hCG concentration 48 h before the MTX treatment may predict the early failure of medical treatment for an EP.

Abdominal heterotopic pregnancy after in vitro fertilization and embryo transfer following bilateral salpingectomy: A case report and literature review.

Background: Risk of heterotopic pregnancy following bilateral salpingectomy has increased considerably due to the widespread use of assisted reproductive technology. Poor understanding of this condition often causes delayed or missed diagnosis. Objective: In this report, we describe the case of a 30-year-old pregnant woman with lower abdominal pain lasting for half a day and a history of bilateral salpingectomy. Two embryos had been transferred 21 days preceding her presentation. Methods: Case report. Results: Laparoscopic surgery revealed intraperitoneal hemorrhage and proper ovarian ligament pregnancy confirmed by histopathology. Viable intrauterine pregnancy was verified 3 days later by ultrasound examination. Conclusion: Heterotopic pregnancy is a serious condition that may be life-threatening. Clinicians should be aware of the potential for heterotopic pregnancy in patients receiving in vitro fertilization and embryo transfer after bilateral salpingectomy.

Comprehensive analyses identify RIPOR2 as a genomic instability-associated immune prognostic biomarker in cervical cancer.

Cervical cancer (CC) is a malignancy that tends to have a poor prognosis when detected at an advanced stage; however, there are few studies on the early detection of CC at the genetic level. The tumor microenvironment (TME) and genomic instability (GI) greatly affect the survival of tumor patients via effects on carcinogenesis, tumor growth, and resistance. It is necessary to identify biomarkers simultaneously correlated with components of the TME and with GI, as these could predict the survival of patients and the efficacy of immunotherapy. In this study, we extracted somatic mutational data and transcriptome information of CC cases from The Cancer Genome Atlas, and the GSE44001 dataset from the Gene Expression Omnibus database was downloaded for external verification. Stromal components differed most between genomic unstable and genomic stable groups. Differentially expressed genes were screened out on the basis of GI and StromalScore, using somatic mutation information and ESTIMATE methods. We obtained the intersection of GI- and StromalScore-related genes and used them to establish a four-gene signature comprising RIPOR2, CCL22, PAMR1, and FBN1 for prognostic prediction. We described immunogenomic characteristics using this risk model, with methods including CIBERSORT, gene set enrichment analysis (GSEA), and single-sample GSEA. We further explored the protective factor RIPOR2, which has a close relationship with ImmuneScore. A series of in vitro experiments, including immunohistochemistry, immunofluorescence, quantitative reverse transcription PCR, transwell assay, CCK8 assay, EdU assay, cell cycle detection, colony formation assay, and Western blotting were performed to validate RIPOR2 as an anti-tumor signature. Combined with integrative bioinformatic analyses, these experiments showed a strong relationship between RIPOR2 with tumor mutation burden, expression of genes related to DNA damage response (especially PARP1), TME-related scores, activation of immune checkpoint activation, and efficacy of immunotherapy. To summarize, RIPOR2 was successfully identified through comprehensive analyses of the TME and GI as a potential biomarker for forecasting the prognosis and immunotherapy response, which could guide clinical strategies for the treatment of CC patients.

A Model to Identify Candidates for Lymph Node Dissection Among Patients With High-Risk Endometrial Endometrioid Carcinoma According to Mayo Criteria.

Background: The Mayo criteria are the most widely accepted algorithm for predicting the risk of lymph node metastasis in endometrial endometrioid carcinoma (EEC). However, the clinical value of these criteria in high-risk patients is limited and inconclusive. Methods: A total of 240 patients with EEC meeting the Mayo high-risk criteria between January 1, 2015, and December 31, 2018 were included in our study. We retrospectively collected the laboratory reports, basic clinical information, clinicopathological and immunohistochemistry (IHC) findings, and the sequences of molecular pathological markers of these patients. A nomogram for predicting the likelihood of positive lymph node status was established based on these parameters. Results: Among the 240 patients, 17 were diagnosed with lymph node metastasis. The univariable analyses identified myometrial invasion >50%, aberrant p53 expression, microsatellite instable (MSI), and cancer antigen 125 (CA125) ≥35 U/ml as potential risk factors for lymph node metastasis. The multivariable analyses showed that aberrant p53 expression, MSI, and CA125 ≥35 U/ml were independent predictors of lymph node metastasis. The area under the curve (AUC) for the nomogram was 0.870, as compared to 0.665 for the Mayo criteria. Conclusions: Our novel prediction model effectively identifies patients at high risk for lymphatic metastasis. This model is a promising strategy for personalized surgery in patients with high risk according to the Mayo criteria.

Elevated mid-trimester 4-h postprandial triglycerides for predicting late-onset preeclampsia: a prospective screening study.

BACKGROUND: Abnormal maternal lipid concentrations are associated with increased risk of preeclampsia. However, previous studies mainly focused on fasting lipid concentrations, scarce data have been published on the relationship between postprandial triglyceride (TG) concentrations in the second trimester and the risk of preeclampsia. Our aim is to evaluate the potential of triglyceride (TG) concentrations at the time of oral lipid tolerance test (OLTT) measurement in the second trimester to predict preeclampsia and to elucidate the lipid metabolic changes related to these diseases. METHODS: This is a prospective cohort study of Pregnant women at 12-24 weeks of gestation undergone an OLTT in a university affiliated hospital between May 2019 and January 2020. Data were stratified into binaries according to the OLTT results. The receiver operating characteristic (ROC) curve analysis was conducted to determine the optimal cut-off points of TG, HDL-C, LDL-C, sd-LDL, FFA, and BG for predicting preeclampsia. RESULTS: 438 pregnant women were recruited to undergo an OLTT at 12-24 weeks of gestation. Among these, 24 women developed preeclampsia and 414 women remained normotensive. Women who subsequently developed preeclampsia had higher concentrations of 4-h postprandial TG than those who remained normotensive. In the linear logistic regression analyses of potential confounding factors, mid-trimester 4-h postprandial TG concentrations at the time of OLTT measurement were significantly higher in preeclamptic cases than in controls. CONCLUSIONS: Dyslipidemia in the second trimester of pregnancy, particularly postprandial hypertriglyceridemia, appears to be associated with an increased risk of preeclampsia. Mid-trimester 4-h postprandial TG concentration at the time of OLTT measurement may be a potential predictive marker of preeclampsia. Trial registration Data of registration: 2018/10/15. Date of initial participant enrollment: 2019/05/01. Clinical trial identification number: chiCTR1800018884. URL of the registration site: http://www.chictr.org.cn/showproj.aspx?proj=25526 . Data sharing information: The data including individual participant data, detailed study protocols, statistical analysis plans will be shared upon request to the corresponding author.

Evaluation of the effectiveness and safety of acupuncture in the treatment of premature ventricular contractions: A protocol for systematic review and meta-analysis.

BACKGROUND: Premature ventricular contractions are the most common type of arrhythmia. The clinical symptoms are mainly palpitations. In severe cases, syncope, angina pectoris and heart failure may occur, which seriously affect people's lives and ability to work. Antiarrhythmic drugs have many side effects and should not be taken for long periods. Acupuncture has a significant effect on the treatment of premature ventricular contractions. Therefore, to evaluate the effectiveness and safety of acupuncture in the treatment of premature ventricular contractions, we conducted this study, with the goal of providing a scientific methodology for this alternative treatment. METHODS: We searched PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, China Science Journal Database, and China Biomedical Literature Database. We selected all randomized clinical trials related to the use of acupuncture in the treatment of premature ventricular contractions published on or before October 10, 2021, and we will conduct literature screening and data extraction based on specific inclusion and exclusion criteria. We will use the bias risk assessment tool from the Cochrane Systematic Review Manual to evaluate the quality of the research selected for inclusion in our study. RevMan5.3 software will be used to perform statistical analysis on the data. RESULTS: The results of this study will provide evidence for the effectiveness and safety of acupuncture in the treatment of premature ventricular contractions. CONCLUSION: The purpose of this study is to explore the efficacy of acupuncture in the treatment of patients with premature ventricular contractions and to provide an effective reference for clinicians and patients on its use. INPLASY REGISTRATION NUMBER: INPLASY2021100040.

Abnormally increased DNA methylation in chorionic tissue might play an important role in development of ectopic pregnancy.

BACKGROUND: Human Ectopic Pregnancy (hEP) is the second most common cause of pregnancy-related deaths in the first trimester. Without timely detection, EPs can lead to an increased rate of infertility and an elevated risk for future tubal EPs. In addition, most studies in the field focus on the effect of the fallopian tube (maternal factors) and ignore epigenetic changes in genes and proteins of the embryo, which may also cause EPs. Therefore, the present study hypothesized that embryos also play an important role in the development of EP. The study also speculated that DNA methylation is associated with ectopic pregnancy. Consequently, the effects of DNA methylation on the occurrence and development of ectopic pregnancy were investigated. Moreover, genome-wide DNA methylation of chorionic tissue from ectopic and intrauterine pregnancies was detected using Illumina HumanMethylation450 arrays. RESULTS: Forty-three hypermethylated genes involved in the regulation of adhesion as well as gene transcription and translation were identified. Furthermore, the PPI network showed that AMOTL1, SDR42E1, CAMTA1, PIP5K1C, KIAA1614, TSTD1 and DNER may play important roles in the occurrence and development of ectopic pregnancy. In addition, SDR42E1, CAMTA1 and TSTD1 displayed higher levels of methylation in ectopic pregnancy while PIP5K1C and DNER showed low degrees of methylation. CONCLUSIONS: The study reveals that abnormal increase in methylation may be an early indicator or an inducer of ectopic pregnancy. In addition, AMOTL1, SDR42E1, CAMTA1, PIP5K1C, KIAA1614, TSTD1 and DNER might play important roles in the occurrence and development of ectopic pregnancy. However, the specific molecular mechanisms are still unclear and require further studies.

Serum calponin 2 is a novel biomarker of tubal ectopic pregnancy.

OBJECTIVE: To evaluate serum protein calponin 2 (CNN2) as a candidate biomarker for tubal ectopic pregnancy (EP). DESIGN: Retrospective study. SETTING: Single University affiliated tertiary hospital. PATIENT(S): Serum samples were obtained from 84 patients with EP, 39 with viable intrauterine pregnancy (vIUP), and 42 with miscarriage. Moreover, 10 fallopian tube and corresponding villous tissue samples from patients with EP, 6 villous tissue samples from patients with vIUP, and 10 villous tissue samples from patients with miscarriage were collected. INTERVENTION(S): Serum CNN2 concentrations were measured using enzyme-linked immunosorbent assay; CNN2 expression in tissues was evaluated via immunohistochemistry and quantitative real-time polymerase chain reaction analysis. MAIN OUTCOME MEASURE(S): The diagnostic performance of serum CNN2 to discriminate an EP from vIUP and miscarriage. RESULT(S): CNN2 was highly expressed in villous stromal cells isolated from patients with EP, and CNN2 messenger ribonucleic acid expression was upregulated in villous tissues from women with EP compared with that in women with vIUPs and miscarriages. Serum CNN2 concentration was higher in women with EP than that in women with vIUP and miscarriage. The serum CNN2 predicted EP from vIUP and miscarriage with areas under the curve (AUCs) of 0.931 (95% confidence interval: 0.889-0.975). For discriminating EP from miscarriage only, the AUC was 0.906 (95% confidence interval: 0.835-0.977). In contrast, the AUCs for serum human chorionic gonadotropin were 0.809 and 0.637, respectively. CONCLUSION(S): Our data highlight the possibility of serum CNN2 as a single biomarker for the diagnosis of EP. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR 1900020483.

Hypoxia induces an endometrial cancer stem-like cell phenotype via HIF-dependent demethylation of SOX2 mRNA.

Endometrial cancer stem cells (ECSCs) are stem-like cells endowed with self-renewal and differentiation abilities, and these cells are essential for cancer progression in endometrial cancer (EC). As hallmarks of the tumour microenvironment (TME), hypoxia and hypoxia-inducing factors (HIFs) give rise to the dysregulation of tumour stemness genes, such as SOX2. Against this backdrop, we investigated the regulatory mechanisms regulated by HIFs and SOX2 in ECSCs during EC development. Here, ECSCs isolated from EC cell lines and tissues were found to express stemness genes (CD133 and aldehyde dehydrogenase, ALDH1) following the induction of their ECSC expansion. Notably, m6A methylation of RNA and HIF-1α/2α-dependent AlkB homologue 5 (ALKBH5) participate in the regulation of HIFs and SOX2 in EC, as confirmed by the observations that mRNA levels of m6A demethylases and ALKBH5 significantly increase under hypoxic conditions in ECSCs. Moreover, hypoxia and high ALKBH5 levels restore the stem-like state of differentiated ECSCs and increase the ECSC-like phenotype, whereas the knockdown of HIFs or ALKBH5 significantly reduces their tumour initiation capacity. In addition, our findings validate the role of ALKBH5 in promoting SOX2 transcription via mRNA demethylation, thereby maintaining the stem-like state and tumorigenicity potential of ECSCs. In conclusion, these observations demonstrate a critical role for m6A methylation-mediated regulation of the HIF-ALKBH5-SOX2 axis during ECSC expansion in hypoxic TMEs.

Kuijieyuan Decoction Improved Intestinal Barrier Injury of Ulcerative Colitis by Affecting TLR4-Dependent PI3K/AKT/NF-κB Oxidative and Inflammatory Signaling and Gut Microbiota.

ETHNOPHARMACOLOGICAL RELEVANCE: In Traditional Chinese medicine (TCM) theory, ulcerative colitis (UC) is associated with damp-heat, blood stasis, and intestinal vascular ischemia. Kuijieyuan decoction (KD) is a traditional Chinese medicine based on the above theory and used clinically to alleviate UC injury. METHODS: The main components of KD were analyzed by using high-pressure liquid chromatography (HPLC) and confirmed by UPLC-MS/MS. A UC model was established in rats by using dextran sulfate sodium (DSS) and dead rats (caused by DSS) were excluded from the study. Forty-eight rats were divided into 6 groups, health control (CG), UC model (UG), sulfasalazine (SG), low-dose KD (LG), middle-dose KD (MG), and high-dose KD (HG) groups. UC damage was assessed by hematoxylin and eosin staining and scan electron microscopy. We measured Toll-like receptor 4 (TLR4), p-phosphatidylinositol 3-kinase (PI3K), PI3K, p-Protein kinase B (AKT), AKT, p-nuclear factor kappa B (NF-κB), NF-κB, oxidative stress marker (superoxidase dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx), and malondialdehyde) and inflammatory markers (tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6 and IL-10) in UC tissues. Gut microbiota was analyzed through16S rRNA sequencing. RESULTS: The main components of KD consist of gallic acid, paeoniflorin, emodin, berberine, coptisine, palmatine, jatrorrhizine, baicalein and baicalin. The UC model was successfully established by causing intestinal barrier injury with the loss of intestinal villi and destructed mitochondria of intestinal epithelial cells. Both sulfasalazine and KD treatment repaired UC injury, reduced the levels of malondialdehyde, TNFα, IL-1, IL-6, TLR4, p-PI3K, p-AKT, and p-NF-κB, and increased the levels of SOD, GPx, CAT, and IL-10. KD showed a protective function for the UC model in a dose-dependent way. The serum levels of paeoniflorin and baicalin had a strong relationship with the levels of inflammatory and oxidative stress biomarkers. KD treatment increased the proportion of Alloprevotella, Treponema, Prevotellaceae, and Prevotella, and reduced the proportion of Escherichia_Shigella and Desulfovibrio in gut microbiota. CONCLUSIONS: KD improved intestinal barrier injury of ulcerative colitis, antioxidant and anti-inflammatory properties by affecting TLR4-dependent PI3K/AKT/NF-κB signaling possibly through the combination of its main compounds, and improving gut microbiota.

POLE Mutation Characteristics in a Chinese Cohort with Endometrial Carcinoma.

OBJECTIVE: To study the characteristics of polymerase epsilon (POLE) exonuclease domain mutations in Chinese patients with endometrial carcinoma (EC). METHODS: This study analyzed data from 529 patients with EC in The Cancer Genome Atlas (TCGA) and 467 EC patients evaluated at the Shanghai First Maternity and Infant Hospital (SFMIH). POLE mutation heterogeneity was analyzed in paired curettage and hysterectomy samples from 120 SFMIH patients. Sanger sequencing identified mutations in the POLE exonuclease domain, and correlations between POLE mutation status and various clinicopathological features were determined by chi-squared testing and Cohen's kappa analysis, with Kaplan-Meier survival curves generated to assess correlations between POLE mutation status and overall survival (OS). RESULTS: Thirty-five mutations were identified in 467 samples (7.5%), and novel mutations were detected in the SFMIH cohort. Compared to the TCGA cohort, the SFMIH cohort had fewer POLE mutations when matched by age (<60) and histology (endometrioid) (p < 0.001 and p = 0.010, respectively). In our study cohort, POLE mutations were significantly associated with adjuvant treatment (p = 0.029), and patients with POLE mutations who underwent chemoradiotherapy had a poor OS (p < 0.0001). Notably, shorter OS was significantly associated with POLE mutations in hysterectomy samples from patients aged >60 years or with stage I disease in the paired curettage-hysterectomy group. CONCLUSION: The significant difference in POLE mutation profiles between the TCGA and SFMIH cohorts, as well as the poor consistency between the curettage and hysterectomy samples, suggests that different parameters need to be applied to determine the prognosis of patients with EC in China.

An HMGA2-p62-ERα axis regulates uterine leiomyomas proliferation.

Uterine leiomyomas (ULM) are a major public health issue contributing to high morbidity and poor pregnancy outcomes. However, its molecular pathogenesis is poorly understood. HMGA2-ULM is the second major subtype of human ULM and associates with large sizes, fast-growth, and high percentages of estrogen receptor α (ERα). As altered ERα expression plays a distinct role in ULM growth, here, we investigate a regulatory mechanism driving ULM growth via HMGA2 and ERα. We reveal a positive correlation of HMGA2 with ERα protein and demonstrate that HMGA2 promotes ULM cells proliferation via ERα. In addition, autophagy pathway and p62/SQSTM1 (a selective autophagy receptor) are found to participate in the regulation of HMGA2 and ERα. Moreover, HMGA2 suppresses the transcription of p62 by binding to its promoter, meanwhile, p62 interacts with ERα, and inhibition of p62 increases ERα expression and enhances cell viability in ULM, suggesting a novel mechanism of the HMGA2-p62-ERα axis in ULM proliferation. Notably, rapamycin, a familiar autophagy agonist, reduces ERα levels and the proliferation ability of ULM cells. This study demonstrates a causal role of the HMGA2-p62-ERα axis in preventing autophagy and increasing ERα expression in HMGA2-ULM. Therefore, blocking HMGA2-p62-ERα axis and targeting autophagy pathway establish a roadmap toward HMGA2-ULM medical treatment.

Picroside II Improves Severe Acute Pancreatitis-Induced Intestinal Barrier Injury by Inactivating Oxidative and Inflammatory TLR4-Dependent PI3K/AKT/NF-κB Signaling and Improving Gut Microbiota.

BACKGROUND: Picroside II exerts anti-inflammatory and antidiarrheal effects for treating the diseases associated with oxidative injury. However, its function on pancreatitis-induced intestinal barrier injury remains unclear. Hypothesis/Purpose. We hypothesized that picroside II will have protective effects against pancreatitis-induced intestinal barrier injury by affecting oxidative and inflammatory signaling (Toll-like receptor 4- (TLR4-) dependent phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and nuclear factor kappa B (NF-κB)). Study Design and Methods. A Sprague-Dawley (SD) rat model with severe acute pancreatitis (SAP) was induced via the injection of sodium taurocholate (4% wt/vol; 1 mL/kg). All rats were divided into 3 groups: sham (CG), SAP-induced intestinal barrier injury (MG), and picroside II (PG) groups. Intestinal barrier injury was assessed by scanning electron microscopy (SEM), hematoxylin and eosin staining, and pathological scores. We measured the levels of pancreatitis biomarkers (amylase and lipase), oxidative and inflammatory signaling (TLR4-dependent PI3K/AKT/NF-κB), oxidative stress marker (superoxidase dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx), and malondialdehyde), and inflammatory markers (tumor necrosis factor α (TNFα), interleukin- (IL-) 1, IL-6, and IL-10) in serum and/or gut tissues. Gut microbiota composition in feces was measured by using 16S rRNA sequencing. RESULTS: SEM showed that intestinal barrier injury was caused with the loss of intestinal villi and mitochondria destruction, and pathological scores were increased in the MG group. The levels of amylase, lipase, malondialdehyde, TNFα, IL-1, IL-6, TLR4, PI3K, AKT, and NF-κB were increased, and the levels of SOD, GPx, CAT, and IL-10 was reduced in the MG group when compared with CG group (P < 0.05). Picroside II treatment inhibited the symptoms in the MG group and showed antioxidant and anti-inflammatory activities. The serum levels of picroside II had strong correlation with the levels of inflammatory and oxidative stress biomarkers (P < 0.05). Picroside II treatment increased the proportion of Lactobacillus and Prevotella and decreased the proportion of Helicobacter and Escherichia_Shigella in the model. CONCLUSIONS: Picroside II improved the SAP-induced intestinal barrier injury in the rat model by inactivating oxidant and inflammatory signaling and improving gut microbiota.

Systematic retrospective analysis of 13 cases of uterine arteriovenous fistula: Pathogeny, diagnosis, treatment and follow-up.

AIM: To analyze the causes, clinical manifestations, diagnosis and treatment of uterine arteriovenous fistula (UAVF). METHODS: We retrospectively analyzed 13 patients with UAVF admitted to our hospital from October 2016 to April 2019. RESULTS: All patients had a history of intrauterine surgery (curettage for abortion, artificial removal of placenta, hysteroscopy, diagnostic curettage and intrauterine device removal). The main clinical manifestation of UAVF is paroxysmal massive vaginal bleeding; this involved a massive gush of vaginal blood that stopped suddenly. Sonographic images with typical features of UAVF were observed for 12 patients. Pelvic contrast-enhanced magnetic resonance imaging was performed as a noninvasive adjuvant examination method for diagnosis. Twelve patients underwent uterine arteriography and a diagnosis of UAVF was confirmed. Then, bilateral uterine artery embolization (UAE) was performed. One patient underwent laparoscopic hysterectomy directly instead of uterine arteriography because of unstable vital signs and one patient underwent laparoscopic hysterectomy 25 weeks after the second UAE. The median time until menstrual recovery was 33 days (range, 20-70 days) after UAE. The median time until normal ultrasound examination results was 10 weeks (range, 2-35 weeks). CONCLUSION: Acquired UAVF was associated with a history of previous intrauterine surgery. The ultrasound examination and pelvic contrast-enhanced MRI were noninvasive adjuvant examination method to effectively assist in diagnosis. Uterine arteriography is considered the gold standard for the diagnosis of UAVF, and UAE is considered an effective intervention for treating UAVF and maintaining reproductive function with less damage. Hysterectomy is an appropriate option when conservative measures have failed to prevent a life-threatening hemorrhage.

p190A inactivating mutations cause aberrant RhoA activation and promote malignant transformation via the Hippo-YAP pathway in endometrial cancer.

The Rho family of GTPases is strictly regulated by a large family of GTPase-activating proteins (GAPs) that stimulate the relatively weak intrinsic GTP-hydrolyzing activity of Rho GTPases. p190A is a potent and widely expressed GAP that acts on RhoA GTPases. p190A is frequently mutated in endometrial cancer, but the contribution of p190A mutations to endometrial tumorigenesis remains unclear. Here we identified that p190A is an upstream regulator of the Hippo-YAP signaling pathway, which is a critical regulator of cell proliferation, apoptosis, and cell fate. p190A knockout in endometrial cancer cells promoted cell proliferation, migration, and epithelial-mesenchymal transition (EMT), which were partially dependent on YAP activation. Wild-type p190A, but not endometrial cancer-associated mutants, suppressed the nuclear localization, transcriptional activity, and malignant transformation function of YAP. Moreover, the nuclear localization of YAP was enhanced in p190A-mutated endometrial cancer. These findings reveal novel molecular mechanisms underlying Hippo-YAP pathway-driven endometrial tumorigenesis and elucidate the potential for therapy targeting the Hippo-YAP pathway in p190A-mutated endometrial cancer.

Small Molecules that Promote Self-Renewal of Stem Cells and Somatic Cell Reprogramming.

The ground state of embryonic stem cells (ESCs) is closely related to the development of regenerative medicine. Particularly, long-term culture of ESCs in vitro, maintenance of their undifferentiated state, self-renewal and multi-directional differentiation ability is the premise of ESCs mechanism and application research. Induced pluripotent stem cells (iPSC) reprogrammed from mouse embryonic fibroblasts (MEF) cells into cells with most of the ESC characteristics show promise towards solving ethical problems currently facing stem cell research. However, integration into chromosomal DNA through viral-mediated genes may activate proto oncogenes and lead to risk of cancer of iPSC. At the same time, iPS induction efficiency needs to be further improved to reduce the use of transcription factors. In this review, we discuss small molecules that promote self-renewal and reprogramming, including growth factor receptor inhibitors, GSK-3ß and histone deacetylase inhibitors, metabolic regulators, pathway modulators as well as EMT/MET regulation inhibitors to enhance maintenance of ESCs and enable reprogramming. Additionally, we summarize the mechanism of action of small molecules on ESC self-renewal and iPSC reprogramming. Finally, we will report on the progress in identification of novel and potentially effective agents as well as selected strategies that show promise in regenerative medicine. On this basis, development of more small molecule combinations and efficient induction of chemically induced pluripotent stem cell (CiPSC) is vital for stem cell therapy. This will significantly improve research in pathogenesis, individualized drug screening, stem cell transplantation, tissue engineering and many other aspects.