The cannabinoid receptor CB1 affects the proliferation and apoptosis of adenomyotic human uterine smooth muscle cells of the junctional zone: a mechanism study.

BACKGROUND: The denomyotic junctional zone (JZ) plays an important role in the pathogenesis of adenomyosis. Proliferating cell nuclear antigen (PCNA) is an important nuclear marker of cell proliferation. This study aimed to evaluate the effects of the cannabinoid receptor CB1 on proliferation and apoptosis in the JZ in women with and without adenomyosis. METHODS: JZ smooth muscle cells (JZSMCs) of the adenomyosis and control groups were collected and cultivated. Immunohistochemistry and immunoblotting were used for protein localization and expression detection of CB1 and PCNA. Additionally, qRT-PCR was used to quantitatively analyse the mRNA expression of the two. AM251 and ACEA were used to regulate the function of CB1 receptors, and CCK-8 assay and flow cytometry assay were used to verify the proliferation and apoptosis of JZSMCs after regulation. RESULTS: We demonstrated that in normal JZSMCs CB1 and PCNA messenger RNA (mRNA) and protein expression was significantly higher in the proliferative phase of the menstrual cycle than in the secretory phase. CB1 and PCNA expression in JZSMCs from women with ADS was significantly higher than that in control women and did not significantly differ across the menstrual cycle. CB1 receptor antagonist AM251 inhibited the proliferation of adenomyotic JZSMCs in a dose-dependent manner. The CB1 receptor agonist ACEA significantly promoted the proliferation of adenomyotic JZSMCs. The apoptosis rate of adenomyotic JZSMCs treated with AM251 was significantly higher than that of JZSMCs from the untreated control group. The apoptosis rate was significantly decreased in the ACEA group compared with that in the untreated control group. Furthermore, AM251 suppressed the phosphorylation of AKT and Erk1/2 in adenomyotic JZSMCs. The CB1 agonist ACEA significantly promoted the phosphorylation of AKT and Erk1/2. CONCLUSIONS: Our results indicated that the levels of CB1 and PCNA were increased in patients with adenomyosis and that cyclic changes were lost. CB1 may affect uterine JZ proliferation and apoptosis in adenomyosis by enhancing AKT and MAPK/Erk signalling.

Chemical-induced disease relation extraction via attention-based distant supervision.

BACKGROUND: Automatically understanding chemical-disease relations (CDRs) is crucial in various areas of biomedical research and health care. Supervised machine learning provides a feasible solution to automatically extract relations between biomedical entities from scientific literature, its success, however, heavily depends on large-scale biomedical corpora manually annotated with intensive labor and tremendous investment. RESULTS: We present an attention-based distant supervision paradigm for the BioCreative-V CDR extraction task. Training examples at both intra- and inter-sentence levels are generated automatically from the Comparative Toxicogenomics Database (CTD) without any human intervention. An attention-based neural network and a stacked auto-encoder network are applied respectively to induce learning models and extract relations at both levels. After merging the results of both levels, the document-level CDRs can be finally extracted. It achieves the precision/recall/F1-score of 60.3%/73.8%/66.4%, outperforming the state-of-the-art supervised learning systems without using any annotated corpus. CONCLUSION: Our experiments demonstrate that distant supervision is promising for extracting chemical disease relations from biomedical literature, and capturing both local and global attention features simultaneously is effective in attention-based distantly supervised learning.

Human amniotic mesenchymal stromal cell transplantation improves endometrial regeneration in rodent models of intrauterine adhesions.

BACKGROUND AIMS: Intrauterine adhesion (IUA) is a common uterine cavity disease characterized by the unsatisfactory regeneration of damaged endometria. Recently, stem cell transplantation has been proposed to promote the recovery process. Here we investigated whether human amniotic mesenchymal stromal cells (hAMSCs), a valuable resource for transplantation therapy, could improve endometrial regeneration in rodent IUA models. METHODS: Forty female Sprague-Dawley rats were randomly assigned to five groups: normal, sham-operated, mechanical injury, hAMSC transplantation, and negative control group. One week after intervention and transplantation, histological analyses were performed, and immunofluorescent and immunohistochemical expression of cell-specific markers and messenger RNA expression of cytokines were measured. RESULTS: Thicker endometria, increased gland numbers and fewer fibrotic areas were found in the hAMSC transplantation group compared with the mechanical injury group. Engraftment of hAMSCs was detected by the presence of anti-human nuclear antigen-positive cells in the endometrial glands of the transplantation uteri. Transplantation of hAMSCs significantly decreased messenger RNA levels of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß), and increased those of anti-inflammatory cytokines (basic fibroblast growth factor, and interleukin-6) compared with the injured uterine horns. Immunohistochemical expression of endometrial epithelial cells was revealed in specimens after hAMSC transplantation, whereas it was absent in the mechanically injured uteri. CONCLUSIONS: hAMSC transplantation promotes endometrial regeneration after injury in IUA rat models, possibly due to immunomodulatory properties. These cells provide a more easily accessible source of stem cells for future research into the impact of cell transplantation on damaged endometria.

Direct Bilirubin, but not Indirect Bilirubin, is Associated with Short-term Adverse Events in HFpEF.

OBJECTIVE: Abnormal live function tests have been identified as independent risk factors for ominous prognosis in patients with heart failure. However, most of the previous studies have failed to determine the contribution of direct bilirubin (DBIL) and indirect bilirubin (IBIL) separately. Hence, we aimed to explore whether DBIL or IBIL is correlated with the prognosis of heart failure with preserved ejection fraction (HFpEF). METHODS: A total of 19837 patients were hospitalized for HFpEF between January 2012 and January 2022 in Fuqing City Hospital affiliated with Fujian Medical University. The primary endpoint was in-hospital all-cause mortality. Secondary endpoints included in-hospital cardiovascular mortality and 30-day re-admission for heart failure. RESULTS: Univariable analysis indicated that patients with elevated DBIL or IBIL were exposed to a higher risk of mortality and re-admission. However, in multivariable models, both ln-transformed DBIL and TBIL, but not IBIL, were independent risk factors for in-hospital all-cause mortality (hazard ratio (HR)=1.796, 95% confidential interval (CI)=1.477-2.183, P<0.001; HR=1.854, 95% CI=1.461-2.352, P.0.001; HR=1.161, 95% CI=0.959-1.407, P=0.126) and in-hospital cardiovascular mortality (HR=1.831, 95% CI=1.345-2.492, P.0.001; HR=1.899, 95% CI=1.300-2.773, P=0.001; HR=1.145, 95% CI=0.841-1.561, P=0.389). Only DBIL remained independently associated with 30-day readmission for heart failure (HR=1.361, 95% CI=1.036-1.787, P=0.027). Adding ln-transformed DBIL to model 1 increased its discriminatory capacity (C-statistic: 0.851 to 0.869, respectively), whereas adding ln-transformed IBIL yielded little increment (C-statistic: 0.851 to 0.852, respectively). CONCLUSION: DBIL, but not IBIL, was associated with short-term ominous prognosis in patients with HFpEF. Hence, DBIL may be the superior predictor for prognosis in HFpEF.

Radical trachelectomy versus radical hysterectomy for the treatment of early cervical cancer: a systematic review.

OBJECTIVE: To assess the efficacy and safety of radical trachelectomy (RT) and radical hysterectomy (RH) for patients with early cervical cancer. DESIGN: Systematic review with meta-analysis. POPULATION: Women who had early cervical cancer. METHODS: Prospective controlled clinical trials comparing RT with RH were identified using a predefined search strategy. Recurrence, five-year recurrence-free survival rate, five-year overall survival rate, postoperative mortality, intraoperative and postoperative complications between the two operations were compared by using the methods provided by the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Three controlled clinical trials involving 587 participants were included. Meta-analysis showed that there was no significant difference between the two groups in recurrence rate [1.38; 95% confidence interval (CI) 0.58-3.28, p=0.47], five-year recurrence-free survival rate (1.17; 95% CI 0.54-2.53, p=0.69), five-year overall survival rate (0.86; 95% CI 0.30-2.43, p=0.78), postoperative mortality (1.14; 95% CI 0.42-3.11, p=0.80), intraoperative complications (1.66; 95% CI 0.11-25.28, p=0.72), postoperative complications (0.52; 95% CI 0.11-2.48, p=0.41), blood transfusion (0.29; 95% CI 0.06-1.36, p=0.12) and number of harvested lymph nodes. However, RT, compared with RH, reduced blood loss and shortened duration to normal urine residual volume and postoperative hospital stay. Moreover, RT may achieve to normal conception rates, while RH makes patients sterile. CONCLUSIONS: Radical trachelectomy has similar efficacy and safety to RH as the surgical treatment for early cervical cancer. Moreover, it reduced blood loss and shortened the duration to normal urine residual volumes and postoperative hospital stay. Radical trachelectomy can be used to treat early stage cervical cancer as an alternative operation for patients who wish to preserve fertility.

The Dose-Dependent Effects of Spironolactone on TGF-ß1 Expression and the Vulnerability to Atrial Fibrillation in Spontaneously Hypertensive Rats.

OBJECTIVE: This study tends to assess the dose-dependent effects of spironolactone on TGF-ß1 expression, atrial fibrosis, and the vulnerability to atrial fibrillation in spontaneously hypertensive rats (SHRs) and tries to clarify the association of atrial fibrosis with the vulnerability to atrial fibrillation. METHODS: Forty 20-week-old male SHRs were randomly divided into 4 groups (10 rats per group): 3 spironolactone groups were lower-dose group (10 mg·kg-1·d-1, dissolved in 2 ml saline solution, group SL), medium-dose group (40 mg·kg-1·d-1, dissolved in 2 ml saline solution, group SM), higher-dose group (80 mg·kg-1·d-1, dissolved in 2 ml saline solution, group SH) and one hypertension group (2 ml saline solution for stomach gavage, group H). Ten matched homologous WKY rats were set as the control group (group C). After 7 weeks of gavage, a multiple electroconductive physiological recorder was used to detect atrial electrical parameters, including P-wave duration, PR interval, and atrial effective refractory period (AERP), the inducibility, and duration of atrial fibrillation. HE staining was used to determine myocardial cell size. Masson staining was used to detect the deposition of the interstitial collagen fibers in atrial muscle. The expression of TGF-ß1 was detected by immunohistochemistry and western blot. RESULTS: Compared with group C, the myocardial cell size, atrial fibrosis, TGF-ß1 expression, P-wave duration, PR interval, AERP, inducibility, and duration of atrial fibrillation in group H were conspicuously increased (p < 0.05); compared with group H, there was no significant difference in the myocardial cell size, atrial fibrosis, TGF-ß1 expression, and electrophysiological indexes in group SH upon spironolactone intervention (p > 0.05); compared with group H, the myocardial cell size, atrial fibrosis, the expression of TGF-ß1, P-wave duration, PR interval, the inducibility, and duration of atrial fibrillation in the group SL and group SM were all decreased (p < 0.05); compared with group SM, the effect in the group SL was more prominent (p < 0.01). CONCLUSION: Hypertension can lead to cardiomyocyte hypertrophy, deposition of interstitial fibrosis in myocardial tissue, and an increase in the vulnerability to atrial fibrillation. Spironolactone showed a certain dose-dependent effect in SHRs. Lower-dose spironolactone was superior to higher-dose spironolactone in the aspect of reducing hypertensive atrial fibrosis and TGF-ß1 expression, as well as preventing the occurrence of atrial fibrillation.

Chemical-induced disease relation extraction via convolutional neural network.

This article describes our work on the BioCreative-V chemical-disease relation (CDR) extraction task, which employed a maximum entropy (ME) model and a convolutional neural network model for relation extraction at inter- and intra-sentence level, respectively. In our work, relation extraction between entity concepts in documents was simplified to relation extraction between entity mentions. We first constructed pairs of chemical and disease mentions as relation instances for training and testing stages, then we trained and applied the ME model and the convolutional neural network model for inter- and intra-sentence level, respectively. Finally, we merged the classification results from mention level to document level to acquire the final relations between chemical and disease concepts. The evaluation on the BioCreative-V CDR corpus shows the effectiveness of our proposed approach. Database URL: http://www.biocreative.org/resources/corpora/biocreative-v-cdr-corpus/.

Efficacy of freeze-dried amnion graft following hysteroscopic adhesiolysis of severe intrauterine adhesions.

OBJECTIVE: To evaluate the efficacy of freeze-dried amnion graft for prevention of intrauterine adhesion (IUA) reformation after hysteroscopic adhesiolysis. METHODS: A prospective randomized controlled trial was conducted among 88 women with severe IUAs who underwent hysteroscopic adhesiolysis at Beijing Obstetrics and Gynecology Hospital between July 15, 2015, and July 1, 2016. All participants had a balloon inserted into the uterine cavity for 1 week. Sterilized freeze-dried amnion graft covered the balloon portion of the Foley catheter among patients allocated to the amnion group (n=44), whereas patients in the control group (n=44) did not receive the graft. Follow-up hysteroscopy was performed 3 months after surgery. Preoperative and postoperative IUA scores, menstruation scores, and pregnancy rates were assessed. RESULTS: Both groups exhibited reductions in IUA scores and improvements in menstruation scores following treatment (P<0.001 for each measure). Compared with the control group, the amnion group had a lower IUA score (P=0.032) and a higher menstruation score (P<0.001) at follow-up. By contrast, the rates of IUA reformation and pregnancy were not significantly different between the two groups. CONCLUSION: Use of freeze-dried amnion graft was effective in reducing IUA reformation and improving menstruation (according to pictorial blood-loss assessment chart) following hysteroscopic adhesiolysis of severe IUAs. ClinicalTrials.gov: (NCT02496052).

Expression Pattern of G-Protein-Coupled Estrogen Receptor in Myometrium of Uteri with and without Adenomyosis.

OBJECTIVE: To compare the expression of G-protein-coupled estrogen receptor (GPER) in the junctional zone and outer myometrium of the proliferative and secretory phases of women with and without adenomyosis. METHODS: A total of 76 women were included in this study, 42 with adenomyosis (proliferative phase, n = 23; secretory phases, n = 19) and 34 controls (proliferative phase, n = 16; secretory phases, n = 18). Protein and total RNA were extracted from the junctional zone (JZ) and outer myometrium (OM). GPER protein and mRNA expression levels were evaluated by the use of western blotting and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: The expression of GPER protein and mRNA in women with adenomyosis was significantly higher than that of control subjects, both in the junctional zone and in the outer myometrium and both in the proliferative and in the secretory phases. CONCLUSION: The significant and consistent increase in GPER expression in adenomyosis compared with control subjects, regardless of whether it was in the proliferative or secretory phases and regardless of whether it was in the JZ or OM, suggests that GPER plays an important role in the pathogenesis of the adenomyosis.

17ß-Estradiol Induces Overproliferation in Adenomyotic Human Uterine Smooth Muscle Cells of the Junctional Zone Through Hyperactivation of the Estrogen Receptor-Enhanced RhoA/ROCK Signaling Pathway.

Adenomyosis (ADS) is a common estrogen-dependent gynecological disease with unknown etiology. Recent models favor abnormal thickening of the junctional zone (JZ) may be the causative factor in the development of ADS. RhoA, a small guanosine triphosphatase which controls multiple cellular processes, is involved in the control of cell proliferation. Here we demonstrate that treatment of human uterine smooth muscle cells (SMCs) of the JZ with 17ß-estradiol (E2) increased expression of RhoA and its downstream effectors (-associated coiled coil containing protein kinase [ROCK] 1 and ROCK2). Compared with non-ADS cells, RhoA, ROCK1, and ROCK2 were overexpressed and hyperactivated in ADS cells. These effects were suppressed in the presence of ICI 182,780, supporting an estrogen receptor (ER)-dependent mechanism. Hyperactivation of ER-enhanced RhoA/ROCK signaling was associated with overproliferation in ADS human uterine SMCs of the JZ. Moreover, E2-induced overproliferation was accompanied by downregulation of cyclin-dependent kinases inhibitors (CKIs; p21(Waf1/Cip1) and p27(Kip1)) and upregulation of cyclin-dependent kinases (CDKs) and cyclins (cyclin D1, cyclin E1, CDK2, CDK4, and CDK6).