Rab27b promotes endometriosis by enhancing invasiveness of ESCs and promoting angiogenesis.

PROBLEM: Endometriosis (EMS) is an estrogen-dependent disease which is characterized with estrogen-dependent growth of ectopic endometrium and increased local estrogen production. EMS performs tumor-like biological functions such as invasiveness and angiogenesis. Rab27b is a member of the Rab family of GTPases, which is strongly associated with the growth, invasion and metastasis of a variety of tumors. However, little is known about the function of Rab27b in EMS. In this study, we intended to investigate the impact of Rab27b and its downstream molecule in the development of EMS. METHOD OF STUDY: Normal endometrium and endometriotic lesions were collected to investigate the expression levels of Rab27b. Then, ESCs were transfected with Rab27b siRNA. We analyzed the influence of Rab27b on the proliferation and invasive activity of ESCs. Conditioned media harvested from Rab27b siRNA-treated ESCs were used to treat HUVECs. HUVEC Tube formation and ELISA were performed to explored the interactions between ESCs and HUVEC. In addition, ESCs were treated with different concentrations of estrogen. Based on biological database predictions, we explored possible mechanisms through which estrogen regulates the expression of Rab27b. RESULTS: The expressions of Rab27b were significantly higher in endometriotic lesions than that in normal endometrium. Rab27b can promote the cell proliferation, migration and invasion of ESCs. The elevated expression of Rab27b, on the one hand, promotes the secretion of MMP9 and increases the invasiveness of ESCs. On the other hand, Rab27b may play a key role in the communication between ESC and endothelial cells, by simulating VEGF secretion and neovascularization. Besides, estrogen upregulated phosphorylated FOXO1 levels in ectopic ESCs, resulting in the promotion of Rab27b expression levels. CONCLUSION: Rab27b plays a key role in the development of EMS, which may provide new insights into the pathogenesis of EMS. Our findings may also contribute to the development of therapeutic interventions for EMS.

Synergy between Th1 and Th2 responses during endometriosis: A review of current understanding.

Endometriosis is widely perceived as an estrogen-dependent chronic disorder with infertility and pelvic pain. Although the etiology of endometriosis has remained elusive, many studies have proclaimed the relevance of immune system disorders with endometriosis. With the discovery that the dysregulation of multiple biological functions in endometriosis is caused by the aberrant differentiation of T helper cells, a shift towards Th2 immune response may account for the disease progression. This review attempts to present mechanisms of cytokines, chemokines, signal pathways, transcription factors and some other factors related with the derivation of Th1/Th2 immune response involved in the development of endometriosis. The current understanding of treatment approaches and potential therapeutic targets will also be outlined with brief discussion.

Towards a Better Understanding of Endometriosis-Related Infertility: A Review on How Endometriosis Affects Endometrial Receptivity.

Endometriosis is the most common cause of infertility. Endometrial receptivity has been suggested to contribute to infertility and poor reproductive outcomes in affected women. Even though experimental and clinical data suggest that the endometrium differs in women with endometriosis, the pathogenesis of impaired endometrial receptivity remains incomplete. Therefore, this review summarizes the potential mechanisms that affect endometrial function and contribute to implantation failure. Contemporary data regarding hormone imbalance, inflammation, and immunoregulatory dysfunction will be reviewed here. In addition, genetic, epigenetic, glycosylation, metabolism and microRNA in endometriosis-related infertility/subfertility will be summarized. We provide a brief discussion and perspectives on their future clinical implications in the diagnosis and therapy to improve endometrial function in affected women.

Acupuncture combined with traditional Chinese medicine e-aid cognitive behavioral therapy for insomnia (TCM-eCBT-I) for chronic insomnia: study protocol for a randomized controlled trial.

INTRODUCTION: The incidence of insomnia is getting higher and higher. Long-term insomnia seriously affects people's health. Drug use is usually accompanied with adverse events. Both acupuncture and cognitive behavioral therapy for insomnia (CBT-I) have been proven to be safe and effective non-pharmacological treatments for insomnia. As the insomniacs' bad sleep behavior and wrong cognition have not been effectively corrected, acupuncture has a quick effect, high patient compliance but unstable long-term efficacy, while CBT-I is complex, time-consuming, and expensive; additionally, patient compliance is low, and the number of trained therapists is limited, making it difficult to carry out. Therefore, this study aims to use the insomnia TCM system to construct a convenient and feasible traditional Chinese medicine e-aid cognitive behavioral therapy for insomnia (TCM-eCBT-I) for Chinese people, and combine the advantages of acupuncture and TCM-eCBT-I for maintaining long-term efficacy, and three treatments will be evaluated to provide clinicians with a more effective clinical protocol METHODS AND ANALYSIS: This study is a single-center, open-label, randomized controlled trial. Ninety subjects will be recruited and randomly assigned to three groups: the acupuncture group, the TCM-eCBT-I group, and the acupuncture combined with TCM-eCBT-I group, in a ratio of 1:1:1. We will evaluate the Pittsburgh Sleep Quality Index (PSQI) and Dysfunctional Beliefs and Attitudes About Sleep Scale (DBAS), Insomnia Severity Index (ISI), sleep diary, Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), and Fatigue Scale-14 Scale (FS-14) scales. All adverse reactions will be assessed through the ADVERSE event table. All outcomes will be evaluated online at 0 weeks, 4 weeks, 8 weeks, 16 weeks, and 28weeks. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board of the Affiliated Hospital of Nanjing University of Chinese Medicine (2020 NL-018-02). Informed consent will be obtained from all the subjects. The results will be shared with sleep researchers, public, and relevant academic institutions through high-impact peer-reviewed publications. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000032960. Registered on 17 May 2020.

Effect of Acupuncture on Cognitive Function of Insomnia Patients Compared with Drugs: A Protocol for Meta-analysis and Systematic Review.

Insomnia, one of the most common sleep disorders, is thought to have an adverse effect on cognitive function. At the same time, people with cognitive dysfunction are more prone to insomnia. At present, pharmacotherapy is the main treatment for insomnia, but there are some shortcomings such as poor long-term efficacy and potential dependence. There is some evidence that acupuncture has some advantages in alleviating insomnia and improving cognitive function. This study is aimed at investigating the effects of acupuncture and drugs on cognitive function in patients with insomnia and evaluating the efficacy and safety of these two interventions, providing strong evidence for clinical decision-making. The study will retrieve eight major databases: China National Knowledge Infrastructure, Wanfang Database, VIP Database for Chinese Technical Periodicals, SinoMed, PubMed, Web of Science, Embase, and Cochrane Library. Dissertations, conference papers, and ongoing experiments will also be retrieved for supplement. Literature screening and data extraction will be completed by two authors independently (JJ and X-QW). If there were any disagreements, they would be discussed or referred to a third person for adjudication (W-ZW). Authors will use Cochrane risk of bias tool to assess the included studies. The Review Manager Statistical (RevMan) software is used to conduct the statistical process of meta-analysis, and funnel plot is used to evaluate reporting biases. The Grading of Recommendations Assessment Development and Evaluation (GRADE) Profiler can be used to be aware of the quality of evidence.

The efficacy of acupuncture on the sleep structure of patients with insomnia: A systematic review and meta-analysis.

This study aims to evaluate the efficacy of acupuncture on the sleep structure of patients with insomnia, so as to provide a valuable basis for the effectiveness of acupuncture in the treatment of insomnia. We conducted searches based on MeSH terms and free words in Cochrane Library, PubMed, Web of science, CKNI (China Knowledge Resource Integrated Database), WanFang Database, and Chongqing VIP Information from the inception of these database until 10 July 2020 for randomized controlled trials (RCTs) that investigated acupuncture treatment in patients with insomnia, and pertinent details of the results were saved. Comprehensive analysis showed that: (1) compared with the Western medicine groups, the acupuncture groups showed significant advantages in reducing the percentage of N1 sleep stage and N2 sleep stage, as well as increasing that of N3 sleep stage and REM sleep stage. However, no significant difference was found in increasing the effective rate, reducing total PSQI score, improving the total sleep time, reducing sleep latency, and improving sleep efficiency between the Western medicine groups and the acupuncture groups. (2) Compared with the sham acupuncture groups, the acupuncture treatment showed advantages in increasing the effective rate, reducing Pittsburgh Sleep Quality Index (PSQI) score, increasing the total sleep time, and improving sleep efficiency. However, no significant difference was observed between the sham acupuncture groups and the acupuncture groups with regard to reducing sleep latency, the percentage of N1 sleep stage and N2 sleep stage, as well as increasing that of N3 sleep stage and REM sleep stage.

[Effect of Tiaoshen needling on plasma melatonin and cortisol in patients with chronic insomnia].

OBJECTIVE: To observe the clinical efficacy of Tiaoshen needling (dredging Governor Vessel and regulating mind)in the treatment of chronic insomnia (CI) and its effect on plasma melatonin (MT) and cortisol (CORT) levels, so as to explore its underlying mechanism. METHODS: Sixty patients with CI were randomly divided into the treatment group and the control group, with 30 cases in each group. Both groups were given sleep hygiene education before treatment. Patients in the treatment group received acupuncture or electroacupuncture at Baihui (GV20), Shenting (GV24), Yintang (GV29), bilateral Shenmen (HT7) and Sanyinjiao (SP6). Patients in the control group received acupuncture or electroacupuncture at bilateral Shousanli (LI10), Futu (ST32) and Feiyang(BL58). Both groups were treated every other day, 3 times a week, for a total of 4 weeks. Before and after treatment, Pittsburgh sleep quality index (PSQI) and fatigue severity scale (FSS) were used to evaluate sleep qua-lity and daytime fatigue, the plasma MT and CORT levels were measured by enzyme-linked immunosorbent assay. RESULTS: Compared with before treatment, the PSQI scores and total FSS score of the treatment group decreased significantly (P<0.01，P<0.05), and the plasma MT content increased and CORT decreased significantly in the treatment group (P<0.01)，while the sleep-onset time score, sleep disturbance score and the PSQI total score of the control group decreased significantly (P<0.05). Compared with the control group, the PSQI sleep disorder score and total score, and the total FSS score as well as plasma CORT level were significantly down-regulated (P<0.01，P<0.05), while the plasma MT content was up-regulated (P<0.05) in the treatment group. CONCLUSION: Tiaoshen acupuncture can significantly improve the sleep quality of patients with CI and relieve daytime fatigue, which may be related to the increase of plasma MT content in patients with CI, thereby inhibiting the excessive activation of the hypothalamic-pituitary-adrenal axis.

[Effect of Tongdu Tiaoshen acupuncture on serum GABA and CORT levels in patients with chronic insomnia].

OBJECTIVE: To observe the clinical effect of Tongdu Tiaoshen acupuncture on chronic insomnia, and explore its possible mechanism. METHODS: A total of 60 patients with chronic insomnia were randomly divided into an observation group (30 cases) and a control group (30 cases, 1 case dropped off ). The observation group was treated with Tongdu Tiaoshen acupuncture at Baihui (GV 20), Yintang (GV 29), Shenting (GV 24), etc. once every other day, 3 times a week. The control group was treated with estazolam tablets (1 mg) orally before going to bed every night. The treatments of both groups were required 4 weeks. The Pittsburgh sleep quality index (PSQI) scores, serum gamma-aminobutyric acid (GABA) and cortisol (CORT) levels were observed before and after treatment in the two groups, and the clinical effect was compared. RESULTS: After treatment, the sleep quality, day dysfunction scores of PSQI in the observation group and the falling asleep time, sleep time, sleep efficiency, sleep disturbance scores and total scores of PSQI in the two groups were lower than before treatment (P<0.01, P<0.05). After treatment, the daytime dysfunction score of PSQI in the observation group was lower than that in the control group (P<0.05). After treatment, the serum GABA levels in the two groups were higher than before treatment (P<0.05), and the serum CORT levels were lower than before treatment (P<0.01). The total effective rate was 90% (27/30) in the observation group and 93.1% (27/29) in the control group, the difference was not statistically significant (P>0.05). CONCLUSION: Tongdu Tiaoshen acupuncture has the same effect as western medication estazolam tablets in the treatment of patients with chronic insomnia, and has little effect on daytime dysfunction. The mechanism may be related to the increase of serum GABA level and the inhibition of the hyperactivation of hypothalamus-pituitary-adrenal (HPA) axis.

Rapidly progressing primary pulmonary lymphoma masquerading as lung infectious disease: A case report and review of the literature.

BACKGROUND: Primary anaplastic large cell lymphoma of the lung represents a diagnostic challenge due to diverse manifestations and non-specific radiological findings, particularly in cases that lack extra-pulmonary manifestations and lung biopsy. CASE SUMMARY: A 40-year-old woman presented with a 6-d history of fever, dry coughing, and dyspnea. Her white blood cell count was 20100/mm3 with 90% neutrophils. PaO2 was 60 mmHg and SaO2 was 90% when breathing ambient air. Chest computed tomography (CT) identified a solid nodule, 15 mm in diameter, with a poorly defined boundary in the upper right lung, and several smaller solid nodules throughout both lungs. Pulmonary artery CT and subsequent bedside X-ray showed diffuse patchy shadows throughout both lungs. Repeated cultures of blood samples and alveolar lavage failed to identify any pathogen. Due to the mismatch between clinical and imaging features, we conducted a bone marrow biopsy, and the results showed proliferation along all three lineages but no atypical or malignant cells. The patient received empirical antibacterial, antiviral, and antifungal treatments, as well as corticosteroids. The patient's condition deteriorated rapidly despite treatment. The patient died 6 d after hospitalization due to respiratory failure. Post-mortem lung biopsy failed to show inflammation but identified widespread infiltration of alveolar septum by anaplastic lymphoma kinase (ALK)-positive anaplastic cells. CONCLUSION: ALK-positive anaplastic large cell lymphoma could present as a primary pulmonary disease without extra-pulmonary manifestations.

[Effect of electroacupuncture on serum melatonin and dopamine in aged insomnia].

OBJECTIVE: To observe the clinical effect of electroacupuncture (EA) on aged insomnia, and explore its possible mechanism. METHODS: A total of 60 patients with aged insomnia were randomly divided into an EA group (30 cases) and a sham EA group (30 cases, 1 case dropped off). The patients in the EA group were treated with acupuncture at Baihui (GV 20), Yintang (GV 29), Shenmen (HT 7), Sanyinjiao (SP 6), Xinshu (BL 15) and Shenshu (BL 23), and EA was used at Baihui (GV 20) and Yintang (GV 29), with intermittent wave, 2 Hz in frequency. In the sham EA group, the acupoints and the EA connection acupoints were the same as those in the EA group, 2-3 mm in depth, but no current was connected. The intervention was given 30 min each time, once every other day, 3 times a week for 4 weeks in the both groups. Before and after treatment, the Pittsburgh sleep quality index (PSQI) and Montreal cognitive assessment (MoCA) scale were used to assess sleep quality and cognitive function, and serum melatonin (MT) and dopamine (DA) levels were detected. RESULTS: After treatment, the total score and sub-item scores of PSQI in the EA group were lower than those before treatment (P<0.01, P<0.05), among them, the sub-item scores of sleep quality, time to fall asleep, sleep time and sleep efficiency, daytime dysfunction and total score were all lower than those in the sham EA group (P<0.01, P<0.05). After treatment, the MoCA score and serum MT and DA levels in the EA group were higher than those before treatment (P<0.01), and the MoCA score and serum MT level in the EA group were higher than the sham EA group (P<0.01, P<0.05). CONCLUSION: Electroacupuncture can improve sleep quality and cognitive function in aged insomnia patients, and its mechanism may be related to regulating serum MT and DA levels.

[Effect of acupuncture at Tiaoshen acupoints on hyperarousal state in chronic insomnia].

OBJECTIVE: To observe the clinical effect of acupuncture at Tiaoshen (regulating the spirit) acupoints on chronic insomnia and hyperarousal state, and explore its possible mechanism. METHODS: A total of 60 patients with chronic insomnia were randomly divided into an acupuncture group (30 cases, 1 case dropped off) and a sham acupuncture group (30 cases, 1 cases dropped off). Both groups were given basic sleep health education. The acupuncture group was treated with acupuncture at Tiaoshen acupoints including Baihui (GV 20), Shenting (GV 24), Yintang (GV 29), Shenmen (HT 7) and Sanyinjiao (SP 6). The sham acupuncture group was treated with non-effective point shallow acupuncture. Both groups were treated once every other day, 3 times a week for 4 weeks. The Pittsburgh sleep quality index (PSQI) score, pre-sleep arousal scale (PSAS) score, hyperarousal scale (HAS) score, and serum gamma-aminobutyric acid (GABA) level before and after treatment were compared between the two groups. RESULTS: Compared before treatment, the sleep quality, time to fall asleep, sleep time, sleep efficiency, sleep disturbance, daytime dysfunction scores and total score of PSQI, various scores and total score of PSAS, and HAS score in the acupuncture group after treatment were decreased (P<0.05, P<0.01); in the sham acupuncture group, the time to fall asleep, daytime dysfunction scores and total score of PSQI, and cognitive arousal score of PSAS after treatment were decreased (P<0.05). After treatment, the sleep quality, time to fall asleep, sleep time, sleep efficiency, sleep disturbance, daytime dysfunction scores and total score of PSQI, various scores and total score of PSAS, and HAS score in the acupuncture group were lower than those in the sham acupuncture group (P<0.05, P<0.01). Compared before treatment, the serum GABA level in the acupuncture group were increased (P<0.05), and the serum GABA level in the acupuncture group was higher than that in the sham acupuncture group after treatment (P<0.05). CONCLUSION: Acupuncture at Tiaoshen acupoints can obviously improve the sleep and hyperarousal state of patients with chronic insomnia, and up-regulating serum GABA content is one of its possible mechanisms.

Regulatory T cells induce polarization of pro-repair macrophages by secreting sFGL2 into the endometriotic milieu.

An increased number of highly active regulatory T cells (Tregs) and macrophages has been found in peritoneal fluid from women with endometriosis. Here, we show that the level of Tregs-derived soluble fibrinogen-like protein 2 (sFGL2) increases in the peritoneal fluid of women with endometriosis. Higher expression of FGL2 and its receptor CD32B is observed in eutopic endometrium and ectopic tissues. The production of sFGL2 in Tregs may be enhanced by several cytokines. sFGL2 selectively induces pro-repair macrophage polarization mainly through the activation of the SHP2-ERK1/2-STAT3 signaling pathway, and the suppression of the NF-κB signaling pathway. Furthermore, sFGL2 induces a much higher level of metallothionein (MT) expression that in turn facilitates pro-repair macrophages polarization. sFGL2-induced pro-repair macrophages promote Th2 and Tregs differentiation, creating a positive feedback loop. These findings suggest that sFGL2 secreted by Tregs skews macrophages toward a pro-repair phenotype via SHP2-ERK1/2-STAT3 signaling pathway, which is involved in the progression of endometriosis.

[Effect of Tongdu Tiaoshen needling in treatment of chronic insomnia by regulating the hypothalamic-pituitary-adrenal axis].

OBJECTIVE: To investigate the clinical effect of Tongdu Tiaoshen needling in the treatment of chronic insomnia and its mechanism based on the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: A total of 60 patients with chronic insomnia were randomly divided into treatment group and control group, with 30 patients in each group. In addition to the health education on sleep, the patients in the treatment group were given Tongdu Tiaoshen needling, i．e., electroacupuncture at Baihui (GV20), Shenting (GV24), Yintang (EX-HN3), bilateral Shenmen (HT7), and bilateral Sanyinjiao (SP6), and those in the control group were given superficial acupuncture at Shousanli (LI10), Futu (ST32), and Feiyang (BL58) at both sides, once every other day and three times a week for 4 consecutive weeks. Before and after treatment, the Pittsburgh Sleep Quality Index (PSQI) was used to assess the quality and efficiency of sleep, and ELISA was used to measure the serum levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosterone (CORT). RESULTS: After treatment, the treatment group had significant reductions in the total PSQI score and the score of each component of PSQI (P<0.01), and the control group had significant reductions in the total PSQI score (P<0.01) and the scores of all components except sleep duration (P<0.05); compared with the control group, the treatment group had significantly lower total PSQI score and the score of each component (P<0.01). After treatment, the treatment group had significant reductions in the serum levels of CRH, ACTH and CORT (P<0.05，P <0.01), and compared with the control group, the treatment group had significant reductions in the serum levels of CRH, ACTH and CORT (P<0.01，P<0.05). CONCLUSION: Tongdu Tiaoshen needling has a good clinical effect in the treatment of chronic insomnia and can significantly improve the sleep condition of patients with chronic insomnia, possibly by reducing the hormones associated with the HPA axis.

[Insomnia treated with three acupuncture combinations guided by theory of Tongdu Tiaoshen: a randomized controlled trial].

OBJECTIVE: To compare the clinical therapeutic effect and safety on insomnia among three acupuncture combinations, named Tongdu Tiaowei (promoting the circulation of the governor vessel and regulating the defensive system), Tongdu Yangxin (promoting the circulation of the governor vessel and nourishing the heart) and Tongdu Tiaozang (promoting the circulation of the governor vessel and regulating zang functions). METHODS: A total of 90 patients with insomnia were randomized into a Tongdu Tiaowei group (30 cases, 1 case dropped off ), a Tongdu Yangxin group (30 cases, 2 cases dropped off ) and a Tongdu Tiaozang group (30 cases, 1 case dropped off ). Besides electroacupuncture (EA) applied to Baihui (GV 20) and Yintang (GV 29) in all of the three groups, acupuncture was added at Shenmai (BL 62) and Zhaohai (KI 6), Shenmen (HT 7) and Sanyinjiao (SP 6) as well as back-shu points of five zang organs [Feishu (BL 13), Xinshu (BL 15), Ganshu (BL 18), Pishu (BL 20) and Shenshu (BL 23)] in the Tongdu Tiaowei group, the Tongdu Yangxin group and the Tongdu Tiaozang group successively. The treatment was given once every two days, 3 times weekly, consecutively for 4 weeks. The score of Pittsburgh sleep quality index (PSQI) before and after treatment was observed, the therapeutic effect was evaluated and the adverse reactions were recorded in the patients of each group. RESULTS: After treatment, the score of each of 6 factors, named sleep quality, sleep latency, sleep time, sleep efficiency, sleep disturbance and daytime dysfunction, as well as the total score of PSQI scale were all reduced as compared with the scores before treatment in the patients of each group (P<0.05). After treatment, the scores of sleep latency and daytime dysfunction in the Tongdu Tiaowei group were lower than the other two groups (P<0.05). The score of sleep time in the Tongdu Yangxin group was lower than the other two groups (P<0.05) and the score of sleep quality in the Tongdu Tiaozang group was lower than the other two groups (P<0.05). After treatment, the total effective rates were 96.6% (28/29), 96.4% (27/28) and 96.6% (28/29) in the Tongdu Tiaowei group, the Tongdu Yangxin group and the Tongdu Tiaozang group successively, without significant difference in comparison among the three groups (P>0.05). During treatment, 1 case of mild adverse reaction occurred in each group. CONCLUSION: All of the three acupuncture combinations, named Tongdu Tiaowei, Tongdu Yangxin and Tongdu Tiaozang can effectively improve the sleep conditions in the patients with insomnia and are satisfactory in safety. The acupuncture combinations of Tongdu Tiaowei has the potential advantage in shortening sleep latency and relieving daytime dysfunction, the combinations of Tongdu Yangxin has the potential advantage in increasing sleep time and the combinations of Tongdu Tiaozang has the potential advantage in improving sleep quality.

Cyclooxygenase-2 in Endometriosis.

Endometriosis (EMS) is the most common gynecological disease in women of reproductive age, and it is associated with chronic pelvic pain, dyspareunia and infertility. As a consequence of genetic, immune and environmental factors, endometriotic lesions have high cyclooxygenase (COX)-2 and COX-2-derived prostaglandin E2 (PGE2) biosynthesis compared with the normal endometrium. The transcription of the PTGS2 gene for COX-2 is associated with multiple intracellular signals, which converge to cause the activation of mitogen-activated protein kinases (MAPKs). COX-2 expression can be regulated by several factors, such as estrogen, hypoxia, proinflammatory cytokines, environmental pollutants, metabolites and metabolic enzymes, and platelets. High concentrations of COX-2 lead to high cell proliferation, a low level of apoptosis, high invasion, angiogenesis, EMS-related pain and infertility. COX-2-derived PGE2 performs a crucial function in EMS development by binding to EP2 and EP4 receptors. These basic findings have contributed to COX-2-targeted treatment in EMS, including COX-2 inhibitors, hormone drugs and glycyrrhizin. In this review, we summarize the most recent basic research in detail and provide a short summary of COX-2-targeted treatment.

Correction: Trophoblast-derived CXCL16 induces M2 macrophage polarization that in turn inactivates NK cells at the maternal-fetal interface.

In this article, published online 27 March 2018, in the "ACKNOWLEDGEMENTS", it should be supplemented as follows: "This study was funded by a grant from the National Natural Science Foundation of China, number 81490744, awarded to Da-Jin Li." The authors regret the omission.

Trophoblast-derived CXCL16 induces M2 macrophage polarization that in turn inactivates NK cells at the maternal-fetal interface.

Decidual macrophages (dMΦ) are distinct from the conventional macrophages present in other tissues and express M2 macrophage markers, but the molecular mechanisms of formation and the roles of M2 MΦ during pregnancy have not been completely elucidated. The crosstalk between decidual natural killer cells (dNK) and dMΦ plays an important role in the maintenance of maternal-fetal immune tolerance. Here, CXCL16 derived from first-trimester trophoblast cells induces the polarization of human M2 macrophages. The M2 MΦ polarized by CXCL16 exhibit decreased interleukin-15 production, which facilitates the inactivation of NK cells. The cytotoxicity of NK cells is attenuated by the CXCL16-polarized M2 MΦ. The data shown in the present study provide evidence to support the hypothesis that CXCL16 secreted by trophoblast cells is a key molecule involved in decidual M2 MΦ polarization, which in turn regulates the killing ability of NK cells, thereby contributing to the homeostatic and immune-tolerant milieu required for successful fetal development.

[Expression and Clinical Prognostical Significance of RIP2 in Diffuse Large B Cell Lymphoma].

OBJECTIVE: To investigate the expression and prognosis significance of receptor interacting protein 2 (RIP2) in diffuse large B-cell lymphoma (DLBCL). METHODS: The expression of RIP2 in DLBCL GCB and non-GCB type was detected by immunohistochemistry, at same time the expressions of BCL-2 and C-MYC were detected. Then, the role of RIP2 in development of DLBCL was analyzed by related clinical and pathological parameters. RESULTS: The expression of RIP2 was related with middle-high risk group by IPI score, the An Arbor stage III+IV and intranodal lesions, and the differences were statistically significant (P<0.05). Besides, the single factor survival analysis suggested that GCB-type DLBCL showed a higher survival rate than that in non-GCB type(P<0.05). Patients with RIP2+ showed a lower survival rate as compared with patients with PIP2- (P<0.05), among which the patients receiving R-CHOP had a higher survival rate than that of those receiving CHOP (P<0.01). The expression of RIP2 in DLBCL cell lines was higher than that in peripheral mononuclear cells of normal subjects (P<0.01) and expressed differently in DLBCL of GCB and non-GCB type (P<0.01). CONCLUSION: The expression of RIP2 may relate with the poor prognosis and specific subtype of DLBCL.

Synergistic effect of regulatory T cells and proinflammatory cytokines in angiogenesis in the endometriotic milieu.

STUDY QUESTION: Do regulatory T cells (Tregs) contribute to angiogenesis in endometriosis? SUMMARY ANSWER: High levels of CCL17 and CCL22 cause the recruitment of Tregs, upregulate the immunosuppression of Tregs and, in turn, may promote angiogenesis in endometrial cells in synergy with proinflammatory cytokines. WHAT IS ALREADY KNOWN: The peritoneal fluid of patients with endometriosis has a higher percentage of Tregs than that of normal individuals; however, the regulatory role of Tregs in the disease remains unclear. STUDY DESIGN, SIZE, DURATION: This study used primary human endometrial stromal cells (ESCs), monocytes (Mo), Tregs and human umbilical vein endothelial cells (HUVECs). All experiments were performed at least three times. PARTICIPANTS/MATERIALS, SETTING, METHODS: The migration of Tregs was evaluated by the transwell migration assay. The activation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase and p38 signaling pathways was examined using the In-Cell WesternTM (LI-COR®) western blot analysis system, as well as by traditional western blot analysis. Changes in the expression of CCL22, CCL17, transforming growth factor-beta 1 (TGF-ß1), Interleukin (IL)-1ß, tumor necrosis factor alpha (TNF-α), IL-8 and vascular endothelial growth factor (VEGF) in cell-culture supernatant were detected by ELISA. We analyzed the Tregs by multicolor flow cytometry to directly test the expression of CCR4, CD4, CD25, Foxp3, CTLA-4, CD39 and CD73. MAIN RESULTS AND THE ROLE OF CHANCE: Our results showed that ESCs-Mo co-culture produced significantly higher levels of CCL22 and CCL17 than ESCs or Mo cultured alone, and that estradiol (E2) or progesterone (P) further promoted this upregulation, demonstrating stronger chemotaxis on Tregs. The co-culture of ESCs with Mo stimulated TGF-ß1 secretion by Tregs, which could be inhibited by anti-CCL22 or/and anti-CCL17 neutralizing antibodies (Abs). The expression of CCR4 by Tregs was upregulated in ESCs-Mo co-culture, especially by treatment with E2 and/or P, and this effect could be abolished by anti-CCL22 and/or anti-CCL17-neutralizing Abs. The Treg-ESCs-Mo co-culture treated with E2 (10-8 mol/l) and P (10-8 mol/l) could enhance the immunosuppression of Tregs, as proved by the elevated expression of Foxp3, CTLA-4, CD39 and CD73 on Tregs. ESCs-Mo co-culture could significantly promote the secretion of IL-1ß and TNF-α. TGF-ß1 from Tregs could activate p38/ERK1/2 signaling pathways in ESCs, and IL-1ß and TNF-α produced by ESCs-Mo co-culture had synergistic roles with TGF-ß1. TGF-ß1 and the proinflammatory cytokines IL-1ß or TNF-α could synergistically promote IL-8 and VEGF expression in ESCs via the p38/ERK1/2 signaling pathways. The high levels of IL-8 and VEGF in the supernatant of ESCs stimulated the angiogenesis of HUVECs. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: This study was only performed in vitro using eutopic ESCs, instead of ectopic cells, from endometriosis patients. Therefore, it is necessary to do further experiments to determine whether Tregs promote angiogenesis in the endometriotic milieu in synergy with proinflammatory cytokines in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Co-targeting Tregs and proinflammatory cytokines may be an effective treatment for endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Ministry of Science and Technology of China 2015CB943300 to L.D.-J.; National Natural Science Foundation of China, item number 81200425 to  W.X.-Q.; National Natural Science Foundation of China, item number 81471548 to L.D.-J.; and The Research Fund for the Doctoral Program of Higher Education of China to W.X.-Q. (20110071120093). The authors have no conflicts of interest to declare.