Correlation study of NF-κB, IER3, and recurrence of ovarian endometrioid cysts

Correlation study of NF-κB, IER3, and recurrence of ovarian endometrioid cysts | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Correlation study of NF-κB, IER3, and recurrence of ovarian endometrioid cysts Ni Yang, Gu Huang, Xiang Fan, Chao Zhang, Li Wang, Xian Jiang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2128626/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Objective To investigate the expression of nuclear actor-k-gene binding(NF-κB) and immediate early response 3(IER3) in nuclear factor-activated B cells in ovarian endometrioid cysts. To analyze the correlation between the expression of NF-κB and IER3 and the recurrence of the ovarian endometrioid cyst. Methods From January 2018 to March 2019, a total of 80 patients who underwent laparoscopic ovarian cyst excision due to ovarian endometrioid cyst in the Department of Gynecology, Changzhou Maternal and Child Health Hospital were selected, including 40 patients without postoperative recurrence and 40 patients with recurrence, and the patients with recurrence were further divided into the primary recurrence and the secondary recurrence groups. The general clinical data of the patients were collected. The patient's Revised American Fertility Society (R-AFS) score, least function(LF) score, and endometriosis fertility index (EFI) were calculated, and immunohistochemical staining was performed to detect the expression of IER3 and NF-κB in the pathological tissues of the three groups. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of IER3 and NF-κB expression on postoperative recurrence of the ovarian endometrioid cyst. Cox proportional hazards model was fitted to analyze the related influencing factors of ovarian endometrioid cyst recurrence. Results The expression intensity of NF-κB was positively correlated with IER3 (P < 0.001). ROC curve showed that the area under curve (AUC) of NF-κB and IER3 combined diagnosis was 0.844, 95%CI was 0.754–0.933, sensitivity was 77.5% and specificity was 90.00%. Multivariate Cox survival regression showed that the IER3 expression intensity > 4.5 (HR = 4.661,95%CI: 1.712–12.690, P = 0.003) and the NF-κBexpression intensity > 4.5 (HR = 2.878,95%CI: 1.181–7.011, P = 0.020) were independent risk factor for postoperative recurrence, and EFI score (HR = 1.289,95%CI: 1.037–1.602, P = 0.022) was a protective factor for postoperative recurrence. Conclusion EFI score is a protective factor for postoperative recurrence, and the expression intensity of NF-κB and IER3 has a certain correlation with the recurrence of ovarian endometrioid cysts. The expression levels of NF-κB and IER3 > 4.5 are independent risk factors for postoperative recurrence. ovarian endometrioid cyst recurrence NF-κB IER3 Figures Figure 1 Figure 2 Figure 3 Introduction Endometriosis (EMs) plays an important role in gynecological diseases. The characteristics of recurrence, infertility, and pain cause a serious burden on women's bodies and minds. There is still a lack of reliable biomarkers for early diagnosis of recurrent endometriosis. The ovarian endometrioid cyst is the most common pathological type in EMs. So far, its treatment methods are mainly surgery and drug therapy. Although there are many emerging surgical methods nowadays, such as ultrasound-guided cyst puncture, cyst puncture combined with sclerotherapy, etc. Although the trauma is less, it is limited to a single lesion and requires no adhesion or damage to the lesion. The first choice for diagnosis and treatment of ovarian endometrioid cyst is still laparoscopic endometrioid cyst excision, but the recurrence rate is high. Finding effective prognostic markers to screen patients with possible recurrence can greatly improve the quality of life of patients and reduce the recurrence rate after surgery. Nf-κb is a dimeric transcription factor that promotes the expression of more than 150 genes involved in cellular processes, including immune responses and inflammatory processes [ 1 ] . The NF-κB pathway has been considered a classical proinflammatory signaling pathway, mainly based on the role of NF-κB in the expression of proinflammatory genes, including inflammatory mediators, cytokines, adhesion molecules, apoptosis inhibitors, and chemokines. The pleiotropic result of its activated nuclear factor is caused by the combinatorial effects of the five subunits forming homologous and heterodimeric NF-κB complexes [ 2 ] . Nf-κB can be activated by oxidants and cytokines, and then cause endometriosis. Subsequently, NF-κB plays an important role in the maintenance of oxidative stress [ 3 ] . Song et al. [ 4 ] found that down-regulation of NF-κB could reduce oxidative stress and inflammation, thereby alleviating nephropathy induced by doxorubicin. Nf-κB plays an important role in the development and progression of cancer and is a new target for the diagnosis or treatment of tumors [ 5 ] . IER3 is a stress-inducing gene that can be rapidly regulated by a variety of factors, including transcription factors, inflammatory cytokines, viral infections, chemical carcinogens, growth factors, and hormones, et al [ 6 ] . IER3 plays a key role in the development of cancer and can be used as a prognostic predictor for some tumors, such as bladder cancer, liver cancer, and ovarian cancer [ 7 ] . IER3 has been established as a target gene of NF-κB in response to stress, and studies have shown that IER3 can be induced and activated through the NF-κB pathway [ 8 ] . Endometriosis is an estrogen-dependent inflammatory disease, as well as a disease associated with high levels of chronic oxidative stress [ 9 ] , and has similar characteristics to tumors in many aspects, such as invasiveness, adhesion, and metastatic potential. As mentioned above, NF-κB plays an important role in inflammation, oxidative stress, and tumor development. IER3 is a target gene of NF-κB and a prognostic predictor of a variety of tumors. In recent years, NF-κB and IER3 have been widely studied in the field of tumor prevention and treatment. Based on the correlation between endometriosis and inflammation and oxidative stress, and its similar characteristics to tumors, this study intends to detect the expression of NF-κB and IER3 in recurrent and non-recurrent ovarian endometrioid cyst tissues by immunohistochemical method, and investigate the correlation between NF-κB and IER3 and the recurrence of the ovarian endometrioid cyst. Materials And Methods 1. Experimental materials and methods 1.1 Specimen source and clinical data collection A total of 181 patients with ovarian endometrioid cysts who underwent laparoscopic ovarian cyst excision in the Department of Gynecology, Changzhou Maternal and Child Health Hospital from January 2018 to March 2019 were selected. All patients were confirmed to be ovarian endometrioid cysts by pathological results after surgery. The end time of follow-up was June 30, 2020, or the second surgical visit date for patients with recurrence. Follow-up methods include telephone and database. General clinical data were collected, including age, ovarian cyst diameter, R-AFS score, LF score, EFI score, and recurrence time. Informed consent was obtained from the patients before obtaining the specimens and medical records, which were approved by the Ethics Committee of Changzhou Maternal and Child Health Hospital affiliated with Nanjing Medical University. The flow chart designed in this study is shown in Figure 1. 1.2 Inclusion and exclusion criteria Inclusion criteria: 1. age 24-45 years; 2. surgery to preserve fertility function surgery, without removing the fallopian tube, ovary; 3. Unilateral ovarian cyst; 4. Complete clinical medical records and follow-up information; 5. Postoperative follow-up time > 12 months; 6. No pregnancy after surgery; 7. All patients were treated with GnRH-A for 3 courses after operation without the use of other hormones; 8. The recurrence of the two operations was carried out in our hospital. Exclusion criteria: 1. patients with radical surgical treatment or gynecological malignant tumors or patients with other malignant tumors; 2. patients who are lost to follow-up, unwilling to cooperate with follow-up or with incomplete medical records; 3. conversion to open surgery; 4. patients with other inflammatory diseases; 5. patients with other hormone diseases; 6. use GnRH-A for more than 3 courses of treatment or continue to use hormone drugs after treatment. After screening, 9 patients with postoperative pregnancy, and 13 patients with a bilateral ovarian cyst, medical records are not complete, and not willing to accept the follow-up of patients with 8 cases, more than three courses of treatment with GnRH - a or continue to use hormonal drugs after treatment of 22 cases and 5 patients with other diseases，these cases were excluded. Eventually, twice relapse patients in the surgical treatment were 40 cases, there were 84 patients without recurrence. In order to balance the data, 40 patients without recurrence were randomly screened by SPSS 26.0 system, and 80 patients were finally enrolled, including 40 patients without recurrence and 40 patients with recurrence. Two operations were performed in our hospital for patients with recurrence, including the first operation after recurrence and the second operation after recurrence. We collected the wax block specimens archived in the pathology department and divided them into three groups: the non-recurrence group, the first recurrence group after surgery and the secondary recurrence group after surgery, with 40 specimens in each group and a total of 120 cases. 2. Immunohistochemistry was used to detect the expression of NF-κB and IER3 in each tissue 2.1 IHC procedure The sections were dewaxed in xylene and hydrated in concentration gradient alcohol. The sections were heated with repair solution in a pressure cooker at 140℃ for 2.5min and treated with H2O2 solution at indoor temperature for 10min to complete antigen repair. Add primary antibody according to kit instructions and incubate overnight at 4℃. The next day, the corresponding secondary antibody was added and allowed to stand at indoor temperature for 20min. Then the colorant was added by drop. After dehydration in concentration gradient alcohol, the tablets were transparent with xylene for 2min, and the slide was sealed after drying. 2.2 Interpretation of immunohistochemical results The positive staining of NF-κB was mainly located in the cytoplasm and nucleus, and the positive staining of IER3 was mainly located in the cell membrane and cytoplasm, and the positive staining was brown. The sections were observed under a high-power microscope, and high-definition images were collected. The degree of staining was evaluated by two pathology experts who don't know the clinical information of the patients. The positive staining intensity and the number of cells in each field were counted and averaged to obtain the final staining fraction. NF-κb and IER3 staining scores were determined by staining intensity (0-3 grade: level 0 was negative, level 1 was weak positive, level 2 was medium positive, level 3 was strong positive) and percentage of positive cells (0-4 grade: level 0 was 0%, level 1 was 1%-25%, level 2 was 26%-50%, level 3 was > 50%), divided into different fractions (0, 1, 2, 3, 4, 5, 6). 0-1 was defined as negative expression, 2-3 as weak positive expression, 4-5 as moderate positive expression, and 6 as strong positive expression. 3. Statistical analysis Statistical software SPSS 26.0 was used for data analysis. Measurement data were expressed as Mean±SD, and enumeration data were expressed as percentage or rate. Kruskal-Wallis test was used for multiple comparisons between groups. Spearman rank correlation test was used to analyze the correlation between rank data and count data. Cox proportional hazards model was fitted to analyze the related influencing factors of ovarian endometrioid cyst recurrence, and P<0.05 was considered statistically significant. Results 1. A total of 120 specimens were included in this study, including 40 cases in the non-recurrence group, 40 cases in the first recurrence after surgery group(first recurrence group), and 40 cases in the secondary recurrence after surgery group(second recurrence group). There were no significant differences in age and the maximum diameter of cysts among the three groups (P > 0.05), but there were significant differences in r-AFS score, LF score and EFI score among the three groups (P < 0.05). The specific clinical data are shown in Table 1 . 2. NF-κb and IER3 were positively expressed in the three groups ( Figure 2 ). There were 40 cases in the non-recurrence group, 40 cases in the first recurrence group, and 40 cases in the secondary recurrence group. The expression intensity of NF-κB and IER3 in the first recurrence group and the second recurrence group was significantly different from that in the non-recurrence group (P0.05), as shown in Table 2 . 3. Spearman analysis showed that the positive degree of IER3 was positively correlated with the positive degree of NF-κB in the three groups ( Table 3 ). The correlation between the expression of NF-κB and IER3 and R-AFS score, LF score and EFI score in each group is shown in Table 4 . 4. According to the receiver operating characteristic curve (ROC), the cut-off value of NF-κB expression score after the initial operation was 4.5, the area under the curve was 0.748, P<0.05, 95% confidence interval was 0.636 to 0.859, and Youden index was 0.5. The cut-off value of the IER3 expression score was 4.5, the area under the curve was 0.819, P < 0.05, 95% confidence interval was 0.723-0.914, and the Youden index was 0.55. The combination of the two has the highest diagnostic accuracy ( Figure 3 and Table 5 ). 4. IER3 and NF-κB were correlated with R-AFS score, LF score and EFI score, the above five variables were included in multivariate COX survival analysis by stepwise regression method. The final model included three variables, IER3, NF-κB and EFI score. IER3 expression > 4.5 (HR = 4.272,95%CI: 1.625-11.229, P = 0.003), NF-κB expression > 4.5 (HR = 2.757,95%CI: 1.134-6.704, P = 0.025) was an independent risk factor for postoperative recurrence, EFI score (HR = 1.306,95%CI: 1.060-1.609, P = 0.012) was a protective factor for postoperative recurrence, and there was no statistically significant difference between R-AFS score and LF score on recurrence (P > 0.05), as shown in Table 6 . Discussion In recent years, the incidence of endometriosis is about 10–15% and has a trend of increasing year by year [ 10 ] . More and more evidence has confirmed the multifactorial nature of endometriosis, which is the result of the combined effects of anatomical, immune, reactive, hormonal, genetic, epigenetic, and environmental factors in affected women [ 11 ] . Currently, laparoscopic surgery is still the standard treatment for ovarian endometrioid cysts [ 12 , 13 ] . The recurrence rate of ovarian endometrioid cysts in patients without appropriate postoperative treatment can be as high as 40% within 2 years [ 14 ] , and even for patients receiving appropriate postoperative treatment, the incidence rate is still about 10% [ 15 ] . Due to such a high recurrence rate and the lack of effective biological markers, many scholars have started to study the related cell, protein and gene biomarkers in urine, blood, cervical mucus and other body fluids from a non-invasive perspective, but the results are still not ideal. The NF -κB pathway is one of the major markers of inflammation, which can regulate cell proliferation, apoptosis and inflammatory processes [ 16 ] . NF-κB regulates various proinflammatory such as Tumor necrosis factor(TNF-α), Interleukin(IL-1, IL-6, IL-12), chemokines(CXCL1, CXCL2), recombinant human chemokine-5, adhesion molecules(vascular cell adhesion factor-1) and so on, involved in the activation and recruitment of inflammatory regulatory cells. The NF-κB pathway is down-regulated in normal endometrium [ 17 ] , but its expression is increased in all stages of endometriosis [ 18 ] , which is consistent with the findings of this study that NF-κB is expressed in almost all ovarian endometrioid cysts. In our study, the expression intensity of NF-κB in the first recurrence group was higher than that in the non-recurrence group. As mentioned above, NF-κB plays an important role in the occurrence and development of ovarian endometrioid cysts. Patients with recurrent endometrioid cysts may be more prone to recurrent ovarian endometrioid cysts due to stronger expression of NF-κB and more severe inflammatory reactions in vivo. Nf-κb can regulate the expression of genes and play a key role in the development and progression of cancer, especially in inflammatory tumors, such as the proliferation, migration and apoptosis of cancer cells, and is related to the occurrence of lung cancer [ 19 ] , nasopharyngeal carcinoma [ 19 ] , breast cancer [ 5 ] , liver cancer [ 20 ] and other tumors. In recent years, NF-κB has also been studied as a new target for the diagnosis or treatment of tumors, such as endocrine therapy of breast cancer [ 5 ] . In the study of the tumor and inflammatory diseases, scholars have found that EMs seems to fit another disease -- endometriosis very well. EMs has many characteristics similar to malignant cells, such as invasion and proliferation of ectopic cells. In this study, the high expression of NF-κB in the recurrence group suggests that the recurrence group is more prone to adhesion and invasion. Nf-κb may also be used as a target for the treatment of ovarian endometrioid cysts, reducing the inflammatory response of patients with ovarian endometrioid cysts by reducing the expression of NF-κB, to achieve the purpose of controlling the recurrence. Gonzalez-ramos et al. [ 21 ] found that the NF-κB pathway is related to the occurrence of endometriosis in the early development stage. In this study, the expression intensity of NF-κB in the first recurrence group and the recurrence group was significantly higher than that in the non-recurrence group, and NF-κB promoted the occurrence of ectopic lesions. One of the NF-κB subunits of Rel family proteins is p65, which assembles as a dimer in the cytoplasm. In the inactive state, NF-κB binds to its inhibitor IκB, forming the NF-κb-IκB complex. After activation, NF-κB translocates to the nucleus, where IκB is phosphorylated in response to different stimuli. IL-6 and IL-8 in endometriosis can thus be activated. Inhibition of the action of the complex can reduce the maintenance and development of EMs [ 22 ] , so patients with higher NF-κB expression are more likely to develop endometriosis. The expression of NF-κB was stronger in the patients with postoperative recurrence in this study, which can be speculated that the higher the expression of NF-κB, the stronger the inflammation, and the easier the recurrence of the ovarian endometrioid cyst. IER3 plays a key role in the regulation of cell proliferation and apoptosis, and its overexpression can inhibit or enhance cell apoptosis according to the nature of stress [ 23 ] . Positive expression of IER3 in ovarian cancer [ 7 ] and pancreatic cancer [ 24 ] is associated with a good prognosis, while increased expression of IER3 in other diseases has a poor survival rate, such as acute myeloid leukemia, bladder cancer, liver cancer, breast cancer, Sezary syndrome and colorectal cancer [ 6 ] , this may be related to the excess IER3 mediating cancer cell survival. IER3 has been widely reported in cancer, but rarely in EMs with oxidative stress and inflammatory diseases. Given the great advances in diagnostic imaging (such as transvaginal ultrasound and nuclear magnetic resonance), the diagnosis of endometrioid cysts tends to be simplified and become a structured process based on a combination of patient interviews, clinical examination and imaging. The diagnosis of endometriosis is not difficult, but recurrence is very troublesome [ 25 ] . Endometriosis is deeply affected by oxidative stress. Samimi et al. [ 26 ] found that the concentrations of glutathione peroxidase and catalase were higher in EMs ectopic cells, and in EMs follicular fluid, Higher concentrations of malondialdehyde (MDA), NO and reactive oxygen species (ROS) were observed. As a stress-inducer gene, IER3 was involved in oxidative stress and inflammatory reactions. Reactive oxygen species (ROS) can also activate the NF-κB pathway, promote oxidative stress-mediated proinflammatory signals, and promote the development of endometriosis [ 27 ] . The results of this study were consistent with that of IER3 expression in almost all ovarian endometrioid cysts, and the expression intensity of IER3 in the recurrence group was higher than that in the non-recurrence group, and the difference was statistically significant (P < 0.05), indicating that the patients with recurrent ovarian endometrioid cysts had strong oxidative stress and inflammatory response in the body. The high expression of IER3 provides a good basis for the recurrence of the ovarian endometrioid cyst. In this study, the expression of NF-κB and IER3 was highly expressed in patients with recurrent ovarian endometrioid cysts. The area under the ROC curve of NF-κB and IER3 expression score in the tissues of patients with ovarian endometrioid cysts in the primary operation was 0.844, and the diagnostic accuracy was as high as 83.75%. NF-κB and IER3 have a high accuracy in predicting the recurrence of ovarian endometrioid cysts, which may be related to the disease recurrence by enhancing the inflammatory and oxidative stress response in vivo. Multivariate Cox survival regression showed that the expression of IER3 > 4.5 (HR = 4.272, 95%CI:1.625–11.229, P = 0.003) and NF-κB > 4.5(HR = 2.757, 95%CI: 1.134–6.704, P = 0.025) were an independent risk factor for postoperative recurrence, and EFI score (HR = 1.306,95%CI:1.060–1.609, P = 0.012) was a protective factor for postoperative recurrence. The expression levels of NF-κB and IER3 in the two recurrence group was significantly higher than those in the non-recurrence group, and the differences were statistically significant (P < 0.05), which also suggested that the level of oxidative stress in patients with recurrent ovarian endometrioid cyst was higher. Therefore, drugs targeting NF-κB and IER3 may inhibit the recurrence of ovarian endometrioid cysts. The high expression of NF-κB and IER3 suggests that the risk of ovarian endometrioid cyst recurrence may be higher. For patients who are more prone to recurrence, more systematic treatment should be taken to avoid recurrence after surgery. Moreover, therapeutic drugs targeting NF-κB and IER3 may also reduce the recurrence of ovarian endometrioid cysts. Patients who plan to become pregnant should be encouraged to become pregnant as early as possible, and individualized precise medication should be realized to reduce patients' pain. Regrettably, the sample size of this study is relatively small, the data results are not representative, and other types of EMs cases (such as deep infiltrating type and superficial peritoneal EMs, etc.) are not included. Therefore, the sample size should be expanded and the types of cases should be enriched in subsequent research to get more convincing conclusions. Declarations Acknowledgments We thank all of the authors listed in this manuscript. Funding This study was supported by Major Scientific Research Project of Changzhou Health Commission (No. ZD202121) and Jiangsu Maternal and Child Health Research Project (No. F202166). Author information These authors contributed equally and considered as co-first authors: Ni Yang and Gu Huang. Contributions Ni Yang and Gu Huang designed, wrote, and edited the manuscript, analyzed the data, and finished figures. Xiang Fan, Li Wang, and Chao Zhang participated in data statistics and analysis. Gang Fan provided data analysis support, Xian Jiang helped and supervised the experiment. Pengfeng Zhu and Lina Zhang provided the design ideas and revised the manuscript. All authors approved the final manuscript. Corresponding authors Correspondence to Pengfeng Zhu, Email: [email protected] . Lina Zhang, Email: [email protected] . Ethical approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Changzhou Maternal and Child Health Care Hospital (Date 04.03.2020). Conflict of Interest The authors have declared no conflicts of interest. Data Availability Statement The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. References Guo SW. Nuclear factor-kappaB (NF-kappaB): an unsuspected major culprit in the pathogenesis of endometriosis that is still at large?[J]. Gynecol Obstet Invest. 2007;63(2):71–97. Martin M, Mundade R, Hartley AV, et al. Using VBIM Technique to Discover ARMC4/ODAD2 as a Novel Negative Regulator of NF-κB and a New Tumor Suppressor in Colorectal Cancer[J]. Int J Mol Sci. 2022;23(5):2732. Bozdag G. Recurrence of endometriosis: risk factors, mechanisms and biomarkers[J]. Women's health (London England). 2015;11(5):693–9. Song IH, Jung KJ, Lee TJ, et al. 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Tables Table 1 General clinical data of the patients Groups non-recurrence group first recurrence group second recurrence group H P Number 40 40 40 Age 34.08 ± 5.22 35.20 ± 5.79 36.13 ± 5.79 3.908 0.142 Maximum cyst diameter(cm) 5.05 ± 1.36 5.00 ± 0.99 4.83 ± 0.78 0.708 0.702 r-AFS score 30.85 ± 12.11 35.5 ± 13.97 40.85 ± 12.98* 12.658 0.002 LF score 6.13 ± 1.93 5.78 ± 2.51 4.05 ± 1.58* # 25.004 0.000 EFI score 5.52 ± 1.50 5.03 ± 1.83 3.28 ± 1.30* # 35.867 0.000 Maximum cyst diameter(months) 21.75 ± 4.11 15.45 ± 2.79* - -0.680 0.000 Compared with the non-recurrence group, * P < 0.05; Compared with the first recurrence group, # P < 0.05 Table 2 Expression of NF-κB and IER3 in each group Number NF-κB expression IER3 expression - + ++ +++ - + ++ +++ Non-recurrence group 40 5 20 12 3 4 22 10 4 First recurrence group 40 4 8 12 16* 0 6 14 20* Second recurrence group 40 2 10 11 17* 1 4 11 24* H 15.205 35.046 P 0.000 0.000 Compared with the non-recurrence group, *P < 0.05 Table 3 Correlation between IER3 and NF-κB expression in non-recurrence group and first recurrence group r P Non-recurrence group 0.948 <0.001 First recurrence group 0.888 <0.001 Second recurrence group 0.577 <0.001 Table 4 Relationship between the expression of NF-κB and IER3 in each group and general clinical data r-AFS score LF score EFI score r P r P r P Non-recurrence group NF-κB 0.416 0.008 -0.460 0.003 -0.387 0.014 IER3 0.382 0.015 -0.441 0.004 -0,383 0.015 First recurrence group NF-κB 0.519 0.001 -0.581 0.000 -0.438 0.005 IER3 0.406 0.009 -0.653 0.000 -0.567 0.000 Second recurrence group NF-κB 0.390 0.014 -0.450 0.004 -0.514 0.001 IER3 0.453 0.004 -0.414 0.009 -0.506 0.001 Table 5 Combined expression of IER3 and NF-κB predicts ovarian endometrioid cyst recurrence NF-κB IER3 Combined expression Sensitivity(%) 60.00 65.00 77.50 Specificity(%) 92.50 90.00 90.00 Accuracy(%) 76.25 77.50 83.75 AUC 0.748 0.819 0.844 95% CI 0.636 ~ 0.859 0.723 ~ 0.914 0.754 ~ 0.933 Table 6 Multivariate Cox survival regression analysis Univariate Multivariate HR 95% CI P HR 95% CI P IER3(༞4.5/< 4.5) 4.598 2.387–8.857 <0.001 4.272 1.625–11.229 0.003 NF-κB(༞4.5/< 4.5) 4.529 2.377–8.631 <0.001 2.757 1.134–6.704 0.025 r-AFS评分 1.017 0.994–1.041 0.149 - - - LF评分 0.911 0.791–1.050 0.199 - - - EFI评分 0.916 0.772–1.087 0.316 1.306 1.060–1.609 0.012 Additional Declarations No competing interests reported. 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Huang","email":"","orcid":"","institution":"Bazhong Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gu","middleName":"","lastName":"Huang","suffix":""},{"id":152627559,"identity":"2abfecaf-eba6-40f1-9add-b4db6d9622d9","order_by":2,"name":"Xiang Fan","email":"","orcid":"","institution":"Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Fan","suffix":""},{"id":152627560,"identity":"605d1b63-c181-4fa7-bc9b-2ac8c2387455","order_by":3,"name":"Chao Zhang","email":"","orcid":"","institution":"Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Zhang","suffix":""},{"id":152627561,"identity":"25cbb2f8-3ca6-4a75-a87e-c24b0cda5023","order_by":4,"name":"Li Wang","email":"","orcid":"","institution":"Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Wang","suffix":""},{"id":152627562,"identity":"7b4b2a21-bdee-48a7-a1e1-474aa9c3c6d1","order_by":5,"name":"Xian Jiang","email":"","orcid":"","institution":"Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xian","middleName":"","lastName":"Jiang","suffix":""},{"id":152627563,"identity":"d13fd5a4-8bc9-4bea-9d3e-64acf4fa80ef","order_by":6,"name":"Gang Fan","email":"","orcid":"","institution":"Bazhong Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gang","middleName":"","lastName":"Fan","suffix":""},{"id":152627564,"identity":"629eecec-2ec2-47d5-a584-706f23650540","order_by":7,"name":"Lina Zhang","email":"","orcid":"","institution":"Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lina","middleName":"","lastName":"Zhang","suffix":""},{"id":152627565,"identity":"feebc98b-69c8-45af-bfd5-b2d45b0d1fee","order_by":8,"name":"Pengfeng Zhu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYFACxocPPlTYyPEzMx9+QKQWZmPDGWfSjCXb2dIMiNViJszbdjhxw3keBQmiNMjPbmZjnAnUsvkwD4MBQ41NNEEtjHMOsz34cC7deNth3gMPGI6l5TYQdJZE/nHDGWXWstsO8yUYMDYcJqyFTSKZTZqHjZlxczOPgQRRWnjAWtqcFTcwE6tFQuYwMziQJQ4DAzmBGL8AQ4wREpX9hw8/+FBjQ1gLA0pcJBBUjqFlFIyCUTAKRgE2AADOIj5mlGxH/wAAAABJRU5ErkJggg==","orcid":"","institution":"Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Pengfeng","middleName":"","lastName":"Zhu","suffix":""}],"badges":[],"createdAt":"2022-10-03 13:59:31","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.3.rs-2128626/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-2128626/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":29206954,"identity":"9625880b-e4ed-48ad-a75b-c3b0cc4aec97","added_by":"auto","created_at":"2022-11-17 19:37:46","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1046373,"visible":true,"origin":"","legend":"\u003cp\u003eThe flow chart designed in this study\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2128626/v2/ace8d8c63fa7f3ab36a99e6a.jpeg"},{"id":29207580,"identity":"aec7c42f-8ae6-4f12-b0c0-31a5a60e35a8","added_by":"auto","created_at":"2022-11-17 19:45:46","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1232493,"visible":true,"origin":"","legend":"\u003cp\u003eExpression of NF-κB and IER3 in each group (SP, ×400)\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2128626/v2/b35b054364abf9e56a3e9e1c.jpeg"},{"id":29206956,"identity":"b2fa6a2f-c4bd-4171-bda2-8b5c7111f879","added_by":"auto","created_at":"2022-11-17 19:37:46","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":141004,"visible":true,"origin":"","legend":"\u003cp\u003eROC curves of NF-κB and IER3 after the primary operation\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2128626/v2/7b71f7a190625620848ee985.jpg"},{"id":31824235,"identity":"ac4ce4b7-c392-4968-bcdd-2c684ec91a99","added_by":"auto","created_at":"2023-01-19 20:14:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":648274,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2128626/v2/4193e942-b067-41d4-b74f-0d2fbdcf8f0f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Correlation study of NF-κB, IER3, and recurrence of ovarian endometrioid cysts","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometriosis (EMs) plays an important role in gynecological diseases. The characteristics of recurrence, infertility, and pain cause a serious burden on women's bodies and minds. There is still a lack of reliable biomarkers for early diagnosis of recurrent endometriosis. The ovarian endometrioid cyst is the most common pathological type in EMs. So far, its treatment methods are mainly surgery and drug therapy. Although there are many emerging surgical methods nowadays, such as ultrasound-guided cyst puncture, cyst puncture combined with sclerotherapy, etc. Although the trauma is less, it is limited to a single lesion and requires no adhesion or damage to the lesion. The first choice for diagnosis and treatment of ovarian endometrioid cyst is still laparoscopic endometrioid cyst excision, but the recurrence rate is high. Finding effective prognostic markers to screen patients with possible recurrence can greatly improve the quality of life of patients and reduce the recurrence rate after surgery.\u003c/p\u003e \u003cp\u003eNf-κb is a dimeric transcription factor that promotes the expression of more than 150 genes involved in cellular processes, including immune responses and inflammatory processes\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. The NF-κB pathway has been considered a classical proinflammatory signaling pathway, mainly based on the role of NF-κB in the expression of proinflammatory genes, including inflammatory mediators, cytokines, adhesion molecules, apoptosis inhibitors, and chemokines. The pleiotropic result of its activated nuclear factor is caused by the combinatorial effects of the five subunits forming homologous and heterodimeric NF-κB complexes\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Nf-κB can be activated by oxidants and cytokines, and then cause endometriosis. Subsequently, NF-κB plays an important role in the maintenance of oxidative stress\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Song et al.\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e found that down-regulation of NF-κB could reduce oxidative stress and inflammation, thereby alleviating nephropathy induced by doxorubicin. Nf-κB plays an important role in the development and progression of cancer and is a new target for the diagnosis or treatment of tumors\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIER3 is a stress-inducing gene that can be rapidly regulated by a variety of factors, including transcription factors, inflammatory cytokines, viral infections, chemical carcinogens, growth factors, and hormones, et al\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. IER3 plays a key role in the development of cancer and can be used as a prognostic predictor for some tumors, such as bladder cancer, liver cancer, and ovarian cancer\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. IER3 has been established as a target gene of NF-κB in response to stress, and studies have shown that IER3 can be induced and activated through the NF-κB pathway\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEndometriosis is an estrogen-dependent inflammatory disease, as well as a disease associated with high levels of chronic oxidative stress\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e, and has similar characteristics to tumors in many aspects, such as invasiveness, adhesion, and metastatic potential. As mentioned above, NF-κB plays an important role in inflammation, oxidative stress, and tumor development. IER3 is a target gene of NF-κB and a prognostic predictor of a variety of tumors. In recent years, NF-κB and IER3 have been widely studied in the field of tumor prevention and treatment. Based on the correlation between endometriosis and inflammation and oxidative stress, and its similar characteristics to tumors, this study intends to detect the expression of NF-κB and IER3 in recurrent and non-recurrent ovarian endometrioid cyst tissues by immunohistochemical method, and investigate the correlation between NF-κB and IER3 and the recurrence of the ovarian endometrioid cyst.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003e1. Experimental materials and methods\u003c/p\u003e\n\u003cp\u003e1.1 Specimen source and clinical data collection\u003c/p\u003e\n\u003cp\u003eA total of 181 patients with ovarian endometrioid cysts who underwent laparoscopic ovarian cyst excision in the Department of Gynecology, Changzhou Maternal and Child Health Hospital from January 2018 to March 2019 were selected. All patients were confirmed to be ovarian endometrioid cysts by pathological results after surgery. The end time of follow-up was June 30, 2020, or the second surgical visit date for patients with recurrence. Follow-up methods include telephone and database. General clinical data were collected, including age, ovarian cyst diameter, R-AFS score, LF score, EFI score, and recurrence time. Informed consent was obtained from the patients before obtaining the specimens and medical records, which were approved by the Ethics Committee of Changzhou Maternal and Child Health Hospital affiliated with Nanjing Medical University. The flow chart designed in this study is shown in \u003cstrong\u003eFigure 1.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1.2 Inclusion and exclusion criteria\u003c/p\u003e\n\u003cp\u003eInclusion criteria: 1. age 24-45 years; 2. surgery to preserve fertility function surgery, without removing the fallopian tube, ovary; 3. Unilateral ovarian cyst; 4. \u0026nbsp; Complete clinical medical records and follow-up information; 5. Postoperative follow-up time \u0026gt; 12 months; 6. No pregnancy after surgery; 7. All patients were treated with GnRH-A for 3 courses after operation without the use of other hormones; 8. The recurrence of the two operations was carried out in our hospital.\u003c/p\u003e\n\u003cp\u003eExclusion criteria: 1. patients with radical surgical treatment or gynecological malignant tumors or patients with other malignant tumors; 2. patients who are lost to follow-up, unwilling to cooperate with follow-up or with incomplete medical records; 3. conversion to open surgery; 4. patients with other inflammatory diseases; 5. patients with other hormone diseases; 6. use GnRH-A for more than 3 courses of treatment or continue to use hormone drugs after treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter screening, 9 patients with postoperative pregnancy, and 13 patients with a bilateral ovarian cyst, medical records are not complete, and not willing to accept the follow-up of patients with 8 cases, more than three courses of treatment with GnRH - a or continue to use hormonal drugs after treatment of 22 cases and 5 patients with other diseases，these cases were excluded. Eventually, twice relapse patients in the surgical treatment were 40 cases, there were 84 patients without recurrence. In order to balance the data, 40 patients without recurrence were randomly screened by SPSS 26.0 system, and 80 patients were finally enrolled, including 40 patients without recurrence and 40 patients with recurrence. Two operations were performed in our hospital for patients with recurrence, including the first operation after recurrence and the second operation after recurrence. We collected the wax block specimens archived in the pathology department and divided them into three groups: the non-recurrence group, the first recurrence group after surgery and the secondary recurrence group after surgery, with 40 specimens in each group and a total of 120 cases.\u003c/p\u003e\n\u003cp\u003e2. Immunohistochemistry was used to detect the expression of NF-\u0026kappa;B and IER3 in each tissue\u003c/p\u003e\n\u003cp\u003e2.1 IHC procedure\u003c/p\u003e\n\u003cp\u003eThe sections were dewaxed in xylene and hydrated in concentration gradient alcohol. The sections were heated with repair solution in a pressure cooker at 140℃\u0026nbsp;for 2.5min and treated with H2O2 solution at indoor temperature for 10min to complete antigen repair. Add primary antibody according to kit instructions and incubate overnight at 4℃. The next day, the corresponding secondary antibody was added and allowed to stand at indoor temperature for 20min. Then the colorant was added by drop. After dehydration in concentration gradient alcohol, the tablets were transparent with xylene for 2min, and the slide was sealed after drying.\u003c/p\u003e\n\u003cp\u003e2.2 Interpretation of immunohistochemical results\u003c/p\u003e\n\u003cp\u003eThe positive staining of NF-\u0026kappa;B was mainly located in the cytoplasm and nucleus, and the positive staining of IER3 was mainly located in the cell membrane and cytoplasm, and the positive staining was brown. The sections were observed under a high-power microscope, and high-definition images were collected. The degree of staining was evaluated by two pathology experts who don\u0026apos;t know the clinical information of the patients. The positive staining intensity and the number of cells in each field were counted and averaged to obtain the final staining fraction. NF-\u0026kappa;b and IER3 staining scores were determined by staining intensity (0-3 grade: level 0 was negative, level 1 was weak positive, level 2 was medium positive, level 3 was strong positive) and percentage of positive cells (0-4 grade: level 0 was 0%, level 1 \u0026nbsp;was 1%-25%, level 2 was 26%-50%, level 3 was \u0026gt; 50%), divided into different fractions (0, 1, 2, 3, 4, 5, 6). 0-1 was defined as negative expression, 2-3 as weak positive expression, 4-5 as moderate positive expression, and 6 as strong positive expression.\u003c/p\u003e\n\u003cp\u003e3. Statistical analysis\u003c/p\u003e\n\u003cp\u003eStatistical software SPSS 26.0 was used for data analysis. Measurement data were expressed as Mean\u0026plusmn;SD, and enumeration data were expressed as percentage or rate. Kruskal-Wallis test was used for multiple comparisons between groups. \u0026nbsp;Spearman rank correlation test was used to analyze the correlation between rank data and count data. Cox proportional hazards model was fitted to analyze the related influencing factors of ovarian endometrioid cyst recurrence, and P\u0026lt;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e1. A total of 120 specimens were included in this study, including 40 cases in the non-recurrence group, 40 cases in the first recurrence after surgery group(first recurrence group), and 40 cases in the secondary recurrence after surgery group(second recurrence group). There were no significant differences in age and the maximum diameter of cysts among the three groups (P \u0026gt; 0.05), but there were significant differences in r-AFS score, LF score and EFI score among the three groups (P \u0026lt; 0.05). The specific clinical data are shown in \u003cstrong\u003eTable 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e2. NF-\u0026kappa;b and IER3 were positively expressed in the three groups (\u003cstrong\u003eFigure 2\u003c/strong\u003e). There were 40 cases in the non-recurrence group, 40 cases in the first recurrence group, and 40 cases in the secondary recurrence group. The expression intensity of NF-\u0026kappa;B and IER3 in the first recurrence group and the second recurrence group was significantly different from that in the non-recurrence group (P\u0026lt;0.05). There was no significant difference in the expression intensity of NF-\u0026kappa;B and IER3 between the two recurrence groups (P\u0026gt;0.05), as shown in \u003cstrong\u003eTable 2\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e3. Spearman analysis showed that the positive degree of IER3 was positively correlated with the positive degree of NF-\u0026kappa;B in the three groups (\u003cstrong\u003eTable 3\u003c/strong\u003e). The correlation between the expression of NF-\u0026kappa;B and IER3 and R-AFS score, LF score and EFI score in each group is shown in \u003cstrong\u003eTable 4\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e4. According to the receiver operating characteristic curve (ROC), the cut-off value of NF-\u0026kappa;B expression score after the initial operation was 4.5, the area under the curve was 0.748, P\u0026lt;0.05, 95% confidence interval was 0.636 to 0.859, and Youden index was 0.5. The cut-off value of the IER3 expression score was 4.5, the area under the curve was 0.819, P \u0026lt; 0.05, 95% confidence interval was 0.723-0.914, and the Youden index was 0.55. The combination of the two has the highest diagnostic accuracy (\u003cstrong\u003eFigure 3\u003c/strong\u003e and \u003cstrong\u003eTable 5\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e4. IER3 and NF-\u0026kappa;B were correlated with R-AFS score, LF score and EFI score, the above five variables were included in multivariate COX survival analysis by stepwise regression method. The final model included three variables, IER3, NF-\u0026kappa;B and EFI score. IER3 expression \u0026gt; 4.5 (HR = 4.272,95%CI: 1.625-11.229, P = 0.003), NF-\u0026kappa;B expression \u0026gt; 4.5 (HR = 2.757,95%CI: 1.134-6.704, P = 0.025) was an independent risk factor for postoperative recurrence, EFI score (HR = 1.306,95%CI: 1.060-1.609, P = 0.012) was a protective factor for postoperative recurrence, and there was no statistically significant difference between R-AFS score and LF score on recurrence (P \u0026gt; 0.05), as shown in \u003cstrong\u003eTable 6\u003c/strong\u003e.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn recent years, the incidence of endometriosis is about 10\u0026ndash;15% and has a trend of increasing year by year\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. More and more evidence has confirmed the multifactorial nature of endometriosis, which is the result of the combined effects of anatomical, immune, reactive, hormonal, genetic, epigenetic, and environmental factors in affected women\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Currently, laparoscopic surgery is still the standard treatment for ovarian endometrioid cysts \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. The recurrence rate of ovarian endometrioid cysts in patients without appropriate postoperative treatment can be as high as 40% within 2 years\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e, and even for patients receiving appropriate postoperative treatment, the incidence rate is still about 10%\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Due to such a high recurrence rate and the lack of effective biological markers, many scholars have started to study the related cell, protein and gene biomarkers in urine, blood, cervical mucus and other body fluids from a non-invasive perspective, but the results are still not ideal.\u003c/p\u003e \u003cp\u003eThe NF -κB pathway is one of the major markers of inflammation, which can regulate cell proliferation, apoptosis and inflammatory processes\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. NF-κB regulates various proinflammatory such as Tumor necrosis factor(TNF-α), Interleukin(IL-1, IL-6, IL-12), chemokines(CXCL1, CXCL2), recombinant human chemokine-5, adhesion molecules(vascular cell adhesion factor-1) and so on, involved in the activation and recruitment of inflammatory regulatory cells. The NF-κB pathway is down-regulated in normal endometrium\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e, but its expression is increased in all stages of endometriosis\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e, which is consistent with the findings of this study that NF-κB is expressed in almost all ovarian endometrioid cysts.\u003c/p\u003e \u003cp\u003eIn our study, the expression intensity of NF-κB in the first recurrence group was higher than that in the non-recurrence group. As mentioned above, NF-κB plays an important role in the occurrence and development of ovarian endometrioid cysts. Patients with recurrent endometrioid cysts may be more prone to recurrent ovarian endometrioid cysts due to stronger expression of NF-κB and more severe inflammatory reactions in vivo. Nf-κb can regulate the expression of genes and play a key role in the development and progression of cancer, especially in inflammatory tumors, such as the proliferation, migration and apoptosis of cancer cells, and is related to the occurrence of lung cancer\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, nasopharyngeal carcinoma\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, breast cancer\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, liver cancer\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e and other tumors. In recent years, NF-κB has also been studied as a new target for the diagnosis or treatment of tumors, such as endocrine therapy of breast cancer\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. In the study of the tumor and inflammatory diseases, scholars have found that EMs seems to fit another disease -- endometriosis very well. EMs has many characteristics similar to malignant cells, such as invasion and proliferation of ectopic cells. In this study, the high expression of NF-κB in the recurrence group suggests that the recurrence group is more prone to adhesion and invasion. Nf-κb may also be used as a target for the treatment of ovarian endometrioid cysts, reducing the inflammatory response of patients with ovarian endometrioid cysts by reducing the expression of NF-κB, to achieve the purpose of controlling the recurrence.\u003c/p\u003e \u003cp\u003eGonzalez-ramos et al.\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e found that the NF-κB pathway is related to the occurrence of endometriosis in the early development stage. In this study, the expression intensity of NF-κB in the first recurrence group and the recurrence group was significantly higher than that in the non-recurrence group, and NF-κB promoted the occurrence of ectopic lesions. One of the NF-κB subunits of Rel family proteins is p65, which assembles as a dimer in the cytoplasm. In the inactive state, NF-κB binds to its inhibitor IκB, forming the NF-κb-IκB complex. After activation, NF-κB translocates to the nucleus, where IκB is phosphorylated in response to different stimuli. IL-6 and IL-8 in endometriosis can thus be activated. Inhibition of the action of the complex can reduce the maintenance and development of EMs\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e, so patients with higher NF-κB expression are more likely to develop endometriosis. The expression of NF-κB was stronger in the patients with postoperative recurrence in this study, which can be speculated that the higher the expression of NF-κB, the stronger the inflammation, and the easier the recurrence of the ovarian endometrioid cyst.\u003c/p\u003e \u003cp\u003eIER3 plays a key role in the regulation of cell proliferation and apoptosis, and its overexpression can inhibit or enhance cell apoptosis according to the nature of stress \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Positive expression of IER3 in ovarian cancer\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e and pancreatic cancer\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e is associated with a good prognosis, while increased expression of IER3 in other diseases has a poor survival rate, such as acute myeloid leukemia, bladder cancer, liver cancer, breast cancer, Sezary syndrome and colorectal cancer\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, this may be related to the excess IER3 mediating cancer cell survival. IER3 has been widely reported in cancer, but rarely in EMs with oxidative stress and inflammatory diseases. Given the great advances in diagnostic imaging (such as transvaginal ultrasound and nuclear magnetic resonance), the diagnosis of endometrioid cysts tends to be simplified and become a structured process based on a combination of patient interviews, clinical examination and imaging. The diagnosis of endometriosis is not difficult, but recurrence is very troublesome\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. Endometriosis is deeply affected by oxidative stress. Samimi et al.\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e found that the concentrations of glutathione peroxidase and catalase were higher in EMs ectopic cells, and in EMs follicular fluid, Higher concentrations of malondialdehyde (MDA), NO and reactive oxygen species (ROS) were observed. As a stress-inducer gene, IER3 was involved in oxidative stress and inflammatory reactions. Reactive oxygen species (ROS) can also activate the NF-κB pathway, promote oxidative stress-mediated proinflammatory signals, and promote the development of endometriosis\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. The results of this study were consistent with that of IER3 expression in almost all ovarian endometrioid cysts, and the expression intensity of IER3 in the recurrence group was higher than that in the non-recurrence group, and the difference was statistically significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that the patients with recurrent ovarian endometrioid cysts had strong oxidative stress and inflammatory response in the body. The high expression of IER3 provides a good basis for the recurrence of the ovarian endometrioid cyst.\u003c/p\u003e \u003cp\u003eIn this study, the expression of NF-κB and IER3 was highly expressed in patients with recurrent ovarian endometrioid cysts. The area under the ROC curve of NF-κB and IER3 expression score in the tissues of patients with ovarian endometrioid cysts in the primary operation was 0.844, and the diagnostic accuracy was as high as 83.75%. NF-κB and IER3 have a high accuracy in predicting the recurrence of ovarian endometrioid cysts, which may be related to the disease recurrence by enhancing the inflammatory and oxidative stress response in vivo. Multivariate Cox survival regression showed that the expression of IER3\u0026thinsp;\u0026gt;\u0026thinsp;4.5 (HR\u0026thinsp;=\u0026thinsp;4.272, 95%CI:1.625\u0026ndash;11.229, P\u0026thinsp;=\u0026thinsp;0.003) and NF-κB\u0026thinsp;\u0026gt;\u0026thinsp;4.5(HR\u0026thinsp;=\u0026thinsp;2.757, 95%CI: 1.134\u0026ndash;6.704, P\u0026thinsp;=\u0026thinsp;0.025) were an independent risk factor for postoperative recurrence, and EFI score (HR\u0026thinsp;=\u0026thinsp;1.306,95%CI:1.060\u0026ndash;1.609, P\u0026thinsp;=\u0026thinsp;0.012) was a protective factor for postoperative recurrence. The expression levels of NF-κB and IER3 in the two recurrence group was significantly higher than those in the non-recurrence group, and the differences were statistically significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), which also suggested that the level of oxidative stress in patients with recurrent ovarian endometrioid cyst was higher. Therefore, drugs targeting NF-κB and IER3 may inhibit the recurrence of ovarian endometrioid cysts.\u003c/p\u003e \u003cp\u003eThe high expression of NF-κB and IER3 suggests that the risk of ovarian endometrioid cyst recurrence may be higher. For patients who are more prone to recurrence, more systematic treatment should be taken to avoid recurrence after surgery. Moreover, therapeutic drugs targeting NF-κB and IER3 may also reduce the recurrence of ovarian endometrioid cysts. Patients who plan to become pregnant should be encouraged to become pregnant as early as possible, and individualized precise medication should be realized to reduce patients' pain. Regrettably, the sample size of this study is relatively small, the data results are not representative, and other types of EMs cases (such as deep infiltrating type and superficial peritoneal EMs, etc.) are not included. Therefore, the sample size should be expanded and the types of cases should be enriched in subsequent research to get more convincing conclusions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all of the authors listed in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Major Scientific Research Project of Changzhou Health Commission (No. ZD202121) and Jiangsu Maternal and Child Health Research Project (No. F202166).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese authors contributed equally and considered as co-first authors: Ni Yang and Gu Huang.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNi Yang and Gu Huang designed, wrote, and edited the manuscript, analyzed the data, and finished figures. Xiang Fan, Li Wang, and Chao Zhang participated in data statistics and analysis. Gang Fan provided data analysis support, Xian Jiang helped and supervised the experiment. Pengfeng Zhu and Lina Zhang provided the design ideas and revised the manuscript. All authors approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding authors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Pengfeng Zhu, Email: [email protected]. Lina Zhang, Email: [email protected].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Changzhou Maternal and Child Health Care Hospital (Date 04.03.2020).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have declared no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGuo SW. Nuclear factor-kappaB (NF-kappaB): an unsuspected major culprit in the pathogenesis of endometriosis that is still at large?[J]. Gynecol Obstet Invest. 2007;63(2):71\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartin M, Mundade R, Hartley AV, et al. 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Rethinking mechanisms, diagnosis and management of endometriosis [J]. Nat Rev Endocrinol. 2019;15(11):666\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSamimi M, Pourhanifeh MH, Mehdizadehkashi A, et al. The role of inflammation, oxidative stress, angiogenesis, and apoptosis in the pathophysiology of endometriosis: Basic science and new insights based on gene expression[J]. J Cell Physiol. 2019;234(11):19384\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcKinnon BD, Kocbek V, Nirgianakis K, et al. Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics[J]. Hum Reprod Update. 2016;22(3):382\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cdiv class=\"gridtable\"\u003e\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eGeneral clinical data of the patients\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eGroups\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enon-recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003efirst recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esecond recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eH\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34.08\u0026thinsp;\u0026plusmn;\u0026thinsp;5.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.20\u0026thinsp;\u0026plusmn;\u0026thinsp;5.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.13\u0026thinsp;\u0026plusmn;\u0026thinsp;5.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.908\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.142\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMaximum cyst diameter(cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.05\u0026thinsp;\u0026plusmn;\u0026thinsp;1.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.83\u0026thinsp;\u0026plusmn;\u0026thinsp;0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.708\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.702\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003er-AFS score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.85\u0026thinsp;\u0026plusmn;\u0026thinsp;12.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40.85\u0026thinsp;\u0026plusmn;\u0026thinsp;12.98*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.658\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLF score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.13\u0026thinsp;\u0026plusmn;\u0026thinsp;1.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.78\u0026thinsp;\u0026plusmn;\u0026thinsp;2.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.05\u0026thinsp;\u0026plusmn;\u0026thinsp;1.58*\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEFI score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.03\u0026thinsp;\u0026plusmn;\u0026thinsp;1.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.28\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30*\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.867\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMaximum cyst diameter(months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.75\u0026thinsp;\u0026plusmn;\u0026thinsp;4.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.45\u0026thinsp;\u0026plusmn;\u0026thinsp;2.79*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.680\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eCompared with the non-recurrence group, \u003csup\u003e*\u003c/sup\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Compared with the first recurrence group, \u003csup\u003e#\u003c/sup\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eExpression of NF-\u0026kappa;B and IER3 in each group\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNumber\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eNF-\u0026kappa;B expression\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eIER3 expression\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e+\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e++\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e+++\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e+\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e++\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e+++\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSecond recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eH\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e15.205\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e35.046\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\"\u003eCompared with the non-recurrence group, *P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCorrelation between IER3 and NF-\u0026kappa;B expression in non-recurrence group and first recurrence group\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.948\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSecond recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.577\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab4\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRelationship between the expression of NF-\u0026kappa;B and IER3 in each group and general clinical data\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003er-AFS score\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eLF score\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEFI score\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"9\"\u003e\n \u003cp\u003eNon-recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNF-\u0026kappa;B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.416\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.460\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.387\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIER3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.382\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.441\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0,383\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"9\"\u003e\n \u003cp\u003eFirst recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNF-\u0026kappa;B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.519\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.438\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIER3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.406\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.653\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.567\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"9\"\u003e\n \u003cp\u003eSecond recurrence group\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNF-\u0026kappa;B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.390\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.514\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIER3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.453\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.414\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.506\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab5\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCombined expression of IER3 and NF-\u0026kappa;B predicts ovarian endometrioid cyst recurrence\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNF-\u0026kappa;B\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIER3\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCombined expression\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSensitivity(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e77.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpecificity(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e92.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAccuracy(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e77.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83.75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAUC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.748\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.819\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.844\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.636\u0026thinsp;~\u0026thinsp;0.859\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.723\u0026thinsp;~\u0026thinsp;0.914\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.754\u0026thinsp;~\u0026thinsp;0.933\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab6\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMultivariate Cox survival regression analysis\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUnivariate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eHR\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e95% CI\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eHR\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e95% CI\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIER3(༞4.5/\u0026lt; 4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.598\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.387\u0026ndash;8.857\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.272\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.625\u0026ndash;11.229\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNF-\u0026kappa;B(༞4.5/\u0026lt; 4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.529\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.377\u0026ndash;8.631\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.757\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.134\u0026ndash;6.704\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003er-AFS评分\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.994\u0026ndash;1.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLF评分\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.911\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.791\u0026ndash;1.050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.199\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEFI评分\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.916\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.772\u0026ndash;1.087\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.306\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.060\u0026ndash;1.609\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ovarian endometrioid cyst, recurrence, NF-κB, IER3","lastPublishedDoi":"10.21203/rs.3.rs-2128626/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2128626/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo investigate the expression of nuclear actor-k-gene binding(NF-κB) and immediate early response 3(IER3) in nuclear factor-activated B cells in ovarian endometrioid cysts. To analyze the correlation between the expression of NF-κB and IER3 and the recurrence of the ovarian endometrioid cyst.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eFrom January 2018 to March 2019, a total of 80 patients who underwent laparoscopic ovarian cyst excision due to ovarian endometrioid cyst in the Department of Gynecology, Changzhou Maternal and Child Health Hospital were selected, including 40 patients without postoperative recurrence and 40 patients with recurrence, and the patients with recurrence were further divided into the primary recurrence and the secondary recurrence groups. The general clinical data of the patients were collected. The patient's Revised American Fertility Society (R-AFS) score, least function(LF) score, and endometriosis fertility index (EFI) were calculated, and immunohistochemical staining was performed to detect the expression of IER3 and NF-κB in the pathological tissues of the three groups. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of IER3 and NF-κB expression on postoperative recurrence of the ovarian endometrioid cyst. Cox proportional hazards model was fitted to analyze the related influencing factors of ovarian endometrioid cyst recurrence.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe expression intensity of NF-κB was positively correlated with IER3 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). ROC curve showed that the area under curve (AUC) of NF-κB and IER3 combined diagnosis was 0.844, 95%CI was 0.754\u0026ndash;0.933, sensitivity was 77.5% and specificity was 90.00%. Multivariate Cox survival regression showed that the IER3 expression intensity\u0026thinsp;\u0026gt;\u0026thinsp;4.5 (HR\u0026thinsp;=\u0026thinsp;4.661,95%CI: 1.712\u0026ndash;12.690, P\u0026thinsp;=\u0026thinsp;0.003) and the NF-κBexpression intensity\u0026thinsp;\u0026gt;\u0026thinsp;4.5 (HR\u0026thinsp;=\u0026thinsp;2.878,95%CI: 1.181\u0026ndash;7.011, P\u0026thinsp;=\u0026thinsp;0.020) were independent risk factor for postoperative recurrence, and EFI score (HR\u0026thinsp;=\u0026thinsp;1.289,95%CI: 1.037\u0026ndash;1.602, P\u0026thinsp;=\u0026thinsp;0.022) was a protective factor for postoperative recurrence.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eEFI score is a protective factor for postoperative recurrence, and the expression intensity of NF-κB and IER3 has a certain correlation with the recurrence of ovarian endometrioid cysts. The expression levels of NF-κB and IER3\u0026thinsp;\u0026gt;\u0026thinsp;4.5 are independent risk factors for postoperative recurrence.\u003c/p\u003e","manuscriptTitle":"Correlation study of NF-κB, IER3, and recurrence of ovarian endometrioid cysts","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2022-11-17 19:37:41","doi":"10.21203/rs.3.rs-2128626/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2022-10-11 14:22:47","doi":"10.21203/rs.3.rs-2128626/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2d53d374-7a26-41f3-9ff3-c6c061299b82","owner":[],"postedDate":"November 17th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-01-19T20:14:12+00:00","versionOfRecord":[],"versionCreatedAt":"2022-11-17 19:37:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-2128626","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2128626","identity":"rs-2128626","version":["v2"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}