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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 10  |  Page : 667-674

Association of serum annexin A1 with treatment response and prognosis in patients with esophageal squamous cell carcinoma


1 Department of Oncology, Taizhou People's Hospital of Nantong University, Taizhou 225300, China
2 Department of Thoracic Surgery, Taizhou People's Hospital of Nantong University, Taizhou 225300, China
3 Department of Laboratory Medicine, Taizhou People's Hospital of Nantong University, Taizhou 225300, China
4 Department of Medical Imaging, Taizhou People's Hospital of Nantong University, Taizhou 225300, China

Date of Web Publication24-Sep-2018

Correspondence Address:
Jun-Xing Huang
Department of Oncology, Taizhou People's Hospital of Nantong University, No. 210 Yingchun Road, Taizhou 225300, Jiangsu Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.187297

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 > Abstract 


Objective: Annexin A1 (ANXA1), a calcium-dependent phospholipid binding protein, is known to be regulated by microRNA-196a (miR-196a) in esophageal adenocarcinoma, and its high expression in tumor tissue is correlated with the poor prognosis of esophageal squamous cell carcinoma (ESCC). However, the role of ANXA1 in the serum of patients with ESCC remains unclear.
Materials and Methods: In this study, we used enzyme-linked immunosorbent assay to evaluate the levels of ANXA1 and real-time polymerase chain reaction to detect the expression of miR-196a in the serum of ESCC patients (healthy donors as controls) and evaluated the relationship between ANXA1 and clinical outcomes.
Results: The results showed that the level of serum ANXA1 in ESCC patients was significantly lower than that in controls (P = 0.001) but increased after chemoradiotherapy (P = 0.001). There was no correlation between the baseline level of serum ANXA1 and the short-term efficacy of treatment (P = 0.26) as well as the 1-year progression-free survival (PFS) (P = 0.094). However, there existed a significant correlation between the increases of serum ANXA1 expression and the 1-year PFS (P = 0.04). A higher increase (>2-fold of baseline) in the serum ANXA1 levels was correlated with a poorer PFS (hazard ratio = 3.096, 95% confidence interval 1.239–7.861). There was an inverse correlation between the expressions of miR-196a and ANXA1 in serum (Pearson's correlation of –0.54, P = 0.021).
Conclusion: Our data revealed that the expression of serum ANXA1 in ESCC patients increases after chemoradiotherapy and the increased fold change in serum ANXA1 confers independent negative prognostic impact in ESCC. The higher the increase in serum ANXA1 levels, the poorer the outcome.

Keywords: Annexin A1, esophageal squamous cell carcinoma, microRNA 196a, prognosis


How to cite this article:
Han GH, Lu KJ, Huang JX, Zhang LX, Dai SB, Dai CL. Association of serum annexin A1 with treatment response and prognosis in patients with esophageal squamous cell carcinoma. J Can Res Ther 2018;14, Suppl S3:667-74

How to cite this URL:
Han GH, Lu KJ, Huang JX, Zhang LX, Dai SB, Dai CL. Association of serum annexin A1 with treatment response and prognosis in patients with esophageal squamous cell carcinoma. J Can Res Ther [serial online] 2018 [cited 2020 Dec 1];14:667-74. Available from: https://www.cancerjournal.net/text.asp?2018/14/10/667/187297




 > Introduction Top


Esophageal cancer is the fifth most common cancer and the fourth most common cause of cancer-related deaths in China.[1] Although the incidence of Barrett's adenocarcinoma is increasing rapidly in Western countries, esophageal squamous cell carcinoma (ESCC) is still dominant in East Asia, accounting for >90% of esophageal carcinoma cases.[2] Despite significant progress in treatment strategies, the prognosis of ESCC remains poor, with a 5-year survival rate of ~30%.[3] Further ESCC patients at the same tumor node metastasis (TNM) clinical stage sometimes have significantly different outcomes to treatment. This implies that there exist factors other than the disease itself that affects the response to treatment and prognosis of ESCC. Further, there is an urgent need to identify these factors to develop safer and more effective therapies aimed at improving the prognosis of ESCC.

Annexins are a family of Ca2+-regulated phospholipid-binding proteins involved in modulating arachidonic acid metabolism and the epidermal growth factor receptor tyrosine kinase pathway and are known to regulate several biological processes, including cell differentiation, proliferation, and apoptosis.[4] In addition, annexins are known to play an important role in the development and progression of cancer.[5],[6],[7],[8],[9],[10],[11] Annexin A1 (ANXA1), the first characterized member of the annexin superfamily, is an intracellular protein that plays an important role in growth factor signaling, repairing DNA damage, and regulating apoptosis. Previous researches showed that the high expression of ANXA1 in cancer tissue is correlated to the poor prognosis of several cancers including ESCC. However, the relationship between the expression of ANXA1 in serum and the response to treatment/prognosis of ESCC has never been studied.

MicroRNAs (miRNAs) are a class of small, noncoding, single-stranded RNAs, about 21–23 nucleotides in length. miRNAs are partially complementary to one or more mRNA molecules and interact with the 3'-untranslated region (3'-UTR) of target mRNA molecules to downregulate translation of the target mRNA.[12] Some studies had demonstrated that miRNAs could affect the response to treatment and prognosis in various cancers.[13],[14],[15] Luthra et al. claimed that miRNA-196a (miR-196a) could affect the therapeutic efficacy and prognosis of adenocarcinoma of the esophagus by regulating ANXA1.[16] Therefore, we sought to determine whether miR-196a plays a similar role in ESCC. This study aimed to measure the expression of ANXA1 and miR-196a in the serum of patients with ESCC before and after chemoradiotherapy. Further, we sought to investigate the relationship between the expression of ANXA1 and the therapeutic response and prognosis of ESCC and examine whether ANXA1 expression is regulated by miR-196a in vivo.


 > Materials and Methods Top


Patient groups and sample preparation

Fifty treatment-naive ESCC patients were recruited as the experimental group and twenty healthy blood donors were recruited as controls at the Department of Oncology of the Taizhou people's Hospital from January 2012 to June 2013. Endoscopic biopsy was used for diagnosis of ESCC. Every patient with ESCC underwent concurrent three-dimensional conformal radiation therapy (delineation of target volume according to the International Commission on Radiation Units and Measurements Report)[17] and chemotherapy with a paclitaxel + cisplatin regimen (PTX 135 mg/m2 day 1, cisplatin 40 mg days 1–3) ×2 cycles. Serum samples were obtained from the peripheral venous blood of patients before treatment and within 1 week after treatment. All serum samples were stored at −80°C until RNA extraction. Follow-up information available from the follow-up registry of Taizhou people's Hospital was used for analysis of therapeutic efficacy and survival. This study was approved by the Ethical Committees of Taizhou People's Hospital (No. 20120109). Written informed consent was obtained from each patient before recruitment.

Evaluation of short-term clinical efficacy

Short-term clinical efficacy was evaluated 1 month after treatment based on the Response Evaluation Criteria in Solid Tumors Group (Document number: A00426 revision 1).[18] Clinical outcomes were classified as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). CR and PR were considered effective response to treatment while SD and PD were considered failure to respond.

Enzyme-linked immunosorbent assay

Human ANXA1 protein levels were determined using commercially available enzyme-linked immunosorbent assay (ELISA) kit (R and D Systems China Co., Ltd., Shanghai, China), following the manufacturer's instructions. Briefly, ANXA1 protein standards were used to generate a standard curve between concentrations 0.1 and 20 ng/ml. Samples were assayed in duplicate on a 96-well high-binding ELISA plate. Capture antibody was diluted to a final concentration of 10 μg/ml in bicarbonate buffer (pH 9.6) and incubated overnight at 4°C. Blocking was achieved using 1% solution of bovine serum albumin for 1 h at 37°C. Anti-ANXA1 polyclonal antibody was used for detection (final concentration 1 μg/ml in 1% Tween-20/phosphate-buffered saline buffer, pH 7.4). An alkaline phosphatase-conjugated secondary antibody incubated with phosphatase substrate was used to detect the primary antibody. The samples were measured on a plate reader at a wavelength of 450 nm. The ANXA1 level of each specimen was calculated from the location on the standard curve.

Real-time polymerase chain reaction analysis

For verification of miR-196a expression, stem-loop real-time polymerase chain reaction (RT-PCR) of total RNA with specific primers was performed. Total RNA was extracted from serum using Trizol, following the manufacturer's instructions. For cDNA synthesis, 10 ng total RNA was reverse transcribed using gene-specific reverse transcription primer (5'-CAGAAGGAATGATGCACAGCCAACAACA-3') and SuperScript II Reverse Transcriptase. RT-PCR was performed using the TaqMan probe and FastStart DNA Master SYBR Green I kit and a LightCycler according to the manufacturer's protocol, respectively. The PCR reaction contained 2 μl reverse transcription product, 10 μl PCR master mix, 2 μl of forward primer (5'-CGTCAGAAGGAATGATGCACAG-3'), and 2 μl of reverse primer (5'-ACCTGCGTAGGTAGTTTCATGT-3') in RNase-free water up to a final volume of 20 μl. The reactions were incubated at 95°C for 10 min, followed by 40 cycles of 95°C for 15 s, 60°C for 35 s, and 72°C for 3 s. miR-16 was selected as the internal control. All samples, including no-template controls, were run in triplicate for RT-PCR. The relative expression of miR-196a was determined with the crossing point as the cycle number using the delta Ct method: 2−ΔCt, where Ct = threshold cycle and ΔCt = Ct (specimen) − Ct (internal control).

Statistical analysis

Statistical analysis was carried out using SPSS Statistics 19.0 (SPSS China, Shanghai, China). Significance was determined using either two-tailed Student's t-test or nonparametric Mann–Whitney U-test. A paired t-test was used to analyze data on differences in gene expression in pre- and post-chemoradiotherapy samples. The relationship between ANXA1 and short-term efficacy of treatment was analyzed using the Chi-square test. The Kaplan–Meier method and the log-rank test were used to compare the survival rates. Hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs) were calculated using Cox regression models for progression-free survival (PFS) in uni- and multi-variate analyses. Pearson correlation was used to measure the correlation between ANXA1 and miR-196a levels. P <0.05 was considered statistically significant.


 > Results Top


Clinicopathological characteristics of patients with esophageal squamous cell carcinoma

Treatment was completed by 46 of the fifty ESCC patients; these 46 cases were enrolled for analysis. The clinicopathological features of these ESCC patients are summarized in [Table 1].
Table 1: Clinicopathological characteristics of patients with esophageal squamous cell carcinoma

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Expression levels of annexin A1 in serum

Expression of ANXA1 in the serum of ESCC patients and healthy donors (controls) was evaluated using ELISA. The baseline levels of serum ANXA1 of patients before treatment were significantly lower than that of the controls (0.24 ± 0.106 vs. 0.575 ± 0.14; P = 0.001) [Figure 1]a. However, a significant increase of serum ANXA1 levels was observed in ESCC patients after treatment (0.24 ± 0.106 vs. 0.39 ± 0.134; paired t-test, P = 0.001) [Figure 1]b.
Figure 1: The expression of annexin A1 in serum of patients with esophageal squamous cell carcinoma. (a) The expression of annexin A1 in esophageal squamous cell carcinoma patients' serum before treatment was lower than that in healthy controls (t-test, t = 10.4, P = 0.001). (b) The expression of annexin A1 in esophageal squamous cell carcinoma patients' serum before treatment was lower than that in serum after treatment (paired t-test, t = 10.99, P = 0.001)

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The association of serum annexin A1 with the clinicopathological characteristics of esophageal squamous cell carcinoma patients

The previous study has demonstrated that the expression of ANXA1 in tumor tissue correlates with the clinicopathological features of patient.[19] However, in the present study, no relationship was found between the levels of serum ANXA1 in ESCC patients and their clinicopathological characteristics [Table 2].
Table 2: Associations between the expressions of serum annexin A1 and the clinicopathological features of esophageal squamous cell carcinoma patients

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The association of serum annexin A1 in esophageal squamous cell carcinoma patients with short-term response to chemoradiotherapy

The short-term response to treatment was evaluated 1 month after chemoradiation therapy. An efficient response (CR + PR) was exhibited by forty ESCC cases, while six cases failed to show any response to treatment (SD). There was no significant difference in ANXA1 levels between the group of patients that responded to treatment (CR + PR) and the group that showed no response (SD) (P = 0.26). Depending on the baseline ANXA1 levels, the patients were all grouped into three subsets: Group A: expression levels of ANXA1 >0.2 ng/ml; Group B: ANXA1 levels higher than 0.2 but lower than 0.3 ng/ml; Group C: ANXA1 levels higher than 0.3 ng/ml.

No significant difference was observed in short-term response to treatment between the three groups (P = 0.059). This implied that there was no relationship between the baseline levels of serum ANXA1 of ESCC patients and the short-term response to treatment.

Survival analysis

One of the goals of this study was evaluation of PFS. Up to August 2014, the mean follow-up was 19 ± 6.4 (range: 12–30) months. One year after treatment, disease progression was observed in 17 cases including three cases of recurrence of the primary tumor, two cases of new metastases in the mediastinal lymph nodes, two cases of recurrence in the positive mediastinal nodes, six cases of new metastases in nonregional lymph nodes, and four cases of distant metastases. No significant difference in PFS (P = 0.094) [Figure 2]a was observed between patient Groups A, B, and C (described above). The PFS of patients with ANXA1 levels higher than 0.3 ng/ml (Group C) seemed to decrease in the curve, but the trend was not statistically significant.
Figure 2: Kaplan–Meier survival curves of esophageal squamous cell carcinoma patients according to serum expression of annexin A1. (a) Patients were grouped based on the baseline annexin A1 level: group A – The thick black line curve represents the patients with annexin A1 < 0.2 ng/ml; Group B – The thin black line curve represents the patients with annexin A1 0.2–0.3 ng/ml; Group C – The gray dotted line curve represents the patients with annexin A1 > 0.3 ng/ml. Log-rank test: P = 0.094. (b) Patients were grouped based on the increased fold change in annexin A1: group L – The black line curve represents the patients with increase < 2-fold of baseline; Group H – The gray line curve represents the patients with increase higher than 2-fold of baseline. Log-rank test: P = 0.04

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Based on the increased fold change in ANXA1 levels after treatment relative to baseline, 46 patients were divided into two groups: Group L: less than 2-fold increase in ANXA1 levels posttreatment; Group H: more than 2-fold increase in ANXA1 levels posttreatment.

A significant difference in PFS was observed between the Groups L and H (P = 0.04), [Figure 2]b. Further, univariate analyses [Table 3] showed a significant association between PFS and TNM stage, lymph nodes metastasis (LNM) status, and increased fold change in ANXA1. Multivariate analysis showed a significant association of PFS with LNM status and the increased fold change in ANXA1 (HR = 1.735, 95% CI 0.949–4.672, P = 0.037, HR = 3.096, 95% CI 1.239–7.861, P = 0.015, respectively) [Table 3].
Table 3: Univariate and multivariable Cox regression analysis of 1-year progression-free survival (n=46)

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Association of serum annexin A1 levels in esophageal squamous cell carcinoma patients with microRNA-196a expression

The expression levels of miR-196a in the serum of patients with ESCC were evaluated using RT-PCR. A significant decrease in expression of miR-196a was observed in serum of patients posttreatment (t = 15.37, P < 0.001); [Figure 3]a. In contrast, serum ANXA1 levels in ESCC patients were observed to increase significantly after treatment. Combined, these data implied that there is an inverse correlation between expression of miR-196a and serum ANXA1 levels (Pearson's correlation of −0.54, P = 0.021), [Figure 3]b. The data are consistent with some previous studies which propose that miR-196a may be a negative regulator of ANXA1.
Figure 3: (a) The expression of microRNA-196a in esophageal squamous cell carcinoma patients' serum before and after treatment. The black column represents the samples before treatment and the gray column represents the samples after treatment (*paired t-test, P < 0.001). (b,c) The reverse change trend between annexin A1 and microRNA-196a in serum before and after treatment. The gray line curve represents the samples before treatment and the black line curve represents the samples after treatment, it reveals inverse correlation with the levels of microRNA-196a and annexin A1 (Pearson correlation coefficient = −0.54, P = 0.021)

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 > Discussion Top


In this study, the serum levels of ANXA1 in ESCC patients were evaluated before and after chemoradiotherapy, and relationships between the ANXA1 level, clinicopathological characteristics, and clinical outcomes were investigated. Data from the current study revealed that serum ANXA1 levels in ESCC patients are significantly lower than those in healthy people. This is similar to previous findings that show lower ANXA1 expression in ESCC cells as compared to normal esophageal squamous cells.[20] These findings imply that ANXA1 may act as a tumor suppressor. We also demonstrated that ANXA1 levels increase after chemoradiotherapy, and the increased fold change in ANXA1 levels is correlated with the prognosis of ESCC patients. Patients with more than a 2-fold increase in ANXA1 levels presented poorer 1-year PFS than those with a less fold change. These data implied that ANXA1 might play a role in stimulating metastasis and invasion as an oncogene.

Some previous studies have demonstrated that expression of ANXA1 is downregulated in ESCC tissue;[21],[22] in the present study, the serum ANXA1 level of ESCC patients was lower than that in the serum of healthy people. This leads to the hypothesis that a decrease in synthesis and secretion of ANXA1 by ESCC cells results in the downregulation of ANXA1 in serum. However, more research is needed to elucidate the mechanism behind this.

Previous studies have demonstrated that the high expression of ANXA1 in tumor tissue measured using immunohistochemical method is related to the poor prognosis of patients.[23],[24] In the current study, no correlation was found between the baseline level of serum ANXA1 and the 1-year PFS. Although the 1-year PFS of patients with a serum ANXA1 level higher than 0.3 ng/ml was lower than that of other group patients, this was not statistically significant. Too short follow-up period may be one of the main reasons for the resemblance of 1-year PFS in those groups. We hope for the results of 3-year follow-up. However, we found that the serum ANXA1 levels increased when patients received chemoradiotherapy, and the increased fold change in serum ANXA1 levels was related to the 1-year PFS. Patients with more than a 2-fold increase in serum ANXA1 levels presented a higher risk of recurrence or metastasis and had poorer prognosis than patients with a lower fold change. This implies that a high level of ANXA1 might facilitate invasion and metastasis in ESCC. This is similar to what has been reported in other cancers such as rectal cancer, pancreatic cancer, and malignant melanoma.[19],[25],[26],[27] Further, knockdown of ANXA1 reduces the risk of recurrence and metastasis.[28],[29]

The expressions of ANXA1 in esophageal cancer tissues and serum were downregulated, suggesting that low level of ANXA1 was associated with the occurrence of esophageal cancer, and esophageal cancer with high expression of ANXA1 might easily progress, suggesting ANXA1 could promote the proliferation and metastasis of cancer cells; this kind of conflicts was confusing. One possible explanation was that as a DNA damage repairing protein, ANXA1 began to decrease in the early stage when the esophageal epithelial cells exhibited malignant transformation; therefore, the DNA damages could not be repaired in time, and a variety of damages were then accumulated, which eventually led to the DNA aberration and tumor formation. The mechanism of high ANXA1 expression-promoted processes of esophageal cancer included inhibition of cell adhesion, enhancement of cellular proliferation, and inhibition of apoptosis. In addition to actin remodeling, ANXA1 takes part in the signaling pathways that increase cellular proliferation.[30],[31] Tumor necrosis factor alpha-induced apoptosis is inhibited by upregulation of ANXA1.[32] Further, ANXA1 can stimulate the expression of matrix metalloproteinase (MMP)-9 by activating nuclear factor (NF)-κB.[7],[33] MMP-9 is a member of the MMP superfamily and facilitates invasion and migration of cancer cells by participating in the degradation and remodeling of extracellular matrix.[34] Here exists a clear correlation between higher ANXA1 levels and resistance to chemoradiotherapy and poor prognosis. However, some results contradictory to our observations have also been reported. Luthra et al.[35] demonstrated patients with esophageal carcinoma resistant to chemotherapy or radiotherapy exhibit downregulation of ANXA1. de Graauw et al.[36] documented that ANXA1 can inhibit metastasis by suppressing the transforming growth factor beta-induced epithelial-mesenchymal transition.

In the current study, we have demonstrated for the first time that the ANXA1 expression is significantly upregulated in the serum of patients treated with chemoradiotherapy. The exact mechanism of increase in ANXA1 levels after treatment is unknown. However, there are several potential explanations for the upregulation:

DNA damage induced upregulation of ANXA1 expression. DNA repair genes including ANXA1 are activated by the DNA damage response genes (such as ataxia-telangiectasia-mutated [ATM]) when DNA is damaged by radiation or chemical drugs. Previous studies[28],[37],[38] have shown that ANXA1 is activated by ATM kinase and interacts with inhibitor of κB kinase, activating NF-κB and eventually protecting the cells from radiation-induced cell death. Upregulation of ANXA1 expression was also observed in HeLa cell lines in which DNA damage was induced by benzopyrene, and the increase in ANXA1 level was helpful DNA damage repair and preventing cell death.[39]

Hypoxia induced increase in ANXA1 expression.[40],[41] Tumor cells in oxygen-rich environment are sensitive to radiation while hypoxic cells are resistant to radiation. Thus, hypoxic cells survive after radiotherapy. Moreover, radiation can induce apoptosis of endothelial cells, resulting in capillary occlusion creating a hypoxic environment in the tumor.[42] Therefore, patients with ESCC exhibited higher levels of ANXA1 after radiotherapy.

Decrease in expression of miR-196a resulted in elevated ANXA1 levels. A previous study[16] showed that miR-196a includes the recognition sequence from the ANXA1 3'-UTR, confirming that ANXA1 is a direct target of miR-196a and can negatively regulate the expression of ANXA1. miR-196a expression shows a significant inverse correlation with ANXA1 mRNA levels in 12 cancer cell lines of esophageal, breast, and endometrial origin (Pearson's correlation −0.66, P = 0.019). In the present study, higher expression of miR-196a was accompanied by low levels of ANXA1 in the serum of ESCC patients before chemoradiotherapy; we also found that expression of miR-196a is downregulated after treatment while the levels of ANXA1 are upregulated. Together, these data indicate that miR-196a negatively regulates the expression of ANXA1 in ESCC.

The current clinicopathological staging methods (such as AJCC staging system) have limited success in predicting ESCC patient survival. Patients with identical clinicopathological characteristics can present with varied outcomes ranging from complete cure to recurrence and metastasis or even death after treatment. We have shown that the high serum ANXA1 levels can predict high risk of recurrence and metastasis. Since serum is more readily available than tumor tissue, our finding may enable doctors to easily identify and select high-risk patients for effective therapy in addition to chemoradiotherapy, resulting in improved treatment outcome in ESCC patients. In this study, we used ELISA to determine the serum ANXA1 levels. It should be noted use of ELISA is associated with the occurrence of false positives. Therefore, the potentially clinical application of this study should be examined in a larger independent cohort with more precise biological assays.


 > Conclusion Top


Our study is the first to demonstrate that an increase in serum ANXA1 levels of ESCC patients is accompanied by a decrease in expression of miR-196a after chemoradiotherapy. High increase of serum ANXA1 level is a strong risk factor for the progression and poor prognosis of ESCC. Although further investigations are required to precisely elucidate the role of serum ANXA1 in invasion and metastasis of ESCC, it may be a valuable biomarker for the prediction of prognosis and potential treatment target of ESCC.

Financial support and sponsorship

This work was supported by the Jiangsu Province Ministry of Health, China (Grant No. H201260), and the Taizhou Committee of Science and Technology, China (Grant No. TS201346).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

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