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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 343-349

Prediction of radiotherapy effect by diffusion-weighted imaging in esophageal carcinoma xenograft model


1 Department of Radiotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
2 Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China
3 Department of CT and MRI, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

Date of Submission20-Aug-2019
Date of Decision01-Jan-2020
Date of Acceptance08-Mar-2020
Date of Web Publication28-May-2020

Correspondence Address:
Gao-Feng Shi
Department of CT and MRI, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_627_19

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 > Abstract 


Aim: This study was to evaluate the value of diffusion-weighted imaging (DWI) in predicting the efficacy of radiotherapy for esophageal cancer from xenograft model level.
Subjects and Methods: Thirty-two tumor-bearing mice from the Eca-109 cell line nude mice models were established. The experimental group (n = 16) received a single dose of 15 Gy (6MV X-ray), whereas the control group (n = 16) did not receive any treatment. The tumor volume and apparent diffusion coefficient (ADC) were obtained. The cell density, tissue necrosis ratio, and CD31 expression were determined at matched time points.
Results: The tumor volume was smaller in the experimental group than in the control group (P < 0.05) on the 7th day after radiotherapy (1.580 ± 0.965 cm3 vs. 2.671 ± 0.915 cm3). The ADC values were higher in the experimental group than in the control group on the 3rd day (P < 0.05) (998.15 ± 163.76 ×10− 6 mm2/s vs. 833.32 ± 142.15 ×10− 6 mm2/s). On the 3rd day after radiotherapy, the differences in cell density and necrosis ratio between the two groups were statistically significant; the tumor cell density was lower in the experimental group (25.56 ± 1.40%) than in the control group (33.48 ± 4.18%) (P < 0.05), and the proportion of tissue necrosis was higher in the experimental group (32.19 ± 1.21%) than in the control group (29.16 ± 2.16%) (P < 0.05). The negative and weak positive rate of CD31 expression in the experimental group was higher than the control group, whereas the generally positive and strong positive rate of CD31 expression was significantly lower than the control group in the early stage (P < 0.05).
Conclusion: ADC values may change at the early stage before the morphological changes of tumors. Changes in cell density and necrosis ratio of transplanted tumors correspond to the changes in ADC values. DWI can be used for the early prediction of esophageal cancer radiotherapy efficacy.

Keywords: Apparent diffusion coefficient, diffusion-weighted imaging, esophageal carcinoma, radiotherapy


How to cite this article:
Zhang A, Su X, Wang Y, Shi GF, Han C, Zhang J, Wang L, Zhang R. Prediction of radiotherapy effect by diffusion-weighted imaging in esophageal carcinoma xenograft model. J Can Res Ther 2020;16:343-9

How to cite this URL:
Zhang A, Su X, Wang Y, Shi GF, Han C, Zhang J, Wang L, Zhang R. Prediction of radiotherapy effect by diffusion-weighted imaging in esophageal carcinoma xenograft model. J Can Res Ther [serial online] 2020 [cited 2020 Jul 4];16:343-9. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/343/285193




 > Introduction Top


Diffusion-weighted imaging (DWI) is a functional imaging technique that is based on the microscopic random translational motion of water molecules in biological tissues.[1] At present, DWI has been used in tumor detection, staging, treatment response, and prognosis in clinical applications.[2],[3],[4],[5],[6] A previous pilot study[7] demonstrated that the combination of magnetic resonance imaging (MRI) and DWI could provide important, additional information for staging and selecting the initial treatment. A systematic review[8] indicated that a large apparent diffusion coefficient (ADC) increase after 2 weeks of chemo- and/or radiotherapy treatment is a good predictor of good response to esophageal cancer. According to Vollenbrock et al.,[9] the preoperative assessment of residual tumor on T2 weighted with DWI after neoadjuvant chemoradiotherapy for esophageal cancer is feasible with high sensitivity. This study aimed to determine the application value and mechanism of DWI in the early prediction of esophageal cancer radiotherapy efficacy and provide a theoretical basis for the clinical application of this technique.


 > Subjects and Methods Top


Experimental materials

Cell culture

Eca-109 cells of human esophageal carcinoma (purchased from Shanghai Institutes for Biological Sciences) were cultured at 37°C in a 5% CO2 incubator with Roswell Park Memorial Institute 1640 medium. Adherent cell culture was used to increase growth during passage.

Experimental animals

Four- to six-week-old immune deficiency type BALB/c nude mice (male, 18–20 g) were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. (certificate no.: 1605200), and they were reared in the Animal Experiment Center of the Fourth Hospital of Hebei Medical University. No specific pathogen environment was provided. Other environmental conditions were as follows: 12 h alternating light and shade, free drinking water and feeding, 50% ± 10% relative humidity, and 23°C ± 2°C temperature.

Transplant tumor model construction

The cell suspension was amplified by the pancreatic digestion enzyme method. The tumor cells were digested with 0.25% ethylenediaminetetraacetic acid and collected by centrifugal tube centrifugation (1000 rpm, 5 min). The supernatant was discarded, and then, the cells were counted with an inverted phase microscope. The blood count board was matched into the cell suspension at a concentration of 1 × 107/ml. Using a 1-ml injection to extract the collected cell suspensions, the right forelimbs of nude mice were chosen as the inoculation site, and the number of inoculated cells in every nude mouse was 5 × 106/0.2 ml. Approximately 2 weeks after inoculation, a subcutaneous tumor was formed with a diameter of approximately 10 mm.

Experimental grouping and processing factors

Experimental Group 1

Thirty-two tumor-bearing nude mice with successful modeling were divided into two groups according to the method of random number table. The experimental group (n = 16) received 15 Gy of 6 MV radiotherapy, whereas the control group (n = 16) did not receive any treatment. The two groups were scanned before and after radiotherapy at different time points (once every other day, observation time of 1 month, a total of 16 time points).

Experimental Group 2

According to the results of experiment 1, seven key time points were selected and were divided into seven groups. Twelve mice were randomly divided into the experimental and control groups. MRI scans were performed in seven groups before radiotherapy and 1, 3, 5, 7, 17, and 29 days after radiotherapy. After completing the MRI scan, the tumor-bearing nude mice were immediately executed (cervical vertebral dislocation method), and the tumor tissue was stripped and soaked with a 10% formalin solution.

Irradiation mode

An Ikeda linear accelerator (Synergy 2349) was utilized with a 6 MV-X line. The shooting field was 2 cm × 2 cm, the source skin distance was 100 cm, the dose rate was 300 cGy/min, and a single dose of 15 Gy was delivered, with the use of a 1-cm tissue compensation membrane. All the tumor-bearing nude mice in the experimental group were placed in the prone position and received radiotherapy under sober conditions.

Magnetic resonance imaging examination

Germany Siemens 3.0 T MRI scanner, loop coil, and scanning sequence, including T1WI, T2WI, and DWI sequences, were used. DWI used an HD dispersion sequence at b-values (dispersion-sensitive gradient) between 0 and 600 s/mm2.[10],[11],[12] The mice were anesthetized using 2% pentobarbital injections (0.05 ml/mouse) before scanning, and the tumor-bearing nude mice were wrapped in fresh pork and placed in loop coils.

Measurement of the volume of transplanted tumor

The maximal diameter (a) and the short diameter (b) of the transplanted tumor were measured using an electronic Vernier caliper. The volume of the transplanted tumor was calculated using the formula V = ab2/2,[13],[14],[15] and VX indicates the volume of transplanted tumor on the X-day after radiotherapy. All data were measured independently by two researchers, and the average was edited as the final data.

Image analysis

The DWI image at the maximal level of the tumor was taken at the b-value of 0 and 600 s/mm2, and the ADC image was generated on a postprocessing workstation. Five regions of interest (ROIs) were selected randomly within the tumor tissue to avoid the necrotic areas, and the ADC value of the tumor was measured. The ADC value before radiotherapy (ADC0) and that after radiotherapy (ADCX) were measured.

Detection of cell density and necrosis ratio in transplanted tumors

The pathological sections of transplanted tumors of human esophageal carcinoma in nude mice were stained with hematoxylin and eosin. Cell density: Five complete and nonoverlapping high-magnification lenses (×400) were randomly selected for each tissue slice. The ImageJ software (National Institutes of Health, Maryland, Bethesda, US) was used to convert pathological photos into black-and-white images with the black parts representing the nucleus. Cell density = nucleus area/photo total area of transplanted tumor tissue ×100%, and the average value of five fields was calculated. Necrosis ratio: Three complete and nonoverlapping macroscopic views (×40) were randomly selected for each tissue slice using the ImageJ software computation: Tumor necrosis ratio = necrosis area/tumor area ×100%.

Detection of CD31 expression in transplanted tumors

Immunohistochemistry streptavidin-peroxidase method was used for staining. CD31 expression is primarily located in the cell membrane, and positive cells were defined as cells with brown matter on the cell membrane. Five complete and nonoverlapping high-spec lenses (field of view, ×400) were randomly selected from each tissue slice to count positive cell percentages. Percentage of positive cells = positive cells/total number of cells ×100%. The expression of CD31 was divided into four levels according to the percentage of positive cells: (1) negative (− ): Positive cell percentage 0%–5%; (2) weak positive (+): Positive cell percentage 6%–25%; (3) generally positive (++): Positive cell percentage 26%–50%; and (4) strong positive (+++): Positive cell percentage 51%–100%.

All research programs were approved by the Animal Protection Committee of the Fourth Hospital of Hebei Medical University (approval no. 201618).

Statistics processing

All statistical analyses were performed using the Statistical Package for the Social Sciences software, version 22.0 (IBM Corporation, Armonk, NY, USA). The normality of quantitative data was assessed using the Kolmogorov–Smirnov test. The variables at different time points were determined using the variance analysis of repeated measurements. The t-test was used to compare the two independent samples. P < 0.05 was considered statistically significant.


 > Results Top


Comparison of the volume of transplanted tumors between the experimental and control groups before and after radiotherapy

In experiment 1, the growth doubling time was 17 days in the experimental group and 5 days in the control group. There were differences in the volume of transplanted tumors in the experimental group at different time points (F = 22.159, P < 0.001), and there were differences in the volume of transplanted tumors in the control group at different time points (F = 61.561, P < 0.001). The volume V0 of the two groups was 0.935 cm3 ± 0.354 cm3 and 0.917 cm3 ± 0.310 cm3, respectively, and no statistical significance was observed (P = 0.879). The volume of transplanted tumors in the control group was approximately equal to that of the experimental group on the 1st and 3rd days, and the growth rate in the experimental group decreased on the 5th day. The control group was slightly larger than the experimental group, but there was no statistically significant difference between the two groups (P = 0.184). Significant differences between the two groups were observed on the 7th day after radiotherapy, and the xenograft volume of the experimental group was significantly smaller than that of the control group (P < 0.05) [Figure 1] and [Table 1].
Figure 1: (a) A magnetic resonance imaging sample shows the volume (1.404 cm3) of a transplanted tumor in the 7th day after radiotherapy in the experimental group. (b) A magnetic resonance imaging sample shows the volume (3.064 cm3) of a transplanted tumor in the 7th day after radiotherapy in the control group

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Table 1: Comparison of the volumes of transplanted tumors in two groups (cm3, x1±s)

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Comparison of apparent diffusion coefficient values before and after radiotherapy between the experimental and control groups

The ADC values of the experimental group decreased on the 1st day and increased rapidly on the 3rd day and up to the greatest point on the 5th day. The ADC value remained at a relatively stable level and gradually declined after 17 days. However, the ADC values of the control group began to decline on the 1st day and showed a monotonical decrease and continued at a relatively low level on the 7th day. There were differences in ADC values in the experimental group at different time points (F = 5.421, P < 0.001). There were also significant differences in the ADC values in the control group at different time points (F = 8.021, P < 0.001). There was no significant difference between the two groups in ADC0 and ADC1(P = 0.966 and 0.194). The ADC values of the two groups began to show a significant difference on the 3rd day after radiotherapy, that is, the ADC values were significantly higher in the experimental group than in the control group (P < 0.05) [Figure 2] and [Table 2].
Figure 2: (a) A magnetic resonance imaging sample shows the apparent diffusion coefficient value (1045.20 × 10-6 mm2/s) of a transplanted tumor in the 3rd day after radiotherapy in the experimental group. (b) A magnetic resonance imaging sample shows the apparent diffusion coefficient value (861.20 × 10 − 6 mm2/s) of a transplanted tumor in the 3rd day after radiotherapy in the control group

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Table 2: Comparison of the apparent diffusion coefficient values of transplanted tumors on MRI images in two groups (×10-6 mm2/s, x±s)

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Comparison of the cell density of transplanted tumors between the experimental and control groups

The results are shown in [Table 3]. The cell density of the experimental group decreased on the 3rd day after radiotherapy, and the lowest density occurred on the 7th day. The control group showed a gradual increase in cell density. The highest density occurred on the 5th day, but it eventually decreased. The cell density of the control group was higher than that of the experimental group on the 3rd day after radiotherapy (P < 0.05) [Figure 3] and [Table 3].
Table 3: Comparison of the cell densities of transplanted tumors on pathological images in two groups (%, x±s)

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Figure 3: (a) A pathological sample shows the cell density (17.63%) of a transplanted tumor in the 7th day after radiotherapy in the experimental group. (b) A pathological sample shows the cell density (31.07%) of a transplanted tumor in the 7th day after radiotherapy in the control group

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Comparison of necrosis ratio between the experimental and control groups

The results are shown in [Table 4]. The rate of necrosis in the experimental group gradually increased and gradually decreased after the 7th day. The control group showed a gradual downward trend and stabilized after the 7th day. The proportion of necrosis in the experimental group was higher than that in the control group on the 3rd day after radiotherapy (P < 0.05) [Figure 4] and [Table 4].
Table 4: Comparison of the necrosis ratios of transplanted tumors on pathological images in two groups (%, x±s)

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Figure 4: (a) A pathological sample shows the necrosis ratio (53.17%) of a transplanted tumor in the 7th day after radiotherapy in the experimental group. (b) A pathological sample shows the necrosis ratio (29.16%) of a transplanted tumor in the 7th day after radiotherapy in the control group

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Comparison of CD31 expression between the experimental and control groups

The positive expression rate (+, ++, and +++) of CD31 in the whole group was 82.14% (69/84). In the early stage after radiotherapy (D1, D3, D5, and D7), the negative and weak positive rate of CD31 expression was 23/48 in the experimental group and 4/48 in the control group (χ2 = 18.602, P < 0.001), whereas the generally positive and strong positive rate was 1/48 in the experimental group and 20/48 in the control group (χ2 = 22.004, P < 0.001). In the late stage after radiotherapy (D17 and D29), the negative and weak positive rate of CD31 expression was 11/24 in the experimental group and 10/24 in the control group (χ2 = 0.085, P = 0.771), whereas the generally positive and strong positive rate was 1/24 in the experimental group and 2/24 in the control group (χ2 = 0.356, P = 0.551) [Figure 5] and [Table 5].
Figure 5: (a) A pathological sample shows the CD31 expression (+) of a transplanted tumor in the 7th day after radiotherapy in the experimental group. (b) A pathological sample shows the CD31 expression (+++) of a transplanted tumor in the 7th day after radiotherapy in the control group

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Table 5: Comparison of CD31 expression of transplanted tumors on pathological images in two groups

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 > Discussion Top


The comprehensive treatment based on radiotherapy is the main treatment method for advanced esophageal carcinoma; however, the traditional imaging method from the anatomical form is very limited to predict the radiation sensitivity and evaluate the therapeutic effect of the tumor in the early stages of treatment. Changes in functional MRI images often indicate anatomical changes and might, therefore, be early indicators of treatment response.[16] The clinical value of DWI in evaluating the efficacy of early tumor treatment and the radiosensitivity of tumors has become a research hotspot[17],[18],[19] in recent years. The ADC value is a quantitative index of DWI, which is negatively correlated with tissue cell density. When the tissue cell density increases, the extracellular space decreases, the interstitial fluid pressure increases, the dispersion ability of the water molecule weakens, the DWI signal increases, and the ADC value decreases.[20],[21] Cytotoxic therapy can result in the loss of cell membrane integrity, which is indicated by an increase in the mean tumor ADC.[22] Animal experiments are an indispensable research cornerstone for the rational extension of DWI for clinical applications. The aim of this study was to discuss the mechanism of DWI in the early prediction of esophageal cancer radiotherapy effects in the animal model level and provide a theoretical basis for the clinical application of this technique.

The results showed that a single radiation dose of 15 Gy did not cause death in nude mice. Moreover, there were changes in the volume of transplanted tumors. There was a significant growth delay in human esophageal carcinoma implanted in nude mice treated with a single high dose of radiation. The tumor transplanted in the experimental group had a slow growth rate, and the tumor volume increased ones at the end of the observation period. Meanwhile, the tumor transplanted in the control group showed a stable growth and increased approximately eight times as the initial volume. The rate of tumor growth in the experimental group began to decrease on the 5th day after radiotherapy and slightly decreased on the 7th day. The tumor volume increased due to the occurrence of tissue edema. It could also be a secondary effect after delivering a single dose of radiation. Cells can perform several mitotic cycles before death, which is defined as compensatory cell proliferation. Due to the gradual disappearance of the compensatory proliferative effect of tumor cells, apoptotic signaling pathways were activated by radiotherapy, and tumor cells exhibited apoptosis.[23] During this time, the cell dissolution caused by radiotherapy, tumor necrosis, and the removal of the cell fragments were manifested as a decrease in tumor growth or even tumor shrinkage. However, a single dose of 15 Gy radiotherapy was not enough to kill all the tumor cells. Hence, the volume of transplanted tumor in the experimental group continued to increase due to the redistribution of the cloned cells that survived the treatment. The ADC values of the experimental group decreased on the 1st day. In the initial stage after high-energy X-ray exposure, the cell membranes of tumor tissue could be damaged and led to the dysfunction of active transmembrane transportation of water molecules.[24] Before radiotherapy, water molecules were transported in active transportation, and after radiotherapy, the cell membranes could be damaged, water molecules were transported in passive transportation, which could caused cell edema. Therefore, the cell interstitial gap was smaller than that before the treatment, and the dispersion ability of the water molecule decreased. The microcirculation disturbance caused by radiotherapy can also cause a decrease in the ADC value, and fine tissue repair after radiotherapy possibly contributed to the decrease in the ADC value. With the occurrence of tumor tissue injury caused by radiotherapy, the cell density decreased, the movement restriction of water molecules was relatively relieved before treatment, and the ADC value increased gradually and reached the highest point when the tumor volume started to decrease (on the 5th day). These findings indicate a substantial decrease in restriction of water diffusion within the extracellular space, intercellular space, or both.[25] With the proliferation of transplanted tumors in the experimental group, the volume gradually increased, whereas the ADC value gradually decreased. The ADC values of both the groups reached a relatively stable level when the size of the transplanted tumor was doubled (on the 17th day of the experimental group and on the 7th day in the control group). The significant differences in the volumes of transplanted tumors in the two groups were observed on the 7th day, whereas the reduction in the ADC values was observed on the 3rd day. Reduction in the ADC values was preceded by changes in tumor morphological structures. Thus, the observed variations in ADC values in our study appear to be in line with the expected effect of successful treatment.

Experiment 1 mainly observed the relationship between the growth of transplanted tumors and the dynamic changes of ADC values after radiotherapy. The 1st, 3rd, 5th, 7th, and 17th days after radiotherapy were the key time points, and the two groups had notable changes in both volume and ADC values. Therefore, the seven time points were divided into seven groups in experiment 2, and a pathologic comparison of the corresponding time points was performed after the MRI scan.

Based on the abovementioned points, the cell density of the experimental group decreased on the 3rd day after radiotherapy, and the lowest density occurred on the 7th day. This finding indicated that as the proportion of tissue necrosis increased, the cell density and proliferative ability decreased in the early stage of tumor transplantation after radiotherapy, which is related to cell dissolution and tissue necrosis caused by radiotherapy; moreover, the intercellular space, water molecule diffusion capacity, and ADC value increased. Due to the proliferation and redistribution of tumor cells, the cell density increased in the later stages after radiotherapy, whereas the ADC value decreased. The ADC value gradually increased on the 3rd day after radiotherapy and reached the highest point on the 5th day. The ADC value gradually decreased on the 17th day and remained stable in the prophase of the experiment. The cell density in the control group gradually increased. The highest density was observed on the 5th day and then eventually decreased. The analysis was conducted to determine why the tumor cells proliferated rapidly in the early stage; with the increasing tumor volume, the hypoxia increased and proliferation slowed, which was consistent with the ADC value of the control group (decreasing gradually in the previous experiment and remaining at the lower level on the 7th day). The results of the comparison between the two groups showed a statistically significant difference on the 3rd day after radiotherapy; the cell density in the experimental group was lower than that in the control group, whereas the necrosis ratio in the experimental group was higher than that in the control group. Although the mechanism underlying the increase in water diffusion following cytotoxic chemotherapy in experimental and human tumors is not fully understood, this phenomenon coincides with the reduced cell density and enlarged extracellular space due to apoptosis or necrosis.[26] Since a negative correlation between ADC and cell density has been reported,[27] it appears that the viable cells in highly proliferative solid tumors (with lower ADC) have better outcomes to chemoradiation than those that have higher ADC (possibly including areas of necrosis).

CD31 is a well-known marker of endothelial cells and plays roles in cell proliferation, apoptosis, migration, and cellular immunity. CD31 is also expressed on tumor cells and contributes to tumor cell invasion.[28],[29] In this study, the generally positive and strong positive rate of CD31 expression in the control group was significantly higher than that of the experimental group in the early stage, which indicated that the tumor growth in the control group grew faster than that of the experimental group, and this result was well reflected in experiment 1: The tumor volume doubled on the 5th day in the control group, and the experimental group did not double until the 17th day. Radiotherapy inhibited the angiogenesis of the tumor to a certain extent and delayed the growth of the tumor in the experimental group. There were no statistical differences in CD31 expression rate in the late stage between the two groups, which may be related to the cell proliferation in the experimental group in the late stage.

The advantage of this study is that several time points were selected in the experiment. We were able to observe the changes in various indicators clearly. However, there are several limitations in the present study. First, the ROIs were drawn manually. Second, the investigated animal population was relatively small. Another limitation is that ADC measurement depends on the diffusion sensitivity coefficient (b-value), which lacks consensus.[30],[31] From the results of this study, single high-dose radiotherapy can inhibit the growth of transplanted tumors after radiotherapy. Moreover, the ADC value can be used to determine the tumor's response to treatment, especially in the early stages and before the tumor tissue morphology changes. In addition, the ADC value is consistent with the pathological changes; the ADC value can be used for the early prediction of tumor radiosensitivity and to evaluate the curative effect of radiotherapy. DWI can be used in the clinical setting and in predicting the effects of radiotherapy in patients with esophageal carcinoma.

Acknowledgment

Thank for the Public Health Commission of Hebei Province which funded my research. I am particularly grateful to my mentor Professer Shi Gaofeng and Professor Han Chun for the guidance given in this study, and thanks to the other authors of this study for their help. Thanks to my family for their strong support.

Financial support and sponsorship

This study was financially supported by the Public Health Commission of Hebei Province, Approval No: 20170170.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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