|Year : 2016 | Volume
| Issue : 1 | Page : 271-276
Effect of gemcitabine on the uptake of 18F-fluorodeoxyglucose and 18F-fluorothymidine in lung adenocarcinoma A549 cells and the animal tumor model
Bin Zhang1, Sheng-Ming Deng1, Ling-Chuan Guo2, Jia-Jia Dong1, Yan-Bo Zhu3, Yuan Gao3, Zhen-Xin Wang3, William C Cho4
1 Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China
2 Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China
3 Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China
4 Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong Special Administrative Region, Hong Kong, China
|Date of Web Publication||13-Apr-2016|
The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu
Source of Support: None, Conflict of Interest: None
Background: Gemcitabine is the first-line drug for nonsmall cell lung cancer, and 18F-fluorodeoxyglucose. (18F-FDG) and 18F-fluorothymidine. (18F-FLT) are positron emission tomography. (PET) imaging agents. The aim of this study was to explore the effect of gemcitabine on the uptake of 18F-FDG and 18F-FLT in A549 cells and the animal tumor model.
Materials and Methods: The inhibitory effects of gemcitabine on cell growth were determined by tetrazolium blue method, and uptake rates of 18F-FDG and 18F-FLT were determined under the same conditions. The adenocarcinoma-bearing nude mice before and after gemcitabine treatments were performed microPET imaging with 18F-FDG and 18F-FLT. Hematoxylin and eosin staining and immunohistochemical analysis of tumor specimens were conducted.
Results: After the administration of gemcitabine, positive correlations were observed between inhibition of 18F-FDG or 18F.FLT uptake and cell growth. (r = 0.957 or 0.981, P < 0.01). SUVmax values by 18F-FDG in the tumor, before and after administration of gemcitabine at the dose of 60 mmol/L, revealed an increase by. (35.83 ± 10.58) %. After administration of 120 mmol/L gemcitabine, the SUVmax values decreased by (12.37 ± 7.33) %. The SUVmax values by 18F-FLT at the dose of 60 mmol/L gemcitabine revealed a decrease by (56.47 ± 10.83) %. Pathological staining showed obvious vasodilation and invasion of lymphocytes and plasma cells at the dose of 60 mmol/L, and the expression of glucose transporter protein-1, Ki-67 and proliferating cell nuclear antigen in tumor cells were inhibited.
Conclusion: 18F-FLT imaging can assess the proliferation of tumor cells and 18F-FDG imaging can reflect the changes of the tumor microenvironment after administration of gemcitabine.
Keywords: 18 F-fluorodeoxyglucose, 18 F-fluorothymidine, gemcitabine, nonsmall cell lung cancer
|How to cite this article:|
Zhang B, Deng SM, Guo LC, Dong JJ, Zhu YB, Gao Y, Wang ZX, Cho WC. Effect of gemcitabine on the uptake of 18F-fluorodeoxyglucose and 18F-fluorothymidine in lung adenocarcinoma A549 cells and the animal tumor model. J Can Res Ther 2016;12:271-6
|How to cite this URL:|
Zhang B, Deng SM, Guo LC, Dong JJ, Zhu YB, Gao Y, Wang ZX, Cho WC. Effect of gemcitabine on the uptake of 18F-fluorodeoxyglucose and 18F-fluorothymidine in lung adenocarcinoma A549 cells and the animal tumor model. J Can Res Ther [serial online] 2016 [cited 2020 Apr 4];12:271-6. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/271/147713
| > Introduction|| |
Lung cancer is the most common primary malignant tumor and the first cause of cancer death worldwide. In 2003, the World Health Organization reported that the mortality rate of lung cancer is 1.1 million each year, and the incidence of lung cancer is 1.2 million each year. The incidence of lung cancer in women presents an increasing trend. Due to the difficult diagnosis at the early stage of lung cancer, approximately two-thirds of patients diagnosed with lung cancer have already missed the opportunity of surgical treatments. For patients with advanced nonsmall cell lung cancer (NSCLC), chemotherapy is the primary choice. Among the chemical drugs, gemcitabine, an anticancer drug targeting the metabolism, is one of the most effective chemotherapeutic agents. Currently, it is the first-line drug for the treatment of local advanced or metastatic NSCLC., Gemcitabine is uptaken by cells through a nucleoside transport mechanism. In the cells, under the catalysis of deoxyribonucleoside kinase, it is converted to its 5-monophosphate form (dFdCMP). The dFdCMP was further phosphorylated to generate 5'-diphosphate and 5'-triphosphate (dFdCTP) forms under the catalysis of nucleoside monophosphate kinase and diphosphate kinase. The active forms of gemcitabine inhibit ribonucleotide reductase and DNA synthesis and repairing. dFdCTP can be competitively incorporated into DNA, resulting in the termination of DNA synthesis, DNA breakage and cell apoptosis.
Currently,18 F-fluorodeoxyglucose (18 F-FDG) is the most widely used positron emission tomography (PET) imaging agent.18 F-FDG is uptaken by tumor cells mainly through glucose transporter protein-1 (GLUT-1).18 F-FDG imaging can be used to accurately evaluate the efficacy of chemotherapy for lung cancer, which is confirmed by a series of experimental studies and clinical observations., In NSCLC, two studies showed that the early evaluation by 18 F-FDG PET could predict progression-free survival and overall survival in patients treated with erlotinib.,18 F-FDG imaging can sensitively reflect the treatment efficacy of gemcitabine for lung cancer. However, as an imaging agent for nonspecific tumors,18 F-FDG also can result in false positive imaging due to inflammation.18 F-fluorothymidine (18 F-FLT) is an imaging agent for cell proliferation, and it can be phosphorylated to generate 18 F-FLT-MP in cytoplasm of the cells in the presence of the catalysis of thymidine kinase1 (TK1). Due to the displacement of 3'-OH by fluoride, its phosphorylated metabolites can't be further involved in DNA synthesis, and can't return to the tissue fluid through the membrane either, so that they remain inside the cells. TK1 is a key enzyme in the rescue pathway of DNA synthesis. The activity of TK1 in quiescent cells is very low; in contrast, during the rapid proliferation of the cells, the late G1 phase revealed a significant increase in TK1 activity. Theoretically,18 F-FLT can reflect the synthesis rate of DNA and proliferation rate of tumor cells as well as early response to chemotherapy due to its sensitive detection. The feasibility of using 18 F-FLT for evaluating tumor chemotherapy has been confirmed in different tumor cell cultures and animal models., According to literature reports,18 F-FDG and 18 F-FLT can be used for the early evaluation of targeted therapy for lung cancer., Proliferating cell nuclear antigen (PCNA) and Ki-67 are PCNAs that are closely correlated with DNA synthesis, which are important indicators for the proliferation of tumor cells and the degree of malignancy.
In this report, we studied the effect of gemcitabine on the uptake of 18 F-FDG and 18 F-FLT in A549 cells and the animal tumor model through imaging analysis of cancer cells and tumor-bearing nude mice with and without gemcitabine administration, and immunohistochemical analysis of tumor specimens.
| > Materials and Methods|| |
Cell culture and 18 F-fluorodeoxyglucose and 18 F-fluorothymidine uptake
A549 cells were cultured in RPMI-1640 medium (GIBCO, NY, USA) containing 10% fetal bovine serum (FBS) (GIBCO), 100 U/mL penicillin, and 100 mg/L streptomycin at a 37°C incubator (Jouan, Cedex, France) supplemented with 5% CO2 and 95% humidity. The cells were passaged every 2 or 3 days. During the logarithmic growth phase, the cells (1 × 106/mL) were seeded in six 25-cm 2 cell culture flask with glucose-free medium (GIBCO) at 37°C for 12 h, and then 50 μL of 74 kBq/mL 18 F-FDG or 18 F-FLT (Nanjing AnDike Company, Nanjing, China) was added into the cell culture medium. Following incubation at 37°C for 60 min, the cells were harvested and centrifuged. The supernatant was collected, and the cells were rinsed with 1 mL of phosphate-buffered saline for 2 times. The collected supernatant was mixed. The counts per minute in cells (B) and in the supernatant (F) were measured by a γ-measuring instrument (Shanghai Optical Instrument Company, Shanghai, China). The uptake rate of 18 F-FDG or 18 F-FLT was calculated using the following formula:
Uptake rate (%) = B/(B + F).
Effect of gemcitabine on A549 cell proliferation evaluated by MTT method
During the logarithmic growth phase of A549 cells, the cells (2 × 105/mL) were cultured in 96-well plates with 100 μL of RPMI-1640 medium containing 10% FBS for each well. The A549 cells were cultured at a 37°C incubator supplemented with 5% CO2. After 24 h cell culture, gemcitabine (Lilly Pharmaceuticals, USA) was added to the experimental groups at the final concentrations of 5, 10, 20, 40, 60, and 120 mmol/L. Each concentration condition was used in 6 wells. Meanwhile, saline at the same volume was added as a control group or zero point. Following 1 h incubation with gemcitabine, each well was supplemented with 90 μL of RPMI-1640 with 10% FBS and continue to culture in a 37°C incubator supplied with 5% CO2. Upon continuous culturing for 24 h, the wells were added with 20 μL MTT (final concentration of 5 mg/mL) (Sigma, USA) and 80 μL 1640 medium with serum. The cell plates with MTT were incubated at 37°C for another 4 h. After removing the medium, 150 μL of dimethylsulfoxide (Duchefa, Netherland) was added to each well to completely dissolve the residues with shaking for 10 min. The optical density (OD) was measured at 492 nm on a microplate reader (Thermo electron corporation, Shanghai, China). The inhibitory rate of cell growth was calculated using the following formula:
Inhibitory rate = (ODcontrolgroup − ODexperimentalgroup)/ODcontrolgroup.
Effect of gemcitabine on the uptake of 18 F-fluorodeoxyglucose and 18 F-fluorothymidine
Totally 2 mL A549 cells (5 × 105/mL) were seeded in the 25-cm 2 cell culture flasks. After 24 h culturing, the medium was removed, and the experimental groups were supplied with gemcitabine at the concentrations of 5, 10, 20, 40, 60, and 120 mmol/L in medium. The control group was supplied with saline at the same volume. After gemcitabine treatment for 1 h, the cells were supplemented with 1900 µL of RPMI-1640 containing 10% FBS and cultured for another 24 h. Then 50 μL of 74 kBq/mL 18 F-FDG and 18 F-FLT were added into the cell culture medium, and the uptake rate of 18 F-FDG or 18 F-FLT was calculated. The inhibitory rate for the uptake of 18 F-FDG and 18 F-FLT in cells were determined using following formula:
Inhibitory rate = (Uptake rate of cellscontrol − Uptake rate of cellsexperiment)/Uptake rate of cellscontrol
Establishment of tumor-bearing nude mouse model and micro positron emission tomography imaging
The study was approved by our institutional review board/local ethics committee, and the experiments followed the guidelines on experiments with animals. Male BALB/c nude mice of 4 weeks old were purchased from Shanghai Laboratory Animal Commission animal laboratory. Animal certificate number was 2007000532623. The cells at the logarithmic phase were trypsinized and suspended in serum-free culture medium RPMI-1640 at the density of 1 × 107/mL. Totally 0.2 mL of cell suspension was inoculated in BALB/C nude mice through subcutaneous injection at the armpit of the right forelimb. When the tumor size was about 0.6-1.0 cm, pathological examination of tumor tissues were conducted, which was consistent with the characteristics of human lung adenocarcinoma.18 F-FDG and 18 F-FLT imaging of tumor-bearing nude mice were performed before and 24 h after 150 μL gemcitabine injected via the tail vein. Meanwhile, the mice for the 18 F-FDG imaging group was also divided into two subgroups including 60 mmol/L gemcitabine group and 120 mmol/L gemcitabine group, while the 18 F-FLT imaging group included the mice treated only with 60 mmol/L gemcitabine. After the nude mice were injected with 0.1-0.15 mL of 18 F-FDG (3.94-7.47 MBq) or 18 F-FLT (3.94-7.47 MBq), and subjected to isoflurane anesthesia, as well as limb fixation in microPET bed, systemic microPET static scanning was started upon drug administration for 20 min. The scanning time was 20 min. Inveon Micro-PET scanner (SIMENS, Germany) was equipped with ring LYSO crystal array 80, a detector with a diameter of 120 mm, an entrance for the subject with a diameter of 120 mm, axial distance of 127 mm and imaging resolution of 1.4 mm. Using OSEM three-dimensional image reconstruction method, the SUV values of the tumors were calculated.
For the determination of the SUV value, ASIProVMTM software (CTI concorde Microsystems) was used to collect the region of interest, and the computer can automatically acquire an average PET unit as the U-value. The SUV value was calculated using the following equation: SUV value = U-value × conversion factor (nCi/mL) ÷ 1000 × weight (g) ÷ injected dose (μCi), where conversion factor was 4947368 nCi/mL.
Pathological and immunohistochemical examinations
Tumor tissue samples from tumor-bearing mice with and without gemcitabine treatments were fixed in 10% formalin and paraffin embedded. The specimens were subjected to sectioning, hematoxylin and eosin (HE) staining and immunohistochemical analysis for GLUT-1, PCNA and Ki-67. PCNA and Ki-67 immunohistochemical kits were from Beijing Zhongshan Golden Bridge Biotechnology (Beijing, China). According to the immunohistochemical procedures, tumor specimens were subjected to paraffin sections at the thickness of 4 μm, stepwise hydration, blockage with 3% H2O2 for endogenous peroxidase and antigen recovery with tris-buffered saline buffer. FBS and GLUT1 antibodies (Santa Cruz Biotechnologies, USA) at the dilution ratio of 1:400, biotinylated secondary antibody, horseradish peroxidase-labeled avidin streptomycin, and diaminobenzidine staining were sequentially added to tumor specimens. The stained specimens were finally treated with hematoxylin, dehydration and mounting. The cells with GLUT-1 antibody staining on the cell membrane were defined as the positive cells. Under a microscope with magnification of ×400, at least five representative fields with total cell number of 500 were observed to count the positive cells with GLUT-1 staining. Similarly, the immunohistochemical analysis for PCNA and Ki-67 was conducted following the same procedure as GLUT-1.
All data were expressed as x- ± S, and SPSS 14.0 software (IBM Company, USA) was used to analyze the ANOVA for random factors. A statistically significant difference was considered at P < 0.05.
| > Results|| |
Inhibitory rate of the proliferation of A549 cells by gemcitabine
After treatment with gemcitabine at various concentrations (5, 10, 20, 40, 60, and 120 mmol/L) for 24 h, the growth of A549 cells was obviously inhibited with the inhibitory rates of (10.38 ± 7.42) %, (11.25 ± 6.70) %, (20.65 ± 12.05) %, (56.71 ± 34.07) %, (82.25 ± 21.53) %, and (95.75 ± 4.03) %, respectively. Meanwhile, inhibitory rate of cell growth was increased with the increase of gemcitabine dose, and they exhibited positive correlation (r = 0.831, P < 0.01).
Inhibition of 18 F-fluorodeoxyglucose and 18 F-fluorothymidine uptake in A549 cells by gemcitabine
After treatment with gemcitabine at the concentrations of 5, 10, 20, 40, 60 and 120 mmol/L for 24 h, the uptake rates and inhibitory rates of 18 F-FDG and 18 F-FLT were measured, and the results are listed in [Table 1] and[Table 2]. The inhibitory rate on cell uptake of 18 F-FDG and 18 F-FLT was enhanced with the increase of the gemcitabine concentration, which was positively correlated with the inhibitory rate of cell growth (r = 0.957 and 0.981, P < 0.01).
|Table 1: Uptake rates of 18F-FDG and 18F-FLT of A549 cells by gemcitabine (%)|
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|Table 2: Inhibitory rates of 18F-FDG and 18F-FLT uptake of A549 cells by gemcitabine (%)|
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The micro positron emission tomography imaging of tumor-bearing nude mice
After treatment with 60 mmol/L gemcitabine for 24 h, the SUVmax values of 18 F-FDG imaging before and after gemcitabine administration were 0.67 ± 0.12 and 0.91 ± 0.18, respectively, which revealed an increase by (35.83 ± 10.58) %. In contrast, after treatment with 120 mmol/L gemcitabine, the SUVmax values of 18 F-FDG imaging before and after administration were 0.69 ± 0.04 and 0.61 ± 0.09, respectively, which exhibited a reduction by (12.37 ± 7.33) %. Similarly, in the 60 mmol/L gemcitabine group, the SUVmax values of 18 F-FLT imaging before and after administration were 0.66 ± 0.38 and 0.27 ± 0.11, respectively, which exhibited a decrease by (56.47 ± 10.83) % [Figure 1].
|Figure 1: The micro positron emission tomography images of tumor-bearing nude mice. No obvious decrease of SUV values of tumors in 18F-fluorodeoxyglucose (18F-FDG) imaging before (a) and after (b) 60 mmol/L gemcitabine treatments was observed, and SUV values of 18F-FDG imaging were 0.53 and 0.71, respectively. A decrease in 18F-FDG imaging before (c) and after (d) 120 mmol/L gemcitabine treatment was observed, and SUV values of 18F-FDG imaging were 0.67 and 0.55, respectively. An obvious decrease in 18F-fluorothymidine (18F-FLT) imaging before (e) and after (f) 60 mmol/L gemcitabine treatment was observed, and SUV values of 18F-FLT imaging were 1.10 and 0.38, respectively|
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Pathological and immunohistochemical results
After treatment with gemcitabine at the dose of 60 mmol/L, HE staining of tumor tissues showed obvious vasodilation, and invasion of lymphocytes and plasma cells [Figure 2]; meanwhile, the positive cells with GLUT-1 [Figure 3], Ki-67 [Figure 4] and PCNA [Figure 5] staining in tumor specimens without and with gemcitabine treatments were approximately (72.00 ± 8.34) %, (57.40 ± 13.18) % and (72.40 ± 5.03) %, and (10.40 ± 3.36) %, (6.40 ± 2.41) % and (9.00 ± 2.24) %, respectively, which revealed a statistically significant difference (P < 0.05). However, upon the treatment with gemcitabine at the dose of 120 mmol/L, HE staining of tumor specimens showed a wide range of tumor cell necrosis and decomposition; and immunohistochemical analysis showed no positive tumor cells. All of these results suggested that the gemcitabine could inhibit the expression of GLUT-1, Ki-67, and PCNA in tumor cells from tumor-bearing nude mice.
|Figure 2: H and E staining of tumor tissues (×400) from A549 cell-transplanted nude mice. (a) Before administration; (b) After 60 mmol/L treatment for 24 h, showed obvious vasodilation, and invasion of lymphocytes and plasma cells; (c) After 120 mmol/L gemcitabine treatment, showed a wide range of tumor cell necrosis and decomposition|
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|Figure 3: Glucose transporter protein 1 (GLUT-1) expression in tumor tissues (×400) from A549 cell transplanted nude mice. (a) Before administration, the positive cells with GLUT-1 staining showed brown on cell membranes; (b) After 60 mmol/L gemcitabine treatment, the positive cells visibly decreased; (c) After 120 mmol/L gemcitabine treatment, showed no positive tumor cells|
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|Figure 4: Ki-67 expression in tumor tissues (×400) from A549 cell transplanted nude mice. (a) Before administration, the positive cells with Ki-67 staining showed brown in the cell nucleus; (b) After 60 mmol/L gemcitabine treatment, the positive cells visibly decreased; (c) After 120 mmol/L gemcitabine treatment, showed no positive tumor cells|
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|Figure 5: Proliferating cell nuclear antigen (PCNA) expression in tumor tissues (×400) from A549 cell transplanted nude mice. (a) Before administration, the positive cells with PCNA staining showed brown in the cell nucleus; (b) After 60 mmol/L gemcitabine treatment, the positive cells visibly decreased; (c) After 120 mmol/L gemcitabine treatment, showed no positive tumor cells|
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| > Discussion|| |
Early assessment of treatment response in NSCLC by 18 F-FDG and 18 F-FLT PET has the potential to reduce the side effects and cost of ineffective therapy. One study has reported that the change in the uptake of 18 F-FDG after 2 days of gefitinib treatment could be useful to predict clinical therapeutic outcome in patients with lung adenocarcinoma. Totally four patients out of 20 have experienced an increase of Δ SUV ranging from 6% to 36% and two patients among them have been evaluated to have progressive metabolic diseases. Another study has reported that erlotinib-sensitive tumors reveal a striking and reproducible 18 F-FLT uptake after only 2 days of treatment, but 18 F-FDG PET-based imaging reveals no consistent reduction of glucose uptake in tumors.
In the present study, we investigated the effect of gemcitabine on the uptake of 18 F-FDG and 18 F-FLT in A549 cells and the animal tumor model. After treatment with various concentrations of gemcitabine, the uptake rates of 18 F-FLT and 18 F-FDG showed an obvious decrease, and the inhibitory rate of 18 F-FLT and 18 F-FDG uptake was positively correlated with the cell grow inhibitory rate evaluated by MTT assay. The uptake rate of 18 F-FLT was generally lower than that of 18 F-FDG, but treatment with 5 mmol/L gemcitabine for 24 h could result in an obvious decrease in the uptake rate of 18 F-FLT. The inhibitory rate of 18 F-FLT was up to (64.13 ± 5.50) %, which was higher than the inhibitory rate of 18 F-FDG.
After treatment with gemcitabine for 24 h, the inhibitory rates of A549 cell growth, and the inhibitory rates of 18 F-FLT and 18 F-FDG uptake were positively correlated with the concentrations of gemcitabine. However, imaging of tumor-bearing nude mice showed that the treatment with 60 mmol/L gemcitabine led to the increase in SUVmax value of 18 F-FDG imaging; in contrast, treatment with 120 mmol/L gemcitabine resulted in the decrease of SUVmax value of 18 F-FDG imaging. Meanwhile, treatment with 60 mmol/L gemcitabine could cause a decrease in SUVmax value of 18 F-FLT imaging. In the 60 mmol/L gemcitabine group, the total amount of gemcitabine injection in each nude mouse was 2.7 mg, which was slightly higher than the dose used for adult patients based on the injection unit of 1000 mg/m 2. After treatment with gemcitabine at the dose of 60 mmol/L, only a small amount of cells were GLUT-1, Ki-67 and PCNA positive as revealed by immunohistochemical analysis; while 120 mmol/L gemcitabine treatment resulted in a wide range of tumor cell necrosis and decomposition, as well as no positive tumor cells, which was confirmed by HE staining and immunohistochemical analysis. These results indicated that gemcitabine administration could inhibit the expression of GLUT-1, Ki-67 and PCNA in tumor xenograft, which was consistent with the change in SUVmax value of 18 F-FLT imaging. However, in the 60 mmol/L gemcitabine treatment group, HE staining showed obvious vasodilation, and the invasion of lymphocytes and plasma cells. Therefore, vasodilation and invasion of lymphocytes were the major reason for the increase in the SUVmax value of 18 F-FDG imaging in tumor. In contrast, little effect on the SUVmax value of 18 F-FLT imaging was observed, which suggested that 18 F-FDG imaging was affected by tumor microenvironment more significantly than 18 F-FLT imaging. As an indicator for cell proliferation,18 F-FLT imaging can overcome the shortages of pathological examination and traditional imaging methods. Moreover,18 F-FLT imaging can achieve the noninvasive and quantitative evaluation of tumor growth at the cellular and molecular levels, which plays an important role in the evaluation of treatment efficacy and the guidance for the clinical use of drugs.,
| > Conclusion|| |
18 F-fluorothymidine imaging can be used to assess the proliferation of tumor cells after the administration of gemcitabine, and 18 F-FDG imaging can reflect the changes of the tumor microenvironment.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]