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Table of Contents
Year : 2020  |  Volume : 63  |  Issue : 1  |  Page : 43-49

The role of genotype/phenotype at apurinic/apyrimidinic endonuclease Rs1130409 in renal cell carcinoma

1 Graduate Institute of Biomedical Sciences, China Medical University; Taichung Armed Forces General Hospital, Taichung; National Defense Medical Center, Taipei, Taiwan
2 Graduate Institute of Biomedical Sciences, China Medical University; Terry Fox Cancer Research Laboratory, Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
3 Department of Physiology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, Taiwan
4 Terry Fox Cancer Research Laboratory, Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
5 School of Pharmacy, China Medical University, Taichung, Taiwan
6 Graduate Institute of Biomedical Sciences, China Medical University; Terry Fox Cancer Research Laboratory, Translational Medicine Research Center, China Medical University Hospital; Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan

Date of Submission06-Oct-2019
Date of Acceptance19-Dec-2019
Date of Web Publication7-Feb-2020

Correspondence Address:
Dr. Chien-Chih Yu
School of Pharmacy, China Medical University, No.91, Hsueh-Shih Road, Taichung 404
Prof. Da-Tian Bau
Terry Fox Cancer Research Laboratory, Translational Medicine Research Center, China Medical University Hospital, 2 Yuh-Der Road, Taichung
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Source of Support: This study was supported by research grants from Taichung Armed Forces General Hospital (108A12) to Dr. Liao CH and Taiwan Ministry of Science and Technology (MOST-107-2320-B-040-028) to Dr. Liao JM., Conflict of Interest: None

DOI: 10.4103/CJP.CJP_72_19

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The DNA repair capacity plays a critical role in maintaining the genomic stability and gatekeeping for individual cancer risk. In this study, we aim at evaluation the role of the Asp148Glu (rs1130409) variant at apurinic/apyrimidinic endonuclease (APE) gene in renal cell carcinoma (RCC) risk and the contribution of different genotypes to its transcriptional mRNA levels. In the case–control study, 92 RCC patients and 580 cancer-free patients matched by age and gender were recruited. The apurinic/APE genotyping work was conducted with typical restriction fragment length polymorphism methodology after polymerase chain reaction. At the meanwhile, thirty renal tissue samples with variant genotypes were examined for their apurinic/APE mRNA and protein expressions by real-time quantitative reverse transcription method and Western blotting. The results showed that compared with the wild-type TT genotype, the people with TG and GG genotypes of apurinic/APE Asp148Glu had 0.88- and 1.09-fold risk of RCC, respectively. We have also examined the in vivo transcriptional (RNA) and translational (protein) levels with renal tissues of various apurinic/APE Asp148Glu genotypes, revealing that the apurinic/APE mRNA and protein were of similar levels among people of TT, TG, or GG genotypes. There was no joint gene-environment effect of apurinic/APE Asp148Glu genotype and smoking habit on RCC risk. The evidence indicated that apurinic/APE Asp148Glu genotypic variants did not alter its mRNA and protein expression among RCC patients. The genotype of apurinic/APE Asp148Glu may not serve as a proper predictive marker for RCC risk in Taiwan.

Keywords: Apurinic/apyrimidinic endonuclease, DNA repair, polymorphism, renal cell carcinoma

How to cite this article:
Liao CH, Chang WS, Liao JM, Wu HC, Shen TC, Yang JS, Tsai FJ, Tsai CW, Yu CC, Bau DT. The role of genotype/phenotype at apurinic/apyrimidinic endonuclease Rs1130409 in renal cell carcinoma. Chin J Physiol 2020;63:43-9

How to cite this URL:
Liao CH, Chang WS, Liao JM, Wu HC, Shen TC, Yang JS, Tsai FJ, Tsai CW, Yu CC, Bau DT. The role of genotype/phenotype at apurinic/apyrimidinic endonuclease Rs1130409 in renal cell carcinoma. Chin J Physiol [serial online] 2020 [cited 2021 Jul 28];63:43-9. Available from: https://www.cjphysiology.org/text.asp?2020/63/1/43/277953

Cheng-Hsi Liao, Wen-Shin Chang and Jiuan-Miaw Liao contributed to the study equally.

  Introduction Top

According to global statistic report, renal cell carcinoma (RCC) is the most common (>80%) kidney malignancy, and the frequency of which is keeping increasing in both male and female worldwide.[1] Taiwan is the second-highest prevalence country of end-stage renal disease in the world, following the first country Japan. According to the most updated national statistics, there were 908 male and 456 female of RCC new cases identified in 2016 in Taiwan.[2] RCC accounts for 3% of total tumors in Japan, while only 1.5% in Taiwan. Statistically, the incidence ranks of RCC in Taiwan are 15th in males and 18th in females, and mortality ranks of RCC in Taiwan are 14th in males and 16th in females.[2] Although the exact etiology of RCC has not been well identified yet, the epidemiological investigations have demonstrated that cigarette smoking, hypertension, obesity, occupational exposures, diet, and family history of cancer are associated with RCC.[3],[4],[5] However, very few people exposure to these risk environmental factors were reported to develop RCC during their lifetime, suggesting that genomic susceptibility may also play a role in the development of RCC.

The DNA repair capacity of human cell is vital to the integrity of its genome and thus to its normal functioning and that of the organism,[6] and subtle mutations or variations on those DNA repair genes are reported to be associated with cancer risks.[7],[8] Therefore, it is reasonable that the genetic variants on these DNA repair genes might be involved in the RCC initiation and development.

One of the DNA repair pathways is the DNA base excision repair (BER) pathway, which repairs the DNA damage induced by mainly oxidation and alkylation and thus protects cells against the cytotoxic effects from both endogenous and exogenous agents.[9],[10] The altered bases of purine or pyrimidine are recognized and excised by specific DNA glycosylases in the early repair stage, resulting in some basic sites. Then apurinic/apyrimidinic endonucleases (APEX1, also known as APE, APE1, APEX, HAP1 and Ref-1) incise the DNA 5' to the abasic sites; further, repair proceeds to short-patch (when the gap is only one nucleotide) or long-patch (when the gap is two or more nucleotides) subpathways of BER system.[11] The major human apurinic/APE plays a central role in the BER system, which initiates the repair of apurinic/apyrimidinic sites in altered DNA produced either spontaneously hydrolyzing the 5'-phosphodiester bone of the apurinic/apyrimidinic site or after enzymatic removal of damaged bases. To sum up, the repair activity of apurinic/APE serves to protect the cell from the apurinic/apyrimidinic sites that can accumulate in DNA via endogenous and exogenous sources. In addition to the well-known apurinic/APE activity, it also has the capacity of a 3'-phosphodiesterase.[12],[13] Moreover, apurinic/APE also functions as a reduction-oxidation activator of several transcription factors that are identified to be important in carcinogenesis, such as activator protein (Fos/Jun), hypoxia-inducible factor 1, cAMP-responsive element-binding protein, and p53.[14],[15] Deficiency in apurinic/APE induces embryonic lethality in knockout mice showed that and highlights the importance of its function to the genomic stability and cellular functions.[16],[17]

In literature, mounting evidence have shown that genetic variations in DNA repair genes have conferred predisposition to many types of cancer, and Hirata et al. have examined the association between some polymorphisms of DNA repair genes and the risk for RCC, such as XRCC1, XPC, ERCC1, XRCC3, and XRCC7.[18] However, no study had yet investigated the association between the polymorphisms of apurinic/APE, which is a central gene in BER machinery, and the risk of RCC. In recent year, a few epidemiological groups have investigated the association between the apurinic/APE polymorphism and the risk for several types of cancers, including bladder,[19],[20] lung,[21],[22],[23],[24],[25],[26],[27],[28] prostate,[29] and gastric cancer,[30] with not any conclusive findings whether apurinic/APE is associated with the cancer risk. For instance, there were several papers investigated the common polymorphic site apurinic/APE, Asp 148Glu (rs1130409) with the risk of lung cancer. Up to now, only one epidemiological study has reported a significant association between the apurinic/APE Asp 148Glu variant and lung cancer risk for the ever smokers in Japan[20] and the Ile 64 Val genotypes was associated with an altered risk for smokers in Norway,[26] whereas other studies have shown that there was no association at all[22],[23],[24],[25] or an inverse association with the risk of lung cancer.[31] The discrepancy of these previous studies might be due to differences in the levels of cigarette smoking consumption and other potential effect modifiers (such as the occupational exposures to lung carcinogens) that were not taken into consideration or accounted. Regarding the biological significance, although one study on the apurinic/APE Asp 148Glu polymorphism have shown that the Glu allelic carriers were of elevated mitotic delay after ionizing radiation,[32] while this variant had no influence on its protein level or its DNA binding affinities,[33] supporting the idea that Asp 148Glu polymorphism of apurinic/APE is unlikely to affect the DNA repair capacity of the apurinic/APE protein. In this study, we can assume that the apurinic/APE polymorphism at Asp 148Glu polymorphic site may also contribute to RCC risk. Thus, the present hospital-based matched case–control study is aiming at evaluating the relationship between polymorphisms of apurinic/APE and the risk for RCC in the high-prevalent Taiwan population. Among the identified single-nucleotide polymorphisms in the apurinic/APE gene, we selected the most commonly investigated polymorphic site of apurinic/APE in literature, the Asp 148Glu (rs1130409) polymorphic site, to evaluate the potential association of the apurinic/APE genetic polymorphism with RCC risk. Furthermore, we have examined the mRNA expression levels of various apurinic/APE genotypes in vivo by reversed transcript polymerase chain reaction (PCR). To the best of our knowledge, this is the first study to evaluate the association between the apurinic/APE Asp 148Glu polymorphism and RCC susceptibility.

  Materials and Methods Top

Study population

The current case–control study had recruited 92 RCC patients and 580 cancer-free controls matched by gender and age frequency. All the recruited RCC patients were diagnosed and histopathologically confirmed with RCC by Drs. Wu and Chang, without any record of prior history of other types of cancer. All the gender- and age-matched healthy controls were checked for their unrelated to any RCC patient and also should have no individual history of cancer. All the controls and cases are the citizens of Republic of China, whom visited our hospital in central Taiwan. Extra exclusion criteria for recruiting the controls were that they should not have symptoms suggestive of RCC, like that of hematuria. All the participants were queried about their age at onset of smoking, number of cigarettes smoked per day, number of smoking days per week, and age when they quit smoking. In the questionnaire, there was a series of records about the personal smoking habit for each participant. That is to say, all participants were subgrouped according to whether they had never smoked, formerly smoked, or currently smoked, and the former and current smokers were put together as ever smokers. In detail, former smokers were defined as those who had abstained from smoking for ≥1 year at the time of the study. Individuals who were currently smoking were labeled as current smokers. Assuming 20 cigarettes/pack, pack-years were estimated using the following formula: Cigarettes/day/20 × years smoked. Furthermore, there was a series of records about the personal alcohol consumption habit for each participant. Those who had consumed beer, wine, or distilled spirits more than 1 time/week for at least 6 months during his life were defined as alcohol drinkers. Each participant donated 3–5 ml venous blood after providing written informed consent. The study was approved by the Institutional Review Board of China Medical University (DMR98-IRB-209).

Genotyping protocol

The total genomic DNA extracted from the leukocytes of peripheral blood from each investigated participant with a small-scale QIAamp Blood Mini Kit (Blossom, Taipei, Taiwan) was collected and stored as previously published.[34],[35],[36] The primers used for apurinic/APE Asp 148Glu (rs1130409) were designed in our own laboratory, as we previously published.[27],[37] In detail, the sequences of paired (forward and reverse) primers for apurinic/APE Asp 148Glu genotyping were designed as 5'-CCAGCTGAACTTCAGGAGCT-3' and 5'-CTCGGCCTGCATTAGGTACA-3, respectively. The following cycling conditions were conducted: one start cycle at 94°C for 5 min; 35 cycles of 94°C for 30 s, 55°C for 30 s, and 72°C for 30 s and a final extension step at 72°C for 10 min. The PCR resultant products of 350 bp PCR of each well were mixed with 2 U Mnl I carefully after the PCR. In the digestion step, the G form PCR products could be further digested, while the T form could not. Two fragments 252 and 98 bp were present if the product was digestible G form. The reaction was incubated for 2 h at 37°C. Then, 10 μL of product was loaded into a 3% agarose gel for a 25 min electrophoresis under 100 Volt with ethidium bromide staining after the electrophoresis. For a conformation about the sequences of PCR-restriction fragment length polymorphism analyses, 5%–10% of the samples were direct sequenced, and the results were 100% fitted between the two systems.

Apurinic/apyrimidinic endonuclease mRNA expression pattern

To evaluate the correlation between the apurinic/APE mRNA expression and apurinic/APE genotype, 30 surgically accessed RCC tissue samples adjacent to tumors with the three genotypes at Asp 148Glu were subjected to extraction of the total RNA using Trizol Reagent (Invitrogen, Carlsbad, CA, USA). The quantitation of RNA was conducted by real-time quantitative reverse transcription-PCR (RT-PCR) using FTC-3000 real-time quantitative PCR instrument series (Funglyn Biotech Inc., Canada). In all the RNA analysis, GAPDH was used as the internal control. As for apurinic/APE mRNA, 5'-GCCCACTCAAAGTTTCTTAC-3' and 5'-TGTGCCACATTGAGGTCTCC-3' were used as the forward and reverse primers. As for the internal standard GAPDH, 5'-GAAATCCCATCACCATCTTCCAGG-3' and 5'-GAGCCCCAGCCTTCTCCATG-3' were used for forward and reverse primers. During the analysis procedure, the alteration of apurinic/APE mRNA was normalized by the levels of GAPDH expression and compared with each other. Each assay in RNA analysis was conducted for at least thrice.

Western blotting analysis of apurinic/apyrimidinic endonuclease expression level

The specimens were homogenized in RIPA lysis buffer (Upstate Inc., Lake Placid, NY, USA) with the guidance of the manuscripts from the producer; the homogenates were then centrifuged at 10,000 g for 30 min at 4°C, and discard the pellets. The supernatants were collected into a new eppendorf and each sample was denatured by heating at 95°C for 10 min, separated on a 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel, transferred to a nitrocellulose membrane (Bio-Rad) as we previously conducted.[38],[39] The successfully transferred membranes were blocked with 5% nonfat milk and incubated overnight at 4°C with anti-apurinic/APE antibody in a 1000-fold dilution (Santa Cruz Biotechnology), then with the corresponding horseradish peroxidase-conjugated goat antimouse IgG secondary antibody in 10,000-fold dilution (Chemicon, Temecula, CA, USA) for 2 h at room temperature. Finally, the specifically bound antibodies were visualized and taken pictures under the imaging system (Syngene, Cambridge, UK), after the staining of enhanced chemoluminescent solution kit (Amersham, Arlington Heights, IL, USA). The optical density of each specific band in the pictures was measured using a computer-assisted imaging analysis system (Gene Tools Match software; Syngene) as we published before.[40]

Statistical analyses

To ensure that the control group was in represent of the general population of Taiwan and to exclude the possible genotyping errors, the genotypic frequencies of apurinic/APE Asp 148Glu of the controls was evaluated via the goodness-of-fit test under the Hardy–Weinberg equilibrium. As for the potential association evaluation, the typical Pearson's Chi-square test or Fisher's exact test (when any cell in the subgroup was less than of five in its value) was adopted for comparing the distribution of the numbers of participants between any couple of subgroups or among three or more subgroups. The associations between the apurinic/APE polymorphisms and RCC risk were checked by figuring the odds ratios (ORs) and their 95% confidence intervals (CIs) via the typical unconditional logistic regression methodology with or without the adjustment for possible confounders as indicated in table footnotes. The transcriptional expression levels of apurinic/APE mRNA and translational expression levels of apurinic/APE protein were examined by unpaired Student's t-test between the groups. Any P value outcome <0.05 was recognized as statistically significant as usual.

  Results Top

Basal comparisons between the case and control groups

The basal characteristics of the control and case individuals are summarized and compared in [Table 1]. No difference between the case and control groups was found in the aspects of age, gender, smoking or alcohol drinking status, diabetes, or family history of cancer (P > 0.05). However, there was more hypertension syndrome in RCC cases than in the controls (66.3% vs. 52.1%), and the significance (P = 0.0130) suggested that hypertension may be one of the risky factors for RCC.
Table 1: Distributions of selected characteristics among renal cell carcinoma cases and controls

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Association of apurinic/apyrimidinic endonuclease genotypes with renal cell carcinoma risk

The distributions of the apurinic/APE Asp 148Glu polymorphic genotypes among RCC cases and controls in Taiwan are firstly figured out and presented in [Table 2]. The observed genotype frequencies of apurinic/APE Asp 148Glu in the controls fit the expected Hardy–Weinberg frequencies. The ORs after adjusting the confounding factors (age, gender, smoking, alcohol drinking, and hypertension status) for the people carrying TG and GG genotypes were 0.88 (95% CI = 0.54–1.36) and 1.09 (95% CI = 0.56–2.01), respectively, compared to those people with TT wild-type genotype. P value for the trend was not statistically significant (P = 0.5555). In the dominant (TG plus GG versus TT) or recessive (GG versus TT plus TG) analyzing models, the association between apurinic/APE Asp 148Glu polymorphism with the risk for RCC was not statistically significant either [Table 2]. To sum up, the above genotypic analysis indicated that individuals carrying the minor G allele at apurinic/APE Asp 148Glu may not have a relatively higher risk of RCC.
Table 2: Distributions of apurinic/apyrimidinic endonuclease genotypic frequencies and their association with risk of renal cell carcinoma

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Association of joint effect of the polymorphism of apurinic/apyrimidinic endonuclease genes stratified by smoking status

We found that apurinic/APE Asp 148Glu genotype was not associated with a higher risk of RCC [Table 3], suggesting that apurinic/APE Asp 148Glu genotype had no effect on adding the risk for RCC among smokers or nonsmokers.
Table 3: Association between apurinic/apyrimidinic endonuclease genotype and risk of renal cell carcinoma stratified by personal smoking habits

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Association of the apurinic/apyrimidinic endonuclease Asp 148Glu genotypes with its mRNA and protein expression levels

Of the thirty surgically excised nontumor renal tissue samples adjacent to tumors obtained from the RCC patients before any therapy, the frequencies of the TT, TG, and GG genotypes of the apurinic/APE Asp 148Glu were 13, 12, and 5, respectively. The potential correlations of the three genotypes at Asp 148Glu (TT, TG, and GG), on the transcriptional expression of mRNA levels, and/or translational expression of protein levels were measured and evaluated by real-time quantitative RT-PCR and Western blotting assay, respectively. The comparison results were summarized that there was no statistically difference about their mRNA or protein levels found among the samples from the TT, TG, or GG genotypes [Figure 1].
Figure 1: Analysis of apurinic/apyrimidinic endonuclease transcriptional and translational expression levels. (a) Quantitative reverse transcription-polymerase chain reaction for apurinic/apyrimidinic endonuclease from the renal tissue samples of the patients with TT, TG, and GG genotypes at apurinic/apyrimidinic endonuclease Asp148Glu was performed and GAPDH was used as an internal control in the assay. The relative alterations in folds were normalized by the levels of internal standard GAPDH, and each assay was conducted for at least thrice. (b) The Western blotting methodology was conducted with the renal tissue samples from the patients with TT, TG and GG genotypes at apurinic/apyrimidinic endonuclease Asp148Glu. The detail methods were written in the Materials and Methods and the final comparison methodology was similar to that of (a). Noticeably, the α-tubulin protein was used as an internal standard. Each assay was also conducted for at least thrice.

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  Discussion Top

In this study, the association of apurinic/APE genotype and RCC risk was worldwide firstly investigated in Taiwan, where the prevalence of end-stage renal disease was the second highest in the world (only after Japan). The apurinic/APE Asp 148Glu variants are the most common apurinic/APE alterations that result in single amino acid substitutions identified in the general population.[41] In previous literature, the association of apurinic/APE Asp 148Glu genotype in other types of cancer is very few and controversial. The reports of apurinic/APE Asp 148Glu genotype in lung cancer is most common, but the findings are conflicting.[20],[42],[43] However, there is no report investigating its association with RCC.

In the genotyping results, we found that individuals carrying TG or GG genotypes were not of higher risk of RCC compared with those carrying TT genotype on apurinic/APE Asp 148Glu polymorphic site [Table 1]. We have further investigated the correlation of apurinic/APE Asp 148Glu genotype on its transcriptional (mRNA) and translational (protein) expression levels. The results showed that the renal tissues from people of TT, TG, or GG apurinic/APE Asp 148Glu genotypes were of similar level of apurinic/APE mRNA and protein levels [Figure 1]. All the data collected from DNA, RNA, and protein levels may tell us the following stories. First, apurinic/APE indeed plays such a critical role in BER that the subtle polymorphism on apurinic/APE Asp 148Glu, which causes the amino acid substitution variants may lead to a decrease in the overall DNA repair capacity, was not found among RCC patients. Of course, further work aiming at revealing other potential polymorphic sites of apurinic/APE gene, such as the promoter-141T/G (rs1760944), is urgently warranted.[21] Second, as mentioned, we have provided evidence that the genetic variants of apurinic/APE Asp 148Glu may not cause a significant difference at the consequent RNA or protein levels [Figure 1]. Very possibly, the functional enzyme activity of apurinic/APE, measured as the overall BER capacity, will be found to be of different levels among people of apurinic/APE TT, GT, and GG Asp 148Glu genotypes.

The apurinic/APE gene consists of five exons and four introns with a 2.21-kb span. It is located at chromosome 14q11.2-q12 and encodes a 317 amino acid protein. It is the essential enzyme in the BER pathway, which is the primary mechanism for the repair of endogenous DNA damage resulting from cellular metabolisms, including those resulting from reactive oxygen species, methylation, deamination, and hydroxylation.[10] In addition to its role in DNA repair, apurinic/APE is also known as a transcriptional coactivator for numerous transcription factors such as AP-1, NF-kB, Myb, HIF-1a, HLF, PAX, and p53 that are involved in cancer promotion and progression by regulating the expression of their target downstream genes.[44]

We have also evaluated the joint effect of the polymorphism of apurinic/APE genes stratified by smoking status. We found that apurinic/APE Asp 148Glu genotype was not associated with a higher risk of RCC [Table 3], suggesting that apurinic/APE Asp 148Glu genotype had no effect on adding the risk of smokers or nonsmokers to RCC risk.

The present study has some limitations to be improved in the future. First, our sample size is small since it is really a rare disease, which may restrict the reliability and feasibility of stratification and interaction analyses. Second, the insufficient clinical and behavioral information, such as occupational exposure, daily diet, and physical exercise habits, limited our capacity of performing risky factor analysis. Finally, the small sample size of both mRNA and Western blot analysis, especially those tissues from people with the GG genotype on apurinic/APE Asp 148Glu, should be further validated in both tumor tissues and normal adjacent tissues in our future studies.

Although in this study, we did not find any significant association of apurinic/APE genotype, which is very critical in BER system, we could not ignore the contribution of apurinic/APE in the etiology of RCC. It is possible that some other polymorphic sites, such as the apurinic/APE promoter-141T/G (rs1760944) may related to an alteration in the expression level of mRNA, protein, and consequently its function, which lead to an increased risk of RCC. Furthermore, the personal habits of smoking and alcohol drinking, which may cause lots of oxidative damage related to BER, should be adaptively prohibited by all of the participants in our society. Only by doing so, the predictive, preventive, personalized, and participatory medicine and therapy are actionable and feasible.

  Conclusion Top

The present study has provided evidence at DNA, RNA, and protein levels of the central dogma of molecular biology, evaluating the contribution of functional apurinic/APE Asp 148Glu polymorphism to the RCC in Taiwan. The strategy and system are very promising and further functional studies are warranted to reveal the role of DNA repair genes, such as apurinic/APE, in RCC carcinogenesis.

Financial support and sponsorship

This study was supported by research grants from Taichung Armed Forces General Hospital (108A12) to Dr. Liao CH and Taiwan Ministry of Science and Technology (MOST-107-2320-B-040-028) to Dr. Liao JM.

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2], [Table 3]


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