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Predictive value of the monocyte-to-lymphocyte
ratio in the diagnosis of prostate cancer
Zhanping Xu, MS
a
, Jing Zhang, MS
b
, Yuxiang Zhong, BS
a
, Yuan Mai, BS
a
, Danxuan Huang, MS
c
,
Wei Wei, MS
a
, Jianhua Huang, MS
a
, Pengpeng Zhao, MS
a
, Fuxiang Lin, MS
a
, Jingmiao Jin, MD
a,∗
Abstract
It has been reported that inflammation and immune system are related to prostate cancer. The neutrophil-to-lymphocyte ratio (NLR),
as well as the platelet-to-lymphocyte ratio (PLR), have already been proposed as new indices to help diagnose prostate cancer (PCa).
However, the monocyte-to-lymphocyte ratio (MLR) with regard to PCa has rarely been mentioned.
To investigate the capability of the MLR to predict PCa.
Patients who were pathologically diagnosed with PCa in our hospital and healthy control subjects who conformed to the inclusion
criteria were enrolled. Patient data were recorded, including age, complete blood counts, blood biochemistry, and serum prostate-
specific antigen (PSA) levels. The differences in these data between the groups were analyzed and the diagnostic value of the MLR
was compared with PSA.
Our study included a total of 100 patients with PCa and 103 healthy control subjects. Patients with PCa presented with a
significantly higher NLR, MLR, and PLR compared to control subjects. However, the hemoglobin and lymphocyte levels were lower
(P<.05) in PCa patients. The area under the curve (AUC) of PSA and ratio of free/total serum prostate-specific antigen were 0.899
(95% confidence interval [CI]: 0.857–0.942) and 0.872 (95% CI: 0.818–0.926), respectively, while the AUC of the MLR was 0.852
(95% CI: 0.798–0.906), which was higher than that of the NLR, PLR, and any other blood parameters. Additionally, the optimal cut-off
value of the MLR for PCa was 0.264, with a specificity of 87.4% and a sensitivity of 72.0%. An evaluation of the diagnostic value of
MLR + PSA gave an AUC of 0.936 (95% CI: 0.902–0.970). However, the AUC of MLR + PSA + f/tPSA was 0.996 (95% CI: 0.991–
1.000). The diagnostic value of MLR + NLR + PSA gave an AUC of 0.945 (95% CI: 0.913–0.977), and the specificity is 0.971.
PSA remains the most important diagnostic indicator. MLR combined with PSA and f/tPSA has the higher predictive value than
PSA. It suggests that MLR may be another good predictive indicator of PCa. It can help reduce the clinical false positive rate.
Abbreviations: AUC =area under the curve, CI =confidence interval, GS =Gleason scores, MLR =monocyte-to-lymphocyte
ratio, NLR =neutrophil-to-lymphocyte ratio, PLR =platelet-to-lymphocyte ratio, PSA =prostate-specific antigen, R(f/tPSA) =ratio of
free/total serum prostate-specific antigen, TAMs =tumor-associated macrophages.
Keywords: monocyte-to-lymphocyte ratio, predictive value, prostate cancer
1. Introduction
Prostate cancer (PCa) is the most frequent malignancy affecting
American men, and it is also one of the most common causes of
death.
[1]
In the meantime, the morbidity due to PCa has been
rapidly increasing in Chinese men over the past decade.
[2]
Although many studies have presented different insights about
PCa, the exact underlying mechanism of its development still
remains to be explained.
[3–5]
Tumor cells can develop a variety of
immunosuppressive mechanisms, and tumor immune escape or
immune suppression are important parts of tumorigenesis and
development.
[6]
Tumor-associated inflammation and the microen-
vironment are knownto be key factors for neoplasia, proliferation,
and metastasis.
[7,8]
Systemic inflammatory responses have been
reported to be involved in PCa progression.
[9]
Some clues can be
found from thesepast reports, and among them,inflammation is an
important trigger factor. It has been recognized that inflammation
increases the risk of PCa, similar to some other cancers.
[10,11]
A
lot of oxidative materials are released by inflammatory cells that
may cause cellular and gene damage, ultimately leading to gene
mutations and PCa. These findings have been confirmed by
epidemiologic and molecular biology studies.
[12–15]
Prostate-specific antigen (PSA) is currently the dominant
diagnostic biomarker for this cancer today.
[16]
If a significant
increase in serum PSA is detected, a prostate biopsy should be
Editor: Xiaodong Li.
No funding was received to support this research.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are
available from the corresponding author on reasonable request.
a
Department of Urology, Foshan Hospital of Traditional Chinese Medicine,
Foshan, Guangdong, PR China,
b
Department of Gynecology, Family Planning
Research Institute of Guangdong Province, Guangzhou, Guangdong, PR China,
c
Health Management Center, Foshan Hospital of Traditional Chinese Medicine,
Foshan, Guangdong, PR China.
∗
Correspondence: Jingmiao Jin, Department of Urology, Foshan Hospital of
Traditional Chinese Medicine, Foshan, Guangdong, PR China
(e-mail: 1105884611@qq.com).
Copyright ©2021 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is
permissible to download, share, remix, transform, and buildup the work provided
it is properly cited. The work cannot be used commercially without permission
from the journal.
How to cite this article: Xu Z, Zhang J, Zhong Y, Mai Y, Huang D, Wei W, Huang
J, Zhao P, Lin F, Jin J. Predictive value of the monocyte-to-lymphocyte ratio in
the diagnosis of prostate cancer. Medicine 2021;100:38(e27244).
Received: 2 May 2020 / Received in final form: 25 August 2021 / Accepted: 25
August 2021
http://dx.doi.org/10.1097/MD.0000000000027244
Observational Study Medicine®
OPEN
1
performed. A biopsy is the only available method for establishing
a diagnosis of PCa, and they are usually performed if an elevated
PSA or abnormalities on a digital rectal examination are
found.
[10]
However, owing to its inherent limitations, PSA is
not PCa specific, yet it is prostate-specific.
[17]
Besides PCa, acute
prostatitis and benign prostate hyperplasia can also lead to an
elevated PSA level. Researchers have found that PSA has only a
25% positive predictive value for PCa.
[18]
Due to this low
specificity, numerous unnecessary biopsies are currently being
performed.
The neutrophil-to-lymphocyte ratio (NLR) has been previously
recommended as a biomarker not only in inflammatory diseases,
but also in a number of different cancers.
[19–25]
One study
showed that NLR may function as a biomarker to predict
prostate cancer in men undergoing prostate needle biopsy.
[26]
Another study suggested that increased NLR could predict poor
prognosis in patients with PCa.
[27]
Monocyte-to-lymphocyte ratio (MLR) is the absolute mono-
cyte count divided by the absolute lymphocyte count and has
been demonstrated to be a novel hematological and inflammatory
parameter. Monocytes are able to suppress lymphocyte activa-
tion and enhance tumor progression.
[28]
While an elevated
monocyte count may promote tumorigenesis and angiogenesis
through local immune suppression and stimulation of tumor
neovasculogenesis.
[29]
On the other hand, lymphocytes have an
important role in the immune responses against cancer both in the
circulation and in the tumor microenvironment, for example, via
T-cell mediated cellular cytotoxicity.
[30]
A low lymphocyte count
might result in a weak, insufficient immunologic reaction to a
tumor.
[31]
A high MLR, as a simple biomarker of host immune
system, has been suggested to be related to poor prognosis in
various cancers.
[32]
So far, no studies have been found to pay
attention to the role of MLR in the prediction of prostate
cancer. This study aimed to evaluate the predictive value of the
MLR in PCa.
2. Patients and methods
2.1. Patient characteristics
One hundred patients diagnosed with PCa by prostate biopsy in
the Department of Urology, Foshan Hospital of Traditional
Chinese Medicine, from February 1, 2018, to December 31,
2019, were enrolled in our study as the PCa group. Biopsy was
performed within 4 weeks after the blood tests. One hundred
three healthy control subjects were recruited as the control (C)
group. Those subjects with symptomatic prostatitis, an active
infection, hypertension, liver failure, renal failure, diabetes
mellitus, rheumatic disease, or malignancy were excluded. Our
research was approved by the ethics committee office of the
Foshan Hospital of Chinese Medicine (2018-136).
2.2. Laboratory and clinical assessments
The following information was recorded: age, complete blood
counts, white blood cell counts, hemoglobin, neutrophils,
lymphocytes, monocytes, platelets, creatinine, alanine amino-
transferase, aspartate aminotransferase, PSA, and its f/t ratio (f/
tPSA) from all of the subjects, and the Gleason score of the
patients with PCa. Complete blood counts and biochemistry
indicators were obtained simultaneously with PSA. The NLR,
MLR, and platelet-to-lymphocyte ratio (PLR) were also deter-
mined.
2.3. Statistical analysis
SPSS 13.0 was used for data analysis. Normally distributed
parameters data were analyzed by Student’sttest, and for non-
normally distributed data, we used the Wilcoxon rank sum test.
Continuous variables are presented as the mean ±standard
deviation. Categorical variables are expressed as numbers (n) and
percentages (%). Qualitative variables were compared with chi-
square tests. Specificity and sensitivity were summarized by
receiver operating characteristic curves. Ultimately, we used
Pearson’s correlation to analyze the associations of different data.
P<.05 was considered significant.
3. Results
3.1. Basic characteristics of all of the subjects
Table 1 presents the main characteristics of the patients with PCa
and the healthy control subjects. There were no significant
differences between the two groupsin terms of age, white blood cell
counts, platelets, aspartate aminotransferase, alanine aminotrans-
ferase, or creatinine between the two groups (100 PCa patients and
103 healthy subjects). Monocytes were slightly higher in patients
with PCa than in the healthysubjects (P<.05), but the f/tPSA ratio,
hemoglobin, and lymphocytes of the patients with PCa were
significantly lower than those of the healthy subjects (P<.001).
The NLR, MLR, and PLR values were 1.81±0.68, 0.21±0.08,
and 108.61±34.12 for the control subjects, which were
significantly lower than those in the patients with PCa (3.76±
2.50, 0.39±0.22, and 182.70 ±108.02, respectively; P<.001). In
the patients with PCa, PSA (17.71±23.51) and neutrophils (4.48
±1.96) were significantly higher than those in the healthy subjects
(4.32±1.87 and 3.66±1.23, respectively; P<.001), and the mean
Gleason score of the PCa group was 7.73±1.07.
3.2. MLR has high diagnostic value for PCa following PSA
We researched the diagnostic value ofthese mentioned parameters
for PCa by receiver operating characteristic and compared them
Table 1
Basic features of the patients with PCa and controls.
Parameters Control (n =103) Patients (n =100) P
Age (yrs) 73.94 ±6.90 74.59 ±8.10 .540
WBCs (10
9
/L) 6.49 ±1.80 6.74 ±2.11 .371
Neutrophils (10
9
/L) 3.66 ±1.23 4.48 ±1.96 <.001
Lymphocytes (10
9
/L) 2.23 ±1.26 1.39 ±0.52 <.001
Monocytes (10
9
/L) 0.42±0.16 0.48 ±0.20 .019
Platelets (10
9
/L) 218.74 ±55.90 218.95 ±64.27 .98
Hemoglobin (g/dL) 144.34 ±13.36 119.29 ±22.24 <.001
NLR 1.81 ±0.68 3.76 ±2.50 <.001
PLR 108.61 ±34.12 182.70±108.02 <.001
MLR 0.21 ±0.08 0.39 ±0.22 <.001
AST (U/L) 19.69 ±6.72 21.09 ±6.60 .136
ALT (U/L) 19.52 ±4.85 20.59 ±5.56 .147
CREA (mmol/L) 77.48 ±10.81 76.65±10.69 .584
PSA (ng/mL) 4.32 ±1.87 17.71 ±23.51 <.001
f/t PSA ratio 0.37 ±0.09 0.20 ±0.12 <.001
Gleason score 7.73 ±1.07
ALT =alanine aminotransferase, AST=aspartate aminotransferase, CREA =creatinine, MLR =
monocyte-to-lymphocyte ratio, NLR =neutrophil-to-lymphocyte ratio, PLR =platelet-to-lymp hocyte
ratio, PSA =prostate- specific antigen, R(f/tPSA) =ratio(free/total prostate-specific antigen), WBCs =
white blood cell counts.
Xu et al. Medicine (2021) 100:38 Medicine
2
with PSA. The results revealed that the area under the curves
(AUCs) of these parameters were as follows: neutrophils, 0.626
(95% confidence interval [CI]: 0.548–0.704); monocytes, 0.596
(95% CI: 0.517–0.675); platelets, 0.518 (95% CI: 0.438–0.599);
lymphocytes, 0.822 (95% CI: 0.765–0.878); MLR, 0.852 (95%
CI: 0.798–0.906); NLR, 0.831 (95% CI: 0.773–0.888); PLR,
0.764 (95% CI:0.699–0.829); PSA, 0.899 (95% CI: 0.857–0.942);
and ratio of free/total serum prostate-specific antigen (R(f/tPSA)),
0.872 (95% CI: 0.818–0.926). Except for PSA and R(f/tPSA), the
MLR had the highest AUC value among the parameters.
Additionally, the optimal cut-off value of the MLR for PCa was
0.264, and the specificity and sensitivity were 87.4% and 72.0%,
respectively (Fig. 1 and Table 2). An evaluation of the diagnostic
value of MLR combined with PSA (MLR+ PSA) gave an AUC of
0.936 (95% CI: 0.902–0.970). However, when MLR combined
with PSA and f/tPSA (MLR+PSA+ f/tPSA), AUC ascended to
0.996 (95% CI: 0.991–1.000). An evaluation of the diagnostic
value of MLR+NLR+ PSA gave an AUC of 0.945 (95% CI:
0.913–0.977), and the specificity is 0.971.
3.3. Correlations among the variables
The NLR, MLR, and PLR were weakly positively correlated with
PSA (r=0.223, P=.001; r=0.196, P=.005; r=0.201, P=.004;
respectively). Lymphocytes showed a weak negative correlation
with PSA (r=0.169, P=.016), and it was weakly positively
correlated with R(f/tPSA) (r=0.162, P=.021). Neutrophils,
NLR, MLR, and PLR were all weakly negatively correlated with
R(f/tPSA) (r=0.173, P=.013; r=0.303, P<.001; r=
0.288, P<.001; r=0.282, P<.001, respectively). The Gleason
score had a moderately positive correlation with PSA and was
weakly positively correlated with f/tPSA (r=0.514, P<.001; r=
0.318, P=.001, respectively) (Table 3).
4. Discussion
This study estimated the diagnostic value of the NLR, MLR, and
PLR in patients with PCa, which in prior studies have been
reported as cost-effective and non-invasive markers of many
inflammatory or infectious diseases. In addition, we compared
the predictive value of the NLR, MLR, and PLR with PSA and f/
tPSA. In our study, PSA remains the most important diagnostic
marker for PCa, with the highest diagnostic value. The Gleason
score was positively correlated with PSA. Interestingly, patients
with PCa had higher NLR, MLR, and PLR values. Except for
PSA and f/tPSA, the diagnostic value of the MLR was higher than
that of the NLR, PLR, and any other parameters. The NLR,
MLR, PLR were weakly positively associated with PSA, and they
Table 2
ROC curves were used to assess the diagnostic value of different blood parameters for PCa.
Parameters AUC 95% CI POptimal cut-off value Specificity Sensitivity
PSA 0.899 0.857–0.942 <.001 7.505 0.951 0.70
R(f/tPSA) 0.872 0.818–0.926 <.001 0.202 0.961 0.72
MLR 0.852 0.798–0.906 <.001 0.264 0.874 0.72
NLR 0.831 0.773–0.888 <.001 2.429 0.883 0.73
Lymphocytes 0.822 0.765–0.878 <.001 1.625 0.806 0.72
PLR 0.764 0.699–0.829 <.001 142.72 0.864 0.56
Neutrophils 0.626 0.548–0.704 .002 4.285 0.796 0.46
Monocytes 0.596 0.517–0.675 .018 0.505 0.825 0.37
Age 0.536 0.457–0.616 .371 84.5 0.981 0.12
Platelets 0.518 0.483–0.599 .652 244.5 0.738 0.39
95% CI=95%confidence interval; AUC =the area under the curve; MLR =monocyte-to-lymphocyte ratio; NLR =neutrophil-to-lymphocyte ratio; PCa =prostate cancer; PLR =platelet-to-lymphocyte ratio;
PSA =prostate-specific antigen; R(f/tPSA) =ratio(free/total prostate-specific antigen); ROC =receiver operating c haracteristic.
Figure 1. ROC curves were used to evaluate the diagnostic value of different blood parameters for PCa. (A) Diagnostic value of age, neutrophils, monocytes,
platelets, MLR, NLR, PLR, and PSA; (B) diagnostic value of lymphocytes and R(f/tPSA). MLR=monocyte-to-lymphocyte ratio; NLR =neutrophil-to-lymphocyte
ratio; PCa =prostate cancer; PLR =platelet-to-lymphocyte ratio; PSA =prostate-specific antigen; ROC =receiver operating characteristic.
Xu et al. Medicine (2021) 100:38 www.md-journal.com
3
were all negatively correlated with f/tPSA. Additionally, we found
that lymphocytes were negatively correlated with PSA. According
to these findings, we drew the conclusion that MLR maybe a
good auxiliary indicator for the diagnosis of PCa.
With the development of molecular biology, immunology,
biochemistry, ultrasound diagnostics, and radiography, as well as
MRI diagnosis, great progress has been made in the management
of PCa. Early diagnosis of PCa is of great value because it
increases the probability of a complete clinical cure being
achieved. In recent years, a lot of evidence has shown that
inflammation plays a potential role in tumorigenesis and
progression.
[5]
Researchers have also recognized the association
between inflammation and PCa.
[33]
Some researchers have shown
that the longer the duration of prostatitis symptoms, the higher is
the risk of PCa.
[4]
Some prospective studies have reported that
chronic inflammation and infection of the prostate, as well as
sexual transmitted diseases, may lead to men being much more
susceptible to PCa.
Recently, nonsteroidal anti-inflammatory medicines were
recommended to reduce the risk of PCa, which further indicates
that there is a very important relationship between inflammation
and PCa.
[34,35]
Excitingly, some inflammation-related biomark-
ers were found to be useful during early diagnosis of PCa, for
example, serum interleukin-7 (IL-7) levels and C-reactive protein,
among others.
[36,37]
However, since they lack satisfactory
specificity and sensitivity, none of the newly reported markers
can completely replace PSA.
Nowadays, PSA is still the most important serum indicator for
the diagnosis of PCa.
[16]
Our study also confirm this opinion. As is
well known, PSA has its disadvantages, since it is a prostate-specific
antigen but is not PCa specific. Acute prostatitis and benign
prostate hyperplasia can often raiseserum PSA, which increases the
diagnostic complexity of PCa when using a screening method of
PSA alone.
[38,39]
In addition, its overuse leads to numerous
unnecessary biopsies and related complications. Excitingly, we
found that the combination of PSA+ MLR + NLR has the highest
specificity (0.971) in diagnosing PCa in our study. The combina-
tion of the three indicators has not been reported in the current
study. The combination of PSA + MLR+ NLR may make up for the
shortcomings of PSA. It may help to reduce unnecessary clinical
biopsy. However, this has not been fully confirmed clinically. The
confirmation of this clinical advantage requires further study. We
hope that more similar research to be reported.
At present, the leukocyte subpopulation test is the most
common way to detect inflammation.
[40]
Yet, recent reports have
revealed that the MLR, NLR, and PLR could be more suitable for
detecting inflammation than leukocyte subpopulations. These
tests are simple, cost-effective, and useful indicators of
inflammation.
[41–44]
Although changing physiological conditions
can alter the absolute value of each test, the influence on the
MLR, NLR, and PLR is slight.
[45]
In our study, the results showed that for patients with PCa, the
NLR, MLR, and PLR were all significantly higher than those in
healthy subjects. Except for PSA and f/tPSA, the AUCs of these
three parameters (MLR, NLR, and PLR) showed the highest
diagnostic value for PCa, especially the MLR, with the highest
AUC among them. It has been proven that the NLR in peripheral
blood is a potential marker to predict PCa,
[26]
and some reports
found that the PLR can be an important assistant predictor of
PCa,
[46]
A few immune disease reports showed the diagnose
values of MLR, revealed that it might reflect systemic inflamma-
tion and the severity of immune injury.
[47,48]
In this research,
except for PSA with the highest diagnostic value, a valuable
finding is that the MLR has a superior predictive value for PCa
than the NLR and PLR.
The exact reason why the MLR increases in patients with PCa
remains unclear and needs further research. Our study showed
that most patients with PCa had higher serum monocytes and
lower serum lymphocytes. Some studies have shown that the
MLR is an important indicator of advanced disease-stages, which
refers to immune regulation as well as immune escape.
Monocytes and lymphocytes are two critical components of
natural and acquired immunity, and thus, the MLR shows the
condition of disease-related immunity progression.
[47]
In addi-
tion, circulating monocytes, which are often supposed to
differentiate into tumor-associated macrophages (TAMs), play
a key role in the tumor microenvironment. A large amount of
serum monocytes may accelerate the production of TAMs within
the tumor microenvironment and further promote tumor growth,
angiogenesis, and metastasis. Conversely, lymphocytes can
suppress tumor cell proliferation and migration.
[49,50]
Therefore,
the observed increase in monocytes and decrease in lymphocytes
may accelerate the progression of immunity damage, which
reflects the severity of the disease.
In some previous research, the monocyte proportion of the
peripheral blood was correlated with the Gleason score (GS),
[51]
and they found that the monocyte proportion was significantly
increased in patients with high Gleason PCa, but the exact
mechanism needs further research. None of our 100 patients with
PCa had metastatic disease. These 100 pathological findings
included a signet ring cell carcinoma of the prostate, the GS of the
remaining 99 patients with PCa is available: 1 (1%) GS5, 10
(10%) GS6, 30 (30%) GS7, 39 (39%) GS8, 12 (12%) GS9, and 7
(7%) GS10. However, in our research, there were no significant
correlations to be found between these blood inflammatory
parameters and the GS.
In vitro studies showed that monocytes induce PCa cell
invasion and mediate NF-kB and chemokine ligand 2 activity.
[52]
TAMs may interact with PCa cells to facilitate the disease
progression by releasing different chemokines and cytokines.
[53]
Numerous studies of prostate biopsy specimens have shown that
there is a lot of TAM infiltration around the PCa cells. It was
Table 3
Correlations among the variables.
Neutrophils Lymphocytes Monocytes Platelets NLR MLR PLR Gleason score
rP r P rPrPr P r P r P r P
PSA 0.071 .315 0.169 .016 0.048 .498 0.098 .165 0.223 .001 0.196 .005 0.201 .004 0.514 <.001
R(f/tPSA) 0.173 .013 0.162 .021 0.084 .235 0.080 .256 0.303 <.001 0.288 <.001 0.282 <0.001 0.318 .001
Gleason score 0.042 .679 0.192 .057 0.072 .477 0.040 .691 0.121 .234 0.136 .181 0.091 .369 1
MLR =monocyte-to-lymphocyte ratio; NLR =neutrophil-to-lymphocyte ratio; PLR =platelet-to-lymphocyte ratio; PSA =prostate-specific antigen; R(f/tPSA) =ratio(free/total prostate-specific antigen).
Xu et al. Medicine (2021) 100:38 Medicine
4
previously reported that TAM infiltration in biopsy specimens
was an important sign of PCa progression.
[54]
Several limitations exist in our study that should be pointed
out. First, this was a retrospective single-centre study, and it
enrolled a relatively small cohort of patients. Second, we have not
researched the pathogenesis behind the elevated NLR, MLR, and
PLR. Third, the peripheral MLR is a biomarker that indicates an
inflammatory condition, which is not specific to PCa. Conse-
quently, multi-centre investigations and molecular biology
studies are urgently needed in the future.
In conclusion, the MLR, which can easily be evaluated, may be
a good auxiliary indicator for PCa. Though this needs further
study and proof. Men with an increased PSA and MLR should be
recommended for prostate biopsy.
Acknowledgments
We thank all patients and healthy control subjects enrolled in this
study.
Author contributions
Data curation: Zhanping Xu, Jing Zhang, Yuxiang Zhong,
Danxuan Huang.
Formal analysis: Zhanping Xu, Jing Zhang, Jianhua Huang,
Fuxiang Lin.
Investigation: Zhanping Xu, Danxuan Huang, Jingmiao Jin.
Methodology: Zhanping Xu, Wei Wei, Fuxiang Lin.
Project administration: Yuan Mai.
Software: Wei Wei, Jianhua Huang.
Supervision: Pengpeng Zhao.
Writing –original draft: Jingmiao Jin.
Writing –review & editing: Jingmiao Jin.
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