Journal of Cancer Research and Clinical Oncology (2023) 149:8077–8086

https://doi.org/10.1007/s00432-023-04710-5

REVIEW

Molecular markers predicting the progression and prognosis

of human papillomavirus‑induced cervical lesions to cervical cancer
Fatema Alzahraa Samy Amin1 · Zeba Un Naher1 · P. Shaik Syed Ali1

Received: 21 February 2023 / Accepted: 17 March 2023 / Published online: 31 March 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023

Abstract
Introduction Persistent Human Papillomavirus (HPV) infection is linked to 99% of cervical cancer (CC) cases. HPV types
16 and 18 alone result in 75% of CC cases and thus are considered to be high-risk types (HR-HPV). CC is the third most
common cancer among women globally. Approximately, 7000 patients die from it yearly. It is worthy to note that not every
patient with HPV precancerous lesions will progress to CC.
Objectives The objectives of this review is to explore the utilization of molecular and viral biomarkers as a tool for early
detection and prediction of HPV-induced cervical lesions that might progress to CC.
Methods The data bases PubMed, Google Scholar, EBSCO were searched using keywords CC screening, HPV, and recent
molecular biomarkers. The search time frame was within the last 7 years. Studies on HPV-induced cancers other than CC
were excluded; a total of 200 eligible articles were retrieved.
Results In this review we explored the current literature about HPV virology, virulence genes and early diagnostic/prognostic
molecular biomarkers in CC. The oncogenic property of HPV is attributed to viral expression of various early proteins (E5,
E6, E7). The interaction between viral oncoproteins and the cellular genetic apparatus alters the expression of many genes
at different phases of the disease. There was an association between cervical lesions induced by HR-HPV and the overex-
pression of markers of oxidative DNA damage and other proteins. The markers ­p16INK4a, programmed cell death-1 (PD-1)/
programmed cell death ligand 1, mismatch repair enzymes (MMR), miRNA-377, claudin family (CLDN) are dysregulated
and are associated with high risk lesions. Furthermore, advanced older cervical lesions were associated with high methyla-
tion levels and higher risk to progress to CC.
Conclusion Adding different the above markers to the CC screening program scheme might offer a triage for prioritizing
patient management.

Keywords Human papilloma virus · Cervical cancer · Molecular markers · Screening · Prognosis

Introduction women (Seong et al. 2021). 75% of CC cases are caused by

Human papillomavirus (HPV) is a member of the papilloma-
viridae family, icosahedral small non-enveloped viruses with
double-stranded circular DNA (Albert and Laimins 2020).
HPV shows tropism for stratified squamous epithelium.
(Sharmin et al. 2021). In most cases, HPV infections regress,
unfortunately 10–15% of patients will have persistent infec-
tion and high-grade cervical lesions. High grade lesions have
a great potential to progress to CC in more than 99.7% of
* Fatema Alzahraa Samy Amin
fathema.alzahraa@mnu.edu.mv
1
School of Medicine, Maldives National University, Male’,
Maldives
HPV types 16 and 18 which has a pivotal role in carcinogen-
esis via the activation of its genomic products. The remain-
ing 10% are caused by other HPV types such as 31 and 45
(Sharmin et al. 2021). Worldwide, CC is the 4th among all
cancers and the third common one among women (Dong
et al. 2021). 3.2% of all new cancer cases and 7.5% of cancer
deaths in women in 2018 were due to CC (Bray et al. 2018).
Every year over 11,500 females are diagnosed with CC and
almost half of the patients are lost as a complication of CC
making it the fourth leading cause of cancer-related death in
women globally (Bray et al. 2018; Arbyn et al. 2019). Major-
ity of CCs occur in developing countries (Hasan et al. 2021).
Cervical cancer has other risk factors other than HPV infec-
tion which include, prolonged use of oral contraceptives,

13
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8078
cigarette smoking, multiple pregnancies, multiple sexual
partners, low socioeconomic status and immunocompro-
mised state (Sharmin et al. 2021).
HPV infections are eliminated by the immune system
and stay asymptomatic for the majority of patients. For
poorly understood reasons, other asymptomatic HPV
infections will progress to precancerous lesions and some
will result in CC. Theories that explain this progression
include factors such as genetics, immune system response,
lifestyle, viral load and differences in virus genomes (Dong
et al. 2021). Pap smear is the cornerstone of prevention
programs for early detection of HPV-associated cervical
dysplastic changes (Kumar et al. 2019). Since carcinogenic
HPV infection causes precancerous lesions and CC over
a long period of time, HPV screening has been able to
prevent CC to a great extent. As a screening technique,
cytology has limitations with 20–25% of false-negative
results. Inaccurate sampling technique or lack of experi-
enced readers attributes to a false-negative result (Chrys-
ostomou et al. 2018). Furthermore, one limitation of cytol-
ogy is under reporting of endocervical glands precursor
lesions (Kumar et al. 2019). This limitation should be
PRISMA flow chart.
13
Journal of Cancer Research and Clinical Oncology (2023) 149:8077–8086
taken into consideration owing to the rising number of
patients with glandular disease and adenocarcinomas in
some countries reaching up to 20–30% of cervical neo-
plasms. Additionally, delayed detection of endocervical
glands lesions results in delay in diagnosis, higher clini-
cal stage and thus poorer prognosis (Kumar et al. 2019).
Screening programs introduce HPV testing to screening
programs to improve screening for CC in many countries,
especially in women above the age of 30 (Chrysostomou
et al. 2018). The use of molecular markers offers another
way for more efficient cervical cancer screening.
We hope that this review will have the required back-
ground information to guide interested researchers to walk
this path to reduce the burden of CC
Materials and methods
Three databases (PubMed, Google Scholar, EBSCO) were
searched for articles covering CC screening, HPV, and
recent molecular biomarkers. The Search time frame was
within the last 7 years to get the most updated scientific
evidence HPV studies in relation to cancers other than CC
Journal of Cancer Research and Clinical Oncology (2023) 149:8077–8086
were excluded independently; a total of 200 eligible arti-
cles were retrieved by authors. In this review we explored
the current literature about HPV virology, virulence genes
and novel molecular biomarkers for early detection and of
prognostic value in case of cervical cancer.
1. HPV virology morphology and nature
In the USA, HPV is one of the two most common sexually
transmitted infections (Soheili et al. 2021). According to the
CDC, at least once in a lifetime, most sexually active persons
will contract HPV infection New HPV infections are com-
mon during adolescence and young adulthood. At any age,
having a new sex partner is a risk factor for acquiring a new
infection (Park et al. 2015; CDC 2021).
Although Papillomaviruses are associated with a range
of diseases, they all have a similar structure of icosahedral
small, nearly 60 nm, non-enveloped particles.
(a) HPV genome
The viral genome is composed of circular double-stranded
8000 base paired DNA which encodes for a great number
of proteins even more than the actual gene number. This
is aided by complex splicing and presence of diverse pro-
moters. (Doorbar et al. 2015) Based on their functional
role, the HPV genome can be grouped as three domains,
early(E), late (L) and non-coding part. The E region encodes
Fig. 1  HPV structure
8079
for proteins essential for viral replication (E1 to E7). The L
region encodes the proteins (L1—L2) needed for assembly
of viral capsomeres. 360 L1 proteins are arranged into 72
capsomeres with 5 L1 units for each capsomere (Fig. 1).
Variable number of L2 proteins will be embedded within
the surface of the virion exposing only its N-terminal amino
acids. The non-coding part, the long control region, has the
crucial elements for viral DNA replication and transcription
(Doorbar et al. 2015).
(b) HPV oncogenic process:
Efficient HPV infection runs integral to the normal keratino-
cyte differentiation process. Infection starts when HPV par-
ticles invade the basal epithelial layers. The viral double-
stranded DNA genome will replicate autonomously in an
extrachromosomal location in the nucleus of infected cells
(Albert and Laimins 2020), Then, the virus utilizes the cel-
lular replication system to synthesize its own DNA particles.
By the time the infected basal cuboidal cell are differentiated
to surface squamous cells, the cell will host more than 1000
copies of fully infectious virions assembled and ready to be
released (Albert and Laimins 2020).
(c) Role of the early genes in HPV oncogenesis
Early genes (E5, E6, E7) orchestrate the oncogenic property
of HPV. E5 protein induces evasion immune response and
13
8080
enhances cell autonomous proliferation. E6 protein binds to
p53 and induces its degradation. E7 protein forms complexes
with retinoblastoma protein causing its degradation through
the ubiquitin–proteasome pathway (Moody 2017). Keratino-
cytes in differentiated post-mitotic phase lack some essential
host cell factors integral for HPV replication; those factors
are usually expressed during synthesis phase (S) of the cell
cycle. The oncogenic property of E6 and E7 comes handy at
this stage. E7 will pull infected cells back to S phase while
still in a state of differentiation, E6 will inhibit cell cycle
arrest and apoptosis (Fig. 2).
Other players of HPV-induced cervical oncogenesis are
dependent on epigenetic viral/host cell interaction from his-
tone modification to DNA methylation (Moody 2017). This
is played by E6 and E7 as well, they disrupt the function
of the enzymes of epigenetic control, histone modification,
DNA methylation and chromatin remodeling. Furthermore,
HPV alters cellular pathways such as growth factor-mediated
receptor, Notch, RAS, and PI3K/Akt/mTOR (Doorbar et al.
2015).
(d) HPV‑associated cancers
Globally, HPV has been associated with 600,000 cancers
every year. HPV oncogenic potential was established in
the 1970s, when HPV particles were retrieved from CC
samples and genital warts (zur Hausen 1994). Following
Fig. 2  HPV genome
13
Journal of Cancer Research and Clinical Oncology (2023) 149:8077–8086
this observation, persistent infection with HPV has been
documented as a causative risk of male and female uro-
genital cancer and oropharyngeal cancer (Rai et al. 2016).
Out of the identified 200 HPV genotypes, 40 genotypes
can infect the genital tract and 13 are considered to be of
high risk in humans (Doorbar et al. 2015). Persistent HPV
infections by high-risk HPV types (16, 18, 31, 33, 35, 39,
45, 51, 52, and 58) are the reason for 99% of CC and other
cancers. 70% CC cases are attributed to HPV genotypes
with maximum oncogenic potential HPV 16 and 18 (Eck-
hardt et al. 2018).
(e) HPV Genotypes distribution
Distribution of HPV 16, 8 and non-16, 18 types are vari-
able in different parts of the world. In the USA, HPV16
is the predominant genotype followed by other genotypes
(Xia et al. 2021). In Asia, genotypes 16, 18, 52 and 58
show similar prevalence. In Korea, HPV 16 and 58 showed
almost equal frequency. A significantly higher progression
to high-grade dysplasia was noticed with HPV 58 (So et al.
2016). A high prevalence of HPV non-16,18 genotypes
is observed in the Middle East. In Kuwait and Yemen
HPV 31 is the most prevalent type followed by genotypes
39,39,45,52 and 58 (Al-Awadhi et al. 2011). Infection with
HP 35 was highly prevalent in young black patients and
Journal of Cancer Research and Clinical Oncology (2023) 149:8077–8086
was associated with a high rate of recurrence. Moreover,
infection with non-16, 18 HPV types had worse prognosis
in the same patients (Mendoza et al. 2021). Among races
Hispanic blacks have far higher incidence and mortality
rate when compared to non-Hispanic whites (Mendoza
et al. 2021).
2. HPV screening
Prevention of CC is done by two approaches: detection
of precursor lesions through cytology (exfoliative/liquid-
based) and HPV vaccination (Fig. 3). In 2012 to augment
the sensitivity of screening programs, testing of HPV
Fig. 3  Screening and diagnosis
of cervical cancer
Fig. 4  Concept summary
8081
was introduced in the USA to be repeated every 5 years
(Saslow et al. 2012) Cytology and HPV testing are two
elements of screening programs in countries with estab-
lished CC screening programs though they have difference
in recommended start age, screening interval and the pri-
mary screening method (Wang et al. 2022) (Fig. 4).
(a) Testing for high‑risk HPV
HR-HPV assays without genotyping might offer the benefit
of reducing the screening cost and benefiting low resourced
regions (Dong et al. 2021).
13
8082
On the other hand, HR-HPV genotyping assays can iden-
tify the specific HPV genotypes, facilitating the triaging of
women who have cytological abnormalities or HR-HPV
positivity (Bray et al. 2018).
HR-HPV genotyping proved to be an effective screen-
ing strategy for CC screening. It enabled earlier detection
of CIN2 compared to when it was not implemented as it
allowed direct and timely referral to colposcopy of patients
who are positive to HPV16/18 genotypes but normal cytol-
ogy (Dong et al. 2021).
(b) Advantages of HR‑HPV assays
HR-HPV assays are more sensitive with a negative predic-
tive value for screening HSIL when compared to cytol-
ogy; those assays offer more than 60% protection against
invasive CC in females older than 30 years (Ronco et al.
2014), Allowing self-sampling with high sensitivity com-
parable with professional sampling is another advantage
particularly for screening programs in remote areas which
does not have proper access to healthcare facilities (Torres
et al. 2018).
(c) Disadvantages of HR genotyping assays
The use of HR-HPV primary screening in women under
30 years of age is not advised, because of the high preva-
lence of HR-HPV infections in this age group resulting in
over diagnosis and it is likely those patients might not even
progress to CC (Weston et al. 2021). Furthermore, it might
increase the burden on the healthcare system by over refer-
ral colposcopy. Some might argue against this by stating
that those patients who are HPV 16,18 positive with normal
cytology will be more prone to have CIN3 when compared
with others who are infected with other types so this can be
a part of detection of CC (Weston et al. 2021). As any triage
strategy, a balance between the ability to accurately detect
high-grade lesions (CIN3 and CC) and not to overestimate
the burden of disease (avoid over referral without significant
cervical lesion) is needed (Weston et al. 2021). HSIL (CIN2
and CIN3) are treated widely and are not taken into consid-
eration that the majority of CIN2 might not progress to CC
and only up to 50% of CIN3 progress to invasive CC after a
long period of time (Hallowell et al. 2018).
3. Molecular markers to increase the specificity
of HPV screening/genes with high mutation rates
in CC/genes of prognostic Values in CC
New biomarkers may have a role in CC screening with cytol-
ogy and HPV testing to identify precancerous lesions that
have a strong potential to evolve into CC.
13
Journal of Cancer Research and Clinical Oncology (2023) 149:8077–8086
(a) ­p16INK4A
A tumor suppressor protein which blocks cell cycle pro-
gression through interaction with cyclin dependent kinases
4 and 6 (Lin et al. 2014). In CC, level of expression of
­p16INK4A was found to have a prognostic value. A negative
­p16INK4A profile was associated with poor prognosis and
worse overall survival compared to positive profile (Mata
et al. 2021). Additionally, ­p16INK4A was found to be useful in
differentiating cervical adenocarcinoma and cervical polyp.
(b) Programmed cell death‑1 (PD‑1)/programmed cell
death ligand 1 (PD‑L1)
The PD-1 and PD-L1 axis is one of the immune-checkpoint
pathways that have been associated with immune evasion.
High expression of PD-1 and PD-L1 might be triggered by
HPV E6 oncoprotein. The PD-1 and PD-L1 axis has shown
to have a therapeutic and prognostic role (Meng et al. 2018).
As a prognosis marker, its high expression is a predictor of
poor survival particularly in cervical adenocarcinoma (Meng
et al. 2018). From the therapeutic aspect, targeted immu-
notherapy can be a treatment option in patients with high
expression of PD-1, patients resistant to chemotherapy and
those with locally advanced disease (Meng et al. 2018). It
was noticed that using early immunotherapy is particularly
useful in black patients since studies demonstrated that they
exhibit a strong PD-L1 expression (Mendoza et al. 2021).
(c) ­p16INK4A and PD‑1
High expression PD-1, and PD-L1, was not significantly
different in relation to ­p16INK4A expression. This might be
explained by the fact that undifferentiated malignant cells
will not be able to express p­ 16INK4A any more (Ishikawa
et al. 2021).
(d) DNA methylation
DNA methylation is an epigenetic mechanism which
involves covalently binding a methyl group to a cytosine
molecule of CpG dinucleotides. Extensive methylation of
the promoter regions can result in cancer through inactiva-
tion of tumor suppressor genes (Moore et al. 2012). As cer-
vical lesions progress to become more aggressive in nature,
it shows an increase in DNA methylation levels. The older
the lesion the higher the methylation level (Kremer et al.
2021). HIV patients with high risk of progression to cervi-
cal cancer had the same observation. Moreover, methyla-
tion positivity was independent of histotype, clinical stage,
HPV status and genotype, sample type and geographical
region. Methylation targets which are currently explored
in CC include miR124-2, CADM1, MAL, PAX1, RAB3C,
Journal of Cancer Research and Clinical Oncology (2023) 149:8077–8086
GABRA2, ZNF257, and SLC5A8 (Kremer et al. 2021). The
possible use of FAM19A4/miR124-2 methylation as a tri-
age test additional or as a substitute to cytology is prom-
ising. It showed 77% sensitivity for CIN3 with an overall
specificity of more than 75%. (Vink et al. 2021; Zhu et al.
2019). Technically, detection of methylation status showed
a high reliability whatever is the method of sample collec-
tion (self, clinician collected). This makes it a strong candi-
date for facilitation of cervical screening in areas with less
established healthcare system as well as in middle- and low-
income countries (Bonde et al. 2020).
(e) PIK3CA, KRAS and EGFR
PIK3CA, KRAS and EGFR genes which encode for proteins
involved in signal transduction and cellular growth, were
noticed to have high mutation rates in CC. Non-synonymous
mutations in PIK3CA and EGFR functional domains may
lead to the production of nonfunctional proteins (Sharmin
et al. 2021). In CC, their mutation increases patient’s vul-
nerability to carcinogenesis and advanced metastatic dis-
ease. KRAS mutation was encountered more with patients
with adenocarcinoma of the cervix. Furthermore, survival
of patients with KRAS mutation is poor when compared to
patients without mutations. EGFR gene amplification was
associated with poor prognosis in patients with cervical
squamous cell carcinoma (Sharmin et al. 2021).
(f) Mismatch repair (MMR) or microsatellite instability (MSI)
Microsatellite instability is the consequence of dysfunc-
tional DNA mismatch repair enzymes such as (MLH1,
MSH2, MSH6, PMS2). Tumors with MSI are associated
with an exaggerated number of somatic mutations and
increased antigenic and immunogenic burden. Almost 30%
of patients samples with CC had MMR deficiency Addition-
ally, patients with MSI were noticed to have a significant
correlation with PD-L1 expression on tumor cells which
opened the door to immunotherapy as a possible approach
for treating those patients (Deshpande et al. 2020).
(g) MicroRNA (miRNAs) in CC
Aberrant expression of a large number of miRNAs is linked
to the onset and progression of cancers including CC.
miRNA exert its function through influencing the function of
an oncogene or a tumor suppressor gene. In CC, overexpres-
sion of miR-377, functioning as tumor suppressor, was found
to interfere with cellular proliferation and invasion (Wang
and Chen 2019). Decreased expression of miR-377 showed
strong correlation with metastatic disease and clinical stage
(Ye et al. 2019) Zinc finger E-box- binding homeobox 2
8083
(ZEB2) was confirmed as a direct target gene of miR-377 in
CC. Its overexpression in CC was inversely correlated with
miR-377 level, restoration of ZEB2 expression rescued sup-
pressive effects of miR-377 on CC proliferation and inva-
sion (Ye et al. 2019). Other cellular targets of miRNA in
CC include Wnt/β-catenin, Notch, and phosphoinositide-3
kinase miR-29 and miR-21 were found to be upregulated,
down regulated respectively. (Wang et al. 2022)
(h) The claudin (CLDN) family
The CLDN family is a group of tight junction proteins which
act as barricades for ions and as platforms of cellular sign-
aling pathways. In many cancers, aberrant expression of
the CLDN family can result in either enhanced or inhibited
neoplasm progression (Bhat et al. 2020). In CC, decreased
CLDN12 expression was associated with a decreased sur-
vival and poorer outcome when compared with high expres-
sion. (Rahman et al. 2021)
(i) Apolipoprotein B mRNA editing enzyme (APOBEC)
APOBEC is a family of deaminases which deaminate cyti-
dine to uridine in RNA and DNA. Many cellular processes
are controlled by the family members including viral restric-
tion in both retroviruses and DNA viruses such as HPV.
When overexpressed, it was noticed to be associated with
molecular alteration and genomic instability in cancer cells
(Rahman et al. 2021; Zou et al. 2017). In CC, HPV E6 and
E7 proteins induce a high expression of APOBEC3A and
APOBEC3B in cervical cells early in disease and during
the progression phase (Warren et al. 2017). APOBEC3A is
suggested to play a crucial role in HPV restriction (Warren
et al. 2017). A deletion mutation of APOBEC3A/3B was
noted to produce a catalytically inactive APOBEC3A which
was associated with reduced HPV restriction (Revathidevi
et al. 2021) doi:https://​doi.​org/​10.​1111/​cas.​13658.
(j) Candidate for future research
Using microarray analysis to identify frequently dysregu-
lated genes in a small sample of patients with CC unmasked
over 100 dysregulated genes. 75% of the dysregulated genes
were upregulated. Further enrichment analysis highlighted
eight genes (SPP1, TTK, MELK, FOXM1, LYN, ARRB2,
CCL21, and COL6A3) to be validated experimentally by
real time PCR. The relative expression of the identified
genes allowed to order them as the following: TTK > AR
RB2 > SPP1 > FOXM1 > LYN > MELK > CCL21 > COL6
A3. SPP1 and CCL21 are two identified genes coding for
secretory molecules and are promising candidates for future
studies on CC progression and targeted therapy (S. D. et al.
2021).
13
8084
• i) Secreted phosphor—protein 1/osteopontin (SPP1)
Osteopontin is a multifunctional protein which regu-
lates several cellular physiological functions. It has been
proven to be overexpressed in inflammation and several
types of cancers (Lund et al. 2009). Overexpression
of SPP1 was evident in every tested CC sample. Over-
expression was considered as a marker of invasion and
associated with a poor prognostic value. Expression of
SPP1 was evident in CC compared to benign cervical
lesions. Furthermore, population studies showed similar
findings (S. D. et al. 2021; Deepti et al. 2022).
• ii) CC chemokine ligand (CCL21) Involved T regula-
tory cell maturation and function, it is also a player in
peripheral tolerance. When overexpressed it facilitates
cancer cells migration and proliferation (Mo et al. 2015).
• iii) Tyrosine kinase and serine/threonine kinase
(TTK) A protein kinase which exhibits altered
expression in several cancers and is linked to cellular
proliferation and malignant transformation (Kaistha
et al. 2014).
• iv) Maternal embryonic leucine zipper kinase
(MELK) A serine/threonine-protein kinase which
takes part in regulation of the cell cycle. High
expression level was noticed in CC as well as ovar-
ian and hepatic cancers (Li et al. 2017).
• v) Collagen alpha-3 chain (COL6A3S) Struc-
tural protein involved in microfibril assembly and
with cell anchoring. It plays a role in creating a
tumor microenvironment. COL6A3 was signifi-
cantly upregulated in bladder cancer, gastric cancer
and colorectal cancer (Czogalla et al. 2020). In CC
it was noticed to be downregulated and this could be
attributed to the presence of mucous secreting glands
in cervical cervical epithelium (S. D. et al. 2021).
• vi) β-Arrestin 2 (ARRB2) A regulator of G protein
coupled receptors trafficking and desensitization. It is
speculated to have an important prognostic role in ovar-
ian cancers (Czogalla et al. 2020).
Conclusions
Contracting a HRHPVpersistent infection is a major risk
factor for CC. CC screening programs aim at identifying
patients with cervical lesions together with HR-HPV infec-
tion. Different panel cellular markers can be useful as a tri-
age of cytology and high-risk HPV patients with cervical
lesions who are at an alarming risk to develop CC. The study
of altered genes in CC can suggest molecular markers that
will improve the screening programs capacity to identify
high-risk cervical lesions and even categorize the patients
13
Journal of Cancer Research and Clinical Oncology (2023) 149:8077–8086
according to their prognosis so that adequate and aggressive
treatment options are directed towards patients with poorer
survival. It will also show the possibility of using specific
immunotherapy with those patients as a step towards preci-
sion medicine. Several gene markers ­(p16ink4a- DNA methyl-
ation—MicroRNA—CLDN—APOBEC—SPP1—CCL21)
have been identified to either ring the bell of danger of an
impending neoplastic progression or a prognosis that needs
attention, still not used extensively in clinical practice. Some
of the identified markers were proven to give reliable results
with self-sampling. Making such tests valuable for decreas-
ing CC burden in low- and middle-income countries will
help reduce the global CC burden and mortality.
Author contributions FASA—conception and design. ZN—data
acquisition and analysis. PSSA—draft revision. All authors read and
approved the final manuscript.
Funding The authors declare that no funds, Grants, or other support
were received during the preparation of this manuscript.
Data availability No data are available.
Declarations
Conflict of interests The authors have no relevant financial or non-
financial interests to disclose.
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