I wrote the introduction and i want to amend it and increase the reference in it up to 10 and write the preliminary suggestion and implications and write referances with harvard design , and i want the number of words to be 5000 words without references . These are the links to the references from which the introduction was written
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC68247…
https://nyaspubs.onlinelibrary.wiley.com/doi/abs/1…
file:///C:/Users/nidaj/Downloads/Molecular%20Oncology%20-%202022%20-%20Mainguen%20-%20Human%20papilloma%20virus%20integration%20sites%20and%20genomic%20signatures%20in%20head%20and%20neck.pdf
file:///C:/Users/nidaj/Downloads/ISTHER1.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC70625…
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC45929…
An attached file contains the most important points that must be followed in writing
The associations between Human papilloma Viruses among different
squamous cell carcinoma
Introduction
Squamous cell carcinoma (SCC) is the second most common skin malignancy after basal cell carcinoma
(BCC), and its prevalence is increasing in many countries (1). SCC affects every part of the skin and mucosa
with squamous epithelium, especially areas exposed to sunlight, such as the face, hands, and arms (2). Other
risk factors of this disease are light skin, aging, chronic ulcers, male gender, actinic keratosis as a precursor
of skin cancer, and a Human papillomavirus (HPV) infection .Human papillomaviruses (HPVs) are a group
of double-stranded Deoxyribonucleic acid (DNA)-viruses, which are responsible for one of the most
common sexually transmitted diseases. Most HPV infections are asymptomatic or subclinical. According
to epidemiological studies, the global prevalence of HPV is 11.7%. The socioeconomic burden HPV poses
due to its oncogenic effect makes the virus a popular topic in medicine. Along with Helicobacter pylori,
HPV is the most common cause of infection-related malignancies. Moreover, HPV is held responsible for
7–8% of all human malignancies. To date, >200 types of HPV have been identified, and about 40 of these
cause anogenital infections [3]. Unlike most viruses, HPVs are classified based on their DNA sequence
homology instead of their antigenic structure. Thus, they are categorized according to their genotypes
instead of their serotypes, and numbered in the order in which they are discovered [4]. On the other hand,
based on their oncogenic potential, HPVs are classified as high-risk HPVs (types 16,18, 26, 31,35, 39, 45,
48, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82) which are infamous for being the primary causes of carcinomas
and low-risk HPVs (types 6, 11, 40, 42, 43, 44, 54,61, 70, 72, and 81), which evoke lowgrade lesions such
as condyloma accuminata. High-risk HPVs exert their oncogenic effect via the E6 and E7 oncoproteins.
The disruption of the E2 protein during the replication of the virus inactivates the inhibitory effects of the
virus on the E6 and E7 oncoproteins. Subsequently, the degradation of the tumor-suppressor p53 protein
by E6 and the degradation of the RB1 protein of the tumor suppressor retinoblastoma gene by E7 disrupt
cell cycle control and causes a deficiency in DNA repair, leading to genomic instability and increasing the
risk of malignant transformation.Given the tropism of HPV for squamous epithelium, squamous cell
carcinoma is the most common type of cancer related to HPV. The relationship between HPV and squamous
cell carcinomas of the anogenital region has been defined clearly. An HPV infection is the underlying cause
in 96% of cervical cancers, 36% of penile cancers, and 64% of anal cancers [8]. High-risk types of HPV
cause cervical, anogenital, and oropharyngeal cancers, whereas cutaneous types are mainly related to
benign and malignan.HPV18, 16, and 56, the common types of high risk mucosal HPV, have been
frequently found in non-melanoma skin cancers (4, 7-9). Although the main cause of nonmelanoma skin
cancer is exposure to UV radiation, cutaneous HPV can also contribute to carcinogenesis with UV radiation
. On the other hand, despite the close anatomical relationship between the bladder and the anogenital
region.There is a significant relationship between Urothelial Carcinoma of the Bladder and HPV infection
and this association is particularly between high-risk HPV genotypes, whereas there was no association
between tumor grade and HPV infection. More than 90% of head and neck cancers are squamous cell
carcinomas (HNSCC), predominantly affecting the oropharynx, but also the oral cavity, hypopharynx and
larynx. HNSCC is the seventh most common cancer worldwide [1]. HNSCC main risk factors are alcohol
and tobacco use and human papillomavirus (HPV) infection. The overall HPV prevalence in HNSCC is
26% and reaches up to 80–90% for oropharyngeal squamous cell carcinomas (OSCC) [6]. A recent review
highlighted that the incidence of HPV-related HNSCC cancers increased in the last decades regardless of
age group [7]. The causal link between high-risk human papillomavirus (hr-HPV) infection and esophageal
squamous cell carcinoma (ESCC) . The association between HPV and esophageal squamous cell carcinoma
(ESCC) remains controversial, as is the true prevalence of HPV infection in ESCC. The wide range in
reported rates reflects variability in the primary literature, with some larger scale case–control studies
suggesting the infection rates range from 0% to 78%. Interactions between HPV and the Barrett’s
metaplasia–dysplasia–carcinoma sequence have been explored, and these studies have shown some
conflicting data. Overall, systematic reviews have reported the prevalence of HPV-positive DNA in
esophageal adenocarcinoma patients of between 13% and 35%.
Cervical cancer is by far the most common HPV-related disease (Burd 2003). Nearly all cases of cervical
cancer are due to chronic HPV infection (Harro et al 2001). Cervical cancer is the fourth most common
cancer in women worldwide and it accounts for an estimated 570,000 new cases with about 85% occurring
in the less developed regions. In 2018, an estimated 311,000 deaths were attributed to cervical cancer,
accounting for 7.5% of all female cancer deaths with almost 90% these deaths occurring in the less
developed regions (Bray et al 2018, GLOBOCAN 2012). In these developing countries, cervical cancer
may constitute up to 25% of all female cancer deaths (Jin et al 1999) and is only preceded by breast cancer
. Several epidemiologic studies have clearly shown that the risk of contracting genital
high-risk HPV infection and cervical cancer is influenced by sexual activity (Erickson et al 2013, ACOG
2017). An individual is at increased risk of having HPV infection if he or she has had multiple sexual
partners at any time or if he or she has a partner who has had multiple sexual partners. Having sexual
activity at an early age as well as having a history of other sexually transmitted infections, genital warts, or
cervical or penile cancer in an individual or sexual partner may also increase the risk of becoming infected
with HPV. In addition to sexual activity, age is an important determinant of the risk of HPV infection
(Adam et al 2000, Burk et al 1996). The infection is most common among sexually active young women
between the age of 18 and 30 years with a sharp decline in prevalence after the age of 30 years. Although,
cervical cancer is more common in older women of 35 years and above, thus suggesting that the infection
occurs at a younger age with a slow progression to cancer at an older age. Persistence of HPV infection is
commoner with the high-risk or oncogenic types and this plays an important role in the development of
invasive cancer of the cervix (Burd 2003). Cervical cancer arises at the transformation zone, which is the
region between the squamous epithelium of the ectocervix and the columnar epithelium of the endocervix,
where continuous metaplastic changes occur. The period of greatest metaplastic activity coincides with the
greatest risk of HPV infection and this occurs at puberty and the first pregnancy and subsequently declines
slowly after the occurrence of menopause.In the past three to four decades, the natural history of cervical
cancer has been well studied, and persistent infection of the cervix with certain types of HPV has been
reported as a necessary causative factor for its occurrence (Walboomers et al 1999). The link between HPV
and cervical squamous cell carcinoma has become well established since the early 80s. The magnitude of
the association between HPV and squamous cell carcinoma of the cervix is higher than that for the
association between smoking and lung cancer (Franco 1995). About 30 HPV types that are transmitted
through sexual contact and infect primarily the cervix, vagina, vulva, penis, and anus have been identified.
One or more of these HPV types has been implicated in 99.7% of cases of squamous cell carcinoma of the
cervix (Walboomers et al 1999). HPV is a family of closely related viruses with each designated as a type
based on their nucleic acid sequencing and then numbered in the order of discovery. Adenocarcinomas of
the cervix are also less commonly related to HPV infection and are age dependent (Andersson et al 2001).
Almost 90% of adenocarcinoma of the cervix in women younger than 40 years of age are related to HPV
infection, whereas it was observed in only 43% of adenocarcinomas in those aged 60 years and older. Most
HPV-induced cervical changes are transient with 90% regressing spontaneously within 12 to 36 months
(Chua et al 1996, Ho et al 1998, Moscicki et al 1993, Ostor 1993, Syrjänen 1996). However, various other
factors such as the individual’s genetic predisposition i.e. polymorphic genes of the major
histocompatibility complex, as well as a particular polymorphism in the p53 gene involved in the clearance
and maintenance of HPV infection (de Araujo Souza et al 2003), genetic variation within different HPV
type, coinfection with more than one type of HPV, frequency of reinfection, hormone levels, and immune
response may alter an individual’s ability to clear the infection. Therefore, the detection of high-risk HPV
is necessary but may not be enough for the development of cervical cancer. Whether a woman will develop
cervical cancer depends on several factors that act in conjunction with oncogenic HPV types in a process
that leads to cervical cancer. These factors or modifiers of HPV activities include
Suppressed primary immune response:
Immune response to HPV infection is cell-mediated and thus conditions that impair cellmediated responses
such as renal transplantation or HIV disease increase the risk of acquisition and progression of HPV [Calore
et al 2001, Cubie et al 2000, Torrisi et al 2000). Studies have consistently shown a higher prevalence of
HPV infection and cervical cancer precursors in HIV infected women (Conely et al 2002, Harris et al 2005,
Singh et al 2009).
Long-term use of oral contraceptives:
This is a significant risk factor for high-grade cervical disease according to some studies (Adam et 2000,
Brisson et al 1994). This is because the upstream regulatory region of highrisk HPV contains sequences
which are similar to the responsive elements of glucocorticoid that can be induced by steroid hormones
such as progesterone which is the active componen of oral contraceptives and dexamethasone.
Cigarette smoking:
The suppression of local immune response induced by smoking and the mutagenic activity of tobacco
components have been demonstrated in cervical cells and this may contribute to HPV persistence or to
malignant changes in the cervix (Philips et al 1993, Villa 1996, Yang et al 1996). It appears that smoking
is the most important risk factor independent of HPV infection for high-grade cervical disease (Adam et al
2000). Smoking shows little or no relationship to low-grade cervical disease (Burd 2003).
Increasing parity:
Having an increasing number of full-term pregnancies is a significant independent risk factor for persistent
HPV infection and cervical cancer (Shields et al 2004, Juneja et al 2003). The possible mechanisms
proposed for this are the increased hormone levels and impaired immune response of pregnancies (Appleby
2006). In multiparous women, the transformation zone remains longer on the ectocervix and this facilitates
its direct exposure to the virus and other potential cofactors (Autier 1996). However, the most plausible
mechanism is the local tissue damage occurring during vaginal childbirth or cellular oxidative stress with
the increased likelihood of DNA damage and HPV integration (Castle 2004, Williams 2011). Several
studies and meta-analyses have assessed the relationship between HPV infection and the different type of
squamous cell carcinoma but the topic still remains highly controversial. The ongoing debates on this topic
arise from the variable clinical presentations of HPV and the methodological shortcomings of the previous
studies. These shortcomings may be summarized as follows: the limited number of patients in published
studies, the lack of studies on fresh samples, and the shortage of case-control studies .Sp the aim of this
study is to prove the relationship of the HPV infection with the different type of squamous cell carcinoma
in various regions of the body with high rates and find out the link between different grads of cancer and
nucleoular organizing region .
Objective
1- To demonstrate associations between Human papilloma Viruses among different squamous cell
carcinoma.
2- To find out the associations between different grads of cancer and nucleoular organizing region
Department of Clinical laboratory Sciences
MSc Applied Cytology Techniques
Dear student
Your research proposal is an important part of your MSc project. We do not
expect the proposal to be perfect at this stage, nor do we expect you to stick to it
rigidly, as your ideas will certainly change once you start your project. However,
we do expect it to show convincing evidence of your ability to plan and organise
independent research. Please read and follow the guidelines carefully.
Your proposal should be plagiarism-free and adhere to Taif University policy
and academic integrity.
Your proposal should be at least 5000 words long, excluding bibliography, using
the following sections:
Introduction
Literature review
Objectives
Study design and methods
Preliminary suppositions and implications
Time plan Budget
bibliography
Your proposal should follow the following format
Font Size: 12
Titles Font Size: 16 Bold
Font Type: Times New Roman
Line Spacing 1.5
Text Margins: Justified
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‘ &%%%%%
‘%$#”!
,%%%%+
0) /.#-“!
! ‘)(“!
Kingdom of Saudi Arabia
Ministry of Education
Taif University
College of {Name}
Department of {Name}
{Title of The proposal}
By
{Name of Student}
A proposal submitted in partial fulfillment of the requirements
for the Master Degree of
Supervisor
Co-supervisor (if any)
Prof. Dr. ……………………
Prof. Dr. ……………………
Professor of {Specialism} Professor of {Specialism} {Department},
{College}
{Department}, {College} Taif University
Taif
University
1443-2022
INTRODUCTION (Research problem/ research questions/ rationale)
1.
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Literature Review
2.
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Objective
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3.
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DESIGN AND METHODS:
4.1 Study design
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4.
4.2 Sample and population (types/ size/ sampling/ collection/ inclusion and exclusion
criteria)
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4.3. Techniques / instruments
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4.4. Data collection and analysis:
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4.5 . Ethical consideration
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5 Preliminary suppositions and implications
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6 Time plan
Gantt chart for the project’s time plan
Duration Year/Months
Task
2022
Jan
Prepare a proposal
Registration
Collection sample
Prepare kits & reagent
Start practical
Collection of data
Statistical analysis
Write the result
Finishing the research
2023
Feb
Mar-June
July- Aug
Sep-
Jan-
Dec
Apr
May
June
July
AugDec
7 Budget
Item
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Quantity
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Price
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TOTAL
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Bibliography (Harvard style)
• Books
• Articles in Journals
• Websites
• Other Resources
• Personal Communication
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Formatting
Title Page
Citation
Outline
