Use of HPV Vaccines for Cervical Cancer Prevention

Use of HPV Vaccines for Cervical Cancer Prevention HPV Vaccines: Will They Prevent Cervical cancer Introduction Human papilloma viruses (HPV) belong to the papillomaviridae family, they are double stranded DNA viruses. HPV is the most common sexually transmitted infection (STI) in the world (Urman et al. 2008). HPV is strongly associated with cervical cancer; more than 99% what are the other causes/factors please of cervical cancer cases are positive for HPV DNA and indeed, cervical cancer is the second most common malignancy in the world (Wang et al. 2007). In developed countries the incidence of cervical cancer has been reduced significantly by the introduction of a cervical screening programme. In developing countries where 83% of mortalities due to cervical cancer occur, there are no such programmes (Parkin et al. 2006). Can the introduction of a vaccine against HPV further reduce globally the incidence of cervical cancer? Many diseases caused by viruses are controlled in the developed world by ongoing successful vaccination programmes; Polio, Measles, Mumps and Rubella are a few examples. Smallpox caused by Variola virus was eradicated in 1979 through a successful worldwide vaccination programme. The factors that affect the Polio and MMR vaccine programmes success and those that affected the successful smallpox programme may also be contributory to the success of the HPV vaccination program. Vaccination of HPV is complex and multi factorial. This investigation studies a number of factors including: Vaccine efficacy Vaccine Cost/affordability/practicality of administration Production and Distribution Government backing and financial commitment Other support organisations such as the WHO, UNICEF, Gates Foundation, Social factors Media effects Public awareness Safety, and perceived fears Currently two prophylactic vaccines against HPV types 16 and 18, the most prevalent causes of HPV have been approved by the food and drug administration (FDA). Many developed countries have already introduced vaccination programmes using one of these vaccines. Can the vaccines and programme prevent cervical cancer? In order to effectively understand the implication of such a vaccination programme we must first fully examine the causative agent (HPV) and the consequential potential diseases including the biology, history and prevalence. Human Papillomavirus Approximately 200 types of HPV are identified of which around 40 infect the genital tract (McCance 2004). The majority of HPV types cause no symptoms, some types can cause warts and a minority may lead to cancer. Genital HPVs are transmitted via sexual contact, mainly intercourse, with an infected individual, and the risk of developing an HPV infection generally increases with the number of sexual partners, the sexual history of that partner or the introduction of a new sexual partner. Studies have shown that at least one type of HPV infection occurs soon after sexual debut, with around 30% of women infected with at least one high risk type within two years (Winer et al 2003; Winer et al 2008). HPVs are classified as either high risk or low risk, on the basis of association with cervical cancer. There are 15 types classified as high risk and three as probable high risk. High risk types include 16,18,31,33,35,39,,45,51,52,56,58,59,68,73,probable high risk types include 26,53,66 Low risk types include 6,11,40,42,43,54,61,70,72,81 and CP6108. More than 99% of cervical cancers are associated with HPV, of these 70% are associated with HPV type 16 and 18, with HPV 16 causing 50% and HPV 18 causing more than 15% in Europe (Smith et al..2007). HPV 16 is thus the single, most common high risk HPV. Interestingly HPV types 16 and 18 also cause 80% of anal cancer and 30% of vaginal and why the difference in % oper area research needed here.vulvar cancer and are associated with cancers of the, oropharynx and some rare cancers of the head and neck. (add reference form cervical cancer burden worldwide paper) The majority of HPV infections are asymptomatic, self limiting, and transient, with 70% of new HPV high risk type infections cleared within one year (with the median duration of an infection at 8 months) and 90% within two years (Ho et al 1998). The transient infection usually causes no clinical problems. A small proportion of high risk type infections persist due to host immune evasion, an evasion that results not only from restriction of HPVs to sites that are relatively inaccessible to host defences but also due to several mechanisms of preventing immune response what are these mechanisms please (a sk Dick if this is what he means . This persistence is the most important factor in the development of pre cancerous and cancerous lesions. The time span between infection by HPV and the development of pre cancerous lesions or cervical carcinoma varies from one to ten years (Moscicki et al 2006) and up to 20 years from other sources. HPV show little evidence of dramatic adaptability with phylogenic studies suggesting that the biology of HPVs has remained the same for over 200,000 years (Halpren et al 2000). While HPVs show historically the influence of point mutations, inserts, deletions and duplications, the predominant pattern of mutation within a given type is point mutation, with large scale rearrangements within the most conserved genes of HPVs such as L1 being rare (Myers et al 1996). Intra patient variation within HPV types is uncommon due to their low mutation rate. This low mutation rate is directly linked to the HPV replication strategy that requires host cell machinery, which has stringent proof reading mechanisms that avoid the incorporation of errors, conferring slow mutagenesis. All HPVs exhibit extreme specificity for infection of epithelial cells and do not infect or express their gene products in the underlying dermis. Although the mechanism of infection is not fully understood, the HPV epitheliotrophy resides for the most part in the interaction of specific transcription factors with the viral regulatory region known as the long control region (LCR). Infection with HPV can result in hyperproliferation of the host cell, and with certain high risk HPV types it may lead to transformation and immortalization. This is because high risk HPVs express two or more protein products (E6, E7 and E5) that transiently disrupt the cell cycle and stimulate cell division, knocking out at the same time the cellular mechanisms for growth inhibition. For a productive infection, HPVs require terminally differentiated cells. This HPV biology feature has impeded studies on the full reproduction life cycle because of the lack of highly efficient models of epithelial terminal di fferentiation in vitro. Most of the different stages in the HPV life cycle have been established using genetic engineering and molecular biology strategies. The dsDNA of HPV exists in a non enveloped icosahedral shaped virion 52-55 nm in diameter. The dsDNA genome is circularised and around 8000base pairs in length (Fig1). The genome encodes eight proteins, six early E1, E2, E4, E5, E6, E7, and two late structural proteins L1 and L2 and the previously mentioned noncoding LCR. Fig 1 HPV type 16 Genome structure, gene and functional domain location http://www.dnachip-link.com/Eng/library/HPV.aspusg 15/11/20009 Fig 1 shows the dsDNA genome of HPV type 16, and the location of the early and late genes along with the LCR that contains the origin of replication. An initial infection requires the access of infectious particles to the basal layer of the epithelium. Some HPVs require a break in the stratified epithelium to achieve this. Such breaks are not necessarily obvious and may occur under conditions where the skin is exposed to water or abraded, or subjected to an environment where micro traumas may occur such as possibly in aswiming pool or ect (must put an example)(in fig 2 shows as a cut). Following infection and uncoating it is thought that the virus maintains its genome as an episome in low copy numbers within basal cells of the epithelium. Although the pattern of gene expression in these cells is not well understood, it is generally thought that viral proteins E1 and E2 are expressed to maintain the viral DNA episome (Wilson et al.2002) and possibly to facilitate the segregation of genomes during cell division (You et all.2004). It is not known whether viral transformation proteins E6 and E7 are also expressed in the basal layer, but it does appear that initial infection is followed by a proliferative phase that results in the increase in the number of basal cells harbouring viral episomes. In normal uninfected epithelium, basal cells leave the cell cycle soon after migration into the superbasal cell layers where they undergo a process of terminal differentiation. During infection E6 and E7 are expressed in these cells stopping normal differentiation (Sherman et all.1997). E6 and E7 are believed to work together to achieve this and in lesions caused by high risk HPV types. During a natural infection the ability of E7 to stimulate S-phase progression is limited to a subset of differentiated cells with low levels of p21/p27, or which express high enough levels of E7 to overcome the block in S-phase entry. The viral E6 protein is thought to prevent apoptosis in response to unscheduled S-phase entry brought on by E7. The association of E6 with p53 and the inactivation of p53 mediated growth suppression and apoptosis is well documented, E6 may also associate with other pro-apoptotic proteins including bak (Thomas and Banks,1998) and bax (Li and Dou,2000). E6 is thus considered a predisposing factor in the development of HPV associated cancers, allowing the accumulation of chance errors in host DNA to go unchecked. Furthermore the E6 protein of high risk HPVs can stimulate cell proliferation independently of E7 via a c-terminal PDZ ligand binding domain. E6 PDZ is enough to mediate superbasal cell proliferation and may contribute to the formation of metastatic tumours by disrupting normal cell adhesion (Nguyen et al.2003) Amplification of the viral genome and the ability to package these genomes into infectious particles is essential for the production of infectious virions. For most HPV types this occurs in the mid or upper epithelial layers following an increase in activity of the late promoter. The late promoter gene is located within the E7 open reading frame, and the upregulation of the late promoter is thought to lead to increased expression of proteins involved in viral DNA replication, without directly affecting the expression of E6 or E7 necessary for S-phase entry. The amplification of the viral genome begins in a subset of cells in the proliferative compartment and requires the expression of all viral early gene products, these include E4 and E5 whose role in replication is not yet clearly understood. Binding of E2 to the HPV upstream regulator region is essential for viral DNA replication that is dependent on the differentiated state of epithelial cells. E2 recruits the E1 DNA helicase to the viral origin of replication. Throughout the virus life cycle, the relative levels of viral proteins are controlled by promoter usage and by differential splice site selection, with an increase in E1 and E2 allowing an increase in viral copy numbers in the upper epithelial layers. Current models suggest that a small increase in promoter activation during differentiation may lead to an increase in the level of E1 and E2 and a subsequent increase in genome copy number. The newly replicated genome could then serve as a further template for expression of E1 and E2, facilitating the amplification of viral genome and in turn further expression of E1 and E2 replication proteins. Viral DNA remains latent (not integrated) in basal cells of benign lesions. Replication occurs in the differentiating cells where capsid proteins and viral particles are found. Viral DNA is integrated in cancer cells, which contain no replicating virus. Once viral genome replication is completed, the expression of two virally encoded structural proteins, expressed in the upper layers of infected epithelia may occur. L1 the major capsid protein is expressed after L2 in a sub set of cells that express E4 (fig 2), this allows the assembly of infectious particles in the upper layers of the epithelium (Florin et al.,2002). A successful infection requires the virus to escape from the infected skin cell and survive extracellularly prior to re-infection. HPVs are non-lytic and are as such not released until the infected cells reach the epithelial surface. The intracellular retention of HPV antigen until the cell reaches the uppermost epithelial layers may contribute the compromised immune detection, especially as the virus has molecular mechanisms that limit the presentation of viral epitopes to the immune system in the lower epithelial layers (Ashrafi et al 2002). What are these mechanisms Figure 2 Papillomavirus type 16 Life Cycle and gene expression location within epithelium Taken from, The papillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Figure 2 diagrammatic representation of the skin with HPV type 16 gene expression incorporated, colour of arrows are representative of genes expressed within epithelial cells. The frequent detection of high risk HPV DNA in cervical lesions in the absence of any obvious disease, may be explained by the presence of the virus in a latent state, with only very few cells able to support the productive virus life cycle during epithelial cell differentiation. Following immune regression, HPV DNA is thought to remain in the basal epithelial cells waiting to be reactivated once levels of immune surveillance decline there are conflicting opinions (Zhang et al.1999). If regression is not achieved lesions may persist and in some instances progress to cancer. The number of lesion that progress to cancer is very low when compared to the prevalence of high risk HPV infection in the general public. The Progression of productive lesion to high grade lesions may result from the deregulation ( what happen to allow thes proteins to be deregulated intergrattion loss of E2 adn p53 association, be specific add biochemistry here please. in the expression of transforming proteins E6 and E7. The inability of a cell to support the whole virus life cycle is often associated with the development of cancerous lesions. The transformation zone (Fig 3) is particularly susceptible to cervical cancer; it appears that high risk types of HPV such as type 16 cannot complete their life cycle at this site Progression from CIN3 to cancer usually occurs in lesions that contain integrated copies of the viral genome in which E7 expression is elevated. Suggesting that retention of E6 and E7genes and the loss of E2 and E4 genes (that exert negative effect on cell growth) usually accompanies the development of invasive cancer. (reference) Remember for CIN refer to in that section or here but Cin must be corrulated with what causes the cancer and with whats happening with the virus that causes the change in CIN or the causes in CIN to occur. Cervical cancerisa considerable contributor to morbidity and mortality. Being the second most common cancer worldwide and the twelfth most common cancer in women in the UK. Cervical cancer in 2002 was the cause of 274,000 deaths worldwide (the most current data available)REF THIS FIGURE and continues to causes more than 1000 deaths in the UK each year. There are two main types of cervical cancer squamous cell cancer (the most common) and adenocarcinoma, although they are often mixed. They are named after the types of cell that become cancerous through neoplasia. Squamous cells are flat cells covering the cervix; adenomatous cells are found in the passageway from the cervix to the womb. Other rarer cancers of the cervix include small cell cancer. Deaths from cervical cancer in the UK have fallen over the last 20 years mainly because of the NHS cervical screening programme that reduced the mortality rates by 62% between 1987-2006. Screening may detect changes in the cells of the cervix at a pre-cancerous stage. Fig 3 TITTLE Showing location of transformation zone. Cell samples are examined for abnormalities, these abnormality are described in a standard format covering cytology and/or histology. What are these standard format CIN 1 CIN2 CIN3 LISL LGSIL HSIL HGSIL USE FIG 4 and explain whats happening with the proteins expressed and genome intergration where CIN number progression is concerned please. MUST DO From Lowy Schiller, J Clin Invest, 116:1167-73, 2006 Low grade squamous intraepithelial lesion (LSIL or LGSIL) indicates possiblecone biopsy, or laser ablation. High grade squamous intraepithelial lesion (HSIL or HGSIL) indicates moderate or severeCIN 2 or CIN3 (fig 3). While cervical screening has reduced the mortality significantly in the developed world cervical cancer is still a significant burden worldwide. Fig 4 Taken from, The popillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Fig. 5. CIN 1 resembles productive infections caused by other HPV types and as such is the most benign form of cervical intraepithelial neoplasia , it is confined to the basal 1/3 of the epithelium, CIN 2 Moderate dysplasia confined to the basal 2/3 of the epithelium,CIN3 Sever dysplasia that spans more than 2/3 of the epithelium, and may involve the full thickness. INCIDENCE An estimated 493,000 new cases and 274,000 deaths in 2002 were caused by cervical cancer. The vast majority, some 83% of these cases, occur in developing countries, where cervical cancer amounts to 15% of female cancers with a risk before age 65 of 1.5%. In developed countries cervical cancer accounts for only 3.6%, with a risk of 0.8% before age 65. REF The highest incidence rates are observed in Sub-Saharan Africa, Melanesia, Latin America and the Caribbean, South-Central Asia, and South East Asia (fig 6) Fig 6 Worldwide Burden of HPV related Cervical Cancer Figures from 2002. Parkin MD et al 2006 The burden of HPV-related cervical cancers The vast majority of cervical cancers are squamous cell carcinoma adenocarcinomas being less common (fig 6). Generally the proportion of adenocarcinoma cases is higher in areas with low incidence of cervical cancer, accounting for up to 25% of cases in western countries (fig 6). This higher incidence of adenocarcinoma may be partially explained by cytological screening, which historically, had little effect in reducing the risk of adenocarcinoma of the cervix, because these cancers, and their precursors, occur within the cervical canal, and were not readily sampled by scraping of the epithelium of the ectocervix. Fig 5 Fig 5 showing the higher % of adenocarcinoma in counties that have screening programmes such as the UK and Denmark What is this showing? Make it clear.do you really need it. MORTALITY RATES Mortality rates are substantially lower than incidence rates. Worldwide 55% (could you double chek that this is the case please misses) of all those that develop the disease die, the figures vary significantly from the developed to the developing world. Low risk regions of the west such as Europe have a death rate of 37% while in developing countries where many cases present at relatively advanced stages, death rates are significantly higher increasing to 70%. Cervical screening programmes in the developed world identify pre-cancerous lesions at a stage where they can be easily treated accounting for the difference in mortality rates. TITTLE IF and figure number staying and refer to in text As cervical cancer affects a relatively high number of young women, it is a significant cause of years of life lost (YLL) in the developing world. Yang et al 2004 found that cervical cancer was responsible for the 2.7 million (age weighted) years of lives lost world wide in 2000, and that it is the single biggest cause of years of life lost from cancer in the developing world. In Latin America, Eastern Europe and the Caribbean, cervical cancer makes a greater contribution to YLL than disease such as Tuberculosis or AIDS. HPV is also associated with many other forms of cancer that could possibly be prevented with use of HPV vaccines; cancers of the penis, anus, vulva, vagina, oropharynx and some rare cancers of the head and neck are included. However cancer of the cervix is by far the most significant, in terms of incidence and mortality (table 1). Cancer of the vulva and vagina have a significantly lower incidence rate compared to cervical cancer, however since 80% of the incidence are caused by HPV types 16 or 18 women vaccinated against these types would also be protected against these forms of cancer. Incidence of squamous cell carcinoma of the anus are twice as common in females as males with HPV types 16 and 18 accounting for 83% of all cases. There is a particularly high incidence of anal cancer among homosexual males, shown by the high incidence rate in populations such as Sanfransisco, where gay incidence are higher than average (fig 7). Globally cancer of the penis is relatively rare accounting for 0.5% of cancers in men (table 1). HPV DNA is detectable in 40-50% of all penile cancers and serological studies have confirmed the role of HPV 16 and 18 (IARC 2005). Cancers of the mouth and oropharynx caused by HPV are very low at 0.06% of all cancers with 0.05% being caused by HPV types 16/18. Due to the small size of most studies and the absence of comparable measurements of prevalence of infection in normal subjects conducted for cancers of the vulva, vagina, penis and anus true prevalence is difficult to quantify. The figures shown in table 1, imply that we are dealing with a virus that discriminates primarily through disease aginst women, in particular young women. Gay men, however are also clearly an at risk group. Currently only young women are vaccinated aginst HPV types 16 and 18, however the JCVI (joint committee on vaccination and immunisation) have noted that the vaccines has not been conclusively trialled on men, and that there is insufficient evidence that the vaccine available would protect against anal, penile or head and neck cancer. However when more data becomes available they will consider vaccinating, high risk groups such as men who have sex with men. Add what this implies for prophylactic use of vaccine with other cancers cause by HPV And what you think about the ue of vaccine on highrisk men and its effectivity against other cancers caused by HPV types 16 and 18. Fig 7 TITTLE add Figure 6 showing that cancer of the anus are more prevalent in women than men with the major noted exception being San Francisco, where the increased incidence can be explained by a large number of homosexual men. Table 3 VACCINATION An effective vaccine should stimulate a suitable range of immune responses, mimic or improve on the protection gained from a wild type infection with little side effects. Critically the vaccine should be inexpensive, easily administered, transported and stored to further reduce cost and maximise convenience, this is especially relevant in the case of HPV vaccine as those that are not protected by the screening programmes of the developed world would benefit the most, ease of administration and storage is paramount in the developing world as stability and healthcare is more sporadic, and people are often more remote. There are many different kinds of vaccines available, and different vaccines have a variety qualities and limitations. Live attenuated vaccines contain a version of the pathogenic microbe that is avirulent, they often elicit an excellent cellular and antibody response with good longevity that can be lifelong with few doses. However there is always the possibility that the vaccine may revert to its virulent form, causing disease. For this reason a live attenuated vaccine is not appropriate for use against oncogenic HPV types. Recombinant vaccines can include one or more proteins that may illicit an immune response. A process has been developed to allow the removal of the genome from an attenuated or avirulent viral vector allowing the insertion of selected genetic material or proteins from another virus. The carrier viruses then ferry that viral DNA into host cells where the genes are expressed. Recombinant vaccines closely mimic a natural infection and therefore illicit a strong immune system. Inactivated vaccines are produced by killing the disease causing microbe by chemical (formaldehyde eg just double check), heat or radioactive means. These vaccines are more stable than live vaccines, and as there is no risk of reversion to virulence. They are also safer than live vaccines. Most inactivated vaccines stimulate a weaker immune response than live vaccines and several doses or boosters may be required to maintain immunity. DNA vaccines dispense with both the whole organism and its parts. They only include the essential part of the microbes genetic material. In particular, DNA vaccines use the genes that code for immunogens. Researchers have found that when the genes for a microbes antigens are introduced into the body, some cells will take up that DNA. The DNA then instructs those cells to make the antigen molecules. The cells secrete the antigens and display them on their surfaces. In other words, the bodys own cells become vaccine-making factories, creating the antigens necessary to stimulate the immune system. A DNA vaccine against a microbe would evoke a strong antibody response to the free antigen secreted by cells, and also stimulate a strong cellular response against the microbial antigens displayed on cell surfaces. The DNA vaccine is unable to cause disease Use of HPV Vaccines for Cervical Cancer Prevention Use of HPV Vaccines for Cervical Cancer Prevention HPV Vaccines: Will They Prevent Cervical cancer Introduction Human papilloma viruses (HPV) belong to the papillomaviridae family, they are double stranded DNA viruses. HPV is the most common sexually transmitted infection (STI) in the world (Urman et al. 2008). HPV is strongly associated with cervical cancer; more than 99% what are the other causes/factors please of cervical cancer cases are positive for HPV DNA and indeed, cervical cancer is the second most common malignancy in the world (Wang et al. 2007). In developed countries the incidence of cervical cancer has been reduced significantly by the introduction of a cervical screening programme. In developing countries where 83% of mortalities due to cervical cancer occur, there are no such programmes (Parkin et al. 2006). Can the introduction of a vaccine against HPV further reduce globally the incidence of cervical cancer? Many diseases caused by viruses are controlled in the developed world by ongoing successful vaccination programmes; Polio, Measles, Mumps and Rubella are a few examples. Smallpox caused by Variola virus was eradicated in 1979 through a successful worldwide vaccination programme. The factors that affect the Polio and MMR vaccine programmes success and those that affected the successful smallpox programme may also be contributory to the success of the HPV vaccination program. Vaccination of HPV is complex and multi factorial. This investigation studies a number of factors including: Vaccine efficacy Vaccine Cost/affordability/practicality of administration Production and Distribution Government backing and financial commitment Other support organisations such as the WHO, UNICEF, Gates Foundation, Social factors Media effects Public awareness Safety, and perceived fears Currently two prophylactic vaccines against HPV types 16 and 18, the most prevalent causes of HPV have been approved by the food and drug administration (FDA). Many developed countries have already introduced vaccination programmes using one of these vaccines. Can the vaccines and programme prevent cervical cancer? In order to effectively understand the implication of such a vaccination programme we must first fully examine the causative agent (HPV) and the consequential potential diseases including the biology, history and prevalence. Human Papillomavirus Approximately 200 types of HPV are identified of which around 40 infect the genital tract (McCance 2004). The majority of HPV types cause no symptoms, some types can cause warts and a minority may lead to cancer. Genital HPVs are transmitted via sexual contact, mainly intercourse, with an infected individual, and the risk of developing an HPV infection generally increases with the number of sexual partners, the sexual history of that partner or the introduction of a new sexual partner. Studies have shown that at least one type of HPV infection occurs soon after sexual debut, with around 30% of women infected with at least one high risk type within two years (Winer et al 2003; Winer et al 2008). HPVs are classified as either high risk or low risk, on the basis of association with cervical cancer. There are 15 types classified as high risk and three as probable high risk. High risk types include 16,18,31,33,35,39,,45,51,52,56,58,59,68,73,probable high risk types include 26,53,66 Low risk types include 6,11,40,42,43,54,61,70,72,81 and CP6108. More than 99% of cervical cancers are associated with HPV, of these 70% are associated with HPV type 16 and 18, with HPV 16 causing 50% and HPV 18 causing more than 15% in Europe (Smith et al..2007). HPV 16 is thus the single, most common high risk HPV. Interestingly HPV types 16 and 18 also cause 80% of anal cancer and 30% of vaginal and why the difference in % oper area research needed here.vulvar cancer and are associated with cancers of the, oropharynx and some rare cancers of the head and neck. (add reference form cervical cancer burden worldwide paper) The majority of HPV infections are asymptomatic, self limiting, and transient, with 70% of new HPV high risk type infections cleared within one year (with the median duration of an infection at 8 months) and 90% within two years (Ho et al 1998). The transient infection usually causes no clinical problems. A small proportion of high risk type infections persist due to host immune evasion, an evasion that results not only from restriction of HPVs to sites that are relatively inaccessible to host defences but also due to several mechanisms of preventing immune response what are these mechanisms please (a sk Dick if this is what he means . This persistence is the most important factor in the development of pre cancerous and cancerous lesions. The time span between infection by HPV and the development of pre cancerous lesions or cervical carcinoma varies from one to ten years (Moscicki et al 2006) and up to 20 years from other sources. HPV show little evidence of dramatic adaptability with phylogenic studies suggesting that the biology of HPVs has remained the same for over 200,000 years (Halpren et al 2000). While HPVs show historically the influence of point mutations, inserts, deletions and duplications, the predominant pattern of mutation within a given type is point mutation, with large scale rearrangements within the most conserved genes of HPVs such as L1 being rare (Myers et al 1996). Intra patient variation within HPV types is uncommon due to their low mutation rate. This low mutation rate is directly linked to the HPV replication strategy that requires host cell machinery, which has stringent proof reading mechanisms that avoid the incorporation of errors, conferring slow mutagenesis. All HPVs exhibit extreme specificity for infection of epithelial cells and do not infect or express their gene products in the underlying dermis. Although the mechanism of infection is not fully understood, the HPV epitheliotrophy resides for the most part in the interaction of specific transcription factors with the viral regulatory region known as the long control region (LCR). Infection with HPV can result in hyperproliferation of the host cell, and with certain high risk HPV types it may lead to transformation and immortalization. This is because high risk HPVs express two or more protein products (E6, E7 and E5) that transiently disrupt the cell cycle and stimulate cell division, knocking out at the same time the cellular mechanisms for growth inhibition. For a productive infection, HPVs require terminally differentiated cells. This HPV biology feature has impeded studies on the full reproduction life cycle because of the lack of highly efficient models of epithelial terminal di fferentiation in vitro. Most of the different stages in the HPV life cycle have been established using genetic engineering and molecular biology strategies. The dsDNA of HPV exists in a non enveloped icosahedral shaped virion 52-55 nm in diameter. The dsDNA genome is circularised and around 8000base pairs in length (Fig1). The genome encodes eight proteins, six early E1, E2, E4, E5, E6, E7, and two late structural proteins L1 and L2 and the previously mentioned noncoding LCR. Fig 1 HPV type 16 Genome structure, gene and functional domain location http://www.dnachip-link.com/Eng/library/HPV.aspusg 15/11/20009 Fig 1 shows the dsDNA genome of HPV type 16, and the location of the early and late genes along with the LCR that contains the origin of replication. An initial infection requires the access of infectious particles to the basal layer of the epithelium. Some HPVs require a break in the stratified epithelium to achieve this. Such breaks are not necessarily obvious and may occur under conditions where the skin is exposed to water or abraded, or subjected to an environment where micro traumas may occur such as possibly in aswiming pool or ect (must put an example)(in fig 2 shows as a cut). Following infection and uncoating it is thought that the virus maintains its genome as an episome in low copy numbers within basal cells of the epithelium. Although the pattern of gene expression in these cells is not well understood, it is generally thought that viral proteins E1 and E2 are expressed to maintain the viral DNA episome (Wilson et al.2002) and possibly to facilitate the segregation of genomes during cell division (You et all.2004). It is not known whether viral transformation proteins E6 and E7 are also expressed in the basal layer, but it does appear that initial infection is followed by a proliferative phase that results in the increase in the number of basal cells harbouring viral episomes. In normal uninfected epithelium, basal cells leave the cell cycle soon after migration into the superbasal cell layers where they undergo a process of terminal differentiation. During infection E6 and E7 are expressed in these cells stopping normal differentiation (Sherman et all.1997). E6 and E7 are believed to work together to achieve this and in lesions caused by high risk HPV types. During a natural infection the ability of E7 to stimulate S-phase progression is limited to a subset of differentiated cells with low levels of p21/p27, or which express high enough levels of E7 to overcome the block in S-phase entry. The viral E6 protein is thought to prevent apoptosis in response to unscheduled S-phase entry brought on by E7. The association of E6 with p53 and the inactivation of p53 mediated growth suppression and apoptosis is well documented, E6 may also associate with other pro-apoptotic proteins including bak (Thomas and Banks,1998) and bax (Li and Dou,2000). E6 is thus considered a predisposing factor in the development of HPV associated cancers, allowing the accumulation of chance errors in host DNA to go unchecked. Furthermore the E6 protein of high risk HPVs can stimulate cell proliferation independently of E7 via a c-terminal PDZ ligand binding domain. E6 PDZ is enough to mediate superbasal cell proliferation and may contribute to the formation of metastatic tumours by disrupting normal cell adhesion (Nguyen et al.2003) Amplification of the viral genome and the ability to package these genomes into infectious particles is essential for the production of infectious virions. For most HPV types this occurs in the mid or upper epithelial layers following an increase in activity of the late promoter. The late promoter gene is located within the E7 open reading frame, and the upregulation of the late promoter is thought to lead to increased expression of proteins involved in viral DNA replication, without directly affecting the expression of E6 or E7 necessary for S-phase entry. The amplification of the viral genome begins in a subset of cells in the proliferative compartment and requires the expression of all viral early gene products, these include E4 and E5 whose role in replication is not yet clearly understood. Binding of E2 to the HPV upstream regulator region is essential for viral DNA replication that is dependent on the differentiated state of epithelial cells. E2 recruits the E1 DNA helicase to the viral origin of replication. Throughout the virus life cycle, the relative levels of viral proteins are controlled by promoter usage and by differential splice site selection, with an increase in E1 and E2 allowing an increase in viral copy numbers in the upper epithelial layers. Current models suggest that a small increase in promoter activation during differentiation may lead to an increase in the level of E1 and E2 and a subsequent increase in genome copy number. The newly replicated genome could then serve as a further template for expression of E1 and E2, facilitating the amplification of viral genome and in turn further expression of E1 and E2 replication proteins. Viral DNA remains latent (not integrated) in basal cells of benign lesions. Replication occurs in the differentiating cells where capsid proteins and viral particles are found. Viral DNA is integrated in cancer cells, which contain no replicating virus. Once viral genome replication is completed, the expression of two virally encoded structural proteins, expressed in the upper layers of infected epithelia may occur. L1 the major capsid protein is expressed after L2 in a sub set of cells that express E4 (fig 2), this allows the assembly of infectious particles in the upper layers of the epithelium (Florin et al.,2002). A successful infection requires the virus to escape from the infected skin cell and survive extracellularly prior to re-infection. HPVs are non-lytic and are as such not released until the infected cells reach the epithelial surface. The intracellular retention of HPV antigen until the cell reaches the uppermost epithelial layers may contribute the compromised immune detection, especially as the virus has molecular mechanisms that limit the presentation of viral epitopes to the immune system in the lower epithelial layers (Ashrafi et al 2002). What are these mechanisms Figure 2 Papillomavirus type 16 Life Cycle and gene expression location within epithelium Taken from, The papillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Figure 2 diagrammatic representation of the skin with HPV type 16 gene expression incorporated, colour of arrows are representative of genes expressed within epithelial cells. The frequent detection of high risk HPV DNA in cervical lesions in the absence of any obvious disease, may be explained by the presence of the virus in a latent state, with only very few cells able to support the productive virus life cycle during epithelial cell differentiation. Following immune regression, HPV DNA is thought to remain in the basal epithelial cells waiting to be reactivated once levels of immune surveillance decline there are conflicting opinions (Zhang et al.1999). If regression is not achieved lesions may persist and in some instances progress to cancer. The number of lesion that progress to cancer is very low when compared to the prevalence of high risk HPV infection in the general public. The Progression of productive lesion to high grade lesions may result from the deregulation ( what happen to allow thes proteins to be deregulated intergrattion loss of E2 adn p53 association, be specific add biochemistry here please. in the expression of transforming proteins E6 and E7. The inability of a cell to support the whole virus life cycle is often associated with the development of cancerous lesions. The transformation zone (Fig 3) is particularly susceptible to cervical cancer; it appears that high risk types of HPV such as type 16 cannot complete their life cycle at this site Progression from CIN3 to cancer usually occurs in lesions that contain integrated copies of the viral genome in which E7 expression is elevated. Suggesting that retention of E6 and E7genes and the loss of E2 and E4 genes (that exert negative effect on cell growth) usually accompanies the development of invasive cancer. (reference) Remember for CIN refer to in that section or here but Cin must be corrulated with what causes the cancer and with whats happening with the virus that causes the change in CIN or the causes in CIN to occur. Cervical cancerisa considerable contributor to morbidity and mortality. Being the second most common cancer worldwide and the twelfth most common cancer in women in the UK. Cervical cancer in 2002 was the cause of 274,000 deaths worldwide (the most current data available)REF THIS FIGURE and continues to causes more than 1000 deaths in the UK each year. There are two main types of cervical cancer squamous cell cancer (the most common) and adenocarcinoma, although they are often mixed. They are named after the types of cell that become cancerous through neoplasia. Squamous cells are flat cells covering the cervix; adenomatous cells are found in the passageway from the cervix to the womb. Other rarer cancers of the cervix include small cell cancer. Deaths from cervical cancer in the UK have fallen over the last 20 years mainly because of the NHS cervical screening programme that reduced the mortality rates by 62% between 1987-2006. Screening may detect changes in the cells of the cervix at a pre-cancerous stage. Fig 3 TITTLE Showing location of transformation zone. Cell samples are examined for abnormalities, these abnormality are described in a standard format covering cytology and/or histology. What are these standard format CIN 1 CIN2 CIN3 LISL LGSIL HSIL HGSIL USE FIG 4 and explain whats happening with the proteins expressed and genome intergration where CIN number progression is concerned please. MUST DO From Lowy Schiller, J Clin Invest, 116:1167-73, 2006 Low grade squamous intraepithelial lesion (LSIL or LGSIL) indicates possiblecone biopsy, or laser ablation. High grade squamous intraepithelial lesion (HSIL or HGSIL) indicates moderate or severeCIN 2 or CIN3 (fig 3). While cervical screening has reduced the mortality significantly in the developed world cervical cancer is still a significant burden worldwide. Fig 4 Taken from, The popillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Fig. 5. CIN 1 resembles productive infections caused by other HPV types and as such is the most benign form of cervical intraepithelial neoplasia , it is confined to the basal 1/3 of the epithelium, CIN 2 Moderate dysplasia confined to the basal 2/3 of the epithelium,CIN3 Sever dysplasia that spans more than 2/3 of the epithelium, and may involve the full thickness. INCIDENCE An estimated 493,000 new cases and 274,000 deaths in 2002 were caused by cervical cancer. The vast majority, some 83% of these cases, occur in developing countries, where cervical cancer amounts to 15% of female cancers with a risk before age 65 of 1.5%. In developed countries cervical cancer accounts for only 3.6%, with a risk of 0.8% before age 65. REF The highest incidence rates are observed in Sub-Saharan Africa, Melanesia, Latin America and the Caribbean, South-Central Asia, and South East Asia (fig 6) Fig 6 Worldwide Burden of HPV related Cervical Cancer Figures from 2002. Parkin MD et al 2006 The burden of HPV-related cervical cancers The vast majority of cervical cancers are squamous cell carcinoma adenocarcinomas being less common (fig 6). Generally the proportion of adenocarcinoma cases is higher in areas with low incidence of cervical cancer, accounting for up to 25% of cases in western countries (fig 6). This higher incidence of adenocarcinoma may be partially explained by cytological screening, which historically, had little effect in reducing the risk of adenocarcinoma of the cervix, because these cancers, and their precursors, occur within the cervical canal, and were not readily sampled by scraping of the epithelium of the ectocervix. Fig 5 Fig 5 showing the higher % of adenocarcinoma in counties that have screening programmes such as the UK and Denmark What is this showing? Make it clear.do you really need it. MORTALITY RATES Mortality rates are substantially lower than incidence rates. Worldwide 55% (could you double chek that this is the case please misses) of all those that develop the disease die, the figures vary significantly from the developed to the developing world. Low risk regions of the west such as Europe have a death rate of 37% while in developing countries where many cases present at relatively advanced stages, death rates are significantly higher increasing to 70%. Cervical screening programmes in the developed world identify pre-cancerous lesions at a stage where they can be easily treated accounting for the difference in mortality rates. TITTLE IF and figure number staying and refer to in text As cervical cancer affects a relatively high number of young women, it is a significant cause of years of life lost (YLL) in the developing world. Yang et al 2004 found that cervical cancer was responsible for the 2.7 million (age weighted) years of lives lost world wide in 2000, and that it is the single biggest cause of years of life lost from cancer in the developing world. In Latin America, Eastern Europe and the Caribbean, cervical cancer makes a greater contribution to YLL than disease such as Tuberculosis or AIDS. HPV is also associated with many other forms of cancer that could possibly be prevented with use of HPV vaccines; cancers of the penis, anus, vulva, vagina, oropharynx and some rare cancers of the head and neck are included. However cancer of the cervix is by far the most significant, in terms of incidence and mortality (table 1). Cancer of the vulva and vagina have a significantly lower incidence rate compared to cervical cancer, however since 80% of the incidence are caused by HPV types 16 or 18 women vaccinated against these types would also be protected against these forms of cancer. Incidence of squamous cell carcinoma of the anus are twice as common in females as males with HPV types 16 and 18 accounting for 83% of all cases. There is a particularly high incidence of anal cancer among homosexual males, shown by the high incidence rate in populations such as Sanfransisco, where gay incidence are higher than average (fig 7). Globally cancer of the penis is relatively rare accounting for 0.5% of cancers in men (table 1). HPV DNA is detectable in 40-50% of all penile cancers and serological studies have confirmed the role of HPV 16 and 18 (IARC 2005). Cancers of the mouth and oropharynx caused by HPV are very low at 0.06% of all cancers with 0.05% being caused by HPV types 16/18. Due to the small size of most studies and the absence of comparable measurements of prevalence of infection in normal subjects conducted for cancers of the vulva, vagina, penis and anus true prevalence is difficult to quantify. The figures shown in table 1, imply that we are dealing with a virus that discriminates primarily through disease aginst women, in particular young women. Gay men, however are also clearly an at risk group. Currently only young women are vaccinated aginst HPV types 16 and 18, however the JCVI (joint committee on vaccination and immunisation) have noted that the vaccines has not been conclusively trialled on men, and that there is insufficient evidence that the vaccine available would protect against anal, penile or head and neck cancer. However when more data becomes available they will consider vaccinating, high risk groups such as men who have sex with men. Add what this implies for prophylactic use of vaccine with other cancers cause by HPV And what you think about the ue of vaccine on highrisk men and its effectivity against other cancers caused by HPV types 16 and 18. Fig 7 TITTLE add Figure 6 showing that cancer of the anus are more prevalent in women than men with the major noted exception being San Francisco, where the increased incidence can be explained by a large number of homosexual men. Table 3 VACCINATION An effective vaccine should stimulate a suitable range of immune responses, mimic or improve on the protection gained from a wild type infection with little side effects. Critically the vaccine should be inexpensive, easily administered, transported and stored to further reduce cost and maximise convenience, this is especially relevant in the case of HPV vaccine as those that are not protected by the screening programmes of the developed world would benefit the most, ease of administration and storage is paramount in the developing world as stability and healthcare is more sporadic, and people are often more remote. There are many different kinds of vaccines available, and different vaccines have a variety qualities and limitations. Live attenuated vaccines contain a version of the pathogenic microbe that is avirulent, they often elicit an excellent cellular and antibody response with good longevity that can be lifelong with few doses. However there is always the possibility that the vaccine may revert to its virulent form, causing disease. For this reason a live attenuated vaccine is not appropriate for use against oncogenic HPV types. Recombinant vaccines can include one or more proteins that may illicit an immune response. A process has been developed to allow the removal of the genome from an attenuated or avirulent viral vector allowing the insertion of selected genetic material or proteins from another virus. The carrier viruses then ferry that viral DNA into host cells where the genes are expressed. Recombinant vaccines closely mimic a natural infection and therefore illicit a strong immune system. Inactivated vaccines are produced by killing the disease causing microbe by chemical (formaldehyde eg just double check), heat or radioactive means. These vaccines are more stable than live vaccines, and as there is no risk of reversion to virulence. They are also safer than live vaccines. Most inactivated vaccines stimulate a weaker immune response than live vaccines and several doses or boosters may be required to maintain immunity. DNA vaccines dispense with both the whole organism and its parts. They only include the essential part of the microbes genetic material. In particular, DNA vaccines use the genes that code for immunogens. Researchers have found that when the genes for a microbes antigens are introduced into the body, some cells will take up that DNA. The DNA then instructs those cells to make the antigen molecules. The cells secrete the antigens and display them on their surfaces. In other words, the bodys own cells become vaccine-making factories, creating the antigens necessary to stimulate the immune system. A DNA vaccine against a microbe would evoke a strong antibody response to the free antigen secreted by cells, and also stimulate a strong cellular response against the microbial antigens displayed on cell surfaces. The DNA vaccine is unable to cause disease

Organizational Systems and Quality Leadership Essay

A. Understanding Nursing Sensitive Indicators Nursing sensitive indicators include the configuration, process and outcomes of nursing care. The configuration of nursing care concludes the nursing staff, their nursing skills, and the level of education that each nurse holds. The process of nursing care concludes the nursing assessments, intervention and implimentation. The outcome of nursing care either positive or negative depends on the quantity and quality of the care provided to the patients by the nursing staff (â€Å"Nursing world,† 2013) Each nurse should hold proper information and knowledge of nursing care such as knowledge of pressure ulcers. In this scenario every nursing personnel should provide the ultimate nursing care in dealing with pressure ulcers. In order to prevent any pressure ulcer each nursing personnel should be aware of the pressure ulcer concept, their prevention and the correct technique of reducing any other complication related to pressure ulcers. In this case the nurse and the CNA should use their knowledge of preventing any pressure ulcer. The first action is to assess completely the patient for any sign of pressure ulcer such as any erythema or bruising. It is essential that the nursing staff know to reposition the patient and reasses the out of sight sites parts of the body for any sign and symptoms of bruising and shearing. Also it is important for nursing staff to know that, the patients with restraint order, are at higher risk of getting pressure ulcer so the nurse is responsible for proper and effective way of using restraints and on the other hand is supposed to know at what time the restrains are not proper to be used. In the nursing sensitive indicator category also it is included,the patient satisfaction, which was missing out in this scenario; due to the fact that the nurse did not consider the patient satisfaction fact, and she dismissed the incorrect diet, which was being so easily delivered for the patient.if the nurse had the patient satisfaction category in her mind, She also would have report the daughter about the increct diet incident, and  also the nurse would also avoid commenting inappropriate words to the daughter. How Hospital Data Could Advance Quality Care In this scenario the hospital in order to advance the quality of care, could have shared the information about the incident with the nursing personnel. The hospital could provide the best quality of care to the patients and achieve the patients’ satisfaction, by sharing the data. Advancing the quality of care would have positive effect on both patient satisfaction and nursing care. Knowledge of nursing care empowers the nursing staff in such cases. In this scenario the knowledge of pressure ulcers, restraints and patient care is significant. On the other hand the nursing care in this scenario could have been better and the family/patient could have been cared better if the nursing staff had gotten the best patient care knowledge. Resources Available Several resources exist in the hospital in order to address the nursing sensitive indicators. In this scenario as a nurse I could partner with dietician in order to address the tray issue and deliver the correct tray to the correct patient. To resolve any misunderstandings I would apologize to the daughter of the patient for the incident. I would speak to the nurse who commented inapprotely to the daughter of the patient. I would discuss the situation and possible solutions with the doctor/nurse in charge. I would educate the CNA the proper information about noticing the signs of any pressure ulcers and proper techniques in avoiding them. I also would ask a wound care consultant to provide proper information to the nursing staff about pressure ulcers. To fully provide the best patient care I also would refer the patient and family to any social worker in dealing with any ethical issue that may interfere in the quality of care. References http://www.nursingquality.org http://www.nursingworld.org/MainMenuCategories/ThePracticeofProfessionalNursing/PatientSafetyQuality/Research-Measurement/The-National-Database/Nursing-Sensitive-Indicators_1 Nursing world. (2013)

Definition and Examples of Newspeak

Adoptive Family Relief Act Policy Analysis - 1449 Words

Adoptive Family Relief Act Policy Analysis Bailey Williams SW 150:01 The adoptive Family Relief Act passed on the 16 of October in 2016 was enacted to provide relief for adoptive family’s form immigrant visa fees in certain situations. It amends the immigration and Nationality Act to refund or waive renewal or replacement fees for an immigrant visa that was issued on or after March 27, 2013, for a child who has been lawfully adopted or is coming to the United States to be adopted by a U.S. citizen. This is used if a child is unable to use the original immigrant visa during its valid period due to extraordinary circumstances. This includes situations like denial of an exit permit. Under these kinds of circumstances, parents or adopting parents have no control, thus, making this act necessary. In 2012, around nine thousand immigrant children were adopted into the United States. That means about nine thousand adoptive families have to renew the validity of their adopted child’s visa every six months. In addition to this expense, families ha ve to pay an extra renewal fee after the Democratic Republic of Congo’s suspension of issuing exit permits. Renewing a visa costs $325 and on top of this the child must complete a medical exam that costs $200. But these expenses are not the end, many families must also pay for monthly childcare or foster care fees. Keep in mind that these expenses are per child and many families adopt more than just one child. These constant burden ofShow MoreRelatedA Brief Note On The And Welfare Of Parents And Senior Citizens Act3646 Words   |  15 Pages(SW), Semester III Topic: Maintenance and Welfare of parents and Senior Citizens Act 2007 Submitted by-Amit kumar M.A (Final) Introduction The culture in India always give the lesson to their children that respect the elders always. 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Ernest Hemingway s Life As A Writer - 1074 Words

Ernest Miller Hemingway was born July 21, 1899 in Chicago, IL to Clarence and Grace Hill-Hemingway. Ernest’s parents were a physician and a musician, respectively, and were both well educated individuals who encouraged their children to follow in their footsteps educationally. Ernest Hemingway began his career as an author and journalist at the age of seventeen. Ernest took a high school course in Journalism taught by Fannie Biggs, which was taught, as though the classroom were a newspaper office (Griffin). Much like many of the early American authors such as Mark Twain, Stephen Crane, and Sinclair Lewis (Myers) Hemingway was a journalist before he became a novelist. It was his career in journalism that sparked his successful career as†¦show more content†¦Hemingway so tastefully describe the art of journalistic writing as the â€Å"Iceberg Theory† (Oliver) the â€Å"Iceberg Theory† is thought to have gotten its name from Hemingway saying, â€Å"If a writer knows enough about what he is writing about, he may omit things that he knows. The dignity of movement of an iceberg is due to only one ninth of it being above water.† (Hemingway, Brainy Quote). It is this quote that defines Hemingway’s career as a short-story author and novelist. When writing short stories Hemingway would often leave key details up to the reader by saying as little as possible. This can be seen in the dialogue of his short stories such as, â€Å"Hills Like White Elephants†. â€Å"’They look like white elephants,† she said. â€Å"I’ve never seen one,† the man drank his beer. â€Å"No, you wouldn’t have.† â€Å"I might have,† the man said. â€Å"Just because you say I wouldn’t have doesn’t prove anything.’† (Hemingway, Lit). This cut and dry excerpt of dialogue shows just how little â€Å"fluff† Hemingway wrote into his short stories. It is â€Å"Hills Like White Elephants† that adequately depicts Hemingway’s â€Å"Iceberg Theory†. It is not what is stated explicitly, but what is not said that is important. Nearly every aspect of â€Å"Hills Like White Elephants† can be interpreted to mean something else. From the train tracks to the hills, the felt pads have even been considered as an allusion to the pads used to soak up

The Meaning of Citizenship Free Essays

The Meaning of Citizenship Essay The Meaning of Citizenship according to the author is what we make it mean. What a bunch of malarkey! The history of how the definition of citizenship has evolved was well done but I kept having this feeling that she was trying to get me to subscribe to some new world order of citizenship. I like the Dictionary definition of citizenship is the state of being vested with the rights, privileges, and duties of a citizen. We will write a custom essay sample on The Meaning of Citizenship or any similar topic only for you Order Now The character of an individual viewed as a member of society; behavior in terms of duties, obligations, and functions of a citizen. She suggested that citizenship was inconsistent from the very beginning of the United States. Yes it was because we were all immigrants from the start. Women were still seen a property to their husband, Africans was slaves, Native American conquered, and a lot of old world racism was in full swing. America was the great experiment by its founding fathers. Never had it been tried to bring all people together as one country of citizens, well at least what they consider â€Å"as people† at that time. Some may argue that the romans were doing the same thing but they were doing it at sword point then by volunteer. Even though some of the founding father was still behind in their thinking others were not. They build the constitution so that future generations could learn from their father’s mistake and improve America for everyone. I was very surprise that the Supreme Court did not rule that the power of husbands over wives is no longer recognizable in law until 1992. Wow that took 216 years to figure that out. Also that if a woman got married to a noncitizen she would lose her citizenship and be seen as a citizen of her husband country but on the flip side of the coin if the wife married an American husband they became a US citizen until the law change in 1934. Currently the married spouse has the option to either become a permanent residence or naturalization. Naturalization is no easy task either. Under the Path to citizenship on the U. S. Citizenship and Immigration Services the spouse has to take a naturalization test. Sad part according to US News and World Report Weekly poll done back in April of 2012 1 in 3 Americans would fail this test. Another big issue today is illegal women having children in the United State in order to not to get deported. This loop-hole has become to be known as â€Å"baby anchor†. In a way they gain citizenship though the kids. Many countries have closed this loop-hole and I think it time for America to do so too. I would give amnesty to all kids and parents here now then set a deadline date 10months out that one of the child parents is must be a U. S. Citizen otherwise that child will be consider as the citizen of one of the parent foreign citizenship. The history about race factor on citizenship was pretty much dead on. Of all the nationalities from around the world the people from African have had it the worst. Even till this day I don’t see why people looked down on Africans. African American has had the hardest time integrate in to American society. It was mostly because their immigration was forced to America by slavery. When they won their freedom they were still treated like 2nd class citizens. Even today most of the culture seems torn about where they fit into America society. The Chinese and Japanese were treated just as badly. They were seen as rats or beasts to use till they dropped over dead. If anything they weren’t even seen as human beings. They fought back hard to earn their rights and somehow moved forward as a culture to integrate with American society. Then the author goes into class warfare for three pages. Most of it did not make sense other then she trying to make the argument that social security is some kind social citizenship. Now the way I see it with immigration most moving from one country to another are lower or poor people. When they move into a very well off country they can bear the cost of it. America is at a point where immigration is collapsing local government fiances. More people are pulling from the system then put in. The states along the Mexican border are suffering majorly from this due to illegal immigration. Immigration is a good thing for a country but it must be controlled. In Europe many countries are having negative birth rates meaning more people are dying faster than babies are born. In a capitalism economy they build the social program are design to be funded by future population grow who pay into the social program. The problem is that most of their growth now is from immigration that are almost doubling unemployment in European country but benefiting from the host country social programs. (See http://www. migrationpolicy. org/pubs/TCM-integration. pdf) Linda Kerber once again starts to ramble on for another five pages. It covers the Boston Tea Party, Dred Scott decision of 1857, Yick Wo the laundry guy vs. Hopkins, War Brides Act of World War II, and a few other Supreme Court rulings to support her views, California Proposition 187, the Cold War, Iran-Contra, Vietnam War, the Gulf War, and something about Peter Pan vs. Captain Hooker. Well not that last thing. All of this was a setup to give you a right hook to the head about her post national citizenship idea. And so she opens up with â€Å"Do we need citizenship? † This is where the final punch gets you. She starts to make hidden points to being a one world citizenship because like as she stated from the start citizenship means what we make it mean. This will not work as many cultures that have such polar views of each other. An example would be that Islam faith is so tie into it governing system that is Islamic law which is set by the religion is law via in United State religion is kept separated from government laws. She is right that we are one world family but we live under different homes with different rules and values. To me illegal immigration is like having the uninvited family member visits you. They say they are only going to be visiting for 3 days but end up staying for years. We can’t just join with other people if they don’t believe in the Bill of Rights created by our founders. What would be the point of freedom of the press if you can’t write about something that will offend a person or group? In the end I think most people keep mixing citizenship and culture together. Becoming a citizenship must mean more then I was able to sneak into this land. We must close the loop-holes in immigration to remove some of the arguments on citizenship but not eliminate immigration itself. We have to end this feeling of it means whatever it means to you. It’s a cop out. We must stand firm that this is what it takes to be a citizen of the United States. How to cite The Meaning of Citizenship, Papers

Bladerunner Humanity Of Deckard Roy Batty Essay Example For Students

Bladerunner: Humanity Of Deckard Roy Batty Essay Roy Batty and Deckard are both able to show us what it means to be human. To what extent do you agree? Through Blade Runner, we see an epic quest filled with meaning and symbolism applicable to the human condition. Replicants are basically human beings, except for the fact that they lack a history. As a consequence of this, perhaps, they also lack proper emotional faculties especially empathy. Empathy is the ability to place oneself in the position of another living being and understand that persons feelings. Blade runner promotes that empathy is the defining characteristics for humanity. The replicants, designed not to show any emotion, develop spiritually and emotionally throughout the film. We will write a custom essay on Bladerunner: Humanity Of Deckard Roy Batty specifically for you for only $16.38 $13.9/page Order now The characters in the movie, even the ones that were not human, had many humanistic and believable qualities. Many of them were able to feel love as well as hate. Although Deckard is supposedly human he at times shows less emotion than Roy. He seems heartless and uncompassionate making himself look very unhuman. We see that Deckard is possibly not ;human; as well, but a replicant. He shows no compassion when he tells Rachel of her being a replicant with implants. In tears, Rachel sneaks out of Deckards apartment and into the streets. The only time in which Deckard really shows emotion is accomplished when Roy, forging Deckard through the fires of a harrowing battle, looks terrified knowing that he is going to die. Through this, Roy tries to communicate his life experiences, and the importance of life before his own flame extinguishes explaining of the horrors of their enslavement. Again, all of these human characteristics that the non-human characters showed makes them more believable for the viewers. The whole definition of humanity is changed by its interaction with the Replicants. For the replicant Roy Batty it was obvious that that he felt strong emotions, perhaps even love for his fellow replicants. After Deckard killed Pris, Roy leaned over her and kissed her showing that he had loved her. He also showed these feelings for Pris and Zhora breaking two of Deckards fingers, one for Pris and one for Zhora. Although this act seemed quite inhuman, the motivation behind it seemed quite believable. He also demonstrates an inhumane role when he kills Tyrell but Tyrell is inhumane to create intelligent beings with such a limited life span displaying greed and manipulation. Batty also showed many human emotions as he talked of the horrors he had endured. It was obviously very difficult for him to take these nightmares as they affected him much in the same way it would have affected any human. He also exhibited human qualities when he saved Deckard from falling off the building. Quote: Quite an experience to live in fear, isnt it? Thats what its like to live as a slave. At the last moment, Roy saves him by grabbing his wrist with the nail-impaled hand. He draws him up to the roof, and lays him down. Pris also shows human qualities. Pris was very naive. She seemed to be the least developed of all of the Replicants and therefore was very much a follower. She also had a certain sort of innocence. Quote: Then were stupid, and well die! She says this after Batty tells of the deaths of their friends, which show that she is scared and starting to get worried that shell die, she has feelings, and starts to panic. Towards the end of the movie it levels it up to see that both Batty and Deckard show us the meaning of what it means to be alive. .u2e31bc76fbba5f330051b59f40f83533 , .u2e31bc76fbba5f330051b59f40f83533 .postImageUrl , .u2e31bc76fbba5f330051b59f40f83533 .centered-text-area { min-height: 80px; position: relative; } .u2e31bc76fbba5f330051b59f40f83533 , .u2e31bc76fbba5f330051b59f40f83533:hover , .u2e31bc76fbba5f330051b59f40f83533:visited , .u2e31bc76fbba5f330051b59f40f83533:active { border:0!important; } .u2e31bc76fbba5f330051b59f40f83533 .clearfix:after { content: ""; display: table; clear: both; } .u2e31bc76fbba5f330051b59f40f83533 { display: block; transition: background-color 250ms; webkit-transition: background-color 250ms; width: 100%; opacity: 1; transition: opacity 250ms; webkit-transition: opacity 250ms; background-color: #95A5A6; } .u2e31bc76fbba5f330051b59f40f83533:active , .u2e31bc76fbba5f330051b59f40f83533:hover { opacity: 1; transition: opacity 250ms; webkit-transition: opacity 250ms; background-color: #2C3E50; } .u2e31bc76fbba5f330051b59f40f83533 .centered-text-area { width: 100%; position: relative ; } .u2e31bc76fbba5f330051b59f40f83533 .ctaText { border-bottom: 0 solid #fff; color: #2980B9; font-size: 16px; font-weight: bold; margin: 0; padding: 0; text-decoration: underline; } .u2e31bc76fbba5f330051b59f40f83533 .postTitle { color: #FFFFFF; font-size: 16px; font-weight: 600; margin: 0; padding: 0; width: 100%; } .u2e31bc76fbba5f330051b59f40f83533 .ctaButton { background-color: #7F8C8D!important; color: #2980B9; border: none; border-radius: 3px; box-shadow: none; font-size: 14px; font-weight: bold; line-height: 26px; moz-border-radius: 3px; text-align: center; text-decoration: none; text-shadow: none; width: 80px; min-height: 80px; background: url(https://artscolumbia.org/wp-content/plugins/intelly-related-posts/assets/images/simple-arrow.png)no-repeat; position: absolute; right: 0; top: 0; } .u2e31bc76fbba5f330051b59f40f83533:hover .ctaButton { background-color: #34495E!important; } .u2e31bc76fbba5f330051b59f40f83533 .centered-text { display: table; height: 80px; padding-left : 18px; top: 0; } .u2e31bc76fbba5f330051b59f40f83533 .u2e31bc76fbba5f330051b59f40f83533-content { display: table-cell; margin: 0; padding: 0; padding-right: 108px; position: relative; vertical-align: middle; width: 100%; } .u2e31bc76fbba5f330051b59f40f83533:after { content: ""; display: block; clear: both; } READ: Loyalty in Twelfth Night Essay Roy Batty shows this by saving Deckard of falling off the building, sitting in front of Deckard releasing a dove to commemorate his death that he most likely learned to accept and appreciate while Deckard demonstrates a humane act when he hurries home to find Rachel, desperate to escape the city with her before someone in the Blade Runner unit finds them. As they leave Rachel knocks over the unicorn that was placed on the floor, symbolizing her escape from the Tyrell Corporation, which only looked upon her as a replicant. Deckard fell in love with her as a human, and by doing so; she became . Bladerunner Humanity of Deckard Roy Batty Essay Example For Students Bladerunner: Humanity of Deckard Roy Batty Essay Roy Batty and Deckard are both able to show us what it means to be human. To what extent do you agree? Through Blade Runner, we see an epic quest filled with meaning and symbolism applicable to the human condition. Replicants are basically human beings, except for the fact that they lack a history. As a consequence of this, perhaps, they also lack proper emotional faculties especially empathy. Empathy is the ability to place oneself in the position of another living being and understand that persons feelings. Blade runner promotes that empathy is the defining characteristics for humanity. The replicants, designed not to show any emotion, develop spiritually and emotionally throughout the film. We will write a custom essay on Bladerunner: Humanity of Deckard Roy Batty specifically for you for only $16.38 $13.9/page Order now The characters in the movie, even the ones that were not human, had many humanistic and believable qualities. Many of them were able to feel love as well as hate. Although Deckard is supposedly human he at times shows less emotion than Roy. He seems heartless and uncompassionate making himself look very unhuman. We see that Deckard is possibly not human as well, but a replicant. He shows no compassion when he tells Rachel of her being a replicant with implants. In tears, Rachel sneaks out of Deckards apartment and into the streets. The only time in which Deckard really shows emotion is accomplished when Roy, forging Deckard through the fires of a harrowing battle, looks terrified knowing that he is going to die. Through this, Roy tries to communicate his life experiences, and the importance of life before his own flame extinguishes explaining of the horrors of their enslavement. Again, all of these human characteristics that the non-human characters showed makes them more believable for the viewers. The whole definition of humanity is changed by its interaction with the Replicants. For the replicant Roy Batty it was obvious that that he felt strong emotions, perhaps even love for his fellow replicants. After Deckard killed Pris, Roy leaned over her and kissed her showing that he had loved her. He also showed these feelings for Pris and Zhora breaking two of Deckards fingers, one for Pris and one for Zhora. Although this act seemed quite inhuman, the motivation behind it seemed quite believable. He also demonstrates an inhumane role when he kills Tyrell but Tyrell is inhumane to create intelligent beings with such a limited life span displaying greed and manipulation. Batty also showed many human emotions as he talked of the horrors he had endured. It was obviously very difficult for him to take these nightmares as they affected him much in the same way it would have affected any human. He also exhibited human qualities when he saved Deckard from falling off the building. Quote: Quite an experience to live in fear, isnt it? Thats what its like to live as a slave. At the last moment, Roy saves him by grabbing his wrist with the nail-impaled hand. He draws him up to the roof, and lays him down. Pris also shows human qualities. Pris was very naive. She seemed to be the least developed of all of the Replicants and therefore was very much a follower. She also had a certain sort of innocence. Quote: Then were stupid, and well die! She says this after Batty tells of the deaths of their friends, which show that she is scared and starting to get worried that shell die, she has feelings, and starts to panic. Towards the end of the movie it levels it up to see that both Batty and Deckard show us the meaning of what it means to be alive. .ua07fe0e9428a7dad734d722d8ee4d435 , .ua07fe0e9428a7dad734d722d8ee4d435 .postImageUrl , .ua07fe0e9428a7dad734d722d8ee4d435 .centered-text-area { min-height: 80px; position: relative; } .ua07fe0e9428a7dad734d722d8ee4d435 , .ua07fe0e9428a7dad734d722d8ee4d435:hover , .ua07fe0e9428a7dad734d722d8ee4d435:visited , .ua07fe0e9428a7dad734d722d8ee4d435:active { border:0!important; } .ua07fe0e9428a7dad734d722d8ee4d435 .clearfix:after { content: ""; display: table; clear: both; } .ua07fe0e9428a7dad734d722d8ee4d435 { display: block; transition: background-color 250ms; webkit-transition: background-color 250ms; width: 100%; opacity: 1; transition: opacity 250ms; webkit-transition: opacity 250ms; background-color: #95A5A6; } .ua07fe0e9428a7dad734d722d8ee4d435:active , .ua07fe0e9428a7dad734d722d8ee4d435:hover { opacity: 1; transition: opacity 250ms; webkit-transition: opacity 250ms; background-color: #2C3E50; } .ua07fe0e9428a7dad734d722d8ee4d435 .centered-text-area { width: 100%; position: relative ; } .ua07fe0e9428a7dad734d722d8ee4d435 .ctaText { border-bottom: 0 solid #fff; color: #2980B9; font-size: 16px; font-weight: bold; margin: 0; padding: 0; text-decoration: underline; } .ua07fe0e9428a7dad734d722d8ee4d435 .postTitle { color: #FFFFFF; font-size: 16px; font-weight: 600; margin: 0; padding: 0; width: 100%; } .ua07fe0e9428a7dad734d722d8ee4d435 .ctaButton { background-color: #7F8C8D!important; color: #2980B9; border: none; border-radius: 3px; box-shadow: none; font-size: 14px; font-weight: bold; line-height: 26px; moz-border-radius: 3px; text-align: center; text-decoration: none; text-shadow: none; width: 80px; min-height: 80px; background: url(https://artscolumbia.org/wp-content/plugins/intelly-related-posts/assets/images/simple-arrow.png)no-repeat; position: absolute; right: 0; top: 0; } .ua07fe0e9428a7dad734d722d8ee4d435:hover .ctaButton { background-color: #34495E!important; } .ua07fe0e9428a7dad734d722d8ee4d435 .centered-text { display: table; height: 80px; padding-left : 18px; top: 0; } .ua07fe0e9428a7dad734d722d8ee4d435 .ua07fe0e9428a7dad734d722d8ee4d435-content { display: table-cell; margin: 0; padding: 0; padding-right: 108px; position: relative; vertical-align: middle; width: 100%; } .ua07fe0e9428a7dad734d722d8ee4d435:after { content: ""; display: block; clear: both; } READ: The novel Victor Essay Roy Batty shows this by saving Deckard of falling off the building, sitting in front of Deckard releasing a dove to commemorate his death that he most likely learned to accept and appreciate while Deckard demonstrates a humane act when he hurries home to find Rachel, desperate to escape the city with her before someone in the Blade Runner unit finds them. As they leave Rachel knocks over the unicorn that was placed on the floor, symbolizing her escape from the Tyrell Corporation, which only looked upon her as a replicant. Deckard fell in love with her as a human, and by doing so; she became . Bladerunner Humanity Of Deckard Roy Batty Essay Example For Students Bladerunner: Humanity Of Deckard Roy Batty Essay Bladerunner: Humanity Of Deckard Roy Batty Essay Roy Batty and Deckard are both able to show us what it means to be human. To what extent do you agree? Through Blade Runner, we see an epic quest filled with meaning and symbolism applicable to the human condition. Replicants are basically human beings, except for the fact that they lack a history. As a consequence of this, perhaps, they also lack proper emotional faculties especially empathy. Empathy is the ability to place oneself in the position of another living being and understand that persons feelings. We will write a custom essay on Bladerunner: Humanity Of Deckard Roy Batty specifically for you for only $16.38 $13.9/page Order now Blade runner promotes that empathy is the defining characteristics for humanity. The replicants, designed not to show any emotion, develop spiritually and emotionally throughout the film. The characters in the movie, even the ones that were not human, had many humanistic and believable qualities. Many of them were able to feel love as well as hate. Although Deckard is supposedly human he at times shows less emotion than Roy. He seems heartless and uncompassionate making himself look very unhuman. We see that Deckard is possibly not human as well, but a replicant. He shows no compassion when he tells Rachel of her being a replicant with implants. In tears, Rachel sneaks out of Deckards apartment and into the streets. The only time in which Deckard really shows emotion is accomplished when Roy, forging Deckard through the fires of a harrowing battle, looks terrified knowing that he is going to die. Through this, Roy tries to communicate his life experiences, and the importance of life before his own flame extinguishes explaining of the horrors of their enslavement. Again, all of these human characteristics that the non-human characters showed makes them more believable for the viewers. The whole definition of humanity is changed by its interaction with the Replicants. For the replicant Roy Batty it was obvious that that he felt strong emotions, perhaps even love for his fellow replicants. After Deckard killed Pris, Roy leaned over her and kissed her showing that he had loved her. He also showed these feelings for Pris and Zhora breaking two of Deckards fingers, one for Pris and one for Zhora. Although this act seemed quite inhuman, the motivation behind it seemed quite believable. He also demonstrates an inhumane role when he kills Tyrell but Tyrell is inhumane to create intelligent beings with such a limited life span displaying greed and manipulation. Batty also showed many human emotions as he talked of the horrors he had endured. It was obviously very difficult for him to take these nightmares as they affected him much in the same way it would have affected any human. He also exhibited human qualities when he saved Deckard from falling off the building. Quote: Quite an experience to live in fear, isnt it? Thats what its like to live as a slave. At the last moment, Roy saves him by grabbing his wrist with the nail-impaled hand. He draws him up to the roof, and lays him down. Pris also shows human qualities. Pris was very naive. She seemed to be the least developed of all of the Replicants and therefore was very much a follower. She also had a certain sort of innocence. Quote: Then were stupid, and well die! She says this after Batty tells of the deaths of their friends, which show that she is scared and starting to get worried that shell die, she has feelings, and starts to panic. Towards the end of the movie it levels it up to see that both Batty and Deckard show us the meaning of what it means to be alive. .u6f8e0e9b4741ff92a4cfcda4c5b512fc , .u6f8e0e9b4741ff92a4cfcda4c5b512fc .postImageUrl , .u6f8e0e9b4741ff92a4cfcda4c5b512fc .centered-text-area { min-height: 80px; position: relative; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc , .u6f8e0e9b4741ff92a4cfcda4c5b512fc:hover , .u6f8e0e9b4741ff92a4cfcda4c5b512fc:visited , .u6f8e0e9b4741ff92a4cfcda4c5b512fc:active { border:0!important; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc .clearfix:after { content: ""; display: table; clear: both; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc { display: block; transition: background-color 250ms; webkit-transition: background-color 250ms; width: 100%; opacity: 1; transition: opacity 250ms; webkit-transition: opacity 250ms; background-color: #95A5A6; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc:active , .u6f8e0e9b4741ff92a4cfcda4c5b512fc:hover { opacity: 1; transition: opacity 250ms; webkit-transition: opacity 250ms; background-color: #2C3E50; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc .centered-text-area { width: 100%; position: relative ; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc .ctaText { border-bottom: 0 solid #fff; color: #2980B9; font-size: 16px; font-weight: bold; margin: 0; padding: 0; text-decoration: underline; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc .postTitle { color: #FFFFFF; font-size: 16px; font-weight: 600; margin: 0; padding: 0; width: 100%; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc .ctaButton { background-color: #7F8C8D!important; color: #2980B9; border: none; border-radius: 3px; box-shadow: none; font-size: 14px; font-weight: bold; line-height: 26px; moz-border-radius: 3px; text-align: center; text-decoration: none; text-shadow: none; width: 80px; min-height: 80px; background: url(https://artscolumbia.org/wp-content/plugins/intelly-related-posts/assets/images/simple-arrow.png)no-repeat; position: absolute; right: 0; top: 0; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc:hover .ctaButton { background-color: #34495E!important; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc .centered-text { display: table; height: 80px; padding-left : 18px; top: 0; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc .u6f8e0e9b4741ff92a4cfcda4c5b512fc-content { display: table-cell; margin: 0; padding: 0; padding-right: 108px; position: relative; vertical-align: middle; width: 100%; } .u6f8e0e9b4741ff92a4cfcda4c5b512fc:after { content: ""; display: block; clear: both; } READ: Western Expansion Of The U.S. Essay Thesis Roy Batty shows this by saving Deckard of falling off the building, sitting in front of Deckard releasing a dove to commemorate his death that he most likely learned to accept and appreciate while Deckard demonstrates a humane act when he hurries home to find Rachel, desperate to escape the city with her before someone in the Blade Runner unit finds them. As they leave Rachel knocks over the unicorn that was placed on the floor, symbolizing her escape from the Tyrell Corporation, which only looked upon her as a replicant. .