Studies of Adoptively Transferred CMV-Specific T Cells

Studies of Adoptively Transferred CMV-Specific T Cells Group Method of Expansion/Selection Riddell, 1992, 1995 Expansion using CMV-infected fibroblasts Einsele, 2002 Expansion with CMV lysate Cobbold, 2005 Tetramer Selection using magnetic beads Micklethwaite, 2008 Antigen-presenting cells (Dendritic cells) transduced with an adenoviral vector encoding CMVpp65 Peggs, 2011 Selection of T cells secreting IFN-ÃŽÂ ³ after exposure to CMV antigen Blyth, 2013 Antigen-presenting cells (Dendritic cells) transduced with an adenoviral vector encoding CMVpp65 or Dendritic cells pulsed with HLA-A02-restricted peptide NLVPMVATV Quoted from (Hanley and Bollard, 2014). The ability to generate CMV, EBV, and adenovirus-specific CTL from the 20% fraction of a cord blood unit by using dendritic cells transduced with an Ad5/f35-CMV-pp65 vector as well as the cytokines IL-7, IL-12, and IL-15 was reported by Hanley and colleagues in 2009. Responding T cells were shown to be derived from the naÃÆ'Â ¯ve T cell population and responded to typical and atypical, novel CMV-pp65 epitopes. Later on, the ability to generate CMV-specific T cells from CMV-seronegative donors was reported by Jedema et al., 2011 and Hanley et al., 2013. Vaccination: On the basis of the cost to the health care system and the impact of the virus on human suffering, the development of an effective prophylactic vaccine to prevent CMV symptomatic congenital disease and/or to prevent disease in immunocompromised individuals is a high priority and would be a highly cost-effective measure (Khanna and Diamond, 2006). A successful vaccine strategy should aim to stimulate the innate and adaptive immune responses at the appropriate time. Both humoral and cell-mediated immune responses might be necessary to prevent congenital disease, whereas cellular immune response alone might be sufficient to prevent virus-associated complications in transplant patients (Khanna and Diamond, 2006). Cytomegalovirus exhibits a high level of molecular diversity and carries many immune evasion genes (Hansen et al., 2010). Thus, infection within a host can occur with multiple virus strains concomitantly, including at the time of initial infection, or sequentially (Renzette et al., 2011). Broad and cross-neutralizing cellular and humoral responses have therefore become a major goal of vaccine design (Arvin et al., 2004). Various strategies have been developed, though a vaccine against CMV remains elusive. CMV vaccines have been obtained using attenuated or chimeric viruses, DBs, recombinant proteins, DNA, peptides and/or viral vectors (poxvirus/adenovirus) (Khanna and Diamond, 2006). A number of subunit CMV vaccines tested in clinical trials targeted the abundant pp65 protein (Sylwester et al., 2005), which is expressed by CMV-infected cells both early and late after infection (La Rosa et al., 2012). Cytomegalovirus vaccines in clinical trials include: glycoprotein B subunit vaccines; alphavirus replicon particle vaccines; DNA vaccines; and live-attenuated vaccines. A variety of vaccine strategies are also being examined in preclinical systems and animal models of infection. These include: recombinant vesicular stomatitis virus vaccines; recombinant modified vaccinia virus Ankara; replication-deficient adenovirus-vectored vaccines; and recombinant live-attenuated virus vaccines generated by mutagenesis of cloned rodent CMV genomes maintained as bacterial artificial chromosomes in Escherichia coli (Sung and Schleiss, 2010). Trial of a subunit vaccine consisting of recombinant HCMV envelope gB with MF59 adjuvant: All HCMV-infected individuals have a significant proportion of neutralizing antibodies to HCMV being specific for epitopes on gB (Sung and Schleiss, 2010). A study of the use of HCMV gB vaccine plus MF59 adjuvant was reported. It was administered following a 0-, 1- and 6-month schedule (Pass et al., 2009). Although the study demonstrated that the gB vaccine could significantly reduce the risk of acquiring primary maternal HCMV infection, the study did not address the question of whether vaccine-induced HCMV immunity was equivalent to natural immunity in modulating either infection rate or sequelae for the fetus (Dekker and Arvin, 2009). Since re-infection with new strains of HCMV with which the host has no prior experience can lead to transmission to the fetus with subsequent sequelae (Boppana et al., 2001), the issue of cross-protection against diverse clinical isolates following administration of gB vaccine from a single genotype must be defined in future studies (Sung and Schleiss, 2010). Clinical trial evaluation of a two-component alphavirus replicon particle vaccine containing HCMV gB and phosphoprotein 65 (pp65)/immediate early fusion proteins: The gB and the pp65 are the most frequently recognized antigens by CD4+ T cells, and pp65 is also one of the antigens most frequently recognized by CD8+ T cells (Sylwester et al., 2005). The HCMV IE1 is also an important target of the CD8+ T-cell response (Slezak et al., 2007). Therefore, vaccination strategies that aimed at eliciting T-cell responses has focused on the pp65 protein andIE1 gene product (Sung and Schleiss, 2010). AVX601 is a two-component alphavirus replicon particle vaccine expressing HCMV gB and a fusion protein of pp65-IE1 (Reap et al., 2007). The vaccine was well tolerated, with only mild local reactogenicity, Mild-to-moderate systemic reactogenicity was reported in some subjects (Sung and Schleiss, 2010). Bivalent HCMV DNA vaccine: The use of a HCMV DNA vaccine in immunocompromised subjects, such as transplant recipients, would eliminate the safety concerns of live-attenuated HCMV or live recombinant viral-vectored vaccines (Selinsky et al., 2006). DNA vaccines elicit robust CD4+ and CD8+ T-cell and antibody responses (Sung and Schleiss, 2010). VCL-CB01, a bivalent HCMV DNA vaccine that contains two plasmids encoding HCMV pp65 and gB (LiuÂÂ   and Ulmer, 2005). This vaccine has the ability to prime antigen-specific T cells, with the capacity to proliferate and secrete IFN-ÃŽÂ ³ on restimulation with antigen (Wloch et al., 2008). Further modifications of this vaccine may be required to optimize immunogenicity, particularly to the gB moiety (Sung and Schleiss, 2010). It was generally well tolerated. The most common adverse event was mild site injection pain (Liu and Ulmer, 2005). Live-attenuated HCMV Towne vaccine with or without adjuvant recombinant IL-12 and/or priming by DNA vaccine: Immunization with Towne vaccine prevented HCMV disease in seronegative renal transplant recipients, although it did not prevent infection in these patients or in parents of HCMV-infected children (Sung and Schleiss, 2010). Evidence suggests that the relative defect in Towne vaccine may be related to inadequate antigen-specific IFN-ÃŽÂ ³ responses by CD4+ and CD8+ T cells following vaccination (Jacobson et al., 2006). Approaches to improve the immunogenicity of the Towne vaccine are being explored (Jacobson et al., 2009). One approach was to generate genetic recombinant vaccines containing regions from the genome of the unattenuated Toledo strain of HCMV, substituted for the corresponding regions of the Towne genome (Heineman et al., 2006). In another approach, HCMV DNA vaccine is used to prime for memory immune responses to Towne vaccine (Jacobson et al., 2009). A third approach is to co-administer Towne with recombinant human IL-12 (Jacobson et al., 2006*). 5) Preclinical vaccine development Recombinant vesicular stomatitis virus expressing murine cytomegalovirus gB: As a recombinant vaccine vector, vesicular stomatitis virus (VSV) can induce strong humoral and cellular immunity, particularly at mucosal surfaces. This attribute makes recombinant VSV (rVSV) an attractive candidate for development of a vectored HCMV vaccine (Wilson etal., 2008). Live rVSV vector expressing a murine CMV homolog of the gB protein has been tested in the mouse model (Wilson etal., 2008). This induced neutralizing antibody responses, and resulted in reduced viral titers. Also, splenocytes from immunized mice produced a CD8+ IFN-ÃŽÂ ³ response to gB (Sung and Schleiss, 2010). Recombinant modified vaccinia virus Ankara: The attenuated poxvirus, modified vaccinia virus Ankara (MVA), was established as a safe and potent antigen delivery system. Its genome has undergone six major deletions during serial passage (Sung and Schleiss, 2010), which, in turn, allows the insertion of multiple HCMV genes (Wang et al., 2007). A recombinant MVA vaccine that expresses a soluble, secreted form of HCMV gB, based on the AD169 strain sequence has been constructed (Wang et al., 2004). High levels of gB-specific neutralizing antibodies were elicited in vaccinated mice (Sung and Schleiss, 2010). A trivalent MVA expressing gB, pp65 and IE1 has been developed (Wang et al., 2006) with ability to induce humoral and cellular immunity to gB (Wang et al., 2006). Recombinant MVAs have also been generated expressing both full-length pp65 and exon 4 of IE1 with induction of robust primary cell-mediated immunity and stimulation of vigorous expansion of memory Tcell responses to both antigens (Wang et al., 2007). Another recombinant MVA expressing pp65 and a fusion protein of HCMV IE1 exon 4 and IE2 exon 5 was constructed to maximize the representation of IE-specific immunity (Wang et al., 2008). Replication-deficient adenovirus-vectored polyepitope vaccine: Systemic and mucosal immunity to MCMV could be induced by intranasal immunization using a replication deficient adenoviral vector expressing murine CMV glycoprotein H in a murine model (Shanley and Wu, 2005). Modified adenoviral vector Ad5F35, Ad5F35-AD-1, has been generated, expressing the immunodominant antigenic domain-1 epitope of HCMV gB based on the sequence from the AD169 strain (Zhao et al., 2009). Since the AD-1 epitope is well conserved between different strains of HCMV (Britt et al., 2005), expression of the AD-1 epitope from AD5F35 elicits neutralizing antibody responses to diverse clinical isolates (Zhao et al., 2009). Another replication deficient adenoviral-vectored vaccine, Ad-gBCMVpoly (Zhong et al., 2008) which encodes 46 HCMV T-cell epitopes from multiple antigens covalently linked to the extracellular domain of HCMV gB antigen (Zhong et al., 2008). This chimeric vaccine elicited neutralizing antibody responses and virus-specific CD4+ and CD8+ T-cell responses (Zhong and Khanna, 2009). Recombinant live CMV vaccine by bacterial artificial chromosome mutagenesis: An ideal live-attenuated HCMV vaccine should grow to high titers in cell culture for easy production, should be severely attenuated in vivo, even in immunocompromised hosts, and should elicit a strong immune response sufficient to protect against HCMV-associated disease (Mohr et al., 2008). An approach to the generation of such a vaccine is the targeted deletion of CMV genes modulating the host immune response (Cicin-Sain et al., 2007). This approach has been facilitated by the advances in mutagenesis of cloned CMV genomes maintained as bacterial artificial chromosomes in Escherichia coli as well as the rapidly expanding knowledge about the role of viral genes in immunopathogenesis and immune evasion (Dunn et al., 2003).

Lucifer in Starlight by George Meredith :: Lucifer in Starlight George Meredith

Lucifer in Starlight by George Meredith Examining a poem in detail can bring out new meanings and ideas. By careful analysis, the full beauty of the poem can be appreciated. The poem "Lucifer in Starlight (p. 959)", by George Meredith, can be analyzed to refine the authors purpose, by examining every subtle hint, every possibility, for a deeper theme. Also, "deciphering" formal literary techniques such as metaphor, connotation, and symbolism is the key to unlock other expressions. The main theme of the poem is that Lucifer has no place out of his hell, and anything he tries to reenter heaven is futile. As with any poem, it is best to first examine how the title, "Lucifer in Starlight" relates to the body of the poem. Obviously, Lucifer is the defiant angel that was banished from heaven, and sent to the underworld of hell, where he known as Satan. The title refers to the devil as "in starlight", so this means he has to rise to a place where the stars are visible, not the fires of hell. This rising from the underworld is summed up in the first line. It is later explained that he is doing so because he is tired of his 'dark dominion." Ironically, the first line refers to Lucifer honorably, as a "Prince", while in the second line he is tagged as a fiend. This leaves the reader feeling perplexed, yet still thinking of Lucifer as the enemy. At first it may seem as Lucifer has risen to the Earth, but it is further clarified that he has elevated himself above the "rolling ball". However, god imagined the world as planar, with heaven on a higher plane, and hell on a lower plane, not spherical as defined here. From his place in the stars above earth, Lucifer looks down through the clouds, a nd observes the sinners. He is talking about the denizens of the earth, for since Adam sinned in the beginning, all of his sons and daughters are also sinners. Perhaps he can relate to them, as he is also trying for entrance to heaven. For now , he sets his mind on the people who will become denizens of his hell eventually. Here Meredith shows how much hubris the devil really has, for the reader can just see Lucifer savoring over the masses entering his vile domain. Then, Lucifer peers at the most extreme places in the world, describing the sands of Africa.

Examining Four Types of Diversity Essay -- demographics, culture, profe

While diversity is often a term used to refer specifically to cultural differences, diversity applies to all the qualities that make people different. From a management perspective, the key to diversity is to understand how different types of diversity and different demographic characteristics can impact human behavior. The four types of diversity that will be examined are: occupation, differences in skills and abilities, personality traits, and value and attitudes. For each type of diversity, the impact on individual behavior will be described. One type of diversity is occupation. For example, an individual in a professional occupation is more likely to make his or her own decisions and is also more likely to reject being managed too strongly. The case of a medical doctor is one example. A medical doctor considers themselves an expert on their area and is also likely to consider that nobody else has the same expertise. Based on this, the individual is likely to make his or her own decisions and to act independently. The same also applies to other professional occupations such as lawyers and scientists. This can be contrasted with positions that are generally considered as requiring less expertise. For example, a salesperson or a secretary would be more likely to accept that their role is a support function, with this meaning that they are less likely to act independently and more likely to take direction. Another important aspect of occupation is that a person's behaviors will change based on the role of that occupat ion. In short, most people will adapt their behavior to match it with what they consider expected behavior for that role. For example, an individual in a supervisory role ... ...ive for the organization and negative for themselves. This shows how values and attitudes influence individual behavior. From this paper one can see that diversity is much more than just cultural differences. Occupation, differences in skills and abilities, personality traits, and values and attitudes are just a few of the types of diversity that impact individual behavior. Diversity is everything that makes up a person from birth. All life experiences play a part in the make up of diversity. References Daft, R.L. (1997). Management. Fort Worth, TX: The Dryden Press. Kandola, R., & Fullerton, J. (2000). "Diversity: More than just an empty slogan." The Effective Manager: Perspective and Illustrations. Ed. Jon Billsberry. Thousand Oaks, CA: SAGE Publications: 287-294. Seamon, J.G., & Kenrick, D.T. (1994). Psychology. Englewood Cliffs, NJ: Prentice Hall.

Alexandru Florea Economic Development and Growth

Indicators of economic development: Labor productivity Weighted Machine tool industry in total industry Weighted Machine tool exports in total exports Weighted Brain drain in total export Weighted Employment in services Economic growth is represented by the evolution of specific economic indexes, with benefits for the social and economic life, in a specific time and area. The most known index for calculating the economic growth is the GAP/ capita. Types of economic growth Extensive economic growth- based on growing the GAP/capita by increasing the number of workers, arable lands etc.Consolidated economic growth: it would be realized at the global scale Zero economic growth: is happening when the economic indexes and the population of the country are increasing with the same percentage. The single way that a state can achieve economic development and growth is by using their economies to make investments. Economic development represents a qualitative process while economic growth is a quantitative one. However the processes of economic development and growth are produced simultaneous therefore they must be considered together. The first part of the analysis will provide an overall picture of Roman's economic performance.It will be presented the current economic development situation and its growth during the analyzed years. The second part of the analysis represents an econometric exercise which will provide the connection between GAP, Urban Population and Employment. At the end of the exercise it will 3 be possible to predict values of GAP depending on Urban Population and the level of employment. The third part of the analysis will provide information regarding the development lacks of Roman's economy. The fourth part of analysis refers to Romania market inefficiency.It will provide the most important issues about market failures in Romania. The fifth part of analysis includes the Development Policies. It will present the main targets to improve Roman's econom y for the next years. B. Analysis 1. Methodology For this analysis were chosen indexes from 5 areas: Romania, Bulgaria, Germany, France and European Union. Besides Romania, which is the main subject of the analysis, it was chosen Bulgaria like a state with similar economic situation. Germany and France were chosen because they represent two of the most developed country in Europe.In the same time they represent examples of how the economic situation should be in a developed country therefore Romania must achieve a close level to them in order to become a State with a developed economy. Nevertheless, all of them are member states of European union therefore all of them must converge to the same level, as result, it is absolutely necessary to include the European union indexes. First part of the analysis contains statistical results about the economic development and growth situation in Romania. The analyzed period refers to 1990-2013.For this part there were seed data series, with an nual frequency, from the official website of World Bank. Second part of the analysis is represented by a linear regression model. For analyzing the correlation between variables, were used data series (1991-2012), with annual frequency, from the official website of World Bank. The data refers only to Romania. The purpose of the exercise was to find the influence Of that urban population and employment have on GAP. The form of linear regression model is: AMPLE+?* POP 4 Where: BIB – Gross Domestic Product AMPLE -? Employment POP – the urban population percentageThe GAP was deflated referring to the year 2005 as the base year. Views was the soft used for testing and correcting the regression model. The intensity between the dependent variable and the independent variables was analyzed considering the correlation coefficient R The sign efficacy of linear correlation coefficients was tested using t-test Starting from the hypothesis: HO: the model is not valid and HI: the mo del is valid, the validity of the regression model was tested using the Fischer test.The model's significance was tested with: – Wald test for testing the regression coefficients F test for testing the significance of the correlation ratio. – graphic method, Durbin Watson test and Breach Godlier test for verifying the independence of the random errors. – White test for verifying the homosexuality. -Jarred-Berea test for verifying the normality hypothesis. Third part of the analysis contains statistical results about the development lacks in Romania. The analyzed period refers to 1990-2013.For this part there were used data series, with annual frequency, from the official website of World Bank. Fourth part of the analysis contains statistical results about the market inefficiency in Romania. The analyzed period refers to 1990-2013. For this part there were used data series, with annual frequency, from the official website of World Bank. Fifth part of the analysis presents the main targets of the current development policy. It represents a summary of the Romania â€Å"National Strategy for Development'. 5 Economic Development and Growth Of Romania 2.Used data Gross Domestic Product: According to Ryan Barnes: â€Å"The GAP is the predecessor of all macroeconomic indexes; as an aggregate measure of the total economic output of a country, GAP represents the total value of goods and services produced by the economy, in a specific period†. Frequency: annual Source of collected data: World Bank website Other changes: *only for the regression model: 1,000,000,000 Expressed in: US$ Inflation: Inflation is defined as a sustained increase in the general level of prices for goods and services. It is measured as an annual percentage increase.As inflation rises, every dollar you own buys a smaller percentage of a good or service. Frequency: annual Expressed in: percentage Urban population index According to National Statistic Office: â€Å"Urban population index refers to the number of people which live in urban areas† Other changes: *only for the regression model: 1 ,OHO Expressed in: percentage of the total population Employment index Employment index refers to the active population (15-64 years old) rate: the ratio between the active population and the total number of people with the same age. Other changes: *only for the regression model: AMPLE( 1)= AMPLE(O)* 1,000 Health Expenditure index Health expenditure refers to the sum of public and private health expenditure. It covers the provision of health services (preventive and curative), family planning activities, nutrition activities, and emergency aid assassinated for health but does not include provision of water and sanitation. It is calculated as the percentage of a nation's GAP. Frequency: annual Pupil-teacher index Pupil-teacher ratio: the number of pupils enrolled in primary school divided by the number of primary school teachers.Expressed in: absolute num ber Public spending on education index Public expenditure on education as % of GAP is the total public expenditure (current and capital) on education expressed as a percentage of the Gross Domestic Product (GAP) in a given year. Public expenditure on education includes government spending on educational institutions (both public and private), education administration, and transfers/subsidies for private entities (students/households and other private entities) 7 3.Literature review About Roman's Economy According to the Constitution of 1991, Economy of Romania is an economy based on supply and demand rule therefore it means that the state must ensure the freedom of trade and the fair competition. In 1 939 the most important branches of industry were the oil and natural gas industries. 6. 24 million tons of oil was produced in Romania in 1939 and the total exports of oil valued 56 million dollars. Furthermore, with a production slightly lower than Germany, Romania had a very good sit uation in terms of grain.However salt and tobacco had also an important role for Roman's economy during this period. Even if it was of poor quality, tobacco was the main source of income for the people from the Danube Plain. After more than four decades, at the end of 1 989, economy of Romania had the basic communist economy, in all branches of industry' it was a state cooperative monopoly. Price, credits, salaries, the interest rate were directed y the â€Å"single national plan† without reflecting the supply and demand needs. On 21st of December 1 989 Romania had no external debt, the external debt was fully paid by the end of February 1989.