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).

Communism :: Communism Essays

The lure of easy women almost made me a spy and traitor to my country "Sex Lead Me To Communism" from Man to Man Vol. 2, No. 2, 1951 SEX, woman's most resistless weapon through the ages for the domination of the male, has proven one of the most successful and insidious devices in the secret arsenal of the Communists to recruit their unsavory army of spies, saboteurs and disruptionists in the grimly declared war on the United States and all decent mankind. In the relentless effort of the Kremlin to turn the whole world into faceless slaves in order that "The International Soviet shall be the human race," as their official song, The Internationale, declares, there is no honor or conscience, and promiscuity is the rule, not the exception. The only vice the Reds frown, upon is drinking! I know, because I was one of those witless persons who fell into the mantrap set by the modern Delilabs who follow the Party line. They stopped at nothing--absolutely nothing--in order to enlist their fellow Americans into the great conspiracy to subjugate, and later to liquidate, every human being who does not deify the unholy trinity of Marx, Lenin and Stalin. First came Sonia, with her full, cherry lips and her brown, limpid eyes. She was a secretary, a graduate of a woman's college and as unscrupulous a little witch as ever shook her clenched fist at a passing flag of her country or stuck a pin into a patrolman's horse. Next came Margie, a full-bosomed redhead, a new comer from England and an expert dress designer. She had made it her life work to lure men into Communism. Then Mildred, a honey blonde with a Vassar degree. She was the gay and sophisticated type on the surface, but underneath she was deadly serious about her radical beliefs. She had a cozy apartment and seemingly plenty of money. She liked to discuss the social significance of Shakespeare over cocktails and make converts to the "cause." Then Terry, Betty and several others whose names I have forgotten. And lastly, Gladys, a banker's daughter who had run away from home, landed in New York's Greenwich Village and become the most radical of all the Communist girls I met. Talk about free love! This was really something. You tired of one, and there was always another at your beck and call. No Turk could boast a more variegated harem.

Police Essay

Police generally perceive the risk of injury, assault, and even death to be greatest for domestic violence calls. Why do police have these beliefs, and what is the reality of the situation? When responding to calls few inspire more dread among police officers than answering to a domestic call. Police have generally the perception of risk of injury, assault and even death. There is always this perception among police officers when answering domestic calls. Such perception cannot be avoided because domestic calls most often than not have the element of unpredictability. Emotions are high and this can run even higher if coupled with drugs and alcohol. Indeed, responding to a domestic call can be very risky on the part of the police officers. When they respond to such call, they are perceived as the threat instead of being the protector. Traditionally, a police officer would respond to a call and restore peace as soon as possible and then clear from the call. The community policing philosophy dictates that the officer review of the problem, analyze it and try to come up with a solution to the problem. (Denise Papagno). However, this theory is not realistic at all. Upon responding to a domestic call, the police officer enters into a domestic abode as a protector, but in the eyes of the owners of the abode despite his good intentions, he will always be the intruder. Hence, the police officer cannot effectively do his job especially if the victim refuses to leave and instead would insist in not doing anything or even file a complaint for that matter. It is essentially difficult for police officers to face and respond to domestic calls as society now views domestic calls as a serious crime and not merely a private family quarrel. The fact that not all of the police are educated in handling domestic issues or why the victim does not leave her abuser or why the batterer abuses the victim. Because of this, the police fail to understand victims of domestic calls and are less inclined to help them in the next call. In your opinion, what is the most problematic myth associated with policing? Explain your answer. As early as the 18th century, police work or policing is associated in being a night watchman. The job basically entails maintaining order against threats to order itself – wild animals, fire or unruly behaviour. However, at the turn of the century, policing has evolved into something more than being a night watchman. Police not only has to maintain order in their respective communities but they are also tasked to solve and fight crimes. Hence, the notion that police can solve any crime reported to them grew. As crime fighters, this notion has proven to be an additional burden to policing. Even simple and private nuisances such as littering, drunkenness and unruly behaviour are called in and reported to the police. Hence, this takes up on the workload of policing instead of focusing more on the serious crime-solving work. But together with the notion of being crime-fighters came the myth of police brutality. The average citizen sees policemen as having â€Å"zero-tolerance†. For example, in domestic calls, instead of turning in their abuser, victims would opt not to do anything for fear of the police. If they fear their abusers, victims fear the police more. It does not help that there are also police mandates such as that of Rudy Giuliani who implemented a version of Broken Windows policing across New York City. Thus, policemen were tasked to become aggressive in stamping out public disorder such as drunkenness, jaywalking and noisiness. In reality however, policing is not just being brutal and aggressive towards those lawbreakers. The concept of â€Å"community policing† has made advancement in policing. Thus, police officers who are on foot patrol have elevated the common myth about policing because admittedly, an officer who is inside the squad car and safely sealed inside cannot relate with the other people from the neighbourhood.

Lord of the Flies- Basic Legal Notions essays

Lord of the Flies- Basic Legal Notions essays The movie the Lord of the flies reflects many basic legal notions. Many of these concepts are identified and questioned throughout the film. The movie starts out with a plane crash. Due to this many private-school boys are left stranded on a deserted island. The boys are left to fend for themselves with no adult authority figures left with them. Piggy and Ralph are the 1st to meet up with each other after escaping from their shot-down plane. They become friends immediately and stick loyally together throughout the movie. They then meet up with Jack and his Choir, Simon, Sam and Eric, and many other characters join in an assembly. Rules are set down, and Ralph is elected to be chief. Ralph calls another assembly, and reminds everyone that they are completely alone on the island, and there are no adults. They are in a state of anarchy (lawlessness). After allocating jobs, laws were loosely set in place to ensure that a society should lightly emerge. Jack and his crew were busy tracking a pig when they were meant to be monitoring the fire. As a result of their lack of involvement they missed an opportunity to get saved by a plane flying ahead. Ralph presses that keeping the signal fire is much more important than hunting and they have displayed a lack of fairness. After a successful hunting expedition, the boys return with a pig which is shared even among the boys, this represent equality as the portions were fair for everyone. Soon, after many more disagreements between Ralph and jack had emerged, they separated into two tribes, Jack went down the savage path turning his crew savage with him. Covering themselves with war-paint, their values consisted of hunting for food and protecting their base camp. Ralphs tribe was based more on ethics; his tribe contained the younger boys and regarded safety and being saved more then a power hierarchy. After a series of murders including Piggys, Jack ...

The Presidents Role in the U.S. Federal Budget Process

The Presidents Role in the U.S. Federal Budget Process The annual federal budget process begins the first Monday in February of each year and should be concluded by October 1, the start of the new Federal Fiscal Year. In some make that most years, the October 1 date is not met. Here is how the process is supposed to work. The President Submits a Budget Proposal to Congress In the first step of the annual U.S. federal budget process, the President of the United States formulates and submits a budget request for the upcoming fiscal year to Congress. Under the Budget and Accounting Act of 1921, the president is required to submit his or her proposed budget to Congress for each government fiscal year, the 12-month period beginning on October 1 and ending on September 30 of the next calendar year. Current federal budget law requires the president to submit the budget proposal budget between the first Monday in January and the first Monday in February. Typically, the president’s budget is submitted during the first week of February. However, especially in years when the new, incoming president belongs to a different party than the former president, submittal of the budget may be delayed. The president’s budget proposal may also be delayed by pressing government financial difficulties. For example, President Barack Obama did not submit his FY 2014 budget proposal until April 10, 2013, due to ongoing negotiations with Congress over the implementation of the budget sequester and mandatory spending cuts dictated by the Budget Control Act of 2011. In fiscal year 2016, the federal budget called for the expenditure of nearly $4 trillion. So, as you might imagine, deciding exactly how that much taxpayer money is to be spent represents a major part of the president’s job. While the formulation of the president’s annual budget proposal takes several months, the Congressional Budget and Impoundment Control Act of 1974 (the Budget Act) requires that it be presented to Congress on or before the first Monday in February. In formulating the budget request, the president is assisted by the Office of Management and Budget (OMB), a major, independent part of the Executive Office of the President. The president’s budget proposals, as well as the final approved budget, are posted on the OMB website. Based on the input of the federal agencies, the presidents budget proposal projects estimated spending, revenue, and borrowing levels broken down by functional categories for the coming fiscal year to start on October 1.The president’s budget proposal includes volumes of information prepared by the president intended to convince Congress that the president’s spending priorities and amounts are justified. In addition, each federal executive branch agency and independent agency includes its own funding request and supporting information. All of these documents are also posted on the OMB website. The presidents budget proposal includes a suggested level of funding for each Cabinet-level agency and all programs currently administered by them. The presidents budget proposal serves as a starting point for the Congress to consider. Congress is under no obligation to adopt all or any of the Presidents budget and often makes significant changes. However, since the President must ultimately approve all future bills they might pass, Congress is often reluctant to completely ignore the spending priorities of the Presidents budget. House and Senate Budget Committees Report the Budget Resolution The Congressional Budget Act requires passage of an annual Congressional Budget Resolution, a concurrent resolution passed in identical form by both House and Senate, but not requiring the Presidents signature. The Budget Resolution is an important document providing Congress an opportunity to lay out its own spending, revenue, borrowing and economic goals for the coming fiscal year, as well as the next five future fiscal years. In recent years, the Budget Resolution has included suggestions for government program spending reforms leading to the goal of a balanced budget. Both the House and Senate Budget Committees hold hearings on the annual Budget Resolution. The committees seek testimony from presidential administration officials, Members of Congress and expert witnesses. Based on testimony and their deliberations, each committee writes or marks-up its respective version of the Budget Resolution. The Budget Committees are required to present or report their final Budget Resolution for consideration by the full House and Senate by April 1. Next Steps: Congress Prepares its Budget Resolution

Research Paper Assignment Example | Topics and Well Written Essays - 1250 words

Research Paper - Assignment Example The government gave a report, and estimated the number of the gas leakage victims was five hundred thousand people (Ferrara, 2012). Three thousand eight hundred of these people had partial injuries, while three thousand nine hundred were permanently injured. There are numerous reasons advanced by scholars as to the cause of the Bhopal disaster. However, most agree that the immediate cause of the disaster was poor management and negligence by the managerial team of Union Carbide India Limited. This paper analyzes the causes of the Bhopal Disaster, in relation to poor managerial and communication skills (Ferrara, 2012). With concrete examples, and well supported facts, this paper looks at how the disaster occurred, and the failure of the management to initiate preventive measures that will protect its workers, from risks emanating from the plant (Rosencranz, 1988). This paper takes a stand that poor management and communication policies at Union Carbide India resulted to the occurrence of the disaster. Failure in communication, before, during and after the Bhopal disaster led to the death of thousands people. In 1984, the Indians comprised of the entire employees at the company. It is the Indians who controlled the machines, and they were involved at virtually all the operations of the company (Dhara et al, 2002). This is because the company implemented its agreement with the Indian government of promoting self-sustenance. On this note, language was a barrier in effectively conducting the affairs of the company. This people lived with their families near the company, and they were the first victims of the gas leakage. Despite this language barrier, the company printed the operating manuals for their equipment’s in English. This was an aspect of mismanagement and negligence; this is because the local community was not proficient in English, and had no idea on know how to react to the warnings contained in the manuals,

Effectiveness of Mentoring in Organizations Essay

Effectiveness of Mentoring in Organizations - Essay Example The performance of employees is dependent upon the degree of alignment achieved with the strategic business objectives which is measured effectively by innovative means in the modern organization. However, it is not easy for the younger talents to understand the detailed aspects of such alignments on their own whereas they bring to table some excellent competencies as an outcome of their respective educational backgrounds. Such talents require effective mentoring to help them align with the organizational goals such that they can gradually build a career in the system by effectively delivering results in line with the strategic objectives of the organization. The mentors need to be those senior experienced colleagues who have been star performers in the system by virtue of their recognized contribution to the goals of the organization. The mentor-protg relationships in organizations, however, are complex and require a lot of organizational focus (as a part of larger strategies) to en sure successful results in building talents for the future. There are numerous benefits to organizations that establish formal mentoring programs within the system and carefully managing the emotional dynamics between the mentors and the protgs by avoiding conflicts of interests. Some organizations practice such strategies for every level in the organization after recognising the need for such programs and clearly setting out their objectives. Such activities are normally carried out through Human Resources department having dedicated functional areas for training & development within the organization. Such a department possesses a senior management representative for effective communication to the top and also possesses their own quality goals in achieving people development in the system. The Human Resources function views the entire organization as a social system and tries to establish models of existing human dynamics prevailing within the organization. These dynamics are then mapped with the growth path that has been established within the organization as per the business requirements in order to build aspirations and healthy competition among people. The employees are then provided guidance and help through senior & experienced employees through well designed mentoring programmes such that every