bluuebunny/crossref_metadata_2025 huggingface dataset:
The application of marketing research in the Birmingham Dental Hospital
Authors: Harrison J.J.H. , Roberts W.R. , Pinson R. , Dorning B.
Published: May 2004

In itself market research is unremarkable ‐ as were the methods in this particular instance ‐ but the context, i.e. the Birmingham Dental Hospital, was untypical, even by contemporary health standards. Reform of the public sector/NHS and the creation of the “internal market” have created conditions increasingly appropriate to the application of the marketing paradigm. This paper reports one such application and demonstrates the organizational benefits to be derived from marketing research in an unusual health care “provider” setting. Particular benefits included: the ability to conduct informed contract negotiation within the internal market; pursue service design and quality strategies to retain customers and maintain market share; and, the generation of an evidence based agenda to provoke internal change. As such it is an important contribution to understanding the changing nature of NHS culture and thus augments the health, dental and marketing literature(s).
British food retail capital in the USA: preface and update
Authors: Wrigley Neil
Published: May 2004

Provides a preface to the two‐part paper on “British food retail capital in the USA” reprinted from International Journal of Retail & Distribution Management, Vol. 25, 1997. Updates that two‐part paper with an account of Sainsbury’s experience with its US food retail businesses in 1997, and reflects on the firm’s corporate prospects in the USA.
Using means‐end structures for benefit segmentation
Authors: Botschen Günther , Thelen Eva M. , Pieters Rik
Published: May 2004

Although the basic idea of benefit segmentation lies in using causal, as opposed to descriptive, factors as segmentation criteria, most of the empirical studies do not differentiate between product attributes and the benefit sought by consumers. The objectives of this article are to clarify the distinction between attributes and benefits sought, and to apply a modified laddering technique, based on means‐end theory to use the elicited benefits to form benefit segments. A comparison with attribute‐based segments demonstrates that means‐end chains provide a powerful tool for “true” benefit segmentation.
Long‐range marketing
Authors: Mercer David
Published: May 2004

Short‐termism, especially in terms of marketing strategy, is supposed to be a problem afflicting various managements. We have found that one solution may be found in separating out longer‐term robust strategies from shorter‐term corporate strategy in a formal long‐range marketing plan. Using this approach, which starts with scenario forecasting and ends with the robust strategies coming out of this being compared with existing corporate strategy. The differences are usually easily reconciled, where the two typically converge on much the same issues. As a result, organisations are better able to ensure survival in the longer term. If they follow sound marketing practices, indeed, the price they might have to pay, in terms of the short‐term steering (changes), is usually small.
Marketing to ethnic minorities in Britain
Authors: Nwankwo Sonny , Lindridge Andrew
Published: May 2004

The ethnic minority population in Britain is sizeable and represents a viable and untapped market segment. In today’s fragmented and increasingly turbulent markets, ethnic marketing offers a new strategic focus for product/market development and, in many respects, companies which ignore this do so at their own competitive peril. Companies wishing to do business with ethnic minority groups will fundamentally have to review the basic premisses of their marketing plans to take account of the growing market pluralism and the multi‐ethnic reality of modern Britain. Accordingly, this paper provides a literature over‐view of the crucial issues which are likely to become the important determinants of success in developing ethnic marketing programmes. It is hoped that this paper will stimulate thought towards detailed examination of good practices, critical success factors and associated principles which might help to improve marketing practices aimed at the ethnic minority population.
Approaches by hotels to the use of the Internet as a relationship marketing tool
Authors: Gilbert David C. , Powell‐Perry Jan , Widijoso Sianandar
Published: May 2004

Offers a study of the current use of the Internet, as a marketing tool, by the hotel industry. Such a study is timely given that the growth rate of the World Wide Web (WWW or the “Web”) is estimated at about 50 per cent per month, with the number of sites doubling every 53 days. Seeks to present an argument for the application of the relationship marketing (RM) model as a framework for the development of hotel Web sites. The authors believe that a successful Web presence depends upon more than just the technology used and the “look and feel” of the site. Hotels need a framework which can bridge the gap between simply connecting to the Web and harnessing its power for competitive advantage.
Negative evaluations of service quality ‐ a framework for identification and response
Authors: Dawes Jillian , Rowley Jennifer
Published: May 2004

The management of the enhancement of the quality of service delivery is often primarily focused on minimising negative responses to product offerings, rather than maximising positive responses. To date there has been little debate on the negative aspects of quality. This paper reviews the origins and use of the concepts dissatisfaction, dissonance, disconfirmation and disaffection which are variously explored in a diverse collection of literature spanning service quality, the service experience and marketing. A framework is proposed that places these four concepts on a grid on the basis of whether the term applies to one incident, or many, and the action that is likely to be taken by customers as a result of experiencing each of these. This grid can be used to better understand the relationship between the various approaches that are used to provide organisations with feedback on customer perceptions of their service quality, such as complaints procedures, surveys, suggestion boxes, focus groups and representation and consultation.
What we know about consumers’ color choices
Authors: Priluck Grossman Randi , Wisenblit Joseph Z.
Published: May 2004

Marketing practitioners know that a product’s color may play an important role in a consumer’s purchase decision, but may not be familiar with the empirical research that has been conducted in this area. The purpose of this paper is to apply an associative learning framework to the color literature to help understand consumer color choices. Specifically, the principles of classical conditioning, a form of associative learning, will be used to make suggestions to practitioners who wish to create or change color associations for their products. The implications of the findings from the color literature are discussed.
Marketing shopping centres: challenges in the UK context
Authors: Kirkup Malcolm H. , Rafiq Mohammed
Published: May 2004

Examines the marketing task facing managed shopping centres in the UK. The industry has generally been reluctant to fully embrace the marketing concept and this needs to change as competition increases. Defines the marketing task and identifies considerable challenges in the UK context. The marketing mix is examined, utilising a new framework (which is proposed as a useful analytical and management tool) and constraints are discussed which arise from both the nature of the shopping centre service itself and traditional industry practices. Problems with resourcing, information, knowledge and attitudes at the coal‐face of active centre marketing are found to be working against effective marketing practice. Draws on literature and a series of exploratory interviews with managers involved in shopping centre management and marketing.
Developments in airline marketing practice
Authors: Driver John C.
Published: May 2004

Discusses how marketing practice is competitively evolving as airlines, in a code‐sharing environment, seek to be more effective, efficient and profitable. It complements changes to airline structures in routeing, staffing levels and technology, and by establishing strong brand presence is a means for customer attraction, retention and network expansion. Distribution channels are changing as travel agencies are affected by airlines’ direct sales and Internet‐based interactive communication. Traditional segmentation tactics directed to business travellers, through frequent flyer programmes and premium services, are threatened by businesses economising, staff reductions and the increasing importance of the leisure traveller. An overview of international practice is taken and points illustrated, where appropriate, by examples of specific airlines.
The outsourcing dilemma: a composite approach to the make or buy decision
Authors: Fill Chris , Visser Elke
Published: May 2004

The decision to outsource a part of an organisation’s activities is often the result of an initiative to realise potential production cost efficiencies. In order to avoid the use of such narrow decision criteria this paper considers the use of a wider array of inputs. Following a review of the literature, a composite outsourcing decision framework is presented. This framework consists of three main components. The first seeks to utilise the unique contextual factors associated with each decision; the second considers the strategic implications of deciding to outsource and the third investigates the traditional cost aspects. The framework is then applied to a case study concerning an engineering organisation which had to decide whether to outsource part of its production facilities. The outcomes suggest that the framework was a useful instrument in assisting management in making this decision, although further work in this area is required.
Turning part‐time students’ feedback into video programs
Authors: Dewald B.W.A.
Published: May 2004

The aim of this project was to collect part‐time students’ feedback on their experiences at the Hong Kong Polytechnic University. The collected data were in turn used to build up a collection of video clips of part‐time hotel and catering students discussing their learning experiences at the university. The edited clips were turned into two video programs. One program was implemented during new adult students’ orientation, to help these non‐traditional students understand more about the potential and challenges of the course, and become better learners. The second video program was put to use during an academic staff seminar on the learning needs and problems of adult learners.
The New York State newspaper project Web site
Authors: Vann William
Published: May 2004

Presents the experiences of setting up the New York State newspaper project Web site. Covers motives including the promotion of the little publicized service in a new format and providing this to a wider number of individuals. briefly outlines the methods employed, and provides some hope for future direction.
Hagerstown‐Jefferson Township public library Internet Web site
Authors: Albertson Marie
Published: May 2004

Discusses the experiences of Hagerstown Indiana and its attempts to create an online public library. Shows how with determination, the small town was able to create a case, obtain its own funding and build its own systems. Describes the choice of equipment and software and the issues these brought. Suggests that the system is now relied upon by many patrons who have come to depend upon this availability.
Competitive inter‐firm interactions: determinants of divergence versus convergence
Authors: Pegels C. Carl , Il Song Yong
Published: May 2004

This paper is a study of competitive and cooperative interactions among members of a competitive industry group. There are few strategic, tactical or market moves that do not affect competition in any industry. Competitive and cooperative interactions among competitive firms are studied to determine how the reactions of competitors to an initiator of an action cause convergent or divergent patterns. It is hypothesized that the patterns, or cycles, of competitive and cooperative interactions are a function of complexity of the interaction cycle, degree of offensiveness of participants’ moves, action reversibility, previous interaction experience, interaction cycle visibility and response time. An empirical test of the hypothesis revealed that the two most strongly supported hypotheses were: interaction cycle complexity increases the likelihood of interaction cycle convergence, and interaction cycle visibility increases the likelihood of interaction cycle divergence.
Business theology
Authors: Vinten Gerald
Published: May 2004

Religions, throughout their existence, have found it difficult to formulate a balanced approach to wealth and the world of business. They have tended to comment more on poverty, with parables about camels fitting through needles demonstrating their ambivalence. Perhaps then, surprisingly, and particularly if we live in a secular, post‐modern society, there has been a persistent trickle of use of religious metaphor which shows no sign of abating. Equally, the language of business is infiltrating the religious sphere, as religions seek to maximize income, as well as, and as a means of, maintaining their essential missions. Advertising agencies draw on religious metaphor, and business leaders sometimes go into religious mode for the high‐spot achievements of corporate life. Work is not always pleasurable fulfilment, but this periodic spiritual underpinning does witness to the potential for self‐actualisation.
Communication apprehension in UK and Spanish business and accounting students
Authors: Hassall Trevor , Joyce John , Ottewill Roger , Arquero José , Donoso José
Published: May 2004

Distinguishes between communication apprehension (CA), the fear of actually communicating, and communication development, the ability to maintain and improve performance as a communicator. Indicates that CA needs to be addressed before progress can be made in developing the communication skills of graduates to which employers attach considerable importance. Reports the results of a study comparing levels of CA amongst business and accounting students in the UK and Spain, which confirm the high levels of CA found in North American students but also indicate differences which may be due to cultural and other factors. Considers implications of findings for curriculum design and staff development.
The call to mentor
Authors: Cox Elaine R.J.
Published: May 2004

The article draws on theories of volunteer motivation, documentary evidence and interview data in an attempt to understand the impact of biographical and motivational factors on perceived success in mentoring relationships. The results presented are part of a wider exploration of the developmental needs of mentors, considering the voluntary nature of mentoring, the social character of action and analyses the incentives of 52 volunteers who were trained as mentors for lone parents between 1996 and 1998, as part of a government‐funded Lone Parent Mentoring Project. The article summarises the recruitment and selection processes used to encourage volunteers to apply for mentor training, and presents results collected from application forms which describe the variety of reasons given by applicants for their decision to apply. It then considers the values and beliefs which underpin these motivations.
The realistic downsizing preview: a management intervention in the prevention of survivor syndrome (part I)
Authors: Appelbaum Steven H. , Donia Magda
Published: May 2004

While downsizing has become an increasingly popular organizational tool in the achievement and/or maintenance of competitiveness and increased productivity, the negative side effect known as survivor syndrome continues to plague many post‐downsizing organizations. This two‐part article examines the full spectrum of research, with the goal of producing a model. The model is based upon the problems survivors experienced and modeled after the John Wanous realistic job preview (RJP). The realistic downsizing preview (RDP), which can be effectively used before the downsizing, is implemented to prevent survivor syndrome in the aftermath of the downsizing. The foundation of the RDP model is that by addressing issues that have been observed as survivor syndromes prior to a downsizing, the negative outcomes can be minimized. Part I considers downsizing, its effects on survivors and their needs, and the importance of good communication and perceived fairness within the process.
Structure of a novel c7‐type three‐heme cytochrome domain from a multidomain cytochrome c polymer
Authors: Pokkuluri P. Raj , Londer Yuri Y. , Duke Norma E.C. , Erickson Jill , Pessanha Miguel , Salgueiro Carlos A. , Schiffer Marianne
Published: May 2004

The structure of a novel c7‐type cytochrome domain that has two bishistidine coordinated hemes and one heme with histidine, methionine coordination (where the sixth ligand is a methionine residue) was determined at 1.7 Å resolution. This domain is a representative of domains that form three polymers encoded by the Geobacter sulfurreducens genome. Two of these polymers consist of four and one protein of nine c7‐type domains with a total of 12 and 27 hemes, respectively. Four individual domains (termed A, B, C, and D) from one such multiheme cytochrome c (ORF03300) were cloned and expressed in Escherichia coli. The domain C produced diffraction quality crystals from 2.4 M sodium malonate (pH 7). The structure was solved by MAD method and refined to an R‐factor of 19.5% and R‐free of 21.8%. Unlike the two c7 molecules with known structures, one from G. sulfurreducens (PpcA) and one from Desulfuromonas acetoxidans where all three hemes are bishistidine coordinated, this domain contains a heme which is coordinated by a methionine and a histidine residue. As a result, the corresponding heme could have a higher potential than the other two hemes. The apparent midpoint reduction potential, Eapp, of domain C is −105 mV, 50 mV higher than that of PpcA.
Two‐promoter vector is highly efficient for overproduction of protein complexes
Authors: Kim Kyung‐Jin , Kim Han‐Eol , Lee Kwang‐Hoon , Han Wondeok , Yi Min‐Ju , Jeong Jinseok , Oh Byung‐Ha
Published: May 2004

The use of bicistronic vectors, which contain two target genes under one promoter, has been the most common practice for the heterologous production of binary protein complexes. The major problem of this method is the much lower expression of the second gene compared with that of the first gene next to the promoter. We tested a simple idea of whether inclusion of an additional promoter in front of the second gene may remove the problem. Compared with bicistronic vectors, corresponding two‐promoter vectors yielded four to nine times larger amounts of the complexes between BCL‐2 family proteins, BCL‐XL:BAD, BCL‐XL:BIM‐S, and CED‐9:EGL‐1 in bacterial cells as a result of significantly increased expression of the second genes in a manner independent of the order of the target genes. With the two‐promoter system, we produced two other complexes in large quantity suitable for extensive crystallization trial. The method does not accompany any technical disadvantages, and represents a significant improvement from the conventional method, which should enjoy wide application for the coexpression of binary or higher order protein complexes by extension.
DNA vaccines expressing antigens with a stress protein‐capturing domain display enhanced immunogenicity
Authors: Reimann Jörg , Schirmbeck Reinhold
Published: May 2004

Summary:  An expression system for DNA vaccines is described, in which a fusion protein with an N‐terminal, viral J‐domain that captures heat‐shock proteins (Hsps) is translated in‐frame with C‐terminal antigen‐encoding sequences (of various lengths and origins). The system supports enhanced expression of chimeric antigens (of >800 residues in length) with an extended half life (>8 h). When used as a DNA vaccine, it delivers antigen together with the intrinsic adjuvant activity provided by bound Hsps. We describe the design of vectors for DNA vaccination that support the expression of different immunogenic domains of different origins as large, Hsp‐capturing chimeric fusion antigens. The immunogenicity of the antigens produced by this expression system (when it is built into DNA vaccines) has been characterized in detail, with particular emphasis on priming CD8+ T‐cell responses. We also discuss areas of vaccine research to which the new technology may provide useful contributions.
DNA vaccines suppress tumor growth and metastases by the induction of anti‐angiogenesis
Authors: Reisfeld Ralph A. , Niethammer Andreas G. , Luo Yunping , Xiang Rong
Published: May 2004

Summary:  Four novel oral DNA vaccines provide long‐lived protection against melanoma, colon, breast, and non‐small cell lung carcinoma in mouse model systems. The vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and are directed against targets such as carcinoembryonic antigen, tyrosine‐related protein, vascular endothelial growth factor receptor‐2 [also called fetal liver kinase‐1 (FLK‐1)], and transcription factor Fos‐related antigen‐1 (Fra‐1). The FLK‐1 and Fra‐1 vaccines are effective in suppressing angiogenesis in the tumor vasculature. All four vaccines are capable of inducing potent cell‐mediated protective immunity, breaking peripheral T‐cell tolerance against these self‐antigens resulting in effective suppression of tumor growth and metastasis. It is anticipated that such research efforts will contribute toward the rational design of future DNA vaccines that will be effective for prevention and treatment of human cancer.
Progress in DNA‐based heterologous prime‐boost immunization strategies for malaria
Authors: Moore Anne C. , Hill Adrian V. S.
Published: May 2004

Summary:  An effective vaccine against malaria is urgently required to relieve the immense human suffering and mortality caused by this parasite. A successful subunit vaccine against the liver stage of malaria will require the induction of high levels of protective T cells. Despite success in small animal models, DNA vaccines fail to induce strong cellular immune responses in humans. However, DNA vaccines can induce a T‐cell response that can be strongly boosted by recombinant viral vectors. We have evaluated this heterologous prime‐boost approach using the Plasmodium berghei mouse model for immunogenicity and protective efficacy against malaria challenge using combinations of plasmid DNA, recombinant modified vaccinia virus Ankara, fowlpox virus, and non‐replicating adenovirus. We have proceeded to test immunogenicity and efficacy of successful heterologous prime‐boost vaccines in phase I/IIa trials in malaria naïve subjects in the UK and in semi‐immune individuals in The Gambia. In these clinical trials, remarkably high levels of effector T‐cell responses have been induced and significant protection documented in a human sporozoite challenge model. We summarize the preclinical design and development of these heterologous prime‐boost vaccines and discuss the encouraging results that have been observed in vaccinated humans.
Cancer immunotherapy with mRNA‐transfected dendritic cells
Authors: Gilboa Eli , Vieweg Johannes
Published: May 2004

Summary:  Bone marrow‐derived dendritic cells (DCs) are the most potent antigen‐presenting cells capable of activating naïve T cells. Loading DCs ex vivo with tumor antigens can stimulate potent antitumor immunity in tumor‐bearing mice. This review describes the use of mRNA‐encoded tumor antigens as a form of antigen loaded onto DCs, including our early experience from clinical trials in urological cancers. Transfection of DCs with mRNA is simple and effective. Comparative studies suggest that mRNA transfection is superior to other antigen‐loading techniques in generating immunopotent DCs. The ability to amplify RNA from microscopic amounts of tumor tissue extends the use of DC vaccination to virtually every cancer patient. The striking observation from two phase I clinical trials, in patients with prostate cancer immunized with prostate‐specific antigen mRNA‐transfected DCs and patients with renal cancer immunized with autologous tumor RNA‐transfected DCs, was that the majority of patients exhibited a vaccine‐induced T‐cell response. Suggestive evidence of clinically related responses was seen in both the trials. Immunization with mRNA‐transfected DCs is a promising strategy to stimulate potent antitumor immunity and could serve as a foundation for developing effective treatments for cancer.
Strategies for improved formulation and delivery of DNA vaccines to veterinary target species
Authors: Van Drunen Littel‐van den Hurk Sylvia , Babiuk Shawn L. , Babiuk Lorne A.
Published: May 2004

Summary:  Interest in DNA immunization of animals continues, despite the fact that immune responses induced by DNA vaccines are generally lower than those elicited by conventional vaccines. In attempts to enhance the immune response to DNA vaccines, individuals have tried a variety of immune modulators, cytokines, and costimulatory molecules, but these only boost immune responses marginally. These results clearly demonstrate that the major challenge to improving DNA‐based vaccines is to improve the transfection efficiency. Gene gun and electroporation can increase transfection and improve immune responses significantly, but these technologies have not yet advanced to the stage of routine use in livestock. Hopefully, transfection efficiency can be increased further in a user‐friendly manner to ensure that the benefits of using DNA vaccines become a reality.
The processing of antigens delivered as DNA vaccines
Authors: Howarth Mark , Elliott Tim
Published: May 2004

Summary:  The ability of DNA vaccines to provide effective immunological protection against infection and tumors depends on their ability to generate good CD4+ and CD8+ T‐cell responses. Priming of these responses is a property of dendritic cells (DCs), and so the efficacy of DNA‐encoded vaccines is likely to depend on the way in which the antigens they encode are processed by DCs. This processing could either be via the synthesis of the vaccine‐encoded antigen by the DCs themselves or via its uptake by DCs following its synthesis in bystander cells that are unable to prime T cells. These different sources of antigen are likely to engage different antigen‐processing pathways, which are the subject of this review. Understanding how to access different processing pathways in DCs may ultimately aid the rational development of plasmid‐based vaccines to pathogens and to cancer.
Cross‐presentation, dendritic cell subsets, and the generation of immunity to cellular antigens
Authors: Heath William R. , Belz Gabrielle T. , Behrens Georg M. N. , Smith Christopher M. , Forehan Simon P. , Parish Ian A. , Davey Gayle M. , Wilson Nicholas S. , Carbone Francis R. , Villadangos Jose A.
Published: May 2004

Summary:  Cross‐presentation involves the uptake and processing of exogenous antigens within the major histocompatibility complex (MHC) class I pathway. This process is primarily performed by dendritic cells (DCs), which are not a single cell type but may be divided into several distinct subsets. Those expressing CD8α together with CD205, found primarily in the T‐cell areas of the spleen and lymph nodes, are the major subset responsible for cross‐presenting cellular antigens. This ability is likely to be important for the generation of cytotoxic T‐cell immunity to a variety of antigens, particularly those associated with viral infection, tumorigenesis, and DNA vaccination. At present, it is unclear whether the CD8α‐expressing DC subset captures antigen directly from target cells or obtains it indirectly from intermediary DCs that traffic from peripheral sites. In this review, we examine the molecular basis for cross‐presentation, discuss the role of DC subsets, and examine the contribution of this process to immunity, with some emphasis on DNA vaccination.
Expression library immunization to discover and improve vaccine antigens
Authors: Barry Michael A. , Howell Dasein P. G. , Andersson Helen A. , Chen Jiang Li , Singh Rana A. K.
Published: May 2004

Summary:  Genetic immunization is a novel method for vaccination in which DNA is delivered into the host to drive both cellular and humoral immune responses against its protein product. While genetic immunization can be potent, it requires that one have, in hand, a gene that encodes a protective protein antigen. Therefore, for many diseases, one cannot make a genetic vaccine because no protective antigen is known or no gene for this antigen is available. This lack of candidate antigens and their genes is a considerable bottleneck in developing new vaccines against old infectious agents, new emerging pathogens, and bioweapons. To address this limitation, we developed expression library immunization (ELI) as a high‐throughput technology to discover vaccine candidate genes at will, by using the immune system to screen the entire genome of a pathogen for vaccine candidate. To date, ELI has discovered new vaccine candidates from a diverse set of bacterial, fungal, and parasitic pathogens. In addition, the process of applying ELI to the genome of pathogens allows one to genetically re‐engineer these antigens to convert immunoevasive pathogen proteins into immunostimulatory vaccine antigens. Therefore, ELI is a potent technology to discover new vaccines and also generate genomic vaccines with amplified, multivalent immunostimulatory capacities.
Modulating vaccine responses with dendritic cells and Toll‐like receptors
Authors: Pulendran Bali
Published: May 2004

Summary:  The immune system is ignorant or even unresponsive to most foreign proteins that are injected in a soluble, deaggregated form, but when injected together with an immune‐stimulating agent (i.e. an adjuvant, such as CpG‐rich DNA), these foreign proteins can generate robust immunity and long‐lived memory to the antigen. In fact, the nature of the adjuvant is what determines the particular type of immune response that follows, which may be biased towards cytotoxic T‐cell responses, antibody responses, particular classes of T‐helper responses, or antibody isotypes. Clearly, the ability of a vaccine to skew the response toward a particular type is of paramount importance, because different pathogens require distinct types of protective immunities. Therefore, the quest to manipulate the immune system to generate optimally effective immunity against different pathogens can justifiably be considered the ‘grand challenge’ of modern immunology. Central to this issue is a rare but widely distributed network of cells known as dendritic cells (DCs). DCs, which have been called ‘Nature's adjuvants,' express pathogen recognition receptors, such as the Toll‐like receptors (TLRs) and C‐type lectins, which enable them to sense and respond to microbes or vaccines. Research in the last decade has demonstrated a fundamental role for DCs in initiating and controlling the quality and strength of the immune response. As such, DCs and TLRs represent attractive immune modulatory targets for vaccinologists. The present review provides a summary of emerging themes in the biology DCs and TLRs, with a particular focus on relevance for vaccine development.
DNA fusion gene vaccines against cancer: from the laboratory to the clinic
Authors: Stevenson Freda K. , Rice Jason , Ottensmeier Christian H. , Thirdborough Stephen M. , Zhu Delin
Published: May 2004

Summary:  Vaccination against target antigens expressed by cancer cells has now become a realistic goal. DNA vaccines provide a direct link between identification of genetic markers in tumors and vaccine formulation. Simplicity of manufacture facilitates construction of vaccines against disease subsets or even for individual patients. To engage an immune system that exists to fight pathogens, we have developed fusion gene vaccines encoding tumor antigens fused to pathogen‐derived sequences. This strategy activates high levels of T‐cell help, the key to induction and maintenance of effective immunity. We have dissected the immunogenic tetanus toxin to obtain specific sequences able to activate antibody, CD4+, or CD8+ T cells to attack selected fused tumor antigens. Principles established in preclinical models are now being tested in patients. So far, objective immune responses against idiotypic antigen of neoplastic B cells have been observed in patients with B‐cell malignancies and in normal transplant donors. These responses provide a platform for testing physical methods to improve DNA delivery and strategies to boost responses. For cancer, demands are high, because vaccines have to activate powerful immunity against weak antigens, often in a setting of immune damage or tolerance. Vaccination strategies against cancer and against microbes are sharing knowledge and technology for mutual benefit.
Use of CpG oligodeoxynucleotides as immune adjuvants
Authors: Klinman Dennis M. , Currie Debra , Gursel Ihsan , Verthelyi Daniela
Published: May 2004

Summary:  Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs directly stimulate human B cells and plasmacytoid dendritic cells (pDCs), thereby promoting the production of T helper 1 (Th1) and pro‐inflammatory cytokines and the maturation/activation of professional antigen‐presenting cells. These activities enable CpG ODNs to act as immune adjuvants, accelerating and boosting antigen‐specific immune responses by 5–500‐fold. These effects are optimized by maintaining close physical contact between the CpG DNA and the immunogen. Animal challenge models establish that protective immunity can be accelerated and magnified by coadministering CpG DNA with vaccines. Ongoing clinical studies indicate that CpG ODNs are safe and well tolerated when administered as adjuvants to humans, and in some cases, they increase vaccine‐induced immune responses.
Antigen–immunostimulatory oligonucleotide conjugates: mechanisms and applications
Authors: Datta Sandip K. , Cho Hearn J. , Takabayashi Kenji , Horner Anthony A. , Raz Eyal
Published: May 2004

Summary:  Conjugation of protein antigen with immunostimulatory oligonucleotides creates a potent immunogen. Physical linking of oligonucleotides to antigen enhances antigen uptake and targets the adjuvant properties of the oligonucleotides to the antigen‐presenting cell. In addition, the conjugated oligonucleotides appear to have improved immunostimulatory abilities compared to free oligonucleotides, presumably due to enhanced activation of Toll‐like receptor 9. Immunization with these conjugate preparations elicits antigen‐specific antibody responses, a T‐helper cell 1‐biased cytokine profile from CD4 T cells, and CD8 cytotoxic T‐lymphocyte activity that is CD4 independent. The humoral and cellular immune responses induced by these conjugates suggest they can be used to create effective vaccines against infectious pathogens and tumors and to beneficially modulate allergic responses. Indeed, recent clinical trial data show symptom relief and immunomodulation of the allergic response in patients with allergic rhinitis. This review considers the mechanisms of action of antigen–oligonucleotide conjugates and discusses available data regarding their use for the prevention and treatment of infectious, oncologic, and allergic diseases.
Enhancement of human immunodeficiency virus type 1‐DNA vaccine potency through incorporation of T‐helper 1 molecular adjuvants
Authors: Calarota Sandra A. , Weiner David B.
Published: May 2004

Summary:  It is clear that the development of a safe and effective vaccine for human immunodeficiency virus type 1 (HIV‐1) remains a crucial goal for controlling the acquired immunodeficiency syndrome epidemic. At present, it is not clear what arm of the immune response correlates with protection from HIV‐1 infection or disease. Therefore, a strong cellular and humoral immune response will likely be needed to control this infection. Among different vaccine alternatives, DNA vaccines appeared more than a decade ago, demonstrating important qualities of inducing both humoral and cellular immune responses in animal models. However, after several years and various clinical studies in humans, supporting the safety of the HIV‐DNA vaccine strategies, it has become clear that their potency should be improved. One way to modulate and enhance the immune responses induced by a DNA vaccine is by including genetic adjuvants such as cytokines, chemokines, or T‐cell costimulatory molecules as part of the vaccine itself. Particularly, vaccine immunogenicity can be modulated by factors that attract professional antigen‐presenting cells, provide additional costimulation, or enhance the uptake of plasmid DNA. This review focuses on developments in the coadministration of molecular adjuvants for the enhancement of HIV‐1 DNA‐vaccine potency.
DNA vaccines against human immunodeficiency virus type 1
Authors: Estcourt Marie J. , McMichael Andrew J. , Hanke Tomás̆
Published: May 2004

Summary:  Development of a vaccine against human immunodeficiency virus type 1 (HIV‐1) is the main hope for controlling the acquired immunodeficiency syndrome pandemic. An ideal HIV vaccine should induce neutralizing antibodies, CD4+ helper T cells, and CD8+ cytotoxic T cells. While the induction of broadly neutralizing antibodies remains a highly challenging goal, there are a number of technologies capable of inducing potent cell‐mediated responses in animal models, which are now starting to be tested in humans. Naked DNA immunization is one of them. This review focuses on the stimulation of HIV‐specific T cells and discusses in the context of the current ‘state‐of‐art’ of DNA vaccines, the areas where this technology might assist either alone or as a part of more complex vaccine formulations in the HIV vaccine development.
B lymphocytes as antigen‐presenting cell‐based genetic vaccines
Authors: Zanetti Maurizio , Castiglioni Paola , Rizzi Marta , Wheeler Matthew , Gerloni Mara
Published: May 2004

Summary:  Inoculation of plasmid DNA is a simple way to immunize, but it is characterized by low immunogenicity, which has hampered the development of effective DNA vaccines for human use. Here, we discuss how poor immunogenicity can be solved and present our proposal: genetically programmed B lymphocytes as antigen‐presenting cell (APC) vaccines. First, we demonstrate that mature B lymphocytes take up plasmid DNA spontaneously, i.e., in the absence of any facilitating molecule or event, spontaneous lymphocyte transgenesis. Second, we demonstrate that transgenic B lymphocytes are easily and reproducibly turned into functional APCs with dual characteristics: upregulation of costimulatory molecules and endogenous synthesis of antigen. Used as immunogens in mice, transgenic B lymphocytes induce robust and long‐lasting T‐cell immunity after single intravenous injection. Surprisingly, immunity and protection against lethal virus challenge can be obtained with a single intravenous injection of 3 × 102 transgenic lymphocytes. The new approach is discussed relative to the advantage of targeting secondary lymphoid organs with genetically programmed B lymphocytes and the advantage offered with respect to low antigen dose. We suggest that these properties reflect on simple characteristics, such as time synchronization and initial localization to secondary lymphoid organs of APCs endowed with protracted synthesis and presentation of antigen to T cells.
Microparticles for the delivery of DNA vaccines
Authors: O'Hagan Derek T. , Singh Manmohan , Ulmer Jeffrey B.
Published: May 2004

Summary:  DNA vaccines have demonstrated a lack of adequate potency in humans, which has necessitated the exploration of various adjunct technologies. Inefficient delivery of DNA vaccines, particularly to antigen‐presenting cells, may be contributing to this lack of potency. One effective means of facilitating delivery of DNA vaccines to APCs is through the use of microparticles. In this article, we review the background and rationale for microparticles as a vaccine delivery system, data demonstrating their utility and mode of action for DNA delivery, and the prospects for their development.
Targeting plasmid‐encoded proteins to the antigen presentation pathways
Authors: Leifert Jens A. , Rodriguez‐Carreno Maria P. , Rodriguez Fernando , Lindsay Whitton J.
Published: May 2004

Summary:  The antigen presentation pathways constitute a fulcrum on which adaptive immunity is balanced, and their manipulation should allow us to induce designer immune responses. The ease and rapidity with which DNA vaccines can be constructed and altered make them ideal candidates with which to test the various targeting strategies that have been conceived to date. These approaches and the mechanisms that may (or may not) underlie their success are reviewed in this article.
Molecular adjuvants for mucosal immunity
Authors: Toka Felix N. , Pack Christopher D. , Rouse Barry T.
Published: May 2004

Summary:  Mucosal surfaces represent the entry route of a multitude of viral pathogens. For many of these viruses, such as the herpes simplex viruses and human immunodeficiency virus, no effective vaccine exists. Hence, it is important that prospective vaccines engender maximal immunity at these susceptible sites. Genetic vaccines encoding adjuvant molecules represent one approach to optimize mucosal as well as systemic immunity. Promising candidates include various inflammatory cytokines and chemokines that might be used to enhance the primary response to a level sufficient for protection. Encouraging studies involving cytokines such as granulocyte/macrophage colony‐stimulating factor, interleukin‐2 (IL‐2), IL‐12, IL‐18, and many others are examined. Notable chemokines that may offer hope in such efforts include IL‐8, RANTES, CCL19, CCL21, and a few others. Combinatorial approaches utilizing several cytokines and chemokines will most likely yield the greatest success. In addition, as more is discovered regarding the requirements for memory development of T cells, boosters involving key cytokines such as IL‐15 and IL‐23 may prove beneficial to long‐term maintenance of the memory pool. This review summarizes the progress in the use of genetic vaccines to achieve mucosal immunity and discusses the needed strategies to maximize long‐term prospective immunity at this vulnerable entry site.
What can dependence theories tell us about assessing the emergence of tobacco dependence?
Authors: Tiffany Stephen T. , Conklin Cynthia A. , Shiffman Saul , Clayton Richard R.
Published: May 2004

Little is known about the processes that underlie changes in smoking that occur between the first use of a cigarette, subsequent regular use and eventual addictive use. At present, assessments of those critical processes are poorly developed and not strongly informed by contemporary models of drug dependence. The preceding three papers in this special issue address explicitly how modern drug‐dependence theories describe the emergence of drug dependence and the implications of those theories for assessment. The papers covered three domains of theories: negative reinforcement, positive reinforcement, and cognitive and social learning. In this paper, we summarize these reviews and extract general themes and issues that emerge across all the articles. These include: (1) the importance of learning processes; (2) limitations of self‐report measures; (3) the view of dependence as a process and not a state; (4) the conception of dependence on a continuum in contrast to the conventional perspective of tobacco dependence as a natural category; (5) the ontological status of the dependence concept; (6) limitations of backward extrapolations from adult assessments; (7) the possibility of multiple dimensions or forms of dependence; and (8) the value of a transdisciplinary approach when studying the emergence of tobacco dependence.
Measuring the emergence of tobacco dependence: the contribution of negative reinforcement models
Authors: Eissenberg Thomas
Published: May 2004

This review of negative reinforcement models of drug dependence is part of a series that takes the position that a complete understanding of current concepts of dependence will facilitate the development of reliable and valid measures of the emergence of tobacco dependence. Other reviews within the series consider models that emphasize positive reinforcement and social learning/cognitive models. This review summarizes negative reinforcement in general and then presents four current negative reinforcement models that emphasize withdrawal, classical conditioning, self‐medication and opponent‐processes. For each model, the paper outlines central aspects of dependence, conceptualization of dependence development and influences that the model might have on current and future measures of dependence. Understanding how drug dependence develops will be an important part of future successful tobacco dependence measurement, prevention and treatment strategies.
Measures and models of nicotine dependence: positive reinforcement
Authors: Glautier Steven
Published: May 2004

This paper addresses the problem of assessing nicotine dependence. The main objective is to develop theory‐led suggestions for measures that will be relevant in the early phases of tobacco use, as well as in established smokers. Theoretical models of addiction falling into the general class of ‘positive reinforcement theories’ were identified and reviewed. From this review a number of drug effects and patterns of behaviour were distilled and categorized as either vulnerability or dependence indicators. A comparison of those features with the International Classification of Diseases (ICD‐10) and Diagnostic and Statistical Manual (DSM‐IV) diagnostic systems shows that neither system includes detailed assessment of vulnerability indicators. It is argued that measurement of vulnerability indicators, in addition to dependence indicators, may add to the predictive validity of assessments carried out in early career tobacco users, especially where there is limited evidence of established dependence. In addition, it is suggested that examination of measures that differentiate a subgroup of early career smokers termed ‘rapid accelerators’ may prove profitable and enable identification of the key parameters of nicotine reinforcement.
Cognitive and social learning models of drug dependence: implications for the assessment of tobacco dependence in adolescents
Authors: Brandon Thomas H. , Herzog Thaddeus A. , Irvin Jennifer E. , Gwaltney Chad J.
Published: May 2004

This paper is part of a series that has the goal of identifying potential approaches toward developing new instruments for assessing tobacco dependence among adolescents. The fundamental assumption underlying the series is that contemporary theories of drug dependence offer a rich source of opportunities for the development of theoretically based assessment tools. The present paper focuses on cognitive and social‐learning models of drug dependence and the implications of these models for novel assessment instruments. In particular, the paper focuses on Mark Goldman's model of drug expectancies, Albert Bandura's model of self‐efficacy, Thomas Wills's model of stress and coping and Stephen Tiffany's cognitive‐processing model of drug urges and cravings. In addition to traditional self‐report measures, naturalistic and laboratory‐based assessments are identified that may yield information relevant to multi‐dimensional measurement of tobacco dependence.