Trafficking of High Avidity HER-2/neu-Specific T Cells into HER-2/neu-Expressing Tumors after Depletion of Effector/Memory-Like Regulatory T Cells

Cancer vaccines are designed to activate and enhance cancer-antigen-targeted T cells that are suppressed through multiple mechanisms of immune tolerance in cancer-bearing hosts. T regulatory cell (Treg) suppression of tumor-specific T cells is one barrier to effective immunization. A second mechanism is the deletion of high avidity tumor-specific T cells, which leaves a less effective low avidity tumor specific T cell repertoire available for activation by vaccines. Treg depleting agents including low dose cyclophosphamide (Cy) and antibodies that deplete CD25-expressing Tregs have been used with limited success to enhance the potency of tumor-specific vaccines. In addition, few studies have evaluated mechanisms that activate low avidity cancer antigen-specific T cells. Therefore, we developed high and low avidity HER-2/neu-specific TCR transgenic mouse colonies specific for the same HER-2/neu epitope to define the tolerance mechanisms that specifically affect high versus low avidity tumor-specific T cells.High and low avidity CD8(+) T cell receptor (TCR) transgenic mice specific for the breast cancer antigen HER-2/neu (neu) were developed to provide a purified source of naïve, tumor-specific T cells that can be used to study tolerance mechanisms. Adoptive transfer studies into tolerant FVB/N-derived HER-2/neu transgenic (neu-N) mice demonstrated that high avidity, but not low avidity, neu-specific T cells are inhibited by Tregs as the dominant tolerizing mechanism. High avidity T cells persisted, produced IFNγ, trafficked into tumors, and lysed tumors after adoptive transfer into mice treated with a neu-specific vaccine and low dose Cy to deplete Tregs. Analysis of Treg subsets revealed a Cy-sensitive CD4(+)Foxp3(+)CD25(low) tumor-seeking migratory phenotype, characteristic of effector/memory Tregs, and capable of high avidity T cell suppression.Depletion of CD25(low) Tregs allows activation of tumor-clearing high avidity T cells. Thus, the development of agents that specifically deplete Treg subsets should translate into more effective immunotherapies while avoiding autoimmunity

Consumer credit information systems: A critical review of the literature. Too little attention paid by lawyers?

This paper reviews the existing literature on consumer credit reporting, the most extensively used instrument to overcome information asymmetry and adverse selection problems in credit markets. Despite the copious literature in economics and some research in regulatory policy, the legal community has paid almost no attention to the legal framework of consumer credit information systems, especially within the context of the European Union. Studies on the topic, however, seem particularly relevant in view of the establishment of a single market for consumer credit. This article ultimately calls for further legal research to address consumer protection concerns and inform future legislation

Teaching medical students about nutrition: from basic principles to practical strategies

Poor nutrition is widely recognised as one of the key modifiable risks to health and life, with doctors in an ideal position to recognise when suboptimal nutrition is impacting on their patients’ health and provide them with advice and support to create sustainable and achievable diet and lifestyle modifications. However, it has been acknowledged that nutrition training within medical schools is extremely varied, and in many cases inadequate. The Association for Nutrition UK Undergraduate Curriculum in Nutrition for Medical Doctors provides medical schools with guidance on what should be included in the training of all medical students. This paper discusses three key ways in which medical schools can support the implementation of nutrition into their teaching; incorporating nutrition within the core medical curriculum teaching, the use of subject specific experts to support and deliver nutrition training, and the inclusion of nutrition within formal assessment so as to reinforce and cement learnings into practical, applicable actions and advice

Disarticulation and the Crisis of Neoliberalism in the United States

Neoliberal policies instituted since the 1980s have transformed the United States economy in ways that have produced serious structural distortions in the basic operation of capitalism. Using Samir Amin’s concept of disarticulation, previously applied exclusively to the periphery of the world economy, this article argues that the twin and mutually reinforcing features of neoliberalism – global corporate restructuring and financialization – have now generated disarticulation in the core nations. This disarticulated structure is responsible for the economic stagnation and sharply unequal income/wealth distributional outcomes that characterize contemporary U.S. capitalism

Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer Patients

Tumor-specific CD8+ T cells can potentially be activated by two distinct mechanisms of major histocompatibility complex class I–restricted antigen presentation as follows: direct presentation by tumor cells themselves or indirect presentation by professional antigen-presenting cells (APCs). However, controversy still exists as to whether indirect presentation (the cross-priming mechanism) can contribute to effective in vivo priming of tumor-specific CD8+ T cells that are capable of eradicating cancer in patients. A clinical trial of vaccination with granulocyte macrophage–colony stimulating factor–transduced pancreatic cancer lines was designed to test whether cross-presentation by locally recruited APCs can activate pancreatic tumor-specific CD8+ T cells. Previously, we reported postvaccination delayed-type hypersensitivity (DTH) responses to autologous tumor in 3 out of 14 treated patients. Mesothelin is an antigen demonstrated previously by gene expression profiling to be up-regulated in most pancreatic cancers. We report here the consistent induction of CD8+ T cell responses to multiple HLA-A2, A3, and A24-restricted mesothelin epitopes exclusively in the three patients with vaccine-induced DTH responses. Importantly, neither of the vaccinating pancreatic cancer cell lines expressed HLA-A2, A3, or A24. These results provide the first direct evidence that CD8 T cell responses can be generated via cross-presentation by an immunotherapy approach designed to recruit APCs to the vaccination site

Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response

A major barrier to successful antitumor vaccination is tolerance of high-avidity T cells specific to tumor antigens. In keeping with this notion, HER-2/neu (neu)-targeted vaccines, which raise strong CD8+ T cell responses to a dominant peptide (RNEU420-429) in WT FVB/N mice and protect them from a neu-expressing tumor challenge, fail to do so in MMTV-neu (neu-N) transgenic mice. However, treatment of neu-N mice with vaccine and cyclophosphamide-containing chemotherapy resulted in tumor protection in a proportion of mice. This effect was specifically abrogated by the transfer of neu-N–derived CD4+CD25+ T cells. RNEU420-429-specific CD8+ T cells were identified only in neu-N mice given vaccine and cyclophosphamide chemotherapy which rejected tumor challenge. Tetramer-binding studies demonstrated that cyclophosphamide pretreatment allowed the activation of high-avidity RNEU420-429-specific CD8+ T cells comparable to those generated from vaccinated FVB/N mice. Cyclophosphamide seemed to inhibit regulatory T (T reg) cells by selectively depleting the cycling population of CD4+CD25+ T cells in neu-N mice. These findings demonstrate that neu-N mice possess latent pools of high-avidity neu-specific CD8+ T cells that can be recruited to produce an effective antitumor response if T reg cells are blocked or removed by using approaches such as administration of cyclophosphamide before vaccination

Post-socialist housing systems in Europe:Housing welfare regimes by default?

This article develops a conceptual framework derived from welfare regime and concomitant literatures to interpret housing reform in post-socialist European countries. In it, settled power structures and collective ideologies are necessary prerequisites for the creation of distinctive housing welfare regimes with clear roles for the state, market and households. Although the defining feature of post-socialist housing has been mass-privatisation to create super-homeownership societies, the emphatic retreat of the state that this represents has not been replaced by the creation of the institutions or cultures required to create fully financialised housing markets. There is, instead, a form of state legacy welfare in the form of debt-free home-ownership, which creates a gap in housing welfare that has been partially filled by households in the form of intergenerational assistance (familialism) and self-build housing. Both of these mark continuities with the previous regime. The latter is especially common in south-east Europe where its frequent illegality represents a form of anti-state housing. The lack of settled ideologies and power structures suggests that these housing welfare regimes by default will persist as part of a process that resembles a path-dependent ‘transformation’ rather than ‘transition’

The Inter-organizational Business Case in ES Implementations: Exploring the Impact of Coordination Structures and Their Properties

Developing the business case (BC) for an inter-organizational network is a major challenge. Factors like competition and differences in semantics between actors influence the stakeholders’ willingness to share information necessary for the BC development. In this paper we develop an exploratory framework showing the effect that coordination structure and project scope have on the development of a shared BC. We defined several coordination properties, such as competition, decision making location and decision power that mitigate this effect. We applied the framework in a case study where a BC is developed for an inter-organizational network. Our findings show that current BC development methods need to be re-stated and complemented by extra tools and interventions to support stakeholders in the inter-organizational specific setting

Variation in DNA methylation of the oxytocin receptor gene predicts children's resilience to prenatal stress

AbstractEmerging research in epigenetics has shown that there is variability in how environmental exposures “get under the skin” through mechanisms like DNA methylation to influence gene expression that may lead to differential adaptations to stress. This is the first study to examine prospectively the relationship between DNA methylation at birth and resilience to prenatal environmental stressors in several domains (conduct, hyperactivity, emotional problems, and global symptomatology) in middle childhood. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously associated with impairments in social–cognitive processes that may underlie a wide range of childhood psychopathology. Participants were 91 youth exposed to pre- and postnatal adversity with established conduct problem trajectories drawn from the Avon Longitudinal Study of Parents and Children. Consistent with our hypothesis, OXTR DNA methylation was predictive of resilience in the conduct problems domain in middle childhood. DNA methylation profiles did not predict resilience in domains of emotional, hyperactivity, and global symptomatology, suggesting a potential role for OXTR in the development of conduct problems in particular. However, individuals who were resilient to conduct problems were also broadly resilient across multiple domains. Therefore, future research should elucidate the biological pathways between OXTR DNA methylation and gene expression and its relation to impairments in social behavior.</jats:p