Chemotherapy enhances vaccine-induced antitumor immunity in melanoma patients

Combination of chemotherapy with cancer vaccines is currently regarded as a potentially valuable therapeutic approach for the treatment of some metastatic tumors, but optimal modalities remain unknown. We designed a phase I/II pilot study for evaluating the effects of dacarbazine (DTIC) on the immune response in HLA-A2(+) disease-free melanoma patients who received anticancer vaccination 1 day following chemotherapy (800 mg/mq i.v.). The vaccine, consisting of a combination of HLA-A2 restricted melanoma antigen A (Melan-A/MART-1) and gp100 analog peptides (250 microg each, i.d.), was administered in combination or not with DTIC to 2 patient groups. The combined treatment is nontoxic. The comparative immune monitoring demonstrates that patients receiving DTIC 1 day before the vaccination have a significantly improved long-lasting memory CD8(+) T cell response. Of relevance, these CD8(+) T cells recognize and lyse HLA-A2(+)/Melan-A(+) tumor cell lines. Global transcriptional analysis of peripheral blood mononuclear cells (PBMC) revealed a DTIC-induced activation of genes involved in cytokine production, leukocyte activation, immune response and cell motility that can favorably condition tumor antigen-specific CD8(+) T cell responses. This study represents a proof in humans of a chemotherapy-induced enhancement of CD8(+) memory T cell response to cancer vaccines, which opens new opportunities to design novel effective combined therapies improving cancer vaccination effectiveness

A realist analysis of hospital patient safety in Wales:Applied learning for alternative contexts from a multisite case study

Background: Hospital patient safety is a major social problem. In the UK, policy responses focus on the introduction of improvement programmes that seek to implement evidence-based clinical practices using the Model for Improvement, Plan-Do-Study-Act cycle. Empirical evidence that the outcomes of such programmes vary across hospitals demonstrates that the context of their implementation matters. However, the relationships between features of context and the implementation of safety programmes are both undertheorised and poorly understood in empirical terms. Objectives: This study is designed to address gaps in conceptual, methodological and empirical knowledge about the influence of context on the local implementation of patient safety programmes. Design: We used concepts from critical realism and institutional analysis to conduct a qualitative comparative-intensive case study involving 21 hospitals across all seven Welsh health boards. We focused on the local implementation of three focal interventions from the 1000 Lives+ patient safety programme: Improving Leadership for Quality Improvement, Reducing Surgical Complications and Reducing Health-care Associated Infection. Our main sources of data were 160 semistructured interviews, observation and 1700 health policy and organisational documents. These data were analysed using the realist approaches of abstraction, abduction and retroduction. Setting: Welsh Government and NHS Wales. Participants: Interviews were conducted with 160 participants including government policy leads, health managers and professionals, partner agencies with strategic oversight of patient safety, advocacy groups and academics with expertise in patient safety. Main outcome measures: Identification of the contextual factors pertinent to the local implementation of the 1000 Lives+ patient safety programme in Welsh NHS hospitals. Results: An innovative conceptual framework harnessing realist social theory and institutional theory was produced to address challenges identified within previous applications of realist inquiry in patient safety research. This involved the development and use of an explanatory intervention–context–mechanism–agency–outcome (I-CMAO) configuration to illustrate the processes behind implementation of a change programme. Our findings, illustrated by multiple nested I-CMAO configurations, show how local implementation of patient safety interventions are impacted and modified by particular aspects of context: specifically, isomorphism, by which an intervention becomes adapted to the environment in which it is implemented; institutional logics, the beliefs and values underpinning the intervention and its source, and their perceived legitimacy among different groups of health-care professionals; and the relational structure and power dynamics of the functional group, that is, those tasked with implementing the initiative. This dynamic interplay shapes and guides actions leading to the normalisation or the rejection of the patient safety programme. Conclusions: Heightened awareness of the influence of context on the local implementation of patient safety programmes is required to inform the design of such interventions and to ensure their effective implementation and operationalisation in the day-to-day practice of health-care teams. Future work is required to elaborate our conceptual model and findings in similar settings where different interventions are introduced, and in different settings where similar innovations are implemented. Funding: The National Institute for Health Research Health Services and Delivery Research programme

Determination of the efficacy of murine dendritic cell-based tumor vaccines in the setting of bone marrow transplantation.

Murine tumor models have contributed much to our understanding of immune rejection processes and afford an opportunity for monitoring the in vivo therapeutic effects of cancer vaccines, adoptively transferred T cells, and bone marrow transplantation (BMT). Dendritic cells (DC), as potent antigen presenting cells, allow whole tumor lysates to be used as a source of tumor-associated antigen(s) for presentation to the immune system. This research project involves studies of murine DC-based cancer vaccines in the setting of syngeneic BMT. Tumor lysate-pulsed dendritic cells (TP-DC) could prime a specific and long-lasting antitumor immune response after BMT, which mediated the rejection of a lethal challenge of a weakly-immunogenic mammary carcinoma. In the therapeutic setting, repetitive immunizations of TP-DC could inhibit the growth of pre-existing tumor metastases as well. Because interleukin-7 (IL-7) has been shown by others to be capable of expediting hematolymphoid reconstitution and mediating antitumor immunity, this cytokine was combined with TP-DC immunizations in an attempt to enhance therapeutic efficacy. Although the systemic administration of IL-7 alone could stimulate hematolymphoid reconstitution, it had no effect on mediating antitumor immunity in the BMT setting. In addition, when used as an adjunct to TP-DC immunizations, IL-7 appeared to negate the antitumor immune response afforded by the vaccine. The antitumor therapeutic efficacy of TP-DC could, however, be further improved by an adoptive immunotherapy strategy. The bone marrow and lymph nodes of TP-DC immunized hosts contain tumor-reactive immune cells, which, when adoptively transferred to the BMT recipients, could mediate the regression of pre-existing metastatic tumors. The antitumor effect manifested by these tumor-reactive immune cells appeared to be tumor-specific and dependent on T cells. The secretion of Th1-type cytokines, including IFN-gamma and GM-CSF, by these tumor-reactive effector cells was detected. Collectively, these findings provide evidence for the antitumor efficacy of DC-based vaccines in the setting of syngeneic BMT and may have important implications for human clinical trials involving autologous bone marrow transplantations in cancer patients.Ph.D.Health and Environmental SciencesImmunologyOncologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/127055/2/3029286.pd

Why are some oxides metallic, while most are insulating?

International audienceA large variety of undoped binary and ternary transition metal oxides, including formally divalent, trivalent and tetravalent metal cations, have been examined. These 76 compounds are classified as either "metals", "insulators", or having a "metal-to-insulator" transition. In an attempt to understand these variations, the Zaanen-Sawatzky-Allen framework was used in which each compound can be characterized by three parameters: the Coulomb correlation or disproportionation energy (U'), the charge-transfer energy (DELTA) and the bandwidth (W). Assuming W is constant, we have calculated U' and DELTA using a simple ionic model, which includes only the gas phase ionization potentials and the bare electrostatic Coulomb interactions between the ions. With this model, the occurrence of metallic conductivity is remarkably well accounted for in these oxides

International Journal for Quality in Health Care Comparison of health care professionals' and surveyors' opinions on problems and obstacles in implementing quality management system in Thailand: a national survey

Abstract Objectives. To explore problems and obstacles of hospitals in Thailand implementing quality management systems according to the hospital accreditation (HA) standards. Design. Questionnaire survey. Setting. Thirty-nine hospitals in all 13 regions of Thailand. Participants. A total of 728 health care professionals and 41 surveyors of the national accreditation program. Main outcome measures. Health care professionals' and surveyors' opinions on problems and obstacles in 24 items representing Thailand HA standards. Results. The response rates were 94.9 and 73.2% in health care professionals and surveyors, respectively. More than 90% of both groups thought that there had been problems in the items such as 'quality improvement (QI) activities' and 'integration and utilization of information'. The items considered by health care professionals as major obstacles included 'adequacy of staff' (34.6%) and 'integration and utilization of information' (26.6%), for example. For surveyors, 'integration and utilization of information' was ranked highest as presenting a major obstacle (43.9%), followed by 'discharge and referral process' (31.7%) and 'medical recording process' (29.3%). The rank orders for the 24 items as problems and major obstacles were similar in both groups (Spearman's rank correlation 0.436, P = 0.033 and 0.583, P = 0.003, respectively). Surveyors had a higher degree of concern and paid more attention to care-related items than health care professionals. Conclusions. Health care professionals have been facing many problems with multidisciplinary process-related issues of the accreditation standard, whereas surveyors might have had some difficulties in conveying the core QI concepts to them. The findings might be explained by the effects of health care reform on the underlying accreditation principles. One of the strategies to respond to the situation was presented

An Essential Role for IFN-γ in Regulation of Alloreactive CD8 T Cells Following Allogeneic Hematopoietic Cell Transplantation

AbstractWe previously found that CD8 T cells from IFN-γ gene knockout (GKO) donors induce more severe lethal GVHD compared with CD8 T cells from wild-type (WT) donors in fully MHC-mismatched strain combinations. In this study, we investigated the mechanisms by which IFN-γ inhibits GVHD in a parent → F1 (B6 → B6D2F1) allogeneic HCT (allo-HCT) model. IFN-γ was strongly protective against GVHD in this parent → F1 haplotype-mismatched allo-HCT model. Irradiated B6D2F1 mice that received GKO B6 CD4-depleted splenocytes developed lethal GVHD with severe lung and liver injury, whereas those receiving a similar cell population from WT B6 donors survived long term. Donor CD8 cells showed rapid activation, accelerated cell division, and reduced/delayed activation-induced cell death in allogeneic recipients in which donor cells were incapable of producing IFN-γ. In consequence, the numbers of activated/effector (ie, CD25+, CD62L−, and CD44high) donor CD8 T cells in the recipients of GKO allo-HCT significantly exceeded those in mice receiving WT allo-HCT. These data show that IFN-γ negatively regulates the CD8 T cell response by inhibiting cell division and promoting cell death and suggest that blockade of IFN-γ could augment the severity of GVHD in patients undergoing allo-HCT