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Diemar S.S.,Nephrology and Endocrinology | Diemar S.S.,Copenhagen University | Sejling A.-S.,Nephrology and Endocrinology | Sejling A.-S.,University of Southern Denmark | And 13 more authors.
Scandinavian Cardiovascular Journal | Year: 2015

Objective. Patients with diabetes are at increased risk of experiencing myocardial infarction. The influence of the prevailing plasma glucose level on infarction and mortality after acute ischaemia is however unknown. The aim was to study the effect of the acute plasma glucose level on the myocardial infarction size in a closed-chest pig model. Design. 38 non-diabetic pigs were randomised to hypoglycaemic (1.8-2.2 mmol/l; n = 15), normoglycaemic (5-7 mmol/l; n = 12) or hyperglycaemic glucose clamping (22-23 mmol/l; n = 11). After 30 min within glucose target myocardial infarction was induced for 30 min followed by reperfusion for 120 min. Hereafter the heart was double-stained to delineate infarction from viable tissue within the area at risk. Results. Mean infarction size was 201 ± 35 mm2 (mean ± SEM) in the hypoglycaemic group, 154 ± 40 mm2 in the normoglycaemic group and 134 ± 40 mm2 in the hyperglycaemic group, with no differences in infarction size, infarct/area at risk ratio or troponin T levels between the groups. There was no difference in incidence of ventricular fibrillation or mortality between the groups. Conclusion. No statistically significant associations were observed between the acute glycaemic level and measures of myocardial infarction, rates of ventricular fibrillation and subsequent premature death in the setting of acute ischaemia and reperfusion. © 2015 Informa Healthcare.

Linnemann C.,Netherlands Cancer Institute | Heemskerk B.,Netherlands Cancer Institute | Kvistborg P.,Netherlands Cancer Institute | Kluin R.J.C.,Netherlands Cancer Institute | And 33 more authors.
Nature Medicine | Year: 2013

The transfer of T cell receptor (TCR) genes into patient T cells is a promising approach for the treatment of both viral infections and cancer. Although efficient methods exist to identify antibodies for the treatment of these diseases, comparable strategies to identify TCRs have been lacking. We have developed a high-throughput DNA-based strategy to identify TCR sequences by the capture and sequencing of genomic DNA fragments encoding the TCR genes. We establish the value of this approach by assembling a large library of cancer germline tumor antigen-reactive TCRs. Furthermore, by exploiting the quantitative nature of TCR gene capture, we show the feasibility of identifying antigen-specific TCRs in oligoclonal T cell populations from either human material or TCR-humanized mice. Finally, we demonstrate the ability to identify tumor-reactive TCRs within intratumoral T cell subsets without knowledge of antigen specificities, which may be the first step toward the development of autologous TCR gene therapy to target patient-specific neoantigens in human cancer. © 2013 Nature America, Inc.

Ekstrom K.,Nephrology and Endocrinology | Ekstrom K.,Copenhagen University | Dalsgaard M.,Rigshospitalet | Iversen K.,Nephrology and Endocrinology | And 8 more authors.
Scandinavian Cardiovascular Journal | Year: 2016

Objectives. Acute STEMI is routinely treated by acute PCI. This treatment may itself damage the tissue (reperfusion injury). Conditioning with GLP-1 analogs has been shown to reduce reperfusion injury. Likewise, ischemic postconditioning provides cardioprotection following STEMI. We tested if combined conditioning with the GLP-1 analog liraglutide and ischemic postconditioning offered additive cardioprotective effect after reperfusion of 45 min coronary occlusion of left anterior descending artery (LAD). Design. Fifty-eight non-diabetic female Danish Landrace pigs (60 ± 10kg) were randomly assigned to four groups. Myocardial infarction (MI) was induced by occluding the LAD for 45 min. Group 1 (n = 14) was treated with i.v. liraglutide after 15 min of ischemia. Group 2 (n = 17) received liraglutide treatment concomitant with ischemic postconditioning, after 45 min of ischemia. Group 3 (n = 15) recieved ischemic postconditioning and group 4 (n = 12) was kept as controls. Results. No intergroup differences in relative infarct size were detected (overall mean 57 ± 3%; p = 0.68). Overall mortality was 34% (CI 25–41%) including 26% post-intervention, with no intergroup differences (p = 0.99). Occurrence of ventricular fibrillation (VF) was 59% (CI 25–80%) including 39% postintervention with no intergroup differences (p = 0.65). Conclusions. In our closed-chest pig-model, we were unable to detect any cardioprotective effect of liraglutide or ischemic postconditioning either alone or combined. © 2016 Informa UK Limited, trading as Taylor & Francis Group

Overgaard N.U.,University of Queensland | Overgaard N.U.,Center for Cancer Immune Therapy | Jung J.-W.,University of Queensland | Steptoe R.J.,University of Queensland | Wells J.W.,University of Queensland
Journal of Leukocyte Biology | Year: 2015

CD4+/CD8+ DP thymocytes are a well-described T cell developmental stage within the thymus. However, once differentiated, the CD4+ lineage or the CD8+ lineage is generally considered to be fixed. Nevertheless, mature CD4+/CD8+ DP T cells have been described in the blood and peripheral lymphoid tissues of numerous species, as well as in numerous disease settings, including cancer. The expression of CD4 and CD8 is regulated by a very strict transcriptional program involving the transcription factors Run×3 and ThPOK. Initially thought to be mutually exclusive within CD4+ and CD8ł T cells, CD4+/CD8+ T cell populations, outside of the thymus, have recently been described to express concurrently ThPOK and Run×3. Considerable heterogeneity exists within the CD47CD8+ DP T cell pool, and the function of CD4+/CD8+ T cell populations remains controversial, with conflicting reports describing cytotoxic or suppressive roles for these cells. In this review, we describe how transcriptional regulation, lineage of origin, heterogeneity of CD4 and CD8 expression, age, species, and specific disease settings influence the functionality of this rarely studied T cell population. © Society for Leukocyte Biology.

Olsen L.R.,Copenhagen University | Olsen L.R.,Dana-Farber Cancer Institute | Campos B.,University of Heidelberg | Barnkob M.S.,University of Southern Denmark | And 5 more authors.
Cancer Immunology, Immunotherapy | Year: 2014

The mechanisms of immune response to cancer have been studied extensively and great effort has been invested into harnessing the therapeutic potential of the immune system. Immunotherapies have seen significant advances in the past 20 years, but the full potential of protective and therapeutic cancer immunotherapies has yet to be fulfilled. The insufficient efficacy of existing treatments can be attributed to a number of biological and technical issues. In this review, we detail the current limitations of immunotherapy target selection and design, and review computational methods to streamline therapy target discovery in a bioinformatics analysis pipeline. We describe specialized bioinformatics tools and databases for three main bottlenecks in immunotherapy target discovery: the cataloging of potentially antigenic proteins, the identification of potential HLA binders, and the selection epitopes and co-targets for single-epitope and multi-epitope strategies. We provide examples of application to the well-known tumor antigen HER2 and suggest bioinformatics methods to ameliorate therapy resistance and ensure efficient and lasting control of tumors. © 2014, Springer-Verlag Berlin Heidelberg.

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