Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration

Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies

Liposome-Coupled Antigens Are Internalized by Antigen-Presenting Cells via Pinocytosis and Cross-Presented to CD8+ T Cells

We have previously demonstrated that antigens chemically coupled to the surface of liposomes consisting of unsaturated fatty acids were cross-presented by antigen-presenting cells (APCs) to CD8+ T cells, and that this process resulted in the induction of antigen-specific cytotoxic T lymphocytes. In the present study, the mechanism by which the liposome-coupled antigens were cross-presented to CD8+ T cells by APCs was investigated. Confocal laser scanning microscopic analysis demonstrated that antigens coupled to the surface of unsaturated-fatty-acid-based liposomes received processing at both MHC class I and class II compartments, while most of the antigens coupled to the surface of saturated-fatty-acid-based liposomes received processing at the class II compartment. In addition, flow cytometric analysis demonstrated that antigens coupled to the surface of unsaturated-fatty-acid-liposomes were taken up by APCs even in a 4°C environment; this was not true of saturated-fatty-acid-liposomes. When two kinds of inhibitors, dimethylamiloride (DMA) and cytochalasin B, which inhibit pinocytosis and phagocytosis by APCs, respectively, were added to the culture of APCs prior to the antigen pulse, DMA but not cytochalasin B significantly reduced uptake of liposome-coupled antigens. Further analysis of intracellular trafficking of liposomal antigens using confocal laser scanning microscopy revealed that a portion of liposome-coupled antigens taken up by APCs were delivered to the lysosome compartment. In agreement with the reduction of antigen uptake by APCs, antigen presentation by APCs was significantly inhibited by DMA, and resulted in the reduction of IFN-γ production by antigen-specific CD8+ T cells. These results suggest that antigens coupled to the surface of liposomes consisting of unsaturated fatty acids might be pinocytosed by APCs, loaded onto the class I MHC processing pathway, and presented to CD8+ T cells. Thus, these liposome-coupled antigens are expected to be applicable for the development of vaccines that induce cellular immunity

Lysophosphatidylcholine as an adjuvant for lentiviral vector mediated gene transfer to airway epithelium: effect of acyl chain length

Extent: 11p.Background Poor gene transfer efficiency has been a major problem in developing an effective gene therapy for cystic fibrosis (CF) airway disease. Lysophosphatidylcholine (LPC), a natural airway surfactant, can enhance viral gene transfer in animal models. We examined the electrophysiological and physical effect of airway pre-treatment with variants of LPC on lentiviral (LV) vector gene transfer efficiency in murine nasal airways in vivo. Methods Gene transfer was assessed after 1 week following nasal instillations of a VSV-G pseudotype LV vector pre-treated with a low and high dose of LPC variants. The electrophysiological effects of a range of LPC variants were assessed by nasal transepithelial potential difference measurements (TPD) to determine tight junction permeability. Any physical changes to the epithelium from administration of the LPC variants were noted by histological methods in airway tissue harvested after 1 hour. Results Gene transduction was significantly greater compared to control (PBS) for our standard LPC (palmitoyl/stearoyl mixture) treatment and for the majority of the other LPC variants with longer acyl chain lengths. The LPC variant heptadecanoyl also produced significantly greater LV gene transfer compared to our standard LPC mixture. LV gene transfer and the transepithelial depolarization produced by the 0.1% LPC variants at 1 hour were strongly correlated (r2 = 0.94), but at the 1% concentration the correlation was less strong (r2 = 0.59). LPC variants that displayed minor to moderate levels of disruption to the airway epithelium were clearly associated with higher LV gene transfer. Conclusions These findings show the LPC variants effect on airway barrier function and their correlation to the effectiveness of gene expression. The enhanced expression produced by a number of LPC variants should provide new options for preclinical development of efficient airway gene transfer techniques.Patricia Cmielewski, Don S. Anson and David W. Parson

Direct Presentation Is Sufficient for an Efficient Anti-Viral CD8+ T Cell Response

The extent to which direct- and cross-presentation (DP and CP) contribute to the priming of CD8+ T cell (TCD8+) responses to viruses is unclear mainly because of the difficulty in separating the two processes. Hence, while CP in the absence of DP has been clearly demonstrated, induction of an anti-viral TCD8+ response that excludes CP has never been purposely shown. Using vaccinia virus (VACV), which has been used as the vaccine to rid the world of smallpox and is proposed as a vector for many other vaccines, we show that DP is the main mechanism for the priming of an anti-viral TCD8+ response. These findings provide important insights to our understanding of how one of the most effective anti-viral vaccines induces immunity and should contribute to the development of novel vaccines

Policy assessment and policy development for physical activity promotion: results of an exploratory intervention study in 15 European Nations

<p>Abstract</p> <p>Background</p> <p>Purpose of the study was to test a theoretical model to assess and develop policies for the promotion of physical activity among older people as part of an international intervention study.</p> <p>Methods</p> <p>248 semi-standardized interviews with policy-makers were conducted in 15 European nations. The questionnaire assessed policy-makers' perceptions of organizational goals, resources, obligations, as well as organizational, political and public opportunities in the area of physical activity promotion among older people. In order to develop policies, workshops with policy-makers were conducted. Workshop outputs and outcomes were assessed for four nations nine months after the workshops.</p> <p>Results</p> <p>Policy assessment: Results of the policy assessment were diverse across nations and policy sectors. For example, organizational goals regarding actions for physical activity promotion were perceived as being most favorably by the sports sector. Organizational obligations for the development of such policies were perceived as being most favorably by the health sector.</p> <p>Policy development: The workshops resulted in different outputs: a national intersectoral action plan (United Kingdom), a national alliance (Sweden), an integrated policy (the Netherlands), and a continuing dialogue (Germany).</p> <p>Conclusions</p> <p>Theory-driven policy assessment and policy-maker workshops might be an important means of scientific engagement in policy development for health promotion.</p

Bioelectrical impedance phase angle as a prognostic indicator in breast cancer

<p>Abstract</p> <p>Background</p> <p>Bioelectrical impedance analysis (BIA) is an easy-to-use, non-invasive, and reproducible technique to evaluate changes in body composition and nutritional status. Phase angle, determined by bioelectrical impedance analysis (BIA), detects changes in tissue electrical properties and has been hypothesized to be a marker of malnutrition. Since malnutrition can be found in patients with breast cancer, we investigated the prognostic role of phase angle in breast cancer.</p> <p>Methods</p> <p>We evaluated a case series of 259 histologically confirmed breast cancer patients treated at Cancer Treatment Centers of America. Kaplan Meier method was used to calculate survival. Cox proportional hazard models were constructed to evaluate the prognostic effect of phase angle independent of stage at diagnosis and prior treatment history. Survival was calculated as the time interval between the date of first patient visit to the hospital and the date of death from any cause or date of last contact/last known to be alive.</p> <p>Results</p> <p>Of 259 patients, 81 were newly diagnosed at our hospital while 178 had received prior treatment elsewhere. 56 had stage I disease at diagnosis, 110 had stage II, 46 had stage III and 34 had stage IV. The median age at diagnosis was 49 years (range 25 – 74 years). The median phase angle score was 5.6 (range = 1.5 – 8.9). Patients with phase angle <= 5.6 had a median survival of 23.1 months (95% CI: 14.2 to 31.9; n = 129), while those > 5.6 had 49.9 months (95% CI: 35.6 to 77.8; n = 130); the difference being statistically significant (p = 0.031). Multivariate Cox modeling, after adjusting for stage at diagnosis and prior treatment history found that every one unit increase in phase angle score was associated with a relative risk of 0.82 (95% CI: 0.68 to 0.99, P = 0.041). Stage at diagnosis (p = 0.006) and prior treatment history (p = 0.001) were also predictive of survival independent of each other and phase angle.</p> <p>Conclusion</p> <p>This study demonstrates that BIA-derived phase angle is an independent prognostic indicator in patients with breast cancer. Nutritional interventions targeted at improving phase angle could potentially lead to an improved survival in patients with breast cancer.</p