Acute exercise enhances the expansion of cytotoxic T-cells specific to leukemia and melanoma antigens: implications for adoptive transfer immunotherapy?

INTRODUCTION: The ex vivo expansion of tumor-associated-antigen (TAA)-specific cytotoxic T-cells from healthy donors for adoptive transfer in cancer patients has been used successfully to prevent relapse after hematopoietic stem cell transplantation (HSCT). However, this therapy is limited by the difficulty in priming and expanding sufficient numbers of functional TAA-specific T-cells, as T-cells recognizing TAA are usually low in frequency and avidity in healthy donors. Furthermore, monocyte-derived dendritic cells (Mo-DC) are used for TAA-presentation, but their manufacture is limited by low blood monocyte numbers. Therefore, large and impractical numbers of blood cells are required to successfully expand TAA-specific T-cells. Acute exercise is well-known to transiently activate and increase the numbers of T-cells and monocytes in peripheral blood. We therefore hypothesized that the immune-enhancing effects of exercise could be harnessed to enhance the ex vivo expansion of TAA-specific T-cells for adoptive transfer immunotherapy. AIMS: To examine the effects of acute exercise on (1) the number and function of TAA-specific T-cells expanded ex vivo, and 2) the generation and function of mo-DC. METHODS: 12 healthy adults (mean ± SD: Age 27±2.6yrs) completed an acute bout of stair-running exercise (time: 104±17sec). Mo-DC generated from pre and post exercise blood samples were pulsed with the melanoma-associated-antigens MAGE-A4 and PRAME, the common tumor-antigen survivin, and the leukemia-associated-antigen WT-1. Autologous DC were used to expand TAA-specific T-cells obtained before and after exercise over 14-days. T-cells were enumerated and phenotyped by flow cytometry and function was assessed by ELISPOT and antigen-specific cytotoxicity. RESULTS: A greater number of mo-DC were generated from post-exercise blood samples (pre: 2.0±1.0 X106cells, post: 5.2±2.6 X106cells). This was due to the 1.7 fold increase in blood monocytes post-exercise, as the number of mo-DC generated per input CD14+cell did not differ (pre: 0.40±0.25, post: 0.59±0.36). Total T-cell expansion was increased post-exercise (fold-increase: pre: 2.48±0.75, post: 2.90±0.74). ELISPOT revealed that the majority of donors had enrichment in TAA-specific T-cells post-exercise, as T-cell lines expanded from post-exercise samples exhibited an increased interferon-gamma response to TAA compared to T-cell lines expanded from pre-exercise samples. Exercise had no effect on T-cell phenotype or antigen-specific cytotoxicity in the expanded cells. CONCLUSION: These data indicate that a single bout of exercise enhances mo-DC generation and the expansion of TAA-specific T-cells ex vivo. Exercise may therefore serve as an adjuvant to enhance the expansion of TAA-specific T-cells in healthy donors and improve the efficacy of adoptive transfer therapy in cancer patients

Economic modeling of the combined effects of HIV-disease, cholesterol and lipoatrophy based on ACTG 5142 trial data

<p>Abstract</p> <p>Background</p> <p>This study examines the cost and consequences of initiating an ARV regimen including Lopinavir/ritonavir (LPV/r) or Efavirenz (EFV), using data from a recent clinical trial in a previously published model of HIV-disease.</p> <p>Methods</p> <p>We populated the Markov model of HIV-disease with data from ACTG 5142 study to estimate the economic outcomes of starting ARV therapy with a PI-containing regimen as compared to an NNRTI-containing regimen, given their virologic and immunologic efficacy and effects on cholesterol and lipoatrophy. CNS toxicities and GI tolerability were not included in the model because of their transient nature or low cost remedies, and therefore lack of economic impact. CD4+ T-cell counts and the HIV-1 RNA (viral load) values from the study were used to assign a specific health state (HS) to each patient for each quarter year. The resulting frequencies used as "raw" data directly into the model obviate the reliance on statistical tests, and allow the model to reflect actual patient behavior in the clinical trial. An HS just below the last observed HS was used to replace a missing value.</p> <p>Results</p> <p>The modeled estimates (undiscounted) for the LPV/r-based regimen resulted in 1.41 quality-adjusted life months (QALMs) gained over a lifetime compared to the EFV-based regimen. The LPV/r-based regimen incurred $7,458 (1.8$88,829/QALY. Most of the higher costs accrue before the 7th year of treatment and were offset by subsequent savings. The estimates are highly sensitive to the effect of lipoatrophy on Health-related Quality of Life (HRQOL), but not to the effect of cholesterol levels.</p> <p>Conclusions</p> <p>The cost effectiveness of ARV regimens may be strongly affected by enduring AEs, such as lipoatrophy. It is important to consider specific AE effects from all drugs in a regimen when ARVs are compared.</p> <p>Trial registration</p> <p>(ClinicalTrials.gov number, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00050895">NCT00050895</a><url>http://[ClinicalTrials.gov]</url>).</p

Thin layer composite unimorph ferroelectric driver and sensor

A method for forming ferroelectric wafers is provided. A prestress layer is placed on the desired mold. A ferroelectric wafer is placed on top of the prestress layer. The layers are heated and then cooled, causing the ferroelectric wafer to become prestressed. The prestress layer may include reinforcing material and the ferroelectric wafer may include electrodes or electrode layers may be placed on either side of the ferroelectric layer. Wafers produced using this method have greatly improved output motion

The Phoenix Deep Survey: Extremely Red Galaxies and Cluster Candidates

We present the results of a study of a sample of 375 Extremely Red Galaxies (ERGs) in the Phoenix Deep Survey, 273 of which constitute a subsample which is 80% complete to K_s = 18.5 over an area of 1160 arcmin^2. The angular correlation function for ERGs is estimated, and the association of ERGs with faint radio sources explored. We find tentative evidence that ERGs and faint radio sources are associated at z > 0.5. A new overdensity-mapping algorithm has been used to characterize the ERG distribution, and identify a number of cluster candidates, including a likely cluster containing ERGs at 0.5 < z < 1. Our algorithm is also used in an attempt to probe the environments in which faint radio sources and ERGs are associated. We find limited evidence that the I - K_s > 4 criterion is more efficient than R - K_s > 5 at selecting dusty star-forming galaxies, rather than passively evolving ERGs.Comment: 14 emulateapj pages, 15 figures, 1 table, accepted for publication in Astronomical Journal. A version with full resolution figures is available at http://www.physics.usyd.edu.au/~asmith/research/ERGpaper.pd

The Effects of Exercise and a Low-Fat Diet on Monocyte TLR Expression and Disease Risk in Mice

Excess adiposity increases systemic inflammation, which is implicated in various diseases. Physical activity is a common treatment to reverse weight gain and increased disease risk; however, little evidence is available to determine if forced or voluntary exercise is more effective in mice. Such information has implications for the refinement of human exercise interventions. PURPOSE: To determine if 8-weeks of exercise combined with low-fat feeding reverses changes in disease risk, monocyte concentration and monocyte TLR2/TLR4 expression. METHODS: For 12-months, 24 CD-1 mice underwent pre-treatment, consuming either a low-fat (10% kcal from fat, N=6) or high-fat (60% kcal from fat, N=18) diet ad libitum. High-fat fed mice were randomly assigned to one of three groups (N=6/group): V-EX (low-fat chow, access to running wheel 5 d/week), F-EX (low-fat chow, forced treadmill running at 22 m/min, 60-min/d, 5 d/week), or SD (low-fat chow, no exercise). Mice pre-treated with low-fat chow served as controls (CN, N=6). Measurements were made on weekly saphenous vein blood samples using 3-color flow cytometry. Blood glucose and cholesterol concentration were analyzed weekly using a glucose and cholesterol analyzer. IPGTT was performed at baseline and week 8 and analyzed as area under the curve. RESULTS: All groups lost significant body weight over 8-weeks (P\u3c0.001). V-EX ran 4.4x more than F-EX (P\u3c0.001). There were no significant effects for blood cholesterol. CN had 26% higher glucose levels than V-EX (P=0.009). On average, there was a 59% decrease in IPGTT AUC from baseline to week 8 and V-EX decreased 37% more than CN. At week 8, monocyte concentration was 6x higher than week 1 (P=0.002). Specifically, V-EX was greater than both CN (49%) and F-EX (59%). Cell-surface TLR2 expression was significantly greater at week 6 (55%) and week 8 (23%) relative to baseline. Monocyte cell-surface TLR4 expression increased from baseline to week 8 (P\u3c0.001). CONCLUSIONS: Combining low-fat diet and exercise caused significantly more weight loss than low-fat diet alone. Overall, there was decreased insulin resistance and decreased glucose, suggesting there may have been a decrease in type II diabetes risk. Lack of difference in monocyte concentration and TLR2/4 cell-surface expression suggest the diet and exercise intervention was not long enough to elicit changes in inflammation following the long-term high-fat feeding. More research is needed to understand the time course of these changes. This study was useful in understanding what occurs during a diet and exercise intervention and in directly comparing forced and voluntary exercise

Alkyl and Hydride Bis (Trimethylsilyl)Amido Derivatives of the Actinide Elements: Preparation and Hydrogen-Deuterium Exchange

The monomeric, hydrocarbon-soluble monohydrides and monodeuterides of the actinide metals (thorium or uranium) of the type HM[N(SiMe{sub 3}){sub 2}]{sub 3} have been prepared. Their reaction chemistry, n-BuLi followed by MeBr yields MeM[N(SiMe{sub 3}){sub 2}]{sub 3} and borane in tetrahydrofuran yields BH{sub 4}M[N(SiMe{sub 3}){sub 2}]{sub 3}, suggests that the hydrogen atom is hydridic. Pyrolysis of the hydrides yields the novel, four-membered ring metallocycle, [(Me{sub 3}Si){sub 2}N]{sub 2} - MCH{sub 2}Si(Me){sub 2}NSiMe{sub 3} where M is Th or U. These metallocycles are the key intermediates in the hydrogen-deuterium exchange reaction that yields {[(CD{sub 3}){sub 3}Si]{sub 2}N}{sub 3}MD

CMV-specific T-cells Mobilized with Exercise have Broad Epitope Specificity and a High-Differentiated Effector Memory Phenotype.

Introduction: Dynamic exercise evokes a rapid redeployment of cytotoxic T-cell subsets with high surface expression of b2 adrenergic receptors, presumably to enhance immunosurveillance during acute stress. As this response is affected by age and infection history, the main aim of this study was to examine latent CMV infection as a potential confounder to age-related differences in blood CD8+ T-cell responses to exercise. The second aim of this study was to examine the impact of acute exercise on the mobilization of CMV-specific T-cells in the peripheral blood compartment. Methods: Healthy young (n=16) and older (n=16) humans counterbalanced by CMV IgG serostatus (positive or negative) exercised for 30-minutes at ~80% peak cycling power. Isolated blood lymphocytes phenotypes were assessed by flow cytometry and Enzyme-linked immunospot (ELISPOT) analysis was used to determine the frequency and function of T-cells secreting IFN-g in response to CMV antigens. Maximum likelihood linear mixed models (LMM) were used to determine main effects of exercise (pre, post and 1h post-exercise), age (young or old) and CMV status (positive or negative) on total numbers of blood lymphocytes and their subsets. Results: Those with CMV redeployed ~2 times more CD8+ T-cells and ~6-times more KLRG1+/CD28- and CD45RA+/CCR7- CD8+ subsets than non-infected exercisers. Seronegative older exercisers had an impaired redeployment of total CD8+ T-cells, CD45RA+/CCR7+ and (KLRG1-/CD28+) CD8+ subsets. Redeployed CD8+ T-cell numbers were similar between infected young and old. CMVpp65 specific CD8+ cells in HLA/A2* subjects increased ~2.7 fold after exercise, a response that was driven by the KLRG1+/CD28-/CD8+ subset. Stimulating PBMCs before and after exercise with CMVpp65 and CMV IE-1 antigens and overlapping peptide pools revealed a 2.1 and 4.4 fold increases in CMVpp65 and CMV IE-1 IFN-g secreting cells respectively. The breadth of the T cell response was maintained after exercise with the magnitude of the response being amplified across the entire epitope repertoire. Conclusion: We conclude that latent CMV infection overrides age-related impairments in CD8+ T-cell redeployment with exercise. We also show for the first time that many T-cells redeployed with exercise are specific to CMVpp65 and CMV IE-1 antigens, have broad epitope specificity, and are mostly of a high-differentiated effector memory phenotype. We anticipate that these findings may have clinical implications, with acute exercise serving as a simple strategy to increase numbers of available antigen-specific cells in blood that can be harvested for expansion and adoptive T-cell transfer in HSCT recipients