CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model

p53 is overexpressed by half of all cancers, and is an attractive target for a vaccine approach to immunotherapy. p53 overexpression is frequently the result of point mutations, which leaves the majority of the protein in its wild-type form. Therefore, the majority of p53 sequence is wild type, making it a self-protein for which tolerance plays a role in limiting immune responses. To overcome tolerance to p53, we have expressed wild-type murine p53 in the nonpathogenic attenuated poxvirus, modified vaccinia virus Ankara (recombinant modified vaccinia virus Ankara expressing wild-type murine p53 (rMVAp53)). Mice immunized with rMVAp53 vaccine developed vigorous p53-specific CTL responses. rMVAp53 vaccine was evaluated for its ability to inhibit the outgrowth of the syngeneic murine sarcoma Meth A, which overexpresses mutant p53. Mice were inoculated with a lethal dose (5 x 10(5) cells injected s.c.) of Meth A tumor cells and vaccinated by i.p. injection 3 days later with 5 x 10(7) PFU of rMVAp53. The majority of mice remained tumor free and resistant to rechallenge with Meth A tumor cells. We wished to determine whether rMVAp53 immunization could effect the rejection of an established, palpable Meth A tumor. In subsequent experiments, mice were injected with 10(6) Meth A tumor cells, and treated 6 days later with anti-CTLA-4 Ab (9H10) and rMVAp53. The majority of treated mice had complete tumor regression along with lasting tumor immunity. In vivo Ab depletion confirmed that the antitumor effect was primarily CD8 and to a lesser extent CD4 dependent. These experiments demonstrate the potential of a novel cell-free vaccine targeting p53 in malignancy.     

Relative performance of clumped vs. experimentally isolated plants in a South African winter-rainfall desert community

We conducted a factorial removal experiment in the arid strandveld onthe west coast of South Africa to test the hypothesis that perennial specieswith a preference for occurring in multi-species clumps shouldderive benefits from their association into clumps. Contrary to our hypothesis,we obtained evidence of competition for water in the clumped non-succulentspecies studied in the form of depressed water potentials. We were not able todetect any effect on leaf water contents associated with isolation, suggestingthat clumped plants are able to compensate physiologically in response tocompetitive stress. We also found that isolating individuals had no effect(positive or negative) on branch growth. Finally, we showed that isolatingindividuals exposed them to a far greater risk of damage by wind or animals. Inlight of these results we conclude that the spatial arrangement of plants inthis community does suggest a situation where the benefits associated withoccurring in clumps exceed any competitive costs.     

A novel series of positive modulators of the AMPA receptor: Structure-based lead optimization

Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.     

Influence of type of muscle contraction, gender, and lifting experience on postactivation potentiation performance

Postactivation potentiation (PAP) or enhanced contractile capabilities may be influenced by a number of factors. This study examined the influence of type of muscle contraction (isometric vs. dynamic), gender, and previous weightlifting experience on PAP as demonstrated by changes in jump height and power output. Thirty young men (n = 15) and women (n = 15), classified as either having previous weightlifting experience (n = 20) or not (n = 10), performed 3 different sets of countermovement jumps, with the first set used to determine baseline measures of jump height and power. The second set was performed after a maximal isometric squat protocol (maximal voluntary contraction [MVC]-PAP) to induce PAP, and the third set of jumps was performed after a maximal dynamic squat (DS) protocol (DS-PAP). A 3-way repeated measures analysis of variance determined that jump height after the MVC-PAP protocol was significantly higher than both the pretest and DS-PAP values, that men performed significantly better than women, and that the experienced lifters responded more favorably than the inexperienced lifters. Jump power was also significantly greater for the MVC-PAP condition compared with the other 2 conditions, and DS-PAP power also improved when compared with the pretest values, with men performing significantly better than women. All results remained consistent after accounting for height and weight differences (body mass index) between the groups. In conclusion, the isometric condition (MVC-PAP) evoked a greater muscle postactivation potentiation than the dynamic condition (DS-PAP), and postactivation was enhanced by previous weightlifting experience. The practical manipulation of MVC by pushing, squatting, or both against fixed objects, such as walls and low ceilings, could be a very simple and cost-effective way to arouse a state of PAP before sports performance that requires high force and power outputs.     

The Serratia-type hemolysin of Chromobacterium violaceum

Chromobacterium violaceum is a Gram-negative opportunistic human pathogen and an inhabitant of tropical soils and waterways. Although known primarily for the synthesis of the pigment violacein, and more recently as a reporter strain for quorum sensing, clinical reports of chromobacteriosis comprise the largest block of published literature on this organism. Genome sequencing has revealed many potential virulence factors in this microorganism, and this paper establishes the presence in C. violaceum of a Serratia type-hemolysin (ChlA) and transporter (ChlB). We also show that the hemolysin operon includes a third gene (chlC) that is predicted to encode a phosphorylation domain similar to the receiver domain of response regulators in bacterial signal transduction systems.     

Global gene expression profile after Salmonella enterica Serovar enteritidis challenge in two F8 advanced intercross chicken lines

A chicken 13K cDNA microarray was used to profile global gene expression after Salmonella enteritidis (SE) challenge of young chickens. Two F8 advanced intercross lines (AIL), broiler by Leghorn, and broiler by Fayoumi, were studied. Day-old chicks were orally inoculated with SE, and spleens were harvested at day 7 or 8 post-inoculation. The SE bacteria burden in the spleen was quantified. The 20% high and 20% low SE burden birds within each AIL and harvest time were studied by microarray. The loop design was used for pair-comparison between high and low SE burden challenged birds and unchallenged birds, within each AIL and harvest time. The signal intensity of each gene was globally normalized and expressed on the natural log scale. A mixed model including line, treatment, time, array (random effect), dye, and all two-way interactions among treatment, time, and line was used to identify differentially expressed candidate genes at the 1% significance level. The results suggest that genetics, time, and interaction between genetics and time play important roles in gene regulation of SE infection and colonization in chickens. The differentially expressed genes identified in the current study are candidates for detailed hypothesis-driven investigation of genes determining resistance to SE in chickens.     

Fitness and evolution of resprouters in relation to fire

There are many ways that plants may recover vegetatively from dieback caused by fires. Compared with fire-killed species, the presence of woody resprouters in fire-prone floras increases with fire frequency, though this is affected by site productivity that may have opposing correlates along different gradients. Population recovery is enhanced by resprouting when fecundity is low and/or seedling recruitment is not guaranteed. There is resource cycling between vegetative growth and storage but no clear trade-off between fecundity and storage, and more attention needs to be given to the role of somatic mutations in reducing fecundity. Seven fitness benefits of post-fire resprouting are noted that centre around the rapid return to adult growth rates and early flowering and seed set without the risks of recruitment failure. The extent of resprouting at the individual, population, and species levels varies greatly but it is under genetic control. Recent studies on the evolution of resprouting in fire-prone systems have shown that types of resprouting (clonality, rootstocks, epicormic bud strands) are derived from surrounding parent lineages lacking these traits and confined to non-fire-prone environments. The oldest lineages with fire-related resprouting date to at least 61 million years ago, indicating that seed plants have had a long evolutionary relationship with fire. Various genetic mechanisms, including beneficial somatic mutations, have been invoked to explain how speciation of resprouters may keep pace with non-sprouters.