Bi-specific TCR-anti CD3 redirected T-cell targeting of NY-ESO-1- and LAGE-1-positive tumors

NY-ESO-1 and LAGE-1 are cancer testis antigens with an ideal profile for tumor immunotherapy, combining up-regulation in many cancer types with highly restricted expression in normal tissues and sharing a common HLA-A*0201 epitope, 157–165. Here, we present data to describe the specificity and anti-tumor activity of a bifunctional ImmTAC, comprising a soluble, high-affinity T-cell receptor (TCR) specific for NY-ESO-1_157–165 fused to an anti-CD3 scFv. This reagent, ImmTAC-NYE, is shown to kill HLA-A2, antigen-positive tumor cell lines, and freshly isolated HLA-A2- and LAGE-1-positive NSCLC cells. Employing time-domain optical imaging, we demonstrate in vivo targeting of fluorescently labelled high-affinity NYESO-specific TCRs to HLA-A2-, NY-ESO-1_157–165-positive tumors in xenografted mice. In vivo ImmTAC-NYE efficacy was tested in a tumor model in which human lymphocytes were stably co-engrafted into NSG mice harboring tumor xenografts; efficacy was observed in both tumor prevention and established tumor models using a GFP fluorescence readout. Quantitative RT-PCR was used to analyze the expression of both NY-ESO-1 and LAGE-1 antigens in 15 normal tissues, 5 cancer cell lines, 10 NSCLC, and 10 ovarian cancer samples. Overall, LAGE-1 RNA was expressed at a greater frequency and at higher levels than NY-ESO-1 in the tumor samples. These data support the clinical utility of ImmTAC-NYE as an immunotherapeutic agent for a variety of cancers.     

Assessment of systematic effects of methodological characteristics on candidate genetic associations

Candidate genetic association studies have been found to have a low replication rate in the past. Here, we aimed to assess whether aspects of reported methodological characteristics in genetic association studies may be related to the magnitude of effects observed. An observational, literature-based investigation of 511 case–control studies of genetic association studies indexed in 2007, was undertaken. Meta-regression analyses were used to assess the relationship between 23 reported methodological characteristics and the magnitude of genetic associations. The 511 studies had been conducted in 52 countries and were published in 220 journals (median impact factor 5.1). The multivariate meta-regression model of methodological characteristics plus disease category accounted for 17.2 % of the between-study variance in the magnitude of the reported genetic associations. Our findings are consistent with the view that better conducted and better reported genetic association research may lead to less inflated results.     

Probing antioxidant activity of 2′-hydroxychalcones: Crystal and molecular structures, in vitro antiproliferative studies and in vivo effects on glucose regulation

In order to better understand the antioxidant behavior of a series of polyphenolic 2′-hydroxychalcones, we describe the results of several chemical and biological studies, in vitro and in vivo. Single crystal X-ray methods elucidated their molecular structures and important intermolecular interactions such as H-bonding and molecular stacking in the crystal structures that contribute to our knowledge in explaining antioxidant activity. The results of experiments using the 1,1-diphenyl-2-dipicrylhydrazyl (DPPH) UV–vis spectroscopic method indicate that a hydroxyl group in position 5′ induces the highest antioxidant activity. Consequently, 2,2′,5′-trihydroxychalcone was selected for further study in vitro towards ROS scavenging in L-6 myoblasts and THP-1 human monocytes, where it shows an excellent antioxidant activity in a concentration range lower than that reported by most studies of related molecules. In addition, this chalcone shows a very selective activity: it inhibits the proliferation of leukemic cells, but it does not affect the normal L-6 myoblasts and human fibroblasts. In studying 2,2′,5′-trihydroxychalcone's effect on weight gain and serum glucose and insulin levels in Zucker fatty (fa⁻/fa⁻) rats we found that supplementing the diet with a 10 mg/kg dose of this chalcone (3 times weekly) blunted the increase in glucose that co-occurs with weight gain over the 6-week treatment period. It is concluded that 2,2′,5′-trihydroxychalcone has the potential to serve as a protective agent for some debilitating diseases.     

Interannual variation of reach specific migratory success for Sacramento River hatchery yearling late-fall run Chinook salmon (Oncorhynchus tshawytscha) and steelhead trout (Oncorhynchus mykiss)

The release of hatchery reared salmonid smolts is a common management tool aimed at enhancing depleted wild stocks and maintaining fisheries throughout Northern California and the Pacific Northwest. In the Sacramento River watershed, smolts must migrate through the river, delta and estuary in order to successfully reach the Pacific Ocean. Migration success (success defined as apparent survival from one monitor location to another) may vary between species, year and habitat. We released 500 late-fall run Chinook salmon and 500 steelhead smolts in 2009 and 2010 in the Sacramento River (river kilometer 207). Each smolt was implanted with a coded ultrasonic tag, which was detected by an array of over 300 underwater receiver stations deployed throughout the system. Less than 25 % of fish migrated successfully to the Pacific Ocean in both years. We found that reach specific success was greater in the Delta in 2009 (>60 %) than in 2010 (<33 %), whereas this pattern was reversed in the Bay (<57 % in 2009, >75 % in 2010). Identifying the location, timing and causes of smolt mortality can lead to improved management of the resource.     

Computational structure characterisation tools in application to ordered and disordered porous materials

In this article, we present a set of computational tools for systematic characterisation of ordered and disordered porous materials. These tools include calculation of the accessible surface area and geometric pore size distribution, analysis of the structure connectivity and percolation analysis of the porous space. We briefly discuss the algorithms behind these calculations. To demonstrate the capabilities of the tools and the type of insights that can be gained from their application, we consider a series of case studies. These case studies include small molecular fragments, several crystalline metal-organic materials, and variants of these materials with induced defects and disorder in their structure. The simulation package is available upon request.     

Specificity, rank preference, and the colonization of a non-native host plant by the Melissa blue butterfly

Animals often express behavioral preferences for different types of food or other resources, and these preferences can evolve or shift following association with novel food types. Shifts in preference can involve at least two phenomena: a change in rank preference or a change in specificity. The former corresponds to a change in the order in which hosts are preferred, while a shift in specificity can be an increase in the tendency to utilize multiple hosts. These possibilities have been examined in relatively few systems that include extensive population-level replication. The Melissa blue butterfly, Lycaeides melissa, has colonized exotic alfalfa, Medicago sativa, throughout western North America. We assayed the host preferences of 229 females from ten populations associated with novel and native hosts. In four out of five native-associated populations, a native host was preferred over the exotic host, while preference for a native host characterized only two out of five of the alfalfa-associated populations. Across all individuals from alfalfa-associated populations, there appears to have been a decrease in specificity: females from these populations lay fewer eggs on the native host and more eggs on the exotic relative to females from native-host populations. However, females from alfalfa-associated populations did not lay more eggs on a third plant species, which suggests that preferences for specific hosts in this system can potentially be gained and lost independently. Geographic variation in oviposition preference in L. melissa highlights the value of surveying a large number of populations when studying the evolution of a complex behavioral trait.     

Observations of below-ground characteristics of young redwood trees (Sequoia sempervirens) from two sites in New Zealand – implications for erosion control

Aims

Radiata pine (Pinus radiata D. Don) plantations are widely used to control erosion in New Zealand. However, other species with similar growth but longer rotation lengths and ability to coppice may offer future alternatives to radiata pine. Comparing performance of alternative species to radiata thus becomes important if policy is to be developed to promote them.

Methods

The below-ground characteristics (roots) of young redwood (Sequoia sempervirens (D. Don) Endl.) trees from two established plantations in New Zealand were examined and compared with those of radiata pine, and selected poplar and New Zealand native species.

Results

Roots with diameters less than 10 mm comprised over 99 % of total root length in 3-yr-old trees and 98 % of total root length in 4-yr-old trees. For roots greater than 2 mm in diameter, total root length of young redwood trees was greater than that of young radiata pine, poplar and the best performing New Zealand native plant. Total root length at a given root collar diameter for young (1–4 year old) redwood trees was significantly greater than for radiata pine trees. Roots of redwoods were finer and more numerous than for radiata but the below-ground biomass for a given root collar diameter showed no statistical difference between the two species.

Conclusions

Redwood, because of its comparable growth rate and the production of many fine lateral roots, has the potential to become a keystone erosion-control species in New Zealand, especially on steep lands where there is an increased risk of post-harvest landsliding associated with moderate to severe rainstorm events.     

The Upper Palaeolithic site of Kalavan 1 (Armenia): An Epigravettian settlement in the Lesser Caucasus

The open-air site of Kalavan 1 is located in the Aregunyats mountain chain (at 1640 m above sea level) on the northern bank of Lake Sevan. It is the first Upper Palaeolithic site excavated in Armenia. Led by an Armenian-French team, several excavations (2005–2009) have revealed a well preserved palaeosoil, dated to around 14,000 BP (years before present), containing fauna, lithic artefacts, as well as several hearths and activity areas that structure the settlement. The initial studies enable placement of the site in its environment and justify palaeoethnological analysis of the Epigravettian human groups of the Lesser Caucasus.