Nanoparticle-based drug delivery: case studies for cancer and cardiovascular applications

Nanoparticles (NPs) comprised of nanoengineered complexes are providing new opportunities for enabling targeted delivery of a range of therapeutics and combinations. A range of functionalities can be included within a nanoparticle complex, including surface chemistry that allows attachment of cell-specific ligands for targeted delivery, surface coatings to increase circulation times for enhanced bioavailability, specific materials on the surface or in the nanoparticle core that enable storage of a therapeutic cargo until the target site is reached, and materials sensitive to local or remote actuation cues that allow controlled delivery of therapeutics to the target cells. However, despite the potential benefits of NPs as smart drug delivery and diagnostic systems, much research is still required to evaluate potential toxicity issues related to the chemical properties of NP materials, as well as their size and shape. The need to validate each NP for safety and efficacy with each therapeutic compound or combination of therapeutics is an enormous challenge, which forces industry to focus mainly on those nanoparticle materials where data on safety and efficacy already exists, i.e., predominantly polymer NPs. However, the enhanced functionality affordable by inclusion of metallic materials as part of nanoengineered particles provides a wealth of new opportunity for innovation and new, more effective, and safer therapeutics for applications such as cancer and cardiovascular diseases, which require selective targeting of the therapeutic to maximize effectiveness while avoiding adverse effects on non-target tissues.     

A new anatomy of the prestalk zone in Dictyostelium

The characteristic structure of the mature Dictyostelium culminant is created by the regionalized cellular differentiation and directed movement of prestalk cells. The front prestalk zone of the migratory slug has previously been considered to be a homogeneous tissue. Here we demonstrate, however, the existence of multiple classes of prestalk cells located in different parts or the slug anterior. The pDd56 and pDd63 genes encoding closely related extracellular matrix proteins are dependent for their expression upon DIF-1, the specific stalk-cell inducer. We have fused the promoters of the two genes to a modified chloramphenicol acetyltransferase (cat) gene to produce immunologically detectable proteins which localize to the cell nucleus. These two markers define three distinct kinds of 'prestalk' cells. One class, which we term 'prestalk A' cells, expressed the pDd63 gene. 'Prestalk B' cells express pDd56 and may also express the pDd63 gene. A third class, which we term 'prestalk 0' cells, expresses neither marker.     

Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.     

A permutation-based algorithm for block clustering

Hartigan (1972) discusses the direct clustering of a matrix of data into homogeneous blocks. He introduces a stepwise divisive method for block clustering within a certain class of block structures which induce clustering trees for both row and column margins. While this class of structures is appealing, the stopping criterion for his method, which is based on asymptotic theory and the assumption that the individual elements of the data matrix are normally distributed, is quite restrictive. In this paper we propose a permutation-based algorithm for block clustering within the same class of block structures. By using permutation arguments to decide where to split and when to stop, our algorithm becomes applicable in a wide variety of cases, including matrices of categorical data and matrices of small-to-moderate size. In addition, our algorithm offers considerable flexibility in how block homogeneity is defined. The algorithm is studied in a series of simulation experiments on matrices of known structure, and illustrated in examples drawn from the fields of taxonomy, political science, and data architecture.     

Diversity and dispersal interactively affect predictability of ecosystem function

Theory and small-scale experiments predict that biodiversity losses can decrease the magnitude and stability of ecosystem services such as production and nutrient cycling. Most of this research, however, has been isolated from the immigration and emigration (dispersal) processes that create and maintain diversity in nature. As common anthropogenic drivers of biodiversity change--such as habitat fragmentation, species introductions and climate change--are mediated by these understudied processes, it is unclear how environmental degradation will affect ecosystem services. Here we tested the interactive effects of mobile grazer diversity and dispersal on the magnitude and stability of ecosystem properties in experimental seagrass communities that were either isolated or connected by dispersal corridors. We show that, contrary to theoretical predictions, increasing the number of mobile grazer species in these metacommunities increased the spatial and temporal variability of primary and secondary production. Moreover, allowing grazers to move among and select patches reduced diversity effects on production. Finally, effects of diversity on stability differed qualitatively between patch and metacommunity scales. Our results indicate that declining biodiversity and habitat fragmentation synergistically influence the predictability of ecosystem functioning.     

Common sequence variants on 20q11.22 confer melanoma susceptibility

We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.