A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity

Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients.

Adsorption Study using Optimised 3D Organised Mesoporous Silica Coated with Fe and Al Oxides for Specific As(III) and As(V) Removal from Contaminated Synthetic Groundwater

This work presents the possibility of optimising 3D Organised Mesoporous Silica (OMS) coated with both iron and aluminium oxides for the optimal removal of As(III) and As(V) from synthetic contaminated water. The materials developed were fully characterised and were tested for removing arsenic in batch experiments. The effect of total Al to Fe oxides coating on the selective removal of As(III) and As(V) was studied. It was shown that 8% metal coating was the optimal configuration for the coated OMS materials in removing arsenic. The effect of arsenic initial concentration and pH, kinetics and diffusion mechanisms was studied, modelled and discussed. It was shown that the advantage of an organised material over an un-structured sorbent was very limited in terms of kinetic and diffusion under the experimental conditions. It was shown that physisorption was the main adsorption process involved in As removal by the coated OMS. Maximum adsorption capacity of 55 mg As(V).g-1 was noticed at pH 5 for material coated with 8% Al oxides while 35 mg As(V).g-1 was removed at pH 4 for equivalent material coated with Fe oxides.

Bead array for Listeria monocytogenes detection using specific monoclonal antibodies

To develop a detection method for human pathogenic Listeria monocytogenes, novel specific antibodies were obtained from hybridoma libraries generated by using formalin-killed and heat-killed L. monocytogenes as immunogens. Several monoclonal antibodies found to be specific to Listeria spp or L. monocytogenes were evaluated for their applicability as binders for bead array and sandwichELISA for detection of L. monocytogenes in buffer and in 11 different food types. The bead array format consistently demonstrated lower detection limits and was less affected by interference from food matrices than the sandwich ELISA format. However, the obtained detection limits were not sufficient to satisfy the required standard for L. monocytogenes testing. Therefore, the international organizationfor standardization (ISO 11290-1:1996) methods for pre-enrichment and enrichment were employed to increase the bacteria numbers. When compared to the standard plating method, the bead array was able to detect the bacteria with the same accuracy even at the 1 CFU level after only 24 hours of the enrichment period. In addition, Listeria-specific 3C3 and L. monocytogenes-specific 7G4 antibodies were successfully employed to construct a multiplex detection for Listeria, Salmonella and Campylobacter in a bead array format by combining with commercial Salmonella-specific and available Campylobacter-specific antibodies.

Post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific survival: a nested case-control study in a breast cancer cohort from the UK Clinical Practice Research Datalink

INTRODUCTION: Recent observational studies indicate that post-diagnostic use of aspirin in breast cancer patients may protect against cancer progression perhaps by inhibiting cyclooxygenase-2 dependent mechanisms. Evidence also supports a crucial role for interactions between tumour cells and circulating platelets in cancer growth and dissemination, therefore, use of low-dose aspirin may reduce the risk of death from cancer in breast cancer patients.

METHODS: A cohort of newly diagnosed breast cancer patients (1998 to 2006) were identified in the UK Clinical Practice Research Datalink (and confirmed by cancer registry linkage). Cancer-specific deaths were identified up to 2011 from Office for National Statistics mortality data. A nested case-control analysis was conducted using conditional logistic regression to compare post-diagnostic aspirin exposure using General Practice prescription data in 1,435 cases (breast cancer deaths) with 5,697 controls (matched by age and year of diagnosis).

RESULTS: After breast cancer diagnosis, 18.3% of cancer-specific deaths and 18.5% of matched controls received at least one prescription for low-dose aspirin, corresponding to an odds ratio (OR) of 0.98 (95% CI 0.83, 1.15). Adjustment for potential confounders (including stage and grade) had little impact on this estimate. No dose response relationship was observed when the number of tablets was investigated and no associations were seen when analyses were stratified by receipt of prescriptions for aspirin in the pre-diagnostic period, by stage at diagnosis or by receipt of prescriptions for hormone therapy.

CONCLUSIONS: Overall, in this large population-based cohort of breast cancer patients, there was little evidence of an association between receipt of post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific death. However, information was not available on medication compliance or over-the-counter use of aspirin, which may have contributed to the null findings.

Representations of specific acoustic patterns in the auditory cortex and hippocampus

Previous behavioural studies have shown that repeated presentation of a randomly chosen acoustic pattern leads to the unsupervised learning of some of its specific acoustic features. The objective of our study was to determine the neural substrate for the representation of freshly learnt acoustic patterns. Subjects first performed a behavioural task that resulted in the incidental learning of three different noise-like acoustic patterns. During subsequent high-resolution functional magnetic resonance imaging scanning, subjects were then exposed again to these three learnt patterns and to others that had not been learned. Multi-voxel pattern analysis was used to test if the learnt acoustic patterns could be 'decoded' from the patterns of activity in the auditory cortex and medial temporal lobe. We found that activity in planum temporale and the hippocampus reliably distinguished between the learnt acoustic patterns. Our results demonstrate that these structures are involved in the neural representation of specific acoustic patterns after they have been learnt.

Element-specific depth profile of magnetism and stoichiometry at the La0.67Sr0.33MnO3/BiFeO3 interface

Depth-sensitive magnetic, structural and chemical characterization is important in the understanding and optimization of novel physical phenomena emerging at interfaces of transition metal oxide heterostructures. In a simultaneous approach we have used polarized neutron and resonant X-ray reflectometry to determine the magnetic profile across atomically sharp interfaces of ferromagnetic La0.67Sr0.33MnO3 / multiferroic BiFeO3 bi-layers with sub-nanometer resolution. In particular, the X-ray resonant magnetic reflectivity measurements at the Fe and Mn resonance edges allowed us to determine the element specific depth profile of the ferromagnetic moments in both the La0.67Sr0.33MnO3 and BiFeO3 layers. Our measurements indicate a magnetically diluted interface layer within the La0.67Sr0.33MnO3 layer, in contrast to previous observations on inversely deposited layers. Additional resonant X-ray reflection measurements indicate a region of an altered Mn- and O-content at the interface, with a thickness matching that of the magnetic diluted layer, as origin of the reduction of the magnetic moment.

Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs () across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of  from imputed SNPs (5.1× enrichment; p = 3.7 × 10⁻¹⁷) and 38% (SE = 4%) of  from genotyped SNPs (1.6× enrichment, p = 1.0 × 10⁻⁴). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of  despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.

Correlation of phantom-based and log file patient-specific QA with complexity scores for VMAT

The motivation for this study was to reduce physics workload relating to patient- specific quality assurance (QA). VMAT plan delivery accuracy was determined from analysis of pre- and on-treatment trajectory log files and phantom-based ionization chamber array measurements. The correlation in this combination of measurements for patient-specific QA was investigated. The relationship between delivery errors and plan complexity was investigated as a potential method to further reduce patient-specific QA workload. Thirty VMAT plans from three treatment sites - prostate only, prostate and pelvic node (PPN), and head and neck (H&amp;N) - were retrospectively analyzed in this work. The 2D fluence delivery reconstructed from pretreatment and on-treatment trajectory log files was compared with the planned fluence using gamma analysis. Pretreatment dose delivery verification was also car- ried out using gamma analysis of ionization chamber array measurements compared with calculated doses. Pearson correlations were used to explore any relationship between trajectory log file (pretreatment and on-treatment) and ionization chamber array gamma results (pretreatment). Plan complexity was assessed using the MU/ arc and the modulation complexity score (MCS), with Pearson correlations used to examine any relationships between complexity metrics and plan delivery accu- racy. Trajectory log files were also used to further explore the accuracy of MLC and gantry positions. Pretreatment 1%/1 mm gamma passing rates for trajectory log file analysis were 99.1% (98.7%-99.2%), 99.3% (99.1%-99.5%), and 98.4% (97.3%-98.8%) (median (IQR)) for prostate, PPN, and H&amp;N, respectively, and were significantly correlated to on-treatment trajectory log file gamma results (R = 0.989, p &lt; 0.001). Pretreatment ionization chamber array (2%/2 mm) gamma results were also significantly correlated with on-treatment trajectory log file gamma results (R = 0.623, p &lt; 0.001). Furthermore, all gamma results displayed a significant correlation with MCS (R &gt; 0.57, p &lt; 0.001), but not with MU/arc. Average MLC position and gantry angle errors were 0.001 ± 0.002 mm and 0.025° ± 0.008° over all treatment sites and were not found to affect delivery accuracy. However, vari- ability in MLC speed was found to be directly related to MLC position accuracy. The accuracy of VMAT plan delivery assessed using pretreatment trajectory log file fluence delivery and ionization chamber array measurements were strongly correlated with on-treatment trajectory log file fluence delivery. The strong corre- lation between trajectory log file and phantom-based gamma results demonstrates potential to reduce our current patient-specific QA. Additionally, insight into MLC and gantry position accuracy through trajectory log file analysis and the strong cor- relation between gamma analysis results and the MCS could also provide further methodologies to both optimize the VMAT planning and QA process.