Bystander Signalling: Exploring Clinical Relevance Through New Approaches and New Models

Classical radiation biology research has centred on nuclear DNA as the main target of radiation-induced damage. Over the past two decades, this has been challenged by a significant amount of scientific evidence clearly showing radiation-induced cell signalling effects to have important roles in mediating overall radiobiological response. These effects, generally termed radiation-induced bystander effects (RIBEs) have challenged the traditional DNA targeted theory in radiation biology and highlighted an important role for cells not directly traversed by radiation. The multiplicity of experimental systems and exposure conditions in which RIBEs have been observed has hindered precise definitions of these effects. However, RIBEs have recently been classified for different relevant human radiation exposure scenarios in an attempt to clarify their role in vivo. Despite significant research efforts in this area, there is little direct evidence for their role in clinically relevant exposure scenarios. In this review, we explore the clinical relevance of RIBEs from classical experimental approaches through to novel models that have been used to further determine their potential implications in the clinic. 

Quantum chemistry and in situ FTir spectroscopy studies on potential-dependent properties of CO adsorbed on Pt electrodes

The electronic and vibrational properties of CO adsorbed on Pt electrodes at different potentials have been studied, by using methods of self-consistent-charge discrete variational Xa (SCC-DV-Xa) cluster calculations and in situ FTir spectroscopy. Two new models have been developed and verified to be successful: (1) using a "metallic state cluster" to imitate a metal (electrode) surface; and (2) charging the cluster and shifting its Fermi level (e{lunate}) to simulate, according to the relation of -d e{lunate}e dE, quantitatively the variation of the electrode potential (E). It is shown that the binding of PtCO is dominated by the electric charge transfer of dp ? 2p, while that of s ? Pt is less important in this binding. The electron occupancy of the 2p orbital of CO weakens the CO bond and decreases the v. Variation of E mainly influences the charge transfer process of dp ? 2p, but hardly influences that of s ? Pt. A linear potential-dependence of v has been shown and the calculated dv/dE = 35.0 cm V. All results of calculations coincide with the ir experimental data. © 1993.

A potential vulnerability locus for schizophrenia on chromosome 6p24-22:evidence for genetic heterogeneity

In 265 Irish pedigrees, with linkage analysis we find evidence for a vulnerability locus for schizophrenia in region 6p24-22. The greatest lod score, assuming locus heterogeneity, is 3.51 (P = 0.0002) with D6S296. Another test, the C test, also supported linkage, the strongest results being obtained with D6S296 (P = 0.00001), D6S274 (P = 0.004) and D6S285 (P = 0.006). Non-parametric analysis yielded suggestive, but substantially weaker, findings. This locus appears to influence the vulnerability to schizophrenia in roughly 15 to 30% of our pedigrees. Evidence for linkage was maximal using an intermediate phenotypic definition and declined when this definition was narrowed or was broadened to include other psychiatric disorders.

Body shadowing mitigation using differentiated LOS/NLOS channel models for RSSI-based Monte Carlo personnel localization

Research into localization has produced a wealth of algorithms and techniques to estimate the location of wireless network nodes, however the majority of these schemes do not explicitly account for non-line of sight conditions. Disregarding this common situation reduces their accuracy and their potential for exploitation in real world applications. This is a particular problem for personnel tracking where the user's body itself will inherently cause time-varying blocking according to their movements. Using empirical data, this paper demonstrates that, by accounting for non-line of sight conditions and using received signal strength based Monte Carlo localization, meter scale accuracy can be achieved for a wrist-worn personnel tracking tag in a 120 m indoor office environment. © 2012 IEEE.

Investigating the Potential Impact of Four-dimensional Computed Tomography (4DCT) on Toxicity, Outcomes and Dose Escalation for Radical Lung Cancer Radiotherapy

AIMS: To investigate the potential dosimetric and clinical benefits predicted by using four-dimensional computed tomography (4DCT) compared with 3DCT in the planning of radical radiotherapy for non-small cell lung cancer.

MATERIALS AND METHODS:
Twenty patients were planned using free breathing 4DCT then retrospectively delineated on three-dimensional helical scan sets (3DCT). Beam arrangement and total dose (55 Gy in 20 fractions) were matched for 3D and 4D plans. Plans were compared for differences in planning target volume (PTV) geometrics and normal tissue complication probability (NTCP) for organs at risk using dose volume histograms. Tumour control probability and NTCP were modelled using the Lyman-Kutcher-Burman (LKB) model. This was compared with a predictive clinical algorithm (Maastro), which is based on patient characteristics, including: age, performance status, smoking history, lung function, tumour staging and concomitant chemotherapy, to predict survival and toxicity outcomes. Potential therapeutic gains were investigated by applying isotoxic dose escalation to both plans using constraints for mean lung dose (18 Gy), oesophageal maximum (70 Gy) and spinal cord maximum (48 Gy).

RESULTS:
4DCT based plans had lower PTV volumes, a lower dose to organs at risk and lower predicted NTCP rates on LKB modelling (P < 0.006). The clinical algorithm showed no difference for predicted 2-year survival and dyspnoea rates between the groups, but did predict for lower oesophageal toxicity with 4DCT plans (P = 0.001). There was no correlation between LKB modelling and the clinical algorithm for lung toxicity or survival. Dose escalation was possible in 15/20 cases, with a mean increase in dose by a factor of 1.19 (10.45 Gy) using 4DCT compared with 3DCT plans.

CONCLUSIONS:
4DCT can theoretically improve therapeutic ratio and dose escalation based on dosimetric parameters and mathematical modelling. However, when individual characteristics are incorporated, this gain may be less evident in terms of survival and dyspnoea rates. 4DCT allows potential for isotoxic dose escalation, which may lead to improved local control and better overall survival.

Lactobacillus strains isolated from infant faeces possess potent inhibitory activity against intestinal alpha- and beta-glucosidases suggesting anti-diabetic potential

Purpose: Inhibitors of intestinal alpha-glucosidases are used therapeutically to treat type 2 diabetes mellitus. Bacteria such as Actinoplanes sp. naturally produce potent alpha-glucosidase inhibitor compounds, including the most widely available drug acarbose. It is not known whether lactic acid bacteria (LAB) colonising the human gut possess inhibitory potential against glucosidases. Hence, the study was undertaken to screen LABs having inherent alpha- and beta-glucosidase inhibitory potential. Methods: This study isolated, screened, identified and extracted Lactobacillus strains (Lb1–15) from human infant faecal samples determining their inhibitory activity against intestinal maltase, sucrase, lactase and amylase. Lactobacillus reference strains (Ref1–7), a Gram positive control (Ctrl1) and two Gram negative controls (Ctrl2–3), were also analysed to compare activity. Results: Faecal isolates were identified by DNA sequencing, with the majority identified as unique strains of Lactobacillus plantarum. Some strains (L. plantarum, L. fermentum, L. casei and L. rhamnosus) had potent and broad spectrum inhibitory activities (up to 89 %; p < 0.001; 500 mg/ml wet weight) comparable to acarbose (up to 88 %; p < 0.001; 30 mg/ml). Inhibitory activity was concentration-dependent and was freely available in the supernatant, and was not present in other bacterial genera (Bifidobacterium bifidum and Escherichia coli or Salmonella typhimurium). Interestingly, the potency and spectrum of inhibitory activity across strains of a single species (L. plantarum) differed substantially. Some Lactobacillus extracts had broader spectrum activities than acarbose, effectively inhibiting beta-glucosidase activity (lactase) as well as alpha-glucosidase activities (maltase, sucrase and amylase). Anti-diabetic potential was indicated by the fact that oral gavage with a L. rhamnosus extract (1 g/kg) was able to reduce glucose excursions (Area under curve; 22 %; p < 0.05) in rats during a carbohydrate challenge (starch; 2 g/kg). Conclusion: These results definitively demonstrate that Lactobacillus strains present in the human gut have alpha- and beta-glucosidase inhibitory activities and can reduce blood glucose responses in vivo. Although the potential use of LAB such as Lactobacillus as a dietary supplement, medicinal food or biotherapeutic for diabetes is uncertain, such an approach might offer advantages over drug therapies in terms of broader spectrum activities and fewer unpleasant side effects. Further characterisation of this bioactivity is warranted, and chronic studies should be undertaken in appropriate animal models or diabetic subjects.

Synergistic effects of proteasome inhibitor carfilzomib in combination with tyrosine kinase inhibitors in imatinib-sensitive and -resistant chronic myeloid leukemia models

The tyrosine kinase inhibitor (TKI) imatinib has transformed the treatment and outlook of chronic myeloid leukemia (CML); however, the development of drug resistance and the persistence of TKI-resistant stem cells remain obstacles to eradicating the disease. Inhibition of proteasome activity with bortezomib has been shown to effectively induce apoptosis in TKI-resistant cells. In this study, we show that exposure to the next generation proteasome inhibitor carfilzomib is associated with a decrease in ERK signaling and increased expression of Abelson interactor proteins 1 and 2 (ABI-1/2). We also investigate the effect of carfilzomib in models of imatinib-sensitive and -resistant CML and demonstrate a potent reduction in proliferation and induction of apoptosis in a variety of models of imatinib-resistant CML, including primitive CML stem cells. Carfilzomib acts synergistically with the TKIs imatinib and nilotinib, even in imatinib-resistant cell lines. In addition, we found that the presence of immunoproteasome subunits is associated with an increased sensitivity to carfilzomib. The present findings provide a rational basis to examine the potential of carfilzomib in combination with TKIs as a potential therapy for CML, particularly in imatinib-resistant disease.

Pharmacological evaluation of selective α2c-adrenergic agonists in experimental animal models of nasal congestion

Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective α2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of α2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 µl). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike d-pseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC(80)) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that α2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.

The Applicability of Two Strengths-based Systemic Psychotherapy Models for Young People Following Type 1 Trauma

This paper will consider the inter-relationship of a number of overlapping disciplinary theoretical concepts relevant to a strengths-based orientation, including well-being, salutogenesis, sense of coherence, quality of life and resilience. Psychological trauma will be referenced and the current evidence base for interventions with children and young people outlined and critiqued. The relational impact of trauma on family relationships is emphasised, providing a rationale for systemic psychotherapeutic interventions as part of a holistic approach to managing the effects of trauma. The congruence between second-order systemic psychotherapy models and a strengths-based philosophy is noted, with particular reference to solution-focused brief therapy and narrative therapy, and illustrated; via a description of the process of helping someone move from a victim position to a survivor identity using solution-focused brief therapy, and through a case example applying a narrative therapy approach to a teenage boy who suffered a serious assault. The benefits of a strength-based approach to psychological trauma for the clients and therapists will be summarised and a number of potential pitfalls articulated.

Integrating Multiple Point Statistics with Aerial Geophysical Data to assist Groundwater Flow Models

The process of accounting for heterogeneity has made significant advances in statistical research, primarily in the framework of stochastic analysis and the development of multiple-point statistics (MPS). Among MPS techniques, the direct sampling (DS) method is tested to determine its ability to delineate heterogeneity from aerial magnetics data in a regional sandstone aquifer intruded by low-permeability volcanic dykes in Northern Ireland, UK. The use of two two-dimensional bivariate training images aids in creating spatial probability distributions of heterogeneities of hydrogeological interest, despite relatively ‘noisy’ magnetics data (i.e. including hydrogeologically irrelevant urban noise and regional geologic effects). These distributions are incorporated into a hierarchy system where previously published density function and upscaling methods are applied to derive regional distributions of equivalent hydraulic conductivity tensor K. Several K models, as determined by several stochastic realisations of MPS dyke locations, are computed within groundwater flow models and evaluated by comparing modelled heads with field observations. Results show a significant improvement in model calibration when compared to a simplistic homogeneous and isotropic aquifer model that does not account for the dyke occurrence evidenced by airborne magnetic data. The best model is obtained when normal and reverse polarity dykes are computed separately within MPS simulations and when a probability threshold of 0.7 is applied. The presented stochastic approach also provides improvement when compared to a previously published deterministic anisotropic model based on the unprocessed (i.e. noisy) airborne magnetics. This demonstrates the potential of coupling MPS to airborne geophysical data for regional groundwater modelling.

Combining global climate and regional landscape models to improve prediction of invasion risk

Aim
It is widely acknowledged that species distributions result from a variety of biotic and abiotic factors operating at different spatial scales. Here, we aimed to (1) determine the extent to which global climate niche models (CNMs) can be improved by the addition of fine-scale regional data; (2) examine climatic and environmental factors influencing the range of 15 invasive aquatic plant species; and (3) provide a case study for the use of such models in invasion management on an island.

Location
Global, with a case study of species invasions in Ireland.

Methods
Climate niche models of global extent (including climate only) and regional environmental niche models (with additional factors such as human influence, land use and soil characteristics) were generated using maxent for 15 invasive aquatic plants. The performance of these models within the invaded range of the study species in Ireland was assessed, and potential hotspots of invasion suitability were determined. Models were projected forward up to 2080 based on two climate scenarios.

Results
While climate variables are important in defining the global range of species, factors related to land use and nutrient level were of greater importance in regional projections. Global climatic models were significantly improved at the island scale by the addition of fine-scale environmental variables (area under the curve values increased by 0.18 and true skill statistic values by 0.36), and projected ranges decreased from an average of 86% to 36% of the island.

Main conclusions
Refining CNMs with regional data on land use, human influence and landscape may have a substantial impact on predictive capacity, providing greater value for prioritization of conservation management at subregional or local scales.

Enforcing Employment Discrimination Law - Potential Transplants from Italy to Britain and Vice Versa?

While substantive EU non-discrimination law has been harmonized in great detail, the enforcement regime for EU non-discrimination law consists merely of a few isolated elements. Thus, the pursuit of unity through harmonization in substantive EU law is accompanied by considerable regulatory autonomy for Member States in securing the efficiency of those laws, reflecting the diversity of national enforcement regimes, and resulting in twenty-seven different national models for enforcing discrimination law in labour markets. This article pursues two connected arguments through a comparison of rules for enforcing non-discrimination law in labour markets in Britain and Italy. First, it argues that enforcing non-discrimination law in labour markets is best achieved when responsive governance, repressive regulation and mainstreaming equality law are combined. Second, the article submits that diversity of national legal orders within the EU is not necessarily detrimental, as it offers opportunities for mutual learning across legal systems.The notion of mutual learning across systems is proposed in order to analyse the transnational migration of legal ideas within the EU. Such migration has been criticized in debates about the ‘transplantation’ of legal concepts or legal irritation through foreign legal ideas, in particular by comparative labour lawyers. However, EU harmonization policies in the field of non-discrimination law aim to impact on national labour laws. The article develops the notion of mutual learning across legal systems in order to establish conditions for transnational migration of legal ideas, and demonstrates the viability of these concepts by applying them to the field of non-discrimination law

Irish Timber – Characterisation, Potential and Innovation

In order to increase the utilisation of Irish timber in construction and novel engineered wood products, the mechanical and physical properties of the material must be established. For timber products used for structural applications, the fundamental properties are the modulus of elasticity, bending strength, density and dimensional stability, as these define the structural grade of the material. In order to develop engineering design models for applications such as reinforced timber, knowledge of the nonlinear stress-strain behaviour in compression is also required.
The paper presents the programme and results of an ongoing research project ‘Innovation in Irish Timber Usage’ which focuses on the characterisation of Sitka spruce as it is the most widely grown species in Ireland. In the past, a number of studies have been conducted to determine the properties of Irish-grown Sitka spruce. Nevertheless, due to the changes that have taken place in silvicultural practices since the publication of these studies, there is a need to determine how these properties have changed. This paper presents the data gathered from historical studies together with the results of an extensive test programme undertaken to characterise the properties of the present resource.
Moreover, the study preliminary examines the potential use of Irish grown Sitka spruce in novel timber products. Construction applications, such as fibre-reinforced polymer reinforced timber elements and connections, and cross-laminated timber are investigated.

Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity

The simultaneous delivery of multiple cancer drugs in combination therapies to achieve optimal therapeutic effects in patients can be challenging. This study investigated whether co-encapsulation of the BH3-mimetic ABT-737 and the topoisomerase I inhibitor camptothecin (CPT) in PEGylated polymeric nanoparticles (NPs) was a viable strategy for overcoming their clinical limitations and to deliver both compounds at optimal ratios. We found that thrombocytopenia induced by exposure to ABT-737 was diminished through its encapsulation in NPs. Similarly, CPT-associated leukopenia and gastrointestinal toxicity were reduced compared with the administration of free CPT. In addition to the reduction of dose-limiting side effects, the co-encapsulation of both anticancer compounds in a single NP produced synergistic induction of apoptosis in both in vitro and in vivo colorectal cancer models. This strategy may widen the therapeutic window of these and other drugs and may enhance the clinical efficacy of synergistic drug combinations.

Characterization of Bose-Hubbard models with quantum nondemolition measurements

We propose a scheme for the detection of quantum phase transitions in the one-dimensional (1D) Bose-Hubbard (BH) and 1D Extended Bose-Hubbard (EBH) models, using the nondemolition measurement technique of quantum polarization spectroscopy. We use collective measurements of the effective total angular momentum of a particular spatial mode to characterize the Mott insulator to superfluid phase transition in the BH model and the transition to a density wave state in the EBH model. We extend the application of collective measurements to the ground states at various deformations of a superlattice potential.