Proteasome inhibitors in cancer therapy

The ubiquitin proteasome pathway plays a critical role in regulating many processes in the cell which are important for tumour cell growth and survival. Inhibition of proteasome function has emerged as a powerful strategy for anti-cancer therapy. Clinical validation of the proteasome as a therapeutic target was achieved with bortezomib and has prompted the development of a second generation of proteasome inhibitors with improved pharmacological properties. This review summarises the main mechanisms of action of proteasome inhibitors in cancer, the development of proteasome inhibitors as therapeutic agents and the properties and progress of next generation proteasome inhibitors in the clinic.

Preservation methods alter stable isotope values in gelatinous zooplankton: implications for interpreting trophic ecology

Jellyfish are increasingly topical within studies of marine food webs. Stable isotope analysis represents a valuable technique to unravel the complex trophic role of these long-overlooked species. In other taxa, sample preservation has been shown to alter the isotopic values of species under consideration, potentially leading to misinterpretation of trophic ecology. To identify potential preservation effects in jellyfish, we collected Aurelia aurita from Strangford Lough (54(o)22'44.73aEuro(3)N, 5(o)32'53.44aEuro(3)W) during May 2009 and processed them using three different methods prior to isotopic analysis (unpreserved, frozen and preserved in ethanol). A distinct preservation effect was found on delta N-15 values: furthermore, preservation also influenced the positive allometric relationship between individual size and delta N-15 values. Conversely, delta C-13 values remained consistent between the three preservation methods, conflicting with previous findings for other invertebrate, fish and mammalian species. These findings have implications for incorporation of jellyfish into marine food webs and remote sampling regimes where preservation of samples is unavoidable.

AGEs, RAGE, and Diabetic Retinopathy

Diabetic retinopathy is a major diabetic complication with a highly complex etiology. Although there are many pathways involved, it has become established that chronic exposure of the retina to hyperglycemia gives rise to accumulation of advanced glycation end products (AGEs) that play an important role in retinopathy. In addition, the receptor for AGEs (RAGE) is ubiquitously expressed in various retinal cells and is upregulated in the retinas of diabetic patients, resulting in activation of pro-oxidant and proinflammatory signaling pathways. This AGE-RAGE axis appears to play a central role in the sustained inflammation, neurodegeneration, and retinal microvascular dysfunction occurring during diabetic retinopathy. The nature of AGE formation and RAGE signaling bring forward possibilities for therapeutic intervention. The multiple components of the AGE-RAGE axis, including signal transduction, formation of ligands, and the end-point effectors, may be promising targets for strategies to treat diabetic retinopathy.

Performance analysis of a metro WDM ring networks with variable-length packets under symmetric and asymmetric traffic

In this paper, we discuss and evaluate two proposed metro wavelength division multiplexing (WDM) ring network architectures for variable-length packet traffic in storage area networks (SANs) settings. The paper begins with a brief review of the relevant architectures and protocols in the literature. Subsequently, the network architectures along with their medium access control (MAC) protocols are described. Performance of the two network architectures is studied by means of computer simulation in terms of their queuing delay, node throughput and proportion of packets dropped. The network performance is evaluated under symmetric and asymmetric traffic scenarios with Poisson and self-similar traffic. (C) 2011 Elsevier Inc. All rights reserved.

Pharmacokinetics of UC781-loaded intravaginal ring segments in rabbits: a comparison of polymer matrices

UC781 is a potent and poorly water-soluble nonnucleoside reverse transcriptase inhibitor being investi- gated as a potential microbicide for preventing sexual transmission of HIV-1. This study was designed to evaluate the in vivo release and pharmacokinetics of UC781 delivered from matrix-type intravaginal ring segments in rabbits. Three polymer matrices (polyurethane, ethylene vinyl acetate copolymer, and silicone elastomer) and two drug loadings (5 and 15 mg/segment) were evaluated in at least one of two independent studies for up to 28 days in vivo. Inter-study comparison of in vivo release, vaginal tissue, and plasma concentrations for similar formulations demonstrated good reproducibility of the animal model. Mean estimates for a 28-day in vivo release ranged from 0.35 to 3.17 mg UC781 per segment. Mean proximal vaginal tissue levels (adjacent to the IVR segment) were 8– 410 ng/g and did not change significantly with time for most formulations. Distal vaginal tissue levels of UC781 were 6- to 49-fold lower than proximal tissue levels. Mean UC781 plasma levels were low for all formulations, at 0.09–0.58 ng/mL. All formulations resulted in similar UC781 concentrations in vaginal tissue and plasma, except the low loading polyurethane group which provided significantly lower levels. Loading dependent release and pharmacokinetics were only clearly observed for the polyurethane matrix. Based on these results, intravaginal ring segments loaded with UC781 led to vaginal tissue concen- trations ranging from below to approximately two orders of magnitude higher than UC781’s EC50 under in vitro conditions (2.8 ng/mL), with little influence by polymer matrix or UC781 loading. Moreover, these findings support the use of rabbit vaginal pharmacokinetic studies in preclinical testing of microbicide intravaginal rings.

Increasing incidence of Barrett's oesophagus: a population-based study

Oesophageal adenocarcinoma, a highly fatal cancer, has risen in incidence in Western societies, but it is unclear whether this is due to increasing incidence of its pre-cursor condition, Barrett's oesophagus (BO) or whether the proportion of BO patients undergoing malignant progression has increased in the face of unchanged BO incidence. Data from population-based studies of BO incidence is limited, with equivocal results to date difficult to distinguish from changes in endoscopic practices. The aim of this study was to assess population trends in Barrett's oesophagus (BO) diagnoses in relation to endoscopy and biopsy rates over a 13 year period. The Northern Ireland Barrett's oesophagus Register (NIBR) is a population-based register of all 9,329 adults diagnosed with columnar epithelium of the oesophagus in Northern Ireland between 1993 and 2005, of whom 58.3% were male. European age-standardised annual BO incidence rates were calculated per 100,000 of the population, per 100 endoscopies and per 100 endoscopies including an oesophageal biopsy. Average annual BO incidence rates rose by 159% during the study period, increasing from 23.9/100,000 during 1993-1997 to 62.0/100,000 during 2002-2005. This elevation far exceeded corresponding increases in rates of endoscopies and oesophageal biopsies being conducted. BO incidence increased most markedly in individuals aged <60 years, and most notably amongst males aged <40 years. This study points towards a true increase in the incidence of BO which would appear to be most marked in young males. These findings have significant implications for future rates of oesophageal adenocarcinoma and surveillance programmes. © 2011 Springer Science+Business Media B.V.

Changes in the prevalence of badger persecution in Northern Ireland.

Animal populations generally increase after release from hunting pressure and/or cessation of illegal persecution. Implementation of full legislative protection of the Eurasian badger Meles meles in Great Britain is thought to have led to increases in badger abundance due to reduced levels of persecution. Conversely, prevalence of badger persecution in Northern Ireland was historically much higher than in Great Britain, and badger abundance remained stable over time despite similar legislative protection. We examined temporal changes in the prevalence of badger sett disturbance in Northern Ireland from 1990/1993 to 2007/2008 in relation to population status. A total of 56 (12.6%) of 445 setts surveyed during 1990/1993 had been disturbed compared to 29 (4.4%) of 653 setts during 2007/2008. This was a significant decline (-65%) in the incidence of sett disturbance over the 14–18-year period. Most notably, the incidence of digging at badger setts, indicative of local badger baiting activity, declined from 50% to 3.5% of disturbed setts. Signs of recent disturbance were significantly more frequent at disused setts suggesting that once disturbed, badgers may vacate a sett. The number of badger social groups in Northern Ireland did not differ between the two study periods, suggesting that previously high levels of badger persecution did not limit the number of badger social groups. The stability of the badger population in Northern Ireland compared to the growing population in Great Britain cannot be attributed to changes in the prevalence of persecution. Differences in the trajectories of both populations could be due to a range of factors including climate, habitat composition and structure, farming practices or food availability. More work is needed to determine how such factors influence badger population dynamics.

Effects of particle plasticity characteristics on local interface stress in particle reinforced composite during uniaxial tension

For elastoplastic particle reinforced metal matrix composites, failure may originate from interface debonding between the particles and the matrix, both elastoplastic and matrix fracture near the interface. To calculate the stress and strain distribution in these regions, a single reinforcing particle axisymmetric unit cell model is used in this article. The nodes at the interface of the particle and the matrix are tied. The development of interfacial decohesion is not modelled. Finite element modelling is used, to reveal the effects of particle strain hardening rate, yield stress and elastic modulus on the interfacial traction vector (or stress vector), interface deformation and the stress distribution within the unit cell, when the composite is under uniaxial tension. The results show that the stress distribution and the interface deformation are sensitive to the strain hardening rate and the yield stress of the particle. With increasing particle strain hardening rate and yield stress, the interfacial traction vector and internal stress distribution vary in larger ranges, the maximum interfacial traction vector and the maximum internal stress both increase, while the interface deformation decreases. In contrast, the particle elastic modulus has little effect on the interfacial traction vector, internal stress and interface deformation.

Developments in the production of biological and synthetic binders for immunoassay and sensor-based detection of small molecules

The need for chemical and biological entities of predetermined selectivity and affinity towards target analytes is greater than ever, in applications such as environmental monitoring, bioterrorism detection and analysis of natural toxin contaminants in the food chain.

Application of Nonlinear PCA for Fault Detection in Polymer Extrusion Processes

This paper describes the application of an improved nonlinear principal component analysis (PCA) to the detection of faults in polymer extrusion processes. Since the processes are complex in nature and nonlinear relationships exist between the recorded variables, an improved nonlinear PCA, which incorporates the radial basis function (RBF) networks and principal curves, is proposed. This algorithm comprises two stages. The first stage involves the use of the serial principal curve to obtain the nonlinear scores and approximated data. The second stage is to construct two RBF networks using a fast recursive algorithm to solve the topology problem in traditional nonlinear PCA. The benefits of this improvement are demonstrated in the practical application to a polymer extrusion process.