Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL

Monoclonal antibodies (MAbs) form a central part of chronic lymphocytic leukaemia (CLL) treatment. We therefore evaluated whether complement defects in CLL patients reduced the induction of complement-dependent cytotoxicity (CDC) by using anti-CD20 MAbs rituximab (RTX) and ofatumumab (OFA). Ofatumumab elicited higher CDC levels than RTX in all CLL samples examined, particularly in poor prognosis cohorts (11q− and 17p−). Serum sample analyses revealed that 38.1% of patients were deficient in one or more complement components, correlating with reduced CDC responses. Although a proportion of patients with deficient complement levels initially induced high levels of CDC, on secondary challenge CDC activity in sera was significantly reduced, compared with that in normal human serum (NHS; P<0.01; n=52). In addition, a high CLL cell number contributed to rapid complement exhaustion. Supplementing CLL serum with NHS or individual complement components, particularly C2, restored CDC on secondary challenge to NHS levels (P<0.0001; n=9). In vivo studies revealed that complement components were exhausted in CLL patient sera post RTX treatment, correlating with an inability to elicit CDC. Supplementing MAb treatment with fresh-frozen plasma may therefore maintain CDC levels in CLL patients with a complement deficiency or high white blood cell count. This study has important implications for CLL patients receiving anti-CD20 MAb therapy

Nanoelectromechanical Resonator Arrays for Ultrafast, Gas-Phase Chromatographic Chemical Analysis

Miniaturized gas chromatography (GC) systems can provide fast, quantitative analysis of chemical vapors in an ultrasmall package. We describe a chemical sensor technology based on resonant nanoelectromechanical systems (NEMS) mass detectors that provides the speed, sensitivity, specificity, and size required by the microscale GC paradigm. Such NEMS sensors have demonstrated detection of subparts per billion (ppb) concentrations of a phosphonate analyte. By combining two channels of NEMS detection with an ultrafast GC front-end, chromatographic analysis of 13 chemicals was performed within a 5 s time window

Can we predict the time of seedling emergence of spring wheat?

Non-Peer Reviewe

Global nomads, cultural chameleons, strange ones or immigrants? An exploration of Third Culture Kid terminology with reference to the United Arab Emirates

© The Author(s) 2019. The term ‘Third Culture Kid’ (TCK) is commonly used to denote children living in a host culture other than their passport culture during their developmental years. However, its meaning in relation to other terminology referring to a similar concept is a source of interest for many stakeholders. This paper opens up opportunities for further exploring and critiquing the definition of TCK, and opening this up to case studies within the context of the United Arab Emirates and more widely. It is critical to clarify the terminology in light of unprecedented levels of international migration throughout the world. This paper reviews the meaning of culture in relation to TCKs, and explores the meaning of the TCK concept as well as a number of other terms used as alternatives to TCK. A contextualization of the literature follows in relation to the researchers’ own lived experiences in the United Arab Emirates. The term TCK can be seen as part of the general stock of theoretical concepts. This paper acknowledges that it cannot catch all nuances of migrant children in the global context

A rigorous approach to investigating common assumptions about disease transmission: Process algebra as an emerging modelling methodology for epidemiology

Changing scale, for example the ability to move seamlessly from an individual-based model to a population-based model, is an important problem in many fields. In this paper we introduce process algebra as a novel solution to this problem in the context of models of infectious disease spread. Process algebra allows us to describe a system in terms of the stochastic behaviour of individuals, and is a technique from computer science. We review the use of process algebra in biological systems, and the variety of quantitative and qualitative analysis techniques available. The analysis illustrated here solves the changing scale problem: from the individual behaviour we can rigorously derive equations to describe the mean behaviour of the system at the level of the population. The biological problem investigated is the transmission of infection, and how this relates to individual interaction

Induction of the cell survival kinase Sgk1: A possible novel mechanism for α-phenyl-N-tert-butyl nitrone in experimental stroke.

Nitrones (e.g. α-phenyl-N-tert-butyl nitrone; PBN) are cerebroprotective in experimental stroke. Free radical trapping is their proposed mechanism. As PBN has low radical trapping potency, we tested Sgk1 induction as another possible mechanism. PBN was injected (100 mg/kg, i.p.) into adult male rats and mice. Sgk1 was quantified in cerebral tissue by microarray, quantitative RT-PCR and western analyses. Sgk1+/+ and Sgk1-/- mice were randomized to receive PBN or saline immediately following transient (60 min) occlusion of the middle cerebral artery. Neurological deficit was measured at 24 h and 48 h and infarct volume at 48 h post-occlusion. Following systemic PBN administration, rapid induction of Sgk1 was detected by microarray (at 4 h) and confirmed by RT-PCR and phosphorylation of the Sgk1-specific substrate NDRG1 (at 6 h). PBN-treated Sgk1+/+ mice had lower neurological deficit ( p < 0.01) and infarct volume ( p < 0.01) than saline-treated Sgk1+/+ mice. PBN-treated Sgk1-/- mice did not differ from saline-treated Sgk1-/- mice. Saline-treated Sgk1-/- and Sgk1+/+ mice did not differ. Brain Sgk3:Sgk1 mRNA ratio was 1.0:10.6 in Sgk1+/+ mice. Sgk3 was not augmented in Sgk1-/- mice. We conclude that acute systemic treatment with PBN induces Sgk1 in brain tissue. Sgk1 may play a part in PBN-dependent actions in acute brain ischemia

Large scale three-dimensional modelling for wave and tidal energy resource and environmental impact : methodologies for quantifying acceptable thresholds for sustainable exploitation

We describe a modelling project to estimate the potential effects of wave & tidal stream renewables on the marine environment. • Realistic generic devices to be used by those without access to the technical details available to developers are described. • Results show largely local sea bed effects at the level of the currently proposed renewables developments in our study area. • Large scale 3D modelling is critical to quantify the direct, indirect and cumulative effects of renewable energy extraction. • This is critical to comply with planning & environmental impact assessment regulations and achieve Good Environmental Status

Have the changes introduced by the 2004 Higher Education Act made higher education admissions in England wider and fairer?

'Widening participation' and 'fair access' have been contested policy areas in English higher education since at least the early 1990s. They were key facets of the 2003 White Paper - The Future of Higher Education - and the subsequent 2004 Higher Education Act, with stated objectives that the reach of higher education should be wider and fairer. In particular, there has been considerable concern about admissions to 'top universities', which have remained socially as well as academically exclusive. The principal policy tools used by the Act were the introduction of variable tuition fees, expanded student grants, discretionary bursaries and the new Office for Fair Access (OFFA). This paper draws on publicly available statistics to assess whether the changes implemented by the 2004 Act have indeed made access to English higher education wider and fairer in relation to young people progressing from state schools and colleges and from lower socio-economic groups. It concludes that, while there is some evidence for modest improvements, these have been concentrated outside the 'top universities', which have seen slippage relative to the rest of the sector. The paper concludes with a discussion of the reasons why financial inducements appear to be a flawed and naive approach to influencing student demand. © 2011 Taylor & Francis

Immunohistochemical expression of insulin-like growth factor binding protein-3 in invasive breast cancers and ductal carcinoma in situ: implications for clinicopathology and patient outcome

INTRODUCTION: Insulin-like growth factor binding protein-3 (IGFBP-3) differentially modulates breast epithelial cell growth through insulin-like growth factor (IGF)-dependent and IGF-independent pathways and is a direct (IGF-independent) growth inhibitor as well as a mitogen that potentiates EGF (epidermal growth factor) and interacts with HER-2. Previously, high IGFBP-3 levels in breast cancers have been determined by enzyme-linked immunosorbent assay and immunoradiometric assay methods. In vitro, IGFBP-3's mechanisms of action may involve cell membrane binding and nuclear translocation. To evaluate tumour-specific IGFBP-3 expression and its subcellular localisation, this study examined immunohistochemical IGFBP-3 expression in a series of invasive ductal breast cancers (IDCs) with synchronous ductal carcinomas in situ (DCIS) in relation to clinicopathological variables and patient outcome. METHODS: Immunohistochemical expression of IGFBP-3 was evaluated with the sheep polyclonal antiserum (developed in house) with staining performed as described previously. RESULTS: IGFBP-3 was evaluable in 101 patients with a variable pattern of cytoplasmic expression (positivity of 1+/2+ score) in 85% of invasive and 90% of DCIS components. Strong (2+) IGFBP-3 expression was evident in 32 IDCs and 40 cases of DCIS. A minority of invasive tumours (15%) and DCIS (10%) lacked IGFBP-3 expression. Nuclear IGFBP-3 expression was not detectable in either invasive cancers or DCIS, with a consistent similarity in IGFBP-3 immunoreactivity in IDCs and DCIS. Positive IGFBP-3 expression showed a possible trend in association with increased proliferation (P = 0.096), oestrogen receptor (ER) negativity (P = 0.06) and HER-2 overexpression (P = 0.065) in invasive tumours and a strong association with ER negativity (P = 0.037) in DCIS. Although IGFBP-3 expression was not an independent prognosticator, IGFBP-3-positive breast cancers may have shorter disease-free and overall survivals, although these did not reach statistical significance. CONCLUSIONS: Increased breast epithelial IGFBP-3 expression is a feature of tumorigenesis with cytoplasmic immunoreactivity in the absence of significant nuclear localisation in IDCs and DCIS. There are trends between high levels of IGFBP-3 and poor prognostic features, suggesting that IGFBP-3 is a potential mitogen. IGFBP-3 is not an independent prognosticator for overall survival or disease-free survival, to reflect its dual effects on breast cancer growth regulated by complex pathways in vivo that may relate to its interactions with other growth factors