PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation.

A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available

Stellar Coronal and Wind Models: Impact on Exoplanets

Surface magnetism is believed to be the main driver of coronal heating and stellar wind acceleration. Coronae are believed to be formed by plasma confined in closed magnetic coronal loops of the stars, with winds mainly originating in open magnetic field line regions. In this Chapter, we review some basic properties of stellar coronae and winds and present some existing models. In the last part of this Chapter, we discuss the effects of coronal winds on exoplanets.Comment: Chapter published in the "Handbook of Exoplanets", Editors in Chief: Juan Antonio Belmonte and Hans Deeg, Section Editor: Nuccio Lanza. Springer Reference Work

Cariostatic effect of fluoride-containing restorative materials associated with fluoride gels on root dentin

Secondary caries is still the main cause of restoration replacement, especially on the root surface OBJECTIVE: This in vitro study evaluated the cariostatic effects of fluoride-containing restorative materials associated with fluoride gels, on root dentin. MATERIALS AND METHODS: A randomized complete block design was used to test the effects of the restorative systems, fluoride regimes and the interactions among them at different distances from restoration margins. Standardized cavities were prepared on 240 bovine root specimens and randomly assigned to 15 groups of treatments (n=16). Cavities were filled with the following restorative materials: Ketac-Fil (3M-ESPE); Vitremer (3M-ESPE); Dyract/Prime & Bond NT (Dentsply); Charisma/Gluma One Bond (Heraeus Kulzer) and the control, Z250/Single Bond (3M-ESPE). The specimens were subjected to a pH-cycling model designed to simulate high-caries activity. During the cycles, 1.23% acidulated phosphate fluoride, 2.0% neutral sodium fluoride or deionized/distilled water (control) was applied to the specimens for 4 min. The surface Knoop microhardness test was performed before (KHNi) and after (KHNf) the pH cycles at 100, 200 and 300 mm from the margins. Dentin microhardness loss was represented by the difference in initial and final values (KHNi - KHNf). Data were analyzed by Friedman's and Wilcoxon's tests, ANOVA and Tukey's test (α=5%). RESULTS: The interaction of restorative systems and topical treatments was not significant (p=0.102). Dentin microhardness loss was lowest closer to the restoration. Ketac-fil presented the highest cariostatic effect. Vitremer presented a moderate effect, while Dyract and Charisma did not differ from the control, Z250. The effects of neutral and acidulated fluoride gels were similar to each other and higher than the control. CONCLUSION: Conventional and resin-modified glass ionomer cements as well as neutral and acidulated fluoride gels inhibit the progression of artificial caries adjacent to restorations. The associated effect of fluoride-containing restorative materials and gels could not be demonstrated

Magnetism and its microscopic origin in iron-based high-temperature superconductors

High-temperature superconductivity in the iron-based materials emerges from, or sometimes coexists with, their metallic or insulating parent compound states. This is surprising since these undoped states display dramatically different antiferromagnetic (AF) spin arrangements and N$\rm \acute{e}$el temperatures. Although there is general consensus that magnetic interactions are important for superconductivity, much is still unknown concerning the microscopic origin of the magnetic states. In this review, progress in this area is summarized, focusing on recent experimental and theoretical results and discussing their microscopic implications. It is concluded that the parent compounds are in a state that is more complex than implied by a simple Fermi surface nesting scenario, and a dual description including both itinerant and localized degrees of freedom is needed to properly describe these fascinating materials.Comment: 14 pages, 4 figures, Review article, accepted for publication in Nature Physic

Optimizing Metapopulation Sustainability through a Checkerboard Strategy

The persistence of a spatially structured population is determined by the rate of dispersal among habitat patches. If the local dynamic at the subpopulation level is extinction-prone, the system viability is maximal at intermediate connectivity where recolonization is allowed, but full synchronization that enables correlated extinction is forbidden. Here we developed and used an algorithm for agent-based simulations in order to study the persistence of a stochastic metapopulation. The effect of noise is shown to be dramatic, and the dynamics of the spatial population differs substantially from the predictions of deterministic models. This has been validated for the stochastic versions of the logistic map, the Ricker map and the Nicholson-Bailey host-parasitoid system. To analyze the possibility of extinction, previous studies were focused on the attractiveness (Lyapunov exponent) of stable solutions and the structure of their basin of attraction (dependence on initial population size). Our results suggest that these features are of secondary importance in the presence of stochasticity. Instead, optimal sustainability is achieved when decoherence is maximal. Individual-based simulations of metapopulations of different sizes, dimensions and noise types, show that the system's lifetime peaks when it displays checkerboard spatial patterns. This conclusion is supported by the results of a recently published Drosophila experiment. The checkerboard strategy provides a technique for the manipulation of migration rates (e.g., by constructing corridors) in order to affect the persistence of a metapopulation. It may be used in order to minimize the risk of extinction of an endangered species, or to maximize the efficiency of an eradication campaign

Agrobacterium rhizogenes-Mediated Transformation of the Parasitic Plant Phtheirospermum japonicum

Background: Plants within the Orobanchaceae are an agriculturally important group of parasites that attack economically important crops to obtain water and nutrients from their hosts. Despite their agricultural importance, molecular mechanisms of the parasitism are poorly understood. Methodology/Principal Findings: We developed transient and stable transformation systems for Phtheirospermum japonicum, a facultative parasitic plant in the Orobanchaceae. The transformation protocol was established by a combination of sonication and acetosyringone treatments using the hairy-root-inducing bacterium, Agrobacterium rhizogenes and young seedlings. Transgenic hairy roots of P. japonicum were obtained from cotyledons 2 to 3 weeks after A. rhizogenes inoculation. The presence and the expression of transgenes in P. japonicum were verified by genomic PCR, Southern blot and RT-PCR methods. Transgenic roots derived from A. rhizogenes-mediated transformation were able to develop haustoria on rice and maize roots. Transgenic roots also formed apparently competent haustoria in response to 2,6dimethoxy-1,4-benzoquinone (DMBQ), a haustorium-inducing chemical. Using this system, we introduced a reporter gene with a Cyclin B1 promoter into P. japonicum, and visualized cell division during haustorium formation. Conclusions: We provide an easy and efficient method for hairy-root transformation of P. japonicum. Transgenic marker analysis revealed that cell divisions during haustorium development occur 24 h after DMBQ treatment. The protocol

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

African Communitarianism and Difference

There has been the recurrent suspicion that community, harmony, cohesion, and similar relational goods as understood in the African ethical tradition threaten to occlude difference. Often, it has been Western defenders of liberty who have raised the concern that these characteristically sub-Saharan values fail to account adequately for individuality, although some contemporary African thinkers have expressed the same concern. In this chapter, I provide a certain understanding of the sub-Saharan value of communal relationship and demonstrate that it entails a substantial allowance for difference. I aim to show that African thinkers need not appeal to, say, characteristically Euro-American values of authenticity or autonomy to make sense of why individuals should not be pressured to conform to a group’s norms regarding sex and gender. A key illustration involves homosexuality

Systematic NMR Analysis of Stable Isotope Labeled Metabolite Mixtures in Plant and Animal Systems: Coarse Grained Views of Metabolic Pathways

BACKGROUND: Metabolic phenotyping has become an important 'bird's-eye-view' technology which can be applied to higher organisms, such as model plant and animal systems in the post-genomics and proteomics era. Although genotyping technology has expanded greatly over the past decade, metabolic phenotyping has languished due to the difficulty of 'top-down' chemical analyses. Here, we describe a systematic NMR methodology for stable isotope-labeling and analysis of metabolite mixtures in plant and animal systems. METHODOLOGY/PRINCIPAL FINDINGS: The analysis method includes a stable isotope labeling technique for use in living organisms; a systematic method for simultaneously identifying a large number of metabolites by using a newly developed HSQC-based metabolite chemical shift database combined with heteronuclear multidimensional NMR spectroscopy; Principal Components Analysis; and a visualization method using a coarse-grained overview of the metabolic system. The database contains more than 1000 (1)H and (13)C chemical shifts corresponding to 142 metabolites measured under identical physicochemical conditions. Using the stable isotope labeling technique in Arabidopsis T87 cultured cells and Bombyx mori, we systematically detected >450 HSQC peaks in each (13)C-HSQC spectrum derived from model plant, Arabidopsis T87 cultured cells and the invertebrate animal model Bombyx mori. Furthermore, for the first time, efficient (13)C labeling has allowed reliable signal assignment using analytical separation techniques such as 3D HCCH-COSY spectra in higher organism extracts. CONCLUSIONS/SIGNIFICANCE: Overall physiological changes could be detected and categorized in relation to a critical developmental phase change in B. mori by coarse-grained representations in which the organization of metabolic pathways related to a specific developmental phase was visualized on the basis of constituent changes of 56 identified metabolites. Based on the observed intensities of (13)C atoms of given metabolites on development-dependent changes in the 56 identified (13)C-HSQC signals, we have determined the changes in metabolic networks that are associated with energy and nitrogen metabolism