Exploring the immune microenvironment in small bowel adenocarcinoma using digital image analysis.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare malignancy of the small intestine associated with late stage diagnosis and poor survival outcome. High expression of immune cells and immune checkpoint biomarkers especially programmed cell death ligand-1 (PD-L1) have been shown to significantly impact disease progression. We have analysed the expression of a subset of immune cell and immune checkpoint biomarkers in a cohort of SBA patients and assessed their impact on progression-free survival (PFS) and overall survival (OS). METHODS: 25 patient samples in the form of formalin fixed, paraffin embedded (FFPE) tissue were obtained in tissue microarray (TMAs) format. Automated immunohistochemistry (IHC) staining was performed using validated antibodies for CD3, CD4, CD8, CD68, PD-L1, ICOS, IDO1 and LAG3. Slides were scanned digitally and assessed in QuPath, an open source image analysis software, for biomarker density and percentage positivity. Survival analyses were carried out using the Kaplan Meier method. RESULTS: Varying expressions of biomarkers were recorded. High expressions of CD3, CD4 and IDO1 were significant for PFS (p = 0.043, 0.020 and 0.018 respectively). High expression of ICOS was significant for both PFS (p = 0.040) and OS (p = 0.041), while high PD-L1 expression in tumour cells was significant for OS (p = 0.033). High correlation was observed between PD-L1 and IDO1 expressions (Pearson correlation co-efficient = 1) and subsequently high IDO1 expression in tumour cells was found to be significant for PFS (p = 0.006) and OS (p = 0.034). CONCLUSIONS: High levels of immune cells and immune checkpoint proteins have a significant impact on patient survival in SBA. These data could provide an insight into the immunotherapeutic management of patients with SBA

A Comparison of Multivariate and Pre-Processing Methods for Quantitative Laser-Induced Breakdown Spectroscopy of Geologic Samples

The ChemCam instrument selected for the Curiosity rover is capable of remote laser-induced breakdown spectroscopy (LIBS).[1] We used a remote LIBS instrument similar to ChemCam to analyze 197 geologic slab samples and 32 pressed-powder geostandards. The slab samples are well-characterized and have been used to validate the calibration of previous instruments on Mars missions, including CRISM [2], OMEGA [3], the MER Pancam [4], Mini-TES [5], and Moessbauer [6] instruments and the Phoenix SSI [7]. The resulting dataset was used to compare multivariate methods for quantitative LIBS and to determine the effect of grain size on calculations. Three multivariate methods - partial least squares (PLS), multilayer perceptron artificial neural networks (MLP ANNs) and cascade correlation (CC) ANNs - were used to generate models and extract the quantitative composition of unknown samples. PLS can be used to predict one element (PLS1) or multiple elements (PLS2) at a time, as can the neural network methods. Although MLP and CC ANNs were successful in some cases, PLS generally produced the most accurate and precise results

Synthesis and cytotoxicity of a biotinylated CC-1065 analogue

BACKGROUND: The use of pretargeting technology for cancer imaging and treatment has made significant progress in the last few years. This approach takes advantage of the fact that biotin binds strongly to proteins avidin and streptavidin. Thus, a non-toxic tumor cell specific antibody is conjugated with avidin/streptavidin, and is administered to patients. After the antibody binds to tumor cells (usually 24–48 h); a clearing agent is given to remove the residual circulating antibodies in blood. Lastly, a toxic biotin-radioisotope conjugate is administered. Due to the small size of the biotin-radioisotope molecule and tight binding between biotin and avidin/streptavidin, the biotin-radioisotope rapidly binds to tumor cells with high specificity. CC-1065 (1) is one of a few classes of extremely potent antitumor agents, and a biotinalyted CBI-bearing CC-1065 analogue is a promising candidate to be used in the pretargeting technology to treat cancer. RESULTS: A biotinalyted CBI-bearing CC-1065 analogue, 6, was synthesized. The IC(50) of 6 was 0.7 nM against U937 cells. Compound 6 caused apototsis of U937 cells. CONCLUSIONS: For the first time, a biotinalyted CBI-bearing CC-1065 analogue, 6, was synthesized. The biotinylated 6 can serve as a model compound to explore the usefulness of non-radioactive small molecule anticancer drugs in the pretargeting strategy for cancer imaging and therapy

Phase separation effects and the nematic-isotropic transition in polymer and low molecular weight liquid crystals doped with nanoparticles

Properties of the nematic–isotropic phase transition in polymer and low molecular weight liquid crystals doped with nanoparticles have been studied both experimentally and theoretically in terms of molecular mean-field theory. The variation of the transition temperature and the transition heat with the increasing volume fraction of CdSe quantum dot nanoparticles in copolymer and low molecular weight nematics has been investigated experimentally and the data are interpreted using the results of the molecular theory which accounts for a possibility of phase separation when the system undergoes the nematic–isotropic transition. The theory predicts that the nematic and isotropic phases with different concentrations of nanoparticles may coexist over a broad temperature range, but only if the nanoparticle volume fraction exceeds a certain threshold value which depends on the material parameters. Such unusual phase separation effects are determined by the strong interaction between nanoparticles and mesogenic groups and between nanoparticles themselves

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The interest in relativistic beam-plasma instabilities has been greatly rejuvenated over the past two decades by novel concepts in laboratory and space plasmas. Recent advances in this long-standing field are here reviewed from both theoretical and numerical points of view. The primary focus is on the two-dimensional spectrum of unstable electromagnetic waves growing within relativistic, unmagnetized, and uniform electron beam-plasma systems. Although the goal is to provide a unified picture of all instability classes at play, emphasis is put on the potentially dominant waves propagating obliquely to the beam direction, which have received little attention over the years. First, the basic derivation of the general dielectric function of a kinetic relativistic plasma is recalled. Next, an overview of two-dimensional unstable spectra associated with various beam-plasma distribution functions is given. Both cold-fluid and kinetic linear theory results are reported, the latter being based on waterbag and Maxwell–Jüttner model distributions. The main properties of the competing modes (developing parallel, transverse, and oblique to the beam) are given, and their respective region of dominance in the system parameter space is explained. Later sections address particle-in-cell numerical simulations and the nonlinear evolution of multidimensional beam-plasma systems. The elementary structures generated by the various instability classes are first discussed in the case of reduced-geometry systems. Validation of linear theory is then illustrated in detail for large-scale systems, as is the multistaged character of the nonlinear phase. Finally, a collection of closely related beam-plasma problems involving additional physical effects is presented, and worthwhile directions of future research are outlined.Original Publication: Antoine Bret, Laurent Gremillet and Mark Eric Dieckmann, Multidimensional electron beam-plasma instabilities in the relativistic regime, 2010, Physics of Plasmas, (17), 12, 120501-1-120501-36. http://dx.doi.org/10.1063/1.3514586 Copyright: American Institute of Physics http://www.aip.org/</p

Network 'small-world-ness': a quantitative method for determining canonical network equivalence

Background: Many technological, biological, social, and information networks fall into the broad class of 'small-world' networks: they have tightly interconnected clusters of nodes, and a shortest mean path length that is similar to a matched random graph (same number of nodes and edges). This semi-quantitative definition leads to a categorical distinction ('small/not-small') rather than a quantitative, continuous grading of networks, and can lead to uncertainty about a network's small-world status. Moreover, systems described by small-world networks are often studied using an equivalent canonical network model-the Watts-Strogatz (WS) model. However, the process of establishing an equivalent WS model is imprecise and there is a pressing need to discover ways in which this equivalence may be quantified. Methodology/Principal Findings: We defined a precise measure of 'small-world-ness' S based on the trade off between high local clustering and short path length. A network is now deemed a 'small-world' if S. 1-an assertion which may be tested statistically. We then examined the behavior of S on a large data-set of real-world systems. We found that all these systems were linked by a linear relationship between their S values and the network size n. Moreover, we show a method for assigning a unique Watts-Strogatz (WS) model to any real-world network, and show analytically that the WS models associated with our sample of networks also show linearity between S and n. Linearity between S and n is not, however, inevitable, and neither is S maximal for an arbitrary network of given size. Linearity may, however, be explained by a common limiting growth process. Conclusions/Significance: We have shown how the notion of a small-world network may be quantified. Several key properties of the metric are described and the use of WS canonical models is placed on a more secure footing

The host dark matter haloes of [O II] emitters at 0.5 < z < 1.5

Emission line galaxies (ELGs) are used in several ongoing and upcoming surveys (SDSS-IV/eBOSS, DESI) as tracers of the dark matter distribution. Using a new galaxy formation model, we explore the characteristics of [OII] emitters, which dominate optical ELG selections at z ≃ 1. Model [OII] emitters at 0.5 < z < 1.5 are selected to mimic the DEEP2, VVDS, eBOSS and DESI surveys. The luminosity functions of model [OII] emitters are in reasonable agreement with observations. The selected [OII] emitters are hosted by haloes with Mhalo ≥ 1010.3h−1M⊙, with ∼90 per cent of them being central star-forming galaxies. The predicted mean halo occupation distributions of [OII] emitters have a shape typical of that inferred for star-forming galaxies, with the contribution from central galaxies, ⟨N⟩[OII]cen⁠, being far from the canonical step function. The ⟨N⟩[OII]cen can be described as the sum of an asymmetric Gaussian for discs and a step function for spheroids, which plateau below unity. The model [OII] emitters have a clustering bias close to unity, which is below the expectations for eBOSS and DESI ELGs. At z ∼ 1, a comparison with observed g-band-selected galaxy, which is expected to be dominated by [OII] emitters, indicates that our model produces too few [OII] emitters that are satellite galaxies. This suggests the need to revise our modelling of hot gas stripping in satellite galaxies

Improving detection of familial hypercholesterolaemia in primary care using electronic audit and nurse-led clinics

RATIONALE, AIMS AND OBJECTIVES: In the UK fewer than 15% of familial hypercholesterolemia (FH) cases are diagnosed, representing a major gap in coronary heart disease prevention. We wished to support primary care doctors within the Medway Clinical Commissioning Group (CCG) to implement NICE guidance (CG71) and consider the possibility of FH in adults who have raised total cholesterol concentrations, thereby improving the detection of people with FH. METHODS: Utilizing clinical decision support software (Audit+) we developed an FH Audit Tool and implemented a systematic audit of electronic medical records within GP practices, first identifying all patients diagnosed with FH or possible FH and next electronically flagging patients with a recorded total cholesterol of >7.5 mmol L(-1) or LDL-C > 4.9 mmol L(-1) (in adults), for further assessment. After a 2-year period, a nurse-led clinic was introduced to screen more intensely for new FH index cases. We evaluated if these interventions increased the prevalence of FH closer to the expected prevalence from epidemiological studies. RESULTS: The baseline prevalence of FH within Medway CCG was 0.13% (1 in 750 persons). After 2 years, the recorded prevalence of diagnosed FH increased by 0.09% to 0.22% (1 in 450 persons). The nurse advisor programme ran for 9 months (October 2013-July 2014) and during this time, the recorded prevalence of patients diagnosed with FH increased to 0.28% (1 in 357 persons) and the prevalence of patients 'at risk and unscreened' reduced from 0.58% to 0.14%. CONCLUSIONS: Our study shows that two simple interventions increased the detection of FH. This systematic yet simple electronic case-finding programme with nurse-led review allowed the identification of new index cases, more than doubling the recorded prevalence of detected disease to 1 in 357 (0.28%). This study shows that primary care has an important role in identifying patients with this condition