Development and validation of a novel bioassay to determine glucocorticoid sensitivity

BACKGROUND: Glucocorticoids (GCs) remain the first line treatment for almost all non-infectious inflammatory diseases, ranging from acute asthma to rheumatoid arthritis. However, across all conditions, patients have a variable response to GCs with approximately 30% being non-responders. This group of GC resistant patients is typically exposed to high-dose GCs and their side-effects before more appropriate immunotherapy is instituted. Hence, there is a pressing clinical need for a predictive biomarker of GC responsiveness. The availability of such a tool would also enable patient stratification for the conduct of smart clinical trials in GC resistance. Lymphocyte GC sensitivity has been shown to be closely associated with clinical GC sensitivity in a number of inflammatory diseases. However, the method for determining in vitro GC response is not standardized and requires the use of specialist equipment, including a radioisotope to quantify cellular proliferation, making it challenging to translate into clinical practice. RESULTS: Here we describe the optimization and validation of a novel non-radioactive in vitro bioassay based on measuring cellular proliferation by incorporation of bromodeoxyuridine (BrdU), termed the BrdU incorporation in lymphocyte steroid sensitivity assay (BLISS). In comparison to the current gold standard lymphocyte GC sensitivity assay in 101 healthy control samples, BLISS has an area under receiver operating characteristic of 0.82 and a sensitivity of 83% for correctly identifying GC resistant subjects. CONCLUSIONS: The performance of the novel BLISS bioassay makes it a strong candidate biomarker for clinical application. It now requires validation in a prospective patient cohort. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40364-016-0079-y) contains supplementary material, which is available to authorized users

Central Exclusive Production in QCD

We investigate the theoretical description of the central exclusive production process, h1+h2 -> h1+X+h2. Taking Higgs production as an example, we sum logarithmically enhanced corrections appearing in the perturbation series to all orders in the strong coupling. Our results agree with those originally presented by Khoze, Martin and Ryskin except that the scale appearing in the Sudakov factor, mu=0.62 \sqrt{\hat{s}}, should be replaced with mu=\sqrt{\hat{s}}, where \sqrt{\hat{s}} is the invariant mass of the centrally produced system. We confirm this result using a fixed-order calculation and show that the replacement leads to approximately a factor 2 suppression in the cross-section for central system masses in the range 100-500 GeV.Comment: 41 pages, 19 figures; minor typos fixed; version published in JHE

Development and validation of a novel bioassay to determine glucocorticoid sensitivity

Background: Glucocorticoids (GCs) remain the first line treatment for almost all non-infectious inflammatory diseases, ranging from acute asthma to rheumatoid arthritis. However, across all conditions, patients have a variable response to GCs with approximately 30% being non-responders. This group of GC resistant patients is typically exposed to high-dose GCs and their side-effects before more appropriate immunotherapy is instituted. Hence, there is a pressing clinical need for a predictive biomarker of GC responsiveness. The availability of such a tool would also enable patient stratification for the conduct of smart clinical trials in GC resistance. Lymphocyte GC sensitivity has been shown to be closely associated with clinical GC sensitivity in a number of inflammatory diseases. However, the method for determining in vitro GC response is not standardized and requires the use of specialist equipment, including a radioisotope to quantify cellular proliferation, making it challenging to translate into clinical practice. / Results: Here we describe the optimization and validation of a novel non-radioactive in vitro bioassay based on measuring cellular proliferation by incorporation of bromodeoxyuridine (BrdU), termed the BrdU incorporation in lymphocyte steroid sensitivity assay (BLISS). In comparison to the current gold standard lymphocyte GC sensitivity assay in 101 healthy control samples, BLISS has an area under receiver operating characteristic of 0.82 and a sensitivity of 83% for correctly identifying GC resistant subjects. / Conclusions: The performance of the novel BLISS bioassay makes it a strong candidate biomarker for clinical application. It now requires validation in a prospective patient cohort

Prospects for Spin Physics at RHIC

Colliding beams of 70% polarized protons at up to $\sqrt{s}$=500 GeV, with high luminosity, L=2$\times10^{{\rm 32}}$ cm$^{-2}$sec$^{-1}$, will represent a new and unique laboratory for studying the proton. RHIC-Spin will be the first polarized-proton collider and will be capable of copious production of jets, directly produced photons, and $W$ and $Z$ bosons. Features will include direct and precise measurements of the polarization of the gluons and of $\bar{u}$, $\bar{d}$, $u$, and $d$ quarks in a polarized proton. Parity violation searches for physics beyond the standard model will be competitive with unpolarized searches at the Fermilab Tevatron. Transverse spin will explore transversity for the first time, as well as quark-gluon correlations in the proton. Spin dependence of the total cross section and in the Coulomb nuclear interference region will be measured at collider energies for the first time. These qualitatively new measurements can be expected to deepen our understanding of the structure of matter and of the strong interaction.Comment: 51 pages, 22 figures. Scheduled to appear in the Annual Review of Nuclear and Particle Science Vol. 50, to be published in December 2000 by Annual Reviews, http://AnnualReviews.or

Ab initio prediction of Boron compounds arising from Borozene: Structural and electronic properties

Structure and electronic properties of two unusual boron clusters obtained by fusion of borozene rings has been studied by means of first principles calculations, based on the generalized-gradient approximation of the density functional theory, and the semiempirical tight-binding method was used for the transport calculations. The role of disorder has also been considered with single vacancies and substitutional atoms. Results show that the pure boron clusters are topologically planar and characterized by (3c-2e) bonds, which can explain, together with the aromaticity (estimated by means of NICS), the remarkable cohesive energy values obtained. Such feature makes these systems competitive with the most stable boron clusters to date. On the contrary, the introduction of impurities compromises stability and planarity in both cases. The energy gap values indicate that these clusters possess a semiconducting character, while when the larger system is considered, zero-values of the density of states are found exclusively within the HOMO-LUMO gap. Electron transport calculations within the Landauer formalism confirm these indications, showing semiconductor-like low bias differential conductance for these stuctures. Differences and similarities with Carbon clusters are highlighted in the discussion.Comment: 10 pages, 2 tables, 5 figure

A search for heavy Kaluza-Klein electroweak gauge bosons at the LHC

The feasibility for the observation of a certain leptonic Kaluza-Klein (KK) hard process in {\em pp} interactions at the LHC is presented. Within the $S^1/Z_2$ TeV$^{-1}$ extra dimensional theoretical framework with the focus on the KK excitations of the Standard Model $\gamma$ and $Z^0$ gauge bosons, the hard-process, $f\bar f \to \sum_n\left(\gamma^*/Z^*\right)_n \to F \bar F$, has been used where $f$ is the initial state parton, $F$ the final state lepton and $\left(\gamma^*/Z^*\right)_{n}$ is the $n^{\rm th}$ KK excitation of the $\gamma/Z^0$ boson. For this study the analytic form for the hard process cross section has been independently calculated by the authors and has been implemented using the {\sc Moses} framework. The Moses framework itself, that has been written by the authors, was used as an external process within the {\sc Pythia} Monte Carlo generator which provides the phase space generation for the final state leptons and partons from the initial state hadrons, and the simulation of initial and final state radiation and hadronization. A brief discussion of the possibility for observing and identifying the unique signature of the KK signal given the current LHC program is also presented.Comment: 16 pages 10 figures, MCnet number: MCnet/10/06, Accepted by JHE

Isolation of anonymous, polymorphic DNA fragments from human chromosome 22q12-qter

A series of 195 random chromosome 22-specific probes, equivalent to approximately 1% of the size of this chromosome, have been isolated from a chromosome 22-specific bacteriophage lambda genomic library. These probes were mapped to four different regions of chromosome 22 on a panel of five somatic cell hybrids. Restriction fragment length polymorphisms were detected by 28 of the probes mapping to 22q12-qter. Evolutionarily conserved sequences in human, mouse, and Chinese hamster DNA were detected by 12% of the isolated probes

The impact of predation by marine mammals on Patagonian toothfish longline fisheries

Predatory interaction of marine mammals with longline fisheries is observed globally, leading to partial or complete loss of the catch and in some parts of the world to considerable financial loss. Depredation can also create additional unrecorded fishing mortality of a stock and has the potential to introduce bias to stock assessments. Here we aim to characterise depredation in the Patagonian toothfish (Dissostichus eleginoides) fishery around South Georgia focusing on the spatio-temporal component of these interactions. Antarctic fur seals (Arctocephalus gazella), sperm whales (Physeter macrocephalus), and orcas (Orcinus orca) frequently feed on fish hooked on longlines around South Georgia. A third of longlines encounter sperm whales, but loss of catch due to sperm whales is insignificant when compared to that due to orcas, which interact with only 5% of longlines but can take more than half of the catch in some cases. Orca depredation around South Georgia is spatially limited and focused in areas of putative migration routes, and the impact is compounded as a result of the fishery also concentrating in those areas at those times. Understanding the seasonal behaviour of orcas and the spatial and temporal distribution of “depredation hot spots” can reduce marine mammal interactions, will improve assessment and management of the stock and contribute to increased operational efficiency of the fishery. Such information is valuable in the effort to resolve the human-mammal conflict for resources

The Quark Beam Function at NNLL

In hard collisions at a hadron collider the most appropriate description of the initial state depends on what is measured in the final state. Parton distribution functions (PDFs) evolved to the hard collision scale Q are appropriate for inclusive observables, but not for measurements with a specific number of hard jets, leptons, and photons. Here the incoming protons are probed and lose their identity to an incoming jet at a scale \mu_B << Q, and the initial state is described by universal beam functions. We discuss the field-theoretic treatment of beam functions, and show that the beam function has the same RG evolution as the jet function to all orders in perturbation theory. In contrast to PDF evolution, the beam function evolution does not mix quarks and gluons and changes the virtuality of the colliding parton at fixed momentum fraction. At \mu_B, the incoming jet can be described perturbatively, and we give a detailed derivation of the one-loop matching of the quark beam function onto quark and gluon PDFs. We compute the associated NLO Wilson coefficients and explicitly verify the cancellation of IR singularities. As an application, we give an expression for the next-to-next-to-leading logarithmic order (NNLL) resummed Drell-Yan beam thrust cross section.Comment: 54 pages, 9 figures; v2: notation simplified in a few places, typos fixed; v3: journal versio