Antibiotic treatment targeting gram negative bacteria prevents neratinib-induced diarrhea in rats

Background: Neratinib is a pan-ErbB tyrosine kinase inhibitor used for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the main adverse event associated with neratinib treatment. We aimed here to determine whether antibiotic-induced gut microbial shifts altered development of neratinib-induced diarrhea. Methods: Female Albino Wistar rats (total n = 44) were given antibiotics (vancomycin, neomycin, or a cocktail of vancomycin, neomycin and ampicillin) in drinking water for four weeks, and then treated daily with neratinib (50 mg/kg) for 28 days. Diarrhea, along with markers of gastrointestinal damage and microbial alterations were measured by histopathology and 16S sequencing, respectively. Results: Rats treated with vancomycin or neomycin had significantly lower levels of diarrhea than rats treated with neratinib alone. In the distal ileum, neratinib was associated with a statistically significant increase in histological damage in all treatment groups expect the antibiotic cocktail. Key features included villous blunting and fusion and some inflammatory infiltrate. Differences in microbial composition at necropsy in vehicle control, neratinib and neratinib + neomycin groups, were characterized by a neratinib-induced increase in gram-negative bacteria that was reversed by neomycin. Neomycin shifted bacterial composition so that Blautia become the dominant genus. Conclusions: Narrow spectrum antibiotics reduced neratinib-induced diarrhea. This suggests that the microbiome may play a key role in the development and prolongation of diarrhea following neratinib treatment, although further research is required to understand the key bacteria and mechanisms by which they reduce diarrhea, as well as how this may impact presentation of diarrhea in clinical cohorts.Kate R. Secombe, Imogen A. Ball, Anthony D. Wignall, Emma Bateman, Dorothy M. Keefe, Joanne M. Bowe

Pinch Technique and the Batalin-Vilkovisky formalism

In this paper we take the first step towards a non-diagrammatic formulation of the Pinch Technique. In particular we proceed into a systematic identification of the parts of the one-loop and two-loop Feynman diagrams that are exchanged during the pinching process in terms of unphysical ghost Green's functions; the latter appear in the standard Slavnov-Taylor identity satisfied by the tree-level and one-loop three-gluon vertex. This identification allows for the consistent generalization of the intrinsic pinch technique to two loops, through the collective treatment of entire sets of diagrams, instead of the laborious algebraic manipulation of individual graphs, and sets up the stage for the generalization of the method to all orders. We show that the task of comparing the effective Green's functions obtained by the Pinch Technique with those computed in the background field method Feynman gauge is significantly facilitated when employing the powerful quantization framework of Batalin and Vilkovisky. This formalism allows for the derivation of a set of useful non-linear identities, which express the Background Field Method Green's functions in terms of the conventional (quantum) ones and auxiliary Green's functions involving the background source and the gluonic anti-field; these latter Green's functions are subsequently related by means of a Schwinger-Dyson type of equation to the ghost Green's functions appearing in the aforementioned Slavnov-Taylor identity.Comment: 45 pages, uses axodraw; typos corrected, one figure changed, final version to appear in Phys.Rev.

The B-Meson Distribution Amplitude in QCD

The B-meson distribution amplitude is calculated using QCD sum rules. In particular we obtain an estimate for the integral relevant to exclusive B-decays \lambda_B = 460 \pm 110 MeV at the scale 1 GeV. A simple QCD-motivated parametrization of the distribution amplitude is suggested.Comment: 17 pages, 8 figures, Latex styl

Selective MMP inhibition, using AZD3342, to reduce gastrointestinal toxicity and enhance chemoefficacy in a rat model

BACKGROUND:The common cytotoxic mechanisms that underpin chemoefficacy and toxicity have hampered efforts to deliver effective supportive care interventions, particularly for gastrointestinal (GI) toxicity. Matrix metalloproteinases (MMPs) have been implicated in both tumor growth and GI toxicity, and as such MMP inhibitors present as a novel therapeutic avenue to simultaneously enhance treatment efficacy and reduce toxicity. OBJECTIVES:The aim of this study was to determine the efficacy of an MMP-9/12 inhibitor, AZD3342, on tumor growth and GI toxicity in a rat model. METHODS:Female tumor-bearing Dark Agouti rats (n = 90) were divided into 4 groups: vehicle control; methotrexate (MTX); AZD3342, and MTX + AZD3342. Tumors were measured daily (for 5 days) using digital calipers. GI toxicity was assessed using well-established clinical markers (diarrhea/weight loss), histopathological analysis, and functional assessment of intestinal barrier permeability. RESULTS:AZD3342 delayed the onset of severe diarrhea by 1 day (vs. MTX) but was unable to improve the overall severity of diarrhea. No changes were detected in tissue morphology or intestinal barrier function. AZD3342 alone suppressed tumor growth (p = 0.003 vs. vehicle) but did not enhance the efficacy of MTX. CONCLUSIONS:This study showed partial efficacy of AZD3342 in reducing tumor growth and delaying the onset of severe diarrhea caused by MTX in rats. We suggest further studies be undertaken targeting appropriate scheduling of AZD3342 as well as investigating different cytotoxic therapies that strongly activate MMP signaling.Rachel J. Gibson, Ysabella Z.A. van Sebille, Hannah R. Wardill, Anthony Wignall, Joseph Shirren, Imogen A. Ball, Nicole Williams, Kiara Wanner, Joanne M. Bowe

Study of the radiative decay ϕ→ηγ\phi \to \eta \gamma with CMD-2 detector

Using the $1.9 pb^{-1}$ of data collected with the CMD-2 detector at VEPP-2M the decay mode $\phi \to \eta \gamma$, $\eta \to \pi^+\pi^-\pi^0$ has been studied. The obtained branching ratio is B($\phi \to \eta \gamma) = (1.18 \pm 0.03 \pm 0.06)$.Comment: 13 pages, 5 figures, LaTex2e, to be published in Phys. Lett.

Serum outperforms plasma in small extracellular vesicle microRNA biomarker studies of adenocarcinoma of the esophagus

Background: To compare computed tomography coronary angiography (CTCA) with intravascular ultrasound (IVUS) in quantitative and qualitative plaque assessment. Methods: Patients who underwent IVUS and CTCA within 3 months for suspected coronary artery disease were retrospectively studied. Plaque volumes on CTCA were quantified manually and with automated-software and were compared to IVUS. High-risk plaque features were compared between CTCA and IVUS. Results: There were 769 slices in 32 vessels (27 patients). Manual plaque quantification on CTCA was comparable to IVUS per slice (mean difference of 0.06 ± 0.07, p = 0.44; Bland-Altman 95% limits of agreement -2.19–2.08 mm3, bias of -0.06 mm3) and per vessel (3.1 mm3 ± -2.85 mm3, p = 0.92). In contrast, there was significant difference between automated-software and IVUS per slice (2.3 ± 0.09mm3, p < 0.001; 95% LoA -6.78 to 2.25 mm3, bias of -2.2 mm3) and per vessel (33.04 ± 10.3 mm3, p < 0.01). The sensitivity, specificity, positive and negative predictive value of CTCA to detect plaques that had features of echo-attenuation on IVUS was 93.3%, 99.6%, 93.3% and 99.6% respectively. The association of ≥2 high-risk plaque features on CTCA with echo attenuation (EA) plaque features on IVUS was excellent (86.7%, 99.6%, 92.9% and 99.2%). In comparison, the association of high-risk plaque features on CTCA and plaques with echo-lucency on IVUS was only modest. Conclusion: Plaque volume quantification by manual CTCA method is accurate when compared to IVUS. The presence of at least two high-risk plaque features on CTCA is associated with plaque features of echo attenuation on IVUS.Ravi Kiran Munnur, Jordan Andrews ... Dorothy Keefe ... Lorelle Smith ... Joanne Bowen ... Sarah Thompson ... et al

Survey of nucleon electromagnetic form factors

A dressed-quark core contribution to nucleon electromagnetic form factors is calculated. It is defined by the solution of a Poincare' covariant Faddeev equation in which dressed-quarks provide the elementary degree of freedom and correlations between them are expressed via diquarks. The nucleon-photon vertex involves a single parameter; i.e., a diquark charge radius. It is argued to be commensurate with the pion's charge radius. A comprehensive analysis and explanation of the form factors is built upon this foundation. A particular feature of the study is a separation of form factor contributions into those from different diagram types and correlation sectors, and subsequently a flavour separation for each of these. Amongst the extensive body of results that one could highlight are: r_1^{n,u}>r_1^{n,d}, owing to the presence of axial-vector quark-quark correlations; and for both the neutron and proton the ratio of Sachs electric and magnetic form factors possesses a zero.Comment: 43 pages, 17 figures, 12 tables, 5 appendice

Gluon polarization in the nucleon from quasi-real photoproduction of high-pT hadron pairs

We present a determination of the gluon polarization Delta G/G in the nucleon, based on the helicity asymmetry of quasi-real photoproduction events, Q^2<1(GeV/c)^2, with a pair of large transverse-momentum hadrons in the final state. The data were obtained by the COMPASS experiment at CERN using a 160 GeV polarized muon beam scattered on a polarized 6-LiD target. The helicity asymmetry for the selected events is = 0.002 +- 0.019(stat.) +- 0.003(syst.). From this value, we obtain in a leading-order QCD analysis Delta G/G=0.024 +- 0.089(stat.) +- 0.057(syst.) at x_g = 0.095 and mu^2 =~ 3 (GeV}/c)^2.Comment: 10 pages, 3 figure

The Spin-dependent Structure Function of the Proton g_1^p and a Test of the Bjorken Sum Rule

The inclusive double-spin asymmetry, A_1^p, has been measured at COMPASS in deepinelastic polarised muon scattering off a large polarised NH3 target. The data, collected in the year 2007, cover the range Q2 > 1 (GeV/c)^2, 0.004 < x < 0.7 and improve the statistical precision of g_1^p(x) by a factor of two in the region x < 0.02. The new proton asymmetries are combined with those previously published for the deuteron to extract the non-singlet spin-dependent structure function g_1^NS(x,Q2). The isovector quark density, Delta_q_3(x,Q2), is evaluated from a NLO QCD fit of g_1^NS. The first moment of Delta_q3 is in good agreement with the value predicted by the Bjorken sum rule and corresponds to a ratio of the axial and vector coupling constants g_A/g_V = 1.28+-0.07(stat)+-0.10(syst).Comment: 12 pages, 5 figure

The COMPASS Experiment at CERN

The COMPASS experiment makes use of the CERN SPS high-intensitymuon and hadron beams for the investigation of the nucleon spin structure and the spectroscopy of hadrons. One or more outgoing particles are detected in coincidence with the incoming muon or hadron. A large polarized target inside a superconducting solenoid is used for the measurements with the muon beam. Outgoing particles are detected by a two-stage, large angle and large momentum range spectrometer. The setup is built using several types of tracking detectors, according to the expected incident rate, required space resolution and the solid angle to be covered. Particle identification is achieved using a RICH counter and both hadron and electromagnetic calorimeters. The setup has been successfully operated from 2002 onwards using a muon beam. Data with a hadron beam were also collected in 2004. This article describes the main features and performances of the spectrometer in 2004; a short summary of the 2006 upgrade is also given.Comment: 84 papes, 74 figure