300 research outputs found
Inflammation, insulin resistance, and diabetes-mendelian randomization using CRP haplotypes points upstream
Background
Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.
Methods and Findings
We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29-1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p=0.52-0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p=0.007-0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p=0.25-0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations.
Conclusions
Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP
Measurement of Angular Distributions and R= sigma_L/sigma_T in Diffractive Electroproduction of rho^0 Mesons
Production and decay angular distributions were extracted from measurements
of exclusive electroproduction of the rho^0(770) meson over a range in the
virtual photon negative four-momentum squared 0.5< Q^2 <4 GeV^2 and the
photon-nucleon invariant mass range 3.8< W <6.5 GeV. The experiment was
performed with the HERMES spectrometer, using a longitudinally polarized
positron beam and a ^3He gas target internal to the HERA e^{+-} storage ring.
The event sample combines rho^0 mesons produced incoherently off individual
nucleons and coherently off the nucleus as a whole. The distributions in one
production angle and two angles describing the rho^0 -> pi+ pi- decay yielded
measurements of eight elements of the spin-density matrix, including one that
had not been measured before. The results are consistent with the dominance of
helicity-conserving amplitudes and natural parity exchange. The improved
precision achieved at 47 GeV,
reveals evidence for an energy dependence in the ratio R of the longitudinal to
transverse cross sections at constant Q^2.Comment: 15 pages, 15 embedded figures, LaTeX for SVJour(epj) document class
Revision: Fig. 15 corrected, recent data added to Figs. 10,12,14,15; minor
changes to tex
First Measurement of the Tensor Structure Function of the Deuteron
The \Hermes experiment has investigated the tensor spin structure of the
deuteron using the 27.6 GeV/c positron beam of \Hera. The use of a tensor
polarized deuteron gas target with only a negligible residual vector
polarization enabled the first measurement of the tensor asymmetry \At and
the tensor structure function \bd for average values of the Bj{\o}rken
variable and of the squared four-momentum transfer . The quantities \At and \bd are found to be
non-zero. The rise of \bd for decreasing values of can be interpreted to
originate from the same mechanism that leads to nuclear shadowing in
unpolarized scattering
Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer
Introduction
Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach.
Methods
Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n = 84), gene expression profiling (n = 47), matched pre- and post-AI aCGH (n = 19 pairs) and Ki67-based AI-response analysis (n = 39).
Results
Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1).
Conclusions
These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response
Nuclear Polarization of Molecular Hydrogen Recombined on a Non-metallic Surface
The nuclear polarization of molecules formed by recombination
of nuclear polarized H atoms on the surface of a storage cell initially coated
with a silicon-based polymer has been measured by using the longitudinal
double-spin asymmetry in deep-inelastic positron-proton scattering. The
molecules are found to have a substantial nuclear polarization, which is
evidence that initially polarized atoms retain their nuclear polarization when
absorbed on this type of surfac
Exclusive Leptoproduction of rho^0 Mesons from Hydrogen at Intermediate Virtual Photon Energies
Measurements of the cross section for exclusive virtual-photoproduction of
rho^0 mesons from hydrogen are reported. The data were collected by the HERMES
experiment using 27.5 GeV positrons incident on a hydrogen gas target in the
HERA storage ring. The invariant mass W of the photon-nucleon system ranges
from 4.0 to 6.0 GeV, while the negative squared four-momentum Q^2 of the
virtual photon varies from 0.7 to 5.0 GeV^2. The present data together with
most of the previous data at W > 4 GeV are well described by a model that
infers the W-dependence of the cross section from the dependence on the Bjorken
scaling variable x of the unpolarized structure function for deep-inelastic
scattering. In addition, a model calculation based on Off-Forward Parton
Distributions gives a fairly good account of the longitudinal component of the
rho^0 production cross section for Q^2 > 2 GeV^2.Comment: 10 pages, 6 embedded figures, LaTeX for SVJour(epj) document class.
Revisions: curves added to Fig. 1, several clarifications added to tex
Quark helicity distributions in the nucleon for up, down, and strange quarks from semi--inclusive deep--inelastic scattering
Polarized deep--inelastic scattering data on longitudinally polarized
hydrogen and deuterium targets have been used to determine double spin
asymmetries of cross sections. Inclusive and semi--inclusive asymmetries for
the production of positive and negative pions from hydrogen were obtained in a
re--analysis of previously published data. Inclusive and semi--inclusive
asymmetries for the production of negative and positive pions and kaons were
measured on a polarized deuterium target. The separate helicity densities for
the up and down quarks and the anti--up, anti--down, and strange sea quarks
were computed from these asymmetries in a ``leading order'' QCD analysis. The
polarization of the up--quark is positive and that of the down--quark is
negative. All extracted sea quark polarizations are consistent with zero, and
the light quark sea helicity densities are flavor symmetric within the
experimental uncertainties. First and second moments of the extracted quark
helicity densities in the measured range are consistent with fits of inclusive
data
- …