3,463 research outputs found
Selective activation of oxidized PTP1B by the thioredoxin system modulates PDGF-ß receptor tyrosine kinase signaling
The inhibitory reversible oxidation of protein tyrosine phosphatases (PTPs) is an important regulatory mechanism in growth factor signaling. Studies on PTP oxidation have focused on pathways that increase or decrease reactive oxygen species levels and thereby affect PTP oxidation. The processes involved in reactivation of oxidized PTPs remain largely unknown. Here the role of the thioredoxin (Trx) system in reactivation of oxidized PTPs was analyzed using a combination of in vitro and cell-based assays. Cells lacking the major Trx reductase TrxR1 (Txnrd1-/-) displayed increased oxidation of PTP1B, whereas SHP2 oxidation was unchanged. Furthermore, in vivo-oxidized PTP1B was reduced by exogenously added Trx system components, whereas SHP2 oxidation remained unchanged. Trx1 reduced oxidized PTP1B in vitro but failed to reactivate oxidized SHP2. Interestingly, the alternative TrxR1 substrate TRP14 also reactivated oxidized PTP1B, but not SHP2. Txnrd1-depleted cells displayed increased phosphorylation of PDGF-ß receptor, and an enhanced mitogenic response, after PDGF-BB stimulation. The TrxR inhibitor auranofin also increased PDGF-ß receptor phosphorylation. This effect was not observed in cells specifically lacking PTP1B. Together these results demonstrate that the Trx system, including both Trx1 and TRP14, impacts differentially on the oxidation of individual PTPs, with a preference of PTP1B over SHP2 activation. The studies demonstrate a previously unrecognized pathway for selective redox-regulated control of receptor tyrosine kinase signaling
Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1
Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cellconditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment
Transverse-momentum-dependent Multiplicities of Charged Hadrons in Muon-Deuteron Deep Inelastic Scattering
A semi-inclusive measurement of charged hadron multiplicities in deep
inelastic muon scattering off an isoscalar target was performed using data
collected by the COMPASS Collaboration at CERN. The following kinematic domain
is covered by the data: photon virtuality (GeV/), invariant
mass of the hadronic system GeV/, Bjorken scaling variable in the
range , fraction of the virtual photon energy carried by the
hadron in the range , square of the hadron transverse momentum
with respect to the virtual photon direction in the range 0.02 (GeV/ (GeV/). The multiplicities are presented as a
function of in three-dimensional bins of , , and
compared to previous semi-inclusive measurements. We explore the
small- region, i.e. (GeV/), where
hadron transverse momenta are expected to arise from non-perturbative effects,
and also the domain of larger , where contributions from
higher-order perturbative QCD are expected to dominate. The multiplicities are
fitted using a single-exponential function at small to study
the dependence of the average transverse momentum on , and . The power-law behaviour of the
multiplicities at large is investigated using various
functional forms. The fits describe the data reasonably well over the full
measured range.Comment: 28 pages, 20 figure
Multiplicities of charged pions and unidentified charged hadrons from deep-inelastic scattering of muons off an isoscalar target
Multiplicities of charged pions and unidentified hadrons produced in
deep-inelastic scattering were measured in bins of the Bjorken scaling variable
, the relative virtual-photon energy and the relative hadron energy .
Data were obtained by the COMPASS Collaboration using a 160 GeV muon beam and
an isoscalar target (LiD). They cover the kinematic domain in the photon
virtuality > 1(GeV/c, , and . In addition, a leading-order pQCD analysis was performed using the
pion multiplicity results to extract quark fragmentation functions
Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.
Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation
ATHENA Detector Proposal — A Totally Hermetic Electron Nucleus Apparatus Proposed for IP6 at the Electron-Ion Collider
ATHENA has been designed as a general purpose detector capable of delivering the full scientific scope of the Electron-Ion Collider. Careful technology choices provide fine tracking and momentum resolution, high performance electromagnetic and hadronic calorimetry, hadron identification over a wide kinematic range, and near-complete hermeticity. This article describes the detector design and its expected performance in the most relevant physics channels. It includes an evaluation of detector technology choices, the technical challenges to realizing the detector and the R&D required to meet those challenges
Journal Staff
We present the first measurements of the differential cross section d sigma/dp(T)(gamma) for the production of an isolated photon in association with at least two b-quark jets. The measurements consider photons with rapidities vertical bar y(gamma)vertical bar < 1.0 and transverse momenta 30 < p(T)(gamma) < 200 GeV. The b-quark jets are required to have p(T)(jet) > 15 GeVand vertical bar y(jet)vertical bar < 1.5. The ratio of differential production cross sections for gamma + 2 b-jets to gamma + b-jet as a function of p(T)(gamma) is also presented. The results are based on the proton-antiproton collision data at root s = 1.96 TeV collected with the D0 detector at the Fermilab Tevatron Collider. The measured cross sections and their ratios are compared to the next- to- leading order perturbative QCD calculations as well as predictions based on the k(T)- factorization approach and those from the sherpa and pythia Monte Carlo event generators
A search for charged massive long-lived particles
We report on a search for charged massive long-lived particles (CMLLPs),
based on 5.2 fb of integrated luminosity collected with the D0 detector
at the Fermilab Tevatron collider. We search for events in which one
or more particles are reconstructed as muons but have speed and ionization
energy loss inconsistent with muons produced in beam collisions.
CMLLPs are predicted in several theories of physics beyond the standard model.
We exclude pair-produced long-lived gaugino-like charginos below 267 GeV and
higgsino-like charginos below 217 GeV at 95% C.L., as well as long-lived scalar
top quarks with mass below 285 GeV.Comment: submitted to Phys. Rev. Letter
Measurement of Leptonic Asymmetries and Top Quark Polarization in ttbar Production
We present measurements of lepton (l) angular distributions in ttbar -> W+ b
W- b -> l+ nu b l- nubar bbar decays produced in ppbar collisions at a
center-of-mass energy of sqrt(s)=1.96TeV, where l is an electron or muon. Using
data corresponding to an integrated luminosity of 5.4fb^-1, collected with the
D0 detector at the Fermilab Collider, we find that the angular distributions of
l- relative to anti-protons and l+ relative to protons are in agreement with
each other. Combining the two distributions and correcting for detector
acceptance we obtain the forward-backward asymmetry A^l_FB = (5.8 +- 5.1(stat)
+- 1.3(syst))%, compared to the standard model prediction of A^l_FB (predicted)
= (4.7 +- 0.1)%. This result is further combined with the measurement based on
the analysis of the l+jets final state to obtain A^l_FB = (11.8 +- 3.2)%.
Furthermore, we present a first study of the top-quark polarization.Comment: submitted versio
Measurements of single top quark production cross sections and |Vtb| in ppbar collisions at sqrt{s}=1.96 TeV
We present measurements of production cross sections of single top quarks in
\ppbar collisions at in a data sample corresponding
to an integrated luminosity of collected by the D0 detector
at the Fermilab Tevatron Collider. We select events with an isolated electron
or muon, an imbalance in transverse energy, and two, three, or four jets, with
one or two of them containing a bottom hadron. We obtain an inclusive cross
section of \sigma({\ppbar}{\rargap}tb+X, tqb+X) = 3.43\pm^{0.73}_{0.74}\;\rm
pb and use it to extract the CKM matrix element at
the 95% C.L. We also measure \sigma({\ppbar}{\rargap}tb+X) =
0.68\pm^{0.38}_{0.35}\;\rm pb and \sigma({\ppbar}{\rargap}tqb+X) =
2.86\pm^{0.69}_{0.63}\;\rm pb when assuming, respectively, and
production rates as predicted by the standard model.Comment: 11 pages, 8 figures, submitted to Phys. Rev.
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