143 research outputs found
Correction:Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer
Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer
BACKGROUND: Hypoxia-induced glycogen turnover is implicated in cancer proliferation and therapy resistance. Triple-negative breast cancers (TNBCs), characterized by a hypoxic tumor microenvironment, respond poorly to therapy. We studied the expression of glycogen synthase 1 (GYS1), the key regulator of glycogenesis, and other glycogen-related enzymes in primary tumors of patients with breast cancer and evaluated the impact of GYS1 downregulation in preclinical models.METHODS: mRNA expression of GYS1 and other glycogen-related enzymes in primary breast tumors and the correlation with patient survival were studied in the METABRIC dataset (n = 1904). Immunohistochemical staining of GYS1 and glycogen was performed on a tissue microarray of primary breast cancers (n = 337). In four breast cancer cell lines and a mouse xenograft model of triple-negative breast cancer, GYS1 was downregulated using small-interfering or stably expressed short-hairpin RNAs to study the effect of downregulation on breast cancer cell proliferation, glycogen content and sensitivity to various metabolically targeted drugs.RESULTS: High GYS1 mRNA expression was associated with poor patient overall survival (HR 1.20, P = 0.009), especially in the TNBC subgroup (HR 1.52, P = 0.014). Immunohistochemical GYS1 expression in primary breast tumors was highest in TNBCs (median H-score 80, IQR 53-121) and other Ki67-high tumors (median H-score 85, IQR 57-124) (P < 0.0001). Knockdown of GYS1 impaired proliferation of breast cancer cells, depleted glycogen stores and delayed growth of MDA-MB-231 xenografts. Knockdown of GYS1 made breast cancer cells more vulnerable to inhibition of mitochondrial proteostasis.CONCLUSIONS: Our findings highlight GYS1 as potential therapeutic target in breast cancer, especially in TNBC and other highly proliferative subsets.</p
Quantum Metrology: Towards an alternative definition for the meter
The motivation for this article came from an attempt to give an alternative
definition for the meter, the SI unit for measuring length. As a starting point
towards this goal, in this piece of work we present the underlying theory
behind our approach which uses ideas from quantum field theory and
noncommutative geometry, in particular the notion of an odd K-cycle which is
based on the Dirac operator (and its inverse, the Dirac propagator). Using (the
perhaps more familiar) physics terminology, the key point in our strategy is
this: instead of measuring length directly in space-time we measure the
"algebraic (spectral) length" in the space of the corresponding quantum states
of some particle (fermion) acted upon by the Dirac propagator. This approach
shares the spirit of the unanimus vote of the 24th General Conference of
Standards and Measures (21st October 2011) in Serves, France for the
redefinition of the fundamental units using Planck's constant.Comment: Extended version of an invited talk during the 4th Tactical
Conference on Metrology, 3-4 February 2012, National Technical University of
Athens, Athens Greec
A Study of Muon Neutrino Disappearance Using the Fermilab Main Injector Neutrino Beam
We report the results of a search for muon-neutrino disappearance by the Main
Injector Neutrino Oscillation Search. The experiment uses two detectors
separated by 734 km to observe a beam of neutrinos created by the Neutrinos at
the Main Injector facility at Fermi National Accelerator Laboratory. The data
were collected in the first 282 days of beam operations and correspond to an
exposure of 1.27e20 protons on target. Based on measurements in the Near
Detector, in the absence of neutrino oscillations we expected 336 +/- 14
muon-neutrino charged-current interactions at the Far Detector but observed
215. This deficit of events corresponds to a significance of 5.2 standard
deviations. The deficit is energy dependent and is consistent with two-flavor
neutrino oscillations according to delta m-squared = 2.74e-3 +0.44/-0.26e-3
eV^2 and sin^2(2 theta) > 0.87 at 68% confidence level.Comment: In submission to Phys. Rev.
Measurement of the Atmospheric Muon Charge Ratio at TeV Energies with MINOS
The 5.4 kton MINOS far detector has been taking charge-separated cosmic ray
muon data since the beginning of August, 2003 at a depth of 2070
meters-water-equivalent in the Soudan Underground Laboratory, Minnesota, USA.
The data with both forward and reversed magnetic field running configurations
were combined to minimize systematic errors in the determination of the
underground muon charge ratio. When averaged, two independent analyses find the
charge ratio underground to be 1.374 +/- 0.004 (stat.) +0.012 -0.010(sys.).
Using the map of the Soudan rock overburden, the muon momenta as measured
underground were projected to the corresponding values at the surface in the
energy range 1-7 TeV. Within this range of energies at the surface, the MINOS
data are consistent with the charge ratio being energy independent at the two
standard deviation level. When the MINOS results are compared with measurements
at lower energies, a clear rise in the charge ratio in the energy range 0.3 --
1.0 TeV is apparent. A qualitative model shows that the rise is consistent with
an increasing contribution of kaon decays to the muon charge ratio.Comment: 16 pages, 17 figure
Neutrino and Antineutrino Inclusive Charged-current Cross Section Measurements with the MINOS Near Detector
The energy dependence of the neutrino-iron and antineutrino-iron inclusive
charged-current cross sections and their ratio have been measured using a
high-statistics sample with the MINOS Near Detector exposed to the NuMI beam
from the Main Injector at Fermilab. Neutrino and antineutrino fluxes were
determined using a low hadronic energy subsample of charged-current events. We
report measurements of neutrino-Fe (antineutrinoFe) cross section in the energy
range 3-50 GeV (5-50 GeV) with precision of 2-8% (3-9%) and their ratio which
is measured with precision 2-8%. The data set spans the region from low energy,
where accurate measurements are sparse, up to the high-energy scaling region
where the cross section is well understood.Comment: accepted by PR
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New constraints on muon-neutrino to electron-neutrino transitions in MINOS
This paper reports results from a search for ν_μ → ν_e transitions by the MINOS experiment based on a 7×10^(20) protons-on-target exposure. Our observation of 54 candidate ν_e events in the far detector with a background of 49.1±7.0(stat)±2.7(syst) events predicted by the measurements in the near detector requires 2sin^2(2θ_(13))sin^2θ_(23)<0.12(0.20) at the 90% C.L. for the normal (inverted) mass hierarchy at δ_(CP)=0. The experiment sets the tightest limits to date on the value of θ_(13) for nearly all values of δ_(CP) for the normal neutrino mass hierarchy and maximal sin^2(2θ_(23))
Measurement of neutrino velocity with the MINOS detectors and NuMI neutrino beam
The velocity of a ~3 GeV neutrino beam is measured by comparing detection times at the near and far detectors of the MINOS experiment, separated by 734 km. A total of 473 far detector neutrino events was used to measure (v-c)/c=5.12.910-5 (at 68% C.L.). By correlating the measured energies of 258 charged-current neutrino events to their arrival times at the far detector, a limit is imposed on the neutrino mass of mnu<50 MeV/c2 (99% C.L.)
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