10,096 research outputs found
Phosphatidylinositol 3-kinase pathway genomic alterations in 60,991 diverse solid tumors informs targeted therapy opportunities.
BackgroundThe phosphatidylinositol 3-kinase (PI3K) pathway is frequently altered in cancer. This report describes the landscape of PI3K alterations in solid tumors as well as co-alterations serving as potential resistance/attenuation mechanisms.MethodsConsecutive samples were analyzed in a commercial Clinical Laboratory Improvement Amendment-certified laboratory using comprehensive genomic profiling performed by next-generation sequencing (315 genes). The co-alterations evaluated included the Erb-B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, RAS, MET proto-oncogene tyrosine kinase (MET), and mitogen-activated protein kinase kinase (MAP2K) genes as well as tumor protein 53 (TP53), estrogen receptor 1 (ESR1), and androgen receptor (AR).ResultsAlterations in any of 18 PI3K-pathway associated genes were identified in 44% of 60,991 tumors. Although single base and insertions/deletions (indels) were the most frequent alterations, copy number changes and rearrangements were identified in 11% and 0.9% of patients, respectively. Overall, the most frequently altered genes were PIK3 catalytic subunit α (PIK3CA) (13%), phosphatase and tensin homolog (PTEN) (9%), and serine/threonine kinase 11 (STK11) (5%). Tumor types that frequently harbored at least 1 PI3K alteration were uterine (77%), cervical (62%), anal (59%), and breast (58%) cancers. Alterations also were discerned frequently in tumors with carcinosarcoma (89%) and squamous cell carcinoma (62%) histologies. Tumors with a greater likelihood of co-occurring PI3K pathway and MAPK pathway alterations included colorectal cancers (odds ratio [OR], 1.64; P < .001), mesotheliomas (OR, 2.67; P = .024), anal cancers (OR, 1.98; P = .03), and nonsquamous head and neck cancers (OR, 2.03; P = .019). The co-occurrence of ESR1 and/or AR alterations with PI3K alterations was statistically significant in bladder, colorectal, uterine, prostate, and unknown primary cancers.ConclusionsComprehensive genomic profiling reveals altered PI3K-related genes in 44% of solid malignancies, including rare disease and histology types. The frequency of alterations and the co-occurrence of resistance pathways vary by tumor type, directly affecting opportunities for targeted therapy
Kinetically Inhibited Order in a Diamond-Lattice Antiferromagnet
Frustrated magnetic systems exhibit highly degenerate ground states and
strong fluctuations, often leading to new physics. An intriguing example of
current interest is the antiferromagnet on a diamond lattice, realized
physically in A-site spinel materials. This is a prototypical system in three
dimensions where frustration arises from competing interactions rather than
purely geometric constraints, and theory suggests the possibility of unusual
magnetic order at low temperature. Here we present a comprehensive
single-crystal neutron scattering study of CoAl2O4, a highly frustrated A-site
spinel. We observe strong diffuse scattering that peaks at wavevectors
associated with Neel ordering. Below the temperature T*=6.5 K, there is a
dramatic change in the elastic scattering lineshape accompanied by the
emergence of well-defined spin-wave excitations. T* had previously been
associated with the onset of glassy behavior. Our new results suggest instead
that T* signifies a first-order phase transition, but with true long-range
order inhibited by the kinetic freezing of domain walls. This scenario might be
expected to occur widely in frustrated systems containing first-order phase
transitions and is a natural explanation for existing reports of anomalous
glassy behavior in other materials.Comment: 40 pages, 9 figures, Introduction and discussion altered and
expanded. Additional section and figure added to Supplementary Informatio
A cyclic-di-GMP receptor required for bacterial exopolysaccharide production
Bis-(3′,5′)-cyclic-dimeric-guanosine monophosphate (c-di-GMP) has been shown to be a global regulatory molecule that modulates the reciprocal responses of bacteria to activate either virulence pathways or biofilm formation. The mechanism of c-di-GMP signal transduction, including recognition of c-di-GMP and subsequent phenotypic regulation, remain largely uncharacterized. The key components of these regulatory pathways are the various adaptor proteins (c-di-GMP receptors). There is compelling evidence suggesting that, in addition to PilZ domains, there are other unidentified c-di-GMP receptors. Here we show that the PelD protein of Pseudomonas aeruginosa is a novel c-di-GMP receptor that mediates c-di-GMP regulation of PEL polysaccharide biosynthesis. Analysis of PelD orthologues identified a number of conserved residues that are required for c-di-GMP binding as well as synthesis of the PEL polysaccharide. Secondary structure similarities of PelD to the inhibitory site of diguanylate cyclase suggest that a common fold can act as a platform to bind c-di-GMP. The combination of a c-di-GMP binding site with a variety of output signalling motifs within one protein domain provides an explanation for the specificity for different cellular responses to this regulatory dinucleotide
Exact Results for the BTZ Black Hole
In this review, we summarize exact results for the three-dimensional BTZ
black hole. We use rigorous mathematical results to clarify the general
structure and properties of this black hole spacetime and its microscopic
description. In particular, we study the formation of the black hole by point
particle collisions, leading to an exact analytic determination of the Choptuik
scaling parameter. We also show that a `No Hair Theorem' follows immediately
from a mathematical theorem of hyperbolic geometry, due to Sullivan. A
microscopic understanding of the Bekenstein-Hawking entropy, and decay rate for
massless scalars, is shown to follow from standard results of conformal field
theory.Comment: 24 pages, Latex, Review article to appear in Int. J. Mod. Phys. D, v2
additional reference
Destruction of density-wave states by a pseudo-gap in high magnetic fields: application to (TMTSF)ClO
A model is presented for the destruction of density-wave states in
quasi-one-dimensional crystals by high magnetic fields. The model is consistent
with previously unexplained properties of the organic conductors
(TMTSF)ClO and (BEDT-TTF)MHg(SCN) (M=K,Rb,Tl). As the magnetic
field increases quasi-one-dimensional density-wave fluctuations increase,
producing a pseudo-gap in the electronic density of states near the transition
temperature. When the pseudo-gap becomes larger than the mean-field transition
temperature formation of a density-wave state is not possible.Comment: 4 pages, RevTeX, 2 figures in uuencoded compressed tar file. Small
changes to text and Figure 1. Final version to appear in Physical Review
Letter
An Engineered Bivalent Neuregulin Protects Against Doxorubicin-Induced Cardiotoxicity With Reduced Proneoplastic Potential
Background—Doxorubicin (DOXO) is an effective anthracycline chemotherapeutic, but its use is limited by cumulative dose-dependent cardiotoxicity. Neuregulin-1β is an ErbB receptor family ligand that is effective against DOXO-induced cardiomyopathy in experimental models but is also proneoplastic. We previously showed that an engineered bivalent neuregulin-1β (NN) has reduced proneoplastic potential in comparison with the epidermal growth factor–like domain of neuregulin-1β (NRG), an effect mediated by receptor biasing toward ErbB3 homotypic interactions uncommonly formed by native neuregulin-1β. Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced proneoplastic effects in comparison with NRG.
Methods and Results—NN was expressed as a maltose-binding protein fusion in Escherichia coli. As established previously, NN stimulated antineoplastic or cytostatic signaling and phenotype in cancer cells, whereas NRG stimulated proneoplastic signaling and phenotype. In neonatal rat cardiomyocytes, NN and NRG induced similar downstream signaling. NN, like NRG, attenuated the double-stranded DNA breaks associated with DOXO exposure in neonatal rat cardiomyocytes and human cardiomyocytes derived from induced pluripotent stem cells. NN treatment significantly attenuated DOXO-induced decrease in fractional shortening as measured by blinded echocardiography in mice in a chronic cardiomyopathy model (57.7±0.6% versus 50.9±2.6%, P=0.004), whereas native NRG had no significant effect (49.4±3.7% versus 50.9±2.6%, P=0.813).
Conclusions—NN is a cardioprotective agent that promotes cardiomyocyte survival and improves cardiac function in DOXO-induced cardiotoxicity. Given the reduced proneoplastic potential of NN versus NRG, NN has translational potential for cardioprotection in patients with cancer receiving anthracyclines.Stem Cell and Regenerative Biolog
B -> Xs l_i^+ l_j^+ Decays with R-parity Violation
We derive the upper bounds on certain products of R-parity- and
lepton-flavor-violating couplings from B \ra X_s {l_i}^+ {l_j}^- decays.
These modes of B-meson decays can constrain the product combinations of the
couplings with one or more heavy generation indices which are comparable with
or stronger than the present bounds. From the studies of the invariant dilepton
mass spectrum and the forward backward asymmetry of the emitted leptons we note
the possibility of detecting R-parity-violating signals even when the total
decay rate due to R-parity violating couplings is comparable with that in the
standard model and discriminating two types of R-parity-violating signals. The
general expectation of the enhancement of the forward backward asymmetry of the
emitted leptons in the minimal supersymmetric standard model with R-parity may
be corrupted by R-parity violation.Comment: 10 pages, Revtex, 1 table and 2 figure
Light-Scattering Observation Of Surface Acoustic Modes In High-Order Brillouin Zones Of A Si(001) Grating
In Brillouin light-scattering (BLS) measurements of an ion-milled Si(001) surface grating with grating wavelength Lambda(G) =0.35 mu m, we have observed numerous high-order zone-folded surface acoustic modes between the second and third zone boundaries associated with the grating. A surprisingly intense signal from a zone-folded longitudinal resonance was observed in the absence of direct hybridization with the Rayleigh modes. The relative intensities of all of the modes have been calculated by allowing for coupling between modes related by up to two grating reciprocal-lattice vectors, and for a grating profile with nonzero first and second Fourier amplitudes. The Fourier amplitudes inferred from the BLS measurements and calculations agree very well with those obtained from a direct measurement of the grating profile using atomic-force microscopy
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