407 research outputs found
A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling
Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS- mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA E545K mutation as conferring drug resistance. We demonstrate that PIK3CA E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CA E545K -induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. SIGNIFICANCE: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA E545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA E545K -expressing NRAS-mutant melanoma cells to MEKi + CDK4i. © 2018 AAC
Extensive translation of circular RNAs driven by N6-methyladenosine
Extensive pre-mRNA back-splicing generates numerous circular RNAs (circRNAs) in human transcriptome. However, the biological functions of these circRNAs remain largely unclear. Here we report that N6-methyladenosine (m6A), the most abundant base modification of RNA, promotes efficient initiation of protein translation from circRNAs in human cells. We discover that consensus m6A motifs are enriched in circRNAs and a single m6A site is sufficient to drive translation initiation. This m6A-driven translation requires initiation factor eIF4G2 and m6A reader YTHDF3, and is enhanced by methyltransferase METTL3/14, inhibited by demethylase FTO, and upregulated upon heat shock. Further analyses through polysome profiling, computational prediction and mass spectrometry reveal that m6A-driven translation of circRNAs is widespread, with hundreds of endogenous circRNAs having translation potential. Our study expands the coding landscape of human transcriptome, and suggests a role of circRNA-derived proteins in cellular responses to environmental stress
The fermion dynamical symmetry model for the even--even and even--odd nuclei in the Xe--Ba region
The even--even and even--odd nuclei Xe-Xe and
Ba-Ba are shown to have a well-realized fermion dynamical symmetry. Their low-lying energy levels can be
described by a unified analytical expression with two (three) adjustable
parameters for even--odd (even--even) nuclei that is derived from the fermion
dynamical symmetry model. Analytical expressions are given for wavefunctions
and for transition rates that agree well with data. The distinction
between the FDSM and IBM limits is discussed. The experimentally
observed suppression of the the energy levels with increasing quantum
number can be explained as a perturbation of the pairing interaction on
the symmetry, which leads to an Pairing effect for nuclei.Comment: submitted to Phys. Rev. C, LaTeX, 31 pages, 8 figures with postscript
files available on request at [email protected]
Measurements of psi(2S) decays to octet baryon-antibaryon pairs
With a sample of 14 million psi(2S) events collected by the BESII detector at
the Beijing Electron Positron Collider (BEPC), the decay channels psi(2S)->p
p-bar, Lambda Lambda-bar, Sigma0 Sigma0-bar, Xi Xi-bar are measured, and their
branching ratios are determined to be (3.36+-0.09+-0.24)*10E-4,
(3.39+-0.20+-0.32)*10E-4, (2.35+-0.36+-0.32)*10E-4, (3.03+-0.40+-0.32)*10E-4,
respectively. In the decay psi(2S)->p p-bar, the angular distribution parameter
alpha is determined to be 0.82+-0.17+-0.04.Comment: 8 pages, 8 figure
Measurements of the observed cross sections for exclusive light hadrons containing at , 3.650 and 3.6648 GeV
By analyzing the data sets of 17.3, 6.5 and 1.0 pb taken,
respectively, at , 3.650 and 3.6648 GeV with the BES-II
detector at the BEPC collider, we measure the observed cross sections for
, , ,
and at the three energy
points. Based on these cross sections we set the upper limits on the observed
cross sections and the branching fractions for decay into these
final states at 90% C.L..Comment: 7 pages, 2 figure
Partial wave analysis of J/\psi \to \gamma \phi \phi
Using events collected in the BESII detector, the
radiative decay is
studied. The invariant mass distribution exhibits a near-threshold
enhancement that peaks around 2.24 GeV/.
A partial wave analysis shows that the structure is dominated by a
state () with a mass of
GeV/ and a width of GeV/. The
product branching fraction is: .Comment: 11 pages, 4 figures. corrected proof for journa
Direct Measurements of Absolute Branching Fractions for D0 and D+ Inclusive Semimuonic Decays
By analyzing about 33 data sample collected at and around 3.773
GeV with the BES-II detector at the BEPC collider, we directly measure the
branching fractions for the neutral and charged inclusive semimuonic decays
to be and , and determine the ratio of the two branching
fractions to be
Measurements of the observed cross sections for exclusive light hadron production in e^+e^- annihilation at \sqrt{s}= 3.773 and 3.650 GeV
By analyzing the data sets of 17.3 pb taken at GeV
and 6.5 pb taken at GeV with the BESII detector at the
BEPC collider, we have measured the observed cross sections for 12 exclusive
light hadron final states produced in annihilation at the two energy
points. We have also set the upper limits on the observed cross sections and
the branching fractions for decay to these final states at 90%
C.L.Comment: 8 pages, 5 figur
Search for the Rare Decays J/Psi --> Ds- e+ nu_e, J/Psi --> D- e+ nu_e, and J/Psi --> D0bar e+ e-
We report on a search for the decays J/Psi --> Ds- e+ nu_e + c.c., J/Psi -->
D- e+ nu_e + c.c., and J/Psi --> D0bar e+ e- + c.c. in a sample of 5.8 * 10^7
J/Psi events collected with the BESII detector at the BEPC. No excess of signal
above background is observed, and 90% confidence level upper limits on the
branching fractions are set: B(J/Psi --> Ds- e+ nu_e + c.c.)<4.8*10^-5, B(J/Psi
--> D- e+ nu_e + c.c.) D0bar e+ e- + c.c.)<1.1*10^-5Comment: 10 pages, 4 figure
A study of charged kappa in
Based on events collected by BESII, the decay
is studied. In the invariant mass
spectrum recoiling against the charged , the charged
particle is found as a low mass enhancement. If a Breit-Wigner function of
constant width is used to parameterize the kappa, its pole locates at MeV/. Also in this channel,
the decay is observed for the first time.
Its branching ratio is .Comment: 14 pages, 4 figure
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