77 research outputs found
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Genotype Directed Therapy in Murine Mismatch Repair Deficient Tumors
The PI3K/AKT/mTOR pathway has frequently been found activated in human tumors. We show that in addition to Wnt signaling dysfunction, the PI3K/AKT/mTOR pathway is often upregulated in mouse Msh2−/− initiated intestinal tumors. NVP-BEZ235 is a dual PI3K/mTOR inhibitor toxic to many cancer cell lines and currently involved in clinical trials. We have treated two mouse models involving Msh2 that develop small intestinal and/or colonic tumors with NVP-BEZ235, and a subset of animals with NVP-BEZ235 and MEK inhibitor ADZ4266. The disease phenotype has been followed with pathology, 18F FDG PET imaging, and endoscopy. Intestinal adenocarcinomas are significantly decreased in multiplicity by both drug regimens. The majority of tumors treated with combined therapy regress significantly, while a small number of highly progressed tumors persist. We have examined PTEN, AKT, MEK 1&2, MAPK, S6K, mTOR, PDPK1, and Cyclin D1 and find variable alterations that include downregulation of PTEN, upregulation of AKT and changes in its phosphorylated forms, upregulation of pMEK 1&2, p42p44MAPK, pS6K, and Cyclin D1. Apoptosis has been found intact in some tumors and not in others. Our data indicate that NVP-BEZ235 alone and in combination with ADZ4266 are effective in treating a proportion of colorectal cancers, but that highly progressed resistant tumors grow in the presence of the drugs. Pathways upregulated in some resistant tumors also include PDPK1, suggesting that metabolic inhibitors may also be useful in treating these tumors
Architecture of Kepler's Multi-transiting Systems: II. New investigations with twice as many candidates
We report on the orbital architectures of Kepler systems having multiple
planet candidates identified in the analysis of data from the first six
quarters of Kepler data and reported by Batalha et al. (2013). These data show
899 transiting planet candidates in 365 multiple-planet systems and provide a
powerful means to study the statistical properties of planetary systems. Using
a generic mass-radius relationship, we find that only two pairs of planets in
these candidate systems (out of 761 pairs total) appear to be on Hill-unstable
orbits, indicating ~96% of the candidate planetary systems are correctly
interpreted as true systems. We find that planet pairs show little statistical
preference to be near mean-motion resonances. We identify an asymmetry in the
distribution of period ratios near first-order resonances (e.g., 2:1, 3:2),
with an excess of planet pairs lying wide of resonance and relatively few lying
narrow of resonance. Finally, based upon the transit duration ratios of
adjacent planets in each system, we find that the interior planet tends to have
a smaller transit impact parameter than the exterior planet does. This finding
suggests that the mode of the mutual inclinations of planetary orbital planes
is in the range 1.0-2.2 degrees, for the packed systems of small planets probed
by these observations.Comment: Accepted to Ap
Validation of Kepler's Multiple Planet Candidates. III: Light Curve Analysis & Announcement of Hundreds of New Multi-planet Systems
The Kepler mission has discovered over 2500 exoplanet candidates in the first
two years of spacecraft data, with approximately 40% of them in candidate
multi-planet systems. The high rate of multiplicity combined with the low rate
of identified false-positives indicates that the multiplanet systems contain
very few false-positive signals due to other systems not gravitationally bound
to the target star (Lissauer, J. J., et al., 2012, ApJ 750, 131). False
positives in the multi- planet systems are identified and removed, leaving
behind a residual population of candidate multi-planet transiting systems
expected to have a false-positive rate less than 1%. We present a sample of 340
planetary systems that contain 851 planets that are validated to substantially
better than the 99% confidence level; the vast majority of these have not been
previously verified as planets. We expect ~2 unidentified false-positives
making our sample of planet very reliable. We present fundamental planetary
properties of our sample based on a comprehensive analysis of Kepler light
curves and ground-based spectroscopy and high-resolution imaging. Since we do
not require spectroscopy or high-resolution imaging for validation, some of our
derived parameters for a planetary system may be systematically incorrect due
to dilution from light due to additional stars in the photometric aperture.
None the less, our result nearly doubles the number of verified exoplanets.Comment: 138 pages, 8 Figures, 5 Tables. Accepted for publications in the
Astrophysical Journa
Kepler-16: A Transiting Circumbinary Planet
We report the detection of a planet whose orbit surrounds a pair of low-mass
stars. Data from the Kepler spacecraft reveal transits of the planet across
both stars, in addition to the mutual eclipses of the stars, giving precise
constraints on the absolute dimensions of all three bodies. The planet is
comparable to Saturn in mass and size, and is on a nearly circular 229-day
orbit around its two parent stars. The eclipsing stars are 20% and 69% as
massive as the sun, and have an eccentric 41-day orbit. The motions of all
three bodies are confined to within 0.5 degree of a single plane, suggesting
that the planet formed within a circumbinary disk.Comment: Science, in press; for supplemental material see
http://www.sciencemag.org/content/suppl/2011/09/14/333.6049.1602.DC1/1210923.Doyle.SOM.pd
Planetary Candidates Observed by Kepler. VIII. A Fully Automated Catalog With Measured Completeness and Reliability Based on Data Release 25
We present the Kepler Object of Interest (KOI) catalog of transiting
exoplanets based on searching four years of Kepler time series photometry (Data
Release 25, Q1-Q17). The catalog contains 8054 KOIs of which 4034 are planet
candidates with periods between 0.25 and 632 days. Of these candidates, 219 are
new and include two in multi-planet systems (KOI-82.06 and KOI-2926.05), and
ten high-reliability, terrestrial-size, habitable zone candidates. This catalog
was created using a tool called the Robovetter which automatically vets the
DR25 Threshold Crossing Events (TCEs, Twicken et al. 2016). The Robovetter also
vetted simulated data sets and measured how well it was able to separate TCEs
caused by noise from those caused by low signal-to-noise transits. We discusses
the Robovetter and the metrics it uses to sort TCEs. For orbital periods less
than 100 days the Robovetter completeness (the fraction of simulated transits
that are determined to be planet candidates) across all observed stars is
greater than 85%. For the same period range, the catalog reliability (the
fraction of candidates that are not due to instrumental or stellar noise) is
greater than 98%. However, for low signal-to-noise candidates between 200 and
500 days around FGK dwarf stars, the Robovetter is 76.7% complete and the
catalog is 50.5% reliable. The KOI catalog, the transit fits and all of the
simulated data used to characterize this catalog are available at the NASA
Exoplanet Archive.Comment: 61 pages, 23 Figures, 9 Tables, Accepted to The Astrophysical Journal
Supplement Serie
Kepler-20: A Sun-like Star with Three Sub-Neptune Exoplanets and Two Earth-size Candidates
We present the discovery of the Kepler-20 planetary system, which we
initially identified through the detection of five distinct periodic transit
signals in the Kepler light curve of the host star 2MASSJ19104752+4220194. We
find a stellar effective temperature Teff=5455+-100K, a metallicity of
[Fe/H]=0.01+-0.04, and a surface gravity of log(g)=4.4+-0.1. Combined with an
estimate of the stellar density from the transit light curves we deduce a
stellar mass of Mstar=0.912+-0.034 Msun and a stellar radius of
Rstar=0.944^{+0.060}_{-0.095} Rsun. For three of the transit signals, our
results strongly disfavor the possibility that these result from astrophysical
false positives. We conclude that the planetary scenario is more likely than
that of an astrophysical false positive by a factor of 2e5 (Kepler-20b), 1e5
(Kepler-20c), and 1.1e3 (Kepler-20d), sufficient to validate these objects as
planetary companions. For Kepler-20c and Kepler-20d, the blend scenario is
independently disfavored by the achromaticity of the transit: From Spitzer data
gathered at 4.5um, we infer a ratio of the planetary to stellar radii of
0.075+-0.015 (Kepler-20c) and 0.065+-0.011 (Kepler-20d), consistent with each
of the depths measured in the Kepler optical bandpass. We determine the orbital
periods and physical radii of the three confirmed planets to be 3.70d and
1.91^{+0.12}_{-0.21} Rearth for Kepler-20b, 10.85 d and 3.07^{+0.20}_{-0.31}
Rearth for Kepelr-20c, and 77.61 d and 2.75^{+0.17}_{-0.30} Rearth for
Kepler-20d. From multi-epoch radial velocities, we determine the masses of
Kepler-20b and Kepler-20c to be 8.7\+-2.2 Mearth and 16.1+-3.5 Mearth,
respectively, and we place an upper limit on the mass of Kepler-20d of 20.1
Mearth (2 sigma).Comment: accepted by ApJ, 58 pages, 12 figures revised Jan 2012 to correct
table 2 and clarify planet parameter extractio
Transit Timing Observations from Kepler: III. Confirmation of 4 Multiple Planet Systems by a Fourier-Domain Study of Anti-correlated Transit Timing Variations
We present a method to confirm the planetary nature of objects in systems
with multiple transiting exoplanet candidates. This method involves a
Fourier-Domain analysis of the deviations in the transit times from a constant
period that result from dynamical interactions within the system. The
combination of observed anti-correlations in the transit times and mass
constraints from dynamical stability allow us to claim the discovery of four
planetary systems Kepler-25, Kepler-26, Kepler-27, and Kepler-28, containing
eight planets and one additional planet candidate.Comment: Accepted to MNRA
Planetary Candidates Observed by Kepler VI: Planet Sample from Q1-Q16 (47 Months)
\We present the sixth catalog of Kepler candidate planets based on nearly 4
years of high precision photometry. This catalog builds on the legacy of
previous catalogs released by the Kepler project and includes 1493 new Kepler
Objects of Interest (KOIs) of which 554 are planet candidates, and 131 of these
candidates have best fit radii <1.5 R_earth. This brings the total number of
KOIs and planet candidates to 7305 and 4173 respectively. We suspect that many
of these new candidates at the low signal-to-noise limit may be false alarms
created by instrumental noise, and discuss our efforts to identify such
objects. We re-evaluate all previously published KOIs with orbital periods of
>50 days to provide a consistently vetted sample that can be used to improve
planet occurrence rate calculations. We discuss the performance of our planet
detection algorithms, and the consistency of our vetting products. The full
catalog is publicly available at the NASA Exoplanet Archive.Comment: 18 pages, to be published in the Astrophysical Journal Supplement
Serie
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Genomic DNA transposition induced by human PGBD5
Transposons are mobile genetic elements that are found in nearly all organisms, including humans. Mobilization of DNA transposons by transposase enzymes can cause genomic rearrangements, but our knowledge of human genes derived from transposases is limited. In this study, we find that the protein encoded by human PGBD5, the most evolutionarily conserved transposable element-derived gene in vertebrates, can induce stereotypical cut-and-paste DNA transposition in human cells. Genomic integration activity of PGBD5 requires distinct aspartic acid residues in its transposase domain, and specific DNA sequences containing inverted terminal repeats with similarity to piggyBac transposons. DNA transposition catalyzed by PGBD5 in human cells occurs genome-wide, with precise transposon excision and preference for insertion at TTAA sites. The apparent conservation of DNA transposition activity by PGBD5 suggests that genomic remodeling contributes to its biological function. DOI: http://dx.doi.org/10.7554/eLife.10565.00
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