2,159 research outputs found
A novel approach to identify driver genes involved in androgen-independent prostate cancer
Abstract
Background
Insertional mutagenesis screens have been used with great success to identify oncogenes and tumor suppressor genes. Typically, these screens use gammaretroviruses (ÎłRV) or transposons as insertional mutagens. However, insertional mutations from replication-competent ÎłRVs or transposons that occur later during oncogenesis can produce passenger mutations that do not drive cancer progression. Here, we utilized a replication-incompetent lentiviral vector (LV) to perform an insertional mutagenesis screen to identify genes in the progression to androgen-independent prostate cancer (AIPC).
Methods
Prostate cancer cells were mutagenized with a LV to enrich for clones with a selective advantage in an androgen-deficient environment provided by a dysregulated gene(s) near the vector integration site. We performed our screen using an in vitro AIPC model and also an in vivo xenotransplant model for AIPC. Our approach identified proviral integration sites utilizing a shuttle vector that allows for rapid rescue of plasmids in E. coli that contain LV long terminal repeat (LTR)-chromosome junctions. This shuttle vector approach does not require PCR amplification and has several advantages over PCR-based techniques.
Results
Proviral integrations were enriched near prostate cancer susceptibility loci in cells grown in androgen-deficient medium (pâ<â0.001), and five candidate genes that influence AIPC were identified; ATPAF1, GCOM1, MEX3D, PTRF, and TRPM4. Additionally, we showed that RNAi knockdown of ATPAF1 significantly reduces growth (pâ<â0.05) in androgen-deficient conditions.
Conclusions
Our approach has proven effective for use in PCa, identifying a known prostate cancer gene, PTRF, and also several genes not previously associated with prostate cancer. The replication-incompetent shuttle vector approach has broad potential applications for cancer gene discovery, and for interrogating diverse biological and disease processes.http://deepblue.lib.umich.edu/bitstream/2027.42/109477/1/12943_2014_Article_1323.pd
An Improved Canine Genome and a Comprehensive Catalogue of Coding Genes and Non-Coding Transcripts
The domestic dog, Canis familiaris, is a well-established model system for mapping trait and disease loci. While the original draft sequence was of good quality, gaps were abundant particularly in promoter regions of the genome, negatively impacting the annotation and study of candidate genes. Here, we present an improved genome build, canFam3.1, which includes 85 MB of novel sequence and now covers 99.8% of the euchromatic portion of the genome. We also present multiple RNA-Sequencing data sets from 10 different canine tissues to catalog âŒ175,000 expressed loci. While about 90% of the coding genes previously annotated by EnsEMBL have measurable expression in at least one sample, the number of transcript isoforms detected by our data expands the EnsEMBL annotations by a factor of four. Syntenic comparison with the human genome revealed an additional âŒ3,000 loci that are characterized as protein coding in human and were also expressed in the dog, suggesting that those were previously not annotated in the EnsEMBL canine gene set. In addition to âŒ20,700 high-confidence protein coding loci, we found âŒ4,600 antisense transcripts overlapping exons of protein coding genes, âŒ7,200 intergenic multi-exon transcripts without coding potential, likely candidates for long intergenic non-coding RNAs (lincRNAs) and âŒ11,000 transcripts were reported by two different library construction methods but did not fit any of the above categories. Of the lincRNAs, about 6,000 have no annotated orthologs in human or mouse. Functional analysis of two novel transcripts with shRNA in a mouse kidney cell line altered cell morphology and motility. All in all, we provide a much-improved annotation of the canine genome and suggest regulatory functions for several of the novel non-coding transcripts
Measurement of ISR-FSR interference in the processes e+ e- --> mu+ mu- gamma and e+ e- --> pi+ pi- gamma
Charge asymmetry in processes e+ e- --> mu+ mu- gamma and e+ e- --> pi+ pi-
gamma is measured using 232 fb-1 of data collected with the BABAR detector at
center-of-mass energies near 10.58 GeV. An observable is introduced and shown
to be very robust against detector asymmetries while keeping a large
sensitivity to the physical charge asymmetry that results from the interference
between initial and final state radiation. The asymmetry is determined as
afunction of the invariant mass of the final-state tracks from production
threshold to a few GeV/c2. It is compared to the expectation from QED for e+ e-
--> mu+ mu- gamma and from theoretical models for e+ e- --> pi+ pi- gamma. A
clear interference pattern is observed in e+ e- --> pi+ pi- gamma, particularly
in the vicinity of the f_2(1270) resonance. The inferred rate of lowest order
FSR production is consistent with the QED expectation for e+ e- --> mu+ mu-
gamma, and is negligibly small for e+ e- --> pi+ pi- gamma.Comment: 32 pages,29 figures, to be submitted to Phys. Rev.
Recommended from our members
Measurement of B(B-->X_s {\gamma}), the B-->X_s {\gamma} photon energy spectrum, and the direct CP asymmetry in B-->X_{s+d} {\gamma} decays
The photon spectrum in B --> X_s {\gamma} decay, where X_s is any strange
hadronic state, is studied using a data sample of (382.8\pm 4.2) \times 10^6
e^+ e^- --> \Upsilon(4S) --> BBbar events collected by the BABAR experiment at
the PEP-II collider. The spectrum is used to measure the branching fraction B(B
--> X_s \gamma) = (3.21 \pm 0.15 \pm 0.29 \pm 0.08)\times 10^{-4} and the
first, second, and third moments = 2.267 \pm 0.019 \pm 0.032 \pm
0.003 GeV,, )^2> = 0.0484 \pm 0.0053 \pm 0.0077 \pm
0.0005 GeV^2, and )^3> = -0.0048 \pm 0.0011 \pm 0.0011
\pm 0.0004 GeV^3, for the range E_\gamma > 1.8 GeV, where E_{\gamma} is the
photon energy in the B-meson rest frame. Results are also presented for
narrower E_{\gamma} ranges. In addition, the direct CP asymmetry A_{CP}(B -->
X_{s+d} \gamma) is measured to be 0.057 \pm 0.063. The spectrum itself is also
unfolded to the B-meson rest frame; that is the frame in which theoretical
predictions for its shape are made.Comment: 37 pages, 19 postscript figures, submitted to Phys. Rev. D. No
analysis or results have changed from previous version. Some changes to
improve clarity based on interactions with Phys. Rev. D referees, including
one new Figure (Fig. 13), and some minor wording/punctuation/spelling
mistakes fixe
Improved Limits on decays to invisible final states
We establish improved upper limits on branching fractions for B0 decays to
final States 10 where the decay products are purely invisible (i.e., no
observable final state particles) and for final states where the only visible
product is a photon. Within the Standard Model, these decays have branching
fractions that are below the current experimental sensitivity, but various
models of physics beyond the Standard Model predict significant contributions
for these channels. Using 471 million BB pairs collected at the Y(4S) resonance
by the BABAR experiment at the PEP-II e+e- storage ring at the SLAC National
Accelerator Laboratory, we establish upper limits at the 90% confidence level
of 2.4x10^-5 for the branching fraction of B0-->Invisible and 1.7x10^-5 for the
branching fraction of B0-->Invisible+gammaComment: 8 pages, 3 postscript figures, submitted to Phys. Rev. D (Rapid
Communications
Recommended from our members
Precise Measurement of the e+ e- --> pi+ pi- (gamma) Cross Section with the Initial-State Radiation Method at BABAR
A precise measurement of the cross section of the process
from threshold to an energy of 3GeV is obtained
with the initial-state radiation (ISR) method using 232fb of data
collected with the BaBar detector at center-of-mass energies near
10.6GeV. The ISR luminosity is determined from a study of the leptonic process
, which is found to agree with the
next-to-leading-order QED prediction to within 1.1%. The cross section for the
process is obtained with a systematic uncertainty
of 0.5% in the dominant resonance region. The leading-order hadronic
contribution to the muon magnetic anomaly calculated using the measured
cross section from threshold to 1.8GeV is .Comment: 58 pages, 56 figures, to be submitted to Phys. Rev.
Measurement of Branching Fractions and Rate Asymmetries in the Rare Decays B -> K(*) l+ l-
In a sample of 471 million BB events collected with the BABAR detector at the
PEP-II e+e- collider we study the rare decays B -> K(*) l+ l-, where l+ l- is
either e+e- or mu+mu-. We report results on partial branching fractions and
isospin asymmetries in seven bins of di-lepton mass-squared. We further present
CP and lepton-flavor asymmetries for di-lepton masses below and above the J/psi
resonance. We find no evidence for CP or lepton-flavor violation. The partial
branching fractions and isospin asymmetries are consistent with the Standard
Model predictions and with results from other experiments.Comment: 16 pages, 14 figures, accepted by Phys. Rev.
Branching fraction and form-factor shape measurements of exclusive charmless semileptonic B decays, and determination of |V_{ub}|
We report the results of a study of the exclusive charmless semileptonic
decays, B^0 --> pi^- l^+ nu, B^+ --> pi^0 l^+ nu, B^+ --> omega l^+ nu, B^+ -->
eta l^+ nu and B^+ --> eta^' l^+ nu, (l = e or mu) undertaken with
approximately 462x10^6 B\bar{B} pairs collected at the Upsilon(4S) resonance
with the BABAR detector. The analysis uses events in which the signal B decays
are reconstructed with a loose neutrino reconstruction technique. We obtain
partial branching fractions in several bins of q^2, the square of the momentum
transferred to the lepton-neutrino pair, for B^0 --> pi^- l^+ nu, B^+ --> pi^0
l^+ nu, B^+ --> omega l^+ nu and B^+ --> eta l^+ nu. From these distributions,
we extract the form-factor shapes f_+(q^2) and the total branching fractions
BF(B^0 --> pi^- l^+ nu) = (1.45 +/- 0.04_{stat} +/- 0.06_{syst})x10^-4
(combined pi^- and pi^0 decay channels assuming isospin symmetry), BF(B^+ -->
omega l^+ nu) = (1.19 +/- 0.16_{stat} +/- 0.09_{syst})x10^-4 and BF(B^+ --> eta
l^+ nu) = (0.38 +/- 0.05_{stat} +/- 0.05_{syst})x10^-4. We also measure BF(B^+
--> eta^' l^+ nu) = (0.24 +/- 0.08_{stat} +/- 0.03_{syst})x10^-4. We obtain
values for the magnitude of the CKM matrix element V_{ub} by direct comparison
with three different QCD calculations in restricted q^2 ranges of B --> pi l^+
nu decays. From a simultaneous fit to the experimental data over the full q^2
range and the FNAL/MILC lattice QCD predictions, we obtain |V_{ub}| = (3.25 +/-
0.31)x10^-3, where the error is the combined experimental and theoretical
uncertainty.Comment: 35 pages, 14 figures, submitted to PR
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