A mammalian functional-genetic approach to characterizing cancer therapeutics

Supplementary information is available online at http://www.nature.com/naturechemicalbiology/. Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/.Identifying mechanisms of drug action remains a fundamental impediment to the development and effective use of chemotherapeutics. Here we describe an RNA interference (RNAi)–based strategy to characterize small-molecule function in mammalian cells. By examining the response of cells expressing short hairpin RNAs (shRNAs) to a diverse selection of chemotherapeutics, we could generate a functional shRNA signature that was able to accurately group drugs into established biochemical modes of action. This, in turn, provided a diversely sampled reference set for high-resolution prediction of mechanisms of action for poorly characterized small molecules. We could further reduce the predictive shRNA target set to as few as eight genes and, by using a newly derived probability-based nearest-neighbors approach, could extend the predictive power of this shRNA set to characterize additional drug categories. Thus, a focused shRNA phenotypic signature can provide a highly sensitive and tractable approach for characterizing new anticancer drugs.National Institute of Mental Health (U.S.) (grant RO1 CA128803-03)American Association for Cancer ResearchMassachusetts Institute of Technology. Dept. of BiologyNational Cancer Institute (U.S.). Integrative Cancer Biology Program (grant 1-U54-CA112967

Search for lepton-number violating processes in B+ -> h- l+ l+ decays

We have searched for the lepton-number violating processes B+ -> h- l+ l+ with h- = K-/pi- and l+ = e+/mu+, using a sample of 471+/-3 million BBbar events collected with the BaBar detector at the PEP-II e+e- collider at the SLAC National Accelerator Laboratory. We find no evidence for these decays and place 90% confidence level upper limits on their branching fractions Br(B+ -> pi- e+ e+) K- e+ e+) pi- mu+ mu+) K- mu+ mu+) < 6.7 x 10^{-8}.Comment: 8 pages, 4 postscript figures, submitted to Phys. Rev. D. R

Measurement of the Time-Dependent CP Asymmetry of Partially Reconstructed B0->D*+D*- Decays

We present a new measurement of the time-dependent CP asymmetry of B0->D*+D*- decays using (471+-5) million BBbar pairs collected with the BaBar detector at the PEP-II B Factory at the SLAC National Accelerator Laboratory. Using the technique of partial reconstruction, we measure the time-dependent CP asymmetry parameters S=-0.34+-0.12+-0.05$ and C=+0.15+-0.09+-0.04. Using the value for the CP-odd fraction R_perp=0.158+-0.028+-0.006, previously measured by BaBar with fully reconstructed B0->D*+D*- events, we extract the CP-even components S+=-0.49+-0.18+-0.07+-0.04 and C+=+0.15+-0.09+-0.04. In each case, the first uncertainty is statistical and the second is systematic; the third uncertainty on S+ is the contribution from the uncertainty on R_perp. The measured value of the CP-even component S+ is consistent with the value of sin(2Beta) measured in b->(ccbar)s transitions, and with the Standard Model expectation of small penguin contributions.Comment: 17 pages, 7 figures, submitted to Physical Review

Improved Limits on B0B^{0} decays to invisible (+γ)(+\gamma) 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

Study of Upsilon(3S,2S) -> eta Upsilon(1S) and Upsilon(3S,2S) -> pi+pi- Upsilon(1S) hadronic trasitions

We study the Upsilon(3S,2S)->eta Upsilon(1S) and Upsilon(3S,2S)->pi+pi- Upsilon(1S) transitions with 122 million Upsilon(3S) and 100 million Upsilon(2S) mesons collected by the BaBar detector at the PEP-II asymmetric energy e+e- collider. We measure B[Upsilon(2S)->eta Upsilon(1S)]=(2.39+/-0.31(stat.)+/-0.14(syst.))10^-4 and Gamma[Upsilon(2S)->eta Upsilon(1S)]/Gamma[Upsilon(2S)-> pi+pi- Upsilon(1S)]=(1.35+/-0.17(stat.)+/-0.08(syst.))10^-3. We find no evidence for Upsilon(3S)->eta Upsilon(1S) and obtain B[Upsilon(3S)->eta Upsilon(1S)]<1.0 10^-4 and Gamma[Upsilon(3S)->eta Upsilon(1S)]/Gamma[Upsilon(3S)->pi+pi- Upsilon(1S)]<2.3 10^-3 as upper limits at the 90% confidence level. We also provide improved measurements of the Upsilon(2S) - Upsilon(1S) and Upsilon(3S) - Upsilon(1S) mass differences, 562.170+/-0.007(stat.)+/-0.088(syst.) MeV/c^2 and 893.813+/-0.015(stat.)+/-0.107(syst.) MeV/c^2 respectively.Comment: 8 pages, 16 encapsulated postscript figures, submitted to Phys.Rev.

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 $e^+e^-\to\pi^+\pi^-(\gamma)$ from threshold to an energy of 3GeV is obtained with the initial-state radiation (ISR) method using 232fb$^{-1}$ of data collected with the BaBar detector at $e^+e^-$ center-of-mass energies near 10.6GeV. The ISR luminosity is determined from a study of the leptonic process $e^+e^-\to\mu^+\mu^-(\gamma)\gamma_{\rm ISR}$, which is found to agree with the next-to-leading-order QED prediction to within 1.1%. The cross section for the process $e^+e^-\to\pi^+\pi^-(\gamma)$ is obtained with a systematic uncertainty of 0.5% in the dominant $\rho$ resonance region. The leading-order hadronic contribution to the muon magnetic anomaly calculated using the measured $\pi\pi$ cross section from threshold to 1.8GeV is $(514.1 \pm 2.2({\rm stat}) \pm 3.1({\rm syst}))\times 10^{-10}$.Comment: 58 pages, 56 figures, to be submitted to Phys. Rev.

Cross Sections for the Reactions e+e- --> K+ K- pi+pi-, K+ K- pi0pi0, and K+ K- K+ K- Measured Using Initial-State Radiation Events

We study the processes e+e- --> K+ K- pi+pi-gamma, K+ K- pi0pi0gamma, and K+ K- K+ K-gamma, where the photon is radiated from the initial state. About 84000, 8000, and 4200 fully reconstructed events, respectively, are selected from 454 fb-1 of BaBar data. The invariant mass of the hadronic final state defines the \epem center-of-mass energy, so that the K+ K- pi+pi- data can be compared with direct measurements of the e+e- --> K+ K- pi+pi- reaction. No direct measurements exist for the e+e- --> K+ K-pi0pi0 or e+e- --> K+ K-K+ K- reactions, and we present an update of our previous result with doubled statistics. Studying the structure of these events, we find contributions from a number of intermediate states, and extract their cross sections. In particular, we perform a more detailed study of the e+e- --> phi(1020)pipigamma reaction, and confirm the presence of the Y(2175) resonance in the phi(1020) f0(980) and K+K-f0(980) modes. In the charmonium region, we observe the J/psi in all three final states and in several intermediate states, as well as the psi(2S) in some modes, and measure the corresponding product of branching fraction and electron width.Comment: 35 pages, 42 figure

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

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

Study of CP violation in Dalitz-plot analyses of B0 --> K+K-KS, B+ --> K+K-K+, and B+ --> KSKSK+

We perform amplitude analyses of the decays $B^0 \to K^+K^-K^0_S$, $B^+ \rightarrow K^+K^-K^+$, and $B^+ \to K^0_S K^0_S K^+$, and measure CP-violating parameters and partial branching fractions. The results are based on a data sample of approximately $470\times 10^6$ $B\bar{B}$ decays, collected with the BABAR detector at the PEP-II asymmetric-energy $B$ factory at the SLAC National Accelerator Laboratory. For $B^+ \to K^+K^-K^+$, we find a direct CP asymmetry in $B^+ \to \phi(1020)K^+$ of $A_{CP}= (12.8\pm 4.4 \pm 1.3)$, which differs from zero by $2.8 \sigma$. For $B^0 \to K^+K^-K^0_S$, we measure the CP-violating phase $\beta_{\rm eff} (\phi(1020)K^0_S) = (21\pm 6 \pm 2)^\circ$. For $B^+ \to K^0_S K^0_S K^+$, we measure an overall direct CP asymmetry of $A_{CP} = (4 ^{+4}_{-5} \pm 2)$. We also perform an angular-moment analysis of the three channels, and determine that the $f_X(1500)$ state can be described well by the sum of the resonances $f_0(1500)$, $f_2^{\prime}(1525)$, and $f_0(1710)$.Comment: 35 pages, 68 postscript figures. v3 - minor modifications to agree with published versio