The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukemia cells through downregulation of Mcl-1

The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose- and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression. However, normal B and T cells were less sensitive than CLL cells (P=0.006 and P<0.001, respectively). SSA altered the splicing of anti-apoptotic MCL-1L to MCL-1s in CLL cells coincident with induction of apoptosis. Overexpression studies in Ramos cells suggested Mcl-1 was important for SSA-induced killing since its expression inversely correlated with apoptosis (P=0.001). IL4 and CD40L, present in patient lymph nodes, are known to protect tumor cells from apoptosis and significantly inhibited SSA, ABT-263 and ABT-199 induced killing following administration to CLL cells (P=0.008). However, by combining SSA with the Bcl-2/Bcl-xL antagonists ABT-263 or ABT-199, we were able to overcome this pro-survival effect. We conclude that SSA combined with Bcl-2/Bcl-xL antagonists may have therapeutic utility for CL

Large genomic aberrations detected by SNP array are independent prognosticators of a shorter time to first treatment in chronic lymphocytic leukemia patients with normal FISH

Background Genomic complexity can predict the clinical course of patients affected by chronic lymphocytic leukemia (CLL) with a normal FISH. However, large studies are still lacking. Here, we analyzed a large series of CLL patients and also carried out the so far largest comparison of FISH versus single-nucleotide polymorphism (SNP) array in this disease. Patients and methods SNP-array data were derived from a previously reported dataset. Results Seventy-seven of 329 CLL patients (23%) presented with a normal FISH. At least one large (>5 Mb) genomic aberration was detected by SNP array in 17 of 77 patients (22%); this finding significantly affected TTT. There was no correlation with the presence of TP53 mutations. In multivariate analysis, including age, Binet stage, IGHV genes mutational status and large genomic lesion, the latter three factors emerged as independent prognosticators. The concordance between FISH and SNP array varied between 84 and 97%, depending on the specific genomic locus investigated. Conclusions SNP array detected additional large genomic aberrations not covered by the standard FISH panel predicting the outcome of CLL patient

Correcting pervasive errors in RNA crystallography through enumerative structure prediction

Three-dimensional RNA models fitted into crystallographic density maps exhibit pervasive conformational ambiguities, geometric errors and steric clashes. To address these problems, we present enumerative real-space refinement assisted by electron density under Rosetta (ERRASER), coupled to Python-based hierarchical environment for integrated 'xtallography' (PHENIX) diffraction-based refinement. On 24 data sets, ERRASER automatically corrects the majority of MolProbity-assessed errors, improves the average Rfree factor, resolves functionally important discrepancies in noncanonical structure and refines low-resolution models to better match higher-resolution models

Measurement of Exclusive rho^0 rho^0 Production in Two-Photon Collisions at High Q^2 at LEP

Exclusive rho rho production in two-photon collisions involving a single highly virtual photon is studied with data collected at LEP at centre-of-mass energies 89GeV < \sqrt{s} < 209GeV with a total integrated luminosity of 854.7pb^-1 The cross section of the process gamma gamma^* -> rho rho is determined as a function of the photon virtuality, Q^2 and the two-photon centre-of-mass energy, Wgg, in the kinematic region: 1.2GeV^2 < Q^2 < 30GeV^2 and 1.1GeV < Wgg < 3GeV

Search for a Higgs Boson Decaying to Weak Boson Pairs at LEP

A Higgs particle produced in association with a Z boson and decaying into weak boson pairs is searched for in 336.4 1/pb of data collected by the L3 experiment at LEP at centre-of-mass energies from 200 to 209 GeV. Limits on the branching fraction of the Higgs boson decay into two weak bosons as a function of the Higgs mass are derived. These results are combined with the L3 search for a Higgs boson decaying to photon pairs. A Higgs produced with a Standard Model e+e- --> Zh cross section and decaying only into electroweak boson pairs is excluded at 95% CL for a mass below 107 GeV

Search for an invisibly decaying Higgs boson in e^+e^- collisions at \sqrt{s} = 183 - 189 GeV

A search for a Higgs boson decaying into invisible particles is performed using the data collected at LEP by the L3 experiment at centre-of-mass energies of 183 GeV and 189 GeV. The integrated luminosities are respectively 55.3 pb^-1 and 176.4 pb^-1. The observed candidates are consistent with the expectations from Standard Model processes. In the hypothesis that the production cross section of this Higgs boson equals the Standard Model one and the branching ratio into invisible particles is 100%, a lower mass limit of 89.2 GeV is set at 95% confidence level

Search for Manifestations of New Physics in Fermion-Pair Production at LEP

The measurements of hadron and lepton-pair production cross sections and leptonic forward-backward asymmetries performed with the L3 detector at centre-of-mass energies between 130 GeV and 189 GeV are used to search for new physics phenomena such as: contact interactions, exchange of virtual leptoquarks, scalar quarks and scalar neutrinos, effects of TeV strings in models of quantum gravity with large extra dimensions and non-zero sizes of the fermions. No evidence for these phenomena is found and new limits on their parameters are set

Higgs Candidates in e+e- Interactions at root(s) = 206.6 GeV

In a search for the Standard Model Higgs boson, carried out on 212.5 pb-1 of data collected by the L3 detector at the highest LEP centre-of-mass energies, including 116.5 pb-1 above root(s) = 206GeV, an excess of candidates for the process e+e- -> Z* -> HZ is found for Higgs masses near 114.5GeV. We present an analysis of our data and the characteristics of our strongest candidates.Comment: Footnote added, matches the version to be published in Physics Letters

Measurement of the Tau Branching Fractions into Leptons

Using data collected with the L3 detector near the Z resonance, corresponding to an integrated luminosity of 150pb-1, the branching fractions of the tau lepton into electron and muon are measured to be B(tau->e nu nu) = (17.806 +- 0.104 (stat.) +- 0.076 (syst.)) %, B(tau->mu nu nu) = (17.342 +- 0.110 (stat.) +- 0.067 (syst.)) %. From these results the ratio of the charged current coupling constants of the muon and the electron is determined to be g_mu/g_e = 1.0007 +- 0.0051. Assuming electron-muon universality, the Fermi constant is measured in tau lepton decays as G_F = (1.1616 +- 0.0058) 10^{-5} GeV^{-2}. Furthermore, the coupling constant of the strong interaction at the tau mass scale is obtained as alpha_s(m_tau^2) = 0.322 +- 0.009 (exp.) +- 0.015 (theory)

Measurement of Hadron and Lepton-Pair Production at 130GeV < \sqrt{s} < 189 GeV at LEP

We report on measurements of e+e- annihilation into hadrons and lepton pairs. The data have been collected with the L3 detector at LEP at centre-of-mass energies between 130 and 189 GeV. Using a total integrated luminosity of 243.7 pb^-1, 25864 hadronic and 8573 lepton-pair events are selected for the measurement of cross sections and leptonic forward-backward asymmetries. The results are in good agreement with Standard Model predictions