Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

Measurement of Charged Particle Multiplicities and Densities in pp Collisions at √s = 7 TeV in the Forward Region

Charged particle multiplicities are studied in proton–proton collisions in the forward region at a centre-of-mass energy of √s = 7 TeV with data collected by the LHCb detector. The forward spectrometer allows access to a kinematic range of 2.0 &lt; η &lt; 4.8 in pseudorapidity, momenta greater than 2 GeV/c and transverse momenta greater than 0.2 GeV/c. The measurements are performed using events with at least one charged particle in the kinematic acceptance. The results are presented as functions of pseudorapidity and transverse momentum and are compared to predictions from several Monte Carlo event generators

Searches for B(s)0 →J/ψpp‾ B_{(s)}^0\ \to {J \left/ {{\psi p}} \right.}\overline{p} and B + → J/ψ p p‾ \overline{p} π + decays

The results of searches for B0(s)→J/ψ pp¯ and B + → J/ψ p p¯ π+ decays are reported. The analysis is based on a data sample, corresponding to an integrated luminosity of 1.0 fb−1 of pp collisions, collected with the LHCb detector. An excess with 2.8 σ significance is seen for the decay B0s→J/ψ pp¯ and an upper limit on the branching fraction is set at the 90 % confidence level: B(B0s→J/ψ pp¯) &#60; 4.8 × 10−6, which is the first such limit. No significant signals are seen for B 0 → J/ψ p p¯ and B + → J/ψ p p¯ π + decays, for which the corresponding limits are set: B(B0→J/ψ pp¯) &#60; 5.2 × 10−7, which significantly improves the existing limit; and B(B+→J/ψ pp¯π+) &#60; 5.0 × 10−7, which is the first limit on this branching fraction

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Measurement of CP asymmetries in D± → η′π± and Ds±→η′π± decays

A search for CP violation in D±→η′π± and Ds±→η′π± decays is performed using proton–proton collision data, corresponding to an integrated luminosity of 3 fb−1, recorded by the LHCb experiment at centre-of-mass energies of 7 and 8 TeV. The measured CP-violating charge asymmetries are ACP(D±→η′π±)=(−0.61±0.72±0.53±0.12)% and ACP(Ds±→η′π±)=(−0.82±0.36±0.22±0.27)%, where the first uncertainties are statistical, the second systematic, and the third are the uncertainties on the ACP(D±→KS0π±) and ACP(Ds±→φπ±) measurements used for calibration. The results represent the most precise measurements of these asymmetries to date

Model-independent measurement of mixing parameters in D0 → K S 0 π+π− decays

The first model-independent measurement of the charm mixing parameters in the decay D 0 → K S 0 π + π − is reported, using a sample of pp collision data recorded by the LHCb experiment, corresponding to an integrated luminosity of 1.0 fb−1 at a centre-of-mass energy of 7 TeV. The measured values are x=(−0.86±0.53±0.17)×10−2,y=(+0.03±0.46±0.13)×10−2, x=(−0.86±0.53±0.17)×10−2,y=(+0.03±0.46±0.13)×10−2, where the first uncertainties are statistical and include small contributions due to the external input for the strong phase measured by the CLEO collaboration, and the second uncertainties are systematic