The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.

ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated.MethodsA randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699).ResultsTofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo.ConclusionsTofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response.Trial registration numberNCT00976599

Thirty Years After Michael E. Porter: What Do We Know About Business Exit?

Although a business exit is an important corporate change initiative, the buyer’s side seems to be more appealing to management researchers than the seller’s because acquisitions imply growth, i.e., success. Yet from an optimistic viewpoint, business exit can effectively create value for the selling company. In this paper we attempt to bring the relevance of the seller’s side back into our consciousness by asking: What do we know about business exit? We start our exploration with Porter (1976), focusing on literature that investigates the antecedents of, barriers to, and outcomes of business exit. We also include studies from related fields such as finance and economics.1 Through this research we determine three clusters of findings: factors promoting business exit, exit barriers, and exit outcomes. Overall, it is the intention of this paper to highlight the importance of business exit for research and practice. Knowing what we know about business exits and their high financial value we should bear in mind that exit need not mean failure but a new beginning for a corporation

Studies of the Response of the Prototype CMS Hadron Calorimeter, Including Magnetic Field Effects, to Pion, Electron, and Muon Beams

We report on the response of a prototype CMS hadron calorimeter module to charged particle beams of pions, muons, and electrons with momenta up to 375 GeV/c. The data were taken at the H2 and H4 beamlines at CERN in 1995 and 1996. The prototype sampling calorimeter used copper absorber plates and scintillator tiles with wavelength shifting fibers for readout. The effects of a magnetic field of up to 3 Tesla on the response of the calorimeter to muons, electrons, and pions are presented, and the effects of an upstream lead tungstate crystal electromagnetic calorimeter on the linearity and energy resolution of the combined calorimetric system to hadrons are evaluated. The results are compared with Monte Carlo simulations and are used to optimize the choice of total absorber depth, sampling frequency, and longitudinal readout segmentation.Comment: 89 pages, 41 figures, to be published in NIM, corresponding author: P de Barbaro, [email protected]

An Analysis of the Corporate Cash Holding Decision

We investigate the tradeoff theory as an explanation for how managers allocate cash to post-spin-off parent and subsidiary firms. Spin-offs provide an opportunity to examine the determinants of cash holdings free from the confounding effects of the pecking order theory. Our results indicate that difference in asset size, sales growth, research and development expenses, net working capital, and leverage significantly affect the difference in cash holdings of post-spin-off entities. These results suggest that cash holdings are decreasing in the ease of raising cash and availability of cash from internal sources, and are increasing in growth opportunities, asymmetric information levels, and financial distress costs

Geochronological studies in Santa Barbara Basin: <SUP>55</SUP>Fe as a unique tracer for particulate settling

Sediments accumulate in the Santa Barbara Basin relatively rapidly: about 3-4 mm yr-1 based on the analysis of varves. These deposits are ideal for studying the applicability of nuclear geochronological techniques in a natural situation. Studies of the depth distribution of several radionuclides, manmade 55Fe and naturally occurring 210Pb and Th isotopes, in recent Santa Barbara sediment layers permit an evaluation of the geochemical behavior of Fe, Pb, and Th in coastal waters and have established the usefulness of 55Fe and 210Pb for dating coastial or near coastal sediments deposited during the last decade and half-century respectively

A modeling assessment of the role of reversible scavenging in controlling oceanic dissolved Cu and Zn distributions

The balance of processes that control elemental distributions in the modern oceans is important in understanding both their internal recycling and the rate and nature of their eventual output to sediment. Here we seek to evaluate the likely controls on the vertical profiles of Cu and Zn. Though the concentrations of both Cu and Zn increase with depth, Cu increases in a more linear fashion than Zn, which exhibits a typical "nutrient-type" profile. Both elements are bioessential, and biological uptake and regeneration has often been cited as an important process in controlling their vertical distribution. In this study, we investigate the likely importance of another key vertical process, that of passive scavenging on sinking particles, via a simple one-dimensional model of reversible scavenging. We find that, despite the absence of lateral or vertical water advection, mixing, diffusion, or biological uptake, our reversible scavenging model is very successful in replicating dissolved Cu concentration profiles on a range of geographic scales. We provide preliminary constraints on the scavenging coefficients for Cu for a spectrum of particle types (calcium carbonate, opal, particulate organic carbon, and dust) while emphasizing the fit of the shape of the modeled profile to that of the tracer data. In contrast to Cu, and reaffirming the belief that Zn behaves as a true micronutrient, the scavenging model is a poor match to the shape of oceanic Zn profiles. Modeling a single vertical process simultaneously highlights the importance of lateral advection in generating high Zn concentrations in the deep Pacific. Key Points A 1-D reversible scavenging model is applied to oceanic [Cu] and [Zn]Dissolved Cu is well described by the process of reversible scavengingDissolved Zn is not, reflecting its behaviour as a true nutrient-type element ©2013. American Geophysical Union. All Rights Reserved