Co-Depletion of Cathepsin B and uPAR Induces G0/G1 Arrest in Glioma via FOXO3a Mediated p27Kip1 Upregulation

Cathepsin B and urokinase plasminogen activator receptor (uPAR) are both known to be overexpressed in gliomas. Our previous work and that of others strongly suggest a relationship between the infiltrative phenotype of glioma and the expression of cathepsin B and uPAR. Though their role in migration and adhesion are well studied the effect of these molecules on cell cycle progression has not been thoroughly examined.Cathepsin B and uPAR single and bicistronic siRNA plasmids were used to downregulate these molecules in SNB19 and U251 glioma cells. FACS analysis and BrdU incorporation assay demonstrated G0/G1 arrest and decreased proliferation with the treatments, respectively. Immunoblot and immunocyto analysis demonstrated increased expression of p27(Kip1) and its nuclear localization with the knockdown of cathepsin B and uPAR. These effects could be mediated by alphaVbeta3/PI3K/AKT/FOXO pathway as observed by the decreased alphaVbeta3 expression, PI3K and AKT phosphorylation accompanied by elevated FOXO3a levels. These results were further confirmed with the increased expression of p27(Kip1) and FOXO3a when treated with Ly294002 (10 microM) and increased luciferase expression with the siRNA and Ly294002 treatments when the FOXO binding promoter region of p27(Kip1) was used. Our treatment also reduced the expression of cyclin D1, cyclin D2, p-Rb and cyclin E while the expression of Cdk2 was unaffected. Of note, the Cdk2-cyclin E complex formation was reduced significantly.Our study indicates that cathepsin B and uPAR knockdown induces G0/G1 arrest by modulating the PI3K/AKT signaling pathway and further increases expression of p27(Kip1) accompanied by the binding of FOXO3a to its promoter. Taken together, our findings provide molecular mechanism for the G0/G1 arrest induced by the downregulation of cathepsin B and uPAR in SNB19 and U251 glioma cells

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Observation of the Decay Λ0b→Λ+cτ−¯ν

The first observation of the semileptonic b-baryon decay Λb0→Λc+τ-ν¯τ, with a significance of 6.1σ, is reported using a data sample corresponding to 3 fb-1 of integrated luminosity, collected by the LHCb experiment at center-of-mass energies of 7 and 8 TeV at the LHC. The τ- lepton is reconstructed in the hadronic decay to three charged pions. The ratio K=B(Λb0→Λc+τ-ν¯τ)/B(Λb0→Λc+π-π+π-) is measured to be 2.46±0.27±0.40, where the first uncertainty is statistical and the second systematic. The branching fraction B(Λb0→Λc+τ-ν¯τ)=(1.50±0.16±0.25±0.23)% is obtained, where the third uncertainty is from the external branching fraction of the normalization channel Λb0→Λc+π-π+π-. The ratio of semileptonic branching fractions R(Λc+)B(Λb0→Λc+τ-ν¯τ)/B(Λb0→Λc+μ-ν¯μ) is derived to be 0.242±0.026±0.040±0.059, where the external branching fraction uncertainty from the channel Λb0→Λc+μ-ν¯μ contributes to the last term. This result is in agreement with the standard model prediction

Observation of the doubly charmed baryon decay Ξcc++→Ξc′+π+

The Ξcc++→Ξc′+π+ decay is observed using proton-proton collisions collected by the LHCb experiment at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 5.4 fb−1. The Ξcc++→Ξc′+π+ decay is reconstructed partially, where the photon from the Ξc′+→Ξc+γ decay is not reconstructed and the pK−π+ final state of the Ξc+ baryon is employed. The Ξcc++→Ξc′+π+branching fraction relative to that of the Ξcc++→Ξc+π+ decay is measured to be 1.41 ± 0.17 ± 0.10, where the first uncertainty is statistical and the second systematic. [Figure not available: see fulltext.

A study of CP violation in the decays B±→[K+K-π+π-]Dh± (h= K, π) and B±→[π+π-π+π-]Dh±

The first study of CP violation in the decay mode B±→[K+K-π+π-]Dh± , with h= K, π , is presented, exploiting a data sample of proton–proton collisions collected by the LHCb experiment that corresponds to an integrated luminosity of 9 \,fb - 1 . The analysis is performed in bins of phase space, which are optimised for sensitivity to local CP asymmetries. CP -violating observables that are sensitive to the angle γ of the Unitarity Triangle are determined. The analysis requires external information on charm-decay parameters, which are currently taken from an amplitude analysis of LHCb data, but can be updated in the future when direct measurements become available. Measurements are also performed of phase-space integrated observables for B±→[K+K-π+π-]Dh± and B±→[π+π-π+π-]Dh± decays

Measurement of antiproton production from antihyperon decays in pHe collisions at √sNN=110GeV

The interpretation of cosmic antiproton flux measurements from space-borne experiments is currently limited by the knowledge of the antiproton production cross-section in collisions between primary cosmic rays and the interstellar medium. Using collisions of protons with an energy of 6.5 TeV incident on helium nuclei at rest in the proximity of the interaction region of the LHCb experiment, the ratio of antiprotons originating from antihyperon decays to prompt production is measured for antiproton momenta between 12 and 110GeV\!/c . The dominant antihyperon contribution, namely Λ¯ → p¯ π+ decays from promptly produced Λ¯ particles, is also exclusively measured. The results complement the measurement of prompt antiproton production obtained from the same data sample. At the energy scale of this measurement, the antihyperon contributions to antiproton production are observed to be significantly larger than predictions of commonly used hadronic production models

Study of charmonium and charmonium-like contributions in B+ → J/ψηK+ decays

A study of B+→ J/ψηK+ decays, followed by J/ψ → μ+μ− and η → γγ, is performed using a dataset collected with the LHCb detector in proton-proton collisions at centre-of-mass energies of 7, 8 and 13 TeV, corresponding to an integrated luminosity of 9 fb−1. The J/ψη mass spectrum is investigated for contributions from charmonia and charmonium-like states. Evidence is found for the B+→ (ψ2(3823) → J/ψη)K+ and B+→ (ψ(4040) → J/ψη)K+ decays with significance of 3.4 and 4.7 standard deviations, respectively. This constitutes the first evidence for the ψ2(3823) → J/ψη decay

Angular analysis of D0→π+π−μ+μ−D^0 \to \pi^+\pi^-\mu^+\mu^- and D0→K+K−μ+μ−D^0 \to K^+K^-\mu^+\mu^- decays and search for CPCP violation

The first full angular analysis and an updated measurement of the decay-rate $CP$ asymmetry of the $D^0 \to \pi^+\pi^-\mu^+\mu^-$ and $D^0 \to K^+K^-\mu^+\mu^-$ decays are reported. The analysis uses proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7, 8 and 13 TeV. The data set corresponds to an integrated luminosity of 9 fb$^{-1}$. The full set of $CP$-averaged angular observables and their $CP$ asymmetries are measured as a function of the dimuon invariant mass. The results are consistent with expectations from the standard model and with $CP$ symmetry.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2021-035.html (LHCb public pages

Searches for rare Bs0 and B 0 decays into four muons

Searches for rare Bs0 and B0 decays into four muons are performed using proton-proton collision data recorded by the LHCb experiment, corresponding to an integrated luminosity of 9 fb−1. Direct decays and decays via light scalar and J/ψ resonances are considered. No evidence for the six decays searched for is found and upper limits at the 95% confidence level on their branching fractions ranging between 1.8 × 10−10 and 2.6 × 10−9 are set. [Figure not available: see fulltext.