Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Targeting AKT Kinase in Hydroxytamoxifen-Resistant Breast Cancer Cells

More than 650,000 people die each year from breast cancer, making it a particularly significant disease worldwide. The development of about 70% of breast tumors depends on steroid hormones, namely, estrogens. Estrogens trigger signaling pathways that support tumor growth and progression. Hydroxytamoxifen (HT) halting estrogen-induced tumor growth is among the most effective drugs in current anticancer therapy. The purpose of this work was to investigate approaches to overcome breast cancer cell resistance to hydroxytamoxifen. Cells with resistance to the antiestrogen hydroxytamoxifen were obtained by long-term incubation of parental MCF7 cells with this drug. Estrogen receptor α (ERα) expression and progesterone receptor (PR) expression were analyzed by immunoblotting. The resistant MCF7/HT cells were found not to lose ERα expression. These cells were found to have slightly reduced ERα activity when compared to parental MCF7 cells. The expression of PR, one of the ERα targets, was downregulated in hydroxytamoxifen-resistant cells. AKT kinase belongs to the PI3K/AKT/mTOR signaling pathway, and its activity is associated with resistance. Three types of AKT inhibitors were evaluated, including AKT inhibitor IV (6-(2-benzothiazolyl)-1-ethyl-2-[2-(methylphenylamino)ethenyl]-3-phenyl-1H-benzimidazolium, monoiodide), 10-DEBC (2-chloro-N,N-diethyl-10H-phenoxazine-10-butanamine, monohydrochloride), and luminespib (HSP90 inhibitor, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide). All three compounds showed high antiproliferative activity against hydroxytamoxifen-resistant cells. The IC50 value of 10-DEBC was 4.2 µM, and this was when the AKT inhibitor IV was more active with IC50 value of 390 nM. The HSP90 inhibitor luminespib, which reduces AKT expression, showed the highest activity against parental and hydroxytamoxifen-resistant breast cancer cells, with IC50 values of 14 and 18 nM, respectively. Thus, the hydroxytamoxifen-resistant cells were found to partially retain hormone signaling and to be sensitive to selective AKT inhibitors. The best effects were discovered for HSP90-AKT blocker luminespib, with an IC50 value of about 20 nM

Design, Synthesis and In Vitro Investigation of Cabozantinib-Based PROTACs to Target c-Met Kinase

(1) Background: This investigation aimed at developing a series of c-Met-targeting cabozantinib-based PROTACs. (2) Methods: Purification of intermediate and target compounds was performed using column chromatography, in vitro antiproliferation activity was measured using a standard MTT assay and a c-Met degradation assay was performed via the immunoblotting technique. (3) Results: Several compounds exhibited antiproliferative activity towards different cell lines of breast cancer (T47D, MDA-MB-231, SKBR3, HCC1954 and MCF7) at the same level as parent cabozantinib and 7-demethyl cabozantinib. Two target conjugates, bearing a VHL-ligand as an E3-ligase binding moiety and glycol-based linkers, exhibited the effective inhibition of c-Met phosphorylation and an ability to decrease the level of c-Met in HCC1954 cells at micromolar concentrations. (4) Conclusions: Two compounds exhibit c-Met inhibition activity in the nanomolar range and can be considered as PROTAC molecules due to their ability to decrease the total level of c-Met in HCC1954 cells. The structures of the offered compounds can be used as starting points for further evaluation of cabozantinib-based PROTACs

High-quality green-emitting nanodiamonds fabricated by HPHT sintering of polycrystalline shockwave diamonds

Abstract We demonstrate a high-pressure, high-temperature sintering technique to form nitrogen-vacancy-nitrogen centres in nanodiamonds. Polycrystalline diamond nanoparticle precursors, with mean size of 25 nm, are produced by the shock wave from an explosion. These nanoparticles are sintered in the presence of ethanol, at a pressure of 7 GPa and temperature of 1300 °C, to produce substantially larger (3–4 times) diamond crystallites. The recorded spectral properties demonstrate the improved crystalline quality. The types of defects present are also observed to change; the characteristic spectral features of nitrogen-vacancy and silicon-vacancy centres present for the precursor material disappear. Two new characteristic features appear: (1) paramagnetic substitutional nitrogen (P1 centres with spin ½) with an electron paramagnetic resonance characteristic triplet hyperfine structure due to the I = 1 magnetic moment of the nitrogen nuclear spin and (2) the green spectral photoluminescence signature of the nitrogen-vacancy-nitrogen centres. This production method is a strong alternative to conventional high-energy particle beam irradiation. It can be used to easily produce purely green fluorescing nanodiamonds with advantageous properties for optical biolabelling applications

Measurement of electrons from heavy-flavour hadron decays in p–Pb collisions at √sNN = 5.02 TeV

The production of electrons from heavy-flavour hadron decays was measured as a function of transverse momentum (pT) in minimum-bias p–Pb collisions at √sNN = 5.02 TeV using the ALICE detector at the LHC. The measurement covers the pT interval 0.5 < pT < 12 GeV/c and the rapidity range −1.065 < ycms < 0.135 in the centre-of-mass reference frame. The contribution of electrons from background sources was subtracted using an invariant mass approach. The nuclear modification factor RpPb was calculated by comparing the pT-differential invariant cross section in p–Pb collisions to a pp reference at the same centre-of-mass energy, which was obtained by interpolating measurements at √s = 2.76 TeV and √s = 7 TeV. The RpPb is consistent with unity within uncertainties of about 25%, which become larger for pT below 1 GeV/c. The measurement shows that heavy-flavour production is consistent with binary scaling, so that a suppression in the high-pT yield in Pb–Pb collisions has to be attributed to effects induced by the hot medium produced in the final state. The data in p–Pb collisions are described by recent model calculations that include cold nuclear matter effects

Freeze-out radii extracted from three-pion cumulants in pp, p–Pb and Pb–Pb collisions at the LHC

In high-energy collisions, the spatio-temporal size of the particle production region can be measured using the Bose–Einstein correlations of identical bosons at low relative momentum. The source radii are typically extracted using two-pion correlations, and characterize the system at the last stage of interaction, called kinetic freeze-out. In low-multiplicity collisions, unlike in high-multiplicity collisions, two-pion correlations are substantially altered by background correlations, e.g. mini-jets. Such correlations can be suppressed using three-pion cumulant correlations. We present the first measurements of the size of the system at freeze-out extracted from three-pion cumulant correlations in pp, p–Pb and Pb–Pb collisions at the LHC with ALICE. At similar multiplicity, the invariant radii extracted in p–Pb collisions are found to be 5–15% larger than those in pp, while those in Pb–Pb are 35–55% larger than those in p–Pb. Our measurements disfavor models which incorporate substantially stronger collective expansion in p–Pb as compared to pp collisions at similar multiplicity