Efficacy and epigenetic interactions of novel DNA hypomethylating agent guadecitabine (SGI-110) in preclinical models of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a deadly malignancy characterized at the epigenetic level by global DNA hypomethylation and focal hypermethylation on the promoter of tumor suppressor genes. In most cases it develops on a background of liver steatohepatitis, fibrosis, and cirrhosis. Guadecitabine (SGI-110) is a second-generation hypomethylating agent, which inhibits DNA methyltransferases. Guadecitabine is formulated as a dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase (CDA) degradation and results in prolonged in vivo exposure to decitabine following small volume subcutaneous administration of guadecitabine. Here we found that guadecitabine is an effective demethylating agent and is able to prevent HCC progression in pre-clinical models. In a xenograft HCC HepG2 model, guadecitabine impeded tumor growth and inhibited angiogenesis, while it could not prevent liver fibrosis and inflammation in a mouse model of steatohepatitis. Demethylating efficacy of guadecitabine on LINE-1 elements was found to be the highest 8 d post-infusion in blood samples of mice. Analysis of a panel of human HCC vs. normal tissue revealed a signature of hypermethylated tumor suppressor genes (CDKN1A, CDKN2A, DLEC1, E2F1, GSTP1, OPCML, E2F1, RASSF1, RUNX3, and SOCS1) as detected by methylation-specific PCR. A pronounced demethylating effect of guadecitabine was obtained also in the promoters of a subset of tumor suppressors genes (CDKN2A, DLEC1, and RUNX3) in HepG2 and Huh-7 HCC cells. Finally, we analyzed the role of macroH2A1, a variant of histone H2A, an oncogene upregulated in human cirrhosis/HCC that synergizes with DNA methylation in suppressing tumor suppressor genes, and it prevents the inhibition of cell growth triggered by decitabine in HCC cells. Guadecitabine, in contrast to decitabine, blocked growth in HCC cells overexpressing macroH2A1 histones and with high CDA levels, despite being unable to fully demethylate CDKN2A, RUNX3, and DLEC1 promoters altered by macroH2A1. Collectively, our findings in human and mice models reveal novel epigenetic anti-HCC effects of guadecitabine, which might be effective specifically in advanced states of the disease

Exponential stability of the wave equation with memory and time delay

We study the asymptotic behaviour of the wave equation with viscoelastic damping in presence of a time-delayed damping. We prove exponential stability if the amplitude of the time delay term is small enough

Detection of an optical transient following the 13 March 2000 short/hard gamma-ray burst

We imaged the error box of a gamma-ray burst of the short (0.5 s), hard type (GRB 000313), with the BOOTES-1 experiment in southern Spain, starting 4 min after the gamma-ray event, in the I-band. A bright optical transient (OT 000313) with I = 9.4 +/- 0.1 was found in the BOOTES-1 image, close to the error box (3-sigma) provided by BATSE. Late time VRIK'-band deep observations failed to reveal an underlying host galaxy. If the OT 000313 is related to the short, hard GRB 000313, this would be the first optical counterpart ever found for this kind of events (all counterparts to date have been found for bursts of the long, soft type). The fact that only prompt optical emission has been detected (but no afterglow emission at all, as supported by theoretical models) might explain why no optical counterparts have ever been found for short, hard GRBs.This fact suggests that most short bursts might occur in a low-density medium and favours the models that relate them to binary mergers in very low-density enviroments.Comment: Revised version. Accepted for publication in Astronomy and Astrophysics Letters, 5 pages, 3 figure

Lack of superstable trajectories in linear viscoelasticity: a numerical approach

Given a positive operator $A$ on some Hilbert space, and a nonnegative decreasing summable function $\mu$, we consider the abstract equation with memory $$\ddot u(t)+ A u(t)- \int_0^t \mu(s)Au(t-s) ds=0$$ modeling the dynamics of linearly viscoelastic solids. The purpose of this work is to provide numerical evidence of the fact that the energy \E(t)=\Big(1-\int_0^t\mu(s)ds\Big)\|u(t)\|^2_1+\|\dot u(t)\|^2 +\int_0^t\mu(s)\|u(t)-u(t-s)\|^2_1ds, of any nontrivial solution cannot decay faster than exponential, no matter how fast might be the decay of the memory kernel $\mu$. This will be accomplished by simulating the integro-differential equation for different choices of the memory kernel $\mu$ and of the initial data

Delayed benign surgery during the COVID-19 pandemic. The other side of the coin

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Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum