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

Evidence for WW production from double-parton interactions in proton–proton collisions at √s = 13 TeV

A search for WW production from double-parton scattering processes using same-charge electron-muon and dimuon events is reported, based on proton-proton collision data collected at a center-of-mass energy of 13 TeV. The analyzed data set corresponds to an integrated luminosity of 77.4fb⁻¹, collected using the CMS detector at the LHC in 2016 and 2017. Multivariate classifiers are used to discriminate between the signal and the dominant background processes. A maximum likelihood fit is performed to extract the signal cross section. This leads to the first evidence for WW production via double-parton scattering, with a significance of 3.9 standard deviations. The measured inclusive cross section is 1.41±0.28(stat)±0.28(syst)pb

Searches for physics beyond the standard model with the M_(T2) variable in hadronic final states with and without disappearing tracks in proton–proton collisions at √s = 13 TeV

Two related searches for phenomena beyond the standard model (BSM) are performed using events with hadronic jets and significant transverse momentum imbalance. The results are based on a sample of proton–proton collisions at a center-of-mass energy of 13TeV, collected by the CMS experiment at the LHC in 2016–2018 and corresponding to an integrated luminosity of 137fb⁻¹. The first search is inclusive, based on signal regions defined by the hadronic energy in the event, the jet multiplicity, the number of jets identified as originating from bottom quarks, and the value of the kinematic variable M_(T2) for events with at least two jets. For events with exactly one jet, the transverse momentum of the jet is used instead. The second search looks in addition for disappearing tracks produced by BSM long-lived charged particles that decay within the volume of the tracking detector. No excess event yield is observed above the predicted standard model background. This is used to constrain a range of BSM models that predict the following: the pair production of gluinos and squarks in the context of supersymmetry models conserving R-parity, with or without intermediate long-lived charginos produced in the decay chain; the resonant production of a colored scalar state decaying to a massive Dirac fermion and a quark; or the pair production of scalar and vector leptoquarks each decaying to a neutrino and a top, bottom, or light-flavor quark. In most of the cases, the results obtained are the most stringent constraints to date

Search for low mass vector resonances decaying into quark-antiquark pairs in proton-proton collisions at √s = 13 TeV

A search for low mass narrow vector resonances decaying into quark-antiquark pairs is presented. The analysis is based on data collected in 2017 with the CMS detector at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 41.1  fb⁻¹. The results of this analysis are combined with those of an earlier analysis based on data collected at the same collision energy in 2016, corresponding to 35.9  fb⁻¹. Signal candidates will be recoiling against initial state radiation and are identified as energetic, large-radius jets with two pronged substructure. The invariant jet mass spectrum is probed for a potential narrow peaking signal over a smoothly falling background. No evidence for such resonances is observed within the mass range of 50–450 GeV. Upper limits at the 95% confidence level are set on the coupling of narrow resonances to quarks, as a function of the resonance mass. For masses between 50 and 300 GeV these are the most sensitive limits to date. This analysis extends the earlier search to a mass range of 300–450 GeV, which is probed for the first time with jet substructure techniques

Search for Higgs and Z boson decays to J/ψ or Y pairs in the four-muon final state in proton-proton collisions at √s = 13 TeV

A search for decays of the Higgs and Z boson to pairs of J/ψ or Y(nS) (n = 1, 2, 3) mesons, with their subsequent decay to μ^+μ^− pairs, is presented. The analysis uses data from proton-proton collisions at √s = 13 TeV, collected with the CMS detector at the LHC in 2017 and corresponding to an integrated luminosity of 37.5fb^(-1). While an observation of such a decay with this sample would indicate the presence of physics beyond the standard model, no significant excess is observed. Upper limits at 95% confidence level are placed on the branching fractions of these decays. In the J/ψ pair channel, the limits are 1.8×10^(-3) and 2.2×10^(-6) for the Higgs and Z boson, respectively, while in the combined Y(nS) pair channel, the limits are 1.4×10^(-3) and 1.5×10^(-6), respectively, when the mesons from the Higgs and Z boson decay are assumed to be unpolarized. When fully longitudinal and transverse polarizations are considered the limits reduce by about 22–29% and increase by about 10–13%, respectively