Development of a Cx46 Targeting Strategy for Cancer Stem Cells

Gap-junction-mediated cell-cell communication enables tumor cells to synchronize complex processes. We previously found that glioblastoma cancer stem cells (CSCs) express higher levels of the gap junction protein Cx46 compared to non-stem tumor cells (non-CSCs) and that this was necessary and sufficient for CSC maintenance. To understand the mechanism underlying this requirement, we use point mutants to disrupt specific functions of Cx46 and find that Cx46-mediated gap-junction coupling is critical for CSCs. To develop a Cx46 targeting strategy, we screen a clinically relevant small molecule library and identify clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuates proliferation, self-renewal, and tumor growth and synergizes with temozolomide to induce apoptosis. Although clofazimine does not cross the blood-brain barrier, the combination of clofazimine derivatives optimized for brain penetrance with standard-of-care therapies may target glioblastoma CSCs. Furthermore, these results demonstrate the importance of targeting cell-cell communication as an anti-cancer therapy

TET2 mutations as a part of DNA dioxygenase deficiency in myelodysplastic syndromes

Decrease in DNA dioxygenase activity generated by TET2 gene family is crucial in myelodysplastic syndromes (MDS). The general downregulation of 5-hydroxymethylcytosine (5-hmC) argues for a role of DNA demethylation in MDS beyond TET2 mutations, which albeit frequent, do not convey any prognostic significance. We investigated TETs expression to identify factors which can modulate the impact of mutations and thus 5-hmC levels on clinical phenotypes and prognosis of MDS patients. DNA/RNA-sequencing and 5-hmC data were collected from 1665 patients with MDS and 91 controls. Irrespective of mutations, a significant fraction of MDS patients exhibited lower TET2 expression, whereas 5-hmC levels were not uniformly decreased. In searching for factors explaining compensatory mechanisms, we discovered that TET3 was upregulated in MDS and inversely correlated with TET2 expression in wild type cases. Although TET2 was reduced across all age groups, TET3 levels were increased in a likely feedback mechanism induced by TET2 dysfunction. This inverse relationship of TET2 and TET3 expression also corresponded to the expression of L-2-hydroxyglutarate dehydrogenase, involved in agonist/antagonist substrate metabolism. Importantly, elevated TET3 levels influ-enced the clinical phenotype of TET2 deficiency whereby the lack of compensation by TET3 (low TET3 expression) was associated with poor outcomes of TET2 mutant carriers

Measurement of jet track functions in pp collisions at s=13 TeV with the ATLAS detector

Measurements of jet substructure are key to probing the energy frontier at colliders, and many of them use track-based observables which take advantage of the angular precision of tracking detectors. Theoretical calculations of track-based observables require ‘track functions’, which characterize the transverse momentum fraction rq carried by charged hadrons from a fragmenting quark or gluon. This letter presents a direct measurement of rq distributions in dijet events from the 140 fb−1 of proton–proton collisions at s=13 TeV recorded with the ATLAS detector. The data are corrected for detector effects using machine-learning methods. The scale evolution of the moments of the rq distribution is sensitive to non-linear renormalization group evolution equations of QCD, and is compared with analytic predictions. When incorporated into future theoretical calculations, these results will enable a precision program of theory-data comparison for track-based jet substructure observables

Search for a resonance decaying into a scalar particle and a Higgs boson in final states with leptons and two photons in proton-proton collisions at s = 13 TeV with the ATLAS detector

A search for a hypothetical heavy scalar particle, X, decaying into a singlet scalar particle, S, and a Standard Model Higgs boson, H, using 140 fb−1 of proton-proton collision data at the centre-of-mass energy of 13 TeV recorded with the ATLAS detector at the LHC is presented. The explored mass range is 300 ≤ mX ≤ 1000 GeV and 170 ≤ mS ≤ 500 GeV. The signature of this search is one or two leptons (e or μ) from the decay of vector bosons originating from the S particle, S → W±W∓/ZZ, and two photons from the Higgs boson decay, H → γγ. No significant excess is observed above the expected Standard Model background. The observed (expected) upper limits at the 95% confidence level on the cross- section for gg → X → SH, assuming the same S → WW/ZZ branching ratios as for a SM-like heavy Higgs boson, are between 530 (800) fb and 120 (170) fb

Search for heavy resonances decaying into a pair of Z bosons in the ℓ + ℓ - ℓ ′ + ℓ ′ - and ℓ + ℓ - ν ν ¯ final states using 139 fb - 1 of proton–proton collisions at s = 13 TeV with the ATLAS detector

Abstract: A search for heavy resonances decaying into a pair of Z bosons leading to ℓ+ℓ-ℓ′+ℓ′- and ℓ+ℓ-νν¯ final states, where ℓ stands for either an electron or a muon, is presented. The search uses proton–proton collision data at a centre-of-mass energy of 13 TeV collected from 2015 to 2018 that corresponds to the integrated luminosity of 139 fb-1 recorded by the ATLAS detector during Run 2 of the Large Hadron Collider. Different mass ranges spanning 200 GeV to 2000 GeV for the hypothetical resonances are considered, depending on the final state and model. In the absence of a significant observed excess, the results are interpreted as upper limits on the production cross section of a spin-0 or spin-2 resonance. The upper limits for the spin-0 resonance are translated to exclusion contours in the context of Type-I and Type-II two-Higgs-doublet models, and the limits for the spin-2 resonance are used to constrain the Randall–Sundrum model with an extra dimension giving rise to spin-2 graviton excitations

A detailed map of Higgs boson interactions by the ATLAS experiment ten years after the discovery

The standard model of particle physics1–4 describes the known fundamental particles and forces that make up our Universe, with the exception of gravity. One of the central features of the standard model is a field that permeates all of space and interacts with fundamental particles5–9. The quantum excitation of this field, known as the Higgs field, manifests itself as the Higgs boson, the only fundamental particle with no spin. In 2012, a particle with properties consistent with the Higgs boson of the standard model was observed by the ATLAS and CMS experiments at the Large Hadron Collider at CERN10,11. Since then, more than 30 times as many Higgs bosons have been recorded by the ATLAS experiment, enabling much more precise measurements and new tests of the theory. Here, on the basis of this larger dataset, we combine an unprecedented number of production and decay processes of the Higgs boson to scrutinize its interactions with elementary particles. Interactions with gluons, photons, and W and Z bosons—the carriers of the strong, electromagnetic and weak forces—are studied in detail. Interactions with three third-generation matter particles (bottom (b) and top (t) quarks, and tau leptons (τ)) are well measured and indications of interactions with a second-generation particle (muons, μ) are emerging. These tests reveal that the Higgs boson discovered ten years ago is remarkably consistent with the predictions of the theory and provide stringent constraints on many models of new phenomena beyond the standard model

Search for Higgs boson decays into a Z boson and a light hadronically decaying resonance in pp collisions at s=13 TeV with the ATLAS detector

A search for decays of the Higgs boson into a Z boson and a light resonance, with a mass of 0.5–3.5 GeV, is performed using the full 140 fb−1 dataset of 13 TeV proton–proton collisions recorded by the ATLAS detector during LHC Run 2. Leptonic decays of the Z boson and hadronic decays of the light resonance are considered. The resonance can be interpreted as a J/ψ or ηc meson, an axion-like particle, or a light pseudoscalar predicted in two-Higgs-doublet models. Due to its low mass, this resonance is produced with a high Lorentz boost in the laboratory frame and therefore reconstructed as a single small-radius jet of hadrons. A neural network is used to correct the Monte Carlo simulation of the total expected background using data from sideband regions. Two additional neural networks are used to distinguish signal from background, enhancing the purity of the signal region. A binned profile-likelihood fit is performed on the final-state invariant mass distribution. No significant excess of events relative to the expected background is observed, and upper limits at 95% confidence level are set on the Higgs boson's branching fraction to a Z boson and a light resonance. The exclusion limit is ∼10% for the lower masses, and increases for higher masses. Upper limits on the effective coupling CZHeff/Λ of an axion-like particle to a Higgs boson and Z boson are also set at 95% confidence level, and range from 0.9 to 2 TeV−1