Optical imaging in vivo with a focus on paediatric disease: technical progress, current preclinical and clinical applications and future perspectives

To obtain information on the occurrence and location of molecular events as well as to track target-specific probes such as antibodies or peptides, drugs or even cells non-invasively over time, optical imaging (OI) technologies are increasingly applied. Although OI strongly contributes to the advances made in preclinical research, it is so far, with the exception of optical coherence tomography (OCT), only very sparingly applied in clinical settings. Nevertheless, as OI technologies evolve and improve continuously and represent relatively inexpensive and harmful methods, their implementation as clinical tools for the assessment of children disease is increasing. This review focuses on the current preclinical and clinical applications as well as on the future potential of OI in the clinical routine. Herein, we summarize the development of different fluorescence and bioluminescence imaging techniques for microscopic and macroscopic visualization of microstructures and biological processes. In addition, we discuss advantages and limitations of optical probes with distinct mechanisms of target-detection as well as of different bioluminescent reporter systems. Particular attention has been given to the use of near-infrared (NIR) fluorescent probes enabling observation of molecular events in deeper tissue

Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase

Introduction: Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance.Methods: Altered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy.Results: Moderate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression.Conclusions: Moderate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients

Combined measurement of differential and total cross sections in the H → γγ and the H → ZZ* → 4ℓ decay channels at s=13 TeV with the ATLAS detector

A combined measurement of differential and inclusive total cross sections of Higgs boson production is performed using 36.1 fb−1 of 13 TeV proton–proton collision data produced by the LHC and recorded by the ATLAS detector in 2015 and 2016. Cross sections are obtained from measured H→γγ and H→ZZ*(→4ℓ event yields, which are combined taking into account detector efficiencies, resolution, acceptances and branching fractions. The total Higgs boson production cross section is measured to be 57.0−5.9 +6.0 (stat.) −3.3 +4.0 (syst.) pb, in agreement with the Standard Model prediction. Differential cross-section measurements are presented for the Higgs boson transverse momentum distribution, Higgs boson rapidity, number of jets produced together with the Higgs boson, and the transverse momentum of the leading jet. The results from the two decay channels are found to be compatible, and their combination agrees with the Standard Model predictions

Operation and performance of the ATLAS Tile Calorimeter in Run 1

The Tile Calorimeter is the hadron calorimeter covering the central region of the ATLAS experiment at the Large Hadron Collider. Approximately 10,000 photomultipliers collect light from scintillating tiles acting as the active material sandwiched between slabs of steel absorber. This paper gives an overview of the calorimeter’s performance during the years 2008–2012 using cosmic-ray muon events and proton–proton collision data at centre-of-mass energies of 7 and 8TeV with a total integrated luminosity of nearly 30 fb−1. The signal reconstruction methods, calibration systems as well as the detector operation status are presented. The energy and time calibration methods performed excellently, resulting in good stability of the calorimeter response under varying conditions during the LHC Run 1. Finally, the Tile Calorimeter response to isolated muons and hadrons as well as to jets from proton–proton collisions is presented. The results demonstrate excellent performance in accord with specifications mentioned in the Technical Design Report

Performance of missing transverse momentum reconstruction with the ATLAS detector using proton–proton collisions at √s = 13 TeV

The performance of the missing transverse momentum (EmissT) reconstruction with the ATLAS detector is evaluated using data collected in proton–proton collisions at the LHC at a centre-of-mass energy of 13 TeV in 2015. To reconstruct EmissT, fully calibrated electrons, muons, photons, hadronically decaying τ -leptons, and jets reconstructed from calorimeter energy deposits and charged-particle tracks are used. These are combined with the soft hadronic activity measured by reconstructed charged-particle tracks not associated with the hard objects. Possible double counting of contributions from reconstructed charged-particle tracks from the inner detector, energy deposits in the calorimeter, and reconstructed muons from the muon spectrometer is avoided by applying a signal ambiguity resolution procedure which rejects already used signals when combining the various EmissT contributions. The individual terms as well as the overall reconstructed EmissT are evaluated with various performance metrics for scale (linearity), resolution, and sensitivity to the data-taking conditions. The method developed to determine the systematic uncertainties of the EmissT scale and resolution is discussed. Results are shown based on the full 2015 data sample corresponding to an integrated luminosity of 3.2 fb−1

Search for pairs of highly collimated photon-jets in pp collisions at √s = 13 TeV with the ATLAS detector

Results of a search for the pair production of photon-jets—collimated groupings of photons—in the ATLAS detector at the Large Hadron Collider are reported. Highly collimated photon-jets can arise from the decay of new, highly boosted particles that can decay to multiple photons collimated enough to be identified in the electromagnetic calorimeter as a single, photonlike energy cluster. Data from proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 36.7  fb−1, were collected in 2015 and 2016. Candidate photon-jet pair production events are selected from those containing two reconstructed photons using a set of identification criteria much less stringent than that typically used for the selection of photons, with additional criteria applied to provide improved sensitivity to photon-jets. Narrow excesses in the reconstructed diphoton mass spectra are searched for. The observed mass spectra are consistent with the Standard Model background expectation. The results are interpreted in the context of a model containing a new, high-mass scalar particle with narrow width, X, that decays into pairs of photon-jets via new, light particles, a. Upper limits are placed on the cross section times the product of branching ratios σ×B(X→aa)×B(a→γγ)2 for 200  GeV<mX<2  TeV and for ranges of ma from a lower mass of 100 MeV up to between 2 and 10 GeV, depending upon mX. Upper limits are also placed on σ×B(X→aa)×B(a→3π0)2 for the same range of mX and for ranges of ma from a lower mass of 500 MeV up to between 2 and 10 GeV

Search for squarks and gluinos in final states with jets and missing transverse momentum using 139 fb−1 of s√ = 13 TeV pp collision data with the ATLAS detector

A search for the supersymmetric partners of quarks and gluons (squarks and gluinos) in final states containing jets and missing transverse momentum, but no electrons or muons, is presented. The data used in this search were recorded by the ATLAS experiment in proton-proton collisions at a centre-of-mass energy of s√ = 13 TeV during Run 2 of the Large Hadron Collider, corresponding to an integrated luminosity of 139 fb−1. The results are interpreted in the context of various R-parity-conserving models where squarks and gluinos are produced in pairs or in association and a neutralino is the lightest supersymmetric particle. An exclusion limit at the 95% confidence level on the mass of the gluino is set at 2.30 TeV for a simplified model containing only a gluino and the lightest neutralino, assuming the latter is massless. For a simplified model involving the strong production of mass-degenerate first- and second-generation squarks, squark masses below 1.85 TeV are excluded if the lightest neutralino is massless. These limits extend substantially beyond the region of supersymmetric parameter space excluded previously by similar searches with the ATLAS detector

Measurement of Azimuthal Anisotropy of Muons from Charm and Bottom Hadrons in pp Collisions at √s = 13 TeV with the ATLAS Detector

The elliptic flow of muons from the decay of charm and bottom hadrons is measured in p p collisions at √ s = 13     TeV using a data sample with an integrated luminosity of 150     pb − 1 recorded by the ATLAS detector at the LHC. The muons from heavy-flavor decay are separated from light-hadron decay muons using momentum imbalance between the tracking and muon spectrometers. The heavy-flavor decay muons are further separated into those from charm decay and those from bottom decay using the distance-of-closest-approach to the collision vertex. The measurement is performed for muons in the transverse momentum range 4–7 GeV and pseudorapidity range | η | < 2.4 . A significant nonzero elliptic anisotropy coefficient v 2 is observed for muons from charm decays, while the v 2 value for muons from bottom decays is consistent with zero within uncertainties

Properties of jet fragmentation using charged particles measured with the ATLAS detector in pp collisions at root s=13 TeV

This paper presents a measurement of quantities related to the formation of jets from high-energy quarks and gluons (fragmentation). Jets with transverse momentum 100 GeV 500 MeV and |η| < 2.5 are used to probe the detailed structure of the jet. The fragmentation properties of the more forward and the more central of the two leading jets from each event are studied. The data are unfolded to correct for detector resolution and acceptance effects. Comparisons with parton shower Monte Carlo generators indicate that existing models provide a reasonable description of the data across a wide range of phase space, but there are also significant differences. Furthermore, the data are interpreted in the context of quark- and gluon-initiated jets by exploiting the rapidity dependence of the jet flavor fraction. A first measurement of the charged-particle multiplicity using model-independent jet labels (topic modeling) provides a promising alternative to traditional quark and gluon extractions using input from simulation. The simulations provide a reasonable description of the quark-like data across the jet Pt range presented in -this measurement, but the gluon-like data have systematically fewer charged particles than the simulation

Reconstruction and identification of boosted di-τ systems in a search for Higgs boson pairs using 13 TeV proton-proton collision data in ATLAS

In this paper, a new technique for reconstructing and identifying hadronically decaying τ+τ− pairs with a large Lorentz boost, referred to as the di-τ tagger, is developed and used for the first time in the ATLAS experiment at the Large Hadron Collider. A benchmark di-τ tagging selection is employed in the search for resonant Higgs boson pair production, where one Higgs boson decays into a boosted bb¯¯ pair and the other into a boosted τ+τ− pair, with two hadronically decaying τ-leptons in the final state. Using 139 fb−1 of proton-proton collision data recorded at a centre-of-mass energy of 13 TeV, the efficiency of the di-τ tagger is determined and the background with quark- or gluon-initiated jets misidentified as di-τ objects is estimated. The search for a heavy, narrow, scalar resonance produced via gluon-gluon fusion and decaying into two Higgs bosons is carried out in the mass range 1–3 TeV using the same dataset. No deviations from the Standard Model predictions are observed, and 95% confidence-level exclusion limits are set on this model