Transporter Expressions as Part of Required Scaling Factor to Support In vitro In vivo Extrapolation for Blood-Brain Barrier Drug Permeability.

Access of drugs to the central nervous system is limited by the blood-brain barrier, and this in turn affects drug efficacy/toxicity. To date, most drug discovery optimization paradigms have relied heavily on in vitro transporter assays and preclinical species pharmacokinetic evaluation to provide a qualitative assessment of human brain penetration. Because of the lack of human brain pharmacokinetic data, mechanistic models for preclinical species, combined with in vitro and in silico data, are useful for translation to human.

Establishing a physiologically based pharmacokinetic framework for aldehyde oxidase and dual aldehyde oxidase-CYP substrates.

Aldehyde oxidase (AO) contributes to the clearance of many approved and investigational small molecule drugs, which are often dual substrates of AO and drug-metabolizing enzymes such as cytochrome P450s (CYPs). As such, the lack of established framework for quantitative translation of the clinical pharmacologic correlates of AO-mediated clearance represents an unmet need. This study aimed to evaluate the utility of physiologically based pharmacokinetic (PBPK) modeling in the development of AO and dual AO-CYP substrates.

Ontogeny of Human Liver Aldehyde Oxidase: Developmental Changes and Implications for Drug Metabolism.

Despite the increasing importance of aldehyde oxidase (AO) in the drug metabolism of clinical candidates, ontogeny data for AO are limited. The objective of our study was to characterize the age-dependent AO content and activity in the human liver cytosolic fraction (HLC) and human hepatocytes (HH). HLC ( = 121 donors) and HH ( = 50 donors) were analyzed for (1) AO protein content by quantitative proteomics and (2) enzyme activity using carbazeran as a probe substrate.

Challenges and Opportunities for In Vitro-In Vivo Extrapolation of Aldehyde Oxidase-Mediated Clearance: Toward a Roadmap for Quantitative Translation.

Underestimation of aldehyde oxidase (AO)-mediated clearance by current in vitro assays leads to uncertainty in human dose projections, thereby reducing the likelihood of success in drug development. In the present study we first evaluated the current drug development practices for AO substrates. Next, the overall predictive performance of in vitro-in vivo extrapolation of unbound hepatic intrinsic clearance (CL) and unbound hepatic intrinsic clearance by AO (CL) was assessed using a comprehensive literature database of in vitro (human cytosol/S9/hepatocytes) and in vivo (intravenous/oral) data collated for 22 AO substrates (total of 100 datapoints from multiple studies).

Azimuthal Correlations within Exclusive Dijets with Large Momentum Transfer in Photon-Lead Collisions.

The structure of nucleons is multidimensional and depends on the transverse momenta, spatial geometry, and polarization of the constituent partons. Such a structure can be studied using high-energy photons produced in ultraperipheral heavy-ion collisions. The first measurement of the azimuthal angular correlations of exclusively produced events with two jets in photon-lead interactions at large momentum transfer is presented, a process that is considered to be sensitive to the underlying nuclear gluon polarization.

Dissecting Parameters Contributing to the Underprediction of Aldehyde Oxidase-Mediated Metabolic Clearance of Drugs.

We investigated the effect of variability and instability in aldehyde oxidase (AO) content and activity on the scaling of in vitro metabolism data. AO content and activity in human liver cytosol (HLC) and five recombinant human AO preparations (rAO) were determined using targeted proteomics and carbazeran oxidation assay, respectively. AO content was highly variable as indicated by the relative expression factor (REF; i.

Industry Perspective on the Pharmacokinetic and Absorption, Distribution, Metabolism, and Excretion Characterization of Heterobifunctional Protein Degraders.

Targeted protein degraders (TPDs), specifically the bifunctional protein degraders discussed in this manuscript, consist of two linked ligands for a protein of interest and an E3 ligase, resulting in molecules that largely violate accepted physicochemical limits (e.g., Lipinski's Rule of Five) for oral bioavailability.

Measurements of the associated production of a W boson and a charm quark in proton-proton collisions at .

Measurements of the associated production of a W boson and a charm ( ) quark in proton-proton collisions at a centre-of-mass energy of 8 are reported. The analysis uses a data sample corresponding to a total integrated luminosity of 19.7 collected by the CMS detector at the LHC.

Search for low-mass dilepton resonances in Higgs boson decays to four-lepton final states in proton-proton collisions at .

A search for low-mass dilepton resonances in Higgs boson decays is conducted in the four-lepton final state. The decay is assumed to proceed via a pair of beyond the standard model particles, or one such particle and a boson. The search uses proton-proton collision data collected with the CMS detector at the CERN LHC, corresponding to an integrated luminosity of 137 , at a center-of-mass energy .

Using Z Boson Events to Study Parton-Medium Interactions in Pb-Pb Collisions.

The spectra measurements of charged hadrons produced in the shower of a parton originating in the same hard scattering with a leptonically decaying Z boson are reported in lead-lead nuclei (Pb-Pb) and proton-proton (pp) collisions at a nucleon-nucleon center-of-mass energy of 5.02 TeV. Both Pb-Pb and pp data sets are recorded by the CMS experiment at the LHC and correspond to an integrated luminosity of 1.

Search for strongly interacting massive particles generating trackless jets in proton-proton collisions at .

A search for dark matter in the form of strongly interacting massive particles (SIMPs) using the CMS detector at the LHC is presented. The SIMPs would be produced in pairs that manifest themselves as pairs of jets without tracks. The energy fraction of jets carried by charged particles is used as a key discriminator to suppress efficiently the large multijet background, and the remaining background is estimated directly from data.

Evidence for X(3872) in Pb-Pb Collisions and Studies of its Prompt Production at sqrt[s_{NN}]=5.02 TeV.

The first evidence for X(3872) production in relativistic heavy ion collisions is reported. The X(3872) production is studied in lead-lead (Pb-Pb) collisions at a center-of-mass energy of sqrt[s_{NN}]=5.02  TeV per nucleon pair, using the decay chain X(3872)→J/ψπ^{+}π^{-}→μ^{+}μ^{-}π^{+}π^{-}.

Precision luminosity measurement in proton-proton collisions at in 2015 and 2016 at CMS.

The measurement of the luminosity recorded by the CMS detector installed at LHC interaction point 5, using proton-proton collisions at in 2015 and 2016, is reported. The absolute luminosity scale is measured for individual bunch crossings using beam-separation scans (the van der Meer method), with a relative precision of 1.3 and 1.

Search for a heavy vector resonance decaying to a boson and a Higgs boson in proton-proton collisions at .

A search is presented for a heavy vector resonance decaying into a boson and the standard model Higgs boson, where the boson is identified through its leptonic decays to electrons, muons, or neutrinos, and the Higgs boson is identified through its hadronic decays. The search is performed in a Lorentz-boosted regime and is based on data collected from 2016 to 2018 at the CERN LHC, corresponding to an integrated luminosity of 137 . Upper limits are derived on the production of a narrow heavy resonance , and a mass below 3.

Development and validation of HERWIG 7 tunes from CMS underlying-event measurements.

This paper presents new sets of parameters ("tunes") for the underlying-event model of the event generator. These parameters control the description of multiple-parton interactions (MPI) and colour reconnection in , and are obtained from a fit to minimum-bias data collected by the CMS experiment at , 7, and . The tunes are based on the NNPDF 3.

Measurements of angular distance and momentum ratio distributions in three-jet and + two-jet final states in collisions.

Collinear (small-angle) and large-angle, as well as soft and hard radiations are investigated in three-jet and  + two-jet events collected in proton-proton collisions at the LHC. The normalized production cross sections are measured as a function of the ratio of transverse momenta of two jets and their angular separation. The measurements in the three-jet and  + two-jet events are based on data collected at a center-of-mass energy of 8 , corresponding to an integrated luminosity of 19.

MUSiC: a model-unspecific search for new physics in proton-proton collisions at .

Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 , corresponding to an integrated luminosity of 35.9 , are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model.

Measurements of production cross sections of the Higgs boson in the four-lepton final state in proton-proton collisions at .

Production cross sections of the Higgs boson are measured in the ( ) decay channel. A data sample of proton-proton collisions at a center-of-mass energy of 13 , collected by the CMS detector at the LHC and corresponding to an integrated luminosity of 137 is used. The signal strength modifier , defined as the ratio of the Higgs boson production rate in the channel to the standard model (SM) expectation, is measured to be at a fixed value of .

Measurement of the Higgs boson production rate in association with top quarks in final states with electrons, muons, and hadronically decaying tau leptons at .

The rate for Higgs ( ) bosons production in association with either one ( ) or two ( ) top quarks is measured in final states containing multiple electrons, muons, or tau leptons decaying to hadrons and a neutrino, using proton-proton collisions recorded at a center-of-mass energy of by the CMS experiment. The analyzed data correspond to an integrated luminosity of 137 . The analysis is aimed at events that contain , , or decays and each of the top quark(s) decays either to lepton+jets or all-jet channels.

Observation of Forward Neutron Multiplicity Dependence of Dimuon Acoplanarity in Ultraperipheral Pb-Pb Collisions at sqrt[s_{NN}]=5.02 TeV.

The first measurement of the dependence of γγ→μ^{+}μ^{-} production on the multiplicity of neutrons emitted very close to the beam direction in ultraperipheral heavy ion collisions is reported. Data for lead-lead interactions at sqrt[s_{NN}]=5.02  TeV, with an integrated luminosity of approximately 1.

Constraints on the Initial State of Pb-Pb Collisions via Measurements of Z-Boson Yields and Azimuthal Anisotropy at sqrt[s_{NN}]=5.02 TeV.

The CMS experiment at the LHC has measured the differential cross sections of Z bosons decaying to pairs of leptons, as functions of transverse momentum and rapidity, in lead-lead collisions at a nucleon-nucleon center-of-mass energy of 5.02  TeV. The measured Z boson elliptic azimuthal anisotropy coefficient is compatible with zero, showing that Z bosons do not experience significant final-state interactions in the medium produced in the collision.

Measurement of the Wγ Production Cross Section in Proton-Proton Collisions at sqrt[s]=13 TeV and Constraints on Effective Field Theory Coefficients.

A fiducial cross section for Wγ production in proton-proton collisions is measured at a center-of-mass energy of 13 TeV in 137  fb^{-1} of data collected using the CMS detector at the LHC. The W→eν and μν decay modes are used in a maximum-likelihood fit to the lepton-photon invariant mass distribution to extract the combined cross section. The measured cross section is compared with theoretical expectations at next-to-leading order in quantum chromodynamics.

Observation of a New Excited Beauty Strange Baryon Decaying to Ξ_{b}^{-}π^{+}π^{-}.

The Ξ_{b}^{-}π^{+}π^{-} invariant mass spectrum is investigated with an event sample of proton-proton collisions at sqrt[s]=13  TeV, collected by the CMS experiment at the LHC in 2016-2018 and corresponding to an integrated luminosity of 140  fb^{-1}. The ground state Ξ_{b}^{-} is reconstructed via its decays to J/ψΞ^{-} and J/ψΛK^{-}. A narrow resonance, labeled Ξ_{b}(6100)^{-}, is observed at a Ξ_{b}^{-}π^{+}π^{-} invariant mass of 6100.

Contribution of Extrahepatic Aldehyde Oxidase Activity to Human Clearance.

Aldehyde oxidase (AOX) is a soluble, cytosolic enzyme that metabolizes various -heterocyclic compounds and organic aldehydes. It has wide tissue distribution with highest levels found in liver, kidney, and lung. Human clearance projections of AOX substrates by in vitro assessments in isolated liver fractions (cytosol, S9) and even hepatocytes have been largely underpredictive of clinical outcomes.