Race and smoking status associated with paclitaxel drug response in patient-derived lymphoblastoid cell lines

The use of ex-vivo model systems to provide a level of forecasting for in-vivo characteristics remains an important need for cancer therapeutics. The use of lymphoblastoid cell lines (LCLs) is an attractive approach for pharmacogenomics and toxicogenomics, due to their scalability, efficiency, and cost-effectiveness. There is little data on the impact of demographic or clinical covariates on LCL response to chemotherapy. Paclitaxel sensitivity was determined in LCLs from 93 breast cancer patients from the University of North Carolina Lineberger Comprehensive Cancer Center Breast Cancer Database to test for potential associations and/or confounders in paclitaxel dose-response assays. Measures of paclitaxel cell viability were associated with patient data included treatment regimens, cancer status, demographic and environmental variables, and clinical outcomes. We used multivariate analysis of variance to identify the in-vivo variables associated with ex-vivo dose-response. In this unique dataset that includes both in-vivo and ex-vivo data from breast cancer patients, race (P = 0.0049) and smoking status (P = 0.0050) were found to be significantly associated with ex-vivo dose-response in LCLs. Racial differences in clinical dose-response have been previously described, but the smoking association has not been reported. Our results indicate that in-vivo smoking status can influence ex-vivo dose-response in LCLs, and more precise measures of covariates may allow for more precise forecasting of clinical effect. In addition, understanding the mechanism by which exposure to smoking in-vivo effects ex-vivo dose-response in LCLs may open up new avenues in the quest for better therapeutic prediction

Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2

The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold possess outstanding potency and selectivity for CSNK2, but bioavailability and metabolic stability are often challenging. By strategically installing a fluorine atom on an electron-rich phenyl ring of a previously characterized inhibitor 1, we discovered compound 2 as a promising lead compound with improved in vivo metabolic stability. Compound 2 maintained excellent cellular potency against CSNK2, submicromolar antiviral potency, and favorable solubility, and was remarkably selective for CSNK2 when screened against 192 kinases across the human kinome. We additionally present a co-crystal structure to support its on-target binding mode. In vivo, compound 2 was orally bioavailable, and demonstrated modest and transient inhibition of CSNK2, although antiviral activity was not observed, possibly attributed to its lack of prolonged CSNK2 inhibition

More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-a]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication

The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-a]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53. Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of 53 in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an antiviral target in vivo

Genetic variants in CPA6 and PRPF31 are associated with variation in response to metformin in individuals with type 2 diabetes

Metformin is the first-line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here, we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA 1c response to metformin treatment and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6 were associated with worse and better metformin response, respectively (P < 5 3 10 26 ), and meta-analysis in independent cohorts displayed similar associations with metformin response (P = 1.2 3 10 2 8 and P = 0.005, respectively). Previous studies have shown that PRPF31(+/2) knockout mice have increased total body fat (P = 1.78 3 10 26 ) and increased fasted circulating glucose (P = 5.73 3 10 26 ). Furthermore, rare variants in STAT3 associated with worse metformin response (q <0.1). STAT3 is a ubiquitously expressed pleiotropic transcriptional activator that participates in the regulation of metabolism and feeding behavior. Here, we provide novel evidence for associations of common and rare variants in PRPF31, CPA6, and STAT3 with metformin response that may provide insight into mechanisms important for metformin efficacy in T2D

Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10 -6 ). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D

Measurement of the cross section for isolated-photon plus jet production in pp collisions at √s=13 TeV using the ATLAS detector

The dynamics of isolated-photon production in association with a jet in proton–proton collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset with an integrated luminosity of 3.2 fb−1. Photons are required to have transverse energies above 125 GeV. Jets are identified using the anti- algorithm with radius parameter and required to have transverse momenta above 100 GeV. Measurements of isolated-photon plus jet cross sections are presented as functions of the leading-photon transverse energy, the leading-jet transverse momentum, the azimuthal angular separation between the photon and the jet, the photon–jet invariant mass and the scattering angle in the photon–jet centre-of-mass system. Tree-level plus parton-shower predictions from Sherpa and Pythia as well as next-to-leading-order QCD predictions from Jetphox and Sherpa are compared to the measurements

A search for resonances decaying into a Higgs boson and a new particle X in the XH → qqbb final state with the ATLAS detector

A search for heavy resonances decaying into a Higgs boson (H) and a new particle (X) is reported, utilizing 36.1 fb−1 of proton–proton collision data at collected during 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. The particle X is assumed to decay to a pair of light quarks, and the fully hadronic final state is analysed. The search considers the regime of high XH resonance masses, where the X and H bosons are both highly Lorentz-boosted and are each reconstructed using a single jet with large radius parameter. A two-dimensional phase space of XH mass versus X mass is scanned for evidence of a signal, over a range of XH resonance mass values between 1 TeV and 4 TeV, and for X particles with masses from 50 GeV to 1000 GeV. All search results are consistent with the expectations for the background due to Standard Model processes, and 95% CL upper limits are set, as a function of XH and X masses, on the production cross-section of the resonance

Multiplicity dependence of inclusive J/psi production at midrapidity in pp collisions at root s=13 TeV

Measurements of the inclusive J/psi yield as a function of charged-particle pseudorapidity density dN(ch)/d eta in pp collisions at root s = 13 TeV with ALICE at the LHC are reported. The J/psi meson yield is measured at midrapidity (vertical bar y vertical bar <0.9) in the dielectron channel, for events selected based on the charged-particle multiplicity at midrapidity (vertical bar eta vertical bar <1) and at forward rapidity (-3.7 <eta <-1.7 and 2.8 <eta <5.1); both observables are normalized to their corresponding averages in minimum bias events. The increase of the normalized J/psi yield with normalized dN(ch)/d eta is significantly stronger than linear and dependent on the transverse momentum. The data are compared to theoretical predictions, which describe the observed trends well, albeit not always quantitatively. (C) 2020 European Organization for Nuclear Research. Published by Elsevier B.V.Peer reviewe

Searches for lepton-flavour-violating decays of the Higgs boson in s=13\sqrt{s}=13 TeV pp\mathit{pp} collisions with the ATLAS detector

This Letter presents direct searches for lepton flavour violation in Higgs boson decays, H → eτ and H → μτ , performed with the ATLAS detector at the LHC. The searches are based on a data sample of proton–proton collisions at a centre-of-mass energy √s = 13 TeV, corresponding to an integrated luminosity of 36.1 fb−1. No significant excess is observed above the expected background from Standard Model processes. The observed (median expected) 95% confidence-level upper limits on the leptonflavour-violating branching ratios are 0.47% (0.34+0.13−0.10%) and 0.28% (0.37+0.14−0.10%) for H → eτ and H → μτ , respectively.publishedVersio

Combination of searches for Higgs boson pairs in pp collisions at \sqrts = 13 TeV with the ATLAS detector

This letter presents a combination of searches for Higgs boson pair production using up to 36.1 fb(-1) of proton-proton collision data at a centre-of-mass energy root s = 13 TeV recorded with the ATLAS detector at the LHC. The combination is performed using six analyses searching for Higgs boson pairs decaying into the b (b) over barb (b) over bar, b (b) over barW(+)W(-), b (b) over bar tau(+)tau(-), W+W-W+W-, b (b) over bar gamma gamma and W+W-gamma gamma final states. Results are presented for non-resonant and resonant Higgs boson pair production modes. No statistically significant excess in data above the Standard Model predictions is found. The combined observed (expected) limit at 95% confidence level on the non-resonant Higgs boson pair production cross-section is 6.9 (10) times the predicted Standard Model cross-section. Limits are also set on the ratio (kappa(lambda)) of the Higgs boson self-coupling to its Standard Model value. This ratio is constrained at 95% confidence level in observation (expectation) to -5.0 &lt; kappa(lambda) &lt; 12.0 (-5.8 &lt; kappa(lambda) &lt; 12.0). In addition, limits are set on the production of narrow scalar resonances and spin-2 Kaluza-Klein Randall-Sundrum gravitons. Exclusion regions are also provided in the parameter space of the habemus Minimal Supersymmetric Standard Model and the Electroweak Singlet Model. For complete list of authors see http://dx.doi.org/10.1016/j.physletb.2019.135103</p