Adaphostin toxicity in a sensitive non-small cell lung cancer model is mediated through Nrf2 signaling and heme oxygenase 1

<p>Abstract</p> <p>Background</p> <p>Preclinical toxicity of adaphostin has been related to oxidative stress. This study investigated the regulatory mechanism underlying adaphostin induction of heme oxygenase 1 (HMOX1) which plays a significant role in modulation of drug-induced toxicity in the non-small cell lung cancer cell line model, NCI-H522.</p> <p>Methods</p> <p>The transcriptional response of NCI-H522 to adaphostin prominently involved oxidative stress genes, particularly HMOX1. Reactive oxygen species (ROS) involvement was additionally established by generation of ROS prior to modulation of adaphostin-toxicity with antioxidants. To identify up-stream regulatory elements of HMOX1, immunofluorescence was used to evaluate nuclear translocation of the transcription factor, NF-E2-related factor 2 (Nrf2), in the presence of adaphostin. The PI3-kinase inhibitor, wortmannin, was employed as a pharmacological inhibitor of this process.</p> <p>Results</p> <p>Generation of ROS provided a substantial foundation for the sensitivity of NCI-H522 to adaphostin. However, in contrast to leukemia cell lines, transcriptional response to oxidative stress was associated with induction of HMOX1, which was dependent on nuclear translocation of the transcription factor, Nrf2. Pretreatment of cells with wortmannin inhibited translocation of Nrf2 and induction of HMOX1. Wortmannin pretreatment was also able to diminish adaphostin induction of HMOX1, and as a consequence, enhance the toxicity of adaphostin to NCI-H522.</p> <p>Conclusions</p> <p>Adaphostin-induced oxidative stress in NCI-H522 was mediated through nuclear translocation of Nrf2 leading to upregulation of HMOX1. Inhibition of Nrf2 translocation by wortmannin inhibited this cytoprotective response, and enhanced the toxicity of adaphostin, suggesting that inhibitors of the PI3K pathway, such as wortmannin, might augment the antiproliferative effects of adaphostin in solid tumors that depend on the Nrf2/ARE pathway for protection against oxidative stress.</p

Evaluation of the selectivity and sensitivity of isoform- and mutation-specific RAS antibodies

Researchers rely largely on antibodies to measure the abundance, activity, and localization of a protein, information that provides critical insight into both normal and pathological cellular functions. However, antibodies are not always reliable or universally valid for the methods in which they are used; in particular, the reliability of commercial antibodies against RAS is highly variable. Waters et al . rigorously assessed 22 commercially available RAS antibodies for their utility to detect the distinct RAS isoforms in various cell types and for their use in specific analytical methods. Their findings show how reliably one can interpret the data acquired from each reagent

Measurement of charged particle spectra in minimum-bias events from proton-proton collisions at root s =13 TeV

Pseudorapidity, transverse momentum, and multiplicity distributions are measured in the pseudorapidity range vertical bar eta vertical bar 0.5 GeV in proton-proton collisions at a center-of-mass energy of root s = 13 TeV. Measurements are presented in three different event categories. The most inclusive of the categories corresponds to an inelastic pp data set, while the other two categories are exclusive subsets of the inelastic sample that are either enhanced or depleted in single diffractive dissociation events. The measurements are compared to predictions from Monte Carlo event generators used to describe high-energy hadronic interactions in collider and cosmic-ray physics.Peer reviewe

Search for supersymmetric partners of electrons and muons in proton–proton collisions at s=13TeV

A search for direct production of the supersymmetric (SUSY) partners of electrons or muons is presented in final states with two opposite-charge, same-flavour leptons (electrons and muons), no jets, and large missing transverse momentum. The data sample corresponds to an integrated luminosity of 35.9 fb−1 of proton–proton collisions at s=13TeV, collected with the CMS detector at the LHC in 2016. The search uses the MT2 variable, which generalises the transverse mass for systems with two invisible objects and provides a discrimination against standard model backgrounds containing W bosons. The observed yields are consistent with the expectations from the standard model. The search is interpreted in the context of simplified SUSY models and probes slepton masses up to approximately 290, 400, and 450 GeV, assuming right-handed only, left-handed only, and both right- and left-handed sleptons (mass degenerate selectrons and smuons), and a massless lightest supersymmetric particle. Limits are also set on selectrons and smuons separately. These limits show an improvement on the existing limits of approximately 150 GeV.0info:eu-repo/semantics/publishe

Search for resonant pair production of Higgs bosons decaying to bottom quark-antiquark pairs in proton-proton collisions at 13 TeV

A search for a narrow-width resonance decaying into two Higgs bosons, each decaying into a bottom quark-antiquark pair, is presented. The search is performed using proton-proton collision data corresponding to an integrated luminosity of 35.9 fb$^{-1}$ at $\sqrt{s}=$ 13 TeV recorded by the CMS detector at the LHC. No evidence for such a signal is observed. Upper limits are set on the product of the production cross section for the resonance and the branching fraction for the selected decay mode in the resonance mass range from 260 to 1200 GeV