Genetic Variation and Antioxidant Response Gene Expression in the Bronchial Airway Epithelium of Smokers at Risk for Lung Cancer

Prior microarray studies of smokers at high risk for lung cancer have demonstrated that heterogeneity in bronchial airway epithelial cell gene expression response to smoking can serve as an early diagnostic biomarker for lung cancer. As a first step in applying functional genomic analysis to population studies, we have examined the relationship between gene expression variation and genetic variation in a central molecular pathway (NRF2-mediated antioxidant response) associated with smoking exposure and lung cancer. We assessed global gene expression in histologically normal airway epithelial cells obtained at bronchoscopy from smokers who developed lung cancer (SC, n=20), smokers without lung cancer (SNC, n=24), and never smokers (NS, n=8). Functional enrichment analysis showed that the NRF2-mediated, antioxidant response element (ARE)-regulated genes, were significantly lower in SC, when compared with expression levels in SNC. Importantly, we found that the expression of MAFG (a binding partner of NRF2) was correlated with the expression of ARE genes, suggesting MAFG levels may limit target gene induction. Bioinformatically we identified single nucleotide polymorphisms (SNPs) in putative ARE genes and to test the impact of genetic variation, we genotyped these putative regulatory SNPs and other tag SNPs in selected NRF2 pathway genes. Sequencing MAFG locus, we identified 30 novel SNPs and two were associated with either gene expression or lung cancer status among smokers. This work demonstrates an analysis approach that integrates bioinformatics pathway and transcription factor binding site analysis with genotype, gene expression and disease status to identify SNPs that may be associated with individual differences in gene expression and/or cancer status in smokers. These polymorphisms might ultimately contribute to lung cancer risk via their effect on the airway gene expression response to tobacco-smoke exposure.Intramural Research Program of the National Institute of Environmental Health Sciences; National Institutes of Health (Z01 ES100475, U01ES016035, R01CA124640

Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study.

BackgroundCabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts.Patients and methodsEligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS).ResultsAmong the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients.ConclusionsCabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.Trial registration numberNCT00940225

Roots of the derivative of the Riemann zeta function and of characteristic polynomials

We investigate the horizontal distribution of zeros of the derivative of the Riemann zeta function and compare this to the radial distribution of zeros of the derivative of the characteristic polynomial of a random unitary matrix. Both cases show a surprising bimodal distribution which has yet to be explained. We show by example that the bimodality is a general phenomenon. For the unitary matrix case we prove a conjecture of Mezzadri concerning the leading order behavior, and we show that the same follows from the random matrix conjectures for the zeros of the zeta function.Comment: 24 pages, 6 figure

Next-to-leading order jet distributions for Higgs boson production via weak-boson fusion

The weak-boson fusion process is expected to provide crucial information on Higgs boson couplings at the Large Hadron Collider at CERN. The achievable statistical accuracy demands comparison with next-to-leading order QCD calculations, which are presented here in the form of a fully flexible parton Monte Carlo program. QCD corrections are determined for jet distributions and are shown to be modest, of order 5 to 10% in most cases, but reaching 30% occasionally. Remaining scale uncertainties range from order 5% or less for distributions to below +-2% for the Higgs boson cross section in typical weak-boson fusion search regions.Comment: 19 pages, 8 figure

Distinct roles for strigolactones in cyst nematode parasitism of Arabidopsis roots

Phytohormones play an essential role in different stages of plant-nematode interactions. Strigolactones (SLs) are a novel class of plant hormones which play an important role in plant development. Furthermore, certain soil-inhabiting organisms exploit this plant molecule as allelochemical. However, whether SLs play a role in plant parasitism by nematodes is as yet unknown. This prompted us to investigate the potential role of SLs in different stages of the nematode life cycle using the beet cyst nematode Heterodera schachtii and Arabidopsis as a model system. We analyzed the effect of SLs on cyst nematode hatching, host attraction and invasion, and the establishment of a feeding relation upon infection of the SL deficient mutant max4-1 and the SL signaling mutant max2-1. In addition, infection assays were performed under phosphate shortage to enhance SL production and in the presence of the synthetic SL analog GR24. From this study, we can conclude that SLs do not contribute to cyst nematode hatching at the levels tested but that they do play a role in host attraction and subsequent invasion in a MAX2 dependent manner. Furthermore, we observed that increased levels of exogenous and endogenous SLs change the root invasion zone. Upon root infection, cyst nematode development was enhanced in both the max2-1 and max4-1 mutants due to the formation of enlarged feeding cells. These data provide evidence for distinct roles of SLs during cyst nematode parasitism of plant roots

Neutral Higgs-Boson Pair Production at Hadron Colliders: QCD Corrections

Neutral Higgs-boson pair production provides the possibility of studying the trilinear Higgs couplings at future high-energy colliders. We present the QCD corrections to the gluon-initiated processes in the limit of a heavy top quark in the loops and the Drell-Yan-like pair production of scalar and pseudoscalar Higgs particles. The pp cross sections are discussed for LHC energies within the Standard Model and its minimal supersymmetric extension. The QCD corrections are large, enhancing the total cross sections significantly.Comment: 26 pages, latex, 9 ps figure

Determining the Higgs Boson Self Coupling at Hadron Colliders

Inclusive Standard Model Higgs boson pair production at hadron colliders has the capability to determine the Higgs boson self-coupling, lambda. We present a detailed analysis of the gg\to HH\to (W^+W^-)(W^+W^-)\to (jjl^\pm\nu)(jj{l'}^\pm\nu) and gg\to HH\to (W^+W^-)(W^+W^-)\to (jjl^\pm\nu)({l'}^\pm\nu {l''}^\mp\nu) (l, {l'}, {l''}=e, \mu) signal channels, and the relevant background processes, for the CERN Large Hadron Collider, and a future Very Large Hadron Collider operating at a center-of-mass energy of 200 TeV. We also derive quantitative sensitivity limits for lambda. We find that it should be possible at the LHC with design luminosity to establish that the Standard Model Higgs boson has a non-zero self-coupling and that lambda / lambda_{SM} can be restricted to a range of 0-3.8 at 95% confidence level (CL) if its mass is between 150 and 200 GeV. At a 200 TeV collider with an integrated luminosity of 300 fb^{-1}, lambda can be determined with an accuracy of 8 - 25% at 95% CL in the same mass range.Comment: 28 pages, Revtex3, 9 figures, 3 table

Robust LHC Higgs Search in Weak Boson Fusion

We demonstrate that an LHC Higgs search in weak boson fusion production with subsequent decay to weak boson pairs is robust against extensions of the Standard Model or MSSM involving a large number of Higgs doublets. We also show that the transverse mass distribution provides unambiguous discrimination of a continuum Higgs signal from the Standard Model.Comment: 12p, 2 figs., additional comments on backgrounds, version to appear in PR