187 research outputs found
The molecular basis of dapsone activation of CYP2C9-catalyzed non-steroidal anti-inflammatory drug (NSAID) oxidation
OnlinePublPositive heterotropic cooperativity, or ‘activation’, results in an instantaneous increase in enzyme activity in the absence of an increase in protein expression. Thus, cytochrome P450 (CYP) enzyme activation presents as a potential drug-drug interaction mechanism. It has been demonstrated previously that dapsone activates the CYP2C9-catalyzed oxidation of a number of NSAIDs in vitro. Here, we conducted molecular dynamics simulations (MDS) together with enzyme kinetic investigations and site-directed mutagenesis to elucidate the molecular basis of the activation of CYP2C9-catalyzed S-flurbiprofen 4’-hydroxylation and S-naproxen Odemethylation by dapsone. Supplementation of incubations of recombinant CYP2C9 with dapsone increased the catalytic efficiency of flurbiprofen and naproxen oxidation by 2.3- and 16.5-fold, respectively. MDS demonstrated that activation arises predominantly from aromatic interactions between the substrate, dapsone, and the phenyl rings of Phe114 and Phe476 within a common binding domain of the CYP2C9 active site, rather than involvement of a distinct effector site. Mutagenesis of Phe114 and Phe476 abrogated flurbiprofen and naproxen oxidation, and MDS and kinetic studies with the CYP2C9 mutants further identified a pivotal role of Phe476 in dapsone activation. MD simulations additionally showed that aromatic stacking interactions between two molecules of naproxen are necessary for binding in a catalytically favorable orientation. In contrast to flurbiprofen and naproxen, dapsone did not activate the 4’-hydroxylation of diclofenac, suggesting that the CYP2C9 active site favors cooperative binding of NSAIDs with a planar or near planar geometry. More generally, the work confirms the utility of MDS for investigating ligand binding in CYP enzymes.Pramod C. Nair, Kushari Burns, Nuy Chau, Ross A. McKinnon, John O. Miner
The expression profiles of ADME genes in human cancers and their associations with clinical outcomes
ADME genes are a group of genes that are involved in drug absorption, distribution, metabolism, and excretion (ADME). The expression profiles of ADME genes within tumours is proposed to impact on cancer patient survival; however, this has not been systematically examined. In this study, our comprehensive analyses of pan-cancer datasets from the Cancer Genome Atlas (TCGA) revealed di erential intratumoral expression profiles for ADME genes in 21 di erent cancer types. Most genes also showed high interindividual variability within cancer-specific patient cohorts. Using Kaplan-Meier plots and logrank tests, we showed that intratumoral expression levels of twenty of the thirty-two core ADME genes were associated with overall survival (OS) in these cancers. Of these genes, five showed significant association with unfavourable OS in three cancers, including SKCM (ABCC2, GSTP1), KIRC (CYP2D6, CYP2E1), PAAD (UGT2B7); sixteen showed significant associations with favourable OS in twelve cancers, including BLCA (UGT2B15), BRCA (CYP2D6), COAD (NAT1), HNSC (ABCB1), KIRC (ABCG2, CYP3A4, SLC22A2, SLC22A6), KIRP (SLC22A2), LIHC (CYP2C19, CYP2C8, CYP2C9, CYP3A5, SLC22A1),LUAD(SLC15A2), LUSC (UGT1A1), PAAD (ABCB1), SARC (ABCB1), and SKCM (ABCB1, DYPD). Overall, these data provide compelling evidence supporting ADME genes as prognostic biomarkers and potential therapeutic targets. We propose that intratumoral expression of ADME genes may impact cancer patient survival by multiple mechanisms that can include metabolizing/transporting anticancer drugs, activating anticancer drugs, and metabolizing/transporting a variety of endogenous molecules involved in metabolically fuelling cancer cells and/or controlling pro-growth signalling pathways.Dong Gui Hu, Peter I. Mackenzie, Pramod C. Nair, Ross A. McKinnon and Robyn Meec
Young-Onset Gastrointestinal Adenocarcinoma Incidence and Survival Trends in the Northern Territory, Australia, with Emphasis on Indigenous Peoples
Background and Aims: A concerning rise in incidence of young-onset cancers globally led to the examination of trends in incidence and survival of gastrointestinal (GI) adenocarcinomas in the Northern Territory (NT), Australia, over a 28-year period, with a special emphasis on Indigenous peoples. Methods: This cross-sectional analysis of a prospective longitudinal database, NT Cancer Registry (1990–2017), includes all reported cases of GI (oesophagus, gastric, small intestinal, pancreas, colon, and rectum) adenocarcinomas. Poisson regression was used to estimate incidence ratio ratios, and survival was modelled using Cox proportional hazard models separately for people aged 18–50 years and >50 years. Results: A total of 1608 cases of GI adenocarcinoma were recorded during the time of the study. While the overall incidence in people 18–50 years remained unchanged over this time (p = 0.51), the rate in individuals aged >50 years decreased (IRR = 0.65 (95% CI 0.56–0.75; p 50 years (IRR = 0.67 95% CI 0.59–0.75; p 50 years IRR = 0.48 95% CI 0.40–0.57; p 50 years HR = 1.66 95% CI 1.32–2.08; p < 0.0001). Conclusions: There is a trend towards an increased incidence of young-onset GI adenocarcinomas in the NT. Young Indigenous patients have lower incidence but worse survival across all GI subsites, highlighting significant health inequities in life expectancy. Targeted, culturally safe Indigenous community-focussed programs are needed for early detection and patient-centred management of GI adenocarcinomas.Mia Shepherdson, Shalem Leemaqz, Gurmeet Singh, Courtney Ryder, Shahid Ullah, Karla Canuto, Joanne P. Young, Timothy J. Price, Ross A. McKinnon, Stephen J. Pandol, Claire T. Roberts, and Savio George Barret
Differential cross section and recoil polarization measurements for the gamma p to K+ Lambda reaction using CLAS at Jefferson Lab
We present measurements of the differential cross section and Lambda recoil
polarization for the gamma p to K+ Lambda reaction made using the CLAS detector
at Jefferson Lab. These measurements cover the center-of-mass energy range from
1.62 to 2.84 GeV and a wide range of center-of-mass K+ production angles.
Independent analyses were performed using the K+ p pi- and K+ p (missing pi -)
final-state topologies; results from these analyses were found to exhibit good
agreement. These differential cross section measurements show excellent
agreement with previous CLAS and LEPS results and offer increased precision and
a 300 MeV increase in energy coverage. The recoil polarization data agree well
with previous results and offer a large increase in precision and a 500 MeV
extension in energy range. The increased center-of-mass energy range that these
data represent will allow for independent study of non-resonant K+ Lambda
photoproduction mechanisms at all production angles.Comment: 22 pages, 16 figure
A Bayesian analysis of pentaquark signals from CLAS data
We examine the results of two measurements by the CLAS collaboration, one of
which claimed evidence for a pentaquark, whilst the other found no
such evidence. The unique feature of these two experiments was that they were
performed with the same experimental setup. Using a Bayesian analysis we find
that the results of the two experiments are in fact compatible with each other,
but that the first measurement did not contain sufficient information to
determine unambiguously the existence of a . Further, we suggest a
means by which the existence of a new candidate particle can be tested in a
rigorous manner.Comment: 5 pages, 3 figure
Electron Scattering From High-Momentum Neutrons in Deuterium
We report results from an experiment measuring the semi-inclusive reaction
where the proton is moving at a large angle relative to the
momentum transfer. If we assume that the proton was a spectator to the reaction
taking place on the neutron in deuterium, the initial state of that neutron can
be inferred. This method, known as spectator tagging, can be used to study
electron scattering from high-momentum (off-shell) neutrons in deuterium. The
data were taken with a 5.765 GeV electron beam on a deuterium target in
Jefferson Laboratory's Hall B, using the CLAS detector. A reduced cross section
was extracted for different values of final-state missing mass ,
backward proton momentum and momentum transfer . The data
are compared to a simple PWIA spectator model. A strong enhancement in the data
observed at transverse kinematics is not reproduced by the PWIA model. This
enhancement can likely be associated with the contribution of final state
interactions (FSI) that were not incorporated into the model. A ``bound neutron
structure function'' was extracted as a function of and
the scaling variable at extreme backward kinematics, where effects of
FSI appear to be smaller. For MeV/c, where the neutron is far
off-shell, the model overestimates the value of in the region of
between 0.25 and 0.6. A modification of the bound neutron structure
function is one of possible effects that can cause the observed deviation.Comment: 33 pages RevTeX, 9 figures, to be submitted to Phys. Rev. C. Fixed 1
Referenc
Measurement of the nuclear multiplicity ratio for hadronization at CLAS
The influence of cold nuclear matter on lepto-production of hadrons in
semi-inclusive deep inelastic scattering is measured using the CLAS detector in
Hall B at Jefferson Lab and a 5.014 GeV electron beam. We report the
multiplicity ratios for targets of C, Fe, and Pb relative to deuterium as a
function of the fractional virtual photon energy transferred to the
and the transverse momentum squared of the . We find that the
multiplicity ratios for are reduced in the nuclear medium at high
and low , with a trend for the transverse momentum to be
broadened in the nucleus for large .Comment: Submitted to Phys. Lett.
eta-prime photoproduction on the proton for photon energies from 1.527 to 2.227 GeV
Differential cross sections for the reaction gamma p -> eta-prime p have been
measured with the CLAS spectrometer and a tagged photon beam with energies from
1.527 to 2.227 GeV. The results reported here possess much greater accuracy
than previous measurements. Analyses of these data indicate for the first time
the coupling of the etaprime N channel to both the S_11(1535) and P_11(1710)
resonances, known to couple strongly to the eta N channel in photoproduction on
the proton, and the importance of j=3/2 resonances in the process.Comment: 6 pages, 3 figure
Coherent Photoproduction of pi^+ from 3^He
We have measured the differential cross section for the
He reaction. This reaction was studied using
the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Lab. Real photons
produced with the Hall-B bremsstrahlung tagging system in the energy range from
0.50 to 1.55 GeV were incident on a cryogenic liquid He target. The
differential cross sections for the He
reaction were measured as a function of photon-beam energy and pion-scattering
angle. Theoretical predictions to date cannot explain the large cross sections
except at backward angles, showing that additional components must be added to
the model.Comment: 11 pages, 16 figure
Measurement of the Deuteron Structure Function F2 in the Resonance Region and Evaluation of Its Moments
Inclusive electron scattering off the deuteron has been measured to extract
the deuteron structure function F2 with the CEBAF Large Acceptance Spectrometer
(CLAS) at the Thomas Jefferson National Accelerator Facility. The measurement
covers the entire resonance region from the quasi-elastic peak up to the
invariant mass of the final-state hadronic system W~2.7 GeV with four-momentum
transfers Q2 from 0.4 to 6 (GeV/c)^2. These data are complementary to previous
measurements of the proton structure function F2 and cover a similar
two-dimensional region of Q2 and Bjorken variable x. Determination of the
deuteron F2 over a large x interval including the quasi-elastic peak as a
function of Q2, together with the other world data, permit a direct evaluation
of the structure function moments for the first time. By fitting the Q2
evolution of these moments with an OPE-based twist expansion we have obtained a
separation of the leading twist and higher twist terms. The observed Q2
behaviour of the higher twist contribution suggests a partial cancellation of
different higher twists entering into the expansion with opposite signs. This
cancellation, found also in the proton moments, is a manifestation of the
"duality" phenomenon in the F2 structure function
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