2,474 research outputs found
Light driven water oxidation by a single site cobalt salophen catalyst
A salophen cobalt(II) complex enables water oxidation at neutral pH
in photoactivated sacrificial cycles under visible light, thus confirming
the high appeal of earth abundant single site catalysis for artificial
photosynthesis
Exceptional chemotherapy response in metastatic colorectal cancer associated with hyper-indel-hypermutated cancer genome and comutation of POLD1 and MLH1
Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years.Wesequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients withPOLE- and/orPOLD1- mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G > A[p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel-hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy
An Integrated Pharmacological Counselling Approach to Guide Decision-Making in the Treatment with CDK4/6 Inhibitors for Metastatic Breast Cancer
A wide inter-individual variability in the therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) has been reported. We herein present a case series of five patients treated with either palbociclib or ribociclib referred to our clinical pharmacological counselling, including therapeutic drug monitoring (TDM), pharmacogenetics, and drug–drug interaction analysis to support clinicians in the management of CDKis treatment for metastatic breast cancer. Patients’ plasma samples for TDM analysis were collected at steady state and analyzed by an LC-MS/MS method for minimum plasma concentration (Cmin) evaluation. Under and overexposure to the drug were defined based on the mean Cmin values observed in population pharmacokinetic studies. Polymorphisms in selected genes encoding for proteins involved in drug absorption, distribution, metabolism, and elimination were analyzed (CYP3A4, CYP3A5, ABCB1, SLCO1B1, and ABCG2). Three of the five reported cases presented a CDKi plasma level above the population mean value and were referred for toxicity. One of them presented a low function ABCB1 haplotype (ABCB1-rs1128503, rs1045642, and rs2032582), possibly causative of both increased drug oral absorption and plasmatic concentration. Two patients showed underexposure to CDKis, and one of them was referred for early progression. In one patient, a CYP3A5*1/*3 genotype was found to be potentially responsible for more efficient drug metabolism and lower drug plasma concentration. This intensified pharmacological approach in clinical practice has been shown to be potentially effective in supporting prescribing oncologists with dose and drug selection and could be ultimately useful for increasing both the safety and efficacy profiles of CDKi treatment
CYP2D6 and CYP2C8 pharmacogenetics and pharmacological interactions to predict imatinib plasmatic exposure in GIST patients
Patients on treatment with oral fixed dose imatinib are frequently under- or overexposed to the drug. We investigated the association between the gene activity score (GAS) of imatinib-metabolizing cytochromes (CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2C8) and imatinib and nor-imatinib exposure. We also investigated the impact of concurrent drug-drug-interactions (DDIs) on the association between GAS and imatinib exposure
A Study of Time-Dependent CP-Violating Asymmetries and Flavor Oscillations in Neutral B Decays at the Upsilon(4S)
We present a measurement of time-dependent CP-violating asymmetries in
neutral B meson decays collected with the BABAR detector at the PEP-II
asymmetric-energy B Factory at the Stanford Linear Accelerator Center. The data
sample consists of 29.7 recorded at the
resonance and 3.9 off-resonance. One of the neutral B mesons,
which are produced in pairs at the , is fully reconstructed in
the CP decay modes , , , () and , or in flavor-eigenstate
modes involving and (). The flavor of the other neutral B meson is tagged at the time of
its decay, mainly with the charge of identified leptons and kaons. The proper
time elapsed between the decays is determined by measuring the distance between
the decay vertices. A maximum-likelihood fit to this flavor eigenstate sample
finds . The value of the asymmetry amplitude is determined from
a simultaneous maximum-likelihood fit to the time-difference distribution of
the flavor-eigenstate sample and about 642 tagged decays in the
CP-eigenstate modes. We find , demonstrating that CP violation exists in the neutral B meson
system. (abridged)Comment: 58 pages, 35 figures, submitted to Physical Review
Measurement of ISR-FSR interference in the processes e+ e- --> mu+ mu- gamma and e+ e- --> pi+ pi- gamma
Charge asymmetry in processes e+ e- --> mu+ mu- gamma and e+ e- --> pi+ pi-
gamma is measured using 232 fb-1 of data collected with the BABAR detector at
center-of-mass energies near 10.58 GeV. An observable is introduced and shown
to be very robust against detector asymmetries while keeping a large
sensitivity to the physical charge asymmetry that results from the interference
between initial and final state radiation. The asymmetry is determined as
afunction of the invariant mass of the final-state tracks from production
threshold to a few GeV/c2. It is compared to the expectation from QED for e+ e-
--> mu+ mu- gamma and from theoretical models for e+ e- --> pi+ pi- gamma. A
clear interference pattern is observed in e+ e- --> pi+ pi- gamma, particularly
in the vicinity of the f_2(1270) resonance. The inferred rate of lowest order
FSR production is consistent with the QED expectation for e+ e- --> mu+ mu-
gamma, and is negligibly small for e+ e- --> pi+ pi- gamma.Comment: 32 pages,29 figures, to be submitted to Phys. Rev.
Measurement of inclusive D*+- and associated dijet cross sections in photoproduction at HERA
Inclusive photoproduction of D*+- mesons has been measured for photon-proton
centre-of-mass energies in the range 130 < W < 280 GeV and a photon virtuality
Q^2 < 1 GeV^2. The data sample used corresponds to an integrated luminosity of
37 pb^-1. Total and differential cross sections as functions of the D*
transverse momentum and pseudorapidity are presented in restricted kinematical
regions and the data are compared with next-to-leading order (NLO) perturbative
QCD calculations using the "massive charm" and "massless charm" schemes. The
measured cross sections are generally above the NLO calculations, in particular
in the forward (proton) direction. The large data sample also allows the study
of dijet production associated with charm. A significant resolved as well as a
direct photon component contribute to the cross section. Leading order QCD
Monte Carlo calculations indicate that the resolved contribution arises from a
significant charm component in the photon. A massive charm NLO parton level
calculation yields lower cross sections compared to the measured results in a
kinematic region where the resolved photon contribution is significant.Comment: 32 pages including 6 figure
Measurement of event shapes in deep inelastic scattering at HERA
Inclusive event-shape variables have been measured in the current region of
the Breit frame for neutral current deep inelastic ep scattering using an
integrated luminosity of 45.0 pb^-1 collected with the ZEUS detector at HERA.
The variables studied included thrust, jet broadening and invariant jet mass.
The kinematic range covered was 10 < Q^2 < 20,480 GeV^2 and 6.10^-4 < x < 0.6,
where Q^2 is the virtuality of the exchanged boson and x is the Bjorken
variable. The Q dependence of the shape variables has been used in conjunction
with NLO perturbative calculations and the Dokshitzer-Webber non-perturbative
corrections (`power corrections') to investigate the validity of this approach.Comment: 7+25 pages, 6 figure
Measurement of CP Asymmetries and Branching Fractions in Charmless Two-Body B-Meson Decays to Pions and Kaons
We present improved measurements of CP-violation parameters in the decays
, , and , and of
the branching fractions for and . The
results are obtained with the full data set collected at the
resonance by the BABAR experiment at the PEP-II asymmetric-energy factory
at the SLAC National Accelerator Laboratory, corresponding to
million pairs. We find the CP-violation parameter values and
branching fractions where in each case, the first uncertainties are statistical
and the second are systematic. We observe CP violation with a significance of
6.7 standard deviations for and 6.1 standard deviations for
, including systematic uncertainties. Constraints on the
Unitarity Triangle angle are determined from the isospin relations
among the rates and asymmetries. Considering only the solution
preferred by the Standard Model, we find to be in the range
at the 68% confidence level.Comment: 18 pages, 11 postscript figures, submitted to Phys. Rev.
Recommended from our members
Measurement of B(B-->X_s {\gamma}), the B-->X_s {\gamma} photon energy spectrum, and the direct CP asymmetry in B-->X_{s+d} {\gamma} decays
The photon spectrum in B --> X_s {\gamma} decay, where X_s is any strange
hadronic state, is studied using a data sample of (382.8\pm 4.2) \times 10^6
e^+ e^- --> \Upsilon(4S) --> BBbar events collected by the BABAR experiment at
the PEP-II collider. The spectrum is used to measure the branching fraction B(B
--> X_s \gamma) = (3.21 \pm 0.15 \pm 0.29 \pm 0.08)\times 10^{-4} and the
first, second, and third moments = 2.267 \pm 0.019 \pm 0.032 \pm
0.003 GeV,, )^2> = 0.0484 \pm 0.0053 \pm 0.0077 \pm
0.0005 GeV^2, and )^3> = -0.0048 \pm 0.0011 \pm 0.0011
\pm 0.0004 GeV^3, for the range E_\gamma > 1.8 GeV, where E_{\gamma} is the
photon energy in the B-meson rest frame. Results are also presented for
narrower E_{\gamma} ranges. In addition, the direct CP asymmetry A_{CP}(B -->
X_{s+d} \gamma) is measured to be 0.057 \pm 0.063. The spectrum itself is also
unfolded to the B-meson rest frame; that is the frame in which theoretical
predictions for its shape are made.Comment: 37 pages, 19 postscript figures, submitted to Phys. Rev. D. No
analysis or results have changed from previous version. Some changes to
improve clarity based on interactions with Phys. Rev. D referees, including
one new Figure (Fig. 13), and some minor wording/punctuation/spelling
mistakes fixe
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