Human colorectal cancers are known to possess multiple mutations, though how these mutations interact in tumor development and progression has not been fully investigated. We have previously ...described the FCPIK3ca* murine colon cancer model, which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K results in hyperplasia and invasive mucinous adenocarcinomas. These cancers form via a non-canonical mechanism of tumor initiation that is mediated through activation of PI3K and not through aberrations in WNT signaling. Since the Adenomatous Polyposis Coli (APC) gene is mutated in the majority of human colon cancers and often occurs simultaneously with PIK3CA mutations, we sought to better understand the interaction between APC and PIK3CA mutations in the mammalian intestine. In this study, we have generated mice in which the expression of a constitutively active PI3K and the loss of APC occur simultaneously in the distal small intestine and colon. Here, we demonstrate that expression of a dominant active PI3K synergizes with loss of APC activity resulting in a dramatic change in tumor multiplicity, size, morphology and invasiveness. Activation of the PI3K pathway is not able to directly activate WNT signaling through the nuclear localization of CTNNB1 (β-catenin) in the absence of aberrant WNT signaling. Alterations at the transcriptional level, including increased CCND1, may be the etiology of synergy between these activated pathways.
Measurements of the D(d,p)T (dd) and T(t,2n)(4)He (tt) reaction yields have been compared with those of the D(t,n)(4)He (dt) reaction yield, using deuterium-tritium gas-filled inertial confinement ...fusion capsule implosions. In these experiments, carried out on the OMEGA laser, absolute spectral measurements of dd protons and tt neutrons were obtained. From these measurements, it was concluded that the dd yield is anomalously low and the tt yield is anomalously high relative to the dt yield, an observation that we conjecture to be caused by a stratification of the fuel in the implosion core. This effect may be present in ignition experiments planned on the National Ignition Facility.
Neutron time-of-flight spectra from inertial confinement fusion experiments with tritium-filled targets have been measured at the National Ignition Facility. These spectra represent a significant ...improvement in energy resolution and statistics over previous measurements, and afford the first definitive observation of a peak resulting from sequential decay through the ground state of (5)He at low reaction energies E(c.m.) 100 </~ keV. To describe the spectrum, we have developed an R-matrix model that accounts for interferences from fermion symmetry and intermediate states, and show these effects to be non-negligible. We also find the spectrum can be described by sequential decay through ℓ=1 states in (5)He, which differs from previous interpretations.
The dynamics of optically detected nuclear magnetic resonance is studied in n-GaAs via time-resolved Kerr rotation using an on-chip microcoil for rf field generation. Both optically allowed and ...optically forbidden NMR are observed with a dynamics controlled by the interplay between dynamic nuclear polarization via hyperfine interaction with optically generated spin-polarized electrons and nuclear spin depolarization due to magnetic resonance absorption. Comparing the characteristic nuclear spin relaxation rate obtained in experiment with master equation simulations, the underlying nuclear spin depolarization mechanism for each resonance is extracted.
Escherichia coli isolates that were tolerant of incorporation of high proportions of 4-fluorotryptophan were evolved by serial growth. The resultant strain still preferred tryptophan for growth but ...showed improved growth relative to the parental strain on other tryptophan analogues. Evolved clones fully substituted fluorotryptophan for tryptophan in their proteomes within the limits of mass spectral and amino acid analyses. Of the genes sequenced, many genes were found to be unaltered in the evolved strain; however, three genes encoding enzymes involved in tryptophan uptake and utilization were altered: the aromatic amino acid permease (aroP) and tryptophanyl-tRNA synthetase (trpS) contained several amino acid substitutions, and the tyrosine repressor (tyrR) had a nonsense mutation. While kinetic analysis of the tryptophanyl-tRNA synthetase suggests discrimination against 4-fluorotryptophan, an analysis of the incorporation and growth patterns of the evolved bacteria suggest that other mutations also aid in the adaptation to the tryptophan analogue. These results suggest that the incorporation of unnatural amino acids into organismal proteomes may be possible but that extensive evolution may be required to reoptimize proteins and metabolism to accommodate such analogues.
Realization of matching conditions for high-resolution spectrometers Fujita, H; Fujita, Y; Berg, G.P.A ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
05/2002, Letnik:
484, Številka:
1
Journal Article
Recenzirano
For precise measurements of nuclear-reaction spectra using a beam from an accelerator, a high-resolution magnetic spectrometer is a powerful tool. The full capability of a magnetic spectrometer, ...however, can be achieved only if the characteristics of the beam coming from the accelerator are matched to those required by the spectrometer by properly adjusting the beam line conditions. The matching methods,
lateral dispersion matching,
focus matching and also the
kinematic correction compensate the spectrum line-broadening effects caused by the beam momentum spread and reaction kinematics. In addition,
angular dispersion matching should be performed if good resolution of the scattering angle is important. Diagnostic methods developed to realize these matching conditions for the spectrometers K600 at IUCF and Grand Raiden at RCNP are presented.
Alternative donor transplantation is increasingly used for high-risk lymphoma patients. We analyzed 1593 transplant recipients (2000-2010) and compared transplant outcomes in recipients of 8/8 allele ...HLA-A, -B, -C and DRB1 matched unrelated donors (MUDs; n=1176), 7/8 allele HLA mismatched unrelated donors (MMUDs; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared with MUD (35%; P=0.004), but similar to UCB recipients (37%; P=0.19), although UCB had lower rates of neutrophil and platelet recovery compared with unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, P=0.003) but similar between UCB and MUD (30% vs 33%; P=0.48). In multivariate analysis, UCB recipients had lower risks of acute and chronic GVHD compared with adult donor groups (UCB vs MUD: hazard ratio (HR)=0.68, P=0.05; HR=0.35; P<0.001). Adjusted 3-year OS was comparable (43% MUD, 37% MMUD and 41% UCB). These data highlight the observation that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can extend the curative potential of allotransplant to patients who lack suitable HLA matched sibling or MUD.
A measurement of the CP-violating observables from B -> (DK +/-)-K-* and B-+/- -> D-*pi(+/-) decays is presented, where D-*(D) is an admixture of D-*0 and D-0 (D-0 and (0)) states and is ...reconstructed through the decay chains D-*-> D pi(0)/gamma and D -> KS0 pi+pi-/KS0K+K-. The measurement is performed by analysing the signal yield variation across the D decay phase space and is independent of any amplitude model. The data sample used was collected by the LHCb experiment in proton-proton collisions and corresponds to a total integrated luminosity of 9 fb(-1) at centre-of-mass energies of 7, 8 and 13 TeV. The CKM angle gamma is determined to be (69(-14)(+13))degrees using the measured CP-violating observables. The hadronic parameters r(B)(D)*(K +/-),r(B)(D)*(pi +/-),delta(D)(B)*(K +/-),delta(D)(B)*(pi +/-), which are the ratios and strong phase differences between favoured and suppressed B-+/- decays, are also reported.
Persons with high normal blood pressure (BP) or mild hypertension who also have an exaggerated BP response to exercise are at risk for worsening hypertension. The mechanisms that explain this ...relationship are unknown. We examined the relationships of endothelial vasodilator function and of aortic stiffness with exercise BP.
Subjects were 38 men and 44 women, aged 55 to 75 years, with untreated high normal BP or mild hypertension but otherwise healthy. Exercise was performed on a treadmill. Endothelial vasodilator function was assessed as brachial artery flow-mediated vasodilation (FMD) during reactive hyperemia. Aortic stiffness was measured as pulse wave velocity (PWV).
Among men, resting systolic BP explained 34% of the variance (
P < .01) in maximal exercise systolic BP and FMD explained an additional 11% (
P < .01); resting systolic BP explained 23% of the variance in maximal pulse pressure (PP) (
P < .01), and FMD explained an additional 10% (
P < .01). Among women, resting systolic BP was the only independent correlate of maximal systolic BP (
R
2 = 0.12,
P < .03) and FMD correlated negatively with maximal PP (
R
2 = 0.12,
P < .03). Among men, FMD was the only independent correlate of the difference between resting and maximal systolic BP (
R
2 = 0.20,
P < .02). The FMD was the only independent correlate of the difference between resting and maximal PP among men (
R
2 = 0.17,
P < .03) and among women (
R
2 = 0.12,
P < .03). The PWV did not correlate with exercise BP responses.
These results suggest that impaired endothelial vasodilator function may be a mechanism contributing to exercise hypertension and may also be one link between exaggerated exercise BP and worsening hypertension.
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