We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of ...melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Some hexavalent chromium (Cr(VI))-containing compounds are human lung carcinogens. While ample information is available on the genetic lesions produced by Cr, surprisingly little is known regarding ...the cellular mechanisms involved in the removal of Cr-DNA adducts. Nucleotide excision repair (NER) is a highly versatile pathway that is responsive to a variety of DNA helix-distorting lesions. Binary Cr-DNA monoadducts do not produce a significant degree of helical distortion. However, these lesions are unstable due to the propensity of Cr(III) to form DNA adducts (DNA interstrand crosslinks, DNA-protein/amino acid ternary adducts) which may serve as substrates for NER. Therefore, the focus of this study was to determine the role of NER in the processing of Cr-DNA damage using normal (CHO-AA8) and NER-deficient UV-5 (XP-D); UV-41 (ERCC4/XP-F) hamster cells. We found that both UV-5 and UV-41 cells exhibited an increased sensitivity towards Cr(VI)-induced clonogenic lethality relative to AA8 cells and were completely deficient in the removal of Cr-DNA adducts. In contrast, repair-complemented UV-5 (expressing hamster XPD) and UV-41 (expressing human ERCC4) cells exhibited similar clonogenic survival and removed Cr-DNA adducts to a similar extent as AA8 cells. In order to extend these findings to the molecular level, we examined the ability of Cr(III)-damaged DNA to induce DNA repair synthesis in cell extracts. Repair synthesis was observed in reactions using extracts derived from AA8, or repair-complemented, but not NER-deficient cells. Cr(III)-induced repair resynthesis was sensitive to inhibition by the DNA polymerase delta/epsilon inhibitor, aphidicolin, but not 2',3'-dideoxythymidine triphosphate (ddTTP), a polymerase beta inhibitor. These results collectively suggest that NER functions in the protection of cells from Cr(VI) lethality and is essential for the removal of Cr(III)-DNA adducts. Consequently, NER may represent an important mechanism for preventing Cr(VI)-induced mutagenesis and neoplastic transformation.
We report a study of ν(μ) charged-current quasielastic events in the segmented scintillator inner tracker of the MINERvA experiment running in the NuMI neutrino beam at Fermilab. The events were ...selected by requiring a μ- and low calorimetric recoil energy separated from the interaction vertex. We measure the flux-averaged differential cross section, dσ/dQ², and study the low energy particle content of the final state. Deviations are found between the measured dσ/dQ² and the expectations of a model of independent nucleons in a relativistic Fermi gas. We also observe an excess of energy near the vertex consistent with multiple protons in the final state.
Design, calibration, and performance of the MINERvA detector Aliaga, L.; Bagby, L.; Baldin, B. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
04/2014, Letnik:
743
Journal Article
Recenzirano
Odprti dostop
The MINERvA66Main INjector ExpeRiment ν-A. experiment is designed to perform precision studies of neutrino-nucleus scattering using νμ and ν¯μ neutrinos incident at 1–20GeV in the NuMI beam at ...Fermilab. This article presents a detailed description of the MINERvA detector and describes the ex situ and in situ techniques employed to characterize the detector and monitor its performance. The detector is composed of a finely segmented scintillator-based inner tracking region surrounded by electromagnetic and hadronic sampling calorimetry. The upstream portion of the detector includes planes of graphite, iron and lead interleaved between tracking planes to facilitate the study of nuclear effects in neutrino interactions. Observations concerning the detector response over sustained periods of running are reported. The detector design and methods of operation have relevance to future neutrino experiments in which segmented scintillator tracking is utilized.
We have isolated ν(μ) charged-current quasielastic (QE) interactions occurring in the segmented scintillator tracking region of the MINERvA detector running in the NuMI neutrino beam at Fermilab. We ...measure the flux-averaged differential cross section, dσ/dQ², and compare to several theoretical models of QE scattering. Good agreement is obtained with a model where the nucleon axial mass, M(A), is set to 0.99 GeV/c² but the nucleon vector form factors are modified to account for the observed enhancement, relative to the free nucleon case, of the cross section for the exchange of transversely polarized photons in electron-nucleus scattering. Our data at higher Q² favor this interpretation over an alternative in which the axial mass is increased.
The beam-spin asymmetries in the hard exclusive electroproduction of photons on the proton (e p-->epgamma) were measured over a wide kinematic range and with high statistical accuracy. These ...asymmetries result from the interference of the Bethe-Heitler process and of deeply virtual Compton scattering. Over the whole kinematic range (x(B) from 0.11 to 0.58, Q2 from 1 to 4.8 GeV2, -t from 0.09 to 1.8 GeV2), the azimuthal dependence of the asymmetries is compatible with expectations from leading-twist dominance, A approximately a sinphi/(1+c cosphi). This extensive set of data can thus be used to constrain significantly the generalized parton distributions of the nucleon in the valence quark sector.
In an exclusive measurement of the reaction gammad-->K(+)K(-)pn, a narrow peak that can be attributed to an exotic baryon with strangeness S=+1 is seen in the K(+)n invariant mass spectrum. The peak ...is at 1.542+/-0.005 GeV/c(2) with a measured width of 0.021 GeV/c(2) FWHM, which is largely determined by experimental mass resolution. The statistical significance of the peak is (5.2+/-0.6)sigma. The mass and width of the observed peak are consistent with recent reports of a narrow S=+1 baryon by other experimental groups.
The reaction gamma p-->pi(+)K(-)K(+)n was studied at Jefferson Laboratory using a tagged photon beam with an energy range of 3-5.47 GeV. A narrow baryon state with strangeness S=+1 and mass ...M=1555+/-10 MeV/c(2) was observed in the nK(+) invariant mass spectrum. The peak's width is consistent with the CLAS resolution (FWHM=26 MeV/c(2)), and its statistical significance is (7.8+/-1.0)sigma. A baryon with positive strangeness has exotic structure and cannot be described in the framework of the naive constituent quark model. The mass of the observed state is consistent with the mass predicted by the chiral soliton model for the Theta(+) baryon. In addition, the pK(+) invariant mass distribution was analyzed in the reaction gamma p-->K(-)K(+)p with high statistics in search of doubly charged exotic baryon states. No resonance structures were found in this spectrum.
The longitudinal target-spin asymmetry AUL for the exclusive electroproduction of high-energy photons was measured for the first time in ep-->e;'pgamma. The data have been accumulated at JLab with ...the CLAS spectrometer using 5.7 GeV electrons and a longitudinally polarized NH3 target. A significant azimuthal angular dependence was observed, resulting from the interference of the deeply virtual Compton scattering and Bethe-Heitler processes. The amplitude of the sinvarphi moment is 0.252+/-0.042stat+/-0.020sys. Theoretical calculations are in good agreement with the magnitude and the kinematic dependence of the target-spin asymmetry, which is sensitive to the generalized parton distributions H and H.
Light vector mesons in the nuclear medium Wood, M. H.; Mosel, U.; Muehlich, P. ...
Physical review. C, Nuclear physics,
07/2008, Letnik:
78, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The light vector mesons ({rho},{omega}, and {phi}) were produced in deuterium, carbon, titanium, and iron targets in a search for possible in-medium modifications to the properties of the {rho} meson ...at normal nuclear densities and zero temperature. The vector mesons were detected with the CEBAF Large Acceptance Spectrometer (CLAS) via their decays to e{sup +}e{sup -}. The rare leptonic decay was chosen to reduce final-state interactions. A combinatorial background was subtracted from the invariant mass spectra using a well-established event-mixing technique. The {rho}-meson mass spectrum was extracted after the {omega} and {phi} signals were removed in a nearly model-independent way. Comparisons were made between the {rho} mass spectra from the heavy targets (A>2) with the mass spectrum extracted from the deuterium target. With respect to the {rho}-meson mass, we obtain a small shift compatible with zero. Also, we measure widths consistent with standard nuclear many-body effects such as collisional broadening and Fermi motion.
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