In a quest for prognostic biomarkers in early-stage colorectal cancer, we investigated NNMT (nicotinamide N-methyltransferase) in large cohorts of patients. Immunohistochemical examination of 679 ...patients illustrates that NNMT protein is predominantly expressed in the cancer stroma at varying levels, and about 20% of cancer tissues overexpress NNMT when compared to levels observed in normal colorectal mucosa. Clinical correlation analyses of 572 patients with early-stage cancers reveal that NNMT protein overexpression is significantly associated with shorter overall and disease-free survival, but no such correlation is found in late-stage colorectal cancer. Analyses of TCGA and CPTAC colorectal cancer cohorts show that NNMT mRNA expression is positively correlated with protein levels, is significantly higher in CIMP-high or MSI subtypes than in CIMP-low or MSS subtypes, and is positively correlated with its paralog INMT but not with its interaction partners such as PNMT, ADK, APP, ATF6, BMF, BRD4, CDC37, or CRYZ. In early-stage cancers, NNMT expression is higher in BRAF-mutated than in BRAF wild type tumors but is not affected by KRAS or PIK3CA mutation status. As a cancer stromal protein with important roles in metabolism and cancer epigenetics, NNMT is emerging as a promising biomarker for risk stratification of early-stage cancers.
Abstract
Measurements of the muonic helium atom hyperfine structure (HFS) are a sensitive tool to test the theory of three-body atomic systems and bound-state quantum electrodynamics (QED) and to ...determine fundamental constants of the negative muon magnetic moment and mass. The world’s most intense pulsed negative muon beam at J-PARC MUSE brings an opportunity to improve previous measurements and test further CPT invariance by comparing the magnetic moments and masses of positive and negative muons. Test measurements at D-line are now in progress utilizing MuSEUM apparatus at zero field. The first results already have better accuracy than previous measurements in the 1980s. Also, the investigation of a new experimental approach to improve HFS measurements by repolarizing muonic helium atoms using a spin-exchange optical pumping (SEOP) technique was started. If successful, this would drastically improve the measurement accuracy.
Cosmic-ray-muon spallation-induced radioactive isotopes with beta decays are one of the major backgrounds for solar, reactor, and supernova relic neutrino experiments. Unlike in scintillator, ...production yields for cosmogenic backgrounds in water have not been exclusively measured before, yet they are becoming more and more important in next generation neutrino experiments designed to search for rare signals. We have analyzed the low-energy trigger data collected at Super-Kamiokande IV in order to determine the production rates of B super(12), N super(12), N super(16), Be super(11), Li super(9), He super(8), C super(9), Li super(8), B super(8), and C super(15). These rates were extracted from fits to time differences between parent muons and subsequent daughter beta 's by fixing the known isotope lifetimes. Since Li super(9) can fake an inverse-beta-decay reaction chain via a beta +n cascade decay, producing an irreducible background with detected energy up to a dozen MeV, a dedicated study is needed for evaluating its impact on future measurements; the application of a neutron tagging technique using correlated triggers was found to improve this Li super(9) measurement. The measured yields were generally found to be comparable with theoretical calculations, except the cases of the isotopes Li super(8)/B super(8) and Li super(9).
We have measured for the first time simultaneously both the mean charge states and stopping powers of (35-280) MeV/u 208Pb ions in gases and solids with an accuracy of 1%. The existence at lower ...energies and disappearance at higher of density effects in the charge-state distribution and the corresponding stopping power are directly confirmed and comparisons with widely used theories and simulations for heavy ions demonstrate strong deviations of up to 27%. However, an unprecedented prediction power of better than 3% has been achieved for the energy loss when the measured mean charge-states are implemented in the Lindhard-Sørensen theory. Our present benchmark data contribute to an improved understanding of the basic atomic collision processes and to numerous applications in nuclear physics. Extending the GANIL data 1 to higher accuracy and energies, we can now answer at which velocities the Bohr-Lindhard density effect in stopping will vanish.
Abstract Tick-borne diseases in animals are increasing rapidly worldwide, but there is insufficient information about tick-borne diseases infecting dogs in southern Egypt. Thus, in the current study, ...we detected the presence of Anaplasma marginale (A. marginale) and Babesia canis vogeli ( B. canis vogeli ) in the blood of dogs. The results revealed that 4/100 (4%) were positive, and a higher infection rate was found in males (75%), than females (25%). The phylogenetic analysis for the major surface protein 4 ( msp4 ) gene in this study was compared with amplicons separate from other reported isolates with alignment by identity 100% with cattle and camels from Egypt, and the phylogenetic analysis for the B. canis vogeli small subunit ribosomal RNA ( SSU rRNA ) gene in this study identified identity by 99.89% with dogs from Egypt. This report is considered the first report in southern Egypt about A. marginale in dogs based on the sequence analysis of the msp4 gene, providing new data for the classification and identification of A. marginale in dogs compared to A. marginale isolated from other animals in southern Egypt.
Abstract
The MuSEUM collaboration is planning measurements of the ground-state hyperfine structure (HFS) of muonium at the Japan Proton Accelerator Research Complex (J-PARC), Materials and Life ...Science Experimental Facility. The high-intensity beam that will soon be available, the H-line, allows for more precise measurements by one order of magnitude. We plan to conduct two staged measurements. First, we will measure the Mu-HFS in a near-zero magnetic field, and thereafter we will measure it in a strong magnetic field. We have developed two microwave cavities for this purpose. Furthermore, we evaluated the systematic uncertainties from such a fluctuation of microwave fields and confirmed the requirements for the microwave system; we use a microwave field distribution calculated with the finite element method.
The NEUT intranuclear cascade model is described and fit to a large body of π± -nucleus scattering data. Methods are developed to deal with deficiencies in the available historical data, and robust ...uncertainty estimates are produced. The results are compared to a variety of simulation packages and the data. This work provides a method for tuning final state interaction models, which are of particular interest to neutrino experiments that operate in the few-GeV energy region, and provides results which can be used directly by the T2K and Super-Kamiokande Collaborations, for whom NEUT is the primary simulation package.
We report the results of a joint analysis of neutrino and antineutrino oscillations at T2K with the ν μ ( ν ¯ μ ) disappearance and ν μ ( ν ¯ μ ) → ν e ( ν ¯ e ) appearance channels. The ...disappearance channel is primarily sensitive to sin2 2θ 23 and the mass splitting Δ m 32 2 , while νμ → νe is sensitive to sin2 θ23 and sin2 2θ13, with the CP violating phase δCP and matter effects inducing asymmetries in the oscillation probabilities between the CP conjugate channels. Since the Neutrino 2016 conference, a small increment of data has been added to the analysis, so that the accumulated protons-on-target are 7.48 × 1020 in ν-mode and 7.47 × 1020 in ν ¯ mode. The data continue to favor maximal mixing in θ23 with a 1 σ confidence interval of 0.464, 0.578 for sin2 θ23, while the large νe appearance observed in the data favors δCP ∼ −π/2 with a 90% confidence interval of -3.13, -0.39 in normal hierarchy and -2.09, -0.74 in inverted hierarchy. We comment briefly on the future prospects for T2K, including a proposal for extended running to accumulate 20 × 1021 protons-on-target, nearly three times the currently approved amount by 2026, to gain substantial sensitivity to CP violating effects in ν μ ( ν ¯ μ ) → ν e ( ν ¯ e ) oscillations if parameters are favorable.
Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody–drug conjugate consisting ...of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd.
Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC.
In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% 95% confidence interval (CI) 30.0% to 52.7%, median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified.
In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.
•The phase I U31402-A-U102 study evaluated HER3-DXd in heavily pretreated patients with EGFR-mutated NSCLC.•Ninety-seven patients previously treated with EGFR TKI and PBC received HER3-DXd 5.6 mg/kg intravenously every 3 weeks.•Responses were seen across the range of HER3 expression and across diverse mechanisms of resistance to EGFR TKI therapy.•Acquired mutations in ERBB3 were characterized.•OS was 15.8 months (95% CI 10.8-21.5 months).
Electron antineutrino appearance is measured by the T2K experiment in an accelerator-produced antineutrino beam, using additional neutrino beam operation to constrain parameters of the ...Pontecorvo-Maki-Nakagawa-Sakata (PMNS) mixing matrix. T2K observes 15 candidate electron antineutrino events with a background expectation of 9.3 events. Including information from the kinematic distribution of observed events, the hypothesis of no electron antineutrino appearance is disfavored with a significance of 2.40σ and no discrepancy between data and PMNS predictions is found. A complementary analysis that introduces an additional free parameter which allows non-PMNS values of electron neutrino and antineutrino appearance also finds no discrepancy between data and PMNS predictions.
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