Many extensions of the standard model of particle physics suggest that neutrinos should be Majorana-type fermions-that is, that neutrinos are their own anti-particles-but this assumption is difficult ...to confirm. Observation of neutrinoless double-β decay (0νββ), a spontaneous transition that may occur in several candidate nuclei, would verify the Majorana nature of the neutrino and constrain the absolute scale of the neutrino mass spectrum. Recent searches carried out with (76)Ge (the GERDA experiment) and (136)Xe (the KamLAND-Zen and EXO (Enriched Xenon Observatory)-200 experiments) have established the lifetime of this decay to be longer than 10(25) years, corresponding to a limit on the neutrino mass of 0.2-0.4 electronvolts. Here we report new results from EXO-200 based on a large (136)Xe exposure that represents an almost fourfold increase from our earlier published data sets. We have improved the detector resolution and revised the data analysis. The half-life sensitivity we obtain is 1.9 × 10(25) years, an improvement by a factor of 2.7 on previous EXO-200 results. We find no statistically significant evidence for 0νββ decay and set a half-life limit of 1.1 × 10(25) years at the 90 per cent confidence level. The high sensitivity holds promise for further running of the EXO-200 detector and future 0νββ decay searches with an improved Xe-based experiment, nEXO.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated ...preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC.
In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible.
Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months 95% confidence interval (CI) 8.5-23.8 months in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm.
Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.
•This randomized phase II trial demonstrated promising activity of cediranib with a median PFS of 14.8 months and an objective response rate of 44%.•The addition of lenalidomide to cediranib alone did not improve PFS or OS.•This highlights the activity of antiangiogenic TKIs in RAI-refractory differentiated thyroid carcinoma and the need for novel combinatorial therapeutic strategies in this disease.
Multiple cytosolic innate sensors form large signalosomes after activation, but this assembly needs to be tightly regulated to avoid accumulation of misfolded aggregates. We found that the eIF2α ...kinase heme-regulated inhibitor (HRI) controls NOD1 signalosome folding and activation through a process requiring eukaryotic initiation factor 2α (eIF2α), the transcription factor ATF4, and the heat shock protein HSPB8. The HRI/eIF2α signaling axis was also essential for signaling downstream of the innate immune mediators NOD2, MAVS, and TRIF but dispensable for pathways dependent on MyD88 or STING. Moreover, filament-forming α-synuclein activated HRI-dependent responses, which suggests that the HRI pathway may restrict toxic oligomer formation. We propose that HRI, eIF2α, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK/eIF2α/HSPA5 axis of the endoplasmic reticulum UPR.
By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we ...investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC
mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.
Background
Serelaxin showed beneficial effects on clinical outcome and trajectories of renal markers in patients with acute heart failure. We aimed to study the interaction between renal function and ...the treatment effect of serelaxin.
Methods
In the current post hoc analysis of the RELAX-AHF trial, we included all patients with available estimated glomerular filtration rate (eGFR) at baseline (
n
= 1132). Renal impairment was defined as an eGFR <60 ml/min/1.73 m
2
estimated by creatinine.
Results
817 (72.2 %) patients had a baseline eGFR <60 ml/min/1.73 m
2
. In placebo-treated patients, baseline renal impairment was related to a higher 180 day cardiovascular (HR 3.12, 95 % CI 1.33–7.30) and all-cause mortality (HR 2.81, 95 % CI 1.34–5.89). However, in serelaxin-treated patients, the risk of cardiovascular and all-cause mortality was less pronounced (HR 1.19, 95 % CI 0.54 –2.64;
p
for interaction = 0.106, and HR 1.15 95 % CI 0.56–2.34 respectively;
p
for interaction = 0.088). In patients with renal impairment, treatment with serelaxin resulted in a more pronounced all-cause mortality reduction (HR 0.53, 95 % CI 0.34–0.83), compared with patients without renal impairment (HR 1.30, 95 % CI 0.51–3.29).
Conclusion
Renal dysfunction was associated with higher cardiovascular and all-cause mortality in placebo-treated patients, but not in serelaxin-treated patients. The observed reduction in (cardiovascular) mortality in RELAX-AHF was more pronounced in patients with renal dysfunction. These observations need to be confirmed in the ongoing RELAX-AHF-2 trial.
The EXO-200 Collaboration is searching for neutrinoless double β decay using a liquid xenon (LXe) time projection chamber. This measurement relies on modeling the transport of charge deposits ...produced by interactions in the LXe to allow discrimination between signal and background events. Here we present measurements of the transverse diffusion constant and drift velocity of electrons at drift fields between 20 V/cm and 615 V/cm using EXO-200 data. At the operating field of 380 V/cm EXO-200 measures a drift velocity of 1.705+0.014 -0.010 mm/μs and a transverse diffusion coefficient of 55 ± 4 cm2/s.
A search for Lorentz- and CPT-violating signals in the double beta decay spectrum of super(136) Xe has been performed using an exposure of 100kgmiddotyr with the EXO-200 detector. No significant ...evidence of the spectral modification due to isotropic Lorentz-violation was found, and a two-sided limit of -2.65x10 super(-5)GeV(ProQuest: Formulae and/or non-USASCII text omitted) <7.60x10 super(-6)GeV (90% C.L.) is placed on the relevant coefficient within the Standard-Model Extension (SME). This is the first experimental study of the effect of the SME-defined oscillation-free and momentum-independent neutrino coupling operator on the double beta decay process.
A xenon gas purity monitor for EXO Dobi, A.; Hall, C.; Herrin, S. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
12/2011, Letnik:
659, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We discuss the design, operation, and calibration of two versions of a xenon gas purity monitor (GPM) developed for the EXO double beta decay program. The devices are sensitive to concentrations of ...oxygen well below 1ppb at an ambient gas pressure of one atmosphere or more. The theory of operation of the GPM is discussed along with the interactions of oxygen and other impurities with the GPM's tungsten filament. Lab tests and experiences in commissioning the EXO-200 double beta decay experiment are described. These devices can also be used on other noble gases.
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