The RENO experiment reports more precisely measured values of θ_{13} and |Δm_{ee}^{2}| using ∼2200 live days of data. The amplitude and frequency of reactor electron antineutrino (νover ¯_{e}) ...oscillation are measured by comparing the prompt signal spectra obtained from two identical near and far detectors. In the period between August 2011 and February 2018, the far (near) detector observed 103 212 (850 666) νover ¯_{e} candidate events with a background fraction of 4.8% (2.0%). A clear energy and baseline dependent disappearance of reactor νover ¯_{e} is observed in the deficit of the measured number of νover ¯_{e}. Based on the measured far-to-near ratio of prompt spectra, we obtain sin^{2}2θ_{13}=0.0896±0.0048(stat)±0.0047(syst) and |Δm_{ee}^{2}|=2.68±0.12(stat)±0.07(syst)×10^{-3} eV^{2}.
We report a fuel-dependent reactor electron antineutrino (νover ¯_{e}) yield using six 2.8 GW_{th} reactors in the Hanbit nuclear power plant complex, Yonggwang, Korea. The analysis uses 850 666 ...νover ¯_{e} candidate events with a background fraction of 2.0% acquired through inverse beta decay (IBD) interactions in the near detector for 1807.9 live days from August 2011 to February 2018. Based on multiple fuel cycles, we observe a fuel ^{235}U dependent variation of measured IBD yields with a slope of (1.51±0.23)×10^{-43} cm^{2}/fission and measure a total average IBD yield of (5.84±0.13)×10^{-43} cm^{2}/fission. The hypothesis of no fuel-dependent IBD yield is ruled out at 6.6σ. The observed IBD yield variation over ^{235}U isotope fraction does not show significant deviation from the Huber-Mueller (HM) prediction at 1.3 σ. The measured fuel-dependent variation determines IBD yields of (6.15±0.19)×10^{-43} and (4.18±0.26)×10^{-43} cm^{2}/fission for two dominant fuel isotopes ^{235}U and ^{239}Pu, respectively. The measured IBD yield per ^{235}U fission shows the largest deficit relative to the HM prediction. Reevaluation of the ^{235}U IBD yield per fission may mostly solve the reactor antineutrino anomaly (RAA) while ^{239}Pu is not completely ruled out as a possible contributor to the anomaly. We also report a 2.9 σ correlation between the fractional change of the 5 MeV excess and the reactor fuel isotope fraction of ^{235}U.
This multicenter, phase II trial tested the tolerability and efficacy of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma (FL).
Patients with grade 1–3a FL, stage ...3–4 or bulky stage 2, FL international prognostic index (FLIPI) 0–2, and no prior therapy were eligible to receive rituximab 375mg/m2 weekly during cycle 1 and day 1 of cycles 4, 6, 8, and 10, plus lenalidomide 20–25mg on days 1–21 for twelve 28-day cycles. The primary objectives were to evaluate response rates complete (CR) and overall and time to progression. Secondary objectives included toxicity, response according to polymorphisms in FcgR2A and FcgR3A, and changes in circulating pro-angiogenic cells.
From October 2010 to September 2011, 66 patients were enrolled. Median age was 53years, 34 were female, 15 had bulky disease, 21 were FLIPI 0-1, 43 FLIPI 2, and 2 FLIPI 3. One patient withdrew before receiving treatment. Fifty-one patients completed 12 cycles of lenalidomide. Reasons for discontinuation included withdrawal (n=6), adverse events (n=6), progression (n=2). Grade 3–4 hematologic toxicity included neutropenia (21%), lymphopenia (9%), and thrombocytopenia (2%), infection (11%), and rash (8%). Grade 1–2 toxicity included fatigue (78%), diarrhea (37%), rash (32%), and febrile neutropenia in one patient. The overall response rate was 95%; the CR rate was 72% (95% confidence interval, 60% to 83%). With a median follow-up of 5years, the 2- and 5-year progression-free survival were 86% and 70%, respectively, and the 5-year overall survival was 100%. There was no association between CR rate or PFS and FLIPI, histological grade, bulky disease, FcgR2A/FcgR3A polymorphism, or change in circulating endothelial cell/hematopoietic progenitor cell.
Lenalidomide plus rituximab was associated with low rates of grade 3–4 toxicity, yielded a CR rate and PFS similar to chemotherapy-based treatment and may represent a reasonable alternative to immunochemotherapy in previously untreated FL.
NCT01145495.
Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), ...particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2).
Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS) were assessed.
Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 95% confidence interval (CI) 0.39-0.78; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed.
MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.
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•Niraparib + AAP reduced risk of radiographic progression/death by 45% in BRCA1/2-altered mCRPC (median follow-up 24.8 mo).•Niraparib + AAP improved secondary endpoints and patient-reported outcomes in the BRCA1/2 subgroup.•Adverse events of niraparib + AAP were tolerable, manageable, and consistent with previous reports; no new safety signals.•MAGNITUDE second interim analysis continues to support niraparib + AAP for mCRPC and HRR alterations, especially BRCA1/2.•MAGNITUDE supports genomic testing for BRCA1/2 alterations in mCRPC due to poor outcomes and emerging treatment options.
We report a search result for a light sterile neutrino oscillation with roughly 2200 live days of data in the RENO experiment. The search is performed by electron antineutrino (νe) disappearance ...taking place between six 2.8 GW th reactors and two identical detectors located at 294 m (near) and 1383 m (far) from the center of the reactor array. A spectral comparison between near and far detectors can explore reactor νe oscillations to a light sterile neutrino. An observed spectral difference is found to be consistent with that of the three-flavor oscillation model. This yields limits on sin 22θ14 in the 10−4 ≲ | Δm412 | ≲ 0.5 eV2 region, free from reactor νe flux and spectrum uncertainties. The RENO result provides the most stringent limits on sterile neutrino mixing at | Δm412 | ≲ 0.002 eV2 using the νe disappearance channel.
L-ascorbate (L-ascorbic acid, vitamin C) clearly has an inhibitory effect on cancer cells. However, the mechanism underlying differential sensitivity of cancer cells from same tissue to L-ascorbate ...is yet to be clarified. Here, we demonstrate that L-ascorbate has a selective killing effect, which is influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human breast cancer cells. Treatment of human breast cancer cells with L-ascorbate differentially induced cell death, dependent on the SVCT-2 protein level. Moreover, knockdown of endogenous SVCT-2 via RNA interference in breast cancer cells expressing high levels of the protein induced resistance to L-ascorbate treatment, whereas transfection with SVCT-2 expression plasmids led to enhanced L-ascorbate chemosensitivity. Surprisingly, tumor regression by L-ascorbate administration in mice bearing tumor cell xenograft also corresponded to the SVCT-2 protein level. Interestingly, SVCT-2 expression was absent or weak in normal tissues, but strongly detected in tumor samples obtained from breast cancer patients. In addition, enhanced chemosensitivity to L-ascorbate occurred as a result of caspase-independent autophagy, which was mediated by beclin-1 and LC3 II. In addition, treatment with N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, suppressed the induction of beclin-1 and LC3 II, implying that the differential SVCT-2 protein-dependent L-ascorbate uptake was attributable to intracellular ROS induced by L-ascorbate, subsequently leading to autophagy. These results suggest that functional SVCT-2 sensitizes breast cancer cells to autophagic damage by increasing the L-ascorbate concentration and intracellular ROS production and furthermore, SVCT-2 in breast cancer may act as an indicator for commencing L-ascorbate treatment.
Terrestrial ecosystems sequester 2.1 Pg of atmospheric carbon annually. A large amount of the terrestrial sink is realized by forests. However, considerable uncertainties remain regarding the fate of ...this carbon over both short and long timescales. Relevant data to address these uncertainties are being collected at many sites around the world, but syntheses of these data are still sparse. To facilitate future synthesis activities, we have assembled a comprehensive global database for forest ecosystems, which includes carbon budget variables (fluxes and stocks), ecosystem traits (e.g. leaf area index, age), as well as ancillary site information such as management regime, climate, and soil characteristics. This publicly available database can be used to quantify global, regional or biome‐specific carbon budgets; to re‐examine established relationships; to test emerging hypotheses about ecosystem functioning e.g. a constant net ecosystem production (NEP) to gross primary production (GPP) ratio; and as benchmarks for model evaluations. In this paper, we present the first analysis of this database. We discuss the climatic influences on GPP, net primary production (NPP) and NEP and present the CO2 balances for boreal, temperate, and tropical forest biomes based on micrometeorological, ecophysiological, and biometric flux and inventory estimates. Globally, GPP of forests benefited from higher temperatures and precipitation whereas NPP saturated above either a threshold of 1500 mm precipitation or a mean annual temperature of 10 °C. The global pattern in NEP was insensitive to climate and is hypothesized to be mainly determined by nonclimatic conditions such as successional stage, management, site history, and site disturbance. In all biomes, closing the CO2 balance required the introduction of substantial biome‐specific closure terms. Nonclosure was taken as an indication that respiratory processes, advection, and non‐CO2 carbon fluxes are not presently being adequately accounted for.
We present a new synthesis, based on a suite of complementary approaches, of the primary production and carbon sink in forests of the 25 member states of the European Union (EU-25) during 1990-2005. ...Upscaled terrestrial observations and model-based approaches agree within 25% on the mean net primary production (NPP) of forests, i.e. 520±75 g C m⁻² yr⁻¹ over a forest area of 1.32 x 10⁶ km² to 1.55 x 10⁶ km² (EU-25). New estimates of the mean long-term carbon forest sink (net biome production, NBP) of EU-25 forests amounts 75±20 g C m⁻² yr⁻¹. The ratio of NBP to NPP is 0.15±0.05. Estimates of the fate of the carbon inputs via NPP in wood harvests, forest fires, losses to lakes and rivers and heterotrophic respiration remain uncertain, which explains the considerable uncertainty of NBP. Inventory-based assessments and assumptions suggest that 29±15% of the NBP (i.e., 22 g C m⁻² yr⁻¹) is sequestered in the forest soil, but large uncertainty remains concerning the drivers and future of the soil organic carbon. The remaining 71±15% of the NBP (i.e., 53 g C m⁻² yr⁻¹) is realized as woody biomass increments. In the EU-25, the relatively large forest NBP is thought to be the result of a sustained difference between NPP, which increased during the past decades, and carbon losses primarily by harvest and heterotrophic respiration, which increased less over the same period.
A
bstract
The Reactor Experiment for Neutrino Oscillation (RENO) experiment has been taking data using two identical liquid scintillator detectors since August 2011. The experiment has observed the ...disappearance of reactor neutrinos in their interactions with free protons, followed by neutron capture on hydrogen (n-H). Based on 1500 live days of data taken with 16.8 GW
th
reactors at the Hanbit Nuclear Power Plant in Korea, the near (far) detector observes 567690 (90747) electron antineutrino candidate events with the n-H data. This provides an independent measurement of neutrino mixing angle
θ
13
and a consistency check on the validity of the result obtained from the data with neutron capture on Gadolinium (n-Gd). Furthermore, it provides an important cross-check on the systematic uncertainties of the n-Gd measurement. Based on a rate-only analysis, we obtain sin
2
2
θ
13
= 0
.
086 ± 0
.
008(stat
.
) ± 0
.
014(syst
.
). The combination of this result with that of n-Gd is also reported.
Despite extensive analysis of pRB phosphorylation in vitro, how this modification influences development and homeostasis in vivo is unclear. Here, we show that homozygous Rb∆K4 and Rb∆K7 knock‐in ...mice, in which either four or all seven phosphorylation sites in the C‐terminal region of pRb, respectively, have been abolished by Ser/Thr‐to‐Ala substitutions, undergo normal embryogenesis and early development, notwithstanding suppressed phosphorylation of additional upstream sites. Whereas Rb∆K4 mice exhibit telomere attrition but no other abnormalities, Rb∆K7 mice are smaller and display additional hallmarks of premature aging including infertility, kyphosis, and diabetes, indicating an accumulative effect of blocking pRb phosphorylation. Diabetes in Rb∆K7 mice is insulin‐sensitive and associated with failure of quiescent pancreatic β‐cells to re‐enter the cell cycle in response to mitogens, resulting in induction of DNA damage response (DDR), senescence‐associated secretory phenotype (SASP), and reduced pancreatic islet mass and circulating insulin level. Pre‐treatment with the epigenetic regulator vitamin C reduces DDR, increases cell cycle re‐entry, improves islet morphology, and attenuates diabetes. These results have direct implications for cell cycle regulation, CDK‐inhibitor therapeutics, diabetes, and longevity.
Synopsis
The tumor suppressor pRB is frequently inactivated by mutation or hyper‐phosphorylation in diverse types of cancer, yet the effect of specifically blocking its phosphorylation in vivo is ill‐defined. Here, novel knock‐in mice show that expression of hypo‐phosphorylated pRb does not impede normal development, but promotes hallmarks of aging and diabetes by inhibiting cell‐cycle re‐entry and regeneration.
Rb∆K4 and Rb∆K7 knock‐in mice, in which four or all, respectively, phosphorylation sites at the C‐terminal are genetically abolished, exhibit normal embryogenesis and neonatal growth.
Inhibition of pRb phosphorylation at the C‐terminal selectively suppresses phosphorylation of additional upstream sites.
Rb∆K7 mice develop hallmarks of aging and severe diabetes, caused by inability of pancreatic β‐cells to reduplicate in response to mitogenic signals, leading to a DDR and senescence.
Vitamin C diet reduces the DDR and senescence of pancreatic β‐cells and attenuates diabetes in Rb∆K7 mice.
Both activation and inactivation of pRb have deleterious long‐term effects on cancer and regeneration/aging.
Abolishing cell‐cycle‐related hyperphosphorylation of the retinoblastoma tumor suppressor in vivo does not impede normal mammalian development, but blocks cell‐cycle reentry and triggers senescence of pancreatic beta‐cells.
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