We demonstrate a novel technique for calibrating the energy scale of the EPIC-pn detector on XMM-Newton , which allows us to measure bulk flows in the intracluster medium (ICM) of the Perseus and ...Coma galaxy clusters. The procedure uses the fluorescent instrumental background lines present in all observations, in particular, Cu-K α . By studying their spatial and temporal variations, in addition to incorporating calibration observations, we refined the absolute energy scale of the detector to better than 150 km s −1 at the Fe-K line, a large improvement over the nominal calibration accuracy of 550 km s −1 . With our calibration, we mapped the bulk motions over much of the central 1200 and 800 kpc of Perseus and Coma, respectively, in spatial regions down to 65 and 140 kpc size. We cross-checked our procedure by comparing our measurements with those found in Perseus by Hitomi for an overlapping 65 kpc square region, finding consistent results. For Perseus, there is a relative line-of-sight velocity increase of 480 ± 210 km s −1 (1 σ ) at a radius of 250 kpc east of the nucleus. This region is associated with a cold front, providing direct evidence of the ICM sloshing in the cluster potential well. Assuming the intrinsic distribution of bulk motions is Gaussian, its width is 214 ± 85 km s −1 , excluding systematic uncertainties. Removing the sloshing region, this is reduced to 20–150 km s −1 , which is similar in magnitude to the Hitomi line width measurements in undisturbed regions. In Coma, the line-of-sight velocity of the ICM varies between the velocities of the two central galaxies. Maps of the gas velocity and metallicity provide clues about the merger history of the Coma, with material to the north and east of the cluster core having a velocity similar to NGC 4874 , while that to the south and west has velocities close to NGC 4889 . Our results highlight the difference between a merging system, such as Coma, where we observe a ∼1000 km s −1 range in velocity, and a relatively relaxed system, such as Perseus, with much weaker bulk motions.
Extreme storms present a major risk to coasts. Increasing populations worldwide, together with sea level rise, exacerbate concerns for coastal settlements, but the low frequency of extreme storms ...makes an assessment of risk difficult. In southeast Australia, the severest beach retreat on record relates to a series of extratropical cyclones in the 1970s, but the relatively short observational record hinders assessment of how frequent these events are. At Moruya in New South Wales, four decades of beach monitoring has provided new insights into response of beaches to extreme storms. We augment this recorded history with morphostratigraphic analysis of beach ridge evolution by using ground‐penetrating radar and optically stimulated luminescence dating. We find an episode of extreme retreat over 550 years, proving that the 1970s extreme event is a recurrent phenomenon. Our high‐precision morphostratigraphic analysis provides evidence with which to better plan coastal adaptation.
Key Points
Short observational history in SE Australia hinders assessment of whether extreme beach retreat in the 1970s is an isolated or recurrent event
High‐precision morphostratigraphic analysis of beach ridge evolution augments 40 years of beach profiling at Moruya in NSW
Extreme beach retreat is found to have occurred around 1650–1700, revealing that the 1970s event is a recurrent phenomenon
A fourth production region for the globally important Antarctic bottom water has been attributed to dense shelf water formation in the Cape Darnley Polynya, adjoining Prydz Bay in East Antarctica. ...Here we show new observations from CTD-instrumented elephant seals in 2011-2013 that provide the first complete assessment of dense shelf water formation in Prydz Bay. After a complex evolution involving opposing contributions from three polynyas (positive) and two ice shelves (negative), dense shelf water (salinity 34.65-34.7) is exported through Prydz Channel. This provides a distinct, relatively fresh contribution to Cape Darnley bottom water. Elsewhere, dense water formation is hindered by the freshwater input from the Amery and West Ice Shelves into the Prydz Bay Gyre. This study highlights the susceptibility of Antarctic bottom water to increased freshwater input from the enhanced melting of ice shelves, and ultimately the potential collapse of Antarctic bottom water formation in a warming climate.
Background: To compare the efficacy and toxicity of three platinum-based combination regimens against cisplatin plus irinotecan (IP) in patients with untreated advanced non-small-cell lung cancer ...(NSCLC) by a non-inferiority design.
Patients and methods: A total of 602 patients were randomly assigned to one of four regimens: cisplatin 80 mg/m2 on day 1 plus irinotecan 60 mg/m2 on days 1, 8, 15 every 4 weeks (IP) carboplatin AUC 6.0 min × mg/mL (area under the concentration–time curve) on day 1 plus paclitaxel 200 mg/m2 on day 1 every 3 weeks (TC); cisplatin 80 mg/m2 on day 1 plus gemcitabine 1000 mg/m2 on days 1, 8 every 3 weeks (GP); and cisplatin 80 mg/m2 on day 1 plus vinorelbine 25 mg/m2 on days 1, 8 every 3 weeks (NP).
Results: The response rate, median survival time, and 1-year survival rate were 31.0%, 13.9 months, 59.2%, respectively, in IP; 32.4%, 12.3 months, 51.0% in TC; 30.1%, 14.0 months, 59.6% in GP; and 33.1%, 11.4 months, 48.3% in NP. No statistically significant differences were found in response rate or overall survival, but the non-inferiority of none of the experimental regimens could be confirmed. All the four regimens were well tolerated.
Conclusion: The four regimens have similar efficacy and different toxicity profiles, and they can be used to treat advanced NSCLC patients.
This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous ...non-small-cell lung cancer (NSCLC).
Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC).
Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively.
The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.
•Nivolumab with carboplatin, paclitaxel, and bevacizumab was evaluated as first-line therapy for nonsquamous NSCLC.•The nivolumab combination therapy provided superior PFS across all patients with any PD-L1 expression levels.•The median PFS of 12.1 months is the longest among all phase III studies for nonsquamous NSCLC without driver mutations.•No new safety signals were observed.
Hepatocellular carcinoma (HCC) is a frequent form of cancer with a poor prognosis and with limited possibilities for medical intervention. Recent evidence has accumulated that long noncoding RNAs ...(lncRNAs) are important regulators of disease processes including cancer. Chromatin remodeling in cancer cells may result in an unusual expression of lncRNAs and indeed it has been shown that more than 7000 unannotated lncRNAs are expressed in HCCs. We identified a novel long intergenic noncoding RNA, Linc00176, that plays a role in proliferation and survival of HCC. Linc00176 regulates expression of more than 200 genes by the sponge function for tumor suppressor miRNAs, miR-9 and miR-185. Linc00176 is expressed at a high level only in HCC, and is activated by Myc, Max and AP-4 transcription regulators. Myc also upregulates miR-9 and miR-185. In Linc00176-depleted HCC, these miRNAs were released from Linc00176 and downregulated their target mRNAs. Thus, depletion of Linc00176 disrupted the cell cycle and induced necroptosis in HCC via released tumor suppressor miRNAs. These data indicate that atypically expressed lncRNAs may be useful targets for cancer therapy.
FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab.
WJOG4407G was a randomized, ...open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396.
Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively HR, 0.905; 95% confidence interval (CI) 0.723–1.133; P = 0.003 for non-inferiority. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785–1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months.
FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC.
UMIN000001396.
In this paper, we present the analysis and results of a direct measurement of the cosmic-ray proton spectrum with the CALET instrument onboard the International Space Station, including the detailed ...assessment of systematic uncertainties. The observation period used in this analysis is from October 13, 2015 to August 31, 2018 (1054 days). We have achieved the very wide energy range necessary to carry out measurements of the spectrum from 50 GeV to 10 TeV covering, for the first time in space, with a single instrument the whole energy interval previously investigated in most cases in separate subranges by magnetic spectrometers (BESS-TeV, PAMELA, and AMS-02) and calorimetric instruments (ATIC, CREAM, and NUCLEON). The observed spectrum is consistent with AMS-02 but extends to nearly an order of magnitude higher energy, showing a very smooth transition of the power-law spectral index from -2.81±0.03 (50-500 GeV) neglecting solar modulation effects (or -2.87±0.06 including solar modulation effects in the lower energy region) to -2.56±0.04 (1-10 TeV), thereby confirming the existence of spectral hardening and providing evidence of a deviation from a single power law by more than 3σ.
Extended results on the cosmic-ray electron + positron spectrum from 11 GeV to 4.8 TeV are presented based on observations with the Calorimetric Electron Telescope (CALET) on the International Space ...Station utilizing the data up to November 2017. The analysis uses the full detector acceptance at high energies, approximately doubling the statistics compared to the previous result. CALET is an all-calorimetric instrument with a total thickness of 30 X_{0} at normal incidence and fine imaging capability, designed to achieve large proton rejection and excellent energy resolution well into the TeV energy region. The observed energy spectrum in the region below 1 TeV shows good agreement with Alpha Magnetic Spectrometer (AMS-02) data. In the energy region below ∼300 GeV, CALET's spectral index is found to be consistent with the AMS-02, Fermi Large Area Telescope (Fermi-LAT), and Dark Matter Particle Explorer (DAMPE), while from 300 to 600 GeV the spectrum is significantly softer than the spectra from the latter two experiments. The absolute flux of CALET is consistent with other experiments at around a few tens of GeV. However, it is lower than those of DAMPE and Fermi-LAT with the difference increasing up to several hundred GeV. The observed energy spectrum above ∼1 TeV suggests a flux suppression consistent within the errors with the results of DAMPE, while CALET does not observe any significant evidence for a narrow spectral feature in the energy region around 1.4 TeV. Our measured all-electron flux, including statistical errors and a detailed breakdown of the systematic errors, is tabulated in the Supplemental Material in order to allow more refined spectral analyses based on our data.
There have been limited reports on mastication speed during cattle rumination. The objective of this study was to establish a method to detect mastication speed based on data obtained during ...rumination through the use of a 3-axis accelerometer attached to the neck. A 3-axis accelerometer was attached to 6 dry Holstein cattle. When rumination behavior was observed, the accelerometer and the high-speed camera simultaneously recorded acceleration at the neck and moving image of the head movement. Based on the number of mastication movements recorded on video, mastication speed A was calculated. Data obtained from the 3-axis accelerometer were analyzed with fast Fourier transfer algorithm and identified as mastication speed B. The vibration of the neck recorded in the accelerometer during rumination was considered as mastication movement. Using Bland-Altman plot analysis, the mean difference between mastication speed A and mastication speed B was 0.041 s/bite, and the 95% limits of agreement ranged from −0.080 to 0.161. Since mastication movement occurred periodically, it was possible to detect the movement using spectrum analysis, as mastication speed B. Although there were some differences between calculated speeds and speeds obtained from spectrum analysis, there was clinical compatibility between mastication speed A and B. This study showed the feasibility of establishing a detection method for mastication speed during rumination, which might provide a basic procedure for studying the purpose of mastication and the variable factors involved.
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