We report the first results of a light weakly interacting massive particles (WIMPs) search from the CDEX-10 experiment with a 10 kg germanium detector array immersed in liquid nitrogen at the China ...Jinping Underground Laboratory with a physics data size of 102.8 kg day. At an analysis threshold of 160 eVee, improved limits of 8×10^{-42} and 3×10^{-36} cm^{2} at a 90% confidence level on spin-independent and spin-dependent WIMP-nucleon cross sections, respectively, at a WIMP mass (m_{χ}) of 5 GeV/c^{2} are achieved. The lower reach of m_{χ} is extended to 2 GeV/c^{2}.
We present results on light weakly interacting massive particle (WIMP) searches with annual modulation (AM) analysis on data from a 1-kg mass p-type point-contact germanium detector of the CDEX-1B ...experiment at the China Jinping Underground Laboratory. Datasets with a total live time of 3.2 yr within a 4.2-yr span are analyzed with analysis threshold of 250 eVee. Limits on WIMP-nucleus (χ-N) spin-independent cross sections as function of WIMP mass (m_{χ}) at 90% confidence level (C.L.) are derived using the dark matter halo model. Within the context of the standard halo model, the 90% C.L. allowed regions implied by the DAMA/LIBRA and CoGeNT AM-based analysis are excluded at >99.99% and 98% C.L., respectively. These results correspond to the best sensitivity at m_{χ}<6 GeV/c^{2} among WIMP AM measurements to date.
We present reverberation-mapping (RM) lags and black hole mass measurements using the C ivλ1549 broad emission line from a sample of 348 quasars monitored as a part of the Sloan Digital Sky Survey RM ...Project. Our data span four years of spectroscopic and photometric monitoring for a total baseline of 1300 days, allowing us to measure lags up to ∼750 days in the observed frame (this corresponds to a rest-frame lag of ∼300 days in a quasar at z = 1.5 and ∼190 days at z = 3). We report significant time delays between the continuum and the C ivλ1549 emission line in 48 quasars, with an estimated false-positive detection rate of 10%. Our analysis of marginal lag measurements indicates that there are on the order of ∼100 additional lags that should be recoverable by adding more years of data from the program. We use our measurements to calculate black hole masses and fit an updated C iv radius-luminosity relationship. Our results significantly increase the sample of quasars with C iv RM results, with the quasars spanning two orders of magnitude in luminosity toward the high-luminosity end of the C iv radius-luminosity relation. In addition, these quasars are located at some of the highest redshifts (z 1.4-2.8) of quasars with black hole masses measured with RM. This work constitutes the first large sample of C iv RM measurements in more than a dozen quasars, demonstrating the utility of multiobject RM campaigns.
Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, flat dosing is expected ...to shorten preparation time and improve ease of administration. With knowledge of nivolumab safety, efficacy, and pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment of the benefit–risk profile of a 240-mg flat dose relative to the approved 3-mg/kg dose was approached by quantitative clinical pharmacology.
A flat dose of 240 mg was selected based on its equivalence to the 3-mg/kg dose at the median BW of ∼80 kg in patients in the nivolumab program. The benefit–risk profile of nivolumab 240 mg was evaluated by comparing exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC; and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC, and RCC.
The median nivolumab exposure and its distribution at 240 mg Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did not demonstrate a clinically meaningful relationship between BW or nivolumab exposure quartiles and frequency or severity of adverse events. The predicted safety and efficacy were similar across nivolumab exposure ranges achieved with 3 mg/kg Q2W or 240 mg Q2W flat dose.
Based on population pharmacokinetic modeling, established flat exposure–response relationships for efficacy and safety, and clinical safety, the benefit–risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology approach provided evidence for regulatory decision-making on dose modification, obviating the need for an independent clinical study.
Proxy records of temperature from the Atlantic clearly show that the Younger Dryas was an abrupt climate change event during the last deglaciation, but records of hydroclimate are underutilized in ...defining the event. Here we combine a new hydroclimate record from Palawan, Philippines, in the tropical Pacific, with previously published records to highlight a difference between hydroclimate and temperature responses to the Younger Dryas. Although the onset and termination are synchronous across the records, tropical hydroclimate changes are more gradual (>100 years) than the abrupt (10-100 years) temperature changes in the northern Atlantic Ocean. The abrupt recovery of Greenland temperatures likely reflects changes in regional sea ice extent. Proxy data and transient climate model simulations support the hypothesis that freshwater forced a reduction in the Atlantic meridional overturning circulation, thereby causing the Younger Dryas. However, changes in ocean overturning may not produce the same effects globally as in Greenland.
Background Aberrant airway epithelial remodeling is one of the cardinal histopathologic features of inflammatory airway diseases, but whether it alters the mucociliary apparatus remains unknown. ...Objective We sought to investigate the morphologic pattern of motile cilia and ciliogenesis-associated makers in hyperplastic nasal epithelium from nasal polyps (NPs) both in vivo and in vitro. Methods Biopsy specimens obtained from patients with NPs (n = 44) and inferior turbinate from healthy control subjects (n = 38) were analyzed by using scanning electron microscopy, immunofluorescence staining, single-cell (cytospin) staining, quantitative real-time PCR, and human nasal epithelial stem/progenitor cell culture and differentiation. Results Abnormal cilia architecture (untidy, overly dense, and lengthened) was more commonly observed in patients with NPs by using scanning electron microscopy. Ectopic lengthened cilia were visualized by means of immunofluorescence (patients with NPs: 6.33 μm 5.51-7.43 μm vs control subjects: 3.73 μm 3.50-4.27 μm, P < .0001), at the site of epithelial hyperplasia in isolated single cells (patients with NPs: 6.55 ± 0.23 μm vs control subjects 4.89 ± 0.24 μm, P < .0001), and in differentiated ciliated cells derived from human nasal epithelial stem/progenitor cells (patients with NPs: 9.20 ± 0.56 μm vs control subjects: 5.21 ± 0.37 μm, P < .0001). Ciliary beat frequency was found to be significantly slower in patients with NPs than control subjects in vitro . Both protein and mRNA levels of ciliogenesis-associated markers (centrosomal protein 110 CP110, forkhead box J1 Foxj1, and P73 isoform with an N-terminal transactivation domain TAp73) were significantly increased in patients with NPs versus those seen in control subjects and were positively correlated with cilia length. Conclusion For the first time, this study demonstrates for that motile cilia impairment is a co-condition of epithelial hyperplasia in patients with NPs, and this impairment of function is a likely cause of chronic mucosal inflammation or infection (eg, biofilm) observed in patients with chronic rhinosinusitis.
Abstract
Mid-infrared (mid-IR) observations are powerful in identifying heavily obscured active galactic nuclei (AGN) that have weak emission in other wavelengths. Data from the Mid-Infrared ...Instrument (MIRI) on board the James Webb Space Telescope provides an excellent opportunity to perform such studies. We take advantage of the MIRI imaging data from the Cosmic Evolution Early Release Science Survey to investigate the AGN population in the distant universe. We estimate the source properties of MIRI-selected objects by utilizing spectral energy distribution (SED) modeling, and classify them into star-forming galaxies (SFs), SF-AGN mixed objects, and AGN. The source numbers of these types are 433, 102, and 25, respectively, from four MIRI pointings covering ∼9 arcmin
2
. The sample spans a redshift range of ≈0–5. We derive the median SEDs for all three source types, respectively, and publicly release them. The median MIRI SED of AGN is similar to the typical SEDs of hot dust-obscured galaxies and Seyfert 2s, for which the mid-IR SEDs are dominated by emission from AGN-heated hot dust. Based on our SED-fit results, we estimate the black hole accretion density (BHAD; i.e., total BH growth rate per comoving volume) as a function of redshift. At
z
< 3, the resulting BHAD agrees with the X-ray measurements in general. At
z
> 3, we identify a total of 27 AGN and SF-AGN mixed objects, leading to that our high-
z
BHAD is substantially higher than the X-ray results (∼0.5 dex at
z
≈ 3–5). This difference indicates MIRI can identify a large population of heavily obscured AGN missed by X-ray surveys at high redshifts.
B7-H4 belongs to the immune costimulatory B7 family and is thought to negatively regulate T-cell mediated immunity, and may contribute an important role in tumor immune evasion. Although the ...expression of B7-H4 has been observed in human pancreatic cancer, the prognostic significance of this expression is poorly understood. This present study explored the prognostic value of B7-H4 in pancreatic cancer. Patients with pancreatic cancer and healthy controls were recruited at the Second Affiliated Hospital to Zhejiang University from January 2011 to December 2014. Expression of B7-H4 was assessed by immunohistochemistry. Immunohistochemical analysis indicated that B7-H4 was expressed in 100% (188/188) of the pancreatic cancer tumor tissue samples, while only in 68% (17/25) of normal pancreatic tissue samples. Furthermore, the expression levels of B7-H4 in pancreatic cancer patients were significantly higher than in controls (P < .01). A significant difference in B7-H4 expression was observed between patients with late tumor-node-metastasis (TNM) stage (III and IV) and early TNM stage (I and II) (P < .01). The expression of B7-H4 was associated with distant metastasis (P < .01) and differentiation (P < .01). In addition, B7-H4 expression (P < .01), distant metastasis (P < .01), TNM stage (P < .01), differentiation (P < .01) and chemotherapy treatment (P < .05) were indicators of poor overall survival time. Multivariate survival analysis indicated that B7-H4 expression, distant metastasis, and chemotherapy treatment (P < .05) were independent prognostic indicators of poor overall survival. In conclusion, B7-H4 is highly expressed in pancreatic cancer, and is an independent predictor of poor prognosis in patients with pancreatic cancer. B7-H4 may represent an immunotherapeutic target in pancreatic cancer.
Quasar broad emission lines are largely powered by photoionization from the accretion continuum. Increased central luminosity will enhance line emissivity in more distant clouds, leading to increased ...average distance of the broad-line-emitting clouds and decreased averaged line width, which is known as the "breathing" broad-line region. However, different lines breathe differently, and some high-ionization lines, such as C iv, can even show "anti-breathing" where the line broadens when luminosity increases. Using multi-year photometric and spectroscopic monitoring data from the Sloan Digital Sky Survey Reverberation Mapping project, we quantify the breathing effect ( ) of broad H , Hβ, Mg ii, C iv, and C iii for statistical quasar samples over z 0.1-2.5. We find that Hβ displays the most consistent normal breathing expected from the virial relation ( ∼ −0.25), Mg ii and H on average show no breathing ( ∼ 0), and C iv (and similarly C iii and Si iv) mostly shows anti-breathing ( > 0). The anti-breathing of C iv can be well understood by the presence of a non-varying core component in addition to a reverberating broad-base component, which is consistent with earlier findings. The deviation from canonical breathing introduces extra scatter (a luminosity-dependent bias) in single-epoch virial BH mass estimates due to intrinsic quasar variability, which underlies the long-argued caveats of C iv single-epoch masses. Using the line dispersion instead of FWHM leads to fewer, albeit still substantial, deviations from canonical breathing in most cases. Our results strengthen the need for reverberation mapping to provide reliable quasar BH masses and to quantify the level of variability-induced bias in single-epoch BH masses based on various lines.
Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung ...cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes.
Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-resolution diffraction data collected with synchrotron radiation.
RETG810C/S mutations at the solvent front and RETY806C/N mutation at the hinge region were found in cfDNAs of an MTC patient with RETM918T/V804M/L, who initially responded to selpercatinib and developed resistance. RETG810C mutant was detected in cfDNAs of a CCDC6-RET-fusion NSCLC patient who developed acquired resistance to selpercatinib. Five RET kinase domain mutations at three non-gatekeeper residues were identified from 39 selpercatinib-resistant cell lines. All five selpercatinib-resistant RET mutants were cross-resistant to pralsetinib. X-ray crystal structures of the RET-selpercatinib and RET-pralsetinib complexes reveal that, unlike other TKIs, these two RET TKIs anchor one end in the front cleft and wrap around the gate wall to access the back cleft.
RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.
•Resistance to selpercatinib and pralsetinib are found at the solvent front and hinge sites of the RET kinase domain.•The identified selpercatinib-resistant RET mutants are cross-resistant to pralsetinib.•Selpercatinib and pralsetinib use an unprecedented binding mode to dock into the RET kinase.•The new kinase inhibitor binding mode avoids the interference from gatekeeper mutations but remains vulnerable to non-gatekeeper mutations.
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