Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the ...purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM.
Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled.
A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P<0.001). There was a trend towards a higher frequency of concomitant resistance mutations in patients with TP53 LOH than those without (70.6% versus 33.3%; P=0.162). EGFR T790M was identified in CSF cfDNA of 30.4% (7/23) of patients who experienced TKI progression.
CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.
Flavonoids are a group of polyphenolic compounds, diverse in chemical structure and characteristics, found ubiquitously in plants. Until now, more than 9000 different flavonoid compounds were ...described in plants, where they play important biological roles by affecting several developmental processes. There has been increasing interest in the research of flavonoids from dietary sources, due to growing evidence of the versatile health benefits of flavonoids including anti-inflammatory, antioxidant, antiproliferative and anticancer activity, freeradical scavenging capacity, antihypertensive effects, coronary heart disease prevention and anti-human immunodeficiency virus functions. This paper reviews the current advances in flavonoids in food with emphasis on mechanism aspects on the basis of the published literature, which may provide some guidance for researchers in further investigations and for industries in developing practical health agents.
•Evaluate the performances of four inflow turbulence generation methods.•Identify their advantages and limitations for LES of wind effects on tall building.•Provide remedial measures to improve the ...performances of the methods.•Propose a procedure for accurate LES of wind effects on tall building.
Generation of turbulent inflow conditions matching realistic wind flow characteristics in atmospheric boundary layer (ABL) is essential for accurate predictions of wind effects on buildings and structures using large eddy simulation (LES). It is thus necessary to evaluate the performances of different inflow turbulence generation techniques. In this study, four inflow turbulence generation methods (including three synthetic turbulence methods and the recycling method) were used to simulate wind flows in ABL for LES of wind loadings on a tall building. The advantages and limitations of these inflow turbulence generation methods were discussed through comparisons with available wind tunnel measurements and previous numerical simulation results. Several remedial measures were presented to improve the performances of these inflow turbulence generation methods. The findings of this paper are of use and interest to researchers and designers involved in the wind-resistant design of tall buildings, since one can follow the established procedure to predict the dynamic wind loadings on tall buildings by LES.
A clearer definition of the molecular determinants that drive the development and progression of prostate cancer (PCa) is urgently needed. Efforts to map recurrent somatic deletions in the tumor ...genome, especially homozygous deletions (HODs), have provided important positional information in the search for cancer-causing genes. Analyzing HODs in the tumors of 244 patients from two independent cohorts and 22 PCa xenografts using high-resolution single-nucleotide polymorphism arrays, herein we report the identification of CHD1, a chromatin remodeler, as one of the most frequently homozygously deleted genes in PCa, second only to PTEN in this regard. The HODs observed in CHD1, including deletions affecting only internal exons of CHD1, were found to completely extinguish the expression of mRNA of this gene in PCa xenografts. Loss of this chromatin remodeler in clinical specimens is significantly associated with an increased number of additional chromosomal deletions, both hemi- and homozygous, especially on 2q, 5q and 6q. Together with the deletions observed in HEK293 cells stably transfected with CHD1 small hairpin RNA, these data suggest a causal relationship. Downregulation of Chd1 in mouse prostate epithelial cells caused dramatic morphological changes indicative of increased invasiveness, but did not result in transformation. Indicating a new role of CHD1, these findings collectively suggest that distinct CHD1-associated alterations of genomic structure evolve during and are required for the development of PCa.
Abstract
As a novel X-ray focusing technology, lobster-eye micropore optics (MPO) feature both a wide observing field of view and true imaging capability, promising sky monitoring with significantly ...improved sensitivity and spatial resolution in soft X-rays. Since first proposed by Angel, the optics have been extensively studied, developed and trialed over the past decades. In this Letter, we report on the first-light results from a flight experiment of the Lobster Eye Imager for Astronomy, a pathfinder of the wide-field X-ray telescope of the Einstein Probe mission. The piggyback imager, launched in 2022 July, has a mostly unvignetted field of view of 18.°6 × 18.°6. Its spatial resolution is in the range of 4′–7′ in FWHM and the focal spot effective area is 2–3 cm
2
, both showing only mild fluctuations across the field of view. We present images of the Galactic center region, Sco X-1, and the diffuse Cygnus Loop nebular taken in snapshot observations over 0.5–4 keV. These are truly wide-field X-ray images of celestial bodies observed, for the first time, by a focusing imaging telescope. Initial analyses of the in-flight data show excellent agreement between the observed images and the on-ground calibration and simulations. The instrument and its characterization are briefly described, as well as the flight experiment. The results provide a solid basis for the development of the present and proposed wide-field X-ray missions using lobster-eye MPO.
In this work, we report the in-orbit demonstration of X-ray pulsar navigation with Insight-Hard X-ray Modulation Telescope (Insight-HXMT) Satellite, which was launched on 2017 June 15. The new pulsar ...navigation method "Significance Enhancement of Pulse-profile with Orbit-dynamics" is adopted to determine the orbit with observations of only one pulsar. In this test, the Crab pulsar is chosen and observed by Insight-HXMT from 2017 August 31 to September 5. Using the five-day long observation data, the orbit of Insight-HXMT is determined successfully with the three telescopes onboard: High Energy X-ray Telescope, Medium Energy X-ray Telescope, and Low Energy X-ray Telescope, respectively. By combining all the data, the position and velocity of the Insight-HXMT are pinpointed to within 10 km (3 ) and 10 m s−1 (3 ), respectively.
The evolution of beam phase space in ionization injection into plasma wakefields is studied using theory and particle-in-cell simulations. The injection process involves both longitudinal and ...transverse phase mixing, leading initially to a rapid emittance growth followed by oscillation, decay, and a slow growth to saturation. An analytic theory for this evolution is presented and verified through particle-in-cell simulations. This theory includes the effects of injection distance (time), acceleration distance, wakefield structure, and nonlinear space charge forces, and it also shows how ultralow emittance beams can be produced using ionization injection methods.
Background The consistent finding of a genetic susceptibility to prostate cancer suggests that there are germline sequence variants predisposing individuals to this disease. These variants could be ...useful in screening and treatment. Methods We performed an exploratory genome-wide association scan in 498 men with aggressive prostate cancer and 494 control subjects selected from a population-based case–control study in Sweden. We combined the results of this scan with those for aggressive prostate cancer from the publicly available Cancer Genetic Markers of Susceptibility (CGEMS) Study. Single-nucleotide polymorphisms (SNPs) that showed statistically significant associations with the risk of aggressive prostate cancer based on two-sided allele tests were tested for their association with aggressive prostate cancer in two independent study populations composed of individuals of European or African American descent using one-sided tests and the genetic model (dominant or additive) associated with the lowest value in the exploratory study. Results Among the approximately 60000 SNPs that were common to our study and CGEMS, we identified seven that had a similar (positive or negative) and statistically significant (P<.01) association with the risk of aggressive prostate cancer in both studies. Analysis of the distribution of these SNPs among 1032 prostate cancer patients and 571 control subjects of European descent indicated that one, rs1571801, located in the DAB2IP gene, which encodes a novel Ras GTPase-activating protein and putative prostate tumor suppressor, was associated with aggressive prostate cancer (one-sided P value = .004). The association was also statistically significant in an African American study population that included 210 prostate cancer patients and 346 control subjects (one-sided P value = .02). Conclusion A genetic variant in DAB2IP may be associated with the risk of aggressive prostate cancer and should be evaluated further.
•Carry out a combined wind tunnel test and CFD study on the wind effects on an elliptical cylinder.•Investigate the surface roughness effects on the wind loading of an elliptical cylinder using ...DES.•DES and LES models and numerical treatments adopted in this study can provide reasonably good correspondence with wind tunnel tests.•DES model can reproduce the effects of surface roughness effects on the wind loading with the modified wall function.
In this study, detached-eddy simulations (DES) and large-eddy simulations (LES) of wind effect on a high-rise structure with elliptical shape are performed. The aim of this study is to examine the accuracy of the numerical simulations for wind flow around a complex high-rise structure and investigate the effects of surface roughness on the wind loading. In order to reproduce appropriate inflow turbulence, the improved recycling method combined with the weighted amplitude wave superposition (WAWS) method is used to generate the inflow turbulence in the streamwise direction. Also, to study the surface roughness effects on the wind loading, the rough wall boundary conditions are adopted in the DES models. Typical results including the mean and fluctuating pressure coefficients, force spectra, Reynolds stresses and wind-induced top-floor response are obtained and compared with the corresponding wind tunnel experimental data. Through the cross-comparisons, the numerical results by the DES and LES models are found to be comparable with the experimental results. Additionally, the surface roughness effects on the wind loading is well reproduced with the DES models, such as the slow pressure recovery in the separation regions and the increased mean drag force coefficients. It is demonstrated through the validations that the DES and LES models and the numerical treatments adopted in this study can provide reasonably good results.
The pulmonary epithelial glycocalyx, an anionic cell surface layer enriched in glycosaminoglycans such as heparan sulfate and chondroitin sulfate, contributes to the alveolar barrier. Direct injury ...to the pulmonary epithelium induces shedding of heparan sulfate into the air space; the impact of this shedding on recovery after lung injury is unknown. Using mass spectrometry, we found that heparan sulfate was shed into the air space for up to 3 wk after intratracheal bleomycin-induced lung injury and coincided with induction of matrix metalloproteinases (MMPs), including MMP2. Delayed inhibition of metalloproteinases, beginning 7 days after bleomycin using the nonspecific MMP inhibitor doxycycline, attenuated heparan sulfate shedding and improved lung function, suggesting that heparan sulfate shedding may impair lung recovery. While we also observed an increase in air space heparanase activity after bleomycin, pharmacological and transgenic inhibition of heparanase in vivo failed to attenuate heparan sulfate shedding or protect against bleomycin-induced lung injury. However, experimental augmentation of airway heparanase activity significantly worsened post-bleomycin outcomes, confirming the importance of epithelial glycocalyx integrity to lung recovery. We hypothesized that MMP-associated heparan sulfate shedding contributed to delayed lung recovery, in part, by the release of large, highly sulfated fragments that sequestered lung-reparative growth factors such as hepatocyte growth factor. In vitro, heparan sulfate bound hepatocyte growth factor and attenuated growth factor signaling, suggesting that heparan sulfate shed into the air space after injury may directly impair lung repair. Accordingly, administration of exogenous heparan sulfate to mice after bleomycin injury increased the likelihood of death due to severe lung dysfunction. Together, our findings demonstrate that alveolar epithelial heparan sulfate shedding impedes lung recovery after bleomycin.
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