Elevated pretreatment neutrophil-to-lymphocyte ratio indicate low survival rate in apatinib-treated patients with non-small cell lung cancer: A STROBE-compliant article

This study aimed to analyze the predictive value of the neutrophil-to-lymphocyte ratio (NLR) to better clarify which patients with advanced non-small cell lung cancer (NSCLC) would benefit most from apatinib after multiline treatment for drug resistance. This observational cohort study involved patients with advanced NSCLC who were treated with apatinib between May 2016 to May 2018. The participants in this study had previously been treated with at least two treatment regimens. Multivariate logistic regression and Cox proportional risk models were used to evaluate the overall survival (OS) and progression-free survival (PFS) of the pretreatment NLR. A total of 125 patients were reviewed. The median age was 64 years (range, 33–92); and 32.8% of the patients were female. Only 0.8% of the patients had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score ≥ 2. In multivariate analysis, pretreatment NLR ≥ 5 had an independent correlation with inferior OS (median 2.07 vs 3.40 months; HR 1.493, 95% CI 1.022–2.182; P = .038) and inferior PFS (median 1.83 vs 2.76 months; HR 1.478, 95% CI 1.015–2.153; P = .042). Elevated pretreatment NLR is associated with shorter OS and PFS in patients with advanced NSCLC treated with apatinib after multiline treatment for drug resistance.     

Origin recognition complex harbors an intrinsic nucleosome remodeling activity

Eukaryotic DNA replication is initiated at multiple chromosomal sites known as origins of replication that are specifically recognized by the origin recognition complex (ORC) containing multiple ATPase sites. In budding yeast, ORC binds to specific DNA sequences known as autonomously replicating sequences (ARSs) that are mostly nucleosome depleted. However, nucleosomes may still inhibit the licensing of some origins by occluding ORC binding and subsequent MCM helicase loading. Using purified proteins and single-molecule visualization, we find here that the ORC can eject histones from a nucleosome in an ATP-dependent manner. The ORC selectively evicts H2A-H2B dimers but leaves the (H3-H4)₂ tetramer on DNA. It also discriminates canonical H2A from the H2A.Z variant, evicting the former while retaining the latter. Finally, the bromo-adjacent homology (BAH) domain of the Orc1 subunit is essential for ORC-mediated histone eviction. These findings suggest that the ORC is a bona fide nucleosome remodeler that functions to create a local chromatin environment optimal for origin activity.

DNA replication is a vital life process for all cell types—bacterial, eukaryotic, and archaeal. While there are important differences among the replication proteins of the three domains of life, they mostly function in similar ways. All of them use an origin binding protein that acts with other factors to load two hexameric helicases onto DNA for bidirectional unwinding of the duplex, and thus the ability to simultaneously replicate both strands of the cellular genome (1–3). The eukaryotic origin binding protein is a heterohexamer referred to as the origin recognition complex (ORC) (4). The sequences of the Orc1-6 subunits are conserved from yeast to human, and several of the subunits contain an adenosine triphosphate (ATP)-binding AAA⁺ module as in the Escherichia coli DnaA initiator. Origins in the budding yeast Saccharomyces cerevisiae occur in 100- to 200-bp DNA regions known as autonomously replicating sequences (ARSs) (5–10). However, the existence of ARSs is limited to only some species of budding yeast. Origins of replication with defined DNA sequences are not known at this time to exist in other eukaryotes (1, 2).The special feature of a defined origin sequence in S. cerevisiae has facilitated extensive characterization of the mechanism of DNA replication initiation (1). ORC interacts with Cdc6, Cdt1, and the minichromosome maintenance protein complex (Mcm)2–7 heterohexamer to assemble a Mcm2-7 double hexamer (referred to here as MCM DH) onto DNA in G1 phase (1–3). The loaded MCM DH is the “licensing” factor for replication because it acts as the marker for origin firing in S phase (11). Specifically, the MCM DH is acted upon by several initiation factors to form 2 larger 11-subunit CMG (Cdc45/Mcm2-7/GINS) helicases (12, 13). The two CMG helicases are oriented toward and pass each other to unwind DNA, and recruit the replicative machinery to form bidirectional replication forks (14, 15). ORC and the many other factors required to license an origin and form bidirectional replication forks are conserved in all eukaryotes.The yeast ARS is AT rich, which is not favorable to nucleosome binding (16, 17). Indeed, chromatin immunoprecipitation sequencing (ChIP-seq) studies indicate that many ARSs have a nucleosome-free region (NFR) that expands in G1/S phase (10, 18–20). Presumably the nucleosomes are moved aside to make way for ORC-mediated MCM DH formation at origins in G1 phase, and for CMG formation in S phase. In vitro studies demonstrate that in the presence of saturating nucleosomes, the ARS is functional for replication initiation without need for classic nucleosome remodelers (21), indicating that the expansion of the NFR at an ARS site may be achieved intrinsically by the origin recognition and replication machinery.We have recently reported that ORC binding to nucleosomes facilitates the loading of MCM DHs onto DNA, regardless of the DNA sequence (22). In that study, we observed the loss of the fluorescently labeled histone signal after ORC–nucleosome interaction, but did not investigate further the source and mechanism of this observation as it was not the focus of the study. Considering that ORC binding is the first step of origin licensing and that ORC harbors multiple ATPase sites, here, we explored the possibility that ORC itself may possess an ATP-facilitated nucleosome remodeling activity. Using single-molecule fluorescence microscopy combined with optical trapping, we find that ORC is indeed an ATP-dependent nucleosome remodeler with the ability to eject H2A-H2B dimers. ORC-mediated nucleosome remodeling may represent the inaugural event toward creating a local chromatin environment permissive to replication initiation.     

Hard Carbon Embedded with FeSiAl Flakes for Improved Microwave Absorption Properties

Carbon-based composites have been proven to be strong candidates for microwave absorbers in recent years. However, as an important member, magnetic hard carbon (HC)-based composites have rarely been studied in the field of microwave absorption. In this study, HC embedded with FeSiAl (FeSiAl@HC) was synthesized by pyrolyzing a mixture of FeSiAl flakes and phenolic resin (PR). The as-synthesized HC-FeSiAl exhibited a layered structure, and the detailed microstructures were modified by changing the mass ratio of FeSiAl flakes and PR. Thus, the as-synthesized HC-FeSiAl exhibited tunable magnetic properties, wealthy functional groups, excellent thermal stability, and enhanced microwave absorption properties. The optimal minimum reflection loss is lower up to −36.1 dB, and the effective absorption bandwidth is wider up to 11.7 GHz. These results indicated that HC-FeSiAl should be a strong candidate for practical applications of microwave absorption, which may provide new insight into the synthesis of magnetic HC-based composites.     

Study on Coated Zr-V-Cr Getter with Pore Gradient Structure for Hydrogen Masers

As the core component of satellite navigation, the hydrogen maser needs a high vacuum environment to maintain the stability of the frequency signal. The getter pump, composed of various non-evaporable getters, plays an important role in maintaining the high vacuum. In this paper, the Zr_100-xCu_x (x = 0, 2, 4, 6)/Zr_56.97V_35.85Cr_7.18 getter was studied and the contradiction between sorption performance and mechanical properties was solved. The Zr-V-Cr getter, a better candidate for getter pump, exists for problems which will destroy the high vacuum and affect the service life of the hydrogen maser. To solve the problem of dropping powder from Zr-V-Cr getter, Zr-Cu films were coated on the surface of Zr-V-Cr matrix to obtain the pore gradient structure. After vacuum sintering, the interface showed gradient structure and network change in pore structure from Zr-Cu film to Zr-V-Cr matrix. These characteristic structures made Zr-V-Cr getter have good absorption properties, which is better than a similar product of SAES company and mechanical properties. Because the Zr-Cu film on Zr-V-Cr matrix effectively prevented dropping powders from the matrix, (Zr-Cu)/(Zr-V-Cr) getter solved the problem of dropping powder. The self-developed new getter with pore gradient structure is of great significance for maintaining the high vacuum of hydrogen maser in the future.     

An Easily Used Phenomenological Magnetization Model and Its Empirical Expressions Based on Jiles–Atherton Parameters

In this paper, a simple magnetization model convenient for engineering applications is presented based on the expressions of the first-order LTI system model. Considering the trade-off between the nonlinearity of anhysteretic magnetization and the hysteresis width, the proposed model employs two different equations with different magnetic field amplitudes. Furthermore, the proposed model utilizes the first-order LTI system model with a low magnetic field amplitude and a simple nonlinear function, based on the amplitude–frequency function, with a high magnetic field amplitude. Two important characteristic parameters for engineering applications, namely, amplitude and the equivalent phase lag, were exacted and analyzed to validate the computation precision of the proposed model. Then, the model was verified through comparisons to the validated Jiles–Atherton model. For easy use, similar to a physics-based model instead of a fitting method, empirical expressions for the model parameters were given, and applicable ranges of these equations were determined using the parameters of the Jiles–Atherton model. Finally, an example of the magnetization model applied to an on/off type device was computed to further verify the effectiveness of the proposed model with quite a simple expression.     

Effect of Lanthanum Addition on Formation Behaviors of Inclusions in Q355B Weathering Steel

The effect of lanthanum addition on the formation behaviors of inclusions in Q355B weathering steel was investigated by laboratory experiments and thermodynamic calculations. The results demonstrate that the main inclusions in weathering steel without La addition are large-sized irregular Al₂O₃ and MnS, with an average size of about 5.35 μm. As La content increases from 0.0075 to 0.0184 wt.%, the dominant inclusions transform from MnS, LaAlO₃, and Al₂O₃-LaAlO₃ into MnS, La₂O₃, and LaAlO₃-La₂O₃. Meanwhile, the average size of inclusions significantly decreases from 3.4 to 2.48 μm and the distribution is more dispersive. When the La content increases to 0.0425 wt.%, the original MnS and Al₂O₃ inclusions are completely modified into La₂O₂S and La₂O₃ but the inclusions demonstrate serious agglomeration and growth. The thermodynamic calculations indicate that Al₂O₃ and various lanthanum-containing inclusions are formed in the liquid phase. As the La content in molten steel increases from 0 to 0.0425 wt.%, the Al₂O₃ inclusion is inclined to be modified into lanthanum oxide and lanthanum oxysulfide and the modification process is Al₂O₃ → LaAlO₃ → La₂O₃ → La₂O₂S, which is very consistent with the experimental observations.     

Microstructure and Properties of a Graphene Reinforced Cu–Cr–Mg Composite

To improve the graphene/copper interfacial bonding and the strength of the copper matrix, Cu–Cr–Mg alloy powder and graphene nanosheets (GNPs) have been used as raw materials in the preparation of a layered graphene/Cu–Cr–Mg composite through high-energy ball-milling and fast hot-pressing sintering. The microstructure of the composite after sintering, as well as the effect of graphene on the mechanical properties and conductivity of the composite, are also studied. The results show that the tensile strength of the composite material reached a value of 349 MPa, which is 46% higher than that of the copper matrix, and the reinforcement efficiency of graphene is as large as 136. Furthermore, the electrical conductivity of the composite material was 81.6% IACS, which is only 0.90% IACS lower than that of the copper matrix. The Cr and Mg elements are found to diffuse to the interface of the graphene/copper composite during sintering, and finely dispersed chromium carbide particles are found to significantly improve the interfacial bonding strength of the composite. Thus, graphene could effectively improve the mechanical properties of the composite while maintaining a high electrical conductivity.     

Experimental Study on Mechanical Properties and Failure Laws of Granite with Artificial Flaws under Coupled Static and Dynamic Loads

Rock is the main construction material of rock engineering, such as the engineering of mines and tunnels; in addition, its mechanical properties and failure laws are of great significance to the stability evaluation of rock engineering, especially under the conditions of coupled static–static stresses. In this study, granite specimens were manufactured with artificial flaws. Coupled static and dynamic loads tests were carried out with a modified split Hopkinson pressure bar (SHPB) apparatus; and six typical levels of axial pre-stresses and three crack inclination angles were designed. Three-dimensional digital image correlation (3D-DIC) was also applied to record and analyze the fracturing process and damage evolution of the specimens. The test results show that there was no compaction stage in the stress–strain curve under combined dynamic and static loading. The dynamic strength of the specimens increased first and then decreased with the increase in the static pressure; moreover, the specimens reached the maximum dynamic strength when the static pressure was 10% UCS. The dynamic strength decreased first and then increased with the increase in the crack inclination angle; and the lowest strength appeared when the inclination angle was 45°. The change in axial compression had a significant influence on the failure mode, and the failure mode gradually transformed from shear–tensile failure to shear failure with the increase in the pre-stress. The tensile strain was usually generated at the end of the fractures or near the rock bridge. When the axial pressure was small, the tensile strain zone parallel to the loading direction was easily generated; and when the axial pressure was large, a shear strain zone developed, extending along the diagonal direction. The research results can provide a theoretical reference for the correct understanding of the failure mechanisms of granite and its engineering stability under actual conditions.