Variable genomic breakpoints have been identified through the application of target-capture DNA next-generation sequencing (NGS) for ALK, ROS1, and RET fusion detection in NSCLC. We investigated ...whether ALK, ROS1, and RET genomic breakpoint location can predict matched targeted therapy efficacy.
NSCLCs were analyzed by DNA NGS, target-specific RNA NGS, whole-transcriptome sequencing, and immunohistochemistry.
In total, 3787 NSCLC samples were analyzed. DNA NGS detected ALK, ROS1, and RET fusions in 241, 59, and 76 cases, respectively. These fusions were divided into canonical (single EML4-ALK, CD74/EZR/TPM3/SDC4-ROS1, and KIF5B/CCDC6-RET fusions), noncanonical (single non–EML4-ALK, non–CD74/EZR/TPM3/SDC4-ROS1, and non–KIF5B/CCDC6-RET fusions), and primary/reciprocal (both primary and reciprocal rearrangements were detected) subtypes on the basis of genomic breakpoint position, and noncanonical and primary/reciprocal subtypes were defined as uncommon fusions. Further RNA sequencing and immunohistochemistry revealed that six of 47 (12.8%) uncommon fusions were actually nonproductive rearrangements that generated no aberrant transcripts or proteins. Moreover, genomic breakpoints of canonical ALK and RET, but not ROS1, fusions always predicted breakpoints at the transcript level, whereas 85.4% (35 of 41) of uncommon fusions actually produced canonical fusion transcripts. Patients with uncommon ALK fusion (n = 31) who received first-line crizotinib exhibited shorter median progression-free survival than those with canonical ALK fusion (n = 53, 8.4 mo versus 12.0 mo, p = 0.004). However, no difference in progression-free survival was observed when only ALK RNA or protein-positive cases were analyzed (p = 0.185).
Uncommon ALK, ROS1, and RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for the accurate detection and interpretation of rare fusions.
Fingerprinting localization using received signal strength (RSS) has been considered as a promising solution for indoor localization systems, due to its ease of use in deployed wireless networks. A ...major bottleneck is the difficult trade-off between localization accuracy and site survey costs. Crowdsourcing-based fingerprint collection is cost efficient because of user participation, but its accuracy is questioned due to the noisy sample locations. In this paper, we present a probabilistic radio map construction scheme with crowdsourcing collection, considering both accuracy and survey costs. In particular: 1) based on further studies of RSS properties, we introduce a concept of unfixed data collection-in which sample locations are estimated by an additional localization mechanism-and verify its effectiveness, although sample locations are noisy; 2) we present a modified parametric fitting method to better describe location signatures by transforming RSS into signal envelope; and 3) we propose a clustering-based space partitioning algorithm to improve the fitting effect by reducing the number of multimodal distributions. Extensive simulations and experiments show the proposed method can construct an accurate radio map at a low cost, and achieve a localization accuracy of about 2.5 m, 20% improvement compared to using the classical radio map in our experimental scenario.
Carbon dioxide reduction (CO
2
RR) has become a promising way to address the energy and environmental crisis, of which the fundamental development of the optimal electrocatalysts is the crucial part. ...Herein, we develop Fe and N doping porous carbon nematosphere (FeNPCN) as an excellent CO
2
RR electrocatalyst in aqueous electrolyte. Featuring with the high conductivity, pore structure and abundant Fe and N doping, FeNPCN exhibits high catalytic activity with a high faradaic selectivity of CO (94%) and long-term durability. Moreover, the ratio of CO and H
2
can be changed by the applied potential for the different syngas related industry. Density functional theory (DFT) calculation results also reveal that the excellent catalytic activity is likely attributed to C and N hybrid coordination with atomic Fe.
•We study the frost resistance of air-entrained recycled aggregate concrete (ARAC).•The effects of four parent concretes and three mixing approaches are investigated.•The failure mechanism of ARAC ...after freezing and thawing is established.•This is done on the basis of a mesostructural analysis of the test samples.
We elucidated the effects of the parent concrete and mixing approach used on the freezing/thawing resistance of air-entrained recycled aggregate concrete (ARAC). Three non-air-entrained concretes and one air-entrained concrete were used to prepare recycled coarse aggregate (RCA) samples. Three mixing approaches were also investigated. The frost resistances of the ARAC samples produced using an RCA obtained from the non-air-entrained concrete with high strength as well as the air-entrained one were close to that of conventional concrete. The mixing approach used had no effect on the frost resistance. A possible mechanism for the failure of ARAC is proposed.
State-of-the-art radio frequency identification (RFID)-based indoor autonomous vehicles localization methods are mostly based on received signal strength indicator (RSSI) measurements. However, the ...accuracy of these methods is not high enough for real-world scenarios. To overcome this problem, a novel dual-frequency phase difference of arrival (PDOA) ranging-based indoor autonomous vehicle localization and tracking scheme was developed. Firstly, the method gets the distance between the RFID reader and the tag by dual-frequency PDOA ranging. Then, a maximum likelihood estimation and semi-definite programming (SDP)-based localization algorithm is utilized to calculate the position of the autonomous vehicles, which can mitigate the multipath ranging error and obtain a more accurate positioning result. Finally, vehicle traveling information and the position achieved by RFID localization are fused with a Kalman filter (KF). The proposed method can work in a low-density tag deployment environment. Simulation experiment results showed that the proposed vehicle localization and tracking method achieves centimeter-level mean tracking accuracy.
The mechanisms of the exposure to fine particulate matter (PM) as a risk factor for pulmonary injury are not fully understood. The transcription factor, NF-E2-related factor 2 (Nrf2), plays a key ...role in protection lung against PM insult and cancer chemoprevention. In this study, F3-S fly ash particles from a municipal waste incinerator were evaluated as a PM model. We found that F3-S triggered hierarchical oxidative stress responses involving the prolonged activation of the cytoprotective Nrf2 transcriptional program via Keap1 Cys151 modification, and c-Jun NH2-terminal kinase (JNK) phosphorylation at higher doses. In mouse lungs exposed to fly ash particles at a low dose (10–20 mg/kg), Nrf2 signalling was upregulated, while in those exposed to a high fly ash particle dose (40 mg/kg), there was significant activation of JNK, and this correlated with Nrf2 phosphorylation and the downregulation of antioxidant response element (ARE)-driven genes. The JNK inhibitor, SP600125, reversed Nrf2 phosphorylation, and downregulation of detoxifying enzymes. Silencing JNK expression in mouse lungs using adenoviral shRNA inhibited JNK activation and Nrf2 phosphorylation, promoted ARE-driven gene expression, and reduced pulmonary injury. Furthermore, we found that the 452–515 amino acid region within the Neh1 domain of Nrf2 was required for its interaction with P-JNK. We demonstrated that Nrf2 was an important P-JNK target in fly ash-induced pulmonary toxicity. JNK phosphorylated Nrf2, leading to a dysfunction of the Nrf2-mediated defence system.
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•Fly ash particles have a dual effect on Nrf2 signalling pathway.•Fly ash particles activate Nrf2 via Keap1 Cys151 modification.•Fly ash particles at high doses cause dysfunction of Nrf2 via P-JNK.•Nrf2 is an important P-JNK target in fly ash-induced pulmonary toxicity.
•This is a pilot study on seismic performance of recycled aggregate concrete (RAC) columns in freeze-thaw environment.•Seismic behavior of RAC columns after different freeze-thaw cycles was ...investigated.•Load-carrying capacity, ductility, energy dissipation, stiffness degradation and lateral deformation were discussed.
The deterioration of concrete structures due to freeze-thaw cycles is a common problem in cold regions. In this paper, the seismic behavior of recycled aggregate concrete (RAC) columns after freeze-thaw cycles (FTCs) was investigated. RAC columns with three recycled coarse aggregate (RCA) replacement ratios (0, 50% and 100%) and subjected to different FTCs (0, 40 and 80) were tested under constant axial and reversed cyclic lateral loading. The seismic performance was analyzed in terms of various factors: failure patterns, load-displacement relationship, ductility, energy dissipation and stiffness degradation. The deformation in the plastic hinge region was also discussed. The experimental results indicated that all specimens failed in a flexure-dominated mode. Compared with conventional concrete columns, columns with higher RCA replacement ratios had lower load-carrying capacity and poor ductility after FTCs due to poor frost resistance. The equivalent viscous damping ratio increased slightly at the same displacement level for RAC columns due to a larger residual plastic displacement. The initial stiffness was more sensitive to FTCs compared with the degradation rate of stiffness. FTCs and RCA replacement ratio had little effect on the contributions of the flexural, shear and slip deformations to the total lateral deformation.
Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland, with a relatively high cure rate. Distant metastasis (DM) of PTC is uncommon, but when it occurs, it ...significantly decreases the survival of PTC patients. The molecular mechanisms of DM in PTC have not been systematically studied. We performed whole exome sequencing and GeneseeqPrime (425 genes) panel sequencing of the primary tumor, plasma and matched white blood cell samples from 20 PTC with DM and 46 PTC without DM. We identified somatic mutations, gene fusions and copy number alterations and analyzed their relationships with DM of PTC. BRAF‐V600E was identified in 73% of PTC, followed by RET fusions (14%) in a mutually exclusive manner (P < 0.0001). We found that gene fusions (RET, ALK or NTRK1) (P < 0.01) and chromosome 22q loss (P < 0.01) were independently associated with DM in both univariate and multivariate analyses. A nomogram model consisting of chromosome 22q loss, gene fusions and three clinical variables was built for predicting DM in PTC (C‐index = 0.89). The plasma circulating tumor DNA (ctDNA) detection rate in PTC was only 38.9%; however, it was significantly associated with the metastatic status (P = 0.04), tumor size (P = 0.001) and invasiveness (P = 0.01). In conclusion, gene fusions and chromosome 22q loss were independently associated with DM in PTC and could serve as molecular biomarkers for predicting DM. The ctDNA detection rate was low in non–DM PTC but significantly higher in PTC with DM.
The study identified gene fusion and somatic copy number alterations, particularly chromosome 22q loss, to be risk factors for distance metastasis (DM) of PTC and provided a convenient tool for the prediction of PTC DM.
The occupational and environmental toxicant hexavalent chromium Cr(VI) can cause severe damage to the liver; however, the exact mechanisms associated with its toxicity have not been thoroughly ...demonstrated. In the present study, the underlying mechanisms of Cr(VI)-induced hepatotoxicity were investigated. Our results showed that Cr(VI) inhibited the growth and proliferation of L-02 hepatocytes. Further study revealed that Cr(VI) significantly induced S-phase cell cycle arrest and apoptosis accompanying with the overproduction of reactive oxygen species (ROS). Cr(VI)-induced apoptosis could be prevented by inhibiting ROS with N-acetyl-l-cysteine (NAC). Additionally, our data showed that Cr(VI)-induced endoplasmic reticulum (ER) stress and mitochondrial dysfunction were concentration- and time-dependent. Moreover, inhibition of C/EBA homologous protein (CHOP) expression by siRNA partially prevented Cr(VI)-induced cell apoptosis, mitochondrial dysfunction and ROS generation. We also found that Cr(VI) treatment inhibited the PI3K/Akt pathway in a concentration- and time-dependent manner. After using IGF-1 (50ng/mL), the specific agonist of the PI3K/AKT signaling pathway, the facilitating effects of Cr(VI) were depressed. This finding demonstrated the relationship between the PI3K/Akt pathway, ER stress and mitochondrial dysfunction. Collectively, these findings indicated that Cr(VI) increased ROS production. Increased ROS production may account for inhibition of the PI3K/Akt pathway and lead to ER stress and mitochondrial dysfunction, which consequently induces apoptosis in L-02 hepatocytes. This study provides novel insights into the molecular mechanisms of Cr(VI)-induced cytotoxicity.
•Cr(VI) caused change in expression of CHOP and cytochrome c in L-02 hepatocytes.•The formation of ROS may account for ER stress and mitochondrial dysfunction.•Inhibition of CHOP suppressed the formation of ROS and mitochondrial dysfunction.•Activation of PI3K can ameliorate Cr(VI)-induced cytotoxicity in L-02 hepatocytes.
Using recycled aggregates for substituting natural aggregates to prepare recycled aggregate concrete (RAC) has been regarded as an effective way to realize the sustainability of the construction ...industry. To promote RAC technologies in cold regions, it is necessary to ensure its frost durability. In this paper, three types of soft computing methods, including artificial neural network (ANN), Gaussian process regression (GPR), and multivariate adaptive regression spline (MARS), were used to model the frost durability of RAC based on the durability factor (DF) value. The results show that all the proposed models can predict DF values in good agreement with the experimental results. Compared with the GPR model and the MARS model, the ANN model showed the highest prediction accuracy. Based on the sensitivity analysis, the air-entraining type of RAC was the dominant variable that influenced the output for the experimental dataset and the three developed models.
•Innovative prediction models for the frost durability of RAC were proposed.•A comparison between the performance of proposed models was studied.•The sensitivity analysis of inputs on the output for proposed models was performed.
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