Investigation of the prevalence and clinical implications of ERBB2 exon 16 skipping mutations in Chinese pan-cancer patients

BackgroundAlthough rare, ERBB2 exon 16 skipping mutations (ERBB2ΔEx16) have been implicated in resistance to anti-HER2 and anti-EGFR targeted agents. Our study investigated the prevalence and clinical significance of ERBB2ΔEx16 in Chinese pan-cancer patients.MethodsWe retrospectively screened 40996 patients, spanning 19 cancer types, who had available genomic profiles acquired with DNA-based next-generation sequencing (NGS). We characterized the clinical and molecular features of the ERBB2ΔEx16-positive patients. Furthermore, we also analyzed a pan-cancer dataset from the Cancer Genome Atlas (TCGA; n=8705).ResultsA total of 22 patients were detected with ERBB2ΔEx16, resulting in an overall prevalence rate of 0.054% (22/40996). Of them, 16 patients had lung cancer (LC; 0.05%, 16/30890), five patients had gastric cancer (GC; 0.35%, 5/1448), and one patient had ovarian cancer (0.12%, 1/826). Among the 16 LC patients, ERBB2ΔEx16 was detected in four treatment-naïve EGFR/ALK-negative patients and 12 EGFR-positive patients after the onset of resistance to EGFR tyrosine kinase inhibitors (TKIs). The treatment-naïve patients harbored no LC-associated oncogenic drivers except ERBB2 amplification, suggesting a potential oncogenic role for ERBB2ΔEx16. Consistently, ERBB2ΔEx16+ patients from TCGA data also carried no known drivers despite various concurrent alterations. In the 12 EGFR TKI-resistant LC patients, relative variant frequencies for ERBB2ΔEx16 were lower than in untreated patients, suggesting ERBB2ΔEx16 as secondary alterations following TKI treatment and thereby implicating ERBB2ΔEx16 in mediating therapeutic resistance.ConclusionsOur study identified an overall ERBB2ΔEx16 prevalence rate of 0.054% and provided insights into the clinical implications of ERBB2ΔEx16 in Chinese pan-cancer patients

Evolutionary Dynamics Analysis of Human Metapneumovirus Subtype A2: Genetic Evidence for Its Dominant Epidemic

Human metapneumovirus (hMPV) is a respiratory viral pathogen in children worldwide. hMPV is divided into four subtypes: hMPV_A1, hMPV_A2, hMPV_B1, and hMPV_B2. hMPV_A2 can be further divided into hMPV_A2a and A2b based on phylogenetic analysis. The typical prevalence pattern of hMPV involves a shift of the predominant subtype within one or two years. However, hMPV_A2, in particular hMPV_A2b, has circulated worldwide with a several years long term high epidemic. To study this distinct epidemic behavior of hMPV_A2, we analyzed 294 sequences of partial G genes of the virus from different countries. Molecular evolutionary data indicates that hMPV_A2 evolved toward heterogeneity faster than the other subtypes. Specifically, a Bayesian skyline plot analysis revealed that hMPV_A2 has undergone a generally upward fluctuation since 1997, whereas the other subtypes experienced only one upward fluctuation. Although hMPV_A2 showed a lower value of mean dN/dS than the other subtypes, it had the largest number of positive selection sites. Meanwhile, various styles of mutation were observed in the mutation hotspots of hMPV_A2b. Bayesian phylogeography analysis also revealed two fusions of diffusion routes of hMPV_A2b in India (June 2006) and Beijing, China (June 2008). Sequences of hMPV_A2b retrieved from GenBank boosted simultaneously with the two fusions respectively, indicating that fusion of genetic transmission routes from different regions improved survival of hMPV_A2. Epidemic and evolutionary dynamics of hMPV_A2b were similar to those of hMPV_A2. Overall, our findings provide important molecular insights into hMPV epidemics and viral variation, and explain the occurrence of an atypical epidemic of hMPV_A2, particularly hMPV_A2b

Thioredoxin Glutathione Reductase as a Novel Drug Target: Evidence from Schistosoma japonicum

Background: Schistosomiasis remains a major public health concern affecting billions of people around the world. Currently, praziquantel is the only drug of choice for treatment of human schistosomiasis. The emergence of drug resistance to praziquantel in schistosomes makes the development of novel drugs an urgent task. Thioredoxin glutathione reductase (TGR) enzymes in Schistosoma mansoni and some other platyhelminths have been identified as alternative targets. The present study was designed to confirm the existense and the potential value of TGR as a target for development of novel antischistosomal agents in Schistosoma japonicum, a platyhelminth endemic in Asia. Methods and Findings: After cloning the S. japonicum TGR (SjTGR) gene, the recombinant SjTGR selenoprotein was purified and characterized in enzymatic assays as a multifunctional enzyme with thioredoxin reductase (TrxR), glutathione reductase (GR) and glutaredoxin (Grx) activities. Immunological and bioinformatic analyses confirmed that instead of having separate TrxR and GR proteins in mammalian, S. japonicum only encodes TGR, which performs the functions of both enzymes and plays a critical role in maintaining the redox balance in this parasite. These results were in good agreement with previous findings in Schistosoma mansoni and some other platyhelminths. Auranofin, a known inhibitor against TGR, caused fatal toxicity in S. japonicum adult worms in vitro and reduced worm and egg burdens in S. japonicum infected mice. Conclusions: Collectively, our study confirms that a multifunctional enzyme SjTGR selenoprotein, instead of separate Trx

A Hybrid Picture Fuzzy Similarity Measure and Improved VIKOR Method

Abstract Picture fuzzy set (PFS) can intuitively express the answers of “yes”, “neutral”, “no” and “reject”, which have strong advantages in solving uncertain information. The similarity measure is an effective tool to determine the relationship between two picture fuzzy sets (PFSs). In this paper, we propose a hybrid picture fuzzy (PF) similarity measure which combines the Hamming distance and the transformed tetrahedral centroid distance and verifies that it satisfies the four properties of the similarity measure. The proposed and existing picture fuzzy similarity measures are compared and investigated through numerical examples and some applications of pattern recognition. The results show that the proposed similarity measure not only produces no unreasonable results, but also overcomes the shortcomings of the existing similarity measures. Furthermore, we investigate an improved VIKOR method based on the proposed similarity measure of PFS. Finally, through an example, several multi-attribute decision-making (MADM) methods are compared and analyzed to illustrate the effectiveness and practicability of the improved VIKOR method

Prediction of Soil Organic Carbon in a New Target Area by Near-Infrared Spectroscopy: Comparison of the Effects of Spiking in Different Scale Soil Spectral Libraries

Near-infrared (NIR) spectroscopy is widely used to predict soil organic carbon (SOC) because it is rapid and accurate under proper calibration. However, the prediction accuracy of the calibration model may be greatly reduced if the soil characteristics of some new target areas are different from the existing soil spectral library (SSL), which greatly limits the application potential of the technology. We attempted to solve the problem by building a large-scale SSL or using the spiking method. A total of 983 soil samples were collected from Zhejiang Province, and three SSLs were built according to geographic scope, representing the provincial, municipal, and district scales. The partial least squares (PLS) algorithm was applied to establish the calibration models based on the three SSLs, and the models were used to predict the SOC of two target areas in Zhejiang Province. The results show that the prediction accuracy of each model was relatively poor regardless of the scale of the SSL (residual predictive deviation (RPD) < 2.5). Then, the Kennard-Stone (KS) algorithm was applied to select 5 or 10 spiking samples from each target area. According to different SSLs and numbers of spiking samples, different spiked models were established by the PLS. The results show that the predictive ability of each model was improved by the spiking method, and the improvement effect was inversely proportional to the scale of the SSL. The spiked models built by combining the district scale SSL and a few spiking samples achieved good prediction of the SOC of two target areas (RPD = 2.72 and 3.13). Therefore, it is possible to accurately measure the SOC of new target areas by building a small-scale SSL with a few spiking samples

Thinning Effects on Stand Structure and Carbon Content of Secondary Forests

In, this study, we analysed the effects of thinning on stand structure and carbon stocks for a mixed conifer and broadleaf natural secondary forests in the Small Khingan Mountains, China. Stand structure and carbon stocks were assessed in trees from unthinned control (CK), lightly thinned (LT), moderately thinned (MT) and heavily thinned (HT) treatments. Results showed that the heavier the thinning, the larger the crown area became. Under the MT treatment, trees tended to be evenly distributed when compared to trees under the other treatments. All the trees of the LT and HT treatments were mixed strongly compared to those of the CK treatment. As the thinning intensitiy increased, the distributions of size differentiation and crowding degree gradually decreased. As a result, the competitive pressure diminished, and more dominant trees emerged. In addition, there was a significant positive correlation between individual tree carbon stock and canopy under all treatments. Carbon tends to accumulate in individuals with a random distribution, sparse spacing, strong mingling index and large competitive advantage. However, the results varied slightly under the HT treatment. Individuals in a dominant position occupied abundant resources and great niche space

The Effect of Thinning Management on the Carbon Density of the Tree Layers in Larch–Birch Mixed Natural Secondary Forests of the Greater Khingan Range, Northeastern China

Natural secondary forests not only contribute to the total balance of terrestrial carbon, but they also play a major role in the future mitigation of climate change. In China, secondary forests have low productivity and carbon sequestration, which seriously restricts the sustainable development of the forest. Thinning is a core measure of scientific management of forest ecosystems and is a primary natural forest management technique. The carbon density of the tree layer is most affected by thinning. Taking larch–birch mixed natural secondary forests in the Greater Khingan Range, Northeast China, as the research object, we analyzed the changes in tree layer carbon density of secondary forests under different thinning intensities. The results showed that in five thinned groups, when intensity was 49.6%, the diameter at breast height (DBH) and individual tree biomass significantly increased. Thinning had no significant effect on the carbon content of the tree stem, branches and bark, but had significant effects on the carbon content of leaves. Our result showed that the carbon content of birch leaves increased and that of larch decreased. As the thinning intensity increases, the proportion of broad-leaved tree species (birch) increased, yet larch decreased. In the short term, thinning will reduce the total biomass and carbon density of tree layers. However, when the thinning intensity was 49.6%, the carbon accumulation was higher than that of the blank control group (CK group) after thinning for 12 years. This shows that after a long period of time, the carbon density of tree layers will exceed that of the CK group. Reasonable thinning intensity management (49.6% thinning intensity) of natural secondary forests can make trees grow better, and the proportion of broad-leaved trees increases significantly. It can also increase the carbon sequestration rate and lead to more accumulation of biomass and carbon density. This can not only promote the growth of secondary forests, but also shows great potential for creating carbon sinks and coping with climate change

Thinning Effects on Stand Structure and Carbon Content of Secondary Forests

In, this study, we analysed the effects of thinning on stand structure and carbon stocks for a mixed conifer and broadleaf natural secondary forests in the Small Khingan Mountains, China. Stand structure and carbon stocks were assessed in trees from unthinned control (CK), lightly thinned (LT), moderately thinned (MT) and heavily thinned (HT) treatments. Results showed that the heavier the thinning, the larger the crown area became. Under the MT treatment, trees tended to be evenly distributed when compared to trees under the other treatments. All the trees of the LT and HT treatments were mixed strongly compared to those of the CK treatment. As the thinning intensitiy increased, the distributions of size differentiation and crowding degree gradually decreased. As a result, the competitive pressure diminished, and more dominant trees emerged. In addition, there was a significant positive correlation between individual tree carbon stock and canopy under all treatments. Carbon tends to accumulate in individuals with a random distribution, sparse spacing, strong mingling index and large competitive advantage. However, the results varied slightly under the HT treatment. Individuals in a dominant position occupied abundant resources and great niche space