Characterization of immune microenvironment identifies prognostic and immunotherapy benefit for trastuzumab-based therapy

Background and Purpose: The tumor immune microenvironment (TIME) of breast cancer with positive human epidermal growth factor receptor 2 (HER2) is significantly related to the efficacy of trastuzumab, indicating the clinical potential of immunocheckpoint therapy combined with trastuzumab. This study aimed to explore the predictors of HER2-positive breast cancer combination therapy and screen the potential beneficiaries of combination therapy. Methods: Transcriptome and genome data of 509 HER2-positive breast cancer samples of patients receiving trastuzumab treatment from Gene Expression Omnibus (GEO) database and 67 HER2-positive breast cancer samples from The Cancer Genome Atlas (TCGA) databases were collected. Trastuzumab-resistant group’s differentially expressed genes were identified and analyzed for functional enrichment and protein-protein interaction. The log-rank test and multivariate COX proportional hazards regression were used with clinical data to create the prediction model. The TIME landscape was characterized using the CIBERSORT. The immunotherapy benefit was valued by the tumor immune dysfunction and exclusion (TIDE) score. Results: The trastuzumab related genetic prognostic index (TRGPI) consisting of four hub genes (GATA6, TRPV6, AMACR, ZHX2) was constructed by analyzing the immune microenvironment and gene expression characteristics between trastuzumab-remission group and trastuzumab-resistance group. Importantly, the results revealed that patients with lower TRPGI were trastuzumab-sensitive and more likely to benefit from immunotherapy because of the increased percentages of CD8+ T cells, active natural killer cells and programmed death-1 (PD-1) expression. Conclusion: This study redefined the benefit population through TIME and provided a selectable strategy of trastuzumab plus immunotherapy for HER2-positive breast cancer

Toxic Effects of Silica Nanoparticles on Zebrafish Embryos and Larvae

Silica nanoparticles (SiNPs) have been widely used in biomedical and biotechnological applications. Environmental exposure to nanomaterials is inevitable as they become part of our daily life. Therefore, it is necessary to investigate the possible toxic effects of SiNPs exposure. In this study, zebrafish embryos were treated with SiNPs (25, 50, 100, 200 μg/mL) during 4-96 hours post fertilization (hpf). Mortality, hatching rate, malformation and whole-embryo cellular death were detected. We also measured the larval behavior to analyze whether SiNPs had adverse effects on larvae locomotor activity. The results showed that as the exposure dosages increasing, the hatching rate of zebrafish embryos was decreased while the mortality and cell death were increased. Exposure to SiNPs caused embryonic malformations, including pericardial edema, yolk sac edema, tail and head malformation. The larval behavior testing showed that the total swimming distance was decreased in a dose-dependent manner. The lower dose (25 and 50 μg/mL SiNPs) produced substantial hyperactivity while the higher doses (100 and 200 μg/mL SiNPs) elicited remarkably hypoactivity in dark periods. In summary, our data indicated that SiNPs caused embryonic developmental toxicity, resulted in persistent effects on larval behavior. © 2013 Duan et al.published_or_final_versio

New insights into β-glucan-enhanced immunity in largemouth bass Micropterus salmoides by transcriptome and intestinal microbial composition

β-glucan is widely used in aquaculture due to its immunostimulatory effects, but the specific effect and potential regulatory mechanism on largemouth bass (Micropterus salmoides) are still unclear. Here, we evaluated the effects of β-glucan on growth, resistance to Aeromonas schubertii, intestinal health, and transcriptome of largemouth bass to reveal the potential regulators, metabolic pathways, and altered differential microbiota. Four experimental diets were designed with β-glucan supplementation levels of 0 (control), 100 (LA-100), 200 (MA-200), and 300 (HA-300) mg kg-1, and each diet was fed to largemouth bass (79.30 ± 0.50 g) in triplicate for 70 days, followed by a 3-day challenge experiment. Results showed that different β-glucan supplementations had no significant effects on growth performance and whole-body composition. Fish fed a diet with 300 mg kg-1 β-glucan significantly increased the activity of lysozyme than those fed diets with 0 and 100 mg kg-1 β-glucan. In addition, the survival rate of largemouth bass in β-glucan supplementation groups was significantly higher than the control group at 12- and 24-h challenge by Aeromonas schubertii. Transcriptome analysis showed that a total of 1,245 genes were differentially expressed [|log2(fold change)| ≥1, q-value ≤0.05], including 109 immune-related differentially expressed genes (DEGs). Further analysis revealed that significantly upregulated and downregulated DEGs associated with immunity were mapped into 12 and 24 pathways, respectively. Results of intestinal microflora indicated that fish fed a diet with 300 mg kg-1 β-glucan had higher bacterial richness and diversity as evaluated by Sobs, Chao, Ace, and Simpson indices, but no significant differences were found in the comparison groups. Furthermore, 300 mg kg-1 β-glucan significantly increased the relative abundance of Mycoplasma and decreased Proteobacteria (mainly Escherichia-Shigella and Escherichia coli) and Bacillus anthracis in largemouth bass intestinal microflora. The findings of this study provided new insights that will be valuable in future studies to elucidate the mechanism of immunity enhancement by β-glucan

Climate warming accelerates temporal scaling of grassland soil microbial biodiversity.

Determining the temporal scaling of biodiversity, typically described as species-time relationships (STRs), in the face of global climate change is a central issue in ecology because it is fundamental to biodiversity preservation and ecosystem management. However, whether and how climate change affects microbial STRs remains unclear, mainly due to the scarcity of long-term experimental data. Here, we examine the STRs and phylogenetic-time relationships (PTRs) of soil bacteria and fungi in a long-term multifactorial global change experiment with warming (+3 °C), half precipitation (-50%), double precipitation (+100%) and clipping (annual plant biomass removal). Soil bacteria and fungi all exhibited strong STRs and PTRs across the 12 experimental conditions. Strikingly, warming accelerated the bacterial and fungal STR and PTR exponents (that is, the w values), yielding significantly (P < 0.001) higher temporal scaling rates. While the STRs and PTRs were significantly shifted by altered precipitation, clipping and their combinations, warming played the predominant role. In addition, comparison with the previous literature revealed that soil bacteria and fungi had considerably higher overall temporal scaling rates (w = 0.39-0.64) than those of plants and animals (w = 0.21-0.38). Our results on warming-enhanced temporal scaling of microbial biodiversity suggest that the strategies of soil biodiversity preservation and ecosystem management may need to be adjusted in a warmer world

IκBα polymorphism at promoter region (rs2233408) influences the susceptibility of gastric cancer in Chinese

<p>Abstract</p> <p>Background</p> <p>Nuclear factor of kappa B inhibitor alpha (IκBα) protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of <it>IκBα </it>to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients.</p> <p>Methods</p> <p>A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in <it>IκBα </it>were analyzed by TaqMan SNP genotyping assay.</p> <p>Results</p> <p>Both rs2233408 T homozygote (TT) and T heterozygotes (TC and TT) had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, <it>P </it>= 0.035; TC and TT: OR = 0.721, 95% CI = 0.530-0.981, <it>P </it>= 0.037), compared with rs2233408 C homozygote (CC). rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, <it>P </it>= 0.014), but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age>40) (OR = 0.674, 95% CI = 0.484-0.939, <it>P </it>= 0.02). rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, <it>P </it>= 0.006), but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients.</p> <p>Conclusions</p> <p><it>IκBα </it>rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population.</p

Truss geometry and topology optimization with global stability constraints

In this paper, we introduce geometry optimization into an existing topology optimization workflow for truss structures with global stability constraints, assuming a linear buckling analysis. The design variables are the cross-sectional areas of the bars and the coordinates of the joints. This makes the optimization problem formulations highly nonlinear and yields nonconvex semidefinite programming problems, for which there are limited available numerical solvers compared with other classes of optimization problems. We present problem instances of truss geometry and topology optimization with global stability constraints solved using a standard primal-dual interior point implementation. During the solution process, both the cross-sectional areas of the bars and the coordinates of the joints are concurrently optimized. Additionally, we apply adaptive optimization techniques to allow the joints to navigate larger move limits and to improve the quality of the optimal designs

Temperature Variability and Mortality: A Multi-Country Study

Background: The evidence and method are limited for the associations between mortality and temperature variability (TV) within or between days. Objectives: We developed a novel method to calculate TV and investigated TV-mortality associations using a large multicountry data set. Methods: We collected daily data for temperature and mortality from 372 locations in 12 countries/regions (Australia, Brazil, Canada, China, Japan, Moldova, South Korea, Spain, Taiwan, Thailand, the United Kingdom, and the United States). We calculated TV from the standard deviation of the minimum and maximum temperatures during the exposure days. Two-stage analyses were used to assess the relationship between TV and mortality. In the first stage, a Poisson regression model allowing over-dispersion was used to estimate the community-specific TV-mortality relationship, after controlling for potential confounders. In the second stage, a meta-analysis was used to pool the effect estimates within each country. Results: There was a significant association between TV and mortality in all countries, even after controlling for the effects of daily mean temperature. In stratified analyses, TV was still significantly associated with mortality in cold, hot, and moderate seasons. Mortality risks related to TV were higher in hot areas than in cold areas when using short TV exposures (0–1 days), whereas TV-related mortality risks were higher in moderate areas than in cold and hot areas when using longer TV exposures (0–7 days). Conclusions: The results indicate that more attention should be paid to unstable weather conditions in order to protect health. These findings may have implications for developing public health policies to manage health risks of climate change. Citation: Guo Y, Gasparrini A, Armstrong BG, Tawatsupa B, Tobias A, Lavigne E, Coelho MS, Pan X, Kim H, Hashizume M, Honda Y, Guo YL, Wu CF, Zanobetti A, Schwartz JD, Bell ML, Overcenco A, Punnasiri K, Li S, Tian L, Saldiva P, Williams G, Tong S. 2016. Temperature variability and mortality: a multi-country study. Environ Health Perspect 124:1554–1559; http://dx.doi.org/10.1289/EHP14