Identification and validation of SERPINE1 as a prognostic and immunological biomarker in pan-cancer and in ccRCC

Background:SERPINE1, a serine protease inhibitor involved in the regulation of the plasminogen activation system, was recently identified as a cancer-related gene. However, its clinical significance and potential mechanisms in pan-cancer remain obscure.Methods: In pan-cancer multi-omics data from public datasets, including The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), and online web tools were used to analyze the expression of SERPINE1 in different cancers and its correlation with prognosis, genetic alteration, DNA promoter methylation, biological processes, immunoregulator expression levels, immune cell infiltration into tumor, tumor mutation burden (TMB), microsatellite instability (MSI), immunotherapy response and drug sensitivity. Further, two single-cell databases, Tumor Immune Single-cell Hub 2 (TISCH2) and CancerSEA, were used to explore the expression and potential roles of SERPINE1 at a single-cell level. The aberrant expression of SERPINE1 was further verified in clear cell renal cell carcinoma (ccRCC) through qRT-PCR of clinical patient samples, validation in independent cohorts using The Gene Expression Omnibus (GEO) database, and proteomic validation using the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database.Results: The expression of SERPINE1 was dysregulated in cancers and enriched in endothelial cells and fibroblasts. Copy number amplification and low DNA promoter methylation could be partly responsible for high SERPINE1 expression. High SERPINE1 expression was associated with poor prognosis in 21 cancers. The results of gene set enrichment analysis (GSEA) indicated SERPINE1 involvement in the immune response and tumor malignancy. SERPINE1 expression was also associated with the expression of several immunoregulators and immune cell infiltration and could play an immunosuppression role. Besides, SERPINE1 was found to be related with TMB, MSI, immunotherapy response and sensitivity to several drugs in cancers. Finally, the high expression of SERPINE1 in ccRCC was verified using qRT-PCR performed on patient samples, six independent GEO cohorts, and proteomic data from the CPTAC database.Conclusion: The findings of the present study revealed that SERPINE1 exhibits aberrant expression in various types of cancers and is associated with cancer immunity and tumor malignancy, providing novel insights for individualized cancer treatment

Proposed clinical phases for the improvement of personalized treatment of checkpoint inhibitor–related pneumonitis

BackgroundCheckpoint inhibitor–related pneumonitis (CIP) is a lethal immune-related adverse event. However, the development process of CIP, which may provide insight into more effective management, has not been extensively examined.MethodsWe conducted a multicenter retrospective analysis of 56 patients who developed CIP. Clinical characteristics, radiological features, histologic features, and laboratory tests were analyzed. After a comprehensive analysis, we proposed acute, subacute, and chronic phases of CIP and summarized each phase’s characteristics.ResultsThere were 51 patients in the acute phase, 22 in the subacute phase, and 11 in the chronic phase. The median interval time from the beginning of CIP to the different phases was calculated (acute phase: ≤4.9 weeks; subacute phase: 4.9~13.1 weeks; and chronic phase: ≥13.1 weeks). The symptoms relieved from the acute phase to the chronic phase, and the CIP grade and Performance Status score decreased (P<0.05). The main change in radiologic features was the absorption of the lesions, and 3 (3/11) patients in the chronic phase had persistent traction bronchiectasis. For histologic features, most patients had acute fibrinous pneumonitis in the acute phase (5/8), and most had organizing pneumonia in the subacute phase (5/6). Other histologic changes advanced over time, with the lesions entering a state of fibrosis. Moreover, the levels of interleukin-6, interleukin-10 and high-sensitivity C-reactive protein (hsCRP) increased in the acute phase and decreased as CIP progressed (IL-6: 17.9 vs. 9.8 vs. 5.7, P=0.018; IL-10: 4.6 vs 3.0 vs. 2.0, P=0.041; hsCRP: 88.2 vs. 19.4 vs. 14.4, P=0.005).ConclusionsThe general development process of CIP can be divided into acute, subacute, and chronic phases, upon which a better management strategy might be based devised

Epidemiological Survey of Grass Carp (Ctenopharyngodon idella) Reovirus in South China, and Genetic Variations of VP6 gene

To study the molecular biology characteristics, phylogenetic relationship, and status quo of grass carp reovirus (GCRV) prevalent isolates, we conducted an epidemiological survey in South China from 2012 to 2016. We sampled 126 fish collected from five provinces. Eight strains of GCRV were isolated and examined in order to understand their genetic characteristics and evolution regularity. The results showed three genotypes of GCRV, of which. Genotype Ⅱ was found to be the prevalent strain in South China. SDS-PAGE electrophoresis further suggested that all viruses possess 11 segments of dsRNA, which have typical characteristics of GCRV. Based on amino acid sequence phylogenetic tree of VP6 gene, all eight isolates belonged to genotype Ⅱ and had significant variations compared to genotype Ⅰ. Analysis of amino acid sequence showed that these two genotypes of GCRV had no immunological cross-reactions. These results indicated that genotype Ⅱ GCRV is an extensive pandemic, and revealed new genetic diversity in China

Mechanical metamaterials associated with stiffness, rigidity and compressibility: A brief review

Mechanical metamaterials are man-made structures with counterintuitive mechanical properties that originate in the geometry of their unit cell instead of the properties of each component. The typical mechanical metamaterials are generally associated with the four elastic constants, the Young\u27s modulus E, shear modulus G, bulk modulus K and Poisson\u27s ratio υ the former three of which correspond to the stiffness, rigidity, and compressibility of a material from an engineering point of view. Here we review the important advancements in structural topology optimisation of the underlying design principles, coupled with experimental fabrication, thereby to obtain various counterintuitive mechanical properties. Further, a clear classification of mechanical metamaterials have been established based on the fundamental material mechanics. Consequently, mechanical metamaterials can be divide into strong-lightweight (E/ρ), pattern transformation with tunable stiffness, negative compressibility (−4G/3 \u3c K \u3c 0), Pentamode metamaterials (G ≪ K) and auxetic metamaterials (G ≫ K), simultaneously using topology optimisation to share various fancy but feasible mechanical properties, ultralight, ultra-stiffness, well-controllable stiffness, vanishing shear modulus, negative compressibility and negative Poisson\u27s ratio. We provide here a broad overview of significant potential mechanical metamaterials together with the upcoming challenges in the intriguing and promising research field

Electrical Double Layers near Charged Nanorods in Mixture Electrolytes

The electrical double layers (EDLs) in the mixtures of room-temperature ionic liquids and water play an important role in many applications but have only begun to receive widespread attention recently. Here, we report the molecular dynamics simulations of EDLs near rigid polyanion nanorods immersed in electrolytes containing ionic liquids [C₂mim]­[TfO], water, and Na⁺ ions. When the water content in bulk electrolyte is high, the EDLs near the rods are similar to those in aqueous electrolytes except that TfO^– ions accumulate notably near the cation layer adsorbed on the rods. When the water content in the bulk electrolyte becomes very low, even though water is greatly enriched in the interfacial region, the microenvironment in the region offers weak dielectric screening and the EDL exhibits features common to those in neat ionic liquids, e.g., charge overscreening. Na⁺ ions are readily adsorbed on the sulfonate groups of the polyanion rod in the range of water contents explored here but can experience an energy barrier when moving from the bulk electrolyte to the rod surface if the water content is very low. Introducing Na⁺ ions into the system displaces C₂mim⁺ ions from the rod’s surface. However, the number of displaced C₂mim⁺ ions is far less than the Na⁺ newly adsorbed on the rod, and thus, charge overscreening is enhanced. We highlight the important role of ion–ion correlations in determining the EDL characteristics and their response to the variation of mixture electrolytes’ water/Na⁺ ion contents revealed here and discuss their technical implications

Association between Peak Neutrophil Count, Clopidogrel Loading Dose, and Left Ventricular Systolic Function in Patients with Primary Percutaneous Coronary Intervention

Inflammation plays an important role in plaque development and left ventricular remodeling during acute myocardial infarction (AMI). Clopidogrel may exhibit some anti-inflammatory properties and high loading dose of clopidogrel results in improved clinical outcomes in patients with AMI. 357 patients who received successful primary percutaneous coronary intervention from January 2008 to March 2011 in Peking University Third Hospital were included in this study. Different loading dose of clopidogrel (300 mg, 450 mg, or 600 mg) was given at the discretion of the clinician. Neutrophils reached their peak values on the first day after AMI. Higher levels of peak neutrophil and lower left ventricular ejection fraction (LVEF) were found in patients of low clopidogrel loading dose group (300 mg or 450 mg). After adjusting for the related confounders, a logistic regression model showed that low clopidogrel loading dose remained an independent predictor of low LVEF (LVEF ≤ 50%) [OR: 1.97, 95% CI: 1.03–3.79, P = 0.04]. Low clopidogrel loading dose was associated with higher peak neutrophil count and poor left ventricular systolic function, suggesting an important role of clopidogrel loading dose in the improvement of left ventricular function and high loading dose may exhibit better anti-inflammatory properties

Plasma Catestatin: A Useful Biomarker for Coronary Collateral Development with Chronic Myocardial Ischemia.

BACKGROUNDS:Catestatin is an endogenous multifunctional neuroendocrinepeptide. Recently, catestatin was discovered as a novel angiogenic cytokine. The study was to investigate the associations between endogenous catestatin and coronary collateral development among the patients with chronic myocardial ischemia. METHODS:Thirty-eight patients with coronary artery chronic total occlusions (CTO) (CTO group) and 38 patients with normal coronary arteries (normal group) were enrolled in the series. Among the patients with CTO, coronary collateral development was graded according to the Rentrop score method. Rentrop score 0-1 collateral development was regarded as poor collateral group and 2-3 collateral development was regarded as good collateral group. Plasma catestatin level and vascular endothelial growth factor (VEGF) were measured by ELISA kits. RESULTS:The plasma catestatin levels in CTO group were significantly higher than that in normal group (1.97±1.01 vs 1.36±0.97ng/ml, p = 0.009). In the CTO group, the patients with good collateral development had significantly higher catestatin and VEGF levels than those with poor collateral development (2.36±0.73 vs 1.61±1.12 ng/ml, p = 0.018; 425.23±140.10 vs 238.48±101.00pg/mL, p<0.001). There is a positive correlation between plasma catestatin levels and Rentrop scores (r = 0.40, p = 0.013) among the patients with CTO. However, there is no correlations between plasma catestatin levels and VEGF (r = -0.06, p = 0.744). In the multiple linear regression models, plasma catestatin level was one of the independent factors of coronary collateral development after adjustment for confounders. CONCLUSIONS:Plasma catestatin was associated with coronary collateral developments. It may be a useful biomarker for coronary collateral development and potential target for therapeutic angiogenesis in patients with CTO

Comparing Experts and Novices for AI Data Work: Insights on Allocating Human Intelligence to Design a Conversational Agent

Many AI system designers grapple with how best to collect human input for different types of training data. Online crowds provide a cheap on-demand source of intelligence, but they often lack the expertise required in many domains. Experts offer tacit knowledge and more nuanced input, but they are harder to recruit. To explore this trade off, we compared novices and experts in terms of performance and perceptions on human intelligence tasks in the context of designing a text-based conversational agent. We developed a preliminary chatbot that simulates conversations with someone seeking mental health advice to help educate volunteer listeners at 7cups.com. We then recruited experienced listeners (domain experts) and MTurk novice workers (crowd workers) to conduct tasks to improve the chatbot with different levels of complexity. Novice crowds perform comparably to experts on tasks that only require natural language understanding, such as correcting how the system classifies a user statement. For more generative tasks, like creating new lines of chatbot dialogue, the experts demonstrated higher quality, novelty, and emotion. We also uncovered a motivational gap: crowd workers enjoyed the interactive tasks, while experts found the work to be tedious and repetitive. We offer design considerations for allocating crowd workers and experts on input tasks for AI systems, and for better motivating experts to participate in low-level data work for AI

Heat shock protein 70 acts as a potential biomarker for early diagnosis of heart failure.

Early identification for heart failure (HF) may be useful for disease modifying treatment in order to reduce heart disease progression or even to reverse it. In our previous studies, we have revealed a group of heat shock proteins (HSPs) which might be related to neonatal rat cardiomyocyte hypertrophy by proteomic approach. Here, we confirm that HSPs, including HSP27 and HSP70, altered in the early stage of cardiac remodeling in vivo animal model. Furthermore, plasma concentrations of those HSPs and their potential screening value were evaluated at different stages in 222 patient subjects. Plasma HSP27, HSP70 and HSP90 were measured using enzyme-linked immunosorbent assay. Results indicate that HSP70 was positively correlated to the severity (progression) of HF (r = 0.456, p<0.001). The area under the rate of change (ROC) curve was 0.601 (p = 0.017) in patients with stage B HF and 0.835 (p<0.001) in those with stage C HF. However, HSP27 and HSP90 did not display significant changes in any stage of HF in this study. Taken together, plasma concentrations of HSP70 elevated with the progression of HF and might act as a potential screening biomarker for early diagnosis of HF