Identification of novel gene signature for lung adenocarcinoma by machine learning to predict immunotherapy and prognosis

BackgroundLung adenocarcinoma (LUAD) as a frequent type of lung cancer has a 5-year overall survival rate of lower than 20% among patients with advanced lung cancer. This study aims to construct a risk model to guide immunotherapy in LUAD patients effectively.Materials and methodsLUAD Bulk RNA-seq data for the construction of a model, single-cell RNA sequencing (scRNA-seq) data (GSE203360) for cell cluster analysis, and microarray data (GSE31210) for validation were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We used the Seurat R package to filter and process scRNA-seq data. Sample clustering was performed in the ConsensusClusterPlus R package. Differentially expressed genes (DEGs) between two groups were mined by the Limma R package. MCP-counter, CIBERSORT, ssGSEA, and ESTIMATE were employed to evaluate immune characteristics. Stepwise multivariate analysis, Univariate Cox analysis, and Lasso regression analysis were conducted to identify key prognostic genes and were used to construct the risk model. Key prognostic gene expressions were explored by RT-qPCR and Western blot assay.ResultsA total of 27 immune cell marker genes associated with prognosis were identified for subtyping LUAD samples into clusters C3, C2, and C1. C1 had the longest overall survival and highest immune infiltration among them, followed by C2 and C3. Oncogenic pathways such as VEGF, EFGR, and MAPK were more activated in C3 compared to the other two clusters. Based on the DEGs among clusters, we confirmed seven key prognostic genes including CPA3, S100P, PTTG1, LOXL2, MELTF, PKP2, and TMPRSS11E. Two risk groups defined by the seven-gene risk model presented distinct responses to immunotherapy and chemotherapy, immune infiltration, and prognosis. The mRNA and protein level of CPA3 was decreased, while the remaining six gene levels were increased in clinical tumor tissues.ConclusionImmune cell markers are effective in clustering LUAD samples into different subtypes, and they play important roles in regulating the immune microenvironment and cancer development. In addition, the seven-gene risk model may serve as a guide for assisting in personalized treatment in LUAD patients

Diagnosis and prognostic value of circDLGAP4 in acute ischemic stroke and its correlation with outcomes

Rationale and aimsCircular RNAs are a subclass of noncoding RNAs in mammalian cells and highly expressed in the central nervous system. Although their physiological functions are not yet completely defined, they are thought to promise as stroke biomarkers because of their stability in peripheral blood.Sample Size Estimate: 222 participants.Methods and designThe plasma of patients with acute ischemic stroke (AIS) (n = 111) and non-stroke controls (n = 111) from November 2017 to February 2019 were enrolled in our research. The expression of circDLGAP4 in plasma was evaluated using real-time PCR.Study outcomesIn patients with AIS, circDLGAP4 was significantly decreased in comparison with non-stroke controls. The CircDLGAP4 level had a significant AUC of 0.7896 with 91.72% sensitivity and 64.83% specificity in diagnosing AIS. Furthermore, the circDLGAP4 level was related to smoking history and previous transient ischemic attack/stroke/myocardial infarction in all samples. The change rate in circDLGAP4 within the first 7 days showed an AUC curve of 0.960 in predicting an stroke outcome.ConclusioncircDLGAP4 could serve as biomarker for AIS diagnosis and prediction of stroke outcomes

Search for light dark matter from atmosphere in PandaX-4T

We report a search for light dark matter produced through the cascading decay of $\eta$ mesons, which are created as a result of inelastic collisions between cosmic rays and Earth's atmosphere. We introduce a new and general framework, publicly accessible, designed to address boosted dark matter specifically, with which a full and dedicated simulation including both elastic and quasi-elastic processes of Earth attenuation effect on the dark matter particles arriving at the detector is performed. In the PandaX-4T commissioning data of 0.63 tonne$\cdot$year exposure, no significant excess over background is observed. The first constraints on the interaction between light dark matter generated in the atmosphere and nucleus through a light scalar mediator are obtained. The lowest excluded cross-section is set at $5.9 \times 10^{-37}{\rm cm^2}$ for dark matter mass of $0.1$ MeV$/c^2$ and mediator mass of 300 MeV$/c^2$. The lowest upper limit of $\eta$ to dark matter decay branching ratio is $1.6 \times 10^{-7}$

A Search for Light Fermionic Dark Matter Absorption on Electrons in PandaX-4T

We report a search on a sub-MeV fermionic dark matter absorbed by electrons with an outgoing active neutrino using the 0.63 tonne-year exposure collected by PandaX-4T liquid xenon experiment. No significant signals are observed over the expected background. The data are interpreted into limits to the effective couplings between such dark matter and electrons. For axial-vector or vector interactions, our sensitivity is competitive in comparison to existing astrophysical bounds on the decay of such dark matter into photon final states. In particular, we present the first direct detection limits for an axial-vector (vector) interaction which are the strongest in the mass range from 25 to 45 (35 to 50) keV/c$^2$

ATM inhibitor KU60019 synergistically sensitizes lung cancer cells to topoisomerase II poisons by multiple mechanisms

Abstract Type II topoisomerases (TOP2) poisons represent one class of the most successful and widely prescribed chemotherapeutics, which is frontline therapy for a myriad of systemic cancers and solid tumors, including lymphomas, leukemias, and lung cancer. Despite this, treatment with this class of drugs induces unwanted side effects (including cardiovascular morbidity and secondary malignancies). Additionally, the emergence of drug resistance also greatly compromises the clinical use of these drugs. To enhance therapeutic efficiency while lowering unwanted side effects, new insights into effective combination therapy are required. In this study we found that KU60019, a novel, and highly specific ATM kinase inhibitor interferes with the association of ATM with TOP2β and stabilizes TOP2β-DNA cleavage complex, thereby impairing the repair of TOP2 poison-induced DSBs and contributes to genome stability, leading to accelerated cell death. In H1299 as well as in A549 lung cancer cell lines, biologically, KU60019 combined with VP-16 (one of the TOP2 poisons) synergistically suppressed the growth of cells and survival and triggered a much higher apoptosis rate. In summary, we provide a proof-of-concept strategy that ATM inhibitors combined with TOP2 poison would synergistically suppresses lung cancer cell survival as well as reduce DNA damage responses, thus may lowering the possibility of cardiotoxicity and secondary malignancy linked to therapy

Lumped cluster analysis for understanding spatial and temporal patterns of groundwater geochemistry and hierarchically nested flow systems

Hydrogeochemical tracing is an important tool to identify groundwater flow systems.However, the complexity of regional hierarchically nested groundwater flow systems makes it more difficult to explain chemical compositions of groundwater.This study takes the Hutongchahan groundwater flow system in the lakes-controlling discharge area in the northern Ordos Basin as a typical example, and applies a cluster and principal component analysis to explore the hydrochemical data of groundwater sampled from different depths in both dry and wet seasons, aimed to reveal spatial and temporal patterns of groundwater chemistry and its controlling mechanism and to examine the reliability of identification of hierarchically nested groundwater flow systems.The groundwater samples were classified into three clusters.The C1 is the deep groundwater characterized by Na-HCO3 type, more negative δD(-70‰) and δ18O(>-9‰) and high NO3- concentration.The C3 is characterized by mixing of deep and shallow groundwater, with no dominant cations, δD and δ18O having wide range but significant linear correlation.The groundwater samples of C2 and part of the C3, which are mainly distributed along the north-south strip in the Subei-Hutongchahan lake drainage area, showed seasonal variations in chemical compositions.This study verified the spatial distribution of the shallow local and deep regional groundwater flow system controlled by the topography and lake discharge, and identified the Subei-Hutongchahan drainage area as the zone influenced by shallow and deep circulation.The lumped cluster analysis is proved as an effective method to understand spatial and temporal patterns of groundwater geochemistry and hierarchically nested flow systems

Anti-cancer Effects of Glypican-3 on Huh-7 Hepatocellular Carcinoma Cells

Aim: Previous studies have suggested Glypican-3 (GPC3) could be a valuable diagnostic marker for hepatocellular carcinoma. This study examined the effects of overexpression of GPC3 on Huh-7 hepatoma cells. Methods: We constructed a recombinant plasmid vector pcDNA3.1 (+)-GPC3 for GPC3 overexpression studies in Huh-7 cells. RT-PCR and Western blotting were used to confirm GPC3 gene expression. Cell proliferation was evaluated by 5-ethynyl-2-deoxyuridine (EdU) incorporation assay. Cell cycle progression and apoptosis were determined by flow cytometry using propidium iodide (PI) and Annexin V-FITC/PI staining, respectively. Cell migration and invasion were examined by Boyden Transewll and Matrigel assays. Results: GPC3 overexpression effectively inhibited proliferation, induced cell cycle arrest at S phase and increased apoptosis in Huh-7 cells. Furthermore, GPC3 overexpression significantly inhibited the migration and invasion ability of Huh-7 cells. Conclusion: Our results demonstrate that GPC3 could be a new therapeutic target for hepatocellular carcinoma

Rational design of highly dispersed Fe-N-C based on 1,10phenanthroline-2,9-dicarboxylic acid as preorganized ligand for precursor: boosted electrochemiluminescence detection of tetracycline

International audienceIn view of the shortcomings of the current coreactant electrochemiluminescence (ECL) and inspired by natural oxygen (O 2) reduction metalloenzymes, a novel ECL amplification strategy was established. A pyrolytic iron and nitrogen-doped (Fe-N-C) material rich in V O • defects was rationally designed by destroying the highly saturated coordination with preorganized ligand PDA. Extraordinary catalytic activity for O 2 activation was obtained via screening a special pyrolysis temperature using spectroscopic and electrochemical methods. The high-spin ferric centers of highly dispersed FeC nanoclusters, abundant carbon and oxygen vacancy defects, fully contributed to the inherent catalytic activity. ECL amplification was achieved by integrating the material with luminol to generate redox active radicals in situ from dissolved O 2 and simultaneously shorten the transferring distance of radicals. Tetracycline (TC), which posed a growing threat to aquatic biodiversity and environmental safety, as the model antibiotic was successfully detected with a detection limit of 3.88 nM (S/N = 3), clarifying a promising application prospect of this new effective ECL amplification strategy in biological analysis and environmental monitoring