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Cancerous genetic mutations result in a complex and comprehensive post-translational modification (PTM) dynamics, in which protein succinylation is well known for its ability to reprogram cell metabolism and is involved in the malignant evolution. Little is known about the regulatory interactions between succinylation and other PTMs in the PTM network. Here, we developed a conjoint analysis and systematic clustering method to explore the intermodification communications between succinylome and phosphorylome from eight lung cancer patients. We found that the intermodification coorperation in both parallel and series. Besides directly participating in metabolism pathways, some phosphosites out of mitochondria were identified as an upstream regulatory modification directing succinylome dynamics in cancer metabolism reprogramming. Phosphorylated activation of histone deacetylase (HDAC) in lung cancer resulted in the removal of acetylation and favored the occurrence of succinylation modification of mitochondrial proteins. These results suggest a tandem regulation between succinylation and phosphorylation in the PTM network and provide HDAC-related targets for intervening mitochondrial succinylation and cancer metabolism reprogramming. [ABSTRACT FROM AUTHOR]

Fibrinogen-like protein-1 (FGL1) is confirmed a major ligand of lymphocyte activation gene-3 which could inhibit antigen-mediated T-cell response and evade immune supervision. Although hepatocytes secrete large amounts of FGL1, its high expression also be detected in solid tumors such as lung cancer, leading to a poor efficacy of immune checkpoint inhibitors therapy. Here we reported that FGL1 was overexpressed in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma. However, FGL1 in tissue and plasma can only distinguish LUAD patients from healthy donors and cannot correlate with clinical Tumor Node Metastasis (TNM) stage. Using lung cancer cell lines, we confirmed that FGL1 can be detected on extracellular vesicles (EVs) and we established a method using flow cytometry to detect FGL1 on the surface of EVs, which revealed that FGL1 could be secreted via EVs. Both animal model and clinical samples proved that plasma FGL1 in EVs would increase when the tumor was loaded. The level of FGL1 in plasma EVs was correlated with clinical TNM stage and tumor size, and a higher level indicated non-responsiveness to anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy. Its effect on tumor progression and immune evasion may be achieved by impairing the killing and proliferating capacities of CD8+ T cells. Our result demonstrates that FGL1 levels in plasma EVs, but not total plasma FGL1, could be a promising biomarker that plays an important role in predicting anti-PD-L1 immune therapy in LUAD and suggests a new strategy in LUAD immunotherapy. Fibrinogen-like protein-1 (FGL1) was overexpressed in lung adenocarcinoma and could be secreted via extracellular vesicles (EVs). FGL1 on plasma EVs, not total plasma FGL1, is correlated with clinical TNM(Tumor Node Metastasis)staging and non-responsiveness to anti-programmed cell death ligand 1 therapy, which could be a new potential target for immunotherapy Graphical Abstract [ABSTRACT FROM AUTHOR]

Objective(s): The aim of this study is to explore the potential neuroprotective effects of Ginkgolide B (GB), a main terpene lactone and active component in Ginkgo biloba, in hypoxia-induced neuronal damage, and to further investigate its possible mechanisms.Materials and Methods: 54 Sprague-Dawley rats were randomly divided into three groups: the untreated control group (n=18); the hypoxia group (n=18; exposed to 6000 m simulated plateau altitude for six days); and the GB group (n=18; intragastric administration of 12 mg/kg GB three days prior to rapid adaption to 6000 m and on the first two days of hypoxia). After hypoxia exposure for six days, we dissected out the brain hippocampi and performed hematoxylin and eosin staining, Nissl staining, and TUNEL staining. Homogenates of the hippocampi were used to test the oxidative stress indices including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and catalase. Bax and caspase-3 expression in the hippocampal tissue was measured using qRT-PCR.Results: Treatment with GB before exposure to hypoxia could protect neural cells and increase the number of Nissl bodies. TUNEL and qRT-PCR results demonstrated that GB treatment could decrease apoptotic cells in different areas of the hippocampus. Antioxidant defense systems such as SOD, GSH, and catalase were decreased (P

In our country, the Yellow River Basin ecological protection and development are put forward under the background of high quality. Among the 14 large-scale coal bases in our country, 9 coal bases are located in the Yellow River Basin, and the Shenfu-Dongsheng Coalfield, which is currently the largest under development, is located here. The region is in the process of coal mining, and the movement of overlying strata will cause the stress redistribution and coal seam in overlying aquifers also due to the effect of pore water pressure along the seepage of rock fracture and damage of overlying aquifer, so in the same formation, stress and the coupled action of seepage flow will produce mutual influence. This article through the early stage of the theoretical results discussed the application of numerical simulation method for simulating 2301 face, and the effect of stress on seepage is concluded. It is proved that the numerical simulation analysis has an important reference value for the coupling problem of stress and seepage. At the same time, the protective mining of aquifers is the basic condition for the surface ecological protection of the area, and it also provides a theoretical basis for the restoration of the ecological environment in the coal mining areas of the Yellow River Basin.

BackgroundEsophageal Squamous Cell Carcinoma (ESCC) is a major subtype of esophageal cancer causing significant morbility and mortality in Asia. Mechanism of initiation and progression of this disease is unclear. Tumor initiating cells (TICs) are the subpopulation of cells which have the ability to self-renew, as well as, to drive initiation and progression of cancer. Increasing evidence has shown that TICs exist in a variety of tumors. However, the identification and characterization of TICs in esophageal carcinoma has remained elusive.Methodology/principal findingsto identify TICs in ESCC, ESCC cell lines including two primary cells were used for screening suitable surface marker. Then colony formation assay, drug resistant assay and tumorigenicity assay in immune deficient mice were used to characterize TICs in ESCC. We found that just the CD44 expression correlated with tumorigenicity in ESCC cell lines. And then induced differentiation of ESCC cells by all-trans retinoic acid treatment led to decreased expression of CD44. The FACS isolated cell subpopulations with high CD44 expression showed increased colony formation and drug resistance in vitro, as well as significantly enhanced tumorigenicity in NOD/SICD mice, as compared to the low expressing CD44 ESCC cells.Conclusions/significanceour study has discovered a novel TIC surface marker, CD44, which can be utilized to enrich efficiently the TICs in ESCC. These findings will be useful for further studies of these cells and exploring therapeutic approaches.