Despite the tremendous success of targeted and conventional therapies for lung cancer, therapeutic resistance is a common and major clinical challenge. RNF8 is a ubiquitin E3 ligase that plays ...essential roles in the DNA damage response; however, its role in the pathogenesis of lung cancer is unclear. Here, we report that RNF8 is overexpressed in lung cancer and positively correlates with the expression of p-Akt and poor survival of patients with non-small-cell lung cancer. In addition, we identify RNF8 as the E3 ligase for regulating the activation of Akt by K63-linked ubiquitination under physiological and genotoxic conditions, which leads to lung cancer cell proliferation and resistance to chemotherapy. Together, our study suggests that RNF8 could be a very promising target in precision medicine for lung cancer.
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•RNF8 promotes lung cancer progression by regulating Akt activity•RNF8 ubiquitinates and activates Akt upon DNA damage•RNF8-mediated Akt activation promotes chemoresistance in lung cancer
Xu et al. show that E3 ligase RNF8 is overexpressed in lung cancer and regulates the activation of Akt by K63-linked ubiquitination under physiological and genotoxic conditions, leading to lung cancer cell survival and resistance to DNA damage.
In this report, we describe the spontaneous malignant transformation of long-term cultured human fetal striatum neural stem cells (hsNSCs, passage 17). After subcutaneous transplantation of long-term ...cultured hsNSCs into immunodeficient nude mice, 2 out of 15 mice formed xenografts which expressed neuroendocrine tumor markers CgA and NSE. T1 cells, a cell line that we derived from one of the two subcutaneous xenografts, have undergone continuous expansion in vitro. These T1 cells showed stem cell-like features and expressed neural stem cell markers nestin and CD133. The T1 cells were involved in abnormal karyotype, genomic instability and fast proliferation. Importantly, after long-term in vitro culture, the T1 cells did not result in subcutaneous xenografts, but induced intracranial tumor formation, indicating that they adjusted themselves to the intracranial microenvironment. We further found that the T1 cells exhibited an overexpressed level of EGFR, and the CD133 positive T1 cells showed a truncation mutation in the exons 2-7 of the EGFR (EGFRvIII) gene. These results suggest that continuous expansion of neural stem cells in culture may lead to malignant spontaneous transformation. This phenomenon may be functionally related to EGFR by EGFRvIII gene mutation.
Ankylosing spondylitis (AS) is a common chronic progressive inflammatory autoimmune disease. T helper 17 (Th17) cells are the major effector cells mediating AS inflammation. Histone 3 Lys 27 ...trimethylation (H3K27me3) is an inhibitory histone modification that silences gene transcription and plays an important role in Th17 differentiation. The objective of this study was to investigate the expression of H3K27me3 in patients with AS and to explore its epigenetic regulation mechanism of Th17 differentiation during AS inflammation. We collected serum samples from 45 patients with AS at various stages and 10 healthy controls to measure their Interleukin-17 (IL-17) levels using ELISA. A quantitative polymerase chain reaction was used to quantify the mRNA levels of RORc and the signaling molecules of the JAK2/STAT3 pathway, JMJD3, and EZH2. Additionally, Western blot analysis was performed to quantify the protein levels of H3K27me3, RORγt, JAK2, STAT3, JMJD3, and EZH2 in cell protein extracts. The results showed that H3K27me3 expression in peripheral blood mononuclear cells (PBMCs) was significantly lower in patients with active AS compared to both the normal control groups and those with stable AS. Moreover, a significant negative correlation was observed between H3K27me3 expression and the characteristic transcription factor of Th17 differentiation, RORγt. We also discovered that patients with active AS exhibited significantly higher levels of JMJD3, an inhibitor of H3K27 demethylase, compared to the normal control group and patients with stable AS, while the expression of H3K27 methyltransferase (EZH2) was significantly lower. These findings suggest that H3K27me3 may be a dynamic and important epigenetic modification in AS inflammation, and JMJD3/EZH2 regulates the methylation level of H3K27me3, which may be one of the key regulatory factors in the pathogenesis of AS. These findings contribute to our understanding of the role of epigenetics in AS and may have implications for the development of novel therapeutic strategies for AS.
Lung cancer is the leading cause of cancer-related deaths worldwide, with a five-year survival rate of only 18%. Non-small cell lung cancer (NSCLC) in addition to large cell lung cancer, comprise ...85%-90% of all lung cancer diagnoses. Chemoresistance of the cancer cells is one of the reasons for the poor survival rate. In this research, we used mitoxantrone-induced resistant (MXR) NCl-H460 cells to find the mechanism of chemoresistance. We found that the MXR-resistant cells had high single-cell clonogenic ability like cancer stem cells. From the quantitative proteomics study, we found that the MXR-resistant cells high upregulated many metabolism and stem cell-related proteins, such as STAT3 and ALDH. The high level expression of histone 3.1 showed the possibility of genetic changing of resistant cells. Using Western blot assays, we confirmed enhancement of EZH2 in MXR-resistant NCl-H460 cells. Therefore, the EZH2-STAT3 pathway has an important role in the MXR-resistant NCI-H460 cancer cells. Both EZH2 and STAT3 can be used as new target proteins for chemotherapy in the treatment of large cell lung cancer.
Mitoxantrone is one kind of chemical therapy medicine for cancer but certain kinds of cancer cells are chemical-resistant to it. In this research, we analyzed the quantitative proteomic difference ...between tumors
xenograft by mitoxantrone-resistant (M group) and wild NCI-H460 cells (N group). Protein expression profiling in combination with pathway analysis was deployed to investigate molecular events associated with the tumors using a label-free quantitative proteomic approach. A total of 173 proteins were significantly differentially expressed in mitoxantrone-resistant tumors. Bioinformatics analysis using the cytoscape platform indicated that biological processes, including actin-mediated cell contraction, muscle system process, muscle filament sliding, and muscle contraction, are involved in mitoxantrone-resistance. As KEGG pathway enrichment analysis has shown, systemic lupus erythematosus, alcoholism, viral carcinogenesis, and tight junction are strongly regulated with chemical-resistance. By protein-protein interaction analysis, three protein clusters were found using k-means clustering algorithm. Dysregulation results can be verified by Western blotting. Further studies into the molecular functions of dysregulated proteins will help to provide new perspectives regarding chemoresistance for non-small cell lung cancers.
LyGDI is an inhibitor of Rho protein activation by blocking its transformation between guanosine 5'-diphosphate- and guanosine 5'-triphosphate-bound states. The aim of this study was to investigate ...the usefulness of LyGDI as a biomarker for the detection of ovarian cancer, and its specificity and sensitivity were compared with those of cancer antigen 125 (CA125).
The serum levels of LyGDI were determined by enzyme-linked immunosorbent assay in 42 patients with ovarian disease, including 30 ovarian cancers and 12 benign ovarian lesions, and 76 healthy controls. The expression of LyGDI was also evaluated by immunohistochemical staining in resected ovarian tissues of these patients.
The serum LyGDI level of cancers was significantly greater than those of the benign and healthy groups (P = 0.002 and P < 0.0001, respectively), whereas no difference was observed between the benign and control groups (P = 0.889). Based upon receiver operating characteristic curve analysis, LyGDI levels were able to distinguish ovarian cancer from benign ovarian disease (P = 0.0001) and healthy control (P < 0.0001; areas under the receiver operating characteristic curves, 0.876 and 0.833, respectively). For ovarian cancers, 83.3% (25/30) or 80.0% (24/30) was identified by serum LyGDI (> or = 1.5 ng/mL) alone or by CA125 (>35 U/mL) alone. It is of particular importance to note that all cancer patients were identified by use of both markers, and the specificity was 83.3% for the benign group. Moreover, in early-stage cancers, 88.9% (8/9) had elevated serum LyGDI levels as compared with 44.4% (4/9) elevation of CA125 levels (P = 0.125). Immunohistochemical staining confirmed the expression of LyGDI on cancerous epithelial cells other than benign ovarian epithelium.
These results suggest that LyGDI has significant potential as a marker for detection of ovarian cancer in the patients with ovarian enlargement, including detection of early-stage cancers.
A series of novel catalysts consisting of nanosized Au particles confined in micro-mesoporous ZSM-5/SBA-15 （ZSBA） materials with platelet （PL）, rod （RD）, and hexagonal-prism （HP） morphologies have ...been synthesized in situ. These catalysts possess both SBA-15 and ZSM-5 structures and exhibit excellent stability of their active sites by confinement of the Au nanoparticles （NPs） within ZSBA. The catalysts have been characterized in depth to understand their structure-property relationships. The gold NP dimensions and the pore structure of the catalysts, which were found to be sensitive to calcination temperature and synthetic conditions, are shown to play vital roles in the reduction of 4-nitrophenol. Au/ZSBA-PL, with short mesochannels （210 nm） and a large pore diameter （6.7 nm）, exhibits high catalytic performance in the reduction of 4-nitrophenol, whereas Au/ZSBA-HP and Au/ZSBA-RD, with long mesochannels and relatively smaller pore sizes, show poor catalytic activities. In the case of catalysts with different gold NP sizes, Au/ZSBA-PL-350 with an Au NP diameter of 4.0 nm exhibits the highest reaction rate constant （0.14 min-1） and turnover frequency （0.0341 s-1）. In addition, the effect of the reaction parameters on the reduction of 4-nitrophenol has been systematically investigated. A possible mechanism for 4-nitrophenol reduction over the Au/ZSBA catalysts is proposed.
A 2-year field experiment was conducted to analyze the growth conditions, physical features, yield, and nitrogen use efficiency (NUE) of sugar-beet under limited irrigation conditions in northeast of ...China. A cultivar H003 was used as plant materials; six treatments (C1-C6) were included: C1, no nitrogen applied, rain-fed; C2, nitrogen (120.00 kg ha
), rain-fed; C3, no nitrogen applied, hole irrigation for seeding; C4, nitrogen (120.00 kg ha
), hole irrigation for seeding; C5, no nitrogen applied, hole irrigation for seeding; and C6, nitrogen (120.00 kg ha
), hole irrigation for seeding, and irrigation at foliage rapid growth stage. The irrigation supply was only 500 mL/plant once. Results showed C6 showed the highest chlorophyll content, dry matter accumulation, yield, etc. and had the best NUE among all the treatments. In conclusion, under the routine fertilization conditions of northeast of China, the cultivation measure of hole irrigation 500 mL/plant for seeding combined with irrigation 500 mL/plant at foliage rapid growth stage greatly improved sugar-beet yield and NUE.
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•Humidity is intensively impact the instability of hybrid organic-inorganic perovskites.•For unpacked device, symmetric hysteresis loop rotation converts from anticlockwise to ...clockwise.•For one-end packed device, hysteresis loops transform from anticlockwise symmetry to antisymmetry.•Modulable hysteresis is from the decrease of surface state and the formation of PbI2 and bulk defect.•Electrical field-triggered filling and emptying of traps dominate adjustable electric transport.
The instability of hybrid organic-inorganic perovskites (HOIP) in environment, especially in high humidity causes different conductance that should be addressed to improve its large-scale application and development. Here, the electrical transport of an individual CH3NH3PbI3 micro/nanowire-based two-terminal device with encapsulating different ends was investigated in a condensed water environment. For an unencapsulated device, linear I-V curve transforms first into two symmetrical counterclockwise hysteresis loops with positive resistive switching (RS) feature, and eventually converts into two symmetrical clockwise hysteresis loops with negative RS feature. For the device encapsulated at one end, the linear I-V curve first transforms into two symmetrical counterclockwise hysteresis loops with positive RS behavior, and then converts into two antisymmetric hysteresis loops with a bipolar RS feature. The origin of modulable hysteresis with different RS characteristics is mainly from the decomposition-induced decrease of surface states and formation of PbI2 and structure defects. As a consequence, the electrical field-triggered filling and emptying of traps in different regions dominate the adjustable performance of electrical transport. The controllable electrical transport can not only demonstrate clearly that condensed water can promote the decomposition of CH3NH3PbI3, but also verify that the hysteresis behavior with different RS memory effect originate from the decomposition-induced traps.
Insufficient dissolved oxygen (DO) concentration is recognized as one of the major factors limiting efficient nitrogen removal in constructed wetlands (CWs). This study investigated four ...biochar-based vertical subsurface flow constructed wetlands (VSFCWs) (system I: intermittent aeration without biochar addition; system II: intermittent aeration with biochar addition; system III: tidal flow without biochar addition; system IV: tidal flow with biochar addition) to compare the effect of oxygen supply strategies on the performance and mechanism of nitrogen removal. The results showed that NH4+N removal efficiencies were 85.83%, 87.88%, 96.19%, and 98.30% for systems I–IV respectively. The abundance of microbes involved in nitrogen transformation also increased in all VSFCWs, particularly in the tidal flow mode with biochar addition. The higher oxygen utilization rate and higher surface area provided by biochar could significantly improve microbial abundance and then enhance nitrogen removal. Most notably, the rate of nitritation (2.92, 3.82, 3.14 and 4.27 mg N L−1 h−1) was higher than that of nitration (0.51, 0.66, 0.83 and 0.89 mg N L−1 h−1) in systems I–IV, respectively, and the percentages of NO2−-N denitrified via simultaneous nitrification denitrification (SND) in systems I–IV were 58.20%, 55.10%, 50.89% and 51.89%, respectively. Therefore, in addition to conventional nitrification denitrification, partial nitrification and SND via NO2−-N were also the significant nitrogen transformation pathways in the four VSFCWs at high DO concentrations (2.43–6.84 mg L−1). These results demonstrated that the tidal flow biochar-based VSFCWs performed well in nitrogen removal due to efficient oxygen supplementation and enhanced microbial community abundance.
•Intermittent aeration and tidal flow strategies markedly improved DO concentration.•The tidal flow biochar-based VSFCW removed nitrogen most effectively.•Partial nitrification and SND via nitrite were main nitrogen removal pathways.
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