STUDY ON THE DEVELOPMENT OF INTELLIGENT ASSISTANT EVALUATION SYSTEM FOR POWER GRID ENTERPRISES' OVERSEAS INVESTMENT

Based on the comparison and induction of existing market investment evaluation methods at home and abroad as well as in-depth analysis of the elements and characteristics of the overseas power market regulatory environment (OPMRE), this paper constructed the OPMRE evaluation index system of six elements, containing policy stability, business risk, return on investment, asset growth, incentive strength and bilateral relations, and then the OPMRE evaluation model based on fuzzy comprehensive evaluation method was proposed. Finally, the corresponding intelligent assistant evaluation system was developed. The model and system were employed to evaluate the regulatory environment of six selected countries, and the results reveal that the evaluation model and system have strong practicability, which can generate the evaluation report quickly and automatically, indicating them has good realistic significance and practical value for the grid enterprises' overseas investment decisions

Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair

Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival. In the present study, we found that defects in oxidative metabolism and 2-HG production confer chemosensitization in IDH1-mutated glioma cells. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells. The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD+ availability. Targeting the PARP DNA repair pathway extensively sensitized IDH1-mutated glioma cells to TMZ. Our findings demonstrate a novel molecular mechanism that defines chemosensitivity in IDH-mutated gliomas. Targeting PARP-associated DNA repair may represent a novel therapeutic strategy for gliomas

Oncometabolites in Cancer: Current Understanding and Challenges

Abstract Oncometabolites are pathognomonic hallmarks in human cancers, including glioma, leukemia, neuroendocrine tumors, and renal cancer. Oncometabolites are aberrantly accumulated from disrupted Krebs cycle and affect the catalytic activity of α-ketoglutarate–dependent dioxygenases. Oncometabolites indicate distinct cancer-related patterns ranging from oncogenesis and metabolism to therapeutic resistance. Here we discuss the current understanding of oncometabolites as well as the controversies and challenges associated with oncometabolite-driven cancers. New insights into the relationship between cancer and oncometabolites will elucidate novel therapeutic avenues for improved cancer treatment.</jats:p

Abstract 3807: Histone deacetylase inhibitors repress hypoxia signaling through affecting Hsp90

Abstract Histone deacetylase inhibitors (HDACis) are among the most promising recently developed anti-cancer agents. Recent work suggests that HDACis suppress both malignant cell metabolism and progression by interfering with the hypoxia-inducible factor (HIF) signaling, which plays a key role in tumor progression in both actual and falsely perceived cellular hypoxia (pseudohypoxia). However, the precise biochemical mechanism of HDACis repression of HIFs function remains unclear. In this study, we demonstrated that the class-2 histone deacetylase inhibitor SAHA potently inhibits hypoxia signaling via interfering with heat shock protein 90 (Hsp90). HDACis increase in the acetylation of Hsp90, resulting in less HIF-α recognition and nuclear translocation. Accumulated cytoplasmic HIF-α is not transcriptionally active and degradaded through proteosomal pathway. Finally, we demonstrated that SAHA remarkably reduces hypoxia signaling and decreases tumor growth in vivo. These findings provide insight into new possible therapeutic strategies for using HDACis in tumors with known HIF pathway aberrations. Citation Format: Chunzhang Yang, Zhengping Zhuang. Histone deacetylase inhibitors repress hypoxia signaling through affecting Hsp90. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3807.</jats:p

High-speed nano-bearings constructed from double-walled carbon nanotubes : effect of flexile deformation

Double-walled carbon nanotubes (DWCNTs) have been proposed to be the leading candidates for high-speed nanobearings owing to superlubric characteristics between adjacent nanotubes. Performance of the DWCNT bearings is closely related to intertube friction, which is influenced by many factors, and in this work, we focus on the issue of flexibility of the nanotubes. Using molecular dynamics simulation, it has been found that considerable deformation of the nanotubes can emerge in the (5, 5)/(18, 0) DWCNT bearing with a length of ∼80 Å if the angular speed of the shaft reaches 1.3 rev/ps. Such flexile deformation results in two distinct states with differing frictional characteristics. One of the two states, the slippery rotation, represents an interim period characterized by in-phase distortions of the inner and outer tubes, while the other state, the resistant rotation, is a steady state with the inner-tube curving lags behind that of the outer tube. Such a lag leads to a considerable increase of circular deflection of the outer tube and a sharp decrease of the minimal distance between tubes, therefore preventing the inner tube from slippery rotation.Published versio

CSIG-02. NRF2-GUIDED GLUTATHIONE SYNTHESIS IS AN ESSENTIAL METABOLIC PATHWAY IN IN IDH1-MUTATED GLIOMA

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in WHO Grade II/III glioma, which result in the reprogramming of cellular metabolism and redox homeostasis. Many lines of evidence showed that IDH mutations are critical for glioma formation, whereas the therapeutic options for IDH-mutated cancers remain limited. METHODS In the present study, we used the patient-derived glioma cell lines to investigate the role of nuclear factor erythroid 2-related factor 2 (NRF2) governed glutathione de novo synthesis. Further, we evaluated the therapeutic value of NRF2 inhibitors in IDH1-mutated cells and preclinical orthotopic models. RESULTS The neomorphic activity of mutant IDH reprogrammed the metabolic pathways involving enzyme cofactors such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The depletion of NAD(P) in IDH1-mutated cells resulted in elevated oxidative stress and constitutive activation of NRF2-governed cytoprotective pathways through the decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1 (Keap1). Activation of NRF2 enhanced glutathione synthesis by enhancing the gene transcription of GCLC, GCLM, and SLC7A11, which are the critical for glutathione de novo synthesis. Further, evidence from both in vitro assays and patient cohort indicated that NRF2 governed glutathione synthesis is important for maintaining the redox homeostasis and cell survival, especially in IDH1-mutated glioma. Finally, Blockade of the NRF2/glutathione metabolic pathway exhibited synergistic cytotoxicity with the metabolic stress in IDH1-mutated cells, which results in overwhelming oxidative damage, as well as a substantial reduction in tumor cell proliferation and xenograft expansion. CONCLUSION In this study, we highlighted that NRF2 plays critical roles in the disease progression of IDH1-mutated glioma by prompting glutathione synthesis. Targeting NRF2 governed glutathione metabolism could serve as a valuable synthetic lethality approach for IDH1-mutated malignancies. </jats:sec