Rs10757274 gene polymorphisms in coronary artery disease: A systematic review and a meta-analysis.

BACKGROUND: It has been reported the rs10757274 SNP (present on locus 9p21 in the gene for CDKN2BAS1) might be associated with susceptibility to coronary artery disease (CAD). Owing to mixed and inconclusive results, we conducted a meta-analysis to investigate the association between rs10757274 polymorphism and the risk of CAD. OBJECTIVES: The present study aimed to investigate the relationship between rs10757274 polymorphism and the risk of CAD. METHODS: All studies of the rs10757274 SNP with CAD that were published between 2007 and 2018 were retrieved from the PubMed database. Meta-analysis was performed with Stata 14.0 software. The effect size of the rs10757274 SNP with CAD risk was assessed based on the odds ratios (ORs) with calculation of 95% confidence interval (CI). RESULTS: Eleven studies including 52,209 subjects (cases: 7990, controls: 44,219) were included in the final data combination. Pooled overall analyses showed that rs10757274 (allele model: P < .001; dominant model: P < .001; recessive model: P < .001; Heterozygote codominant: P = .002; Homozygote codominant: P < .001) polymorphisms were significantly associated with the likelihood of CAD. Significant heterogeneity between individual studies appears in all 5 models. Further subgroup analyses revealed that rs10757274 polymorphisms were all significantly correlated with the likelihood of CAD and no heterogeneity were observed in West Asians. CONCLUSIONS: Our findings indicated that rs10757274 polymorphisms may serve as genetic biomarkers of CAD, especially in West Asians.

Identification of small molecule inhibitors targeting the SMARCA2 bromodomain from a high-throughput screening assay.

SMARCA2 is a critical catalytic subunit of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes. Dysregulation of SMARCA2 is associated with several diseases, including some cancers. SMARCA2 is multi-domain protein containing a bromodomain (BRD) that specifically recognizes acetylated lysine residues in histone tails, thus playing an important role in chromatin remodeling. Many potent and specific inhibitors targeting other BRDs have recently been discovered and have been widely used for cancer treatments and biological research. However, hit discovery targeting SMARCA2-BRD is particularly lacking. To date, there is a paucity of reported high-throughput screening (HTS) assays targeting the SMARCA2-BRD interface. In this study, we developed an AlphaScreen HTS system for the discovery of SMARCA2-BRD inhibitors and optimized the physicochemical conditions including pH, salt concentrations and detergent levels. Through an established AlphaScreen-based high-throughput screening assay against an in-house compound library, DCSM06 was identified as a novel SMARCA2-BRD inhibitor with an IC50 value of 39.9±3.0 µmol/L. Surface plasmon resonance demonstrated the binding between SMARCA2-BRD and DCSM06 (Kd=38.6 µmol/L). A similarity-based analog search led to identification of DCSM06-05 with an IC50 value of 9.0±1.4 µmol/L. Molecular docking was performed to predict the binding mode of DCSM06-05 and to decipher the structural basis of the infiuence of chemical modifications on inhibitor potency. DCSM06-05 may be used as a starting point for further medicinal chemistry optimization and could function as a chemical tool for SMARCA2-related functional studies.

Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search.

SET7, serving as the only histone methyltransferase that monomethylates 'Lys-4' of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What's more, SET7 is involved inthe pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Therefore, there is urgent need to develop novel SET7 inhibitors. In this paper, based on DC-S239 which has been previously reported in our group, we employed scaffold hopping- and 2D fingerprint-based similarity searches and identified DC-S285 as the new hit compound targeting SET7 (IC50 = 9.3 µM). Both radioactive tracing and NMR experiments validated the interactions between DC-S285 and SET7 followed by the second-round similarity search leading to the identification ofDC-S303 with the IC50 value of 1.1 µM. In cellular level, DC-S285 retarded tumor cell proliferation and showed selectivity against MCF7 (IC50 = 21.4 µM), Jurkat (IC50 = 2.2 µM), THP1 (IC50 = 3.5 µM), U937 (IC50 = 3.9 µM) cell lines. Docking calculations suggested that DC-S303 share similar binding mode with the parent compoundDC-S239. What's more, it presented good selectivity against other epigenetic targets, including SETD1B, SETD8, G9a, SMYD2 and EZH2. DC-S303 can serve as a drug-like scaffold which may need further optimization for drug development, and can be used as chemical probe to help the community to better understand the SET7 biology.

Heteroatom-doped nanoporous carbon from recyclable Pueraria lobata and its dual activities for oxygen reduction and hydrogen evolution reactions.

Many efficient and non-precious metal catalysts for oxygen reduction or hydrogen evolution reactions have been developed, but bifunctional catalysts for both oxygen reduction reaction and hydrogen evolution reactions are seldom reported despite their advantages. Herein, we designed the bulk preparation of heteroatom-doped nanoporous carbon catalysts using widely available and recyclable Pueraria lobata powder as the carbon source. The typical product was N, P and Fe Tri-doped nano-porous carbon (N,P,Fe-NPC) with high surface area (BET surface area of 776.68 m2 g-1 and electrochemical surface area of 55.0 mF cm-2). The typical N,P,Fe-NPC sample simultaneously exhibited high activities for oxygen reduction and hydrogen evolution reactions. Because of the high surface area and the tri-doping of N, P and Fe elements, the prepared material may have applications in other fields such as gas uptake, sensors, sewage treatment, and supercapacitors. The suggested approach is low-cost, simple and readily scalable.

Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors.

Protein arginine methylation, a post-translational modification critical for a variety of biological processes, is catalyzed by protein arginine N-methyltransferases (PRMTs). In particular, PRMT1 is responsible for over 85% of the arginine methylation in mammalian cells. Dysregulation of PRMT1 is involved in diverse pathological diseases including cancers. However, most current PRMT1 inhibitors are lack of specificity, efficacy, and bioavailability. Herein, a series of alkyl bis(oxy)dibenzimidamide derivatives were identified as selective PRMT1 inhibitors. Among them, the most potent compound corresponds to hexamidine (IC50  = 5.9 ± 1.7 µm), which is an antimicrobial agent. The binding between hexamidine and PRMT1 was further validated by thermal shift assays and nuclear magnetic resonance (NMR) experiments. Molecular docking and NMR assays indicated that hexamidine occupied the substrate binding pocket. Furthermore, hexamidine effectively blocked cell proliferation in cancer cell lines related to PRMT1 overexpression. Taken together, this study has provided a druggable scaffold targeting PRMT1 as well as a new way to repurpose old drugs which is a complementary tool for the discovery of new lead compounds.

[Plasma Mass Spectrometry of Sea Mountain Basalts in the Western Pacific and Its Geological Significance].

Seamount basalts recorded important information of seamount and deep evolution process. Through the analysis of petrology and REE geochemical characteristics of Govorov Guyot, Niulang Guyot, Arnold Guyot, Skornyakova Guyot, Gordin Guyot, McDonnell Guyot, Lingyi Seamount, Xufu Seamounts basalts in the western Pacific, it shows that basalts in study area have amygdaloidal, fumarolic-amygdaloidal and porphyritic texture. Rocks are mainly composed of phenocrysts and matrix. Mineral composition of phenocrysts is mainly plagioclase, olivine and clinopyroxene. Mineral composition of matrix is plagioclase, olivine, clinopyroxene and glassy etc. REE patterns and parameters of each sea mountain basalts reflect the typical characteristics of oceanic island basalts. It indicates that the seamount in study area is a typical volcanic seamount in plate caused by multiple hotspots. At the same time, it may have been influenced by multi-stage fault and magmatic activity.

Fibulin-5 is a prognostic marker that contributes to proliferation and invasion of human glioma cells.

Fibulin-5 has recently been considered as a potential tumor suppressor in human cancers. Several studies have shown that it is down-regulated in a variety of tumor types and inhibits tumor growth and metastasis. This study was aimed to investigate the clinical significance of fibulin-5 in glioma and its role in cell proliferation and invasion. We found that the expression of fibulin-5 in glioma tissues was significantly lower than those in normal brain (NB) tissues. Negative expression was significantly correlated with advanced clinical stage (grade III+IV). Furthermore, Fibulin-5 negative expression was correlated with a shorter overall survival of glioma patients. Multivariate Cox repression analysis indicated that fibulin-5 was an independent factor for predicting overall survival of glioma patients. Overexpression obviously inhibited cell proliferation in U251 and U87 cells. Furthermore, it significantly reduced the number of migrating and invading glioma cells. In conclusion, impaired expression of fibulin-5 is correlated with the advanced tumor stage in glioma. Otherwise, Fibulin-5 is an independent prognostic marker for predicting overall survival of glioma patients. Mechanistically, it may function as a tumor suppressor via inhibiting cell proliferation and invasion in gliomas.

Early pressure dressing for the prevention of subdural effusion secondary to decompressive craniectomy in patients with severe traumatic brain injury.

This study was performed to investigate the effect of early pressure dressing on the prevention of postoperative subdural effusion secondary to decompressive craniectomy (DC) in patients with severe traumatic brain injury (STBI). Patients with STBI who had undergone DC for refractory increased intracranial pressure between January 2008 and December 2011 (n = 169) were randomly divided into early pressure dressing (n = 82) and control (n = 87) groups. Early pressure dressing with an elastic bandage or general wrapping (control treatment) was applied 7 to 10 days after DC. Patients' age, sex, preoperative Glasgow Coma Scale score, incidence rate of subdural effusion, hospitalization time, and postoperative Glasgow Outcome Scale score were compared between groups. Intracranial pressure was measured immediately before and on the day after pressure dressing. No significant difference in age, sex, preoperative Glasgow Coma Scale score, or postoperative Glasgow Outcome Scale score was observed between groups (P > 0.05). Subdural effusion incidence rates were significantly lower in the early pressure dressing group than those in the control group (χ² = 5.449, P = 0.021), and a larger proportion of patients in the early pressure dressing group was hospitalized for 30 days or less (χ² = 5.245, P = 0.027). Early pressure dressing 7 to 10 days after DC, which is a noninvasive, simple procedure, reduced the incidence rate of subdural effusion and shortened hospitalization time after DC for STBI.

[Spectral characteristics and implications of quartz from Heliao lead-zinc polymetallic ore district in the south of Qinzhou-Hangzhou joint belt].

The XRD, FTIR and Raman spectrum were employed to study the characters of quartz from three types of rock samples, which are mineralized rock sample, near ore body rock sample and far away from ore body rock sample in Heliao lead-zinc polymetallic ore district. The research shows that the quartz in the mineralized rock and far away from ore body rock is pure, while the quartz in near ore body rock contains a small amount of impurities. But such small amounts of impurities did not cause apparent change in the quartz lattice parameters. From far away from ore body rock-->near ore body rock-->mineralized rock, the crystallinity and order degree of quartz are higher and higher. And the quartz in the mineralized rock has a trend to change into low symmetry quartz. It's a unique to mineralized rock that the quartz's absorption peak at 1 050 cm(-1) was split into two strongest ones. It can be used as the signs of whether exists mineralization. The cause for the quartz microstructure changes may be related to the activities of late mineralized hydrothermal fluids. Late hydrothermal influence was very weak to the quartz far away from ore body rock. And through the impact of the multi-stage hydrothermal effect, the quartz in mineralized rock may be purified by recrystallization and structural adjustment. However the quartz in near ore body rock didn't have enough hydrothermal influence, so it's not pure. Genealogy research technology is a useful technique for in-depth exploration of study area mineralization process and metallogenic regularity.