Objective: To analyze the status of statins use and low-density lipoprotein cholesterol (LDL-C) management in patients with atrial fibrillation (AF) and very high/high risk of atherosclerotic cardiovascular disease (ASCVD) from Chinese Atrial Fibrillation Registry (CAFR). Methods: A total of 9 119 patients with AF were recruited in CAFR between January 1, 2015 to December 31, 2018, patients at very high and high risk of ASCVD were included in this study. Demographics, medical history, cardiovascular risk factors, and laboratory test results were collected. In patients with very high-risk, a threshold of 1.8 mmol/L was used as LDL-C management target and in patients with high risk, a threshold of 2.6 mmol/L was used as LDL-C management target. Statins use and LDL-C compliance rate were analyzed, multiple regression analysis was performed to explore the influencing factors of statins use. Results: 3 833 patients were selected (1 912 (21.0%) in very high risk of ASCVD group and 1 921 (21.1%) in high risk of ASCVD group). The proportion of patients with very high and high risk of ASCVD taking statins was 60.2% (1 151/1 912) and 38.6% (741/1 921), respectively. Attainment rate of LDL-C management target in patients with very high and high risk were 26.7% (511/1 912) and 36.4% (700/1 921), respectively. Conclusion: The proportion of statins use and attainment rate of LDL-C management target are low in AF patients with very high and high risk of ASCVD in this cohort. The comprehensive management in AF patients should be further strengthened, especially the primary prevention of cardiovascular disease in AF patients with very high and high risk of ASCVD.
Humans ; Atrial Fibrillation/drug therapy* ; Cardiovascular Diseases ; Cholesterol, LDL ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use* ; Atherosclerosis ; Dyslipidemias/drug therapy*

Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)-mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes, particularly those involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling pathways. In addition to FOXK1/K2, we also identify other DNA-binding transcription regulators including transcription factors (TFs) which interact with wild-type ASXL1, but not C-terminally truncated mutant. Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.

This study was aimed to elucidate the expression of costimulatory molecule CD80 and CD86 in HL-60 cells induced by proteasome inhibitor MG132 and its effect on allogeneic mixed lymphocyte reaction. Acute myelocytic leukemia cell line HL-60 and chronic myelocytic leukemia cell line K562 were cultured. The viability of the cells was measured by flow cytometry. Proteasome inhibitor MG132 at the concentrations of 2 or 3 µmol/L was used to stimulate the HL-60 cell cultured for 24 h and 48 h respectively, and the Annexin V/7-AAD staining and flow cytomotry were used to detect the apoptosis of the HL-60 cells. HL-60 and K562 cells were treated with 1 µmol/L MG132 for 24 h and 48 h respectively, then CD80 and CD86 antibodies were added, finally the expression of CD80 and CD86 was analysed by flow cytomery. The mRNA expression of CD86 in the HL-60 cells treated with 1 µmol/L MG132 was detected by RT-PCR. HL-60 and K562 cells were treated by 1 µmol/L MG132 and then underwent irradiation of 75 Gy (60)Co to kill the cells with their antigenicity preserved. Peripheral blood mononuclear cells (PBMNCs) of healthy volunteers, as reactive cells, were isolated and inoculated into the (60)Co irradiated HL-60 cells of different concentrations, as stimulating cells, CCK-8 was added and then the A value of absorbance was measured at the wave length of 450 nm in an enzyme labeling instrument. The results showed that the cell viability of the HL-60 cells treated with 1 µmol/L MG132 for 24 h an d 48 h was 92.95% and 85.87% respectively. The apoptotic rates of the HL-60 cells treated with MG132 increased in dose-and time-dependent manner. High-concentration of MG132 directly killed HL-60 cells. Before MG132 treatment K562 cells did not express CD86, but the CD86 expression of the HL-60 cells was up-regulated time-dependently after MG132 treatment (P < 0.01). The mRNA expression of CD86 in the HL-60 treated with MG132 was up-regulated time-dependently (P < 0.01). CCK-8 test showed that the proliferation level of PBMNC gradually increased along with the concentration of HL-60 cells treated with MG132 and reached its peak when the concentration of the HL-60 cells was 1×10(5) (P < 0.01). No remarkable proliferation of PBMNC was observed in the K562 groups no matter if the HL-60 cells had been treated with MG132. It is concluded that the high concentration of MG132 can directly kill HL-60 cells, low-concentration of MG132 can induce the expression of costimulatory molecule CD86 in HL-60 cells, also can improve the proliferation of PBMNC.
Apoptosis ; B7-2 Antigen ; immunology ; Cell Survival ; Flow Cytometry ; HL-60 Cells ; Humans ; K562 Cells ; Leukocytes, Mononuclear ; drug effects ; Leupeptins ; pharmacology ; Lymphocyte Culture Test, Mixed ; Proteasome Inhibitors ; pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Up-Regulation

Objective To investigate the clinical results of occlusal splint in the treatment of sagittal fracture of mandibular condyle (SFMC) in children.Methods Thirty-nine patients (48 condyles) aged 3-8 years with sagittal fracture of mandibular condyle were included in this study.All the patients were treated by occlusal splint.Slight open occlusion was maintained by occlusal splint for 3-6 months.Clinical and radiological examination was performed six mouths and every year after treatment.Results Good mandibular function was observed in 39 patients.Maximal mouth opening over 35 mm was achieved at 6 months.But 11 of the 39 patients presented with deviation on mouth opening at 6 months.The radiology showed an complete remodeling in 32 condyles (28 patients) and partial remodeling in 16 condyles (11 patients).Poor remodelling was not observed in any patients.Conclusions Good clinical results can be obtained by using occlusal splint in the treatment of pediatric sagittal fracture of mandibular condyle.

BACKGROUNDBariatric surgery offers successful resolution of type 2 diabetes mellitus (T2DM). However, recurrence of T2DM has been observed in a number of patients with initial resolution after bariatric surgery. This study aimed to induce reversal of the improvement of diabetes in T2DM rats after duodenal-jejunal bypass (DJB), and identify the effects of weight changes and gut hormones that might be involved.

METHODSDJB surgery was performed in two T2DM rat models (n=20 for each group): non-obese Goto-Kakizaki (GK) rats, and moderately-obese T2DM rats induced by a combination of a high-fat diet (HFD) and low-dose streptozotocin (HS rats). The controls were sham-operated and non-treated rats. All rats were then randomly divided into HFD- and low-fat diet (LFD)-fed groups. Glucose tolerance, insulin tolerance, glucose-stimulated insulin, glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion, food intake and body weight were measured and compared with controls.

RESULTSDJB surgery resulted in a significant improvement in glucose tolerance in both GK and HS rats fed with either HFD or LFD. In contrast to LFD-fed rats, improved glucose tolerance was impaired in GK and HS rats fed with an HFD, accompanied by re-impairment of insulin tolerance and failure in enhancement of insulin secretion. There was no significant difference in food intake and body weight between DJB-operated and control rats, and between HFD- and LFD-fed rats. Glucose-stimulated GLP-1 and PYY levels were significantly increased after DJB surgery; however, they were not significantly different between HFD- and LFD-fed rats.

CONCLUSIONAn HFD reverses the improvement in glucose tolerance induced by DJB surgery in T2DM rats, primarily ascribing to the re-impairment of insulin sensitivity, but does not change body weight, GLP-1 and PYY levels.

Animals ; Blood Glucose ; drug effects ; Diabetes Mellitus, Type 2 ; blood ; chemically induced ; pathology ; surgery ; Diet, High-Fat ; adverse effects ; Gastric Bypass ; Glucose Tolerance Test ; Male ; Rats ; Rats, Sprague-Dawley

Adenoviridae ; genetics ; Animals ; Apoptosis ; drug effects ; Carcinoma, Squamous Cell ; genetics ; metabolism ; therapy ; Cell Cycle ; drug effects ; Clinical Trials as Topic ; Genes, p53 ; Genetic Therapy ; Genetic Vectors ; Humans ; Mouth Neoplasms ; genetics ; metabolism ; therapy ; Mutation ; Tumor Suppressor Protein p53 ; genetics ; metabolism ; Viral Vaccines ; pharmacology ; therapeutic use

BACKGROUNDStatins are one of the most common agents prescribed for ischemic stroke patients, but their side effects on the liver are worrisome to both physicians and patients. This study aimed to analyze the features and related factors of the hepatic side effects of statins in patients with ischemic stroke.

METHODSFour hundred and eighty-one patients with ischemic stroke who had been treated with statins at our department from July 1, 2008 to June 30, 2009 were investigated retrospectively. Liver function, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), within 6 months after they began to use statins and related factors were analyzed.

RESULTSThe incidence of mild ALT and AST elevation, less than three times the upper limit of normal, and the incidence of moderate elevation, ALT and AST levels 3-10 times the upper limit of normal, in ischemic stroke patients who had been treated with statins were 2.3% and 2.1%, respectively. These incidences were higher than in patients with common hyperlipidemia or coronary heart disease. The relatively high incidence was associated with older age (≥ 65 years) and chronic liver diseases, and was not related to the type of stroke, gender, and reduction of low-density lipoprotein. The levels of ALT and AST normalized after withdrawal of statins or lowering the dosage. None of the patients developed hepatic failure.

CONCLUSIONSAsymptomatic elevation of ALT and AST after administration of statins is more likely to occur in ischemic stroke patients than in others, and the elevation is related to age and chronic liver diseases. However, statins are still safe for ischemic stroke patients.

Age Distribution ; Aged ; Alanine Transaminase ; metabolism ; Aspartate Aminotransferases ; metabolism ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; adverse effects ; therapeutic use ; Liver ; drug effects ; metabolism ; Male ; Middle Aged ; Retrospective Studies ; Stroke ; drug therapy

OBJECTIVETo observe the cellular expression of (R127W) HSPB1 and its influence on neurofilament light chain (NFL) self-assembly and co-localization with NFL.

METHODSEukaryotic expression vectors pEGFPN1-(wt) HSPB1 and pEGFPN1- (R127W) HSPB1 were constructed. Hela cells were transiently transfected with pEGFPN1-(wt) HSPB1 or pEGFPN1- (R127W) HSPB1 and observed under a confocal microscope. Hela cells were also transiently co-transfected with Pcl-NFL and pEGFPN1-(wt)HSPB1, or pCL-NFL and pEGFPN1-(R127W)HSPB1. The self-assembly of NFL was observed and the co-localization study of HSPB1/ (R127W)HSPB1 with NFL was carried out in these two cell models by immunofluorescence technique.

RESULTSThe aggregates formed by EGFP-(R127W)HSPB1 predominantly located around the nucleus, and EGFP-(wt)HSPB1 showed diffusion pattern in Hela cells. When co expressed with EGFP-(wt)HSPB1, NFL formed homogeneous structure in cytosol. When co-expressed with EGFP-(R127W)HSPB1, however, NFL had amorphous staining pattern predominantly consisting of NFL aggregates, and NFL co-localized with (R127W)HSPB1 in these aggregates.

CONCLUSIONThe R127W mutant of HSPB1 may have reduced capacity to serve as a chaperone to prevent aggregate formation, and fail to correctly organize the neurofilament network. Dysfunction of the axon cytoskeleton and axon transport may be the primary mechanism of R127W mutation of HSPB1 in the pathogenesis of Charcot-Marie-Tooth disease.

Base Sequence ; Charcot-Marie-Tooth Disease ; genetics ; metabolism ; Gene Expression Regulation ; Genetic Vectors ; genetics ; HSP27 Heat-Shock Proteins ; genetics ; metabolism ; HeLa Cells ; Humans ; Intracellular Space ; metabolism ; Mutant Proteins ; genetics ; metabolism ; Neurofilament Proteins ; metabolism ; Protein Binding ; genetics ; Protein Transport ; Transfection

OBJECTIVETo assay the expression of cytidine deaminase (CDA), ribonucleotide reductase subunit 1 (RRM1), phosphatase and tensin homologue deleted from chromosome 10 (PTEN), excision repair cross-complementation group 1 (ERCC1), deoxycytidine kinase (dCK) and RRM1(-)37A/C polymorphism, which have been shown relevant to gemcitabine resistance in two human gemcitabine-resistant non-small cell lung cancer cell lines A549/Gem and NCI-H460/Gem, so as to make clear how do they vary during the course of acquiring resistance to gemcitabine.

METHODSThe human gemcitabine-resistant non-small cell lung cancer cell lines A549/Gem and NCI-H460/Gem were established in our Department by repeated clinical serum peak concentration and gradually increasing doses. Real-time fluorescent quantitative PCR was used to examine the expression of CDA, RRM1, PTEN, ERCC1, dCK and RRM1(-)37A/C polymorphism in those cell lines at different time points during their induction process.

RESULTSThe resistance indexes of A549/Gem and NCI-H460/Gem cells reached 163.228 and 181.684, and then remained stable at 115.297 and 129.783, respectively. The expression of CDA, RRM1, PTEN and ERCC1 varied along with the changing gemcitabine resistance indexes, but expression of dCK did not change apparently. The wild type promoter was able to amplify the genomic DNA in different induction stages of A549/Gem and NCI-H460/Gem cells, but allelotype did not, indicating that the gene type of A549/Gem, NCI-H460/Gem and their parental cells remaining still wild type.

CONCLUSIONCompared with their parental cells, the expressions of CDA, RRM1, PTEN and ERCC1 in human gemcitabine-resistant non-small cell lung cancer cell lines A549/Gem and NCI-H460/Gem rise, the expression of dCK changes inapparently, therefore, their gene type are remaining wild type.

Antimetabolites, Antineoplastic ; pharmacology ; Carcinoma, Large Cell ; genetics ; metabolism ; pathology ; Carcinoma, Non-Small-Cell Lung ; genetics ; metabolism ; pathology ; Cell Line, Tumor ; Cytidine Deaminase ; genetics ; metabolism ; DNA-Binding Proteins ; genetics ; metabolism ; Deoxycytidine ; analogs & derivatives ; pharmacology ; Deoxycytidine Kinase ; genetics ; metabolism ; Drug Resistance, Neoplasm ; Endonucleases ; genetics ; metabolism ; Humans ; Lung Neoplasms ; genetics ; metabolism ; pathology ; PTEN Phosphohydrolase ; genetics ; metabolism ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; RNA, Messenger ; metabolism ; Tumor Suppressor Proteins ; genetics ; metabolism