OBJECTIVE: To investigate the efficacy and safety of arsenic trioxide combined with ATRA and chemo- therapy for treatment of relapsed acute promyelocytic leukemia (APL) patients. METHODS: The clinic data of 25 patients with relapse APL treated in our hospital from 1996 to 2013 were collected and analyzed. Among the 25 patients, 15 patients suffered first-time hematological relapse (HR), and the other 10 patients showed first-time molecular relapse (MR). The patients with first-time replase were treated with ATO+ATRA+Anthracycline re-induction chemotherapy. The clinical features, complete remission (CR) rate, overall survival (OS), disease-free survival (DFS) and adverse events after re-induction therapy were analyzed. RESULTS: Fourteen of 15 hematological relapsed patients achieved the second-time hematological complete remission (CR2) after re-induction therapy except one patient died of bleeding complication during the re-induction. 8 of 14 patient showed molecular complete remission (CRm) after two cycles of therapy with this regimen. Totally, eleven out of the 14 HR patients were alive without disease till the last follow-up, and 3 of the 14 HR patients died because of bleeding complications. All of the 10 molecular relapsed patients received the second CRm after treated by the regimen. Among these 10 patients, 6 patients suffered only once relapse and continued with the molecular CR2 status, and for the other 4 patients with more than two-relapses, only 1 survived untill 89.3 months after achieved second-time CRm, and other 3 patients died because of bleeding complications. CONCLUSION For relapsed APL patients, the treatment with ATO+ATRA+chemotherapy regimen after relapse still shows encouraging efficacy, no matter whether or not the application of ATO in the previous regimens. In addition, patients with more than two molecular relapses show a poor prognosis.

Objective To investigate the causal association between hip circumference (HC) and type 2 diabetes mellitus (T2DM) based on Mendelian randomization. Methods The genetic variants data of the HC and T2DM from the Genetic Investigation of Anthropometric Traits (GIANT) and DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) database were matched according to the single nucleotide polymorphism (SNP) rsID. Genetic loci strongly related to the HC were used as instrumental variables; and the inverse-variance weighting, MR-Egger regression model and weighting median method were carried out to analyze the causal effect of HC on T2DM. Results Fifty-two, nine and fifteen SNPs were matched in the total cohort, female cohort and male cohort, respectively. Heterogeneity test suggested the SNPs were homogeneous. We found HC to be positively associated with T2DM risk (OR=1.065, 95% CI: 1.030-1.100, OR=1.103, 95% CI: 1.057-1.150 and OR=1.583, 95% CI: 1.273-1.968, respectively) in above three cohorts, respectively. Sensitivity analysis showed the results were robust. Conclusions There is a relationship between HC and T2DM of people, and HC may be the risk factor of T2DM.

STUDY DESIGN: In Vitro cell culture study. PURPOSE: This study aims to investigate the impact of transforming growth factor-beta1 (TGF-β1) and lovastatin on differentiating human mesenchymal stem cells (MSCs) toward nucleus pulposus (NP)-like phenotype. OVERVIEW OF LITERATURE: MSCs offer a cell source to the cell-based therapy for intervertebral disc degeneration. TGF-β1 is used to induce MSCs to differentiate into NP-like cells; however, an undesired expression of collagen type I has been reported. Statins reportedly stimulate expression of bone morphogenetic protein-2 (BMP-2) and promote the chondrogenic phenotype to NP cells. However, the effects of statins with or without TGF-β1 on the differentiation of MSCs into NP-like cells remain unclear. METHODS: Human MSCs were treated with TGF-β1 alone, lovastatin alone, and simultaneous or sequential treatment with TGF-β1 and lovastatin. After the proposed stimulation, the total RNA was extracted to assess the expression profile of NP cells-specific genes. Hematoxylin–eosin staining was used for examining the microscopic morphology. Furthermore, we detected the syntheses of S-100 protein, aggrecan, and collagen type II in the extracellular matrix using immunohistochemical staining. RESULTS: Simultaneous or sequential treatment of TGF-β1 and lovastatin could further augment the BMP-2 overexpression compared with lovastatin-alone treatment. However, the mRNA expression of aggrecan and collagen type II was not compatible with the expression level of BMP-2. Immunohistochemical studies revealed compatible production of aggrecan, collagen type II, and S-100 protein in all three groups treated with lovastatin. Cells in groups treated with lovastatin were less populated than that in the group treated with TGF-β1 alone. CONCLUSIONS: This study demonstrates a promising role of lovastatin in inducing human MSCs into NP-like cells. However, further optimization of cell density before lovastatin treatment, treatment duration, and combination with TGF-β1 are warranted to attain better stimulatory effects.

The aim of this paper was to systematically evaluate the toxicity-reducing effect of Tripterygium-licorice in animal experiments,and also to provide evidence for basic research on the toxicity reduction of Tripterygium wilfordii. The PubMed,EMbase,Web of Science,CBM,CNKI and Wan Fang Databases from their establishment to August 31 th,2018 were searched. Two independent reviewers screened the papers,extracted the data,assessed the risk of bias using SYRCLE assessment tool and conducted Meta-analysis with Rev Man 5. 3 software. A total of 10 papers involving 31 studies were finally included,15 studies of which were used for Meta-analysis. Four studies were included for chronic hepatotoxicity animal model. In experimental group( 34 animals),Tripterygium was administered at dose of 0. 09-0. 1 mg·kg-1·d-1,and glycyrrhizic acid was administered at dose of 90-100 mg·kg-1,both for 2 weeks; in control group( 34 animals),glycyrrhizic acid was replaced with equal volume of normal saline. Eleven studies were included for acute hepatotoxicity animal model. In experimental group( 66 animals),glycyrrhizic acid was administered at dose of 75-480 mg·kg-1 for 7 days,then glycyrrhizic acid was stopped,and Tripterygium began to be administered at dose of 0. 6-1. 0 mg·kg-1 per 24 h or 48 h for a total of 1-2 times; in control group( 66 animals),glycyrrhizic acid was replaced with equal volume of normal saline or corresponding solvent. The results of Meta-analysis showed that in both chronic hepatotoxicity animal model and acute hepatotoxicity animal model,the transaminase levels in the experimental group were lower than those in the control group( P < 0. 05). Subgroup analysis of acute hepatotoxicity animal model showed that the transaminase levels in the experimental group were lower than those in the control group for every subgroup except " glycyrrhizic acid 75 mg·kg-1" subgroup. However,in terms of the mean difference( MD) and confidence interval( CI),there was no significant difference in transaminase decline between each subgroup. Low dose of glycyrrhizic acid( 90-100 mg·kg-1) has a toxicity-reduction effect on chronic hepatotoxicity induced by tripterygium( 0. 09-0. 10 mg·kg-1). Middle and high doses of glycyrrhizic acid( 120-480 mg·kg-1) have a toxicity-reduction effect on acute hepatotoxicity induced by tripterygium( 0. 6-1. 0 mg·kg-1),but with no significant dose-effect relationship.
Animals ; Chemical and Drug Induced Liver Injury ; prevention & control ; Drugs, Chinese Herbal ; administration & dosage ; toxicity ; Glycyrrhiza ; Glycyrrhizic Acid ; administration & dosage ; Tripterygium ; chemistry ; toxicity

OBJECTIVE: To study the clinical value of serum neuroglobin in evaluating hypoglycemic brain injury in neonates. METHODS: A total of 100 neonates with hypoglycemia were enrolled as subjects. According to amplitude-integrated EEG (aEEG) findings and/or clinical manifestations, they were divided into symptomatic hypoglycemic brain injury group (n=22), asymptomatic hypoglycemic brain injury group (n=37) and hypoglycemic non-brain injury group (n=41). The three groups were compared in terms of blood glucose, duration of hypoglycemia, levels of neuroglobin and neuron-specific enolase (NSE), and modified aEEG score. The correlation of neuroglobin with NSE and modified aEEG score was analyzed. The receiver operating characteristic (ROC) curve was plotted. RESULTS: Compared with the asymptomatic hypoglycemic brain injury and hypoglycemic non-brain injury groups, the symptomatic hypoglycemic brain injury group had significantly lower blood glucose and modified aEEG score, significantly higher neuroglobin and NSE levels, and a significantly longer duration of hypoglycemia (P<0.05). Compared with the hypoglycemic non-brain injury group, the asymptomatic hypoglycemic brain injury group had significantly lower blood glucose and modified aEEG score, significantly higher neuroglobin and NSE levels, and a significantly longer duration of hypoglycemia (P<0.05). Neuroglobin was positively correlated with NSE and duration of hypoglycemia (r=0.922 and 0.929 respectively; P<0.05) and negatively correlated with blood glucose and modified aEEG score (r=-0.849 and -0.968 respectively; P<0.05). The areas under the ROC curve of neuroglobin, NSE and modified aEEG score were 0.894, 0.890 and 0.941 respectively, and neuroglobin had a sensitivity of 80.8% and a specificity of 95.8% at the optimal cut-off value of 108 mg/L. CONCLUSIONS Like NSE and modified aEEG score, serum neuroglobin can also be used as a specific indicator for the assessment of brain injury in neonates with hypoglycemia and has a certain value in clinical practice.
Brain Injuries ; Electroencephalography ; Humans ; Hypoglycemic Agents ; Infant, Newborn ; Neuroglobin ; blood ; Phosphopyruvate Hydratase

OBJECTIVE: To investigate the clinical features, accompanying gene mutation characteristics and prognostic factors of adult patients with acute myeloid leukemia with mutated NPM1 (NPM1AML). METHODS: Seventy-three patients with newly diagnosed adult NPM1AML were selected. The mutations of 22 genes were detected by second generation sequencing and 43 fusion genes of AML were detected by real-time fluorescent quantitative PCR. The Kaplan-Meier survival curve and Cox multivariate regression analysis were used to study the prognostic factors. RESULTS: A total of 74 NPM1 site mutations were detected in 73 patients with NPM1AML. The incidence rates were 92.0% L287fs, 2.7% Q289fs and W288fs, 1.4% L258fs and Q289H, among which 1 patient had 2 NPM1 mutations; the different mutation sites had no effect on the prognosis of NPM1AML. The median value of NPM1 variant allele frequency (VAF) was 35.4% (1.8%-56.6%). Based on the uppermost quartile of 38.4%, the patients were classified as NPM1 VAF>38.4% (NPM1AML) and NPM1 VAF≤38.4% (NPM1AML). Compared with NPM1AML, the early mortality rate was statistically significantly higher (33.3% vs 7.3%, P<0.05), and median EFS (148 d，95%CI 58-238 d vs 372 d，95%CI 264-480 d) (P<0.01) and median OS (179 d 95%CI 6-352 d vs 444 d) (P<0.01) were significantly shorter in NPM1 AML. A total of 126 accompanying gene mutation sites were detected in 87.7% of patients with NPM1AML. The patients with NRAS gene mutation displayed a higher rate of complete remission (100% vs 58%) (P<0.05) and longer median OS (not reached to 320 d, 95%CI 150-490 d) (P<0.05). The 43 fusion genes were examined in 65 out of 73 cases of NPM1AML, and in all the patients the fusion gene test was negative. Multivariate analysis showed that NPM1 VAF>38.4% was an independent prognostic factor for EFS (HR=3.1, 95% CI 1.6-6.4, P<0.01) and OS (HR=3.0, 95% CI 1.4-6.2, P<0.01). CONCLUSION The NPM1 gene mutation in AML patients often is accompanied by other gene mutations, while the coexistence of fusion genes is rare; high NPM1 mutant allele burden is an independent prognostic factor for adult AML patients with mutated NPM1.
Alleles ; Humans ; Leukemia, Myeloid, Acute ; genetics ; Mutation ; Nuclear Proteins ; genetics ; Prognosis ; fms-Like Tyrosine Kinase 3

OBJECTIVE: To investigate the change of calcium sensing receptor (CaSR) expression at different time in rat tissue with acute myocardial infarction (AMI) and its effect on cardiomyocyte apoptosis. METHODS: The healthy Wistar rats were randomly divided into Sham and AMI groups, the rat myocardial infarction model was established by ligating left anterior descending coronary artery. The changes of cardiac morphology and hemodynamics were detected at 1, 2 and 4 weeks,respectively. The expressions of CaSR mRNA and protein in myocardial tissue were detected by RT-PCR and Western blot, respectively. The expressions of Bax, Bcl-2, caspase-3 and caspase-9 proteins were detected by Western blot. The serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) activity and cardiac troponin (cTnT) were determined. The apoptosis of cardiomyocytes were tested by TUNEL staining. RESULTS: Compared with the sham group, the expressions of CaSR mRNA and protein, the apoptosis index were increased significantly with the development of AMI (P＜0.05). The ultrastructural damage of cardiomyocytes was serious; the levels of LVSP, +dp/dt and -dp/dt were decreased,while the levels of LVEDP was increased (P＜0.05); In AMI group, the cTnT level, CK and LDH activities were all increased (P＜0.05). With the development of myocardial infarction, the cTnT level and CK activity were gradually decreased, while the activity of LDH was not significantly changed. The expressions of promote apoptosis-related Bax, caspase-3 and caspase-9 were significantly increased, and the expression of inhibited apoptosis-related protein(factor)Bcl-2 was significantly decreased (P＜0.05). CONCLUSION With the development of myocardial infarction,the expressions of CaSR mRNA and protein,the apoptosis index in rat myocardial tissue were increased with time prolongation after AMI. The increased expression of CaSR is involved in rat myocardial infarction, which is related with apoptosis.
Animals ; Apoptosis ; Myocardial Infarction ; metabolism ; Myocardium ; metabolism ; Random Allocation ; Rats ; Rats, Wistar ; Receptors, Calcium-Sensing ; metabolism

OBJECTIVE: To investigate the effects of apple polyphenols on pulmonary vascular remodeling in rats with pulmonary arterial hypertension and its mechanism. METHODS: Rats were randomly divided into 4 groups:control (Con) group, monocrotaline (MCT) group, apple polyphenol (APP) group,monocrotaline + apple polyphenol (MCT+APP) group. In Con group, rats received a subcutaneous injection of physical saline. In APP group, rats received intraperitoneal injection of 20 mg/kg APP, every other day. In MCT group, rats received a single subcutaneous injection of MCT(60 mg/kg). In MCT+APP group, rats received subcutaneous injection of 60 mg/kg MCT followed by an intraperitoneal injection of 20 mg/kg APP every other day. All the disposal lasted 3 weeks. Then the PAH-relevant indicators, such as mean pulmonary artery pressure(mPAP), pulmonary vascular resistance(PVR), right ventricular hypertrophy index (RVHI) ,wall thickness (WT%) and wall area (WA%) were tested. After that, the inflammatory pathway related indicators, such as interleukin1(IL-1),interleukin1(IL-6), tumor necrosis factor α(TNF-α), cyclooxygenase 2(COX-2) and myeloperoxidase(MPO) in pulmonary tissue and free intracellular Ca in pulmonary smooth muscle cell(PASMC), content of eNOS and NO in endothelial cells were determined. RESULTS: Compared with the control group, the levels of mPAP, PVR, RVHI, WA%, WT%, and IL-1, IL-6, TNF-α, COX-2, MPO in tissue and the expression of Ca in PASMC of MCT group were increased significantly, while the contents of eNOS and NO in endothelial cells were decreased significantly (P＜0.05). Compared with the MCT group, the apple polyphenol treatment could improve the above mentioned situation, and the COX-2 and Ca indicators of the apple polyphenol treatment group were decreased significantly (P＜0.05). CONCLUSION MCT can increase COX-2 expression and intracellular Ca in pulmonary artery smooth muscle cells, decrease the contents of eNOS and NO in endothelial cells, while apple polyphenols can significantly inhibit these effects.
Animals ; Calcium ; metabolism ; Cyclooxygenase 2 ; metabolism ; Cytokines ; metabolism ; Malus ; chemistry ; Monocrotaline ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type III ; metabolism ; Polyphenols ; pharmacology ; Pulmonary Artery ; drug effects ; pathology ; Random Allocation ; Rats ; Vascular Remodeling ; drug effects

OBJECTIVE: To evaluate the efficacy and safety of salvianolate in elderly patients with unstable angina pectoris (UAP). METHODS: A prospective double-blind randomized placebo-controlled multicenter trial in elderly patients with UAP from 13 third-grade class-A hospitals in China was performed. A total of 318 patients were randomly allocated in a 1:1 ratio to an experimental group (160 patients) and a control group (158 patients). The experimental group was treated with salvianolate for 14 days on the basis of conventional medicine, and the control group was given a placebo for 14 days with the same criteria. Follow-up was lasted 28 days in both groups. The primary endpoint was biweekly frequency of angina pectoris attacks. The secondary endpoints included biweekly dosage of nitroglycerin, the Seattle Angina Questionnaire, angina pectoris severity and duration, myocardial injury markers, high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), as well as major adverse cardiovascular events (MACEs). Safety was assessed according to adverse events and serious adverse events. RESULTS: Baseline characteristics were similar between treatment groups. Compared with those in the control group, the frequency of biweekly angina attacks (2.92 vs . 4.08, P=0.025), the biweekly dosage of nitroglycerin, as well as the severity and duration of angina attacks (P<0.01) were reduced by salvianolate. The Seattle Angina Questionnaire score was also significantly improved in the experimental group than in the control group (P<0.05). No significant differences were observed between the two groups with respect to the incidence of MACEs. Salvianolate was well tolerated. CONCLUSIONS Salvianolate appear to have efficacy and well tolerated for elderly patients with UAP. [ClinicalTrials.gov identifier: NCT03037047].

Objective To understand the major genotype-resistant mutation sites and change trends of HIV/AIDS patients with failure of antiviral therapy (ART) in Lincang City, Yunnan Province. Methods The In-House method was used to amplify the Pol gene region in the plasma samples of HIV/AIDS patients with failure of ART in Lincang City from 2011 to 2018. The target sequence was spliced and submitted to the HIV resistance database to identify and analyze the HIV-1 subtypes and resistant mutation sites. Results The 950 strains of HIV/AIDS patients with antiviral failure were mainly CRF08_BC, accounting for 75.5% (717/950), and the total gene mutation rate was 67.1% (637/950), which was dominated by non-nucleoside reverse transcriptase inhibitors (NNRTIs), accounting for 62.4% (593/950); followed by nucleoside reverse transcriptase inhibitors (NRTIs), accounting for 34.7% (330/950); protease inhibitors (PIs) was 7.5% (71/950). A total of 15 NRTIs of resistance-related mutation sites were detected, mainly M184V (29.3%) which was detected mostly in AZT/D4T+3TC+NVP programs; including 17 kinds of NNRTIs, mainly was K103N/S (25.1%)，the most detected in AZT/TDF+3TC+EFV programs. There were 22 kinds of PIs，mainly secondary sites were L10F/V/I (2.2%) and L33F (2.1%). The top three NRTIs mutation sites in the area were changed from T69D/N/G，M184I/V and D67N/G/S to M184I/V, K70R/Q/E/T and T215Y/F/V/I/N/A/D. NNRTIs mutation sites were changed from V179D/T/E/F, E138A/K/G/R and Y181C/F/G/V to K103N/S, E138A/K/G/R and V179D/T/E/F. The mutation sites of the first three PIs did not change much. Conclusions The second-line regimen based on PIs is a better choice in free antiviral treatments. Mastering the drug resistance of different gene mutations is beneficial to the compatibility of first-line drugs, thus delaying the use of second-line drugs.