The Synergistic Inhibitory Effect of STI571 in Combination with Arsenic Trioxide (As2O3) on Multidrug-Resistant Leukemic Cells

OBJECTIVE To study the synergistic effect of STI571, an inhibitor of tyrosine kinase, in combination with arsenic trioxide As2O3 on a multidrug-resistant leukemia cell line expressing bcr-abl.METHODS The cytotoxic effect of STI571 alone or in combination with different concentrations of As2O3 on the bcr-abl and mdr1 -positive leukemia cell line, K562-n/VCR, was examined by the MTT method.RESULTS One μmol/L of STI571 alone had no significant cytotoxic effect on K562-n/VCR cells. However the cytotoxic effect increased markedly when combined with As2O3 at concentrations of 10-5, 10-6, 10-7 and 10-8 mol/L. The IC50 of K562-n/VCR cells in As2O3 group was 1.879 μmol/L, with. Upon addition of STI571, the IC50 decreased to 0.155 μmol/L resulting in a synergistic cytotoxic effect on K562-n/VCR ceils that was increased 12.1 times.CONCLUSION A combination of STI571 with As2O3 has a more powerful inhibitory effect on leukemia cells expressing positive bcr-abl and positive mdrl compared to the effect with As2O3 alone.     

The interactions of phenytoin and its binding site in DI‐S6 segment of Na+ channel voltage‐gated peptide by NMR spectroscopy and molecular modeling study

Abstract: Nuclear magnetic resonance (NMR) spectra of a model peptide (BL‐DIS6), in the presence of anticonvulsant diphenyl drug, phenytoin (DPH), were measured to obtain the interactions between the selected drug and the model peptide. BL‐DIS6's sequence corresponds to the S6 segment in domain I of rat brain type IIA Na⁺‐channel. NMR studies have demonstrated that the magnitude of the chemical shifts of amide‐ and α‐protons can be used as a measurement of the complex stability and binding site of the peptide. Our NMR results propose a 3₁₀‐helical structure for BL‐DIS6, and suggest a binding cavity for DPH that involves the hydrophobic particles of residues Ans‐7, Leu‐8, Val‐11, and Val‐12. Furthermore, molecular modeling was performed to provide a possible complex conformation that the phenyl portion of DPH is accommodated in the proximity of the C‐terminal residues Ala‐11 and Val‐12, and simultaneously the heterocyclic amine ring of DPH is perching at the residue Asn‐7 periphery and stabilizing the phenyl portion deep insertion into the peptide.     

CYP1A2 and NAT2 genotype/phenotype relations and urinary excretion of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a human dietary intervention study.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking, and is subsequently metabolically activated by cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2). Respective genes encoding for these enzymes, display polymorphic distribution in the human population and are thus believed to cause interindividual differences in cancer risk susceptibility. The present study investigated the influence of dietary exposure and CYP1A2 and NAT2 genotypes and phenotypes on differential urinary PhIP excretion levels in 71 human volunteers after consumption of either a high (7.4 ng/g) or low (1.7 ng/g) dose of PhIP. Urinary PhIP excretion levels were found to reflect recent dietary exposure levels, with average levels of 174% (high dose group) and 127% (low dose group), as compared to pre-feed levels. Urinary caffeine metabolite ratios were significantly different between the two NAT2 genotypes, whereas for CYP1A2, the apparent difference in metabolic ratios between the genotypes was statistically non-significant. Significant correlations were firstly found between the CYP1A2-164A-->C (CYP1A2*1F) polymorphism and differential urinary PhIP excretion levels. Although the found correlations are driven primarily by a small number of subjects possessing the homozygous variant constellation, the strong influence of this genotype indicates that the CYP1A2*1F polymorphism could play an important role in human cancer risk susceptibility.     

Personalized aspheric intraocular lens implantation based on corneal spherical aberration: a review

With the evolution of cataract surgery from visual rehabilitation to refractive surgery, aspheric intraocular lenses (IOLs) are being increasingly used in the field of ophthalmology. This increased use can be attributed to negative or zero spherical aberrations with unique optical designs, which counteract some of the positive spherical aberrations of the cornea. These alterations reduce the total spherical aberration of human eyes and improve the visual acuity in patients with cataract postoperatively. At present, various types of aspheric IOLs are used worldwide. Although the implantation of aspheric IOL is beneficial to the patients who need correction of spherical aberrations, much controversy is still associated with ocular residual spherical aberrations that facilitate the best visual quality for patients postoperatively. In order to provide reference for future clinical work and scientific research, this report reviews the relationship between the ocular residual spherical aberration of human eyes and visual quality.     

微信干预对青光眼患者体力活动量的影响

观察利用微信干预增加青光眼患者体力活动的效果。方法：前瞻性随机对照研究。选择2018年 6-12月于温州医科大学附属眼视光医院门诊确诊的青光眼患者102例作为研究对象。利用Excel生成的随机数随机分为对照组和干预组。对照组患者仅在门诊入组时进行运动宣教,并告知其可增加每天的运动步数;干预组患者入组时进行运动宣教,告知其可增加每天的运动步数的同时,加入微信群进行运动提醒干预。所有患者均需利用运动监测仪器完成基线1周和随访1个月的体力活动监测。采用卡方检验、独立样本t检验、Mann-Whitney U检验、配对t检验及Wilcoxon符号秩检验进行数据分析。结果：排除30例基线运动量较大（步数>12 000步/d）、依从性不好及其他原因失访的患者,最终纳入72例（对照组42例,干预组30例）。干预组患者干预后的步数（t=4.94,P<0.001）,运动消耗的卡路里（Z=-2.87,P=0.004）,代谢当量（Z=-3.30,P=0.001）,中等强度体力活动时间（Z=-2.89, P=0.004）,高强度体力活动时间（t=2.57,P=0.016）及中高强度体力活动时间（Z=-3.01,P=0.003）均较基线增加;轻度体力活动时间（t=-2.14,P=0.041）和久坐静止不动次数较干预前减少（t=-2.76, P=0.022）。对照组随访的步数也较基线增加（t=3.29,P<0.001）,轻度体力活动时间较基线减少（t=-2.57,P=0.014）。另外,干预组的高强度体力活动时间增加量（随访-基线）（Z=-3.04,P=0.002）和超高强度体力活动时间增加量（Z=-2.06,P=0.040）明显高于对照组,差异均有统计学意义。结论：微信干预可以增加青光眼患者的每天运动步数和中高强度体力活动时间,减少患者的轻度体力活动时间和久坐静止次数。     

The Role of Self-Beliefs in Predicting Postschool Outcomes for Deaf Young Adults

The aim of this study was to explore the role of self-beliefs in predicting postschool outcomes for deaf young adults in transition from secondary settings. Three self-level constructs were explored: self-concept, self-determination, and expectations about the future. This study utilized data from the National Longitudinal Transition Study-2 (NLTS2) that collected longitudinal data from youths with disabilities across the nation, 550 of which were deaf or hard of hearing and met the selection criteria in this study. This study examined the relationships between these deaf adolescents’ self-beliefs and actual future achievements that were reached as they transitioned to adult life, in three domains: life, employment, and education. Despite the generally positive self-beliefs of deaf individuals, which were, in some cases, related to postschool outcomes, the self-beliefs assessed in this study did not emerge as comprehensive predictors of postschool attainments. Findings suggest that for deaf individuals, successfully navigating transitions to adult life involves dimensions beyond individual agency. Positive self-beliefs are clearly a part of successfully attaining postschool outcomes, but deaf individuals may not have full access to equitable opportunities to capitalize on these beliefs.     

Measurement of multiple biomarkers in advanced stage heart failure patients treated with pulmonary artery catheter guided therapy

ABSTRACT: INTRODUCTION: This study was carried out to investigate the prognostic utility of biomarkers in advanced stage heart failure (HF) patients requiring ICU admission for pulmonary artery catheter (PAC) guided therapy. METHODS: Thirty patients admitted to an ICU for PAC guided HF therapy were enrolled; concentrations of soluble ST2 (sST2), highly sensitive troponin I, an experimental ultrasensitive troponin I, amino-terminal pro-B type natriuretic peptide, cystatin C, and myeloperoxidase were measured over the first 48 hours. Outcomes included response of filling pressures and hemodynamics to tailored therapy and 90-day event-free survival (death, left ventricular assist device implantation, transplant). RESULTS: Of the biomarkers evaluated, only sST2 concentrations were higher in those who failed to achieve goals for central venous pressure ((CVP), 225.3 versus 104.6 ng/mL; P = 0.003) and pulmonary capillary wedge pressure ((PCWP), 181.7 versus 88.2 ng/mL; P = 0.05). Only sST2 concentrations were associated with adverse events (186.7 versus 92.2 ng/mL; P = 0.01). In age-adjusted Cox proportional hazards analysis, an elevated sST2 during the first 48 hours following ICU admission independently predicted 90-day outcomes (Hazard Ratio = 5.53; P = 0.03) superior to the Simplified Acute Physiology Score for this application; in Kaplan-Meier analysis the risk associated with elevated sST2 concentrations was present early and sustained through the duration of follow-up (log rank P = 0.01). CONCLUSIONS: In patients undergoing HF therapy guided by invasive monitoring, sST2 concentrations were associated with impending failure to reduce filling pressures and predicted impending events. Elevated sST2 values early in the ICU course theoretically could assist therapeutic decision-making in advanced stage HF patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00595738.     

人参皂苷抑制去势抵抗性前列腺癌的分子生物学机制

人参皂苷单体Rh2和Rg3具有促进细胞凋亡的作用，研究发现Toll样受体中的TLR4可通过MYD88等下游信号蛋白经由NF-κB反应途径激活白介素6和白介素8的表达，而IL-6和IL-8可以进一步通过JAK-STAT、Src类酪氨酸蛋白激酶、FAK-Ras-MAPK等配体非依赖性的细胞信号传导途径活化雄激素受体，而非配体依赖性AR的激活则进一步促进了前列腺癌肿瘤细胞的增殖，由此推测TLR4、IL-6/IL-8、AR的逐级活化正是去势抵抗性前列腺癌进展的重要机制，研究发现人参皂苷可以下调Toll样受体的表达及活性，由此推测人参皂苷通过下调TLR4，进而抑制IL-6/IL-8和AR受体的表达，最终抑制去势抵抗性前列腺癌的进展。