Vitamin D and the hepatitis B vaccine response: a prospective cohort study and a randomized, placebo-controlled oral vitamin D3 and simulated sunlight supplementation trial in healthy adults.

PURPOSE: To determine serum 25(OH)D and 1,25(OH)2D relationship with hepatitis B vaccination (study 1). Then, to investigate the effects on hepatitis B vaccination of achieving vitamin D sufficiency (serum 25(OH)D ≥ 50 nmol/L) by a unique comparison of simulated sunlight and oral vitamin D3 supplementation in wintertime (study 2). METHODS: Study 1 involved 447 adults. In study 2, 3 days after the initial hepatitis B vaccination, 119 men received either placebo, simulated sunlight (1.3 × standard-erythema dose, 3 × /week for 4 weeks and then 1 × /week for 8 weeks) or oral vitamin D3 (1000 IU/day for 4 weeks and 400 IU/day for 8 weeks). We measured hepatitis B vaccination efficacy as percentage of responders with anti-hepatitis B surface antigen immunoglobulin G ≥ 10 mIU/mL. RESULTS: In study 1, vaccine response was poorer in persons with low vitamin D status (25(OH)D ≤ 40 vs 41-71 nmol/L mean difference [95% confidence interval] - 15% [- 26, - 3%]; 1,25(OH)2D ≤ 120 vs ≥ 157 pmol/L - 12% [- 24%, - 1%]). Vaccine response was also poorer in winter than summer (- 18% [- 31%, - 3%]), when serum 25(OH)D and 1,25(OH)2D were at seasonal nadirs, and 81% of persons had serum 25(OH)D < 50 nmol/L. In study 2, vitamin D supplementation strategies were similarly effective in achieving vitamin D sufficiency from the winter vitamin D nadir in almost all (~ 95%); however, the supplementation beginning 3 days after the initial vaccination did not effect the vaccine response (vitamin D vs placebo 4% [- 21%, 14%]). CONCLUSION: Low vitamin D status at initial vaccination was associated with poorer hepatitis B vaccine response (study 1); however, vitamin D supplementation commencing 3 days after vaccination (study 2) did not influence the vaccination response. CLINICAL TRIAL REGISTRY NUMBER: Study 1 NCT02416895; https://clinicaltrials.gov/ct2/show/study/NCT02416895; Study 2 NCT03132103; https://clinicaltrials.gov/ct2/show/NCT03132103

Contextualizing legal norms: a multi-dimensional view of the 2014 legal capital reform in China

This paper intends to shed light on the contentious theme of the reception of legal transplantation in the host environment, by examining the 2014 legislative reform of legal capital in China, which at least on paper imitates the enabling settings of US Revised Model Business Corporation Act (RMBCA). The paper looks at the interconnections between national-specific contextual elements, the resultant complexities, and the spillover effects of transplanted configurations in the unique Chinese socio-cultural setting, implicating the discrepancy between the ‘law in practice’ and the borrowed words ‘on the books’, and suggesting the importance of gaining a holistic understanding of ‘law’ involving the legal traditions in both the donor country and the recipient nation

Drug analyses by capillary electrophoresis and gas chromatography-mass spectrometry

Chiral separation of enantiomers of ten β-blockers is examined by using cyclodextrin-mediated capillary zone electrophoresis. The separation is based on the differential affinity in the formation of inclusion complex of the andyte with the cyclodextrin which leads to a discrepancy in the electrophoretic mobility of the free and complexed enantiomers. Results show that many factors will affect the chiral separation, including the buffer strength, concentration and type of β-cyclodextrin, and type of capillary. In general, higher ionic strength and C-l8 coated capillary give higher resolution of enantiomers of β-blockers. Moreover, three chemically modified β-cyclodextrins - heptakis-(2,6-di-O-methyl)-, hydroxypropyl-, and hydroxyethyl- β-cyclodextrins exhibit higher enantioselectivity for these β-blockers. Higher concentration of β-cyclodextrin is required for hydrophilic β-blockers, whilst hydrophobic β-blockers require low concentration of β-cyclodextrin for optimum chiral separation. In this investigation, enantiomers of alprenolol, atenolol, isoproterenol, oxprenolol, pindolol and propranolol are resolved. Partial resolution is obtained for nadolol, metoprolol and labetalol. Acebutolol is not enantioseparated by all means. Compared with chiral GC and HPLC, CD-mediated CZE possesses many assets including low consumption of exotic and expensive chiral selector, simple instrumentation and ease of automation and its use as a new alternative method in chiral separation will increase rapidly in the near future. In another part of my research, a selective and sensitive method in analysing artemisinin and dihydro-artemisinin is developed. By measuring their gas chromatographic decomposition products using gas chromatography/mass spectrometry/selected ion monitoring (GC/MS/SIM), the concentration of their parent compounds present in plasma can be indirectly determined. Human blood plasma, with triphenylmethanol (internal standard) added, is extracted by n-chlorobutane. The extract is then analysed by GC/MS. Artemisinin and dihydro-artemisinin are first pyrolysed into compounds 1 and 2 respectively in the GC injector at 260 ℃ and separated by the capillary column (30mx0.25μm film thickness HP-5MS) in a HP5890 Series II Gas Chromatograph equipped with HP7673 autosampler. [Figure 1 and 2 are obmitted here.] Higher sensitivity is obtained by selected ion monitoring. Ion groups of 152, 180, 210; 166, 165, 151; and 260, 154 amu are monitored for compounds 2, 1 and the internal standard triphenylmethanol respectively. Good linearity is attained for both compounds (1 and 2) in the concentration range of O-lOOOng/ml, with the correlation coefficient (r) greater than 0.999. The extraction recoveries([plus and minus]SD) of both 20ng/ml of QHS and DHQHS are 109.2[plus and minus]17.9% and 98.5[plus and minus]2.3% (n=4) respectively. The intra-and inter-day precisions of QHS at either 20ng/ml or 200ng/ml are found to be less than 3% and 7%CV respectively. The accuracy is within 3%. Similarly, for DHQHS, the intra- and inter-day repeatability at both 20ng/ml and 200ng/ml are less than 7%CV. The accuracy is found to be within 6%. By the present method, the limits of quantitation for QHS and DHQHS are found to be 2ng/ml and 4nglml respectively in l-ml plasma. Although artemether and arteether do interfere in the analysis of dihydro-artemisinin, no interference is observed by the endogenous contaminants from the plasma and another antimalarial drug, quinine, in the analyses of artemisinin and dihydro-artemisinin in human blood plasma. The concentration of artemether in plasma is determined by a similar approach. It is performed by measuring its gas chromatographic decomposition product using on-column gas chromatography/mass spectrometrykelected ion monitoring (on-column GC/MS/SIM). Quantitation of this compound can thus reflect the amount of artemether present in plasma samples. The human blood plasma, with arteether (internal standard) added, is extracted by n-chlorobutane. The extract is pyrolysed in the capillary column and separated by the same column (28mx0.25mm i.d.0.25μm film thickness HP-5MS connected with lmxO.53mm i.d. deactivated retention gap in front of it) in HP5890 Series II Gas Chromatograph equipped with HP7673 autosampler. For achieving a lower detection limit, selected ion monitoring is employed. Ions of 138 amu are monitored for both pyrolysed products of artemether and arteether. In the concentration of 0-3OOng/ml artemether in plasma, the linearity is excellent with the correlation coefficient (r) greater than 0.9999. Moreover, the extraction recovery is high (>95%). Both intra- and inter-day precisions are less than 5% CV for the concentrations of 2, 3, 4, and 2OOng/ml and accuracy is within 10% for the concentrations of 3, 4, and 200ng/ml. This method has the limit of quantitation of lng/ml for the sample size of l-ml plasma and it shows a high selectivity as the endogenous contaminant, dihydro-artemisinin(a major metabolite of artemether in plasma), artemisinin and quinine do not interfere in the analysis. The methods developed for analysing these antimalarial drugs can be utilized in human pharmacokinetics studies, especially in the low nanogram level of drugs in plasma

The Anticancer Effect of a Novel Quinoline Derivative 91b1 through Downregulation of Lumican

Quinoline derivatives have been reported to possess a wide range of pharmaceutical activities. Our group previously synthesized a series of quinoline compounds, in which compound 91b1 showed a significant anticancer effect. The purpose of this study was to evaluate the anticancer activity of compound 91b1 in vitro and in vivo, and screen out its regulated target. A series of cancer cell lines and nontumor cell lines were treated with compound 91b1 by MTS cytotoxicity assay and cell-cycle assay. In vivo anticancer activity was evaluated by a xenografted model on nude mice. Target prediction of 91b1 was assessed by microarray assay and confirmed by pancancer analysis. Relative expression of the target gene Lumican was measured by qRT-PCR. 91b1 significantly reduced tumor size in the nude mice xenograft model. Lumican was downregulated after 91b1 treatment. Lumican was proven to increase tumorigenesis in vivo, as well as cancer cell migration, invasion, and proliferation in vitro. The results of this study suggest that the anticancer activity of compound 91b1 probably works through downregulating the gene Lumican.ISSN:1422-006

Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma

Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-κB to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-κB inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma