Optimal Control Strategy of Plasmodium vivax Malaria Transmission in Korea

ObjectiveTo investigate the optimal control strategy for Plasmodium vivax malaria transmission in Korea.MethodsA Plasmodium vivax malaria transmission model with optimal control terms using a deterministic system of differential equations is presented, and analyzed mathematically and numerically.ResultsIf the cost of reducing the reproduction rate of the mosquito population is more than that of prevention measures to minimize mosquito-human contacts, the control of mosquito-human contacts needs to be taken for a longer time, comparing the other situations. More knowledge about the actual effectiveness and costs of control intervention measures would give more realistic control strategies.ConclusionMathematical model and numerical simulations suggest that the use of mosquito-reduction strategies is more effective than personal protection in some cases but not always.     

Prognostic Role of Methylation Status of the MGMT Promoter Determined Quantitatively by Pyrosequencing in Glioblastoma Patients

Objective

This study investigated whether pyrosequencing can be used to determine the methylation status of the MGMT promoter as a clinical biomarker using relatively old archival tissue samples of glioblastoma. We also examined other prognostic factors for survival of glioblastoma patients.

Methods

The available study set included formalin-fixed paraffin-embedded (FFPE) tissue from 104 patients at two institutes from 1997 to 2012, all of which were diagnosed histopathologically as glioblastoma. Clinicopathologic data were collected by review of medical records. For pyrosequencing analysis, the PyroMark Q96 CpG MGMT kit (Qiagen, Hilden, Germany) was used to detect the level of methylation at exon 1 positions 17–39 of the MGMT gene, which contains 5 CpGs.

Results

Methylation of the MGMT promoter was detected in 43 (41.3%) of 104 samples. The average percentage methylation was 14.0±16.8% overall and 39.0±14.7% for methylated cases. There was no significant pattern of linear increase or decrease according to the age of the FFPE block (p=0.687). In multivariate analysis, age, performance status, extent of surgery, method of adjuvant therapy, and methylation status estimated by pyrosequencing were independently associated with overall survival. Additionally, patients with a high level of methylation survived longer than those with low methylation (p=0.016).

Conclusion

In this study, the status and extent of methylation of the MGMT promoter analyzed by pyrosequencing were associated with overall survival in glioblastoma patients. Pyrosequencing is a quantitative method that overcomes the problems of MSP and a simple technique for accurate analysis of DNA sequences.     

Drug release characteristics from nanoclay hybrids and their dispersions in organic polymers

This study establishes and compares structure-property-processing relationships on three drug delivery systems containing an anionic active pharmaceutical ingredient (API) in the following excipient carriers: (a) an inorganic anionic nanoclay, (b) pH responsive acrylic polymers, and (c) combinations thereof. The effects of the excipients on the APIs dissolution rate were studied from their release profile in simulated body fluids (SBFs) with different pH. In the API-nanoclay system, calcination of the clay followed by its reconstitution in an API solution was successfully used to intercalate the API in its amorphous state in the clay. As a result, the API showed increased apparent solubility vs. its crystalline form with its release mechanism from the clay being predominantly diffusion controlled and depending on the pH of the SBFs. In melt mixed ternary polymer systems containing the above hybrids, as a result of an additional diffusional step due to presence of nanoplatelets, the API showed a more controlled release vs. polymer systems that contained only API. By comparison to the low pH SBF, the ternary system in the pH 7.4 SBF showed a reduced diffusion contribution due to the presence of clay platelets, the latter unaffected by the high pH value. Reasonable agreement was found with predictions from literature diffusion/erosion models. It is confirmed that hot melt mixing offers opportunities to produce systems with enhanced API apparent solubility. The presence of nanoclays can also increase the API's apparent solubility and affect its release in a controlled manner.     

Tissue response to poly(L-lactic acid)-based blend with phospholipid polymer for biodegradable cardiovascular stents

A temporary cardiovascular stent device by bioabsorbable materials might reduce late stent thrombosis. A water-soluble amphiphilic phospholipid polymer bearing phosphorylcholine groups (PMB30W) was blended with a high-molecular-weight poly(l-lactic acid) (PLLA) to reduce unfavorable tissue responses at the surface. The PLLA implants and the polymer blend (PLLA/PMB30W) implants were inserted into subcutaneous tissues of rats, the infrarenal aorta of rats, and the internal carotid arteries of rabbits. After 6 months subcutaneous implantation, the PLLA/PMB30W maintained high density of phosphorylcholine groups on the surface without a significant bioabsorption. After intravascular implantation, the cross-sectional areas of polymer tubing with diameters less than 1.6?mm were histomorphometrically measured. Compared to the PLLA tubing, the PLLA/PMB30W tubing significantly reduced the thrombus formation during 30?d of implantation. Human peripheral blood mononuclear cells were cultured on the PLLA and the PLLA/PMB30W to compare inflammatory reactions. Enzyme-linked immunosorbent assay quantified substantially decreased proinflammatory cytokines in the case of the PLLA/PMB30W. They were almost the same level as the negative controls. Thus, we conclude that the phosphorylcholine groups could reduce tissue responses significantly both in vivo and in vitro, and the PLLA/PMB30W is a promising material for preparing temporary cardiovascular stent devices.     

Expression of hepatic and ovarian cytochrome P450 during estrous cycle in rats

It is known that gender differences in drug metabolism are largely attributed to changes in sex and growth hormones. Serum concentrations of estradiol, progesterone, prolactin, follicle-stimulating hormone, and luteinizing hormone change markedly during the human menstrual cycle and the rat estrous cycle. However, little information is available regarding the effects of the human menstrual cycle or the rat estrous cycle on expression and activity of cytochrome P450 (CYP) isoforms. The present study was carried out to determine the expression and activity of CYP-dependent drug-metabolizing enzymes in the liver and ovary during the estrous cycle. The expression and activity of microsomal CYP isoforms (CYP1A1, CYP1A2, CYP1B1, CYP2B1, CYP2C11, CYP2C12, CYP2E1, CYP3A1, CYP3A2, and CYP4A), cytochrome b₅ and NADPH-dependent CYP reductase in the liver and ovary were measured in female rats in diestrus and proestrus. Our results indicated that hepatic and ovarian expression and activity of CYP isoforms, cytochrome b₅, and NADPH-dependent CYP reductase were not different between diestrus and proestrus, although serum estradiol concentration and uterus weight were markedly increased in the proestrus phase. These results suggest that the cytochrome P450-dependent system is not sensitive to changes in the estrous cycle, and further studies are warranted to determine the effects of the estrous cycle on in vivo metabolism of xenobiotics.     

Metabolic engineering of microorganisms: general strategies and drug production

Many drugs and drug precursors found in natural organisms are rather difficult to synthesize chemically and to extract in large amounts. Metabolic engineering is playing an increasingly important role in the production of these drugs and drug precursors. This is typically achieved by establishing new metabolic pathways leading to the product formation, and enforcing or removing the existing metabolic pathways toward enhanced product formation. Recent advances in system biology and synthetic biology are allowing us to perform metabolic engineering at the whole cell level, thus enabling optimal design of a microorganism for the efficient production of drugs and drug precursors. In this review, we describe the general strategies for the metabolic engineering of microorganisms for the production of drugs and drug precursors. As successful examples of metabolic engineering, the approaches taken toward strain development for the production of artemisinin, an antimalarial drug, and benzylisoquinoline alkaloids, a family of antibacterial and anticancer drugs, are described in detail. Also, systems metabolic engineering of Escherichia coli for the production of L-valine, an important drug precursor, is showcased as an important strategy of future metabolic engineering effort.