Meta-analysis of the population and phenotypic expression of CYP2C9/2C19 polymorphism on drug metabolism in different ethnicities

The term "pharmacogenetics" has been defined as the scientific study of inherited factors that affect the human drug response. Many pharmacogenetie studies have been published since 1995 and have focussed on the principal enzyme family involved in drug metabolism, the cytochrome P450 family, particularly cytochrome P4502C9 and 2C19. In order to investigate the pharmacogenetic aspect of pharmacotherapy, the relevant studies describing the association of pharmacogenetic factor(s) in drug responses must be retrieved from existing literature using a systematic review approach. In addition, the estimation of variant allele prevalence for the gene under study between different ethnic populations is important for pharmacogenetic studies. In this thesis, the prevalence of CYP2C9/2C19 alleles between different ethnicities has been estimated through meta-analysis and the population genetic principle. The clinical outcome of CYP2C9/2C19 allelic variation on the pharmacotherapy of epilepsy has been investigated; although many new antiepileptic drugs have been launched into the market, carbamazepine, phenobarbital and phenytoin are still the major agents in the pharmacotherapy of epilepsy. Therefore, phenytoin was chosen as a model AED and the effect of CYP2C9/2C19 genetic polymorphism on phenytoin metabolism was further examined.An estimation of the allele prevalence was undertaken for three CYP2C9/2C19 alleles respectively using a meta-analysis of studies that fit the Hardy-Weinberg equilibrium. The prevalence of CYP2C9*1 is approximately 81%, 96%, 97% and 94% in Caucasian, Chinese, Japanese, African populations respectively; the pooled prevalence of CYP2C19*1 is about 86%, 57%, 58% and 85% in these ethnic populations respectively. However, the studies of association between CYP2C9/2C19 polymorphism and phenytoin metabolism failed to achieve any qualitative or quantitative conclusion. Therefore, mephenytoin metabolism was examined as a probe drug for association between CYP2C19 polymorphism and mephenytoin metabolic ratio. Similarly, analysis of association between CYP2C9 polymorphism and warfarin dose requirement was undertaken.It was confirmed that subjects carrying two mutated CYP2C19 alleles have higher S/R mephenytoin ratio due to deficient CYP2C19 enzyme activity. The studies of warfarin and CYP2C9 polymorphism did not provide a conclusive result due to poor comparability between studies.The genetic polymorphism of drug metabolism enzymes has been studied extensively, however other genetic factors, such as multiple drug resistance genes (MDR) and genes encoding ion channels, which may contribute to variability in function of drug transporters and targets, require more attention in future pharmacogenetic studies of antiepileptic drugs

Fabrication of three-dimensional microdisk resonators in calcium fluoride by femtosecond laser micromachining

We report on fabrication of on-chip calcium fluoride (CaF2) microdisk resonators using water-assisted femtosecond laser micromachining. Focused ion beam (FIB) milling is used to create ultra-smooth sidewalls. The quality (Q)-factors of the fabricated microresonators are measured to be 4.2x10^4 at wavelengths near 1550 nm. The Q factor is mainly limited by the scattering from the bottom surface of the disk whose roughness remains high due to the femtosecond laser micromachining process. This technique facilitates formation of on-chip microresonators on various kinds of bulk crystalline materials, which can benefit a wide range of applications such as nonlinear optics, quantum optics, and chip-level integration of photonic devices.Comment: 7 pages, 3 figure

On-chip electro-optic tuning of a lithium niobate microresonator with integrated in-plane microelectrodes

We demonstrate electro-optic tuning of an on-chip lithium niobate microresonator with integrated in-plane microelectrodes. First two metallic microelectrodes on the substrate were formed via femtosecond laser process. Then a high-Q lithium niobate microresonator located between the microelectrodes was fabricated by femtosecond laser direct writing accompanied by focused ion beam milling. Due to the efficient structure designing, high electro-optical tuning coefficient of 3.41 pm/V was observed.Comment: 6 pages, 3 figure

Functional role of MicroRNA/PI3K/AKT axis in osteosarcoma

Osteosarcoma (OS) is a primary malignant bone tumor that occurs in children and adolescents, and the PI3K/AKT pathway is overactivated in most OS patients. MicroRNAs (miRNAs) are highly conserved endogenous non-protein-coding RNAs that can regulate gene expression by repressing mRNA translation or degrading mRNA. MiRNAs are enriched in the PI3K/AKT pathway, and aberrant PI3K/AKT pathway activation is involved in the development of osteosarcoma. There is increasing evidence that miRNAs can regulate the biological functions of cells by regulating the PI3K/AKT pathway. MiRNA/PI3K/AKT axis can regulate the expression of osteosarcoma-related genes and then regulate cancer progression. MiRNA expression associated with PI3K/AKT pathway is also clearly associated with many clinical features. In addition, PI3K/AKT pathway-associated miRNAs are potential biomarkers for osteosarcoma diagnosis, treatment and prognostic assessment. This article reviews recent research advances on the role and clinical application of PI3K/AKT pathway and miRNA/PI3K/AKT axis in the development of osteosarcoma

Dissolved carbon in a large variety of lakes across five limnetic regions in China

Dissolved carbon in lakes play a vital role in the global carbon cycling. The concentration and dynamics of lake dissolved carbon can be influenced by both the surrounding landscape and a combination of physical, chemical and biological processes within the lakes themselves. From 2009 to 2016, we conducted a large-scale assessment of dissolved organic carbon (DOC) and dissolved inorganic carbon (DIC) in 249 lakes across a diverse range of climatic, geopedologic, topographical and hydrological conditions in five Chinese limnetic regions: the East Limnetic Region (ELR), the Northeast Limnetic Region (NLR), the Inner Mongolia-Xinjiang Limnetic Region (MXR), the Yungui Limnetic Region (YGR), and the Tibet-Qinghai Limnetic Region (TQR). We found that the density of the organic matter in the soil in the surrounding landscape plays an important role in the DOC and DIC in lake water, as was evidenced by the high DOC and DIC levels in the NLR, where the soil is respectively organically rich. Conditions in the arid and semi-arid environments (i.e. TQR and MXR) have created a number of brackish/saline lakes and here we found that, DOC and DIC levels (median: 21.79 and 93.72 mg/L, respectively) are significantly higher than those in the freshwater lakes (median: 5.80 and 29.38 mg/L). It also appears to be the case that the trophic state of freshwater lakes influences the spatial variation of DOC. This can be seen in the relationships between DOC and trophic state index (TSI) in agriculturally-dominated regions such as the ELR (R2 = 0.59, p < 0.01), NLR (R2 = 0.65, p < 0.001), and YGR (R2 = 0.78, p < 0.001). Additionally, a close relationship between DOC and DIC can be found in lake waters with different trophic states (eutrophic: slp = 0.63, R2= 0.69; mesotrophic: slp = 1.03, R2 = 0.65; oligotrophic: slp = 1.00, R2 = 0.64). This indicates that human activities influence the quantity and quality of dissolved carbon in inland water across China. This study is able to provide insights regarding the potential effects of climate change and changes in land-use upon the amount of dissolved carbon in lake water

Concise Review: Targeting Cancer Stem Cells Using Immunologic Approaches

Cancer stem cells (CSCs) represent a small subset of tumor cells which have the ability to self‐renew and generate the diverse cells that comprise the tumor bulk. They are responsible for local tumor recurrence and distant metastasis. However, they are resistant to conventional radiotherapy and chemotherapy. Novel immunotherapeutic strategies that specifically target CSCs may improve the efficacy of cancer therapy. To immunologically target CSC phenotypes, innate immune responses to CSCs have been reported using Natural killer cells and γδ T cells. To target CSC specifically, in vitro CSC‐primed T cells have been successfully generated and shown targeting of CSCs in vivo after adoptive transfer. Recently, CSC‐based dendritic cell vaccine has demonstrated significant induction of anti‐CSC immunity both in vivo in immunocompetent hosts and in vitro as evident by CSC reactivity of CSC vaccine‐primed antibodies and T cells. In addition, identification of specific antigens or genetic alterations in CSCs may provide more specific targets for immunotherapy. ALDH, CD44, CD133, and HER2 have served as markers to isolate CSCs from a number of tumor types in animal models and human tumors. They might serve as useful targets for CSC immunotherapy. Finally, since CSCs are regulated by interactions with the CSC niche, these interactions may serve as additional targets for CSC immunotherapy. Targeting the tumor microenvironment, such as interrupting the immune cell, for example, myeloid‐derived suppressor cells, and cytokines, for example, IL‐6 and IL‐8, as well as the immune checkpoint (PD1/PDL1, etc.) may provide additional novel strategies to enhance the immunological targeting of CSCs. Stem Cells 2015;33:2085–2092Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112006/1/stem2039.pd

Interactive Effects of Methionine and Lead Intake on Cognitive Function among Chinese Adults.

The association between methionine intake and cognitive function is inconclusive. We aimed to assess the association between methionine intake and cognitive function in Chinese adults and to explore the interaction between methionine and lead intake. Data from 4852 adults aged ≥55 years from the China Health and Nutrition Survey were used. Cognitive function was measured in 1997, 2000, 2004, and 2006. A 3-day, 24-hour recall was used to assess methionine and lead intake from different protein sources. Multivariable mixed linear regression was used in the analyses. Total methionine intake was positively correlated with cognition. There was a significant interaction between animal methionine and lead intakes. In subgroup analyses, across the quartiles of animal methionine intake, the regression coefficients (95% CI) for global cognition were 0.00, 0.57 (0.17 to 0.98), 1.18 (0.73 to 1.62), and 1.80 (1.31 to 2.29), respectively, while they were 0.00, -0.73 (-1.12 to -0.34), -0.83 (-1.26 to -0.41), and -1.72 (-2.22 to -1.22) across the quartiles of plant methionine intake, respectivelyThe association between animal methionine intake and cognition was stronger among adults with a low lead intake. In conclusion, animal methionine and plant methionine intake were positively and inversely associated with cognition, respectively. Lead intake modified the association between animal methionine intake and cognition.This study was supported in part by research grants from the Natural Scientific Foundation in Qinghai Province (2019-ZJ-932Q), and the National Key Research and Development Program of China (grant numbers: 2017YFC0907200 and 2017YFC0907201)

Ga III triarylcorroles with push–pull substitutions

Two A2B type H3corroles and two GaIIItriarylcorroles with carbazole substitutions at 10-positions were synthesized and characterized. An analysis of structure–property relationships of the corroles has been carried out by investigating the optical spectroscopy of the dyes to trends predicted in DFT and TD-DFT calculations. Interestingly, the photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) activity properties of the GaIIItriarylcorroles were determined against the MCF-7 breast cancer line, and Staphyloccocus aureus (S. aureus) and Escherichia coli (E. coli), respectively. The cationic G-2Q species exhibited the most favorable properties with an IC50 value of 7.8 μM against MCF-7 cells, and Log reduction values of 7.78 and 3.26 against planktonic S. aureus and E. coli at 0.5 and 10 μM, respectively