Study Objective
The objective of the present study was to examine the frequency distribution of five single‐nucleotide polymorphisms (SNPs; rs1801394 A>G, rs1532268 C>T, rs162036 A>G, rs10380 C>T, ...and rs9332 C>T) of the methionine synthase reductase (MTRR) gene, their effects on methotrexate (MTX) concentration, and the risk of relapse in a Chinese pediatric population with acute lymphoblastic leukemia (ALL).
Design
This was a retrospective single‐center study, and all analyses were exploratory.
Setting
Pediatric Department of Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
Patients
One hundred and forty pediatric patients with ALL.
Intervention
All patients were treated according to the Chinese Children's Leukemia Group (CCLG)‐ALL 2008 protocol.
Measurements and Main Results
Serum MTX concentrations were measured using fluorescence polarization immunoassay. Genotyping of five SNPs was performed using the Sequenom MassARRAY iPLEX platform. Chinese children with ALL had a significantly lower frequency of rs1801394 G than European (EUR) and South Asian (SAS) populations; significantly lower frequency of rs1532268 T than American (AMR), EUR, and SAS populations; and significantly lower frequencies of rs162036 G, rs10380 T, and rs9332 T than African and AMR populations (p < 0.01). Seven haplotypes were observed, with the ACACC being the most common haplotype (49.9%) in our study. The median dose‐normalized concentrations of MTX in serum at 24 h in children with rs1532268 CT and TT genotypes were significantly higher than those with CC genotype (p = 0.04). Compared with children with AA‐CC‐AA‐CC‐CC diplotype, a significantly higher risk of relapse was observed in children with AG‐CC‐AA‐CC‐CC and AG‐CC‐AG‐CC‐CC diplotypes (p = 0.03 and 0.003, respectively).
Conclusions
The present study confirmed the ethnic differences in the distribution of MTRR rs1801394, rs1532268, rs162036, rs10380, and rs9332 polymorphisms. The rs1532268 polymorphism had greater effects on MTX disposition. The AG‐CC‐AA‐CC‐CC and AG‐CC‐AG‐CC‐CC diplotypes were significantly associated with higher risk of relapse of ALL.
Background
It is known that γ‐glutamyl hydrolase (GGH) is involved in the disposition of methotrexate (MTX), and GGH activity is regulated by DNA methylation in acute lymphoblastic leukemia (ALL) ...cells. The present study explores the methylation status of the GGH promoter in peripheral blood and its association with MTX levels and toxicities in Chinese children with ALL.
Methods
Serum MTX concentrations were determined by fluorescence polarization immunoassay. Methylation quantification and genotyping for GGH rs3758149 and rs11545078 was performed by Sequenom MassARRAY in 50 pediatric patients with ALL.
Results
Overall, the investigated region of the GGH promoter was in hypomethylated status. The methylation levels of cytosine phosphate guanine (CpG)_7, CpG_12, CpG_17, and CpG_20 were significantly higher in patients with B‐cell ALL than other immunotypes (p<0.05). The methylation levels of CpG_13.14, CpG_17, and CpG_19 showed a significant negative correlation with MTX C24 hr (p<0.05). The methylation level of CpG_8.9 correlated significantly with MTX C42 hrs (p<0.05). The methylation level of CpG_19 was significantly lower in patients with MTX toxicities (p<0.05).
Conclusions
The methylation levels of the GGH promoter might affect MTX exposure and toxicities. These findings provided reasonable explanations for the variability of MTX responses in patients with childhood ALL.
As an indigenous breed, the Tibetan chicken is found in highland regions and shows physiological adaptations to high altitude; however, the genetic changes that determine these adaptations remain ...elusive. We assumed that the microevolution of the Tibetan chicken occurred from lowland to highland regions with a continuous elevation range. In this study, we analyzed the genome of 188 chickens from lowland areas to the high‐altitude regions of the Tibetan plateau with four altitudinal levels. Phylogenetic analysis revealed that Tibetan chickens are significantly different from other altitude chicken populations. Reconstruction of the demographic history showed that the migration and admixture events of the Tibetan chicken occurred at different times. The genome of the Tibetan chicken was also used to analyze positive selection pressure that is associated with high‐altitude adaptation, revealing the well‐known candidate gene that participates in oxygen binding (HBAD), as well as other novel potential genes (e.g., HRG and ANK2) that are related to blood coagulation and cardiovascular efficiency. Our study provides novel insights regarding the evolutionary history and microevolution mechanisms of the high‐altitude adaptation in the Tibetan chicken.
Purpose
Adenosine triphosphate (ATP)-binding cassette (ABC) transporters play an important role in the response to methotrexate (MTX). In this study, we investigated the frequency distribution of ...three splicing-regulatory polymorphisms in ABC transporters (
ABCC2
rs2273697 G>A,
ABCG2
rs2231142 G>T, and
ABCB1
rs1128503 A>G) and their effects on MTX concentrations and the clinical outcome in a Chinese pediatric population with acute lymphoblastic leukemia (ALL).
Methods
A fluorescence polarization immunoassay was used to measure the serum MTX concentrations in 24 h (C
24h
) and 42 h (C
42h
). The Sequenom MassARRAY system was used for single-nucleotide polymorphism (SNP) genotyping.
Results
The study population had significantly lower frequencies of
ABCC2
rs2273697 A,
ABCG2
rs2231142 G, and
ABCB1
rs1128503 G than African and European samples (
P
< 0.05). The dose-normalized MTX concentrations after 24 h and the proportion of C
42h
> 0.5 µmol/L were significantly lower in patients with the
ABCG2
rs2231142 GG genotype than in patients with the GT or TT genotype (
P
= 0.01 and 0.006, respectively). No significant effects on MTX pharmacokinetics were observed for
ABCC2
rs2273697 and
ABCB1
rs1128503 polymorphisms. Bioinformatics analysis suggested that the three SNPs overlapped with the putative binding sites of several splicing factors.
Conclusion
In conclusion, our study confirmed the ethnicity-based differences in the distribution of the three investigated SNPs. The
ABCG2
rs2231142 polymorphism exerted a significant effect on the level of MTX exposure. These findings may help explain the variability in MTX responses and optimize MTX treatment in pediatric patients with ALL.
Abstract
Abundant and diverse domestic mammals living on the Tibetan Plateau provide useful materials for investigating adaptive evolution and genetic convergence. Here, we used 327 genomes from ...horses, sheep, goats, cattle, pigs and dogs living at both high and low altitudes, including 73 genomes generated for this study, to disentangle the genetic mechanisms underlying local adaptation of domestic mammals. Although molecular convergence is comparatively rare at the DNA sequence level, we found convergent signature of positive selection at the gene level, particularly the EPAS1 gene in these Tibetan domestic mammals. We also reported a potential function in response to hypoxia for the gene C10orf67, which underwent positive selection in three of the domestic mammals. Our data provide an insight into adaptive evolution of high-altitude domestic mammals, and should facilitate the search for additional novel genes involved in the hypoxia response pathway.
To investigate the preventive effects of Salvia miltiorrhiza (SM) on multiple organ edema in the rats which suffered from hind limb ischemia/reperfusion( LI/R).
Twenty four Wistar rats were randomly ...divided into 3 groups (n = 8): control group (C group), ischemia/reperfusion group (I/R group ), Salvia miltiorrhiza group (SM group). Referring to Tourniquet method, the model rats which underwent 4 hours ischemia and 4 hours reperfusion of hind limbs were made. Thirty minutes before reperfusion, SM was given to the rats in SM group by tail vein injection at the dose of 5 mL/kg. Accurately weighed one gram of heart, liver, kidney, lung, brain, intestine and skeletal muscle from every animals, weigh these specimens after baking (60 degrees C, 55 hours), calculated the ratio of wet and dry (Wet/Dry,W/D). The levels of interleukin-1 (IL-1) ,interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) in plasma and the contents of Superoxide dismutase (SOD) and malonaldehyde (MDA) were measured. The morphologic chan
The band structures of a new two-dimensional triangle-shaped array geometry of 4340 steel cylinders of square cross section in an epoxy resin were studied by the plane-wave expansion and supercell ...calculation method. The band gaps of this type of phononic crystals with different defects were calculated such as defect-free, 60degrees crystal linear defect states, 120degrees crystal linear defect states, and 180degrees crystal linear defect states. It was found that the band gap will emerge in different linear defects of the phononic crystals and the bandwidth of linear defect states is larger than that of the free-defect crystal by about 2.14 times within the filling fraction F = 0.1-0.85. In addition, the influence of the filling fraction on the relative width of the minimum band gap is discussed.
To observe the effects of taurine on hemorheology and oxidative stress of diabetic rats.
40 rats were divided into control group, diabetes group and treatment group at random. Diabetic model was ...reproduced by intraperitoneal injection of streptozotocin. After having been treated with taurine for 8 weeks, glycosylated hemoglobin (HbA1c) and the serum contents of glucose, superoxide dismutase(SOD), malondialdehyde (MDA) were measured. The changes of hemorheology in different groups were detected respectively.
Compared with control group, the content of glucose, MDA and HbA1c in diabetic rats was increased, the activity of SOD was decreased, the levels of whole blood viscosity and the aggregation index of red blood cells and hematocrit were increased and RBC deformability index was decreased in diabetic rats. Moreover, taurine was able to apparently reduce high blood glucose and HbA1c (P < 0.05), markedly elevated the activity of SOD, lowered the content of MDA (P < 0.01); and taurine also could significantly re
To study preventive and therapeutic effect of anisodamine on acute respiratory distress syndrome(ARDS) induced by oleic acid and their mechanism of action.
Model of ARDS was made in rabbits by oleic ...acid (OA). The effect of anisodamine on the malondialdehyde (MDA), fibronectin (FN), lactate dehydrogenase (LDH) and acid phosphatase (ACP) in plasma, and superoxide dismutase (SOD) in erythrocyte and MDA, SOD and pulmonary surfactant (PS) in lung tissues homogenate and pathological examination of lung were observed.
The administration of anisodamine before and after 30 minutes of injection OA decreased MDA, LDH and ACP, prevented the reduction of SOD, FN and PS. Compared with ARDS group, there was marked difference between the two, and alleviated lung injury.
Anisodamine possesses preventive and therapeutic effects on ARDS by inhibiting lipid peroxidation and stabilizing membranes.
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