Yuyu Xiong

MiR-140 is co-expressed with Wwp2-C transcript and activated by Sox9 to target Sp1 in maintaining the chondrocyte proliferation

MiR‐140 is a microRNA specially involved in chondrogenesis and osteoarthritis pathogenesis. However, its transcriptional regulation and target genes in cartilage development are not fully understood. Here we detected that miR‐140 was uniquely expressed in chondrocyte and suppressed by Wnt/β‐catenin signalling. The miR‐140 primary transcript was an intron‐retained RNA co‐expressed with Wwp2‐C isoform, which was directly induced by Sox9 through binding to the intron 10 of Wwp2 gene. Knockdown of miR‐140 in limb bud micromass cultures resulted in arrest of chondrogenic proliferation. Sp1, the activator of the cell cycle regulator p15INK4b, was identified as a target of miR‐140 in maintaining the chondrocyte proliferation. Collectively, our findings expand our understanding of the transcriptional regulation and the chondrogenic role of miR‐140 in chondrogenesis.

The PstI/RsaI and DraI polymorphisms of CYP2E1 and head and neck cancer risk: a meta-analysis based on 21 case-control studies

BackgroundCYP2E1 encodes a member of the cytochrome P450 superfamily of enzymes which play a central role in activating and detoxifying many carcinogens and endogenous compounds thought to be involved in the development of cancer. The PstI/RsaI and DraI polymorphism are two of the most commonly studied polymorphisms of the gene for their association with risk of head and neck cancer, but the results are conflicting.MethodsWe performed a meta-analysis using 21 eligible case-control studies with a total of 4,951 patients and 6,071 controls to summarize the data on the association between the CYP2E1 PstI/RsaI and DraI polymorphism and head and neck cancer risk, especially by interacting with smoking or alcohol.ResultsCompared with the wild genotype, the OR was 1.96 (95% CI: 1.33-2.90) for PstI/RsaI and 1.56 (95% CI: 1.06-2.27) for DraI polymorphism respectively. When stratified according to ethnicity, the OR increased in the Asians for both polymorphisms (OR = 2.04, 95% CI: 1.32-3.15 for PstI/RsaI; OR = 2.04, 95% CI: 1.27-3.29 for DraI), suggesting that the risk is more pronounced in Asians.ConclusionOur meta-analysis suggests that individuals with the homozygote genotypes of PstI/RsaI or DraI polymorphism might be associated with an increased risk of head and neck cancer, especially in Asians.

Quantitative assessment of the effect of LRRK2 exonic variants on the risk of Parkinson’s disease: A meta-analysis

Leucine-rich repeat kinase 2 (LRRK2, PARK8) gene has attracted considerable attention since the variants in this gene are recognized as the most common cause of Parkinsons disease (PD) so far. A number of association studies concerning variants of LRRK2 gene and PD susceptibility have been conducted in various populations. However, some results were inconclusive. To derive a more precise estimation of the relationship between LRRK2 and genetic risk of PD, we performed a comprehensive meta-analysis which included 27,363 cases and 29,741 controls from 61 published case-control studies. Totally, the effect of five LRRK2 variants all within the coding regions, i.e. G2019S, G2385R, R1628P, P755L and A419V, were evaluated in the meta-analysis using fixed effect model or random effects model if heterogeneity existed. There were genetic associations between four variants (G2019S, G2385R, R1628P and A419V) and increased PD risk, while there was no evidence of statistically significant association between P755L and PD. Publication bias and heterogeneity were absent in most analyses. Within its limitations, this meta-analysis demonstrated that the G2019S, G2385R, R1628P and A419V variations are risk factors associated with increased PD susceptibility. However, these associations vary in different ethnicities.

Pharmacogenomics can improve antipsychotic treatment in schizophrenia.

Schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population, and heritability of up to 80%. Drug therapy is an important approach to treating the disease. However, the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects. Many studies have indicated that about 30% of the patients exhibit little or no improvements associated with antipsychotics. The response of individual patients who are given the same dose of the same drug varies considerably. In addition, antipsychotic drugs are often accompanied by adverse drug reactions (ADRs), which can cause considerable financial loss in addition to the obvious societal harm. So, it is strongly recommended that personalized medicine should be implemented both to improve drug efficacy and to minimize adverse events and toxicity. There is therefore a need for pharmacogenomic studies into the factors affecting response of schizophrenia patients to antipsychotic drugs to provide informed guidance for clinicians. Individual differences in drug response is due to a combination of many complex factors including ADEM (absorption, distribution, metabolism, excretion) process, transporting, binding with receptor and intracellular signal transduction. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this interindividual variability in antipsychotics response. In addition, epigenetic factors such as methylation of DNA and regulation by miRNA have also been reported to play an important role in the complex interactions between the multiple genes and environmental factors which influence individual drug response phenotypes in patients. In this review, we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolic enzymes (CYP2D6, CYP1A2, CYP3A4, etc.), drug transporters (mainly ABCB1) and neurotransmitter receptors (dopamine receptors and serotonin receptors, etc.). We also discuss the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics and potential clinical applications.

Identification of aberrant microRNA expression pattern in pediatric gliomas by microarray

BackgroundBrain tumor remains the leading cause of disease-related death in children. Many studies have focused on the complex biological process involved in pediatric brain tumors but little is know about the possible role of microRNAs in the genesis of these tumors.MethodsIn this study, we used a microRNA microarray assay to study the expression pattern of microRNAs in pediatric gliomas and matched normal tissues.ResultsWe found 40 differentially expressed microRNAs, among which miR-1321, miR-513b, miR-769-3p were found be related to cancer genesis for the first time. The expression of selected microRNAs were then confirmed by qRT-PCR. Furthermore, GO and pathway analysis showed that the target genes of the 40 differentially expressed microRNAs were significantly enriched in nervous system-related and tumor-related biological processes and signaling pathways. Additionally, an apoptosis-related network of microRNA–mRNA interaction, representing the critical microRNAs and their targets, was constructed based on microRNA status.ConclusionsIn the present study we identified the changed expression pattern of microRNAs in pediatric gliamas. Our study also provides a better understanding of pediatric brain tumor biology and may assist in the development of less toxic therapies and in the search for better markers for disease stratification.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1323049861105720

Dynamic Network of Transcription and Pathway Crosstalk to Reveal Molecular Mechanism of MGd-Treated Human Lung Cancer Cells

Recent research has revealed various molecular markers in lung cancer. However, the organizational principles underlying their genetic regulatory networks still await investigation. Here we performed Network Component Analysis (NCA) and Pathway Crosstalk Analysis (PCA) to construct a regulatory network in human lung cancer (A549) cells which were treated with 50 uM motexafin gadolinium (MGd), a metal cation-containing chemotherapeutic drug for 4, 12, and 24 hours. We identified a set of key TFs, known target genes for these TFs, and signaling pathways involved in regulatory networks. Our work showed that putative interactions between these TFs (such as ESR1/Sp1, E2F1/Sp1, c-MYC-ESR, Smad3/c-Myc, and NFKB1/RELA), between TFs and their target genes (such as BMP41/Est1, TSC2/Myc, APE1/Sp1/p53, RARA/HOXA1, and SP1/USF2), and between signaling pathways (such as PPAR signaling pathway and Adipocytokines signaling pathway). These results will provide insights into the regulatory mechanism of MGd-treated human lung cancer cells.

A Systematically Combined Genotype and Functional Combination Analysis of CYP2E1, CYP2D6, CYP2C9, CYP2C19 in Different Geographic Areas of Mainland China – A Basis for Personalized Therapy

The cytochrome P450 is the major enzyme involved in drug metabolism. Single CYP genotypes and metabolic phenotypes have been widely studied, but no combination analysis has been conducted in the context of specific populations and geographical areas. This study is the first to systematically analyze the combined genotypes and functional combinations of 400 samples of major CYP genes—CYP2E1, CYP2D6, CYP2C9, and CYP2C19 in four geographical areas of mainland China. 167 different genotype combinations were identified, of which 25 had a greater than 1% frequency in the Chinese Han population. In addition, phenotypes of the four genes for each sample were in line with the predictions of previous studies of the four geographical areas. On the basis of the genotype classification, we were able to produce a systemic functional combinations analysis for the population. 25 of the combinations detected had at least two non-wild phenotypes and four showed a frequency above 1%. A bioinformatics analysis of the relationship between particular drugs and multi-genes was conducted. This is the first systematic study to analyze genotype combinations and functional combinations across whole Chinese population and could make a significant contribution in the field of personalized medicine and therapy.

Association of dopamine receptor D1 (DRD1) polymorphisms with risperidone treatment response in Chinese schizophrenia patients.

Evidence suggests that dopamine receptor D1 (DRD1) may be involved in the pathophysiology of schizophrenia and the pharmacodynamics of antipsychotics. We conducted a comprehensive pharmacogenomics study to investigate the association of genetic polymorphisms in DRD1 with treatment response to risperidone. Two independent cohorts of Han Chinese schizophrenic patients (n = 185) from two different geographic areas treated with risperidone monotherapy for 4 weeks and four SNPs (rs5326, rs4867798, rs4532 and rs686) in the DRD1 gene were analyzed. Clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). The definition of risperidone response is based on a cut-off of 50% in terms of corrected percent change of PANSS score. The significant confounding effects of non-genetic factors were included as covariates for adjustment. No significant association of DRD1 polymorphisms with risperidone treatment response was found in either single marker or haplotype analysis in this study. The current results provide the first evidence that DRD1 polymorphisms may not influence the clinical efficacy of risperidone in Chinese schizophrenia patients.

Functional Characterization of Human CYP2C9 Allelic Variants in COS-7 Cells

Variability in activity of CYP2C9, which is involved in the metabolism of approximately 15% of current therapeutic drugs, is an important contributor to interindividual differences in drug response. To evaluate the functional alternations of CYP2C9*2, CYP2C9*3, CYP2C9*8, CYP2C9*11 and CYP2C9*31, identified in our previous study in Chinese Han population, allelic variants as well as the wild-type CYP2C9 were transiently expressed in COS-7 cells. Kinetic parameters (Km, Vmax, and Clint) for S-warfarin 7-hydroxylation by these recombinant CYP2C9s were determined. Relative to CYP2C9.1, recombinant CYP2C9.3 and CYP2C9.11 exhibited significantly higher Km values, and all allelic variants showed significantly decreased Vmax and Clint values. Among all allelic variants, catalytic activity of CYP2C9.3 and CYP2C9.11 reduced the most (8.2% and 9.8% of Clint ratio, respectively; P < 0.001). These findings should be useful for predicting the phenotype profiles of CYP2C9 in Chinese Han population, comparing the functional results of these alleles accurately, and finally optimizing pharmacotherapy of drug treatment.

A pharmacogenetic study of risperidone on chemokine (C-C motif) ligand 2 (CCL2) in Chinese Han schizophrenia patients.

Previous observations of the pathophysiological distribution and pharmacological profile of the chemokine (C-C motif) ligand 2 (CCL2) have indicated its potential role in antipsychotic drug actions. More information on the pharmacogenetics of CCL2 may therefore be useful in developing individualized therapy. However, to our knowledge, rare studies have been reported in this area. This investigation was attempted to clarify whether CCL2 polymorphism could affect risperidone efficacy. We genotyped four SNPs (rs4795893, rs1024611, rs4586 and rs2857657) distributed throughout the CCL2 gene and examined them for association using the Positive and Negative Syndrome Scale (PANSS) score in two independent cohorts of Chinese schizophrenic patients (n = 208) from two different geographic areas, following an 8-week period of risperidone monotherapy. We found that all genotyped SNPs were significantly associated with risperidone treatment (rs4795893: p = 1.66E-04, rs4586: p = 0.001, rs2857657: p = 0.004, at week 4, in ANOVA). Our results indicate that there may be some effect of variations in the CCL2 gene on therapeutic efficacy of risperidone, and the associated polymorphisms may be a potential genetic marker for predicting the therapeutic effect of risperidone.