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1.  MicroRNAs as Potential Biomarkers in Human Solid Tumors 
Cancer letters  2012;329(2):125-136.
MicroRNAs (miRNAs) regulate the expression of approximately 30% of protein-coding genes. Functions of miRNAs are essential to maintain a steady state of cellular machinery. Dysregulations of miRNAs play pivotal roles in the initiation and progression of malignancies. Abnormal miRNA expressions have been found in a variety of human solid tumors. Furthermore, extracellular miRNAs could circulate in body fluids, and hence show great promise for refining diagnosis and prognosis of cancer. Here we review the progress of analysis of microRNAs as a potential approach for diagnosis and prognosis of solid cancer. We will also discuss obstacles in developing miRNAs as circulating biomarkers.
PMCID: PMC3552101  PMID: 23196059
MicroRNA; biomarkers; diagnosis; prognosis; circulation; cancer
2.  MiR-15b and miR-152 reduce glioma cell invasion and angiogenesis via NRP-2 and MMP-3 
Cancer letters  2012;329(2):146-154.
Invasion and angiogenesis are two major pathophysiological features of malignant gliomas. Anti-angiogenic treatment lead to enhanced tumor cell invasion and metastasis. In the current study, we tested invasion and angiogenesis related mRNA expression profiles of glioma cells via RT2Profiler PCR Array by employing an in vivo 9L homograft glioma tumor animal model and an in vitro hypoxic cell culture model. The miRNA profile was also obtained via miRNA array. Genes with mRNA expression that changed significantly in the mRNA array were selected to predict possible miRNAs that regulate mRNA expression using the TargetScan database, and were then matched with miRNA array results. Based on these criteria, NRP-2 with the matching miRNA miR-15b, and MMP-3 with the matching miRNA miR-152 were selected for further study, and to determine whether they regulate tumor microenviroment changes and affect glioma angiogenesis and invasion. The protein expression of NRP-2 and MMP-3 were verified in 9L glioma cells and were negatively correlated to miR-15b and miR-152 level, respectively. Rat astrocytes (primary and cell line), when co-cultured with 9L glioma cells, showed significantly elevated NRP-2, MMP-3 expression and reduced miR-15b, miR-152 expression compared to non co-cultured astrocytes. Luciferase activity assay confirmed that miR-15b and miR-152 attenuate expression of NRP-2 and MMP-3 protein by binding to NRP-2 and MMP-3 transcript, respectively. In vitro invasion assay data showed that miR-15b and miR-152 significantly decreased 9L cell invasiveness. Anti-miR-15b and anti-miR-152 inhibitors counteracted the inhibition of invasion caused by miR-15b and miR-152. In vitro tube formation assay data showed that miR-15b, but not miR-152, reduced tube formation in cultured endothelial cells, and anti-miR-15b inhibitor counteracted the inhibition of tube formation caused by miR-15b. A preliminary pathway study indicated that miR-15b and miR-152 deactivated the MEK-ERK pathway via NRP-2 and MMP-3 in 9L cells, respectively. In conclusion, our current study indicates that miR-15b reduces invasion of glioma cells and angiogenesis via NRP-2, and miR-152 reduces invasion of glioma cells through MMP-3.
PMCID: PMC3553580  PMID: 23142217
Glioma; tumor model; angiogenesis; invasion; miR-15b; miR-152; NRP-2; MMP-3
3.  MicroRNA-133 Inhibits Behavioral Aggregation by Controlling Dopamine Synthesis in Locusts 
PLoS Genetics  2014;10(2):e1004206.
Phenotypic plasticity is ubiquitous and primarily controlled by interactions between environmental and genetic factors. The migratory locust, a worldwide pest, exhibits pronounced phenotypic plasticity, which is a population density-dependent transition that occurs between the gregarious and solitary phases. Genes involved in dopamine synthesis have been shown to regulate the phase transition of locusts. However, the function of microRNAs in this process remains unknown. In this study, we report the participation of miR-133 in dopamine production and the behavioral transition by negatively regulating two critical genes, henna and pale, in the dopamine pathway. miR-133 participated in the post-transcriptional regulation of henna and pale by binding to their coding region and 3′ untranslated region, respectively. miR-133 displayed cellular co-localization with henna/pale in the protocerebrum, and its expression in the protocerebrum was negatively correlated with henna and pale expression. Moreover, miR-133 agomir delivery suppressed henna and pale expression, which consequently decreased dopamine production, thus resulting in the behavioral shift of the locusts from the gregarious phase to the solitary phase. Increasing the dopamine content could rescue the solitary phenotype, which was induced by miR-133 agomir delivery. Conversely, miR-133 inhibition increased the expression of henna and pale, resulting in the gregarious-like behavior of solitary locusts; this gregarious phenotype could be rescued by RNA interference of henna and pale. This study shows the novel function and modulation pattern of a miRNA in phenotypic plasticity and provides insight into the underlying molecular mechanisms of the phase transition of locusts.
Author Summary
Phenotypic plasticity refers to the ability of an organism to alter its phenotypes in response to environmental changes. Genetic factors, such as coding and non-coding RNAs, contribute to phenotypic variation. MicroRNAs (miRNAs), which are non-coding RNAs, function as post-transcriptional repressors of gene expression. Migratory locusts show remarkable phenotypic plasticity, referred to as phase transition, which is dependent on population density changes. In the present study, we elucidated the miRNA-133-mediated post-transcriptional mechanisms involved in dopamine production that result in behavioral phase changes. We found that miR-133 directly represses two genes, henna and pale, in the dopamine pathway. Administration of the miR-133 agomir decreased dopamine production and induced a behavioral shift from the gregarious to the solitary phase. Additionally, miR-133 targeted henna in the coding region and pale in the 3′ untranslated region, possibly indicating that different mechanisms of post-transcriptional regulation by miR-133 occur in the dopamine pathway. Moreover, the rescue experiments significantly eliminated the effects of miR-133 overexpression and inhibition on the behavioral phase changes of locusts. Our results demonstrate the role of miR-133 in phenotypic plasticity in locusts, in which the miR-133 regulates behavioral changes by controlling dopamine synthesis.
PMCID: PMC3937255  PMID: 24586212
4.  Stochastic θ-Methods for a Class of Jump-Diffusion Stochastic Pantograph Equations with Random Magnitude 
The Scientific World Journal  2014;2014:589167.
This paper is concerned with the convergence of stochastic θ-methods for stochastic pantograph equations with Poisson-driven jumps of random magnitude. The strong order of the convergence of the numerical method is given, and the convergence of the numerical method is obtained. Some earlier results are generalized and improved.
PMCID: PMC3933539  PMID: 24672340
5.  Association Study to Evaluate FoxO1 and FoxO3 Gene in CHD in Han Chinese 
PLoS ONE  2014;9(1):e86252.
Coronary heart disease (CHD) is one of the leading causes of mortality and morbidity in China. Genetic factors that predispose individuals to CHD are unclear. In the present study, we aimed to determine whether the variation of FoxOs, a novel genetic factor associated with longevity, was associated with CHD in Han Chinese populations.
1271 CHD patients and 1287 age-and sex-matched controls from Beijing and Harbin were included. We selected four tagging single nucleotide polymorphisms (SNPs) of FoxO1 (rs2755209, rs2721072, rs4325427 and rs17592371) and two tagging SNPs of FoxO3 (rs768023 and rs1268165). And the genotypes of these SNPs were determined in both CHD patients and non-CHD controls.
For population from Beijing, four SNPs of FoxO1 and two SNPs of FoxO3 were found not to be associated with CHD (p>0.05). And this was validated in the other population from Harbin (p>0.05). After combining the two geographically isolated case-control populations, the results showed that the six SNPs did not necessarily predispose to CHD in Han Chinese(p>0.05). In stratified analysis according to gender, the history of smoking, hypertension, diabetes mellitus, hyperlipidemia and the metabolic syndrome, we further explored that neither the variants of FoxO1 nor the variants of FoxO3 might be associated with CHD (p>0.05).
The variants of FoxO1 and FoxO3 may not increase the prevalence of CHD in Han Chinese population.
PMCID: PMC3904908  PMID: 24489705
6.  CRP-Cyclic AMP Dependent Inhibition of the Xylene-Responsive σ54-Promoter Pu in Escherichia coli 
PLoS ONE  2014;9(1):e86727.
The expression of σ54-dependent Pseudomonas putida Pu promoter is activated by XylR activator when cells are exposed to a variety of aromatic inducers. In this study, the transcriptional activation of the P. putida Pu promoter was recreated in the heterologous host Escherichia coli. Here we show that the cAMP receptor protein (CRP), a well-known carbon utilization regulator, had an inhibitory effect on the expression of Pu promoter in a cAMP-dependent manner. The inhibitory effect was not activator specific. In vivo KMnO4 and DMS footprinting analysis indicated that CRP-cAMP poised the RNA polymerase at Pu promoter, inhibiting the isomerization step of the transcription initiation even in the presence of an activator. Therefore, the presence of PTS-sugar, which eliminates cAMP, could activate the poised RNA polymerase at Pu promoter to transcribe. Moreover, the activation region 1 (AR1) of CRP, which interacts directly with the αCTD (C-terminal domain of α-subunit) of RNA polymerase, was found essential for the CRP-mediated inhibition at Pu promoter. A model for the above observations is discussed.
PMCID: PMC3900584  PMID: 24466213
7.  Microstructure and Nonohmic Properties of SnO2-Ta2O5-ZnO System Doped with ZrO2 
The Scientific World Journal  2014;2014:754890.
The microstructure and nonohmic properties of SnO2-Ta2O5-ZnO varistor system doped with different amounts of ZrO2 (0–2.0 mol%) were investigated. The proposed samples were sintered at 1400°C for 2 h with conventional ceramic processing method. By X-ray diffraction, SnO2 cassiterite phase was found in all the samples, and no extra phases were identified in the detection limit. The doping of ZrO2 would degrade the densification of the varistor ceramics but inhibit the growth of SnO2 grains. In the designed range, varistors with 1.0 mol% ZrO2 presented the maximum nonlinear exponent of 15.9 and lowest leakage current of 110 μA/cm2, but the varistor voltage increased monotonously with the doping amount of ZrO2.
PMCID: PMC3918401  PMID: 24578658
8.  Association between MCP-1 -2518A/G Polymorphism and Cancer Risk: Evidence from 19 Case-Control Studies 
PLoS ONE  2013;8(12):e82855.
Single nucleotide polymorphisms (SNPs) may affect the development of diseases. The -2518A/G polymorphism in the regulatory region of the monocyte chemo-attractant protein-1 (MCP-1) gene has been reported to be associated with cancer risk. However, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to obtain a more precise estimation of the relationship between the -2518A/G polymorphism and cancer risk.
Methodology/Principal Findings
We performed a meta-analysis, including 4,162 cases and 5,173 controls, to evaluate the strength of the association between the −2518A/G polymorphism and cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Overall, the results indicated that the −2518A/G polymorphism was not statistically associated with cancer risk. However, sub-group analysis revealed that individuals with GG genotypes showed an increased risk of cancer in digestive system compared with carriers of the A allele (GG vs. AA: OR = 1.43, 95%CI = 1.05–1.96, Pheterogeneity = 0.08; GG vs. AG/AA: OR = 1.29, 95%CI = 1.02–1.64, Pheterogeneity = 0.14). In addition, the increased risk of GG genotype was also observed in Caucasians (GG vs. AG/AA: OR = 1.81, 95%CI = 1.10–2.96, Pheterogeneity = 0.02).
This meta-analysis suggests that the MCP-1 −2518A/G polymorphism may have some relation to digestive system cancer susceptibility or cancer development in Caucasian. Large-scale and well-designed case-control studies are needed to validate the findings.
PMCID: PMC3867394  PMID: 24367564
9.  NEXN Is a Novel Susceptibility Gene for Coronary Artery Disease in Han Chinese 
PLoS ONE  2013;8(12):e82135.
Coronary artery disease (CAD) is the leading cause of death and disability in the world. Genome-wide association studies have implicated the importance of the genetic contribution of vascular smooth muscle cells (VSMCs) function in CAD susceptibility. The aberrant phenotypic modulation of VSMC is responsible for the pathological vascular intima hyperplasia that is the hallmark for atherosclerotic morphology. NEXN is a muscle-specific F-actin binding protein and is regulated by inflammatory cytokines in VSMCs. Whether NEXN contributes to human vascular disorders is still unknown. In this study, we genotyped 5 SNPs, tagging all of the 17 common SNPs within 54 kilobases (kb) covering NEXN gene and its flanking region, in 1883 patients with CAD and 1973 healthy individuals from Han Chinese, and identified one SNP, rs1780050, which was strongly associated with CAD trait. The Bonferroni corrected P-value was 7.65×10−5. The odds ratio (95% confidence interval) was 1.23 (1.12–1.36) with statistical power of 0.994. Functional analysis showed that NEXN promotes VSMC to a contractile phenotype in vitro and inhibits balloon-injury induced neointima formation in vivo. Further eQTL analysis demonstrated that the risk allele T of rs1780050 is associated with decreased expression of NEXN, thus contributing to a higher risk of CAD susceptibility in the population. This is, to our knowledge, the first study to identify NEXN as a novel CAD susceptibility gene with both genetic and functional evidence.
PMCID: PMC3859596  PMID: 24349201
10.  Small nucleolar RNAs in cancer 
Biochimica et biophysica acta  2012;1826(1):10.1016/j.bbcan.2012.03.005.
Non-coding RNAs (ncRNAs) are important regulatory molecules involving in various physiological cellular processes. Alterations of ncRNAs, particularly microRNAs, play crucial roles in tumorigenesis. Accumulating evidence indicates that small nucleolar RNAs (snoRNAs), another large class of ncRNAs, are gaining prominence and more actively involved in carcinogenesis than previously thought. Some snoRNAs exhibit differential expression patterns in a variety of human cancers and demonstrate capability to affect cell transformation, tumorigenesis, and metastasis. We are beginning to comprehend the functional repercussions of snoRNAs in the development and progression of malignancy. In this review, we will describe current studies that have shed new light on the functions of snoRNAs in carcinogenesis and the potential applications for cancer diagnosis and diagnosis.
PMCID: PMC3842010  PMID: 22498252
Cancer; non-coding RNAs; small nucleolar RNAs; diagnosis; therapy
11.  Association of Genetic Variants of BMP4 with Type 2 Diabetes Mellitus and Clinical Traits in a Chinese Han Population 
BioMed Research International  2013;2013:238150.
BMP4 is one of the transforming growth factor-β superfamily, which can participate in adipogenesis. Gene encoding BMP4 is acknowledged as a convincing candidate that may contribute to both glucose and lipid metabolism. In this paper, we aimed to test the impacts of BMP4 variants on type 2 diabetes in a large sample of Chinese population. We genotyped 10 tagging single nucleotide polymorphisms within the BMP4 region in 6822 participants and acquired detailed clinical investigations and biochemistry measurements. We found that BMP4 rs8014363 showed nominal association towards type 2 diabetes, with the T allele conferring a high risk of type 2 diabetes (OR = 1.108, 95%CI 0.999–1.229, P = 0.051 for allele; OR = 1.110, 95%CI 1.000–1.231, P = 0.050 for genotype), but it was no longer statistically significant after adjusting for multiple testing (empirical P = 0.3689 for allele based on 10,000 permutations). Moreover, we observed a significant association of rs8014363 with triglyceride level and a trend towards association with high-density lipoprotein cholesterol after adjusting for age, gender, and BMI (P = 0.035 and 0.068, resp.). Our data suggested that the genetic variants of BMP4 may not play a dominant role in glucose metabolism in Chinese Han population, but a minor effect cannot be ignored.
PMCID: PMC3855940  PMID: 24350253
12.  Quantification of Plasma miRNAs by Digital PCR for Cancer Diagnosis 
Biomarker Insights  2013;8:127-136.
Analysis of plasma microRNAs (miRNAs) by quantitative polymerase chain reaction (qPCR) provides a potential approach for cancer diagnosis. However, absolutely quantifying low abundant plasma miRNAs is challenging with qPCR. Digital PCR offers a unique means for assessment of nucleic acids presenting at low levels in plasma. This study aimed to evaluate the efficacy of digital PCR for quantification of plasma miRNAs and the potential utility of this technique for cancer diagnosis. We used digital PCR to quantify the copy number of plasma microRNA-21-5p (miR-21–5p) and microRNA-335–3p (miR-335–3p) in 36 lung cancer patients and 38 controls. Digital PCR showed a high degree of linearity and quantitative correlation with miRNAs in a dynamic range from 1 to 10,000 copies/μL of input, with high reproducibility. qPCR exhibited a dynamic range from 100 to 1×107 copies/μL of input. Digital PCR had a higher sensitivity to detect copy number of the miRNAs compared with qPCR. In plasma, digital PCR could detect copy number of both miR-21–5p and miR-335–3p, whereas qPCR was only able to assess miR-21–5p. Quantification of the plasma miRNAs by digital PCR provided 71.8% sensitivity and 80.6% specificity in distinguishing lung cancer patients from cancer-free subjects.
PMCID: PMC3836484  PMID: 24277982
digital PCR; miRNAs; plasma; diagnosis; lung cancer
13.  Correction: FASL rs763110 Polymorphism Contributes to Cancer Risk: An Updated Meta-Analysis Involving 43,295 Subjects 
PLoS ONE  2013;8(10):10.1371/annotation/6f1720b5-73e8-428d-87f5-3eb671c77a98.
PMCID: PMC3815399  PMID: 24223097
14.  Overexpression of N-Myc Downstream-Regulated Gene 2 (NDRG2) Regulates the Proliferation and Invasion of Bladder Cancer Cells In Vitro and In Vivo 
PLoS ONE  2013;8(10):e76689.
N-Myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor gene, which plays an important role in controlling tumor growth. The aim of this study was to investigate the expression of NDRG2 gene in bladder cancer (BC) tissues and several bladder cancer cell lines, and to seek its clinical and pathological significance. Ninety-seven bladder carcinoma and 15 normal bladder tissue sections were analyzed retrospectively with immunohistochemistry. The human bladder cancer cell line T24 was infected with LEN-NDRG2 or LEN-LacZ. The effects of NDRG2 overexpression on T24 cells and T24 nude mouse xenografts were measured via cell growth curves, tumor growth curves, flow cytometric analysis, western blot and Transwell assay. NDRG2 was highly expressed in normal bladder tissue, but absent or rarely expressed in cacinomatous tissues (χ2=8.761, p < 0.01). The NDRG2 level was negatively correlated with tumor grade and pathologic stage(r=-0.248, p < 0.05), as well as increased c-myc level (r=-0.454, p< 0.001). The expression of NDRG2 was low in the three BC cell lines. T24 cells infected with LEN-NDRG2 showed inhibition of proliferation both in vitro and in vivo, and NDRG2 overexpression can inhibit tumor growth and invasion in vitro.
PMCID: PMC3797857  PMID: 24146910
15.  XRCC3 Thr241Met Is Associated with Response to Platinum-Based Chemotherapy but Not Survival in Advanced Non-Small Cell Lung Cancer 
PLoS ONE  2013;8(10):e77005.
A lot of studies have investigated the correlation between x-ray repair cross-complementing group 3 (XRCC3) Thr241Met polymorphism and clinical outcomes in non-small cell cancer (NSCLC), while the conclusion is still conflicting.
Materials and Methods
We conducted this meta-analysis to evaluate the predictive value of XRCC3 Thr241Met polymorphism on response and overall survival of patients with NSCLC. Pooled odds ratios (ORs) and hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs) were used to estimate the association strength.
A total of 14 eligible studies with 2828 patients were identified according to our inclusion criteria. Meta-analysis results showed that carriers of the variant 241Met allele were significantly associated with good response, compared with those harboring the wild 241Thr allele (Met vs. Thr, OR = 1.453, 95% CI: 1.116–1.892, Pheterogeneity = 0.968 and ThrMet+MetMet vs. ThrThr, OR = 1.476, 95% CI: 1.087–2.004, Pheterogeneity = 0.696). This significant association was observed in Caucasian population but not in Asian population. On the other hand, there was no significant association of XRCC3 Thr241Met polymorphism with survival (ThrMet+MetMet vs. ThrThr, HR = 1.082, 95% CI: 0.929–1.261, Pheterogeneity = 0.564), and there was no difference between Asian and Caucasian population.
These findings suggest a predictive role of XRCC3 Thr241Met polymorphism on response to platinum-based chemotherapy in patients with advanced NSCLC. Additionally, we first report that the XRCC3 Thr241Met polymorphism is associated with response to platinum-based chemotherapy and highlights the prognostic value of the XRCC3 Thr241Met polymorphism.
PMCID: PMC3792919  PMID: 24116196
16.  Activation of mammalian target of rapamycin mediates rat pain-related responses induced by BmK I, a sodium channel-specific modulator 
Molecular Pain  2013;9:50.
The mammalian target of rapamycin (mTOR) is known to regulate cell proliferation and growth by controlling protein translation. Recently, it has been shown that mTOR signaling pathway is involved in long-term synaptic plasticity. However, the role of mTOR under different pain conditions is less clear. In this study, the spatiotemporal activation of mTOR that contributes to pain-related behaviors was investigated using a novel animal inflammatory pain model induced by BmK I, a sodium channel-specific modulator purified from scorpion venom. In this study, intraplantar injections of BmK I were found to induce the activation of mTOR, p70 ribosomal S6 protein kinase (p70 S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) in rat L5-L6 spinal neurons. In the spinal cord, mTOR, p70 S6K and 4E-BP1 were observed to be activated in the ipsilateral and contralateral regions, peaking at 1–2 h and recovery at 24 h post-intraplantar ( BmK I administration. In addition, intrathecal (i.t.) injection of rapamycin – a specific inhibitor of mTOR – was observed to result in the reduction of spontaneous pain responses and the attenuation of unilateral thermal and bilateral mechanical hypersensitivity elicited by BmK I. Thus, these results indicate that the mTOR signaling pathway is mobilized in the induction and maintenance of pain-activated hypersensitivity.
PMCID: PMC3842742  PMID: 24099268
BmK I; mTOR; p70S6K; 4E-BP1; Rapamycin; Pain; Mirror-image mechanical hypersensitivity
17.  FASL rs763110 Polymorphism Contributes to Cancer Risk: An Updated Meta-Analysis Involving 43,295 Subjects 
PLoS ONE  2013;8(9):e74543.
Published studies investigating the association between genetic polymorphism -884C/T (rs763110) of the FAS ligand (FASL) promoter and cancer risk reported inconclusive results. To derive a more precise estimation of the relationship, we performed an updated meta-analysis of all eligible studies.
Methodology/Principal Findings
We carried out a meta-analysis, including 47 studies with 19,810 cases and 23,485 controls, to confirm a more conclusive association between the FASL rs763110 polymorphism and cancer susceptibility. Overall, significantly reduced cancer risk was associated with the variant -884T when all studies were pooled (TC vs. CC: OR = 0.83, 95%CI = 0.75–0.92; Pheterogeneity<0.001; TT+TC vs. CC: OR = 0.85, 95%CI = 0.77–0.94; Pheterogeneity<0.001). Stratified analysis revealed that there was a statistically reduced cancer risk in Asians (TC vs. CC: OR = 0.76, 95%CI = 0.67–0.87; Pheterogeneity<0.001; TT+TC vs. CC: OR = 0.79, 95%CI = 0.70–0.90; Pheterogeneity<0.001) and in patients with cancers of head and neck (TC vs. CC: OR = 0.87, 95%CI = 0.77–0.99; Pheterogeneity = 0.118; TT+TC vs. CC: OR = 0.88, 95%CI = 0.78–0.99; Pheterogeneity = 0.168) and ovarian cancer (TC vs. CC: OR = 0.67, 95%CI = 0.49–0.90; Pheterogeneity = 0.187; TT+TC vs. CC: OR = 0.64, 95%CI = 0.48–0.86; Pheterogeneity = 0.199). Meta-regression showed that ethnicity (p = 0.029) and genotyping method (p = 0.043) but not cancer types (p = 0.772), sample size (p = 0.518), or source of controls (p = 0.826) were the source of heterogeneity in heterozygote comparison.
Our results suggest that the FASL polymorphism rs763110 is associated with a significantly reduced risk of cancer, especially in Asian populations.
PMCID: PMC3781150  PMID: 24086353
18.  Evaluation of lung flute in sputum samples for molecular analysis of lung cancer 
Molecular analysis of sputum provides a promising approach for lung cancer diagnosis, yet is limited by the difficulty in collecting the specimens from individuals who can’t spontaneously expectorate sputum. Lung Flute is a small self-powered audio device that can induce sputum by generating sound waves and vibrating in the airways of the lungs. Here we propose to evaluate the usefulness of Lung Flute for sputum sampling to assist diagnosis of lung cancer.
Forty-three stage I lung cancer patients and 47 cancer-free individuals who couldn’t spontaneously cough sputum were instructed to use Lung Flute for sputum sampling. Expressions of two microRNAs, miRs-31 and 210, were determined in the specimens by qRT-PCR. The results were compared with sputum cytology.
Sputum was easily collected from 39 of 43 (90.7%) lung cancer patients and 42 of 47 (89.4%) controls with volume ranges from 1 to 5 ml (median, 2.6 ml). The specimens had less than 4% oral squamous cells, indicating that sputum was obtained from low respiratory tract. Expressions of miRs-31 and 210 in sputum were considerably higher in cancer patients than cancer-free individuals (8.990 vs. 4.514; 0.6847 vs. 0.3317; all P <0.001). Combined use of the two miRNAs produced a significantly higher sensitivity (61.5% vs. 35.9%, P = 0.002) and a slightly lower specificity (90.5% vs. 95.2%, p = 0.03) compared with cytology for lung cancer diagnosis.
Lung Flute could potentially be useful in convenient and efficient collection of sputum for molecular diagnosis of lung cancer.
PMCID: PMC3848735  PMID: 24053570
Lung flute; Sputum; microRNAs; Lung cancer; Diagnosis
19.  A phase II study of paclitaxel and nedaplatin as front-line chemotherapy in Chinese patients with metastatic esophageal squamous cell carcinoma 
AIM: To evaluate the efficacy and safety of paclitaxel-nedaplatin combination as a front-line regimen in Chinese patients with metastatic esophageal squamous cell carcinoma (ESCC).
METHODS: A two-center, open-label, single-arm phase II study was designed. Thirty-nine patients were enrolled and included in the intention-to-treat analysis of efficacy and adverse events. Patients received 175 mg/m2 of paclitaxel over a 3 h infusion on 1 d, followed by nedaplatin 80 mg/m2 in a 1 h infusion on 2 d every 3 wk until the documented disease progression, unacceptable toxicity or patient’s refusal.
RESULTS: Of the 36 patients assessable for efficacy, there were 2 patients (5.1%) with complete response and 16 patients (41.0%) with partial response, giving an overall response rate of 46.1%. The median progression-free survival and median overall survival for all patients were 7.1 mo (95%CI: 4.6-9.7) and 12.4 mo (95%CI: 9.5-15.3), respectively. Toxicities were moderate and manageable. Grade 3/4 toxicities included neutropenia (15.4%), nausea (10.3%), anemia (7.7%), thrombocytopenia (5.1%), vomiting (5.1%) and neutropenia fever (2.6%).
CONCLUSION: The combination of paclitaxel and nedaplatin is active and well tolerated as a first-line therapy for patients with metastatic ESCC.
PMCID: PMC3793146  PMID: 24124338
Esophageal squamous cell cancer; Front-line chemotherapy; Paclitaxel; Nedaplatin
20.  Association of Interleukin-18 Gene Promoter −607 C>A and −137G>C Polymorphisms with Cancer Risk: A Meta-Analysis of 26 Studies 
PLoS ONE  2013;8(9):e73671.
Evidence suggest that IL-18 gene polymorphisms may be risk factors for several cancers. Increasing studies investigating the association between IL-18 gene promoter polymorphisms (−607 C>A and −137G>C) and cancer risk have yielded conflicting results.
Methodology/Principal Findings
We performed a meta-analysis of 26 studies including 4096 cases and 5222 controls. We assessed the strength of the association of IL-18 gene promoter −607 C>A and −137G>C polymorphisms with cancer risk and performed sub-group analyses by cancer types, ethnicities, source of controls and sample size. The pooled results revealed a significant increased risk of cancer susceptibility for −607 C>A (CA vs. CC: OR = 1.19, 95%CI: 1.04, 1.37, Pheterogeneity = 0.033; CA/AA vs. CC: OR = 1.17, 95% CI: 1.01, 1.34, Pheterogeneity = 0.007), but no significant association for −137 G>C was observed with overall cancer risk. Sub-group analyses revealed that an increased risk of nasopharyngeal carcinoma was both found for −607 C>A (CA/AA vs. CC: OR = 1.32, 95% CI: 1.04, 1.69, Pheterogeneity = 0.823) and −137G>C (GC/CC vs. GG: OR = 1.57, 95%CI: 1.26, 1.96, Pheterogeneity = 0.373). Consistent with the results of the genotyping analyses, the −607A/−137C and −607C/−137C haplotypes were associated with a significantly increased risk of nasopharyngeal carcinoma as compared with the −607C/−137G haplotype (−607A/−137C vs. −607C/−137G: OR = 1.26, 95%CI: 1.13, 1.40; Pheterogeneity = 0.569; −607C/−137C vs. −607C/−137G: OR = 1.14, 95%CI: 1.03, 1.27; Pheterogeneity = 0.775). As for gastrointestinal cancer, we also found that −607 C>A polymorphism was significantly associated with increased cancer risk (CA/AA vs. CC: OR = 1.25, 95% CI: 1.05, 1.50, Pheterogeneity = 0.458). Further sub-group analysis revealed that −137G>C polymorphism contributed to cancer risk in Asians but not in Caucasians (GC/CC vs. GG: OR = 1.31, 95%CI: 1.05, 1.64, Pheterogeneity<0.001).
The meta-analysis results suggest that IL-18 gene promoter −607 C>A polymorphism is significantly associated with overall cancer risk, especially in nasopharyngeal carcinoma and gastrointestinal cancer; and the −137 G>C polymorphism is associated with increased overall cancer risk in Asian populations and also significantly increases the risk of nasopharyngeal carcinoma.
PMCID: PMC3774799  PMID: 24066061
21.  Altered DNA Methylation Patterns of the H19 Differentially Methylated Region and the DAZL Gene Promoter Are Associated with Defective Human Sperm 
PLoS ONE  2013;8(8):e71215.
DNA methylation disturbance is associated with defective human sperm. However, oligozoospermia (OZ) and asthenozoospermia (AZ) usually present together, and the relationship between the single-phenotype defects in human sperm and DNA methylation is poorly understood. In this study, 20 infertile OZ patients and 20 infertile AZ patients were compared with 20 fertile normozoospermic men. Bisulfate-specific PCR was used to analyze DNA methylation of the H19-DMR and the DAZL promoter in these subjects. A similar DNA methylation pattern of the H19-DMR was detected in AZ and NZ(control), with only complete methylation and mild hypomethylation(<50% unmethylated CpGs) identified, and there was no significant difference in the occurrence of these two methylation patterns between AZ and NZ (P>0.05). However, the methylation pattern of severe hypomethylation (>50% unmethylated CpGs ) and complete unmethylation was only detected in 5 OZ patients, and the occurrence of these two methylation patterns was 8.54±10.86% and 9±6.06%, respectively. Loss of DNA methylation of the H19-DMR in the OZ patients was found to mainly occur in CTCF-binding site 6, with occurrence of 18.15±14.71%, which was much higher than that in patients with NZ (0.84±2.05%) and AZ (0.58±1.77%) (P<0.001).Additional, our data indicated the occurrence of >20% methylated clones in the DAZL promoter only in infertile patients, there was no significant difference between the AZ and OZ patients in the proportion of moderately-to-severely hypermethylated clones (p>0.05). In all cases, global sperm genome methylation analyses, using LINE1 transposon as the indicator, showed that dysregulation of DNA methylation is specifically associated with the H19-DMR and DAZL promoter. Therefore, abnormal DNA methylation status of H19-DMR, especially at the CTCF-binding site 6, is closely associated with OZ. Abnormal DNA methylation of the DAZL promoter might represent an epigenetic marker of male infertility.
PMCID: PMC3756053  PMID: 24015185
22.  Predictive Value of XPD Polymorphisms on Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(8):e72251.
The correlation between xeroderma pigmentosum group D (XPD) polymorphisms (Lys751Gln and Asp312Asn) and clinical outcomes of non-small cell lung cancer (NSCLC) patients, who received platinum-based chemotherapy (Pt-chemotherapy), is still inconclusive. This meta-analysis was aimed to systematically review published evidence and ascertain the exact role of XPD polymorphisms.
Databases of MEDLINE and EMBASE were searched up to April 2013 to identify eligible studies. A rigorous quality assessment of eligible studies was conducted according the Newcastle-Ottawa Quality Assessment Scales. The relationship between XPD polymorphisms and response to Pt-chemotherapy and survival was analyzed.
A total of 22 eligible studies were included and analyzed in this meta-analysis. The overall analysis suggested that the XPD Lys751Gln polymorphism was not associated with response to Pt-chemotherapy or survival. However, the XPD 312Asn allele was significantly associated with poor response to Pt-chemotherapy compared with the Asp312 allele (Asn vs. Asp: OR = 0.435, 95% CI: 0.261–0.726). Additionally, the variant genotype of XPD Asp312Asn polymorphism was associated with favorable survival in Caucasian (AspAsn vs. AspAsp: HR = 0.781, 95% CI: 0.619–0.986) but unfavorable survival in Asian (AspAsn+AsnAsn vs. AspAsp: HR = 1.550, 95% CI: 1.038–2.315).
These results suggest that XPD Asp312Asn polymorphism may function as a predictive biomarker on platinum-based chemotherapy in NSCLC and further studies are warranted.
PMCID: PMC3747109  PMID: 23977265
23.  Serum GP73 is complementary to AFP and GGT-II for the diagnosis of hepatocellular carcinoma 
Oncology Letters  2013;6(4):1152-1158.
Golgi protein 73 (GP73) is a resident Golgi type II transmembrane protein that has been reported to markedly increase in chronic liver disease, particularly in hepatocellular carcinoma (HCC). However, it remains unclear as to whether serum GP73 represents a reliable serum marker for the diagnosis of HCC. The aim of the present study was to evaluate the diagnostic value of serum GP73 in patients with HCC and to determine the diagnostic accuracy of measuring serum GP73 in combination with α-fetoprotein (AFP) and γ-glutamyl transferase isoenzyme II (GGT-II) in HCC. Serum GP73 was detected using a time-resolved fluorescence immunological assay (TRFIA) and enzyme-linked immunosorbent assay (ELISA) in 79 HCC cases, including 16 liver cirrhosis, 30 chronic hepatitis and 28 healthy individuals. The correlation between serum GP73 and tumor size and HCC grading was analyzed and the complementary diagnostic value of serum GP73, AFP and GGT-II was evaluated. TRFIA was established for the detection of serum GP73 and was sensitive and reproducible. The expression levels of serum GP73 were markedly higher in the patients with HCC when compared with those of the individuals with liver cirrhosis and chronic hepatitis or the healthy individuals. According to the receiver operating characteristic (ROC) curve, diagnostic sensitivity and specificity for HCC with a cut-off value of 78.1 ng/l were 73.4 and 79.0%, respectively. However, no correlation was identified among serum GP73 and tumor size or grading, and no correlations were identified among serum GP73, AFP and GGT-II. The diagnostic sensitivities for HCC, as detected by TRFIA of GP73, AFP and GGT-II, were 73.4, 55.6 and 68.4%, respectively, and the specificities were 80.0, 86.7 and 97.1%, respectively. The combined determination of these markers increased the diagnostic sensitivity to 96.3% for HCC. TRFIA functions as a sensitive and replicable assay for the detection of serum GP73. The levels of serum GP73 were significantly higher in the HCC group when compared with the individuals with benign liver diseases. Serum GP73 may serve as a potential independent diagnostic candidate for HCC and the combined determination of serum GP73, AFP and GGT-II may increase the diagnostic efficiency of HCC.
PMCID: PMC3796428  PMID: 24137480
time-resolved fluorescence immunological assay; golgi protein 73; hepatocellular carcinoma
24.  Adult Hirschsprung’s disease: report of four cases 
Adult Hirschsprung’s disease (HD) is a rare motor disorder of the gut that is frequently misdiagnosed as refractory constipation. The primary pathogenic defect in adult HD is identical to that seen in infancy or childhood, and is characterized by the total absence of intramural ganglion cells of the submucosal (Meissner) and myenteric (Auerbach) neural plexuses in the affected segment of the bowel. Ninety-four percent of HD cases are diagnosed before the patient reaches 5 years of age, however, on rare occasion, mild cases of HD may go undiagnosed until he or she reaches adulthood. In this study, we describe four cases of adult HD with a history of longstanding recurrent constipation, relieved by laxatives, and presenting to the Department of Gastrointestinal Surgery with progressive abdominal distention, colicky pain or acute intestinal obstruction. Barium enema or computed tomography revealed a grossly distended proximal large colon with fecal retention. Intraoperative frozen section biopsy was performed in all cases and showed aganglionosis of the stenotic segment and a normal distal rectum. In all cases, patient symptoms were completely resolved and there were no complications arising immediately post-surgery or at one-year follow-up. Adult HD should be considered in the differential diagnosis of cases where adult patients present with chronic constipation or even acute intestinal obstruction. The modified one-stage Martin-Duhamel or Rehbein’s procedure is a feasible surgical option for treating cases of adult HD involving a segment or the entire bowel.
PMCID: PMC3726979  PMID: 23923081
Adult; constipation; treatment; Hirschsprung’s disease
25.  Exceptionally high cumulative percentage of NUMTs originating from linear mitochondrial DNA molecules in the Hydra magnipapillata genome 
BMC Genomics  2013;14:447.
In contrast to most animal genomes, mitochondrial genomes in species belonging to the phylum Cnidaria show distinct variations in genome structure, including the mtDNA structure (linear or circular) and the presence or absence of introns in protein-coding genes. Therefore, the analysis of nuclear insertions of mitochondrial sequences (NUMTs) in cnidarians allows us to compare the NUMT content in animals with different mitochondrial genome structures.
NUMT identification in the Hydra magnipapillata, Nematostella vectensis and Acropora digitifera genomes showed that the NUMT density in the H. magnipapillata genome clearly exceeds that in other two cnidarians with circular mitochondrial genomes. We found that H. magnipapillata is an exceptional ancestral metazoan with a high NUMT cumulative percentage but a large genome, and its mitochondrial genome linearisation might be responsible for the NUMT enrichment. We also detected the co-transposition of exonic and intronic fragments within NUMTs in N. vectensis and provided direct evidence that mitochondrial sequences can be transposed into the nuclear genome through DNA-mediated fragment transfer. In addition, NUMT expression analyses showed that NUMTs are co-expressed with adjacent protein-coding genes, suggesting the relevance of their biological function.
Taken together, our results provide valuable information for understanding the impact of mitochondrial genome structure on the interaction of mitochondrial molecules and nuclear genomes.
PMCID: PMC3716686  PMID: 23826818
Cnidaria; Mitochondrial DNA; NUMT; Linear mitochondrial genome

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