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1.  Functional Study of -724I/D Polymorphism in Apolipoprotein M (apoM) Gene Promoter Region and its Association with Myocardial Infarction 
Background
The aim of this study was to detect the function of -724I/D polymorphism in the apolipoprotein M (apoM) gene promoter region and to determine its relationship with myocardial infarction (MI).
Material/Methods
We selected 309 patients with MI and 309 healthy controls for this case-control study. The PCR products of the apoM gene promoter region were directly sequenced to analyze the -724I/D polymorphism. Differences in frequency distributions of genotype and allele were compared between the MI group and the control group. We used gene recombination and site-directed mutagenesis technique to observe the impact of -724 I/D on transcription activity of apoM gene promoter in vitro.
Results
The allele frequency of the -724Del in the MI group was higher than that in the control group (9.5% vs. 3.2%, OR=3.156, 95% CI (1.876~5.309), P<0.001). Compared to the I/I genotype carriers, the apoM levels decreased but the total cholesterol (TC) levels increased significantly in the -724Del allele carriers in plasma. The activity of apoM I/I genotype promoter decreased significantly after the deletion mutation at -724 position in apoM gene.
Conclusions
-724 I/D polymorphism decreases the apoM promoter activity, down-regulates the apoM protein expression level, and increases the risk of MI.
doi:10.12659/MSM.893077
PMCID: PMC4321410  PMID: 25637426
Amplified Fragment Length Polymorphism Analysis; Apoprotein(a); Coronary Artery Disease
2.  FCRL3 Gene Polymorphisms Confer Autoimmunity Risk for Allergic Rhinitis in a Chinese Han Population 
PLoS ONE  2015;10(1):e0116419.
Background
Heredity and environmental exposures may contribute to a predisposition to allergic rhinitis (AR). Autoimmunity may also involve into this pathologic process. FCRL3 (Fc receptor-like 3 gene), a novel immunoregulatory gene, has recently been reported to play a role in autoimmune diseases.
Objective
This study was performed to evaluate the potential association of FCRL3 polymorphisms with AR in a Chinese Han population.
Methods
Five single-nucleotide polymorphisms of FCRL3, rs945635, rs3761959, rs7522061, rs10489678 and rs7528684 were genotyped in 540 AR patients and 600 healthy controls using a PCR-restriction fragment length polymorphism assay. Allele, genotype and haplotype frequencies were compared between patients and controls using the χ2 test. The online software platform SHEsis was used to analyze their haplotypes.
Results
This study identified three strong risk SNPs rs7528684, rs10489678, rs7522061 and one weak risk SNP rs945635 of FCRL3 in Chinese Han AR patients. For rs7528684, a significantly increased prevalence of the AA genotype and A allele in AR patients was recorded. The frequency of the GG genotype and G allele of rs10489678 was markedly higher in AR patients than those in controls. For rs7522061, a higher frequency of the TT genotype, and a lower frequency of the CT genotype were found in AR patients. Concerning rs945635, a lower frequency of the CC genotype, and a higher frequency of G allele were observed in AR patients. According to the analysis of the three strong positive SNPs, the haplotype of AGT increased significantly in AR cases (AR = 38.8%, Controls = 24.3%, P = 8.29×10-14, OR [95% CI] 1.978 [1.652~2.368]).
Conclusions
This study found a significant association between the SNPs in FCRL3 gene and AR in Chinese Han patients. The results suggest these gene polymorphisms might be the autoimmunity risk for AR.
doi:10.1371/journal.pone.0116419
PMCID: PMC4296936  PMID: 25594855
3.  Treatment strategies for the surgical complications of thoracic spinal stenosis: a retrospective analysis of two hundred and eighty three cases 
International Orthopaedics  2013;38(1):117-122.
Purpose
Our aim was to investigate the causes of and treatment strategies for surgical complications of thoracic spinal stenosis.
Methods
Between May 1990 and May 2010, 283 patients with thoracic spinal stenosis were treated in our department. Three physicians were assigned to patient follow-up. Patient medical records and radiographs were reviewed. Complications were categorised as perioperative, mid- to long-term and donor-site.
Results
Follow-up was completed for 254 patients; 249 patients survived. Follow-up time ranged from one to 19 years, with a mean of six years and two months. There were 107 cases with complications an incidence rate of 42.1 %. Eleven cases were pulmonary infection, seven transient nerve-root injury, three pulmonary injury and one vertebral canal haematoma, all of which resolved. Thirteen cases of spinal cord injury postoperatively were treated using dehydration and corticosteroid therapy; eight recovered to the preoperation level, and five deteriorated. Eleven cases resulted in dural injury, and four led to cerebrospinal fluid leakage. There were five cases of wound-fat liquefaction and one of wound infection. Seven cases with deep venous thrombosis of the lower limb resolved by elevating the affected limb and administration of low-molecular-weight dextran. Seven cases of delayed wound healing recovered following change of dressings and antibiotic administration. Four cases of delayed bone-graft fusion recovered by extending the external fixation time. One case of bone-graft absorption was treated by iliac bone grafting and bracing. Two cases of internal fixation breakage were treated by removing the internal fixation.
Conclusions
Thoracic spinal stenosis surgery may result in various complications but has a good prognosis with proper treatment. The key points in reducing complications are the surgeon’s familiarity with operative imperatives and the appropriate surgical approach.
doi:10.1007/s00264-013-2103-2
PMCID: PMC3890145  PMID: 24057658
Thoracic spinal stenosis; Complications; Surgery; Postoperative
4.  14-3-3ζ Orchestrates Mammary Tumor Onset and Progression via miR221-Mediated Cell Proliferation 
Cancer research  2013;74(1):363-373.
14-3-3ζ is overexpressed in over 40% of breast cancers but its pathophysiological relevance to tumorigenesis has not been established. Here we show that 14-3-3ζ overexpression is sufficient to induce tumorigenesis in a transgenic mouse model of breast cancer. MMTV-LTR promoter driven HA-14-3-3ζ transgenic mice (MMTV-HA-14-3-3ζ) developed mammary tumors whereas control mice did not. Whey acidic protein promoter driven HA-14-3-3ζ transgenic mice (WAP-HA-14-3-3ζ) developed hyperplastic lesions and showed increased susceptibility to carcinogen-induced tumorigenesis. When crossed with MMTV-neu transgenic mice, 14-3-3ζ.neu transgenic mice exhibited accelerated mammary tumorigenesis and metastasis compared to MMTV-neu mice. Mechanistically, 14-3-3ζ overexpression enhanced MAPK/c-Jun signaling leading to increased miR-221 transcription, which inhibited p27 CDKI translation, and consequently, promoted cell proliferation. Importantly, this 14-3-3ζ/miR-221/p27/proliferation axis is also functioning in patients' breast tumors and associates with high grade cancers. Taken together, our findings show that 14-3-3ζ overexpression has a causal role in mammary tumorigenesis and progression, acting through miR-221 in cooperation with known oncogenic events to drive neoplastic cell proliferation.
doi:10.1158/0008-5472.CAN-13-2016
PMCID: PMC3947305  PMID: 24197133
Breast cancer; 14-3-3ζ; microRNA; transgenic mice
5.  Thoracolumbar fracture dislocations treated by posterior reduction, interbody fusion and segmental instrumentation 
Indian Journal of Orthopaedics  2014;48(6):568-573.
Background:
Literature describing the application of modern segmental instrumentation to thoracic and lumbar fracture dislocation injuries is limited and the ideal surgical strategy for this severe trauma remains controversial. The purpose of this article was to investigate the feasibility and efficacy of single-stage posterior reduction with segmental instrumentation and interbody fusion to treat this type of injury.
Materials and Methods:
A retrospective review of 30 patients who had sustained fracture dislocation of the spine and underwent single stage posterior surgery between January 2007 and December 2011 was performed. All the patients underwent single stage posterior pedicle screw fixation, decompression and interbody fusion. Demographic data, medical records and radiographic images were reviewed thoroughly.
Results:
Ten females and 20 males with a mean age of 39.5 years were included in this study. Based on the AO classification, 13 cases were Type B1, 4 cases were B2, 4 were C1, 6 were C2 and 3 cases were C3. The average time of the surgical procedure was 220 min and the average blood loss was 550 mL. All of the patients were followed up for at least 2 years, with an average of 38 months. The mean preoperative kyphosis was 14.4° and reduced to -1.1° postoperatively. At the final followup, the mean kyphosis was 0.2°. The loss of correction was small (1.3°) with no significant difference compared to postoperative kyphotic angle (P = 0.069). Twenty seven patients (90%) achieved definitive bone fusion on X-ray or computed tomography imaging within 1 year followup. The other three patients were suspected possible pseudarthrosis. They remained asymptomatic without hardware failure or local pain at the last followup.
Conclusion:
Single stage posterior reduction using segmental pedicle screw instrumentation, combined with decompression and interbody fusion for the treatment of thoracic or lumbar fracture-dislocations is a safe, less traumatic and reliable technique. This procedure can achieve effective reduction, sagittal angle correction and solid fusion.
doi:10.4103/0019-5413.144219
PMCID: PMC4232825  PMID: 25404768
Fracture dislocation; posterior interbody fusion; segmental instrumentation; spine trauma; thoracolumbar spine; Spine; spinal fractures; dislocations; spinal fusion; instrumentation
6.  ERCC1, RRM1 and TUBB3 mRNA expression on the tumor response and overall survival of non-small cell lung cancer treated with platinum-based chemotherapy 
Pakistan Journal of Medical Sciences  2014;30(6):1403-1408.
Objective: We aimed to analyze the expression of ERCC1, RRM1 and TUBB3 in 305 patients with advanced non-small cell lung cancer (NSCLC) and investigate whether these genes can be used as biomarkers for predicting tumor response and clinical outcome.
Methods: Total 305 patients with unresectable and locally advanced NSCLC were collected between January 2007 and December 2008. cDNA of ERCC1, RRM1 and TUBB3 was isolated by a fluorescence-based real-time detection method.
Results: All the patients were followed up until December 2012. One hundred seventy five patients showed good response and 130 patients showed poor response to chemotherapy. 126 patients died and 166 patients showed progressive disease during the follow-up period. The median levels of ERCC1, RRM1 and TUBB3 mRNA were 0.53±0.13, 0.31±0.15 and 0.18±0.16, respectively. We found that patients with low ERCC1 expression showed a significantly higher rate of good tumor response, and the adjusted OR (95% CI) was 2.16(1.32-3.45). By Cox regression analysis. We also found that low ERCC1 expression level were correlated with longer overall survival of NSCLC patients, with the adjusted HR (95% CI) was 2.15 (1.26–3.35).
Conclusion: This study showed that ERCC1 mRNA expression can not affect the response to chemotherapy and clinical outcome of advanced non-small cell lung cancer (NSCLC) patients.
doi:10.12669/pjms.306.5768
PMCID: PMC4320739
ERCC1; RRM1; TUBB3; mRNA; non-small cell lung cancer; Tumor response; Overall survival
7.  Rapid Detection and Differentiation of Clonorchis sinensis and Opisthorchis viverrini Using Real-Time PCR and High Resolution Melting Analysis 
The Scientific World Journal  2014;2014:893981.
Clonorchis sinensis and Opisthorchis viverrini are both important fish-borne pathogens, causing serious public health problem in Asia. The present study developed an assay integrating real-time PCR and high resolution melting (HRM) analysis for the specific detection and rapid identification of C. sinensis and O. viverrini. Primers targeting COX1 gene were highly specific for these liver flukes, as evidenced by the negative amplification of closely related trematodes. Assays using genomic DNA extracted from the two flukes yielded specific amplification and their identity was confirmed by sequencing, having the accuracy of 100% in reference to conventional methods. The assay was proved to be highly sensitive with a detection limit below 1 pg of purified genomic DNA, 5 EPG, or 1 metacercaria of C. sinensis. Moreover, C. sinensis and O. viverrini were able to be differentiated by their HRM profiles. The method can reduce labor of microscopic examination and the contamination of agarose electrophoresis. Moreover, it can differentiate these two flukes which are difficult to be distinguished using other methods. The established method provides an alternative tool for rapid, simple, and duplex detection of C. sinensis and O. viverrini.
doi:10.1155/2014/893981
PMCID: PMC4217323  PMID: 25386621
8.  A designed peptide targeting CXCR4 displays anti-acute myelocytic leukemia activity in vitro and in vivo 
Scientific Reports  2014;4:6610.
Leukemia cells highly expressing chemokine receptor CXCR4 can actively response to stroma derived factor 1α (CXCL12), trafficking and homing to the marrow microenvironment, which causes poor prognosis and relapse. Here we demonstrate that a novel designed peptide (E5) targeting CXCR4 inhibits CXCL12- and stroma-induced activation in multiple acute myelocytic leukemia (AML) cell lines and displays anti-AML activity. We show that E5 has high affinity to multiple AML cells with high CXCR4 level in a concentration dependent manner. E5 significantly inhibits CXCL12- or murine stromal cell (MS-5)-induced migration of leukemia cells and prevents the cells from adhering to stromal cells. Mechanistic studies demonstrate that E5 down-regulates CXCL12-induced phosphorylation of Akt, Erk, and p38, which affects the cytoskeleton F-actin organization and ultimately results in the inhibition of CXCL12- and stroma-mediated leukemia cell responses. E5 can induce concentration-dependent apoptosis in the four AML cell lines tested while did not affect the viability of MS-5 or human umbilical vein cell (ea.hy926) even at 80 µM, both of which have a low level of CXCR4. In vivo experimental results show that immunocompromised mice transplanted with HL-60 cells survived longer when treated with E5 twice a week in comparison to those treated with cyclophosphamide.
doi:10.1038/srep06610
PMCID: PMC4196105  PMID: 25312253
9.  MicroRNA-223-3p Inhibits the Angiogenesis of Ischemic Cardiac Microvascular Endothelial Cells via Affecting RPS6KB1/hif-1a Signal Pathway 
PLoS ONE  2014;9(10):e108468.
Background
MicroRNAs (miRNAs) are a recently discovered class of posttranscriptional regulators of gene expression with critical functions in the angiogenesis and cardiovascular diseases; however, the details of miRNAs regulating mechanism of angiogenesis of ischemic cardiac microvascular endothelial cells (CMECs) are not yet reported.
Methods and Results
This study analyzes the changes of the dynamic expression of miRNAs during the process of angiogenesis of ischemic CMECs by applying miRNA chip and real-time PCR for the first time. Compared with normal CMECs, ischemic CMECs have a specific miRNAs expression profile, in which mir-223-3p has the most significant up-regulation, especially during the process of migration and proliferation, while the up-regulation is the most significant during migration, reaching 11.02 times. Rps6kb1 is identified as a potential direct and functional target of mir-223-3p by applying bioinformatic prediction, real-time PCR and Western blot. Pathway analysis report indicates Rps6kb1 regulates the angiogenesis by participating into hif-1a signal pathway. Further analysis reveals that both the gene and protein expression of the downstream molecules VEGF, MAPK, PI3K and Akt of Rps6kb1/hif-1a signal pathway decrease significantly during the process of migration and proliferation in the ischemic CMECs. Therefore, it is confirmed that mir-223-3p inhibits the angiogenesis of CMECs, at least partly, via intervening RPS6KB1/hif-1a signal pathway and affecting the process of migration and proliferation.
Conclusion
This study elucidates the miRNA regulating law in the angiogenesis of CMECs; mir-223-3p inhibits the process of migration and proliferation of ischemic CMECs probably via affecting RPS6KB1/hif-1a signal pathway, which in turn suppresses the angiogenesis. It is highly possible that mir-223-3p becomes a novel intervention core target in the treatment of angiogenesis of ischemic heart diseases.
doi:10.1371/journal.pone.0108468
PMCID: PMC4196764  PMID: 25313822
10.  Fenobam Sulfate Inhibits Cocaine-Taking and Cocaine-Seeking Behavior in Rats: Implications for Addiction Treatment in Humans 
Psychopharmacology  2013;229(2):253-265.
Rationale
The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be critically involved in drug reward and addiction. Because the mGluR5 negative allosteric modulators (NAMs) MPEP and MTEP significantly inhibit addictive-like behaviors of cocaine and other drugs of abuse in experimental animals, it has been suggested that mGluR5 NAMs may have translational potential for treatment of addiction in humans. However, neither MPEP nor MTEP have been evaluated in humans due to their off-target actions and rapid metabolism.
Objectives
Herein, we evaluate a potential candidate for translational addiction research: a new sulfate salt formulation of fenobam, a selective mGluR5 NAM that has been investigated in humans.
Results
In rats, fenobam sulfate had superior pharmacokinetics compared to the free base, with improved Cmax (maximal plasma concentration) and longer half life. Oral (p.o.) administration of fenobam sulfate (30 or 60 mg/kg) inhibited intravenous cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior and cocaine-associated cue-induced cocaine-seeking behavior in rats. Fenobam sulfate also inhibited oral sucrose self-administration and sucrose-induced reinstatement of sucrose-seeking behavior, but had no effect on locomotion.
Conclusions
This study provides additional support for the role of mGluR5 signaling in cocaine addiction and suggests that fenobam sulfate may have translational potential in medication development for the treatment of cocaine addiction in humans.
doi:10.1007/s00213-013-3106-9
PMCID: PMC4191672  PMID: 23615919
Cocaine; fenobam; self-administration; reinstatement; cocaine-seeking behavior; incubation of cocaine craving; mGluR5
11.  Src family kinases as novel therapeutic targets to treat breast cancer brain metastases 
Cancer research  2013;73(18):5764-5774.
Despite better control of early stage disease and improved overall survival of patients with breast cancer, the incidence of life-threatening brain metastases continues to increase in some of these patients. Unfortunately, other than palliative treatments there is no effective therapy for this condition. In this study, we reveal a critical role for Src activation in promoting brain metastasis in a preclinical model of breast cancer, and we show how a Src-targeting combinatorial regimen can treat HER2+ brain metastases in this model. We found that Src was hyperactivated in brain-seeking breast cancer cells derived from human cell lines or from patients’ brain metastases. Mechanistically, Src activation promoted tumor cell extravasation into the brain parenchyma via permeabilization of the blood-brain barrier. When combined with the EGFR/HER2 dual-targeting drug lapatinib, a Src-targeting combinatorial regimen prevented outgrowth of disseminated breast cancer cells_through the induction of cell cycle arrest. More importantly, this combinatorial regimen inhibited the outgrowth of established experimental brain metastases, prolonging the survival of metastases-bearing mice. Our results provide a rationale for clinical evaluation of Src-targeting regimens to treat breast cancer patients suffering from brain metastasis.
doi:10.1158/0008-5472.CAN-12-1803
PMCID: PMC3781592  PMID: 23913825
Src; Breast cancer; Brain metastasis; Blood brain barrier; Lapatinib; Saracatinib
12.  The Role of Interleukin-28b Gene Polymorphisms in Chinese Patients With Chronic Hepatitis C Treated With Pegylated Interferon and Ribavirin 
Hepatitis Monthly  2014;14(8):e18793.
Background:
Interleukin-28B (IL28B) single nucleotide polymorphism (SNP) rs8099917 has been described to be associated with response to treatment with pegylated interferon and ribavirin (PEG-IFN/RBV) in patients with chronic hepatitis C from the North America, Europe, Asia countries like Japan and Taiwan. Whether this holds true for Chinese patients remains unknown.
Objectives:
We aimed to study the effects of IL28B rs8099917 on antiviral therapy responses in Chinese patients with hepatitis C.
Patients and Methods:
IL28B rs8099917 was genotyped in 263 patients with hepatitis C virus (HCV) infection and 244 healthy controls in Tianjin, China using TaqMan SNP genotyping method. The roles of rs8099917 and clinical characteristics in antiviral treatment were analyzed by logistic regression.
Results:
Among 263 patients with chronic HCV infection, 223 had a TT genotype (84.8%). Frequencies of TG/GG genotypes in patients with hepatitis C were significantly different from those of healthy controls (15.2% vs. 9.0%; P = 0.033). Patients with HCV infection had a higher G allele frequency than healthy controls (7.8% vs. 4.7%; P = 0.044). Univariate analysis revealed no significant association between rs8099917 and sustained virological response (SVR) (P = 0.612). However, it was found that HCV genotypes 2a/3a, age, prothrombin time (PT), albumin (ALB) and cholesterol (CHO) were associated with SVR. In multivariate analysis, only ALB was significantly an independent predictor of SVR (OR = 1.223; 95%CI: 1.046−1.430; P = 0.011).
Conclusions:
In contrast with T, rs8099917 G is a susceptible allele to HCV in China. ALB can independently predict SVR. Rs8099917 may play a quiet role to predict treatment response of patients with hepatitis C who received PEG−IFN/RBV therapy in China.
doi:10.5812/hepatmon.18793
PMCID: PMC4199147  PMID: 25337144
China; Polymorphism; Hepatitis C; Interleukin-28B; Therapy
13.  PanIN-specific regulation of Wnt signaling by HIF2α during early pancreatic tumorigenesis 
Cancer research  2013;73(15):4781-4790.
Hypoxia promotes angiogenesis, proliferation, invasion and metastasis of pancreatic cancer. Essentially all studies of the hypoxia pathway in pancreatic cancer research to date have focused on fully malignant tumors or cancer cell lines, but the potential role of HIFs in the progression of pre-malignant lesions has not been critically examined. Here, we show that HIF2α is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer. HIF2α is a potent oncogenic stimulus but its role in Kras-induced pancreatic neoplasia has not been discerned. We used the Ptf1aCre transgene to activate KrasG12D and delete Hif2α solely within the pancreas. Surprisingly, loss of Hif2α in this model led to not reduced but rather markedly higher number of mPanIN lesions. These low-grade mPanIN lesions, however, failed to progress to high-grade mPanINs, associated with exclusive loss of β-catenin and SMAD4. The concomitant loss of HIF2α as well as β-catenin and Smad4 was further confirmed in vitro, whereby silencing of Hif2α resulted in reduced β-catenin and Smad4 transcription. Thus, with oncogenic Ras expressed in the pancreas, HIF2α modulates Wnt-signaling during mPanIN progression, by maintaining appropriate levels of both Smad4 and β-catenin.
doi:10.1158/0008-5472.CAN-13-0566
PMCID: PMC3736839  PMID: 23749643
Pancreas; cancer; HIF2-alpha; Wnt-signaling; neoplasia
14.  The complete mitochondrial genome of the scab mite Psoroptes cuniculi (Arthropoda: Arachnida) provides insights into Acari phylogeny 
Parasites & Vectors  2014;7:340.
Background
Limited available sequence information has greatly impeded population genetics, phylogenetics and systematics studies in the subclass Acari (mites and ticks). Mitochondrial (mt) DNA is well known to provide genetic markers for investigations in these areas, but complete mt genomic data have been lacking for many Acari species. Herein, we present the complete mt genome of the scab mite Psoroptes cuniculi.
Methods
P. cuniculi was collected from a naturally infected New Zealand white rabbit from China and identified by morphological criteria. The complete mt genome of P. cuniculi was amplified by PCR and then sequenced. The relationships of this scab mite with selected members of the Acari were assessed by phylogenetic analysis of concatenated amino acid sequence datasets by Bayesian inference (BI), maximum likelihood (ML) and maximum parsimony (MP).
Results
This mt genome (14,247 bp) is circular and consists of 37 genes, including 13 genes for proteins, 22 genes for tRNA, 2 genes for rRNA. The gene arrangement in mt genome of P. cuniculi is the same as those of Dermatophagoides farinae (Pyroglyphidae) and Aleuroglyphus ovatus (Acaridae), but distinct from those of Steganacarus magnus (Steganacaridae) and Panonychus citri (Tetranychidae). Phylogenetic analyses using concatenated amino acid sequences of 12 protein-coding genes, with three different computational algorithms (BI, ML and MP), showed the division of subclass Acari into two superorders, supported the monophylies of the both superorders Parasitiformes and Acariformes; and the three orders Ixodida and Mesostigmata and Astigmata, but rejected the monophyly of the order Prostigmata.
Conclusions
The mt genome of P. cuniculi represents the first mt genome of any member of the family Psoroptidae. Analysis of mt genome sequences in the present study has provided new insights into the phylogenetic relationships among several major lineages of Acari species.
doi:10.1186/1756-3305-7-340
PMCID: PMC4223567  PMID: 25052180
Psoroptes cuniculi; Mitochondrial genome; Mitochondrial DNA; Phylogenetic analyses
15.  Identification of miR-140-3p as a marker associated with poor prognosis in spinal chordoma 
Objective: To investigate the expression profile of miR-140-3p in formalin-fixed paraffin-embedded (FFPE) tissues of spinal chordoma, and its correlation with the prognosis of spinal chordoma patients. Methods: Dysregulated miRNAs in FFPE tissues of spinal chordoma were identified by microarray analysis. MiR-140-3p expression in surgically removed spinal chordoma tissues of 42 spinal chordoma patients (27 males and 15 females, aged 29-76 years) and corresponding nucleus pulposus tissues of 14 patients with disc herniation as the healthy control group (8 males and 6 females, aged 24-73 years) was measured by real-time quantitative RT-PCR assay. The association of miR-140-3p expression with clinicopathologic characteristics of spinal chordoma patients was analyzed. Additionally, we investigated the prognostic significance of miR-140-3p with the use of Kaplan-Meier methods and a Cox proportional hazard model. Results: The expression of miR-140-3p was significantly higher in chordoma tissues than nucleus pulposus tissues (t = 3.530, P = 0.001). The expression of miR-140-3p positively correlated with surrounding muscle invasion. The Kapan-Meier survival analysis showed that the patients with high miR-140-3p expression had a significantly worse recurrence-free survival than those with a low expression (χ 2 = 31.270, P = 0.000, log-rank test). In addition, univariate and multivariate analyses for recurrence-free survival showed that miR-140-3p expression was an independent prognostic factor for patients with spinal chordoma (HR = 1.361, 95% CI: 1.135-1.633, P = 0.001). Conclusion: Over-expression of miR-140-3p is correlated with recurrence and tumor invasion, suggesting that miR-140-3p could be a new predictor for recurrence and prognosis in patients with spinal chordoma.
PMCID: PMC4152048  PMID: 25197358
MicroRNA; chordoma; spine; prognosis; recurrence; case-control study
16.  Characterization of the complete mitochondrial genomes of Nematodirus oiratianus and Nematodirus spathiger of small ruminants 
Parasites & Vectors  2014;7:319.
Background
Nematodirus spp. are among the most common nematodes of ruminants worldwide. N. oiratianus and N. spathiger are distributed worldwide as highly prevalent gastrointestinal nematodes, which cause emerging health problems and economic losses. Accurate identification of Nematodirus species is essential to develop effective control strategies for Nematodirus infection in ruminants. Mitochondrial DNA (mtDNA) could provide powerful genetic markers for identifying these closely related species and resolving phylogenetic relationships at different taxonomic levels.
Methods
In the present study, the complete mitochondrial (mt) genomes of N. oiratianus and N. spathiger from small ruminants in China were obtained using Long-range PCR and sequencing.
Results
The complete mt genomes of N. oiratianus and N. spathiger were 13,765 bp and 13,519 bp in length, respectively. Both mt genomes were circular and consisted of 36 genes, including 12 genes encoding proteins, 2 genes encoding rRNA, and 22 genes encoding tRNA. Phylogenetic analyses based on the concatenated amino acid sequence data of all 12 protein-coding genes by Bayesian inference (BI), Maximum likelihood (ML) and Maximum parsimony (MP) showed that the two Nematodirus species (Molineidae) were closely related to Dictyocaulidae.
Conclusions
The availability of the complete mtDNA sequences of N. oiratianus and N. spathiger not only provides new mtDNA sources for a better understanding of nematode mt genomics and phylogeny, but also provides novel and useful genetic markers for studying diagnosis, population genetics and molecular epidemiology of Nematodirus spp. in small ruminants.
doi:10.1186/1756-3305-7-319
PMCID: PMC4105107  PMID: 25015379
Nematodirus oiratianus; Nematodirus spathiger; Mitochondrial genome; Phylogenetic analyses
17.  Self-Assembly and Horizontal Orientation Growth of VO2 Nanowires 
Scientific Reports  2014;4:5456.
Single-crystalline vanadium dioxide (VO2) nanostructures have attracted an intense research interest recently because of their unique single-domain metal-insulator phase transition property. Synthesis of these nanostructures in the past was limited in density, alignment, or single-crystallinity. The assembly of VO2 nanowires (NWs) is desirable for a “bottom-up” approach to the engineering of intricate structures using nanoscale building blocks. Here, we report the successful synthesis of horizontally aligned VO2 NWs with a dense growth mode in the [1-100]quartz direction of a polished x-cut quartz surface using a simple vapor transport method. Our strategy of controlled growth of VO2 NWs promisingly paves the way for designing novel metal-insulator transition devices based on VO2 NWs.
doi:10.1038/srep05456
PMCID: PMC4071308  PMID: 24965899
18.  Detecting Deep Divergence in Seventeen Populations of Tea Geometrid (Ectropis obliqua Prout) in China by COI mtDNA and Cross-Breeding 
PLoS ONE  2014;9(6):e99373.
The tea geometrid (Ectropis obliqua Prout, Lepidoptera: Geometridae) is a dominant chewing insect endemic in most tea-growing areas in China. Recently some E. obliqua populations have been found to be resistant to the nucleopolyhedrovirus (EoNPV), a host-specific virus that has so far been found only in E. obliqua. Although the resistant populations are morphologically indistinguishable from susceptible populations, we conducted a nationwide collection and examined the genetic divergence in the COI region of the mtDNA in E. obliqua. Phylogenetic analyses of mtDNA in 17 populations revealed two divergent clades with genetic distance greater than 3.7% between clades and less than 0.7% within clades. Therefore, we suggest that E. obliqua falls into two distinct groups. Further inheritance analyses using reciprocal single-pair mating showed an abnormal F1 generation with an unbalanced sex ratio and the inability to produce fertile eggs (or any eggs) through F1 self-crossing. These data revealed a potential cryptic species complex with deep divergence and reproductive isolation within E. obliqua. Uneven distribution of the groups suggests a possible geographic effect on the divergence. Future investigations will be conducted to examine whether EoNPV selection or other factors prompted the evolution of resistance.
doi:10.1371/journal.pone.0099373
PMCID: PMC4051655  PMID: 24915522
19.  Activation of the TLR/MyD88/NF-κB Signal Pathway Contributes to Changes in IL-4 and IL-12 Production in Piglet Lymphocytes Infected with Porcine Circovirus Type 2 In Vitro 
PLoS ONE  2014;9(5):e97653.
Porcine circovirus type 2 (PCV2) causes immunosuppression in pigs. One causative factor is an imbalance in cytokine levels in the blood and lymphoid tissues. Many studies have reported changes in cytokine production, but the regulatory mechanisms involved have not yet been elucidated. In this study, we investigated alteration and regulation of IL-4 and IL-12 production in lymphocytes following incubation with PCV2 in vitro. The levels of IL-4 decreased and levels of IL-12 increased in lymphocyte supernatants, and the DNA-binding activity of NF-κB and the expression of p65 in the nucleus and p-IκB in the cytoplasm of lymphocytes increased after incubation with PCV2. However, these effects were reversed when lymphocytes were coincubated with PCV2 and the NF-κB inhibitor BAY11-7082. In addition, the expression of MyD88 protein increased and the expression of mRNA for the toll-like receptors (TLRs) TLR2, TLR3, TLR4 and TLR9 was upregulated when lymphocytes were incubated with PCV2. However, no change was seen in TLR7 and TLR8 mRNA expression. In conclusion, this study showed that PCV2 induced a decrease in IL-4 and an increase in IL-12 production in lymphocytes, and these changes were regulated by the TLR-MyD88-NF-κB signal pathway.
doi:10.1371/journal.pone.0097653
PMCID: PMC4026386  PMID: 24841678
20.  Risk factors for liver-related mortality in chronic hepatitis C patients: A deceased case-living control study 
AIM: To investigate the risk factors for liver-related mortality in chronic hepatitis C (CHC) patients.
METHODS: All deceased CHC inpatient data were collected from the Beijing 302 Hospital clinical database, which includes more than 8250 CHC inpatients during the period from 2002 to 2012. The controls were matched to cases by age (± 2 years), sex and date of hospital admission (within the same year). Potential risk factors were included for the evaluation, and odds ratios (OR) and 95%CI were estimated using univariate (unadjusted) and multivariate (adjusted OR, AOR) conditional logistic regression. All statistical tests were two-sided. P values < 0.05 were considered statistically significant.
RESULTS: Based on examinations of 144 CHC-related deceased cases and 576 controls, we found that antiviral therapy with interferon-α was associated with a 47% decrease in the risk of hepatic mortality (AOR = 0.53, 95%CI: 0.28-0.99, P = 0.048). Additionally, the initial diagnostic stage of the disease (AOR = 2.89, 95%CI: 1.83-4.56 and P < 0.001 for liver cirrhosis/AOR = 8.82, 95%CI: 3.99-19.53 and P < 0.001 for HCC compared with CHC), diabetes (AOR = 2.35, 95%CI: 1.40-3.95, P = 0.001), hypertension (AOR = 1.76, 95%CI: 1.09-2.82, P = 0.020), alcohol consumption (AOR = 1.73, 95%CI: 1.03-2.81, P = 0.037) and HBsAg positivity (AOR = 22.28, 95%CI: 5.58-89.07, P < 0.001) were associated with a significant increase in the risk of liver-related mortality in CHC patients.
CONCLUSION: This study indicates that interferon-α treatment, the stage at the initial diagnosis of the disease and comorbidities are all independent risk factors for liver-related mortality in CHC patients.
doi:10.3748/wjg.v20.i18.5519
PMCID: PMC4017067  PMID: 24833882
Hepatitis C virus; Chronic hepatitis C; Risk factor; Mortality; Case control study
21.  The Significance of Removing Ruptured Intervertebral Discs for Interbody Fusion in Treating Thoracic or Lumbar Type B and C Spinal Injuries through a One-Stage Posterior Approach 
PLoS ONE  2014;9(5):e97275.
Objectives
To identify the negative effect on treatment results of reserving damaged intervertebral discs when treating type B and type C spinal fracture-dislocations through a one-stage posterior approach.
Methods
This is a retrospective review of 53 consecutive patients who were treated in our spine surgery center from January 2005 to May 2012 due to severe thoracolumbar spinal fracture-dislocation. The patients in Group A (24 patients) underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression. In Group B (29 patients), the patients underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression evacuating of the ruptured disc and inserting of a bone graft into the evacuated disc space for interbody fusion. The mean time between injury and operation was 4.1 days (range 2–15 days). The clinical, radiologic and complication outcomes were analyzed retrospectively.
Results
Periodic follow-ups were carried out until an affirmative union or treatment failure took place. A progressive kyphosis angle larger than 10°, loss of disc height, pseudoarthrosis, recurrence of dislocation or subluxation, or instrument failure before fusion were considered treatment failures. Treatment failures were detected in 13 cases in Group A (failure rate was 54.2%). In Group B, there were 28 cases in which definitive bone fusion was demonstrated on CT scans, and CT scans of the other cases demonstrated undefined pseudoarthrosis without hardware failure. There were statistically significant differences between the two groups (p<0.001 chi-square test). The neurologic recoveries, assessed by the ASIA scoring system, were not satisfactory for the neural deficit patients in either group, indicating there was no significant difference with regard to neurologic recovery between the two groups (p>0.05 Fisher's exact test).
Conclusion
Intervertebral disc damage is a common characteristic in type B and C spinal fracture-dislocation injuries. The damaged intervertebral disc should be removed and substituted with a bone graft because reserving the damaged disc in situ increases the risk of treatment failure.
doi:10.1371/journal.pone.0097275
PMCID: PMC4020822  PMID: 24827733
22.  Efficacy and Safety of Sitagliptin Versus Glipizide in Patients With Type 2 Diabetes and Moderate-to-Severe Chronic Renal Insufficiency 
Diabetes Care  2013;36(5):1067-1073.
OBJECTIVE
Patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease have an increased risk of micro- and macrovascular disease, but limited options for antihyperglycemic therapy. We compared the efficacy and safety of sitagliptin with glipizide in patients with T2DM and moderate-to-severe chronic renal insufficiency and inadequate glycemic control.
RESEARCH DESIGN AND METHODS
Patients (n = 426) were randomized 1:1 to sitagliptin (50 mg every day [q.d.] for moderate renal insufficiency and 25 mg q.d. for severe renal insufficiency) or glipizide (2.5 mg q.d., adjusted based on glycemic control to a 10-mg twice a day maximum dose). Randomization was stratified by: 1) renal status (moderate or severe renal insufficiency); 2) history of cardiovascular disease; and 3) history of heart failure.
RESULTS
At week 54, treatment with sitagliptin was noninferior to treatment with glipizide in A1C change from baseline (−0.8 vs. −0.6%; between-group difference −0.11%; 95% CI −0.29 to 0.06) because the upper bound of the 95% CI was less than the prespecified noninferiority margin of 0.4%. There was a lower incidence of symptomatic hypoglycemia adverse events (AEs) with sitagliptin versus glipizide (6.2 and 17.0%, respectively; P = 0.001) and a decrease in body weight with sitagliptin (−0.6 kg) versus an increase (1.2 kg) with glipizide (difference, −1.8 kg; P < 0.001). The incidence of gastrointestinal AEs was low with both treatments.
CONCLUSIONS
In patients with T2DM and chronic renal insufficiency, sitagliptin and glipizide provided similar A1C-lowering efficacy. Sitagliptin was generally well-tolerated, with a lower risk of hypoglycemia and weight loss versus weight gain, relative to glipizide.
doi:10.2337/dc12-1365
PMCID: PMC3631833  PMID: 23248197
23.  Fabrication and Characterization of a Micromachined Swirl-Shaped Ionic Polymer Metal Composite Actuator with Electrodes Exhibiting Asymmetric Resistance 
Sensors (Basel, Switzerland)  2014;14(5):8380-8397.
This paper presents a swirl-shaped microfeatured ionic polymer-metal composite (IPMC) actuator. A novel micromachining process was developed to fabricate an array of IPMC actuators on a glass substrate and to ensure that no shortcircuits occur between the electrodes of the actuator. We demonstrated a microfluidic scheme in which surface tension was used to construct swirl-shaped planar IPMC devices of microfeature size and investigated the flow velocity of Nafion solutions, which formed the backbone polymer of the actuator, within the microchannel. The unique fabrication process yielded top and bottom electrodes that exhibited asymmetric surface resistance. A tool for measuring surface resistance was developed and used to characterize the resistances of the electrodes for the fabricated IPMC device. The actuator, which featured asymmetric electrode resistance, caused a nonzero-bias current when the device was driven using a zero-bias square wave, and we propose a circuit model to describe this phenomenon. Moreover, we discovered and characterized a bending and rotating motion when the IPMC actuator was driven using a square wave. We observed a strain rate of 14.6% and a displacement of 700 μm in the direction perpendicular to the electrode surfaces during 4.5-V actuation.
doi:10.3390/s140508380
PMCID: PMC4063077  PMID: 24824370
IPMC; Nafion; asymmetric electrode; actuator
24.  Broad Suppression of NADPH Oxidase Activity Exacerbates Ischemia/Reperfusion Injury Through Inadvertent Downregulation of HIF-1α and Upregulation of PPARα 
Circulation research  2013;112(8):10.1161/CIRCRESAHA.111.300171.
Rationale
Nox2 and Nox4 are major components of the NADPH oxidase (Nox) family, which purposefully produce reactive oxidative species (ROS), namely O2− and H2O2, in the heart. The isoform-specific contribution of Nox2 and Nox4 to ischemia/reperfusion (I/R) injury is poorly understood.
Objective
We investigated the role of Nox2 and Nox4 in mediating oxidative stress and myocardial injury during I/R using loss of function mouse models.
Methods and Results
Systemic (s) Nox2 KO, sNox4 KO, and cardiac-specific (c) Nox4 KO mice were subjected to I (30 min)/R (24 h). Both myocardial infarct size/area at risk (MI/AAR) and O2− production were lower in sNox2 KO, sNox4 KO, and cNox4 KO than in wild-type (WT) mice. Unexpectedly, however, the MI/AAR was greater, despite less O2− production, in sNox2 KO+cNox4 KO (DKO) mice and transgenic mice with cardiac-specific expression of dominant-negative Nox (Tg-DN-Nox), which suppresses both Nox2 and Nox4, than in WT or single KO mice. Hypoxia-inducible factor-1α (HIF-1α) was downregulated while peroxisome proliferator-activated receptor-alpha (PPARα) was upregulated in Tg-DN-Nox mice. A cross with mice deficient in prolyl hydroxylase 2, which hydroxylates HIF-1α, rescued the I/R injury and prevented upregulation of PPARα in Tg-DN-Nox mice. A cross with PPARα KO mice also attenuated the injury in Tg-DN-Nox mice.
Conclusions
nBoth Nox2 and Nox4 contribute to the increase in ROS and injury by I/R. However, low levels of ROS produced by either Nox2 or Nox4 regulate HIF-1α and PPARα, thereby protecting the heart against I/R, suggesting that Noxs also act as a physiological sensor for myocardial adaptation.
doi:10.1161/CIRCRESAHA.111.300171
PMCID: PMC3871171  PMID: 23476056
Reactive oxygen species; oxidative stress; free radicals; ischemia/reperfusion
25.  Primary Prevention of Macroangiopathy in Patients With Short-Duration Type 2 Diabetes by Intensified Multifactorial Intervention 
Diabetes Care  2013;36(4):978-984.
OBJECTIVE
To explore whether intensified, multifactorial intervention could prevent macrovascular disease in patients with recently diagnosed type 2 diabetes.
RESEARCH DESIGN AND METHODS
A total of 150 type 2 diabetic patients, with disease duration of <1 year and without clinical arteriosclerotic disease or subclinical atherosclerotic signs confirmed by ultrasonographic scanning of three conducting arteries, were randomized into an intensive intervention group and a conventional intervention group. They then received intensive, multifactorial intervention or conventional intervention over 7 years of follow-up. The patients’ common carotid intima-media thicknesses (CC-IMTs) were measured every year. The primary outcome was the time to the first occurrence of CC-IMTs ≥1.0 mm and/or development of atherosclerosis plaques in the carotid artery. The secondary outcome was clinical evidence of cardiovascular disease.
RESULTS
A total of 70 patients in the intensive group and 68 patients in the conventional group completed the 7-year follow-up. Subclinical macrovascular (primary) outcomes occurred in seven cases in the intensive group and 22 cases in the conventional group for a cumulative prevalence of 10.00 and 32.35%, respectively (P < 0.05). No significant differences between the two groups were observed regarding the secondary outcome.
CONCLUSIONS
Primary prevention of macrovascular diseases can be achieved through intensified, multifactorial intervention in patients with short-duration type 2 diabetes. Type 2 diabetic patients should undergo intensive multifactorial interventions with individual targets for the prevention of macrovascular diseases.
doi:10.2337/dc12-0227
PMCID: PMC3609518  PMID: 23230099

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