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author:("Wu, qing")
1.  Immunological characteristics and T-cell receptor clonal diversity in children with systemic juvenile idiopathic arthritis undergoing T-cell-depleted autologous stem cell transplantation 
Immunology  2014;142(2):227-236.
Children with systemic Juvenile Idiopathic Arthritis (sJIA), the most severe subtype of JIA, are at risk from destructive polyarthritis and growth failure, and corticosteroids as part of conventional treatment can result in osteoporosis and growth delay. In children where there is failure or toxicity from drug therapies, disease has been successfully controlled by T-cell-depleted autologous stem cell transplantation (ASCT). At present, the immunological basis underlying remission after ASCT is unknown. Immune reconstitution of T cells, B cells, natural killer cells, natural killer T cells and monocytes, in parallel with T-cell receptor (TCR) diversity by analysis of the β variable region (TCRVb) complementarity determining region-3 (CDR3) using spectratyping and sequencing, were studied in five children with sJIA before and after ASCT. At time of follow up (mean 11·5 years), four patients remain in complete remission, while one child relapsed within 1 month of transplant. The CD8+ TCRVb repertoire was highly oligoclonal early in immune reconstitution and re-emergence of pre-transplant TCRVb CDR3 dominant peaks was observed after transplant in certain TCRVb families. Further, re-emergence of pre-ASCT clonal sequences in addition to new sequences was identified after transplant. These results suggest that a chimeric TCR repertoire, comprising T-cell clones developed before and after transplant, can be associated with clinical remission from severe arthritis.
PMCID: PMC4008230  PMID: 24405357
autologous stem cell transplantation; childhood arthritis; immune reconstitution; T-cell receptor repertoire clonal diversity
2.  Chromatin modifications and genomic contexts linked to dynamic DNA methylation patterns across human cell types 
Scientific Reports  2015;5:8410.
DNA methylation is related closely to sequence contexts and chromatin modifications; however, their potential differences in different genomic regions across cell types remain largely unexplored. We used publicly available genome-scale DNA methylation and histone modification profiles to study their relationships among different genomic regions in human embryonic stem cells (H1), H1-derived neuronal progenitor cultured cells (NPC), and foetal fibroblasts (IMR90) using the Random forests classifier. Histone modifications achieved high accuracy in modelling DNA methylation patterns on a genome scale in the three cell types. The inclusion of sequence features helped improve accuracy only in non-promoter regions of IMR90. Furthermore, the top six feature combinations obtained by mean decrease Gini were important indicators of different DNA methylation patterns, suggesting that H3K4me2 and H3K4me3 are important indicators that are independent of genomic regions and cell types. H3K9me3 was IMR90-specific and exhibited a genomic region-specific correlation with DNA methylation. Variations of essential chromatin modification signals may effectively discriminate changes of DNA methylation between H1 and IMR90. Genes with different co-variations of epigenetic marks exhibited genomic region-specific biological relevance. This study provides an integrated strategy to identify systematically essential epigenetic and genetic elements of genomic region-specific and cell type-specific DNA methylation patterns.
PMCID: PMC4325317  PMID: 25673498
3.  Mucinous tubular and spindle cell carcinoma and solid variant papillary renal cell carcinoma: a clinicopathologic comparative analysis of four cases with similar molecular genetics datum 
Diagnostic Pathology  2014;9(1):194.
Mucinous tubular and spindle cell carcinoma (MTSC) was first recognized as a specific entity in the World Health Organization 2004 classification. The “classic” tumor presentation includes an extracellular blue-gray mucinous/myxoid matrix accompanying the typical tubular and spindle cell epithelial components. Tubules are lined by cuboidal to columnar cells with bland nuclei, central small to medium sized nucleoli, and few to no mitoses. By expanding the histologic spectrum, a number of studies highlighted the distinction between MTSC and solid variant of papillary renal cell carcinoma (sPRCC), although controversy still exists. Here, we evaluated two cases of MTSC and compared two cases of sPRCC by light microscopy, special staining, immunohistochemical staining and fluorescence in situ hybridization (FISH). We found that morphologic and immunophenotyping features showed more overlap between MTSC and sPRCC. In addition, gains of chromosomes 7 and 17 and loss of Y, which are characteristic of PRCC, were observed in two cases of sPRCC and one case of MTSC, suggesting that MTSC is similar to sPRCC or may be a subtype of PRCC.
Virtual Slides: The virtual slide(s) for this article can be found here:
PMCID: PMC4262063  PMID: 25476569
Carcinoma; Renal cell; Mucinous tubular and spindle cell carcinoma; Fluorescence in situ hybridization; Immunohistochemistry
4.  Prognostic role of SPARC expression in gastric cancer: a meta-analysis 
Archives of Medical Science : AMS  2014;10(5):863-869.
Secreted protein acidic and rich in cysteine (SPARC) is involved in regulating cell adhesion, proliferation, migration, and tissue remodeling. We performed a meta-analysis to evaluate the association between SPARC expression and the clinicopathologic features and outcomes of gastric cancer patients.
Material and methods
Publications that assessed the clinical or prognostic significance of SPARC in gastric cancer up to October 2013 were identified. A meta-analysis was performed to clarify the association between SPARC expression and clinical outcomes.
Ten studies, including 1417 cases, met the inclusion criteria. The data were analyzed and the results show that SPARC is not significantly associated with the depth of gastric cancer invasion (odds ratio (OR) = 1.17, 95% confidence interval (CI): 0.60–2.29, Z = 0.47, p = 0.64) or tumor differentiation (OR = 0.59, 95% CI: 0.22–1.58, Z = 1.06, p = 0.29). Moreover, SPARC was not significantly correlated with lymph node metastasis (OR = 0.72, 95% CI: 0.37–1.41, Z = 0.96, p = 0.34). However, SPARC overexpression was highly correlated with reduced overall survival (relative risk (RR) = 1.78, 95% CI: 1.52–2.09, Z = 7.10, p = 0.43).
The SPARC may play an important role in the progression of gastric cancer, and SPARC overexpression is closely correlated with poor patient survival. The SPARC is a potential clinical marker for the survival of gastric cancer patients; however, well-designed prospective studies are needed to confirm these findings.
PMCID: PMC4223132  PMID: 25395936
secreted protein acidic and rich in cysteine; tumor progression; gastric cancer; prognosis
5.  MicroRNA-137 Upregulation Increases Bladder Cancer Cell Proliferation and Invasion by Targeting PAQR3 
PLoS ONE  2014;9(10):e109734.
There is increasing evidence suggesting that dysregulation of some microRNAs (miRNAs) may contribute to tumor progression and metastasis and have been proposed to be key regulators of diverse biological processes such as transcriptional regulation, cell growth and tumorigenesis. Previous studies have shown that miR-137 is dysregulated in some malignancies, but its role in bladder cancer is still unknown. In our study, we find that miR-137 is up-regulated in human bladder cancer tissues and cell lines. Moreover, the higher level of miR-137 was associated with pM or pTNM stage in clinical bladder cancer patients. Enforced expression of miR-137 in bladder cancer cells significantly enhanced their proliferation, migration and invasion. Bioinformatics analysis identified the tumor suppressor gene PAQR3 as a potential miR-137 target gene. Further studies indicated that miR-137 suppressed the expression of PAQR3 by binding to its 3′-untranslated region. Silencing of PAQR3 by small interfering RNAs phenocopied the effects of miR-137 overexpression, whereas restoration of PAQR3 in bladder cancer cells bladder cancer cells overexpressing miR-137, partially reversed the suppressive effects of miR-137. These findings indicate that miR-137 could be a potential oncogene in bladder cancer.
PMCID: PMC4199610  PMID: 25330156
6.  Scorpion Venom Heat-Resistant Peptide (SVHRP) Enhances Neurogenesis and Neurite Outgrowth of Immature Neurons in Adult Mice by Up-Regulating Brain-Derived Neurotrophic Factor (BDNF) 
PLoS ONE  2014;9(10):e109977.
Scorpion venom heat-resistant peptide (SVHRP) is a component purified from Buthus martensii Karsch scorpion venom. Although scorpions and their venom have been used in Traditional Chinese Medicine (TCM) to treat chronic neurological disorders, the underlying mechanisms of these treatments remain unknown. We applied SVHRP in vitro and in vivo to understand its effects on the neurogenesis and maturation of adult immature neurons and explore associated molecular mechanisms. SVHRP administration increased the number of 5-bromo-2’-dexoxyuridine (BrdU)-positive cells, BrdU- positive/neuron-specific nuclear protein (NeuN)-positive neurons, and polysialylated-neural cell adhesion molecule (PSA-NCAM)-positive immature neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) of hippocampus. Furthermore immature neurons incubated with SVHRP-pretreated astrocyte-conditioned medium exhibited significantly increased neurite length compared with those incubated with normal astrocyte-conditioned medium. This neurotrophic effect was further confirmed in vivo by detecting an increased average single area and whole area of immature neurons in the SGZ, SVZ and olfactory bulb (OB) in the adult mouse brain. In contrast to normal astrocyte-conditioned medium, higher concentrations of brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF) was detected in the conditioned medium of SVHRP-pretreated astrocytes, and blocking BDNF using anti-BDNF antibodies eliminated these SVHRP-dependent neurotrophic effects. In SVHRP treated mouse brain, more glial fibrillary acidic protein (GFAP)-positive cells were detected. Furthermore, immunohistochemistry revealed increased numbers of GFAP/BDNF double-positive cells, which agrees with the observed changes in the culture system. This paper describes novel effects of scorpion venom-originated peptide on the stem cells and suggests the potential therapeutic values of SVHRP.
PMCID: PMC4192587  PMID: 25299676
7.  Multiplex sequencing of pooled mitochondrial genomes—a crucial step toward biodiversity analysis using mito-metagenomics 
Nucleic Acids Research  2014;42(22):e166.
The advent in high-throughput-sequencing (HTS) technologies has revolutionized conventional biodiversity research by enabling parallel capture of DNA sequences possessing species-level diagnosis. However, polymerase chain reaction (PCR)-based implementation is biased by the efficiency of primer binding across lineages of organisms. A PCR-free HTS approach will alleviate this artefact and significantly improve upon the multi-locus method utilizing full mitogenomes. Here we developed a novel multiplex sequencing and assembly pipeline allowing for simultaneous acquisition of full mitogenomes from pooled animals without DNA enrichment or amplification. By concatenating assemblies from three de novo assemblers, we obtained high-quality mitogenomes for all 49 pooled taxa, with 36 species >15 kb and the remaining >10 kb, including 20 complete mitogenomes and nearly all protein coding genes (99.6%). The assembly quality was carefully validated with Sanger sequences, reference genomes and conservativeness of protein coding genes across taxa. The new method was effective even for closely related taxa, e.g. three Drosophila spp., demonstrating its broad utility for biodiversity research and mito-phylogenomics. Finally, the in silico simulation showed that by recruiting multiple mito-loci, taxon detection was improved at a fixed sequencing depth. Combined, these results demonstrate the plausibility of a multi-locus mito-metagenomics approach as the next phase of the current single-locus metabarcoding method.
PMCID: PMC4267667  PMID: 25294837
8.  Emerging roles of PDGF-D in EMT progression during tumorigenesis 
Cancer treatment reviews  2012;39(6):640-646.
Platelet-derived growth factor-D (PDGF-D) signaling pathway has been reported to be involved in regulating various cellular processes, such as cell growth, apoptotic cell death, migration, invasion, angiogenesis and metastasis. Recently, multiple studies have shown that PDGF-D plays a critical role in governing Epithelial-to-Mesenchymal Transition (EMT), although the underlying mechanism of PDGF-D-mediated acquisition of EMT is largely unclear. Therefore, this mini review will discuss recent advances in our understanding of the role of PDGF-D in the acquisition of EMT during tumorigenesis. Furthermore, we will summarize the function of chemical inhibitors and natural compounds that are known to inactivate PDGF-D signaling pathway, which leads to the reversal of EMT. In summary, inactivation of PDGF-D could be a novel strategy for achieving better treatment outcome of patients inflicted with cancers.
PMCID: PMC3619006  PMID: 23261166
PDGF-D; EMT; migration; invasion; miRNA; natural compounds; stem cells
9.  NMR Characterization of an Oligonucleotide Model of the MiR-21 Pre-Element 
PLoS ONE  2014;9(9):e108231.
We have used NMR spectroscopy to characterize an oligonucleotide stem loop structure based on the pre-element of an oncogenic microRNA, miR-21. This predicted stem-loop structure is cleaved from the precursor of miR-21 (pre-miR-21) by the nuclease Dicer. It is also a critical feature recognized by the protein complex that converts the primary transcript (pri-miR-21) into the pre-miRNA. The secondary structure of the native sequence is poorly defined by NMR due to rapid exchange of imino protons with solvent; however, replacement of two adjacent putative G•U base pairs with G•C base pairs retains the conformation of the hairpin observed by chemical probing and stabilizes it sufficiently to observe most of the imino proton resonances of the molecule. The observed resonances are consistent with the predicted secondary structure. In addition, a peak due to a loop uridine suggests an interaction between it and a bulged uridine in the stem. Assignment of non-exchangeable proton resonances and characterization of NOEs and coupling constants allows inference of the following features of the structure: extrahelicity of a bulged adenosine, deviation from A-form geometry in a base-paired stem, and consecutive stacking of the adenosines in the 5′ side of the loop, the guanosine of the closing base pair, and a cross-strand adenosine. Modeling of the structure by restrained molecular dynamics suggests a basis for the interaction between the loop uridine, the bulged uridine in the stem, and an A•U base pair in the stem.
PMCID: PMC4177108  PMID: 25250627
10.  A Test Data Compression Scheme Based on Irrational Numbers Stored Coding 
The Scientific World Journal  2014;2014:982728.
Test question has already become an important factor to restrict the development of integrated circuit industry. A new test data compression scheme, namely irrational numbers stored (INS), is presented. To achieve the goal of compress test data efficiently, test data is converted into floating-point numbers, stored in the form of irrational numbers. The algorithm of converting floating-point number to irrational number precisely is given. Experimental results for some ISCAS 89 benchmarks show that the compression effect of proposed scheme is better than the coding methods such as FDR, AARLC, INDC, FAVLC, and VRL.
PMCID: PMC4166428  PMID: 25258744
11.  Hypomethylation at the Regulatory T Cell–Specific Demethylated Region in CD25hi T Cells Is Decoupled from FOXP3 Expression at the Inflamed Site in Childhood Arthritis 
The maintenance of FOXP3 expression in CD25hi regulatory T cells (Tregs) is crucial to the control of inflammation and essential for successful Treg transfer therapies. Coexpression of CD25 and FOXP3 in combination with a hypomethylated region within the FOXP3 gene, called the Treg-specific demethylated region (TSDR), is considered the hallmark of stable Tregs. The TSDR is an epigenetic motif that is important for stable FOXP3 expression and is used as a biomarker to measure Treg lineage commitment. In this study, we report that, unlike in peripheral blood, CD4+ T cell expression of CD25 and FOXP3 is frequently dissociated at the inflamed site in patients with juvenile idiopathic arthritis, which led us to question the stability of human Tregs in chronic inflammatory environments. We describe a novel CD4+CD127loCD25hi human T cell population that exhibits extensive TSDR and promoter demethylation in the absence of stable FOXP3 expression. This population expresses high levels of CTLA-4 and can suppress T conventional cell proliferation in vitro. These data collectively suggest that this population may represent a chronically activated FOXP3lo Treg population. We show that these cells have defects in IL-2 signaling and reduced expression of a deubiquitinase important for FOXP3 stability. Clinically, the proportions of these cells within the CD25hi T cell subset are increased in patients with the more severe courses of disease. Our study demonstrates, therefore, that hypomethylation at the TSDR can be decoupled from FOXP3 expression in human T cells and that environment-specific breakdown in FOXP3 stability may compromise the resolution of inflammation in juvenile idiopathic arthritis.
PMCID: PMC4157061  PMID: 25092890
12.  Poor infant and young child feeding practices and sources of caregivers’ feeding knowledge in rural Hebei Province, China: findings from a cross-sectional survey 
BMJ Open  2014;4(7):e005108.
To obtain a general overview of infant and young child feeding practices in one rural county in China and identify current delivery channels and challenges.
A cross-sectional study.
A rural county, Zhao County, in Hebei Province, China.
10 clusters were first selected within each township (16 townships in total) with proportional to population size sampling. In each cluster, a name list was used to select 13 children aged 0–23 months. We interviewed caregivers of all the selected children.
Primary and secondary outcomes measures
Coverage of infant feeding practices, reasons for low coverage of infant feeding practices and current delivery channels of infant feeding practices.
Findings from our survey indicated that infant feeding practices were poor. Early initiation of breastfeeding was only 22.4%, exclusive breastfeeding for 6 months was less than 10% and continued breastfeeding up to the age of two was just 38.2%. Only 32.5% of children were given iron-rich or iron-fortified foods. The leading sources of infant feeding information were family members, neighbours, friends and popular media. Only around 20% of the information came from health facilities and nearly none came from communities. Household property data showed that 99.9% of households owned televisions and 99.4% owned mobile phones. In addition, 61.2% of the households owned computers, with 54.8% having access to the internet.
Few caregivers of children in Zhao County received feeding information during pregnancy and after delivery. Moreover, their feeding knowledge and practices were poor. Multi-channel approaches, delivered through health facilities, community resources, popular media, the internet and mobile phones, hold potential to improve infant feeding practices and should be explored in future studies.
Strengths and limitations
Although this study took place only within one county, a full range of globally standard feeding indicators was used to assess the feeding practices of caregivers in our study. The name lists of children in some villages may not be complete, and therefore selection bias may have occurred. Some indicators may have recall bias due to long recall time.
Trial registration number
PMCID: PMC4120327  PMID: 25079931
Nutrition & Dietetics; Public Health
13.  Genome Sequence of Borrelia garinii Strain SZ, Isolated in China 
Genome Announcements  2014;2(4):e00010-14.
We announce the genome sequence of Borrelia garinii strain SZ, isolated from Dermacentor ticks collected in northeastern China. B. garinii strain SZ carries numerous plasmids, both 10 circular and 9 linear plasmids. The 902,487-bp linear chromosome (28.2% GC content) contains 820 open reading frames, 33 tRNAs, and 4 complete rRNAs. The plasmid cp32-10 contains one clustered regularly interspaced short palindromic repeat (CRISPR) with four repeats.
PMCID: PMC4102854  PMID: 25035317
14.  Combining direct and proxy assessments to reduce attrition bias in a longitudinal study 
Retaining severely impaired individuals poses a major challenge in longitudinal studies of determinants of dementia or memory decline. In the Health and Retirement Study (HRS), participants complete direct memory assessments biennially until they are too impaired to complete the interview. Thereafter, proxy informants, typically spouses, assess the subject’s memory and cognitive function using standardized instruments. Because there is no common scale for direct memory assessments and proxy assessments, proxy reports are often excluded from longitudinal analyses. The Aging and Demographics Memory Study (ADAMS) implemented full neuropsychological exams on a subsample (n=856) of HRS participants, including respondents with direct or proxy cognitive assessments in the prior HRS core interview. Using data from ADAMS, we developed an approach to estimating a dementia probability and a composite memory score based on either proxy or direct assessments in HRS core interviews. The prediction model achieved a c-statistic of 94.3% for DSM diagnosed dementia in the ADAMS sample. We applied these scoring rules to HRS core sample respondents born 1923 or earlier (n=5,483) for biennial assessments 1995-2008. Compared to estimates excluding proxy respondents in the full cohort, incorporating information from proxy respondents increased estimated prevalence of dementia by 12 percentage points in 2008 (average age = 89) and suggested accelerated rates of memory decline over time.
PMCID: PMC3731387  PMID: 22992720
Dementia; Memory decline; HRS; Cognitive assessments; Proxy informants
15.  Biological Role of Trichoderma harzianum-Derived Platelet-Activating Factor Acetylhydrolase (PAF-AH) on Stress Response and Antagonism 
PLoS ONE  2014;9(6):e100367.
We investigated the properties of platelet-activating factor acetylhydrolase (PAF-AH) derived from Trichoderma harzianum. The enzyme, comprised of 572 amino acids, shares high homology with PAF-AH proteins from T. koningii and other microbial species. The optimum enzymatic activity of PAF-AH occurred at pH 6 in the absence of Ca2+ and it localized in the cytoplasm, and we observed the upregulation of PAF-AH expression in response to carbon starvation and strong heat shock. Furthermore, PAF-AH knockout transformant growth occurred more slowly than wild type cells and over-expression strains grown in SM medium at 37°C and 42°C. In addition, PAF-AH expression significantly increased under a series of maize root induction assay. Eicosanoic acid and ergosterol levels decreased in the PAF-AH knockouts compared to wild type cells, as revealed by GC/MS analysis. We also determined stress responses mediated by PAF-AH were related to proteins HEX1, Cu/Zn superoxide dismutase, and cytochrome c. Finally, PAF-AH exhibited antagonistic activity against Rhizoctonia solani in plate confrontation assays. Our results indicate PAF-AH may play an important role in T. harzianum stress response and antagonism under diverse environmental conditions.
PMCID: PMC4070952  PMID: 24964161
16.  Experimental Study on Effect of Simulated Microgravity on Structural Chromosome Instability of Human Peripheral Blood Lymphocytes 
PLoS ONE  2014;9(6):e100595.
Experimental study was made by keeping human peripheral blood lymphocytes under simulated microgravity in a Rotary Cell Culture System bioreactor to investigate the changes that occur in the number of chromosomes, the expression rate of chromosome fragile site, and the expressions of DNA replication- and repair-related genes. Experimental results indicate simulated microgravity has no effect on the numerical chromosome instability of human peripheral blood lymphocytes, but it enhances the structural chromosome instability of human peripheral blood lymphocytes through the inhibition of DNA replication and the reduction of DNA repair. So, the mechanism of chromosome fragile site induced by simulated microgravity can be explained using the changes that occur in the chromosome structure of human peripheral blood lymphocytes, the DNA replication and repair under the effect of simulated microgravity.
PMCID: PMC4070949  PMID: 24963972
17.  Expression of ALDH1 and TGFβ2 in benign and malignant breast tumors and their prognostic implications 
The specific mechanism underlying the role of putative stem cell marker aldehyde dehydrogenase 1 (ALDH1) playing in development and progression of breast cancer is currently unclear. Transforming growth factor β (TGFβ) signaling pathway is reported to be activated in most cancers. Thus a study was initiated to explore possible differences and correlation of ALDH1 and TGFβ2 expression in the most common malignant and benign tumors of the breast in Chinese women. Samples of 75 breast cancer tissues, 30 paracancerous normal tissues, and 39 fibroadenoma breast tissues were investigated for the expression of ALDH1 and TGFβ2 using immunohistochemistry. The positive rates of ALDH1 and TGFβ2 protein were 62.67% and 66.67%, respectively, in breast cancer tissues, which were significantly higher than that in normal fibroadenoma breast (P<0.05) and paracancerous tissues (P<0.01). ALDH1 and TGFβ2 status were significantly associated with tumor histological grade and receptor status (P<0.05). Expression of ALDH1 was found to be positively correlative to TGFβ2 in breast cancer (r = 0.33, P<0.01). Expression of both proteins remained significantly associated with reduced overall survival (OS) by univariate analysis (P<0.05). Multivariate Cox regression analysis showed that ALDH1 expression, tumor stage, and lymph node status are independent prognostic factors in invasive breast cancer patients. Thus ALDH1 and TGFβ2 play important roles in the development of breast cancer. The ALDH1 phenotype is an independent predictor of poor prognosis, and TGFβ2 signaling pathway activation might be involved in the pathological regulation of ALDH1 in breast cancer.
PMCID: PMC4129032  PMID: 25120797
ALDH1; TGFβ2; breast cancer; fibroadenoma; stem-like cells; prognosis
18.  Is right ventricular mid-septal pacing superior to apical pacing in patients with high degree atrio-ventricular block and moderately depressed left ventricular function?*  
Objective: We are aimed to investigate whether right ventricular mid-septal pacing (RVMSP) is superior to conventional right ventricular apical pacing (RVAP) in improving clinical functional capacity and left ventricular ejection fraction (LVEF) for patients with high-degree atrio-ventricular block and moderately depressed left ventricle (LV) function. Methods: Ninety-two patients with high-degree atrio-ventricular block and moderately reduced LVEF (ranging from 35% to 50%) were randomly allocated to RVMSP (n=45) and RVAP (n=47). New York Heart Association (NYHA) functional class, echocardiographic LVEF, and distance during a 6-min walk test (6MWT) were determined at 18 months after pacemaker implantation. Serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured using an enzyme-linked immunosorbent assay (ELISA) kit. Results: Compared with baseline, NYHA functional class remained unchanged at 18 months, distance during 6MWT (485 m vs. 517 m) and LVEF (36.7% vs. 41.8%) were increased, but BNP levels were reduced (2352 pg/ml vs. 710 pg/ml) in the RVMSP group compared with those in the RVAP group, especially in patients with LVEF 35%–40% (for all comparisons, P<0.05). However, clinical function capacity and LV function measurements were not significantly changed in patients with RVAP, despite the pacing measurements being similar in both groups, such as R-wave amplitude and capture threshold. Conclusions: RVMSP provides a better clinical utility, compared with RVAP, in patients with high-degree atrioventricular block and moderately depressed LV function whose LVEF levels ranged from 35% to 40%.
PMCID: PMC4116854  PMID: 24903987
Mid-septal pacing; Apical pacing; Impaired heart function
19.  Pharmacokinetics of liver-targeted docetaxel liposomes modified with 6-O-acyl-D-galactose esters in rabbits 
Biomedical Reports  2014;2(4):545-548.
The purpose of the present study was to investigate the pharmacokinetics of docetaxel liposomes modified with 6-O-acyl-D-galactose esters (Gal-DOC-L) in rabbits. A simple, rapid and sensitive high-performance liquid chromatography (HPLC) method was developed for the determination of docetaxel. Gal-DOC-L was intravenously administered to rabbits with norethisterone as the internal standard and the blood samples were collected from ear marginal veins at 0.083, 0.25, 0.5, l, 2, 4, 6, 8, 12, 16 and 24 h after treatment. The plasma concentration of docetaxel was determined by HPLC and the pharmacokinetic parameters were calculated. Docetaxel injection (DOC-I) was studied simultaneously. The results showed that the area under the curve(0-∞), t1/2α and t1/2β of Gal-DOC-L was significantly higher, while the total body clearance was lower than that of DOC-I. The results indicated that Gal-DOC-L was able to maintain a relatively high blood concentration in vivo and prolong the treatment time.
PMCID: PMC4051490  PMID: 24944805
pharmacokinetics; docetaxel liposomes; 6-O-acyl-D-galactose; high-performance liquid chromatography
20.  Expression and Imprinting Analysis of AK044800, a Transcript from the Dlk1-Dio3 Imprinted Gene Cluster during Mouse Embryogenesis 
Molecules and Cells  2013;35(4):285-290.
Recent advances of induced pluripotent stem cells (iPSCs) has demonstrated that full development potential is closely related with the expression state of non-coding RNAs (ncRNAs) of the Dlk1-Dio3 imprinted gene cluster. However, few of them, especially the long noncoding RNAs (lncRNAs), have been characterized in detail. AK044800 is a transcript from the Dlk1-Dio3 imprinted region with little known information. This study reports original data on the expression pattern of AK044800 during embryogenesis. Expression analysis showed that AK044800 was specifically expressed in the brain at mid-gestation, E9.5 and E11.5. And at E15.5, its expression was mainly concentrated in the forebrain. In the late-gestation stage (E18.5), AK044800 expression was weaker in the brain and began to emerge in some other tissues during this period. Notably, the expression of AK044800 was biallelic in the brain, unlike other non-coding transcripts from this imprinted region. In addition, its expression was dependent on inbred mouse strains. This may be the first lncRNA that has been identified with a different expression between inbred mouse strains. This study may provide useful clues for further investigations of expression regulation and functions of lncRNAs of the Dlk1-Dio3 imprinted region.
PMCID: PMC3887882  PMID: 23515577
AK044800; expression patterns; imprinting analysis; inbred mouse strains; long non-coding RNAs
21.  Kidney Diseases Enhance Expression of Tetraspanin-8: A Possible Protective Effect against Tubular Injury 
Nephron Extra  2014;4(1):70-81.
TSPAN8 encoding tetraspanin-8 was identified as a candidate gene for immunoglobulin A nephropathy (IgAN) by a genome-wide association study using microsatellites in the Japanese population. Tetraspanin-8 is a cell surface protein that contributes to the migration and invasion of epithelial cells.
We performed immunohistochemistry for tetraspanin-8 on human renal biopsy specimens associated with IgAN, antineutrophil cytoplasmic antibody-associated nephropathy and interstitial nephritis, as well as normal renal tissue. Furthermore, to study the potential function of tetraspanin-8, we performed cell migration and invasion assays using human renal tubule cells transfected with tetraspanin-8.
Tetraspanin-8 was often expressed in vascular smooth muscle cells and occasionally in tubule cells in normal kidney. In the kidneys of all types of nephropathy, tetraspanin-8 staining in the arteries was unaffected, but that in the tubules was enhanced. The degree of tubular staining negatively correlated with the estimated glomerular filtration rate, independently of the type of nephropathy. Tetraspanin-8-expressing tubule cells were found predominantly in distal and collecting tubules, identified by cytokeratin 7 or aquaporin 2 staining. In vitro studies using cultured tubule cells revealed that tetraspanin-8 promoted migration by 2.7-fold without laminin, by 2.8-fold with laminin and invasion into Matrigel by 3.5-fold, suggesting that enhanced tetraspanin-8 may be involved in the repair of tubules.
The obtained findings indicate that tetraspanin-8 expression is enhanced in injured distal tubules, which may be involved in the repair of tubules by facilitating migration and invasion.
PMCID: PMC4036207  PMID: 24926311
Immunoglobulin A nephropathy; Tetraspanin; Tubulointerstitial injury; Migration

23.  Clinical research of genetically modified dendritic cells in combination with cytokine-induced killer cell treatment in advanced renal cancer 
BMC Cancer  2014;14:251.
Renal cell carcinoma (RCC) is a malignant disease that demonstrates resistance to standard chemotherapeutic agents. Yet Active immunization using genetically modified dendritic cells holds promise for the adjuvant treatment of malignancies to eradicate or control residual disease. Cytokine-induced killer (CIK) cells are a heterogeneous population of effector CD8+ T cells with diverse TCR specificities, possessing non-MHC-restricted cytolytic activities against tumor cells. Clinical studies have confirmed benefit and safety of CIK cell-based therapy for patients with malignancies. This clinical trial was conducted to evaluate efficacy and safety of genetically modified dendritic cells in combination with Cytokine-Induced Killer Cell (gmDCs-CIK) treatment of patients with RCC.
28 patients with advanced renal cancer were admitted to Affiliated Hospital of Academy of Military Medical Sciences from December 2010 to March 2012 and treated by gmDCs-CIK. Clinical efficacy and safety between pre- and post-treatment were compared.
This analysis showed an objective response rate (ORR) of 39% and a disease control rate (DCR) of as 75%. There is no significant relationship between clinical efficacy and whether metastasis occurred or not (P > 0.05). There is no significant relationship between ORR and cycles of treatment (P > 0.05), but DCR was significantly related with cycles of treatment (P < 0.05). No clinically significant side effects were observed. There were no significant changes of T cell subsets including CD3+, CD4+, CD8+, CD4+ CD25+ Treg cells except Th1 in peripheral blood between day 30 after immunotherapy and 1 day before immunotherapy in 11 patients.
DC-CIK is feasible and effective in treating advanced renal cancer and thus provides a new approach.
Trial registration Identifier: NCT01924156. Registration date: August 14, 2013.
PMCID: PMC3997215  PMID: 24720900
Clinical research; Dendritic cells; Cytokine-Induced Killer cell; Advanced renal cancer
24.  Endocardial focal activation originating from Purkinje fibers plays a role in the maintenance of long duration ventricular fibrillation 
Croatian Medical Journal  2014;55(2):121-127.
To determine the role of repetitive endocardial focal activations and Purkinje fibers in the maintenance of long duration ventricular fibrillation (LDVF, VF>1 minute) in canine hearts in vivo.
The study was conducted in electrophysiological laboratory of Shanghai Ruijin hospital from July 2010 to August 2012. A 64-electrode basket was introduced through a carotid artery into the left ventricle (LV) of 11 beagle dogs for global endocardial electrical mapping. In the Lugol’s solution group (n = 5), the subendocardium was ablated by washing with Lugol’s solution. In the control group, (n = 6) saline was used for ablation. Before and after saline or Lugol ablation, we determined QRS duration and QT/QTc interval in sinus rhythm (SR). We also measured the activation rates in the first 2 seconds of each minute during 7 minutes of VF for each group. If VF terminated spontaneously in less than 7 minutes, the VF segments used in activation rate analysis were reduced accordingly.
At the beginning of VF there was no difference between the groups in the activation rate. However, after 1 minute of LDVF the Lugol’s solution group had significantly slower activation rate than the control group. In the control group, all episodes of LDVF (6/6) were successfully sustained for 7 minutes, while in the Lugol’s solution group 4/5 episodes of LDVF spontaneously terminated before 7 minutes (4.8 ± 1.4 minutes) (P = 0.015). In the control group, at 5.1 ± 1.3 minutes of LDVF, a successive, highly organized focal LV endocardial activation pattern was observed. During this period, activations partly arose in PF and spread to the working ventricular myocardium. Mapping analysis showed that these events were consistent with repetitive endocardial focal activations. No evidence of similar focal activations was observed in the Lugol’s solution group.
Repetitive endocardial focal activations in the LV endocardium may be associated with activation of subendocardial PFs. This mechanism may play an important role in the maintenance of LDVF.
PMCID: PMC4009712  PMID: 24778098
25.  Effectiveness of a smart phone app on improving immunization of children in rural Sichuan Province, China: study protocol for a paired cluster randomized controlled trial 
BMC Public Health  2014;14:262.
Although good progress has been achieved in expanding immunization of children in China, disparities exist across different provinces. Information gaps both from the service supply and demand sides hinder timely vaccination of children in rural areas. The rapid development of mobile health technology (mHealth) provides unprecedented opportunities for improving health services and reaching underserved populations. However, there is a lack of literature that rigorously evaluates the impact of mHealth interventions on immunization coverage as well as the usability and feasibility of smart phone applications (apps). This study aims to assess the effectiveness of a smart phone-based app (Expanded Program on Immunization app, or EPI app) on improving the coverage of children’s immunization.
This cluster randomized trial will take place in Xuanhan County, Sichuan Province, China. Functionalities of the app include the following: to make appointments automatically, record and update children’s immunization information, generate a list of children who missed their vaccination appointments, and send health education information to village doctors. After pairing, 36 villages will be randomly allocated to the intervention arm (n = 18) and control arm (n = 18). The village doctors in the intervention arm will use the app while the village doctors in the control arm will record and manage immunization in the usual way in their catchment areas. A household survey will be used at baseline and at endline (8 months of implementation). The primary outcome is full-dose coverage and the secondary outcome is immunization coverage of the five vaccines that are included in the national Expanded Program on Immunization program as well as Hib vaccine, Rotavirus vaccine and Pneumococcal conjugate vaccine. Multidimensional evaluation of the app will also be conducted to assess usability and feasibility.
This study is the first to evaluate the effectiveness of a smart phone app for child immunization in rural China. This study will contribute to the knowledge about the usability and feasibility of a smart phone app for managing immunization in rural China and to similar populations in different settings.
Trial registration
Chinese Clinical Trials Registry (ChiCTR): ChiCTR-TRC-13003960
PMCID: PMC3999920  PMID: 24645829
Randomized controlled trial; Immunization [MeSH]; Usability; Feasibility Studies [MeSH]

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