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1.  Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency 
The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired antigen-induced lymphocyte proliferation, reduced cytokine production by CD8+ T lymphocytes, and decreased numbers of natural killer (NK) cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.
PMCID: PMC4355235  PMID: 25667416
2.  Prospective Study of Optimal Obesity Index Cut-Off Values for Predicting Incidence of Hypertension in 18–65-Year-Old Chinese Adults 
PLoS ONE  2016;11(3):e0148140.
Overweight and obesity increase the risk of elevated blood pressure; most of the studies that serve as a background for the debates on the optimal obesity index cut-off values used cross-sectional samples. The aim of this study was to determine the cut-off values of anthropometric markers for detecting hypertension in Chinese adults with data from prospective cohort.
This study determines the best cut-off values for the obesity indices that represent elevated incidence of hypertension in 18–65-year-old Chinese adults using data from the China Health and Nutrition Survey (CHNS) 2006–2011 prospective cohort. Individual body mass index (BMI), waist circumference (WC), waist:hip ratio (WHR) and waist:stature ratio (WSR) were assessed. ROC curves for these obesity indices were plotted to estimate and compare the usefulness of these obesity indices and the corresponding values for the maximum of the Youden indices were considered the optimal cut-off values.
Five-year cumulative incidences of hypertension were 21.5% (95% CI: 19.4–23.6) in men and 16.5% (95% CI: 14.7–18.2) in women, and there was a significant trend of increased incidence of hypertension with an increase in BMI, WC, WHR or WSR (P for trend < 0.001) in both men and women. The Youden index indicated that the optimal BMI, WC, WHR, WSR cut-off values were 23.53 kg/m2, 83.7 cm, 0.90, and 0.51 among men. The optimal BMI, WC, WHR, WSR cut-off values were 24.25 kg/m2, 79.9 cm, 0.85 and 0.52 among women.
Our study supported the hypothesis that the cut-off values for BMI and WC that were recently developed by the Working Group on Obesity in China (WGOC), the cut-off values for WHR that were developed by the World Health Organization (WHO), and a global WSR cut-off value of 0.50 may be the appropriate upper limits for Chinese adults.
PMCID: PMC4775051  PMID: 26934390
3.  MRS in Mild Cognitive Impairment: Early Differentiation of Dementia with Lewy Bodies and Alzheimer's Disease 
Background and Purpose
Mild cognitive impairment (MCI) precedes both Alzheimer's disease (AD) dementia and with Lewy bodies (DLB). We investigated proton magnetic resonance spectroscopy (MRS) characteristics of MCI patients who progressed to DLB compared to those who progressed to AD dementia or remained stable.
Consecutive MCI patients who underwent single voxel MRS at baseline and progressed to DLB (n=10) were identified during a median follow-up period of 18 months. From the same cohort, we identified age- and sex-matched MCI patients who progressed to AD dementia (n=27) or remained stable (n=20) during a similar follow-up period. This study was approved by the Institutional Review Board and informed consent was from every subject.
MCI patients who progressed to AD dementia were characterized by lower N-acetylaspartate (NAA)/Cr ratio in the posterior cingulate voxel compared to those who progressed to DLB (p=0.001). Decreased NAA/Cr in the posterior cingulate voxel differentiated MCI patients who progressed to DLB from those who progressed to AD with an area under the receiver operating characteristic curve of 0.85 (p<0.001) on logistic regression analysis.
MRS may be useful in differentiating MCI patients with prodromal AD dementia from those with prodromal DLB for early disease-specific interventions.
PMCID: PMC4295004  PMID: 25039916
Magnetic resonance spectroscopy (MRS); mild cognitive impairment (MCI); dementia with Lewy Bodies (DLB); Alzheimer's disease; MRI
4.  Hydrogen sulfide inhalation decreases early blood–brain barrier permeability and brain edema induced by cardiac arrest and resuscitation 
The effects of hydrogen sulfide (H2S) on blood–brain barrier (BBB) and brain edema after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) remain poorly understood. We investigated the effects of exogenous 80-p.p.m. H2S gas on BBB, brain water content, neurologic outcome, and survival rate after CA and CPR. Cardiopulmonary resuscitation followed CA induced in rats by ventricular fibrillation for 6 minutes. Results show that inhalation of 80-p.p.m. H2S significantly reduced the permeability of the BBB in both in the cortex and hippocampus at 24 hours after resuscitation. Hydrogen sulfide also lessened brain edema in the cortex and hippocampus, ameliorated neurologic outcome as evaluated by neurologic deficit score and tape removal test, and improved the 14-day survival rate. Hydrogen sulfide also attenuated CA and CPR-induced increases of matrix metalloproteinase-9 (MMP-9) activity and vascular endothelial growth factor (VEGF) expression, and increased the expression of angiogenin-1 (Ang-1). These results indicate that inhalation of 80-p.p.m. H2S immediately after CPR attenuated BBB permeability and brain edema, and improved neurologic outcome and 14-day survival of rats after CA. The therapeutic benefits of H2S could be associated with suppression of MMP-9 and VEGF expression and increased expression of Ang-1.
PMCID: PMC4348391  PMID: 25492119
blood–brain barrier; brain recovery; cardiac arrest; cardiopulmonary resuscitation; hydrogen sulfide; matrix proteins
5.  MiR-1180 promotes apoptotic resistance to human hepatocellular carcinoma via activation of NF-κB signaling pathway 
Scientific Reports  2016;6:22328.
Apoptosis resistance in human hepatocellular carcinoma (HCC) is a significant factor in carcinogenesis. Therefore, understanding the molecular mechanisms involved in apoptosis resistance is crucial for developing anticancer therapies. Importantly, small non-coding microRNAs (miRNAs) have been reported as key biomarkers for detecting tumour onset and progression. In the present study, we demonstrate that miR-1180 is upregulated in HCC. Ectopic expression of miR-1180 has an anti-apoptotic effect in HCC, while miR-1180 inhibition increases cell apoptosis, both in vitro and in vivo. Moreover, our results show that miR-1180 directly targets key inhibitors of the nuclear factor (NF)-κB signaling pathway (i.e., OTUD7B and TNIP2) and the pro-apoptotic Bcl-2 associated death promoter (BAD) protein by post-transcriptional downregulation. Therefore, the anti-apoptotic function of miR-1180 in HCC may occur through NF-κB pathway activation via downregulation of its negative regulators. In conclusion, our study reveals the critical role of miR-1180 during apoptosis resistance in HCC.
PMCID: PMC4772113  PMID: 26928365
6.  C14orf166 overexpression correlates with tumor progression and poor prognosis of breast cancer 
Chromosome 14 open reading frame 166 (C14orf166) is upregulated in various tumors, but its role in breast cancer has not been reported.
Quantitative real-time PCR and western blot were used to determine C14orf166 expression in normal breast epithelial cells (NBEC), breast cancer cells, and four matched pairs of breast cancer tissues and adjacent noncancerous tissues. Using immunohistochemistry, we determined C14orf166 expression in paraffin-embedded tissues from 121 breast cancer patients. Statistical analyses were performed to examine the associations among C14or166 expression, clinicopathological parameters and prognosis outcome of breast cancer. MTT and colony formation assay were used to determine the effect of C14orf166 on cell proliferation by overexpression or knockdown of C14orf166 level.
C14orf166 was upregulated in breast cancer cell lines and tissues compared with the normal cells and adjacent normal breast tissues, high C14orf166 expression was positively with advancing clinical stage. The correlation analysis between C14orf166 expression and clinicopathological characteristics suggested C14orf166 expression was significantly correlated with clinical stages, T classification, N classification and PR expression, Kaplan–Meier curves with log rank tests showed patients with low C14orf166 expression had better survival, Cox-regression analysis suggested C14orf166 was an unfavorable prognostic factor for breast cancer patients. C14orf166 overexpression promoted breast cancer cell proliferation, whereas knockdown of C14orf166 inhibited this effect. Further analysis found C14orf166 overexpression inhibited cell cycle inhibitors P21 and P27 expression, and increased the levels of Cyclin D1 and phosphorylation of Rb, suggesting C14orf166 contributed to cell proliferation by regulating G1/S transition.
Our findings suggested C14orf166 could be a novel prognostic biomarker of breast cancer, it also contributes to cell proliferation by regulating G1/S transition.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-016-0805-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4756411  PMID: 26883017
Breast cancer; C14orf166; Prognostic factor; Cell proliferation
7.  Identification of genes regulated by histone acetylation during root development in Populus trichocarpa 
BMC Genomics  2016;17:96.
Histone deacetylases (HDACs) are key enzymes catalyzing the removal of acetyl groups from histones. HDACs act in concert with histone acetyltransferases (HATs) to regulate histone acetylation status, which modifies chromatin structure, affecting gene transcription and thus regulating multiple biological processes such as plant growth and development. Over a decade, certain HDACs in herbaceous plants have been deeply studied. However, functions of HDACs in woody plants are not well understood.
Histone deacetylase specific inhibitor trichostatin A (TSA) was used to investigate the role of HDACs in organogenesis of roots and root development in Populus trochocarpa. The adventitious roots were regenerated and grown on medium supplemented with 0, 1, and 2.5 μM TSA. TSA treatment delayed root regeneration and inhibited primary root growth. To examine the genes modified by TSA in the regenerated roots, tag-based digital gene expression (DGE) analysis was performed using Illumina HiSeqTM 2000. Approximately 4.5 million total clean tags were mapped per library. The distinct clean tags for the three libraries corresponding to 0, 1 and 2.5 μM TSA treatment were 166167, 143103 and 153507, from which 38.45 %, 31.84 % and 38.88 % were mapped unambiguously to the unigene database, respectively. Most of the tags were expressed at similar levels, showing a < 5-fold difference after 1 μM and 2.5 μM TSA treatments and the maximum fold-change of the tag copy number was around 20. The expression levels of many genes in roots were significantly altered by TSA. A total of 36 genes were up-regulated and 1368 genes were down-regulated after 1 μM TSA treatment, while 166 genes were up-regulated and 397 genes were down-regulated after 2.5 μM TSA treatment. Gene ontology (GO) and pathway analyses indicated that the differentially expressed genes were related to many kinds of molecular functions and biological processes. The genes encoding key enzymes catalyzing gibberellin biosynthesis were significantly down-regulated in the roots exposed to 2.5 μM TSA and their expression changes were validated by using real-time PCR.
HDACs were required for de novo organogenesis and normal growth of populus roots. DGE data provides the gene profiles in roots probably regulated by histone acetylation during root growth and development, which will lead to a better understanding of the mechanism controlling root development.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-2407-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4743431  PMID: 26847576
Populus trichocarpa; Histone deacetylase; Trichostatin A; Digital gene expression
8.  Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice 
Acta Pharmacologica Sinica  2015;37(2):166-176.
N-methyl-D-aspartic acid (NMDA) receptor modulators have shown promising results as potential antidepressant agents, whereas timosaponins extracted from the Chinese herb Rhizoma Anemarrhenae exhibit antidepressant activities. In the present study we examined whether YY-23, a modified metabolite of timosaponin B-III, could affect NMDA receptors in rat hippocampal neurons in vitro, and evaluated its antidepressant-like effects in stressed mice.
NMDA-induced currents were recorded in acutely dissociated rat hippocampal CA1 neurons using a whole-cell recording technique. C57BL/6 mice were exposed to a 6-week chronic mild stress (CMS) or a 10-d chronic social defeat stress (CSDS). The stressed mice were treated with YY-23 (20 mg·kg−1·d−1) or a positive-control drug, fluoxetine (10 mg·kg−1·d−1) for 3 weeks. Behavioral assessments were carried out every week.
In acutely dissociated rat hippocampal CA1 neurons, YY-23 selectively and reversibly inhibited NMDA-induced currents with an EC50 value of 2.8 μmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltage-dependency or use-dependency. Treatment of the stressed mice with YY-23 not only reversed CMS-induced deficiency of sucrose preference and immobility time, and CSDS-induced reduction of social interaction, but also had faster onset as compared to fluoxetine.
YY-23 is a novel non-competitive antagonist of NMDA receptors with promising rapid antidepressant-like effects in mouse models of CMS and CSDS depression.
PMCID: PMC4753364  PMID: 26687936
Rhizoma Anemarrhenae; timosaponin; YY-23; depression; NMDA receptor antagonist; chronic mild stress; chronic social defeat stress; fluoxetine
9.  High Uric Acid (UA) Negatively Affects Serum Tartrate-Resistant Acid Phosphatase 5b (TRACP 5b) Immunoassay 
PLoS ONE  2016;11(1):e0147554.
Bone metastases often occur in the majority of patients with advanced cancer, such as prostate cancer, lung cancer and breast cancer. Serum tartrate-resistant acid phosphatase 5b (TRACP 5b), a novel bone resorption marker, has been used gradually in the clinics as a specific and sensitive marker of bone resorption for the early diagnosis of cancer patients with bone metastasis. Here, we reported that high concentrations of uric acid (UA) lead to decrease of TRACP 5b levels and determined whether TRACP 5b level was associated with UA in interference experiment.
A total of 77 patients with high concentrations of UA and 77 healthy subjects were tested to evaluate the differences in their TRACP 5b levels. Serial dilutions of UA were respectively spiked with a known concentration of TRACP 5b standard sample, then Serum TRACP 5b was detected by using bone TRAP® Assay. A correction equation was set to eliminate UA-derived TRACP 5b false-decrease. The effect of this correction was evaluated in high-UA individuals.
The average TRACP level of the high-UA individuals (1.47± 0.62 U/L) was significantly lower than that of the healthy subjects (2.62 ± 0.63 U/L) (t-test, p<0.0001). The UA correction equation derived: ΔTRACP 5b = -1.9751lgΔUA + 3.7365 with an R2 = 0.98899. Application of the UA correction equation resulted in a statistically non-significant difference in TRACP 5b values between the healthy subjects and high-UA individuals (p = 0.24).
High UA concentrations can falsely decrease TRACP 5b levels due to a method-related systematic error. To avoid misdiagnoses or inappropriate therapeutic decisions, increased attention should be paid to UA interference, when TRACP 5b is used for early diagnosis of cancer patients with bone metastasis, evaluation of the aggressiveness of osteosarcoma or prediction of survival in prostate cancer and breast cancer with bone metastases.
PMCID: PMC4723035  PMID: 26800211
11.  The double burden of under- and overnutrition and nutrient adequacy among Chinese preschool and school-aged children in 2009-2011 
European journal of clinical nutrition  2015;69(12):1323-1329.
Coincident with economic development, China has experienced a dramatic transition from undernutrition to overweight/obesity over the last few decades. We aimed to explore the burden of under- and overnutrition and nutrient adequacy among 2-12 y-old Chinese children.
We included anthropometry, dietary intake and biomarkers from 2-12-y-olds who participated in the 2009-2011 China Health and Nutrition Survey (n=1,191 in 2009; n=1,648 in 2011). Dietary intakes were compared with the 2013 Chinese Dietary Recommended Intakes.
In 2011, approximately 19% of 2-6 y-old children were underweight, 4% were stunted, 10% were overweight and 12% were obese. Among 7-12 y-old children, stunting was almost 0% whereas approximately 21% were underweight, 13% were overweight and 6% were obese in 2011. Overweight and obesity were more prevalent among children from urban areas and higher income households. In particular, 2-6 y-old children from urban areas and higher income households experienced the highest increase in obesity from 2009 to 2011 (P<0.05). Children from urban areas and higher income households had overall higher intakes of total daily energy and most macro- and micronutrients (P<0.05). However, a significant proportion of children did not meet the recommendations for important micronutrients.
Underweight and stunting currently coexist with overweight and obesity among Chinese children <12 y-old. We found critical disparities in the prevalence of under- and overweight/obesity, as well as in nutrient intakes and dietary adequacies between children from different incomes, revealing that the burden of childhood under- and overnutrition may constitute a public health concern in modern China.
PMCID: PMC4668216  PMID: 26130296
undernutrition; overweight; children; China; nutrients
12.  Measles Outbreak among Adults, Northeastern China, 2014 
Emerging Infectious Diseases  2016;22(1):144-146.
PMCID: PMC4696708  PMID: 26689632
Measles; viruses; China; adults; disease outbreaks; vaccines
13.  Fas-670A>G polymorphism is not associated with an increased risk of acute myeloid leukemia development 
Biomedical Reports  2015;4(2):153-160.
The association between the increased risk of acute myeloid leukemia (AML) and Fas promoter polymorphisms has been reported previously; however, the results are inconclusive. The present study performed one case-control study to investigate the association, and a total of 98 AML patients and 2,014 healthy controls were genotyped. The data showed that the distribution of Fas-670AA, GA and GG genotypes among the AML patients were not significantly different from those of the healthy controls, all P>0.05. Following this a sub-study was conducted to analyze individuals who neither smoked nor drank. The results demonstrated that there was still no significant association between the Fas-670 polymorphism and risk of AML development, all P>0.05. Furthermore, in order to address a more accurate estimation of the association, a meta-analysis was conducted. Data were systematically collected from the Pubmed, EMBASE and the Wanfang Library. A total of 3 studies were included in this meta-analysis, which contained 1,144 AML cases and 3,806 controls. No significant association was detected between the Fas-670A>G polymorphism and AML risk [GA+GG vs. AA: odds ratio (OR) 0.93; 95% confidence interval (CI), 0.79–1.09; GG vs. AA: OR, 1.01; 95% CI, 0.82–1.24; GA vs. AA: OR, 1.12; 95% CI, 0.94–1.32; GG vs. AA+GA: OR, 0.94; 95% CI, 0.79–1.12; G vs. A: OR, 1.01; 95% CI, 0.91–1.12; all P>0.05). The analysis clearly indicated that there was no significant connection between the Fas-670A>G polymorphism and the increased risk of AML.
PMCID: PMC4734045  PMID: 26893830
acute myeloid leukemia; Fas-670A>G polymorphism; case-control study; genotyping; meta-analysis
14.  Differential Expression of Hepatic Genes of the Greater Horseshoe Bat (Rhinolophus ferrumequinum) between the Summer Active and Winter Torpid States 
PLoS ONE  2015;10(12):e0145702.
Hibernation is one type of torpor, a hypometabolic state in heterothermic mammals, which can be used as an energy-conservation strategy in response to harsh environments, e.g. limited food resource. The liver, in particular, plays a crucial role in adaptive metabolic adjustment during hibernation. Studies on ground squirrels and bears reveal that many genes involved in metabolism are differentially expressed during hibernation. Especially, the genes involved in carbohydrate catabolism are down-regulated during hibernation, while genes responsible for lipid β-oxidation are up-regulated. However, there is little transcriptional evidence to suggest physiological changes to the liver during hibernation in the greater horseshoe bat, a representative heterothermic bat. In this study, we explored the transcriptional changes in the livers of active and torpid greater horseshoe bats using the Illumina HiSeq 2000 platform. A total of 1358 genes were identified as differentially expressed during torpor. In the functional analyses, differentially expressed genes were mainly involved in metabolic depression, shifts in the fuel utilization, immune function and response to stresses. Our findings provide a comprehensive evidence of differential gene expression in the livers of greater horseshoe bats during active and torpid states and highlight potential evidence for physiological adaptations that occur in the liver during hibernation.
PMCID: PMC4689453  PMID: 26698122
15.  Precision methylome characterization of Mycobacterium tuberculosis complex (MTBC) using PacBio single-molecule real-time (SMRT) technology 
Nucleic Acids Research  2015;44(2):730-743.
Tuberculosis (TB) remains one of the most common infectious diseases caused by Mycobacterium tuberculosis complex (MTBC). To panoramically analyze MTBC's genomic methylation, we completed the genomes of 12 MTBC strains (Mycobacterium bovis; M. bovis BCG; M. microti; M. africanum; M. tuberculosis H37Rv; H37Ra; and 6 M. tuberculosis clinical isolates) belonging to different lineages and characterized their methylomes using single-molecule real-time (SMRT) technology. We identified three m6A sequence motifs and their corresponding methyltransferase (MTase) genes, including the reported mamA, hsdM and a newly discovered mamB. We also experimentally verified the methylated motifs and functions of HsdM and MamB. Our analysis indicated the MTase activities varied between 12 strains due to mutations/deletions. Furthermore, through measuring ‘the methylated-motif-site ratio’ and ‘the methylated-read ratio’, we explored the methylation status of each modified site and sequence-read to obtain the ‘precision methylome’ of the MTBC strains, which enabled intricate analysis of MTase activity at whole-genome scale. Most unmodified sites overlapped with transcription-factor binding-regions, which might protect these sites from methylation. Overall, our findings show enormous potential for the SMRT platform to investigate the precise character of methylome, and significantly enhance our understanding of the function of DNA MTase.
PMCID: PMC4737169  PMID: 26704977
16.  PEDOT/PSS-Halloysite Nanotubes (HNTs) Hybrid Films: Insulating HNTs Enhance Conductivity of the PEDOT/PSS Films 
Scientific Reports  2015;5:18641.
We have for the first time found that completely insulating Halloysite nanotubes (HNTs) significantly enhance electrical conductivity of PEDOT/PSS films by simply mixing. Based on this accident finding we have created highly porous and conductive PEDOT/PSS films hybridized with the HNTs. Through further optimization of the mixing condition we have obtained flexible and conductive hybrid films with high specific surface area. Based on experimental evidences we proposed a plausible mechanism of the phenomenon where the PEDOT/PSS colloidal particle with particle size of several tens nanometers well pack at the nano-channels into well-ordered structures of PEDOT/PSS particles, which show conductivity as higher as several order of magnitude than that of PEDOT/PSS particles in outside of the HNTs.
PMCID: PMC4685446  PMID: 26686395
17.  Differential associations of urbanicity and income with physical activity in adults in urbanizing China: findings from the population-based China Health and Nutrition Survey 1991-2009 
High urbanicity and income are risk factors for cardiovascular-related chronic diseases in low- and middle-income countries, perhaps due to low physical activity (PA) in urban, high income areas. Few studies have examined differences in PA over time according to income and urbanicity in a country experiencing rapid urbanization.
We used data from the China Health and Nutrition Survey, a population-based cohort of Chinese adults (n = 20,083; ages 18-75y) seen a maximum of 7 times from 1991-2009. We used sex-stratified, zero-inflated negative binomial regression models to examine occupational, domestic, leisure, travel, and total PA in Chinese adults according to year, urbanicity, income, and the interactions among urbanicity, income, and year, controlling for age and region of China.
We showed larger mean temporal PA declines for individuals living in relatively low urbanicity areas (1991: 500 MET-hours/week; 2009: 300 MET-hours/week) compared to high urbanicity areas (1991: 200 MET-hours/week; 2009: 125 MET-hours/week). In low urbanicity areas, the association between income and total PA went from negative in 1991 (p < 0.05) to positive by 2000 (p < 0.05). In relatively high urbanicity areas, the income-PA relationship was positive at all time points and was statistically significant at most time points after 1997 (p < 0.05). Leisure PA was the only domain of PA that increased over time, but >95 % of individuals in low urbanicity areas reported zero leisure PA at each time point.
Our findings show changing associations for income and urbanicity with PA over 18 years of urbanization. Total PA was lower for individuals living in more versus less urban areas at all time points. However, these differences narrowed over time, which may relate to increases in individual-level income in less urban areas of China with urbanization. Low-income individuals in higher urbanicity areas are a particularly critical group to target to increase PA in China.
Electronic supplementary material
The online version of this article (doi:10.1186/s12966-015-0321-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4676871  PMID: 26653097
Urbanization; Epidemiology; Longitudinal; Globalization
18.  Silica Vesicle Nanovaccine Formulations Stimulate Long-Term Immune Responses to the Bovine Viral Diarrhoea Virus E2 Protein 
PLoS ONE  2015;10(12):e0143507.
Bovine Viral Diarrhoea Virus (BVDV) is one of the most serious pathogen, which causes tremendous economic loss to the cattle industry worldwide, meriting the development of improved subunit vaccines. Structural glycoprotein E2 is reported to be a major immunogenic determinant of BVDV virion. We have developed a novel hollow silica vesicles (SV) based platform to administer BVDV-1 Escherichia coli-expressed optimised E2 (oE2) antigen as a nanovaccine formulation. The SV-140 vesicles (diameter 50 nm, wall thickness 6 nm, perforated by pores of entrance size 16 nm and total pore volume of 0.934 cm3g-1) have proven to be ideal candidates to load oE2 antigen and generate immune response. The current study for the first time demonstrates the ability of freeze-dried (FD) as well as non-FD oE2/SV140 nanovaccine formulation to induce long-term balanced antibody and cell mediated memory responses for at least 6 months with a shortened dosing regimen of two doses in small animal model. The in vivo ability of oE2 (100 μg)/SV-140 (500 μg) and FD oE2 (100 μg)/SV-140 (500 μg) to induce long-term immunity was compared to immunisation with oE2 (100 μg) together with the conventional adjuvant Quil-A from the Quillaja saponira (10 μg) in mice. The oE2/SV-140 as well as the FD oE2/SV-140 nanovaccine generated oE2-specific antibody and cell mediated responses for up to six months post the final second immunisation. Significantly, the cell-mediated responses were consistently high in mice immunised with oE2/SV-140 (1,500 SFU/million cells) at the six-month time point. Histopathology studies showed no morphological changes at the site of injection or in the different organs harvested from the mice immunised with 500 μg SV-140 nanovaccine compared to the unimmunised control. The platform has the potential for developing single dose vaccines without the requirement of cold chain storage for veterinary and human applications.
PMCID: PMC4668082  PMID: 26630001
19.  Eighteen year weight trajectories and metabolic markers of diabetes in modernising China: which time scale is most relevant? Reply to Vistisen D and Færch K [letter] 
Diabetologia  2014;57(12):2607-2608.
PMCID: PMC4221418  PMID: 25265878
Fasting glucose; Insulin resistance; Latent class trajectory analysis; Weight trajectories
20.  NFAT transcriptional activity is associated with metastatic capacity in colon cancer 
Cancer research  2014;74(23):6947-6957.
Metastatic recurrence is the leading cause of cancer death in patients with colorectal carcinoma. In order to capture the molecular underpinnings for metastasis and tumor progression, we performed integrative network analysis on 11 independent human colorectal cancer gene expression data sets and applied expression data from an immunocompetent mouse model of metastasis as an additional filter for this biological process. In silico analysis of one metastasis-related co-expression module predicted Nuclear Factor of Activated T-cell (NFAT) transcription factors as potential regulators for the module. Cells selected for invasiveness and metastatic capability expressed higher levels of NFATc1 as compared with poorly metastatic and less invasive parental cells. We found that inhibition of NFATc1 in human and mouse colon cancer cells resulted in decreased invasiveness in culture and down-regulation of metastasis-related network genes. Overexpression of NFATc1 significantly increased the metastatic potential of colon cancer cells while inhibition of NFATc1 reduced metastasis growth in an immunocompetent mouse model. Finally, we found that an 8-gene signature comprising genes up-regulated by NFATc1 significantly correlated with worse clinical outcomes in Stage II and III colorectal cancer patients. Thus, NFATc1 regulates colon cancer cell behavior and its transcriptional targets constitute a novel, biologically-anchored gene expression signature for the identification of colon cancers with high risk of metastatic recurrence.
PMCID: PMC4252979  PMID: 25320007
21.  Leveraging the complementary nature of RNA-Seq and shotgun proteomics data 
Proteomics  2014;14(0):2676-2687.
RNA sequencing (RNA-Seq) and mass spectrometry-based shotgun proteomics are powerful high-throughput technologies for identifying and quantifying RNA transcripts and proteins respectively. With the increasing affordability of these technologies, many projects have started to apply both to the same samples to achieve a more comprehensive understanding of biological systems. A major analytical challenge for such integrative projects is how to effectively leverage the complementary nature of RNA-Seq and shotgun proteomics data. RNA-Seq provides comprehensive information on mRNA abundance, alternative splicing, nucleotide variation and structure alteration. Sample-specific protein databases derived from RNA-Seq data can better approximate the real protein pools in cell and tissue samples and thus improve protein identification. Meanwhile, proteomics data provides essential confirmation of the validity and functional relevance of novel findings from RNA-Seq data. At the quantitative level, mRNA and protein levels are only modestly correlated, suggesting strong involvement of post-transcriptional regulation in controlling gene expression. Here we review recent studies at the interface of RNA-Seq and proteomics data. We discuss goals, accomplishments and challenges in RNA-Seq-based proteogenomics. We also examine the current status and future potential of parallel transcriptome and proteome quantification in revealing post-transcriptional regulatory mechanisms.
PMCID: PMC4270470  PMID: 25266668
Proteogenomics; RNA-Seq; Proteomics; Post-transcriptional regulation; data integration
22.  DAG/PKCδ and IP3/Ca2+/CaMK IIβ Operate in Parallel to Each Other in PLCγ1-Driven Cell Proliferation and Migration of Human Gastric Adenocarcinoma Cells, through Akt/mTOR/S6 Pathway 
Phosphoinositide specific phospholipase Cγ (PLCγ) activates diacylglycerol (DAG)/protein kinase C (PKC) and inositol 1,4,5-trisphosphate (IP3)/Ca2+/calmodulin-dependent protein kinase II (CaMK II) axes to regulate import events in some cancer cells, including gastric adenocarcinoma cells. However, whether DAG/PKCδ and IP3/Ca2+/CaMK IIβ axes are simultaneously involved in PLCγ1-driven cell proliferation and migration of human gastric adenocarcinoma cells and the underlying mechanism are not elucidated. Here, we investigated the role of DAG/PKCδ or CaMK IIβ in PLCγ1-driven cell proliferation and migration of human gastric adenocarcinoma cells, using the BGC-823 cell line. The results indicated that the inhibition of PKCδ and CaMK IIβ could block cell proliferation and migration of BGC-823 cells as well as the effect of inhibiting PLCγ1, including the decrease of cell viability, the increase of apoptotic index, the down-regulation of matrix metalloproteinase (MMP) 9 expression level, and the decrease of cell migration rate. Both DAG/PKCδ and CaMK IIβ triggered protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/S6 pathway to regulate protein synthesis. The data indicate that DAG/PKCδ and IP3/Ca2+/CaMK IIβ operate in parallel to each other in PLCγ1-driven cell proliferation and migration of human gastric adenocarcinoma cells through Akt/mTOR/S6 pathway, with important implication for validating PLCγ1 as a molecular biomarker in early gastric cancer diagnosis and disease surveillance.
PMCID: PMC4691063  PMID: 26633375
PLCγ1; DAG/PKCδ; IP3/Ca2+/CaMK IIβ; Akt/mTOR/S6; cell proliferation; migration; human gastric adenocarcinoma cells
24.  Use of taxane-containing induction chemotherapy in combination with concurrent chemoradiotherapy in Chinese patients with locally advanced nasopharyngeal carcinoma: a meta-analysis 
OncoTargets and therapy  2015;8:3255-3263.
Taxane-containing induction chemotherapy (IC) regimens in combination with concurrent chemoradiotherapy (CCRT) have been compared with non-taxane-containing IC combined with CCRT in randomized controlled trials (RCTs) in Chinese patients with advanced nasopharyngeal carcinoma (NPC). This meta-analysis aimed to systematically evaluate their clinical efficacy and safety profiling in this ethnic population.
The electronic databases, PubMed, Embase, MEDLINE, and Chinese Biomedical Database, were searched for eligible studies. The outcomes included overall response rate (ORR), 1-year survival rate, and different types of adverse events. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations.
A total of 12 RCTs (representing 835 patients) were identified. The pooled analysis showed that taxane-containing regimens had a significant improvement in ORR for nasopharyngeal lesion (OR =4.57, 95% CI =1.14–18.30, P=0.032, z=2.15) but not in cervical lymph nodes (OR =1.23, 95% CI =0.65–2.36, P=0.532, z=0.64) and in 1-year survival rates (OR =1.19, 95% CI =0.10–14.82, P=0.893, z=0.13) compared with non-taxane-containing regimens. Regarding the adverse events and toxicities, grade 3–4 leukopenia and neutropenia were significantly different between the two groups (P<0.001) in favor of the non-taxane-containing regimens, but grade 3–4 vomiting was significantly different between the two groups (P<0.005) in favor of the taxane-containing regimens.
When combined with CCRT, taxane-containing IC regimens may be more efficient for short-term local control in Chinese patients with locally advanced NPC than the non-taxane-containing IC regimens. Moreover, the major toxic effects, which were bone marrow suppression, could be tolerated by majority of patients. More long-term follow-up and high-quality trials of NPC are needed to validate our findings.
PMCID: PMC4640226  PMID: 26604792
randomized controlled trials; clinical efficacy; safety; survival rate; adverse events; cervical lymph nodes
25.  Meta-analysis: Influence of host and viral factors in patients with chronic hepatitis C genotype 4 treated with pegylated interferon and ribavirin 
The burden of hepatitis C virus genotype 4 (HCV-4) is high in Africa and East Mediterranean countries. Previous reports estimate sustained virologic response (SVR) rates in HCV-4 to be ~20–70%. However, many of these studies are limited by different study designs and small sample sizes.
Our aim was to evaluate treatment outcome and host/viral factors on SVR in HCV-4 patients treated with pegylated interferon and ribavirin (PEG IFN+RBV) in a systematic and quantitative fashion.
A comprehensive literature search in MEDLINE and EMBASE for ‘genotype 4’ was conducted in November 2013. Abstracts from AASLD, APASL, DDW, and EASL in 2012/2013 were reviewed. Inclusion criteria were original studies with ≥25 treatment-naïve HCV-4 patients treated with PEG IFN+RBV. Exclusion criteria were co-infection with HIV, HBV, or other genotypes. Effect sizes were calculated using random-effects models. Heterogeneity was determined by Cochrane Q-test (p-value <0.05) and I-squared statistic (>50%).
We included 51 studies (11,102 HCV-4 patients) in the primary analysis. Pooled SVR was 53% (95% CI: 50–55%) (Q-statistic = 269.20, p<0.05; I2 = 81.43). On sub-group analyses, SVR was significantly associated with lower viral load, OR 3.05 (CI 1.80–5.17, p<0.001); mild fibrosis, OR 3.17 (CI 2.19–4.59, p<0.001); and favorable IL28B polymorphisms, rs12979860 CC versus CT/TT, OR 4.70 (CI 2.87–7.69, p<0.001), and rs8099917 TT versus GT/GG, OR 5.21 (CI 2.31–11.73, p<0.001).
HCV-4 patients treated with PEG IFN+RBV may expect SVR rate of ~50%. Lower viral load, mild fibrosis, and favorable IL28B (rs12979860 CC and rs8099917 TT) are positively associated with SVR.
PMCID: PMC4180769  PMID: 25171028
sustained virologic response; pegylated interferon and ribavirin; hepatitis C; genotype 4

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